Cardiopulmonay Bypass 1

Editors
Glenn P. Gravlee MD
Professor
Vice Chair for Faculty Affairs
Department of Anesthesiology
University of Colorado School of Medicine
Anschutz Medical Campus
Aurora, Colorado
Richard F. Davis MD, MBA

Affiliate Professor of Anesthesiology (Retired)
Department of Anesthesiology and Perioperative Medicine
Oregon Health and Science University
Portland, Oregon
John W. Hammon MD
Professor of Surgery, Emeritus
Department of Cardiothoracic Surgery
Wake Forest University School of Medicine
Winston-Salem, North Carolina
Barry D. Kussman MBBCh, FFA(SA)

Associate Professor of Anaesthesia
Harvard Medical School
Senior Associate in Cardiac Anesthesia
Department of Anesthesiology, Perioperative & Pain Medicine
Boston Children’s Hospital
Boston, Massachusetts
Contributors List
Darryl Abrams, MD
Assistant Professor of Medicine
Division of Pulmonary, Allergy, and Critical Care
Columbia University Medical Center
New York, New York
Iki Adachi, MD
Associated Surgeon, Co-Director of Mechanical Circulatory Support
Congenital Heart Surgery, Texas Children’s Hospital
Assistant Professor
Department of Surgery and Pediatrics
Baylor College of Medicine
Houston, Texas
Sarah K. Armour, MD
Assistant Professor
Mayo Clinic
Rochester, Minnesota
Frank A. Baciewicz Jr., MD

Professor Cardiothoracic Surgery, Chief
Division of Cardiothoracic Surgery
Wayne State University
Chief, Thoracic Surgery
Karmanos Cancer Center
Detroit, Michigan
Karsten Bartels, MD
Assistant Professor of Anesthesiology and Surgery
Aurora, Colorado
Daniel Brodie, MD
Associate Professor of Medicine
Department of Medicine
Columbia University College of Physicians and Surgeons
New York, New York
John F. Butterworth IV, MD

Professor and Chairman
Virginia Commonwealth University Health System
Richmond, Virginia
Paul J. Chai, MD
Congenital and Pediatric Cardiac Surgery
Morgan Stanley Children’s Hospital of NY
Columbia University Medical Center
New York, New York
W. Randolph Chitwood Jr., MD, FACS, FRCS (England)

Emeritus Professor and Chairman
Department of Surgery, Founder
East Carolina Heart Institute, East Carolina University, Vidant
Medical Center
Greenville, North Carolina
Joseph C. Cleveland Jr., MD

Professor of Surgery
Surgical Director Cardiac Transplantation and Mechanical
Circulatory Support
Anschutz Medical Center
Aurora, Colorado
Mark E. Comunale, MD
Professor of Anesthesiology
Loma Linda University School of Medicine
Chief Medical Officer for Patient Safety, Associate Medical Director for Perioperative Services and Chairman
Arrowhead Regional Medical Center
Colton, California
Vincent R. Conti, MD, FACS

Professor and Chief Cardiothoracic Surgery
University of Texas Medical Branch
Galveston, Texas
David J. Cook, MD
Professor
Mayo Clinic College of Medicine
Rochester, Minnesota
John R. Cooper Jr., MD

Attending Anesthesiologist
Department of Cardiovascular Anesthesia
Texas Heart Institute
Clinical Professor of Anesthesiology
Houston, Texas
Joseph S. Coselli, MD
Professor and Chief of the Division of Cardiothoracic Surgery
Michael E. DeBakey, Department of Surgery
Baylor College of Medicine, and Chief of the Section of Adult Cardiac Surgery
The Texas Heart Institute
Houston, Texas
Terry N. Crane, BS, CCP, LP

Director
Texas Heart Institute School of Perfusion
Houston, Texas
Laurie K. Davies, MD
Associate Professor of Anesthesiology & Surgery
University of Florida
Gainesville, Florida
Richard F. Davis, MD, MBA

Affiliate Professor of Anesthesiology (Retired)
Oregon Health & Science University
Portland, Oregon
Anthony de la Cruz, MD
Assistant Professor
Rush University Medical Center
Chicago, Illinois
Kim I. de la Cruz, MD
Assistant Professor
Michael E. DeBakey Department of Surgery
Attending Surgeon
Department of Thoracic & Cardiovascular Surgery
Texas Heart Institute
Baylor St. Luke’s Medical Center, CHI St. Luke’s Health System
Houston, Texas
James A. DiNardo, MD
Professor of Anaesthesia
Chief
Division of Cardiac Anesthesia
Francis X. McGowan Jr., MD Chair in Cardiac Anesthesia
Alan Finley, MD, FASE

Associate Professor
Anesthesia and Perioperative Medicine
Medical University of South Carolina
Charleston, South Carolina
Charles D. Fraser Jr., MD

Surgeon-in-Chief
Texas Children’s Hospital
Houston, Texas
Alan Gaffney, MB, BCh, PhD
Assistant Professor of Anesthesiology
College of Physicians & Surgeons of Columbia University
New York, New York
Jeffrey C. Gardner, MD
Assistant Professor
Wake Forest School of Medicine
J. William Gaynor, MD
Professor of Surgery
Children’s Hospital of Philadelphia
Philadelphia, Pennsylvania
N. Martin Giesecke, MD
M.T. “Pepper” Jenkins Professor, Vice Chairman
University Hospitals
Department of Anesthesiology and Pain Management
UT Southwestern Medical Center
Dallas, Texas
Glenn P. Gravlee, MD
Professor
Vice Chair for Faculty Affairs
Aurora, Colorado
Michael S. Green, DO
Chair and Program Director
Hahnemann University Hospital
Drexel University College of Medicine
Jonathan W. Haft, MD
Associate Professor of Adult Cardiac Surgery & Anesthesia
Director
Extracorporeal Life Support Program
Associate Director
Cardiovascular Intensive Care Units
Department of Cardiac Surgery
University of Michigan Health Systems
Ann Arbor, Michigan
Richard I. Hall, MD
Critical Care Medicine and Pharmacology
Dalhousie University
Halifax, Nova Scotia, Canada
John W. Hammon, MD
Professor of Surgery, Emeritus
Wake Forest University School of Medicine
Deepak Hanumanthaiah, MD, FCARCSI, FRCPC

Clinical Fellow
Department of Anesthesia
St. Michael’s Hospital
University of Toronto
Toronto, Ontario, Canada
Izumi Harukuni, MD
Assistant Professor
Adult Cardiac Anesthesia Division
Portland, Oregon
Eugene A. Hessel II, MD, FACS

Professor Anesthesiology, Surgery (Cardiothoracic) Neurosurgery, and Pediatrics
University of Kentucky College of Medicine
Lexington, Kentucky
Michael H. Hines, MD, FACS

Professor of Pediatric Cardiovascular Surgery
Professor of Cardiothoracic Surgery
University of Texas Medical School at Houston
Houston, Texas
Justin Horricks, MD
Cardiac Anesthesiologist
Loma Linda University Faculty Medical Group
Loma Linda, California
Jay C. Horrow, MD, MS, FACC, FAHA
Professor of Anesthesiology & Perioperative Medicine
Drexel University College of Medicine
Eric Jenkins, CCT, CCP, FPP

Cardiovascular Perfusionist
University of Michigan
Detroit, Michigan
David Kiamanesh, MD
Assistant Professor of Anesthesiology and Critical Care
Columbia University College of Physicians and Surgeons
New York, New York
Mark Kurusz, CCP (Emeritus)

Adjunct Assistant Professor
Department of Surgery
The University of Texas Medical Branch
Galveston, Texas
Barry D. Kussman, MBBCh, FFA(SA)

Associate Professor of Anaesthesia
Senior Associate in Cardiac Anesthesia
Department of Anesthesiology, Perioperative & Pain Medicine
Alan P. Kypson, MD, FACS

Professor and Chief of Cardiothoracic Surgery
East Carolina Heart Institute
Brody School of Medicine
East Carolina University
Vidant Medical Center
Scott A. LeMaire, MD
Professor and Vice Chair for Research
Michael E. DeBakey Department of Surgery
Department of Cardiovascular Surgery
Texas Heart Institute and Baylor St. Luke’s Medical Center
Houston, Texas
Adair Q. Locke, MD
Assistant Professor
Section of Cardiothoracic Anesthesiology
Christopher E. Mascio, MD
Pediatric Cardiothoracic Surgery
The Children’s Hospital of Philadelphia
Assistant Professor of Clinical Medicine
Perelman School of Medicine
University of Pennsylvania
Gregory S. Matte, CCP, LP, FPP

Co-Chief of Perfusion/Clinical Coordinator
C. David Mazer, MD, FRCPC

Professor and Vice-Chair for Research
Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute of St. Michael’s Hospital
Niamh A. McAuliffe, MBBCh, FCARCSI, FRCPC

Clinical Fellow
St. Michael’s Hospital
Noel L. Mills, MD
Ochsner Health System
New Orleans, Louisiana
Josef Nile Mueksch, MD, MBA

Providence Anesthesia Associates
Division Chief
Brunswick Novant Medical Center
Chief of Surgery
Brunswick Novant Medical Center Supply
Wilmington, North Carolina
Glenn S. Murphy, MD
Director
Clinical Research and Cardiac Anesthesia
North Shore University Health System
Clinical Professor
University of Chicago Pritzker School of Medicine
Chicago, Illinois
Mark T. Nelson, MD, Med

Assistant Professor
Fellowship Program Director
Director
Perioperative Echocardiography
Virginia Commonwealth University
Richmond, Virginia
L. Wiley Nifong, MD
Associate Professor Cardiothoracic Surgery
East Carolina Heart Institute
Priv. Doz. Dr. med. Andreas Pape

Associate Professor
Department of Anaesthesia
Intensive Care Medicine and Pain Therapy
University Hospital Frankfurt
Frankfurt, Germany
Steven A. Raskin, CCP

Chief Perfusionist
Houston, Texas
Murphy Rayle, BA, CCP, LP

Perfusionist
Medical City Dallas
Dallas, Texas
Heather Reed, MD
Chief Resident
University of Florida
Gainesville, Florida
Derek J. Roberts, BSc (Pharm), MD, PhD
Resident
Division of General Surgery
University of Calgary
Calgary, Alberta, Canada
Eduardo S. Rodrigues, MD
Assistant Professor Anesthesiology
Anesthesia Quality and Safety
Mayo Clinic Florida
Jacksonville, Florida
David M. Rothenberg, MD, FCCM

The Max S. Sadove Professor of Anesthesiology
Vice Chair, Academic Affairs & Program Director
Associate Dean
Academic Affiliations
Rush University Medical Center
Chicago, Illinois
Roger L. Royster, MD, FACC

Professor and Executive Vice Chair
Derek A. Sanderson Jr., BS, CCP, LP

Senior Perfusionist, Chief of Pediatric Perfusion and Extracorporeal Perfusion
Department of Cardiovascular Sciences, East Carolina Heart Institute
East Carolina University
Valerie Sera, MD, DDS

Clinical Associate Professor, Division Chief
Adult Cardiac Anesthesia, Anesthesiology and Perioperative Medicine
Portland, Oregon
Kenneth G. Shann, CCP

Director, Perfusion Services
Massachusetts General Hospital
Linda Shore-Lesserson, MD, FAHA, FASE
Hofstra Northshore-LIJ School of Medicine
Director
Cardiovascular Anesthesiology, Northshore LIJ Medical Center
New Hyde Park, New York
Robert N. Sladen, MBChB, FCCM

Allen Hyman Professor of Critical Care Anesthesiology, Executive Vice-Chair and Chief
Division of Critical Care
Medical Director
Cardiothoracic and Surgical Intensive Care Units, Department of Anesthesiology
College of Physicians & Surgeons of Columbia University
New York, New York
Larry W. Stephenson, MD
Professor Emeritus, Ford-Webber Professor of Surgery
Wayne State University
Detroit, Michigan
Robin G. Sutton, MS, CCP

Director
Biomed Training and Education Division
Biomed Simulation, Inc.
Poway, California
Ravi R. Thiagarajan, MBBS, MPH

Senior Associate in Cardiology
Cardiac Intensive Care Unit
Department of Cardiology
Associate Professor of Pediatrics
Neil J. Thomas, MD
Attending Cardiac Surgeon
Northwestern Medicine-Central Dupage Hospital
Winfield, Illinois
Victoria Vasileiadou, RN
Cardiovascular Perfusionist
General Army Hospital of Athens
Athens, Greece
Jakob Vinten-Johansen, MS, PhD
Professor of Cardiothoracic Surgery (retired)
Emory University School of Medicine
Atlanta, Georgia
Nicholas Weber, DO
Staff Anesthesiologist
Infinity Healthcare
Milwaukee, Wisconsin
Kai Zacharowski, MD, PhD, FRCA

Director and Chair
Department of Anesthesiology, Intensive Care Medicine & Pain
Therapy
University Hospital Frankfurt
Frankfurt, Germany
Mustafa Zakkar, PhD, MRCS

University of Bristol
Bristol Heart Institute
Bristol, United Kingdom
Preface
For the fourth edition, the editors decided that the term “Cardiopulmonary Bypass” remained relevant but
insufficient, because cardiopulmonary technology has evolved to encompass both short-term and long-term
forms of cardiac and pulmonary support. As a result, we have renamed this edition Cardiopulmonary Bypass and
Mechanical Support: Principles and Practice. Our intent is for this terminology to encompass univentricular and
biventricular assist devices as well as forms of pulmonary support that involve blood-gas exchange outside the
lungs. In so doing, we aspire to provide a single source of broad-based information that is highly relevant to the
clinical practices of cardiac surgery, cardiac anesthesiology, and perfusion technology. In addition, there is much
information that is useful to all types of intensive care specialists as well as to neonatologists and interventional
cardiologists. As in previous editions, we seek to provide underlying basic science principles as well as practical
clinical applications. The book remains unique in its multidisciplinary comprehensive approach to this
increasingly broad and complex discipline.
This edition sustains the same general organization as the third edition, but several chapters have been
eliminated or merged with others, while some new ones have been added. Of note, mechanical circulatory
support has been divided into short-term and long-term applications. The introductory history section brings a
new perspective. Although it would seem that history is history, viewing it through different eyes reinvigorates its
analysis, so the editors welcome the insightful narrative of Drs. Stephenson and Baciewicz. The editors refer
readers to previous editions for the still-riveting historical accounts of C. Walton Lillehei and Harris B.
Schumacker.
Editors Gravlee and Davis welcome colleagues John Hammon and Barry Kussman as coeditors. Their presence
has injected new ideas and creative energy into the rewarding process of planning and assembling this book. All
of the editors thank Wolters Kluwer/Lippincott Williams and Wilkins for its continued interest in and support for
this important multidisciplinary subject.
Glenn P. Gravlee, MD
Richard F. Davis, MD, MBA
John W. Hammon, MD
Barry D. Kussman, MBBCh, FFA(SA)
Acknowledgments
Glenn P. Gravlee thanks his wife, Joyce, for her patience and understanding about the time one must commit to
a book such as this. Despite dedicated weekday time for academic pursuits, book projects inevitably invade
evenings and weekends.
Richard F. Davis thanks his wife, Elaine, for her consistent support and encouragement and for her gift of time
during the many hours spent preparing the book for publication.
John W. Hammon gratefully acknowledges the support of his wife Lisa and secretary Donna Smitherman. He is
thankful to have had the opportunity to learn much about perfusion technology from the teams of dedicated
perfusionists during his surgical training at Duke University and later while on the faculty at Vanderbilt and Wake
Forest University.
Barry D. Kussman thanks his loving wife, Belinda, and wonderful daughters, Toni and Mia, for their
understanding and support during the many hours spent working on this book. He is grateful for the outstanding
education and training he received in South Africa and Boston, and appreciates the support of the Department of
Anesthesiology, Perioperative and Pain Medicine at Boston Children’s Hospital, for this and other academic
projects.
Chapter 1
Development of Cardiopulmonary Bypass
Larry W. Stephenson
Frank A. Baciewicz Jr.
INTRODUCTION
The development of cardiopulmonary bypass or a machine that could temporarily take over the function of the
heart and provide oxygenation of the blood (bypass the pulmonary circuit) was a major development in clinical
medicine. With the ability to bypass both the heart and lungs, surgeons were now able to correct cardiac defects,
replace diseased valves, and bypass obstructed coronary arteries. It has led to the ability to remove the heart
itself, and perform a transplant.
It has also been instrumental in the development of ventricular assist devices, which can be implanted on a
temporary or permanent basis, to provide partial or complete perfusion for the entire body.
EARLY RESEARCH
This development was initiated in the early 1800s when physicians were experimenting with forms of external
perfusion, which meant drawing blood from a living animal or person and injecting it into an excised organ or
subject. The external perfusion techniques soon led to processes which infused oxygen into the perfused blood.
However, it was not until Dr. Gibbon’s development of the heart-lung machine in the 1950s that the dreams and
aspirations of the early visionaries were realized.
In 1812, Cesar-Julian-Jean LeGallois (1) postulated that tissues and organs of dead animals could be returned
to a functioning living state by restoring blood flow via a perfusion machine. This theory was based on
experiments which had restored function to organs of dead animals by perfusing their organs with blood. The
perfusion was by hand syringe. Similar studies followed, such as artificial perfusion of muscles and organs. In the
1850s, Charles Eduard Brown-Sequard (2) attributed the success of these perfusions of muscles and organs to
oxygenated blood. He made the observation that rigor mortis temporarily disappeared from the muscles of
guillotined criminals when these muscles were perfused with their own blood. His techniques for perfusing
organs were rather simple—he used syringes for perfusion, and introduced oxygen into the blood by agitating
the blood vigorously. Other investigators at that time, such as Waldemar Von Schroder (3), used a bubbling
method or passing bubbles of air or oxygen through the blood in an attempt to increase the oxygen in these
primitive perfusion systems. Unfortunately, the bubble technique resulted in significant foaming in the blood and
gas embolism. The solution would await the development of antifoaming agents in the following century.
Another technique was used for introducing oxygen into the blood—the filming technique, which was developed
in 1885 by Max Von Frey and Max Gruber. They were able to oxygenate blood by running blood inside a rotating
cylinder filled with oxygen (4). They used this device for the perfusion of isolated organs. Other investigators at
that time were also using a filming technique to oxygenate blood in their experimental apparatus. Richards and
Drinker (5) directed the blood flow through a cloth cylinder inside an oxygen chamber, and Baylis dispersed the
blood over a series of disks and cones and then oxygenated over with flowing oxygen (6,7). Other researchers
dispersed the blood on a glass cylinder into which oxygen jets were blowing. Nevertheless, oxygenating the
blood for these perfusion studies remained a difficult problem to overcome. The apparatus were very complex,
utilizing very low volumes of blood per minute, and they could be maintained for only short time periods.
Investigators such as Patterson and Starling (8) and Jacob (9) oxygenated the blood by having it first perfuse
through the animal’s own lungs and then into the investigated organ. In that way the blood was being auto-
oxygenated. These devices were cleverly designed, but very difficult to maintain.
These efforts at organ perfusion were taken to another level by the Russian duo Brukhonenko and Tchetchuline
(10), who perfused oxygenated blood through the carotid arteries of guillotined heads of dogs, and were able to
keep the head functional for several hours. The blood that was being infused into the carotid arteries was being
oxygenated through the lungs of a second dog (see Fig 1.2). These experiments foreshadowed the cross-
circulation work of Dr. Walt Lillehei at the University of Minnesota (10), decades later, in which he used the
parent of a child as both pump and oxygenator for pediatric patients undergoing cardiac surgery.
After success with keeping the dog heads functional for several hours, Brukhonenko used a similar method of
P.4
oxygenation in an attempt to bypass the nonfunctioning hearts of dogs. Although some of these animals lived for
a short period of time after termination of the experiments, he was not able to restore heart function. These
studies by Brukhonenko (11) were unsuccessful, but suggested how a bypass device with an oxygenator had
potential applications in humans. His foresight at this juncture regarding the possibility of being able to bypass
the heart was far ahead of its time (12).
The famous aviator, Charles Lindbergh, was also involved in the research related to the heart pump. Mr.
Lindbergh’s sister-in-law had rheumatic fever, and at that time there were no operations for the correction of a
diseased heart valve. In an effort to design a mechanical heart that would maintain blood circulation while his
sister-in-law’s heart was being operating on, he continually queried doctors, which eventually led to a meeting
with Dr. Alexis Carrell, winner of the Nobel Prize and the director of the Rockefeller Institute for medical research
(13). Dr. Lindbergh discussed his ideas with Carrell, and the potential problems such as infection, blood clotting,
and hemolysis of red blood cells. Carrell was very interested in tissue culture perfusion and made the point that
he had not been successful in finding an infection-free organ-perfusing device. Following these conversations,
Lindbergh went to work part-time at the Rockefeller Institute in New York. He worked on trying to perfuse whole
organs and was able to develop a sterile pulsatile perfusion system which could work at various flow rates and
variable perfusion pressures. This work led to a picture of Carrell (13) and Lindbergh on the cover of Time
magazine in June 1938. This pump system was able to perfuse various organs for multiple days, including a
thyroid gland for 18 days in 1935 (14). They were able to grow epithelial cells of the organ in tissue cultures after
that perfusion period. They were also able to keep hearts beating for several days with the pumps that they
developed. These organs survived well over several days, but developed interstitial edema.
THE DEVELOPMENT OF CARDIOPULMONARY BYPASS FOR HEART

SURGERY
The development of the heart-lung machine made repair of intracardiac lesions possible. Lillehei wrote, “A
physician at the bedside of a child dying of an intracardiac malformation as recently as 1952 could only pray for a
recovery! Today with the heart-lung machine, correction is routine” (12). To bypass the heart, one needs a basic
understanding of the physiology of the circulation, a method of preventing the blood from clotting, a pump to
pump blood, and finally, a method to ventilate the blood.
ANTICOAGULATION
One of the key requirements of the heart-lung machine is anticoagulation of blood. Heparin was discovered by a
medical student, Jay McLean, working in the laboratory of Dr. William Howell, a physiologist at Johns Hopkins
(15). In 1915, Howell gave McLean the task of studying a crude brain extract known to be a powerful
thromboplastin. Howell believed that the thromboplastic activity was caused by cephalin contained in the extract.
McLean's job was to fractionate the extract and purify the cephalin. McLean also studied extracts prepared from
heart and liver. McLean discovered that a substance in the extract was retarding coagulation. McLean (16)
wrote:
I went one morning to the door of Dr. Howell’s office, and standing there (he was seated at
his desk), I said, “Dr. Howell, I have discovered antithrombin.” He smiled and said,
“Antithrombin is a protein and you are working with phospholipids. Are you sure that salt is
not contaminating your substance?” I told him that I was sure of that, but it was [a]
powerful anticoagulant. He was most skeptical, so I had the diener, John Schweinhand,
bleed a cat. Into a small beaker full of its blood, I stirred all the proven batch of
heparphosphotides, and placed this on Dr. Howell’s laboratory table and asked him to tell
when it clotted. It never did.
McLean described his finding in February 1916 at a medical society meeting in Philadelphia and later reported it
in an article titled “The Thromboplastic Action of Cephalin” (16,17). Howell and Holt (18) reported their work on
heparin in 1918. In the 1920s, animal experiments confirmed that heparin was an effective anticoagulant (19).
JOHN GIBBON’S EARLY RESEARCH

John Gibbon (20) probably contributed more to the success of the development of the heart-lung machine than
anyone else. His interest began one night in 1931 in Boston during an all-night vigil by the side of a patient with
a massive embolus:
My job that night was to take the patient’s blood pressure and pulse every 15 minutes and
plot it on a chart. During the 17 hours by the patient’s side, the thought constantly recurred
that the patient’s hazardous condition could be improved if some of the blue blood in the
patient’s distended veins could be continuously withdrawn into an apparatus where the
blood could pick up oxygen and discharge carbon dioxide and then pump this blood into
the patient’s arteries. At 8 a.m. the patient’s blood pressure could not be measured. Dr.
Edward Churchill, the chief of surgery, immediately opened the chest through an anterior
left thoracotomy, then occluded both the pulmonary artery and the aorta as they exited
from the heart. He opened the pulmonary artery and removed massive blood clots. The
patient did not survive.
Gibbon's work on the heart-lung machine took place over the next 20 years, in laboratories at the Massachusetts
General
P.5
Hospital, the University of Pennsylvania, and Thomas Jefferson University.
In 1937, Gibbon (21) reported the first successful demonstration that life could be maintained by an artificial heart
and lung and that the native heart and lungs could resume function. Unfortunately, only three animals recovered
adequate cardiorespiratory function after total pulmonary artery occlusion and bypass, but they died a few hours
later. Gibbon reported at the 1939 meeting of the American Association for Thoracic Surgery that the survival of
cats in good condition had been achieved after a period of total CPB. Clarence Crafoord, the widely respected
head of thoracic surgery at the Karolinska Institute in Stockholm, commented in response to the report that a
virtual pinnacle of success in surgery had been reached. Leo Eleosser, a distinguished San Francisco surgeon,
remarked that Gibbon's work reminded him of the visions of Jules Verne, thought impossible at the time but
accomplished somewhat later (22).
Gibbon’s work was interrupted due to his military service during World War II; afterward he resumed his work at
Thomas Jefferson Medical College in Philadelphia. Meanwhile, other groups, including Clarence Crafoord in
Stockholm, Sweden, J. Jongbloed at the University of Utrecht in Holland, Clarence Dennis at the University of
Minnesota, Mario Dogliotti and coworkers at the University of Turin in Italy, and Forest Dodrill at Harper Hospital
in Detroit, also worked on a heart-lung machine (23).
CLARENCE DENNIS
Clarence Dennis’s first clinic attempt at open-heart surgery was in a 6-year-old girl with end-stage cardiac
disease. Her heart was already massive, and her only hope was surgical closure of an atrial septal defect (24).
At operation on April 5, 1951, her circulation was supported by a heart-lung machine that Dennis and coworkers
had developed. The atrial septal defect was very difficult to close. Although the heart-lung machine functioned
well, the patient did not survive, probably because of a combination of blood loss and surgically induced tricuspid
stenosis (25).
MARIO DIGLIOTTI
In August 1951, Mario Digliotti used his heart-lung machine to support the circulation in a 49-year-old patient
during resection of a large mediastinal tumor. During the operation, the patient developed hypotension and
cyanosis (26). He was placed on partial bypass at 1 L/min. Although the mass was resected successfully, the
Italian machine was never used for open-heart surgery in humans.
FOREST DODRILL
Forest Dodrill and colleagues used the mechanical blood pump they developed with General Motors in a 41-
year-old man. General Motors called it the Dodrill-GMR pump—GMR for General Motors Research laboratories,
where it was developed. The machine was used to substitute for the left ventricle for 50 minutes while a surgical
procedure was carried out on the mitral valve. Although Dodrill’s report lacks details of the procedure and omits
important hemodynamic information, it nevertheless represents a landmark in the field of cardiothoracic surgery
(27). This, the first clinically successful total left-sided heart bypass, was performed on July 3, 1952, and
followed from Dodrill’s experimental work with a mechanical pump for univentricular, biventricular, or
cardiopulmonary bypass. Dodrill had used their pump with an oxygenator for total heart bypass in animals, but he
felt left-sided heart bypass was the most practical method for their first clinical case because it was not
associated with a profound “hypotensive reflex” that occurred in other forms of bypass (28). When their patient
was interviewed at age 68, he recalled seeing dogs romping on the roof of a nearby building from his hospital
room in 1952. Later, he learned that they had been used in the final test of the Dodrill-General Motors
mechanical heart machine.
Later, on October 21, 1952, Dodrill et al. (29) used their machine in a 16-year-old boy with congenital pulmonary
stenosis to perform a pulmonary valvuloplasty under direct vision; this was the first successful right-sided heart
bypass.
Between July 1952 and December 1954, Dodrill performed approximately 13 clinical operations on the heart and
thoracic aorta using the Dodrill-General Motors machine, with at least five hospital survivors. While he used this
machine with an oxygenator in the animal laboratory, he did not start using an oxygenator with the Dodrill-
General Motors mechanical heart clinically until early 1955 (30).
WILFRED BIGELOW
Hypothermia was another method to stop and open the heart. In 1950, Bigelow et al. (31) reported on 20 dogs
that had been cooled to 20°C, with 15 minutes of circulatory arrest; 11 animals also had a cardiotomy. Only six
animals survived after rewarming. Bigelow and colleagues continued to study hypothermia and hibernation and
learned that a groundhog could be cooled to a body temperature of 5°C and be revived (32,33). This
temperature allowed circulatory arrest with a cardiotomy procedure lasting 2 hours without ill effects (34).
JOHN LEWIS
In 1953, F. J. Lewis and M. Taufic (35) reported on 26 dogs that had surgically induced atrial septal defects
which they attempted to close using a hypothermia technique. In this paper, the authors also reported on a 5-
year-old girl who had closure of her atrial septal defect on September 2, 1952, using a hypothermic technique.
She was anesthetized and the trachea was intubated. She was then wrapped in refrigerated blankets until after a
period
P.6
of 2 hours and 10 minutes her rectal temperature had fallen to 28°C. At this point, the chest was entered through
the bed of the right 5th rib. The cardiac inflow was occluded for a total of 5½ minutes and during this time the
septal defect measuring 2 cm in diameter was closed under direct vision. The patient was rewarmed by placing
her in hot water kept at 45°C; after 35 minutes, her rectal temperature had risen to 36°C, at which time she was
removed from the bath. Recovery from the anesthesia was prompt and her subsequent postoperative
convalescence was uneventful.
This was the first successful repair of an atrial septal defect in a human with surface cooling under direct vision.
Shortly after, Swan et al. (36) reported successful results in 13 clinical cases using a similar technique. The use
of systemic hypothermia for open intracardiac surgery was relatively short-lived. After the heart-lung machine
was introduced clinically, it appeared that deep hypothermia was obsolete. However, during the 1960s, it
became apparent that operative results in infants under 1 year of age using cardiopulmonary bypass were poor.
In 1967, Hikasa et al. (37), from Kyoto, Japan, published an article that reintroduced profound hypothermia for
cardiac surgery in infants and used the heart-lung machine for rewarming. Their technique involved surface
cooling to 20°C, cardiac surgery during circulatory arrest for 15 to 75 minutes, and rewarming with
cardiopulmonary bypass. At the same time, other groups reported using profound hypothermia with circulatory
arrest in infants with the heart-lung machine for cooling and rewarming (38,39,40,41). Results were much
improved, and subsequently the technique was applied also for resection of aortic arch aneurysms in adults.
GIBBON’S RESEARCH CONTINUES

After World War II, John Gibbon resumed his research. He eventually met Thomas Watson, chairman of the
board of the International Business Machines (IBM) Corporation. Watson was fascinated by Gibbon’s research
and promised help. Soon afterward, six IBM engineers arrived and built a machine that was similar to Gibbon’s
earlier machine, which contained a rotating vertical cylinder oxygenator and a modified DeBakey rotary pump.
Gibbon successfully used this new machine for intercardiac surgery on small dogs and had several longterm
survivors, but the blood oxygenator was too small for patients. Eventually, the team developed a larger
oxygenator that the IBM engineers incorporated into a new machine (42).
In 1949, Gibbon’s early mortality in dogs was 80%, but it gradually improved (23). The first patient was a 15-
monthold girl with severe congestive heart failure. The preoperative diagnosis was atrial septal defect, but at
operation, none was found. She died, and a huge patient ductus was found at autopsy. The second patient was
an 18-year-old girl with congestive heart failure also due to an atrial septal defect. This defect was closed
successfully on May 6, 1953, with the Gibbon-IMB heart-lung machine. The patient recovered, and several
months later, the defect was confirmed closed at cardiac catheterization. This was the first successful clinical
case using the heart-lung machine (43). Unfortunately, Gibbon’s next two patients did not survive intracardiac
procedures when the heart-lung machine was used. These failures distressed Dr. Gibbon, who declared a 1-
year moratorium for the heart-lung machine until more work could be done to solve the problem causing the
deaths.
C. WALTON LILLEHEI
During this period, C. Walton Lillehei and colleagues at the University of Minnesota studied a technique called
controlled cross-circulation. With this technique, the circulation of one dog was temporarily used to support that
of a second dog while the second dog’s heart was temporarily stopped and opened. After a simulated repair in
the second dog, the animals were disconnected and allowed to recover, Lillehei (44) remarked.
Clinical cross-circulation for intracardiac surgery was an immense departure from the established surgical
practice. This thought of taking a normal human to the operating room to serve as a donor circulation (with
potential risk, however small), even temporarily, was considered by critics of the time to be unacceptable, even
“immoral” as one prominent surgeon was heard to say. Some others, skilled in the art of criticism, were quick to
point out that this proposed operation was the first in all of surgical history to have the potential (even the
probability in their judgment) for a 200% mortality.
However, the continued lack of any success in the other centers around the world that were working actively on
heart-lung bypass led to the decision to go ahead inevitable. I felt the technique was ready to use in man;
however, even in such a progressive and pioneering medical school as Minnesota University, there was
opposition to the idea. Dr. Owen Wangenstein, chairman of the Department of Surgery, was a tremendous help.
He was well aware of these experiments and whole-heartedly supported them. Where there seemed a possibility
that the first clinical operation might be canceled the night before because of this opposition, I left a note for Dr.
Wangenstein asking, “Is our case still on in the morning?” His answer, “Dear Walt, by all means, go ahead.”
Lillehei et al. (12) used their technique at the University of Minnesota to correct a ventricular septal defect (VSD)
in a 12-month-old infant on March 26, 1954. The patient had been hospitalized for 10 months for uncontrollable
heart failure and pneumonitis. At operation, a 2-cm membranous VSD was closed with suture. The patient made
an uneventful recovery until death on the eleventh postoperative day from a rapidly progressing tracheal
bronchitis. At autopsy, the VSD was closed, and the respiratory infection was confirmed as the cause of death.
Two weeks later, the second and third patients had VSDs closed by the same technique 3 days apart. Both
remained long-term survivors with normal hemodynamics confirmed by cardiac catheterization.
P.7
In 1955, Lillehei et al. (45) published a report of 32 patients which included repairs of VSDs, tetralogy of Fallot,
and atrioventricularis communis defects. By May 1955, the pump used for systemic cross-circulation by Lillehei
et al. was coupled with a bubble oxygenator developed by Drs. DeWall and Lillehei. Cross-circulation was
abandoned after use in 45 patients during 1954 and 1955. Although its clinical use was short-lived, clinical cross-
circulation was an important stepping stone in the development of cardiac surgery (44).
JOHN W. KIRKLIN
Meanwhile, at the Mayo Clinic only 90 miles away, John W. Kirklin and colleagues (46) launched their open-
heart program on March 5, 1955. They used a heart-lung machine based on the Gibbon-IBM machine but with
their own modifications. Dr. Kirklin (47) wrote:
In 1951, now on the surgical staff on the Mayo Clinic, I did a closed pulmonary valvulotomy
on a 30-year-old man with pulmonary stenosis and intact ventricular septum. He had
massive ventricular hypertrophy and died about 2 days after the operation. At autopsy it
was apparent that the pulmonary valve was open, but also that the subvalvular muscle
hypertrophy was enormous. The patient could not survive without relief of the muscular
obstruction. Dr. Earl Wood, a great physiologist and my co-worker and I went back to his
office after we viewed that autopsy and decided that we would either have to be content
with cardiac surgery as a rather minor specialty, limited to passing instruments into the
heart or we would need a heart-lung machine. In earlier times, Earl Wood had worked with
Maurice Vissher at the University of Minnesota and had experience with the Starling heart-
lung preparation. “It’s the oxygenator that is the problem,” said Earl Wood.
Kirklin (47) goes on to say:
We investigated and visited the groups working intensively with the mechanical pump
oxygenators. We visited Dr. Gibbon in his laboratories in Philadelphia, and Dr. Forest
Dodrill in Detroit, among others. The Gibbon pump oxygenator had been developed and
made by the International Business Machine Corporation and looked quite a bit like a
computer. Dr. Dodrill’s heart-lung machine had been developed and built for him by
General Motors and it looked a great deal like a car engine. We came home, reflected and
decided to try to persuade the Mayo Clinic to let us build a pump oxygenator similar to the
Gibbon machine, but somehow different. We already had had about a year’s experience in
the animal laboratory with David Donald using a simple pump and bubble oxygenator when
we set about very early in 1953, the laborious task of building a Mayo Gibbon pump
oxygenator and continuing the laboratory research.
Most people were very discouraged with the laboratory progress. The American Heart
Association and the National Institute of Health had stopped funding any projects for the
study of heart-lung machines, because it was felt that the problem was physiologically
insurmountable. David Donald and I undertook a series of laboratory experiments lasting
about a year and a half during which time the engineering shops at the Mayo Clinic
constructed a pump oxygenator based on the Gibbon model (48).
Of course a number of visitors came our way and some of them came to the laboratory to
see what we were doing. One of those visitors was Ake Senning (from Stockholm,
Sweden). I still remember the day when he was there and one of the connectors came
loose and we ruined his beautiful suit as well as the ceiling of the laboratory by spraying
blood all around the room.
The electrifying day came in the spring of 1954 when the newspapers carried an account
of Walt Lillehei’s successful open heart operation on a small child. Of course, I was terribly
envious and yet I was terribly admiring at the same moment. That admiration increased
exponentially when a short time later, a few of my colleagues and I visited Minneapolis and
observed one of what was now a series of successful open-heart operation with control
cross-circulation. Walt then took us on rounds and it was absolutely exciting to see
children recovering from these miraculous operations. However, it was also for a time, a
difficult period for me. Some of my colleagues at the Mayo Clinic, and some of my
influential ones, indicated to me that we had wasted much time and money. After all, this
young fellow in Minneapolis was successful with a very simple apparatus and did not even
require an oxygenator. Visitors coming from Minneapolis to Rochester asked, “What are
you working on these days?” When I said we were working with an integrated pump
oxygenator, most said, “Oh, yes, but I understand even Gibbon had given up.” As the
months went by, my anxiety grew and I was worried that we too might not make the effort a
successful one. My apprehension was heightened early in 1955 when Time magazine
published an interview with Dick Varco, who described all too accurately the damaging
effects of artificial oxygenators and why they were impractical and dangerous.
However, in the winter of 1954 and 1955, we had 9 surviving dogs out of 10
cardiopulmonary bypass runs. With my wonderful colleague and pediatric cardiologist,
P.8
Jim DuShane, we had earlier selected eight patients for intracardiac repair. Two had to be
put off because two babies with very serious congenital heart disease came along and we
decided to fit them into the schedule. We had determined to do [the repair in] all eight
patients even if the first seven died. All of this was planned with the knowledge and
approval of the governance of the Mayo Clinic. Our plan was then to return to the
laboratory and spend the next 6 to 12 months solving the problems that had arisen in the
first planned clinical trial of a pump oxygenator. Gibbon, of course, had done a successful
case in 1953, but it was an isolated case and the next four patients died. In the deepest
recesses of my heart, I felt that those four patients died in part because of the lack of
appreciation of some of the technical aspects of the cardiac surgery.
Kirklin (47) goes on to state:
We did our first open heart operation on Tuesday in March 1955. That evening I had a
telephone call from Dick Varco in Minneapolis, who indicated that Sir Russell Brock was
visiting their cardiac surgical program at the University of Minnesota at that time. Walt
Lillehei and Dick Varco indicated to Sir Russell that we had done the operation earlier that
day and they called to see if he could come to Rochester the next day to see the patient,
to which I said “Certainly.” I was afraid that they would ask if we had planned to do another
case, and they did. I replied: Yes, and we will be doing another case on Thursday.” They
asked if Sir Russell could watch the operation. Well, as you can imagine, I had enough on
my mind without having a world-famous surgeon sitting in the gallery watching this young
guy try to work his way through the second open heart operation. However, we acceded to
Sir Russell’s coming and I am happy to say he was a marvelous guest during the second
operation, and the patient did well as had the first one.
Kirklin (47) continued:
Four of our first eight patients survived, but the press of the clinical work prevented our
ever being able to return to the laboratory with the force that we had planned. By now,
Walt Lillehei and I were on parallel, but intertwined paths. I witnessed an earlier parallel
pathway existing between Dwight Harken and Charles Bailey in the first days of closed
mitral valve surgery. I felt, and I hope you will forgive me, that their interactions were in
some ways demeaning to themselves and to the scientific progress of cardiac surgery. I
am extremely grateful to Walt Lillehei and am very proud of the two of us, that during that
12 to 18 months when we were the only surgeons in the world performing open
intracardiac operations with cardiopulmonary bypass and surely in intense competition
with each other, we shared our gains and losses with each other. We continued to
communicate and we argued privately in nightclubs and on airplanes rather than publicly
over our differences. Walt was more cheerful and more optimistic than I when we
discussed problems. I remember saying to him one day, “Walt, I am so discouraged with
complete atrial ventricular canal.” “Oh, sure,” he said, “that is a tough lesion, but we will
learn to do well with it.”
DEVELOPMENT AND EVOLUTION OF THREE KEY COMPONENTS OF HEART-
LUNG MACHINES: PUMPS, OXYGENATORS, AND HEAT EXCHANGERS
This section follows the development of pumps, oxygenators, and heat exchangers from those used by the heart
surgery pioneers through their evolution to the present day.
Pumps
When Dr. Gibbon was developing cardiopulmonary devices in the animal laboratory, he used rubber finger cot
pumps. The pumps were derived from the Dale-Schuster modification of the deBurgh-Daly pumps (49,50). These
pumps used flap valves made from rubber stoppers to keep the flow unidirectional, and the flow resulted from
alternately compressing and expanding the finger cot with compressed air. The Gibbons device limited the total
flow that could be achieved, and the best output that Dr. Gibbon could achieve in his animal model was 500
cc/min. The Dodrill-General Motors pump also used a variation of the finger cot pump, which they developed and
could pump up to 4 L/min. It was used clinically from 1952 through at least 1956 (30) (Fig. 1.1).
FIGURE 1.1. Dodrill-GMR mechanical pump being used in the animal laboratory with the row of finger cot pumps
being adjusted.
P.9
After Gibbon returned from his stint with Pennsylvania Hospital’s Evacuation Hospital Unit during World War II,
he fortuitously received help from IBM to develop a cardiopulmonary bypass machine. The pump now utilized
was the DeBakey-Schmidt modification of the Porter-Bradley roller pump (51).
The DeBakey-Schmidt modification of the roller pump added a flange to the outer circumference of the blood
tubing which prevented its migration in the rigid housing. The roller pump also eliminated the need for valves in
the Dale-Schuster pump. DeBakey had suggested to Gibbon years earlier that the roller pump should be the
preferred method of perfusion in the heart-lung machine. DeBakey’s contribution was not so much the
modification of the roller pump, but rather the concept of using the roller pump for the bypass machine.
Subsequently, improvements were made by Melrose in 1959 (52) to place a grooved plate in the housing and
match the radii of the roller pump and the groove to decrease blood trauma.
The roller pump (Fig. 1.2) uses tubing which is encased within a curved runway such that one roller or clamp is
always compressing the tubing (52). In this way, blood is always being pushed ahead of the roller giving a
continuous blood flow. The output can be calculated from the revolutions of the roller pump per minute, and the
volume per revolution. Roller pumps have been used since the 1950s, and are still in use today.
The roller pump’s advantages are that it is afterload-independent and has a low priming volume and no potential
for reversal of flow. The roller pump’s afterload independence means that it delivers the calculated output
regardless of the patient’s peripheral vascular resistance, which varies depending on temperature, pH, and
intrinsic tone. A disadvantage is that excessive line pressure will develop if the outflow becomes occluded with
the pressure in the tubing progressively increasing until the tubing either disconnects or breaks (53). Other
disadvantages are the possibility of creating high negative pressure with the production of air bubbles or
cavitation, and the capacity to pump grossly visible air. In addition, the roller pump can cause damage to the
tubing with possible micro emboli and rupture of the tubing, and the possibility of a large air embolus. The roller
pump requires close attention to address these potential problems while on cardiopulmonary bypass.
FIGURE 1.2. Diagram of Debakey-Schmidt pump utilized in the Gibbon-IBM cardiopulmonary bypass machine.
Another positive displacement pump is the Sigma motor pump, which propelled blood via a series of keys
pressing in sequence against the resilient pump tubing (50). This pump was used in the 1950s at the University
of Minnesota by Lillehei in the cross-circulation cases. This pump (Fig. 1.3) was eventually replaced by the roller
pump, which caused less red blood cell damage.
In 1976, the Medtronic centrifugal pump became available. The first centrifugal pump was developed in the 17th
century by Denis Papin (54). The centrifugal pump used for heart surgery consists of an impeller with flanges
mounted on a rotating central shaft, inside a plastic housing. The central shaft is coupled magnetically with an
electric motor. The magnet inside the pump head moves in conjunction (53,54) with another magnet in the drive
console. The blood enters through the eye of the plastic housing, is caught up in the impeller blades, and is
swirled radially through the output part of the housing. As the centrifugal pump rotates more rapidly, it creates a
pressure differential resulting in blood flow (Fig. 1.4). A Doppler flow meter is required on the outflow side of the
centrifugal pump to measure forward blood flow and the speed of rotation. The afterload of the arterial line
determines the forward flow. In the event input to the centrifugal pump decreases, the pump outflow decreases
and if air enters the circuit, the afterload increases so that only a small amount of air is pumped out before the
pump revolutions cease.
The centrifugal pump is considered to have advantages over the roller pump, and is used in most cardiac
operating rooms today. The advantages are that the centrifugal pump cannot develop excessive arterial
pressures, is preload-dependent, afterload-dependent, and has a decreased risk of pumping significant amounts
of air into the arterial line. The disadvantages are its higher cost compared to roller pumps, larger priming
volume, the potential for reversal of flow if an
P.10
arterial check valve is not used, and the less precise measurement of flow generated by the pump (55).
FIGURE 1.3. Diagram of Sigma motor pump with series of keys pressing in sequence against resilient tubing.
FIGURE 1.4. Diagram depicting blood flow as it enters centrifugal pump, its route through the pump as the
impeller blades spin around, and then exits pump.
Currently, most heart surgery teams use the centrifugal pump for their arterial bypass, and roller pumps for
cardioplegia delivery, suction, and ventricular decompression.
Oxygenators
The various groups working on the heart-lung machine in the laboratory during the early 1950s, and some even
earlier, developed several different types of devices to oxygenate the venous blood returning from the animal to
the excorporeal apparatus. These oxygenators worked on the principle of spreading the blood out into a thin
layer over a relatively large surface area where the blood was exposed to oxygen, which caused it to give up
CO2 and take on the oxygen. Some of the devices had moving parts, such as the disk rotating oxygenator, while
others were completely stationary. It was discovered that causing some degree of turbulence of the blood as it
flowed over the surface improved the oxygen uptake of the blood. Too much turbulence, however, caused
damage to the blood elements.
John Gibbon’s research group in Philadelphia, Pennsylvania, found that if they passed the blood over a
stationary screen it caused enough turbulence to significantly increase the oxygen uptake by the blood. They
used such an oxygenator, incorporating several of these stationary screens in their first clinical cases, including
the patient with the successful outcome in 1953 (43). At the Mayo Clinic, John Kirklin, who built a similar heart-
lung machine, also used a stationary-screen oxygenator for their clinical work starting in March 1955 (46).
Meanwhile, C. Walton Lillehei’s group at the University of Minnesota had been performing pediatric open-heart
surgery using the cross-circulation method, wherein an adult was connected to the child’s circulation and that
adult’s lungs served as the oxygenator while the child’s heart was repaired (45). During the winter of 1954-1955,
Dr. Richard DeWall, working in Dr. Lillehei’s research laboratory, developed an oxygenator whereby oxygen was
bubbled through the returning venous blood. As the red blood cells came in contact with the bubbles, they gave
off CO2 and took on O2. This method was found to be very effective. DeWall then rapidly worked out methods to
prevent the blood, which still contained bubbles, from returning to the patient with these bubbles, which would
cause gas emboli.
The University of Minnesota group began clinically using a heart-lung machine with DeWall’s bubble oxygenator
in May 1955 (56). Sometime after, they developed a disposable plastic version that was made available for
commercial use. Dr. Denton Cooley from Houston, Texas, visited the University of Minnesota in 1955 and
observed the DeWall oxygenator. Upon his return to Houston, he set about to develop his own version, which he
did. Like the DeWall oxygenator, Cooley’s was made of plastic, disposable, and became commercially available.
By the early 1970s, the bubble oxygenators became the oxygenator of choice at most centers performing open-
heart surgery. Because they were made of disposable plastic, they did not require the long and intense effort
needed to clean the screen and disk oxygenators after each use, and they required less blood prime.
Willem Kolff, a physician living in the Netherlands in the 1940s, conducted research in renal dialysis technology
that ultimately led to renal dialysis becoming a clinical reality. He later immigrated to the United States, and as a
researcher at the Cleveland Clinic, he developed a disposable membrane oxygenator for experimental use in
1956 (57). George Clowes and William Neville, working at Western Reserve University Medical School and at
Cleveland City Hospital, developed their own variant of the membrane oxygenator. They became pioneers in
using it clinically for open-heart surgery in 1958 (58,59,60).
The choice of material used to build the membrane oxygenator is important because it must be compatible with
blood, permeable to O2 and CO2, and very thin, with minimal resistance to blood and respiratory gas flow (61).
In recent years, the membrane oxygenator has replaced the bubble oxygenator in the United States because it
has been proven to be safer: it produces less particulate and micro emboli, is less reactive to blood elements,
and allows superior control of blood gases (62).
Blood Heat Exchanger

In 1956, Dr. Ivan Brown from Duke University asked the Harrison Radiator Division of General Motors if company
engineers could design a device that would allow the cooling and heating of blood as needed during a heart
operation. The device would be used in conjunction with the heart-lung machine. Prior to this time, if hypothermia
was required during a procedure, the patient’s body temperature was lowered by a refrigerated blanket or by ice
packs. This necessitated 1 to 2 hours under anesthesia before the operative procedure could begin. Rewarming
the patient after the heart repair was complete could take another 3 to 4 hours.
P.11
Working on this project were, from Duke University, Drs. Brown, Will Sealy, W. Glenn Young, and Wirt Smith.
The Harrison engineering research team included W.O. Emmons, D.B. Sacca, and C.C. Eckles. The project took
10 months of planning and experimentation. The resulting blood heat exchanger consisted of a group of slender
stainless steel tubes enclosed in a steel jacket. As the blood flowed through the tubes, water circulated within the
steel jacket outside the tubes. Hot and cold water were directed through a special mixing valve in conjunction
with a thermostat, so that the exact desired temperature could be controlled and maintained (63,64,65). The heat
exchanger was placed upstream from the oxygenator in the heart-lung machine circuit, which allowed the
patient’s body temperature via the blood to be either cooled or warmed. The application of heat exchangers for
open-heart surgery soon became standard.
In 1966, Dr. Richard DeWall made a significant advance in oxygenator design when he developed the hard-shell
bubble oxygenator with an integrated heat exchanger. The entire unit was disposable and set the standard for
bubble oxygenators (66). Most membrane oxygenator units incorporate the heat exchanger upstream to the
oxygenator to avoid possible bubble emboli formation during rewarming.
A BUMPY ROAD DURING THE EARLY'50s

Table 1.1 is meant to further emphasize two aspects of this chapter. The first is to show the bumpy clinical road
heart surgery pioneers traveled from 1951 through 1955. The second is to underscore the fact that although Dr.
John Gibbon’s successful case using a heart-lung machine in May 1953 was of monumental importance, more
work was necessary on the heart-lung machine and understanding its physiologic effects before open-heart
surgery could progress to the next level, which was widespread clinical application. This work would occur over
the next couple of years.
By the end of 1956, many university groups around the world had launched into open-heart programs. Currently,
it
P.12
P.13
is estimated that more than 500,000 cardiac operations are performed each year worldwide with the use of the
heart-lung machine. In most cases, the operative mortality is quite low, approaching 1% for some operations.
Little thought is given to the courageous pioneers in the 1950s whose contributions made all this possible.
TABLE 1.1. Clinical status of open-heart surgery, as well as blood pumps and oxygenators
(1951 through 1955)
1951 April 6: Clarence Dennis at the University of Minnesota used a heart-lung machine to repair an
ostium primum or AV canal defect in a 5-yearold girl. The patient could not be weaned from
cardiopulmonary bypass (24).
May 31: Dennis attempted to close an atrial septal defect using heart-lung machine in a 2-year-
old girl who died intraoperatively of a massive air embolus (25).
August 7: Achille Mario Digliotti at the University of Turin, Italy, used a heart-lung machine of
his own design to partially support the circulation (flow at 1 L/min for 20 minutes) while he
resected a large mediastinal tumor compressing the right side of the heart (26). The
cannulation was through the right axillary vein and artery. The patient survived. This was the
first successful clinical use of a heart-lung machine, but the machine was not used as an
adjunct to heart surgery.
1952 February (1952 or 1953, John Gibbon; see February 1953)

March: John Gibbon used his heart-lung machine for right-sided heart bypass only while
surgeon Frank Allbritten at Pennsylvania Hospital, Philadelphia operated to remove a large clot
or myxomatous tumor suspected by angiogram. No tumor or clot was found (75). The patient
died of heart failure in the operating room shortly after discontinuing right-sided heart bypass.
April 3: James Helmsworth and associates at Cincinnati General Hospital used a pump
oxygenator of their own design to treat a patient suffering from end-stage lung disease. During
the 75-minute pump run, partial veno-veno bypass was used. The patient’s symptoms
improved but recurred soon after bypass was discontinued. Samples for arterial blood
saturation were taken from an indwelling needle placed in the brachial artery. The control
prebypass sample was not suitable for analysis. During bypass, the arterial O2 saturation
varied from 58% to 65% and dropped to 43% after bypass was discontinued (76).
July 3: Dodrill used the Dodrill-GMR pump to bypass the left side of the heart while he
repaired a mitral valve. The patient survived. This was the first successful use of a mechanical
pump for total substitution of the left ventricle in a human being (27).
September 2: John Lewis, at the University of Minnesota, closed an atrial septal defect under
direct vision in a 5-year-old girl. The patient survived. This was the first successful clinical
heart surgery procedure using total-body hypothermia. A mechanical pump and oxygenator
were not used. Others, including Dodrill, soon followed, using total-body hypothermia
techniques to close atrial septal defects (ASDs) and perform pulmonary valvulotomies. By
1954, Lewis reported on 11 ASD closures using hypothermia with two hospital deaths (35). He
also operated on two patients with ventricular septal defect (VSD) in early 1954 using this
technique. Both resulted in intraoperative deaths.
October 21: Dodrill performed pulmonary valvulotomy under direct vision using Dodrill-GMR
pump to bypass the right atrium, ventricle, and main pulmonary artery. The patient survived
(29).
Although Dr. William Mustard in Toronto would describe a type of “corrective” surgical
procedure for transposition of the great arteries (TGA), in 1964, which, in fact, for many years,
would become the most popular form of surgical correction of TGA, his early results with this
lesion were not good. In 1952, he used a mechanical pump coupled to the lung that had just
been removed from a monkey to oxygenate the blood in seven children while attempts were
made to correct their TGA defect (77). There were no survivors.
1953 February (or 1952): Gibbon at Jefferson Hospital in Philadelphia operated to close an ASD.
No ASD was found. The patient died intraoperatively. Autopsy showed a large patent ductus
arteriosus (78).
May 6: Gibbon used his heart-lung machine to close an ASD in an 18-year-old woman with
symptoms of heart failure. The patient survived the operation and became the first patient to
undergo successful open-heart surgery using a heart-lung machine (78).
July: Gibbon used the heart-lung machine in two 5-year-old girls to close atrial septal defects.
Both died intraoperatively. Gibbon was extremely distressed and declared a moratorium on
further cardiac surgery at Jefferson Medical School until more work could be done to solve
problems related to heart-lung bypass. These were probably the last heart operations he
performed using the heart-lung machine.
1954 March 26: C. Walton Lillehei and associates at the University of Minnesota closed a VSD in a
15-month-old boy using a technique to support the circulation that they called controlled cross-
circulation. An adult (usually a parent) with the same blood type was used more or less as the
heart-lung machine. The adult’s femoral artery and vein were connected with tubing and a
pump to the patient’s circulation. The adult’s heart and lung oxygenated and supported the
circulation while the child’s heart defect was corrected. The first patient died 11 d
postoperatively from pneumonia, but six of their next seven patients survived (79). Between
March 1954 and the end of 1955, 45 heart operations were performed by Lillehei on children
using this technique before it was phased out. Although controlled cross-circulation was a
short-lived technique, it was an important stepping stone in the development of open-heart
surgery.
July: Clarence Crafoord and associates at the Karolinska Institute in Stockholm, Sweden used
a heart-lung machine of their own design coupled with total-body hypothermia (patient was
initially submerged in an ice-water bath) to remove a large atrial myxoma in a 40-year-old
woman (80). She survived.
1955 March 22: John Kirklin at the Mayo Clinic used a heart-lung machine similar to Gibbon’s but
with modifications his team had worked out over 2 yr in the research laboratory, to successfully
close a VSD in a 5-year-old patient. By May of 1955, they had operated on eight children with
various types of VSDs, and four were hospital survivors. This was the first successful series of
patients (i.e., more than one) to undergo heart surgery using a heart-lung machine (48).
May 13: Lillehei and colleagues began using a heart-lung machine of their own designed to
correct intracardiac defects. By May of 1956, their series included 81 patients. Initially they
used their heart-lung machine for lower-risk patients and used controlled cross-circulation, with
which they were more familiar, for the higher-risk patients. Starting in March 1955, they also
tried other techniques in patients to oxygenate blood during heart surgery, such as canine lung,
but with generally poor results (79).
Dodrill had been performing heart operations with the GM heart pump since 1952 and used the
patient’s own lungs to oxygenate the blood. Early in the year 1955, he attempted repairs of
VSDs in two patients using the heart pump, but with a mechanical oxygenator of his team’s
design both died. On December 1, he closed a VSD in a 3-year-old girl using his heart-lung
machine. She survived. In May 1956, at the annual meeting of the American Association for
Thoracic Surgery, he reported on six children with VSDs, including one with tetralogy of Fallot,
who had undergone open-heart surgery using his heart-lung machine. All survived at least 48
hr postoperatively. Three were hospital survivors, including the patient with tetralogy of Fallot
(81).
June 30: Clarence Dennis, who had moved from the University of Minnesota to the State
University of New York, successfully closed an ASD in a girl using a heart-lung machine of his
own design (82).
Mustard successfully repaired a VSD and dilated the pulmonary valve in a 9-month-old child
with a diagnosis of tetralogy of Fallot using a mechanical pump and a monkey lung to
oxygenate the blood. He did not give the date in 1955, but the patient is listed as Human Case
7 (83). Unfortunately, in the same report, cases 1-6 and 8-15 operated on between 1951 and
the end of 1955 with various congenital heart defects did not survive the surgery using the
pump and monkey lung, nor did another seven children in 1952, all with TGA (see timeline for
1952) using the same bypass technique.
Note: This list is not all-inclusive but likely includes most of the historically significant clinical open-heart
events in which a blood pump was used to support the circulation during this period.
EXTRACORPOREAL LIFE SUPPORT

Extracorporeal life support (ECLS) is an extension of cardiopulmonary bypass. Cardiopulmonary bypass initially
was limited to no more than 6 hours. The development of membrane oxygenators in the 1960s permitted longer
support. Donald Hill and colleagues, in 1972, treated a 24-year-old man who developed shock lung after blunt
trauma (67). The patient was supported for 75 hours using a heart-lung machine with a membrane oxygenator,
cannulated via the femoral vein and artery. The patient was weaned and recovered. Hill’s second patient was
supported for 5 days and recovered. This led to a randomized trial supported by the National Institutes of Health
to determine the efficacy of this therapy for adults with respiratory failure. The study was conducted from 1972 to
1975 and showed no significant difference in survival between patients managed by extracorporeal life support
(9.5%) and those who received conventional ventilator therapy (8.3%) (68). Because of these results, most US
centers abandoned efforts to support adult patients using ECLS, also known as extracorporeal membrane
oxygenation (ECMO).
One participant in the adult trial decided to study neonates. The usual causes of neonatal respiratory failure
have in common abnormal postnatal blood shunts known as persistent fetal circulation (PFC) (69,70,71,72).
This is a temporary, reversible phenomenon. In 1976, Bartlett and colleagues, at the University of Michigan,
were the first to successfully treat a neonate using ECLS. Since that time, two prospective studies have shown
the efficacy of ECLS for management of neonatal respiratory failure. More than 8,000 neonatal patients have
been treated worldwide with a survival rate of 82% (ELSO registry data) (73,74).
KEY Points
Early attempts to oxygenate the blood of animals in vitro dating from 1812 are discussed. Then, various
methods to perfuse animals with oxygenated blood during this early period are described.
Famous aviator Charles Lindbergh, working with Nobel Laureate Alexis Carrel during the 1930s,
developed methods to keep isolated perfused organs alive for several days.
Jay McLean, working in William Howell’s laboratory, isolated heparin in 1915 and studied its effects as an
anticoagulant. This was an important discovery for those researchers who would begin to work on the
heart-lung machine since it was a practical way to rapidly anticoagulate blood, and heparin’s effects
could also be quickly reversed.
During the 1930s, John Gibbon began his work on developing a heart-lung machine and although his
efforts toward that goal seemed slow, he continued to make progress until his research was interrupted
by his military service in World War II.
After the War, Gibbon resumed his research, but by then a number of other physician researchers had
begun their own work in this field. Among them were Clarence Crafoord in Sweden, Mario Digliotti in Italy,
and Clarence Dennis and Forest Dodrill in the United States.
Wilfred Bigelow in Canada and John Lewis in Minnesota worked independently with total-body
hypothermia in laboratory animals as an alternative means to protect the brain, heart, and other body
organs while the heart was stopped in order to be repaired.
On July 3, 1952, Dodrill used a blood pump to bypass the left heart in a patient while he repaired the
mitral valve. The patient survived. Dodrill did not use a mechanical oxygenator but rather the patient’s
own lungs to oxygenate the blood during the procedure.
Two months later, Lewis used total-body hypothermia to close a child’s atrial septal defect. That patient
survived.
Gibbon had developed a heart-lung machine with both a pump and an oxygenator, and on May 6, 1953,
he used this machine to support a patient’s circulation while repairing a heart defect. The patient
survived, and this became the first successful clinical case in which a heart-lung machine was used.
Over the next few years, a number of other successful cases by other surgeons were performed, using
various methods to pump blood to the patient and oxygenate it while repairing the heart. During this
period, however, mortality rates were very high, but as more knowledge was gained in this new field of
surgery the mortality rates gradually decreased.
The development and evolution of three key components of the heart-lung machine are presented from
their inception to the present: pumps, oxygenators, and heat exchangers.
P.14
REFERENCES
1. LeGallois CJJ. Experiences sur le principe de la vie, notamment sur celui des mouvemens du Coeur, et
sur le siege de ce principe; survies du rapport fait a la premiere classe de I’Institut sur celles relatives aux
mouvemens du Coeur. Paris, UK: d’Hautel, 1812.
2. Brown-Sequard CE. Recherches experimentales sur les proprieties physologiques et les usages du sang
rouge et du sang noir et de leurs principaux elements gazeux, l’oxygene et I’acide corbonique. J Physiol
Homme 1858;1:729-735.
3. Von Schroder W. Uber die bildungstatte des harnstoffs. Arch Exp Pathol Pharmacol 1882;15:364-402.
4. Von Frey M. Gruber M. Untersuchungen uber den stoffwechsel isolierte organe. Ein respiration-apparat fur
isolierte oregano. Virchow’s Arch Physiol 1885;9:519-532.
5. Richards AN, Drinker CK. An apparatus for perfusion of isolated organs. J Pharmacol Exp Ther
1915;7:467-483.
6. Bayliss LE, Fee AR, Ogden EA. Method of oxygenating blood. J Physiol 1928;66:443-448.
7. Daly IB, Thorpe WV. An isolated mammalian heart preparation capable of performing work for long
periods. J Physiol 1933;79:199-217.
8. Patterson SW, Starling EH. On the mechanical features which determine the output of the ventricles. J
Physiol 1914;48:357-379
9. Jacob JC. Ein beitrag zur technik der kunstiliechen durchblutung ueberlebender organe. Arch Exp Pathol
Pharmacol 1895;36:330-348.
10. Brukhonenko S. Tchetchuline S. Experiences avec la tete isolee du chien.1.Technique et conditions des
experiences. J Physiol Pathol Gen 1929;27:31-45.
11. Brukhonenko S. Circulation artificelle du sang dans l’organisme entire d’un chien avec Coeur exclus. J
Physiol Pathol Gen 1929;27:257-272.
12. Lillehei CW, Cohen M, Warden HE, et al. The results of direct vision closure of ventricular septal defects
in eight patients by means of controlled cross circulation. Surg Gynecol Obstet 1955;101:447-466.
13. Lindberg CA. Autobiography of values. New York, NY: Harcourt Brace Jovanovich, 1977.
14. Lindbergh CA. An apparatus for the culture of whole organs. J Exp Med 1935;62:409-432.
15. Johnson SL. The History of cardiac surgery, 1896-1955. Baltimore, MD: Johns Hopkins Press, 1970:121.
16. McLean J. The discovery of heparin. Circulation 1959;19:75-78.
17. Letter from Jay McLean to Charles H. Best on November 14, 1940; quoted in Best CH: Preparation of
heparin and its use in the first clinical case. Circulation 1959;19:79.
18. Howell WH, Holt E. Two new factors in blood coagulation: heparin and pro-antithrombin. Am J Physiol
1918;47:328-341.
19. Best C. Preparation of heparin and its use in the first clinical case. Circulation 1959;19:79-86.
20. Gibbon JH Jr. The gestation and birth of an idea. Phila Med 1963;59:913-916.
21. Gibbon JH Jr. Artificial maintenance of circulation during experimental occlusion of the pulmonary artery.
Arch Surg 1937;34:1105-1131.
22. Shumacker HB, The birth of an idea and the development of cardiopulmonary bypass. In: Gravlee GP,
ed. Cardiopulmonary bypass and mechanical support: principles and practice. 3rd ed. Philadelphia, PA:
Lippincott, Williams, and Wilkins, 2008:29.
25. Dennis C, Spreng DS, Nelson GE, et al. Development of a pump oxygenator to replace the heart and
lungs: an apparatus applicable to human patients, and application to one case. Ann Surg 1951;134:709-721.
26. Digliotti AM. Clinical use of the artificial circulation with a note on intra-arterial transfusion. Bull Johns
Hopkins Hosp 1951;90:131-133.
27. Dodrill FD, Hill E, Gerisch RA. Temporary mechanical substitute for the left ventricle in man. JAMA
1952;150:642-644.
28. Dodrill FD, Hill E, Gerisch RA. Some physiologic aspects of the artificial heart problem. J Thorac Surg
1952;24:134-150.
29. Dodrill FD, Hill E, Gerisch RA, et al. Pulmonary valvuloplasty under direct vision using the mechanical
heart for a complete bypass of the right heart in a patient with congenital pulmonary stenosis. J Thorac Surg
1953;25:584-594.
30. Stephenson LW. The Michigan Heart: first successful open heart operation? Part I. J Card Surg
2002;17(3):238-246.
31. Bigelow WG, Callaghan JC, Hopps JA. General hypothermia for experimental intracardiac surgery; the
use of electrophrenic respirations, an artificial pacemaker for cardiac standstill and radio-frequency
rewarming in general hypothermia. Am Surg 1950;132:531-539.
32. Bigelow WG, Lindsay WK, Harrison RC, et al. Oxygen transport and utilization in dogs at low body
temperatures. Am J Physiol 1950;160:125-137.
33. Bigelow WG, Hopps JA, Callaghan JA. Radiofrequency rewarming in resuscitation from severe
hypothermia. Can J Med Sci 1952;30:185-193.
34. Bigelow WG. Intellectual humility in medical practice and research. Surgery 1969;65(1):1-9.
35. Lewis FJ, Taufic M. Closure of atrial septal defects with the aid of hypothermia: Experimental
accomplishments and the report of one successful case. Surgery 1953;33:52-59.
36. Swan H, Zeavin I, Blount SG Jr, et al. Surgery by direct vision in the open heart during hypothermia.
JAMA 1953;153:1081-1085.
37. Hikasa Y, Shirotani H, Satomura K, et al. Open heart surgery in infants with the aid of hypothermic
anesthesia. Arch Jpn Chir 1967;36:496-508.
38. Horiuchi T, Koyamada K, Matano I, et al. Radical operation for ventricular septal defect in infancy. J
Thorac Cardiovasc Surg 1963;46:180-190.
39. Dillard DH, Mohri H, Hessel EA II, et al. Correction of total anomalous pulmonary venous drainage in
infancy utilizing deep hypothermia with total circulatory arrest. Circulation 1967;35(Suppl I):I-105.
40. Wakusawa R, Shibata S, Saito H, et al. Clinical experience in 52 case of open heart surgery under
simple profound hypothermia. Jpn J Anesth 1968;18:240.
41. Barrett-Boyes BG, Simpson MM, Neutze JM. Intracardiac surgery in neonates and infants using deep
hypothermia. Circulation 1970;60(Suppl III):III-73.
42. Johnson SL. The history of cardiac surgery, 1896-1955. Baltimore, MD: Johns Hopkins Press, 1970:143.
43. Gibbon JH Jr. Application of a mechanical heart and lung apparatus to cardiac surgery. Minn Med 1954;
37:171-185.
44. Lillehei CW. Historical development of cardiopulmonary bypass. In: Davis RF, Utley JR, eds.
Cardiopulmonary bypass. Baltimore, MD: Williams and Wilkins, 1993:1-26.
45. Lillehei CW, Choen M, Warden HE, et al. The direct vision intracardiac correction of congenital
anomalies by controlled cross circulation; results in thirty-two patients with ventricular septal defects,
tetralogy of Fallot, and atrioventricularis communis defects. Surgery 1955; 38:11-29.
46. Kriklin JW, DuShane JW, Patrick RT, et al. Intracardiac surgery with the aid of a mechanical pump-
oxygenator system (Gibbon type): report of eight cases. Proc Staff Meet Mayo Clin 1955;30:201-206.
47. Kirklin JW. The middle 1950s and C. Walton Lillehei. J Thorac Cardiovasc Surg 1989;98:822-824.
48. Spencer FC. Intellectual creativity in thoracic surgeon. J Thorac Cardiovasc Surg 1983;86:167-179.
49. Shumacker HB Jr. The evolution of cardiac surgery. Bloomington, IN: Indiana University Press, 1992:17.
50. National Academy of Sciences. Mechanical devices to assist the failing heart: Proceedings of a
conference, September 9 & 10, 1964, Chapters 4-11, pp. 45-143. Washington, DC: National Academy of
Sciences, National Research Council. NRC Publication 1283.
51. Johnson SL. The history of cardiac surgery 1896-1955. Baltimore, MD: Johns Hopkins, 1970:140-151.
52. Cooley, DA, Development of the roller pump for use in the cardiopulmonary bypass circuit. Tex Heart Inst
J 1987;14(2):113-118.
53. Tayama E, Raskin SA, Nose Y. Blood pumps (Chapter 3). In: Gravlee G, ed. Cardiopulmonary bypass:
principles and practice. 2nd ed. Philadelphia, PA: Lippincott Williams, and Wilkins, 2000:37-48.
54. Centrifugal pump. Wikipedia May 5, 2015:1-11.
55. Cohn L. Cardiac surgery in the adult. 4th ed. New York, NY: McGraw-Hill Companies, 2012:283-329.
56. Dewall RA, Warden HE, Gott VL, et al. Total body perfusion for open cardiotomy utilizing the bubble
oxygenator; physiologic responses in man. J Thorac Surg 1956;32(5):591-603.
57. Westaby S, Bosher C. Landmarks in cardiac surgery. Oxford, UK: Isis Medical Media Ltd., 1997:64.
58. Lim MW. The history of extracorporeal oxygenators. Anaesthesia 2006;61:984-995.
59. Clowens GHA Jr, Neville WE. Further development of a blood oxygenator dependent upon the diffusion
of gases through plastic membranes. Trans Am Soc Artif Intern Organs 1957;3:52-58.
60. Clowes GHA Jr, Hopkins AL, Neville WE. An artificial lung oxygenator dependent upon diffusion of
oxygen and carbon dioxide through plastic membranes. Thorac Surg 1956;32:630-637.
61. Drummond M, Braile DM, Lima-Oliveira AM, et al. Technological evolution of membrane oxygenators.
Braz J Cardiovasc Surg 2005;20(4):432-437.
P.15
62. Cohn LH, Virginia MD, Hubbard J. Cardiac Surgery in the adult. New York, NY: McGraw Hill Medical,
2012:228.
63. Emmons WO, Sacca DB. The design and development of a blood heat exchanger for open heart surgery.
Gen Motors Eng J July-September 1958;39.
64. Brown IW, Smith WW, Emmons WO. An efficient blood heat exchanger for use with extracorporeal
circulation. Surgery 1958;44(2):372-375.
65. Brown IW, Smith WW, Young WG, et al. Experimental and clinical studies of controlled hypothermia
rapidly produced and corrected by a blood heat exchanger during extracorporeal circulation. J Thorac Surg
1958;36:497-404.
66. Stoney WS. Pioneers of cardiac surgery. Nashville, TN: Vanderbilt University Press, 2008:108-109.
67. Hill JD, O’Brien TG, Murray JJ, et al. Prolonged extracorporeal oxygenation for acute post-traumatic
respiratory failure (shock lung syndrome): use of the Bramson membrane lung. N Engl J Med 1972;286:629-
634.
68. Zapol WM, Snider MT, Hill JD, et al. Extracorporeal membrane oxygenation in severe acute respiratory
failure: a randomized prospective study. JAMA 1979;242:2193-2196.
69. Bartlett RH, Gazzaniga AB, Jefferies R. Extracorporeal membrane oxygenation (ECMO) cardiopulmonary
support in infancy. ASAIO Trans 1976;22:80-93.
70. Bartlett RH, Andrews AF, Toomasian J. Extracorporeal membrane oxygenation (ECMO) for newborn
respiratory failure: 45 cases. Surgery 1982;92:425-433.
71. Bartlett RH, Gazzaniga AV, Toomasian J, et al. Extracorporeal membrane oxygenation (ECMO) in
neonatal respiratory failure: 100 cases. Ann Surg 1986;204:236.
72. Toomasian JM, Snedecor SM, Cornell RG, et al. National experience with extracorporeal membrane
oxygenation for newborn respiratory failure: data from 715 cases. ASAIO Trans 1988;34:140-147.
73. Bartlett RH, Roloff DW, Cornell RG, et al. Extracorporeal circulation in neonatal respiratory failure: a
prospective randomized study. Pediatrics 1985;76:479-487.
74. O’Rourke PP, Crone RK, Vacanti JP, et al. Extracorporeal membrane oxygenation and conventional
medical therapy in neonates with persistent pulmonary hypertension of the newborn: a prospective
randomized study. Pediatrics 1989;84:957-963.
75. Schumaker HB Jr. A dream of the heart. Santa Barbara, CA: Fithian Press, 1999.
76. Helmsworth JA, Clark LC Jr, Kaplan, S, et al. Clinical use of extracorporeal oxygenation with oxygenator-
pump. JAMA 1952;150(5):451-453.
77. Mustard WT, Chute AL, Keith JD, et al. A surgical approach to transposition of the great vessels with
extracorporeal circuit. Surgery 1954;36(1):39-51.
78. Romaine-Davis A. John Gibbon and his heart-lung machine. Philadelphia, PA: University of
Pennsylvania Press, 1991.
79. Lillehei CW. Overview. Section III. Cardiopulmonary bypass and myocardial protection. In: Stephenson
LW, Ruggiero R, eds. Heart surgery classics. Boston, MA: Adams Publishing Group, 1994:121.
80. Radegram KL. The early history of open-heart surgery in Stockholm. J Cardiac Surg 2003;18:564-572.
81. Dodrill FD, Marshall N, Nyboer J, et al. The use of the heart-lung apparatus in human cardiac surgery. J
Thorac Surg 1957;33(1):60-74.
82. Acierno LJ. The history of cardiology. New York, NY: Parthenon, 1994.
83. Mustard WT, Thompson JA. Clinical experience with the artificial heart lung preparation. Can Med Assoc
J 1957;76(4):265-269.
Chapter 2
Blood Pumps, Circuitry, and Cannulation Techniques in
Cardiopulmonary Bypass
Eugene A. Hessel II
Kenneth G. Shann
GENERAL SURVEY OF THE CIRCUIT

The primary function of cardiopulmonary bypass (CPB) is to divert blood away from the heart and lungs and return it to
the systemic arterial system, thereby allowing cardiac surgery. Therefore, it must replace the function of both the lungs
(gas exchange) and the heart (provide circulation of blood). Typically, blood is drained by gravity (or with some vacuum
assistance) through the cannulas in the superior vena cava (SVC) and inferior vena cava (IVC) or IVC and right atrium
(RA) (cavo-atrial position) into the heart-lung machine, where it is pumped (with a roller or centrifugal pump) through the
artificial membrane-type lung (“oxygenator”) back into the systemic vasculature through an arterial cannula placed in the
ascending aorta. (See simplified schematic drawing of basic extracorporeal circuit [ECC] in Fig. 2.1.) A more detailed
depiction of the ECC is provided in Figure 2.2.
Because of the need to offset cooling during the extracorporeal passage of blood and the frequent need to intentionally
cool and then rewarm the patient, a heat exchanger is included as part of the oxygenator, either before or contiguous
with the gas exchange unit.
Peripheral cannulation, using the femoral or other veins and arteries, is occasionally used electively for cardiac surgery
when central cannulation is not technically possible. Examples of such situations include initiating bypass before opening
the chest, emergent situations, for aortic surgery, for minimal access surgery, and for extracorporeal membrane
oxygenation. Left heart bypass or proximal aorta bypass (with “venous cannulation” of the left atrium, left ventricle, or
proximal aorta) and distal infusion into the distal aorta or femoral artery, incorporating only an extracorporeal pump, is
sometimes used for aortic surgery.
Besides the major venous and arterial connections and the oxygenator, heat exchanger, and pump, there are many other
components to the heart-lung machine (Fig. 2.2). An adjustable clamp or remote venous line occluder regulates the main
venous drainage line, and a separate tubing clamp is used on the systemic arterial inflow line whenever the patient is not
on CPB to prevent backflow out of the arterial cannula, particularly when a centrifugal pump is used. The venous
reservoir serves as a buffer for fluctuations in venous drainage and is a source of fluid for rapid transfusion. It is usually
positioned proximal to a membrane oxygenator, that is, before the pump but physically attached to the membrane
oxygenator housing. Fluids (e.g., blood and crystalloid solutions) and drugs may be added to this reservoir. Several
suction devices and systems, usually using one or more of the roller pumps, are used to aspirate blood and gas from the
open-heart chambers (hence the term “cardiotomy suction”), pericardium and surgical field, aortic root (during aortic
cross-clamping as a left ventricular vent and after unclamping, as an air vent), and left ventricular vent. This blood is then
passed into the cardiotomy reservoir, which may be incorporated in the housing of an open (hard-shell) venous reservoir
or may first flow into a separate free-standing cardiotomy reservoir before emptying into a separate venous reservoir.
A cardioplegia delivery and/or coronary perfusion system is another component that typically uses one of the roller
pumps for administering blood or crystalloid cardioplegia solution into the coronary arteries, aortic root, or coronary
sinus. This circuit usually includes a separate heat exchanger and may include a reservoir and sometimes a recirculation
line from the surgical field, which is used when cardioplegic solution is not being administered into the heart, although a
single-pass delivery system is more commonly used. Often, arterial blood is simultaneously mixed with crystalloid-based
cardioplegia solution (often in a 4:1 blood-to-crystalloid ratio) to produce blood cardioplegia.
A source of oxygen, air, and sometimes carbon dioxide, with appropriate flow meters and blenders, supplies ventilating
gas to the oxygenator, usually through an in-line anesthetic vaporizer. Although hot and cold water are at times supplied
from wall outlets to a mixing valve for adjusting water temperature in the heat exchangers, most commonly a dedicated
stand-alone water cooler and heater is used for this purpose. A number of filters (macro or micro) are often included at
various sites in the CPB circuit (e.g., cardiotomy reservoir, venous reservoir, oxygenator, arterial line, and cardioplegia
system). Also included are sampling ports (pre- and postoxygenator), pressure-monitoring sites such as the cardioplegia-
coronary
P.20
perfusion delivery line and the arterial line (after the systemic pump but before the arterial filter), and arterial and venous
inline blood-gas monitors. Temperature-monitoring sites, such as water inflow and outflow for major heat exchangers,
venous and arterial blood, cardioplegia solution, and water bath, are also present. A hemoconcentrator is sometimes
attached between the systemic flow line, or some other source of blood under pressure, and the venous or cardiotomy
reservoir.
FIGURE 2.1. Simplified extracorporeal circuit diagram. Blood flows by gravity from right atrium and IVC though a cavo-
atrial cannula into a venous reservoir. It is then pumped (in this schematic utilizing a centrifugal pump) through a heat
exchanger and oxygenator (which are usually integrated as a single membrane oxygenator/heat exchanger) and then
through an arterial-line microfilter and is returned to the systemic arterial system (typically the ascending aorta). Also
shown are an in-line monitor of venous oxygen saturation, a bubble detector, an arterial-line flow meter, and a
cardioplegia delivery system which adds a crystalloid potassium-containing fluid to a source of oxygenated blood, which
is then pumped through a separate heat exchanger either into the aortic root (antegrade cardioplegia) or coronary sinus
(retrograde cardioplegia). (Redrawn from Miller RD, Pardo MC, eds. Basics of anesthesia. 6th ed. Philadelphia, PA:
Elsevier, 2011; used with permission.)
Whenever a centrifugal pump is used, a flowmeter must be included in the systemic outflow line, and a system to prevent
retrograde flow (e.g., one-way valve or electronic clamp). Various safety devices and monitors, besides those already
mentioned, are frequently incorporated into the CPB circuit. These include pressure monitoring of the systemic arterial
and cardioplegia delivery lines, a bubble trap on the arterial line, often incorporating a microfilter and a purge line that
includes a one-way
P.21
valve that drains back to the venous or cardiotomy reservoir, a bypass line that goes around the arterial filter in case the
latter becomes obstructed, an air bubble detector on the systemic arterial inflow line, and a low-level detector and alarm
on the venous reservoir.
FIGURE 2.2. Detailed schematic diagram of the arrangement of a typical cardiopulmonary bypass circuit using a
membrane oxygenator with integral hardshell venous reservoir (lower center) and systemic heat exchanger and external
cardiotomy reservoir. Venous cannulation is by a cavo-atrial cannula and arterial cannulation is in the ascending aorta.
Some circuits do not incorporate a membrane recirculation line; in these cases the cardioplegia blood source is a
separate outlet connector built into the oxygenator near the arterial outlet. The systemic blood pump may be either a
roller or centrifugal type. The cardioplegia delivery system (right) is a one-pass combination blood/crystalloid type. The
cooler-heater water source may be operated to supply water to both the oxygenator heat exchanger and cardioplegia
delivery system. The air bubble detector sensor may be placed on the line between the venous reservoir and systemic
pump, between the pump and membrane oxygenator inlet, or between the oxygenator outlet and arterial filter (neither
shown), or on the line after the arterial filter (optional position on drawing). One-way valves prevent retrograde flow
(some circuits with a centrifugal pump also incorporate a one-way valve after the pump and within the systemic flow line).
Other safety devices include an oxygen analyzer placed between the anesthetic vaporizer (if used) and the oxygenator
gas inlet and a reservoir level sensor attached to the housing of the hard-shell venous reservoir (on the left). Arrows,
directions of flow; X, placement of tubing clamps; P and T (within circles), pressure and temperature sensors,
respectively. Hemoconcentrator and Venous cannula (described in text) not shown.
The interested reader may find several other chapters and reviews on heart-lung machines (1,2,3,4,5,6) as well as the
recent AmSECT Standards and Guidelines for Perfusion Practice (7) informative.
CANNULATION TO THE PATIENT

Venous Cannulation and Drainage
Principles of Venous Drainage
Venous drainage, often referred to as “venous return,” has traditionally been accomplished by gravity siphonage.
However, recently there has been a renewed interest in applying suction to the venous lines, a technique that had been
discarded early in the practice of CPB. Siphonage places two constraints on
P.22
successful venous drainage. First, the venous reservoir must be below the level of the patient, and second, the lines
must be full of blood (or fluid) or else an air lock will occur and disrupt the siphon effect. The amount of venous drainage
is determined by the pressure in the central veins (patient’s blood volume), the difference in height between the patient
and the top of the blood level in the venous reservoir (negative pressure exerted by gravity equals this height differential
in centimeters of water), and the resistance in the venous cannulas, venous line and connectors, and venous clamp, if
one is in use.
During CPB, the central venous pressure is influenced by intravascular volume and venous compliance, which is
influenced by medications, sympathetic tone, and anesthesia. Excessive drainage (i.e., drainage faster than the speed at
which blood is returning to the central veins, which may be caused by an excessive negative pressure caused by gravity
or suction) may cause the compliant vein walls to collapse around the ends of the venous cannulas (manifested by line
“chattering” or “fluttering” in the venous lines) and intermittent reduction of venous drainage. This may be ameliorated by
partially occluding the clamp on the venous line, which may, paradoxically, improve venous drainage, or by increasing
the systemic blood volume or administering a vasoconstrictive drug. Obviously, the amount of blood returning to the
great veins from the body ultimately limits venous return to the oxygenator.
Types and Sizes of Cannulas

Venous cannulas are either single-stage or “two-stage” (“cavo-atrial”) (Figs. 2.3 and 2.4). The latter has a wider portion
with holes in the section designed to be situated in the right atrium and a narrower tip designed to rest in the IVC.
Cannulas are usually made of a flexible plastic; most are wire-reinforced to prevent kinking. They may be straight or
right-angled. Some of the tips of the right-angled venous cannulas are fabricated out of thin hard plastic or metal for
optimal inner diameter (ID) to outer diameter (OD) ratio. The venous cannulas are typically the narrowest component of
the CPB venous system and are therefore a limiting factor for venous drainage. Knowing the flow characteristics of the
particular cannula, which should be provided by the manufacturer or established by bench-top testing, and the required
flow (approximately one-third of total flow from SVC and twothirds of total flow from IVC), one can select the appropriate
P.23
venous cannula for a patient. For example, a 1.8 m2 body surface area (BSA) patient (total estimated flow, 5.4 L/min;
SVC, 1.8 L/min; IVC, 3.6 L/min) at a siphon (gravity) gradient of 40 cmH2O would require at least a 30 French (F) SVC, a
34F IVC, or a single 38F single-stage catheter (8,9). The sizes of two-stage right atrial catheters, based on the BSA of
the patient and maximal achievable flow rates, recommended by Shann and Melnitchouk (10) are listed in Table 2.1.
Delius et al. (11) offered a method for describing the performance of cannulas used in extracorporeal circulation, called
the M number. They reported the M numbers of several different cannulas and provided a nomogram for determining the
“M number” and for predicting the pressure gradient across any cannula at any flow based on this number.
FIGURE 2.3. Drawings of conventional venous cannulas. A: Standard, tapered, two-stage cavo-atrial cannula for
insertion into the right atrium (RA) and inferior vena cava (IVC). B: Wire-reinforced cannula for atrial or caval cannulation.
C: Cannula with right-angled tip (usually made of metal or hard plastic because the thin wall optimizes the ratio of internal
to external diameters). This type of cannula is often used for congenital or pediatric cases and may be inserted directly
into the vena cava near its junction with the RA.
FIGURE 2.4. Other venous cannulas. (Kaplan JA, Reich DL, Savino JS, et al. Kaplan’s cardiac anesthesia. 6th ed.
Philadelphia, PA: Elsevier, 2011, used with permission.)
TABLE 2.1. Right atrial two-stage cannula, estimated flow rates
BSA (m2) Size (F) Max flow (L/min) Model Manufacturer
≤1.8 29/37 4.5 Thin-Flex Edwards Life Science
>1.8 to <2.5 32/40 6.0 MC2 Medtronic
≥2.5 36/46 8.0 MC2 Medtronic
Source: Modified from Table 2-5 of Shann K, Melnitchouk S. Advances in perfusion techniques: minimally
invasive procedures. Semin Cardiothorac Vasc Anesth 2014;18(2):146-142.
Connection to the Patient (Sites for Venous Cannulation)

Usually, the venous connection for CPB is accomplished by inserting cannulas into the RA. Three basic approaches are
used (Table 2.2 and Fig. 2.5): bicaval, in which separate cannulas are inserted into the SVC and IVC; single atrial; and
cavo-atrial (i.e., the “two-stage” approach). The latter has a wider proximal section with holes that lie within the RA and a
narrower extension with end and side holes that extends into the IVC. When bicaval cannulas are used, tapes are
frequently placed around the cavae and passed through small tubes so that they may be cinched down as tourniquets or
snares around the cannula. This forces all the venous return of the patient to pass to the extracorporeal circuit (ECC),
preventing any systemic venous blood from getting into the right heart and any air (if the right heart is opened) from
getting into the venous lines. This is sometimes referred to as “caval occlusion,” or total CPB.
Other ways of accomplishing this include the use of elastic tapes placed around the cavae and held together with
vascular clips and the use of specially designed external clamps that go around the cavae and their contained cannulas.
Cuffed venous cannulas may be used, either specially manufactured for this purpose (e.g., model 191037, Medtronic
DLP, Inc., Grand Rapids, MI) or cuffed endotracheal tubes. The latter may be helpful in emergency cases and when
dissection around the vena cava to place tapes could be particularly difficult or dangerous. When there is a hole in the
atrium and it is not possible (or there is not enough time) to insert a purse-string suture, or the suture breaks, a cuffed
endotracheal tube may also be used for venous drainage. After insertion, the cuff is inflated and gentle traction
tamponades the hole in the atrium so that adequate venous drainage may be provided.
Arom et al. (12) and Bennett et al. (13) compared the efficiency of the various approaches for venous drainage (Table
2.2). Bicaval cannulation with caval occlusion is required any time the right heart is entered. This approach may provide
the best caval decompression if properly positioned. However, caval cannulas cause greater interference with venous
flow (and hence cardiac output) when not on CPB (i.e., after cannulation but before going on bypass and after bypass
but before decannulation). When the caval tapes are tightened, no provision for decompression of the right heart (atrium
and ventricle) is provided. If the right ventricle is not able to eject, then the coronary sinus blood returning to the RA must
be removed by opening or venting the right heart or releasing the caval tourniquets. This would be aggravated by the
presence of a left SVC (LSVC) (see below). When the aorta is cross-clamped, coronary sinus flow is greatly reduced.
However, the problem of right heart decompression recurs whenever antegrade cardioplegia or direct coronary perfusion
is administered.
Bicaval cannulation without caval tourniquets is often preferred for mitral valve surgery, because the retraction that is
necessary often distorts the cavo-atrial junctions and interferes with venous drainage if only a single atrial cannula is
used. Right heart decompression is much better without caval tourniquets than when caval tourniquets are used, but
may not be as good as with atrial cannulation.
Single atrial cannulation has the advantage of being simpler, faster, and less traumatic, with one less incision, and
provides fairly good drainage of both the cavae and the right heart. It interferes least with caval return when off bypass.
However, the quality of its drainage of the cavae and right heart is very sensitive to positioning, especially with distortion
of the heart (e.g., “circumflex position” when lifting the heart
P.24
to make an anastomosis to posterior branches of the circumflex coronary arteries). The cavo-atrial cannula shares many
of the advantages of a single right atrial cannula but may provide superior drainage of the right heart, especially in the
circumflex position, perhaps by providing some stability to the position of the atrial holes (13).
TABLE 2.2. Comparison of venous cannulation methods
Bicaval Single
With Without Atrial Cavo-atrial

tourniquet tourniquet
Atrial incisions 2 2 1 1
Speed of cannulation Slowest Slow Fast Fast
Technical difficulty Most Difficult Easy Moderately

difficult easy
Right heart exclusion Complete Incomplete No No
Coronary sinus return Excluded Partial Included Included
Right heart decompression None Fair Good Best
Right heart decompression with heart Bad Bad Bad Good

lifted up
Caval drainage Best About as Good (not as Good (not as

good good for IVC) good for SVC)
Caval drainage with heart lifted up Good Good Bad IVC adequate;
SVC bad
Adequate venous drainage for all Yes Yes No No

types of surgery
Potential rewarming of heart by No Yes Yes Yes

systemic venous return
Myocardial preservation Best Good Suboptimal Controversiala
Note: When performing bicaval cannulation, some surgeons place both catheters through a
single atriotomy. Assessments were derived from multiple sources. IVC, inferior vena cava;
SVC, superior vena cava.
aSee Bennett et al (15).
Although drainage of the IVC remains good with cavo-atrial cannulation in the “circumflex position” (i.e., when the heart is
lifted up to work on the side or back of the left ventricle), drainage of the SVC is often compromised by this maneuver.
Proper location of the atrial holes is critical for optimal drainage by this cannula, and adequacy of decompression of the
right heart must be monitored and appropriate adjustments made when needed.
Some controversy exists regarding the effect of the type of venous cannulation on the adequacy of myocardial protection
during aortic cross-clamping with cardioplegic arrest. The concern is that with atrial cannulation alone, relatively warm
(approximately 25°C-36°C) blood returning from the body may bathe the right heart and interfere with myocardial
protection (14); therefore, monitoring the myocardial temperature may be helpful (12). Bennett et al. (15) studied the
effects of venous drainage on myocardial preservation in a dog model and compared cavo-atrial cannulation with biatrial
cannulation with or without caval tourniquets. They observed the greatest myocardial cooling, the slowest rewarming
(between doses of cardioplegic solution), and the least evidence of myocardial ischemia with cavo-atrial cannulation,
which they attributed to superior decompression of the right heart. The fact that most surgeons use a cavo-atrial cannula
for coronary artery bypass grafting (CABG) surgery, with apparent good results, corroborates these observations.
Specially designed swirl-tip atriocaval catheters (model VC2, Medtronic DLP, Inc.) and 45° two-stage cannulas
(Research Medical, Inc., Midvale, UT) (16) may facilitate venous drainage, especially during limited-access surgery.
Taylor and Effler (17) and Kirklin and Barratt-Boyes (9) reviewed the surgical technique of venous cannulation. Single
P.25
atrial cannulas are usually inserted through the right atrial appendage after placing a purse-string suture. Bicaval
cannulas may also be placed through incisions in the right atrium or directly into the vena cavae. In the former case, the
SVC cannula is usually passed through the right atrial appendage. The IVC cannula is usually passed through a purse-
string suture placed in the postero-inferior portion of the lateral wall of the RA near the IVC and avoiding the right
coronary artery. The cavo-atrial junctions may be dangerously thin. Often, for bicaval cannulation, surgeons place purse-
string sutures directly in the SVC and IVC, but these can cause narrowing when closed.
FIGURE 2.5. Methods of venous cannulation: bicaval and cavo-atrial or “two-stage.” A: Single cannulation of right atrium
(RA) with a “two-stage” cavo-atrial cannula. This is typically inserted through the right atrial appendage. Note that the
narrower tip of the cannula is in the inferior vena cava (IVC), where it drains this vein. The wider portion, with additional
drainage holes, resides in the RA, where blood is received from the coronary sinus and superior vena cava (SVC). The
SVC must drain through the RA when a cavo-atrial cannula is used. B: Separate cannulation of the SVC and IVC. Note
that there are loops placed around the cavae and venous cannulas and passed through tubing to act as tourniquets or
snares. The tourniquet on the SVC has been tightened to divert all SVC flow into the SVC cannula and prevent
communication with the RA.
Potential for Venous Air Entry

It is now recognized that air entering the circuit through the venous system can pass through the membrane oxygenator
and arterial filter and contribute to systemic gaseous microemboli (GME). Stock et al. (18) observed that approximately
60% of the GME in the line coming out of the venous reservoir reached the arterial line past a membrane oxygenator
(Jostra Quadrox) and an arterial filter (Jostra Quart 40 μm), whereas Perthel et al. (19) found even more microbubbles
(but about the same volume of microscopic air [“microair” or “foam”]) in the blood after passage through a membrane
oxygenator and arterial-line microfilter (Jostra Quart HBF 140) as compared with the blood before the centrifugal pump.
Leaks around the exit site of the venous cannulas from the atria or cavae are a frequent source of venous air entry;
therefore, great care must be taken to make sure that the purse-string sutures are airtight. Placing a second suture
around the atrial tissue and the cannula proximal to the initial purse-string suture, or a second precise purse-string
suture, may correct this problem. This is an especially important problem when augmented venous return (kinetic or
vacuum) and/or unitized minimal circuits are being used, but is probably a good practice for all cases. Monitoring for the
presence of microair in the venous or arterial lines gives warning to the team that there is an air entrainment problem and
quality assurance when the problem has been resolved (19,20,21). Stock et al. (18) showed that by completely
eliminating all visible air from the venous cannulas and lines before initiating CPB they could reduce the amount of GME
passing through the circuit by 98%.
Peripheral (Extrathoracic) Venous Cannulation
At times, venous cannulation is accomplished peripherally, usually through the femoral or iliac veins. This is used for
emergency closed cardiopulmonary assist, for support of particularly ill patients before induction of anesthesia, for
prevention or management of bleeding complications during sternotomy for reoperations, during minimal access surgery,
and for certain types of aortic and thoracic surgery. The key to achieving adequate flow rates with peripheral cannulation
is use of as large a cannula as possible and advancing the catheter
P.26
into the RA guided by transesophageal echocardiography (TEE), if available. Specially designed, commercially available
(e.g., Medtronic BioMedicus, Inc., Eden Prairie, MN), long, ultrathin, nonkinkable, wire-reinforced catheters are available
for this purpose. Insertion may be facilitated by the use of an internal stylet and guidewire. Jones et al. (22) documented
flows of up to 3.6 L/min (25F) to 4.0 L/min (27 and 29F) with simple gravity drainage. Using another brand of femoral
venous catheter (model Fem-Flex II, Research Medical, Inc.) and gravity drainage, Merin et al. (23) obtained flows of up
to 2.5 L/min with 20F catheters and flows of 3.5 to 4.5 L/min with 28F catheters. This flow can be augmented by the use
of kinetic or vacuum assistance, which is discussed in the subsequent text. Flow through various femoral venous
cannulas augmented by gravity and applied suction have been discussed by Shann and Melnitchouk (10) and are
summarized in Table 2.3.
Westaby (24) suggested that in cases where IVC drainage alone does not provide adequate venous return, adding a
32F cannula inserted into the SVC through a surgical approach to the right internal jugular (IJ) vein is effective. In
contrast, Flege and Wolf (25) described using the right IJ vein as the sole source of venous drainage for conduct of CPB
using percutaneously placed 21F 20-cm-long femoral arterial catheters (Medtronic DLP, Inc.) advanced into the RA and
augmented venous drainage. Coaxial wire-reinforced polyvinyl chloride (PVC) bicaval femoral venous cannulas
(“Carpentier”) (24-29F and 30-33F) are also available (DLP, Grand Rapids, MI). They possess two series of holes, one
set near the tip (for draining the SVC) and another approximately 18 cm more proximally (for draining the IVC), with a
nonperforated 18-cm segment designed to rest in the right atrium. This allows drainage of the SVC and IVC while
isolating the RA by snaring the proximal SVC and IVC around the cannula; however, Tevaerarai et al. found it necessary
to employ augmented venous return (kinetic) to achieve near full (93%) flow (26).
TABLE 2.3. Femoral venous cannula, estimated flow rates
Size (F) Augmented max flow (L/min)a Model Manufacturer
17 2.6 BioMedicus one piece Medtronic
19 3.8 BioMedicus multistage Medtronic
22 4.6 Remote Access Perfusion (RAP) Sorin
23/25 5.2 RAP Sorin

aApproximate cardiopulmonary bypass flow with net (gravity + applied) negative pressure of -80 to -100 mmHg.
Source: Modified from Table 5 of Shann K, Melnitchouk S. Advances in perfusion techniques: minimally invasive
procedures. Semin Cardiothorac Vasc Anesth 2014;18(2):146-142; used with permission.
Impact of Persistent Left Superior Vena Cava

An LSVC is present in approximately 0.3% to 0.5% of the general population, but in 2% to 10% of patients with
congenital heart disease and in up to 40% when such patients have abnormal situs. It usually drains into the coronary
sinus and then into the right atrium (27,28,29,30,31). In approximately 10% of cases, usually associated with other
congenital heart diseases, the LSVC drains into the left atrium. In some cases, there are defects in the wall between the
coronary sinus and the left atrium, permitting intercommunication between the left atrium and RA (the so-called coronary
sinus-type atrial septal defect [ASD]).
The presence of an LSVC should be suspected when a large coronary sinus is noted on echocardiography (differential
diagnosis includes right-sided venous hypertension, tricuspid regurgitation, and stenosis of the ostium of the coronary
sinus in the absence of an LSVC) (32). Sometimes the LSVC itself can be seen on echocardiography posteriorly and
laterally to the left atrium above the atrioventricular groove beside the aorta. Its presence can be confirmed by injection
of agitated saline echocontrast into a left arm vein or left IJ vein and
P.27
noting its passage into the coronary sinus before its arrival into the right atrium. The surgeon should suspect an LSVC
when the (right) SVC looks small, and when the left innominate vein is small or absent.
The presence of an LSVC poses a number of problems during cardiac surgery. It may confuse and complicate passage
of a pulmonary artery (PA) catheter or interfere with administration of retrograde cardioplegic solution (33). The latter is
compromised because the coronary sinus is usually quite large in this circumstance and therefore the balloon on the
retrograde catheter does not seal, and the cardioplegic solution leaks into the RA. Furthermore, the cardioplegia solution
may run off into the persistent LSVC, and it will be diluted with systemic venous blood draining down the LSVC. Finally,
the presence of an LSVC poses obvious problems if the right heart is to be entered, or with right heart decompression
and adequacy of venous return if bicaval cannulation is used, because of the flow of the additional systemic venous
blood into the right atrium.
If the right heart is not going to be opened and a single- or two-staged venous cannula is used for venous drainage and
retrograde cardioplegia is not used, the presence of an LSVC poses no problems. However, if the right heart needs to be
entered, several options are available. If an adequate-sized innominate vein is present (true in approximately 30% of
cases), the LSVC can simply be occluded during CPB. However, one must be wary of the rare possibility of the
associated anomaly of atresia of the coronary sinus, in which case the LSVC provides the main outlet for cardiac venous
drainage, and occlusion of the LSVC could injure the myocardium (34,35). This condition should be suspected if the
coronary sinus is not enlarged, by failure of echocontrast injected in the left arm or LSVC to enter the RA through the
coronary sinus during TEE, and if there is evidence by echo-Doppler of reversed flow in the LSVC (i.e., away from the
coronary sinus instead of toward it). Another obvious circumstance, in which the LSVC cannot be occluded despite the
presence of an adequately sized innominate vein, is when there is an associated absence of the right SVC (true in
approximately 20% of cases).
If the innominate vein is absent (true in approximately 40% of cases) or small (true in approximately 33% of cases),
occlusion of the LSVC may cause serious venous hypertension and potentially cerebral injury or ischemia, in which case
this should not be done without documenting acceptable venous pressure in the LSVC cephalad to the occlusion.
Otherwise, some other arrangement must be made to provide drainage of the LSVC. Use of cardiotomy suction in the
coronary sinus ostium may be adequate, but cannulation, usually through a cannula passed retrograde into the LSVC
through the ostium of the coronary sinus, is preferred, with a caval tape (tourniquet) placed around the LSVC.
Alternatively, a cuffed caval cannula or endotracheal tube may be used (28). A caval cannula can also be placed directly
into the LSVC through a purse-string suture placed externally. Finally, in small infants, induction of deep hypothermia
with CPB cooling using a single venous cannula followed by circulatory arrest obviates the need for extra cannulation of
the LSVC.
Augmented Venous Drainage

Early in the history of CPB, suction pumps (roller or finger) were used for venous drainage, but because they were
difficult to control, these were discarded in favor of the simpler and effective gravity siphon method described earlier.
During the last two decades, there has been a renewed interest in the use of regulated suction to overcome the
resistance of longer and/or narrower venous cannulas used during limited (transthoracic) access or peripheral venous
(e.g., jugular or femoral veins) access. With these narrower and longer venous cannulas, gravity siphon alone may not
provide adequate flow for full CPB even with a maximal height differential between the patient and the venous reservoir.
Augmented venous return has also been used to reduce circuit volume by being able to raise the pump oxygenator (e.g.,
minimized circuits, explained later) up to the level of the patient.
Three methods to augment the venous return have been described. One is to place a roller pump in the venous line
between the venous cannula and the venous reservoir (36). This carries a high risk of generating excess negative
pressure and collapsing the RA or great veins around the cannula tip and requires constant attention and adjustment of
the roller pump flow rate; so this technique is rarely used. Currently two methods are employed and have been reviewed
recently by Shann and Melnitchouk (see Fig. 2.6) (10). One utilizes a kinetic (centrifugal) pump in the venous line and is
referred to as kinetic- or centrifugal-assisted venous drainage (KAVD or CAVD) (37). The other method involves applying
a regulated vacuum to a closed hard-shell venous reservoir attached to the venous line and is referred to as vacuum-
assisted venous drainage (VAVD) (38,39). This system is relatively simple and does not require regulation of a second
pump.
With KAVD a second systemic pump (centrifugal or roller) then pumps blood out of the venous reservoir through the
oxygenator and to the patient. Fried et al. (40) described the use of a single pump for KAVD. Using their method, one
centrifugal pump both aspirates venous blood and pumps it to the patient. This requires that the venous reservoir be
excluded from the venous line. This method reduces the problem of balancing the flow of two pumps but runs the risk of
systemic air embolization. The use of a single centrifugal pump for both augmenting venous return and providing
systemic flow (with no intervening venous reservoir) is employed in some minimized circuits. (See subsequent section).
Use of any of these systems requires careful regulation of the degree of negative pressure applied to the venous line.
This is best accomplished by monitoring the pressure in the venous line approximately 10 cm before the inlet to the
venous pump (roller or kinetic) or in the hard-shell reservoir (if using a
P.28
vacuum-assisted system). The negative pressure (or vacuum) measured at this site should not exceed -60 to -100 mmHg
(37), but usually -20 mmHg is sufficient. Jones et al. (41) found that vacuum exceeding 40 mmHg increased the amount
of GME in a CPB model. It is also desirable to observe the RA directly or through TEE. When the vacuum-assisted
system is used, the degree of vacuum applied should be controlled with a vacuum regulator that can be adjusted and
can display low levels of suction in 10-mmHg increments. It is important that vacuum should never be applied when there
is no forward blood flow through the oxygenator, to prevent air from being pulled across the microporous membrane into
the blood path (“bubble transgression”) (42). For this reason and to prevent other causes of air embolization, it is
recommended that the venous lines and cannula be filled with fluid, and that vacuum assistance should not be applied
until after initiation of CPB. The reservoir should also be open to the atmosphere when vacuum is not being applied to
prevent over-pressurization of the venous reservoir with reduction of venous return and risk of retrograde or antegrade
air embolization. The venous reservoir should have a low positive (approximately ±5 mmHg) and a high negative
(approximately -100 mmHg) pressure relief valve. Usually, adequate venous drainage is achieved with speeds of 1,000
to 1,200 revolutions per minute (rpm) of the kinetic pump or application of 20 mmHg vacuum to the venous reservoir.
FIGURE 2.6. VAVD and CAVD augmented venous drainage. VAVD, vacuum-assisted venous drainage; CAVD,
centrifugal-assisted venous drainage. (Figure 1 from Shann K, Melnitchouk S. Advances in perfusion techniques:
minimally invasive procedures. Semin Cardiothor Vasc Anesth 2014;18(2): 146-152,2014;18(2): 146-152, used with
permission.)
When a vacuum-assisted system is used with a closed reservoir, the degree of vacuum within the reservoir is influenced
not only by the amount of vacuum applied to the system but also the relative flow of blood and air into the reservoir (from
the venous line and cardiotomy suction and vents) and blood out of the reservoir (by the systemic pump).
There are a number of potential problems and risks associated with the use of augmented venous drainage methods.
Excessive negative pressure may cause hemolysis because red blood cells (RBCs) are more easily damaged by
negative than positive pressure (43,44,45), although Mueller et al. (46) were not able to detect increased RBC damage
associated with 6 hours of CPB in calves with vacuum-assisted versus gravity venous drainage. There may also be
collapse of right atrial, tricuspid valve, or venous structures around the cannula tip, resulting in impaired venous return
and “chattering” in the venous line and possible damage to cardiovascular structures. Application of additional negative
pressure (beyond gravity) increases the risk and amount of macro- and microair aspiration from around the venous
cannula insertion sites (loose or imprecise purse-string sutures), or through holes in the walls of the RA or great veins.
Air may also enter through a patent foramen ovale (PFO) if the left heart is open, or through any intravenous lines or
introducers that may be in place (these should be closed or placed in occlusive infusion pumps during augmented
venous return). Any aspirated air may cause an air
P.29
lock or can de-prime a centrifugal pump and stop blood flow, or enter the venous reservoir, and can then pass into the
arterial circuit and contribute to systemic air embolization and cerebral injury (47,48,49,50). As mentioned earlier,
application of an extra ligature around the atrial tissue where the venous cannula exits is advocated to reduce the risk of
air aspiration. If vacuum is applied to the closed reservoir system during a no-flow state, there is the theoretic risk of
pulling air across the microporous membrane into the blood path, with subsequent systemic air embolism. If the venous
reservoir is closed to atmosphere when vacuum is not being applied, the venous reservoir can become overpressurized
and reduce venous return while increasing the risk of retrograde or antegrade air embolization (51). If intracardiac septal
defects or PFO are present, air pushed into the right heart can lead to massive paradoxical systemic air embolization
(49,52). When a pump is being used to augment venous return, there is also a potential for imbalance of flow between
the venous drainage and the systemic flow pump, resulting in a change in intravascular volume in the patient or a risk of
systemic air embolism. Therefore, the use of assisted venous drainage requires application of special safety monitors
and devices, which do not always work (51), and adherence to detailed protocols, and the perfusionist must be even
more attentive than when using conventional gravity siphon drainage (1,52). To minimize the risk of retrograde air
embolism into the atrium through accidental pressurization of the venous reservoir, it is not prudent to apply vacuum if
the venous lines are not full of fluid (as might be done for retrograde autologous priming [RAP]), nor at the time of
initiating CPB. It is best to wait until extracorporeal circulation is well established before applying vacuum to the system.
Shann and Melnitchouk (10) recommend the following practices to safely utilize augmented venous return: (1) when
using VAVD, use of an approved vacuum regulator (e.g., Boehringer model 3930); (2) total negative pressure (gravity +
applied vacuum) should not be more than 100 mmHg; (3) use the minimum amount of applied negative pressure to
achieve the desired flow; (4) monitor venous reservoir positive and negative pressure with visual and audible alarms; (5)
when using a centrifugal arterial pump, incorporate a one-way valve between the venous reservoir and oxygenator; (6)
eliminate venous air entrainment in all clinical situations.
Complications Associated with Achieving Venous Drainage

These include atrial dysrhythmias, laceration and bleeding of the atrium, air embolization (especially if the atrial pressure
is low, which could cause systemic embolization with potential right-to-left shunts), laceration of the vena cavae (the IVC
is particularly prone to this), and malposition of the tips (or atrial portion of the cavo-atrial catheter), including inserting
the tips into the azygous, innominate, or hepatic veins or across an ASD into the left heart. Placement of the low atrial
purse-string suture for cannulation of the IVC requires retraction of the heart, which may have adverse hemodynamic
consequences and is sometimes deferred until the patient is placed on bypass with a single cannula (SVC). Placing
tapes around the cavae may lacerate the cavae themselves or branches off the cavae or, when encircling the SVC, the
right PA. Once the venous cannulas are in place, they may interfere with venous return and cardiac output until CPB is
initiated. Placing venous cannulas may displace the central venous or PA catheters inserted for hemodynamic
monitoring. Caval tapes may occlude these lines and, conversely, their presence may prevent tight caval occlusion by
the tapes. Further, these monitor lines may become caught in the atrial purse-string sutures, causing malfunction and
preventing their removal (53). Finally, the cavae may become obstructed when purse-string sutures placed in the cavae
are closed after cannula removal (54).
Causes of Low Venous Return

Reduced venous drainage may be due to reduced venous pressure, inadequate height of the patient above the venous
reservoir, malposition of the venous cannulas (sometimes due to surgical manipulation of the heart), or obstruction or
excess resistance in the lines and cannulas. Inadequate venous pressure may be caused by venodilation with drugs
(e.g., nitroglycerin, inhalation anesthetics) or hypovolemia. Other causes of low venous return include kinks, air locks,
and cannulas that are too small. An air lock occurs in the venous line when sufficient air enters the line to de-
functionalize the siphon. This is most often due to dislodgment of a venous cannula. When this occurs, the arterial pump
must be stopped immediately to prevent emptying the venous reservoir and possible air embolism until the air lock is
eliminated. The latter is accomplished by clamping the venous line near where it enters the venous reservoir and then
the venous lines are refilled with fluid, or the air is moved out of the venous line by serial elevation of the line so that the
air progressively moves downstream and then allowed into the venous reservoir. During rewarming, the tendency for
kinking of cannulas is potentially aggravated by softening of the tubing and/or surgical manipulation of the heart.
Arterial Cannulation
Cannulas
Many different types of cannulas made of various materials are available (Figs. 2.7 and 2.8). Some that are designed for
insertion into the ascending aorta have right-angled tips, some are tapered, and some have flanges to aid in fixation and
to prevent the introduction of too great a length into the aorta. The arterial cannula is usually the narrowest part of the
ECC. High flow through narrow cannulas may lead to high pressure gradients, high velocity of flow (jets), turbulence,
and cavitation, with undesirable consequences, which are discussed later.
Hemodynamic evaluations of arterial cannulas have traditionally been based on measurement of the pressure drop.
P.30
FIGURE 2.7. Conventional arterial cannulas. (From Kaplan JA, Reich DL, Savino JS, et al. Kaplan’s cardiac anesthesia.
6th ed. Philadelphia, PA: Elsevier, 2011, used with permission.)
FIGURE 2.8. Other arterial cannulas. A: Metal-tipped right-angled cannula with plastic molded flange for securing
cannula to aorta. B: Similar design but with a plastic right-angled tip and molded flange. C: (Left) Diffusion-tipped angled
cannula designed to direct systemic flow in four directions to avoid a “jetting effect” that may occur with conventional
single-lumen arterial cannulas. An inverted cone occludes the tip. (Right) Drawing with arrows depicts the flow patterns.
D: Integral cannula connector and Luer port (for de-airing) incorporated into some arterial cannulas; newer arterial
cannulas may contain a self-venting cap (not shown) for removal of air during insertion.
A useful descriptive characteristic of an arterial cannula is its “performance index” (pressure gradient vs. OD at any given
flow) (55). The narrowest portion of the catheter that enters the aorta should be as short as compatible with safety, and
thereafter the cannula size should enlarge to minimize the gradient. Long catheters with a uniform narrow diameter are
undesirable. The use of thin metal or hard plastic (e.g., polycarbonate) for the tip provides the best ID-to-OD ratio.
Pressure gradients exceeding 100 mmHg are associated with excessive hemolysis and protein denaturation (56).
Therefore, it is preferable to select a cannula that will provide adequate flow with no more than 100-mmHg pressure
gradient. Drews et al. (57) suggested that in small-sized cannulas, the right-angle configuration (as compared with
straight configuration) may aggravate hemolysis. New approaches to hemodynamic evaluation of arterial cannula include
velocimetry (58) and detailed analysis of flow patterns using laser Doppler anemometry (59), color Doppler ultrasound,
and high-field magnetic resonance imaging (MRI) (60), but the clinical relevance of these studies is yet to be
demonstrated. Shann and Melnitchouk (10) recommend use of a 6-mm arterial cannula for patients ≤2 m2, a 7-mm
cannula for patients 2.1 to 2.4 m2, and 8-mm cannula for patients ≥2.5 m2.
The jetting effect produced by small cannulas may damage the interior aortic wall, dislodge atheroemboli
(“sandblasting”) and cause arterial dissections, and disturb the flow into nearby vessels. Several new designs of aortic
cannulas have been introduced to disperse the flow out of the cannulas tips to reduce the sandblasting effect. Muehrcke
et al. (59) described an aortic cannula ( Soft-Flow cannula, Sarns, Ann Arbor, MI) that had a closed tip (with an internal
cone) and multiple side holes and was designed to reduce exit forces and velocities to reduce these adverse jet effects
(Fig. 2.8C). Hemolysis rates were similar, whereas pressure gradients were intermediate compared with a number of
other cannulas in common use. However, this cannula is no longer being marketed. Edwards Lifescience Research
Medical (formerly Baxter RMI, Midvale, UT) distributes the dispersion cannula, which is designed to emit a soft fan-
shaped jet of lower velocity (61). Grooters et al. (62) compared, in three patients each, the exit jet pattern and velocities
(using TEE) between an 8-mm soft-flow cannula, an 8-mm dispersion cannula, and a 7.3-mm end-hole steel-tip cannula
(Sarns). At similar systemic flow rates (approximately 5.2 L/min), perfusion line pressures were similar, but jet velocities
at 1-, 2-, and 3-cm distances were significantly lower with the dispersion cannula compared with the other two, whereas
the velocity at 1 cm was slightly higher and at 2 and 3 cm somewhat lower with the soft-flow cannula compared with the
end-hole cannula. (See comparative photographs of the jets exiting these three types of cannulas in the paper by
Weinstein (63).) Gerdes et al. (64) have described an aortic cannula ( Medos X-flow) that incorporates a helical stator
in its tip to reduce the jet effects as documented by in vitro studies, and Scharfschwerdt et al. (65) have described a new
P.31
prototype cannula tip that contains circular lamellae (Stockert Instrumente, Munich, Germany), designed to produce a
divergent diffuse flow pattern. These authors compared the hydrodynamics of this new catheter with a standard end-hole
cannula (Argyle THI) and the aforementioned Sarns Soft-Flow and Medos X-flow cannulas. The new cannula exhibited
the lowest pressure gradient, lowest back-pressure (pressures at various distances and locations beyond the tip), and a
broad uniform centric flow dispersion pattern. Reports of clinical studies with the Medos and prototype Stockert arterial
cannulas have not been found.
White and colleagues (66) developed a novel expanding funnel tip cannula and compared it with a 45 ° straight-tip,
80° angled straight-tip, Sarns Soft-Flow (Terumo Cardiovascular Systems Corp, Ann Arbor, MI), and the Dispersion
cannula (Research Medical, Inc.) regarding pressure drop, exit velocity mapping using MRI, flow pattern visualization,
and athero-embolization (particle dislodgment). They reported that the funnel-tipped cannula exhibited lower pressure
drop, exit velocity and least particle dislodgment compared to the other cannulae. They found that the Soft-Flow cannula
had the next lowest pressure drop but had twice the exit velocity and particle dislodgment as their Funnel-tipped cannula
and that the Dispersion cannula reduced neither velocity or particle dislodgment as compared with standard tip
cannulae.
Menon and colleagues (67) described their analysis of neonatal arterial cannulas. Jet wake analysis was performed
using direct numerical simulation computational fluid dynamics (CFD) in a cuboidal test rig and particle image
velocimetry. Blood damage indices were assessed in an aortic model. They described a novel diffuser type cannula for
improved jet flow control and decrease blood damage but also noted that surgically relevant cannula orientation may be
important factor in hemodynamic performance.
Brodman et al. (55) evaluated 29 different types of arterial cannulas. They found that an 8-mm OD high-flow aortic arch
cannula (model 15235, 3M Healthcare, Inc., Ann Arbor, MI) and an 8-mm OD aortic cannula with or without flange
(models 1858 and 1860, CR Bard, Billerica, MA) were best (gradient <50 mmHg at flows of 5 L/min), whereas several
others were unacceptable (gradient >100 mmHg at flows of 4 L/min). For cannulas not studied by them, one should refer
to the gradient-flow data provided by the manufacturer, or conduct bench-top tests. Unfortunately, the data of Brodman
et al. may underestimate the clinical gradients because they used water rather than blood or a blood analog as the fluid
in their studies. Size and shape of aortic cannulas did not influence the rate of transcranial Doppler (TCD)-detected
microemboli in one study (67b).
Special-Purpose Arterial Cannulas

An innovative dual-stream aortic perfusion catheter (“Cobra”) was developed to reduce cerebral embolization and permit
selective cerebral cooling and was evaluated clinically but has not been approved for use in the United States (68,69).
The Aegis aortic cannula (Cardeon Inc., Cupertino, CA) was a modification of the Cobra dual-stream catheter, which
had only a single lumen (70). It is also no longer available for clinical use.
Another novel 24F OD arterial cannula, the Embol-X, incorporates a side port through which a heparin-coated 120-μm
mesh butterfly net type filter can be inserted to catch particulate emboli exiting the ascending aorta (Embol-X, Embol-X
Inc., Mountain View, CA) (71). Hydrodynamically, this catheter produces 50% higher pressure gradient and jet pressure
than conventional cannulas of comparable size (72). In a multicenter European case series of 185 patients at high risk
for neurologic complications, the International Council of Emboli Management (ICEM) Study Group observed a lower risk
of type I outcome compared with the Multicenter Study of Perioperative Ischemia (McSPI) data (73). However, the same
group reported a multicenter randomized control trial (RCT) involving 1,289 patients older than 59 years (mean 72 years)
undergoing CABG (86%) or valve surgery in the United States (74). Although particulate emboli were identified in 97% of
the filters and its use was not associated with any complications, there was no difference in incidence of adverse
neurologic, gastrointestinal (GI), renal, or composite events. Horvath et al. (75) documented the number (0-74 average
8), size (area 1-188 average 6 mm2), and nature (79% fibrous atheromata) of the emboli captured in 98% of 2,297
patients following use of this catheter. Christenson et al. (76) advocate deploying the filter of this catheter (EMBOL-X
Slim Protection System, Edwards) both just before applying and again just before removing the aortic clamp for maximal
effectiveness, although the former retrieved significantly more embolic particles. Gerriets et al. (77) observed no
difference in cognitive function or in number of small ischemic brain lesions (per MRI) in a small RCT (43 vs. 50 patients)
with use of the Embol-X device. This device clearly captures emboli, but high-level evidence of clinical benefits (or
adverse effects) is wanting.
In their evidence-based appraisal, Hogue and colleagues (78) concluded that the evidence supporting the use of
modified arterial cannula to improve neurologic outcome was “indeterminate”.
Connection to the Patient
Ascending Aorta
In the early days of CPB, arterial inflow was through the subclavian or femoral artery (79), but currently, as first proposed
by Nunez and Bailey in 1959 (80), it is usually through a cannula inserted into the ascending aorta The advantages of
this approach over the femoral (or iliac arteries) (Table 2.4) include ease, safety, and the fact that it does not require an
additional incision. The surgical technique for aortic cannulation has been reviewed in detail by others (9,17,81,82). The
site for cannulation is selected on the basis of the type of cannula to be used, the operation planned (i.e., how much of
the
P.32
ascending aorta is available), the quality of the aorta, and the surgeon’s preference.
TABLE 2.4. Comparison of arterial cannulation sites
Characteristic Ascending Femoral artery Axillary/subclavian

aorta/arch
Accessibility Readily Requires separate incision Requires separate incision
Cannula size Relatively Limited Limited

unlimited
Risk of Yes No Possible
malperfusion of
arch vessels
Perfusion Antegrade Retrograde Antegrade

direction
Risk of limb No Yes Yes

ischemia
Aortic dissection 0.01%-0.1% 0.2%-1.0% ˜0.75%

incidence
Local artery No Yes Yes

complications
Wound infection ˜4% <1%

0%
Advantages Convenient Allows peripheral cannulation Less risk of atheroembolism

Low risk of Allows cannulation before Less malperfusion during
dissection sternotomy in high-risk patients surgery for aortic dissection
Permits selective antegrade
cerebral perfusion
Disadvantages Atheroembolism Retrograde dissection Limb Separate incision Injury to

May not be ischemia Local wound brachial plexus and artery
acceptable complications When aortic cannulation not
(e.g., Porcelain feasible or desirable
aorta)
Indications Most cases When aortic cannulation not When aortic cannulation not
feasible or desirable Peripheral feasible or desirable Aortic
cannulation before Induction of dissection surgery
general anesthesia Emergency
“rescue” cannulation
Contraindications Disease of Asc. Occlusive disease in vessel Occlusive disease in vessel

Aorta Extensive atheroma in descending
aorta or arch
Atherosclerosis with or without calcification frequently involves the ascending aorta and poses problems with arterial
cannulation and application of clamps and vascular grafts. Dislodgment of atheromatous debris either by direct
mechanical disruption or from the “sand-blasting” effect of the jet coming out of the arterial cannula is thought to be a
major cause of perioperative stroke (83,84,85). Atherosclerosis is also considered a risk factor for perioperative aortic
dissection (86) and postoperative renal dysfunction (87).
Traditionally, surgeons have relied on palpation to detect these changes and select sites for cannulation, cross-
clamping, and so on, and this should continue to be one component of the evaluation of the aorta. Mills and Everson (88)
recommend using a 10- to 20-second period of venous inflow occlusion to reduce systemic arterial pressure to 40 to 50
mmHg to improve the reliability of palpation of the ascending aorta. However, palpation is much less sensitive and
accurate than epivascular ultrasonic scanning (89,90,91,92). Details on how to perform an intraoperative epiaortic
ultrasonographic examination are provided in the 2007 ASE/SCA guideline (93). Unfortunately, TEE, which is more
convenient, is not as sensitive because of limited views it can provide of the more distal ascending aorta where cross-
clamping and cannulation are performed (91,92,94). However, some believe it can be used as a screening method to
determine which patients need epiaortic scanning. If no significant atherosclerosis is detected in the ascending,
transverse, or proximal descending aorta, it has been suggested that epiaortic imaging is not necessary (95), but others
disagree (95b).
P.33
Epiaortic and transesophageal scanning should be considered complementary (92). Beique et al. (85) suggested using
epiaortic scanning in all patients who have a history of transient ischemic attacks, strokes, severe peripheral vascular
disease, and palpable calcification in the ascending aorta, calcified aortic knob on chest X-ray, those older than 60
years, and those with TEE findings of moderate aortic atherosclerosis. Others advocate epiaortic scanning of the
ascending aorta in all patients older than 50 years (96). Three evidence-based guidelines recommend that
“intraoperative TEE or epiaortic ultrasound scanning of the aorta should be considered (Class IIa, level of evidence B)”
(97), that “epiaortic ultrasound-guided changes in surgical approach… (provide) neuroprotection during CPB (IIb)” (78),
and that “routine epiaortic ultrasound scanning is reasonable to reduce the incidence of atheroembolic complications
(Class IIa, level of evidence B)” (98). If atherosclerosis is detected, then the sites for insertion of cannulas, grafts, and
application of vascular clamps are modified. If extensive atherosclerosis precludes arterial cannulation in the ascending
aorta, then the femoral route should be considered (see subsequent text). However, in this case, the transverse and
descending aorta should be evaluated by TEE to rule out extensive atheroma that might be embolized into the brain or
elsewhere with retrograde flow from a femoral cannula. If such is the case, then axillary-subclavian or innominate artery
cannulation should be considered. Studies using historical control subjects suggest improved neurologic outcome with
echocardiographic-based modification of surgical techniques in handling the ascending aorta (85,90,99).
If atheroma is extensive in the ascending or transverse aorta, some clinicians have suggested using a long arterial
cannula that is inserted in the ascending aorta and threaded around into the proximal descending aorta to reduce the
“sand-blasting” effect (100). Others have advocated doing an endarterectomy under deep hypothermic circulatory arrest
(DHCA) if severely protruding or mobile atheromas are detected (101), but in one study of 268 patients with severe
protruding atheromas, aortic arch endarterectomy (in 43 patients) was associated with a higher stroke rate (35% vs.
12%) and mortality (19% vs. 12%) than when endarterectomy was not performed (102). In addition, endarterectomy was
found, on multivariate analysis, to be an independent predictor of stroke (Odds Ratio [OR] 3.6) (103).
If the ascending aorta is totally calcified and rigid (so-called “porcelain” aorta), then entirely different strategies for
cannulation and surgery must be used. These include no clamping of the ascending aorta, use of an alternate site for
arterial cannulation, performing the operation “off-pump” if feasible, or, in selected cases, graft replacement or
endarterectomy of the ascending aorta during DHCA (96,104). Unfortunately, graft replacement of the atherosclerotic
ascending aorta is intrinsically a high-risk procedure (105). If there is no intraluminal debris, Liddicoat et al. (106) used
an intraluminal balloon designed for port-access surgery, which is inserted through a purse-string suture in an
atherosclerosis-free portion of the aortic arch to occlude the aorta. Others used a urinary (Foley) catheter in a similar
manner (107).
Cannulation of the Ascending Aorta

Many surgeons insert two concentric purse-string sutures into the aortic wall. Surgeons differ as to whether these should
be shallow, deep, or full-thickness bites. Unal et al. (108) discuss in detail the placement of the aortic purse-string suture
and extol the virtues of a tangential suture technique (TST). Most surgeons then incise and dissect away the adventitia
within the purse-string suture. Most avoid using a partial occluding clamp, except in pediatric patients, to minimize clamp
trauma to the aorta. Optimal arterial blood pressure during cannulation (mean arterial pressure of approximately 70 to 80
mmHg, systolic pressure of approximately 100 to 120 mmHg) is probably important: if too high, there may be a greater
chance of tears and dissection and blood loss and spray; if too low, the aorta tends to collapse, it is harder to make an
incision and insert the cannula, and there is a greater risk of damaging the back wall of the aorta. An appropriately long
full-thickness incision is then made, and the leak is controlled with a finger or by approximating the adventitia or by
simultaneously inserting the cannula.
Dilators are sometimes used. If a right-angled cannula tip is used, it is often initially directed toward the heart and then
rotated 180° to confirm intraluminal placement. Brief vigorous back bleeding out of the open cannula is then allowed to
eliminate air or atheromatous debris and to further confirm intraluminal placement. This can be additionally confirmed by
noting a pulsatile pressure approximating radial artery pressure in the CPB circuit arterial-line pressure monitor. Proper
position of the cannula tip is critical. Most surgeons insert only 1 to 2 cm of the tip into the aorta and direct it toward the
middle of the transverse arch to avoid entering the arch vessels (Fig. 2.9). Grooters et al. (61) point out that
atherosclerosis is often more severe in the aortic arch, against which the jets from these short cannulas are directed,
which may become the source of cerebral emboli, especially when the ascending aorta is relatively free of
atherosclerosis. Barbut et al. (109) noted high-grade plaque with greater frequency in the arch (18%) than in the
ascending aorta (5.3%), and Weinstein (63) has attributed the fact that more strokes occur in the left than the right
cerebral hemisphere to jets striking atheroma in the arch. To minimize this risk, Grooters et al. (61) have advocated
directing the jet toward the ascending aorta (when it is free of atherosclerosis) and/or the use of dispersion type arterial
cannulas. As mentioned earlier, others have advocated threading a long cannula into the proximal descending aorta to
reduce the velocity and turbulence in the aortic arch to reduce the “sand-blast” effect and emboli (100), although
atheromata may be dislodged by the act of inserting this cannula through the intervening thoracic aorta. Mullges et al.
(110), in
P.34
a small RCT of 60 patients undergoing CABG, found that using an elongated cannula with the tip in the descending
aorta, as compared with a short cannula in the ascending aorta, was associated with fewer microembolic signals (TCD),
but there was no difference in cognitive performance (seven neuropsychological tests) 9 days postoperatively.
FIGURE 2.9. Aortic cannulation problems. A: cannula extends into carotid owing to excessive length causing excessive
carotid flow. B: Cannula is directed into innominate causing hyperperfusion of right carotid and hypoperfusion of left. C:
Correct cannula direction. D: Cannula diameter too small; high velocity jet may damage intima or cause decrease flow
(venturi effect in some arch branches. (Hensley FA, Martin DE, Gravlee GP, eds. A practical approach to cardiac
anesthesia. 5th ed. Philadelphia, PA: Wolters Kluwer, 2013, used with permission.)
After the arterial cannula is inserted, a test infusion with the systemic pump through the arterial line before initiating CPB
is recommended (regardless of location of the arterial cannula, i.e., ascending aorta/arch, femoral artery,
axillary/subclavian, etc.). A higher-than-expected pressure in the circuit arterial line warns of possible dissection and may
help avoid a more extensive dissection. Another method to assess this was described by DeBois and colleagues (111).
The lack of negative flow or a flow of <500 mL/min during retrograde arterial priming suggests cannula misplacement or
occlusion.
Complications of aortic root cannulation include inability to introduce the cannula (interference by adventitia or plaques,
too small an incision, fibrosis of the wall, low arterial pressure); intramural placement; dislodgment of atheroemboli, air
embolism from the cannula, injury to the back wall of the aorta; persistent bleeding around the cannula or at the site after
its removal; malposition of the tip (Fig. 2.9), or also to a retrograde position possibly even across the aortic valve, against
the vessel wall, or into the arch vessels; abnormal cerebral perfusion; obstruction of the aorta in infants; aortic
dissection; and high CPB arterial-side line pressure. High CPB circuit arterial-line pressure may be a clue to malposition
of the tip against the vessel wall or into an arch vessel, cannula occlusion by the aortic cross-clamp, aortic dissection, a
kink in the inflow system, an arterial-line clamp that is still on, or the use of too small a cannula for the intended CPB
flow.
Inadvertent cannulation of the arch vessels or directing the jet into an arch vessel may cause irreversible cerebral injury
and reduced systemic perfusion. Suggestive evidence includes high systemic line pressure in the CPB circuit; high
pressure in the radial artery if supplied by the inadvertently cannulated vessel (or low pressure if not supplied by the
cannulated vessel); unilateral facial blanching when initiating bypass with a clear priming solution; asymmetric cooling of
the neck during perfusion cooling; and unilateral hyperemia, edema, petechiae, conjunctival tearing, or dilated pupils.
Before CPB, palpation of the carotid arteries may reveal asymmetric pulsation (reduced on the cannulated side) and the
opposite may be observed during pulsatile bypass (increased pulsation on the cannulated side). Before CPB, the radial
artery catheter may reveal sudden damping if the cannula is inserted in the arch vessel supplying the monitored radial
artery.
It has been suggested that the Coanda effect (in which a jet stream adheres to the boundary wall and hence produces a
lower pressure along the opposite wall) may be associated with carotid hypoperfusion (112). This has been shown
experimentally and may account for some cerebral dysfunction after CPB using aortic cannulation. Salerno et al. (113)
detected major electroencephalographic abnormalities due to malposition of a cannula in 3 of 84 patients undergoing
arch perfusion, possibly on the basis of the Coanda effect. Recently, a number of groups have studied this in mock
circulations. Kaufmann and colleagues (114) studied the impact of cannula position on flow distribution utilizing CFD
validated by particle imaging velocimetry. They found that direction of the cannula jet and its distance from a branch
vessel could result in localized retrograde flow from a Venturi effect. Tokuda and colleagues (115) have also used CFD
to analyze blood flow in the aortic arch during CPB, and Menon et al. (116) showed that neonatal cannula orientation
could induce backward flow due to Venturi effect.
Antegrade aortic dissection (Table 2.5) associated with ascending aortic cannulation has been reported in 0.01% to
0.09% of cases (82,86,117,118,119,120). Aortic dissection should be suspected when any of the following are observed:
a sudden decrease in both venous return and arterial pressure, excessive loss of perfusate, increased circuit arterial-line
pressure, evidence of decreased organ perfusion (oliguria, dilated pupil, electroencephalographic changes,
electrocardiographic evidence of myocardial ischemia), blue discoloration of the aortic
P.35
root (because of intramural hematoma), and bleeding from needle or cannulation sites in the aortic root. Subadventitial
hematomas tend to be less extensive and softer, and usually resolve when incised. TEE and/or epiaortic ultrasound
scanning are useful in diagnosing aortic dissection (93,119,120,121,122).
TABLE 2.5. Ascending aortic dissection complicating cardiac surgery
Murphy et al. (86) Gott et al. (118) Still et al. (117) Combined
Year published 1983 1990 1992 -
Institution Emory Emory MGH -
Years covered 1971-1981 1982-1988 1982-1990 1971-1990

Total cases 6,943 11,145 14,877 32,965
Dissectionsa 24 (0.35) 27 (0.24) 24 (0.16) 75 (0.23)
Site of origin
Aortic cannulationa 4 (0.06) 10 (0.09) 10 (0.07) 24 (0.07)
Partial occlusion clamp 8 3 7 18
Aortic cross-clamp 1 4 8 13
Proximal SV anastomosis 4 2 1 7
Cardioplegia cannula 2 5 - 7
Vent site - 1 - 1
Aortotomy 2 - - 2
Unknown or other 3 2 1 6
When recognized
Operating room 15 27 20 62
Postoperatively 9 - 4 13
Mortality
If recognized in operating room 33% 15% 20% 21%
If recognized postoperatively 78% - 50% 60%
Values are number of cases or incidents unless otherwise noted.
MGH, Massachusetts General Hospital; SV, saphenous vein.
aValues are number of incidents, with percentages in parentheses.
Gott et al. (118) and Still et al. (117) have discussed iatrogenic aortic dissection in detail. Management usually involves
prompt cessation of CPB, recannulation distal to the dissection (usually femoral but occasionally into the distal aortic
arch), induction of deep hypothermia, and a period of circulatory arrest while the aorta is opened and the extent of the
injury analyzed and repaired by direct closure, use of a patch, or replacement of the ascending aorta with a tubular graft.
Occasionally, small injuries can be repaired off CPB by closed
P.36
plication (118), but such repairs may fail early or later and therefore graft replacement is generally favored (124,120).
Survival of those cases recognized and treated in the operating room has ranged from 66% to 85%. When not
recognized until postoperatively, survival has been 50% or less (Table 2.5).
False aneurysms, which may rupture or become infected, are late complications of aortic cannulation (123,124). In a
review of the literature (123) and the experience of a single institution (124), the arterial cannulation site was found to be
the source of approximately one third of the ascending aortic aneurysms that follow cardiac surgery, of which
approximately 40% were infected. The mortality of such complications was approximately 50%.
Femoral Arteries (See Table 2.4)

Cannulation of the femoral or iliac arteries (exposed through a retroperitoneal suprainguinal approach) is indicated when
there is an aneurysm of the ascending aorta or when it is otherwise unsatisfactory for cannulation. This may also be
indicated when there is inadequate space available due to multiple procedures involving the ascending aorta, for
peripheral cannulation under local anesthesia in unstable patients, during reoperations prophylactically, when bleeding
complications occur during reentry, or when an antegrade dissection complicates aortic cannulation. Femoral
cannulation requires a second incision and limits the size of the cannula that can be used. Hence, the adverse
consequences of fluid jetting effects and high pressure gradients are more likely. Lees et al. (125) found no difference in
the distribution of blood flow and vascular resistance between retrograde (femoral artery infusion) and antegrade (aortic
root infusion) flow in monkeys. Shann and Melnitchouk (10) made recommendations for size and model and maximal flow
rates of various femoral artery cannulas based on patient’s size and these are summarized in Table 2.6.
Femoral cannulation is associated with many complications (23,113,126) including trauma to the cannulated vessel, such
as tears, dissection, late stenosis or thrombosis, and bleeding; lymph fistula; infection; embolization; and limb ischemia.
Muhs et al. (127) reported their experience with five (0.7% incidence) arterial injuries early (<30 days) following femoral
perfusion utilizing the port-access system in 739 patients. Because the retrograde perfusion cannula usually totally
occludes the direct blood supply to the cannulated limb, ischemic complications (acidosis, compartment syndrome,
muscle necrosis, and neuropathy) may develop if cannulation exceeds 3 to 6 hours (128,129,130). The risk of distal
ischemia can be minimized by placing a Y-connector or Luer-lock port in the arterial line and attaching a smaller cannula
(e.g., 8-14F pediatric arterial cannula) which is then inserted distally through the same arteriotomy (130) or an 8.5F
introducer catheter inserted into the distal superficial femoral artery using the Seldinger technique (131) to maintain
perfusion of the leg. Alternately, VanderSalm (132) advocated suturing a 10-mm polytetrafluoroethylene graft end-to-side
on the common femoral artery into which the 24F femoral cannula is inserted. This latter technique not only prevents
lower extremity ischemia but also may reduce risk of arterial injury and retrograde dissection. Use of a coated Dacron
graft may be associated with less bleeding. If distal limb perfusion is used and the ipsilateral femoral vein has also been
cannulated, then a method to provide better venous drainage of that limb is suggested to reduce edema. Edema can be
minimized either by not taping the vein around the cannula (130) or by placing a second (12F) venous cannula through
the saphenous vein into the distal femoral vein (133). If limb ischemia does occur, Beyersdorf et al. (134) described a
method of controlled limb reperfusion to improve outcome.
TABLE 2.6. Femoral artery cannula, estimated flow rates
BSA (m2) Size (F) Max flow (L/min) Model Manufacturer
≤1.3 15 2.5 BioMedicus Medtronic
≤1.3 16 3.2 Fem-Flex Edwards Life Science
1.3-1.7 17 4.0 BioMedicus Medtronic
1.3-1.9 18 4.6 Fem-Flex Edwards Life Science

1.9-2.2 19 5.3 BioMedicus Medtronic
>1.9 20 6.0 Fem-Flex Edwards Life Science
>2.2 21 6.0 BioMedicus Medtronic
Source: Modified from Table 3 of Shann K, Melnitchouk S. Advances in perfusion techniques: minimally invasive
procedures. Semin Cardiothorac Vasc Anesth 2014;18(2):146-142, used with permission.
Femoral perfusion may lead to cerebral and coronary atheroembolism if there are extensive atheromas in the aortic arch
or descending aorta; ideally, this should be assessed by TEE before selecting the femoral route. If severe
atherosclerosis is present, an alternate route should be used if possible. Femoral perfusion may also aggravate
preexisting aortic dissections, and an alternate site for cannulation (see subsequent text) is recommended by some
authors (135).
The most serious complication of femoral cannulation is retrograde arterial dissection, which may lead to retroperitoneal
hemorrhage or retrograde dissection extension all the way to the aortic root. The incidence of this complication has been
reported at between 0.2% and 1.3% (136,137,138,139,140,141), although rates as high as 1 in 30 (3%) and 2 in 51 (4%)
(142,143) and as low as 0 in 702 (113) have been reported. Kay et al. (136) noted a rate of 3% in 378 patients older
than 40 years. Femoral cannulation is being more frequently used during
P.37
limited-access surgery and has been complicated by fatal dissection (143,144,145). Galloway et al. (141) reported an
arterial dissection rate of approximately 0.8% in a registry of 1,063 patients undergoing retrograde femoral cannulation
and CPB with a port-access system (HeartPort, Inc., Redwood City, CA), whereas Grossi et al. (145b) reported a rate of
0.3% in a single-center experience with 714 patients undergoing minimally invasive mitral valve surgery. (In 564 of these
patients, arterial cannulation was into the femoral artery.)
Retrograde arterial dissection is thought to be caused by either direct (cannula) or indirect (jet) trauma and to be more
likely in the presence of atherosclerosis or cystic medial necrosis and in patients older than 40 years (126,136).
Retrograde aortic dissection may present like antegrade aortic dissection already described, but may be more difficult to
recognize if it does not extend into the ascending aorta. In these cases, it may present only as a sudden decrease in
venous return and arterial pressure, excessive loss of perfusate, increased circuit arterial-line pressure, and oliguria. In
this situation, TEE scanning of the proximal descending aorta is extremely helpful in making the correct diagnosis.
Because of the nature of the dissection and the flap, discontinuation of retrograde perfusion and resumption of
antegrade flow (through a cannula in the ascending aorta or by normal cardiac function) may resolve the problem. This
may permit different management from antegrade dissections. If the dissection occurs early in the procedure, simply
discontinuing CPB immediately (and hence retrograde femoral perfusion) and restoring intravascular volume (which can
be facilitated by attaching the arterial line to the venous cannula and infusing residual blood from the extracorporeal
circuit) and then aborting the planned operation and doing nothing further to the ascending aorta, even if it is affected by
the dissection, can be successful (138). If the dissection occurs later, when it is not possible or desirable to come off
CPB, retrograde perfusion is immediately discontinued and the arterial cannula is introduced into the true lumen in the
ascending aorta (often through the false lumen). Bypass is then resumed with antegrade perfusion and the planned
operation may sometimes be completed without repair of the dissection itself or the ascending aorta. Carey et al. (140)
reported long-term success in six of seven patients using this approach. Others recommend graft replacement of the
ascending aorta (139,146).
There is particular concern about the use of the femoral artery for arterial infusion during the repair of spontaneous (type
A or B) aortic dissection because of the risk of malperfusion (135,147,148), and for this reason use of the axillary artery
is often recommended. However, others have reported good results utilizing femoral cannulation in this circumstance.
Fusco et al. (149) and Shimokawa et al. (150) reported malperfusion requiring change in cannulation after starting out
with femoral cannulation in only 2/79 and 3/107 attempts, respectively. Dhareshwar et al. (151) have also found femoral
artery cannulation safe for surgery in cases of acute type A dissections. On the other hand, Voci et al. (152) used
sonicated albumen in 27 cases of type A dissections to determine which lumen was perfused with femoral artery infusion.
In 13 cases (48%) only the true lumen was perfused, whereas in 11 (41%) both lumens were perfused, and in 3 (11%)
only the false lumen was perfused. In the latter three cases, this was corrected by cannulating the other femoral artery.
Interestingly, the false lumen was partially or completely perfused in 13 of 19 (68%) cases when the left femoral artery
was cannulated, and in only 1/8 (13%) when the right femoral artery was cannulated. Unfortunately, the strength of the
pulse has not been helpful in deciding which femoral artery to perfuse into. Orihashi et al. (153) found evidence of a new
dissection in the abdominal aorta by TEE (loss of flow in celiac or superior mesenteric arteries or appearance of a flap)
in 3 of 11 patients with acute (5) or chronic (6) dissecting aortic aneurysms (DAA) which had not previously involved the
abdominal aorta. All new dissections occurred at some delay after initiation of perfusion and were associated with
metabolic acidosis that resolved with antegrade perfusion. These studies provide further evidence of the liability of
femoral artery inflow in patients with aortic dissections.
Abdominal Aorta
Coselli and Crawford (154) described retrograde perfusion through a graft sewn onto the abdominal aorta when distal
occlusive disease prevented femoral cannulation and when ascending aortic cannulation was infeasible.
Axillary/Subclavian Arteries (See Table 2.4)

Use of the axillary artery (either by direct cannulation or through an attached 8-mm graft) instead of the femoral artery
when ascending aortic cannulation is infeasible or undesirable is increasingly advocated (155,156,157,158,159) (Fig.
2.10). During a left thoracotomy, the intrathoracic subclavian artery may be cannulated (160). The putative advantages
of the axillary artery over the femoral artery include lower likelihood of atherosclerosis, better collateral flow with lower
risk of ischemic complications, and better healing with fewer wound complications. By avoiding retrograde descending
thoracic and abdominal aortic flow, it is also less likely to cause cerebral athero-embolization. Hedayati et al. (161)
demonstrated in an animal model that axillary cannulation reduced cerebral microemboli compared with aortic
cannulation. Kaufmann and colleagues (114,162), utilizing CFD, found that cannulation of the right subclavian artery
provided better flow into the arch vessels than direct aortic cannulation as long as the cannula tip was sufficiently far
away from the origin of the right vertebral artery (otherwise, it could cause retrograde flow in that vessel).
Some advocate axillary artery cannulation for type A aortic dissections, because it is thought to be less likely to result in
malperfusion and further expansion of the dissection, as may occur with femoral arterial perfusion (135,147,148). In this
situation, some favor use of the right axillary artery (135) while others favor the left side (148). Adequate arch
P.38
vessel hydrodynamics have been demonstrated during perfusion through the right subclavian artery in a mock circulation
(163); however, the absence of subclavian artery stenosis should first be documented by comparing noninvasive or
invasive arterial pressure in each arm (164) before choosing this route.
FIGURE 2.10. Cannulation of right subclavian artery. (Figure 1 from Di Luozzo G, Griepp R. Cerebral protection for aortic
arch surgery: deep hypothermia. Semin Thoracic Surg 2012; 24:127-130, used with permission.)
The axillary artery is approached through a 4- to 10-cm incision below and parallel to the lateral two thirds of the clavicle,
or in the deltopectoral groove (157,165). Care must be taken to avoid traction on the brachial plexus. The axillary vein is
retracted away from the artery (but may be used for venous cannulation) (156). A purse-string suture may then be placed
in the axillary artery and a 20 to 22F right-angled or flexible arterial cannula is inserted in a retrograde direction 2 to 3
cm. In this circumstance the contralateral radial or brachial artery (usually the left) must be used for intra-arterial pressure
monitoring. Alternately, an 8- to 10-mm nonporous graft may be sewn end-to-side to the axillary artery (157) and the
perfusion cannula inserted only partially into this graft or the arterial line from the ECC is connected directly into this
graft via a °inch (into an 8-mm graft) or 3/8 inch (into a 10-mm graft) connector. This maintains the functionality of
ipsilateral radial artery pressure monitoring. An advantage to cannulating the right axillary artery is that subsequent to
occlusion of the innominate artery this provides a route for administering antegrade arterial cerebral perfusion (at least
partial, through the right carotid and vertebral arteries) during DHCA for surgery involving the aortic arch. In this
circumstance, some practitioners also selectively perfuse (antegrade) the left common carotid artery as well (166). If a
sidearm graft is used for cannulation, then monitoring the pressure in the right radial artery provides a clue to cerebral
perfusion pressure during antegrade cerebral perfusion. During lateral thoracotomies, either the axillary artery may be
approached via the axilla through a vertical incision along the lateral border of the pectoralis major muscle (156) or the
subclavian artery may be cannulated intrathoracically.
Many reports of the use of the subclavian artery in small series have observed a low incidence of complications (see
summaries by Fusco et al. (149) and Schachner et al. (167)), but four larger series of a total of 823 cases (two with 284
and 399 cases, respectively (168,169)) have painted a more realistic picture (167,168,169,170). Axillary artery injury,
thrombosis, or dissection occurred in 12 patients, brachial plexus injury in 9, new aortic dissection in 5, malperfusion in
3/65 patients (but all among the 35 undergoing repair of acute type A DAA) in one series (167), and ischemia or
compression syndrome in the arm in 4. On 17 occasions in three series (approximately 4%), the authors reported that
they were unable to perfuse through the axillary artery (nine due to poor back bleeding or high resistance, four due to the
development of local dissection, three due to a small artery or unusual anatomy, and one because it was involved by a
chronic dissection). On the other hand, no local wound problems were encountered. The right subclavian/axillary artery
was used in the vast majority of cases (97%). Direct cannulation was employed in 77% and a side graft in only 23%,
although perfusion through a side graft is favored by several authors (168,169,170,171). These authors believe that this
approach minimizes the risks of arterial injury, inadequate flow, dissection, and compartment syndrome, and better
enables cerebral perfusion pressure monitoring through the right radial artery during selective antegrade arterial cerebral
perfusion. A propensity score analysis by the Cleveland Clinic Group found a lower rate of arterial injury and aortic
dissection when a side-arm graft was employed (169). However, all three cases of malperfusion from Schachner et al.
occurred when a side graft was employed (167). The latter group had to switch from the use of subclavian perfusion (to
aorta in two and femoral artery in five) in 7/65 attempts due to malperfusion in three, inadequate flow in two, and local
dissection and aortic dissection in one each (167). The Mount Sinai Medical Center group in New York City favors direct
cannulation because it is less time-consuming, lowers the risk of bleeding, is technically easier to perform, and is not
associated with hyperperfusion of the cannulated arm. They have used direct cannulation with a 20 to 26F wire-
reinforced right-angled cannula (Edwards Life Science, Irvine, CA) in all of their 284 patients (168). Schachner et al.
(167) considers the choice of direct cannulation versus a side graft to still be a matter of debate.
P.39
At least three case reports of aortic or innominate dissections associated with use of the subclavian arteries for arterial
inflow have appeared (172,173,174) and were reported in 4/539 patients (0.7%) in three large series (167,169,170). This
complication is likely less common when a side graft is employed (169) but indicates the need to carefully monitor for and
be suspicious of this possibility (165,172,174).
Despite the reputed advantage of a lower risk of malperfusion using the right axillary/subclavian artery (compared with
the use of femoral artery) when operating on acute type A aortic dissections (135,147,148,165), as mentioned earlier
others have reported favorable results using the femoral artery in this circumstance (149,150,151). Furthermore,
malperfusion was encountered in 3 of 37 cases in one series in which the subclavian artery was used for arterial inflow
(167), although this complication was not reported in four other reports of the use of right subclavian artery in a total of
132 acute type A dissecting aortic aneurysms (165,169,170,171).
Dhareshwar et al. (151) assert that “the benefits of using the axillary artery as opposed to the femoral artery for
cannulation have yet to be proven conclusively,” and believe that the use of cerebral monitoring to identify malperfusion
is more important than the site of arterial cannulation. Fusco (149) and Shimokawa (150) also emphasize the need to
monitor for malperfusion regardless of the vessel chosen for arterial cannulation and recommended monitoring bilateral
radial artery pressures, use of TEE (size of the true lumen and flow into the arch vessels), and palpation of the aorta.
Estrera and colleagues found monitoring with power M-mode multichannel TCD helpful in this regard (175), and others
have used two-channel TCD, near-infrared spectroscopy (NIRS) (i.e., bilateral cerebral oximetry) (176,177),
electroencephalography (EEG), and jugular venous oxygen monitoring for this purpose.
In a systematic review of the literature, Gulbins and Colleagues (178) concluded that there was a trend toward improved
neurologic outcome when the axillary artery was used as compared to the femoral artery, but this conclusion was
weakened by the lack of any RCT and by the low number of patients compared. In a recent invited commentary,
Geirsson concluded that this debate is far from resolved and opined that an RCT will never be possible (179). Di
Eusanio and colleagues (180) compared their aortic arch surgery results in 200 patients utilizing central cannulation
(right axillary in 128, innominate artery in 26, and ascending aorta in 46) to 273 patients utilizing femoral cannulation with
propensity score analysis. They found a similar risk of postoperative death and permanent neurologic dysfunction in the
two groups. Etz et al. (181) compared their experience with antegrade perfusion (via the right axillary artery in 297 and
direct aortic cannulation in 15) with retrograde perfusion (via the femoral artery) in 90 patients undergoing repair of acute
Type A dissection. The incidence of early complications (mortality and postoperative stroke) was no different in the two
groups but survival at 10 years was greater (71% compared with 51%) when antegrade perfusion was used.
Innominate Artery
Cannulation of the innominate artery instead of the axillary artery has been advocated because it eliminates the need for
a second incision. Di Eusanio et al. described their techniques and use of the innominate artery in 55 patients (182).
They preferred sewing an 8 to 10 mm vascular graft end-to-side 4 to 5 cm distal to its origin while the artery is partially
sideclamped and then inserted the arterial-line cannula into this graft. Preventza et al. (183) used a similar technique in
68 patients. The cannula can also be inserted directly into the innominate artery through a purse-string suture. Usually
the vessel is of sufficient size to permit antegrade flow into the carotid artery around a 7- to 8-mm cannula that has been
directed toward the aortic arch (184,185), but it is important that the innominate artery be substantially larger than the
cannula inserted. For this method Di Eusanio and colleagues used a 22F side-holes cannula (Soft-Flow, Terumo Sarns)
(182) and compared their results using the axillary artery in 27 patients and the innominate artery in 44 patients in a
nonrandomized observational study. There were two cannulation related problems with use of the subclavian artery (one
dissection and one brachial plexus injury) and none with the innominate artery (not a statistically significant difference).
Clinical outcomes were comparable. Use of the innominate artery also permits unilateral selective cerebral perfusion if
cerebral circulation needs to be interrupted during aortic arch and/or circulatory arrest.
Brachial Arteries
Three groups have successfully perfused 101 patients through the brachial artery (usually direct cannulation of the right)
with few reported complications (186,187,188). Subsequently, Küçüker and colleagues (189) reported their results with
use of the right upper brachial artery in 181 patients undergoing aortic arch repair. They inserted a 16 to 18F venous
return catheter directly into the artery but limited flow to 4.5 L/min. They compared adequacy of visceral protection in 50
of these patients compared to 50 utilizing conventional aortic cannulation and observed no significant difference (190).
Common Carotid Arteries

Veron et al. (191) reported successful use of the left common carotid artery (LCCA) in 42 patients during surgery on the
descending thoracic aorta through a left posterior thoracotomy. The LCCA was approached through the neck, and an 8-
mm graft was sutured onto it end-to-side, into which a 22F cannula was inserted. They also used this cannula to provide
selective unilateral antegrade cerebral perfusion during circulatory arrest.
Urbanski and colleagues (192) described their experience with use of the left common carotid artery in 100 patients. The
carotid artery was approached through a median
P.40
sternotomy in 30 patients and a separate neck incision in 70. They attached an 8- to 10-mm vascular graft end-to-side to
the carotid artery during a period of carotid cross-clamping, through which the arterial cannula was inserted. They also
used this cannula to provide selective unilateral antegrade cerebral perfusion during circulatory arrest. This group has
also used the right common carotid artery for arterial annulation (193,194).
Left Ventricular Apex

Antegrade aortic perfusion can be accomplished by cannulating through the left ventricular apex and passing the
cannula (19-28F) across the aortic valve into the aortic root (195,196,197,198,199,200). A 10F wire-reinforced arterial
cannula has been used in a similar manner in an infant (199). When cannulating the ascending aorta through the left
ventricular apex, Robicsek (196) used a special padded vascular clamp (Heinrich Ulrich Co., Ulm, Germany) that allowed
clamping of the ascending aorta around the perfusion cannula. Both Robicsek (196) and Norman (195) described the
use of special double-lumen or double-barreled cannulas that allow for both aortic perfusion and venting of the left
ventricle. Wada et al. (201) and Matsushita et al. (202) reported their results with transapical cannulation for repair of
type A aortic dissections in 138 and 52 patients, respectively. They inserted a 7-mm cannula (Sarns Soft-flow 4948
Extended Aortic Cannulae, Terumo) with a stylet through a 1-cm incision in the apex of the left ventricle without a purse-
string suture. The cannula was passed across the aortic valve and the tip was positioned at the level of the sino-tubular
junction and in the true lumen utilizing TEE guidance. Wada et al. (201) reported no failures or malperfusion events in
their 138 attempts, while Matsushita et al. (202) reported 5 failures requiring conversion to another site in their 52
attempts: 4 due to evidence of malperfusion and 1 due to aortic regurgitation.
TABLE 2.7. Priming volume and maximum flow rates for various-sized tubing
Maximum flow (L/min)
To maintain
Reynolds To maintain
Tubing size (ID) To maintain pressure gradienb numberb velocityc
Inch mm Volumea To avoid all <5 <10 <1,000 <2,000 <100 <200
(mL/m) hemolysisb mmHg/m mmHg/m cm/s cm/s
3/16 4.5 15 <0.1 0.1 0.2 1.8 4.0 1.0 2.0
1/4 6 30 0.11 0.5 0.9 2.1 4.5 1.7 3.4
3/8 9 65 0.35 2.0 4.0 3.7 6.5 3.9 >6
1/2 12 115 0.45 3.8 7.0 5.0 9.5 >6 -
3/4 18 255 - - - - - - -
In general, turbulence occurs when disrupting forces (inertial) overcome the retaining forces (viscous). This
relation is expressed by the Reynolds number (== [density × velocity × diameter]/viscosity). Empirically,
turbulence has been found to occur in blood when this number exceeds 1,000, although curvature, smoothness,
and inlet conditions also influence its occurrence.
aSource: Peirce EC II. Extracorporeal circulation for open-heart surgery. Springfield, IL: Charles C. Thomas
Publisher; 1969:37, fig.13, with permission.
bSource: Peirce EC II. Extracorporeal circulation for open-heart surgery. Springfield, IL: Charles C. Thomas
Publisher, 1969:36, fig.12, with permission.
cCalculated by the author.
TUBING AND CONNECTORS

Minimizing blood trauma, prime volume, resistance to flow, and avoiding leaks (either outward flow of blood or aspiration
of air) are considerations in selection of tubing and connectors. To minimize blood trauma, one should strive to have
smooth nonwettable inside walls of nontoxic materials, avoid velocities above 100 cm/sec, and avoid exceeding a critical
Reynolds number above 1,000 (Table 2.7). The gradient necessary to propel the blood through the tubing should also
be minimized (Table 2.7). The selection of large ID tubing aids in achieving these objectives. On the other hand, the
larger the tubing, the greater the priming volume. Keeping the tubing as short as possible will reduce prime volume,
pressure gradients (resistance to flow), and blood trauma.
Desirable tubing characteristics include: transparency, resilience (re-expands after compression), flexibility, kink
resistance, hardness (resists collapse), toughness (resists cracking and rupture), low spallation rate (the release of
particles from the inner surface of the tubing), inertness, smooth and nonwettable inner surface, toleration for heat
sterilization, and blood compatibility. Medical-grade PVC seems to meet these
P.41
standards and has met the test of time for several decades. However, some of the plasticizers used (e.g., di-(2)-
ethylhexyl-phthalate [DEHP] and bisphenol A [BPA]) may have bioincompatibility. Therefore, the search for better
materials continues. Polyolefin is a possible alternative to PVC and has the advantage of containing no plasticizers and
therefore is nontoxic and noninflammatory. However, widespread use is hampered by its relatively high cost (203).
Silicone rubber and latex rubber tubing were sometimes used in roller pumps in the past; however, spallation and blood
incompatibility were problematic. New formulations of PVC that minimize spallation are being developed for use in roller
pumps.
Disposable clear polycarbonate connectors with smooth nonwettable inner surfaces that make smooth junctions with
plastic tubing (to minimize turbulence) are desirable. Smooth curves rather than sharp-angled bends will minimize
turbulence. Connections must be tight enough to prevent leakage of blood when exposed to positive pressures (up to
500 mmHg beyond the systemic flow pump) and aspiration of air on the venous side. The friction of fluted connectors
with a larger OD than the ID of the plastic tubing or cannula into which the connector is inserted may provide sufficient
tightness; otherwise, plastic bands may be applied tightly around all such connections at the time of use. Most tubing
and connectors are prepackaged and preassembled for convenience and safety. Binding heparin or other surface-
modifying additives (SMAs) onto the inner surface of the tubing and other components of the circuit may improve
biocompatibility.
THE ARTERIAL PUMP

This section is limited to a discussion of the pumps used to transfer the blood back into the systemic circulation and
hence provide the energy for systemic perfusion, the so-called arterial pump. Some portions of this section are
reproduced from Chapter 3 of the third edition of this book (204). Arterial pumps can be classified into two main
categories: displacement pumps (e.g., the roller pump) and rotary pumps (also referred to as centrifugal pump) (Fig.
2.11). In the past, teams have also explored the use of ventricular-type displacement pumps but these are rarely used for
conventional CPB (although they were frequently used as ventricular assist devices until recently).
FIGURE 2.11. Types of arterial pumps: roller and rotary (centrifugal). A: Roller pump-plastic (“pump head”) tubing rests
inside the raceway. The rollers mounted on arms 180° apart nearly occlude the tubing and act like a rolling pin,
squeezing the blood ahead of it and out the pump. It is insensitive to afterload. B: Centrifugal pump. (From Fig. 12.6 in
Estafanous FG, Barash PG, Reves JG. Cardiac anesthesia: principles and clinical practice. 2nd ed. Philadelphia, PA:
Lippincott Williams & Wilkins, 2001, used with permission.)
Tayama and colleagues (205) suggested that the ideal blood pump for extracorporeal circulation must have the capacity
to deliver flows up to 7 L/min against a pressure of 500 mmHg, should not damage the cellular or acellular components
of the blood, should have smooth surfaces, must be free of areas of stasis or turbulence, should have accurate and
reproducible flow measurement, and should have a backup or manual mode of operation should a motor or power failure
occur.
Roller Displacement Pumps

These consist of a length of tubing located inside a curved raceway at the perimeter of the travel of rollers mounted on
the ends of rotating arms (usually two, 180° apart), arranged in such a way that one roller compresses the tubing at all
times (Fig. 2.12). Flow of blood is induced by compressing the tubing, thereby pushing the blood ahead of the moving
roller. Flow rate depends on the size of the tubing, length of the raceway, and the rpm of the rollers. For a given pump
and type and size of tubing, flow is proportional to pump speed in rpm. In vitro calibration curves should be constructed
and checked periodically. This is done by measuring the output of the pump over a measured period at various pump
settings in a bench-top circulation, preferably using blood or blood analog.
The degree of compression, or “occlusiveness,” of the tubing by the rollers can be adjusted, and appears to be
important.
P.42
Excessive compression aggravates hemolysis and tubing wear, whereas too little occlusion may also aggravate
hemolysis but, more important, may reduce forward output and invalidate flow assumptions or readings based on rpm.
The magnitude of hemolysis is related to both the time and exposure of the blood to shear forces generated by the
pump. A region of high pressure and shear force is created at the leading edge of the roller where the tubing is
compressed, which is followed by period of negative pressure as the tubing expands behind the roller. This momentary
negative pressure under certain conditions may induce the cavitation of air dissolved in the solution (5). Although there is
some disagreement, most authorities
P.43
believe that the least hemolysis occurs when compression is adjusted to be barely nonocclusive (43). This is
accomplished by holding the outflow line vertically so that the top of the fluid (blood or asanguinous) is 60 to 75 or 100
cm (24-30 or 39 inches) above the pump and then gradually decreasing the occlusiveness until the fluid level falls at a
rate of 1 cm every 5 seconds (43) or 1 inch/min (206) or 1 cm/min (207)—the socalled drop rate. Groom and Stammers
(4) recommend a fall of 1 cm/min or 1 inch/min when the column is raised to 30 cm or 30 inches, respectively. Mongero
et al. (208) described a dynamic method of setting occlusion utilizing the Better Header device (Circulatory Technology,
Oyster Bay, NY). The tighter setting ensures more accurate forward flow, makes the roller pump relatively insensitive to
afterload, and may not be associated with more hemolysis. Tamari and colleagues (209) also described a dynamic
method of adjusting occlusion which they claim to be simpler, faster and more precise than the drop rate technique and
to reduce the amount of hemolysis caused by roller pumps. Recently, Vieira et al. (210) have described an auxiliary
device to facilitate such calibration which they observed to lead to less variability in hemolysis rates during CPB. These
investigators also describe the impact of variation in raceway profile of various roller pumps on the degree of hemolysis
(211).
FIGURE 2.12. Roller pump. Drawing of a dual roller pump and tubing. The principle of the roller pump is demonstrated
by the hand roller in the lower drawing moving along a section of tubing pushing fluid ahead of it and suctioning fluid
behind it. The upper four drawings in sequence (A-D) show the roller B first moves fluid ahead of it and suctions fluid
from behind it (A). As the pump rotates clockwise the second roller A begins to engage the tubing (B) and then occludes
the tubing trapping fluid between the two rollers (C). Finally roller B releases and roller A continues to move fluid in the
forward direction. Not shown are the backing plate, tubing holders and tube guides for maintaining the tubing within the
raceway. Fluid flows in the direction of the arrows. (From Stofer RC. A technique for extracorporeal circulation.
Springfield: Springfield, IL: C Thomas, 1968:22, with permission.)
TABLE 2.8. Stroke volume and blood flows for a standard roller pump
Tubing diameter (inch) Stroke volume (mL) Blood flow (L/min) at 150 rpm
3/16 17 1,050
1/4 13 1,950
3/8 27 4,050
1/2 54 8,100
rpm, revolutions per minute.

The disposable tubing used in the pump head of the roller pump is the only part of the pump in contact with blood. The
internal diameter of the tubing is a major determinant of the maximum blood flow that can be achieved (Table 2.8), the
others being the length of the tubing in contact with the roller as it rotates and the rpm of the pump head. Thus, the flow
may be calculated as the product π × the internal radius of the tubing squared × the length of the tubing in contact with
the roller × the RPM. As can be anticipated, the mechanical stress caused by the repeated compression of the rollers on
the tubing will cause material fatigue (212) and generate microparticles, a process termed spallation (213). These
particulate emboli are generated by micro-fragmentation of the inner surface of the tubing where the roller contacts the
tubing and where the fold at the edges of the tubing occurs. Studies of tubing wear over time have shown that PVC
fragments generated from roller pumps are numerous, frequently less than 20 μm in diameter, and begin to occur during
the first hour of use (214). The degree of fatigue and the amount and size of the particles will depend on the chemical
characteristics of the tubing, the occlusion setting, and the working conditions (RPM, resistance) (213,214,215,216).
Most pump loops are made of silicone or PVC or, to a lesser extent, of latex rubber. PVC is temperature-sensitive and
will stiffen at lower temperatures, whereas silicone is more temperature-insensitive. From a mechanical standpoint, PVC
is better because of its durability, whereas from a biocompatibility standpoint, silicone is the more biocompatible (217). A
specific disadvantage of PVC, when used in the pump loop, is the possible buildup of an electrostatic charge (218). This
characteristic is mainly important when PVC is used in combination with an oxygenator with a polymeric heat exchanger.
If the generated electrostatic charge exceeds the dielectric strength of one of the fibers used in the polymeric heat
exchanger, a hole may develop, which can result in blood or fluid leakage (219). When using silicone, it is important to
use a material specifically designed for use in a roller pump. These silicones have a lower spallation rate compared with
regular silicone. Roller pumps are capable of generating more powerful pulsatile flow than are centrifugal pumps, and
this can be a reason for choosing to use them as the arterial pump.
Complications associated with roller pumps include malocclusion (with the consequences noted in the preceding text),
miscalibration or miscalculation, including setting the wrong tube size into the pump controller; fracture of the pump
tubing; “run away”; loss of power or pump failure (220,221); pumping of large amounts of air; and spallation. If the
outflow becomes occluded, pressure in the line will progressively rise until the tubing in the pump ruptures or connectors
and the tubing separate. This can be avoided by the use of a pressure-regulated shunt (Better Header, Circulatory
Technology, Oyster Bay, NY) between the outflow and inflow lines of the roller pump (208) or the use of servo-regulation
of the pump to arterial-line pressure so that it will slow down and even turn off when excessive pressures are detected. If
inflow becomes limited, the roller pumps will develop high negative pressures producing cavitation, microbubbles, and
hemolysis. Milano and colleagues (222) and Dodonov et al. (223) found that roller pumps functioning in the pulsatile
mode produce increased numbers of gaseous microbubbles (GME) but with no increase in total volume of air,
suggesting that they do so by splitting the size of existing bubbles.
Nonocclusive Roller Pump

Rhône-Poulenc in France originally designed a nonocclusive roller pump for use in routine CPB procedures (Rhône-
Poulenc 06, or RP06) (224). This pump became
P.44
known worldwide after its successful use in neonatal respiratory support (225,226). The pump was further developed
over time (227,228) for routine CPB and mechanical support (226,229,230,231). The MC3—a model of this pump
available in the United States (MC3 Inc, Ann Arbor, MI)—is a passive filling, peristaltic pump that combines many
advantages of both the centrifugal pump and the roller pump. This pump is nonocclusive and should be used, as for all
nonocclusive pumps, in combination with a flow meter. It consists of a completely flat pump chamber that is wrapped
under tension around rollers. The rollers are mounted on a rotor. Rotation of the rotor imparts a peristaltic motion to the
blood within the pumping chamber. When the inlet of the chamber is supplied with blood at a pressure above ambient,
blood is moved toward the outlet (Fig. 2.13) (227,228). Because of its design, the pump chamber can only fill when there
is a positive hydrostatic pressure at the inlet. When there is no fluid in the chamber or when the pressure is below or
equal to the ambient pressure, the pump chamber will be completely flat in the portion engaged by the rollers (Fig.
2.13B). If the tubing upstream from the inlet is blocked, the pump chamber will collapse to its natural flat shape.
Consequently, the pump can no longer pump blood because no blood is available in the pump chamber. At the same
time, no negative pressure will be generated because the flat design of the pump chamber will not expand, as would a
normal pump loop made of PVC or silicone tubing (227,228). This pumping concept offers some unique safety benefits.
Air cannot be pumped because the pump needs a preload, which is only present with fluid in the reservoir (Fig. 2.13A).
The natural flat shape of the pump chamber allows for a total collapse, thereby preventing retrograde flow when the
pump is stopped. The fact that the pump cannot generate negative pressure will attenuate blood damage and reduce
microbubble generation. The nonocclusive nature of the pump will prevent failure of tubing connections. Durandy et al.
(232) recently reviewed the assets of this pump and Teman and colleagues (233) reported on testing of a pediatric
variety of this pump (the pediatric pulsatile rotary ventricular pump or PRVP) in a piglet model. Although little research
has been done, the MC3 pump seems to be at least as hemocompatible as a centrifugal pump. In vitro results showed a
lesser activation of neutrophils and platelets as well as a lower hemolysis level than in a centrifugal pump (227,231).
These results might be explained by the fact that the MC3 pump cannot generate negative pressure, in contrast to a
roller pump and a centrifugal pump. An in vivo study that compared platelet counts and free plasma hemoglobin in tidal
flow ECMO showed similar hematologic values for a roller pump with a bladder box and the MC3 pump (234). Although
this pump is available commercially, and appears to have major advantages, it has never become popular for routine
clinical CPB (235).
Rotary Pumps (See Fig. 2.14)

Centrifugal (rotary) pumps consist of a nest of smooth plastic cones or a vaned impeller located inside a plastic housing.
When rotated rapidly (2,000-3,000 rpm), these pumps generate a pressure differential that causes the movement of fluid.
The cones or impellers are suspended within a polycarbonate housing and are coupled with a motor drive by magnets.
There have been reports of thrombus formation when these pumps are used with low anticoagulation or for prolonged
periods of time (236). Improved designs have addressed issues of stasis, heat generation, and bearing wear (5). Unlike
roller pumps, they are totally nonocclusive and afterload dependent (i.e., an increase in downstream resistance or
pressure decreases forward flow delivered to the patient if no adjustment is made in the rpm) (see Fig. 2.15). This has
both favorable and unfavorable consequences. Flow is not determined by rotational rate alone, and therefore a flow
meter must be incorporated in the outflow line to quantify pump flow (See description below.) Furthermore, when the
pump is connected to the patient’s arterial system but is not rotating sufficiently to generate a pressure above that in the
patient’s aorta, blood will flow backward through the pump and out of the patient unless the CPB arterial-side tubing is
clamped. This can cause exsanguination of the patient and may result in aspiration of air into the arterial line (e.g., from
around the purse-string sutures) (237). This could lead to systemic air embolism if arterial flow is resumed. Therefore,
whenever the centrifugal pump is not running, the arterial line must be clamped. The 2013 AmSECT Perfusion
Standards have recommended precautions to minimize this risk (7). Kolff et al. (237) described a check valve to prevent
this problem. Such a valve (RetroGard Valve) is commercially available from Quest Medical (Allen, TX) (see Fig. 2.16).
On the other hand, if the arterial line becomes occluded, these pumps will not generate excessive pressure (the
maximum is only approximately 700-900 mmHg) and will not usually rupture the systemic flow line. Likewise, they will not
generate as much negative pressure, and hence as much cavitation and microembolus production, as a roller pump
because the maximum is only approximately 500 mmHg if inflow becomes occluded. There are currently a number of
commercially available centrifugal pumps for extracorporeal perfusion. These include the BioMedicus
(Medtronic/Minneapolis, MN), Delphin (3M Health Care, Ann Arbor, MI) Capiox SP (Terumo Medical, Comaset, NJ),
Rotoflow Lifestream Isoflow (St. Jude Medical Inc., Chelmsford, MA), and CentriMag (Thoratec Corporation, Pleasanton,
CA). Smaller, vaned, and impeller-type rotary (centrifugal) pumps (e.g., Medos DeltaStream, Cobe RevOlution [Sorin,
Arvada, CO] [see Fig. 2.17], and Jostra Rotaflow [Maquet, Wayne, NJ]) have been developed and are being used
clinically in place of the traditional cone-type centrifugal pump (e.g., Medtronic BioMedicus). These have smaller prime
volumes and may cause less hemolysis (238,239,240,241,242,243). The CentriMag pump is 20 to 30 times more
expensive that the
P.45
P.46
P.47
others and thus is mainly reserved for use of more prolonged ventricular assist rather than for CPB for cardiac surgery.
The characteristics of some of the various commercially available centrifugal pumps are summarized in Table 2.9.
FIGURE 2.13. Nonocclusive MC3 roller pump. A: General view and illustration of operating principles of the M-pump. B:
Pump chamber’s cross section in a free, pre-priming condition. Also seen when blood is not supplied at a pressure above
ambient. C: Method of preventing venous reservoir from emptying by orienting the pump such that the “safety level” is at
a height even with the pump inlet. Note that the center of circles (+) in A, B and C shows direction of flow. (Reprinted
with permission from Montoya JP, Merz SI, Bartlett RH, et al. Significant safety advantages gained with an improved
pressure-regulated blood pump. J Extra Corpor Technol 1996;28:72-73.)
FIGURE 2.14. Rotary (centrifugal) pumps. Drawing of centrifugal pump-heads. A cross sectional view of a smooth, cone-
type pump is shown on the top. Blood enters at A and is expelled on the right at B due to kinetic forces crated by the
rapidly spinning cones. Impeller-type pumps with vanes are shown in the bottom. (From Mora CT, ed. Cardiopulmonary
bypass: principles and techniques of extracorporeal circulation. New York, NY: Springer-Verlag, 1995, used with
permission.)
FIGURE 2.15. Typical pressure-flow curve for a centrifugal pump.

FIGURE 2.16. Quest Medical RetroGuard valve. Blood enters from the 3/8-inch inlet, passes through a duck-billed valve,
and exits through a 3/8-inch outlet. This valve prevents retrograde flow, and it may also be placed on an inlet port of the
venous reservoir to prevent pressurization of the hard-shell venous reservoir (provided by Quest Medical, Allen, TX).
(Kaplan JA, Reich DL, Savino JS, et al. Kaplan’s cardiac anesthesia. 6th ed. Philadelphia, PA: Elsevier, 2011, used with
permission.)
Blood Handling
Although commercially available centrifugal pumps work similarly, differences in hemolysis and cell activation can be
found among the pumps available (242,244,245,246). The major cause of blood activation and damage in centrifugal
pumps by fluid dynamics finds its origin in the existence of high-shear spots and zones of stagnation and recirculation.
The suboptimal flow in these zones will lead to damage and activation of red blood cells, white blood cells, and platelets
(242,244,245,246,247,248,249). In contrast to roller pumps, the blood cell damage in centrifugal pumps is not dependent
on operator skills in setting a correct occlusion, but on improper use. For example, low-flow high-resistance settings may
worsen blood handling.
FIGURE 2.17. Sorin revolution centrifugal pump. (Kaplan JA, Reich DL, Savino JS, et al. Kaplan’s cardiac anesthesia.
6th ed. Philadelphia, PA: Elsevier, 2011 [provided by Sorin Group, Arvado, CO], used with permission.)
TABLE 2.9. Characteristics of commercially available centrifugal pumps
Priming volume Rated flow Rated pressure Maximum speed

Model (mL) (L/min) (mmHg) (rpm)
Maquet Rotaflow 32 10 750 5,000
Lifestream Isoflow 65 9.9 800 3,500
Medtronic 89 8 900 4,400

BioMedicus
Sorin revolution 57 8 800 3,500
Terumo Delphin 52 9.9 700 3,600
Terumo Capiox 45 8 800 3,000
rpm, revolutions per minute.
Data obtained from the manufacturer’s instructions for use (IFU).
A reputed advantage of centrifugal pumps over roller pumps is the lower risk of pumping massive air emboli into the
arterial line. This is because they will become de-primed
P.48
and stop pumping if more than approximately 50 mL of air is introduced into the circuit. However, they will pass smaller
but still potentially lethal quantities of smaller bubbles.
FIGURE 2.18. Transit-time flow probe for measuring output of arterial pumps. (Reprinted with permission from Laustsen
J, Pedersen EM, Terp K, et al. Validation of a new transit-time ultrasound flow meter in man. Eur J Endovasc Surg
1996;12:91-96.)
All centrifugal pumps will generate heat depending on the amount of energy that is imparted into the blood. If a pump
needs a high amount of energy, more energy will be lost as heat. The loss of heat, in combination with the low flow in the
center of the pump head, may create blood clots and blood cell activation in the pump. The main areas where energy
can be lost are bearings and seals.
Flow Meters
Flow meters are indispensable parts of centrifugal pumps. Two types of measuring techniques are used clinically. One
uses an ultrasonic principle, and the other uses an electromagnetic principle. The ultrasonic flow meters utilize either the
Doppler principle or a variant known as ultrasound transit-time. The Doppler principle is less frequently used in flow
probes because the signal becomes “noisy” at low velocities and this results in inaccurate, low-flow readings (250,251).
A transit-time flow probe consists of two small piezoelectric crystals, one upstream and one downstream, mounted in a
common tip that can be clipped on to the tubing (see Fig. 2.18). The times are measured for an ultrasound pulse signal
emitted from the upstream crystal to arrive at the downstream crystal through the reflector and for a signal from the
downstream crystal to reach the upstream crystal through the reflector. Because ultrasound travels faster when it is
transmitted in the same direction as flow, a small time difference for the two signals as expressed in a shift of phase can
be determined. All blood flow velocity components are detected by the wide ultrasound beam, and transit-time
determinations are sampled at all points across the tubing diameter, so the measurement of volume of blood flow is
theoretically independent of the blood flow velocity profile because of this integration procedure. Transit-time flow meters
have an excellent correlation with direct measured blood flows even in very low flow ranges (251,252,253). An
advantage of these probes is that they can be clipped on to the outside of the tubing and therefore no immediate contact
between the blood and probe exists.
Diagonal Pump
There is currently only one diagonal pump available, the Delta-Stream (Medos Medizintechnik AG, Stolberg, Germany)
(see Fig. 2.19). This pump was developed by the Helmholtz Institute in Aachen to provide a highly integrated blood pump
for use not only in CPB procedures but also for longer-duration support, such as ECMO and ventricular assist (239,240).
Two systems were developed, one with a built-in electric motor for ventricular assist and ECMO procedures and the
other with a disposable pump head and an external motor for short-term procedures. Major advantages of this pump are
its capability of generating pulsatile flow, small size, and simple design (254,255). The basic design has a hydraulic
efficiency and a priming volume between that of an axial pump and a centrifugal pump. The pump consists of a
cylindrical electric motor integrated into the pump and an annular blood flow path that surrounds the motor for cooling
purposes. The impeller is positioned between the pump inlet and the motor. The motor cylinder and the impeller have a
diameter of approximately 25 mm. Color-flow Doppler was used to optimize the blood path in the pump head. As could be
expected from a diagonal design, the RPM necessary to achieve a certain flow against a given resistance will be higher
than that in impeller centrifugal pumps. Blood handling with respect to hemolysis and cell counts produced similar results
as those obtained for centrifugal pumps (239,240,254). Owing to its small size, the pump may be able to operate at low
heparinization (254).
Mechanical or Electrical Failure

Mechanical or electrical failure of an arterial pump, including that due to loss of electric power to the heart-lung machine
or the entire operating room is obviously a critical event during CPB. Modern heart-lung machine consoles include an
uninterrupted backup power source which is designed to activate in the event of main electrical power failure. But even
they can fail and thus hand cranks must be available. For centrifugal pumps, these cranks are geared to deliver 2 to
4,000 rpm at speeds normally achievable with human arms. When hand-cranking roller pumps, care must be taken to
ensure proper direction of flow during cranking (4), and venting must also be considered to prevent flooding out of the
surgical field.
The Choice of Arterial Pump: Roller Versus Centrifugal

Controversy persists regarding the preference of use of a roller versus a centrifugal pump for generating arterial flow (5).
A summary of the comparisons between roller and centrifugal pumps is provided in Table 2.10. If one believes that
pulsatile flow is desirable (see discussion below) then this favors use of roller pumps since they appear to be capable of
generating greater pulsatile flow than centrifugal pumps.
P.49
FIGURE 2.19. Diagonal pump. (Courtesy: Medos Medizintechnik AG, Stolberg, Germany.)
A number of investigators have performed in vitro studies comparing centrifugal pumps and roller pumps in terms of
blood handling during short- and long-term use (256,257,258,259,260,261,262,263,264,265), which has been reviewed
by Murphy and colleagues (5). Several studies reported less hemolysis with the centrifugal pump when tested in vitro
(256,257,258,259). Others have not (e.g., see Fig. 2.20) (242). Tamari et al. (261) examined hemolysis under various
flow and pressure conditions in vitro using porcine blood and concluded that the hemolysis index was related to the
duration of blood exposure to shear, the ratio of pump pressure difference between the inflow and outflow and the flow
rate of the pump. Rawn and colleagues compared an underocclusive roller pump to a centrifugal pump and found a
significantly higher index of hemolysis in the centrifugal pump (3.38-14.65 vs. 29.58 g/100 L pumped) (262). The
relevance of these often very long-term (24 hours or longer) in vitro studies to the relatively short-term (<6 hours) CPB
times employed for supporting cardiac surgery remains unclear.
A number of clinical trials have been conducted comparing emboli generation, blood trauma, and clinical outcomes
between centrifugal and roller pumps (see list of additional references provided by the review of Murphy and colleagues
(5)). Centrifugal pumps are reputed to cause less trauma, less activation of coagulation, and to produce fewer
microemboli, but these claims have been refuted by other studies (266,267,268,269), with some suggesting that
centrifugal pumps may actually increase the inflammatory response to CPB (270,271). In a trial by Wheeldon and
colleagues (272), significantly less microemboli generation, less complement activation, and better preservation of
platelet count were observed in patients
P.50
randomized to the centrifugal pump. A similar improvement in platelet preservation in the centrifugal group was observed
in a retrospective review of 785 cases, particularly with bypass times of greater than 2 hours (273). Rates of hemolysis
have been compared in seven randomized clinical trials. Two reported greater hemolysis with roller pumps (274,275),
one observed greater evidence of hemolysis with centrifugal pump (272), and four found no difference between the two
types of pumps (276,277,278,279).
TABLE 2.10. Comparison of roller versus centrifugal pumps
Centrifugal Roller
Output inversely proportional to afterload (i.e., arterial Output independent of afterload

pressure)
Output not directly related to rpm Require flowmeter to Output = rpm × volume per revolution
determine output
Will allow retrograde flow out of aorta when turned off if Better pulsatile flow capability
line not clamped
Will not blow out arterial line Will blow out arterial line if line clamped
Would not pump massive air (but can pass amounts of Must adjust occlusiveness
air that can harm the patient)
Perhaps less blood trauma Can pump massive air
Perhaps safer Wear (release particles of plastic (“spallation”); can

rupture with prolonged use)
Both require constant attention to adapt to available

venous return
Source: From Table 21.2 in Hensley FA, Martin DE, Gravlee GP, eds. A practical approach to cardiac
anesthesia. 5th ed. Philadelphia, PA: Wolters Kluwer, 2013, used with permission.
Results of clinical studies comparing clinically relevant outcomes have been inconclusive. In the largest reported RCT
involving 1,000 patients undergoing CABG (69%), valve (21%), and combined valve-CABG and other cardiac operations,
Klein et al. (277) found fewer new peripheral and central nervous system deficits (not defined), less chest tube drainage
(but less transfusions only in high-risk patients), lower postoperative serum creatinine concentrations in low- and high-
risk patients, shorter intubation time only in high-risk patients (but shorter intensive care unit [ICU] time only in low-risk
patients), and similar hemodynamics, cardiac complications, need for renal dialysis, infection, and mortality for patients in
various risk groups in whom a Medtronic centrifugal pump (BP-80) was used as compared with those in whom a Stockert
Multiflow roller pump was used. In another RCT involving 40 pediatric cases, Morgan et al. (275) reported less blood
trauma and inflammation, better urine output, and shorter time on ventilator and in ICU and hospital when a centrifugal
pump was used. Parolari et al. (266), in a retrospective review of 2,213 patients undergoing cardiac surgery utilizing a
centrifugal pump, as compared with 1,787 patients operated on during the same period (1994-1999) utilizing a roller
pump, observed no difference in hospital mortality, but an approximately 50% reduction in coma (0.9% vs. 1.8%) and
permanent neurologic deficits (1.5% vs. 2.66%) when centrifugal pumps were employed. These benefits were also
shown with multivariate logistic regression analysis (ORs of 0.46 [95% confidence intervals (CI) of 0.25-0.75] and 0.57
[CI of 0.38-0.87] and p values of 0.025 and 0.036, respectively). On the other hand, Scott et al. (280) observed no
difference in platelet counts, blood loss, or transfusions in an RCT of centrifugal versus roller pumps in 113 patients
undergoing CABG. Another retrospective analysis of data from 3,438 consecutive patients revealed that the use of the
centrifugal pump was associated with a risk reduction for adverse neurologic events of 23% to 84% (281). Randomized
trials with neurologic measures as a primary outcome variable, however, have not demonstrated significant differences in
neuropsychologic outcomes or S100B levels between types of pump (268,282).
FIGURE 2.20. Hemolysis generation for different blood pumps. Open triangle, Cobe Century roller pump; solid
diamonds, BioMedicus BP-80 centrifugal pump; closed circles, Jostra Rotaflow centrifugal pump; X marks, Cobe
Revolution centrifugal pump; plus signs, static blood. (Reprinted with permission from Lawson DS, Ing R, Cheifetz IM, et
al. Hemolytic characteristics of three commercially available centrifugal blood pumps. Pediatr Crit Care Med 2005;6:573-
577.)
In a recent meta-analysis of 18 RCTs involving 1,868 patients comparing centrifugal versus roller pumps in adult
P.51
cardiac surgery patients (˜88% coronary artery surgery), Saczkowski et al. (283) found no difference in hematological
variables, postoperative blood loss or transfusions, neurological outcomes, ICU or hospital length of stay or mortality.
Keyser and colleagues (284) conducted a prospective RCT of 240 patients undergoing CABG comparing use of a roller
pump with a peristaltic pump (Avecor affinity blood pump) and three other centrifugal pumps (Sarns Delphin, Maquet
Rotaflow, and BioMedicus Bio-Pump BP-80) with 38 patients in each group and observed no differences in hematologic
changes, duration of postoperative mechanical ventilation, or durations of ICU and hospital stay. In a small matched
group of 50 patients, each undergoing CABG, Holinski and colleagues (285) observed a barely significantly greater
decline in overall cognitive function with centrifugal versus roller pumps, but the latter group underwent surgery more
recently.
Murphy and colleagues (5) concluded that most of the recent studies that examine centrifugal pumps also incorporated
other variables in the study design that could impact outcomes including surface coating and reservoir design (open vs.
closed). While the majority of the randomized trials show benefit to systems designed with centrifugal pumps, it is difficult
to determine the influence of these other variables (such as lower prime volume, surface coating, more limited surface
area, or reduced air-to-blood contact) on clinical outcomes. According to the recently published guidelines by the Society
of Thoracic Surgeons and the Society of Cardiovascular Anesthesiologists, it is not unreasonable to select a centrifugal
pump rather than a roller pump, but primarily for safety reasons rather than for blood conservation (Class IIb, level of
evidence B) (286) or other clinical outcomes. In 2000, approximately 50% of the cardiac centers in the United States
routinely used centrifugal pumps (221). In a survey of perfusion groups in Great Britain and Ireland in 2007, Warren et al.
(287) found that 25% solely used roller pumps and 18% solely used centrifugal pumps while 50% use both, although
95% of the latter used roller pumps in the vast majority of their cases.
Pulsatile Versus Nonpulsatile Perfusion

The importance or superiority of use of pulsatile flow during CPB has remained controversial and unresolved as
summarized in the following update of a review by one of the authors and his colleagues (5). “The early mechanical
pumps introduced into clinical practice in the 1950s delivered non-pulsatile flow. The lack of a suitable pump that would
deliver physiological pulsatile flow led to the widespread application of non-pulsatile CPB. Technological advances in
biomedical engineering that have occurred over the past 30 years have allowed for the delivery of intermittent high-
amplitude pressure and flow pulses during bypass” (5). The putative benefits of pulsatile flow are summarized in Table
2.11. “Proponents of pulsatile perfusion argue that pulsatile flow patterns improve major organ blood flow and augment
oxygen delivery at the tissue level. Others have concluded that pulsatile pumps increase the complexity of the CPB
circuit and enhance the destruction of red blood cells and platelets. Despite over five decades of intensive research,
vigorous debate about the advantages vs disadvantages of pulsatile perfusion continues. Over 150 basic science and
clinical investigations have been published which directly compared pulsatile and nonpulsatile perfusion. Although an
extensive body of literature exists, there remains uncertainty about the effects of pulsatile perfusion on clinical outcomes”
(5).
TABLE 2.11. Putative benefits of pulsatile flow during CPB
Increased capillary patency

Less venous “sludging”
Enhanced lymphatic drainage reducing edema
Enhanced nitric oxide and attenuated endothelin-1 release reducing cerebral vascular resistance
Attenuation of inflammatory response to CPB
Increased regional CBF after hypothermic circulatory arrest leading to increased tissue oxygenation and
metabolism
Increased CBF when blood flow is pressure dependent (i.e., impaired autoregulation)
Lower neuropathologic score in ischemic penumbra after experimental stroke
Less neuronal cell loss to CA1 hippocampal region and caudate nucleus after global cerebral ischemia
Decreased number of SjVO2 desaturations
CBF, cerebral blood flow; CPB, cardiopulmonary bypass; SjVO2, jugular venous oxygen saturation.
Source: From Table 2 of Hogue CW Jr, Palin CA, Arrowsmith JE. Cardiopulmonary bypass management and
neurologic outcomes: an evidence-based appraisal of current practices. Anesth Analg 2006;103(1):21-37, used
with permission.
See Table 2.12, modified from Murphy et al.’s review (5), for a comparison of some of the conflicting results from clinical
studies comparing outcomes between pulsatile and nonpulsatile perfusion. A similar comparison may be found in Table
28-3 in Grocott et al.’s review (288). Murphy and colleagues concluded, “No randomized trials that have been published
have been adequately powered to definitively establish an effect of pulsatility on mortality” (5). An RCT in 316 patients
observed a reduced in-hospital mortality (289), while two observational investigations enrolling 350 and 1,820 patients,
respectively, observed no impact on hospital mortality (290,291) with the use of pulsatile flow. “Conflicting findings have
also been reported about the effects of pulsatile flow on major organ dysfunction after cardiac surgery. Renal, cerebral,
and gastrointestinal blood flow and function have been noted to be improved or unchanged when pulsatile pumps are
used on CPB. Similarly, clinical studies investigating the role of pulsatile versus non-pulsatile perfusion on the
perioperative inflammatory or stress response have observed that humoral mediator release was attenuated or
unaffected by the use of
P.52
pulsatile pumps.” See Murphy et al.’s paper (5) for references to these studies.
TABLE 2.12. Clinical studies comparing the effects of pulsatile and nonpulsatile perfusion on
outcomes
No difference between
Improved with pulsatile pulsatile and nonpulsatile
flow flow
Mortality Murkin JM (1995) Taylor KM (1982) Abramov D

(2003)
Myocardial infarction Murkin JM (1995) Abramov D (2003)
Requirement for mechanical or Song Z (1997) Taylor KM

pharmacologic circulatory support (1982) Murkin JM (1995)
Neurologic injury (stroke or neurocognitive Takahara Y (2000) Murkin JM (1995) Henze T

dysfunction) (1990) Abramov D (2003)
Renal injury Kocakulak M (2005) Badner NH (1992) Abramov D

(2003)
Splanchnic perfusion Hamulu A (1998) Gaer JA Mathie RT (1997)

(1994)
Inflammatory mediator release Sezai A (2005) Driessen JJ Dapper F (1992)

(1995)
Release of endogenous vasoactive Zamparelli R (2000) Sezai A Goto M (1993)

mediators (catacholamines, plasma renin) (2005) Canivet JL (1990)
Source: From Table 6 in Murphy GS, Hessel EA, Groom RC. Optimal perfusion during cardiopulmonary bypass:
an evidence-based approach. Anesth Analg 2009;108(5): 1394-1417, for references, please see original paper.
A recent meta-analysis of eight mainly small (5 with fewer than 20 patients per group) RCTs involving 970 patients
evaluating pulmonary function observed superior Pa PaO2/FIO2 ratios, chest radiograph scores, a lower incidence of
requiring noninvasive ventilation for acute respiratory insufficiency as well as shorter durations of postoperative
endotracheal intubation, ICU stays, and hospital stays with pulsatile flow (292). Notably, in three of the four most recent
studies included in this meta-analysis, intra-aortic balloon pumps (IABPs) were used to produce pulsatility. In another
meta-analysis of 10 RCTs involving 1,185 patients, Sievert and Sistino (293) examined the impact of pulsatile perfusion
on renal function. They found no difference in mean postoperative creatinine or BUN concentrations, although
postoperative creatinine clearance was significantly greater with pulsatile perfusion and lactate levels were lower.
Interestingly they observed that studies using an IABP to generate pulsatile perfusion had more favorable results than
other methods. In an RCT of 46 patients >75 years old undergoing CPB for aortic valve stenosis, Milano and colleagues
(294) observed better maintenance of glomerular filtration and lower release of renal tubular injury markers when the
MEDO Delta Stream DP3 centrifugal pump was set in the pulsatile mode. In an RCT comparing use of the Stockert roller
pump in the pulsatile versus nonpulsatile mode in 89 neonates and infants undergoing repair of transposition of the great
arteries with VSDs, Alkan-Bozkaya et al. (295) observed that patients in the pulsatile group required less inotropic
support, had lower lactate concentrations, higher urine output and shorter ICU and hospital stays. Conflicting results of
the impact of pulsatile perfusion on microcirculation during clinical CPB have been reported recently (296,297). As
mentioned earlier, Milano and colleagues (222) and Dodonov et al. (223) noted that roller pumps functioning in the
pulsatile mode produce increased numbers of gaseous microbubbles (GME) but no increase in total volume of air, which
suggests that they do so by fragmenting existing bubbles.
“An assessment of the benefits and risks of pulsatile perfusion is complicated by important limitations in the experimental
design in all published investigations. Most importantly, no precise and widely recognized definition of what constitutes or
quantifies pulsatile flow exists. Traditionally, pulse pressure is used to quantify pulsatility. However, the generation of a
normal pulse pressure does not ensure the delivery of a normal pulse flow waveform. Pulsatility should be defined in
terms of hemodynamic energy levels (e.g., energy equivalent pressure [EEP] and surplus hemodynamic energy [SHE]),
since additional hydraulic energy is required to generate pulsatile flow and improve capillary perfusion (298,299). Studies
have demonstrated that with identical pulse pressures, the surplus energy produced by two different pulsatile pumps
may differ by more than 100% (300). In addition, the hemodynamic energy delivered by currently approved pulsatile
pumps is significantly less than normal physiologic pulsatility (301). Transmission of the pressure-flow wave generated
by the pulsatile pump can be affected by other CPB circuit components. A pressure drop occurs as blood flows through
the membrane oxygenator, and the type of oxygenator (hollow-fiber vs. flat-sheet) can influence the quality of the
pulsatility (302). The design of the aortic cannula can also affect the pulsatile waveform morphology (303). In order to
clearly determine the benefits of pulsatile flow during CPB, future clinical investigators should attempt to quantify the
energetics of the different perfusion modes, standardize the components of the CPB circuit (membrane oxygenator,
arterial cannula) and carefully control the conduct of bypass.” (5)
P.53
As mentioned before, roller pumps can generate pulsatile flow and energy more easily than centrifugal pumps, although
many commercially available centrifugal pumps are advertised as being capable of producing pulsatile flow. Recently, in
a small RCT of 32 patients, Gu et al. (304) evaluated the ability of the Rotaflow centrifugal pump to produce effective
pulsatile flow during adult CPB. They found that it produced a clinically insignificant increase in energy equivalent
pressure (EEP), but a significant increase in surplus hemodynamic energy. However, they observed no difference in
multiple clinical outcome parameters.
In their 2006 evidence-based review of pulsatile CPB flow, Alghamdi and Latter (305) concluded that the data were
conflicting or insufficient to support recommendations for or against pulsatile perfusion to reduce the incidence of
mortality, myocardial infarction, stroke, or renal failure. Hogue and colleagues (78) concluded that the evidence weakly
favored nonpulsatile flow (Class IIB) for neuroprotection in low-risk patients, but that there were insufficient data
regarding its possible benefit in high-risk patients. In their review of this controversy, Grocott and colleagues (288)
concluded that most studies do not present convincing evidence to suggest that routine pulsatile flow during CPB (as
achieved by widely available current technologies) is warranted. Groom and Stammers also concluded that the effects of
pulsatile perfusion on clinical outcome remain uncertain (4).
On the other hand, Ündar and colleagues (306) argue that the evidence favoring use of pulsatile flow for pediatric CPB
is convincing. They indicate that engineering advances have made conversion to pulsatile flow easy and that hollow-
fiber membrane oxygenators with integrated arterial filters allow adequate quality of pulsatility with minimal pressure
drop. They emphasize that multiple components of the circuitry impact the generation of an adequate quality of pulsatility
and the need to precisely quantify the pressure/flow wave form.
FIGURE 2.21. Arrangement of components for extracorporeal circuits. A: Sequence of components when a bubble
oxygenator (BO) is used. B: Sequence when a membrane oxygenator (MO) is used. C: Arrangement for pulsatile
perfusion with MO and two pumps: one removes blood from a venous reservoir and pumps it through the MO to an
arterial reservoir where it can be pumped by a pulsatile pump back into the patient’s arterial system. (Modified from
Kirson LE, Laurnen ME, Tornbene MA. Position of oxygenators in the bypass circuit [Letter]. J Cardiothorac Anesth
1989;3:817-818, with permission.)
Finally, strong support for the use of pulsatile perfusion during CPB may have been muffled by the successful outcome
track record of nonpulsatile left ventricular assist devices (LVADs), as used not only as a bridge to transplantation but for
long-term destination therapy. It has been estimated that pulsatile flow is used by approximately 25% of teams in Europe,
but only by approximately 5% of the teams in North America.
BLOOD-GAS EXCHANGING DEVICES (“MEMBRANE OXYGENATORS”)

Although numerous types of oxygenators have been used in the past, currently only two varieties are in use: bubble
(BOs) and membrane oxygenators (MOs). BOs are rapidly disappearing from use in most parts of the world, and thus will
be minimally discussed. The details concerning the function of these two classes of oxygenators and the advantages
various types of membrane oxygenators are discussed in the next chapter. The oxygenator used does influence the
configuration of the ECC (Fig. 2.21). Often, the oxygenator includes other components of the circuit. The heat exchanger
is usually an integral part of the oxygenator and is usually situated just proximal to the gas exchanging section, or
sometimes integrated with the
P.54
hollow-fiber membranes of MOs. BOs are positioned proximal to the pump and include an arterial reservoir, which is
located distal to the oxygenating column and defoaming area and proximal to the systemic pump for which it serves as an
“atrium.” No additional venous reservoir is included in this circuit because the venous return empties directly into the
oxygenating column of the oxygenator, as does the cardiotomy reservoir (Fig. 2.21A).
FIGURE 2.22. Typical hollow-fiber microporous membrane oxygenator. (Figure 7 in Murphy GS, Hessel EA, Groom RC.
Optimal perfusion during cardiopulmonary bypass: an evidence-based approach. Anesth Analg 2009;108:1394-1417,
used with permission.)
Virtually all current membrane oxygenators are positioned after the pump because the resistance in the blood path
requires blood to be pumped through them (Fig. 2.21B). A venous reservoir receives the venous return and the drainage
from the cardiotomy reservoir and serves as the atrium for the systemic pump, which pumps the blood through the
oxygenator and into the patient. For pulsatile bypass with some membrane oxygenator circuits, a second (the pulsatile)
pump is placed beyond the membrane oxygenator to avoid the damping that would occur if it were placed proximal to the
membrane oxygenator (Fig. 2.21C). This requires inclusion of a second (arterial) reservoir and a bypass line to handle
the excess flow of the first (venous) pump, which must run slightly faster than the arterial pump. If there is no arterial
reservoir between the membrane oxygenator and the arterial pump, there is a risk of drawing gas bubbles across the
membrane and into the CPB circuit due to pressure changes as the roller rapidly decelerates and accelerates. Pulsatile
flow can also be achieved with the use of relatively noncompliant membrane oxygenators configured as shown in Figure
2.21B.
Most MOs used for clinical CPB for cardiac surgery employ microporous polypropylene (PPL) membranes whose pores
become filled with autologous plasma to create the gas exchanging membrane. (See Fig. 2.22) A nonporous true
diffusion membrane constructed from polymethyl pentene (PMP) is also available. These MOs may be more
biocompatible and more suitable for long-term perfusion (e.g., ECMO) but they do limit the transfer of volatile anesthetics
and thus during CPB anesthesia may best be provided by intravenous agents. Because of this limitation and higher cost,
MOs utilizing this membrane are not commonly used in the United States for clinical CPB for cardiac surgery.
Oxygenators require a gas supply system. This requires at least a source of oxygen, but usually also air (through an
oxygen-air blender for membrane oxygenators) and sometimes carbon dioxide, a flow regulator, and a flowmeter. An
oxygen analyzer should be incorporated in the gas supply line after the blender and a gas filter and moisture trap. An
anesthetic vaporizer is usually incorporated in the gas supply line to the oxygenator. In this regard, one must be aware
that volatile anesthetic liquids may destroy plastic components of ECCs, and hence one must consider the location of
these vaporizers and use extreme care when filling them with anesthetic liquid so as not to contaminate any plastic
(including tubing) component. When a vaporizer is used, a method of scavenging waste gas from the oxygenator outlet
should be provided. (AmSECT 2013 standard 6.8) (7). When BOs are used, gas flow must be initiated before the
oxygenator is primed and continued thereafter to avoid back leakage of fluid through the bubble disperser plate, which
may degrade its efficiency (307).
Membrane oxygenators were thought to serve as bubble filters and to prevent venous GME from passing into the arterial
system, but most venous gas microemboli (GME) do pass through membrane oxygenators (18,19), and the effectiveness
of GME removal varies among the different membrane oxygenators (308,309). The integration of an arterial microfilter
into some of the newer MOs is a way to reduce the passage of GME through MOs.
Because high pressure gradients develop across membrane oxygenators approximately 1% of the time (310,311), and
emergent oxygenator change-out during CPB is required in 0.05% to 0.2% of cases (220,221,310); teams must monitor
for and be prepared to deal with such problems. Monitoring the line pressure just proximal and distal to the MO permits
recognition of this problem. Groom et al. (312) described the “PRONTO (parallel replacement of the oxygenator that is
not transferring oxygen)” protocol to deal with membrane oxygenator occlusion or near-occlusion. This technique
requires that a shunt line be routinely placed around each membrane oxygenator for use in such emergencies.
P.55
AUTOLOGOUS LUNG OXYGENATION
Because the oxygenator contributes to blood activation, and bypass of the lungs may cause ischemia/reperfusion
damage to the lung, interest in an old form oxygenation (use of the patient’s own lungs, so-called autologous
oxygenation (313) and also referred to as the Drew-Anderson technique) has been re-explored. As usually performed,
this technique requires two pumps (for right and left heart bypass) and quadruple cannulation (right atrium or vena cavae
to PA and left atrium to aorta) and two reservoirs, and careful balancing of flow through the lungs and the body (typically
the right-sided pump is run slightly faster [0.2-0.3 L/min] than the left, and a shunt is placed between the two reservoirs
to maintain balance). In a canine study, Mendler et al. (314) observed superior preservation of pulmonary mechanics and
function with this technique. This same group (The German Heart Center in Munich), in two small RCTs (30 and 18
patients, respectively, undergoing CABG), observed lower proinflammatory mediator levels, less blood loss, and better
oxygenation early postoperative and shorter time to extubation with autologous oxygenation (315,316). Marques et al.
(317) demonstrated, at least in dogs, that the technique can be simplified by using only a single (left-sided) pump and
cannulation and allowing the blood to flow passively through the fibrillating right heart and lungs by elevating right atrial
pressure (volume expansion) and lowering the left atrial pressure (gravity drainage), although the clinical applicability
and advisability of this technique is suspect. Conversely, Shivaprakasha et al. (318) described using single right heart
bypass (with autologous lung oxygenation) for congenital heart surgery (predominantly bidirectional Glenn shunts) in 15
children. These different techniques have also been applied to beating-heart coronary artery surgery by various groups.
The application of autologous lung oxygenation is complicated and requires rethinking on the part of the entire cardiac
surgical team (surgeon, perfusionist, anesthesiologist, nurses), and cannot be used when the left side of the heart will be
surgically opened. Its role and place is yet to be defined, but is an interesting approach to reducing the adverse sequelae
of CPB.
HEAT EXCHANGERS
Heat exchangers are designed to add or remove heat from the blood, thereby controlling the patient’s body temperature.
During its flow through the ECC circuit, the blood cools and hence heat must be added to avoid patient cooling. In
addition, the patient’s temperature is often deliberately lowered and then restored to normothermia before discontinuing
CPB.
Although separate heat exchangers were used in ECCs in the past, currently they are invariably included as an integral
part of the disposable oxygenator. The details concerning the function and performance of blood heat exchangers are
discussed in the next chapter. They are usually located proximal to the gas exchanging section of the circuit to minimize
the risk of releasing microbubbles of gas from the blood, which could occur if the blood is warmed after being saturated
with gas. An additional risk of heat exchangers is water leakage into the blood path. Although this incident is rare, when it
occurs it is most often manifested by the appearance of hemolysis and elevated serum potassium.
A source of hot and cold water, a regulator/blender, and temperature sensors are supplemental requirements of heat
exchangers. Although hospital water supply may provide such a source, a stand-alone water cooler and heater is used
more often. Malfunction of these cooler-heaters is one of the more common incidents during CPB (220). Separate heat
exchangers are needed for administration of cardioplegia solution and/or blood for coronary perfusion.
VENOUS RESERVOIR
A reservoir is placed immediately before the systemic pump to serve as its “holding tank” or atrium and act as a buffer for
fluctuation and imbalances between venous return and arterial flow. It also serves as a high capacitance (i.e., low
pressure) receiving chamber for venous return and hence facilitates gravity drainage of venous blood. Additionally, it is a
place to store excess blood when the heart and lungs are exsanguinated. Additional venous blood may become available
from the patient when CPB is initiated and systemic venous pressure is reduced to low levels. Therefore, as much as 1
to 3 L of blood may need to be translocated from the patient to the ECC when full CPB begins, especially in patients who
have been in congestive heart failure or have long-standing valvular disease.
This reservoir also serves as a gross bubble trap for air that enters the venous tubing, as the site where blood, fluids, or
drugs may be added, into which the cardiotomy reservoir empties, and as a ready source of blood for transfusion into the
patient. One of its most important functions, however, is to provide time for the perfusionist to act if venous drainage is
sharply reduced or stopped, to avoid pumping the CPB system dry and risking massive air embolism.
When a BO is used, the reservoir is placed beyond the oxygenating and defoaming chambers and is usually included as
an integral part of the oxygenator. This may be referred to as an “arterial reservoir” (Fig. 2.21A). In this case, venous
return and cardiotomy drainage blood enter directly into the oxygenating chamber of the BO; hence, this inlet must be as
low as possible to facilitate venous return. With membrane oxygenators, the reservoir is the first component of the ECC,
directly receiving the venous drainage and the cardiotomy drainage (Fig. 2.21B). Blood then passes through the
systemic pump and then through the membrane oxygenator. However, this reservoir (if hard-shelled and open) may be
physically attached to the membrane oxygenator housing.
P.56
Reservoirs may be rigid (hard-shell) plastic canisters (also referred to as “open”) or soft collapsible plastic bags (also
referred to as “closed”). Hard-shell open reservoirs have the advantages of making it easier to measure volume,
handling gross venous air more effectively, often having a larger capacity and being easier to prime, and permitting the
application of suction for vacuum-assisted venous return. Virtually all hard-shell venous reservoirs incorporate macro-
and microfilters and can also serve as the cardiotomy reservoir by directly receiving suctioned and vented blood. The
soft bag closed reservoirs eliminate the gas-blood interface and reduce the risk of massive air embolism because they
will collapse when emptied and do not permit air to enter the systemic pump. Closed collapsible reservoirs also make the
aspiration of air by the venous cannulas more obvious to the perfusion team, but in turn require a way to empty the air
out of the reservoir. Schonberger et al. (319) observed more blood activation with use of hard-shell reservoirs compared
to collapsible venous reservoirs, which they attributed to additional integral filter exposure and to the blood-air interface.
Another limitation of hard-shell reservoirs is that their defoaming elements may be coated with silicone compounds
(antifoam) that may cause systemic microembolization (320).
“The prime volume may be slightly reduced by use of an open venous reservoir. With open systems, however, the
circulating blood is exposed to a larger and more complex surface that contains defoaming sponges and antifoam
agents. Furthermore, with use of an open system air entrained in the venous line is likely to be ignored since it is not
necessary to actively purge the air as required with use of the closed system. Thousands of GME can be introduced into
the patient’s arterial circulation if air becomes continuously entrained into the venous inflow, a condition that would not
be overlooked or easily tolerated with a collapsible reservoir” (5).
“The advantages of the open system are largely related to ease of use. Some of the disadvantages of open systems
may be attenuated by systematically adopting good techniques (eliminating the entrainment of air in the venous line
should it occur, careful use of the cardiotomy suction system, maintaining a safe operating level in the venous reservoir,
and use of a level detector on the venous reservoir). However, cardiac surgery teams need to be well aware that the use
of open systems with integrated cardiotomy suction renders the patient vulnerable to the unintended consequences of
gaseous and lipid emboli” (5).
In a small (9-10 patients per group) RCT of patients undergoing valve surgery employing identical heparin-coated
circuits, except for closed versus open reservoirs, Tanaka et al. (321) observed no difference in white blood cell (WBC)
count, platelet count, fibrinogen, thrombin-antithrombin (TAT), plasma-α2-plasmin inhibitor complex (PIC), D-dimer,
interleukin 6 (IL-6), polymorphonuclear (PMN) elastase, or plasma-free hemoglobin, but the small size of the study and
use of cell salvage and cardiotomy suction in both groups may have obscured significant differences. “Less complement
activation and release of PMN elastase has been observed with the use of a closed system (322). Schönberger et al.
(319) prospectively studied differences in inflammatory and coagulation activation of blood in cardiac patients treated
with open and closed reservoir systems. Levels of complement 3a, thromboxane B2, fibrin degradation products, and
elastase were significantly higher in open reservoir patients during bypass. Furthermore, the largest amount of shed
blood loss and the greatest need for colloid-crystalloid infusion was observed in the patients supported with open
reservoir systems” (5).
Clinical outcome studies comparing the use of these two types of reservoirs have been conflicting. Schonberger et al.
(319) observed more blood loss and blood administration with hard-shell versus collapsible reservoirs. Nishida et al.
(323) noted only small differences in laboratory tests and no difference in clinical outcomes between groups employing
closed versus open reservoirs. In a retrospective study of patients undergoing partial CPB for descending aortic surgery,
Fukada et al. (324) observed no difference in renal dysfunction, duration of ventilation, or transfusion requirements.
Recently, several randomized clinical trials have demonstrated superior clinical outcomes with systems equipped with a
closed reservoir and a centrifugal arterial pump (5). However, in a small RCT (25 patients in each group), Nakahira et al.
(325) observed no difference in activation of coagulation or fibrinolysis, bleeding or transfusion during CABG surgery
between use of an open venous reservoir versus closed system as long as cardiotomy suction was not returned
unprocessed to the circuit.
The 2011 STS/SCA blood conservation evidence-based practice guidelines state that open venous reservoir membrane
oxygenator system during CPB may be considered for reduction in blood utilization and improved safety. (Class IIb, level
of evidence C) (286). This is a carryover from the recommendations of their 2007 document. However, the statement that
accompanies this recommendation in their 2007 document (on page S46) does not appear to fully support this option:
“No clear benefit in improved biocompatibility, lower embolic load, or reduced blood transfusion accrues to either open or
closed systems. One serious drawback to the closed venous reservoir in membrane oxygenator systems is the handling
of air in the venous reservoir. Either a venous air filter or an extra source of venous reservoir is required to remove air in
the closed membrane systems. This constitutes a potential perfusion difficulty that can be eliminated by using the open
membrane oxygenator systems.” (See Society of Thoracic Surgeons Blood Conservation Guideline Task Force.
Perioperative blood transfusion and blood conservation in cardiac surgery. Ann Thorac Surg 2007;83(5, Suppl):S27-
S86.)
P.57
FIELD SUCTION, CARDIOTOMY RESERVOIR, AND CELL SALVAGE AND WASHING
SYSTEMS
Field Suction and Cardiotomy Reservoirs
During cardiac surgery and CPB, it is necessary to aspirate variable but often large amounts of blood from the cardiac
chambers and surgical field (pericardium, pleural cavities and wound) to prevent distension of the cardiac chambers and
air embolization and provide adequate exposure of the surgical field. If the volume of blood is large and ongoing, it may
not be optimal or practical to discard or even process the blood from the surgical field (see the later discussion on cell
processors), and therefore it is often returned to the ECC through the cardiotomy suction and reservoir. The amount of
cardiotomy suction is influenced by the type of surgery, and is generally greater with surgery for valvular and congenital
heart disease, especially if the patient is cyanotic, as compared with patients undergoing coronary artery bypass grafting
(CABG) (326).
Cardiotomy Reservoir
The cardiotomy reservoir receives blood that has been aspirated from the heart or pericardium or out of the various
vents. It includes a defoaming chamber containing a plastic sponge material impregnated with a substance (usually
antifoam A) that lowers surface tension, a storage chamber with markings on the outer shell to measure volume, and
macro-and microfilters. Blood is then returned, usually by gravity, to the venous reservoir (with membrane oxygenator
systems) or into the BO, either continuously or intermittently (controlled with a tubing clamp), or it may be first processed
(washed and concentrated) before being returned to the ECC.
When a hard-shell (rigid) venous reservoir is used this often serves as a combined or integrated venous and cardiotomy
reservoir. However, the blood path for the cardiotomy suction usually includes more extensive defoaming and
microfiltration before this blood joins the venous return blood in the common reservoir section, and the use of such an
integrated system may preclude separate processing of the cardiotomy blood.
Methods of Applying Suction

Suction is usually and most conveniently generated by use of a roller pump. The disadvantage of this system is that if
the suction tip becomes occluded, a high degree of negative pressure will develop in the suction system, which can
cause hemolysis of RBCs. Groom and Stammers recommend that the occlusion of roller pumps used for field suction and
venting should be slightly nonocclusive to reduce RBC trauma (4). It also requires constant adjustment of the roller pump
speed by the perfusionist and coordination with the surgeon in the event that the vent or suction does not function.
Alternatively, connecting a port on a separate closed hard-shell cardiotomy reservoir to a regulated vacuum source (e.g.,
wall suction) can generate suction. This may avoid developing excessive negative pressure, but requires an unvented
closed cardiotomy reservoir. In this circumstance, if the suction fails or if one switches to use of a roller pump for
cardiotomy suction, this increases the risk of developing positive pressure in the reservoir, with an attendant risk of
systemic air embolization. Another innovation is one in which the surgeon controls the degree of cardiotomy suction with
a foot-controlled switch, but this is rarely used. A jet-driven aspirator has been described that removes air from the blood
immediately within the suction tip and limits the degree of negative pressure to only 1 inch of water and reportedly
reduces blood trauma (327).
Von Segesser’s group (328,329) described an automatically controlled suction device (“Smart Suction” system, Cardio-
Smart, Fribourg, Switzerland) designed to minimize the mixing of air with blood and limit the degree of negative suction
applied, with the aim of reducing the blood damage caused by conventional cardiotomy suction and cell processing (e.g.,
Cell Saver) devices. In animal models, its use appears to be associated with less hemolysis and possibly less platelet
loss (328,329).
Adverse Sequelae of Cardiotomy Suction (330,331)

Blood suctioned from the surgical field (especially if exposed to the pericardium) is highly activated in terms of
coagulation (325,332), fibrinolysis, WBCs (including monocytes and platelets), is quite thrombogenic (333), and may or
may not contribute to bleeding and need for blood transfusion (325,332). The cardiotomy suction and reservoir have
been found to be a major source of hemolysis, particulate microparticles, and GME, fat, cellular aggregates, inflammatory
mediators (e.g., cytokines), S100B, and endotoxin, and to be the cause of platelet injury and loss
(326,334,335,336,337,338,339,340,341,342,343,344,345,346,347). In a canine study, Brooker et al. (340) identified
cardiotomy suction as the major source of SCADs (small capillary arterial dilatations) in the brain following CPB. SCADs
were also found in humans following CPB and are thought to reflect lipid microemboli (LME).
A major contributor to the blood damage associated with cardiotomy suction is the amount of air that is aspirated along
with the blood. Not only does this add GME to the blood, but the air-blood mixture also causes turbulence and high shear
stresses that can damage RBCs and platelets. Wright and Sanderson (326) documented the adverse effects of co-
aspiration of air on platelet count and formation of microaggregates. These various microemboli, activated WBCs and
platelets, cytokines, and so on, are thought to contribute to reperfusion injury, organ damage, and the systemic
inflammatory response that often follows CPB (330,331). Unfortunately, conventional cardiotomy reservoirs (with their
integral filters) and the conventional microfilters on the arterial inflow
P.58
line do not remove most of the fat, microemboli and microparticles, and activated blood components.
Pearson et al. (348) analyzed the ability of various commercial cardiotomy reservoirs to remove bubbles from aspirated
blood and described the following desirable features: direct injection of blood onto the defoamer, avoidance of
turbulence at the inlet, ensuring that all blood passes through the defoamer, avoiding free fall of blood into the reservoir,
and incorporation of a micropore filter. Storing the blood in the cardiotomy reservoir for as long as possible, rather than
letting it continuously flow into the main ECC, will also reduce the number of GME, as will reducing the air-to-blood ratio
in the aspirated blood (348).
Edmunds et al. (335) found that the fall in platelet count during CPB was proportional to the amount of cardiotomy
suction, expressed as either total amount (liters per case) or as a fraction of the total extracorporeal flow during CPB. de
Jong et al. (349) observed a progressively greater reduction in platelet number and function and prolongation of the
bleeding time with increasing amounts of air being aspirated along with blood during cardiotomy suction. Boonstra et al.
(350) noted less release of b-thromboglobulin ( p < 0.05), but no statistically significant difference in adenosine
diphosphate-induced platelet aggregation or postoperative bleeding time when they used an automatically controlled
cardiotomy suction device that prevented aspiration of air with the blood when compared to conventional suction.
However, they did observe significantly less postoperative bleeding in patients in whom controlled suction was used, if
large volumes (>65 L) with longer perfusion times (mean 3 hours) of cardiotomy suction were required.
Cardiotomy suction during CPB also appears to be a principal source of hemolysis (267). This has been attributed to
blood contact with the pericardium (338) [although Wright and Sanderson did not find this to be true if the pericardium
had been previously washed with saline (326)], excessive negative pressure (45,351,352), and most important, co-
aspiration of air (45,326,349). Less hemolysis has been observed when a vacuum suction pump is used rather than a
roller pump (326,352), and with the use of the “Smart” suction (329).
TABLE 2.13. Methods to minimize the adverse effects of the use of cardiotomy suction
1. Doing cases off-pump

2. Careful surgical technique and assiduous hemostasis to minimize the amount of shed blood
3. Discarding shed blood
4. Minimize use of cardiotomy suction
5. Minimizing co-aspiration of air
6. Special filtration of the cardiotomy suction blood.
7. Not employing cardiotomy suction/reservoir, or
1. Processing (washing and concentrating) the blood in the cardiotomy reservoir with a cell saver before
returning it to the ECC.
2. Using cell salvaging and washing systems instead
Methods to minimize the adverse effects of the use of cardiotomy suction are summarized in Table 2.13.The amount of
blood damage can be minimized by avoiding or minimizing co-aspiration of air (i.e., the suction tip should be kept below
the blood level and the field not sucked “dry”) (353)—this may be facilitated by use of the “Smart Suction” (329), using
the slowest flow rates and largest suction tips possible, and avoiding generation of high degrees of negative pressure by
not occluding the sucker tip and using a controlled vacuum suction rather than a roller pump (see also the earlier
discussion on more sophisticated suction systems).
Tabuchi et al. (339) advocated avoidance of leaving blood in the pericardium for periods of time and use of topical
heparin to minimize activation of clotting. If the use of cardiotomy suction cannot be totally avoided, then confining it to
the aspiration of blood from cardiac chambers and vessels (before it comes in contact with other tissues and the
pericardium), and using the cell processing system (see subsequent text) for retrieving the blood and irrigation fluid and
ice-melt out of the pericardium, pleural cavities, and wound is probably a desirable practice (333).
Special filtration of cardiotomy suction blood requires that there be a separate cardiotomy reservoir (i.e., one that is not
integrated into the venous reservoir and/or oxygenator) so that this blood can be filtered before returning to the venous
reservoir. Kincaid et al. (354) found that the Bentley AF1025D and the Pall LeukoGuard LD and Stat Prime arterial
microfilters in the arterial line were equally ineffective in eliminating SCADs in a canine study when cardiotomy suction
was employed, but Kaza et al. (355) found that a Cobe Sentry 21- μm arterial filter greatly reduced 10- to 50- μm fat
microemboli and eliminated those more than 50 μm in diameter when placed downstream from a Cobe cardiotomy
suction reservoir with a 30- μm filter in patients undergoing CABG. Booke et al. (356), in an in vitro study of outdated
packed red blood cells (PRBCs) to which soybean oil had been added, found that a regular blood microfilter (Braun
Medical Sangopur 40 μm) and a Pall LipiGuard fat filter removed only approximately two thirds of the fat load whereas
the Pall Purecell RC 400 leukocyte filter removed 99% of the fat. In a study of shed blood scavenged during orthopedic
surgery, Ramirez et al. (357) found that standard blood filters (Braun Sangofix 200 μm, Pall Medical SQ40SJKL 40 μm,
and the Fresenius BIOM 40) were totally ineffective in removing fat particles, whereas a “fat removal filter” (Pall
Biomedical LeukoGuard RS) was only partially effective, but the WBC reduction filters (Fresenius BIO R, BIO R Plus;
Pall Medical RC100KLE, and the Asahi Medical Sepacell) removed almost all of the fat. Engstrom (358) found that the
Pall LipiGard SB lipid filter removed fat more effectively (77% vs. 47%), at 10°C versus 37°C, but the
P.59
low temperature dramatically increased filtration pressure and hemolysis. ten Brinke et al. (345) studied the filtration
efficiency of the Fresenius HemoCare Leukocyte-depleting filter (Bio RS-02) with diluted fresh porcine whole blood and
found that it removed more than 99% of PMNs, more than 96% of eosinophils, more than 93% of monocytes, more than
80% of lymphocytes, and approximately 65% of platelets.
In an RCT of 28 patients undergoing CABG, deVries et al. (344) compared the effect of filtering (with a Pall LipiGuard fat
removal filter) or not filtering cardiotomy suction blood (ART120) (average volume 1,100 mL). A new filter was used every
600 mL. The filter removed 30% of the triglycerides, 35% of the platelets, and 47% of the leukocytes. The platelet count
and creatinine clearance were higher on the first postoperative day, and hospital length of stay (LOS) was shorter in the
filter group, but there were no significant differences in post-CPB alveolar-arterial Pa PaO2, blood loss, or myocardial
injury.
Minimizing indiscriminate use of cardiotomy suction and instead discarding the shed blood is a reasonable practice if
there is not much shed blood (e.g., during CABG surgery in the hands of a fastidious surgeon) (330,331). Westerberg et
al. (343), in an RCT of 29 patients undergoing CABG surgery (average CPB time of 48-59 minutes), compared
administering the cardiotomy suction blood versus discarding all shed blood. They excluded four patients who received
more than 500 mL of shed blood. They found that cardiotomy suction blood had significantly elevated levels of TNF-α,
IL-6, and C3a as compared with systemic arterial blood. Postoperatively, those patients who received cardiotomy suction
blood had higher levels of TNF-α, IL-6, and C3a at 10 minutes and 2 hours post-CPB, but not at 24 hours. There were
no differences in postoperative levels of erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), troponin-T,
creatinine, or hemoglobin, or in the postoperative bleeding or ventilator times between the two groups, and no patients in
either group required homologous transfusion. Controversy continues about the cost/benefit of routine use of cell
salvage during cardiac surgery (359,360,361,362). Baker and Merry (360) reviewed the arguments and evidence for and
against cell salvage in cardiac surgery and concluded that there was no unequivocal answer and suggested a well-
designed, appropriately powered multicenter study.
An evidence-based guideline for perfusion practice of CPB stated that “direct infusion to the CPB circuit of unprocessed
blood exposed to pericardial or mediastinal surfaces should be avoided” (Class I, level of evidence B) and that “blood
cell processing and secondary filtration can be considered to decrease the deleterious effects of reinfusion shed blood”
(Class IIb, level of evidence B) (97).
Cell Salvage and Washing Systems

Cell salvage and washing systems constitute an alternative method for handling blood and fluid in the surgical field
(330,331). These systems aspirate the blood (typically simultaneously adding some heparinized saline or citrate) with a
controlled vacuum, and the red cells are then automatically washed with saline and separated from the fluid by a
centrifugation process. The washed RBCs may be returned to the ECC or administered intravenously by anesthesia
personnel. The advantage of this method is that it removes some of the undesirable materials (microaggregates, fat,
gross air, tissue debris, potassium, hormones, bioactivators, etc.) and raises the hematocrit of the perfusate. Alternatively
one may simply use the cell washer/salvaging system to process (wash and concentrate) the blood in the cardiotomy
reservoir before returning it to the ECC.
There are two main types of cell saver devices: Continuous (CATS) and discontinuous (DATS) cell-washing
autotransfusion systems. The latter (DATS) employ one of several available Latham centrifugal bowl systems with
intermittent filling and washing cycles, while the former (CATS) features continuous filling and washing (of which there is
only one commercially available system, manufactured by Fresenius Kabi AG, and available in the United States from
Terumo Cardiovascular Group, Ann Arbor, MI). Not all cell washers are equally effective, and their performance is
undoubtedly influenced by how they are used (volume of saline and number of washes employed, administration of
partial bowls, etc.), and some may permit administration of microparticles, activated WBCs, platelets, inflammatory
mediators, and much fat. Other cell washer limitations include delay in processing and blood availability, loss of plasma
proteins (especially albumen and coagulation factors) and platelets, expense, and the need for operator attention and
time. Their use may also contribute to bacterial contamination (341). If the volume of salvaged RBCs is modest (e.g., 225
mL or less), it may be more beneficial to discard them than to return potentially harmful substances to the patient.
Dai et al. (363) have thoroughly reviewed, described, and compared the two major types of cell-washing systems: the
CATS, represented by the Fresenius AG, and the DATS, which included the Medtronic Sequestra 1000, the
Haemonetics Cell Saver 5, the Sorin Dideco Compact Advanced, and the Cobe Brat 2. In summarizing, Dai et al. state
that these two types of systems are almost equally effective at red cell recovery and quality, as well as with cytokine and
complement removal (approximately 93% of complement, but less IL-8). Amand et al. (364) assessed the removal of
inflammatory markers during cardiac surgery in groups of 10 patients each by five different cell washers (Brat 2,
Sequestra, Compact, CS5, and CATS). Although some differences were noted, most devices were associated with an
increase in IL-1b levels and only a moderate decrease (approximately 40%) in IL-8 (except for the CATS and CS5, which
decreased IL-8 by 98% and 93%, respectively). IL-6, TNF-α, myeloperoxidase (MPO), and elastase were reduced by
more than 95% with most devices, and IL-2 was reduced by more than 85% with most devices except Brat 2 (65%
reduction). These authors
P.60
suggest that removal efficiency was probably influenced by design, function, and operation of each device, making
generalizations problematic.
DATS cause greater leukocyte and platelet activation, but are also superior at their removal. DATS remove
approximately 50% to 90% of the leukocytes, whereas CATS remove only approximately 35% to 50%. DATS remove
approximately 80% to 90% of platelets, whereas CATS remove approximately 65% to 75% (363). CATS are markedly
more effective at fat removal. Booke et al. (365) compared the efficiency of removal of fat (added soybean oil) from
outdated PRBCs by a DATS (Haemonetics CS5) and a CATS (Fresenius). The CS5 removed only 85% of the fat
whereas the CATS removed all of it. CATS also permits cell salvage from less volume of shed blood. Innerhofer et al.
(366) found that cell salvage with the continuous autotransfusion systems (CATS) (Fresenius Terumo Cardiovascular,
Ann Arbour, MI) during orthopedic surgery neither impaired (chemotactic response) nor activated (respiratory burst)
PMNs.
Dai et al. (363) suggest that while filtering the product of cell washers with ordinary blood filters and the Pall LipiGuard
lipid filter are of little benefit, filtering the product with a leukocyte-depleting filter markedly reduces both lipid content and
WBCs. ten Brinke et al. (345) in an in vitro study of fresh porcine blood, found that cell washings with a CATS device
enhanced the leukocyte and platelet removal of a leukocyte depletion filter (Fresenius Bio RS-02).
In a small pilot study, Wang et al. (367) demonstrated that RBC product generated by three cell saver/washer devices
(Haemonetics Cell Saver 5+, Medtronic Autolog, and Fresenius Hemocare CATS) varied widely. The CATS device
produced the highest hematocrit but also was associated with the greatest fall in 2,3-DPG and deduction in RBC
deformability and viscosity. The Cell Saver 5+ had the highest efficiency of lactate removal, and both this device and the
Autolog had the best free hemoglobin removal. The clinical implications of these differences remain unknown.
The clinical benefit of utilizing cell washing in place of cardiotomy suction, and whether one cell processing system is
superior to another, is less clear. In a canine study, Kincaid et al. (354) observed half as many SCADs when a cell
washer was used, and a nonstatistically significant trend toward superiority of the CATS over the Medtronic AutoLog
DATS. A number of small RCTs have observed improved levels of biomarkers and blood components with use of cell
washing but not in clinical outcome. In RCTs during CABG surgery, Kaza et al. (355) and Jewell et al. (368) also noted
superior fat removal when DATS were used (BRAT 2 vs. Cobe, cardiotomy reservoir, and Haemonetics 5 versus
Polystan Soft-shell cardiotomy reservoir), but no clinical differences were looked for (355) or found (368) in these small
studies. Aldea et al. (369), in an RCT of 36 patients undergoing CABG, compared the use of a BCR3500 cardiotomy
suction with a BRAT II cell washer. Coagulation was better preserved in the patients on whom the cell washer was used,
but there was no difference in bleeding or transfusion. However, there was a significant decrease in neuron-specific
enolase (NSE) and S100B protein and better neurocognitive function at discharge in the cell washer group. In a small
RCT (40 patients >65 years old) comparing direct infusion versus cell processing of cardiotomy suction blood, Carrier et
al. (370) observed lower levels of S100B in the serum 30 minutes postoperatively when cell processing was used, but
observed no difference in cerebral near-infrared spectroscopy (NIRS) brain tissue oxygen saturation during surgery or in
postoperative stroke scores. Svenmarker et al. (371), in an RCT of 60 CABG patients, found no difference in early
memory disturbance (87% vs. 69%, respectively) when a Medtronic AutoLog cell washer was used instead of an Avant
D-903 cardiotomy suction. They noted that protein S100B was very high in pericardial suction blood (which was returned
with cardiotomy suction and largely eliminated by cell washing), but they found no correlation between memory loss and
S100B levels. Because of its extracerebral origin, they questioned the suitability of S100B as a marker of cerebral injury.
In another RCT of 33 patients undergoing CABG, Svenmarker et al. (342) noted that the use of the cell washer
(Medtronic Auto Log) was associated with lower plasma-free hemoglobin levels, but there was no difference in
inflammatory response (C3a, IL-6, -8, TNF-α, eosinophils, myeloperoxidase, terminal complement complex [TCC], and
platelet count) or in clinical outcomes (e.g., chest drainage, blood component therapy, ventilator duration, ICU or hospital
length of stay). In an RCT of 100 patients, Marchiex et al. (372) found that use of cell processing was associated with
less activation of the alternative complement pathway but clinical outcomes were not reported.
The two largest and highest quality RCTs to date compared cell processing of cardiotomy suction blood to direct
reinfusion into the heart-lung machine and reported conflicting effects on neurologic outcomes (373,374). Djaiani et al.
(373) randomized 226 patients over 65 years of age (mean age 67 ± 6) undergoing CABG to cell processing of
cardiotomy suction blood with a continuous flow cell saver (CATS, Fresenius Corporation, Concord, CA) versus direct
infusion of cardiotomy suction blood and observed a lower incidence of cognitive dysfunction at 6 weeks (6% [95% CI
1.3-10.7] vs. 15% [CI 8-22], p < 0.036), when the cell saver was employed. Conversely, Rubens et al. (374) randomized
266 patients (mean age 59 ± 9) undergoing predominantly CABG to cell processing of cardiotomy suction blood with an
intermittent flow cell saver (BRAT, COBE Cardiovascular Inc) plus filtration of that blood with a lipid/leukocyte versus
direct infusion of cardiotomy suction blood and found no difference in cognitive dysfunction at 5 days and 3 months
postoperatively. Whether these different results occurred by chance, or were related to the different types of cell savers
employed, age differences, the fact that one study (Djaiani’s) confined use of cell salvage to the period of full
anticoagulation while the other
P.61
continued to process cell salvaged blood until 4 hours postoperatively, or differences in methods of defining cognitive
dysfunction is unknown (375,376). Notably both studies observed increased administration of fresh frozen plasma (FFP)
(25% vs. 12% and 2.1 L vs. 1.1 L) in patients assigned to the use of the cell saver, and higher international normalized
ratio (INR) and activated partial thromboplastin time (PTT) and lower platelet counts (although these were not
statistically significant in the Djaiani study). Neither study observed a difference in morbidity or mortality or in duration of
endotracheal intubation or hospital stay. Furthermore, at 1 year postoperatively, the cognitive function differences in the
Djaiani study were no longer significant (377).
In a meta-analysis of 31 RCTs assessing the efficacy of intraoperative use of cell saver devices during cardiac surgery
involving 2,282 patients (including the Ruben and Djaiani studies), Wang and colleagues (378) found that their use was
associated with reduced exposure to allogeneic RBCs, no difference in exposure to FFP or platelets, and no difference
in hospital mortality or in the incidence of postoperative stroke, transient ischemic attacks (TIAs), atrial fibrillation, renal
dysfunction, or infection. A subgroup analysis suggested the benefits of cell processing of salvaged blood were found
only when cell salvage was used for shed and or residual blood during the entire operative period. When limited only to
processing of cardiotomy suction blood during CPB, it had no effect on blood conservation but did increase FFP
transfusion. A Cochrane review by Carless and colleagues (379) included 33 studies of the use of cell savers during
cardiac surgery and concluded that their use reduced exposure to allogeneic RBCs, but opined that the limited quality
and potential for bias in these studies limited the reliability of these conclusions and indicated the need for large trials of
high methodological quality to assess the cost effectiveness and safety of their use. Such trials have not been
forthcoming.
The fact that cell washing alone is ineffective at removal of all of the WBCs and that DATS washers do not remove much
of the fat, both of which are suspected to be responsible for some of the pathophysiology of CPB, suggest that filtering
washed cells with leukocyte-depleting filters (380), which are effective at removing nearly all of the fat and WBCs, could
augment the benefits of the use of cell washers. This hypothesis has not been tested clinically. Disadvantages would
include a delayed processing time and the likely need to replace filters periodically (344).
Cell salvage systems can also be used after CPB to process residual blood in the ECC to recover the RBCs for
transfusion. Daane et al. (381) compared the effects of transfusing unprocessed or cell-washed (Haemonetics Haemolite
2-Plus) residual blood in the ECC following cardiac surgery in an RCT of 40 patients. Equal abnormalities in coagulation,
fibrinolysis, and complement activation were observed in both groups, but there was less postoperative blood loss and
less allogeneic RBCs were administered in the cell-washed group. Eichert et al. (382) compared transfusing
unprocessed blood left in the circuit with first processing it with a cell saver (Dideco STAT) or passing it through an
ultrafilter (BC 140) in an RCT of 60 patients following CABG (average duration of CPB, 60-63 minutes) They observed
no difference in postoperative hematocrit, platelet count, activated clotting time (ACT), PTT, or blood loss in the three
groups.
A combined approach employing reduced direct reinfusion of shed blood (i.e., minimizing the use of cardiotomy suction,
with or without the use of a cell scavenger/washer), circuits that have been surface-modified (e.g., heparin bonding),
closed venous reservoir, and centrifugal pump may lead to less activation of inflammation and microemboli generation
than the use of any one component alone (274,322,383,384,385,386,387).
The use of cell salvage/washing systems for scavenging extra-cardiac blood and fluid (e.g., pericardial, pleural, and
wound), and limiting cardiotomy suction to intra-cardiac and vented blood, is a rational compromise, although cost
considerations reduced the use of cell salvage systems for routine CPB cases in recent years. The cost/benefit value of
routine use of intraoperative cell salvage continues to be debated (359,360,361,362). One evidence-based guideline
advocated use of cell processing of cardiotomy suction blood (Class IIb, level of evidence B) (97); however, in their
evidence-based appraisal, Hogue and colleagues concluded that the evidence supporting cell processing of pericardial
aspirate to improve neurologic outcome was “indeterminate” (78). The 2011 STS/SCA blood conservation evidence-
based practice guidelines state that routine use of RBC salvage using centrifugation is helpful in blood conservation
(Class I, level of evidence A) and centrifugation of pump salvaged blood instead of direct infusion is reasonable for
minimizing post-CPB allogeneic RBC transfusion (Class IIa, level of evidence A) but it also states that intraoperative
autotransfusion either directly from the cardiotomy suction or recycled using centrifugation to concentrate may be
considered as part of blood conservation (Class IIb, level of evidence C) (286). In 2012, Riley bemoaned the fact that we
still do not know the definitive answer to how to handle cardiotomy suction and indicated that this is an area “ripe for
research” (353).
FILTERS AND BUBBLE TRAPS

Gross and microembolic gas (GME), clumps of leukocytes and platelets, fat, and other microparticles are ever-present
during CPB (346,388,389,390,391,392,393,394). Willcox and colleagues (395) measured microemboli in a clinical study
of a CPB circuit which included a hard-shell venous reservoir (HSVR), Avant 903 or EOS hollow-fiber membrane
oxygenator (MO) (Sorin), and Pall AL6 arterial-line filter]. They utilized the EDAC (Luna Innovations, Roanoke, VA)
bubble detector to measure microemboli. They found that the hard-shell venous reservoir (HSVR) generated emboli (˜2-
fold increase over venous line)
P.62
and this was aggravated by use of a left ventricular vent (˜50% increase) but emboli were reduced 75% by passage
through the MO and arterial-line filter. Maneuvers increasing microemboli included repositioning the venous cannulas,
insertion of a retrograde cardioplegia cannula, adding volume to the reservoir, rapid bolus injection via the sampling
manifold and excessive venous line negative pressure resulting in “chatter” in the line. Groom and colleagues in the
Northern New England Cardiovascular Disease Study group noted a weak ( p = 0.03) association between numbers of
microemboli during CPB (measured with Power M-Mode Doppler) and postoperative serum levels of S100B (a surrogate
of neurologic injury.) (396) This group found that utilizing a smaller pore arterial-line filter (27 μm), a venous reservoir
with a smaller pore size integrated filters (30 μm), and a centrifugal instead of a roller pump reduced the median number
of microemboli coming from the CPB circuit by 89% and those in the central arteries by 77%. However, the impact of
these observations on clinical outcome including cognitive function was not reported (397).
Multiple strategies have been suggested to reduce embolization, but the most obvious is the use of micropore filters
(398,399,400). In the 1960s, two types of microfilters were introduced: the Dacron wool depth filter (Swank) and the
polyester mesh screen micropore filter (Patterson). Screen filters have gradually become dominant and, for unclear
reasons, the depth filter has become obsolete (400). Screen filters are usually made of woven polymer thread that has a
defined pore size and filters by interception, although the screen filters with the smallest pore (0.2-5.0 μm, used for
prebypass filtration) are made of membranes. Screen filters vary in pore size and configuration. They block not only
particulate emboli but also gross and microscopic air emboli. The latter is accomplished because the pores are filled with
liquid that is maintained by surface-active forces. Excessive pressure can overcome this barrier by exceeding the so-
called bubble point pressure (401).
Micropore filters may be used in several locations in the ECC. A survey conducted in 1993 found their frequency of use
in various locations as follows: arterial line, 92%; cardiotomy reservoir, 89%; gas flow line to the oxygenator, 83%; blood
product administration sets, 80%; prebypass (i.e., after priming but before connection of the circuit to the patient), 78%;
and cardioplegia delivery line, 46% (402).
Most commercial cardiotomy reservoirs now contain an integrated micropore filter. Because the cardiotomy suction is a
major source of microemboli (337) and because a micropore filter is more effective if placed in the cardiotomy reservoir
line than the arterial line (348), this practice appears reasonable. Several studies have compared the performance of
various micropore filters designed for cardiotomy reservoirs (403,404). In an in vitro study of three different integrated
hard-shell reservoirs and membrane oxygenators containing integral cardiotomy reservoirs filters, Myers et al. (405)
noted a dramatic increase in GME (per Hatteland probe) when simulated left ventricular vent return was added to the
cardiotomy reservoir.
A relatively new approach to arterial filtering is the integration of screen filters into membrane oxygenators, thereby
eliminating the need for an additional external arterial-line filter. These appear to be as effective as the latter
(222,223,406,407,408,409,410,411). Milano and colleagues (222) and Dodonov et al. (223) noted that roller pumps
functioning in the pulsatile mode produce increased numbers of gaseous microbubbles (GME) with no increase in the
total volume of air, suggesting they split up existing bubbles. They observed that two membrane oxygenators with
integrated screen type arterial filters reduced these microemboli.
With the demonstrated presence of various foreign particulates in the disposables used for ECCs and other
microparticles in the circuit, Merkle et al. (390) make a convincing argument for the continued need to use a prebypass
filter with a pore size of 0.2 mm during circuit priming. The need for micropore filters on the cardioplegia delivery system
has been questioned (412).
Arterial-Line Microfiltration (Figs. 2.23 and 2.24)

Although arterial-line conventional microfilters (distinct from leukocyte-depleting filters) are used in nearly all adult (221)
and pediatric (413) CPB cases in the United States, a 2007 survey of perfusion groups in Great Britain and Ireland (287)
found that only 85% of groups used arterial-line filters in all cases and 10% never used them. Several studies have
compared the performance of various arterial-line micropore filters (348,414,415,416,417,418), and most have found the
Dacron wool (depth) filter to be the most effective, but these are no longer used! Gourlay et al. (414,415,416) studied 13
commercially available arterial-line filters and found them all to have a similar pressure drop (24-34 mmHg at a flow of 5
L/min), but also found them to exhibit varying degrees of hemolysis, platelet loss and capture of gross and microscopic
air. These findings did not appear to be related to pore size or type of material, except that, again, the Dacron wool
(Swank) was best at removal of both microscopic and gross air. However, all filters tested were vastly superior to the
absence of a filter in reducing transmission of microemboli into systemic arteries. Some concern has also been
expressed that nylon screen filters may activate complement (398,399). Heparin-coated arterial-line micropore filters
have been introduced to reduce platelet aggregation and loss, and to facilitate debubbling and priming (419). However,
studies have shown that the heparin-benzalkonium coating may leach off the screen during priming, rendering it
ineffective or increasing the risk of passage of microscopic air (420). Riley (421) performed an in vitro study utilizing the
EDAC emboli detection system to compare the GME reduction performance of 10 different arterial-line
P.63
filters. They identified the Cobe 21 and the Gisk 25-mm filters as the most effective, with the Pall LG6, the Medtronic 20
and Dideco 27- μm filters as next most effective, and the Cobe 43, Terumo 40, Medtronic 38, Terumo 37 and Gish 40-
mm filters as least effective; however, all were at least moderately effective. Subsequently, Yarham and Mulholland (422)
compared 10 different arterial-line filters (Sorin Sentry 21, Sorin AF620, Sorin AF640, Sorin D734, Sorin D733, Sorin
AF840, Pall AL6, PallAL8, Medtronic Affinity, and Maquet Quart) in a test circuit, comparing GME handling efficiency
(using BCC 200 GAMPT microemboli detector), pressure drop, limit bolus (the largest bolus of air that could be handled),
and prime volume and surface area. Filters varied in all of these characteristics and no one filter excelled in all. The
Sorin AF620 and 640 had the smallest prime volumes, surface areas and pressure drops while the Sorin Sentry 21 and
Sorin 620 were observed to have the best GME handling (percent air removal). In a small RCT (12 patients each group),
Jabur et al. (423) observed that a 20-mm arterial-line filter removed twice as many microemboli (per EDAC quantifier) as
a 40-mm filter.
FIGURE 2.23. Schematic drawings of arterial-line bubble traps and filters. A: Conventional adult arterial-line microfilter
and bubble trap. Blood enters tangentially at the top (A), which encourages any possibly entrained bubbles to rise to the
top where they are vented out through a continuous purge line connecting the three-way stopcock to the cardiotomy or
venous reservoir. Blood then passes through a screen microfilter (20-40-μm pore size), which also serves as a barrier to
the passage of gaseous microemboli. B: Arterial-line bubble trap. The design and flow dynamics are similar to the arterial
filter, but blood only passes through a coarse screen strainer (approximately 170-μm pore size).
FIGURE 2.24. Some commercial arterial-line filters. (Kaplan JA, Reich DL, Savino JS, et al. Kaplan’s cardiac anesthesia.
6th ed. Philadelphia, PA: Elsevier, 2011, used with permission.)
De Somer (424) has questioned if existing arterial-line filter design and position are optimal in the era of membrane
oxygenators. In 2001, Whitaker et al. (400) published a systematic review of clinical studies evaluating the benefits of
conventional arterial-line microfilters. The level of evidence was disappointing. Although there was abundant evidence
that these filters reduce microemboli, especially when used with bubble oxygenators, high-level evidence that they
reduce neuropsychological dysfunction (except when a BO was used (425)) was lacking, and Aries et al. (426) and
Sellman et al. (427) did not find any benefit even when used with BOs. Evidence from evaluation of MRI, cerebral
perfusion,
P.64
and S100B was inconclusive (400). Except for the study by Connell et al. (428), who reported less pulmonary damage
when a Dacron wool depth filter was used, Whitaker found no clinical reports investigating potential noncerebral benefits
of conventional arterial microfilters (400). Kruis and colleagues (429) reported a systematic review of the literature
examining the relationship between cerebral microemboli and cognitive decline during adult cardiac surgery. They
examined 22 studies involving 2,208 CPB patients mostly undergoing CABG or CABG combined with another cardiac
procedure. All used neuropsychological tests to determine cognitive outcome. Fifteen studies used TCD and seven used
new ischemic lesions detected in postoperative MRI to assess cerebral emboli. Seven compared on-pump versus off-
pump CABG. Of the 15 TCD studies, 10 did not find an association with cognitive outcome while 5 found an association,
although in 3 it was only present at 1-week follow-up (and not thereafter). Of the seven MRI studies, only one found an
association. The authors concluded that, while there is solid evidence that the use of CPB is associated with production
of cerebral microemboli, they could neither confirm nor rule out a causal link between CPB microemboli and
postoperative cognitive decline. Nevertheless, they opined that it is prudent to minimize microemboli load in practice.
Van Dijk and Kalkman (430) analyzed the apparent lack of association between cerebral microemboli and cognitive
decline measured by psychometric testing. Possible explanations include that microemboli are not the cause of the
observed cognitive impairment, or problems with the accuracy or relevance of psychometric testing, as well as the small
numbers of patients in most studies (which they suggest would need to be in the thousands). They point out that the
impact of microemboli is likely influenced by their size and composition, that contemporary CPB technology has reduced
these risks and that other factors such as inflammation, anesthetic drugs, generalized atherosclerosis, and advanced
age are more likely responsible for cognitive decline observed following cardiac surgery. Furthermore, De Somer and
colleagues (431) have elaborated on significant limitations of even the newest (Gampt Bc200 and EBAC) as well as the
older “Gold Standard” (Hatteland Ultrasound Bubble Detector) microbubble counters used in these studies.
Besides the lack of proven benefit, other limitations of arterial-line microfilters include the fact that they add to the cost,
may obstruct flow, are harder to de-air (and therefore may be a source of GME), may generate microemboli, and cause
some hemolysis, platelet loss, and complement activation. However, their widespread use and available studies suggest
little adverse effect from their use (432). Micropore arterial filters are excellent gross bubble traps, and their routine use
can probably be justified on this basis alone. On the other hand, they may not be as effective at removing microbubbles
(18,19). If they are used as gross air bubble traps, they must have a continuously open purge line (unless they are self-
venting), which includes a one-way valve, and which goes from the filter to the cardiotomy or venous reservoir to allow
the escape of trapped air. Self-venting (“auto-venting”) arterial microfilters (e.g., Pall AV6SV) have a hydrophobic
membrane, and the GME that coalesce are trapped and pass across the membrane directly into the atmosphere.
Although less critical in that case, the use of a vent line is still recommended. In a sequential study of patients
undergoing CABG surgery with CPB, Whitaker et al. (433) observed no difference in the number of cerebral emboli (as
measured by TCD) or in neuropsychological outcome at 6 to 8 weeks postoperatively, between 73 patients in whom a
vent line arterial microfilter (Medtronic Avecor Affinity Medtronic, Minneapolis, MN) was used as compared with 37 in
whom an auto-venting filter (Pall Medical AV6) was used. Filter manufacturers recommend that a bypass line be
incorporated around all arterial-line filters. This bypass line is normally clamped but can be opened in case the filter
becomes obstructed.
Despite the lack of high-level clinical evidence of benefit, the theoretic advantages and near-ubiquitous use in North
America makes nonuse of arterial-line microfilters hard to justify at this time. Furthermore, a 2006 evidence-based
guideline on perfusion practice stated that “arterial-line filters should be incorporated in the CPB circuit” (Class I, level of
evidence A) (97) and the 2013 AmSECT Standards and Guidelines for Perfusion Practice state that “[a]n arterial-line
filter shall be used during CPB procedures” (Standard 6.5) (7).
Other Approaches to Arterial- Line Filtration

Herbst and Najm (434) reviewed the benefit of numerical modeling utilizing computational fluid dynamic analysis to guide
new filter design. Sauren and colleagues (435,436) described a novel method of diverting flow of microemboli away from
the cerebral vasculature using application of ultrasound to the ascending aorta with the EmBlocker (Neurosonix Ltd.,
Rehovot, Israel). They documented its effectiveness first in animal studies (435) followed by a pilot study in 21 patients in
which they demonstrated its ability to reduce cerebral microemboli signals (TCD) by 53% (436). Schönburg et al. (437)
described a new device, the Dynamic Bubble Trap (DBT), to reduce cerebral microembolization. It causes microbubbles
to congregate in the center of the flow line from which they are captured by a microbubble collector tube which returns
them to the cardiotomy reservoir. In an RCT of 50 patients, they documented that this device decreased the number of
microbubbles in the arterial line (Doppler bubble detection, ODBC, GAMPTmbH, Halle/Saale, Germany) and the number
of emboli detected by TCD in the middle cerebral arteries. In a subsequent RCT (50 patients each group), these
investigators observed improved cognitive outcomes with use of the DBT but with no difference in small ischemic brain
lesions on MRI (77). Neither of these new approaches to arterial-line filtration appears to have received widespread
clinical adoption.
P.65
Leukocyte-Depleting Filters
The use of leukocyte-depleting (LD) filters is another area of controversy (400,438,439,440,441). Activation of
leukocytes and release of cytokines are thought to be major contributors to the systemic inflammatory response
syndrome (SIRS) and organ injury that may follow CPB, especially in organs subject to ischemia/reperfusion (e.g., heart
and lungs). Active removal of leukocytes and platelets with a cell separator throughout CPB seems to have clinical
benefit (442,443). As an alternative approach, LD filters have been developed, which have obvious appeal and potential
for benefit. These contain nonwoven polyester fibers that have been surface-modified to remove leukocytes. Animal
studies have been encouraging (444), but most clinical studies have failed to document significant leukocyte depletion or
clinical benefits (445,446), or have provided mixed results (400,438,439,440,441).
LD filters may be placed in many different locations in the ECC, including the arterial line, venous line, and cardioplegia
line, and leukofiltration may be performed on cardiotomy suction blood, cell saver blood, residual pump blood, and
transfused blood products (RBCs, platelets, fresh frozen plasma [FFP]). Studies have varied in terms of location and
timing of leukofiltration, clinical subjects (type of surgery and risk factors), and parameters monitored (e.g., amount of
leukoreduction, WBC counts, cytokines, and evidence of leukocyte activation), surrogates of organ injury (e.g., cardiac
enzymes, pulmonary shunt fraction, serum creatinine, and S100B), and clinical outcome. The effects of LD filters are
probably influenced by both pressure and flow passing through them (447), and they probably become saturated and
less efficient over time. They appear to be more selective at removing activated than nonactivated WBCs (446,448,449).
LD Filtration in the Arterial Line

Whitaker et al. (400) systematically reviewed the literature on the effects of arterial-line LD filtration and did not find
impressive benefits. Subsequent studies have also not been encouraging (450,451,452,453). In an RCT of patients
undergoing coronary artery bypass surgery, Whitaker et al. found that the use of arterial LD filters (as compared with
conventional microfilters) reduced the number of cerebral emboli but did not improve neuropsychological outcomes, nor
did their use reduce myocardial injury as assessed with troponin-T levels (454,455).
LD Filtration of Residual Pump Circuit Blood

In two small (26-30 patients) RCTs, Gu et al. (456) and Heerdt et al. (457) studied the benefits of LD filtration of residual
pump circuit blood. Both observed lower early postoperative WBC counts, but no statistically significant difference in
blood loss or in duration of endotracheal intubation, ICU stay or hospital stay.
LD Filtration of Blood Cardioplegia

The most favorable evidence for leukocyte depletion filters is in their use with blood cardioplegia. In 2003, Martin et al.
(458) reviewed the clinical evidence of the benefits from this application. They concluded that this is most effective when
conducted just before unclamping (e.g., “Hot shot” reperfusion), and of most benefit in ischemically compromised or
functionally impaired ventricles. This conclusion was based on a number of relatively small RCTs, which observed higher
rates of spontaneous defibrillation, less release of cardiac enzymes, and lower inotrope requirement with LD blood
cardioplegia. Palatianos et al. (459) noted a lower incidence of low cardiac index, reperfusion ventricular fibrillation, and
lower levels of cardiac enzymes early postoperatively when LD blood cardioplegia was used in an RCT of 160 patients
undergoing CABG. Hayashi et al. (460) observed benefits (lower creatine kinase-MB [CK-MB]) levels and catecholamine
requirements, and higher rate of spontaneous defibrillation) with LD terminal blood cardioplegia, but only in patients with
cross-clamp times of 120 minutes or more in an RCT of 54 patients undergoing aortic valve replacement. Of various LD
strategies, Samankatiwat et al. (461) found cardioplegic LD to be associated with the lowest troponin levels. However,
no studies have demonstrated either a reduction in the incidence of severe cardiac failure or improved survival. In their
systematic review of clinical studies of leukocyte filtration, in regard to cardioplegic leukocyte filtration, Warren and
colleagues concluded that although there is evidence that its use attenuates reperfusion injury and improves early
cardiac recovery immediately post-CPB, there is no evidence that its use is associated with reduced duration of
ventilation, ICU and hospital lengths of stay, or improved survival. However, they noted that most studies were small and
had methodological limitations (462).
“Total Leukocyte Control”

Salamonsen et al. (463) tested the benefits of what they termed “total leukocyte control” (TLC) in a large RCT of 300
low-risk patients undergoing CABG. In the experimental arm (TLC), this consisted of using LD filters in arterial line,
cardioplegia line, and of all salvaged blood and transfused blood products. Notably, they did not use LD filters in the
cardiotomy suction blood. Although WBC count was transiently lower, they observed no difference in primary outcomes
(mortality, ICU, and hospital LOS) or in other morbidities, including hemodynamics, pulmonary or renal function, bleeding,
blood product use, wound infection, or cardiac enzyme release. This contrasts with the results of other studies.
Olivencia-Yurvanti et al. (464) observed lower pulmonary artery (PA) pressures and pulmonary shunt fractions early
postoperatively, and shorter mechanical ventilation times and hospital lengths of stay in an RCT of 225 CABG patients
employing similar TLC (except that arterial-line LD filtration was only started 30 minutes before they resumed PA
perfusion). This technique of employing
P.66
LD only during part of the time is sometimes referred to as a strategic leukoreduction and is aimed at applying LD only at
periods of greatest theoretic risk of infusion of activated WBC, that is, just before reperfusion, thereby avoiding “filter
exhaustion” by prolonged filtration throughout CPB. The group at Baylor University Medical Center (465,466) compared
outcomes using an LD filter on the arterial line and on blood cardioplegia in 350 patients undergoing valve surgery with a
matched cohort using no LD filtration (details of patient selection were not provided). These authors reported a
significant decrease in time to endotracheal extubation, the incidences of prolonged intubation and reintubation, and
decreased hospital length of stay in the LD filter group. In a study that is frequently cited, Gott et al. (467) compared TLC
(112 patients) in an RCT of patients who underwent predominantly primary CABG (90%). Although they reported no
difference in morbidity or transfusion requirements, in an apparent post hoc analysis, they found a 1 day shorter hospital
stay in “low-risk” patients who received leukocyte filtration (although they did not comment on the fact that the LOS was
4 days longer in the high-risk patients who received leukocyte filtration). In their review of measures to prevent
pulmonary injury associated with CPB, Apostalakis et al. (468) concluded that leukocyte filtration did not appear to
prevent lung injury.
In a systematic review of 34 RCTs and 9 nonrandomized studies of the effects of leukocyte filtration during cardiac
surgery, Warren and colleagues (462) concluded that although some studies reported that systemic (venous or arterial
line) leukocyte-depleting filters reduced various markers of organ injury and early cardiac and lung function, the majority
failed to report statistically significant improvement in hard clinical endpoints such as durations of mechanical ventilation,
ICU or hospital lengths of stay, or blood loss, transfusion requirement, sepsis, neurologic outcome, or mortality.
However, they noted that most studies were small and had methodological limitations. It is also possible that leukocyte
depletion could be helpful in patients with preoperative limited organ (e.g., heart, lung, kidney) function. These authors
also performed a systematic review and meta-analysis of 13 studies (12 RCTs including 630 patients) of the impact of
systemic leukocyte filtration on perioperative hemorrhage and reported no improvement in 24-hour chest drainage (10
studies) nor total RBC transfusion (469).
Although provocative and promising, it would appear that the proper role and optimal type of leukocyte filtration during
cardiac surgery must await further investigation. In their evidence-based appraisal of CPB management on neurologic
outcome, Hogue and colleagues concluded that evidence supporting use of leukocyte depletion filters was
“indeterminate” (78), and the 2011 STS/SCA blood conservation evidence-based practice guidelines state that
“available leukocyte filters placed on the CPB circuit for leukocyte depletion are not indicated for perioperative blood
conservation and may prove harmful by activating leukocytes during CPB” (Class III, level of evidence B) (286). In the
previously mentioned survey of perfusion groups in Great Britain and Ireland in 2007, Warren et al. (287) found that 60%
never used leukocyte-depleting filters.
VENTING THE HEART
Venting the Right Heart
The right heart is normally drained or vented by the venous cannula(s). The relative efficiency of various types of venous
lines at venting the right heart has been studied by Arom et al. (12) and Bennett et al. (13) and has been discussed
earlier in this chapter. Sources of blood to the right heart include systemic venous return blood that gets around the
venous cannulas and coronary sinus drainage. If a patient has a persistent LSVC this blood also drains into the right
atrium through the coronary sinus (see prior discussion). When bicaval cannulation with caval occlusion is used, venting
of the right heart is not provided, and if the right ventricle is not able to eject, the right heart must be vented by releasing
a caval tourniquet, placing a separate cannula or cardiotomy suction into the right atrium, or by surgically opening it to
drain into the pericardial sac. This will require attention when antegrade cardioplegia is administered. The remainder of
this section relates to venting of the left ventricle.
Venting the Left Heart

Purpose of Venting the Left Heart
The purposes of left ventricular venting are to prevent distension of the ventricle, reduce myocardial rewarming, prevent
cardiac ejection of air, and to facilitate surgical exposure. Prevention of distension of the left ventricle is desirable to
prevent mechanical damage to the muscle from excessive stretching. Myocardial preservation may also be improved by
decreasing myocardial oxygen demand (decreased wall tension due to decreased radius of ventricle), facilitating
subendocardial perfusion (subendocardial perfusion pressure equals aortic pressure minus left ventricular pressure),
and preventing pulmonary venous hypertension, with possible pulmonary injury, edema or hemorrhage, and PA
hypertension.
Sources of Blood Returning to the Left Ventricle

The normal sources of blood returning to the left ventricle during CPB include the bronchial and Thebesian veins and
blood returning to the right heart that gets around the CPB venous cannulas and passes through the pulmonary circuit.
Abnormal sources include a LSVC, patent ductus arteriosus (PDA) or a systemic-to-PA shunt (e.g., Blalock-Taussig or
Waterston), atrial or ventricular septal defects, anomalous systemic venous drainage into the left heart, and aortic
regurgitation.
Even if not present to a significant degree preoperatively, aortic regurgitation commonly occurs when administering
cardioplegic solution into the aortic root, and from distortion
P.67
of the aortic root with other surgical manipulations. Even hemodynamically mild aortic regurgitation (e.g., <1 L/min) can
be catastrophic when the heart fibrillates during CPB, yielding continuous aortic regurgitation without the ability of the left
ventricle to empty itself.
Bronchial blood flow (systemic arteries branching from thoracic aorta) to the periphery of the lungs normally drains
through the pulmonary veins. On bypass, this averages approximately 40±182 mL/min (470), and the amount is
influenced by the mean arterial pressure (which is one rationale for maintaining low perfusion pressures during CPB).
Patients with chronic lung infections or inflammatory lung disease (e.g., bronchiectasis) and cyanotic congenital heart
disease have exaggerated bronchial blood flow.
Coronary sinus flow into the right heart should greatly diminish with aortic cross-clamping, except for noncoronary
collateral flow, which averages 48 ± 74 mL/min, when cardioplegic solution is administered, and in the presence of an
LSVC (470). Most coronary sinus blood should be removed if the venous cannulas are working properly, unless bicaval
cannulas with caval tourniquets are used.
When excessive return of blood to the left heart is encountered, improper function or placement of the venous cannulas,
an LSVC, PDA, or aortic regurgitation should be considered. Unsuspected PDA has been discovered in approximately 1
in 3,500 coronary artery bypass operations (471), and Tunick and Kronzon (472) reported discovering five unsuspected
PDAs in 8,772 adults (1/1,750) undergoing echocardiograms. PDA may be detected during intraoperative TEE, but may
not be obvious unless it is specifically sought (473).
Monitoring for Left Ventricular Distension

Monitoring for left ventricular distension requires the constant attention of the surgical team, which at times may be
obvious, but attention may be directed elsewhere. The most common and simplest method is inspection and palpation of
the heart. Particular attention should be paid to evidence of left heart distension when first establishing CPB, if the heart
fibrillates, when the aorta is cross-clamped, and whenever antegrade cardioplegic solution is administered.
Unfortunately, moderate distension of the left ventricle may not be that easy to detect because of the posterior location of
this ventricle and because it is often covered by blood, fluid, or ice, and also because of its thick walls.
One benefit of a PA catheter is that it can provide an indication of left atrial hypertension that accompanies left heart
distension. However, the PA pressure may be somewhat late in rising if the cause of left heart distension is aortic
regurgitation and it is rendered invalid by a PA vent. The PA pressure may show a falsely high value if the tip of the
pulmonary artery catheter (PAC) becomes wedged against a wall or is caught in the aortic cross-clamp or SVC
tourniquet; therefore, a high reading of PA pressure should be confirmed by examination of the PA or left ventricle. If a
left atrial monitoring line is placed in the course of CPB, it can provide an early warning of left heart distension; however,
these lines are infrequently used.
TEE is one of the best monitors of left heart distension during CPB. The trans-gastric short-axis view is optimal, but it
can be obscured if a sponge or pad has been placed behind the left ventricle to aid exposure or to protect the phrenic
nerve from ice and the heart from warming. In this case, mid-esophageal views of the LV are usually informative.
Indications for Venting the Left Heart

Venting of the left heart is indicated whenever the left ventricle is unable to handle the amount of blood that is returning
to it. This may occur with cooling, ventricular fibrillation, aortic cross-clamping, and administration of cardioplegia. It
should be especially anticipated with the onset of CPB and with release of the aortic cross-clamp. There is considerable
debate about the need to vent the left heart during CPB, especially in the era of cold cardioplegia and for coronary artery
bypass surgery in particular (474,475,476,477). Excellent results have been reported without the use of venting in aortic
and coronary surgery. Contrary to these clinical results, experimental studies suggest that optimal myocardial recovery
after an ischemic insult is best provided by full CPB and venting of the left ventricle (478). Otherwise, myocardial oxygen
demand may be considerable, although the left ventricular diastolic pressure is low and the heart is not ejecting (478).
Therefore, left ventricular venting during reperfusion may be warranted in hearts with decreased ejection fraction or
those that have been incompletely revascularized or have sustained a period of severe ischemia. Olinger and Bonchek
(479) found improved left ventricular performance immediately after coronary artery bypass surgery when a vent was
used.
Methods of Venting the Left Heart

During coronary artery surgery, either no venting or venting through the aortic root cardioplegia cannula is commonly
practiced (Table 2.14, Fig. 2.25A). Special cardioplegia cannulas are available with a Y-arm, which allows one limb to be
connected to suction when cardioplegic solution is not being administered through the main arm of the cannula. Other
antegrade cardioplegia cannulas have a third lumen for monitoring aortic root pressure.
A limitation of aortic root venting is that it does not function during the time the cardioplegia solution is being
administered. If there is any aortic regurgitation or excessive return of blood to the left heart, it may be necessary to
intermittently interrupt delivery of cardioplegia solution and apply suction to the vent with or without external compression
of the left ventricle. Furthermore, a vent in the aortic root cannot decompress the left ventricle before the aortic cross-
clamp is applied and after it is removed (although it can still help remove air from the aortic root as described later).
P.68
TABLE 2.14. Methods of venting the left heart

Method Advantages Disadvantages
Ascending aortic Simple; no additional Only works when aorta is cross-clamped

(cardioplegia cannula) cannula Does not work during administration of antegrade
Also vents air when aorta is cardioplegia
unclamped and when LV Can permit or cause air to be aspirated into the
starts to eject aortic root
Can be used to monitor
aortic root infusion pressure
Indirect LV (through stab Handles all sources of blood Somewhat difficult exposure of insertion site
wound in RSPV, through causing LV distension May be difficult to thread cannula into LV and
LA and MV) Best for aortic regurgitation position correctly
Provides optimal Risk of bleeding and tears at insertion site in
decompression of LV RSPV
Avoids problems of direct LV Potential for air entry into the left heart
vent Potential problem if mechanical prosthesis in mitral
valve
Potential embolism if there are tumors or clots in
LA or LV
Direct LV (through stab Direct and simple Positioning may be a problem—tip becomes easily
wound in apex) Avoids going across obstructed by LV wall or MV apparatus
prosthetic mitral valve Risk of damage to LV and injury to coronary
Handles all sources of blood arteries and collaterals (myocardial ischemia)
causing LV distension May be difficult to control bleeding from stab
wound
Late LV aneurysm
Potential embolism if there are clots in LV
Potential for air entry into the left heart
Direct LA (through LA Relatively simple Does not handle AR

appendage, roof of LA, Avoids going across the MV Potential embolism if there are clots in LA
or RSPV) Potential for air entry into the left heart
Pulmonary artery Simple Does not handle AR

Reduces the risk of Renders the use of PA pressure as a monitor of
admitting air into the left LV distension invalid Risk of damage and bleeding
heart (but it can still occur) from pulmonary artery
AR, aortic regurgitation; LV, left ventricle; LA, left atrium; MV, mitral valve; PA, pulmonary artery; RSPV, right
superior pulmonary vein.
When direct venting of the left ventricle is desired, this is most commonly accomplished by inserting a catheter through a
purse-string suture placed at the junction of the right superior pulmonary vein (RSPV) and the left atrium and advancing
the catheter across the mitral valve into the left ventricle (Fig. 2.25B). One study observed less microemboli during
coronary surgery when a left ventricular vent was used instead of an aortic root vent (480). If the surgeon prefers, this
vent can be left only in the left atrium at the beginning or end of surgery, rather than in the left ventricle.
Currently, vents are seldom placed directly through the apex of the left ventricle (Fig. 2.25C) because of the risk of
hemorrhage and myocardial injury. Some surgeons insert vents directly into the left atrium only or into the PA (Fig.
2.25D) (475,481,482), which eliminates some of the risks of direct left ventricular venting but exhibits variable
effectiveness. PA venting may not prevent left ventricular distension in the presence of aortic valve insufficiency if the
mitral valve remains competent (482).
The vents are then usually attached to suction (roller pump or vacuum) and the blood is returned to the cardiotomy or
venous reservoir. When the tip of the vent is in the ventricle, the degree of suction must be constantly adjusted to avoid
excessive suction (with collapse and trauma to the ventricle and the risk of aspirating air) or inadequate suction (with the
risk of over-distension of the ventricle or obscuring the operative site). For this reason, some surgeons use gravity
siphon or passive drainage to the vents instead of suction. This requires that the drainage reservoir is placed below the
patient, and it may not provide adequate drainage if large
P.69
volumes of blood are returning to the left heart, or if an air lock occurs.
FIGURE 2.25. Sites for venting left ventricle. A: Aortic root cannula; one limb of the “Y” is connected to the cardioplegia
delivery system and the other limb to suction (siphon or roller pump) for venting the aortic root and hence the left
ventricle. B: Cannula inserted at the junction of the right superior pulmonary vein (RSPV) with the left atrium and then
threaded through the left atrium and mitral valve (mv) and into the left ventricle. C: Cannula inserted directly into the
apex of the left ventricle. D: Cannula is inserted into the pulmonary artery. AO, aorta; PA pulmonary artery; LA, left
atrium; RV, right ventricle; LV, left ventricle.
Some circuits incorporate a Y-connector in the vent line coming from the ventricular vent so that either gravity or suction
drainage can be used. Lundy et al. (483) described a combined gravity siphonage and active suction system using a
roller pump and collapsible plastic bag reservoir. The reservoir bag is placed between the left ventricular vent and the
cardiotomy/venous reservoir and the roller pump is placed between the two limbs of the reservoir bag. Using this system,
the volume in the plastic reservoir bag will reflect ventricular volume. The degree of gravity suction is adjusted by the
level of the reservoir bag. Active suction may be applied by clamping the outlet limb of the reservoir bag and activating
the roller pump. Excessive suction is recognized by collapse of the reservoir bag.
Another method of applying suction to these vents, whether they are in the left atrium, left ventricle, PA, or aortic root, is
to connect them to a Y-connector or straight connector in the systemic venous drainage line. This provides automatic
gravity (siphon) and/or Venturi suction of approximately 18 to 35 mmHg without generating excessive suction and the
need for extra pumps (484,485), but increases the risk of air entrainment in the venous line.
Complications Associated with Venting the Left Heart
Left ventricular venting is not without complications, and Utley and Stephens (486) reviewed these problems in detail.
These include introduction of air into the left heart and subsequent systemic air embolism. This is most likely to occur at
the time of insertion or removal of the vent if the left heart volume is low. To minimize this risk, the heart is usually
allowed to fill before vent insertion, and the vents are preferably removed while the insertion site is covered with fluid.
Excessive suction is another source of air introduction. Air may be drawn in from around the purse-string sutures in the
left atrium or aorta, or retrograde through the open coronary arteries during coronary artery surgery (487). Even PA
vents may suck air into the left heart and pulmonary veins, as demonstrated by TEE. Finally, errors in function of the
suction (positive pressure in reservoir, misdirection of tubing into roller pump head, reversal of roller pump) may cause
air to be pumped into the ventricle. To minimize the risk of this complication, the latest AmSECT standard for Perfusion
Practice recommends use of one-way check valves on cardiac vents (Standard 6.6) (7). Most surgeons will test the
function of the vent line at the sterile field to ensure that it aspirates fluid before connecting it to a vent in the heart. Other
risks of venting are bleeding and damage to the heart, including late left ventricular aneurysms (488). If there is a
significant return of blood through the left heart vent due to aortic regurgitation or bronchial blood flow, this will reduce
(“steal” from) the amount of systemic tissue perfusion. Increasing the systemic pump flow by an equivalent amount
should compensate for this deficit. Myers et al. (404) in an in vitro study, and Willcox and colleagues (395), in a clinical
study, both noted a dramatic increase in GME when left ventricular vent return was added to the cardiotomy reservoir.
Aortic Root Air Venting

Any time the heart is opened, even by simply placing a catheter in a chamber air may collect in the heart which, if not
removed, will embolize with resumption of normal cardiac contractions. Even air in the right heart has the potential to
pass into the left heart through septal defects or through the lungs. In addition to vigorous attempts at air removal before
closing the left heart, use of left heart vents, and repeated
P.70
aspirations of left-sided chambers, the use of venting at the highest point of the aorta is considered the final safety
maneuver against systemic air embolism (489).
Brenner et al. (490) analyzed the physiologic principles relevant to the efficiency of aortic root air vents and studied
various systems in an in vitro model. They found that a freely bleeding stab wound containing a nonobstructing
fenestrated 10F plastic catheter connected to suction was the most efficient (97%). A freely bleeding stab wound was
almost as efficient (91%), but inserting a catheter into the stab wound that was not connected to suction decreased its
efficiency to 79%. Freely bleeding needles and catheter vents not connected to suction were very inefficient (20%-36%),
but efficiency was improved (to 90%) by applying suction. Marco and Barner (489) demonstrated that the larger the vent
needle area and the greater the flow out of the vent (suction), the greater its efficiency. There are obvious limits to this
approach, including loss of forward flow and hemolysis.
Milsom and Mitchell (491) described a dual-vent (aortic root and left ventricle through the RSPV) de-airing technique in
which the ventricle ejects blood out through the vents for a certain period before unclamping the aorta. They noted
significantly fewer GME during Doppler monitoring of the carotid artery when this technique was used as compared with
standard de-airing techniques. Gundry (492) described infusing blood into a left ventricular vent using the blood
cardioplegia circuit to facilitate de-airing the aortic root before unclamping the aorta. Verification of the effectiveness of
various de-airing techniques can be accomplished by the use of TEE.
CARDIOPLEGIA DELIVERY SYSTEMS

To provide a quiet surgical field and/or access to the aortic root for aortic valve surgery, the aorta is cross-clamped,
which deprives the heart of its blood supply (1). In the past the resulting myocardial ischemia was ameliorated by topical
hypothermia (with cold saline or ice slush or a coolant flow pad that was placed around the heart) or by continuous direct
coronary artery perfusion. These techniques have virtually been replaced by the administration of cardioplegia solutions,
which typically contain potassium and may be asanguineous or mixed with blood. They may be administered at very cold
(4°C), “tepid” (28°C-35°C), or normothermic (35°C-37°C) temperatures and may be given either antegrade (i.e., into the
aortic root, coronary ostia, or the proximal end of bypass grafts that have been sewn onto coronary arteries) or
retrograde (i.e., into the coronary sinus), and these techniques are often combined. If cold cardioplegia is administered, it
is often supplemented with topical hypothermia. The simplest cardioplegia system is an ice-cold bag of crystalloid
cardioplegia solution placed under external pressure (150-300 mmHg), sometimes managed by the anesthesiologist.
This bag is connected to a weighing scale to monitor volume administered. Care must be taken to avoid infusing air.
However, most groups deliver cardioplegia from the heart-lung machine managed by the perfusionist.
FIGURE 2.26. Dedicated heat exchanger for cardioplegia. Unit also includes a bubble trap microfilter and temperature-
and pressure-monitoring ports. Water from a dedicated heater-cooler enters and leaves through specific ports, and the
blood-cardioplegia solution enters and leaves through their ports. (Kaplan JA, Reich DL, Savino JS, et al. Kaplan’s
cardiac anesthesia. 6th ed. Philadelphia, PA: Elsevier, 2011 [provided by Medtronic Cardiovascular, Inc., Minneapolis,
MN], used with permission.)
Two general types of delivery systems are employed: recirculating and nonrecirculating. Both systems include a pump
(usually roller), a heat exchanger (which may simply be a coil of plastic tubing in a water bath), or a formal metal heat
exchanger (which requires a dedicated water temperature control unit) (Fig. 2.26), a bubble trap with an incorporated
microfilter, and a site for monitoring line pressure and temperature of the fluid going into the patient. The circuits now
used primarily are commercially available single-use disposable systems. With the recirculating system (Fig. 2.27), the
cardioplegia fluid (asanguineous crystalloid or mixed with oxygenated pump blood) is stored in a reservoir bag. One line
goes from this bag via the pump and heat exchanger to the surgical field and a switching device, which directs it either
into the cardioplegia cannula (antegrade or retrograde) or back to the reservoir bag for recirculation. Nonrecirculating
(Fig. 2.28) systems lack the recirculation line. When the nonrecirculating system is used to administer blood.
cardioplegia, often this is accomplished by running two lines of different caliber through a single roller pump. One line is
connected to a source of oxygenated blood ( typically from the oxygenator, recirculation line, or the arterial line) and
the other to concentrated crystalloid cardioplegia. Based on the relative size of the tubing in the pump head, a mixture of
blood and crystalloid (typically 4 parts blood to 1 part crystalloid) is mixed and joined in a single tube before passing
through the heat exchanger and to the patient. With this system, the ratio of crystalloid to blood is fixed by the size of the
tubing employed and the composition by the content in the bag of crystalloid. To change the latter
P.71
(i.e., to go from high concentration of potassium for induction [e.g., ˜20 mEq] to lower concentration for maintenance
[e.g., ˜10 mEq]), or to another solution for rewarming, one must switch bags of crystalloid. There are also commercially
available dedicated cardioplegia systems that feature separate roller pumps that permit mixing of blood and crystalloid in
variable ratios [e.g., Maquet HL20 HI30 systems (Maquet Cardiovascular, LLC, Wayne, NJ), Sorin S-3 and S-5 Console
(Milan, Italy, and Arvada, CO), and Terumo System 1 (Terumo Cardiovascular, Tustin, CA)]. When roller pumps are
employed for delivery of cardioplegia, Groom and Stammers recommend that they be fully occlusive to prevent
retrograde flow and possible air entrainment (and thus coronary air embolization) when cardioplegia is not being
administered (4). Quest Medical (Allen, TX) produces a dedicated, self-contained cardioplegia console (Myocardial
Protection System or MPS) which utilizes four piston pumps, one for blood, a second for crystalloid, a third for the
arresting agent, and a fourth for other additives, which permits rapid adjustments of the blood-to-crystalloid ratios as well
as of the cardioplegia composition.
FIGURE 2.27. Recirculating type of cardioplegia delivery system. This can be used for sanguineous or asanguineous
cardioplegia solution. (Kaplan JA, Reich DL, Savino JS, et al. Kaplan’s cardiac anesthesia. 6th ed. Philadelphia, PA:
Elsevier, 2011, used with permission.)
FIGURE 2.28. Nonrecirculating type of cardioplegia delivery system. Nonrecirculating cardioplegia delivery system for
use in blood-to-crystalloid mixed solutions of various ratios (1:1, 4:1, or 8:1 crystalloid to blood). (Kaplan JA, Reich DL,
Savino JS, et al. Kaplan’s cardiac anesthesia. 6th ed. Philadelphia, PA: Elsevier, 2011, used with permission.)
Microplegia
“Mini-” or “micro-” or “all blood” cardioplegia refers to a method in which blood from the oxygenator (temperature may be
manipulated) is infused into the coronaries while adding small volumes of highly concentrated cardioplegia solutions via
a syringe pump before the solution enters the coronary circulation (493,494,495,496,497). This permits great reduction
in the amount of crystalloid administered (blood-to-crystalloid ratios typically about 60:1). In a propensity-matched
observational study, Algari et al. (496) observed that microplegia was associated with a lower incidence of postoperative
low cardiac output syndrome (2.7% vs. 5%), although there was no difference in hospital mortality. However, in a meta-
analysis of five small (<40 patients in each group) studies (4 of 5 were RCTs), Gong et al. (497) found that, although the
patients in the microplegia group received less volume of cardioplegia, there was no difference in the incidence of low
cardiac output syndrome, return to spontaneous rhythm or perioperative myocardial infarction. The 2011 STS/SCA blood
conservation evidence-based practice guidelines state that routine use of microplegia reduces the volume of crystalloid
administered, but does not reduce RBC exposure when
P.72
compared with 4:1 conventional blood cardioplegia (Class IIb, level of evidence B) (286).
FIGURE 2.29. Antegrade and retrograde cardioplegia cannulae. Top and bottom on right are retrograde cannulae with
balloon occlusive devices. At bottom on left is a y-type antegrade cannula for insertion into aortic root. Top left and
middle bottom are single-lumen cannulas for delivering cardioplegia into the aortic root. (Kaplan JA, Reich DL, Savino
JS, et al. Kaplan’s cardiac anesthesia. 6th ed. Philadelphia: Philadelphia, PA: 2011; used with permission.)
Antegrade Cardioplegia
Antegrade cardioplegia is administered either into the aortic root or directly into the coronary ostia. In the former case a
cannula is placed in the aortic root proximal to the aortic cross-clamp (and the arterial inflow cannula) (see Fig. 2.29).
These cannulas are often attached at the proximal end to a Y-type connector to which one end is connected to
cardioplegia solution and the other to suction for venting the left ventricle via the aortic root when antegrade cardioplegia
is not being administered. Some of these cannulas possess a third lumen for measuring aortic root pressure during
cardioplegia administration (e.g., Medtronic DPL pressure monitoring tip [Medtronic, Inc, Minneapolis, MN]). This is
desirable because the size of the cardioplegia cannula is usually small (9-16 gauge) so that a considerable gradient
exists between the cardioplegia line pressure and the aortic root; yet it is important to maintain an adequate but not
excessive pressure (60-100 mmHg) in the aortic root during cardioplegia administration to ensure adequate perfusion of
the myocardium, especially in the presence of obstructive coronary artery disease. In the absence of an aortic root
pressure-monitoring port, surgeons often palpate the aortic root to estimate this pressure. Antegrade cardioplegia is
typically administered at a rate of 200 to 300 mL/min. Pressure in the cardioplegia line should be monitored. A higher-
than-expected pressure (based upon flow rate and cannula size) suggests obstruction or misplacement of the cannula
while a low pressure may indicate displacement, severe aortic regurgitation or a leak in the system. It is also important to
watch for left ventricular distention (most accurately utilizing TEE) during administration of antegrade cardioplegia. This
distension most often results from aortic regurgitation into an arrested LV (see section on venting the left heart). Even in
the absence of preexisting regurgitation, significant aortic regurgitation can occur during delivery of cold cardioplegia
because of distortion or leaflet rigidity from the hypothermia. In the presence of significant aortic regurgitation or when
the aorta root must be opened for aortic valve or intraventricular surgery, antegrade cardioplegia must be given by
inserting cannulas directly into the coronary artery orifices (sometimes handheld) through the aortotomy. These cannulas
come in various sizes and should fit snugly in the coronary ostia to avoid significant back-leak. Care must be taken to
avoid injuring the coronary artery or inserting the catheter too far (thereby failing to perfuse critical proximal branches),
especially with left dominant coronary circulation. When performing coronary artery surgery, surgeons will often infuse
cardioplegia periodically directly into the proximal end of vein grafts after the distal end has been sewn into a coronary
artery.
Retrograde Cardioplegia
Retrograde cardioplegia is administered into the coronary sinus. Frequency of use varies among surgical teams. It may
be particularly desirable in the presence of severe proximal coronary artery disease that can impair antegrade
distribution, when aortic regurgitation negates antegrade administration, while the aortic root is open (as for aortic valve
surgery), and in repeat coronary operations (to limit or wash out atheroemboli from vein grafts). Many groups use both
antegrade and retrograde methods in the same patient and some even administer it simultaneously in both directions.
Special cannulas are designed for administering retrograde cardioplegia (see Fig. 2.29). Nearly all have an extra port
near the tip for monitoring coronary sinus pressure and a cuff or balloon to prevent back- leakage. Some cuffs require
manual inflation, and some autoinflate with infusion of the cardioplegia solution. In a pig model, Menasche (498)
observed much less (<1% vs. 22%) leakage when manually inflated balloons were employed. The cannula may be
inserted blindly into the coronary sinus through a stab wound in the lower portion of the right atrium, which may be aided
by intra-atrial palpation with a finger passed through a separate atrial incision or by the use of TEE. It is often easier to
insert the retrograde cardioplegia cannula before the atrial cannulas are inserted and CPB has begun, but the patient
may not tolerate this in terms of hemodynamics or rhythm. When the cannula is inserted during CPB, there may be
problems with air entrainment and subsequent air lock. Special care must be taken not to insert the cannula too far into
the coronary sinus (which would prevent the perfusion of the most distal coronary venous branches and hence adequate
delivery to the right ventricle). Clements et al. (499) reviewed the anatomy and variability of the cardiac venous
P.73
system, which helps explain some of the limitations associated with retrograde cardioplegia. The same cardioplegia
delivery systems are employed as for antegrade cardioplegia. Coronary sinus pressure should be monitored during
infusion, and pressures lower than 20 to 30 mmHg or higher than 40 to 50 mmHg should be avoided (500). Optimal flow
is probably between 200 and 400 mL/min (501). In the presence of a persistent LSVC, retrograde coronary sinus
cardioplegia may still be administered by intermittent occlusion of the LSVC with a tourniquet and application of external
finger pressure at the junction of the IVC and right atrium to occlude the coronary sinus ostium during administration of
cardioplegia (33). Rupture, perforation, and hematoma have been observed during retrograde coronary sinus
cardioplegia, usually during insertion or manipulation of the catheter (500). Low pressure may indicate rupture of the
coronary sinus. Although retrograde delivery may provide superior cardioplegia distribution to the left ventricle in the
presence of coronary artery disease, it may provide less optimal protection of the right ventricle (499,502).
When first inducing cardioplegia, one should watch for prompt cooling and electrical arrest of the heart. This should
occur within about 30 seconds with antegrade administration, but may require several minutes with retrograde
administration. When cooling or arrest is delayed with antegrade administration, one should consider inadequate flow or
pressure, aortic regurgitation, incomplete occlusion by the aortic cross-clamp, malposition of the cannula, or error in
temperature or composition of the cardioplegia solution. When induction is slower than expected with retrograde delivery,
one should consider, in addition, malposition of the cannula (too deep, too shallow, or not in the coronary sinus), leak
around the cuff, persistent LSVC, or a coronary sinus-left atrial fenestration.
HEMOCONCENTRATORS/ULTRAFILTRATION
Hemoconcentrators (also referred to as hemofilters or ultrafiltration devices) contain semipermeable membranes
(typically hollow fibers) that permit passage of water and electrolytes out of the blood. They are used in lieu of diuretics
to remove excess fluid or electrolytes (e.g., potassium) and to raise the hematocrit of the perfusate. The pressure inside
the blood path causes the movement of permeable fluids and electrolytes out of the blood and through the membrane.
They can be connected to the CPB circuit in several different configurations. Blood may be drawn from the venous line,
the venous reservoirs, or the systemic flow line, and filtered blood may be returned to the venous line or the cardiotomy
or venous reservoirs. Except when blood is taken from a high-pressure port or line (e.g., the systemic flow line), a pump
must be used to propel blood through the device and may be used to control flow even if blood comes from the systemic
flow line. Pressure is generated within the blood channels by resistance to flow through the hollow fibers or by placing a
partially occluding clamp downstream. Suction may or may not be applied to nonblood channel of the membrane to
facilitate filtration. Ultrafiltration is covered in more detail in Chapter 4.
MINIATURIZATION AND INTEGRATED CIRCUITS

In recent years, stimulated in part by the challenge of offpump coronary artery bypass (OPCAB), there has been interest
on the part of perfusion teams and ingenuity on the part of industry in developing minimized or minimal extracorporeal
circuits (“MECCs”), also referred to as simplified bypass systems (SBS), and minimally invasive extracorporeal circuits
(MIECs). These circuits are designed to minimize the adverse effects of CPB by reducing the foreign surface area, the
amount of hemodilution, and exposure to air and unprocessed shed pericardial blood. They all feature decreased foreign
surface area, priming volume and blood-air contact, and a fixed volume in the ECC, with the intent to decrease
hemodilution, inflammatory response, and volume shifts between patient and the ECC. They are basically a closed veno-
arterial loop incorporating a single centrifugal pump (which simultaneously provides both kinetic assisted venous
drainage (KAVD) and systemic perfusion p\ressure), a membrane oxygenator, and usually some type of surface
modification, but eliminate (or isolate from the closed circuit) a venous reservoir and introduction of blood with cardiotomy
suction, and often the heat exchanger and arterial filter. Most recent devices feature multi-site bubble detection and
innovative air removal systems (4). The priming volumes of these circuits are typically approximately 500 mL and the
degree of hemodilution can be further decreased by retrograde autologous priming (RAP). The rationale for reducing the
foreign surface area is based on the experimental work in rats demonstrating a reduced inflammatory response (503).
Two approaches have been introduced: a totally integrated device that includes a specialized air handling and
elimination system with a centrifugal pump and membrane oxygenator, or one constructed with a combination of
conventional components. Many different systems have been described including the CORx system (CardioVention Inc,
Santa Clara, CA) (504), the Cobe/Sorin Synergy System (Cobe Cardiovascular Inc, Arvada, CO) (Fig. 2.30) (505), the
MECC System (Jostra AG/Maquet Cardiopulmonary AG, Hirrlingen, Germany) (Fig. 2.31) (506), the miniaturized CPB
(MCPB) system (507), the Delta Stream ERP (Medos AG Stolberg, Germany) (508), the Medtronic Resting Heart System
(Fig. 2.32), the ExtraCorporeal Circulation Optimized system (ECCO, Sorin group, Mirandola, Italy and Dideco S.p.A), the
Terumo ROCSafe Hybrid, and “homemade” systems (e.g., the Hammersmith miniaturize CPB (“mCPB”) (509,510).
P.74
FIGURE 2.30. Sorin group synthesis mini-bypass system. The oxygenator has an integral air detection and evacuation
system and a single integral Revolution® centrifugal pump (providing both kinetic-assisted venous drainage and arterial
blood propulsion). An integrated arterial-line filter surrounds the oxygenator fiber bundle. A separate cardiotomy reservoir
is incorporated into the circuit. The system may be converted to an open system by repositioning clamps and redirecting
blood flow to the reservoir. (Kaplan JA, Reich DL, Savino JS, et al. Kaplan’s cardiac anesthesia. 6th ed. Philadelphia,
PA: Elsevier, 2011 [provided by Sorin Group, Arvado, CO], used with permission.)
There are numerous reports of “successful” clinical use of these systems (mainly for CABG surgery but also for aortic
and mitral value surgery). Some RCTs comparing the use of minimal circuits with conventional circuits have found less
inflammatory reaction, activation of coagulation and fibrinolysis, and less hemodilution and use of autologous blood, and
marginally improved renal and neurologic function or improved microcirculation (506,511,512,513,514), whereas others
have failed to detect clinical benefits (507,515,516,517). These different findings may partly be explained by confounding
variables such as administration of corticosteroids and aprotinin, the nature of any surface modification employed,
degree of heparin-induced anticoagulation, the details of the “conventional” circuits to which they were compared, and
the patient population studied. Whether the benefits demonstrated primarily derive from reduced hemodilution, reduced
foreign surface, and/or elimination of the venous reservoir or cardiotomy suction are unclear and would be important to
define. Some suggest that equal benefits can be obtained by the practice of meticulous hemostasis, use of closed
venous reservoirs and totally heparin-bonded circuits, and elimination of cardiotomy suction (518).
The greatest concern about the use of these minimized circuits is their air handling characteristics and the risk of
systemic air embolization, because of their use of KAVD, lack of a venous reservoir, and often the absence of an arterial
microfilter/bubble trap. Norman et al. (519) compared the air handling capabilities of low prime circuits without a venous
reservoir with a conventional CPB circuit when air was introduced into the venous line in an in vitro study. They found 8
to 10 times more microemboli in the arterial line in the low prime ECCs. Furthermore, both Nollert et al. (507) and Remadi
et al. (512) have encountered serious venous air intake problems while using minimized circuits, which were fortunately
managed without adverse consequences. Ovendevest and colleagues (520) applied their Heath Care Failure Mode
P.75
Effect Analysis (hFMEA) to evaluate one miniaturized extracorporeal bypass circuit (ECCO, Sorin Group). They identified
one component with a high-risk score for failure which led to system modification. Their hFMEA also indicated that extra
individual simulator training of perfusionists was needed for handling critical failures during use of these miniaturized
bypass systems.
FIGURE 2.31. Maquet minimal extracorporeal circulation system (MECC). The system includes venous air bubble
detection and venous bubble trap, a single integral pump (providing both kinetic-assisted venous drainage and arterial
blood propulsion), and quadrox oxygenator. (Kaplan JA, Reich DL, Savino JS, et al. Kaplan’s cardiac anesthesia. 6th ed.
Philadelphia, PA: Elsevier, 2011 [provided by Maquet Cardiovascular, Wayne, NJ]; used with permission.)
FIGURE 2.32. The Medtronic “Resting Heart” mini-bypass system includes a centrifugal pump (that provides both
kinetic-assisted drainage and propulsion of blood to the patient), venous air detection and evacuation system, a
membrane oxygenator, and arterial-line filter. (Kaplan JA, Reich DL, Savino JS, et al. Kaplan’s cardiac anesthesia. 6th
ed. Philadelphia, PA: Elsevier, 2011 [provided by Medtronic Cardiopulmonary, Minneapolis, MN], used with permission.)
In response to these concerns, various manufacturers have developed new, sophisticated air elimination systems and
some groups have added sensitive bubble detectors into their systems. The use of these systems requires that the
surgeon take care to avoid air entrainment from around the venous cannula purse-string (usually by adding an extra tie
around the atrial appendage), and increased attentiveness by the perfusionists. Mueller et al. (521) demonstrated
“excellent air filtering capacity” of the Cardiovention device (CORx) to boluses of 5 to 20 mL of air in vitro, and in a small
clinical study, Perthel et al. (19) found fewer microbubbles in the venous and arterial lines and middle cerebral arteries
with the MECC system compared with a conventional circuit in a cohort study of 10 patients, each undergoing CABG.
However, these authors placed an additional ligature on the right atrium around the venous cannula in the MECC group,
but not in
P.76
the conventional circuit group. These authors also noted that while the volume of air did not increase, the number of
bubbles did increase as the blood passed through the MECC circuit, suggesting that the centrifugal pump may
fractionate the air into a higher number of smaller bubbles, the clinical significance of which is unknown.
Other limitations of miniaturized circuits include the lack of a reservoir to handle excess venous return and to permit
immediate volume infusion when needed, the lack of a heat exchanger, the need to use a separate cell processing
system when salvage of cardiotomy suction is deemed necessary, and increased cost. The first two limitations place an
added burden on anesthesiologists to be prepared to handle intravascular volume and temperature homeostasis. Some
teams have added separate venous and cardiotomy reservoirs, heat exchangers, and arterial-line filters to overcome
some of these limitations, but of course these negate some of the reputed benefits of the minimal systems. Another
concern is the adaptability to unanticipated surgical needs or complications, which would require the use of a
conventional ECC. Whether the potential benefits of minimal systems will justify the inconvenience, limitations, cost, and
potential risk remains to be clarified.
In 2009, Ranucci and Castelvecchio (522) reviewed the evidence (7 observational studies, 9 RCTs) supporting the use
of mini CPB devices and concluded that there was strong evidence that their use reduced hemodilution and transfusion
needs but opined that other benefits are not well established, that their use raises safety issues, requires expertise and a
long learning curve and increases cost.
Harling et al. (523) reported the largest meta-analysis including 29 RCTs comparing outcome with use of minimized
extracorporeal circuits (“MECC”) compared to conventional circuits in 2,355 patients undergoing mainly isolated CABG
(23 studies) (4 studies involved isolated AVR and 2 included both CABG and AVR procedures). Fourteen studies used
the Jostra MECC System, and three each the CorX, Sorin Synergy, the Terumo ROC Safe Hybrid, and Medtronic
Resting Heart System. Thirteen studies randomized fewer than 50 patients while 7 included 100 to 400 patients. This
analysis found a statistically significant decrease in mean blood loss (average 131 mL less (results reported in 12
studies), percent transfused (10 studies) and incidence of arrhythmias (9 studies). There were no statistically significant
differences in 24-hour chest drainage (6 studies), units of blood products administered (7 studies) reoperation for
bleeding (7 studies), duration of ventilation (14 studies), or length of stay in ICU (13 studies) or in hospital (11 studies),
nor in incidence of myocardial infarction (12 studies), renal failure (7 studies), CVA (13 studies), neurocognitive changes
(6 studies) or 30 day mortality (19 studies). Two earlier and smaller meta-analyses found a decrease in neurologic
damage (524) or stroke rate (barely significant with 95% CI of OR ranging from 0.06 to 1.00) (525) with use of MECC.
Harling et al. (523) concluded that their meta-analysis dispels the safety concerns about MECC (with which we do not
necessarily agree because most were under-powered to evaluate safety), but they suggested that further large RCTs
are required to confirm these observations.
Harling and colleagues (526) also reviewed the use of miniature extracorporeal circulation (MECC) for CABG as
compared to off-pump CABG (OPCAB) surgery including two RCTs, four prospective and two retrospective case control
studies. They concluded that these two approaches produced comparable results in terms of mortality, length of stay,
neurologic outcome, blood loss, and transfusion requirements and that both were superior to conventional CPB
regarding blood loss and transfusion requirement. However, they emphasized that more large RCTs looking not only at
short-term end points but also at long-term outcomes were needed. Since that review, Formica et al. (527) reported
results in a small (19-22 in each group) RCT comparing CABG using MECC with standard CPB for CABG and OPCAB.
MECC and OPCAB were associated with a lesser inflammatory response, but there were no differences in other
outcomes, including bleeding and blood transfusion.
One evidence-based guideline advocated decreasing surface area and use of biocompatible surface-modified circuits
(Class IIa, level of evidence B) and reducing hemodilution (Class I, level of evidence A) (both features of closed
miniaturized circuits) (97). The recent ATS/SCA blood management guideline states that mini-circuits (miniaturized CPB
circuits) reduce hemodilution and are indicated for blood conservation (Class I, level of evidence A) (286), while the
recent ACCF/AHA CABG guidelines opined that “it is uncertain (if use of closed mini-circuits) have a discernible effect of
outcomes after CABG” (98). Warren et al. (287) reported that only 20% of perfusion groups in Great Britain and Ireland
used minimal extracorporeal circulation systems (“Mini” bypass) in 2007.
Curtis et al. (528) provided an optimistic review of the potential role of mini extracorporeal circuits (MECC) for cardiac
surgery. They opined that they have an acceptable safety profile but that there were insufficient data to adapt this as a
standard of care. Baikoussis and colleagues (529) are convinced that MECCs represent a promising advance in CPB.
More conservative teams will employ other methods, such as reducing the prime volume of their conventional circuit and
utilizing autologous priming techniques to avoid hemodilution. In so doing, the patient benefits from the closed
miniaturized systems could prove to be small or nonexistent. In order for these systems to realize widespread use, more
teams will need to become adept in their technical management and further studies will need to better substantiate the
benefit. However, as the early adopters gain more experience and the technical challenges are overcome, use of “mini”
systems could become the standard (R Groom, Personal communication, 2007).
P.77
TABLE 2.15. Monitors, safety devices, and emergency supplies and equipment
Monitors
1. Pressure monitoring of the arterial line with audible and visual alarms. (AmSECT 2013 Standard 6.1 and 7.2
(7))
2. Pressure monitoring of the cardioplegia delivery system (AmSECT 2013 Standard 6.1 (7))
3. Pressure monitoring of venous reservoir when augmented venous drainage is used (AmSECT 2013 Standard
6.1 (7))
4. Level sensor in hard-shell venous reservoir with audible and visual alarms (AmSECT 2013 Standard 6.3 (7))
5. Use of low-level sensors on soft-shell reservoirs (AmSECT 2013 Guideline #6.1 (7))
6. Bubble/air detector with audible and visual alarms. and servo-regulated to control the arterial pump or allow
interruption of arterial flow (AmSECT 2013 Standard 6.2 (7))
7. In-line venous oxygen saturation (AmSECT 2013 Standard 7.10 (7)) and/or arterial oxygen saturation or PO2
monitor (AmSECT 2013 Guideline 7.2 (7)), ± in-line monitors for other gases, electrolytes, glucose, lactate,
and hematocrit/hemoglobin
8. Temperature of blood coming out of oxygenator (and going into the patient) (AmSECT 2013 Standard 6.4 and
7.5 (7))
9. Temperature of water going to the heat exchangers (AmSECT 2013 Standard 7.5 (7))
10. Temperature of cardioplegia solution (AmSECT 2013 Standard 7.5 (7))
11. Temperature of venous blood coming from the patient. (AmSECT 2013 Standard 7.5 (7))
12. Oxygen analyzer on gas going to the oxygenator (AmSECT 2013 Standard 7.8 (7))
13. Arterial flow going into the patient (AmSECT 2013 Guideline 7.6 (7))
14. Pressure in gas line going to the oxygenator
15. Analyze expired gas coming out of the oxygenator for concentrations of carbon dioxide, volatile anesthetic,
and oxygen
16. Pressure gradient across membrane oxygenator
17. Use of echocardiography and epiaortic vascular ultrasound to assess cannulation of decompression of left
ventricle
Safety devices
1. High arterial-line pressure alarm with audible and visual alarms and servo-regulated to control the arterial
pump or allow interruption of arterial flow (AmSECT 2013 Standard 6.1 (7))
2. High cardioplegia delivery line pressure alarm with audible and visual alarms and servo-regulated to control
the cardioplegia delivery pump or allow interruption of cardioplegia flow (AmSECT 2013 Standard 6.1 (7))
3. Low level in venous reservoir alarm with audible and visual alarms, and servo-regulated to control the arterial
pump or allow interruption of arterial flow (AmSECT 2013 Standard 6.3 (7))
4. Air/Bubble detector alarm on line coming out of the oxygenator with audible and visual alarms and servo-
regulated to control the arterial pump or allow interruption of arterial flow (AmSECT 2013 Standard 6.2 (7))
5. May also have air/bubble detector alarm on the venous line coming out of the patient
6. One-way check valves in the arterial line, cardiac vents, and arterial-line filter/bubble trap purge line (The
latter is a AmSECT 2013 Standard 6.6 (7))
7. A method to avoid retrograde flow when a centrifugal pump is used (e.g., one-way flow valve, or hard-stop
prevent accidental reduction of pump speed, or electronically activated arterial-line clamp, or low-speed visual
and audible alarm) (AmSECT 2013 Standard 6.7 (7))
8. Arterial-line filter (AmSECT 2013 Standard 6.5 (7))
9. Bypass line around the arterial-line filter/bubble trap
10. Purge line off of the arterial-line filter/bubble trap which goes to the venous reservoir
11. Bypass line around the oxygenator
Emergency supplies and equipment
1. Battery backup for heart-lung machine including for the pumps and monitors (AmSECT 2013 Standard 6.11
(7))
2. Portable lighting and flashlights
3. Backup oxygen supply (cylinders with regulators) (AmSECT 2013 Standard 6.10 (7))
4. Hand cranks to drive the arterial and other pumps (AmSECT 2013 Standard 6.9 (7))
5. Spare oxygenator and other essential perfusion supplies readily available (AmSECT 2013 Standard 14.4 (7))
Source: AmSECT Standard for Perfusion Practice 2013 (Baker RA, Bronson SL, Dickinson TA, et al;
International Consortium for Evidence-Based Perfusion for the American Society of ExtraCorporeal Technology.
Report from AmSECT’s International Consortium for Evidence-Based Perfusion: American Society of
Extracorporeal Technology Standards and Guidelines for Perfusion Practice: 2013. J Extra Corpor Technol
2013;45:156-166.)
P.78
MONITORING AND SAFETY EQUIPMENT
Overall monitoring of the patient and the safe conduct of CPB are covered in other chapters. This discussion focuses on
the ancillary devices used to monitor CPB circuit performance. Lists of monitors, safety devices on the extracorporeal
circuit, and emergency CPB equipment and supplies that should be used or available are summarized in Table 2.15.
Most, but not all, of these recommendations are considered the standard of care.
The use of echocardiography (epiaortic and TEE) during cardiac surgery has become ubiquitous but its use is mainly
advocated in identifying pathology and assessing results of surgical procedures. However, its use can also be valuable
in guiding cannulation and the conduct of CPB, which is frequently overlooked.
In addition to its role in evaluating the ascending aorta before arterial cannulation, TEE is accurate in detecting
atherosclerosis in the descending aorta, which might discourage the use of femoral artery cannulation. It can also detect
clots or tumors in the left atrium, left atrial appendage, or left ventricle, and in the right-sided chambers, which could
influence venous cannulation and left-sided venting. Detection of a patent foramen ovale using two-dimensional images,
color-flow Doppler, and agitated saline echocontrast (530) may anticipate a source of venous air if the left heart is to be
opened, and the risk of paradoxical systemic air embolization if air enters the right heart. Detection of a PDA may warn of
or explain excessive return of blood to the left heart during CPB (473). Evaluations of the degree of aortic regurgitation
and the presence of a dilated coronary sinus impact the administration of antegrade and retrograde cardioplegia. TEE
may diagnose a persistent LSVC, which has an obvious impact on venous cannulation and administration of retrograde
cardioplegia.
During introduction of various cannulas, TEE can evaluate the positioning of peripherally introduced systemic venous
cannulas, long arterial cannulas introduced into ascending aorta, retrograde coronary sinus cannulas, and left-sided
venting cannulas. This is particularly helpful when the surgeon cannot directly inspect or palpate the heart due to limited
access or adhesions. Use of TEE is essential to the placement of various cannulas during port-access surgery and is
helpful in proper placement and assessing proper function of intra-aortic balloon pumps, especially when they are placed
antegrade through the ascending aorta.
During bypass, TEE also can be used to assess the degree of left ventricular distension and decompression and assist
with differential diagnosis of ascending aortic hematoma and aortic dissection. This is particularly important during
femoral artery cannulation for systemic perfusion. TEE may also help detect malperfusion during surgery for dissecting
aortic aneurysms. During partial left heart bypass (femoral vein to femoral artery and left atrium to distal aorta or femoral
artery), TEE can be helpful in assessing the balance of flow between the right and left heart and blood volume
regulation. Finally, TEE is useful in detecting intra-cardiac air and assessing adequacy of de-airing after cardiac surgery.
OTHER TOPICS
Surface Coatings
Various coatings have been applied to all of the foreign surfaces of the circuit to improve biocompatibility in an effort to
attenuate the inflammatory response and adverse hematologic effects at the interface between the foreign surfaces and
the circulating blood (”pacify”), and reduce heparin requirements. “Although not definitively proven, attenuation of the
inflammatory and coagulation pathways should translate into decreased postoperative morbidity directly related to
platelet dysfunction, bleeding complications and end organ damage” (5). This approach began with the introduction of
benzalkonium-heparin-bonded shunts by Gott in the 1960s. Other methods to bond heparin to CPB circuits (e.g.,
Carmeda and Duraflo) introduced in the 1980s have been thoroughly studied. They do seem to reduce inflammation, and
may reduce the minimum safe level of heparinization, although the latter is debatable, but benefits in clinically significant
outcome parameters have been more difficult to demonstrate (see below). Several new surface-modification methods
have been introduced commercially [e.g., Trillium [Medtronic], SMA [surface-modifying additive], polymethoxy-
ethylacrylate [PMEA] X Coating [Terumo Cardiovascular], SMART [SMA Treated] [Sorin Biomedical], P.H.I.S.I.O.
Phosphorylcholine [Sorin Biomedica], Safeline synthetic immobilized albumin treatment [Maquet], Corline heparin
surface, Bioline heparin coating [Jostra], and GBS Coating [hyaluronan-based heparin bonding, Gish Biomedical Inc,
California]), with only a modest amount of data supporting their benefits and with little side-by-side comparison to the
older heparin-based surface coatings (531,532).
In vitro and in vivo studies of these surfaces demonstrated reductions in coagulation and systemic inflammatory
processes. Some of the numerous clinical studies that have compared the effectiveness of heparin-treated surfaces to
non-heparin-coated surfaces have been reviewed by Murphy and colleagues (5). They state that most investigations
have shown evidence of reduced platelet activation and attenuation of inflammation, and some have reported
improvement in clinical outcomes (bleeding and transfusions, pulmonary function and cognitive outcomes). (See their
paper (5) for references.) These authors go on to state that “unfortunately most of the studies are small and differ
substantially in regards to anticoagulation management with heparin, the use of a partially coated or completely coated
circuit, the method by which cardiotomy blood was managed, type of heparin coating, and variations in measured
endpoints. The heterogeneity of the randomized trials related to heparin coatings confounds
P.79
the use of meta-analysis as a method of summarizing the effectiveness of these circuits” (5).
In 1999, Stammers and colleagues (533) published a quantitative analysis of 26 prospective, randomized trials
comparing heparin-coated circuits (HCC, consisting of Duraflo II or Carmeda coating techniques) and non-HCC in
patients undergoing coronary artery bypass grafting or valvular surgery which included 1,515 patients. Statistically
significant benefits (using weighted means) of HCC were found in postoperative blood loss, time in the ICU, end-bypass
C3a concentrations, time to extubation, end-bypass lactoferrin and platelet count, but not in postoperative chest tube
drainage, red blood cell transfusions, and end-bypass plasma thrombin-antithrombin complex, D-dimer, and b-
thromboglobulin concentrations. Data comparing the use of coated to uncoated cardiotomy reservoirs failed to
demonstrate a benefit to heparin coating. Several immunological variables were ameliorated when Carmeda HCC were
utilized, although data were insufficient to perform a cost-benefit analysis. In a small RCT of 30 patients in each group,
Nuttall et al. (534) noted a brief improvement in platelet function tests but no difference in chest tube drainage or amount
of blood transfusion with use of a Trillium-coated versus an uncoated circuit.
In a 2007 systematic review and meta-analysis of 46 RCTs comparing heparin-bonded circuits (HBC) with non-HBC in
3,434 patients, Mangoush et al. (535) found no decrease in 24-hour chest drainage (7 studies) or amount of blood
products transfused (15 studies) but did find a decrease in total chest drainage (164 mL, 13 studies), percent of patients
receiving RBCs (20% decrease, OR 0.6, 22 studies), and need for re-sternotomy (40% decrease OR 0.6, 17 studies) in
the HBC groups. They also found a modest decrease in duration of mechanical ventilation (1.3 hours less, 17 studies),
ICU stay (9 hours less, 12 studies) and hospital stay (0.5 fewer days, 9 studies) with use of HBC, but no effect on
mortality (13 studies), stroke (13 studies), acute myocardial infarction (10 studies), atrial fibrillation (8 studies), or wound
infection (4 studies) but a decrease in the composite endpoint of adverse events which included need for re-sternotomy
(OR 0.6, 25 studies) in the HBC groups. The authors concluded that heparin-coated circuits appear to confer a benefit.
However, they emphasized the small size of many of the included studies (nearly a half included less than 30 patients,
and less than 25% included more than 100 patients), the presence of much heterogeneity between the studies, the lack
of data on cost-benefit, and that mainly the studies were limited to nonemergent, low-risk patients rather than high-risk
patients, in which clinically relevant end points such as death and stroke would be more prevalent. In a relatively small
(50 patients in each group) multicenter (4) study, Gunaydin and colleagues (536) compared use of heparin-bonded (with
hyaluronan) circuits to noncoated circuits in patients undergoing reoperative CABG. They reported better preservation of
platelet count, and lower IL-2 and C3a levels, shorter intubation time (5 hours less) and postoperative chest drainage
(280 mL less) and lower incidence of arrhythmias (10% vs. 24%) in the coated circuit patients but no difference in
transfusion, inotrope use, ICU stay, and hospital mortality.
In the latest systematic review of 12 RCTs published between 1995 and 2010 comparing various coated circuits (3
Trillium, 2 Duraflo II, 2 Bioline, and 1 hyaluronan based, and 3 other “HBC”), Mahmood and colleagues (537) concluded
that coated circuits decrease blood loss, reoperation, time on ventilator, and length of stay in ICU and hospital. Use of
coated circuits also was associated with improved platelet preservation, decreased activation of WBCs and complement,
and decreased proinflammatory cytokine production. The authors concluded that various coatings have comparable
biocompatibility, and that the benefits of use of coated circuits outweigh their increased cost. However they did not
display their meta-analyses, and our review of the data they did present did not seem to support their conclusions. Three
of the studies only examined effects of blood activation on inflammation, and of the remaining nine, five studied fewer
than 91 patients. Although some studies reported less blood drainage (4 of 9), less blood transfusion (2 of 8), shorter
length of intubation (2 of 7), and/or shorter ICU stay (1 of 4) with use of coated circuits, the majority did not. Two of three
studies did report shorter hospital stay (average 1 day). In their review Apostolakis et al. (468) concluded that the use of
heparin-coated circuits did not reduce lung injury associated with CPB. Whether the use of heparin-coated circuits
permits a reduction in heparin administration during CPB remains unresolved (4).
The 2011 STS/SCA blood conservation evidence-based practice guidelines states that use of biocompatible CPB
circuits may be considered as part of a program for blood conservation (Class IIb, level of evidence A) (286). Another
evidence-based recommendation on perfusion practice concluded that “reduction of circuit surface and the use of
biocompatible surface-modified circuits might be useful—effective in reducing the systemic inflammatory response (Class
IIa-Level of Evidence B)” (97). However, in their 2007 survey of perfusion groups’ practices in Great Britain and Ireland,
Warren et al. (287) found that 62% did not use heparin-bonded circuits while 5% always used tip-to-tip coated circuits
and 10% always used some heparin-coated components.
Circuits for Pediatric CPB

Circuits for pediatric CPB are discussed in Chapter 28.
CPB Consoles
The current manufacturers of heart-lung machine consoles in the Western world include Maquet (Jostra HL20 and HL30
[the latter is not available in USA]), Maquet Cardiovascular LLC (Wayne, NJ), Medtronic (Century HLM) (Medtronic,
Minneapolis, MN), Terumo Medical Corporation (System 1) (Somerset, NJ), and the Sorin Group (S-3 and S-5)
P.80
(Milan, Italy, and Arvada, CO). These modern consoles feature an uninterruptible power supply (i.e., battery backup
which when fully charged is designed to last >45 minutes), movable/replaceable modular single and double-roller pump
heads, the ability to provide pulsatile arterial flow, centrifugal arterial pumps, cardioplegia delivery systems, gas
blenders, built-in safety systems (e.g., level control, bubble detection, and arterial and cardioplegia delivery line pressure
monitors, all with servo-connection and control of the respective pumps), mast-mounted control panels, and data
management systems.
FIGURE 2.33. The Orpheus hydraulic simulator of cardiopulmonary bypass. The first commercially available system is a
computer-controlled hydraulic model of human circulation. ECG, electrocardiograph; LA, left atrium; RA, right atrium.
(Figure 2 in Morris RW, Pybus DA. “Orpheus” cardiopulmonary bypass simulation system. J Extra Corpor Technol
2007;39:228-233, used with permission.)
Computer Control of CPB

Computerized control of CPB has been described and is used clinically (538), but it is not a commonly used practice.
The potential for automatic control of CPB was discussed by Kurusz (539). Examples include use to regulate blood
gases (540) and control of blood level in the venous reservoir (541).
Simulators for Training and Competency Testing

As in other fields of medicine and high-tech industries, development of simulators and use of simulation has expanded
into the practice of CPB (542). Simulation can play an important role in introductory education, maintenance of core
skills, and practice of emergency situation responses of and by perfusionists. It has also found a role in developing team
resource management and multidisciplinary team education. Various low- and high-fidelity simulators have been
introduced for these purposes (543,544,545,546,547,548,549,550,551). Powers and Miller (552) used the Manbit High-
Fidelity CPB Simulator to study perfusionists’ strategies in managing routine and failure-mode scenarios using work
domain analysis (WDA).
A number are hybrid systems that interface with the “Orpheus” simulator to a standard clinical CPB machine/console.
The Orpheus CPB simulation system (Orpheus, Ulco Technologies, Marrickville, New South Wales, Australia), as
introduced by Morris and Pybus in 2007 (545) (JECT 2007), features a hydraulic simulator (see Fig. 2.33) which
functions as the patient and is controlled by a computer, which is mated to any conventional heart-lung machine. It
generates hemodynamic, ECG and temperature data that can be displayed on a clinical physiologic monitoring system.
This system can simulate both routine CPB and patient emergencies (see Table 2.16) and can be used to train basic
skills in operating a heart-lung machine as well as for certification and accreditation of perfusionists, practice of crisis and
team management protocols and evaluation of new or existing perfusion equipment
P.81
and techniques (545). Others have described the use of the Orpheus system in their simulation facilities (553,554).
Fouilloux and colleagues have advocated the advantages of an animal (pig) simulator over high-fidelity simulators (more
realistic and reliable, easily reproducible and cheap) (555) and have demonstrated their use in training cardiac surgeons
(556) and of cardiac surgery teams (555).
TABLE 2.16. Conditions that can be simulated by the Orpheus System
Routine bypass Patient emergencies
Initiation of bypass Blood loss
Weaning from bypass Left ventricular dysfunction
Cooling and rewarming Cardiac arrhythmias
Use of centrifugal and roller pumps Air embolism
Variations in vascular resistance Anaphylaxis
Use of vasoactive drugs Malignant hyperthermia
Variations in blood coagulation Protamine reaction
Changes in oxygen consumption Transfusion reaction
Administration of cardioplegia Drug errors
CO2 insufflation of the operative site Failure to wean
Equipment malfunctions
Aortic cannula obstruction Heat exchanger failure
Aortic cannula displacement Patient monitor failure
Venous air entrainment Circuit leaks

Venous cannula obstruction Oxygenator failure
Oxygen supply failure HLM power supply failure
Aortic cannula obstruction Heat exchanger failure
HLM, heart-lung machine.
Source: From Table 1 in Morris RW, Pybus DA. “Orpheus” cardiopulmonary bypass simulation system. J Extra
Corpor Technol 2007;39(4):228-233.
The benefits of simulation training in CPB have been demonstrated by a number of groups
(547,553,554,555,556,557,558,559,560,561,562). The use of simulators and simulation training have been found to
speed up students’ progress in conducting clinical CPB and also to expose them to rare adverse events. Such training
not only teaches proper technique but also lessens the stress when problems occur during clinical CPB. Simulators have
also been used for proficiency checking and continuing education of practicing perfusionists and also for exposing and
orienting nonperfusionists (e.g., cardiac surgeons and anesthesiologists) to what is involved with conducting CPB).
Periodic performance of drills involving the entire team (i.e., perfusionists, surgeons, anesthesiologists and nurses) to
simulate CPB crisis may be conducted in any OR setting using a mock setup and scripted scenarios (4).
SUMMARY
Robert Groom, the editor of JECT, has succinctly summarized the issue of the selection of equipment and
techniques for CPB as follows: “It is important to be careful and thorough regarding device selection to support
cardiac surgery patients. It is of equal importance to have an understanding of the context in which they are used
and to develop appropriate guidelines locally that allow for their use in a way that is safe and affords the best
possible outcome for heart surgery patients. Device selection requires careful consideration of a number of factors
including, cost, utility, safety, and measurable benefit to the patient. The quality of care depends not only on the
devices selected but also the fine details of the processes of care related to device use. Some device design
characteristics may make devices easier to use however if they are not used carefully the patient may be unwittingly
subjected to increased risk of injury. Further understanding of the variation that occurs during the use of CPB
devices and the underlying precursors to patient injury are important areas for future study that will lead to
substantial improvements in the care of patients requiring CPB support.” (Robert Groom, personal communication,
July 2007).
KEY Points
Major components of the extracorporeal circuit include the membrane oxygenator (for gas exchange) with
integral heat exchanger (for temperature regulation) and the systemic blood flow pump (roller or centrifugal
type) for whole-body perfusion.
Systemic venous drainage is provided either by gravity siphonage through large-bore cannulas inserted into
the RA/IVC or SVC and IVC or (more commonly) augmented by regulated negative pressure provided either
by vacuum or by kinetic (mechanical pump) assistance.
Cavoatrial venous cannulation is simpler than separate cannulation of the superior and inferior vena cavae
and provides good drainage of both cavae and the right heart.
Use of augmented venous drainage (kinetic or vacuum) requires proper cannula placement and careful
regulation of the degree of vacuum applied to the venous line, and poses the risk of systemic air
embolization.
Because air that enters the venous drainage system can pass through the extracorporeal circuit and enter
the systemic arterial system, air in the venous cannulas must be eliminated before the start of CPB and
minimized during CPB.
P.82
To minimize blood trauma, arterial cannulas should be chosen to achieve a pressure drop of less than 100
mmHg at full CPB flow.
Use of either long or diffusion-tipped arterial cannulas may minimize the risk of dislodgment of atheroma in
the ascending or transverse aorta.
The risk of complications with femoral arterial cannulation (especially arterial dissection) is much higher than
with ascending aortic cannulation.
Cannulation of the axillary-subclavian artery, or innominate artery, or through the left ventricle apex should
be considered in special circumstances when cannulation of the ascending aorta is not feasible or desirable.
Dissection of the aorta can occur with all sites of arterial cannulation, and must be promptly recognized and
surgically corrected to decrease the risk of patient morbidity or mortality. Ultrasound (echo) imaging (TEE
and epiaortic) facilitates diagnosis.
Blood pumps commonly used in CPB are of two principal types: Displacement (roller) pumps and Rotary
(centrifugal) pumps.
Roller pumps require occlusion adjustment (barely nonocclusive) for optimum function and avoidance of
hemolysis and activation of leukocytes and platelets. Flow is determined by pump head tubing diameter,
roller RPM, and length of tubing in contact with the rollers.
Roller pumps are insensitive to afterload, can cause tubing rupture if clamped, and can pump massive
amounts of air. Tubing spallation produced by breakdown of the tubing due to roller contact can produce
significant amounts of particulate microemboli.
The most commonly used rotary pumps are centrifugal. Flow is not directly related to RPM and therefore
must be determined by an in-line flowmeter. They are very dependent on afterload and if run at low rates or
turned off will permit blood to flow backward out of the patient and into the ECC unless the arterial line is
occluded or guarded by a one-way valve.
Both roller and centrifugal type pumps are used, without any convincing evidence that one is superior to the
other.
Despite theoretical advantages, evidence that pulsatile flow during CPB is superior remains unconvincing,
and it is rarely used in North America.
Hollow fiber membrane oxygenators have virtually replaced all other types of artificial oxygenators for CPB.
Tubing sizes and lengths and connectors should be chosen to minimize blood velocity and priming volume.
CPB reservoirs may be either hard-shell (“open”) or soft collapsible (“closed”) types, but there appears to
be no major advantage of one over the other in terms of patient outcome. Vacuum-assisted venous return
requires the use of a hard-shell type reservoir.
Cardiotomy suction is a major source of microemboli and activated blood (humoral and cellular). Minimizing
the need for, and amount of, field suction (e.g., compulsive hemostasis), substitution by cell salvage and
washing devices, and/or special filtration of salvaged blood should be considered.
Several different systems are available for administering antegrade and retrograde cardioplegia.
Hemoconcentrators can be used during and after CPB to remove plasma water and raise the hematocrit,
and may be more cost effective than cell salvage and washing devices.
Maintaining adequate decompression of the right and left ventricles demands vigilance, and may require
special cannulations with their associated risks.
The use of conventional microfilters in the arterial line is a nearly ubiquitous practice with strong rationale,
although evidence of their clinical benefit with the current practice of CPB is limited.
The need and benefits of leukocyte depletion filters at various times and in various locations remain
unresolved, but the evidence supporting their use is most convincing for cardioplegia delivery systems.
There is great interest and movement toward the development and use of miniaturized integrated circuits.
Although these promise benefits, they also pose hazards, which compel adoption with caution.
Although nearly ubiquitous, the clinical benefits of surface modification systems (e.g., heparin bonding) have
not been well proven.
Special monitors, safety devices on the heart-lung machine, and emergency equipment must be employed
to assure safe conduct of CPB.
TEE (and epiaortic scanning) is a useful adjunct to CPB for assessing the aorta before cannulation, for
cannula placement, for determining cardiac and valvular function, and for evaluating the effectiveness of
cardiac decompression and de-airing maneuvers.
P.83
REFERENCES
1. Hessel EA II. Cardiopulmonary bypass equipment. In: Estafanous FG, Barash PG, Reves JG, eds. Cardiac
anesthesia. Principles and clinical practice. 2nd ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2001:335-386.
2. Hessel EA II, Edmunds H Jr. Perfusion systems. In: Cohn L, Edmunds LH Jr, eds. Cardiac surgery in the adult.
2nd ed. New York, NY: McGraw-Hill, 2003:317-337.
3. Hessel EA II, Murphy GS, Groom RC, Ghansah JN. Cardiopulmonary bypass: equipment, circuits and
pathophysiology. In: Hensley FA Jr, Martin DE, Gravlee GP, eds. A practical approach to cardiac anesthesia. 5th ed.
Philadelphia, PA: Lippincott Williams & Wilkins, 2013:587-629.
4. Groom RC, Stammers AH. Extracorporeal devices and related technologies. In: Kaplan JA, Reich DL, Savino J,
eds. Kaplan’s cardiac anesthesia. 6th ed. St. Louis: Elsevier/Saunders, 2011.
5. Murphy GS, Hessel EA, Groom RC. Optimal perfusion during cardiopulmonary bypass: an evidence-based
approach. Anesth Analg 2009; 108:1394-1417.
6. Hessel EA 2nd. A brief history of cardiopulmonary bypass. Semin Cardiothorac Vasc Anesth 2014;18:87-100.
7. Baker RA, Bronson SL, Dickinson TA, et al; International Consortium for Evidence-Based Perfusion for the
American Society of ExtraCorporeal Technology. Report from AmSECT’s International Consortium for Evidence-
Based Perfusion: American Society of Extracorporeal Technology Standards and Guidelines for Perfusion Practice:
2013. J Extra Corpor Technol 2013;45:156-166.
8. Peirce EC II. Extracorporeal circulation for open-heart surgery. Springfield, IL: Charles C Thomas Publisher, 1969.
9. Kirklin JW, Barratt-Boyes BG. Hypothermia, circulatory arrest, and cardiopulmonary bypass. In: Kirklin JW, Barratt-
Boyes BG, eds. Cardiac surgery. 2nd ed. New York, NY: Churchill Livingstone, 1993:61-127.
10. Shann K, Melnitchouk S. Advances in perfusion techniques: minimally invasive procedures. Semin Cardiothorac
Vasc Anesth 2014;18:146-152.
11. Delius RF, Montoya JP, Merz SJ, et al. A new method for describing the performance of cardiac surgery
cannulas. Ann Thorac Surg 1992;33:278-281.
12. Arom KV, Ellestad C, Grover FL, et al. Objective evaluation of the efficacy of various venous cannulas. J Thorac
Cardiovasc Surg 1981;81:464-469.
13. Bennett EV Jr, Fewel JG, Ybarra J, et al. Comparison of flow differences among venous cannulas. Ann Thorac
Surg 1983;36:59-65.
14. Rosenfeldt FL, Watson DA. Interference with local myocardial cooling by heat gain during aortic cross-clamping.
Ann Thorac Surg 1979;27:13-16.
15. Bennett EV Jr, Fewel JG, Grover FL, et al. Myocardial preservation: effect of venous drainage. Ann Thorac Surg
1983;36:132-142.
16. Lawrence DR, Desai JB. Forty-five degree, two-stage cannula: advantages over standard two-stage venous
cannula. Ann Thorac Surg 1997;63:253-254.
17. Taylor PC, Effler DB. Management of cannulation for cardiopulmonary bypass in patients with adult-acquired
heart disease. Surg Clin North Am 1975;55:1205-1215.
18. Stock UA, Muller T, Bienek R, et al. Deairing of the venous drainage in standard extracorporeal circulation results
in a profound reduction of arterial micro bubbles. Thorac Cardiovasc Surg 2006;54:39-34.
19. Perthel M, Kseibi S, Sagebiel F, et al. Comparison of conventional extracorporeal circulation and minimal
extracorporeal circulation with respect to microbubbles and microembolic signals. Perfusion 2005;20(6):329-333.
20. Groom RC, Likosky DS, Forest RJ, et al. A model for cardiopulmonary bypass redesign. Perfusion 2004;19:257-
261.
21. Groom RC. A systematic approach to the understanding and redesigning of cardiopulmonary bypass. Semin
Cardiothorac Vasc Anesth 2005;9:159-161.
22. Jones RE, Fitzgerald D, Cohn LH. Reoperative cardiac surgery using a new femoral venous right atrial cannula. J
Card Surg 1990;5:170-173.
23. Merin O, Silberman S, Brauner R, et al. Femoro-femoral bypass for repeat open-heart surgery. Perfusion
1998;13:455-459.
24. Westaby S. Extrathoracic cannulation for urgent cardiopulmonary bypass in cardiac tamponade: use of internal
jugular vein. J Cardiovasc Surg 1988;29:103-105.
25. Flege JB Jr, Wolf RK. Venous drainage to the heart-lung machine via the internal jugular vein. Ann Thorac Surg
1997;63:861.
26. Tevaearai HT, Mueller XM, Jegger D, et al. Venous drainage with a single peripheral bicaval cannula for less
invasive atrial septal defect repair. Ann Thorac Surg 2001;72:1772-1773.
27. Winter FS. Persistent left superior vena cava: survey of world literature and report of thirty additional cases.
Angiology 1954;5:90-132.
28. Harris AM, Shawkat S, Bailey JS. The use of an endotracheal tube for cannulation of left superior vena cava via
coronary sinus for repair of a sinus venosus atrial septal defect. Br Heart J 1987;58:676-677.
29. Choudhry AK, Conacher ID, Hilton CJ, et al. Persistent left superior vena cava. J Cardiothorac Anesth
1989;3:616-619.
30. Horrow JC, Lingaraju N. Unexpected persistent left superior vena cava: diagnostic clues during monitoring. J
Cardiothorac Anesth 1989;3:611-615.
31. Peltier J, Destrieus C, Desme J, et al. The persistent left superior vena cava: anatomical study, pathogenesis
and clinical considerations. Surg Radiol Anat 2006;28:206-210.
32. Hasel R, Barash PG. Dilated coronary sinus on prebypass echocardiography. J Cardiothorac Vasc Anesth
1996;10:430-435.
33. Shahian DM. Retrograde coronary sinus cardioplegia in the presence of persistent left superior vena cava. Ann
Thorac Surg 1992;54:1214-1215.
34. Yokota M, Kyoku I, Kitano M, et al. Atresia of the coronary sinus orifice: fatal outcome after intraoperative division
of the drainage left superior vena cava. J Thorac Cardiovasc Surg 1989;98:30-32.
35. Santoscoy R, Walters HL III, Ross RD, et al. Coronary sinus ostial atresia with persistent left superior vena cava.
36. Babka RM. A comparison of the use of venous pumping to gravity return of blood to the oxygenator during
cardioplegic arrest. Proc Am Acad Cardiovasc Perfus 1988;9:47-50.
37. Toomasian JM, McCarthy JP. Total extrathoracic cardiopulmonary support with kinetic assisted venous drainage:
experience in 50 patients. Perfusion 1998;13:137-143.
38. Taketani S, Sawa Y, Massai T, et al. A novel technique for cardiopulmonary bypass using vacuum system for
venous drainage with pressure relief value: an experimental study. Artif Organs 1998;22:337-341.
39. Darling E, Kaemmer D, Lawson S, et al. Experimental use of an ultra-low prime neonatal cardiopulmonary bypass
circuit utilizing vacuum-assisted venous drainage. J Extra Corpor Technol 1998;30:184-189.
40. Fried DW, Zombolas TL, Weiss SJ. Single pump mechanically aspirated venous drainage (SPMAVD) for cardiac
reoperation. Perfusion 1995;10:327-332.
41. Jones TJ, Deal DD, Vernon JC, Blackburn N, Stump DA. Does vacuum-assisted venous drainage increase
gaseous microemboli during cardiopulmonary bypass? Ann Thorac Surg 2002;74:2132-2137.
42. Jegger D, Tevaearai HT, Mueller XM, et al. Limitations using the vacuum-assist venous drainage technique
during cardiopulmonary bypass procedures. J Extra Corpor Technol 2003;35(3):207-211.
43. Bernstein EF, Gleason LR. Factors influencing hemolysis with roller pumps. Surgery 1967;61:432-442.
44. Indeglia RA, Shea MA, Varco RE, et al. Mechanical and biologic considerations in erythrocyte damage. Surgery
1967;114:126-138.
45. Gregoretti S. Suction-induced hemolysis at various vacuum pressures: implications for intraoperative blood
salvage. Transfusion 1996;36(1):57-60.
46. Mueller XM, Tevaearai HT, Horisberger J, et al. Vacuum assisted venous drainage does not increase trauma to
blood cells. ASAIO J 2001;47:651-654.
47. Willcox TW, Mitchell SJ, Gorman DF. Venous air in the bypass circuit: a source of arterial line emboli
exacerbated by vacuum-assisted drainage. Ann Thorac Surg 1999;68:1285-1289.
48. La Pietra A, Groggi EA, Pua BB, et al. Assisted venous drainage presents the risk of undetected air
microembolism. J Thorac Cardiovasc Surg 2000;120:856-863.
49. Jahangiri M, Rayner A, Keogh B, et al. Cerebrovascular accident after vacuum-assisted venous drainage in a
Fontan patient: a cautionary tale. Ann Thorac Surg 2001;72:1727-1728.
50. Willcox TW. Vacuum-assisted venous drainage: to air or not to air, that is the question. Has the bubble burst? J
Am Extra Corpor Technol 2002;34:24-28.
51. Almany DK, Sistino JJ. Laboratory evaluation of the limitations of positive pressure safety valves on hard-shell
venous reservoirs. J Extra Corpor Technol 2002;34:115-117.
52. Davila RM, Rawles T, Mack MJ. Venoarterial air embolus: a complication of vacuum-assisted venous drainage.
Ann Thorac Surg 2001;71:1369-1371.
53. Troianos CA. Transesophageal echocardiographic diagnosis of pulmonary artery catheter entrapment and
coiling. Anesthesiology 1993;79:602-604.
54. Ambesh SP, Singh SK, Dubey DK, et al. Inadvertent closure of the superior vena cava after decannulation: a
potentially catastrophic complication after termination of bypass [Letter]. J Cardiothorac Vasc Anesth 1998;12: 723-
724.
55. Brodman R, Siegel H, Lesser M, et al. A comparison of flow gradients across disposable arterial perfusion
cannulas. Ann Thorac Surg 1985;39:225-233.
P.84
56. Galletti PM, Brecher GA. Heart-lung bypass, principles and techniques of extracorporeal circulation. New York,
NY: Grune & Stratton, 1962:184-188.
57. Drews JA, Cleveland RJ, Nelson RJ. An approach to aortic cannulation with a caution on hemolysis associated
with angled cannulas. Rev Surg 1974;31:57-59.
58. Groom RC, Hill AG, Kuban B, et al. Aortic cannula velocimetry. Perfusion 1995;10:183-188.
59. Muehrcke DD, Cornhill JF, Thomas JD, et al. Flow characteristics of aortic cannulas. J Card Surg 1995;10:514-
519.
60. Ringgaard S, Madsen T, Pedersen EM, et al. Quantitative evaluation of flow patterns in perfusion cannulas by a
new magnetic resonance imaging method. Perfusion 1997;12:411-416.
61. Grooters RK, Thieman KC, Schneider RF, et al. Assessment of perfusion toward the aortic valve. Tex Heart Inst
J 2000;27:361-368.
62. Grooters RK, Ver Steeg DA, Stewart MJ, et al. Echocardiographic comparison of the standard end-hole cannula,
the soft-flow cannula, and the dispersion cannula during perfusion into the aortic arch. Ann Thorac Surg
2003;75:1919-1923.
63. Weinstein GS. Left hemispheric strokes in coronary surgery; implications for end-hole aortic cannulas. Ann
Thorac Surg 2001;71:128-132.
64. Gerdes A, Hanke T, Sievers H-H. Hydrodynamics of the new Medos aortic cannula. Perfusion 2002;17:217-220.
65. Scharfschwerdt M, Richter A, Boehmer K, et al. Improved hydrodynamics of a new aortic cannula with a novel tip
design. Perfusion 2004;19:193-197.
66. White JK, Jagannath A, Titus J, et al. Funnel-tipped aortic cannula for reduction of atheroemboli. Ann Thorac
Surg 2009;88(2):551-557.
67. Menon PG, Teslovich N, Chen CY, et al. Characterization of neonatal aortic cannula jet flow regimes for
improved cardiopulmonary bypass. J Biomech 2013;46(2):362-372.
67b. Benaroia M, Baker AJ, Mazer D, et al. Effect of aortic cannula characteristics and blood velocity on transcranial
doppler-detected microemboli during cardiopulmonary bypass. J Cardiothorac Vasc Anesth 1998;12:266-269.
68. Cook DJ, Orszulak TA, Zehr KJ, et al. Effectiveness of the Cobra aortic catheter for dual-temperature
management during adult cardiac surgery. J Thorac Cardiovasc Surg 2003;125(2):378-384.
69. Kaukuntla H, Walker A, Harrington D, et al. Differential brain and body temperature during cardiopulmonary
bypass—a randomized clinical study. Eur J Cardiothorac Surg 2004;26:571-579.
70. Cook DJ, Zehr KJ, Orszulak TA, et al. Reduction in brain embolization using the Aegis aortic cannula during
bypass in swine. Ann Thorac Surg 2002;74:825-829.
71. Reichenspurner H, Navia JA, Benny G, et al. Particulate embolic capture by an intra-aortic filter device during
cardiac surgery. J Thorac Cardiovasc Surg 2000;119:233-244.
72. Gerdes A, Hanke T, Sievers H-H. Hydrodynamics of the new Medos aortic cannula. Perfusion 2002;17:217-220.
73. Wimmer-Greinecker G; on behalf of the ICEM Study Group. Reduction of neurology complications by intra-aortic
filtration in patients undergoing combined intracardiac and CABG procedures. Eur J Cardiothorac Surg 2003;23:159-
164.
74. Banbury MK, Kouchoukos NT, Allen KB, et al. Emboli capture using the Embol-X intraortic filter in cardiac
surgery: a multicentered randomized trial of 1289 patients. Ann Thorac Surg 2003;76:508-515.
75. Horvath KA, Berry GJ; ICEM investigators. The incidence of emboli during cardiac surgery: a histopathologic
analysis of 2297 patients. Heart Surg Forum 2005;8:E161-E166.
76. Christenson JT, Vala DL, Licker M, et al. Intra-aortic filtration capturing particulate emboli during aortic cross-
clamping. Tex Heart Inst J 2005;32:515-521.
77. Gerriets T, Schwarz N, Sammer G, et al. Protecting the brain from gaseous and solid micro-emboli during
coronary artery bypass grafting: a randomized controlled trial. Eur Heart J 2010;31:360-368.
78. Hogue CW Jr, Palin CA, Arrowsmith JE. Cardiopulmonary bypass management and neurologic outcomes: an
evidence-based appraisal of current practices. Anesth Analg 2006;103:21-37
79. Magner JB. Complications of aortic cannulation for open-heart surgery. Thorax 971;26:172-173.
80. Nunez LE, Bailey CP. A new method for systemic arterial perfusion in extracorporeal circulation. J Thorac
81. Taylor PC, Groves LK, Loop FD, et al. Cannulation of the ascending aorta for cardiopulmonary bypass. J Thorac
82. Davidson KG. Cannulation for cardiopulmonary bypass. In: Taylor KM, ed. Cardiopulmonary bypass: principles
and management. Baltimore, MD: Williams & Wilkins, 1987:55-89.
83. Blauth CI, Cosgrove DM, Webb BW, et al. Atheroembolism from the ascending aorta. J Thorac Cardiovasc Surg
1992;103:1104-1112.
84. Barbut D, Grassineau D, Lis E, et al. Posterior distribution of infarcts in strokes related to cardiac operation. Ann
Thorac Surg 1998;65: 1656-1659.
85. Beique FA, Joffe D, Tousignant G, et al. Echocardiographic-based assessment and management of
atherosclerotic disease of the thoracic aorta. J Cardiothorac Vasc Anesth 1998;12:206-220.
86. Murphy DA, Craver JM, Jones EL, et al. Recognition and management of ascending aortic dissection
complicating cardiac surgical operations. J Thorac Cardiovasc Surg 1983;85:247-256.
87. Davila-Roman VG, Kouchoukos NT, Schechtman KB, et al. Atherosclerosis of the ascending aorta is a predictor
of renal dysfunction after cardiac operations. J Thorac Cardiovasc Surg 1999;117:111-116.
88. Mills NL, Everson CT. Atherosclerosis of the ascending aorta and coronary artery bypass: pathology, clinical
correlates, and operative management. J Thorac Cardiovasc Surg 1991;102:546-553.
89. Ohteki H, Itoh T, Natsuaki M, et al. Intraoperative ultrasonic imaging of the ascending aorta in ischemic heart
disease. Ann Thorac Surg 1990;50:539-542.
90. Wareing TH, Davilla-Roman VG, Barzilai B, et al. Management of the severely atherosclerotic ascending aorta
during cardiac operations: a strategy for detection and treatment. J Thorac Cardiovasc Surg 1992;103:453-462.
91. Sylivris S, Calafiore P, Matalanis G, et al. The intraoperative assessment of ascending aortic atheroma: epiaortic
imaging is superior to both transesophageal and direct palpation. J Cardiothorac Vasc Anesth 1997;11:704-707
92. Davila-Roman V, Phillips K, Davila R, et al. Intraoperative transesophageal echocardiography and epiaortic
ultrasound for assessment of atherosclerosis of the thoracic aorta. J Am Coll Cardiol 1996;28:942-947.
93. Glas KE, Swaminathan M, Reeves ST, et al; Council for Intraoperative Echocardiography of the American
Society of Echocardiography; Society of Cardiovascular Anesthesiologists; Society of Thoracic Surgeons. Guidelines
for the performance of a comprehensive intraoperative epiaortic ultrasonographic examination: recommendations of
the American Society of Echocardiography and the Society of Cardiovascular Anesthesiologists; endorsed by the
Society of Thoracic Surgeons. Anesth Analg 2008;106(5):1376-1384.
94. Konstadt SN, Reich DL, Quintana C, et al. The ascending aorta: how much does transesophageal
echocardiography see? Anesth Analg 1994;78:240-244.
95. Konstadt SN, Reich DL, Kahn R, et al. Transesophageal echocardiography can be used to screen for ascending
aortic atherosclerosis. Anesth Analg 1995;81:225-228.
95b. Guzzetta NA, Lee E, Sadel SM, et al. Does the degree of atheromatous disease in the descending aorta
correlate with atheromatous disease in the ascending aorta? [abstract]. Anesth Analg 1995;80:SCA80.
96. Rokkos CF, Kouchoukos NT. Surgical management of the severely atherosclerotic ascending aorta during
cardiac operations. Semin Thorac Cardiovasc Surg 1998;10:240-246.
97. Shann KG, Likosky DS, Murkin JM, et al. An evidence-based review of the practice of cardiopulmonary bypass in
adults: a focus on neurologic injury, glycemic control, hemodilution, and the inflammatory response. J Thorac
98. Hillis LD, Smith PK, Anderson JL, et al; American College of Cardiology Foundation; American Heart Association
Task Force on Practice Guidelines; American Association for Thoracic Surgery; Society of Cardiovascular
Anesthesiologists; Society of Thoracic Surgeons. 2011 ACCF/AHA Guideline for Coronary Artery Bypass Graft
Surgery. A report of the American College of Cardiology Foundation/American Heart Association Task Force on
Practice Guidelines. Developed in collaboration with the American Association for Thoracic Surgery, Society of
Cardiovascular Anesthesiologists, and Society of Thoracic Surgeons. J Am Coll Cardiol 2011 6;58(24):e123-e210
99. Duda AM, Letwin LB, Sutter FP, et al. Does routine use of aortic ultrasonography decrease the stroke rate in
coronary artery bypass surgery? J Vasc Surg 1995;21:98-107.
100. Grossi EA, Kanchuger MS, Schwartz DS, et al. Effect of cannula length on aortic arch flow: protection of the
atheromatous aortic arch. Ann Thorac Surg 1995;59:710-712.
101. Ribakov GH, Katz ES, Galloway AC, et al. Surgical implications of transesophageal echocardiography to grade
atheromatous aortic arch. Ann Thorac Surg 1992;53:758-763.
P.85
102. Stern A, Tunick PA, Culliford AT, et al. Aortic arch endarterectomy increases the risk of stroke during heart
surgery in patients with protruding aortic arch atheromas [abstract # 1024]. Circulation 1997;96:I-185.
103. Stern A, Tunick PA, Culliford AT, et al. Protruding aortic arch atheromas: risk of stroke during heart surgery with
and without aortic arch endarterectomy. Am Heart J 1999;138:746-752.
104. Svensson LG, Sun J, Cruz HA, et al. Endarterectomy for calcified porcelain aorta associated with aortic value
stenosis. Ann Thorac Surg 1996;61: 149-152.
105. King RC, Kanithanon RC, Shockley KS, et al. Replacing the atherosclerotic ascending aorta is a high-risk
procedure. Ann Thorac Surg 1998;66:396-401.
106. Liddicoat JR, Doty JR, Stuart RS. Management of the atherosclerotic ascending aorta with endoaortic
occlusion. Ann Thorac Surg 1998;65:1133-1135.
107. Paul D, Hartman GS. Foley balloon occlusion of the atheromatous ascending aorta: the role of transesophageal
echocardiography. J Cardiothorac Vasc Anesth 1998;12:61-64.
108. Unal M, Konuralp C, Idiz M, et al. Novel approach aortic cannulation suturing: tangential suture technique. ANZ
J Surg 2005;75:897-900.
109. Barbut D, Lo YW, Hartman GS, et al. Aortic atheroma is related to outcome but not numbers of emboli during
coronary bypass. Ann Thorac Surg 1997;64:454-459.
110. Mullges W, Franke D, Reents W, et al. Reduced rate of microembolism by optimized aortic cannula position
does not influence early postoperative cognitive performance in CABG patients. Cerebrovasc Dis 2003;15:192-198.
111. DeBois WJ, Girardi LN, Lee LY, et al. Negative fluid displacement: an alternative method to assess patency of
arterial line cannulation. Perfusion 2003;18(1):67-70.
112. Magilligan DJ Jr, Eastland MW, Lell WA, et al. Decreased carotid flow with ascending aortic cannulation.
Circulation 1972;45(Suppl I):I-130-I-133.
113. Salerno TA, Lince DP, White DN, et al. Arch versus femoral artery perfusion during cardiopulmonary bypass. J
114. Kaufmann TA, Hormes M, Laumen M, et al. Flow distribution during cardiopulmonary bypass in dependency on
the outflow cannula positioning. Artif Organs 2009;33(11):988-992.
115. Tokuda Y, Song MH, Ueda Y, et al. Three-dimensional numerical simulation of blood flow in the aortic arch
during cardiopulmonary bypass. Eur J Cardiothorac Surg 2008;33(2):164-167.
116. Menon PG, Antaki JF, Undar A, Pekkan K. Aortic outflow cannula tip design and orientation impacts cerebral
perfusion during pediatric cardiopulmonary bypass procedures. Ann Biomed Eng 2013;41(12):2588-2602.
117. Still RJ, Hilgenberg AD, Akins CW, et al. Intraoperative aortic dissection. Ann Thorac Surg 1992;53:374-380.
118. Gott JP, Cohen CL, Jones EL. Management of ascending aortic dissections and aneurysms early and late
following cardiac operations. J Card Surg 1990; 5:2-13.
119. Ruchat P, Hurni M, Stumpe F, et al. Acute ascending aortic dissection complicating open heart surgery: cerebral
perfusion defines the outcome. Eur J Cardiothorac Surg 1998;14:449-452.
120. Aoyagi S, Tayama E, Masaru N, et al. Aortic dissections complicating open cardiac surgery: report of three
cases. Surg Today 2000;30:1022-1025.
121. Troianos CA, Savino JS, Weiss RL. Transesophageal echocardiographic diagnosis of aortic dissection during
cardiac surgery. Anesthesiology 1991;75: 149-153.
122. Varghese D, Riedel BJ, Fletcher SN. Successful repair of intraoperative aortic dissection detected by
transesophageal echocardiography. Ann Thorac Surg 2002;73:953-955.
123. Sullivan KL, Steiner RM, Smullens SN, et al. Pseudoaneurysm of the ascending aorta following cardiac surgery.
Chest 1998;93:138-143.
124. Razzouk A, Gundry S, Wang N, et al. Pseudoaneurysms of the aorta after cardiac surgery or chest trauma. Ann
Surg 1993;59:818-823.
125. Lees MH, Herr RH, Hill JD, et al. Distribution of systemic blood flow of the rhesus monkey during
cardiopulmonary bypass. J Thorac Cardiovasc Surg 1971;61:570-586.
126. McAlpine WA, Selman MW, Kawakami T. Routine use of aortic cannulation in open heart operations. Am J Surg
1967;114:831-834.
127. Muhs BE, Galloway AC, Lombino M, et al. Arterial injuries from femoral artery cannulation with port access
cardiac surgery. Vasc Endovascular Surg 2005;39:153-158.
128. Herman BE, Wallace HW, Gadboys HL, et al. Anterior crural syndrome as a complication of cardiopulmonary
bypass. J Thorac Cardiovasc Surg 1966;52:755-758.
129. Gates JD, Bichell DP, Rizzu RJ, et al. Thigh ischemia complicating femoral vessel cannulation for
cardiopulmonary bypass. Ann Thorac Surg 1996;61:730-733.
130. Hendrickson SC, Glower DD. A method for perfusion of the leg during cardiopulmonary bypass via femoral
cannulation. Ann Thorac Surg 1998;65:1807-1808.
131. Greason KL, Hemp JR, Maxwell JM, et al. Prevention of distal leg ischemia during cardiopulmonary support via
femoral cannulation. Ann Thorac Surg 1995;60:209-210.
132. VanderSalm TJ. Prevention of lower extremity ischemia during cardiopulmonary bypass via femoral cannulation.
133. Utoh J, Gotto H, Ashimura K, et al. A simple switching technique from cardiopulmonary bypass to a long-term
extracorporeal life support system. J Thorac Cardiovasc Surg 1996;112:206-207.
134. Beyersdorf F, Mitrev Z, Ihnken K, et al. Controlled limb reperfusion in patients having cardiac operations. J
135. Svensson LG. Editorial comment: autopsies in acute type A aortic dissection, surgical implications. Circulation
1998;98:II-302-II-304.
136. Kay JH, Dykstra DC, Tsuji HK. Retrograde ilio-aortic dissection. A complication of common femoral artery
perfusion during open-heart surgery. Am J Surg 1966;111:464-468.
137. Matar AF, Ross DN. Traumatic arterial dissection in open-heart surgery. Thorax 1967;22:82-87.
138. Benedict JS, Buhl TL, Henney RP. Acute aortic dissection during cardiopulmonary bypass. Arch Surg
1974;108:810-813.
139. Bigutay AM, Garamella JJ, Danyluk M, et al. Retrograde aortic dissection occurring during cardiopulmonary
bypass. JAMA 1976;236:465-468.
140. Carey JS, Skow JR, Scott C. Retrograde aortic dissection during cardiopulmonary bypass: “nonoperative”
management. Ann Thorac Surg 1977;24:44-48.
141. Galloway AC, Shemin RJ, Glower DD, et al. First report of the Port-Access International Registry. Ann Thorac
Surg 1999;67:51-58.
142. Jones TW, Vetto RR, Winterscheid LC, et al. Arterial complications incident to cannulation in open-heart
surgery. Ann Surg 1960;152:969-974.
143. Mohr FW, Falk V, Diegeler A, et al. Minimally invasive port-access mitral valve surgery. J Thorac Cardiovasc
Surg 1998;115:567-576.
144. Reichenspurner H, Gulielmos V, Wunderlich J, et al. Port-access coronary artery bypass grafting with the use of
cardiopulmonary bypass and cardioplegic arrest. Ann Thorac Surg 1998;65:413-419.
145. Casselman FP, Van Slycke S, Wellens F, et al. Mitral valve surgery can now routinely be performed
endoscopically. Circulation 2003;108(Suppl II):II-48-II-54.
145b. Grossi EA, Galloway AC, LaPietra A, et al. Minimally invasive mitral valve surgery: a 6-year experience with
714 patients. Ann Thorac Surg 2002;74: 660-3.
146. Turkoz R, Gulcan O, Oguzkurt L, et al. Successful repair of iatrogenic acute aortic dissection with cerebral
malperfusion. Ann Thorac Surg 2006; 81:345-347.
147. Van Arsdell GS, David TE, Butany J. Autopsies in aortic type A aortic dissection. Surgical implications.
Circulation 1998;98:II-299-II-304.
148. Neri E, Massetti M, Capannini G, et al. Axillary artery cannulation in type A aortic dissection operations. J
Thorac Cardiovascular Surg 1999;118: 324-329.
149. Fusco DS, Shaw RK, Tranquilli M, Kopf GS, Elefteriades JA. Femoral cannulation is safe for type A dissection
repair. Ann Thorac Surg 2004;78:1285-1289.
150. Shimokawa T, Takanashi S, Ozawa N, Itoh T. Management of intraoperative malperfusion syndrome using
femoral artery cannulation for repair of acute type A aortic dissection. Ann Thorac Surg 2008;85:1619-1624.
151. Dhareshwar J, Estrear AL, Achouh P, et al. Letter concerning cannulation strategy for acute type A aortic
dissection. Ann Thorac Surg 2006;81: 2335-2342.
152. Voci P, Testa G, Tritapepe L, et al. Detection of false lumen perfusion at the beginning of cardiopulmonary
bypass in patients undergoing repair of aortic dissection. Crit Care Med 2000;28:1841-1846.
153. Orihashi K, Sueda T, Okada K, et al. Newly developed aortic dissection in the abdominal aorta after femoral
arterial perfusion. Ann Thorac Surg 2005;79:1945-1949.
154. Coselli JS, Crawford ES. Femoral artery perfusion for cardiopulmonary bypass in patients with aortoiliac artery
obstruction. Ann Thorac Surg 1987;43:437-439.
155. Sabik JF, Lytle BW, McCarthy PM, et al. Axillary artery: an alternative site of arterial cannulation for patients
with extensive aortic and peripheral vascular disease. J Thorac Cardiovasc Surg 1995;109:885-891.
P.86
156. Bichell DP, Balaguer JM, Aranki SF, et al. Axilloaxillary cardiopulmonary bypass: a practical alternative to
femorofemoral bypass. Ann Thorac Surg 1997;64:702-705.
157. Baribeau YR, Westerbrook BM, Charlesworth DC, et al. Arterial inflow via an axillary artery graft for the severely
atherosclerotic aorta. Ann Thorac Surg 1998;66:33-37.
158. Whitlark JD, Goldman SM, Sutter FP. Axillary artery cannulation in acute ascending aortic dissections. Ann
Thorac Surg 2000;69:1127-1129.
159. Aebert H, Reber D, Kobuch R, et al. Aortic arch surgery using moderate systemic hypothermia and antegrade
cerebral perfusion via the right subclavian artery. Thorac Cardiovasc Surg 2001;49:283-286.
160. Whitlark JD, Sutter FP. Intrathoracic subclavian artery cannulation as an alternative to femoral or axillary artery
cannulation [Letter]. Ann Thorac Surg 1998;66:303.
161. Hedayati N, Sherwood JT, Schomisch SJ, et al. Axillary artery cannulation for cardiopulmonary bypass reduces
cerebral microemboli. J Thorac Cardiovasc Surg 2004;128(3):386-390.
162. Kaufmann TA, Hormes M, Laumen M, et al. The impact of aortic/subcla vian outflow cannulation for
cardiopulmonary bypass and cardiac support: a computational fluid dynamics study. Artif Organs 2009;33(9): 727-
732.
163. Gerdes A, Joubert-Hubner E, Esders K, et al. Hydrodynamics of aortic arch vessel during perfusion through the
right subclavian artery. Ann Thorac Surg 2000;69:1425-1430.
164. Frank SM, Norris EJ, Christpherson R, et al. Right and left-arm blood pressure discrepancies in vascular
surgery patients. Anesthesiology 1991;75:457-463.
165. Pasic M, Shubel J, Bauer M, et al. Cannulation of the right axillary artery for surgery of acute type A aortic
dissection. Eur J Cardiothorac Surg 2003;24:231-236.
166. Mazzola A, Gregorini R, Villani C, et al. Antegrade cerebral perfusion by axillary artery and left carotid artery
inflow at moderate hypothermia. Eur J Cardiothorac Surg 2002;21:930-931.
167. Schachner T, Nagiller J, Zimmer A, et al. Technical problems and complications of axillary artery cannulation.
Eur J Cardiothorac Surg 2005;27:634-637.
168. Strauch JT, Spielvogel D, Laufen A, et al. Artillary artery cannulation: routine use in ascending aorta and aortic
arch replaced. Ann Thorac Surg 2004;78:103-109.
169. Sabik JF, Nemeh H, Lytle B, et al. Cannulation of the axillary artery with a side graft reduces morbidity. Ann
Thorac Surg 2004;77:1315-1320.
170. Sinclair MC, Singer RL, Manley NJ, et al. Cannulation of the axillary artery for cardiopulmonary bypass:
safeguards and pitfalls. Ann Thorac Surg 2003;75:931-934.
171. Kokotsakis J, Lazopoulos G, Skouteli M, et al. Right axillary artery cannulation for surgical management of the
hostile ascending aorta. Tex Heart Inst J 2005;32:189-193.
172. Sakakibara Y, Matsuda K, Sato F, et al. Aortic dissection complicating cardiac surgery in a patient with calcified
ascending aorta. Jpn J Thorac Cardiovasc Surg 1999;47:625-628.
173. Imanaka K, Kyo S, Tanabe H, et al. Fatal intraoperative dissection of the innominate artery due to perfusion
through the right axillary artery. J Thorac and Cardiovasc Surg 2000;120:405-406.
174. Miytake T, Matsui Y, Suto Y, et al. A case of intraoperative acute aortic dissection caused by cannulation into
an axillary artery. J Cardiovasc Surg (Torino) 2001;42:809-811.
175. Estrera AL, Garami Z, Miller CC III, et al. Cerebral monitoring with transcranial doppler ultrasonography
improves neurologic outcome during repairs of acute type A aortic dissection. J Thorac Cardiovasc Surg
2005;129:277-285.
176. Janelle G, Stephen M, Gravenstein N, et al. Unilaterasl cerebral oxygen desaturation during emergent repair of
a DeBakey type I aortic dissection: potential aversion of a major catastrophe. Anesthesiology 2002;96: 1293-1295.
177. Fukuda J, Morishita K, Kawaharada N, et al. Isolated cerebral perfusion for intraoperative cerebral malperfusion
in type A aortic dissection. Ann Thorac Surg 2003;75:266-268.
178. Gulbins H, Pritisanac A, Ennker J. Axillary versus femoral cannulation for aortic surgery: enough evidence for a
general recommendation? Ann Thorac Surg 2007;83:1219-1224.
179. Geirsson A. Invited commentary. Ann Thorac Surg 2014;97(1):85-86.
180. Di Eusanio M, Pantaleo A, Petridis FD, et al. Impact of different cannulation strategies on in-hospital outcomes
of aortic arch surgery: a propensity-score analysis. Ann Thorac Surg 2013;96:1656-1663.
181. Etz CD, von Aspern K, da Rocha E Silva J, et al. Impact of perfusion strategy on outcome after repair for acute
type a aortic dissection. Ann Thorac Surg 2014;97:78-85.
182. Di Eusanio M, Ciano M, Labriola G, et al. Cannulation of the innominate artery during surgery of the thoracic
aorta: our experience in 55 patients. Eur J Cardiothorac Surg 2007;32:270-273.
183. Preventza O, Bakaeen FG, Stephens EH, et al. Innominate artery cannulation: an alternative to femoral or
axillary cannulation for arterial inflow in proximal aortic surgery. J Thorac Cardiovasc Surg 2013;145(3 Suppl):S191-
S196.
184. Banbury MK, Cosgrove DM III. Arterial cannulation of the innominate artery. Ann Thorac Surg 2000;69:957.
185. Prifti E, Frati G. Innominate artery cannulation in patients with severe porcelain aorta. Ann Thorac Surg
2001;71:399-400.
186. Tasdemir O, SaritaŞ A, Kuşcuker S, et al. Aortic arch repair with right brachial artery perfusion. Ann Thorac
Surg 2002;73:1837-1842.
187. Galajda Z, Szentkiralyi I, Peterffy A, et al. Brachial artery cannulation in type A aortic dissection operations. J
Thorac Cardiovasc Surg 1999;125:407.
188. Dermirkilic U, Kuralay E, Cingoz F, et al. Brachial artery cannulation facilitates lower ministernotomy cardiac
surgery. J Card Surg 2004;19: 260-263.
189. Küçüker SA, Ozatik MA, Saritaş A, Taşdemir O. Arch repair with unilateral antegrade cerebral perfusion. Eur J
Cardiothorac Surg 2005;27:638-643.
190. Saritas A, Kervan U, Vural KM, et al. Visceral protection during moderately hypothermic selective antegrade
cerebral perfusion through right brachial artery. Eur J Cardiothorac Surg 2010;37:669-676.
191. Veron S, Neri E, Buklas D, et al. Cannulation of the extrathoracic left common carotid artery for thoracic aorta
operations through left posterolateral thoracotomy. Ann Vasc Surg 2004;18:677-684.
192. Urbanski PP, Lenos A, Lindemann Y, et al. Carotid artery cannulation in aortic surgery. J Thorac Cardiovasc
Surg 2006;132:1398-1403
193. Urbanski PP, Lenos A, Lindemann Y, et al. Use of a carotid artery for arterial cannulation: side-related
differences. Thorac Cardiovasc Surg 2010; 58:276-279.
194. Urbanski PP, Lenos A, Zacher M, Diegeler A. Unilateral cerebral perfusion: right versus left. Eur J Cardiothorac
Surg 2010;37:1332-1336.
195. Norman JC. A single cannula for aortic perfusion and left ventricular decompression. Chest 1970;58:378-379.
196. Robicsek F. Apical aortic cannulation: application of an old method with new paraphernalia. Ann Thorac Surg
1991;51:320-322.
197. Yamamoto S, Hosoda Y, Yamasaki M, et al. Transapical aortic cannulation for acute aortic dissection to prevent
malperfusion and cerebral complications. Tex Heart Inst J 2001;28:42-43.
198. Fukuda I, Aikawa S, Imazuru T, et al. Transapical aortic cannulation for acute aortic dissection with diffuse
atherosclerosis. J Thorac Cardiovasc Surg 2002;123:369-370.
199. Wantanabe K, Fukuda I, Osaka M, et al. Axillary artery and transapical aortic cannulation as an alternative to
femoral artery cannulation. Eur J Cardiothorac Surg 2003;23:842-843.
200. Flege JB Jr, Aberg T. Transventricular aortic cannulation for repair of aortic dissection. Ann Thorac Surg
2001;72(3):955-956.
201. Wada S, Yamamoto S, Honda J, et al. Transapical aortic cannulation for cardiopulmonary bypass in type A
aortic dissection operations. J Thorac Cardiovasc Surg 2006;132(2):369-372.
202. Matsushita A, Manabe S, Tabata M, et al. Efficacy and pitfalls of transapical cannulation for the repair of acute
type A aortic dissection. Ann Thorac Surg 2012;93:1905-1909.
203. Gourlay T, Connolly P. Does cardiopulmonary bypass still represent a good investment? The biomaterials
perspective. Perfusion 2003;18: 225-231.
204. De Somer FMJJ, Van Nooten G. Blood pumps in cardiopulmonary bypass. In: Gravlee GP, Davis RF, Stammers
AH, Ungerleider RM. Cardiopulmonary bypass. Principles and practice. 3rd ed. Philadelphia, PA: Wolters
Kluwer/Lippincott Williams & Wilkins, 2008:35-46.
205. Tayama E, Raskin SA, Nosé Y. Blood pumps. In: Gravlee GP, Davis RF, Kurusz M et al., eds. Cardiopulmonary
bypass. Principles and practice. Baltimore, MD: Lippincott Williams & Wilkins, 2000:37-48.
206. Stammers AH. Extracorporeal devices and related technologies. In: Kaplan JA, ed. Cardiac anesthesia. 4th ed.
Philadelphia, PA: WB Saunders, 1999: 1017-1060.
207. Reed CC, Stafford TB. Cardiopulmonary bypass. 2nd ed. Houston, TX: Medical Press, 1985.
208. Mongero LB, Beck JR, Orr TR, et al. Clinical evaluation of setting pump occlusion by the dynamic method:
effect on flow. Perfusion 1998;13:360-368.
P.87
209. Tamari Y, Lee-Sensiba K, Leonard EF, et al. A dynamic method for setting roller pumps non-occlusively reduces
hemolysis and predicts retrograde flow. ASAIO J 1997;43:39-52.
210. Vieira FU Jr, Dantas de Medeiros J Jr, Antunes N, et al. Auxiliary device for calibration of roller pumps:
development and experimental results. Perfusion 2012;27:512-519.
211. Vieira FU Jr, Costa ET, Vieira RW, et al. The effect on hemolysis of the raceway profile of roller pumps used in
cardiopulmonary bypass. ASAIO J 2012;58:40-45.
212. Snyder EJ, McElwee DL, Harb HM, et al. Investigation of fatigue failure of S-65-HL “Super Tygon” roller pump
tubing. J Extra Corpor Technol 1996;28:79-87.
213. Uretzky G, Landsburg G, Cohn D, et al. Analysis of microembolic particles originating in extracorporeal circuits.
Perfusion 1987;2:9-17.
214. Peek GJ, Thompson A, Killer HM, Firmin RK. Spallation performance of extracorporeal membrane oxygenation
tubing. Perfusion 2000;15:457-466.
215. Kurusz M. Roller pump induced tubing wear: another argument in favor of arterial line filtration. J Extra Corpor
Technol 1980;12:49-59.
216. Briceno JC, Runge TM. Tubing spallation in extracorporeal circuits. An in vitro study using an electronic particle
counter. Int J Artif Organs 1992;15:222-228.
217. Lemm W. The reference materials of the European communities. Dordrecht, The Netherlands: Kluwer
Academic Publishers, 1992.
218. Snijders J, de Bruyn P, Bergmans M, et al. Study on causes and prevention of electrostatic charge build-up
during extracorporeal circulation. Perfusion 1999;14:363-370.
219. Elgas RJ. Investigation of the phenomenon of electrostatic compromise of a plastic fiber heat exchanger.
Perfusion 1999;14:133-140.
220. Jenkins OF, Morris R, Simpson JM. Australasian perfusion incident survey. Perfusion 1997;12:279-288.
221. Mejak BL, Stammers A, Rauch E, et al. A retrospective study on perfusion incidents and safety devices.
Perfusion 2000;15:51-61.
222. Milano AD, Dodonov M, Onorati F, et al. Pulsatile flow decreases gaseous micro-bubble filtering properties of
oxygenators without integrated arterial filters during cardiopulmonary bypass. Interact Cardiovasc Thorac Surg
2013;17:811-817.
223. Dodonov M, Milano A, Onorati F, et al. Gaseous micro-emboli activity during cardiopulmonary bypass in adults:
pulsatile flow versus nonpulsatile flow. Artif Organs 2013;37:357-367.
224. Butruille Y, Chevallet J, Granger A. Rhone-Poulenc oxygenator and associated pumping system. In: Zapol WM,
Qvist J, eds. Artificial lungs for acute respiratory failure, theory and practice. New York, NY: Academic Press,
1976:223-233.
225. Chevalier Y, Couprie C, Larroquet M, et al. Venovenous single lumen cannula extracorporeal lung support in
neonates. A five year experience. ASAIO J 1993;39:M654-M658.
226. Trittenwein G, Golej J, Burda G, et al. Neonatal and pediatric extracorporeal membrane oxygenation using non-
occlusive blood pumps: the Vienna experience. Artif Organs 2001;25:994-999.
227. Montoya JP, Merz SI, Bartlett RH. Laboratory experience with a novel, non-occlusive pressure-regulated
peristaltic blood pump. ASAIO J 1992; 38:M406-M411.
228. Montoya JP, Merz SI, Bartlett RH. Significant safety advantages gained with an improved pressure-regulated
blood pump. J Extra Corpor Technol 1996;28:71-78.
229. Jaggy C, Lachat M, Leskosek B, et al. Affinity pump system: a new peristaltic blood pump for cardiopulmonary
bypass. Perfusion 2000;15:77-83.
230. Jaggy C, Lachat M, Inderbitzin D, et al. Optimized veno-venous bypass with the affinity pump. ASAIO J
2001;47:56-59.
231. Skogby M, Mellgren K, Adrian K, et al. Induced cell trauma during in vitro perfusion: a comparison between two
different perfusion systems. Artif Organs 1998;22:1045-1051.
232. Durandy Y. Characteristics of a nonocclusive pressure-regulated blood roller pump. Artif Organs 2013;37:97-
100.
233. Teman NR, Mazur DE, Toomasian J, et al. A novel rotary pulsatile flow pump for cardiopulmonary bypass.
ASAIO J 2014;60:322-328.
234. Griffith GW, Toomasian JM, Schreiner RJ, et al. Hematological changes during short-term tidal flow
extracorporeal life support. Perfusion 2004;19: 359-363.
235. Stammers AH, Mejak BL. An update on perfusion safety: does the type of perfusion practice affect the rate of
incidents related to cardiopulmonary bypass? Perfusion 2001;16:189-198.
236. Morin BJ, Riley JB. Thrombus formation in centrifugal pumps. J Extra Corpor Technol 1992;24:20-25.
237. Kolff J, McClurken JB, Alpern JB. Beware centrifugal pumps: not a one-way street, but a dangerous siphon!
[Letter]. Perfusion 1990;5:225-226.
238. Orime Y, Shiono M, Shinya M, et al. Jostra Rota Flow RF-30 pump system: a new centrifugal blood pump for
cardiopulmonary bypass. Artif Organs 2000;24:437-441.
239. Göbel C, Arvand A, Eilers R, et al. Development of the MEDOS/HIA DeltaStream extracorporeal rotary blood
pump. Artif Organs 2001;25:358-365.
240. Göbel C, Arvand A, Rau G, et al. A new rotary blood pump for versatile extracorporeal circulation: the
DeltaStream. Perfusion 2002;17:373-382.
241. Papparella D, Galeone A, Venneri MT, et al. Blood damage related to cardiopulmonary bypass: in-vivo and in-
vitro comparison of two different centrifugal pumps. ASAIO J 2004;50:473-478.
242. Lawson DS, Ing R, Cheifetz IM, et al. Hemolytic characteristics of three commercially available centrifugal blood
pumps. Pediatr Crit Care Med 2005;6:573-577.
243. Meyns B. Indications for rotary blood pumps in clinical practice. Artif Organs 2001;25:323-323.
244. Takami Y, Yamane S, Makinouschi K, et al. Mechanical white blood cell damage in rotary blood pumps. Artif
Organs 1997;21:138-142.
245. Naito K, Suenaga E, Cao ZL, et al. Comparative hemolysis study of clinically available centrifugal pumps. Artif
Organs 1996;20:560-563.
246. Tanaka M, Kawahito K, Adachi H, et al. Platelet damage caused by the centrifugal pump: Laser-light scattering
analysis of aggregation patterns. Artif Organs 2001;25:719-723.
247. Zhang J, Gellman B, Koert A, et al. Computational and experimental evaluation of the fluid dynamics and
hemocompatibility of the CentriMag blood pump. Artif Organs 2006;30:168-177.
248. Takiura K, Masuzawa T, Endo S, et al. Develoment of design methods of a centrifugal pump pump with in vitro
tests, flow visualization and computational fluid dynamics: results in hemolysis tests. Artif Organs 1998;22:393-398.
249. Mohara J, Kawahito K, Misawa J, et al. Evaluation of platelet damage in two different centrifugal pumps based
on measurements of alpha-granule packing proteins. Artif Organs 1998;22: 371-374.
250. Shima H, Trubel W, Moritz A, et al. Noninvasive monitoring of rotary blood pumps: necessity, possibilities, and
limitations. Artif Organs 1992;16: 195-202.
251. Shima H, Huber L, Schmalleger H, et al. Flow measurement at the pump head of centrifugal pumps: comparison
of ultrasonic transit time and ultrasonic Doppler systems. Artif Organs 1997;21:808-815.
252. Laustsen J, Pedersen EM, Terp K, et al. Validation of a new transit time ultrasound flowmeter in man. Eur J
Vasc Endovasc Surg 1996;12:91-96.
253. Beldi G, Bosshard A, Hess OM, et al. Transit time flow measurement: experimental validation and comparison of
three different systems. Ann Thorac Surg 2000;70:212-217.
254. Dembinsky R, Kopp R, Henzler D, et al. Extracorporeal gas exchange with the DeltaStream rotary blood pump
in experimental lung injury. Artif Organs 2003;27:530-536.
255. Agati S, Mignosa C, Ciccarello C, et al. Pulsatile ECMO in neonates and infants: first European clinical
experience with a new device. ASAIO J 2005;51:508-512.
256. Oku T, Haraski H, Smith W, et al. Hemolysis. A comparative study of four nonpulsatile pumps. ASAIO Trans.
1988;34:500-504.
257. Jakob H, Kutschera Y, Palzer B, et al. In-vitro assessment of centrifugal pumps for ventricular assist. Artif
Organs. 1990;14:278-283.
258. Englehardt H, Vogelsang B, Reul H, et al. Hydrodynamical aand hemodynamical evaluation of rotary blood
pumps. In: Thoma H, Schima H, eds. Proceeding of the International Workshop on Rotary Blood Pumps. Vienna;
1988.
259. Hoerr HR, Kraemer MF, Williams JL, et al. In vitro comparison of the blood handling by the constrained vortex
and twin roller pumps. J Extra Corpor Technol 1987;19:316-321
260. Kress DC, Cohen DJ, Swanson DK, et al. Pump-induced hemolysis in rabbit model of neonatal ECMO. Trans.
Am Soc Artif Intern Organs 1987;33:446-452.
261. Tamari Y, Lee-Sensiba K, Leonard EF, et al. The effects of pressure and flow on hemolysis casued by bio-
medicus centrifugal pumps and roller pumps. J Thorac Cardiovasc Surg 1993;106;997-1007.
262. Rawn D, Harris H, Riley J, et al. An under-occluded roller pump is less hemolytic than a centrifugal pump. J
Extra Corpor Technol 1997;29:15-18.
263. Horton AM, Butt W. Pump-induced haemolysis: Is the constrined vortex pump better or worse that the roller
pump? Perfusion 1992;7:103-108.
P.88
264. Moen O, Fosse E, Braten J, et al. Roller and centrifugal pumps compared in vitro with regard to hemolysis,
granulocyte, and complement activation. Perfusion 1994;9:109-117.
265. Palder SB, Shaheen KW, Whittlesey GS, et al. Prolonged extracorporeal membrane oxygenation in sheep with
hollow-fiber oxygenators and centrifugal pumps. Trans Am Soc Artif Intern Org 1988;34:820-822.
266. Parolari A, Alamanni F, Naliato M, et al. Adult cardiac surgery outcomes: role of the pump type. Eur J
Cardiothorac Surg 2000;18:575-582
267. Hansbro SD, Sharpe D, Catchpole R, et al. Haemolysis during cardiopulmonary bypass: an in vivo comparison
of standard roller pumps, nonocclusive roller pumps and centrifugal pumps. Perfusion 1999;14:3-10.
268. Ashraf S, Bhattacharya K, Zacharias S, et al. Serum S100beta release after coronary artery bypass grafting:
roller versus centrifugal pump. Ann Thorac Surg. 1998;66:1958-1962.
269. Babin-Ebell J, Misoph M, Müllges W, et al. Reduced release of tissue factor by application of a centrifugal pump
during cardiopulmonary bypass. Heart Vessels 1998;13:147-151.
270. Ashraf SS, Butler J, Tian Y, et al. Inflammatory mediators in adults undergoing cardiopulmonary bypass:
comparison of centrifugal and roller pumps. Ann Thorac Surg 1998;65;480-484.
271. Baufreton C, Intrator L, Jansen PG, et al. Inflammatory response to cardiopulmonary bypass using roller or
centrifugal pumps. Ann Thorac Surg 1999;67:972-977
272. Wheeldon DR, Bethune DW, Gill RD. Vortex pumping for routine cardiac surgery: a comparative study.
Perfusion 1990;5:135-143
273. Parault BG, Conrad SA. The effect of extracorporeal circulation time and patient age on platelet retention during
cardiopulmonary bypass: a comparison of roller and centrifugal pumps. J Extra Corpor Technol 1991;23:34-38.
274. Moen O, Fosse E, Dregelid E, et al. Centrifugal pump and heparin coating improves cardiopulmonary bypass
biocompatibility. Ann Thorac Surg 1996;62:1134-1140.
275. Morgan IS, Codispoti M, SangerK, et al. Superiority of centrifugal pump over roller pump in paediatric cardiac
surgery: prospective randomized trial. Eur J Cardiothorac Surg 1998;13:526-532.
276. Salo M, Perttila J, Pulkki K, et al. Proinflammatory mediator response to coronary bypass surgery using a
centrifugal or a roller pump. J Extra Corpor Technol 1995;27:146-151
277. Klein M, Dauben HP, Schulte HD, et al. Centrifugal pumping during routine open heart surgery improves clinical
outcome. Artif Organs 1998;22:326-336.
278. Wahba A, Phillip A, Bauer MF, et al. The blood saving potential of vortex versus roller pump with and without
aprotinin. Perfusion 1995;10:111-141.
279. Andersen LS, Nygreen O, Grong L, et al. Comparison of the centrifugal and roller pump in elective coronary
artery bypass surgery—a prospective randomized study with special emphasis upon platelet activation. Scand
Cardiovasc J 2003;37:356-362.
280. Scott DA, Silber BS, Blyth C, et al. Blood loss in elective coronary artery surgery: a comparison of centrifugal
versus roller pump heads during cardiopulmonary bypass. J Cardiothorac Vasc Anesth 2001;15:322-325.
281. Alamanni F, Parolari A, Zanobini M, et al. Centrifugal pump and reduction of neurological risk in adult cardiac
surgery. J Extra Corpor Technol 2001;33:4-9.
282. Scott DA, Silbert BS, Doyle TJ, et al. Centrifugal versus roller head pumps for cardiopulmonary bypass: effect
on early neuropsychologic outcomes after coronary artery surgery. J Cardiothorac Vasc Anesth 2002;16:715-722.
283. Saczkowski R, Maklin M, Mesana T, et al. Centrifugal pump and roller pump in adult cardiac surgery: a meta-
analysis of randomized controlled trials. Artif Organs 2012;36(8):668-676.
284. Keyser A, Hilker MK, Diez C, et al. Prospective randomized clinical study of arterial pumps used for routine on
pump coronary bypass grafting. Artif Organs 2011;35(5):534-542
285. Holinski S, Claus B, Haeger N, et al. Effect of different pump heads for CPB on early cognitive outcome after
coronary artery bypass surgery. Ann Thorac Cardiovasc Surg 2013;19(4):273-278.
286. Society of Thoracic Surgeons Blood Conservation Guideline Task Force, Ferraris VA, Brown JR, Despotis GJ,
et al; Society of Cardiovascular Anesthesiologists Special Task Force on Blood Transfusion, Shore-Lesserson LJ,
Goodnough LT, Mazer CD, et al; International Consortium for Evidence Based Perfusion, Baker RA, Dickinson TA,
FitzGerald DJ, et al. 2011 update to the Society of Thoracic Surgeons and the Society of Cardiovascular
Anesthesiologists blood conservation clinical practice guidelines. Ann Thorac Surg 2011;91(3):944-982.
287. Warren OJ, Wallace S, de Wit KL, et al. Variations in the application of various perfusion technologies in Great
Britain and Ireland—a national survey. Artif Organs 2010;34(3):200-205.
288. Grocott HP, Stfford-Smith M, Mora Mangano CT. Cardiopulmonary bypass management and organ protection.
In: Kaplan JA, Reich DL, Savino J, eds. Kaplan’s cardiac anesthesia. 6th ed. St. Louis, MO: Elsevier/Saunders,
2011.
289. Murkin JM, Martzke JS, Buchan AM, et al. A randomized study of the influence of perfusion technique and pH
management strategy in 316 patients undergoing coronary artery bypass surgery. I. Mortality and cardiovascular
morbidity. J Thorac Cardiovasc Surg 1995;110: 340-348.
290. Taylor KM, Bain WH, Davidson KG, et al. Comparative clinical study and pulsatile and non-pulsatile perfusion in
350 consecutive patients. Thorax 1982;37:324-330.
291. Abramov D, Tamariz M, Serrick CI, et al. The influence of cardiopulmonary bypass flow characteristics on the
clinical outcome of 1820 coronary bypass patients. Can J Cardiol 2003;19:237-243.
292. Lim CH, Nam MJ, Lee JS, et al. A meta-analysis of pulmonary function with pulsatile perfusion in cardiac
surgery. Artif Organs 2015;39(2):110-117.
293. Sievert A, Sistino J. A meta-analysis of renal benefits to pulsatile perfusion in cardiac surgery. J Extra Corpor
Technol 2012;44:10-14.
294. Milano AD, Dodonov M, Van Oeveren W, et al. Pulsatile cardiopulmonary bypass and renal function in elderly
patients undergoing aortic valve surgery. Eur J Cardiothorac Surg 2015;47(2):291-298.
295. Alkan-Bozkaya T, Akçevin A, Türkoglu H, et al. Impact of pulsatile perfusion on clinical outcomes of neonates
and infants with complex pathologies undergoing cardiopulmonary bypass procedures. Artif Organs 2013;37(1):82-
86.
296. Elbers PW, Wijbenga J, Solinger F, et al. Direct observation of the human microcirculation during
cardiopulmonary bypass: effects of pulsatile perfusion. J Cardiothorac Vasc Anesth 2011;25(2):250-255.
297. O'Neil MP, Fleming JC, Badhwar A, et al. Pulsatile versus nonpulsatile flow during cardiopulmonary bypass:
microcirculatory and systemic effects. Ann Thorac Surg 2012;94(6):2046-2053.
298. Mavroudis C. To pulse or not to pulse. Ann Thorac Surg 1978;25:259-262.
299. Undar A, Rosenberg G, Myers JL. Major factors in the controversy of pulsatile versus nonpulsatile flow during
acute and chronic support. ASAIO J 2005;51:173-175.
300. Undar A, Masai T, Frazier OH, Fraser CD. Pulsatile and nonpulsatile flows can be quantified in terms of energy
equivalent pressure during cardiopulmonary bypass for direct comparisons. ASAIO J 1999;45:610-614.
301. Undar A. Pulsatile versus nonpulsatile cardiopulmonary bypass procedures in neonates and infants: from bench
to clinical practice. ASAIO J 2005;51:6-10.
302. Gourlay T, Taylor KM. Pulsatile flow and membrane oxygenators. Perfusion 1994;9:189-196.
303. Undar A, Lodge AJ, Daggett CW, et al. The type of aortic cannula and membrane oxygenator affect the pulsatile
waveform morphology produced by a neonate-infant cardiopulmonary bypass system in vivo. Artif Organs
1998;22:681-686.
304. Gu YJ, van Oeveren W, Mungroop HE, et al. Clinical effectiveness of centrifugal pump to produce pulsatile flow
during cardiopulmonary bypass in patients undergoing cardiac surgery. Artif Organs 2011;35:E18-E26.
305. Alghamdi AA, Latter DA. Pulsatile versus nonpulsatile cardiopulmonary bypass flow: an evidence-based
approach. J Card Surg 2006;21: 347-354.
306. Ündar A, Palanzo D, Qiu F, et al. Benefits of pulsatile flow in pediatric cardiopulmonary bypass procedures: from
conception to conduction. Perfusion 2011;26(Suppl 1):35-39.
307. Dickson TA. Hypoxemia after intraluminal oxygen line obstruction during cardiopulmonary bypass [Letter]. Ann
Thorac Surg 1990;49:512.
308. Weitkemper HH, Oppermann B, Spilker A, et al. Gaseous microemboli and the influence of microporous
membrane oxygenators. J Extra Corpor Technol 2005;37:256-264.
309. Georgiadis D, Stets R, Schorch A, et al. Doppler microembolic signals during cardiopulmonary bypass:
comparison of two membrane oxygenators. Neurol Res 2004;26:99-102.
310. Fisher AR, Baker M, Buffin M, et al. Normal and abnormal trans-oxygenator pressure gradients during
cardiopulmonary bypass. Perfusion 2003;18:25-30.
311. Myers GJ, Weighell PR, McCloskey BJ, et al. A multicenter investigation into the occurrence of high-pressure
excursions. J Extra Corpor Technol 2003;35:127-132.
P.89
312. Groom RC, Forest RJ, Cormack JE, et al. Parallel replacement of the oxygenator that is not transferring oxygen:
the PRONTO procedure. Perfusion 2002;17:447-450.
313. Helmsworth JA, Shabetay R, Cole WR, et al. A method of cardiac bypass with autologous oxygenation. Surgery
1959;45:129-137.
314. Mendler N, Weimisch W, Schad H. Pulmonary function after biventricular bypass for autologous lung
oxygenation. Eur J Cardiothorac Surg 2000;17:325-330.
315. Richter JA, Meisner H, Tassani P, et al. Drew-Anderson technique attenuates systemic inflammatory response
syndrome and improves respiratory function after coronary artery bypass grafting. Ann Thorac Surg 1999;69: 77-83.
316. Massoudy P, Zahler S, Tassani P, et al. Reduction of pro-inflammatory cytokine levels and cellular adhesion in
CABG procedure with separated pulmonary and systemic extracorporeal circulation without an oxygenator. Eur J
317. Marques E, Cestari IS, Cestari IA, et al. A simplified single pump circuit for cardiac bypass with autogenous
oxygenation. Artif Organs 1999;23: 124-127.
318. Shivaprakasha K, Rameshkumar I, Kumar RK, et al. New technique of right heart bypass in congenital heart
surgery with autologous lung an oxygenator. Ann Thorac Surg 2004;77:988-993.
319. Schonberger JP, Everts PA, Hoffmann JJ. Systemic blood activation with open and closed venous reservoirs.
Ann Thorac Surg 1995;59:1549-1555.
320. Orenstein JM, Soto N, Aaron B, et al. Microemboli observed in deaths following cardiopulmonary bypass
surgery: silicone antifoam agents and polyvinyl chloride tubing as sources of emboli. Hum Pathol 1982;13:1082-
1090.
321. Tanaka H, Oshiyama T, Narisawa T, et al. Clinical study of biocompatibility between open and closed heparin-
coated cardiopulmonary bypass circuits. J Artif Organs 2003;6:245-252.
322. Jensen E, Andreasson S, Bengtsson A, et al. Influence of two different perfusion systems on inflammatory
response in pediatric heart surgery. Ann Thorac Surg 2003;75:919-925.
323. Nishida H, Aomi S, Tomizawa Y, et al. Comparative studies of biocompatiability between open circuit and closed
circuit in cardiopulmonary bypass. Artif Organs 1999;23:547-551.
324. Fukada J, Morishita K, Ingu A, et al. Comparative study of the effect on clinical outcome of the use of an open
circuit and the use of a closed circuit in cardiopulmonary bypass for a graft replacement of the descending thoracic or
thoracoabdominal aorta. Surg Today 2004;34:11-15.
325. Nakahira A, Sasaki Y, Hirai H, et al. Cardiotomy suction, but not open venous reservoirs, activates
coagulofibrinolysis in coronary artery surgery. J Thorac Cardiovasc Surg 2011;141:1289-1297.
326. Wright G, Sanderson JM. Cellular aggregation and trauma in cardiotomy suction systems. Thorax 1979;34:621-
628.
327. Clague CT, Blackshear PL Jr. A low-hemolysis blood aspirator conserves blood during surgery. Biomed Instrum
Technol 1995;29:219-224.
328. Tevaearai HT, Mueller XM, Horisberger J, et al. In situ control of cardiotomy suction reduces blood trauma.
ASAIO J 1998;44:M380-M383.
329. Mueller XM, Tevaearai HT, Horisberger J, et al. Smart suction device for less blood trauma: a comparison with
Cell Saver. Eur J Cardiothorac Surg 2001;19:507-511.
330. Lau K, Shah H, Kelleher A, et al. Coronary artery surgery: cardiotomy suction or cell salvage? J Cardiothorac
Surg 2007;2:46.
331. Svitek V, Lonsky V, Anjum F. Pathophysiological aspects of cardiotomy suction usage. Perfusion 2010;25:147-
152.
332. Gäbel J, Hakimi CS, Westerberg M, et al. Retransfusion of cardiotomy suction blood impairs haemostasis: ex
vivo and in vivo studies. Scand Cardiovasc J 2013;47(6):368-376.
333. Weerwind PW, Lindhout T, Caberg NE, et al. Thrombin generation during cardiopulmonary bypass: the possible
role of retransfusion of blood aspirated from the surgical field. Thromb J 2003;1:3.
334. Solis RT, Moon CP, Beall AC Jr, et al. Particulate microembolism during cardiac operations. Ann Thorac Surg
1974;17:332-344.
335. Edmunds LH Jr, Saxena NC, Hillyer P, et al. Relationship between platelet count and cardiotomy suction return.
336. Pearson DT. Microemboli: gaseous and particulate. In: Taylor KM, ed. Cardiopulmonary bypass: principles and
management. Baltimore, MD: Williams & Wilkins, 1986:313-354.
337. Liu JF, Su ZK, Ding WX. Quantitation of particulate micro-emboli during cardiopulmonary bypass: experimental
and clinical studies. Ann Thorac Surg 1992;54:1196-1202.
338. Siderys H. Pericardial fluid and hemolysis [Letter]. Ann Thorac Surg 1993;56:595.
339. Tabuchi N, deHaan J, Boonstra PW, et al. Activation of fibrinolysis in the pericardial cavity during
340. Brooker RF, Brown WR, Moody DM, et al. Cardiotomy suction: a major source of brain lipid emboli during
341. Reents W, Babin-Ebell J, Misoph MR, et al. Influence of different autotransfusion devices on the quality of
salvaged blood. AnnThorac Surg 1999;68:58-62.
342. Svenmarker S, Engstrom KG. The inflammatory response to recycled pericardial suction blood and the
influence of cell-saving. Scand Cardiovasc J 2003;37:158-164.
343. Westerberg M, Bengtsson A, Jeppsson A. Coronary surgery without cardiotomy suction and autotransfusion
reduces the postoperative systemic inflammatory response. Ann Thorac Surg 2004;78:54-59.
344. de Vries AJ, Gu YJ, Douglas YL, et al. Clinical evaluation of a new fat removal filter during cardiac surgery. Eur
J Cardiothorac Surg 2004;25:261-266.
345. ten Brinke MJ, Weerwind PW, Teerenstra S, et al. Leukocyte removal efficiency of cell-washed and unwashed
whole blood: an in vitro study. Perfusion 2005;20:335-341.
346. Bronden B, Dencker M, Allers M, et al. Differential distribution of lipid microemboli after cardiac surgery. Ann
Thorac Surg 2006;81:643-649.
347. Gäbel J, Westerberg M, Bengtsson A, Jeppsson A. Cell salvage of cardiotomy suction blood improves the
balance between pro- and anti-inflammatory cytokines after cardiac surgery. Eur J Cardiothorac Surg
2013;44(3):506-511.
348. Pearson DT, Watson BG, Waterhouse PS. An ultrasonic analysis of the comparative efficiency of various
cardiotomy reservoirs and micropore blood filters. Thorax 1978;33:352-358.
349. de Jong JCF, ten Duis HJ, Sibinga CT. Hematologic aspects of cardiotomy suction in cardiac operations. J
350. Boonstra PW, van Imhoff GW, Eysman L, et al. Reduced platelet activation and improved hemostasis after
controlled cardiotomy suction during clinical membrane oxygenator perfusions. J Thorac Cardiovasc Surg
1985;89:900-906.
351. Wielogorske JW, Cross DE, Nwadlike EV. The effects of subatmospheric pressure on the hemolysis of blood. J
Biomech 1975;8:321-325.
352. Hirose T, Burman SD, O’Connor RA. Reduction of perfusion hemolysis by use of atraumatic low pressure
suction. J Thorac Cardiovasc Surg 1964;47:242-247.
353. Riley JB. Pump sucker discipline. J Extra Corpor Technol 2012;44:81-83.
354. Kincaid EH, Jones TJ, stump DA, et al. Processing scavenged blood with a cell saver reduces cerebral lipid
microembolization. Ann Thorac Surg 2000;70:1296-1300.
355. Kaza AK, Cope JT, Fiser SM, et al. Elimination of fat microemboli during cardiopulmonary bypass. Ann Thorac
Surg 2003;75:555-559.
356. Booke M, Van Aken H, Storm M, et al. Fat elimination from autologous blood. Anesth Analg 2001;92:341-343.
357. Ramirez G, Romero A, Garcia-Vallejo JJ, et al. Detection and removal of fat particles from postoperative
salvaged blood in orthopedic surgery. Transfusion 2002;42:66-75.
358. Engstrom KG. The embolic potential of liquid fat in pericardial suction blood and its elimination. Perfusion
2003;18:69-71.
359. Vonk AB, Meesters MI, Garnier RP, et al. Intraoperative cell salvage is associated with reduced postoperative
blood loss and transfusion requirements in cardiac surgery: a cohort study. Transfusion 2013;53:2782-2789.
360. Baker RA, Merry AF. Cell salvage is beneficial for all cardiac surgical patients: arguments for and against. J
Extra Corpor Technol 2012;44(1): P38-P41.
361. Attaran S, McIlroy D, Fabri BM, et al. The use of cell salvage in routine cardiac surgery is ineffective and not
cost-effective and should be reserved for selected cases. Interact Cardiovasc Thorac Surg 2011;12(5):824-826.
362. Klein AA, Nashef SA, Sharples L, et al. A randomized controlled trial of cell salvage in routine cardiac surgery.
Anesth Analg 2008;107(5):1487-1495
363. Dai B, Wang L, Djaiani G, et al. Continuous and discontinuous cell-washing autotransfusion systems. J
364. Amand T, Pincemail J, Blaffart F, et al. Levels of inflammatory markers in the blood processed by
autotransfusion devices during cardiac surgery associated with cardiopulmonary bypass circuit. Perfusion
2002;17:117-123.
365. Booke M, Fobker M, Fingerhut D, et al. Fat elimination during intraoperative autotransfusion: an in vitro
investigation. Anesth Analg 1997;85:959-962.
P.90
366. Innerhofer P, Wiedermann FJ, Tiefenthaler W, et al. Are leukocytes in salvaged washed autologous blood
harmful for the recipient? The results of a pilot study. Anesth Analg 2001;93:566-572.
367. Wang X, Ji B, Zhang Y, et al. Comparison of the effects of three cell saver devices on erythrocyte function
during cardiopulmonary bypass procedure—a pilot study. Artif Organs 2012;36(10):931-935.
368. Jewell AE, Akowuah EF, Suvarna SK, et al. A prospective randomized comparison of cardiotomy suction and
cell saver for recycling shed blood during cardiac surgery. Eur J Cardiothorac Surg 2003;23:633-636.
369. Aldea GS, Soltow LO, Chandler WL, et al. Limitation of thrombin generation, platelet activation, and
inflammation by elimination of cardiotomy suction in patients undergoing coronary artery bypass grafting treated with
heparin-bonded circuits. J Thorac Cardiovasc Surg 2002;123:742-755.
370. Carrier M, Denault A, Lavoie J, et al. Randomized controlled trial of pericardial blood processing with a cell-
saving device on neurologic markers in elderly patients undergoing coronary artery bypass graft surgery. Ann Thorac
Surg 2006;82(1):51-55.
371. Svenmarker S, Engstrom KG, Karlsson T, et al. Influence of pericardial suction blood retransfusion on memory
function and release of protein S100B. Perfusion 2004;19:337-343.
372. Marcheix B, Carrier M, Martel C, et al. Effect of pericardial blood processing on postoperative inflammation and
the complement pathways. Ann Thorac Surg 2008;85(2):530-535.
373. Djaiani G, Fedorko L, Borger MA, et al. Continuous-flow cell saver reduces cognitive decline in elderly patients
after coronary bypass surgery. Circulation 2007;116(17):1888-1895.
374. Rubens FD, Boodhwani M, Mesana T, et al; Cardiotomy Investigators. The cardiotomy trial: a randomized,
double-blind study to assess the effect of processing of shed blood during cardiopulmonary bypass on transfusion
and neurocognitive function. Circulation 2007;116(Suppl):I89-I97.
375. Djaiani G, Fedorko L, Carroll J,et al. Response to letter regarding article, “Continuous-flow cell saver reduces
cognitive decline in elderly patients after coronary bypass surgery”. Circulation 2008;117:e349.
376. Rubens FD, Wells GA, Nathan HJ. Letter by Rubens et al regarding article, “Continuous-flow cell saver reduces
cognitive decline in elderly patients after coronary bypass surgery”. Circulation 2008;117:e348.
377. Djaiani G, Katznelson R, Fedorko L, et al. Early benefit of preserved cognitive function is not sustained at one-
year after cardiac surgery: a longitudinal follow-up of the randomized controlled trial. Can J Anaesth 2012;59(5):449-
455.
378. Wang G, Bainbridge D, Martin J, et al. The efficacy of an intraoperative cell saver during cardiac surgery: a
meta-analysis of randomized trials. Anesth Analg 2009;109:320-330.
379. Carless PA, Henry DA, Moxey AJ, et al. Cell salvage for minimising perioperative allogeneic blood transfusion.
Cochrane Database Syst Rev 201014;(4):CD001888.
380. Tabuchi N, Sunamori M. Remaining procoagulant property of wound blood washed by a cell-saving device. Ann
Thorac Surg 2001;71:1749-1750.
381. Daane CR, Golab HD, Meeder JH, et al. Processing and transfusion of residual cardiopulmonary bypass
volume: effects on haemostasis, complement activation, postoperative blood loss and transfusion volume. Perfusion
2003;18:115-121.
382. Eichert I, Isgro F, Kiessling AH, et al. Cellsavers, ultrafiltration, and direct transfusion: comparative study of
three blood processing techniques. Thorac Cardiovasc Surg 2001;49:149-152.
383. Borowiec JW, Rozdayi M, Jaramillo A, et al. Influence of two blood conservation techniques (cardiotomy
reservoir versus cell saver) on biocompatibility of the heparin coated cardiopulmonary bypass circuit during coronary
revascularization surgery. J Card Surg 1997;12:190-197.
384. Aldea GS, Doursounian M, O’Gara P, et al. Heparin-bonded circuits with a reduced anticoagulation protocol in
primary CABG: a prospective, randomized study. Ann Thorac Surg 1996;62:410-418.
385. Jensen E, Andreasson S, Bengtsson A, et al. Changes in hemostasis during pediatric heart surgery: impact of a
biocompatible heparin-coated perfusion system. Ann Thorac Surg 2004;77:962-967.
386. Eisses MJ, Seidel K, Aldea GS, et al. Reducing hemostatic activation during cardiopulmonary bypass: a
combined approach. Anesth Analg 2004;98:1208-1216.
387. Lindholm L, Westerberg M, Bengtsson A, et al. A closed perfusion system with heparin coating and centrifugal
pump improves cardiopulmonary bypass biocompatibility in elderly patients. Ann Thorac Surg 2004;78: 2131-2138.
388. Butler BD, Kurusz M. Gaseous microemboli: a review. Perfusion 1990;5:81-99.
389. Nieuwland R, Berckmans RJ, Rotteveel-Eijkman RC, et al. Cell-derived microparticles generated in patients
during cardiopulmonary bypass are highly procoagulant. Am Heart Assoc 1997;96:3534-3541.
390. Merkle F, Boettcher W, Schulz F, et al. Reduction of microemboli count in the priming fluid of cardiopulmonary
bypass circuits. J Extra Corpor Technol 2003;35:133-138.
391. Merkle F, Bottcher W, Hetzer R. Prebypass filtration of cardiopulmonary bypass circuits: an outdated
technique? Perfusion 2003;18:81-88.
392. Kurusz M, Butler BD. Bubbles and bypass: an update. Perfusion 2004;19: S49-S55.
393. Barak M, Katz Y. Microbubbles: pathophysiology and clinical implications. Chest 2005;128:2918-2932.
394. Blauth CI. Macroemboli and microemboli during cardiopulmonary bypass. Ann Thorac Surg 1995;59:1300-1303.
395. Willcox TW, Mitchell SJ. Microemboli in our bypass circuits: a contemporary audit. J Extra Corpor Technol
2009;41:31-37.
396. Groom RC, Quinn RD, Lennon P, et al; Northern New England Cardiovascular Disease Study Group.
Microemboli from cardiopulmonary bypass are associated with a serum marker of brain injury. J Extra Corpor
Technol 2010;42(1):40-44.
397. Groom RC, Quinn RD, Lennon P, et al; Northern New England Cardiovascular Disease Study Group. Detection
and elimination of microemboli related to cardiopulmonary bypass. Circ Cardiovasc Qual Outcomes 2009;2(3):191-
198.
398. Marshall L. Filtration in cardiopulmonary bypass: past, present and future. Perfusion 1988;3:135-147.
399. Joffe D, Silvay G. The use of microfilters in cardiopulmonary bypass. J Cardiothorac Vasc Anesth 1994;8:685-
692.
400. Whitaker DC, Stygall JA, Newman SP, et al. The use of leucocyte-depleting and conventional arterial line filters
in cardiac surgery: a systematic review of clinical studies. Perfusion 2001;16:433-446.
401. Pascale F. Removal of gaseous microemboli from extracorporeal circulation. Med Instrum 1985;19:70-72.
402. Silvay G, Ammar T, Reich DL, et al. Cardiopulmonary bypass for adult patients: a survey of equipment and
techniques. J Cardiothorac Vasc Anesth 1995;9:420-424.
403. Solis RT, Horak J. Evaluation of a new cardiotomy blood filter. Ann Thorac Surg 1979;28:487-488.
404. Ware JA, Scott MA, Horak JK, et al. Platelet aggregation during and after cardiopulmonary bypass: effect of two
different cardiotomy filters. Ann Thorac Surg 1982;34:204-206.
405. Myers GJ, Voorhees C, Haynes R, et al. Post-arterial filter gaseous microemboli activity of five integral
cardiotomy reservoirs during venting: an in vitro study. J Extra Corpor Technol . 2009;41:20-27.
406. Gomez D, Preston TJ, Olshove VF, et al. Evaluation of air handling in a new generation neonatal oxygenator
with integral arterial filter. Perfusion 2009;24:107-112.
407. Myers GJ, Gardiner K, Ditmore SN, et al. Clinical evaluation of the Sorin synthesis oxygenator with integrated
arterial filter. J Extra Corpor Technol 2005;37:201-206.
408. Deptula J, Valleley M, Glogowski K, et al. Clinical evaluation of the Terumo Capiox FX05 hollow fiber
oxygenator with integrated arterial line filter. J Extra Corpor Technol 2009;41:220-225.
409. Onorati F, Santini F, Raffin F, et al. Clinical evaluation of new generation oxygenators with integrated arterial
line filters for cardiopulmonary bypass. Artif Organs 2012;36(10):875-885.
410. Preston TJ, Gomez D, Olshove VF Jr, et al. Clinical gaseous microemboli assessment of an oxygenator with
integral arterial filter in the pediatric population. J Extra Corpor Technol 2009;41:226-230.
411. Lin J, Dogal NM, Mathis RK, et al. Evaluation of Quadrox-i and Capiox FX neonatal oxygenators with integrated
arterial filters in eliminating gaseous microemboli and retaining hemodynamic properties during simulated
412. Munsch C, Rosenfeldt F, Chang V. Absence of particle-induced coronary vasoconstriction during cardioplegic
infusion: is it desirable to use a microfilter in the infusion line? J Thorac Cardiovasc Surg 1991;101:473-480.
413. Groom RC, Froebe S, Martin J, et al. Update on pediatric perfusion practice in North America: 2005 survey. J
414. Gourlay T, Gibbons M, Fleming J, et al. Evaluation of a range of arterial line filters. Part I. Perfusion 1987;2:297-
302.
P.91
415. Gourlay T, Gibbons M, Taylor KM. Evaluation of a range of arterial line filters. Part II. Perfusion 1988;3:29-35.
416. Gourlay T. The role of arterial line filters in perfusion safety. Perfusion 1988;3:195-204.
417. Patterson RH Jr, Wasser JS, Porro RS. The effect of various filters on microembolic cerebrovascular blockade
following cardiopulmonary bypass. Ann Thorac Surg 1974;17:464-473.
418. Pedersen T, Hatteland K, Semb BKH. Bubble extraction by various arterial filters measured in vitro with doppler
ultrasound techniques. Ultrasound Med Biol 1982;8:71-81.
419. Hsu LC. Principles of heparin-coating techniques. Perfusion 1991;6:209-219.
420. Palanzo DA, Kurusz M, Butler BD. Surface tension effects of heparin coating on arterial line filters. Perfusion
1990;5:277-284.
421. Riley JB. Arterial line filters ranked for gaseous micro-emboli separation performance: an in vitro study. J Extra
Corpor Technol 2008;40:21-26.
422. Yarham G, Mulholland J. Pre-clinical laboratory evaluation of the new ‘AF’ arterial line filter range. Perfusion
2010;25:267-276.
423. Jabur GN, Willcox TW, Zahidani SH, et al. Reduced embolic load during clinical cardiopulmonary bypass using
a 20 micron arterial filter. Perfusion 2014;29(3):219-225.
424. De Somer F. Evidence-based used, yet still controversial: the arterial filter. J Extra Corpor Technol
2012;44:P27-P30.
425. Pugsley W, Klinger L, Paschalis C, et al. The impact of microemboli on neuropsychological functioning. Stroke
1994;25;1393-1399.
426. Aris A, Solanes H, Camara ML, et al. Arterial line filtration during cardiopulmonary bypass. Neurologic,
neuropsychologic, and hematologic studies. J Thorac Cardiovasc Surg 1986;91:526-533.
427. Sellman M, Holm L, Ivert T, et al. A randomized study of neuropsychological function in patients undergoing
coronary bypass surgery. Thorac Cardiovasc Surg 1993;41:349-354.
428. Connell RS, Page US, Bartley TD, et al. The effect on pulmonary ultrastructure of dacron-wool filtration during
429. Kruis RW, Vlasveld FA, Van Dijk D. The (un)importance of cerebral microemboli. Semin Cardiothorac Vasc
Anesth 2010;14:111-118.
430. van Dijk D, Kalkman CJ. Why are cerebral microemboli not associated with cognitive decline? Anesth Analg
2009;109:1006-1008.
431. De Somer FM, Vetrano MR, Van Beeck JP, et al. Extracorporeal bubbles: a word of caution. Interact Cardiovasc
Thorac Surg 2010;10:995-1001.
432. Kurusz M. Arterial line filtration during cardiopulmonary bypass: history and controversy. Proc Am Acad
Cardiovasc Perfus 1983;4:76-86.
433. Whitaker DC, Stygall J, Hope-Wynne C, et al. A prospective clinical study of cerebral microemboli and
neuropsychological outcome comparing vent-line and auto-venting arterial line filters: both filters are equally safe.
Perfusion 2006;21:83-86.
434. Herbst DP, Najm HK. Development of a new arterial-line filter design using computational fluid dynamics
analysis. J Extra Corpor Technol 2012;44:139-144.
435. Sauren LD, la Meir M, Palmen M, et al. New ultrasonic radiation reduces cerebral emboli during extracorporeal
circulation. Eur J Cardiothorac Surg 2007;32(2):274-280.
436. Sauren LD, la Meir M, Bolotin G, et al. The EmBlocker: efficiency of a new ultrasonic embolic protection device
adjunctive to heart valve surgery. Ann Thorac Surg 2009;88:253-257.
437. Schönburg M, Urbanek P, Erhardt G, et al. Significant reduction of air microbubbles with the dynamic bubble
trap during cardiopulmonary bypass. Perfusion 2001;16:19-25.
438. Morris SJ. Leukocyte reduction in cardiovascular surgery. Perfusion 2001;16:371-380.
439. Matheis G, Scholz M, Simon A, et al. Leukocyte filtration in cardiac surgery: a review. Perfusion 2001;16:361-
370.
440. Ortolano GA, Aldea GS, Lilly K, et al. A review of leukofiltration in cardiac surgery: the time course of
reperfusion injury may facilitate study design of anti-inflammatory effects. Perfusion 2002;17:53-62.
441. Asimakopoulios G. The inflammatory response to CPB: the role of leukocyte filtration. Perfusion 2002;17:7-10.
442. Morioka K, Muraoka R, Chiba Y, et al. Leukocyte and platelet depletion with a blood separator: effects on lung
injury after cardiac surgery with cardiopulmonary bypass. J Thorac Cardiovasc Surg 1996;111:45-54.
443. Chiba Y, Morioka K, Muraoka R, et al. Effect of depletion of leukocytes and platelets on cardiac dysfunction
after cardiopulmonary bypass. Ann Thorac Surg 1998;65:107-114.
444. Lazar HL, Zhang X, Hamasaki T, et al. Role of leukocyte depletion during cardiopulmonary bypass and
cardioplegic arrest. Ann Thorac Surg 1995;60:1745-1748.
445. Baksaas ST, Videm V, Mollnes TE, et al. Leukocyte filtration during cardiopulmonary bypass hardly changed
leukocyte counts and did not influence myeloperoxidase, complement, cytokinin or platelets. Perfusion 1998;13:429-
436.
446. Hurst T, Johnson D, Cujec B, et al. Depletion of activated neutrophils by a filter during cardiac valve surgery.
Can J Anaesth 1997;44:131-139.
447. de Vries AJ, Gu YJ, Post WJ, et al. Leucocyte depletion during cardiac surgery: a comparison of different
filtration strategies. Perfusion 2003; 18:31-38.
448. Smit JJ, de Vries AJ, Gu YJ, et al. Filtration of activated granulocytes during cardiopulmonary bypass surgery: a
morphologic and immunologic study to characterize the trapped leukocytes. J Lab Clin Med 2000;135:238-246.
449. Thurlow PJ, Doolan L, Sharp R, et al. Laboratory studies of the effect of Pall extracorporeal leucocyte filters
LG6 and AV6 on patients undergoing coronary bypass grafts. Perfusion 1996;11:29-37.
450. Stefanou DC, Gourlay T, Asimakopoulos G, et al. Leucodepletion during cardiopulmonary bypass reduces
blood transfusion and crystalloid requirements. Perfusion 2001;16:51-58.
451. Chen YF, Tsai WC, Lin CC, et al. Effect of leukocyte depletion on endothelial cell activation and
transendothelial migration of leukocytes during cardiopulmonary bypass. Ann Thorac Surg 2004;78:634-642.
452. Leal-Noval SR, Amaya R, Herruzo A, et al. Effects of a leukocyte depleting arterial line filter on perioperative
morbidity in patients undergoing cardiac surgery: a controlled randomized trial. Ann Thorac Surg 2005;80(4):1394-
1400.
453. Ilmakunnas M, Pesonen EJ, Ahonen J, et al. Activation of neutrophils and monocytes by a leukocyte-depleting
filter used throughout cardiopulmonary bypass. J Thorac Cardiovasc Surg 2005;129:851-859.
454. Whitaker DC, Newman SP, Stygall J, et al. The effect of leucocyte-depleting arterial line filters on cerebral
microemboli and neuropsychological outcome following coronary artery bypass surgery. Eur J Cardiothorac Surg
2004;25:267-274.
455. Whitaker DC, Stygall J, Harrison MJ, et al. Leucocyte-depleting arterial line filtration does not reduce myocardial
injury assessed by troponin T during routine coronary artery bypass grafting using crossclamp fibrillation. Perfusion
2006;21:55-60.
456. Gu YJ, de Vries AJ, Boonstra PW, et al. Leukocyte depletion results in improved lung function and reduced
inflammatory response after cardiac surgery. J Thorac Cardiovasc Surg 1996;112:494-500.
457. Heerdt EM, Fransen EJ, Maessen JG, et al. Efficacy of leukocyte depletion of residual pump blood. Perfusion
2004;19:3-5.
458. Martin J, Krause M, Benk C, et al. Blood cardioplegia filtration. Perfusion 2003;18:75-80.
459. Palatianos GM, Foroulis CN, Vassili MI, et al. A prospective, double-blind study on the efficacy of the bioline
surface-heparinized extracorporeal perfusion circuit. Ann Thorac Surg 2003;76:129-135.
460. Hayashi Y, Sawa Y, Fukuyama N, et al. Leukocyte-depleted terminal blood cardioplegia provides superior
myocardial protective effects in association with myocardium-derived nitric oxide and peroxynitrite production for
patients undergoing prolonged aortic crossclamping for more than 120 minutes. J Thorac Cardiovasc Surg
2003;126:1813-1821.
461. Samankatiwat P, Samartzis I, Lertsithichai P, et al. Leucocyte depletion in cardiopulmonary bypass: a

comparison of four strategies. Perfusion 2003;18:95-105.
462. Warren O, Alexiou C, Massey R, et al. The effects of various leukocyte filtration strategies in cardiac surgery.
Eur J Cardiothorac Surg 2007;31(4):665-676.
463. Salamonsen RF, Anderson J, Anderson M, et al. Total leukocyte control for elective coronary bypass surgery
does not improve short-term outcome. Ann Thorac Surg 2005;79:2032-2039.
464. Olivencia-Yurvati AH, Ferrara CA, Tierney N, et al. Strategic leukocyte depletion reduces pulmonary
microvascular pressure and improves pulmonary status post-cardiopulmonary bypass. Perfusion 2003;18(Suppl
1):23-31.
465. Sutton SW, Patel AN, Chase VA, et al. Clinical benefits of continuous leukocyte filtration during cardiopulmonary
bypass in patients undergoing valvular repair or replacement. Perfusion 2005;20:21-29.
466. Patel AN, Sutton SW, Livingston S, et al. Clinical benefits of leukocyte filtration during valve surgery. Am J Surg
2003;186:636-640.
467. Gott JP, Cooper WA, Schmidt FE, et al. Modifying risk for extracorporeal circulation: trial of four anti-
inflammatory strategies. Ann Thorac Surg 1998;66:747-754.
P.92
468. Apostolakis EE, Koletsis EN, Baikoussis NG, et al. Strategies to prevent intraoperative lung injury during
cardiopulmonary bypass. J Cardiothorac Surg 2010;5:1.
469. Warren O, Wallace S, Massey R, et al. Does systemic leukocyte filtration affect perioperative hemorrhage in
cardiac surgery? A systematic review and meta-analysis. ASAIO J 2007;53(4):514-521.
470. Baile EM, Ling IT, Heyworth JR, et al. Bronchopulmonary anastomotic and noncoronary collateral blood flow in
humans during cardiopulmonary bypass. Chest 1985;87:749-754.
471. Killen DA, Piehler JM, Borkon AM, et al. Occult patent ductus arteriosus encountered during coronary artery
bypass procedures [Letter]. J Thorac Cardiovasc Surg 1994;108:588-589.
472. Tunick PA, Kronzon I. Diagnoses of patent ductus arteriosus by serendipity in the adult. J Am Soc Echocardiogr
1988;1:446-449.
473. Amir IM, Maranets I, Barash P. Transesophageal echocardiography of the distal aortic arch. J Cardiothorac
Vasc Anesth 1998;12:599-603.
474. Arom KV, Vinas JF, Fewel JE, et al. Is a left ventricular vent necessary during cardiopulmonary bypass? Ann
Thorac Surg 1977;24:566-573.
475. Burton NA, Graeber GM, Zajtchuk R. An alternate method of ventricular venting-the pulmonary artery sump.
Chest 1984;85:814-815.
476. Breyer RH, Meredity JW, Mills SA, et al. Is a left ventricular vent necessary for coronary artery bypass
procedures performed with cardioplegic arrest? J Thorac Cardiovasc Surg 1983;86:338-349.
477. Buckberg GD. The importance of venting the left ventricle [Editorial]. Ann Thorac Surg 1975;20:488-490.
478. Kanter KR, Schaff HV, Gott VL. Reduced oxygen consumption with effective left ventricular venting during
postischemic reperfusion. Circulation 1982;66(Suppl I):I-50-I-54.
479. Olinger GN, Bonchek LI. Ventricular venting during coronary revascularization: assessment of benefit by
intraoperative ventricular function curves. Ann Thorac Surg 1978;26:525-534.
480. Hammon JW, Stump DA, Hines M, et al. Prevention of embolic events during coronary artery bypass graft
surgery. Perfusion 1994;9:412-413.
481. Little AG, Lin CY, Wernley JA, et al. Use of the pulmonary artery for left ventricular venting during cardiac
operations. J Thorac Cardiovasc Surg 1984;87:532-538.
482. Roach GW, Bellows WH. Left ventricular distension during pulmonary artery venting in a patient undergoing
coronary artery bypass surgery. Anesthesiology 1992;76:655-658.
483. Lundy EF, Gassmann CJ, Bonchek LI, et al. A simple and safe technique of left ventricular venting. Ann Thorac
Surg 1992;53:1127-1129.
484. Casha AR. A simple method of aortic root venting for CABG [Letter]. Ann Thorac Surg 1998;66:608-609.
485. Victor S, Kabeer M. Venting and de-airing without a roller pump [Letter]. Ann Thorac Surg 1993;55:807.
486. Utley JR, Stephens DB. Venting during cardiopulmonary bypass. In: Utley JR, ed. Pathophysiology and
techniques of cardiopulmonary bypass. Baltimore, MD: Williams & Wilkins, 1983:115-127.
487. Robicsek F, Duncan GD. Retrograde air embolization in coronary operations. J Thorac Cardiovasc Surg
1987;94:110-114.
488. Weesner KM, Byrum C, Rosenthal A. Left ventricular aneurysms associated with intraoperative venting of the
cardiac apex in children. Am Heart J 1981;101:622-625.
489. Marco JD, Barner HB. Aortic venting: comparison of vent effectiveness. J Thorac Cardiovasc Surg
1977;73:287-292.
490. Brenner WI, Wallsh E, Spencer FC. Aortic vent efficiency: a quantitative evaluation. J Thorac Cardiovasc Surg
1971;61:258-264.
491. Milsom FP, Mitchell SJ. A dual-vent left heart deairing technique markedly reduces carotid artery micro emboli.
492. Gundry SR. Facile left ventricular de-airing by administration of cardioplegia into the left ventricular vent. Ann
Thorac Surg 1998;66:2117-2118.
493. Menasché P, Touchot B, Pradier F, et al. Simplified method for delivering normothermic blood cardioplegia. Ann
Thorac Surg 1993;55:177-178.
494. Menasché P. Blood cardioplegia: do we still need to dilute? Ann Thorac Surg 1996;62:957-960.
495. Velez DA, Morris CD, Budde JM, et al. All-blood (miniplegia) versus dilute cardioplegia in experimental surgical
revascularization of evolving infarction. Circulation 2001;104(12, Suppl 1):I296-I302.
496. Algarni KD, Weisel RD, Caldarone CA, et al. Microplegia during coronary artery bypass grafting was associated
with less low cardiac output syndrome: a propensity-matched comparison. Ann Thorac Surg 2013;95:1532-1538.
497. Gong B, Ji B, Sun Y, et al. Is microplegia really superior to standard blood cardioplegia? The results from a
meta-analysis. Perfusion 2015;30(5):375-382.
498. Menasché P. Experimental comparison of manually inflatable versus autoinflatable retrograde cardioplegia
catheters. Ann Thorac Surg 1994; 58(2):533-535.
499. Clements F, Wright SJ, de Bruijn N. Coronary sinus catheterization made easy for Port-Access miimally invasive
cardiac surgery. J Cardiothorac Vasc Anesth 1998;12(1):96-101.
500. Panos AL, Ali IS, Birnbaum PL, et al. Coronary sinus injuries during retrograde continuous normothermic blood
cardioplegia. Ann Thorac Surg 1992;54(6):1137-1138.
501. Ikonomidis JS, Yau TM, Weisel RD, et al. Optimal flow rates for retrograde warm cardioplegia. J Thorac
Cardiovasc Surg 1994;107(2):510-519
502. Honkonen EL, Kaukinen L, Pehkonen EJ, et al. Myocardial cooling and right ventricular function in patients with
right coronary artery disease: antegrade vs. retrograde cardioplegia. Acta Anaesthesiol Scand 1997;41(2):287-296
503. Gourlay T, Stefanou DC, Asimakopuolos G, et al. The effect of circuit surface area on CD11b(mac-1)
expression in a rat recirculation model. Artif Organs 2001;25:475-479.
504. Mueller XM, Jegger D, Augstburger A, et al. A new concept of integrated cardiopulmonary bypass circuit. Eur J
505. Huybregts MA, de Vroege R, Christiaans HM, et al. The use of a mini bypass system (Cobe Synergy) without
venous and cardiotomy reservoir in a mitral valve repair: a case report. Perfusion 2005;20:121-124.
506. Fromes Y, Gaillard D, Ponzio O, et al. Reduction of the inflammatory response following coronary bypass
grafting with total minimal extracorporeal circulation. Eur J Cardiothorac Surg 2002;22:527-533.
507. Nollert G, Schwabenland I, Maktav D, et al. Miniaturized cardiopulmonary bypass in coronary artery bypass
surgery: marginal impact on inflammation and coagulation but loss of safety margins. Ann Thorac Surg
2005;80:2326-2332.
508. Christiansen S, Gobel C, Buhre W, et al. Successful use of a miniaturized bypass system with the DeltaStream
extracorporeal rotary blood pump. J Thorac Cardiovasc Surg 2003;125:43-44.
509. Momin A, Sharabiani M, Mulholland J, et al. Miniaturized cardiopulmonary bypass: the Hammersmith technique.
J Cardiothorac Surg 2013;8:143.
510. Momin AU, Sharabiani MT, Kidher E, et al. Feasibility and safety of minimized cardiopulmonary bypass in major
aortic surgery. Interact Cardiovasc Thorac Surg 2013;17:659-663.
511. Remadi J-P, Marticho P, Butoi I, et al. Clinical experience with the mini-extracorporeal circulation system: an
evolution or a revolution? Ann Thorac Surg 2004;77:2172-2176.
512. Remadi J-P, Rakotoarivelo Z, Marticho P, et al. Prospective randomized study comparing coronary artery
bypass grafting with the new mini-extracorporeal circulation jostra system or with a standard cardiopulmonary
bypass. Am Heart J 2006;151:198.
513. Abdel-Rahman U, Martens S, Risteski P, et al. The use of minimized extracorporeal circulation system has a
beneficial effect on hemostasis—a randomized clinical study. Heart Surg Forum 2006;9:E543-E548.
514. Wiesenack C, Liebold A, Philipp A, et al. Four years’ experience with a miniaturized extracorporeal circulation
system and its influence on clinical outcome. Artif Organs 2004;28:1082-1088.
515. Rex S, Brose S, Metzelder S, et al. Normothermic beating heart surgery with assistance of miniaturized bypass
systems: the effects on intraoperative hemodynamics and inflammatory response. Anesth Analg 2006;102:352-362.
516. Kiaii B, Fox S, Swinamer SA, et al. The early inflammatory response in a mini-cardiopulmonary bypass system:
a prospective randomized study. Innovations (Phila). 2012;7:23-32.
517. Yuruk K, Bezemer R, Euser M, et al. The effects of conventional extracorporeal circulation versus miniaturized
extracorporeal circulation on microcirculation during cardiopulmonary bypass-assisted coronary artery bypass graft
surgery. Interact Cardiovasc Thorac Surg 2012;15:364-370.
518. Lilly KJ, O’Gara PJ, Treanor PR, et al. Cardiopulmonary bypass: it’s not the size, it’s how you use it! Review of
a comprehensive blood-conservation strategy J Extra Corpor Technol. 2004;36:263-268.
519. Norman MJ, Sistino JJ, Acsell JR. The effectiveness of low-prime cardiopulmonary bypass circuits at removing
gaseous emboli. J Extra Corpor Technol 2004;36:336-342.
520. Overdevest E, van Hees J, Lagerburg V, et al. Healthcare failure mode effect analysis of a miniaturized
extracorporeal bypass circuit. Perfusion 2014;29(4):301-306.
P.93
521. Mueller XM, Tevaearai HT, Jegger D, et al. Air filtering capacity of an integrated cardiopulmonary bypass unit.
ASAIO J 2003;49:365-369.
522. Ranucci M, Castelvecchio S. Management of mini-cardiopulmonary bypass devices: is it worth the energy? Curr
Opin Anaesthesiol 2009;22(1): 78-83.
523. Harling L, Warren OJ, Martin A, et al. Do miniaturized extracorporeal circuits confer significant clinical benefit
without compromising safety? A meta-analysis of randomized controlled trials. ASAIO J 2011;57:141-151.
524. Zangrillo A, Garozzo FA, Biondi-Zoccai G, et al. Miniaturized cardiopulmonary bypass improves short-term
outcome in cardiac surgery: a meta-analysis of randomized controlled studies. J Thorac Cardiovasc Surg
2010;139:1162-1169.
525. Biancari F, Rimpiläinen R. Meta-analysis of randomised trials comparing the effectiveness of miniaturised
versus conventional cardiopulmonary bypass in adult cardiac surgery. Heart 2009;95:964-969.
526. Harling L, Punjabi PP, Athanasiou T. Miniaturized extracorporeal circulation vs. off-pump coronary artery bypass
grafting: what the evidence shows? Perfusion. 2011;26(Suppl 1):40-47.
527. Formica F, Mariani S, Broccolo F, et al. Systemic and myocardial inflammatory response in coronary artery
bypass graft surgery with miniaturized extracorporeal circulation: differences with a standard circuit and off-pump
technique in a randomized clinical trial. ASAIO J 2013;59:600-606.
528. Curtis N, Vohra HA, Ohri SK. Mini extracorporeal circuit cardiopulmonary bypass system: a review. Perfusion
2010;25(3):115-124.
529. Baikoussis NG, Papakonstantinou NA, Apostolakis E. The “benefits” of the mini-extracorporeal circulation in the
minimal invasive cardiac surgery era. J Cardiol 2014;63(6):391-396
530. Sukernik MR, Mets B, Bennett-Guerrero E, et al. Patent foramen ovale and its significance in the perioperative
period. Anesth Analg 2001;93: 1137-1146.
531. Gu YJ, Boonstra PW, Rijnsburger AA, et al. Cardiopulmonary bypass circuit treated with surface-modifying
additives: a clinical evaluation of blood compatibility. Ann Thorac Surg 1998;65:1343-1347.
532. Wimmer-Greinecker G, Matheis G, Martens S, et al. Synthetic protein treated versus heparin coated
cardiopulmonary bypass surfaces: similar clinical results and minor biochemical differences. Eur J Cardiothorac Surg
1999;16(2):211-217.
533. Stammers AH, Christensen KA, Lynch J, et al. Quantitative evaluation of heparin-coated versus non-heparin-
coated bypass circuits during cardiopulmonary bypass. J Extra Corpor Technol 1999;31:135-141.
534. Nuttall GA, Oliver WC, Fass DN, et al. A prospective, randomized platelet-function study of heparinized
oxygenators and cardiotomy suction. J Cardiothorac Vasc Anesth 2006;20:554-561.
535. Mangoush O, Purkayastha S, Haj-Yahia S, et al. Heparin-bonded circuits versus nonheparin-bonded circuits:
an evaluation of their effect on clinical outcomes. Eur J Card Thorac Surg 2007;31:1058-1069.
536. Gunaydin S, Farsak B, McCusker K, et al. Clinical and biomaterial evaluation of hyaluronan-based heparin-
bonded extracorporeal circuits with reduced versus full systemic anticoagulation in reoperation for coronary
revascularization. J Cardiovasc Med (Hagerstown) 2009;10:135-142.
537. Mahmood S, Bilal H, Zaman M, et al. Is a fully heparin-bonded cardiopulmonary bypass circuit superior to a
standard cardiopulmonary bypass circuit? Interact Cardiovasc Thorac Surg 2012;14:406-414.
538. Beppu T, Imai Y, Fukui Y. A computerized control system for cardiopulmonary bypass. J Thorac Cardiovasc
Surg 1995;109:428-438.
539. Kurusz M. Perfusion safety: new initiatives and enduring principles. Perfusion 2011;26(Suppl 1):6-14.
540. Misgeld BJ, Werner J, Hexamer M. Simultaneous automatic control of oxygen and carbon dioxide blood gases
during cardiopulmonary bypass. Artif Organs 2010;34(6):503-512.
541. Momose N, Yamakoshi R, Kokubo R, et al. Development of a new control device for stabilizing blood level in
reservoir during extracorporeal circulation. Perfusion 2010;25(2):77-82.
542. Fernandez A. Simulation in perfusion: where do we go from here? Perfusion. 2010;25(1):17-20.
543. Ninomiya S, Tokumine A, Yasuda T, et al. Development of an educational simulator system, ECCSIM-Lite, for
the acquisition of basic perfusion techniques and evaluation. J Artif Organs 2007;10(4):201-215.
544. Ninomiya S, Tokaji M, Tokumine A, et al. Virtual patient simulator for the perfusion resource management drill. J
Extra Corpor Technol 2009;41(4):206-212.
545. Morris RW, Pybus DA. “Orpheus” cardiopulmonary bypass simulation system. J Extra Corpor Technol
2007;39(4):228-233.
546. Turkmen A, Rosinski D, Noyes N. A simulator for perfusion training. Perfusion 2007;22(6):397-400.
547. Momose N, Tomizawa Y. Incident-simulating device with wireless control for extracorporeal circulation crisis
management drills. Perfusion 2008;23(1):17-21.
548. Raasch D, Austin J, Tallman R. Self-priming hemodynamic reservoir and inline flow meter for a cardiopulmonary
bypass simulation. J Extra Corpor Technol 2010;42(2):145-149.
549. Schiralli MP, Hicks GL, Angona RE. An inexpensive cardiac bypass cannulation simulator: facing challenges of
modern training. Ann Thorac Surg 2010;89(6):2056-2057.
550. Tokaji M, Ninomiya S, Kurosaki T, et al. An educational training simulator for advanced perfusion techniques
using a high-fidelity virtual patient model. Artif Organs 2012;36(12):1026-1035.
551. Tokumine A, Ninomiya S, Tokaji M, et al. Evaluation of basic perfusion techniques, ECCSIM-Lite simulator. J
Extra Corpor Technol 2010;42(2): 139-144.
552. Power G, Miller A. Preliminary analysis of perfusionists’ strategies for managing routine and failure mode
scenarios in cardiopulmonary bypass. J Extra Corpor Technol 2007;39(3):160-167.
553. Sistino JJ, Michaud NM, Sievert AN, et al. Incorporating high fidelity simulation into perfusion education.
Perfusion 2011;26(5):390-394.
554. Burkhart HM, Riley JB, Hendrickson SE, et al. The successful application of simulation-based training in
thoracic surgery residency. J Thorac Cardiovasc Surg 2010;139(3):707-712.
555. Fouilloux V, Gsell T, Lebel S, et al. Assessment of team training in management of adverse acute events
occurring during cardiopulmonary bypass procedure: a pilot study based on an animal simulation model (Fouilloux,
Team training in cardiac surgery). Perfusion. 2014;29(1):44-52.
556. Fouilloux V, Doguet F, Kotsakis A, et al. A model of cardiopulmonary bypass staged training integrating
technical and non-technical skills dedicated to cardiac trainees. Perfusion 2015;30(2):132-139.
557. Bruppacher HR, Alam SK, LeBlanc VR, et al. Simulation-based training improves physicians’ performance in
patient care in high-stakes clinical setting of cardiac surgery. Anesthesiology 2010;112(4):985-992.
558. Darling E, Searles B. Oxygenator change-out times: the value of a written protocol and simulation exercises.
Perfusion 2010;25(3):141-143.
559. Martin JT, Reda H, Dority JS, et al. Surgical resident training using real-time simulation of cardiopulmonary
bypass physiology with echocardiography. J Surg Educ 2011;68(6):542-546.
560. Fann JI, Feins RH, Hicks GL Jr, et al; Senior Tour in Cardiothoracic Surgery. Evaluation of simulation training in
cardiothoracic surgery: the Senior Tour perspective. J Thorac Cardiovasc Surg 2012;143(2):264-272.
561. Stevens LM, Cooper JB, Raemer DB, et al. Educational program in crisis management for cardiac surgery
teams including high realism simulation. J Thorac Cardiovasc Surg 2012;144(1):17-24.
562. Ji B, Undar A. An evaluation of the benefits of pulsatile versus nonpulsatile perfusion during cardiopulmonary
bypass procedures in pediatric and adult cardiac patients. ASAIO J 2006;52:357-361.
Chapter 3
Principles of Oxygenator Function: Gas Exchange, Heat Transfer,
and Operation
Michael H. Hines
INTRODUCTION
Since the early 1950s when the development of a heart-lung machine first began, there has been a tremendous
evolution of devices and machinery for cardiac support (1,2). However, despite the diversity in designs through
the years, they all contain three essential components: a mechanism to circulate the blood, a method of gas
exchange for oxygen and carbon dioxide, and some mechanism for temperature control. Chapter 2 has covered
the first important component, and we will now focus on the two subsequent elements: gas exchange and heat
transfer. And while it is referred to as the “oxygenator,” we must recognize that it is responsible for the movement
of both oxygen in, as well as carbon dioxide out. The discussion will start with a basic review of the principles of
physics, and then we will apply those principles to the devices used specifically in extracorporeal support,
including cardiopulmonary bypass (CPB) and extracorporeal membrane oxygenation (ECMO).
You may notice as you go through this chapter that there is a scarcity of trade and manufacturer names. The
author has intentionally avoided using these. The intent was primarily to focus on the physiology, physics, and
chemistry of the oxygenator and heat exchanger, but also to emphasize the fact that there are a large number of
manufacturers producing many products that have all been shown to function extremely well. While we have
witnessed dramatic improvements with the evolution from bubble to membrane to hollow fiber oxygenators, there
is little, if any, data demonstrating definitive superiority of one product over another within one class, for example,
polypropylene hollow fiber oxygenators. In fact, many comparisons have demonstrated only subtle differences
that have minimal impact on clinical practice (3). This includes the multitude of different coatings which we will
discuss using generic chemical names. We have on occasion provided references that have specifically
compared different products such as biocompatibility coatings, but will not include this information in the text. In
doing this, we can more easily remove any commercial bias, and hope to offer the reader a better understanding
of the principles and functionality of the devices so that they can then evaluate the available commercial options
themselves and select products that best suit their needs based on applications, availability, margins of safety,
cost, and track records.
PHYSICS OF GAS EXCHANGE

The movement of gas molecules of oxygen (O2) and carbon dioxide (CO2) between air and blood across a
biologic or synthetic barrier is controlled by several specific laws of physics. We will first review the principles of
those laws and then discuss their direct application to the natural process in the human lung, as well as our
attempt to imitate the natural process with various devices and techniques.
Dalton’s Law (John Dalton, 1801):
The total pressure of a mixture of gases is equal to the sum of the partial pressures of all the individual gases in
that volume. At sea level this must equal 760 mm Hg.
Fick's First Law of Diffusion (Adolf Fick, 1855):
In this mathematical formula, J represents the diffusion flux or amount of substance (e.g., O2) moved per unit
area, per unit time. D, the diffusion coefficient, is a constant for the particular barrier, based on its composition,
and so forth. It is also referred to as the “diffusivity,” and the preceding negative sign simply makes the flux J
positive when the movement is down the concentration gradient. The diffusion coefficient for specific molecules
of gas across biologic membranes such as the alveoli may change relatively rapidly due to inflammation, edema,
or injury that may change the characteristics of the membrane. However, it should be constant for synthetic
barriers such as membrane oxygenators, affected only by significant changes in temperature and pressure (or at
least until it is placed in the biologic setting when it can be affected by clotting, etc.). The substance
concentration is represented by φ and the length by x. For purposes of the discussion of gas transfer across
membranes, Fick’s first law of diffusion tells us that the movement of O2 and CO2 across a barrier will be in the
direction of higher to lower concentration (partial pressure) with a magnitude that is proportional to the gradient,
and proportional to the area involved, and inversely
P.96
proportional to the diffusion coefficient or “diffusivity.” Simply put, gas diffusion occurs faster when the gradient
across the membrane is higher, and a “thinner” barrier allows more diffusion of gas than a “thicker” one, while a
barrier of equal “thickness” but much larger surface area will allow more gas to diffuse during the same time
interval.
Graham’s Law (Thomas Graham, 1848):
The diffusion rate of a gas is inversely proportional to the square root of its molecular weight.
Henry’s Law (William Henry, 1803):
The amount of gas that can dissolve in a volume of liquid is directly proportional to the partial pressure of the gas
in that liquid. Mathematically, where p is the partial pressure of a particular gas, c is the concentration of the
dissolved gas, and kH is a constant for a particular gas in a particular solution; for example, kH for O2 dissolved
in water at 298 K is 769.2 L atm/mol. It is this principle that allows gas bubbles to come out of solution in the
blood during depressurization, as when scuba divers get “the bends” from too rapid an ascent from diving.
Henry’s law allows larger quantities of gases inhaled at depths under much higher partial pressure due to the
surrounding water to become dissolved into solution in the blood, particularly with longer time periods of
exposure. If the diver ascends rapidly before the lungs are able to gradually expel the absorbed gas, then the
excess gas forms air bubbles in the blood, which are responsible for the symptoms and organ damage of
decompression illness, also known as “the bends” or Caisson disease.
FIGURE 3.1. Concurrent versus countercurrent flow. Increased transfer occurs due to movement along the entire
system with countercurrent flow, rather than the maximum 50:50 equilibrium achievable with concurrent flow.
Principle of Countercurrent Exchange

Given two parallel tubes filled with fluid or gas separated by a membrane with some degree of permeability to
components of that fluid or gas, the exchange of molecules or particles across the barrier is more efficient if the
movements of the liquids are opposite in direction. In a theoretical example with a readily diffusible gas G that we
want to move from one system to another through diffusion, we will assume that the concentration of G in what
we will refer to as the “donor” system is 100%, and that there is zero amount of G in the “recipient” side of the
system (Fig. 3.1). If the two systems are moving in parallel (concurrent), then at the entrance the concentrations
are 100% and 0%. As the two systems move along, there is continued diffusion of G across the barrier with
reduction of the concentration of G on the donor side, and increase in the concentration on the recipient side.
Gradually the concentrations change to 90%:10%, 80%:20%, and so on until equilibrium is reached at 50%:50%.
Continued movement along the additional length of the tube does not provide any additional exchange of G into
the recipient system, and the end result at the exit site remains 50%. If we now reverse the direction of one of the
systems so that the donor and recipient systems are flowing in opposite directions (countercurrent), the
movement of G can occur throughout the entire length of the system, because the gradient driving the diffusion
can be maintained. If there is sufficient length to the systems, the concentration of G can potentially reach 100%
at its exit site, immediately adjacent to the inlet side of the donor system
P.97
where the concentration is also 100%. Thus the equilibrium is reached at 100% rather than 50%. The gas
exchange across the gills of fish is an example of the natural biologic application of this efficient principle of
countercurrent exchange. Countercurrent exchange applies not only to the transfer of gases as in the example,
but equally to movement of substances between liquids, a gas and a liquid, as well as to transfer of heat
between two fluids (liquids or gases).
OXYGENATORS FOR EXTRACORPOREAL SUPPORT

Basic Oxygenator Design
The natural process of gas exchange in the lung involves directing the blood into small capillaries adjacent to the
thin-walled alveolus containing inhaled air so that oxygen may diffuse in and carbon dioxide may diffuse out,
based on the principles of diffusion in Fick’s law outlined above. The capillary size is such that the cells move
through essentially one at a time to provide maximal exposure and time for gas exchange. The massive
respiratory surface area of the normal human lung provides for extremely efficient and large-volume exchange of
O2 and CO2. Appropriate exchange does require the efficient movement of air in and out of the alveoli through
the same passages, which creates the potential for dead space ventilation issues.
In designing an artificial lung equivalent to be used for short periods during CPB, many factors must be
considered which frequently play against each other. For example, having a very large surface area will maximize
the potential for gas exchange, but then also increase the size of the device, and thus the priming volume
required to fill it, and the associated hemodilution and potential transfusion requirement. Mimicking the natural
lung with tiny “capillary-like” blood passages would also maximize the efficiency of exchange, yet would create
extremely high resistances within the membrane, requiring a very large surface area, and leading to more shear
stresses, hemolysis, and so forth. Thus, the development of the ideal device for gas exchange has been built
upon a series of compromises between the advantages and disadvantages of available surface area, resistance
to flow, size, priming volume, diffusion capability, plasma leakage, and biocompatibility.
Measurements of Oxygenator Performance and Capabilities

In an attempt to create industry standards for comparison of capabilities between oxygenators, the Association
for the Advancement of Medical Instrumentation previously developed a set of standards for oxygenators.
However, the reliability of those standards was questioned because they failed to consider the impact of
variability in inlet conditions which affects the variability of gas transfer. It was subsequently shown that
improvements in gas transfer in some devices could be demonstrated by changing the conditions under which
the oxygenators were evaluated (4,5,6). Despite the lack of acceptance of those standards, there are a series of
measurements that help to define the physical and functional capacity of oxygenators. As previously referred to,
the priming volume is the volume of fluid (crystalloid or blood) required to fill the blood phase of the device,
including any integrated heat exchanger. This may also include some minimal level in the reservoir depending on
the device and the manufacturer. Manufacturers also provide minimum and maximum operating volumes for
their specific devices. The ability of an oxygenator to oxygenate blood is expressed in the oxygen reference
blood flow, which is defined as the flow rate of whole blood at normothermia, with a normal hemoglobin (12
g/dL), with a base excess of zero, that will increase the oxygen content of venous blood with an oxygen
saturation of 65%, by 45 mL/L of flow. Similar measurements of a device’s ability to remove CO2 are expressed
in the carbon dioxide reference blood flow. Also provided is the index of hemolysis for the device, expressed as
the amount of free hemoglobin/100 cc of blood pumped through the oxygenator during an in vitro test. Finally,
the rated flow or reference flow is the maximal recommended flow to achieve adequate gas exchange, and is
equal to the lowest flow among the oxygen reference blood flow, carbon dioxide reference blood flow,
manufacturer’s recommended maximal flow, or 8 L/min (7).
Direct Contact Oxygenators (Bubble, Screen, Rotating Disc, Drum)

Without repeating the history of the development of the early-generation oxygenators covered in the previous
chapters of this book, we will discuss only the physiologic concepts of gas exchange where there is direct
contact of blood with the gas phase, rather than the specifics of the designs of the various early machines. In all
of the devices, the blood from the patient’s body would enter the machine and at some point directly mix with a
gas mixture of primarily oxygen in the form of very small bubbles generated through several mechanisms,
frequently using a device called a sparger that generated the gas bubbles (8). Each bubble provided the surface
area within the blood for gas exchange. The size of the bubbles became very important, since the available
surface area for gas exchange is inversely proportional to the bubble diameter: smaller bubbles provided more
surface area and more efficient transfer of oxygen. However, if the bubbles were too small, the rapid rise in CO2
tension limited the amount of CO2 removal that was possible. Gradually, manufacturers determined the proper-
sized bubbles that would provide an ideal respiratory quotient for the system of about 0.8 (CO2 elimination: O2
uptake). Once the bubbles are generated and mix with the venous blood, the mixture has sufficient time for the
transfer of oxygen directly onto the hemoglobin molecules in the blood (with a very small proportion going into
solution). Simultaneously, the CO2 would leave the solution and enter the bubbles, exiting near the top of the
device or in a separator. As the blood progresses, any residual bubbles would gradually coalesce and be filtered
from the blood prior to it being returned
P.98
to the patient. One of the biggest hurdles with this design was the formation of foam from the aeration of the
blood, and various de-foaming agents and designs were used to try to minimize this problem. A major advantage
was the very efficient gas exchange that the direct contact provided. However, the same direct exposure was
also severely injurious to the cellular blood components if used for prolonged periods. Another advantage was
the very low pressure drop or resistance in the bubble oxygenator design, since there was no need to direct the
blood through small conduits adjacent to the gas phase for O2 and CO2 exchange as in a membrane. The
driving force of the venous blood was simply the hydrostatic column, and its upward motion during the gas
exchange was facilitated by the rising bubbles. The large size and capacitance of the devices meant they could
also serve as the venous reservoirs for the system.
Despite the physiology simplicity of the bubble oxygenators and the other direct contact devices, the cost and
complexity of the setup, along with the limitations caused by direct damage to the blood, made it less practical for
longer or more complex cardiac operations, and led to the development of more sophisticated oxygenators.
Membrane Oxygenators
Many different materials were trialed in the early designs of gas exchange devices, including ceramics, plastics,
rubber, and a number of synthetic products like cellulose, polyethylene, and Teflon. During this time, much
understanding was gained in the mechanisms of gas exchange across a membrane oxygenator (9). However,
the first widely applicable clinical oxygenator which completely eliminated the direct contact of the blood and gas
phases, making it a true membrane oxygenator, was designed by Kolobow and colleagues (10,11). The
advantages the new membrane offered were the separation of the blood and gas, reducing the damage and
thrombosis seen with bubble oxygenators (12), as well as the reduction of gaseous emboli (13). In addition, with
the new oxygenators, the blood was no longer pushed upward by the moving gas bubbles, but was pumped
through the membrane independent of the gas flow, thus allowing separate regulation of the rate and
composition of the gas phase to manage O2 and CO2 exchange. The membrane was constructed as a long
rolled coil from a sheet of a silicone polymer which completely divided the gas and blood phases. Gas exchange
was not as efficient as through other materials, in that the oxygen had to essentially diffuse into the silicone
polymer phase and then diffuse out into the blood, with the same process in reverse for carbon dioxide. Thus,
much larger surface areas were required and concurrently larger priming volumes. The membrane also had
relatively high resistance or pressure drop from the inlet to outlet of the blood phase. The membrane had
acceptable biocompatibility, requiring significant anticoagulation and was recognized to stimulate the fibrinolytic
system, and was also found to absorb large quantities of certain drugs, making therapeutic levels often difficult to
achieve. However, unlike other synthetic plastics in use for clinical oxygenators, primarily polypropylene, the
silicone membrane remained essentially impermeable to plasma proteins and could often be used for weeks
without failure, making it ideal for long-term support such as ECMO. In the operating room where the oxygenator
was required to be functional for only few hours, and where plasma leakage and oxygenator failure were less of
an issue, the large size and priming volumes made it much less practical than other available options.
Microporous Oxygenators
Unlike the large, less efficient silicone membrane oxygenators, the so-called microporous hollow fiber
oxygenators were designed specifically for the needs of the operating room where short-term use with small
devices requiring low priming volumes and low resistances were very advantageous. The vast majority of
oxygenators were made of polypropylene hollow fibers, although a few utilized sheets of polypropylene, where
micropores less than 1 ìm are created through a process of heating and stretching the material. The gas moves
through the small fibers which are surrounded by blood moving in countercurrent fashion. Once exposed to
blood, the pores in the fibers become coated with plasma proteins through which gas molecules may pass, but
through which the plasma proteins and water do not due to the surface tension of the blood. Over time, the pores
eventually allow plasma components across the pores into the gas phase, known as plasma leakage. This
usually takes a number of hours or even days, much longer than needed for CPB support; so it is usually not
clinically relevant, except when these membranes are used for longer-term support such as ECMO. In those
cases, very close monitoring of oxygenator function and frequent oxygenator changes are required.
While the goal of the oxygenator is to mimic the function of the native lung by providing sufficient oxygen supply
and carbon dioxide removal, it is not feasible to reproduce the structure of the lung. Gas flow moves across the
oxygenator instead of in and out of airways, which provides some advantage for oxygenator efficiency, perhaps
compensating for the fact that the oxygenator cannot begin to reproduce the lung model of gas exchange.
Oxygen-rich air enters the alveoli with inspiration and spends a short time within the massive respiratory surface
area that is the lung. Adjacent to the millions of alveoli are a similar number of tiny capillaries so small that the
red blood cells (RBCs) line up one by one to pass through as they perform the required exchange of gas
molecules. The hollow fiber oxygenators cannot begin to compete with such an efficient system. However, with
additional understanding of fluid dynamics and gas exchange, engineers have been able to design remarkably
efficient devices by compensating for weaknesses with additional strengths. This involves extremely complex
physics of fluid dynamics, which has been explained in detail elsewhere (14), and which we will try to simplify
here for the application of oxygenators. We noted earlier that the smallest feasible constructible pathway for
blood is still
P.99
over 100 times the size of capillaries, and if made any smaller the resistance becomes prohibitive for the
purposes of extracorporeal support. This is compensated for by increasing the length of the blood path over
1,000-fold. So instead of each cell briefly passing along an individual alveolus, we now have larger amounts of
blood passing through wider, but very long distances to create more effective surface area for gas exchange.
Because the blood is a viscous fluid, the velocity of the flow is not consistent everywhere within the oxygenator.
And while the gas actually flows within the microfibers, and the blood around them, let us consider the movement
of blood as if it were in a tube, to get a better understanding of the fluid dynamics and its impact on gas
exchange. Within the “tube,” the velocity of the blood varies, with the fastest flow in the center and the
surrounding blood moving at gradually decreasing velocities as it gets further from the center and closer to the
outer edge, which would be the interface with the gas phase. At this point, the velocity is theoretically zero and
the central flow is maximal. At the interface where there is zero velocity, a boundary layer is formed where
diffusion of oxygen takes place across the membrane. Since the solubility of oxygen into the liquid portion of
blood is very low, the majority of diffusion occurs at or near the interface onto the hemoglobin within the blood
near the boundary layer. Diffusion further into stream is more difficult because of distance. If the length of the
blood path is short and there is perfectly laminar flow, little to no oxygen would get to the hemoglobin in the
central stream of blood. However, the flow is not laminar and turbulence acts to disrupt the layers of the velocity
gradient and increases eddy currents and mixing. In this circumstance, this is highly desirable so as to increase
the ability of oxygen to diffuse onto more available hemoglobin molecules. This problem could be also solved by
increasing the blood path length and dwell time, but this would dramatically increase the surface area, the size of
the oxygenator, and thus the prime volume. Another solution would be to decrease the width of the blood path,
reducing the distance between the interface and the central stream, but as previously stated, this would
significantly increase the resistance to flow to an impractical level. By putting the gas through the fibers instead
of the blood, the resistance is much lower and allows adequate contact for gas exchange. The gas-containing
microfibers are placed in nonlinear fashion with a number of gentle twists and turns creating turbulence and
increased mixing, but not so much as to increase shear stress and cause damage to the RBCs. Additional fans
or small blades are placed within the blood phase to achieve the same effect, which is known as “secondary
flow” (15).
Unlike oxygen, carbon dioxide is much more soluble in blood where it is quickly converted to bicarbonate.
Additional molecules of CO2 are transported on amine groups of plasma proteins, including hemoglobin, making
the excretion of CO2 much less problematic than the delivery of oxygen (Figs. 3.2 and 3.3).
FIGURE 3.2. A typical adult open system showing the cardiotomy reservoir (A), collapsible venous collection
chamber (B), and combined polypropylene oxygenator and heat exchanger (C).
“Plasma-Tight” Hollow Fiber Oxygenators

In 2008, the first polymethylpentene (PMP) hollow fiber oxygenator was approved by the Food and Drug
Administration (FDA) for use in the United States for extracorporeal support. While PMP oxygenators had been
used in Europe for many years, their introduction in the United States provided an important new tool for long-
term extracorporeal support. Like the polypropylene predecessor, the PMP oxygenators had very efficient gas
exchange, low surface areas and priming volumes, excellent biocompatibility, and very low resistance to blood
flow. However, the hollow fibers of PMP were truly nonporous, instead of being covered with a very thin
membrane, which allowed efficient gas exchange without the eventual plasma leakage, although rare cases have
been reported (16). While this made little difference in the operating theater, it revolutionized ECMO support in
this country and around the world by providing a low-volume, low-resistance, biocompatible, and efficient
oxygenator that could be used for days or weeks at a stretch (Fig. 3.4). The only disadvantage this author has
noted with these oxygenators in comparison to the
P.100
previously employed silicone membranes is the rapidity with which they fail when they do get thrombosis. While
the stimulus for coagulation does seem to be less with the PMP and its various coatings, because the surface
area and volume are so small, when thrombosis is initiated, it can progress extremely rapidly causing relatively
sudden oxygenator failure. This becomes extremely important in light of the trends in ECMO support and the
desire for a simpler and more “automated” and compact system, which has led to less monitoring of pre- and
postmembrane pressures and less close observation by experienced staff. With that comes less warning of
potential problems, and perhaps less safety margin in preventing a sudden and potentially catastrophic failure of
the system.
FIGURE 3.3. A miniaturized pediatric circuit for infants, with the venous reservoir (A) and the polypropylene
oxygenator/heat exchanger (B). Also shown are the roller pump (C) and a hemofilter (D).
Reservoirs
Systems for CPB also include some form of reservoir—either a soft-collapsible device or a solid container that
serves a number of functions, or some combination (see Figs. 3.2 and 3.3). The primary function is the regulation
of volume and provides the pump a continued source of blood for delivery to the patient, even if there is
temporary interruption of venous return from the patient, either intentional or inadvertent. The reservoir is made
large enough to completely exsanguinate the patient’s blood volume in cases of deep hypothermic circulatory
arrest. After entering the reservoir, the blood spends a short amount of time there, allowing any bubbles that may
have entered to rise to the top, as the blood is then drained from the bottom of the reservoir to be then pumped
through the oxygenator and heat exchanger. This transient stasis is very useful in de-airing the blood,
particularly with the use of suction devices that return shed blood directly back to the pump, but is also the
reason that CPB requires a higher level of anticoagulation (usually activated clotting times over 400 seconds)
when compared to ECMO circuits which have no reservoir, minimal areas of stasis, and can be run with much
lower levels of anticoagulation. But because the ECMO circuits do not have any reservoir (other than a small
servo-regulator or compliance chamber), their continued function is completely dependent on a steady and
uninterrupted supply of venous return from the patient. There are additional safety devices such as arterial filters
(which are now optionally integrated within the oxygenator itself) and bubble detectors, but these will be
discussed in more detail in Chapter 23. ECMO systems are “closed,” in that they do not have reservoirs; so
every cubic centimeter of blood that is pumped into the patient must be replaced by a cubic centimeter coming
into the venous return side. While many systems do have very small collapsible compartments used as either
servo-regulators for roller pumps or compliance
P.101
chambers to minimize cavitation of air from the high negative pressures generated by centrifugal pumps, these
are not reservoirs and do not have the capacity to store or supply blood volume. However, this also eliminates
much of the stasis of blood within the system and is the reason ECMO can run on significantly lower levels of
anticoagulation when compared to CPB.
FIGURE 3.4. A polymethylpentene oxygenator with combined internal heat exchanger commonly used for long-
term support (ECMO).
Operation of the Oxygenator

The heart-lung machine is usually controlled by a perfusionist, who is responsible for maintaining adequate
oxygen delivery to all the body’s tissues and organs during the period of support. Similarly, the ECMO circuit is
maintained by personnel who perform similar roles on a longer-term basis. This involves all three highly
interrelated components of support: the pump, the oxygenator, and temperature control. Providing adequate
pump flow is the equivalent to the native cardiac output. Controlled hypothermia results in a protective effect
during support or after acute ischemia/hypoperfusion by decreasing metabolic demands. And adequate gas
exchange provides the needed oxygen to the tissues (provided adequate flow and adequate oxygen carrying
capacity by hemoglobin) as well as carbon dioxide removal. The movement of O2 and CO2 across the
oxygenator is governed by the same principles and laws of physics regarding diffusion coefficients and
gradients; however, our strategy on CPB or ECMO is somewhat different since we are driving oxygen in, while
removing carbon dioxide. So while the partial pressures and gradients control the movement of the gases, we
only have control of one side of the equation: the driving gradient for oxygen, but the “downhill” side of the
gradient for carbon dioxide. Because of this, their management can be uncoupled and we will discuss them
separately. Just as with management of the native lung, we can increase the amount of diffused oxygen across a
membrane by increasing the gradient with a higher concentration of oxygen. For a patient on ventilator, we refer
to the inspired oxygen concentration of air, or F FIO2. We use the same terminology for the inflow gas of the
oxygenator even though it is technically not inspired or expired like the lungs, but rather enters at one end and
exits at the other. This is referred to as the “sweep gas” and the flow referred to as the “sweep rate,” as given in
L/min or mL/min. Physiologically, it is equivalent to the minute ventilation of native lung function, but without the
issue of dead space ventilation of the native airways. Unlike the lung tissue, the artificial surface of the
oxygenator is not susceptible to oxygen toxicity, so that flow of 100% oxygen into the sweep gas does not carry
the risk of inflammation seen in the alveoli. There is some theoretical concern regarding the effect of an
extremely high PO2 in the blood, such that many recommend maintaining the PO2 in the 150 to 250 range during
CPB (17). However, even with long-term ECMO support, where many centers maintain the sweep concentration
at 100% for the entire course, with infusion of arterial blood on VA ECMO with very high PO2s, there has been
no documented ill effect or evidence that this is harmful.
Since we do not have direct control over the concentration of CO2 within the blood phase, but only control the
concentration in the sweep, we can only control the diffusion by increasing the gradient across the membrane by
keeping the sweep gas concentration as low as possible, essentially zero, with the infusion of 100% oxygen. The
quicker the CO2 that diffuses across the membrane from the blood to the gas phase is removed from the oxygen,
the quicker the gradient is reestablished, and the quicker more CO2 can be removed. Simply put, the faster the
sweep rate, the more the CO2 removal. Patients undergoing cardiac surgery on CPB support are under deep
anesthesia, and do not contribute additional gas exchange until the ventilator is again initiated prior to weaning
from support. However, with long-term ECMO support, not only are the patients not under anesthesia, they are
frequently awake and breathing, and often contributing some gas exchange as the native lungs slowly improve.
Many times they are able to remove CO2 at a more efficient rate than oxygen can diffuse into the blood, due to a
combination of residual pulmonary inflammation and edema as well as intrapulmonary shunting. It is not
uncommon that the sweep gas may be reduced to very low rates to maintain a normal partial pressure in the
patient’s blood; yet the patient would still require significant support with oxygenation before the lungs are well
enough to take over fully. In this circumstance, we can continue to provide maximal oxygen support with 100%
oxygen in the sweep gas, while decreasing or minimizing the removal of CO2 from the blood by adding CO2 into
the sweep gas in the form of a combination of O2 and CO2 known as Carbogen (Meduna’s mixture) which can
be carefully regulated with a flow meter and gas blender. Using the same law of diffusion, we are controlling the
gradient to control the amount of gas movement. Other gases such as volatile anesthetics may be added to the
sweep gas as well, primarily during CPB, using specially designed canisters that convert liquid agents to gas,
identically to the mechanism in the anesthetic machine. The movement of these agents into the blood follows the
same principles of diffusion as oxygen based on size, solubility, diffusion coefficients, and concentration
gradients.
Modern oxygenators are provided with a predetermined “rated flow” which is an expression of the maximal flow
that will still allow appropriate oxygenation (see earlier section on Measurements of Oxygenator Performance
and Capabilities). Flows above the rated flow are more likely to produce blood that is not fully oxygenated.
During CPB, patients are under general anesthesia and have generally decreased metabolism; so the ability to
provide sufficient gas exchange is rarely a problem. During ECMO, however, patients are more commonly awake
and mobile, occasionally ambulatory, and so with larger patients it may be difficult to meet their metabolic needs
without adding a second oxygenator. This should be done in parallel rather than in series to maximize gas
exchange as well as to not increase the resistance.
P.102
CHEMISTRY AND PHYSICS OF HEAT EXCHANGE
The principles within the laws of physics that regulate the transfer of heat (energy) are similar to those which
control the movement of gases, in that
direction and rate of movement are determined by the gradient, the area of interaction, and
the resistance to movement or transfer based on the properties of the materials involved.
Temperature Effect on Gas Solubility

The solubility of gases is inversely proportional to the temperature; so gases are more soluble in colder
temperatures and less so at warmer temperatures.
Le Chatelier's Principle (Henry Louis Le Châtelier circa 1899)

Also known as “the equilibrium law,” it describes the effect on equilibrium due to changes in temperature,
pressure, volume, and so forth. It states that when changes in the environment stress an equilibrium, the
equilibrium will shift to relieve that stress.
Fourier’s Law (Jean-Baptiste Joseph Fourier, 1822)

The rate of heat transfer through a particular material is proportional to the temperature gradient, and the area of
transfer.
Modes of Heat Transfer

Heat is transferred as kinetic energy from an area of higher temperature to an area of lower temperature by three
modes known as conduction, convection, and radiation. Radiation involves the transfer of energy by the
movement of charged particles within the atom as it is converted to electromagnetic radiation (this will not be
discussed here, as it does not apply to our discussion of heat transfer in CPB systems). Conduction involves the
transfer of energy between two objects that are in physical contact, and the rate of transfer is determined by the
thermal conductivity property of the material conducting the energy, or heat. Heat transfer by convection involves
the movement of molecules within “fluids” (liquids or gases) through the properties of diffusion (random
movement of individual particles or molecules), or by advection (related to bulk movement of fluids or currents)
during which the transfer of energy is from an object to its environment. In all modes of transfer, the energy
moves from the area of higher temperature to lower temperature until equilibrium is reached. In systems of
extracorporeal support, this primarily involves the transfer of heat out of the blood into cooler water in the
exchange system during a cooling phase and from warmer water back into the blood during active warming.
Determination of Heat Transfer Rate

The exact amount of energy (as heat) that is transferred from water to blood within the oxygenator system can be
accurately quantified using the laws of thermodynamics if one knows the specific heat of blood, the blood flow
rate, and the temperature at the beginning and end of the transfer process. And while this measurement is
important in the design, manufacturing, and testing of heat exchangers, it is not particularly practical or useful in
the direct management of patients on CPB. Rather more important is a firm understanding of the basic principles
of heat exchange, and how they are affected by the patient and the local environment of the circuit. Many of the
principles that direct heat exchange are parallel in nature to those discussed with gas exchange, namely the
principles of diffusion. As outlined above, Fourier’s law tells us that the rate of heat transfer between the water
and the blood is proportional to the temperature gradient and to the amount of surface area available for the
transfer, and also determined by the ability of the material between the two fluids to allow the transfer or its
thermal conductivity. Highly conductive materials are chosen for use in circumstances where rapid heat transfer
is desired, such as in CPB, whereas poorly conductive materials provide insulation by minimizing the transfer of
heat. Assuming the material between the water and blood has high thermal conductivity, the rate of transfer
depends on the temperature gradient and the area, which in moving fluids also includes the rate of flow and
diameter of the channel. When there is a large gradient in temperature, the rate of heat transfer is much faster.
As the heat moves from the warmer side to the cooler side toward thermal equilibrium, the rate of transfer slows.
In the clinical application, this means the larger the gradient between the water bath and the patient’s blood, the
quicker we can warm or cool them. However, because solubility of gases is directly affected by temperature,
excessive rates of transfer can cause gas to come out of solution, causing gas emboli or organ dysfunction,
particularly in the brain. Excessive heating of the blood can cause direct damage to proteins and cellular
elements. So although the physics would permit very rapid exchange of heat, the biology limits the practical use
of the principles. This will be discussed more in the next section as well as in Chapter 8.
The second variable in the rate and efficiency of heat transfer is the area. In static systems, this is the actual
surface area where the contact occurs for heat transfer, but in systems with fluid in motion, the situation is more
complex. Just as gas exchange occurs more quickly at the area closest to the site of diffusion, so too heat
transfer occurs more quickly adjacent to the conductor of the heat. Areas farther from the wall of the conduit
where transfer occurs, toward the more central flow, will exchange heat more slowly. The diameter and length of
the conduit as well as the flow rates all affect the rate of transfer as well. Given a wider, shorter conduit with
rapid flow, one can see that a very small proportion of the fluid is exposed directly to the site of heat transfer, and
for a very short time period. If there is not sufficient time for equilibrium to be reached locally at the wall, then
very little to no heat will be transferred to the flow as you move toward the center of the stream. However, given
a smaller-diameter conduit where the distance between the contacting wall and the center stream is
P.103
very small, and with a longer conduit, the potential area for exchange is much greater and more heat transfer will
occur. The rate of flow of blood or water through the conduit must also be considered to allow adequate time for
the transfer of heat, yet not be so slow that the blood and water reach equilibrium long before the end of the
conduit. Additional efficiency in heat transfer is provided by the countercurrent mechanism as previously
described. Subsequently, manufacturers have taken all these factors into consideration in the design of the
modern heat exchanger to maximize the efficiency of heat transfer with the smallest possible prime volume.
Heat Exchangers for Extracorporeal Support

Although an integral part of CPB and extracorporeal support, in some respects the heat exchanger is the
forgotten step-child of CPB systems. Efficient, reliable, and relatively simplistic in function, it has minimal direct
interaction and impact on the blood other than the exchange of energy in the form of heat, allowing accurate
control of the patient’s temperature and thereby, the patient’s metabolism. The designs of the devices have
changed very little over the years, and there is little if any difference in the efficiency of the many commercial
options (18). The integration of the heat exchanger compartment into the oxygenator complex has made it even
less noticeable. Traditionally in longer-term support with ECMO, the heat exchanger was a separate unit through
which the blood was directed after the oxygenator, allowing rewarming of the blood back to normothermia just
prior to reinfusion into the patient to prevent loss of heat over time. However, with the development of the PMP
oxygenator and its applicability for longer-term support, along with its integrated heat exchanger element, the
individual heat exchanger component is now limited to uncommon circumstances of temperature regulation in
which gas exchange is not required, such as isolated limb perfusion, and, in some centers, isolated venovenous
rewarming for hypothermic trauma patients or victims of exposure. In most systems of integrated heat
exchangers, the blood passes through the heat exchanger just prior to moving into the oxygenator compartment
for gas exchange.
The structure of the heat exchanger component of the oxygenator complex consists of a highly conductive
material, usually stainless steel or aluminum which allows rapid and efficient transfer of heat (high thermal
conductivity), yet which will be inert to the fluids to which it is exposed. The blood passage portion is usually
coated with silicone or another polymer coating to minimize activation of coagulation and inflammation. Integrated
devices are often coated with the same coating found within the oxygenator. An outside water source is provided
and circulated through a heater-cooler unit with specific control of the temperature of the water that bathes the
heating elements in a countercurrent direction from the passage of the blood, allowing the most efficient transfer
of heat. The energy transfer is from blood to the water during cooling phases and from water to blood during
warming. Current technology for use with CPB in the operating room is frequently digital, provides excellent
control of temperature, and is also extremely efficient; so caution must be used to prevent overheating of the
blood, or warming with excessive gradients or over too short a period of time. It has been generally
recommended that cooling and warming strategies should include a maximum temperature gradient between the
patient’s core temperature and the arterial inflow temperature of no more than 10°C, due to concerns over gas
bubble formation and subsequent cerebral emboli due to the changes in gas solubility based on temperature;
that is, oxygen is more soluble in colder blood, and will come out of solution as the blood is warmed, potentially
forming bubbles if warmed too quickly. Similarly, there are concerns during cooling that with higher gradients in
temperature, gas will come out of solution when much cooler blood from the circuit mixes with still warm blood in
the patient’s aorta, again potentially leading to gas emboli to the central circulation and the brain. While many
perfusionists continued to use the 10° rule of thumb, others have reduced the maximum gradient to 4° to 6°. In a
2002 study, data suggested that perhaps even this was too great a gradient when compared to much slower
warming (no more than a 2° gradient); more rapid warming was shown to potentially contribute to poorer
neurologic outcomes based on detailed neuropsychological testing (although there was no difference in stroke
rate between the groups) (19). On the basis of their findings, the authors cautioned practitioners on using rapid
rewarming strategies and recommended considering lower acceptable gradients. However, general concerns
over the inherent risk to organ function from prolonged bypass times that might be required for much longer
rewarming periods at the slower rate, particularly after deeper hypothermia, have led many to continue with the
generally accepted 4° to 6° gradient. It is also recommended to not allow the heat exchanger temperature to
exceed 40°C-42°C because of concerns over the potential denaturation of proteins in the blood if exposed to
more excessive heat, a concept recently validated with an in vitro study of temperature and blood protein
denaturation (20). More detailed patient and circuit temperature management during CPB will be discussed in
Chapter 8.
BLOOD INTERACTION WITH OXYGENATORS AND HEAT EXCHANGERS

Coagulation and Fibrinolysis
Contact of blood with the foreign surfaces of the extracorporeal circuit stimulates the activation of the coagulation
cascade through the contact activation pathway (formerly called the intrinsic pathway). The administration of
heparin prior to the initiation of CPB will prevent the propagation of coagulation through its action with
antithrombin III later in the pathway, but does not prevent its initiation. In addition, the contact with foreign
surfaces and early initiation of coagulation is accompanied by stimulation of fibrinolysis via the conversion
P.104
of plasminogen to plasmin. This process can also be inhibited pharmacologically with e-aminocaproic acid,
tranexamic acid, or the serine protease aprotinin (not currently available in the United States), preferably prior to
the initiation of CPB. Efforts to prevent the initiation of both processes through circuit surface modification will be
discussed in detail below. The topic of anticoagulation for CPB will be discussed in detail in Chapter 19.
Trauma to Cellular Elements

In addition to stimulation of the coagulation cascade, the exposure of the blood causes direct trauma to cellular
elements of the blood, primarily platelets and RBCs. Engineers have worked through the years with computer
models and sophisticated analyses to minimize these effects, including the use of computational fluid dynamics
to predict specific areas of shear stress and drops in pressure which can lead to direct cell damage, thrombosis,
and hemolysis. Similar works to minimize the effect of the pump on the formed elements in the blood have led to
modern-day devices that, while they still stimulate coagulation and inflammation, cause minimal amounts of
hemolysis. When significant hemolysis is observed during or after CPB or ECMO, usually the sources are
something other than forces caused by the oxygenator (21), such as excessive negative pressure in centrifugal
pumps, excessive return of shed blood into the circuit during CPB, or areas of significant turbulence in tubing or
cannulas such as partially occluding bridges during weaning, in addition to physiologic causes of hemolysis from
the patient’s underlying condition, such as severe sepsis.
Inflammatory Response
As early as the 1980s, investigators documented the stimulation of the inflammatory response via the activation
of the complement pathway during CPB (22,23). Numerous methods to minimize this response have been tried.
The administration of steroids has been used for many years in pediatric patients on CPB due to documentation
of a decrease in inflammatory markers, but without confirmation of clinical improvement even in the most recent
trials (24). Other methods such as continuous ultrafiltration have been employed to remove inflammatory
mediators during bypass, but again, without a documented basis of clinical effect. The inflammatory response
stimulated by the exposure of the patient’s blood to the surfaces of the circuit will be discussed in greater detail
in Chapter 13, but we will focus on the efforts which have focused on the development of surface modifications
to prevent or minimize the response (25,26).
Hemodilution
Since the circuit must be filled with fluid and all air removed prior to initiation of CPB, by necessity the patient will
either be exposed to hemodilution with an associated relative anemia and dilution of coagulation factors, or will
be exposed to transfusion of exogenous erythrocytes and/or clotting factors, usually in the form of fresh frozen
plasma. The degree of anemia can be easily predicted based on the volume of the circuit, the patient’s blood
volume, and the patient’s hematocrit, and a decision made about the need for adding RBCs to the prime. In
borderline cases, close monitoring of the mixed venous saturation and the serum lactate will guide the
administration of cells based on the adequacy of oxygen carrying capacity and delivery. The management of
coagulation factors is more difficult as the preoperative evaluation is usually limited to quantitative measures of
clotting times, rather than actual measures of factor levels; so any effect of dilution by a crystalloid priming
volume cannot be easily predicted. Postbypass bleeding and coagulopathy must be evaluated after appropriate
reversal of anticoagulation, along with an assessment of clotting function with standard tests, including
prothrombin time, partial thromboplastin time, quantitative platelet counts, and, more recently,
thromboelastography (TEG) to evaluate many aspects of coagulation, including qualitative platelet function,
remaining heparin effect, overall anticoagulation status, and the presence of ongoing fibrinolysis. Later we will
discuss efforts to minimize this effect by minimizing the hemodilution during CPB.
OXYGENATOR MODIFICATIONS
In an attempt to minimize the effect of the artificial surfaces on the blood and the body, a number of modifications
to the oxygenator surfaces that contact the blood have been developed, not only to minimize stimulation of the
coagulation cascade and preserve the function of the membrane, but also to reduce the overall inflammatory
response of the body to the many components of the CPB circuit.
Surface Coatings
It has been well documented that when blood is exposed to the artificial surfaces of the extracorporeal circuit,
particularly the oxygenator, there is a significant stimulus of the coagulation cascade, fibrinolysis, and
inflammatory mediators which can be the source of postoperative complications including bleeding, need for
transfusion, edema, prolonged mechanical ventilation, and organ dysfunction or failure. In an attempt to minimize
this effect, essentially every manufacturer of extracorporeal circuit components has devoted time, energy, and
large amount of resources to the biocompatibility projects and the development of more “gentle” components that
mimic the natural environment of the circulation as much as possible. As it is not yet possible to reproduce the
natural blood vessel and lung outside the body, work has focused primarily on special coatings to line the
surfaces to which the blood is exposed. Coatings including heparin, heparin-benzalkonium chloride, albumin,
silicone, hyaluronan, polyethelenoxide, acrylic phosphorylcholine, and poly(2-methoxyethylacrylate) are attached
to the exposed surfaces using a variety of techniques, including ionic attachment, covalent attachment, as well
as other methods, the specifics of which are often protected as proprietary interests (27).
P.105
Following the development and use of these protective coatings, the reduction in the inflammatory response has
been demonstrated in several in vitro studies as well as clinical randomized trials comparing identical circuits
with and without specific coatings, as measured by levels of tumor necrosis factor (TNF-a), neutrophil elastase,
myeloperoxidase, lactoferrin, IL-1b, IL-2, IL-6, IL-8, IL-10, C3a, C4a, C5a, inactivated C3b, and the terminal
complement complex (TCC) of C5a + C5b-9 as well as other markers of inflammation (28,29,30,31,32) which
have been documented to affect both erythrocytes and leukocytes (33). However, the results are not uniform,
with some studies showing little to no improvement with these modifications, one suggesting a superior effect
with covalent versus ionic bonding techniques (34), and one very recent study demonstrating an actual increase
in inflammation (35). Results also vary among evaluations of the same coating (36,37,38,39). Despite some
reports of documented clinical improvement attributed to the coated circuit’s reduction of inflammation
(40,41,42,43,44), other studies have failed to document any clinical benefit despite demonstrating reduction in
measured markers of inflammation (45,46).
Similar findings are encountered in the evaluation of the protective effects of various coatings on the coagulation
cascade. A number of studies have demonstrated decreased stimulation of coagulation, fibrinolysis, and platelet
activation through various measurements, including platelet counts, levels of fibrinogen and D-dimers, as well as
b-thromboglobulin, fibrinogen absorption, platelet factor 4, tissue plasminogen activator (tPA), plasminogen
activator inhibitor I, plasmin a-2 antiplasmin complex, thrombin-antithrombin III complex, and prothrombin
fragment F1.2. Although one study with heparin-coated circuits failed to demonstrate any decrease in thrombin
formation during CPB (46), most studies have shown improvement or reduction in the activation of coagulation.
Yet, despite near-universal documentation of the reduction of the activation of coagulation and fibrinolysis, the
associated clinical improvement has been more difficult to document. While some reports demonstrate a
decrease in chest tube drainage, postoperative bleeding, or a reduced incidence of oxygenator failure from
thrombosis (43,47), others have failed to demonstrate any clinical significance or outcome differences (36,37).
One study evaluated five different oxygenator coatings and their effect on preserving the thromboelastogram
profile during CPB, and could not demonstrate any improvement with any of the five coatings (48). It has been
demonstrated specifically with heparin-bonded circuits that CPB can be achieved with lower levels of
anticoagulation, with a decrease in the need for transfusion and without an increase in thrombotic complications
such as stroke or clotted circuits (49); however, severe thrombotic complications have also been reported with
ECMO support without heparin despite the use of heparin-bonded circuit components (50).
The evaluation of the protective effects of circuit modifications becomes even more complex when during CPB
the addition of shed blood from the surgical field is mixed into the circuit during CPB. While the major concerns
with this technique are related to potential impact on neurologic outcomes because of fat emboli (discussed more
in Chapter 15), this practice has also been shown to increase the inflammatory response independent of the
circuit exposure (51,52,53,54), increase measurements of coagulopathy and fibrinolysis (55), and increase the
amount of hemolysis (55,56).
Many of the studies also were performed during the era of extensive use of aprotinin, a potent serine protease
used during CPB for its antifibrinolytic effects as well as its anti-inflammatory and platelet protective actions,
making demonstration of the benefits of coating more difficult, yet more significant since the withdrawal of the
drug from the US market. Overall, the majority of the numerous studies strongly suggest that the protective
coatings most likely do significantly diminish the stimulus to inflammation, coagulation, fibrinolysis, and hemolysis
by CPB. But to date, that has not yet fully translated to a proven clinical benefit for the clear increase in cost for
these coated components and circuits. While some studies have suggested clinical benefits, others have
demonstrated no clinical benefits despite the documented decrease in measured inflammatory response and the
theoretical advantages of such reduction. With this in mind, one must consider the considerable increase in cost
of coated components. If there is true clinical benefit to the demonstrated reduction in inflammatory markers, and
the reduction in stimulation of coagulation, then the subsequent clinical improvement and savings from
decreased length of stay, intubation time, intensive care unit (ICU) days, and so forth, might more than cover the
added expense of the coating (34).
Miniaturization
In addition to the potential deleterious stimulation of the inflammatory response, coagulation cascade, fibrinolysis,
and hemolysis, concerns over the potential morbidity and mortality following transfusion have led to another area
of research to reduce the overall size of the circuit, thus minimizing the priming volume and resultant
hemodilution. Reduction of tubing size and increasing the proximity of the circuit to the patient can have some
limited benefit, realized primarily in the pediatric population. However, the main source of the priming volume
required is for the oxygenator complex itself (including the heat exchanger and reservoir). Several manufacturers
have worked to combine and miniaturize the oxygenator complex to reduce the priming volume as much as
possible, including very small circuits for infants and neonates (57,58,59,60). Many products have also utilized
some of the previously described coatings to simultaneously minimize the inflammatory response, in hopes of
reducing systemic effects and capillary leaks which would potentially require additional fluid administration during
CPB. Randomized trials to document the benefits of smaller circuits have provided mixed results, frequently
demonstrating reduction in hemodilution
P.106
and inflammatory markers, but without clear evidence of clinical benefit (61,62,63). Another mechanism to make
the circuit smaller included the development of a “closed” system that removed the cardiotomy reservoir, instead
using the patient’s vascular space as the “reservoir,” depending on additional vacuum-assisted venous drainage
to maintain inflow into the pump for use. In a report of one such circuit, the authors demonstrated marginal
decrease in inflammatory markers and coagulation variables, without measureable differences in clinical
outcome, and noted that this was at the cost of a decreased safety margin for potential volume loss, air emboli,
and the ability to wean from CPB (64). While there remains significant enthusiasm for the development of smaller
circuits, the clear clinical benefit has yet to be definitively demonstrated.
Accidents and Safety

Considering the serious nature of extracorporeal support, the patient’s complete dependency on the technology
during cardiac surgery, the complexity of the circuit as well as the implications of its interaction with the patient’s
blood, one can easily imagine the potential for catastrophic events. These include thrombosis of the oxygenator
or other oxygenator leaks or failures (65,66), rupture or leakage of the heat exchanger (67,68), failure of one of
the numerous connections within the system, in addition to other potential failures of blenders, gas supplies, or
main power supplies (69,70). Many of these can be minimized with careful preparation prior to bypass (71), and
strict attention to detail during support (72). Close monitoring of line pressures and oxygenator function through
continuous in-line invasive or noninvasive technology usually will alert the user to potential problems before
there is complete oxygenator failure (17,73,74,75). Manufacturing standards have eliminated most defects that
previously led to ruptures and leaks within the devices or in the manufactured connections between the devices.
However, accidents do still occur at times, and rarely lead to serious patient injury or death (69,70).
KEY Points
The movement of oxygen and carbon dioxide follows the principles of diffusion according to Fick’s first
law, which tells us that the diffusion is based upon the difference in the gradient of partial pressures on
the two sides of the barrier, the surface area available for diffusion (including the time interval spent at
that area), and the properties of the barrier that encourage or inhibit that diffusion.
The transfer of heat follows much of the same principles based on Fourier’s law, where the important
variables are the gradient in temperature, the available surface area for heat transfer, and the thermal
conductivity properties of the material that makes up the barrier.
Modern-day hollow fiber oxygenators have replaced direct contact systems such as bubble oxygenators
as well as true membrane oxygenators because of their increased efficiency, reliability, and relative
gentleness to the blood elements.
Surface modifications continue to be created and researched to further minimize the effects of the blood-
surface interactions which lead to thrombosis, hemolysis, activation of granulocytes and platelets, as well
as stimulation of the inflammatory response, and fibrinolysis. While some data support the benefits of
special coatings and treatments, there is conflicting evidence that brings to question whether the added
cost is worth the potential benefit. Additional research in these areas as well as the miniaturization will
hopefully continue to make extracorporeal safer in years to come.
REFERENCES
1. Black S, Bolman RM III. C. Walton Lillehei and the birth of open heart surgery. J Card Surg 2006;21:205-
208.
2. Stoney WS. Evolution of cardiopulmonary bypass. Circulation 2009,119(21): 2844-2853
3. Segers PAM, Heida JF, de Vries I, et al. Clinical evaluation of nine hollow-fibre membrane oxygenators.
Perfusion 2001;16:95-106.
4. Fried DW, DeBenedetto BN, Leo JJ. Rethinking the AAMI/ISO “International Standard” for oxygen transfer
performance of artificial lungs. Perfusion 1994;9:335-342.
5. Fried DW. Performance evaluation of blood-gas exchange devices. Int Anesthesiol Clin 1996;34:47-60.
6. Ueyama K, Niimi Y, Nosé Y. How to test oxygenators for extracorporeal membrane oxygenation: is the
Association for the Advancement of Medical Instrumentation’s protocol enough? Artif Organs 1996;20:741-
742.
7. Holdefer WF, Tracy WG. The use of rated blood flow to describe the oxygenating capability of membrane
lungs. Ann Thorac Surg 1973;15:156-162.
8. Marx TI, Snyder WE, St. John AD, et al. Diffusion of oxygen into a film of whole blood. J Appl Physiol
1960;15(5):1123-1129.
9. Marx TI, Baldwin BR, Miller DR. Factors influencing oxygen uptake by blood in membrane oxygenators:
report of a study. Ann Surg 1962;156:204-213.
10. Kolobow T, Bowman RL. Construction and evaluation of an alveolar membrane artificial heart-lung. Trans
Am Soc Artif Intern Organs 1963;9:238-243.
11. Kolobow T, Zapol WM, Sigman RL, et al. Partial cardiopulmonary bypass lasting up to seven days in
alert lambs with membrane lung blood oxygenation. J Thorac Cardiovasc Surg 1970;60(6):781-788.
12. van Oeveren W, Kazatchkine MD, Descamps-Latscha B, et al. Deleterious effects of cardiopulmonary
bypass. A prospective study of bubble versus membrane oxygenation. J Thorac Cardiovasc Surg
1985;89(6):888-899.
13. Blauth CI, Smith PL, Arnold JV, et al. Influence of oxygenator type on the prevalence and extent of
microembolic retinal ischemia during cardiopulmonary bypass. Assessment by digital image analysis. J
Thorac Cardiovasc Surg 1990;99(1):61-69
14. Lehle K, Philipp A, Hiller KA et al. Efficiency of gas transfer in venovenous extracorporeal membrane
oxygenation: analysis of 317 cases with four different ECMO systems. Intensive Care Med 2014;40:1870-
1877.
15. Drinker PA, Bartlett RH, Bialer RM et al. Augmentation of membrane gas transfer by induced secondary
flows. Surgery 1969;66(4):775-781.
16. Gill MC, O’Shaughnessy K, Dittmer J. Case report: a paediatric ECMO case of plasma leakage through a
polymethylpentene oxygenator. Perfusion 2015. doi:10.1177/0267659114567556.
17. Stammers AH. Monitoring controversies during cardiopulmonary bypass: how far have we come?
Perfusion 1998;13:35-43.
18. Ueyama K, Jones JW, Varvitsiotis PS, et al. Rewarming: comparison of contemporary heat-exchangers.
Biomed Mater Eng 1996;6(3):191-197.
P.107
19. Grigore AM, Grocott HP, Mathew JP, et al. The rewarming rate and increased peak temperature alter
neurocognitive outcome after cardiac surgery. Anesth Analg 2002;94:4-10.
20. Vazquez R, Larson DF. Plasma protein denaturation with graded heat exposure. Perfusion
2013;28(6):557-559.
21. De Somer F. Does contemporary oxygenator design influence haemolysis? Perfusion 2013;28(4):280-
285.
22. Kirklin JK, Westaby S, Blackstone EH, et al. Complement and the damaging effects of cardiopulmonary
bypass. J Thorac Cardiovasc Surg 1983;86(6):845-857.
23. Moore FD, Warner KG, Assousa S, et al. The effects of complement activation during cardiopulmonary
bypass: attenuation by hypothermia, heparin and hemodilution. Ann Surg 1988;208(1):95-103.
24. Amanullah MM, Hamid M, Hanif HM, et al. Effect of steroids on inflammatory markers and clinical
parameters in congenital open heart surgery: a randomised controlled trial. Cardiol Young 2015;28:1-10.
25. Hsu LC. Biocompatibility in heparin-coated extracorporeal circuits. Perfusion 1996;11:256-263.
26. Hsu LC. Biocompatibility in cardiopulmonary bypass. J Cardiothor Vasc Anesth 1997;11(3):376-382.
27. von Segesser LK. Coatings for cardiovascular devices: extracorporeal circuits. In: Driver M ed. Coatings
for biomedical applications. Philadelphia, PA: Woodhead Publishing, 2012: 251-263.
28. Borowiec J, Thelin S, Bagge L, et al. Heparin-coated circuits reduce activation of granulocytes during
cardiopulmonary bypass. A clinical study. J Thorac Cardiovasc Surg 1992;104(3):642-647.
29. Fosse E, Moen O, Johnson E, et al. Reduced complement and granulocyte activation with heparin-
coated cardiopulmonary bypass. Ann Thorac Surg 1994;58(2):472-477.
30. Penka M, Hagman L, Haldén E, et al. Complement activation during cardiopulmonary bypass: effects of
immobilized heparin. Ann Thorac Surg 1994;58(2):421-424.
31. Videm V, Svennevig JL, Fosse E, et al. Reduced complement activation with heparin-coated oxygenator
and tubings in coronary bypass operations. J Thorac Cardiovasc Surg 1992;103(4):806-813.
32. Simsek E, Karapinar K, Bugra O, et al. Effects of albumin and synthetic polypeptide-coated oxygenators
on IL-1, IL-2, IL-6 and IL-10 in open heart surgery. Asian J Surg 2014;37(2):93-99.
33. Salama A, Hugo F, Heinrich D, et al. Deposition of terminal C5b-9 complement complexes on
erythrocytes and leukocytes during cardiopulmonary bypass. N Engl J Med 1988;318(7):408-414.
34. Mahoney CB. Heparin-bonded circuits: clinical outcomes and costs. Perfusion 1998;13:192-204.
35. Karakisi SO, Kunt AG, Çankaya I, et al. Do phosphorylcholine-coated and uncoated oxygenators differ in
terms of elicitation of cellular immune response during cardiopulmonary bypass surgery? Perfusion 2015.
doi:10.1177/0267659114567137.
36. van den Goor JM, van Oeveren W, Rutten PM, et al. Adhesion of thrombotic components to the surface
of a clinically used oxygenator is not affected by Trillium coating. Perfusion 2006;21:165-172.
37. Ereth MH, Nuttall GA, Clarke SH, et al. Biocompatibility of Trillium biopassive surface-coated oxygenator
versus uncoated oxygenator during cardiopulmonary bypass. J Cardiothor Vasc Anesth 2001;15(5):545-550.
38. Myers GJ, Johnstone DR, Swyer WJ, et al. Evaluation of Mimesys phosphorylcholine (PC)-coated
oxygenators during cardiopulmonary bypass in adults. J Extra Corpor Technol 2003;35(1):6-12.
39. Lorusso R, De Cicco G, Totaro P, et al. Effects of phosphorylcholine coating on extracorporeal circulation
management and postoperative outcome: a double-blind randomized study. Interact Cardiovasc Thorac Surg
2009;8(1):7-11.
40. Jansen PG, te Velthuis H, Huybregts RA, et al. Reduced complement activation and improved
postoperative performance after cardiopulmonary bypass with heparin-coated circuits. J Thorac Cardiovasc
Surg 1995;110:829-834.
41. Goudeau JJ, Clermont G, Guillery O, et al. In high-risk patients, combination of anti-inflammatory
procedures during cardiopulmonary bypass can reduce incidences of inflammation and oxidative stress. J
Cardiovasc Pharmacol 2007;49:39-45.
42. Shimamoto A, Kanemitsu S, Fujinaga K, et al. Biocompatibility of silicone-coated oxygenator in

43. Svenmarker S, Sandström E, Karlsson T, et al. Clinical effects of the heparin coated surface in
cardiopulmonary bypass. Eur J Cardiothorac Surg 1997;11:957-964.
44. Palatianos GM, Foroulis CN, Vassili MI, et al. A prospective, double-blind study on the efficacy of the
Bioline surface-heparinized extracorporeal perfusion circuit. Ann Thorac Surg 2003; 76:129-135.
45. Onorati F, Santini F, Raffin F, et al. Clinical evaluation of new generation oxygenators with integrated
arterial line filters for cardiopulmonary bypass. Artif Organs 2012;36(10):875-885.
46. Gorman RC, Ziats N, Rao AK, et al. Surface-bonded heparin fails to reduce thrombin formation during
clinical cardiopulmonary bypass. J Thorac Cardiovasc Surg 1996;111(1):1-11.
47. Wahba A, Philipp A, Behr R, et al. Heparin-coated equipment reduces the risk of oxygenator failure. Ann
Thorac Surg 1998;65:1310-1312.
48. Marcoux JE, Mycyk TR. Are any biocompatible coatings capable of attenuating the deleterious effects of
cardiopulmonary bypass? Perfusion 2013;28(5):433-439.
49. Aldea GS, O’Gara P, Shapira OM, et al. Effect of anticoagulation protocol on outcome in patients
undergoing CABG with heparin-bonded cardiopulmonary bypass circuits. Ann Thorac Surg 1998;65:425-433.
50. Muehrcke DD, McCarthy PM, Stewart RW, et al. Complications of extracorporeal life support systems
using heparin-bonded surfaces. J Thorac Cardiovasc Surg 1995;110:843-851.
51. Aldea GS, Soltow LO, Chandler WL, et al. Limitation of thrombin generation, platelet activation, and
inflammation by elimination of cardiotomy suction in patients undergoing coronary artery bypass grafting
treated with heparin-bonded circuits. J Thorac Cardiovasc Surg 2002;123:742-755.
52. De Somer F, Van Belleghem Y, Caes F, et al. Tissue factor as the main activator of the coagulation
system during cardiopulmonary bypass. J Thorac Cardiovasc Surg 2002;123(5):951-958.
53. Westerberg M, Gäbel J, Bengtsson A, et al. Hemodynamic effects of cardiotomy suction blood. J Thorac
Cardiovasc Surg 2006;131(6):1352-1357.
54. Westerberg M, Bengtsson A, Jeppsson A. Coronary surgery without cardiotomy suction and
autotransfusion reduces the postoperative systemic inflammatory response. Ann Thorac Surg 2004;78:54-59.
55. Skrabal CA, Khosravi A, Choi YH, et al. Pericardial suction blood separation attenuates inflammatory
response and hemolysis after cardiopulmonary bypass. Scand Cardiovasc J 2006;40:219-223.
56. Peirangeli A, Masieri V, Bruzzi F, et al. Haemolysis during cardiopulmonary bypass: how to reduce the
free haemoglobin by managing the suctioned blood separately. Perfusion 2001;16:519-524.
57. Lilly KJ, O’Gara PJ, Treanor PR, et.al. Heparin-bonded circuits without a cardiotomy: a description of a
minimally invasive technique of cardiopulmonary bypass. Perfusion 2002;17:95-97.
58. von Segesser LK, Tozzi P, Mallbiabrrena I, et al. Miniaturization in cardiopulmonary bypass. Perfusion
2003;18:219-224.
59. De Rita F, Marchi D, Lucchese G, et al. Comparison between D901 Lilliput 1 and Kids D100 neonatal
oxygenators: toward bypass circuit miniaturization. Artif Organs 2013;37(1):E24-E28.
60. Arens J, Schnöring H, Reisch F, et al. Development of a miniaturized heart-lung machine for neonates
with congenital heart defect. ASAIO J 2008;54:509-513.
61. Yuruk K, Bezemer R, Euser M, et al. The effects of conventional extracorporeal circulation versus
miniaturized extracorporeal circulation on microcirculation during cardiopulmonary bypass-assisted coronary
artery bypass graft surgery. Interact Cardiovasc Thorac Surg 2012;15(3):364-370.
62. Abdel-Rahman U, Martens S, Risteski P, et al. The use of minimized extracorporeal circulation system
has a beneficial effect on hemostasis—a randomized clinical study. Heart Surg Forum 2006;9:E543-E548.
63. Abdel-Rahman U, Özaslan F, Risteski P, et al. Initial experience with a minimized extracorporeal bypass
system: is there a clinical benefit? Ann Thorac Surg 2005;80:238-244.
64. Nollert G, Schwabenland I, Maktav D, et al. Miniaturized cardiopulmonary bypass in coronary artery
bypass surgery: minimal impact on inflammation and coagulation but loss of safety margins. Ann Thorac Surg
2005;80:2326-2332.
65. Fisher AR. The incidence and cause of emergency oxygenator changeovers. Perfusion 1999;14:207-
212.
66. Svenmarker S, Häggmark S, Jansson E, et al. The relative safety of an oxygenator. Perfusion
1997;12:289-292.
67. Gukop P, Tiezzi A, Mattam K, et al. Emergency management of heat exchanger leak on cardiopulmonary
bypass with hypothermia. Perfusion 2015. doi:10.1177/0267659115581673.
68. Henrick BM. Unrehearsed circuit failure during neonatal ECMO: critical trans-heat exchange pressure.
ASAIO J 2006; 52:601-602.
P.108
69. Mejak BL, Stammers A, Rauch E, et al. A retrospective study on perfusion incidents and safety devices.
Perfusion 2000;15:51-61.
70. Jenkins OF, Morris R. Australasian perfusion incident survey. Perfusion 1997;12:279-288.
71. Carlton M, Campbell J. A survey of membrane oxygenator heat-exchanger integrity testing at cardiac
surgery centres in Great Britain and Ireland. Int J Artif Organs 2013;36(11):758-761.
72. Palanzo DA. Perfusion safety: past, present and future. J Cardiothor Vasc Anesth 1997;11(3):383-390.
73. Trowbridge CC, Vasquez M, Stammers AH, et.al. The effects of continuous blood gas monitoring during
cardiopulmonary bypass: a prospective randomized study—Part I. J Extra Corpor Technol 2000;32(3):120-
128.
74. Trowbridge CC, Vasquez M, Stammers AH, et al. The effects of continuous blood gas monitoring during
cardiopulmonary bypass: a prospective, randomized study—Part II. J Extra Corpor Technol 2000;32(3):129-
131.
75. Schreur A, Niles S, Ploessl J. Use of the CDI blood parameter monitoring system 500 for continuous
blood gas measurement during extracorporeal membrane oxygenation simulation. J Extra Corpor Technol
2005;37(4):377-380.
Chapter 4
Ultrafiltration and Dialysis
Robin G. Sutton
David M. Rothenberg
Patients undergoing cardiopulmonary bypass (CPB) often develop fluid overload and electrolyte imbalances
(1,2,3). In addition, exposure to foreign surfaces of the extracorporeal circuit and surgical trauma can itself
promote capillary permeability and shifting of fluid to the extravascular space (1,2,3). Ultrafiltration and dialysis
can help attenuate these changes and are therefore important adjuncts to CPB and related extracorporeal
technologies. Ultrafiltration and dialysis are both utilized to manage blood volume, hemoglobin, protein, and
certain electrolyte concentrations (2,4). In addition, several studies suggest that ultrafiltration and dialysis may
reduce mediators that initiate a systemic inflammatory response syndrome (SIRS) (5,6,7).
Ultrafiltration is the movement of water across a membrane as the result of a hydrostatic pressure gradient or
transmembrane pressure (TMP) (8). No dialysate on the opposite side of the membrane is required. As water
diffuses, it creates a solute concentration gradient across the membrane. These solutes then diffuse across the
membrane, equalizing the concentrations in a process of solute removal called convection. The fluid removed
during ultrafiltration is called ultrafiltrate or plasma water.
Dialysis refers to a process in which the blood is separated from a crystalloid solution or dialysate by a
semipermeable membrane (9). A solute concentration gradient exists between the blood and the dialysate,
resulting in solute transport by diffusion from a higher to a lower concentration. Ultrafiltration may be employed
during dialysis by altering the TMP (10).
The purpose of this chapter is to describe the theory of ultrafiltration and dialysis and explain their various uses
and benefits in the extracorporeal circuit during CPB.
HISTORY OF DIALYSIS AND ULTRAFILTRATION

In 1854, Thomas Graham, a Scottish chemist, presented a paper entitled “Osmotic Force,” which described the
process of separating substances using a semipermeable membrane (11). He later demonstrated that treated
parchment paper could be used to separate larger molecules or colloids from crystalloids. He was also the first to
describe the direct relation between solute molecular weight and solute diffusion rate. After Graham's paper was
published, other investigators continued to study various membrane materials that might be used to separate
colloids from crystalloids. In 1855, Adolf Fick described the use of collodion, a cellulose-trinitrate derivative, as a
diffusive membrane (12).
In 1913, John Jacob Abel’s interest in deriving usable solutes from animal blood led to the first reported dialysis
procedure (13). Abel used a collodion membrane and, because blood was circulated outside the animal, it was
necessary for Abel to find a way to keep the blood from clotting when exposed to foreign surfaces. Abel solved
this problem by creating hirudin, an anticoagulant derived from crushed leech heads.
The first clinical dialysis procedure was performed by George Haas in 1924 (9). Between 1924 and 1928 he
dialyzed six patients, but unfortunately had no survivals. However, Haas made significant progress in the field of
hemodialysis in 1927 by the addition of a blood pump and use of a newly discovered anticoagulant, heparin.
Throughout the 1930s, many investigators developed and studied various semipermeable membrane materials,
including cellophane and chemically modified cellulose (14,15). After World War II, Willem Kolff, at the University
of Groningen in the Netherlands, built an artificial kidney employing the regenerated cellulose membrane,
cellophane. This device was a rotating drum barrel made of slats, with open spaces between the slats. The
membrane material used was a relatively new material originally developed for food packaging. The cellophane
sausage casing was wound around the drum. The drum was rotated by an electric motor and submerged in a
tank filled with dialysate solution. The blood was drawn from the patient into the cellophane casing by gravity
(Fig. 4.1). Between 1943 and 1944, Kolff dialyzed a total of 15 patients; however, only one survived. In 1945, he
dialyzed a comatose patient in acute renal failure for 1 week. Her renal function returned and she eventually
recovered to be released from the hospital (16). Kolff’s book, “New Ways of Treating Uremia” (17) became the
first manual for treating patients on hemodialysis, and following World War II he collaborated with colleagues at
Brigham Hospital to make significant improvements to his original device, which became known as the Kolff-
Brigham kidney. Between 1954 and 1962, he shipped his dialysis machines to 22 centers worldwide. This
dialysis machine
P.110
was copied by others and by the mid-1940s there were many dialysis programs throughout the world. In 1950,
Kolff collaborated with Drs. Victor Vertes and Bruno Watschinger to improve a previously described coil-type
dialyzer in which cellulose acetate tubing was wrapped around a plastic core. He developed the first ready-to-
use disposable artificial kidney by placing the devices in polyethylene bags for sterilization (18).
FIGURE 4.1. Rotating drum kidney designed by Willen Kolff in the 1940s.
The development of the flat or parallel plate dialyzer began in 1947 by Leonard Skeggs and Jack Leonards (19).
In this design, sheets of membrane material were sandwiched between two rubber pads and incorporated
multiple membrane layers to reduce the blood volume and increase the membrane surface area. By the early
1950s, Kiil reported results with a flat plate dialyzer in which blood was made to flow between two sheets of
cellophane supported by solid mats with grooves for the circulation of dialysate.(20) In 1956, Richard Stewart
began the development of the hollow fiber dialyzer design (21). It was made from a modified cellulose material,
cellulose diacetate, and provided a high-efficacy solute transport while maintaining a low priming volume and a
low resistance to blood flow. The membrane material, extruded in hollow fibers, was cut and bundled together,
then potted in polyurethane on each end and encased in a polycarbonate shell. Blood flowed through the hollow
fiber and the dialysate flowed around the hollow fibers. This model became commercially available in 1970 and is
the type of dialyzer and ultrafiltrator most widely used currently.
ULTRAFILTRATION (HEMOCONCENTRATION)
Ultrafiltration is achieved through the filtration of water across a semipermeable membrane using the energy
derived from a hydrostatic pressure gradient (11). When water crosses the membrane, it creates a solute
concentration gradient between the blood and the ultrafiltrate side of the membrane, which has no solutes. The
dissolved solutes, which have a higher concentration in the blood, follow the concentration gradient and are
transferred from the blood to the ultrafiltrate, the so-called solute drag or convection. This process of removing
plasma water or ultrafiltrate from the blood utilizes a microporous membrane material commonly manufactured in
a hollow fiber configuration.
Mechanism of Action
Consider a tank separated by a semipermeable membrane. A semipermeable membrane implies that certain
substances will penetrate the membrane while others will not. This relates to microscopic holes in the membrane,
which only allow water and small molecular weight solutes to pass. If one side of the tank is filled with blood and
a pressure is exerted on that compartment, water from the blood will move across the membrane into the other
compartment. Because of their higher concentration in the blood compartment, the solutes with small molecular
weight will move to the water side of the compartment until there is an equal concentration on both sides. This
results in a concentration of blood cells and large molecules on one side of the membrane and water and small
molecules on the other side (Fig. 4.2).
During ultrafiltration, the blood passes through a bundle of hollow fibers made from a microporous membrane.
The hollow fibers are between 180 and 200 μm in diameter and the pores of the microporous membrane are
between 5 and 10 nm (22,23). Thousands of hollow fibers are configured in a bundle and encased in a
polycarbonate shell (Fig. 4.3). As blood flows through the hollow fibers of an ultrafiltrator, also called a
hemoconcentrator, it creates a positive pressure within the hollow fibers. This pressure differential between the
blood side and the atmospheric pressure on the ultrafiltrate side of the membrane drives water across the
membrane. As in the tank analogy, water is shifted from the blood path to the ultrafiltrate compartment; a solute
concentration gradient is generated between the blood and the ultrafiltrate. By convection, solutes smaller than
the membrane pore size move with the water to equalize the solute concentration gradient. In many ways the
process mimics glomerular filtration (Table 4.1).
The pressure gradient between the blood path and the ultrafiltrate compartment is called the transmembrane
pressure. The TMP can be expressed by the formula
TMP = (Pin + Pout)/2 + V
where Pin = Blood inlet pressure, Pout = Blood outlet pressure, and V = Negative pressure applied to the effluent
side of the hemoconcentrator.
To avoid membrane rupture, the TMP must not exceed the manufacturer's recommended pressures of 500 to
600 mm Hg. The rate of fluid removal depends on the membrane permeability, blood flow, TMP, and hematocrit
(22). The membrane permeability is related to the pore size, membrane material, and membrane thickness, and
is described by the ultrafiltration coefficient ( KUF) (22,24,25). The KUF relates the rate of water removal to the
TMP for a particular device at a constant
P.111
blood flow. Typical rates are between 2 and 50 mL/hr/mm Hg. As the KUF units imply, increase in the TMP
increases the rate of water removal. The KUF is also dependent on the blood flow through the ultrafiltrator, with
higher blood flow resulting in a higher KUF (Fig. 4.4). Just as lower hematocrit levels and lower plasma protein
concentrations will increase glomerular filtration rate, they will also increase the ultrafiltration rate.
FIGURE 4.2. Convection. A: Blood compartment is pressurized and water from the blood moves across the
membrane. B: Results in blood on one side of the membrane and water on the other side, which creates a solute
concentration gradient between the two components. C: Small molecular weight solutes diffuse across the
membrane to equalize the concentration gradient.
FIGURE 4.3. Hollow fiber hemoconcentrator.
TABLE 4.1. Dialyzer-nephron comparison
Dialyzer Nephron
Blood inflow tubing Afferent arteriole
Hollow fibers Glomerulus
Dialyzer collection compartment Bowman capsule
Drainage tubing Collecting tubule
Blood outflow tubing Efferent arteriole
Because the process of ultrafiltration removes plasma water and diffusible solutes in equal concentration to the
plasma water, the overall concentration of the diffusible solutes are not affected. Although dependent on the
membrane material and pore size, typically, solutes greater than 65,000 Da are not removed by ultrafiltration.
Cellular elements, plasma proteins,
P.112
and protein-bound solutes will not be removed and will therefore be concentrated (26).
FIGURE 4.4. Transmembrane pressure (TMP) versus ultrafiltration rate (KUF) for a typical hemoconcentrator.
To maximize KUF, both the blood flow (Q) and the TMP must be adjusted.
Sieving Coefficient
The ability of a solute to be filtered through the ultrafiltrator membrane depends on the molecular weight of the
solute compared with the membrane pore size, the proportion of the solute that is protein bound, and the surface
charge of the solute (27). The sieving coefficient is the ratio of ultrafiltrate solute concentration to plasma solute
concentration and ranges from 0 to 1.0. A sieving coefficient of 1.0 indicates that the ultrafiltrate solute
concentration and the plasma solute concentration are equal and that the solute passes freely across the
membrane. A sieving coefficient of 0 indicates that none of the solute passes through the membrane. Small
molecular weight solutes that are not protein bound are easily removed by ultrafiltration and have a sieving
coefficient of 1.0. In the case of partially protein-bound small molecular weight solutes, the ultrafiltrate solute
concentration will be equal to the non-protein-bound solute concentration.
Indications and Outcomes

The use of ultrafiltration during CPB was first reported in 1979 by Darup et al. (4). In the early 1980s, several
other investigators reported utilizing ultrafiltration in the extracorporeal circuit and found that removing plasma
water during CPB resulted in improvement in a number of aspects of patient care (28,29,30,31,32).
Patients undergoing CPB are subject to significant hemodilution, primarily due to the extracorporeal circuit prime
of 1 to 2 L of crystalloid solution, with homologous blood products and plasma proteins rarely added to the
extracorporeal circuit prime to minimize bank blood usage (33). During CPB, excess crystalloid may accumulate
in the venous reservoir through cardioplegia and surgical irrigation from cardiotomy suction. Patients undergoing
CPB for heart surgery may have increased blood volumes due to congestive heart failure and/or renal failure
(34). Ultrafiltration may remove excess fluid; however, the amount of fluid removed is limited by the minimal level
allowed in the venous reservoir of the extracorporeal circuit. Once the minimum reservoir volume has been
achieved, further increases in hematocrit and plasma protein levels may only be accomplished by the addition of
homologous red blood cells or albumin. After the addition of the red cells or albumin, ultrafiltration may continue
until the volume equal to the added red cells or albumin is removed (Fig. 4.5).
The extracorporeal circuit also exposes the patient's blood to foreign surfaces that may trigger SIRS and, in
particular, increase capillary permeability (35). Therefore, as CPB is initiated, the patient is subject to a dilutional
decline in hemoglobin and serum protein concentrations and contact activated inflammatory capillary leak,
leading to fluid movement to the interstitial space, tissue edema, and decreased end-organ perfusion.
Ultrafiltration can concentrate the blood without the removal of plasma proteins, can be utilized during CPB when
there is excess reservoir volume, and is particularly useful when the patient is resistant to diuretics (28,29).
Studies have shown that patients who undergo ultrafiltration demonstrate increased protein and red blood cell
concentrations (28,36) and decreased lung waters (29), reduced fluid balance (29), and reduced tissue edema
(37,38,39). It has also been found to improve perioperative hemostasis and reduce postoperative ventilatory
support (4).
Technical Applications
The hemoconcentrator or ultrafiltrator is configured in parallel to the extracorporeal circuit. Blood may be
propelled through a pump (28,40), but for simplicity, it is generally configured in the extracorporeal circuit as a
passive shunt from a point of higher pressure to lower pressure. In the pumpless configuration, the inflow to the
ultrafiltrator originates from a port or connection off the high-pressure arterial line (distal to the arterial pump) and
the outflow of the ultrafiltrator returns to a lower pressure port or connection located either on the venous line or
the venous reservoir (Fig. 4.6). Without the pump, the flow through the ultrafiltrator is dependent on the pressure
differential between the inflow and outflow of the ultrafiltrator. This can be easily approximated in the adult
patient by using the principles of flow and resistance. During CPB, the perfusionist monitors line pressure distal
to the arterial pump, which ranges between 150 and 250 mm Hg, and is dependent on blood-flow rate and
resistance. The resistance to flow is determined by arterial cannula size, design, and placement, as well as the
patient's arterial blood pressure. If the ultrafiltrator shunt, which is parallel to the main circuit, is opened and the
pump flow and other resistance-related variables remain the same, blood flow to the patient through the arterial
cannula will decline and the line pressure will drop due to diminished resistance to blood flow. If the arterial pump
flow is increased
P.113
to the point where line pressure returns to baseline, then, theoretically, flow to the patient should also return to
baseline. The difference between old pump flow and new pump flow is the flow shunted to the hemoconcentrator
(Fig. 4.7). A clamp on the ultrafiltrator blood outflow line will reduce shunting, but it will not increase pressure
inside the hollow fibers nor will it increase TMP or ultrafiltration rate. It will, in fact, reduce ultrafiltration rate
because blood flow through the ultrafiltrator has been reduced. A flowmeter may be used for more precise
measurements and is highly recommended
P.114
in pediatric patients (41). When using a centrifugal pump, the flow probe should be distal to the ultrafiltrator shunt
to determine the actual blood flow to the patient and not the combined blood flow to the patient and ultrafiltrator.
FIGURE 4.5. Ultrafiltration can maximize the effect of homologous red blood cell administration. PRBC, packed
red blood cells; Hct, hematocrit.
FIGURE 4.6. The hemoconcentrator is configured as a passive shunt parallel to the cardiopulmonary bypass
(CPB) circuit.
FIGURE 4.7. Example of blood flow through a hemoconcentrator setup as a passive shunt from the arterial line
that shunts blood away from the patient. This shunt varies and is based on the arterial line pressure. A:
Hemoconcentrator shunt is closed. The pump blood flow is 5 L/min, which is delivered to the patient through the
arterial line requiring a line pressure of 150 mm Hg. B: Hemoconcentrator shunt is opened. If the pump flow
remains at 5 L/min the line pressure will drop; however, the distribution of blood flow through the
hemoconcentrator and to the patient is unknown. C: If the pump flow is increased such that the line pressure
returns to baseline, then it can be assumed that the blood flow to the patient has returned to 5 L/min and that the
blood flow through the hemoconcentrator is the difference between the old pump flow and the new pump flow (in
this case 0.25 L/min).
Tubing from the effluent side of the ultrafiltrator is attached to a collection canister and, given that ultrafiltrators
used for CPB have relatively high ultrafiltration rates (also termed high flux), sufficient rates of fluid removal are
achieved by establishing a hydrostatic pressure gradient by altering the height between the ultrafiltrator and the
canister. The hydrostatic gradient can vary between 60 and 90 cm, resulting in an effective hydrostatic pressure
of approximately 45 to 65 mm Hg. The TMP may be augmented by applying a vacuum source to the effluent side
of the ultrafiltrator.
The process of ultrafiltration may potentially lead to hypovolemia, with increased osmolarity in the intravascular
volume causing interstitial fluid to slowly shift into the vascular space (30). A patient supported on CPB can
tolerate a higher rate of ultrafiltration without becoming hemodynamically unstable because the cardiac output is
controlled by the bypass pump and does not depend on the intravascular volume.
ZERO-BALANCED ULTRAFILTRATION (Z-BUF)

The primary purpose of ultrafiltration during CPB is to remove excess water and to concentrate the cellular
elements and proteins in the blood. Electrolytes and other solutes are also removed but in equal concentration to
the patient's plasma water. Therefore, the patient's plasma concentration of diffusible solutes remains
unchanged. As mentioned previously, investigators studying ultrafiltration during and immediately after CPB
found improvements in patient hemodynamics, cardiac contractility, and oxygenation. Originally these benefits
were attributed to water removal; however, subsequent investigations testing for various substances in the
ultrafiltrate found measurable levels of cytokines (42,43,44,45,46). Because most cytokine and complement
levels reach their peak during rewarming, Journois et al. (47) hypothesized that continuous ultrafiltration during
this period would further attenuate the inflammatory response. To allow continuous ultrafiltration during the
rewarming phase of CPB, the authors replaced the ultrafiltrate with a balanced electrolyte solution. They
matched the ultrafiltration rate with the infusion rate by loading the ultrafiltration effluent line and the electrolyte
solution infusion tubing into a single roller pump. The effluent and infusion tubing were loaded in opposite
directions so that the ultrafiltration rate was equal to the infusion rate and the patient remained isovolemic. When
comparing patients who received Z-BUF during rewarming to a control group that did not receive ultrafiltration
during CPB, an improvement was noted in postoperative alveolar-arterial oxygen gradient that significantly
correlated with the volume of ultrafiltrate removed in the Z-BUF group. The treatment group also had less blood
loss and a lower body temperature in the intensive care, further supporting the theory that the inflammation
process had been attenuated. Z-BUF is similar to hemofiltration utilized in dialysis units, whereby plasma water is
ultrafiltrated at a high rate with the volume removed replaced with a balanced electrolyte solution (48,49).
A form of Z-BUF has also been used by perfusionists to correct hyperkalemia (49,50). Potassium loads during
cardiopulmonary bypass originate from potassium-based cardioplegia and homologous red blood cells and may
exceed the patient's ability to clear excess potassium through normal glomerular filtration (51,52,53). As the
patient's blood volume is reduced by ultrafiltration, the potassium level is not affected because the ultrafiltrate
potassium levels will always be in equal concentration to the plasma. When ultrafiltration is continuous, the
potassium levels can be lowered by replacing the volume with a solution low in potassium.
Z-BUF has also been used to correct severe electrolyte and acid-base disturbances in adults undergoing cardiac
surgery.
P.115
Electrolyte and acid-base corrections can be accomplished rapidly, and because the clinician can select the
concentration of diffusible solutes in the replacement fluid, they can more accurately predict treatment effects
(54,55).
Circuitry and Management of Z-BUF

In Z-BUF, the hemoconcentrator is positioned in the CPB circuit and plasma water is removed similar to
ultrafiltration. However, in Z-BUF, the volume of plasma water removed is replaced by an equal amount of a
balanced electrolyte solution.
When the purpose of Z-BUF is to remove inflammatory mediators, the replacement fluid can be commercially
manufactured solutions such as Hartman solution, lactated Ringers, Plasma-Lyte-A, or Normosol. These
replacement solutions contain acetate or lactate, both of which undergo conversion to bicarbonate in the liver
and muscle and provide the necessary buffer to offset the bicarbonate loss during Z-BUF. Bicarbonate-
containing solutions are themselves unstable and can form precipitates when mixed with solutions containing
calcium or magnesium. When using Z-BUF to reduce potassium levels, the previously mentioned replacement
solutions do not efficiently dilute potassium levels because they all contain more than 4 mEq/L of potassium. It is
a challenge to find an easily available, cost-effective, balanced electrolyte solution low in potassium, and
therefore 0.9% sodium chloride is often used. Because 0.9% sodium chloride does not contain bicarbonate, it
must be replaced in the form of sodium bicarbonate. If Z-BUF with 0.9% sodium chloride is used in excess, the
patient can develop hypernatremia due to the high sodium content of 0.9% sodium chloride (154 mEq/L). If 20
mEq of sodium bicarbonate is added to each liter of 0.9% sodium chloride to replace the lost bicarbonate, each
liter will contain 174 mEq of sodium. In the event that these solutions are given, the clinician must be sure to
monitor sodium levels to avoid hypernatremia. In addition, because many patients are on preoperative diuretics,
they present to the operating room with low sodium levels. If the sodium levels are normalized quickly (>2
mEq/L/hr), patients may be at risk for central pontine myelinolysis, which is characterized by focal demyelination
in the pons and extrapontine areas of the brain (56). Z-BUF with 0.9% sodium chloride also depletes magnesium
and calcium and can elevate chloride, resulting in hyperchloremic metabolic acidosis (57) (Table 4.2).
TABLE 4.2. Zero-balanced ultrafiltration solutions
0.9% NaCl
Ion Premixed dialysate with 24- Commercial
concentration for hemodiafiltration Plasma- Lactated mmol bicarbonate
(mmol/L) solutiona lyte-Aa ringersa NaHCO3 solutionb
Sodium 140 140 130 178 140
Potassium 2 5 4 0 0
Calcium 3.5 0 2.7 0 3
Magnesium 1.5 3 0 0 1
Chloride 117 98 109 154 109
Lactate 30 0 28 0 0
Acetate 0 27 0 0 0
Bicarbonate 0 0 0 24 35
aBaxter Healthcare Corporation, Deerfield, IL.
bNxStage RFP-402,Lawrence, MA.
Normalizing Prime Prior To CPB Initiation

The CPB and long-term extracorporeal membrane oxygenation (ECMO) circuits used in pediatric patients have a
high priming volume relative to the patient's blood volume, which may sometimes be less than 400 mL. To avoid
dangerous levels of hemodilution, the extracorporeal circuit is primed with homologous blood components. Blood
priming may result in high levels of potassium, and lactate, which should be reduced before CPB initiation to
avoid arresting the heart and other complications (58,59). Because of their small molecular weight, these solutes
can be removed from the prime before CPB or extracorporeal life support initiation by Z-BUF and replaced with a
balanced electrolyte solution such as Plasma-Lyte-A (55,59,60). In a randomized study using neonatal piglets,
Ugaki et al. (61) found that the subjects undergoing prime ultrafiltration not only had lower potassium levels, but
also lower serotonin and interleukin (IL)-8 levels during CPB.
P.116
USING ULTRAFILTRATION TO PROCESS POST-CPB EXTRACORPOREAL
CIRCUIT BLOOD
After weaning from CPB, blood conservation requires that the volume of blood remaining in the extracorporeal
circuit be reinfused into the patient (62). Remembering that it is prudent to maintain the extracorporeal circuit
primed for a potential emergency, the residual circuit blood is displaced by crystalloid solution. This residual
circuit blood can then be pumped or drained into a transfusion bag and readministered when indicated. Residual
circuit blood can also be infused while the arterial cannula is in place, and until the venous reservoir is emptied.
Crystalloid solution is then added to replete the venous reservoir. Because the residual extracorporeal circuit
volume is often diluted, these techniques are indicated only if the patient has adequate renal and myocardial
function (63). There is therefore an advantage in concentrating the circuit contents by ultrafiltration before
infusion to avoid the risk of volume overload.
Concentrating the circuit volume can be accomplished in many ways, depending on the circuit used
(63,64,65,66). Various methods are used to displace blood into the venous reservoir and create a small
recirculating circuit through the hemoconcentrator (67). Additional protamine must be administered directly to the
patient to reverse the effect of heparin in the residual circuit blood. Protamine should never be added directly to
this blood as it will cause marked hemocoagulation. Ultrafiltration of residual CPB volume in adults undergoing
isolated coronary artery bypass graft (CABG) surgery has not been shown to reduce the need for transfusion or
decrease bleeding (68). Red cell centrifugation and washing is superior with respect to postoperative
hemoglobin gain and washout of free hemoglobin when compared to ultrafiltration (69). However, ultrafiltration
preserves plasma proteins and platelets.
MODIFIED ULTRAFILTRATION
Ultrafiltration during CPB is limited by the blood reservoir level. For pediatric patients, it is a challenge post-CPB
to concentrate the residual circuit blood down to a volume that can be readily transfused into a small
intravascular space. In 1991, Naik et al. (70) described a procedure in pediatric patients in which, following
termination of CPB, the residual contents of the extracorporeal circuits were ultrafiltrated and transfused while
the patients were still cannulated and attached to the extracorporeal circuit. They called this procedure modified
ultrafiltration or MUF. In MUF, nearly all of the circuit contents are concentrated and transferred to the patient
without the risk of hypervolemia, while the circuit remains primed with crystalloid solution. One disadvantage of
MUF is that it requires the patient to remain cannulated for 10 to 20 minutes after CPB termination, and, to
maintain the integrity of the extracorporeal circuit, protamine may not be administered during MUF.
In a subsequent study, Naik et al. (71) conducted a prospective randomized trial comparing a MUF group to
nonfiltered controls. The authors noted decreased blood loss, fewer blood transfusions, and an increase in
arterial blood pressure, particularly in the low-temperature and low-flow patients, while achieving a post-MUF
hematocrit of 40%.
Technical Applications
At the termination of CPB, Naik's (70) MUF circuit requires a separate roller pump to transfer blood from the
patient through the arterial line to an ultrafiltrator and back into the patient through the venous line. As the
patient's blood volume is concentrated, the arterial pump is used to transfuse blood from the circuit to maintain
hemodynamic stability. Once the venous reservoir is emptied, crystalloid solution is added to the reservoir. While
the circuit blood continues to be transfused to the patient, it is displaced by the crystalloid solution until all the
residual blood is transfused to the patient and the circuit is left primed with crystalloid.
Because the blood is being aspirated from the arterial cannula with the use of a pump, there is a risk of air being
entrained from the arterial cannulation purse strings. Once MUF is initiated, the arterial cannula must be checked
for air, particularly if the blood flow through the arterial cannula changes from retrograde to antegrade flow (72).
This would occur if CPB has to be reinstituted or if the infusion rate of the circuit blood exceeds the flow rate of
the MUF pump. The pressure in the circuit must be monitored to avoid any negative pressure occurring in the
circuit, which would draw air across the pores of a microporous membrane oxygenator. Negative pressure would
result if the arterial line were to be kinked or clamped.
There are many circuit designs that are utilized to accomplish MUF (73,74,75,76,77,78,79). Some investigators
report pumping the blood from the patient using the cardioplegia pump, which is already connected to the arterial
side of the extracorporeal circuit. The cardioplegia system works well, because it contains a heat exchanger to
avoid cooling the patient, pressure monitoring, a bubble trap, and a cardioplegia infusion line that is easily
attached to the venous line (76,80,81). Some investigators have also advocated venous-to-venous MUF;
however, recirculation may limit efficiency (82) and others have suggested that venoarterial MUF offers unique
benefits (83) (Fig. 4.8).
To increase the efficiency of fluid removal during MUF, high blood flows have been used to pull blood from the
arterial line. This procedure raises concerns regarding the increased aortic diastolic runoff and the potential for
intracranial steal. Rodriguez et al. (84) studied the effect of MUF blood-flow rates on cerebral blood velocities
and cerebral mixed venous oxygen saturations during various MUF blood flows in a group of pediatric patients
(85). They found that MUF bloodflow rates above 20 mL/kg in patients weighing less than 10 kg resulted in a
decrease in cerebral blood-flow velocities and cerebral mixed venous oxygen saturations.
Outcomes
Most studies evaluating the effects of MUF have focused on pediatric patients (86,87,88). Specifically in
this group, it has
P.117
been shown to decrease postoperative blood loss (89) and transfusion requirements (5,75,87,90). Studies
have also demonstrated increases in arterial blood pressure and cardiac output (86,91,92,93,94,95),
improved pulmonary function (94,96,97,98,99,100), reduced postoperative ventilator requirement (5,87,99),
and fewer days in the intensive care unit (ICU) (87). It has also been shown to improve myocardial
contractility (93,101) and decrease myocardial edema (95,102). Investigators hypothesized that these
improvements were due to decreased myocardial water, increased viscosity and systemic vascular
resistance, removal of anesthetic agents and/or vasodilators, removal of myocardial depression factors, or
stimulation of the sympathetic reflex by removing volume from the aorta (70). After several studies detected
inflammatory mediators in the ultrafiltrate, most research efforts have focused on correlations between
blood and ultrafiltrate levels of cytokines and other proinflammatory mediators and postoperative outcomes
(103,104). The results of these studies have been inconclusive, but they suggest that the removal of
inflammatory mediators during MUF is at least in part related to the improved outcomes (105). MUF seems
to be most effective in pediatric patients, probably due to the large prime volume relative to the patient's
blood volume. A few studies have demonstrated the positive effects of MUF in adult patients, but the effects
do not extend past the immediate postoperative period (77,106,107,108,109). A meta-analysis conducted by
Kuratani et al. (110) found that immediately after MUF patients had higher hematocrits and higher blood
pressure, but that postoperative outcomes were not significant. Inconsistent results may be explained by
use of various protocols and equipment, different end points, patient type, and measurement technique
(35,82).
FIGURE 4.8. Circuit used after cardiopulmonary bypass (CPB) for modified ultrafiltration.
The benefits of MUF may be more obvious in patients with specific risk factors. El-Tahan et al. (111)
showed that when a group of 60 cirrhotic patients undergoing heart valve surgery were randomized to a
conventional ultrafiltration group (CUF) + MUF or CUF alone, the CUF + MUF group had significantly less
ventilation time, perioperative bleeding, packed red blood cell transfusions, and ICU length of stay. The
authors also reported increased serum albumin levels and lower bilirubin and liver enzymes in the CUF +
MUF group; these improvements persisted into postoperative day 7.
Pediatric Applications
An international pediatric perfusion survey of 289 centers reported that 86% of centers used ultrafiltration during
CPB, 71% utilized MUF, and 47% used ultrafiltration to concentrate the circuit prime (112). Many consider MUF
as one of the significant advances in pediatric heart surgery (113,114).
In a randomized trial of 65 pediatric patients, Zhou et al. (36) compared patients who underwent CUF with MUF
to a group that underwent prime ultrafiltration, Z-BUF, and MUF. The prime ultrafiltration, Z-BUF, MUF group
showed improved respiratory indices in the immediate postoperative period and the perioperative lactic acid,
glucose, and tumor necrosis factor (TNF) were significantly lower when using prime ultrafiltration and Z-BUF with
MUF. Several authors
P.118
agree that a strategy combining prime solution ultrafiltration, Z-BUF, and MUF is associated with a modest
improvement in clinical outcomes in the early postoperative period, but the principal clinical outcomes are similar
(103,115).
Removal of Direct Thrombin Inhibitors

Heparin-induced thrombocytopenia (HIT) is a life-threatening complication of heparin administration that occurs
in up to 5% of patients exposed to heparin, regardless of the dose, schedule, or route of administration (116).
HIT is an increasingly common clinical finding in patients presenting for cardiac surgery utilizing CPB. Bivalrudin,
a reversible direct thrombin inhibitor, is a molecular anticoagulant with short half-life and the potential to remove
45% to 65% of the drug using MUF (117,118,119).
HEMODIALYSIS DURING CARDIOPULMONARY BYPASS
Hemodialysis uses a microporous membrane material in a hollow fiber configuration similar to previously
described ultrafiltrators. Hemodialysis differs from ultrafiltration in that a dialysate solution is passed through the
nonblood side of the membrane. Hemodialysis removes diffusible solutes based on a concentration gradient
established by the dialysate solution. Because the blood is under pressure when flowing through the
hemodialysis circuit, water and solutes are also removed by convection, as in ultrafiltration. Hemodialysis during
CPB was first reported by Soffer et al. (120) in 1979.
Theory and Indications

Consider a tank partitioned into two compartments separated by a semipermeable membrane. Each side
contains a solution with dissolved solutes. Diffusion across the membrane is the net movement of molecules from
a region of higher concentration to a region of lower concentration. If there are no other forces, diffusion goes on
until the gradient becomes zero. Diffusion rate is directly affected by blood and dialysis flow rate, temperature,
membrane surface area, membrane thickness, and solute concentration gradient and indirectly by viscosity and
solute molecule size (23) (Fig. 4.9).
Hemodialysis during CPB has been utilized in patients with end-stage renal disease or those who have renal
insufficiency (36). In recent years, the number of patients presenting for heart surgery with these comorbidities
has increased (121).
Circuit Design and Management

Although hemodialysis can be performed by attaching a conventional hemodialysis machine to the CPB circuit,
this would require an additional technician and unnecessary complexities to the procedure. A more common
approach is to position the dialyzer in parallel to the extracorporeal circuit, similar to where the ultrafiltrator would
be positioned. Indeed, an ultrafiltrator can also be used for dialysis, but it must be modified by removing the plug
from the extra-effluent port. Dialysate solutions have been as simple as 0.9% sodium chloride (122), or may be
more complex and require a continuous source of water to be used for mixing the concentrated dialysate. Others
have utilized premixed peritoneal dialysate and premixed hemodiafiltrate (123,124). The premixed solutions may
either be set up to recirculate through the dialyzer in which the bag is changed periodically, or set up as a “one
pass system” in which it flows through the dialysate compartment into a collection canister to remove the solutes
more efficiently (124). To achieve the most efficient diffusion rate, the concentration gradient should be
maximized by configuring the dialysate to flow countercurrent to the dialyzer blood flow. Optimally, the dialysate
flow should be three times the blood flow. However, if the dialyzer blood flow is 300 to 400 mL/min, this would
require 900 to 1,200 mL/min of dialysate flow. Dialysate flows during CPB are generally in the range of 200 to
300 mL/min.
FIGURE 4.9. Diffusion is the movement of solutes in a solution from an area of higher concentration to an area of
lower concentration.
Outcomes
Hemodialysis is effective in removing potassium and other small molecular weight solutes. Studies on
patients with renal failure have determined that hemofiltration treatments are as effective as hemodialysis in
removing small molecular weight solutes such as urea and electrolytes. However, hemofiltration can more
efficiently remove the middle-molecule solutes compared with hemodialysis, because middle-molecule
removal is accomplished primarily by convection rather than diffusion (48,125).
MISCELLANEOUS USES OF ULTRAFILTRATION

Ultrafiltration and Hemodialysis in ECMO
Critically ill patients undergoing long-term ECMO often present with fluid overload due to renal insufficiency or
failure (126). Because these patients often have limited vascular access, the ultrafiltrator or dialyzer is
incorporated into the extracorporeal circuit (127,128,129).
Because the circuit is closed in ECMO and the patient is only on partial bypass, they are still dependent on their
native cardiac output. If too much fluid is removed from the vascular space the patient may become hypovolemic,
causing the ECMO flow as well as the patient’s native cardiac output to decrease.
P.119
Systemic Inflammatory Effect with the Use of a Semipermeable Membrane
SIRS is triggered during heart surgery owing to contact with the artificial surfaces of the CPB circuit, ischemia-
reperfusion injury, and operative trauma (42,130,131,132,133). Myocardial dysfunction, respiratory failure, renal
dysfunction, neurologic complications, and bleeding are at least partially attributed to SIRS (133,134).
The older cellulose and modified cellulose hemodialysis and ultrafiltration membrane materials have been shown
to increase inflammatory mediators and initiate complement activation (135,136). However, the newer synthetic
membrane materials such as polysulphone invoke minimal complement activation (136).
When a few small studies documented the positive effects of MUF, researchers questioned whether these
benefits were related to a decreased systemic inflammatory response or were simply due to plasma water
removal (71,75,90). Studies sampling content of the ultrafiltrate detected various proinflammatory mediators
(125,137,138). Since proinflammatory mediators were capable of crossing the ultrafiltrator membrane, questions
arose when studies showed decreases in certain cytokines concentrations in the plasma, but an insignificant
amount was detected in the ultrafiltrate (139). This evidence led researchers to theorize that some of the
mediators were adhering to the surface of the ultrafiltrator membrane rather than diffusing across the membrane.
In contrast, a few studies have measured specific mediators in the ultrafiltrate, but plasma concentration did not
change and sometimes increased after MUF (55,140,141).
These inconsistencies in data can be rationalized by examining various characteristics of the proinflammatory
mediators. Blood cytokine and other proinflammatory mediator levels are affected by their expression and
elimination rates. In addition, proinflammatory mediators peak at different times during the inflammatory process
(6,46,139,142). One theory suggested by Honoré et al. is that changes in inflammatory mediators and cytokine
levels during ultrafiltration, while not evident in the blood compartment, represent depletion in these elements
from the tissue and interstitial space (143,144).
Interestingly, the effects of removing cytokines and other inflammatory mediators with ultrafiltration to treat sepsis
can be found in nephrology, dialysis, and blood purification journals. Patients with sepsis are being studied
because of its association with high mortality, but it is important to recognize that cytokine production in septic
shock is not unique to infection. Multiple traumas, ischemic reperfusion injury, acute transplant rejection, and
other acute inflammatory states initiate the same cytokine cascade and result in systemic and local inflammation
processes. Specialists who are using ultrafiltration to treat sepsis have found that the techniques that seem to
have the best effects are variations of high-volume, high-cutoff hemofiltration. This technique involves filtration
volumes of 1 to 6 L/hr over 6 to 24 hours with high-cutoff hemofilters. High-cutoff hemofilters differ from those
traditionally used in CPB and ECMO circuits in that they have membrane pore sizes of 15 to 20 nm compared to
hemoconcentrators used on CPB which have a pore size of 5 to 10 nm. The high-cutoff hemofilters allow
particles as large as 60 kDa, such as TNF-α, to more readily pass across the membrane. Unfortunately, with this
pore size a certain amount of albumin is also lost. The long treatment time (24 hours), high volumes (50
mL/kg/hr), and high clearance rates associated with high-volume, high-cutoff hemofiltration are likely more
effective in reducing proinflammatory mediators than Z-BUF and MUF, which use lower volumes and shorter
treatment times. However, this information supports using Z-BUF in combination with MUF during CPB to
increase volume exchange and potentially coincide with some of the peak cytokine expression times.
New research involving newly developed membrane materials and coating to optimize specific molecule
adsorption offers new opportunities for reducing cytokine levels in patients deemed to have hypercytokinia
(145,146).
KEY Points
CPB presents challenges to the management of hemodilution, electrolyte levels, as well as fluid shifts
because of the capillary leak associated with the systemic inflammatory response.
Ultrafiltration can reduce hemodilution by removing excess body water, and can also be utilized to
concentrate the residual CPB circuit blood as in MUF.
Z-BUF functions like hemofiltration by removing plasma water but, as opposed to ultrafiltration, the
amount of water removed is in excess of what is necessary to reverse hemodilution.
As additional water is removed, it is replaced with a balanced electrolyte solution.
Z-BUF can be used to correct certain electrolyte imbalances.
Use of Z-BUF with MUF has demonstrated improved post-CPB outcomes and reduced levels of
inflammatory mediators.
The conventional dialysis circuit is simplified for use in the extracorporeal circuit.
Dialysis can be used to manage patient volume and electrolyte imbalances, similar to Z-BUF or
hemofiltration.
Ultrafiltration appears to more efficiently remove middle-molecule uremic solutes than dialysis.
P.120
REFERENCES
1. Weiland AP, Walker WE. Physiologic principles and clinical sequelae of cardiopulmonary bypass. Heart
Lung 1986;15:34-39.
2. Silverstein ME, Ford CA, Lysaght MJ, et al. Treatment of severe fluid overload by ultrafiltration. N Engl J
Med 1974;291:747-751.
3. Kirklin JK, Blackstone EH, Kirklin JW. Cardiopulmonary bypass: studies on its damaging effects. Blood
Purif 1987;5:168-178.
4. Darup J, Bleese N, Kalmar P, et al. Hemofiltration during extracorporeal circulation (ECC). Thorac
5. Bando K, Turrentine MW, Vijay P, et al. Effect of modified ultrafiltration in high-risk patients undergoing
operations for congenital heart disease. Ann Thorac Surg 1998;66:821-827; discussion 828.
6. Brancaccio G, Villa E, Girolami E, et al. Inflammatory cytokines in pediatric cardiac surgery and variable
effect of the hemofiltration process. Perfusion 2005;20:263-268.
7. Eising GP, Schad H, Heimisch W, et al. Effect of cardiopulmonary bypass and hemofiltration on plasma
cytokines and protein leakage in pigs. Thorac Cardiovasc Surg 2000;48:86-92.
8. Peetoom F, Gerald PS. A simple and inexpensive method for the concentration of protein solutions by
means of ultrafiltration. Clin Chim Acta 1964;10: 375-376.
9. Wizemann V, Benedum J. Nephrology dialysis transplantation 70th anniversary of haemodialysis—the

pioneering contribution of Georg Haas (1886-1971). Nephrol Dial Transplant 1994;9:1829-1831.
10. Schneditz D. Technological aspects of hemodialysis and peritoneal dialysis. In: Nissenson A, Fine R,
eds. Clinical dialysis. 4th ed. New York: McGraw Hill, 2005:47-83.
11. Graham T. Osmotic force. Philo Trans R Soc Lond 1854;144:177-228.
12. Ferry J. Ultrafiltration membranes and ultrafiltration. Chem Rev 1936; 18(3): 375.
13. Abel J, Rowntree L, Turner B. On the removal of diffusible substances from the circulating blood of living
animals by dialysis. J Pharmacol Exp Ther 1914;5: 275-316.
14. Thalhimer W. Experimental exchange transfusions for reducing azotemia. Proc Soc Exp Biol Med
1938;37:641-643.
15. McBain J, Stuewer R. Ultrafiltration through cellophane of porosity adjusted between collodial and
molecular dimensions. J Phys Chem 1936;40: 1157-1168.
16. Kolff W. New ways of treating uremia: the artificial kidney, peritoneallavage, intestinal lavage. 1st ed.
London: Churchill-Livingstone, 1947.
17. Kolff WJ. First clinical experience with the artificial kidney. Ann Intern Med 1965;62:608-619.
18. Kolff WJ, Watschinger B, Vertes V. Results in patients treated with the coil kidney (disposable dialyzing
unit). J Am Med Assoc 1956;161:1433-1437.
19. Skeggs L, Leonards J. Studies on the artificial kidney. Science 1947;108: 212-213.
20. Kiil F. Development of a parallel-flow artificial kidney in plastics. Acta Chir Scand Suppl 1960;Suppl
253:142-150.
21. Stewart RD, Cerny J, CMahon HI. The capillary “kidney”: preliminary report. Med Bull (Ann Arbor)
1964;30:116-118.
22. Ronco C, Clark W. Hollow-fiber dialyzers: technical and clinical considerations. In: Nissenson A, Fine R,
eds. Clinical dialysis. 4th ed. New York: McGraw-Hill, 2005:85-100.
23. Wheeldon D, Bethune D. Haemofiltration during cardiopulmonary bypass. Perfusion 1990;5:39-51.
24. Gohl H, Buck R, Strathmann H. Basic features of the polyamide membranes. Contrib Nephrol 1992;96:1-
25.
25. Strathmann H, Gohl H. Membranes for blood purification: state of the art and new developments. Contrib
Nephrol 1990;78:119-140; discussion 140-141.
26. Ronco C, Ballestri M, Cappelli G. Dialysis membranes in convective treatments. Nephrol Dial Transplant
2000;15 (Suppl 2):31-36.
27. Clar A, Bowers MC, Larson DF. Derivation of sieving coefficients to determine the efficacy of the
hemoconcentrator in removal of four inflammatory mediators produced during cardiopulmonary bypass.
ASAIO J 1997;43:163-170.
28. Klineberg PL, Kam CA, Johnson DC, et al. Hematocrit and blood volume control during cardiopulmonary
bypass with the use of hemofiltration. Anesthesiology 1984;60:478-480.
29. Magilligan DJ Jr. Indications for ultrafiltration in the cardiac surgical patient. J Thorac Cardiovasc Surg
1985;89:183-189.
30. Walpoth B, von Albertini B. Ultrafiltration in cardiac surgery. J Extra Corpor Technol 1984;16:68-70.
31. Hopeck J, Lane R, Schroeder J. Oxygenator volume control by parallel ultrafiltration to remove plasma
water. J Extra Corpor Technol 1981;13:267-271.
32. Tamari Y, Nelson R, Levy R, et al. Effects of the hemo-concentrator on blood. J Extra Corpor Technol
1984;16:89-94.
33. Yeh T Jr, Shelton L, Yeh TJ. Blood loss and bank blood requirement in coronary bypass surgery. Ann
Thorac Surg 1978;26:11-16.
34. Francis G, Tang W, Walsh RA. Pathophysiology of heart failure. In: Fuster V, Walsh RA, Harrington R,
eds. Hurst’s the heart. 13th ed. New York: McGraw Hill, 2011:719-738.
35. Rubens FD, Mesana T. The inflammatory response to cardiopulmonary bypass: a therapeutic overview.
Perfusion 2004;19 (Suppl 1):S5-S12.
36. Zhou G, Feng Z, Xiong H, et al. A combined ultrafiltration strategy during pediatric cardiac surgery: a
prospective, randomized, controlled study with clinical outcomes. J Cardiothorac Vasc Anesth 2013;27:897-
902.
37. Shin’oka T, Shum-Tim D, Laussen PC, et al. Effects of oncotic pressure and hematocrit on outcome after
hypothermic circulatory arrest. Ann Thorac Surg 1998;65:155-164.
38. Nagashima M, Shin’oka T, Nollert G, et al. High-volume continuous hemofiltration during

cardiopulmonary bypass attenuates pulmonary dysfunction in neonatal lambs after deep hypothermic
circulatory arrest. Circulation 1998;98(19, Suppl):II378-II384.
39. Sakurai H, Maeda M, Sai N, et al. Extended use of hemofiltration and high perfusion flow rate in
cardiopulmonary bypass improves perioperative fluid balance in neonates and infants. Ann Thorac
40. Segesser L, Garcia E, Lachat M, et al. A convertible cardiopulmonary bypass system for optimized
hemofiltration. J Extra Corpor Technol 1990;22:68-71.
41. Lee-Sensiba K, Azzaretto N, Carolina C, et al. Errors in flow and pressure related to the arterial filter
purge line. J Extra Corpor Technol 1998;30:77-82.
42. Millar AB, Armstrong L, van der Linden J, et al. Cytokine production and hemofiltration in children
undergoing cardiopulmonary bypass. Ann Thorac Surg 1993;56:1499-1502.
43. Andreasson S, Gothberg S, Berggren H, et al. Hemofiltration modifies complement activation after
extracorporeal circulation in infants. Ann Thorac Surg 1993;56:1515-1517.
44. Tallman RD, Dumond M, Brown D. Inflammatory mediator removal by zero-balance ultrafiltration during
cardiopulmonary bypass. Perfusion 2002; 17:111-115.
45. Fitzgerald DJ, Cecere G. Hemofiltration and inflammatory mediators. Perfusion 2002;17 (Suppl):23-28.
46. Berdat PA, Eichenberger E, Ebell J, et al. Elimination of proinflammatory cytokines in pediatric cardiac
surgery: analysis of ultrafiltration method and filter type. J Thorac Cardiovasc Surg 2004;127:1688-1696.
47. Journois D, Israel-Biet D, Pouard P, et al. High-volume, zero-balanced hemofiltration to reduce delayed
inflammatory response to cardiopulmonary bypass in children. Anesthesiology 1996;85:965-976.
48. Kellum JA, Johnson JP, Kramer D, et al. Diffusive vs. convective therapy: effects on mediators of
inflammation in patient with severe systemic inflammatory response syndrome. Crit Care Med 1998;26:1995-
2000.
49. Lee LW, Gabbott S. High-volume ultrafiltration with extracellular fluid replacement for the management of
dialysis patients during cardiopulmonary bypass. J Cardiothorac Vasc Anesth 2002;16:70-72.
50. Nakamura K, Koga Y, Onitsuka T, et al. Ultrafiltration for hyperkalemia during cardiopulmonary bypass.
Kyobu Geka 1986;39:771-774.
51. Kao YJ, Mian T, Kleinman S, et al. Hyperkalaemia: a complication of warm heart surgery. Can J Anaesth
1993;40:67-70.
52. Weber DO, Yarnoz MD. Hyperkalemia complicating cardiopulmonary bypass: analysis of risk factors. Ann
Thorac Surg 1982;34:439-445.
53. Myles PS, Buckland MR, Pastoriza-Pinol JV, et al. Massive hyperkalemia during combined heart-lung
transplantation: inadvertent contamination with modified euro-collins solution. J Cardiothorac Vasc Anesth
1992;6:600-602.
54. Mick S, Hilberath JN, Davidson MJ, et al. Zero balance ultrafiltration for the correction of acute acidosis
after a period of prolonged deep hypothermic circulatory arrest. Perfusion 2012;27:9-11.
55. Osthaus WA, Gorler H, Sievers J, et al. Bicarbonate-buffered ultrafiltration during pediatric cardiac
surgery prevents electrolyte and acid-base balance disturbances. Perfusion 2009;24:19-25.
56. Goh KP. Management of hyponatremia. Am Fam Physician 2004;69: 2387-2394.
57. Kellum JA. Saline-induced hyperchloremic metabolic acidosis. Crit Care Med 2002;30:259-261.
P.121
58. Nagashima M, Imai Y, Seo K, et al. Effect of hemofiltrated whole blood pump priming on hemodynamics
and respiratory function after the arterial switch operation in neonates. Ann Thorac Surg 2000;70:1901-1906.
59. Zimrin AB, Hess JR. Current issues relating to the transfusion of stored red blood cells. Vox Sang
2009;96:93-103.
60. Delaney M, Axdorff-Dickey RL, Crockett GI, et al. Risk of extracorporeal life support circuit-related
hyperkalemia is reduced by prebypass ultrafiltration. Pediatr Crit Care Med 2013;14:e263-e267.
61. Ugaki S, Honjo O, Kotani Y, et al. Ultrafiltration of priming blood before cardiopulmonary bypass
attenuates inflammatory response and maintains cardiopulmonary function in neonatal piglets. ASAIO J
2009;55:291-295.
62. Sirvinskas E, Lenkutis T, Raliene L, et al. Influence of residual blood autotransfused from
cardiopulmonary bypass circuit on clinical outcome after cardiac surgery. Perfusion 2005;20:71-75.
63. Sutton RG, Kratz JM, Spinale FG, et al. Comparison of three blood-processing techniques during and
after cardiopulmonary bypass. Ann Thorac Surg 1993;56:938-943.
64. Brickley J, Kalshoven D, Wilds S, et al. A comparison of two methods of post-bypass hemoconentration.
J Extra Corpor Technol 1982;14:431-436.
65. Smigla GR, Lawson DS, Shearer IR, et al. An ultrafiltration technique for directly reinfusing residual
cardiopulmonary bypass blood. J Extra Corpor Technol 2004;36:231-234.
66. Colli A, Balduzzi S, Ruyra X. The hemobag: the modern ultrafiltration system for patients undergoing
cardiopulmonary bypass. J Cardiothorac Surg 2012;7:55.
67. Samolyk KA, Beckmann SR, Bissinger RC. A new practical technique to reduce allogeneic blood
exposure and hospital costs while preserving clotting factors after cardiopulmonary bypass: the hemobag.
Perfusion 2005; 20:343-349.
68. Whitlock RP. Processing residual pump blood using ultrafiltration during cardiovascular surgery.
Transfusion 2013;53:2107-2108.
69. Vonk AB, Muntajit W, Bhagirath P, et al. Residual blood processing by centrifugation, cell salvage or
ultrafiltration in cardiac surgery: effects on clinical hemostatic and ex-vivo rheological parameters. Blood
Coagul Fibrinolysis 2012;23:622-628.
70. Naik SK, Knight A, Elliott MJ. A successful modification of ultrafiltration for cardiopulmonary bypass in
children. Perfusion 1991;6:41-50.
71. Naik SK, Knight A, Elliott M. A prospective randomized study of a modified technique of ultrafiltration
during pediatric open-heart surgery. Circulation 1991;84(5, Suppl):III422-III431.
72. Darling EM, King CL, Nanry K, et al. Comparison of four stainless steel heat exchangers for neonatal
ECMO applications. J Extra Corpor Technol 1994;26:68-73.
73. Myers GJ, Leadon RB, Mitchell LB, et al. Simple modified ultrafiltration. Perfusion 2000;15:447-452.
74. Quattro L, Bowser M, Schwendt A. Performing modified ultrafiltration on pediatric patients. AORN J
2002;76:300-302, 304-305.
75. Elliott M. Modified ultrafiltration and open heart surgery in children. Paediatr Anaesth 1999;9:1-5.
76. Trowbridge CC, Stammers AH, Klayman MH, et al. Use of the quest myocardial protection system (MPS)
for modified ultrafiltration during pediatric cardiac surgery. J Extra Corpor Technol 2005;37:219-221.
77. Kiziltepe U, Uysalel A, Corapcioglu T, et al. Effects of combined conventional and modified ultrafiltration
in adult patients. Ann Thorac Surg 2001; 71:684-693.
78. Forsberg BC, Novick WM. A simplified approach to pediatric modified ultrafiltration: a novel circuit design.
79. Choudhary SK, Talwar S, Airan B, et al. A simplified circuit of modified ultrafiltration. Heart Lung Circ
2007;16:113-115.
80. Groom RC, Akl BF, Albus RA, et al. Alternative method of ultrafiltration after cardiopulmonary bypass.
81. Portela FA, Pensado A, Sanchez A, et al. A simple technique to perform combined ultrafiltration. Ann
Thorac Surg 1999;67:859-861.
82. Keenan HT, Thiagarajan R, Stephens KE, et al. Pulmonary function after modified venovenous
ultrafiltration in infants: a prospective, randomized trial. J Thorac Cardiovasc Surg 2000;119:501-505;
discussion 506-507.
83. Mohanlall R, Adam J, Nemlander A. Venoarterial modified ultrafiltration versus conventional arteriovenous
modified ultrafiltration during cardiopulmonary bypass surgery. Ann Saudi Med 2014;34:18-30.
84. Rodriguez RA, Ruel M, Broecker L, et al. High flow rates during modified ultrafiltration decrease cerebral
blood flow velocity and venous oxygen saturation in infants. Ann Thorac Surg 2005;80:22-28.
85. Wang W, Zhu DM, Huang HM, et al. Effect of flow rate, negative pressure, and duration of modified
ultrafiltration on hemodynamics and inflammatory mediators. ASAIO J 2007;53:41-45.
86. Gaynor JW, Kuypers M, van Rossem M, et al. Haemodynamic changes during modified ultrafiltration
immediately following the first stage of the Norwood reconstruction. Cardiol Young 2005;15:4-7.
87. Sever K, Tansel T, Basaran M, et al. The benefits of continuous ultrafiltration in pediatric cardiac
surgery. Scand Cardiovasc J 2004;38:307-311.
88. Koutlas TC, Gaynor JW, Nicolson SC, et al. Modified ultrafiltration reduces postoperative morbidity after
cavopulmonary connection. Ann Thorac Surg 1997;64:37-42; discussion 43.
89. Weber CF, Jambor C, Strasser C, et al. Normovolemic modified ultrafiltration is associated with better
preserved platelet function and less postoperative blood loss in patients undergoing complex cardiac
surgery: a randomized and controlled study. J Thorac Cardiovasc Surg 2011;141:1298-1304.
90. Draaisma AM, Hazekamp MG, Frank M, et al. Modified ultrafiltration after cardiopulmonary bypass in
pediatric cardiac surgery. Ann Thorac Surg 1997;64:521-525.
91. Ricci Z, Polito A, Netto R, et al. Assessment of modified ultrafiltration hemodynamic impact by pressure
recording analytical method during pediatric cardiac surgery. Pediatr Crit Care Med 2013;14:390-395.
92. Elliott MJ. Ultrafiltration and modified ultrafiltration in pediatric open heart operations. Ann Thorac Surg
1993;56:1518-1522.
93. Davies MJ, Nguyen K, Gaynor JW, et al. Modified ultrafiltration improves left ventricular systolic function
in infants after cardiopulmonary bypass. J Thorac Cardiovasc Surg 1998;115:361-369; discussion 369-370.
94. Schlunzen L, Pedersen J, Hjortholm K, et al. Modified ultrafiltration in paediatric cardiac surgery.
Perfusion 1998;13:105-109.
95. Aggarwal NK, Das SN, Sharma G, et al. Efficacy of combined modified and conventional ultrafiltration
during cardiac surgery in children. Ann Card Anaesth 2007;10:27-33.
96. Aeba R, Katogi T, Omoto T, et al. Modified ultrafiltration improves carbon dioxide removal after
cardiopulmonary bypass in infants. Artif Organs 2000;24:300-304.
97. Mahmoud AB, Burhani MS, Hannef AA, et al. Effect of modified ultrafiltration on pulmonary function after
cardiopulmonary bypass. Chest 2005;128:3447-3453.
98. Bando K, Vijay P, Turrentine MW, et al. Dilutional and modified ultrafiltration reduces pulmonary
hypertension after operations for congenital heart disease: a prospective randomized study. J Thorac
Cardiovasc Surg 1998;115:517-525; discussion 525-527.
99. Kameyama T, Ando F, Okamoto F, et al. The effect of modified ultrafiltration in pediatric open heart
surgery. Ann Thorac Cardiovasc Surg 2000;6:19-26.
100. Sahoo T, Kiran U, Kapoor P, et al. Effects of combined conventional ultrafiltration and simplified
modified ultrafiltration in adult cardiac surgery. Ind J Thorac Cardiovasc Surg 2007;23:116-124.
101. Chaturvedi RR, Shore DF, White PA, et al. Modified ultrafiltration improves global left ventricular systolic
function after open-heart surgery in infants and children. Eur J Cardiothorac Surg 1999;15:742-746.
102. Chew MS, Brix-Christensen V, Ravn HB, et al. Effect of modified ultrafiltration on the inflammatory
response in paediatric open-heart surgery: a prospective, randomized study. Perfusion 2002;17:327-333.
103. Yndgaard S, Andersen LW, Andersen C, et al. The effect of modified ultrafiltration on the amount of
circulating endotoxins in children undergoing cardiopulmonary bypass. J Cardiothorac Vasc Anesth
2000;14:399-401.
104. Myung RJ, Kirshbom PM, Petko M, et al. Modified ultrafiltration may not improve neurologic outcome
following deep hypothermic circulatory arrest. Eur J Cardiothorac Surg 2003;24:243-248.
105. Li J, Hoschtitzky A, Allen ML, et al. An analysis of oxygen consumption and oxygen delivery in euthermic
infants after cardiopulmonary bypass with modified ultrafiltration. Ann Thorac Surg 2004;78:1389-1396.
106. Luciani GB, Menon T, Vecchi B, et al. Modified ultrafiltration reduces morbidity after adult cardiac
operations: a prospective, randomized clinical trial. Circulation 2001;104(12, Suppl 1):I253-I259.
107. Boga M, Islamoglu, Badak I, et al. The effects of modified hemofiltration on inflammatory mediators and
cardiac performance in coronary artery bypass grafting. Perfusion 2000;15:143-150.
108. Grunenfelder J, Zund G, Schoeberlein A, et al. Modified ultrafiltration lowers adhesion molecule and
cytokine levels after cardiopulmonary bypass without clinical relevance in adults. Eur J Cardiothorac Surg
2000;17:77-83.
P.122
109. Zahoor M, Abbass S, Khan AA, et al. Modified ultrafiltration: role in adult cardiac surgical haemostasis. J
Ayub Med Coll Abbottabad 2007;19:49-54.
110. Kuratani N, Bunsangjaroen P, Srimueang T, et al. Modified versus conventional ultrafiltration in

pediatric cardiac surgery: a meta-analysis of randomized controlled trials comparing clinical outcome
parameters. J Thorac Cardiovasc Surg 2011;142:861-867.
111. El-Tahan MR, Hamad RA, Ghoneimy YF, et al. A prospective, randomized study of the effects of
continuous ultrafiltration in hepatic patients after cardiac valve surgery. J Cardiothorac Vasc Anesth
2010;24:63-68.
112. Harvey B, Shann KG, Fitzgerald D, et al. International pediatric perfusion practice: 2011 survey results.
113. McRobb CM, Mejak BL, Ellis WC, et al. Recent advances in pediatric cardiopulmonary bypass. Semin
114. Itoh H, Sano S, Pouard P. Pediatric perfusion in Japan: 2010 practice survey. Perfusion 2012;27:72-77.
115. Wang S, Palanzo D, Undar A. Current ultrafiltration techniques before, during and after pediatric
cardiopulmonary bypass procedures. Perfusion 2012;27:438-446.
116. Parekh PJ, Merrell J, Clary M, et al. New anticoagulants and antiplatelet agents: a primer for the clinical
gastroenterologist. Am J Gastroenterol 2014; 109:9-19.
117. Gates R, Yost P, Parker B. The use of bivalirudin for cardiopulmonary bypass anticoagulation in
pediatric heparin-induced thrombocytopenia patients. Artif Organs 2010;34:667-669.
118. Mann MJ, Tseng E, Ratcliffe M, et al. Use of bivalirudin, a direct thrombin inhibitor, and its reversal with
modified ultrafiltration during heart transplantation in a patient with heparin-induced thrombocytopenia. J
Heart Lung Transplant 2005;24:222-225.
119. Reed MD, Bell D. Clinical pharmacology of bivalirudin. Pharmacotherapy 2002;22:105S-111S.
120. Soffer O, MacDonnell RC Jr, Finlayson DC, et al. Intraoperative hemodialysis during cardiopulmonary
bypass in chronic renal failure. J Thorac Cardiovasc Surg 1979;77:789-791.
121. Kundhal K, Pierratos A, Chan CT. Newer paradigms in renal replacement therapy: will they alter
cardiovascular outcomes? Cardiol Clin 2005;23:385-391.
122. Wiggins D, Dearing J. Simultaneous cardiopulmonary bypass and dialysis. J Extra Corpor Technol
1985;17:117-120.
123. Niles S, Sutton R, Embrey R. Ultrafiltration/hemodialysis during cardiopulmonary bypass: a case report.
124. Hamilton CC, Harwood SJ, Deemar KA, et al. Haemodialysis during cardiopulmonary bypass using a
haemofilter. Perfusion 1994;9:135-139.
125. Hoffmann JN, Faist E. Removal of mediators by continuous hemofiltration in septic patients. World J
Surg 2001;25:651-659.
126. Heiss KF, Pettit B, Hirschl RB, et al. Renal insufficiency and volume overload in neonatal ECMO
managed by continuous ultrafiltration. ASAIO Trans 1987;33:557-560.
127. Tagaya M, Matsuda M, Yakehiro M, et al. Prospects for using a hemoconcentrator as an alternative
hemodialysis method in cardiopulmonary bypass surgeries. Perfusion 2014;29:117-123.
128. Yorgin PD, Kirpekar R, Rhine WD. Where should the hemofiltration circuit be placed in relation to the
extracorporeal membrane oxygenation circuit? ASAIO J 1992;38:801-803.
129. Summar M, Pietsch J, Deshpande J, et al. Effective hemodialysis and hemofiltration driven by an
extracorporeal membrane oxygenation pump in infants with hyperammonemia. J Pediatr 1996;128:379-382.
130. Hauser GJ, Ben-Ari J, Colvin MP, et al. Interleukin-6 levels in serum and lung lavage fluid of children
undergoing open heart surgery correlate with postoperative morbidity. Intensive Care Med 1998;24:481-486.
131. Punjabi PP, Taylor KM. The science and practice of cardiopulmonary bypass: from cross circulation to
ECMO and SIRS. Glob Cardiol Sci Pract 2013;2013:249-260.
132. Baehner T, Boehm O, Probst C, et al. Cardiopulmonary bypass in cardiac surgery. Anaesthesist
2012;61:846-856.
133. Litmathe J, Boeken U, Bohlen G, et al. Systemic inflammatory response syndrome after extracorporeal
circulation: a predictive algorithm for the patient at risk. Hellenic J Cardiol 2011;52:493-500.
134. Paparella D, Yau TM, Young E. Cardiopulmonary bypass induced inflammation: pathophysiology and
treatment—an update. Eur J Cardiothorac Surg 2002;21:232-244.
135. Clark WR. Hemodialyzer membranes and configurations: a historical perspective. Semin Dial
2000;13:309-311.
136. Schmaldienst S, Horl W. Biocompatability. In: Nissenson A, Fine R, eds. Clinical dialysis. 4th ed. New
York: McGraw-Hill, 2005:101-125.
137. Onoe M, Magara T, Yamamoto Y, et al. Modified ultrafiltration removes serum interleukin-8 in adult
cardiac surgery. Perfusion 2001;16:37-42.
138. Cole L, Bellomo R, Davenport P, et al. The effect of coupled haemofiltration and adsorption on
inflammatory cytokines in an ex vivo model. Nephrol Dial Transplant 2002;17:1950-1956.
139. Saatvedt K, Lindberg H, Geiran OR, et al. Ultrafiltration after cardiopulmonary bypass in children:
effects on hemodynamics, cytokines and complement. Cardiovasc Res 1996;31:596-602.
140. Torina AG, Silveira-Filho LM, Vilarinho KA, et al. Use of modified ultrafiltration in adults undergoing
coronary artery bypass grafting is associated with inflammatory modulation and less postoperative blood
loss: a randomized and controlled study. J Thorac Cardiovasc Surg 2012;144:663-670.
141. Fujita M, Ishihara M, Kusama Y, et al. Effect of modified ultrafiltration on inflammatory mediators,
coagulation factors, and other proteins in blood after an extracorporeal circuit. Artif Organs 2004;28:310-313.
142. 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;22:1-12.
143. Honoré PM, Joannes-Boyau O, Collin V, et al. Continuous hemofiltration in 2009: what is new for
clinicians regarding pathophysiology, preferred technique and recommended dose? Blood Purif
2009;28:135-143.
144. Honore PM, Joannes-Boyau O, Boer W, et al. High-volume hemofiltration in sepsis and SIRS: current
concepts and future prospects. Blood Purif 2009; 28:1-11.
145. Atan R, Crosbie DC, Bellomo R. Techniques of extracorporeal cytokine removal: a systematic review of
human studies. Ren Fail 2013;35:1061-1070.
146. Saito A, Kawanishi H, Yamashita AC, et al., eds. Contributions to nephrology: high performance
membrane dialyzers, Vol. 173. 1st ed. Basel: Karger, 2011.
Chapter 5
Short-Term Uses of Mechanical Circulatory Support Devices
Jonathan W. Haft
Temporary mechanical circulatory support (TMCS) involves the use of artificial blood pumps to provide
hemodynamic assistance for a period of hours to days to weeks. Indications may include procedural support
during surgical or catheter-based interventions, postcardiotomy support for myocardial dysfunction following
cardiac surgery, or resuscitation of refractory shock or cardiac arrest from a multitude of causes. At present,
there are a variety of devices and techniques available to provide TMCS. These devices differ greatly in their
pumping mechanisms, available applications, cannulation strategies, as well as their potential complications and
adequacy of support under specific clinical circumstances. This chapter reviews the currently utilized techniques
and tools for TMCS of the failing heart.
It is important to recognize the distinction between TMCS and “durable” mechanical circulatory support. Durable
devices currently available in the United States include implantable left ventricular assist devices (LVAD) such as
the HeartMate II, Jarvik Flowmaker, Heart Ware HVAD, HeartMate III, as well as the Syncardia Total Artificial
Heart. The use of durable mechanical cardiac support has been traditionally limited to specialized centers either
as a bridge to heart transplantation or for permanent use as Destination Therapy. They are most frequently
indicated for patients who have chronic heart failure rather than acute cardiogenic shock. These pumps are
specifically engineered for years of reliable ambulatory support and are substantially more expensive than the
temporary devices discussed in this chapter. In addition, there are extensive training requirements for surgeons
and the entire caregiver team. Patients in critical cardiogenic shock are not ideal candidates for durable
mechanical circulatory support. This is where TMCS is ideally applied to stabilize and resuscitate, allowing time
to determine if the patients will recover native cardiac function, or if the clinical circumstances are suitable for
durable mechanical circulatory support.
A number of factors have to be considered when planning TMCS. Cannulation can be performed either centrally
or peripherally using open surgical or percutaneous techniques. Urgency of the patient’s condition and severity
of their shock may impact cannulation choice. In post-cardiotomy settings, the patient is often on
cardiopulmonary bypass, allowing full circulatory assistance while transitioning to TMCS systems. However,
patients in cardiac arrest on the telemetry ward or emergency department require initiation of support in the
shortest interval possible, mandating a strategy that minimizes delays. Some devices have specific flow
constraints, limiting their utility to scenarios that only demand partial circulatory support. Requirements for
biventricular support may demand a different strategy then when patients only require support for a single
ventricle. Furthermore, some patients may have cardiorespiratory failure, and thus mandate a treatment strategy
which can accomplish gas exchange in addition to circulatory support. One also needs to consider the expected
duration of support when choosing a device and treatment strategy that seems best suited for the clinical
situation, particularly considering infectious risks and potential for patient mobility.
EXTRACORPOREAL BLOOD PUMPS

Abiomed AB 5000
The Abiomed AB 5000 (Abiomed Inc., Danvers, MA) is an extracorporeal pneumatically driven pulsatile pump
with a compliant bladder capable of producing a maximum stroke volume of approximately 100 cc (Fig. 5.1). The
bladder is compressed by a surrounding air sac which actuates ejection of blood. There are polyurethane valves
on the inflow and outflow conduits which ensure unidirectional flow. The air is produced by an external
compressor which senses movement of air created by blood displacement. The compressor determines when
the bladder has reached full expansion and initiates ejection. The AB 5000 replaces the BVS 5000 pump, which
was the most frequently used temporary blood pump worldwide. The BVS 5000 pump used a similar mechanism
of pneumatic actuation; however, it was associated with thrombus formation within the sinuses of the valves from
stagnant flow (1). In addition, the BVS 5000 pump relied upon gravity drainage, requiring larger priming volume
and made for challenging patient ambulation. The newer AB 5000 sits in a paracorporeal position, reducing
prime and blood transit time. Operator prescribed vacuum assistance has been added to the external pneumatic
driver, obviating the need
P.124
for gravity-based drainage. There have also been design advances within the inflow and outflow valves,
improving their biocompatibility and thrombotic profile (2).
FIGURE 5.1. Abiomed AB 5000.
FIGURE 5.2. Thoratec CentriMag.
The Abiomed AB 5000 is provided with special cannulae for attachment to the cardiac chambers. Drainage
cannulae are wire wound and malleable, allowing adaptation to the anatomic features of the chamber designated
for cannulation. For left ventricular support, drainage can be accomplished in the left atrium via the right superior
pulmonary vein, the interatrial groove, the left atrial dome, or the apex of the left ventricle. For right ventricular
support, drainage is typically accomplished via the right atrial appendage. Reinfusion into the patient is directed
into specialized cannulae bonded to woven polyester grafts for stable attachment to the ascending aorta or
pulmonary artery for left and right ventricular support, respectively.
By nature of its inherent pumping mechanism, the Abiomed AB 5000 operates without specific speed setting by
the clinician. Vacuum can be set to achieve the desired flow; however, the pump output automatically varies with
the volume status of the patient. By functioning in a “fill to empty” mode, the pump rate will increase or decrease
depending on the speed with which the bladder fills. In any individual patient, this is largely a reflection of the
intravascular filling pressure of the cannulated chamber. In this way, the pump operates in an automatic mode,
adjusting the output based on conditions of the patient rather than relying on a provider to determine the ideal
speed. There is a mode of operation designed to be used during weaning of support, where a desired flow rate
is set to allow assessment of myocardial performance under loading conditions and gradual reduction in the
circulatory support provided. The AB 5000 can be used to provide left or right or biventricular support as
necessary, and this versatility has made this pump, along with its predecessor the BVS 5000, well situated for
application to postcardiotomy support.
Despite the improved design elements in the AB 5000, its use has gradually declined. The expansion of
peripheral techniques to provide TMCS, as will be described later in this chapter, has dampened the enthusiasm
for emergent sternotomy and central cannulation, as is mandated with this device. In addition, concerns have
been raised about hemolysis generated by the vacuum-assisted drainage (3). Although the valve redesign has
improved biocompatibility, the pulsatile nature of the pump output necessarily produces stagnant zones near the
valves, and thrombogenicity remains a concern.
CentriMag
The CentriMag (Thoratec Inc, Pleasanton, CA) is a magnetically levitated centrifugal design pump with unique
features that make it more durable than conventional centrifugal pumps (Fig. 5.2). This device uses magnetic
levitation to allow suspension and rotation of the pump rotor without seals or bearings. While most centrifugal
pumps have found medical utility as components of cardiopulmonary bypass systems (CPB), some have been
used for prolonged mechanical support. However, the flow characteristics, shear forces, and heat generation
create an environment that can lead to adverse events during prolonged use (4). The CentriMag was developed
with these limitations in mind to create an intermediate-use rotary blood pump to provide an alternative to the
pulsatile pneumatic pumps like the Abiomed AB 5000 and BVS pump. The disposable pumphead consists of a
two-piece plastic outer shell and a magnetic impeller. The motor unit is reusable and generates both the
magnetic field to produce rotation and radial force to suspend the rotor. There are large gaps around the rotor
which are important in reducing shear forces from the turbulent secondary flows which exist in all centrifugal
pumps (5). There are also no zones of flow stagnation which may predispose to thrombus formation.
P.125
The CentriMag was designed to provide short-term ventricular support in similar applications to the Abiomed AB
5000. It can be used for right ventricular assistance, left ventricular assistance, or biventricular support. The
manufacturer provides a 34F drainage cannula which is wire reinforced to be kink resistant, but is malleable,
allowing flexible manipulation to gain access to a variety of central cannulation sites. There is also a 24F
reinfusion cannula with accessories to allow either direct insertion or use of Seldinger technique. The console
was also conceived with prolonged intensive care unit support in mind. Its small footprint and simplistic push
button interface with integral alarms differ favorably from the larger consoles of traditional centrifugal pumps
which are intended to be operated with the continuous presence of a CPB perfusionist.
Clinical use of the CentriMag for cardiogenic shock has been favorable overall (6). The initial report from
Harefield Medical Center, UK, demonstrated excellent pump performance with no hemolysis and no evidence of
pump-related thrombus. In the US multicenter pilot trial, 38 patients underwent open-label nonrandomized
implantation of a CentriMag for cardiac failure (7). Twelve patients received right ventricular assistance only for
right ventricular failure following implantation of a durable LVAD. Fourteen patients who presented in shock
following acute myocardial infarctions underwent implantation with biventricular devices (8) or CentriMag LVAD
only (1). Twelve patients required postcardiotomy support, with five as biventricular assistance and seven with
isolated LVADs. Overall survival was 42%. Adverse events were common, as expected in this patient population.
There were no cases of pump failure or malfunction. There were two cases of hemolysis (5%), thought to be
cannula related rather than attributed to the pump itself. There was one (3%) patient who had an embolic
cerebrovascular accident felt to be pump related. Takayama and colleagues (9) reported a large single-
institutional series of 143 patients undergoing CentriMag implantation. There were no device malfunctions or
device thrombosis. There were two cases of clot within the external tubing requiring component exchange.
Overall survival to hospital discharge was 57%, the highest in non-postcardiotomy shock (66%) or in failing heart
transplants (73%). Development of renal failure was independently associated with death.
Based on published clinical use, the CentriMag appears to have improved biocompatibility with reduced need for
pump exchange and lower incidence of thromboembolic complications and minimal hemolysis, as compared to
clinical experience with the AB 5000. Its use for postcardiotomy support has increased substantially because of
its ease of use and superior durability. However, there are some drawbacks to centrifugal design pumps for
short-term circulatory assistance which must be considered. These devices operate at a fixed rotational speed.
Although there may be some limited intrinsic responsiveness to changes in preload, providers must be aware
that manual adjustments in speed may be required as patient conditions change. For example, a progressive rise
in intravascular volume from transfusion or fluid administration may result in congestion if the pump speed is not
increased accordingly. On the other hand, a drop in venous return from diuresis, bleeding, or tamponade can
result in suction generated by the pump, leading to hemolysis, vascular trauma, or, in extreme cases, cavitation.
Unlike the pulsatile pumps which operate automatically based on sensing of bladder fill, continuous flow
centrifugal pumps must have the adequacy of their pump speed carefully monitored by echocardiography,
intracardiac filling pressures, or astute clinical acumen of an experienced provider.
PERIPHERAL VENTRICULAR ASSISTANCE

TandemHeart
The TandemHeart percutaneous left ventricular assist device (pVAD) system (Cardiac Assist Inc, Pittsburgh, PA)
consists of a unique centrifugal design pump along with a venous cannula designed for percutaneous transeptal
drainage of the left atrium via the femoral vein (Fig. 5.3). The centrifugal pump is designed to produce an
extremely small footprint allowing
P.126
placement immediately adjacent to the patient, reducing profile and prime. This is accomplished by integrating
the pump motor and pumphead housing into a sterile single-use unit. The rotor is suspended by a bearing which
is lubricated and cooled by a continuous infusion of saline, potentially reducing thrombus formation and
hemolysis. The transeptal cannula is specifically designed for insertion via the femoral vein across the interatrial
septum into the left atrium. The cannula is created with a curved distal tip for stable placement, and the array of
side holes is located distally to prevent cyanosis from inadvertent drainage of right atrial blood. Flow is returned
via a 15F or 17F arterial cannula which is wire reinforced to prevent obstruction. The entire system is inserted
percutaneously using fluoroscopic and echocardiographic guidance.
FIGURE 5.3. Cardiac Assist TandemHeart.
A prospective multicenter randomized trial was conducted comparing the efficacy of the TandemHeart pVAD
versus an intra-aortic balloon pump for patients in cardiogenic shock (10). Thirty-three patients were randomized
at 12 different centers. Patients treated with the TandemHeart saw greater increase in cardiac output and mean
arterial pressure as well as reduction in pulmonary capillary wedge pressure. There was no difference in overall
survival or rates of weaning from either strategy.
Kar (11) reported a large single-institution series of patients undergoing TandemHeart pVAD for cardiogenic
shock. In their series of 117 patients, most were on intra-aortic balloon pumps, required multiple vasopressors,
and nearly half had required cardiopulmonary resuscitation (CPR). Average flow rates from the device were 3.3
L/min. Postimplant cardiac index increased to 2.8 L/min/m2, heart rate fell from 103 to 85, and lactate levels were
reduced by half within 24 hours. Thirty-one patients were transitioned to durable LVADs and five patients
underwent heart transplantation. Overall survival was 60% at 30 days. Average duration of TandemHeart
support was approximately 6 days. Need for CPR was an independent predictor of death.
The TandemHeart pVAD system, when compared to surgically placed extracorporeal blood pumps has the
attractive feature of peripheral insertion, reducing bleeding risks and increasing the speed with which support
can be initiated. However, there are potential drawbacks. This device is currently only capable of providing left
ventricular assistance; so for patients with biventricular failure, the TandemHeart may not adequately reverse
cardiogenic shock. Percutaneous insertion in the femoral vessels prevents patient ambulation causing additional
debility and limiting any degree of functional rehabilitation while awaiting more definitive treatment. There is also
the hazard of limb ischemia from the large-size cannula obstructing distal flow in the femoral artery, although the
reported incidence was low. The venous cannula can become malpositioned with only a several-centimeter
window in which the drainage side holes must reside entirely within the left atrium. Nursing and patient education
must be strictly enforced to prevent inadvertent withdrawal and the resulting cyanosis. There is also a concern
that excessive unloading of the dysfunctional left ventricle could create an environment with absent ejection
producing stasis and thrombosis within the ventricle or aortic root (Fig. 5.4). Most users of the TandemHeart
recommend pump speed setting that allows some degree of left ventricular ejection and arterial pulsatility. The
largest barrier to more widespread adoption of the Tandem-Heart pVAD system has been the availability of
interventional cardiologists with the specialized skills required for insertion of the transeptal cannula.
FIGURE 5.4. Abiomed Impella.
Impella
The Impella blood pumps (Abiomed Inc.) are a group of rotary microaxial design catheter-based pumps designed
to produce left ventricular support from a single site of arterial cannulation (Fig. 5.5). They can be inserted via
the femoral artery, axillary artery, or ascending aorta and are advanced across the aortic valve using either
fluoroscopic or echocardiographic guidance, typically over a guidewire. The inflow portion of the pump resides
within the left ventricular cavity. The body of the pump houses a rotor which generates flow by rotating at high
speed (25,000-50,000 rpm). The outlet of the catheter is directed via side holes in the proximal aortic root. The
pump rotor is connected to a motor which sits within the catheter just proximal to the outlet portion. The motor
components are sealed from the blood flow within the catheter by an occlusive gasket. Leakage of blood into the
motor housing is prevented by continuous infusion of a purge solution into the motor compartment using an
automated system that continuously measures the pressure of the
P.127
purge fluid. There is an external reservoir within the purge system which allows temporary maintenance of purge
pressure during the required replacement of purge fluid. Prolonged interruption of purge flow will result in blood
leakage into the motor housing, causing pump failure.
FIGURE 5.5. Echocardiographic image of thrombus in the aortic root from peripheral TMCS (Image courtesy of
Jonathan Haft).
An opening in the catheter just proximal to the motor allows direct measurement of aortic pressure through a fluid
channel running the length of the catheter and connected to a pressure transducer. This helps confirm the
position of the pump outlet within the aortic root. Power consumption by the pump motor will vary as the pressure
difference between pump inlet and pump outlet oscillates during the cardiac cycle. Both the pressure signal and
power consumption are continuously displayed on the system monitor. There is an intuitive user interface which
pictorially reports catheter position relative to the aortic valve. In order for the pump to operate effectively, the
inlet and outlet must be separated by a competent aortic valve. When both outlet and inlet are located within the
left ventricle, there will be no pressure difference across the rotor throughout the cardiac cycle, producing a flat
power consumption waveform (Fig. 5.6A). The pressure sensor will display a ventricular waveform confirming
that the pump has migrated too far into the left ventricle. As the pump is withdrawn, a diastolic pressure
difference between inlet and outlet during systole will result in phasic power consumption and the pressure
sensor will produce an aortic waveform, consistent with appropriate pump position (Fig. 5.6B). When the catheter
is withdrawn further allowing the inlet portion to cross the aortic valve, there will again be no diastolic gradient
between inlet and outlet, producing a flat power consumption waveform (Fig. 5.6C) alerting the provider to
advance the catheter.
There is a family of Impella catheters currently available in the United States. The Impella 2.5, as its name
implies, can produce a maximum flow of 2.5 L/min. The outer diameter of the motor is 12 Fr and the provided
repositioning sheath allowing position adjustment is 15 Fr. The shaft of the catheter is 9F in size and there is a
pigtail at the end to help stabilize the catheter within the left ventricle. The Impella CP is a redesign of the 2.5
with slightly enlarged pump diameter to 14F but improved maximum flow to 3.3 L/min. The repositioning sheath is
identical in size. The Impella 5.0, as one would expect, can produce a maximum flow of 5 L/min. The pump
diameter is 21F with a similar 9F catheter shaft. Because of its larger size, the Impella 5.0 is designed to be
inserted into the femoral artery or axillary artery via surgical exposure. A purse-string suture can be placed to
accommodate a 23F peelaway introducer sheath leaving behind an 11F repositioning sheath. Alternatively, a 10-
mm end-to-side graft of woven polyester can be anastomosed, minimizing the intravascular component to just the
9F catheter shaft and reducing the risk of limb ischemia. The Impella 5.0 is also unique, in that instead of relying
on the open fluid coupled aortic position pressure sensor, there is an integrated electronic pressure-sensing
device which compares pressure inside (ventricular) and outside (aortic) the pump lumen. The catheter also has
a pigtail at the end to help maintain stable position in the ventricle. The Impella LD is nearly identical to the 5.0 in
terms of flow capabilities and catheter dimensions. The LD is designed to be inserted directly into the ascending
aorta without the use of a guidewire. A 10-mm woven polyester graft is anastomosed to the ascending aorta at
least 7 cm from the aortic valve to ensure adequate distance allowing full insertion of the pump body. The Impella
LD is advanced though the graft and across the aortic valve, using echocardiographic guidance. If insertion is
performed because of failure to wean from cardiopulmonary bypass, the heart must be allowed to fill enough to
open the aortic valve. The electronic differential pressure sensor will display pulsations on the Impella console,
signifying proper position across the aortic valve. Two silicone hemostatic plugs placed around the catheter are
secured within the vascular graft to create a seal.
The Impella 2.5 was studied in a prospective multicenter randomized trial in patients receiving high-risk
percutaneous coronary intervention (PCI), as compared to insertion of an intra-aortic balloon pump (12). Patients
with impaired left ventricular function and either unprotected left main disease or 3-vessel coronary artery
disease undergoing elective PCI were eligible for inclusion. Of the 448 patients randomized, there was no
difference in the rate of major adverse events at 30 days and no differences in rates of in-hospital death, stroke,
or myocardial infarction. However, there was a reduction in post-discharge major events as well as the rate of
repeat revascularization in those that were randomized to Impella, suggesting that percutaneous
revascularization was more complete. Hemodynamic support during the procedure was better for patients
supported with the Impella 2.5, potentially allowing a more aggressive interventional strategy. Although the trial
did not achieve success in the primary end point,
P.128
there were suggestions that TMCS during high-risk PCI can improve completeness of revascularization. Critics of
the trial point out the substantial difference in cost of the Impella catheter (>$20,000) versus balloon pumps
(<$1,000) and that a more meaningful benefit should have been expected.
FIGURE 5.6. A: Abiomed Impella console screen shot of the pressure and current waveforms when the pump is
positioned too far into the left ventricle. B: Waveforms when the pump is appropriately positioned with the inlet in
the left ventricle and the outlet in the aortic root. C: Waveforms when the pump has been withdrawn too far into
the aorta.
Since introduction in the United States in 2009, a voluntary registry collects data regarding the use of the Impella
2.5. A report from the registry evaluated a group of patients implanted specifically for cardiogenic shock following
acute myocardial infarction (13). One hundred and fifty-four patients were identified, 81% of which were on
inotropes, 49% had received cardiopulmonary resuscitation, 49% had an intra-aortic balloon pump, and 66%
were mechanically ventilated. Survival to hospital discharge was 51%, with higher survival seen (by multivariable
analysis) in patients who underwent insertion of the Impella 2.5 prior to PCI than in those who underwent
insertion at a later point in time. This large multicenter study suggests that earlier initiation of mechanical support
can improve outcomes in cardiogenic shock associated with myocardial infarction. While this registry report did
not have a control group, there are ample data from published clinical trials in acute myocardial infarctions to
suggest that early initiation of TMCS may be beneficial.
A multicenter prospective open-label trial was conducted using the Impella 5.0 and Impella LD for postcardiotomy
shock (8). Patients with low cardiac output despite adequate intracardiac filling pressures on two moderate-dose
inotropes or one high-dose inotrope were eligible for inclusion. Sixteen patients were implanted at seven sites
into patients who underwent coronary bypass grafting (12), bypass grafting plus mitral replacement (3), mitral
replacement (1), and heart transplantation (1). The Impella devices were inserted either peripherally through the
femoral artery (5) or directly into the ascending aorta (12). Insertion required less than 15 minutes in 80% of
cases. Average pump flow was 4.0 L/min and duration of support was 3.7 days. There were two pump
malfunctions related to obstruction of the purge line requiring removal of the catheter. Cardiac index increased by
1.6 L/min/m2 and mean arterial pressure increased by 12 mm Hg. Overall survival to 30 days was 94%. While
this survival rate was
P.129
substantially better than any other report of TMCS in postcardiotomy shock, it is unclear if this represented a
healthier cohort.
The Impella devices are an attractive strategy to TMCS. The flexible sites of implantation allow opportunities to
provide peripheral support, avoiding sternotomy and even allowing ambulation when the axillary approach is
chosen. Support initiation is simplified by eliminating the need for separate arterial and venous cannulae. It is
much easier and faster to place an Impella across the aortic valve than to place the transeptal cannula required
for TandemHeart support. However, there are drawbacks and potential complications from Impella use, including
aortic or mitral valve injury, hemolysis, challenges with pump positioning, as well as inadequate support from
right ventricular failure. Despite these limitations, there has been substantial expansion in the use of Impella
devices and it is likely that similar catheter-based TMCS pumps will emerge in the near future.
ECMO
Extracorporeal membrane oxygenation (ECMO) was first described in the 1970s with the discovery that silicone
rubber was permeable to oxygen and carbon dioxide and thus could serve as a gas exchange membrane. This
differed from the bubble and disk oxygenators used for cardiopulmonary bypass which created a large air-blood
interface, causing substantial cellular activation and destruction with prolonged use. In its early phase, ECMO
was predominantly employed to treat neonatal respiratory failure, but its use expanded to adults suffering from
both respiratory and cardiac failure. An ECMO circuit consists of a blood pump, an oxygenator, and tubing to
connect to the vascular access cannulae. ECMO can be provided in one of two applications: veno-venous (VV)
or veno-arterial (VA), depending on the location of return of oxygenated blood. VV ECMO is used to treat primary
respiratory failure since there is no hemodynamic support provided other than that achieved from resolution of
hypoxemia and hypercarbic acidosis. VA ECMO can be used to treat either respiratory failure or cardiac failure,
since it bypasses both chambers of the heart and the lungs.
A variety of blood pumps can be used for ECMO support. Historically, roller pumps were most frequently used,
as they are inexpensive and durable. Roller pumps, however, can create excessive negative pressure if venous
return is insufficient to maintain complete filling of the tubing at the pump rpm speed. In order to avoid cavitation
and vascular injury from suction, these roller pumps must be servoregulated to stop or reduce speed when
conditions suggest impending suction. In addition, gravity drainage is required, necessitating a larger circuit with
limited mobility. Roller pumps can also generate extremely high positive pressure, hazarding circuit rupture if
there is obstruction of the outflow tubing. For this reason, ECMO circuits that use roller pumps require the
continuous presence of trained personnel to monitor the pump and make immediate adjustments to prevent
catastrophic complications. Centrifugal design pumps are increasingly used for ECMO support. They generate
blood flow with a rapidly spinning impeller creating radial force. Centrifugal pumps are not occlusive, which
means that the amount of pressure generated, either positive or negative, is far less than with a roller pump.
They are considered safer in that the risks of cavitation or circuit rupture are minimal. Centrifugal pumps
generate suction, which obviates the need for gravity drainage, but the suction can produce hemolysis and
vascular injury if not carefully titrated. In addition, early centrifugal pumps were associated with excessive heat
generation and thrombus formation in zones of stagnant flow. Contemporary centrifugal pumps are now
magnetically levitated, reducing shear forces, cellular activation, and the possibility for clot formation (14).
Gas exchange in ECMO circuits has evolved significantly since the first ECMO case in 1972 (15). The silicone
membrane oxygenator (Fig. 5.7) was a tightly wound spiral creating a large surface area for gas exchange.
These devices were reliable and durable, but resistance across the device was extremely high, creating shear
forces that resulted in cellular activation. Microporous hollow fiber oxygenators rely on the porosity of
polypropylene fibers for respiratory gas diffusion. Despite the tight packaging of the microfibers into very low
prime devices, the resistance to blood flow is quite low. However, the microporous hollow fiber oxygenators are
prone to leakage of plasma across the pores, typically initiated after lipid deposition reduces surface tension.
Plasma leakage renders the oxygenators ineffective. The introduction of gas exchange fibers made out of
polymethyl-pentene in the early
P.130
21st century was one of the most important innovations in ECMO support. These oxygenators are low in prime
volume, have minimal resistance to blood flow, and are impervious to plasma leakage. There is only one
oxygenator approved for use in the United States: the Quadrox D (Fig. 5.8) (Maquet, Rastatt, Germany).
FIGURE 5.7. Silicone membrane oxygenator (Image courtesy of the Extracorporeal Life Support Organization).
CARDIOHELP
The Cardiohelp (Maquet) is the first completely contained ECMO system consisting of an integrated centrifugal
pump and polymethyl-pentene oxygenator (Fig. 5.9). The system is ultracompact, reducing priming volume and
facilitating patient transport either within a hospital or between hospitals. The console provides data using
numerous pressure, temperature, saturation, and bubble sensors. Cardiohelp sales have grown dramatically in
the United States since its introduction shortly before the time of this chapter submission.
Cannulation for VA ECMO can be variable, depending on the clinical circumstances. For postcardiotomy shock,
central cannulation easily provides ideal flow rates. Standard CPB cannulae can be used, but surgeons must be
meticulous with hemostasis as the ongoing anticoagulation requirement will predispose to bleeding
complications. Peripheral cannulation can also be performed, most commonly using the femoral artery and vein.
This can be accomplished either percutaneously or via direct surgical exposure. Peripheral cannulation usually
mandates smaller cannula sizes, potentially effecting maximal flow rates. Lower extremity ischemia is common
(16), but there have been several techniques described to address these concerns (17,18).
There have been no prospective randomized trials examining the efficacy of ECMO for cardiogenic shock. Data
on outcomes in this patient population are limited to single-institution retrospective series or publications from the
Extracorporeal Life Support Organization (ELSO), which houses a voluntary international registry. Rastan (19)
reported the outcomes of 517 patients placed on ECMO for postcardiotomy shock, 42% during the initial attempt
to wean from CPB, and the remainder delayed by an average of 63 hours. The average ECMO duration was
only 3.3 days, and survival to hospital discharge was 25%. Age, history of diabetes, and lactate levels were
independently associated with mortality. Wu (20) described their institutional experience of non-postcardiotomy
VA ECMO use for cardiogenic shock. Of the 60 patients supported, 28 were receiving active cardiopulmonary
resuscitation during cannulation for ECMO. Twenty-six patients had acute myocardial infarctions, 16 had
myocarditis, 5 with massive pulmonary emboli, and 13 with other causes of cardiogenic shock. Overall survival to
hospital discharge was 53%, with requirement of CPR >60 minutes independently associated with death. Paden
(21) brought out the ELSO Registry report in 2012. There has been steady growth in adult use of VA ECMO for
cardiac failure with survival rates of approximately 40%.
FIGURE 5.8. Maquet Quadrox D oxygenator.
FIGURE 5.9. Maquet CARDIOHELP.
ECMO provides biventricular support via the simplest form of cannulation possible. Initiation can be achieved
peripherally and percutaneously, or centrally for postcardiotomy scenarios. There is a perception that ECMO is
technically complex and thus requires highly specialized personnel at the bedside continuously manipulating the
circuitry. Contemporary ECMO technology with newer centrifugal pumps and low-resistance durable oxygenators
has made support simpler than ever before. However, there are limitations with ECMO which can affect its utility.
ECMO does not directly decompress the left ventricle, unlike other forms of TMCS.
P.131
When patients are placed on ECMO for shock, careful attention must be paid to identify and rapidly treat left
ventricular distension. Although ECMO bypass both chambers of the heart, some blood inevitably returns to the
left ventricle, either from ongoing ejection from the right ventricle into the pulmonary circulation, or from bronchial
flow and thebesian veins directly into the left ventricle. If myocardial dysfunction is severe enough, or in the
presence of persistent ventricular fibrillation, left ventricular pressure will rise, leading to pulmonary edema and
eventually pulmonary hemorrhage. Inotropic support is often required to maintain left ventricular ejection. When
this is ineffective, intra-aortic balloon pumps may provide enough afterload reduction to allow native cardiac
ejection. When these strategies do not work, venting of the left ventricle is required. For postcardiotomy cases, a
direct vent can be placed via the right superior pulmonary vein and connected to the venous limb of the ECMO
circuit. When ECMO support is peripheral, venting can be accomplished with a percutaneous interatrial
septostomy (22), insertion of a transeptal drain (23), or placement of an Impella 2.5 across the aortic valve for
active mechanical venting (24).
FIGURE 5.10. Abiomed Impella RP.
RIGHT VENTRICULAR ASSISTANCE

The extracorporeal blood pumps described earlier can serve as right-sided ventricular assist devices when the
drainage is attached to the right atrium and the infusion is directed into the pulmonary artery. However, this
approach requires invasive sternotomy. ECMO supports right ventricular failure but creates the additional
complications from arterial access, thrombotic and inflammatory risk of the increased extracorporeal surface area
within the oxygenator, and concerns about left ventricular and aortic root thrombus. There have been two
peripheral and percutaneous approaches to isolated right ventricular failure recently introduced in the United
States which will be presented here.
Impella RP
The Impella RP recently was approved for use in the United States and has found favorable results (25). The
device has essentially the same platform as the other left-sided Impella catheters. This pump also uses a
microaxial rotor to generate up to 4 L/min flow using the 22F-diameter pump. It can be inserted percutaneously
from the femoral vein and advanced across the tricuspid and pulmonary valves. There is inherent memory in the
sigmoid-shaped catheter, improving maintenance of proper positioning (Fig. 5.10). The drainage port is located
within the right atrial body with the infusion directed into the pulmonary artery. Its greatest utility may be for
temporary right ventricular assistance following durable LVAD placement.
PROTEK Duo Cannula

The PROTEK Duo Cannula (Cardiac Assist Inc.) is a dual-lumen cannula designed for right ventricular
assistance. The catheter is inserted percutaneously via the right internal jugular vein and advanced using
fluoroscopic guidance across the tricuspid and pulmonary valves and into the main pulmonary artery (Fig. 5.11).
The drainage ports lie within the right atrium. Blood is extracted via a centrifugal pump and infused into the return
lumen in the pulmonary artery. The catheter can be used to treat isolated right ventricular failure or for
hypoxemic respiratory failure when an oxygenator is added to the circuit.
CLINICAL CONSIDERATIONS
There are a multitude of devices available which can be used for temporary mechanical support of the failing
heart. Which strategy do you choose? Which device do you ask your hospital administrator to purchase? As
each section of this chapter suggests, there are no perfect devices or approaches to this problem. However,
there is one thing we can be sure of: patients in persistent cardiogenic shock will do poorly. For your patients in
cardiogenic shock, whether you choose to use an extracorporeal blood pump like the AB 5000 or CentriMag, or
insert a TandemHeart transeptal cannula, or an Impella 5.0 from the femoral artery, or to place the patient on
ECMO, there will likely be complications or limitations from the strategy you have selected. However, those
limitations are clearly not as bad as standing and watching your patient deteriorate with low cardiac output
despite inotropes and balloon counterpulsation. With nearly every device, there is a published single-institution
retrospective report characterizing the
P.132
relationship between end organ injury, lactate levels, CPR duration, and death. The central message should be
that TMCS of any kind is better than shock.
FIGURE 5.11. Chest X-ray of a patient with the Cardiac Assist PROTEK Duo cannula (Image courtesy of
Jonathan Haft).
While it is important to rapidly determine when TMCS is necessary, it is also wise to consider when it may be
inappropriate. TMCS is a bridge to myocardial recovery, to durable ventricular assist device (VAD) implantation,
or to heart transplantation. Myocardial recovery may be expected in acute myocardial infarctions, myocarditis, or
postcardiotomy failure. However, it seems highly unlikely for patients with longstanding chronic heart failure who
abruptly decompensate to successfully wean from TMCS. These patients characteristically will require
permanent cardiac replacement, either with durable VAD or transplantation. These treatments are unique and
not necessarily appropriate for all patients. Durable VADs are expensive and resource consuming. There is great
public scrutiny on outcomes as they represent a substantial burden on society. It is our obligation to ensure that
they are implanted in appropriately selected patients, excluding those with chronic organ failure, demonstrated
medical noncompliance, or have untreated psychiatric illness. Heart transplantation is of limited supply and
should be offered only to potential recipients who are believed to have a reasonable probability of long-term
survival. It is therefore essential that during consideration of TMCS, the bridge is visualized along its length to be
certain there is in fact a potential exit.
Our center’s strategy has evolved through the years but offers different approaches for each unique clinical
situation. Impella is typically used for catheterization lab procedural support. TandemHeart is chosen for chronic
decompensated heart failure as a bridge to durable LVAD implant. Active cardiac arrest from any cause is treated
with percutaneous ECMO via the femoral vessels. Postcardiotomy shock is supported with ECMO for
biventricular failure, or CentriMag for isolated single ventricular dysfunction. We have recently begun using the
PROTEK Duo cannula for right ventricular support following durable LVAD implantation. These choices will likely
change over the next several years as new technology and techniques become available. TMCS will evolve
considerably as future innovations move their way from computer simulation to the animal laboratories to the
hospitals.
KEY Points
Temporary mechanical circulatory support can be used to resuscitate patients in cardiogenic shock.
There are a variety of devices currently used for this application, with substantial differences in pumping
mechanisms, cannulation techniques, limitations, and potential complications.
Extracorporeal blood pumps, such as the Abiomed AB 5000 or the Thoratec Centrimag, can be
connected directly to the cardiac chambers, providing left, right, or biventricular assistance.
The Cardiac Assist TandemHeart is a percutaneous extracorporeal left ventricular assist device which
uses a peripherally inserted cannula advanced across the interatrial septum to bypass the failing left
ventricle.
The Abiomed Impella is a microaxial blood pump which is positioned across the native aortic valve and
actively pumps blood from the left ventricle into the aortic root with a high-speed rotor.
ECMO uses a blood pump, oxygenator, and cannulae to bypass the heart and lungs, providing
hemodynamic and respiratory support.
Before initiating temporary mechanical circulatory support, feasibility of myocardial recovery, transplant,
or transition to durable ventricular assistance should be considered to establish realistic exit strategies.
P.133
REFERENCES
1. Samuels LE, Holmes EC, Thomas MP, et al. Management of acute cardiac failure with mechanical assist:
experience with the ABIOMED BVS 5000. Ann Thorac Surg 2001;71(3, Suppl):S67-S72.
2. Anderson M, Smedira N, Samuels L, et al. Use of the AB5000TM ventricular assist device in cardiogenic
shock after acute myocardial infarction. Ann Thorac Surg 2010;90:706-712.
3. Samuels LE, Holmes EC, Garwood P, et al. Initial experience with the Abiomed AB5000 ventricular assist
device system. Ann Thorac Surg 2005; 80:309-312.
4. Bennett M, Horton S, Thuys C, et al. Pump-induced haemolysis: a comparison of short-term ventricular

assist devices. Perfusion 2004;19:107-111.
5. Zhang J, Gellman B, Koert A, et al. Computational and experimental evaluation of the fluid dynamics and
hemocompatibility of the CentriMag blood pump. Artif Organs 2006;30(3):168-177.
6. Robertis FD, Birks EJ, Rogers P, et al. Clinical performance with the Levitronix Centrimag short-term
ventricular assist device. J Heart Lung Transplant 2006;25:181-186.
7. John R, Long JW, Massey HT, et al. Outcomes of a multicenter trial of the Levitronix CentriMag ventricular
assist system for short-term circulatory support. J Thorac Cardiovasc Surg 2011;141:932-939.
8. Griffith BP, Anderson MB, Samuels LE, et al. The RECOVER I: a multicenter prospective study of Impella
5.0/LD for postcardiotomy circulatory support. J Thorac Cardiovasc Surg 2013;145:548-554.
9. Takayama H, Soni L, Kalesan B, et al. Bridge-to-decision therapy with a continuous-flow external

ventricular assist device in refractory cardiogenic shock of various causes. Circ Heart Fail 2014;7:799-806.
10. Burkhoff D, Cohen H, Brunckhorst C, et al. A randomized multicenter clinical study to evaluate the safety
and efficacy of the TandenHeart percutaneous ventricular assist device versus conventional therapy with
intraaortic balloon pumping for treatment of cardiogenic shock. Am Heart J 2006;152:469. e1-469.e8.
11. Kar B, Gregoric ID, Basra SS, et al. The percutaneous ventricular assist device in severe refractory
cardiogenic shock. J Am Coll Cardiol 2011;57: 688-696.
12. O'Neill WW, Kleiman NS, Moses J, et al. A prospective, randomized clinical trial of hemodynamic support
with Impella 2.5 versus intra-aortic balloon pump in patients undergoing high-risk percutaneous coronary
intervention, the PROTECT II study. Circulation 2012;126:1717-1727.
13. O’Neill WW, Schreiber T, Wohns DHW, et al. The current use of Impella 2.5 in acute myocardial
infarction complicated by cardiogenic shock: results from the USpella Registry. J Interv Cardiol 2014;27:1-
11.
14. Sobieski MA, Giridharan GA, Ising M, et al. Blood trauma testing of Centrimag and Rotaflow centrifugal
flow devices: a pilot study. Artif Organs 2012;36(8):677-682.
15. Hill JD, O’Brien TG, Murray JJ, et al. Prolonged extracorporeal oxygenation for acute posttraumatic
respiratory failure (shock-lung syndrome). Use of the Bramson membrane lung. N Engl J Med 1972;286:629-
634.
16. Foley PJ, Morris RJ, Woo EY, et al. Limb ischemia during femoral cannulation for cardiopulmonary
support. J Vasc Surg 2010;52(4):850-853.
17. Spurlock DJ, Toomasian JM, Romano MA, et al. A simple technique to prevent limb ischemia during
veno-arterial ECMO using the femoral artery: the posterior tibial approach. Perfusion 27(2):141-145.
18. Madershahian N, Nagib R, Wippermann J, et al. A simple technique of distal limb perfusion during
prolonged femoro-femoral cannulation. J Card Surg 2006;21:168-169.
19. Rastan AJ, Dege A, Mohr M, et al. Early and late outcomes of 517 consecutive adult patients treated with
extracorporeal membrane oxygenation for refractory postcardiotomy cardiogenic shock. J Thorac Cardiovasc
Surg 2010;139:302-311.
20. Wu MY, Lee MY, Lin CC, et al. Resuscitation of non-postcardiotomy cardiogenic shock or cardiac arrest
with extracorporeal life support: the role of bridging to intervention. Resuscitation 2012;83(8):976-981.
21. Paden ML, Conrad SA, Rycus PT, et al. Extracorporeal Life Support Organization Registry Report 2012.
ASAIO J 2013;59:202-210.
22. Seib PM, Faulkner SC, Erickson CC, et al. Blade and balloon atrial septostomy for left heart
decompression in patients with severe ventricular dysfunction on extracorporeal membrane oxygenation.
Catheter Cardiovasc Interv 1999;46:179-186.
23. Aiyagari RM, Rocchini AP, Remenapp RT, et al. Decompression of the left atrium during extracorporeal
membrane oxygenation using a transseptal cannula incorporated into the circuit. Crit Care Med
2006;34:2603-2606.
24. Cheng, A, Swartz MF, Massey HT. Impella to unload the left ventricle during peripheral extracorporeal
membrane oxygenation. ASAIO J 2013;59:533-536.
25. Margey R, Chamakura S, Siddiqi S, et al. First experience with implantation of a percutaneous right
ventricular Impella right side percutaneous support device as a bridge to recovery in acute right ventricular
infarction complicated by cardiogenic shock in the United States. Circ Cardiovasc Interv 2013;6:e37-e38.
Chapter 6
Long-Term Uses of Mechanical Circulatory Support Devices
Joseph C. Cleveland Jr.
OVERVIEW OF THE MECHANICAL CIRCULATORY SUPPORT LANDSCAPE

Mechanical circulatory support (MCS) has undergone a very rapid evolution during the past decade. Heart
failure continues to increase at a rate which predicts that nearly 8 million Americans will have a diagnosis of
heart failure by 2030, which represents a 25% increase in prevalence (1). Given that at most 2,300 donor hearts
become available for transplantation in the United States each year, one can appreciate this huge
supply/demand problem that exists for treating heart failure (2). The concept of treating patients with a
permanent, lifetime replacement of a failing left ventricle (LV) is not a new concept. The development of an
“artificial heart” or permanent left ventricular assist device (LVAD) began in lockstep with the idea of the Apollo
Space Missions in the 1960s. However, LVADs have just recently—within the past 5 years—proved efficacious
as a viable long-term replacement therapy. Coupled with this exponential rise in heart failure, the concept of
long-term or destination therapy (DT) has evolved to be an accepted practice for a patient with advanced heart
failure at present.
DT: DEFINITION, INDICATIONS, AND EVOLUTION

DT is defined as the use of an LVAD for lifelong support in a patient who is ineligible for cardiac transplantation.
Usually, advanced age (>65-70 years of age) and comorbid conditions which preclude cardiac transplantation
are responsible for deciding that a particular patient is eligible for DT. It must be emphasized that medical
therapy is quite successful and appropriate for patients with lesser degrees of heart failure (New York Heart
Association [NYHA Class I-III]). However, there has been little improvement in survival for patients with advanced
(NYHA Class IV) heart failure with medical therapy. Indeed, the pivotal landmark study, the REMATCH trial which
was published in 2001, is a strong example of the contrast between medical therapy and long-term LVAD use (3).
This study prospectively randomized 129 patients who were not candidates for heart transplantation to either
best medical therapy or treatment with a HeartMate XVE LVAD. Arguably, the patients studied were the sickest
group of patients entered into a clinical trial in the history of medicine. Nearly three-fourths of the patients were
inotrope dependent, and all patients were in NYHA Class IV heart failure. The LVAD group had a much improved
survival rate and quality of life compared to the medical group; indeed 23% of the LVAD patients were alive at 2
years follow-up versus only 8% of the medical group. Further, scores on quality of life indices such as the SF-36
and Beck Depression Index were significantly better in the LVAD group. Based on these data, the HeartMate
XVE pump was approved for DT in 2002 by the Food and Drug Administration (FDA), and the indications in the
REMATCH trial led to the National Coverage Decision (NCD) by Centers for Medicare and Medicaid Services
(CMS), which outlined the indications for DT.
While REMATCH demonstrated that LVADs were superior to medical therapy for advanced heart failure patients
without a cardiac transplantation option, there were many important “pearls” gleaned from this trial. Firstly, there
was a sobering early mortality rate from patients who were past the point of recovery. For example, patients who
were mechanically ventilated or patients with anuric renal failure, hepatic failure, or evidence of severe
biventricular failure/cardiogenic shock at the time of implantation all died very early, and one could argue that
they derived no benefit from this therapy. Thus, patient selection and earlier intervention (before irreversible
cardiogenic shock develops) for LVAD were an important lesson from REMATCH. Secondly, despite extensive
bench testing of the HeartMate XVE pump, this pump predictably failed between 18 and 24 months from bearing
wear, cam failure, or rapid failure of the bioprosthetic valves that were inside the pump. In brief, the XVE was not
going to be a long-term pump as configured, as mechanical failure of the pump became obvious after 18 months.
The MCS community needed a pump that could provide longer-term support. Lastly, the cost of this therapy was
quite high, and one or two complications (bleeding or infection) could double or triple the cost. Clearly, if DT
were to become a sustainable, widely adopted therapy, patient selection, an improved pump with fewer
complications, and a lower cost of therapy would need to occur. A useful algorithm is presented (Fig. 6.1) for
patient selection.
Two clinical trials conducted after REMATCH led to a paradigm shift away from volume displacement pumps
such as the HeartMate XVE. Both of these trials established continuous
P.136
flow as the dominant form of long-term MCS. The first trial was conducted as a multicenter study of 133 patients
who were listed for transplantation and subsequently underwent placement of a continuous-flow pump (3). The
pump used in this study was the HeartMate II. This axial flow pump (Fig. 6.2) represented a much different pump
than any of the volume pumps studied to date. The HeartMate II is smaller than the XVE. Most noteworthy is that
there is only one moving part—a rotor—in the HeartMate II. Thus, the mechanical reliability is far superior to the
HeartMate XVE. Lastly, the HeartMate II has no valves; thus, another potential mode of failure of the XVE is
eliminated. The survival at 6 months was 75% and 68% at 1 year. Both functional status (NYHA Class) and
quality of life (Minnesota Living with Heart Failure and Kansas City Cardiomyopathy Questionnaire) were
improved. Patients require anticoagulation with warfarin (target INR 2.0-3.0) and aspirin with this pump. Based
on the data in this clinical trial, the HeartMate II was approved as a bridge-to-transplant (BTT) device in early
2008.
FIGURE 6.1. Algorithm for selection of LVAD candidates. (Reused from Miller LW, Guglin M. Patient Selection
for ventricular assist devices. J Am Coll Cardiol 2013;61:1209-1221, with permission.)
The subsequent clinical trial with the HeartMate II pump enrolled 200 patients who were ineligible for
transplantation in a randomized clinical trial (4). The randomization was a 2:1 format, such that 134 patients
received the HeartMate II and 66 received the HeartMate XVE. The primary end point assessed was a composite
end point of survival at 2 years, free of disabling stroke or pump replacement. The HeartMate II vastly
demonstrated superior survival—58% at 2 years versus 24% for the HeartMate XVE. Several interesting facets
emerged from these data. Firstly, the survival in the HeartMate XVE group was identical to that in the original
REMATCH trial—24% in both groups. This finding confirmed the inability of the HeartMate XVE to provide a
long-term MCS platform. Secondly, survival in the HeartMate II group approached 66% in the latter part of the
trial, indicating that the technology with continuous flow was a viable platform for long-term survival for patients
ineligible for transplantation. This trial also tracked quality of life outcomes, and these outcomes were superior in
the HeartMate II continuous-flow group. Based on these data, the FDA approved the HeartMate II pump for DT.
A subsequent analysis of the HeartMate II BTT cohort of 281 patients further extended and confirmed the
outstanding outcomes with this pump (5). This analysis included 281 patients of 336 who were treated under the
continuous access protocol in the multicenter trial, which examined outcomes in patients listed for transplant who
received a HeartMate II pump. The reason that only 281 patients were analyzed is because these 281 had either
met study end points or met an 18-month follow-up end point. Survival at 18 months had now increased to 72%.
In brief, these data offered a completely new horizon for MCS. In less than a decade, survival increased from
25% to over 70% with the HeartMate II pump at a 2-year end point.
PUMPS CURRENTLY UNDER EVALUATION FOR DT

While the HeartMate II offers many advantages over its predecessor pump, the introduction of a third-generation
centrifugal pump the HeartWare ventricular assist device (HVAD) offers a different platform for long-term MCS.
The HVAD shares similarity with the HeartMate II as a continuous-flow LVAD. However,
P.137
the HVAD is also quite different in that it has no bearing—the pump is suspended in the bloodstream by
principally a hydrodynamic force. Further, the HVAD is implanted with an intrapericardial location—no pocket is
required for this pump (Fig. 6.3). The HVAD also has a driveline that is tunneled subcutaneously. Two batteries
provide several hours of energy for this pump.
FIGURE 6.2. Components of the continuous-flow left ventricular assist device (LVAD). (Reused from Miller LW,
Pagani FD, Russell SD, et al. Use of a continuous flow device in patients awaiting heart transplantation. N Engl
J Med 2007;357:887, with permission.)
FIGURE 6.3. Components of the HeartWare left ventricular assist system. (Reused from Aaronson KD, Slaughter
MS, Miller LW, et al. Use of an intrapericardial, continuous flow, centrifugal pump in patients awaiting heart
transplantation. Circulation 2012;125:1524-1529, with permission.)
Currently, the HVAD is FDA approved for BTT only. The multicenter investigational study which evaluated this
pump for BTT included 140 patients who received the HVAD pump (6). The control or comparison group was
499 patients who contemporaneously received the HeartMate II pump and had data reported to INTERMACS.
The primary end point was
P.138
defined as survival on the originally implanted pump, transplantation, or recovery at 180 days. Impressively,
“success” as defined by the primary end point for the HVAD was 90.7% and for the control HeartMate II pump
was 90.1%. A variety of secondary quality of life outcomes and functional capacity for the HVAD also were met.
Based on these data, the FDA granted approval for the HVAD pump as a BTT in 2012. The HVAD is currently
undergoing clinical evaluation for a DT indication with the endurance trial.
The Jarvik pump is an axial flow pump which is still undergoing evaluation for BTT. The Jarvik pump like the
HVAD is implanted in an intrapericardial location. A unique feature of the Jarvik pump is that its outflow is
directed into the descending thoracic aorta—both the HVAD and HeartMate II have outflow principally designed
for placement in the ascending aorta. Thus, the Jarvik pump is usually placed via a left thoracotomy. The other
unique feature of the Jarvik is that the driveline is anchored to a cochlear screw that immobilizes the exit site in a
more secure fashion than either the HVAD or HeartMate II. The Jarvik has been evaluated in several single-
institution studies and may have advantages for a nonsternotomy implantation over the current FDA-approved
devices (7). It currently does not have an FDA-approved indication for either BTT or DT.
SELECTION OF PATIENTS FOR DT

It must be emphasized that appropriate patient selection is the dominant variable which dictates success with
MCS support. Finding the “sweet spot” for implantation remains challenging as many patients are referred late in
their course of heart failure for LVAD implantation. A general starting point for consideration of a patient for LVAD
as DT originates from the inclusion criteria for the patients enrolled in DT clinical trials. (Fig. 6.1) These patients
should undergo a thorough evaluation as a potential candidate for heart transplantation. Obviously, advanced
age (>65) is the overwhelmingly most common factor for why a patient who meets criteria for MCS is offered an
LVAD as destination rather than for transplantation candidacy. Other factors including severe chronic obstructive
pulmonary disease, peripheral vascular disease, chronic kidney disease secondary to diabetic nephropathy, and
sometimes psychosocial reasons preclude cardiac transplantation. Relative contraindications to transplantation
also exist as such as pulmonary hypertension that may reverse with LVAD unloading of the failing LV. In these
circumstances, the LVAD is placed as a “BTT as likely or BTT as moderate.” The latest INTERMACs data show
that 33% of LVAD implants were placed as either BTT likely or moderate.
A strong word of caution is offered regarding the implantation of LVADs in patients with poor social support, or a
strong history of noncompliance with medications or clinic visits. If these two reasons are the sole
contraindication to heart transplantation, then LVAD implantation must be offered only after very thoughtful
consideration, as patients must still adhere to strict oral anticoagulation regimens with an LVAD and they must
care for a driveline and keep follow-up appointments. Many centers have developed a “contract” which must be
signed by patient and provider describing in detail the expectations that must be met over a 2- to 3-month period
(including adherence to clinic appointments and medications) before we will consider them for an LVAD.
Obviously, the situation is more challenging if a patient is inotrope dependent, but the MCS community has
learned that patients with poor social support/history of noncompliance often consume an inordinate amount of
ventricular assist device (VAD) coordinators’ time and they often have suboptimal outcomes with repeated
hospitalizations for noncompliance.
THE DEVELOPMENT OF A REGISTRY: THE IMPORTANCE OF INTERMACS

In concert with the improvement in continuous-flow pumps, the organization and development of a national
registry is critical to the ongoing success and responsible implementation and growth of MCS technology.
INTERMACS was launched in 2006 and is unique in that it is supported by multiple entities. INTERMACS has
input from the FDA, the Centers for Medicare and Medicaid Services (CMS), the National Heart, Lung, and Blood
Institute (NHLBI), and the industry (device manufacturers), and also receives financial support from its
participating organizations. Currently, over 150 LVAD centers in North America report data to INTERMACS, and
over 12,000 pumps have been enrolled in this database (8). In a relatively brief time, the MCS community now
has data from any FDA-approved durable LVAD entered and reported. It is now possible to benchmark one’s
program against a national outcome. The latest LVAD survival is reported in the sixth annual INTERMACS report
(Fig. 6.4). Before INTERMACS, the MCS community relied upon a few major centers to report their data and use
these data to guide expected outcomes and learn important lessons of implantation. Clearly, the limitations of this
approach were obvious with extrapolation of single center results to other centers. An INTERMAC has developed
a greater comprehensive data registry. The scientific yield is outstanding as the dissemination of these registry
data currently sets the standards for complications and outcomes of LVADs. Lastly, as demonstrated by the
HVAD BTT study (6), control pump data now can be taken from INTERMACS. This critical development
facilitates new LVAD trials and will enable new technology to be evaluated against an established benchmark.
Clearly, as we investigate new pumps, the INTERMACS registry will continue to objectively demonstrate pump
performance and complications. Such a registry will continue to guide the MCS community toward quality
improvement and data analysis.
PERIOPERATIVE MANAGEMENT OF THE LVAD PATIENT

The perioperative management of the LVAD patient is essential to providing excellent outcomes. In general,
there are three
P.139
main categories that play a direct role in successful LVAD outcomes: the management of intra- and perioperative
bleeding, right ventricle (RV) dysfunction, and establishment of anticoagulation in the days following LVAD
implant.
Bleeding remains the most common LVAD-associated complication (9). It is not surprising that bleeding is a
problem as these patients are critically ill when they undergo implantation; they have long-standing hepatic
congestion from congestive heart failure, which negatively affects production of clotting factors; and they are
often maintained on anticoagulation prior to the LVAD implant. Lastly heart failure is a proinflammatory clinical
syndrome which is also associated with abnormalities in blood coagulation. During the implantation of the LVAD,
careful coordination among the surgical team, anesthesia team, and the blood bank or whoever controls access
to blood products is essential. As one is transitioning from cardiopulmonary bypass to LVAD function, rapid
correction of any bleeding disorder is paramount. Aggressive repletion of coagulation factors with plasma and
correction of any platelet dysfunction with platelets is warranted. It is best to avoid the use of agents such as
Factor VIIa or factor eight inhibitor bypass activity unless the rate of bleeding is such that it will not abate with
standard factor repletion and time. Not surprisingly, an increased rate of thromboembolic events in LVAD patients
who receive Factor VIIa exists (10). Meticulous surgical technique and close attention to the inflow suture
placement and the outflow graft suture line are a must to ensure hemostasis.
Right Ventricular Function

Once an LVAD is placed, there are complex factors that interrelate and ultimately dictate whether the RV is able
to provide adequate function for LVAD support. Preoperative evaluation of RV function is critical—obviously
nearly all patients considered for an LVAD have some inherent RV dysfunction, as LV dysfunction remains the
most common cause of RV dysfunction. However, certain hemodynamic parameters strongly predict the need for
a right ventricular assist device (RVAD) or significant RV dysfunction. Of all the hemodynamic parameters
available, a central venous pressure/pulmonary capillary wedge pressure ratio of >0.63 strongly predicted
significant RV dysfunction following LVAD implantation. Further, for patients undergoing an LVAD, 20% have RV
dysfunction, with 6% of the patients requiring an RVAD, 6% of patients requiring extended inotropes, and 7%
requiring late inotropes (11). The patients who manifested RV failure/dysfunction in this study had a markedly
inferior survival compared with those patients without RV dysfunction.
Intraoperatively, the management of pulmonary vascular resistance is critical to help the RV. Measures
commonly employed to assist the RV include promoting alkalosis, lowering CO2, vasoactive agents such as
milrinone which promote pulmonary vasodilation, and direct pulmonary vasodilators such as nitric oxide and
inhaled prostacyclin.
If significant RV dysfunction exists despite utilizing these maneuvers, then early placement of an RVAD is
advised. It is well accepted, and data exist showing improved outcomes for “early” RVAD placement rather than
“late” RVAD placement (12).
Anticoagulation
The institution of anticoagulation after LVAD placement is necessary. Both the HeartMate II LVAD and the HVAD
require anticoagulation with Coumadin and ASA (aspirin). The ASA dose for the HeartMate II is 81 mg and for the
HVAD is 325 mg. The dosage of ASA was increased for the HVAD based on a few isolated pump thrombosis
episodes with 81-mg ASA, and the increase to 325-mg ASA seemed to eliminate this problem. In general,
anticoagulation should be started with either heparin or a thrombin inhibitor within 24 hours of implantation if
bleeding has subsided (13). Most institutions start IV heparin as a bridge until the INR reaches 2.0.
Anticoagulation for LVAD patients remains challenging, and many centers also use thromboelastography (TEG),
platelet inhibition assays, and other methods to attempt to tailor anticoagulation for these patients. Given the
need to balance the risk of bleeding events versus the risk of pump thrombosis, much further work toward
individualizing anticoagulation with these pumps is needed. In this regard, a very large multicenter analysis of
bleeding and stroke during support with the HeartMate II pump was undertaken (9). Of interest, female gender
was a risk factor for both late bleeding, stroke, and pump thrombosis. Advanced age, ischemic etiology, lower
preoperative hematocrit, and female gender were risk factors for bleeding. Clearly, the gender issue requires
further elucidation as a risk factor.
LONG-TERM OUTCOMES AFTER DT
Survival
The survival of patients after implantation of LVAD for DT continues to improve. If one places the 2-year survival
rate from RE-MATCH of 24% as the “benchmark” for survival in 2001, then survival in 2014 is vastly improved.
Indeed, survival from the sixth annual INTERMACS report for LVAD patients was 69% at 2 years and 47% at 4
years (Fig. 6.4). Clearly, this landscape is changing rapidly, as survival from BTT trials now routinely exceeds
90% at 1 year. The culmination of improved patient selection, continuous-flow technology with more durable
pumps, and growth of the MCS community with collective sharing of date in the INTERMACS registry all have
produced this positive signal in survival. As newer pumps emerge on the horizon, and the prospect of moving
therapy toward earlier implantation with clinical trials such as ROADMAP and REVIVE-IT ongoing, we will
hopefully observe improved outcomes.
Bleeding
Bleeding after LVAD implantation remains the most common complication. INTERMACS data again confirm that
bleeding event rate—defined as events/100 patient-months—is quite common. Of interest, nearly all patients
who have undergone placement of a HeartMate II LVAD develop a defect in
P.140
von-Willebrand factor that results in the cleavage of the factor into multimers (14). About 25% of these patients
have subsequent significant mucosal surface (gastrointestinal or epistaxis) related bleeding. While centers differ
in their approach to these bleeding complications, most will stop ASA if patients develop recurrent bleeding
events. Bleeding complications do develop with other continuous-flow pumps such as the HVAD and Jarvik
pump. Thus, there is likely some component of continuous-flow technology as it interacts with patients of
advanced age who undergo LVAD placement that promotes bleeding. This area as well requires much further
characterization.
FIGURE 6.4. Actuarial and parametric survival curve for adult primary continuous-flow LVADs, including patients
receiving additional right ventricular support. The lower line depicts the hazard function. The dashed lines
indicate the 70% confidence limits. Patients are censored at transplant or device explant. The numbers at the
bottom of the figure indicate the number of patients available at specified follow-up intervals. LVAD, left
ventricular assist device; BIVAD, biventricular assist device. (Reused from Kirklin JK, Naftel DC, Pagani FD, et
al. Sixth INTERMACS annual report: a 10,000 patient database. J Heart Lung Transplant 2014;33(6):555-564,
with permission.)
Infection
Infection after LVAD implantation can range in spectrum from a localized infection of a driveline to systemic
sepsis with LVAD-associated endocarditis (15). Clearly, one can intuitively deduce that localized driveline
infections usually respond to antimicrobial therapy and patients can live a relatively normal existence with such
an infection. The concern for a driveline infection is that it can progress to a pump pocket infection in the case of
the HeartMate II LVAD. Pump pocket infections usually require some sort of surgical intervention—that is, limited
debridement, or occasionally a full debridement with a wound VAC placement. Clearly, in patients who are not
transplant candidates, the infection usually cannot be eradicated—one can only hope to control it. Decision
making for each patient must be individualized: consider the organism, the goals of the patient, and his or her
desire for more invasive procedures versus palliation. Clearly, LVAD-associated endocarditis is a life-threatening
condition, and if the patient is deemed appropriate for pump exchange, then pump exchange is indicated. The
outcome of LVAD-associated endocarditis without cardiac transplant as a strategy is usually quite poor.
Stroke
Stroke after LVAD is a devastating complication. Currently, the rate of thrombotic and ischemic strokes varies
between 5% and 20% and is both device and clinical trial specific with regards to occurrence (16). Indeed, it
remains difficult to ascertain a specific rate or risk factors in the DT population for the rate of both ischemic and
hemorrhagic cerebrovascular accident (CVA) events. Indeed, the HeartWare ENDURANCE Supplemental Trial
has as a prespecified primary end point as reduction in stroke at 12 months (ClinicalTrials.gov NCT01966458).
Highly valuable information regarding CVA reduction will hopefully emerge when this trial is completed.
VAD Thrombosis
There has been an increase in LVAD thrombosis—specifically with the HeartMate II LVAD since 2011. A study
from four high-volume VAD centers revealed that the rate of LVAD thrombosis at 3 months increased from 2.2%
to 8.4% by January 2013 (17,18). In the patients who underwent pump replacement or heart transplantation,
outcomes were equivalent to patients without thrombosis. In patients who did not undergo transplantation or
LVAD replacement, mortality was 48%. In further analyses, the source of this increased rate of thrombosis is
unclear. Several points deserve mention. Firstly, blood levels of lactate dehydrogenase (LDH) now correlate with
LVAD thrombosis, such that a doubling of baseline LDH levels predicted LVAD thrombosis. Most centers now
follow LDH levels in all LVAD patients—a significant rise from baseline usually warrants admission, systemic
anticoagulation, and Transthoracic Echocardiogram (TTE) to evaluate for aortic valve opening—which implies
that LVAD is not emptying the ventricle and may have a thrombus. Once clinical signs of hemolysis occur, prompt
pump exchange through a subcostal incision should occur if the patient is a candidate for exchange. The story
and etiology of LVAD thrombosis is far from complete, and it is likely that pump and patient factors combine to
produce this complication.
Future LVADs on the Horizon and the Future of LVAD Technology

Pumps that are soon to be studied in clinical trials are smaller and hopefully will be completely implantable
without a driveline. HeartWare is transitioning to an axial flow platform—the miniaturized ventricular assist
device. The miniaturized ventricular assist device likely will lend itself to a thoracotomy-based insertion.
Conversely, Thoratec has launched trials in Europe with the HeartMate III. This pump is a centrifugal pump. A
completely implantable pump is the goal of both HeartWare
P.141
and Thoratec, and both have prototypes in development. These new pumps will likely be placed via
nonsternotomy and less-invasive incisions. When a completely implantable system is released, the benefit to
patients will be dramatic. The future of the LVAD landscape is very bright. It is foreseeable that a completely
internal system with a low CVA rate will emerge soon. Continuing challenges and opportunities for improvement
include the development of a continuous-flow biventricular assist device, extension of the long-term survival to 5
to 10 years with current LVAD technology, and improvement in the quality of life/patient satisfaction measures.
KEY Points
Mechanical circulatory support will continue to evolve and grow as the incidence of heart failure
increases and heart transplantation rates remain static.
Continuous-flow pumps—both axial and centrifugal—have replaced volume displacement pumps.
Outcomes for mechanical circulatory support are improving—with nearly 80% of patients alive at 2 years.
Complications including bleeding, infection, pump thrombosis, and stroke remain as present barriers to
overcome.
Newer pumps will be smaller and ultimately completely self-contained with no external drive-line.
REFERENCES
1. Heidenreich PA, Albert NM, Allen LA, et al. Forecasting the impact of heart failure in the United States: a
policy statement from the American Heart Association. Circ Heart Fail 2013;6(3):606-619.
2. Miller LW, Guglin M. Patient selection for ventricular assist devices. J Am Coll Cardiol 2013;61;1209-
1221.
3. Miller LW, Pagani FD, Russell SD, et al. Use of a continuous-flow device in patients awaiting heart
transplantation. N Engl J Med 2007;357:885-896.
4. Slaughter MS, Rogers JG, Milano CA, et al. Advanced heart failure treated with continuous-flow left
ventricular assist device. N Engl J Med 2009;361:2241-2251.
5. Pagani FD, Miller LW, Russell SD, et al. Extended mechanical circulatory support with a continuous-flow
rotary left ventricular assist device. J Am Coll Cardiol 2009;54:312-321.
6. Aaronson KD, Slaughter MS, Miller LW, et al. Use of an intrapericardial, continuous-flow, centrifugal pump
in patients awaiting heart transplantation. Circulation 2012;125:3191-3200.
7. Sorenson EN, Pierson RN III, Feller ED, et al. University of Maryland surgical experience with the Jarvik
2000 axial flow ventricular assist device. Ann Thor Surg 2012;93:133-140.
8. Kirklin JK, Naftel DC, Pagani FD, et al. Sixth INTERMACS annual report: a 10,000-patient database. J
Heart Lung Transplant 2014;33:555-564.
9. Boyle AJ, Jorde UP, Sun B, et al. Pre-operative risk factors for bleeding and stroke during left ventricular
assist device implantation. J Am Coll Cardiol 2014;63:880-888.
10. Bruckner BA, Dibardino DJ, Ning Q, et al. High incidence of thromboembolic events in left ventricular
assist device patients treated with recombinant activated factor VII. J Heart Lung Transplant 2009;28:785-
790.
11. Kormos RL, Teuteberg JJ, Pagani FD, et al. Right ventricular failure in patients with the HeartMate II
continuous-flow left ventricular assist device: incidence, risk factors, and effect on outcomes. J Thorac
12. Fitzpatrick JR III, Frederick JR, Hiesinger W, et al. Early planned institution of biventricular mechanical
circulatory support results in improved outcomes with delayed conversion of a left ventricular assist device to
a biventricular assist device. J Thorac Cardiovasc Surg 2009;137:971-977.
13. Feldman D, Pamboukian SV, Teuteberg JJ, et al. The 2013 International Society for Heart and Lung
Transplantation guidelines for mechanical circulatory support: executive summary. J Heart Lung Transplant
2013;32:157-187.
14. Crow S, Chen D, Milano C, et al. Acquired von Willebrand syndrome in continuous-flow ventricular assist
device recipients. Ann Thor Surg 2010;90: 1263-1269.
15. Nienaber JC, Kusne S, Riaz T, et al. Clinical manifestations and management of left ventricular assist
device-associated infections. Clin Infect Dis 2013;57:1438-1448.
16. Backes D, van den Bergh WM, van Duijn AL, et al. Cerebrovascular complications of left ventricular
assist devices. Eur J Cardiothorac Surg 2012;42: 612-620.
17. Starling RC, Moazami N, Silvestry SC, et al. Unexpected abrupt increase in left ventricular assist device
thrombosis. N Engl J Med 2014;370: 33-40.
18. Kirklin JK, Naftel DC, Kormos RL, et al. Interagency Registry for Mechanically Assisted Circulatory
Support (INTERMACS) analysis of pump thrombosis in the HeartMate II left ventricular assist device. J Heart
Lung Transplant 2014;33:12-22.
Chapter 7
Cardiopulmonary Bypass and Myocardial Protection for Minimally
Invasive Cardiac Surgery
Alan P. Kypson
Derek A. Sanderson Jr.
L. Wiley Nifong
W. Randolph Chitwood Jr.
HISTORICAL BACKGROUND
Eversince Gibbon used the first heart-lung machine (1953) and Lillehei cross-circulated patients with parents
(1954), cardiopulmonary perfusion and vascular cannulation methods have evolved in a serpiginous pathway
(1,2). Disc and screen oxygenators were replaced eventually by bubble devices. In the early 1970s, we
cannulated the common femoral artery for perfusion inflow and for venous return to the pump both vena cavae
were drained by gravity. Thus, by adjusting the operating table height above the pump, return to the cardiotomy
reservoir and bubble oxygenator was regulated. We primed the pump with a mixture of crystalloid and a great
deal of whole blood. Often family members were solicited to provide fresh blood donations. As the cannula
occluded the distal common femoral artery, blood flow to the leg was negligible and only through collaterals. It is
interesting that we did not observe more irreversible leg ischemia.
At Duke University, Drs. Sealy, Young, and Brown developed and used the first commercial heat exchanger,
where cooling and rewarming were regulated by a mixing valve and “tap water” temperatures (3). Myocardial
protection was by aortic clamping with coronary ostial blood perfusion, ventricular fibrillation, or intermittent
ischemic arrest. Cardiac dysfunction was common even after some of the simplest valve and coronary
operations. The use of high-dose postoperative inotropic support was the norm for many patients. Although
Melrose had used high-dose potassium cardioplegia before in England, the use of depolarizing solutions was not
accepted until Gay and Ebert published their seminal 1975 paper (4,5). In Germany Kirsch, Bretschneider, and
Bleese and in Britain Braimbridge and Hearse developed various cardioplegic solutions (6,7,8,9,10). Thereafter,
Buckberg and associates introduced blood-based cardioplegia (11). By the mid-1970s, cold crystalloid
cardioplegia was advocated by most surgeons. During this era, retrograde peripheral arterial perfusion had been
replaced by central aortic cannulation. By the mid-1980s, most programs were using membrane oxygenators,
high-flow cannulas, better in-line filters, less pump prime, and improved myocardial preservation techniques.
Retrograde catheters were developed by the 1980s, and transvenous cardioplegia was particularly helpful
protection in the presence of diffuse coronary artery disease (12,13). Little had changed in perfusion technology
until the mid-1990s with the exception of widespread use of cold-blood cardioplegia.
In 1995, several surgeons began MICS in the United States. Cosgrove and Cohn started to use less invasive
sternal incisions with modified cannulation techniques (14,15). Carpentier performed the first videoscopic mitral
valve repair at Broussais Hospital in 1996 (16). Several months later, our group performed the first videoscopic
minimally invasive mitral valve replacement (17). We cannulated the right atrium directly to provide gravity pump
by inserting the venous cannula through the 5-cm minithoracotomy. Retrograde arterial inflow was provided
through the right common femoral artery. We occluded the aorta with a newly developed transthoracic clamp and
used antegrade crystalloid cardioplegia to protect the heart. Our result was pleasing, and we presented the first
videoscopic MICS mitral valve series at the AATS meeting in 1997 (18). Soon thereafter, we converted to vortex
pump kinetic venous drainage through higher-flow long femoral vein cannulas. As some surgeons had done
earlier, we purged air from the thoracic cavity with CO2.
These modified approaches heralded the desire for better cannulas and perfusion circuits. Originally introduced
in 1996, the Heart-Port (Edwards Lifesciences, Irvine, CA) system permitted a new minimally invasive surgical
platform with avoidance of a median sternotomy as well as closed-chest cardiopulmonary bypass with an
arrested heart (19). The technique had a meteoric launching and appeared to be the solution for surgeons and
patients desiring MICS. However, early complications and cost blunted the enthusiasm of many surgeons who
were initial advocates.
Over the next 15 years, MICS was done through small incisions with direct vision and was used mostly for
valvular disease. Using peripheral perfusion techniques, developed for MICS earlier, robotic mitral repairs were
begun in the United States in 2000 (20). Newer cannulas enabled safe peripheral vascular insertion with high-
flow characteristics. The use of assisted venous return (kinetic or suction) was a major advance that enabled the
best flow characteristics through thinwalled cannulas. Either vortex centrifugal pumps or vacuum assistance
became used widely in all MICS cases. Only after
P.144
making these modifications were the possibilities of MICS fully realized. MICS advanced remarkably after several
clinical series showed that the approach rendered the same quality and safety as the traditional sternal
approach, while providing advantages to the patient (21,22,23,24). The success that MICS has achieved would
have been impossible without major advances in perfusion technology and techniques.
CARDIOPULMONARY BYPASS MONITORING

In all of our MICS operations, we monitor closely cardiac dynamics and function as well as leg and brain
perfusion. In each patient, a left arm radial arterial catheter is inserted for systemic pressure monitoring. If intra-
aortic balloon occlusion (clamping) is planned, arterial pressures should be monitored in both arms. This is done
to ensure that the balloon has not inadvertently occluded the innominate artery. For hemodynamic monitoring, a
thermo-dilution Swan-Ganz pulmonary artery catheter (Edwards Lifesciences) is inserted and passed via the
right internal jugular vein. In each patient, a transesophageal echocardiographic probe is placed to evaluate
abnormal valve pathology and ventricular function. Moreover, all cannulas are positioned under
echocardiographic guidance. We use BIS (Bispectral Index) (Covidien, Inc., Boulder, CO) flow to monitor
cerebral blood flow and anesthetic levels. To determine the adequacy of blood flow in a cannulated extremity, we
place oxygen saturation patches (Somanetics, Inc., Troy, MI) on each lower leg for comparison. Should the
saturation fall significantly in the perfused leg, we insert a distal arterial shunt (5F catheter), which then is
hooked to the arterial perfusion circuit. Generally, oxygen saturation levels return to baseline in the perfused leg
after shunt insertion and blood flow improvement.
Cannulation
Hemisternotomy
When using a ministernotomy either for aortic or mitral valve surgery, direct aortic and right atrial cannulation is
effective. For minimally invasive aortic surgery, we insert a 17 or 19F Bio-Medicus high-flow cannula (Medtronic,
Inc., St Paul, MN) into the aorta at the level of the innominate artery. This can be done either by direct insertion
or over a guide wire. For venous return, either a direct right atrial “pancake” two-stage VC2 caval cannula
(Medtronic, Inc.) or a long percutaneous right femoral to right atrial cannula can be used. The “pancake” cannula
is flattened against the incision wall for greater exposure through a small incision.
Minithoracotomy
Typically, peripheral cardiopulmonary perfusion is established via the right internal jugular vein and femoral
vessels. Although some surgeons prefer a single long femoral venous cannula, we prefer “bicaval” return to
optimize drainage and myocardial cooling. Under sterile conditions, and using the Seldinger guide-wire
technique, the anesthesiologist directs a 17F thin-walled Bio-Medicus cannula into the distal superior vena cava
via the right internal jugular vein under transesophageal echocardiogram (TEE) guidance. A Swan-Ganz
pulmonary artery catheter is placed via either the subclavian or the internal jugular vein (using a “double-
puncture” method) (Fig. 7.1). Both the right femoral artery and vein are exposed through a 2-cm oblique groin
incision (Fig. 7.2). Proximal and distal vascular control is not required typically. Adventitial 4-0 Prolene oval
(longitudinal)
P.145
purse-string sutures (Johnson & Johnson, Piscataway, NJ) are placed in both vessels and near the inguinal
ligament. After adequate heparinization, arterial (17-19F) and venous (21F) Bio-Medicus cannulas are passed
into the proximal common femoral artery and right atrium, respectively, by the Seldinger guide-wire technique
using TEE guidance (Fig. 7.3). In corpulent patients, it is advantageous to create a counterincision and tunnel
the cannulas through the subcutaneous tissue of the upper thigh. This is done to allow entrance into each vessel
at a 30° to 45° angle, which makes easier and safer passage of coaxial dilators and cannulas. If the angle is too
acute, entry is difficult, and the potential for posterior arterial and/or vein wall disruption or dissection is
increased.
P.146
After confirmation of appropriate cannula positioning, cardiopulmonary perfusion can be initiated.
FIGURE 7.1. Superior vena caval venous drainage cannula—using the “double stick” internal jugular technique,
a Swan-Ganz pulmonary artery catheter is passed along with a 15 to 18F Bio-Medicus thin-walled cannula.
FIGURE 7.2. Arterial and inferior vena cava cannulation: femoral arterial (AC) and vein (VC) cannulas are shown
in place through a small incision.
FIGURE 7.3. Femoral arterial and venous cannulation using the Seldinger guide-wire technique. A: A 2-cm
oblique incision over the right femoral vessels. B: Guide wires are passed into the femoral artery and vein under
echocardiographic guidance. C: Progressive vascular dilators are passed over the guide wires. D: Finally, the
arterial perfusion and venous drainage cannulas are passed over the guide wire. (Permission of Author:
Chitwood WR, ed. Atlas of robotic cardiac surgery. London, UK: Springer, 2014.)
Alternate Arterial Cannulation Techniques

Atherosclerotic disease within the ileo-femoral vessels, or descending thoracic and abdominal aorta, may
preclude safe retrograde femoral artery perfusion.
Direct Ascending Aorta Cannulation through the Minithoracotomy

The ascending aorta can be cannulated directly through a purse-string suture. We use either a Bio-Medicus
guide-wiredirected cannula or a 23F Straight Shot device (Edwards Lifesciences), which is passed through the
chest wall via a 10-mm trocar. It is most important to place two concentric pledgeted purse strings in the
ascending aorta near the innominate artery origin.
Axillary Arterial Cannulation
If it is not feasible to cannulate the ascending aorta directly, we use the right axillary artery for antegrade
perfusion. The artery is exposed through an infra-clavicular incision. Generally, we sew an 8-mm GelSoft knitted
graft (Vascutek, Terumo, Ann Arbor, MI) end-to-side to the axillary artery with 5-0 polypropylene suture (Fig. 7.4).
Thereafter, the graft is connected to the bypass circuit using either an appropriate-size arterial cannula or a 3/8-
inch pump tubing connector. Alternately, the axillary artery can be cannulated directly; however, distal arm
perfusion must be monitored while the cannula is in place.
Arterial Cannulation for the Balloon EndoClamp

When using the EndoClamp aortic balloon occlusion technique, a specialized EndoReturn (Edwards
Lifesciences, Inc.) femoral arterial cannula (21 or 23F) must be used. It has a one-way valve for balloon catheter
passage into the aorta. This arterial cannula is significantly larger than that used in the transthoracic clamp
method described below. Therefore, distal leg perfusion should be monitored continuously using oxygen
saturation patches. Should the perfused limb become compromised or the coaxial balloon catheter limit optimal
arterial inflow, the opposite femoral artery must be cannulated either for perfusion or for direct aortic balloon
insertion.
Aortic Occlusion
In both hemisternotomy and second interspace minimally invasive aortic valve operations, the aorta can be
clamped directly using one of the flexible arm clamps. Two versions are the Cosgrove Flex Clamp (V. Mueller-
Carefusion, Inc., Waukegan, IL) and the Cygnet flexible clamp (VitalItec, Inc., Plymouth, MA). Both allow clamping
with the majority of the mechanism positioned well out of the surgical field.
When using a minithoracotomy for either minimally invasive or robotic mitral valve surgery, either the
transthoracic aortic clamp or the EndoClamp balloon occluder can be used. We prefer to use the transthoracic
aortic clamp as it is economical, simple to place, requires no echo monitoring, is reproducible to use, and is very
safe. In comparison, the EndoClamp is costly and has a necessary learning curve to introduce and position it in
the ascending aorta. Moreover, it requires echocardiographic guidance and monitoring throughout the cardiac
arrest period. Nevertheless, experienced users have been very satisfied with this use as it does not require
aortic cardioplegia needle insertion, occludes the aorta well, and provides excellent air venting.
FIGURE 7.4. Right axillary artery cannulation: after exposure of the axillary artery, an 8-mm woven graft is
sutured end-to-side, and a similar sized inflow cannula is “plugged” into the graft and secured with multiple
heavy ligatures.
Transthoracic Aortic Clamping

The ascending aorta cardioplegia needle/vent should be placed just lateral and distal to the right coronary origin
and secured with a 4-0 PTFE adventitial purse-string suture. Care must be taken to not enter the aortic lumen
with the suture needle. To occlude the ascending aorta (Fig. 7.5), we use a specialized transthoracic aortic
cross-clamp (Scanlan International, Minneapolis, MN). The clamp is passed into the right thoracic cavity through
a 4-mm incision in the 2nd intercostal space and along the posterior axillary line. Inside the chest,
P.147
the clamp arm should cross the superior vena cava at the level of the pericardial junction. In robotic surgery, the
posterior clamp position is important to avoid collisions with the left instrument arm. The posterior jaw of the
clamp is passed under endoscopic control through the transverse sinus. During insertion and clamping, care
must be taken to avoid injury to the right pulmonary artery, the left atrial appendage, or the left main coronary
artery. After both jaws have been positioned along each side of the aorta (Fig. 7.6), gentle clamp occlusive
pressure should be applied under either endoscopic or direct visualization, but only after reducing the pump flow.
FIGURE 7.5. Transthoracic aortic clamp technique. A: The Scanlan transthoracic aortic clamp has a long handle
that slides—opening and closing the “jaws.” B: Clamp insertion via 2nd intercostal space. Note that the surgeon
is palpating the tip as it penetrates the chest wall. After the clamp tip enters, it is turned toward the patient’s head
before passing it through the transverse sinus.
FIGURE 7.6. Transthoracic aortic clamp technique. A: The transthoracic aortic clamp (TT-XCL) is shown in the
closed position. The ascending aorta (Asc Aorta), main pulmonary artery (MPA), right pulmonary artery (RPA),
superior vena cava (SVC), and right atrium (Rt. Atrium) are shown in relationship to the clamp as it has been
passed through the transverse sinus. The clamp should be placed posterior and as high in the 2nd interspace as
possible. B: A ventral view of the ascending aorta with the clamp in correct position with respect to the
pericardium and left atrial appendage (LAA).
EndoClamp Balloon Aortic Occlusion

Over an echo-directed guide wire, the EndoClamp (Edwards Lifesciences) balloon should be positioned in the
ascending aorta just above the sino-tubular junction and proximal to the innominate artery (Fig. 7.7). TEE
monitoring must be continuous during balloon inflation and ascending aortic occlusion. If fluoroscopic position
confirmation is needed, the balloon is filled with dilute contrast solution. To optimally seal the saline-filled balloon
against the ascending aortic wall, it is important to empty the heart in order to minimize left
P.148
ventricular ejection, which can cause dislodgment. By simultaneously decreasing pump arterial inflow and
initiating aortic root venting, ventricular ejection becomes limited. Alternatively, brief asystole can be induced by a
single adenosine bolus infusion. This eliminates ejection and helps stabilize the balloon during inflation just
above the sino-tubular junction. After saline inflation, the intra-balloon pressure should be monitored and
maintained between 300 and 350 torr. During this time, the perfusionist must monitor right radial arterial pressure
to signal distal balloon migration, which can cause innominate artery occlusion. A sudden drop in the balloon
pressure suggests displacement across the aortic valve and into the left ventricle. To remove any residual
cardiac air, the aortic root should be vented through the catheter tip after balloon deflation.
FIGURE 7.7. Endoballoon aortic occlusion technique. The aortic occlusion balloon is shown in the ascending
aorta. A flow-directed pulmonary artery vent is shown in place along with a retrograde coronary sinus
cardioplegia catheter. A single venous drainage catheter has been passed from the femoral vein into the superior
vena cava. (Permission of Author: Chitwood WR, ed. Atlas of robotic cardiac surgery. London, UK: Springer,
2014.)
Myocardial Protection
The general tenets of myocardial protection during cardiac surgery relate to reducing myocardial oxygen
consumption. Figure 7.8 shows the effects of cardiac emptying, ventricular fibrillation, asystole, and systemic
hypothermia on myocardial oxygen consumption (25). During MICS, the thoracic “jacket” prevents topical
hypothermic lavage, device cooling, or myocardial temperature measurement. Therefore, we systemically
perfuse these patients at 28 °C throughout the major portion of the operation. Moreover, complete cardiac
emptying is paramount to achieve the best protection and operative visualization. This reduces cardiac warming,
especially in the thin-walled right atrium and ventricle.
As most mitral and aortic valve patients do not have occlusive coronary artery disease, aortic root antegrade
cardioplegia gives good transmural ventricular protection. In patients with either obstructive coronary artery
lesions or aortic insufficiency, retrograde cardioplegia infusions should be considered. As mentioned with the
transthoracic clamping method, an ascending aortic root cardioplegia/vent cannula must be placed. This
catheter should not be placed too far distal along the ascending aorta as the cross-clamp may interfere with
antegrade infusions.
When infusing antegrade cardioplegia via the EndoClamp, the distal pressure must be verified to confirm
delivery and/or inadvertent aortic root vent suction recirculation. Cardioplegia infusion pressure should not
exceed 350 torr at maximal flow rates of between 250 and 300 mL/min. With these infusion metrics, the aortic
root pressure should rise to between 60 and 80 torr. Failure to observe a pressure rise indicates either an
incompetent aortic valve or EndoClamp malposition. To prevent balloon migration toward the innominate
P.149
artery, the delivery pressure should be maintained below the systemic perfusion pressure. During cardioplegia
delivery, the EndoClamp tip should be monitored continuously by TEE.
FIGURE 7.8. Decreasing myocardial oxygen consumption: effects of hypothermia and cardioplegia. (Permission
of Author: Chitwood WR, Sink JD, Hill RC, et al. The effects of hypothermia on myocardial oxygen consumption
and trans-mural coronary artery blood flow in the potassium-arrested heart. Ann Surg 1979;190:106-116.)
Retrograde cardioplegia can be infused through a percutaneous EndoPlege coronary sinus balloon-tipped
catheter (Edwards Laboratories, Irvine, CA). This is especially prudent in patients with aortic insufficiency. The
anesthesiologist places this infusion catheter in the right internal jugular vein before surgical draping. The intra-
coronary sinus position is confirmed by TEE and is verified by monitoring pressure waveforms during balloon
inflation. We advocate fluoroscopy to confirm ideal coronary sinus positioning. Low-flow-rate (50 mL/min)
cardioplegia infusions should be begun initially and increased slowly to 150 to 200 mL/min. Simultaneously,
coronary sinus pressure should not exceed 40 torr. The aortic root should be vented concurrently through the
EndoClamp aortic root lumen. Our cardioplegia regimen for minimally invasive valve surgery is described below.
Specialized Perfusion Circuits

In median sternotomy-based cardiac surgery, gravity venous drainage with large-diameter cannulas was the
mainstay of cardiopulmonary perfusion. For minithoracotomy minimally invasive and robotic cardiac surgery,
direct access for inserting large cannulas is not feasible. New, ultra-thin catheter designs with multiple side holes
optimize flow rates and provide maximum drainage. With MICS, gravity-based venous drainage systems usually
are inadequate because of cannula length and small diameters. Most minimally invasive operations require ideal
venous return to provide total cardiopulmonary support and adequate cardiac decompression. Most commonly,
either kinetically assisted (KVAD) or vacuum-assisted (VAVD) venous drainage is used.
KVAD utilizes a centrifugal pump, placed between the venous cannula and reservoir. This method improves
venous drainage by 20% to 40% compared with gravity circuits. With KVAD, venous blood is pumped actively
into either an open or a closed venous reservoir. Centrifugal pump inertia regulates siphoning of venous blood,
and as the pump speed is increased, more central suction is generated. Pressure in the venous conduit is
monitored proximal to the pump inlet, allowing the perfusionist to regulate the amount of blood returned to the
pump. Excessive negative pressure can cause hemolysis and/or right atrial collapse around the venous cannula,
thus impeding venous return. Major drawbacks surrounding KVAD include the additional cost of the centrifugal
pump head, and the potential of de-priming the pump if enough gross air is introduced from the venous
cannulation site.
To increase return, VAVD utilizes regulated vacuum suction connected to the venous circuitry. VAVD was
accomplished originally by connecting the wall vacuum directly into an open-system hard shell venous reservoir.
Recent improvements to soft-shell or collapsible venous reservoir bag technology allow the perfusionist to utilize
VAVD with a venous bag system (V-Bag) (Circulatory Technology, Inc., Oyster Bay, NY). This system enables
the venous bag to be placed in a sealed box where regulated vacuum is placed inside the inner housing as well
as the cardiotomy reservoir (Fig. 7.9). Equal negative pressure is exerted on the venous circuit, creating
augmented venous drainage. VAVD requires close regulation of the vacuum source to avoid blood component
trauma and either cracking or imploding of the venous reservoir. Positive and negative pressure relief valves
must be incorporated into the reservoir to prevent both over- and underpressurization and to ensure consistent
extracorporeal flow rates.
Operative Perfusion and Cardioplegia for MICS

Our perfusion circuit for MICS is shown in Figure 7.10. We use the Sorin S5 heart-lung machine, which is
modified for use with a venous bag reservoir (V-Bag) and equipped with magnetic drive for Revolution centrifugal
pump suction (Sorin Group USA Inc., Arvada, CO). The V-Bag reduces the blood-air interface, which is
associated with increased inflammatory mediators. An open system (hard-shell) also can be used in
P.150
situations when venous air is expected. VAVD is utilized in every case to ensure adequate drainage, avoiding
right heart distention and providing optimal arterial inflow. To sequester excess operative field blood, our circuit
includes a cardiotomy reservoir, which is served by two additional roller pumps. Intra-atrial blood is scavenged to
the reservoir via a sump sucker placed in the left superior pulmonary vein.
FIGURE 7.9. Vacuum-assisted venous bag-drainage system (V-Bag)—the closed-system bag is placed in a
plastic “box” vacuum chamber that regulated the rate of venous return to the pump.
The perfusion circuit is primed with lactated Ringer’s solution, 50 mEq/L sodium bicarbonate, and 12.5 g of
mannitol for a total volume of 1,100 mL. For venous drainage and prior to the V-Bag, Y-branched tubing is
connected to the internal jugular and femoral venous cannulas described previously. Our perfusionists confirm
the safety and integrity of the circuit prior to beginning cardiopulmonary bypass. During bypass initiation,
retrograde autologous priming is done to replace the circuit crystalloid. Just after perfusion is initiated, 100 mL of
25% albumin is infused.
After the surgeon inserts the antegrade cardioplegia cannula, we initiate perfusion, and cool to 28°C systemically
using α-stat ventilation via a Terumo RX25 oxygenator (Terumo Cardiovascular Group, Inc., Ann Arbor, MI).
Currently, we have been using commercial Bretschneider HTK solution or Custodiol HTK (Franz Köhler Chemie
GmbH, Bensheim, Germany) as a single large-dose (20-25 mL/kg) infusion at 4°C to 6°C (Table 7.1) (26,27).
After the aortic cross-clamp has been applied, it is delivered through the Vanguard cardioplegia heat exchanger
(Sorin Group USA Inc.) by a separate roller pump. An alternate to Custodiol is Del Nido cardioplegia solution,
which works by a similar hyperpolarizing extracellular mechanism (28,29). Many other groups in the United
States are using these types of cardioplegia as a single-dose application. If antegrade cold-blood cardioplegia is
used, it should be infused every 15 to 20 minutes during the cardiac arrest period. For repeat infusions of any
cardioplegia, care must be taken not to introduce air into the ascending aorta.
The initial large infusion of Custodiol usually protects the heart for up to 1.5 hours. However, if electrical activity
emerges during the arrest period, subsequent 250- to 400-mL infusions are recommended. This solution is acidic
and causes acute systemic hyponatremia. For this reason, 150 mEq/L of sodium bicarbonate is infused slowly
into the venous line. With this protocol, sodium levels generally become restored to baseline levels prior to
weaning from bypass.
To remove the excess volume that is related to crystalloid cardioplegia administration, a hemoconcentrator is a
crucial part of the circuit. Patient rewarming is begun after threefourths of the annuloplasty ring or prosthetic
valve has been implanted. To evacuate cardiac air following mitral valve surgery, the aortic vent roller pump
should turn slowly just prior to left atrium closure. After de-airing and cross-clamp release, generally only 15 to 20
minutes of reperfusion is needed before weaning the patient from cardiopulmonary bypass.
COMMENT
At the East Carolina Heart Institute, we have used the cardiopulmonary perfusion and myocardial protection
techniques described herein in over 2,600 MICS patients since 1996. We have had two aortic dissections, three
left atrial appendage clamp injuries, five internal jugular-innominate vein injuries, two vena caval injuries (before
TEE guidance), and five conversions to a sternotomy for either bleeding or a dissection. None of the jugular-
innominate or right pulmonary artery injuries required a conversion as they were repaired using videoscopic
visualization. We have had very few strokes with peripheral perfusion; however, we have been very respectful of
aorto-iliac disease and use alternative cannulation techniques in these patients. Today, most MICS
complications related to perfusion, aortic clamping, and myocardial protection can be avoided by following the
guidelines described in this chapter.
P.151
FIGURE 7.10. East Carolina Heart Institute MICS perfusion circuit. Art. Pump, arterial pump; Art. Line Filter,
arterial line filter; CPS heat exchanger, cardioplegia system heat exchanger; Ao Root, aortic root vent; Pulm Vein
Vent, pulmonary vein vent; Oxy, oxygenator; leg sat monitor, leg saturation monitor; Cardio Reserv, cardiotomy
reservoir.
PITFALLS AND TIPS

MICS does not eliminate some of the pathophysiologic consequences of cardiopulmonary bypass and especially
those related to retrograde perfusion.
Vascular visualization is critical for all peripheral cannulation techniques. Experience in transesophageal
echocardiographic guidance of catheters is essential in preparing for both open robotic and MICS. Any
condition that prevents transesophageal echo probe insertion (i.e., esophageal stricture) also contraindicates
peripheral cannulation.
Arterial dissections following cannulation, retrograde perfusion, and/or endoballoon clamp placement are the
most feared complications. Severe peripheral vascular disease and/or atheromatous aortas predispose to
retrograde visceral and cerebral atherosclerotic embolization as well as retrograde arterial dissections.
Preoperative computed tomography is beneficial for planning cannulation strategies in patients with vascular
disease.
Direct arterial injury during femoral cannulation can be avoided by adhering to meticulous guide-wire insertion
techniques. One must avoid pushing wires and dilators against any resistance. Guide-wires must move freely
within the catheter, while it is coaxially passed into the vessel. If it does not slide without resistance, either a
wire-bend or obstruction exists.
Other complications related to femoral arterial cannulation include acute limb ischemia during
cardiopulmonary perfusion, residual femoral arterial stenosis following cannula removal, perioperative arterial
thrombosis, lymphocele formation, and local groin infections. To monitor the adequacy of distal arterial
perfusion, pulse-oximetry sensors are
P.152
applied to both legs. If a significant drop in oxygen saturation is noted in the cannulated leg, a 5F catheter is
placed in the distal artery and connected to the perfusion cannula side-port. To date, we had no disastrous
limb complications, such as compartment syndromes or abject necrosis.
Deep venous thrombosis can occur with femoral vein cannulation. Only limited dissection is needed for the
Seldinger guide-wire insertions, making this complication very rare. However, direct femoral vein and vena
caval injuries are possible, especially if guide-wire technology is not combined with echo guidance.
In the presence of a vena caval filter or prior deep venous thrombosis, the inferior vena caval cannula should
be passed through the chest wall for direct right atrial access.
Care must be taken when placing an ascending aortic cardioplegia cannula through a minithoracotomy.
Meticulous suture and stabilization techniques are important as bleeding in this area can be very difficult to
control.
Aortic cross-clamping requires special attention. When using the transthoracic clamp, careful attention must
be paid to the posterior tine as it passes through the transverse sinus. Damage to either the left atrial
appendage or right pulmonary artery can occur. EndoClamp aortic balloon occlusion generates pressures of
250 to 350 torr for a tight seal. Therefore, patients having significant ascending aortic ectasia should not be
considered for this approach. Moreover, in the presence of severe aortic insufficiency, EndoClamp
deployment is not advised. Leaking antegrade cardioplegia infusions likely will cause left ventricular distension
and possible inadequate myocardial preservation.
Central nervous system complications most commonly relate to cannulation and cardiopulmonary perfusion.
These include embolization with cerebrovascular arterial occlusion. As mentioned earlier, retrograde arterial
blood flow can cause embolization of either atheroma or air. Moreover, passage of cannulas and catheters
can dislodge atheromatous plaques. EndoClamp balloon migration can cause innominate artery occlusion,
resulting in adverse neurologic events. In the presence of significant aorto-iliac disease, axillary or
transthoracic direct aortic arterial cannulation should be considered.
MICS operations provide limited access to facilitate “ de-airing.” Intrathoracic CO2 insufflation (1-2 L/min) has
been helpful in purging air from the thorax. However, air still can become sequestered in the pulmonary veins
and along the interventricular septum. Near the end of the operation, bilateral ventilation helps draw the CO2
deep into the pulmonary veins. Constant CO2 insufflation can elevate blood Paco2, especially if pump suckers
are maintained open continuously. After atriotomy closure and upon cross-clamp release, we apply suction to
the aortic root vent, while compressing the right coronary artery. As the heart beats, we gently reclamp the
aorta to expel the residual air into the vent suction. With the EndoClamp, similar maneuvers should be applied
to remove residual cardiac air. Constant TEE monitoring should assure adequate air removal before weaning
the patient from cardiopulmonary bypass. For mitral valve surgery, a vent catheter should be left in the left
atrium during the de-airing process.
Ventricular distention must be avoided. This is especially a problem during periods of ventricular fibrillation
and/or with aortic insufficiency. Leaving a ventricular vent helps to prevent distention. Nevertheless, returning
the heart to an ejecting rhythm is the best way to avoid distention at the end of the operation. TEE monitoring
at this time is important to alert surgeons to this dangerous problem. Should these measures be inadequate,
re-arrest and reopening the left atriotomy is the last resort to decompress the heart via the mitral valve.
For more details regarding perfusion and myocardial protection during MICS, refer to Chitwood (30).
TABLE 7.1. Custodiol (Bretschneider HTK solution)
Formulation ingredient Value
Na+ 15 mmol/L
K+ 9 mmol/L
Mg2+ 4 mmol/L
Ca2+ 0.015 mmol/L
Histidine 198 mmol/L
Tryptophan 2 mmol/L
Ketoglutarate 1 mmol/L
Mannitol 30 mmol/L
pH 7.02-1.20
Adapted from Viana FF, Shi WY, Hayward PA, et al. Custodiol versus blood cardioplegia in complex
cardiac operations: an Australian experience. Eur J Cardiothorac Surg 2013;43:526-531.
KEY Points
Minimally invasive cardiac surgery (MICS) requires modifications in cardiopulmonary bypass (CPB)
circuits, aortic occlusion, and myocardial protection.
Aortic valve MICS is done either through a hemisternotomy or right second interspace mini-thoracotomy.
Cannulation can be directly through the incision or from peripheral vessels.
Mitral valve MICS is most often performed through a right mini-thoracotomy. Generally, peripheral
cannulation for CPB has been used; however, with peripheral vascular disease, inflow should be either
by direct aortic cannulation or by axillary artery access.
P.153
During MICS, the aorta can be occluded using a transthoracic clamp, a modified flexible handle clamp, or
an endoaortic balloon occluder.
Significant systemic hypothermia and complete cardiac decompression are paramount for adequate
cardiac protection.
Frequent blood cardioplegia infusions have been the standard protectant; however, both Bretschneider’s
HTK and del Nido solution are popular for “one shot” longer protection.
Most CPB perfusion circuits for MICS are based on vacuum-assisted venous drainage. The V-Box
reservoir, combined with a vortex pump, as well as a mini-oxygenator and heat exchanger, has been ideal
for our team.
REFERENCES
1. Gibbon JH. Application of a mechanical heart and lung apparatus to cardiac surgery. Minn Med
1954;37:171-180.
2. Lillehei CW. Controlled cross circulation for direct-vision intracardiac surgery; correction of ventricular
septal defects, atrioventricularis communis, and tetralogy of Fallot. Postgrad Med 1955;17:388-396.
3. Brown IW, Smith WW, Emmons WO. An efficient blood heat exchanger for use with extracorporeal
circulation. Surgery 1958;44(2):372-375.
4. Melrose DG, Dreyer B, Bentall HH, et al. Elective cardiac arrest: preliminary communication. Lancet
1955;2:21-22.
5. Gay WA, Ebert PA, Kass RM. Protective effects of induced hyperkalemia during total circulatory arrest.
Surgery 1975;78:22-26.
6. Kirsch U, Rodewald G, Kalmar P. Induced ischemic arrest and clinical experience with cardioplegia in
open heart surgery. J Thorac Cardiovasc Surg 1972;63:121-130.
7. Bretschneider HJ. Uberlebenszeit und Wiederbelebungszeit des Herzens bei Normo- und Hypothermie.
Verh Deutsch Ges Kreislaufforschung 1964;30:11-34.
8. Bretschneider HJ. Myocardial protection. Thorac Cardiovasc Surg 1980;28:295-302.
9. Bleese N, Døring V, Kalmar P, et al. Intraoperative myocardial protection by cardioplegia in hypothermia. J

10. Hearse DJ, Braimbridge MV, Jynge P. Formulation and administration. In: Hearse DJ, Braimbridge MV,
Jynge P, eds. Protection of the ischemic myocardium: cardioplegia. New York, NY: Raven, 1981:300-326.
11. Follette D, Steed DL, Foglia R, et al. Advantages of intermittent blood cardioplegia over intermittent
ischemia during prolonged hypothermic aortic clamping. Circulation 1978;58(Suppl 1):200-209.
12. Gundry SR, Kirsh MM. A comparison of retrograde cardioplegia versus antegrade cardioplegia in the
presence of coronary artery obstruction. Ann Thorac Surg 1984;38:124-127.
13. Menasché P, Kural S, Fauchet M, et al. Retrograde coronary sinus perfusion: a safe alternative for
insuring cardioplegic delivery in aortic valve surgery. Ann Thorac Surg 1982;34:647-658.
14. Navia JL, Cosgrove DM III. Minimally invasive mitral valve operations. Ann Thorac Surg 1996;62:1542-
1544.
15. Cohn LH, Adams DH, Couper GS, et al. Minimally invasive cardiac valve surgery improves patient
satisfaction while reducing costs of cardiac valve replacement and repair. Ann Surg 1997;226:421-426.
16. Carpentier A, Loulmet D, Carpentier A, et al. Chirurgie à coer ouvert par vidéo-chirurgie et mini-
thoracotomie: Premier cas (valvuloplastie mitrale) opéré avec succès [Open heart operation under video-
surgery and minithoracotomy. First case (mitral valvuloplasty) operated with success]. C R Acad Sci III
1996;319:219-223.
17. Chitwood WR Jr, Elbeery JR, Chapman WH, et al. Video-assisted minimally invasive mitral valve surgery:
the “micro-mitral” operation. J Thorac Cardiovasc Surg 1997;113(2):413-414.
18. Chitwood WR Jr, Wixon CL, Elbeery JR, et al. Video-assisted minimally invasive mitral valve surgery. J
19. Mohr FW, Falk V, Diegeler A, et al. Minimally invasive port-access mitral valve surgery. J Thorac
20. Nifong LW, Rodriguez E, Chitwood WR Jr. 540 consecutive robotic mitral valve repairs including
concomitant atrial fibrillation cryoablation. Ann Thorac Surg 2012;94:38-42.
21. Svensson LG, Atik FA, Cosgrove DM, et al. Minimally invasive versus conventional mitral valve surgery: a
propensity-matched comparison. J Thorac Cardiovasc Surg 2009;139:926-932.
22. Iribarne A, Easterwood R, Russo MJ, et al. Comparative effectiveness of minimally invasive versus
traditional sternotomy mitral valve surgery in elderly patients. J Thorac Cardiovasc Surg 2012;143:S86-S90.
23. Modi P, Hassan A, Chitwood WR Jr. Minimally invasive mitral valve surgery: a systematic review and
meta-analysis. Eur J Cardiothorac Surg 2008;34:943-952.
24. Falk V, Cheng DC, Martin J. Minimally invasive versus open mitral valve surgery: a consensus statement
of the International Society of Minimally Invasive Cardiothoracic Surgery. Innovations 2011; 666-676.
25. Chitwood WR, Sink JD, Hill RC, et al. The effects of hypothermia on myocardial oxygen consumption and
transmural coronary artery blood flow in the potassium-arrested heart. Ann Surg 1979;190:106-116.
26. Viana FF, Shi WY, Hayward PA, et al. Custodiol versus blood cardioplegia in complex cardiac operations:
an Australian experience. Eur J Cardiothorac Surg 2013;43:526-531.
27. Edleman J, Seco M, Dunne B, et al. Custodiol for myocardial protection and preservation: a systematic
review. Ann Cardiothorac Surg 2013;2:717-728.
28. Matte GS, del Nido PJ. History and use of del Nido cardioplegia solution at Boston Children’s Hospital. J
29. Sorabella RA, Akashi H, Yerebakan H, et al. Myocardial protection using del Nido cardioplegia solution in
adult reoperative aortic valve surgery. J Card Surg 2014;29:445-449.
30. Chitwood WR, ed. Atlas of robotic cardiac surgery. London, UK: Springer, 2014:1-326.
Chapter 8
Temperature Management in Cardiac Surgery
Laurie K. Davies
Heather Reed
The use of hypothermia as an adjunct to the treatment of a wide variety of disorders has been advocated for
centuries. Lowered body temperature has been employed to combat cancer, infection, trauma, and central
nervous system diseases, and as a regional method to induce anesthesia for amputation (1,2). However, it was
not until 1950 that Bigelow et al. (3) demonstrated longer tolerance to inflow occlusion in hypothermic animals
than in their normothermic counterparts. This work led to the first clinical application of hypothermia in cardiac
surgery. Lewis and Taufic (4) used surface cooling to 28°C with 5.5 minutes of inflow occlusion to facilitate
successful closure of an atrial septal defect in a 5-year-old child. In 1952, Gibbon (5) introduced the pump
oxygenator to clinical practice, and in 1958, Sealy et al. (6) used hypothermia in conjunction with the
cardiopulmonary bypass (CPB) circuit for intracardiac repairs. The use of the pump oxygenator and hypothermia
has allowed cardiac surgery to flourish. Complex lesions are repaired routinely with remarkably low mortality.
However, it is now recognized that inadvertent hyperthermia occurs relatively frequently in the perioperative
setting. Evidence is accumulating that elevated temperatures may be deleterious in both animals and humans
(7,8). A better understanding of the principles of temperature management may maximize the benefits to our
patients while minimizing potential complications.
PHYSIOLOGY OF HYPOTHERMIA
One of the main difficulties in devising a reasonable strategy for the application of hypothermia in humans is the
fact that they are naturally homeothermic beings. Humans and other homeothermic species have very effective
homeostatic systems, which ensure that the body temperature remains consistently near 37°C regardless of
changes in environmental temperatures. This tight regulation of temperature is accomplished by multiple
mechanisms. Cold is sensed by the thermoreceptors in the skin, which then causes the hypothalamus to trigger
a strong sympathetic nervous system response. Vasoconstriction of skin vessels, which decreases convective
heat loss, occurs simultaneously with vasodilation of the skeletal muscle vascular beds, which augments
muscular activity to produce heat by tensing and shivering. The endocrine system is activated, oxygen
consumption is increased, and heart rate, cardiac output, and blood pressure are elevated. Because of the
complexity of these interactions, one can appreciate the difficulty in understanding the physiologically
appropriate response to the unnatural state of induced hypothermia in humans. One must extrapolate from
animal studies, biochemical equations, accidental hypothermia survivors, and normal organ temperature
gradients to try and develop the most effective management strategy when using deliberate hypothermia.
Rationale for the Use of Hypothermia

Why is hypothermia often employed during CPB? The obvious purpose of using hypothermia is to provide a
degree of organ (and organism) protection and safety margin during CPB. Hypothermia exerts its protective
effect by multiple mechanisms. The most obvious mechanism is a reduction in metabolic rate and oxygen
consumption (9) (Fig. 8.1). This metabolic suppression may not explain all the protective effects observed.
Hypothermia also helps preserve high-energy phosphate stores and reduces excitatory neurotransmitter release,
which is especially important to central nervous system protection (10,11). Normally, ischemic neuronal cells
rapidly release neuroexcitatory amines, especially glutamate (12). The accumulation of these excitotoxic amines
causes the opening of calcium channels and activation of multiple destructive enzymatic systems. Hypothermia
attenuates this excitotoxic cascade, helping to prevent calcium entry into the cell and restricting membrane
permeability (13) (Fig. 8.2).
Alteration of temperature causes a change in the reaction rate of all biochemical processes, especially enzymatic
reactions. This temperature dependence of reaction rates has been described by the concept of Q10, which is
defined as the increase or decrease in reaction rates or metabolic processes in relation to a temperature change
of 10°C. For instance, the reaction rate of a process with a Q10 of 2 will double with a 10°C increase in
temperature or be halved with a drop of 10°C. Most reactions, including total body oxygen consumption, have a
Q10 of 2 to 3 (9).
Some biochemical processes, especially those localized to cell membranes, show an abrupt change in reaction
rates at certain critical temperatures. This has been termed a phase
P.158
P.159
transition and is thought to be the result of a change in the cell membrane from a fluid to a gel state (14). In
mammalian tissues, phase transitions often occur at approximately 25°C to 28°C and may disturb cell
homeostasis. Biophysical processes such as osmosis and water diffusion are also affected by temperature.
Typically, a linear change of approximately 3%/10°C is seen. Therefore, this effect is minimal at clinical levels of
hypothermia. However, if the freezing point of water is approached, ice is formed in the tissue, a condition that is
not tolerated. The solutes concentrate in a hyperosmolar manner in the residual nonfrozen water, causing
marked fluid shifts and membrane disruption. Mammalian tissue does not regain function on thawing from a
frozen state. For this reason, there is a limit to the beneficial effects of hypothermia.
FIGURE 8.1. Whole-body oxygen consumption as a function of body temperature in dogs made hypothermic by
surface cooling. (From Kirklin JW. Cardiac surgery. New York: Churchill Livingstone, 1993:61-127, with
permission.)
FIGURE 8.2. Line plot of time-course changes in the perfusate levels of dopamine (pmol/ml) in animals whose
intraischemic brain temperature was maintained at 36°C (n = 10) (•—•), 33°C (n = 4) (°—°), and 30°C (n = 8) (*—
*). The data presented are mean ± SEM. Statistical significance was assessed by two-way ANOVA. In animals
whose intraischemic brain temperature was maintained at 36°C, a massive increase in dopamine levels was
observed (*significantly higher than control values, p < 0.01). In animals whose intraischemic brain temperature
was maintained at 33°C or 30°C, a significant reduction in the ischemia-induced increased dopamine levels was
demonstrated (a, significantly lower than the corresponding level in the 36°C group, p < 0.01).
In cardiac surgery, CPB in conjunction with systemic hypothermia allows lower pump flows, better myocardial
protection, less blood trauma, and better organ protection than does normothermic perfusion (15). Oxygen needs
predictably fall with lowered temperature. It was recognized early that lowered bypass flows could be employed
in this setting and still provide adequate perfusion, as assessed by mixed venous oxygen tension and return of
organ function following bypass. Relating oxygen consumption (VO2) to perfusion flow rate at various
temperatures can also be valuable in assessing adequacy of tissue perfusion (Fig. 8.3). At a given temperature,
a fall in VO2 with a decrease in flow rate implies a flow-limited VO2, indicating that oxygen delivery is not
adequate. Hickey and Hoar (16) have shown in humans that a reduction in flow rate from 2.1 to 1.2 L/min/m2 of
body surface area at 25°C does not alter VO2 or tissue perfusion. Slogoff et al. (17) were unable to correlate low
flows (<40 mL/kg/min) or pressures (<50 mm Hg) during bypass in which moderate hypothermia and
hemodilution were used with postoperative renal or central nervous system dysfunction. Lower perfusion flow
rates allow better visualization by the surgeon. Venous return from the bronchial, pulmonary, and noncoronary
collateral vessels is also decreased. Because this returning blood is at systemic temperature, it can
inappropriately warm the heart when cardioplegia-induced myocardial hypothermia is at a lessthan-systemic
temperature and can jeopardize myocardial protection. Blood trauma is minimized because of both the lower
pump flows and the hemodilution employed during bypass. Because the etiology of most central nervous system
damage on bypass may be embolic in origin (18), lower bypass flows can minimize these focal insults. Systemic
hypothermia also provides some margin of safety for organ protection if equipment failure occurs or circulatory
arrest must be employed.
FIGURE 8.3. Nomogram of an equation expressing the relation of oxygen consumption to perfusion flow rate at
different temperatures in animals. The x represents the perfusion flow rates used clinically at these
temperatures. (From Kirklin JW. Hypothermia, circulatory arrest, and cardiopulmonary bypass. In: Kirklin JW,
Barratt-Boyes BG, eds. Cardiac surgery. New York: Churchill Livingstone, 1993:61-127, with permission.)
Acid-Base Alteration with Temperature Change

One of the more often discussed aspects of clinical hypothermia is the appropriate acid-base management
strategy during hypothermia. To understand acid-base regulation during hypothermia, it is helpful to consider
several example conditions. “Normal” values for pH and Pco2 are usually thought of as 7.40 pH units and 40 mm
Hg, respectively. However, it must be kept in mind that these values are appropriate only at 37°C in blood. There
is a temperature-dependent spectrum of “normal” values, depending on the temperature of the specific site in the
body. For example, arterial blood leaves the heart at 37°C with a pH of 7.40 and a Pco2 of 40 mm Hg. When that
same blood perfuses working skeletal muscle, where the ambient temperature may be 40°C, it will have a pH of
approximately 7.35 and a somewhat higher Pco2, despite a constant CO2 content before any respiratory
exchange with the muscle. In contrast, the same arterial blood perfusing exposed skin, where temperature may
be 20°C in cool weather, will have a pH of 7.65 and a proportionately lower Pco2, again with no change in CO2
content. Stated another way, a sample of arterial blood held in a gas-tight syringe will have a Pco2 that varies
directly with temperature, and a pH that varies inversely with temperature, despite constant CO2 content.
This change in Pco2 with temperature is a consequence of the change in solubility of gases in liquids with
change in temperature. As a general rule, decreasing the temperature of a liquid increases the solubility of a
given gas in that liquid and therefore decreases the partial pressure of that gas while the overall content of the
gas in the liquid remains constant. Increasing the temperature of a liquid increases the kinetic energy of the
molecules in the liquid, which both increases the tendency of dissolved gas molecules to leave the liquid
(decreased solubility) and increases the partial pressure of those gas molecules remaining in the liquid. This
concept is intuitive to anyone who has opened a container of warm carbonated beverage and observed that its
tendency to “fizz” (CO2 bubbling out of solution) is much greater than that of a cold beverage.
The relation of pH to temperature is somewhat more complex than the change in Pco2 with temperature. There is
clearly a direct relation between the concentration of H+ [H+]
P.160
in a water solution and the CO2 content of that solution. The higher the CO2, the more H+ in solution, and hence
lower the pH. This is largely caused by the tendency of CO2 to combine chemically with water to produce
carbonic acid, which then dissociates in solution to yield H+. Accordingly, one might expect that the change in pH
of blood with temperature is caused by the changes in Pco2 with temperature, as discussed in the preceding text.
It is true that cooling an anaerobic blood sample decreases both the Pco2 and the [H+]. However, and very
importantly, the change in [H+] and pH that occurs with change in temperature is independent of a change in
CO2 content, and therefore does not depend on the change in CO2 solubility with the temperature change.
All acids and bases, including water, exist in solution in equilibrium between the undissociated form and the
ionized components of the parent molecule. The dissociation constant (K) is the equilibrium ratio of the product
of the concentrations of the ionized components to the unionized component. For water at 25°C, the equilibrium
dissociation equation is as follows:
K(H2O, 25°C) = [H+] × [OH-]/[H2O] = 1.08 × 10-14
Because, at equilibrium in water, [H+] equals [OH-], and because the concentration of H2O is essentially 1, [H+]
equals [OH-] equals ✓10-14, or 10-7. Because the definition of pH is the negative log10 of [H+], the pH of pure
water at equilibrium at 25°C is 7. This pH value has come to be called the neutral pH, or pN, of water.
Temperature change has a significant effect on the tendency of molecules in solution to dissociate. In
thermodynamic terms, the increased kinetic energy associated with increased temperature promotes
dissociation, whereas decreased temperature has the opposite effect. For example, within the temperature range
seen in clinical CPB (approximately 15°C-40°C), the dissociation constant of water increases from 0.451 × 10-14
to 2.919 × 10-14. These values of KH2O relate to a change in [H+] from approximately 67 nmol/L at 15°C to 170
nmol/L at 40°C. This nearly 3-fold change in [H+] is solely a consequence of the effects of temperature change
on dissociation. Pure water may be considered the simplest weak acid-base solution. The major importance of
these concepts is that water is the fundamental solvent of all biologic systems, and the dissociation of virtually all
weak acids and bases in biologic solutions follows the same pattern as that described for water.
The behavior of body fluids (intracellular and extracellular, intravascular and extravascular) is far more complex
than the simple scenario described earlier for water, but biologic fluids behave much like water in terms of the
intrinsic temperature-related changes in the dissociation constants of the many weak acids and weak bases, of
which they are composed. The amino acids in proteins, the simple sugars in polysaccharides, the fatty acids in
lipids, and the major buffer systems, all follow this same basic pattern. As the temperature decreases, the
tendency to dissociate decreases, and the concentrations of the ionized components (H+ and R-) also decrease.
At normal body temperature (37°C), blood and tissue fluids are alkaline (lower [H+] and correspondingly higher
pH) relative to water at the same temperature. A number of buffer systems create and maintain this relative
alkalinity so that the ratio of [OH-] to [H+] remains constant at approximately 16:1 despite temperature variation.
As temperature changes, the intrinsic dissociation of these buffer systems also changes to maintain the ratio of
[OH-] to [H+] constant. Therefore, the intrinsic pH shift of blood and tissue fluid parallels the pNH2O as
temperature changes, and this relative alkalinity remains constant in comparison with water (19) (Fig. 8.4).
FIGURE 8.4. Blood pH of various ectothermic species and the pH of neutral water as a function of body
temperature. (From Rahn H. Body temperature and acid-base regulation [Review Article]. Pneumonologie
A major buffering system responsible for this constant relation of blood and tissue fluid pH to pN, with
temperature change, is the imidazole moiety of the amino acid histidine, which is commonly found in body
proteins. The pKa of this component of histidine is close to 7.0 at body temperature, a property that confers
potent buffering capacity for maintaining a constant ratio of [H+] to [OH-] despite significant changes in the
absolute concentration of each as temperature varies. These considerations are applicable to the previous
example of arterial blood with a constant CO2 content perfusing tissues with different temperatures. The
observed shift in pH with cooling follows the pNH2O, and the buffering capacity of the imidazole moiety of histidine
preserves the constant relative alkalinity and ratio of [OH-] to [H+] in the blood (Fig. 8.5). In cold-blooded
vertebrates, the blood pH-temperature curve also runs parallel to the pH of neutral water. Intracellular pH has
also been measured in various animals and shows changes with temperature identical to those that have been
described for pNH2O (20) (Fig. 8.6). The intracellular pH parallels the pN and blood pH slopes with temperature
changes and differs from the extracellular pH by a constant but species-specific factor of approximately -0.6 to -
0.8 pH units. Therefore, at 37°C, intracellular pH is approximately 6.8 to 6.9 and so the [H+] is somewhat higher.
In a manner similar to the observed change in blood pH with temperature, the reaction kinetics of numerous
respiratory enzyme systems (lactate dehydrogenase, Na+-K+-ATPase [sodium-potassium adenosine
triphosphatase], acetyl CoA carboxylase, fatty acid
P.161
synthetase, NADH [reduced nicotinamide adenine dinucleotide] cytochrome c reductase, and succinate
cytochrome c reductase) all show optimal catalytic function with temperature change when the pH of the reaction
medium parallels the temperature-mediated pNH2O change (21).
FIGURE 8.5. Changes in arterial pH and PCO2 as blood at 37°C arrives at skin and exercising muscles at
temperatures of 25°C and 41°C, respectively. Neutrality of water (pN) changes in parallel with changes in blood
pH. Therefore, the relative alkalinity of the blood or the ratio between [OH-] and [H+] ions remains constant.
(From Rahn H. Body temperature and acid-base regulation [Review Article]. Pneumonologie 1974;151:87-94,
with permission.)
FIGURE 8.6. Arterial and intracellular pH as a function of body temperature in ectothermic animals. Intracellular
pH closely follows the neutral pH of water; relative arterial alkalinity is maintained at all temperatures. (From
White FN, Weinstein Y. Carbon dioxide transport and acid-base regulation during hypothermia. In: Utley JR, ed.
Pathophysiology and techniques of cardiopulmonary bypass, Vol. II. Baltimore: Williams & Wilkins, 1983:40-48,
with permission.)
This constant internal milieu is accomplished, as has been mentioned, predominantly by the buffering capacity of
the imidazole group of the amino acid histidine. As temperature changes, the imidazole groups in protein change
pKa in parallel with the pN of water. The ratio of the unprotonated histidine imidazole groups to H+, a value
known in the world of chemistry as alpha, remains constant, total CO2 also remains constant, and the pH
changes as per the changes in temperature. The term α-stat has come to indicate an acid-base management
strategy in which the net charge (dissociation) of proteins remains constant as temperature changes. Typically,
this is managed during CPB by keeping total CO2 stores constant and allowing pH and PaCO2 to follow their
thermodynamically mediated dissociation changes with changes in temperature. In other words, during cooling,
exogenous CO2 is not added to the system when following the α-stat strategy.
The alternative method of acid-base strategy is termed pH-stat. With this method, pH is the value that is
maintained constant at varying temperatures. Obviously, if the pH-stat strategy is used when blood is cooled,
CO2 must be added to maintain a Paco2 of 40 and a pH of 7.40. Extracellular and intracellular ratios of [OH-] to
[H+] are altered and the total CO2 stores are elevated.
Why might one strategy be chosen over another? During the first two decades of hypothermic CPB, pH-stat
management with the addition of 5% CO2 to the oxygenator gas flow was used almost exclusively. An
understanding of the expected changes in pH with temperature seemed to be lacking, and CO2 was thought to
be beneficial for cerebral vasodilation and maintenance of cerebral blood flow (CBF). In the last 30 years, this
practice has been questioned, and many institutions have shifted toward an α-stat management protocol. It is
only recently that sufficient data have accumulated to enable a rational decision to be made for employing the
more suitable of the two strategies in a given situation.
On a theoretical basis, α-stat management may be preferable in certain situations. Maintenance of constant
intracellular electrochemical neutrality appears to be essential for normal cellular function (22). Intracellular
metabolic intermediates of high-energy phosphates can be depleted if there are changes in the intracellular pH
and these metabolites lose their charged state. These substrates are then free to diffuse across lipid
membranes. Most enzymes depend on optimal pH for their function. Electrochemical neutrality is also important
in maintaining the Donnan equilibrium across cellular membranes to allow normal intracellular anion
concentrations and water content (23).
Poikilothermic animals, whose tissues must function optimally despite wide variations in temperature, follow an α-
stat acid-base strategy. On the other hand, hibernating mammals appear
P.162
to maintain a pH-stat strategy, with constant (temperature-corrected) blood pHa and PCO2 (22). These animals
hypoventilate as they hibernate, the tissue CO2 stores increase, and intracellular pH becomes acidotic in most
tissues. This acidotic state causes a further depression of metabolism that teleologically may be useful by further
decreasing the energy consumption of nonfunctioning tissues, such as skeletal muscle, gastrointestinal tract,
and higher brain centers. In contrast, active tissues, such as heart and liver, adopt a different strategy by actively
extruding H+ across their cell membranes to maintain intracellular pH at or near the values predicted by the α-stat
methodology. Therefore, hibernating mammals are able to vary their intracellular-to-extracellular pH gradient
differently in different tissues, depending on the state of metabolic activity of the tissue. Functionally, this
provides different types of acid-base regulation in different tissues, depending on the metabolic activity of the
tissue. The first noticeable change associated with arousal from hibernation is hyperventilation. This depletes
the CO2 stores, raises intracellular pH, and increases the metabolic rate. The animal reverts to an overall α-stat
pH control pattern during awakening, which allows tissues to regain optimal function. Therefore, in hibernating
mammals, the issue of acid-base maintenance is not clearly defined because intracellular acid-base regulation
can be independent of blood regulation both within and among different tissues in the same animal.
Despite the preceding discussion, the practical question of how acid-base status should be regulated during
hypothermic bypass in humans remains open. Some animal studies suggest that α-stat acid-base management is
beneficial in terms of myocardial protection. McConnell et al. (24) evaluated α-stat regulation during hypothermia
in dogs and demonstrated that significant elevations in coronary blood flow, left ventricular oxygen consumption,
and lactate utilization occurred with maintenance of a pH of 7.7 at 28°C ( α-stat) in comparison with a pH of 7.4
(pH-stat). There was also a significant increase in peak ventricular pressure when a standard preload was
applied. Poole-Wilson and Langer (25) demonstrated a greater contractility in hypothermic perfused papillary
muscle when the pH of the perfusate was more alkaline than 7.4. They also demonstrated a rapid fall in
myocardial tension in addition to changes in Ca2+ flux when the perfusate PaCO2 was increased (26). On the
other hand, Sinet et al. (27) found no effect of pH on the performance of isolated rat heart. The myocardium is
often not perfused but is purposely made ischemic to facilitate cardiac surgery. In this setting, alkalinization of the
blood before ischemia has been shown to decrease the development of acidosis in coronary sinus blood and
improve contractility on reperfusion (28). It also appears that the pH of the blood reperfusing the heart may be
critical to the recovery of ventricular performance. Becker et al. (29) studied the myocardial effects of an acid-
base strategy in which alkalinization greater than that of α-stat was used. They found improvements in
myocardial performance after 1 hour of circulatory arrest and cardioplegia, with moderate alkalinization in
comparison with α-stat. Acid-base management also appears to be important in cardiac electrophysiology. Swain
et al. (30) showed the electrical stability of the heart to be increased, with less spontaneous ventricular
fibrillation, when α-stat blood regulation was compared with pH-stat. Kroncke et al. (31) found a 40% incidence
of ventricular fibrillation in patients cooled to 24°C during pH-stat management and a 20% incidence in those
managed with α-stat.
The appropriate acid-base management for optimal cerebral perfusion has also been questioned. Clearly, CBF
decreases significantly with hypothermia. Cerebral metabolic rate also decreases during hypothermic bypass.
The response of the cerebral circulation to changes in PaCO2 is preserved, at least during moderate hypothermia
(32); therefore, α-stat management will result in lower cerebral flows than those seen with pH-stat management.
However, because of the lowered metabolic demands, a lower CBF may be appropriate and indicative of a
maintained coupling of blood flow and metabolic demand. Govier et al. (33) demonstrated intact autoregulation in
humans using an α-stat strategy at temperatures ranging from 21°C to 29°C. Murkin et al. (34) showed coupling
of CBF and metabolism that was independent of cerebral perfusion pressure (CPP) within the range of 20 to 100
mm Hg when α-stat management was employed. In contrast, cerebral autoregulation was abolished and CBF
varied with perfusion pressure when pH-stat strategy was used (Fig. 8.7). It has been argued that the CBF
during pH-stat hypothermia actually represents excessive blood flow and may be detrimental. Unnecessarily high
blood flows may put the brain at risk of damage by microemboli or high intracranial pressure. With deep
hypothermia (i.e., temperatures <20°C), the normal vascular responses are lost and CBF becomes pressure
dependent (35,36). At deep hypothermic temperatures, coupling of cerebral flow and metabolism is also lost. It is
important to note, however, that the responses of CBF and CMRO2 (cerebral metabolic rate of oxygen) are
quantitatively different at deep hypothermic conditions. CBF decreases linearly with the decrease in temperature,
whereas CMRO2 drops exponentially. The net result is that CBF becomes more luxuriant at deep hypothermic
temperatures. At normothermia, the mean ratio of CBF to CMRO2 is 20:1, and at deep hypothermia, the ratio
increases to 75:1 (37). This situation is important in the context of low-flow CPB. At very low temperatures, data
indicate that pump flow rates may be reduced to as little as 10 mL/kg/min before flow becomes inadequate for
cerebral metabolic requirements (38).
On a microcirculatory level, some evidence suggests that α-stat management may be beneficial to the brain.
Norwood et al. (39) studied the brains of hypothermic dogs perfused with anoxic blood and found a decrease in
extent and magnitude of lesions when the perfusate had a higher pH. Acidic perfusate enhanced the extent of
the lesions. On the other hand, Priestley et al. (40) compared neurologic and histologic outcome in a survival
piglet model of deep hypothermic circulatory arrest.
P.163
They showed that the pH-stat group demonstrated better neurologic performance and less severe functional
disability scores than those piglets in the α-stat group. Histologic injury was also more severe in the α-stat group.
FIGURE 8.7. Simple linear regression of cerebral blood flow (CBF) versus cerebral perfusion pressure (CPP) or
cerebral oxygen consumption (CMRO2) for temperature-corrected and temperature-uncorrected groups. Upper
panel: There is no significant correlation between CBF and CMRO2 in the temperature-corrected group (A1),
whereas CBF significantly correlates with CMRO2 in the temperature-uncorrected group (B1). Lower panel: CBF
is significantly correlated with CPP in the temperature-corrected group (A2), whereas CBF is independent of
CPP in the temperature-uncorrected group (B2). (From Murkin JM, Farrar JK, Tweed, WA, et al. Cerebral
autoregulation and flow/metabolism coupling during cardiopulmonary bypass: the influence of PaCO2. Anesth
Analg 1987;66:825-832, with permission.)
Theoretically, hypocarbia (and increased pH) result in a leftward shift of the oxyhemoglobin dissociation curve,
which causes oxygen to be less readily available to the tissues. However, more oxygen is dissolved in the
plasma during hypothermia, so that these two effects tend to cancel out each other. The relatively low CBF
during α-stat management has still been shown to be in excess of cerebral metabolic needs (34).
In adults, the preponderance of evidence suggests either that CO2 management on CPB does not matter or that
an α-stat strategy is advantageous. Bashein et al. (41) examined the influence of pH management in 86 adults in
whom mild hypothermia was utilized (approximately 30°C). They found no difference in cardiac or
neuropsychologic outcome regardless of acid-base management. It is important to realize, however, that it would
have been unlikely for them to be able to demonstrate a difference in this study under the conditions of the study.
The differences in PCO2 between the two groups amounted only to approximately 6 to 7 mm Hg, and the degree
of hypothermia was not very profound. Contrast the scenario in their study to that of a patient in deep
hypothermia, for whom the difference in PCO2 between the two strategies approaches 80 mm Hg! In addition,
their analysis looked for differences in mean group performances rather than changes in individual patient
performance, a methodology that may have decreased the sensitivity of the study to detect any existing
difference. Three randomized prospective studies of moderate hypothermia in adults have demonstrated that
postoperative neurologic or neuropsychological outcome is slightly, but consistently, better with α-stat
management (42,43,44). The notion that α-stat management may be beneficial in this setting in adults makes
sense if one considers that the most likely mechanism for neurologic injury in these patients is probably emboli.
Therefore, α-stat management would be expected to provide lower CBFs that are more aligned with the cerebral
metabolic rate and a lesser embolic load.
P.164
FIGURE 8.8. Regional blood flow in the brain during α-stat or pH-stat blood gas management. BS, baseline on
normothermic cerebral blood pressure (CBP); HT, at the end of 30 minutes of hypothermic cardiopulmonary
bypass (CPB); R5, 5 minutes after initiation of reperfusion and rewarming after 1 hour of circulatory arrest; N0,
after 45 minutes of rewarming, when normothermia was achieved; N3, after 3 hours of reperfusion at
normothermia.*p < 0.01, #p < 0.05 for group difference. (From Aoki M, Nomura F, Stromski ME, et al. Effects of
pH on brain energetics after hypothermic circulatory arrest. Ann Thorac Surg 1993;55:1093-1103, with
permission.)
Although acid-base management is probably not as important when moderate hypothermic temperatures are
used, it may be critical in the setting of deep hypothermia. Proponents of the α-stat method suggest that
unnecessarily high blood flows (with pH-stat management) may put the brain at risk for damage from
microemboli, cerebral edema, or high intracranial pressure, or may actually predispose to an adverse
redistribution of blood flow (“steal”) away from marginally perfused areas in patients with cerebrovascular
disease. On the other hand, proponents of the pH-stat strategy suggest that enhanced CBF may be helpful in
improving cerebral cooling before the initiation of circulatory arrest. In fact, total CBF is increased, global cerebral
cooling is enhanced, and brain blood flow is redistributed during pH-stat management. An increased proportion
of CBF is distributed to deep brain structures (thalamus, brainstem, and cerebellum) when pH-stat management
is used (45) (Figs. 8.8 and 8.9). However, other data suggest that cerebral metabolic recovery after circulatory
arrest may be better with the α-stat method than with the pH-stat mode. This variation in results has led some
authors to advocate a crossover strategy in which a pH-stat approach is used during the first 10 minutes of
cooling to provide maximal cerebral metabolic suppression, followed by an α-stat strategy to remove the severe
acidosis that accumulates during profound hypothermia during pH-stat. This approach appears to offer maximal
metabolic recovery in animals (46) (Fig. 8.10).
The choice of acid-base management may be particularly important in the subgroup of pediatric patients with
aortopulmonary collaterals, for whom cerebral cooling is problematic. It appears that the addition of CO2 during
cooling enhances cerebral perfusion and improves cerebral metabolic recovery (47). Kurth et al. (48)
demonstrated in a piglet model two mechanisms by which pH-stat management may be beneficial to the brain.
They showed that pH-stat increases the rate of brain cooling and that the rate of depletion of brain oxygen
during deep hypothermic circulatory arrest (DHCA) is considerably slower with pH-stat management than with α-
stat management (Fig. 8.11). In addition to the increase in CBF seen with elevated CO2, one would also expect
to see an increase in pulmonary vascular resistance and a decrease in pulmonary blood flow with the pH-stat
strategy. In fact, in a randomized clinical trial of 40 cyanotic children, Sakamoto et al. (49) demonstrated a
reduction in the systemic-pulmonary collateral circulation in the pH-stat group. They also showed improved
cerebral oximetry values and lower lactate levels in the patients in the pH-stat group. No neurologic deficits were
noted in the patients from either group.
P.165
FIGURE 8.9. Intracerebral distribution of blood flow: α-stat versus pH-stat. Rep(5), 5 minutes after initiation of
reperfusion and rewarming after 1 hour of circulatory arrest; NT(0), after 45 minutes of rewarming, when
normothermia was achieved; NT(180), after 180 minutes of reperfusion at normothermia. “+” indicates p < 0.05
for the within-group increase by paired t test; “-” indicates p < 0.05 for the within-group decrease by paired t test.
(From Aoki M, Nomura F, Stromski ME, et al. Effects of pH on brain energetics after hypothermic circulatory
arrest. Ann Thorac Surg 1993;55:1093-1103, with permission.)
FIGURE 8.10. This figure demonstrates the effects of three different cooling strategies (α-stat, pH-stat, and a
crossover of pH-stat followed by α-stat) on cerebral metabolic suppression before deep hypothermic circulatory
arrest (DHCA) and the recovery of cerebral metabolism after DHCA. The addition of CO2 (i.e., the pH-stat
strategy) provides better cerebral metabolic suppression before DHCA, but cerebral metabolic recovery after
DHCA is poor. Initial cooling with a pH-stat strategy followed by conversion to α-stat before DHCA results in the
greatest cerebral metabolic recovery. CMRO2, cerebral metabolic rate of oxygen. (From Kern FH, Greeley WJ.
pH-stat management of blood gases is not preferable to α-stat in patients undergoing brain cooling for cardiac
surgery. J Cardiothorac Vasc Anesth 1995;9:215-218, with permission.)
A recent randomized single-center trial in human infants younger than 9 months found that the infants who were
managed with a pH-stat strategy had a trend toward better shortterm outcomes than those managed with the α-
stat strategy (50). The pH-stat group had a shorter recovery time to first electroencephalographic activity and a
tendency to fewer electroencephalographically manifested seizures. In this study, within the subset of infants
with transposition of the great vessels, those assigned to pH-stat tended to have a higher cardiac index despite a
lower requirement for inotropic agents, less frequent acidosis ( p = 0.02) and hypotension ( p = 0.05), and a
shorter duration of mechanical ventilation and intensive care
P.166
unit stay ( p = 0.01). Although the number of infants studied in this investigation was small, their findings
challenge the concept that α-stat management is more physiologic and protective during deep hypothermia in
infants than pH-stat management.
FIGURE 8.11. Cortical oxygen saturation (Sco2) during DHCA in the pHstat and α-stat groups. Mean ± SD, eight
animals per group. *p < 0.05 between groups. The Sco2 half-life during arrest was significantly greater in the pH-
stat than in the α-stat group. (From Kurth CD, O’Rourke MM, O’Hara IB. Comparison of pH-stat and α-stat
cardiopulmonary bypass on cerebral oxygenation and blood flow in relation to hypothermic circulatory arrest in
piglets. Anesthesiology 1998;89:110-118, with permission.)
A follow-up paper examined the developmental and neurologic outcome in the same children at 2 to 4 years of
age (51). They found no difference in the neurodevelopmental outcomes with α-stat versus pH-stat. Interestingly
enough, there were some differences noted, depending on which type of lesion was being repaired. In the
cyanotic subgroup (transposition and Tetralogy of Fallot), a slightly higher (but not statistically significant) Mental
Development Index score was found in those patients managed using pH-stat. However, in the ventricular septal
defect subgroup, the patients on pHstat scored significantly worse. These data must be interpreted with caution
because the number of patients in each subgroup was small and there were differences in age at the time of
surgery, depending on the diagnosis.
Why is there an apparent difference in outcome between adults and children relative to pH management? It may
relate to differences in the mechanism of brain injury on CPB. In adults, emboli appear to play a prominent role in
adverse neurologic outcome (52). It is therefore postulated that the reduced CBF associated with α-stat
management may be protective by limiting the dispersion of cerebral microemboli. On the other hand, the
mechanism of injury in children may relate more to hypoperfusion or activation of excitotoxic pathways (53). If a
pH-stat strategy is employed, the increase in CBF may be beneficial in ensuring complete brain cooling and
slowing oxygen consumption, thereby increasing the tolerance of the brain for DHCA.
Alterations in Organ Function

Hypothermia causes a decrease in blood flow to all organs of the body. However, some areas experience a
greater decline than others. Skeletal muscle and the extremities have the greatest reduction in flow, followed by
the kidneys, splanchnic bed, heart, and brain. Despite this decrease in flow, differences in the arteriovenous
oxygen content are seen to either decrease or remain unchanged, which implies that the oxygen supply is
adequate to meet the metabolic requirements.
With cooling, heart rate decreases but contractility remains stable or may actually increase. Dysrhythmias
become more frequent as temperature decreases and may include nodal, premature ventricular beats,
atrioventricular block, atrial and ventricular fibrillation, and asystole. The mechanism of this dysrhythmogenic
effect is unknown but may involve electrolyte disturbances, uneven cooling, and autonomic nervous system
imbalance. Because coronary blood flow is well preserved during hypothermia, it is unlikely that myocardial
hypoxia plays a role in the genesis of these dysrhythmias.
The pulmonary system is characterized by a progressive decrease in ventilation as the temperature is lowered.
Physiologic and anatomic dead space increases during dilation of the bronchi by cold. Gas exchange is largely
unaffected.
The kidneys show the largest proportional decrease in blood flow of all the organs. Hypothermia increases renal
vascular resistance, with diminished outer and inner cortex blood flow and oxygen delivery. Tubular transport of
sodium, water, and chloride are decreased, and the ability to concentrate becomes impaired. Tubular
reabsorption is decreased. Urine flow may be increased with hypothermia, but this effect can be masked by the
stress-induced release of antidiuretic hormone (ADH). The ability of the hypothermic kidney to handle glucose is
impaired, and glucose often appears in the urine. Hemodilution in combination with hypothermic CPB improves
renal blood flow and protects the integrity of the renal tubules postoperatively.
In general, significant hepatic injury with hypothermic CPB is rare. Hepatic arterial blood flow is reduced in
proportion to the fall in cardiac output. The most significant effect of hypothermia is the decrease in metabolic
and excretory function of the liver. Obviously, drug actions and requirements will be modified by this change in
liver function. With rewarming, hepatic efficiency reverts to normal.
Marked hyperglycemia is often a feature of hypothermic CPB. Endogenous insulin production is decreased, and
glycogenolysis and gluconeogenesis may be increased because of increases in catecholamines. Even if
exogenous insulin is administered, its efficacy is reduced during hypothermia, and hyperglycemia may develop.
It is difficult to separate the effects of hypothermia from those of hemodilution and CPB. Tissue water content is
increased during hypothermic bypass, primarily as a consequence of hemodilution (54). Cell swelling and edema
occur,
P.167
which may be related to an accumulation of sodium and chloride within cells secondary to a decrease in reaction
rates of membrane Na+ -K+ -ATPase (15). Hypothermia decreases free water clearance and causes a decrease
in plasma potassium and an increase in osmolarity.
Hypothermia causes marked changes in the peripheral circulation. Systemic and pulmonary vascular resistance
typically rise with cooling below 26°C (55). This increase in vascular resistance relates to increases in blood
viscosity and catecholamines, hemoconcentration, cell swelling, and perhaps active vasoconstrictor substances
in the lung. In addition, arteriovenous shunts appear at low temperatures (56) and may cause a further diminution
in tissue oxygen delivery. The increase in blood viscosity occurs because of fluid shifts, with loss of plasma
volume from capillary leak and cell swelling. The red blood cell volume remains unchanged although the
hematocrit rises. Red blood cell aggregation and rouleaux formation can occur, further impeding blood flow.
These changes can be somewhat attenuated by adequate anesthesia, hemodilution, heparinization, and the use
of vasodilators. Hypothermia also causes thrombocytopenia by a reversible sequestration of platelets in the
portal circulation.
The hormonal response to hypothermia depends on the level of anesthesia. Nonanesthetized subjects
demonstrate a marked sympathetic response to cold. This response can be almost ablated if deep anesthesia is
used. After deep hypothermia and total circulatory arrest, a massive release of catecholamines occurs (57),
which may contribute to the impaired cerebral perfusion found by Greeley et al. (58). Corticosteroid release is
suppressed with long-term hypothermia below 28°C, but appears to be normal during short periods of
hypothermia (59). Complement activation occurs during CPB and is associated with neutrophil activation.
Respiratory complications correlate with the degree of complement activation (60). Hypothermia, hemodilution,
and heparin reduce complement activation and subsequent neutrophil response and may protect patients from
harmful sequelae. Circulating bradykinin increases during hypothermia and CPB and may contribute to altered
vascular permeability and circulatory instability (61).
CLINICAL USE OF HYPOTHERMIA

Currently, hypothermia is used most commonly in cardiac surgery, although its use has also been described for
major vascular procedures, intracranial surgery, and removal of hepatic and renal tumors. In most cardiac
procedures, mild to moderate systemic hypothermia (>25°C) is used for its protective effects, as previously
described. More profound selective myocardial hypothermia is also often used during aortic cross-clamping to
aid in the preservation of ischemic myocardium. Myocardial hypothermia is typically obtained in two ways: by
coronary perfusion with cold cardioplegic solution, and by topical application of an ice slush or cold pericardial
lavage. The optimal temperature for myocardial protection is controversial; however, most studies have
demonstrated superior protection at temperatures as low as 2°C to 4°C, as long as freezing temperatures are
avoided, alkalosis is present, and the heart is promptly arrested during cooling (62).
Deep Hypothermic Circulatory Arrest

The most dramatic application demonstrating the protective effects of hypothermia is in DHCA. Systemic
temperatures of 20°C to 22°C or less are used to allow cessation of the circulation for periods up to 40 to 60
minutes, often without detectable organ injury (9). DHCA can be used in a variety of situations. In pediatric
cardiac surgical patients (particularly those weighing <8-10 kg), the repair of complex congenital cardiac lesions
is often facilitated by the asanguineous surgical field provided with circulatory arrest. It is often used in
procedures requiring occlusion of multiple cerebral vessels, particularly repair of aortic arch aneurysms. It may
be used to enhance surgical exposure and speed in procedures that could lead to uncontrollable hemorrhage.
Central Nervous System Effects of DHCA

The brain is the organ at greatest risk for injury; this fact limits the duration of “safe” arrest time. Cerebral
metabolic activity is decreased with temperature, but it never ceases altogether, even at temperatures
approaching 0°C. As mentioned earlier, the protective effect of hypothermia may involve more than just a
reduction in cerebral metabolic rate. A Q10 of 2.7 would predict only a “safe” arrest time of approximately 15
minutes at 20°C. Clinical and experimental evidence indicate, however, that 30 to 45 minutes is typically
tolerated, so there appears to be a disproportionate cerebral protective effect to profound levels of hypothermia.
Other factors, such as extracellular pH, may play a role. Swain et al. (63) showed that hypothermia significantly
increases the tissue energy state and intracellular pH in both heart and brain. This increase in high-energy
phosphate levels may partially explain the beneficial effects of hypothermia on organ tolerance to ischemia. On
the other hand, it may be that cerebral oxygen consumption decreases in a nonlinear manner and more
precipitously with profound hypothermia than was previously thought. Michenfelder and Milde (64) showed a
change in Q10 from 2.23 between 37°C and 27°C to 4.53 between 27°C and 14°C. They postulated that this
marked drop in oxygen consumption at lower temperatures could be explained by a primary effect of hypothermia
on integrated neuronal function (as shown by suppression of the electroencephalogram).
The rate of cooling also appears to be important in the occurrence of brain injury. Wide gradients between body
and perfusate temperature in dogs correlated with brain cell necrosis and death (65). The optimal site for
temperature monitoring is controversial, but it must be remembered that gradients exist among the different
regions (66) (Fig. 8.12). Monitoring multiple sites to ensure uniform cooling before
P.168
circulatory arrest is advisable. Coselli et al. (67) suggested using electroencephalographic monitoring to
determine the ideal depth of cooling for safe circulatory arrest. They advocated using electroencephalographic
silence as the appropriate end point in cooling, but found that no peripheral body temperature consistently
predicts this level of hypothermia. There was a wide variation in temperature among body sites when
electroencephalographic silence occurred.
FIGURE 8.12. Average temperature [±SEM (standard error of mean)] of arterial cannula, myocardium, cerebral
cortex, nasopharynx, and rectum during 40 minutes of cooling and 90 minutes of rewarming under
cardiopulmonary bypass in six pigs. (From Stefaniszyn HJ, Novick RJ, Keith FM, et al. Is the brain adequately
cooled during deep hypothermic cardiopulmonary bypass? Curr Surg 1983;40:294-297, with permission.)
A consequence of ischemia and anoxia is the “no-reflow” phenomenon. The cerebral microcirculation can shut
down multifocally, causing incomplete reperfusion when flow is resumed. The etiology of this problem is not
completely understood, but may involve increased blood viscosity, vascular smooth-muscle contraction resulting
from increased extracellular potassium, and precapillary shunting (68). It can occur with or without total
circulatory arrest and can be prevented by hypothermia (39). Microscopic cellular damage in the brain occurs to
some degree following hypothermia to 18°C, regardless of whether pulsatile or nonpulsatile perfusion or total
circulatory arrest is employed (69).
The main concern with the use of DHCA is the potential harmful effects on the organ most at risk, the brain. As
mortality decreases with improvements in technique, the question of an effect on later intellectual development
after hypothermic bypass, with or without circulatory arrest, becomes critical. Several studies have shown
evidence of a decreased intelligence quotient and developmental capacity related to the duration of circulatory
arrest (70,71,72). However, other studies
P.169
have not been able to demonstrate an adverse effect on intellectual capacity and development when circulatory
arrest times were less than 60 minutes at nasopharyngeal temperatures of approximately 20°C (73,74,75). It is
difficult to interpret many of these studies because of the difficulty in defining an appropriate control group.
Blackwood et al. (76) used each child as his or her own control and found no difference between preoperative
and postoperative scores with arrest intervals as long as 74 minutes. In 1993, Newburger et al. (77) reported a
greater neurologic risk to neonates and infants with DHCA than with continuous low-flow bypass. They reported
modest but statistically significant reductions in psychomotor developmental performance in those children in the
circulatory arrest group (78). Many investigators have tried to determine a “safe” duration for DHCA, but the
answer is still not known. Extensive clinical experience suggests that periods of DHCA as long as 60 minutes are
often well tolerated. Although patients vary widely, the data of Newburger et al. suggest minimal adverse effects
on psychomotor test results with circulatory arrest times of approximately 35 minutes at 18°C.
Choreoathetosis
Choreoathetosis has been reported in 1% to 20% of children undergoing DHCA (74,79). Choreoathetosis usually
appears 2 to 6 days postoperatively and generally lessens in severity with time. However, in severe cases,
choreoathetoid movements or generalized hypotonia may persist indefinitely. Choreoathetosis has also been
occasionally observed following continuous CPB, especially with profound hypothermia (10°C-12°C) (80).
Numerous etiologies have been proposed, including hyperglycemia (81), uneven cooling (77), the no-reflow
phenomenon (39,82), dopaminergic neurotransmitter alterations (83), and cerebral excitatory amino acid
neurotoxicity (84). It is generally thought that this hyperkinetic movement disorder is a result of injury to basal
ganglia, although often the pathology is not detectable by conventional cranial computed tomography or
magnetic resonance imaging (MRI). It appears that there may also be an age-related phenomenon with regard to
choreoathetosis. Data from Boston Children’s Hospital suggest that the most vulnerable period starts at 6 to 9
months and ends after 5 to 6 years (85). A mild, transient form of the condition was observed to develop in
younger children, whereas older children manifested a severe, persistent disorder with a high mortality. The
Boston group also noted that choreoathetosis is most likely to occur in children with significant systemic-
pulmonary collateral vessels. Perhaps the phenomenon of “steal” from the cerebral circulation to the pulmonary
arteries, particularly in the setting of inadequate brain cooling, contributes to this problem.
Seizures
Seizures following CPB in neonates are much more common than in adults. Seizures have been reported to
occur clinically in as many as 20% of neonates following CPB (86,87). Seizures detected by
electroencephalogram occur even more commonly than clinically observed seizures, a fact to be kept in mind if it
becomes necessary to induce pharmacologic paralysis in the postoperative period. The seizures are generally
self-limited and can occur irrespective of whether circulatory arrest has been used. Some series have reported
no long-term adverse sequelae, whereas others have suggested a decrement in psychomotor developmental
performance in addition to neurologic and MRI abnormalities (88,89,90). The long-term prognosis for these
children is still unclear. The question of whether seizures themselves actually add to the damage, or are just a
reflection of severe underlying brain pathology, also arises. At present the answer is unknown, and further
research is necessary in this important area. Also, the relative involvement of hypothermia or other elements of
CPB has not been determined.
Therefore, the question of a “safe” circulatory arrest time is complex and cannot be answered with certainty.
Hypothermia can delay, but not prevent, the appearance of metabolic and structural changes during ischemia
that lead to functional neurologic impairment. A nomogram has been devised that, although not rigorously
defined, provides a best estimate of the safe circulatory arrest times at three temperatures (9) (Fig. 8.13).
Although patients vary widely, the data of Newburger et al. (77) in children suggest minimal adverse effects on
psychomotor testing with circulatory arrest times of approximately 35 minutes at 18°C.
Central Nervous System Cooling and Rewarming

Because deep hypothermia and very low-flow rates or circulatory arrest will most likely remain important tools in
cardiac surgery, especially in congenital heart surgery and aortic arch repair, much effort has been expended in
trying to understand better the physiology involved. Newer monitoring and protective strategies are being
evolved in an attempt to improve cerebral outcome in these patients. One of the areas of focus has been cooling
methods before circulatory arrest. The rate of cooling and the efficiency of brain cooling are important factors in
neurologic protection. There is marked variability in cerebral cooling, and sufficient time must be allotted before
circulatory arrest to ensure that there is uniform brain cooling. One group of investigators reported slower brain
cooling in one-third of the neonates studied by jugular venous saturation monitoring (91). It appears that cooling
periods of less than 20 to 25 minutes before the initiation of circulatory arrest with α-stat regulation are
associated with a lower developmental quotient in neonates undergoing DHCA (92) (Fig. 8.14). Uniform cerebral
cooling may also be problematic in certain groups of patients. Cyanotic patients with aortopulmonary collaterals
appear to be at increased risk for neurologic injury during CPB (93). A reduction in total and regional measures
of CBF occurs in these patients, resulting in less efficient cerebral cooling. Because the brain is acidotic and a
tremendous metabolic debt develops during DHCA, the method of reestablishing CPB and rewarming may also
be
P.170
critically important. Some intriguing data suggest that a period of cold reperfusion with delayed rewarming after
reestablishment of CPB may be beneficial (94). These authors demonstrated an improvement in CBF velocity in
the group of infants in whom rewarming was delayed by 10 minutes. It is also becoming clear that too aggressive
rewarming, with hyperthermic overshoot, is deleterious to neurologic outcome and should be avoided. Martin et
al. (95) and Mora et al. (96) reported an increased risk for neurologic injury in adult patients actively warmed to
37°C, with a CPB circuit water bath maintained at 39°C to 40°C, in comparison with patients allowed to “drift” to
systemic temperatures of 33°C to 36°C in a more tepid approach to warm heart bypass. They suggested that
many, if not all, of their “normothermic” patients experienced cerebral hyperthermia (>37°C), which may
potentiate ischemic pathologic processes in the brain during cardiac operations. Animal data have demonstrated
that even small (2°C) increases in brain temperature can exacerbate neuronal injury, with changes in blood-brain
permeability, increases in postischemic release of glutamate, and increased mortality (97,98). Elevated
temperatures must be strenuously avoided, not just in the operating room but also in the postoperative period.
Several authors have demonstrated that hyperthermia occurs commonly after cardiac surgery in both adults and
children (99,100,101). The etiology is not entirely related to CPB per se, because patients having off-pump
coronary artery bypass surgery also commonly have fever postoperatively. Aggressive cooling measures should
be taken because this hyperthermia has been shown to be deleterious to outcome. Grocott et al. (7) carefully
studied 300 patients with hourly postoperative temperatures and cognitive testing before and 6 weeks after
surgery. They demonstrated that the maximum postoperative temperature was associated with a greater degree
of postoperative cognitive dysfunction. Of course, it is not entirely clear whether the fever observed
postoperatively is in itself deleterious or whether it is a manifestation of an exaggerated inflammatory response
with subsequent brain injury. Further research is necessary in this area.
FIGURE 8.13. Nomogram of an estimate (not rigorously derived) of the probability of “safe” total circulatory
arrest (absence of structural or functional damage) according to the arrest time at nasopharyngeal temperatures
of 37°C, 28°C, and 18°C. (From Kirklin JW. Cardiac surgery. New York: Churchill Livingstone, 1993:61-127, with
permission.)
FIGURE 8.14. Scatter plot of duration of core cooling (minutes of cardiopulmonary bypass before DHCA) and
developmental index for infants with “short” periods of core cooling (<20 minutes). The best-fit regression line
and its 95% confidence interval (CI) are shown. DHCA, deep hypothermic circulatory arrest. (From Bellinger DC,
Wernovsky G, Rappaport LA, et al. Cognitive development of children following repair of transposition of the
great arteries using deep hypothermic circulatory arrest. Pediatrics 1991;87:701-707, with permission.)
Tepid Temperature Management

Over the last few decades, an interest in tepid CPB has arisen. There are many theoretical and clinically evident
advantages and disadvantages detailed in the literature. Several variables come into play when comparing
multiple studies utilizing
P.171
tepid CPB to normothermia, mild hypothermia, and moderate hypothermia. This section will attempt to summarize
the current data available. Based on a recent consensus paper on hypothermic circulatory arrest (102), we will
use the following definitions for the degree of hypothermia throughout this section: profound hypothermia as
≤14°C, deep hypothermia as 14.1°C to 20°C, and moderate hypothermia as 20.1°C to 28°C. The article defines
mild hypothermia as 28.1°C to 34°C. For this section, we will consider mild hypothermia as 28.1°C to 32°C and
consider tepid temperatures, often termed “drift”, to range from 32.1°C to 36°C and normothermia as ≥36°C.
In the early 1990s, Tonz et al. (103,104) described theoretical objections to warm CPB including extended
cellular and humoral activation, decreased tolerance to ischemia resulting in more evident effects of
nonhomogeneous perfusion, and additional blood trauma due to higher flow rates. Although logical, the evidence
available does not support these objections. One retrospective review comparing normothermia to moderate
hypothermia found a significant decrease in intubation times with the use of normothermic CPB. In addition, there
was no difference in mortality, myocardial infarction rates, or use of an intra-arterial balloon pump for support.
This study also found significantly shorter CPB times with the use of warm cardioplegia during normothermic
CPB compared to the use of cold cardioplegia, although significantly higher doses of warm cardioplegia were
necessary (104). Two small prospective studies compared coronary artery bypass graft (CABG) and valve
procedures utilizing moderate hypothermia to normothermia (103,105). Lehot et al. focused on hemodynamic and
hormonal responses and found significantly longer cross-clamp and CPB times in the moderate hypothermia
group compared to the normothermic group. Hemodynamically, tachycardia was significantly greater in the
moderate hypothermia group at the termination of CPB. Although systemic vascular resistance (SVR) was
significantly lower in the normothermic group, concentrations of norepinephrine and epinephrine were
significantly higher in the normothermic group. There were no other significant humoral responses found
between the two groups (105). A decrease in SVR was also described by others (103,104,105). Tonz et al. (103)
reported significant hemodynamic changes including a lower SVR and higher cardiac index immediately
postoperatively in the normothermic group, but this difference disappeared by postoperative day 1 (POD 1). In
this study, the total volume of blood shed through chest and pleural tubes was significantly higher in the
moderate hypothermia group. This group also had an increased use of blood products including packed red
blood cells and fresh frozen plasma. There was no significant difference in inflammatory mediators or blood
chemistries in this study (103).
Engelman et al. (106) randomized 291 CABG patients to moderate hypothermia, tepid temperatures, or
normothermia. They found no significant difference among groups in mortality, length of stay, or atrial arrhythmia.
A subset of 53 patients was further analyzed to evaluate for fibrinolysis potential. Of these, 42 patients were
tested for preoperative and postoperative prekallikrein activity. There was a significantly increased degradation
of prekallikrein activity with increasing temperatures. The authors state that this indicates increasing fibrinolysis
at normothermia, although from their larger patient population of 291 patients, they were unable to show any
significant difference in blood loss or product use at the three different temperatures. In 2002, Guadino et al.
(107) evaluated hemostatic and inflammatory activation in 113 CABG patients at moderate hypothermia or
normothermia. There was no significant difference in mortality, myocardial infarction, blood loss, or product use
at the different temperatures. There was no difference in hemostatic markers including fibrinogen concentration,
plasminogen activator inhibitor, and coagulation labs. They were also unable to detect a significant difference in
inflammatory markers including C-reactive protein, interleukin-6, white blood cell, neutrophil, and monocyte
counts.
In the last two decades, several prospective studies (some small and some well-powered) have compared
neurologic outcomes after CPB at various temperatures. One prospective study from Duke University
randomized 300 CABG patients to receive either tepid CPB (35.5°C-36.5°C) or mild hypothermia (28°C-30°C)
(108). Both groups received intermittent cold cardioplegia, and the maximal perfusate temperature for rewarming
was 38°C. All patients underwent preoperative cognitive testing and the patients in the mild hypothermia group
were found to have slightly decreased performance preoperatively. There was no significant difference in
neurocognitive decline at 6 weeks. In another well-powered study, Heyer et al. (109) found no difference in
postoperative neurologic or neuropsychometric performance in 99 CABG patients randomized to moderate
hypothermia or tepid CPB. Guadino et al. reports that although the prevalence of neurologic events was similar
between groups in his study, there was an association with superior extension of brain damage and worse
neurologic outcomes, specifically in those patients who suffered intraoperative strokes with normothermic CPB.
Additionally, there was 6.6% mortality among the hypothermic group, whereas the normothermic group had a
50% mortality rate in patients with intraoperative stroke (110). Mora et al. (111) compared 138 patients
undergoing CABG procedures with moderate hypothermia or tepid temperatures. They report a significantly
higher rate of new perioperative central neurologic deficits in the tepid group. At baseline, the tepid group had a
significantly higher mean age which may have contributed. In addition, cardioplegia administration varied
between the two groups. The tepid group received continuous retrograde cardioplegia after initial antegrade
administration while the moderate hypothermia group received only intermittent antegrade and retrograde
cardioplegia.
In another article, using the same study population of 300 CABG patients described above, the Duke group
compared
P.172
the change in creatinine clearance at different temperatures (112). There were no significant differences in the
change in creatinine clearance or the lowest creatinine clearance values between the mild hypothermia and tepid
CPB groups. Based on these results, the authors state that there is no renal protective effect from hypothermia
although only creatinine clearance was evaluated in this study. Although maximal perfusate temperature was well
controlled in this study, there was a higher mean duration of temperatures >37°C and an increased mean
temperature >37°C in the mild hypothermia group (108,112). There is strong evidence to support the detrimental
effects of hyperthermia on neurocognitive function and acute kidney injury (AKI) (113,114,115,116) and the need
to rewarm patients increases their risk of hyperthermia. A 2002 article also suggests improved outcomes with
slower rewarming (114). This study compared 165 patients rewarmed with perfusate temperatures either 2°C or
6°C apart and found lower peak temperatures and a significantly greater improvement in cognitive performance
with slower rewarming. A recent observational study of 1,393 patients describes a 34% increase in likelihood of
AKI for every 10 minutes of arterial outlet temperatures >37°C (116).
Analysis of the varying studies leaves one somewhat confused as to the appropriate temperature management
for CPB. It appears that the majority of studies do not show a marked difference in outcomes by using
hypothermia for routine cases. There may be some limited benefit to lower temperatures in minimizing neurologic
injury in the setting of a stroke. So there may be some benefit to letting the patient’s temperature drift, using a
tepid approach. However, strict attention to a careful rewarming strategy is imperative to avoid inadvertent
hyperthermia, which is likely to exacerbate any injury.
Cardiac surgery has advanced remarkably during the last 50 years. Hypothermia has contributed substantially
toward improving patient outcome in selected cases. Current efforts must be directed toward defining methods of
maximizing cerebral protection and refining critical techniques.
KEY Points
Acid-base balance is significantly affected by hypothermia.
Biologic fluids are water solutions of weak acids and weak bases.
Hypothermia decreases the tendency for weak acids and bases to dissociate in solution.
Blood pH is maintained at moderately alkaline values (0.4 pH units) relative to water.
Maintenance of a constant ratio of [OH-] to [H+] (16:1) as temperature decreases allows optimum
function of many respiratory enzymes.
α-stat regulation preserves the ratio of [OH-] to [H+] with change in temperature and produces an
alkaline shift with cooling.
pH-stat regulation maintains an absolute constant [H +] regardless of temperature, and requires added
H+, usually as CO2, with cooling.
The solubility of gases in biologic fluids increases with hypothermia.
At a constant CO2 content, Paco2 decreases as temperature falls.
Appropriate acid-base strategy during hypothermic CPB may be different between children and adults
based on different mechanisms of cerebral injury.
pH-stat may be beneficial in infants to increase CBF and allow more efficient cooling.
α-stat appears advantageous in adults by limiting the microembolic load to the brain.
Protection of the brain during deep hypothermia (temperature <20°C) may be best accomplished with a
mixed acid-base strategy:
pH-stat during the initial cooling phase.
α-stat during reperfusion, rewarming, and termination of CPB.
Hypothermia causes a decrease in blood flow to all vascular beds in proportion to the reduced metabolic
demands.
The most profound effects occur in skeletal muscles and the extremities, followed by the kidneys,
splanchnic bed, heart, and brain.
Hyperthermia occurs commonly after cardiac surgery and should be aggressively treated because it may
worsen ischemic damage.
REFERENCES
1. Fay T. Observations on prolonged human refrigeration. N Y State J Med 1940;40:1351-1354.
2. Crossman LW, Ruggiero WF, Hurley V, et al. Reduced temperatures in surgery. II. Amputations for
peripheral vascular disease. Arch Surg 1942;44:139-156.
3. Bigelow WG, Callaghan JC, Hopps JA. General hypothermia for experimental intra-cardiac surgery. Ann
Surg 1950;132:531-539.
4. Lewis FJ, Taufic M. Closure of atrial septal defects with the aid of hypothermia: experimental
accomplishments and the report of one successful case. Surgery 1953;33:52-59.
5. Gibbon JH. Application of a mechanical heart and lung apparatus to cardiac surgery. Minn Med
1954;37:171-180.
6. Sealy WC, Brown IW Jr, Young WG Jr. A report on the use of both extracorporeal circulation and
hypothermia for open heart surgery. Ann Surg 1958;147:603-613.
7. Grocott HP, Mackensen GB, Grigore AM, et al. Postoperative hyperthermia is associated with cognitive
dysfunction after coronary artery bypass graft surgery. Stroke 2002;33:537-541.
8. Minamisawa H, Smith ML, Siesjo BK. The effect of mild hyperthermia and hypothermia on brain damage
following 5, 10, and 15 minutes of forebrain ischemia. Ann Neurol 1990;28:26-33.
9. Kirklin JW, Barratt-Boyes BG, eds. Hypothermia, circulatory arrest, and cardiopulmonary bypass. Cardiac
surgery. 2nd ed. New York: Churchill Livingstone, 1993:61-127.
10. Swain JA, McDonald TJ, Griffith PK, et al. Low-flow hypothermic cardiopulmonary bypass protects the
brain. J Thorac Cardiovasc Surg 1991;102:76-84.
P.173
11. Michenfelder JD. The hypothermic brain. In: Michenfelder JD, ed. Anesthesia and the brain. New York:
Churchill Livingstone, 1988:23-34.
12. Rothman SM, Olney JW. Glutamate and the pathophysiology of hypoxic-ischemic brain damage. Ann
Neurol 1986;19:105-111.
13. Busto R, Globus MYT, Dietrich WD, et al. Effect of mild hypothermia on ischemia-induced release of
neurotransmitters and free fatty acids in rat brain. Stroke 1989;20:904-910.
14. Hearse DJ, Braimbridge MV, Jynge P. Protection of the ischemic myocardium: cardioplegia. New York:
Raven Press, 1981.
15. Cameron DE, Gardner TJ. Principles of clinical hypothermia. Cardiac Surg 1988;2:13-25.
16. Hickey RF, Hoar PF. Whole body oxygen consumption during low-flow hypothermic cardiopulmonary
17. Slogoff S, Reul GJ, Keats AS, et al. Role of perfusion pressure and flow in major organ dysfunction after
18. Nussmeier NA, Arlund C, Slogoff S. Neuropsychiatric complications after cardiopulmonary bypass:
cerebral protection by a barbiturate. Anesthesiology 1986;64:165-170.
19. Rahn H. Body temperature and acid-base regulation [Review Article]. Pneumonologie 1974;151:87-94.
20. Malan A, Wilson TL, Reeves RB. Intracellular pH in cold-blooded vertebrates as a function of body
temperature. Respir Physiol 1976;28:29-47.
21. Hazel JR, Garlick WS, Sellner PA. The effects of assay temperature upon the pH optima of enzymes from
poikilotherms: a test of imidazole alphastat hypothesis. J Comp Physiol 1978;123:97-102.
22. Hickey PR, Hansen DD. Temperature and blood gases: the clinical dilemma of acid-base management
for hypothermic cardiopulmonary bypass. In: Tinker JH, ed. Cardiopulmonary bypass: current concepts and
controversies. Philadelphia: WB Saunders, 1989:1-20.
23. Reeves RB. Temperature-induced changes in blood acid-base status: donnan rCl and red cell volume. J
Appl Physiol 1976;40:762-767.
24. McConnell DH, White F, Nelson RL, et al. Importance of alkalosis in maintenance of “ideal” blood pH
during hypothermia. Surg Forum 1975;26:263-265.
25. Poole-Wilson PA, Langer GA. Effect of pH on ionic exchange and function in rat and rabbit myocardium.
Am J Physiol 1975;229:570-581.
26. Poole-Wilson PA, Langer GA. Effects of acidosis on mechanical function and Ca2+ exchange in rabbit
myocardium. Am J Physiol 1979;236:H525-H533.
27. Sinet M, Muffat-Joly M, Bendaace T, et al. Maintaining blood pH at 7.4 during hypothermia has no
significant effect on work of the isolated rat heart. Anesthesiology 1985;62:582-587.
28. Austen WG. Experimental studies on the effects of acidosis and alkalosis on myocardial function after
aortic occlusion. J Surg Res 1965;5:191-194.
29. Becker H, Vinten-Johansen J, Buckberg G, et al. Myocardial damage caused by keeping pH 7.40 during
systemic deep hypothermia. J Thorac Cardiovasc Surg 1981;82:810-820.
30. Swain JA, White FN, Peters RM. The effect of pH on the hypothermic ventricular fibrillation threshold. J
31. Kroncke GM, Nichols RD, Mendenhall JT, et al. Ectothermic philosophy of acid-base balance to prevent
fibrillation during hypothermia. Arch Surg 1986;121:303-304.
32. Prough DS, Stump DA, Roy RC, et al. Response of cerebral blood flow to changes in carbon dioxide
during hypothermic cardiopulmonary bypass. Anesthesiology 1986;64:576-581.
33. Govier AV, Reves JG, McKay RD, et al. Factors and their influence on regional cerebral blood flow during
nonpulsatile cardiopulmonary bypass. Ann Thorac Surg 1984;38:592-600.
34. Murkin JM, Farrar JK, Tweed WA, et al. Cerebral autoregulation and flow/metabolism coupling during
cardiopulmonary bypass: the influence of PaCO2. Anesth Analg 1987;66:825-832.
35. Greeley WJ, Kern FH, Ungerleider RM, et al. The effect of hypothermic cardiopulmonary bypass and
total circulatory arrest on cerebral metabolism in neonates, infants and children. J Thorac Cardiovasc Surg
1991;101:783-794.
36. Greeley WJ, Ungerleider RM, Kern FH, et al. Effects of cardiopulmonary bypass on cerebral blood flow in
neonates, infants and children. Circulation 1989;80(Suppl I):I209-I215.
37. Swain JA. Acid-base status, hypothermia and cardiac surgery. Perfusion 1986;1:231-238.
38. Kern FH, Ungerleider RM, Reves JG, et al. The effect of altering pump flow rate on cerebral blood flow
and metabolism in neonates, infants and children. Ann Thorac Surg 1993;56:1366-1372.
39. Norwood WI, Norwood CR, Castaneda AR. Cerebral anoxia: effect of deep hypothermia and pH. Surgery
1979;86:203-209.
40. Priestley MA, Golden JA, O’Hara IB, et al. Comparison of neurologic outcome after deep hypothermic
circulatory arrest with alpha-stat and pHstat cardiopulmonary bypass in newborn pigs. J Thorac Cardiovasc
Surg 2001;121:336-343.
41. Bashein G, Townes BD, Nessly ML, et al. A randomized study of carbon dioxide management during
hypothermic cardiopulmonary bypass. Anesthesiology 1990;72:7-15.
42. Stephan H, Weyland A, Kazmaier S, et al. Acid-base management during hypothermic cardiopulmonary
bypass does not affect cerebral metabolism but does affect blood flow and neurological outcome. Br J
Anaesth 1992;69:51-57.
43. Patel RL, Turtle MR, Chambers DJ, et al. Alpha-stat acid-base regulation during cardiopulmonary bypass
improves neuropsychologic outcome in patients undergoing coronary artery bypass grafting. J Thorac
44. Murkin JM, Martzke JS, Buchan AM, et al. A randomized study of the influence of perfusion technique
and pH management strategy in 316 patients undergoing coronary artery bypass surgery. II. Neurologic and
cognitive outcomes. J Thorac Cardiovasc Surg 1995;110:349-362.
45. Aoki M, Nomura F, Stromski ME, et al. Effects of pH on brain energetics after hypothermic circulatory
arrest. Ann Thorac Surg 1993;55:1093-1103.
46. Skaryak LA, Chai PJ, Kern FH, et al. Blood gas management and degree of cooling: effects on cerebral
metabolism before and after circulatory arrest. J Thorac Cardiovasc Surg 1995;110:1649-1657.
47. Kirshbom PM, Skaryak LA, DiBernardo LR, et al. pH-stat cooling improves cerebral metabolic recovery
after circulatory arrest in a piglet model of aorto-pulmonary collaterals. J Thorac Cardiovasc Surg
1996;111:147-157.
48. Kurth CD, O’Rourke MM, O’Hara IB. Comparison of pH-stat and alpha-stat cardiopulmonary bypass on
cerebral oxygenation and blood flow in relation to hypothermic circulatory arrest in piglets. Anesthesiology
1998;89:110-118.
49. Sakamoto T, Kurosawa H, Shin’oka T, et al. The influence of pH strategy on cerebral and collateral
circulation during hypothermic cardiopulmonary bypass in cyanotic patients with heart disease: results of a
randomized trial and real-time monitoring. J Thorac Cardiovasc Surg 2004;127:12-19.
50. DuPlessis AJ, Jonas RA, Wypij D, et al. Perioperative effects of alpha-stat versus pH-stat strategies for
deep hypothermic cardiopulmonary bypass in infants. J Thorac Cardiovasc Surg 1997;114:990-1001.
51. Bellinger DC, Wypij D, du Plessis AJ, et al. Developmental and neurologic effects of alpha-stat versus
pH-stat strategies for deep hypothermic cardiopulmonary bypass in infants. J Thorac Cardiovasc Surg
2001;121:374-383.
52. Hammon JW, Stump DA, Kon ND, et al. Risk factors and solutions for the development of
neurobehavioral changes after coronary artery bypass grafting. Ann Thorac Surg 1997;63:1613-1618.
53. Vannucci RC. Mechanisms of perinatal ischemic brain damage. In: Jonas RA, Newburger JW, Volpe JJ,
eds. Brain injury and pediatric cardiac surgery. Boston: Butterworth-Heineman, 1996:201-214.
54. Utley JR, Wachtel C, Cain RB, et al. Effects of hypothermia, hemodilution, and pump oxygenation on
organ water content, blood flow and oxygen delivery, and renal function. Ann Thorac Surg 1981;31:121-133.
55. Cooper KE. The circulation in hypothermia. Br Med Bull 1961;17:48-51.
56. Suzuki M, Penn I. A reappraisal of the microcirculation during general hypothermia. Surgery
1965;58:1049-1060.
57. Wood M, Shand DG, Wood AJJ. The sympathetic response to profound hypothermia and circulatory
arrest in infants. Can Anaesth Soc J 1980;27:125-132.
58. Greeley WJ, Ungerleider RM, Smith LR, et al. The effects of deep hypothermic cardiopulmonary bypass
and total circulatory arrest on cerebral blood flow in infants and children. J Thorac Cardiovasc Surg
1989;97:737-745.
59. Blair E. Clinical hypothermia. New York: McGraw-Hill, 1964.
60. Moore FD Jr, Warner KG, Assousa S, et al. The effects of complement activation during cardiopulmonary
bypass: attenuation by hypothermia, heparin, and hemodilution. Ann Surg 1988;208:95-103.
61. Pang LM, Stalcup SA, Lipset JS, et al. Increased circulating bradykinin during hypothermia and
cardiopulmonary bypass in children. Circulation 1979;60:1503-1507.
62. Swanson DK, Dufek JH, Kahn DR. Improved myocardial preservation at 4°C. Ann Thorac Surg
1980;30:519-526.
63. Swain JA, McDonald TJ Jr, Balaban RS, et al. Metabolism of the heart and brain during hypothermic
64. Michenfelder JD, Milde JH. The relationship among canine brain temperature, metabolism, and function
during hypothermia. Anesthesiology 1991;75:130-136.
65. Almond CH, Jones JC, Snyder HM, et al. Cooling gradients and brain damage with deep hypothermia. J
P.174
66. Stefaniszyn HJ, Novick RJ, Keith FM, et al. Is the brain adequately cooled during deep hypothermic
cardiopulmonary bypass? Curr Surg 1983;40:294-297.
67. Coselli JS, Crawford ES, Beall AC Jr, et al. Determination of brain temperatures for safe circulatory arrest
during cardiovascular operation. Ann Thorac Surg 1988;45:638-642.
68. Mavroudis C, Greene MA. Cardiopulmonary bypass and hypothermic circulatory arrest in infants. In:
Jacobs ML, Norwood WI, eds. Pediatric cardiac surgery: current issues. Boston: Butterworth-Heineman,
1992.
69. Molina JE, Einzig S, Mastri AR, et al. Brain damage in profound hypothermia: perfusion versus circulatory
arrest. J Thorac Cardiovasc Surg 1984;87:596-604.
70. Wells FC, Coghill S, Caplan HL, et al. Duration of circulatory arrest does influence the psychological
development of children after cardiac operation in early life. J Thorac Cardiovasc Surg 1983;86:823-831.
71. Wright JS, Hicks RG, Newman DC. Deep hypothermic arrest: observations on later development in
children. J Thorac Cardiovasc Surg 1979;77:466-468.
72. Settergren G, Öhqvist G, Lundberg S, et al. Cerebral blood flow and cerebral metabolism in children
following cardiac surgery with deep hypothermia and circulatory arrest: clinical course and follow-up of
psychomotor development. Scand J Thorac Cardiovasc Surg 1982;16:209-215.
73. Dickinson DF, Sambrooks JE. Intellectual performance in children after circulatory arrest with profound
hypothermia in infancy. Arch Dis Child 1979;54:1-6.
74. Clarkson PM, MacArthur BA, Barratt-Boyes BG, et al. Developmental progress after cardiac surgery in
infancy using hypothermia and circulatory arrest. Circulation 1980;62:855-861.
75. Messmer BJ, Schallberger U, Gattiker R, et al. Psychomotor and intellectual development after deep
hypothermia and circulatory arrest in early infancy. J Thorac Cardiovasc Surg 1976;72:495-502.
76. Blackwood MJA, Haka-Ikse K, Steward DJ. Developmental outcome in children undergoing surgery with
profound hypothermia. Anesthesiology 1986;65:437-440.
77. Newburger JW, Jonas RA, Wernovsky G, et al. A comparison of the perioperative neurologic effects of
hypothermic circulatory arrest versus low-flow cardiopulmonary bypass in infant heart surgery. N Engl J Med
1993;329:1057-1064.
78. Bellinger DC, Jonas RA, Rappaport LA, et al. Developmental and neurologic status of children after heart
surgery with hypothermic circulatory arrest or low-flow cardiopulmonary bypass. N Engl J Med
1995;332:549-555.
79. Brunberg JA, Reilly EL, Doty DB. Central nervous system consequences in infants of cardiac surgery
using deep hypothermia and circulatory arrest. Circulation 1974;50(Suppl II):II60-II68.
80. Egerton N, Egerton WS, Kay JH. Neurologic changes following profound hypothermia. Ann Surg
1963;157:366-374.
81. Brunberg JA, Doty DB, Reilly EL. Choreoathetosis in infants following cardiac surgery with deep
hypothermia and circulatory arrest. J Pediatr 1974;84:232-235.
82. Ames A III, Wright RL, Kowada M, et al. Cerebral ischemia. II. The no-reflow phenomenon. Am J Pathol
1968;52:437-453.
83. Robinson RO, Samuels M, Pohl KR. Choreic syndrome after cardiac surgery. Arch Dis Child
1988;63:1466-1469.
84. Wical BS, Tomasi LG. A distinctive neurologic syndrome after induced profound hypothermia. Pediatr
Neurol 1990;6:202-205.
85. Wessel DL, duPlessis AJ. Choreoathetosis. In: Jonas RA, Newburger JW, Volpe JJ, eds. Brain injury and
pediatric cardiac surgery. Boston: Butterworth-Heineman, 1996:353-362.
86. Tharion J, Johnson DC, Celermajer JM, et al. Profound hypothermia with circulatory arrest: nine years’
clinical experience. J Thorac Cardiovasc Surg 1982;84:66-72.
87. Coles JG, Taylor JM, Pearce JM, et al. Cerebral monitoring of somatosensory evoked potentials during
profoundly hypothermic circulatory arrest. Circulation 1984;70(Suppl I):I96-I102.
88. Ehyai A, Fenichel GM, Bender HW Jr. Incidence and prognosis of seizures in infants after cardiac
surgery with profound hypothermia and circulatory arrest. JAMA 1984;252:3165-3167.
89. O’Dougherty M, Wright FS, Garmezy N, et al. Later competence and adaptation in infants who survive
severe heart defects. Child Dev 1983;54:1129-1142.
90. Rappaport LA, Wypij D, Bellinger DC, et al. Relation of seizures after cardiac surgery in early infancy to
neurodevelopmental outcome (Boston Circulatory Arrest Study Group). Circulation 1998;97:773-779.
91. Kern FH, Greeley WJ. Con: monitoring of nasopharyngeal and rectal temperatures is not an adequate
guide of brain cooling before deep hypothermic circulatory arrest [Editorial Pro-Con]. J Cardiothorac Vasc
Anesth 1994;8:363-365.
92. Bellinger DC, Wernovsky G, Rappaport LA, et al. Cognitive development of children following repair of
transposition of the great arteries using deep hypothermic circulatory arrest. Pediatrics 1991;87:701-707.
93. Kirshbom PM, Skaryak LA, DiBernardo LR, et al. Effects of aortopulmonary collaterals on cerebral
cooling and cerebral metabolic recovery after circulatory arrest. Circulation 1995;92(Suppl II):II490-II494.
94. Rodriguez RA, Austin EH III, Audenaert SM. Postbypass effects of delayed rewarming on cerebral blood
flow velocities in infants after total circulatory arrest. J Thorac Cardiovasc Surg 1995;110:1686-1691.
95. Martin TC, Craver JM, Gott JP, et al. Prospective, randomized trial of retrograde warm-blood
cardioplegia: myocardial benefit and neurologic threat. Ann Thorac Surg 1994;57:298-304.
96. Mora CT, Henson MB, Weintraub WS, et al. The effect of temperature management during
cardiopulmonary bypass on neurologic and neuropsychological outcomes in coronary revascularization
patients. J Thorac Cardiovasc Surg 1996;112:514-522.
97. Dietrich WD, Busto R, Valdes I, et al. Effects of normothermic versus mild hyperthermic forebrain
ischemia in rats. Stroke 1990;21:1318-1325.
98. Mitani A, Kataoka K. Critical levels of extracellular glutamate mediating gerbil hippocampal delayed
neuronal death during hypothermia: brain microdialysis study. Neuroscience 1991;32:661-670.
99. Thong WY, Strickler AG, Li S, et al. Hyperthermia in the forty-eight hours after cardiopulmonary bypass.
Anesth Analg 2002;95:1489-1495.
100. Clark JA, Bar-Yosef S, Anderson A, et al. Postoperative hyperthermia following off-pump versus on-
pump coronary artery bypass surgery. J Cardiothorac Vasc Anesth 2005;19:426-429.
101. Tabbutt S, Ittenbach RF, Nicolson SC, et al. Intracardiac temperature monitoring in infants after cardiac
surgery. J Thorac Cardiovasc Surg 2006;131:614-620.
102. Yan T, Bannon P, Bavaria J, et al. Consensus on hypothermia in aortic arch surgery. Ann Cardiothorac
Surg 2013;2:163-168.
103. Tönz M, Mihaljevic T, von Segesser LK, et al. Normothermia versus hypothermia during
cardiopulmonary bypass: a randomized, controlled trial. Ann Thorac Surg 1995;59:137-143.
104. Tönz M, Mihaljevic T, Pasic M, et al. The warm versus cold perfusion controversy: a clinical
comparative study. Eur J Cardiothorac Surg 1993;7:623-627.
105. Lehot JJ, Villard J, Piriz H, et al. Hemodynamic and hormonal responses to hypothermic and
normothermic cardiopulmonary bypass. J Cardiothorac Vasc Anesth 1992;6:132-139.
106. Engelman RM, Pleet AB, Rousou JA, et al. Influence of cardiopulmonary bypass perfusion temperature
on neurologic and hematologic function after coronary artery bypass grafting. Ann Thorac Surg
1999;67:1547-1556.
107. Guadino M, Zamparelli R, Andreotti F, et al. Normothermia does not improve postoperative hemostasis
nor does it reduce inflammatory activation in patients undergoing primary isolated coronary artery bypass. J
108. Grigore AM, Mathew J, Grocott HP et al. Prospective randomized trial of normothermic versus
hypothermic cardiopulmonary bypass on cognitive function after coronary artery bypass graft surgery.
Anesthesiology 2001;95:1110-1119.
109. Heyer EJ, Adams DC, Delphin E, et al. Cerebral dysfunction after coronary artery bypass grafting done
with mild or moderate hypothermia. J Thorac Cardiovasc Surg 1997;114:270-277.
110. Guadino M, Martinelli L, DiLella G, et al. Superior extension of intraoperative brain damage in case of
normothermic systemic perfusion during coronary artery bypass operations. J Thorac Cardiovasc Surg
1999;118:432-437.
111. Mora CT, Henson MB, Weintraub WS, et al. The effect of temperature management during
cardiopulmonary bypass on neurologic and neuropsychologic outcomes in patients undergoing coronary
revascularization. J Thorac Cardiovasc Surg 1996;112:514-522.
112. Swaminathan M, East C, Phillips-Bute B, et al. Report of a substudy on warm versus cold
cardiopulmonary bypass: changes in creatinine clearance. Ann Thorac Surg 2001;72:1603-1609.
113. Grocott HP, Newman MF, Croughwell ND, et al. Continuous jugular venous versus nasopharyngeal
temperature monitoring during hypothermic cardiopulmonary bypass for cardiac surgery. J Clin Anesth
1997;9:312-316.
114. Grigore AM, Grocott HP, MathewJP, et al. The rewarming rate and increased peak temperature alter
neurocognitive outcome after cardiac surgery. Anesth Analg 2002;94:4-10.
115. Shum-Tim D, Nagashima M, Shinoka T, et al. Postischemic hyperthermia exacerbates neurologic injury
after deep hypothermic circulatory arrest. J Thorac Cardiovasc Surg 1998;116:780-792.
116. Amir G, Ramamoorthy C, Riemer RK, et al. Deep brain hyperthermia while rewarming from hypothermic
circulatory arrest. J Card Surg 2009;24:606-610.
Chapter 9
Surgical Myocardial Protection
Jakob Vinten-Johansen
Neil J. Thomas
INTRODUCTION
The science of myocardial protection had its beginnings in the 1950s, and has enjoyed a robust and often
controversial development since. Great strides were made in the 1980s and 1990s which shaped the
cornerstones of the cardioplegia strategy that we largely use today (crystalloid or blood, warm, tepid or cold,
continuous or intermittent, antegrade or retrograde). Mortality has substantially decreased over the past decades
as a result of applying cornerstone as well as novel cardioprotective strategies and new technologies.
However, the patient of the 1980s and 1990s during which cardioplegia was developed has morphed
considerably in the 2000s. Active lifestyles have changed to more sedentary lifestyles beginning in the early
school years with less emphasis placed on physical activity, and more distractions from active lifestyles imposed
by the digital-age gadgets. This, coupled with the availability of fast food with high caloric, high fat, and high
sodium content, has conspired to radically change our body habitus and biology; indeed, diabetes, obesity,
hypercholesterolemia, and the metabolic syndrome are more prevalent today. These more prevalent
comorbidities have impacted the efficacy of modern surgical therapies and the outcomes (1) of myocardial
protection strategies. Experimental animal models in which effective cardioplegia strategies were developed
decades ago, and observed to be effective in the healthier patients with normal myocardial tissue substrate
preoperatively in which they were initially tested clinically seems to apply in fewer and fewer patients today. The
“one formula-fits-all” strategies of the past must be rethought in the current era. With patients living longer as
well, advancing age and the more senescent myocardium can display altered responsiveness to some
therapeutics. So we may ask, is myocardial protection developed in the 1980s and 1990s being used as
effectively on the patient of the 2010s? And, furthermore, the yardstick by which our results are measured is
changing in the world of health care today, where a 30-day surgical mortality rate may no longer be the gold
standard. Our results must now be viewed in terms of longer-term, event-free survival and with measure of long-
term myocardial performance after an index event or surgery.
The concepts of cardioprotective strategies have changed significantly as our understanding of the
pathophysiologic determinants of ischemia, and particularly the complex mechanisms involved in reperfusion,
have expanded. Early empiric, largely physiologic observations have given way to complex biochemical and
molecular interactions, which in some cases have reinforced physiologic intuition and in other cases have
redirected our thinking, but has nonetheless provided a scientific underpinning to a more molecular approach in
developing target-specific strategies of myocardial protection. This chapter will discuss the pathobiology of
ischemia-reperfusion injury, provide the basis by which the severity and duration of evolving ischemic conditions
set the stage for reperfusion and oxygen-related injury and its impact on affected tissues as a basis for
understanding cardioprotective strategies to attenuate injury. It will also discuss new, emerging concepts of
myocardial protection that have developed out of a better understanding of the pathobiology of ischemia-
reperfusion injury, and a growing appreciation that the preoperative condition of the tissue may be equally, if not
more important, than any intraoperative strategy employed in previously normal tissue. It will also discuss the all-
elusive “golden ring” of arresting the heart in a nondepolarized state.
The goal of this chapter is to provide the reader with scientific and practical knowledge of myocardial protection
that can be applied to design appropriate strategies to meet the need of specific patients, their unique
demographics and clinical scenarios, and to provide flexibility in the approach based on both preoperative
condition and intraoperative events. It will also provide some guided reading to enhance the background of
relevant topics
HISTORICAL PERSPECTIVES ON MYOCARDIAL PROTECTION AND

REPERFUSION INJURY
The need to protect the myocardium from intraoperative and postoperative damage was realized before the
development of cardiopulmonary bypass (CPB). Temporary inflow occlusion techniques to limit blood flow to the
heart permitted the
P.176
repair of simple intracardiac defects, and in many cases the occlusion time could be increased by adding
moderate systemic hypothermia (30°C) (2). After the development of CPB by Gibbon and colleagues in 1954
(3,4), profound systemic hypothermia could be used safely to provide a hemodynamic safety net, and to provide
protection of the heart and other body organs by permitting longer periods of ischemic cardiac arrest for the
repair of more complicated lesions.
The development of extracorporeal circulation techniques allowed cardiac procedures to proceed without threat
of hemodynamic collapse. However, performing complicated procedures on the heart was made difficult by its
continuous motion and blood in the field. Ischemia was known to achieve cardiac arrest (ischemic or anoxic
arrest) through the depletion of high-energy phosphate stores on which cardiac contraction depends. However,
myocardial ischemia led to necrosis and contractile dysfunction upon reperfusion, the worst of which was an
irreversible “stone” heart (5,6). The conundrum of surgeon convenience at the expense of acceptable outcomes
provided a driving force for innovation.
Once the severe complications of ischemic arrest were recognized, chemical methods were used to arrest the
heart. Based on reports from Ringer in 1883 that high concentrations of potassium would arrest the heart (7),
Melrose and associates in 1955 (8) and 1957 (9) used hyperkalemia to induce asystole during CPB. The
combination of immediate arrest and hypothermia would ostensibly reduce energy (i.e., oxygen) demands of the
heart, and thereby avoid injury imposed by hypothermia alone. Melrose made a hyperkalemic solution by mixing
potassium citrate solution (77 mM) with 18 mL of blood, which was then infused by hand-held syringe into the
aortic root proximal to the aortic cross-clamp. This hyperkalemic arresting solution was later called “cardioplegia”
solution by Lam et al. (10) and Sergeant et al. (11). Other contemporaries of Melrose used alternative arresting
agents, such as acetylcholine alone (10,11) or in combination with other drugs (12).
Although asystole was indeed achieved with the Melrose potassium citrate solution, the concept of elective
cardiac arrest was abandoned in the United States for some 20 years following reports of high morbidity and
pathologic complications in chemically arrested hearts (13). Chemical cardioplegia was supplanted by alternative
techniques of arresting the heart or limiting blood flow in the surgical field, including ventricular fibrillation,
intermittent aortic cross-clamping, and profound systemic (14) or topical hypothermia (15). Laboratory studies
demonstrated that topical hypothermia protected inadequately against intraoperative injury, which resulted in
postoperative myocardial subendocardial necrosis, and postischemic metabolic and functional depression
(16,17,18). In the late 1960s, reports described scattered myocardial or subendocardial necrosis in patients who
had died after otherwise technically successful cardiac surgical operations, suggesting that the current
techniques of myocardial protection were inadequate (19,20). This set the stage for a later re-emergence of
chemical cardioplegia in the United States.
During the surgeon-imposed moratorium on the use of the Melrose solution, cardioplegia solutions continued
development and clinical use in Europe. Bretschneider et al. (16) and Kirsch et al. (17) used crystalloid
formulations which mimicked intracellular ionic concentrations (intracellular crystalloid solutions). The
Bretschneider HTK (histidine, tryptophan, α-ketoglutarate)-ketoglutarate) solution used low calcium, low sodium,
and procaine with histidine buffers to achieve a nondepolarized arrest, rather than hyperkalemia-induced
depolarized arrest. In the 1970s, Hearse and associates (18,21) at St. Thomas’ Hospital in London developed an
extracellular hyperkalemic solution based on a rigorous series of experiments that established a scientific
understanding of the determinants of injury incurred during global ischemia. Braimbridge introduced St. Thomas’
cardioplegia solution into clinical use in 1975 (22). St. Thomas’ solution was later modified based on further
experimental studies to the St. Thomas’ solution No. 2 (23), an intracellular ionic concentration, normocalcemic,
and hyperkalemic (16 mmol/L) solution; it is currently marketed as Plegisol in the United States. The
Bretschneider HTK solution is currently marketed as Custodiol HTK solution.
Chemical cardioplegia was revived in the United States by Gay and Ebert (24) and Tyers et al. (25,26), who
found that the constituents in the Melrose formulation were inappropriate rather than the concept of hyperkalemic
chemical cardioplegia itself being erroneous. These reports popularized the use of potassium-based cardioplegia
to achieve electromechanical arrest. In the late 1970s and early 1980s, Follette and colleagues from Dr.
Buckberg’s laboratory (see reference 224 below) introduced the concept of cold hyperkalemic blood
cardioplegia. The physiologic attributes of blood, including its superior buffering capacity, endogenous oxygen
radical scavengers, detoxifying substances, and superior oxygen-transport capacity, has established this
concept as a popular strategy that has facilitated surgery and vastly improved patient outcomes. Today, a variety
of both crystalloid and blood cardioplegia solutions are used clinically worldwide to achieve elective cardiac
arrest and a bloodless field.
The cornerstones of myocardial protection that had been laid by the end of the early 1980s are: (1) rapid
chemical arrest to conserve high-energy phosphate stores and reduce ischemia, (2) hypothermia to reduce the
metabolic rate, (3) adjunctive agents to reduce the effects of ongoing ischemia (anti-ischemic agents), and (4)
continuous or intermittent delivery to restore or maintain tissue oxygenation. Further developments in
cardioplegia-related myocardial protection strategies focused on (1) optimizing delivery (retrograde, gentle
cardioplegia delivery pressures), (2) overcoming the adverse effects of hypothermia, (3) identifying metabolic
enhancements (ATP generation and pH management) and buffers, (4) managing calcium (Ca2+) accumulation,
and (5) understanding the pathophysiology
P.177
of ischemia and reperfusion, which would drive further developments of strategies to avoid these mechanisms of
both ischemic and postischemic patterns of injury. There has also been a persistent search for agents that
induce polarized arrest which overcome the disadvantages of hyperkalemia (reviewed in Dobson et al. (27) and
Maruyama et al. (28)). With the recent rapid developments in molecular and cellular biology, experimental focus
has shifted away from the organ and physiologic aspects toward cellular and molecular areas to improve the
understanding of the effects of ischemia-reperfusion injury, inflammation, and cell death processes.
Understanding the mechanisms involved in the transition to cell death would direct developments in Ca2+
handling and preventing Ca2+ dyshomeostasis, the role of oxidant injury, and a newly recognized role of
mitochondria in determining the transition from reversible to irreversible injury, and whether the cell pursues a
necrotic pathway or apoptotic pathway to cell death. Finally, the concept of conditioning, which recruits complex
endogenous biologic mechanisms of self-protection against stressors such as ischemia-reperfusion injury,
oxidants and apoptosis, has been incorporated into pretreatment (preconditioning), intraoperative
(preconditioning), and reperfusion (postconditioning) phases of cardiac surgery. Although human beings have
been evolving for hundreds of thousands of years, it has only been in the past 60 years or less that the human
heart has been subjected to the kind of induced ischemia and surgical reperfusion discussed in these pages.
PATHOPHYSIOLOGY OF SURGICAL ISCHEMIA-REPERFUSION INJURY

Because many factors affect postoperative outcomes of hearts with various and complex preoperative
pathophysiologic features, developing strategies that adequately protect all hearts during cardiac surgery is often
problematic. The heart under consideration may present a complex picture of preoperative disease, variable age,
gender, metabolic and cellular dysfunction, global or regional ischemia (both acute and chronic), each of which
contribute to differing vulnerabilities to ischemia and reperfusion injuries. However, adequate myocardial
protection must be based on a sound scientific basis. Obviously, a single cardioprotective strategy may be
inadequate to suit all surgeon preferences and target all patient pathologies. Hence, the surgical team must often
mold the composition of the cardioplegic solution or its modality of delivery to meet the requirements of the
patient’s pathologic profile as presented. The measures taken to protect the heart during elective cardiac arrest
should represent a balance struck between the requirements of the heart during aortic cross-clamp or
reperfusion, with appropriate adjustments made for special considerations (hypertrophy, diffuse coronary
disease), and avoid distraction from the surgical procedure. Ischemia and reperfusion injury (29) and the choice
of cardioplegia technique (30) represent primary contributors to patient outcomes.
Ischemic Injury
When Does Ischemia and Reperfusion Injury Occur during Cardiac Surgery?
It is critical for the surgical team to understand that the presence of acute, ongoing and evolving or progressing
ischemia must impact the protection strategy. Ischemia-reperfusion injury can occur in the surgical setting at
three major time points during the surgical procedure (summarized in Fig. 9.1). (a) Before CPB has been
instituted or cardioplegia solution has been delivered: “Unprotected” clinical ischemia before CPB usually
results from the presenting acute coronary syndrome and can be exacerbated by hypotension, arrhythmias (e.g.,
atrial or ventricular fibrillation), and other hemodynamic changes (e.g., cardiogenic shock, coronary artery
spasm). In most cases, acute ischemia is active in both the distribution of the principally involved artery
(cardiologists call this the “infarct artery”) but also distributions in which preexistent collateral flow may be
compromised. Patients referred for bypass surgery in these circumstances almost always have multi-vessel
disease patterns making the myocardial substrate dangerous from the standpoint of the severity and duration of
the syndrome, which can be extremely difficult if not impossible to determine. Reperfusion and reoxygenation
injury occur when these conditions change abruptly before effective measures are implemented. Recent
attention has been paid to avoiding over-oxygenating such patients systemically, and this will be discussed in
more detail in later sections.
FIGURE 9.1. Events occurring before the institution of cardiopulmonary bypass, during delivery of cardioplegia
and at reperfusion that predispose the myocardium to ischemia and reperfusion injuries. Arrhythmias, ventricular
fibrillation (VF) or severe hypotension can cause antecedent global ischemia. During the delivery of cardioplegia,
the composition of the solution can cause edema, further ischemia if oxygen and nutrients are inadequate to
meet ongoing albeit lower demands, and Ca2+ concentration is either too high or too low. Coronary obstructions,
air or low cardioplegia infusion pressure can lead to maldistribution of solution. Too high infusion pressure can
lead to microvascular injury and edema. Potassium itself has negative effects secondary to placing the cell in a
depolarized state. Ischemia may be encountered if air emboli, graft kinks, tight anastomoses, or systemic
hypotension cause inadequate distribution of blood flow. Finally, reperfusion injury can cause reversible
(stunning, arrhythmias, edema) or irreversible (necrosis, apoptosis) injury.
P.178
(b) At the initiation of cardiopulmonary bypass: At the moment bypass is initiated, blood is immediately diverted
from the right atrial drainage system into a venous reservoir where it is then pumped through the oxygenator.
This configuration does more to the heart than merely oxygenate venous blood and send it back to the
ascending aorta. As the heart is emptied into the venous side of the pump, the oxygen demand of the
metabolizing myocardium decreases by 50%, but the high oxygen content of blood extracorporeally oxygenated
makes the tissue vulnerable to reoxygenation damage if no steps are taken to mitigate this injury. This might be
viewed as an abrupt interruption of antecedent ischemic conditions. While this is one of the principal goals of
bypass (to give the heart a “rest”), it must be recognized that the heart is also vulnerable to a pattern of injury
that has been, at best, underappreciated in the past. Ihnken et al. (31) suggested as early as 1998 that initiation
of bypass is also, perhaps paradoxically, a dangerous moment for the heart. In this work, he observed clear,
reproducible biochemical evidence of injury in samples of blood drawn from the coronary sinus. Since Buckberg
(32) published his work on the reoxygenation injury in 1995, it has been observed that abrupt over-exposure of
the ischemic heart to oxygen increases injury in a pO2-dependent pattern of injury that can be mitigated by
altering the oxygen tension of the perfusate.
(c) During the “protected” period of arrest and delivery of cardioplegia: Ischemia or reperfusion injury can occur
during the cardioplegia phase. Ischemia can develop or be worsened under several circumstances (1) the
unintentional maldistribution of cardioplegia solution distal to stenotic or totally occluded coronary arteries, (2)
between intermittent infusions of cardioplegia solution, (3) during interruption of continuous cardioplegia
strategies, (4) inadequate delivery of retrograde cardioplegia to areas of the right heart whose venous blood
drains directly into the Thebesian system, or areas that are simply under-filled due to malposition of a retrograde
delivery device. Though the cardioplegia phase is considered “protected time,” the potential for worsening of, or
the development of, ischemic conditions followed by reperfusion injury can occur with the initial administration of
cardioplegia and with each subsequent delivery of cardioplegia solution [(re)perfusion] for a variety of reasons:
(1) excessive pressure (microvascular injury), (2) low onconicity favoring extravasation of fluids into the
extracellular space, (3) formation of oxygen radicals from over-oxygenation and oxidative stress, and (4) other
mechanisms of reperfusion injury as discussed below. While delivery of cardioplegia should provide protection,
this phase also offers opportunity for additional injury to occur unintentionally. Any surgeon who has been faced
with postoperative low-cardiac output and who suspects inadequate protection knows this to be true.
(d) After release of the cross-clamp and attempts to reanimate the heart: Additional ischemia may be
encountered at the release of the cross-clamp when (1) coronary blood flow is impaired through kinked grafts or
(2) tight anastomoses (3) air emboli are present in the coronary arteries, (4) ventricular fibrillation occurs at low
perfusion pressures, or (5) poor ventricular performance or dysrhythmias cause hypotension once the heart is
converted and off bypass. Clearly, when the clamp is removed reperfusion injury can occur as blood flow is
restored and oxygen exposure is reestablished after any of the above events. In terms of surgically induced
ischemia, this is intuitively the major time when one thinks of reperfusion injury occurring .
Understanding the pathophysiologic mechanisms of myocardial injury occurring at these intervals and applying
the principles of myocardial protection will help avoid injury induced by the very techniques intended to preserve
the myocardium. Unlike the cardiologist, the surgical team has the opportunity to intervene directly to control
many facets of ischemia and reperfusion injury, and to limit at some point the mechanisms causing injury, thereby
more favorably directing the outcome of the postischemic heart. The pathophysiology of ischemia and
reperfusion is described in the following sections. Interventions targeting these various pathologic processes are
discussed under Myocardial Protection Therapy.
Determinants of Ischemic Injury

Ischemia encountered either before arrest or during cardioplegic arrest, is a major cause of postcardioplegia
injury. Ischemia sets the stage for reperfusion injury; without ischemia you cannot have reperfusion injury.
Ischemia is defined as inadequate energy supply to meet the current demands, that is, an energy supply/demand
ratio of less than 1; normally, the O2 supply/demand ratio is >1. Since the adenosine triphosphate (ATP)
necessary to support the energetic needs of the heart is provided predominantly by oxidative phosphorylation,
with scant generation of high-energy phosphates through anaerobic metabolism, the heart is nearly an obligate
aerobic tissue. Therefore, the energy consumption of the heart can be approximated by the oxygen consumption.
The limited availability of anaerobic energy-generating pathways mandates that O2 be in constant supply. A very
brief discussion of the determinants of O2 supply and demand follows.
Oxygen supply: Ischemia may be caused by either a decrease in O2 supply relative to demands (supply
ischemia) or an increase in O2 demands relative to supply (demand ischemia). O2 supply is determined by the
O2 extraction (arterial-coronary venous O2 difference) and coronary blood flow. Since O2 extraction by the heart
is normally ˜75%, and its physiologic limit is approximately 95%, only limited amounts of oxygen may be obtained
through additional extraction. The majority of O2 is therefore supplied by adjustments in coronary blood flow,
which under normal conditions may increase 4- to 5-fold to meet demands. This O2 is largely present as
hemoglobin-bound, with only a minor fraction (˜1.5%) dissolved in plasma. This limited dissolved O2 will become
important when we discuss crystalloid cardioplegia solutions in which oxygen availability is limited to that
dissolved in solution.
P.179
Oxygen demand: Overall myocardial oxygen demand of the normal working heart is determined by the work of
the entire heart. The majority of this overall O2 consumption is attributed to utilization by the left ventricle. In a
nutshell, the determinants of left ventricular O2 demand include pressure-volume work or wall stress, heart rate,
temperature, inotropic state, basal metabolism, and ionic homeostatic mechanisms (ATP-dependent pumps)
required to re-equilibrate ionic balance after electromechanical activity. In the immediate postoperative heart,
energy demands may be related to oxidative energy diverted to myocyte repair.
The energy related to maintain ionic equilibrium (˜5% of total demand) is an ongoing demand even when the
heart is not contracting since ATP-dependent pumps are constantly adjusting calcium and sodium influx, as well
as potassium efflux. This energy demand of ionic equilibration is important in determining ongoing oxygen
demands in the arrested heart, as discussed below. How oxygen demands are changed by hypothermia is
discussed later.
Severity and Duration of Ischemia in Cardiac Surgery

The potential for myocardial injury is related, in part, to the duration of ischemia. The time to onset of irreversible
ischemic injury will depend on many factors, including the severity of ischemia, myocardial temperature, ambient
energy demands, and collateral blood flow. However, irreversible injury can become apparent after as little as 30
to 45 minutes of coronary occlusion in the working myocardium. However, shorter durations of global ischemia
can result in mild to severe systolic and diastolic dysfunction without irreversible tissue necrosis (left ventricular
“stunning” (33)). Therefore, the duration of ischemia, both preceding CPB and intraoperatively after application
of the cross-clamp, has often been used as a predictor of postoperative myocardial injury in experimental
models, and is one of the underlying considerations in the correlation between total ischemic time (CPB,
cardioplegia) and clinical outcomes. Because the surgical team often does not have control over the duration of
warm ischemia (particularly antecedent ischemia caused by coronary occlusive disease), other aspects of
elective ischemic time are more often targeted for modification to reduce the severity of ischemia and hence
postischemic injury. Therefore, strategies such as (1) initiating rapid asystole, (2) venting the left ventricle to
reduce consequences of chamber distension resulting in increased wall stress, and (3) imposing cardiac
hypothermia all specifically target the reduction of myocardial energy/oxygen demands, thereby increasing the
limits of “safe” ischemic time during aortic cross-clamping. With these cardioprotective strategies in place, the
duration of aortic clamping that can be safely imposed can be increased from as little as 15 to 45 minutes to
several hours using hypothermic cardioplegia (Fig. 9.2). Reducing to almost zero the determinants of myocardial
work and oxygen demand is the sine qua non of myocardial protection. In the section on future directions,
eliminating ischemic conditions without additional oxygen-related injury and changing the milieu more gradually
will be discussed.
FIGURE 9.2. Left ventricular performance measured by in situ Starling curves (A) or end-systolic pressure-
volume relations (conductance catheter) (B) after 45 minutes of normothermic unprotected global ischemia and
reperfusion. C: Left ventricular stroke work index in patients before (Baseline) or after (pCPB) 15 minutes, or 4
and 24 hours postcardiopulmonary bypass (CPB). The dashed line between 4 and 24 hours after
discontinuation of CPB represents further decreases in cardiac performance secondary to onset of irreversible
injury. (A, adapted from Rosenkranz ER, Buckberg GD. Myocardial protection during surgical coronary
reperfusion. J Am Coll Cardiol 1983;1:1235-1246, with permission.)
The determinants of surgical ischemic injury can be summarized as:
The duration and severity of antecedent” and “unprotected” ischemia: Although it has been recognized for
decades that ischemia time (duration) impacts tissue injury and postischemic salvage and function, an
increasing appreciation for the caveat that the manner in which the tissue is reperfused significantly alters the
outcome. It is now increasingly understood that reperfusion injury can occur
P.180
by merely eliminating ischemic conditions abruptly or in the presence of an inappropriate oxygen gradient. In
the case of the imposition of aortic cross-clamping, there is total elimination of native flow with the exception of
that supplied by noncoronary collateral flow. Global contractile function may be impaired before necrosis or
apoptosis are evident (“stunning”). It is the reduction of myocardial oxygen demand that protects the heart in
this circumstance.
The elimination of electromechanical activity during cross-clamping is paramount because its mechanical
activity increases O2 demands even in the presence of hypothermia (discussed further in the section on
Hypothermia).
Myocardial temperature: Temperature influences metabolism by the “Q10 effect,” in which the tissue
metabolic rate decreases by half for each 10°C decrease in temperature; conversely, myocardial metabolism
doubles when the heart rewarms by 10°C. Hypothermia can buy biologic time during ischemia.
The nutritional and stress status of the heart: For example, catecholamines increase the O2 demands by
increasing contractility and exerting an O2 wasting effect.
Presentation of comorbidities such as hyperlipidemia which increase the vulnerability to ischemia-reperfusion

injury for any given duration of ischemia. This effect is independent of energy demands, but is influenced more
by mechanisms exerted at reperfusion, that is, the capacity to generate O2 radicals, a pro-inflammatory state
of the endothelium and inflammatory cells, and calcium handling by the tissue.
Determinants of Reperfusion Injury

Although reperfusion of the myocardium is the ultimate goal of both surgical and nonsurgical revascularization,
abrupt reperfusion carries with it the potential for extending postischemic injury to cardiomyocytes, coronary
vascular endothelium, and the microvasculature. Indeed, reperfusion injury associated with rapid changes in
circulatory conditions may be responsible for ˜50% (34) or more of the ultimate infarct size, and is an important
contributor to postsurgical mortality and morbidity as well (29). We can define surgical reperfusion injury as an
incremental increase in the pathology that is observed after ischemic injury alone. Reperfusion injury extends or
accelerates damage from that observed during ischemia alone, and occurs after the onset of reperfusion (i.e.,
cardioplegia) or reperfusion (i.e., cross-clamp removal). Viewed another way, reperfusion injury can occur at the
instant of the elimination of ischemic conditions with reestablishment of flow. Hence, reperfusion injury can be
viewed as representing an increment of injury that had begun during ischemia but progresses or manifests
during the reperfusion phase. Other investigators have described de novo injury starting at reflow or, in a newer
construct, at the time of the elimination of ischemia (even if that is accomplished by a reduction in oxygen
demand). Reperfusion injury can be categorized as either reversible or irreversible. (1) Reversible injury includes
temporary contractile dysfunction (“stunning”) in the absence of morphologic injury or necrosis, or (2)
irreversible, which includes necrosis and apoptosis. Biomarker enzymes such as creatine kinase (CK) or cardiac
troponin T (cTnT) or I (cTnI) released by disrupted cells have been observed to be elevated during reperfusion
rather than during ischemia. In the past, debate has often been spirited regarding whether reperfusion injury
even exists (35,36,37,38) and whether reperfusion injury kills cells that are salvageable at the end of ischemia.
However, a consensus has developed in both the surgical, cardiology, and cardiovascular research communities
that reperfusion is indeed an important component of postischemic cardiac injury in animal models (39) and in
humans (34,40) and that alterations in reperfusion strategies can mitigate injury.
Among the more important mechanisms in the pathophysiology of myocardial ischemia-reperfusion injury are (1)
the duration and severity of antecedent ischemia, (2) oxygen radicals generated not only by neutrophils but also
by myocytes and vascular endothelium, (3) sodium (Na+) and Ca2+ influx and loss of normal intracellular Ca2+
homeostasis, (4) neutrophils and neutrophil-derived products that constitute a generalized inflammatory
response to reperfusion, and (5) mitochondrial dysfunction and opening of the mitochondrial permeability
transition pore (mPTP). Interestingly, the presence of hyperoxic or even relatively hyperoxic conditions can ramp
up or trigger all of these mechanisms. As such, these mechanisms do not operate independently, nor are they
mutually exclusive. Importantly, reperfusion injury is a malleable process that can be attenuated by utilizing a
number of strategies targeting these various perpetrators of injury. In the operating room during cardiac surgery,
and more and more frequently in the modern era in the interventional lab, various forms of circulatory support
techniques and cardioprotective drugs are employed. The realization that circulatory support can manipulate
reperfusion therapy by altering oxygen supply/demand relationships is critical for any operator that employs it.
Such pumps provide an avenue for both the reduction of oxygen demand and for the delivery of therapeutic
agents via the pump, which can be administered intravenously or by using cardioplegia as a vehicle. Using
cardioplegia offers a unique opportunity to modify the conditions of reperfusion (hydrodynamics, temperature,
route of delivery) and the composition of the solution (blood, crystalloid, pH, metabolic substrates, hypocalcemia,
oxygen, pharmaceuticals) that target the pathophysiologic mechanisms of injury. It is now also recognized that
the initiation of circulatory support in it itself offers an opportunity to mitigate injury by paying attention to
conditions at the moment support is begun and ischemic conditions are eliminated.
Reactive Oxygen Species (ROS) and Reactive Nitrogen Species (RNS)

Molecular oxygen is relatively inert by virtue of the shared electron pair in the outer molecular shell. However,
oxygen
P.181
must be viewed as a pharmaceutical and potentially toxic agent in cardiovascular medicine and surgery. ROS
are radicals or unstable oxygen molecules derived from oxygen. Important oxygen radicals are superoxide anion
(-O2) and hydroxyl anion (•OH).OH). However, other oxygen-related molecules that are not technically radicals
are considered biologically reactive nonetheless. An example of this would be hydrogen peroxide (H2O2). In
addition, hypochlorous acid (HOCl) and chloramines derived from neutrophils exert potent oxidative injury to
biologic tissues.
Free-radical molecules that are derived from nitrogen are termed RNS and include nitric oxide (NO•),
peroxynitrite (ONOO-), nitrogen dioxide (NO2•) and nitrosyl hydride (HNO). In vascular endothelium, NO• is
constitutively generated by endothelial nitric oxide synthase (eNOS or NOS-3). eNOS activity is dependent on
Ca2+-calmodulin, flavin, NADPH, and tetrahydrobiopterin (BH4). NO• is generated by an electron from the
guanadino nitrogen of L-arginine to incorporate oxygen to generate NO• and the byproduct L-citrulline. NO• has
an extremely short half-life (seconds) in vivo, and binds tightly to hemoglobin. OONO- is formed by a
nonenzymatic biradical reaction between NO• and -O2. NO• has been linked to biologic signaling in
cardioprotection, particularly anti-inflammatory effects, endothelial function, vasorelaxation (hence its early name
as endothelial-derived relaxing factor, EDRF), neurotransmission, immune regulation and defense mechanisms.
NO• homeostasis is key in normal regulation of blood flow and responses to stress, and in preventing endothelial
dysfunction. NO• homeostasis is a balance between NO• generation, bioavailability, and degradation or
quenching by oxidants such as -O2. NO• has pleiotropic effects in the cardiovascular system by paracrine effects:
(1) NO• is a physiologic regulator of blood pressure and flow, and counteracts local and systemic
vasoconstrictors such as endothelin (ET-1); (2) it inhibits neutrophil adhesion to vascular endothelium; (3) it
inhibits platelet aggregation; (4) it reduces myocardial oxygen consumption (41); (5) it has positive lusitropic and
inotropic effects; (6) it scavenges -O2 and therefore is directly antioxidant; and (7) it is anti-proliferative. The
effects on oxygen consumption and inotropy are somewhat controversial (42,43). The role of NO• in ischemia-
reperfusion injury and cardioprotection is discussed in more detail under the section on endothelial dysfunction
and NO• donors.
Reactive Oxygen Species

The oxygen radical is highly reactive with a broad range of biologic substances including sugars, amino acids,
phospholipids, and DNA. With such a large catalog of biologic targets, ROS and their metabolites are potentially
toxic to cells, and at the same time they are critical in the host defense mechanism and bactericidal activities of
neutrophils and phagocytes (44) and participate in cardioprotective signaling. In this dualistic role of ROS as
good guy-bad guy, it is proposed that low-level production of ROS, particularly from mitochondria, acts as a
signal for cardioprotective conditioning responses (preconditioning, postconditioning) and stimulation of
cardioprotective kinase pathways, while large-scale generation of ROS from inflammatory cells or dysfunctional
mitochondria is deleterious. In the ischemic-reperfused myocardium, ROS-induced injury includes peroxidation of
lipid components of cellular membranes leading to damage to sarcolemmal cell membrane and other
membranous organelles such as mitochondria and sarcoplasmic reticulum (45). ROS also cause the mPTP to
open when generated in an environment of Ca2+ accumulation and normalized pH (conditions achieved during
reperfusion), which leads to a collapse of the membrane potential, loss of metabolic capacity, and release of pro-
apoptotic factors. This is discussed in more detail below under the role of mitochondria in reperfusion injury. The
vascular endothelium is particularly vulnerable to ROS-mediated injury, which manifests as impairment of
vascular endothelial function through attenuated production of vasoactive and anti-inflammatory autacoids such
as adenosine (46,47,48) and NO• (49), and increased production of pro-inflammatory and vasoconstrictive
molecules. These injury mechanisms contribute significantly to postischemic dysfunction, dysrhythmias, and
morphologic injury such as necrosis and apoptosis.
Sources of Oxygen Radicals

Both enzymatic and nonenzymatic reactions produce oxygen radicals. The major reactions and their sources are
shown in Figure 9.3. ROS are generated by a number of sources, including activated neutrophils, cardiac
myocytes, mitochondria, and the vascular endothelium.
Neutrophils: Activated neutrophils represent the major source of ROS in the heart under stress, including -O2,
•OH, and HOCl species. Neutrophils are activated by various chemotactic factors stimulated by either CPB or
ischemia-reperfusion, including the complement anaphylatoxins C3a and C5a, f-Met-Leu-Phe, tumor necrosis
factor alpha (TNFα), interleukin-8 (IL-8), and platelet-activating factor. These factors trigger a “respiratory burst”
of ROS. CPB (independent of ischemia) activates the complement cascade (50,51), with the subsequent
activation and adherence of neutrophils (52) to the vascular endothelium primarily, which subsequently triggers
the release of cytotoxic products, all of which contribute to tissue injury in the ischemic-reperfused myocardium
(52,53). During the respiratory burst that occurs seconds after stimulation by cytokines or ischemia-reperfusion,
the -O2 in the neutrophil is produced by the membrane-associated NADP oxidase, which transfers an electron to
molecular oxygen (Fig. 9.3, reviewed in Sheppard et al. (54)). Production of H2O2 by neutrophils or the reduction
of -O2 to H2O2 by superoxide dismutase (SOD) provides substrate for generation of •OH, or the oxidant HOCl by
myeloperoxidase. HOCl reacts with low molecular weight amines to give rise to lipophilic chloramines, which can
promote membrane lipid peroxidation.
P.182
FIGURE 9.3. The species and sources of reactive oxygen species (ROS) generated by neutrophils,
cardiomyocytes and their mitochondria, and vascular endothelium. SOD, superoxide dismutase; CAT, catalase;
GP, glutathione peroxidase; MPO, myeloperoxidase; HOCl, hypochlorous acid; e-1, electron; NOX, NAD(P)H
oxidase.
Cardiomyocytes: Xanthine oxidase (XO) is a major source of ROS from cardiomyocytes. Normally, XO exists
mostly in the dehydrogenase form and uses nicotinamide adenine dinucleotide (NAD) as an electron acceptor.
Xanthine dehydrogenase is converted to the oxidant-generating enzyme XO during ischemia. Both hypoxanthine
and xanthine accumulate during ischemia. Hypoxanthine is converted to xanthine by XO, which is in turn
converted to uric acid by the same enzyme, which forms -O2. During ischemia, however, two events favor the
xanthine oxidase reaction: (1) hypoxanthine accumulates as a result of the sequential catabolism of purine high-
energy phosphates (ATP, ADP, AMP) and deamination of adenosine, and (2) the dehydrogenase form of the
enzyme is converted to the superoxide-producing oxidase form by a protease activated by increased levels of
intracellular calcium (55). XO is reported to be localized to the vascular endothelium in substantial quantities (56).
However, the importance of XO to the pathologic generation of ROS in humans remains controversial (57).
Mitochondria: Mitochondria are a major noninflammatory site of ROS generation (58). ROS are generated at
complex I (NADH/ubiquinone oxidoreductase) and complex III (ubiquinol/cytochrome c oxidoreductase). The latter
site catalyzes the conversion of O2 to -O2• by a single-electron transfer. -O2 can be converted in the
mitochondrial matrix to H2O2 by matrix superoxide dismutase. Since mitochondria do not have catalase, the H2O2
can be degraded by nonenzymatic reaction with glutathione (GSH) by glutathione peroxidase or by enzymatic
reaction with thioredoxin reductase. The ROS species target cysteine residues on the protein moieties of the
mitochondrial membrane and polyunsaturated fatty acids, and cause intramolecular cross-linkages and protein
aggregates. The •OH causes peroxidation of membrane lipids. ROS induce Ca2+ release from the mitochondria,
which may cause an imbalance in Ca2+ handling and stimulation of Ca2+-dependent proteases, nucleases and
phosphatases leading to functional and morphologic damage to the cell.
Vascular endothelium: Superoxide anion is produced by vascular endothelium by XO as described above for
cardiomyocytes (Fig. 9.3). A more important source of -O2 from the vascular endothelium may be the NAD(P)H
(reduced NAD phosphate) oxidase system. This enzyme is a membrane-bound, flavin-containing NADH/NADPH-
dependent oxidase present in endothelial and vascular smooth-muscle cells. The molecular structure, function,
and regulation are somewhat similar to those of the neutrophil enzyme system, requiring assembly of cytosolic
components onto the membrane components before -O2 generation can occur. However, -O2 production in the
presence of NO• produced by endothelium favors the biradical neutralization and elimination of NO• and the
formation of peroxynitrite (ONOO-). The elimination of NO• impairs not only vascular relaxation and
autoregulatory control of postischemic myocardial perfusion, but also fails to inhibit neutrophil-mediated
postischemic inflammatory responses.
P.183
Other sources of ROS include the oxidation of catecholamines, metabolism of arachidonic acid to peroxy
compounds, and generation of •OH by the cyclooxygenase and lipoxygenase pathways, and by the metal-
catalyzed Haber-Weiss reactions. The latter series of reactions may be important in the setting of CPB because
they can be recruited by neutrophil activation during CPB (59). In addition, iron-containing products released by
hemolysis may facilitate this reaction.
When are Oxygen Radicals Generated?

Myocardial ischemia favors the generation of ROS. However, the myocardium has a cadre of the endogenous
antioxidants superoxide dismutase, catalase, reduced glutathione (GSH), glutathione peroxidase, glutathione
reductase. Normally, upregulation of these antioxidants and phase 2 enzymes reduces oxidant-mediated injury
(60), but they are depleted or can be overwhelmed during ischemia, thereby attenuating the natural defense
mechanisms of the heart (61). Therefore, ischemia creates the biochemical setting for oxyradical production and
tissue vulnerability to ROS-mediated damage. However, the primary substrate, oxygen, is in limited supply during
ischemia, and is not readily available until reperfusion. Oxygen radicals are not seen in great abundance until the
onset of reperfusion. A clinical study by Prasad et al. (62) show that oxygen radicals are released during and 24
hours after CPB in CABG patients. Indirect evidence to support this reperfusion oxidative burst comes from a
wealth of data in which inhibitors or scavengers of oxygen radicals, or anti-neutrophil agents, exerted beneficial
effects when administered during reperfusion.
In the surgical setting, the myocardium may be vulnerable to ROS-induced injury at several points when oxygen
is introduced into the myocardium: (1) the initial delivery of cardioplegia into the heart with antecedent
unprotected ischemia, or initial delivery of oxygenated cardioplegia to a newly revascularized myocardial
segment; (2) intermittent reinfusions of cardioplegia if a multidose strategy is being used; and (3) release of the
aortic cross-clamp to initiate reperfusion after the cardioplegia phase. The quantity of ROS generated during
cardiac surgery depends on the severity of the preceding ischemic injury, activation and recruitment of
neutrophils, the level of oxygen in cardioplegic solutions or blood oxygenated by the extracorporeal circuit, and
the status of endogenous scavengers and inhibitors potentially depleted during ischemia. Blood cardioplegia
theoretically provides a greater oxygen substrate for oxygen radical production than do crystalloid solutions.
However, plasma-dissolved oxygen may be the pool from which oxygen is drawn for the generation of oxygen
radicals, and the oxygen content in this compartment may not differ dramatically between blood and crystalloid
solutions. The oxygen in blood cardioplegia may be reduced with “normoxic” or even “deoxygenated” blood
cardioplegia (63) or during reperfusion (64,65). In addition, blood cardioplegia may offer the advantage of
endogenous antioxidants (superoxide dismutase, catalase, glutathione, and albumin) that are not present in
crystalloid cardioplegia solutions.
Intracellular Na+ and Ca2+ Dyshomeostasis

Under normal physiologic conditions, intracellular Ca2+ concentrations are maintained at low concentrations
(<200 nmol) against a 5,000-fold trans-sarcolemmal gradient by voltage-gated Ca2+ channels that remain closed
until activation during phase 2 of the action potential. The regulation of intracellular and intramitochondrial Ca2+
is tightly linked to regulation of intracellular Na+. Intracellular Na+ concentration is normally controlled by the
ATP-dependent Na+/K+ pump which moves Na+ outward and K+ inward against their respective concentration
gradients, and the energy-independent Na+/H+ exchanger which normally removes one H+ from the cytosol in
exchange for one Na+ moving into the cytosol. Further Na+ accumulation mainly occurs through the Na+/Ca2+
exchanger which normally operates in the forward direction during diastole to extrude intracellular Ca2+ in
exchange for influx of Na+ into the cytosol.
In ischemic-reperfusion myocardium, Ca2+ influx occurs through multiple pathways: (1) diffusion through overt
membrane disruptions or opened Ca2+ channels, fueled by the differential concentration gradient; (2) reversal or
inhibition of the Na+/Ca2+ exchanger driven by the intracellular accumulation of Na+, (3) attenuated cyclical Ca2+
uptake and release from the sarcoplasmic reticulum and mitochondria, and (4) facilitation of entry via α-
adrenoreceptor activation and cyclic adenosine monophosphate (AMP)-dependent processes, which increase
during postischemic catecholamine release.
The accumulation of intracellular Na+ and Ca2+ during ischemia-reperfusion are linked events leading to Ca2+
overload which stimulates Ca2+-dependent proteases that damage membranes and ion transport mechanisms at
the moment of re-exposure to molecular oxygen, opening of the mPTP, depletion of high-energy phosphate
stores, the development of local or global contracture (“stone heart”), and triggers the transition to cell death
through both apoptosis and necrosis. The balanced Ca2+ transport systems are potentially injured by exposure
to oxygen radicals, cytokines, and activated complement during CPB and reperfusion. Na+ and Ca2+
dyshomeostasis occurs to differing degrees during ischemia and during reperfusion, as described below.
Ischemia
During ischemia, glycolysis generates an abundance of H+ and only a limited amount of ATP (2 moles/mole
glucose) compared to oxidative phosphorylation (36 moles ATP/mole glucose). The accumulation of intracellular
H+ stimulates activity of the Na+/H+ exchanger (NHE1) in favor of H+ efflux and Na+ influx; at this time, the
reduced availability of ATP decreases Na+/K+ ATPase activity. Therefore, both the attenuated Na+/K+ pump
activity and increased activity of the Na+/H+ exchanger result in intracellular Na+ accumulation. Additional Na+
may
P.184
enter the cell through sarcolemmal nonactivating Na+ channels, for example, the “window currents” generated
during ischemia-induced cellular depolarization. However, some evidence suggests that the accumulation of H+
in both the extracellular and intracellular spaces attenuates the H+ gradient, thereby reducing but not eliminating
the participation of the Na+/H+ exchange mechanism in intracellular Na+ accumulation during ischemia (66).
However, the accumulation of Na+ in the cytosol during ischemia would favor reversal of the energy-independent
Na+/Ca2+ exchanger in favor of extruding Na+ in exchange for Ca2+ influx, thereby favoring its accumulation in
the cytosol. Entry of Ca2+ into the mitochondria through the Ca2+ uniporter depends on the Ca2+ electrochemical
gradient and the presence of a mitochondrial transmembrane potential. Ca2+ enters the mitochondria during
early ischemia, but further increases and overload are prevented by dissipation of the mitochondrial
transmembrane potential (67). In addition, the unregulated activation of Ca2+-dependent protease enzymes such
as calpains is inhibited by intracellular acidosis, and is delayed until intracellular pH is renormalized during
reperfusion (68). Therefore, Ca2+ accumulation and Ca2+-mediated damage occurs to a greater extent during
reperfusion (69,70,71) as discussed below.
Reperfusion
Na+ and Ca2+ dyshomeostasis during reperfusion is a significant factor contributing to postischemic myocardial
injury and functional impairment (72,73). The ion dyshomeostasis described above sets the stage for explosive
reperfusion/reoxygenation damage. It is increasingly recognized that abrupt re-exposure to oxygen itself is the
trigger for damage. Excessive gradients of perfusate-to-tissue oxygen tension can be mitigated. In addition, the
events leading to abnormal Ca2+ handling which determine cell survival versus cell death are as follows:
Rapid renormalization of intracellular pH: Reperfusion washes out lactate and re-establishes the intracellular-
extracellular H+ gradient (extracellular < intracellular) which allows the forward motion of the Na+/H+
exchanger favoring removal of H+ (renormalization of intracellular pH) and subsequent intracellular
accumulation of Na+; other factors contributing to normalization of intracellular pH are activation of lactate/H+
co-transport mechanism and activation of the NaHCO3 co-transporter.
Renormalization of intracellular Na+: During the initial phase of reperfusion, ATP is regenerated, and if the
Na+/K+ AT-Pase is not damaged by proteolytic actions of calpain enzymes, intracellular Na+ levels are
renormalized and the linked Na+/H+ exchange—Na+/Ca2+ exchange systems will not be activated. Otherwise,
if the Na+/K+ ATPase pump is damaged, intracellular Na+ accumulation will engage the Na+/Ca2+ exchange
mechanism with net intracellular accumulation of Ca2+.
Ca2+ uptake and release by the sarcoplasmic reticulum (SR): The SR is the main Ca2+ storage site of the
cardiomyocytes. Ca2+ in the micro-domain proximate to the closely co-localized SR and interfibrillar
mitochondria is cyclically taken up by the SR (lowering of cytosolic concentration) during diastole, and Ca2+ is
released into that micro-domain by the ryanodine receptors (RyR) during systole. During both unprotected and
protected ischemia, sequestration of Ca2+ into the sarcoplasmic reticulum competes for a limited amount of
ATP. This paradox creates a cycle whereby a high intracellular Ca2+ level binds high-energy phosphates to
further limit ATP availability, which then attenuates the ability of the SR to remove the Ca2+ actively from the
cytoplasm, resulting in a further increase in cytosolic Ca2+. If other Ca2+ handling mechanisms are not
engaged, the release of Ca2+ from the SR RyR may lead to overload. This activity of the SR mechanism may
be related to the severity of ischemia, being less so during short periods of ischemia.
So, what events in the balance of Ca2+ regulation determines if a cell lives or dies during reperfusion? Some
evidence suggests that the timing of normalization of pH and Ca2+ handling mechanisms are important. If pH
normalization occurs before Ca2+ handling mechanisms are restored, then Ca2+ overload, in conjunction with
ROS generation and a normalized intracellular pH environment, will trigger opening of the mPTP causing cell
death. However, if Ca2+ handling mechanisms are restored before pH is normalized, for example, by maintaining
tissue acidosis during early reperfusion, then Ca2+ overload can be avoided. Interestingly, venous blood-based
perfusate has been preliminarily observed to mitigate both over-oxygenation during early reperfusion and
delayed normalization of pH, thereby creating a “permissive acidemia.”
The Inflammatory and Innate Immunity Responses to Ischemia-Reperfusion and Cardiopulmonary

Bypass
Injury mechanisms of ischemia-reperfusion and CPB involve inflammatory and innate immune responses.
Cardiomyocytes generate pro-inflammatory cytokines, chemokines and adhesion molecules that direct the
emigration of inflammatory cells into ischemic-reperfused tissue regions and amplify the inflammatory response.
The following sections will describe the inflammatory process involving neutrophils, pro-inflammatory cytokines,
and complement, and the innate immune response involving toll-like receptors (TLRs).
Neutrophils and Neutrophil-Mediated Injury

Neutrophils play a critical role in the pathogenesis of myocardial reperfusion injury (74,75,76). The inflammatory
component of reperfusion injury requires an interaction between activated neutrophils and vascular endothelium
during the early moments of reperfusion, which is prerequisite to activation of the full local inflammatory cascade.
A well-orchestrated sequence of events mediates the interaction between adhesion molecules on neutrophils
and endothelium. These adhesion molecules are categorized into three families:
The selectins (P-selectin, L-selectin, E-selectin) are glycoproteins involved in the interactions between
neutrophils
P.185
and the vascular endothelium in the early moments of reperfusion (77,78,79). P-selectin is stored in Weibel-
Palade bodies in endothelial cells, and its surface expression is triggered by pro-inflammatory mediators such
as oxygen radicals, thrombin, complement components, cytokines, histamine, and H2O2 released during
ischemia-reperfusion and CPB. IL-8 released from hypoxic endothelial cells also increases the adhesiveness
of endothelial cells for neutrophils (80). P-selectin surface expression peaks after 10 to 20 minutes of
reperfusion, and P-selectin is subsequently shed to soluble fragments in blood. In contrast to P-selectin, L-
selectin is constitutively expressed on the surface of neutrophils and may be the counterligand for P-selectin
during early reperfusion (81). Loose adherence and “rolling” of neutrophils on endothelium involves interaction
with a glycoprotein sialyl Lewisx or a high-affinity glycoprotein ligand termed P-selectin glycoprotein ligand-1
(PSGL-1) (82). The third member of the selectin family, E-selectin, is expressed on the surface of endothelial
cells. It is expressed later in reperfusion (4-6 hours) and may therefore be involved in later events, such as
infarct extension.
The β2-integrins (CD11/CD18 complex) are a family of glycoproteins located on external membranes of
neutrophils. There are three distinct α-chains (CD11a, CD11b, CD11c) and a common β-subunit. Surface
expression of perhaps the major complex CD11b/CD18 is triggered by a number of pro-inflammatory
mediators, including circulating and endothelium-derived (acylated) platelet-activating factor. After initial
tethering of neutrophils by endothelial P-selectin, firm adherence is mediated by interaction with CD11b/CD18
and its counterligand ICAM-1 on the endothelium.
The third family of adhesion molecules is the immunoglobulin superfamily, including ICAM-1 (intercellular
adhesion molecule-1), VCAM-1 (vascular cell adhesion molecule-1), and PECAM-1 (platelet-endothelial cell
adhesion molecule-1). ICAM-1, the counterligand for CD11/CD18 on neutrophils, is constitutively expressed
on endothelial cells and is upregulated by cytokines 2 to 4 hours after myocardial ischemia-reperfusion (83),
coincident with the upregulation of CD11/CD18. Subsequently, a high-affinity bond between the neutrophil
and endothelial cell occurs via integrins (CD11/CD18) on neutrophils and ICAM-1 and ICAM-2 on endothelial
cells. Once the neutrophil has firmly attached to the endothelial surface, it migrates through the endothelial cell
junctions to the myocardium, partly mediated by IL-8. The shedding of L-selectin from the neutrophil and the
presence of PECAM on the endothelium may be required for neutrophil transendothelial migration. The
prerequisite nature of this interaction between neutrophils and adhesion molecules makes anti-neutrophil and
anti-adhesion therapy a potentially effective strategy, as these agents intervene at proximal points in the
cascade (discussed below).
Evidence supporting the rapid accumulation of neutrophils within ischemic-reperfused myocardium following the
neutrophil-endothelial cell interactions was appreciated not only by our laboratory, but also by Sommers and
Jennings (84). We (85,86,87,88,89) and others (90) have demonstrated an association between the extent of
postischemic injury and neutrophil accumulation within ischemic-reperfused myocardium as well as a reduction of
postischemic injury associated with neutrophil suppression. As shown in Figure 9.4, Lefer et al. (91)
demonstrated that neutrophil adherence to coronary artery endothelium occurs in advance of accumulation in
extravascular sites, representing the lag time involved in transmigration of intravascular neutrophils. In addition,
neutrophil accumulation occurs in advance of the development of necrosis, consistent with active neutrophil
participation in cell demise. Brix-Christensen et al. (92) reported that neutrophils accumulated in the hearts and
other organs of neonatal pigs placed on CPB. Therefore, neutrophil accumulation occurs in both postischemic
and post-CPB hearts.
The importance of neutrophils in postbypass reperfusion injury has been well-established in both animal and
human models. The myocardium is exposed to neutrophils during the delivery of intermittent or continuous blood
cardioplegia, or during reperfusion (after cross-clamp removal) following either crystalloid or blood cardioplegia.
Schwartz et al. (93) showed that CPB circuitry directly “primes” neutrophils by depositing C3b on extracorporeal
tubing, leading to neutrophil activation and sequestration. Further evidence for the activation of neutrophils
following CPB was suggested by the finding of increased neutrophil surface expression of CD11b/CD18 and
decreased surface expression of L-selectin on cells circulated in simulated CPB circuits (94,95). Finn et al. (96)
noted in patients undergoing CPB that a rise in circulating IL-8 begins at reperfusion with rewarming of the
patient after systemic hypothermia, and closely correlates with the rise in neutrophil count and circulating
elastase. Similarly, Schwartz et al. (93) and Gessler et al. (97) found higher levels of the pro-inflammatory
mediators soluble IL-6 and IL-8 6 hours after bypass than before bypass.
The time course for the upregulation of neutrophils and various adhesion molecules is equally important in
designing treatment strategies for patients undergoing extracorporeal bypass. In a clinical study, Galiñanes et al.
(98) investigated the perioperative temporal changes in the expression of various neutrophil surface adhesion
molecules, concluding that downregulation of PECAM-1 is an early indicator of neutrophil activation and may
therefore represent a target for therapy aimed at reducing the inflammatory response associated with CPB.
The role of temperature in the activation of neutrophils or other inflammatory mediators following CPB in humans
has been investigated. Hypothermia has been reported to attenuate expression of adhesion molecules in some
models of tissue injury (99,100). Some investigators have reported minimal
P.186
or no difference in neutrophil activation and expression of neutrophil adhesion molecules between normothermic
(34°C-37°C) and hypothermic (28°C-30°C) CPB (101,102), whereas others note an attenuation in the expression
of IL-8 and neutrophil elastase activity during normothermic CPBsurgery (103). Hypothermia has been shown to
delay, but not prevent, the increased expression of adhesion molecules such as CD11b and CD11c (101). When
measured 4 hours after bypass, the levels of IL-1 α, soluble ICAM-1 (sICAM-1), and elastase are higher after
normothermic CPB than after hypothermic CPB (104,105). In conclusion, further research is required to
determine the most appropriate temperature of cardioplegic administration to minimize the deleterious
consequences of neutrophil-mediated damage. Interventions designed to attenuate neutrophil-related myocardial
injury following CPB will be discussed later.
FIGURE 9.4. The postischemic time course of endothelial injury, contractile dysfunction, neutrophil (PMN)
adherence and accumulation in tissue, necrosis, and apoptosis. These events are indicated on the y-axis as a
percent completion of that event (0% not started, 100% is complete). Note that PMN adherence parallels that of
endothelial dysfunction representing PMN-mediated damage. Note also that accumulation in tissue lags behind
adherence representing emigration time. (Data obtained, in part, from Zhao ZQ, Nakamura M, Wang NP, et al.
Dynamic progression of contractile and endothelial dysfunction and infarct extension in the late phase of
reperfusion. J Surg Res 2000;94:133-144.) Apoptosis is a slower process than necrosis as observed by Zhao et
al. (565). (Adapted in part from Lefer AM, Tsao PS, Lefer DJ, et al. Role of endothelial dysfunction in the
pathogenesis of reperfusion injury after myocardial ischemia. FASEB J 1991;5:2029-2034.)
Complement in CPB and Myocardial Reperfusion Injury

The complement cascade, particularly the alternative pathway stimulated by contact activation, is activated
independently by myocardial ischemia-reperfusion and CPB, and contributes importantly to the pathologic
sequelae of CPB (106). Complement fragments such as the anaphylatoxins C3a and C5a are generated and
released both systemically and locally by the ischemic-reperfused myocardium (107). The activation and
migration of neutrophils to ischemic-reperfused myocardium requires stimulation by chemotactic factors, most
notably complement fragments (C3a and C5a), eicosanoid products such as leukotriene B4, and platelet-
activating factor (108,109). Complement fragments (C5a) can be found in lymph from ischemic myocardium
(110), are temporally associated with reperfusion (111), and correlate with increased neutrophil accumulation in
reperfused myocardium. Furthermore, C5a directly stimulates neutrophil -O2 production and enhances
adherence to coronary artery endothelium (112), whereas C3 activates monocyte adherence (113). The
chemoattractant and chemotactic properties of C5a cause progressive generalized vascular leukosequestration
(114) during CPB. The interaction between blood and extracorporeal surfaces also stimulates deposition of C3b
(115), which in turn amplifies the complement alternative pathway to release C3a and C5a, and subsequently
form the membrane attack complex (C5b 9) (115). Accordingly, plasma levels of the anaphylatoxin C5a increase
in patients undergoing CPB (115,116), which activates neutrophils to generate -O2 and promotes adhesion to
endothelial cells, stimulates degranulation of mast cells, stimulates vascular smooth-muscle contraction, and
increases vascular permeability. Complement activation constitutes an early-phase response to CPB, which then
progresses
P.187
to a second, slower response phase in which de novo synthesis of proteins (E-selectin, ICAM, IL-8) and
expression of adhesion molecules on cell surfaces occurs. The magnitude of the complement response has been
linked to the duration of CPB and the type of circuitry used (116). The combined stimuli of myocardial ischemia-
reperfusion and CPB may synergize to exacerbate postischemic neutrophil-mediated inflammatory responses in
patients undergoing CPB for myocardial revascularization.
Actions of Toll-like Receptors

Recent evidence has shown that activation of TLRs is involved in the pathogenesis of reperfusion injury
(117,118). TLRs are transmembrane receptors expressed on endothelial cells, cardiomyocytes, platelets,
monocytes, and neutrophils. Cardiomyocytes participate in the inflammatory and innate immune response to
ischemia-reperfusion by releasing cytokines (TNF α, IL-1 β, IL-6, IL-8, IFN- γ), chemokines, and by expressing
cell surface adhesion molecules. TLRs are pattern recognition receptors (PRRs) that recognize pathogen-
associated molecular patterns (PAMPs) such as LPS or viral RNA on foreign pathogens, and sense endogenous
danger molecules and signals from injured cells. TLRs also recognize and are activated by endogenous ligands
such as danger-associated molecular patterns (DAMPS) (e.g., heat shock proteins, HSP70) induced in cardiac
tissue during stress (119) and cardiac surgery (120,121). Inducible HSP70 has been found in plasma from CABG
patients immediately after surgery (122). ROS may also stimulate TLRs. Ten to eleven human TLRs have been
identified; (123,124) TLR receptor-1, -2, -4, -5, and -6 are located on the cell surface, with TLR-2 and TLR-4
being the most involved in ischemia-reperfusion of the group of TLRs; TLR-2 works with other TLRs in co-
receptor cooperativity to recognize diacyl- and triacyl-lipoproteins, while TLR4 recognizes LPS from gram-
negative bacteria and DAMPs such as HSP70. Neutrophils constitutively express all TRLs except TLR3.
The stimulation of TLRs during ischemia-reperfusion and cardiac surgery can lead to cell injury. Dybdahl et al.
(122) reported the release of HSP70 into the circulation of CABG patients and a concomitant increase in
monocyte TLR-2 and TLR-4 one day after surgery. Human monocytes exposed to HSP70 released IL-6 and TNF
α. Stimulation of TLRs by interaction with DAMPs during ischemia-reperfusion is transduced by numerous
molecular signaling pathways, which ultimately results in the activation and translocation of NF- κB to the
nucleus, where it stimulates gene expression and release of cytokines and innate inflammatory factors. ROS
generated during reperfusion also stimulate TLR-dependent (most likely TLR-4) generation of NF- κB through
the PI3-K/Akt pathway, which suggests cross talk between the TLR and reperfusion injury survival kinase (RISK)
pathways. Inhibitors of TLRs, intermediary pathways, or NF- κB will attenuate ischemia-reperfusion injury.
The Mitochondrial Permeability Transition Pore as a Determinant of Cell Death

Mitochondria are best known for being the power house of the cell, where ATP is generated through oxidative
phosphorylation. However, the mitochondria have been shown to function as a “molecular switch” that governs
cardiomyocyte viability; indeed it is a critical fulcrum point in the transition from reversible to irreversible injury.
Mitochondria can direct the cell to pursue either an apoptotic or a necrotic pathway to cell death. The key event
of this molecular life/death switch is opening of the mPTP. This pore is a transmitochondrial membrane voltage-
dependent and Ca2+-dependent high-conductance channel located in the inner mitochondrial membrane that
permits water and solutes with a mass up to 1.5 kDa to enter the mitochondrion. Under normal physiologic
conditions, the mPTP is in a closed state. It opens in response to high levels of intracellular ROS, Ca2+ and
inorganic phosphate when mitochondria matrix and intracellular pH are in the normal range. The mPTP remains
closed during ischemia because intracellular acidosis and the intracellular levels of Mg2+ and ADP counteract the
opening triggered by ROS and Ca2+. However, the mPTP opens during the early moments of reperfusion (125)
when there is an accumulation of ROS, Ca2+ and inorganic phosphate, and when there is a rapid renormalization
of intracellular and mitochondrial matrix pH (126). The opening of the mPTP increases the permeability of
mitochondria to water and small solutes, causing swelling of the matrix and collapse of the mitochondrial
transmembrane potential that drives oxidative phosphorylation and ATP generation. mPTP opening also
stimulates the release of the pro-apoptotic factors cytochrome c and apoptosis-inducing factor (AIF). The switch
function comes into play based on the availability of intracellular ATP; if ATP is present then the cell pursues an
apoptotic pathway because apoptosis requres ATP. If ATP levels are depleted then the cell pursues a necrotic
pathway. With prolonged antecedent ischemia mPTP is irreversible, but milder or short periods of ischemia
trigger transient reversible opening (127).
PHYSIOLOGIC CONSEQUENCES OF REPERFUSION INJURY

The multiple etiologies of reperfusion injury following nonsurgical or surgical reperfusion can present as
numerous abnormalities in electrophysiology, contractile function, biochemistry, and morphology. Ischemia-
reperfusion injury falls into reversible and lethal injuries. Reversible injury includes impaired contractile and
relaxation mechanics (e.g., low output syndrome) in the absence of cell death (stunning), edema, and
arrhythmias. Lethal injury includes apoptosis and necrosis. Myocardium can transition from reversible to
irreversible injury by increasing the duration of ischemia, or by the advancing penumbra of the reperfusion
“wavefront.” In any event, reperfusion injury begins within the first few minutes of the onset of reperfusion or
even the elimination of ischemic
P.188
conditions due to manipulation of oxygen demand. It progresses over approximately 24 hours in larger animal
models and, presumably, in humans. The clinical manifestations of ischemic-reperfusion injury can be grouped
into the categories listed below.
Reperfusion Dysrhythmias
Benign or more malignant arrhythmias and conduction disturbances may be observed following significant
ischemia followed by reperfusion. Varying degrees of loss of automaticity requiring temporary pacing strategies,
heart block, and arrhythmias manifested as premature ventricular contractions, ventricular tachycardia, or
ventricular fibrillation may be observed. Clearly, with the previous discussion on ionic imbalance, the reader can
appreciate the degree to which the movement of Na+, K+ and Ca2+ ions can be deranged in this type of setting. It
is not at all surprising that postoperative/postprocedure arrhythmias are a frequent complication of both adult and
pediatric cardiac surgery (128,129), acute coronary syndromes and various types of reperfusion therapy, and
such can contribute to postoperative morbidity and mortality. The financial burden of anti-arrhythmic therapy is
significant. Atrial fibrillation is a consequence of cardiac surgery affecting ˜30% or more of all surgical patients,
whose treatment reaches billions of dollars. We will not discuss atrial fibrillation further in this chapter because it
is complex and its relation of cardioprotective strategies is not yet clear. Failure of spontaneous resumption of
sinus rhythm, ventricular fibrillation, and persistence of dysrhythmias requiring direct-current countershock and
anti-arrhythmic therapy are common consequences of inadequate myocardial protection.
A number of mechanisms are involved in the genesis of reperfusion dysrhythmias. First, as with many
reperfusion-related events, the incidence and severity of reperfusion dysrhythmias relate to the severity of the
preceding ischemia and consequent reperfusion injury. The relationship is characterized by a bell-shaped
response curve, in which vulnerability to arrhythmias is maximal after short intervals of normothermic ischemia
induce reversible changes, then decreases as irreversible injury and electrical silence develop with more
prolonged ischemia. Second, an accumulation of intracellular Ca2+ during ischemia may interfere with normal
Ca2+ cycling at the level of the sarcoplasmic reticulum (Ca2+-dependent arrhythmias). Third, oxygen-derived free
radicals such as -O2 and •OH, produced as a respiratory burst by mitochondria, endothelium, or neutrophils
during reperfusion, can damage membrane lipids and various transport proteins involved in ionic homeostasis,
which in turn can precipitate reperfusion-related dysrhythmias (130,131). Current hypotheses merge the Ca2+-
related events and the ROS-related events as “interacting triggers” for reperfusion dysrhythmias. Fourth,
hyperkalemia is also a contributing factor to postoperative arrhythmias (reviewed in Dobson et al. (27)) as
suggested by the correlation found by Ellis and coworkers between potassium concentration in cardioplegia
solutions and the incidence of arrhythmias (132) There is an anatomical hierarchy of sensitivity to potassium,
with the atria being most sensitive and the sino-atrial node and internodal tracts being less sensitive. Differences
in sensitivity to potassium also exist across the ventricular wall at the base and apex of the heart, where
repolarization times are less in the basal epicardium versus the endocardium during hyperkalemia. These
transmural differences in repolarization times may lead to arrhythmias on rewarming and reanimation.
Postischemic Systolic and Diastolic Dysfunction

Reperfusion with unmodified blood following short periods of normothermic regional or global ischemia produces
a severe degree of contractile dysfunction (Fig. 9.2A, B). While short periods of ischemia followed by unmodified
reperfusion may be benign in regard to contractile function, it may be injurious to other targets (endothelium,
mitochondria). Readily reversible (within hours or days) postischemic contractile dysfunction can occur in the
absence of obvious morphologic injury and may therefore be “stunned,” whereas longer periods of ischemia are
associated with both morphologic injury (necrosis, apoptosis) and persistent contractile dysfunction. Previously,
postischemic contractile dysfunction was thought to be attributable to a depletion of high-energy phosphate
supply (i.e., ATP). However, numerous studies have failed to show a direct correlation between postischemic
myocardial ATP levels and contractile function. The ATP turnover rate, roughly approximated by myocardial
oxygen consumption, may be more important as a barometer of oxidative rate than the static tissue level of ATP.
Recently, postischemic contractile dysfunction has been more related to impairment of Ca2+ kinetics in excitation-
contraction coupling and in the sarcoplasmic reticulum (133). In addition to these pathologic origins of
postischemic systolic contractile dysfunction, iatrogenic dysfunction related to CPB per se may occur as a result
of systemic hemodilution (reduced oxygen delivery) and systemic hyperkalemia, or as a result of systemic
hypocalcemia caused by Ca2+ chelating agents in cardioplegia solutions.
Myocardial diastolic characteristics (compliance or chamber stiffness, rate of relaxation) are highly sensitive to
ischemia and reperfusion. In the ischemic myocardial segment, there is a rightward shift in the position of the
end-diastolic pressure-segment length relation, with little change in the shape or curvature of the end-diastolic
pressure-segment length relation, which is consistent with the concept of regional myocardial “creep” (Fig. 9.2A.
Other reports show little or no change in segmental stiffness after up to 1 hour of coronary occlusion (134,135).
In contrast to ischemia, reperfusion is associated with immediate loss of myocardial compliance (135),
characterized by a leftward shift and increase in slope of the
P.189
exponential pressure-segment length relationship (indicating a degree of local “contracture”). A similar pattern is
observed with global ischemia. In several studies in which hearts were sensitized to reperfusion injury by 30
minutes of normothermic ischemia preceding 1 hour of hypothermic (4°C) multidose blood cardioplegia, a
rightward shift in the end-diastolic pressure-dimension relations (dilation) and increased chamber stiffness were
noted after blood reperfusion (136,137) (Fig. 9.2B). Acute increases in postischemic chamber stiffness are
caused by myocardial edema and abnormal Ca2+ handling in the myocardium. A decrease in diastolic relaxation
impairs diastolic ventricular filling, which reduces stroke volume independent of any postischemic or
postcardioplegia abnormalities in inotropic state or contractility.
Myocardial Necrosis
Necrosis is “accidental” injury to the cell in which the cell swells and the sarcolemma bursts. The process of
necrosis does not require energy. In histologic terms, local hypercontracture occurs which is consistent with
contraction bands. Intracellular contents are released into the extracellular space and subsequently into the
circulation. Large molecules such as creatine kinase (MB isoenzyme) and cTnT or cTnI released into the
circulation have been used as biomarkers of cell death by necrosis. In cardiac surgery, infarction is largely
localized to the previously ischemic and revascularized (or non-revascularizable) segments of myocardium.
Global necrosis related to contracture may be observed as stone heart. Release of cardiac enzymes during
surgery above that observed preoperatively suggests that myocardium suffers necrosis (diffuse global or discrete
regional infarction) despite restoration of blood flow, and suggests further that myocardial protection is not
optimal. The ARTS (Arterial Revascularization Therapies Study) trial linked the increased CK release to clinical
mortality (138). The association of increased plasma CK and other markers with clinical outcomes and mortality
has been confirmed by other studies (139,140,141,142,143). A meta-analysis showed that increased release of
plasma biomarkers was associated with 1-year and >3-year risk of mortality (144). CK-MB, cTnI, or cTnT have
often been used in clinical studies as end points to discriminate benefits my myocardial protection strategies.
Apoptosis
In contrast to necrosis, apoptosis (Greek for “dropping off of leaves”) is a form of cell death that is highly
regulated and energy-requiring (145). Cells targeted for apoptosis undergo DNA fragmentation in specific areas
by endonucleases which cause condensation of nuclear material rather than the disintegration seen in necrosis;
the cell begins to break apart in discreet membrane-enclosed vesicles (apoptotic bodies) which results in
shrinkage of the cell, with ultimate phagocytosis by macrophages without disturbing nontargeted cells next door.
The morphologic changes of apoptosis can be observed as after less than 2 hours after exposure to the
stimulus, and can last for 12 to 24 hours. The average adult human will lose between 50 and 70 billion cells each
day by apoptosis. Apoptosis is responsible for cell dropout during development such as resorption of a tadpole
tail, or removal of webbing between the phalanges to define the fingers during fetal development. Likewise,
mature cells that are damaged or dysfunctional are removed by apoptosis. Apoptosis is known to be a major
cause of progressive heart failure (146), local infarction, cardiomyopathy, myocarditis, and ischemia-reperfusion
of the myocardium (147). Apoptosis has been reported in patients undergoing cardiac surgery
(148,149,150,151,152,153). It has been linked to cardiac dysfunction and stunning after cardiac surgery (see an
excellent review by Anselmi et al. (154)). In 2000, Aebert et al. (149) reported that plasma from patients
undergoing CPB caused apoptosis in cultured endothelial cells, suggesting that the substances that induce
apoptosis are carried in the blood likely as cytokines, as well as originating locally.
Apoptosis follows either extrinsic or intrinsic pathways. In the extrinsic pathway, apoptosis is stimulated by FAS
(first apoptosis signal) and inflammatory mediators interacting with membrane receptors. TNFα is a major
stimulator of the extrinsic pathway by interaction with TNFα receptor type 1 (TNF-R1) or 2 (TNF-R2). The FAS-
FAS ligand pathway is engaged when FAS ligand (a member of the TNF family) binds to its cognate FAS
receptor to ultimately stimulate downstream apoptosis-activating proteins (caspases). Some of these factors that
trigger the extrinsic pathway such as IL-6, IL-8, TNFα (155), and FAS are released during CPB and/or chemical
cardioplegia. The intrinsic pathway is stimulated by oxidants, hypoxia and ischemia, and reperfusion. Evidence
suggests that apoptosis is initiated by ischemia, but executed at reperfusion (156,157). Ischemia-reperfusion
stimulated apoptosis processes are regulated by pro (bcl2) and anti (bax) apoptotic proteins; this pro- and anti-
regulatory scheme provides a degree of prevention and reversibility to the demise of the cell, unlike necrosis.
However, the cleavage of downstream cysteine-dependent protease enzymes, notably caspase 8, 9, and 3,
executes the apoptotic cell death program. The extrinsic and intrinsic pathways ultimately converge on the
mitochondria, which undergo either swelling or opening of the mPTP, and release pro-apoptotic cytochrome c
and AIF. The AIF pathway is independent of the caspase activation cascade.
Consistent with the conditions that initiate apoptosis, inhibitors of oxidant generation or activity and, more
recently, inference regarding avoidance of over-oxygenation, can mitigate apoptosis in surgical experimental
models (158,159,160,161). ATP-sensitive potassium (KATP) channel openers have also been found to reduce
apoptosis in surgical cardioplegia experimental models (162,163). In addition, endonuclease inhibitors such as
aurintricarboxylic acid (ATA) attenuate the development of myocardial apoptosis after ischemia-reperfusion.
P.190
However, these and other anti-apoptotic therapies have yet to be tested in human cardiac surgery.
A significant postischemic, postreperfusion increment of injury is known to lead to unfavorable remodeling of the
left ventricle. The contribution of such injury to the development of ischemic cardiomyopathy after myocardial
infarction is not disputed and therapies to avoid this type of injury are discussed further below.
Endothelial Dysfunction
Effects of Ischemia-Reperfusion on NO• Homeostasis and Endothelial Dysfunction
The general assumption has been that the consequences of ischemia-reperfusion injury affect primarily the
cardiac myocyte. However, abundant data indicate that ischemia and reperfusion affect other cell types in the
heart, notably the coronary vascular endothelium. For example, the vascular endothelium of both arteries
(91,164) and veins (165) sustains significant injury during ischemia and reperfusion, and reduces both basal and
stimulated NO• release (164,166). The endothelium may be the primary site of complement activation and
neutrophil activity after ischemia and reperfusion. This dysfunction may persist beyond the immediate acute
phase of reperfusion for days and weeks (167) following ischemia-reperfusion. Endothelial dysfunction plays a
critical role in the pathogenesis of myocardial reperfusion injury and infarction (168,169).
Data presented by Malinski and Taha (170) suggest that there is an initial burst of NO• release during early
ischemia that consumes local substrate L-arginine and the cofactor BH4; depletion of substrate and cofactor is
associated with the uncoupling of eNOS and NO• generation in favor of -O2 generation by transfer of the electron
to molecular oxygen rather than to nitrogen (171). This -O2 may quench NO• to form ONOO- at reperfusion,
thereby further depleting local NO• and creating NO• dyshomeostasis. It is possible that ischemia associated with
unprotected global ischemia or intermittent cardioplegia is associated with a similar uncoupling of eNOS and
generation of -O2.
FIGURE 9.5. Relaxation response of epicardial coronary arteries to agonist stimulators of nitric oxide synthase
preconstricted with U46619. A: Maximal relation responses to acetylcholine (ACH), and endothelium-dependent,
receptor-dependent agonist. B: Maximal relaxation responses to the direct (endothelium-independent) smooth
muscle relaxing agent acidified NaNO2. Cntl, normal control artery; Isch Only, after 45 minutes of global
normothermic ischemia (cross-clamping); Rep, ischemia was followed by 1 hour of unmodified blood reperfusion;
Cardioplegia + Isch, 45 minutes of global normothermic ischemia followed by 1 hour of intermittent (q 20 minutes)
4°C hyperkalemic blood cardioplegia without reperfusion (declamping); Cardioplegia + Rep, cardioplegia as
described previously followed by 1 hour of reperfusion (declamping). *p < 0.05 versus unstarred groups. (From
Nakanishi K, Zhao Z-Q, Vinten-Johansen J, et al. Coronary artery endothelial dysfunction after ischemia, blood
cardioplegia, and reperfusion. Ann Thorac Surg 1994;58:191-199, with permission.)
Since NO• has pleiotropic effects in the cardiovascular system, impaired release is expected to have multiple
consequences. Impaired release of NO• is expressed physiologically as an increase in the adherence of
neutrophils to the surface of the endothelium and impaired vasodilator responses to endothelium-specific
stimulators of NO• synthase, such as acetylcholine. Decreases in in vitro NO•, measured directly following
ischemia-reperfusion, parallel the increased adherence of neutrophils to coronary artery endothelium and
blunted endothelium-dependent vasodilator responses to acetylcholine and bradykinin (86,172). Figure 9.5
shows coronary artery segment function following 45 minutes of global normothermic ischemia with and without
blood reperfusion (release of cross-clamp). Endothelial function, assayed as maximal vasorelaxation responses
to the endothelium-dependent, receptor-dependent agonist acetylcholine, was not significantly reduced in hearts
subjected to ischemia without reperfusion, but were significantly reduced in reperfused hearts in comparison with
controls (164). These data suggest that endothelial damage occurs during reperfusion rather than during
shortterm global ischemia. At least a portion of this postcardioplegia endothelial dysfunction may be induced by
CPB per se. Zanaboni et al. (173) reported that pulmonary endothelial function is impaired for 3 to 4 days after
CPB. Inflammatory
P.191
mediators (174) and gaseous microemboli (175) may be involved in this endothelial injury by CPB.
Myocardial Edema
Myocardial ischemia and reperfusion are associated with abnormalities in the regulation of intracellular and
interstitial fluid balance. Specifically, certain aspects of these mechanisms, including the Starling forces
governing tissue fluid movement, lymphatic drainage, and cell membrane function, are altered to favor water
retention in the cell or extravasation into the interstitial space. Although the pathophysiology involved in
producing myocardial edema during ischemia-reperfusion injury has not been completely elucidated, Garcia-
Dorado et al. (176) and others (177) have observed an increase in myocardial water content following coronary
occlusion-reperfusion in animal models. Although some cell swelling may occur during ischemia, major
intracellular and interstitial edema formation seems to be a reperfusion phenomenon (176,178,179). Potential
mechanisms of myocardial edema during ischemia-reperfusion include the following: (1) increased intracellular
osmotic pressure secondary to an accumulation of metabolic end-products of anaerobic glycolysis, lipolysis, and
ATP hydrolysis; (2) interference during ischemia with the maintenance of electrical potentials across cell
membranes, in which an intracellular accumulation of Na+ and Cl- (ionic dyshomeostasis) leads to a movement of
water into the intracellular space; (3) increases in both microvascular permeability and osmotic pressure within
the interstitial space. Water may not only be passively regulated but may be regulated by several membrane
pores called aquaporins. Select aquaporins (types -1, -3, and -7) are expressed in human hearts (180).
Aquaporins facilitate the movement of
water between spaces along osmotic gradients, and function in reabsorption of water by the kidneys. Recently,
focus has been aimed at the role of aquaporins in volume regulation in endothelial cells and myocytes, as well as
between vascular, interstitial and lymphatic spaces during ischemia and reperfusion (180,181,182). However,
aquaporins in endothelial cells and cardiomyocytes may have a role in edema of those tissues. The inhibition or
experimental (gene) deletion of aquaporins reduces edema, suggesting that these membrane pores may be a
future target of therapy in surgical and nonsurgical ischemia-reperfusion injury.
Edema may increase microvascular resistance to a point of impeding blood flow (no-reflow phenomenon,
discussed below) and increase diffusion distance to myofibrils, leading to inadequate oxygen delivery at the
tissue level. Edema can arise with the use of cardioplegic solutions, especially in ischemic myocardium, because
of (1) high delivery pressures, particularly in severely damaged myocardium; (2) hemodilution and hypo-
osmolarity from crystalloid primes or crystalloid cardioplegia solutions; (3) physiologic changes in ionic pump
systems (i.e., Na+-K+ ATPase) or Donnan equilibrium for chloride ions induced by hypothermia; and (4) decrease
in lymphatic drainage during arrest. Although normal myocardium tolerates relatively high infusion pressures,
myocardium within (135,183) and surrounding (184) ischemic segments is vulnerable to edema induced by high
delivery pressure. The extent to which reperfusion with unmodified blood following CPB induces myocardial
edema depends primarily on the duration and severity of the previous ischemic episode (176). On reperfusion,
the normo-osmotic blood quickly displaces the hyperosmotic intravascular fluid, creating an osmotic gradient
between the intravascular and extravascular spaces that results in myocardial edema (179). Myocardial edema
following ischemia and reperfusion is also partly caused by an influx of Na+ ions into the cell, accompanied by
interstitial water. Correspondingly, the Na+-H+ exchanger plays a major role in producing a net influx of Na+ into
the cell, which leads to intramyocardial edema (178,185). Inhibition of this Na+-H+ exchange system has been
shown to decrease postischemic myocardial edema (61).
Cardioplegia may contribute to edema formation in ischemically injured hearts. The composition of cardioplegic
solutions (onconicity, hemodilution) and the conditions of delivery (hypothermia, high delivery pressure) are
known to exaggerate the development of edema resulting from ischemia or systemic inflammatory responses.
Microvascular Injury and the “No-Reflow” Response

One of the physiologic consequences of reperfusion injury is impaired microvascular blood flow. Tissue blood
flow defects after ischemia were first reported by Krug et al. (186) in 1966, and the name no-reflow was later
applied by Ames and colleagues (187) in 1968. In 1974, Kloner et al. (188) described the “no-reflow”
phenomenon as a derangement in postischemic blood flow to the myocardium at risk despite resolution of the
coronary obstruction. The etiologies of the “no-reflow” or “low-reflow” phenomenon include (1) postischemic
tissue edema and interstitial hemorrhage compressing the vascular space, (2) active vasoconstriction from loss
of endothelium-derived vasodilators and release of neutrophil-derived vasoconstrictors, (3) capillary plugging by
neutrophils adhering to a dysfunctional endothelium, and (4) air emboli and/or intravascular debris (detached
endothelial cells, clot, atherosclerotic plaque) obstructing blood flow. Microvascular injury and postischemic
defects in myocardial blood flow may be a reperfusion phenomenon because (1) the absence of a significant
perfusion pressure during ischemia prevents the migration of fluid out of the extravascular space, so that
edematous fluid fails to accumulate significantly, (2) endothelial damage with adherence and trapping of
neutrophils and loss of NO-induced regulation of vascular resistance occurs during the early moments of
reperfusion (91), and (3) the boundaries of no-reflow zone widen as reperfusion continues (189) consistent with
the “wavefront” of ischemia-reperfusion injury.
P.192
In surgery, perfusion pressure is important not only at the release of cross-clamp, but during delivery of
cardioplegia. Delivery pressures of 150 to 200 mm Hg measured proximal to the cardioplegia delivery cannula
are sometimes experienced; aortic root pressure will be somewhat less than this because of the relatively high
resistance at the catheter tip. However, it would be important to balance the vulnerability of the myocardium to
pressure-induced damage with adequate pressures necessary to ensure delivery of cardioplegia solution.
STRATEGIES TO PROTECT THE HEART DURING CARDIAC SURGERY

Role of Cardioplegia in Reducing Surgical Ischemic-Reperfusion Injury
Cardioplegia offers selective perfusion to the heart and the administration of agents in higher concentrations that
may otherwise not be well tolerated by other organs or systemically without complications (e.g., toxicity,
hypotension). During selective cardiac delivery, drugs at cardioprotective or anti-inflammatory concentrations
may be diluted below effective or active concentrations after admixture with systemic blood. This is certainly the
case with the most basic component of cardioplegia, K+, which is often administered at greater than five times
the normal blood concentration. It is important to understand that cardioplegia exerts cardioprotection during both
ischemia and reperfusion because of the intimate link between ischemic injury and reperfusion injury.
Cardioplegia exerts cardioprotection by modifying the conditions of (re)perfusion and the composition of the
perfusate (cardioplegia solution) or reperfusate (terminal cardioplegia, hot shot) if given during the early
moments of reperfusion to reanimate the heart. In its simplest formulations, cardioplegia avoids ischemic injury
primarily by reducing oxygen demands to less than 10% of that of the working heart by (1) producing immediate
asystole, (2) rapidly initiating hypothermia, (3) providing intermittent reoxygenation (multidose regimens), and (4)
improving anaerobic metabolism (190). Cardioplegia also avoids reperfusion injury by targeting specifically the
pathophysiologic mechanisms and mediators involved in ischemia-reperfusion injury. Beneficial modifications to
the conditions of cardioplegia infusion apply to infusion pressure and volume, duration of infusion, and
temperature of the solution. Modifications to the composition of cardioplegia during delivery or at reperfusion
include addition of metabolic substrates, osmotic agents, buffers, and cardioprotective pharmacologic agents, as
well as whether K+ is used as the arresting agent or some nondepolarizing arresting agent (see below).
Cardioplegia can be viewed as a vector for pharmacologic therapies to the heart with agents that target specific
aspects of either ischemic or reperfusion injury.
The inclusion of any pharmacologic agent in a cardioplegic solution should be based on scientific principles
tested in the laboratory and supported by literature. There should be a defined target(s) toward which the agent
or additive is aimed. The timing of pharmaceutical delivery is also very important. “What comes first must be
treated first” (191) is a mantra worth using as a guide to deliver therapies at the appropriate time relevant to the
pathophysiologic events of ischemia and/or reperfusion injuries. To administer a pharmacologic agent either
before or after the occurrence of its targeted event is a missed opportunity. If the therapy is designed to exert
actions on mechanisms operative during ischemia, administration of the agent at reperfusion or after declamping
may be ineffective. On the other hand, if events are occurring during early reperfusion, administration during later
reperfusion will be ineffective. In addition, the physiologic environment must be considered, such as hypothermia
versus normothermia, or blood versus crystalloid. Although hypothermia has numerous advantages, as
discussed below, it also reduces membrane fluidity and potentially attenuates the ligand-receptor interactions on
which the effects of many drugs depend. Therefore, the effectiveness of certain cardioprotective drugs can be
attenuated when hypothermic strategies are used. Finally, adequate delivery is extremely important, particularly
to areas with occlusive coronary disease, because the cardioplegic solution cannot exert the effect for which it is
designed if it is not adequately delivered to the target area.
Phases of Myocardial Protection

There are four phases of myocardial protection in cardiac surgery: pretreatment, induction, maintenance, and
reanimation, consistent with the time points of injury shown in shown schematically in Figure 9.1.
Pretreatment therapy includes ischemic and pharmacologic preconditioning (192). Pharmacologic
pretreatment or preconditioning would include volatile anesthetic agents or propofol which exert protection at
the cellular and mitochondrial levels (193).
The induction phase is intended to not only arrest the heart and reduce myocardial temperature, but is also an
opportunity to resuscitate the heart that is energy-depleted or failing (194). Warm induction is an example of a
therapeutic role of the induction phase. This is discussed further below.
The maintenance of arrest is an opportunity to reoxygenate and restore nutrients to the myocardium, wash out
metabolic byproducts, and restore ionic balance to the myocardium. Maintenance can be achieved by
intermittent infusions of solution, for example, every 20 to 30 minutes, or continuous infusion, usually in the
retrograde mode.
The reperfusion and reanimation period at the time of declamping is very important to the overall conduct of
myocardial protection (27), but is a 5- to 10-minute interval that is sometimes underappreciated. It is an
opportunity to remove or lessen the thermal gradient between the
P.193
cold heart and the warm systemic blood, establish ionic homeostasis, increase the aerobic metabolic capacity
after suppression by hypothermia, repolarize the heart if hyperkalemic depolarizing arrest is used, and to
deliver drugs that work specifically at reperfusion. The avoidance of arrhythmias and the use of direct current
countershocks may well depend on how the reperfusion and reanimation period is conducted. Controlled
perfusion through the cardioplegia cannula with the clamp still on has been used to provide warm blood and
cardioprotective drugs to the heart. It is not necessary to maintain arrest during this period as has been
practiced in the past since the heart is being perfused continuously.
What End Points Should Cardioprotective Strategies Target?

Surgical mortality has been driven to historically low levels, especially in low-risk isolated CABG. Although
mortality rates are slightly greater in high-risk patients with multiple procedures, longer cross-clamp times, poor
or failing preoperative ventricular performance, or advanced age (195), even highrisk cohorts face mortality risk
much lower than ever before. In today’s healthcare environment, however, longer-term measures of ventricular
function, subsequent admissions and events as well as nonmortality complications will be scrutinized. These
represent new and ongoing challenges to the outcomes of surgery, and allude to costs and resource utilization.
Postoperative atrial fibrillation continues to be a nuisance with an incidence of approximately 20% to 40% with a
cost of over $1.5 billion in the US alone (196). Perioperative stroke remains a rare but devastating complication
of cardiac surgery, but is not directly related to cardiac protection. Hence, while in-hospital and 30-day mortality
is still an important metric, others are also being viewed as critical to the yardstick of appropriate surgical
outcomes. Cardioprotective efforts during surgery should focus on reducing the ischemia-reperfusion injury,
insuring improvement rather than diminishment in postischemic cardiac function, and reducing the contribution to
the heart failure epidemic especially in patients operated on during evolving myocardial infarction. Relative to
mortality alone, postischemic heart failure represents the larger part of the iceberg that is under the surface (27).
Formulations of Cardioplegia
Approximately 98% of cardiac surgeons use some form of chemical cardioplegia (197), with 72% of surgeons in
the United States using blood cardioplegia and 28% using crystalloid cardioplegia. There are no formal federal
guidelines for cardioplegia solution composition or method of use historically. In fact, in the past, the FDA has
classified cardioplegia solutions as a “medical device”; however, more rigorous testing in vitro and in in vivo
models incorporating CPB is being requested by the FDA. However, there are hundreds of solutions and
methods of use based on mentor teaching, personal preference, and either experimental or clinical experience.
Based on a limited survey in Missouri (198), there is little uniformity in formulation of cardioplegia solutions, with
many being formulated by hospital pharmacies despite availability of FDA-approved compounding pharmacies.
Cardioplegia vehicles are categorized as crystalloid or blood, and the crystalloid formulations are further
subdivided into intracellular or extracellular ionic compositions.
Crystalloid Cardioplegia
Celsior
The introduction of Celsior by Philippe Menasché in 1994 used the isolated rat heart that was arrested, placed in
cold storage for 5 hours, and reanimated to obtain recovery of left ventricular developed pressure, LV dP/dt, and
compliance post-storage. The data from this isolated-perfused preparation was recapitulated in other small
animal preparations (199), in large animal in situ isolated-perfused studies (200), in transplant models (201,202),
and was finally translated in human clinical trials (203,204,205,206). Currently, Celsior is used primarily for
preservation during cold storage.
Plegisol
Plegisol is the commercial name for St. Thomas’ II solution, formulated and tested by David Hearse (18,21,207).
It was clinically validated in 1989 (208); it is sold commercially in the United States by Hospira. This crystalloid
solution is used for clinical cardioplegia internationally, specifically in Britain, variably in other European
countries, and in about 15% of cases in the US.
Del Nido Solution

The del Nido solution, developed by Dr. Pedro del Nido, was patented in 1995 (USPTO # 5,407,793). It was
developed as a cardioplegia solution for protection of immature hearts (209), but its use has been extended to all
hearts in Boston Children’s Hospital (210,211) and other institutions (212,213). The base of the solution is
Plasma-Lyte A (Baxter Healthcare) which has electrolyte composition similar to that of extracellular fluid. The
salient compositional features of the del Nido Solution are low Ca2+ content (provided by the 20% of volume
blood), hyperkalemia (24 mEq/L); mannitol for oxygen radical scavenging and osmotic properties, sodium
bicarbonate for buffering of acidosis during arrest; and lidocaine to stabilize membrane potential and reduce
arrhythmias. Its use as a cardioplegia solution in adult patients is currently under investigation, but contemporary
studies involve small numbers of patients, are retrospective in design, and show only safety and noninferiority to
other solutions based on lack of significant differences between del Nido solution and other solutions
(214,215,216).
Custodiol
Custodiol is the former Bretschneider solution, also called HTK (histidine, tryptophan, ketoglutarate) solution. It is
an
P.194
intracellular composition crystalloid solution originally developed as a cardioplegia solution in Germany (217), but
now used for perfusing and flushing of organs from the donor, preservation of organs for transplant (218), and
for cardioplegia in cardiac surgery. Custodiol was successfully translated into large animal simulations of
cardioplegia (219) and transplantation, which predicted success in subsequent clinical trials and reports
(220,221,222,223).
Blood Cardioplegia
Hemodiluted Blood Cardioplegia

Blood is viewed by some as an “ideal” vehicle to carry cardioplegia components because blood has (1) an
increased carrying capacity to provide greater oxygen delivery to maintain oxygenation and repay oxygen debt;
(2) an innate buffering capacity from histidine moieties; (3) “natural” osmotic properties that exceed that of
crystalloid solutions; (4) blood-borne nutrients such as glucose and free fatty acids; and (5) endogenous oxygen
radical scavengers such as glutathione and glutathione peroxidase, and catalase. On average, O2 consumption
of the normally working heart is ˜8 mL O2/min/100 g, or 28 mL/min for a 350 g heart. In contrast, in a crystalloid
solution, 700 mL/min of cold (10°C) solution/min would be required to deliver this much oxygen based on an O2
carrying capacity for crystalloid solution of 4 mL O2/100 mL. Although the argument has been made that O2
bound by hemoglobin is not available at cold temperatures because hypothermia shifts the hemoglobin
dissociation curve to the left, experiments have shown that oxygen is indeed released at cold temperatures
during delivery of cardioplegia (137), ostensibly facilitated by a low tissue PO2, and the effects of pH and 2,3-
DPG on oxygen dissociation from hemoglobin. The first blood cardioplegia solutions were hemodiluted with
crystalloid-dissolved agents in a 4-parts blood-to-1-part crystalloid ratio (224). Newer delivery techniques have
incorporated methods to continuously blend blood from the CPB reservoir with the contents of the crystalloid bag
in any number of given ratios or variable ratios (e.g., the Quest MPS unit). With the recent focus on limiting the
crystalloid load, higher ratios have been used clinically.
Blood cardioplegia maintains an aerobic arrest which is important to avoiding ischemia and reperfusion injuries.
Accordingly, we found that oxygen was a critical factor in the benefits of cold-blood cardioplegia (137). However,
blood does contain inflammatory cells (i.e., neutrophils) and pro-inflammatory cytokines. Whether these potential
negative effects are translated to postcardioplegia injury depends in large part on avoidance of ischemia, which
sensitizes the myocardium to other aspects of reperfusion- and inflammatory-based injuries.
All-Blood Cardioplegia
Menasché and colleagues have coined the term “miniplegia,” now referred to as “microplegia,” to describe a
technique of administering a small quantity of a prepared arresting solution via a pump-driven syringe to
otherwise unmodified blood originating from the CPB circuit (225,226,227). The volume and delivery rate of the
concentrated potassium (and magnesium) solution is incrementally decreased to the lowest level possible to
maintain quiescence. The key to this type of myocardial protection is the nearly continuous delivery of the blood
solution to the myocardium at a tepid temperature. The continuous administration obviates the need for added
buffers such as tromethamine (THAM) and citrate-phosphate dextrose because aerobic metabolism is
maintained throughout the duration of arrest, resulting in sufficiently high production of energy to drive the ionic
pumps responsible for Na+, Cl- and Ca2+ homeostasis, and avoid intracellular acidosis. The reduction in
crystalloid “diluants” avoids progressive hemodilution.
The potential benefit of microplegia solutions are numerous and include (1) increased oxygen supply and
increased presence of endogenous antioxidants and detoxification factors lost with hemodilution; (2) improved
control of blood volume to reduce edema resulting from hypo-osmolality, bleeding complications, and potassium
overdose; (3) increased convenience and practicality; and (4) better cost effectiveness. Reports indicate good
clinical satisfaction with this technique (228). This philosophy of “all-blood cardioplegia,” however, does not
inherently embrace the application of additives addressing mediators of ischemia-reperfusion injury that may be
of clinical benefit. In addition, this “microplegia” philosophy challenges the need for other strategies of myocardial
protection developed during the past two decades, including buffering of intracellular acidosis, calcium
management, and use of hyperosmolar conditions. However, perhaps a resolution to this conundrum is
avoidance of ischemia altogether, which prevents injury from occurring in the first place. These issues bear
further examination, as they relate to newer strategies of myocardial protection.
Major Strategies of Protection with Cardioplegia

The major characteristics of cardioplegia solutions in regard to the phases of protection, actions of constituents,
and methods of achieving the actions are summarized in Table 9.1.
Depolarized Arrest Using Hyperkalemia

Exogenous potassium causes a concentration-dependent depolarization of the cell transmembrane potential. For
example, at 10 mM (10 mEq/L) the transmembrane potential is depolarized from its normal -85 mV to
approximately -65 mV, rendering the myocardium unexcitable. At this transmembrane potential the voltage-
dependent fast Na+-channels are blocked, and there theoretically is no phase 0 of the action potential, and
hence no generation of the action potential; this is a state of “depolarized” arrest. Potassium concentrations in
cardioplegic solutions ranging from 12 to 30 mEq/L are typically used to achieve cardiac standstill within 1 to 2
minutes under hypothermic conditions, although more moderate levels of potassium have been reported (229).
Higher potassium
P.195
concentrations are used to arrest the heart with normothermic induction techniques (230) or to maintain arrest
during a warm reperfusate cardioplegia (i.e., “hot shot”) delivered just before aortic declamping. Potassium
concentrations above 40 to 50 mEq/L have been avoided because of the potential for tissue and coronary
vascular endothelial damage, although this point remains unsettled. Washout of hyperkalemic cardioplegic
solutions by noncoronary collateral flow, or an increase in myocardial temperature permits resumption of both
electrical and mechanical activity, which may escape detection and can be counteracted by intermittent (every
20-30 minutes) replenishment of cardioplegic solutions. Such a multidose approach to infusion of cardioplegia
solutions maintains or re-establishes electromechanical silence and pays additional dividends of restoring
hypothermia, providing the ischemic myocardium with oxygen (aerobic arrest) and nutrients, and washing out
metabolites of anaerobiosis.
TABLE 9.1. Strategic cardioprotection with cardioplegia: strategic principles, mechanisms

of action, and methods used to achieve the strategies. References appear in parentheses.
Principle Mechanism (s) Method
Pretreatment Resuscitate; restore Ischemic preconditioning; adenosine;

(preconditioning) metabolism and NO•; warm induction
biochemistry; adapt
myocardium to ischemia
Delivery vehicle Blood (hemodiluted, From oxygenator

Aerobic arrest microplegia) Premixed bags
Crystalloid (intracellular,
extracellular)
Induce, maintain Transmembrane Hyperkalemia (20-30 mEq/L)

arrest depolarization Adenosine (235), KATP channel openers
Polarized arrest, lock (563), hypocalcemia (563), high-dose
membrane potential at adenosine-lidocaine-magnesium
resting state (234,447)
Avoid ischemia Reduce energy supply- Hypothermia; blood vehicle Intermittent

demand mismatch; (cold, q 20-30 min) Continuous delivery
conserve ATP stores (warm or cold)
Optimize O2 supply,
washout metabolites
Optimize metabolism Adjuncts: glucose; pyruvate;

glutamate/aspartate; GIK
Warm or tepid myocardial temperature
Ensure adequate delivery Adequate pressure

Adequate volume
Adequate time of infusion (564)
Retrograde infusion
Avoid reperfusion Prevent ischemia Arrest, polarized arrest, oxygenation,

injury Oxidant-induced injury hypothermia, nutrients
Endothelial protection Antioxidants; scavengers, blood
Inflammatory responses to antioxidants
I/R, CPB Adenosine, NO•, anti-neutrophil (PMN)
Interstitial edema therapy
Anti-complement, anti-PMN therapy
Oncotic agents; controlled delivery
pressure
Reanimate/resuscitate Optimize oxidative Oxygen, blood

metabolism Anti-arrhythmic agents; low-dose
Stabilize cell membrane Adenosine-lidocaine-magnesium
Reduce time to Exclude K+
reanimation Progressive warming before declamping
Avoid warm/cold blood-
tissue interface
Asystole: Reducing Oxygen Supply/Demand Mismatch

When the aorta is cross-clamped without cardioplegia, ischemia rapidly depletes the myocardial high-energy
phosphate pool, which initiates the complex cascade of ionic, biochemical, and morphologic sequences
described above under pathogenesis of ischemia and reperfusion injuries, potentially leading to reversible and/or
irreversible myocardial injury. The
P.196
rapid rate of high-energy phosphate depletion is accelerated by continued electromechanical activity after aortic
cross-clamping, so that a more rapid depletion of ATP reserves occurs before anoxic arrest ensues. Biochemical
changes initiated by anoxic arrest increase the severity of ischemia and consequent reperfusion injury within a
short period of time. The intentional induction of diastolic arrest by chemical cardioplegia solutions avoids
depletion of and conserves myocardial energy reserves which can be utilized in the interim between infusions
(multidose strategies) or throughout (single-dose strategies) to maintain ionic and metabolic homeostasis. The
mechanism of conserving energy stores with immediate asystole is illustrated in Figure 9.6. Decompression of
the heart by venting on CPB alone reduces oxygen consumption (as a surrogate measure of ATP utilization) by
˜40%. Combining asystole and decompression of the heart diminishes O2 demands by approximately 80% to
90%. Although the heart is arrested, there is an ongoing O2 consumption due to maintenance of cellular ionic
gradients and viability processes. This residual O2 consumption can be reduced considerably by hypothermia,
but there is still an ongoing consumption that accrues over time, that is, between intermittent infusions of
cardioplegia as shown in Figure 9.6.
Historically, rapid asystole has been achieved by a number of methods, including hyperkalemia, hypocalcemia,
administration of Ca2+ channel blockers, and infusion of local anesthetic agents as discussed in the Historical
Perspectives section of the chapter. Newer primary arresting strategies include the use of nondepolarizing or
hyperpolarizing agents, such as KATP channel openers (231,232), and adenosine alone (233) or in combination
with a local anesthetic (234,235).
FIGURE 9.6. Oxygen consumption as an indicator of energy demands under conditions of normal working state,
vented beating empty on CPB, vented and electrically-induced fibrillation (VF), and arrested under normothermic
(37°C) and 20°C and 4°C. Perfusion was continuously supplied so that oxygen supply was adequate to meet
demands, that is, oxygen consumption is equivalent to demands. Inset gives reductions in oxygen consumption
attributed to venting and decompression on CPB, arrest with normothermic cardioplegia, and hypothermia to
4°C. (Adapted from Vinten-Johansen J, Dobson GP, Shi W, et al. Surgical myocardial protection. In: Franco KL,
Thourani VH, eds. Cardiothoracic surgery: review. Philadelphia, PA: Wolters Kluwer, Lippincott Williams &
Wilkins, 2012:83-98.)
Restoring O2 Supply to the Heart

Implied in the title of this section is the notion that the cardiac O2 supply-demand ratio must be out of balance in
a variety of circumstances from which it must then be restored. This section covers the manner in which this
should progress based upon nearly 20 years of ongoing research and knowledge gained from clinical
experience. Although surgically induced ischemia at the onset or during the cross-clamp or cardioplegia phase of
an operation conducted in this manner is one example, the authors intend to convey some newer concepts as
well.
Coronary artery disease

For patients presenting with acute coronary events, periods of antecedent warm ischemia prior to reperfusion in
the catheterization laboratory or in the operating room are frequent in clinical practice in patients for whom a
percutaneous option is not available or not feasible. The degree or severity of such ischemia and the duration of
the preceding syndrome in most cases can only be estimated. Recognition of the need for the institution of
circulatory support in certain (“high-risk”) patients as an adjunct to reperfusion therapy has proliferated in recent
years as more surgical therapies are delivered in hybrid areas or in the Cath lab, and as cardiologists and
surgeons work more closely together to achieve improved outcomes. It must be recognized that the elimination of
ischemic conditions can occur by manipulation of the demand side of the O2 supply/demand equation in clinical
scenarios where circulatory support is (or other adjuncts are) used as a strategy to reduce risk. The over-
administration of O2 by exposure to the oxygenator (hyperoxic blood) in this setting to patients with varying
degrees of hemodynamic instability including cardiogenic shock or postarrest and during resuscitation must be
rethought to be more consistent with recent observations around the world suggesting that this is a dangerous
practice contributing to reperfusion injury ostensibly by ROS-related events (236).
Cyanotic Infants and Children

In 1995, Buckberg et al. (32,65,237,238,239,240,241,242,243,244,245,246,247) published a series of
experimental studies looking at the impact of the exposure of previously hypoxic myocardial tissue to hyperoxic
perfusate during CPB. This series of studies using the immature porcine heart in a model of cyanosis led to
further investigation by their group and others in an attempt to define the effect of extremely high gradients of
perfusate-to-tissue O2 tension. In most clinical situations currently, CPB is initiated with membrane oxygenators
exposed to high concentrations of oxygen (60%-100%) rendering perfusate PO2 in the 400 to 600 mm Hg range.
Animals exposed to such elevated perfusate oxygen tensions, even for a brief period (minutes), did
P.197
not tolerate subsequent ischemic intervals, even when taken in the best circumstances (with highly advanced
cardioplegia strategies) These observations have clear clinical implications, and it has been observed by
numerous investigators (248) since the 1990s that cyanotic children undergoing complex cardiac surgery are
more difficult to protect than noncyanotic children having equally complex surgery.
New Observations; Reversing Ischemic Conditions

More recent experimental and clinical observations (63,249) have been consistent with Ihnken’s (250) data
clearly documenting the presence of biochemical markers of myocardial injury in coronary sinus effluents, even
in normoxic adult human hearts (250). Hyperoxic conditions at initiation bypass have consistently been observed
to lead to this pattern of PO2-dependent injury and can be mitigated by controlling the exposure of the heart to
less significant oxygen gradients; particularly when antecedent ischemic conditions exist.
Myocardium at risk during acute coronary ischemia may be more successfully resuscitated if oxygen re-exposure
in the operating room and, possibly, in the heart catheterization laboratory could be carefully controlled.
Experimental cardioprotective and resuscitative perfusate has been given and observed to salvage critically
ischemic hearts. Thomas and associates (249) and D’Alessandro et al. (251) observed that lowering the initial
PO2 of the cardioplegic perfusate could lead to better postischemic cardiac function.
Rethinking a Conventional Strategy

Examples of conventional strategies in modern medicine include the administration of penicillin for pneumococcal
pneumonia and insulin for hyperglycemia. It would be safe to say that no randomized clinical trial was ever
performed (nor would it have been ethical to do so) for the treatment of pneumococcal pneumonia with penicillin.
Along those lines, the routine administration of supplemental, inhaled oxygen for patients presenting with acute
coronary syndrome (or stroke, for that matter (252)) was never really studied because the fundamental defect in
such a syndrome is the sudden cutoff of oxygen supply to a particular territory. Furthermore, it has been
recognized for some time that “time is myocardium” and every modern recommendation from the joint guidelines
committee of the ACC/AHA pits the cardiologist against the clock for opening an infarct-related vessel. It
therefore has seemed intuitive for decades that giving someone “extra oxygen” must be a good thing.
It should be noted that at the European Society of Cardiology Congress in Paris, France in 2011, there was
nearly unanimous support for a reassessment of the manner in which oxygen is administered to patients with
acute myocardial infarction. In 2010, routine oxygen administration in this setting was also questioned by
Moradkhan and Sinoway (253), from the Penn State Heart and Vascular Institute. These investigators reviewed
and published their analysis of recent studies suggesting that hyperoxic conditions not only could ramp up
inflammation and contribute to oxygen radical injury but could lead to reduced coronary blood flow and cardiac
output/index, while also evoking a rise in blood pressure and systemic vascular resistance (253).
As has been covered in this chapter, a number of publications in surgical journals and in abstract form suggest
that the administration of oxygen in a conventional manner during CPB leads to a reproducible, PO2-dependent-
pattern of injury that relates to oxidative stress and increased inflammation. Other publications over the past 15
years have suggested further that upregulated expression of various genes involved in inflammation and
apoptosis may contribute to an increment of injury around the time of reperfusion therapy, and such may add to
the phenotypic expression of heart failure due to ventricular remodeling over time (254,255).
It could be inferred from these data that postmyocardial infarction scarring and ventricular remodeling known to
involve apoptosis and inflammation could be mitigated by a controlled strategy to compartmentalize oxygen
delivery to the heart and the rest of the body. This could be accomplished in the operating room utilizing
cardiopulmonary bypass. Alternatively, it could work in the interventional and hybrid situations in which surgeons
and cardiologists might work together to implement both percutaneous strategies and strategies intended to
manipulate the oxygen demand side of the ischemia equation with controlled cardiopulmonary bypass. A
recognition that a high oxygen gradient between perfusate (blood) and tissue (heart, brain, etc.) may contribute
to injury at the moment that ischemic conditions are eliminated may alter the way the tissue is oxygenated, even
if it is accomplished by manipulating oxygen demand by initiating CPB.
Myocardial Hypothermia
Since its initial introduction in the 1950s by Bigelow et al. (256,257), hypothermia has remained a cornerstone of
myocardial protection. The effects of hypothermia on the myocardium are complex and must be considered in
regard to their positive and negative aspects, summarized in Table 9.2. The major cardioprotective mechanisms
of hypothermia center on the reduction in metabolic rate and hence O2 demands of the myocardium. In
conjunction with cardiac arrest, hypothermia reduces myocardial O2 consumption by ˜97% if profound (4°C)
cooling is achieved (Fig. 9.6). The relationship between myocardial O2 consumption and temperature is relatively
exponential. Generally, the relationship conforms to Van’t Hoff’s law or the Q10 effect, whereby myocardial O2
consumption in the arrested heart decreases by 50% for every 10°C reduction in temperature. The greatest
reduction in myocardial O2 consumption in the arrested heart occurs between 37°C and 25°C, with a relatively
small decrease in energy requirements achieved thereafter. Hypothermia of the arrested heart increases the
tolerance to ischemia for a given period of time and expands the window of “safe ischemic
P.198
time” between infusions of cardioplegia solution. Therefore, 45 minutes of 4°C global ischemia is well tolerated,
whereas 15 minutes of normothermic ischemia precipitates failure on reperfusion (Fig 9.2A). By reducing the
basal metabolic rate in proportion to the temperature achieved, myocardial hypothermia decreases the O2 deficit
during intervals of nonperfusion, and thereby retards the progression of ischemia and consequent postischemic
(and reperfusion) injury. The degree of protection conferred by hypothermia is related to the myocardial
temperatures achieved.
TABLE 9.2. Positive and negative effects of hypothermia
Positive Negative
Decreases metabolic rate Decreases rate of restoration and repair

Decreases oxygen requirements Impairs oxygen delivery, dissociation
Temporarily decreases cell-cell interactions Decreases rate of contraction
Decreases rate of degradative reactions Induces ventricular fibrillation
Increases tolerance to ischemia, increases Increases intracellular swelling, Na+ accumulation

biologic time
Reduces [K+] necessary to arrest the heart Impairs blood flow autoregulation
Prolongs electrical silence Potentially damages phrenic nerve
Inhibits intracellular Ca2+ accumulation Decreases RBC deformation, increases rouleaux

formation
Decreases rate of NF-κB translocation Decreases membrane fluidity
Decreases receptor transduction mechanisms
Inhibits sarcoplasmic reticulum Ca2+ uptake,

release
Because the difference in O2 demands between 22°C and 4°C are relatively minor, small differences in regional
or global myocardial temperature may be well tolerated, provided that other principles of myocardial protection
(i.e., reduction of O2 demands, hypocalcemia) are observed and impediments to the delivery of cardioplegia are
overcome in a timely manner. Many reports suggest that hypothermia below 22°C does not significantly reduce
the oxygen demands of the arrested heart (258) or fails to improve the degree of myocardial protection after
moderate periods of arrest (21). The benefits of more profound levels of hypothermia may not be apparent
unless prolonged ischemia is imposed (i.e., 4-6 hours). Therefore, the surgeon does not need to be preoccupied
with achieving the lowest levels of hypothermia possible, but must ensure a reasonable degree of myocardial
cooling (unless continuous cardioplegia is used) and a timely induction of local hypothermia in regions of the
heart where distribution of cardioplegic solution has been compromised (i.e., infusion through grafts). However,
the accrual of an O2 deficit between infusions of cardioplegia is the major reason that intermittent infusions are
given. Many surgeons use moderate hypothermia (approximately 24°C-28°C) for intermittent cardioplegia
because significant reductions in energy demands are achieved without invoking the deleterious effects of
hypothermia, listed in Table 9.2. However, intermittent infusions may be important in maintaining aerobic
conditions during arrest.
The benefits of hypothermia relate not only to reduced metabolic demands but also to other biologic reactions
involved in signaling the ischemia-reperfusion injury process. Johnson et al. (259) and Haddix et al. (260) have
shown that hypothermia attenuates the surface expression of adhesion molecules on the vascular endothelium
and delays the translocation of the nuclear transcription factor NF- κB from the cytosol to the nucleus, thereby
delaying the generation of pro-inflammatory mediators and synthesis of adhesion molecules. However, in this
regard, hypothermia provides only a transient benefit that may offer no permanent reduction in cell activation
after rewarming.
Hypothermia is associated with several disadvantages, which are also listed in Table 9.2. Concern has been
expressed over the issue of cold injury to the heart (edema,
P.199
morphologic alterations). The edema sometimes observed following infusion of hypothermic cardioplegic
solutions is of complex etiology and may be related, in part, to the osmolality of the solution used or to sodium
accumulation resulting from temporary inhibition of the Na+-K+-ATPase pump. This edema may be transient and
readily reversible after reperfusion (261). In the intervals between infusions of cardioplegic solution, topical saline
slush may be applied to prevent myocardial rewarming by convection. However, injury to extracardiac structures
(i.e., phrenic nerve) and epicardial freezing have been concerns. In a retrospective study of 505 patients who
underwent coronary artery bypass in which systemic hypothermia and intermittent cold blood cardioplegia was
used with or without topical cooling with iced slush, Nikas et al. (262) reported that topical hypothermia did not
offer any additional cardioprotective benefit over systemic hypothermia and cold blood cardioplegia alone. In
addition, patients receiving topical hypothermia had a significantly increased incidence of diaphragmatic
paralysis and associated pulmonary complications. Another deleterious effect of hypothermia is potentiation of
citrate toxicity, which leads to depressed myocardial contractility and thrombocytopenia (263).
Some of the negative aspects of hypothermia are essentially neutralized when cardioplegic arrest is used. For
example, the paradoxical increase in inotropic state and O2 demands per beat, and the possible induction of
fibrillation by hypothermia, are avoided with cardioplegia. Also, normothermic cardioplegia can be used to
overcome some of the disadvantages of hypothermia. In a small series of patients who underwent coronary
artery bypass, those randomized to tepid or warm antegrade or retrograde cardioplegia showed reduced
anaerobic release of lactic acid during cardioplegic arrest and greater left and right ventricular cardiac function in
comparison with patients who received cold cardioplegic solution (264). Although a number of physiologic effects
of hypothermia appear to contradict the concepts of myocardial protection, the net myocardial protective effects
are clear: the pathogenic tide of ischemia is stemmed and the unwelcome consequences of surgical ischemia-
reperfusion injury are thereby limited.
Warm-Cold Induction
While hypothermia reduces energy demands of the heart, it also reduces the rate of reparative and beneficial
biochemical reactions. This may pose a disadvantage to hearts that are energy-depleted, failing, or need a
period of resuscitation before plunging into the hypothermic domain. A warm phase of induction using
normothermic cardioplegia preceding delivery of hypothermic cardioplegia may provide a period of resuscitation
where arrest reduces energy demands but normothermic reaction rates in conjunction with adequate O2 delivery
favors repayment of any O2 debt, restoration of high-energy phosphates, divergence of oxygen to reparative
metabolic processes, and restabilization of ionic balance (Fig. 9.7). This is not to be confused with warm
cardioplegia in which warmer temperatures are used throughout the delivery of cardioplegia solution.
Experimentally, a warm induction preceding hypothermic induction (warm-cold induction) has been shown to
restore postcardioplegia function better than cold induction blood cardioplegia (230), possibly by improving
function of the Na+/K+ pump (265). Clinically warm-cold induction strategies have been shown to be beneficial in
high-risk patients (266) or procedures with long cross-clamp times (267), but these benefits may (268,269) or
may not (270,271) be observed in low-risk patients, which parenthetically is not necessarily the target group for
this modality. A warm induction phase has been reported to be beneficial in pediatric hearts (272).
FIGURE 9.7. Oxygen consumption in a vented, perfused heart on CPB during normothermic and hypothermic
induction of cardioplegia. (Adapted from Vinten-Johansen J, Dobson GP, Shi W, et al. Surgical myocardial
protection. In: Franco KL, Thourani VH, eds. Cardiothoracic surgery: review. Philadelphia, PA: Wolters Kluwer,
Lippincott Williams & Wilkins, 2012:83-98.)
Terminal Cardioplegia, Hot Shot, Reanimation Cardioplegia

Reperfusion of previously ischemic/arrested hearts is a time of enhanced vulnerability to all the manifestations of
reperfusion injury reviewed above. Control of reperfusion can be applied before the cross-clamp is removed by
using the extracorporeal cardioplegia circuit to deliver warm blood (with or without additives at controlled
pressures) selectively to the heart; hyperkalemia is not necessary to maintain arrest during this reanimation
phase since adequate O2 is being delivered by blood. A controlled terminal reperfusate, often called terminal
cardioplegia or “hot shot,” has the potential to (1) washout of metabolites and improve postischemic metabolic
derangements that may have occurred during arrest (273), (2) act as a vehicle for the delivery of drugs targeting
specifically reperfusion injury, (3) attenuate the instabilities associated with a cold-warm interface if the
temperature is gradually ramped to normothermia, and (4) re-establish transmural homogeneities in tissue
potassium (274), temperature, and acidosis to attenuate postoperative arrhythmias (275). Warm terminal
cardioplegia has been shown to be beneficial in postoperative recovery in pediatric heart surgery (276). This
controlled
P.200
terminal perfusion phase therefore provides an opportunity to resuscitate and stabilize the heart electrically,
mechanically, and metabolically before it has to assume command of the circulation. However, this phase of
resuscitation may require a modicum of patience by the surgical team.
Avoiding Ca2+ Overload and “Manhandling”

Despite uniform agreement on the importance of limiting intracellular Ca2+ during reperfusion, the optimal
technique to achieve this continues to be debated. In addition, arriving at a uniform solution for Ca2+
management may be virtually impossible because of wide variations in the composition of cardioplegia solutions
used in clinical practice. However, an abundance of data is available regarding strategies of Ca2+ management
and improved myocardial protection.
Ideal concentrations of Ca2+ in cardioplegia solutions must be tailored to the type of solution used (i.e.,
crystalloid or blood). The concentration-response curve for the Ca2+ concentration is bell-shaped, with both
extreme hypocalcemia (<50 mmol/L) and hypercalcemia having deleterious effects. Extreme hypocalcemia may
set the stage for the Ca2+ paradox once normal Ca2+ levels are achieved at reperfusion. The Ca2+ paradox is a
sudden influx of Ca2+ that occurs when Ca2+in reperfusates are normalized after a period of profound
hypocalcemia (277,278,279). Ischemia sensitizes the myocardium to Ca2+ levels in cardioplegia solutions that
are otherwise well tolerated by normal myocardium. The picture is further complicated by the dynamic interaction
of Ca2+ with other cardioplegia components, such as sodium, potassium, magnesium, and pH (280,281), and its
behavior under conditions of hypothermia (282). In addition, the systemic release of catecholamines in response
to CPB alters the influx of Ca2+ through adrenergic receptor mechanisms and increases oxygen consumption
(oxygen wasting effect), hence, increases the vulnerability of the myocardium to ischemia-reperfusion injury.
Calcium Chelation
The reduction of extracellular Ca2+ by direct chelation, which restricts transmembrane Ca2+ influx regardless of
route of entry, is a common strategy, especially when blood cardioplegia is used. Sodium citrate, often obtained
in combination with phosphate and dextrose for storage of blood (CPD), is the most popular agent to chelate
Ca2+. This agent, however, is relatively nonspecific for Ca2+ and may chelate other divalent cations including
magnesium. In addition, citrate is a direct inhibitor of glycolysis, on which the ischemic myocardium depends
when tissue oxygen stores are depleted during ischemia. The benefits of citrate, however, seem to outweigh its
negative effects, and it is a key component in blood cardioplegia.
Newer strategies to attenuate Ca2+ influx during reperfusion focus on the inhibition of Ca2+ transport into the cell
through calcium channels rather than the relatively nonselective transport described earlier. Magnesium in
cardioplegia also prevents Ca2+ influx by its innate Ca2+ antagonist effects (283,284). Adenosine limits K+-
induced Ca2+ influx (285) potentially by opening of KATP channels. Direct opening of the KATP channel with
channel openers such as cromakalim, aprikalim, or diazoxide also attenuate Ca2+ influx during reperfusion
(286,287), but their adoption into clinical practice has met with resistance as a result of their pro-arrhythmic
effects. Manipulation of protein kinase C plays an important role in Ca2+ management (72). Investigators have
attempted to harness this mechanism through ischemic preconditioning and postconditioning (discussed below),
both of which activate protein kinase C isoforms and confers cardioprotection in part by attenuating Ca2+ influx.
Buffering of Acidosis
During both normothermic and hypothermic ischemia, aerobic metabolism is short-lived, and the myocardium
relies on the relatively low yield of ATP (2 moles/mole of glucose used) from anaerobiosis. However, tissue
acidosis resulting from continued metabolism and lactate production during ischemia strongly inhibits
enzymatically catalyzed metabolic reactions, further diminishing the yield of ATP. Buffering of cardioplegic
solutions to counteract myocardial H+ accumulation therefore is a logical strategy for limiting the consequences
of ischemia (190). Episodic reinfusion of cardioplegic solution further rectifies tissue acidosis by washing out
metabolic by-products to re-establish acid-base homeostasis. Buffering of acidosis can be accomplished by
using the cardioplegia solutions as vehicles, either exploiting the endogenous capabilities of the solution (i.e.,
buffering capacity of blood) or adding exogenous buffers such as histidine, bicarbonate, or THAM.
The pH buffering approach selected to manage the acid-base status of cardioplegic solutions should be based
on the biophysical changes imposed by hypothermia and pharmacologic efforts to adjust acid-base balance,
which can affect buffering capacity. In aqueous solutions, the neutral pH of water is temperature-dependent,
increasing by 0.017 pH/°C decrease in temperature (Rosenthal correction factor). In blood, pH is alkaline relative
to the neutrality point of water, but a parallel adjustment upward in arterial pH occurs with hypothermia in that the
change in pH/°C is approximately 0.0147. Therefore, a sample of blood cardioplegia with a pH of 7.4 as
measured by electrodes warmed to 37°C would actually have a pH of 7.72 if corrected to a temperature of 10°C.
Alkalotic cardioplegic solutions maintain better metabolism (288) and buffer intracellular as well as extracellular
acidosis (289,290) during arrest/ischemia. Neethling et al. (291) report that aggressive buffering of cardioplegia
solution buffers acidotic changes in interstitial pH and favorably affects postcardioplegia contractile recovery.
However, a number of reports (292,293) contradict this conclusion by suggesting that acidotic solutions
decrease energy demands during ischemia and attenuate intracellular Ca2+ accumulation during ischemia and
reperfusion. In addition, the recently
P.201
appreciated role of intracellular acidosis in maintaining the mPTP in a closed state (discussed above) may
support imposing an acidotic environment at least during early reperfusion. Although this may seem like going
over old ground, the role of acidosis versus buffering should be revisited in light of the cardioprotective role of
mPTP inhibition, particularly at the onset of reperfusion.
Various buffering agents have been used, either as a primary method of pH adjustment or to supplement and
amplify the intrinsic buffering capabilities of the cardioplegic solution. The “ideal” buffer has a dissociation
constant (pK) within 1 pH unit of the neutrality point of the solution (sanguineous or asanguineous) used at a
given temperature, should be independent of changes in PCO2, and should be able to buffer the intracellular and
interstitial (extracellular) compartments. Bicarbonate, THAM, histidine, and phosphate buffers are used in various
cardioplegic solution formulations. Bicarbonate is a weak extracellular buffer with a pK that is both outside the
desirable range of physiologic pH at lower temperatures and unable to adjust appropriately to temperature. Poor
results have been obtained with bicarbonate-buffered solutions (294,295). Histidine (pK of 6.04) and the active
component imidazole (pK of 6.7), the dominant buffer systems in blood, provide good buffering capacity, with an
appropriate pK range and appropriate adjustment of pK to hypothermia. Histidine is a primary buffer in HTK
Bretschneider or Custodiol) solution (296,297). Experimental studies show good preservation of high-energy
phosphate stores and postischemic ventricular function with these buffers. The imidazole-histidine buffering
system may be one of the mechanisms underlying the effective buffering capacity of blood in blood cardioplegia
(298). THAM is an excellent buffer because its pK (8.08) is nearly identical to the physiologically adjusted pH at
4°C to 10°C, and it buffers both the intracellular and extracellular compartments. There are strong advocates for
both THAM and histidine as “optimal” buffering agents in cardioplegia solutions.
Avoidance of Myocardial Edema and Microvascular Injury

Myocardial edema following coronary artery bypass and global ischemia can be reduced by a number of
strategies that involve modifying the conditions of delivery and composition of cardioplegia solutions as they
affect the movement of intracellular and interstitial fluid.
Conditions: Controlled delivery pressure—limiting the pressure (measured at the aortic root, not from the
cardioplegia delivery line (299)) at which antegrade cardioplegic solutions are infused to between 50 and 100
mm Hg—may reduce the development of edema and postischemic vascular defects (190,300). Constraining
cardioplegia pressure as measured in the aortic root to within these limits may be more important in ischemically
injured hearts than in normal (no antecedent ischemia) myocardium (301,302,303) because the vascular
endothelium is sensitive to perfusion pressure (304,305). A number of investigators (134,183,303,306,307,308)
have reported that slowly increasing coronary pressure and blood flow (i.e., “gradual or gentle reperfusion”)
during the early part of reperfusion reduces endothelial injury and microvascular injury, limits infarct size and
improves functional recovery of reperfused myocardium. However, delivery of cardioplegia solution is impaired
by coronary artery obstruction and air, which may call for higher delivery pressures.
Composition (hyperosmolarity): Osmotic agents such as mannitol and glucose have been used to prevent the
development of edema. Mannitol acts as an osmotic agent and an oxygen free radical scavenger (309). Addition
of mannitol to cardioplegia has been reported to be beneficial (310). However, glucose and potassium serve as
osmotic agents. Although some concern has been voiced over extremely hyperosmolar solutions (>400 mOsm)
because of the threat of myocardial dehydration and subsequent “rebound edema” after reperfusion with normal
blood, Okamoto et al. (311) showed the greatest protection in a regionally ischemic revascularized segment with
a cardioplegia solution having an osmolarity greater than 400 mOsm.
Treating O2-Induced Injury
Gradually Restoring Oxygen Tension in the Reperfused Heart

As in any biochemical or biological system, the laws of thermodynamics are at all times paramount. However,
nowhere in clinical medicine have these laws been set aside more purposefully to achieve rapid reoxygenation
and reperfusion in a timely fashion than in the revascularization era of clinical cardiovascular treatment. In the
following sections, important research gathered over decades regarding the molecular basis for cardiac
protection is discussed. A reexamination of every mechanism of reperfusion-related injury as it relates to oxygen
re-exposure may be instructive as the development or creation of abrupt gradients of perfusate oxygen tension
compared to tissue oxygen tension have been observed to be unintentionally injurious in multiple clinical and
experimental studies.
Piper et al. (312) showed in a series of exquisite studies on shaved cardiac tissue that the reintroduction of
oxygen into the milieu after a period of hypoxia led to violent Ca2+ oscillations that led ultimately to myofibrillar
contracture and cell death. The Ca2+ “paradox” and Ca2+ overload have been appreciated for years as
contributing to tissue injury after ischemia. However, it was not until Piper’s work that an appreciation for the
contribution of molecular O2 itself has evolved (e.g., oxygen paradox). As discussed elsewhere in this chapter, as
ischemic conditions progress, an accumulation of intracellular Na+ ions is observed as rapid ATP depletion leads
to a shift in membrane bound pump activity. Ischemic conditions allow the Na+/H+ pump to become active. The
Na+/H+ pump inhibitors cariporide and eniporide have been studied extensively because of their ability to block
at least some of the intracellular
P.202
Na+ accumulation that occurs during the ischemic interval. Much more could be reviewed here but suffice to say
that the intimate interaction between the accumulation of intracellular Na+ ions and the development of rigor
contracture (one hallmark of reperfusion injury) is clearly related to the reintroduction of O2. One could infer that
a more gradual reintroduction of O2 and an avoidance of an extremely high gradient between tissue and
perfusate could mitigate such injury. The administration of cariporide has never worked because it must be given
during the ischemic period, which is something that begins clinically hours before a patient is seen (313).
However, the avoidance of hyperoxic conditions is something that can be achieved easily in the clinical
environment.
Piper’s work has suggested that in vivo protection could be enhanced if the heart was exposed to relative
normoxia at the moment of reperfusion by the administration of deoxygenated (venous) blood followed by a
gradual ramping up of O2 tension for several reasons: (1) a slightly lower pH can uncouple Ca2+-related
contraction of the myofibrils, and (2) more matched perfusate-to-tissue O2 tension would limit oxidative stress
and mitigate Ca2+ oscillations in the vicinity of the mitochondrial membrane. More gradual O2 re-exposure in the
ischemic milieu comports with the laws of thermodynamics and, while counterintuitive clinically, is consistent with
more recent observations that over-oxygenated patients may do worse rather than better.
The contribution of oxidative stress and elevated perfusate-to-tissue oxygen gradient at the time of the
elimination of ischemic conditions has also been observed recently to contribute directly to mitochondrial edema,
dysfunction and, ultimately, cell death. The exquisite sensitivity of the mPTP to hyperoxic conditions and its
contribution to postischemic injury of the cell cannot be overstated. This is a raging area of ongoing research
and there is intense focus on the mitochondria currently as discussed in this chapter. In unpublished data, one of
the authors (NJT) recently observed mitigation of mitochondrial edema and damage in a porcine model of
ischemia-reperfusion injury (Fig. 9.8). In this trial, blinded observers, including a cardiac pathologist, almost
uniformly graded over-oxygenated tissue as having more intense mitochondrial edema as compared to those pig
hearts exposed to more gradual reoxygenation.
The concepts of “antioxidant therapy” described in sections of this chapter might be revisited and re-explored in
the context of having newer mechanism by which to avoid hyperoxia in the first place. This will be examined in
the section on future directions and the role of the surgical team.
Oxygen Radical Therapy

Therapy targeting oxygen radical-induced myocardial injury must take into consideration several factors,
including (1) the time during the operative course when oxygen radicals are generated, (2) the source of the
oxygen radicals (endothelial cell, neutrophil, myocyte or mitochondrial), and (3) the species of radical toward
which the intervention is directed. In general, the choice of pharmacologic intervention should consider the
cascade of oxygen radical generation shown in Figure 9.3.
FIGURE 9.8. Transmission electron micrographs (TEM) of myocardium. A: Normal porcine myocardium
(5,000×); B: TEM of porcine myocardium after 90 minutes of ischemia followed by reperfusion with blood at Po2
250 to 350 mm Hg (30,000×). Note mitochondrial swelling and disruption; C: TEM of porcine myocardium after
90 minutes of ischemia followed by reperfusion with blood at pO2 of 40 to 45 mm Hg and gradual increase to 100
to 150 mm Hg (30,000×). Note relative preservation of mitochondrial architecture with controlled reoxygenation.
Because the infusion of cardioplegia is a form of reperfusion during which key sources for ROS production are
delivered to the myocardium, the cardioplegic vehicle must also be scrutinized for its potential to produce or
exaggerate oxygen
P.203
radical production. For example, crystalloid cardioplegia carries less O2 as a substrate for oxygen radical
production than its blood cardioplegia counterpart. Blood, on the other hand, contains abundant O2, neutrophils,
lipids, and iron moieties, which may generate radicals. Reducing the participation of neutrophils by depleting
blood reperfusates and blood cardioplegia solutions of neutrophils (314,315) may be effective if leukodepletion is
complete (316). Pharmacologic inhibition of leukocyte adherence to endothelium and oxidant production (317)
with agents such as adenosine or authentic NO• or NO• donors has proved beneficial for the most part (318) and
further highlights the role of neutrophil-mediated damage during surgical ischemia and reperfusion (319).
However, blood also carries important endogenous scavengers (i.e., superoxide dismutase, catalase, and
glutathione in erythrocytes).
Scavengers and enzymes that inhibit or neutralize oxygen radicals are most effective if administered either as a
pretreatment or as an additive to the cardioplegic solution. Experiments using various animal models under a
number of conditions relevant to the surgical setting have evaluated a host of oxygen radical scavengers and
inhibitors as cardioplegic solution adjuvants (136,320) These observations generally reflect the consensus of
efficacy of antioxidant therapy obtained from extensive nonsurgical studies about short-term myocardial
ischemia-reperfusion (131,321). The failure of SOD to reduce oxygen radical-related injury may be related to the
proximal position of its target molecule, -O2, and the fact that other radical species (i.e., H2O2, •OH) generated
during ischemia-reperfusion would not be targeted by SOD. On the other hand, SOD plus catalase or catalase
alone interrupts the accumulation of two radical species (-O2•, H2O2), allowing only the •OH originating from
sources other than the -O2-H2O2 cascade (i.e., Haber-Weiss reaction) to persist. In addition, the relatively large
peptide structure of SOD may impair its interaction with superoxide anions at the neutrophil-endothelial cell
interface. Exogenous SOD does not attenuate intracellular sources of superoxide anion, which may allow
intracellular production of oxygen radicals by xanthine oxidase and mitochondria to go unchecked. The xanthine
oxidase inhibitors allopurinol and oxypurinol improve postischemic function in experimental and clinical
(322,323,324) studies. The benefit of using allopurinol and oxypurinol may be derived from the accessibility of
the molecules to their respective targets. N-(2-mercaptopropionyl) glycine (MPG) is a purported scavenger of
hydroxyl radicals and superoxide anions that enters the intracellular compartment. However, when used as an
adjuvant to cardioplegia in two models of cardioplegia-based myocardial protection, MPG conferred no additional
benefit to postischemic function (136).
Several clinical studies support the appearance of ROS during CPB and cardioplegic arrest (325,326,327).
Although experimental evidence strongly supports the beneficial effects of antioxidant therapy in cardioplegia, the
clinical benefits of this strategy are not clear. Bical et al. (328) showed no attenuation of oxygen radical
metabolites in patients undergoing cardioplegic arrest when crystalloid cardioplegia enhanced with allopurinol
was used. The inclusion of allopurinol only after cardioplegia (as a controlled phase of reperfusion) had been
delivered, so that the generation of oxygen radicals during cardioplegia was not prevented. On the other hand,
Castelli et al. (329) demonstrated that allopurinol given intravenously for 1 hour after bypass improved cardiac
output while decreasing plasma xanthine oxidase, implying that the protective effect was mediated through
decreases in free radicals. Allopurinol pretreatment has shown potential cardioprotective effects (310).
In other clinical studies in which oxygen radical scavengers (mannitol) or inhibitors (allopurinol) were delivered as
additives to the cardioplegic solution, postischemic myocardial injury was reduced (310,330). The dichotomous
results between these studies are likely a consequence of the wide range of myocardial protective techniques
employed coupled with the variability in endpoints evaluated, which makes comparisons between results difficult
and leaves the question of optimal antioxidant therapies still unanswered. Although a recent study by Larsen et
al. (309) showed no significant difference in patients receiving mannitol in cardioplegia versus a control group,
trends to less oxygen radical generation were observed; this lack of significance is likely related to the very small
number of patients (11 patients in each group).
Glutathione (readily available in tissue, red blood cells, and plasma) as an adjunct to both cardioplegia and
transplant preservation solutions has received attention for its antioxidant properties (331,332,333). In addition to
its potent antioxidant properties through glutathione peroxidase, glutathione may be involved in neutralizing
peroxynitrite (ONOO-), a potentially injurious by-product of NO• (334,335,336). Animal studies have
demonstrated a direct correlation between endogenous glutathione production and cardioprotection by using
genetic knockout and overproduction models of glutathione synthesis (333,337). Human studies evaluating the
efficacy of glutathione in CPB patients are sparse, but some investigators have shown improved myocardial
preservation in transplanted hearts when perfusate solutions containing glutathione were used (338,339).
Enhancing Myocardial Metabolism

Amino Acid-Enhancement
Cardioplegia formulations that adequately protect the myocardium of normal hearts have often been found to
provide inadequate protection for severely damaged hearts exposed to antecedent ischemia, reperfusion injury,
or present in cardiac failure or cardiogenic shock. Failure to protect these hearts adequately may be related to
the inability to maintain sufficient levels of high-energy phosphates in the already energy-depleted myocardium,
or failure to sustain adequate levels of glycolysis or other metabolic processes during the periods of hypothermic
ischemia, or to ward off other
P.204
ischemia-reperfusion injury processes. Limitation of energy production by anaerobiosis during hypothermic
ischemia may be in part related to depletion of key Krebs cycle intermediates and their precursors, glutamate
and aspartate, and to the failure of the malate-aspartate shuttle mechanism to remove protons and prevent
intracellular acidosis. Although shorter periods of ischemia may not reduce Krebs cycle activity per se (340), both
glutamate and aspartate are lost during prolonged ischemia or reperfusion (341) and are actively incorporated
into the myocardium when exogenously supplied (342). This conclusion is not supported by Reed et al. (343),
who showed no incorporation of either glutamate or aspartate into the Krebs cycle. Glutamate purportedly enters
into the Krebs cycle by conversion to α-ketoglutarate, whereas aspartate enters the Krebs cycle via
transamination to oxaloacetic acid. Both precursors are subsequently metabolized within the Krebs cycle to
succinate, each ultimately producing 1 mole of ATP by substrate-level phosphorylation independent of glycolysis.
Therefore, high-energy phosphates can be derived from amino acid metabolism even when the level of
glycolysis is reduced during ischemia. In addition, glutamate and aspartate may inhibit the mitochondrial
accumulation of protons by sustaining the malate-aspartate shuttle, thereby preventing uncoupling of oxidative
phosphorylation and the generation of ROS.
Addition of glutamate and aspartate to the cardioplegia solution increases myocardial oxygen uptake during
induction of arrest (i.e., independent of cardiac work) and improves postischemic myocardial performance and
oxygen utilization (344) after discontinuation of CPB. The improvement observed was greater in energy-depleted
hearts compared to uninjured hearts (345). The study by Rosenkranz et al. (344) suggests that glutamate and
aspartate used together act synergistically by providing greater protection than either amino acid alone. In
addition, greater benefits may be obtained by combining amino acid supplementation with normothermic
induction of cardioplegia, as both strategies augment oxygen uptake during induction of cardioplegia. Because
amino acid supplementation acts mainly by replenishing lost Krebs cycle intermediates and facilitating both
anaerobic and aerobic metabolism, the addition of glutamate, aspartate, or both may be indicated in other
situations in which the myocardium may be extremely depressed or subjected to prolonged ischemia or hypoxia,
such as hypoxia-reoxygenation injury (244), reperfusion of hypoxic or ischemic immature hearts (346,347),
cardiac transplantation (348), and storage of donor hearts (349,350). Amino acid supplementation has been
shown to increase high-energy phosphate stores in human myocardium (351). In addition, it has been shown that
glutamate administered intravenously to patients after coronary bypass operations is taken up and has a
beneficial effect on oxidative metabolism, with some indication of better postcardioplegia cardiac performance
(342). In a clinical study of 22 patients with moderate preoperative ejection fraction (30%-40%) undergoing
CABG, Uyar et al. (352) reported that cardioplegia enhanced with glutamate and aspartate had no benefit
compared to standard cardioplegia in CABG patients. However, Duman et al. (353) reported in a similarly sized
study of CABG patients that there was no difference in either CK-MB or cTnT, but there was transient
improvement in cardiac functional parameters postbypass in agreement with the experimental study by Asai et al.
(270) Since biologic significance (a type II error) can escape detection with small study populations, larger
studies on the benefits of amino acid-enhancement of cardioplegia solutions incorporating randomized, blinded
designs are warranted. However, since not all cardioprotective strategies fit all situations, differentiating the
patient populations which benefit from amino acid enhanced therapy from the populations that do not would be
very helpful.
Anti-inflammatory Therapy
Specific Anti-neutrophil Therapy in Surgical Myocardial Protection
With strong evidence supporting a role for neutrophils and inflammatory responses in the pathogenesis of
surgical ischemia-reperfusion injury, new myocardial protective strategies have targeted individual components
of the inflammatory cascade, or a number of components collectively (broad-range therapy). Therapy to limit
neutrophil-endothelial cell interaction could dramatically reduce myocardial dysfunction and morbidity after CPB
despite the intense activation of the inflammatory cascade during coronary operations. Many specific monoclonal
antibodies that inhibit neutrophil adherence to the endothelium are currently available, including antibodies for
CD18, P-selectin, and L-selectin. However, enthusiasm for antibody therapy has been blunted by systemic
immunosuppressive effects, which may predispose to postoperative infection. In addition, a single target
(monotherapy) approach has been found to be less effective than broader-range drugs that interdict several
targets.
Hypothermia is the simplest method for inhibiting cell surface adhesion molecules. In addition to minimizing
cellular metabolic activity, hypothermia slows the expression of endothelial adhesion molecules (260,354).
Decreases in temperature to 25°C will temporarily almost eliminate expression of E-selectin. These findings have
been confirmed by others, but no hypothermia-induced lasting reduction of adhesion molecule expression has
been observed (101,104).
The temporary effects of hypothermia highlight the time-dependent nature of adhesion molecule expression,
indicating that therapy must coincide with the expression of these molecules. For example, the expression of P-
selectin, an endothelial adherence molecule responsible for the initial slowing or “rolling” of neutrophils along
endothelial surfaces in the early phase of reperfusion, must be addressed within the first 30 minutes of
reperfusion to limit neutrophil-endothelial interaction, but firmer adherence would need to be addressed with E-
selectin and ICAM-1 blockade several hours later (355,356). This has prompted investigators to examine the
transcription
P.205
factors responsible for families of surface adhesion molecules. The best studied of these factors is NF- κB.
Mutations in regulatory proteins for the NF- κB family of transcription factors decrease the production of both E-
selectin and VCAM following endothelial activation (357,358). Speculation about the potential for an increased
risk for perioperative infection with systemic limitation of neutrophil infiltration has slowed clinical investigation of
this potentially powerful protective tool, but short-term therapy would avoid the deleterious effects on aneurysm
formation in infarcted myocardium previously observed with long-term therapy.
Targeting the neutrophil represents an alternative to attenuation of endothelial adhesion molecule expression.
The transition from bubble oxygenators to membrane oxygenators was driven, in part, by the decreased
complement activation and subsequent neutrophil-induced injury seen with the membrane-type devices. Like
those targeting endothelial adhesion molecules, strategies to attenuate the actions of adhesion molecules on the
neutrophil have been investigated with limited success. (359) However, Flynn et al. (360) have demonstrated
that an oligosaccharide that binds the sialyl Lewisx receptor on the neutrophil is able to reduce infarct size
following ischemia and reperfusion in dogs. The clinical application of this strategy remains unknown. Filtration of
neutrophils with leukocyte-specific filters directly reduces neutrophil accumulation and decreases subsequent
inflammatory injury (361,362,363,364). An advantage to this approach is that the filter can be interposed in the
cardioplegia delivery line to filter neutrophils selectively from blood cardioplegia, rather than simply filter systemic
blood (365). However, the potential for activation of leukocytes by the filters themselves may impact enthusiasm
for this approach (366). The clinical advantages in postcardioplegia outcomes of filtering neutrophils are still
under debate.
Complement-related therapy
Complement is involved in the pathophysiology of myocardial postischemic injury and infarct development. As
described above, both myocardial ischemia and extracorporeal circulation increase the generation of
complement fragments and other components of the complement cascade, notably the terminal membrane attack
complex C5b-9 (367). Complement products such as C3a, C5a, and C5b are activated during exposure of blood
to extracorporeal surfaces during CPB procedures. The setting of surgical revascularization of acute evolving
infarction by means of CPB and cardioplegia techniques may therefore offer a strong stimulus for complement
production and consequent complement-mediated injury. This complement-mediated injury may aggravate
ischemia-reperfusion injury in the surgical setting and, hence, reduce the benefits of surgical revascularization.
However, as Gillinov et al. (106) and others have suggested, the redundant pathways in the inflammatory
cascade may require more broad-acting therapy that inhibits multiple arms of the inflammatory response.
A number of strategies have been adopted to attenuate complement-mediated damage in the surgical setting of
CPB. Coating of extracorporeal surfaces with heparin and other agents that inhibit the inflammatory response
has provided some benefit. The use of leukocyte-specific filters temporarily removes the offending neutrophils
from the circulation as discussed above, but this approach does not address the interaction between blood and
foreign surfaces that results in complement activation, does not prevent the rapid rebound of neutrophils into the
circulation after transient leukosequestration and margination, and does not prevent direct cell injury by the
membrane attack complex. Antibodies directed against cytokines, complement fragments, adhesion molecules,
and the complement receptors themselves (i.e., complement receptor type 1 (CR-1)) constitute another approach
to attenuating the complement-induced inflammatory component of surgical ischemia-reperfusion injury.
Attenuation of complement activation with soluble human CR-1 was shown by Gillinov et al. (368) to reduce
complement hemolytic activity and functional activities of C3 and C5 in a porcine model of hypothermic (28°C)
CPB. Soluble complement CR-1 improved post-CPB pulmonary function and vascular resistance (367,369) and
cardiac performance (369) in experimental models. Lazar et al. (370) investigated the CR-1 inhibitor TP10 in 564
high-risk patients undergoing cardiac surgery (CABG, valve). There was no overall significant difference in
composite end point (death, MI, use of prolonged intra-aortic balloon counterpulsation, duration of intubation),
but there was significant outcomes advantage in the subgroup of males undergoing CABG.
Pexelizumab: Pexelizumab is a 25-kDa humanized single-chain monoclonal antibody to C5. It has undergone
several large-scale studies in cardiac surgery or safety and efficacy. Shernan et al. (371) tested composite
outcomes endpoints of death, incidence of MI, and LV dysfunction in 914 patients undergoing CABG with or
without concomitant valve surgery. Patients received pexelizumab as either a bolus or bolus plus infusion, which
set the treatment protocol for subsequent trials. They reported that there was no overall group difference
(treatment vs. placebo) in the primary composite end point, but a sub-analysis showed a significant difference in
death/MI for isolated CABG using the bolus plus infusion protocol. The subsequent PRIMO-CABG I trial showed
that pexelizumab was associated with a significant decrease in the primary end point of death/MI in the intent-to-
treat group compared to placebo, but not in the isolated CABG group (372). However, death/MI was reduced
through 180 postoperative days in a subgroup of patients with two or more risk factors. In addition, another
subset analysis of the PRIMO-CABG I dataset showed that pexelizumab decreased death/MI through 30
postoperative days and death alone at 30, 90 and 180 days in patients with cross-clamp times exceeding 90
minutes (373). In contrast to PRIMO-CABG I, the follow-on PRIMO-CABG II trial did not meet the primary end
point of death/MI at 30 days, death
P.206
alone at 30 days or incidence of new heart failure. An analysis of the combined PRIMO-CABG I and II trials with
7,353 patients did show a reduction in death at 30 days that persisted to 180 postoperative days for the highest-
risk subset (374). These data suggest that inhibiting the complement cascade at a critical point may provide
outcomes benefits in at least high-risk patients. It seems that meaningful cardioprotective strategies are most
beneficial in the worst patients, similar to other cardioprotective strategies discussed above.
Adenosine Therapy
There has been abundant research focused on the mechanisms by which adenosine protects the heart from
both reversible and irreversible injury after myocardial ischemia and reperfusion. There are some extensive
reviews of adenosine’s cardioprotection and the physiologic and molecular levels
(375,376,377,378,379,380,381,382). Adenosine has a broad spectrum of physiologic effects that exert
cardioprotection (382,383,384). A distinct advantage of the physiologic and pharmacologic profile of adenosine is
that it exerts effects during multiple time windows that are important to the pathogenesis of ischemia-reperfusion
injury (i.e., before ischemia, during ischemia, and at onset of reperfusion), and it acts via multiple transduction
mechanisms on multiple targets (myocytes, platelets, neutrophils, endothelium). Hence, adenosine has a built-in
redundancy that may block the multiple mechanisms of ischemia-reperfusion injury at several points, that is, it is
a broad-spectrum cardioprotective agent.
Adenosine produces a majority of its physiologic effects by interacting with specific purinergic receptors. There
are at least four types of adenosine receptors: A1, A2a, A2b, and A3. Stimulation of A1 receptors, located mainly
on neutrophils and myocytes, decreases adenylate cyclase activity via inhibitory G-protein (Gi) or stimulates the
phospholipase C-diacyl glycerol (DAG)—inositol phosphate (IP3) pathway to cause a release of Ca2+ from
intracellular stores and a translocation of protein kinase C from the cytosol to the cell membrane. The primary
effector linked to the A1 receptor subtype may be the KATP channel, the stimulation of which induces
hyperpolarization, inhibition of transmembrane Ca2+ conductance, and cardioprotection. Physiologic effects of
adenosine A1 receptor activation include negative chronotropy and dromotropy, antiadrenergic effects, increased
rate of glycolysis, and stimulation of neutrophil adherence. Activation of adenosine A2 receptors, located mainly
on neutrophils, endothelial cells, vascular smooth-muscle cells, and platelets, stimulates adenylate cyclase
through the stimulatory G-protein (Gs), which results in vasodilation, renin release, and inhibition of neutrophil
events (-O2 generation, adherence to endothelium, and endothelial dysfunction) (385,386). The adenosine A3
receptor has been localized in heart tissue and myocytes. The A3 receptor is similar to the A1 receptor in that it
inhibits adenylate cyclase, stimulates protein kinase C translocation, and may activate KATP channels. Its
cardioprotective profile differs substantially from that of the A1 receptor, however, as discussed below.
In the surgical setting, cardioprotective strategies can be applied as a pretreatment before cross-clamping,
during ischemia (arrest), and during the early phase of reanimation and reperfusion. Adenosine’s effects are
expressed beyond its short half-life because receptor transduction perpetuates the effects. The benefit of
adenosine treatment partly depends on effectively targeting the mechanism of injury operative at the time of
administration (387).
Pretreatment
The pretreatment infusion of adenosine (“pharmacological preconditioning”) may protect the heart by attenuating
detrimental intraoperative ischemia. The cardioprotective effects of adenosine when administered before or
during ischemia may be mediated primarily by activation of A1 receptors (388) and opening of KATP channels,
with the consequent reduction of cytosolic Ca2+ overload (389). Pretreatment administration of adenosine has
been reported by Lee et al. (390) in patients with poor left ventricular performance and multi-vessel coronary
artery disease. They reported an improvement in the postsurgical cardiac index immediately after separation
from CPB, which persisted for 40 hours postoperatively in patients who received adenosine (250-350 mg/kg/min)
for 10 minutes just before CPB. Furthermore, creatine kinase levels 24 hours postoperatively were significantly
lower in adenosine-treated patients. This study (390) shows that a pretreatment window is available for the
effective administration of adenosine, without significant untoward complications such as hypotension or
bradycardia.
Adenosine-Enhanced Cardioplegia
One of the most obvious applications of adenosine is as an adjunct to cardioplegia solutions. In 1976, Hearse et
al. (21) reported that adenosine, used either alone during ischemia or as an adjunct to cardioplegia, improved
postischemic function. Since then, numerous studies have been performed to investigate the role of adenosine
as an adjunct to crystalloid hypothermic cardioplegic solutions (233,391,392,393). Most of these studies showed
that adenosine in a wide range of concentrations (100 μmol/L to 10 mmol/L) was associated with improved
postischemic contractile function in comparison with unsupplemented crystalloid counterparts. The beneficial
effects of adenosine-enhanced crystalloid cardioplegia have been attributed to a number of mechanisms
independent of neutrophil inhibition, including improvement in the rate of anaerobic glycolysis and energy status,
and reduction in Ca2+ accumulation resulting from cell hyperpolarization. Although some studies report that
adenosine restores tissue ATP content lost during ischemia (393), others show no correlation between tissue
ATP content after reperfusion and functional recovery (389,394,395,396).
P.207
Administration of adenosine as an adjunct to hypothermic cardioplegia without treatment at reperfusion may not
be the most optimal modality. Indeed, this has been suggested by studies by Ledingham et al. (395) and Thelin
et al. (396), in which transient adenosine infusion only at the start of surgical reperfusion was associated with
improved functional recovery. Thourani and colleagues (397) found in an experimental model of cardioplegia
delivery that administered adenosine either as an adjunct to blood cardioplegia (100 μmol/L) alone, or as a
reperfusion treatment during terminal cardioplegia and during the first 30 minutes after aortic declamping (140
μg/kg/min) reduced infarct size, improved postischemic contractile function, and decreased both myocardial
edema and neutrophil accumulation (myeloperoxidase activity) in the area at risk compared to unsupplemented
blood cardioplegia. This observation is consistent with the potent anti-neutrophil effects of adenosine. Hence,
reflecting the importance of timing with action of a drug, adenosine is most effective when used in all windows of
cardioprotection against ischemic injury and reperfusion injury.
Adenosine-supplemented cardioplegia has been studied in a limited number of human clinical trials. In 1996,
Fremes et al. (398) reported an open-label, nonrandomized, phase I adenosine dose-ranging study in patients
undergoing elective coronary artery bypass. A range of adenosine concentrations (15-50 μmol/L) to supplement
antegrade warm blood potassium cardioplegia was tested in the initial 1,000-mL cardioplegia dose and the final
500-mL dose. It was concluded that adenosine can safely be administered during CPB and that adenosine at a
concentration of 15 to 50 μmol/L is the optimal dose. In a follow-up study by the same group, Cohen and
colleagues (399) performed a double-blinded, randomized, placebo-controlled trial in patients undergoing
primary, isolated, nonemergent coronary artery bypass surgery. Adenosine (15, 50, or 100 μmol/L) or placebo
was added to antegrade warm blood cardioplegia in the initial 1,000 mL and last 500 mL of cardioplegia delivery.
They found no significant differences between groups in the incidence of individual primary or secondary
outcomes (including death, low-output syndrome, postoperative myocardial infarction, use of inotropes, or intra-
aortic balloon pump requirement). In contrast, Mentzer et al. (400,401,402) tested the efficacy of adenosine as
an additive to cold blood cardioplegia in an open-labeled, randomized study of patients with ejection fractions
greater than 30% undergoing elective coronary artery bypass grafting. The patients were randomized to
standard antegrade cold blood cardioplegia without adenosine or to one of five adenosine doses: 100 μM, 500
μM, 1 mM, and 2 mM plus an intravenous pretreatment infusion of 140 μg/kg/min. Patients were followed for 24
hours after discontinuation of CPB. Increasing concentrations of adenosine in cardioplegia were associated with
lower requirements for postoperative dopamine and nitroglycerine and improved ejection fraction in comparison
with placebo and 100- μM adenosine. In a follow-up study, Mentzer et al. (402) reported that the high-dose
adenosine cardioplegia groups (2 and 200 mM followed by 140 μg/kg/min) had significantly reduced
postoperative thoracic drainage at 6 hours and 24 hours in comparison with the control and low-dose adenosine
cardioplegia group (100 μM). This was associated with a significant reduction in the use of platelets, fresh frozen
plasma, and packed erythrocyte in the high-dose adenosine cardioplegia group. In the Phase II study, in which
patients received cold blood cardioplegia with 500 μM or 2 mM adenosine and an infusion of 200 μg/kg/min 10
minutes before and 15 minutes after declamping, a trend toward a decrease in high-dose dopamine use was
observed. Liu et al. (403) tested whether adenosine in blood cardioplegia (1 mmol/L) supplemented with a
pretreatment infusion (10 minutes of 100 μg/kg/min) was cardioprotective in valve replacement surgery. They
found that adenosine was associated with a reduction in perioperative cTn I, IL-6, and IL-8, and less
ultrastructural damage in biopsies. However, Ahlsson et al. (404) conducted a prospective double-blind study in
80 patients undergoing isolated aortic valve replacement in which adenosine (400 μm/L adenosine) or placebo
was included in continuous antegrade or retrograde cold blood cardioplegia. They found no difference in cTnT
release over 24 hours compared with a placebo group. Therefore, the results of clinical trials with adenosine as
an adjunct to cardioplegia are inconsistent but encouraging, but as yet demonstrate no clear advantage to
adenosine over unsupplemented cardioplegia. There are many reasons why adenosine can be cardioprotective
in animal experiments but not in clinical trials beyond the usual reasons for disparity between preclinical and
clinical trials. Adenosine has a very short (˜7-12 seconds) halflife in blood; it is deaminated by plasma adenosine
deaminase. Hence, it can quickly become deaminated in blood cardioplegia even when delivered cold. Delivering
adenosine via a separate line to admix with cardioplegia at the tip of the delivery cannula would reduce the
exposure time and ensure that the delivery concentration approximates that intended by calculations. Further
studies of adenosine alone or in combination with other agents are warranted with this thought in mind.
Nitric Oxide and NO-Donors

Two general approaches have been taken to harness the cardioprotective potential of NO: (1) modulation of
endogenous NO• by addition of precursors or agents that stimulate native NO• production by NO• synthase such
as L-arginine or the cofactor tetrahydrobiopterin (BH4), and (2) administration of authentic NO• or NO• donors.
NO• homeostasis depends on a balance of NO• generation, availability and breakdown or quenching. NO•
generation depends on a healthy endothelium, and on the presence of Ca2+, NADPH, flavin, and BH4. Both BH4
and L-arginine are depleted during ischemia. Hence, a therapeutic approach to increase the endogenous
production of NO• must take into consideration that supplementation of substrate will not be effective without
adequate provision of cofactors.
P.208
Enhancing Endogenous NO• Release by Substrate or Cofactor Enhancement

Enhancing the release of endogenous NO• can be achieved by providing the precursor L-arginine. Although L-
arginine appears in the blood in sufficient concentrations to saturate the endothelial isoform of NO synthase,
supplemental L-arginine has been shown to increase NO• release (directly or indirectly measured) by the
coronary vascular endothelium (172,405). In in vitro studies of neutrophil adherence and neutrophil-induced
damage to coronary artery endothelium, supplementation with 10-mM L-arginine resulted in significantly
attenuated neutrophil adherence to activated coronary artery endothelium, and significantly attenuated
neutrophil-mediated injury to endothelium-dependent vasorelaxation responses, although L-arginine did not
directly attenuate neutrophil -O2 production (405). Neutrophil adherence was not inhibited by D-arginine (10
mM), and 600- μM carboxy-PTIO, a direct scavenger of NO•, reversed the effects of L-arginine.
In surgical models of antecedent ischemia (regional or global) with subsequent cardioplegia and reperfusion,
supplementation of blood cardioplegia with L-arginine has been shown to provide significant benefit, consistent
with its potent anti-neutrophil effects (134). These beneficial effects of L-arginine were also associated with a
significant decrease in neutrophil accumulation in the reperfused area at risk (135). The effects of L-arginine
were reversed by the NO synthase inhibitor L-nitro-arginine infused before administration of L-arginine-enhanced
blood cardioplegia. These results have been corroborated by other studies in which cardioplegia solutions were
supplemented with L-arginine (406,407).
Several clinical studies in coronary artery bypass surgery have supported beneficial effects of supplementary L-
arginine. Carrier et al. (408) reported a negative study of supplemental L-arginine in cardioplegia in a small study
of 50 patients randomized to a control group or a group receiving blood cardioplegia supplemented with 1 gm of
L-arginine. There was no difference between groups in 72-hour TnT or peak TnT release. In a subsequent study
of 200 patients in which the treatment group received blood cardioplegia enhance with 7.5 g L-arginine in 500
mL or induction cardioplegia, this group showed decreased TnT over 48 hours (409). The difference between
the two studies may be related to the higher dose of L-arginine or greater statistical power in the larger patient
cohort. Kiziltepe et al. (410) gave L-arginine in cardioplegia and in the warm reperfusion just before declamping,
and found that this increased systemic NO• (nitrite) levels, decreased the presumptive marker of oxidant injury
plasma malondialdehyde, reduced CK-MB/CPK ratio at 6 hours postoperatively, decreased perioperative MI, and
reduced both ICU and overall hospital stays. Using a similar protocol to that used by Carrier et al. (409),
Colagrande et al. (411) showed similar results as Kiziltepe et al. (410), but also found that L-arginine reduced
postoperative pulmonary artery wedge pressure and plasma IL-6 levels, consistent with the anti-inflammatory
effect of NO•. Hence clinical results are encouraging with higher and multiple doses of L-arginine covering both
arrest and reperfusion.
Other strategies to Increase Endogenous NO•

Since eNOS activity and NO• generation depend on cofactors such as BH4, both substrate and cofactors may be
necessary to enhance endogenous NO• generation and prevent -O2 production by uncoupling of eNOS. This
dependence on cofactors may explain some of the negative studies discussed above in which cofactor may have
been depleted in the heart. Supplementation of BH4 has been reported to be protective in a rat Langendorff
model of global ischemia-reperfusion and in human ventricular myocytes (412), and increased NO• levels in
perfusate, and increased postischemic cardiac function in isolated-perfused hearts subjected to normothermic
ischemia and reperfusion (413). Finally, bradykinin and agents that affect bradykinin levels (e.g., ACE inhibitors)
may enhance the generation of NO• and vasodilator peptides. Clinical studies are needed to confirm these
results further.
Protection by NO• Donors

A limitation may be encountered in utilizing the endogenous cardioprotective mechanisms evoked with L-arginine
therapy in that the increased release of NO• depends on the functional state of the endothelium. Consequently,
an injured endothelium in which NO• generation mechanisms are impaired not only may show attenuated
responses to L-arginine, but also may produce -O2 (414), thereby exaggerating postischemic injury. This
limitation in the endogenous generation of NO• can be overcome by the administration of NO• donor agents
(415). Organic donors release NO• either spontaneously or after bioconversion. Nitroglycerine is the prototype
NO• donor agent but is a poor donor because of its prerequisite bioconversion by a cysteine-containing enzyme
that is partially depleted in the microvasculature after ischemia-reperfusion. One such cysteine-containing
compound that readily releases NO• after biotransformation is SPM-5185 [ N-(3-hydroxy-pivaloyl)- S-( N′-
acetylalanoyl) L-cysteine ethyl ester] (Schwarz Pharma AG, Monheim, Germany). An experimental study by
Nakanishi et al. (416) using cardioplegic arrest in an ischemically injured canine heart model showed that
cardioplegia supplemented with 10- μM SPM-5185 improved postischemic ventricular performance (pressure-
volume loops) and postcardioplegia endothelial function in part by attenuating neutrophil-mediated damage.
Other nitrosothiol-based NO• donors have been tested in preclinical studies (417,418).
EMERGING CONCEPTS AND STRATEGIES IN CARDIOPROTECTION

Polarized Arrest and Hyperpolarizing Agents
Advantages and Disadvantages of Potassium-Induced Depolarized Arrest
Concentrations of potassium used in most cardioplegia solutions range between 20 and 30 mM (mEq/L), the
upper limit
P.209
being set by the observation that the L-type Ca2+ channel is activated at this concentration causing an influx of
Ca2+. However, at 16 to 20 mM K+ there is a persistent Na+ influx following the electrochemical gradient for Na+,
the so-called Na+ “window current” (419), even though conductance for Na+ is 0.1% of maximal relative to -80
mV transmembrane potential. This slow Na+ window current promotes the intracellular accumulation of Na+ over
time; Na+ accumulation is further facilitated by a decrease in Na+ extrusion by the ATP-driven Na+/K+ pump
during ischemia or inadequate oxygen supply relative to demand when ATP is depleted. This reduced Na+/K+
pump activity fails to correct the increase in intracellular Na+ accumulation. In addition, an accumulation of H+
during intracellular acidosis seen during ischemia leads to the efflux of H+ for the influx of Na+ by the Na+/H+
exchanger. Both events increase intracellular Na+ which then stimulates the reversal of the non-ATP-dependent
Na+/Ca2+ exchanger (3Na+ outward exchange for 1Ca2+ inward exchange) leading to Ca2+ overload. Hence,
although hyperkalemia produces rapid onset and reversible arrest, the K+-depolarized state has numerous
disadvantages that impact cell viability and cardiac function. In addition, K+-induced depolarization has been
associated with coronary vasoconstriction and maldistribution of cardioplegia, and activation of the coronary
vascular endothelium to promote pro-inflammatory, pro-coagulant and pro-oxidant states (reviewed in Dobson et
al. (27)). Postcardioplegia ventricular dysfunction (stunning), which occurs in approximately 10% of patients, may
be associated with the aforementioned pathologies aggravated by hyperkalemia. Furthermore, long cases or use
of continuous cardioplegia may lead to systemic hyperkalemia which has been associated with arrhythmias at
reanimation, and is not well-tolerated by patients with renal failure. Nondepolarizing alternatives are discussed in
a later section.
Alternatives to Hyperkalemia
Investigations on alternatives to hyperkalemia were initiated in the 1950s by the moratorium placed on the
“Melrose technic.” Bretschneider and colleagues tested low Na+, low Ca2+ and the Na+ channel blocker procaine
as a combination that would arrest the heart (420). Others used procaine (421), lidocaine (422), acetylcholine
(10) and the Na+ channel blocker tetrodotoxin (25,423,424). However, these alternative nondepolarizing
arresting agents have not translated into clinical practice. Adenosine was also tested as a potential
nondepolarizing arresting agent because of its ability to hyperpolarize cells. This will be discussed further below.
Opening of the KATP channels has been shown to hyperpolarize the cell membrane by increasing K+ efflux from
the cell (425,426). Notably, hyperpolarizing KATP channel openers such as nicorandil, pinacidil and aprikalim
have been previously investigated as alternative arresting agents in experimental models and found to provide
good postcardioplegia functional recovery (232,427). However, off-target effects and concerns over the safety
profile and postcardioplegia arrhythmias have reduced enthusiasm for KATP channel openers. Hence, they will
not be discussed further. However, the quest for effective and reliable nondepolarizing alternatives to
hyperkalemia continues and some promising candidates have emerged as discussed below.
Magnesium
Magnesium is nature’s L-type Ca2+ channel blocker by displacing calcium, and has been shown to attenuate
Ca2+ accumulation during ischemia (428). In high concentrations, it can induce cardioplegia (429). Hearse and
colleagues (430) showed that 16 mM magnesium was beneficial in St. Thomas’ cardioplegia solution; higher or
lower concentrations were less effective. Magnesium also has anti-ischemic effects by improving high-energy
phosphate availability. It is a standard constituent in Plegisol, and is often used as a key adjunctive
cardioprotective component in blood cardioplegia.
Magnesium as a primary arresting agent was examined experimentally by Maruyama and Chambers in 2008
(431). Magnesium (25 mmol/L) cardioplegia was slower to arrest the heart than its hyperkalemic counterpart, but
arrest was adequately maintained. Magnesium cardioplegia also delayed the onset of contracture and provided
the best functional recovery (developed pressure) compared to other concentrations of magnesium, and
compared to St. Thomas’s solution. Higher or lower concentrations showed delayed or incomplete recovery in a
bell-shaped curve fashion. Multidose delivery of cardioplegia improved the functional recovery of magnesium
cardioplegia.
Esmolol
Esmolol is an ultra-short-acting cardioselective β-blocking agent with a half-life of approximately 9 minutes. It is
used clinically to treat hypertension and tachycardia, but is also used in cardiac surgery to induce profound
bradycardia during off-pump surgery or during beating heart surgery. Warters et al. (432) showed in a canine
model of CPB that continuous normothermic perfusion enhanced with intravenous esmolol (10 mg/kg bolus, 500
μg/kg/min infusion) reduced cardiac contraction and hence blood pressure to <10 mm Hg (hypocontractile, not
arrested) during bypass support avoided lactate build-up and myocardial edema from biopsies compared to a
group arrested with conventional cross-clamping and multidose hyperkalemic crystalloid cardioplegia. The
esmolol group had function (pressure-volume relations) comparable to the conventional cardioplegia group after
120 minutes off bypass. At higher concentrations (1 mmol/L), esmolol was reported to arrest isolated rat hearts
perfused in the Langendorff mode (433), and oxygenated multidose esmolol cardioplegia (esmolol with Krebs
Henseleit buffer) provided better functional recovery than similar modalities of St. Thomas’ solution after 60 or 90
minutes global normothermic arrest.
The cardioplegic effect of esmolol may be derived from blockade of L-type Ca2+ channels and fast Na+ channels,
P.210
thereby preventing formation of an action potential and inducing nondepolarized arrest (434). Esmolol is
hydrolyzed by red blood cell esterases, which on the one hand limits its presence in the blood, but on the other
hand may reduce its efficacy in blood cardioplegia or other blood solutions. Fujii and Chambers (435) reported
that blood-based esmolol cardioplegia was superior to a similar but hyperkalemic blood cardioplegia solution.
Two clinical studies, each of 60 patients destined for CABG surgery received either continuous perfusion with
blood enhanced with esmolol or cold crystalloid (436) or blood cardioplegia (437). Esmolol induced a
hypocontractile (nonarrested) state; esmolol patients had less cardiac edema, less morphologic changes in LV
biopsies, reduced lactate release, and comparable cardiac function (fractional area of contraction by TEE) with
decreased inotropic support in one study (436). The clinical efficacy of esmolol as a primary arresting agent has
not yet been reported, but inducing a hypocontractile state during continuous perfusion on bypass has been
reported as discussed (436,437,438,439).
Adenosine-Lidocaine-Magnesium
The combination of adenosine and the local anesthetic lidocaine (AL) has been used to arrest the heart at
normokalemia. Adenosine opens KATP channels (440), hyperpolarizes the cell and reduces the action potential
duration of conduction tissue, while lidocaine blocks the fast Na+ channels and hence the inward depolarizing
Na+ current. The combination of adenosine and lidocaine, also referred to as Adenocaine, is effective in
arresting the heart in a polarized state at its resting membrane potential (234). Maintaining membrane polarity
has a number of advantages. Ward et al. (441) showed that maintaining the ventricular myocyte membrane
potential near its resting potential prevented neutrophil-induced myocyte depolarization and neutrophil-induced
contracture and cell death. Shi and colleagues (46) have recently confirmed that AL has potent anti-neutrophil
properties that go beyond those observed for adenosine and lidocaine alone. Therefore, AL fulfills a broader
concept of cardioplegia that arrests and exerts broad-spectrum protection in a simple formulation.
The concept of AL cardioplegia was developed by Geoffrey P. Dobson’s laboratory. Both adenosine and
lidocaine have cardioprotective (379,442), vasodilatory, anti-arrhythmic and anti-inflammatory (382,443)
properties. Dobson and Jones (234,444) first reported the arresting capabilities of AL in the isolated-perfused rat
heart preparation in which AL arrested the heart, and was superior to St. Thomas’s solution in restoring
ventricular function (developed pressure). Further studies confirmed that AL cardioplegia arrests and protects the
heart at normal potassium concentrations (445) (i.e., arrest can be achieved best when blood levels of potassium
are present), can be used warm or cold, and is protective when delivered intermittently or continuously (446).
Independence of temperature makes the concept of AL cardioplegia appealing for those who want to avoid the
disadvantages of hypothermia. Multidose AL cardioplegia delivered warm or cold (12°C myocardial temperature)
in a canine model of CPB and blood cardioplegia gave complete functional recovery (pressure-volume indices)
comparable to standard hyperkalemic cold blood cardioplegia (447). Subsequent studies should test the efficacy
of AL cardioplegia in hearts injured by prolonged global ischemia, which is the best proving ground for
cardioprotective strategies.
Clinical studies have not tested the efficacy of AL as a primary arresting combination. However, two clinical
reports have used lower nonarresting concentrations of AL and magnesium (ALM) as an adjunct to blood
cardioplegia, which ostensibly uses the anti-inflammatory properties of AL; lower potassium in the maintenance
doses of cardioplegia may have maintained a state of nondepolarized arrest (448,449). Onorati et al (449)
conducted a prospective randomized clinical trial using ALM with insulin in microplegia or a Buckberg-style 4:1
hemodiluted cardioplegia in 80 adult patients with unstable angina. This study showed that ALM-insulin
cardioplegia reduced transmyocardial troponin I and lactate release, improved postcardioplegia cardiac
performance, increased the incidence of spontaneous rhythm after unclamping, reduced the use of blood
transfusions and blood products, and decreased the length of both ICU and hospital stays. Further clinical
studies need to be done to determine whether protection is observed in other adult subgroups, and in pediatric
patients.
Along the same lines of pairing a local anesthetic with adenosine, Jakobsen et al. (235,450) reported that
normokalemic cold multidose crystalloid cardioplegia with adenosine-procaine and magnesium arrested and
improved postcardioplegia cardiac performance (pressure-volume relations) and reduced cTnT (235) and
endothelial function (450) in porcine hearts. The adenosine concentration was 1.2 mM, which was less than that
used clinically by Mentzer et al. (401). This formulation was tested in low-risk patients undergoing CABG surgery
by Jakobsen et al. (451). The adenosine-procaine combination was associated with decreased time to arrest
(confirming that this formulation arrests without hyperkalemia), and a decrease in the incidence of atrial
fibrillation. However, there were no differences in postcardioplegia cardiac index, troponin T, or CK-MB.
Other agents may theoretically be used to reversibly arrest the heart without depolarizing the myocardium. 2,3-
butanedione monoxime (BDM) is a reversible blocker of actomyosin ATPase which prevents cross-bridge
formation (452) and contraction. Early studies confirm its use as a cardioplegic agent (453) or adjunct to
normokalemic reperfusate (e.g., hot shot) (454). However, BDM or other similar agents such as bebbistatin (455)
have not been tested clinically as a cardioplegic agent.
Targeting the Mitochondrial Transition Pore

Cardioprotection from lethal reperfusion injury has been reported when mPTP opening is inhibited by
cyclosporine A, NIM811 or sanglifehrin A given at reperfusion (456,457,458).
P.211
Some inhalational anesthetics may also exert cardioprotective effects by inhibiting mPTP opening when given
specifically at the onset of reperfusion (459,460). In addition, opening of the mPTP is inhibited by several
endogenous cardioprotective mechanical “conditioning” interventions including ischemic preconditioning
(461,462) and postconditioning (463,464,465,466). These conditioning strategies are discussed more in-depth in
a later section of the chapter. The mechanisms underlying the inhibition of mPTP opening can be broadly
categorized by (1) indirect inhibitors which target ROS and Ca2+, and (2) direct inhibition by intracellular signal
transduction pathways. Both preconditioning and postconditioning exert cardioprotection by indirect and direct
mechanisms (465,467,468). Indirect mechanisms include preventing realkalinization of the cell and mitochondria
during the early moments of reperfusion, reducing the accumulation of intracellular and intramitochondrial Ca2+,
reducing the generation of ROS, and maintaining ATP levels. Direct intracellular mechanisms engaged by
preconditioning and postconditioning include the RISK pathway in which interaction of autacoids (adenosine,
bradykinin, and opioids) released during the conditioning ischemia interact with cardiomyocytes cell surface G-
coupled proteins which in turn recruit PI3-kinase/Akt or ERK1/2 pathways. These pathways converge on the
mitochondria and activate KATP channels (469) or close the mPTP (470,471), with resulting decrease in
apoptosis and necrosis. Shanmuganathan et al. (472) tested whether the mPTP was involved in cell survival in
human hearts from patients undergoing cardiac surgery. Atrial tissue was harvested from surgery patients and
subjected to lethal hypoxia-reoxygenation. The mPTP opening inhibitors cyclosporine A and Sanglifehrin A,
introduced at the time of reoxygenation or oxidative stress, improved contractile performance of atrial trabeculae,
and survival of isolated atrial myocytes from necrosis (propidium iodide exclusion) but not apoptosis. While
necrosis occurs quickly after onset of reoxygenation, apoptosis may take longer than the observation time in this
study. Nevertheless, this study highlighted the importance of the mPTP in human tissue.
The first clinical translation of this mPTP inhibition strategy was reported by Ovize’s group in France. In patients
presenting with acute myocardial infarction, a single dose of cyclosporine A was administered intravenously just
prior to primary coronary angioplasty reduced infarct size by 30% to 40% compared to untreated patients (473).
Endogenous Cardioprotection: The “Conditioning” Response

Experimental studies conducted over the past 28 years have shown that the myocardium can be “conditioned” to
increase its tolerance to ischemia and to reduce reperfusion injury. This innate cardioprotection is triggered by
short periods of nonlethal ischemia that reduce lethal tissue injury caused by a longer period of “index” ischemia,
that is, that which is experienced during evolving myocardial infarction or cardiac surgery. An expanded view of
the conditioning response in the heart is that protection from ischemia-reperfusion injury can be gained when the
short ischemic conditioning stimuli is applied before (preconditioning), during (perconditioning), or immediately
after (postconditioning) the index ischemia or surgical ischemia.
Preconditioning
The concept of conditioning the myocardium was first introduced in 1986 by Murry et al. (474). Four 5-minute
cycles of LAD occlusion preceding prolonged LAD occlusion reduced infarct size by 75%, a reduction which had
not been seen with any other therapy at the time. A further spin-off from the discovery of IPC was intense
investigation into the pathophysiology of ischemia and reperfusion injuries at the cellular and molecular levels.
IPC has historically been thought to stimulate adaptive molecular and cellular changes in the myocardium which
thereby increased its tolerance to ischemia. These preconditioning stimuli can be applied either immediately after
the preconditioning ischemia (early or classical preconditioning) or 24 hours before the index ischemia (delayed
IPC or second window of protection) (475). Protection by classical IPC is thought to trigger kinase pathways,
while delayed IPC likely stimulates modifications in gene expression and their products (e.g., protein synthesis).
The mechanisms of IPC were thought to be exerted primarily during ischemia. However, recent data suggests
that some major mechanisms are exerted during reperfusion.
The protective effects and targets of IPC are quite broad; the classic observation is a reduction in infarct size, but
IPC also reduces microvascular damage, mitochondrial dysfunction, endothelial injury function (476),
arrhythmias, apoptosis and neutrophil accumulation (477) in postischemic myocardium. Metabolically, IPC has
been shown to increase ATP stores, and reduce tissue acidosis, lactate production and glucose utilization during
the index ischemia. However, the ability of IPC to restore postischemic contractility is controversial and the data
are equivocal.
Preconditioning in Cardiac Surgery

The first application of preconditioning to cardiac surgery was in 1993 by Yellon et al. (478) in the UK in fourteen
patients undergoing CABG surgery randomized to either normothermic intermittent cross-clamp with ventricular
fibrillation (seven patients) or preconditioning (seven patients) preceding cross-clamp fibrillation. The surgeons
clamped the aorta for two 3-minute intervals each followed by 2 minutes of reperfusion before intermittent (10
minutes) aortic clamping-induced ventricular fibrillation. The preconditioned patients had higher ATP levels in
myocardial biopsy samples from the LAD-perfused territory. A later study in 33 patients randomized to control or
preconditioning groups reported lower
P.212
plasma troponin T values 72 hours postbypass in the preconditioned patients, but no difference in ATP levels
(479). A reduction in cTnT was also observed by Teoh et al. (480). However, the role of IPC as an adjunct to
other protective strategies, such as cardioplegia and hypothermia, is also unclear. IPC does not seem to afford
any additional improvement in postischemic contractile function over conventional myocardial protection
techniques (481,482,483,484). A meta-analysis of 22 randomized clinical trials of surgical revascularization in
which the patients received either cardioplegia or intermittent aortic clamping fibrillation showed that
preconditioning was associated with significant reductions in ventricular arrhythmias, decreased use of inotropes
and shorter stay in the ICU in the patients receiving other protection by cardioplegia, but there was no significant
difference in mortality (485). There are two multicenter randomized trials of remote conditioning going on: the
Effect of Remote Ischemic Preconditioning on Clinical Outcomes in Patients Undergoing Coronary Artery Bypass
Graft Surgery (ERICCA) trial (486), and the Remote Ischemic Preconditioning for Heart Surgery (RIPHeart) trial
(487). In the ERICCA trial, 1,610 patients undergoing CABG with or without concomitant valve surgery at 27
tertiary centers in the UK will be enrolled over 2 years. The hearts are protected with blood cardioplegia. The
primary end point is combined cardiovascular death, nonfatal MI, repeat coronary revascularization, and stroke
within the first year of discharge. Clearly, more controlled, randomized clinical studies are needed to ascertain
whether these conditioning protocols are beneficial beyond conventional cardioprotective strategies, and in what
subgroups of patients and procedures they are potentially beneficial. However, it is recognized that clinical
application of IPC is limited by (1) the potential to create further injury to the heart by repeated clamping of the
aorta, (2) the threat of thromboembolic events when repeatedly clamping the aorta, and (3) prolongation of the
operation while preconditioning stimuli are applied (488,489).
Remote Preconditioning
Significant progression was made in the clinical application of preconditioning when Przyklenk et al (490)
reported that cardioprotection could still be exerted if the ischemic stimulus was applied to a remote site, either a
remote side of the heart as originally reported (490), or a remote organ. This study reported that transient
occlusion/reperfusion of the left circumflex coronary artery preceding prolonged LAD occlusion reduced infarct
size comparable to classical IPC. The paradigm of intracardiac RIPC has been expanded to include the kidney
and skeletal muscle as providers of the preconditioning stimulus (491). In fact, ischemia in many organs can
protect other remote recipient organs from ischemia-reperfusion. Relevant to cardiac surgery, here was a
technique that potentially could stimulate IPC without repetitive aortic clamping. In contrast to direct (intra-organ)
preconditioning of the same area of myocardium that is undergoing the prolonged ischemia, remote ischemic
preconditioning must involve the transfer of the protective mediator from the stimulus organ (i.e., skeletal muscle)
to the heart. Such transfer was first shown by Dickson et al. (492) who reported that hearts could be
preconditioned by transfer of coronary effluent from a preconditioned heart to a naïve isolated-perfused acceptor
heart, or by transfer of whole blood from a preconditioned rabbit heart to a naïve rabbit. This transfer of
protection was subsequently confirmed by Shimizu et al. (493) in a rabbit model of transient limb ischemia as the
rIPC trigger and cardiac index ischemia. The transfer factors may be humorally borne (492,493) such as
adenosine or opioids, or transmitted by neuro-humoral pathways. Like IPC, RIPC stimulates receptors for
adenosine, bradykinin B2, opioids ( δ1 or κ), CB2 cannabinoid, and angiotensin AT1 (494). RIPC may also
suppress leukocyte activation (495,496) which would potentially attenuate the neutrophil-mediated component of
ischemia-reperfusion injury (75).
RIPC in Cardiac Surgery

Clinical application of RIPC became feasible when it was reported that conditioning could be achieved in an
organ remote to the heart by occluding an arm or a leg (497,498). The increased muscle mass of the lower limbs
may be more effective at providing the conditioning signal (499). Gunaydin et al. (498) first investigated RIPC in
a study involving 8 CABG patients. RIPC induced by arm cuff inflated for two cycles of 3 minutes each followed
by 2 minutes of reperfusion before heart surgery was associated with an increase in lactate dehydrogenase at
only one time point, and was therefore a lackluster study. However, this study did demonstrate the feasibility of
the RIPC protocol in cardiac surgery. Cheung et al. (500) conducted a study on 37 pediatric patients undergoing
surgery for correction of noncongenital heart disease in which the conditioning stimulus was provided by cyclical
inflation of a cuff around the lower limb prior to cross-clamping. The RIPC group had significantly lower troponin I
and inotropic scores. Hausenloy et al. (501) showed in adults undergoing CABG with or without concomitant
valve surgery that RIPC was associated with a 43% lower troponin area under the curve (72-hour troponin
duration). Inhalational anesthetics were not used in this study to avoid the potential inherent cardioprotective
effects of inhalational anesthetics. Other studies have been performed with mixed results. Negative studies were
reported by Rahman et al. (502) and Karuppasamy et al. (503). In Rahman et al. (502), the RIPC stimulus was
introduced after skin incision, whereas the recommendation is to apply the stimulus prior to skin incision. In the
study of Karuppasamy et al. (503), patients received isoflurane and propofol, which have been associated with
exerting cardioprotective effects (504,505,506). Negative results were also reported by Young et al (507) in high-
risk patients undergoing cardiac surgery (double or triple valves, CABG plus valves, LV impaired function, re-do
surgery). A meta-analysis investigated the effects of
P.213
RIPC on postoperative cardiac troponin. Data were extracted from published studies, and included 693 patients.
In most cases remote preconditioning was applied after induction of anesthesia; operative procedures included
on-pump and offpump CABG with or without concomitant valve surgery, and pediatric surgery. This analysis
showed a significant reduction in plasma cTnI in remotely preconditioned patients.
The reasons for inconsistent results among the existing literature include: (1) timing of application of the RIPC
stimulus and whether upper or lower limbs were used for the ischemic stimulus, (2) patient selection and surgical
procedure—patients may be all-comers, or may be low-risk or high-risk with very differing cardiopathologic
profiles and comorbidities, and whether isolated CABG or concomitant procedures were performed; (3) the
choice of concomitant cardioprotection, for example, type of cardioplegia, use and degree of hypothermia; (4)
duration of the surgery and bypass/cardioplegia time, (5) susceptibility of the myocardium to preconditioning by
anesthesia and cardiopulmonary bypass, so-called “iatrogenic preconditioning”; and (6) incomplete blinding of
the patient and surgical team to the protocol (508).
Perconditioning
Perconditioning (PerC) is achieved when the ischemic conditioning stimulus is applied during the prolonged
ischemia, rather than before the prolonged ischemia as in IPC. PerC was first described by Schmidt et al. (509)
in a porcine model of coronary artery occlusion in which the PerC stimulus was provided by four 5-minute cycles
of hind limb occlusion-reperfusion (therefore “remote” perconditioning, RPerC) were applied immediately after
the coronary artery was occluded but before reperfusion. This form of conditioning significantly reduced infarct
size compared to a control group with no perconditioning. Perconditioning was quickly translated clinically by
Bötker et al. (510) in a study in which PerC was induced by inflating a blood pressure cuff around the arm in 166
patients with suspected acute ST-segment elevation MI during transport to the hospital; 167 other STEMI
patients did not receive remote perconditioning; all patients had primary percutaneous coronary intervention.
Remote PerC reduced infarct size (myocardial salvage index estimated by myocardial perfusion imaging) at 30
days in patients with large areas at risk. A subsequent study by Rentoukas et al. (511) reported a reduction in
infarct size estimated by peak plasma cTnI in STEMI patients undergoing primary PCI when perconditioning was
applied 10 minutes before onset of reperfusion.
PerC in Cardiac Surgery
In 81 adult patients undergoing valve replacement, Li et al. (512) applied a preconditioning stimulus by cyclical
tightening of a tourniquet placed on a lower limb (3 cycle of 4 minutes occlusion and 4 minutes release) either
after induction of anesthesia (i.e., RIPC) or during aortic cross-clamp (i.e., RPerC). Peak plasma cTnI levels
between 30 minutes to 4 hours after aortic cross-clamp removal and the incidence of defibrillation at reanimation
were significantly lower in the rPerC group compared to control patients in which a tourniquet was not tightened
around the thigh. However, further studies are needed to determine whether RPerC improves clinical outcomes
(e.g., length of stay, mortality, or indices of morbidity).
Postconditioning
Ischemic postconditioning (IPostC) stimulated by cyclically interrupting the early moments of reperfusion with
brief periods of ischemia before full reperfusion is allowed to continue (Fig. 9.9). Such “stutter reperfusion” could
be applied by cyclically clamping and unclamping the aorta, but this raises the same issues as faced with IPC
applied in this manner. In an alternative method, the perfusionist would perfuse with warm blood for 1 minute,
halt delivery for 1 minute, and repeat this “on-off” cycle three to four times before removal of the cross-clamp. In
the “Buckbergian” scheme of modifying the conditions and composition of reperfusion, this algorithm represents
a modification of the conditions of reperfusion alone; there are no compositional modifications (pharmacologic
postconditioning involves the administration of drugs or agents only during reperfusion, and therefore represents
compositional modifications). IPostC differs from the time course during which either IPC or PerC in that it does
not adapt the myocardium to ischemia, but targets only reperfusion events; IPostC calls into question the
mechanism of adaption to ischemia. IPostC can and should be combined with other conventional
cardioprotective methods such as cardioplegia. The mechanisms of action in all the conditioning responses
share a large measure in common, as will be discussed very briefly below.
IPostC as a treatment for lethal reperfusion injury was first reported by Zhao and colleagues as an abstract
presented at the 2002 American Heart Association (513) and in print in 2003 (514) using a canine model of LAD
occlusion-reperfusion. The IPostC algorithm was three cycles of alternating re-occlusion
P.214
(30 seconds) and reperfusion (30 seconds) applied at the end of ischemia (i.e., preceding full reperfusion). This
report was soon confirmed by Halkos et al. (515) after some editorial comments about the plausibility of such a
short and seemingly benign method to target the complex pathology of reperfusion injury, and its similarity to
preconditioning (516). IPostC has also been reported to reduce apoptosis in vivo (517), coronary endothelial cell
injury, neutrophil adherence to endothelium, ROS generation, and opening of the mPTP (reviewed in
(467,468,518,519)). Numerous studies from independent international laboratories have since confirmed that
IPostC reduces infarct size in all species tested (reviewed in Vinten-Johansen et al. (468)), including humans
(summarized in Hansen et al. (520) and Hausenloy and Yellon (521)).
FIGURE 9.9. Coronary blood flow (flow probe on LAD) under normal baseline conditions, during coronary artery
occlusion, and during application of a postconditioning algorithm in an anesthetized, open-chest canine
preparation. Postcon, postconditioning; Rep, reperfusion.
Postconditioning in Cardiac Surgery

One interesting question is whether postconditioning can stimulate innate protection against mechanisms of
reperfusion injury in the presence of other cardioprotective strategies such as cardioplegia and hypothermia.
Shinohara et al. (522) reported in a porcine model of CPB and cardioplegia that IPostC, applied by alternate
declamping and reclamping of the aorta before full reperfusion. Improved left ventricular systolic (pressure-
volume relations and function curves) and diastolic (Tau) characteristics, and postcardioplegia cTnT was
reduced. Protection was associated with a reduction in lipid peroxide suggesting a reduction in oxidant burden
consistent with experimental studies.
In clinical studies, Luo et al. (523) studied 24 children undergoing surgery for Tetralogy of Fallot who were
randomized to receive uninterrupted reperfusion or IPostC with three cycles of unclamping the aorta for 30
seconds (reperfusion phase) and reclamping for 30 seconds (ischemic phase) at the time of reperfusion. Patient
and operative characteristics were similar in both groups. Cold intermittent antegrade cardioplegia was used.
The authors found that plasma cTnI and CK-MB were reduced at 2 hours in the IPostC group. In addition, the
use of inotropic agents was significantly less in the IPostC group, although it is not clear that the use of inotropes
was protocol-driven. The study was later expanded to include 99 tetralogy of Fallot patients randomized to
IPostC or no treatment at cross-clamp release. This study showed less major nonfatal morbidity and fewer ICU
days, lower plasma cTnI, transcardiac lactate release, and inotropic score in postconditioned patients. A follow-
on study showed similar results in pediatric patients undergoing surgical correction of congenital malformations
(524). This group also reported the use of IPostC in 50 adult patients undergoing surgical valve replacement.
Patients were equally randomized to treatment with cold blood cardioplegia or cardioplegia with IPostC as
defined above using repeated aortic clamping and reclamping for three 30 second cycles on reperfusion.
Postoperative CK-MB was lower in the IPostC group compared to the control group, but cTnI was statistically
similar. The use of inotropes was less and the transcardiac neutrophil count was lower in the IPostC group, but
there were only trends to lower transcardiac lactate release. IPostC was therefore able to add cardioprotection
above and beyond that provided by cold blood cardioplegia as used by this group.
In 2012, Durdu et al. (525) reported a prospective, randomized study of 79 patients undergoing isolated CABG
using antegrade 4: hemodiluted blood cardioplegia. The patients were selected to have ≥99% occlusion of the
proximal LAD; concomitant valve repair or replacement and previous revascularization (PCI) were excluded.
IPostC consisted of three alternating cycles of reperfusion and occlusion applied directly to the vascular grafts
(including internal mammary grafts) immediately at the onset of reperfusion; this procedure did not lengthen
overall operative time. In this study, postoperative plasma CK, CK-MB, and cTn I were lower than the non-
postconditioned group. Postoperative cardiac index was higher with less requirement for inotropic support than
control group from 2 to 48 hours postoperatively. Importantly, there was no difference in incidence of myocardial
infarction, but length of stay in ICU and in hospital were significantly less than in controls. In contrast to the more
selected patients and procedures reported by Durdu et al. (525), a recent study by Hong et al. (526) in a total of
1,280 patients undergoing a broad range of procedures (valve, CABG, valve + CABG, aortic arch surgery,
congenital defect repair, on-pump and offpump surgery) combined RIPC and IPostC; 644 patients were remotely
preconditioned before CPB and postconditioned at reperfusion using the upper arm as the conditioning stimulus,
while 636 received no conditioning treatment. This study reported no benefit in clinical outcomes (composite of
major adverse events including death, MI, stroke, arrhythmias, renal failure, cardiogenic shock, multi-organ
failure, or number of days in ICU and hospital) with the combination of RIPC and RPostC, which is consistent
with the lack of additive protection with conventional IPC and PostC reported by Halkos et al. (515). There are
many reasons for a negative outcome in this study: (1) the broad range in age; (2) use of inhalational anesthetics
or propofol with cardioprotective effects; (3) the breadth of surgical procedure and bypass and/or cross-clamp
times, or the use of bypass of off-pump surgery; (4) a lack of clarity whether RPostC was applied immediately at
the onset of declamping; (5) the question of whether the arm may have insufficient muscle mass to provide a
preconditioning/postconditioning stimulus compared to the leg. Further studies of this nature are required to
determine efficacy of RPostC alone or in combination with RIPC in cardiac surgery.
Mechanisms of Conditioning
An in-depth discussion of the mechanisms of conditioning is beyond the scope of this chapter. However, there
are a number of reviews that discuss the various complex physiologic
P.215
and molecular pathways involved in the innate cardioprotective conditioning response
(192,521,527,528,529,530,531). All three conditioning protocols have common mechanisms for the most part,
although least is known about PerC. There are generally three stages involved in the conditioning response:
triggers of conditioning released from the stimulus organ that include autacoid substances (adenosine (532),
endogenous opioids, bradykinin) released during ischemia or the reperfusion phase of conditioning that
activate cell surface G-protein coupled receptors or other receptors of the target organ;
mediator pathways located between receptor transduction and the end effectors that include molecular kinase
cascades. The RISK (533,534) and SAFE pathways are the primary pathways common to the conditioning
responses. The anti-inflammatory properties of some of the autacoids stimulated by conditioning, notably
adenosine, may be considered a mediator pathway separate from the RISK and SAFE molecular pathways.
end effectors, notably the KATP channel (535,536) and the mPTP (465) which purportedly exert the
cardioprotective effect, that is, attenuates necrosis and/or apoptosis.
Anesthetic Agents
Anesthetic agents may contribute to cardioprotection and mimic IPC and IPostC when given either before
ischemia or at reperfusion, respectively (537,538,539,540). Hence, volatile anesthetics potentially provide a
backdrop of cardioprotection on which other strategies must layer their cardioprotective mechanisms. Clinical
evidence that volatile anesthetics exert cardioprotection was first reported by Belhomme et al. (541) in 1999 who
compared isoflurane anesthesia with intravenous anesthesia in CABG patients. This group reported that
isoflurane anesthesia was associated with lower plasma troponin I and CK-MB levels. Several meta-analyses of
thousands of patients and numerous clinical studies confirm this finding (542,543,544), and collectively show that
volatile anesthetics (isoflurane, desflurane, sevoflurane) compared to intravenous anesthetic agents are
associated with increased cardiac function and decreased need for inotropic support, decreased
postcardioplegia biomarkers of morphologic injury, decreased ventilator support, decreased incidence of
postoperative MI and (in some cases) mortality, and decreased hospital stay. This cardioprotective profile may
add to overall cardioprotection, but also confounds studies investigating the cardioprotective potential of
candidate agents and strategies as mentioned above.
Cyclosporine A to Close the mPTP

Cyclosporine A is a common chemotherapeutic agent with anti-inflammatory and protein 2B or
calcium/calmodulin-dependent phosphatase inhibitory effects. This and related compounds (e.g., sanglifehrin A
and nonimmunosuppressive NIM811) also inhibit opening of the mPTP (457,545,546). Experimental studies have
shown that cyclosporine A and similar compounds given as a pretreatment (547,548,549) before reperfusion
reduced infarct size. In a clinical study in patients undergoing PCI, cyclosporine A given just before reperfusion
reduced infarct size PCI (473). In a single-center, prospective, randomized, single-blinded, trial, 61 patients
scheduled for elective aortic valve surgery, were randomly assigned to receive either an intravenous bolus of
cyclosporine (2.5 mg/kg, n = 30) or normal saline ( n = 31) 10 minutes before release of the aortic cross-
clamping. The primary endpoint was cTnI 72-hour area under the curve. The authors reported a 35% reduction
of cTnI area under the curve in the cyclosporine group compared with the nontreated group; a significant
reduction still remained when adjustment was made for cross-clamp time. None of the treated patients had
significant side effects. This trial was relatively small, but the positive results in experimental studies and in this
study warrants confirmation by larger clinical trials.
Statin Therapy
Statins are known from experimental studies to protect cardiac tissue by mechanisms unrelated to their LDL
cholesterol-lowering effect. Notably the vascular endothelium is protected by statin treatment (550,551)
associated with better nitric oxide release. Treatment with statins either before ischemia or at reperfusion has
been associated with a reduction of infarct size (550,551,552). Better outcomes have been reported in CABG
patients taking statin therapy before surgery (553) which has been confirmed by a meta-analysis of patients
taking preoperative statins (554). Kawai et al. (555) have reported that statin therapy initiated just before cross-
clamping and again before reperfusion was associated with less oxidant and inflammatory markers than
nontreated patients, but there was no difference in CK release. Because many patients have
hypercholesterolemia as a comorbidity, and take statin therapy routinely, it is not clear whether increasing the
dose of statins acutely before surgery will provide demonstrable benefit. However, this treatment may benefit the
subset of patients not already on statin therapy.
Evolving Role of the Surgical Team in Applying Myocardial Protective Strategies

As the specialty of cardiac surgery embarks into the next phase in its evolution, attention to the quality of the
outcomes delivered can also be expected to mature and evolve. Twenty years ago, the 30-day and in-hospital
mortality was the key metric, and 20 years from now we can expect ongoing scrutiny, not only of mortality risk,
but of the postprocedural outcomes in terms of cardiac function and whether we are making an
P.216
impact on efficiencies of care. Patients presenting with hemodynamic instability or shock syndromes, and clear
evidence of ongoing or evolving myocardial ischemia and infarction that require surgical rescue, must not limp
through the rest of their lives with heart failure.
As a specialty, we are uniquely positioned to benefit from the decades of research now clearly documenting that
multi-vessel coronary bypass surgery is a better therapy (556) (and probably more cost effective) than multi-
vessel PCI in various cohorts of patients. This would include those with diabetes and, possibly, those with acute
coronary syndromes who present with high-risk lesions and hemodynamic instability. The situation allows the
surgeon an opportunity to not merely revascularize the ischemic heart, but to support the circulation and provide
optimal myocardial protection. Eliminating ischemic conditions with carefully controlled systemic and
compartmentalized strategies for oxygen exposure and delivery is only possible in the surgical arena or in
carefully controlled hybrid environments in which surgeons will be expected to play a leadership role (557).
Cardiac surgery must not squander the opportunity to demonstrate that it can continue to develop strategies to
eliminate risks of additional injury to the heart, brain, lungs, and kidneys. Incremental cardiac (or systemic) injury
that occurs to some degree during reperfusion can be mitigated first by developing an appreciation for the
manner in which the compromised systemic circulation and individual organ systems might be rescued differently
(558). If the heart is intensely ischemic but the systemic circulation is not compromised, the scenario may call for
one type of strategy (e.g., a balloon pump and emergency surgery). If the heart has been shocked out of
ventricular fibrillation and the heart is ischemic but the systemic circulation is also struggling, that scenario may
require a different strategy. If the heart is functioning well but the patient presents early with ST elevation, a
completely different strategy of opening the infarct vessel without any adjuncts (or surgery) might be appropriate.
Along these lines, an appreciation for the degree of antecedent or preexisting ischemia must be developed. The
surgeon who protects every heart the same way, and fails to view the myocardium substrate as potentially
harboring a setup for reperfusion injury of the types described in this chapter, may be surprised when the patient
either fails to come off bypass or requires multiple inotropes, pressor agents and, potentially, mechanical
circulatory support. Furthermore, in the setting of a patient presenting with profound and advanced preexistent
ischemic tissue, future scrutiny of our results will and should mandate that the patient not only survive but have a
heart with a relatively normal ejection fraction, and not saddled with debilitating heart failure for the rest of his or
her life. While there may be scenarios where this cannot be avoided, the authors believe that the operating team
can and will play a role in altering cardiac surgery’s contribution to this epidemic.
The patient presenting to the operating room with a variable and, likely, unpredictable amount of antecedent or
preexistent acute ischemia presents a challenge to the anesthesiologist, surgeon and perfusionists in a manner
that now can be rethought. Based upon detailed studies and decades of research in molecular cardiology and
the science of myocardial protection, new technology and new concepts can allow the surgical team to approach
such a patient in a safer way. In the future we can expect newer sensor technology to help guide the operator
with real-time data on the degree of or severity of ischemia. In such a scenario, we would expect the
perfusionists to be able to accurately define the PO2 of the perfusate to more closely match that of the
myocardium, and ramp it up gradually with an in-line monitor. In so doing, the avoidance of even relative
hyperoxia or the acid-base balance of the myocardium at the moment ischemic conditions are eliminated could
be avoided.
A patient in cardiogenic shock that makes it to the cardiac surgery operating room may require immediate
institution of CPBupon arrival. More than one FDA-approved technology enables the institution of veno-arterial
extracorporeal membrane oxygenation (ECMO) with “mini” heart-lung machines for support in a matter of
minutes. These are currently being used in some settings by cardiologists independently, at least prior to
movement of the patient to the surgical suite for attention by a surgeon. While this may represent a real advance
in the availability of such circuits, their portability and the ease of implementation may save lives, extreme caution
must be employed. The use of such technology can contribute to an oversupply of oxygen to the patient or the
infarct coronary territory at precisely the wrong time. While this type of injury is unintentional, an appreciation
between and among members of the surgical team must develop if a catastrophe with additional oxygen-related
or other technique-related injury in some circumstances is to be avoided, and surgeons must remain involved
with the use of such therapies at their hospitals.
In the operating room, at induction, anesthesiologists may be preconditioning the heart already. However, they
may play a more integrated role in cardioprotection by avoiding hyperoxia especially when the patient has been
in shock or is postresuscitation from a cardiac arrest. Information is now available regarding hyperoxic brain
injury as well in certain situations. The practice of hyperoxygenation at the time of induction of anesthesia is not
being challenged here as a general rule. However, as circumstances warrant, deviations from such a practice
may be warranted. Strict and close collaboration between surgeon and anesthetist to plan the right strategy is
paramount. In a manner similar to that associated with congenital heart disease and ductus-dependent systemic
circulation, one would no sooner hyperoxygenate such a patient with the realization that doing so would cause
more serious physiologic derangement. The surgeon and anesthesiologist must also have seamless
communication on the use of
P.217
inotropic agents, since protocol-driven use of such agents may be more useful in monitoring adequacy of
myocardial protection over habitual use in all patients. Furthermore, we have found that routine atrial and
ventricular pacing to drive heart rate can be substituted for routine use of drugs (dopamine, dobutamine, etc.)
that often exert most of their effect on the heart rate in the post-op period anyway.
The perfusionist must always be prepared for changes in the method of delivery of cardioplegia solutions and the
philosophy of such delivery. Careful communication between surgeon and perfusionist is a must during any
cardiac procedure, but the future of surgical results may mandate even more careful collaboration than in the
past. A one-size-fits-all approach to myocardial protection is likely not in the patients’ best interests over the long
term and an appreciation for the ways in which the perfusionist can be involved in the evolution of practice is
going to be of increasing relevance in the near future.
Not only will newer concepts and technology allow the administration of drugs or the manipulation of drug
concentrations or other metabolic additives, but technology will also allow the real-time monitoring of the status
of the myocardium, that is, perfusate oxygen tension, pH, metabolic status, and release of biomarkers.
Technologies are currently being developed that will allow this type of control at everyone’s fingertips, but
effective use of such techniques will require the surgeons, anesthesiologists, and perfusionists to work as a
close-knit, seamless team. It is important to understand the link between perfusate temperature and the
availability of oxygen bound to hemoglobin. The importance of warm induction will become increasingly clear in
the near future as methods and technology become available that allow for real-time assessment of tissue
condition, redox potential within the myocardium, salvageability, and the ability to precisely control oxygen
delivery during warm cardioplegia or perfusate delivery.
Translating Experimental Cardioprotection to the Clinical Setting

Research has always been fundamental in cardiac surgery. Unlike earlier developments that formed
cornerstones of cardioprotection, newer experimental drugs and approaches have had great difficulty translating
into the clinical setting. Other areas of cardiovascular therapeutics have found the same difficulty (559,560,561).
There are many reasons for this failure of potentially effective candidate drugs or procedures to be adopted into
clinical practice: (1) the young, healthy, often anesthetized, often rodent experimental models do not accurately
represent the CABG patient who is older, with comorbidities (diabetes, hyperlipidemia, metabolic syndrome), and
has some degree of cardiac dysfunction, all of which can prevent actions of some drugs; a human is not a mouse
or a rat. By the same token, a Langendorff isolated-perfused system does not mimic in vivo physiology; (2) drugs
may work on a single target, but its effects may be masked by other multicomponent pathologic processes; (3)
the effectiveness of a drug may also be masked or nullified by concomitant medications, including hyperkalemia,
and hypothermia, and may have different effects on blood versus a crystalloid solution; (4) the target of the drug
must have some relationship to the expected outcome; for example a drug that reduces necrosis may not
improve contractile dysfunction; (5) the timing of administration may miss the intended target entirely; for example
adenosine may be useful as a pretreatment, but if not used at onset of reperfusion an important window has
been missed; (6) differing protocols from different laboratories produce different and often contradictory results,
leading to an unclear picture of the therapeutic efficacy and developmental path forward. That many effective
candidate drugs may fail to be translated and adopted into clinical use creates a lost opportunity to improve
surgical outcomes. Better models that incorporate comorbidities, and appropriate age and gender may be
helpful. More rigorous experimental designs in large animal models of CPB and cardioplegia may avoid the
variables inserted by small animal models. Finally, not only understanding “what happens first must be treated
first” but also when it happens (ischemia versus reperfusion) may improve the efficacy of drugs in the surgical
setting.
CONCLUSIONS
Cardioprotection combines the surgical team’s art with knowledge of the best strategies suited for a given
patient. But as not all patients are alike in the presentation of comorbidities, heart failure, and age, not all
protective strategies will be effective. The expectation of a one-size-fits-all cardioprotective strategy is
unrealistic. Younger patients that are more tolerant of ischemia-reperfusion and have a more active
conditioning response may be adequately protected by simple strategies. However, higher-risk patients may
require more complex formulations with components targeting their specific pathology. Some strategies are
tailored for the highrisk patient, and the failure of these strategies to improve results in lower risk patients
has often been interpreted as a “negative result.” That patients live with their diseases but can die after
surgery suggests that cardioprotection is still not optimal. The difficulty is to determine what strategy is
appropriate for which patient, and align expectations accordingly. Hopefully, this chapter has given the
surgical team the knowledge base to assess the preoperative status of a patient and develop an effective
cardioprotective strategy. Because there are numerous pathologic processes working in concert during
ischemia-reperfusion and inflammation, pleiotropic drugs that exert their target effects may be more effective
in the complex milieu of cardiac surgery than monotherapeutics, which have not been adopted into clinical
practice (562). Whatever strategy is contemplated, a key consideration is that what happens first in the
network of ischemia-reperfusion responses must be treated first.
P.218
KEY Points
Intraoperative myocardial injury can occur before, during, or after cardiopulmonary bypass.
Injury before CPB is commonly “unprotected” (i.e., lacking CPB or cardioplegia).
Injury during CPB can be multifactorial, related to the composition or delivery of cardioplegic protective
solutions or to the reperfusion period after cardioplegic arrest.
Injury after CPB commonly results from postischemic reperfusion.
The degree of permanent myocardial injury after ischemia is a function of the severity and duration of
ischemia, which can be modified by numerous factors.
Reperfusion injury is defined as additional myocardial injury incurred after restoration of blood flow to
ischemic myocardium. Important contributors to this injury include calcium influx into cells, oxygen
radicals, neutrophil activation and extravasation, complement, edema, and opening of the mitochondrial
transition pore. Hyperoxygenation and abrupt reoxygenation may contribute to oxygen-related reperfusion
injury. Reperfusion injury starts within minutes of blood flow restoration, and follows a time-dependent
cascade. What happens first has to be treated first is a good philosophy.
Impaired microvascular blood flow (“no-reflow” response) can result from these injury mechanisms.
Endothelial dysfunction and injury contribute to this phenomenon.
Reperfusion injury can cause atrial and ventricular dysrhythmias, reversible systolic and diastolic left
ventricular dysfunction (stunning), myocardial necrosis, endothelial dysfunction, and apoptosis.
A variety of strategies for myocardial protection have been identified, which can be divided into
established, emerging, and experimental strategies:
Established strategies:
Chemically induced cardiac arrest in diastole, most often induced by controlled hyperkalemia localized
to the heart.
Hypothermia to decrease myocardial oxygen consumption. The benefits of this approach appear to be
optimal at myocardial temperatures between 12°C and 28°C.
Avoidance or reduction of myocardial edema by limiting the pressure of cardioplegia infusions and by
providing moderately hyperosmolar cardioplegia solutions achieved by osmotic agents such as
mannitol, albumin, glucose, or blood. There is concern over the effect of added glucose on
hyperglycemia which needs to be monitored and treated by perioperative and intraoperative insulin.
Buffering the acidosis that results from ischemia by including bicarbonate (poor buffer), THAM,
histidine-imidazole, or blood buffers in such solutions as microplegia.
Gradual restoration of blood pressure or blood oxygen levels; Near-normoxic CPB and reperfusion
may avoid oxygen-induced injury
Close management of myocardial calcium balance to avoid extremes of intracellular hypercalcemia or
hypocalcemia, especially during reperfusion.
Anti-inflammatory therapies, including antibodies such as pexelizumab, complement inhibitors, nitric
oxide, and adenosine.
Addition of adenosine and nitric oxide donors to cardioplegia or “reperfusion” solutions.
Emerging strategies:
Therapies to avoid injury caused by reactive oxygen species; RNS generated by interactions of
nitrogen compounds with ROS create damage. Therapies include superoxide dismutase and xanthine
oxidase inhibitors. Amino acid-enhancement with glutamate and aspartate to sustain anaerobic
glycolysis during ischemia.
Avoidance of depolarized arrest induced by hyperkalemia using agents such as magnesium, esmolol,
and adenosine paired with a local anesthetic.
Experimental strategies:
These include agents such as cyclosporine A that close the mitochondrial transition pore, and
recruiting conditioning responses in the heart before (preconditioning), during (perconditioning) or after
(postconditioning) surgical ischemia.
References
1. Angeloni E, Melina G, Benedetto U, et al. Metabolic syndrome affects midterm outcome after coronary
artery bypass grafting. Ann Thorac Surg 2012;93:537-544.
2. Brock RC, Ross DN. Hypothermia. III. The clinical application of hypothermic techniques. Guy’s Hosp Rev
1955;104:99.
3. Gibbon JH Jr, Miller BJ, Dobell AR, et al. The closure of interventricular septal defects in dogs during open
cardiotomy with the maintenance of the cardiorespiratory functions by a pump-oxygenator. J Thorac Surg
1954;28:235-240.
4. Gibbon JH Jr. Application of a mechanical heart and lung apparatus to cardiac surgery. Minn Med
1954;37:171-185; passim.
5. Katz AM, Tada M. The “stone heart”: a challenge to the biochemist. Am J Cardiol 1972;29:578-580.
6. Cooley DA, Reul GJ, Wukasch DC. Ischemic contracture of the heart: “stone heart”. Am J Cardiol
1972;29:575-577.
7. Ringer S. A further Contribution regarding the influence of the different constituents of the blood on the
contraction of the heart. J Physiol 1883;4:29-42.3.
8. Melrose DG, Dreyer B, Bentall HH. Elective cardiac arrest. Lancet 1955;2:21-22.
9. Baker JBE, Bentall HH, Dreyer B, et al. Arrest of isolated heart with potassium citrate. Lancet 1957:555-
559.
10. Lam CR, Gahagan T, Sergeant C, et al. Acetylcholine-induced asystole. In: Allen JG, et al., ed.
Extracorporeal circulation. Springfield, IL: Charles C. Thomas, 1958:451-458.
P.219
11. Sergeant CK, Geoghegan T, Lam CR. Further studies in induced cardiac arrest using the agent
acetylcholine. Surg Forum 1957:254-257.
12. Sealy WC, Young WG Jr, Brown I, et al. Potassium, magnesium and neostigmine for controlled
cardioplegia. Arch Surg 1958;77:33-38.
13. Helmsworth JA, Kaplan S, Clark LC Jr, et al. Myocardial injury associated with asystole induced with
potassium citrate. Ann Surg 1959;149: 200-206.
14. Drew CE, Anderson IM. Profound hypothermia in cardiac surgery: report of 3 cases. Lancet 1959;1:748-
750.
15. Shumway NE, Lower RR. Topical cardiac hypothermia for extended periods of anoxic arrest. Surg Forum
1959;10:563-566.
16. Bretschneider HJ, Hübner G, Knoll D, et al. Myocardial resistance and tolerance to ischemia:
physiological and biochemical basis. J Cardiovasc Surg 1975;16:241-260.
17. Kirsch U, Rodewald G, Kalmár P. Induced ischemic arrest. Clinical experience with cardioplegia in open-
heart surgery. J Thorac Cardiovasc Surg 1972;63:121-130.
18. Hearse DJ, Stewart DA, Braimbridge MV. Hypothermic arrest and potassium arrest. Metabolic and
myocardial protecting during elective cardiac arrest. Circ Res 1975;36:481-489.
19. Taber RE, Morales AR, Fine G. Myocardial necrosis and the postoperative low-cardiac-output syndrome.
20. Morales AR, Fine G, Taber RE. Cardiac surgery and myocardial necrosis. Arch Pathol Lab Med
1967;83:71-79.
21. Hearse DJ, Stewart DA, Braimbridge MV. Cellular protection during myocardial ischemia. The
development and characterization of a procedure for the induction of reversible ischemic arrest. Circulation
1976;54: 193-202.
22. Braimbridge MV, Chayen J, Bitensky L, et al. Cold cardioplegia or continuous coronary perfusion? Report
on preliminary clinical experience as assessed cytochemically. J Thorac Cardiovasc Surg 1977;74:900-906.
23. Jynge P, Hearse DJ, Feuvray D, et al. The St. Thomas’ hospital cardioplegic solution: a characterization
in two species. Scand J Thorac Cardiovasc Surg Suppl 1981;30:1-28.
24. Gay JWA, Ebert PA. Functional, metabolic, morphologic effects of potassium-induced cardioplegia.
Surgery 1973;74:284-290.
25. Tyers GFO, Todd GJ, Niebauer IM, et al. The mechanism of myocardial damage following potassium
citrate (Melrose) cardioplegia. Surgery 1975;78:45-53.
26. Tyers GFO, Manley CJ, Williams EH, et al. Preliminary clinical experience with isotonic hypothermic
potassium induced arrest. J Thorac Cardiovasc Surg 1977;74:674-681.
27. Dobson GP, Faggian G, Onorati F, et al. Hyperkalemic cardioplegia for adult and pediatric surgery: end
of an era? Front Physiol 2013;4:228.
28. Maruyama Y, Chambers DJ, Ochi M. Future perspective of cardioplegic protection in cardiac surgery. J
Nippon Med Sch 2013;80:328-341.
29. Weman SM, Karhunen PJ, Penttila A, et al. Reperfusion injury associated with one-fourth of deaths after
coronary artery bypass grafting. Ann Thorac Surg 2000;70:807-812.
30. Flack JE, Cook JR, May SJ, et al. Does cardioplegia type affect outcome and survival in patients with
advanced left ventricular dysfunction? Results from the CABG Patch Trial. Circulation 2000;102:84-89.
31. Ihnken K, Morita K, Buckberg GD. Delayed cardioplegic reoxygenation reduces reoxygenation injury in
cyanotic immature hearts. Ann Thorac Surg 1998;66:177-182.
32. Buckberg GD. Studies of hypoxemic/reoxygenation injury. I. Linkage between cardiac function and
oxidant damage. J Thorac Cardiovasc Surg 1995;110:1164-1170.
33. Kloner RA, Przyklenk K, Kloner RA, et al. First evidence: postischemic dysfunction of viable myocardium.
In: Kloner RA, Przyklenk K, eds. Stunned myocardium: properties, mechanisms, and clinical manifestations.
New York, NY: Marcel Dekker, Inc., 1993:17-39.
34. Yellon DM, Hausenloy DJ. Myocardial reperfusion injury. N Eng J Med 2007;357:1121-1135.
35. Przyklenk K. Lethal myocardial “reperfusion injury”: the opinions of good men. J Thromb Thrombolysis
1997;4:5-6.
36. Robicsek F, Schaper J. Reperfusion injury: fact or myth? J Card Surg 1997;12:133-137.
37. Kloner RA. Does reperfusion injury exist in humans? [Review]. J Am Coll Cardiol 1993;21:537-545.
38. Opie LH. Reperfusion injury—fad, fashion, or fact? Cardiovasc Drugs Ther 1991;5(Suppl 2):223-224.
39. Gross GJ, Auchampach JA. Reperfusion injury: does it exist? J Mol Cell Cardiol 2007;42:12-18.
40. Mehta JL, Jayaram K. Reperfusion injury in humans: existence, clinical relevance, mechanistic insights,
and potential therapy. J Thromb Thrombolysis 1997;4:75-77.
41. Walsh EK, Huang H, Wang Z, et al. Control of myocardial oxygen consumption in transgenic mice
overexpressing vascular eNOS. Am J Physiol Heart Circ Physiol 2004;287:H2115-H2121.
42. Weyrich AS, Ma XL, Buerke M, et al. Physiological concentrations of nitric oxide do not elicit an acute
negative inotropic effect in unstimulated cardiac muscle. Circ Res 1994;75:692-700.
43. Lefer DJ, Ma XL, Lefer AM, et al. Lack of inotropic effects of nitric oxide donors in cat and dog
myocardium. FASEB J 1993;7:A244.
44. Zweier JL, Talukder MA. The role of oxidants and free radicals in reperfusion injury. Cardiovasc Res
2006;70:181-190.
45. Goldhaber JI, Qayyum MS. Oxygen free radicals and excitation-contraction coupling. Antioxid Redox
Signal 2000;2:55-64.
46. Shi W, Jiang R, Dobson GP, et al. The nondepolarizing, normokalemic cardioplegia formulation
adenosine-lidocaine (adenocaine) exerts anti-neutrophil effects by synergistic actions of its components. J
47. Jordan JE, Zhao ZQ, Sato H, et al. Adenosine A2 receptor activation attenuates reperfusion injury by
inhibiting neutrophil accumulation, superoxide generation and coronary endothelial adherence. J Pharm Exp
Ther 1997;280:301-309.
48. Nakamura M, Zhao ZQ, Clark KL, et al. A novel adenosine analog, AMP579, inhibits neutrophil activation,
adherence and neutrophil-mediated injury to coronary vascular endothelium. Eur J Pharmacol 2000;397:197-
205.
49. Beckman JS, Koppenol WH. Nitric oxide, superoxide, peroxynitrite: the good, the bad, and the ugly. Am J
Physiol 1996;271:C1424-C1437.
50. Chenowith DE, Cooper SW, Hugli TE, et al. Complement activation during cardiopulmonary bypass:
evidence for generation of C3a and C5a anaphylatoxins. N Eng J Med 1981;304:497-503.
51. Videm V, Fosse E, Mollnes TE, et al. Complement activation with bubble and membrane oxygenators in
aortocoronary bypass grafting. Ann Thorac Surg 1990;50:387-391.
52. Faymonville ME, Pincemail J, Duchateau J, et al. Myeloperoxidase and elastase as markers of leukocyte
activation during cardiopulmonary bypass in humans. J Thorac Cardiovasc Surg 1991;102:309-317.
53. Sprague AH, Khalil RA. Inflammatory cytokines in vascular dysfunction and vascular disease. Biochem
Pharmacol 2009;78:539-552.
54. Sheppard FR, Kelher MR, Moore EE, et al. Structural organization of the neutrophil NADPH oxidase:
phosphorylation and translocation during priming and activation. J Leukoc Biol 2005;78:1025-1042.
55. McCord JM. Oxygen-derived free radicals in postischemic tissue injury. N Eng J Med 1985;312:159-163.
56. Zweier JL, Broderick R, Kuppusamy P, et al. Determination of the mechanism of free radical generation in
human aortic endothelial cells exposed to anoxia and reoxygenation. J Biol Chem 1994;269:24156-24162.
57. Berry CE, Hare JM. Xanthine oxidoreductase and cardiovascular disease: molecular mechanisms and
pathophysiological implications. J Physiol 2004;555:589-606.
58. Fleury C, Mignotte B, Vayssiere JL. Mitochondrial reactive oxygen species in cell death signaling.
Biochimie 2002;84 131-141.
59. Jacob HS, Vercellotti GM, Halliwell B. Granulocyte-mediated endothelial injury: oxidant damage amplified
by lactoferrin and platelet activating factor. In: Halliwell B, ed. Oxygen radicals and tissue injury. Rockville,
MD: FASEB Publications, 1998:57-62.
60. Cao Z, Zhu H, Zhang L, et al. Antioxidants and phase 2 enzymes in cardiomyocytes: chemical inducibility
and chemoprotection against oxidant and simulated ischemia-reperfusion injury. Exp Biol Med (Maywood)
2006;231:1353-1364.
61. Tritto FP, Inserte J, Garcia-Dorado D, et al. Sodium/hydrogen exchanger inhibition reduces myocardial
reperfusion edema after normothermic cardioplegia. J Thorac Cardiovasc Surg 1998;115:709-715.
62. Prasad K, Kalra J, Bharadwaj B, et al. Increased oxygen free radical activity in patients on
cardiopulmonary bypass undergoing aortocoronary bypass surgery. Am Heart J 1992;123:37-45.
63. Thomas NJ, Grassman E, Walloch M, et al. Controlled cardiac reoxygenation in adults with ischemic
heart disease. J Thorac Cardiovasc Surg 1999;117:630-632.
P.220
64. Ihnken K, Morita K, Buckberg GD, et al. Controlling oxygen content during cardiopulmonary bypass to
limit reperfusion/reoxygenation injury. Transplant Proc 1995;27:2809-2811.
65. Ihnken K, Morita K, Buckberg GD, et al. Studies of hypoxemic/reoxgenation injury with aortic clamping. XI.
Cardiac advantages of normoxemic versus hyperoxemic management during cardiopulmonary bypass. J
66. Pike MM, Luo CS, Clark MD, et al. NMR measurements of Na+ and cellular energy in ischemic rat heart:
role of Na+-H+ exchange. Am J Physiol 1993;265:H2017-H2026.
67. Garcia-Dorado D, Ruiz-Meana M, Inserte J, et al. Calcium-mediated cell death during myocardial
reperfusion. Cardiovasc Res 2012;94:168-180.
68. Inserte J, Hernando V, Garcia-Dorado D. Contribution of calpains to myocardial ischaemia/reperfusion

injury. Cardiovasc Res 2012;96:23-31.
69. Shen AC, Jennings RB. Kinetics of calcium accumulation in acute myocardial ischemic injury. Am J
Pathol 1972;67:441-452.
70. Miller TW, Tormey JM. Subcellular calcium pools of ischaemic and reperfused myocardium characterised
by electron probe. Cardiovasc Res 1995;29:85-94.
71. Walsh LG, Tormey JM. Subcellular electrolyte shifts during in vitro myocardial ischemia and reperfusion.
Am J Physiol 1988;255:H917-H928.
72. Meldrum DR, Cleveland JC, Sheridan BC, et al. Cardiac surgical implications of calcium dyshomeostasis
in the heart. Ann Thorac Surg 1996;61:1273-1280.
73. Piper HM, Siegmund B, Ladilov Yu V, et al. Calcium and sodium control in hypoxic-reoxygenated
cardiomyocytes [Review]. Basic Res Cardiol 1993;88:471-482.
74. Lefer AM, Ma XL, Weyrich A, et al. Endothelial dysfunction and neutrophil adherence as critical events in
the development of reperfusion injury. Agents Actions Suppl 1993;41:127-135.
75. Vinten-Johansen J. Involvement of neutrophils in the pathogenesis of lethal myocardial reperfusion injury.
Cardiovasc Res 2004;61:481-497.
76. Jordan JE, Zhao ZQ, Vinten-Johansen J. The role of neutrophils in myocardial ischemia-reperfusion
injury. Cardiovasc Res 1999;43:860-878.
77. Lefer AM. Role of selectins in myocardial ischemia-reperfusion injury. Ann Thorac Surg 1995;60:773-777.
78. Lefer AM, Weyrich AS, Buerke M. Role of selectins, a new family of adhesion molecules, in ischaemia-
reperfusion injury. Cardiovasc Res 1994;28: 289-294.
79. Ley K, Tedder TF. Leukocyte interactions with vascular endothelium. New insights into selectin-mediated
attachment and rolling. J Immunol 1995;155:525-528.
80. Abe Y, Kawakami M, Kuroki M, et al. Transient rise in serum interleukin-8 concentration during acute
myocardial infarction. Br Heart J 1993;70:132-134.
81. Kubes P, Jutila M, Payne D. Therapeutic potential of inhibiting leukocyte rolling in ischemia/reperfusion. J
Clin Invest 1995;95:2510-2519.
82. Moore KL, Patel KD, Bruehl RE, et al. P-selectin glycoprotein ligand-1 mediates rolling of human
neutrophils on p-selectin. J Cell Biol 1995;128:661-671.
83. Youker KA, Hawkins HK, Kukielka GL, et al. Molecular evidence for induction of intracellular adhesion
molecule-1 in the viable border zone associated with ischemia-reperfusion injury of the dog heart. Circulation
1994;89:2736-2746.
84. Sommers HM, Jennings RB. Experimental acute myocardial infarction: histological and histochemical
studies of early myocardial infarcts induced by temporary or permanent occlusion of a coronary artery. Lab
Invest 1964;13:1491-1503.
85. Nakanishi K, Lefer DJ, Johnston WE, et al. Transient hypocalcemia during the initial phase of reperfusion
extends myocardial necrosis after 2 hours of coronary occlusion. Coron Artery Dis 1991;2:1009-1021.
86. Nakanishi K, Vinten-Johansen J, Lefer DJ, et al. Intracoronary L-arginine during reperfusion improves
endothelial function and reduces infarct size. Am J Physiol 1992;263:H1650-H1658.
87. Lefer DJ, Nakanishi K, Johnston WE, et al. Antineutrophil and myocardial protecting actions of a novel
nitric oxide donor after acute myocardial ischemia and reperfusion of dogs. Circulation 1993;88:2337-2350.
88. Lefer DJ, Nakanishi K, Johnston WE, et al. Anti-neutrophil and myocardial protecting actions of SPM-
5185, a novel nitric oxide (NO) donor, following acute myocardial ischemia and reperfusion in dogs. Biol
Nitric Oxide 1992:188-190.
89. Zhao ZQ, Nakamura M, Wang NP, et al. Dynamic progression of contractile and endothelial dysfunction
and infarct extension in the late phase of reperfusion. J Surg Res 2000;94:133-144.
90. Tsao PS, Aoki N, Lefer DJ, et al. Time course of endothelial dysfunction and myocardial injury during
myocardial ischemia and reperfusion in the cat. Circulation 1990;82:1402-1412.
91. Lefer AM, Tsao PS, Lefer DJ, et al. Role of endothelial dysfunction in the pathogenesis of reperfusion
injury after myocardial ischemia. FASEB J 1991;5:2029-2034.
92. Brix-Christensen V, Tonnesen E, Hjortdal VE, et al. Neutrophils and platelets accumulate in the heart,
lungs, and kidneys after cardiopulmonary bypass in neonatal pigs. Crit Care Med 2002;30 670-676.
93. Schwartz JD, Shamamian P, Schwartz DS, et al. Cardiopulmonary bypass primes polymorphonuclear
leukocytes. J Surg Res 1998;75:177-182.
94. Kappelmayer J, Bernabei A, Gikakis N, et al. Upregulation of Mac-1 surface expression on neutrophils
during simulated extracorporeal circulation. J Lab Clin Med 1993;121:118-126.
95. Finn A, Rebuck N, Moat N. Neutrophil activation during cardiopulmonary bypass. J Thorac Cardiovasc
Surg 1992;104:1746-1748.
96. Finn A, Moat N, Rebuck N, et al. Changes in neutrophil CD11b/CD18 and L-selectin expression and
release of interleukin 8 and elastase in paediatric cardiopulmonary bypass. Agent Actions 1993;38:C44-C46.
97. Gessler P, Pfenninger J, Pfammatter JP, et al. Plasma levels of interleukin-8 and expression of
interleukin-8 receptors on circulating neutrophils and monocytes after cardiopulmonary bypass in children. J
98. Galinanes M, Watson C, Trivedi U, et al. Differential patterns of neutrophil adhesion molecules during
cardiopulmonary bypass in humans. Circulation 1996;94(9 Suppl):II364-II369.
99. Kira S, Daa T, Kashima K, et al. Mild hypothermia reduces expression of intercellular adhesion molecule-
1 (ICAM-1) and the accumulation of neutrophils after acid-induced lung injury in the rat. Acta Anaesthesiol
Scand 2005;49:351-359.
100. Rowin ME, Xue V, Irazuzta J. Hypothermia attenuates beta1 integrin expression on extravasated
neutrophils in an animal model of meningitis. Inflammation 2001;25:137-144.
101. Le Deist F, Menasch, P, Kucharski C, et al. Hypothermia during cardiopulmonary bypass delays but
does not prevent neutrophil-endothelial cell adhesion: a clinical study. Circulation 1995;92(Suppl 2):354-358.
102. Boldt J, Osmer C, Linke LC, et al. Hypothermic versus normothermic cardiopulmonary bypass: influence
on circulating adhesion molecules. J Cardiothorac Vasc Anesth 1996;10:342-347.
103. Ohata T, Sawa Y, Kadoba K, et al. Normothermia has beneficial effects in cardiopulmonary bypass
attenuating inflammatory reactions. ASAIO J 1995;41:M288-M291.
104. Menasche P, Peynet J, Haeffner-Cavaillon N, et al. Influence of temperature on neutrophil trafficking

during clinical cardiopulmonary bypass. Circulation 1995;92:II-334-II-340.
105. Menasche P, Peynet J, Lariviere J, et al. Does normothermia during cardiopulmonary bypass increase
neutrophil-endothelium interactions? Circulation 1994;90(5, Part 2):II275-II279.
106. Gillinov AM, Redmond JM, Winkelstein JA, et al. Complement and neutrophil activation during
cardiopulmonary bypass: a study in the complement-deficient dog. Ann Thorac Surg 1994;57:345-352.
107. Rossen RD, Swain JL, Michael LH, et al. Selective accumulation of the first component of complement
and leukocytes in ischemic canine heart muscle. A possible initiator of an extra myocardial mechanism of
ischemic injury. Circ Res 1985;57:119-130.
108. Homeister JW, Satoh P, Lucchesi BR. Effects of complement activation in the isolated heart. Role of the
terminal complement components. Circ Res 1992;71:303-319.
109. Kubes P. Polymorphonuclear leukocyte—endothelium interactions: a role for pro-inflammatory and anti-
inflammatory molecules [Review]. Can J Physiol Pharm 1993;71:88-97.
110. Dreyer WJ, Michael LH, Nguyen T, et al. Kinetics of C5a release in cardiac lymph of dogs experiencing
coronary artery ischemia-reperfusion injury. Circ Res 1992;71:1518-1524.
111. Ivey CL, Williams FM, Collins PD, et al. Neutrophil chemoattractants generated in two phases during
reperfusion of ischemic myocardium in the rabbit. Evidence for a role for C5a and interleukin-8. J Clin Invest
1995;95:2720-2728.
112. Riley RD, Sato H, Zhao ZQ, et al. Recombinant human complement C5a receptor antagonist reduces
infarct size following surgical revascularization. Circulation 1997;96:I-679.
P.221
113. McNally AK, Anderson JM. Complement C3 participation in monocyte adhesion to different surfaces.
Proc Natl Acad Sci USA 1994;91:10119-10123.
114. Engler RL, Roth DM, del Balzo U, et al. Intracoronary C5a induces myocardial ischemia by mechanisms
independent of the neutrophil: leukocyte filters desensitize the myocardium to C5a. FASEB J 1991;5:2983-
2991.
115. Steinberg JB, Kapelanski DP, Olson JD, et al. Cytokine and complement levels in patients undergoing
116. Ovrum E, Mollnes TE, Fosse E, et al. Complement and granulocyte activation in two different types of
heparinized extracorporeal circuits. J Thorac Cardiovasc Surg 1995;110:1623-1632.
117. Arslan F, Keogh B, McGuirk P, et al. TLR2 and TLR4 in ischemia reperfusion injury. Mediators Inflamm
2010;2010:704202.
118. Arslan F, Smeets MB, O’Neill LA, et al. Myocardial ischemia/reperfusion injury is mediated by leukocytic
toll-like receptor-2 and reduced by systemic administration of a novel anti-toll-like receptor-2 antibody.
Circulation 2010;121:80-90.
119. Jaattela M. Heat shock proteins as cellular lifeguards. Ann Med 1999;31:261-271.
120. Demidov ON, Tyrenko VV, Svistov AS, et al. Heat shock proteins in cardiosurgery patients. Eur J
121. Valen G, Hansson GK, Dumitrescu A, et al. Unstable angina activates myocardial heat shock protein 72,
endothelial nitric oxide synthase, and transcription factors NFκBB and AP-1. Cardiovasc Res 2000;47:49-56.
122. Dybdahl B, Wahba A, Lien E, et al. Inflammatory response after open heart surgery: release of heat-
shock protein 70 and signaling through toll-like receptor-4. Circulation 2002;105:685-690.
123. Kaczorowski DJ, Nakao A, McCurry KR, et al. Toll-like receptors and myocardial ischemia/reperfusion,
inflammation, and injury. Curr Cardiol Rev 2009;5:196-202.
124. Ha T, Liu L, Kelley J, et al. Toll-like receptors: new players in myocardial ischemia/reperfusion injury.
Antioxid Redox Signal 2011;15:1875-1893.
125. Griffiths EJ, Halestrap AP. Mitochondrial non-specific pores remain closed during cardiac ischaemia, but
open upon reperfusion. Biochem J 1995;307:93-98.
126. Di Lisa F, Bernardi P. Mitochondria and ischemia-reperfusion injury of the heart: fixing a hole.
127. Weiss JN, Korge P, Honda HM, et al. Role of the mitochondrial permeability transition in myocardial
disease. Circ Res 2003;93 292-301.
128. Flack JE 3rd, Hafer J, Engelman RM, et al. Effect of normothermic blood cardioplegia on postoperative
conduction abnormalities and supraventricular arrhythmias. Circulation 1992;86:II385-II392.
129. Valsangiacomo E, Schmid ER, Schupbach RW, et al. Early postoperative arrhythmias after cardiac
operation in children. Ann Thorac Surg 2002;74:792-796.
130. Jeroudi MO, Hartley CJ, Bolli R. Myocardial reperfusion injury: role of oxygen radicals and potential
therapy with antioxidants [Review]. Am J Cardiol 1994;73:2B-7B.
131. Bolli R. Oxygen-derived free radicals and myocardial reperfusion injury: an overview [Review].
Cardiovasc Drugs Ther 1991;5(Suppl 2):249-268.
132. Ellis RJ, Mavroudis C, Gardner C, et al. Relationship between atrioventricular arrhythmias and the
concentration of K+ ion in cardioplegic solution. J Thorac Cardiovasc Surg 1980;80:517-526.
133. Pridjian AK, Levitsky S, Krukenkamp I, et al. Intracellular sodium and calcium in the postischemic
myocardium. Ann Thorac Surg 1987;43:416-419.
134. Sato H, Jordan JE, Zhao ZQ, et al. Gradual reperfusion reduces infarct size and endothelial injury but
augments neutrophil accumulation. Ann Thorac Surg 1997;64:1099-1107.
135. Sato H, Zhao ZQ, McGee DS, et al. Supplemental L-arginine during cardioplegic arrest and reperfusion
avoids regional postischemic injury. J Thorac Cardiovasc Surg 1995;110:302-314.
136. Vinten-Johansen J, Chiantella V, Johnston WE, et al. Adjuvant N-(2-mercaptopropionyl)-glycine in blood

cardioplegia does not improve myocardial protection in ischemically damaged hearts. J Thorac Cardiovasc
Surg 1990;100:65-76.
137. Vinten-Johansen J, Julian JS, Yokoyama H, et al. Efficacy of myocardial protection with hypothermic
blood cardioplegia depends on oxygen. Ann Thorac Surg 1991;52:939-948.
138. Costa MA, Carere RG, Lichtenstein SV, et al. Incidence, predictors, and significance of abnormal
cardiac enzyme rise in patients treated with bypass surgery in the Arterial Revascularization Therapies Study
(ARTS). Circulation 2001;104:2689-2693.
139. Gavard JA, Chaitman BR, Sakai S, et al. Prognostic significance of elevated creatine kinase MB after
coronary bypass surgery and after an acute coronary syndrome: results from the GUARDIAN trial. J Thorac
140. Klatte K, Chaitman BR, Theroux P, et al. Increased mortality after coronary artery bypass graft surgery
is associated with increased levels of postoperative creatine kinase-myocardial band isoenzyme release. J
Am Coll Cardiol 2001;38:1070-1077.
141. Lehrke S, Steen H, Sievers HH, et al. Cardiac troponin T for prediction of short- and long-term morbidity
and mortality after elective open heart surgery. Clin Chem 2004;50:1560-1567.
142. Nesher N, Alghamdi AA, Singh SK, et al. Troponin after cardiac surgery: a predictor or a phenomenon?
Ann Thorac Surg 2008;85:1348-1354.
143. Croal BL, Hillis GS, Gibson PH, et al. Relationship between postoperative cardiac troponin I levels and
outcome of cardiac surgery. Circulation 2006;114:1468-1475.
144. Domanski MJ, Mahaffey K, Hasselblad V, et al. Association of myocardial enzyme elevation and survival
following coronary artery bypass graft surgery. JAMA 2011;305:585-591.
145. Hale AJ, Smith CA, Sutherland LC, et al. Apoptosis: molecular regulation of cell death. Eur J Biochem
1996;236:1-26.
146. Narula J, Haider N, Virmani R, et al. Apoptosis in myocytes in end-stage heart failure. N Eng J Med
1996;335:1182-1189.
147. Fliss H, Gattinger D. Apoptosis in ischemic and reperfused rat myocardium. Circ Res 1996;79:949-956.
148. Aebert H, Cornelius T, Birnbaum DE, et al. Induction of early immediate genes and programmed cell
death following cardioplegic arrest in human hearts. Eur J Cardiothorac Surg 1997;12:261-267.
149. Aebert H, Kirchner S, Keyser A, et al. Endothelial apoptosis is induced by serum of patients after
cardiopulmonary bypass. Eur J Cardio Thorac Surg 2000;18:589-593.
150. Schmitt JP, Schröder J, Schunkert H, et al. Role of apoptosis in myocardial stunning after open heart
surgery. Ann Thorac Surg 2002;73:1229-1235.
151. Fischer UM, Klass O, Stock U, et al. Cardioplegic arrest induces apoptosis signal-pathway in
myocardial endothelial cells and cardiac myocytes. Eur J Cardiothorac Surg 2003;23:984-990.
152. Yeh CH, Wang YC, Wu YC, et al. Continuous tepid blood cardioplegia can preserve coronary
endothelium and ameliorate the occurrence of cardiomyocyte apoptosis. Chest 2003;123:1647-1654.
153. Vahasilta T, Malmberg M, Saraste A, et al. Cardiomyocyte apoptosis after antegrade and retrograde
cardioplegia during aortic valve surgery. Ann Thorac Surg 2011;92:1351-1357.
154. Anselmi A, Abbate A, Girola F, et al. Myocardial ischemia, stunning, inflammation, and apoptosis during
cardiac surgery: a review of evidence. Eur J Cardiothorac Surg 2004;25:304-311.
155. Meldrum DR. Tumor necrosis factor in the heart. Am J Physiol 1998;274:R577-R595.
156. Freude B, Master TN, Robicsek F, et al. Apoptosis is initiated by myocardial ischemia and executed
during reperfusion. J Am Coll Cardiol 2000;32:197-208.
157. Fliss H. Accelerated apoptosis in reperfused myocardium: friend of foe? Basic Res Cardiol 1998;93:90-
93.
158. Galang N, Sasaki H, Maulik N. Apoptotic cell death during ischemia/reperfusion and its attenuation by
antioxidant therapy. Toxicology 2000;148:111-118.
159. Maulik N, Yoshida T. Oxidative stress developed during open heart surgery induces apoptosis:
reduction of apoptotic cell death by ebselen, a glutathione peroxidase mimic. J Cardiovasc Pharmacol
2000;36:601-608.
160. Dobsak P, Courderot-Masuyer C, Zeller M, et al. Antioxidative properties of pyruvate and protection of
the ischemic rat heart during cardioplegia. J Cardiovasc Pharmacol 1999;34:651-659.
161. Dobsak P, Siegelova J, Wolf JE, et al. Prevention of apoptosis by deferoxamine during 4 hours of cold
cardioplegia and reperfusion: in vitro study of isolated working rat heart model. Pathophysiology
2002;9(1):27.
162. McCully JD, Wakiyama H, Cowan DB, et al. Diazoxide amelioration of myocardial injury and
mitochondrial damage during cardiac surgery. Ann Thorac Surg 2002;74 2138-2146.
163. Wakiyama H, Cowan DB, Toyoda Y, et al. Selective opening of mitochondrial ATP-sensitive potassium
channels during surgically induced myocardial ischemia decreases necrosis and apoptosis. Eur J Cardio
Thorac Surg 2002;21:424-433.
P.222
164. Nakanishi K, Zhao ZQ, Vinten-Johansen J, et al. Coronary artery endothelial dysfunction after global
ischemia, blood cardioplegia, reperfusion. Ann Thorac Surg 1994;58:191-199.
165. Lefer DJ, Nakanishi K, Vinten-Johansen J, et al. Cardiac venous endothelial dysfunction after
myocardial ischemia and reperfusion in dogs. Am J Physiol 1992;263:H850-H856.
166. Dignan RJ, Dyke CM, Abd-Elfattah AS, et al. Coronary artery endothelial cell and smooth muscle
dysfunction after global myocardial ischemia. Ann Thorac Surg 1992;53:311-317.
167. Pearson PJ, Schaff HV, Vanhoutte PM. Long-term impairment of endothelium-dependent relaxations to
aggregating platelets after reperfusion injury in canine coronary arteries. Circulation 1990;81:1921-1927.
168. Boyle EM Jr, Pohlman TH, Cornejo CJ, et al. Endothelial cell injury in cardiovascular surgery: ischemia-
reperfusion. Ann Thorac Surg 1996;62:1868-1875.
169. Lefer AM, Lefer DJ. Pharmacology of the endothelium in ischemia-reperfusion and circulatory shock.
Annu Rev Pharm Toxicol 1993;33:71-90.
170. Malinski T, Taha Z. Nitric oxide release from a single cell measured in situ by a porphyrinic-based
microsensor. Nature 1992;358:676-678.
171. Xia Y, Tsai AL, Berka V, et al. Superoxide generation from endothelial nitricoxide synthase. A
Ca2+/calmodulin-dependent and tetrahydrobiopterin regulatory process. J Biol Chem 1998;273:25804-
25808.
172. Guo JP, Murohara T, Buerke M, et al. Direct measurement of nitric oxide release from vascular
endothelial cells. J Appl Physiol 1996;81:774-779.
173. Zanaboni P, Murray PA, Simon BA, et al. Selective endothelial dysfunction in conscious dogs after
cardiopulmonary bypass. J Appl Physiol 1997;82:1776-1784.
174. Dauber IM, Parsons PE, Welsh CH, et al. Peripheral bypass-induced pulmonary and coronary vascular
injury. Association with increased levels of tumor necrosis factor. Circulation 1993;88:726-735.
175. Feerick AE, Johnston WE, Steinsland O, et al. Cardiopulmonary bypass impairs vascular endothelial
relaxation: effects of gaseous microemboli in dogs. Am J Physiol 1994;267:H1174-H1182.
176. Garcia-Dorado D, Theroux P, Munoz R, et al. Favorable effects of hyperosmotic reperfusion on

myocardial edema and infarct size. Am J Physiol 1992;262(1, Part 2):H17-H22.
177. Karolle BL, Carlson RE, Aisen AM, et al. Transmural distribution of myocardial edema by NMR
relaxometry following myocardial ischemia and reperfusion. Am Heart J 1991;122:655-664.
178. Inserte J, Garcia-Dorado D, Ruiz-Meana M, et al. The Na+-H+ exchange occuring during hypoxia in the
genesis of reoxygenation-induced myocardial oedema. J Mol Cell Cardiol 1997;29:1167-1175.
179. Garcia-Dorado D, Oliveras J. Myocardial oedema: a preventable cause of reperfusion injury? [Review].
Cardiovasc Res 1993;27:1555-1563.
180. Rutkovskiy A, Valen G, Vaage J. Cardiac aquaporins. Basic Res Cardiol 2013;108:393.
181. Garcia-Dorado D, Andres-Villarreal M, Ruiz-Meana M, et al. Myocardial edema: a translational view. J
Mol Cell Cardiol 2012;52:931-939.
182. Rutkovskiy A, Stenslokken KO, Mariero LH, et al. Aquaporin-4 in the heart: expression, regulation and
functional role in ischemia. Basic Res Cardiol 2012;107:280.
183. Vinten-Johansen J, Lefer DJ, et al. Controlled coronary hydrodynamics at the time of reperfusion
reduces postischemic injury. Coron Artery Dis 1992;3:1081-1093.
184. Gunnes S, Ytrehus K, Sorlie D, et al. Improved energy preservation following gentle reperfusion after
hypothermic, ischemic cardioplegia in infarcted rat hearts. Eur J Cardio Thorac Surg 1987;1:139-143.
185. Yamauchi T, Ichikawa H, Sawa Y, et al. The contribution of Na+/H+ exchange to ischemia-reperfusion
injury after hypothermic cardioplegic arrest. Ann Thorac Surg 1997;63:1107-1112.
186. Krug A, Du Mesnil de R, Korb G. Blood supply of the myocardium after temporary coronary occlusion.
Circ Res 1966;19:57-62.
187. Ames A 3rd, Wright RL, Kowada M, et al. Cerebral ischemia. II. The no-reflow phenomenon. Am J
Pathol 1968;52:437-453.
188. Kloner RA, Ganote CE, Jennings RB. The “no-reflow” phenomenon after temporary coronary occlusion
in the dog. J Clin Invest 1974;54:1496-1508.
189. Reffelmann T, Kloner RA. The no-reflow phenomenon: a basic mechanism of myocardial ischemia and
reperfusion. Basic Res Cardiol 2006;101:359-372.
190. Buckberg GD. Myocardial protection: an overview. Semin Thorac Cardiovasc Surg 1993;5:98-106.
191. Piper HM, Abdallah Y, Schafer C. The first minutes of reperfusion: a window of opportunity for
cardioprotection. Cardiovasc Res 2004;61 365-371.
192. Hausenloy DJ, Boston-Griffiths E, Yellon DM. Cardioprotection during cardiac surgery. Cardiovasc Res
2012;94:253-265.
193. Swyers T, Redford D, Larson DF. Volatile anesthetic-induced preconditioning. Perfusion 2014;29:10-15.
194. Buckberg GD. Normothermic blood cardioplegia. Alternative or adjunct?. J Thorac Cardiovasc Surg
1994;107:860-867.
195. Speziale G, Nasso G, Barattoni MC, et al. Short-term and long-term results of cardiac surgery in elderly
and very elderly patients. J Thorac Cardiovasc Surg 2011;141:725-731.e1.
196. Steinberg JS. Postoperative atrial fibrillation: a billion-dollar problem. J Am Coll Cardiol 2004;43:1001-
1003.
197. Robinson LA, Schwarz GD, Goddard DB, et al. Myocardial protection for acquired heart disease
surgery: results of a national survey. Ann Thorac Surg 1995;59:361-372.
198. Demmy TL, Haggerty SP, Boley TM, et al. Lack of cardioplegia uniformity in clinical myocardial
preservation. Ann Thorac Surg 1994;57:648-651.
199. Kevelaitis E, Nyborg NC, Menasche P. Coronary endothelial dysfunction of isolated hearts subjected to
prolonged cold storage: patterns and contributing factors. J Heart Lung Transplant 1999;18:239-247.
200. Ackemann J, Gross W, Mory M, et al. Celsior versus custodiol: early postischemic recovery after
cardioplegia and ischemia at 5 degrees C. Ann Thorac Surg 2002;74:522-529.
201. Mohara J, Takahashi T, Oshima K, et al. The effect of Celsior solution on 12-hour cardiac preservation
in comparison with University of Wisconsin solution. J Cardiovasc Surg (Torino) 2001;42:187-192.
202. Tsutsumi H, Takeyoshi I, Ohshima K, et al. Effect of coronary perfusion with an oxygenated Celsior
solution on 24-hour preservation in canine hearts. Transplant Proc 2000;32:2415-2416.
203. 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;71:1442-1447.
204. De Santo LS, Amarelli C, Romano G, et al. High-risk heart grafts: effective preservation with Celsior
solution. Heart Vessels 2006;21:89-94.
205. Hernandez A, Borrego JM, Gomez S, et al. Myocardial preservation using Celsior: clinical results in
high-risk cardiac transplantation. Transplant Proc 2005;37:1543-1545.
206. Wildhirt SM, Weis M, Schulze C, et al. Effects of Celsior and University of Wisconsin preservation
solutions on hemodynamics and endothelial function after cardiac transplantation in humans: a single-center,
prospective, randomized trial. Transpl Int 2000;13(Suppl 1):S203-S211.
207. Hearse DJ, Stewart DA, Chain EB. Recovery from cardiac bypass and elective cardiac arrest. The
metabolic consequences of various cardioplegic procedures in the isolated rat heart. Circ Res 1974;35:448-
457.
208. Chambers DJ, Sakai A, Braimbridge MV, et al. Clinical validation of St. Thomas’ Hospital cardioplegic
solution No. 2 (Plegisol). Eur J Cardiothorac Surg 1989;3:346-352.
209. Kotani Y, Tweddell J, Gruber P, et al. Current cardioplegia practice in pediatric cardiac surgery: a North
American multiinstitutional survey. Ann Thorac Surg 2013;96:923-929.
210. Matte GS, del Nido PJ. History and use of del Nido cardioplegia solution at Boston Children’s Hospital.
211. del Nido PJ. Myocardial protection and cardiopulmonary bypass in neonates and infants. Ann Thorac
Surg 1997;64:878-879.
212. Ginther RM Jr, Gorney R, Forbess JM. Use of del Nido cardioplegia solution and a low-prime
recirculating cardioplegia circuit in pediatrics. J Extra Corpor Technol 2013;45:46-50.
213. Charette K, Gerrah R, Quaegebeur J, et al. Single dose myocardial protection technique utilizing del
Nido cardioplegia solution during congenital heart surgery procedures. Perfusion 2012;27:98-103.
214. Ferguson Z, Yarborough D, Jarvis B, et al. Evidence-based medicine and myocardial protection—where
is the evidence? Perfusion 2014. doi:10.1177/0267659114551856.
215. Yerebakan H, Sorabella RA, Najjar M, et al. Del Nido Cardioplegia can be safely administered in high-
risk coronary artery bypass grafting surgery after acute myocardial infarction: a propensity matched
comparison. J Cardiothorac Surg 2014;9:141.
216. Sorabella RA, Akashi H, Yerebakan H, et al. Myocardial protection using del nido cardioplegia solution
in adult reoperative aortic valve surgery. J Card Surg 2014;29:445-449.
217. Gebhard MM, Preusse CJ, Schnabel PA, et al. Different effects of cardioplegic solution HTK during
single or intermittent administration. Thorac Cardiovasc Surg 1984;32:271-276.
P.223
218. Dyszkiewicz W, Minten J, Flameng W. Long-term preservation of donor hearts: the effect of intra- and
extracellular-type of cardioplegic solutions on myocardial high energy phosphate content. Mater Med Pol
1990;22:147-152.
219. Mollhoff T, Sukehiro S, Borgers M, et al. Influence of superoxide dismutase on reperfusion injury in
donor hearts preserved with Bretschneider-HTK cardioplegic solution. Cardiovasc Surg 1993;1:357-361.
220. Reichenspurner H, Russ C, Uberfuhr P, et al. Myocardial preservation using HTK solution for heart
transplantation. A multicenter study. Eur J Cardiothorac Surg 1993;7:414-419.
221. Korner MM, Posival H, Korfer R. Myocardial preservation using HTK solution for heart transplantation
[letter; comment]. Eur J Cardio Thorac Surg 1994;8:337-337.
222. Reichenspurner H, Russ C, Wagner F, et al. Comparison of UW versus HTK solution for myocardial
protection in heart transplantation. Transpl Int 1994;7(Suppl 1):S481-S484.
223. Hachida M, Ookado A, Nonoyama M, et al. Effect of HTK solution for myocardial preservation. J
Cardiovasc Surg (Torino) 1996;37:269-274.
224. Follette DM, Mulder DG, Maloney JV, et al. Advantages of blood cardioplegia over continuous coronary
perfusion or intermittent ischemia. Experimental and clinical study. J Thorac Cardiovasc Surg 1978;76:604-
619.
225. Menasche P, Fleury JP, Veyssie L, et al. Limitation of vasodilation associated with warm heart operation
by a “mini-cardioplegia” delivery technique. Ann Thorac Surg 1993;56:1148-1153.
226. Menasche P, Touchot B, Pradier F, et al. Simplified method for delivering normothermic blood
cardioplegia. Ann Thorac Surg 1993;55:177-178.
227. Menasche P. Blood cardioplegia: do we still need to dilute? Ann Thorac Surg 1996;62:957-960.
228. Machiraju VR, Lima CAB, Culig MH. The value of minicardioplegia in the clinical setting. Ann Thorac
Surg 1997;64:887.
229. Liu Y, Zhang SL, Duan WX, et al. The myocardial protective effects of a moderate-potassium blood
cardioplegia in pediatric cardiac surgery: a randomized controlled trial. Ann Thorac Surg 2012;94:1295-1301.
230. Rosenkranz ER, Vinten-Johansen J, Buckberg GD, et al. Benefits of normothermic induction of blood
cardioplegia in energy-depleted hearts, with maintenance of arrest by multidose cold blood cardioplegic
infusions. J Thorac Cardiovasc Surg 1982;84:667-677.
231. Cohen NM, Damiano RJ Jr, Wechsler AS. Is there an alternative to potassium arrest? Ann Thorac Surg
1995;60:858-863.
232. Jayawant M, Stephenson ER Jr, Damiano RJ Jr. Advantages of continuous hyperpolarized arrest with
pinacidil over St. Thomas’ Hospital solution during prolonged ischemia. J Thorac Cardiovasc Surg
1998;116:131-138.
233. Boehm DH, Human PA, von Oppell U, et al. Adenosine cardioplegia: reducing reperfusion injury of the
ischaemic myocardium? Eur J Cardio Thorac Surg 1991;5:542-545.
234. Dobson GP, Jones MW. Adenosine and lidocaine: a new concept in nondepolarizing surgical
myocardial arrest, protection, and preservation. J Thorac Cardiovasc Surg 2004;127 794-805.
235. Jakobsen O, Muller S, Aarsaether E, et al. Adenosine instead of supranormal potassium in cardioplegic
solution improves cardioprotection. Eur J Cardiothorac Surg 2007;32:493-500.
236. Stub D, Smith K, Bernard S, et al. A randomized controlled trial of oxygen therapy in acute myocardial
infarction air verses oxygen in myocardial infarction study (AVOID Study). Am Heart J 2012;163:339-345,
331.
237. Ihnken K, Morita K, Buckberg GD, et al. Studies of hypoxemic/reoxygenation injury: without aortic
clamping. II. Evidence for reoxygenation damage. J Thorac Cardiovasc Surg 1995;110:1171-1181.
clamping. III. Comparison of the magnitude of damage by hypoxemia/reoxygenation versus
ischemia/reperfusion. J Thorac Cardiovasc Surg 1995;110:1182-1189.
clamping. VI. Counteraction of oxidant damage by exogenous antioxidants: N-(2-mercaptopropionyl)-glycine
and catalase. J Thorac Cardiovasc Surg 1995;110:1212-1220.
240. Ihnken K, Morita K, Buckberg GD, et al. Studies of hypoxemic/reoxygenation injury: with aortic clamping.
XIII. Interaction between oxygen tension and cardioplegic composition in limiting nitric oxide production and
oxidant damage. J Thorac Cardiovasc Surg 1995;110:1274-1286.
241. Morita K, Ihnken K, Buckberg GD, et al. Studies of hypoxemic/reoxygenation injury: without aortic
clamping. IV. Role of the iron-catalyzed pathway: deferoxamine. J Thorac Cardiovasc Surg 1995;110:1190-
1199.
242. Morita K, Sherman MP, Buckberg GD, et al. Studies of hypoxemic/reoxygenation injury: without aortic
clamping. V. Role of the L-arginine-nitric oxide pathway: the nitric oxide paradox. J Thorac Cardiovasc Surg
1995;110:1200-1211.
clamping. VII. Counteraction of oxidant damage by exogenous antioxidants: coenzyme Q10. J Thorac
clamping. VIII. Counteraction of oxidant damage by exogenous glutamate and aspartate. J Thorac
clamping. IX. Importance of avoiding perioperative hyperoxemia in the setting of previous cyanosis. J Thorac
246. Morita K, Ihnken K, Buckberg GD. Studies of hypoxemic/reoxygenation injury: with aortic clamping. XII.
Delay of cardiac reoxygenation damage in the presence of cyanosis: a new concept of controlled cardiac
reoxygenation. J Thorac Cardiovasc Surg 1995;110:1265-1273.
247. Morita K, Ihnken K, Buckberg GD, et al. Studies of hypoxemic/reoxygenation injury: with aortic clamping.
X. Exogenous antioxidants to avoid nullification of the cardioprotective effects of blood cardioplegia. J Thorac
248. Allen BS, Rahman S, Ilbawi MN, et al. Detrimental effects of cardiopulmonary bypass in cyanotic infants:
preventing the reoxygenation injury. Ann Thorac Surg 1997;64:1381-1388.
249. Thomas NJ, Harvey AT. Controlled cardiac reoxygenation improves outcome in a porcine model of
severe reperfusion injury. Ann Thorac Surg 1999;68:2392.
250. Ihnken K, Winkler A, Schlensak C, et al. Normoxic cardiopulmonary bypass reduces oxidative
myocardial damage and nitric oxide during cardiac operations in the adult. J Thorac Cardiovasc Surg
1998;116:327-334.
251. D’Alessandro DA, Barbone A, Burton EA, et al. Venous blood cardioplegia provides superior
preservation of ventricular function in ischemic myocardium. Circulation 2001;104:II-473.
252. Rincon F, Kang J, Maltenfort M, et al. Association between hyperoxia and mortality after stroke: a
multicenter cohort study. Crit Care Med 2014;42:387-396.
253. Moradkhan R, Sinoway LI. Revisiting the role of oxygen therapy in cardiac patients. J Am Coll Cardiol
2010;56:1013-1016.
254. Opie LH, Commerford PJ, Gersh BJ, et al. Controversies in ventricular remodelling. Lancet
2006;367:356-367.
255. Gladden JD, Ahmed MI, Litovsky SH, et al. Oxidative stress and myocardial remodeling in chronic mitral
regurgitation. Am J Med Sci 2011;342:114-119.
256. Bigelow WG, Callaghan JC, Hopps JA. General hypothermia for experimental intracardiac surgery. Ann
Surg 1950;132:531-539.
257. Bigelow WG, Lindsay WK, Greenwood WF. Hypothermia; its possible role in cardiac surgery: an
investigation of factors governing survival in dogs at low body temperatures. Ann Surg 1950;132:849-866.
258. Buckberg GD, Brazier JR, Nelson RL, et al. Studies of the effects of hypothermia on regional myocardial
blood flow and metabolism during cardiopulmonary bypass. I. The adequately perfused beating, fibrillating,
arrested heart. J Thorac Cardiovasc Surg 1977;73:87-94.
259. Johnson M, Haddix T, Pohlman T, et al. Hypothemia reversibly inhibits endothelial cell expression of E-
selectin and tissue factor. J Card Surg 1995;10:428-435.
260. Haddix TL, Pohlman TH, Noel RF, et al. Hypothermia inhibits human E-selectin transcription. J Surg
Res 1996;64:176-183.
261. Swanson DK, Myerowitz PD. Distribution of adenylates, water, potassium, sodium within the normal and
hypertrophied canine heart following 2 hr of preservation. J Surg Res 1982;32:515-525.
262. Nikas DJ, Ramadan FM, Elefteriades JA. Topical hypothermia: ineffective and deleterious as adjunct to
cardioplegia for myocardial protection [see comments]. Ann Thorac Surg 1998;65:28-31.
263. Khuri SF, Michelson AD, Valeri CR, et al. The effect of cardiopulmonary bypass on hemostasis and
coagulation. In: Thrombosis and hemorrhage. Cambridge, MA: Blackwell, 1994:1051-1073.
264. Hayashida N, Ikonomidis JS, Weisel RD, et al. The optimal cardioplegic temperature. Ann Thorac Surg
1994;58:961-971.
265. Ko T, Otani H, Imamura H, et al. Role of sodium pump activity in warm induction of cardioplegia
combined with reperfusion of oxygenated cardioplegic solution. J Thorac Cardiovasc Surg 1995;110:103-
110.
P.224
266. Rosenkranz ER, Buckberg GD, Laks H, et al. Warm induction of cardioplegia with glutamate-enriched
blood in coronary patients with cardiogenic shock who are dependent on inotropic drugs and intra-aortic
balloon support. J Thorac Cardiovasc Surg 1983;86:507-518.
267. Du XL, Lan HJ, Sun ZQ. Effects of warm blood cardioplegic solution on myocardial protection. J Tongji
Med Univ 1995;15:212-216.
268. Ji B, Liu M, Lu F, et al. Warm induction cardioplegia and reperfusion dose influence the occurrence of
the post CABG TnI level. Interact Cardiovasc Thorac Surg 2006;5:67-70.
269. Wallace AW, Ratcliffe MB, Nose PS, et al. Effect of induction and reperfusion with warm substrate-
enriched cardioplegia on ventricular function. Ann Thorac Surg 2000;70:1301-1307.
270. Asai T, Grossi EA, LeBoutillier M III, et al. Resuscitative retrograde blood cardioplegia. Are amino acids
or continuous warm techniques necessary? J Thorac Cardiovasc Surg 1995;109:242-248.
271. Roberts AJ, Woodhall DD, Knauf DG, et al. Coronary artery bypass graft surgery: clinical comparison of
cold blood potassium cardioplegia, warm cardioplegic induction, and secondary cardioplegia. Ann Thorac
Surg 1985;40:483-487.
272. Williams WG, Rebeyka IM, Tibshirani RJ, et al. Warm induction blood cardioplegia in the infant. A
technique to avoid rapid cooling myocardial contracture. J Thorac Cardiovasc Surg 1990;100:896-901.
273. Caputo M, Dihmis WC, Bryan AJ, et al. Warm blood hyperkalaemic reperfusion (‘hot shot’) prevents
myocardial substrate derangement in patients undergoing coronary artery bypass surgery. Eur J Cardio
Thorac Surg 1998;13:559-564.
274. Gettes LS, Cascio WE, Fozzard HA, et al. Effect of acute ischemia on cardiac electrophysiology. In:
Fozzard HA, Jennings RB, Haber E, et al., eds. The heart and cardiovascular system. New York, NY: Raven
Press, 1992:2021-2054.
275. Hattori Y, Yang Z, Sugimura S, et al. Terminal warm blood cardioplegia improves the recovery of
myocardial electrical activity. A retrospective and comparative study. Jpn J Thorac Cardiovasc Surg
2000;48:1-8.
276. Toyoda Y, Yamaguchi M, Yoshimura N, et al. Cardioprotective effects and the mechanisms of terminal
warm blood cardioplegia in pediatric cardiac surgery. J Thorac Cardiovasc Surg 2003;125:1242-1251.
277. Siegmund B, Schluter KD, Piper HM. Calcium and the oxygen paradox. Cardiovasc Res 1993;27:1778-
1783.
278. Rebeyka IM, Axford-Gatley RA, Bush BG, et al. Calcium paradox in an in vivo model of multidose
cardioplegia and moderate hypothermia. Prevention with diltiazem or trace calcium levels. J Thorac
279. Hearse DJ, Humphrey SM, Boink AB, et al. The calcium paradox: metabolic, electrophysiological,
contractile and ultrastructural characteristics in four species. Eur J Cardiol 1978;7:241-256.
280. Vinten-Johansen J, Mentzer RM Jr. Attenuation of postcardioplegia injury with inhibitors of the sodium-
hydrogen exchanger. J Thorac Cardiovasc Surg 2003;126:1265-1267.
281. Corvera JS, Zhao ZQ, Schmarkey LS, et al. Optimal dose and mode of delivery of Na+/H+ exchange-1
inhibitor are critical for reducing postsurgical ischemia-reperfusion injury. Ann Thorac Surg 2003;76:1614-
1622.
282. Lahorra JA, Torchiana DF, Tolis G Jr, et al. Rapid cooling contracture with cold cardioplegia. Ann
Thorac Surg 1997;63:1353-1360.
283. Ataka K, Chen D, McCully J, et al. Magnesium cardioplegia prevents accumulation of cytosolic calcium
in the ischemic myocardium. J Mol Cell Cardiol 1993;25:1387-1390.
284. Fukuhiro Y, Wowk M, Ou RC, et al. Cardioplegic strategies for calcium control—low Ca2+, high Mg2+,
citrate, or Na+/H+ exchange inhibitor HOE-642. Circulation 2000;102:319-325.
285. Jovanovic A, Lopez JR, Alekseev AE, et al. Adenosine prevents K+-induced Ca2+ loading: insight into
cardioprotection during cardioplegia. Ann Thorac Surg 1998;65:586-591.
286. Baczko I, Jones L, McGuigan CF, et al. Plasma-membrane KATP channel-mediated cardioprotection
involves posthypoxic reductions in calcium overload and contractile dysfunction: mechanistic insights into
cardioplegia. FASEB J 2005:1-26.
287. Li HY, Wu S, He GW, et al. Aprikalim reduces the Na+-Ca2+ exchange outward current enhanced by
hyperkalemia in rat ventricular myocytes. Ann Thorac Surg 2002;73:1253-1259.
288. Buckberg GD, Becker H, Vinten-Johansen J, et al. Myocardial function resulting from varying acid-base
management during and following deep surface and perfusion hypothermia and circulatory arrest. In: Rahn
H, Prakash O, eds. Acid-base regulation and body temperature. Boston, MA: Martinus Nijhoff, 1985:135-
159.
289. Geffin GA, Reynolds TR, Titus JS, et al. Relation of myocardial protection to cardioplegic solution pH:
modulation by calcium and magnesium. Ann Thorac Surg 1991;52:955-964.
290. del Nido PJ, Wilson GJ, Mickle DAG, et al. The role of cardioplegic solution buffering in myocardial
protection. A biochemical and histopathological assessment. J Thorac Cardiovasc Surg 1985;89:689-699.
291. Neethling WM, van den Heever JJ, Cooper S, et al. Interstitial pH during myocardial preservation:
assessment of five methods of myocardial preservation. Ann Thorac Surg 1993;55:420-426.
292. Kitakaze M, Weisfeldt ML, Marban E. Acidosis during early reperfusion prevents myocardial stunning in
perfused ferret hearts. J Clin Invest 1988;82:920-927.
293. Tian GH, Mainwood GW, Biro GP, et al. The effect of high buffer cardioplegia and secondary
cardioplegia on cardiac preservation and postischemic functional recovery: a 31P NMR and functional study
in Langendorff perfused pig hearts. Can J Physiol Pharmacol 1991;69:1760-1768.
294. Nugent WC, Levine FH, Liapis CD, et al. Effect of the pH of cardioplegic solution on postarrest
myocardial preservation. Circulation 1982;66:I-68-I-72.
295. Tait GA, Booker PD, Wilson GJ, et al. Effect of multidose cardioplegia and cardioplegic solution
buffering on myocardial tissue acidosis. J Thorac Cardiovasc Surg 1982;83:824-829.
296. Edelman JJ, Seco M, Dunne B, et al. Systematic review protocol: single-dose histidine-tryptophan-
ketoglutarate vs. intermittent crystalloid or blood cardioplegia. Ann Cardiothorac Surg 2013;2:677.
297. Liu J, Feng Z, Zhao J, Li B, et al. The myocardial protection of HTK cardioplegic solution on the long-
term ischemic period in pediatric heart surgery. ASAIO J 2008;54:470-473.
298. Warner KG, Josa M, Butler MD, et al. Regional changes in myocardial acid production during ischemic
arrest: a comparison of sanguineous and asanguineous cardioplegia. Ann Thorac Surg 1988;45:75-81.
299. Kato NS, Buckberg GD, Cushen CK, et al. Inaccuracies and variability of indirect pressure
measurements during cardioplegia administration. Ann Thorac Surg 1994;58:1188-1191.
300. Buckberg GD. Myocardial protection: an overview. Semin Thorac Cardiovasc Surg 1993;5(2):98-106.
301. Okamoto F, Allen BS, Buckberg GD, et al. Studies of controlled reperfusion after ischemia. XIV.
Reperfusion conditions: importance of ensuring gentle versus sudden reperfusion during relief of coronary
occlusion. J Thorac Cardiovasc Surg 1986;92:613-620.
302. Gunnes S, Ytrehus K, Sorlie D. Effects of initial reperfusion temperature and pressure after prolonged
cardioplegic ischemic arrest. A metabolic and functional study in rat hearts. Scand J Thorac Cardiovasc Surg
1990;24:135-139.
303. Lindal S, Gunnes S, Lund I, et al. Myocardial and microvascular injury following coronary surgery and its
attenuation by mode of reperfusion. Eur J Cardio-Thorac Surg 1995;9:83-89.
304. Katayama O, Amrani M, Ledingham S, et al. Effect of cardioplegia infusion pressure on coronary artery
endothelium and cardiac mechanical function. Eur J Cardiothorac Surg 1997;11:751-762.
305. Sawatari K, Kadoba K, Bergner KA, et al. Influence of initial reperfusion pressure after hypothermic
cardioplegiac ischemia on endothelial modulation of coronary tone in neonatal lambs: impaired coronary
vasodilator response to acetylcholine. J Thorac Cardiovasc Surg 1991;101:777-782.
306. Ozmen S, Ayhan S, Demir Y, et al. Impact of gradual blood flow increase on ischaemia-reperfusion
injury in the rat cremaster microcirculation model. J Plast Reconstr Aesthet Surg 2008;61:939-948.
307. Bopassa JC, Michel P, Gateau-Roesch O, et al. Low-pressure reperfusion alters mitochondrial
permeability transition. Am J Physiol (Heart Circ Physiol) 2005;288:H2750-H2755.
308. Musiolik J, van Caster P, Skyschally A, et al. Reduction of infarct size by gentle reperfusion without
activation of reperfusion injury salvage kinases in pigs. Cardiovasc Res 2010;85:110-117.
309. Larsen M, Webb G, Kennington S, et al. Mannitol in cardioplegia as an oxygen free radical scavenger
measured by malondialdehyde. Perfusion-UK 2002;17:51-55.
310. Ferreira R, Burgos M, Llesuy S, et al. Reduction of reperfusion injury with mannitol cardioplegia. Ann
Thorac Surg 1989;78:77-84.
P.225
311. Okamoto F, Allen BS, Buckberg GD, et al. Studies of controlled reperfusion after ischemia. XI.
Reperfusate composition: interaction of marked hyperglycemia and marked hyperosmolarity in allowing
immediate contractile recovery after four hours of regional ischemia. J Thorac Cardiovasc Surg 1986;92:583-
593.
312. Piper HM, Garcia-Dorado D. Prime cause of rapid cardiomyocyte death during reperfusion. Ann Thorac
Surg 1999;68 1913-1919.
313. Avkiran M, Marber MS. Na(+)/H(+) exchange inhibitors for cardioprotective therapy: progress, problems
and prospects. J Am Coll Cardiol 2002;39:747-753.
314. Palatianos GM, Balentine G, Papadakis EG, et al. Neutrophil depletion reduces myocardial reperfusion
morbidity. Ann Thorac Surg 2004;77(3):956-961.
315. Schmidt FE Jr, MacDonald MJ, Murphy CO, et al. Leukocyte depletion of blood cardioplegia attenuates
reperfusion injury. Ann Thorac Surg 1996;62:1691-1696; discussion 1696-1697.
316. Roth M, Bauer EP, Reuthebuch O, et al. Single leukocyte filter (Pall BC1B) fails in multidose cold blood
cardioplegia. J Thorac Cardiovasc Surg 1997;113:1116-1117.
317. Maggirwar SB, Dhanraj DN, Somani SM, et al. Adenosine acts as an endogenous activator of the
cellular antioxidant defense system. Biochem Biophys Res Commun 1994;201:508-515.
318. Juneau CF, Ito BR, del Balzo U, et al. Severe neutrophil depletion by leucocyte filters or cytotoxic drug
does not improve recovery of contractile function in stunned porcine myocardium. Cardiovasc Res
1993;27:720-727.
319. Kofsky ER, Julia PL, Buckberg GD, et al. Studies of controlled reperfusion after ischemia. XXII.
Reperfusate composition: effects of leukocyte depletion of blood and blood cardioplegic reperfusates after
acute coronary occlusion. J Thorac Cardiovasc Surg 1991;101:350-359.
320. Vinten-Johansen J, Chiantella V, Faust KB, et al. Myocardial protection with blood cardioplegia in
ischemically injured hearts: reduction of reoxygenation injury with allopurinol. Ann Thorac Surg 1988;45:319-
326.
321. Bolli R. Oxygen-derived free radicals and postischemic myocardial dysfunction (“Stunned Myocardium”)
reviews. J Am Coll Cardiol 1988;12:239-249.
322. Coghlan JG, Flitter WD, Clutton SM, et al. Allopurinol pretreatment improves postoperative recovery and
reduces lipid peroxidation in patients undergoing coronary artery bypass grafting. J Thorac Cardiovasc Surg
1994;107:248-256.
323. Gimpel JA, Lahpor JR, Van der Molen AJ, et al. Reduction of reperfusion injury of human myocardium
by allopurinol: a clinical study. Free Rad Biol Med 1995;19:251-255.
324. Sisto T, Paajanen H, Metsa-Ketela T, et al. Pretreatment with antioxidants and allopurinol diminishes
cardiac onset events in coronary artery bypass grafting. Ann Thorac Surg 1995;59:1519-1523.
325. Cavarocchi NC, England MD, Schaff HV, et al. Oxygen free radical generation during cardiopulmonary
bypass: correlation with complement activation. Circulation 1986;74:III-130-III-133.
326. England MD, Cavarocchi NC, O’Brien JF, et al. Influence of antioxidants (mannitol and allopurinol) on
oxygen free radical generation during and after cardiopulmonary bypass. Circulation 1986;74:III-134-III-137.
327. Weisel JW, Mickle DAG, Finkle CD, et al. Myocardial free-radical injury after cardioplegia. Circulation
1989;80(Suppl III):14-18.
328. Bical O, Gerhardt MF, Paumier D, et al. Comparison of different types of cardioplegia and reperfusion
on myocardial metabolism and free radical activity. Circulation 1991;84(Suppl III):III-375-III-379.
329. Castelli P, Condemi AM, Brambillasea C, et al. Improvement in cardiac function by allopurinol on
patients undergoing cardiac surgery. J Cardiovasc Pharmacol 1995;25:119-125.
330. Emerit I, Fabiani JN, Ponzio O, et al. Clastogenic factor in ischemia-reperfusion injury during open-heart
surgery: protective effect of allopurinol. Ann Thorac Surg 1995;60:736-737.
331. Seiler KS, Kehrer JP, Starnes JW. Exogenous glutathione attenuates stunning following intermittent
hypoxia in isolated rat hearts. Free Rad Res 1996;24:115-122.
332. Konorev EA, Joseph J, Tarpey MM, et al. The mechanisms of cardioprotection by S-nitrosoglutathione
monoethyl ester in rat isolated heart during cardioplegic ischemic arrest. Br J Pharmacol 1996;119:511-518.
333. Kevelaitis E, Nyborg NC, Menasch, P. Protective effect of reduced glutathione on endothelial function of
coronary arteries subjected to prolonged storage. Transplantation 1997;64:660-663.
334. Ma XL, Lopez BL, Liu GL, et al. Peroxynitrite aggravates myocardial reperfusion injury in the isolated
perfused rat heart. Cardiovasc Res 1997;36:195-204.
335. Wu M, Pritchard KA Jr, Kaminski PM, et al. Involvement of nitric oxide and nitrosothiols in relaxation of
pulmonary arteries to peroxynitrite. Am J Physiol 1994;266:H2108-H2113.
336. Cheung PY, Schulz R. Glutathione causes coronary vasodilation via a nitric oxide- and soluble
guanylate cyclase-dependent mechanism. Am J Physiol 1997;273:H1231-H1238.
337. Yoshida T, Maulik N, Engelman RM, et al. Glutathione peroxidase knockout mice are susceptible to
myocardial ischemia reperfusion injury. Circulation 1997;96 (9, Suppl):II-216-II-220.
338. Menasche P, Termignon JL, Pradier F, et al. Experimental evaluation of Celsior, a new heart
preservation solution. Eur J Cardio Thorac Surg 1994;8: 207-213.
339. Pietri S, Culcasi M, Albat B, et al. Direct assessment of the antioxidant effects of a new heart
preservation solution, Celsior. A hemodynamic and electron spin resonance study. Transplantation
1994;58:739-742.
340. Weiss RG, Kalil-Filho R, Herskowitz A, et al. Tricarboxylic acid cycle activity in postischemic rat hearts.
Circulation 1993;87:270-282.
341. Kimose HH, Ravkilde J, Helligso P, et al. Myocardial loss of glutamate after cold chemical cardioplegia
and storage in isolated blood-perfused pig hearts. Thorac Cardiovasc Surg 1993;41:93-100.
342. Svedjeholm R, Vanhanen I, Hakanson E, et al. Metabolic and hemodynamic effects of intravenous
glutamate infusion early after coronary operations. J Thorac Cardiovasc Surg 1996;112:1468-1477.
343. Reed MK, Barak C, Malloy CR, et al. Effects of glutamate and aspartate on myocardial substrate
oxidation during potassium arrest. J Thorac Cardiovasc Surg 1996;112:1651-1660.
344. Rosenkranz ER, Okamoto F, Buckberg GD, et al. Safety of prolonged aortic clamping with blood
cardioplegia. III. Aspartate enrichment of glutamate-blood cardioplegia in energy-depleted hearts after
ischemic and reperfusion injury. J Thorac Cardiovasc Surg 1986;91:428-435.
345. Robertson JM, Vinten-Johansen J, Buckberg GD, et al. Safety of prolonged aortic clamping with blood
cardioplegia. I. Glutamate enrichment in normal hearts. J Thorac Cardiovasc Surg 1984;88:395-401.
346. Kofsky E, Julia P, Buckberg GD, et al. Studies of myocardial protection in the immature heart. V. Safety
of prolonged aortic clamping with hypocalcemic glutamate/aspartate blood cardioplegia. J Thorac Cardiovasc
Surg 1991;101:33-43.
347. Julia P, Young HH, Buckberg GD, et al. Studies of myocardial protection in the immature heart. IV.
Improved tolerance of immature myocardium to hypoxia and ischemia by intravenous metabolic support [see
comments]. J Thorac Cardiovasc Surg 1991;101:23-32.
348. Keith F. Oxygen free radicals in cardiac transplantation [Review]. J Card Surg 1993;8:245-248.
349. Tixier D, Matheis G, Buckberg GD, et al. Donor hearts with impaired hemodynamics. Benefit of warm
substrate-enriched blood cardioplegic solution for induction of cardioplegia during cardiac harvesting. J
Thorac Cardiovasc Surg 1991;102:207-213; discussion 213-204.
350. Kimose HH, Helligso P, Randsbaek F, et al. Improved recovery after cold crystalloid cardioplegia using
low-dose glutamate enrichment during reperfusion after aortic unclamping: a study in isolated blood-perfused
pig hearts. Thorac Cardiovasc Surg 1996;44:118-125.
351. Pisarenko OI, Portnoy VF, Studneva IM, et al. Glutamate-blood cardioplegia improves ATP preservation
in human myocardium. Biomed Biochim Acta 1987;46:499-504.
352. Uyar I, Mansuroglu D, Kirali K, et al. Aspartate and glutamate-enriched cardioplegia in left ventricular
dysfunction. J Card Surg 2005;20: 337-344.
353. Duman U, Dogan OF. Transient beneficial effects of glutamate-aspartate-enriched cardioplegia on

ventricular functions in coronary artery bypass grafting. J Card Surg 2006;21:523-525.
354. Choi JS, Park J, Suk K, et al. Mild hypothermia attenuates intercellular adhesion molecule-1 induction
via activation of extracellular signal-regulated kinase-1/2 in a focal cerebral ischemia model. Stroke Res
Treat 2011;2011:846716.
355. Boyle EM, Pohlman TH, Johnson MC, et al. Endothelial cell injury in cardiovascular surgery: the
systemic inflammatory response. Ann Thorac Surg 1997;63:277-284.
356. Sluiter W, Pietersma A, Lamers JMJ, et al. Leukocyte adhesion molecules on the vascular endothelium:
their role in the pathogenesis of cardiovascular disease and the mechanisms underlying their expression. J
Cardiovasc Pharmacol 1993;22(Suppl 4):S37-S44.
357. Collins T, Read MA, Neish AS, et al. Transcriptional regulation of endothelial cell adhesion molecules:
NF-κBB and cytokine-inducible enhancers. FASEB J 1995;9:899-909.
P.226
358. Weber C, Erl W, Pietsch A, et al. Aspirin inhibits nuclear factor-κBB mobilization and monocyte adhesion
in stimulated human endothelial cells. Circulation 1995;91:1914-1917.
359. Wilson I, Gillinov AM, Curtis WE, et al. Inhibition of neutrophil adherence improves postischemic
ventricular performance of the neonatal heart. Circulation 1993;88:II372-II379.
360. Flynn DM, Buda AJ, Jeffords PR. A sialyl Lewis (x)-containing carbohydrate reduces infarct size: role of
selectins in myocardial reperfusion injury. Am J Physiol 1996;271(5, Part 2):H2080-H2096.
361. Gu YJ, Obster R, Haan J, et al. Biocompatibility of leukocyte removal filters during leukodyte filtration of
cardiopulmonary bypass perfusate. Artif Organs 1993;17:660-665.
362. Wilson IC, Gardner TJ, DiNatale JM, et al. Temporary leukocyte depletion reduces ventricular
dysfunction during prolonged postischemic reperfusion. J Thorac Cardiovasc Surg 1993;106:805-810.
363. Wilson IC, DiNatale JM, Gillinov AM, et al. Leukocyte depletion in a neonatal model of cardiac surgery.
Ann Thorac Surg 1993;55:12-19; discussion 19.
364. Lazar HL, Zhang X, Hamasaki T, et al. Role of leukocyte depletion during cardiopulmonary bypass and
cardioplegic arrest. Ann Thorac Surg 1995;60:1745-1748.
365. Gott JP, Cooper WA, Schmidt FE Jr, et al. Modifying risk for extracorporeal circulation: trial of four
antiinflammatory strategies. Ann Thorac Surg 1998;66:747-753.
366. Ilmakunnas M, Pesonen EJ, Ahonen J, et al. Activation of neutrophils and monocytes by a leukocyte-
depleting filter used throughout cardiopulmonary bypass. J Thorac Cardiovasc Surg 2005;129:851-859.
367. Finn A, Morgan BP, Rebuck N, et al. Effects of inhibition of complement activation using recombinant
soluble complement receptor 1 on neutrophil CD11B/CD18 and L-selectin expression and release of
interleukin-8 and elastase in simulated cardiopulmonary bypass. J Thorac Cardiovasc Surg 1996;111:451-
459.
368. Gillinov AM, DeValeria PA, Winkelstein JA, et al. Complement inhibition with soluble complement
receptor Type 1 in cardiopulmonary bypass. Ann Thorac Surg 1993;55:619-624.
369. Chai PJ, Nassar R, Oakeley AE, et al. Soluble complement receptor-1 protects heart, lung, and cardiac
myofilament function from cardiopulmonary bypass damage. Circulation 2000;101:541-546.
370. Lazar HL, Bokesch PM, van Lenta F, et al. Soluble human complement receptor 1 limits ischemic
damage in cardiac surgery patients at high risk requiring cardiopulmonary bypass. Circulation
2004;110(Suppl II) II-279.
371. Shernan SK, Fitch JC, Nussmeier NA, et al. Impact of pexelizumab, an anti-C5 complement antibody, on
total mortality and adverse cardiovascular outcomes in cardiac surgical patients undergoing cardiopulmonary
bypass. Ann Thorac Surg 2004;77:942-949; discussion 949-950.
372. Verrier ED, Shernan SK, Taylor KM, et al. Terminal complement blockade with pexelizumab during
coronary artery bypass graft surgery requiring cardiopulmonary bypass: a randomized trial. JAMA
2004;291:2319-2327.
373. Smith PK, Carrier M, Chen JC, et al. Effect of pexelizumab in coronary artery bypass graft surgery with
extended aortic cross-clamp time. Ann Thorac Surg 2006;82:781-788; discussion 788-789.
374. Smith PK, Shernan SK, Chen JC, et al. Effects of C5 complement inhibitor pexelizumab on outcome in
high-risk coronary artery bypass grafting: combined results from the PRIMO-CABG I and II trials. J Thorac
375. Granger CB. Adenosine for myocardial protection in acute myocardial infarction. Am J Cardiol
1997;79:44-48.
376. Hori M, Kitakaze M. Adenosine, the heart, coronary circulation [Review]. Hypertension 1991;18:565-
574.
377. Peart JN, Headrick JP. Adenosinergic cardioprotection: multiple receptors, multiple pathways.
Pharmacol Ther 2007;114:208-221.
378. Pelleg A. Adenosine in the heart: its emerging roles. Hosp Pract (Off Ed) 1993;28:71-73, passim.
379. Vinten-Johansen J, Thourani VH, Ronson RS, et al. Broad-spectrum cardioprotection with adenosine.
Ann Thorac Surg 1999;68:1942-1948.
380. Vinten-Johansen J, Zhao ZQ, Sato H. Reduction in surgical ischemic-reperfusion injury with adenosine
and nitric oxide therapy. Ann Thorac Surg 1995;60:852-857.
381. Headrick JP, Lasley RD. Adenosine receptors and reperfusion injury of the heart. Handb Exp
Pharmacol 2009:189-214.
382. Cronstein BN. Adenosine, an endogenous anti-inflammatory agent. J Appl Physiol 1994;76:5-13.
383. Vinten-Johansen J, Zhao ZQ, Abd-Elfattah AS, et al. Cardioprotection from ischemic-reperfusion injury
by adenosine. In: Vinten-Johansen J, Zhao ZQ, eds. Purines and myocardial protection. Boston, MA: Kluwer
Academic Publishers, 1995:315-344.
384. Lasley RD, Mentzer RM Jr. Protective effects of adenosine in the reversibly injured heart. Ann Thorac
Surg 1995;60:843-846.
385. Zhao ZQ, Sato H, Williams MW, et al. Adenosine A2-receptor activation inhibits neutrophil-mediated
injury to coronary endothelium. Am J Physiol 1996;271:H1456-H1464.
386. Jordan JE, Zhao ZQ, Sato H, et al. Adenosine A2 activation attenuates reperfusion injury by inhibiting
neutrophil accumulation, superoxide generation and coronary endothelial adherence. Circulation 1995;92:I-
524.
387. Vinten-Johansen J, Hammon JW Jr. Cardioprotection by adenosine: is it a question of effective dose,
timing, or the target compartment? J Thorac Cardiovasc Surg 1996;112:202-204.
388. Thornton JD, Liu GS, Olsson RA, et al. Intravenous pretreatment with A 1-selective adenosine
analogues protects the heart against infarction. Circulation 1992;85:659-665.
389. Hohlfeld T, Hearse DJ, Yellon DM, et al. Adenosine-induced increase in myocardial ATP: Are there
beneficial effects for the ischaemic myocardial? Basic Res Cardiol 1989;84:499-509.
390. Lee HT, LaFaro RJ, Reed GE. Pretreatment of human myocardium with adenosine during open heart
surgery. J Card Surg 1995;10:665-676.
391. Boehm DH, Human PA, Reichenspurner H, et al. Adenosine and its role in cardioplegia: effects on
postischemic recovery in the baboon. Transplant Proc 1990;22:545-546.
392. Bolling SF, Bove EL, Gallagher KP. ATP precursor depletion and postischemic myocardial recovery. J
Surg Res 1991;50:629-633.
393. Bolling SF, Bies LE, Bove EL, et al. Augmenting intracellular adenosine improves myocardial recovery. J
394. Rosenkranz ER, Okamoto F, Buckberg GD, et al. Biochemical studies: failure of tissue adenosine
triphosphate levels to predict recovery of contractile function after controlled reperfusion. J
ThoracCardiovasc Surg 1986;92:488-501.
395. Ledingham S, Katayama O, Lachno D, et al. Beneficial effect of adenosine during reperfusion following
prolonged cardioplegic arrest. Cardiovasc Res 1990;24:247-253.
396. Thelin S, Hultman J, Ronquist G. Effects of adenosine infusion on the pig heart during normothermic
ischemia and reperfusion. Scand J Thor Cardiovasc Surg 1991;25:207-213.
397. Thourani VH, Ronson RS, Van Wylen DG, et al. Adenosine-supplemented blood cardioplegia
attenuates postischemic dysfunction after severe regional ischemia. Circulation 1999;100:II376-II383.
398. Fremes SE, Levy SL, Christakis GT, et al. Phase 1 human trial of adenosine-potassium cardioplegia.
399. Cohen G, Feder-Elituv R, Iazetta J, et al. Phase 2 studies of adenosine cardioplegia. Circulation
1998;98:II-225-II-233.
400. Mentzer RM Jr, Birjiniuk V, Khuri S, et al. Adenosine myocardial protection. Preliminary results of a
Phase II clinical trial. Ann Surg 1999;229: 643-650.
401. Mentzer RM Jr, Rahko PS, Molina-Viamonte V, et al. Safety, tolerance, and efficacy of adenosine as an
additive to blood cardioplegia in humans during coronary artery bypass surgery. Am J Cardiol 1997;79:38-
43.
402. Mentzer RM Jr, Rahko PS, Canver CC, et al. Adenosine reduces postbypass transfusion requirements
in humans after heart surgery. Ann Surg 1996;234:523-530.
403. Liu R, Xing J, Miao N, et al. The myocardial protective effect of adenosine as an adjunct to intermittent
blood cardioplegia during open heart surgery. Eur J Cardiothorac Surg 2009;36:1018-1023.
404. Ahlsson A, Sobrosa C, Kaijser L, et al. Adenosine in cold blood cardioplegia—a placebo-controlled
study. Interact Cardiovasc Thorac Surg 2012;14:48-55.
405. Sato H, Zhao ZQ, Vinten-Johansen J. L-Arginine inhibits neutrophil adherence and coronary artery
dysfunction. Cardiovasc Res 1996;31:63-72.
406. Hiramatsu T, Forbess JM, Miura T, et al. Effect of L-arginine cardioplegia on recovery of neonatal lamb
hearts after 2 hours of cold ischemia. Ann Thorac Surg 1995;60:1187-1192.
407. Engelman DT, Watanabe M, Maulik N, et al. L-Arginine reduces endothelial inflammation and
myocardial stunning during ischemia/reperfusion. Ann Thorac Surg 1995;60:1275-1281.
408. Carrier M, Pellerin M, Page PL, et al. Can L-arginine improve myocardial protection during cardioplegic
arrest? Results of a Phase I pilot study. Ann Thorac Surg 1998;66:108-112.
P.227
409. Carrier M, Pellerin M, Perrault LP, et al. Cardioplegic arrest with L-arginine improves myocardial
protection: results of a prospective randomized clinical trial. Ann Thorac Surg 2002;73:837-842.
410. Kiziltepe U, Tunctan B, Eyileten ZB, et al. Efficiency of L-arginine enriched cardioplegia and non-
cardioplegic reperfusion in hearts. Int J Cardiol 2004;97 93-100.
411. Colagrande L, Formica F, Porta F, et al. Reduced cytokines release and myocardial damage in coronary
artery bypass patients due to L-arginine cardioplegia supplementation. Ann Thorac Surg 2006;81:1256-1261.
412. Verma S, Maitland A, Weisel RD, et al. Novel cardioprotective effects of tetrahydrobiopterin after anoxia
and reoxygenation: identifying cellular targets for pharmacologic manipulation. J Thorac Cardiovasc Surg
2002;123:1074-1081.
413. Yamashiro S, Noguchi K, Kuniyoshi Y, et al. Role of tetrahydrobiopterin on ischemia-reperfusion injury

in isolated perfused rat hearts. J Cardiovasc Surg 2003;44 37-49.
414. Xia Y, Dawson VL, Dawson TM, et al. Nitric oxide synthase generates superoxide and nitric oxide in
arginine-depleted cells leading to peroxynitrite-mediated cellular injury. Proc Natl Acad Sci USA
1996;93:6770-6774.
415. Johnson G III, Tsao PS, Lefer AM. Cardioprotective effects of authentic nitric oxide in myocardial
ischemia with reperfusion. Crit Care Med 1991;19:244-252.
416. Nakanishi K, Zhao ZQ, Vinten-Johansen J, et al. Blood cardioplegia enhanced with nitric oxide donor
SPM-5185 counteracts postischemic endothelial and ventricular dysfunction. J Thorac Cardiovasc Surg
1995;109:1146-1154.
417. Hallstrom S, Gasser H, Neumayer C, et al. S-nitroso human serum albumin treatment reduces
ischemia/reperfusion injury in skeletal muscle via nitric oxide release. Circulation 2002;105:3032-3038.
418. Methner C, Chouchani ET, Buonincontri G, et al. Mitochondria selective S-nitrosation by mitochondria-
targeted S-nitrosothiol protects against post-infarct heart failure in mouse hearts. Eur J Heart Fail
2014;16:712-717.
419. Bers DM, Barry WH, Despa S. Intracellular Na+ regulation in cardiac myocytes. Cardiovasc Res
2003;57:897-912.
420. Reidemeister JC, Heberer G, Bretschneider HJ. Induced cardiac arrest by sodium and calcium depletion
and application of procaine. Int Surg 1967;47:535-540.
421. Hoelscher B. Studies by electron microscopy on the effects of magnesium chloride-procaine amide or
potassium citrate on the myocardium in induced cardiac arrest. J Cardiovasc Surg (Torino) 1967;8:163-166.
422. Leicher FG, Magrassi P, LaRaia PJ, et al. Blood cardioplegia delivery. Deleterious effects of potassium
versus lidocaine. Ann Surg 1983;198:266-272.
423. Snabaitis AK, Shattock MJ, Chambers DJ. Comparison of polarized and depolarized arrest in the
isolated rat heart for long-term preservation. Circulation 1997;96:3148-3156.
424. Snabaitis AK, Shattock MJ, Chambers DJ. Long-term myocardial preservation: effects of hyperkalemia,
sodium channel, and Na+/K+/2Cl(-) cotransport inhibition on extracellular potassium accumulation during
hypothermic storage. J Thorac Cardiovasc Surg 1999;118:123-134.
425. Nichols CG, Ripoll C, Lederer WJ. ATP-sensitive potassium channel modulation of the guinea pig
ventricular action potential and contraction. Circ Res 1991;68:280-287.
426. Nichols CG, Lederer WJ. Adenosine triphosphate-sensitive potassium channels in the cardiovascular
system. Am J Physiol 1991;261:H1675-H1686.
427. Jayawant AM, Stephenson ER Jr, Matte GS, et al. Hyperpolarized arrest with pinacidil is superior to
traditional St. Thomas’ solution in the intact animal. Surg Forum 1998;49:192-194.
428. Steenbergen C. Correlation between cytosolic free calcium contracture, ATP, and irreversible ischemic
injury in perfused rat heart. Circ Res 1990;66:135-146.
429. Shattock MJ, Hearse DJ, Fry CH. The ionic basis of the anti-ischemic and anti-arrhythmic properties of
magnesium in the heart. J Am Coll Nutr 1987;6:27-33.
430. Hearse DJ, Stewart DA, Braimbridge MV. Myocardial protection during ischemic cardiac arrest. The
importance of magnesium in cardioplegic infusates. J Thorac Cardiovasc Surg 1978;75:877-885.
431. Maruyama Y, Chambers DJ. Myocardial protection: efficacy of a novel magnesium-based cardioplegia
(RS-C) compared to St Thomas’ Hospital cardioplegic solution. Interact Cardiovasc Thorac Surg 2008;7:745-
749.
432. Warters RD, Allen SJ, Davis KL, et al. β-blockade as an alternative to cardioplegic arrest during
cardiopulmonary bypass. Ann Thorac Surg 1998;65: 961-966.
433. Bessho R, Chambers DJ. Myocardial protection: the efficacy of an ultra-short-acting beta-blocker,
esmolol, as a cardioplegic agent. J Thorac Cardiovasc Surg 2001;122:993-1003.
434. Fallouh HB, Bardswell SC, McLatchie LM, et al. Esmolol cardioplegia: the cellular mechanism of
diastolic arrest. Cardiovasc Res 2010;87:552-560.
435. Fujii M, Chambers DJ. Cardioprotection with esmolol cardioplegia: efficacy as a blood-based solution.
436. Mehlhorn U, Sauer H, Kuhn-Regnier F, et al. Myocardial beta-blockade as an alternative to cardioplegic

arrest during coronary artery surgery. Cardiovasc Surg 1999;7:549-557.
437. Kuhn-Regnier F, Natour E, Dhein S, et al. Beta-blockade versus Buckberg blood-cardioplegia in

coronary bypass operation. Eur J Cardiothorac Surg 1999;15:67-74.
438. Geissler HJ, Mehlhorn U, Laine GA, et al. Myocardial protection with esmolol during coronary artery
bypass grafting surgery. Anesthesiology 2003;98:1024-1025; author reply 1025.
439. Kuhn-Regnier F, Geissler HJ, Marohl S, et al. Beta-blockade in 200 coronary bypass grafting
procedures. Thorac Cardiovasc Surg 2002;50:164-167.
440. Terzic A, Jahangir A, Kurachi Y. Cardiac ATP-sensitive K+ channels: regulation by intracellular

nucleotides and K+ channel-opening drugs. Am J Physiol 1995;269:C525-C545.
441. Ward CA, Bazzazi H, Clark RB, et al. Actions of emigrated neutrophils on Na(+) and K(+) currents in rat
ventricular myocytes. Prog Biophys Mol Biol 2006;90:249-269.
442. Vinten-Johansen J, Zhao ZQ, Corvera JS, et al. Adenosine in myocardial protection in on-pump and off-
pump cardiac surgery. Ann Thorac Surg 2003;75:S691-S699.
443. Jordan JE, Thourani VH, Auchampach JA, et al. A(3) adenosine receptor activation attenuates
neutrophil function and neutrophil-mediated reperfusion injury. Am J Physiol 1999;277:H1895-H1905.
444. Dobson GP, Jones MW. Adenosine and lignocaine: a new concept in cardiac arrest and preservation.
Ann Thorac Surg 2003;75 S746.
445. Sloots KL, Dobson GP. Normokalemic adenosine-lidocaine cardioplegia: importance of maintaining a
polarized myocardium for optimal arrest and reanimation. J Thorac Cardiovasc Surg 2010;139:1576-1586.
446. Sloots KL, Vinten-Johansen J, Dobson GP. Warm nondepolarizing adenosine and lidocaine
cardioplegia: continuous versus intermittent delivery. J Thorac Cardiovasc Surg 2007;133:1171-1178.
447. Corvera JS, Kin H, Dobson GP, et al. Polarized arrest with warm or cold adenosine/lidocaine blood
cardioplegia is equivalent to hypothermic potassium blood cardioplegia. J Thorac Cardiovasc Surg
2005;129:599-606.
448. O’Rullian JJ, Clayson SE, Peragallo R. Excellent outcomes in a case of complex re-do surgery requiring
prolonged cardioplegia using a new cardioprotective approach: adenocaine. J Extra Corpor Technol
2008;40:203-205.
449. Onorati F, Santini F, Dandale R, et al. “Polarizing” microplegia improves cardiac cycle efficiency after
CABG for unstable angina. Int J Cardiol 2012;167(6):2739-2734.
450. Jakobsen O, Stenberg TA, Losvik O, et al. Adenosine instead of supranormal potassium in cardioplegic
solution preserves endothelium-derived hyperpolarization factor-dependent vasodilation. Eur J Cardiothorac
Surg 2008;33:18-24.
451. Jakobsen O, Naesheim T, Aas KN, et al. Adenosine instead of supranormal potassium in cardioplegia: it
is safe, efficient, and reduces the incidence of postoperative atrial fibrillation. A randomized clinical trial. J
452. Brixius K, Schwinger RHG. Modulation of cross-bridge interaction by 2,3-butanedione monoxime in

human ventricular myocardium. Naunyn-Schmiedebergs Arch Pharm 2000;361:440-444.
453. Jayawant AM, Stephenson ER Jr, Damiano RJ Jr. 2,3-Butanedione monoxime cardioplegia: advantages
over hyperkalemia in blood-perfused isolated hearts. Ann Thorac Surg 1999;67:618-623.
454. Habazettl H, Palmisano BW, Bosnjak ZJ, et al. Initial reperfusion with 2,3 butanedione monoxime is
better than hyperkalemic reperfusion after cardioplegic arrest in isolated guinea pig hearts. Eur J Cardio
Thorac Surg 1996;10:897-904.
455. Yumoto M, Watanabe M. Blebbistatin, a myosin II inhibitor, suppresses Ca(2+)-induced and

“sensitized”-contraction of skinned tracheal muscles from guinea pig. J Smooth Muscle Res 2013;49:89-98.
456. Griffiths EJ, Halestrap AP. Protection by Cyclosporin A of ischemia/reperfusion-induced damage in

isolated rat hearts. J Mol Cell Cardiol 1993;25:1461-1469.
P.228
457. Halestrap AP, Kerr PM, Javadov S, et al. Elucidating the molecular mechanism of the permeability
transition pore and its role in reperfusion injury of the heart. Biochim Biophys Acta 1998;1366:79-94.
458. Argaud L, Gateau-Roesch O, Muntean D, et al. Specific inhibition of the mitochondrial permeability
transition prevents lethal reperfusion injury. J Mol Cell Cardiol 2005;38:367-374.
459. Ge ZD, Pravdic D, Bienengraeber M, et al. Isoflurane postconditioning protects against reperfusion
injury by preventing mitochondrial permeability transition by an endothelial nitric oxide synthase-dependent
mechanism. Anesthesiology 2010;112:73-85.
460. Yao Y, Li L, Gao C, et al. Sevoflurane postconditioning protects chronically-infarcted rat hearts against
ischemia-reperfusion injury by activation of pro-survival kinases and inhibition of mitochondrial permeability
transition pore opening upon reperfusion. Biol Pharm Bull 2009;32:1854-1861.
461. Hausenloy DJ, Yellon DM, Mani-Babu S, et al. Preconditioning protects by inhibiting the mitochondrial
permeability transition. Am J Physiol Heart Circ Physiol 2004;287:H841-H849.
462. Argaud L, Gateau-Roesch O, Raisky O, et al. Post-conditioning inhibits mitochondrial permeability

transition. Circulation 2005;111:194-197.
463. Argaud L, Gateau-Roesch O, Augeul L, et al. Increased mitochondrial calcium coexists with decreased
reperfusion injury in postconditioned (but not preconditioned) hearts. Am J Physiol Heart Circ Physiol
2008;294:H386-H391.
464. Fang J, Wu L, Chen L. Postconditioning attenuates cardiocyte ultrastructure injury and apoptosis by
blocking mitochondrial permeability transition in rats. Acta Cardiol 2008;63:377-387.
465. Hausenloy DJ, Ong SB, Yellon DM. The mitochondrial permeability transition pore as a target for
preconditioning and postconditioning. Basic Res Cardiol 2009;104:189-202.
466. Hausenloy DJ, Tsang A, Yellon DM. The reperfusion injury salvage kinase pathway: a common target
for both ischemic preconditioning and postconditioning. Trends Cardiovasc Med 2005;15:69-75.
467. Shi W, Vinten-Johansen J. Endogenous cardioprotection by ischaemic postconditioning and remote

conditioning. Cardiovasc Res 2012;94:206-216.
468. Vinten-Johansen J, Granfeldt A, Mykytenko J, et al. The multidimensional physiological responses to

postconditioning. Antioxid Redox Signal 2011;14:791-810.
469. Hausenloy DJ, Wynne AM, Yellon DM. Ischemic preconditioning targets the reperfusion phase. Basic
Res Cardiol 2007;102:445-452.
470. Bopassa JC, Ferrera R, Gateau-Roesch O, et al. PI 3-kinase regulates the mitochondrial transition pore
in controlled reperfusion and postconditioning. Cardiovasc Res 2006;69:178-185.
471. Davidson SM, Hausenloy D, Duchen MR, et al. Signalling via the reperfusion injury signalling kinase
(RISK) pathway links closure of the mitochondrial permeability transition pore to cardioprotection. Int J
Biochem Cell Biol 2006;38:414-419.
472. Shanmuganathan S, Hausenloy D, Duchen M, et al. Inhibiting mitochondrial permeability transition pore
opening protects the human heart from lethal reoxygenation injury. Cardiovasc J S Afr 2004;15:S11.
473. Piot C, Croisille P, Staat P, et al. Effect of cyclosporine on reperfusion injury in acute myocardial
infarction. N Engl J Med 2008;359:473-481.
474. Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: a delay of lethal cell injury in
ischemic myocardium. Circulation 1986;74:1124-1136.
475. Yellon DM, Baxter GF. A “second window of protection” or delayed preconditioning phenomenon: future
horizons for myocardial protection? J Mol Cell Cardiol 1995;27:1023-1034.
476. DeFily DV, Chilian WM. Preconditioning protects coronary arteriolar endothelium from ischemia-
reperfusion injury. Am J Physiol 1993;265:H700-H706.
477. Bufkin BL, Shearer ST, Vinten-Johansen J, et al. Preconditioning during simulated MIDCABG
attenuates blood flow defects and neutrophil accumulation. Ann Thorac Surg 1998;66:726-731.
478. Yellon DM, Alkhulaifi AM, Pugsley WB. Preconditioning the human myocardium. Lancet 1993;342:276-
277.
479. Jenkins DP, Pugsley WB, Alkhulaifi AM, et al. Ischaemic preconditioning reduces troponin T release in
patients undergoing coronary artery bypass surgery. Heart 1997;77:314-318.
480. Teoh LK, Grant R, Hulf JA, et al. The effect of preconditioning (ischemic and pharmacological) on
myocardial necrosis following coronary artery bypass graft surgery. Cardiovasc Res 2002;53:175-180.
481. Teoh LKK, Grant R, Hulf JA, et al. A comparison between ischemic preconditioning, intermittent cross-
clamp fibrillation and cold crystalloid cardioplegia for myocardial protection during coronary artery bypass
graft surgery. Cardiovasc Surg 2002;10:251-255.
482. Kaukoranta PK, Lepoj MP, Ylitalo KV, et al. Normothermic retrograde blood cardioplegia with or without
preceding ischemic preconditioning. Ann Thorac Surg 1997;63:1268-1274.
483. Juggi JS, Al-Awadi F, Joseph S, et al. Ischemic preconditioning is not additive to preservation with
hypothermia or crystalloid cardioplegia in the globally ischemic rat heart. Mol Cell Biochem 1997;176:303-
313.
484. Cleveland JC, Meldrum DR, Rowland RT, et al. Preconditioning and hypothermic cardioplegia protect
human heart equally against ischemia. Ann Thorac Surg 1997;63:147-152.
485. Walsh SR, Tang TY, Kullar P, et al. Ischaemic preconditioning during cardiac surgery: systematic
review and meta-analysis of perioperative outcomes in randomised clinical trials. Eur J Cardio Thorac Surg
2008;34:985-994.
486. Hausenloy DJ, Candilio L, Laing C, et al. Effect of remote ischemic preconditioning on clinical outcomes
in patients undergoing coronary artery bypass graft surgery (ERICCA): rationale and study design of a multi-
centre randomized double-blinded controlled clinical trial. Clin Res Cardiol 2012;101:339-348.
487. Meybohm P, Zacharowski K, Cremer J, et al. Remote ischaemic preconditioning for heart surgery. The
study design for a multi-center randomized double-blinded controlled clinical trial—the RIPHeart-Study. Eur
Heart J 2012;33:1423-1426.
488. Perrault LP, Menasch, P, Bel A, et al. Ischemic preconditioning in cardiac surgery: a word of caution. J
489. Perrault LP, Menasche P. Preconditioning: can nature’s shield be raised against surgical ischemic-
reperfusion injury? Ann Thorac Surg 1999;68: 1988-1994.
490. Przyklenk K, Bauer B, Ovize M, et al. Regional ischemic ‘preconditioning’ protects remote virgin
myocardium from subsequent sustained coronary occlusion. Circulation 1993;87:893-899.
491. Przyklenk K, Whittaker P. Remote ischemic preconditioning:current knowledge, unresolved questions,

and future priorities. J Cardiovasc Pharmacol Ther 2011;16:255-259.
492. Dickson EW, Lorbar M, Porcaro WA, et al. Rabbit heart can be “predconditioned” via transfer of
coronary effluent. Am J Physiol (Heart Circ Physiol) 1999;277:H2451-H2457.
493. Shimizu M, Tropak M, Diaz RJ, et al. Transient limb ischaemia remotely preconditions through a
humoral mechanism acting directly on the myocardium: evidence suggesting cross-species protection. Clin
Sci (Lond) 2009;117:191-200.
494. Hausenloy DJ, Yellon DM. Preconditioning and postconditioning: underlying mechanisms and clinical
application. Atherosclerosis 2008; 204(2): 334-341.
495. Konstantinov IE, Arab S, Kharbanda RK, Li J, et al. The remote ischemic preconditioning stimulus
modifies inflammatory gene expression in humans. Physiol Genomics 2004;19:143-150.
496. Shimizu M, Saxena P, Konstantinov IE, et al. Remote ischemic preconditioning decreases adhesion and
selectively modifies functional responses of human neutrophils. J Surg Res 2010;158:155-161.
497. Kharbanda RK, Mortensen UM, White PA, et al. Transient limb ischemia induces remote ischemic
preconditioning in vivo. Circulation 2002;106:2881-2883.
498. Gunaydin B, Cakici I, Soncul H, et al. Does remote organ ischaemia trigger cardiac preconditioning
during coronary artery surgery? Pharmacol Res 2000;41:493-496.
499. Loukogeorgakis SP, Williams R, Panagiotidou AT, et al. Transient limb ischemia induces remote
preconditioning and remote postconditioning in humans by a K(ATP)-channel dependent mechanism.
Circulation 2007;116:1386-1395.
500. Cheung MM, Kharbanda RK, Konstantinov IE, et al. Randomized controlled trial of the effects of remote
ischemic preconditioning on children undergoing cardiac surgery: first clinical application in humans. J Am
Coll Cardiol 2006;47:2277-2282.
501. Hausenloy DJ, Mwamure PK, Venugopal V, et al. Effect of remote ischaemic preconditioning on
myocardial injury in patients undergoing coronary artery bypass graft surgery: a randomised controlled trial.
Lancet 2007;370:575-579.
502. Rahman IA, Mascaro JG, Steeds RP, et al. Remote ischemic preconditioning in human coronary artery
bypass surgery: from promise to disappointment? Circulation 2010;122:S53-S59.
503. Karuppasamy P, Chaubey S, Dew T, et al. Remote intermittent ischemia before coronary artery bypass
graft surgery: a strategy to reduce injury and inflammation? Basic Res Cardiol 2011;106:511-519.
P.229
504. Huang Z, Zhong X, Irwin MG, et al. Synergy of isoflurane preconditioning and propofol postconditioning
reduces myocardial reperfusion injury in patients. Clin Sci (Lond) 2011;121:57-69.
505. Kwok WM, Aizawa K. Preconditioning of the myocardium by volatile anesthetics. Curr Med Chem
Cardiovasc Hematol Agents 2004;2:249-255.
506. Roscoe AK, Christensen JD, Lynch C III. Isoflurane, but not halothane, induces protection of human
myocardium via adenosine A1 receptors and adenosine triphosphate-sensitive potassium channels.
507. Young PJ, Dalley P, Garden A, et al. A pilot study investigating the effects of remote ischemic
preconditioning in high-risk cardiac surgery using a randomised controlled double-blind protocol. Basic Res
Cardiol 2012;107:256.
508. Pilcher JM, Young P, Weatherall M, et al. A systematic review and meta-analysis of the cardioprotective
effects of remote ischaemic preconditioning in open cardiac surgery. J R Soc Med 2012;105:436-445.
509. Schmidt MR, Smerup M, Konstantinov IE, et al. Intermittent peripheral tissue ischemia during coronary
ischemia reduces myocardial infarction through a KATP-dependent mechanism: first demonstration of remote
ischemic perconditioning. Am J Physiol Heart Circ Physiol 2007;292:H1883-H1890.
510. Botker HE, Kharbanda R, Schmidt MR, et al. Remote ischaemic conditioning before hospital admission,
as a complement to angioplasty, and effect on myocardial salvage in patients with acute myocardial
infarction: a randomised trial. Lancet 2010;375:727-734.
511. Rentoukas I, Giannopoulos G, Kaoukis A, et al. Cardioprotective role of remote ischemic

periconditioning in primary percutaneous coronary intervention: enhancement by opioid action. JACC
Cardiovasc Interv 2010;3:49-55.
512. Li L, Luo W, Huang L, et al. Remote perconditioning reduces myocardial injury in adult valve
replacement: a randomized controlled trial. J Surg Res 2010;164:e21-e26.
513. Zhao ZQ, Corvera JS, Wang NP, et al. Reduction in infarct size and preservation of endothelial function
by ischemic postconditioning: comparison with ischemic preconditioning. Circulation 2002;106(19,
Suppl):II314.
514. Zhao ZQ, Corvera JS, Halkos ME, et al. Inhibition of myocardial injury by ischemic postconditioning
during reperfusion: comparison with ischemic preconditioning. Am J Physiol Heart Circ Physiol
2003;285:H579-H588.
515. Halkos ME, Kerendi F, Corvera JS, et al. Myocardial protection with postconditioning is not enhanced
by ischemic preconditioning. Ann Thorac Surg 2004;78:961-969.
516. Heusch G. Postconditioning: old wine in a new bottle? J Am Coll Cardiol 2004;44:1111-1112.
517. Kin H, Wang NP, Mykytenko J, et al. Inhibition of myocardial apoptosis by postconditioning is
associated with attenuation of oxidative stress-mediated nuclear factor-kappa B translocation and TNF alpha
release. Shock 2008;29:761-768.
518. Ovize M, Baxter GF, Di Lisa F, et al. Postconditioning and protection from reperfusion injury: where do
we stand? Position paper from the Working Group of Cellular Biology of the Heart of the European Society of
Cardiology. Cardiovasc Res 2010;87:406-423.
519. Granfeldt A, Lefer DJ, Vinten-Johansen J. Protective ischaemia in patients: preconditioning and
postconditioning. Cardiovasc Res 2009;83:234-246.
520. Hansen PR, Thibault H, Abdulla J. Postconditioning during primary percutaneous coronary intervention:
a review and meta-analysis. Int J Cardiol 2010;144:22-25.
521. Hausenloy DJ, Yellon DM. The therapeutic potential of ischemic conditioning: an update. Nat Rev
Cardiol 2011; 8(11):619-629.
522. Shinohara G, Morita K, Nagahori R, et al. Ischemic postconditioning promotes left ventricular functional
recovery after cardioplegic arrest in an in vivo piglet model of global ischemia reperfusion injury on
523. Luo W, Li B, Lin G, et al. Postconditioning in cardiac surgery for tetralogy of Fallot. J Thorac Cardiovasc
Surg 2007;133:1373-1374.
524. Luo W, Li B, Lin G, Chen R, et al. Does cardioplegia leave room for postconditioning in paediatric
cardiac surgery? Cardiol Young 2008;18:282-287.
525. Durdu S, Sirlak M, Cetintas D, et al. The efficacies of modified mechanical post conditioning on
myocardial protection for patients undergoing coronary artery bypass grafting. J Cardiothorac Surg
2012;7:73.
526. Hong DM, Lee EH, Kim HJ, et al. Does remote ischaemic preconditioning with postconditioning improve
clinical outcomes of patients undergoing cardiac surgery? Remote ischaemic preconditioning with
postconditioning outcome Trial. Eur Heart J 2014;35:176-183.
527. Hausenloy DJ. Signalling pathways in ischaemic postconditioning. Thromb Haemost 2009;101:626-634.
528. Huffmyer J, Raphael J. Physiology and pharmacology of myocardial preconditioning and

postconditioning. Semin Cardiothorac Vasc Anesth 2009;13:5-18.
529. Mewton N, Ivanes F, Cour M, et al. Postconditioning: from experimental proof to clinical concept. Dis
Model Mech 2010;3:39-44.
530. Saxena P, Newman MA, Shehatha JS, et al. Remote ischemic conditioning: evolution of the concept,
mechanisms, and clinical application. J Card Surg 2010;25:127-134.
531. Cour M, Gomez L, Mewton N, et al. Postconditioning: from the bench to bedside. J Cardiovasc
532. Kin H, Zatta AJ, Lofye MT, et al. Postconditioning reduces infarct size via adenosine receptor activation
by endogenous adenosine. Cardiovasc Res 2005;67:124-133.
533. Hausenloy DJ, Lecour S, Yellon DM. RISK and SAFE pro-survival signalling pathways in ischaemic
postconditioning: two sides of the same coin. Antioxid Redox Signal 2010;14(5):893-907.
534. Hausenloy DJ, Yellon DM. Reperfusion injury salvage kinase signalling: taking a RISK for
cardioprotection. Heart Fail Rev 2007;12:217-234.
535. Obal D, Dettwiler S, Favoccia C, et al. The influence of mitochondrial KATP-channels in the
cardioprotection of preconditioning and postconditioning by sevoflurane in the rat in vivo. Anesth Analg
2005;101: 1252-1260.
536. Mykytenko J, Reeves JG, Kin H, et al. Persistent beneficial effect of postconditioning against infarct
size: role of mitochondrial K(ATP) channels during reperfusion. Basic Res Cardiol 2008;103:472-484.
537. Feng J, Lucchinetti E, Ahuja P, et al. Isoflurane postconditioning prevents opening of the mitochondrial
permeability transition pore through inhibition of glycogen synthase kinase 3β. Anesthesiology
2005;103:987-995.
538. Pagel PS. Postconditioning by volatile anesthetics: salvaging ischemic myocardium at reperfusion by
activation of prosurvival signaling. J Cardiothorac Vasc Anesth 2008;22:753-765.
539. Krolikowski JG, Weihrauch D, Bienengraeber M, et al. Role of Erk1/2, p70s6K, and eNOS in isoflurane-
induced cardioprotection during early reperfusion in vivo. Can J Anaesth 2006;53:174-182.
540. Weber NC, Schlack W. Inhalational anaesthetics and cardioprotection. Handb Exp Pharmacol
2008:187-207.
541. Belhomme D, Peynet J, Louzy M, et al. Evidence for preconditioning by isoflurane in coronary artery
bypass graft surgery. Circulation 1999;100: II340-344.
542. Symons JA, Myles PS. Myocardial protection with volatile anaesthetic agents during coronary artery
bypass surgery: a meta-analysis. Br J Anaesth 2006;97:127-136.
543. Yu CH, Beattie WS. The effects of volatile anesthetics on cardiac ischemic complications and mortality
in CABG: a meta-analysis. Can J Anaesth 2006;53:906-918.
544. Landoni G, Biondi-Zoccai GG, Zangrillo A, et al. Desflurane and sevoflurane in cardiac surgery: a meta-
analysis of randomized clinical trials. J Cardiothorac Vasc Anesth 2007;21:502-511.
545. Clarke SJ, McStay GP, Halestrap AP. Sanglifehrin A acts as a potent inhibitor of the mitochondrial
permeability transition and reperfusion injury of the heart by binding to eyelophilin-D at a different site from
cyclosporin A. J Biol Chem 2002;277 34793-34799.
546. Halestrap AP, Davidson AM. Inhibition of Ca2(+)-induced large-amplitude swelling of liver and heart
mitochondria by cyclosporin is probably caused by the inhibitor binding to mitochondrial-matrix peptidyl-prolyl
cis-trans isomerase and preventing it interacting with the adenine nucleotide translocase. Biochem J
1990;268:153-160.
547. Niemann CU, Saeed M, Akbari H, et al. Close association between the reduction in myocardial energy
metabolism and infarct size: dose-response assessment of cyclosporine. J Pharm Exp Ther 2002;302:1123-
1128.
548. Weinbrenner C, Liu GS, Downey JM, et al. Cyclosporine A limits myocardial infarct size even when
administered after onset of ischemia. Cardiovasc Res 1998;38:676-684.
549. Weinbrenner C, Downey JM, Cohen MV. Cyclosporine a preconditions rabbit heart when administered
before as well as after onset of ischemia. Circulation 1997;96:1401-1401.
550. Elrod JW, Lefer DJ. The effects of statins on endothelium, inflammation and cardioprotection. Drug
News Perspect 2005;18(4):229-236.
551. Jones SP, Gibson MF, Rimmer DM III, et al. Direct vascular and cardioprotective effects of rosuvastatin,
a new HMG-CoA reductase inhibitor. J Am Coll Cardiol 2002;40:1172-1178.
552. Ludman A, Venugopal V, Yellon DM, et al. Statins and cardioprotection—more than just lipid lowering?
P.230
553. Collard CD, Body SC, Shernan SK, et al. Preoperative statin therapy is associated with reduced cardiac
mortality after coronary artery bypass graft surgery. J Thorac Cardiovasc Surg 2006;132:392-400.
554. Liakopoulos OJ, Choi YH, Haldenwang PL, et al. Impact of preoperative statin therapy on adverse
postoperative outcomes in patients undergoing cardiac surgery: a meta-analysis of over 30,000 patients. Eur
Heart J 2008;29:1548-1559.
555. Kawai T, Wada Y, Nishiyama K, et al. Usefulness of ulinastatin as a radical scavenger for protection of
reperfusion injury after myocardial ischemia in open heart surgery [Japanese]. Nippon Kyobu Geka Gakkai
Zasshi 1991;39:2157-2162.
556. Hlatky MA, Boothroyd DB. Comparative effectiveness of multivessel coronary artery bypass graft
surgery and multivessel percutaneous coronary intervention. Ann Intern Med 2013;159:435.
557. Inoue T, Ku K, Kaneda T, et al. Cardioprotective effects of lowering oxygen tension after aortic
unclamping on cardiopulmonary bypass during coronary artery bypass grafting. Circ J 2002;66:718-722.
558. Kilgannon JH, Jones AE, Shapiro NI, et al. Association between arterial hyperoxia following
resuscitation from cardiac arrest and in-hospital mortality. JAMA 2010;303:2165-2171.
559. Schwartz Longacre L, Kloner RA, et al. New horizons in cardioprotection: recommendations from the
2010 national heart, lung, and blood institute workshop. Circulation 2011;124:1172-1179.
560. Bolli R, Becker L, Gross G, et al. Myocardial protection at a crossroads: the need for translation into
clinical therapy. Circ Res 2004;95 125-134.
561. Ludman AJ, Yellon DM, Hausenloy DJ. Cardiac preconditioning for ischaemia: lost in translation. Dis
Model Mech 2010;3:35-38.
562. Menger MD, Vollmar B. Pathomechanisms of ischemia-reperfusion injury as the basis for novel
preventive strategies: is it time for the introduction of pleiotropic compounds? Transplant Proc 2007;39:485-
488.
563. Chambers DJ, Fallouh HB. Cardioplegia and cardiac surgery: pharmacological arrest and
cardioprotection during global ischemia and reperfusion. Pharmacol Ther 2010;127:41-52.
564. Allen BS, Okamoto F, Buckberg GD, et al. Studies of controlled reperfusion after ischemia. XII. Effects of
“duration” of reperfusate administration versus reperfusate “dose” on regional functional, biochemical, and
histochemical recovery. J Thorac Cardiovasc Surg 1986;92:594-604.
565. Zhao ZQ, Nakamura M, Wang NP, et al. Reperfusion induces myocardial apoptotic cell death.
Chapter 10
Changes in the Pharmacokinetics and Pharmacodynamics of Drugs
Administered during Cardiopulmonary Bypass
Richard I. Hall
Derek J. Roberts
Cardiac surgery may be performed with or without cardiopulmonary bypass (CPB) (1). When utilized, practitioners
should be aware that CPB profoundly affects the way drugs are distributed and cleared by the body (i.e., drug
pharmacokinetics [PK]) and how they interact with the body to produce their effects (i.e., pharmacodynamics [PD]) (2).
This chapter reviews some basic pharmacokinetic and pharmacodynamic concepts and then describes the role that
CPB (and the systemic inflammatory response that it generates) may play in altering the pharmacokinetics and
pharmacodynamics of drugs administered during cardiac surgery. An understanding of the above may allow for
practitioners to explain apparent anomalies in drug action. This may include enhanced intravenous anesthetic effect in
the presence of hemodilution during CPB (3,4,5,6,7,8,9,10,11) or the potential for development of awareness during
CPB under anesthesia due to insufficient volatile anesthetic drug administration (12,13,14).
BASIC PRINCIPLES AND DEFINITION OF TERMS

To understand how CPB may alter the effect of drugs, one must first understand some basic pharmacokinetic and
pharmacodynamic principles.
Pharmacokinetics
Pharmacokinetics is defined as the mathematical description of the processes through which a drug is handled once
introduced into the body, that is, what the body does to the drug. Because the vast majority of drugs given during
cardiac surgery are administered intravenously, this discussion will be primarily limited to a description of the
pharmacokinetic principles involved in describing the fate of a drug administered during intravenous drug administration.
Following injection of a single intravenous dose of a drug (e.g., induction of anesthesia), a number of processes are
initiated that serve to reduce drug concentrations. The drug is delivered to and taken up by tissues within the body—a
process known as distribution. Distribution to highly perfused tissues such as the brain, heart, lungs, liver, and kidneys
occurs first. Tissue uptake at this stage is variable, depending on factors such as protein binding (typically decreased
uptake with increased plasma protein binding) and the lipid solubility of the drug (typically increased uptake with
increased lipid solubility). Thereafter, distribution occurs into less well perfused tissues such as muscle and fat. As the
drug is delivered to organs such as the liver, kidneys, and lungs, elimination by biotransformation and excretion occurs.
Elimination may be influenced by age (15), gender (16), disease (17), and CPB (18,19). For most drugs employed
during cardiac surgery, elimination occurs as a constant fraction of drug remaining in the body per unit time. This is
known as first-order kinetics.
Various mathematical models have been developed to quantify what happens to a drug once it is introduced into the
body. For the high-potency opioids, during cardiac surgery, a simple two- (20) or three (21)-compartmental analysis has
been shown to adequately serve for clinical purposes. Figure 10.1 depicts a two-compartment model. Following drug
injection, distribution occurs within a central compartment (blood) and to the peripheral compartments (tissues). Transfer
of the drug between the central and peripheral compartments can be described by appropriate rate constants
P.232
(Fig. 10.1). Elimination occurs from the central compartment and can be described by the elimination rate constant. By
measuring plasma concentrations over a time period from the injection of the drug, it is possible to describe the
concentration-versus-time profile for the drug (Fig. 10.2) (22). Distribution and elimination phases can be determined
and a mathematical description (model) of the change in drug concentration versus time can be developed.
FIGURE 10.1. A two-compartment pharmacokinetic model illustrating the distribution of a drug within a central
compartment (blood) and peripheral compartment (tissues), and its ultimate biotransformation and elimination from the
body. K12 and K21 are first-order rate constants for transfer of drug between the peripheral and central compartments,
whereas Ke is the elimination rate constant. (From Hall RI, Thomas BL, Hug CC Jr. Pharmacokinetics and
pharmacodynamics during cardiac surgery and cardiopulmonary bypass. In: Mora CT, ed. Cardiopulmonary bypass:
Principles and techniques of extracorporeal circulation. New York, NY: Springer-Verlag, 1995:56.)
More sophisticated compartmental models can also be developed. For example, a three-compartment model that
characterizes distribution to both highly perfused tissues and less highly perfused tissues and also describes the
elimination phase can be developed. Other models account for additional pharmacokinetic details, including the very
early distribution phase (23), tissue distribution (24), gender, weight, hemodilution (25), and institution of CPB (26).
Strategies exist to determine which mathematical model best describes the observed concentration-versus-time profile
for any drug administered (27). Derivation of the rate constants then allows for the development of computer programs
designed to produce continuous infusions of drugs (e.g., computer-assisted continuous infusion [CACI]) at rates that
maintain a stable targeted plasma concentration (21,25,28,29,30,31,32,33). Such information can be used to investigate
concentration-versus-effect relations (10,34,35,36,37,38) and the influence of drug interactions (32,39,40,41,42).
Characterization of concentration-versus-time profiles for intravenously administered drugs also allows derivation of
other pharmacokinetic parameters such as the volume of distribution ( Vd), clearance (Cl), and elimination half-time (
t1/2β).
FIGURE 10.2. Plasma [log] concentration-versus-time curve for a hypothetical drug after a single intravenous dose. The
curve (A + B) is the sum of the contributions from the rapid distribution (A) phase and the slow elimination (B) phase to
the logarithmic decline in concentration after a bolus dose. The concentration at any time is given by the equation Cp(t)
= Ae-at + Be-βt, where Cp(t) is the drug concentration in plasma at time t; A, constant determined from the Y-axis
intercept (time = 0) of the distribution portion of the log concentration-versus-time curve, derived by subtracting the
contribution of the (constant, first order) elimination phase of the curve; α, slope of the log concentration-versus-time
curve of the distribution phase, derived by subtracting the contribution due to elimination; B, constant determined from
the Y-axis intercept (time = 0) of the elimination phase of the log concentration-versus-time curve; β, slope of the log
concentration-versus-time curve of the elimination phase. (From Hall RI, Thomas BL, Hug CC Jr. Pharmacokinetics and
pharmacodynamics during cardiac surgery and cardiopulmonary bypass. In: Mora CT, ed. Cardiopulmonary bypass.
Principles and techniques of extracorporeal circulation. New York: Springer-Verlag, 1995:56.)
Table 10.1 provides a list of terms commonly employed in the description of a drug’s pharmacokinetic properties (43).
Volume of distribution (Vd) is defined as that volume of fluid into which a drug would be administered in order to
produce the observed concentration of drug in plasma. It does not correspond directly to any particular tissue
compartment but is rather useful in predicting drug concentrations based on pharmacokinetic parameters. Vd is used to
characterize the total volume of distribution, whereas Vdc describes the volume of the central compartment, or the initial
volume of distribution (also termed Vi). Vdss describes the volume of distribution when steady-state plasma
concentrations of a drug are achieved. Clearance (Cl ) refers to the removal of a drug from the body, usually by way of
the central compartment, and is expressed as the volume of blood completely cleared of the drug per unit of time.
Elimination half-time (t1/2β) is the time required for the concentration of a drug in plasma to decrease by half. It can be
determined by examining the elimination portion of the concentration-versus-time curve, or by substituting the relevant
parameters in the following equation:
Similarly, distribution half-times (t1/2ρ, t1/2α) can be determined by examining the distribution phase(s) of the
concentration-versus-time curve. Drugs with short elimination half-times are characterized by small volumes of
distribution and/or rapid clearance. Drugs that have a long elimination half-time tend to be highly lipid soluble (most
anesthetic agents) with a large volume of distribution and/or slow rate of elimination.
The degree to which drug effect terminates depends on the rapidity of drug redistribution to the central compartment
once the injection stops, and the capacity of the elimination processes to clear the drug. Although this concept is
important following the injection of a single dose, it is also important when drugs are given by continuous infusion or in
repeated doses. If drug administration exceeds the body’s ability to clear it, drug accumulation will occur, leading to
prolonged drug effect. At times, drug administration may completely saturate clearance mechanisms (e.g., excess
alcohol ingestion), leading to a situation where clearance is no longer a function of drug level in the plasma and instead
occurs at a relatively constant rate (so-called zero-order kinetics). More commonly,
P.233
as drug administration continues, there is accumulation of drug in tissues over time, which increases with the duration of
drug infusion. On termination of the infusion, offset of drug effect then depends on redistribution of the drug out of
tissues (greater with longer infusions) back into the central compartment as well as the rate of elimination. Thus, when a
drug has accumulated in peripheral tissues, reliance on the elimination half-time will not adequately predict termination
of drug effect because it does not take into account the role of redistribution. This has led to the introduction of the term
context-sensitive half-time as a better description of the phenomenon of increased duration of drug effect with
increased drug infusion time (Fig. 10.3) (44).
TABLE 10.1. Definition of basic pharmacokinetic parameters
Parameter Abbreviation Definition
Area under AUC Area under the concentration vs. time curve, which is commonly bounded
the curve by a time period, e.g., 0-4 h.
Bioavailability F The fraction of an administered dose which reaches the systemic

circulation unchanged. Typically applied in reference to oral drug
administration as the F of an intravenous drug is, by definition, equal to 1.
Clearance Cl The volume of blood cleared completely of drug per unit of time.
Elimination Ke The rate at which a drug is eliminated from the body per unit of time. Ke is
rate constant inversely proportional to the elimination half-life of the drug.
Extraction ER The percentage of medication removed from the blood as it passes through
ratio the eliminating organ. The extraction ratio depends not only on the blood
flow rate but also on the free fraction of drug and the intrinsic ability of the
organ to eliminate the drug. Typically used to describe how the liver
handles a given drug.
Half-life t1/2 The amount of time required for the drug concentration to decrease by
50%. The half-life may be determined for both the distribution (e.g., t1/2α)
and elimination (e.g., t1/2β) phases of drug handling.
Plasma Fu The process by which a drug binds to proteins in the plasma until an
protein equilibrium is established between the fraction bound (Fb) and the fraction
binding unbound (Fu). Only the Fu is available to distribute, exert its pharmacologic
effect, and be metabolized and eliminated.
Steady state A condition where the rate of drug administration is equal to the rate of
elimination. Steady state is generally reached after four or five half-lives of
drug administration. Once achieved, drug elimination is generally
considered to be complete after four or five half-lives once drug
administration has been terminated.
Time to TMAX The time required to reach maximal blood concentration after drug
maximum administration.
concentration
Volume of Vd The apparent or theoretical volume into which the drug distributes that
distribution relates the plasma concentration to the administered dose.
Equilibration Ke0 Rate constant for equilibration at the site of drug effect.
rate constant
Modified from Smith BS, Yogaratnam D, Levasseur-Franklin KE, et al. Introduction to pharmacokinetics in the
critically ill. Chest 2012;141(5):1327-1336.
Computer-driven infusions of drugs use the pharmacokinetic parameters previously derived from concentration-versus-
time profiles to set their infusion rates. The accuracy of these infusions in achieving the desired plasma concentrations
therefore depends on the accuracy of the initial parameter estimates. Errors in these parameters can occur due to a
variety of reasons, including number of drug measurement points (too few), duration of drug measurements (too short),
sensitivity of the drug assay employed (too low), and nature
P.234
of the population studied (e.g., young, healthy men versus elderly women with congestive heart failure [CHF]). Drug in
the blood exists in several forms, including that which is free (active), bound to plasma proteins (e.g., albumin, and
therefore subject to changes in plasma protein concentrations), or sequestered in red blood cells. CPB has the potential
to alter all of these factors, which makes the description of pharmacokinetic parameters during CPB problematic.
FIGURE 10.3. A: Context-sensitive half-times as a function of infusion duration for each pharmacokinetic model
simulated. Solid and dashed lines are used to permit overlapping lines to be distinguished. B: Context-sensitive half-
times (bars) redrawn from (A) for each pharmacokinetic model after terminating a 1-minute, 1-hour, 3-hour, 8-hour, or
infinitely long (i.e., to steady state) computer-designed infusion designed to instantaneously achieve and maintain a
target concentration shown relative to the elimination half-life (dots) computed for each model. (From Hughes MA, Glass
PSA, Jacobs Jr. Context-sensitive half-time in multicompartment pharmacokinetic models for intravenous anesthetic
drugs. Anesthesiology 1992;76:336.)
Where infusions are administered at constant rates (so-called zero-order infusions), drug accumulation over time is
likely. To prevent drug accumulation, adjustment of infusion rates according to patient response is therefore strongly
suggested (20). This should maintain plasma drug concentration in the lower therapeutic range and permit optimal
reduction in concentration (and termination of drug effect) once the infusion is terminated.
Termination of drug effect depends highly on clearance mechanisms. For most drugs, this involves some degree of liver
metabolism and/or renal excretion. Lipophilic drugs are metabolized in the liver in either one or two phases, which need
not occur sequentially. Phase I reactions convert lipophilic drugs to more water-soluble compounds through oxidation,
reduction, or hydrolytic reactions. Oxidation-reduction reactions occur in the endoplasmic reticulum and are frequently
mediated by the cytochrome P-450 superfamily of mixed-function oxidases. These enzymes exist in a number of
isoforms, each of which has a separate, but somewhat overlapping, list of particular drug and xenobiotic substrates (45).
The cytochrome P-450 enzymes are regulated by gene transcription, and their activities can be modified by drugs and
disease processes (46,47,48) as a result of enzyme induction (e.g., rifampin) (48) or inhibition (e.g., erythromycin (49),
propofol (47), and fluconazole (50)). Their activities are also affected by genetic predisposition (e.g., heterogeneity in
the ability to metabolize certain drugs (51)). Phase II differs from phase I reactions as they couple the drug (or its
metabolites) to an endogenous substrate such as sulfate, acetate, or glucuronide to form a highly polar, water-soluble
compound that is more easily excreted (52).
The ability of the liver to metabolize a drug in the absence of limitations imposed by hepatic blood flow or drug-protein
binding is termed intrinsic hepatic clearance (53). The hepatic extraction ratio is the fraction of a drug contained in
hepatic arterial blood that is removed as it passes through the liver. These two concepts are related by the following
equation:
where Clhepatic = hepatic clearance rate of a drug, Q = liver blood flow, Cli = intrinsic hepatic clearance, Ca = arterial
drug concentration, Cv = venous drug concentration, and E = hepatic extraction ratio.
Drugs with a low extraction ratio (e.g., diazepam (54)) depend on hepatic metabolism for their elimination and are much
more affected by changes in protein binding and the liver’s ability to metabolize drugs (e.g., through induction or
inhibition of cytochrome P-450 enzymes) than by changes in liver blood flow. In contrast, the metabolism of drugs with a
moderate (e.g., alfentanil (55)) or a high extraction ratio (e.g., sufentanil (56) and propofol (8)) may be critically affected
by changes in blood flow in the liver.
For drugs cleared by the kidneys, excretion depends on renal blood flow, glomerular filtration rate, tubular secretion,
and reabsorption (57). When excreted by filtration (e.g., mannitol (58)), the rate will depend on the plasma concentration
and renal blood flow. Drugs excreted by tubular processes (tubular secretion and reabsorption, e.g., cefazolin (59)) may
be subject to saturation of active transport processes.
P.235
Pharmacodynamics
Pharmacodynamics describes how a drug interacts with the body to produce changes in patient physiology. Most drugs
produce these effects by interaction with a specific receptor, that is, the macromolecular component of the organism
with which the drug interacts through a lock-and-key or other type of mechanism (Fig. 10.4) (60). Activation of the
receptor leads to changes intracellularly, often through secondary messengers, which in turn leads to changes in cell
function (e.g., muscle contraction). Although other types exist (e.g., nucleic acids), receptors are most often proteins.
Proteins that serve as receptors for endogenous ligands are particularly important because drugs that interact with
these receptors produce physiologic effects mimicking those in nature (61,62,63,64). Drugs with this mechanism of
action are referred to as agonists. In contrast, drugs that possess no intrinsic pharmacologic activity, but bind to
receptors and interfere with binding of endogenous ligands, are termed antagonists.
Whether a drug acts as an agonist or antagonist depends on its structure, and this aspect is exploited in drug design.
The degree to which a compound can mimic the effect of the endogenous ligand is also a function of receptor number,
receptor affinity for the drug, and the drug concentration to which the receptor is exposed.
FIGURE 10.4. Structural motifs of physiologic receptors and their relation to signaling pathways. Schematic diagram of
the diversity of mechanisms for control of cell function by receptors for endogenous agents acting through the cell
surface or in the nucleus. (From Ross EM. Pharmacodynamics. Mechanisms of drug action and the relationship
between drug concentration and effect. In: Hardman JG, Limbird LE, eds. Goodman and Gilman's the pharmacological
basis of therapeutics. 9th ed. Montreal, QC: McGraw-Hill, 1996:32.)
Receptor Types and Functions
Receptors serve two functions: to bind the appropriate ligand and, following that, to propagate the regulatory signal into
the target cell. This has led to the functional localization of two regions within the receptor—a ligand-binding domain and
an effector domain. Receptor effects may be produced by action directly on its cellular target(s), effector proteins, or
may be conveyed to other cellular targets by intermediary cellular molecules termed transducers (Fig. 10.4) (60). The
combination of the receptor, its target proteins, and transducers constitutes the signal transduction pathway. In some
cases, the effector protein may cause activation of another signaling pathway through secondary messengers (Fig.
10.5) (60).
P.236
FIGURE 10.5. Interactions between the second messengers cyclic adenosine monophosphate (cAMP) and Ca2+.
Generation of second messengers cAMP and Ca2+ permits distribution of cell-surface regulatory input into the cell
interior, amplification of the initial signal, and opportunities for synergistic or antagonistic regulation of other signaling
pathways. PIP2, phosphatidylinositol 4,5-biophosphate; DAG, diacylglycerol; IP3, 1,4,5-inositol triphosphate; CaM,
calmodulin; R2, regulatory subunits of cyclic AMP-dependent protein kinase, which bind cyclic AMP; cAPK2, catalytic
subunits of cyclic AMP-dependent protein kinase; PKC, protein kinase C, activated by DAG and Ca2+. (From Ross EM.
Pharmacodynamics. Mechanisms of drug action and the relation between drug concentration and effect. In: Hardman
JG, Limbird LE, eds. Goodman and Gilman's the pharmacological basis of therapeutics. 9th ed. Montreal, QC:
McGraw-Hill, 1996:34.)
Families of receptors mediating a variety of functions have been characterized. Receptors for neurotransmitters (and
exogenously administered drugs) are frequently in the form of an agonist-regulated, ion-selective channel in the plasma
membrane, termed a ligand-gated ion channel (Fig. 10.6) (65). Stimulation of the receptor leads to changes in ion flux
across the cell membrane, with subsequent alteration in the cell membrane potential or the cell’s ionic composition.
Receptors in this group include nicotinic cholinergic receptors (site of skeletal muscle relaxant activity) (66) and the γ-
aminobutyric acid type A (GABAA) receptor (which also serves as the receptor for benzodiazepines, propofol, and
barbiturates) (67).
Many receptors (including opioid receptors (68)) are G-protein-coupled receptors (69). Occupation of the receptor by its
ligand initiates binding of guanosine triphosphate (GTP) to specific G-proteins on the inner membrane surface, causing
changes in the conformation of the G-protein complex and consequent signal transduction to specific effectors often
mediated by second messenger enzymes such as adenyl cyclase and phospholipases A2, C1, and D. Effectors include
channels specific for Na+, K+, and Ca2+ conductance and certain transport and regulatory proteins. The G-protein
receptor has been well characterized and consists of seven α-helical segments spanning the cell plasma membrane
(70). Ligand binding changes the conformation of α , β, and γ heterotrimetic G-protein-coupled receptor polypeptides on
the inner surface of the plasma membrane (71). When receptor activation occurs, GTP binds to these subunits,
resulting in disassociation of the a subunit from the βγ subunit such that interaction with the effector occurs (Fig. 10.7)
(72). The βγ subunit may also interact with and influence effector activity. Termination of signal transmission occurs
when G-protein-coupled receptor kinases (GRKs) phosphorylate the activated receptor, which leads to recruitment of β-
arrestins and subsequent receptor desensitization. β-Arrestins may also serve as signal transducers (Fig. 10.8) (73).
After CPB, GRK activity is reduced (74). Examples of G-protein-coupled receptors and their second messenger systems
are given in Table 10.2 (69).
G-protein receptors are subject to regulatory and homeostatic controls. As an example, continuous stimulation of a
receptor by an agonist (ligand) may result in a reduced effect as a result of processes known as desensitization,
endocytosis, or downregulation. Desensitization is defined as any process that alters the functional coupling of a
receptor to its G-protein/second messenger signaling pathway. Endocytosis is defined as the translocation of receptors
from the cell surface to an intracellular compartment. Lastly, downregulation is defined as any process that decreases
the number of ligand-binding sites (64,70).
P.237
FIGURE 10.6. Synthesis and release of γ-hydroxybutyric acid (GHB) and γ-aminobutyric acid (GABA) at synapses—an
example of a ligand-gated ion channel . The diagram shows the presynaptic and postsynaptic effects of endogenously
released GHB (as indicated by dashed arrows) and (GABA) (as indicated by solid arrows) and the effects of
exogenously administered GHB, as in abuse and addiction. GABA is synthesized from glutamate in inhibitory neurons
and in turn gives rise to GHB. Both GHB and GABA are released upon depolarization of the GABA-releasing
(GABAergic) presynaptic neuron. GABA, in forms that are either endogenous or derived from exogenously administered
GHB, acts on GABAA and GABAB receptors (GABAAR and GABABR, respectively). GABAA receptors are ionotropic and,
when activated by GABA, cause fast postsynaptic inhibition by the efflux of chloride ions (Cl-). GABAB receptors are
metabotropic and, when activated by either GABA or high concentrations of GHB, induce slow postsynaptic inhibition by
activating outward potassium (K+) currents. Presynaptic GABAB autoreceptors—when activated by GHB, GABA, or both
—reduce the release of GABA by suppressing the influx of calcium (Ca2+). Both endogenous and exogenous forms of
GHB have a dual action on the GHB receptor (GHBR) and the GABAB receptor. GHB that binds with high affinity to the
presynaptic GHB receptor decreases the release of GABA; GHB that binds to a low-affinity site on the GABAB receptor
increases activation of cell-surface receptors by inhibiting constitutive and agonist-induced endocytosis. The result is
enhancement of GHB function mediated by GABAB receptors, with a greater effect on presynaptic inhibition than on
postsynaptic inhibition. (From Snead OC III, Gibson KM. γ-Hydroxybutyric acid. N Engl J Med 2005;352:26;2724.)
P.238
FIGURE 10.7. G-protein-coupled receptors. Schematic of signal transduction cascade for receptors coupling to G-
protein [α]s subunit. ATP, adenosine triphosphate; cAMP, cyclic adenosine monophosphate; PDE, phospho-diesterase;
PKA, protein kinase A; GRK, G-protein receptor kinase; GDP, guanosine diphosphate; GTP, guanosine triphosphate.
(From Johnson JA, Lima JJ. Drug receptor polymorphisms and pharmacogenetics: current status and challenges.
Pharmacogenetics 2003;13(9):531.)
FIGURE 10.8. Signal transduction by seven transmembrane receptors. A: Classical paradigm. The active form of the
receptor (R*) stimulates heterotrimeric G-proteins and is rapidly phosphorylated by GRKs, which leads to β-arrestin
recruitment. The receptor is thereby desensitized, and the signaling is stalled. B: New paradigm. β-Arrestins not only
mediate desensitization of G-protein-signaling but also act as signal transducers themselves. TMR, transmembrane
receptor; cAMP, cyclic adenosine monophosphate; DAG, diacylglycerol; IP3, 1,4,5-inositol triphosphate; Gα,γ,β, trimeric
G-protein subunits; GRK, G-protein-coupled receptor kinases; MAPKs, mitogen-activated protein kinases; AKT, protein
kinase B pathway; PI3, phosphatidylinositol-3-kinase pathway. (From Lefkowitz RJ, Shenoy SK. Transduction of
receptor signals by β-arrestins. Science 2005;308:513.)
P.239
TABLE 10.2. Examples of G-protein-coupled receptors and the intracellular second messengers
they generate
Receptor Second messenger
Adrenoceptors
α1A/1B/1C IP3+
α2A/2B/2C cAMP-
β1/2/3 cAMP+
Bradykinin (B1-3) IP3+
Calcitonin gene-related peptide cAMP+
Dopamine (D1-5) IP3+/cAMP-
Glutamate (metabotropic) IP3+
Histamine cAMP+/IP3+
5-HT (1A-1D/2/3/4) cAMP-/cAMP+/IP3+
Muscarinic (M1-5) IP3+/cAMP-
Opioid (μ/δ/κ) cAMP-
Vasopressin (V1A,1B/2) IP3+/cAMP+
cAMP+, receptor stimulates generation of cAMP; cAMP-, receptor inhibits generation of cAMP; IP3+, receptor
stimulates generation of IP3; cAMP, cyclic adenosine monophosphate; IP3, inositol(1,4,5) triphosphate; HT,
hydroxytryptamine. Reprinted from Lambert DG. Signal transduction: G proteins and second messengers. Br J
Anaesth 1993:71;86-95.
Tolerance is a phenomenon whereby an increased amount of drug is required to produce the same level of
pharmacologic effect after repeated use of the drug. The mechanism by which tolerance occurs is gradually being
elucidated but is thought to represent a complex multifaceted process involving multiple regulatory processes at the
cellular and neural circuit levels (75). High-potency opioids (e.g., fentanyl, sufentanil) with substantial intrinsic receptor
affinity appear to produce tolerance faster than lower-potency opioids such as buprenorphine.
While the term tolerance is usually used to describe a loss of drug efficacy over hours to days, desensitization involves
a more rapid loss of receptor activity. Desensitization can occur within a short time frame and lasts a short period of time
(˜1 hour) in the absence of continued receptor stimulation. The mechanism appears to be multifactorial and includes
phosphorylation of activated receptors, which results in their binding with a group of intracytoplasmic proteins termed
arrestins (75,76). This binding causes an uncoupling of receptors from G-proteins and receptor desensitization. Once
bound, the receptors may be dephosphorylated and returned to the cell surface, or be degraded by lysosomes (77). In
the presence of an antagonist, the number of cell-surface receptors may also increase (78).
Traditionally, receptors have been classified by their physiologic effects and relative potencies. Examples include
muscarinic versus nicotinic cholinergic receptors (79), α - and β -adrenergic receptors (80), and μ (mu), κ (kappa), and δ
(delta) opioid receptors (81). Subtypes of receptors exist, for example, β1 and β2, and are targets for drug-selective
effects (Fig. 10.9) (80). Molecular cloning techniques have allowed tissue-specific receptor subtypes to be identified and
localized (61,64).
Soluble DNA-binding proteins that regulate transcription of specific genes serve as the receptor for steroid hormones,
thyroid hormone, vitamin D, and the retinoids. They are part of a larger family of transcription factors that are regulated
by phosphorylation, association with other protein factors, and/or by binding to metabolites or cellular regulatory ligands
(82). Glucocorticoid receptors bind circulating adrenal steroids and are translocated into the cell nucleus, where they
bind to glucose response elements to activate genes that encode anti-inflammatory proteins (83). The receptor is
composed of three domains: a hormone binding region near the carboxyl terminus; a central region that interacts with
nuclear DNA to activate or inhibit gene transcription (which, for glucocorticoids, is termed the “glucocorticoid-responsive
element”); and an amino-terminal region whose function is not well defined (84).
Second Messenger Systems

Transduction of the signal from the receptor to the intracellular effector is often mediated by second messenger
systems. These systems are relatively few in number. However, they affect the activity of many pathways, and receptor
binding of a ligand may influence second messenger systems by altering the messenger’s function through activation
(Gs) or inhibition (Gi) of G-proteins (Fig. 10.10) (85).
Cyclic adenosine monophosphate (cAMP) exemplifies the second messenger function. cAMP is synthesized by adenyl
cyclase in response to receptor activation. Stimulation of adenyl cyclase activity is mediated by Gs and inhibited by Gi
proteins (Fig. 10.11) (86). Its activation results in phosphorylation of phosphorylase kinase and downstream cellular
responses, which may include glycogenolysis (87) or muscle contraction (86,88). Termination of cAMP activity is by
targeted hydrolysis—a process catalyzed by several phosphodiesterases.
Intracellular Ca2+ serves as another second messenger (89). Intracellular calcium concentrations are controlled by
P.240
regulation of several different Ca2+-specific channels in the plasma membrane and by its release from intracellular
storage sites (Fig. 10.12) (69,86,89). Ca2+-dependent ion channels are opened by electrical depolarization,
phosphorylation by a cAMP-dependent protein kinase, and by Gs, K+, and Ca2+ itself (89). Opening of the channel may
be inhibited by other proteins (e.g., Gi).
FIGURE 10.9. Features of the cardiac sympathetic nervous system. (—)-Noradrenaline released from sympathetic
nerve terminals is complemented by circulating (—)-adrenaline. The release of (—)-noradrenaline is modulated by
facilitatory, prejunctional β2-adrenoceptors and autoinhibitory, prejunctional α2-adrenoceptors. A deletion polymorphism
of the autoinhibitory α2c-adrenoceptor reduces its function and leads to heightened noradrenaline release from
prejunctional nerve terminals. In heart failure, the activity of the sympathetic nervous system increases, with a
consequent increase in the plasma concentration of (—)-noradrenaline. (—)-Noradrenaline activates postjunctional β1-
adrenoceptors that couple to the Gsα-cAMP pathway. Gsα activates adenyl cyclase (AC), which catalyzes the formation
of cAMP. cAMP, in turn, activates cAMP-dependent protein kinase (PKA). PKA phosphorylates several proteins that
contribute to increased force of contraction and hastening of relaxation. There are two forms of β1-adrenoceptors, β1H
and β1L. In the human heart, β2-adrenoceptors also couple to the Gsα-cAMP pathway. Recently, it has been
demonstrated that β1- and β2-adrenoceptors couple to additional signaling pathways that are of interest in heart
disease. These include β2-adrenoceptor stimulation of Giα signaling pathways. Agonist-activated β2-adrenoceptor-Giα
signaling has putative antiapoptotic effects through phosphatidylinositol 3-kinase (PI3K)-protein kinase B (PKB)
signaling. The β2-adrenoceptor antagonist ICI118551 reduces human ventricular myocyte maximal shortening and
contraction duration. β1-Adrenoceptor-mediated increase in Ca2+ stimulates Ca2+/calmodulin-dependent protein kinase
II (CaMKII) proapoptotic signaling in animals. Antagonists given in parentheses are not used in the management of heart
failure. RY2 channels, ryanodine RY2 receptor channels. (From Molenaar P, Parsonage WA. Fundamental
considerations of β-adrenoceptor subtypes in human heart failure. Trends in Pharmacol Sci 2005;26:369.)
Release of Ca2+ from intracellular stores may also be mediated by the second messenger inositol 1,4,5-triphosphate
(IP3). IP3 is formed by hydrolysis of the membrane lipid phosphatidylinositol 4,5-bisphosphate (PIP2), a reaction which is
catalyzed by phospholipase C (PLC) (69). Ca2+ regulates intracellular activity through its interactions with protein kinase
C (PKC), calmodulin, and other proteins. Activation of PKC by Ca2+ is potentiated by diacylglycerol (DAG)—another
second messenger released by the phospholipase C-catalyzed reaction that liberates IP3 (69).
The complexity of the second messenger system is obvious, and therefore the interactions among its members continue
to be unraveled. The internal milieu is tightly controlled by these interactions and subject to perturbation by drugs at any
of the steps that were outlined earlier.
P.241
FIGURE 10.10. Receptor systems and their signal transduction mechanisms in the aging (left) and failing (right) human
heart. β1, β2, α1 Stands for β1-, β2-, and α1-adrenoceptors, respectively; H2, histamine H2-receptors; 5-HT4, serotonin 5-
HT4-receptors; M2, muscarinic M2-receptors; A1, adenosine A1-receptors; ETA, endothelin ETA-receptors; AT1,
angiotensin II AT1-receptors; Gs, stimulatory G-protein; Gi, inhibitory G-protein; Gq/11, the G-protein that couples ET-,
AT-receptors and α1-adrenoceptors to phospholipase C (PLC); AC, adenyl cyclase; PIP2, phosphatidylinositol 4,5-
bisphosphate; DAG, diacylglycerol; IP3, inositol trisphosphate; GRK, G-protein-coupled receptor kinase; uptake1,
noradrenaline reuptake transporter (+, activation; -, inhibition). (From Brodde OE, Leineweber K. Autonomic receptor
systems in the failing and aging human heart: similarities and differences. Eur J Pharmacol 2004;500:168.)
CHANGES IN DRUG PHARMACOKINETICS DUE TO CARDIOPULMONARY BYPASS

CPB may affect the pharmacokinetics of drugs in a variety of ways, including changes resulting from hemodilution,
hypothermia, altered organ perfusion, acid-base status, drug sequestration into the lungs and CPB circuit, and altered
metabolism and clearance due to development of a systemic inflammatory response syndrome (SIRS) (Fig. 10.13)
(90,91,92,93,94).
Hemodilution
The CPB apparatus is primed with fluid—usually some combination of crystalloid and colloid. At the time of initiation of
CPB, the addition of this fluid to the circulation has several effects:
An immediate reduction in concentrations of circulating proteins such as albumin and a1-acid glycoprotein (α1AGP).
This has implications for protein binding of drugs resulting from alteration in the ratio of bound drug to free drug in the
circulation (5,6,7,8,9,10,95,96,97,98,99,100,101,102,103).
An immediate reduction in red blood cell concentration, which has implications for compounds that are sequestered to
a significant degree in red blood cells (3,8,104,105).
An immediate reduction in the amount of free drug in the circulation at the initiation of CPB. This will reduce the
amount of drug available for interaction with the receptor, with the potential for adverse events, for example,
lightening of the level of anesthesia (5,6,7,36,106).
Alteration in organ blood flow, which may affect drug distribution and clearance (107).
A number of studies have examined these issues and determined their relative importance to clinical practice
(5,6,7,8,9,95,97,98,99,101,108). Typical findings include a reduction in total drug concentration in plasma, with
increased free drug concentration, while on CPB (Fig. 10.14) (8,101). Although the clinical significance of this finding is
unclear, others have described a transient (usually <5 minutes) reduction in both free and total drug concentration at the
initiation of CPB as a result of hemodilution (Fig. 10.15) (3,36).
The explanation for free drug concentrations being sustained during CPB is a pharmacokinetic one. The large volume of
distribution for most anesthetic agents is largely due to their high
P.242
lipid solubility relative to the volume of the CPB prime. Thus, following intravenous administration, the tissues serve as a
reservoir that sequesters the drug. At the onset of CPB, when plasma concentrations fall due to hemodilution, the drug
moves down its concentration gradient from the tissue stores to plasma. As protein concentrations fall, the free drug
concentration increases to reestablish an equilibrium based on its solubility in plasma (8,11,101). Because free drug
concentration is responsible for drug effect (109,110), the increase in free drug concentration from altered protein
binding may explain the increased pharmacodynamic effect observed during and after CPB (9,10,111).
FIGURE 10.11. Agonist activation and coupling/signaling properties of β-adrenergic receptor subtypes. GRK, G-protein-
coupled receptor kinase; βArr, β-arrestin; PDE, phosphodiesterase; PI3K, phosphatidylinositol 3-kinase; AC, adenyl
cyclase; Gs, stimulatory G-protein; Gi, inhibitory G-protein; cAMP, cyclic adenosine monophosphate; PKA, protein
kinase A; NOS, nitric oxide synthase; ERK, extracellular signal-regulated kinases. (From Lohse MJ, Engelhardt S,
Eschenhagen T. What is the role of β-adrenergic signaling in heart failure. Circ Res 2003;93:897.)
Hypothermia
CPB is frequently conducted under varying degrees of hypothermia. The independent effect of hypothermic CPB on
physiologic function has been extensively examined, and the findings of these studies have frequently been generalized
to other patient populations (112). Although the mechanism is debated, hypothermia has anesthetic properties
(113,114,115). Decreased body temperature appears to shift fluid from the intravascular to the interstitial space (116).
This may alter the volume of distribution by shifting protein-poor fluid from the intravascular to the interstitial fluid
compartment. Moreover, hypothermia activates autonomic and endocrine reflexes (117), which may produce peripheral
vasoconstriction and alter the distribution of blood flow (118). Finally, hypothermia depresses metabolism by inhibiting
enzyme function. As a consequence of these changes, pharmacokinetics may be altered through the following
mechanisms:
Peripheral vasoconstriction may decrease absorption of drugs administered other than by the intravenous route
(119).
Fluid extravasation may alter drug distribution from central to peripheral compartments (i.e., changes in the volume of
distribution, Vd) (94,120).
P.243
P.244
Vasoconstriction may reduce the rate of reuptake of drug from peripheral tissues to the central compartment
(120,121).
Temperature-induced reductions in enzyme-mediated biotransformation may decrease clearance of drugs and
increase their elimination half-time (Fig. 10.16) (120,121,122,123,124,125,126,127,128,129,130,131).
Changes in organ perfusion may produce altered renal drug excretion as a result of decreased renal perfusion,
glomerular filtration rate, and tubular secretion (132). However, studies comparing renal function during normothermic
versus hypothermic bypass have not demonstrated any clinically important differences (117,130,133,134).
Hypothermia-induced increases in drug solubility in blood of volatile anesthetics (135).
FIGURE 10.12. Calcium cycling in cardiac myocytes and regulation by protein kinase A (PKA). AC, adenyl cyclase;
RyR, ryanodine receptor; PLB, phospholamban; SERCA, sarcoplasmic reticulum calcium ATPase; CaM, calmodulin;
CaMK, calmodulin-dependent kinase; CaN, calcineurin; GRK, G-protein-coupled receptor kinase; NCX, sodium-calcium
exchanger; NHE, sodium-proton exchanger; PP, protein phosphatase; Gs, stimulatory G-protein; BAR, β-adrenergic
receptor; PPI-1, protein phosphatase inhibitor-1; MyBPC-C, myosin binding protein C, slow type; P, phosphorylation.
(From Lohse MJ, Engelhardt S, Eschenhagen T. What is the role of β-adrenergic signaling in heart failure. Circ Res
2003;93:897.)
FIGURE 10.13. Plasma drug levels and factors affecting their concentration during cardiopulmonary bypass. All drug
names indicate the level of plasma concentration unless the column denotes plasma free fraction change (italics and
underlines). AAG increases after surgery. AAG, α1-acid glycoprotein. (From Mets B. The pharmacokinetics of anesthetic
drugs and adjuvants during cardiopulmonary bypass. Acta Anaesthesiol Scand 2000;44:264.)
FIGURE 10.14. A: Total plasma concentration, unbound fraction, and unbound plasma concentration for propofol as a
function of time for prebypass, bypass, and post-bypass periods. Each data point represents n = 12 (mean ± SEM).
Numbers adjacent to the data points indicate n, where n is less than 12. The square data point to the left of t = 0 of the
bypass period in each graph represents the mean of the final prebypass samples (mean ± SEM) plotted at the time
(mean ± SEM) they occurred. The square data point to the left of the t = 0 of the post-bypass period in each graph
represents the mean of the final bypass samples (mean ± SEM) plotted at the time (mean ± SEM) they occurred. Total
plasma concentrations fall at the initiation of CPB, with little change in free drug concentrations, leading to an increase
in the free fraction. B: Total plasma concentration, unbound fraction, and unbound plasma concentration for midazolam
as a function of time for prebypass, bypass, and post-bypass periods. Each data point represents n = 12 (mean ± SEM).
Numbers adjacent to the data points indicate n, where n is less than 12. The square data point to the left of the E = 0 of
the bypass period in each graph represents the mean of the final prebypass samples (mean ± SEM) plotted at the time
(mean ± SEM) they occurred. The square data point to the left of t = 0 of the post-bypass time period in each graph
represents the mean of the final bypass samples (mean ± SEM) plotted at the time (mean ± SEM) they occurred. Total
plasma concentrations fall at initiation of CPB, with little change in free drug concentrations, leading to an increase in
free fraction. (From Dawson PJ, Bjorksten AR, Blake DW, et al. The effects of cardiopulmonary bypass on total and
unbound plasma concentrations of propofol and midazolam. J Cardiothorac Vasc Anesth 1997;11:559.)
Hypothermia during CPB alters the clearance of drugs that require enzymatic degradation to terminate their effect (e.g.,
P.245
esmolol, remifentanil, clevidipine, atracurium, and cis-atracurium) (123,124,125,127). The net result is a prolonged drug
effect that requires dosage reductions.
FIGURE 10.15. Plasma fentanyl concentrations (mean ± SD) in patients connected to cardiopulmonary bypass (CPB)
circuits with primes containing no fentanyl (•—•) or containing a calculated fentanyl concentration of 140 (°—°) or 280 (°
——°) ng/mL. X, lowest drug concentration measured at each stage during the first 1.5 minutes of CPB in patients not
receiving fentanyl in their prime. NB: Regardless of whether the prime is supplemented or not, no difference exists in
fentanyl concentrations within 2.5 minutes. (From Hynynen M. Binding of fentanyl and alfentanil to the extracorporeal
circuit. Acta Anaesthesiol Scand 1987;31:708.)
FIGURE 10.16. Fentanyl plasma concentrations in 18 children during profound hypothermia (18°C-25°C). Time zero is
the initiation of cardiopulmonary bypass. Total plasma fentanyl levels remain essentially unchanged. (From Koren G,
Barker C, Goresky G, et al. The influence of hypothermia on the disposition of fentanyl—human and animal studies. Eur
J Clin Pharmacol 1987;32:374.)
For drugs with a low Vd, the vasoconstriction produced by hypothermia may even further decrease their Vd. This may
explain the increase in plasma concentrations of neuromuscular relaxants observed during hypothermic CPB
(94,136,137). When normothermia is being reestablished, reperfusion of tissues leads to washout of drug sequestered
in underperfused tissues during the hypothermic CPB period. This may explain increases in plasma opioid
concentrations observed during the rewarming phase (138) and postoperatively (139).
FIGURE 10.17. Mean fentanyl levels in seven cardiac surgery patients as ventilation and perfusion to the lung are
resumed near the end of cardiopulmonary bypass. Systemic fentanyl concentrations rise with ventilation, whereas levels
in the pulmonary artery fall, suggesting washout of fentanyl sequestered in the lungs during CPB. Unclamp, removal of
aortic crossclamp. (Bently JB, Canahan TJ III, Cork RC. Fentanyl sequestration in lungs during cardiopulmonary
bypass. Clin Pharmacol Ther 1983;34:705.)
Perfusion
CPB may be conducted with or without pulsatile perfusion (140). Nonpulsatile perfusion alters tissue perfusion (140).
However, no difference in thiopental concentrations during CPB was detected when pulsatile versus nonpulsatile flow
was studied (141). In contrast, as compared to those receiving nonpulsatile perfusion, cefamandole tissue
concentrations were higher and elimination half-time prolonged in patients undergoing pulsatile perfusion (142). The
degree to which pulsatile perfusion alters drug pharmacokinetics is therefore unpredictable and requires further study.
During CPB, the lungs are excluded from the circulation. Drugs taken up by the lungs (e.g., opioids
(143,144,145,146,147), propofol (148), diazepam (149)) are therefore sequestered during CPB. Thus, the lungs may
serve as a reservoir for drug release when normal circulation is reestablished (Fig. 10.17) (143). However, this effect is
quite transient (143,146,147). In an animal model of drug administration post-CPB, regional concentration differences of
the antibiotic levofloxacin (higher in upper lobes) persisted in lung fields which were not seen in an off-pump coronary
artery bypass (OPCAB) (not receiving CPB) group suggesting that altered lung perfusion may persist post-CPB (150).
Similar findings were demonstrated in cardiac surgery patients,
P.246
in whom postoperative lung concentrations of levofloxacin administered in the intensive care unit (ICU) were lower
among those undergoing CPB versus a group not undergoing CPB. This finding was attributed to a higher degree of
atelectasis (and hence altered tissue distribution) in postoperative CPB patients (151).
Although not a universal finding (152), most studies indicate that splanchnic blood flow is altered during CPB
(19,118,122,153,154,155,156,157,158) and by drugs administered during CPB, such as vasopressin, dopamine,
dobutamine, nitroglycerin (53,159), and anesthetic agents (160). This may affect the metabolism of drugs with a high
hepatic intrinsic clearance (122) (e.g., fentanyl (56,90,120,161) and propofol (8,17,162)).
Acid-Base Status
CPB may be conducted using pH-stat or a-stat blood gas management (163,164). While there is debate about which
blood gas management strategy is best (165,166), the change in pH (164,167) with either of these schemes may affect
organ blood flow (e.g., increased cerebral blood flow with pH-stat (168)), which may, in turn, affect drug distribution
(163,168,169). pH management may also affect the degree of ionization and protein binding of certain drugs, leading to
either increased or decreased free (active) drug concentrations (Fig. 10.18) (169,170).
Sequestration
Drugs may be taken up by various components of the CPB circuit itself (94). Various oxygenators have been reported to
bind drugs in vitro, including volatile anesthetic agents (171,172,173,174,175), propofol (176,177), opioids
(3,169,178,179,180), barbiturates (141), nitroglycerin (181,182), benzodiazepines (183), nifedipine (184), and antibiotics
(91,185). For intravenous drugs, this phenomenon has rarely been demonstrated to be clinically important in vivo, likely
because, depending on protein binding and lipophilicity, any free drug given intravenously and removed by the circuit is
replaced from the much larger tissue reservoir (3,94,141,176). Nevertheless, unless the priming solution is primed with
drug, and particularly for more hydrophilic drugs (e.g., antibiotics (186)), the potential exists for sequestration to lower
the concentration below a minimum acceptable therapeutic level when CPB is initiated (94,185). This effect may be
transient and counterbalanced by increases in plasma-free drug concentrations induced by reduced protein binding.
In the case of volatile agents added to the CPB circuit, wash in, wash out, and equilibration are accomplished quickly
(104,105,187). Uptake by the oxygenator may occur in vitro (94,179), but in vivo uptake typically is clinically
insignificant. Exhaust gas measurements from the oxygenator have been used as surrogate measures to indicate
arterial concentrations of volatile agents. However, the anesthetic levels reported by Wiesenack et al. (173) have drawn
our attention to the possibility of difficulties with the plasma-tight poly-(4-methyl-1-pentene) (PMP) type of oxygenator.
Following introduction of these oxygenators into their practice, they noted an increased incidence of elevated perfusion
pressure (indicative of light anesthesia) in patients undergoing CPB who were receiving a volatile agent (13). They
examined this issue by performing an in vivo comparison of the uptake of isoflurane by two types of microporous
polypropylene (PPL) oxygenators versus two types of PMP oxygenators. Significant differences in gas transfer rates
were observed between the two groups (Fig. 10.19) (173). They attributed this difference to a significantly reduced
diffusion coefficient for the volatile agent in the solid layer of the new membrane. Similar findings were reported by
Prasser et al. (175). Hinz et al. reported that the exhaust gas measurement of sevoflurane showed washout of the gas in
the PPL group during CPB but not in the PMP group. However, while they declined in the PLP group, plasma
concentrations of sevoflurane in this study were steady in the PMP group during CPB in the face of a constant gas
concentration and flow rate. The decline in sevoflurane concentration in the
P.247
PLP group was associated with an increase in blood pressure and Bispectral Index (BIS) scores (BIS—a measure of
anesthetic level), indicative of lightening of anesthesia, a finding which was not observed in the PMP group.
FIGURE 10.18. Changes in the concentrations of alfentanil (top) and fentanyl (bottom) in extracorporeal circuit prime
with time (shown on the same logarithmic scale—vertical axis). Dotted lines represent predicted concentrations.
Numbers on the right side are pH values of each priming solution. L, low temperature (24.4°C-25.70°C); N,
normothermic (34.1°C-37.0°C); NB: The differences in binding to the cardiopulmonary bypass apparatus occur as a
result of dissimilarities in the ionization of the two drugs with changes in pH. (From Skacel M, Knott C, Reynolds F, et al.
Extracorporeal circuit sequestration of fentanyl and alfentanil. Br J Anaesth 1986;58:948.)
FIGURE 10.19. Isoflurane blood concentrations (Cisoflurane [μm]) for the uptake and elimination sequence in the four
oxygenator groups. Each line represents a single patient. During hypothermic cardiopulmonary bypass, isoflurane 1%
was administered to each patient. A: CapioxRX25; B: Hilite7000; C: QuadroxD; D: Hilite7000LT. (From Wiesenack C, et
al. In vivo uptake and elimination of Isoflurane by different membrane oxygenators during cardiopulmonary bypass.
Anesthesiology 2002;97:133-138.)
The above results suggest that the use of exhaust gas measurement of volatile anesthetic concentrations as surrogates
for arterial concentrations or anesthetic effect may be inappropriate in some circumstances. Thus, as newer technology
becomes available, each membrane must be tested to determine its relative ability to transport volatile agents during
CPB in order to prevent inadequate levels of anesthesia at the time of separation from CPB.
The red blood cell may serve as a reservoir for drugs, and the anemia associated with CPB may alter drug
concentrations (3). The clinical relevance of this mechanism remains uncertain. Drug concentrations in red blood cells
increase during CPB—presumably a reflection of the increased distribution of drugs as a result of hemodilution (8).
Hemofiltration is often performed to remove excess fluid administered during CPB, particularly in pediatric cardiac
surgery and in patients with renal dysfunction (188,189,190,191). Factors affecting the degree to which a drug is
removed by hemofiltration are listed in Table 10.3 (192). Koster et al. (190) examined the ability of four hemofilters
(Renoflow 11, Baxter; Arylane H4, Cobe; Ultraflux AV 600, Fresenius; and BCS 110 Plus, Ios-tra) and two
plasmapheresis filters (ASAHI Plasmaflow OP, Diamed; PF 2000 N, Gambro) to remove hirudin in an in vitro simulation
of CPB. They determined that the plasmapheresis filters were more efficient at removing hirudin. O’Rullian et al. (193)
determined that cefazolin concentrations were not different when a hemofilter was employed as part of the circuit.
Similarly, aprotinin concentrations were not reduced by hemofiltration (194). In contrast, tirofiban was removed to the
same degree in an in vitro study comparing two hemofilters (Hospal Arylane H4 and Minntech Hemocor HPH 700) and a
plasmapheresis filter (ASAHI Plasmaflow OP) (195). In a pediatric population, use of modified ultrafiltration reduced the
concentration of the poorly protein-bound antibiotic flomoxef by an amount equivalent to that removed by the kidney
(196). It therefore appears that the degree to which drugs are removed by hemofiltration during CPB will require further
study of individual drugs and filters. While in
P.248
theory the use of a cell saver device might have an effect on clearance of protein-bound drugs, this has not been
demonstrated to be a clinical concern to date (197).
TABLE 10.3. Factors influencing movement across a membrane
Protein binding of the solute
Volume of distribution (Vd)
Solute/membrane interaction
Solute charge
Protein concentration (which influences both solute binding and oncotic pressure)
Ultrafiltrate line suction
Blood flow through hemofilter
Viscosity of blood (degree of hypothermia)
Length and diameter of tubing
Venous resistance
Filter surface area and properties
Reprinted from Clar A, et al. Derivation of sieving coefficients to determine the efficacy of the hemoconcentrator
in removal of four inflammatory mediators produced during cardiopulmonary bypass. ASAIO J 1997;43:63-170.
CHANGES IN PHARMACODYNAMICS DURING CARDIOPULMONARY BYPASS

The ability of a drug to produce its effect depends on the ability of free (unbound) drug to reach its receptor, bind with it,
and translate the receptor-initiated signal to its effectors (109,110,198). A number of factors encountered during cardiac
surgery and CPB may affect this sequence of events.
Protein Binding
In the blood, drugs exist as free (unbound) drug in equilibrium with the bound (i.e., bound to plasma proteins) drug. Only
free drug is capable of interacting with its receptor and producing pharmacologic effects (9,110). In plasma, drugs bind
primarily to the proteins albumin (acidic drugs) and a1AGP (basic drugs, e.g., fentanyl, lidocaine), an acute-phase
reactant (110). The concentration of a1AGP rises during stress, including that produced by the systemic inflammatory
response initiated during CPB, and this reduces lidocaine (199,200,201), quinidine (201), and propranolol (201) free
drug concentrations following CPB. This may result in the return of arrhythmias despite adequate measured total drug
concentrations after CPB.
Changes in protein binding are clinically significant only for drugs that are highly protein-bound (11). The degree of
drug-protein binding depends on the total drug concentration, the available protein concentration, the affinity of the
protein for the drug, and the presence of other substances that may compete with the drug or alter drug binding sites
(202). Measurement of total drug concentrations in plasma during CPB may therefore fail to elucidate the true picture of
changes in drug effect unless the unbound concentration is also measured (Fig. 10.14) (6,8,11,101).
The degree of protein binding may be altered by pathologic states existing before CPB, for example, acute myocardial
infarction (MI) (200), renal disease (203), and diabetes (204), or as a result of changes occurring during CPB, for
example, development of the SIRS, leading to a reduction in albumin production and an increase in a1AGP
concentrations (93,108,199,201,205). In the presence of renal failure and liver disease there may be reduced plasma
albumin concentrations (206). Further, the affinity of albumin for drugs such as phenytoin, thiopentone, and diazepam
may be reduced in the presence of chronic disease states (e.g., cirrhosis) (15,206,207).
Heparin is administered before and during CPB to prevent clot formation. Heparin releases free fatty acids, which may
in turn displace drugs from protein binding sites and increase free drug concentrations, resulting in an enhanced
pharmacologic effect (96,208,209,210).
Tissue Binding
Following drug administration, free drug penetrates into tissues where it may bind to tissue proteins. Certain tissues, for
example, those of the heart and lung, have an affinity for certain drugs (29,143,144,145,146,147,148,209,211,212). This
has two relevant pharmacodynamic consequences. First, tissue binding may limit access of a drug to its receptor if that
tissue is not the site of the desired drug action, thereby potentially limiting the magnitude of effect (147). Second, the
tissue may also serve as a drug reservoir, thereby extending drug effect, particularly if the tissue (e.g., lung) is out of
circuit during CPB (Fig. 10.17) (143).
Age
Adult cardiac surgical patients are frequently elderly (defined as an age > 65 years). Independent of pathologic
processes, aging is associated with a variety of physiologic processes that may influence drug effect (15). The functions
of organs such as the heart are reduced while blood flow to the kidneys and liver are decreased (213). These factors
may reduce drug clearance (214). Elderly humans also have increased adipose tissue, which may serve as a reservoir
for lipid-soluble drugs. Albumin concentrations may be reduced, resulting in higher free drug concentrations when
standard doses are administered (15,214).
A number of investigations have recently examined the sensitivity of the central nervous system (CNS) to drugs in the
elderly. While CNS sensitivity to barbiturates may be unaltered (215), reductions in dose are required because of a
P.249
slower return of drug from the effect site to the central compartment (a pharmacokinetic difference) (216). In contrast, a
true difference in CNS sensitivity to opioids (fentanyl, alfentanil, and remifentanil) (217,218) and volatile agents (219)
has been described in the elderly. For the elderly patient undergoing CPB, a reduction in dose to limit the high free drug
concentrations and the potential for prolonged or toxic drug effects therefore seems prudent.
At the other end of the age spectrum, infants and children may have altered drug effects owing to differences in
distribution of body fat, maturity of clearance mechanisms, and disease-related changes in drug handling
(38,220,221,222,223,224,225,226,227,228,229). Although the degree to which infants and children may have
differences in drug sensitivity has received little scientific scrutiny, differences appear to exist. Thus, it cannot be
assumed that doses of drugs considered adequate for adults undergoing CPB will suffice for the pediatric population
(222,224,230,231).
Central Nervous System Penetration

For anesthetic agents, the site of drug effect is presumed to be the CNS. Differences in CNS pharmacodynamic effects
between drugs have been measured by comparing the time difference between their peak plasma concentrations and
electroencephalographic (EEG) changes (232). A hysteresis (i.e., less time to equilibrium with alfentanil) has been
observed between the peak plasma concentration of fentanyl versus alfentanil and the shift in the spectral edge
frequency of the EEG (233). A similar time lag has been observed as drug concentrations fall. These findings most likely
represent disposition of the more lipophilic fentanyl to highly lipophilic brain tissue, preventing fentanyl concentrations
from rising at the CNS opioid receptors and prolonging time to peak effect (a pharmacokinetic difference). This
hypothesis is substantiated by the demonstration that hysteresis for sufentanil (another lipophilic opioid) more closely
approximates that of fentanyl than the more hydrophilic alfentanil (234). A similar rationale has been used to describe
differences in onset of action between midazolam and diazepam (232,235). Utilization of these time differences and
concentrations can be measured and modeled, and has led to the development of computer programs with a rate
constant ( Ke0) designed to target stable drug concentrations at the effect site compartment (receptor level) (31,37,236).
Such programs have been utilized in studies of drug administration to target concentrations during cardiac surgery
(28,37,40,41,42,224). By providing stable plasma concentrations, determination of concentration-versus-effect relations
during CPB can be made by utilizing various monitors of CNS activity, such as auditory evoked potentials (AEP) (237)
and the BIS (10,21,25,28,31,32,33,34,35,39,40,42,114,238,239,240).
The lysine analogs e-aminocaproic acid and tranexamic acid are commonly employed to prevent excessive bleeding
during cardiac surgery. Although these agents effectively inhibit the fibrinolytic system that is activated during CPB
(241), their use has unfortunately been associated with development of seizures in the postoperative period (242). In
part, this may be attributable to the variable penetration of these drugs into the CNS. In a study of tranexamic acid,
cerebrospinal fluid (CSF) levels of the drug differed 9-fold despite administration of a fixed body weight dose (243). At
clinically relevant CSF concentrations, the mechanism for production of seizures with tranexamic acid may be related to
blockade of the receptor for the inhibitory neurotransmitter glycine, which has been prevented in animal models by
administration of propofol or isoflurane (244).
Temperature
Hypothermia produces a number of pharmacodynamic effects. Anesthetic requirements are reduced by hypothermia
(113,114,245). Changes in receptor affinity (e.g., decreased opioid receptor affinity (246) and nicotinic acetylcholine
receptor sensitivity (247)) also occur during hypothermia. The action of neuromuscular receptor blocking agents is
enhanced, which may reflect a pharmacodynamic and a pharmacokinetic effect (91,130,137,248,249,250,251,252)
(Table 10.4).
Use of hypothermia may decrease release of the excitatory neurotransmitters glutamate and glycine into the CNS (253),
thereby attenuating central excitotoxicity and exerting a cerebroprotective effect. The implications of such an effect on
drug action are unknown, but hypothermia has not reduced the incidence of neurocognitive deficits in most (but not all
(254)) prospective randomized clinical trials (238,255).
TABLE 10.4. Muscle relaxants and hypothermic cardiopulmonary bypass
Plasma concentration on CPB
Medication Initial Later Clearance N-M sensitivity
Steroids
Pancuronium ↓ ↑ • ↑ 1.8-fold
Vecuronium • • • ↑ 5-fold
Rocuronium • • • ↑
Benzylisoquinoliniums
d-Tubocurarine ↑ ↑ ↓ -
Metocurine • -
Atracurium • • ↓ •
cis-Atracurium • • ↓ ↑ 2-fold
Toxiferines
Alcuronium ↑ ↓ •
N-M, neuromuscular; ↑, Increase; ↓, decrease; •, not known.
Modified from Mets B. The pharmacokinetics of anesthetic drugs and adjuvants during cardiopulmonary
bypass. Acta Anaesthesiol Scand 2000;44:261-273.
P.250
Acid-Base and Electrolyte Changes
Altered peripheral perfusion produces tissue acidosis during CPB (256). This may affect the response to
catecholamines (257). The degree of ionization and protein binding (hence free drug concentrations) of weak acids and
bases may also be affected by the blood gas management strategy employed during CPB (Fig. 10.18) (169). Changes
in pH may also affect electrolyte balance. Calcium, magnesium, and potassium concentrations decline during CPB
(258,259,260), and associated muscle weakness, arrhythmias, and enhanced digitalis toxicity may ensue. Whether
intraoperative replacement of calcium (261,262) or magnesium (263,264) reduces complications such as arrhythmias is
still debated.
Cardiopulmonary Bypass
Volatile anesthetic agents are commonly employed during CPB, usually in combination with intravenous anesthetic
agents to avoid hemodynamic aberrations (265,266). Volatile agents may disrupt ion channels and intracellular
transduction mechanisms (267). Although the nature of the priming solution (acetate) may prove important by acting as
a supplemental anesthetic agent, the anesthetic requirements for volatile agents are reduced by an as of yet
unidentified mechanism following CPB in dogs (268,269,270).
Using the brain’s electrical activity and “depth of anesthesia” monitors (which may be problematic in terms of sensitivity
(9,114,239)) to examine the independent role of CPB in reducing anesthetic requirements in man has yielded mixed
results. Yoshitani et al. (10) demonstrated a greater pharmacodynamic effect for a given concentration of propofol pre-
versus post-CPB under normothermic conditions. Takizawa et al. (9) similarly reported an enhanced propofol effect for a
given dose following normothermic CPB, which was in part related to an increased free (but not total) drug
concentration during CPB. In contrast, Ahonen et al. (271) examined the need for propofol to maintain a fixed BIS in a
group of patients randomized to on- versus off-pump surgery, and could not detect any difference in anesthetic
requirements. A randomized trial of patients undergoing cardiac surgery by Mathew et al. (245) reported that CPB
produced a reduction in BIS levels that was further enhanced with use of hypothermia. Lundell et al. (272) examined the
concentration-effect relation for isoflurane in combination with a computer-driven infusion of fentanyl designed to
maintain a constant effect site concentration of 3 ng/mL and noted a 25% reduction in the concentration of isoflurane
required to maintain a stable BIS level post- versus pre-CPB. These findings suggest that the CPB itself may reduce
anesthetic requirements.
Receptor Density
The number of receptors available for interaction with a ligand will determine the magnitude of drug effect. Patients
presenting for cardiac surgery frequently have CHF (266,273). These patients frequently have a reduced number of
cardiac β-receptors, defects in receptor transduction, and impaired synthesis and reuptake of norepinephrine
(78,88,274). Chronic β-adrenergic receptor agonist administration has a pharmacodynamic effect (275), and continued
use of these agonists has been linked to therapeutic failure, including increased mortality (276). As chronic
administration of β-adrenergic receptor blocking agents in those with CHF improves morbidity (277) and mortality
(276,277,278), affected patients typically take these agents preoperatively. As a consequence of both a reduced
number of receptors and pharmacologic blockade of β receptors, β-adrenergic agonists may exhibit reduced
pharmacodynamic effects during and following CPB (279).
Discontinuation of β-adrenergic receptor blocking agents in patients treated for angina pectoris and CHF in the
perioperative period may lead to β-adrenergic receptor upregulation and increased adrenergic responsiveness (280).
Increases in myocardial oxygen demand due to increased heart rate and contractility may lead to myocardial ischemia,
worsened symptomatology, and even death (281). A retrospective database analysis suggested that continuation of β-
adrenergic receptor blocking agents might also have a neuroprotective effect (282). It is therefore generally
recommended that chronic cardiovascular medications, including β-adrenoceptor receptor blocking agents, be
continued until surgery commences (280).
Changes in receptor density and function may occur quickly (77), even during the conduct of cardiac surgery (283).
Changes in the density and function of the β-adrenergic receptor have been examined the most among the cardiac
surgery population. β-adrenergic receptor function is impaired following CPB (284). Possible mechanisms include
ischemia-reperfusion injury (285) and acute β-adrenergic receptor desensitization (286) occurring as a result of the
catecholamine release accompanying CPB (117). At the cellular level, there is a reduction in GRK activity (74). Attempts
to ameliorate β-adrenergic receptor dysfunction during CPB have included administration of β-adrenergic receptor
blocking agents (287) and the use of warm blood cardioplegia (288) or high spinal anesthesia (289). Further work is
required to elucidate the mechanisms and identify the best therapeutic options to reduce undesirable changes in
receptor density and function.
Hyperalgesia
Tissue injury, including surgical trauma, may result in hyperalgesia (exaggerated nociceptive responses to noxious
stimuli) and allodynia (nociceptive responses to innocuous stimuli) (290,291). Although the mechanism(s) by which this
occurs is likely multifactorial (292), emerging evidence suggests that excitatory amino acids (e.g., N-methyl-D-aspartate
(NMDA) at the spinal cord level may play a key role (290). Stimulation
P.251
of excitatory amino acid receptors in the spinal cord triggers intracellular events leading to Ca2+ release and
phosphokinase C (PKC) activation. PKC is associated with a number of neuronal changes, including development of
hyperalgesia (290). As tolerance to morphine administration shares many of the same pathways (290), studies in
animals and humans have also implicated these pathways in the development of hyperalgesia (so-called opioid-induced
hyperalgesia [OIH]) (291,293). Whether hyperalgesia develops in the perioperative period is debated, but recent meta-
analysis concluded that, at least for the administration of remifentanil, it does (294). Representative studies, in patients
undergoing cardiac surgery, include that of Richebe and colleagues (295) who examined the incidence of hyperalgesia
following remifentanil administration by CACI with a target concentration of 7 ng/mL as compared to a group of patients
receiving a zero-order infusion of 0.3 μg/kg/min. Use of the targeted infusion led to a reduction in total remifentanil dose
and a reduction in hyperalgesia. In a randomized study of 40 patients undergoing coronary artery bypass graft (CABG)
surgery comparing sufentanil targeted to a plasma concentration of 0.4 or 0.8 ng/mL, it was observed that the higher-
dose sufentanil group had increased postoperative analgesic requirements, but assessments for hyperalgesia indicated
that, while present and diminishing over time, the degree of hyperalgesia was not different between the two groups
(296). In contrast, in a randomized study of 90 patients undergoing cardiac surgery and receiving either sufentanil 0.3
μg/kg/min intraoperatively or placebo (in addition to a sufentanil/propofol-based anesthetic), no difference in
postoperative analgesic requirements was observed. Although the authors concluded that hyperalgesia did not occur
(297), it must be acknowledged that it was not specifically tested for as in the studies of Fechner et al. (296) and
Richebe et al. (295).
Therapeutic approaches to the management of OIH have varied (298). The role of ketamine (an NMDA receptor
antagonist) was examined in a group of patients undergoing abdominal surgery and receiving high doses of remifentanil
intraoperatively (299). Ketamine administration reduced the degree of hyperalgesia.
The results of these investigations suggest that use of opioids should be restricted to what is necessary to control pain
and unwanted hemodynamic responses so as to minimize the development of hyperalgesia in the perioperative period.
Measures such as administration of ketamine to reduce hyperalgesia when recognized merit further investigation.
THE SYSTEMIC INFLAMMATORY RESPONSE SYNDROME

Cardiac surgery and CPB initiate a systemic inflammatory response as a consequence of operative trauma, blood
contact with foreign surfaces with resultant complement activation, development of ischemia-reperfusion injury, and the
presence of endotoxin (Fig. 10.20) (205). The magnitude of the response is influenced by a number of factors
(93,205,300,301), including genetics (302), and may have an adverse effect on clinical outcomes (92,303,304),
including development of multiple organ dysfunction syndrome (MODS) (19,134,154,305,306). The pathophysiologic
mechanisms by which this occurs are gradually being elucidated (307,308,309,310,311,312,313).
Attempts to ameliorate the systemic inflammatory response are of interest as inflammation may have a profound effect
on drug handling (Fig. 10.20) (92,314). During evolution of the inflammatory response, a host of cytokines and other
mediators are released, including tumor necrosis factor alpha (TNF-α), interleukin 1 (IL-1), IL-6, IL-2, IL-8, IL-10,
interferon γ (IFN-γ) and nitric oxide (NO) (93,205). Each of these mediators (e.g., TNF-α, IL-1, and IL-6 (93,315,316))
subserves a number of functions, including increasing transcription of acute-phase proteins (which may reduce free
drug concentrations (108,199,201)) and inhibition of drug metabolism through downregulation of cytochrome P-450
activity (162,317). The metabolism of most clinically important drugs, including those utilized for the provision of cardiac
anesthesia, is restricted to a relatively small number of cytochrome P-450 (CYP-450) isoenzymes, including CYP 1A2,
2A6, 2C8, 2C9, 2D6, and 3A4 (45,318,319,320). Of particular note, cytochrome P-450 3A4 (CYP3A4) is partly
responsible for the metabolism of many of the opioids (321), propofol (322), and is exclusively responsible for the
metabolism of midazolam (323,324).
Factors that affect CYP3A4 function can thus have a significant effect on drug metabolism. In addition to inflammatory
cytokines (325), these include endotoxin (326), drugs (327,328,329,330), food (331), hypoxia (332), neurotransmitters
(including adrenaline) (333), CPB (334), preexisting disease (335), and race (336). The variability in drug handling seen
during cardiac surgery may be partly explained by these factors.
Myocardial depression may be induced by IL-6 (93,337,338) and NO (338), which may, in turn, alter the distribution of
drugs. Activation of neutrophils with generation of oxygen-derived free radicals may injure tissue, particularly
endothelium, leading to a capillary leak syndrome that may affect the volume of distribution for drugs and drug
penetration into tissue receptor sites (339,340,341,342). Inflammation mediated reductions in liver blood flow may also
reduce clearance of drugs with a high hepatic extraction ratio (e.g., fentanyl) (122,343,344,345,346,347).
The inflammatory response may have pharmacodynamic effects as well. TNF-α, IL-1β, and IL-6 are endogenous
pyrogens (315,348) that may produce an anesthetic-sparing effect (349). Inflammation induces brain swelling (350),
which intuitively would be expected to reduce anesthetic requirements. Inflammation may also alter drug penetration
across
P.252
the blood-brain barrier (BBB). Animal studies have demonstrated that inflammation causes changes in brain CYP-450
function as well as alterations in the activity of p-glycoprotein, which is thought to comprise a key component of the
biochemical BBB (46,351,352,353,354,355). The BBB is composed of the endothelial cells lining the cerebrospinal
capillaries. Its role is largely to restrict the entry of toxins (and therefore drugs) into the CNS. CNS injury, as may occur
during the conduct of CPB (356), may produce a central inflammatory response that leads to an alteration in BBB
function resulting in either an increased or decreased uptake of drugs into the CNS (with a resultant increase or
decrease in central pharmacodynamic effects and/or toxicity) (357). Agents employed during cardiac surgery may also
affect intracellular signaling pathway(s) following stimulation by inflammatory cytokines. For example, agents that
increase intracellular cAMP (e.g., catecholamines, phosphodiesterase inhibitors, glucocorticoids, opioids) will reduce
TNF-α production (205,358).
FIGURE 10.20. Systemic inflammatory response and approaches that have been used to attenuate various
components. On the left-hand side are factors thought to be involved in the generation of the inflammatory response.
On the right-hand side are therapies that have been used to alter the inflammatory response. (From Hall R.
Identification of inflammatory mediators and their modulation by strategies for the management of the systemic
inflammatory response during cardiac surgery. J Cardiothorac Vasc Anesth 2013;27(5):983-1033 and Garfinkel D,
Mamelok RD, Blaschke TF. Altered therapeutic range for quinidine after myocardial infarction and cardiac surgery. Ann
Intern Med 1987;107(1):48-50.)
The systemic inflammatory response during CPB may therefore significantly impact drug pharmacokinetics and
pharmacodynamics. Although many strategies designed to ameliorate the systemic inflammatory response to cardiac
surgery have been employed (Fig. 10.20) (93), few have proven beneficial. Thus, further investigation into this area is
required.
SPECIFIC DRUG CLASSES

Studies examining the influence of the factors outlined above on the pharmacokinetics and pharmacodynamics of drugs
administered during hypothermia and CPB are provided in Table 10.5. However, caution should be exercised in the
interpretation and comparison of the reported results
P.253
P.254
P.255
P.256
P.257
P.258
P.259
P.260
P.261
P.262
P.263
P.264
P.265
P.266
P.267
P.268
P.269
P.270
P.271
P.272
P.273
P.274
P.275
P.276
P.277
P.278
P.279
P.280
P.281
P.282
P.283
P.284
P.285
P.286
P.287
P.288
P.289
P.290
P.291
P.292
P.293
P.294
P.295
P.296
P.297
P.298
P.299
because they may be influenced by a variety of unreported and unquantified factors, including the coadministration of
other agents (e.g., vasoconstrictors and vasodilators that might alter the volume of distribution and clearance),
differences in anesthetic techniques (changes in cardiac output and tissue distribution), type of oxygenator utilized
(differential drug uptake), use and magnitude of hypothermia (changes in distribution and pharmacodynamics),
hemodilution (changes in protein binding), and nature of the priming solution (blood, colloid, or crystalloid and
implications for drug binding).
TABLE 10.5. Studies of pharmacokinetic and pharmacodynamic changes of drugs administered
during cardiopulmonary bypass
Bypass
Drug class and temperature
study Drug (n)a (°C) Oxygenator Relevant findings
Antiarrhythmic agents
Morrell and Group 1: Lidocaine 1.5 28°C Polystan Forty percent of

Harrison (95) mg/kg (n = 10) Venotherm VT patients receiving
Group 2: Lidocaine 2.5 5000 Bubble lowest dose had
mg/kg (n = 9) subtherapeutic
Group 3: Lidocaine 3.5 [lidocaine] within 2
mg/kg (n = 5) during min; 90% of those
hypothermic CPB patients receiving
2.5 mg/min had
subtherapeutic
[lidocaine] at 30 min;
at highest dose
[lidocaine] was >1.5
μg/mL for 20 min;
t1/2β, Vdss were
doubled relative to
previously reported
values; Cl was the
same.
Holley et al. Lidocaine 100 mg 27°C Harvey H-1500 No change in PK

(199) Group 1: Preoperative, parameters post-
15 min postoperative, 1 CPB in Group 1.
d post-CPB (n = 5) In Group 2, the 3 d
Group 2: Preoperative postoperative Cl ↓ to
and days 3 and 7 58% while Vdss ↓ to
postoperative (n = 5) + 60%; and recovered
3 patients from Group 1 by day 7.
at 3 d No change in t1/2β.
[lidocaine]-free
fraction fell from
30% to 16% at day
3 and remained low
at day 7.
α1-Acid glycoprotein
levels increased
200% at day 3.
Schiavello et al. Lidocaine 2 mg/kg at 25°C Harvey H-1500 During CPB, t1/2β ↑,
(121) induction of anesthesia Bubble CI ↑, and Vdss ↑
and again during CPB
(n = 10)
Landow et al. Lidocaine 1.5 mg/kg 27°C Maxima 5K 1380 Free [lidocaine]
(97) bolus 10 s before (Medtronic) or within therapeutic
release of aortic cross- BOS CM 50 window, although
clamp, then 2 mg/min for (Bentley) or M- total [lidocaine]
6 hr (n = 28) 2000 (Shiley) or below therapeutic
Terumo 5.4 range from 20 to
(Terumo) 120 min.
Landow and Lidocaine 1.5 mg/kg 27°C Maxima 5K 1380 Infusion regimen
Wilson (98) bolus 10 s before (Medtronic) or resulted in more
release of aortic cross- BOS CM 50 patients with total
clamp, 5 mg/min for 1 (Bentley) or M- [lidocaine]
hr, then 2 mg/min for 23 2000 (Shiley) or consistently in
hr (n = 10) Terumo 5.4 therapeutic range
(Terumo) (7/10).
Free [lidocaine] at
therapeutic range
(9/10).
Hsu et al. (359) Lidocaine 1 mg/kg bolus 30°C-32°C Membrane Lidocaine and
at induction, then 4 metabolite
mg/min for 1 hr, then 2 concentrations
mg/min for 1 hr, then 1 increased over time.
mg/min for 46 hr (n = Two-compartment
99) PK model showed
best fit for the
parameter
estimates.
Body weight
identified as a
significant covariant
for Cl from the
central compartment
and Vdc.
Lidocaine levels
above 5 μg/mL were
identified in only
6.4% of patients at
48 hr. Parameter
estimates:
V1 (volume of
central
compartment) 0.056
L/kg
V2 (Volume of
peripheral
compartment) 187 L.
Cl1 (Clearance of
central
compartment)
0.0042 L/kg/min.
Cl2 (Clearance of
peripheral
compartment) 6.76
L/min.
t1/2β 6.9 hr.
Weight-based
infusion scheme
suggested:
1 mg/kg bolus
followed by 50
μg/kg/min for 1 hr
then 25 μg/kg/min
for 1 hr then 12
μg/kg/min for 22 hr
then 12 μg/kg/min
for 24-48 hr.
Antibiotics
Aminoglycosides
Kaiser et al. Group 1: Cefazolin 2 g NA NA Cefamandole

(368) at induction, 1 g every 4 provided better
hr intraoperatively, and protection than
then every 6 hr cefazolin.
postoperatively for 72 hr Gentamicin was of
(n = 255) no additional
Group 2: Cefazolin 2 g benefit.
at induction, 1 g every 4 To ensure adequate
hr intraoperatively, and levels during CPB,
then every 6 hr cefamandole dosing
postoperatively for 72 hr interval should be
+ gentamicin 1.5 mg/kg every 2 hr.
at induction (n = 253)
Group 3: Cefamandole
2 g at induction, 1 g
every 2 hr
intraoperatively, and
then every 4 hr
postoperatively for 72 hr
(n = 259)
every 2 hr
then 1 g every 4 hr
+ gentamicin 1.5 mg/kg
iv at induction (n = 263)
Klamerus et al. Vancomycin 1 g 1 27°C Shiley S-100A Renal Cl ↓ during

(443) netilmicin 3 mg/kg iv (n HED CPB.
= 10) At onset of CPB
[vancomycin] ↓ 17%
and [netilmicin] ↓
29%. [netilmicin]
rebounded over time
during CPB.
[vancomycin] ↑ with
removal of aortic
cross-clamp.
Lippert et al. Gentamicin 80 mg 1 28°C NA t1/2β not different

(444) cefuroxime 1.5 g at skin during CPB vs. post-
incision and repeated at CPB. Therapeutic
3 hr, then before levels achieved.
midnight, then every 8
hr (n = 8)
Lehot et al. Cefazolin 25 mg/kg at 28°C BOS10 Bentley Cefazolin kinetics

(445) induction and every 8 hr Bubble not different during
for 48 hr + netilmicin 2 CPB vs. post-CPB.
mg/kg at induction and 1 Netilmicin t1/2β ↑, Vd
mg/kg every 8 hr for 48 ↑, CI ↓ during CPB.
hr (n = 10) [cefazolin] ↓ 28%
30% at start of CPB.
Therapeutic levels
achieved
intraoperatively.
Heylen et al. Flucloxacillin 500 mg at NA NA Toxic [gentamicin] in

(380) induction, then 500 mg 15 patients.
4 times daily for 48 hr + Postoperative
gentamicin 1.5 mg/kg at concentrations could
induction and 80 mg 3 not be predicted
times daily for 48 hr based on
adjusted as necessary preoperative patient
for CrCl (n = 95) characteristics.
Heylen et al. Flucloxacillin 500 mg at NA NA Gentamicin median

(382) induction, then 500 mg Cl 37 mL/min (1/2
4 times daily for 48 hr + the CrCl) and
gentamicin 1.5 mg/kg at median t1/2β 2.5 hr.
induction and then 80 Trough levels above
mg 3 times daily for 48 therapeutic but
hr (n = 10) decreased renal
elimination in
postoperative period
was associated with
elevated plasma
concentrations.
Lewis et al. Gentamicin 4 mg/kg at 28°C NA Gentamicin CI ↓ on

(381) induction + flucloxacillin CPB.
1 g at induction, then t1/2β ↑ with ↑
every 6 hr for 48 hr (9) duration of CPB. 3/9
patients had
[gentamicin] >1
mg/mL at 24 hr thus
resulting in the
potential for toxicity.
Haessler et al. Cefazolin 40 mg/kg on 18°C-24°C D701 Membrane [cefazolin]

(446) induction, then in ICU (Dideco)(9) therapeutic.
35 mg/kg, and then Safe Micro [cefazolin] ↓ 32% on
every 8 hr for 48 hr + Membrane CPB. [gentamicin] ↓
gentamicin 5 mg/kg on (Polystan) (10) 28% on CPB. Peak
induction, then in ICU 2 [gentamicin]
mg/kg every 12 hr for 48 potentially toxic.
hr (n = 19). Vd ↑, Cl ↓ for both
Pediatric population drugs.
Cephalosporins
Miller et al. Cefazolin 1 or 2 g 26°C Bentley Q200A [cefazolin] ↓ with

(447) preoperatively, at initiation of CPB
induction, and then stable.
postoperatively (n = 8) CI ↓, and t1/2β ↑ vs.
preoperatively and
postoperatively.
Renal Cl ↓
intraoperatively vs.
preoperatively and
postoperatively but
no further ↓ with
CPB.
Nightingale et Group 1: Cefazolin 2 g NA NA [cefazolin] >

al. (448) (n = 16) [cephradine] in
Group 2: Cephradine 2 serum and tissue.
g (n = 17) Both dosing
30-118 min before regimens provided
removal of right atrial therapeutic levels.
appendage Free [cephradine] >
free [cefazolin] in
serum and
pericardial fluid.
Olson et al. Cefamandole 2 g (n = NA NA [cefamandole]

(449) 23) 20-120 min before therapeutic in atrial
removal of atrial and pericardial fluid
appendage up to 225 min.
76% protein bound
in pericardial fluid.
Mullany et al. Group 1: Ceforanide 30 NA NA [ceforanide] >
(450) mg/kg (n = 13) [cefamandole] but
Group 2: Cefamandole both achieved
30 mg/kg 32-214 min therapeutic levels in
before removal of right atria, pericardial
atrial appendage (n = fluid, plasma, aorta,
13) muscle, and sternum
for CPB durations
<200 min.
Cl ↓ during CPB
Bryan et al. Group 1: Cefamandole NA NA [cefazolin] >

(370) 2 g (n = 16) [cefamandole] but
Group 2: Cefazolin 2 g [cefazolin]
(n = 16) subtherapeutic in
60 min before incision 3/16 bone samples.
Better relative tissue
penetration of
cefamandole.
Despite lower bone
and atrial tissue
levels in some
patients, overall
tissue levels higher
with cefazolin.
Bergeron et al. Group 1: Cefamandole NA NA [cefamandole] and

(371) 1 g at induction and [fusidic acid]
then every 4 hr for 24 hr therapeutic in
(n = 37) cardiac tissue but
Group 2: Cloxacillin 1 g [cloxacillin]
at induction and then subtherapeutic in
every 4 hr for 24 hr (n = 13% of heart
34) specimens.
Group 3: Fusidic acid Cl ↓ for cefamandole
580 mg over 2 hr and and cloxacillin
then every 8 hr for 24 hr during CPB.
(n = 29)
Frank et al. Ceftazidime 2 g 25°C NA Therapeutic levels

(451) preoperatively (n = 24) achieved in serum,
valve, muscle, and
fat.
Kaiser et al. Group 1: Cefazolin 2 g NA NA Cefamandole

(368) at induction, 1 g every 4 provided higher
hr intraoperatively, and therapeutic levels
then 1 g every 6 hr than cefazolin.
postoperatively × 72 hr Gentamicin of no
(n = 255) additional benefit.
Group 2: Cefazolin 2 g To ensure adequate
at induction, 1 g every 4 levels during CPB,
hr intraoperatively, and they recommended
then 1 g every 6 hr cefamandole dosing
postoperatively for 72 hr interval should be
+ gentamicin 1.5 mg/kg every 2 hr.
every 2 hr
then 1 g every 4 hr
(n = 259)
every 2 hr
then 1 g every 4 hr
+ gentamicin 1.5 mg/kg
Oksenhendler et Ceftriaxone 2 g at NA NA Ceftriaxone free

al. (452) induction (n = 15) fraction unchanged
at initiation of CPB.
Vd ↑, t1/2β ↑ relative
to baseline values.
Therapeutic
concentrations
maintained
throughout surgery.
Martin et al. Ceftriaxone 1 g 30 min 28°C NA Group 1 had ↑ Cl

(453) prior to skin incision (23 vs. 18 mL/min),
Group 1 (n = 10). ↑ Vdss (18 vs. 12 L)
In Group 2 (n = 10) an when compared to
additional 1 g was given Group 2.
at initiation of CPB. t1/2β (8.1 vs. 7.1 hr)
Both groups received 1 not different. No
g at 24 hr difference in tissue
postoperatively (thoracic wall fat,
sternal bone,
pericardium, or
heart)
concentrations.
Tissue [ceftriaxone]
below MIC for select
bacteria in some
tissues.
Van der Starre Group 1: Cefamandole 28°C NA [cefamandole] ↑ with

et al. (372) 30 mg/kg at induction (n supplemental dose
= 11) before CPB.
Group 2: Cefamandole Subtherapeutic
30 mg/kg at induction + levels in 6/11
15 mg/kg just before patients in Group 1.
CPB (n = 11)
Weiner et al. Cefamandole 20 mg/kg NA NA [cefamandole] in
(142) at midnight the day serum, fat, and
before surgery, at 6 muscle therapeutic
a.m., and just before during CPB in both
initiation of CPB groups but higher in
Group 1: Pulsatile pulsatile perfusion
perfusion (n = 6) group.
Group 2: Nonpulsatile t1/2β ↓ in
perfusion (n = 6) nonpulsatile group.
Rooney et al. Cephradine 2 g (n = 10) 28°C Optiflow 2 Bubble Monoexponential

(197) or Cefamandole 2 g (n = Oxygenator (Cobe) decline in serum
10) at induction of levels.
anesthesia Concentration not
affected by use of a
cell saver.
Jungbluth et al. Ceftriaxone 14 mg/kg at 28°C Membrane (6) [ceftriaxone] free

(210) induction (n = 7) Bubble (1) fraction increased
postheparin
administration and
further increased
during CPB.
CI ↑, Vd ↑, t1/2β ↑
relative to previously
reported normal
values.
Lippert et al. Gentamicin 80 mg + 28°C NA t1/2β not different

(444) cefuroxime 1.5 g at skin during CPB vs. post-
incision and then at 3 CPB Therapeutic
hr, before midnight, and levels achieved.
then every 8 hr (n = 8)
Sue et al. (454) Cefazolin 1 g at NA NA t1/2β ↑ post-CPB.

induction + 1 g in CPB t1/2β ↑ as blood loss
priming solution (n = 8) ↑.
No correlation
between amount of
chest tube drainage
and serum levels of
antibiotic.
Lehot et al. Cefazolin 25 mg/kg at 28°C BOS10 Bentley Cefazolin kinetics

(445) induction and every 8 hr Bubble not different during
for 48 hr + netilmicin 2 vs. post-CPB.
mg/kg at induction and 1 Netilmicin t1/2β ↑, Vd
mg/kg every 8 hr for 48 ↑, CI ↓ during CPB.
hr (n = 10) [cefazolin] ↓ 28%
30% at initiation of
CPB.
Therapeutic levels
achieved
intraoperatively.
Menges et al. Group 1: Cefamandole NA NA [cefamandole] ↓

(455) 2 g before incision (n = 20% at start of CPB
24) in Groups 1 and 3.
Group 2: Cefamandole Supplementation of
2 g at induction + 2 g 10 dose before CPB
min before aortic maintained
cannulation (n = 22) therapeutic
Group 3: Cefamandole concentrations in
4 g before incision (n = blood and tissue
23) until postoperative
day 1.
Vuorisalo et al. Cefuroxime 1.5 g NA NA [cefuroxime]

(456) preoperatively and 0.75 adequate for all
g at 8 and 16 hr (n = 10) groups.
Cefuroxime 1.5 g [vancomycin]
preoperatively + 0.75 g adequate for all
1 hr after initiation of groups.
CPB and at 8 and 16 hr One sternal wound
(n = 10) infection in Group 1.
Cefuroxime 3 g One
preoperatively (n = 10) Staphylococcus
Vancomycin 1 g aureus infection and
preoperatively and at 12 death in Group 3.
hr (n = 10)
Vancomycin 1 g
preoperatively, 0.5 g 1
hr after initiation of CPB
and 1 g at 12 hr (n = 10)
Vancomycin 1.5 g at
induction (n = 10)
O'Rullian et al. Cefazolin using NA Optima (Cobe) [cefazolin] not

(193) Minntech (Hemocor) removed or
hemoconcentrator (n = concentrated by
5) vs. not using hemofiltration.
hemoconcentrator (n =
6)
Dose not reported
Lonsky et al. Group 1: Ceftazidime 1 30°C SAFE II (Polystan [ceftazidime] ↓ by

(374) g on induction, then A/S) 55%, [ciprofloxacin]
every 8 hr for 48 hr (n = ↓ by 42%,
25) [clindamycin] ↓ by
Group 2: Ciprofloxacin 78% at initiation of
400 mg on induction, CPB.
then every 12 hr for 48 [ceftazidime]
hr (n = 25) subtherapeutic for
Group 3: Clindamycin procedures lasting
900 mg on induction >298 min.
then every 8 hr for 48 hr One wound infection
(n = 25) in [clindamycin]
group.
Fellinger et al. Cefazolin 1 g at NA NA Estimated free

(373) induction and 1 g at [cefazolin] adequate
initiation of CPB (n = for Staphylococcus
10) and Streptococcus
spp.
Briefly inadequate at
initiation of CPB
before second dose
for Escherichia coli
and P. mirabilis.
Subtherapeutic for
Enterobacter or
Serratia sp. during
entire case
Haessler et al. Cefazolin 40 mg/kg on 18°C-24°C D701 Membrane [cefazolin] achieved

(446) induction, then in ICU (Dideco) (9) therapeutic
35 mg/kg and every 8 hr Safe Micro concentrations.
for 48 hr Membrane [cefazolin] ↓ 32% on
Gentamicin 5 mg/kg on (Polystan) (10) initiation of CPB.
induction, then in ICU 2 [gentamicin] ↓ 28%
mg/kg every 12 hr for 48 on initiation of CPB.
hr (n = 19) Peak [gentamicin]
Pediatric population potentially toxic.
Vd ↑, Cl ↓ for both
drugs.
Miglioli et al. Cefazolin 2 g before NA Monolith (Sorin) [cefazolin] ↓ by

(457) induction (n = 60) 46.6% on initiation
of CPB.
[cefazolin] above
MIC for
Staphylococcus
epidermidis,
Staphylococcus
aureus, and E. coli
for 8 hr.
Nascimento et Cefuroxime 1.5 g every NA NA [cefuroxime] higher

al. (375) 6 hr on- vs. off-pump.
On-pump (n = 10). Subtherapeutic
Off-pump (n = 7) concentrations for
both groups before
next dose.
Cl ↓ in on-pump
group.
Mandak et al. Cefuroxime 3 g at 34°C-35°C NA Free [cefuroxime]

(458) induction, 1.5 g after fell during CPB and
protamine continued to decline
administration, and 1.5 throughout surgery
gm at 8 hr but was still above
postoperatively (n = 9) the MIC for most
relevant pathogens.
Free [cefuroxime]
below tissue levels
as measured by
microdialysis.
Adembri et al. Group 1: Cefazolin 2 g NA NA Free [cefazolin]

(367) prior to skin incision and higher and above
then 1 g at 3, 9, and 15 MIC for Staph
hr post op (n = 10) aureus 90% of time
Group 2: Cefazolin 2 g in 9/10 patients in
prior to skin incision and the continuous
then a continuous infusion group but in
infusion so as to receive only 3/10 in the
1 g every 6 hr for 18 hr intermittent group.
(n = 10)
Ferreira et al. Cefuroxime 1.5 g on CPB group Membrane Although

(379) induction then 750 mg cooled to [cefuroxime] 50%
every 6 hr for 24 hr 28°C lower on initiation of
CPB Group (n = 10) CPB than at
OPCAB group (n = 9) equivalent time point
for OPCAB, there
was a large degree
of variability and no
statistically
significant difference
between groups
overall.
t1/2β (2.2 vs. 2.3 hr),
Vd (0.3 vs. 0.4 L/kg),
Cl (1.7 vs. 1.6 m
L/kg/min).
On- vs. off-pump not
different between
groups.
Subtherapeutic
concentrations
observed following
termination of
surgery.
Knoderer et al. Cefuroxime 25 mg/kg 27°C NA PK best described

(459) prior to skin incision and by two-compartment
12.5 mg/kg added to PK model.
pump priming solution Cl 0.04 L/hr/kg, Vdss
Pediatric population (n = 0.21 L/kg, Vdc 0.08
15) median age 11 mo L/kg, t1/2β 3.76 hr.
and weight 9.5 kg
Prime dose not
required to maintain
[cefuroxime] above
MIC for
Staphylococcus sp.
Kosaka et al. Cefazolin 2 g at 33°C-34°C NA Binding to Maquet

(388) induction, then 1 g BC-140
every 6 hr for 24 hr and Hemoconcentrator
1 g added to pump not observed.
priming solution in CPB Free [cefazolin]
group. below threshold of 4
On CPB Group (n = 12) μg/mL in patients
with CrCl >50 mL/min, with CrCl >50
(n = 12) with CrCl 10-49 mL/min.
mL/min [cefazolin] ↑ in CPB
Off CPB (n = 9) with group prior to
CrCl >50 mL/min (n = 5) second dose.
with CrCl 10-49 mL/min Vd ↑ (11.5 vs. 7.6 L),
t1/2β ↓ (2.7 vs. 5.8
hr), Cl ↑ (3.1 vs. 1.2
mL/min) in group
with CrCl > 50
mL/min. Shorter
dosing interval
recommended when
CrCl > 50 mL/min.
Pojar et al. (460) Cefuroxime 1.5 g at NA D903 AVANT [cefuroxime] in

induction of anesthesia, Membrane tissue mirrored
following administration (Dideco) plasma with both
of protamine and at 8 hr being above the MIC
postoperatively (n = 11) for most relevant
pathogens.
[cefuroxime]
decreased
throughout CPB but
above therapeutic
levels.
Fluoroquinolones
Mertes et al. Group 1: Ciprofloxacin 28°C Shiley S100A [ciprofloxacin] ↑ in
(461) 400 mg IV at 12, 6, 3, or Membrane Group 2 multiple
1 hr preoperatively, or dose regime.
on arrival in OR, at Good penetration to
induction, or at skin myocardium, valve,
incision (n = 18) and bone tissue but
Group 2: Ciprofloxacin poor and delayed
750 mg PO every 12 hr penetration into fat.
for 48 hr + 400 mg iv as
for Group 1 (n = 18)
Pryka et al. Ciprofloxacin 300 mg 24 23°C Sarns S-100 HED CI ↓, Vd ↓, t1/2β ↑

(462) hr preoperatively, during Membrane during surgery.
surgery and 48-72 hr
postoperatively (n = 5)

(374) g on induction, then A/S) 55%, [ciprofloxacin]
25) [clindamycin] ↓ by
hr (n = 25). subtherapeutic if
Group 3: Clindamycin procedures lasted
900 mg on induction, >298 min.
(n = 25). in [clindamycin]
group.
Masuda et al. Flomoxef 30 mg/kg at 28°C-34°C NA PK model derived to

(196) induction + 1 g (<10 kg) account for MUF.
or 2 g (10 kg) added to [flomoxef] declined
CPB priming solution. biexponentially prior
Pediatric population (n = to CPB, increased
15). during CPB and
Modified ultrafiltration declined
(MUF) employed post- biexponentially post-
CPB. CPB.
Flomoxef removed
by ultrafiltration
which was attributed
to low flomoxef
protein binding.
Metallidis et al. Moxifloxacin 400 mg 1 NA NA Moxifloxacin

(463) hr prior to induction (n = penetration into
8) sternal bone was
41% at 2 hr and
48% at 5 hr.
[moxifloxacin] was
above MIC for most
relevant pathogens
in both plasma and
bone.
Wiesner et al. Moxifloxacin 400 mg at 32°C CompactFlo EVO In vitro experiments

(464) induction of anesthesia membrane (Sorin) did not demonstrate
(n = 14) any sequestration in
membrane
oxygenator.
Vdss 2.0 L/kg, Cl
11.2 L/hr, t1/2β 9.47
hr.
Glycopeptides
Daschner et al. Vancomycin 15 mg/kg 25°C NA Adequate valve,

(465) up to 7 hr before muscle, and
surgery (n = 33) subcutaneous tissue
and blood levels
achieved.
Klamerus et al. Vancomycin 1 gm + 27°C Shiley S-100A Renal Cl ↓ during

(443) netilmicin 3 mg/kg iv (n HED CPB.
= 10) At initiation of CPB
[vancomycin] ↓ 17%,
[netilmicin] ↓ 29%,
[netilmicin]
rebounded over time
during CPB.
[vancomycin] ↑ with
removal of the aortic
cross-clamp.
Massias et al. Vancomycin 10 mg/kg NA NA [vancomycin] stable

(466) every 8 hr for 48 hr and indicative of
preoperatively.Group 1 steadystate
(n = 5) had sternal bone conditions.
sampling pre-CPB and Vc 0.19-0.24 L/kg,
Group 2 (n = 5) had t1/2β 8.3-18.5 hr.
sternal bone sampling Sternal
post-CPB [vancomycin] not
different between
groups.
Hatzopoulos et Vancomycin 15 mg/kg 1 19°C Shiley S-070/S OR Cl 2.94 mL/min/kg,

al. (389) hr before surgery (n = 6) Sci-Med 1500 Vdss 0.59 L/kg, t1/2β
Pediatric population Membrane 2.4 hr.
[vancomycin] ↓ by
44.5% at initiation of
CPB but still above
MIC for MRSA.
Martin et al. Vancomycin 15 mg/kg 28°C NA [vancomycin] higher
(467) prior to skin incision in Group 2 on
Group 1: (n = 10) initiation of CPB and
Vancomycin 15 mg/kg at remained higher
skin incision and 7.5 until 8 hr
mg/kg at start of CPB postoperatively.
Group 2: (n = 10) Tissue penetration
Both groups received 10 into sternal fat and
mg/kg at 8, 16, and 24 bone, pericardium,
hr postoperatively and right atrium did
not differ between
the two groups.
Vuorisalo et al. Group 1: Cefuroxime 1.5 NA NA [cefuroxime]

(456) g preoperatively + 0.75 therapeutic for all
g at 8 and 16 hr groups.
postoperatively (n = 10) [vancomycin]
Group 2: Cefuroxime 1.5 therapeutic for all
g preoperatively + 0.75 groups.
g 1 hr after initiation of One sternal wound
CPB and at 8 and 16 hr infection Group 1.
postoperative (n = 10) One
Group 3: Cefuroxime 3 g Staphylococcus
preoperatively (10) aureus infection and
Group 4: Vancomycin 1 death in Group 3.
g preoperatively and at
12 hr postoperatively (n
= 10)
Group 5: Vancomycin 1
g preoperatively, 0.5 g 1
hr after initiation of CPB,
and 1 g at 12 hr
postoperatively (n = 10)
Group 6: Vancomycin
1.5 g at induction (n =
10)
Miglioli et al. Vancomycin 15 mg/kg 27°C Monolith (Sorin) [vancomycin] ↓ 41%

(468) prior to CPB (n = 10) 5 min after initiation
of CPB.
[vancomycin] fitted
to two-compartment
PK model.
Measured
[vancomycin]
concentration
always below
expected
concentration but
[vancomycin] still
above MIC.
Vd ↑ after CPB.
Kitzes-Cohen et Vancomycin 15 mg/kg 1 32°C Dideco Mirandola [vancomycin]

al. (376) hr before skin incision (n 1300 Membrane therapeutic
= 15) (Medtronic) throughout surgery.
Vd, t1/2β not affected
by CPB.
[vancomycin] ↓ by
65% on initiation of
CPB. [vancomycin]
in bone,
pericardium, heart,
and fat tissue at
times
subtherapeutic.
Krivoy et al. Vancomycin 1 g at 32°C SpiralGold Two-compartment

(185) induction (n = 11) Membrane PK model employed.
(Baxter/Bentley) Sequestration of
vancomycin by the
oxygenator
observed.
Vd ↑, CI ↑, t1/2β ↑.
[vancomycin] ↓ 11%
on initiation of CPB.
Desmond et al. Topical vancomycin 500 NA NA Significant

(469) mg as powder or absorption
solution applied to observed.
sternum at sternal Trough
wound closure (n = 14) [vancomycin] 3 mg/L
in plasma and 24
mg/L in urine.
[vancomycin] below
MIC for
Staphylococcus sp.
Garcia et al. Vancomycin 1 g 1 hr 30°C Optima XP VVR [vancomycin] ↓ 38%

(186) preoperatively (n = 18) (Cobe) at initiation of CPB.
Cl ↑ post-CPB.
Vd ↑ during CPB by
58%. [vancomycin]
above MIC.
Cotogni et al. Vancomycin 1 g given 30°C-32°C NA No difference in

(378) prior to skin incision in [vancomycin] over
215 patients undergoing time between
CPB and 21 undergoing groups including
OPCAB CPB interval.
In CPB group
t1/2β ↑ (4.03 vs. 2.82
hr), Vd (31 vs. 28.2
L), and Cl (6.23 vs.
7.05 L/hr) were not
significantly
different.
Oxazolidinones
Metallidis et al. Linezolid 600 mg at NA NA Linezolid penetration

(470) induction (n = 8) into sternal bone 44
% at 2 hr and 32%
at 5 hr.
Sternal bone
[linezolid] was below
MIC for relevant
organisms despite
[linezolid] within
therapeutic range.
Shime et al. Vancomycin 15 mg/kg 25°C-30°C SAFE MICRO Dose added to CPB
(471) preoperatively, in the membrane priming solution
priming solution, at ICU oxygenator (Senko maintained
admission and every 8 Medical Industry [vancomycin] at
hr for 48 hr (n = 11) Co) + initiation of CPB with
Teicoplanin 8 mg/kg Hemodiafiltration 77% ↓ during CPB.
preoperatively, in the circuit which Dose added to
priming solution, at ICU consisted of a priming solution
admission, and every 24 dialysis membrane maintained
hr for 48 hr (n = 11) of polymethyl [teicoplanin] at start
Pediatric population. methacrylate of CPB with 53% ↓
(HEMOFEEL CH- during CPB.
0.6N, Toray) Patients treated with
teicoplanin had ↑
[teicoplanin] and a
greater number of
patients had
[teicoplanin]
concentrations
above the MIC for
most susceptible
pathogens.
Farber et al. Vancomycin 15 mg/kg 20°C-28°C BOS-10 (Bentley) [vancomycin] ↓ from

(472) prior to CPB then 10 bubble 12 μg/mL pre-CPB
mg/kg every 8 hr for 48 to 7 μg/mL during
hr (n = 10) CPB.
Penicillins

every 4 hr for 24 hr (n = adequate in cardiac
37) tissue but
at induction and every 4 insufficient in 13% of
hr for 24 hr (34) heart specimens.
Group 3: Fusidic acid Cl ↓ for cefamandole
580 mg over 2 hr, then and cloxacillin
every 8 hr for 24 hr (n = during CPB.
29)
Pieper et al. Cloxacillin 2 g + 25°C NA Antibiotic

(473) benzylpenicillin 6 g at concentrations
induction and 4 hr (n = greater than MIC for
10) Staphylococcus
aureus and
Staphylococcus
epidermidis in valve
and atrial tissue.
Cl ↓ for both
antibiotics.
Lehot et al. Oxacillin 50 mg/kg + 25°C BOS10 Bentley No uptake of either

(369) Group 1: Tobramycin 1 Bubble agent by
mg/kg (n = 30) oxygenator.
Group 2: Tobramycin 2 [oxacillin]
mg/kg (n = 15) therapeutic.
[tobramycin]
therapeutic only in
the high-dose group.
Kullberg et al. Cloxacillin 1 g at 26°C Sarns Hollow Fibre Therapeutic

(474) induction + 1 g in pump Membrane concentrations
priming solution (n = 10) achieved at the
beginning but not at
the end of CPB
(duration ˜120 min)
Lonsky et al. Group 1: Oxacillin 2 g (n 28°C Polystan [oxacillin]

(475) = 15) Venotherm Bubble subtherapeutic at
Group 2: Cefazolin 1 g 180 min and for
(n = 15) at induction and [cefazolin] at 150
at end of CPB min.
Duration of CPB
extended beyond
the effective
duration of antibiotic
coverage in some
patients.
Heylen et al. Flucloxacillin 500 mg at NA NA Toxic [gentamicin] in

(380) induction, then 500 mg 15 patients.
4 times daily for 48 hr + Postoperative
gentamicin 1.5 mg/kg at concentrations could
induction and 80 mg 3 not be predicted
times daily for 48 hr based on
adjusted as necessary preoperative patient
for CrCl (n = 95) characteristics.
Lewis et al. Gentamicin 4 mg/kg at 28°C NA Gentamicin CI ↓ on

(381) induction + flucloxacillin CPB.
1 g at induction, then t1/2β ↑ with ↑
every 6 hr for 48 hr (n = duration of CPB. 3/9
9) patients had
[gentamicin] > 1
mg/L at 24 hr with
potential for toxicity.
Vargas et al. Flucloxacillin 30 mg/kg NA NA [flucloxacillin] ↓

(226) Amoxicillin 30 mg/kg at 42.5% on CPB.
induction and then [amoxacillin] ↓
every 8 hr for 48 hr (n = 36.2% on CPB.
11). Concentrations in
Pediatric population plasma and muscle
tissue above MIC.
t1/2β ↑ for both
drugs.
Cl ↓ for both drugs.
Vd ↑ for both drugs.
Other

every 4 hr for 24 hr (n = adequate in cardiac
37) tissue but
at induction and every 4 insufficient in 13% of
hr for 24 hr (n = 34) heart tissue
Group 3: Fusidic acid specimens.
580 mg iv over 2 hr, Cl ↓ for cefamandole
then every 8 hr for 24 hr and cloxacillin
(n = 29) during CPB.

(374) g at induction, then A/S) 55%, [ciprofloxacin]
25). [clindamycin] ↓ by
hr (n = 25). inadequate for
Group 3: Clindamycin procedures lasting
900 mg at induction, longer than 298 min.
(n = 25) in [clindamycin]
group.
Kanellakopoulou Group 1: Fusidic acid 1 NA NA [fusidic acid] high in

et al. (476) g at induction (n = 15) plasma and equal to
Group 2: Cefepime 2 g serum in tissues
at induction (n = 15) including
Blood and tissue myocardium and
samples taken pericardium
throughout
procedure.
[cefepime] above
MIC for most
relevant pathogens
in serum and tissues
including valves and
myocardium and
peaked 2-4 hr after
administration.
Nguyen et al. Daptomycin 6 mg/kg (n NA NA [daptomycin] ↓ 37%

(477) = 15) at initiation of CPB
when compared to
Cmax.
Cl = 10.8 mL/hr/kg,
t1/2β = 13.8 hr, Vdc =
0.21 L/kg.
[daptomycin] above
MIC for most
responsible
pathogens
throughout
procedure.
Antifibrinolytics
Aprotinin
Bennett- Aprotinin 2 million KIU at 28°C Membrane [aprotinin]

Guerrero et al. incision + 0.5 million maintained at >179
(478) KIU/hr for 4 hr on KIU/mL throughout
initiation of CPB + 2 × procedure.
106 units added to CPB [aprotinin] ˜200
priming solution (n = KIU/mL required to
14). inhibit kallikrein.
O'Connor et al. Aprotinin 2 million KIU 28°C NA Aprotinin Cl ↓ as

(479) over 30 min at incision, CrCl ↑.
then 0.25 million KIU/hr t1/2β ↑ in patients
until chest closure (n = with renal failure.
29)
Beath et al. Aprotinin: NA Univox Membrane Large variation in
(480) Full dose: 2 million KIU (Bentley) [aprotinin].
(280 mg) bolus, then 0.5 [aprotinin] peaked at
million KIU/hr (70 mg/hr) 5 min after initiation
+ 2 million (280 mg) KIU of CPB, then
added to pump priming declined.
solution (n = 10) Weight-based
Half dose: 1 million KIU relation to [aprotinin]
(140 mg) bolus, then in full but not half-
0.25 million KIU/hr (35 dose group.
mg/hr) + 1 million KIU [aprotinin] <200
(140 mg) added to pump KIU/mL in 70% of
priming solution (n = 10) patients during CPB
Control (n = 10) with half dose
regimen.
Suggested dosing
scheme: 3.5 mg/kg
bolus + 70 mg to
pump prime + 3.5
mg/kg/hr × 1 hr,
then 1 mg/kg/hr
Van Norman et Aprotinin: NA Membrane [aprotinin] higher in

al. (194) Regimen A: 2 million Groups 1 and 3.
KIU before incision, then [aprotinin] not
0.5 million KIU/hr until altered by
protamine and 2 million hemofiltration.
KIU added to pump [aprotinin] below
priming solution. 200 KIU/mL in
Regimen B: 1 million Groups 2 and 4.
KIU before incision, 0.25
KIU/hr until protamine
and 1 million KIU added
to pump priming
solution.
Group 1: A +
hemofiltration (n = 5)
Group 2: B +
hemofiltration (n = 5)
using a Biofilter TM140
(Research Medical Inc.)
Group 3: A alone (n = 5)
Group 4: B alone (n = 5)
Royston et al. Aprotinin: Weight-based 28°C Hollow-fiber Larger variability in

(481) 40,000 KIU/kg bolus + Membrane [aprotinin] in fixed-
40,000 KIU/kg added to dose group.
pump priming solution (n NSD in [aprotinin]
= 10). between groups.
Fixed dose: 2 million No patient had
KIU as bolus, 0.5 million [aprotinin] >200
KIU/hr + 2 million KIU KIU/mL at end of
added to pump priming CPB.
solution (n = 20).
Tae et al. (229) Aprotinin 25,000 KIU/kg NA NA Two-compartment

bolus, 35,000 KIU PK model adjusted
added to pump priming for CPB best fit of
solution, 12,500 the data.
KIU/kg/hr until 2 hr after Cl ↑ on CPB (687
ICU arrival. vs. 350 mL/hr pre-
Pediatric population of and post-CPB), Vd ↑
23 neonates and 4 on CPB (1,577 vs.
children <100 d. 1,352 mL).
Suggested dosage
regimen
50,000 KIU/kg
bolus, 40,000 KIU
added to pump
priming solution,
54,000 KIU/kg/hr for
3.4 hr (time from
infusion initiation to
CPB stop), and
10,000 KIU/kg/hr for
3.4 hr (time from
CPB stop to
termination of
continuous infusion).
Nuttal et al. Aprotinin to achieve: NA NA [aprotinin] variability

(482) 100 KIU/mL: 1.75 mg/kg less for weight-
bolus, 35 mg added to adjusted regimens
pump priming solution, 2 but still
mg/kg/hr for 1 hr, then considerable.
0.5 mg/kg/hr (n = 10) Target levels
150 KIU/mL: 2.6 mg/kg achieved for
bolus, 53 mg added to suggested dosing
pump priming solution, regimens.
2.6 mg/kg/hr for 1 hr, [aprotinin] seldom
then 0.75 mg/kg/hr (n = >200 KIU/mL for any
10) dosing regimen.
200 KIU/mL: 3.5 mg/kg
bolus, 70 mg added to
pump priming solution,
3.5 mg/kg/hr for 1 hr,
then 1 mg/kg/hr (n = 10)
250 KIU/mL: 4.4 mg/kg
bolus, 88 mg added to
pump priming solution,
4.4 mg/kg/hr for 1 hr,
then 1.25 mg/kg/hr (n =
10)
Full dose: 280 mg (2
million KIU) bolus, then
500,000 KIU/hr (70
mg/hr) + 2 million KIU
(280 mg) added to pump
priming solution (n =
10).
Oliver et al. Aprotinin 25,000 KIU/kg Variable Sci-Med [aprotinin] affected

(555) bolus, 35,000 KIU to Membrane by age and weight.
pump priming solution, Vd ↑ as weight ↓.
12,500 KIU/kg/hr (n =
30)
Pediatric population
Lysine analogs
Bennett- ε-Aminocaproic acid 28°C Membrane [ε-aminocaproic

Guerrero et al. (EACA) 150 mg/kg on acid] maintained at
(483) incision + 30 mg/kg for 4 >130 μg/mL
hr on initiation of CPB (n throughout
= 27) procedure in almost
all patients.
Large variability in
[ε-aminocaproic
acid].
[ε-aminocaproic
acid] > 130 μg/mL
required to inhibit
fibrinolysis.
Butterworth et ε-Aminocaproic acid 28°C Turbo 440 Weight-adjusted

al. (484) (EACA) 30 mg/kg (n = 7) Membrane (Sarns) two-compartment
or 100 mg/kg after PK model provided
protamine (n = 6) or 100 adequate
mg/kg bolus, then 10 parameters.
mg/kg/hr for 4 hr after Vd ↑, t1/2β ↑ on
heparin (n = 7) initiation of CPB.
Recommended
infusion scheme to
obtain 2 × ED50
(130 μg/mL) = 50
μg/kg over 20 min,
then 25 mg/kg/hr.
Butterworth et ε-Aminocaproic acid 31°C NA [ε-aminocaproic

al. (485) (EACA) 50 mg/hr over acid] > 130 mg/L but
20 min, then 25 less than predicted.
mg/kg/hr × 4 hr No gender effect.
Men (n = 10) Revised two-
Women (n = 10) compartment PK
model developed.
Suggested dosing
scheme: 70 mg/kg
over 20 min, then 30
mg/kg/hr.
Fiechtner et al. Tranexamic acid (TA) NA Univox Membrane [tranexamic acid]

(486) 10 mg/kg over 20 min, (Bentley) >ED80 (10 μg/mL)
then 1 mg/kg/hr until 2 required to inhibit
hr after ICU arrival (n = plasmin during CPB
19) in all patients.
[tranexamic acid]
>16 μg/mL required
to protect platelets
in 16/19 patients.
[tranexamic acid] ↑
in presence of renal
insufficiency.
Suggested dosing
scheme to achieve
>20 μg/mL:
5.4 mg/kg loading
dose, 50 mg in 2.5 L
CPB priming
solution and 5
mg/kg/hr infusion.
Dowd et al. Tranexamic Acid (TA): 33°C Maxima Membrane PK best described
(397,486) 50 mg/kg (n = 11) 100 (Medtronic) by a two-
mg/kg (n = 10) 10 mg/kg compartment model.
bolus, then 1 mg/kg/hr Cl ↓, Vd ↑ on
(n = 10) initiation of CPB.
Dosing scheme to
permit [TA] >127
μM/mL (100%
inhibition of
fibrinolysis):
12.5 mg/kg bolus, 1
mg/kg to pump
priming solution, 6.5
mg/kg/hr infusion.
Ririe et al. (227) ε-Aminocaproic acid 28°C Turbo 440 PK best described
(EACA) 50 mg/kg after Membrane (Sarns) by a two-
heparin administration, compartment model
50 mg/kg on initiation of adjusted for weight
CPB, and 50 mg/kg and CPB.
post-CPB (n = 8) [ε-aminocaproic
Pediatric population acid] ↓ 46% at start
of CPB.
Suggested dosing
regimen to achieve
target [ε-
aminocaproic acid]
of 260 μg/mL:
5 mg/kg over 10
min, 75 mg/kg
added to pump
priming solution, 75
mg/kg/hr as infusion
In children:
Vi ↑, CI ↑, t1/2β ↓ with
adjustments for CPB
Kluger et al. ε-Aminocaproic acid 30°C Optima XP (Cobe) EACA reduced
(487) (EACA) blood loss vs.
Placebo (n = 30) placebo.
Postheparin 150 mg/kg, No difference
then 15 mg/kg/hr (n = between the two
30) EACA treatment
Preincision 150 mg/kg, groups.
then 15 mg/kg/hr (n =
28)
Sharma et al. Tranexamic acid (TA) 34°C NA PK best described

(488) 30 mg/kg bolus over 15 by a two-
min, then 16 mg/kg/hr compartment model.
until chest closure with All patients had
2 mg/kg added to pump [tranexamic acid]
priming solution. above the threshold
for antifibrinolytic
activity of 100
μg/mL.
Elimination rate
constant during
surgery 0.77/hr and
0.65/hr during CPB.
Cl during surgery
(1.73 mL/min/kg)
and during CPB
(1.46 mL/min/kg)
equivalent to a
normal glomerular
filtration rate.
Bojko et al. Tranexamic acid (TA) NA NA [tranexamic acid]

(489) 30 mg/kg bolus over 15 variable during CPB
min, then 16 mg/kg/hr with a mean
until chest closure with concentration of 135
2 mg/kg added to pump μg/mL and range
priming solution (n = 16) 70-197 μg/mL with
target set at 125
μg/mL.
Following
discontinuation of
infusion there was
variable reduction in
plasma
concentrations with
mean value at 24 hr
of 13 μg/mL.
Grassin-Delyle Group 1: Tranexamic 33°C NA PK best described

et al. (398) acid (TA) 10 mg/kg by a two-
bolus, then 1 mg/kg/hr compartment open
plus 1 mg/kg added to model.
pump priming solution (n [tranexamic acid] in
= 30) the low-dose group
Group 2: TA 30 mg/kg 15.4-82.5 μg/L while
bolus the 16 mg/kg/hr in the high-dose
plus 2 mg/kg added to group >114 μg/L.
pump priming solution (n Body mass most
= 31) important covariate.
Cl 4.8 L/hr 70/kg, Vc
6.6 L 70/kg.
Suggested dosing
scheme:
46 mg/kg for 1 hr,
then
11 mg/kg/hr for
50-75 kg weight
10 mg/kg/hr for
75-100 kg
9 mg/kg/hr for
100-125 kg
Grassin-Delyle Tranexamic acid (TA) 35.4°C-37°C Kids D101 Capiox PK best described
et al. (399) Group 1: Continuous (n Baby FX by a two-
= 9) TA 10 mg/kg as compartment model.
bolus then 1 mg/kg/hr [tranexamic acid] in
plus 10 mg/kg added to the discontinuous
pump priming solution. group below 20
Group 2: Discontinuous μg/mL target prior to
(n = 12) TA 10 mg/kg as CPB. Continuous
bolus pre-CPB, 10 infusion
mg/kg post-CPB and 10 recommended.
mg/kg added to pump Weight-based
priming solution. infusion scheme
Pediatric population provided based on
randomized and observed increased
stratified by weight. central and
peripheral Vd and
decreased Cl which
varied with body
weight.
Cl 0.34-1.61 L/hr, Vc
1-8 L, t1/2β 8.4-14.1
hr.
Anticoagulants
Heparin
Arsenault et al. Hepalean (n = 10) vs. NA NA Equivalent weight

(490) PPC heparin (n = 11) adjusted dosing of
for anticoagulation PPC heparin
during CPB demonstrated
decreased
pharmacodynamic
effect with
decreased ACT,
requiring higher
amounts to obtain
equivalent
pharmacodynamic
effect.
Protamine dosing
requirements were
not different but
postoperative aPTT
was increased in the
PPC group.
Davidson et al. Heparin 400 U/kg + 18°C-32°C NA [heparin] measured

(491) 2,000 U added to pump 3.4 U/mL post bolus
priming solution (n = (below target of 4
11). U/mL) and declined
Neonates to <2 during CPB.
Ignjatovic et al. Heparin 300 IU units 28°C-32°C Terumo RX-05, Heparin

(492) (porcine) as bolus, then RX-10 or RX-18 concentrations
sufficient to maintain Membrane variable between
ACT >400 s. Protamine patients.
reversal of heparin Activated partial
effect. Aprotinin thromboplastin time
(administered to 72%) at (APTT), thrombin
discretion of clotting time (TCT),
anesthesiologist. and activated
Blood added to CPB clotting time (ACT)
priming solution. all elevated but only
Pediatric population (n = ACT useful as
60) undergoing CPB. measure of heparin
effect intra-
operatively.
Anti-FXa (-AT) and
Anti-FXa (+AT) not
accurate assays in
this population.
Thrombin levels
below normal post-
CPB even following
protamine
administration.
Tissue Factor
Pathway active in
ongoing thrombin
inhibition following
CPB.
Bivalirudin
Koster et al. Bivalirudin 1 mg/kg, NA Affinity Oxygenator As compared to no

(493) then 2.5 mg/kg/hr until ultrafiltration, use of
end of CPB plus 50 mg zero-based modified
added to pump priming ultrafiltration
solution. (ZBMUF) with HPH
Five groups (n = 7) 700 Mintech
each differing by the Hemocor device ↓
strategy of ultrafiltration t1/2β from 0.6 to 0.47
employed at end of CPB hr and was
to terminate drug effect. associated with
reduced blood loss.
Glycoprotein IIB/IIIA antagonists
Koster et al. Tirofiban added to CPB NA Monolyth (Sorin) [tirofiban] ↓ in all

(195) circuit to achieve [TIRO] Membrane groups, i.e., tirofiban
= 200 ng/mL (n = 9) 1. Hospal Arylane is capable of being
In vitro study H4 eliminated by
2. Minntech filtration.
Hemocor HPH t1/2β ↓ as dose ↑.
700
(Hemofilters)
3. ASAHI
Plasmaflow OP
(Plasmapheresis
filter)
β-Adrenergic receptor blocking agents
Esmolol
De Bruijn et al. Esmolol given as a NA NA t1/2β 9.9 min, Vd(1.9

(494) timed infusion of 100- L/kg) ↓, Cl (128
500 μg/kg/min (n = 19) mL/kg/min) ↓ relative
Pre-CPB study. to healthy patients.
(All study subjects
receiving chronic β-
receptor blocking
agents.)
Jacobs et al. Esmolol 0.5 mg/kg 30 26°C COBE CML [esmolol] ↑ on CPB
(125) min pre-CPB + 100 Membrane during hypothermia.
μg/kg/min (n = 10) Independent effect
of temperature and
infusion duration on
[esmolol].
No uptake by
oxygenator.
Propranolol
McAllister et al. Propranolol 40-320 27°C NA [propranolol] ↑

(208) mg/d discontinued 12 hr during hypothermic
preoperatively (n = 12) CPB after initial ↓ at
+ dog studies initiation of CPB.
Accompanying dog
studies suggested
reduction in Cl due
to effect of
hypothermia on in
vivo metabolic
activity.
Wood et al. Propranolol 80-240 NA NA Heparin

(403) mg/d discontinued over administration
48 hr; last dose at least doubled the
9 hr preoperative (n = 7) [propranolol] free
fraction (7%-14%).
Protamine
administration ↓ the
[propranolol] free
fraction from 13% to
9%.
No change in
[propranolol] free
fraction during CPB.
Free fatty acid levels
↑ with heparin
administration.
Plachetka et al. Group 1: Propranolol 31°C NA [propranolol] ↓ 60%

(209) 0.1 mg/kg at induction with onset of CPB
(n = 7) and ↑ 57% at CPB
Group 2: Placebo (n = termination.
7) t1/2β ↑ from 2 to 5.5
(All patients taking hr.
propranolol chronically).
Sill et al. (402) Group 1: Chronic 30°C NA [propranolol] ↓ 55%-

therapy of propranolol 71% during initiation
40-240 mg/d of CPB. Adverse
discontinued hemodynamic
preoperatively (n = 14) responses
Group 2: Chronic correlated with
therapy + propranolol reduced
bolus 2-7 mg + infusion [propranolol].
0.4-0.9 μg/kg/min (n =
12)
Carmona et al. Propranolol 32°C NA t1/2β ↑ by 236%, Vd

(404) 20-80 mg preoperatively ↑ 208%, Cl not
10 mg 18 hr changed.
postoperatively (n = 11). No correlation
(All patients receiving between duration of
chronic therapy with CPB or temperature
propranolol). with magnitude of
alteration of PK.
Atenolol
Leite et al. (405) Patients were receiving NA NA [atenolol] ↓ over time

atenolol 25-100 mg daily in the OFF-CPB
and undergoing CABG group and were
with ON-CPB (n = 11) lower after surgery
vs. OFF-CPB (n = 8). as compared to ON-
Patients with EF < 35% CPB group.
or Cr > 1.4 mg/dL (124 In the ON-CPB
mmol/dL) excluded. group [atenolol] ↑ at
end of CPB to pre-
CPB levels.
Carmona et al. Patients were receiving 32°C-34°C Oxim II-34 Ultra Propranolol: t1/2β ↑
(406) chronic therapy with (Edwards Life from 5.4 to 11.5 hr,
propranolol (80-240 Sciences) Vdss ↑ from 8.7 to
mg/d) and atenolol (25- membrane 19.3 L/kg, Cl was
100 mg/d) unchanged (16.1-
Propranolol 10 mg (n = 17.2 mL/min/kg)
11) preoperatively or Atenolol: t1/2β (11.2-
Atenolol 25 mg
11.4 hr), Vdss (2.9-
preoperatively (n = 8)
3.8 L/kg), and Cl
(3.6-4.7 mL/min/kg)
were unchanged.
Landiolol
Matsumoto et al. Landiolol 10 μg/kg/min NA NA [landiolol] ↓ following

(407) post induction until heparin
CPB. administration.
t1/2β not different
from normal
volunteers
suggesting that the
observed reduction
in hepatic blood flow
had minimal effect
on landiolol Cl.
Calcium channel blocking agents
Katz et al. (184) Nifedipine 10-20 mg q8h 23°C Shiley M2000 [nifedipine] fell
chronically (n = 10) + in Membrane following initiation of
vitro study CPB.
[nifedipine]
subtherapeutic in
some patients pre-
and at end of CPB.
No drug binding to
oxygenator.
Ahonen et al. Diltiazem 0.1 mg/kg/hr 32°C-34°C NA As compared to

(495) started pre-CPB (n = placebo, Diltiazem ↑
15) AUC for midazolam
Placebo (n = 15) + 15% and alfentanil
Midazolam 0.1 μg/kg/hr 24%.
and Alfentanil 0.1 t1/2β ↑ for midazolam
μg/kg/hr until skin 43% and for
closure alfentanil ↑ 50%.
[diltiazem] did not
change during CPB.
Changes in
[midazolam] and
[alfentanil] attributed
to inhibition of
metabolism by CYP
3A by diltiazem.
Finegan et al. Diltiazem 60 or 90 mg NA NA Dose-dependent

(496) the day before surgery PK.
and on the day of [diltiazem] ↓ 50% at
surgery (n = 10) initiation of CPB.
[diltiazem] free
fraction ↑ 100%
while on CPB.
Metabolite levels
unchanged during
CPB.
Vuylsteke et al. Clevidipine 30°C Maxima PRFT Cl ↓ during CPB,

(123) 0.7 μg/kg/min adjusted Membrane Vdss not changed,
to treat hemodynamics. (Medtronic) t1/2β ↑.
Max 22 μg/kg/min (n = Pulmonary
17) extraction negligible
(8%).
˜50% reduction in
infusion rate to
maintain MAP pre-
vs. on-CPB.
Effects attributed to
hypothermia-
induced reduction in
metabolism.
Bergman et al. Diltiazem 0.25 mg/kg 30°C Membrane [diltiazem] ↓ on CPB.
(497) bolus, then 1.7 [diltiazem] ↑ post-
μg/kg/min (n = 12) CPB.
Placebo (n = 12) Cl ↑.
Hynynen et al. Nimodipine 15 mg/kg/hr 28°C D703 CompactFlo Unbound fraction ↑

(498) (n = 7) Membrane with heparin
Nimodipine 30 mg/kg/hr (Dideco) administration.
(n = 7) Total [nimodipine] ↓
Infusion starting night on CPB but
before surgery until unbound
second morning [nimodipine] ↑.
following CPB Cl ↓.
+ in vitro study In vitro study
showed significant
binding to CPB
circuit which was
attenuated by
adding blood to
priming solution.
Boulieu et al. Diltiazem 180-360 mg/d. NA BOS 10 (Bentley) Diltiazem

(499) 60 mg prior to induction. bubble sequestration in
(n = 12) oxygenator not
evident. [diltiazem] ↓
during CPB.
No lung
sequestration
evident.
Digoxin
Carruthers et al. Group 1: Digoxin 0.25 NA Rygg-Kyvsgaard [digoxin] ↓ if drug

(500) mg discontinued 24 hr Bubble stopped 48 vs. 24 hr
preoperatively (n = 8). preoperatively and ↓
Group 2: Digoxin 0.25 in Group 4 vs.
mg discontinued 48 hr Group 1. [digoxin] ↓
preoperatively (n = 8) at start of CPB and
Group 3: Digoxin 0.5 mg ↑ during CPB.
discontinued 24 hr Digoxin
preoperatively (n = 8) concentrated in the
Group 4: Digoxin 0.5 mg heart with
discontinued 48 hr concentration in the
preoperatively (n = 8) papillary muscle
higher than in atrial
muscle.
No correlation of
tissue to plasma
levels.
Atrial levels stable
during CPB.
Koren et al. Digoxin to achieve 25 20°C Sci-Med 0800-2A No binding of

(178) ng/mL in CPB prime in Membrane digoxin to CPB
vitro study apparatus.
Anaokar et al. Digoxin 0.25 mg/d NA Bentley 10 Plus [digoxin] ↓ from 0.94
(501) ON CPB (n = 11) Bubble (Baxter) to 0.56 ng/mL during
OFF CPB (n = 10) CPB and remained
Undergoing MV surgery low post-CPB.
In OFF group there
was no change in
[digoxin].
Glucocorticoid agents
Thompson et al. Group 1: NA NA [methylprednisolone]

(502) Methylprednisolone 30 maintained by
mg/kg (n = 10) second dose given
Group 2: Saline (n = 10) just before CPB.
at induction and just
before CPB
Kong et al. (409) Group 1: 28°C Membrane (5) Converted to

Methylprednisolone Bubble (1) methylprednisolone
Hemisuccinate 1.7-2.4 g rapidly.
in cardioplegia solution Methylprednisolone
(n = 6) PK during cardiac
Group 2: Healthy male surgery:
controls not undergoing Cl 181 mL/hr/kg, Vd
surgery 50.8 mg (n = 6) 1.3 L/kg, t1/2β 7.9 hr.
Compared to
methylprednisolone
PK in normal males:
Cl ↓ 50%, Vd
unchanged, and
t1/2β ↑.
Inotropes including phosphodiesterase III inhibitors
Dopamine
Hayashi et al. Dopamine (n = 48) 28°C Membrane Cl (uptake) of

(415) dopamine by the
lung pre- and post-
CPB demonstrated.
Epinephrine
Oualha et al. Epinephrine infusions NA NA PK best described

(503) (0.01-0.23 μg/kg/min) in by a one-
children (n = 39) at risk compartment model.
for low cardiac output Body weight main
syndrome initiated post- covariate influencing
CPB. Cl.
Pediatric population. Population PK
model derived.
Phosphodiesterase inhibitors
Bailey et al. Group 1: Milrinone 25 23°C COBE CML Dose-related

(504) μg/kg (n = 5) Membrane increases in
Group 2: Milrinone 50 [milrinone] with rapid
μg/kg (n = 5) decline in single-
Group 3: Milrinone 75 dose groups.
μg/kg (n = 5) [milrinone] sustained
Group 4: Milrinone 50 by continuous
μg/kg + 0.5 μg/kg/min at infusion.
rewarming (n = 5) No difference if
Group 5: Milrinone 50 given post-CPB.
μg/kg just after CPB (n
= 5)
CPB does not

substantially alter
milrinone
pharmacokinetics.
Calculation of
contextsensitive
half-time showed
milrinone to be more
rapidly removed
than amrinone if
duration of infusion
<400 min.
Maintenance of
therapeutic levels
(>100 ng/mL)
achieved by bolus +
infusion regimen.
Das et al. (505) Milrinone 50 μg/kg + 0.5 28°C NA Cl ↓ (120 mL/min),

μg/kg/min post-CPB (n Vd (0.3 L/kg) ↑, t1/2β
= 6) (1.69 hr) ↑
vs. those reported
for healthy controls
but were similar to
reports in patients
with CHF.
[milrinone] >100
ng/mL.
Butterworth et Group 1: Milrinone 25 NA NA Milrinone increased

al. (506) μg/kg (n = 10) CO. Phenylephrine
Group 2: Milrinone 50 required to maintain
μg/kg (n = 10) BP in most patients.
Group 3: Milrinone 75 Unable to define a
μg/kg (n = 9) [milrinone] vs. effect
post-CPB relationship.
PK not affected by
dose.
Loading dose of 50
μg/kg
recommended.
DeHert et al. Group 1: Milrinone 20 26°C NA More

(507) μg/kg (n = 10) norepinephrine
Group 2: Milrinone 40 required to maintain
μg/kg (n = 10) + 0.5 BP in high-dose
μg/kg/min group.
20 min before weaning [milrinone] above
from CPB after initial previously predicted
failure to wean levels at all dose
and time intervals.
Cl = 1.4 L/hr for low
dose vs. 4.0 L/hr for
high dose, t1/2β 58
vs. 13 hr,
respectively.
Both clearance and
elimination values
changed over time
likely due to
alterations in renal
function with CPB.
Kikura et al. Milrinone 50 μg/kg bolus 23°C COBE CML [milrinone] for half
(508) (n = 8) Membrane maximum increase
Milrinone 50 μg/kg bolus in velocity of
+ 0.5 μg/kg/min (n = 10) shortening of
Milrinone 75 μg/kg + circumference of the
0.75 μg/kg/min (n = 9) myocardium
Control (n = 10) detected by
After weaning from CPB transesophageal
echocardiography =
139 ng/mL.
All doses of
milrinone effective.
Ramamoorthy et Milrinone: NA NA Two-compartment
al. (413) Small dose: 25 μg/kg pharmacokinetic
bolus, then 0.25 model provided best
μg/kg/min for 30 min, description of data.
then 25 μg/kg bolus and As compared to
increase infusion to 0.5 adults
μg/kg/min (n = 11) Cl ↑
Large dose: 50 μg/kg Vd ↑
bolus, then 0.5 t1/2β ↑
μg/kg/min for 30 min, Pediatric patients
then 25 μg/kg bolus and require higher doses
increase infusion to 0.75 to achieve levels
μg/kg/min (n = 8) comparable to those
+ in vitro study reported in adults.
Pediatric study No significant
binding to CPB
circuit.
Bailey et al. Milrinone: NA NA Three-compartment

(414) Post-CPB 50 μg/kg PK model adjusted
bolus (n = 8) for distribution by
or 50 μg/kg bolus weight and for
followed by 0.5 elimination
μg/kg/min (n = 12) clearance by weight
(Increased to 0.7 and age provided
μg/kg/min in 3 patients) best fit.
Pediatric population Cl ↑ with age.
Suggested dosing
50 μg/kg bolus, then
3 μg/kg/min for 30
min, then
0.5μg/kg/min.
Booker et al. Enoximone NA NA Cl and t1/2β similar

(509) 1 mg/kg bolus 10 min to adults.
before end of CPB, then [enoximone] ↑ in
10 μg/kg/min (n = 20) patients with hepatic
Pediatric study dysfunction.
[enoximone] ↑ in
patients with severe
renal dysfunction.
Pellicer et al. Milrinone 0.5-1 NA NA Cl Milrinone 0.077

(510) μg/kg/min (n = 9) or L/hr/kg
Levosimendan 0.1-0.2 Cl Levosimendan
μg/kg/min (n = 11) 0.67 L/hr/kg
started prior to CPB
Neonates
Tsubokawa et Olprinone 0.2 μg/kg/min 34°C NA Albumin protein

al. (102) starting at time of binding 53%.
surgical incision and No protein binding
continuing until arrival in to α1-
ICU (n = 11) acidglycoprotein.
Free [olprinolone]
increased during
CPB as albumin
levels decreased.
Tsubokawa et Olprinone 0.2 μg/kg/min NA NA Cl 378 mL/min, Vd

al. (102) starting at the time of 40.7 L, t1/2β 97.1
weaning from CPB (n = min Cl dependent on
26) weight and CrCl
while Vd dependent
on weight.
Zuppa et al. Milrinone 100 μg/kg (n = 18°C-20°C NA Modified Two-compartment

(511) 8) or 250 μg/kg (n = 8) + and deep ultrafiltration PK model with MUF
0.5 μg/kg/min hypothermic (MUF) employed as a third
Pediatric patients circulatory post-CPB compartment optimal
undergoing stage-1 arrest PK model.
repair of hypoplastic left MUF ↑ [milrinone]
heart 35% post-CPB.
Postoperative Cl
(0.4 mL/kg/min)
significantly ↓ due to
renal dysfunction.
Intravenous anesthetic agents
Barbiturates
Morgan et al. (5) Thiopental by CACI at <28°C Bentley BOS 10 or [thiopental] ↓ at

induction 1 infusion to COBE Optiflow II initiation of CPB by
maintain a target 50% but unbound
concentration of 15 [thiopental] ↓ by only
μg/mL (n = 7) 24% and recovered
more rapidly than
total levels during
CPB.
Unbound fraction
higher during CPB
and correlated with
albumin levels.
Bjorksten et al. Group 1: Methohexital 1 28°C Bentley BOS 10 [methohexital]:

(99) mg/kg 1 infusion to Bubble or Optiflow Onset of CPB
maintain a target II (Cobe) produced ↓ in total
concentration of 5 mg/L concentration of
(n = 10) ˜40% with gradual ↑
Group 2: Thiopental 2.5 thereafter. Unbound
mg/kg + infusion to fraction ↑ from 27%
maintain a target to 43% pre- vs. on-
concentration of 10 CPB with little
mg/L (n = 10) change in absolute
free drug
concentration level.
[thiopental]: Onset
of CPB produced ↓
in total
concentration of
˜50% with gradual
increase thereafter.
Unbound fraction ↑
from 16% to 30%
pre-vs. on-CPB with
little change in
absolute free
concentration level.
Hynynen et al. Thiopentone 6 mg/kg 29°C Shiley S-100A No differences in PK

(141) before CPB: Bubble parameters in
Group 1: Pulsatile (n = pulsatile vs.
6) nonpulsatile
Group 2: Nonpulsatile (n perfusion groups.
= 7) [thiopental] ↓ 44% at
During CPB: initiation of CPB.
Group 3: Pulsatile (n = No pulmonary
9) sequestration
Group 4: Nonpulsatile detected in vivo but
perfusion (n = 8) + in 50% bound to circuit
vitro study in vitro.
t1/2β ↑ during CPB.
Benzodiazepines
Aaltonen et al. Group 1: Lorazepam 4 30°C NA [lorazepam] ↓ at

(183) mg 1 hr pre-CPB (n = 5) start of CPB, then
Group 2: Lorazepam recovered.
0.03 mg/kg (n = 14) for [lorazepam] ↑ post-
nasal surgery CPB.
t1/2β ↑ from 12
(control population)
to 15 hr (CPB
population).
Boscoe et al. Group 1: Lorazepam NA Bentley BOS 10 [lorazepam] ↓ 27%

(416) night before surgery (n at start of CPB in all
= 12) groups.
Group 2: Lorazepam Only patients given
night before surgery and lorazepam just
at induction (n = 12) before CPB had
Group 3: Lorazepam therapeutic
night before surgery and concentrations (>30
10 min pre-CPB (n = 12) ng/mL) during CPB.
<60 kg = 2 mg
60-80 kg = 3 mg
>80 kg = 4 mg
Harper et al. Group 1: CPB NA NA CPB group had t1/2β

(417) Midazolam 0.3 mg/kg ↑ relative to minor
post-CPB (n = 7) surgery subjects.
Group 2: Minor surgery Cl ↑ with younger
Midazolam 0.3 mg/kg at patients.
induction (n = 25)
Group 3: Major surgery
Midazolam 0.3 mg/kg at
induction (n = 38)
Kanto et al. Group 1: Midazolam NA NA [midazolam] ↓ at

(418) 0.075 mg/kg (n = 6) CPB initiation.
Group 2: Midazolam Following CPB,
0.15 mg/kg (n = 6) at [midazolam] ↑ in the
induction highdose group.
t1/2β ↑ (281 min)
relative to previous
reports in normal
subjects.
Lowry et al. Group 1: Diazepam 5 NA NA [midazolam] stable

(512) mg every 2 hr while [diazepam]
Group 2: Midazolam 5 continued to ↑.
mg every 2 hr for 12 hr Following
post-CPB discontinuation,
[midazolam] ↓
rapidly while
[diazepam] still
remained high.
Mathews et al. Midazolam 0.3 mg/kg NA NA t1/2β ↑ with CPB, Cl

(225) Group 1: Closed ↓ with CPB, No
surgery without CPB (n difference in Vd.
= 6) Postoperative t1/2β
Group 2: Post-CPB (n =
3.1 hr.
6)
Children have Cl ↑
Group 3: Post-CPB +
and t1/2β ↓ relative to
arrest (n = 5)
Group 4: Midazolam reports in adults.
0.05 mg/kg as bolus +
0.05 mg/kg/hr post-CPB
(n = 10)
Children with CHD
Maitre et al. Midazolam 15 mg/hr for NA NA Protein binding

(513) 4 hr postoperative (n = 97%.
12) t1/2β 10.6 hr, Vdss
10.3 L, Cl 0.25
L/min.
t1/2β ↑ and Cl ↓
relative to reports in
normal patients.
Kern et al. (514) Sufentanil to target NA COBE Membrane CACI overestimated

concentration 0.5-3.0 actual [midazolam]
ng/mL by CACI (222) + and [sufentanil] on
midazolam to target CPB.
concentration 25-100
ng/mL by CACI (515) (n
= 17)
Children with CHD
Ng et al. (516) Group 1: Propofol 4 28°C Capiox Terumo [propofol] 1 μg/mL

mg/kg/hr (n = 11) Membrane by 15 min.
Group 2: Concentrations of
Morphine/diazepam (n = cortisol,
10) during CPB epinephrine, and
norepinephrine
lower in propofol
group.
Dawson et al. Group 1: Propofol 1 30°C NA [propofol] ↓ 60% on

(6) mg/kg 1 3 mg/kg/hr (n = CPB. Unbound
12) [propofol] fraction ↑
Group 2: Midazolam 0.2 46%.
mg/kg + 0.07 mg/kg/hr [midazolam] ↓ 53%
(n = 12) on CPB. Unbound
poststernotomy [midazolam] fraction
↑ 50%.
Zomorodi et al. CACI to attain NA NA Three-compartment

(419) [midazolam] of 75-150 model best
and 50 ng/mL adjusted described PK
for effect in ICU (232) + parameters for
[sufentanil] of 1-2, 0.5-1 midazolam.
ng/mL while on CPB, Length of time for
0.3-0.6 ng/mL post- awakening
CPB, and 0.15 ng/mL in dependent on
ICU (517) (n = 63) duration of infusion
in the ICU.
Barr et al. (36) Fentanyl infusion 5 34°C NA No correlation

μg/kg/hr between [fentanyl]
Midazolam infusion 50 and [midazolam]
μg/kg/hr (n = 10) with Bispectral Index
as monitor of depth
of anesthesia.
Barvais et al. Midazolam by CACI to 30°C Membrane (Baxter) PK model

(32) achieve predicted parameters accurate
concentration of 100 pre-CPB but altered
ng/mL (513) during and post-
Sufentanil to predicted CPB.
concentration 1-10
ng/mL depending on
surgical stimulation
(435) (n = 20)
Mathew et al. CACI to maintain effect Mean 32.5°C Cobe CML (Cobe) Hypothermia had
(114) site concentration of independent
fentanyl 2.2 ng/mL (518) anesthetic effect.
and midazolam 60 Age ↓ anesthetic
ng/mL (519) + isoflurane requirements.
(n = 100)
Etomidate
Oduro et al. Etomidate 0.15 mg/kg 1 28°C NA [etomidate] ↓ (33%)

(520) 20 μg/kg/min (n = 6) at start of CPB, ↑
during cooling, ↓
during rewarming
phase.
Post-CPB ↑ due to
transfusion of
oxygenator
contents.
Ketamine
McLean et al. Ketamine 2 mg/kg 1 30°C Bard HF5400 [ketamine] ↓ 33%

(521) infusion of 50 μg/kg/min Membrane with initiation of
(n = 6) CPB, then ↑ during
CPB.
t1/2β = 2.1 hr.
Propofol
Russell et al. Propofol 10 mg/kg/hr for 25°C NA [propofol] ↓ 50%-

(106) 20 min, then 3 mg/kg/hr 78% at initiation of
(n = 10) CPB with
subsequent rapid
recovery to 98% of
pre-CPB levels by
20 min.
Free fraction ↑ by
1.5- to 3-fold with
initiation of CPB.
Boer et al. (522) Group 1: Propofol 0.2 26°C Membrane [propofol] ↓ vascular
mL/kg (n = 14) resistance.
Group 2: 0.2 mL/kg [propofol] ↓ during
Intralipid (n = 14) CPB at a rate less
Group 3: Propofol 2 than that predicted
mg/kg (n = 10) during by PK values
CPB reported in normal
subjects.
Massey et al. Propofol 4 mg/kg/hr (n = 28°C Shiley M2000 [propofol]

(523) 10) maintained at >1
μg/mL throughout
surgery.
No ↓ at initiation of
CPB.
Vd 626 L
Cl 2.2 L/min
t1/2β 356 min
Hynynen et al. In vivo: Propofol 10 28°C D703 CompactFlo In vivo, at initiation

(176) mg/kg/hr for 20 min, Membrane of CPB [propofol] ↓
then 3 mg/kg/hr (n = 14) (Dideco) (45%).
In vitro: Propofol to Some degree of
achieve [propofol] of 2 sequestration in
μg/mL (n = 3) circuit likely as the
predicted [propofol]
↓ by hemodilution
alone was 29%.
In vitro, propofol
taken up by the
circuit ([propofol] ↓
75% following 120
min of perfusion)
Lee et al. (524) Propofol 4 mg/kg/hr 28°C Capiox Terumo t1/2β = 370 min Cl
during CPB (n = 11) Membrane 1.3 L/min Vdss 322 L
Ng et al. (516) Group 1: Propofol 4 28°C Capiox Terumo [propofol] ↓ to 1

mg/kg/hr (n = 11) Membrane μg/mL by 15 min.
Morphine/Diazepam (n cortisol,
= 10) during CPB epinephrine, and
norepinephrine
lower in propofol
group.
Bailey et al. Group 1: Propofol by 23°C NA Lower values for Vc

(420) CACI to maintain and Cl as compared
[PROP] 3-10 μg/mL (n = with previous
11) studies.
Group 2: Propofol by PK model derived
CACI to maintain provided better fit of
[PROP] at 2, 4 or 6 predicted vs. actual
μg/mL (n = 30) pre-CPB
[propofol] in the pre-
CPB group.
Better predictive
capability achieved
by allowing V1 and
Cl1 to increase with
initiation of CPB.
Hammaren et al. Propofol 10 mg/kg/hr for 30°C Membrane Heparin ↑ [propofol]
(96) 20 min, then 3 mg/kg/hr free fraction from
(n = 15) 1.5% to 2.3%.
[propofol] free
fraction ↑ again
during CPB from
2.3% to 3.5%.
D'Attellis et al. Propofol by CACI (525) 25°C Membrane All patients

(240) to achieve target extubated within 5
concentration of 1 hr.
μg/mL No evidence of
+ sufentanil 1.8 μg/kg/hr development of
until CPB, then 0.9 myocardial
μg/kg/hr (n = 15) ischemia.
No significant
adverse
hemodynamic
effects occurred.
Dawson et al. Group 1: Propofol 1 30°C NA [propofol] ↓ 60%

(6) mg/kg 1 3 mg/kg/hr (n = during CPB while
12) unbound fraction ↑
Group 2: Midazolam 0.2 46%.
mg/kg + 0.07 mg/kg/hr [midazolam] ↓ 53%
(12) post-sternotomy during CPB while
unbound fraction ↑
50%.
Doi et al. (31) Propofol by CACI (526) 28°C Membrane [propofol] and
+ Alfentanil by CACI [alfentanil] stable
(527) (n = 12) during CPB.
Hammaren et al. In vitro study 28°C 1. Spiralgold and [propofol] ↓ 68%-

(177) Propofol in stages to BMR-1900 Gold 78% on initiation of
produce 2 μg/mL, then (Baxter) (3) perfusion.
22 μg/mL, then 200 2. Maxima with Binding to heparin-
μg/mL Carmeda Bio- coated circuits not
Active Surface different from non-
(Medtronic) (3) heparin-coated
3. Spiraloxy and circuits.
BMR-1900 Propofol
(Baxter) (3) sequestered by the
4. Maxima membranes.
(Medtronic) (3)
Palm et al. (528) Propofol 2 mg/kg bolus NA NA Propofol 2 mg/kg

+ 1.5 mg/kg/hr (n = 20) bolus + 3.5 mg/kg/hr
2.0 mg/kg/hr (n = 20) required to produce
2.5 mg/kg/hr (n = 20) changes in mid-
3.5 mg/kg/hr (n = 20) latency auditory-
Control (n = 20) + evoked potentials of
opioids/benzodiazepines sufficient magnitude
to eliminate recall of
events occurring
during anesthesia
and surgery.
Geisler et al. Remifentanil 1 28°C NA No difference in

(529) μg/kg/min (n = 45) 1.5 hypertensive,
μg/kg/min (n = 44) 2.0 tachycardic, or
μg/kg/min (n = 43) + somatic responses
propofol 3 mg/kg/min to stimuli during
surgery.
Muscle rigidity
required
modification of
induction sequence.
No dose-response
relationship
demonstrated.
Yoshitani et al. Propofol by CACI (530) 36°C Membrane Pre-CPB no

(10) to maintain effect site differences in
concentration of 3 [propofol] among
μg/mL, then at start of groups. [propofol] ↓
CPB 30%-41% on
Group A: 4 mg/kg/hr (n initiation of CPB.
= 15) No change over time
Group B: 5 mg/kg/hr (n on CPB for Group A.
= 15) Gradual return to
Group C: 6 mg/kg/hr (n above pre-CPB
= 15) levels in Groups B
+ fentanyl 5 μg/kg/min and C. EEG burst
suppression ratio
occurred at
[propofol] below that
required in patients
not undergoing
CPB, suggesting
independent
anesthetic effect of
CPB.
Ahonen et al. Propofol bolus infusion 35°C NA Duration of

(271) of 1.5 mg/kg and then anesthesia longer in
sufficient to maintain off-pump group.
Bispectral Index at 40 ± Bispectral Index
5 values similar.
On-pump (n = 22) No difference in
Off-pump (n = 18) propofol
+ alfentanil 50 μg/kg/min requirements On
on induction and at skin (7.5 mg/kg/hr) vs.
incision, then 1.5 Off (7.5 mg/kg/hr)
μg/kg/min for 30 min, CPB.
then 1.0 μg/kg/min until No anesthetic effect
sternal closure attributable to CPB.
Hiraoka et al. (8) Propofol 4 mg/kg/hr 1 NA NA [PROP] ↓ ˜30%-40%
midazolam, fentanyl at initiation of CPB,
then ↑ to pre-CPB
level over 15-30
min.
Unbound [propofol]
↑ ˜200% during
CPB.
No difference in Cl.
Distribution to RBCs
↑ 1.6-fold.
Hepatic extraction
ratio >0.8 at all
times.
Takizawa et al. Propofol 35°C NA [propofol]

(9) Group P-4: Propofol unchanged over
infusion at 4 mg/kg/hr (n time.
= 15) In Group P-6
Group P-6: Propofol [propofol] ↑ 1.5
infusion at 6 mg/kg/hr (n times over that
= 15) found in Group P-4.
+ fentanyl 4 μg/kg/min [propofol] unbound
fraction ↑ 200% on
CPB vs. pre-CPB.
[propofol] ↑ 1.6
times in RBC on- vs.
pre-CPB indicating
sequestration by
RBCs.
Burst suppression
ratio ↑ during CPB
suggesting
enhanced
pharmacodynamic
effects likely as a
result of ↑ in
unbound fraction.
Changes in propofol
binding to proteins
due to hemodilution.
Barbosa et al. Propofol by CACI (530) 32°C-34°C Membrane [propofol]
(111) to achieve [propofol] of significantly lower in
2 μg/mL in CPB group CPB group during
(n = 10) and OPCAB CPB.
group (n = 10) CPB group
demonstrated a
reduction in
Bispectral Index for
equivalent [propofol]
by 33%.
t1/2β ↓, Cl ↑, Vd
unchanged in CPB
Group.
Grossherr et al. Propofol administered at NA NA [propofol] measured

(421) 3 mg/kg/hr (n = 6) or 6 in exhaled gas did
mg/kg/hr (n = 6) with not reach
simultaneous sampling equilibrium with
of plasma and exhaled plasma [propofol]
gas [propofol] during initial infusion
period and
continued to
increase despite
stable plasma
[propofol] prior to
CPB. Equilibrium
still not achieved at
time of propofol
discontinuation
following CPB.
Attributed to
possibility of altered
pulmonary
permeability post-
CPB or differences
in mechanical
ventilation in the OR
vs. the ICU.
Mathew et al. Propofol titrated to 35°C-37°C or Membrane Propofol

(245) Bispectral Index 28°C-39°C requirements to
Normothermic (n = 25) maintain Bispectral
Hypothermic (n = 25) Index reduced
during CPB and
further reduced in
hypothermic group.
Propofol
requirements pre-
and post-CPB
similar within groups
and not different
between groups.
Neuromuscular receptor blocking agents
Quaternary ammonium agents
Pancuronium
D’Hollander et Pancuronium 0.07 24°C Optiflow II Bubble [pancuronium] ↓

al. (248) mg/kg at induction and 33% on initiation of
thereafter to maintain CPB due to
10% of control muscle hemodilution.
twitch height (n = 10) [pancuronium] ↓ to
maintain
neuromuscular
blockade during
hypothermic period.
[pancuronium] ↑
during rewarming.
[pancuronium] pre-
vs. post-CPB to
achieve same effect
not different.
Concluded that
temperature has a
significant impact on
pancuronium effect.
Futter et al. Pancuronium 0.06-0.09 26°C NA Pancuronium

(251) mg/kg 1 infusion to requirements ↓ 84%
maintain first muscle during hypothermic
twitch in train-of-four period.
<10% of control (n = 8) During rewarming
pancuronium
requirements ↑.
Pancuronium
requirements ↑ in
the post-CPB period
when compared to
the pre-CPB period.
Buzello et al. Group 1: Pancuronium 26°C NA Recovery from

(252) 0.075 mg/kg bolus 1 neuromuscular
maintenance dose blockade prolonged
0.015 mg/kg (n = 10) during hypothermia
Group 2: Vecuronium (Pancuronium effect
0.075 mg/kg bolus + ↑ 1.8 times and
0.015 mg/kg Vecuronium effect ↑
maintenance dose (n = 5 times that is
10) to maintain required in the pre-
electromyographic CPB period).
response <25% of Some recovery with
control. rewarming but
duration of
neuromuscular
blockade still
prolonged relative to
prebypass and
impairment of
recovery of muscle
function persisted
into postbypass
period.
Buzello et al. Group 1: Alcuronium 26°C NA Speed of recovery

(531) 0.15 mg/kg 1 0.03 of muscle action
mg/kg/hr (n = 10) potential ↑ for d-
Group 2: d- tubocurarine,
Tubocurarine 0.3 mg/kg alcuronium, and
+ 0.06 mg/kg/hr (n = 10) pancuronium during
Group 3: Pancuronium hypothermic CPB.
0.05 mg/kg + 0.01 ↓ for vecuronium
mg/kg/hr (n = 10) during hypothermic
Group 4: Vecuronium CPB.
0.05 mg/kg + 0.05
mg/kg/hr (n = 10)
Wierda et al. Group 1: Pancuronium 28°C Shiley M-2000 No change in

(532) 200 μg/kg (n = 6) Membrane pancuronium PK
Group 2: Pancuronium with addition of
200 μg/kg + dopamine 2 dopamine.
μg/kg/min (n = 6) Pancuronium Cl ↑
during hypothermia.
Rocuronium
Smeulers et al. Rocuronium 0.6 mg/kg 28°C CML II Excel [rocuronium]

(250) (n = 10) Membrane required for return of
5% recovery of
muscle twitch
function ↑ during
normothermia vs.
both hypothermic
CPB and rewarming.
Duration of
neuromuscular
blockade
significantly ↑ during
hypothermia (4
times).
t1/2β = 97 min.
Cammu et al. cis-Atracurium 1.5 33°C NA cis-Atracurium:

(131) μg/kg/min (n = 8) Infusion rates of 1.1,
Rocuronium 10 0.75, and 0.98
μg/kg/min (n = 9) μg/kg/min required
Infusion started before, during, and
following recovery of after CPB to
muscle twitch function to maintain muscle
10% Adjusted to twitch function at
maintain muscle twitch 15%.
function at 15%. Infusion ↓ by 50%
during CPB with ↓
infusion rate
following CPB.
Rocuronium:
Infusion rate of 4.4,
3.6, and 4.2
μg/kg/min required
before, during, and
after CPB to
maintain muscle
twitch function at
15%.
No significant
differences in dosing
requirements pre,
during, or after CPB.
Vecuronium
Buzello et al. Group 1: Pancuronium 26°C NA Recovery from

(252) 0.075 mg/kg + 0.015 neuromuscular
mg/kg (n = 10) blockade prolonged
Group 2: Vecuronium during hypothermia
0.075 mg/kg + 0.015 (pancuronium effect
mg/kg maintenance ↑ 1.8 times,
dose (n = 10) to vecuronium effect ↑
maintain EMG response 5 times that of pre-
<25% of control CPB).
Some recovery with
rewarming but
duration of
neuromuscular
blockade still
prolonged relative to
prebypass and
impairment of
recovery persisted
into postbypass
period.
Denny and Group 1: Atracurium 0.5 30°C NA Infusion

Knee-Shaw mg/kg 1 0.4 mg/kg/hr (n requirements ↓
(533) = 14) (vecuronium 71%
Group 2: Vecuronium and atracurium
0.1 mg/kg + 0.08 35%) for drug to
mg/kg/hr (n = 11) maintain
Adjusted to maintain neuromuscular
muscle twitch function at blockade during
5% of control. hypothermia.
Buzello et al. Group 1: Alcuronium 26°C NA Speed of recovery

(531) 0.15 mg/kg + 0.03 of muscle action
mg/kg/hr (n = 10) potential ↑ for d-
Group 2: d- tubocurarine,
Tubocurarine 0.3 mg/kg alcuronium, and
+ 0.06 mg/kg/hr (n = 10) pancuronium during
Group 3: Pancuronium hypothermic CPB.
0.05 mg/kg + 0.01 ↓ for vecuronium
mg/kg/hr (n = 10) during hypothermic
Group 4: Vecuronium CPB.
0.05 mg/kg + 0.05
mg/kg/hr (n = 10)
Kansanaho et Group 1: Atracurium 0.4 28°C Membrane CACI performance

al. (534) mg/kg 1 CACI (535) poor during
infusion (n = 10) hypothermic CPB.
Group 2: Vecuronium Infusion rates
0.08 mg/kg + CACI reduced by 70%
(535) infusion (n = 10) (atracurium) and
To achieve muscle 90% (vecuronium).
twitch function at 10% of
control
Withington et al. Vecuronium 17.2°C-29°C Membrane Vecuronium infusion

(425) 0.1 mg/kg, then 0.075 rate ↓ (84%-92%)
mg/kg to maintain 90% during hypothermic
depression of muscle CPB to maintain
twitch response (n = 9) adequate
Children with CHD neuromuscular
relaxation.
Post-CPB Cpss
similar to on-CPB
Cpss.
Bimodal distribution
depending on use of
deep vs. moderate
hypothermia.
Benzylisoquinolines
Atracurium
Flynn et al. Atracurium 0.6 mg/kg at 25°C NA Train-of-four

(124) induction + infusion to response
maintain neuromuscular disappeared during
twitch height <10% of hypothermia.
control (n = 12) Atracurium
requirements ↓
(55%) during and
after CPB.
Denny and Group 1: Atracurium 0.5 30°C NA ↓ requirements

Knee-Shaw mg/kg + 0.4 mg/kg/hr (n (vecuronium 71%
(533) = 14) and atracurium
Group 2: Vecuronium 35%) for drug to
0.1 mg/kg + 0.08 maintain
mg/kg/hr (n = 11) neuromuscular
Adjusted to maintain blockade during
neuromuscular twitch hypothermia.
function at 5% of control
Diefenbach et Atracurium 460 μg/kg 1 28°C Membrane ↑ time to onset of

al. (249) maintenance bolus 138 blockade (57%) and
μg/kg to maintain 95% ↑ duration of
neuromuscular twitch neuromuscular
depression (n = 15). blockade (2 times)
during hypothermic
CPB.
Kansanaho et Group 1: Atracurium 0.4 28°C Membrane CACI performance

al. (534) mg/kg 1 CACI (535) poor during
infusion (n = 10) hypothermic CPB.
Group 2: Vecuronium Infusion rates
0.08 mg/kg + CACI reduced by 70%
(535) infusion (n = 10) (atracurium) and
To achieve 90% (vecuronium)
neuromuscular twitch during CPB.
function at 10% of
control.
cis-Atracurium
Cammu et al. cis-Atracurium 1.5 33°C NA cis-Atracurium:

(131) μg/kg/min (n = 8) Infusion rates of 1.1,
Rocuronium 10 0.75, and 0.98
μg/kg/min (n = 9) μg/kg/min required
Infusion started before, during, and
following recovery of after CPB to
neuromuscular twitch to maintain
10%. Adjusted to neuromuscular
maintain neuromuscular twitch function at
twitch function at 15% of 15%.
control. Infusion rate ↓ by
50% during CPB
with ↓ infusion rate
following CPB.
Rocuronium:
Infusion rate of 4.4,
3.6, and 4.2
μg/kg/min required
before, during, and
after CPB to
maintain
neuromuscular
twitch function at
15%.
No significant
differences in dosing
requirements pre-,
during, or after CPB.
Withington et al. cis-Atracurium 0.1 25°C (n = 6) Membrane cis-Atracurium

(536) mg/kg bolus then 0.075 or 32°C (n = infusion rate did not
mg/kg/hr to maintain 4) depending require adjustment
constant degree of on nature of in 32°C group but
neuromuscular blockade surgery required an 89%
as assessed by Datex reduction in 25°C
Relaxograph Monitor. group during CPB.
Infusion rate
returned to pre-CPB
levels following
CPB.
Cl ↓ from 5.47 to
1.10 mL/min/kg
during CPB (85%).
Mivacurium
Diefenbach et Mivacurium 150 μg/kg 1 34°C Membrane Cholinesterase

al. (126) maintenance doses of activity ↓ by 42%
75 μg/kg to maintain during CPB.
neuromuscular twitch Mivacurium onset
depression (n = 9). time ↑ 26% on CPB
but duration of effect
not ↑.
Opioids
Phenylpiperidines
Alfentanil
DeLange and Alfentanil 3 mg/min until 26°C SM 1430 Most hemodynamic

DeBruijn (537) loss of consciousness, (Travenol) responses occurred
then 2 mg at intubation, Membrane pre-CPB (average
then 50 mg/hr, stopped alfentanil dose 60
during cooling on CPB, mg).
12.5 mg/hr during Mean arterial
rewarming and post- pressure not
CPB (n = 14) controlled on CPB in
Adjusted on the basis of 3 patients at
hemodynamic response maximum rate.
with 2.5 mg boluses [alfentanil] ↓ 56% on
CPB. Reduced
requirements for
alfentanil post-CPB.
Skacel et al. Alfentanil 1 mg (n = 8) Low = 25°C Shiley S-100A As pH of priming

(169) Fentanyl 200 μg (n = 9) Normal = Bubble solution ↑, [fentanyl]
In vitro to circuit 37°C ↓ over time.
No effect of pH on
[alfentanil]. No effect
of temperature on
concentration (i.e.,
no change) over
time for either drug.
Hynynen (3) Group 1: Fentanyl 48 34°C Shiley S-100A In vitro, perfusion for
μg/kg 1 0.3 μg/kg/min (n Bubble (21) or 60 min resulted in
= 6) Bentley BOS- 73% ↓ in [fentanyl]
Group 2: Alfentanil 48 CM50 Membrane independent of
μg/kg + 6 μg/kg/min (n = (4) membrane or bubble
6) oxygenator.
Group 3: Fentanyl 48 [alfentanil] 80% of
μg/kg + 0.3 μg/kg/min + predicted in
140 ng/mL in CPB pump nonhemic prime and
priming solution (n = 4) >100% present in
Group 4: Fentanyl 48 blood prime at the
μg/kg + 0.3 μg/kg/min + end of 60 min.
240 ng/mL in CPB pump No effect of
priming solution (n = 6) oxygenator type.
Group 5: Alfentanil 48 In vivo, opioid
μg/kg + 6 μg/kg/min + concentrations ↓ at
700 ng/mL in CPB pump onset of CPB but
priming solution (n = 5) new steady-state
+ in vitro studies concentration was
achieved within 1.5
min. Addition of
fentanyl or alfentanil
to pump priming
solution prevented
initial decline in
concentration but no
difference in opioid
concentration with
vs. without opioids
in prime at 2.5 min.
den Hollander et Alfentanil 20 μg/kg 1 24°C Polystan VT 1500 Early extubation

al. (223) infusion of 1 μg/kg/min or 2000 Bubble possible.
Bolus 5 μg/kg for Cl ↑, Vdss ↑ in
hemodynamic infants.
aberrations No difference in t1/2β
Group 1: Infants <1 y (n in either group.
= 6)
Group 2: Children (n =
5)
Kumar et al. (7) Alfentanil 10 μg/kg/min 28°C Optiflow II (Cobe) [alfentanil] ↓ 48% on
bolus + 1 μg/kg/min Membrane initiation of CPB.
infusion (n = 5) Free [alfentanil] ↑
16%.
Unbound fraction ↑
54%.
Taeger et al. Group 1: Fentanyl base NA NA Fentanyl

(145) 0.3 mg (n = 5) demonstrated
Group 2: Alfentanil base significant first pass
7 mg (n = 6) uptake (43%-87%)
by the lung.
Alfentanil
demonstrated 36%-
80% sequestration
in the lung. Both
drugs demonstrated
an initial rapid
washout phase,
then a slower
washout phase after
perfusion
reestablished
suggesting that the
lungs could serve as
a drug depot.
Robbins et al. Group 1: Alfentanil 250 NA NA No difference in

(538) μg/kg/hr × 1 h + 2.5 incidence of
μg/kg/min (n = 8) response to noxious
Group 2: Alfentanil 300 stimuli between
μg/kg/hr × 1 h + 3.0 groups.
μg/kg/min (n = 10) No difference
Group 3: Alfentanil 350 between groups in
μg/kg/hr × 1 hr + 3.5 [alfentanil].
μg/kg/min (n = 10) [alfentanil] stable
during CPB.
No correlation
between [alfentanil]
and noxious
response.
t1/2β post-CPB = 5.1
hr.
Time to awakening
= 3.2 hr.
Time to extubation =
8.8 hr.
Mantz et al. Alfentanil 10 mg bolus + 29°C Bubble Despite high dose

(427) infusion of 60 mg/hr up technique, there
to sternotomy, then 30 was inability to
mg/hr to end of surgery; obtund all
bolus 5 mg at incision, hemodynamic
sternotomy, initiation of responses.
rewarming, insertion of [alfentanil] ↓ 30% at
sternal wires, transfer to onset of CPB.
ICU. Bolus 2.5 mg as No uptake by the
necessary for oxygenator
hemodynamic demonstrated.
aberrations (n = 10) Possible
development of
acute tolerance
demonstrated as
awakening occurred
at [alfentanil] = 810
ng/mL.
t1/2β = 379 min, Vd =
0.96 mL/kg, Cl =
165 mL/min.
den Hollander et Alfentanil 200 μg/kg pre- 24°C Cobe VPCML Vd ↑ post-CPB in
al. (231) CPB 80 μg/kg post-CPB Dideco Masterflo both age-groups.
Group 1: Infants <1 y (n Membrane Vd ↑, t1/2β ↑, Cl
= 6) unchanged in
Group 2: Children <9 y infants relative to
(n = 6) children.
Boer et al. (144) Group 1: Sufentanil 1 NA NA First pass uptake of

μg/kg (n = 6) sufentanil (˜50%)
Group 2: Alfentanil 30 and alfentanil (˜18%)
μg/kg (n = 8) by the lung was not
affected by the type
of mechanical
ventilation—apnea
vs. IPPV vs. IPPV +
PEEP.
Hug et al. (4) Alfentanil 125 μg/kg pre- 23°C Travenol Vd ↑, t1/2β ↑ post-
and post-CPB (n = 8) Membrane CPB.
Reduced protein
binding.
Minimal change
(13%) in free
[alfentanil] at CPB
initiation despite
55% reduction in
total [alfentanil]
levels.
Fiset et al. (224) Alfentanil to specified NA NA Cl ↓, Vdss ↑, t1/2β ↑

target plasma vs. previously
concentrations by CACI reported
(539) (n = 14) parameters.
Pediatric population New model created
to account for CPB
effect.
Petros et al. Alfentanil 50 μg/kg/min Hypothermic Sarns Bubble Vd ↑ post-CPB vs.

(428) × 10 min 26°C Oxygenator thoracotomy but not
Group 1: Post-CPB Normothermic different for
normothermic (n = 12) 35°C hypothermic group
Group 2: Post-CPB vs. normothermic
hypothermic (n = 12) group.
Group 3: Thoracotomy Protein binding ↓ in
surgery at induction (n = post-CPB groups
12) (82%-87% vs. 91%).
Doi et al. (31) Propofol by CACI (526) 28°C Membrane [propofol] and
+ alfentanil by CACI [alfentanil] stable
(527) (n = 12) during CPB.
Ahonen et al. Alfentanil by CACI (495) 33°C NA No difference in time

(42) to achieve target to awakening.
concentration 400 Fentanyl group had
ng/mL (n = 20) delayed extubation.
Fentanyl by CACI (233) Time to reach 50%
to achieve target of concentration at
concentration 6 ng/mL infusion
(n = 20) discontinuation was
Sufentanil by CACI not different
(234) to achieve target between groups.
concentration 0.6 ng/mL Time to reach 80%
(n = 20) of infusion
+ propofol concentration longer
Zero-order infusions for fentanyl and
utilized correlated with time
to extubation.
t1/2β fentanyl >
sufentanil >
alfentanil.
Ahonen et al. Propofol bolus infusion 35°C NA Duration of

(271) of 1.5 mg/kg and then to anesthesia longer in
maintain Bispectral off-pump group.
Index at 40 ± 5 Bispectral Index
ON-pump (n = 22) values similar.
OFF-pump (n = 18) No difference in
+ alfentanil 50 μg/kg/min propofol
on induction and at skin requirements ON
incision, then 1.5 (7.5 mg/kg/hr) vs.
μg/kg/min for 30 min, OFF (7.5 mg/kg/hr)
then 1.0 μg/kg/min until CPB.
sternal closure No anesthetic effect
attributable to CPB.
Blake et al. Alfentanil infusion 35°C NA Total [alfentanil] ↓

(103) adjusted manually using following onset of
PK data of Scott and CPB but free
Stanski (218) with target [alfentanil] remained
[alfentanil] 200 ng/mL unchanged.
decreasing to 50 ng/mL
post-CPB (218)
(n = 25)
Fentanyl
Lunn et al. (540) Fentanyl 50 μg/kg 32°C Bentley Bubble Patients

induction 1 25 μg/kg unresponsive to
postintubation (n = 18) verbal stimuli at
[fentanyl] = 34
ng/mL.
[fentanyl] ↓ 37% on
CPB.
Bovill and Sebel Fentanyl 60 μg/kg (n = 25°C Polystan Rygg- [fentanyl] ↓ 53% at
(541) 5) Kyvsgaard 5000 initiation of CPB.
Bubble No consistent
pattern of [fentanyl]
vs. time while on
CPB.
No change in
[fentanyl] for 2 hr
post-CPB, then
exponential decline.
t1/2β ↑ (423 min)
post-CPB vs. values
reported in healthy
humans (170-356
min).
Koska et al. Group 1: Fentanyl 0.5 NA NA t1/2β ↑ post-CPB

(347) mg 70/kg with CPB (n = relative to the group
6) without CPB (5.2 vs.
Group 2: Fentanyl 0.5 3.3 hr).
mg 70/kg without CPB Liver blood flow ↓ by
(n = 6) 30% during CPB.
Sprigge et al. Group 1: Fentanyl 30 NA NA Dose-dependent ↑

(429) μg/kg + 0.3 μg/kg/min (n [fentanyl]. [fentanyl]
= 10) ↓ 30% at start of
Group 2: Fentanyl 40 CPB but returned to
μg/kg + 0.4 μg/kg/min (n pre-CPB level by 30
= 10) min.
Group 3: Fentanyl 50 No difference in
μg/kg + 0.5 μg/kg/min (n number of
= 10) responses to
until rewarming on CPB noxious stimuli
or maximum 100 μg/kg between groups
total dose (Group 1:n = 9;
Group 2:n = 7;
Group 3:n = 5).
Patients with the
highest dose had
fewer hemodynamic
changes.
One patient in the
lowest-dose group
had memory of
intraoperative
events.
Bentley et al. Group 1: Fentanyl 100 30°C NA [FEN] ↓ 47% during

(143) μg (n = 5) CPB.
Group 2: Fentanyl 100 [FEN] ↑ 13% with
μg in whom pulmonary resumption of
artery and radial ventilation during
samples taken CPB due to washout
simultaneously (n = 7) of fentanyl from
lungs.
Wynands et al. Group 1: Fentanyl 75 26°C NA No between-group

(431) μg/kg (n = 10) differences in
Group 2: Fentanyl 75 number of
μg/kg + 0.75 μg/kg/min hypertensive
until rewarming (n = 10) episodes requiring
treatment pre-CPB.
[fentanyl] ↑ in the
high-dose group.
All patients in the
low-dose group
hypertensive during
CPB.
No increase in time
to tracheal
extubation (17 vs.
19 hr).
Postoperatively
increased
requirements for
vasopressors in the
high-dose group and
vasodilators in the
low-dose group.
Koren et al. Group 1: Fentanyl 50 <20°C Sci-Med 0800-2A [fentanyl] ↓ 71% with
(542) μg/kg 1 0.15 μg/kg/min Membrane onset of CPB.
(n = 4) Stable [fentanyl]
Group 2: Fentanyl 50 thereafter without
μg/kg + 0.3 μg/kg/min (n requirement for
= 6) additional drug.
Group 3: Fentanyl 30 Significant binding
μg/kg + 0.3 μg/kg/min (n of fentanyl to CPB
= 9) until onset of CPB apparatus in vitro.
In vitro studies of [fentanyl] higher in
fentanyl binding to CPB children with CHD at
circuit same dose rate than
Pediatric population in adults.
Vd (1,385 mL/kg) ↓,
Cl
(13 mL/min/kg), t1/2β
(141 min) not
different from those
reported in adult
cardiac patients.
Koren et al. Group 1: Fentanyl 50 16°C-28°C NA [fentanyl] ↓ 74% at

(178) μg/kg 1 0.15 μg/kg/min start of CPB.
(n = 4) [fentanyl] = 20
Group 2: Fentanyl 50 ng/mL in pump
μg/kg + 0.3 μg/kg/min (n priming solution did
= 6) not prevent ↓ in
Group 3: Fentanyl 30 [fentanyl] (76%) at
μg/kg + 0.3 μg/kg/min (n time of CPB.
= 9) until onset of CPB In vitro binding
+ [fentanyl] 20 ng/mL in studies showed
pump priming solution oxygenator to be the
In vitro studies with principal binding
CPB apparatus site.
Alvis et al. (518) Group 1: Control: NA NA Predicted vs. actual

Fentanyl 150-250 μg [fentanyl] closely
bolus postinduction + correlated in CACI
150-250 μg for groups.
response to surgical More fentanyl given
stimulation (n = 10) in Group 2.
Group 2: Fentanyl by Equivalent numbers
CACI designed to of patients
achieve plasma demonstrated
concentration of 7.5 hemodynamic
ng/mL (n = 10) responses, but
Group 3: Fentanyl by overall better
CACI and varied hemodynamic
according to stimulation control in Group 3.
(n = 10) No difference in time
Sampling up to 60 min to extubation among
or pre-CPB if <60 min groups (Group 1: 14
hr; Group 2: 15 hr;
Group 3: 14 hr)
Koren et al. Group 1: Fentanyl 50 NA NA Vd correlated with

(230) μg/kg 1 0.15 μg/kg/min age in 8 Tetralogy of
(n = 4) Fallot patients (i.e.,
Group 2: Fentanyl 50 with disease
μg/kg + 0.3 μg/kg/min (n severity).
= 6) Cl ↓ with ↑ age.
Group 3: Fentanyl 30
μg/kg + 0.3 μg/kg/min (n
= 9) until CPB onset
Skacel et al. Alfentanil 1 mg (n = 8) Low = 25°C Shiley S-100A As pH of priming

(169) Fentanyl 200 μg (n = 9) Normal = Bubble solution ↑, [fentanyl]
In vitro to circuit 37°C ↓ over time.
No effect of pH on
[alfentanil].
No effect of
temperature on
concentration (i.e.,
no change) over
time for either drug.
Hynynen (3) Group 1: Fentanyl 48 34°C Shiley S-100A In vitro, perfusion for
μg/kg + 0.3 μg/kg/min (n Bubble (n = 21) or 60 min resulted in
= 6) Bentley BOS- 73% ↓ in [fentanyl]
Group 2: Alfentanil 48 CM50 Membrane independent of
μg/kg + 6 μg/kg/min (n = (n = 4) membrane or bubble
6) oxygenator.
Group 3: Fentanyl 48 [alfentanil] 80% of
μg/kg + 0.3 μg/kg/min + predicted in
140 ng/mL in CPB pump nonhemic prime and
prime (n = 4) > 100% present in
Group 4: Fentanyl 48 blood prime at the
μg/kg + 0.3 μg/kg/min + end of 60 min.
240 ng/mL in CPB pump No effect of
prime (n = 6) oxygenator type.
Group 5: Alfentanil 48 in vivo, opioid
μg/kg + 6 μg/kg/min + concentrations ↓ at
700 ng/mL in CPB pump onset of CPB but
prime (n = 5) new steady-state
+ in vitro studies concentration
achieved within 1.5
min.
Addition of fentanyl
or alfentanil to CPB
priming solution
prevented initial
decline in
concentrations but
there was no
difference in opioid
concentration with
vs. without opioids
in the priming
solution at 2.5 min.
Koren et al. Fentanyl 30 or 50 μg/kg <20°C NA During profound

(120) bolus + infusion at 0.15 hypothermia
or 0.30 μg/kg/min until [fentanyl]
onset of CPB (n = 18) unchanged, i.e., not
+ pig study metabolized.
Pediatric population Pig study
demonstrated
hypothermia caused
Vd ↓, Cl ↓, and t1/2β
↑.
Thomson et al. Group 1: Fentanyl 100 NA Bubble No important clinical

Group 2: Sufentanil 15 hemodynamic
μg/kg (n = 17) parameters between
groups.
No correlation
between [fentanyl]
or [sufentanil] and
hemodynamic
responses to
stimulation.
Recall of
intraoperative
events in two
patients.
Caspi et al. Fentanyl 100-135 μg/kg 24°C NA Development of

(139) (n = 29) rigidity with
respiratory acidosis
and hemodynamic
instability 2- to 6-h
postoperatively
likely from
redistribution of
fentanyl from tissue
stores. [fentanyl] =
5-8 ng/mL
Rosen et al. Fentanyl 125 ng/mL (n = 23°C Sci-Med 2A-800 Membrane

(179) 1) Membrane oxygenator identified
Fentanyl 367 ng/mL (n = as site of fentanyl
1) uptake.
In vitro study Saturation of binding
sites possible.
Taeger et al. Group 1: Fentanyl base NA NA Fentanyl

(145) 0.3 mg (n = 5) demonstrated
Group 2: Alfentanil base significant first pass
7 mg (n = 6) uptake, i.e.,
sequestration (43%-
87%) by the lung.
Alfentanil
demonstrated 36%-
80% sequestration.
Both drugs
demonstrated an
initial rapid washout
phase and then a
slower washout
phase after
perfusion
reestablished,
suggesting that the
lungs could serve as
a drug depot.
Newland et al. Fentanyl 5-10 μg/kg + 24°C Sci-Med [fentanyl] ↓ 57% at

(543) 5-10 μg/kg increments Membrane initiation of CPB and
to a total dose of 100 remained stable
μg/kg pre-CPB thereafter on CPB.
Group 1: Infants <1 y (n
= 5)
Group 2: Children <5 y
(n = 3)
Cross and Nikas Group 1: Fentanyl 50 25°C Maxima Blood gas

(170) μg/kg at induction + 25 (Medtronic) management
μg/kg before sternotomy Membrane strategy had no
(α-stat management) (n effect on [fentanyl]
= 8) but [sufentanil] ↓
Group 2: Fentanyl 50 using pH-stat
μg/kg at induction + 25 management.
μg/kg before sternotomy Observations not
(pH-stat management) explained by
(n = 8) changes in protein
Group 3: Sufentanil 7 binding.
μg/kg at induction + 3
μg/kg before sternotomy
(α-stat management) (n
= 8)
Group 4: Sufentanil 7
(pH-stat management)
(n = 8)
Hodges et al. Fentanyl 18-78 μg/kg (n NA If CPB flow rate Using a Gambro FH
(544) = 10) Pediatric <1,500 mL/min 66 polyamide filter
population Shiley-Dideco (Sidcup) post-CPB
(Sorin) 701 for ultrafiltration, no
>1,500 mL/min removal of [fentanyl]
Maxima Hollow demonstrated.
Fiber (Medtronic)
Thomson et al. Sufentanil by CACI NA NA As opioid

(34) (545) to achieve target concentration ↑,
concentration: isoflurane
0.4 ng/mL (n = 11) requirements ↓.
0.8 ng/mL (n = 10) [sufentanil] 0.71
1.2 ng/mL (n = 11) ng/mL and [fentanyl]
Fentanyl by CACI to 7.3 ng/mL optimum
achieve target target
concentration: concentrations.
5 ng/mL (n = 7) [sufentanil] >1.25
10 ng/mL (n = 7) ng/mL and [fentanyl]
15 ng/mL (n = 6) >13.2 ng/mL
+ isoflurane pre-CPB provided no
additional
hemodynamic
control.

Fentanyl by CACI to Time to reach 50%
achieve target of concentration at
concentration 6 ng/mL infusion
(n = 20) discontinuation not
Sufentanil by CACI to different between
achieve target groups.
concentration 0.6 ng/mL Time to reach 80%
(n = 20) of infusion
+ propofol concentration longer
Zero-order infusions for fentanyl and
utilized correlated with time
to extubation.
t1/2β fentanyl >
sufentanil >
alfentanil.
Barr et al. (36) Fentanyl infusion 5 34°C NA No correlation

μg/kg/hr Midazolam between [fentanyl]
infusion 50 μg/kg/hr (n = and [midazolam]
10) with Bispectral Index
as monitor of depth
of anesthesia.
Thomson et al. Fentanyl by CACI (545) NA NA No difference in
(35) to achieve effect site ability to obtund
concentration (Keo) 8.1 hemodynamic
ng/mL (n = 10) response or
Sufentanil by CACI requirements for
(545) to achieve effect isoflurane.
site concentration (Keo)
0.68 ng/mL (n = 11)
+ isoflurane pre-CPB
Lundell et al. Isoflurane (variable) + 30°C Sarns Hollow Fibre [sevoflurane]

(272) CACI fentanyl infusion Membrane required to maintain
to maintain an effect site same Bispectral
concentration of 3 Index Score value
ng/mL to sustain was ↓ by 25% post-
Bispectral Index Score CPB, suggesting
of 55 (n = 20) CPB-induced
changes in
anesthetic
requirements.
Mathew et al. CACI (518) to maintain Mean 32.5°C Cobe CML (Cobe) Hypothermia had
(114) effect site concentration independent
of fentanyl at 2.2 ng/mL anesthetic effect.
CACI (519) to maintain Age ↓ anesthetic
effect site concentration requirements.
of midazolam at 60
ng/mL
+ isoflurane (n = 100)
Hudson et al. Fentanyl by CACI to >33°C Nonsilicone No clinically

(21) maintain effect site Membrane important effect of
concentration from 5-15 CPB on PK.
ng/mL pre-CPB Three-compartment
Model group (n = 29) PK model adequate
Fentanyl by CACI to for clinical use.
maintain effect site
concentration 6 ng/mL
pre-CPB and 1.5 ng/mL
after 30 min on CPB
Validation Group (n =
10)
+ isoflurane
Hudson et al. Fentanyl by CACI (21) 33°C Nonsilicone Hollow [fentanyl] ↓ 27% on
(28) to achieve effect site Fibre Membrane CPB.
concentration of 4-8 PK modeling
ng/mL and ↓ to 1.5 included effect of
ng/mL 30 min on CPB premedication, CPB,
Model group (n = 61) sex, and weight.
Validation group (n = Simple three-
29) compartment PK
+ isoflurane model adequate for
clinical use.
Kussman et al. Fentanyl 30 μg/kg bolus Variable D901 Lilliput 1 [fentanyl] ↓ by 27%
(38) + 0.3 μg/kg/min infusion Open System on CPB. [fentanyl]
adjusted for (Dideco) recovered over 30
hemodynamic min during CPB.
perturbations + No statistical
Bispectral Index Score relationship between
value (15) [fentanyl] and
Pediatric population Bispectral Index
Score, or
temperature.
Morphine
Ng et al. (516) Group 1: Propofol 4 28°C Capiox Terumo [propofol] 1 μg/mL

mg/kg/hr (n = 11) Membrane by 15 min.
Morphine/diazepam (10) cortisol,
during CPB epinephrine, and
norepinephrine
lower in propofol
group.
Remifentanil
Duthie et al. Remifentanil 28°C Membrane Remifentanil did not

(430) Group 1: 1 μg/kg/min (n undergo significant
= 2) pulmonary extraction
Group 2: 1.5 μg/kg/min during CPB.
(n = 4) Cl = 2.18 L/min.
Group 3: 2.0 μg/kg/min [remifentanil] dose
(n = 4) dependent over
range of infusions
tested.
Russell et al. Remifentanil 2-5 μg/kg 28°C NA Cl ↓ during

(127) as a bolus hypothermic CPB by
1. Pre-CPB 20%.
2. On CPB and
hypothermic
3. On CPB and
normothermic (n = 16)
Davis et al. Remifentanil 32°C Membrane No difference in

(228) 5 μg/kg pre-CPB Vdss, Vc, t1/2β, Cl ↑
5 μg/kg post-CPB (n = post-CPB.
12)
Michelsen et al. Remifentanil 1, 2, or 3 Variable ARVADA Two-compartment

(26) μg/kg/min (n = 68) Membrane (Cobe) PK model best
described the data.
Cl ↓ with
hypothermia.
Vd ↑ with CPB.
Geisler et al. Remifentanil 28°C NA No difference in

(529) μg/kg/min (n = 45) hypertensive,
1.5 μg/kg/min (n = 44) tachycardic, or
2.0 μg/kg/min (n = 43) somatic responses
+ propofol 3 mg/kg/min to stimuli during
surgery.
Muscle rigidity
required
modification of
induction sequence.
No dose-response
relationship
demonstrated.
Sam et al. (546) Remifentanil by CACI 28°C-32°C Terumo CapioxC One-compartment

(217) to maintain RX05 Membrane, PK model best
[remifentanil] 1-8 ng/mL Terumo described the data.
(n = 9) Cardiovascular CPB found to ↑ Vd
Pediatric population Systems + by 2.4 times.
polysulfone Pre-CPB Vd 1.4 L
hemofilter used and Cl 0.244 L/min.
(MinntechC HPH Based on the PK
400; Minntech parameters, a
Corporation.) dosing regimen to
achieve 14 ng/mL
target
concentration would
consist of an initial
bolus of 18 μg
followed by 3.7
μg/min as infusion
throughout surgical
procedure with
additional 25 μg at
time of initiation of
CPB.
Sufentanil
Davis et al. Sufentanil 15 μg/kg 32°C or NA Children <10 mo

(221) Group 1: <10 mo not normothermic t1/2β ↓, Cl ↑ vs. adult
cooled to 32°C (n = 7) reports.
Group 2: >10 mo not Vd ↑ in infants vs.
cooled to 32°C (n = 6) children >10 mo and
Group 3: <10 mo cooled adults.
to 32°C (n = 7) and Vd ↑, t1/2β ↑ in
additional sufentanil as surface cooled
required until 120 min or children.
start of CPB No difference in
Pediatric population catecholamine
levels between
groups.
Flezzani et al. Sufentanil by CACI 27°C NA [sufentanil] ↓ from

(30) (518) started 10 min 3.8 to 2.5 ng/mL
prior to CPB to achieve (34%) with initiation
target concentration of 5 of CPB and ↑ to 4.7
ng/mL (n = 10) ng/mL during course
of CPB.
Drug accumulation
evident and likely
due to effects of
hypothermia.
CACI able to
achieve and
maintain stable
[sufentanil] during
CPB.
Greeley et al. Sufentanil 10-15 μg/kg NA NA Three-compartment

(222) pre-CPB PK model best
Group 1: <30 d (n = 9) described the data.
Group 2: <24 mo (n = 7) t1/2β ↑, Cl ↓, Vdss ↑ in
Group 3: <12 y (n = 7) neonates.
Group 4: >12 y (n = 5) Cl ↑ in infants and
Pediatric population with children relative to
CHD adolescents.
Kinetics age related.
Thomson et al. Group 1: Fentanyl 100 NA Bubble No important clinical

Group 2: Sufentanil 15 hemodynamic
μg/kg (n = 17) parameters between
groups.
No correlation
between [fentanyl]
or [sufentanil] and
hemodynamic
responses to
stimulation.
Recall of
intraoperative
events in two
patients.
Okutani et al. Group 1: Sufentanil 30 25°C BOS10 (Bentley) [sufentanil] ↓ on

(138) μg/kg (n = 10) Bubble initiation of CPB
Group 2: Sufentanil 10 (30%-55%).
μg/kg + 0.05 μg/kg/min ↑ with rewarming
(n = 10) with further ↑
Group 3: Sufentanil 20 immediately post-
μg/kg + 0.1 μg/kg/min (n CPB.
= 10) No correlation
Group 4: Sufentanil 40 between [sufentanil]
μg/kg + 0.2 μg/kg/min (n and change
= 10) (increase) in
catecholamine
levels.
[sufentanil] stable
during CPB.
Stone et al. Sufentanil 30 μg/kg at 28°C Membrane Hemoconcentration

(180) induction (n = 20) with a Bentley CPB-
7000 Blood
Processor (n = 3) or
William Harvey H-
4200
Hemoconcentrator
(n = 5) did not result
in ↓ in [sufentanil].
Use of cell-saver
(Haemonetics) (n =
19) ↓ [sufentanil]
0.1%.
[sufentanil] ↓ on
initiation of CPB
(49%).
Kern et al. (514) Sufentanil by CACI NA Cobe Membrane CACI overestimated

(222) to achieve 0.5-3.0 [sufentanil] on CPB.
ng/mL target
concentration
Midazolam by CACI
(515) to achieve 25-100
ng/mL target
concentration (n = 17)
Children with CHD
Bailey et al. (29) Sufentanil by CACI NA NA [sufentanil] vs. effect

(545) to achieve target relationship
concentration of 5 established.
ng/mL, then adjusted by For obtundation of
CACI based on response to
hemodynamics pre-CPB intubation, incision,
(n = 9) and sternotomy
Cp50 = 7 ng/mL.
For mediastinal
dissection Cp50 =
12.7 ng/mL.
Boer et al. (144) Group 1: Sufentanil 1 NA NA First pass uptake of

μg/kg (n = 6) sufentanil (˜50%)
Group 2: Alfentanil 30 and alfentanil (˜18%)
μg/kg (n = 8) by the lung was not
affected by the type
of mechanical
ventilation: apnea
vs. IPPV vs. IPPV +
PEEP.
Cross and Nikas Group 1: Fentanyl 50 25°C Maxima Blood gas

(170) μg/kg at induction + 25 (Medtronic) management
μg/kg before sternotomy Membrane strategy had no
(a-stat management) (n effect on [fentanyl]
= 8) but [sufentanil] ↓
Group 2: Fentanyl 50 using pH-stat
μg/kg at induction + 25 management
μg/kg before sternotomy strategy.
(pH-stat management) Difference was not
(n = 8) explained by
Group 3: Sufentanil 7 changes in protein
μg/kg at induction + 3 binding.
(α-stat management) (n
= 8)
Group 4: Sufentanil 7
(pH-stat management)
(n = 8)
Boer et al. (147) Sufentanil to specified NA NA First pass retention

target concentrations by (60%-68%) of
CACI (547) pre-CPB (n [sufentanil] by the
= 10) lung demonstrated.
Process may be
saturable.
Borenstein et al. Group 1: Sufentanil 30 NA NA No between-group

(548) μg/kg/min for 0.5 min (n differences in Vd, Cl,
= 12) t1/2β (40-47 min).
Group 2: Sufentanil 5 Mean arterial
μg/kg/min for 3 min (n = pressure and
11) systemic vascular
Group 3: Sufentanil 2 resistance
μg/kg/min for 7 min (n = unchanged in Group
9) 1, ↓ in Group 2 with
pre-CPB maximum effect at 3
min, and ↓ in Group
3 with maximum
effect at 15 min.

μg/mL + sufentanil 1.8 No evidence of
μg/kg/hr until CPB, then myocardial
0.9 μg/kg/hr (n = 15) ischemia.
No significant
adverse
hemodynamic
effects.
Thomson et al. Sufentanil by CACI NA NA As opioid

(34) (545) to achieve target concentration ↑,
concentration: isoflurane
0.4 ng/mL (n = 11) requirements ↓.
1.2 ng/mL (n = 11) ng/mL and [fentanyl]
Fentanyl by CACI to 7.3 ng/mL optimum
achieve target target
concentration: concentrations.
5 ng/mL (n = 7) [sufentanil] >1.25
10 ng/mL (n = 7) ng/mL and [fentanyl]
15 ng/mL (n = 6) >13.2 ng/mL
+ isoflurane pre-CPB provided no
additional
hemodynamic
control.
Thomson et al. Sufentanil by CACI NA NA Premedication did

(434) (545) to achieve target not influence
concentration 0.75 [sufentanil] vs. effect
ng/mL (n = 35) + relationship.
isoflurane Clonidine effective
premedication.
Zomorodi et al. CACI to achieve NA NA Three-compartment

(419) [midazolam] (232) of 75- model best
150 ng/mL and 50 described PK data
ng/mL adjusted for for midazolam.
effect in ICU + Length of time for
[sufentanil] (517) of 1-2 awakening
ng/mL pre-CPB, 0.5-1 dependent on
ng/mL while on CPB, duration of infusion
0.3-0.6 ng/mL post- in the ICU.
CPB, 0.15 ng/mL in ICU
(n = 63)
Thomson et al. Sufentanil by CACI NA NA [sufentanil] 3.0
(39) (545) to achieve target ng/mL need not be
concentration: exceeded to provide
1.5 ng/mL (n = 14) hemodynamic
3.0 ng/mL (n = 13) control.
+ isoflurane pre-CPB ng/mL may be
minimal effective
level.
[isoflurane]
decreased by
increasing
[sufentanil].

Fentanyl target Time to reach 50%
concentration 6 ng/mL of concentration at
(n = 20) infusion
Sufentanil target discontinuation not
concentration 0.6 ng/mL different between
(n = 20) groups.
+ propofol Time to reach 80%
Zero-order infusions of infusion
utilized concentration longer
for fentanyl and
correlated with time
to extubation.
t1/2β fentanyl >
sufentanil >
alfentanil.
Barvais et al. Midazolam by CACI 30°C Membrane (Baxter) PK models accurate

(32) (513) to achieve pre-CPB but
predicted concentration performed poorly
of 100 ng/mL during and post-
Sufentanil by CACI CPB.
(435) to achieve
predicted concentration
1-10 ng/mL depending
on surgical stimulation
(n = 20)
Thomson et al. Fentanyl by CACI (545) NA NA No difference in

(35) to achieve effect site ability to obtund
concentration (Keo) 8.1 hemodynamic
ng/mL (n = 10) response or
Sufentanil by CACI requirements for
(545) to achieve effect isoflurane.
site concentration (Keo)
0.68 ng/mL (n = 11)
+ isoflurane pre-CPB
Hudson et al. Population NA NA Parameters derived

(33) pharmacokinetic for three-
modeling of 529 compartment model
sufentanil samples from provided better
103 subjects in previous accuracy than
studies (34,39,434) previous models for
computer-driven
infusions.
Forestier et al. Sufentanil by CACI 30°C NA [sufentanil] vs. effect

(40) (435) to maintain effect relationship (as
site concentration reflected by
0.5 ng/mL (n = 21) changes in
0.75 ng/mL (n = 22) Bispectral Index
1.0 ng/mL (n = 23) Score values)
1.25 ng/mL (n = 21) determined.
1.5 ng/mL (n = 23) Predicted
+ propofol (Diprifusor) to [sufentanil] of 1.25
target concentration 1.5 ng/mL pre-
μg/mL sternotomy and 0.8
ng/mL until skin
closure provided
optimum effect with
best hemodynamic
control. Four
patients reported
recall of
intraoperative
events.
Hudson et al. Sufentanil infusion 0.5 >33°C Nonsilicone Hollow PK modeling applied
(25) μg/kg loading dose, Fibre Membrane including adjustment
then CACI (33) to for CPB.
achieve effect site Simple three-
concentration 0.7 ng/mL compartment PK
preincision, 0.5 ng/mL model adequate for
post-sternotomy, 0.15 clinical use.
ng/L 30 min on CPB +
isoflurane (n = 21)

μg/mL + sufentanil 1.8 No evidence of
μg/kg/hr until CPB, then myocardial
0.9 μg/kg/hr (n = 15) ischemia.
No significant
adverse
hemodynamic
effects.
Zomorodi et al. CACI to attain NA NA Three-compartment

(419) [midazolam] (232) of 75- PK model best
150 ng/mL and 50 described
ng/mL adjusted for pharmacokinetic
effect in ICU + data for midazolam.
[sufentanil] (517) of 1-2 Length of time for
ng/mL, 0.5-1 ng/mL awakening
while on CPB, 0.3-0.6 dependent on
ng/mL post-CPB, 0.15 duration of infusion
ng/mL in ICU (n = 63) in the ICU.
Jeleazcov et al. Propofol by CACI (530) 35.7°C- NA CACI using the

(101) to maintain BIS 35-45 + 36.2°C Gept’s model led to
Sufentanil by Gept’s higher total
model for CACI (435) to [sufentanil] pre-CPB
maintain [sufentanil] at than target. During
0.4 (n = 18) or 0.8 (n = CPB, total
20) ng/mL concentrations
declined but free
fraction increased.
Population PK
model derived
based on increased
elimination and
interdepartmental
clearance during
CPB, unchanged Vc
until the end of CPB,
and unchanged
peripheral Vd.
Vasodilator agents
Nitric oxide
Solina et al. Nitric oxide (NO) 28°C Turbo Membrane No concentration vs.
(549) administered through (SARNS) effect relationship
INOvent delivery device demonstrated
Group 1: NO 10 ppm (n between groups in ↓
= 11) PVR.
Group 2: NO 20 ppm (n
= 12)
= 12)
= 12)
Group 5: Milrinone (n =
15) at termination of
CPB
Nitroglycerine
Dasta et al. Group 1: Nitroglycerin 32°C Cobe Optiflow II [nitroglycerin] ↓ 82%

(181) 100 μg/mL to prime Bubble indicating uptake by
solution to achieve a CPB circuit, mostly
target concentration of by the oxygenator
100 ng/mL (n = 1) (65%) during the
Group 2: Nitroglycerin first pass in the
100 μg/mL at 90 mL/hr circuit.
added to prime (n = 1)
In vitro study
Dasta et al. Nitroglycerin 200 μg/mL 27°C Bentley Spiraflow Cl ↑ 20% during
(436) at 5-10 μg/min pre-CPB BOS-10S Bubble CPB. [nitroglycerin]
(n = 7) ↓ 67% due to uptake
by oxygenator.
Booth et al. Nitroglycerin 5 mg/mL to 25°C or 37°C Bentley Nitroglycerine

(182) obtain [nitroglycerin] of Spiraflow BOS- uptake by
6 × 10-8 M 10S Bubble (n = 4) oxygenator
In vitro study or Maxima Hollow substantial:
Fibre Membrane (n BOS-10S 67%
= 4) or Cobe CML Cobe 47%
Membrane (n = 3) Maxima 21%
No effect of
temperature.
Booth et al. Group 1: Nitroglycerin NA COBE CML [nitroglycerin] higher

(550) 0.5 μg/kg/min Membrane in men.
throughout During CPB Cl ↓ by
normothermic surgery (n 66% in men and
= 8) 53% in women.
Group 2: Nitroglycerin Nitroglycerin
0.5 μg/kg/min pre- and metabolism ↓ by
post-CPB + 5 μg/kg/min hypothermia.
during normothermic
CPB (n = 12)
Group 3: Nitroglycerin
0.5 μg/kg/min pre-and
post-CPB and 1.0
μg/kg/min during
hypothermic CPB
Nitroprusside
Moore et al. Nitroprusside 0.45 25°C Bentley BOS-10 Nonenzymatic

(437) mg/kg/hr into conversion to
oxygenator (n = 6) cyanide unaffected
In vitro study by hypothermic CPB
but enzymatic
conversion of
cyanide to
thiocyanate ↓.
Recovered with
rewarming.
Lundquist et al. Nitroprusside 29°C Bubble Infusion rate for

(438) 0-1 μg/kg/min (n = 9) or nitroprusside ↓
0-1 μg/kg/min + 0.3 g during hypothermic
thiosulphate (n = 9) CPB. [cyanide] ↑
adjusted to maintain during hypothermic
hemodynamics CPB with
attenuation by
thiosulphate.
Toxic RBC [cyanide]
in some patients.
Przybylo et al. Nitroprusside titrated to 28°C NA Cyanide levels ↑ as

(128) hemodynamics while on dose ↑.
CPB t1/2β = 0.58 hr
Max dose 10 μg/kg/min Six children had
(10) toxic levels >0.5
Pediatric population μg/mL but not
correlated to dose.
Volatile anesthetic agents
Desflurane
Mets et al. (187) Desflurane 6% added to 32°C Sarns 440 Turbo Arterial [desflurane]
gas inflow to CPB circuit Membrane reached 50% within
(n = 10) (Terumo) 4 min and 68% of
inflow concentration
at 32 min.
Washout rapid with
only 18% remaining
at 4 min and 8% at
20 min.
Yu et al. (135) Isoflurane Variable NA Volatile anesthetic

Desflurane solubility in whole
Halothane blood not different
1. Solubility in fresh than in plasma but
whole blood and eight significantly different
CPB pump priming from other priming
solutions at 37° solutions.
2. Effect of temperature As blood is diluted
on solubility in by pump priming
Ringers lactate, fluid volatile gas
gelofusin, banked solubility is ↓.
blood, plasma As temperature ↓,
3. Solubility in Ringers volatile gas solubility
lactate, gelofusin, in all fluids ↑.
blood, plasma in
different mixes at
different temperatures
4. Estimated and actual
solubility in blood
during hypothermic
CPB (n = 20)
In vitro study
Mierdl et al. Sevoflurane (n = 5) NA Membrane Significant exposure

(551) Desflurane (n = 5) of anesthesiologist,
Volatile anesthetic surgeon, and
discontinued at onset of perfusionist to waste
CPB and measurements gas administered
obtained before and during cardiac
during CPB surgery.
They suggested
connecting the
oxygenator to a
waste gas
scavenger.
Enflurane
Nussmeier et al. Group 1: Isoflurane (n = 24°C Bentley Ben-10 Isoflurane washin

(104) 6) Bubble showed >50%
Group 2: Isoflurane 0.3 equilibration by 4
MAC (n = 5) min and >90% by 16
Enflurane 0.3 MAC (n = min. Washout was
5) >75% by 4 min and
Halothane 0.3 MAC (n = >90% by 16 min.
5) Washin was faster
In vitro study at higher gas flow
rates as was
washout. Neither
washin nor washout
rate was affected by
pump flow rates.
Initial washin rates
higher for isoflurane
and enflurane vs.
halothane.
Isoflurane had the
highest washout
rate.
Tarr and Enflurane 0.6% v/v 24°C COBE Membrane Solubility and
Snowden (552) fresh gas flow (n = 10) [enflurane] ↓ (25%)
with onset of CPB.
[enflurane] ↑ during
hypothermic CPB.
No tissue
redistribution to
blood phase during
rewarming
demonstrated.
Goucke et al. Enflurane delivered at a 28°C Capiox E [enflurane] at 28°C

(441) concentration of 0.5% Membrane unchanged at 0.5
v/v (n = 5), 0.8% v/v (n and 0.8% v/v but
= 7), and 1.0% v/v (n = increased by 26% at
14) 1% v/v.
Concentrations
returned to pre-CPB
levels in all groups
following rewarming.
t1/2α = 1.3 min, t1/2β
= 11 min, V1 = 3.1 L
Halothane
Moore et al. Halothane NA Sci-Med Reductive

(553) Group 1: Acyanotic (n = Membrane metabolism ↑ in the
10) cyanotic group.
Group 2: Cyanotic (n =
10)

(104) 6) Bubble >50% equilibration
Group 2: Isoflurane 0.3 by 4 min and >90%
MAC (n = 5) by 16 min.
Enflurane 0.3 MAC (n = Washout was >75%
5) by 4 min and >90%
Halothane 0.3 MAC (n = by 16 min.
rates as was
washout.
Neither washin nor
washout rate was
affected by pump
flow rates.
and enflurane vs.
halothane.
Isoflurane had the
highest washout
rate.
Yu et al. (135) Isoflurane Variable NA As blood is diluted

Desflurane by priming fluid
Halothane volatile gas solubility
1. Solubility in fresh is ↓.
whole blood and eight As temperature ↓,
CPB priming fluids at volatile gas solubility
37°C in all fluids ↑.
2. Effect of temperature Volatile anesthetic
on solubility in solubility in whole
Ringers lactate, blood not different
gelofusin, banked than plasma but
blood, plasma significantly different
3. Solubility in Ringers from other priming
lactate, gelofusin, solutions.
blood, plasma in As blood is diluted
different mixes at by pump priming
different temperatures fluid volatile gas
4. Estimated and actual solubility is ↓.
solubility in blood As temperature ↓,
during hypothermic volatile gas solubility
CPB (n = 20) in all fluids ↑.
Isoflurane
Loomis et al. Isoflurane to maintain 25°C Cobe Membrane Concentration

(554) MAP 50-80 mm Hg on dependent ↓ in EEG
CPB (n = 10) a-stat activity with ↑
blood gas management [isoflurane] until
burst suppression at
46.5 μg/mL. Rapid
offset of action with
t1/2β of 19 min.
Hypothermia ↓ EEG
amplitude but did
not produce burst
suppression.
Mean vaporizer
setting 2.2% at
onset of burst
suppression.
Henderson et al. Isoflurane 1% inspired 28°C Bentley Bio Bubble Washin of isoflurane
(439) (n = 14) α-stat blood (n = 7) had a rapid phase
gas management Terumo Capiox followed by a slow
Membrane (n = 7) phase with a
continued slow rise
in concentration in
plasma up to 48 min.
Washout was
characterized by a
rapid phase followed
by a slower
elimination with a
t1/2β of 9.4 min
(Bubble) to 14.9 min
(Membrane).
[isoflurane] ↓ >50%
within 2 min.

(104) 6) Bubble >50% equilibration
Group 2: Isoflurane 0.3 by 4 min and >90%
MAC (n = 5) by 16 min.
Enflurane 0.3 MAC (n = Washout was >75%
5) by 4 min and >90%
Halothane 0.3 MAC (n = by 16 min.
rates as was
washout. Neither
washin nor washout
rate was affected by
pump flow rates.
and enflurane vs.
halothane.
Isoflurane had the
highest washout
rate.
Nussmeier et al. Isoflurane 1% to 23°C Bentley Ben-10 Washin 41% at 16

(105) oxygenator inlet during Bubble min, 51% at 32 min
CPB (n = 9) and 57% at 48 min.
Washout 36% of
peak at 8 min, 24%
at 16 min, and 13%
at 32 min.
Venous
concentration
declined more
slowly than arterial.
Washin slower
during hypothermic
CPB due to greater
tissue capacity.
Washout during
rewarming similar to
normothermic rate.
Stern et al. Isoflurane 2% (n = 3) NA Sci-Med Sci-Med oxygenator

(172) In vitro study Membrane No. 1- absorbs significant
35002A amounts of
isoflurane.
Blood equilibration
affected by gas flow
rates but not by
blood flow rate.
Time constant for
isoflurane
elimination = 7 min.
Hickey et al. Isoflurane 1.15% 28°C and SM-35 (Avecor) or Uptake of isoflurane
(171) Group 1: SM-35 37°C CML (Cobe) or was slower by the
oxygenator (n = 4) SAFE II (Polystan SM-35 oxygenator
Group 2: CML AS) Membrane at both
oxygenator (n = 4) temperatures.
Group 3: SAFE II Elimination was also
oxygenator (n = 4) slower with the SM-
In vitro study 35 oxygenator.
Elimination was
faster at 37° vs. 28°
for CML and SM-35
oxygenators but not
for the SAFE II.
Lundell et al. Isoflurane (variable) + 30°C Sarns Hollow Fibre [sevoflurane]

(272) CACI (545) fentanyl Membrane required to maintain
infusion to maintain an same Bispectral
effect site concentration Index Score value
of 3 ng/mL so as to was ↓ by 25% post-
maintain Bispectral CPB suggesting
Index Score at 55 (n = CPB-induced
20) changes in
anesthetic
requirements.
Yu et al. (135) Isoflurane Variable NA Volatile anesthetic

Desflurane solubility in whole
Halothane blood not different
1. Solubility in fresh than plasma but
whole blood and eight significantly different
CPB priming fluids at from other priming
37° solutions.
2. Effect of temperature As blood is diluted
on solubility in by priming fluid
Ringers lactate, solubility is ↓.
gelofusin, banked As temperature ↓,
blood, plasma solubility in all fluids
3. Solubility in Ringers ↑.
lactate, gelofusin,
blood, plasma in
different mixes at
different temperatures
4. Estimated and actual
solubility in blood
during hypothermic
CPB (n = 20)
Philipp et al. Isoflurane 1% v/v fresh >33°C Hilite 7000 (n = 15) Uptake of
(13) gas flow to gas inlet and Capiox Rx 25 (n = [isoflurane] minimal
measurement of washin 15) into diffusion type
and washout through Hilite 7000 LT (n = oxygenators with or
oxygenator 15) without heparin
QuadroxD (n = 15) coating (i.e., Hilite
7000 LT and
QuadroxD).
[isoflurane] ↓ 62% at
outlet port for the
two microporous
oxygenators
indicating transfer of
[isoflurane] into
membrane (Hilite
7000 and Capiox Rx
25).
They suggested that
patients may be
unable to excrete
isoflurane
administered during
CPB if diffusion type
membrane is
utilized.
Wiesenack et al. Isoflurane 1% v/v fresh 32°C Group 1: Capiox Washin and
(173) gas flow to gas inlet and RX 25 (Terumo) (n washout of
measurement of washin = 6) isoflurane rapid with
and washout through Group 2: Hilite microporous
oxygenator 7000 (Medos) (n = polypropylene
6) (PPL)-type
Group 3: oxygenators
QuadroxD (Jostra) (Groups 1 and 2).
(n = 6) Negligible washin
Group 4: Hilite and washout for
7000 LT (Medes) diffusion plasma-
(n = 6) tight poly-(4-methyl-
1-pentene) (PMP)-
type oxygenators
(Groups 3 and 4).
They suggested that
isoflurane
administered during
CPB may not be
delivered to the
patient depending
on the type of
oxygenator utilized.
Sevoflurane
Bito et al. (386) Sevoflurane pre- and 28°C NA [Fluoride] increased
post-CPB (n = 16) while sevoflurane
administered both
pre- and post-CPB
with peak 2-hr post-
CPB at 17.4/μmol.
Mierdl et al. Sevoflurane (n = 5) NA Membrane Significant exposure
(551) Desflurane (n = 5) of anesthesiologist,
Volatile anesthetic surgeon, and
discontinued at onset of perfusionist to waste
CPB and measurements gas administered
obtained before and during cardiac
during CPB surgery.
They suggested
connecting the
oxygenator to a
waste gas
scavenger.
Prasser et al. Conventional 33°C-34°C Conventional Blood [sevoflurane]

(175) microporous microporous (PPL) declined to greater
polypropylene (PPL) membrane extent in PPL group
membrane oxygenator (Highlite 7000; at onset and during
(n = 10) or plasma tight Medos) or Plasma- CPB. Estimated
poly-(4-methyl-1- tight PMP [sevoflurane] at 60
pentene) (PMP) membrane min when compared
membrane oxygenator oxygenator to CPB level 39% in
(n = 10). (Quadrox D; PMP group vs. 12%
In vivo study using a Jostra) PPL group.
miniaturized Steady-state efflux
extracorporeal at exhaust port 0.1%
circulation (MECC) for PPL group vs.
system 0% for PMP group.
Hinz et al. (174) Effect of two different 32°C-34°C PLP Group [sevoflurane] in
membrane oxygenators (HILITE 7000) with plasma equal at the
on plasma [sevoflurane] polypropylene onset of CPB but
Polypropylene (PPL) membrane PPL group then had
Group (n = 10) PMP Group decline in
Polymethylpentane (HILITE 7000) with [sevoflurane] in
(PMP) Group (n = 10) polymethylpentane plasma, whereas
Bispectral Index used to membrane PMP group had
monitor depth of (MEDOS stable plasma
anesthesia Medizintechnik) [sevoflurane] while
on CPB.
Little sevoflurane
detected at the
exhaust gas flow
port in PMP group.
During reperfusion
[sevoflurane] ↓ in
both groups as the
lung perfusion was
restored.
In PLP group, mean
arterial pressure ↑
and Bispectral Index
↑ as [sevoflurane] ↓.
aUnless otherwise indicated, all doses are given intravenously; unless otherwise indicated, all concentrations
referred to are total drug concentrations.
CPB, cardiopulmonary bypass; [], plasma concentration of drug; t1/2β, terminal elimination half-time; Vdss,
volume of distribution at steady-state plasma concentrations of drug; Cl, drug clearance; PK, pharmacokinetics;
NA, Not available in methods of cited reference; Vd, volume of distribution; ICU, intensive care unit; CHD,
congenital heart disease; MIC, minimal inhibitory concentration; OR, operating room; MRSA, methicillin-
resistant Staphylococcus aureus; CrCl, creatinine clearance; Cp50, plasma concentration at which response to
given stimulus abolished in 50% of patients; RBC, red blood cell; CACI, computer-assisted continuous infusion;
IPPV, intermittent positive pressure ventilation; PEEP, positive end-expiratory pressure; PA, pulmonary artery;
MAC, minimum alveolar concentration; SVR, systemic vascular resistance; PVR, pulmonary vascular
resistance; v/v, volume of vapor/volume of fresh gas flow.
Antiarrhythmic Agents
Lidocaine is frequently administered during cardiac surgery, usually just before release of the aortic cross-clamp, to
prevent ventricular ectopy. Review of data in Table 10.5 suggests that bolus doses of lidocaine should likely be
increased (from 1.5 to 2.5 mg/kg) to ensure that therapeutic concentrations are achieved (95). If an infusion is
subsequently initiated, the free drug concentration may decline over time despite adequate total drug concentrations
because of enhanced protein binding by the acute-phase reactant α1AGP (97,98,199). This effect appears to be
maximal 3 days after CPB in uncomplicated cases.
P.300
Should ectopy occur during this period, an increase in infusion rate is warranted (108). A weight-based infusion scheme
designed to prevent lidocaine toxicity has been proposed (359).
Antibiotics
Infection is a devastating complication following cardiac surgery because it increases morbidity, mortality, and hospital
costs (360). Recognition of risk factors for infection and use of prophylactic antibiotics are key elements in the
prevention of this devastating complication (361). The primary causative bacteria are Staphylococcus sp. While
antibiotic effect may be classified in a number of ways (362), one classification scheme suggests antibiotics achieve
their pharmacodynamic effect generally through two different mechanisms. These include a dose-dependent one where
the peak concentration ( Cmax) achieved is important for efficient microbial killing (e.g., fluoroquinolones,
aminoglycosides, polymyxins (363)), and a time-dependent mechanism (AUC) (e.g., β-lactams, including cephalosporins
(364), penicillins, and carbapenems (363,365)) where time above the effective minimum inhibitory concentration (MIC) is
the important factor. Antibiotics may also be classed as hydrophilic (e.g., β-lactams, aminoglycoside, and glycopeptides)
or lipophilic (e.g., fluoroquinolones, macrolides, and linezolid) (363).
Whatever drug is employed for antibiotic prophylaxis must achieve and sustain therapeutic serum and tissue
concentrations (MIC) against these organisms during surgery and CPB (366). Examination of Table 10.5 reveals that
this is not always the case (367,368,369,370,371,372,373,374,375,376,377). Failure to achieve therapeutic MIC in
plasma/serum and tissue may result from an inadequate dose or from inappropriate timing of an otherwise adequate
dose (367). During cardiac surgery, as a consequence of the inflammatory response (92), there may be tissue
accumulation of administered fluids (162) and there is hemodilution at the onset of CPB. In theory, these factors will
serve to increase the Vd of hydrophilic antibiotics such as the cephalosporins, aminoglycosides, and glycopeptides, and
may reduce the concentration in plasma to a point where, for at least a portion of time, it is below the time-dependent
level for efficient microbial killing (363,367). Cotogni et al. (378) examined the concentration-versus-time profile of
vancomycin given before skin incision in a group of patients undergoing cardiac surgery with or without CPB and
measured a nonsignificant 10% increase in Vd and a significant increase in the elimination half-time in the group
undergoing CPB. A reduction in vancomycin levels was also observed at the start of CPB. However, the minimal
differences in pharmacokinetic parameters observed between the on-pump and off-pump groups (Table 10.5) led the
investigators to conclude that vancomycin pharmacokinetics were not significantly altered by CPB. Similarly, Ferreira et
al. (379) administered cefuroxime to a group of patients undergoing cardiac surgery with or without CPB and again did
not detect any difference in pharmacokinetic parameters. Although there was recovery soon thereafter, they also noted
a 50% reduction in plasma levels at the time of CPB initiation. These findings suggest that factors other than an
increased Vd and hemodilution (e.g., hypothermia and reduced clearance) may play more important roles. Alternatively,
as a result of changes in organ perfusion during CPB, decreased clearance of some drugs (e.g., aminoglycosides) may
lead to toxic drug concentrations (380,381,382). While the choice of prophylactic antibiotic used usually reflects the
local pattern of antibiotic resistance and surgical preference, current evidence suggests that use of a second or third
generation cephalosporin is optimal (383), and that the duration should be at least 24 to 48 hours (383,384). It should
be noted that, for most second-generation cephalosporins (e.g., cefazolin, cefamandole), there is a considerable (>30%)
reduction in plasma concentration at initiation of CPB (385,386). To maintain sufficient plasma levels of antibiotics it may
be preferable to administer a continuous infusion (367), although continued study is necessary (387). The added value
of providing supplementation in the pump priming solution is dependent on drug class but is recommended where
cephalosporins are employed primarily. The presence of preexisting organ dysfunction (e.g., renal dysfunction) may
also influence drug levels (388). In areas where there is a high prevalence of methicillin-resistant Staphylococcus
aureus (MRSA), an alternative class of antibiotic for prophylaxis (e.g., vancomycin) should be chosen. Guidance for
dosing can be found in Table 10.5 (185,186,376,377,389,390).
Antifibrinolytic Agents
Cardiac surgery—with or without CPB—generates a coagulopathy due to tissue factor release, platelet contact
activation generated by interaction of blood with nonendothelial surfaces, and hemodilution (391). Contact activation
leads to fibrin generation, fibrinolysis, and to platelet activation and consumption or sequestration (311,392).
Antifibrinolytic agents are often utilized prophylactically to reduce the coagulopathy generated by surgery and CPB
(391). Two main drug classes are primarily utilized—serine protease inhibitors (represented by aprotinin) and lysine
analogs (represented by tranexamic acid and aminocaproic acid) (393). Although these agents effectively reduce blood
loss, their relative cost-benefit ratio is still under debate (393,394,395).
The use of many different dosing regimens may account for some of the efficacy differences observed with these agents
(396) (Table 10.5). It has recently been suggested that the target tranexamic acid concentration to provide effective
antifibrinolytic activity during CPB is >126 μg/mL (397). Pharmacokinetic models have been derived based on this
assumption and dosing guidelines established for adults (398) and children (399) (Table 10.5). Although controversial,
the potential for increased mortality with aprotinin (395,400) remains unexplained while tissue accumulation in the CNS
for the lysine analogs (243) (and observations of increased risk for seizures (242)) may account for some of the
observed
P.301
toxicity attributed to this drug. As a consequence of these concerns, the search for safer alternatives continues (401).
β-Adrenergic Receptor Blocking Agents

Studies reviewed in Table 10.5 suggest that the effects of esmolol will be enhanced by hypothermia (likely as a result of
inhibition of the esterase enzyme responsible for its metabolism) (125). Studies have also reported that propranolol
disposition is affected by heparin administration (increased free fraction) and CPB (decreased free fraction as CPB
commences). Elimination half-time and volume of distribution were also observed to increase in existing studies,
suggesting that propranolol administration may have enhanced effects during CPB (208,209,402,403,404). In contrast,
atenolol (405,406) and landiolol (407) pharmacokinetics appear to be minimally affected by CPB. On balance, atenolol
would appear to be the optimum agent to initiate preoperatively based on pharmacokinetic considerations alone.
Digitalis Glycosides
Results of studies listed in Table 10.5 suggest that, provided digoxin is continued until the day of surgery, adequate
tissue concentrations are sustained during CPB (212).
Glucocorticoid Agents
Glucocorticoid agents are commonly employed during cardiac surgery to ameliorate the stress or inflammatory response
associated with CPB (205). However, a critical analysis of relevant studies could not demonstrate any benefit for their
use in this context (408). Pharmacokinetic studies suggest that methylprednisolone hemisuccinate is rapidly converted
to the active agent methylprednisolone even during CPB (Table 10.5) (409).
Inotropic Agents (Including Phosphodiesterase Inhibitors)

Because of its enhanced safety profile relative to amrinone (410), milrinone is the most commonly employed
phosphodiesterase III inhibitor during cardiac surgery (411). In contrast to amrinone (412), milrinone appears to bind
minimally to the CPB circuit (413). While dosing recommendations can be made on the basis of pharmacokinetics (414)
(Table 10.5), results show considerable variability. These studies are complicated by the fact that most of them involved
pediatric populations, which differ from adults in clearance capabilities (immature liver/renal function) and volumes of
distribution (differences in fat tissue/lean tissue ratios) (413,414). Dosing regimens utilized in the studies given in Table
10.5 should serve as guides, with knowledge that they may be affected by age, disease, and CPB. Doses should be
adjusted on the basis of the hemodynamic response. With these considerations, it is suggested that an appropriate
initial infusion regimen would be a loading dose of 50 μg/kg with a maintenance infusion of 0.5 μg/kg/min. On initiating
phosphodiesterase inhibitor therapy during CPB, one should anticipate the need for a vasoconstrictor, such as
norepinephrine, to sustain the systemic blood pressure to partially offset the vasodilation induced by these “inodilator”
agents. Finally, while uptake of dopamine by a membrane oxygenator has been demonstrated (415), the degree of
uptake probably lacks clinical significance.
Intravenous Anesthetic Agents

Studies of changes in pharmacokinetic parameters of intravenous anesthetic agents, including thiopental, midazolam,
and propofol, mirror those observed for the opioids (Table 10.5). That is, reductions in total drug concentrations on
initiation of CPB, with rapid readjustment of free drug concentrations to approach those present before initiation of CPB,
and reductions in drug clearance and increased volume of distribution leading to an increased elimination half-time
following termination of CPB (5,6,8,9,10,96,99,106,114,141,177,183,225,240,271,416,417,418,419,420). Utilizing
computer-driven infusions to maintain constant plasma concentrations, the independent anesthetic effects of
hypothermia (114) and CPB (10,271) have been described. Although the ability to measure propofol in exhaled gas is
technically difficult at present, a novel approach to utilizing pharmacokinetics to enhance propofol administration may be
the ability to measure exhaled propofol concentrations and adjust infusion rates accordingly (421).
Neuromuscular Receptor Blocking Agents

It is perhaps in this class of pharmacologic agents that the most contradictory evidence exists for changes in
pharmacokinetics and pharmacodynamics during hypothermic CPB. Table 10.5 shows studies where requirements for
muscle relaxant are increased (248) or reduced (251) for the same agent (pancuronium). Most likely, this represents the
confounding pharmacodynamic effects of hypothermia on the function of the neuromuscular junction, which likely vary
with the magnitude and duration of hypothermia (124,250,422,423,424,425). For agents such as atracurium,
mivacurium, and doxacurium, decreased plasma concentrations of the metabolizing enzyme cholinesterase may play a
greater pharmacokinetic role than the use of CPB per se (126,426). In addition, changes in clearance and volume of
distribution for drugs metabolized or cleared by other mechanisms may alter their pharmacokinetics (136,425). The
importance of monitoring neuromuscular function with a twitch monitor is evident, given the conflicting evidence for
changes in pharmacokinetics and pharmacodynamics with this class of drugs.
Opioids
A review of studies on opioid administration during cardiac surgery (Table 10.5) suggests that there is a normal decline
in concentrations of drugs administered before CPB, a reduction in concentrations at initiation of CPB (with rapid
readjustment of free drug concentrations while on CPB), and
P.302
relatively stable plasma concentrations during hypothermic CPB. Increases in plasma concentrations occur at
termination of CPB, likely from washout of drug sequestered in the lungs, and reduced drug elimination after CPB
(probably as a result of increased volume of distribution and reduced clearance)
(4,7,30,101,127,138,143,144,147,224,228,427,428,429,430). Changes in pH as a result of blood gas management are
more likely to affect fentanyl and sufentanil concentrations. Decreased concentrations of fentanyl have been reported at
neutral or high pH, likely secondary to increased absorption by the circuit (169), while decreased sufentanil
concentrations have been observed when pH-stat blood gas management was employed, likely due to increased tissue
penetration as a result of changes in the degree of ionization of the drug (170). Likely as a result of a hypothermia-
induced reduction in plasma esterase activity, remifentanil clearance is decreased during CPB (26,127). Opioids exhibit
little capacity to suppress the stress response during CPB (34,431,432); so concomitant adjuvant agents (such as
clonidine (433,434), sedative/hypnotics (36,40), or vasodilators (431)) are frequently required to control hemodynamics
(34,431,432).
Pharmacokinetic models permit the use of computer-driven infusions to achieve targeted plasma drug concentrations
during cardiac surgery with CPB. Opioids have received the most scrutiny in this regard. Thomson and colleagues (34)
used a computer-controlled infusion and pharmacokinetic parameters derived from other surgical populations to
determine the concentration-effect relationship for fentanyl and sufentanil when used in the presence of isoflurane. It
was determined that concentrations of sufentanil above 1.25 ng/mL and fentanyl above 13.3 ng/mL minimize isoflurane
requirements but do not provide additional control of hemodynamics.
Next, it was determined that a three-compartment model was adequate for delivery of sufentanil by computer infusion
(33), and that although CPB had effects on pharmacokinetics, these could largely be ignored for all practical purposes
in the clinical arena (25). Similar results were found for fentanyl (21,33). While precise pharmacokinetic models for
delivery of sufentanil during cardiac surgery have been derived (101,435), in reality, a simple infusion scheme can be
utilized to maintain adequate concentrations of opioid titrated to effect during cardiac surgery without adjusting for CPB
(20). It should be emphasized that this applies only to the relatively short-term administration of opioids during the
intraoperative period. More prolonged infusions of opioids for sedation/analgesia in the ICU may be affected by CPB-
induced alterations in the clearance and volume of distribution of these agents.
Significant binding of opioids to some types of oxygenators (principally silicone) occurs, but is of limited clinical
importance (perhaps other than during initiation of CPB) because of a rapid redistribution of drug from peripheral
storage sites (3,178,179). To prevent a reduction in opioid concentrations at the time of initiation of CPB, one should
consider giving supplemental doses.
Vasodilator Agents
Although significant uptake of nitroglycerin by the oxygenator has been demonstrated in vitro (181), this appears to be
of little clinical significance in vivo (436). When sodium nitroprusside is administered during hypothermic CPB, cyanide
concentrations are consistently elevated—at times even to toxic concentrations (128,437,438).
Volatile Anesthetic Agents

In general, wash in and wash out of volatile anesthetic agents is rapid (105,106,187,439,440), but this process slows
with hypothermia (105,171,441), and may be affected by the type of oxygenator employed (13,171,172,173,175).
Uptake by the oxygenator is of particular concern as it may lead to insufficient anesthetic delivery to the patient (13).
Before employing a new type of oxygenator, it would seem prudent to verify that sufficient anesthetic gas transfer occurs
to maintain anesthesia. The development of new types of membrane oxygenators, particularly the PMP type of
oxygenator (which has been associated with fluctuations in hemodynamics during CPB and perhaps inadequate levels
of anesthesia (173)), makes this imperative (175). Heretofore, this could be determined by monitoring the gas
concentration at the outlet port of the oxygenator (175,442). However, with the newer PMP membrane, there is no
exhaust gas volatile agent measurable (although plasma concentrations may be unchanged (or increased) (174)),
suggesting that alternative monitoring methods for anesthetic depth are required when these oxygenators are employed.
For initiation of CPB, overpressurization with high inspired anesthetic concentrations and gas flows may increase the
anesthetic level more rapidly (104). Before termination of CPB, concentrations of volatile agents should be reduced in
order to minimize myocardial depressant effects while still maintaining adequate anesthesia to prevent awareness (441).
Supplementing anesthesia at this time with a benzodiazepine such as midazolam may help to prevent awareness while
minimizing myocardial depression. As compared with the pre-CPB state, concentrations of volatile anesthetic agents
required to achieve similar levels of anesthesia may be diminished following CPB (274).
SUMMARY AND CONCLUSION

This chapter has reviewed pharmacokinetics and pharmacodynamics as well as the potential role of hypothermia
and CPB in altering drug disposition and action. Understanding these concepts and the potential for alteration of
drug effect by CPB allows for appropriate adjustment in drug regimens to prevent unwanted complications,
including inadequate levels of anesthesia, prolonged muscle relaxation, infectious complications, and arrhythmias.
Further work to elucidate the role of ameliorating the occurrence of SIRS during surgery and CPB, and its effects
on drug pharmacokinetics and pharmacodynamics, is required.
P.303
KEY Points
Pharmacokinetics is the description, usually in mathematical terms, of the processes involved in handling a
drug once it is introduced into the body. Key concepts to be familiar with here include:
Volume of distribution
Clearance
Elimination half-time
Hepatic extraction ratio
Pharmacodynamics is the description of how a drug reacts with the body to produce its effects. Key
concepts to be familiar with here include:
Receptors
Second messengers
CPB-induced changes
Pharmacokinetic changes are induced by the following:
Hemodilution
Hypothermia
Perfusion flows
Acid-base status
Sequestration
Pharmacodynamic properties are changed by the following:
Binding (to tissue, proteins, apparatus)
Age
Tissue penetration
Temperature
Receptor density
Acid-base status
Anesthetic agents
Specific drug classes that are influenced by CPB include:
Opioids: Concentrations decrease with onset of CPB, but free drug concentrations rapidly return toward
baseline during CPB.
Intravenous anesthetics (benzodiazepines, propofol, barbiturates): Concentrations decrease with onset
of CPB, but free drug concentrations rapidly return toward baseline during CPB.
Neuromuscular blocking agents: Effects are markedly influenced by hypothermia.
Antibiotics: They have variable tissue penetration.
Lidocaine: A higher loading dose is indicated (2.5 mg/kg).
REFERENCES
1. Diegeler A, Borgermann J, Kappert U, et al. Off-pump versus onpump coronary-artery bypass grafting in elderly
patients. N Engl J Med 2013;368(13):1189-1198.
2. Pea F, Pavan F, Furlanut M. Clinical relevance of pharmacokinetics and pharmacodynamics in cardiac critical
care patients. Clin Pharmacokinet 2008;47(7):449-462.
3. Hynynen M. Binding of fentanyl and alfentanil to the extracorporeal circuit. Acta Anaesthesiol Scand
1987;31(8):706-710.
4. Hug CC Jr, Burm AG, de Lange S. Alfentanil pharmacokinetics in cardiac surgical patients. Anesth Analg
1994;78(2):231-239.
5. Morgan DJ, Crankshaw DP, Prideaux PR, et al. Thiopentone levels during cardiopulmonary bypass. Changes in
plasma protein binding during continuous infusion. Anaesthesia 1986;41(1):4-10.
6. Dawson PJ, Bjorksten AR, Blake DW, et al. The effects of cardiopulmonary bypass on total and unbound plasma
concentrations of propofol and midazolam. J Cardiothorac Vasc Anesth 1997;11(5):556-561.
7. Kumar K, Crankshaw DP, Morgan DJ, et al. The effect of cardiopulmonary bypass on plasma protein binding of
alfentanil. Eur J Clin Pharmacol 1988;35(1):47-52.
8. Hiraoka H, Yamamoto K, Okano N, et al. Changes in drug plasma concentrations of an extensively bound and
highly extracted drug, propofol, in response to altered plasma binding. Clin Pharmacol Ther 2004;75(4):324-330.
9. Takizawa E, Hiraoka H, Takizawa D, et al. Changes in the effect of propofol in response to altered plasma protein
binding during normothermic cardiopulmonary bypass. Br J Anaesth 2006;96(2):179-185.
10. Yoshitani K, Kawaguchi M, Takahashi M, et al. Plasma propofol concentration and EEG burst suppression ratio
during normothermic cardiopulmonary bypass. Br J Anaesth 2003;90(2):122-126.
11. Dawidowicz AL, Kalitynski R, Kobielski M, et al. Influence of propofol concentration in human plasma on free
fraction of the drug. Chem Biol Interact 2006;159(2):149-155.
12. Thomson IR, Hudson RJ, Rosenbloom M, et al. A randomized double-blind comparison of fentanyl and sufentanil
anaesthesia for coronary artery surgery. Can J Anaesth 1987;34(3, Part 1):227-232.
13. Philipp A, Wiesenack C, Behr R, et al. High risk of intraoperative awareness during cardiopulmonary bypass with
isoflurane administration via diffusion membrane oxygenators. Perfusion 2002;17(3):175-178.
14. Phillips AA, McLean RF, Devitt JH, et al. Recall of intraoperative events after general anaesthesia and
cardiopulmonary bypass. Can J Anaesth 1993;40(10):922-926.
15. Grandison MK, Boudinot FD. Age-related changes in protein binding of drugs: implications for therapy. Clin
Pharmacokinet 2000;38(3):271-290.
16. Schwartz JB. The influence of sex on pharmacokinetics. Clin Pharmacokinet 2003;42(2):107-121.
17. De Paepe P, Belpaire FM, Buylaert WA. Pharmacokinetic and pharmacodynamic considerations when treating
patients with sepsis and septic shock. Clin Pharmacokinet 2002;41(14):1135-1151.
18. Stallwood MI, Grayson AD, Mills K, et al. Acute renal failure in coronary artery bypass surgery: independent
effect of cardiopulmonary bypass. Ann Thorac Surg 2004;77(3):968-972.
19. Kumle B, Boldt J, Suttner SW, et al. Influence of prolonged cardiopulmonary bypass times on splanchnic
perfusion and markers of splanchnic organ function. Ann Thorac Surg 2003;75(5):1558-1564.
20. Hall RI, Molderhauer CC, Hug CCJ. Fentanyl plasma concentrations maintained by a simple infusion scheme in
patients undergoing cardiac surgery. Anesth Analg 1993;76(5):957-963.
21. Hudson RJ, Thomson IR, Henderson BT, et al. Validation of fentanyl pharmacokinetics in patients undergoing
coronary artery bypass grafting. Can J Anaesth 2002;49(4):388-392.
22. Hall RI, Thomas BL, Hug CC, Jr. Pharmacokinetics and pharmacodynamics during cardiac surgery and
cardiopulmonary bypass. In: Mora CT, ed. Cardiopulmonary bypass: principles and techniques of extracorporeal
circulation. New York, NY: Springer-Verlag, 1995:55-87.
23. Henthorn TK. Recirculatory pharmacokinetics. Which covariates affect the pharmacokinetics of intravenous
agents? Adv Exp Med Biol 2003;523:27-33.
24. Bjorkman S. Reduction and lumping of physiologically based pharmacokinetic models: prediction of the
disposition of fentanyl and pethidine in humans by successively simplified models. J Pharmacokinet Pharmacodyn
2003;30(4):285-307.
25. Hudson RJ, Thomson IR, Jassal R. Effects of cardiopulmonary bypass on sufentanil pharmacokinetics in
patients undergoing coronary artery bypass surgery. Anesthesiology 2004;101(4):862-871.
26. Michelsen LG, Holford NH, Lu W, et al. The pharmacokinetics of remifentanil in patients undergoing coronary
artery bypass grafting with cardiopulmonary bypass. Anesth Analg 2001;93(5):1100-1105.
27. Boxenbaum HG, Riegelman S, Elashoff RM. Statistical estimations in pharmacokinetics. J Pharmacokinet
Biopharm 1974;2(2):123-148.
P.304
28. Hudson RJ, Thomson IR, Jassal R, et al. Cardiopulmonary bypass has minimal effects on the pharmacokinetics
of fentanyl in adults. Anesthesiology 2003;99(4):847-854.
29. Bailey JM, Schwieger IM, Hug CC Jr. Evaluation of sufentanil anesthesia obtained by a computer-controlled
infusion for cardiac surgery. Anesth Analg 1993;76(2):247-252.
30. Flezzani P, Alvis MJ, Jacobs JR, et al. Sufentanil disposition during cardiopulmonary bypass. Can J Anaesth
1987;34(6):566-569.
31. Doi M, Gajraj RJ, Mantzaridis H, et al. Effects of cardiopulmonary bypass and hypothermia on
electroencephalographic variables. Anaesthesia 1997;52(11):1048-1055.
32. Barvais L, Heitz D, Schmartz D, et al. Pharmacokinetic model-driven infusion of sufentanil and midazolam during
cardiac surgery: assessment of the prospective predictive accuracy and the quality of anesthesia. J Cardiothorac
Vasc Anesth 2000;14(4):402-408.
33. Hudson RJ, Henderson BT, Thomson IR, et al. Pharmacokinetics of sufentanil in patients undergoing coronary
artery bypass graft surgery. J Cardiothorac Vasc Anesth 2001;15(6):693-699.
34. Thomson IR, Henderson BT, Singh K, et al. Concentration-response relationships for fentanyl and sufentanil in
patients undergoing coronary artery bypass grafting. Anesthesiology 1998;89(4):852-861.
35. Thomson IR, Harding G, Hudson RJ. A comparison of fentanyl and sufentanil in patients undergoing coronary
artery bypass graft surgery. J Cardiothorac Vasc Anesth 2000;14(6):652-656.
36. Barr G, Anderson RE, Samuelsson S, et al. Fentanyl and midazolam anaesthesia for coronary bypass surgery: a
clinical study of bispectral electroencephalogram analysis, drug concentrations and recall. Br J Anaesth
2000;84(6):749-752.
37. White M, Schenkels MJ, Engbers FH, et al. Effect-site modelling of propofol using auditory evoked potentials. Br
J Anaesth 1999;82(3):333-339.
38. Kussman BD, Zurakowski D, Sullivan L, et al. Evaluation of plasma fentanyl concentrations in infants during
cardiopulmonary bypass with low-volume circuits. J Cardiothorac Vasc Anesth 2005;19(3):316-321.
39. Thomson IR, Moon M, Hudson RJ, et al. Does sufentanil concentration influence isoflurane requirements during
coronary artery bypass grafting? J Cardiothorac Vasc Anesth 1999;13(1):9-14.
40. Forestier F, Hirschi M, Rouget P, et al. Propofol and sufentanil titration with the bispectral index to provide
anesthesia for coronary artery surgery. Anesthesiology 2003;99(2):334-346.
41. Iwakiri H, Nagata O, Matsukawa T, et al. Effect-site concentration of propofol for recovery of consciousness is
virtually independent of fentanyl effect-site concentration. Anesth Analg 2003;96(6):1651-1655.
42. Ahonen J, Olkkola KT, Hynynen M, et al. Comparison of alfentanil, fentanyl and sufentanil for total intravenous
anaesthesia with propofol in patients undergoing coronary artery bypass surgery. Br J Anaesth 2000;85(4):533-540.
43. Smith BS, Yogaratnam D, Levasseur-Franklin KE, et al. Introduction to drug pharmacokinetics in the critically ill
patient. Chest 2012;141(5):1327-1336.
44. Hughes MA, Glass PS, Jacobs JR. Context-sensitive half-time in multicompartment pharmacokinetic models for
intravenous anesthetic drugs. Anesthesiology 1992;76(3):334-341.
45. Wrighton SA, Stevens JC. The human hepatic cytochromes P450 involved in drug metabolism. Crit Rev Toxicol
1992;22(1):1-21.
46. Renton KW. Cytochrome p450 regulation and drug biotransformation during inflammation and infection. Curr
Drug Metab 2004;5(3):235-243.
47. Chen TL, Ueng TH, Chen SH, et al. Human cytochrome P450 mono-oxygenase system is suppressed by
propofol. Br J Anaesth 1995;74(5):558-562.
48. Kharasch ED, Russell M, Mautz D, et al. The role of cytochrome P450 3A4 in alfentanil clearance. Implications
for interindividual variability in disposition and perioperative drug interactions. Anesthesiology 1997;87(1):36-50.
49. Bartkowski RR, Goldberg ME, Larijani GE, et al. Inhibition of alfentanil metabolism by erythromycin. Clin
Pharmacol Ther 1989;46(1):99-102.
50. Palkama VJ, Isohanni MH, Neuvonen PJ, et al. The effect of intravenous and oral fluconazole on the
pharmacokinetics and pharmacodynamics of intravenous alfentanil. Anesth Analg 1998;87:190-194.
51. Guengerich FP, Distlerath LM, Reilly PE, et al. Human-liver cytochromes P-450 involved in polymorphisms of
drug oxidation. Xenobiotica 1986;16(5):367-378.
52. Le Guellec C, Lacarelle B, Villard PH, et al. Glucuronidation of propofol in microsomal fractions from various
tissues and species including humans: effect of different drugs. Anesth Analg 1995;81(4):855-861.
53. McKindley DS, Hanes S, Boucher BA. Hepatic drug metabolism in critical illness. Pharmacotherapy
1998;18(4):759-778.
54. Benet LZ, Øie S, hwartz JB. Design and optimization of dosage regimens; pharmacokinetic data. In: Hardman
JG, Limbird LE, Molinoff PB, et al., eds. Goodman and Gilman's the pharmacological basis of therapeutics. New
York, NY: McGraw-Hill, 1996:1707-1792.
55. Chauvin M, Bonnet F, Montembault C, et al. The influence of hepatic plasma flow on alfentanil plasma
concentration plateaus achieved with an infusion model in humans: measurement of alfentanil hepatic extraction
coefficient. Anesth Analg 1986;65(10):999-1003.
56. Scholz J, Steinfath M, Schulz M. Clinical pharmacokinetics of alfentanil, fentanyl and sufentanil. An update. Clin
Pharmacokinet 1996;31(4):275-292.
57. Tett SE, Kirkpatrick CM, Gross AS, et al. Principles and clinical application of assessing alterations in renal
elimination pathways. Clin Pharmacokinet 2003;42(14):1193-1211.
58. Jackson EK. Diuretics. In: Hardman JG, Limbird LE, Molinoff PB, et al., eds. Goodman and Gilman's the
pharmacological basis of therapeutics. New York, NY: McGraw-Hill, 1996:685-713.
59. Mandell GL, Petri WA Jr. Antimicrobial Agents (Continued). Penicillins, cephalosporins, and other β-lactam
antibiotics. In: Hardman JG, Limbird LE, Molinoff PB, et al., eds. Goodman and Gilman's the pharmacological basis
of therapeutics. New York, NY: McGraw-Hill, 1996:1073-1101.
60. Ross EM. Pharmacodynamics. Mechanisms of drug action and the relationship between drug concentration and
effect. In: Hardman JG, Limbird LE, Molinoff PB, et al., eds. Goodman and Gilman's the pharmacological basis of
therapeutics. New York, NY: McGraw-Hill, 1996:29-42.
61. Goodchild CS. GABA receptors and benzodiazepines. Br J Anaesth 1993;71(1):127-133.
62. Pleuvry BJ. Opioid receptors and their relevance to anaesthesia. Br J Anaesth 1993;71(1):119-126.
63. Hayashi Y, Maze M. Alpha 2 adrenoceptor agonists and anaesthesia. Br J Anaesth 1993;71(1):108-118.
64. Schwinn DA. Adrenoceptors as models for G protein-coupled receptors: structure, function and regulation. Br J
Anaesth 1993;71(1):77-85.
65. Snead OC III, Gibson KM. Gamma-hydroxybutyric acid. N Engl J Med 2005;352(26):2721-2732.
66. Gotti C, Clementi F. Neuronal nicotinic receptors: from structure to pathology. Prog Neurobiol 2004;74(6):363-
396.
67. Beleboni RO, Carolino RO, Pizzo AB, et al. Pharmacological and biochemical aspects of GABAergic
neurotransmission: pathological and neuropsychobiological relationships. Cell Mol Neurobiol 2004;24(6):707-728.
68. Al-Hasani R, Bruchas MR. Molecular mechanisms of opioid receptor-dependent signaling and behavior.
Anesthesiology 2011;115(6):1363-1381.
69. Lambert DG. Signal transduction: G proteins and second messengers. Br J Anaesth 1993;71(1):86-95.
70. Waldhoer M, Bartlett SE, Whistler JL. Opioid receptors. Annu Rev Biochem 2004;73:953-990.
71. Kenakin T. New concepts in pharmacological efficacy at 7TM receptors: IU-PHAR review 2. Br J Pharmacol
2013;168(3):554-575.
72. Johnson JA, Lima JJ. Drug receptor/effector polymorphisms and pharmacogenetics: current status and
challenges. Pharmacogenetics 2003;13(9): 525-534.
73. Lefkowitz RJ, Shenoy SK. Transduction of receptor signals by beta-arrestins. Science 2005;308(5721):512-517.
74. Hagen SA, Kondyra AL, Grocott HP, et al. Cardiopulmonary bypass decreases G protein-coupled receptor
kinase activity and expression in human peripheral blood mononuclear cells. Anesthesiology 2003; 98(2):343-348.
75. Williams JT, Ingram SL, Henderson G, et al. Regulation of mu-opioid receptors: desensitization, phosphorylation,
internalization, and tolerance. Pharmacol Rev 2013;65(1):223-254.
76. Zuo Z. The role of opioid receptor internalization and beta-arrestins in the development of opioid tolerance.
Anesth Analg 2005;101(3):728-734.
77. Bailey CP, Connor M. Opioids: cellular mechanisms of tolerance and physical dependence. Curr Opin
Pharmacol 2005;5(1):60-68.
78. Clark AL, Cleland JG. The control of adrenergic function in heart failure: therapeutic intervention. Heart Fail Rev
2000;5(1):101-114.
79. Jensen AA, Frolund B, Liljefors T, et al. Neuronal nicotinic acetylcholine receptors: structural revelations, target
identifications, and therapeutic inspirations. J Med Chem 2005;48(15):4705-4745.
P.305
80. Molenaar P, Parsonage WA. Fundamental considerations of beta-adrenoceptor subtypes in human heart failure.
Trends Pharmacol Sci 2005;26(7):368-375.
81. Gourlay GK. Advances in opioid pharmacology. Support Care Cancer 2005;13(3):153-159.
82. Czock D, Keller F, Rasche FM, et al. Pharmacokinetics and pharmacodynamics of systemically administered
glucocorticoids. Clin Pharmacokinet 2005;44(1):61-98.
83. Hayashi R, Wada H, Ito K, et al. Effects of glucocorticoids on gene transcription. Eur J Pharmacol 2004;500(1-
3):51-62.
84. Barnes PJ, Busse WW. Efficacy and safety of inhaled corticosteroids. New developments. Am J Resp Crit Care
Med 1998;157(3, Part 2):S1-S53.
85. Brodde OE, Leineweber K. Autonomic receptor systems in the failing and aging human heart: similarities and
differences. Eur J Pharmacol 2004;500(1-3):167-176.
86. Lohse MJ, Engelhardt S, Eschenhagen T. What is the role of β-adrenergic signaling in heart failure? Circ Res
2003;93(10):896-906.
87. Pawson T, Scott JD. Protein phosphorylation in signaling—50 years and counting. Trends Biochem Sci
2005;30(6):286-290.
88. Pavoine C, Defer N. The cardiac beta2-adrenergic signalling a new role for the cPLA2. Cell Signal
2005;17(2):141-152.
89. Kress HG, Tas PW. Effects of volatile anaesthetics on second messenger Ca2+ in neurones and non-muscular
cells. Br J Anaesth 1993;71(1):47-58.
90. Hall R. The pharmacokinetic behaviour of opioids administered during cardiac surgery. Can J Anaesth
1991;38(6):747-756.
91. Mets B. The pharmacokinetics of anesthetic drugs and adjuvants during cardiopulmonary bypass. Acta
Anaesthesiol Scand 2000;44(3):261-273.
92. Hall RI. Cardiopulmonary bypass and the systemic inflammatory response: effects on drug action. J
Cardiothorac Vasc Anesth 2002;16(1):83-98.
93. Hall R. Identification of inflammatory mediators and their modulation by strategies for the management of the
systemic inflammatory response during cardiac surgery. J Cardiothorac Vasc Anesth 2013;27(5):983-1033.
94. Rosen DA, Rosen KR. Elimination of drugs and toxins during cardiopulmonary bypass. J Cardiothorac Vasc
Anesth 1997;11(3):337-340.
95. Morrell DF, Harrison GG. Lignocaine kinetics during cardiopulmonary bypass. Optimum dosage and effects of
haemodilution. Br J Anaesth 1983;55:1173-1177.
96. Hammaren E, Yli-Hankala A, Rosenberg PH, et al. Cardiopulmonary bypass-induced changes in plasma
concentrations of propofol and in auditory evoked potentials. Br J Anaesth 1996;77(3):360-364.
97. Landow L, Wilson J, Heard SO, et al. Free and total lidocaine levels in cardiac surgical patients. J Cardiothorac
Anesth 1990;4(3):340-347.
98. Landow L, Wilson J. An improved lidocaine infusion protocol for cardiac surgical patients. J Cardiothorac Vasc
Anesth 1991;5(3):209-213.
99. Bjorksten AR, Crankshaw DP, Morgan DJ, et al. The effect of cardiopulmonary bypass on plasma
concentrations and protein binding of methohexital and thiopental. J Cardiothorac Anesth 1988;2(3):281-289.
100. Roth-Isigkeit AK, Dibbelt L, Schmucker P. Blood levels of corticosteroid-binding globulin, total cortisol and
unbound cortisol in patients undergoing coronary artery bypass grafting surgery with cardiopulmonary bypass.
Steroids 2000;65(9):513-520.
101. Jeleazcov C, Saari TI, Ihmsen H, et al. Changes in total and unbound concentrations of sufentanil during target
controlled infusion for cardiac surgery with cardiopulmonary bypass. Br J Anaesth 2012;109(5):698-706.
102. Tsubokawa T, Ishizuka S, Fukumoto K, et al. The effect of hemodilution by cardiopulmonary bypass on protein
binding of olprinone. J Anesth 2013;27(3):346-350.
103. Blake DW, Royse CF, Royse AG, et al. Alfentanil infusion as a component of intravenous anaesthesia for
coronary artery bypass surgery with “fast-track” recovery. Anaesth Intensive Care 2003;31(2):181-183.
104. Nussmeier NA, Moskowitz GJ, Weiskopf RB, et al. In vitro anesthetic washin and washout via bubble
oxygenators: influence of anesthetic solubility and rates of carrier gas inflow and pump blood flow. Anesth Analg
1988;67(10):982-987.
105. Nussmeier NA, Lambert ML, Moskowitz GJ, et al. Washin and washout of isoflurane administered via bubble
oxygenators during hypothermic cardiopulmonary bypass. Anesthesiology 1989;71(4):519-525.
106. Russell GN, Wright EL, Fox MA, et al. Propofol-fentanyl anaesthesia for coronary artery surgery and
cardiopulmonary bypass. Anaesthesia 1989;44(3):205-208.
107. Duebener LF, Hagino I, Schmitt K, et al. Effects of hemodilution and phenylephrine on cerebral blood flow and
metabolism during cardiopulmonary bypass. J Cardiothorac Vasc Anesth 2004;18(4):423-428.
108. Garfinkel D, Mamelok RD, Blaschke TF. Altered therapeutic range for quinidine after myocardial infarction and
cardiac surgery. Ann Intern Med 1987;107(1):48-50.
109. Dawidowicz AL, Kalitynski R, Fijalkowska A. Relationships between total and unbound propofol in plasma and
CSF during continuous drug infusion. Clin Neuropharmacol 2004;27(3):129-132.
110. du Souich P, Verges J, Erill S. Plasma protein binding and pharmacological response. Clin Pharmacokinet
1993;24(6):435-440.
111. Barbosa RA, Santos SR, White PF, et al. Effects of cardiopulmonary bypass on propofol pharmacokinetics and
bispectral index during coronary surgery. Clinics (Sao Paulo) 2009;64(3):215-221.
112. Bert AA. Systemic effects of normothermic cardiopulmonary bypass. Artif Organs 1998;22(1):77-81.
113. Antognini JF. Hypothermia eliminates isoflurane requirements at 20 degrees C. Anesthesiology

1993;78(6):1152-1156.
114. Mathew JP, Weatherwax KJ, East CJ, et al. Bispectral analysis during cardiopulmonary bypass: the effect of
hypothermia on the hypnotic state. J Clin Anesth 2001;13(4):301-305.
115. Schmidlin D, Hager P, Schmid ER. Monitoring level of sedation with bispectral EEG analysis: comparison
between hypothermic and normothermic cardiopulmonary bypass. Br J Anaesth 2001;86(6):769-776.
116. Heltne JK, Koller ME, Lund T, et al. Dynamic evaluation of fluid shifts during normothermic and hypothermic
cardiopulmonary bypass in piglets. Acta Anaesthesiol Scand 2000;44(10):1220-1225.
117. Lehot JJ, Villard J, Piriz H, et al. Hemodynamic and hormonal responses to hypothermic and normothermic
cardiopulmonary bypass. J Cardiothorac Vasc Anesth 1992;6(2):132-139.
118. Okano N, Hiraoka H, Owada R, et al. Hepatosplanchnic oxygenation is better preserved during mild
hypothermic than during normothermic cardiopulmonary bypass. Can J Anaesth 2001;48(10):1011-1014.
119. Ballard BE. Pharmacokinetics and temperature. J Pharm Sci 1974; 63(9):1345-1358.
120. Koren G, Barker C, Goresky G, et al. The influence of hypothermia on the disposition of fentanyl—human and
animal studies. Eur J Clin Pharmacol 1987;32(4):373-376.
121. Schiavello R, Mezza A, Feo L, et al. Compartmental analysis of lidocaine kinetics during extracorporeal
circulation. J Cardiothorac Anesth 1988;2(3):290-296.
122. Mathie RT, Ohri SK, Batten JJ, et al. Hepatic blood flow during cardiopulmonary bypass operations: the effect
of temperature and pulsatility. J Thorac Cardiovasc Surg 1997;114(2):292-293.
123. Vuylsteke A, Milner Q, Ericsson H, et al. Pharmacokinetics and pulmonary extraction of clevidipine, a new
vasodilating ultrashort-acting dihydropyridine, during cardiopulmonary bypass. Br J Anaesth 2000;85(5):683-689.
124. Flynn PJ, Hughes R, Walton B. Use of atracurium in cardiac surgery involving cardiopulmonary bypass with
induced hypothermia. Br J Anaesth 1984;56(9):967-972.
125. Jacobs JR, Croughwell ND, Goodman DK, et al. Effect of hypothermia and sampling site on blood esmolol
concentrations. J Clin Pharmacol 1993;33(4):360-365.
126. Diefenbach C, Abel M, Rump AF, et al. Changes in plasma cholinesterase activity and mivacurium
neuromuscular block in response to normothermic cardiopulmonary bypass. Anesth Analg 1995;80(6):1088-1091.
127. Russell D, Royston D, Rees PH, et al. Effect of temperature and cardiopulmonary bypass on the
pharmacokinetics of remifentanil. Br J Anaesth 1997;79(4):456-459.
128. Przybylo HJ, Stevenson GW, Schanbacher P, et al. Sodium nitroprusside metabolism in children during
hypothermic cardiopulmonary bypass. Anesth Analg 1995;81(5):952-956.
129. Ereth MH, Fisher BR, Cook DJ, et al. Normothermic cardiopulmonary bypass increases heparin requirements
necessary to maintain anticoagulation. J Clin Monit Comput 1998;14(5):323-327.
130. Caldwell JE, Heier T, Wright PM, et al. Temperature-dependent pharmacokinetics and pharmacodynamics of
vecuronium. Anesthesiology 2000;92(1):84-93.
131. Cammu G, Coddens J, Hendrickx J, et al. Dose requirements of infusions of cisatracurium or rocuronium during
hypothermic cardiopulmonary bypass. Br J Anaesth 2000;84(5):587-590.
132. Koren G, Barker C, Bohn D, et al. Influence of hypothermia on the pharmacokinetics of gentamicin and
theophylline in piglets. Crit Care Med 1985;13:844-847.
P.306
133. Regragui IA, Izzat MB, Birdi I, et al. Cardiopulmonary bypass perfusion temperature does not influence
perioperative renal function. Ann Thorac Surg 1995;60(1):160-164.
134. Swaminathan M, East C, Phillips-Bute B, et al. Report of a substudy on warm versus cold cardiopulmonary
bypass: changes in creatinine clearance. Ann Thorac Surg 2001;72(5):1603-1609.
135. Yu RG, Zhou JX, Liu J. Prediction of volatile anaesthetic solubility in blood and priming fluids for extracorporeal
circulation. Br J Anaesth 2001;86(3):338-344.
136. Shanks CA, Ramzan IM, Walker JS, et al. Gallamine disposition in openheart surgery involving
cardiopulmonary bypass. Clin Pharmacol Ther 1983;33:792-799.
137. Avram MJ, Shanks CA, Henthorn TK, et al. Metocurine kinetics in patients undergoing operations requiring
cardiopulmonary bypass. Clin Pharmacol Ther 1987;42(5):576-581.
138. Okutani R, Philbin DM, Rosow CE, et al. Effect of hypothermic hemodilutional cardiopulmonary bypass on
plasma sufentanil and catecholamine concentrations in humans. Anesth Analg 1988;67(7):667-670.
139. Caspi J, Klausner JM, Safadi T, et al. Delayed respiratory depression following fentanyl anesthesia for cardiac
surgery. Crit Care Med 1988;16(3):238-240.
140. Hornick P, Taylor K. Pulsatile and nonpulsatile perfusion: the continuing controversy. J Cardiothorac Vasc
Anesth 1997;11(3):310-315.
141. Hynynen M, Olkkola KT, Naveri E, et al. Thiopentone pharmacokinetics during cardiopulmonary bypass with a
nonpulsatile or pulsatile flow. Acta Anaesthesiol Scand 1989;33(7):554-560.
142. Weiner B, Melby MJ, Faraci PA, et al. Cefamandole pharmacokinetics during standard and pulsatile
cardiopulmonary bypass. J Clin Pharmacol 1988;28(7):655-659.
143. Bentley JB, Conahan TJ, Cork RC. Fentanyl sequestration in lungs during cardiopulmonary bypass. Clin
Pharmacol Ther 1983;34(5):703-706.
144. Boer F, Bovill JG, Burm AG, et al. Effect of ventilation on first-pass pulmonary retention of alfentanil and
sufentanil in patients undergoing coronary artery surgery. Br J Anaesth 1994;73(4):458-463.
145. Taeger K, Weninger E, Schmelzer F, et al. Pulmonary kinetics of fentanyl and alfentanil in surgical patients. Br
J Anaesth 1988;61(4):425-434.
146. Roerig DL, Kotrly KJ, Vucins EJ, et al. First pass uptake of fentanyl, meperidine, and morphine in the human
lung. Anesthesiology 1987;67(4): 466-472.
147. Boer F, Engbers FH, Bovill JG, et al. First-pass pulmonary retention of sufentanil at three different background
blood concentrations of the opioid. Br J Anaesth 1995;74(1):50-55.
148. He YL, Ueyama H, Tashiro C, et al. Pulmonary disposition of propofol in surgical patients. Anesthesiology
2000;93(4):986-991.
149. Roerig DL, Ahlf SB, Dawson CA, et al. First pass uptake in the human lung of drugs used during anesthesia.
Adv Pharmacol 1994;31:531-549.
150. Hutschala D, Skhirtladze K, Kinstner C, et al. Effect of cardiopulmonary bypass on regional antibiotic
penetration into lung tissue. Antimicrob Agents Chemother 2013;57(7):2996-3002.
151. Hutschala D, Kinstner C, Skhirtladze K, et al. The impact of perioperative atelectasis on antibiotic penetration
into lung tissue: an in vivo microdialysis study. Intensive Care Med 2008;34(10):1827-1834.
152. Mohnle P, Kilger E, Adnan L, et al. Indocyanine green clearance after cardiac surgery: the impact of
cardiopulmonary bypass. Perfusion 2012;27(4):292-299.
153. Okano N, Miyoshi S, Owada R, et al. Impairment of hepatosplanchnic oxygenation and increase of serum
hyaluronate during normothermic and mild hypothermic cardiopulmonary bypass. Anesth Analg 2002;95(2):278-286.
154. Braun JP, Schroeder T, Buehner S, et al. Splanchnic oxygen transport, hepatic function and gastrointestinal
barrier after normothermic cardiopulmonary bypass. Acta Anaesthesiol Scand 2004;48(6):697-703.
155. Gardeback M, Settergren G, Brodin LA, et al. Splanchnic blood flow and oxygen uptake during
cardiopulmonary bypass. J Cardiothorac Vasc Anesth 2002;16(3):308-315.
156. Sander M, Spies CD, Berger K, et al. Perioperative indocyanine green clearance is predictive for prolonged
intensive care unit stay after coronary artery bypass grafting—an observational study. Crit Care 2009;13(5):R149.
157. Autschbach R, Falk V, Lange H, et al. Assessment of metabolic liver function and hepatic blood flow during
cardiopulmonary bypass. Thorac Cardiovasc Surg 1996;44(2):76-80.
158. Ohri SK, Bjarnason I, Pathi V, et al. Cardiopulmonary bypass impairs small intestinal transport and increases
gut permeability. Ann Thorac Surg 1993;55(5):1080-1086.
159. Sinclair DG, Houldsworth PE, Keogh B, et al. Gastrointestinal permeability following cardiopulmonary bypass: a
randomised study comparing the effects of dopamine and dopexamine. Intensive Care Med 1997;23(5):510-516.
160. Christiansen CL, Ahlburg P, Jakobsen CJ, et al. The influence of propofol and midazolam/halothane anesthesia
on hepatic SvO2 and gastric mucosal pH during cardiopulmonary bypass. J Cardiothorac Vasc Anesth
1998;12(4):418-421.
161. Miller RS, Peterson GM, McLean S, et al. Effect of cardiopulmonary bypass on the plasma concentrations of
fentanyl and alcuronium. J Clin Pharm Ther 1997;22(3):197-205.
162. Roberts DJ, Hall RI. Drug absorption, distribution, metabolism and excretion considerations in critically ill
adults. Exp Opin Drug Metab Toxicol 2013;9(9):1067-1084.
163. Ali MS, Harmer M, Vaughan RS, et al. Changes in cerebral oxygenation during cold (28 degrees C) and warm
(34 degrees C) cardiopulmonary bypass using different blood gas strategies (alpha-stat and pH-stat) in patients
undergoing coronary artery bypass graft surgery. Acta Anaesthesiol Scand 2004;48(7):837-844.
164. Tallman RD Jr. Acid-base regulation, alpha-stat, and the emperor's new clothes. J Cardiothorac Vasc Anesth
1997;11(3):282-288.
165. Burrows FA. Con: pH-stat management of blood gases is preferable to alpha-stat in patients undergoing brain
cooling for cardiac surgery. J Cardiothorac Vasc Anesth 1995;9(2):219-221.
166. Kern FH, Greeley WJ. Pro: pH-stat management of blood gases is not preferable to alpha-stat in patients
undergoing brain cooling for cardiac surgery. J Cardiothorac Vasc Anesth 1995;9(2):215-218.
167. Piccioni MA, Leirner AA, Auler JO, Jr. Comparison of pH-stat versus Alpha-stat during hypothermic
cardiopulmonary bypass in the prevention and control of acidosis in cardiac surgery. Artif Organs 2004;28(4): 347-
352.
168. Schell RM, Kern FH, Greeley WJ, et al. Cerebral blood flow and metabolism during cardiopulmonary bypass.
Anesth Analg 1993;76(4):849-865.
169. Skacel M, Knott C, Reynolds F, et al. Extracorporeal circuit sequestration of fentanyl and alfentanil. Br J
Anaesth 1986;58(9):947-949.
170. Cross DA, Nikas D. The effects of carbon dioxide management on plasma levels of fentanyl and sufentanil
during hypothermic cardiopulmonary bypass. J Cardiothorac Vasc Anesth 1994;8(6):649-652.
171. Hickey S, Gaylor JD, Kenny GN. In vitro uptake and elimination of isoflurane by different membrane
oxygenators. J Cardiothorac Vasc Anesth 1996;10(3):352-355.
172. Stern RC, Weiss CI, Steinbach JH, et al. Isoflurane uptake and elimination are delayed by absorption of
anesthetic by the Scimed membrane oxygenator. Anesth Analg 1989;69(5):657-662.
173. Wiesenack C, Wiesner G, Keyl C, et al. In vivo uptake and elimination of isoflurane by different membrane
oxygenators during cardiopulmonary bypass. Anesthesiology 2002;97(1):133-138.
174. Hinz J, Molder JM, Hanekop GG, et al. Reduced sevoflurane loss during cardiopulmonary bypass when using
a polymethylpentane versus a polypropylene oxygenator. Int J Artif Organs 2013;36(4):233-239.
175. Prasser C, Zelenka M, Gruber M, et al. Elimination of sevoflurane is reduced in plasma-tight compared to
conventional membrane oxygenators. Eur J Anaesthesiol 2008;25(2):152-157.
176. Hynynen M, Hammaren E, Rosenberg PH. Propofol sequestration within the extracorporeal circuit. Can J
Anaesth 1994;41(7):583-588.
177. Hammaren E, Rosenberg PH, Hynynen M. Coating of extracorporeal circuit with heparin does not prevent
sequestration of propofol in vitro. Br J Anaesth 1999;82(1):38-40.
178. Koren G, Crean P, Klein J, et al. Sequestration of fentanyl by the cardiopulmonary bypass (CPBP). Eur J Clin
Pharmacol 1984;27(1):51-56.
179. Rosen D, Rosen K, Davidson B, et al. Fentanyl uptake by the Scimed Membrane oxygenator. J Cardiothorac
Anesth 1988;2(5):619-626.
180. Stone JG, Damask MC, Khambatta HJ. Is sufentanil removed by blood conservation devices? J Cardiothorac
Anesth 1988;2(5):615-618.
181. Dasta JF, Jacobi J, Wu LS, et al. Loss of nitroglycerin to cardiopulmonary bypass apparatus. Crit Care Med
1983;11(1):50-52.
182. Booth BP, Henderson M, Milne B, et al. Sequestration of glyceryl trinitrate (nitroglycerin) by cardiopulmonary
bypass oxygenators. Anesth Analg 1991;72(4):493-497.
183. Aaltonen L, Kanto J, Arola M, et al. Effect of age and cardiopulmonary bypass on the pharmacokinetics of
lorazepam. Acta Pharmacol Toxicol 1982;51(2):126-131.
P.307
184. Katz RI, Kanchuger MS, Patton KF, et al. Effect of cardiopulmonary bypass on plasma levels of nifedipine.
Anesth Analg 1990;71(4):411-414.
185. Krivoy N, Yanovsky B, Kophit A, et al. Vancomycin sequestration during cardiopulmonary bypass surgery. J
Infect 2002;45(2):90-95.
186. Garcia MPO, Marti-Bonmati E, Guevara SJ, et al. Alteration of vancomycin pharmacokinetics during
cardiopulmonary bypass in patients undergoing cardiac surgery. Am J Health Syst Pharm 2003;60(3):260-265.
187. Mets B, Reich NT, Mellas N, et al. Desflurane pharmacokinetics during cardiopulmonary bypass. J
188. Sutton RG. Renal considerations, dialysis, and ultrafiltration during cardiopulmonary bypass. Int Anesthesiol
Clin 1996;34(2):165-176.
189. Davies LK. Cardiopulmonary bypass in infants and children: how is it different? J Cardiothor Vasc Anesth
1999;13(3):330-345.
190. Koster A, Merkle F, Hansen R, et al. Elimination of recombinant hirudin by modified ultrafiltration during
simulated cardiopulmonary bypass: assessment of different filter systems. Anesth Analg 2000;91(2):265-269.
191. Clar A, Larson DF. Hemofiltration: determinants of drug loss and concentration. J Extra Corpor Technol
1995;27(3):158-163.
192. Clar A, Bowers MC, Larson DF. Derivation of sieving coefficients to determine the efficacy of the
hemoconcentrator in removal of four inflammatory mediators produced during cardiopulmonary bypass. ASAIO J
1997;43(3):163-170.
193. O'Rullian JJ, Wise RK, McCoach RM, et al. The effects of haemofiltration on cefazolin levels during
cardiopulmonary bypass. Perfusion 1998;13(3):176-180.
194. Van Norman GA, Patel MA, Chandler W, et al. Effects of hemofiltration on serum aprotinin levels in patients
undergoing cardiopulmonary bypass. J Cardiothorac Vasc Anesth 2000;14(3):253-256.
195. Koster A, Chew D, Merkle F, et al. Extracorporeal elimination of large concentrations of tirofiban by zero-
balanced ultrafiltration during cardiopulmonary bypass: an in vitro investigation. Anesth Analg 2004;99(4):989-992.
196. Masuda Z, Kurosaki Y, Ishino K, et al. Pharmacokinetic analysis of flomoxef in children undergoing
cardiopulmonary bypass and modified ultrafiltration. Gen Thorac Cardiovasc Surg 2008;56(4):163-169.
197. Rooney R, Neligan MC, Hone R, et al. Serum concentrations of cephalosporins and the cell saver in
cardiopulmonary bypass surgery. J Antimicrob Chemother 1988;22(2):266-268.
198. Ariens EJ. Drug levels in the target tissue and effect. Clin Pharmacol Ther 1974;16(1):155-175.
199. Holley FO, Ponganis KV, Stanski DR. Effects of cardiac surgery with cardiopulmonary bypass on lidocaine
disposition. Clin Pharmacol Ther 1984;35(5):617-626.
200. Routledge PA, Stargel WW, Wagner GS, et al. Increased a1-acid glycoprotein and lidocaine disposition in
myocardial infarction. Ann Intern Med 1980;93(5):701-704.
201. Davies RF, Dube LM, Mousseau N, et al. Perioperative variability of binding of lidocaine, quinidine, and
propranolol after cardiac operations. J Thorac Cardiovasc Surg 1988;96(4):634-641.
202. Rowland M. Plasma protein binding and therapeutic drug monitoring. Ther Drug Monit 1980;2:29-37.
203. Grossman SH, Davis D, Kitchell BB, et al. Diazepam and lidocaine plasma protein binding in renal disease.
Clin Pharmacol Ther 1982;31(3):350-357.
204. Ruiz-Cabello F, Erill S. Abnormal serum protein binding of acidic drugs in diabetes mellitus. Clin Pharmacol
Ther 1984;36(5):691-695.
205. Hall RI, Stafford Smith M, Rocker G. The systemic inflammatory response to cardiopulmonary bypass:
pathophysiological, therapeutic, and pharmacological considerations. Anesth Analg 1997;85(4):766-782.
206. Piafsky KM. Disease-induced changes in the plasma binding of basic drugs. Clin Pharmacokinet
1980;5(3):246-262.
207. Thiessen JJ, Sellers EM, Denbeigh P, et al. Plasma protein binding of diazepam and tolbutamide in chronic
alcoholics. J Clin Pharmacol 1976;16(7):345-351.
208. McAllister RG Jr, Bourne DW, Tan TG, et al. Effects of hypothermia on propranolol kinetics. Clin Pharmacol
Ther 1979;25(1):1-7.
209. Plachetka JR, Salomon NW, Copeland JG. Plasma propranolol before, during, and after cardiopulmonary
bypass. Clin Pharmacol Ther 1981;30(6):745-751.
210. Jungbluth GL, Pasko MT, Beam TR, et al. Ceftriaxone disposition in openheart surgery patients. Antimicrob
Agents Chemother 1989;33(6):850-856.
211. Roth RA, Wiersma DA. Role of the lung in total body clearance of circulating drugs. Clin Pharmacokinet
1979;4:355-367.
212. Coltart DJ, Chamberlain DA, Howard MR, et al. Effect of cardiopulmonary bypass on plasma digoxin
concentrations. Br Heart J 1971;33:334-338.
213. Bender AD. The effect of increasing age on the distribution of peripheral blood flow in man. J Am Geriatr Soc
1965;13(3):192-198.
214. Crooks J, O'Malley K, Stevenson IH. Pharmacokinetics in the elderly. Clin Pharmacokinet 1976;1:280-296.
215. Homer TD, Stanski DR. The affect of increasing age on thiopental disposition and anesthetic requirement.
216. Stanski DR, Maitre PO. Population pharmacokinetics and pharmacodynamics of thiopental: the effect of age
revisited. Anesthesiology 1990;72(3):412-422.
217. Minto CF, Schnider TW, Egan TD, et al. Influence of age and gender on the pharmacokinetics and
pharmacodynamics of remifentanil. I. Model development. Anesthesiology 1997;86(1):10-23.
218. Scott JC, Stanski DR. Decreased fentanyl and alfentanil dose requirements with age. A simultaneous
pharmacokinetic and pharmacodynamic evaluation. J Pharmacol Exp Ther 1987;240(1):159-166.
219. Mapleson WW. Effect of age on MAC in humans: a meta-analysis. Br J Anaesth 1996;76(2):179-185.
220. Prandota J. Clinical pharmacokinetics of changes in drug elimination in children. Dev Pharmacol Ther
1985;8:311-328.
221. Davis PJ, Cook DR, Stiller RL, et al. Pharmacodynamics and pharmacokinetics of high-dose sufentanil in
infants and children undergoing cardiac surgery. Anesth Analg 1987;66(3):203-208.
222. Greeley WJ, de Bruijn NP, Davis DP. Sufentanil pharmacokinetics in pediatric cardiovascular patients. Anesth
Analg 1987;66(11):1067-1072.
223. den Hollander JM, Hennis PJ, Burm AGL, et al. Alfentanil in infants and children with congenital heart defects.
J Cardiothorac Anesth 1988;2(1):12-17.
224. Fiset P, Mathers L, Engstrom R, et al. Pharmacokinetics of computer-controlled alfentanil administration in

children undergoing cardiac surgery. Anesthesiology 1995;83(5):944-955.
225. Mathews HM, Carson IW, Lyons SM, et al. A pharmacokinetic study of midazolam in paediatric patients
undergoing cardiac surgery. Br J Anaesth 1988;61(3):302-307.
226. Vargas MRA, Danton MH, Javaid SM, et al. Pharmacokinetics of intravenous flucloxacillin and amoxicillin in
neonatal and infant cardiopulmonary bypass surgery. Eur J Cardiothorac Surg 2004;25(2):256-260.
227. Ririe DG, James RL, O'Brien JJ, et al. The pharmacokinetics of epsilon-aminocaproic acid in children
undergoing surgical repair of congenital heart defects. Anesth Analg 2002;94(1):44-49.
228. Davis PJ, Wilson AS, Siewers RD, et al. The effects of cardiopulmonary bypass on remifentanil kinetics in
children undergoing atrial septal defect repair. Anesth Analg 1999;89(4):904-908.
229. Tae YM, Kwak JG, Kim BH, et al. Population pharmacokinetic analysis and dosing regimen optimization of
aprotinin in neonates and young infants undergoing cardiopulmonary bypass. J Clin Pharmacol 2011;51(8):1163-
1176.
230. Koren G, Goresky G, Crean P, et al. Unexpected alterations in fentanyl pharmacokinetics in children
undergoing cardiac surgery: age related or disease related? Dev Pharmacol Ther 1986;9(3):183-191.
231. den Hollander JM, Hennis PJ, Burm AG, et al. Pharmacokinetics of alfentanil before and after cardiopulmonary
bypass in pediatric patients undergoing cardiac surgery. Part I. J Cardiothorac Vasc Anesth 1992;6(3):308-312.
232. Buhrer M, Maitre PO, Hung O, et al. Electroencephalographic effects of benzodiazepines. I. Choosing an
electroencephalographic parameter to measure the effect of midazolam on the central nervous system. Clin
Pharmacol Ther 1990;48(5):544-554.
233. Scott JC, Ponganis KV, Stanski DR. EEG quantitation of narcotic effect: the comparative pharmacodynamics of
fentanyl and alfentanil. Anesthesiology 1985;62(3):234-241.
234. Scott JC, Cooke JE, Stanski DR. Electroencephalographic quantitation of opioid effect: comparative
pharmacodynamics of fentanyl and sufentanil. Anesthesiology 1991;74(1):34-42.
235. Buhrer M, Maitre PO, Crevoisier C, et al. Electroencephalographic effects of benzodiazepines. II.
Pharmacodynamic modeling of the electroencephalographic effects of midazolam and diazepam. Clin Pharmacol
Ther 1990;48(5):555-567.
236. Munoz HR, Cortinez LI, Ibacache ME, et al. Estimation of the plasma effect site equilibration rate constant (ke0)
of propofol in children using the time to peak effect: comparison with adults. Anesthesiology 2004;101(6): 1269-
1274.
237. Loveman E, Van Hooff JC, Smith DC. The auditory evoked response as an awareness monitor during
anaesthesia. Br J Anaesth 2001;86(4):513-518.
P.308
238. Grigore AM, Mathew J, Grocott HP, et al. Prospective randomized trial of normothermic versus hypothermic
cardiopulmonary bypass on cognitive function after coronary artery bypass graft surgery. Anesthesiology
2001;95(5):1110-1119.
239. Tiren C, Anderson RE, Barr G, et al. Clinical comparison of three different anaesthetic depth monitors during
cardiopulmonary bypass. Anaesthesia 2005;60(2):189-193.
240. D'Attellis N, Nicolas-Robin A, Delayance S, et al. Early extubation after mitral valve surgery: a target-controlled
infusion of propofol and low-dose sufentanil. J Cardiothorac Vasc Anesth 1997;11(4):467-473.
241. Ortmann E, Besser MW, Klein AA. Antifibrinolytic agents in current anaesthetic practice. Br J Anaesth
2013;111(4):549-563.
242. Sharma V, Katznelson R, Jerath A, et al. The association between tranexamic acid and convulsive seizures
after cardiac surgery: a multivariate analysis in 11 529 patients. Anaesthesia 2014;69(2):124-130.
243. Abou-Diwan C, Sniecinski RM, Szlam F, et al. Plasma and cerebral spinal fluid tranexamic acid quantitation in
cardiopulmonary bypass patients. J Chromatogr B Analyt Technol Biomed Life Sci 2011;879(7/8):553-556.
244. Lecker I, Wang DS, Romaschin AD, et al. Tranexamic acid concentrations associated with human seizures
inhibit glycine receptors. J Clin Invest 2012;122(12):4654-4666.
245. Mathew PJ, Puri GD, Dhaliwal RS. Propofol requirement titrated to bispectral index: a comparison between
hypothermic and normothermic cardiopulmonary bypass. Perfusion 2009;24(1):27-32.
246. Puig MM, Warner W, Tang CK, et al. Effects of temperature on the interaction of morphine with opioid
receptors. Br J Anaesth 1987;59(11):1459-1464.
247. Holmes PEB, Jenden DJ, Taylor DB. The analysis of the mode of action of curare on neuromuscular
transmission; the effect of temperature changes. J Pharmacol 1951;103:382-402.
248. d'Hollander AA, Duvaldestin P, Henzel D, et al. Variations in pancuronium requirement, plasma concentration,
and urinary excretion induced by cardiopulmonary bypass with hypothermia. Anesthesiology 1983;58(6): 505-509.
249. Diefenbach C, Abel M, Buzello W. Greater neuromuscular blocking potency of atracurium during hypothermic
than during normothermic cardiopulmonary bypass. Anesth Analg 1992;75(5):675-678.
250. Smeulers NJ, Wierda JM, van den Broek L, et al. Effects of hypothermic cardiopulmonary bypass on the
pharmacodynamics and pharmacokinetics of rocuronium. J Cardiothorac Vasc Anesth 1995;9(6):700-705.
251. Futter ME, Whalley DG, Wynands JE, et al. Pancuronium requirements during hypothermic cardiopulmonary
bypass in man. Anaesth Intensive Care 1983;11:216-219.
252. Buzello W, Schluermann D, Schindler M, et al. Hypothermic cardiopulmonary bypass and neuromuscular
blockade by pancuronium and vecuronium. Anesthesiology 1985;62(2):201-204.
253. Illievich UM, Zornow MH, Choi KT, et al. Effects of hypothermia or anesthetics on hippocampal glutamate and
glycine concentrations after repeated transient global cerebral ischemia. Anesthesiology 1994;80(1):177-186.
254. Mora CT, Henson MB, Weintraub WS, et al. The effect of temperature management during cardiopulmonary
bypass on neurologic and neuropsychologic outcomes in patients undergoing coronary revascularization. J Thorac
Cardiovasc Surg 1996;112(2):514-522.
255. McLean RF, Wong BI, Naylor CD, et al. Cardiopulmonary bypass, temperature, and central nervous system
dysfunction. Circulation 1994;90(5, Part 2): II250-II255.
256. Fiddian-Green RG, Baker S. Predictive value of the stomach wall pH for complications after cardiac operations:
comparison with other monitoring. Crit Care Med 1987;15(2):153-156.
257. Hindman BJ. Sodium bicarbonate in the treatment of subtypes of acute lactic acidosis: physiologic
considerations. Anesthesiology 1990;72(6): 1064-1076.
258. Lockey E, Ross DN, Longmore DB, et al. Potassium and open-heart surgery. Lancet 1966;1(7439):671-675.
259. Romero EG, Castillo-Olivares JL, O'Connor F, et al. The importance of calcium and magnesium ions in serum
and cerebrospinal fluid during cardiopulmonary bypass. J Thorac Cardiovasc Surg 1973;66(4):668-672.
260. Inoue S, Akazawa S, Nakaigawa Y, et al. Changes in plasma total and ionized magnesium concentrations and
factors affecting magnesium concentrations during cardiac surgery. J Anesth 2004;18(3):216-219.
261. DiNardo JA. Pro: calcium is routinely indicated during separation from cardiopulmonary bypass. J Cardiothorac
Vasc Anesth 1997;11(7):905-907.
262. Prielipp R, Butterworth J. Con: calcium is not routinely indicated during separation from cardiopulmonary
bypass. J Cardiothorac Vasc Anesth 1997;11(7):908-912.
263. Boyd WC, Thomas SJ. Pro: magnesium should be administered to all coronary artery bypass graft surgery
patients undergoing cardiopulmonary bypass. J Cardiothorac Vasc Anesth 2000;14(3):339-343.
264. Grigore AM, Mathew JP. Con: magnesium should not be administered to all coronary artery bypass graft
surgery patients undergoing cardiopulmonary bypass. J Cardiothorac Vasc Anesth 2000;14(3):344-346.
265. Hall RI, Murphy JT, Moffitt EA, et al. A comparison of the myocardial metabolic and haemodynamic changes
produced by propofol-sufentanil and enflurane-sufentanil anaesthesia for patients having coronary artery bypass
graft surgery. Can J Anaesth 1991;38(8):996-1004.
266. Hall RI, Murphy JT, Landymore R, et al. Myocardial metabolic and hemodynamic changes during propofol
anesthesia for cardiac surgery in patients with reduced ventricular function. Anesth Analg 1993;77(4):680-689.
267. Terrar DA. Structure and function of calcium channels and the actions of anaesthetics. Br J Anaesth
1993;71(1):39-46.
268. Hall RI, Sullivan JA. Does cardiopulmonary bypass alter enflurane requirements for anesthesia?
Anesthesiology 1990;73(2):249-255.
269. Doak GJ, Li G, Hall RI, et al. Does hypothermia or hyperventilation affect enflurane MAC reduction following
partial cardiopulmonary bypass in dogs? Can J Anaesth 1993;40(2):176-182.
270. Neumeister MW, Li G, Williams G, et al. Factors influencing MAC reduction after cardiopulmonary bypass in
dogs. Can J Anaesth 1997;44(10):1120-1126.
271. Ahonen J, Sahlman A, Yli-Hankala A, et al. No effect of cardiopulmonary bypass on hypnosis in patients
anaesthetized with propofol and alfentanil. Br J Anaesth 2004;92(1):137-139.
272. Lundell JC, Scuderi PE, Butterworth JF. Less isoflurane is required after than before cardiopulmonary bypass
to maintain a constant bispectral index value. J Cardiothorac Vasc Anesth 2001;15(5):551-554.
273. Wu CL, Raja SN. Treatment of acute postoperative pain. Lancet 2011;377(9784):2215-2225.
274. Fowler MB, Laser JA, Hopkins GL, et al. Assessment of the β-adrenergic receptor pathway in the intact failing
human heart: progressive receptor down-regulation and subsensitivity to agonist response. Circulation
1986;74(6):1290-1302.
275. Colucci WS, Alexander RW, Williams GH, et al. Decreased lymphocyte beta-adrenergic-receptor density in
patients with heart failure and tolerance to the beta-adrenergic agonist pirbuterol. N Engl J Med 1981;305(4):185-
190.
276. The Xamoterol in Severe Heart Failure Study Group. Xamoterol in severe heart failure. Lancet
1990;336(8706):1-6.
277. Waagstein F, Bristow MR, Swedberg K, et al. Beneficial effects of metoprolol in idiopathic dilated
cardiomyopathy. Metoprolol in Dilated Cardiomyopathy (MDC) Trial Study Group. Lancet 1993;342(8885):1441-
1446.
278. Australia-New Zealand Heart Failure Research Collaborative Group. Effects of carvedilol, a vasodilator-beta-
blocker, in patients with congestive heart failure due to ischemic heart disease. Circulation 1995;92(2):212-218.
279. Royster RL. Myocardial dysfunction following cardiopulmonary bypass: recovery patterns, predictors of
inotropic need, theoretical concepts of inotropic administration. J Cardiothorac Vasc Anesth 1993;7(4, Suppl 2):19-
25.
280. Stafford Smith M, Muir H, Hall R. Perioperative management of drug therapy, clinical considerations. Drugs
1996;51(2):238-259.
281. Alderman EL, Coltart DJ, Wettach GE, et al. Coronary artery syndromes after sudden propranolol withdrawal.
Ann Intern Med 1974;81(5):625-627.
282. Amory DW, Grigore A, Amory JK, et al. Neuroprotection is associated with beta-adrenergic receptor
antagonists during cardiac surgery: evidence from 2,575 patients. J Cardiothorac Vasc Anesth 2002;16(3):270-277.
283. Schranz D, Droege A, Broede A, et al. Uncoupling of human cardiac beta-adrenoceptors during
cardiopulmonary bypass with cardioplegic cardiac arrest. Circulation 1993;87(2):422-426.
284. Schwinn DA, Leone BJ, Spahn DR, et al. Desensitization of myocardial beta-adrenergic receptors during
cardiopulmonary bypass. Evidence for early uncoupling and late downregulation. Circulation 1991;84(6):2559-2567.
285. Toleikis PM, Tomlinson CW. Myocardial functional preservation during ischemia: influence of beta blocking
agents. Mol Cell Biochem 1997;176(1/2):205-210.
286. Gerhardt MA, Booth JV, Chesnut LC, et al. Acute myocardial beta-adrenergic receptor dysfunction after
cardiopulmonary bypass in patients with cardiac valve disease. Duke Heart Center Perioperative Desensitization
Group. Circulation 1998;98(19, Suppl):II275-II281.
287. Booth JV, Ward EE, Colgan KC, et al. Metoprolol and coronary artery bypass grafting surgery: does
intraoperative metoprolol attenuate acute beta-adrenergic receptor desensitization during cardiac surgery? Anesth
Analg 2004;98(5):1224-1231.
P.309
288. Chello M, Mastroroberto P, De AV, et al. Intermittent warm blood cardioplegia preserves myocardial beta-
adrenergic receptor function. Ann Thorac Surg 1997;63(3):683-688.
289. Lee TW, Grocott HP, Schwinn D, et al. High spinal anesthesia for cardiac surgery: effects on beta-adrenergic
receptor function, stress response, and hemodynamics. Anesthesiology 2003;98(2):499-510.
290. Mao J, Price DD, Mayer DJ. Mechanisms of hyperalgesia and morphine tolerance: a current view of their
possible interactions. Pain 1995;62(3):259-274.
291. Angst MS, Clark JD. Opioid-induced hyperalgesia: a qualitative systematic review. Anesthesiology
2006;104(3):570-587.
292. Low Y, Clarke CF, Huh BK. Opioid-induced hyperalgesia: a review of epidemiology, mechanisms and
management. Singapore Med J 2012;53(5):357-360.
293. Lee M, Silverman SM, Hansen H, et al. A comprehensive review of opioid-induced hyperalgesia. Pain Phys
2011;14(2):145-161.
294. Kim SH, Stoicea N, Soghomonyan S, et al. Intraoperative use of remifentanil and opioid induced
hyperalgesia/acute opioid tolerance: systematic review. Front Pharmacol 2014;5:108.
295. Richebe P, Pouquet O, Jelacic S, et al. Target-controlled dosing of remifentanil during cardiac surgery reduces
postoperative hyperalgesia. J Cardiothorac Vasc Anesth 2011;25(6):917-925.
296. Fechner J, Ihmsen H, Schuttler J, et al. The impact of intra-operative sufentanil dosing on post-operative pain,
hyperalgesia and morphine consumption after cardiac surgery. Eur J Pain 2013;17(4):562-570.
297. Lahtinen P, Kokki H, Hynynen M. Remifentanil infusion does not induce opioid tolerance after cardiac surgery.
J Cardiothorac Vasc Anesth 2008;22(2):225-229.
298. Ramasubbu C, Gupta A. Pharmacological treatment of opioid-induced hyperalgesia: a review of the evidence. J
Pain Palliat Care Pharmacother 2011;25(3):219-230.
299. Joly V, Richebe P, Guignard B, et al. Remifentanil-induced postoperative hyperalgesia and its prevention with
small-dose ketamine. Anesthesiology 2005;103(1):147-155.
300. Wan S, Le Clerc JL, Vincent JL. Inflammatory response to cardiopulmonary bypass: mechanisms involved and
possible therapeutic strategies. Chest 1997;112(3):676-692.
301. Grunenfelder J, Zund G, Schoeberlein A, et al. Expression of adhesion molecules and cytokines after coronary
artery bypass grafting during normothermic and hypothermic cardiac arrest. Eur J Cardiothorac Surg
2000;17(6):723-728.
302. Grunenfelder J, Umbehr M, Plass A, et al. Genetic polymorphisms of apolipoprotein E4 and tumor necrosis
factor beta as predisposing factors for increased inflammatory cytokines after cardiopulmonary bypass. J Thorac
Cardiovasc Surg 2004;128(1):92-97.
303. Holmes JH, Connolly NC, Paull DL, et al. Magnitude of the inflammatory response to cardiopulmonary bypass
and its relation to adverse clinical outcomes. Inflamm Res 2002;51(12):579-586.
304. Adamik B, Kubler-Kielb J, Golebiowska B, et al. Effect of sepsis and cardiac surgery with cardiopulmonary
bypass on plasma level of nitric oxide metabolites, neopterin, and procalcitonin: correlation with mortality and
postoperative complications. Intensive Care Med 2000;26(9):1259-1267.
305. Perner A, Jorgensen VL, Poulsen TD, et al. Increased concentrations of L-lactate in the rectal lumen in patients
undergoing cardiopulmonary bypass. Br J Anaesth 2005;95(6):764-768.
306. Bhatia M, Moochhala S. Role of inflammatory mediators in the pathophysiology of acute respiratory distress
syndrome. J Pathol 2004;202(2):145-156.
307. Hill GE, Whitten CW, Landers DF. The influence of cardiopulmonary bypass on cytokines and cell-cell
communication. J Cardiothorac Vasc Anesth 1997;11(3):367-375.
308. Hill GE, Whitten CW. The role of the vascular endothelium in inflammatory syndromes, atherogenesis, and the
propagation of disease. J Cardiothorac Vasc Anesth 1997;11(3):316-321.
309. Clermont G, Vergely C, Jazayeri S, et al. Systemic free radical activation is a major event involved in
myocardial oxidative stress related to cardiopulmonary bypass. Anesthesiology 2002;96(1):80-87.
310. Cugno M, Nussberger J, Biglioli P, et al. Increase of bradykinin in plasma of patients undergoing
cardiopulmonary bypass: the importance of lung exclusion. Chest 2001;120(6):1776-1782.
311. De SF, Van BY, Caes F, et al. Tissue factor as the main activator of the coagulation system during
cardiopulmonary bypass. J Thorac Cardiovasc Surg 2002;123(5):951-958.
312. Qing M, Nimmesgern A, Heinrich PC, et al. Intrahepatic synthesis of tumor necrosis factor-alpha related to
cardiac surgery is inhibited by interleukin-10 via the Janus kinase (Jak)/signal transducers and activator of
transcription (STAT) pathway. Crit Care Med 2003;31(12):2769-2775.
313. Waterer GW, Wunderink RG. Science review: Genetic variability in the systemic inflammatory response. Crit
Care 2003;7(4):308-314.
314. Haas CE, Kaufman DC, Jones CE, et al. Cytochrome P450 3A4 activity after surgical stress. Crit Care Med
2003;31(5):1338-1346.
315. Sherwood ER, Toliver-Kinsky T. Mechanisms of the inflammatory response. Best Pract Res Clin Anaesthesiol
2004;18(3):385-405.
316. Pullicino EA, Carli F, Poole S, et al. The relationship between the circulating concentrations of interleukin 6 (IL-
6), tumor necrosis factor (TNF) and the acute phase response to elective surgery and accidental injury. Lymphokine
Res 1990;9(2):231-238.
317. Morgan ET. Regulation of cytochrome p450 by inflammatory mediators: why and how? Drug Metab Dispos
2001;29(3):207-212.
318. Morgan ET. Regulation of cytochromes P450 during inflammation and infection. Drug Metab Rev
1997;29(4):1129-1188.
319. Park GR. Molecular mechanisms of drug metabolism in the critically ill. Br J Anaesth 1996;77(1):32-49.
320. Iber H, Sewer MB, Barclay TB, et al. Modulation of drug metabolism in infectious and inflammatory diseases.
Drug Metab Rev 1999;31(1):29-41.
321. Guitton J, Buronfosse T, Desage M, et al. Possible involvement of multiple cytochrome P450S in fentanyl and
sufentanil metabolism as opposed to alfentanil. Biochem Pharmacol 1997;53(11):1613-1619.
322. Guitton J, Buronfosse T, Desage M, et al. Possible involvement of multiple human cytochrome P450 isoforms
in the liver metabolism of propofol. Br J Anaesth 1998;80(6):788-795.
323. Kharasch ED, Russell M, Garton K, et al. Assessment of cytochrome P450 3A4 activity during the menstrual
cycle using alfentanil as a noninvasive probe. Anesthesiology 1997;87(1):26-35.
324. Kronbach T, Mathys D, Umeno M, et al. Oxidation of midazolam and triazolam by human liver cytochrome
P450IIIA4. Mol Pharmacol 1989;36(1):89-96.
325. Abdel-Razzak Z, Loyer P, Fautrel A, et al. Cytokines down-regulate expression of major cytochrome P-450
enzymes in adult human hepatocytes in primary culture. Mol Pharmacol 1993;44(4):707-715.
326. Shedlofsky SI, Israel BC, McClain CJ, et al. Endotoxin administration to humans inhibits hepatic cytochrome
P450-mediated drug metabolism. J Clin Invest 1994;94(6):2209-2214.
327. Ledirac N, de Sousa G, Fontaine F, et al. Effects of macrolide antibiotics on CYP3A expression in human and
rat hepatocytes: interspecies differences in response to troleandomycin. Drug Metab Dispos 2000;28(12):1391-
1393.
328. Oda Y, Mizutani K, Hase I, et al. Fentanyl inhibits metabolism of midazolam: competitive inhibition of CYP3A4 in
vitro. Br J Anaesth 1999;82(6):900-903.
329. Olkkola KT, Ahonen J, Neuvonen PJ. The effects of the systemic antimycotics, itraconazole and fluconazole,
on the pharmacokinetics and pharmacodynamics of intravenous and oral midazolam. Anesth Analg 1996;82(3):511-
516.
330. Wang JS, Backman JT, Kivisto KT, et al. Effects of metronidazole on midazolam metabolism in vitro and in vivo.
Eur J Clin Pharmacol 2000;56(8):555-559.
331. Ameer B, Weintraub RA. Drug interactions with grapefruit juice. Clin Pharmacokinet 1997;33(2):103-121.
332. Miller E, Park GR. The effect of oxygen on propofol-induced inhibition of microsomal cytochrome P450 3A4.
Anaesthesia 1999;54(4):320-322.
333. Martinez C, Gervasini G, Agundez JA, et al. Modulation of midazolam 1-hydroxylation activity in vitro by
neurotransmitters and precursors. Eur J Clin Pharmacol 2000;56(2):145-151.
334. Maitre PO. Postoperative sedation with midazolam in heart surgery patients: pharmacokinetic considerations.
Acta Anaesthesiol Scand Suppl 1990;92:103-106.
335. Park GR, Miller E. What changes drug metabolism in critically ill patients—III? Effect of pre-existing disease on
the metabolism of midazolam. Anaesthesia 1996;51(5):431-434.
336. Tateishi T, Watanabe M, Nakura H, et al. CYP3A activity in European American and Japanese men using
midazolam as an in vivo probe. Clin Pharmacol Ther 2001;69(5):333-339.
337. Hennein HA, Ebba H, Rodriguez JL, et al. Relationship of the proinflammatory cytokines to myocardial ischemia
and dysfunction after uncomplicated coronary revascularization. J Thorac Cardiovasc Surg 1994;108(4):626-635.
338. 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.
339. Tonz M, Mihaljevic T, von Segesser LK, et al. Acute lung injury during cardiopulmonary bypass. Are the
neutrophils responsible? Chest 1995;108(6):1551-1556.
P.310
340. Sinclair DG, Haslam PL, Quinlan GJ, et al. The effect of cardiopulmonary bypass on intestinal and pulmonary
endothelial permeability. Chest 1995;108(3):718-724.
341. Kharazmi A, Andersen LW, Baek L, et al. Endotoxemia and enhanced generation of oxygen radicals by
neutrophils from patients undergoing cardiopulmonary bypass. J Thorac Cardiovasc Surg 1989;98(3):381-385.
342. Davies SW, Underwood SM, Wickens DG, et al. Systemic pattern of free radical generation during coronary
bypass surgery. Br Heart J 1990; 64(4):236-240.
343. Haisjackl M, Birnbaum J, Redlin M, et al. Splanchnic oxygen transport and lactate metabolism during
normothermic cardiopulmonary bypass in humans. Anesth Analg 1998;86(1):22-27.
344. Takahashi T, Kunimoto F, Ichikawa H, et al. Gastric intramucosal pH and hepatic venous oximetry after
cardiopulmonary bypass in valve replacement patients. Cardiovasc Surg 1996;4(3):308-310.
345. Andersen LW, Landow L, Baek L, et al. Association between gastric intramucosal pH and splanchnic
endotoxin, antibody to endotoxin, and tumor necrosis factor-alpha concentrations in patients undergoing
cardiopulmonary bypass. Crit Care Med 1993;21(2):210-217.
346. Hampton WW, Townsend MC, Schirmer WJ, et al. Effective hepatic blood flow during cardiopulmonary bypass.
Arch Surg 1989;124(4):458-459.
347. Koska AJ, III, Romagnoli A, Kramer WG. Effect of cardiopulmonary bypass on fentanyl distribution and
elimination. Clin Pharmacol Ther 1981;29:100-105.
348. Coceani F, Lees J, Mancilla J, et al. Interleukin-6 and tumor necrosis factor in cerebrospinal fluid: changes
during pyrogen fever. Brain Res 1993;612(1/2):165-171.
349. Pollmacher T, Schreiber W, Gudewill S, et al. Influence of endotoxin on nocturnal sleep in humans. Am J
Physiol 1993;264(6, Part 2):R1077-R1083.
350. Harris DN, Oatridge A, Dob D, et al. Cerebral swelling after normothermic cardiopulmonary bypass.
351. Renton KW. Alteration of drug biotransformation and elimination during infection and inflammation. Pharmacol
Ther 2001;92(2/3):147-163.
352. Goralski KB, Hartmann G, Piquette-Miller M, et al. Downregulation of mdr1a expression in the brain and liver
during CNS inflammation alters the in vivo disposition of digoxin. Br J Pharmacol 2003;139(1):35-48.
353. Nicholson TE, Renton KW. Role of cytokines in the lipopolysaccharide-evoked depression of cytochrome P450
in the brain and liver. Biochem Pharmacol 2001;62(12):1709-1717.
354. Nicholson TE, Renton KW. The role of cytokines in the depression of CYP1A activity using cultured astrocytes
as an in vitro model of inflammation in the central nervous system. Drug Metab Dispos 2002;30(1):42-46.
355. Renton KW, Nicholson TE. Hepatic and central nervous system cytochrome P450 are down-regulated during
lipopolysaccharide-evoked localized inflammation in brain. J Pharmacol Exp Ther 2000;294(2):524-530.
356. Arrowsmith JE, Grocott HP, Reves JG, et al. Central nervous system complications of cardiac surgery. Br J
Anaesth 2000;84(3):378-393.
357. Roberts DJ, Goralski KB, Renton KW, et al. Effect of acute inflammatory brain injury on accumulation of
morphine and morphine 3- and 6-glucuronide in the human brain. Crit Care Med 2009;37(10):2767-2774.
358. Han J, Thompson P, Beutler B. Dexamethasone and pentoxifylline inhibit endotoxin-induced cachectin/tumor
necrosis factor synthesis at separate points in the signaling pathway. J Exp Med 1990;172(1):391-394.
359. Hsu YW, Somma J, Newman MF, et al. Population pharmacokinetics of lidocaine administered during and after
cardiac surgery. J Cardiothorac Vasc Anesth 2011;25(6):931-936.
360. Kirkland KB, Briggs JP, Trivette SL, et al. The impact of surgical-site infections in the 1990s: attributable
mortality, excess length of hospitalization, and extra costs. Infect Control Hosp Epidemiol 1999;20(11):725-730.
361. Rosenberger LH, Politano AD, Sawyer RG. The surgical care improvement project and prevention of post-
operative infection, including surgical site infection. Surg Infect 2011;12(3):163-168.
362. Barbour A, Scaglione F, Derendorf H. Class-dependent relevance of tissue distribution in the interpretation of
anti-infective pharmacokinetic/pharmacodynamic indices. Int J Antimicrob Agents 2010;35(5):431-438.
363. McKenzie C. Antibiotic dosing in critical illness. J Antimicrob Chemother 2011;66(Suppl 2):ii25-ii31.
364. Sinnollareddy MG, Roberts MS, Lipman J, et al. β-lactam pharmacokinetics and pharmacodynamics in critically
ill patients and strategies for dose optimization: a structured review. Clin Exp Pharmacol Physiol 2012;39(6):489-
496.
365. MacGowan A. Revisiting Beta-lactams—PK/PD improves dosing of old antibiotics. Curr Opin Pharmacol
2011;11(5):470-476.
366. Mouton JW, Ambrose PG, Canton R, et al. Conserving antibiotics for the future: new ways to use old and new
drugs from a pharmacokinetic and pharmacodynamic perspective. Drug Resist Updat 2011;14(2):107-117.
367. Adembri C, Ristori R, Chelazzi C, et al. Cefazolin bolus and continuous administration for elective cardiac
surgery: improved pharmacokinetic and pharmacodynamic parameters. J Thorac Cardiovasc Surg 2010;140(2):471-
475.
368. Kaiser AB, Petracek MR, Lea JW, et al. Efficacy of cefazolin, cefamandole, and gentamicin as prophylactic
agents in cardiac surgery. Results of a prospective, randomized, double-blind trial in 1030 patients. Ann Surg
1987;206(6):791-797.
369. Lehot JJ, Reverdy ME, Etienne J, et al. Oxacillin and tobramycin serum levels during cardiopulmonary bypass.
J Cardiothorac Anesth 1989;3(2):163-167.
370. Bryan CS, Smith CW, Jr., Sutton JP, et al. Comparison of cefamandole and cefazolin during cardiopulmonary
371. Bergeron MG, Desaulniers D, Lessard C, et al. Concnetrations of fusidic acid, cloxacillin, and cefamandole in
sera and atrial appendages of patients undergoing cardiac surgery. Antimicrob Agents Chemother 1985; 27(6):928-
932.
372. van der Starre PJ, Trienekens PH, Harinck-de Weerd JE, et al. Comparative study between two prophylactic
antibiotic regimens of cefamandole during coronary artery bypass surgery. Ann Thorac Surg 1988;45(1):24-27.
373. Fellinger EK, Leavitt BJ, Hebert JC. Serum levels of prophylactic cefazolin during cardiopulmonary bypass
surgery. Ann Thorac Surg 2002;74(4):1187-1190.
374. Lonsky V, Dominik J, Mand'ak J, et al. Changes of the serum antibiotic levels during open heart surgery
(ceftazidim, ciprofloxacin, clindamycin). Acta Medica (HradecKralove) 2000;43(1):23-27.
375. Nascimento JW, Carmona MJ, Strabelli TM, et al. Systemic availability of prophylactic cefuroxime in patients
submitted to coronary artery bypass grafting with cardiopulmonary bypass. J Hosp Infect 2005;59(4):299-303.
376. Kitzes-Cohen R, Farin D, Piva G, et al. Pharmacokinetics of vancomycin administered as prophylaxis before
cardiac surgery. Ther Drug Monit 2000;22(6):661-667.
377. Wilson AP, Taylor B, Treasure T, et al. Antibiotic prophylaxis in cardiac surgery: serum and tissue levels of
teicoplanin, flucloxacillin and tobramycin [published erratum appears in J Antimicrob Chemother 1988;21(6):814]. J
Antimicrob Chemother 1988;21(2):201-212.
378. Cotogni P, Passera R, Barbero C, et al. Intraoperative vancomycin pharmacokinetics in cardiac surgery with or
without cardiopulmonary bypass. Ann Pharmacother 2013;47(4):455-463.
379. Ferreira F, Santos S, Nascimento J, et al. Influence of cardiopulmonary bypass on cefuroxime plasma
concentration and pharmacokinetics in patients undergoing coronary surgery. Eur J Cardiothorac Surg
2012;42(2):300-305.
380. Heylen RM, Wilson AP, Hichens M, et al. Antibiotic prophylaxis in cardiac surgery: factors associated with
potentially toxic serum concentrations of gentamicin. J Antimicrob Chemother 1995;35(5):657-667.
381. Lewis DR, Longman RJ, Wisheart JD, et al. The pharmacokinetics of a single dose of gentamicin (4 mg/kg) as
prophylaxis in cardiac surgery requiring cardiopulmonary bypass. Cardiovasc Surg 1999;7(4):398-401.
382. Heylen RM, Wilson AP, Hichens M, et al. Clearance of gentamicin during cardiac surgery. J Antimicrob
Chemother 1995;35(5):649-655.
383. Lador A, Nasir H, Mansur N, et al. Antibiotic prophylaxis in cardiac surgery: systematic review and meta-
analysis. J Antimicrob Chemother 2012;67(3):541-550.
384. Mertz D, Johnstone J, Loeb M. Does duration of perioperative antibiotic prophylaxis matter in cardiac surgery?
A systematic review and meta-analysis. Ann Surg 2011;254(1):48-54.
385. Akl BF, Richardson G. Serum cefazolin levels during cardiopulmonary bypass. Ann Thorac Surg 1980;29:109-
112.
386. Bito H, Atsumi K, Katoh T, et al. Effects of sevoflurane anesthesia on plasma inorganic fluoride concentrations
during and after cardiac surgery. J Anesth 1999;13(3):156-160.
387. Shiu J, Wang E, Tejani AM, et al. Continuous versus intermittent infusions of antibiotics for the treatment of
severe acute infections. Cochrane Database Syst Rev 2013;3:CD008481.
388. Kosaka T, Hosokawa K, Shime N, et al. Effects of renal function on the pharmacokinetics and
pharmacodynamics of prophylactic cefazolin in cardiothoracic surgery. Eur J Clin Microbiol Infect Dis
2012;31(2):193-199.
389. Hatzopoulos FK, Stile-Calligaro IL, Rodvold KA, et al. Pharmacokinetics of intravenous vancomycin in pediatric
cardiopulmonary bypass surgery. Pediatr Infect Dis J 1993;12(4):300-304.
P.311
390. Bergeron MG, Saginur R, Desaulniers D, et al. Concentrations of teicoplanin in serum and atrial appendages of
patients undergoing cardiac surgery. Antimicrob Agents Chemother 1990;34(9):1699-1702.
391. Gorlinger K, Shore-Lesserson L, Dirkmann D, et al. Management of hemorrhage in cardiothoracic surgery. J

Cardiothorac Vasc Anesth 2013;27(4, Suppl):S20-S34.
392. Maslow A, Schwartz C. Cardiopulmonary bypass-associated coagulopathies and prophylactic therapy. Int
Anesthesiol Clin 2004;42(3):103-133.
393. Hutton B, Joseph L, Fergusson D, et al. Risks of harms using antifibrinolytics in cardiac surgery: systematic
review and network meta-analysis of randomised and observational studies. BMJ 2012;345:e5798.
394. Henry DA, Carless PA, Moxey AJ, et al. Anti-fibrinolytic use for minimising perioperative allogeneic blood
transfusion. Cochrane Database Syst Rev 2011(3):CD001886.
395. Deanda A Jr, Spiess BD. Aprotinin revisited. J Thorac Cardiovasc Surg 2012;144(5):998-1002.
396. Ngaage DL, Bland JM. Lessons from aprotinin: is the routine use and inconsistent dosing of tranexamic acid
prudent? Meta-analysis of randomised and large matched observational studies. Eur J Cardiothorac Surg
2010;37(6):1375-1383.
397. Dowd NP, Karski JM, Cheng DC, et al. Pharmacokinetics of tranexamic acid during cardiopulmonary bypass.
398. Grassin-Delyle S, Tremey B, Abe E, et al. Population pharmacokinetics of tranexamic acid in adults undergoing
cardiac surgery with cardiopulmonary bypass. Br J Anaesth 2013;111(6):916-924.
399. Grassin-Delyle S, Couturier R, Abe E, et al. A practical tranexamic acid dosing scheme based on population
pharmacokinetics in children undergoing cardiac surgery. Anesthesiology 2013;118(4):853-862.
400. Takagi H, Manabe H, Kawai N, et al. Aprotinin increases mortality as compared with tranexamic acid in cardiac
surgery: a meta-analysis of randomized head-to-head trials. Interact Cardiovasc Thorac Surg 2009;9(1):98-101.
401. Van Aelbrouck C, Englberger L, Faraoni D. Review of the fibrinolytic system: comparison of different
antifibrinolytics used during cardiopulmonary bypass. Recent Pat Cardiovasc Drug Discov 2012;7(3):175-179.
402. Sill JC, Nugent M, Moyer TP, et al. Influence of propranolol plasma levels on hemodynamics during coronary
artery bypass surgery. Anesthesiology 1984;60(5):455-463.
403. Wood M, Shand DG, Wood AJJ. Propranolol binding in plasma during cardiopulmonary bypass.
404. Carmona MJ, Malbouisson LM, Pereira VA, et al. Cardiopulmonary bypass alters the pharmacokinetics of
propranolol in patients undergoing cardiac surgery. Braz J Med Biol Res 2005;38(5):713-721.
405. Leite Fda S, dos Santos LM, Bonafe WW, et al. Influence of cardiopulmonary bypass on the plasma
concentrations of atenolol. Arq Bras Cardiol 2007;88(6):637-642.
406. Carmona MJ, Pereira VA, Malbouisson LM, et al. Effect of cardiopulmonary bypass on the pharmacokinetics of
propranolol and atenolol. Braz J Med Biol Res 2009;42(6):574-581.
407. Matsumoto N, Aomori T, Kanamoto M, et al. Influence of hemodynamic variations on the pharmacokinetics of
landiolol in patients undergoing cardiovascular surgery. Biol Pharm Bull 2012;35(10):1655-1660.
408. Dieleman JM, van PJ, van DD, et al. Prophylactic corticosteroids for cardiopulmonary bypass in adults.
Cochrane Database Syst Rev 2011;5:CD005566.
409. Kong AN, Jungbluth GL, Pasko MT, et al. Pharmacokinetics of methylprednisolone sodium succinate and
methylprednisolone in patients undergoing cardiopulmonary bypass. Pharmacotherapy 1990;10(1):29-34.
410. Ross MP, Allen-Webb EM, Pappas JB, et al. Amrinone-associated thrombocytopenia: pharmacokinetic
analysis. Clin Pharmacol Ther 1993; 53(6):661-667.
411. Kikura M, Lee MK, Safon RA, et al. The effects of milrinone on platelets in patients undergoing cardiac surgery.
Anesth Analg 1995;81(1):44-48.
412. Williams GD, Sorensen GK, Oakes R, et al. Amrinone loading during cardiopulmonary bypass in neonates,
infants, and children. J Cardiothorac Vasc Anesth 1995;9(3):278-282.
413. Ramamoorthy C, Anderson GD, Williams GD, et al. Pharmacokinetics and side effects of milrinone in infants
and children after open heart surgery. Anesth Analg 1998;86(2):283-289.
414. Bailey JM, Miller BE, Lu W, et al. The pharmacokinetics of milrinone in pediatric patients after cardiac surgery.
Anesthesiology 1999;90(4):1012-1018.
415. Hayashi Y, Sumikawa K, Yamatodani A, et al. Quantitative analysis of pulmonary clearance of exogenous
dopamine after cardiopulmonary bypass in humans. Anesth Analg 1993;76(1):107-112.
416. Boscoe MJ, Dawling S, Thompson MA, et al. Lorazepam in open-heart surgery—plasma concentrations before,
during and after bypass following different dose regimens. Anaesth Intensive Care 1984;12:9-13.
417. Harper KW, Collier PS, Dundee JW, et al. Age and nature of operation influence the pharmacokinetics of
midazolam. Br J Anaesth 1985;57:866-871.
418. Kanto J, Himberg JJ, HeikkilÑ H, et al. Midazolam kinetics before, during and after cardiopulmonary bypass
surgery. Int J Clin Pharmacol Res 1985;5(2):123-126.
419. Zomorodi K, Donner A, Somma J, et al. Population pharmacokinetics of midazolam administered by target
controlled infusion for sedation following coronary artery bypass grafting. Anesthesiology 1998;89(6):1418-1429.
420. Bailey JM, Mora CT, Shafer SL. Pharmacokinetics of propofol in adult patients undergoing coronary
revascularization. The Multicenter Study of Perioperative Ischemia Research Group. Anesthesiology
1996;84(6):1288-1297.
421. Grossherr M, Hengstenberg A, Meier T, et al. Propofol concentration in exhaled air and arterial plasma in
mechanically ventilated patients undergoing cardiac surgery. Br J Anaesth 2009;102(5):608-613.
422. Buzello W, Pollmaecher T, Schluermann D, et al. The influence of hypothermic cardiopulmonary bypass on
neuromuscular transmission in the absence of muscle relaxants. Anesthesiology 1986;64(2):279-281.
423. Heier T, Caldwell JE, Sessler DI, et al. The relationship between adductor pollicis twitch tension and core, skin,
and muscle temperature during nitrous oxide-isoflurane anesthesia in humans. Anesthesiology 1989;71(3):381-384.
424. Mills GH, Khan ZP, Moxham J, et al. Effects of temperature on phrenic nerve and diaphragmatic function during
cardiac surgery. Br J Anaesth 1997;79(6):726-732.
425. Withington D, Menard G, Harris J, et al. Vecuronium pharmacokinetics and pharmacodynamics during
hypothermic cardiopulmonary bypass in infants and children. Can J Anaesth 2000;47(12):1188-1195.
426. Shearer ES, Russell GN. The effect of cardiopulmonary bypass on cholinesterase activity. Anaesthesia
1993;48(4):293-296.
427. Mantz J, Abi-Jaoude F, Ceddaha A, et al. High-dose alfentanil for myocardial revascularization: a hemodynamic
and pharmacokinetic study. J Cardiothorac Vasc Anesth 1991;5(2):107-110.
428. Petros A, Dunne N, Mehta R, et al. The pharmacokinetics of alfentanil after normothermic and hypothermic
cardiopulmonary bypass. Anesth Analg 1995;81(3):458-464.
429. Sprigge JS, Wynands JE, Whalley DG, et al. Fentanyl infusion anesthesia for aortocoronary bypass surgery:
plasma levels and hemodynamic response. Anesth Analg 1982;61(12):972-978.
430. Duthie DJ, Stevens JJ, Doyle AR, et al. Remifentanil and pulmonary extraction during and after cardiac
anesthesia. Anesth Analg 1997;84(4):740-744.
431. Wynands JE, Townsend GE, Wong P, et al. Blood pressure response and plasma fentanyl concentrations
during high- and very highdose fentanyl anesthesia for coronary artery surgery. Anesth Analg 1983;62(7):661-665.
432. Philbin DM, Rosow CE, Schneider RC, et al. Fentanyl and sufentanil anesthesia revisited: how much is
enough? Anesthesiology 1990;73(1):5-11.
433. Flacke JW, Bloor BC, Flacke WE, et al. Reduced narcotic requirement by clonidine with improved
hemodynamic and adrenergic stability in patients undergoing coronary bypass surgery. Anesthesiology
1987;67(1):11-19.
434. Thomson IR, Peterson MD, Hudson RJ. A comparison of clonidine with conventional preanesthetic medication
in patients undergoing coronary artery bypass grafting. Anesth Analg 1998;87(2):292-299.
435. Gepts E, Shafer SL, Camu F, et al. Linearity of pharmacokinetics and model estimation of sufentanil.
Anesthesiology 1995;83(6):1194-1204.
436. Dasta JF, Weber RJ, Wu LS, et al. Influence of cardiopulmonary bypass on nitroglycerin clearance. J Clin
Pharmacol 1986;26(3):165-168.
437. Moore RA, Geller EA, Gallagher JD, et al. Effect of hypothermic cardiopulmonary bypass on nitroprusside
metabolism. Clin Pharmacol Ther 1985;37:680-683.
438. Lundquist P, Rosling H, Tyden H. Cyanide release from sodium nitroprusside during coronary bypass in
hypothermia. Acta Anaesthesiol Scand 1989;33(8):686-688.
439. Henderson JM, Nathan HJ, Lalande M, et al. Washin and washout of isoflurane during cardiopulmonary
bypass. Can J Anaesth 1988; 35(6):587-590.
440. Price SL, Brown DL, Carpenter RL, et al. Isoflurane elimination via a bubble oxygenator during extracorporeal
circulation. J Cardiothorac Anesth 1988;2(1):41-44.
P.312
441. Goucke CR, Hackett LP, Barrett PH, et al. Blood concentrations of enflurane before, during, and after
hypothermic cardiopulmonary bypass. J Cardiothorac Vasc Anesth 2007;21(2):218-223.
442. Lockwood GG, Sapsed-Byrne SM, Adams S. A comparison of anaesthetic tensions in arterial blood and
oxygenator exhaust gas during cardiopulmonary bypass. Anaesthesia 1999;54(5):434-436.
443. Klamerus KJ, Rodvold KA, Silverman NA, et al. Effect of cardiopulmonary bypass on vancomycin and netilmicin
disposition. Antimicrob Agents Chemother 1988;32(5):631-635.
444. Lippert S, Josephsen SD, Jendresen M, et al. Elimination of cefuroxime and gentamicin during and after open
heart surgery. J Antimicrob Chemother 1989;24(5):775-780.
445. Lehot JJ, Reverdy ME, Etienne J, et al. Cefazolin and netilmicin serum levels during and after cardiac surgery
with cardiopulmonary bypass. J Cardiothorac Anesth 1990;4(2):204-209.
446. Haessler D, Reverdy ME, Neidecker J, et al. Antibiotic prophylaxis with cefazolin and gentamicin in cardiac
surgery for children less than ten kilograms. J Cardiothorac Vasc Anesth 2003;17(2):221-225.
447. Miller KW, McCoy HG, Chan KKH, et al. Effect of cardiopulmonary bypass on cefazolin disposition. Clin
448. Nightingale CH, Klimek JJ, Quintiliani R. Effect of protein binding on the penetration of nonmetabolized
cephalosporins into atrial appendage and pericardial fluids in open-heart surgical patients. Antimicrob Agents
Chemother 1980;17:595-598.
449. Olson NH, Nightingale CH, Quintiliani R. Penetration characeristics of cefamandole into the right atrial
appendage and pericardial fluid in patients undergoing open-heart surgery. Ann Thorac Surg 1980;29:104-108.
450. Mullany LD, French MA, Nightingale CH, et al. Penetration of ceforanide and cefamandole onto the right atrial
appendage, pericardial fluid, sternum, and intercostal muscle of patients undergoing open heart surgery. Antimicrob
451. Frank U, Kappstein I, Schmidt-Eisenlohr E, et al. Penetration of ceftazidime into heart valves and subcutaneous
and muscle tissue of patients undergoing open-heart surgery. Antimicrob Agents Chemother 1987;31(5):813-814.
452. Oksenhendler G, Leroy A, Schleifer D, et al. Ceftriaxone pharmacokinetics during cardiopulmonary bypass.
Chemioterapia 1987;6(Suppl 2):271-272.
453. Martin C, Viviand X, Alaya M, et al. Penetration of ceftriaxone (1 or 2 grams intravenously) into mediastinal and
cardiac tissues in humans. Antimicrob Agents Chemother 1996;40(3):812-815.
454. Sue D, Salazar TA, Turley K, et al. Effect of surgical blood loss and volume replacement on antibiotic
pharmacokinetics. Ann Thorac Surg 1989;47(6):857-859.
455. Menges T, Sablotzki A, Welters I, et al. Concentration of cefamandole in plasma and tissues of patients
undergoing cardiac surgery: the influence of different cefamandole dosage. J Cardiothorac Vasc Anesth
1997;11(5):565-570.
456. Vuorisalo S, Pokela R, Syrjala H. Is single-dose antibiotic prophylaxis sufficient for coronary artery bypass
surgery? An analysis of peri-and postoperative serum cefuroxime and vancomycin levels. J Hosp Infect
1997;37(3):237-247.
457. Miglioli PA, Merlo F, Calabro GB, et al. Cefazolin concentrations in serum during cardiopulmonary bypass
surgery. Drugs Exp Clin Res 2005;31(1):29-33.
458. Mand'ak J, Pojar M, Malakova J, et al. Tissue and plasma concentrations of cephuroxime during cardiac
surgery in cardiopulmonary bypass—a microdialysis study. Perfusion 2007;22(2):129-136.
459. Knoderer CA, Saft SA, Walker SG, et al. Cefuroxime pharmacokinetics in pediatric cardiovascular surgery
patients undergoing cardiopulmonary bypass. J Cardiothorac Vasc Anesth 2011;25(3):425-430.
460. Pojar M, Mandak J, Malakova J, et al. Tissue and plasma concentrations of antibiotic during cardiac surgery
with cardiopulmonary bypass—microdialysis study. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub
2008;152(1):139-145.
461. Mertes PM, Voiriot P, Dopff C, et al. Penetration of ciprofloxacin into heart valves, myocardium, mediastinal fat,
and sternal bone marrow in humans. Antimicrob Agents Chemother 1990;34(3):398-401.
462. Pryka RD, Rodvold KA, Ting W, et al. Effects of cardiopulmonary bypass surgery on intravenous ciprofloxacin
disposition. Antimicrob Agents Chemother 1993;37(10):2106-2111.
463. Metallidis S, Charokopos N, Nikolaidis J, et al. Penetration of moxifloxacin into sternal bone of patients
undergoing routine cardiopulmonary bypass surgery. Int J Antimicrob Agents 2006;28(5):428-432.
464. Wiesner G, Martin K, Gertler R, et al. Serum concentrations and pharmacokinetics of moxifloxacin in patients
undergoing coronary artery bypass graft surgery with cardiopulmonary bypass. Int J Antimicrob Agents
2013;41(5):473-476.
465. Daschner FD, Frank U, Kummel A, et al. Pharmacokinetics of vancomycin in serum and tissue of patients
undergoing open-heart surgery. J Antimicrob Chemother 1987;19(3):359-362.
466. Massias L, Dubois C, de Lentdecker P, et al. Penetration of vancomycin in uninfected sternal bone. Antimicrob
467. Martin C, Alaya M, Mallet MN, et al. Penetration of vancomycin into mediastinal and cardiac tissues in humans.
Antimicrob Agents Chemother 1994;38(2):396-399.
468. Miglioli PA, Merlo F, Grabocka E, et al. Effects of cardio-pulmonary bypass on vancomycin plasma
concentration decay. Pharmacol Res 1998;38(4):275-278.
469. Desmond J, Lovering A, Harle C, et al. Topical vancomycin applied on closure of the sternotomy wound does
not prevent high levels of systemic vancomycin. Eur J Cardiothorac Surg 2003;23(5):765-770.
470. Metallidis S, Nikolaidis J, Lazaraki G, et al. Penetration of linezolid into sternal bone of patients undergoing
cardiopulmonary bypass surgery. Int J Antimicrob Agents 2007;29(6):742-744.
471. Shime N, Kato Y, Kosaka T, et al. Glycopeptide pharmacokinetics in current paediatric cardiac surgery
practice. Eur J Cardiothorac Surg 2007;32(4):577-581.
472. Farber BF, Karchmer AW, Buckley MJ, et al. Vancomycin prophylaxis in cardiac operations: determination of an
optimal dosage regimen. J Thorac Cardiovasc Surg 1983;85(6):933-935.
473. Pieper R, Henze A, Josefsson K, et al. Penetration of penicillins into cardiac valves and auricles of patients
undergoing open-heart surgery. Scand J Thorac Cardiovasc Surg 1985;19:49-53.
474. Kullberg BJ, Mattie H, Huysmans HA, et al. Evaluation of cloxacillin concentrations in plasma and muscle tissue
during cardiopulmonary bypass. Scand J Infect Dis 1991;23(2):233-238.
475. Lonsky V, Lonsk V, Rozsival V, et al. Serum oxacillin and cephazolin levels during cardiopulmonary bypass.
Perfusion 1992;7:115-118.
476. Kanellakopoulou K, Tselikos D, Giannitsioti E, et al. Pharmacokinetics of fusidic acid and cefepime in heart
tissues: implications for a role in surgical prophylaxis. J Chemother 2008;20(4):468-471.
477. Nguyen MH, Eells SJ, Tan J, et al. Prospective, open-label investigation of the pharmacokinetics of daptomycin
during cardiopulmonary bypass surgery. Antimicrob Agents Chemother 2011;55(6):2499-2505.
478. Bennett-Guerrero E, Sorohan JG, Howell ST, et al. Maintenance of therapeutic plasma aprotinin levels during
prolonged cardiopulmonary bypass using a large-dose regimen. Anesth Analg 1996;83(6):1189-1192.
479. O'Connor CJ, Brown DV, Avramov M, et al. The impact of renal dysfunction on aprotinin pharmacokinetics
during cardiopulmonary bypass. Anesth Analg 1999;89(5):1101-1107.
480. Beath SM, Nuttall GA, Fass DN, et al. Plasma aprotinin concentrations during cardiac surgery: full-versus half-
dose regimens. Anesth Analg 2000;91(2):257-264.
481. Royston D, Cardigan R, Gippner-Steppert C, et al. Is perioperative plasma aprotinin concentration more
predictable and constant after a weight-related dose regimen? Anesth Analg 2001;92(4):830-836.
482. Nuttall GA, Fass DN, Oyen LJ, et al. A study of a weight-adjusted aprotinin dosing schedule during cardiac
surgery. Anesth Analg 2002;94(2): 283-289.
483. Bennett-Guerrero E, Sorohan JG, Canada AT, et al. Epsilon-Aminocaproic acid plasma levels during
cardiopulmonary bypass. Anesth Analg 1997;85(2):248-251.
484. Butterworth J, James RL, Lin Y, et al. Pharmacokinetics of epsilon-aminocaproic acid in patients undergoing
aortocoronary bypass surgery. Anesthesiology 1999;90(6):1624-1635.
485. Butterworth J, James RL, Lin YA, et al. Gender does not influence epsilon-aminocaproic acid concentrations in
adults undergoing cardiopulmonary bypass. Anesth Analg 2001;92(6):1384-1390.
486. Fiechtner BK, Nuttall GA, Johnson ME, et al. Plasma tranexamic acid concentrations during cardiopulmonary
bypass. Anesth Analg 2001;92(5):1131-1136.
487. Kluger R, Olive DJ, Stewart AB, et al. Epsilon-aminocaproic acid in coronary artery bypass graft surgery:
preincision or postheparin? Anesthesiology 2003;99(6):1263-1269.
488. Sharma V, Fan J, Jerath A, et al. Pharmacokinetics of tranexamic acid in patients undergoing cardiac surgery
with use of cardiopulmonary bypass. Anaesthesia 2012;67(11):1242-1250.
P.313
489. Bojko B, Vuckovic D, Mirnaghi F, et al. Therapeutic monitoring of tranexamic acid concentration: high-
throughput analysis with solid-phase microextraction. Ther Drug Monit 2012;34(1):31-37.
490. Arsenault KA, Paikin JS, Hirsh J, et al. Subtle differences in commercial heparins can have serious
consequences for cardiopulmonary bypass patients: a randomized controlled trial. J Thorac Cardiovasc Surg
2012;144(4):944-950. e943.
491. Davidson SJ, Tillyer ML, Keogh J, et al. Heparin concentrations in neonates during cardiopulmonary bypass. J
Thromb Haemost 2012;10(4):730-732.
492. Ignjatovic V, Than J, Summerhayes R, et al. Hemostatic response in paediatric patients undergoing
cardiopulmonary bypass surgery. Pediatr Cardiol 2011;32(5):621-627.
493. Koster A, Buz S, Krabatsch T, et al. Effect of modified ultrafiltration on bivalirudin elimination and postoperative
blood loss after on-pump coronary artery bypass grafting: assessment of different filtration strategies. J Cardiac
Surg 2008;23(6):655-658.
494. de Bruijn NP, Reves JG, Croughwell N, et al. Pharmacokinetics of esmolol in anesthetized patients receiving
chronic beta blocker therapy. Anesthesiology 1987;66(3):323-326.
495. Ahonen J, Olkkola KT, Salmenpera M, et al. Effect of diltiazem on midazolam and alfentanil disposition in
patients undergoing coronary artery bypass grafting. Anesthesiology 1996;85(6):1246-1252.
496. Finegan BA, Hussain MD, Tam YK. Pharmacokinetics of diltiazem in patients undergoing coronary artery
bypass grafting. Ther Drug Monit 1992;14(6):485-492.
497. Bergman AS, Odar-Cederlof I, Westman L, et al. Diltiazem infusion for renal protection in cardiac surgical
patients with preexisting renal dysfunction. J Cardiothorac Vasc Anesth 2002;16(3):294-299.
498. Hynynen M, Siltanen T, Sahlman A, et al. Continuous infusion of nimodipine during coronary artery surgery:
haemodynamic and pharmacokinetic study. Br J Anaesth 1995;74(5):526-533.
499. Boulieu R, Bonnefous JL, Leho JJ, et al. Effect of cardiopulmonary bypass on plasma concentrations of
diltiazem and its two active metabolites. J Pharm Pharmacol 1994;46(4):310-312.
500. Carruthers SG, Cleland J, Kelly JG, et al. Plasma and tissue digoxin concentrations in patients undergoing
cardiopulmonary bypass. Br Heart J 1975;37:313-320.
501. Anaokar SM, Thorat SP, Tendolkar AG, et al. Cardiac surgery and plasma digoxin levels. J Assoc Phys India
1996;44(10):694-697.
502. Thompson MA, Broadbent MP, English J. Plasma levels of methylprednisolone following administration during
cardiac surgery. Anaesthesia 1982;37:405-407.
503. Oualha M, Urien S, Spreux-Varoquaux O, et al. Pharmacokinetics, hemodynamic and metabolic effects of
epinephrine to prevent post-operative low cardiac output syndrome in children. Crit Care 2014;18(1):R23.
504. Bailey JM, Levy JH, Kikura M, et al. Pharmacokinetics of intravenous milrinone in patients undergoing cardiac
surgery. Anesthesiology 1994;81(3):616-622.
505. Das PA, Skoyles JR, Sherry KM, et al. Disposition of milrinone in patients after cardiac surgery. Br J Anaesth
1994;72(4):426-429.
506. Butterworth JF, Hines RL, Royster RL, et al. A pharmacokinetic and pharmacodynamic evaluation of milrinone
in adults undergoing cardiac surgery. Anesth Analg 1995;81(4):783-792.
507. De Hert SG, Moens MM, Jorens PG, et al. Comparison of two different loading doses of milrinone for weaning
from cardiopulmonary bypass. J Cardiothorac Vasc Anesth 1995;9(3):264-271.
508. Kikura M, Levy JH, Michelsen LG, et al. The effect of milrinone on hemodynamics and left ventricular function
after emergence from cardiopulmonary bypass. Anesth Analg 1997;85(1):16-22.
509. Booker PD, Gibbons S, Stewart JI, et al. Enoximone pharmacokinetics in infants. Br J Anaesth 2000;85(2):205-
210.
510. Pellicer A, Riera J, Lopez-Ortego P, et al. Phase 1 study of two inodilators in neonates undergoing
cardiovascular surgery. Pediatr Res 2013;73(1):95-103.
511. Zuppa AF, Nicolson SC, Adamson PC, et al. Population pharmacokinetics of milrinone in neonates with
hypoplastic left heart syndrome undergoing stage I reconstruction. Anesth Analg 2006;102(4):1062-1069.
512. Lowry KG, Dundee JW, McClean E, et al. Pharmacokinetics of diazepam and midazolam when used for
sedation following cardiopulmonary bypass. Br J Anaesth 1985;57:883-885.
513. Maitre PO, Funk B, Crevoisier C, et al. Pharmacokinetics of midazolam in patients recovering from cardiac
surgery. Eur J Clin Pharmacol 1989;37(2):161-166.
514. Kern FH, Ungerleider RM, Jacobs JR, et al. Computerized continuous infusion of intravenous anesthetic drugs
during pediatric cardiac surgery. Anesth Analg 1991;72(4):487-492.
515. Smith MT, Eadie MJ, Brophy TO. The pharmacokinetics of midazolam in man. Eur J Clin Pharmacol
1981;19(4):271-278.
516. Ng A, Tan SS, Lee HS, et al. Effect of propofol infusion on the endocrine response to cardiac surgery. Anaesth
Intensive Care 1995;23(5):543-547.
517. Hudson RJ, Bergstrom RG, Thomson IR, et al. Pharmacokinetics of sufentanil in patients undergoing
abdominal aortic surgery. Anesthesiology 1989;70(3):426-431.
518. Alvis JM, Reves JG, Govier AV, et al. Computer-assisted continuous infusions of fentanyl during cardiac
anesthesia: comparison with a manual method. Anesthesiology 1985;63:41-49.
519. Theil DR, Stanley TE 3rd, White WD, et al. Midazolam and fentanyl continuous infusion anesthesia for cardiac
surgery: a comparison of computer-assisted versus manual infusion systems. J Cardiothorac Vasc Anesth
1993;7(3):300-306.
520. Oduro A, Tomlinson AA, Voice A, et al. The use of etomidate infusions during anaesthesia for cardiopulmonary
bypass. Anaesthesia 1983;38(Suppl):66-69.
521. McLean RF, Baker AJ, Walker SE, et al. Ketamine concentrations during cardiopulmonary bypass. Can J
Anaesth 1996;43(6):580-584.
522. Boer F, Ros P, Bovill JG, et al. Effect of propofol on peripheral vascular resistance during cardiopulmonary
bypass. Br J Anaesth 1990;65(2):184-189.
523. Massey NJ, Sherry KM, Oldroyd S, et al. Pharmacokinetics of an infusion of propofol during cardiac surgery. Br
J Anaesth 1990;65(4):475-479.
524. Lee HS, Khoo YM, Chua BC, et al. Pharmacokinetics of propofol infusion in Asian patients undergoing
coronary artery bypass grafting. Ther Drug Monit 1995;17(4):336-341.
525. Gepts E, Camu F, Cockshott ID, et al. Disposition of propofol administered as constant rate intravenous
infusions in humans. Anesth Analg 1987;66(12):1256-1263.
526. Kenny GN, White M. A portable target controlled propofol infusion system. Int J Clin Monit Comput
1992;9(3):179-182.
527. Davies FW, White M, Kenny GN. Postoperative analgesia using a computerised infusion of alfentanil following
aortic bifurcation graft surgery. Int J Clin Monit Comput 1992;9(4):207-212.
528. Palm S, Linstedt U, Petry A, et al. Dose-response relationship of propofol on mid-latency auditory evoked
potentials (MLAEP) in cardiac surgery. Acta Anaesthesiol Scand 2001;45(8):1006-1010.
529. Geisler FE, de LS, Royston D, et al. Efficacy and safety of remifentanil in coronary artery bypass graft surgery:
a randomized, double-blind dose comparison study. J Cardiothorac Vasc Anesth 2003;17(1):60-68.
530. Marsh B, White M, Morton N, et al. Pharmacokinetic model driven infusion of propofol in children. Br J Anaesth
1991;67(1):41-48.
531. Buzello W, Schluermann D, Pollmaecher T, et al. Unequal effects of cardiopulmonary bypass-induced

hypothermia on neuromuscular blockade from constant infusion of alcuronium, d-tubocurarine, pancuronium, and
vecuronium. Anesthesiology 1987;66(6):842-846.
532. Wierda JM, van der Starre PJ, Scaf AH, et al. Pharmacokinetics of pancuronium in patients undergoing
coronary artery surgery with and without low dose dopamine. Clin Pharmacokinet 1990;19(6):491-498.
533. Denny NM, Kneeshaw JD. Vecuronium and atracurium infusions during hypothermic cardiopulmonary bypass.
Anaesthesia 1986;41(9):919-922.
534. Kansanaho M, Hynynen M, Olkkola KT. Model-driven closed-loop feedback infusion of atracurium and
vecuronium during hypothermic cardiopulmonary bypass. J Cardiothorac Vasc Anesth 1997;11(1):58-61.
535. Olkkola KT, Schwilden H. Quantitation of the interaction between atracurium and succinylcholine using closed-
loop feedback control of infusion of atracurium. Anesthesiology 1990;73(4):614-618.
536. Withington D, Menard G, Varin F. Cisatracurium pharmacokinetics and pharmacodynamics during hypothermic
cardiopulmonary bypass in infants and children. Paediatr Anaesth 2011;21(3):341-346.
537. de Lange S, DeBruijn NP. Alfentanil-oxygen anaesthesia: plasma concentrations and clinical effects during
variable-rate continuous infusion for coronary artery surgery. Br J Anaesth 1983;55:183S-189S.
538. Robbins GR, Wynands JE, Whalley DG, et al. Pharmacokinetics of alfentanil and clinical responses during
cardiac surgery. Can J Anaesth 1990;37(1):52-57.
539. Goresky GV, Koren G, Sabourin MA, et al. The pharmacokinetics of alfentanil in children. Anesthesiology
1987;67(5):654-659.
540. Lunn JK, Stanley TH, Eisele J, et al. High dose fentanyl anesthesia for coronary artery surgery: plasma
fentanyl concentrations and influence of nitrous oxide on cardiovascular responses. Anesth Analg 1979;58(5):390-
395.
P.314
541. Bovill JG, Sebel PS. Pharmacokinetics of high-dose fentanyl. A study in patients undergoing cardiac surgery.
Br J Anaesth 1980;52:795-801.
542. Koren G, Goresky G, Crean P, et al. Pediatric fentanyl dosing based on pharmacokinetics during cardiac
surgery. Anesth Analg 1984;63:577-582.
543. Newland MC, Leuschen P, Sarafian LB, et al. Fentanyl intermittent bolus technique for anesthesia in infants
and children undergoing cardiac surgery. J Cardiothorac Anesth 1989;3(4):407-410.
544. Hodges UM, Berg S, Naik SK, et al. Filtration of fentanyl is not the cause of the elevation of arterial blood
pressure associated with post-bypass ultrafiltration in children. J Cardiothorac Vasc Anesth 1994;8(6):653-657.
545. Shafer SL, Siegel LC, Cooke JE, et al. Testing computer-controlled infusion pumps by simulation.
546. Sam WJ, Hammer GB, Drover DR. Population pharmacokinetics of remifentanil in infants and children
undergoing cardiac surgery. BMC Anesthesiol 2009;9:5.
547. Bovill JG, Sebel PS, Blackburn CL, et al. The pharmacokinetics of sufentanil in surgical patients.
548. Borenstein M, Shupak R, Barnette R, et al. Cardiovascular effects of different infusion rates of sufentanil in
patients undergoing coronary surgery. Eur J Clin Pharmacol 1997;51(5):359-366.
549. Solina AR, Ginsberg SH, Papp D, et al. Dose response to nitric oxide in adult cardiac surgery patients. J Clin
Anesth 2001;13(4):281-286.
550. Booth BP, Brien JF, Marks GS, et al. The effects of hypothermic and normothermic cardiopulmonary bypass on
glyceryl trinitrate activity. Anesth Analg 1994;78(5):848-856.
551. Mierdl S, Byhahn C, Abdel-Rahman U, et al. Occupational exposure to inhalational anesthetics during cardiac
surgery on cardiopulmonary bypass. Ann Thorac Surg 2003;75(6):1924-1927.
552. Tarr TJ, Snowdon SL. Blood/gas solubility coefficient and blood concentration of enflurane during
normothermic and hypothermic cardiopulmonary bypass. J Cardiothorac Vasc Anesth 1991;5(2):111-115.
553. Moore RA, McNicholas KW, Gallagher JD, et al. Halothane metabolism in acyanotic and cyanotic patients
undergoing open heart surgery. Anesth Analg 1986;65(12):1257-1262.
554. Loomis CW, Brunet D, Milne B, et al. Arterial isoflurane concentration and EEG burst suppression during
cardiopulmonary bypass. Clin Pharmacol Ther 1986;40(3):304-313.
555. Oliver, W. C., Jr., et al. (2004). “Variability of plasma aprotinin concentrations in pediatric patients undergoing
cardiac surgery.” J Thorac Cardiovasc Surg 127(6):1670-1677.
Chapter 11
Endocrine, Metabolic, and Electrolyte Responses to Cardiac Surgery
and Cardiopulmonary Bypass
Mark T. Nelson
Sarah K. Armour
John F. Butterworth IV
Surgical procedures performed with cardiopulmonary bypass (CPB) produce physiologic alterations not found in
other major surgical procedures. During total CPB, the heart and lungs are not perfused and can neither secrete
hormones nor make their normal contributions to drug metabolism. Exposure to the pump-oxygenator and its tubing
traumatizes cellular blood elements, causes plasma proteins to be adsorbed and removed from the circulation, and
stimulates an immune response, as is well described in other chapters in this volume. Hemodilution (from blood-free
priming solutions) and anticoagulation alter blood concentrations of electrolytes, hormones, and serum proteins
during CPB. Finally, moderate to profound hypothermia is often used, reducing the rates of biochemical reactions
and further perturbing hormonal responses.
Certain features of extracorporeal perfusion contribute to the endocrine, metabolic, and electrolyte alterations.
Nonpulsatile perfusion has been shown to change the distribution of flow both among and within organs. As a
consequence, some hormonal alterations during CPB can be lessened or prevented by pulsatile perfusion. CPB
increases “stress” hormones disproportionate to the apparent levels of physiologic disturbance, and it remains
unclear which factor—hypothermia, hemodilution, decreased perfusion of endocrine glands, or denaturation of
hormones by foreign surfaces—most contributes to these changes. Additionally, some hormone concentrations
increase above normal levels after termination of bypass with the return of pulsatile normothermic perfusion to
endocrine glands (1). Consistent with expectations, some data show that deeper planes of anesthesia attenuate or
eliminate the exaggerated endocrine responses to CPB and may reduce mortality (2). Finally, spinal and epidural
anesthesia and analgesia have been used during cardiac surgery, and these techniques inhibit the neuroendocrine
response to cardiac surgery just as they do to abdominal and lower extremity surgery (3).
We find summarizing the literature regarding endocrine, metabolic, and electrolyte responses to CPB a difficult task.
There are marked variations from center to center or study to study in patient populations, perfusion and cardioplegia
techniques, perfusate temperatures, priming solutions, and anesthetic and adjuvant drugs. Earlier studies in which
the hormone assays were not specific for intact, active hormones exacerbate the confusion. With these several
concerns in mind, this chapter emphasizes the most recent studies in which contemporary anesthesia, cardioplegia,
perfusion, and hormone measurement techniques were used.
PITUITARY HORMONES
The anterior portion of the pituitary gland secretes hormones that regulate the adrenal cortex, thyroid, ovaries, and
testes. Several aspects of pituitary response (e.g., those related to the cortisol and thyroid axes) are considered in
subsequent sections. Gonadotropin responses during CPB have not been reported using modern surgical or analytic
techniques (4,5,6). However, Maggio et al. (5) found significant perioperative decreases in testosterone
concentrations in men and increases in women undergoing cardiac surgery. Estradiol levels were conversely
significantly increased in men and decreased in women.
Pituitary apoplexy, a rare but potentially devastating complication, has been reported after CPB (7,8,9,10,11,12),
typically in patients with pituitary adenomas. Rapid pituitary enlargement can compress parasellar structures such as
the optic chiasm and ocular motor nerve resulting in varying combinations of ptosis, ophthalmoplegia, nonreactive
and dilated pupils, decreased visual acuity, and visual field defects in addition to the characteristic hormonal deficits
(13). Pituitary apoplexy presents only rarely as Addisonian crisis; more often oculomotor or visual disturbances or
unexplained fever is the most common initial sign (8). Although ischemia, hemorrhage, and edema of the gland are
usually assigned the blame for pituitary failure after bypass, no specific etiology has been identified in most patients.
Anticoagulation alone has been associated with hemorrhage into pituitary adenomas, with both chronic oral and
short-term heparin therapy (14); and there exists a gender bias with males outnumbering females in the ratio of 10 to
1 (15). The diagnosis can be confirmed with cranial computed tomography (CT) or magnetic resonance imaging
(MRI) (Fig. 11.1). Hormonal replacement and prompt hypophysectomy are indicated, and experience suggests that
the latter may be performed safely early after cardiac surgery (7,9,15). CPB alone does not lead to persisting
hypopituitarism. When there is no
P.316
identifiable pituitary mass on CT or MRI, pituitary hormones are stable following CPB (16).
FIGURE 11.1. Cranial tomographic scan of a 56-year-old man 3 days after mitral valve repair. The patient presented
with unilateral pupillary mydriasis, complete ophthalmoplegia, and loss of sensation in divisions I and II or cranial
nerve V upon extubation several hours after his surgery. Note the mass in the sella turcica and bony erosion of the
sphenoid “wing,” as indicated by the arrows. (From Meek EN, Butterworth J, Kon ND, et al. New onset of cranial
nerve palsies immediately following mitral valve repair. Anesthesiology 1998;89:1580-1582, with permission.)
Vasopressin
Vasopressin, or antidiuretic hormone (ADH), secreted by the posterior pituitary gland, is a potent regulator of renal
water excretion (17). At high concentrations, ADH may increase peripheral vascular resistance and decrease cardiac
contractility and coronary blood flow (17,18). Animal studies have shown that infused arginine vasopressin (AVP)
decreases cardiac oxytocin receptor expression and increases diastolic dysfunction in induced ischemia animal
models (19,20). However, post-cardiac-surgery patients showed no cardiac dysfunction with AVP infusions (21,22).
Similarly, in septic patients, those who received AVP required less vasopressors compared to controls while having
no increase in mortality (23). ADH increases renal vascular resistance, reducing renal blood flow. ADH stimulates the
release of the von Willebrand factor, perhaps improving hemostasis during and after cardiac surgery (see Chapter
22). Stimuli provoking ADH release include increased plasma osmolality, decreased blood volume or blood pressure,
hypoglycemia, angiotensin, stress, and pain (17). General anesthesia and surgery are associated with moderate
increases in ADH (24,25), and angiotensin-converting enzyme (ACE) inhibitors, which are commonly administered to
cardiac surgical patients, have been associated with the syndrome of inappropriate antidiuretic hormone (SIADH)
secretion (26). Cardiac surgery with CPB is associated with striking increases in ADH concentration, far above those
seen during other major surgical procedures, and these effects may persist for hours postoperatively
(25,27,28,29,30) (Fig. 11.2).
FIGURE 11.2. Plasma concentration of arginine vasopressin (AVP) during nonpulsatile bypass for mitral valve
replacement (MVR, n = 8), aortic valve replacement (AVR, n = 5), or coronary artery bypass grafting (CABG, n = 5).
Data are presented as means ± SEM. As indicated, measurements were obtained at (1) anesthesia induction, (2)
sternotomy, (3) 10 minutes after initiation of cardiopulmonary bypass, (4) 10 minutes before termination of
cardiopulmonary bypass, (5) upon arrival in the critical care unit, (6) 6 hours after bypass, (7) 18 hours after bypass,
(8) 30 hours after bypass, and (9) 48 hours after bypass. All three groups of patients demonstrated significant
increases in AVP concentrations during bypass. Only at sample 5 did the mitral valve patients demonstrate
significantly greater AVP concentration than the CABG patients. p values on the figure indicate comparisons between
sample 1 and subsequent samples in the same surgical group. (From Kaul TK, Swaminathan R, Chatrath RR, et al.
Vasoactive pressure hormones during and after cardiopulmonary bypass. Int J Artif Organs 1990;13:293-299, with
permission.)
The exaggerated ADH response to CPB could be initiated by any number of stimuli, including the decrease in
circulating blood volume upon initiating bypass. Left atrial pressure decreases markedly, especially with left-
ventricular venting, thereby simulating volume depletion, which is a potent stimulus for ADH release. The transient
hypotension normally occurring at the onset of bypass could stimulate increased ADH secretion. Pulsatile perfusion
during CPB attenuates the exaggerated ADH response, particularly after bypass, but does not eliminate it (28,30,31)
(Fig. 11.3). Pulsatile perfusion does not seem to significantly increase urinary output, despite reduced ADH
concentrations (30).
Preoperatively, ADH levels were increased in patients with low left-ventricular ejection fraction (EF) or higher New
York Heart Association (NYHA) heart failure class, and higher preoperative ADH concentrations served paradoxically
as a predictor for postoperative vasoplegia. Plasma ADH concentrations did not increase nearly as much
postoperatively in the vasoplegic group (32,33). This finding is consistent with the concept that vasoplegic
P.317
syndrome is related to inappropriately reduced ADH concentrations in those patients that had increased
concentrations preoperatively, which may reduce the ability to increase ADH as part of the stress associated with
cardiac surgery (32). A reduced EF and/or chronic treatment with ACE inhibitors were independently associated with
vasoplegia and with this relative postoperative ADH deficiency (33). This finding is consistent with studies in sepsis
associating inappropriately diminished ADH levels in the presence of chronic stimuli to ADH secretion (34).
FIGURE 11.3. Effect of pulsatile (n = 5) or nonpulsatile (n = 8) perfusion on arginine vasopressin (AVP) responses to
mitral valve replacement. Significant differences between the two groups were observed after cardiopulmonary
bypass (sample 5 and later). In this study, pulsatile bypass did not attenuate AVP responses during coronary bypass
or aortic valve replacement. (From Kaul TK, Swaminathan R, Chatrath RR, et al. Vasoactive pressure hormones
during and after cardiopulmonary bypass. Int J Artif Organs 1990;13:293-299, with permission.)
TABLE 11.1. Blood pressure and plasma catecholamine concentrations during extracorporeal
perfusion in patients undergoing aortocoronary bypass grafting
Core Core Core

Time Before After On temperature temperature temperature
sequence anesthesia intubation bypass (32°C) (28°C) (24°C)
Core
temperature, 37.0 ± 0 34.7 ±
°C 36.1 ± 0.5a 0.4a 31.5 ± 0.5a 27.8 ± 0.4a 24.1 ± 0.2a
MAP, mm
Hg 86 ± 3 76 ± 1 70 ± 4a 73 ± 3a 60 ± 3a 60 ± 2a
416 ±
NE, pg/mL 287 ± 40 360 ± 94 83 662 ± 172a 540 ± 153 312 ± 86
138 ±
EPI, pg/mL 50 ± 15 29 ± 8 47 506 ± 191a 267 ± 136 130 ± 62
Core temperature, rectal temperature; EPI, plasma epinephrine concentration; MAP, mean arterial pressure;
NE, plasma norepinephrine concentration. Catecholamine concentrations were not corrected for
hemodilution.
ap < 0.05 compared with preinduction values.
Source: Reed HL, Chernow B, Lake CR, et al. Alterations in sympathetic nervous system activity with
intraoperative hypothermia during coronary artery bypass surgery. Chest 1989;95:616-622, with permission.
Certain anesthetic techniques, for example, maintenance of anesthesia with large doses of synthetic opioids (fentanyl
or sufentanil) or with regional anesthesia, attenuate the hormonal responses associated with surgical procedures.
Indeed, Kuitunen et al. (35) found that patients anesthetized with 50 μg/kg fentanyl demonstrated significantly lower
AVP concentrations after CPB than patients who received a lighter plane of general anesthesia using inhaled
enflurane. However, even opioid anesthesia will not completely ablate ADH release at the onset of CPB (29).
Unfortunately, multiple studies provide conflicting data as to whether higher peak ADH concentrations occur during
and after CPB in patients undergoing coronary artery surgery or valve surgery (27,28,30) (Fig. 11.2). In summary,
ADH concentrations increase markedly during CPB irrespective of the anesthesia or perfusion technique, and the
level of increase may associate with the likelihood that a patient will develop vasoplegia.
ADRENAL HORMONES
Catecholamines
The catecholamines epinephrine and norepinephrine are products of the adrenal medulla and (in the latter case) of
peripheral sympathetic and central nerve terminals. Marked elevations of plasma epinephrine and norepinephrine
concentrations occurring during CPB underlie many hemodynamic sequelae of bypass, including peripheral
vasoconstriction and shifts in intraorgan blood flow (31,36,37,38,39,40,41). With hypothermia, plasma epinephrine
concentrations may increase as much as 10-fold over the prebypass concentrations; norepinephrine concentrations
typically increase to a lesser extent (4-fold) (2,31,37,39), and deeper levels of hypothermia attenuate these (Table
11.1). In early studies, peak increases in both norepinephrine and
P.318
epinephrine occurred when the heart and lungs were excluded from the circulation (38,39,40). However,
norepinephrine and epinephrine concentrations peaked at different times. In a later study, patients undergoing
cardiac surgery were randomly assigned to have CPB with mild (34°C) or moderate (28°C) hypothermia. With both
bypass temperatures, peak norepinephrine concentrations were observed after release of the aortic crossclamp and
rewarming, whereas peak epinephrine concentrations were observed at the target hypothermic temperature (42). A
more recent study demonstrated a biphasic plasma norepinephrine concentration response to nonpulsatile CPB, with
concentrations peaking at aortic declamping and again 2 to 4 hours after surgery. Epinephrine concentrations did not
show this pattern, nor was it observed during pulsatile CPB (40,41). Neonates, infants, and young children, much like
adults, demonstrate marked increases in catecholamine concentrations during CPB (2,41,43,44,45) (Fig 11.4).
Deeper planes of general anesthesia (whether accomplished with larger doses of synthetic opioids, addition of a
propofol infusion, higher concentrations of volatile anesthetic vapors, or addition of neuraxial anesthesia) significantly
reduce the catecholamine concentrations of patients undergoing coronary artery bypass surgery compared with
patients less deeply anesthetized (46,47,48). Furthermore, in critically ill neonates undergoing correction of
congenital heart disease, deeper planes of general anesthesia from large intravenous doses of sufentanil not only
produced lower catecholamine concentrations in response to CPB, but also reduced mortality compared with lighter
planes of general anesthesia using halothane and morphine (2) (Fig 11.4). Consistent with these observations
regarding anesthetic depth, infusion of propofol during CPB (4 mg/kg/hr) resulted in markedly reduced concentrations
of epinephrine and norepinephrine compared with a single bolus injection of diazepam 0.1 mg/kg (47). Addition of
thoracic epidural anesthesia to a “high-dose” fentanyl or sufentanil general anesthetic significantly reduced
catecholamine concentrations during and after CPB relative to concentrations measured without thoracic epidural
anesthesia (49,50) (Fig. 11.5). Similarly, patients undergoing CPB after “high spinal” intrathecal blockade had
reduced levels of catecholamines compared to a control group, despite neither group receiving a high-dose opioid
general anesthetic (51) (Fig. 11.5).
FIGURE 11.4. Perioperative changes in plasma epinephrine and norepinephrine in neonates undergoing cardiac
surgery with either high-dose sufentanil (○; n = 30) or halothane-morphine (▾; n = 15) anesthesia. Pre-CPB, before
bypass; DHCA, after deep hypothermic circulatory arrest; End op, end of operation; 6 hr, 12 hr, 24 hr, 6, 12, or 24
hours after operation. p values determined with Mann-Whitney U test. (From Anand KJS, Hickey PR. Halothane-
morphine compared with highdose sufentanil for anesthesia and postoperative analgesia in neonatal cardiac surgery.
N Engl J Med 1992;326:1-9, with permission.)
The effect of pulsatile perfusion on catecholamine concentrations during CPB remains controversial (31,52).
Although early studies demonstrated that catecholamine concentrations were increased during CPB whether or not
pulsatile perfusion was used (31), a more recent study of elective coronary surgery patients showed significant
reductions in epinephrine and norepinephrine concentrations with pulsatile (vs. nonpulsatile) perfusion (40,52) (Fig.
11.6).
Some increase in catecholamine concentrations during and after CPB may be unavoidable with current anesthetic
and surgical techniques; nevertheless, deeper planes of general anesthesia (either with larger doses of opioids or
greater concentrations of inhaled general anesthetics) or addition of conduction anesthesia to general anesthesia
can limit the increases.
Adrenal Cortical Hormones

Increased secretion of cortisol is one of the central features of the metabolic stress response. In the classic studies
by Hume et al. (53) of patients undergoing major (noncardiac) surgery, cortisol concentrations rose quickly to a
maximum and then slowly returned
P.319
to baseline 24 hours postoperatively. It is therefore not surprising that even “off-pump” coronary revascularization
procedures are associated with increases in serum cortisol and other markers of the stress response despite the
absence of the stress of CPB (54). It is apparent, however, that CPB modifies cortisol responses to surgery. Total
plasma cortisol concentrations typically briefly decrease immediately upon initiation of bypass, likely as a
consequence of hemodilution (55,56,57,58) (Fig. 11.7). During bypass, cortisol concentrations rise to values
significantly above baseline (2,5,55,56,57,58,59,60). After CPB, patients exhibit markedly elevated concentrations of
cortisol (both free and total) for more than 48 hours (58,59,60,61). In a recent study, cortisol increased 5-fold from
baseline 2 hours after “on pump” coronary artery surgery versus a maximal 3-fold increase after “off pump” coronary
artery surgery (60). Interestingly, the maximal increase occurred significantly earlier in the “off pump” group (4 hours
after surgery) than in the “on pump” group (12 hours after surgery). The authors speculated that this finding resulted
from differences in inflammatory processes between the two forms of coronary artery surgery. Cortisol levels slowly
decreased thereafter in both groups.
FIGURE 11.5. Effects of thoracic epidural anesthesia with bupivacaine 0.5% (▪, n = 8) versus control (♦, n = 9) on
catecholamine concentrations measured during coronary artery surgery. All 17 patients studied received general
anesthesia with sufentanil 20 μg/kg. Samples were obtained (1) before anesthesia, (2) after anesthesia induction, (3)
after 30 minutes of surgery, (4) after 30 minutes of cardiopulmonary bypass (CPB), (5) after 60 minutes of CPB, (6) 1
hour after CPB, (7) 2 hours after CPB, (8) 4 hours after CPB, (9) 6 hours after CPB, and (10) 24 hours after CPB. * p
< 0.05, ** p < 0.01 for between-group differences. Adrenaline, epinephrine; NA, noradrenaline or norepinephrine.
(From Lee TW, Grocott HP, Schwinn D, et al. High spinal anesthesia for cardiac surgery: effects on beta-adrenergic
receptor function, stress response, and hemodynamics. Anesthesiology 2003;98:499-510, with permission.)
Leptin, an adipocyte-derived hormone, is thought to moderate the acute systemic inflammatory response to CPB and
surgery and to interact importantly with the hypothalamic-pituitary-adrenal axis. Leptin binds to receptors in the
hypothalamus and is known to affect energy metabolism. It has structural similarities to cytokines, it affects immunity,
and it may modulate stress responses. Leptin concentrations decrease with cardiac surgery and CPB. “On pump”
coronary surgical cases showed a more pronounced decrease in leptin compared to “off pump” coronary surgeries.
Both groups also showed a subsequent increase in leptin 24 hours postoperatively. Leptin levels correlated inversely
with plasma cortisol levels (60,62,63). Children undergoing surgical repair of congenital heart diseases with CPB
demonstrated similar findings, with leptin concentrations decreasing during CPB and increasing afterward to peak at
12 hours postoperatively. Leptin concentrations were elevated in critically ill patients; thus elevations in leptin
concentrations may serve as a marker for systemic inflammatory response syndrome (64).
Tinnikov et al. (65) studied 14 children undergoing repair of ventricular septal defects with deep hypothermia and
circulatory arrest, but without CPB. Maximal perioperative concentrations of cortisol and minimal perioperative
concentrations of cortisol binding globulin were recorded at the first assessment after circulatory arrest. Thus,
hypothermia and circulatory arrest initiate a cortisol-stress response even in the absence of extracorporeal perfusion.
Cortisol responses during bypass appear to be temperature-dependent. Taggart et al. (66) showed that the increase
in cortisol
P.320
concentration during CPB can be blunted by perfusion with blood at 20°C compared to 28°C. Peak CPB cortisol
concentrations were decreased by deeper planes of anesthesia in both adults and children (2,58,59) (Fig. 11.8).
Winterhalter et al. (48) showed that when continuous remifentanil (0.25 μg/kg/min) was compared to intermittent
bolus dose fentanyl (2.6 ± 0.3 mg/kg total dose) corticotropin (adrenocorticotropic hormone, ACTH), cortisol, and
vasopressin were all significantly decreased. This result could be secondary to the specific agent (remifentanil vs.
fentanyl), variations in the depth of anesthesia, or the steady state produced by continuous anesthetic infusions.
Stenseth et al. (49) found that, compared with high-dose fentanyl anesthesia alone, high-dose fentanyl anesthesia
plus thoracic epidural anesthesia delayed the increase in cortisol concentrations during coronary artery surgery and
reduced concentrations during bypass. Similarly, Moore et al. (50) found that thoracic epidural anesthesia combined
with sufentanil 20 μg/kg was associated with markedly lower cortisol concentrations as compared to sufentanil
anesthesia alone. On the other hand, spinal anesthesia failed to attenuate cortisol responses (compared to
intravenous general anesthesia) in children undergoing correction of congenital heart defects (3).
FIGURE 11.6. Effects of pulsatile (PP) and nonpulsatile (NP) perfusion on catecholamine responses in 30 patients
undergoing coronary artery bypass grafting. Pulsatile perfusion significantly reduced both epinephrine and
norepinephrine concentrations during bypass. Values are means ± SE. (From Minami K, Körner MM, Vyska K, et al.
Effects of pulsatile perfusion on plasma catecholamine levels and hemodynamics during and after cardiac operations
with cardiopulmonary bypass. J Thorac Cardiovasc Surg 1990;99:82-91, with permission.)
CPB modifies ACTH responses in surgical patients. In the previously mentioned study by Hume et al. (53), non-CPB
surgical patients showed no increase in cortisol concentrations after an injection of ACTH, indicating that adrenal
secretion of cortisol was
P.321
already maximal. Amado and Diago (67) observed a blunted response to corticotropin-releasing hormone during
bypass, similar to responses seen in patients with hypothalamic corticotropin-releasing hormone deficiency. In
contrast, an earlier study revealed that when patients undergoing extracorporeal perfusion received ACTH, cortisol
concentrations increased (55).
FIGURE 11.7. The effects of either enflurane or fentanyl anesthesia with or without dexamethasone treatment on
cortisol and adrenocorticotropic hormone responses to cardiac surgery. All groups demonstrated significant
increases in both cortisol and adrenocorticotropic hormone in response to surgery. The combination of fentanyl and
dexamethasone significantly attenuated the adrenocorticotropic hormone response to surgery relative to the other
three groups (‡p < 0.05 compared with the no dexamethasone, no fentanyl group; ‡‡p < 0.05 compared with the
dexamethasone-treated, no fentanyl group). (From Raff H, Norton AJ, Flemma RJ, et al. Inhibition of the
adrenocorticotropin response to surgery in humans: interaction between dexamethasone and fentanyl. J Clin
Endocrinol Metab 1987;65:295-298, with permission.)
FIGURE 11.8. Cortisol responses during and after correction of congenital heart lesions with either halothane-
morphine (n = 15, ▾) or sufentanil (n = 30, ○) anesthesia. The sufentanil-based technique significantly attenuated the
“stress” response to cardiac surgery. (From Anand KJS, Hickey PR. Halothane-morphine compared with high-dose
sufentanil for anesthesia and postoperative analgesia in neonatal cardiac surgery. N Engl J Med 1992;326:1-9, with
permission.)
Taylor et al. (68) measured a progressive fall in ACTH concentrations during bypass, with a subsequent increase 1
hour after pulsatile perfusion was restored. Raff et al. (57) showed that, although neither high-dose fentanyl
anesthesia nor dexamethasone 40 mg alone blunted the increase in ACTH concentration in response to CPB,
concurrent administration of both agents significantly reduced the ACTH concentration (Fig. 11.7). In a 2011 study,
Debono and colleagues (69) demonstrated that at least 25% of patients undergoing coronary artery bypass grafting
(CABG) who had normal cosyntropin stimulation tests prior to surgery developed increased ACTH concentrations
and decreased responses to cosyntropin (an ACTH derivative used in diagnostic testing) postoperatively. The
clinical importance of this relative cortisol deficiency is unclear as postoperative outcomes were comparable
regardless of ACTH concentrations or cosyntropin responses.
Unlike some other hormones, cortisol and ACTH responses to CPB generally have not been influenced by pulsatile
perfusion. To be sure, one study found that total plasma cortisol rose during pulsatile bypass but fell dramatically in
patients undergoing nonpulsatile perfusion (56). In another study, patients with and without pulsatile perfusion
showed initial increases in cortisol, ACTH, and aldosterone, followed by a gradual decline in concentrations of all
three hormones during bypass and then a subsequent increase in all three hormones after bypass perfusion (70).
After correction for the effect of hemodilution, there was no decrease in calculated free cortisol concentrations and a
slight increase in adrenocorticotropic hormone concentrations, irrespective of pulsatile versus nonpulsatile perfusion.
In children with either pulsatile or nonpulsatile perfusion, Pollock et al. (71) found large increases in cortisol and
ACTH during CPB, followed by a slow decline toward baseline concentrations of both hormones over 24 hours with
both techniques.
Although there is no unequivocal evidence for adrenocortical hypofunction during or after CPB, the inflammatory
response initiated by the triad of blood contact with the foreign surfaces of the extracorporeal membrane, reperfusion
injury, and endotoxemia may be attenuated by large doses of exogenous glucocorticoids (72). This inflammatory
response triggers tissue injury in the heart, kidneys, hemostatic system, and especially the lung, which
P.322
is the only organ exposed to the entire cardiac output (except during CPB). Early investigations have studied small
numbers of cardiac surgery patients randomized to variable doses of different corticosteroids (most commonly 1
mg/kg dexamethasone or 30 mg/kg methylprednisolone) initiated at varying intervals between induction of anesthesia
and the start of CPB (72). Overall, study results generally demonstrate an amelioration of the inflammatory response,
with decreases in cytokine formation (tumor necrosis factor and the interleukin [IL]-1, -6, and -8) but inconsistent
effects on C3a and elastase concentrations. Leukotrienes such as LTB4 are decreased in a dose-dependent fashion
(72,73). IL-10, a cytokine with actions that are principally anti-inflammatory, demonstrates increased concentrations
with steroid administration, supporting an anti-inflammatory effect (73). In addition, large doses of methylprednisolone
can block upregulation of neutrophil integrin adhesion receptors, whereas dexamethasone decreases endothelial
production of certain adhesion molecules (74). Clinically, glucocorticoid therapy may increase cardiac index and
decrease systemic vascular resistance (75). Dietzman et al. (76) showed improvement in tissue perfusion and a
decrease in peripheral vascular resistance when a large glucocorticoid dose was given just before CPB. Routine
glucocorticoid supplementation has also been advocated as part of an accelerated recovery program (77), albeit
without much supporting evidence. A small study has shown that cardiac surgery patients receiving glucocorticoids
had shorter lengths of stay and improved quality of life as compared to patients not receiving glucocorticoids (78).
The same research group found that steroid treatment reduced the duration of catecholamine support, length of
intensive care unit (ICU) stay, and likelihood of postoperative atrial fibrillation (79). A 2013 meta-analysis that
included 48 randomized controlled trials (RCTs) of patients receiving corticosteroids undergoing CPB failed to show
any difference in the incidence of myocardial infarction, stroke, renal insufficiency, or death. The only outcome effect
identified was a modest and heterogeneous decreased ICU and hospital length of stay in the groups receiving
steroids (73).
In summary, current data nearly uniformly demonstrate large increases in cortisol and ACTH concentrations with
initiation of CPB. These increases may be attenuated by deeper planes of general anesthesia or by addition of
thoracic epidural (but apparently not spinal) anesthesia to general anesthesia as well as by continuous infusions of
narcotic agents. Pulsatile perfusion does not appear to reduce these exaggerated responses. Moreover, it is not
clear whether elevated corticosteroid concentrations during bypass are deleterious or beneficial.
GLUCOSE HOMEOSTASIS
Carbohydrate metabolism is regulated by insulin, glucagon, cortisol, growth hormone, and epinephrine, the
concentrations of all of which are generally perturbed by surgery, CPB, and hypothermia. After the onset of CPB,
blood glucose concentrations rise steadily if left untreated (80,81,82). Despite marked hyperglycemia, insulin
concentrations decline from their control values during hypothermic bypass. Hyperglycemia, hypoinsulinemia, and
insulin resistance are produced by hypothermic nonpulsatile CPB in adults (80,81,82). This catabolic response is
greater during and following CABG with CPB than during and following off-pump coronary artery bypass, supporting
the importance of CPB in this process (83). Strict normoglycemia can be maintained only with difficulty during
hypothermic, nonpulsatile CPB in nondiabetic adults, even with large doses of insulin.
Studies performed in postoperative surgical patients have had a disproportionate influence in the intraoperative care
of cardiac surgical patients. A prospective single center study in 2001 by van den Berghe et al. (84) in surgical ICU
patients compared groups randomized to receive either insulin infusions to maintain “tight” glucose control (plasma
concentrations 80-110 mg/dL) or insulin infusions maintaining plasma glucose <215 mg/dL demonstrated a
substantial survival benefit in the “tight” glucose control group. Subsequent studies failed to demonstrate a survival
benefit when plasma glucose concentrations were maintained at 80 to 110 mg/dL and in fact demonstrated an
increased incidence of clinically significant hypoglycemia (85,86,87). A 2009 multicenter prospective randomized
international trial (NICE-SUGAR) of medical and surgical ICU patients randomized to either a “tight” glucose control
(plasma glucose concentrations 80-108 mg/dL) strategy or conventional control (glucose maintained <180 mg/dL)
demonstrated decreased survival and increased incidence of hypoglycemia in the more restrictive (80-110 mg/dL
plasma glucose concentration) group (88). This effect was present in both surgical and medical ICU patients. A 2010
meta-analysis by Mark and Prelser (89) of seven RCTs with over 11,400 patients comparing “tight” glucose control
(glucose concentrations of 80-110 mg/dL) to less restrictive protocols failed to identify a survival benefit at 28 days, a
decreased likelihood of renal replacement therapy, or a decreased incidence of blood-borne infections in the more
restrictive (plasma glucose 80-110 mg/dL) group. The incidence of hypoglycemia was significantly increased in the
more restrictive “tight” blood glucose group (89). In 2009, the Society of Thoracic Surgeons and in 2011 the
American College of Physicians released guidelines supporting the use of less restrictive (glucose concentrations
<180-200 mg/dL) blood glucose management strategies (90,91). In summary, current evidence suggests that
attempting to maintain “strict” control of blood glucose (e.g., concentrations 80-120 mg/dL) does not improve
outcome relative to a less restrictive strategy of maintaining blood glucose <180 mg/dL.
Counter-regulatory hormones decline from prebypass concentrations during hypothermic bypass (92). With
rewarming in patients without diabetes, insulin concentrations rise spontaneously to appropriate high levels;
nonetheless blood glucose concentration remains elevated. Normoglycemia is better preserved in children
undergoing hypothermic CPB when washed red blood cells rather than conventional packed red blood cells
(suspended in adenine-glucose-mannitol-saline) are used in the CPB priming solution (92,93). Many clinicians are
likely unaware that blood glucose concentrations in packed red blood cells range from 400 to 700 mg/dL (93).
P.323
TABLE 11.2. Effect of nonpulsatile (n = 18) or pulsatile (n = 20) cardiopulmonary bypass on

glucose metabolism
Sampling times
Postoperative (hr)
Variable Group Preoperative CPB 1 5 24 48
206 ± 253 ± 235 ± 125 ± 115 ±

44a 51a 52a 46 27
P 83 ± 18 254 ± 281 ± 271 ± 208 ± 149 ±
Blood glucose, mg/dL NP 87 ± 27 92a 67a 60a 72a 25
72 ±
71 ± 89 ± 72 ± 64 ±
39a 34a 36a 42 35
Immunoreactive insulin, P 16 ± 9 24 ± 29 ± 40 ± 31 ± 27 ±
mIU/L NP 13 ± 5 15 20b 27b 23 18
150 ± 148 ± 202 ± 225 ± 220 ±

81 73 101 88 91
Immunoreactive P 98 ± 34 200 ± 197 ± 221 ± 175 ± 156 ±
glucagon, ng/L NP 107 ± 45 96 88 79 80 66
CPB, cardiopulmonary bypass; NP, nonpulsatile CPB; P, pulsatile CPB.
Values are means ± SEM.
ap < 0.05 versus preoperative value;
bp < 0.05 versus group P.
Source: Nagaoka H, Innami R, Watanabe M, et al. Preservation of pancreatic beta cell function with pulsatile
cardiopulmonary bypass. Ann Thorac Surg 1989;48:798-802, with permission.
Concentrations of glucose, insulin, and glucagon are greater during hypothermic than normothermic CPB (82,94).
Nagaoka et al. (80) compared pulsatile with nonpulsatile perfusion in patients undergoing cardiac surgery with
moderate hypothermia (body temperature approximately 26°C). In both groups, blood glucose concentrations
increased with CPB and rose further with hypothermia, reaching values greater than 200 mg/dL (Table 11.2). Blood
glucose concentrations remained elevated for at least 5 hours postoperatively, but the patients receiving pulsatile
perfusion showed a more rapid return to baseline glucose concentration than did patients receiving nonpulsatile
perfusion. Insulin concentration, C peptide concentration, and the insulin-to-glucagon molar ratio increased
significantly compared with baseline during pulsatile but not during nonpulsatile CPB. Type I (juvenile) diabetics
require no greater doses of insulin to control blood glucose during CPB than do nondiabetic control subjects,
whereas type II diabetics exhibit greater insulin resistance compared with type I diabetics and nondiabetic control
patients during CPB (82). Children receiving deeper planes of general anesthesia demonstrated lower blood glucose
concentrations upon termination of bypass than did children receiving lighter anesthetic techniques (2,95) (Fig. 11.9).
Similarly, nondiabetic patients undergoing CABG with CPB that received epidural anesthesia required lower infusion
doses of insulin and maintained lower blood glucose concentrations than did control patients that did not receive
epidural anesthesia. Diabetic patients undergoing CABG with CPB who received epidural anesthesia had reduced
blood glucose concentrations without a change in insulin requirements (96).
In adults undergoing coronary artery surgery and in children undergoing correction of congenital heart defects,
growth hormone increased during and after CPB (97,98). The increase in growth hormone could be prevented using
opioid general anesthetic techniques (98). The physiologic significance of this growth hormone response is unclear,
because it can be inhibited by prior administration of somatostatin without an effect on glucose or glutamine
metabolism. However, children whose catabolic hormonal responses waned by postoperative day 5 tended to have
shorter lengths of stay (99).
FIGURE 11.9. Total fentanyl dose is inversely correlated with blood glucose concentrations in 24 children
undergoing correction of congenital heart disease with hypothermic circulatory arrest (but without profound
hypothermia or circulatory arrest). Blood samples were withdrawn within 30 minutes after cessation of bypass. p =
0.0007 for the slope of the regression line. (From Ellis DJ, Steward DJ. Fentanyl dosage is associated with reduced
blood glucose in pediatric patients after hypothermic cardiopulmonary bypass. Anesthesiology 1990;72:812-815, with
permission.)
NATRIURETIC PEPTIDES
Natriuretic peptides are a family of biologically active peptides first isolated from cardiac atria that include atrial
natriuretic
P.324
peptide (ANP, A-type natriuretic peptide), brain natriuretic peptide (BNP, B-type natriuretic peptide), and C-type
natriuretic peptide (CNP), among others (100). ANP and BNP are expressed in cardiac myocytes. The designation of
BNP as “brain” natriuretic peptide derives from its initial discovery in porcine brain, but the role of BNP and ANP in
the central nervous system remains unclear. ANP is produced and stored predominantly in the atrium. BNP is present
in both atrial and ventricular tissue, but in myocardial disease states the ventricle becomes the primary source of
BNP secretion. The nervous system and endothelial cells are the major sites of expression of CNP, which has
significant paracrine vasodilatory effects. The heart is not a significant source of CNP. ANP is released in response
to atrial distention, whereas BNP levels tend to be elevated in the presence of ventricular dysfunction. Other stimuli,
some of which are commonly associated with CPB, may promote ANP and/or BNP release, including myocardial
ischemia (101), catecholamines, endothelin-1, prostacyclin, and cytokines (102). Both peptides increase glomerular
filtration, inhibit renin release, reduce aldosterone concentrations in blood, antagonize renal vasoconstrictors (such
as vasopressin, norepinephrine, and angiotensin), and reduce arterial blood pressure. They regulate vascular
volume by increasing sodium excretion and decreasing vasomotor tone (103). Within the heart natriuretic peptides
regulate myocyte growth and inhibit fibroblast proliferation and extracellular matrix deposition. Natriuretic peptides
have an anti-ischemic (preconditioning-like) function, and influence coronary endothelial and vascular smooth muscle
proliferation and contractility through activation of guanylate cyclase (104,105).
Atrial Natriuretic Peptide

Despite evidence that stimuli associated with CPB may promote the release of natriuretic peptides, plasma ANP has
been measured before, during, and after CPB, with conflicting findings. Patients with cardiac valve lesions, especially
those with arrhythmias and congestive heart failure (CHF), may demonstrate elevated preoperative ANP
concentrations, whereas coronary artery bypass surgery patients may have normal preoperative ANP concentrations
(106,107,108,109,110). In one study, no significant changes were noted during induction of anesthesia or during
CPB; however, after CPB both arterial and venous concentrations of ANP increased in patients undergoing coronary
artery revascularization (110). In contrast, most other studies found significant alterations of ANP concentrations
during bypass, particularly during aortic cross-clamping. Curello et al. (108) measured ANP in patients undergoing
either coronary artery bypass surgery or mitral valve replacement for mitral stenosis. Although there was no change
in ANP concentrations during bypass in the coronary surgery group, patients undergoing mitral valve replacement
demonstrated reduced ANP concentrations during CPB. After release of the aortic clamp, ANP concentrations in both
groups rose to equal those found preoperatively in the mitral valve patients (108).
Nearly identical responses were observed by Northridge et al. (111) in their study of 12 patients undergoing
aortocoronary bypass grafting with hypothermic nonpulsatile perfusion. In another study, arterial concentrations of
ANP decreased significantly after aortic cross-clamping (112). Interestingly, this study also found evidence for ANP
release from the brain during bypass. Ashcroft et al. (107) found a significant reduction in ANP concentrations during
bypass, with return to baseline values postoperatively. Haug et al. (113) studied 33 patients undergoing coronary
artery surgery and found significantly increased concentrations of ANP after CPB, with a further increase measured
at the end of surgery that was maintained in measurements 24 hours after the operation. Pasaoglu et al. (114) found
that ANP concentrations were elevated (relative to normal values) before induction of anesthesia for coronary artery
surgery. ANP concentrations increased significantly (relative to baseline values) after surgical incision and remained
elevated during and after surgery, with the highest mean values recorded on the fifth postoperative day; however, no
measurements were made during CPB. In 16 patients undergoing aortocoronary bypass grafting or mitral valve
replacement, ANP concentrations decreased significantly during hypothermic extracorporeal perfusion and aortic
cross-clamping (109). Kostopanagiotou et al. (115) studied patients undergoing mitral or aortic valve replacement,
and although ANP levels were elevated preoperatively in this population (relative to normal values), these levels did
not change before, during, or up to 1 week after surgery.
Patients with arrhythmias, particularly atrial fibrillation, are prone to elevated ANP levels and may require an interval
of cardiopulmonary bypass for surgical palliation via the maze procedure. Perioperative decreases in ANP
concentrations have been implicated in the frequent manifestation of postoperative fluid retention in these patients
(115,116,117,118). However, this phenomenon may be more related to increases in plasma AVP and aldosterone
than to changes in ANP (119).
Two studies comparing ANP concentrations in systemic and pulmonary venous and arterial blood identified secretion
of ANP into the left atrium and its clearance by the lungs in adults and children (112,120). ANP concentrations
declined significantly during aortic cross-clamping, but rebounded rapidly after release of the aortic clamp
(108,111,112).
Multiple studies of both children and adults demonstrated no correlation between atrial pressure and ANP
concentration during and after cardiac surgery. This is particularly apparent when patients demonstrated paradoxical
increased ANP concentrations during rewarming, despite reduced atrial pressure at the time
(106,108,109,111,112,120,121). After CPB, urine flow and sodium excretion increased concurrently with increased
ANP and normal vasopressin concentrations; thus this diuresis could be the result of elevated ANP concentrations
(121). The relationship between ANP concentration and atrial pressure remained abnormal in the first few hours after
bypass but returned to normal after 24 hours (106,109). Despite
P.325
the absence of correlation between atrial pressure and ANP concentrations during bypass, a 30-minute infusion of
ANP (1.67 μg/min) significantly increased urinary output and sodium excretion compared with placebo, indicating
preserved end-organ responses to the hormone during bypass (122) (Fig. 11.10). In contrast to this finding, Seghaye
et al. (123) and Hayashida et al. (124) studied infants and adults, respectively, undergoing cardiac surgery with CPB
and found a significant decrease in the biologic activity of ANP, as measured by the molar ratio of cGMP to ANP,
during and after CPB. A 2010 study by Voors et al. (125) comparing patients undergoing cardiac surgery receiving
infusions of human ANP to a control group found that the group receiving ANP experienced significantly fewer
arrhythmias, shorter ICU and hospital length of stay, and an increased short- and long-term cardiac event-free rate.
In the group that received ANP, left-ventricular EF was significantly increased and BNP concentration decreased
from the end of surgery to a 1-year postoperative follow-up examination. Serum creatinine was significantly lower and
glomerular filtration rate significantly higher from end of surgery to 1 year postoperatively in the cohort receiving ANP.
Patients with preexisting chronic kidney disease undergoing CPB also showed a decrease in disease progression
and necessity for dialysis (126).
FIGURE 11.10. Diuresis and natriuresis in response to atrial natriuretic factor (n = 6, □) or placebo (n = 6, ▪) infused
during cardiopulmonary bypass. Responses were recorded during and after drug administration. V, urine volume;
UNaV, urine sodium concentration × urine volume. (From Hynynen M, Palojoki R, Heinonen J, et al. Renal and
vascular effects of atrial natriuretic factor during cardiopulmonary bypass. Chest 1991;100:1203-1209, with
permission.)
Amano et al. (127) infused 1 mL/kg of 10% saline to patients before and after heart or lung operations. Patients
having lung surgery showed normal ANP responses to saline before and after surgery; conversely, patients showed
a normal increase in ANP with saline infusion before undergoing cardiac surgery but had no significant response to
the same stimulus delivered after surgery (127).
B-Type Natriuretic Peptide

BNP has become an increasingly studied and recognized predictor of presence and severity of heart failure,
myocardial ischemia, and postoperative morbidity including risk for atrial fibrillation, need for inotropic support, length
of stay in ICU, and death (128,129,130,131,132,133,134,135). ProBNP is released by cardiac myocytes in response
to wall stress such as that produced by volume overload as well as inflammation and tissue hypoxia. ProBNP is
further cleaved by plasma proteases furin and corin to its active form and the inactive fragment N-terminal (NT)-
proBNP. NT-proBNP’s stability and storage half-life make it a more favorable analyte than BNP. NT-proBNP and
BNP concentrations are generally comparable in prognostic and diagnostic value (136). In a 2013 study by Liu et al.
(137), elevated preoperative levels of NT-proBNP were associated with higher NYHA classification, lower EF, higher
pulmonary artery pressures, higher left-ventricular diameter, increased incidence of atrial fibrillation, elevated
creatinine, and elevated Troponin T (cTnT) levels. Elevated preoperative concentrations of NTproBNP also
predicted postoperative NT-proBNP elevations, longer lengths of stay in the ICU and hospital, longer times on a
ventilator, and higher mortality. A 1998 study showed minimal BNP change during CPB relative to preoperative levels
and BNP elevations at 6, 12, and 24 hours after surgery (138). Postoperative BNP levels correlated with
preoperative levels and elevated concentrations were associated with lower preoperative EF, postoperative cardiac
output, and stroke volume, and with greater necessity for inotropic support and longer aortic cross-clamp times.
Although the preponderance of the literature seems clear in this regard, a few studies contradict the trend of elevated
baseline BNP in patients with heart disease. For example, a pediatric study demonstrated normal BNP levels in five
infants with CHF related to left-to-right shunting prior to surgical repair using CPB (139). Significant elevation of BNP
in response to modified ultrafiltration was another unexpected finding of this limited study. However, a larger study of
pediatric patients with congenital heart disease found baseline elevations of BNP not only in the plasma, but also in
the pericardial fluid of patients with Qp:Qs ratios >2 (140). In contrast, Terazawa et al. (141) found that baseline BNP
levels were significantly higher in American Society of Anesthesiologists physical
P.326
status classification II patients than in class III or IV patients undergoing CABG.
Like ANP, studies observing the effect of CPB on BNP concentrations are somewhat contradictory. In Terazawa’s
study, ANP and BNP levels were both decreased relative to baseline during CPB, and neither peptide increased
significantly above baseline postoperatively. Neither ANP nor BNP concentrations correlated with hemodynamic
variables before or after CPB. Berendes et al. (142) also measured ANP and BNP levels in patients having either
CABG or valve surgery, and in a separate study (143) assessed patients undergoing CABG with or without adjunct
thoracic epidural anesthesia (Fig. 11.11). The results of both studies were nearly identical with respect to ANP and
BNP levels. ANP levels increased significantly during CPB, and particularly during volume reloading after aortic
cross-clamping, but levels of BNP remained unchanged during CPB. BNP levels became significantly elevated
compared to baseline only in CABG patients and not until several hours postoperatively. The degree of this elevation
correlated positively with both CPB time and aortic cross-clamp time. In a study by Morimoto et al. (138) BNP levels
were measured during CPB and were found to be relatively unchanged from baseline as well. In this study BNP
increased significantly at 6, 12, and 24 hours postoperatively. Of note, both ANP and BNP responses were
attenuated when general anesthesia was combined with thoracic epidural anesthesia.
FIGURE 11.11. Plasma measurements of natriuretic peptides. Top two graphs (A) compare ANP and BNP levels in
patients with EF>50% vs EF<50% in CABG surgery. Bottom two graphs (B) compare ANP and BMP levels in mitral
valve replacement surgery and aortic valve replacement surgery. Data are presented as means +/- standard
deviation. ANP=A-type natriuretic peptide; BNP=B-type natriuretic peptide; CPB=cardiopulmonary bypass;
ICU=intensive care unit; EF=left ventricular ejection fraction. (From Berendes E, Schmidt C, Van Aken H, et al. A-type
and B-type natriuretic peptides in cardiac surgical procedures. Anesth Analg 2004;98:11-19, with permission.)
In summary, the preponderance of recent evidence suggests that both the level and biologic activity of ANP are
reduced during CPB, especially during hypothermia and aortic cross-clamping. Decreases in ANP concentration are
most evident in patients with preoperative elevations in ANP, which is especially common with valvular heart disease
and atrial arrhythmias. Most patients demonstrate distinctly elevated ANP concentrations (relative to those measured
during aortic cross-clamping) during rewarming and after discontinuation of bypass. Patients also fail to demonstrate
the normal relationship
P.327
between ANP concentrations and atrial pressure during bypass and the early postoperative period or the normal
response of ANP to saline infusion after bypass. BNP concentrations tend to remain unchanged during CPB, but are
commonly elevated in the first 24 hours after CPB, especially in patients with preexisting heart failure not related to
valvular disease. Preoperative BNP or NT-proBNP levels have been shown to correlate with one another and are
associated with increased morbidity and mortality in patients undergoing cardiac surgery.
RENIN-ANGIOTENSIN-ALDOSTERONE AXIS
The renin-angiotensin-aldosterone axis regulates arterial blood pressure, intravascular volume, and electrolyte
balance (144). In patients with heart failure or with conditions that place them at risk for heart failure, activation of the
renin-angiotensin-aldosterone axis leads to hemodynamic and renal dysfunction, inflammation, and cardiac
remodeling (145,146). The renal juxtaglomerular apparatus secretes renin in response to sodium depletion, falls in
blood volume, or reduced renal perfusion. Conversely, increases of blood volume, renal perfusion, or sodium load
inhibit the release of renin. The sympathetic nervous system stimulates renin release in response to pain, emotion,
and stress. Renin catalyzes the conversion of angiotensinogen to the decapeptide angiotensin I in the blood. ACE,
present in blood vessel walls (particularly of the pulmonary vasculature), catalyzes the conversion of angiotensin I to
angiotensin II (an octapeptide). Conversion of angiotensin I to angiotensin II is nearly complete during a single pass
through the lungs. Angiotensin II raises blood pressure through two mechanisms: direct vasoconstriction and
stimulation of aldosterone secretion by the adrenal glands. Aldosterone stimulates the renal distal tubules to reabsorb
sodium and secrete potassium and hydrogen ions into tubular fluid and also promotes cardiac remodeling in heart
failure.
Serial measurements taken before, during, and after CPB have shown that renin activity increases during and shortly
after CPB (147). Similarly, angiotensin II and aldosterone concentrations rise significantly during and shortly after
bypass in patients undergoing nonpulsatile perfusion (147,148,149,150). Pulsatile perfusion during CPB eliminates
the intraoperative and postoperative increases in plasma renin activity and postoperative increases in both
angiotensin II and aldosterone (150,151) (Fig. 11.12). Goto et al. (152) found no significant differences between
pulsatile and nonpulsatile perfusion on concentrations of renin, angiotensin II, or aldosterone, with concentrations of
all three hormones declining upon initiation of CPB and only aldosterone increasing during and after CPB.
ACE concentrations change markedly during and after cardiac surgery; however, if corrected for hemodilution,
minimal response to CPB or hypothermia is observed (39). Absolute and corrected concentrations of ACE are
depressed during rewarming, after separation from bypass, and during the first 24 hours of recovery (39,153,154). By
24 hours after bypass, ACE concentrations recover to baseline values (153,154). Secretion of ACE into the vascular
compartment by the lungs remains diminished in the period immediately after CPB (39,153,154). These studies
suggest that depression of ACE activity during CPB begins after the induction of hypothermia but before rewarming
(39). ACE concentration may also serve as a biologic marker of thyroid hormone [free triiodothyronine (T3)] action
during and after cardiac surgery (154).
FIGURE 11.12. Pulsatile perfusion (○) reduces concentrations of angiotensin II and aldosterone (vs. nonpulsatile
perfusion, •) during cardiopulmonary bypass. (From Nagaoka H, Innami R, Arai H. Effects of pulsatile
cardiopulmonary bypass on the renin-angiotensin-aldosterone system following open heart surgery. Jpn J Surg
The role of the renin-angiotensin-aldosterone axis in the maintenance of blood pressure and peripheral vascular
resistance during and after CPB remains unclear. Preoperative administration of an ACE inhibitor did not impair blood
pressure regulation during anesthesia and CPB (155). Two studies have documented that concentrations of renin,
angiotensin II, and aldosterone during bypass did not correlate with intraoperative or postoperative hypertension
(148,149). In another study, postoperative hypertension and the need for vasodilators were associated with high
vasopressin concentrations but not with angiotensin II concentrations (156). A fourth study found that postoperative
hypertension could not be related to elevated renin levels; moreover, hypertension was not treated effectively by
saralasin blockade of angiotensin II (157). Similarly, preoperative administration of ACE inhibitors failed to prevent
hypertension after CABG (155). Thus, the preponderance of evidence would suggest that both intraoperative and
postoperative hypertension is at best only loosely related to the abnormal concentrations of renin, angiotensin II, or
P.328
aldosterone seen during and after bypass. On the other hand, there has been a profuse literature on the relationship
between treatment with ACE inhibitors or angiotensin receptor blockers and perioperative hypotension (158,159).
THYROID
A variety of acute illnesses lead to alterations of peripheral thyroid hormone metabolism. Characteristically, serum
concentrations of T3 (the active thyroid hormone species) are reduced, thyroxine (T4) is normal or reduced, free
thyroxine is reduced, and thyrotropin (thyroid-stimulating hormone) concentrations are normal, producing the so-
called sick euthyroid syndrome (also referred to as nonthyroidal illness syndrome). Multiple studies have documented
the presence of this syndrome during and after CPB in adults and children. The reduction in thyroid hormone levels
previously observed in patients undergoing cardiac surgery with CPB also occurs during off-pump cases and in
patients undergoing normothermic or mildly hypothermic (35 ± 1°C) CPB (160,161). This implies that the decline in
circulating T3 may not be specifically a hypothermia- or CPB-related phenomenon, but rather a nonspecific stress
response to cardiac surgery. In theory, the concentration of T3 would be especially important for patients having
cardiac surgery because T3 regulates the number of β-adrenergic receptors and their sensitivity to agonists (162).
Jones et al. (163) demonstrated a greater than 10% incidence of preoperative abnormalities in thyroid function in
patients undergoing CPB, but found no association between abnormal laboratory results and adverse outcome. More
recently, however, Cerillo et al. (164) demonstrated that low preoperative T3 levels robustly predicted death and low
cardiac output in CABG patients.
Pre-CPB heparin administration slightly increases free T3 and free T4 because it displaces hormones from binding
proteins (165,166,167,168). Total T3 concentrations drop precipitously with CPB and remain depressed 24 hours
after surgery (39,165,169,170,171) (Fig. 11.13). T3 values corrected for hemodilution (using albumin concentration)
are not altered by the initiation of CPB or by the initiation of hypothermic perfusion (39). Similarly, the free and the
dialyzable fractions of T3 increase after the onset of bypass and hypothermia (39,165). These alterations in T3 and
T4 during bypass are independent of thyrotropin hormone secretion because adjustments in T3 and T4
concentrations normally follow 2 to 4 hours after a change in thyrotropin concentration (171,172). Absolute
thyrotropin and total T3 concentrations return to normal after surgery, after a time that varies from study to study
(170,171,172,173).
The thyrotropin-releasing hormone-thyrotropin axis in the hypothalamus and pituitary gland centrally regulates thyroid
hormone. In adults, thyrotropin concentrations are unchanged during normothermic bypass; however, thyrotropin
declines after induction of anesthesia and then steadily rises during extracorporeal perfusion (165,169) (Fig. 11.14).
During the first postoperative day, thyrotropin concentrations decline below baseline values (154,169,174). During
and shortly after CPB, the thyrotropin response to exogenous administration of thyrotropin-releasing hormone is
blunted (174,175) (Fig. 11.15). Because of the reduced total T3 concentrations during bypass, an increased
sensitivity to thyrotropin-releasing hormone might have been anticipated. The cause of this pituitary hypofunction
remains unknown; however, it could result from nonpulsatile flow-induced rises in endogenous dopamine or
somatostatin concentrations (175,176).
FIGURE 11.13. Response of free T3 concentration to cardiovascular surgery in 14 patients. T3 declined during
cardiopulmonary bypass (CPB) and then declined further during the first 24 hours after operation. Concentrations of
free T3 during cardiac surgery in 14 patients. Concentrations were measured preoperatively (Pre), after
administration of heparin (Hep), after initiation of CPB (CPB), at the nadir of hypothermia (Hypo), after rewarming
(Warm), and at 2 (2 hr), 8 (8 hr), and 24 hours (24 hr) after CPB. Statistical comparisons were made between the
preoperative and subsequent measurements. (From Holland FW II, Brown PS Jr, Weintraub BD, et al.
Cardiopulmonary bypass and thyroid function: a “euthyroid sick syndrome.” Ann Thorac Surg 1991;52:46-50, with
permission.)
Children undergoing correction of congenital heart disease demonstrate thyroid hormonal responses similar to those
of adults, including the sick euthyroid syndrome at 24 hours after surgery (171,177,178,179,180) (Fig. 11.16).
Curiously, patients having deep hypothermia and circulatory arrest demonstrate better preservation of the
relationship between thyrotropin and T3 during and early after CPB than do patients undergoing cardiac repair
without circulatory arrest. In other words, deep hypothermia with circulatory arrest may better preserve the
hypothalamo-pituitary axis than conventional hypothermic bypass without circulatory arrest (171). Nevertheless, any
benefit is only transitory: At 24 hours postoperatively, patients demonstrate decreased thyrotropin and T3
concentrations whether or not circulatory arrest was used. Murzi et al. (178) measured concentrations of thyroid
hormones for up to 8 days after correction of congenital heart defects and observed return of thyrotropin
concentrations to baseline preoperative values by the third postoperative day; nevertheless, T3 concentrations
continued to be depressed below baseline values at the seventh postoperative day.
In 10 neonates undergoing either repair of D-transposition of the great arteries or of total anomalous pulmonary
venous drainage, Mainwaring et al. (179) found that free T3 was unchanged
P.329
immediately after institution of bypass but was reduced 1 hour and 1 day after surgery. Five days after surgery, free
T3 was increasing but remained below baseline values. Thyrotropin was below baseline levels during CPB, 1 hour
and 1 day after the operation. Five days postoperatively, the thyrotropin concentration was higher than baseline,
consistent with a normal relationship between thyrotropin and T3. Saatvedt and Lindberg (180) associated depressed
concentrations of T3 after CPB in children with elevated concentrations of IL-6, an inflammatory cytokine.
FIGURE 11.14. Effect of cardiovascular surgery on thyroid-stimulating hormone (TSH) concentration in 44 patients.
TSH reached its nadir 6 hours after bypass and remained low through the fourth postoperative day. Statistical
comparisons (as indicated on the figure) all compare subsequent TSH concentrations versus those measured before
anesthesia. (From Chu S-H, Huang T-S, Hsu R-B, et al. Thyroid hormone changes after cardiovascular surgery and
clinical implications. Ann Thorac Surg 1991;52:791-796, with permission.)
FIGURE 11.15. Serum thyrotropin hormone response to thyrotropin-releasing hormone (TRH) in euthyroid subjects
before, 1 day after, and 1 week after coronary bypass surgery with hypothermic nonpulsatile perfusion. TSH, thyroid
stimulating hormone. (From Zaloga GP, Chernow B, Smallridge RC, et al. A longitudinal evaluation of thyroid function
in critically ill surgical patients. Ann Surg 1985;201:456-464, with permission.)
In 1978, Taylor et al. (181) showed that pulsatile flow during CPB maintained a normal thyrotropin response to
exogenously administered thyrotropin-releasing hormone, contrasting with the abnormal responses observed during
nonpulsatile perfusion. In 30 patients undergoing coronary artery surgery, Buket et al. (182) found sharp decreases
in free and total T3 and thyrotropin upon initiation of bypass whether or not pulsatile perfusion was used. Later
measurements demonstrated a lesser decrease in free and total T3 in patients undergoing pulsatile bypass
compared to nonpulsatile
P.330
bypass (182). Patients making an uncomplicated recovery from surgery demonstrated a sharp increase in
thyrotropin, total T3, and total T4 on day 4 after surgery, whereas patients with complications did not demonstrate
such pronounced increases (170).
FIGURE 11.16. Concentrations of free triiodothyronine (T3) and thyrotropin (TSH) in infants and young children
undergoing correction of congenital heart disease with cardiopulmonary bypass (CPB) (n = 12) or CPB and deep
hypothermic circulatory arrest (DHCA) (n = 11). Blood samples were obtained Pre-CPB, after anesthesia induction
before heparin; CPB1, immediately after onset of bypass; CPB2, during cooling, halfway to the target temperature;
CPB3, at the lowest core temperature (CPB group); CPB4, during rewarming; CPB5, just before separation from
CPB; Post-CPB, after placement of sternal wires; POD1, on the morning after surgery; POD2, on the second morning
after surgery. Note that both groups have inappropriately low TSH concentrations given the free T3 concentrations
on the first and second postoperative days. (From Ririe DG, Butterworth JF, Hines M, et al. Effects of
cardiopulmonary bypass and deep hypothermic circulatory arrest on the thyroid axis during and after repair of
congenital heart defects: preservation by deep hypothermia? Anesth Analg 1998;87:543-548, with permission.)
These studies of thyroid function during and after CPB may be of more than academic interest. T3 modulates
metabolism, heart rate, myocardial contractility, and oxygen consumption (183). Cyclic adenosine monophosphate
(AMP) production in response to β-adrenergic receptor agonists is markedly reduced in hypothyroid cardiac, adipose,
and hepatic tissue (162,184). Cyclic AMP regulates intracellular calcium transients and myocardial contractility. T3
improves contractility and cyclic AMP production of isolated ischemic, reperfused hearts (185). Experimental studies
have shown improved myocardial contractility in animals receiving T3 after CPB (186,187). When given prophylactic
intravenous T3, patients with preoperative left-ventricular EFs greater than 0.40 demonstrated higher cardiac outputs
after CPB than a control group that did not receive T3. Patients with preoperative left-ventricular EFs less than 0.40
that received prophylactic T3 required much less dobutamine and furosemide than did control patients (188).
Nevertheless, clinical trials have failed to prove a reduced likelihood of requiring inotropic drug support, a reduction
in mortality or a reduced length of stay in adults receiving T3 supplementation (189,190). Children undergoing
correction of congenital heart disease who received prophylactic liothyronine had improved myocardial function and
overall lower therapeutic index scores (a score taking into account invasiveness, intensity, and complexity of
intensive unit care) than the placebo treatment group (191).
A recent study has confirmed that oral T3 replacement can maintain hormone levels within normal limits in children
recovering from repair of congenital heart disease (192,193,194). On the other hand, we urge caution in considering
thyroid replacement in patients with concurrent hypothyroidism and chronic ischemic heart disease. Levothyroxine or
liothyronine replacement therapy may precipitate myocardial ischemia and infarction, or even adrenal insufficiency.
Indeed, patients with mild to moderate hypothyroidism appear to tolerate cardiac surgery without excess morbidity or
mortality, although practitioners must be cognizant of the potential for delayed emergence from anesthesia,
hypotension, bleeding, and the need for exogenous corticosteroids in such patients (189).
EICOSANOIDS
Eicosanoids relevant to a discussion of CPB include the prostaglandins and the leukotrienes (192,193). The lungs
are actively involved in the metabolism of many vasoactive substances, including eicosanoids; thus, the separation of
the lungs from the circulation during extracorporeal perfusion may significantly alter the plasma concentrations and
kinetics of these substances. The endoperoxide prostaglandin H2 can isomerize (catalyzed by isomerases) into
prostaglandin E2 (PGE2), PGF2α, or PGD2, or be chemically converted (catalyzed by either prostacyclin or
thromboxane synthetase, respectively), into either prostacyclin (PGI2) or thromboxane A2 (TXA2). The predominant
prostaglandins formed in the bronchial tree and in the pulmonary vasculature
P.331
are PGE2 and PGI2. PGEs are dilators in most vascular beds. PGD2 and PGF2α are pulmonary vasoconstrictors. In
addition to synthesis and release of prostaglandins, the lungs are a major site for metabolism of prostaglandins of the
E and F types. These substances are nearly completely cleared during a single passage through the pulmonary
circulation. PGI2 can disaggregate platelets and act as a potent vasodilator. Conversely, TXA2 potently stimulates
platelet aggregation and vasoconstricts.
Concentrations of 6-keto-prostaglandin F1α (the stable metabolite of prostacyclin) rose significantly after aortic and
atrial cannulation and remained elevated during CPB in children and adults (194,195,196,197,198,199,200,201). 6-
Keto-prostaglandin F1α concentrations rose at the beginning of bypass, continued rising upon aortic clamping, but
decreased progressively after termination of bypass and reperfusion of the lungs. There were no significant
differences between patients undergoing cardiac surgery with pulsatile bypass or with conventional bypass (201).
One can compare the production of PGF2α in response to either oxidative stress or inflammation by monitoring
concentrations of specific metabolites (8-iso-PGF2α vs. 15-keto-dihydro-PGF2α). When concentrations of these two
metabolites were compared during and after CPB in adults having various types of cardiac surgery, the data were
more consistent with free radical-induced oxidative stress than with inflammation per se in these patients (200).
FIGURE 11.17. Thromboxane metabolite (TXB2) concentrations in children undergoing correction of congenital heart
defects either with (n = 21) or without (n = 9) cardiopulmonary bypass (CPB). The CPB group demonstrated
significantly elevated concentration compared with the non-bypass (control) group. (From Greeley WJ, Bushman GA,
Kong DL, et al. Effects of cardiopulmonary bypass on eicosanoid metabolism during pediatric cardiovascular surgery.
J Thorac Cardiovasc Surg 1988;95:842-849, with permission.)
Concentrations of thromboxane B2 (TXB2, the stable metabolite of TXA2) increased and reached peak arterial levels
just before termination of CPB, a markedly different pattern from that seen in patients undergoing cardiac surgery
without bypass (197) (Fig. 11.17). After completion of the cardiac repair
P.332
and discontinuation of CPB, concentrations of prostacyclin and thromboxane metabolites decreased progressively
(198). A study by Feng et al. (202) investigated the contractile response of human peripheral microvasculature to
TXA2 before and after CPB and found that CPB decreases the response shortly after cardiac surgery. Furthermore,
CPB does not change the protein or gene expression of TXA2 receptors, but perhaps hypothermia during bypass
alters the functionality of the receptor. Children have greater and more sustained increases in thromboxane
metabolites than do adults (198,201). Infants undergoing extracorporeal membrane oxygenation, which may be
thought of as a form of long-term CPB, demonstrate increased prostacyclin metabolite concentrations after initiation
of therapy (203). With continued use of extracorporeal membrane oxygenation, prostacyclin metabolite
concentrations slowly fell. Prostacyclin metabolite concentrations rose again as the patients were weaned from
extracorporeal membrane oxygenation; concentrations remained elevated for about a day thereafter (203).
Although increased concentrations of prostacyclin and thromboxane during bypass may have important effects on
systemic and pulmonary vascular resistance and vasoreactivity, studies have not shown a consistent effect.
Administration of the protease inhibitor aprotinin reduces the surge in TXB2 associated with bypass but has no effect
on 6-keto-prostaglandin F1α concentrations (199). These aprotinin-induced changes in prostaglandin metabolism
were associated with better preserved platelet function, potentially significant in preventing postoperative
hemorrhage (the primary indication for this formerly widely prescribed pharmaceutical).
A rapid increase in PG E2 concentrations at the onset of CPB has been confirmed in several studies (195,197).
Minimal differences between arterial and venous concentrations confirm limited PG E2 metabolism in the lungs during
CPB. PG E2 concentrations fall promptly after termination of bypass and reinstitution of pulmonary perfusion.
Aspiration of shed pulmonary venous blood from open pleural cavities reduces mean arterial pressure during CPB
and increases systemic concentrations of PG E2 and 6-keto-prostaglandin F1α, probably as a consequence of the
high concentrations of PG E2 and 6-keto-prostaglandin F1α measured in shed pulmonary venous blood (204).
In summary, the role of prostanoids and thromboxanes during and after bypass remains controversial. Perhaps most
important in maintaining this controversy is the usual practice of measuring agent concentrations in systemic blood,
which ignores the importance of prostanoids and thromboxanes in local regulation of blood flow within organs.
Leukotriene levels are also affected by CPB but have received only limited scrutiny in clinical studies. Cysteinyl
leukotrienes have been implicated in pulmonary dysfunction. When patients with and without chronic obstructive lung
disease underwent cardiac surgery with CPB, both groups showed significant increases in urinary concentrations of
cysteinyl leukotrienes. Those with chronic lung disease had a significant increase from baseline in plasma cysteinyl
leukotrienes, whereas patients without chronic lung disease did not have a significant increase (205). Plasma and
urinary concentrations of leukotriene B4 were unchanged in either group over time. Among infants dependent on
parenteral nutrition and undergoing repair of congenital heart disease, administration of a complex lipid emulsion
containing medium-chain triglyceride, soybean oil, and fish oil reduced measures of inflammation and downregulated
leukotriene B4 relative to a control group receiving a pure soybean emulsion (206).
OTHER HUMORAL EFFECTS

Histamine
Elevated blood concentrations of histamine may produce vasodilation and hypotension. Numerous drugs
administered to patients undergoing cardiac surgery will induce histamine release, including opioids (especially
morphine), muscle relaxants (notably tubocurarine and metocurine, neither of which are commonly used), antibiotics,
heparin, and protamine (207). Current anesthetic practice favors the use of agents that have negligible likelihood of
inducing histamine release. In adults, plasma histamine concentrations rise at the time of systemic heparinization and
remain elevated throughout the period of CPB (208). Comparable measurements of histamine concentration in
children are problematic because, unlike adults, children often have blood products added to priming solutions used
for CPB to prevent excessive hemodilution (93,209). Marath et al. (209) measured markedly elevated histamine
concentrations in over 70% of blood product-containing priming solutions before their use during pediatric CPB,
prompting speculation by these authors that the delivery of this massive histamine load to patients could have
adverse effects. In children, particularly striking increases in histamine concentrations occur at the time the aortic
crossclamp is released, probably from reperfusion of the lungs (210). Conversely, Wojtecka-Lukasik et al. (211)
demonstrated that blood concentrations of histamine and histamine content in blood lymphocytes remained stable
throughout bypass in children undergoing repair of congenital heart defects. Infusion of prostacyclin during CPB
diminishes the concentrations of histamine (208). van Overveld et al. (212) prevented elevated concentrations of
histamine in serum during and after CPB for coronary artery surgery by administering methylprednisolone 30 mg/kg
during induction of anesthesia. Histamine concentrations in patients with the cold urticaria syndrome, a relatively rare
disorder, are increased nearly 10-fold during hypothermic CPB (213). In current practice, elevated histamine
concentrations may be of greatest concern when blood-containing priming solutions are used or when histamine-
releasing agents must be administered. This opinion is supported by the study by Fayaz et al. (214) in adult patients.
In contrast to previous work, they found no increase in histamine concentrations with induction of anesthesia or with
administration of heparin. These investigators did measure
P.333
significant increases in histamine concentrations with application of the aortic cross-clamp, resumption of ventilation,
and with administration of protamine (Fig 11.18).
FIGURE 11.18. Median [IQR] histamine levels produced at specified time points. *p < 0.00625 from baseline. 1) Pre-
induction (baseline), 2) 15 min postinduction (prior to heparin), 3) 5 min after heparin administration, 4) 5 min after the
aorta was cross-clamped, 5) immediately after aortic X-clamp removal, 6) immediately after reventilating the lungs, 7)
after protamine, 8) 2 h after CPB, 9) 24 h after CPB. (From Fayaz KM, Pugh S, Balachandran S, et al. Histamine
release during adult cardiopulmonary bypass. Anaesthesia 2005;60: 1179-1184, with permission.)
CALCIUM
The availability of calcium ions in the sarcoplasmic reticulum determines the magnitude of the increased intracellular
calcium concentrations during depolarizations, which in turn regulates the inotropic state of the heart (215). Calcium
ions are also necessary for normal cardiac conduction and rhythm. Calcium in blood exists in three fractions: ionized
(approximately 50%), protein bound (approximately 40%), and chelated (approximately 10%). The free ionized
fraction is the physiologically active component. In critical illnesses, the distribution of calcium amongst these forms
can be disturbed; thus, measurements of total calcium may be misleading (216). The blood calcium concentration is
maintained within the normal range by parathormone and 1,25-dihydroxycholecalciferol (calcitriol or vitamin D)
actions on bone and kidney. Parathormone secretion is stimulated by decreasing ionized calcium concentration, overt
hypocalcemia, and by mild hypomagnesemia. Parathormone secretion is suppressed by rising or normal
(unchanging) ionized calcium concentrations and by severe hypomagnesemia.
Changes in the total and ionized calcium fractions during and after CPB are influenced by the inclusion of exogenous
calcium salts, albumin or other blood products in the pump priming solution. Calcium salts are frequently administered
upon discontinuation of extracorporeal perfusion. Clinical studies uniformly demonstrate a fall in ionized calcium
concentration upon initiation of CPB (217,218,219,220,221,222,223,224). When bloodfree priming solutions are used
during bypass, both total and ionized calcium decrease as a consequence of hemodilution; ionized calcium
concentrations may further decrease if albumin (which binds calcium) is added to priming solutions (223). Total
calcium, total magnesium, ultrafiltrable magnesium (analogous to ionized magnesium), and total protein likewise
decline upon initiation of CPB (21). During cardiac surgery, parathormone concentrations rise in response to declines
in ionized calcium concentration and decline in response to rising ionized calcium concentrations.
Change in ionized calcium concentration and the absolute concentration regulates parathormone secretion. As has
been demonstrated in other circumstances, there is hysteresis in the relationship between parathormone and ionized
calcium concentrations measured intraoperatively (223,224,225). When ionized calcium concentration is rising (in
response to increased concentrations of parathormone), secretion of parathormone will decrease at ionized calcium
concentrations
P.334
below “normal” that would elicit increased parathormone secretion if approached from a higher rather than a lower
initial ionized calcium concentration.
Studies of parathormone concentrations using contemporary assays sensitive only to the intact hormone consistently
have found reductions at the beginning of bypass, increases to maximal concentrations during hypothermia, and a
slow return toward normal values as ionized calcium concentrations approach normal values during rewarming (223).
Some early studies using less reliable assays reported falls in parathormone concentration upon initiation of bypass
without appropriate increases in response to hypocalcemia thereafter (218).
Studies in adults have demonstrated that the typical modestly reduced magnesium concentrations during CPB do not
influence the response of the calcium-parathyroid-vitamin D axis (223). Calcium and parathormone concentrations
and responses were identical in patients receiving magnesium salt supplementation during bypass and in control
patients whose magnesium concentrations were permitted to fall without correction. Calcitriol (vitamin D) is a fat-
soluble vitamin; thus, it is not surprising either that calcitriol concentrations are minimally altered by hemodilution and
CPB or that this vitamin plays a minimal role in the alterations in calcium concentration seen during cardiac surgery
(223). Despite much recent interest in the relationship between vitamin D levels and outcomes in a wide variety of
acute and chronic diseases, there is sparse evidence that surgical patients derive outcome benefits from surveillance
for or treatment of hypovitaminosis D (226).
As is well described in this volume, CPB is managed differently in infants and young children than in adults. Even
with the use of smaller extracorporeal circuits, priming solution volumes represent a much greater fraction of the
child’s blood volume, and blood products are often included in the priming solutions to avoid excessive degrees of
hemodilution (92,93). Perioperatively, the responses of the calcium-parathyroid-calcitriol axis in infants and young
children were similar to those of adults (224). Despite demonstrating much greater declines in ionized calcium
concentration upon initiation of CPB, infants’ parathyroid hormone concentrations peaked at values similar to those
achieved by children and adults (223,224). Moreover, parathyroid gland “sensing” of increasing and decreasing
ionized calcium concentrations was also similar, with infants and young children demonstrating hysteresis in a similar
manner to adults (223,224,225). Infants and young children differed from adults in that ionized calcium concentrations
did not recover as completely before termination of CPB. This was likely a consequence of the shorter duration of
bypass in the children compared with the adults that were studied, although impaired bone reabsorption in response
to parathyroid hormone could not be ruled out. There are important clinical implications from these studies. Unlike the
case for many other hormones, parathormone secretion is minimally altered by hypothermic CPB (223,224). Ionized
hypocalcemia, even to severe degrees, produced no obvious adverse effects during CPB in these studies. Moreover,
hypercalcemia may lead to accelerated adenosine triphosphate breakdown (a calcium-dependent process) and
unnecessarily increase contractility and myocardial oxygen consumption (227). Rewarming and reperfusion after
aortic clamp removal, essential for resynthesis of high energy phosphates, ideally should be accompanied by minimal
myocardial oxygen consumption. Administering calcium salts during this time might unnecessarily increase the
myocardial inotropic state, leading to depletion of adenosine triphosphate.
The empirical use of calcium salts at the end of CPB (supposedly for inotropic support) remains a tradition in cardiac
surgery despite sparse evidence of clinical efficacy in controlled trials and the usual absence of serious
hypocalcemia in adult patients. Animal studies suggest that calcium repletion after reperfusion may not produce ill
effects (227). On the other hand, excessive use of calcium salts may cause perioperative pancreatitis, may reduce
the efficacy of β-adrenergic receptor agonists, and likely has no effect on cardiac output
(228,229,230,231,232,233,234). Ideally, calcium salts should be administered only when all of the following three
conditions are met: bypass is about to be terminated, ionized calcium concentration is reduced, and increased
cardiac inotropy and blood pressure will be beneficial (235,236).
MAGNESIUM
Magnesium is the second most abundant intracellular cation (following potassium) and is a key cofactor in enzyme
systems maintaining transmembrane electrolyte gradients and energy metabolism, enzymes involved in synthesis of
second messengers (e.g., adenylyl cyclase), ion channels, and hormone secretion and action (e.g., insulin and
parathormone) (237). Much like calcium, magnesium in the blood exists in three fractions: ionized (approximately
55%), chelated (approximately 15%), and protein bound (approximately 30%). The ultrafiltrable fraction includes only
the ionized and chelated fractions and, due to the small contribution from the chelated ions, approximates the ionized
fraction (238). Because there is a dynamic equilibrium between intracellular and extracellular magnesium, the
magnesium concentration in blood may be normal in the presence of magnesium depletion.
Patients undergoing cardiac surgery frequently develop hypomagnesemia, which may be due to insufficient dietary
intake, increased excretion (secondary to diuretics), diabetes, aminoglycoside antibiotics, cardiac glycosides, ethanol
abuse, pancreatic disease, or administration of citrated blood products or albumin
(223,224,237,239,240,241,242,243). Blood magnesium concentrations decrease during and after CPB in adults and
children. During CPB, total magnesium concentrations decline in concert with the ultrafiltrable fraction as a
consequence of chelation by albumin and other blood products and hemodilution (223). Urinary excretion of
magnesium during bypass is not increased (240). Magnesium concentrations,
P.335
unlike calcium concentrations, once reduced during CPB return to normal only slowly in the absence of active
treatment because of the lack of a specific hormonal regulatory system (223,224) (Fig. 11.19).
Hypomagnesemia in the post-bypass period likely contributes to cardiac arrhythmias. Infusion of magnesium salts
prevents hypomagnesemia and its complications during and after CPB (223,243). During CPB, cardiac muscle is
preferentially depleted of magnesium (compared with skeletal muscle). Magnesium may suppress arrhythmias by
multiple mechanisms that include a direct myocardial membrane effect, a direct or indirect effect on cellular potassium
and sodium concentrations, antagonism of calcium entry into cells, prevention of coronary artery vasospasm,
antagonism of catecholamine action (244), or improvement of the myocardial oxygen supply/demand ratio (245).
Magnesium may inhibit calcium current during the plateau phase of the myocardial action potential. Finally,
magnesium may also inhibit arrhythmias by antagonizing accumulation of excess intracellular calcium induced by
ischemia-related mediators such as lysophosphatidylcholine (246).
Supplemental magnesium decreases the incidence of arrhythmias during myocardial ischemia or infarction and after
cardiac surgery as noted above (247,248,249). The Leicester Intravenous Magnesium Intervention II Trial used 8
mmol of magnesium sulfate acutely, followed by 65 mmol as a continuous infusion over 24 hours in patients having
an acute myocardial infarction (250). This intervention significantly reduced both mortality ( p = 0.04) and left-
ventricular failure ( p = 0.009) without producing excess hypotension. A meta-analysis of 930 patients with myocardial
infarction concluded that intravenous magnesium reduced ventricular tachycardia and fibrillation by 49% and
decreased overall mortality by 54% (251). Two recent published meta-analyses of magnesium for prevention of
postoperative atrial fibrillation in adults have reported opposing conclusions regarding efficacy (252,253). A
Cochrane review has concluded that study heterogeneity and variable study quality limit the ability to draw strong
conclusions about magnesium efficacy (254).
Magnesium is a critical cofactor for numerous cellular enzymes and regulates transmembrane calcium movement
(255). Magnesium salts dilate coronary arteries (256), regulate myocardial metabolism (255), lower systemic vascular
resistance, protect against catecholamine-induced myocardial necrosis (257), and modify platelet aggregation and
thrombus formation. Clinically, magnesium salts have been used for the treatment of both atrial and ventricular
arrhythmias (247,248,249,250,251,252,253,254) as well as coronary artery vasospasm, myocardial ischemia,
myocardial infarction, pregnancy-induced hypertension, and even bronchospasm.
Moderate magnesium supplementation (e.g., magnesium sulfate intravenously 1-2 g/hr of CPB) maintains serum
magnesium concentrations greater than 1 mM and has minimal effects on blood pressure in normotensive patients.
Renal insufficiency may predispose those receiving magnesium supplementation to magnesium toxicity. Typical signs
and symptoms include deep tendon hyporeflexia, somnolence, and even respiratory insufficiency. Very abnormally
increased concentrations of extracellular magnesium directly depress myocardial contractility. Magnesium
supplementation will potentiate neuromuscular blocking drugs, which may produce clinical weakness and respiratory
insufficiency in patients with residual neuromuscular blockade. This may be particularly important for patients who
will be extubated soon after completion of cardiac surgery. An ill-timed bolus of magnesium to an “about to be
extubated” patient can produce “recurarization” despite previously adequate neuromuscular function. Overall,
magnesium salts represent a safe, moderately effective, and low-cost therapy that may be used on a nearly routine
basis for prevention or treatment of many atrial and ventricular arrhythmias (254). The routine occurrence of
hypomagnesemia during CPB and rapid renal excretion of magnesium allows the clinician to administer moderate
doses of magnesium salts intraoperatively on an empiric basis without the need for frequent measurements of
magnesium blood concentrations in those patients who will not be extubated immediately following surgery.
POTASSIUM
Maintaining normal blood potassium concentrations is important in cardiac surgical patients. Patients receiving
diuretics may come to operation with substantial potassium deficiencies; those with renal failure may be
hyperkalemic. During and after CPB, potassium flux is also influenced by myocardial protectant solutions
(cardioplegia), CPB priming solutions, renal function, carbon dioxide tension, arterial pH, hypothermia, insulin
treatment of hyperglycemia, catecholamine infusions, and mineralocorticoids.
In the early days of valve surgery, potassium depletion was present in as many as 40% of patients, likely as a
consequence of diuretic therapy (258,259). Hypokalemia has long been prevalent after CPB (260). Before the era of
potassium cardioplegia, hyperkalemia was rare. Currently, brief episodes of hyperkalemia may be more common,
especially immediately after the release of the aortic cross-clamp. Hyperkalemia may also be more common during
true normothermic bypass than during hypothermic bypass due to the increased volumes of cardioplegic solutions
that are required (261). Potassium loss during CPB is related to urine flow, implying that urine potassium
concentration must remain nearly constant (262). Increased potassium loss is characteristic of the post-bypass
period (263) as all who care for these patients in the critical care unit can attest.
Maintenance of normocalcemia during pediatric CPB may better maintain potassium concentration than the more
usual techniques that tolerate mild hypocalcemia, albeit carrying the risk of exacerbating ischemic damage during
cross-clamping (264). The ionic constituents of blood-free priming solutions (other than calcium and potassium ions)
have little effect on potassium concentration. Careful studies of potassium intake
P.336
and output, rates of hemolysis, and serum hemoglobin have shown that much of the fall in serum potassium
concentration is not accounted for by dilution or excretion (265).
In the absence of potassium cardioplegia (which new research suggests can be improved upon), the fall in potassium
concentration during clinical CPB appears to be proportional to the decrease in body temperature, and potassium
concentration increases with warming (266,267). Blood glucose concentrations rise while insulin concentrations
decline during hypothermic CPB (see previous glucose metabolism discussion). Insulin favors intracellular transport
of glucose and potassium.
Increased concentrations of cortisol, aldosterone, and catecholamines during CPB may contribute to hypokalemia.
Cortisol and aldosterone increase the urinary excretion of potassium. Catecholamines increase potassium uptake by
skeletal muscle and decrease serum potassium. β-adrenergic blockade inhibits uptake of potassium by skeletal
muscle but does not inhibit the hepatic release of potassium by β-adrenergic stimulation (268).
Potassium concentrations are monitored frequently during CPB; nevertheless, strict normokalemia need be present
only when normal cardiac electrical activity is desired (269). Increases in systemic vascular resistance have been
observed with bolus intravenous potassium injections of 8 mEq or greater during CPB. With smaller bolus doses, an
initial fall followed by a slight rise in systemic vascular resistance is common (270).
In summary, potassium concentrations rarely remain constant during or after CPB. Hypokalemia, formerly a frequent
problem during bypass, now is uncommon due to the typical use of potassium-containing cardioplegic solutions.
Postoperative potassium loss and hypokalemia continue to be common after CPB, particularly with the more frequent
use of insulin infusions for attempted maintenance of normoglycemia (81).
FIGURE 11.19. Response of copper, zinc, selenium, magnesium, manganese plasma concentrations to CPB. Note
decreases in zinc and selenium and increases in copper concentration. (From Al-Bader A, Christenson JT, Simonet
F, et al. Inflammatory response and oligo-element alterations following cardiopulmonary bypass in patients
undergoing coronary artery bypass grafting. Cardiovasc Surg 1998;6:406-414, with permission.)
METAL IONS: ZINC, COPPER, AND IRON

Reductions in blood iron, selenium, and zinc concentrations and increases in copper concentrations occur as part of
the nonspecific “acute phase reaction” to trauma, prolonged infections, burns, and major surgery (271). These
reciprocal changes in zinc-selenium and copper were observed in a study of 67 patients undergoing CABG with CPB
(272) (Fig 11.19). In adults, zinc concentrations decline at the onset of CPB and remain low for 1 to 3 days
postoperatively (273,274,275,276). Zinc concentrations usually return to normal by the seventh postoperative day.
Urinary excretion of zinc is unaffected by cardiac surgery. Taggart et al. (276) monitored iron and zinc concentrations
before, during, and after coronary surgery in 20 patients perfused at either 20°C or 28°C. Significant alteration of the
metal-to-protein molar binding ratios preceded falls in the concentrations of both ions as a consequence of the acute
phase reaction to surgical trauma. Patients perfused at 20°C had less alterations of iron and zinc metabolism during
surgery than those perfused at 28°C. No differences were seen after surgery, when both groups demonstrated
reduced serum iron and zinc concentrations. However, a reduced concentration of iron in blood may be
advantageous. Administration of deferoxamine (an iron chelator) was associated with reduced production of free
radicals during CPB (277).
Copper concentrations fell rapidly at the onset of bypass but usually returned to normal by the third postoperative
day (273,275,276). The alterations in copper concentration appear to be caused by hemodilution (273). Zhao (274)
found a more transient (relative to other authors) nadir in blood copper concentration 30 minutes after perfusion, with
a return to normal concentrations 1 to 2 days postoperatively and a rise
P.337
to supranormal concentrations between postoperative days 3 and 9. Finally, as noted previously, a recent study has
found an increase in copper concentrations with initiation of bypass, consistent with the usual responses to
inflammation (272).
Responses in children were similar to those in adults. Alterations in zinc and copper concentrations in blood were
studied in 13 children undergoing correction of congenital heart disease (278). Concentrations of both zinc and
copper were markedly reduced (compared with preoperative measurements) 6 hours after CPB. Recovery toward
baseline values was not seen in the first postoperative 24 hours but was nearly complete 48 hours after bypass
(278).
CONCLUSIONS
CPB produces widespread alterations in endocrine, humoral, and metabolic functions, some of which may be
modified by the use of pulsatile CPB, larger doses or higher concentrations of general anesthetic drugs, or
addition of neuraxial anesthesia. The magnitude and direction of these changes may be influenced by the
duration of bypass and the techniques used (such as the degree of hypothermia, cardiac venting, and contents
of the priming solution). For the most part, the mechanisms underlying these neuroendocrine alterations during
bypass are poorly understood. In only rare patients will the temporary endocrine alterations associated with
CPB influence the likelihood of successful recovery from surgery.
ACKNOWLEDGMENTS
The authors gratefully acknowledge the contributions of Drs. Joe Utley and Julie Swain to the first edition of this
chapter, Dr. Richard C. Prielipp to the second edition of this chapter, and Dr. Scott G. Walker to the third edition of
this chapter. We have freely adapted the earlier versions of this chapter in the current work. The previous coauthors
chose not to participate in the fourth edition.
KEY Points
A variety of pituitary-related hormonal activities is influenced by CPB: ADH and adrenocorticotropin levels
increase markedly and TSH levels are typically normal, but T3 and T4 responses to TSH are reduced,
consistent with “sick euthyroid syndrome.”
Adrenal responses affected by CPB include marked increases in catecholamine, aldosterone, and cortisol
levels that can be attenuated to varying degrees by deeper anesthesia, thoracic epidural anesthesia, and
pulsatile perfusion; and the rise in aldosterone levels is stimulated by activation of the renin-angiotensin
system.
Hyperglycemia, hypoinsulinemia, and insulin resistance occur with hypothermic nonpulsatile CPB.
ANF concentrations decrease early in CPB but typically increase during rewarming. The secretion of ANF in
response to the usual physiologic stimuli is blunted during and after CPB.
Ionized calcium concentrations decrease at the onset of CPB and then rise slowly toward normal, with
physiologic parathormone responses to these changes. Routine calcium supplementation upon emergence
from CPB is not necessary.
Hypomagnesemia commonly occurs during CPB, and prophylactic treatment of this deficiency with
intravenous magnesium supplementation reduces the incidence of post-CPB atrial and ventricular
dysrhythmias and may reduce the incidences of coronary vasospasm and myocardial ischemia.
Plasma potassium concentrations fluctuate during CPB under the influence of a variety of factors, especially
cardioplegia composition and dosing.
REFERENCES
1. Malatinsky J, Vigas M, Jezova D, et al. The effects of open heart surgery on growth hormone, cortisol and
insulin levels in man—hormone levels during open heart surgery. Resuscitation 1984;11:57-68.
2. Anand KJS, Hickey PR. Halothane-morphine compared with high-dose sufentanil for anesthesia and
postoperative analgesia in neonatal cardiac surgery. N Engl J Med 1992;326:1-9.
3. Humphreys N, Bays SM, Parry AJ, et al. Spinal anesthesia with an indwelling catheter reduces the stress
response in pediatric open heart surgery. Anesthesiology 2005;103:1113-1120.
4. Barta E, Babusikova F. Effect of open heart surgery on gonadotropin levels in men. Bratisl Lek Listy
1982;77(5):604-611.
5. Maggio M, Ceda GP, De Cicco G, et al. Acute changes in circulating hormones in older patients with impaired
ventricular function undergoing onpump coronary artery bypass grafting. J Endocrinol Invest 2005;28:711-719.
6. Canbaz S, Ege T, Sunar H, et al. The effects of cardiopulmonary bypass on androgen hormones in coronary
artery bypass surgery. J Intern Med Res 2002;30:9-14.
7. Cooper DM, Bazaral MG, Furlan AJ, et al. Pituitary apoplexy: a complication of cardiac surgery. Ann Thorac
Surg 1986;41:547-550.
8. Mattke A, Vender J, Anstadt M. Pituitary apoplexy presenting as Addisonian crisis after coronary artery bypass
surgery. Tex Heart Inst J 2002;29(3):193-199.
9. Meek EN, Butterworth J, Kon ND, et al. New onset of cranial nerve palsies immediately following mitral valve
repair. Anesthesiology 1998;89:1580-1582.
10. Slavin ML, Budabin M. Pituitary apoplexy associated with cardiac surgery. Am J Ophthalmol 1984;98:291-
296.
11. Absalom M, Rogers KH, Moulton RJ, et al. Pituitary apoplexy after coronary artery surgery. Anesth Analg
1993;76:648-649.
12. Savage EB, Gugino L, Starr PA, et al. Pituitary apoplexy following cardiopulmonary bypass: considerations
for a staged cardiac and neurosurgical procedure. Eur J Cardiothorac Surg 1994;8:333-336.
13. Chen Z, Murry A, Quinian J. Pituitary apoplexy presenting as unilateral third cranial nerve palsy after coronary
artery bypass surgery. Anesth Analg 2004;98(1):46-48.
P.338
14. Oo MM, Krishna AY, Bonavita GJ, et al. Heparin therapy for myocardial infarction: an unusual trigger for
pituitary apoplexy. Am J Med Sci 1997;314:351-353.
15. Pliam M, Cohen M, Cheng L, et al. Pituitary adenomas complicating cardiac surgery: summary and review of
11 cases. J Card Surg 1995;10(2):125-132.
16. Francis F, Burger I, Poll E, et al. Can cardiac surgery cause hypopituitarism? Pituitary 2002;15(1):30-36.
17. Baylis PH. Vasopressin and its neurophysin. In: DeGroot LJ, Jameson JL, eds. Endocrinology, Vol. 1. 5th ed.
Philadelphia: Elsevier Saunders, 2006:406-420.
18. Heyndrickx GR, Boettcher DH, Vatner SF. Effects of angiotensin, vasopressin, and methoxamine on cardiac
function and blood flow distribution in conscious dogs. Am J Physiol 1976;231:1579-1587.
19. Indrambarya T, Boyd JH, Wang Y, et al. Low-dose vasopressin infusion results in increased mortality and
cardiac dysfunction following ischemia-reperfusion injury in mice. Crit Care 2009;13(3):R98.
20. Müller S, How OJ, Hermansen SE, et al. Vasopressin impairs brain, heart and kidney perfusion: an
experimental study in pigs after transient myocardial ischemia. Crit Care 2008;12:R20.
21. Dünser MW, Mayr AJ, Stallinger A, et al. Cardiac performance during vasopressin infusion in postcardiotomy
shock. Intensive Care Med 2002;28:746-751.
22. Suojaranta-Ylinen RT, Vento AE, Pätilä T, et al. Vasopressin, when added to norepinephrine, was not
associated with increased predicted mortality after cardiac surgery. Scand J Surg 2007;96:314-318.
23. Russell JA, Walley KR, Singer J, et al; VASST investigators. Vasopressin versus nor-epinephrine infusion in
patients with septic shock. N Engl J Med 2008;358:877-887.
24. Cochrane JPS, Forsling ML, Gow NM, et al. Arginine vasopressin release following surgical operations. Br J
Surg 1981;68:209-213.
25. Knight A, Forsling M, Treasure T, et al. Changes in plasma vasopressin concentration in association with
coronary artery surgery or thymectomy. Br J Anaesth 1986;58:1273-1277.
26. Izzedine H, Fardet L, Launay-Vacher V, et al. Angiotensin-converting enzyme inhibitor-induced syndrome of

inappropriate secretion of antidiuretic hormone: case report and review of the literature. Clin Pharmacol Ther
2002;71:503-507.
27. Wu W, Zbuzek VK, Bellevue C. Vasopressin release during cardiac operation. J Thorac Cardiovasc Surg
1980;79:83-90.
28. Philbin DM, Levine FH, Emerson CW, et al. Plasma vasopressin levels and urinary flow during
cardiopulmonary bypass in patients with valvular heart disease: effect of pulsatile flow. J Thorac Cardiovasc Surg
1979;78:779-783.
29. Viinamaki O, Nuutinen L, Hanhela R, et al. Plasma vasopressin levels during and after cardiopulmonary
bypass in man. Med Biol 1986;64:289-292.
30. Kaul TK, Swaminathan R, Chatrath RR, et al. Vasoactive pressure hormones during and after
cardiopulmonary bypass. Int J Artif Organs 1990;13: 293-299.
31. Landymore RW, Murphy DA, Kinley CE, et al. Does pulsatile flow influence the incidence of postoperative
hypertension? Ann Thorac Surg 1979;28:261-268.
32. Colson P, Bernard C, Struck J, et al. Post cardiac surgery vasoplegia is associated with high preoperative
copeptin plasma concentration. Crit Care 2011;15:R255.
33. Argenziano M, Chen J, Choudhri A, et al. Management of vasodilatory shock after cardiac surgery:
identification of predisposing factors and use of a novel pressor agent. J Thorac Cardiovasc Surg 1998;116:973-
980.
34. Barrett L, Singer M, Clapp L. Vasopressin: mechanisms of action on the vasculature in health and in septic
shock. Crit Care Med 2007;35(1):33-40.
35. Kuitunen A, Hynynen M, Salmenpera M, et al. Anaesthesia effects plasma concentrations of vasopressin, von
Willebrand factor and coagulation factor VIII in cardiac surgical patients. Br J Anaesth 1993;70:173-180.
36. Balasaraswathi K, Glisson SN, El-Etr AA, et al. Effect of priming volume on serum catecholamines during
cardiopulmonary bypass. Can Anaesth Soc J 1980;27:135-139.
37. Hirvonen J, Huttunen P, Nuutinen L, et al. Catecholamines and free fatty acids in plasma of patients
undergoing cardiac operations with hypothermia and bypass. J Clin Pathol 1978;31:949-955.
38. Reves JG, Karp RB, Buttner EE, et al. Neuronal and adrenomedullary catecholamine release in response to
cardiopulmonary bypass in man. Circulation 1982;66:49-55.
39. Reed HL, Chernow B, Lake CR, et al. Alterations in sympathetic nervous system activity with intraoperative
hypothermia during coronary artery bypass surgery. Chest 1989;95:616-622.
40. Zamparelli Z, De Paulis S, Martinelli L, et al. Pulsatile normothermic cardiopulmonary bypass and plasma
catecholamine levels. Perfusion 2000;15:217-223.
41. Naguib A, Tobias J, Hall M, et al. The role of different anesthetic techniques in altering the stress response
during cardiac surgery in children: a prospective, double-blinded, and randomized study. Pediatr Crit Care Med
2013;14(5):481-490.
42. Sun LS, Adams DC, Delphin E, et al. Sympathetic response during cardiopulmonary bypass: mild versus
moderate hypothermia. Crit Care Med 1997;25:1990-1993.
43. Firmin RK, Bouloux P, Allen P, et al. Sympathoadrenal function during cardiac operations in infants with the
technique of surface cooling, limited cardiopulmonary bypass, and circulatory arrest. J Thorac Cardiovasc Surg
1985;90:729-735.
44. Anand KJ, Hansen DD, Hickey PR. Hormonal-metabolic stress responses in neonates undergoing cardiac
surgery. Anesthesiology 1990;73:661-670.
45. Gruber EM, Laussen PC, Casta A, et al. Stress response in infants undergoing cardiac surgery: a randomized
study of fentanyl bolus, fentanyl infusion, and fentanyl-midazolam infusion. Anesth Analg 2001;92:882-890.
46. Samuelson PN, Reves JG, Kirklin JK, et al. Comparison of sufentanil and enflurane-nitrous oxide anesthesia
for myocardial revascularization. Anesth Analg 1986;65:217-226.
47. Ng A, Tan SSW, Lee HS, et al. Effect of propofol infusion on the endocrine response to cardiac surgery.
Anaesth Intensive Care 1995;23:543-547.
48. Winterhalter M, Brandl K, Rahe-Meyer N, et al. Endocrine stress response and inflammatory activation during
CABG surgery: a randomized trial comparing remifentanil infusion to intermittent fentanyl. Eur J Anaesthesiol
2008;25(4):326-335.
49. Stenseth R, Bjella L, Berg EM, et al. Thoracic epidural analgesia in aortocoronary bypass surgery. II. Effects
on the endocrine metabolic response. Acta Anaesthesiol Scand 1994;38:834-839.
50. Moore CM, Cross MH, Desborough JP, et al. Hormonal effects of thoracic extradural analgesia for cardiac
surgery. Br J Anaesth 1995;75:387-393.
51. Lee TW, Grocott HP, Schwinn D, et al. High spinal anesthesia for cardiac surgery: effects on beta-adrenergic
receptor function, stress response, and hemodynamics. Anesthesiology 2003;98:499-510.
52. Minami K, Körner MM, Vyska K, et al. Effects of pulsatile perfusion on plasma catecholamine levels and
hemodynamics during and after cardiac operations with cardiopulmonary bypass. J Thorac Cardiovasc Surg
1990;99:82-91.
53. Hume DM, Bell CC, Bartter F. Direct measurement of adrenal secretion during operative trauma and
convalescence. Surgery 1962;52:174-186.
54. Velissaris T, Tang AT, Murray M, et al. A prospective randomized study to evaluate stress response during
beating-heart and conventional coronary revascularization. Ann Thorac Surg 2004;78:506-512.
55. Taylor KM, Jones JV, Walker MS, et al. The cortisol response during heart-lung bypass. Circulation
1976;54:20-25.
56. Taylor KM, Wright GS, Reid JM, et al. Comparative studies of pulsatile and nonpulsatile flow during
cardiopulmonary bypass. II. The effects on adrenal secretion of cortisol. J Thorac Cardiovasc Surg 1978;75:574-
578.
57. Raff H, Norton AJ, Flemma RJ, et al. Inhibition of the adrenocorticotropin response to surgery in humans:
interaction between dexamethasone and fentanyl. J Clin Endocrinol Metab 1987;65:295-298.
58. Flezzani P, Croughwell ND, McIntyre RW, et al. Isoflurane decreases the cortisol response to
cardiopulmonary bypass. Anesth Analg 1986;65:1117-1122.
59. Lacoumenta S, Yeo TH, Paterson JL, et al. Hormonal and metabolic responses to cardiac surgery with
sufentanil-oxygen anaesthesia. Acta Anaesthesiol Scand 1987;31:258-263.
60. Hoda M, El-Achkar H, Schmitz E, et al. Systemic stress hormone response in patients undergoing open heart
surgery with or without cardiopulmonary bypass. Ann Thorac Surg 2006;82(6):2179-2186.
61. Uozumi T, Manabe H, Kawashima Y, et al. Plasma cortisol, corticosterone, and nonprotein-bound cortisol in
extra-corporeal circulation. Acta Endocrinol 1972;69:517-525.
62. Modan-Moses D, Kanety H, Dagan O, et al. Leptin and the post-operative inflammatory response—more
insights into the correlation with the clinical course and glucocorticoid administration. J Endocrinol Invest
2010;33(10):701-706.
63. Modan-Moses D, Kanety H, Dagan O, et al. Circulating leptin levels after cardiopulmonary bypass in children.
J Cardiothorac Vasc Anesth 2001;15(6):740-744.
64. Arnalich F, Lopez J, Codoceo R, et al. Relationship of plasma leptin to plasma cytokines and human survival
in sepsis and septic shock. J Infect Dis 1999;180:908-911.
65. Tinnikov AA, Legan MV, Pavlova IP, et al. Serum corticosteroid-binding globulin levels in children undergoing
heart surgery. Steroids 1993;58:536-539.
P.339
66. Taggart DP, Fraser WD, Borland WW, et al. Hypothermia and the stress response to cardiopulmonary
bypass. Eur J Cardiothorac Surg 1989;3:359-363.
67. Amado JA, Diago MC. Delayed ACTH response to human corticotropin releasing hormone during
cardiopulmonary bypass under diazepam-high dose fentanyl anaesthesia. Anaesthesia 1994;49:300-303.
68. Taylor KM, Walker MS, Rao LG, et al. Proceedings: plasma levels of cortisol, free cortisol, and corticotrophin
during cardio-pulmonary by-pass. J Endocrinol 1975;67:29P-30P.
69. Debono M, Sheppard L, Irving S, et al. Assessing adrenal status in patients before and immediately after
coronary artery bypass graft surgery. Eur J Endocrinol 2011;164:413-419.
70. Kono K, Philbin DM, Coggins CH, et al. Adrenocortical hormone levels during cardiopulmonary bypass with
and without pulsatile flow. J Thorac Cardiovasc Surg 1983;85:129-133.
71. Pollock EM, Pollock JC, Jamieson MP, et al. Adrenocortical hormone concentrations in children during
cardiopulmonary bypass with and without pulsatile flow. Br J Anaesth 1988;60:536-541.
72. Hall RI, Smith MS, Rocker G. The systemic inflammatory response to cardiopulmonary bypass:
pathophysiologic, therapeutic, and pharmacologic considerations. Anesth Analg 1997;85:66-82.
73. Guay J, Ochroch E. Steroids for surgery during cardiopulmonary bypass in adults: a meta-analysis. J Clin
Anes 2014;26:36-45.
74. Miller BE, Levy JH. The inflammatory response to cardiopulmonary bypass. J Cardiothorac Vasc Anesth
1997;11:355-366.
75. Niazi Z, Flodin P, Joyce L, et al. Effects of glucocorticosteroids in patients undergoing coronary artery bypass
surgery. Chest 1979;76:262-268.
76. Dietzman RH, Lunseth JB, Goott B, et al. The use of methylprednisolone during cardiopulmonary bypass: a
review of 427 cases. J Thorac Cardiovasc Surg 1975;69:870-873.
77. Engelman RM. Fast-track recovery in the elderly patients. Ann Thorac Surg 1997;63:606-607.
78. Weis F, Kilger E, Roozendaal B, et al. Stress doses of hydrocortisone reduce chronic stress symptoms and
improve health-related quality of life in highrisk patients after cardiac surgery: a randomized study. J Thorac
79. Weis F, Beiras-Fernandez A, Schelling G, et al. Stress doses of hydrocortisone in high-risk patients
undergoing cardiac surgery: effects on interleukin-6 to interleukin-10 ratio and early outcome. Crit Care Med
2009;37:1685-1690.
80. Nagaoka H, Innami R, Watanabe M, et al. Preservation of pancreatic beta cell function with pulsatile
81. Butterworth J, Wagenknecht LE, Legault C, et al. Attempted control of hyperglycemia during cardiopulmonary
bypass fails to improve neurologic or neurobehavioral outcomes in patients without diabetes mellitus undergoing
coronary artery bypass grafting. J Thorac Cardiovasc Surg 2005;130:1319.
82. Kuntschen FR, Galletti PM, Hahn C. Glucose-insulin interactions during cardiopulmonary bypass:
hypothermia versus normothermia. J Thorac Cardiovasc Surg 1986;91:451-459.
83. Anderson RE, Brismar K, Barr G, et al. Effects of cardiopulmonary bypass on glucose homeostasis after
coronary artery bypass surgery. Eur J Cardiothorac Surg 2005;28(3):425-430.
84. van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in critically ill patients. N Engl J
Med 2001;345:1359-1367.
85. De La Rosa Gdel C, Donado JH, Restrepo AH, et al. Strict glycaemic control in patients hospitalised in a
mixed medical and surgical intensive care unit: a randomised clinical trial. Crit Care 2008;12:R120.
86. Arabi YM, Dabbagh OC, Tamim HM, et al. Intensive versus conventional insulin therapy: a randomized
controlled trial in medical and surgical critically ill patients. Crit Care Med 2008;36:3190-3197.
87. Weiner RS, Weiner DC, Larson RJ. Benefits and risks of tight glucose control in critically ill adults: a meta-
analysis. JAMA 2008;300(8):933-944.
88. The NICE-SUGAR Study Investigators. Intensive versus conventional glucose control in critically ill patients.
N Engl J Med 2009;360:1283-1297.
89. Mark PE, Prelser JC. Toward understanding tight glycemic control in the ICU: a systematic review and
metaanalysis. Chest 2010;137(3):544-551.
90. Lazar HL, McDonnell M, Chipkin SR, et al. The society of thoracic surgeons practice guidelines series: blood
glucose management during adult cardiac surgery. Ann Thorac Surg 2009;87:663-669.
91. Qaseem A, Humphrey LL, Chou R, et al. Use of intensive insulin therapy for the management of glycemic
control in hospitalized patients: a clinical practice guideline from the American College of Physicians. Ann Intern
Med 2011;154:260-267.
92. Ridley PD, Ratcliffe JM, Alberti KG, et al. The metabolic consequences of a “washed” cardiopulmonary
bypass pump-priming fluid in children undergoing cardiac operations. J Thorac Cardiovasc Surg 1990;100: 528-
537.
93. Hosking MP, Beynen FM, Raimundo HS, et al. A comparison of washed red blood cells versus packed red
blood cells (AS-1) for cardiopulmonary bypass prime and their effects on blood glucose concentration in children.
94. Lehot JJ, Piriz H, Villard J, et al. Glucose homeostasis: comparison between hypothermic and normothermic
cardiopulmonary bypass. Chest 1992;102: 106-111.
95. Ellis DJ, Steward DJ. Fentanyl dosage is associated with reduced blood glucose in pediatric patients after
96. Anderson RE, Ehrenberg J, Barr G, et al. Effects of thoracic epidural analgesia on glucose homeostasis after
cardiac surgery in patients with and without diabetes mellitus. Eur J Anaesthesiol 2005;22:524-529.
97. Powell H, Castell LM, Parry-Billings M, et al. Growth hormone suppression and glutamine flux associated with
cardiac surgery. Clin Physiol 1994;14:569-580.
98. Desborough JP, Hall GM, Hart G, et al. Hormonal responses to cardiac surgery: effects of sufentanil,
somatostatin and ganglion block. Br J Anaesth 1990;64:688-695.
99. Pons Leite H, Gilberto Henriques Vieira J, Brunow De Carvalho W, et al. The role of insulin-like growth factor
I, growth hormone, and plasma proteins in surgical outcome of children with congenital heart disease. Pediatr Crit
Care Med 2001;2:29-35.
100. Baxter GF. The natriuretic peptides: an introduction. Basic Res Cardiol 2004;99:71-75.
101. Baxter GF. Natriuretic peptides and myocardial ischemia. Basic Res Cardiol 2004;99:90-93.
102. Ruskoaho H. Atrial natriuretic peptide: synthesis, release, and metabolism. Pharmacol Rev 1992;44:479-
602.
103. Atlas SA, Maack T. Effects of atrial natriuretic factor on the kidney and the renin-angiotensin-aldosterone
system. Endocrinol Metab Clin North Am 1987;16:107-143.
104. D’Souza SP, Davis M, Baxter GF. Autocrine and paracrine actions of natriuretic peptides in the heart.
105. Nishikimi T, Maeda N, Matsuoka H. The role of natriuretic peptides in cardioprotection. Cardiovasc Res
2006;69:318-328.
106. Dewar ML, Walsh G, Chiu RC, et al. Atrial natriuretic factor: response to cardiac operation. J Thorac
107. Ashcroft GP, Entwisle SJ, Campbell CJ, et al. Peripheral and intracardiac levels of atrial natriuretic factor
during cardiothoracic surgery. Thorac Cardiovasc Surg 1991;39:183-186.
108. Curello S, Ceconi C, De Giuli F, et al. Time course of human atrial natriuretic factor release during
cardiopulmonary bypass in mitral valve and coronary artery diseased patients. Eur J Cardiothorac Surg
1991;5:205-210.
109. Kharasch ED, Yeo KT, Kenny MA, et al. Influence of hypothermic cardiopulmonary bypass on atrial
natriuretic factor levels. Can J Anaesth 1989;36:545-553.
110. Hedner J, Towle A, Saltzman L, et al. Changes in plasma atrial natriuretic peptide-immunoreactivity in
patients undergoing coronary artery bypass graft placements. Regul Pept 1987;17:151-157.
111. Northridge DB, Jamieson MP, Jardine AG, et al. Pulmonary extraction and left atrial secretion of atrial
natriuretic factor during cardiopulmonary bypass surgery. Am Heart J 1992;123:698-703.
112. Teran N, Rodriguez Iturbe B, Parra G, et al. Atrial natriuretic peptide levels in brain venous outflow during
cardiopulmonary bypass in humans: evidence for extracardiac hormonal production. J Cardiothorac Vasc Anesth
1991;5:343-347.
113. Haug C, Bergmann KP, Hannekum A, et al. Influence of coronary artery bypass graft operation on plasma
atrial natriuretic peptide concentrations. Horm Metab Res 1993;25:399-400.
114. Pasaoglu I, Erbas B, Varoglu E, et al. Changes in the circulating endothelin and atrial natriuretic peptide
levels during coronary artery bypass surgery. Jpn Heart J 1993;34:693-706.
115. Kostopanagiotou G, Apostolakis E, Theodoraki K, et al. Perioperative changes in atrial natriuretic peptide
plasma levels associated with mitral and aortic valve replacement. J Cardiothorac Vasc Anesth 2004;18:30-33.
116. Kim K, Lee C, Kim C, et al. Effect of the Cox maze procedure on the secretion of atrial natriuretic peptide. J
P.340
117. Yoshihara F, Nishikimi T, Kosakai Y, et al. Atrial natriuretic peptide secretion and body fluid balance after
bilateral atrial appendectomy by the maze procedure. J Thorac Cardiovasc Surg 1998;116:213-219.
118. Nakamura M, Niinuma H, Chiba M, et al. Effect of the maze procedure for atrial fibrillation on atrial and brain
natriuretic peptide. Am J Cardiol 1997;79:966-970.
119. Ad N, Tian Y, Verbalis J. The effect of the maze procedure on the secretion of arginine-vasopressin and
aldosterone. J Thorac Cardiovasc Surg 2003;126:1095-1100.
120. Pfenninger J, Shaw S, Ferrari P, et al. Atrial natriuretic factor after cardiac surgery with cardiopulmonary
bypass in children. Crit Care Med 1991;19:1497-1502.
121. Schaff HV, Mashburn JP, McCarthy PM, et al. Natriuresis during and early after cardiopulmonary bypass:
relationship to atrial natriuretic factor, aldosterone, and antidiuretic hormone. J Thorac Cardiovasc Surg
1989;98:979-986.
122. Hynynen M, Palojoki R, Heinonen J, et al. Renal and vascular effects of atrial natriuretic factor during
123. Seghaye MC, Duchateau J, Bruniaux J, et al. Endogenous nitric oxide production and atrial natriuretic
peptide biological activity in infants undergoing cardiac operations. Crit Care Med 1997;25:1063-1070.
124. Hayashida N, Chihara S, Kashikie H, et al. Biological activity of endogenous atrial natriuretic peptide during
cardiopulmonary bypass. Artif Org 2000;24:833-838.
125. Voors A, Van Veldhuisen D. Cardiorenal: effects of recombinant human natriuretic peptides. J Am Col
Cardiol 2010;55(17):1852-1853.
126. Boerrigter G, Burnett J. Natriuretic peptides: renal protective after all? J Am Col Cardiol 2011;58(9):904-
906.
127. Amano J, Suzuki A, Sunamori M, et al. Attenuation of atrial natriuretic peptide response to sodium loading
after cardiac operation. J Thorac Cardiovasc Surg 1995;110:75-80.
128. Dao Q, Krishnaswamy P, Kazanegra R, et al. Utility of B-type natriuretic peptide in the diagnosis of
congestive heart failure in an urgent-care setting. J Am Coll Cardiol 2001;37:379-385.
129. Maisel AS, McCord J, Nowak RM, et al. Bedside B-type natriuretic peptide in the emergency diagnosis of
heart failure with reduced or preserved ejection fraction: results from the breathing not properly multinational
study. J Am Coll Cardiol 2003;41:2010-2017.
130. Goetze JP, Christoffersen C, Perko M, et al. Increased cardiac BNP expression associated with myocardial
ischemia. FASEB J 2003;17:1105-1107.
131. Wazni OM, Martin DO, Marrouche NF, et al. Plasma B-type natriuretic peptide levels predict postoperative
atrial fibrillation in patients undergoing cardiac surgery. Circulation 2004;110;124-127.
132. Cuthbertson BH, McKeown A, Croal BL, et al. Utility of B-type natriuretic peptide in predicting the level of
peri- and postoperative cardiovascular support required after coronary artery bypass grafting. Crit Care Med
2005;33:437-442.
133. Nozohoor S, Nilsson J, Lührs C, et al. B-type natriuretic peptide as a predictor of postoperative heart failure
after aortic valve replacement. J Cardiothorac Vasc Anesth 2009;23:161-165.
134. Attaran S, Sherwood R, Desai J, et al. Brain natriuretic peptide a predictive marker in cardiac surgery.
Interact Cardiovasc Thorac Surg 2009;9:662-666.
135. Crescenzi G, Landoni G, Bignami E, et al. N-terminal B-natriuretic peptide after coronary artery bypass graft
surgery. J Cardiothorac Vasc Anesth 2009;23:147-150.
136. Steiner J, Guglin M. BNP or NTproBNP? A clinician’s perspective. Int J Cardiol 2008;129:5-14.
137. Liu H, Wang C, Liu L, et al. Perioperative application of N-terminal probrain natriuretic peptide in patients
undergoing cardiac surgery. J Cardiothoracic Surg 2013;8:1.
138. Morimoto K, Mori T, Ishiguro S, et al. Perioperative changes in plasma brain natriuretic peptide
concentrations in patients undergoing cardiac surgery. Surg Today 1998;28:23-29.
139. Costello J, Backer CL, Checchia PA. Alterations in the natriuretic hormone system related to
cardiopulmonary bypass in infants with congestive heart failure. Pediatr Cardiol 2004;25:347-353.
140. Ootaki Y, Yamaguchi M, Yoshimura N, et al. Secretion of A-type and B-type natriuretic peptides into the
bloodstream and pericardial space in children with congenital heart disease. J Thorac Cardiovasc Surg
2003;126:1411-1416.
141. Terazawa E, Dohi S, Akamastsu S. Changes in calcitonin gene-related peptide, atrial natriuretic peptide and
brain natriuretic peptide in patients undergoing coronary artery bypass grafting. Anaesthesia 2003;58:223-232.
142. Berendes E, Schmidt C, Van Aken H. A-type and B-type natriuretic peptides in cardiac surgical procedures.
Anesth Analg 2004;98:11-19.
143. Berendes E, Schmidt C, Van Aken H. Reversible cardiac sympathectomy by high thoracic epidural
anesthesia improves regional left ventricular function in patients undergoing coronary artery bypass grafting: a
randomized trial. Arch Surg 2003;138:1283-1290.
144. Carey RM. Newly discovered components and actions of the renin-angiotensin system. Hypertension
2013;62:818-822.
145. Clarke C, Flores-Muñoz M, McKinney CA, et al. Regulation of cardiovascular remodeling by the counter-
regulatory axis of the renin-angiotensin system. Future Cardiol 2013;9:23-38.
146. Bhatia V, Bhatia R, Mathew B. Angiotensin receptor blockers in congestive heart failure: evidence,
concerns, and controversies. Cardiol Rev 2005;13:297-303.
147. Diedericks BJ, Roelofse JA, Shipton EA, et al. The renin-angiotensin-aldosterone system during and after
cardiopulmonary bypass. S Afr Med J 1983;64:946-949.
148. Weinstein GS, Zabetakis PM, Clavel A, et al. The reninangiotensin system is not responsible for
hypertension following coronary artery bypass grafting. Ann Thorac Surg 1987;43:74-77.
149. Taylor KM, Morton IJ, Brown JJ, et al. Hypertension and the reninangiotensin system following open-heart
surgery. J Thorac Cardiovasc Surg 1977;74:840-845.
150. Canivet JL, Larbuisson R, Damas P, et al. Plasma renin activity and urine β2-microglobulin during and after
cardiopulmonary bypass: pulsatile vs non-pulsatile perfusion. Eur Heart J 1990;11:1079-1082.
151. Nagaoka H, Innami R, Arai H. Effects of pulsatile cardiopulmonary bypass on the renin-angiotensin-
aldosterone system following open heart surgery. Jpn J Surg 1988;18:390-396.
152. Goto M, Kudoh K, Minami S, et al. The reninangiotensinaldosterone system and hematologic changes
during pulsatile and nonpulsatile cardiopulmonary bypass. Artif Organs 1993;17:318-322.
153. Gorin AB, Liebler J. Changes in serum angiotensin-converting enzyme during cardiopulmonary bypass in
humans. Am Rev Respir Dis 1986;134:79-84.
154. Smallridge RC, Chernow B, Snyder R, et al. Angiotensin-converting enzyme activity: a potential marker of
tissue hypothyroidism in critical illness. Arch Intern Med 1985;145:1829-1832.
155. Colson P, Grolleau D, Chaptal PA, et al. Effect of preoperative renin-angiotensin system blockade on
hypertension following coronary surgery. Chest 1988;93:1156-1158.
156. Feddersen K, Aurell M, Delin K, et al. Effects of cardiopulmonary bypass and prostacyclin on plasma
catecholamines, angiotensin II and arginine-vasopressin. Acta Anaesthesiol Scand 1985;29:224-230.
157. Townsend GE, Wynands JE, Whalley DG, et al. Role of renin-angiotensin system in cardiopulmonary
bypass hypertension. Can Anaesth Soc J 1984;31:160-165.
158. 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;3:319-325.
159. Oh YJ, Lee JH, Nam SB, et al. Effects of chronic angiotensin II receptor antagonist and angiotensin-
converting enzyme inhibitor treatments on neurohormonal levels and haemodynamics during cardiopulmonary
bypass. Br J Anaesth 2006;97:792-798.
160. Thrush DN, Austin D, Burdash N. Cardiopulmonary bypass temperature does not affect postoperative
euthyroid sick syndrome? Chest 1995;108:1541-1545.
161. Velissaris T, Tang AT, Wood PJ, et al. Thyroid function during coronary surgery with and without
cardiopulmonary bypass. Eur J Cardiothorac Surg 2009;36:148-154.
162. Polikar R, Kennedy B, Maisel A, et al. Decreased adrenergic sensitivity in patients with hypothyroidism. J
Am Coll Cardiol 1990;15:94-98.
163. Jones TH, Hunter SM, Price A, et al. Should thyroid function be assessed before cardiopulmonary bypass
operations? Ann Thorac Surg 1994;58:434-436.
164. Cerillo AG, Storti S, Kallushi E, et al. The low triiodothyronine syndrome: a strong predictor of low cardiac
output and death in patients undergoing coronary artery bypass grafting. Ann Thorac Surg 2014;97:2089-2095.
165. Bremner WF, Taylor KM, Baird S, et al. Hypothalamo-pituitary-thyroid axis function during cardiopulmonary
166. Saeed uz Zafar M, Miller JM, Breneman GM, et al. Observations on the effect of heparin on free and total
thyroxine. J Clin Endocrinol Metab 1971;32:633-640.
167. Hershman JM, Jones CM, Bailey AL. Reciprocal changes in serum thyrotropin and free thyroxine produced
by heparin. J Clin Endocrinol Metab 1972;34:574.
P.341
168. Schwartz HL, Schadlow AR, Faierman D, et al. Heparin administration appears to decrease cellular binding
of thyroxine. J Clin Endocrinol Metab 1973;36:598-600.
169. Holland FW II, Brown PS Jr, Weintraub BD, et al. Cardiopulmonary bypass and thyroid function: a “euthyroid
sick syndrome.” Ann Thorac Surg 1991;52:46-50.
170. Chu S-H, Huang T-S, Hsu R-B, et al. Thyroid hormone changes after cardiovascular surgery and clinical
implications. Ann Thorac Surg 1991;52:791-796.
171. Ririe DG, Butterworth JF, Hines M, et al. Effects of cardiopulmonary bypass and deep hypothermic
circulatory arrest on the thyroid axis during and after repair of congenital heart defects: preservation by deep
hypothermia? Anesth Analg 1998;87:543-548.
172. Lawton NF, Ellis SM, Sufi S. The triiodothyronine and thyroxine response to thyrotrophin-releasing hormone
in the assessment of the pituitary-thyroid axis. Clin Endocrinol 1973;2:57-63.
173. Reinhardt W, Mocker V, Jockenhövel F, et al. Influence of coronary artery bypass surgery on thyroid
hormone parameters. Horm Res 1997;47:1-8.
174. Zaloga GP, Chernow B, Smallridge RC, et al. A longitudinal evaluation of thyroid function in critically ill
surgical patients. Ann Surg 1985;201:456-464.
175. Robuschi G, Medici D, Fesani F, et al. Cardiopulmonary bypass: a low T4 and T3 syndrome with blunted
thyrotropin (TSH) response to thyrotropin-releasing hormone (TRH). Horm Res 1986;23:151-158.
176. Haugen BR. Drugs that suppress TSH or cause central hypothyroidism. Best Pract Res Clin Endocrinol
Metab 2009;23:793-800.
177. Bettendorf M, Schmidt KG, Tiefenbacher U, et al. Transient secondary hypothyroidism in children after
cardiac surgery. Pediatr Res 1997;41:375-379.
178. Murzi B, Iervasi G, Masini S, et al. Thyroid hormones homeostasis in pediatric patients during and after
179. Mainwaring RD, Lamberti JJ, Billman GF, et al. Suppression of the pituitary thyroid axis after
cardiopulmonary bypass in the neonate. Ann Thorac Surg 1994;58:1078-1082.
180. Saatvedt K, Lindberg H. Depressed thyroid function following paediatric cardiopulmonary bypass:
association with interleukin-6 release? Scand J Thorac Cardiovasc Surg 1996;30:61-64.
181. Taylor KM, Wright GS, Bain WH, et al. Comparative studies of pulsatile and nonpulsatile flow during
cardiopulmonary bypass. III. Response of anterior pituitary gland to thyrotropin-releasing hormone. J Thorac
182. Buket S, Alayunt A, Ozbaran M, et al. Effect of pulsatile flow during cardiopulmonary bypass on thyroid
hormone metabolism. Ann Thorac Surg 1994;58:93-96.
183. Mullur R, Liu Y, Brent GA. Thyroid hormone regulation of metabolism. Physiol Rev 2014;94:355-382.
184. Bilezikian JP, Loeb JN. The influence of hyperthyroidism and hypothyroidism on α- and β-adrenergic
receptor systems and adrenergic responsiveness. Endocrinol Rev 1983;4:378-388.
185. Ririe DG, Butterworth JF 4th, Royster RL, et al. Triiodothyronine increases contractility independent of beta-
adrenergic receptors or stimulation of cyclic-3’,5’-adenosine monophosphate. Anesthesiology 1995;82:1004-
1012.
186. Novitzky D, Human PA, Cooper DK. Inotropic effect of triiodothyronine following myocardial ischemia and
cardiopulmonary bypass: an experimental study in pigs. Ann Thorac Surg 1988;45:50-55.
187. Novitzky D, Human PA, Cooper DK. Effects of triiodothyronine (T3) on myocardial high energy phosphates
and lactate after ischemia and cardiopulmonary bypass: an experimental study in baboons. J Thorac Cardiovasc
Surg 1988;96:600-607.
188. Novitzky D, Cooper DK, Barton CI, et al. Triiodothyronine as an inotropic agent after open heart surgery. J
189. Bennett-Guerrero E, Jimenez JL, White WD, et al. Cardiovascular effects of intravenous triiodothyronine in
patients undergoing coronary artery bypass graft surgery: a randomized, double-blind, placebo-controlled trial—
Duke T3 Study Group. JAMA 1996;275:687-692.
190. Klemperer JD, Klein I, Gomez M, et al. Thyroid hormone treatment after coronary-artery bypass surgery. N
Engl J Med 1995;333:1522-1527.
191. Bettendorf M, Schmidt KG, Grulich-Henn J, et al. Tri-iodothyronine treatment in children after cardiac
surgery: a double-blind, randomised, placebo-controlled study. Lancet 2000;356:529-534.
192. Marwali EM, Boom CE, Sakidjan I, et al. Oral triiodothyronine normalizes triiodothyronine levels after surgery
for pediatric congenital heart disease. Pediatr Crit Care Med 2013;14:701-708.
193. Smyth EM, Grosser T, FitzGerald GA. Lipid-derived autacoids: eicosanoids and platelet-activating factor. In:
Brunton LL, Chabner BA, Knollmann BC, eds. Goodman & Gilman’s the pharmacological basis of therapeutics.
12th ed. New York: McGraw-Hill, 2011. http://accessanesthesiology.mhmedical.com/content.aspx?
bookid=374&Sectionid=41266241. Accessed June 13, 2014.
194. Butterworth J. Hypothyroidism. In: Roizen MF, Fleisher LA, eds. Essence of anesthesia practice. 3rd ed.
Philadelphia: W.B. Saunders Company, 2011:209.
195. Ylikorkala O, Saarela E, Viinikka L. Increased prostacyclin and thromboxane production in man during
196. Fleming WH, Sarafian LB, Leuschen MP, et al. Serum concentrations of prostacyclin and thromboxane in
children before, during, and after cardiopulmonary bypass. J Thorac Cardiovasc Surg 1986;92:73-78.
197. Faymonville ME, Deby-Dupont G, Larbuisson R, et al. Prostaglandin E2, prostacyclin, and thromboxane
changes during nonpulsatile cardiopulmonary bypass in humans. J Thorac Cardiovasc Surg 1986;91:858-866.
198. Greeley WJ, Bushman GA, Kong DL, et al. Effects of cardiopulmonary bypass on eicosanoid metabolism
during pediatric cardiovascular surgery. J Thorac Cardiovasc Surg 1988;95:842-849.
199. Nagaoka H, Innami R, Murayama F, et al. Effects of aprotinin on prostaglandin metabolism and platelet
function in open heart surgery. J Cardiovasc Surg 1991;32:31-37.
200. Ulus AT, Aksoyek A, Ozkan M, et al. Cardiopulmonary bypass as a cause of free radical-induced oxidative
stress and enhanced blood-borne isoprostanes in humans. Free Radic Biol Med 2003;34:911-917.
201. Watkins WD, Peterson MB, Kong DL, et al. Thromboxane and prostacyclin changes during cardiopulmonary
bypass with and without pulsatile flow. J Thorac Cardiovasc Surg 1982;84:250-256.
202. Feng J, Liu YH, et al. Impaired contractile response of human peripheral arterioles to thromboxane A-2 after
cardiopulmonary bypass. Surgery 2011;150:263-271.
203. Leuschen MP, Ehrenfried JA, Willett LD, et al. Prostaglandin F1 alpha levels during and after neonatal
extracorporeal membrane oxygenation. J Thorac Cardiovasc Surg 1991;101:148-152.
204. Lavee J, Naveh N, Dinbar I, et al. Prostacyclin and prostaglandin E2 mediate reduction of increased mean
arterial pressure during cardiopulmonary bypass by aspiration of shed pulmonary venous blood. J Thorac
205. de Prost N, El-Karak C, Avila M, et al. Changes in cysteinyl leukotrienes during and after cardiac surgery
with cardiopulmonary bypass in patients with and without chronic obstructive pulmonary disease. J Thorac
206. Larsen BM, Field CJ, Leong AY, et al. Pretreatment with an intravenous lipid emulsion increases plasma
eicosapentanoic acid and downregulates leukotriene B4, procalcitonin, and lymphocyte concentrations after open
heart surgery in infants. J Parenter Enteral Nutr 2015;39(2):171-179.
207. Skidgel RA, Kaplan AP, Erdös EG. Histamine, bradykinin, and their antagonists. In: Brunton LL, Chabner
BA, Knollmann BC, eds. Goodman & Gilman’s the pharmacological basis of therapeutics. 12th ed. New York:
McGraw-Hill, 2011. http://accessmedicine.mhmedical.com/content.aspx?bookid=374&Sectionid= 41266240.
Accessed June 13, 2014.
208. Man WK, Branna JJ, Fessatidis I, et al. Effect of prostacyclin on the circulatory histamine during
cardiopulmonary bypass. Agents Actions 1986;18:182-185.
209. Marath A, Man W Taylor KM. Histamine release in paediatric cardiopulmonary bypass—a possible role in
the capillary leak syndrome. Agents Actions 1987;20:299-302.
210. Withington DE, Elliot M, Man WK. Histamine release during paediatric cardiopulmonary bypass. Agents
Actions 1991;33:200-202.
211. Wojtecka-Lukasik E, Karolczak MA, Maslinska D, et al. Histamine and oxygen radicals of blood in the course
of cardiopulmonary bypass (CPB). Inflamm Res 2006;55(Suppl 1):S75-S76.
212. van Overveld FJ, De Jongh RF, Jorens PG, et al. Pretreatment with methylprednisolone in coronary artery
bypass grafting influences the levels of histamine and tryptase in serum but not in bronchoalveolar lavage fluid.
Clin Sci 1994;86:49-53.
213. Johnston WE, Moss J, Philbin DM, et al. Management of cold urticaria during hypothermic cardiopulmonary
bypass. N Engl J Med 1982;306:219-221.
214. Fayaz KM, Pugh S, Balachandran S, et al. Histamine release during adult cardiopulmonary bypass.
Anaesthesia 2005;60:1179-1184.
215. Eisner DA, Kashimura T, O’Neill SC, et al. What role does modulation of the ryanodine receptor play in
cardiac inotropy and arrhythmogenesis? J Mol Cell Cardiol 2009;46:474-481.
216. Zaloga GP. Hypocalcemia in critically ill patients. Crit Care Med 1992;20:251-262.
P.342
217. Moffitt EA, Tarhan S, Goldsmith RS, et al. Patterns of total and ionized calcium and other electrolytes in
plasma during and after cardiac surgery. J Thorac Cardiovasc Surg 1973;65:751-757.
218. Gray R, Braunstein G, Krutzik S, et al. Calcium homeostasis during coronary bypass surgery. Circulation
1980;62:I57-I61.
219. Auffant RA, Downs JB, Amick R. Ionized calcium concentration and cardiovascular function after
cardiopulmonary bypass. Arch Surg 1976;116:1072-1076.
220. Hysing ES, Kofstad J, Lilleaasen P, et al. Ionized calcium in plasma during cardiopulmonary bypass. Scand
J Clin Lab Invest 1986;184:119-123.
221. Chambers DJ, Dunham J, Braimbridge MV, et al. The effect of ionized calcium, pH, and temperature on
bioactive parathyroid hormone during and after open-heart operations. Ann Thorac Surg 1983;36:306-313.
222. Heining MPD, Linton RAF, Band DM. Plasma ionized calcium during openheart surgery. Anaesthesia
1985;40:237-241.
223. Robertie PG, Butterworth JF IV, Royster RL, et al. Normal parathyroid hormone responses to hypocalcemia
during cardiopulmonary bypass. Anesthesiology 1991;75:43-48.
224. Robertie PG, Butterworth JF IV, Prielipp RC, et al. Parathyroid hormone responses to marked hypocalcemia
in infants and young children undergoing repair of congenital heart disease. J Am Coll Cardiol 1992;20:672-677.
225. Conlin PR, Fajtova VT, Mortensen RM, et al. Hysteresis in the relationship between serum ionized calcium
and intact parathyroid hormone during recovery from induced hyper- and hypocalcemia in normal humans. J Clin
Endocrinol Metab 1989;69:593-599.
226. Zaloga GP, Butterworth JF IV. Hypovitaminosis D in hospitalized patients: a marker of frailty or a disease
requiring treatment? Anesth Analg 2014;119(3):613-618.
227. Yokoyama H, Julian JS, Vinten-Johansen J, et al. Postischemic [Ca2+] repletion improves cardiac
performance without altering oxygen demands. Ann Thorac Surg 1990;49:894-902.
228. Castillo CF del, Harringer W, Warshaw AL. Risk factors for pancreatic cellular injury after cardiopulmonary
bypass. N Engl J Med 1991;325:382-387.
229. Zaloga GP, Strickland RA, Butterworth JF IV, et al. Calcium attenuates epinephrine’s beta-adrenergic effects
in postoperative heart surgery patients. Circulation 1990;81:196-200.
230. Butterworth JF IV, Strickland RA, Mark LJ, et al. Calcium does not augment phenylephrine’s hypertensive
effects. Crit Care Med 1990;18:603-606.
231. Royster RL, Butterworth JF IV, Prielipp RC, et al. A randomized, blinded, placebo-controlled evaluation of
calcium chloride and epinephrine for inotropic support after emergence from cardiopulmonary bypass. Anesth
Analg 1992;74:3-13.
232. Butterworth JF IV, Zaloga GP, Prielipp RC, et al. Calcium inhibits the cardiac stimulating properties of
dobutamine but not amrinone. Chest 1992;101:174-180.
233. Johnston WE, Robertie PG, Butterworth JF IV, et al. Is calcium or ephedrine superior to placebo for
emergence from cardiopulmonary bypass? J Cardiothorac Vasc Anesth 1992;6:528-534.
234. Abernethy WB, Butterworth JF IV, Prielipp RC, et al. Calcium entry attenuates adenylyl cyclase activity: a
possible mechanism for calcium-induced catecholamine resistance. Chest 1995;107:1420-1425.
235. Prielipp RC, Butterworth J. Con: calcium is not routinely indicated during separation from cardiopulmonary
bypass. J Cardiothorac Vasc Anesth 1997;11:908-912.
236. DiNardo JA. Pro: calcium is routinely indicated during separation from cardiopulmonary bypass. J
237. Zaloga GP, Roberts JE. Magnesium disorders. Probl Crit Care Endocr Emerg 1990;4:425-436.
238. Zaloga GP, Wilkens R, Tourville J, et al. A simple method for determining physiologically active calcium and
magnesium concentrations in critically ill patients. Crit Care Med 1987;15:813-816.
239. Turnier E, Osborn JJ, Gerbode F, et al. Magnesium and open-heart surgery. J Thorac Cardiovasc Surg
1972;64:694-705.
240. Scheinman MM, Sullivan RW, Hyatt KH. Magnesium metabolism in patients undergoing cardiopulmonary
bypass. Circulation 1969;39:I235-I241.
241. Aglio LS, Stanford GG, Maddi R, et al. Hypomagnesemia is common following cardiac surgery. J
242. Lum G, Marquardt C, Khuri SF. Hypomagnesemia and low alkaline phosphatase activity in patients’ serum
after cardiac surgery. Clin Chem 1989;35:664-667.
243. Harris MN, Crowther A, Jupp RA, et al. Magnesium and coronary revascularization. Br J Anaesth
1988;60:779-783.
244. Prielipp RC, Zaloga GP, Butterworth JF IV, et al. Magnesium inhibits the hypertensive but not the cardiotonic
actions of low-dose epinephrine. Anesthesiology 1991;74:973-979.
245. Friedman HS, Nguyen TN, Mokraoui AM, et al. Effects of magnesium chloride on cardiovascular
hemodynamics in the neutrally intact dog. J Pharmacol Exp Ther 1987;243:126-130.
246. Prielipp RC, Butterworth JV IV, Roberts PR, et al. Magnesium antagonizes the actions of lysophosphatidyl
choline (LPC) in myocardial cells: a possible mechanism for its antiarrhythmic effects. Anesth Analg 1995;80:
1083-1087.
247. Abraham AS, Rosenmann D, Kramer M, et al. Magnesium in the prevention of lethal arrhythmias in acute
myocardial infarction. Arch Intern Med 1987;147:753-755.
248. Rasmussen HS, Suenson M, McNair P, et al. Magnesium infusion reduces the incidence of arrhythmias in
acute myocardial infarction: a double-blind placebo-controlled study. Clin Cardiol 1987;10:351-356.
249. Rasmussen HS, McNair P, Norregard P, et al. Intravenous magnesium in acute myocardial infarction. Lancet
1986;1:234-236.
250. Woods KL, Fletcher S, Roffe C, et al. Intravenous magnesium sulphate in suspected myocardial infarction:
results of the second Leicester intravenous magnesium intervention trial (LIMIT-2). Lancet 1992;339:1553-1558.
251. Horner SM. Efficacy of intravenous magnesium in acute myocardial infarction in reducing arrhythmias and
mortality: meta-analysis of magnesium in acute myocardial infarction. Circulation 1992;86:774-779.
252. Gu WJ, Wu ZJ, Wang PF, et al. Intravenous magnesium prevents atrial fibrillation after coronary artery
bypass grafting: a meta-analysis of 7 double-blind, placebo-controlled, randomized clinical trials. Trials
2012;13:41.
253. Cook RC, Yamashita MH, Kearns M, et al. Prophylactic magnesium does not prevent atrial fibrillation after
cardiac surgery: a meta-analysis. Ann Thorac Surg 2013;95:533-541.
254. Arsenault KA, Yusuf AM, Crystal E, et al. Interventions for preventing post-operative atrial fibrillation in
patients undergoing heart surgery. Cochrane Database Syst Rev 2013;1:CD003611.
255. Garfinkel L, Garfinkel D. Magnesium regulation of the glycolytic pathway and the enzymes involved.
Magnesium 1985;4:60-72.
256. Altura BM, Altura BT. Magnesium, electrolyte transport and coronary vascular tone. Drugs 1984;28:120-142.
257. Altura BM, Turlapaty PD. Withdraw of magnesium enhances coronary arterial spasms produced by
vasoactive agents. Br J Pharmacol 1982;77:649-659.
258. Walesby RK, Goode AW, Bentall HH. Nutritional status of patients undergoing valve replacement by open
heart surgery. Lancet 1978;1:76-77.
259. Morgan DB, Mearns AJ, Burkinshaw L. The potassium status of patients prior to open-heart surgery. J
260. Ebert PA, Jude JR, Gaertner RA. Persistent hypokalemia following open-heart surgery. Circulation
1965;31:I137-I143.
261. Bert AA, Stearns GT, Feng W, et al. Normothermic cardiopulmonary bypass. J Cardiothorac Vasc Anesth
1997;11:91-99.
262. Patrick J, Sivpragasam S. The prediction of postoperative potassium excretion after cardiopulmonary
bypass. J Thorac Cardiovasc Surg 1977;73: 559-562.
263. Cohn LH, Angell WW, Shumway NE. Body fluid shifts after cardiopulmonary bypass. I. Effects of congestive
heart failure and hemodilution. J Thorac Cardiovasc Surg 1971;62:423-430.
264. Johnston AE, Radde IC, Nisbet HI, et al. Effects of altering calcium in haemodiluted pump primes on sodium
and potassium in children undergoing open-heart operations. Can Anaesth Soc J 1972;19:517-528.
265. Taggart P, Slater JD. Some effects of bypass surgery on myocardial and skeletal muscle electrolytes and
their clinical importance. Br Heart J 1969;31:393.
266. Lim M, Linton RA, Band DM. Rise in plasma potassium during rewarming in open-heart surgery [letter].
Lancet 1983;1:241-242.
267. Dobson GP, Faggian G, Onorati F, et al. Hyperkalemic cardioplegia for adult and pediatric surgery: end of
an era? Front Physiol 2013;4:228.
268. Bethune DW, McKay R. Paradoxical changes in serum-potassium during cardiopulmonary bypass in
association with non-cardioselective beta blockade [letter]. Lancet 1978;2:380.
269. Manning SH, Angaran DM, Arom KV, et al. Intermittent intravenous potassium therapy in cardiopulmonary
bypass patients. Clin Pharmacol 1982;1:234-238.
270. Schwartz AJ, Conahan TJ III, Jobes DR, et al. Peripheral vascular response to potassium administration
during cardiopulmonary bypass. J Thorac Cardiovasc Surg 1980;79:237-240.
P.343
271. Blackburn GL. Metabolic considerations in management of surgical patients. Surg Clin North Am
2011;91:467-480.
272. Al-Bader A, Christenson JT, Simonet F, et al. Inflammatory response and oligo-element alterations following
cardiopulmonary bypass in patients undergoing coronary artery bypass grafting. Cardiovasc Surg 1998;6:406-
414.
273. Fuhrer G, Heller W, Hoffmeister HE, et al. Levels of trace elements during and after cardiopulmonary bypass
operations. Acta Pharmacol Toxicol 1986;59:352-357.
274. Zhao L. Changes in blood zinc and copper and their clinical significance in patients undergoing open-heart
surgery. Chung Hua I Hsueh Tsa Chih 1989;69:76-78.
275. Sjogren A, Luhrs C, Abdulla M. Changed distribution of zinc and copper in body fluids in patients undergoing
open-heart surgery. Acta Pharmacol Toxicol 1986;59:348-351.
276. Taggart DP, Fraser WD, Shenkin A, et al. The effects of intraoperative hypothermia and cardiopulmonary
bypass on trace metals and their protein binding ratios. Eur J Cardiothorac Surg 1990;4:587-594.
277. Menasche P, Pasquier C, Bellucci S, et al. Deferoxamine reduces neutrophil-mediated free radical
production during cardiopulmonary bypass in man. J Thorac Cardiovasc Surg 1988;96:582-589.
278. Mitchell IM, Brady L, Black J, et al. The acute phase response to cardiopulmonary bypass in children.
Perfusion 1996;11:103-112.
Chapter 12
Cardiopulmonary Bypass and the Lung
David Kiamanesh
Alan Gaffney
Robert N. Sladen
INTRODUCTION
Cardiopulmonary bypass (CPB) consistently induces a wide range of acute lung injury, from mild to massive.
Post-CPB pulmonary management is compounded by multiple factors that may compromise function, including
atelectasis, pleural disruption, impaired lung compliance, capillary leak from an acute inflammatory response,
and even fulminant acute respiratory distress syndrome (ARDS). To the patient who enters cardiac surgery with
already limited pulmonary reserve, CPB represents a particular challenge. This chapter addresses the current
state of knowledge of pulmonary function in the setting of CPB, and outlines therapeutic approaches to the
management of the lungs during CPB.
CPB-INDUCED ATELECTASIS
Pathophysiology of Atelectasis
Anesthesia and Neuromuscular Blockade
Atelectasis is common after cardiac surgery and general anesthesia, and several mechanisms have been
proposed to explain this phenomenon (1). After the induction of general anesthesia with neuromuscular
blockade, mechanical ventilation initiates atelectasis within 5 minutes (2). The relaxed diaphragm is displaced
cephalad by the abdominal contents. This increases pleural pressures and compresses adjacent lung tissue
(3,4), and gas flow is preferentially distributed to the nondependent regions of the lung. This promotes
ventilation-perfusion mismatch, hypoventilation, and progressive microatelectasis of the dependent lung zones.
Without interruption by the intermittent “sighs” that occur in the awake patient, the monotonous mechanical
ventilatory pattern during anesthesia allows the extension of atelectasis from alveoli to segments, lobules, and
even lobes of the lung.
Resorption atelectasis is induced when capillary uptake of oxygen exceeds the rate of alveolar oxygen influx (5).
Resorption may also occur in lung zones that have low ventilation/perfusion ( ) ratios; the uptake of oxygen
increases significantly as the fraction of inspired oxygen (FIO2) increases (3).
The proximate cause of pulmonary atelectasis during CPB is cessation of ventilation and lung collapse. There is
some evidence that this may contribute to pulmonary dysfunction postoperatively (6,7). Resumption of ventilation
prior to weaning from CPB is seldom fully successful in lung reexpansion. Following CPB, the patient is left with
a variable degree of residual atelectasis, from microscopic to lobar in magnitude.
Surfactant Depletion
Pulmonary surfactant covers the alveolar surface and lowers surface tension to prevent alveolar and small-
airway collapse. There is laboratory evidence that exposure to anesthesia impairs surfactant function and
increases the permeability of the alveolar capillary barrier (8,9). Alterations in surfactant composition and function
after CPB have been reported, but clinically significant changes in surfactant function have not been studied at
length (10,11). Because of an extensive surfactant reserve and long turnover time, the role of surfactant
depletion in the setting of CPB is unclear. Atelectasis itself promotes the production of proinflammatory
cytokines, which decrease the synthesis of surfactant (12).
Anatomic Considerations
During CPB, the heart rests on the immobile left lower lobe. With blind bronchial suctioning, the catheter usually
enters the more direct right main stem bronchus, resulting in preferential right bronchial drainage. Traumatic
mucosal “pitting” induced by the suction catheter at the carina causes secretions to dam up and promotes airway
collapse (13). When the pleural cavity is opened, blood and fluid can enter and compress the adjacent lung. In
patients who undergo coronary revascularization, dissection of the left internal mammary artery mandates entry
into the left pleural space. Together, these factors account for the 60% to 70% incidence of left lower lobe
atelectasis after CPB (14).
The right lung can be compressed during cannulation of the inferior vena cava. The supine position is
associated with a decrease in functional residual capacity (FRC) as abdominal contents push the diaphragm
cephalad and promote small-airway closure. Significant atelectasis has been observed in the dorsal lung regions
in patients after cardiac surgery (15).
P.346
High Inspired Oxygen Concentration
High inspired concentrations of oxygen (FIO2) during the perioperative period promote atelectasis (16,17,18).
When the alveolar-arterial oxygen concentration gradient (AaDO2) increases, the capillaries rapidly absorb
oxygen, resulting in alveolar atelectasis. The degree of atelectasis varies at different oxygen concentrations, and
it is most notable when the FIO2 is >0.8 (19,20).
Low Tidal Volume Mechanical Ventilation

The use of low tidal volumes as a component of a protective lung strategy is now the standard of care in the
setting of ARDS (21). Although this protects against alveolar stretch-induced injury (volutrauma), it also promotes
atelectasis (atelectrauma). Pressure controlled ventilation (PCV) is a ventilator mode that limits peak airway
pressures in order to decrease the risk of pulmonary barotrauma. However, if lung compliance is very poor, PCV
may result in delivery of small tidal volumes that promote the development of atelectasis.
Comorbid Conditions
In heavy smokers with chronic bronchitis, the ciliated columnar epithelium undergoes metaplasia to mucin-
producing goblet cells (22). Anterograde cilial clearance of mucus and debris is impaired, surfactant production is
diminished, and small airways and alveoli tend to collapse.
Obesity causes a reduction in FRC and predisposes to atelectasis before and after CPB (23). An increase in
extravascular lung water, whether due to congestive heart failure or pulmonary edema, increases the tendency
for small airways to collapse (24).
Clinical Consequences of Atelectasis

It is common for the FRC to be decreased by as much as 20% for up to a week after general anesthesia. CPB-
induced atelectasis causes more severe disruption of the broncho-alveolar tree and as a consequence FRC is
decreased by as much as 40% to 50% (25). This causes a substantial impairment of lung compliance and
promotes a pulmonary inflammatory response that contributes to postoperative pulmonary complications
(26,27,28).
Impaired Oxygenation
The AaDo2 consistently increases after CPB (29,30,31,32,33). It increases to a maximum about 48 hours
postoperatively, does not return to normal for at least 7 days, and is detectable for weeks after surgery (34).
However, the increase in AaDO2 is similar between patients undergoing on-pump or off-pump coronary artery
bypass grafting, suggesting that etiology is the surgical procedure itself, rather than CPB (35,36).
Intrapulmonary shunt (Qs/Qt) and veno-arterial admixture are consistently increased after CPB, but there is a
poor correlation between increases in Qs/Qt and decreases in measured FRC (37,38). When airways collapse,
Qs/ Qt is worsened, secretion clearance is compromised, and the risk of pulmonary infection and pneumonia is
increased. In animal models, induced alveolar collapse results in regional areas of hypoxemia that may reflexly
increase pulmonary vascular resistance to the extent that right ventricular dysfunction develops (39).
Decreased Lung Compliance

The decline in lung compliance induced by atelectasis increases the work of breathing required for alveolar
distention. A decrease in the expiratory reserve volume and FRC promotes further collapse because there is a
lower volume remaining in the lung at the end of a normal tidal ventilation. As a consequence, the inspiratory and
expiratory components of the breath duty cycle occur within a less efficient portion of the pressure-volume curve
(40,41). If severe enough, this can lead to a substantial increase in energy consumption and acute ventilatory
failure, with continued requirement for mechanical ventilation.
Acute Lung Injury

The repetitive opening of collapsing alveoli leads to surfactant inactivation and atelectrauma, and has been
implicated in the development of ventilator-induced lung injury (VILI). When alveoli are stretched by excessively
large tidal volumes, inflammatory mediators and neutrophils are activated, leading to increased alveolar capillary
permeability and hyaline membrane formation. Atelectrauma may be prevented or attenuated by a protective lung
strategy that limits tidal volumes to curtail inspiratory alveolar stretch and adds positive end-expiratory pressure
(PEEP) to prevent expiratory alveolar collapse (21).
Prevention and Treatment of Perioperative Atelectasis

Strategies to prevent and treat atelectasis in patients undergoing CPB have focused on recruitment maneuvers
and efforts to prevent de-recruitment of alveoli. The resultant modifications in mechanical ventilation may
improve gas exchange, increase FRC, and prevent atelectasis-induced lung injury.
Continuous Positive Airway Pressure Ventilation

Static inflation of the lungs by continuous positive airway pressure (CPAP) during CPB has attracted
considerable interest as a means of preventing CPB-induced atelectasis, with initial studies demonstrating
benefit. One demonstrated that application of CPAP at 10 cmH2O during CPB improved postoperative arterial
oxygen tension (PaO2), decreased AaDO2, and Qs/Qt for up to 4 hours after CPB and at the time of tracheal
extubation (42), a response attenuated at lower levels of CPAP (43). It was suggested that the lung expansion
induced by CPAP might preserve pulmonary mechanics by preservation of bronchial perfusion (44). Furthermore,
it was considered that static inflation of the lungs with oxygen might prevent ultrastructural damage by sustaining
cellular oxidative metabolism (45). In small animal studies, CPAP during CPB is associated with lower pulmonary
lactate/pyruvate ratios and greater high-energy phosphate concentrations compared with
P.347
passive lung collapse (46). Several studies have demonstrated a decrease in inflammatory markers (47,48,49).
However, these findings have not been correlated with sustained postoperative benefit. A meta-analysis of eight
studies published between 1990 and 2008 that included 460 patients reviewed the impact of CPAP, low-volume
mechanical ventilation, and vital capacity maneuvers on arterial oxygenation, oxygenation index, AaDo2, and
Qs/Qt (50). Although these maneuvers significantly improved these oxygenation parameters immediately after
separation from CPB, the benefits were short-lived and had no apparent impact on clinical outcomes.
Recruitment Maneuvers
There is considerable evidence that sustained inspiratory recruitment maneuvers on CPB may inflate collapsed
alveoli, and improve arterial oxygenation and lung compliance (3,6,51,52). However, peak inspiratory pressures
of up to 40 cmH2O may be required. Although identical “Valsalva” maneuvers are routinely used after open-heart
procedures to expel air from the left atrium and ventricle, there is a risk of disruption of the internal mammary
graft by excessive distension of the left lung, or rupture of a bleb or weakened lung area. “Sighs” provided after
separation from CPB can impede venous return and add to hemodynamic instability.
The “Open Lung” Concept

The recruitment maneuver has been extrapolated to the socalled open-lung concept, which requires an initial
period of PCV with high airway pressures (40 cmH2O) with inverted inspiratory:expiratory (I:E) ratio from 1:2 to
1:1. This is followed by a protective lung strategy with low tidal volumes and PEEP to minimize atelectrauma.
Application of the open-lung concept to cardiac surgery has minimized post-CPB atelectasis, improved FRC, and
decreased the incidence of postoperative hypoxemia (53). Moreover, when the open-lung concept is commenced
immediately after anesthetic induction and tracheal intubation, the inflammatory response to CPB is attenuated,
with decreased levels of the proinflammatory interleukins IL-8 and IL-10 (54).
CPB AND PULMONARY MECHANICS

There is considerable evidence that CPB has a deleterious effect on pulmonary mechanics (31,55,56,57,58,59),
but it may be difficult to distinguish these from those induced by thoracotomy, pleural resection, and pleural
effusions. Decreases in vital capacity, FRC, lung compliance, and pulmonary function have been shown to
persist for more than 3 months after surgery (60,61,62,63), although in several studies the alterations have been
considered to have a negligible clinical impact (64,65,66).
To resolve the question of the role of CPB versus cardiac surgery itself on pulmonary mechanics, trials have
compared on-pump and off-pump coronary artery bypass surgery. In one prospective randomized trial of 197
cardiac surgery patients, OPCAB surgery was associated with improved oxygenation and decreased time to
tracheal extubation. However, there were no differences in chest radiographs, spirometry, and incidence of
pneumonia, pleural effusion, pulmonary edema, or mortality between groups (67). Although these beneficial
effects have been confirmed by some (36,68), others have found no difference in pulmonary mechanics or
oxygenation (69,70). In fact, a smaller randomized study of 35 patients paradoxically found a worse pulmonary
shunt in patients after OPCAB surgery despite a partial attenuation of the inflammatory response (71). Benefits
have been observed by the avoidance of CPB in patients with chronic obstructive pulmonary disease, in whom
OPCAB or minimally invasive approaches are associated with decreased atelectasis, duration of tracheal
intubation, and intensive care unit length of stay (72).
Airway resistance is consistently increased by CPB, and is more pronounced than in patients undergoing
OPCAB surgery (73). There have been a number of reports of fulminant bronchospasm during CPB
(74,75,76,77). It is most likely related to contact activation with an idiosyncratic excess activation of human C’5a
anaphylatoxin, although other causes of such bronchospasm, for example acute non-cardiogenic pulmonary
edema (“cardiac asthma”), must not be overlooked. (78).
Operative technique and graft selection can also alter pulmonary mechanics. Dissection of the internal mammary
artery with violation of the anterior chest wall and pleural cavity decreases FRC and forced expiratory volume in
1 second (FEV1) to a greater extent than when saphenous vein grafts are used alone (79,80). Lung retraction
and pleurotomy, rather than CPB itself, are major architects of disturbed lung mechanics during cardiac surgery
(31,55).
CPB-INDUCED ACUTE LUNG INJURY

Pathophysiology of Acute Lung Injury
Acute lung injury with fulminant noncardiogenic pulmonary edema is a rare but life-threatening complication of
CPB (81,82,83,84,85). After the advent of CPB in the 1950s, a substantial proportion of deaths following cardiac
surgery occurred consequent to a syndrome of acute respiratory failure referred to as “pump lung.” Its
morphology is identical to that of ARDS associated with other inflammatory syndromes such as sepsis (86).
There is diffuse lung injury and swelling of endothelial cells and pneumocytes, with an uneven distribution of
surfactant (87). Broncho-alveolar lavage (BAL) after CPB demonstrates an increase in IL-8 levels and neutrophil
percentage (88).
Noncardiogenic pulmonary edema results from increased permeability of the alveolar capillary membrane,
creating a capillary leak syndrome with exudation of water and protein into the alveolar space. It is distinguished
from cardiogenic pulmonary edema by the finding of normal or low left atrial or pulmonary artery wedge
pressures, and a high protein concentration in the edema fluid (albumin concentration ≥90%
P.348
of serum albumin). In its most dramatic form, it is heralded by a massive outpouring of frothy, proteinaceous fluid
from the tracheal tube. Fluid loss may culminate in intravascular volume depletion and hypovolemic shock, with
death resulting from low cardiac output syndrome rather than hypoxemia (83). Thus, even in patients with diffuse
pulmonary edema and severe hypoxemia, aggressive restoration of intravascular volume is mandatory, guided
by close monitoring of left ventricular filling pressure.
The Role of CPB in Acute Lung Injury

It was initially assumed that acute lung injury during CPB is triggered by embolism of particulate debris into the
pulmonary microcirculation. This in turn evokes an inflammatory response mediated by complement activation,
neutrophil migration, cytokine production, and arachidonic acid metabolites. However, it soon became apparent
that “pump lung” occurs even when all the perfusate is filtered, suggesting a role for etiologies in addition to or
instead of microembolism. For example, the incidence of postoperative respiratory complications is not
significantly different in OPCAB surgery (70,89). The lung inflammatory response may be as much an
epiphenomenon of surgery on the heart, and its incidence may be related to operator technique. Other factors
also contribute. For example, high FIO2 in the early postoperative period increases cytokine levels and augments
the proinflammatory response of alveolar macrophages (90).
Contact Activation and the Inflammatory Cascade

Complement activation and the potential for pulmonary dysfunction appear to be a consistent response to
contact activation of blood in extracorporeal circuits, such as leukophoresis and hemodialysis (91,92). Contact
activation has not been demonstrated in OPCAB surgery (93).
Contact activation of the blood by the extracorporeal circuit triggers a series of amplification cascades mediated
by proteolytic enzymes, particularly serine proteases. It is initiated by the activation of the circulating
procoagulant, factor XII (Hageman factor), which triggers the intrinsic pathway of coagulation, fibrinolysis, and
complement (C’3a and C’5a) activation via the classical and alternate pathways. C’5a has spasmogenic and
leukocyte-activating properties (78). When C’3a, the central component of the system, is cleaved, the fragments
that result are called anaphylatoxins. These induce smooth muscle contraction and function as a major
chemotactic factor for neutrophils. They trigger the release of arachidonic acid metabolites such as leukotriene
B4, which increases vascular permeability and provokes mast cell degranulation, and induce the formation of
neutrophil adhesion molecules. Higher expression of adhesion molecules after CPB is seen in patients with
diabetes and may increase the risk of postoperative complications (94).
The incidence and severity of postoperative organ dysfunction correlates with plasma complement
concentrations, duration of CPB, and the degree of elevation of C’3a levels (95). Complement-exposed
neutrophils become “sticky”, adhere to surfaces, aggregate, and may block the microcirculation by margination
and leukoembolization. The neutrophils degranulate and release highly reactive oxygen free radicals and
proteolytic enzymes, which damage endothelial cells. The net effect is a dramatic increase in vascular
permeability and capillary leak syndrome.
Neutrophil Activation
Neutrophils are activated during CPB by complement, shear stress, and contact with the CPB circuit
(96,97,98,99). Levels of neutrophil elastase, a measure of neutrophil activation, peak at the end of CPB and are
associated with increased intrapulmonary shunt and postoperative pulmonary dysfunction (100). BAL
demonstrates that neutrophil count, IL-8, and elastase concentration correlate with decreased arterial
oxygenation after CPB (101,102). The central role of neutrophil activation is supported by the action of the
neutrophil elastase inhibitor, sivelestat, which decreases the inflammatory response, and in some studies,
improves pulmonary dysfunction in patients undergoing CPB (102,103,104).
Activated neutrophils migrate to areas of inflammation and ischemia, where they release proteolytic enzymes and
cytotoxins causing direct lung damage and increased capillary permeability (1,100,105,106). CPB also increases
the production of neutrophil matrix metalloproteinase (MMP), and MMP-9 degrades basement membranes.
There is increased expression of neutrophil intracellular adhesion molecule-1 (ICAM-1) on pulmonary
endothelium, which promotes sequestration of neutrophils and is linked with the development of pulmonary
insufficiency after CPB (107).
Cytokines
The CPB-induced inflammatory cascade induces leukocytes to release a variety of cytokines, including tumor
necrosis factor-a (TNF-a), IL-6, and IL-8. These exacerbate the inflammatory response by upregulating
neutrophil adhesion molecules and promoting the accumulation of parenchymal neutrophils (107). In a
prospective observational study, an increased plasma level of IL-6 after CPB was predictive for postoperative
pulmonary infection (108).
The lung itself may play a role in the response to CPB and development of acute lung injury (109). This is
suggested by the finding of a greater inflammatory response (i.e., proinflammatory cytokine levels) in alveolar
macrophages in the lungs than in plasma monocytes in the systemic circulation. There may also be a genetic
predisposition to acute lung injury. Some functional polymorphisms are associated with increased levels of TNF-
a, which may serve as a marker for an enhanced inflammatory response after CPB (109), while polymorphisms
of IL-6 (110) and IL-18 (111) have been shown to predispose patients to the development of acute lung injury
following CPB.
P.349
Arachidonic Acid Metabolites and Thromboxane
The role of vasoactive arachidonic acid metabolites such as thromboxanes, leukotrienes, prostaglandins, and
prostacyclins in acute lung injury is unclear (112). Thromboxane, a pulmonary vasoconstrictor, is released from
platelets activated by the extracorporeal circuit. The finding of greater thromboxane B2 levels in the left than right
atrium at the end of CPB suggests that thromboxane is being produced in the lungs, perhaps in ischemic
pulmonary tissue or intravascular hematologic components (113). A disturbed balance between pro- and anti-
inflammatory arachidonic acid metabolites may play a role in pulmonary injury. Inhibition of thromboxane
synthetase decreases CPB-induced lung injury in sheep (114), and patients who continued the use of aspirin
preoperatively had lower thromboxane levels, owing to aspirin’s antiplatelet effects, as well as improved
postoperative oxygenation (115). In patients with severe lung injury after CPB, levels of thromboxane B2
concentrations are increased relative to those of prostaglandin E2.
Disordered Lung Metabolism

The lung is the only organ that receives blood from the entire circulation and plays an important role in the
production of angiotensin II, prostacyclin, and endothelin I. Pulmonary endothelin I is a powerful vasoconstrictor
released during lung endothelial injury and is implicated in the development of pulmonary hypertension after CPB
(116,117). Increased pulmonary artery pressures after CPB may result from the reduction of nitric oxide
production from pulmonary endothelial dysfunction (118,119,120). The lung also inactivates bradykinin,
serotonin, leukotrienes, and norepinephrine. Bradykinin is a potent vasodilator that is rapidly metabolized and
inactivated by pulmonary vascular endothelium. During CPB, serum levels of bradykinin are increased (121).
Early resumption of blood flow to the lungs may facilitate weaning from CPB in patients whose hypotension is a
result of a bradykinin-induced decrease in systemic vascular resistance (SVR) (86).
In contrast, it has been hypothesized that systemic hypertension after CPB is caused by depressed clearance of
neurohumoral substances, particularly norepinephrine, by the damaged lung (122). There is experimental
evidence that diminution of the lung’s ability to remove circulating norepinephrine and prostaglandin E2 is directly
related to the duration of CPB (123). Pulmonary extraction of serotonin following CPB is also decreased and may
also play a role in postoperative pulmonary complications (124).
Prevention and Treatment of CPB-Induced Acute Lung Injury

Modification of the Extracorporeal Circuit
Numerous attempts have been made to attenuate the inflammatory response to CPB by modification of the
extracorporeal circuit itself. Heparin-coated CPB circuits improve biocompatibility and limit neutrophil activation
and its attendant release of complement activated mediators, cytokines, and proinflammatory enzymes such as
secretory phospholipase A2 (125,126,127,128,129). Their use is associated with improvements in post-CPB
indices such as pulmonary vascular resistance, lung compliance, shunt fraction, and oxygenation, but has not
been correlated with an improved clinical outcome (125,126,127,128,129). Multiple other coating materials for
the CPB circuit have been studied as well, including phosphorylcholine (130,131,132,133,134) and synthetic
polymers, such as poly-2-methoxyethylacrylate (PMEA) (132,133,135,136). These demonstrate similar
biocompatibility to heparin coating, with some decrease in inflammatory markers but similar clinical outcomes.
Membrane oxygenators avoid the potential damage to blood components and plasma proteins caused by direct
gas contact in bubble oxygenators. However, a randomized study of the two devices on 500 patients found that
although use of the membrane oxygenator decreased extravascular lung water, there were no demonstrable
differences in intrapulmonary shunting, duration of ventilation, ICU stay, or mortality (137,138).
Hemofiltration
High-volume continuous hemofiltration is a means of removing fluid and low-molecular-weight molecules from
plasma under a pressure gradient. Its application during CPB could attenuate the inflammatory response by
filtering substances that cause acute lung injury (139). Hemofiltration removes endothelin I, a pulmonary
vasoconstrictor, and may thereby decrease the severity of postoperative pulmonary hypertension (139,140,141).
Improvements in postoperative oxygenation and duration of mechanical ventilation have been observed with this
technique (141,142), although it appears to be more effective in pediatric than in adult patients (143). A
randomized prospective trial on 192 adult cardiac surgery patients demonstrated that hemofiltration during CPB
is more effective than placebo or steroids in decreasing the time to tracheal extubation (144).
Leukocyte Depletion
As elucidated above, leukocytes play an intrinsic role in the inflammatory response to CPB, suggesting that
leukocyte filtration could attenuate pulmonary injury. Although several studies show a benefit on pulmonary
function by leukocyte depletion on CPB (112,145,146,147,148), this has not been a consistent finding (149,150).
In a study of routine coronary artery bypass graft (CABG) surgery, total leukocyte filtration during CPB resulted in
a transient postoperative decrease in white blood cell count, but this was not correlated with improvements in
pulmonary function, respiratory index, or ICU length of stay (151). A smaller study showed some improvement in
pulmonary function and decrease in some inflammatory markers, but the benefits were transient (152).
Protective Lung Ventilation

Excessively large tidal volumes on mechanical ventilation that result in repetitive distension and collapse of
alveoli induce atelectrauma and VILI. As described in the section on atelectasis, early application of the open-
lung concept appears to
P.350
decrease interleukin concentrations after CPB and could attenuate the inflammatory response and acute lung
injury (54).
Although the use of protective ventilation with low tidal volumes (6 mL/kg) has shown benefit in patients with
established ARDS, the role of minimal alveolar distention to prevent CPB-induced acute lung injury remains
unclear. A study comparing conventional tidal volumes with protective tidal volumes did not decrease systemic
cytokine levels, postoperative pulmonary dysfunction, or hospital length of stay (26). In a similar study design,
some benefit was demonstrated in that while there was no difference in the time to tracheal extubation, the low
tidal volume group had more ventilator-free patients at 6 hours after CPB, and a decreased requirement for
tracheal reintubation (153).
Once ARDS has become established, maintenance of oxygenation requires high levels of airway pressure
therapy (154,155). This is provided by volume controlled ventilation with extrinsic PEEP (PEEPe), or PCV with
inverse I: E ratio and intrinsic or auto-PEEP (PEEPi). With either approach, the goals are to support the FRC,
decrease Qs/ Qt, and wean a high FIO2.
Steroids
Under experimental conditions, administration of steroids consistently attenuates the inflammatory response to
CPB. Benefits include decreased concentrations of proinflammatory cytokines, neutrophil activation, endothelial
adhesion molecule upregulation, and complement activation (156,157,158,159).
Unfortunately, the clinical benefits of perioperative steroid administration remain unproven. In fact, there is some
evidence that the perioperative administration of methylprednisolone actually worsens oxygenation and
increases the duration of required mechanical ventilation after cardiac surgery (144,160). There are numerous
explanations for these adverse effects, one of which is steroid-induced sodium retention, increased lung water
retention, and intrapulmonary shunt (161).
A Cochrane review on the use of prophylactic corticosteroids in cardiac surgery patients showed no benefit in
mortality, cardiac and pulmonary complications, although there was no evidence of adverse effects (162).
Another meta-analysis confirmed that steroids do not cause harm, but also provide no benefit with regard to
duration of postoperative mechanical ventilation (163).
Aprotinin
Aprotinin is a serine protease inhibitor that is administered during high-risk cardiac surgery with CPB to decrease
perioperative bleeding caused by fibrinolysis and platelet dysfunction (164). It also attenuates the inflammatory
response to CPB that is triggered by contact activation.
Experimental studies demonstrate that its administration decreases IL-8 levels, lung neutrophil accumulation,
release of TNF-α and neutrophil elastase, and upregulation of neutrophil adhesion molecules (165,166). This
translates into decreased lung edema and improved lung compliance and oxygenation after CPB (167,168,169).
Following a large randomized study that suggested that aprotinin administration was associated with an
increased incidence of renal failure, stroke (170), and mortality compared with the lysine analogs, transaxemic
acid and aminocaproic acid (171,172), Food and Drug Administration (FDA) approval in the United States was
withdrawn. On the basis of further evaluation, it has been reapproved for use in the European Union and
Canada.
Inhaled Nitric Oxide

Endogenous nitric oxide production is decreased after CPB, most likely due to pulmonary endothelial dysfunction
that results in diminished substrate or cofactor activity (88,173). Because endothelial nitric oxide maintains tonic
vasodilation of the pulmonary vasculature, a decrease in endogenous nitric oxide potentiates pulmonary
vasoconstriction after CPB (118,119,120).
Inhaled nitric oxide provides potent selective vasodilation of the pulmonary vasculature because the molecule is
instantaneously bound and inactivated by all heme compounds before it can access the systemic circulation. As
such, it is commonly used to decrease elevated pulmonary vascular resistance after CPB. It also has anti-
inflammatory properties, decreases levels of IL-8 and thereby attenuates neutrophil adhesion and
transendothelial migration, as well as apoptotic changes in the lungs during CPB
(88,118,174,175,176,177,178,179,180,181,182).
Prostaglandins
There is evidence that vasodilator prostaglandins such as PGE1 may be more anti-inflammatory than
corticosteroids during CPB, with greater inhibition of intravascular pulmonary leukocyte aggregation, activation,
and free-radical production (183). PGE1 increases cyclic adenosine monophosphate (AMP) formation, which
stabilizes leukocyte lysosomes. During CPB, infusions of PGE1, prostacyclin, and Iloprost (a more stable
prostacyclin analog) prevent platelet aggregation and thromboxane release and decrease operative bleeding
(184,185). However, these agents are more slowly inactivated than inhaled nitric oxide; so there is increased risk
of inducing systemic hypotension. In dogs, PGI2, a known platelet inhibitor, prevented the formation of occlusive
fibrin, leukocyte, and platelet-based aggregates in pulmonary arterioles, without significant systemic hypotension
(186). However, these experimental findings have yet to be translated into a proven benefit on clinical outcome.
Exogenous Surfactant
Pharmacologic preparations containing surfactant have been used clinically in the treatment of hyaline
membrane disease in premature infants. However, both experimental and clinical studies with exogenously
administered surfactant during CPB have demonstrated no benefit to pulmonary function, and in fact resulted in
deleterious effects on gas transfer (187,188).
P.351
ACKNOWLEDGMENTS
The authors acknowledge and appreciate the contributions to previous editions of this chapter by David
Berkowitz, MD, Jonathan Oster, MD, and Vivek Moitra, MD.
KEY Points
Cardiopulmonary bypass predisposes to the development of atelectasis for a variety of reasons such as:
There is a high frequency of such co-morbidities as obesity and smoking among patients requiring
cardiac surgery, both of which strongly favor development of postoperative atelectasis.
The procedures generally require the use of general anesthesia with tracheal intubation and muscle
relaxation.
Cessation of ventilation during bypass, pulmonary compression during the procedure, the use of high
FIO2 and low-tidal-volume ventilation all support the development of atelectasis.
Postoperative atelectasis has significant clinical consequences.
Pulmonary FRC predictably decreases by 40% to 50% after CPB and may not return to normal for a
week.
A parallel increase in AaDO2 also occurs, peaking at about 48 hours postoperatively and persisting for a
week.
There is an associated increase in Qs/Qt and a decrease of pulmonary compliance, which hampers
clearance of secretions and increases the work of breathing.
Separating the intrinsic adverse effects of CPB on lung function from the effects of the surgical procedure
with pleurotomy and lung manipulation is not clear.
A number of influences of CPB may predispose to acute lung injury.
The histopathology of acute lung injury after cardiac surgery and CPB is very similar to that seen in other
largely inflammatory conditions such as sepsis.
Contact activation of the inflammatory cascade occurs from blood contact with the foreign surface of the
CPB circuit.
As a result, complement activation occurs with elaboration of the C’ system, especially C’3d.
This activation results in an increase of circulating proinflammatory cytokines and leukocytes,
especially neutrophils, in the lung.
Both “pump time” and C’3d concentrations correlate with postoperative organ (including lung)
dysfunction.
Lung metabolism is altered by CPB. Arachidonic acid metabolism is shifted toward thromboxane
derivatives, which are potent pulmonary vasoconstrictors and may predispose to lung injury. Drugs
that inhibit cyclooxygenase such as aspirin appear to protect from lung injury.
Steroids offer no proven protection from CPB-related lung injury in terms of either mortality or cardiac
or pulmonary complications.
Lung-protective ventilation strategies do not consistently improve post-CPB lung function or indicators
of acute lung injury.
Inhaled nitric oxide has strong selective pulmonary vasodilatory and anti-inflammatory effects and is
useful to combat increased pulmonary vascular resistance after CPB, especially in the setting of
depressed right ventricular function.
REFERENCES
1. Ng CS, Wan S, Yim AP, et al. Pulmonary dysfunction after cardiac surgery. Chest 2002;121:1269-1277.
2. Brismar B, Hedenstierna G, Lundquist H, et al. Pulmonary densities during anesthesia with muscular
relaxation—a proposal of atelectasis. Anesthesiology 1985;62:422-428.
3. Duggan M, Kavanagh BP. Pulmonary atelectasis: a pathogenic perioperative entity. Anesthesiology

2005;102:838-854.
4. Tusman G, Bohm SH. Prevention and reversal of lung collapse during the intra-operative period. Clin
Anaesth 2010;24:183-197.
5. Hedenstierna G, Rothen HU. Respiratory function during anesthesia: effects on gas exchange. Compr
Physiol 2012;2:69-96.
6. Magnusson L, Zemgulis V, Tenling A, et al. Use of a vital capacity maneuver to prevent atelectasis after
cardiopulmonary bypass: an experimental study. Anesthesiology 1998;88:134-142.
7. Carvalho EM, Gabriel EA, Salerno TA. Pulmonary protection during cardiac surgery: a systematic literature
review. Asian Cardiovasc Thorac Ann 2008;16:503-507.
8. Wollmer P, Schairer W, Bos JA, et al. Pulmonary clearance of 99mTc-DTPA during halothane
anaesthesia. Acta Anaesthesiol Scand 1990;34:572-575.
9. Woo SW, Berlin D, Hedley-Whyte J. Surfactant function and anesthetic agents. J Appl Physiol
1969;26:571-577.
10. Friedrich B, Schmidt R, Reiss I, et al. Changes in biochemical and biophysical surfactant properties with
cardiopulmonary bypass in children. Crit Care Med 2003;31:284-290.
11. Griese M, Wilnhammer C, Jansen S, et al. Cardiopulmonary bypass reduces pulmonary surfactant
activity in infants. J Thorac Cardiovasc Surg 1999;118:237-244.
12. Pryhuber GS, Bachurski C, Hirsch R, et al. Tumor necrosis factor-alpha decreases surfactant protein B
mRNA in murine lung. Am J Physiol 1996;270:L714-L721.
13. Lindholm CE, Ollman B, Snyder J, et al. Flexible fiberoptic bronchoscopy in critical care medicine.
Diagnosis, therapy and complications. Crit Care Med 1974;2:250-261.
14. Sladen R, Jenkins L. Intermittent mandatory ventilation and controlled mechanical ventilation without
positive end-expiratory pressure following cardio-pulmonary bypass. Can Anaesth Soc J 1978;25:166-172.
15. Tenling A, Hachenberg T, Tyden H, et al. Atelectasis and gas exchange after cardiac surgery.
P.352
16. Benumof JL. Preoxygenation: best method for both efficacy and efficiency. Anesthesiology 1999;91:603-
605.
17. Reber A, Engberg G, Wegenius G, et al. Lung aeration. The effect of pre-oxygenation and
hyperoxygenation during total intravenous anaesthesia. Anaesthesia 1996;51:733-737.
18. Rothen HU, Sporre B, Engberg G, et al. Prevention of atelectasis during general anaesthesia. Lancet
1995;345:1387-1391.
19. Edmark L, Kostova-Aherdan K, Enlund M, et al. Optimal oxygen concentration during induction of general
anesthesia. Anesthesiology 2003;98: 28-33.
20. Edmark L, Auner U, Enlund M, et al. Oxygen concentration and characteristics of progressive atelectasis
formation during anaesthesia. Acta Anaesth Scand 2011;55:75-81.
21. 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;342:1301-1308.
22. Kim V, Criner GJ. Chronic bronchitis and chronic obstructive pulmonary disease. Am J Respir Crit Care
Med 2013;187:228-237.
23. Jones RL, Nzekwu MM. The effects of body mass index on lung volumes. Chest 2006;130:827-833.
24. Santiago VR, Rzezinski AF, Nardelli LM, et al. Recruitment maneuver in experimental acute lung injury:
the role of alveolar collapse and edema. Crit Care Med 2010;38:2207-2214.
25. Nicholson DJ, Kowalski SE, Hamilton GA, et al. Postoperative pulmonary function in coronary artery
bypass graft surgery patients undergoing early tracheal extubation: a comparison between short-term
mechanical ventilation and early extubation. J Cardiothorac Vasc Anesth 2002;16:27-31.
26. Koner O, Celebi S, Balci H, et al. Effects of protective and conventional mechanical ventilation on
pulmonary function and systemic cytokine release after cardiopulmonary bypass. Intensive Care Med
2004;30:620-626.
27. Magnusson L, Zemgulis V, Wicky S, et al. Atelectasis is a major cause of hypoxemia and shunt after
cardiopulmonary bypass: an experimental study. Anesthesiology 1997;87:1153-1163.
28. Kotani N, Hashimoto H, Sessler DI, et al. Cardiopulmonary bypass produces greater pulmonary than
systemic proinflammatory cytokines. Anesth Analg 2000;90:1039-1045.
29. Barat G, De Villota E, Avello F, et al. Study of the oxygenation of cardiac patients submitted to
extracorporeal circulation. Br J Anaesth 1972;44:817-825.
30. Geha H, Seesler H, Kirkin J. Alveolar-arterial oxygen gradients after open intracardiac surgery. J Thorac
31. Ghia J, Andersen N. Pulmonary function and cardiopulmonary bypass. JAMA 1970;212:593-597.
32. Hedley-Whyte J, Corning H, Lauer M, et al. Pulmonary ventilation-perfusion relations after heart valve
replacement or repair in man. J Clin Invest 1965;44:406-416
33. Osborn J, Popper R, Keith W, et al. Respiratory insufficiency following open heart surgery. Ann Surg
1962;156:638-647
34. Turnbull KW, Miyagishima RT, Gerein AN. Pulmonary complications and cardiopulmonary bypass. A
clinical study in adults. Can Anaesth Soc J 1974;21:181-194.
35. Cox CM, Ascione R, Cohen AM, et al. Effect of cardiopulmonary bypass on pulmonary gas exchange: a
prospective randomized study. Ann Thorac Surg 2000;69:140-145.
36. Kochamba GS, Yun KL, Pfeffer TA, et al. Pulmonary abnormalities after coronary arterial bypass grafting
operation: cardiopulmonary bypass versus mechanical stabilization. Ann Thorac Surg 2000;69:1466-1470.
37. Downs J, Mitchell L. Pulmonary effects of ventilatory pattern following cardiopulmonary bypass. Crit Care
Med 1976;4:295-300.
38. Mandelbaum I, Giammona S. Extracorporeal circulation, pulmonary compliance and pulmonary

surfactant. J Thorac Cardiovasc Surg 1964;48:881-889.
39. Duggan M, McCaul CL, McNamara PJ, et al. Atelectasis causes vascular leak and lethal right ventricular
failure in uninjured rat lungs. Am J Respir Crit Care Med 2003;167:1633-1640.
40. Bendixen HH, Hedley-Whyte J, Laver MB. Impaired oxygenation in surgical patients during general
anesthesia with controlled ventilation. a concept of atelectasis. N Engl J Med 1963;269:991-996.
41. Marshall BE, Wyche MQ Jr. Hypoxemia during and after anesthesia. Anesthesiology 1972;37:178-209.
42. Loeckinger A, Kleinsasser A, Lindner KH, et al. Continuous positive airway pressure at 10 cmH2O during
cardiopulmonary bypass improves postoperative gas exchange. Anesth Analg 2000;91:522-527.
43. Berry CB, Butler PJ, Myles PS. Lung management during cardiopulmonary bypass: is continuous positive
airways pressure beneficial? Br J Anaesth 1993;71:864-868.
44. Cogliati AA, Menichetti A, Tritapepe L, et al. Effects of three techniques of lung management on
pulmonary function during cardiopulmonary bypass. Acta Anaesthesiol Belg 1996;47:73-80.
45. Weedn R, Coalson J, Greenfield L. Effects of oxygenation and ventilation on pulmonary mechanics and
ultrastructure during cardiopulmonary bypass. Am J Surg 1970;120:584-590.
46. Hewson J, Shaw M. Continuous airway pressure with oxygen minimizes the metabolic lesion of “pump
lung”. Can Anaesth Soc J 1983;30:37-47.
47. Beer L, Szerafin T, Mitterbauer A, et al. Continued mechanical ventilation during coronary artery bypass
graft operation attenuates the systemic immune response. Eur J Cardiothorac Surg 2013;44:282-287.
48. Imura H, Caputo M, Lim K, et al. Pulmonary injury after cardiopulmonary bypass: beneficial effects of low-
frequency mechanical ventilation. J Thorac Cardiovasc Surg 2009;137:1530-1537.
49. Ng CS, Arifi AA, Wan S, et al. Ventilation during cardiopulmonary bypass: impact on cytokine response
and cardiopulmonary function. Ann Thorac Surg 2008;85:154-162.
50. Schreiber JU, Lance MD, de Korte M, et al. The effect of different lung-protective strategies in patients
during cardiopulmonary bypass: a meta-analysis and semiquantitative review of randomized trials. J
51. Nunn JF, Bergman NA, Coleman AJ. Factors influencing the arterial oxygen tension during anaesthesia
with artificial ventilation. Br J Anaesth 1965;37:898-914.
52. Tusman G, Bohm SH, Vazquez de Anda GF, et al. ‘Alveolar recruitment strategy’ improves arterial
oxygenation during general anaesthesia. Br J Anaesth 1999;82:8-13.
53. Reis Miranda D, Struijs A, Koetsier P, et al. Open lung ventilation improves functional residual capacity
after extubation in cardiac surgery. Crit Care Med 2005;33:2253-2258.
54. Reis Miranda D, Gommers D, Struijs A, et al. Ventilation according to the open lung concept attenuates
pulmonary inflammatory response in cardiac surgery. Eur J Cardiothorac Surg 2005;28:889-895.
55. Andersen N, Ghia J. Pulmonary function, cardiac status, and postoperative course in relation to
56. Garzon AA, Seltzer B, Karlson KE. Respiratory mechanics following open-heart surgery for acquired
valvular disease. Circulation 1966;33(4): 57-64.
57. Garzon A, Seltzer B, Lichtenstein S, et al. Influence of open-heart surgery on respiratory work. Dis Chest
1967;52:392-396.
58. Lesage A, Tsuchioka H, Young W, et al. Pathogenesis of pulmonary damage during extracorporeal
circulation. Arch Surg 1966;93:1002-1008.
59. Shimizu T, Lewis F. An experimental study of pulmonary function following cardiopulmonary bypass. J
60. Braun SR, Birnbaum ML, Chopra PS. Pre- and postoperative pulmonary function abnormalities in
coronary artery revascularization surgery. Chest 1978;73:316-320.
61. Locke TJ, Griffiths TL, Mould H, et al. Rib cage mechanics after median sternotomy. Thorax
1990;45:465-468.
62. Matte P, Jacquet L, Van Dyck M, et al. Effects of conventional physiotherapy, continuous positive airway
pressure and non-invasive ventilatory support with bilevel positive airway pressure after coronary artery
bypass grafting. Acta Anaesthesiol Scand 2000;44:75-81.
63. Shenkman Z, Shir Y, Weiss YG, et al. The effects of cardiac surgery on early and late pulmonary
functions. Acta Anaesthesiol Scand 1997;41:1193-1199.
64. Deal C, Osborn J, Miller CJ, et al. Pulmonary compliance in congenital heart disease and its relation to
65. Karlson K, Saklad M, Paliotta J, et al. Computerized on-line analysis of pulmonary mechanics in patients
undergoing cardiopulmonary bypass. Bull Soc Int Chir 1975;2:121-124.
66. Sullivan S, Patterson R, Malm J, et al. Effect of heart-lung bypass on the mechanics of breathing in man.
J Thorac Cardiovasc Surg 1966;51: 205-212.
P.353
67. Staton GW, Williams WH, Mahoney EM, et al. Pulmonary outcomes of offpump vs on-pump coronary
artery bypass surgery in a randomized trial. Chest 2005;127:892-901.
68. Tschernko EM, Bambazek A, Wisser W, et al. Intrapulmonary shunt after cardiopulmonary bypass: the
use of vital capacity maneuvers versus off-pump coronary artery bypass grafting. J Thorac Cardiovasc Surg
2002;124:732-738.
69. Cimen S, Ozkul V, Ketenci B, et al. Daily comparison of respiratory functions between on-pump and off-
pump patients undergoing CABG. Eur J Cardiothorac Surg 2003;23:589-594.
70. Groeneveld AB, Jansen EK, Verheij J. Mechanisms of pulmonary dysfunction after on-pump and off-
pump cardiac surgery: a prospective cohort study. J Cardiothorac Surg 2007;2:11.
71. Rasmussen BS, Laugesen H, Sollid J, et al. Oxygenation and release of inflammatory mediators after off-
pump compared with after on-pump coronary artery bypass surgery. Acta Anaesthesiol Scand
2007;51:1202-1210.
72. Guler M, Kirali K, Toker ME, et al. Different CABG methods in patients with chronic obstructive
pulmonary disease. Ann Thorac Surg 2001;71:152-157.
73. Babik B, Asztalos T, Petak F, et al. Changes in respiratory mechanics during cardiac surgery. Anesth
Analg 2003;96:1280-1287.
74. Casella ES, Humphrey LS. Bronchospasm after cardiopulmonary bypass in a heart-lung transplant
recipient. Anesthesiology 1988;69:135-138.
75. Durant P, Joucken K. Bronchospasm and hypotension during cardiopulmonary bypass after preoperative
cimetidine and labetolol therapy. Br J Anaesth 1984;56:917-920.
76. Kyosola K, Takkunen O, Maamies T, et al. Brochospasm during cardiopulmonary bypass: a potentially
fatal complication of open-heart surgery. J Thorac Cardiovasc Surg 1987;35:375-377.
77. Tuman KJ, Ivankovich AD. Bronchospasm during cardiopulmonary bypass. Etiology and management.
Chest 1986;90:635-637.
78. Chenoweth DE. The properties of human C5a anaphylatoxin. The significance of C5a formation during
hemodialysis. Contrib Nephrol 1987;59:51-71.
79. Goyal V, Pinto RJ, Mukherjee K, et al. Alteration in pulmonary mechanics after coronary artery bypass
surgery: comparison using internal mammary artery and saphenous vein grafts. Indian Heart J 1994;46:345-
348.
80. Vargas FS, Cukier A, Terra-Filho M, et al. Relationship between pleural changes after myocardial
revascularization and pulmonary mechanics. Chest 1992;102:1333-1336.
81. Culliford A, Thomas S, Spencer F. Fulminating noncardiogenic pulmonary edema. J Thorac Cardiovasc
Surg 1980;80:868-875.
82. Fowler A, Baird M, Eberle D, et al. Attack rates and mortality of the adult respiratory distress syndrome in
patients with known predispositions. Am Rev Respir Dis 1983;125:77.
83. Hashim S, Kay H, Hammond G, et al. Noncardiogenic pulmonary edema after cardiopulmonary bypass:
an anaphylactic reaction to fresh frozen plasma. Am J Surg 1984;147:560-564.
84. Llamas R, Forthman H. Respiratory distress in the adult after cardiopulmonary bypass. A successful
therapeutic approach. JAMA 1973;225:1183-1186.
85. Olinger G, Becker R, Bonchek L. Noncardiogenic pulmonary edema and peripheral vascular collapse
following cardiopulmonary bypass. Rare protamine reaction? Ann Thorac Surg 1980;29:20-25.
86. Conti VR, McQuitty C. Vasodilation and cardiopulmonary bypass: the role of bradykinin and the
pulmonary vascular endothelium. Chest 2001;120:1759-1761.
87. Wasowicz M, Sobezynski P, Biczysko W, et al. Ultrastructural changes in the lung alveoli after cardiac
surgical operations with the use of cardiopulmonary bypass (CPB). Pol J Pathol 1999;50:189-196.
88. El Kebir D, Hubert B, Taha R, et al. Effects of inhaled nitric oxide on inflammation and apoptosis after
89. Celik SK, Cevik A, Buket S, et al. Case 3—2004: acute multisystem organ failure in the immediate
postoperative period after routine CABG surgery. J Cardiothorac Vasc Anesth 2004;18:366-374.
90. Kotani N, Hashimoto H, Sessler DI, et al. Supplemental intraoperative oxygen augments antimicrobial and
proinflammatory responses of alveolar macrophages. Anesthesiology 2000;93:15-25.
91. Craddock PR, Fehr J, Brigham KL, et al. Complement and leukocyte-mediated pulmonary dysfunction in
hemodialysis. N Engl J Med 1977;296(14):769-774.
92. Fountain S, Martin B, Musclow E, et al. Pulmonary leukostatis and its relationship to pulmonary
dysfunction in sheep and rabbits. Circ Res 1980;46:175-180.
93. Hoel TN, Videm V, Mollnes TE, et al. Off-pump cardiac surgery abolishes complement activation.
Perfusion 2007;22:251-256.
94. Chello M, Mastroroberto P, Cirillo F, et al. Neutrophil-endothelial cells modulation in diabetic patients
undergoing coronary artery bypass grafting. Eur J Cardiothorac Surg 1998;14:373-379.
95. Chenoweth DE, Cooper SW, Hugli TE, et al. Complement activation during cardiopulmonary bypass:
evidence for generation of C3a and C5a anaphylotoxins. N Engl J Med 1981;304:497-502.
96. Dreyer WJ, Smith CW, Entman ML. Reply to: neutrophil activation during cardiopulmonary bypass (J
Thorac Cardiovasc Surg 1992;104:1746-1748). J Thorac Cardiovasc Surg 1993;105:763.
97. Gu YJ, Boonstra PW, Graaff R, et al. Pressure drop, shear stress, and activation of leukocytes during
cardiopulmonary bypass: a comparison between hollow fiber and flat sheet membrane oxygenators. Artif
Organs 2000;24:43-48.
98. Tanita T, Song C, Kubo H, et al. Superoxide anion mediates pulmonary vascular permeability caused by
neutrophils in cardiopulmonary bypass. Surg Today 1999;29:755-761.
99. Wachtfogel YT, Kucich U, Greenplate J, et al. Human neutrophil degranulation during extracorporeal
circulation. Blood 1987;69:324-330.
100. Tonz M, Mihaljevic T, von Segesser LK, et al. Acute lung injury during cardiopulmonary bypass. Are the
neutraphils responsible? Chest 1995;108:1151-1156.
101. Kotani N, Hashimoto H, Sessler DI, et al. Neutrophil number and interleukin-8 and elastase
concentrations in bronchoalveolar lavage fluid correlate with decreased arterial oxygenation after
102. Fujii M, Miyagi Y, Bessho R, et al. Effect of a neutrophil elastase inhibitor on acute lung injury after
cardiopulmonary bypass. Interact Cardiovasc Thorac Surg 2010;10:859-862.
103. Ryugo M, Sawa Y, Takano H, et al. Effect of a polymorphonuclear elastase inhibitor (sivelestat sodium)
on acute lung injury after cardiopulmonary bypass: findings of a double-blind randomized study. Surg Today
2006;36:321-326.
104. Kohira S, Oka N, Inoue N, et al. Effect of the neutrophil elastase inhibitor sivelestat on perioperative
inflammatory response after pediatric heart surgery with cardiopulmonary bypass: a prospective randomized
study. Artif Organs 2013;37:1027-1033.
105. Carney DE, Lutz CJ, Picone AL, et al. Matrix metalloproteinase inhibitor prevents acute lung injury after
cardiopulmonary bypass. Circulation 1999;100:400-406.
106. Diegeler A, Doll N, Rauch T, et al. Humoral immune response during coronary artery bypass grafting: a
comparison of limited approach, “offpump” technique, and conventional cardiopulmonary bypass. Circulation
2000;102:III95-III100.
107. Gorlach G, Sroka J, Heidt M, et al. Intracellular adhesion molecule-1 in patients developing pulmonary
insufficiency after cardiopulmonary bypass. Thorac Cardiovasc Surg 2003;51:138-141.
108. Sander M, von Heymann C, von Dossow V, et al. Increased interleukin-6 after cardiac surgery predicts
infection. Anesth Analg 2006;102:1623-1629.
109. Massoudy P, Zahler S, Freyholdt T, et al. Sodium nitroprusside in patients with compromised left
ventricular function undergoing coronary bypass: reduction of cardiac proinflammatory substances. J Thorac
110. Wang J, Bian J, Wan X, et al. Association between inflammatory genetic polymorphism and acute lung
injury after cardiac surgery with cardiopulmonary bypass. Med Sci Monit 2010;16:CR260-CR265.
111. Chen S, Xu L, Tang J. Association of interleukin 18 gene polymorphism with susceptibility to the
development of acute lung injury after cardiopulmonary bypass surgery. Tissue Antigens 2010;76:245-249.
112. Hachida M, Hanayama N, Okamura T, et al. The role of leukocyte depletion in reducing injury to
myocardium and lung during cardiopulmonary bypass. ASAIO J 1995;41:M291-M294.
113. Erez E, Erman A, Snir E, et al. Thromboxane production in human lung during cardiopulmonary bypass;
beneficial effect of aspirin? Ann Thorac Surg 1998;65:101-106.
114. Friedman M, Wang SY, Selke FW, et al. Pulmonary injury after total or partial cardiopulmonary bypass
with thromboxane synthesis inhibition. Ann Thorac Surg 1995;59:598-603.
115. Gerrah R, Elami A, Stamler A, et al. Preoperative aspirin administration improves oxygenation in patients
undergoing coronary artery bypass grafting. Chest 2005;127:1622-1626.
P.354
116. Mathieu P, Dupuis J, Carrier M, et al. Pulmonary metabolism of endothelin 1 during on-pump and
beating heart coronary artery bypass operations. J Thorac Cardiovasc Surg 2001;121:1137-1142.
117. Reddy VM, Hendricks-Munoz KD, Rajasinghe HA, et al. Post-cardiopulmonary bypass pulmonary
hypertension in lambs with increased pulmonary blood flow. A role for endothelin 1. Circulation
1997;95:1054-1061.
118. Kirshbom PM, Jacobs MT, Tsui SS, et al. Effects of cardiopulmonary bypass and circulatory arrest on
endothelium-dependent vasodilation in the lung. J Thorac Cardiovasc Surg 1996;111:1248-1256.
119. Morita K, Ihnken K, Buckberg GD, et al. Pulmonary vasoconstriction due to impaired nitric oxide
production after cardiopulmonary bypass. Ann Thorac Surg 1996;61:1775-1780.
120. Seghaye MC, Duchateau J, Bruniaux J, et al. Endogenous nitric oxide production and atrial natriuretic
peptide biological activity in infants undergoing cardiac operations. Crit Care Med 1997;25:1063-1070.
121. Cugno M, Nussberger J, Biglioli P, et al. Increase of bradykinin in plasma of patients undergoing
cardiopulmonary bypass: the importance of lung exclusion. Chest 2001;120:1776-1782.
122. Pitt B, Gillis N, Hammond G. Depression of pulmonary metabolic function by cardiopulmonary bypass
procedures increases levels of circulating norepinephrine. J Thorac Surg 1984;38:508-613.
123. Eya K, Tatsumi E, Taenaka Y, et al. Importance of metabolic function of the natural lung evaluated by
prolonged exclusion of pulmonary circulation. ASAIO J 1996;42:M805-M809.
124. Gillis L, Greene N, Cronau L, et al. Pulmonary extraction of 5-hydroxtryptamine and norepinephrine
before and after cardiopulmonary bypass in man. Circ Res 1972;30:666-674
125. de Vroege R, van Oeveren W, van Klarenbosch J, et al. The impact of heparin-coated cardiopulmonary
bypass circuits on pulmonary function and the release of inflammatory mediators. Anesth Analg
2004;98:1586-1594.
126. Harig F, Feyrer R, Mahmoud FO, et al. Reducing the post-pump syndrome by using heparin-coated
circuits, steroids, or aprotinin. Thorac Cardiovasc Surg 1999;47:111-118.
127. Ranucci M, Cirri S, Conti D, et al. Beneficial effects of Duraflo II heparin-coated circuits on postperfusion
lung dysfunction. Ann Thorac Surg 1996;61:76-81.
128. Redmond JM, Gillinov AM, Stuart RS, et al. Heparin-coated bypass circuits reduce pulmonary injury.
129. Watanabe H, Miyamura H, Hayashi J, et al. The influence of a heparin-coated oxygenator during
cardiopulmonary bypass on postoperative lung oxygenation capacity in pediatric patients with congenital
heart anomalies. J Card Surg 1996;11:396-401.
130. Schulze CJ, Han L, Ghorpade N, et al. Phosphorylcholine-coated circuits improve preservation of
platelet count and reduce expression of proinflammatory cytokines in CABG: a prospective randomized trial. J
Card Surg 2009;24:363-368.
131. Thiara AS, Andersen VY, Videm V, et al. Comparable biocompatibility of Phisio- and Bioline-coated
cardiopulmonary bypass circuits indicated by the inflammatory response. Perfusion 2010;25:9-16.
132. Thiara AS, Mollnes TE, Videm V, et al. Biocompatibility and pathways of initial complement pathway
activation with Phisio- and PMEA-coated cardiopulmonary bypass circuits during open-heart surgery.
Perfusion 2011;26:107-114.
133. Reser D, Seifert B, Klein M, et al. Retrospective analysis of outcome data with regards to the use of
Phisio(R)-, Bioline(R)- or Softline(R)-coated cardiopulmonary bypass circuits in cardiac surgery. Perfusion
2012;27:530-534.
134. Paparella D, Scrascia G, Rotunno C, et al. A biocompatible cardiopulmonary bypass strategy to reduce
hemostatic and inflammatory alterations: a randomized controlled trial. J Cardiothorac Vasc Anesth
2012;26:557-562.
135. Ikuta T, Fujii H, Shibata T, et al. A new poly-2-methoxyethylacrylate-coated cardiopulmonary bypass

circuit possesses superior platelet preservation and inflammatory suppression efficacy. Ann Thorac Surg
2004;77:1678-1683.
136. Eisses MJ, Geiduschek JM, Jonmarker C, et al. Effect of polymer coating (poly 2-methoxyethylacrylate)
of the oxygenator on hemostatic markers during cardiopulmonary bypass in children. J Cardiothorac Vasc
Anesth 2007;21:28-34.
137. Reeve WG, Ingram SM, Smith DC. Respiratory function after cardiopulmonary bypass: a comparison of
bubble and membrane oxygenators. J Cardiothorac Vasc Anesth 1994;8:502-508.
138. Martin W, Carter R, Tweddel A, et al. Respiratory dysfunction and white cell activation following
cardiopulmonary bypass: comparison of membrane and bubble oxygenators. Eur J Cardiothorac Surg
1996;10:774-783.
139. Nagashima M, Shin'oka T, Nollert G, et al. High-volume continuous hemofiltration during

cardiopulmonary bypass attenuates pulmonary dysfunction in neonatal lambs after deep hypothermic
circulatory arrest. Circulation 1998;98:II378-II84.
140. Bando K, Turrentine MW, Vijay P et al. Effect of modified ultrafiltration in high-risk patients undergoing
operations for congenital heart disease. Ann Thorac Surg 1998;66:821-827; discussion 8.
141. Bando K, Vijay P, Turrentine MW, et al. Dilutional and modified ultrafiltration reduces pulmonary
hypertension after operations for congenital heart disease: a prospective randomized study. J Thorac
Cardiovasc Surg 1998;115:517-525; discussion 25-27.
142. Journois D, Pouard P, Greeley WJ, et al. Hemofiltration during cardiopulmonary bypass in pediatric
cardiac surgery. Effects on hemostasis, cytokines, and complement components. Anesthesiology
1994;81:1181-1189.
143. Laffey JG, Boylan JF, Cheng DC. The systemic inflammatory response to cardiac surgery: implications
for the anesthesiologist. Anesthesiology 2002;97:215-252.
144. Oliver WC Jr, Nuttall GA, Orszulak TA, et al. Hemofiltration but not steroids results in earlier tracheal
extubation following cardiopulmonary bypass: a prospective, randomized double-blind trial. Anesthesiology
2004;101:327-339.
145. Gu YJ, de Vries AJ, Boonstra PW, et al. Leukocyte depletion results in improved lung function and
reduced inflammatory response after cardiac surgery. J Thorac Cardiovasc Surg 1996;112:494-500.
146. Johnson D, Thomson D, Mycyk T, et al. Depletion of neutrophils by filter during aortocoronary bypass
surgery transiently improves postoperative cardiorespiratory status. Chest 1995;107:1253-1259.
147. Komai H, Naito Y, Fujiwara K, et al. The protective effect of a leukocyte removal filter on the lung in
open-heart surgery for ventricular septal defect. Perfusion 1998;13:27-34.
148. Morioka K, Muraoka R, Chiba Y, et al. Leukocyte and platelet depletion with a blood cell separator:
effects on lung injury after cardiac surgery with cardiopulmonary bypass. J Thorac Cardiovasc Surg
1996;111:45-54.
149. Mihaljevic T, Tonz M, von Segesser LK, et al. The influence of leukocyte filtration during
cardiopulmonary bypass on postoperative lung function. A clinical study. J Thorac Cardiovasc Surg
1995;109:1138-1145.
150. Warren O, Alexiou C, Massey R, et al. The effects of various leukocyte filtration strategies in cardiac
surgery. Eur J Cardiothorac Surg 2007;31:665-676.
151. Salamonsen RF, Anderson J, Anderson M, et al. Total leukocyte control for elective coronary bypass
surgery does not improve short-term outcome. Ann Thorac Surg 2005;79:2032-2038.
152. de Amorim CG, Malbouisson LM, da Silva FC Jr, et al. Leukocyte depletion during CPB: effects on
inflammation and lung function. Inflammation 2014;37:196-204.
153. Sundar S, Novack V, Jervis K, et al. Influence of low tidal volume ventilation on time to extubation in
cardiac surgical patients. Anesthesiology 2011;114:1102-1110.
154. Lloyd J, Newman J, Brigham K. Permeability pulmonary edema: diagnosis and management. Arch Intern
Med 1984;144:143-147.
155. Maggart M, Stewart S. The mechanisms and management of noncardiogenic pulmonary edema
following cardiopulmonary bypass. Ann Thorac Surg 1987;43:231-236.
156. Engelman RM, Rousou JA, Flack JE 3rd, et al. Influence of steroids on complement and cytokine
generation after cardiopulmonary bypass. Ann Thorac Surg 1995;60:801-804.
157. Jansen NJ, van Oeveren W, van Vliet M, et al. The role of different types of corticosteroids on the
inflammatory mediators in cardiopulmonary bypass. Eur J Cardiothorac Surg 1991;5:211-217.
158. Tabardel Y, Duchateau J, Schmartz D, et al. Corticosteroids increase blood interleukin-10 levels during
cardiopulmonary bypass in men. Surgery 1996;119:76-80.
159. Teoh KH, Bradley CA, Gauldie J, et al. Steroid inhibition of cytokine-mediated vasodilation after warm
heart surgery. Circulation 1995;92:II347-II353.
160. Fillinger MP, Rassias AJ, Guyre PM, et al. Glucocorticoid effects on the inflammatory and clinical
responses to cardiac surgery. J Cardiothorac Vasc Anesth 2002;16:163-169.
161. Chaney MA, Nikolov MP, Blakeman B, et al. Pulmonary effects of methylprednisolone in patients
undergoing coronary artery bypass grafting and early tracheal extubation. Anesth Analg 1998;87:27-33.
P.355
162. Dieleman J, van Paassen J, van Dijk D, et al. Prophylactic corticosteroids for cardiopulmonary bypass in
adults. Cochrane Database Syst Rev 2011;5:CD005566.
163. Cappabianca G, Rotunno C, de Luca Tupputi Schinosa L, et al. Protective effects of steroids in cardiac
surgery: a meta-analysis of randomized double-blind trials. J Cardiothorac Vasc Anesth 2011;25:156-165.
164. Royston D. The serine antiprotease aprotinin (Trasylol): a novel approach to reducing postoperative
bleeding. Blood Coagul Fibrinolysis 1990;1:55-69.
165. Hill GE, Alonso A, Spurzem JR, et al. Aprotinin and methylprednisolone equally blunt cardiopulmonary
bypass-induced inflammation in humans. J Thorac Cardiovasc Surg 1995;110:1658-1662.
166. Hill GE, Pohorecki R, Alonso A, et al. Aprotinin reduces interleukin-8 production and lung neutrophil
accumulation after cardiopulmonary bypass. Anesth Analg 1996;83:696-700.
167. Lazar HL, Bao Y, Tanzillo L, et al. Aprotinin decreases ischemic damage during coronary
revascularization. J Card Surg 2005;20:519-523.
168. Mathias MA, Tribble CG, Dietz JF, et al. Aprotinin improves pulmonary function during reperfusion in an
isolated lung model. Ann Thorac Surg 2000;70:1671-1674.
169. Roberts RF, Nishanian GP, Carey JN, et al. Addition of aprotinin to organ preservation solutions
decreases lung reperfusion injury. Ann Thorac Surg 1998;66:225-230.
170. Mangano DT, Tudor IC, Dietzel C. The risk associated with aprotinin in cardiac surgery. N Engl J Med
2006;354:353-365.
171. Fergusson D, Hebert P, Mazer C, et al. A comparison of aprotinin and lysine analogues in high-risk
cardiac surgery. N Engl J Med 2008;358:2319-2331.
172. Hutton B, Joseph L, Fergusson D, et al. Risks of harms using antifibrinolytics in cardiac surgery:
systematic review and network meta-analysis of randomised and observational studies. BMJ
2012;345:e5798.
173. McMullan DM, Bekker JM, Parry AJ, et al. Alterations in endogenous nitric oxide production after
cardiopulmonary bypass in lambs with normal and increased pulmonary blood flow. Circulation
2000;102:III172-III178.
174. Beghetti M, Habre W, Friedli B, et al. Continuous low dose inhaled nitric oxide for treatment of severe
pulmonary hypertension after cardiac surgery in paediatric patients. Br Heart J 1995;73:65-68.
175. Bender KA, Alexander JA, Enos JM, et al. Effects of inhaled nitric oxide in patients with hypoxemia and
pulmonary hypertension after cardiac surgery. Am J Crit Care 1997;6:127-131.
176. Bichel T, Spahr-Schopfer I, Berner M, et al. Successful weaning from cardiopulmonary bypass after
cardiac surgery using inhaled nitric oxide. Paediatr Anaesth 1997;7:335-339.
177. Rich GF, Murphy GDJ, Roos CM, et al. Inhaled nitric oxide. Selective pulmonary vasodilation in cardiac
surgical patients. Anesthesiology 1993;78:1028-1035.
178. Schranz D, Huth R, Wippermann CF, et al. Nitric oxide and prostacyclin lower suprasystemic pulmonary
hypertension after cardiopulmonary bypass. Eur J Ped 1993;152:793-796.
179. Snow DJ, Gray SJ, Ghosh S, et al. Inhaled nitric oxide in patients with normal and increased pulmonary
vascular resistance after cardiac surgery. Br J Anaesth 1994;72:185-189.
180. Tonz M, von Segesser LK, Schilling J, et al. Treatment of acute pulmonary hypertension with inhaled
nitric oxide. Ann Thoracic Surg 1994;58: 1031-1035.
181. Wessel DL. Inhaled nitric oxide for the treatment of pulmonary hypertension before and cardiopulmonary
bypass. Crit Care Med 1993;21:S344-S345.
182. Palatianos GM, Paziouros K, Vassili MI, et al. Effect of exogenous nitric oxide during cardiopulmonary
bypass on lung postperfusion histology. ASAIO J 2005;51:398-403.
183. Bolanowski PJ, Bauer J, Machiedo G, et al. Prostaglandin influence on pulmonary intravascular
leukocytic aggregation during cardiopulmonary bypass. J Thorac Cardiovasc Surg 1977;73:221-224.
184. Addonizio V, Fisher C, Jenkin B, et al. Iloprost (ZK36374), a stable analogue of prostacyclin, preserves
platelets during simulated extracorporeal circulation. J Thorac Cardiovasc Surg 1985;89:926-933.
185. Fish K, Sarnquist F, Van Steennis C, et al. A prospective, randomized study of the effects of
prostacyclin on platelets and blood loss during coronary bypass operations. J Thorac Cardiovasc Surg
1986;91:436-442.
186. Fessatidis IT, Brannan JJ, Taylor KM, et al. Effect of prostacyclin PGI2 on cardiopumolary bypass-
induced lung injury. Perfusion 1994;9:23-33.
187. Haslam PL, Baker CS, Hughes DA, et al. Pulmonary Surfactant composition early in the development of
acute lung injury after cardiopulmonary bypass: prophlactic use of surfactant therapy. Int J Exp Pathol
1997;78: 277-289.
188. Macnaughton PD, Evans TW. The effect of exogenous surfactant therapy on lung function following
cardiopulmonary bypass. Chest 1994;105: 421-425.
Chapter 13
Inflammatory Responses to Cardiopulmonary Bypass
Karsten Bartels
Mustafa Zakkar
The development of the heart-lung machine—cardiopulmonary bypass (CPB) in the 1950s—together with the
development of cardiac catheterization and the use of heparin and protamine, made open-heart surgery possible
and led to enormous improvement in patient longevity and quality of life (1). CPB imposes a complex set of
nonphysiologic circumstances during which patients are subjected to severe physiologic alterations. With current
anesthetic and surgical care paradigms, few serious adverse sequelae occur in most patients (2,3,4). Moreover,
multiple recent large-scale clinical trials comparing off-pump coronary artery bypass grafting (CABG) surgery to
conventional CPB (5,6,7,8) have demonstrated few meaningful differences, calling into question the clinical
relevance of inflammation attributable to CPB alone (Table 13.1).
Inflammation is one of the oldest pathophysiologic concepts known to mankind—Galen and Celsus are credited
with describing the pentad of calor (heat), rubor (redness), tumor (swelling), dolor (pain), and function laesa
(altered function) over 2,000 years ago (9). Immunologic responses provide protection from a wide array of
external pathogens, irritants, and endogenous substances. Historically, the immune system has been
categorized into the innate and the adaptive (or acquired) immune system (10,11). The core feature of the
adaptive immune system is its ability to establish memory from joint processing by lymphocytes and antigen-
presenting cells (11). In case of reexposure to a previously encountered antigen, antibodies can then be rapidly
generated. The innate immune system consists of hematopoietic cells such as neutrophils, eosinophils, mast
cells, macrophages, and natural killer cells, as well as nonhematopoietic cells such as endo- and epithelial cells
(10). In sterile inflammation, these can be activated by damage-associated molecular patterns (DAMPs), sterile
particulates, and intracellular cytokines that are released from damaged cells (12). The innate immune response
is then further mediated by soluble factors such as complement, cytokines/chemokines, and acute phase
proteins. It should be noted that the innate and adaptive pathways of immunity are highly interrelated and that
crosstalk is common.
Activation of the immune system occurring in the context of CPB is multifactorial (Fig. 13.1) (13)—a feature that
makes design of experimental models to mimic cardiac surgery especially challenging (14).
THE SYSTEMIC INFLAMMATORY RESPONSE TO CARDIOPULMONARY

BYPASS
Definition
At the outset, it is important to define what the systemic inflammatory response means both in general and
in the specific context of CPB. Both clinical and experimental studies indicate that various infectious and
noninfectious conditions induce a similar host response known as “systemic inflammatory response
syndrome” (SIRS). This concept was advanced by the American College of Chest Physicians/Society of
Critical Care Medicine (ACCP/SCCM) consensus conference in 1992 (5,6,15,16). Two or more of the
following clinical manifestations must be fulfilled for the diagnosis:
Body temperature higher than 38°C or lower than 36°C.
Heart rate more than 90 beats/min.
Respiratory rate more than 20/min or PaCO2 less than 32 mm Hg.
Leukocyte count more than 12,000 cells/mm3 or less than 4,000 cells/mm3, or the presence of more than
10% immature neutrophils.
The 2001 International Sepsis Conference pointed out the nonspecific nature of the SIRS criteria and
further specified the variables that are likely to be affected by an infectious inflammatory stimulus (17). CPB
can produce a “whole-body” noninfectious or “sterile” inflammatory response (18). Inflammation that occurs
after CPB could well be described as an SIRS. However, discriminating the postoperative inflammatory
component that derives from the surgical procedure versus the exposure to CPB proves challenging.
Systemic inflammatory response after cardiopulmonary bypass (SIRAB) therefore includes inflammatory
response from other components of cardiac surgery such as sternotomy or thoracotomy. Organ dysfunction
associated with cardiac surgery can provoke the activation of a plethora of proinflammatory cascades
adding to SIRAB (19). Hypotensive episodes during CPB can
P.358
lead to hypoxia and ischemia, which are strong proinflammatory activators and can initiate more
inflammatory responses that can last long after the termination of bypass and manifest as a vasoplegic state
(20). While most patients experience few clinically adverse sequelae from CPB, and only a minority develop
severe hemodynamic changes or organ failure (21,22), length of CPB has been independently associated
with morbidity and mortality after cardiac surgery (23).
TABLE 13.1. Summary of primary outcomes in recent clinical trials comparing offpump
CABG surgery to conventional CABG using cardiopulmonary bypass
Trial name n Primary outcome Results

for
primary
outcome
ROOBY (5) 2,203 30 d: Composite of death and No

major complications significant
difference
1 yr: Composite of death, Worse outcomes in the off-pump

repeat revascularization, and group
nonfatal myocardial
infarction
CORONARY 4,752 30 d: Composite of death, nonfatal No

(6) stroke, nonfatal myocardial significant
infarction, or new nonfatal renal difference
failure
CORONARY 4,752 1 yr: Composite of death, nonfatal No

(7) stroke, nonfatal myocardial significant
infarction, or new nonfatal renal difference
failure
DOORS (8) 900 30 d: Composite of death, No

myocardial infarction, or stroke significant
difference
n = number of randomized patients.
FIGURE 13.1. Schematic diagram of the sequence of events by which cardiopulmonary bypass (CPB) may
lead to the development of systemic inflammatory response syndrome (SIRS). (From Warltier DC, Laffey
JG, Boylan JF, et al. The systemic inflammatory response to cardiac surgery: implications for the
anesthesiologist. Anesthesiology 2002;97(1):215-252. Copyright © 2002, American Society of
Anesthesiology. Reproduced with permission from Wolters Kluwer Health.)
Initiation of Systemic Inflammatory Response After Bypass

A number of injurious processes that impinge on both cellular and noncellular (humoral) elements of blood initiate
SIRAB. These processes generate microemboli, disrupt hemostasis, and lead to a generalized whole-body
inflammatory response. Most importantly, they set in motion a sequence of cytokine-mediated events that
activate vascular endothelium, allowing further neutrophil-mediated inflammatory injury. The damaging effects of
CPB are most commonly attributed to contact of blood with the foreign surface of the extracorporeal circuit.
However, other factors such as altered arterial blood flow patterns, shear stress generated by blood pumps,
cardiotomy suction devices, tissue ischemia and reperfusion, hypothermia, anemia, and heparin, may be equally
important (24). This inflammatory response may continue long after CPB discontinuation, depending partly on its
magnitude (25).
The repeated passage of blood through the nonphysiologic extracorporeal circuit initiates a “contact activation”
response with deposition of fibrin and activation of contact protein
P.359
cascades upon exposure of the blood to the nonendothelialized surface of the CPB machine. Four proteins are
involved in the contact activation cascades: coagulation factors XII and XI, prekallikrein, and high-molecular-
weight kininogen (HMWK). This activation forms bradykinin and converts plasminogen into plasmin. This in turn
initiates fibrinolysis and can trigger the classical complement cascade. Therefore, multiple inflammatory
mediators are released upon exposure to the extracorporeal circuit (26). These responses initiate a sequence of
chemokine-mediated events that activate vascular endothelium and potentiate neutrophil-mediated injury, which
can disrupt hemostasis and create a generalized inflammatory response.
Cellular Components of Blood

Red Blood Cells
Tissue oxygenation depends upon continuous oxygen delivery, most of which is carried by the hemoglobin
molecules in the red blood cells (RBCs). The extracorporeal circuit exposes RBCs to a challenging environment,
thereby altering their integrity and function. Rheologic shear stress forces mechanically damage RBCs to reduce
their deformability, which is important to maintaining normal RBC microcirculatory flow. As a further consequence
of membrane distortion, RBCs are susceptible to the membrane attack complex (MAC) generated by the
activation of complement (18), leading to hemoglobin leakage into the plasma. Free plasma hemoglobin may
impair tissue function by increasing plasma oncotic pressure and viscosity. The ability of RBCs to aggregate also
diminishes as a consequence of the dilution of blood by the CPB circuit priming solution. In addition to the
obvious potential reduction in tissue oxygenation, this can trigger endothelial activation pathways (27).
Vascular Endothelium
Under resting conditions, vascular endothelium offers a relatively inert surface that regulates the passage of
intravascular substrates to the extravascular space and ensures unhindered flow of cellular and serum
components through the capillary network. Endothelial cells are extremely sensitive to the physiologic trespass
imposed by CPB and surgical manipulation (and hypoxia, should it occur). Release of endogenous substances
such as cytokines (IL-1b and tumor necrosis factor [TNF]-α), thrombin, C’5a, and lipopolysaccharide (endotoxin)
activates endothelial cells to increase surface expression of E-selectin, endothelial leukocytes adhesion
molecule (ELAM), intercellular adhesion molecule-1 (ICAM-1), and vascular adhesion molecule (VCAM), all of
which mediate leukocyte recruitment (28,29,30) (Fig. 13.2).
Leukocytes
The recruitment of leukocytes from the circulation to an inflammatory site is a multistep process (Fig. 13.2)
involving members of several adhesion receptor families (31,32). CPB activates vascular endothelium, leading to
rapid expression of members of the selectin family (33). These are transmembrane molecules, expressed on the
surface of leukocytes and activated endothelial cells. Selectins contain an N-terminal extracellular domain with
structural homology to calcium-dependent lectins, followed by a domain homologous to epidermal growth factor,
and two to nine consensus repeats (CR) similar to sequences found in complement regulatory proteins. Each of
these adhesion receptors is inserted through a hydrophobic transmembrane domain and possesses a short
cytoplasmic tail. During inflammation, bloodstream leukocytes attach to endothelium via selectins, thereby
impairing microcirculatory flow, potentially culminating in transient standstill from leukocyte adhesive “plugs”
along the endothelium. The selectin family includes P-, E-, and L-selectin. P-selectin is largely responsible for
the rolling phase of the leukocyte adhesion cascade. Transmigration, the next step, is mediated by adhesion
molecule upregulation, including platelet endothelial cell adhesion molecule (PECAM)-1, CD99, ICAM-1,
CD11a/CD18, very late antigen (VLA)-4, and endothelium-secreting chemoattractants (34).
FIGURE 13.2. Adherence of circulating neutrophils (A) is triggered by activation of the endothelial cells, which
causes the neutrophils to roll along the endothelium (B), a process mediated by selectin interaction with
carbohydrate ligands. Activation of the neutrophils (e.g., by interleukin [IL]-8, C5a, or platelet activating factor
[PAF]) results in activation of integrin molecules (e.g., by leukocyte function antigen [LFA]-1) on the neutrophil
surface. This results in firm adhesion of the neutrophils to activated endothelium (C) through receptors belonging
to the Ig family (e.g., intercellular adhesion molecules [ICAMs]). Activated adherent neutrophils extravasate
through the endothelium into the tissue interstitial space (D).
Neutrophils
Neutrophils are key mediators of the systemic inflammatory response; their recruitment, activation, and cytotoxic
capability are essential to warding off infection. Neutrophil activation through interaction with activated vascular
endothelium may be responsible for much of the clinical sequelae of SIRAB. Activation of neutrophils during CPB
is shown by the loss of L-selectin and the upregulation of CD11b/CD18 (Mac-1). Increased production of reactive
oxygen intermediate (35) and neutrophil-derived elastase and similar molecules have also been reported (35,36).
Studies in complement-deficient dogs suggest that at least some of the neutrophil activation seen in
P.360
CPB is due to complement activation (37,38). In addition, the release of cytotoxic products by activated cells can
cause direct cellular damage. These cytotoxins include both preformed agents present in neutrophil granules
and newly synthesized molecules. These novel substances include leukotrienes (36) and reactive oxygen
intermediates (35). This synthesis can be readily detected by a dramatic increase in cellular oxygen
consumption. These species are largely responsible for the so-called ischemia-reperfusion injury. Ischemic injury
occurs when the blood supply to a tissue is impaired or suboptimal, which may occur with CPB. The paradox,
however, is that a more severe tissue injury occurs when blood flow is restored upon reperfusion.
Monocytes
Peripheral monocytes are also involved in the systemic inflammatory process. They possess migratory,
chemotactic, pinocytic, and phagocytic activities, as well as receptors for IgG and C’3b. Upon migration to tissue,
they undergo further differentiation to become tissue macrophages, which participate in both specific and
nonspecific immune pathways. Recruitment of these cells occurs as early as 1 hour following insult (39) and is
thought to be mediated mainly by monocyte chemoattractant protein-1 (MCP-1), although other factors such as
C’5a play an important role. Upon activation, they play a pivotal role in inflammation, serving as effector cells
secreting cytokines (40). Monocytes can exhibit both pro- and anti-inflammatory properties, depending on the
signals they receive, and it has been suggested that these cells have the capacity to switch from one state to the
other to participate in both the induction and the resolution of inflammation (39).
Platelets
CPB is associated with a transient deficit in platelet function and number, which can impair postoperative
hemostasis (41). The normal platelet adheres to a damaged endothelial cell or the subendothelial layer. The
multimeric form of von Willebrand factor forms a bridge between endothelium and platelet at the platelet
glycoprotein (GpIb) receptor site. The platelet then undergoes a conformational change to expose different
glycoproteins, including the GpIIb/IIIa complex, which can in turn bind to fibrinogen. Fibrinogen is an essential
cofactor in platelet adhesion and in platelet-to-platelet binding during irreversible aggregation. The protein
complex thrombospondin stabilizes this platelet aggregate. Concurrent thromboxane A2 release produces local
vasoconstriction and further platelet aggregation.
Numerous CPB-related factors contribute to platelet changes. These include physical factors (e.g., hypothermia
and shear forces), exposure to artificial surfaces (42), drugs, and endogenous chemicals (43,44). Hemodilution
contributes to initial thrombocytopenia (45), but mechanical disruption, adhesion to the extracorporeal circuit, and
sequestration in organs explains a disproportionate drop (beyond hemodilution alone) in platelet count, which
can be 30% to 50% below baseline (46). The response of platelets to CPB is complex and multifactorial,
including rapid consumption of platelets during bypass (45), decreased reactivity to known agonists (44),
increase in the concentration of the a-granule compounds in plasma (47), and an increase in the stable
metabolite of thromboxane A2 (thromboxane B2) released from aggregating platelets (48). Morphologic changes,
including spherical appearance and the development of pseudopods, also occur during CPB (49). Prolonged
bleeding time after CPB correlates with duration of bypass; however, its time course and precise mechanism
remain unclear (50).
Platelets activated during CPB form conjugates among themselves and between platelets and leukocytes.
Activated platelets express P-selectin, which contributes to leukocyte conjugate formation by binding PSGL-1
(51). Activated platelets use this P-selectin/PSGL-1 adhesion pathway to stimulate conjoined monocytes, thereby
leading to secretion of the proinflammatory cytokines IL-1b, IL-8, and MCP-1 (52,53). P-selectin also induces
tissue factor expression and fibrin deposition by monocytes, thereby contributing to thrombus evolution (54,55).
Coagulation System
The coagulation cascade can be activated by either intrinsic or extrinsic pathways, each of which consists of a
series of enzymes. Figure 13.3 shows a simplified version of these pathways.
The intrinsic pathway begins with Factor XII activation upon contact of blood with collagen in the damaged
vascular wall or an artificial surface, and ends with the formation of fibrin through a cascade including activated
factors XI, IX, X, and thrombin. Exposure of blood to nonvascular tissue cells expresses a protein called tissue
factor, which binds to factor VII and activates the extrinsic pathway. This in turn activates factor X. Once factor
Xa is generated, the remainder of the cascade is the same as the intrinsic pathway.
FIGURE 13.3. Simplified summary of the coagulation cascade.

P.361
Coagulation cascade activation induces the fibrinolytic system to coactivate, which limits the amount of fibrin clot
formed and localizes clot formation to the injury site. CPB activates both the clotting and fibrinolysis pathways.
Not only does this cause fibrin formation and platelet activation, but also it activates vascular endothelium.
Thrombin-mediated endothelial cell activation elicits leukocyte adhesion as a result of selectin expression. In
addition, the factor VIIa-tissue factor complex and factor Xa activate cells through protease-activated receptors,
and this, in turn, generates cellular responses similar to those mediated by thrombin activation of protease-
activated receptor-1 (56). CPB-induced increases in factor XIIa and kallikrein activate fibrinolysis, which has
been linked to increased postoperative bleeding time, blood loss, and reduction in platelet adhesion and
aggregation capabilities from redistribution of glycoprotein Ib, and IIb/IIIa receptors (57,58).
Humoral Components of Blood

Kirklin and McGriffin (3) initially hypothesized that many of the deleterious effects of CPB derived from exposure
of blood to nonendothelial surfaces, which initiates a “whole-body inflammatory response.” They characterized
this response as activation of coagulation, the kallikrein system, fibrinolysis, and complement (3,59). We now
also recognize the importance of cytokines (60) and the combined effects of these humoral cascades in the
activation of endothelial cells and neutrophil adhesion.
Inflammatory Cascades
The principal event is the activation of factor XII (Hageman factor), which stimulates a number of inflammatory
systems (Fig. 13.3). After surface contact, factor XII undergoes a conformational change and attaches to the
protein HMWK, which is involved in the early stages of intrinsic pathway activation and is a precursor of
bradykinin.
This complex attaches to the foreign surface and, after limited proteolysis, releases kallikrein, bradykinin, and
more factor XIIa. Factor XIIa can initiate the intrinsic coagulation cascade by activating factor XI, which binds to
the foreign surface and activates factor VII, thereby further augmenting the intrinsic coagulation cascade. Factor
XIIa also provides a positive feedback loop by inducing prekallikrein to form kallikrein, which in turn activates
factor XII to produce more factor XIIa (61). Kallikrein activates neutrophils, which further activate inflammatory
cascades to produce oxygen free radicals and proteolytic enzymes. Furthermore, both kallikrein and bradykinin
stimulate the fibrinolytic system. Kallikrein stimulates plasmin production by its action on prourokinase and
bradykinin releases tissue-type plasminogen activator from the endothelium.
Complement System
The complement system comprises one of the preeminent immunologic mechanisms involved in the inflammatory
process and it is activated by CPB (62). More than 30 complement system proteins serve both as an immune
response effector arm and as a primitive self- versus non-self-recognition system. Complement system functions
include mediating inflammation, opsonization of antigenic particles, and causing membrane damage to
pathogens. Complement components interact such that the products of one reaction form the enzyme for the
next. Therefore, a small initial stimulus can trigger a cascade of biologic activation and amplification. The fact
that 5% to 10% of serum proteins are complement components attests to its importance. Blood which collects in
the pericardium has very high levels of Tissue Factor which, if aspirated into the CPB equipment using the
cardiotomy suction, can accelerate the inflammatory response if reinfused back into the patient.
The complement system (Fig. 13.4) was previously interpreted as a cascading system with a common final
pathway forming the MAC. Current understanding views complement as a dynamic network that contains several
hubs such as C1q, C3b, and C5a, each of which is highly integrated within other pathways (63). Complement
activation not only forms the MAC but also interacts complexly with other systems such as proinflammatory
signaling pathways, lipid metabolism, and adaptive immunity (Fig. 13.4). Complement inhibition has been
suggested as a promising target for immunomodulative therapy in the context of cardiac surgery (64).
Further Contributions to Systemic Inflammatory Response After Bypass

In addition to the inflammatory interactions that result from the bypass circuit, cardiogenic shock and
endotoxemia may compound the response (65). Cardiogenic shock can contribute to SIRAB, and prolonged
nonpulsatile perfusion or periods of circulatory arrest can also lead to diffuse endorgan ischemia (66). The end-
organ hypoxic insult likely causes endothelial cells, circulating monocytes, and tissuefixed macrophages to
release cytokines and oxygen-derived
P.362
free radicals that drive this response. After resuscitation from shock and hypoxic end-organ reperfusion, a
systemic ischemicreperfusion injury ensues (65).
FIGURE 13.4. The complement systems. C1q, C3b, and C5a represent key functional elements that crosstalk in
multiple directions. Formation of the MAC leads to lysis, but also leads to cytokine secretion. MBL, mannan-
binding lectin; MAC, membrane attack complex.
Endotoxemia represents another form of inflammatory activation that results from extracorporeal circulation and
ischemia-reperfusion. Frequently detected in high concentrations in the systemic circulation after CPB (67),
endotoxin potently induces macrophage TNF release, which likely explains its increased concentrations after
CPB in some patients. In a rodent CPB model, brain TNF-a levels were elevated in the CPB group compared to
nonoperative control animals. However, a similar effect was seen in animals that underwent cannula placement
without CPB (68). These data suggest that TNF-a release and associated neurologic injury also occur from
surgical manipulation without CPB (69).
IMMUNE RESPONSE AFTER CARDIOPULMONARY BYPASS

The cellular and humoral constituents of the adaptive immune system undergo changes in both function and
number after CPB. The concern is that postoperative infection partially derives from CPB-induced loss of T- and
B cells and associated immunoglobulin consumption. This section examines the effect of CPB on adaptive
immunity in general and T-cell function in particular.
Immunodeficiency and Cardiopulmonary Bypass

Duration of CPB correlates with postoperative infections (70). CPB depresses immunologic reactivity, thereby
increasing susceptibility to perioperative infections and the potential for septic shock (71).
Normally, relatively low levels of immunoglobulins and complement provide adequate bacterial opsonization (72).
However, if the load of infectious microorganisms increases, as may occur in patients undergoing open-heart
surgical procedures, then an imbalance may develop in host defense homeostasis. Quantitative and qualitative
exhaustion of humoral and cell-mediated immune mechanisms may adversely affect clinical outcome when
additional injury occurs postoperatively in a patient with a downregulated immune system. It is therefore
unsurprising that opportunistic pathogens are frequently found in post-CPB patients who experience
complications such as renal failure or low cardiac output. Post-CPB patients exhibit an increased risk for sepsis-
related multisystem organ failure, which accounts for a high proportion of perioperative fatalities (73).
Humoral Immunity
Serum levels of immunoglobulins and complement change markedly during CPB (21,74,75), with a resultant
reduction in host defenses, for example, reduced opsonization of bacteria in vitro (76). Leukocyte counts fall
beyond the affect of hemodilution at the onset of CPB as a result of tissue sequestration after activation by
anaphylatoxins C’3a and C’5a. After CPB, granulocyte chemotaxis is impaired (77), which likely increases
susceptibility to bacterial infections. CPB also impairs leukocyte phagocytosis and metabolic function during and
after CPB (106).
Some investigations report unchanged B-cell numbers after CPB (18), whereas others demonstrate a drop
(107,108). Roth et al. reported that relative B-cell levels (percentage) increase after CPB, with no change in their
absolute number, which may result from a combination of hemodilution and immunosuppression. The secretion
of IgG, IgM, and IgA by B cells in response to pokeweed mitogen diminishes after CPB. Recent work by Lante et
al. showed that IgE levels did not change after CPB until day 3; in contrast, both IgG and IgM levels decreased
significantly on day 1. IgM returned to baseline on day 5, at which time IgG levels remained low. This was
associated with a reduction in the B-cell count on day 1 and a return to baseline by day 3. The bactericidal
activity of serum is depressed after CPB. Whereas complement is consumed during CPB, other components of
humoral immunity decrease in proportion to CPB hemodilution.
When immune proteins contact gaseous and foreign surfaces, denaturation ensues. Surface depolarizing forces
disrupt sulfhydryl and hydrogen bonds that stabilize the secondary and tertiary structure of the protein molecules.
This unfolds globular protein molecules, which may create a randomly coiled molecule and expose previously
masked chemical groups. The macromolecules so formed then tend to flocculate. Plasma protein denaturation
may also coalesce serum lipids and increase plasma viscosity (75).
Mast Cells and Paneth Cells

Mast cells are sentinels that herald gut inflammation. In a rodent model of CPB and deep hypothermic circulatory
arrest, intestinal mast cells in conjunction with Paneth cells mediate ischemia/reperfusion injury (Fig. 13.5) (78).
The impact of unappreciated acute gut injury on adverse outcomes after cardiac surgery is only recently being
appreciated {Karhausen, 2014 #1308}. Since mast cells may be activated by complement, suppressing this
activation may prove valuable in attenuating CPB-induced ischemia/reperfusion injury.
Natural Killer Cells

Natural killer cells, a heterogeneous lymphocyte subpopulation that is neither T nor B, produce cytotoxic
responses in virus-infected cells and transformed target cells (e.g., tumor cells). Decreases in both number and
function of natural killer cells occur after CPB (79,80).
Reticuloendothelial System
The reticuloendothelial system comprises tissue macrophages in the spleen, lymph nodes, lung, and liver. Its
cells derive
P.363
from blood-borne monocytes. Normal reticuloendothelial function includes clearing the blood of bacteria,
endotoxins, platelets, denatured proteins, chylomicrons, plasma hemoglobin, thrombin, fibrin, fibrin degradation
products, thromboplastin, and plasminogen activator. CPB introduces microparticles into the bloodstream, which
in turn depresses reticuloendothelial system function (81).
FIGURE 13.5. Paneth cells and intestinal mast cells release potent effectors to regulate local injury and systemic
inflammation after intestinal ischemia/reperfusion. Most prominently, the Paneth cell-dependent pathway (blue)
depends on release of interleukin (IL)-17 from Paneth cells localized at the base of small-intestinal crypts. Mast
cell responses (purple) use a number of preformed and de novo synthesized products such as proteases
(tryptase, mast cell protease [MCP]-4), lipid mediators (leukotrienes, prostaglandins), and cytokines (tumor
necrosis factor [TNF]-α, IL-6). (Figure prepared by Annemarie B. Johnson, C.M.I., Medical Illustrator, Vivo
Visuals, Winston-Salem, NC, for Bartels K, Karhausen J, Clambey ET, et al. Perioperative organ injury.
Anesthesiology 2013;119:1474-1489. Copyright © 2013, American Society of Anesthesiology. Reproduced with
permission from Wolters Kluwer Health.)
T Cells
T cells are lymphocytes that develop in the thymus, which is seeded by lymphocytic stem cells from the bone
marrow during embryonic development. Following T-cell development, mature naive T cells leave the thymus
and begin to spread throughout the body. These cells then develop their T-cell antigen receptors and
differentiate into the two major peripheral T-cell subsets, one of which expresses the CD4+ marker (helper cells)
and the other CD8+ (cytotoxic cells). Proliferating T helper cells can differentiate into two major subtypes on the
basis of the specific cytokines they produce, known as TH1 and TH2. T helper cells play a central role in the
initiation and regulation of the acquired immune response.
T helper cells recognize antigen presented on the surface of antigen-presenting cells in association with class II
molecules encoded by the major histocompatibility complex (MHC). T-cell activation requires other specific
costimulatory signals generated by the antigen-presenting cell. Cytotoxic T cells recognize antigen presented on
the surface of antigen-presenting cells in association with class I molecules encoded by the MHC.
T helper cells provide “help” in the form of lymphokine secretion. Such lymphokines help B cells to divide,
differentiate, and produce antibodies. Lymphokines are also required for the development of leukocyte lines from
hematopoietic stem cells and development of cytotoxic T cells. They also
P.364
cause activation of macrophages, allowing them to destroy the pathogens they have taken up. Cytotoxic T cells
are capable of destroying virus-infected target cells or allogeneic (transplanted) cells.
Morphologic Correlation
Scanning electron microscopy shows profound alterations to the plasma membrane of the T cells after CPB. The
number of microvilli and lymphocyte surface folding both decrease. Furthermore, after CPB, the membrane does
not accommodate monoclonal microbeads.
Quality and Quantity

Phenotypic changes induced by CPB have been investigated using standard commercially available leukocyte-
labeling monoclonal antibodies together with flow cytometry. CD3+ and CD4+ cells decrease and CD8+ cells
increase, hence the CD4+/CD8+ ratio increases. Such changes peak on postoperative day 1 but remain
abnormal for approximately 1 week (72). T-lymphocyte counts decrease after CPB (82). The capacity of the
immune system to counteract microbial infection decreases after cardiac surgery because of consumed (and
unreplaced) complement factors and decreased cellular immune elements such as neutrophils and natural killer
cells (79,80,81,82).
Mechanisms
The mechanism responsible for the decrease in circulating T lymphocytes after CPB remains undefined.
Elevated cortisol levels probably play an important postoperative immunosuppressant role, yet this is unlikely to
be the only factor in this complex phenomenon. Elevation of serum corticosteroids may induce redistribution of
circulating T cells to lymphoid tissues, although this is usually mild and transient. Although serum cortisol levels
are elevated after surgery, the lack of correlation between changes in serum cortisol and changes in lymphocyte
number and function suggests that serum cortisol is not an etiologic factor in postoperative T-cell dysfunction.
Post-CPB reductions in T-cell activity are both quantitative and qualitative, likely causes for which include
hemodilution, intravascular-to-extravascular fluid shifts, mechanical destruction, consumption, and redistribution
among bone marrow, lymphoid tissue, and peripheral blood (80,83).
THERAPEUTIC APPROACHES
Effective amelioration of SIRAB has yet to become a reality. Difficulty in maintaining adequate perfusion pressure
toward the end of bypass suggests a profoundly low systemic vascular resistance, which is consistent with
SIRAB. Vasoconstrictor and inotropic drugs constitute the primary current treatment of this situation, although
this does not address the pathophysiology. To prevent or ameliorate SIRAB, the optimal strategy would be to
develop a CPB circuit that does not induce contact activation of blood components.
Pharmacologic Manipulation
Pharmacologic attempts to suppress the inflammatory response to cardiac surgery have failed thus far to
improve clinical outcomes (84). This is likely due to the fact that the immunologic response may not be pathologic
per se (as it is in autoimmune diseases), but rather represents a secondary response to the altered physiology of
CPB.
Corticosteroids
The physiologic effects of corticosteroids are numerous and widespread. They possess anti-inflammatory
properties and influence the water/electrolyte balance and the metabolism of carbohydrate, protein, and lipid.
Single-dose dexamethasone for cardiac surgery has failed to affect 30-day mortality in a randomized, controlled
clinical trial of 4,494 patients (85). A subgroup of this trial underwent cognitive testing at 1 and 12 months
following surgery and failed to show any improvement in cognitive function (86). Similarly, preliminary results of
the Canadian Steroids In Cardiac Surgery Trial (SIRS Trial) (NCT00427388) have not been promising. Further
studies might investigate a role for steroid treatment using other doses, administration protocols, or types of
steroids.
Alternative Strategies
The C5 complement inhibitor pexelizumab has been studied in several clinical trials. Pexelizumab was associated
with only a 6.7% nonsignificant reduction in the primary composite end point of death or myocardial infarction in
the PRIMO-CABG II trial (87). These results were surprising as the previous PRIMO-CABG I trial had suggested
more favorable outcomes (88,89). Furthermore, pexelizumab administration had no effect on global cognitive
outcomes after cardiac surgery, with the exception of a possible effect to reduce dysfunction in the visuo-spatial
domain (90). An exploratory analysis of the combined PRIMO I and II data (7,353 patients) suggested a mortality
benefit for certain high-risk cardiac surgery patients (87). Furthermore, a meta-analysis of pexelizumab in
ischemic heart disease suggested benefits in patients undergoing CABG (91).
An interesting novel approach is represented by the administration of cyclosporine. Cyclosporine inhibits the
opening of the mitochondrial permeability transition pore and its ability to prevent ischemia/reperfusion injury in
patients undergoing aortic valve replacement has been studied in a small population (61 patients) (92).
Intravenous cyclosporine bolus dosing reduced the area under the curve for postoperative cardiac troponin I
postoperatively by 35%. Whether these preliminary results will translate into improvement of more meaningful
clinical outcomes needs further study.
Mechanical Manipulation
Depletion of Leukocytes and Inflammatory Mediators
Conducting ultrafiltration at the termination of CPB, such as modified ultrafiltration (MUF), aims to reverse
hemodilution and decrease tissue edema and circulating inflammatory
P.365
mediators. Reducing the number of circulating leukocytes by the use of leukocyte-depleting filters is another way
to modify the inflammatory process. Some studies report reduced lung injury and improved oxygenation (93), as
well as reduced hospital length of stay (94).
Mechanical Considerations
Pulsatile perfusion may have beneficial effects with respect to hemodynamics, microcirculation, and organ
dysfunction, compared with nonpulsatile flow (95), as demonstrated by many experimental and clinical studies
(96,97,98,99). A recent meta-analysis of eight studies including 970 patients suggested improved postoperative
pulmonary function in addition to shorter intensive care unit (ICU) and hospital stay (100). However, as Murphy
et al. (101) point out, there have been over 150 basic and clinical science investigations on the use of pulsatile
versus nonpulsatile technique for CPB and the controversy continues because the results are inconclusive.
Membrane oxygenators currently predominate over bubble oxygenators for cardiopulmonary bypass in
developed nations, as they provide more titratable arterial PO2 values and less blood trauma, especially with
prolonged use. Modern membrane oxygenators provide blood flow to surrounding fibers that are filled with
“inspired” gases that equilibrate across the membrane (102).
Coating of oxygenator membranes and CPB tubing and filters with heparin inhibits the release of proinflammatory
cytokines and reduces complement and platelet activation (103,104). A meta-analysis including 3,434 patients
found that heparin-bonded circuits decreased the incidence of blood transfusion, sternal reexploration for
bleeding, duration of mechanical ventilation, and hospital length of stay. Effects on other outcomes were minimal
(105).
The adverse impact of blood contact with extracorporeal surfaces, air-fluid interface, and cell damage by
cardiotomy suction associated with conventional bypass has led to the development of minimized
cardiopulmonary bypass circuits (mini-CPB). Such circuits use a closed CPB system characterized by reduced
surface area and priming volume, elimination of cardiotomy suction, and prevention of air-blood contact. Studies
comparing mini-CPB to conventional CPB show delayed or reduced secretion of proinflammatory cytokines,
attenuated complement activation, and blunted leukocyte activation (106,107,108). The use of mini-CPB was
associated with less hemodilution and thus less blood transfusion (106,107,108). It remains unclear if this
approach improves major clinical outcomes, but interpretation is complicated by the use of different mini-CPB
systems and the heterogeneity of CPB protocols.
SUMMARY
It appears likely that the inflammatory and immunologic sequelae of CPB are not primarily responsible per
se for a large part of the morbidity and mortality seen postoperatively, although they may contribute. This is
highlighted by the lack of obvious deleterious effects of CPB in the more recent offpump/on-pump CABG
prospective comparison trials. However, perioperative inflammation assumes greater importance in longer,
more complex surgery performed on patients who are at extremes of age and who have significant comorbid
conditions. Furthermore, it appears as if prevention of inflammation through minimizing and preempting
iatrogenic injury is more likely to succeed than pharmacologic intervention after the injury has occurred.
While some substances have shown promise (e.g., the C5 complement inhibitor pexelizumab), effects on
meaningful clinical outcomes have been inconsistent.
KEY Points
CPB is associated with a systemic inflammatory response that includes cellular and noncellular
elements.
Results from recent large-scale clinical trials comparing off-pump CABG surgery to conventional
CABG question the clinical relevance of inflammation attributable to CPB alone.
The complement system is a dynamic network that is highly integrated within other pathways, and is
activated during CPB.
Use of complement inhibitors (e.g., pexelizumab) remains a target for immunomodulative therapy in
the context of cardiac surgery.
Mini-CPB show promise to attenuate the inflammatory response to CPB through surface area and
priming volume reductions, cardiotomy suction elimination, and air-blood contact prevention.
Minimizing occurrence of inflammation by preempting iatrogenic injury is more likely to be successful
than pharmacologic intervention after the injury has occurred.
ACKNOWLEDGMENTS
Mustafa Zakkar, Kenneth Taylor, and Philip I. Hornick wrote the chapter for the third edition. Mustafa Zakkar and
Karsten Bartels updated the chapter for the current edition.
REFERENCES
1. Edmunds LH. Cardiopulmonary bypass after 50 years. N Engl J Med 2004;351:1603-1606.
2. Miedzinski LJ, Keren G. Serious infectious complications of open-heart surgery. Can J Surg 1987;30:103-
107.
3. Kirklin JK, McGiffin DC. Early complications following cardiac surgery. Cardiovasc Clin 1987;17:321-343.
P.366
4. Bartels K, Barbeito A, Mackensen GB. The anesthesia team of the future. Curr Opin Anaesthesiol
2011;24:687-692.
5. Shroyer AL, Grover FL, Hattler B, et al. On-pump versus off-pump coronary-artery bypass surgery. N Engl
J Med 2009;361:1827-1837.
6. Lamy A, Devereaux PJ, Prabhakaran D, et al. Off-pump or on-pump coronary-artery bypass grafting at 30
days. N Engl J Med 2012;366:1489-1497.
7. Lamy A, Devereaux PJ, Prabhakaran D, et al. Effects of off-pump and on-pump coronary-artery bypass
grafting at 1 year. N Engl J Med 2013;368:1179-1188.
8. Houlind K, Kjeldsen BJ, Madsen SN, et al. On-pump versus off-pump coronary artery bypass surgery in
elderly patients: results from the danish on-pump versus off-pump randomization study. Circulation
2012;125:2431-2439.
9. Rather LJ. Disturbance of function (functio laesa): the legendary fifth cardinal sign of inflammation, added
by galen to the four cardinal signs of celsus. Bull N Y Acad Med 1971;47:303-322.
10. Turvey SE, Broide DH. Innate immunity. J Allergy Clin Immunol 2010;125:S24-S32.
11. Bonilla FA, Oettgen HC. Adaptive immunity. J Allergy Clin Immunol 2010;125:S33-S40.
12. Chen GY, Nunez G. Sterile inflammation: sensing and reacting to damage. Nat Rev Immunol
2010;10:826-837.
13. Laffey JG, Boylan JF, Cheng DC. The systemic inflammatory response to cardiac surgery: implications
for the anesthesiologist. Anesthesiology 2002;97:215-252.
14. Bartels K, Ma Q, Venkatraman TN, et al. Effects of deep hypothermic circulatory arrest on the blood brain
barrier in a cardiopulmonary bypass model—a pilot study. Heart Lung Circ 2014; 23(10):981-984.
15. Marik PE. Definition of sepsis: not quite time to dump sirs? Crit Care Med 2002;30:706-708.
16. Bone RC, Balk RA, Cerra FB, et al.; American College of Chest Physicians/Society of Critical Care
Medicine Consensus Conference Committee. Definitions for sepsis and organ failure and guidelines for the
use of innovative therapies in sepsis. Crit Care Med 1992;20:864-874.
17. Levy MM, Fink MP, Marshall JC, et al. 2001 SCCM/ESICM/ACCP/ATS/SIS international sepsis
definitions conference. Crit Care Med 2003;31:1250-1256.
18. Westaby S. Complement and the damaging effects of cardiopulmonary bypass. Thorax 1983;38:321-325.
19. Bartels K, Karhausen J, Clambey ET, et al. Perioperative organ injury. Anesthesiology 2013;119:1474-
1489.
20. Levin MA, Lin HM, Castillo JG, et al. Early on-cardiopulmonary bypass hypotension and other factors
associated with vasoplegic syndrome. Circulation 2009;120:1664-1671.
21. Sablotzki A, Muhling J, Dehne MG, et al. Treatment of sepsis in cardiac surgery: role of immunoglobulins.
Perfusion 2001;16:113-120.
22. Cremer J, Martin M, Redl H, et al. Systemic inflammatory response syndrome after cardiac operations.
Ann Thorac Surg 1996;61:1714-1720.
23. Salis S, Mazzanti VV, Merli G, et al. Cardiopulmonary bypass duration is an independent predictor of
morbidity and mortality after cardiac surgery. J Cardiothorac Vasc Anesth 2008;22:814-822.
24. Royston D. The inflammatory response and extracorporeal circulation. J Cardiothorac Vasc Anesth
1997;11:341-354.
25. Holmes JH 4th, Connolly NC, Paull DL, et al. Magnitude of the inflammatory response to cardiopulmonary
bypass and its relation to adverse clinical outcomes. Inflamm Res 2002;51:579-586.
26. Miller BE, Levy JH. The inflammatory response to cardiopulmonary bypass. J Cardiothorac Vasc Anesth
1997;11:355-366.
27. Morariu AM, Gu YJ, Huet RC, et al. Red blood cell aggregation during cardiopulmonary bypass: a
pathogenic cofactor in endothelial cell activation? Eur J Cardiothorac Surg 2004;26:939-946.
28. Reinhart K, Bayer O, Brunkhorst F, et al. Markers of endothelial damage in organ dysfunction and sepsis.
Crit Care Med 2002;30:S302-S312.
29. Patel KD, Cuvelier SL, Wiehler S. Selectins: critical mediators of leukocyte recruitment. Semin Immunol
2002;14:73-81.
30. Springer TA. Traffic signals for lymphocyte recirculation and leukocyte emigration: the multistep
paradigm. Cell 1994;76:301-314.
31. Bevilacqua MP. Endothelial-leukocyte adhesion molecules. Annu Rev Immunol 1993;11:767-804.
32. Bevilacqua MP, Nelson RM, Mannori G, et al. Endothelial-leukocyte adhesion molecules in human
disease. Annu Rev Med 1994;45:361-378.
33. McEver RP. Selectins: lectins that initiate cell adhesion under flow. Curr Opin Cell Biol 2002;14:581-586.
34. Muller WA. Leukocyte-endothelial-cell interactions in leukocyte transmigration and the inflammatory
response. Trends Immunol 2003;24:327-334.
35. Haga Y, Hatori N, Yoshizu H, et al. Granulocyte superoxide anion and elastase release during
cardiopulmonary bypass. Artif Organs 1993;17:837-842.
36. Gadaleta D, Fahey AL, Verma M, et al. Neutrophil leukotriene generation increases after
37. Gillinov AM, Redmond JM, Winkelstein JA, et al. Complement and neutrophil activation during
cardiopulmonary bypass: a study in the complement-deficient dog. Ann Thorac Surg 1994;57:345-352.
38. Frering B, Philip I, Dehoux M, et al. Circulating cytokines in patients undergoing normothermic
39. Wehlin L, Vedin J, Vaage J, et al. Peripheral blood monocyte activation during coronary artery bypass
grafting with or without cardiopulmonary bypass. Scand Cardiovasc J 2005;39:78-86.
40. Goldstein JI, Goldstein KA, Wardwell K, et al. Increase in plasma and surface CD163 levels in patients
undergoing coronary artery bypass graft surgery. Atherosclerosis 2003;170:325-332.
41. Ferraris VA, Ferraris SP, Singh A, et al. The platelet thrombin receptor and postoperative bleeding. Ann
Thorac Surg 1998;65:352-358.
42. Gemmell CH, Ramirez SM, Yeo EL, et al. Platelet activation in whole blood by artificial surfaces:
identification of platelet-derived microparticles and activated platelet binding to leukocytes as material-
induced activation events. J Lab Clin Med 1995;125:276-287.
43. Day JR, Landis RC, Taylor KM. Heparin is much more than just an anticoagulant. J Cardiothorac Vasc
Anesth 2004;18:93-100.
44. Weerasinghe A, Taylor KM. The platelet in cardiopulmonary bypass. Ann Thorac Surg 1998;66:2145-
2152.
45. Holloway DS, Summaria L, Sandesara J, et al. Decreased platelet number and function and increased
fibrinolysis contribute to postoperative bleeding in cardiopulmonary bypass patients. Thromb Haemost
1988;59:62-67.
46. Verrier ED, Boyle EM Jr. Endothelial cell injury in cardiovascular surgery. Ann Thorac Surg 1996;62:915-
922.
47. Addonizio VP. Platelet function in cardiopulmonary bypass and artificial organs. Hematol Oncol Clin
North Am 1990;4:145-155.
48. Watkins WD, Peterson MB, Kong DL, et al. Thromboxane and prostacyclin changes during
cardiopulmonary bypass with and without pulsatile flow. J Thorac Cardiovasc Surg 1982;84:250-256.
49. Jung G, Razafindranaibe F, Elkouby A, et al. Modifications of platelet shape change and atp release
during cardiopulmonary bypass. Haemostasis 1995;25:149-157.
50. 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;56:824-834.
51. Larsen E, Celi A, Gilbert GE, et al. Padgem protein: a receptor that mediates the interaction of activated
platelets with neutrophils and monocytes. Cell 1989;59:305-312.
52. Neumann FJ, Marx N, Gawaz M, et al. Induction of cytokine expression in leukocytes by binding of
thrombin-stimulated platelets. Circulation 1997;95:2387-2394.
53. Weyrich AS, Elstad MR, McEver RP, et al. Activated platelets signal chemokine synthesis by human
monocytes. J Clin Invest 1996;97:1525-1534.
54. Celi A, Pellegrini G, Lorenzet R, et al. P-selectin induces the expression of tissue factor on monocytes.
Proc Natl Acad Sci USA 1994;91:8767-8771.
55. Palabrica T, Lobb R, Furie BC, et al. Leukocyte accumulation promoting fibrin deposition is mediated in
vivo by P-selectin on adherent platelets. Nature 1992;359:848-851.
56. Esmon CT, Taylor FB Jr, Snow TR. Inflammation and coagulation: linked processes potentially regulated
through a common pathway mediated by protein C. Thromb Haemost 1991;66:160-165.
57. Hunt BJ, Parratt RN, Segal HC, et al. Activation of coagulation and fibrinolysis during cardiothoracic
operations. Ann Thorac Surg 1998;65:712-718.
58. Cramer EM, Lu H, Caen JP, et al. Differential redistribution of platelet glycoproteins Ib and IIb-IIIa after
plasmin stimulation. Blood 1991;77:694-699.
59. Chenoweth DE, Cooper SW, Hugli TE, et al. Complement activation during cardiopulmonary bypass:
evidence for generation of c3a and c5a anaphylatoxins. N Engl J Med 1981;304:497-503.
60. Pober JS, Cotran RS. Cytokines and endothelial cell biology. Physiol Rev. 1990;70:427-451.
61. Kluft C, Dooijewaard G, Emeis JJ. Role of the contact system in fibrinolysis. Semin Thromb Hemost
1987;13:50-68.
P.367
62. Bruins P, te Velthuis H, Yazdanbakhsh AP, et al. Activation of the complement system during and after
cardiopulmonary bypass surgery: postsurgery activation involves C-reactive protein and is associated with
postoperative arrhythmia. Circulation 1997;96:3542-3548.
63. Ricklin D, Hajishengallis G, Yang K, et al. Complement: a key system for immune surveillance and
homeostasis. Nat Immunol 2010;11:785-797.
64. Stahl GL, Shernan SK, Smith PK, et al. Complement activation and cardiac surgery: a novel target for
improving outcomes. Anesth Analg 2012;115:759-771.
65. Boyle EM Jr, Pohlman TH, Johnson MC, et al. Endothelial cell injury in cardiovascular surgery: the
systemic inflammatory response. Ann Thorac Surg 1997;63:277-284.
66. Verrier ED, Shen I. Potential role of neutrophil anti-adhesion therapy in myocardial stunning, myocardial
infarction, and organ dysfunction after cardiopulmonary bypass. J Card Surg 1993;8:309-312.
67. Nilsson L, Kulander L, Nystrom SO, et al. Endotoxins in cardiopulmonary bypass. J Thorac Cardiovasc
Surg 1990;100:777-780.
68. Jungwirth B, Kellermann K, Qing M, et al. Cerebral tumor necrosis factor alpha expression and long-term
neurocognitive performance after cardiopulmonary bypass in rats. J Thorac Cardiovasc Surg 2009;138:1002-
1007.
69. Bartels K, McDonagh DL, Newman MF, et al. Neurocognitive outcomes after cardiac surgery. Curr Opin
Anaesthesiol 2013;26:91-97.
70. Ulicny KS Jr, Hiratzka LF. The risk factors of median sternotomy infection: a current review. J Card Surg
1991;6:338-351.
71. Goris RJ, te Boekhorst TP, Nuytinck JK, et al. Multiple-organ failure. Generalized autodestructive
inflammation? Arch Surg 1985;120:1109-1115.
72. Alexander JW. The role of host defense mechanisms in surgical infections. Surg Clin North Am
1980;60:107-116.
73. Markewitz A, Faist E, Niesel T, et al. Changes in lymphocyte subsets and mitogen responsiveness
following open-heart surgery and possible therapeutic approaches. Thorac Cardiovasc Surg 1992;40:14-18.
74. Sablotzki A, Dehne M, Welters I, et al. Alterations of the cytokine network in patients undergoing
75. Nathan N, Denizot Y, Cornu E, et al. Cytokine and lipid mediator blood concentrations after coronary
artery surgery. Anesth Analg 1997;85:1240-1246.
76. van Velzen-Blad H, Dijkstra YJ, Schurink GA, et al. Cardiopulmonary bypass and host defense functions
in human beings. I. Serum levels and role of immunoglobulins and complement in phagocytosis. Ann Thorac
Surg 1985;39:207-211.
77. Burrows FA, Steele RW, Marmer DJ, et al. Influence of operations with cardiopulmonary bypass on
polymorphonuclear leukocyte function in infants. J Thorac Cardiovasc Surg 1987;93:253-260.
78. Karhausen J, Qing M, Gibson A, et al. Intestinal mast cells mediate gut injury and systemic inflammation
in a rat model of deep hypothermic circulatory arrest. Crit Care Med 2013;41(9):e200-e210.
79. Nguyen DM, Mulder DS, Shennib H. Effect of cardiopulmonary bypass on circulating lymphocyte
function. Ann Thorac Surg 1992;53:611-616.
80. Tajima K, Yamamoto F, Kawazoe K, et al. Cardiopulmonary bypass and cellular immunity: changes in
lymphocyte subsets and natural killer cell activity. Ann Thorac Surg 1993;55:625-630.
81. Shimono T, Yada I, Kanamori Y, et al. Reticuloendothelial function following cardiopulmonary bypass:
laboratory and electron microscopy findings. J Surg Res 1994;56:446-451.
82. Markewitz A, Lante W, Franke A, et al. Alterations of cell-mediated immunity following cardiac operations:
clinical implications and open questions. Shock 2001;16(Suppl 1):10-15.
83. Ide H, Kakiuchi T, Furuta N, et al. The effect of cardiopulmonary bypass on t cells and their
subpopulations. Ann Thorac Surg 1987;44:277-282.
84. Esper SA, Subramaniam K, Tanaka KA. Pathophysiology of cardiopulmonary bypass: current strategies
for the prevention and treatment of anemia, coagulopathy, and organ dysfunction. Semin Cardiothorac Vasc
Anesth 2014;18:161-176.
85. Dieleman JM, Nierich AP, Rosseel PM, et al. Intraoperative high-dose dexamethasone for cardiac
surgery: a randomized controlled trial. JAMA 2012;308:1761-1767.
86. Ottens TH, Dieleman JM, Sauer AC, et al; Dexamethasone for Cardiac Surgery Study Group. Effects of
dexamethasone on cognitive decline after cardiac surgery: a randomized controlled trial. Anesthesiology
2014;121:492-500.
87. Smith PK, Shernan SK, Chen JC, et al. Effects of c5 complement inhibitor pexelizumab on outcome in
high-risk coronary artery bypass grafting: combined results from the PRIMO-CABG I and II trials. J Thorac
88. Verrier ED, Shernan SK, Taylor KM, et al. Terminal complement blockade with pexelizumab during
coronary artery bypass graft surgery requiring cardiopulmonary bypass: a randomized trial. JAMA
2004;291:2319-2327.
89. Shernan SK, Fitch JC, Nussmeier NA, et al. Impact of pexelizumab, an anti-c5 complement antibody, on
total mortality and adverse cardiovascular outcomes in cardiac surgical patients undergoing cardiopulmonary
bypass. Ann Thorac Surg 2004;77:942-949; discussion 949-950.
90. Mathew JP, Shernan SK, White WD, et al. Preliminary report of the effects of complement suppression
with pexelizumab on neurocognitive decline after coronary artery bypass graft surgery. Stroke 2004;35:2335-
2339.
91. Testa L, Van Gaal WJ, Bhindi R, et al. Pexelizumab in ischemic heart disease: a systematic review and
meta-analysis on 15,196 patients. J Thorac Cardiovasc Surg 2008;136:884-893.
92. Chiari P, Angoulvant D, Mewton N, et al. Cyclosporine protects the heart during aortic valve surgery.
93. Alexiou C, Tang AA, Sheppard SV, et al. The effect of leucodepletion on leucocyte activation, pulmonary
inflammation and respiratory index in surgery for coronary revascularisation: a prospective randomised study.
94. Olivencia-Yurvati AH, Ferrara CA, Tierney N, et al. Strategic leukocyte depletion reduces pulmonary
microvascular pressure and improves pulmonary status post-cardiopulmonary bypass. Perfusion
2003;18(Suppl 1):23-31.
95. Hornick P, Taylor K. Pulsatile and nonpulsatile perfusion: the continuing controversy. J Cardiothorac
Vasc Anesth 1997;11:310-315.
96. Herreros J, Berjano EJ, Sola J, et al. Injury in organs after cardiopulmonary bypass: a comparative
experimental morphological study between a centrifugal and a new pulsatile pump. Artif Organs
2004;28:738-742.
97. Undar A, Masai T, Yang SQ, et al. Pulsatile perfusion improves regional myocardial blood flow during
and after hypothermic cardiopulmonary bypass in a neonatal piglet model. ASAIO J 2002;48:90-95.
98. Fukae K, Tominaga R, Tokunaga S, et al. The effects of pulsatile and nonpulsatile systemic perfusion on
renal sympathetic nerve activity in anesthetized dogs. J Thorac Cardiovasc Surg 1996;111:478-484.
99. Sezai A, Shiono M, Nakata K, et al. Effects of pulsatile CPB on interleukin-8 and endothelin-1 levels. Artif
Organs 2005;29:708-713.
100. Lim CH, Nam MJ, Lee JS, et al. A meta-analysis of pulmonary function with pulsatile perfusion in cardiac
surgery. Artif Organs 2014;39(2):110-117.
101. Murphy GS, Hessel EA 2nd, Groom RC. Optimal perfusion during cardiopulmonary bypass: an
evidence-based approach. Anesth Analg 2009;108:1394-1417.
102. Haworth WS. The development of the modern oxygenator. Ann Thorac Surg 2003;76:S2216-S2219.
103. Mollnes TE, Videm V, Gotze O, et al. Formation of c5a during cardiopulmonary bypass: inhibition by
precoating with heparin. Ann Thorac Surg 1991;52:92-97.
104. Moen O, Hogasen K, Fosse E, et al. Attenuation of changes in leukocyte surface markers and
complement activation with heparin-coated cardiopulmonary bypass. Ann Thorac Surg 1997;63:105-111.
105. Mangoush O, Purkayastha S, Haj-Yahia S, et al. Heparin-bonded circuits versus nonheparin-bonded

circuits: an evaluation of their effect on clinical outcomes. Eur J Cardiothorac Surg 2007;31:1058-1069.
106. Ohata T, Mitsuno M, Yamamura M, et al. Minimal cardiopulmonary bypass attenuates neutrophil
activation and cytokine release in coronary artery bypass grafting. J Artif Organs 2007;10:92-95.
107. Kiaii B, Fox S, Swinamer SA, et al. The early inflammatory response in a mini-cardiopulmonary bypass
system: a prospective randomized study. Innovations 2012;7:23-32.
108. Fromes Y, Gaillard D, Ponzio O, et al. Reduction of the inflammatory response following coronary
bypass grafting with total minimal extracorporeal circulation. Eur J Cardiothorac Surg 2002;22:527-533.
Chapter 14
Kidney Function and Cardiopulmonary Bypass
Anthony de la Cruz
David M. Rothenberg
Studies designed to assess, prevent, and treat perioperative myocardial dysfunction are replete in the medical
literature and include the following: detailed approaches for the determination of preoperative cardiac risk (1,2);
methods of perioperative monitoring of cardiac dysfunction with sophisticated techniques such as sensitive
markers of injury, ST-segment analysis, pulmonary artery catheterization, and transesophageal
echocardiography; and pharmacologic interventions designed to prevent and/or treat postoperative myocardial
infarction (3,4). In contrast, when it relates to evaluating and treating perioperative renal dysfunction, the focus
seems to center on whether the patient is making “good urine,” and if not, how to make it appear! To most, the
notion of “good urine” is so deeply rooted in the mythology of perioperative care that to modify this concept
appears sacrilegious. This discussion, irreverent as it may seem, will attempt to dispel the myth of “good urine,”
and provide a more physiologic and analytic strategy to understanding perioperative oliguria in patients
undergoing cardiac surgery. Basic renal physiology and pathophysiology as it relates to renal ischemia,
perioperative risk factors for developing postoperative acute kidney injury (AKI), and modalities intended to
improve renal blood flow will be highlighted.
BASIC RENAL PHYSIOLOGY AND PATHOPHYSIOLOGY

The kidney primarily functions to preserve internal homeostasis by regulating effective arterial blood volume
(EABV), osmolality, and ionic composition, and to concentrate and excrete the daily endogenous and exogenous
load of nitrogenous waste. These actions occur by a complex interplay between glomerular filtration, tubular
reabsorption, and tubular secretion. The kidney also plays a vital role as an organ of endocrine function,
regulating red blood cell mass by the production of erythropoietin, and calcium and phosphorus homeostasis
through the synthesis of vitamin D to its most active form, 1,25-dihydroxycholecalciferol.
The glomerular apparatus is a network of capillaries originating from the afferent arteriole and surrounded by an
extension of the basement membrane of the proximal tubule called Bowman’s capsule. The urinary space, or
Bowman’s space (BS), separates the capsule from the glomerular tuft. The formation of urine commences with a
protein-free ultrafiltrate of plasma passing through the glomerulus into the BS. The rate of formation of tubular
fluid (glomerular ultrafiltration rate or GFR) is dependent on the hydraulic permeability of the glomerular capillary
and the net ultrafiltration pressures across the capillary wall. GFR is a non-energy-requiring process regulated
by the Starling forces, as defined by the following equation:
The difference in hydrostatic pressure between the glomerular capillary (PGC) and Bowman’s space (PBS)
promotes filtration, whereas colloid osmotic pressure in the capillaries (πGC) opposes it. As filtration of a protein-
free fluid transpires, a progressive increase in πGC ensues such that by the termination of the capillary the
ultrafiltration pressure becomes zero (i.e., PGC = πGC + PBS). This physiologic principle stipulates that GFR is
highly dependent on renal plasma flow; the greater the flow rate, the slower the rise in πGC and hence an
increase in GFR.
Normal GFR is approximately 180 L/day and relates to the extensive surface area and permeability of the
glomerular tuft. Despite wide fluctuations in mean arterial pressure, only minute changes arise in GFR due to
renal autoregulation. Renal autoregulation occurs for both renal blood flow and GFR, and is centered on the
afferent arteriole’s inherent ability to sense transmural pressure and alter its wall tension to maintain resistance
proportional to pressure. Although renal blood flow begins to decline at mean arterial pressures less than 50
mmHg, autoregulation of GFR occurs at higher pressures (70-80 mmHg). This concept becomes clinically
relevant during cardiopulmonary bypass (CPB) when perfusion pressure is decreased below the autoregulatory
threshold for GFR, resulting in diminished urine output. The relation of perfusion pressure during CPB to renal
blood flow and hence urine output has never been established, as will be discussed later; however, increasing
perfusion pressure is often considered when managing intraoperative oliguria to theoretically prevent AKI.
P.370
Relative to renal blood flow and perfusion, the kidney receives 20% of the normal cardiac output (Qt), an amount
far in excess of the kidney’s total oxygen and energy requirement. However, this percentage of Qt is essential to
power the processes of filtration, reabsorption, and secretion. Compared with the proportion of overall renal
blood flow, a striking disparity exists between the renal cortex and medulla. The cortex receives more than 90%
of renal blood flow, creating tissue oxygen tensions of approximately 50 versus 8 to 10 mmHg in the medulla.
Although necessary to prevent washout of the hypertonic interstitium and to preserve the osmotic gradient
necessary for tubular secretion and reabsorption, preferential blood flow to the cortex results in the medullary
thick ascending limb (mTAL) of the loop of Henle being extremely vulnerable to hypoperfusion-induced ischemia,
and may explain why AKI can be induced by as little as a 40% decrease in renal blood flow. Prevention of renal
ischemia and AKI is therefore dependent on increasing oxygen delivery as well as reducing oxygen demand. An
intrinsic tubuloglomerular feedback system provides initial protection in the event of medullary hypoperfusion by
renin-mediated afferent arteriolar vasoconstriction, which in turn leads to a decrease in plasma ultrafiltration and
hence a decrease in energy expenditure of the cells of the mTAL (4). A decline in urine output is to be expected
and is termed prerenal success. Prolonged periods of hypoperfusion may however overwhelm this process,
leading to erythrocyte sludging in the medulla and eventual tubular obstruction from necrotic cellular debris. The
ensuing rise in intratubular pressure (↑ PBS) in relation to the decline in glomerular capillary pressure (↓ PGC)
may result in progressive azotemia not amenable to manipulation of EABV, Qt, or other extrarenal factors, and
ultimately AKI.
Therefore, GFR, and consequently urine formation, may be diminished for the following reasons: (1) a decrease
in Kf from exposure to nephrotoxins; (2) a decrease in PGC from hypoperfusion; (3) an increase in PBS from
intratubular obstruction due to cellular debris; and (4) an increase in πGC from concentration of proteins due to
dehydration. Although the decline in GFR will produce a decline in urine output, the contrary is not necessarily
true; that is, a decrease in urine volume does not always mean a decline in GFR, nor does it imply the
diagnosis of AKI.
The additional processes of tubular reabsorption and secretion further refine urine formation. Homeostasis is
preserved by transforming the plasma ultrafiltrate into urine of variable volume, osmolarity, and composition
through a complex interaction between the renin-angiotensin-aldosterone system, the sympathetic nervous
system, and other hormonal and physical factors. The proximal, distal, and collecting tubules each modulate and
control various functions. Of primary significance to those caring for patients during cardiac surgery is an
understanding of sodium and water homeostasis in relation to safeguarding EABV. Despite the vast amount of
sodium that is filtered daily (140 mEq × 180 L = 25,200 mEq), less than 1% is typically excreted in the urine. The
bulk of sodium reabsorption, and therefore volume and osmotic control, occurs in the proximal convoluted tubule,
the loop of Henle, and the distal tubule. During periods of hypovolemia, these segments fractionally reabsorb
more than 99% of the filtered load of sodium and thereby fractionally excrete less than 1%. (This concept of the
fractional excretion of sodium will be addressed in more detail later.) Urine is concurrently refined by the effect of
antidiuretic hormone (ADH) on the collecting duct to reabsorb water, thereby serving to retain plasma tonicity
(normal range, 280-295 mOsm/kg H2O). Osmoreceptor-mediated and baroreceptor-mediated releases of ADH
from the hypothalamus are the result of hypertonicity and low EABV, respectively. Finally, postoperative pain,
anxiety, and/or nausea may also stimulate the release of ADH independent of osmolarity or EABV. As would be
predicted, these patients characteristically develop oliguria despite having normal renal function. This is a
common scenario following cardiac surgery in which efforts to increase urine production by inappropriate volume
challenges may result in hyponatremia and/or pulmonary edema.
PREOPERATIVE RENAL RISK FACTORS

Multiple models for the prediction of AKI after cardiac surgery have been developed (see Table 14.1). The
models in these studies have demonstrated statistical significance in the ability to predict AKI. Although
definitions of AKI slightly differ in each of these studies, the similarities of variables were consistent.
Notwithstanding inconsistencies in the medical literature in defining the criteria for establishing preoperative
renal risk factors (9), virtually all prior studies have established preoperative renal dysfunction, as defined by an
elevated serum creatinine or a decrease in creatinine clearance, as the single greatest risk for developing
postoperative AKI in patients undergoing cardiac surgery. Creatinine, a breakdown product of muscle creatine, is
principally filtered with only nominal reabsorption and secretion and is therefore reflective of eGFR. Prior studies
in patients who had undergone cardiac surgery tended to define perioperative renal dysfunction as a serum
creatinine level that was greater than 1.35 to 1.5 mg% (120-130 mmol/L). The incidence of postoperative AKI in
these studies was less than 1% in patients with normal renal function undergoing routine, elective noncardiac
surgery. However, depending on the degree of renal insufficiency (e.g., whether the patient has chronic kidney
disease (CKD) requiring preoperative dialysis), the nature of surgery, and ensuing perioperative complications,
this incidence exceeded 20% and was associated with a 30% to 80% postoperative mortality
(10,11,12,13,14,15,16,17). Recently, a better preoperative estimation of eGFR (and hence better predictive
parameter of perioperative renal dysfunction) has been described and employs either serum creatinine and/or
cystatin
P.371
C as part of a calculated or measured creatinine clearance or eGFR (18). Wang et al. (19) confirmed that the
preoperative use of the Cockroft-Gault equation (Table 14.2) was a more accurate predictor of renal outcome in
patients undergoing cardiac surgery. In this observational study, it was noted that the odds of AKI requiring
dialysis (AKI-D), death, or having major morbidity increased by 52%, 27%, and 18%, respectively, for each 10
mL/min/1.73 m2 decrement in estimated creatinine clearance. This was in comparison to the risk-adjusted odds
of having the same adverse outcomes increase by 20%, 8%, and 13% for 0.2 mg% increment increases in serum
creatinine levels. Wijeysundera et al. (20) prospectively analyzed 10,751 patients undergoing cardiac surgery,
also assessing the value of preoperative screening of creatinine clearance based on the Cockroft-Gault
equation. The authors noted a 13% incidence of what they termed occult renal insufficiency (i.e., patients with
normal serum creatinine levels but calculated creatinine clearances of ≤60 mL/min), and found them to be at risk
for developing AKI-D. Although this approach to eGFR is not novel, it is clearly underutilized by most clinicians in
evaluating patients’ preoperative renal risk before cardiac surgery. This formula and more recent versions, the
modification of diet in renal disease (MDRD) equation (21), and CKD-EPI (22), offer more precise methods of
assessing preoperative renal risk for patients requiring cardiac surgery. In this regard, Inker et al. (23) have
further refined the eGFR by employing both serum levels of creatine and cystatin C, a protein less influenced by
muscle mass and diet, and solely eliminated by glomerular filtration.
TABLE 14.1. Preoperative variables included in models to predict AKI

Variable Thakar (5) Mheta (6) Demirjian (7) Berg (8)
Age X X
BMI X X
HTN X X
PVD/CVD X X
Diabetes X X X X
Chronic pulmonary disease X X X X
Hg concentration X X
Preoperative renal insufficiency X X X X
Redo cardiac surgery X X X X
Emergency operation X X X
Operation type X X X X
CHF X X
TABLE 14.2. Cockroft-Gault formula
Age in year.
Multiply by a factor of 0.85 for women because of reduced production of muscle creatinine than in men.
CCr, creatinine clearance; SCr, serum creatinine.
The RIFLE criteria were developed by the Acute Dialysis Quality Initiative group (ADQI) in order to unify the
diagnosis and classification of AKI for both research and clinical practice. These criteria utilize biochemical
markers (e.g., serum creatinine and eGFR), and urine output and their respective changes over time (Table
14.3). RIFLE criteria classify AKI patients into three severity categories (risk, injury and failure) as well as two
outcome categories (loss of function and endstage renal disease).
P.372
TABLE 14.3. Acute Dialysis Quality Initiative RIFLE criteria
GFR criteria Urine output criteria
Risk Increased creatinine × 1.5 or GFR decrease > 25% UO < 0.5 mL/kg/hr × 6 hr
Injury Increased creatinine × 2 or GFR decrease > 50% UO < 0.5 mL/kg/hr × 12 hr
Failure Increased creatinine × 3 or GFR decrease > 75% UO < 0.3 mL/kg/hr × 24 hr or anuria ×
12 hr
Loss Persistent ARF = complete loss of renal function >

4 weeks
ESRD End-stage renal disease
Adapted from Acute Dialysis Quality Initiative (www.adqi.net) 2002 fall newsletter.
In patients with chronic, non-dialysis-dependent renal dysfunction, the etiology of the underlying renal disease is
far less critical than their level of overall dysfunction. The preoperative renal risk of a patient with a history of
lupus nephritis and a creatinine clearance of 25 mL/min undergoing CPB is therefore no different from that of a
patient with hypertensive nephrosclerosis with a similar creatinine clearance and undergoing the same
procedure.
Advanced age also constitutes a risk factor for developing postoperative renal dysfunction and AKI. Multiple
studies have concluded that age more than 63 years is an independent variable for developing postoperative
renal failure and may be related to diminished nephron mass as a result of reduced expression of vascular
endothelial growth factor (24), as well as loss of autoregulatory ability. The odds ratio of 1.6 for the development
of AKI increases with every 10 years of age greater than 60 (8). Exposure to nephrotoxic agents may also
contribute to perioperative renal insufficiency. Radiocontrast agents presumably induce calcium-mediated
vasoconstriction leading to medullary ischemia, which is accentuated in highrisk individuals (25). Azotemic
patients who undergo cardiac or major vascular surgery and who are administered radiocontrast as part of their
preoperative evaluation are at particularly high-risk for developing AKI. Higher doses of iodine contrast media are
associated with an increased incidence of AKI. Doses of iodine contrast media approaching 5 g/kg are
associated with the AKI when cardiac operation is performed after angiography (26). Delaying elective surgery is
advisable if the serum creatinine increases by more than 0.5 mg% (25% decrease in creatinine clearance) within
48 hours of exposure, given the additional inherent surgical risk of postoperative AKI-D (27). Perhaps the type of
surgery should influence the time interval between angiography and surgical intervention. Hennessey et al. (28)
found that patients proceeding to the operative room within 24 hours after catheterization for valve surgery were
at increased risk of AKI versus patients with an interval of 48 or 72 hours. However, Ozkaynak et al. (29) found
that time to surgery after angiography was not a risk factor for AKI, in a retrospective study that examined mostly
coronary artery bypass graft (CABG) patients. Drugs with nephrotoxic side effects, such as aminoglycosides and
cyclosporine, may also cause AKI when serum levels are not properly monitored in the perioperative period. The
use of nonsteroidal anti-inflammatory agents per se does not seem to influence the incidence of postoperative
AKI, provided that preoperative renal function is normal (30).
Finally, it has been proposed that there may be a genetic predisposition for developing AKI following cardiac
surgery, particularly as it relates to the inflammatory response to CPB. Gaudino et al. (31) studied 111
consecutive patients undergoing single-vessel CABG, and noted a correlation between postoperative interleukin
6 (IL-6) levels and renal dysfunction in those patients with IL-6-174 G/C polymorphism.
Stafford-Smith et al. (32) isolated deoxyribonucleic acid (DNA) from 1,671 patients undergoing CABG and
depending upon the patients’ race, noted polymorphism of multiple alleles associated with the development
postoperative renal dysfunction. In the future, the ability to determine patients’ preoperative genetic profiles, in
order to gauge their degree of renal risk before cardiac surgery, may become commonplace.
OPERATIVE RENAL RISK FACTORS

Renal dysfunction following CPB continues to be a relatively common occurrence, with AKI-D developing in 1.2%
to 13% of patients, depending on their preoperative eGFR (10,11,14,15,16,17). Perhaps more importantly, the
development of AKI and AKI-D dramatically increases the risk of mortality. Table 14.4 lists several relevant
studies demonstrating the increased mortality risk associated with the development of AKI after cardiac surgery.
Intraoperative renal risk factors include low Qt, decreased EABV, need for intra-aortic balloon counterpulsation,
prolonged CPB times of more than 130 to 180 minutes and the development of a systemic inflammatory
response syndrome (SIRS), inappropriate hemodilution, and embolic phenomenon. Cardiac surgery with CPB is
associated with the development of a SIRS and associated renal dysfunction. Leukocyte activation, as a
component of SIRS, has been suggested as one of the many causes of perioperative renal injury (36). In this
regard, leukodepletion instituted during CPB has been shown to reduce markers of renal injury (37) and, in one
small prospective, randomized clinical trial, led to a decrease in the incidence of AKI-D (38). Aprotinin, a serine
protease inhibitor and antifibrinolytic, has also been postulated to mitigate against the inflammatory response
and have a renoprotective
P.373
effect (39). Although early reports of the use of aprotinin during CPB seemed to support this contention (40), a
recent large prospective, multicenter study noted a profound risk of aprotinin-associated AKI-D (41). In this study
of more than 4,300 patients, the intraoperative use of aprotinin during CABG with CPB resulted in a dose-
dependent doubling or tripling of AKI-D when compared with the use of aminocaproic acid and tranexamic acid.
The use of this drug to limit blood loss during complex or revision cardiac surgeries must be tempered by this
reported higher incidence of AKI and other severe end-organ damage, and the use of alternative antifibrinolytic
therapy to minimize perioperative bleeding while preserving renal function may be prudent (42).
TABLE 14.4. Mortality odds/hazard ratio
N patients No AKI AKI AKI-D
Drews et al. (33) 350 - 4-11 2.8-5
Hix et al. (34) 2,730 3.94 10.45 23.21
Lopez-Delgado et al. (35) 2,840 (409 w/AKI) 2.3 3.1

Relative to the effects of hemodilution on renal function, two recent studies question the role of low hematocrit as
a risk factor for postoperative AKI following cardiac surgery with CPB (43,44). Karkouti et al. (43), in a
prospective, observational study of more than 9,000 patients, raise the question of optimal hematocrit during
hemodilution. The authors found an increase in AKI-D when the hematocrit was less than 21% or more than
25%, suggesting a decrease in renal oxygen-carrying capacity or a decrease in microcirculatory blood flow,
respectively. Habib et al. (44) also suggested that a nadir hematocrit of less than 24% during hemodilution for
CPB was a risk factor for developing AKI-D.
Finally, as it relates to thromboembolic phenomenon and the incidence of AKI after CPB, Davilla-Roman et al.
(45), using intraoperative epiaortic ultrasound, identified ascending aortic atherosclerosis as an independent risk
factor for developing postoperative renal dysfunction. The authors studied 978 patients with normal preoperative
renal function undergoing open-heart surgery and noted that the incidence of postoperative renal dysfunction
increased with the degree of ascending aorta atherosclerosis from 4.1% in normal-mild disease to 9.0% in
moderate disease, and to 17.1% in those with severe disease. Although not assessed in this study, it is
postulated that this increased risk may relate to renal thromboembolism. This atheroma burden may be
associated with a genetic predisposition as noted by MacKensen et al. (46), who found a greater susceptibility of
renal dysfunction in patients with aortic atheromatous disease who lacked the apolipoprotein E ε4 allele. Other
factors such as pulsatile versus nonpulsatile flow and hypothermic versus normothermic CPB are discussed in
later chapters, but in general they have minimal, if any, effect on perioperative renal function (47,48).
Despite the observations that CPB duration is independently associated with AKI-D, the benefits of off-pump
coronary bypass (OPCAB) surgery on renal function remain controversial. An early retrospective analysis by
Gamaso et al. (49) failed to show a difference in renal outcome between OPCAB and CPB surgery, whereas a
similar retrospective study by Hayashida et al. (50) concluded that OPCAB surgery improved renal function as
measured by creatinine clearance, but without a difference in the incidence of AKI-D when compared with the
CPB group. Subsequently, Ascione et al. (51), in a small prospective, randomized controlled trial of 50 patients
undergoing CABG, analyzed creatinine clearance, urinary microalbumin/creatinine ratio, and urinary N-acetyl-
glucosaminidase activity, and concluded that OPCAB offered “superior” renal protection versus conventional
CABG employing CPB. (It should be pointed out that patients with preoperative renal risk factors were excluded
from the study and that no patient in either group developed AKI.) Several other small, prospective studies
assessing levels of cystatin C, urinary by-products of oxidation, and other markers of inflammation have
concluded that OPCAB is less likely to promote renal ischemia than on-pump procedures (52,53,54,55).
However, the clinical relevance of these findings is lacking. Given that urinary microenzymes and other urinary or
serum inflammatory mediators do not correlate with the development of AKI-D, larger prospective trials appear to
be necessary to determine whether OPCAB surgery truly offers renal protection for patients needing CABG.
In addressing this issue, two recent prospective observational studies failed to show any difference in the
incidence of AKI-D in patients undergoing OPCAB versus CPB, as did a recent meta-analysis (56,57,58).
However, Bucerius et al. (59), in a very large prospective study of 9,631 patients (8,870 CPB and 761 OPCAB),
found a 4.1% incidence of postoperative AKI-D in patients undergoing CPB versus 1.8% in patients undergoing
OPCAB procedures. Patients in the OPCAB group who sustained AKI-D were likely to have longer perioperative
length of stay (LOS), high transfusion requirement, and the need for urgent surgery. Although the benefits of
OPCAB on renal function remain under continued study, implications of CPB-associated AKI continue to raise
concern in regards to outcomes. In a study comparing propensity-matched patients undergoing OPCAB versus
CPB, relative risk of death was greater in patients undergoing CPB. Hix et al. (34) discussed survival benefit of
OPCAB having been a reflection of AKI risk reduction.
Thoraco-abdominal aortic surgery yields the greatest risk of developing AKI among the types of cardiac
surgeries. Over 50% of patients undergoing thoracic aortic surgery exhibit AKI (60). Prospective studies
describing the incidence of
P.374
AKI-D following thoracoabdominal aortic surgery ranges from 2.7% to 15% (61,62,63,64). In addition to direct
renal hypoperfusion from suprarenal aortic cross-clamping, the pathophysiology of renal dysfunction from aortic
cross-clamping and unclamping at any level appears to be related to an intricate relation between the renin-
angiotensin system, the sympathetic nervous system, prostaglandin pathways, oxygen-free radicals, the
complement cascade, and the release of cytokines and other inflammatory mediators (65,66). As with patients
undergoing cardiac surgery, preoperative renal function and age contribute considerably to renal outcome, but a
duration of more than 30 minutes of left renal ischemia and an intraoperative blood loss requiring more than 5
units of packed red blood cells are also predictive of developing AKI-D following aortic surgery (61,62,63,64).
Mortality in patients who sustain AKI-D after aortic surgery remains high (50%-60%) despite a variety of
intraoperative interventions such as left atrial to femoral bypass, renal artery cold perfusion, and deep
hypothermic circulatory arrest (67). Data are inconclusive as to whether the use of endovascular grafts for the
treatment of aortic aneurysms will decrease the incidence of AKI (68). A recent study shows prevalence of AKI
with thoracic endovascular aortic repair (TEVAR) is greater than previously reported (33). Further editorial
discussion of this study implies the increasing utilization of contrast media as a suspected reason for these
findings.
Finally, relative to the influence of anesthetic agents on renal function following cardiac surgery, the only factor
that merits consideration is the use of the inhalational anesthetic, sevoflurane. The issue of sevoflurane
nephrotoxicity has been a topic of debate in the anesthesia literature for many years. Sevoflurane is a fluorinated
anesthetic, which undergoes oxidative defluoridation resulting in the release of potentially nephrotoxic free
fluoride ions. Previous experimental data suggest a threshold for fluoride-induced nephrotoxicity to be 50 μM of
inorganic fluoride. Compound A, a by-product of the breakdown of sevoflurane by soda lime and barium
hydroxide lime, has also been shown experimentally to be nephrotoxic. Despite these experimental data, there
are currently no reports of clinically relevant renal dysfunction occurring in patients receiving sevoflurane even
during prolonged exposure, at low flow rates, or in those with preoperative renal insufficiency (69,70,71). These
findings are similar to those seen in patients who received sevoflurane during cardiac surgery. el Azab et al. (72),
in a small retrospective study, noted no difference in postoperative renal function in patients 6 weeks after
undergoing CABG with sevoflurane versus a sufentanil-midazolam anesthetic. In a larger, prospective trial, Story
et al. (73) showed no difference in renal outcome in patients receiving either sevoflurane, isoflurane, or propofol
during CPB. Sakamoto et al. (74) measured another by-product of sevoflurane metabolism,
hexafluoroisopropanol, and found no effect on postoperative renal function even in patients with preoperative
renal insufficiency. Finally, Julier et al. (75), in a multicenter, placebo-controlled, double-blinded study, evaluated
the effect of sevoflurane preconditioning during CPB. Patients undergoing myocardial preconditioning with
sevoflurane during CPB had a decrease in the serum cystatin C levels, suggesting a potential renal protective
effect of the agent. Currently, there are no compelling clinical data to suggest that sevoflurane is deleterious to
renal function for patients undergoing open-heart surgery, and recent experimental data suggest that it may
confer a degree of protection from renal ischemia-reperfusion injury (76). Further data suggest that the renal
protective effects of volatile anesthetics involve anti-inflammatory mediators and immunomodulation of TGF-b1,
CD 73, adenosine generation, and IL-11 expression (77).
PERIOPERATIVE ASSESSMENT OF RENAL FUNCTION

Perioperative assessment of renal failure invariably focuses on the volume of the patient’s urine, with a decline
often precipitating a need for some form of clinical intervention designed to increase urinary volume. Although
oliguria is defined as an abnormal amount of urine necessary to excrete one’s daily solute load over 24 hours,
critical care physicians, anesthesiologists, and surgeons have further defined oliguria on an hourly basis, as a
urine output of less than 0.25 to 0.33 mL/kg/hr. This is based on the presumption that hourly urine output
measurements are crucial in order to detect renal hypoperfusion, especially in hypovolemic oliguric patients,
before permanent damage occurs. Although there are no data to support this concept, hourly urinary volume
measurements are the standard in most cardiac operating rooms and intensive care units (ICUs). If hourly
assessment of urine volume is necessary, then the question that must be considered is: Does perioperative
oliguria predict postoperative AKI? On the basis of most clinical studies, the answer would be a resounding no!
Both Alpert et al. (78) and Knos et al. (79) studied patients undergoing aortic reconstructive surgery and found
no correlation between intraoperative urine volume and postoperative renal dysfunction. Nonetheless, both
groups of authors administered furosemide when the anesthesiologists or surgeons became “uneasy.” Zaloga
and Hughes, recognizing that oliguria could simply be a manifestation of either hypovolemia or normovolemia
with stress-induced ADH secretion, studied 18 critically ill oliguric patients, all of whom had normal renal function
(80). Not surprisingly, the hypovolemic patients responded to a rapid intravenous saline bolus by increasing
urine output. However, the oliguric, normovolemic patients had no response in urine output to the fluid challenge.
Instead, 33% of these otherwise normovolemic patients developed pulmonary edema as a manifestation in part,
of ADH-induced free water reabsorption. Finally, there are no studies correlating urine
P.375
output during CPB with the development of postoperative AKI. Still, there continues to be a perpetuation of the
myth that in patients with normal EABV and Qt, untreated oliguria will cause ARF. This is simply not true. Rather,
assessing perioperative oliguria should focus on the following three key imperatives of patient care:
1. Oliguria and renal perfusion are not analogous to ST-segment elevation and myocardial perfusion, in that
immediate therapy of oliguria is not crucial in preventing renal ischemia and ARF.
2. Adequate or “good” urine output does not exclude the possibility of impending renal dysfunction. On the
contrary, nonoliguric AKI is commonly observed perioperatively, occurring during or after aortic or coronary
revascularization (81,82,83).
3. Oliguria may be a sign of renal hypoperfusion, and while efforts are made to ensure adequate EABV and Qt,
further diagnostic studies must be elicited to distinguish its etiology before any form of renal protective therapy
is considered.
The first assessment of oliguria should include the possibility that the urinary catheter drainage system is
obstructed. Removing a kink or flushing debris from the catheter may be all that is required to correct presumed
AKI.
In addition, a number of simple, rapid, and inexpensive diagnostic tests are useful to distinguish acute, prerenal
oliguria from impending AKI. A urine sample should be analyzed especially for proteinuria, and sediments
examined for microscopic evidence of renal tubular epithelial cells, cellular debris, and pigmented granular casts,
all of which are indicative of AKI (84). Although serum creatinine levels will not change acutely, calculating the
patient’s baseline creatinine clearance with the Cockcroft-Gault formula (Table 14.2) (85) or with more recent
methods of eGFR (16), as has been previously mentioned, may assist in differentiating the oliguric patient with
renal insufficiency from the patient with ADH-induced oliguria. The use of these equations should help us to
appreciate that the calculated creatinine clearance in a 70-year-old, 60-kg woman with a creatinine level of 1.2
mg% is significantly less than a 40-year-old, 70-kg man with the same creatinine. Twenty-four-hour urine
collections to measure creatinine clearance tend to be cumbersome and time consuming. However, the
perioperative uses of 30-minute, 1-hour, and 2-hour creatinine clearances (86) have been shown to be accurate
in estimating changes in GFR, and may be useful following CPB when serum creatinine levels tend to be
decreased secondary to hemodilution. As was mentioned previously, serum levels of the cystine protease
inhibitor, cystatin C, have been considered to be more sensitive and specific than levels of serum creatinine in
the assessment of GFR (53,87). The proposed value of this test has been related to the lack of influence of age,
weight, gender, race, and hemodilution on cystatin C concentration. Serum cystatin C as a routine, “bedside”
estimate of eGFR appears to be gaining acceptance.
Urine indices that determine osmolality, creatinine, and sodium concentration, coupled with simultaneously
obtained serum levels of these corresponding measures, help further differentiate prerenal oliguria/azotemia from
AKI. Table 14.5 summarizes the typical urinary diagnostic indexes used to distinguish these two entities. Miller et
al. (88) originally described the use of urinary diagnostic indexes in a prospective study of patients with AKI,
including nonoliguric and obstructive forms, and concluded that these tests were of diagnostic value
predominantly in patients with oliguria. Patients with prerenal oliguria/azotemia were shown to have urine
osmolalities higher than 500 mOsm/kg H2O, urine sodium less than 20 mEq/L, and fractional excretion of filtered
sodium (FENa+) less than 1% (Table 14.6), signifying the preserved concentrating and reabsorptive capacity of
the kidney. In contrast, patients with oliguric AKI had urine osmolalities lower than 350 mOsm/kg H2O, urine
sodium more than 40 mEq/L, and FENa+ more than 1%, signifying impaired renal function. Although FENa+ is
highly sensitive and specific, a value of less than 1% has been reported in patients with myoglobinuria,
radiocontrast-induced nephropathy, cyclosporine toxicity, sepsis, and urinary tract obstruction (89). The clinical
utility of these indexes is further limited when applied to patients who are nonoliguric, have received diuretic
therapy, or have obstructive uropathy.
In addressing the differential of postoperative oliguria, urinary tract obstruction (including the bladder catheter),
decreased EABV or Qt, and excess secretion of ADH should be considered before pursuing the diagnosis of AKI.
Extracellular volume depletion and acute blood loss remain the most common causes of perioperative
oliguria/azotemia. Central venous or pulmonary artery catheters, and/or transesophageal echocardiography, are
often necessary to assess both EABV and Qt and appropriately direct therapy. Maintaining adequate perfusion
pressure during CPB is crucial to minimizing renal hypoperfusion, and efforts to increase pressure may be
warranted in the initial assessment of intraoperative oliguria.
TABLE 14.5. Urinary diagnostic indexes: prerenal oliguria/azotemia versus acute renal
failure (ARF)
Prerenal ARF
UOsm (mOsm/kg H2O) >500 <350
UNa+/L <20 >40
FeNa+ (%) <1 >1
Urine sediment/dipstick Normal Pigmented granular casts/proteinuria
P.376
TABLE 14.6. Fractional excretion of sodium

U/P, urine-to-plasma ratios of sodium (Na+) and creatinine (Cr).
Although measuring ADH levels is impractical postoperatively, one may assume that a patient who is oliguric but
not azotemic, has no preoperative renal risk factors, has not undergone prolonged CPB, and has no evidence of
urinary tract obstruction, hypovolemia, or low cardiac output, is oliguric on the basis of excess ADH. These
patients will correct over time as the levels of ADH decrease, and therefore do not require any medical
intervention.
PHARMACOLOGIC THERAPY TO PREVENT/TREAT AKI

The major goal of choosing any mode of prophylactic pharmacologic therapy is to prevent AKI-D. Although it is
universally acknowledged that patients with spontaneously induced nonoliguric AKI have significantly less
morbidity and mortality than patients with oliguric AKI, a pharmacologically induced increase in urine volume
does not have similar predictive implications (81,82). Despite the vast array of agents studied, none have
conclusively or consistently shown any beneficial outcome in either preventing AKI-D or death during or after
cardiac surgery (90). Table 14.7 lists the drugs commonly employed to improve renal perfusion in patients at risk
of developing or who develop AKI.
Dopamine
Low-dose dopamine (LDD), often inappropriately referred to as renal-dose dopamine, has been shown
experimentally, in doses of 0.5 μg/kg/min, to stimulate dopamine-specific receptors in the renal vasculature
promoting vasodilation, while inhibiting sodium reabsorption in the proximal tubule causing natriuresis (91).
However, a meta-analysis of 61 trials randomly assigning more than 3,000 patients treated with LDD failed to
show any benefit of therapy (92), and in the few prospective, randomized, controlled clinical studies that have
been performed, LDD failed to alter the outcome in patients undergoing cardiac or aortic surgery (93,94,95,96).
Indeed, most physicians now recognize the ineffectiveness and deleterious effects of LDD and have
recommended that its use be discontinued (86,87,97). In addition to lacking any renal benefit, LDD has also
been associated with an increased incidence of postoperative atrial fibrillation following cardiac surgery (98),
impairment of ventilatory drive in response to hypoxemia and hypercarbia in spontaneously breathing patients
secondary to carotid body depression (99), and suppression of circulating levels of anterior pituitary-dependent
hormones (100,101), including prolactin, an important modulator of cellular immunity. In the critically ill patient
undergoing cardiac surgery, the influence of LDD may therefore increase morbidity. Perhaps, the reason LDD
does not afford any clinical benefit relates to its pharmacokinetics. MacGregor et al. (102) administered
dopamine at doses of 3 μg/kg/min and at 10 μg/kg/min to healthy volunteers, and observed no association
between plasma concentrations and infusion rate, thereby concluding that the “renal” effect of the drug is
unpredictable. Given its lack of proven benefits and potential risks, LDD should not be administered
perioperatively as a renoprotective agent.
TABLE 14.7. Pharmacologic therapy to prevent/treat AKI

Sympathomimetic amines
Dopamine
Fenoldopam
Dopexamine
Natriuretics
Furosemide
Mannitol
Natriuretic peptides
Calcium channel antagonists
Nifedipine
Felodipine
Diltiazem
Anti-inflammatory/antioxidant drugs
Corticosteroids
Aspirin
N-Acetylcysteine
Intravenous fluids
Fenoldopam
Fenoldopam is a synthetic benzazepine derivative that binds selectively to DA1 receptors, causing both systemic
and renal vasodilation (103). Clinical studies describe its use primarily for the treatment of hypertensive
emergencies, including postcardiac surgery hypertension (103). Unlike dopamine, fenoldopam does not have an
effect on the release of anterior pituitary hormones (104), nor does it appear to increase the incidence of
postoperative atrial fibrillation (103). Theoretically, fenoldopam should augment renal blood flow during CPB. A
preliminary study by Caimmi et al. (105) compared the intraoperative effect of fenoldopam versus LDD or
dobutamine on postoperative renal function in azotemic patients
P.377
undergoing CPB, with the authors noting an improvement in creatinine clearance, requirement of less renal-
replacement therapy, and a decreased time of mechanical ventilation and ICU stay in the fenoldopam-treated
group. Halpenny (106), in a double-blind, randomized, placebo-controlled trial, found that fenoldopam, at a dose
of 0.1 μg/kg/min, was able to maintain creatinine clearance for 8 hours after separation from CPB. Garwood et al.
(107), in a nonrandomized study, administered fenoldopam to 70 patients undergoing elective cardiac surgery
who were deemed to be at risk for developing AKI (i.e., preoperative renal insufficiency, advanced age,
congestive heart failure [CHF], and/or diabetes mellitus) and noted a 7.1% incidence of renal dysfunction;
however, no patient developed AKI-D. Bove et al. (108) performed a prospective, double-blind, randomized trial
assessing the renoprotective effects of fenoldopam in high-risk patients undergoing cardiac surgery. In this
study, patients undergoing elective surgery with CPB were randomized to receive either LDD or fenoldopam
(0.05 μg/kg/min) after the induction of standard anesthesia and for the first 24 hours postoperatively. Loop
diuretics were administered to patients who developed oliguria, and continuous venovenous hemofiltration
(CVVH) was instituted if urine output remained less than 20 mL/hr or if the serum creatinine level doubled. The
results revealed no difference in the incidence of AKI-D in either group, with the authors stating that fenoldopam
should not be prescribed as a prophylactic method of preventing AKI during CPB. Unfortunately, each of these
studies has certain flaws in either design or treatment algorithms, preventing any definitive conclusions to be
reached on the use of the drug. Cogliati et al. (109), however, performed a double-blind, randomized clinical trial
in 193 high-risk patients undergoing cardiac surgery, and reported significantly less AKI-D in patients receiving a
24-hour infusion of fenoldopam. Clearly, further research is necessary to determine the usefulness of
fenoldopam during cardiac surgery.
Dopexamine
Dopexamine, a synthetic sympathomimetic amine, stimulates adrenergic β2 and “dopaminergic” DA1 receptors,
thereby exerting both a systemic as well as a renovasodilatory effect. Studies in patients undergoing aortic and
cardiac surgery have shown only modest improvements in creatinine clearances when dopexamine is
administered in doses of 0.5 to 2.0 μg/kg/min (110,111,112). Berendes et al. (112) also reported on the potential
effect of dopexamine as an inhibitor of SIRS following cardiac surgery, presumptively due to a decreased release
of proinflammatory cytokines by dual β2 and DA1 receptor stimulation. Dopexamine is not available in the United
States.
Loop Diuretics
Loop diuretics such as furosemide have been used for decades in an attempt to prevent and/or treat AKI.
Furosemide acts by inhibiting the active transcellular transport of chloride and sodium, thereby producing a
natriuresis and associated diuresis. Experimental data suggest that by reducing active transport, furosemide
decreases cellular oxygen demand and thereby reduces damage to the mTAL. The diuretic effect may also
increase clearance of necrotic cellular debris, thereby diminishing tubular obstruction. Unfortunately, clinical
studies validating these potential therapeutic effects in patients with either impending or established AKI are
lacking (113). In a prospective, randomized, double-blind, placebo-controlled study, 92 patients with AKI
(unrelated to cardiac surgery), randomized to receive furosemide, torsemide, or placebo in addition to LDD and
mannitol, had significant improvements in urine flow rates but no change in their overall dialysis-free survival.
Interestingly, those patients who converted from an oliguric to a nonoliguric state had lower mortality, but they
were also noted to have significantly less illness and less severe renal failure. Lassnigg et al. (114) evaluated
126 patients with normal preoperative renal function undergoing cardiac surgery, and in a randomized, double-
blinded, and placebo-controlled manner, assigned patients to LDD, furosemide, or saline infusion during and for
48 hours after surgery. The results of their study not only confirmed the ineffectiveness of LDD but also showed,
more importantly, a higher rate of renal impairment in the furosemide-treated group. Additional studies also
corroborate these findings (115,116). It now seems clear that the routine use of furosemide for the treatment of
oliguria per se, or impending or established AKI, may worsen renal outcome and possibly increase mortality.
Mehta et al. (117) determined that diuretic-induced forced diuresis was associated with an increased mortality in
critically ill patients with AKI (Fig. 14.1). It is imperative to recognize that in attempting to promote a diuresis,
furosemide may worsen renal function by decreasing EABV and Qt. The routine use of furosemide or other
diuretics merely to make urine appear is potentially harmful and should therefore be discouraged.
Osmotic Diuretics
Mannitol is an osmotic diuretic that has been purported to decrease renal injury when administered before an
ischemic insult such as CPB or aortic cross-clamping (118). Proposed mechanisms of action include a “flushing”
effect of necrotic tubular debris, oxygen free-radical scavenging, and improvement in medullary blood flow by
reducing endothelial edema. In comparative studies of prophylactic therapy, however, mannitol imparts no
greater renal protection than the protection obtained by maintaining EABV with intravenous fluids (119).
Nonetheless, mannitol is often administered in doses of 0.25 to 1.0 g/kg before aortic cross-clamping. However,
the use of mannitol alone or in combination with LDD during CPB, does not appear to improve renal outcome
(120).
P.378
FIGURE 14.1. Time to death or dialysis from the day of consultation in the intensive care unit. (Reprinted with
permission from Mehta RL, Pascual MT, Soroko S et al. Figure 2: Time to death or dialysis from day of
consultation in intensive care unit. In: Diuretics, mortality, and nonrecovery of renal function in acute renal failure.
JAMA 2002;288:2551, Copyright © 2002 American Medical Association. All rights reserved.)
Natriuretic Peptides
Atrial natriuretic peptide (ANP) is a hormone synthesized by the cardiac atria that has been shown experimentally
to improve renal function in models of AKI. ANP dilates afferent arterioles, thereby increasing PGC, and therefore
also GFR. ANP also inhibits the tubular reabsorption of chloride and sodium, redistributes medullary blood flow,
and blocks the effects of endothelin on the renal vasculature. Allgren et al. (121), in a multicenter, randomized,
double-blind, placebo-controlled clinical trial, administered ANP through a 24-hour infusion to patients with AKI.
Results of this large study showed an increase in dialysis-free survival only in those patients with oliguric AKI.
Patients with nonoliguric AKI fared worse, presumably due to hypotension from the ANP infusion. In a
subsequent study in critically ill patients who developed AKI following major abdominal surgery, urodilatin, a
derivative of ANP, failed to improve renal function when administered to patients concomitantly receiving
infusions of LDD and furosemide (122). Human recombinant B-type natriuretic peptide (nesiritide) is a vasodilator
with natriuretic and diuretic activities, which was originally introduced for the treatment of CHF (123). Currently,
data to support its use as a renoprotective agent for patients undergoing cardiac surgery with or without CPB are
limited. Chen et al. (124) performed a double-blinded, placebo-controlled pilot study in 40 highrisk patients
receiving low-dose nesiritide during cardiac surgery. Cystatin C levels were lower and creatinine clearance was
better preserved in the nesiritide group. A meta-analysis analyzing the use of nesiritide, for the treatment of
decompensated heart failure, reported an increased patient mortality (125), calling into question the safety of the
drug (126). Currently, there appears to be no role for ANP in the management of perioperative renal function.
Calcium Channel Antagonists

Calcium channel antagonists have been purported to be beneficial in preserving or improving renal function in
patients undergoing major vascular or cardiac surgery. Antonucci et al. (127) compared the effects of the
intravenous nifedipine to LDD in patients undergoing aortic surgery with infrarenal cross-clamping. Results of
this study showed that nifedipine, but not LDD, improved GFR. Nifedipine was also shown to enhance the
vasodilating prostaglandin E2, suppress the vasoconstricting prostaglandin thromboxane B2, and modulate the
vascular synthesis of endothelin. The same group evaluated nifedipine in patients with normal renal function
undergoing elective CABG and again noted improvements in postoperative renal function as measured by
creatinine clearance (128).
The efficacy of calcium channel antagonism for the prevention of perioperative AKI following cardiac surgery,
however, is uncertain. Andersson et al. (129) assessed the effect of the dihydropyridine calcium channel
antagonist, felodipine, in patients with baseline serum creatinine levels less than 1.3 mg% undergoing elective
CABG with CPB. In this small, nonblinded study, an intravenous infusion of felodipine was administered during
the second half of hypothermic CPB and discontinued before rewarming. GFR and active tubular transport (as
measured by intraoperative p-aminohippurate extraction) improved in the treated group, possibly related to a
preferential increase in regional blood flow to ischemic regions of the kidney. Others have evaluated diltiazem
infusions during CPB and have shown reductions in urinary microenzyme excretion, but little in the way of
protection against AKI (130,131). More recently, Witczak et al. (132) failed to show any postoperative
improvement in renal functions in a small, blinded study of high-risk patients undergoing cardiac surgery who
received infusions of nifedipine. In patients at risk of AKI who have perioperative hypertension, it may be prudent
to consider the use of a calcium channel antagonist to lower blood pressure while possibly preserving renal
function.
ANTI-INFLAMMATORY/ANTIOXIDANT DRUGS
Corticosteroids
The use of corticosteroids (CS) for the prevention or treatment of SIRS during CPB has been discussed in the
previous
P.379
chapter. Relative to the value of CS therapy for minimizing perioperative renal dysfunction, data would suggest
no benefit, but rather potential harm due to the effects of hyperglycemia. Two recent studies suggest that
dexamethasone, when administered before anesthetic induction and 8 hours later, induced renal injury as
evidenced by an increase in urinary N-acetyl-glucosaminidase levels, and further suggest that this injury could
be related to higher postoperative serum glucose levels seen with the CS-treated groups (133,134). Whether a
change in sensitive biochemical markers after CS administration could lead to AKI is unlikely. However, given the
paucity of scientific evidence that CS will prevent AKI, and that it may actually worsen renal function after cardiac
surgery, the use of CS for this purpose should be avoided.
Aspirin/Prostacyclin
In general, aspirin therapy is usually discontinued 7 to 10 days before open-heart surgery in order to minimize
perioperative hemorrhage due to platelet dysfunction. However, preoperative low-dose aspirin therapy (100 mg)
has been shown to be potentially beneficial for preserving postoperative renal function. Gerrah et al. (135)
prospectively randomized 94 patients undergoing CABG with CPB to receive either aspirin 100 mg until the day
of surgery, or no aspirin within 7 days of the procedure. Results of this study revealed significantly less
postoperative renal insufficiency in the aspirin-treated group, although at the expense of an increase in
postoperative bleeding. The presumptive mechanism of renal protection of low-dose aspirin may be due to its
inhibition of thromboxane, a potent renovasoconstrictor (136). In this regard, Morgera et al. (137) noted the
renoprotective effects of low-dose prostacyclin in low-risk patients undergoing cardiac surgery. Future studies
are needed to corroborate its effect in high-risk patients.
N-Acetylcysteine
On the basis of the reports of N-acetylcysteine (NAC) attenuating radiocontrast-induced nephropathy, Burns et
al. (138), in a multicenter, quadruple-blinded, placebo-controlled trial, failed to show any benefit of therapy in the
at-risk patients undergoing CABG with CPB. More recent studies have also failed to show any benefit of NAC
therapy (139,140,141,142). Despite being relatively inexpensive and possessing few side effects, NAC should
not be considered as a prophylactic renoprotective drug.
Intravenous Fluids
The type of intravenous fluid administered for cardiac surgery should take into consideration the chloride
concentration of each solution, as postoperative hyperchloremia has been cited in a number of studies to be
associated with an increased incident of AKI (143,144,145). Experimental data suggest hyperchloremia-induced
reduction in renal blood flow, and the possible implication of an inflammatory response, as mechanisms of injury.
Extrapolating these data from the critically ill and non-cardiac surgery populations would suggest the need to
reduce, if not eliminate the use of 0.9% saline, given its propensity to cause hyperchloremia and hyperchloremic
acidosis, and given its limited role in treating anything other than chloride-responsive metabolic alkalosis.
Similarly, the use of colloids such as hetastarch or albumin should be curtailed, as they are in solution with 0.9%
saline and given their otherwise lack of efficacy (143).
Solutions such as Plasma-lyte or Normosol are superior solutions that tend to minimize, if not prevent,
hyperchloremia. Also, sodium bicarbonate containing solutions have been touted to improved renal function in
patients undergoing cardiac surgery. Haase et al. (146), in a double-blind, randomized, controlled trial, evaluated
100 high-risk patients who received either an infusion of sodium bicarbonate or sodium chloride for 24 hours
after cardiac surgery. A lower incidence of renal dysfunction (as defined by a serum creatinine level increase
greater than 25%) was noted in the sodium bicarbonate-treated group. Although serum chloride levels were not
assessed, there was a statistically significant increase in serum pH in the bicarbonate-treated group. Although a
more recent retrospective study refutes these results (147), it would nonetheless seem prudent to (1) monitor
serum chloride levels perioperatively; (2) avoid 0.9% saline unless treating chloride-responsive metabolic
alkalosis; (3) primarily utilize Plasma-lyte or Normosol to maintain EABV; (4) consider sodium bicarbonate
infusions (e.g., 1 L 0.45% saline with 100 mEq of sodium bicarbonate added per liter) to mitigate against
hyperchloremic metabolic acidosis.
RENAL-REPLACEMENT THERAPY FOR AKI

There are a number of complications of AKI that may require the institution of renal-replacement therapy (RRT)
in the forms of either dialysis or hemofiltration. Clinical indications for RRT include pulmonary edema, symptoms
of uremia, severe metabolic acidosis, hyperkalemia, and accidental drug overdoses. The decision with respect to
which mode of RRT to select (e.g., hemodialysis, peritoneal dialysis, or hemofiltration) is often based on the
patient’s hemodynamic stability and catabolic state. Patients with multiorgan system failure, including AKI, who
are hemodynamically unstable, may benefit from the use of CVVH (148). This technique involves establishing a
large venous access (e.g., subclavian or femoral vein) with a double-lumen dialysis catheter, through which
blood passes under pressure through a highly permeable membrane that allows water and solutes of molecular
weights as great as 20,000 Da to be filtered. In contrast, dialysis membranes only allow for smaller molecules to
be cleared, and that too at a much slower rate. Hemofiltration offers other possible
P.380
advantages, such as the removal of cytokines, and the ability to administer continuous nutritional support (149).
Its disadvantages include the need for continuous anticoagulation and meticulous plasma ion replacement.
The more recent development of biocompatible dialysis membranes for RRT may alter the survival rates in
critically ill patients with AKI (150); however, the overall mortality for AKI remains high. Indeed, hemodialysis-
induced hypotension may paradoxically prolong the course of AKI by causing transient periods of renal ischemia
(148). Preliminary studies suggest that CVVH may improve survival rates in critically ill patients with AKI (148);
however, its precise role has not yet been defined. Finally, peritoneal dialysis can be used in the setting of AKI
but is limited by the increased risk of peritonitis, atelectasis, and pneumonia. A more detailed discussion of RRT
and CPB is found in Chapter 4.
CONCLUSION
Too often, in the setting of perioperative oliguria, clinicians become engrossed in the process of making
urine appear. If intravenous fluid boluses fail, furosemide is usually administered, a routine that can be
euphemistically termed endothelial lavage. However, management of postoperative renal dysfunction and,
in particular, oliguria, requires a more detailed risk assessment, including calculation of a baseline
creatinine clearance, assurance of adequate EABV, and Qt exclusion of urinary tract obstruction, and, if
need be, determination of urinary diagnostic indexes to distinguish prerenal insufficiency from AKI. Patients
suspected of AKI need to have their oxygen delivery maximized, medications adjusted in accordance to
GFR, and agents with potential nephrotoxicity avoided. Although most physicians will attempt to
pharmacologically convert oliguric to nonoliguric AKI, clinical evidence suggests that this approach is
detrimental.
KEY Points
Renal physiology and pathophysiology:
Primary functions of the kidney include regulation of EABV, plasma osmolality and ionic composition,
and the concentration and excretion of nitrogenous waste.
These actions occur through the interplay of glomerular filtration, tubular reabsorption of the filtrate,
and tubular secretion.
The kidney also functions as a vital endocrine organ to produce and secrete erythropoietin and
vitamin D.
Formation of the glomerular filtrate is governed by Starling forces acting across the glomerular
capillaries.
Renal blood flow is approximately 20% of cardiac output and is maintained over a substantial perfusion
pressure range by autoregulation.
The renal cortex receives more than 90% of the renal blood flow.
Juxtamedullary nephrons and the ascending (thick) hub of the loop of Henle are particularly valuable
to ischemia surgery.
A decrease in urine volume does not necessarily imply a decreased glomerular filtration rate or
impending AKI.
Production of urine involves reabsorption of more than 99% of the filtered water and solute.
The single most important preoperative risk factor for predicting postoperative AKI is preexisting abnormal
renal function.
An eGFR is a more accurate assessment of kidney function than is serum creatinine.
The degree of preexisting renal insufficiency is a highly significant predictor of postoperative AKI
requiring dialysis, major morbidity, and death.
There may be certain genetically determined variability in the risk of postoperative AKI.
A number of factors associated with open-heart surgery and CPB increase the postoperative risk of AKI.
These include prolonged CPB, low cardiac output after CPB, SIRS, low hematocrit, ascending aortic
atheroma, and aortic clamping.
Off-pump cardiac surgery does not provide a definitive reduction in the risk of postoperative renal
failure.
Perioperative oliguria does not predict postoperative AKI.
Adequate urine flow does not exclude the possibility of impending AKI.
Oliguria may be indicative of renal hypoperfusion. Initial treatment should ensure adequate blood
volume and cardiac output before renal protective therapy is undertaken.
Although numerous drugs have been assessed for their ability to prevent or ameliorate renal AKI
postoperatively, there is no consensus opinion that any one of them, or a combination, is effective.
Intravenous fluid therapy should focus on preventing hyperchloremia.
In the face of worsening AKI, the clinical indications for RRT with dialysis (hemodialysis or peritoneal
dialysis) or hemofiltration include uremia, CHF, pulmonary edema, severe metabolic acidosis, severe
hyperkalemia, and accidental drug overdoses.
REFERENCES
P.381
1. Fleisher LA, Beckman JA, Brown KA, et al. ACC/AHA 2007 Guidelines on perioperative cardiovascular
evaluation and care for noncardiac surgery: a report of the American College of Cardiology/American Heart
Association task force on practice guidelines (Writing Committee to Revise the 2002 Guidelines in
Perioperative Cardiovascular Evaluation for Noncardiac Surgery). Circulation 2007;116:e418-e499.
2. Botto F, Alonso-Coello P, Chan MT, et al.; The Vascular events In noncardiac Surgery patients cOhort
evaluatioN (VISION) Writing Group, on behalf of The Vascular events In noncardiac Surgery patients cOhort
evaluatioN (VISION) Investigators. Myocardial injury after noncardiac surgery: a large, international,
prospective cohort study establishing diagnostic criteria, characteristics, predictors, and 30-day outcomes. A
large, international, prospective cohort study establishing diagnostic criteria, characteristics, predictors, and
30-day outcomes. Anesthesiology 2014;120:564-578.
3. London MJ, Zaugg M, Schaub MC, et al. Periopeative β-adrenergic receptor blockade. Physiologic
foundations and clinical controversies. Anesthesiology 2004;100:170-175.
4. Ashes C, Judelman S, Wijeysundera DN, et al. Selective β1-antagonism with bisoprolol is associated with
fewer postoperative strokes than atenolol or metoprolol: a single-center cohort study of 44,092 consecutive
patients. Anesthesiology 2013;119:777-787.
5. Thakar CV, Arrigain S, Worley S, et al. A clinical score to predict acute renal failure after cardiac surgery. J
Am Soc Nephrol 2005;16:162-168.
6. Mehta RH, Grab JD, O’Brien SM, et al. Bedside tool for predicting the risk of postoperative dialysis in
patients undergoing cardiac surgery. Circulation 2006 21;114:2208-2216.
7. Demirjian S, Schold JD, Navia J, et al. Predictive models for acute kidney injury following cardiac surgery.
Am J Kidney Dis 2012;59:382-389.
8. Berg KS, Stenseth R, Wahba A, et al. How can we best predict acute kidney injury following cardiac
surgery? A prospective observational study. Eur J Anaesthesiol 2013;30:704-712.
9. Novis BK, Roizen MF, Aronson S, et al. Association of preoperative risk factors with postoperative acute
renal failure. Anesth Analg 1994;78:143-149.
10. Andersson LG, Ekroth R, Bratteby LE, et al. Acute renal failure after coronary surgery—a study of
incidence and risk factors in 2009 consecutive patients. Thorac Cardiovasc Surg 1993;41:237-241.
11. Zanardo G, Michielon P, Paccagnella A, et al. Acute renal failure in the patient undergoing cardiac
operation. J Thorac Cardiovasc Surg 1994;107: 1489-1495.
12. Chertow GM, Lazarus JM, Christiansen CL, et al. Preoperative renal risk stratification. Circulation
1997;95:878-884.
13. Chertow GM, Levy EM, Hammermeister KE, et al. Independent association between acute renal failure
and mortality following cardiac surgery. Am J Med 1998;104:343-348.
14. Mangano CM, Diamondstone LS, Ramsay JG, et al. Renal dysfunction after myocardial revascularization:
risk factors, adverse outcomes, and hospital resource utilization. Ann Intern Med 1998;128:194-203.
15. Conlon PJ, Stafford-Smith M, White WD, et al. Acute renal failure following cardiac surgery. Nephrol Dial
Transplant 1999;14:1158-1162.
16. Khaitan L, Sutter FP, Goldman SM. Coronary artery bypass grafting in patients who require long-term
dialysis. Ann Thorac Surg 2000;69:1135-1139.
17. Liu JY, Birkmeyer NJ, Sanders JH, et al. Risks of morbidity and mortality in dialysis patients undergoing
coronary artery bypass surgery. Circulation 2000;102:2973-2977.
18. Shlipak MG, Matsushita K, Ärnlöv J, et al. Cystatin C versus creatinine in determing risk based on kidney
function. N Engl J Med 2013;369:932-943.
19. Wang F, Dupuis JY, Nathan H, et al. An analysis of the association between preoperative renal
dysfunction and outcome in cardiac surgery: estimated creatinine clearance or plasma creatinine level as
measured of renal function. Chest 2003;124:1852-1862.
20. Wijeysundera DN, Karkouti K, Beattie WS, et al. Improving the identification of patients at risk of
postoperative renal failure after cardiac surgery. Anesthesiology 2006;104:65-72.
21. Levey AS, Bosch JP, Lewis JB, et al. A more accurate method to estimate glomerular filtration rate from
serum creatinine: a new prediction equation. Ann Intern Med 1999;130:461-470.
22. Levey AS, Stevens LA, Schmid CH, et al. A new equation to estimate glomercular filtration rate. Ann
Intern Med 2009;150:604-612.
23. Inker LA, Schmid CH, Tighiouart H, et al. Estimating glomerular filtration rate from serum creatinine and
cystatin C. N Eng J Med 2012;367:20-29.
24. Kang DH, Anderson S, Kim YG, et al. Impaired angiogenesis in the aging kidney: vascular endothelial
growth factor and thrombospondin-1 in renal disease. Am J Kidney Dis 2001;37:601-611.
25. Barrett BJ, Parfrey PS. Preventing nephropathy induced by contrast medium. N Engl J Med
2006;354:379-386.
26. Bianchi P, Carboni G, Pesce G, et al. Cardiac catheterization and postoperative acute kidney failure in
congenital heart pediatric patients. Anesth Analg 2013;117:455-461
27. Berns AS. Nephrotoxicity of contrast media. Kidney Int 1989;36:730-740.
28. Hennessy SA, LaPar DJ, Stukenborg GJ, et al. Cardiac catherization within 24 hours of valve surgery is
significantly associated with acute renal failure. J Thorac Cardiovasc Surg 2010;140:1011-1017.
29. Ozkaynak B, Kayalar N, Gümüş F, et al. Time from cardiac catheterization to cardiac surgery: a risk
factor for acute kidney injury? Interact Cardiovasc Thorac Surg 2014;18:706-712.
30. Lee A, Cooper MC, Craig JC, et al. Effects of nonsteroidal anti-inflammatory drugs on postoperative renal
function in adults with normal renal function. Cochrane Database Syst Rev 2006;1:CD002765.
31. Gaudino M, Di Castelnuovo A, Zamparelli R, et al. Genetic control of postoperative systemic inflammatory
reaction and pulmonary and renal complications after coronary artery surgery. J Thorac Cardiovasc Surg
2003;126:1107-1112.
32. Stafford-Smith M, Podgoreanu M, Swaminathan M, et al. Association of genetic polymorphisms with risk
of renal injury after coronary bypass graft surgery. Am J Kidney Dis 2005;45:519-530.
33. Drews JD, Patel HJ, Williams DM, et al. The impact of acute renal failure on early and late outcomes
after thoracic aortic endovascular repair. Ann Thorac Surg 2014;97:2027-2033.
34. Hix JK, Thakar CV, Katz EM, et al. Effect of off-pump coronary artery bypass graft surgery on
postoperative acute kidney injury and mortality. Crit Care Med 2006;34:2979-2983.
35. Lopez-Delgado JC, Esteve F, Torrado H, et al. Influence of acute kidney injury on short- and long-term
outcomes in patients undergoing cardiac surgery: risk factors and prognostic value of a modified RIFLE
classification. Crit Care 2013;17:R293.
36. Rinder CS, Fontes M, Mathew JP, et al. Neutrophil CD11b upregulation during cardiopulmonary bypass
is associated with postoperative renal injury. Ann Thorac Surg 2003;75:899-905.
37. Tang ATM, Alexiou C, Hsu J, et al. Leukodepletion reduces renal injury in coronary revascularization: a
prospective randomized study. Ann Thorac Surg 2002;74:372-377.
38. Treacher DF, Sabbato M, Brown KA. The effects of leukodepletion in patients who develop the systemic
inflammatory response syndrome following cardiopulmonary bypass. Perfusion 2001;16:67-73.
39. Feindt PR, Walcher S, Volkmer I, et al. Effects of high-dose aprotinin on renal function in aortocoronary
bypass graft. Ann Thorac Surg 1995;60:1076-1080.
40. Schweizer A, Höhn L, Morel DR, et al. Aprotinin does not impair renal haemodynamics and function after
cardiac surgery. Br J Anaesth 2000;84: 16-22.
41. Mangano DT, Tudor IC, Dietzel C. The risk associated with aprotinin in cardiac surgery. N Engl J Med
2006;354:353-365.
42. Stafford-Smith M, Phillips-Bute B, Reddan DN, et al. The association of [epsilon]-aminocaproic acid with
postoperative decrease in creatinine clearance in 1502 coronary bypass patients. Anesth Analg
2000;91:1085-1090.
43. Karkouti K, Beattie WS, Wijeysundera DN, et al. Hemodilution during cardiopulmonary bypass is an
independent risk factor for acute renal failure in adult cardiac surgery. J Thorac Cardiovac Surg
2005;129:391-400.
44. Habib RH, Zacharias A, Schwann TA, et al. Role of hemodilutional anemia and transfusion during
cardiopulmonary bypass in renal injury after coronary revascularization: implications on operative outcome.
Crit Care Med 2005;33:1749-1756.
45. Dávila-Román VG, Kouchoukos NT, Schechtman KB, et al. Atherosclerosis of the ascending aorta is a
predictor of renal dysfunction after cardiac operations. J Thorac Cardiovasc Surg 1999;117:111-116.
46. MacKensen GB, Swaminathan M, Ti LK, et al. Preliminary report on the interaction of apolipoprotein E
polymorphism with aortic atherosclerosis and acute nephropathy after CABG. Ann Thorac Surg 2004;78:520-
526.
47. Swaminathan M, East C, Phillips-Bute B, et al. Report of a substudy on warm versus cold
cardiopulmonary bypass: changes in creatinine clearance. Ann Thorac Surg 2001;72:1603-1609.
48. Provenchère S, Plantefève G, Hufnagel G, et al. Renal dysfunction after cardiac surgery with
normothermic cardiopulmonary bypass: incidence, risk factors, and effect on clinical outcome. Anesth Analg
2003;96:1258-1264.
P.382
49. Gamoso MG, Phillips-Bute B, Landolfo KP, et al. Off-pump versus on-pump coronary artery bypass
surgery and postoperative renal dysfunction. Anesth Analg 2000;91:1080-1084.
50. Hayashida N, Teshima H, Chihara S, et al. Does off-pump coronary artery bypass grafting really
preserve renal function? Circ J 2002;66:921-925.
51. Ascione R, Lloyd CT, Underwood MJ, et al. On-pump versus off-pump coronary revascularization:
evaluation of renal function. Ann Thorac Surg 1999;68:493-498.
52. Gerritsen WBM, van Boven WJP, Driessen AHG, et al. Off-pump versus onpump coronary artery bypass
grafting: oxidative stress and renal function. Eur J Cardiothorac Surg 2001;20:923-929.
53. Abu-Omar Y, Mussa S, Naik MJ, et al. Evaluation of cystatin C as a marker of renal injury following on-
pump and off-pump coronary surgery. Eur J Cardiothorac Surg 2005;27:893-898.
54. Brudney CS, Gosling P, Manji M. Pulmonary and renal function following cardiopulmonary bypass is
associated with systemic capillary leak. J Cardiothorac Vasc Anesth 2005;19:188-192.
55. Gormley SMC, McBride WT, Armstrong MA, et al. Plasma and urinary cytokine homeostasis and renal
function during cardiac surgery without cardiopulmonary bypass. Cytokine 2002;17:61-65.
56. Schwann NM, Horrow JC, Strong MD, et al. Does off-pump coronary artery bypass reduce the incidence
of clinically evident renal dysfunction after multivessel myocardial revascularization? Anesth Analg
2004;99:959-964.
57. Celik JB, Gormus N, Topal A, et al. Effect of off-pump and on-pump coronary artery bypass grafting on
renal function. Ren Fail 2005;27:183-188.
58. Cheng D, Bainbridge D, Martin JE, et al. Does off-pump coronary artery bypass reduce mortality,
morbidity, and resource utilization when compared with conventional coronary artery bypass? A meta-
analysis of randomized trials. Anesthesiology 2005;102:188-203.
59. Bucerius J, Gummert JF, Walther T, et al. On-pump versus off-pump coronary artery bypass grafting:
impact on postoperative renal failure requiring renal replacement therapy. Ann Thorac Surg 2004;77:1250-
1256.
60. Roh GU, Lee JW, Nam SB, et al. Incidence and risk factors of acute kidney injury after thoracic aortic
surgery for acute dissection. Ann Thorac Surg 2012;94:766-771.
61. Schepens MA, Defauw JJ, Hamerlijnck RP, et al. Risk assessment of acute renal failure after
thoracoabdominal aortic aneurysm surgery. Ann Surg 1994;219:400-407.
62. Safi HJ, Harlin SA, Miller CC, et al. Predictive factors for acute renal failure in thoracic and
thoracoabdominal aortic aneurysm surgery. J Vasc Surg 1996;24:338-345.
63. Godet G, Fléron MH, Vicaut E, et al. Risk factors for acute postoperative renal failure in thoracic or
thoracoabdominal aortic surgery: a prospective study. Anesth Analg 1997;85:1227-1232.
64. Kashyap VS, Cambria RP, Davison KJ, et al. Renal failure after thoracoabdominal aortic surgery. J Vasc
Surg 1997;26:949-957.
65. Gamulin Z, Forster A, Morel D, et al. Effects of infrarenal aortic cross-clamping on renal hemodynamics in
humans. Anesthesiology 1984;61:394-399.
66. Gelman S. The pathophysiology of aortic cross-clamping and unclamping. Anesthesiology 1995;82:1026-
1060.
67. Svensson LG, Coselli JS, Safi HJ, et al. Appraisal of adjuncts to prevent acute renal failure after surgery
on the thoracic or thoracoabdominal aorta. J Vasc Surg 1989;10:230-239.
68. Greenberg RK, Chuter TA, Lawrence-Brown M, et al. Analysis of renal function after aneurysm repair
with a device using suprarenal fixation (Zenith AAA Endovascular Graft) in contrast to open surgical repair. J
Vasc Surg 2004;39:1219-1228.
69. Kharasch ED, Frink EJ, Artru A, et al. Long-duration low-flow sevoflurane and isoflurane effects on
postoperative renal and hepatic function. Anesth Analg 2001;93:1511-1520.
70. Conzen PF, Nuscheler M, Melotte A, et al. Renal function and serum fluoride concentrations in patients
with stable renal insufficiency after anesthesia with sevoflurane or enflurane. Anesth Analg 1995;81:569-575.
71. Artru AA. Renal effects of sevoflurane during conditions of possible increased risk. J Clin Anesth
1998;10:531-538.
72. el Azab SR, Scheffer GJ, Lange JJ, et al. Liver and renal function after volatile induction and
maintenance of anesthesia (VIMA) with sevoflurane versus TIVA with sufentanil-midazolam for CABG
surgery. Acta Anaesth Belg 2001;52:281-285.
73. Story DA, Poustie S, Liu G, et al. Changes in plasma creatinine concentration after cardiac anesthesia
with isoflurane, propofol, or sevoflurane. Anesthesiology 2001;95:842-848.
74. Sakamoto H, Mayumi T, Morimoto Y, et al. Sevoflurane metabolite production in a small cohort of
coronary artery bypass graft surgery patients. J Cardiothorac Vasc Anesth 2002;16:463-467.
75. Julier K, da Silva R, Garcia C, et al. Preconditioning by sevoflurane decreases biochemical markers for
myocardial and renal dysfunction in coronary artery bypass graft surgery: a double-blinded, placebo-
controlled, multicenter study. Anesthesiology 2003;98:1315-1327.
76. Lee HT, Ota-Setlik A, Fu Y, et al. Differential protective effects of volatile anesthetics against renal
ischemia-reperfusion injury in vivo. Anesthesiology 2004;101:1313-1324.
77. Fukazawa K, Lee HT. Volatile anesthetics and AKI: risks, mechanisms, and a potential therapeutic
window. J Am Soc Nephrol 2014;25:884-892.
78. Alpert RA, Roizen MF, Hamilton WK, et al. Intraoperative urinary output does not predict postoperative
renal function in patients undergoing abdominal aortic revascularization. Surgery 1984;95:707-711.
79. Knos GB, Berry AJ, Isaacson IJ, et al. Intraoperative urinary output and postoperative blood urea nitrogen
and creatinine levels in patients undergoing aortic reconstructive surgery. J Clin Anesth 1989;1:181-185.
80. Zaloga GP, Hughes SS. Oliguria in patients with normal renal function. Anesthesiology 1990;72:598-602.
81. Anderson RJ, Linas SL, Berns AS, et al. Nonoliguric acute renal failure. N Engl J Med 1977;296:1134-
1138.
82. Dixon BS, Anderson RJ. Nonoliguric acute renal failure. Am J Kidney Dis 1985;VI:71-80.
83. Myers BD, Moran SM. Hemodynamically mediated acute renal failure. N Engl J Med 1986;314:97-105.
84. Baines AD. Strategies and criteria for developing new urinalysis tests. Kidney Int Suppl 1994;47:S137-
S141.
85. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976;16:31-
41.
86. Sladen RN, Endo E, Harrison T. Two-hour versus 22-hour creatinine clearance in critically ill patients.
87. Levin A. Cystatin C, serum creatinine, and estimates of kidney function: searching for better measures of
kidney function and cardiovascular risk. Ann Intern Med 2005;142:586-588.
88. Miller TR, Anderson RJ, Lonas SL, et al. Urinary diagnostic indices in acute renal failure. Ann Intern Med
1978;89:47-50.
89. Kamel KS, Ethier JH, Richardson RMA, et al. Urine electrolytes and osmolality: when and how to use
them. Am J Nephrol 1990;10:89-102.
90. Zacharias M, Mugawar M, Herbison GP, et al. Interventions for protecting renal function in the
perioperative period [Review]. Cochrane Database Syst Rev 2013;9:1-114.
91. Debaveye YA, Van den Berghe GH. Is there still a place for dopamine in the modern intensive care unit?
Anesth Analg 2004;98:461-468.
92. Friedrich JO, Adhikari N, Herridge MS, et al. Meta-analysis: low-dose dopamine increases urine output
but does not prevent renal dysfunction or death. Ann Intern Med 2005;142:510-524.
93. Baldwin L, Henderson A, Hickman P. Effect of postoperative low-dose dopamine on renal function after
elective major vascular surgery. Ann Intern Med 1994;120:744-747.
94. Myles PS, Buckland MR, Schenk NJ, et al. Effect of renal dose dopamine on renal function following
cardiac surgery. Anaesth Intensive Care 1993;21:56-61.
95. Lema G, Urzua J, Jalil R, et al. Renal protection in patients undergoing cardiopulmonary bypass with
preoperative abnormal renal function. Anesth Analg 1998;86:3-8.
96. Woo EBC, Tang ATM, El Gamel A, et al. Dopamine therapy for patients at risk of renal dysfunction
following cardiac surgery: science or fiction? Eur J Cardiothorac Surg 2002;22:106-111.
97. Chertow GM, Sayegh MH, Allgren RL, et al. Is the administration of dopamine associated with adverse or
favorable outcomes in acute renal failure? Am J Med 1996;101:49-53.
98. Argalious M, Motta P, Khandwala F, et al. Renal dose dopamine is associated with the risk of new-onset
atrial fibrillation after cardiac surgery. Crit Care Med 2005;33:1327-1332.
99. van de Borne P, Oren R, Somers VK. Dopamine depresses minute ventilation in patients with heart
failure. Circulation 1998;98:126-131.
100. Bailey AR, Burchett KR. Effect of low-dose dopamine on serum concentrations of prolactin in critically ill
patients. Br J Anaesth 1997;78: 97-99.
101. Van den Berghe G, de Zegher F. Anterior pituitary function during critical illness and dopamine
treatment. Crit Care Med 1996;24:1580-1590.
P.383
102. MacGregor DA, Smith TE, Prielipp RC, et al. Pharmacokinetics of dopamine in healthy male subjects.
103. Murphy MB, Murray C, Shorten GD. Fenoldopam—a selective peripheral dopamine receptor agonist for
the treatment of severe hypertension. N Engl J Med 2001;345:1548-1557.
104. Grodum E, Andersen M, Hangaard J, et al. Lack of effect of the dopamine D1 antagonist, NNC 01-0687,
on unstimulated and stimulated release of anterior pituitary hormones in males. J Endocrinol Invest 1998;21:
291-297.
105. Caimmi PP, Pagani L, Micalizzi E, et al. Fenoldopam for renal protection in patients undergoing
cardiopulmonary bypass. J Cardiothorac Vasc Anesth 2003;17:491-494.
106. Halpenny M, Lakshmi S, O’Donnell A, et al. Fenoldopam: renal and splanchnic effects in patients
undergoing coronary artery bypass grafting. Anaesthesia 2001;56:953-960.
107. Garwood S, Swamidoss CP, Davis EA, et al. A case series of low-dose fenoldopam in seventy cardiac
surgical patients at increased risk of renal dysfunction. J Cardiothorac Vasc Anesth 2003;17:17-21.
108. Bove T, Landoni G, Calabrò MG, et al. Renoprotective action of fenoldopam in high-risk patients
undergoing cardiac surgery: a prospective, double-blind randomized clinical trial. Circulation 2005;111:3230-
3235.
109. Cogiliati AA, Vellutini R, Nardini A, et al. Fenolopam infusion for renal protection in high-risk cardiac
surgery patients: a randomized clinical study. J Cardiothorac Vasc Anesth 2007;21:847-850.
110. Welch M, Newstead CG, Smyth JV, et al. Evaluation of dopexamine hydrochloride as a renoprotective
agent during aortic surgery. Ann Vasc Surg 1995;9:488-492.
111. Berendes E, Möllhoff T, Van Aken H, et al. Effects of dopexamine on creatinine clearance, systemic
inflammation, and splanchnic oxygenation in patients undergoing coronary artery bypass grafting. Anesth
Analg 1997;84:950-957.
112. Dehne MG, Klein TF, Mühling J, et al. Impairment of renal function after cardiopulmonary bypass is not
influenced by dopexamine. Ren Fail 2001;23:217-230.
113. Shilliday IR, Quinn KJ, Allison MEM. Loop diuretics in the management of acute renal failure: a
prospective, double-blind, placebo-controlled, randomized study. Nephrol Dial Transpl 1997;12:2592-2596.
114. Lassnigg A, Donner E, Grubhofer G, et al. Lack of renoprotective effects of dopamine and furosemide
during cardiac surgery. J Am Soc Nephrol 2000;11:97-104.
115. Lim E, Ali AA, Attaran R, et al. Evaluating routine diuretics after coronary surgery: a prospective
randomized controlled trial. Ann Thorac Surg 2002;73:153-155.
116. Lombardi R, Ferreiro A, Servetto C. Renal function after cardiac surgery: adverse effect of furosemide.
Ren Fail 2003;25:775-786.
117. Mehta RL, Pascual MT, Soroko S, et al. Diuretics, mortality, and nonrecovery of renal function in acute
renal failure. JAMA 2002;288:2547-2553.
118. Fisher AR, Jones P, Barlow P, et al. The influence of mannitol on renal function during and after open-
heart surgery. Perfusion 1998;13:181-186.
119. Paul MD, Mazer D, Byrick RJ, et al. Influence of mannitol and dopamine on renal function during
elective infrarenal aortic clamping in man. Am J Nephrol 1986;6:427-434.
120. Carcoana OV, Mathew JP, Davis E, et al. Mannitol and dopamine in patients undergoing
cardiopulmonary bypass: a randomized clinical trial. Anesth Analg 2003;97:1222-1229.
121. Allgren RL, Marbury TC, Rahman SN, et al. Anaritide in acute tubular necrosis. N Engl J Med
1997;336:828-834.
122. Herbert MK, Ginzel S, Mühlschlegel S, et al. Concomitant treatment with urodilatin (ularitide) does not
improve renal function in patients with acute renal failure after major abdominal surgery. Wien Klin
Wochenschr 1999;111:141-147.
123. Samuels LE, Holmes EC, Lee L. Nesiritide as an adjunctive therapy in adult patients with heart failure
undergoing high-risk cardiac surgery. J Thorac Cardiovasc Surg 2004;128:627-629.
124. Chen HH, Sundt TM, Cook DJ, et al. Low dose nesiritide and the preservation of renal function in
patients with renal dysfunction undergoing cardiopulmonary-bypass surgery: a double-blind placebo-
controlled pilot study. Circulation 2007;116:I-134-I-138.
125. Sackner-Bernstein JD, Kowalski M, Fox M, et al. Short-term risk of death after treatment with nesiritide
for decompensated heart failure. JAMA 2005;293:1900-1905.
126. Topol EJ. Nesiritide-not verified. N Engl J Med 2005;353:113-116.
127. Antonucci F, Calò L, Rizzolo M, et al. Nifedipine can preserve renal function in patients undergoing
aortic surgery with infrarenal crossclamping. Nephron 1996;74:668-673.
128. Bertolissi M, Antonucci F, De Monte A, et al. Effects on renal function of a continuous infusion of
nifedipine during cardiopulmonary bypass. J Cardiothorac Vasc Anesth 1996;10:238-242.
129. Andersson LG, Jeppsson A, Bratteby LE, et al. Renal function during cardiopulmonary bypass: influence
of the calcium entry blocker felodipine. Anesth Analg 1996;83:34-40.
130. Bergman ASF, Odar-Cederlöf I, Westman L, et al. Diltiazem infusion for renal protection in cardiac
surgical patients with preexisting renal dysfunction. J Cardiothorac Vasc Anesth 2002;16:294-299.
131. Piper SN, Kumle B, Maleck WH, et al. Diltiazem may preserve renal tubular integrity after cardiac
surgery. Can J Anaesth 2003;50:285-292.
132. Witczak BJ, Hartmann A, Geiran OR, et al. Renal function after cardiopulmonary bypass surgery in
patients with impaired renal function. A randomized study of the effect of nifedipine. Eur J Anaesthesiol
2008;25:319-325.
133. Morariu AM, Loef BG, Aarts LPHJ, et al. Dexamethasone: benefit and prejudice for patients undergoing
on-pump coronary artery bypass grafting: a study on myocardial, pulmonary, renal, intestinal, and hepatic
injury. Chest 2005;128:2677-2687.
134. Loef BG, Henning RH, Epema AH, et al. Effect of dexamethasone on perioperative renal function
impairment during cardiac surgery with cardiopulmonary bypass. Br J Anaesth 2004;93:793-798.
135. Gerrah R, Ehrlich S, Tshori S, et al. Beneficial effect of aspirin on renal function in patients with renal
insufficiency postcardiac surgery. J Cardiovasc Surg 2004;45:545-550.
136. Gerrah R, Izhar U. Beneficial effect of aspirin on renal function post-cardiopulmonary bypass. Asian
Cardiovasc Thorac Ann 2003;11:304-308.
137. Morgera S, Woydt R, Kern H, et al. Low-dose prostacyclin preserves renal function in high-risk patients
after coronary bypass surgery. Crit Care Med 2002;30:107-112.
138. Burns KEA, Chu MWA, Novick RJ, et al. Perioperative N-acetylcysteine to prevent renal dysfunction in
high-risk patients undergoing CABG surgery. JAMA 2005;294:342-350.
139. Ristikankare A, Kuitunen T, Kuitunen A, et al. Lack of renoprotective effect of i.v. N-acetylcysteine in
patients with chronic renal failure undergoing cardiac surgery. Br J Anaesth 2006;97:611-616.
140. Haase M, Hasse-Fielitz A, Bagshaw SM, et al. Phase II, randomized, controlled trial of high-dose N-
acetylcysteine in high-risk cardiac surgery patients. Crit Care Med 2007;35:1324-1331.
141. Adabag AS, Ishani A, Koneswaran S, et al. Utility of N-acetylcysteine to prevent acute kidney injury after
cardiac surgery: a randomized controlled trial. Am Heart J 2008;155:1143-1149.
142. Prasad A, Banakal S, Muralidhar K. N-Acetylcysteine does not prevent renal dysfunction after off-pump
coronary artery bypass surgery. Eur J Anaesthesiol 2010;27:973-977.
143. Shaw AD, Bagshaw SM, Goldstein SL, et al. Major complications, mortality, and resource utilization
after open abdominal surgery: 0.9% saline compared to Plasma-Lyte. Ann Surg 2012;255:821-829.
144. 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;308:1566-1572.
145. McCluskey SA, Karkouti K, Wijeysundera D, et al. Hyperchloremia after noncardiac surgery is
independently associated with increased morbidity and mortality: a propensity matched cohort study. Anesth
Analg 2013;117:412-421.
146. Haase M, Hasse-Fielitz A, Bellomo R, et al. Sodium bicarbonate to prevent increases in serum
creatinine after cardiac surgery: a pilot double-blind, randomized controlled trial. Crit Care Med 2009;37:39-
47.
147. Heringlake M, Heinze H, Schubert M. A perioperative infusion of sodium bicarbonate does not improve
renal function in cardiac surgery patients: a prospective observational cohort study. Crit Care 2012;16:1-12.
148. Forni LG, Hilton PJ. Continuous hemofiltration in the treatment of acute renal failure. N Engl J Med
1997;336:1303-1309.
149. Bellomo R, Farmer M, Boyce N. A prospective study of continuous venovenous hemodiafiltration in

critically ill patients with acute renal failure. J Intensive Care Med 1995;10:187-192.
150. Pastan S, Bailey J. Dialysis therapy. N Engl J Med 1998;338:1428-1437.

Chapter 15
Neurologic Effects of Cardiopulmonary Bypass
Eduardo S. Rodrigues
David J. Cook
This chapter will provide an overview of the neurologic effects of cardiac surgery and cardiopulmonary bypass.
First, the extent and nature of bypass-related neurologic injury will be presented, emphasizing the importance of
patient demographics and comorbidities. In this context etiologies will be considered. Second, basic cerebral
physiology during cardiopulmonary bypass will be reviewed. Third, interventions having the potential to reduce
neurologic morbidity will be considered and fourth, the applicability of neurologic monitoring techniques for
cardiopulmonary bypass will be briefly presented.
THE POPULATION AT RISK, DEMOGRAPHICS, AND COMORBIDITIES

Cardiac operations requiring cardiopulmonary bypass (CPB) are among the most commonly performed surgical
procedures in Europe and North America. Studies describing more than 20,000 cardiac surgical patients indicate
that significant morbidity may be experienced by 20% to 25% of patients (1,2,3). These morbidities include
cardiac and pulmonary failure, neurologic injury, renal insufficiency, bleeding, and infection. Complications have
predictable adverse effects on duration and cost of hospitalization (4,5,6) as well as on patient quality of life and
functional capacity on discharge (6,7,8).
When considering cardiac surgical neurologic morbidity, it is important to understand that many adult cardiac
surgical patients have preexisting risk factors for stroke and cognitive impairment even without the added risk of
cardiac surgery and CPB. Cardiac or noncardiac surgery superimposes incremental risk. The recent European
study of cognitive outcomes after noncardiac surgery superbly illustrated this risk (9). In that study, 1,218 elderly
patients having major noncardiac surgery underwent neurocognitive assessment preoperatively, before
discharge, and at 3 months postoperatively. A large ( n = 321) nonsurgical control group was also enrolled. That
study reported a 26% incidence of cognitive dysfunction 1 week after surgery and a 10% incidence at 3 months.
Cardiac surgery poses greater risks because cardiac surgical patients experience more serious neurologic
morbidity than age- and health-matched controls undergoing noncardiac surgery (Table 15.1) (8). Consequently,
it is useful to regard the perioperative period as one of acute neurologic stress in a subpopulation chronically at
risk.
There is general agreement about preoperative patient-related factors that increase the likelihood of
perioperative stroke, but the role of many intraoperative factors is much less clear. Preoperative risk factors
include advanced age, history of prior neurologic events, aortic atherosclerosis, low cardiac output states, atrial
arrhythmias, hypertension, and diabetes. Advanced age, the most dramatic risk factor, appears to magnify the
other risk factors. The importance of this risk factor cannot be overemphasized, because over the last two
decades the number of cardiac surgery patients over age 60 doubled and the percentage of patients over age 70
increased 7-fold (10). The proportion of cardiac surgical patients over age 80 will grow faster than any other
group. Age alone is an independent risk factor for stroke, with patients under age 60 having ≤1% incidence of
stroke across studies (1,10,11), while those over age 70 have a 4% to 9% incidence of stroke or coma following
operation (Fig. 15.1) (1,10,11,12). This is
P.386
important because the increasing age of the surgical population and the successes provided by the initial heart
surgery are increasing the incidence of redo heart surgery (13) which is known to increase neurologic risk. In a
recent multicenter, retrospective study, Biancari et al. (14) evaluated the risk factors for stroke in a population
undergoing redo heart surgery. This study included seven centers in three different European countries with a
total of 741 patients. The overall incidence of stroke was 6.5%, but extremely variable depending on patient
gender and perioperative events.
TABLE 15.1. Severity of postoperative neuropsychological deterioration in CABG and

surgical control patients
Severity of deterioration CABG (n = 298) Control (n = 48)
Mild (deterioration on 1 or 2 tests) 164 (55%) 15 (31%)
Moderate (deterioration on 3 or 4 tests) 57 (19%) 0
Severe (deterioration on ≥ 5 tests) 14 (4.7%) 0
Only patients completing both preoperative and postoperative test batteries are included.
CABG, coronary artery bypass graft group; Control, peripheral vascular surgery group. Shaw PJ, Bates
D, Cartlidge NE, et al. Neurologic and neuropsychological morbidity following major surgery: comparison
of coronary artery bypass and peripheral vascular surgery. Stroke 1987;18:700-707.
FIGURE. 15.1. Incidence of type I and type II cerebral outcomes according to age. (Roach GW, Kanchuger M,
Mangano CM, et al. Adverse cerebral outcomes after coronary bypass surgery. Multicenter Study of
Perioperative Ischemia Research Group and the Ischemia Research and Education Foundation Investigators. N
Engl J Med 1996;335:1857-1863. Copyright © 1996 Massachusetts Medical Society. All rights reserved.)
As the surgical population has aged, the proportion of patients with multiple risk factors for neurologic injury has
increased. Hypertension and diabetes occur in approximately 55% and 25% of cardiac surgical patients
(10,15,16,17,18,19). Fifteen percent demonstrate ≥50% carotid stenosis and up to 13% may have had a TIA or
prior stroke (15,19). When compared to previous cardiac surgical patients, these intercurrent diseases may
double the risk of perioperative stroke for the present and future patients (10,20).
The Cardiovascular Health Study (CHS) enhances appreciation for preexisting cerebral morbidity and cerebral
risk in the general population (21). In that investigation, a community population of 3,360 individuals over 65
years of age underwent MRI. Of these, 31% had “silent” cerebral infarcts (21). These infarcts were primarily
subcortical, lacunar, and strategically placed or small enough so that clinical signs of stroke were not evident.
However, detailed neurologic testing suggested the possibility that these infarcts may have accounted for
cognitive and gait abnormalities (21). These lesions likely are related to chronic hypertension, which narrows the
penetrating vessels supplying deep white matter, thereby rendering these regions vulnerable to focal ischemia
(22,23). This type of cerebral vascular disease is clearly linked to late-onset dementia (24,25).
These findings have implications for the cardiac surgical population. Of the 5,888 men and women enrolled in
the CHS, those who underwent MRI were “younger… and were more likely never to have smoked and less likely
to have prior cardiovascular disease, hypertension … and diabetes than those who did not undergo scanning”
(21,26). As such, the cardiac surgical population probably has an incidence of preexisting “silent” cerebral
infarction in excess of 31%. One study of 31 neurologically asymptomatic CABG patients reported a 16%
incidence of thromboembolic infarcts and a 58% incidence of lacunar infarcts on preoperative MRI (27).
In addition to the clear predisposition of chronic cerebrovascular disease to adverse neurologic outcome in
cardiac surgery, investigation into other patient factors that may determine or modulate brain outcomes
continues. Females tend to have worse neurologic outcomes (14,28,29), perhaps in part because of referral bias
and small vessel size, but genetic sexlinked factors may also play a role (16,30). Another active area of
investigation is genomics. To date, only apolipoprotein E4 (ApoE4) has been the subject of significant
investigation in cardiac surgical outcomes (31,32,33,34,35). ApoE4 is a protein that plays an important role in
cholesterol transport and metabolism, with three common alleles resulting in E2, E3, and E4 isoforms (36). The
apolipoprotein alleles define a spectrum of LDL (low-density lipoprotein) cholesterol levels (37). Of the isoforms,
the ApoE4 allele has a clear link to the development of atherosclerosis, cerebrovascular disease, and dementia
(37,38,39,40).
In cardiac surgical patients, the relationship of patient factor ApoE4 to cerebral autoregulation (33), inflammatory
cytokines (35), as well as markers of brain injury S100 and neuron-specific enolase (NSE) has been investigated
(31). Because the absence of ApoE4 has been linked to better recovery from neurologic injury, the most
interesting investigation to date was by investigators from Duke University who identified an association of the
ApoE4 allele with worse cognitive outcomes in 65 patients who underwent cardiac surgery (32). However, the
frequency of the E4 allele was only 13%; so the study was underpowered. Additionally, the authors (32) point out
that an association of E4 and adverse neurologic outcomes, or markers of neurologic outcomes (31,36), might
simply be related to a greater burden of atherosclerotic disease in the E4 patients rather than a more specific
interaction of the gene and neurologic outcome.
Neurologic Complications in Cardiac Surgery

Neurologic injury following cardiac surgery has been a source of concern since its inception and this injury can
be generally divided into frank stroke, encephalopathy, and neurocognitive disorders. The incidence of major
neurologic morbidity related to cardiac surgery is 1% to 6% (5,11,14,16,41,42), although select populations may
have a clinically evident stroke risk as high as 8% to 9% (1,6). It is important to note that a recent prospective
study demonstrated that the intensity of evaluation affects reported stroke rate; with greater scrutiny,
P.387
up to 17% of the patients may be diagnosed with postoperative stroke, and if cerebral ischemia is assessed by
MRI, up to 32% to 54% of the patients will show evidence of cerebral insults (43,44).
Two prominent multicenter studies from the Multicenter Study of Perioperative Ischemia (McSPI) group examined
neurologic outcomes and their predictors in patients undergoing CABG (5), or combined CABG and open-
ventricle procedures (6). Morbid neurologic outcomes were classified as type 1 (cerebral deaths, nonfatal
strokes, and new transient ischemic attacks (TIAs) or type 2 (new intellectual deterioration at discharge or new
seizures). Of 2,108 patients in the CABG study, 3.1% had type 1 and 3% had type 2 outcomes (5). The
predictors of type 1 outcomes were aortic atherosclerosis, a history of neurologic disease, and older age; while
the predictors of type 2 outcomes were age, systolic hypertension, pulmonary disease, and excessive alcohol
consumption (Table 15.2). In 273 patients undergoing combined CABG and open-ventricle procedures, adverse
neurologic outcomes occurred in 16% (8.4% type 1 and 7.3% type 2) (6). In that study, predictors of type 1
outcome included aortic atherosclerosis or thrombus, while type 2 outcomes were predicted by aortic
atherosclerosis, a history of endocarditis, postoperative low cardiac output state, a history of alcohol abuse,
perioperative arrhythmias, and elevated systolic blood pressure on admission (6). The latter study also
demonstrates the adverse effect of neurologic morbidity on ICU length of stay, total duration of hospitalization,
and discharge disposition.
In the cardiac surgical population, neurocognitive morbidity (i.e., intellectual function) is much more frequent than
frank neurologic morbidity (i.e., defects present on neurologic physical examination). The incidence of
neurocognitive deficits at discharge ranges from approximately 10% to 80%, with 5% to 20% of deficits still being
present 3 to 6 months after surgery (42,45,46,47,48,49,50). Because the results of cognitive testing prior to
discharge may be confounded by pain, drugs, and sleep deprivation and by long-term CNS recovery capabilities,
longer-term assessment is much more important than predischarge assessment.
Large variations in the reported incidence of neuropsychological impairment result from several factors. First, the
incidence may vary 2-fold depending on whether the investigation is retrospective or prospective (51). Results
also differ depending on the batteries of tests performed and the definition of an abnormal test result. Differences
may also arise secondary to the timing of test administration and to preoperative variables such as preexisting
deficit or impaired language skills (52,53). A 1995 consensus conference addressed these issues and better
agreement now exists over appropriate test batteries, test timing, and the definition of an abnormal result
(54,55,56).
In spite of methodologic differences, specific patterns of deficits are commonly described. These include deficits
in psychomotor speed, attention and concentration, new learning ability, and short-term memory (Table 15.3)
(8,49,50,56,57,58). Ophthalmologic abnormalities have also been described in up to 25% of patients and
primitive reflexes may be seen in 39% (42). While a significant proportion of deficits are clinically silent and
become evident only on testing, Shaw et al (8) reported a 38% incidence of significant intellectual impairment
and a 10% incidence of overt disability in 235 patients showing postoperative neuropsychological test score
deterioration.
The pattern of neurologic injury in children undergoing cardiac surgery differs from that of adults, suggesting a
different etiology. Nonstroke neurologic impairment in children more often includes seizures, movement
disorders, and developmental delays (59). The incidence of these events in children is influenced by the use of
deep hypothermic circulatory arrest and by its duration when it occurs (60,61).
Epidemiologic, clinical, and neuroimaging investigations continue to refine the understanding of postcardiac
surgical cognitive outcomes. Historically, the use of CPB has made cardiac surgery unique, and the working
assumption has been that adverse cognitive outcomes were directly related to that physiologic experience.
However, more recent data do not bear that out. If CPB is responsible for cognitive injury, one must predict that
patients undergoing off-pump coronary artery bypass grafting (CABG) would have significantly different cognitive
outcomes than those having CABG surgery with bypass. While most reports have generally been small or
nonrandomized, one prominent, randomized comparison and meta-analysis and a sufficient number of patients
(62,63) demonstrated virtually no effect of CPB on cognitive decline. In that report, the incidence of impairment 3
months postoperatively was 21% in the off-pump group versus 29% in the on-pump group ( p = 0.15). At 1 year
in the off- and on-pump groups, the incidence was 31% and 34%, respectively ( p = 0.69) (62).
Additional data outside cardiac surgery have shed light on “postcardiac surgical” cognitive dysfunction. A 25% to
30% incidence of cognitive impairment has also been clearly demonstrated in older patients undergoing major
vascular, orthopedic, and thoracic surgeries (9). Finally, when Selnes and colleagues (64) compared cognitive
outcomes at 3 and 12 months in age- and health-matched cardiology and cardiac surgical patients, they were
unable to identify meaningful cognitive outcome differences. Wahrborg and colleagues (65) made similar
observations in a smaller study. While the incidence of neurocognitive disorders in noncardiac surgical patients
is usually lower, this may be a function of the severity and duration of the stresses associated with cardiac
surgery rather than the uniqueness of the experience itself.
If cognitive outcomes are not determined by the presence or absence of CPB and if similar cognitive deficits are
seen in elderly noncardiac surgical patients and in age- and health-matched cardiology patients, one might
logically conclude that cognitive decline is a function of the elderly brain and periprocedural factors rather than
specific intraoperative
P.388
P.389
events in cardiac surgery. MRI results of the Cardiovascular Health Survey suggest the possibility that
perioperative stressors mask underlying disease, as supported by cerebral imaging studies (21,26) and in the
significant incidence of preoperative cognitive dysfunction in cardiac surgical patients (66) (Table 15.4). This
conclusion has tremendous implications for redirecting the thrust of clinical investigation in this area. If
postcardiac surgical cognitive dysfunction does not primarily result from intraoperative events, this would explain
why attempts to reduce adverse cognitive outcomes with perioperative interventions (including mean arterial
pressure [MAP] (67), bypass temperature (47,48,68,69), CO2 and glucose management (70,71,72), pulsatility
(72), pharmacologic neuroprotectants (73,74,75), and surgical devices (76)) have not shown a consistent effect
on cognitive outcomes. On the other hand, improvements in surgical techniques have reduced the number of
neuropsychological deficits by one-half since 2005 (77,78).
TABLE 15.2. Adjusted odds ratios for type I and type II cerebral outcomes associated with
selected risk factorsa
Odds ratio
Factor Model for type I cerebral Model for type II cerebral

outcome outcome
Significant factors (p < 0.05)
Proximal aortic atherosclerosis 4.52
History of neurologic disease 3.19
Use of intraaortic balloon pump 2.60
Diabetes mellitus 2.59
History of hypertension 2.31
History of pulmonary disease 2.09 2.37

History of unstable angina 1.83
Age (per additional decade) 1.75 2.20
Systolic blood pressure >180 mm Hg 3.47

at admission
History of excessive alcohol 2.64

consumption
History of CABG 2.18
Dysrhythmia on day of surgery 1.97
Antihypertensive therapy 1.78
Other factors (p not significant) b
Perioperative hypotension 1.92 1.88
Ventricular venting 1.83
Congestive heart failure on day of 2.46

surgery
History of peripheral vascular disease 1.64
aOdds ratios are forthe risk of a type I or II outcome in patients with the risk factor in question as
compared with those without the risk factor. Odds ratios have been adjusted for all the factors listed for
each model. Excessive alcohol consumption indicates previous hospitalization because of alcohol
consumption or alcohol withdrawal. Perioperative hypotension indicates a systolic blood pressure <80
mm Hg (during surgery but before cardiopulmonary bypass or after bypass) or <40 mm Hg (during
bypass) for more than 10 minutes. CABG denotes coronary artery bypass graft.
bIn addition to factors from Table 1,the following characteristics, studied in unvariable analysis, did not
remain in the model: sex, aortic cross-clamping, duration of cardiopulmonary bypass and surgery, and
institution.
Roach GW, Kanchuger M, Mangano CM, et al. Adverse cerebral outcomes after coronary bypass
surgery. Multicenter Study of Perioperative Ischemia Research Group and the Ischemia Research and
Education Foundation Investigators. N Engl J Med 1996;335:1857-1863. Copyright © 1996
Massachusetts Medical Society. All rights reserved.
TABLE 15.3. Outcome changes within each cognitive domaina
Cognitive No Decline and Persistent Late

domain declineb improvementc (%) declined (%) declinee (%)
(%)
Visuoconstruction 50 15 11 24
Language 56 26 5 13
Verbal memory 63 21 10 6
Attention 71 8 9 12
Executive 82 4 3 11
function
Visual memory 85 2 9 4
Motor speed 85 6 4 5
Psychomotor 90 1 4 5
speed
aEach cognitive domain is considered as a separate entity, and thus, an individual patient will have
different outcomes in different domains.
bNo decline = score does not decline by more than 0.5 standard deviation (SD) from preoperative score.
cDecline and improvement = score declines by more than 0.5 SD at 1 month and then recovers by more
than 0.5 SD at 1 year.
dPersistent decline = score decline reaches -0.5 SD at 1 year.
eLate decline = score declines 0.5 SD or more from 1 month to 1 year.
McKhann GM, Goldsborough MA, Borowicz LM Jr, et al. Cognitive outcome after coronary artery
bypass: a one-year prospective study. Ann Thorac Surg 1997;63:510-515.
There are likely to be parallels with postoperative delirium in cardiac surgery, but isolating the specific effect of
cardiac surgery has not been evaluated by comparing this complication in cardiac surgery to noncardiac surgery
patients. The very high 26% to 52% incidence of postoperative delirium after cardiac surgery is frequently
underappreciated. Not surprisingly, delirium is associated with poor outcomes including long-term cognitive
dysfunction, increased risk of stroke risk, and mortality. A large fraction of these patients present with hypoactive
delirium and if not actively looked for this complication is vastly underrecognized. Unfortunately, strategies to
prevent this complication have been largely unsuccessful in the cardiac surgery population (79) and with
population aging, better understanding the etiology of postoperative delirium is a compelling task ahead.
SURGICAL STRESS AND NEUROLOGIC RISK

Although the perioperative period contains atheroembolic risk, hypo- and hypertension, anemia, arrhythmias,
dehydration, and disorders of coagulation, the contribution of these factors to neurologic risk and outcome
remains difficult to define. Since the incidence of frank neurologic injury in the surgical population is relatively
low, the contribution of individual physiologic factors to neurologic and neuropsychological outcomes is difficult to
determine. Because of the relatively high incidence of postoperative neurocognitive disorders, these outcomes
offer the potential to be more revealing than neurologic morbidity. Nevertheless, with few exceptions
(58,77,78,80,81,82,83,84), surgical or medical interventions to date have failed to demonstrate a clear effect on
neuropsychological outcomes. It is also difficult to isolate perioperative risk factors, because several risk factors
are both common and closely associated with each other. One should therefore regard neurologic morbidity as
resulting from the combination
P.390
of a patient chronically at risk with a variety of surgically related insults or stresses for which the vascular system
is unable to compensate.
TABLE 15.4. Subclinical preoperative cognitive impairment
Percentage of patients by level of impairment in cognitive domains at the preoperative

assessment
Percentage of patients tested
Impaired Low average Average (- High average Very

(Z ≤ - (-1.70 < Z < - 0.67 < Z < (+0.66 < Z < superior
1.70) 0.66) +0.67) +1.70) (+1.70 ≤ Z)
Language 16.3 16.3 37.2 9.3 0
Visuospatial 7.0 25.6 55.8 11.6 0
Attention 9.3 53.5 20.9 11.6 0
Information 4.7 23.3 62.8 9.3 0

processing
speed
Verbal 48.8 20.9 20.9 0 0

memory
Visual 14.0 18.6 46.5 14.0 4.7

memory
Psychomotor 51.2 16.3 23.3 2.3 0
speed
Executive 11.6 34.9 46.5 7.0 0
All cognitive 7.0 58.1 34.9 0 0
N = 43 CABG.
From Table 3 of Rankin KP, Kochamba GS, Boone KB, et al. Presurgical cognitive deficits in patients
receiving coronary artery bypass graft surgery. JINS 2003;9:913-924, with permission.
In the absence of hypoxia, neurologic morbidity results from inadequate tissue perfusion. In its simplest form,
ischemia may result from embolic obstruction of a large or small vessel, from inadequate flow through a fixed or
variable stenosis, or from a failure of collateral circulation. At the level of the microvasculature, inflammation and
endothelial dysfunction could also play a role in compromising oxygen delivery and neuronal functional integrity
(85,86,87,88).
Embolization
Most patients experience cerebral embolization during CPB (58,89,90,91). Transcranial Doppler (TCD) and
echocardiographic (58,89,92), retinal angiographic (93,94), pathologic, and radiographic information
(95,96,97,98,99) indicate that cerebral embolization during CPB may be the primary cause of serious brain injury
during cardiac surgery. These embolic events are related to aortic atheromata (100,101), platelet-fibrin and
leukocyte aggregates (93,102,103), and by bubbles generated in the CPB circuit or in the surgically exposed left-
sided circulation (58,104). The CNS may be exposed to hundreds or thousands of particulate and nonparticulate
emboli and the periods of embolic risk are usually associated with specific surgical events (Fig. 15.2)
(58,83,89,92,105). While air embolization is a primary source of TCD signals, some authors have observed
better cognitive outcomes by reducing embolization (58,77). In the study by Hammon and colleagues (77), the
combination of epiaortic scanning, single-clamp technique, and increased left ventricular venting decreased
cognitive decline modestly. At 1-month assessment, the incidence was 18% in the treatment group versus 29%
in a historical control. However, neuroimaging studies question the importance of air embolization as a significant
determinant of neurologic outcome (106).
In contrast to air, the effect of particulate embolization can be well documented clinically by focal neurologic signs
or by neuroimaging studies. Of the different neuroimaging techniques, diffusion-weighted magnetic resonance
imaging (DW-MRI) is probably the best tool for detecting cerebral ischemia in the early postoperative period.
This highly sensitive modality can detect ischemic areas as small as 0.4 mm in size (107). Furthermore, in
contrast to conventional neuroimaging modalities, for example, computed tomography (CT) and standard T1-
and T2-weighted MRI, impairment of water diffusion occurs minutes after onset of acute ischemia, resulting in
high signal intensity with DW-MRI (107,108). This allows DW-MRI to detect early ischemia as well as distinguish
acute and chronic lesions. Although most studies
P.391
have enrolled small numbers of patients, postoperative DWMRI has typically demonstrated new cerebral
ischemic events in about 30% to 50% of patients (44,109,110,111,112). The largest investigation to use DW-MRI
was at the authors’ institution where scans were done in 50 cardiac surgical patients; in that series, the
incidence of cerebral ischemic events was 32% and all events were embolic in nature (43).
FIGURE. 15.2. Number of embolic events per minute in a representative patient from before insertion of the
aortic cannula to after end of cardiopulmonary bypass (CPB). X-clamp, cross-clamp. (van der Linden J, Casimir-
Ahn H. When do cerebral emboli appear during open heart operations? A transcranial Doppler study. Ann
Thorac Surg 1991;51:237-241.)
Hypoperfusion
Although there are no compelling data that MAP management during CPB is a primary determinant of neurologic
outcome, regional cerebral hypoperfusion probably occurs during CPB secondary to hypertensive, diabetic, or
senile atherosclerotic disease. Both hypertension and diabetes mellitus are independent risk factors for
neurologic complications following cardiac surgery (5,19,113,114) and these forms of vascular disease are
present in at least 50% of adult cardiac surgical patients. In addition to a rightward shift of the autoregulatory
curve (115), chronic hypertension may narrow penetrating arteries, decrease collateral blood flow, and reduce
ischemic tolerance (23). Similarly, diabetes results in macroangiopathies and degenerative changes in cerebral
penetrating arteries, increases the likelihood of embolization (116), and alters cerebral autoregulatory capacity
(117,118). Therefore, the increased neurologic risk associated with hypertension and diabetes may result from
either increased embolization or regional hypoperfusion. However, it is reasonable to assume that the greater
morbidity in these patients may be a function of the interaction of these two processes.
Therefore, even without compelling evidence that perioperative MAP is a primary determinant of neurologic
outcome, regional hypoperfusion (either as a direct result of vascular disease, or as the inability to compensate
for the regional ischemia associated with microembolization), should remain an essential component of our model
for understanding perioperative cerebral ischemia. Depending upon the patient’s preexisting pathology and
intraoperative events such as embolization, MAP may play a role in this regional hypoperfusion and its outcome.
Inflammation
Our thinking about brain injury has moved beyond discussions of vascular obstruction and hypoperfusion. During
CPB, a variety of pathophysiologic mechanisms may impact the vascular lining and these events may contribute
to post-CPB encephalopathy. Because the endothelium regulates vasomotor tone, thrombosis, fluid transport,
and the inflammatory response, alterations in endothelial function may be integral to postbypass CNS integrity.
Although interactions among inflammation, ischemia, and the endothelium remain ill-defined, this is a fertile area
of ongoing research.
P.392
FIGURE. 15.3. White blood cells (WBCs), especially neutrophils, may cause and/or aggravate ischemic lesions
by several mechanisms that may interact and amplify one another. (Ernst E, Hammerschmidt DE, Bagge U, et al.
Leukocytes and the risk of ischemic diseases. JAMA 1987;257:2318-2324. Copyright 1987, American Medical
Association.)
CPB is associated with ischemia and reperfusion injury to the heart and lung as well as a generalized
inflammatory response. Ischemia and reperfusion are potent triggers for activation of leukocytes and for
leukocyte-endothelial or leukocyte-platelet-endothelial binding (Fig. 15.3) (88,119,120). Vascular integrity may
then be impaired either through capillary plugging (121,122) or by the liberation of free radicals, hydrogen
peroxide, and proteolytic enzymes upon leukocyte degranulation (88,119,123). The aspiration of wound blood
into the oxygenator via cardiotomy suction amplifies the inflammatory response as this blood contains tissue
factor which is a potent activator of the complement cascade (124). Endothelial dysfunction has been
demonstrated following CPB reperfusion in pulmonary and coronary vessels (125,126,127). CPB may also alter
endothelial function in nonischemic tissues by a variety of other mechanisms (128,129).
In addition to localized inflammation which may occur during CPB, exposure of the blood to the bypass circuit
results in activation of platelets, monocytes, and neutrophils (103,130,131,132,133,134). The endothelium
normally inhibits platelet aggregation and leukocyte activation and binding (88,119,135,136). However, contact
activation, complement production, and the release of a variety of cytokines (137) stimulate the endothelium to
more actively bind circulating blood elements (138). Therefore, activation of blood elements and the endothelium
during CPB may overwhelm the usual inflammatory homeostatic mechanisms. The extent of the endothelial
dysfunction as a result of CPB has been recently described in two small studies. The first was a prospective
nonrandomized trial of ten patients undergoing aortic valve replacement in Sweden. Spinal fluid was sampled
pre-, intra-, and postoperatively and correlated with TCD and serum measurements of inflammatory cytokines
and proteins. They found marked elevations of inflammatory markers S110B and GFAP without evidence of
neuronal injury or microemboli. In addition, there was evidence of blood-brain barrier breakdown (BBB),
suggesting endothelial damage as a result of inflammation (139). A second study enrolled 19 patients
undergoing CABG or valve replacement. Postoperative brain MRI demonstrated BBB breakdown in 50% with a
similar incidence of embolism (140).
The prospective observational cohort study performed by Mu et al. (141) identified an association of greater
inflammatory process (documented by cortisol levels) during the perioperative period and worse cognitive
function measured by a battery of seven cognitive tests (55), 7 days after surgery. Not surprisingly, the
inflammatory process was also found to be associated with an increased incidence of postoperative delirium and
poorer outcomes by the same group in a previous study (142). Outside of surgery, Yaffe et al. (143) studied
3,031 individuals over a 2-year period and documented the association of inflammation, mainly interleukin-6 (IL-
6) and C-reactive protein (CRP), and worse long-term neurologic outcomes in the general population of well-
functioning elderly individuals. Again, this observation points to population-based issues with the physiology of
aging as the potential sources of poorer neurologic outcomes in surgery.
It remains to be seen if CPB-related inflammation is sufficient to alter CNS endothelial function in the absence of
an ischemic substrate. The relative role of embolic phenomena, localized hypoperfusion, and the influence of
ischemia in other organs also remain to be defined. The inflammatory response triggered by CPB may be
sufficient to magnify minor insults into pathologic ones (144).
CEREBRAL PHYSIOLOGY DURING CPB

For those who regularly work in cardiac surgery operating suites, it becomes easy to take CPB for granted.
However, the physiology of CPB is unique. It is only during bypass that a mammalian species would acutely
undergo up to a 20°C change in body temperature, a rapid reduction in hematocrit (Hct), and a loss of pulsatile
flow. It can be difficult to define what is “normal” under these conditions.
Assuming a steady state of anesthesia, cerebral oxygen demand (CMRO2) during CPB varies primarily in inverse
proportion to brain temperature. Normal values at different temperatures have been established. However, the
same cannot be said of cerebral blood flow (CBF). CBF is strongly influenced by CMRO2, PaCO2, Hct, and
MAP. Each of these variables may act independently or together to increase or decrease CBF. As such,
attempting to define “normal” CBF during bypass may be misleading or counterproductive. Fundamentally,
cerebral oxygen delivery (CDO2) must be sufficient to support metabolic demand. Therefore, in order to
determine the minimum MAP, Hct, or pump flow required at a given temperature, it is best to examine the effect
of these variables on CDO2 at a given predicted CMRO2.
Under nonbypass conditions, cerebral O2 delivery far exceeds cerebral O2 demand such that CMRO2 remains
P.393
independent of CDO2 over a broad range. When CDO2 delivery is progressively reduced, CMRO2 can be
maintained by an increase in O2 extraction but once the capacity for oxygen extraction is exhausted, further
decreases in delivery will result in cerebral ischemia and CMRO2 will decrease. These relationships are
represented schematically in Figure 15.4.
FIGURE. 15.4. Schematic representing the relationship of CMRO2 to cerebral O2 delivery (or the determinants
of CDO2).
Because CDO2 equals the product of CBF and arterial O2 content (CaO2), individual determinants of CBF or
CaO2 can serve as the abscissa in Figure 15.4. Temperature change may shift the curve describing the CDO2-
CMRO2 relationship upward or downward, but at a stable temperature, the physiologic relationship is unaltered.
The minimum O2 delivery supporting oxygen demand is the “critical O2 delivery” (145,146,147). Similarly, during
CPB, the critical Hct (Hctcrit) or critical perfusion pressure for brain can be defined as the minimum Hct or
perfusion pressure maintaining CMRO2 at a given temperature (148,149).
Determinants of CPB
CPB is typically associated with changes in body temperature and Hct. Significant alterations in PaCO2 and MAP
may also be experienced. While it is common for these variables to change simultaneously, each has a
predictable effect on cerebral perfusion.
Temperature
In the context of CPB practice, temperature is the primary determinant of CBF, and it has direct and indirect
effects. Generally the brain regulates its flow in response to its oxygen demand such that increases or decreases
in CMRO2 are associated with proportional changes in CBF. This relationship has been termed “flow-metabolism
coupling.”
The Q10, or CNS respiratory quotient, describes the increase in CMRO2 per 10°C increase in temperature.
Between 27°C and 37°C, this value is approximately 2.4 to 3.0. Therefore, a 10°C temperature reduction
decreases metabolic rate more than 50%, and all other things being equal, CBF is reduced proportionately. The
Q10 is nonlinear, such that at more profound levels of hypothermia (15°C-27°C) the Q10 rises significantly (150).
As temperature decreases, hypothermia’s effects on CBF become more complex. In addition to the change in
metabolic rate, there is a change in blood rheologic character, and probably in cerebral vascular responsiveness.
Below approximately 22°C to 23°C, CBF and metabolism appear to become uncoupled such that changes in
CBF do not track changes in CMRO2 (Fig. 15.5). This is of greatest relevance during profound hypothermia in
children in whom a cerebral “vasoparesis” has been described (151,152). The physiologic or biophysical
reasons for this vasoparesis remain unknown.
Mean Arterial Pressure

Under non-CPB conditions, the healthy brain maintains CBF to an MAP of approximately 50 to 55 mm Hg.
Significant autoregulatory capacity may also be preserved during CPB, but this depends in large part on how
other CPB variables are managed.
Since the determinants of cerebral perfusion are the same under bypass and nonbypass conditions, one would
anticipate that MAP during CPB would determine cerebral perfusion. However, clinical studies in the 1980s
deemphasized the role of MAP, reporting that CBF is maintained with a-stat acid-base management to MAPs as
low as 20 to 35 mm Hg under hypothermic conditions (153,154,155). These results were interpreted to mean that
the cerebral autoregulatory curve was shifted leftward during hypothermia (153,156).
FIGURE. 15.5. Cerebral blood flow (CBF) (▪) and metabolic rate for oxygen (CMRO2) (□) (both 100 mL/g/min)
versus temperature during CPB (Group I, 38°C; Group II, 28°C; and Group III, 18°C) (n = 8 per group). Mean
values for 10 additional animals at 33°C (n = 5) and 22°C (n = 5) are also shown (CBF, %; CMRO2, +). (Cook
DJ, Orszulak TA, Daly RC. Minimum hematocrit at differing cardiopulmonary bypass temperatures in dogs.
Circulation 1998;98:II-170-II-175.)
P.394
However, these clinical results indicating a leftward shift of the autoregulatory curve must be viewed with
caution. Those studies pooled measurements of MAP and CBF from multiple patients under differing
temperature, CO2, and Hct conditions. Because of large between-patient variability in the physiologic
determinants of CBF, the resulting high variability in CBF virtually ensures that no correlation will be found
between MAP and CBF when single data points are pooled in that manner.
These limitations can be overcome in animal models, where multiple cerebral physiologic measurements can be
made at differing MAPs with extremely tight physiologic control. Unlike in patients, the lower limits of
autoregulation can also be evaluated in animal models. In contrast to the clinical studies of the 1980s, laboratory
reports have not indicated a leftward shift of the autoregulatory curve during hypothermic CPB
(149,157,158,159).
Because a large part of CPB is now conducted with mild hypothermia (oft termed “tepid”), Plochl et al. (149)
examined critical cerebral perfusion pressure at 33°C in dogs. The relationship between MAP, CBF, CDO2, and
CMRO2 was described as consisting of two parts, a pressure-independent portion and a pressure-dependent
portion. CBF and CDO2 were preserved at MAPs of 60 mm Hg and higher, while at 50 mm Hg or less, CBF, and
more importantly CDO2, became pressure-dependent (Fig. 15.6). However, cerebral ischemia was not observed
at an MAP of 50 mm Hg because the reduction in CDO2 was compensated for by an increased cerebral O2
extraction. While cerebral ischemia was first statistically significant at an MAP of 40 mm Hg, the authors
suggested that an MAP of 45 mm Hg is probably inadequate at 33°C, because at 45 mm Hg some animals
showed evidence of cerebral ischemia.
FIGURE. 15.6. Cerebral oxygen delivery (CDO2) and CMRO2 versus mean arterial pressure (MAP) during CPB
at 33°C. Values (100 mL/g/min) are mean ± SD (*p < 0.05 vs. MAP of 60 mm Hg by repeated measure analysis of
variance followed by Student-Neuman-Keuls test). (Plöchl W, Cook DJ, Orszulak TA, et al. Critical cerebral
perfusion pressure during tepid heart surgery in dogs. Ann Thorac Surg 1998;66:118-124.)
Laboratory studies in healthy animals indicate that relatively normal MAPs should be maintained during CPB
between 27°C and 37°C (149,157,159). Physiologically, an MAP of at least 50 to 55 mm Hg appears desirable
because at this pressure some safety margin for the brain (increased O2 extraction) will exist because most
patients must be presumed to have cerebral vascular disease or hypertension.
Carbon Dioxide
While hypothermia increases ischemic tolerance, it also introduces unique physiologic questions. One of the
most practical has been the appropriate management of CO2. While CO2 can be managed with pH-stat or a-stat
techniques, discussions of which approach is more “physiologic” are probably less productive than determining
which CO2 management strategy is most consistent with certain physiologic goals.
Carbon dioxide is one of the most potent determinants of CBF and most (160,161,162,163), but not all (164),
studies indicate that CO2 reactivity is preserved during bypass. Depending on CO2 strategy, CBF may vary by
more than 50%. Changes in PaCO2 alter CBF largely independent of CMRO2, so like hemodilution, changes in
PaCO2 may alter the ratio of CBF to CMRO2 without indicating pathology.
Henriksen clearly demonstrated the effect of CO2 on CBF as well as the effect of PaCO2 on cerebral
autoregulation during clinical CPB (160). Figure 15.7 shows that during bypass an
P.395
elevated PaCO2 (upper curve) is associated with a higher CBF for any given MAP. Additionally, Henriksen’s data
show that autoregulation is preserved with an a-stat strategy between MAPs of 55 and 95 mm Hg (Fig. 15.7,
lower curve), while CBF becomes largely pressure passive when PaCO2 is elevated (Fig. 15.7, upper curve).
Subsequent clinical and animal studies have confirmed these findings (162,164,165,166,167). This effect of CO2
is seen across different values of MAP, CMRO2, and Hct. Hematocrit In the adult, CPB hemodilution typically
reduces hemoglobin (Hgb) concentration (and hence Hct) by a third. This reduces blood viscosity and vascular
resistance and increases CBF (148,160,168,169). This rheologically-mediated increase in CBF supports
cerebral oxygen delivery as Hct is reduced, so CMRO2 remains independent of Hct over a broad range.
However, with progressive hemodilution, CDO2 and then O2 consumption are compromised when the CBF
response can no longer compensate for the reduction in arterial oxygen content and when oxygen extraction
capacity has been exhausted. At this point, the Hctcrit is reached (Fig. 15.4) (148).
FIGURE. 15.7. Response of cerebral blood flow (CBF) to changes in mean arterial pressure (MAP) at three
different levels of carbon dioxide tension (mean values of 33, 45, and 57 mm Hg). (Henriksen L. Brain luxury
perfusion during cardiopulmonary bypass in humans. A study of the cerebral blood flow response to changes in
CO2, O2, and blood pressure. J Cereb Blood Flow Metab 1986;6:366-378.)
During hypothermic CPB, the increase in CBF occurring with hemodilution may be offset by the decrease in CBF
associated with the reduction in CMRO2 (168). As such, during hypothermia, CBF may increase, decrease, or
remain largely unchanged. The net change in CBF is a function of both the magnitude of temperature change
and Hct reduction (168).
Hemodilution practice during CPB is relatively unique and this can lead to a misunderstanding of CBF
responses. Under non-CPB conditions, there is a relatively fixed ratio (13,14,15,16,17) between CBF and
CMRO2. Authors have described increases in this ratio (uncoupling) during normothermic or moderately
hypothermic CPB (153,170,171) with a suggestion that this is pathophysiologic. While CBF-CMRO2 uncoupling
may occur with profound hypothermia, a change in this ratio should be expected with hemodilution (as with
variations in PaCO2).
During normothermic CPB, the CBF-to-CMRO2 ratio is elevated; however, this elevated ratio is not pathologic
because the increase in CBF constitutes appropriate physiologic compensation for the reduction in Hct.
Accordingly, CDO2 does not change from the prebypass state (168). For this reason, discussions of the CBF-to-
CMRO2 ratio during CPB can be misleading, whereas focusing instead on cerebral O2 delivery may provide
clarity by accounting for the effects of changing Hct. While experience dictates that very low Hcts can be
tolerated during CPB (172,173), until recently these limits have not been defined. In a recent publication, Loor et
al. (174) prospectively evaluated 7,957 patients who were not transfused looking for association of nadir Hgb
and outcomes. There was linear, organ-dependent association (myocardial injury, glomerular filtration ratio,
ventilator support, hospital stay, and mortality) between the degree of anemia and organ injury (Fig. 19) but no
specific cutoff at which the risk would sharply increase. Additionally, there was no evidence to recommend a
specific transfusion trigger for this patient population. Indeed, studies by Swaminathan et al. in 2003 and a
retrospective study in 2011 suggested that the worsened renal outcomes associated with anemia were not
improved by the use of blood transfusions. This pathophysiology is complex because the severity of kidney injury
associated with blood transfusions might be even more severe in the anemic patients being transfused when
compared to the nontransfused patients (175,176).
To determine temperature-dependent limits on hemodilution, our group placed dogs on bypass at 38°C, 28°C, or
18°C and the cerebral effects of progressive hemodilution were determined (148). We predicted that the critical
Hct would be reduced in proportion to the reduction in CMRO2; however, this was not found. Between 38°C and
18°C, appropriate reductions in metabolic rate were demonstrated; however, the critical Hct at 28°C was only
about 3 units lower than that at 38°C. Similarly, at 18°C, the CMRO2 was less than half that at 28°C, but the
critical Hct at 18°C was only 3 to 4 units lower than that at 28°C (Fig. 15.8). Therefore, the leftward shift in the
Hctcrit is quite small and less than proportionate to the decrease in CMRO2. This occurs because the CBF
response to hemodilution attenuates with progressive hypothermia (148). Finally, there is an impression that
hemodilution increases tolerance for hypotension because it increases organ blood flow. While hemodilution
increases CBF, this is not equivalent to saying that tolerance to hypotension is increased. While CBF may be
“normal” at a lower MAP, cerebral O2 delivery will be reduced. Following hemodilution, autoregulatory curves
can be constructed for brain, and although the absolute levels of CBF shift upward with each level of
hemodilution, the minimum autoregulatory threshold for MAP remains about the same as in the nonhemodiluted
state (160).
CPB Flow and Brain Perfusion

To a large extent, asking whether pump flow or MAP is of greater importance during bypass constitutes an
artificial distinction. As in the intact circulation, changes in pump flow during CPB are usually associated with
changes in MAP. However, this relationship may not be linear. At higher flows, reductions in vascular resistance
may dampen the effect of pump flow changes on MAP, while at low flows, MAP may be reduced in direct
proportion to a change in pump flow (159). A focus on the low-flow range, where cerebral physiologic variables
show pump flow dependence (152,177,178), may lead to the conclusion that pump flow is a primary determinant
of cerebral perfusion. However, the effect of pump flow on cerebral perfusion is indirect.
These relationships were well demonstrated by Sadahiro et al. (159), who described the effect of stepwise CPB
flow reductions on MAP and CBF in dogs. In that report, pump flow did not alter CBF until the MAP decreased
below 50 mm Hg. Below that point, pump flow, MAP, and cerebral perfusion diminished in nearly linear fashion.
Scrutiny of other reports
P.396
examining the effects of pump flow on cerebral physiologic variables show similar CNS dependency on pump
flow when those reduced flows induce MAPs below the autoregulatory threshold (152,179,180,181,182,183).
FIGURE. 15.8. Hct-CMRO2 relationship at 38°C, 28°C, and 18°C. Forty value pairs per group (n = 8 per group).
Linear regression curves were drawn for data points above and below a range of Hcts below which the transition
from Hct independence to Hct dependence occurs. (Cook DJ, Orszulak TA, Daly RC. Minimum hematocrit at
differing cardiopulmonary bypass temperatures in dogs. Circulation 1998;98:II-170-II-175.)
The primacy of perfusion pressure has been demonstrated under conditions where MAP was normal (61 mm Hg)
and pump flow was low (0.75 L/min/m2) as well as when pump flow was normal (2.2 L/min/m2) and MAP was low
(24 mm Hg) (180,184,185). In that investigation, a low MAP with a normal pump flow was achieved by a large
femoral arterial to venous shunt. These studies showed that if MAP was maintained, pump flow rate had no
effect on CBF; however, reduced perfusion pressure reduced CBF even if pump flow rate was normal. Data from
both animal models (158,182,183,186) and during clinical CPB (152,187,188,189) support those conclusions.
These results indicate that CPB flow is important to cerebral perfusion in so much as it generates an MAP and
that maintenance of CPB flow is not sufficient to guarantee cerebral perfusion if MAP is reduced.
Pulsatility
Like the acute changes in temperature and Hct, which may occur during CPB, the loss of pulsatile flow is a
physiologic condition unique to CPB. As such, the effect of pulse pressure on organ perfusion during CPB has
been of interest. Nonpulsatile perfusion has been reported to result in arteriolar closure (190) and a disturbance
in the coupling of blood flow and metabolism (171). Conversely, pulsatile flow has been reported to improve
CBF, microcirculatory perfusion, and tissue oxygen consumption, and to facilitate the recovery of CBF following
ischemia, low-flow CPB, and circulatory arrest (191,192).
At least an equal number of reports have found no significant physiologic effect of pulsatility during CPB.
Hindman and colleagues found no difference in CBF or CMRO2 between pulsatile and nonpulsatile CPB in
rabbits under normothermic (193) or hypothermic (194) conditions. Sadahiro et al. (159) reported similar results
in dogs as did Cook and colleagues (186) under three temperature and CPB-flow conditions. Conflicting reports
about the effects of pulsatile CPB exist for essentially every variable examined. Because convincing evidence of
benefit is lacking and because of the technical complexity and difficulties in generating a meaningful pulse
pressure in the systemic circulation, pulsatile CPB systems have not become a routine of practice.
CPB Duration
Two clinical reports have indicated that CBF during CPB decreases with bypass duration (195,196). In one
study, two CBF measurements were obtained 20 to 30 minutes apart during hypothermia and while
nasopharyngeal temperature, PaCO2, and MAP were stable, a 0.7% to 1%/min decrease in CBF was observed
(196). A second study from the same group concluded that CBF declines over time based on alterations in CO2
responsiveness (195). Although decreases in CBF with time were shown in these studies, there is evidence to
suggest that these decreases in CBF may have been related to other factors.
Hindman et al. (197) were unable to document an effect of CPB duration on CBF in a rabbit model where brain
temperature was directly measured. They speculated that the previous clinical findings were a function of brain
cooling not
P.397
reflected in nasopharyngeal temperature. A study in baboons also failed to show an effect of CPB duration on
CBF (185). The canine study by Johnston et al. (164) is particularly notable. During CPB, blood flow to cerebral
cortex and cerebellum were measured and although some decrease was seen following rewarming, three
measurements over 120 minutes of stable hypothermia demonstrated no decline in CBF under either a-stat or
pH-stat conditions. Subsequent clinical studies have also failed to show a decrease in CBF with bypass time
(168,198).
INTRAOPERATIVE MANAGEMENT AND NEUROLOGIC OUTCOME

Mean Arterial Pressure
A variety of early reports as well as a few from the 1980s (199,200) identified a relationship between
intraoperative MAP and neurologic outcome. This relationship has not been identified in other clinical studies
(5,7,51,57). However, it should be emphasized that no investigation before 1995 was specifically designed to
examine the role of MAP in neurologic outcome. The studies lacked a control group, were often retrospective, or
were designed to examine the neurologic effects of other interventions (51,71,201), and the effect of MAP on
outcome was examined secondarily. Additionally, neurologic follow-up was typically only short-term and the
patients were younger and had fewer comorbidities than our current surgical population. These studies also
used both a-stat and pH-stat management (71,201), bubble and membrane oxygenators (7,201), and may not
have used arterial line filtration (7,51). Therefore, the applicability of all of these studies to our current surgical
population must be viewed with some caution.
TABLE 15.5. Effect of MAP on neurologic cardiac outcomes in patients randomized to lower
or higher MAP during bypass
MAP
50-60 mm Hg (%) 80-100 mm Hg (%)
(n = 124) (n = 124) p
Stroke 7.2 2.4 0.076
Minor neurodeficits 3.2 0.8
Cardiac complications 4.8 2.4 0.3
6-month cognitive deficit 12 11
Overall major cardiac and neurologic outcomes 12.9 4.8 0.026
Total mortality 4 1.6 0.25
The authors do not provide p values for each variable.
Adapted from Gold JP, Charlson ME, Williams-Russo P, et al. Improvement of outcomes after coronary
artery bypass.
A randomized trial comparing intraoperative high versus low mean arterial pressure. J Thorac
The later multicenter study on cerebral outcomes following CABG described a 6% incidence of neurologic deficit
at discharge and reflects our current surgical population (5). While perioperative hypotension was not identified
as a risk factor for adverse neurologic outcome, like earlier studies, patients were not randomized to differing
MAPs. To date, only two studies have done this in a prospective randomized manner (67,202). Gold et al. (67)
randomized 248 patients to either lower (50-60 mm Hg) or higher (80-100 mm Hg) MAP during hypothermic
(28°C-30°C) CPB and examined the outcome at 6 months. Patient characteristics and CPB management were
otherwise equivalent and reflect current perfusion practice and patient risk profile. While statistical differences
were not shown for individual outcomes, the overall incidence of cardiac and neurologic morbidity at 6 months
was significantly reduced in the high MAP group and there was a trend for every variable, except neurocognitive
outcome, to show better results in the higher MAP group (Table 15.5). The authors speculate that their study
size may have been underpowered for relatively low-frequency events. A prospective randomized controlled trial
by the same institution, performed 12 years later, divided patients into two groups: a “high” MAP 80 mm Hg
group and the “custom” MAP group that used the patient preoperative MAP as the goal MAP during CPB. Using
this approach, there was no statistically significant difference in outcomes between the groups, demonstrating
that either approach is adequate. In pragmatic analysis, it was noticed that
P.398
in the MAP “custom” group, for patients in which the MAP was not maintained in the target range, but 20 mm Hg
below, the incidence of cardiac and neurologic complications increased from 7.3% to 15.9%. This finding is then
in agreement with the earlier report (202).
Over the range of temperatures at which most adult CPB is practiced, physiologic data indicate that cerebral
oxygen delivery may become compromised at an MAP of approximately 50 mm Hg. While physiologic
measurements do not translate directly into clinical outcomes, both the clinical report by Gold et al. (67) and the
consecutive study by Charlson (202) are highly suggestive and these studies are arguably the best to have been
conducted on the relationship between MAP and outcome. Finally, our surgical population is older and has
greater stroke risk factors than when many prior “negative” outcome studies were done. Thus, while the data are
not in agreement, it is prudent to be conservative and assume that our patients will benefit from maintenance of
MAP in the autoregulatory range during CPB.
Temperature and Outcomes

The role of CPB temperature in neurologic outcome came to the forefront a decade ago when two large,
randomized outcome studies were published. The Warm Heart Investigators (203) reported a study of 1,732
patients who underwent CPB at either 33°C to 37°C or 25°C to 30°C. In that study, the incidence of stroke at
discharge was equivalent between temperature groups (Table 15.6). However, in the same year, Martin et al.
(204) reported a trial of 1,001 patients undergoing CPB at either ≥35°C ( n = 493) or ≤28°C ( n = 508). The
Martin study reported a 3-fold greater incidence of neurologic morbidity in the warm group.
Reports over the next year (205,206) identified a variety of demographic and intraoperative management issues
that may have accounted for the outcome differences in the Toronto and Emory studies. They pointed out that
the Toronto population had fewer females, a smaller proportion of patients older than 70 years (16% vs. 38%),
and fewer reoperations. Differences in cardioplegia and aortic cross-clamp management may also have placed
the Emory patients at greater risk for cerebral embolism (101,207,208,209). Finally, the warm group at Toronto
was 2°C to 4°C cooler than the warm group at Emory (206).
TABLE 15.6. Neurologic outcome and cardiopulmonary bypass temperature
Cold Warm
Martin et al. (204) (n = 1,001)
Stroke (%) 1.2 4.1
Encephalopathy (%) 0.2 0.4
Total (%) 1.4 4.5
The Warm Heart Investigators (203) (n = 1,732)
Stroke (%) 1.6 1.5
Neurocognitive outcomes for part of these study populations have also been provided. Complete testing was
reported on 89 of the 1,001 patients enrolled at Emory (47). Although CPB resulted in deficits in both
temperature groups, there was no difference in neurocognitive outcome between the warm and cold populations
(47). Neurocognitive outcomes were also reported on 153 patients from the Toronto study. Like the Emory
report, temperature management did not affect neurocognitive injury 3 months postoperatively (48,210).
A variety of other investigations have compared neurologic outcomes using different CPB temperatures. Plourde
et al. (211) randomized 62 patients to CPB at either 34°C to 35°C or 28°C CPB and did not find any
neuropsychologic differences between groups at the seventh postoperative day. Hvass et al. reported 100
patients operated on with a warm-body (37°C)-cold-heart technique and documented a 1% incidence of stroke,
and Birdi et al. randomized 300 CABG patients to CPB at either 37°C, 32°C, or 28°C (212,213), and found a 0%
to 1% incidence of stroke with no difference among the three groups (although the neurologic assessment was
not described). Singh et al. (214) compared 2,585 consecutive patients having CPB at 37°C to a historical cohort
of 1,605 patients operated on with systemic hypothermia (25°C-30°C). In that study, the stroke incidence was 1%
and 1.3% in the warm and cold groups, respectively. Regragui and colleagues (215) conducted neurocognitive
testing on 96 patients randomized to CPB at either 37°C, 32°C, or 28°C and found that the neurocognitive score
was worst in the 37°C group ( n = 31), better in the 32°C group ( n = 36), and equivalent between the 28°C ( n =
29) and 32°C groups. From these results, the authors made an argument for mild hypothermia. However, their
paper was followed by a commentary that faulted the study’s statistical power, neurocognitive testing methods,
and data analysis.
Given the profound effects of temperature on cerebral oxygen demand and the neuroprotective effect of
hypothermia, it is reasonable to expect that lower CPB temperatures would improve cognitive outcomes.
However, such improvement has not been demonstrated in randomized or nonrandomized trials (47,48,68,69).
As such, investigators have turned to examining rewarming rate and postoperative temperature in determining
cognitive outcomes. When the randomized trial of CPB temperature did not show a difference in cognitive
outcomes (68), Grocott and colleagues (216) looked at postoperative temperature in the same patients and
published the data separately. They hypothesized that postoperative cerebral hyperthermia was a determinant of
cognitive dysfunction.
P.399
In that study, cerebral hyperthermia was defined in either of two ways: (1) the maximum temperature in the first
24 hours; and/or (2) the area under the curve for temperature greater than 37°C. Peak temperature was not a
determinant of cognitive outcome while area under the curve for temperature >37°C was associated “…albeit
weakly, with a greater amount of cognitive dysfunction” (216).
Data from the original randomized 2001 Grigore et al. (68) study were reported a third time when a subset of that
negative outcome trial was used to examine the effect of rewarming speed on cognitive outcomes (82). The
cognitive data were analyzed as a continuous variable (better or worse) and as a dichotomous variable (defect
present or not). Neither univariate nor multivariate dichotomous analysis showed an effect of rewarming speed
on cognitive outcomes. However, the authors found that slow rewarming analyzed as a continuous variable was
associated with greater improvement in cognitive performance at 6 weeks than conventional rewarming.
Although there are multiple publications interrogating the effect of perioperative temperature management in
cognitive outcomes, the weight of the evidence is far weaker than the titles would suggest. Of two of those
reporting a positive effect (82,216), the strength of the association is tenuous, and the authors could have
equally chosen the opposite conclusion by another analysis included within those reports. Furthermore, those
positive trials consisted primarily of reporting additional study periods (rewarming phase or postoperatively) from
a larger negative randomized trial (68). This is not to say that perioperative temperature management is
unimportant, only that the evidence for an effect of a perioperative management on cognitive outcome is quite
weak.
Glucose Management
In addition to the absolute temperature difference in the Toronto (203) and Emory (217) neurologic outcome
trials, the Emory group had significantly higher blood glucose levels in their warm CPB group (205). This is of
interest because elevations in blood glucose aggravate neurologic ischemic injury in experimental models
(218,219,220). However, to date, no study has documented an independent effect of glucose on neurologic
outcome in clinical CPB (47,70,205,221,222,223). Although the mean blood glucose in the “warm” Emory group
may have exceeded 275 mg/dL (47), a multivariate analysis did not identify blood glucose as a predictor of
neurologic or neurocognitive outcomes in that study (47,205). This is an area where more investigation is
needed. To date, only one prospective nonrandomized study that included 200 consecutive patients has
suggested an association of significant hyperglycemia and increased incidence of postoperative neurologic
complication (224). One of the important recent investigations in regard to perioperative glucose management in
cardiac surgery is the randomized controlled study from the Mayo Clinic group led by Gandhi (225). This
investigation compared the tight glucose management (90-110 mg/dL) versus conventional management (<200
mg/dL). The intervention group had a higher incidence of deaths (4 vs. 0, p = 0.061) and strokes (8 vs. 1, p =
0.02) when compared with the group under traditional management. Despite the tight glycemic control, this study
did not identify significant hypoglycemia in the treatment group; so this presumed etiology could not explain the
worse outcomes in the intervention group (226). Regardless of establishing an impact on neurologic outcome,
the Society of Thoracic Surgeons (STS) does provide guidance regarding intraoperative glucose management in
diabetic and nondiabetic patients. In summary, the glucose levels should be kept below 180 mg/dL and insulin
should be provided with the use of continuous infusions since these provide better control than subcutaneous
dosing (226).
As previously noted, it appears that neurologic injury arises from a combination of preexisting patient conditions
and intraoperative factors. As with MAP, it is therefore difficult to demonstrate that management of an isolated
physiologic variable, like blood glucose, determines patient outcome.
CO2 Management and Outcome

In the 1990s, studies from four countries examined the effects of PaCO2 management on neurologic outcome in
adults (71,72,162,227). In 1990, Bashein et al. (71) randomized 86 patients to undergo hypothermic (30°C) CPB
with either a-stat or pH-stat management, and those authors also examined neurologic and neurocognitive
outcome at discharge and 7 months postoperatively. Neurologic impairment was unrelated to PaCO2 at either
short-term or long-term follow-up. Stephan et al. (162) randomized 65 patients undergoing CPB at 26°C and
conducted a neurologic exam on the seventh postoperative day. The pH-stat and a-stat groups had a 29% and
7% incidence of neurologic sequelae, respectively, and multivariate analysis identified only PaCO2 as an
etiologic factor in adverse neurologic outcome. In 1996, Patel and colleagues (227) randomized 70 patients
undergoing CPB at 28°C to pHstat or a-stat management and performed neuropsychological testing
preoperatively and at 6 weeks postoperatively. Using deterioration in three or more tests as the criterion for
adverse outcome, a greater proportion of patients in the pH-stat group had an adverse outcome. In 1996, Murkin
et al. (72) also reported on the neurologic effects of CO2 management in 316 patients undergoing CABG
randomized according to CO2 strategy and to pulsatile or nonpulsatile flow. Overall, the stroke rate in the two
CO2 groups did not differ (2.5%), nor did the incidence of neurologic or neurocognitive dysfunction at 7 days.
Approximately half of the patients had CPB times >90 minutes, and in that group only, cognitive dysfunction was
less prevalent in a-stat (27%) than in pH-stat patients (44%) at 2-month follow-up.
While all of these studies have limitations, there is a suggestion that pH-stat management may be associated
with a worsened neurologic outcome and that a-stat CO2 management may be more important in populations at
higher risk.
P.400
The underlying hypothesis is that reductions in CO2 should reduce cerebral embolization but this effect may only
be clinically evident when embolic risk is greater. The hypothesis relating higher CO2 to embolization has been
expressed since the early 1980s (228) but was only recently confirmed in an animal model (229).
The pediatric literature has identified a different effect of CO2 on neurologic outcome. The Boston Children’s
group retrospectively reviewed their outcome data in children undergoing cardiac surgery with profound
hypothermia and found that the introduction of a-stat management worsened neurologic outcome (59). They
speculated that the increased CBF associated with pH-stat management improved cerebral cooling and
neuroprotection in the pre-circulatory arrest period. Subsequent clinical studies using jugular bulb saturation
(230,231) and animal studies measuring brain temperature intracellular pH and high-energy phosphates in
animals (232,233,234) have confirmed their hypothesis. These studies indicate that in the context of profound
hypothermia and circulatory arrest, pH-stat management may have important metabolic advantages in addition to
its facilitation of brain cooling.
From all of these results, it appears that the effect of PaCO2 on outcome is likely to be a function of the type of
cerebral stress introduced by the operation. In adults, a-stat management is probably primarily important in
reducing atheroembolic risk. In children, who lack atherosclerosis, the primary neurologic stress is
hypoperfusion; so pH-stat management should be beneficial, at least in the setting of profound hypothermia
(systemic temperatures below 20°C). While these are reasonable working hypotheses, the literature on the effect
of CO2 management on outcomes in adults is very scanty.
Other CPB Variables

The effects of other CPB variables, pulsatility, Hct, or flow rate on neurologic outcome have received less
attention. Two studies have failed to show an effect of pulsatility on neurocognitive outcome (72,235). Aside from
a single study in infants, the effect of CPB Hct on neurologic outcome has only been addressed secondarily.
Shaw’s study related a drop in Hgb during the operation to worsened outcome, but this was in relation to a
vascular surgery control group which did not undergo hemodilution (8). Short-term neurologic outcome has also
been related to perioperative blood loss, but not to CPB Hct. Finally, well-designed trials relating CPB flow rate
to outcomes have only been conducted in the pediatric CPB population. With profound hypothermia, low flow is
associated with a better outcome than circulatory arrest (60,181), but for adults there is no evidence that CPB
flow rate per se affects neurologic outcome.
INTERVENTIONS
Efforts to reduce neurologic morbidity in cardiac surgery currently proceed in multiple directions. Broadly,
these can be classified as surgical and technical changes in practice, pharmacologic interventions, and
physiologic management strategies.
Surgical and Technical

A greater understanding of surgical causes of neurologic morbidity has resulted in practice change. Recently,
surgical clinical investigators show appreciation for the role of atheroembolism in brain injury and are
emphasizing techniques to reduce this problem. Greater attention to the atherosclerotic aorta has led to the
application of epiaortic ultrasound for assessment and management of aortic cannulation (Fig. 15.9)
(17,101,236) as well as the single cross-clamp and “no touch” techniques (237,238,239). In a recent
retrospective study by the Emory group evaluating 565 total patients undergoing coronary bypass, outcomes in
patients undergoing the revascularization on or off CPB were evaluated. It was observed that from 2002 to 2009,
the use of epiaortic ultrasound increased from 45% in 2002 to 89% in 2009. Furthermore, the use of any cross-
clamp reduced from approximately 97.7% to 72.7%. Among the on-pump cohort, the single-cross-clamp
technique was associated with a decreased risk of stroke compared with the double-clamp (cross-clamp plus
partial clamp) technique (odds ratio, 0.385; p = 0.044). The authors concluded that there has been a change in
their practice with more frequent use of epiaortic ultrasound and more cases being performed without cross-
clamp. These changes were due to surgeons’ increased awareness of complications associated with
manipulation of the aorta (240). To date, multiple publications associate the use of epiaortic ultrasound and
lower postoperative stroke rates (241,242). An extension of the “no touch technique,” together with the greater
long-term durability of arterial grafting, has also contributed to the use of arterial conduits for all CABG grafting
(243).
FIGURE. 15.9. Frequency of moderate or severe atherosclerosis of the ascending aorta necessitating
modifications in operative technique according to age. (Wareing TH, Davila-Roman VG, Barzilai B, et al.
Management of the severely atherosclerotic ascending aorta during cardiac operations. A strategy for detection
and treatment. J Thorac Cardiovasc Surg 1992;103:453-462.)
P.401
Technology solutions are also being directed to reduce aortic instrumentation in cardiac surgery. The European
group of Emmert et al. (244) compared the use of HEARTSTRING (Maquet Cardiovascular LLC, San Jose, CA)
for proximal anastomosis, with total arterial revascularization, off-pump CABG with partial cross-clamp, and on-
pump CABG patients in a total study size of 4,314 patients. In their analysis, patients undergoing off-pump CABG
using partial cross-clamp and patients undergoing the HS approach had significantly lower incidence of stroke
(0.7% vs. 2.3%; CI 95%, 0.16-0.90; p = 0.04), and these results were similar to those of the control group that
underwent no-touch total arterial revascularization (stroke rate, 0.8%). In a separate investigation, the use of the
HS device in 1,380 CABG patients who were separated in four groups according to the severity of
atherosclerotic disease (grades I, II, III, and IV) in the ascending aorta (diagnosed by the use of epiaortic
ultrasound) was studied. The use of the HS device reduced the predicted risk of stroke by 44%, with the
theoretical benefit less apparent in patients with grade I atherosclerotic disease compared with patients with
grade II or higher (245).
The logical extension of reducing aortic manipulation and instrumentation provided impetus for off-bypass CABG
(246,247). Smaller studies associating off-bypass CABG with poorer overall outcomes have reduced the initial
enthusiasm (248,249,250,251). However, a recent publication from Emory University studying 12,079 CABG
patients for postoperative stroke, credits off-bypass technique with a marked decrease in stroke rates (1.5% in
patients having on-bypass surgery versus 0.6% in off-bypass patients with a no-touch technique ( p < 0.01)
(252).
Aortic embolization has also been addressed by devices designed to deflect (252,253) or trap (254,255) emboli
liberated from the root. While these devices appear to serve their intended purpose, an impact on the neurologic
outcome has not been demonstrated.
Echocardiographic assessment of ventricular “de-airing” has become a more prevalent operating-room practice
(256). Insufflation of CO2 into the chest wound has also been advocated (257), because CO2 emboli should be
rapidly absorbed without detrimental effects. While air emboli constitute a primary source of TCD signals, it
remains unclear whether micro-air emboli influence neurologic outcome (83,106,258). CPB circuit management
such as hollow fiber oxygenators, arterial inflow “line” filters, and minimizing transfusion of mediastinal shed
blood may also impact neurologic morbidity (58,104,259,260). The elimination of small debris and/or fat emboli is
quite challenging since the use these can pass through 20 μm in line filters and arterial filters with smaller pores
have excessive resistance (261). Some groups have developed venous and arterial filtering systems to
significantly reduce the emboli load generated by the CPB (262). Biocompatibility of the CPB circuit constitutes
another technical factor that has the potential to impact outcomes. If the CPB surface can mimic the endothelial
glycocalyx, the generalized inflammatory response to CPB may be reduced. Surface heparinization has been the
first step; given the regulatory role of the glycoproteins in neutrophil, platelet, and endothelial interaction
(88,119,135,263), biocompatibility may evolve into more specific glycoprotein surfaces.
Pharmacologic
In addition to surgical and technical interventions to reduce embolic risk, pharmacologic neuroprotection
represents a second line of investigation. At least three forms of pharmacologic neuroprotection can be
considered: metabolic depressants, agents that inhibit different steps in the cellular ischemic pathway, and
antiadhesive agents.
Metabolic Suppression
The fundamental understanding of ischemia as a state of cerebral O2 delivery insufficient for demand
immediately leads to considerations of metabolic suppression as a means of neuroprotection. Although this
inference is obvious, suppressors of CNS metabolism such as barbiturates have not become a routine part of our
practice. Animal models indicate that barbiturate therapy improves outcome in models of incomplete ischemia,
but the usefulness of barbiturate therapy for brain protection during CPB has been difficult to demonstrate
clinically.
The 1982 study of Slogoff et al. (51) randomized 204 cardiac surgical patients to a thiopental (15 mg/kg) or a
control group and evaluated neurologic outcome on the first and fourth postoperative days. While the data
suggested neuroprotection in the thiopental group, the result was not statistically significant. A subsequent study
from the same institution randomized 182 patients undergoing open-ventricle procedures to a control group or to
receive burst suppression doses of thiopental throughout CPB (264). As in the earlier study, patients
approximated normothermia (>34°C); and a bubble oxygenator was used with no arterial line filter. Neurologic
evaluation on the tenth postoperative day demonstrated a 7.5% incidence of neurologic defects in the control
group and 0% in the treatment group. This was the first demonstration of barbiturate cerebral protection in
humans.
To address the side effects associated with the high-dose thiopental infusion (the requirement for greater
inotropic and ventilatory support), Metz and Slogoff (265) conducted a subsequent study where neurologic
outcomes were compared in groups receiving bolus thiopental before aortic declamping or thiopental throughout
CPB. Neurologic outcome was equivalent between groups and the authors concluded that bolus thiopental
administration without EEG monitoring offered the same neuroprotection as the infusion technique. However, an
accompanying editorial pointed out that the lack of a control group required comparison of the bolus thiopental
group to a historical control and that several practice changes occurred between the Nussmeier (264) and Metz
studies which may
P.402
have made the use of Nussmeier’s (266) control group invalid for the later study.
Zaidan et al. (267) published a major study on barbiturate neuroprotection in 1991. In that investigation, 300
patients undergoing CABG at 28°C with a membrane oxygenator and an arterial line filter were randomly
assigned to placebo or to thiopental infusion sufficient to achieve an isoelectric EEG throughout CPB. A
neurologic examination was performed on the second and fifth postoperative days. As in the previous studies,
patients receiving thiopental required more inotropic support (264), but significant neuroprotection was not
provided. An accompanying editorial speculated on reasons why the Nussmeier and Zaidan results differed
(268).
The primary differences between the two studies were CPB temperature (28°C vs. 34°C), closed versus open
ventricles, and the presence or absence of a membrane oxygenator and arterial line filter. It is difficult to
determine the relative importance of these factors. Open-ventricle procedures are usually associated with poorer
outcomes and more air embolism, but the relationship between air embolism and neurophysiologic or neurologic
outcome has not been clearly defined (269,270,271). Additionally, if atheroembolism is the primary cause of
neurologic injury in cardiac surgery, then the use of arterial filters and membrane oxygenators would not be
expected to explain the study differences. Whether CPB temperature differences are sufficient to explain the
outcome differences is also not discernible. Regardless, the results of this combination of studies led the editors
to conclude that “routine thiopental therapy has no place in the management of patients undergoing CABG.”
Furthermore, they note that “demonstration of barbiturate protection in normothermic, unfiltered, bubble-
oxygenator bypass is not a reasonable argument for barbiturate use during alternative bypass circumstances
unless the appropriate trials are performed” (268).
The introduction of propofol led to some interest in its applicability for neuroprotection in cardiac surgery, but
studies similar to Nussmeier’s or Zaidan’s have not been performed. The effect of burst suppression doses of
propofol on CBF and CMRO2 was evaluated and the authors speculated that propofol may have a role in
reducing cerebral embolism during CPB via its reduction in CBF (272). Other investigators have evaluated
propofol’s effect on CBF velocity (273) or whether burst suppression doses can ameliorate cerebral venous O2
desaturation during rewarming (274). Given the body of work on thiopental in cardiac surgery, it is unlikely that
large outcome studies testing the effects of other cerebral metabolic depressants will be conducted in the near
future.
Agents That Inhibit Ischemic Pathways
Calcium Antagonists
Of a variety of neuroprotectant agents showing efficacy in animal models, only a few have found their way into
clinical trials in cardiac surgery. Intracellular accumulation of calcium is one of the key factors leading to cell
death in cerebral ischemia. In nonbypass models, calcium channel blockers limit ischemic injury (275,276).
These agents have also been shown to improve neurologic outcome in human stroke trials (277). In cardiac
surgery, the effect of nimodipine on neurologic outcome was assessed in a small trial by Forsman et al. (278).
Thirty-nine patients undergoing cardiac surgery were randomized to receive nimodipine or placebo and
neurocognitive outcome was determined at 6 months. Six of 28 patients (21%) showed deficits at 6 months.
Nimodipine-treated patients were described as having a slightly better outcome in verbal fluency and visual
retention, but the authors emphasize that study size limited statistical power and prevented any definitive
conclusions from being drawn (278).
A critical trial of calcium channel blockers in cardiac surgery was reported in 1996 (73). Nimodipine
neuroprotection was to be tested in a double-blind, randomized trial of 400 patients undergoing valve
replacement, but the trial was interrupted at 150 patients because of greater morbidity and mortality in the
nimodipine treatment group. At termination, there was a 10.7% incidence of death in the nimodipine group and a
1.3% incidence in the control group. Major bleeding occurred in 13.3% of nimodipine patients versus 4.1% of
control patients. Additionally, there were no differences in neurocognitive outcomes between the two groups at 1
week, 1 month, or 6 months.
The authors attributed the morbidity and mortality with nimodipine treatment to bleeding complications and
speculate that this might have resulted from a combination of vasodilatation and the antiplatelet effects of the
drug (73). The authors do not extend their observations to other calcium antagonists, but based on these results
it will be difficult to justify another large trial of calcium channel blockers as neuroprotectants in cardiac surgery.
Pegorgotein and Other Experimental Ischemic Pathway Inhibitors

More recently, the antioxidant pegorgotein was investigated in a randomized blinded trial of the effect of the drug
on neuropsychological and other outcomes (74). A placebo group was compared to two pegorgotein doses in a
total population of 67 patients. While the study size was small, there were no strokes and no differences in
cognitive outcomes between groups. The same research group also tested the potential neuroprotectant effects
of clomethiazole on CABG patients in another randomized trial (75). Patients were randomized to either
clomethiazole or placebo and cognitive outcome was assessed at 4 to 7 weeks postoperatively. The study size
was larger than the pegorgotein trial, with testing completed in 219 patients (110 drug and 109 controls);
however, differences in cognitive outcomes could not be demonstrated. Finally, a study designed to assess the
potential neuroprotective effect of S(+)-ketamine in 106 patients also failed to show any effect of a perioperative
drug treatment on cognitive outcomes (279).
P.403
A variety of other pharmacologic agents having the potential to inhibit ischemic pathways have not reached
clinical trials in cardiac surgery. These agents include aminosteroid compounds (280), excitatory amino acid
receptor antagonists (281), and agents directed at the nitric oxide pathway (282,283,284).
Leukocyte Inhibition and Endothelial Protection: Antiadhesion Therapies

Investigations from the last decade show that multiple inflammatory mediators contribute to the progression of
ischemic injury (87,120,285). In particular, neutrophils aggregate in the capillary beds of ischemic tissues and
may contribute to plugging, endothelial dysfunction, and tissue damage. Characterization of the receptors
responsible for neutrophil-endothelium binding is leading to the development of specific monoclonal antibodies
against these receptors as well as nonspecific inhibitors of neutrophil-endothelium binding (286,287,288).
Monoclonal antibodies to the adhesion molecules mediating the polymorphonuclear-endothelial binding have
shown promise in laboratory models of transient focal ischemia (86,289,290). Additionally, oligosaccharides and
oligopeptides structurally related to endothelial binding sites competitively inhibit neutrophil binding to the
endothelium (263,291,292,293,294). Application of these oligosaccharides can reduce lung injury and myocardial
reperfusion injury (292,294), and block lymphocyte adhesion to cardiac endothelium in animal models (293).
More specific glycoproteins representing the selectin binding sites for leukocytes have also been shown to
decrease ischemic injury and increase CBF after transient focal ischemia (291). These observations are
interesting because the inhibitory oligosaccharide fragments are structurally related to, and can be generated
from, multiple fractionations of heparin (295,296,297,298) and there is some evidence that heparin itself may
reduce cerebral ischemic injury by acting as an antiadhesion molecule (299). So far no randomized controlled
trials have shown relevant clinical benefit from pharmacologic interventions in regard to the neurologic outcome.
The perioperative neurologic insult is generally multifactorial and interventions touching only one mechanism not
surprisingly have so far been proven to be ineffective (300).
Physiologic Interventions
Temperature
Hypothermia provides flexibility in surgical and perfusion practice. Cerebral hypothermia attenuates the
physiologic impact of reductions in perfusion pressure and Hct, and extends the “safe” period of low-flow CPB
and circulatory arrest. Hypothermia reduces cerebral injury in both regional and global models of cerebral
ischemia; however, the magnitude of neuroprotection is not directly related to the reduction in cerebral O2
demand (301,302,303).
There is a convincing body of evidence in the experimental stroke literature that even small temperature
differences have important effects on neurochemical, neuropathologic, and neurophysiologic outcomes after
ischemia (301,303,304,305). As little as 2°C of hypothermia significantly attenuates brain injury (301,302). These
effects are probably related to reduction in the cascade of injury precipitated by an ischemic insult and so are
independent of the effect of temperature on metabolism (301,302). Mild hypothermia attenuates the depletion of
cerebral ATP following ischemia and decreases the production of the excitatory neurotransmitter glutamate
(303,306); infarct volume is reduced, particularly in the neocortex, and neurologic outcome may be improved
(301,302,303).
The effect of small temperature differences on the EEG, cerebral metabolism, excitatory amino acids (EEA), and
cellular high-energy phosphates was recently evaluated in a swine CPB model (306). When pigs were subjected
to 20 minutes of global ischemia at 37°C, 34°C, 31°C, or 28°C, Conroy and colleagues (306) found that
hypothermia to 28°C and 31°C facilitated recovery from ischemia but that cooling to 28°C did not provide greater
protection than cooling to 31°C. At 34°C metabolic and EEG recovery, EEA release and S100 (a sensitive
marker of cerebral injury) levels were intermediate between that observed at the colder temperatures and at
37°C.
In this context, the avoidance of cerebral hyperthermia deserves comment (307). Just as 2°C to 3°C of
hypothermia may offer significant brain protection in ischemia models, 2°C of hyperthermia significantly worsens
outcome. Minamisawa et al. (301) demonstrated the effect of mild hyperthermia on neuronal necrosis following
10 minutes of ischemia in a rat model. As ischemic temperature was increased from 35°C to 39°C, the
percentage of neurons damaged increased from approximately 15% to 80% (Fig. 15.10). This is clinically
relevant, because cerebral temperatures >39°C have been documented in patients during rewarming (308) and
these high temperatures may occur when cerebral embolic risk is greatest. From these reports, rewarming
practice is being changed to avoid high brain temperatures. Additionally, when CPB is to be conducted “warm,”
systemic temperatures have shifted toward mild hypothermia (33°C-34°C) from strict normothermia (309).
It has been suggested that the risk of cerebral hypothermia might be avoided if patients are weaned from bypass
with mild hypothermia in the core compartment. Additionally, one could speculate that this might offer some
cerebral protection in the early postoperative period. This approach to rewarming has been evaluated in two
trials (81,310), and feasibility has been demonstrated. In an investigation of 13 patients, six served as controls
and seven were rewarmed to a nasopharyngeal (NP) temperature of 35°C during CPB, and then warmed further
by a surface device for the next 4 hours. Peak jugular bulb temperatures during CPB rewarming were lower in
the surface warming group although these values were equivalent in the two groups 4 hours after surgery (310).
The second investigation was also randomized and larger (81). In the trial by Nathan and colleagues (81), 223
patients were randomized
P.404
to undergo CPB with rewarming either to 37°C or 34°C NP temperature. The primary endpoint of the trial was
cognitive outcomes at 1 week, with ICU variables such as chest tube output, intubation time, myocardial
infarction, and infection as secondary outcomes. At 1 week, 62% of the control patients had cognitive decline
versus 48% in the hypothermic group. ICU outcomes such as bleeding, myocardial infarction, and intubation time
did not differ between groups.
FIGURE. 15.10. Influence of temperature on ischemia-induced neuronal necrosis in the hippocampus (CAI sector
and subiculum). Quantitative calculation of percentage of damaged neurons was performed bilaterally in each
animal. There was no statistically significant difference between right and left hemispheres. Values are ±SE.
(Modified from Minamiasawa H, Smith ML, Siesjo BK. The effect of mild hyperthermia and hypothermia on brain
damage following 5, 10, and 15 minutes of forebrain ischemia. Ann Neurol 1990;28(1):26-33.)
Although incomplete rewarming in the operating room is feasible, it may be undesirable for many adult cardiac
surgical patients and it is still not clear if the theoretical benefit is offset by potential disadvantages. The problem
with terminating bypass with mild core hypothermia is that body temperature is likely to continue to decrease
postoperatively. The magnitude of this afterdrop can be related to the temperature at the termination of bypass
(311). If bypass is terminated with an NP or venous return temperature of 37°C, core temperature is often near
35°C on leaving the operating room. This occurs, in part, because bypass rewarming is not uniform. Blood flow
to muscle and viscera may be reduced by 50% to 80% during bypass (312); therefore, temperature in many
skeletal muscles may still be 32°C when NP or cardiac temperature is 37°C at the end of CPB. As such, heat is
shifted from the core to the periphery after weaning from CPB and core temperature then drops. Additionally,
after bypass, the patient continues to lose heat to the environment. One would predict that most patients
weaning from CPB with a core temperature of 35°C will have an unacceptably large whole-body thermal debt in
the ICU. In noncardiac surgery, postoperative hypothermia may contribute to reduced cardiac output and
increased SVR, a greater incidence of ischemia, increased respiratory demands, and more bleeding (313,314).
While the study by Nathan et al. (81) begins to address concerns about postoperative hypothermia in cardiac
surgical patients, the study was underpowered to assess outcomes such as myocardial infarction; additionally,
the wide range in postoperative bleeding makes comparison difficult. Finally, hypothermia is not compatible with
early extubation. In the Nathan report, the mean intubation time was about 17 hours; so this report does not allow
us to assess the effect of postoperative hypothermia on current practice.
Overall, the evidence indicates that tepid CPB (nasopharyngeal 33°C-35°C) (as opposed to strict normothermia)
in
P.405
a relatively healthy patient population does not appear to significantly increase neurologic risk. Awareness of the
importance of temperature management has moved broadly through the anesthesia and cardiac surgical
community such that the practice has matured and hyperthermia is probably much less common now (315) than
when cerebral hyperthermia was first reported (308).
Physiologic Interventions to Reduce Embolization: CO2, Temperature, and CPB Flow

As detailed above, surgical attention to embolic risk and technical changes in the CPB circuit decrease cerebral
embolization. Physiologic interventions may also be relevant. It has been suggested that increases in CBF as
occur with pH-stat management or normothermic CPB may result in a higher incidence of cerebral embolization.
Similarly, acute reductions in CBF during periods of embolic risk might reduce cerebral embolization.
This was tested in a swine CPB model. The effect of PaCO2 on total and regional cerebral embolization of
microspheres was determined during normothermic CPB (229). The study demonstrated that a 25-mm Hg
reduction in PaCO2 during a 5-minute period of embolic risk could reduce total cerebral embolization by more
than 50% (Fig. 15.11). These results indicate that during periods of embolic risk, such as clamping and
unclamping of the aorta and the initial phases of ventricular ejection, a moderate reduction in PaCO2 may
significantly decrease cerebral embolization.
The same model has been used to examine the effect of temperature and bypass flow on cerebral embolization.
The investigators found that 10°C of hypothermia is effective in reducing embolization but that the combination of
hypothermia and hypocarbia did not reduce cerebral embolization more than hypocarbia alone. The relationship
between CPB flow rate and cerebral embolization has also been examined (316). At a stable MAP, an inverse
relationship between cerebral embolization and pump flow was described in dogs. Essentially, at lower pump
flows, a greater proportion of that flow is delivered to the brain. Therefore, if a fixed number of emboli enter the
aortic root, more emboli will be delivered to the brain if CPB flow is lower. The authors suggest that elevating
pump flow during periods of embolic risk may also reduce cerebral embolization during clinical CPB.
FIGURE. 15.11. The regional distribution of cerebral emboli in pigs with a mean Paco2 of 52 mm Hg (▪) or 27 mm
Hg (□). Values are the mean ± SD emboli per gram (n = 10 in each group). *p < 0.05. (Modified from Plöchl W,
Cook, DJ. Quantification and distribution of cerebral emboli during cardiopulmonary bypass in the swine: the
impact of PaCO2. Anesthesiology 1999;90(1):183-190.)
Hypocarbia, hypothermia, and a high flow rate are all effective in reducing cerebral embolization in an animal
model. A combination of these physiologic interventions during periods of embolic risk may reduce neurologic
morbidity. A clinical outcome study applying these physiologic interventions has yet to be conducted.
PaCO2 and Facilitated Cooling

While there is limited clinical evidence that pH-stat management may be associated with worsened neurologic
outcomes in adults, the opposite may be true in certain pediatric populations. A series of reports from the Boston
Children’s Hospital suggest that elevation of PaCO2 during cooling may improve neurologic outcome in children
undergoing circulatory arrest (59,61). Elevation of CBF during the cooling phase may result in improved cerebral
protection (59,61). Second, the rightward shift of the oxyhemoglobin dissociation curve with the more acidotic
strategy might facilitate O2 transfer from Hgb. These hypotheses have largely been confirmed in a series of
laboratory and clinical studies (61,232,233,234). Given these results, elevating PaCO2 to achieve pH-stat
physiology may serve as a useful physiologic intervention to improve neuroprotection in select patient
populations.
NEUROLOGIC MONITORING
Given the unusual physiologic conditions of CPB and incidence of neurologic injury, there have been persistent
efforts to assess the adequacy of cerebral O2 delivery during CPB. Some current techniques include (1)
measurement of venous oxyhemoglobin saturation at the jugular bulb (SjVO2), (2) near-infrared optical
spectroscopy (NIRS), (3) TCD, and (4) electrophysiologic monitors, for example, EEG and evoked potentials.
Sjvo2
Measurement of cerebral venous oxygen saturation offers clinical appeal. Under nonbypass conditions, the
SjVO2 provides an index of the adequacy of global cerebral oxygenation and normal values are established
(317,318). Additionally, fiberoptic oximetry allows for continuous measurement, placement of a jugular bulb
catheter is relatively simple, and the measurement is immediately familiar. Nevertheless, SjVO2 monitoring in
cardiac surgery has remained primarily a
P.406
research tool. While SjVO2 can provide useful trends in cerebral oxygenation, the technique is limited by the fact
that it is a measure of global oxygenation, so focal events may be undetected. SjVO2 is also potentially difficult to
interpret with progressive hypothermia where changes in the P50 become important.
One of the first reports of SjVO2 during clinical CPB was by Croughwell et al. (319), who documented SjVO2 <
50% or a PVO2 < 25 mm Hg in 23% of 133 patients. In the same year, Nakajima and colleagues (320) reported
continuous recording of SjVO2 in 12 patients and described an inverse relationship between CPB temperature
and SjVO2 as well as a relationship between desaturation and rewarming speed. The effect of CPB temperature
on SjVO2 was further examined in a randomized comparison of normothermic and hypothermic CPB (321).
Perhaps the most prominent work on SjVO2 was that identifying a relationship between SjVO2 and post-CPB
cognitive dysfunction (322). In that report, intraoperative SjVO2 and neurocognitive outcome at discharge were
evaluated in 255 patients. Seventeen percent of patients showed desaturation during CPB while 38%
demonstrated neurocognitive impairment at discharge. This neurocognitive impairment was related to the
patients’ baseline scores, their educational level, and the SjVO2 during CPB.
Studies have continued to examine the determinants of cerebral venous desaturation or have used SjVO2 as a
monitor of cerebral O2 balance. Enomoto and colleagues (323) reported that cerebral venous desaturation
during rapid rewarming was a function of CMRO2 increasing more quickly than CBF. Sapire and colleagues
(324) examined SjVO2 during rewarming and found it to be a function of Hct, rewarming speed, and MAP.
Grubhofer et al. (325) also identified a dependency of SjVO2 on MAP during CPB. von Knobelsdorff et al. (326)
could not identify a relationship between rewarming speed and SjVO2, but in that study, patients were rewarmed
from 27°C to 36°C in either 7 or 15 minutes.
Dexter and Hindman (327) published a provocative theoretical analysis of SjVO2 during hypothermia. They
pointed out that the increase in Hgb O2 affinity with progressive hypothermia necessitates that what constitutes
a minimally acceptable SjVO2 must increase as temperature decreases. The most interesting physiologic
question posed by this discussion is whether the high O2 affinity at low temperatures is sufficient to compromise
O2 delivery to tissues. While this has not been answered, another technology may offer insight into this question.
Since the earliest reports of SjVO2 in cardiac surgery more than a decade ago, SjVO2 has not found its way
significantly into clinical practice and has primarily been an investigational tool. In the last few years, SjVO2 has
been used to evaluate changes in rewarming practice (310), anesthetic choice (328), off-pump CABG (329), and
in PaCO2 management (330,331,332). The CO2 studies are of some note because of the consistency of findings
from multiple institutions. Ali and colleagues (330) found that the effect of CO2 management had a greater effect
on SjVO2 than patient temperature. Kiziltan and colleagues (332) reported more favorable cerebral O2 balance
with a higher PaCO2 during bypass and (331) suggested that low SjVO2 values in the early postoperative period
may be related to hypocarbia-related vasoconstriction.
Near-Infrared Spectroscopy
Hgb undergoes a characteristic near-infrared absorption shift with O2 binding, so NIRS has the potential to
provide a continuous, noninvasive, transcutaneous assessment of regional brain oxygenation (333,334). The
Hgb emission spectra is a function of the aggregate of arterial, venous, and capillary blood, so the absence of a
clear correlation between NIRS output and either arterial or venous oxyhemoglobin saturation during CPB is not
surprising (333,335,336). However, trends provided by NIRS are of interest. Various reports show that NIRS is
sensitive to changes in temperature, PaCO2, and Hct as well as the cessation and reestablishment of CPB flow
(Fig. 15.12) (335,337,338,339). Additionally, the rate of NIRS desaturation during circulatory arrest has been
reported to be a function of temperature at arrest (slower at colder temperatures) (339) as well as patient age,
with the youngest patients being most tolerant of global ischemia (338).
Other studies have reported that during hypothermia, NIRS tissue saturation and SjVO2 may move in opposite
directions (335,336,340). This might be interpreted as impaired O2 offloading by Hgb, but at present the
technology is not sufficiently advanced to determine if a low P50 could result in cerebral hypoxia.
FIGURE. 15.12. Near-infrared spectroscopy (NIRS) record of the changes in cerebrovascular hemoglobin
oxygen saturation (+SCO2) illustrating the points at which +SCO2 was captured and the deoxygenation curve
during circulatory arrest. The patient was 9 months old and was undergoing a hemi-Fontan operation. B,
baseline at normothermia; 1, on deep hypothermic cardiopulmonary bypass (cCPB); 2, at the end of circulatory
arrest (arrest); 3, on recirculation 3 min after resuming CPB (rCPB); 4, normothermic CPB (wCPB); 5, after CPB
(end). By definition, +SCO2 = 0 at baseline. (Kurth CD, Steven JM, Nicolson SC. Cerebral oxygenation during
pediatric cardiac surgery using deep hypothermic circulatory arrest. Anesthesiology 1995;82:74-82.)
P.407
While NIRS technology has great potential, its development is ongoing. Currently, (1) quantitative measurements
of HbO2 are not possible (334); (2) the region of interrogation is not clearly defined; (3) there is no external
standard against which NIRS can be calibrated; and (4) scalp blood and skull may contaminate the output of the
devises, particularly in adults (341); and perhaps most importantly, (5) Hbg saturation in the brain—whether
venous, arterial, or capillary—may not reflect tissue O2 utilization because of the high Hgb O2 affinity.
Measurement of the redox state of intracellular cytochrome oxidase (aa3) may solve the latter problem because
the aa3 signal may be intimately related to intracellular high-energy phosphate concentration (342,343,344).
However, at present, the analysis of the aa3 signal remains highly complex.
In the last several years, the most valuable report on the use of NIRS in adult cardiac surgery was the meta-
analysis reported by Taillefer and Denault (345). A review of NIRS in adult cardiac surgery yielded 48 papers
describing almost 6,000 patients. Of the 48 reports, only 1 was a randomized controlled trial, no study reached
level I evidence, and only 1 study was level II. Seventy-five percent of studies were determined to offer level V
evidence. Studies included patients primarily undergoing CABG surgery, but valve surgery, congenital, off-pump,
and arch procedures were also captured. The authors concluded that “…NIRS validity has not been clearly
established clinically along with its predictive value” (345). In addition to multiple problems in study design in
NIRS clinical reports, the authors outline 10 clinically relevant technical limitations in the technology. Despite all
the mentioned limitations, a randomized controlled trial conducted by the Canadian group of researchers led by
Dr. Murkin et al. (346) demonstrated that the use of NIRS was associated with less cerebral desaturation during
CPB and the group of patients being monitored had lower incidence of postoperative organ dysfunction, shorter
ICU stay, and better survival when compared to their control group.
No similar assessment of NIRS use has been performed in pediatric cardiac surgery, although in small children
and infants some of the technical limitations seen with NIRS in adults are probably lessened. In particular, the
presence of open fontanelles, thinner skulls, and lesser extracerebral mass may improve its reliability. Although
studies using NIRS in pediatric heart surgery have been published (347,348), an impact of this technology on
clinical outcomes has not been demonstrated.
Transcranial Doppler
Under non-CPB conditions, TCD measurements of blood flow velocity in the middle cerebral artery may show
good correlation with measured CBF (349). The technique is noninvasive and provides continuous
measurements; so TCD has been evaluated as a monitor of cerebral perfusion during CPB. Blood flow velocity
may be sensitive to temperature change, MAP, and pump flow as well as to PaCO2 and Hct, but for flow velocity
to be a reliable measure of CBF, the diameter of the insolated vessel must not change (350). This condition may
not be met during CPB, so the correlation of TCD flow velocity and measured CBF is relatively poor
(351,352,353). Nevertheless, TCD can provide trending information, and the relative changes in flow velocity
show a better correlation with CBF than flow velocity measurements (352,354,355).
Although strict quantitative CBF measurements are not possible, TCD may have greater application in pediatric
CPB. Obtaining the temporal window is easier in infants and children and this population may be subjected to
profound reductions in CPB flows at stable temperatures and Hcts. Under these conditions, TCD monitoring may
be useful to determine whether these reduced CPB flows and MAPs are sufficient to maintain cerebral perfusion
(356). The response of the cerebral circulation when flow is reestablished following circulatory arrest can also be
evaluated (357).
In adult cardiac surgery, TCD has found much greater use in emboli detection than assessment of cerebral
perfusion. Although not a cerebral monitor per se, TCD emboli detection can be used to indirectly evaluate
surgical technique (89,92) and CPB circuit modifications (94,104,260). TCD could also serve as an independent
predictor of neurologic outcome (58,90,209), although TCD emboli counts have not translated into consistent
differences in embolization detected by neuroimaging (82,358,359) or with cognitive outcomes (258,360).
While becoming more popular, the limits of emboli detection must also be considered (361,362). The resolution
for embolus size has a limit which depends on the physical character of the embolic material. Microthrombi are
difficult to detect against the blood background signal, while air or plaque may provide an adequate signal even if
significantly smaller. In this regard, the inability to determine embolus composition constitutes another limit of the
current technology. Finally, the “gating” used to separate signals from background will, in large part, determine
the results. However, automated signal detection and a technical consensus on microembolus detection (363)
will help limit this source of variability.
EEG/Evoked Potentials
In theory, electrophysiologic monitors should provide one of the best means for determining adequacy of cerebral
oxygenation. Although familiarity with intraoperative EEG deriving from carotid endarterectomy experience dates
back to the 1970s and its use has been periodically advocated for use during CPB, EEG monitoring has never
established a strong presence in that setting. This remains true even though the technology has become simpler
to use and advancements have been made in data acquisition, processing, and display.
Over the last 40 years, numerous studies have used EEG during cardiac surgery and certain EEG changes,
such as slowing at the onset of CPB, have been demonstrated with consistency (364,365,366). Nevertheless, a
clear relationship between the EEG output and intraoperative physiology or
P.408
clinical outcome has been elusive. Most studies advocating the use of EEG have been descriptive and have
typically lacked a control group. The available evidence indicates that intraoperative EEG lacks both sensitivity
and specificity. Patients may show an abnormal EEG during CPB and recover without neurologic deficit while
others may have a normal intraoperative EEG examination and experience stroke. This is not surprising, as
advances in data processing cannot address the primary limitation of EEG. EEG only records superficial cortical
electrical activity. If most neurologic injuries are embolic in origin, the EEG cannot be expected to detect focal
ischemia occurring in small areas deep in the brain (367). Secondarily, the background anesthetic and
hypothermia may alter both the power and frequency spectra of the EEG, as can CPB-related artifact (366).
In the study by Bashein and colleagues (368), 78 patients underwent CPB at 28°C to 32°C with EEG recording;
neurocognitive status was determined preoperatively and at 8 days and 7 months postoperatively. Electrical
noise contaminated the EEG in 40% of patients in spite of extensive computational modeling, and there was no
clear relationship between EEG power or frequency and outcome (368).
Evoked potentials provide another means of assessing functional neurologic integrity during CPB (369,370).
Somatosensory evoked potentials (SSEP), in which a stimulus is delivered peripherally and the integrity of its
transmission from the peripheral nerve through the spinal cord and to the sensory cortex is recorded, have been
most commonly used (371). A decrease in signal amplitude may represent ischemia, as can an increase in signal
latency. In the experimental setting, evoked potentials have been successfully used as monitors for ischemia
(178), although their use in the operating room has been limited (372,373). Like EEG, evoked-potential amplitude
and latency are sensitive to hypothermia (374,375). Proper signals may also be difficult to obtain, and hundreds
of potentials must be averaged to separate signal from noise (369,376). Finally, the definition of what constitutes
an abnormality may not be agreed upon. In clear cases of brachial plexus injury, a 3-standard-deviation change
from the pre-CPB measurement was required to identify neurologic injury (372). As such, the sensitivity and
specificity of evoked-potential monitoring may be at least as limited as EEG monitoring.
Bispectral EEG analysis (BIS) has been the subject of some recent trials in cardiac surgery, and generally the
output of the BIS monitor behaves as one would predict for a processed EEG (377,378). Patient temperature and
anesthetic agents affect BIS (377). However, it seems highly unlikely that ease of use will eliminate the inherent
limitations of EEG in preventing intraoperative neurologic injury.
S100
Although not a technique for cerebral monitoring, the astroglial and Schwann cell protein S100 is of interest
because serum and CSF levels of S100 increase following brain damage from stroke, trauma, and subarachnoid
hemorrhage (379). Therefore, the relationship between S100 and CPB-related cerebral injury has been
evaluated (380). Observational studies describing the time course of S100 release have shown that the protein
is not detected prior to CPB and that peak levels occur intraoperatively between the end of rewarming and the
end of CPB (358,381,382,383). These levels appear to be related to CPB time (359,382) and to patient age
(359,384). Intracardiac operations result in higher S100 levels than CABG procedures (385). Arterial line filtration
may reduce S100 levels (381), and there appears to be some correlation between embolization and S100 levels
(384). Patients undergoing off-pump CABG have undetectable or fractionally raised levels (382).
The sensitivity or specificity of S100 as a marker for cerebral injury has not been established, although it is clear
that levels measured at the end of CPB are not specific (Table 15.7). Unfortunately, some extracranial tissues
can either release S100 or non-S100 substances that are detected by current S100 assays, such that measured
S100 values may not reflect cerebral events (386,387,388). A recent study using mass spectroscopy, gel
electrophoresis, and Western blot analysis demonstrated that a variety of non-S100 proteins in the surgical field
react with the S100 commercial immunoassay (389). This leads to problems with test sensitivity and specificity.
In a study by Jönsson et al. (359), 93% of 515 consecutive patients had detectable S100 at the end of surgery
but less than 10% showed either stroke, encephalopathy, or delayed awakening. In a study of 40 patients, 58%
of patients showed elevated S100 levels 1 hour postoperatively but no patient demonstrated overt cerebral injury
(381). High levels of S100, 48 hours postoperatively, have more sensitivity and specificity for cerebral injury than
early postoperative measurements (359,384,385,386,387,388,389,390), as S100 values that are very high 48
hours after surgery reflect size and predict outcome of stroke (391,392). However, what therapeutic intervention
one might base on a 48-hour measurement remains unclear.
General Approach to the Patient That Developed Acute Stroke

Despite the best surgical technique, patient selection, preparation, and perioperative management, unfortunately
some patients will still develop acute stroke in the postoperative period. For acute-stroke care, American Heart
Association/American Stroke Association society guidelines are available to provide organized and coordinated
care (393). For nonsurgical patients, the early administration of intravenous thrombolytic r-tPA is recommended
within a 4.5-hour window of initial symptoms (393,394). Because intravenous thrombolysis is contraindicated in
patients with recent surgery (393), techniques that provide localized intra-arterial thrombolysis or even
mechanical clot removal can be options for postoperative patients (395,396). These techniques also have a
more generous treatment window (as far as 6-8 hours after initial
P.409
symptoms). Having a well-structured and coordinated stroke management team is pivotal for the success (393)
and this should be evaluated for every cardiac surgery program.
TABLE 15.7. Impact of recorded variables on S100 protein release at the different sampling
intervalsa
Sampling times (p value)
Variable Number of patients T0 T5 T15 T48
Age 515 <0.0001 <0.0001 <0.001 NS
Perfusion time 515 <0.0001 NS NS NS
History of CVA/TIA 42 <0.01 NS NS NS
Diseased ascending aorta 53 <0.001 <0.005 NS <0.005
Renal insufficiency 12 NS <0.05 NS NS
Perioperative stroke 13 NS NS NS <0.0001
Encephalopathy 17 NS NS NS NS
Delayed awakening 12 NS NS NS <0.05
aMultiple linear regression analysis showing the variables significantly influencing the S100 protein
levels after cardiac operation with extracorporeal circulation in the 515 patients studied. The presence of
a diseased ascending aorta was confirmed with palpation intraoperatively. Renal insufficiency was
defined as a preoperative serum creatinine level >2.2 mg/dL. Cerebrovascular accident/transient
ischemic attack (CVA/TIA) relates to a history of stroke or transient ischemic attack. Age and perfusion
time were continuous variables, whereas the other variables were analyzed as dichotomous variables.
All correlations found were positive.
NS, not significant; T0, immediately after termination of extracorporeal circulation; T5, 5 hours, T15, 15
hours, and T48, 48 hours after T0.
Jönsson H, Johnsson P, Alling C, et al. Failure of intraoperative jugular bulb S-100B and neuron-specific
enolase sampling to predict cognitive injury after carotid endarterectomy. Ann Thorac Surg
1998;65:1639-1644.
CONCLUSIONS
In adults, postcardiac surgical brain injury can occur as a result of a variety of neurologic risk factors.
Surgery precipitates those risks and imposes additional ischemic, physiologic, and inflammatory stresses for
which the patient may be unable to compensate.
Because neurologic morbidity derives from interaction of the patient and the surgery, the greatest
reductions in morbidity may come from the application of risk stratification, technical surgical maneuvers,
and the use of modern and appropriate perfusion equipment. Other innovations such as off-bypass surgery,
antiadhesion therapies, and near-infrared monitoring are supportive and complementary to prevent stroke
or significant neurocognitive functional decline. For the patients who do go to surgery, we must be
comprehensive and practical in developing an intraoperative management strategy. Because the risk for
neurologic injury derives largely from preexisting patient risk factors, multivariate analysis indicates that age
and atherosclerotic disease determine outcome.
While patient factors may determine outcome in multivariate analysis, this is not equivalent to saying
surgical, physiologic, and pharmacologic management are unimportant. We have a great deal of
understanding about hypertensive cerebrovascular disease, regional blood flow in focal ischemia, and the
potent effect of temperature on the cascade of injury. This allows us to make well-informed choices about
physiologic management. Similarly, gas physiology can be applied to facilitate absorption of bubbles or
change the distribution of CBF during periods of embolic risk. Echocardiography can tell us when it is
appropriate to not clamp the aorta, remove an aortic or left ventricular vent, and administer a barbiturate if
circulatory arrest must occur before adequate cooling.
Our understanding of “postcardiac surgical cognitive decline” is evolving. First, the best available evidence
suggests that chronic aortic and brachiocephalic atherosclerosis is a primary determinant of the neurologic
outcome of on- and off-pump cardiac surgery and must guide the manipulation
P.410
of these vessels. Second, if patients undergoing interventional cardiology procedures have the same
cognitive outcomes as cardiac surgical patients, it appears that chronic cerebral vascular disease may
constitute the foundation of “postoperative” cognitive decline.
Finally, it appears that cognitive decline, and probably delirium, are nonspecific events occurring in older
patients following noncardiac as well as cardiac surgery. The frequency and severity may be higher in
cardiac surgery simply because it is more physiologically stressful than noncardiac surgery.
Exquisite control of many physiologic variables is possible during CPB and in the perioperative period. Until
more effective interventions to improve neurologic outcomes are more clearly identified, we will help our
patients most by understanding their risk factors and placing them in an anesthetic and surgical milieu that
minimizes the impact of surgical stressors while maximizing compensatory mechanisms.
KEY Points
Age is an independent predictor of postoperative stroke. The proportion of patients older than 80 years
undergoing cardiac surgery will increase faster than any other group.
The conduct of CPB has a significant effect on the development of cognitive decline following cardiac
surgery. Patients with neurodegenerative changes are more susceptible to this disabling condition.
Up to 50% of cardiac surgery patients will develop postoperative delirium and the incidence is often
underappreciated. Strategies to prevent delirium have been largely unsuccessful.
In the absence of hypoxemia, neurologic morbidity results from inadequate tissue perfusion; embolic
phenomena, flow limitation by fixed obstruction, and failure by collateral circulation. All these are
aggravated by low MAP common with CPB.
Maintenance of normal pump flow is not enough for adequate CBF if MAP is reduced.
During CPB, the mean arterial pressure is a determinant of neurologic and cardiac complications. It is
probably prudent to maintain MAPs not less than 20 mm Hg below preoperative MAP. It is also important
to consider having the MAP between 80 and 100 for patients with potential for critical arterial stenosis.
The STS recommends that glucose levels be maintained below 180 mg/dL, with continuous insulin
infusion for diabetic and nondiabetic patients.
The effects of the PaCO2 management (a-stat vs. pHstat) can be beneficial or detrimental depending on
the cerebral circulatory circumstances of the operation, but is primarily relevant below 27°C.
Aortic cannulation guided by epiaortic ultrasound can improve neurologic outcomes in high-risk patients
by reducing embolic risk.
Small changes in the patient’s temperature importantly effect the vulnerability to ischemia. The cardiac
surgery team should be vigilant to avoid hyperthermia during rewarming.
Despite the best care, patients will develop acute stroke; and having a structured stroke team is pivotal
for successful management.
Fifty percent of cardiac surgery-related strokes seem to occur in the postoperative period and further
attention to reducing this risk is indicated.
REFERENCES
1. Tuman KJ, et al. Differential effects of advanced age on neurologic and cardiac risks of coronary artery
2. Tu JV, Jaglal SB, Naylor CD. Multicenter validation of a risk index for mortality, intensive care unit stay,
and overall hospital length of stay after cardiac surgery. Steering Committee of the Provincial Adult Cardiac
Care Network of Ontario. Circulation 1995;91:677-685.
3. Hammermeister KE, et al. Identification of patients at greatest risk for developing major complications at
cardiac surgery. Circulation 1990;82:IV-380-IV-389.
4. Tu JV, et al. A predictive index for length of stay in the intensive care unit following cardiac surgery. Can
Med Assoc J 1994;151:177-185.
5. Roach GW, et al. Adverse cerebral outcomes after coronary bypass surgery. Multicenter Study of
Perioperative Ischemia Research Group and the Ischemia Research and Education Foundation Investigators.
N Engl J Med 1996;335(25):1857-1863.
6. Wolman RL, et al. Cerebral injury after cardiac surgery. Identification of a group of extraordinary risk. The
Multicenter Study of Perioperative Ischemia (McSPI) Research Group and the Ischemia Research and
Education Foundation (IREF) Investigators. Stroke 1999;30:514-522.
7. Gardner TJ, et al. Stroke following coronary artery bypass grafting: a ten-year study. Ann Thorac Surg
1985;40:574-581.
8. Shaw PJ, et al. Neurologic and neuropsychological morbidity following major surgery: comparison of
coronary artery bypass and peripheral vascular surgery. Stroke 1987;18(4):700-707.
9. Moller JT, et al. Long-term postoperative cognitive dysfunction in the elderly ISPOCD1 study. ISPOCD
investigators. International study of post-operative cognitive dysfunction. Lancet 1998;351(9106):857-861.
10. Weintraub WS, et al. Changing clinical characteristics of coronary surgery patients. Differences between
men and women. Circulation 1993;88(Part 2):79-86.
11. Jones EL, et al. Coronary bypass surgery: is the operation different today? J Thorac Cardiovasc Surg
1991;101:108-115.
12. He GW, et al. Determinants of operative mortality in elderly patients undergoing coronary artery bypass
grafting. Emphasis on the influence of internal mammary artery grafting on mortality and morbidity. J Thorac
13. Awad WI, et al. Re-do cardiac surgery in patients over 70 years old. Eur J Cardiothorac Surg
1997;12(1):40-46.
P.411
14. Biancari F, et al. Frequency of and determinants of stroke after surgical aortic valve replacement in
patients with previous cardiac surgery (from the Multicenter RECORD Initiative). Am J Cardiol
2013;112(10):1641-1645.
15. Berens ES, et al. Preoperative carotid artery screening in elderly patients undergoing cardiac surgery. J
Vasc Surg 1992;15:313-323.
16. Mickleborough LL, et al. Is sex a factor in determining operative risk for aortocoronary bypass graft
surgery? Circulation 1995;92(Suppl II):II-80-II-84.
17. Wareing TH, et al. Strategy for the reduction of stroke incidence in cardiac surgical patients. Ann Thorac
Surg 1993;55:1400-1408.
18. Ricotta JJ, et al. Risk factors for stroke after cardiac surgery: Buffalo Cardiac-Cerebral Study Group. J
Vasc Surg 1995;21:359-364.
19. Rao V, et al. Risk factors for stroke following coronary bypass surgery. J Cardiac Surg 1995;10:468-474.
20. McKhann GM, et al. Predictors of stroke risk in coronary artery bypass patients. Ann Thorac Surg
1997;63(2):516-521.
21. Price TR, et al. Silent brain infarction on magnetic resonance imaging and neurological abnormalities in
community-dwelling older adults. The Cardiovascular Health Study. Stroke 1997;28:1158-1164.
22. Skoog I. A review on blood pressure and ischaemic white matter lesions. Dement Geriatr Cogn Disord
1998;9(Suppl 1):13-19.
23. Matsushita K, et al. Periventricular white matter lucency and cerebral blood flow autoregulation in
hypertensive patients. Hypertension 1994;23(5):565-568.
24. Ferrucci L, et al. Cognitive impairment and risk of stroke in the older population. J Am Geriatr Soc
1996;44(3):237-241.
25. Vermeer SE, et al. Silent brain infarcts and the risk of dementia and cognitive decline. N Engl J Med
2003;348(13):1215-1222.
26. Longstreth WT Jr, et al. Clinical correlates of white matter findings on cranial magnetic resonance
imaging of 3301 elderly people. The Cardiovascular Health Study. Stroke 1996;27:1274-1282.
27. Schmidt R, et al. Brain magnetic resonance imaging in coronary artery bypass grafts: a pre- and
postoperative assessment. Neurology 1993;43(4):775-778.
28. Hogue CW, et al. Gender influence on cognitive function after cardiac operation. Ann Thorac Surg
2003;76(4):1119-1125.
29. Hogue CW Jr, et al. Sex differences in neurological outcomes and mortality after cardiac surgery: a
society of thoracic surgery national database report. Circulation 2001;103(17):2133-2137.
30. Steingart RM, et al. Sex differences in the management of coronary artery disease. Survival and
Ventricular Enlargement Investigators. N Engl J Med 1991;325(4):226-230.
31. Kofke WA, et al. The effect of apolipoprotein E genotype on neuron specific enolase and S-100beta
levels after cardiac surgery. Anesth Analg 2004;99(5):1323-1325; table of contents.
32. Tardiff BE, et al. Preliminary report of a genetic basis for cognitive decline after cardiac operations. The
Neurologic Outcome Research Group of the Duke Heart Center. Ann Thorac Surg 1997;64(3):715-720.
33. Ti LK, et al. Effect of apolipoprotein E genotype on cerebral autoregulation during cardiopulmonary
bypass. Stroke 2001;32(7):1514-1519.
34. MacKensen GB, et al. Preliminary report on the interaction of apolipoprotein E polymorphism with aortic
atherosclerosis and acute nephropathy after CABG. Ann Thorac Surg 2004;78(2):520-526.
35. Grunenfelder J, et al. Genetic polymorphisms of apolipoprotein E4 and tumor necrosis factor beta as
predisposing factors for increased inflammatory cytokines after cardiopulmonary bypass. J Thorac
36. Helbecque N, Amouyel P. Commonalities between genetics of cardiovascular disease and

neurodegenerative disorders. Curr Opin Lipidol 2004;15(2):121-127.
37. McCarron MO, Delong D, Alberts MJ. APOE genotype as a risk factor for ischemic cerebrovascular
disease: a meta-analysis. Neurology 1999;53(6):1308-1311.
38. Yip AG, et al. APOE, vascular pathology, and the AD brain. Neurology 2005;65(2):259-265.
39. Slooter AJ, et al. The impact of APOE on myocardial infarction, stroke, and dementia: the Rotterdam
Study. Neurology 2004;62(7):1196-1198.
40. Skoog I, et al. A population study of apoE genotype at the age of 85: relation to dementia,
cerebrovascular disease, and mortality. J Neurol Neurosurg Psychiatry 1998;64(1):37-43.
41. Redmond JM, et al. Neurologic injury in cardiac surgical patients with a history of stroke. Ann Thorac
Surg 1996;61(1):42-47.
42. Shaw PJ, et al. Early neurological complications of coronary artery bypass surgery. Br Med J
1985;291(6506):1384-1387.
43. Cook DJ, Trenerry MR, Huston J. Cognitive deficit following cardiac surgery is not a function of
perioperative cerebral ischemia. Circulation 2004;110(17):III-641.
44. Messe SR, et al. Stroke after aortic valve surgery: results from a prospective cohort. Circulation
2014;129(22):2253-2261.
45. Aberg T, Ronquist G, Tyden H. Cerebral damage during open-heart surgery. Scand J Thorac Cardiovasc
Surg 1987;21:159-163.
46. Newman MF, et al. Predictors of cognitive decline after cardiac operation. Ann Thorac Surg
1995;59:1326-1330.
47. Mora CT, et al. The effect of temperature management during cardiopulmonary bypass on neurologic
and neuropsychologic outcomes in patients undergoing coronary revascularization. J Thorac Cardiovasc
Surg 1996;112(2):514-522.
48. McLean RF, et al. Cardiopulmonary bypass, temperature, and central nervous system dysfunction.
49. Vingerhoets G, et al. Short-term and long-term neuropsychological consequences of cardiac surgery with
extracorporeal circulation. Eur J Cardiothorac Surg 1997;11(3):424-431.
50. McKhann GM, et al. Cognitive outcome after coronary artery bypass: a oneyear prospective study. Ann
Thorac Surg 1997;63(2):510-515.
51. Slogoff S, Girgis KZ, Keats AS. Etiologic factors in neuropsychiatric complications associated with
52. Borowicz LM, et al. Neuropsychologic change after cardiac surgery: a critical review. J Cardiothorac
Vasc Anesth 1996;10(1):105-111; quiz 111-112.
53. Blumethanl JA, et al. Methodological issues in the assessment of neuropsychologic function after cardiac
54. Newman SP. Analysis and interpretation of neuropsychologic tests in cardiac surgery. Ann Thorac Surg
1995;59:1351-1355.
55. Murkin JM, et al. Statement of consensus on assessment of neurobehavioral outcomes after cardiac
56. Stump DA. Selection and clinical significance of neuropsychologic tests. Ann Thorac Surg 1995;59:1340-
1344.
57. Townes BD, et al. Neurobehavioral outcomes in cardiac operations. A prospective controlled study. J
Thorac Cardiovasc Surg 1989;98(5, Part 1):774-782.
58. Pugsley W, et al. The impact of microemboli during cardiopulmonary bypass on neuropsychological
functioning. Stroke 1994;25:1393-1399.
59. Jonas RA, et al. Relation of pH strategy and developmental outcome after hypothermic circulatory arrest.
J Thorac Cardiovasc Surg 1993;106: 362-368.
60. Newburger JW, et al. A comparison of the perioperative neurologic effects of hypothermic circulatory
arrest versus low-flow cardiopulmonary bypass in infant heart surgery. N Engl J Med 1993;329(15):1057-
1064.
61. Jonas RA. Review of current research at Boston Children’s Hospital. Ann Thorac Surg 1993;56:1467-
1472.
62. Van Dijk D, et al. Cognitive outcome after off-pump and on-pump coronary artery bypass graft surgery: a
randomized trial. JAMA 2002;287(11):1405-1412.
63. Marasco SF, Sharwood LN, Abramson MJ. No improvement in neurocognitive outcomes after off-pump
versus on-pump coronary revascularisation: a meta-analysis. Eur J Cardiothorac Surg 2008;33(6):961-970.
64. Selnes OA, et al. Cognitive changes with coronary artery disease: a prospective study of coronary artery
bypass graft patients and nonsurgical controls. Ann Thorac Surg 2003;75(5):1377-1384; discussion 1384-
1386.
65. Wahrborg P, et al. Neuropsychological outcome after percutaneous coronary intervention or coronary
artery bypass grafting: results from the Stent or Surgery (SoS) Trial. Circulation 2004;110(22):3411-3417.
66. Rankin KP, et al. Presurgical cognitive deficits in patients receiving coronary artery bypass graft surgery.
J Int Neuropsychol Soc 2003;9(6):913-924.
67. Gold JP, et al. Improvement of outcomes after coronary artery bypass. A randomized trial comparing
intraoperative high versus low mean arterial pressure. J Thorac Cardiovasc Surg 1995;110:1302-1311.
68. Grigore AM, et al. Prospective randomized trial of normothermic versus hypothermic cardiopulmonary
bypass on cognitive function after coronary artery bypass graft surgery. Anesthesiology 2001;95(5):1110-
1119.
69. Heyer EJ, et al. Cerebral dysfunction after coronary artery bypass grafting done with mild or moderate
hypothermia. J Thorac Cardiovasc Surg 1997;114(2):270-277.
70. Butterworth J, et al. Attempted control of hyperglycemia during cardiopulmonary bypass fails to improve
neurologic or neurobehavioral outcomes in patients without diabetes mellitus undergoing coronary artery
bypass grafting. J Thorac Cardiovasc Surg 2005;130(5):1319.
P.412
71. Bashien G, et al. A randomized study of carbon dioxide management during hypothermic
cardiopulmonary bypass. Anesthesiology 1990;72:7-15.
72. Murkin JM, et al. A randomized study of the influence of perfusion technique and pH management
strategy in 316 patients undergoing coronary artery bypass surgery. II. Neurologic and cognitive outcomes. J
73. Legault C, et al. Nimodipine neuroprotection in cardiac valve replacement: report of an early terminated
trial. Stroke 1996;27(4):593-598.
74. Butterworth J, et al. A randomized, blinded trial of the antioxidant pegorgotein: no reduction in
neuropsychological deficits, inotropic drug support, or myocardial ischemia after coronary artery bypass
surgery. J Cardiothorac Vasc Anesth 1999;13(6):690-694.
75. Kong RS, et al. Clinical trial of the neuroprotectant clomethiazole in coronary artery bypass graft surgery:
a randomized controlled trial. Anesthesiology 2002;97(3):585-591.
76. Cook DJ, et al. First clinical report of differential perfusion during cardiac surgery using the Cardeon
COBRA aortic cannula. Ann Thorac Surg 2002;73:375S.
77. Hammon JW, et al. Risk factors and solutions for the development of neurobehavioral changes after
coronary artery bypass grafting. Ann Thorac Surg 1997;63(6):1613-1618.
78. Hammon JW, et al. CABG with single cross clamp results in fewer persistent neuropsychological deficits
than multiple clamp or OPCAB. Ann Thorac Surg 2007;84:1174-1179.
79. Brown CH. Delirium in the cardiac surgical ICU. Curr Opin Anaesthesiol 2014;27(2):117-122.
80. van Dijk D, et al. Neurocognitive dysfunction after coronary artery bypass surgery: a systematic review. J
Thorac Cardiovasc Surg 2000;120(4):632-639.
81. Nathan HJ, et al. Neuroprotective effect of mild hypothermia in patients undergoing coronary artery
surgery with cardiopulmonary bypass: a randomized trial. Circulation 2001;104:I-85-I-91.
82. Grigore AM, et al. The rewarming rate and increased peak temperature alter neurocognitive outcome
after cardiac surgery. Anesth Analg 2002;94(1):4-10, table of contents.
83. Fearn SJ, et al. Cerebral injury during cardiopulmonary bypass: emboli impair memory. J Thorac
Cardiovasc Surg 2001;121(6):1150-1160.
84. Zierer A, et al. The impact of unilateral versus bilateral antegrade cerebral perfusion on surgical
outcomes after aortic arch replacement: a propensity-matched analysis. J Thorac Cardiovasc Surg
2014;147(4):1212-1217; discussion 1217-1218.
85. Wagerle LC, et al. Endothelial dysfunction in cerebral microcirculation during hypothermic
cardiopulmonary bypass in newborn lambs. J Thorac Cardiovasc Surg 1998;115(5):1047-1054.
86. Verrier ED, Shen I. Potential role of neutrophil anti-adhesion therapy in myocardial stunning, myocardial
infarction, and organ dysfunction after cardiopulmonary bypass. J Card Surg 1993;8(2, Suppl):309-312.
87. Hallenbeck JM. Significance of the inflammatory response in brain ischemia. Acta Neurochir Suppl
1996;66:27-31.
88. Elliott MJ, Finn AHR. Interaction between neutrophils and endothelium. Ann Thorac Surg 1993;56:1503-
1508.
89. Barbut D, et al. Determination of size of aortic emboli and embolic load during coronary artery bypass
grafting. Ann Thorac Surg 1997;63:1262-1267.
90. Barbut D, et al. Impact of embolization during coronary artery bypass grafting on outcome and length of
stay. Ann Thorac Surg 1997;63(4):998-1002.
91. Stump DA, et al. Cerebral emboli and cognitive outcome after cardiac surgery. J Cardiothorac Vasc
Anesth 1996;10(1):113-118; quiz 118-119.
92. van der Linden J, Casimir-Ahn H. When do cerebral emboli appear during open heart operations? A
transcranial Doppler study. Ann Thorac Surg 1991;51:237-241.
93. Blauth CI, et al. Cerebral microembolism during cardiopulmonary bypass. Retinal microvascular studies in
vivo with fluorescein angiography. J Thorac Cardiovasc Surg 1980;95:668-676.
94. Blauth C, et al. Retinal microembolism and neuropsychological deficit following clinical cardiopulmonary
bypass: comparison of a membrane and a bubble oxygenator. A preliminary communication. Eur J
CardioThorac Surg 1989;3:135-139.
95. Steinberg GK, et al. MR and cerebrospinal fluid enzymes as sensitive indicators of subclinical cerebral
injury after open-heart valve replacement surgery. Am J Neuroradiol 1996;17(2):205-212; discussion 213-
215.
96. Hise JH, Nipper ML, Schnitker JC. Stroke associated with coronary artery bypass surgery. Am J
Neuroradiol 1991;12(5):811-814.
97. Blossom GB, et al. Characteristics of cerebrovascular accidents after coronary artery bypass grafting.
Am Surg 1992;58:584-589.
98. Howard R, Trend P, Russell WR. Clinical features of ischemia in cerebral arterial border zones after
periods of reduced cerebral blood flow. Arch Neurol 1987;44:934-940.
99. Moody DM, et al. Brain microemboli associated with cardiopulmonary bypass: a histologic and magnetic
resonance imaging study. Ann Thorac Surg 1995;59:1304-1307.
100. Blauth CI, et al. Atheroembolism from the ascending aorta. An emerging problem in cardiac surgery. J
101. Wareing TH, et al. Management of the severely atherosclerotic ascending aorta during cardiac
operations. A strategy for detection and treatment. J Thorac Cardiovasc Surg 1992;103:453-462.
102. Blauth CI. Macroemboli and microemboli during cardiopulmonary bypass. Ann Thorac Surg
1995;59:1300-1303.
103. Dewanjee MK, et al. Reduction of neutrophil margination by L-arginine during hypothermic
cardiopulmonary bypass in a pig model. ASAIO J 1996;42(5):M661-M666.
104. Padayachee TS, et al. The effect of arterial filtration on reduction of gaseous microemboli in the middle
cerebral artery during cardiopulmonary bypass. Ann Thorac Surg 1988;45:647-649.
105. Barbut D, et al. Comparison of transcranial Doppler ultrasonography and transesophageal

echocardiography to monitor emboli during coronary artery bypass surgery. Stroke 1996;27(1):87-90.
106. Neville MJ, et al. Similar neurobehavioral outcome after valve or coronary artery operations despite
differing carotid embolic counts. J Thorac Cardiovasc Surg 2001;121(1):125-136.
107. van Everdingen KJ, et al. Diffusion-weighted magnetic resonance imaging in acute stroke. Stroke
1998;29(9):1783-1790.
108. Ozsunar Y, Sorensen AG. Diffusion- and perfusion-weighted magnetic resonance imaging in human
acute ischemic stroke: technical considerations. Top Magn Reson Imaging 2000;11(5):259-272.
109. Knipp SC, et al. Evaluation of brain injury after coronary artery bypass grafting. A prospective study
using neuropsychological assessment and diffusion-weighted magnetic resonance imaging. Eur J
Cardiothorac Surg 2004;25(5):791-800.
110. Restrepo L, et al. Diffusion- and perfusion-weighted magnetic resonance imaging of the brain before
and after coronary artery bypass grafting surgery. Stroke 2002;33(12):2909-2915.
111. Stolz E, et al. Diffusion-weighted magnetic resonance imaging and neurobiochemical markers after
aortic valve replacement: implications for future neuroprotective trials? Stroke 2004;35(4):888-892.
112. Wityk RJ, et al. Diffusion- and perfusion-weighted brain magnetic resonance imaging in patients with
neurologic complications after cardiac surgery. Arch Neurol 2001;58(4):571-576.
113. Lynn GM, et al. Risk factors for stroke after coronary artery bypass. J Thorac Cardiovasc Surg
1992;104:1518-1523.
114. Herlitz J, et al. Mortality and morbidity during a period of 2 years after coronary artery bypass surgery in
patients with and without a history of hypertension. J Hypertens 1996;14:309-314.
115. Baumbach GL, Heistad DD. Cerebral circulation in chronic arterial hypertension. Hypertension
1988;12:89-95.
116. Caplan LR. Diabetes and brain ischemia. Diabetes 1996;45:S95-S97.
117. Croughwell N, et al. Diabetic patients have abnormal cerebral autoregulation during cardiopulmonary
bypass. Circulation 1990;82(Suppl IV):IV-407-IV-412.
118. Bentsen N, Larsen B, Lassen NA. Chronically impaired autoregulation of cerebral blood flow in long-
term diabetics. Stroke 1975;6(5):497-502.
119. Granger DN, Kubes P. The microcirculation and inflammation: modulation of leukocyte-endothelial cell
adhesion. J Leukocyte Biol 1994;55:662-675.
120. del Zoppo GJ. Microvascular responses to cerebral ischemia/inflammation. Ann N Y Acad Sci
1997;823:132-147.
121. del Zoppo GJ, et al. Polymorphonuclear leukocytes occlude capillaries following middle cerebral artery
occlusion and reperfusion in baboons. Stroke 1991;22(10):1276-1283.
122. Okada Y, et al. Fibrin contributes to microvascular obstructions and parenchymal changes during early
focal cerebral ischemia and reperfusion. Stroke 1994;25(9):1847-1853; discussion 1853-1854.
123. Hall RI, Smith MS, Rocker G. The systemic inflammatory response to cardiopulmonary bypass:
pathophysiological, therapeutic, and pharmacological considerations. Anesth Analg 1997;85(4):766-782.
124. Downing SW, Edmunds Jr LH. Release of vasoactive substances during cardiopulmonary bypass. Ann
Thorac Surg 1992;54:1236-1243.
P.413
125. Shafique T, et al. Altered pulmonary microvascular reactivity after total cardiopulmonary bypass. J
126. Friedman M, et al. Pulmonary microvascular responses to protamine and histamine. J Thorac
127. Seccombe JF, Schaff HV. Coronary artery endothelial function after myocardial ischemia and
reperfusion. Ann Thorac Surg 1995;60:778-788.
128. Feerick AE, et al. Cardiopulmonary bypass impairs vascular endothelial relaxation: effects of gaseous
microemboli in dogs. Am J Physiol 1994;267:H1174-H1182.
129. Poggetti RS, et al. Liver injury is a reversible neutrophil-mediated event following gut ischemia. Arch
Surg 1992;127:175-179.
130. Bhujle R, et al. Influence of cardiopulmonary bypass on platelet and neutrophil accumulations in internal
organs. ASAIO J 1997;43:M739-M744.
131. Chandler W. The effects of cardiopulmonary bypass on fibrin formation and lysis: is a normal fibrinolytic
response essential? J Cardiovasc Pharmacol 1996;27(Suppl 1):S63-S68.
132. Body SC. Platelet activation and interactions with the microvasculature. J Cardiovasc Pharmacol
1996;27(Suppl 1):S13-S25.
133. Rinder C, Fitch J. Amplification of the inflammatory response: adhesion molecules associated with
platelet/white cell responses. J Cardiovasc Pharmacol 1996;27(Suppl 1):S6-S12.
134. Cameron D. Initiation of white cell activation during cardiopulmonary bypass: cytokines and receptors. J
Cardiovasc Pharmacol 1996;27(Suppl 1):S1-S5.
135. Korthuis RJ, Anderson DC, Granger DN. Role of neutrophil-endothelial cell adhesion in inflammatory
disorders. J Crit Care 1994;9:47-71.
136. Said S, et al. Correlations between morphological changes in platelet aggregates and underlying
endothelial damage in cerebral microcirculation of mice. Stroke 1993;24:1968-1976.
137. Nandate K, et al. Cerebrovascular cytokine responses during coronary artery bypass surgery: specific
production of interleukin-8 and its attenuation by hypothermic cardiopulmonary bypass. Anesth Analg
1999:89(4):823-828.
138. Boyle EM Jr, et al. Endothelial cell injury in cardiovascular surgery: the systemic inflammatory response.
Ann Thorac Surg 1997;63(1):277-284.
139. Reinsfelt B, et al. Cerebrospinal fluid markers of brain injury, inflammation, and blood-brain barrier
dysfunction in cardiac surgery. Ann Thorac Surg 2012;94:549-555.
140. Merino JG, et al. Blood-brain barrier disruption after cardiac surgery. Am J Neuroradiol 2013;34:518-
523.
141. Mu DL, et al. High postoperative serum cortisol level is associated with increased risk of cognitive
dysfunction early after coronary artery bypass graft surgery: a prospective cohort study. PloS One
2013;8(10):e77637.
142. Mu DL, et al. High serum cortisol level is associated with increased risk of delirium after coronary artery
bypass graft surgery: a prospective cohort study. Crit Care 2010;14(6):R238.
143. Yaffe K, et al. Inflammatory markers and cognition in well-functioning African-American and white elders.
Neurology 2003;61(1):76-80.
144. Reinsfelt B, Ricksten SE, Zetterberg H, et al. Cerebrospinal fluid markers of brain injury, inflammation,
and blood-brain dysfunction in cardiac surgery. Ann Thorac Surg 2012;94:549-555.
145. Gutierrez G, Warley AR, Dantzker DR. Oxygen delivery and utilization in hypothermic dogs. J Appl
Physiol 1986;60(3):751-757.
146. Schumacker PT, et al. Effects of hyperthermia and hypothermia on oxygen extraction by tissues during
hypovolemia. J Appl Physiol 1987;63(3):1246-1252.
147. Adams RP, Dieleman LA, Cain SM. A critical value for O2 transport in the rat. J Appl Physiol
1982;53(3):660-664.
148. Cook DJ, Orszulak TA, Daly RC. Minimum hematocrit at differing cardiopulmonary bypass temperatures
in dogs. Circulation 1998;98(19, Suppl):II170-II174.
149. Plochl W, et al. Critical cerebral perfusion pressure during tepid heart surgery in dogs. Ann Thorac Surg
1998;66:118-124.
150. Michenfelder JD, Milde JH. The relationship among canine brain temperature, metabolism, and function
during hypothermia. Anesthesiology 1991;75:130-136.
151. Greeley WJ, et al. The effect of hypothermic cardiopulmonary bypass and total circulatory arrest on
cerebral metabolism in neonates, infants, and children. J Thorac Cardiovasc Surg 1991;101:783-794.
152. Kern FH, et al. Effect of altering pump flow rate on cerebral blood flow and metabolism in infants and
children. Ann Thorac Surg 1993;56(6):1366-1372.
153. Murkin JM, et al. Cerebral autoregulation and flow/metabolism coupling during cardiopulmonary bypass:
the influence of PaCO2. Anesth Analg 1987;66:825-832.
154. Govier AV, et al. Factors and their influence on regional cerebral blood flow during nonpulsatile
155. Brusino FG, et al. The effect of age on cerebral blood flow during hypothermic cardiopulmonary bypass.
J Thorac Cardiovasc Surg 1989;97:541-547.
156. Davis RF, Dobbs JL, Casson H. Conduct and monitoring of cardiopulmonary bypass. In: Gravlee GP,
Davis RF, Utley JR, eds. Cardiopulmonary bypass: principles and practice. Baltimore, MD: Williams &
Wilkins, 1993:578-602.
157. Mutch WAC, et al. Cerebral pressure-flow relationship during cardiopulmonary bypass in the dog at
normothermia and moderate hypothermia. J Cereb Blood Flow Metab 1994;14:510-518.
158. Tanaka J, et al. Cerebral autoregulation during deep hypothermic nonpulsatile cardiopulmonary bypass
with selective cerebral perfusion in dogs. J Thorac Cardiovasc Surg 1988;95:124-132.
159. Sadahiro M, Haneda K, Mohri H. Experimental study of cerebral autoregulation during cardiopulmonary
bypass with or without pulsatile perfusion. J Thorac Cardiovasc Surg 1994;108:446-454.
160. Henriksen L. Brain luxury perfusion during cardiopulmonary bypass in humans. A study of the cerebral
blood flow response to changes in CO2, O2, and blood pressure. J Cereb Blood Flow Metab 1986;6:366-
378.
161. Johnsson P, et al. Cerebral vasoreactivity to carbon dioxide during cardiopulmonary perfusion at
normothermia and hypothermia. Ann Thorac Surg 1989;48:769-775.
162. Stephan H, et al. Acid-base management during hypothermic cardiopulmonary bypass does not affect
cerebral metabolism but does affect blood flow and neurological outcome. Br J Anaesth 1992;69:51-57.
163. Cheng W, et al. Cerebral blood flow during cardiopulmonary bypass: influence of temperature and pH
management strategy. Ann Thorac Surg 1995;59(4):880-886.
164. Johnston WE, et al. Cerebral perfusion during canine hypothermic cardiopulmonary bypass: effect of
arterial carbon dioxide tension. Ann Thorac Surg 1991;52(3):479-489.
165. Hindman BJ, et al. Hypothermic acid-base management does not affect cerebral metabolic rate for
oxygen at 27°C. A study during cardiopulmonary bypass in rabbits. Anesthesiology 1993;79(3):580-587.
166. Patel RL, et al. Hyperperfusion and cerebral dysfunction. Effect of differing acid-base management
during cardiopulmonary bypass. Eur J Cardiothorac Surg 1993;7(9):457-463; discussion 464.
167. Prough DS, et al. Hypercarbia depresses cerebral oxygen consumption during cardiopulmonary bypass.
Stroke 1990;21:1162-1166.
168. Cook DJ, et al. Cardiopulmonary bypass temperature, hematocrit, and cerebral oxygen delivery in
humans. Ann Thorac Surg 1995;60(6):1671-1677.
169. Todd MM, et al. Cerebral blood flow and oxygen delivery during hypoxemia and hemodilution: role of
arterial oxygen content. Am J Physiol 1994;267:H2025-H2031.
170. Croughwell N, et al. The effect of temperature on cerebral metabolism and blood flow in adults during
171. Andersen K, et al. Nonpulsatile cardiopulmonary bypass disrupts the flow-metabolism couple in the
brain. J Thorac Cardiovasc Surg 1985;90: 570-579.
172. Henling CE, et al. Cardiac operation for congenital heart disease in children of Jehovah’s Witnesses. J
173. Eke CC, et al. Neurologic sequelae of deep hypothermic circulatory arrest in cardiac transplant infants.
174. Loor G, et al. Nadir hematocrit during cardiopulmonary bypass: end-organ dysfunction and mortality. J
Thorac Cardiovasc Surg 2012;144(3):654-662.e4.
175. Swaminathan M, et al. The association of lowest hematocrit during cardiopulmonary bypass with acute
renal injury after coronary artery bypass surgery. Ann Thorac Surg 2003;76(3):784-791; discussion 792.
176. Karkouti K, et al. Influence of erythrocyte transfusion on the risk of acute kidney injury after cardiac
surgery differs in anemic and nonanemic patients. Anesthesiology 2011;115(3):523-530.
177. Swain JA, et al. Low-flow hypothermic cardiopulmonary bypass protects the brain. J Thorac Cardiovasc
Surg 1991;102(1):76-83; discussion 83-84.
178. Rebeyka IM, et al. The effect of low-flow cardiopulmonary bypass on cerebral function: an experimental
and clinical study. Ann Thorac Surg 1987;43(4):391-396.
179. Fox LS, et al. Relationship of whole body oxygen consumption to perfusion flow rate during hypothermic
P.414
180. Schwartz AE, et al. Cerebral blood flow is determined by arterial pressure and not cardiopulmonary
bypass flow rate. Ann Thorac Surg 1995;60(1):165-169.
181. Swain JA, Anderson RV, Siegman MG. Low-flow cardiopulmonary bypass and cerebral protection: a
summary of investigations. Ann Thorac Surg 1993;56(6):1490-1492.
182. Hindman BJ, et al. Differences in cerebral blood flow between alpha-stat and pH-stat management are
eliminated during periods of decreased systemic flow and pressure. A study during cardiopulmonary bypass
in rabbits. Anesthesiology 1991;74(6):1096-1102.
183. Fox LS, et al. Relationship of brain blood flow and oxygen consumption to perfusion flow rate during
profoundly hypothermic cardiopulmonary bypass. An experimental study. J Thorac Cardiovasc Surg
1984;87(5):658-664.
184. Michler RE, et al. Low-flow cardiopulmonary bypass: importance of blood pressure in maintaining
cerebral blood flow. Ann Thorac Surg 1995;60(6 Suppl):S525-S528.
185. Schwartz AE, et al. Cerebral blood flow during low-flow hypothermic cardiopulmonary bypass in
baboons. Anesthesiology 1994;81(4): 959-964.
186. Cook DJ, Orszulak TA, Daly RC. The effects of pulsatile cardiopulmonary bypass on cerebral and renal
blood flow in dogs. J Cardiothorac Vasc Anesth 1997;11(4):420-427.
187. Johnsson P, et al. Cerebral blood flow and autoregulation during hypothermic cardiopulmonary bypass.
188. Cook DJ, et al. Effect of pump flow rate on cerebral blood flow during hypothermic cardiopulmonary
bypass in adults. J Cardiothorac Vasc Anesth 1997;11:415-419.
189. Rogers AT, et al. Cerebrovascular and cerebral metabolic effects of alterations in perfusion flow rate
during hypothermic cardiopulmonary bypass in man. J Thorac Cardiovasc Surg 1992;103(2):363-368.
190. Sanderson JM, Wright G, Sims FW. Brain damage in dogs immediately following pulsatile and non-
pulsatile blood flows in extracorporeal circulation. Thorax 1972;27:275-286.
191. Anstadt MP, et al. Pulsatile versus nonpulsatile reperfusion improves cerebral blood flow after cardiac
arrest. Ann Thorac Surg 1993;56:453-461.
192. Watanabe T, et al. Brain tissue pH, oxygen tension, and carbon dioxide tension in profoundly
hypothermic cardiopulmonary bypass. J Thorac Cardiovasc Surg 1989;97:396-401.
193. Hindman BJ, et al. Pulsatile versus nonpulsatile flow. No difference in cerebral blood flow or metabolism
during normothermic cardiopulmonary bypass in rabbits. Anesthesiology 1995;82:241-250.
194. Hindman BJ, et al. Pulsatile versus nonpulsatile cardiopulmonary bypass. No difference in brain blood
flow or metabolism at 27°C. Anesthesiology 1994;80:1137-1147.
195. Prough DS, et al. Cerebral blood flow decreases with time whereas cerebral oxygen consumption
remains stable during hypothermic cardiopulmonary bypass in humans. Anesth Analg 1991;72:161-168.
196. Rogers AT, et al. Response of cerebral blood flow to phenylephrine infusion during hypothermic
cardiopulmonary bypass: influence of PaCO2 management. Anesthesiology 1988;69(4):547-551.
197. Hindman BJ, et al. Brain blood flow and metabolism do not decrease at stable brain temperature during
cardiopulmonary bypass in rabbits. Anesthesiology 1992;77(2):342-350.
198. Croughwell ND, et al. Cardiopulmonary bypass time does not affect cerebral blood flow. Ann Thorac
Surg 1998;65(5):1226-1230.
199. Shaw PJ, et al. An analysis of factors predisposing to neurological injury in patients undergoing
coronary bypass operations. Q J Med 1989;72:633-646.
200. Rorick MB, Furlan AJ. Risk of cardiac surgery in patients with prior stroke. Neurology 1990;40:835-837.
201. Slogoff S, et al. Role of perfusion pressure and flow in major organ dysfunction after cardiopulmonary
bypass. Ann Thorac Surg 1990;50:911-918.
202. Charlson ME, et al. Improvement of outcomes after coronary artery bypass. II. A randomized trial
comparing intraoperative high versus customized mean arterial pressure. J Cardiac Surg 2007;22(6):465-
472.
203. The Warm Heart Investigators. Randomised trial of normothermic versus hypothermic coronary bypass
surgery. Lancet 1994;343(8897):559-563.
204. Martin TD, et al. Prospective, randomized trial of retrograde warm blood cardioplegia: myocardial benefit
and neurologic threat. Ann Thorac Surg 1994;57:298-304.
205. Craver JM, et al. Neurologic events after coronary bypass grafting: further observations with warm
cardioplegia. Ann Thorac Surg 1995;59:1429-1434.
206. Guyton RA, Mellitt RJ, Weintraub WS. A critical assessment of neurological risk during warm heart
surgery. J Cardiac Surg 1995;10(4 Suppl):488-492.
207. Baker AJ, et al. Cerebral microemboli during coronary artery bypass using different cardioplegia
techniques. Ann Thorac Surg 1995;59(5):1187-1191.
208. Ikonomidis JS, et al. Myocardial protection for coronary bypass grafting: the Toronto Hospital
perspective. Ann Thorac Surg 1995;60(3):824-832.
209. Clark RE, et al. Microemboli during coronary artery bypass grafting. Genesis and effect on outcome. J
210. Wong BI, et al. Central-nervous-system dysfunction after warm or hypothermic cardiopulmonary bypass.
Lancet 1992;339(8806):1383-1384.
211. Plourde G, et al. Temperature during cardiopulmonary bypass for coronary artery operations does not
influence postoperative cognitive function: a prospective, randomized trial. J Thorac Cardiovasc Surg
1997;114(1):123-128.
212. Birdi I, et al. Influence of normothermic systemic perfusion during coronary artery bypass operations: a
randomized prospective study. J Thorac Cardiovasc Surg 1997;114(3):475-481.
213. Hvass U, Depoix JP. Clinical study of normothermic cardiopulmonary bypass in 100 patients with
coronary artery disease. Ann Thorac Surg 1995;59(1):46-51.
214. Singh AK, et al. Stroke during coronary artery bypass grafting using hypothermic versus normothermic
perfusion. Ann Thorac Surg 1995;59(1):84-89.
215. Regragui IA, et al. Cardiopulmonary bypass perfusion temperature does not influence perioperative
renal function. Ann Thorac Surg 1995;60(1):160-164.
216. Grocott HP, et al. Postoperative hyperthermia is associated with cognitive dysfunction after coronary
artery bypass graft surgery. Stroke 2002;33(2):537-541.
217. Martin TD, et al. Warm blood versus cold crystalloid cardioplegia: a case matched comparison.
Circulation 1992;86(Suppl I):I-104.
218. Pulsinelli WA, et al. Increased damage after ischemic stroke in patients with hyperglycemia with or
without established diabetes mellitus. Am J Med 1983;74(4):540-544.
219. Dietrich WD, Alonso O, Busto R. Moderate hyperglycemia worsens acute blood-brain barrier injury after
forebrain ischemia in rats. Stroke 1993;24(1):111-116.
220. Chopp M, et al. Global cerebral ischemia and intracellular pH during hyperglycemia and hypoglycemia
in cats. Stroke 1988;19(11):1383-1387.
221. Frasco P, et al. Association between blood glucose level during cardiopulmonary bypass and
neuropsychiatric outcome. Anesthesiology 1991;75(3A):A55.
222. Metz S, Keats AS. Benefits of a glucose-containing priming solution for cardiopulmonary bypass. Anesth
Analg 1991;72(4):428-434.
223. Gandhi GY, et al. Intraoperative hyperglycemia and perioperative outcomes in cardiac surgery patients.
Mayo Clin Proc 2005;80(7):862-866.
224. Ouattara A, et al. Poor intraoperative blood glucose control is associated with a worsened hospital
outcome after cardiac surgery in diabetic patients. Anesthesiology 2005;103(4):687-694.
225. Gandhi GY, et al. Intensive intraoperative insulin therapy versus conventional glucose management
during cardiac surgery: a randomized trial. Ann Intern Med 2007;146(4):233-243.
226. Lazar HL, et al. The Society of Thoracic Surgeons practice guideline series: blood glucose management
during adult cardiac surgery. Ann Thorac Surg 2009;87(2):663-669.
227. Patel RL, et al. Alpha-stat acid-base regulation during cardiopulmonary bypass improves
neuropsychologic outcome in patients undergoing coronary artery bypass grafting. J Thorac Cardiovasc
Surg 1996;111:1267-1279.
228. Henriksen L, Hjelms E, Lindeburgh T. Brain hyperperfusion during cardiac operations. Cerebral blood
flow measured in man by intra-arterial injection of xenon 133: evidence suggestive of intraoperative
microembolism. J Thorac Cardiovasc Surg 1983;86:202-208.
229. Plochl W, Cook DJ. Quantification and distribution of cerebral emboli during cardiopulmonary bypass in
the swine: the impact of PaCO2. Anesthesiology 1999;90(1):183-190.
230. Kern FH, et al. Temperature monitoring during CPB in infants: does it predict efficient brain cooling?
Ann Thorac Surg 1992;54(4):749-754.
231. Kern FH, et al. Comparing two strategies of cardiopulmonary bypass cooling on jugular venous oxygen
saturation in neonates and infants. Ann Thorac Surg 1995;60(5):1198-1202.
232. Aoki M, et al. Effects on pH on brain energetics after hypothermic circulatory arrest. Ann Thorac Surg
1993;55:1093-1103.
233. Kurth CD, et al. Brain cooling efficiency with pH-stat and a-stat cardiopulmonary bypass in newborn
pigs. Circulation 1997;96:II-358-II-363.
234. Hiramatsu T, et al. pH strategies and cerebral energetics before and after circulatory arrest. J Thorac
P.415
235. Henze T, Stephan H, Sonntag H. Cerebral dysfunction following extracorporeal circulation for
aortocoronary bypass surgery: no differences in neuropsychological outcome after pulsatile versus
nonpulsatile flow. Thorac Cardiovasc Surg 1990;38:65-68.
236. Barzilai B, et al. Avoidance of embolic complications by ultrasonic characterization of the ascending
aorta. Circulation 1989;80(3, Part 1):I275-1279.
237. Akpinar B, et al. A no-touch technique for calcified ascending aorta during coronary artery surgery. Tex
Heart Inst J 1998;25(2):120-123.
238. Mills NL, Everson CT. Atherosclerosis of the ascending aorta and coronary artery bypass. Pathology,
clinical correlates, and operative management. J Thorac Cardiovasc Surg 1991;102(4):546-553.
239. Tsang JC, et al. Single aortic clamp versus partial occluding clamp technique for cerebral protection
during coronary artery bypass: a randomized prospective trial. J Card Surg 2003;18(2):158-163.
240. Daniel WT III, et al. Trends in aortic clamp use during coronary artery bypass surgery: effect of aortic
clamping strategies on neurologic outcomes. J Thorac Cardiovasc Surg 2014;147(2):652-657.
241. Zingone B, et al. The impact of epiaortic ultrasonographic scanning on the risk of perioperative stroke.
Eur J Cardiothorac Surg 2006;29(5):720-728.
242. Joo HC, et al. Intraoperative epiaortic scanning for preventing early stroke after off-pump coronary
artery bypass. Br J Anaesth 2013;111(3):374-381.
243. Lev-Ran O, et al. ‘No touch’ techniques for porcelain ascending aorta: comparison between
cardiopulmonary bypass with femoral artery cannulation and off-pump myocardial revascularization. J Card
Surg 2002;17(5):370-376.
244. Emmert MY, et al. Aortic no-touch technique makes the difference in off-pump coronary artery bypass
grafting. J Thorac Cardiovasc Surg 2011;142(6):1499-506.
245. Thourani VH, et al. Incidence of postoperative stroke using the Heartstring device in 1,380 coronary
artery bypass graft patients with mild to severe atherosclerosis of the ascending aorta. Ann Thorac Surg
2014;97(6):2066-2072; discussion 2072.
246. Riess FC, et al. Beating heart operations including hybrid revascularization: initial experiences. Ann
Thorac Surg 1998;66(3):1076-1081.
247. Zenati M, et al. Preoperative risk models for minimally invasive coronary bypass: a preliminary study. J
248. Takagi H, Umemoto T. Worse long-term survival after off-pump than on-pump coronary artery bypass
grafting. J Thorac Cardiovasc Surg 2014;148(5):1820-1829.
249. Kim JB, et al. Long-term survival following coronary artery bypass grafting: off-pump versus on-pump
strategies. J Am Coll Cardiol 2014;63(21): 2280-2288.
250. Bakaeen FG, et al. Performing coronary artery bypass grafting off-pump may compromise long-term
survival in a veteran population. Ann Thorac Surg 2013;95(6):1952-1958; discussion 1959-1960.
251. Shroyer AL, et al. On-pump versus off-pump coronary-artery bypass surgery. N Engl J Med
2009;361(19):1827-1837.
252. Cook D, et al. Profound reduction in brain embolization using an endoaortic baffle during bypass in
swine. Ann Thoracic Surg 2002;73:198-202.
253. Cook D, et al. Effectiveness of the COBRATM aortic catheter for dual temperature management during
adult cardiac surgery. J Thorac Cardiovasc Surg 2003;125:378-384.
254. Reichenspurner H, et al. Particulate emboli capture by an intra-aortic filter device during cardiac
surgery. J Thorac Cardiovasc Surg 2000;119(2):233-241.
255. Harringer W. Capture of particulate emboli during cardiac procedures in which aortic cross-clamp is
used. International Council of Emboli Management Study Group. Ann Thorac Surg 2000;70(3):1119-1123.
256. Hartman GS, et al. Severity of aortic atheromatous disease diagnosed by transesophageal
echocardiography predicts stroke and other outcomes associated with coronary artery surgery: a prospective
study. Anesth Analg 1996;83(4):701-708.
257. Martens S, et al. Optimal carbon dioxide application for organ protection in cardiac surgery. J Thorac
Cardiovasc Surg 2002;124(2):387-391.
258. Lund C, et al. Comparison of cerebral embolization during off-pump and onpump coronary artery bypass
surgery. Ann Thorac Surg 2003;76(3):765-770; discussion 770.
259. Blauth CI, et al. Influence of oxygenator type on the prevalence and extent of microembolic retinal
ischemia during cardiopulmonary bypass. Assessment by digital image analysis. J Thorac Cardiovasc Surg
1990;99:61-69.
260. Pugsley WB, et al. Does arterial line filtration affect the bypass related cerebral impairment in patients
undergoing coronary artery surgery. Clin Sci 1988;76:30-31.
261. Hammon JW. Brain protection during cardiac surgery: circa 2012. J Extra Corpor Technol
2013;45(2):116-121.
262. Groom RC, et al. Detection and elimination of microemboli related to cardiopulmonary bypass.
Circulation 2009;2(3):191-198.
263. Cecconi O, et al. Inositol polyanions. Noncarbohydrate inhibitors of L- and P-selectin that block
inflammation. J Biol Chem 1994;269:15060-15066.
264. Nussmeier NA, Arlund C, Slogoff S. Neuropsychiatric complications after cardiopulmonary bypass:
cerebral protection by a barbiturate. Anesthesiology 1986;64:165-170.
265. Metz S, Slogoff S. Thiopental sodium by single bolus dose compared to infusion for cerebral protection
during cardiopulmonary bypass. J Clin Anesth 1990;2(4):226-231.
266. Prough DS, Mills SA. Should thiopental sodium administration be a standard of care for open cardiac
procedures? J Clin Anesth 1990;2(4):221-225.
267. Zaidan JR, et al. Effect of thiopental on neurologic outcome following coronary artery bypass grafting.
268. Todd MM, Hindman BJ, Warner DS. Barbiturate protection and cardiac surgery: a different result.
269. Johnston WE, et al. Significance of gaseous microemboli in the cerebral circulation during
cardiopulmonary bypass in dogs. Circulation 1993;88(2):319-329.
270. Hindman BJ, et al. Recovery of evoked potential amplitude after cerebral arterial air embolism in the
rabbit. A comparison of the effect of cardiopulmonary bypass with normal circulation. Anesthesiology
1998;88:696-707.
271. Helps SC, et al. The effect of gas emboli on rabbit cerebral blood flow. Stroke 1990;21:94-99.
272. Newman MF, et al. Cerebral physiologic effects of burst suppression doses of propofol during
nonpulsatile cardiopulmonary bypass. CNS Subgroup of McSPI. Anesth Analg 1995;81(3):452-457.
273. Ederberg S, et al. The effects of propofol on cerebral blood flow velocity and cerebral oxygen extraction
during cardiopulmonary bypass. Anesth Analg 1998;86(6):1201-1206.
274. Souter MJ, Andrews PJ, Alston RP. Propofol does not ameliorate cerebral venous oxyhemoglobin
desaturation during hypothermic cardiopulmonary bypass. Anesth Analg 1998;86(5):926-931.
275. Bielenberg GW, et al. Effects of nimodipine on infarct size and cerebral acidosis after middle cerebral
artery occlusion in the rat. Stroke 1990;21(12 Suppl):IV90-IV92.
276. Hara H, Nagasawa H, Kogure K. Nimodipine prevents postischemic brain damage in the early phase of
focal cerebral ischemia. Stroke 1990;21(12 Suppl):IV102-IV104.
277. Gelmers HJ, Hennerici M. Effect of nimodipine on acute ischemic stroke. Pooled results from five
randomized trials. Stroke 1990;21(12 Suppl):IV81-IV84.
278. Forsman M, et al. Effects of nimodipine on cerebral blood flow and neuropsychological outcome after
cardiac surgery. Br J Anaesth 1990;65: 514-520.
279. Nagels W, et al. Evaluation of the neuroprotective effects of S(+)-ketamine during open-heart surgery.
Anesth Analg 2004;98(6):1595-1603, table of contents.
280. Hall ED. Inhibition of lipid peroxidation in central nervous system trauma and ischemia. J Neurol Sci
1995;134(Suppl):79-83.
281. Baumgartner WA, et al. Pathophysiology of cerebral injury and future management. J Cardiac Surg
1997;12(2 Suppl):300-310; discussion 310-311.
282. Tseng EE, et al. Neuronal nitric oxide synthase inhibition reduces neuronal apoptosis after hypothermic
circulatory arrest. Ann Thorac Surg 1997;64(6):1639-1647.
283. Tsui SS, et al. Nitric oxide production affects cerebral perfusion and metabolism after deep hypothermic
circulatory arrest. Ann Thorac Surg 1996;61:1699-1707.
284. Engelman DT, et al. L-arginine reduces endothelial inflammation and myocardial stunning during
ischemia/reperfusion. Ann Thorac Surg 1995;60(5):1275-1281.
285. Becker KJ. Inflammation and acute stroke. Curr Opin Neurol 1998;11(1):45-49.
286. Pantoni L, Sarti C, Inzitari D. Cytokines and cell adhesion molecules in cerebral ischemia: experimental
bases and therapeutic perspectives. Arterioscler Thromb Vasc Biol 1998;18(4):503-513.
287. Gillinov AM, et al. Inhibition of neutrophil adhesion during cardiopulmonary bypass. Ann Thorac Surg
1994;57(1):126-133.
288. Chopp M, Zhang ZG. Anti-adhesion molecule and nitric oxide protection strategies in ischemic stroke.
Curr Opin Neurol 1996;9(1):68-72.
P.416
289. Chopp M, et al. Antibodies against adhesion molecules reduce apoptosis after transient middle cerebral
artery occlusion in rat brain. J Cereb Blood Flow Metab 1996;16(4):578-584.
290. Murohara T, Buerke M, Lefer AM. Polymorphonuclear leukocyte-induced vasocontraction and

endothelial dysfunction. Role of selectins. Arterioscler Thromb Vasc Biol 1994;14:1509-1519.
291. Morikawa E, et al. Treatment of focal cerebral ischemia with synthetic oligopeptide corresponding to
lectin domain of selectin. Stroke 1996;27(5):951-955; discussion 956.
292. Buerke M, et al. Sialyl Lewisx-containing oligosaccharide attenuates myocardial reperfusion injury in
cats. J Clin Invest 1994;93:1140-1148.
293. Turunen JP, et al. De novo expression of endothelial sialyl Lewis(a) and sialyl Lewis(x) during cardiac
transplant rejection: superior capacity of a tetravalent sialyl Lewis(x) oligosaccharide in inhibiting L-selectin-
dependent lymphocyte adjesion. J Exp Med 1995;182:1133-1141.
294. Mulligan MS, et al. Protective effects of sialylated oligosaccharides in immune complex-induced acute
lung injury. J Exp Med 1993;178:623-631.
295. Nelson RM, et al. Heparin oligosaccharides bind L- and P-selectin and inhibit acute inflammation. Blood
1993;82(11):3253-3258.
296. Ishai-Michaeli R, et al. Importance of size and sulfation of heparin in release of basic fibroblast growth
factor from the vascular basic fibroblast growth factor from the vascular endothelium and extracellular matrix.
Biochemistry 1992;31:2080-2088.
297. Sternbergh WC III, Sobel M, Makhoul RG. Heparinoids with low anticoagulant potency attenuate
postischemic endothelial cell dysfunction. J Vasc Surg 1995;21:477-483.
298. Ishihara M, et al. Preparation of affinity-fractionated, heparin-derived oligosaccharides and their effects
on selected biological activities mediated by basic fibroblast growth factor. J Biol Chem 1993;268:4675-
4683.
299. Ryu KH, et al. Heparin reduces neurological impairment after cerebral arterial air embolism in the rabbit.
Stroke 1996;27(2):303-309; discussion 310.
300. Hogue CW Jr, Palin CA, Arrowsmith JE. Cardiopulmonary bypass management and neurologic
outcomes: an evidence-based appraisal of current practices. Anesth Analg 2006;103(1):21-37.
301. Minamisawa H, Smith ML, Siesjo BK. The effect of mild hyperthermia and hypothermia on brain damage
following 5, 10, and 15 minutes of forebrain ischemia. Ann Neurol 1990;28(1):26-33.
302. Busto R, et al. Small differences in intraischemic brain temperature critically determine the extent of
ischemic neuronal injury. J Cereb Blood Flow Metab 1987;7(6):729-38.
303. Ginsberg MD, et al. Therapeutic modulation of brain temperature: relevance to ischemic brain injury.
Cerebrovasc Brain Metab Rev 1992;4(3):189-225.
304. Morikawa E, et al. The significance of brain temperature in focal cerebral ischemia: histopathological
consequences of middle cerebral artery occlusion in the rat. J Cereb Blood Flow Metab 1992;12(3):380-389.
305. Minamisawa H, et al. The influence of mild body and brain hypothermia on ischemic brain damage. J
Cereb Blood Flow Metab 1990;10(3):365-374.
306. Conroy BP, et al. Hypothermic modulation of cerebral ischemic injury during cardiopulmonary bypass in
pigs. Anesthesiology 1998;88:390-402.
307. Ginsberg MD, Busto R. Combating hyperthermia in acute stroke. A significant clinical concern. Stroke
1998;29:529-534.
308. Cook DJ, et al. Cerebral hyperthermia during cardiopulmonary bypass in adults. J Thorac Cardiovasc
Surg 1996;111:268-269.
309. Cook DJ. Changing temperature management for cardiopulmonary bypass [Review]. Anesth Analg
1999;88:1254-1271.
310. Bar-Yosef S, et al. Prevention of cerebral hyperthermia during cardiac surgery by limiting on-bypass
rewarming in combination with post-bypass body surface warming: a feasibility study. Anesth Analg
2004;99(3):641-646, table of contents.
311. Ramsay JG, et al. Site of temperature monitoring and prediction of afterdrop after open heart surgery.
Can Anaesth Soc J 1985;32(6):607-612.
312. Boston US, et al. Hierarchy of regional oxygen delivery during cardiopulmonary bypass. Ann Thorac
Surg 2001;71:260-264.
313. Joachimsson PO, Nystrom SO, Tyden H. Postoperative ventilatory and circulatory effects of extended
rewarming during cardiopulmonary bypass. Can J Anaesth 1989;36:9-19.
314. Insler SR, et al. Association between postoperative hypothermia and adverse outcome after coronary
artery bypass surgery. Ann Thorac Surg 2000;70(1):175-181.
315. Corkey WB, et al. Brief report: the declining incidence of cerebral hyperthermia during cardiac surgery:
a seven-year experience in 6,334 patients. Can J Anaesth 2005;52(6):626-629.
316. Sungurtekin H, et al. Relationship between cardiopulmonary bypass (CPB) flow rate and cerebral
embolization. Anesthesiology 1998;89:A679.
317. Clauss RH, Hass WK, Ransohoff J. Simplified method for monitoring adequacy of brain oxygenation
during carotid artery surgery. N Engl J Med 1965;273:1127-1131.
318. Meyer JS, et al. Effects of anoxia on cerebral metabolism and electrolytes in man. Neurology
1965;15:892-901.
319. Croughwell ND, et al. Warming during cardiopulmonary bypass is associated with jugular bulb
desaturation. Ann Thorac Surg 1992;53:827-832.
320. Nakajima T, et al. Clinical evaluation of cerebral oxygen balance during cardiopulmonary bypass: on-
line continuous monitoring of jugular venous oxyhemoglobin saturation. Anesth Analg 1992;74:630-635.
321. Cook DJ, et al. A prospective, randomized comparison of cerebral venous oxygen saturation during
normothermic and hypothermic cardiopulmonary bypass. J Thorac Cardiovasc Surg 1994;107:1020-1029.
322. Croughwell ND, et al. Jugular bulb saturation and cognitive dysfunction after cardiopulmonary bypass.
Ann Thorac Surg 1994;58:1702-1708.
323. Enomoto S, et al. Rapid rewarming causes an increase in the cerebral metabolic rate for oxygen that is
temporarily unmatched by cerebral blood flow. A study during cardiopulmonary bypass in rabbits.
Anesthesiology 1996;84(6):1392-1400.
324. Sapire KJ, et al. Cerebral oxygenation during warming after cardiopulmonary bypass. Crit Care Med
1997;25(10):1655-1662.
325. Grubhofer G, et al. Jugular venous bulb oxygen saturation depends on blood pressure during
cardiopulmonary bypass. Ann Thorac Surg 1998;65(3):653-657; discussion 658.
326. von Knobelsdorff G, et al. Prolonged rewarming after hypothermic cardiopulmonary bypass does not
attenuate reduction of jugular bulb oxygen saturation. J Cardiothorac Vasc Anesth 1997;11(6):689-693.
327. Dexter F, Hindman BJ. Theoretical analysis of cerebral venous blood hemoglobin oxygen saturation as
an index of cerebral oxygenation during hypothermic cardiopulmonary bypass. A counterproprosal to the
“luxury perfusion” hypothesis. Anesthesiology 1995;83(2):405-412.
328. Kadoi Y, et al. Comparative effects of propofol versus fentanyl on cerebral oxygenation state during
normothermic cardiopulmonary bypass and postoperative cognitive dysfunction. Ann Thorac Surg
2003;75(3):840-846.
329. Diephuis JC, et al. Jugular bulb desaturation during coronary artery surgery: a comparison of off-pump
and on-pump procedures. Br J Anaesth 2005;94(6):715-720.
330. Ali MS, et al. Changes in cerebral oxygenation during cold (28 degrees C) and warm (34 degrees C)
cardiopulmonary bypass using different blood gas strategies (alpha-stat and pH-stat) in patients undergoing
coronary artery bypass graft surgery. Acta Anaesthesiol Scand 2004;48(7):837-844.
331. Millar SM, et al. Cerebral hypoperfusion in immediate postoperative period following coronary artery
bypass grafting, heart valve, and abdominal aortic surgery. Br J Anaesth 2001;87(2):229-236.
332. Kiziltan HT, et al. Comparison of alpha-stat and pH-stat cardiopulmonary bypass in relation to jugular
venous oxygen saturation and cerebral glucose-oxygen utilization. Anesth Analg 2003;96(3):644-650, table
of contents.
333. Brown R, Wright G, Royston D. A comparison of two systems for assessing cerebral venous
oxyhaemoglobin saturation during cardiopulmonary bypass in humans. Anaesthesia 1993;48:697-700.
334. McCormick PW, et al. Regional cerebrovascular oxygen saturation measured by optical spectroscopy in
humans. Stroke 1991;22:596-602.
335. Nollert G, et al. Determinants of cerebral oxygenation during cardiac surgery. Circulation 1995;92:II-
327-II-333.
336. Daubeney PE, et al. Cerebral oxygenation measured by near-infrared spectroscopy: comparison with
jugular bulb oximetry. Ann Thorac Surg 1996;61(3):930-934.
337. Kurth CD, et al. Kinetics of cerebral deoxygenation during deep hypothermic circulatory arrest in
neonates. Anesthesiology 1992;77(4):656-661.
338. Kurth CD, Steven JM, Nicolson SC. Cerebral oxygenation during pediatric cardiac surgery using deep
hypothermic circulatory arrest. Anesthesiology 1995;82(1):74-82.
339. Daubeney PE, et al. Cerebral oxygenation during paediatric cardiac surgery: identification of vulnerable
periods using near infrared spectroscopy. Eur J CardioThorac Surg 1998;13(4):370-377.
340. du Plesis AJ, et al. Cerebral oxygen supply and utilization during infant cardiac surgery. Ann Neurol
1995;37:488-497.
341. Germon TJ, et al. Near-infrared spectroscopy in adults: effects of extracranial ischaemia and intracranial
hypoxia on estimation of cerebral oxygenation. Br J Anaesth 1994;73(4):503-506.
P.417
342. Nollert G, Shin’oka T, Jonas RA. Near-infrared spectrophotometry of the brain in cardiovascular
surgery. Thorac Cardiovasc Surg 1998;46(3): 167-175.
343. Nomura F, et al. Cerebral oxygenation measured by near infrared spectroscopy during cardiopulmonary
bypass and deep hypothermic circulatory arrest in piglets. Pediatr Res 1996;40(6):790-796.
344. Wardle SP, Yoxall CW, Weindling AM. Cerebral oxygenation during cardiopulmonary bypass. Arch Dis
Childhood 1998;78(1):26-32.
345. Taillefer MC, Denault AY. Cerebral near-infrared spectroscopy in adult heart surgery: systematic review
of its clinical efficacy. Can J Anaesth 2005;52(1):79-87.
346. Murkin JM, et al. Monitoring brain oxygen saturation during coronary bypass surgery: a randomized,
prospective study. Anesth Analg 2007;104(1): 51-58.
347. Shaaban Ali M, et al. A pilot study of evaluation of cerebral function by S100beta protein and near-
infrared spectroscopy during cold and warm cardiopulmonary bypass in infants and children undergoing
open-heart surgery. Anaesthesia 2004;59(1):20-26.
348. Tortoriello TA, et al. A noninvasive estimation of mixed venous oxygen saturation using near-infrared
spectroscopy by cerebral oximetry in pediatric cardiac surgery patients. Paediatr Anaesth 2005;15(6):495-
503.
349. Spencer MP, Thomas GI, Moehring MA. Relation between middle cerebral artery blood flow velocity and
stump pressure during carotid endarterectomy. Stroke 1992;23:1439-1445.
350. Kontos HA. Validity of cerebral arterial blood flow calculations from velocity measurements. Stroke
1989;20(1):1-3.
351. Weyland A, et al. Flow velocity measurements as an index of cerebral blood flow. Anesthesiology
1994;81:1401-1410.
352. Nuttall GA, et al. The relationship between cerebral blood flow and transcranial Doppler blood flow
velocity during hypothermic cardiopulmonary bypass in adults. Anesth Analg 1996;82:1146-1151.
353. Grocott HP, et al. Transcranial Doppler blood flow velocity versus 133Xe clearance cerebral blood flow
during mild hypothermic cardiopulmonary bypass. J Clin Monit Comput 1998;14(1):35-39.
354. Endoh H, Shimoji K. Changes in blood flow velocity in the middle cerebral artery during nonpulsatile
hypothermic cardiopulmonary bypass. Stroke 1994;25(2):403-407.
355. Trivedi UH, et al. Relative changes in cerebral blood flow during cardiac operations using xenon-133
clearance versus transcranial Doppler sonography. Ann Thorac Surg 1997;63(1):167-174.
356. Zimmerman AA, et al. The limits of detectable cerebral perfusion by transcranial Doppler sonography in
neonates undergoing deep hypothermic low-flow cardiopulmonary bypass. J Thorac Cardiovasc Surg
1997;114(4):594-600.
357. Jonassen AE, Quaegebeur JM, Young WL. Cerebral blood flow velocity in pediatric patients is reduced
after cardiopulmonary bypass with profound hypothermia. J Thorac Cardiovasc Surg 1995;110(4, Part
1):934-943.
358. Blomquist S, et al. The appearance of S-100 protein in serum during and immediately after
cardiopulmonary bypass surgery: a possible marker for cerebral injury. J Cardiothorac Vasc Anesth
1997;11(6):699-703.
359. Jonsson H, et al. Significance of serum S100 release after coronary artery bypass grafting. Ann Thorac
Surg 1998;65(6):1639-1644.
360. Eifert S, et al. Neurological and neuropsychological examination and outcome after use of an intra-aortic
filter device during cardiac surgery. Perfusion 2003;18(Suppl 1):55-60.
361. Spencer MP. Detection of cerebral arterial emboli. In: Newell DW, Aaslid R, eds. Transcranial Doppler.
New York, NY: Raven Press, 1992:215-230.
362. Markus HS, Tegeler CH. Experimental aspects of high-intensity transient signals in the detection of
emboli. J Clin Ultrasound 1995;23(2):81-87.
363. Ringelstein EB, et al. Consensus on microembolus detection by TCD. International Consensus Group
on Microembolus Detection. Stroke 1998;29:725-729.
364. Theye RA, Patrick RT, Kirklin JW. The electro-encephalogram in patients undergoing open intracardiac
operations with the aid of extracorporeal circulation. J Thorac Surg 1957;34:709-716.
365. Lundar T, et al. Cerebral perfusion during nonpulsatile cardiopulmonary bypass. Ann Thorac Surg
1985;40(2):144-150.
366. Levy WJ. Quantitative analysis of EEG changes during hypothermia. Anesthesiology 1984;60:291-297.
367. Levy WJ. Monitoring of the electroencephalogram during cardiopulmonary bypass. Know when to say
when. Anesthesiology 1992;76(6):876-877.
368. Bashein G, et al. Electroencephalography during surgery with cardiopulmonary bypass and
hypothermia. Anesthesiology 1992;76(6):878-891.
369. Stecker MM, et al. Detection of stroke during cardiac operations with somatosensory evoked responses.
J Thorac Cardiovasc Surg 1996;112:962-972.
370. Rodriguez RA. Human auditory evoked potentials in the assessment of brain function during major
cardiovascular surgery. Semin Cardiothorac Vasc Anesth 2004;8(2):85-99.
371. Lopez JR. Intraoperative neurophysiological monitoring. Int Anesthesiol Clin 1996;34:33-54.
372. Hickey C, et al. Intraoperative somatosensory evoked potential monitoring predicts peripheral nerve
injury during cardiac surgery. Anesthesiology 1993;78(1):29-35.
373. Zimpfer D, et al. Cognitive deficit after aortic valve replacement. Ann Thorac Surg 2002;74(2):407-412;
discussion 412.
374. Hett DA, et al. Effect of temperature and cardiopulmonary bypass on the auditory evoked response. Br J
Anaesth 1995;75(3):293-296.
375. Yang LC, et al. Effects of temperature on somatosensory evoked potentials during open heart surgery.
Acta Anaesthesiol Scand 1995;39(7):956-959.
376. Lam AM, et al. Monitoring electrophysiologic function during carotid endarterectomy: a comparison of
somatosensory evoked potentials and conventional electroencephalogram. Anesthesiology 1991;75(1):15-
21.
377. Schmidlin D, Hager P, Schmid ER. Monitoring level of sedation with bispectral EEG analysis:
comparison between hypothermic and normothermic cardiopulmonary bypass. Br J Anaesth 2001;86(6):769-
776.
378. Doi M, et al. Effects of cardiopulmonary bypass and hypothermia on electroencephalographic variables.
Anaesthesia 1997;52(11):1048-1055.
379. Persson L, et al. S-100 protein and neuron-specific enolase in cerebrospinal fluid and serum: markers of
cell damage in human central nervous system. Stroke 1987;18(5):911-918.
380. Johnsson P. Markers of cerebral ischemia after cardiac surgery. J Cardiothorac Vasc Anesth
1996;10(1):120-126.
381. Taggart DP, et al. Serum S-100 protein concentration after cardiac surgery: a randomized trial of arterial
line filtration. Eur J CardioThorac Surg 1997;11(4):645-649.
382. Westaby S, et al. Serum S100 protein: a potential marker for cerebral events during cardiopulmonary
bypass. Ann Thorac Surg 1996;61(1):88-92.
383. Gao F, Harris DNF, Sapsed-Byrne S. Time course of neurone-specific enolase and S-100 protein
release during and after coronary artery bypass grafting. Br J Anaesth 1999;82(2):266-267.
384. Grocott HP, et al. Cerebral emboli and serum S100beta during cardiac operations. Ann Thorac Surg
1998;65(6):1645-1649; discussion 1649-1650.
385. Taggart DP, et al. Comparison of serum S-100 beta levels during CABG and intracardiac operations.
Ann Thorac Surg 1997;63(2):492-496.
386. Ueno T, et al. Serial measurement of serum S-100B protein as a marker of cerebral damage after
cardiac surgery. Ann Thorac Surg 2003;75(6):1892-1897; discussion 1897-1898.
387. Missler U, et al. Early elevation of S-100B protein in blood after cardiac surgery is not a predictor of
ischemic cerebral injury. Clin Chim Acta 2002;321(1/2):29-33.
388. Jonsson H. S100B and cardiac surgery: possibilities and limitations. Restor Neurol Neurosci
2003;21(3/4):151-157.
389. Fazio V, et al. Peripheral detection of S100beta during cardiothoracic surgery: what are we really
measuring? Ann Thorac Surg 2004;78(1):46-52; discussion 52-53.
390. Snyder-Ramos SA, et al. Cerebral and extracerebral release of protein S100B in cardiac surgical
patients. Anaesthesia 2004;59(4):344-349.
391. Jönsson H, et al. S100B as a predictor of size and outcome of stroke after cardiac surgery. Ann Thorac
Surg 2001;71(5):1433-1437.
392. Johnsson P, et al. Increased S100B in blood after cardiac surgery is a powerful predictor of late
mortality. Ann Thorac Surg 2003;75(1):162-168.
393. Jauch EC, et al. Guidelines for the early management of patients with acute ischemic stroke: a guideline
for healthcare professionals from the American Heart Association/American Stroke Association. Stroke
2013;44(3):870-947.
394. Hacke W, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med
2008;359(13):1317-1329.
395. Blackham KA, et al. Endovascular therapy of acute ischemic stroke: report of the Standards of Practice
Committee of the Society of NeuroInterventional Surgery. J Neurointerv Surg 2012;4(2):87-93.
396. Mashour GA, et al. Perioperative care of patients at high risk for stroke during or after non-cardiac, non-
neurologic surgery: consensus statement from the society for neuroscience in anesthesiology and critical
care. J Neurosurg Anesthesiol 2014;26(4):273-285.
Chapter 16
Hemodilution and Priming Solutions
John R. Cooper Jr.
N. Martin Giesecke
HISTORICAL PERSPECTIVE
Historical perspective is particularly important in assessing the progression of techniques for hemodilution and
how they affect the physiology of extracorporeal circulation and the development of related complications. John
Gibbon (1), who developed the first heart-lung machine and performed the first successful surgery using
cardiopulmonary bypass (CPB), envisioned a perfusion technique employing a prime of normal composition (i.e.,
blood) with “normal” flow rates (70-80 mL/kg/min) and normal blood pressure. When Gibbon withdrew from this
area of research, Kirklin et al. (2) continued Gibbon’s original methods.
Lillehei et al., first in procedures with controlled cross-circulation (3) and then with CPB (4), used significantly
lower flow rates (30-35 mL/kg/min) than did Gibbon. This modification (based on the “azygous flow principle”) (5)
was derived from the observation that dogs could survive when both the superior and inferior vena cavae were
occluded, because the azygous venous drainage of dogs, unlike that of humans, still provided venous return to
the heart on account of its more central confluence with the superior vena cava. In humans, this amount of flow
(10% of normal cardiac output) proved adequate for survival for up to 1 hour. This observation was rapidly
accepted and applied to the practice of CPB by many of those who perceived the harm to blood elements, as
well as the excessive suctioning that results from the use of high flows. Hypothermia was added to many high-
flow-rate and most low-flow-rate techniques to “protect” various organs, although Lillehei’s (3) original cross-
circulation procedures were carried out at normothermia. Despite lower flow rates, the priming solution for the
extracorporeal circuit with oxygenator remained the same—whole blood, which was either freshly drawn and
heparinized or collected into citrated bags, but as fresh as possible.
Around 1960, spurred by animal research and the occasional emergent clinical experience with asanguinous
prime, surgeons began electively using crystalloid solution or plasma-expanding colloids to reduce or eliminate
blood from the prime (Table 16.1) (1,2,3,4,6,7,8,9). Hypothermia was now increasingly applied to protect organs
from the “adverse effects” of not only low flow but also hemodilution. Nevertheless, the technique of hemodilution
gained increasing popularity, and currently it is used almost universally.
TABLE 16.1. Historical perspective of priming solutions and use of hemodilution during
cardiopulmonary bypass
Surgeon(s) Priming solution Technique
Gibbon (1) Whole blood High flow
Kirklin et al. (2) Whole blood High flow
Lillehei et al. (3) Whole blood Low flow
DeWall et al. (4) 5% Dextrose Hemodilution and hypothermia

Cooley et al. (6) 5% Dextrose Hemodilution and hypothermia
Greer et al. (7) 5% Dextrose Hemodilution and hypothermia
Long et al. (8) Dextran and 5% albumin Hemodilution and hypothermia
Panico and Neptune (9) Saline solution Hemodilution
The following discussion pertains to short-duration, clinical CPB used to aid cardiac surgery. Applicability of
hemodilution to longer CPB support times is discussed elsewhere.
IMMEDIATE BENEFITS OF HEMODILUTION

A main reason for using asanguinous primes was to reduce the severe strain placed on hospital blood banks by
the use of whole blood for priming CPB circuits. The need for at least two units of whole blood—and possibly as
many as five or six, just for use as prime in each patient—often caused severe logistic problems for physicians
trying to run an active cardiac surgical service. Many cases were postponed for lack of the correct type or
amount of blood. Crystalloid primes also
P.422
improved access to CPB as an emergency procedure by reducing the time and resources required for having a
usable circuit available (Table 16.1) (1,2,3,4,6,7,8,9).
Another immediate but unforeseen clinical benefit of crystalloid primes was improved oxygenation during CPB.
The types of bubble oxygenators widely used in the 1960s and early 1970s produced a high proportion of
relatively large bubbles. Compared with the smaller, more numerous bubbles produced by later oxygenators,
these larger bubbles were relatively inefficient for the transfer of oxygen, in part because of their lower ratio of
surface area (where the gas transfer occurs) to volume, and in part because of the relatively smaller number of
bubbles in a given volume of blood relative to the number of red blood cells. Hemodilution, especially in patients
with polycythemia, which commonly accompanies congenital heart disease, produced an absolute reduction in
the number of red blood cells and increased each cell’s likelihood of exposure to an oxygen transfer surface
(bubble). Arterial oxygen tension during CPB was generally elevated, and additional crystalloid was given to
maintain hemodilution if oxygen tension started to fall with diuresis.
A special impetus to the development of asanguinous prime techniques was provided by members of the
Jehovah’s Witness faith, who totally refuse to accept transfusions of blood or blood products, although they will
allow their own blood to circulate outside their bodies, as long as fluid continuity is constantly maintained in the
CPB circuit. The use of asanguinous priming techniques has permitted cardiac operations, including
transplantation, to be performed in more than 1,000 Jehovah’s Witnesses at the Texas Heart Institute alone
(10,11). These patients constitute a unique “control” group for comparison with patients who undergo other
techniques of blood conservation.
PHYSIOLOGIC CONSEQUENCES OF HEMODILUTION

Rheology of Blood
A detailed review of the rheologic properties of blood is beyond the scope of this chapter. However, some basic
definitions and concepts are required, because the changes in blood rheology induced by hemodilution are
central to any discussion of hemodilution physiology. Exhaustive reviews may be found elsewhere (12,13).
A force that is applied to an area of a liquid confined between two plates and that is sufficient to set the liquid in
motion is known as shear stress. The velocity at which the liquid moves in proportion to the separation of the
plates is known as the velocity gradient, or shear rate. The shear stress is proportional to the shear rate, and the
coefficient of proportionality is the fluid viscosity (Eq. 1).
For most uniform fluids, such as water, viscosity is constant; these are known as Newtonian fluids. The viscosity
of blood is not constant; rather, it depends on the shear rate when blood is flowing (Fig. 16.1). Therefore, blood
is a non-Newtonian fluid. Lower shear rates are associated with higher viscosity, because the cellular elements
and plasma proteins tend to aggregate, form rouleaux, and resist flow. This aggregation at low shear rates
primarily results from intracellular bridging by fibrinogen; as flow rates increase, these bridges disintegrate. Non-
Newtonian behavior of blood is also influenced by the effective cell volume (14). When solid particles (cells) are
added to a fluid, they influence viscosity not only by their absolute presence but also by their effect on the
surrounding fluid. The effective cell volume is the cell volume plus the surrounding fluid that behaves as though it
were a part of the cell—much like the earth and its atmosphere. Red blood cells are deformable, and as shear
rates increase, the cells tend to form ellipsoid shapes, with their major axes aligned with the direction of flow.
This latter effect, combined with the disaggregation of red blood cells, causes blood to behave in a more
Newtonian manner at higher velocity gradients.
FIGURE 16.1. Viscosity change (in centipoise [cP]) plotted against shear rate (in per second) in a patient whose
hematocrit (HCT) decreased from 37% to 17% after hemodilution at the initiation of cardiopulmonary bypass
(CPB). (Modified from Gordon RJ, Ravin M, Rawitscher RE, et al. Changes in arterial pressure, viscosity and
resistance during cardiopulmonary bypass. J Thorac Cardiovasc Surg 1975;69:552-561, with permission.)
One further concept about the behavior of fluids is important. The amount of shear stress that is necessary to
cause a stationary Newtonian liquid to begin moving is zero or nearly zero. As a non-Newtonian substance,
blood, because of its cellular geometry and aggregation, must be induced to flow by a force known as the yield
stress. At low shear rates, the yield stress represents part of the viscous resistance and depends on both
fibrinogen and hematocrit (15).
Circulatory Effects
Both organ blood flow and total cardiac output are directly proportional to the perfusion pressure and inversely
related to total peripheral resistance (Eq. 2A). This resistance to flow
P.423
is proportional to vascular resistance and the viscosity of the perfusate (Eq. 2B).
These relations are often specifically expressed in the Hagen-Poiseuille equation (Eq. 3):
where Q equals flow, P1dP2 equals the pressure drop along a tube of radius R and length L, and μ equals
viscosity. For measuring blood flow, this equation is limited, because it is accurate only for assessing the laminar
flow of Newtonian liquids in long tubes with rigid walls. However, the equation does serve to further emphasize
the influence of viscosity and vascular geometry on flow. In humans, the aorta and larger vessels provide little
impedance to blood flow; most of the vascular resistance comes from the smaller vessels: the arterioles,
capillaries, and venules. As the vessel diameter decreases, the shear rate also decreases, and because blood
viscosity is inversely related to the shear rate, viscosity increases as flow decreases. As a result, peripheral
resistance also increases. Flow is lowest and viscosity highest in the postcapillary venules (16).
These physiologic effects are potentially quite harmful if CPB is performed without considering viscosity. In most
centers, modern CPB involves the use of flow rates that are somewhat lower than those of “normal” blood: 50
mL/kg/min or 2.0 L/m2/min. Frequently, hypothermia is also used if flow rates are further reduced to provide a
bloodless operative field. In addition, hypothermia is commonly used to augment myocardial and cerebral
protection. Reductions in both flow rate and perfusion pressure would tend to increase viscosity and, thereby,
peripheral resistance. In turn, this would decrease tissue perfusion. Hemodilution works to limit the adverse
effects of CPB by significantly reducing blood viscosity during bypass. Because there is a direct relationship
between viscosity and hematocrit (12) (Fig. 16.1), a reduction in hematocrit produces a marked decrease in total
resistance and an increase in tissue perfusion (Eq. 2B). For example, in canine experiments, a decrease in
hematocrit from 42% to 25% produces a 50% increase in flow at the same pressure (16). Extremes of
hemodilution (hematocrit <10%) permit blood to act as a Newtonian fluid (17).
Clinically, the most noticeable effect of hemodilution is a marked reduction in the perfusion pressure at initiation
of CPB. Gordon et al. (12) showed that when hemodilution is used to decrease the hematocrit and when the flow
rate on CPB is held constant, the perfusion pressure decreases in direct proportion to the change in viscosity
(Fig. 16.2). Additionally, Guyton and Richardson (18) found that hemodilution passively increases venous return
in dogs; this is probably attributable to the marked increase in flow in the small vessels, especially the
postcapillary venules (Fig. 16.3). Cooley et al. (6) noted this same phenomenon during CPB in humans.
FIGURE 16.2. Change in perfusion pressure versus change in viscosity in a series of patients undergoing
cardiopulmonary bypass at constant flow rates. (Modified from Gordon RJ, Ravin M, Rawitscher RE, et al.
Changes in arterial pressure, viscosity and resistance during cardiopulmonary bypass. J Thorac Cardiovasc
Surg 1975;69:552-561, with permission.)
FIGURE 16.3. Decreasing viscosity leads to increasing venous return (at a constant right atrial pressure). Hct,
hematocrit. (Reprinted from Guyton AC, Richardson TQ. Effect of hematocrit on venous return. Circ Res 1961;9:
157-164, with permission.)
P.424
FIGURE 16.4. Relationship between blood viscosity (in centipoise [CP] at a constant shear rate of 213/s) and
temperature. Hct, hematocrit. (Reprinted from Rand PW, Lacombe E, Hunt HE, et al. Viscosity of normal human
blood under normothermic and hypothermic conditions. J Appl Physiol 1964;19:117-122, as modified by Gordon
RJ, Ravin MB, Daicroff GR. Blood rheology. In: Cardiovascular physiology for anesthesiologists. Springfield, IL:
Charles C. Thomas Publisher, 1979:27-71, with permission.)
The addition of induced hypothermia to CPB further influences the rheologic behavior of blood. A temperature
reduction decreases flow by inducing direct vasoconstriction and increasing viscosity (19) (Fig. 16.4). However,
this relationship is not as direct as that of hematocrit and viscosity. For example, a temperature decrease of 10°C
causes an approximately 20 to 25% increase in viscosity. Of course, this adverse effect of hypothermia is
partially or completely offset by the planned reduction in oxygen consumption.
Organ blood flow during hemodilution reflects the interplay of all these concepts. In animals with progressive
normovolemic hemodilution to a hematocrit of 19%, oxygen tension has been shown to increase in the skeletal
muscle, liver, pancreas, small intestine, and kidneys (16). Cerebral blood flow during hemodilution also has been
shown to increase by 50% to 300% when compared with prebypass levels (20,21). Decreases in the hematocrit
correlate with increases in cerebral blood flow velocity, as measured by transcranial Doppler (22). However,
because cerebral flow is also significantly influenced by local autoregulation, changes in carbon dioxide tension
(PCO2), and extremes of perfusion pressure (23), absolute statements about the regional benefits of
hemodilution are difficult to make. Nevertheless, hemodilution, in general, appears to have a salutary effect.
An exceedingly important consequence of hemodilution during CPB is an “uncoupling” of the normal relationship
between perfusion pressure and blood flow. Therefore, perfusion pressure cannot serve as a marker of
adequate flow, because pressure is a function of two variables: flow and viscosity. This pivotal concept bears
directly on both the incidence and the causes of complications associated with the use of CPB (discussed later).
Hemodilution, Anesthetic Agents, and Adjuvants

Anesthetic agents and vasoactive adjuvant drugs can influence vascular geometry during CPB and thereby alter
vascular resistance; these effects are independent of the effects related to hemodilution. Hemodilution can also
alter the pharmacokinetics and pharmacodynamics of drugs, principally by dilution and decreased protein
binding. Although the total drug concentration is usually decreased during CPB because of dilution, the amount
of free active drug probably changes little because of decreased protein binding (24). During CPB, drug kinetics
are also influenced by temperature, pH, oncotic pressure, and, sometimes, sequestration in the CPB circuit or
the excluded vascular beds (i.e., the pulmonary vascular bed). These multiple factors make the study of drug
activity during CPB interesting but exceedingly difficult (25).
Considerations in Oxygen Transport

Hemoglobin Physiology
Oxygen transport is the movement of molecular oxygen from the atmosphere to the cellular mitochondria. This
movement depends on oxygen availability, cardiac output, hemoglobin, tissue perfusion, and the tissues’ ability
to extract oxygen. Hemoglobin provides a tremendous physiologic advantage to the process of oxygen transport,
in that relatively larger volumes of oxygen can be brought to the tissues by oxygen bound to the hemoglobin
molecule than could be transported in a simple solution in the plasma.
Reduction of hemoglobin concentrations to below normal levels still permits adequate oxygen transfer. In fact,
when oxygen transport is expressed as the product of cardiac output and oxygen-carrying capacity and is plotted
against changes in the hematocrit (Fig. 16.5), maximal delivery occurs at a hematocrit of approximately 30%;
more importantly, delivery decreases only approximately 10% below normal between hematocrits of 20% and
50% (26). This preservation of oxygen delivery obviously depends on a compensatory increase in the cardiac
output at lower hematocrit ranges. Hemoglobin concentrations are reduced as a normal consequence of CPB
with hemodilution. Without an increase in the cardiac output, such a reduction will decrease oxygen delivery, but
this is usually well tolerated clinically. The lower limit to which hemoglobin can be reduced under any
circumstance without a compromise in patient safety is not absolutely clear (as discussed later). On the basis of
the previously described oxygen transport concepts, a hemoglobin concentration of 10 g/dL was traditionally
(and institutionally) accepted as adequate for patients undergoing noncardiac surgery; however, it has
P.425
now been shown that a level of 8 g/dL does not increase the frequency of adverse events (27).
FIGURE 16.5. Oxygen transport versus hematocrit level, showing an approximate 10% change in oxygen
transport (cardiac output times oxygencarrying capacity) between hematocrits of 20% and 50%. (From Le Veen
HH, Ip M, Ahmed N, et al. Lowering blood viscosity to overcome vascular resistance. Surg Gynecol Obstet
Environmental Effects
The oxygen-carrying capacity of hemoglobin is influenced by pH, PCO2, temperature, concentration of 2,3-
diphosphoglycerate (2,3-DPG), and the specific type of hemoglobin. These factors may shift the oxygen-
hemoglobin dissociation curve to the right (resulting in easier dissociation of oxygen from hemoglobin—a higher
P50 value) or to the left (resulting in more firmly attached oxygen—a lower P50 value). Metabolic acidosis,
hypercarbia, hyperthermia, increased levels of 2,3-DPG, and anemia shift the curve to the right, whereas
metabolic alkalosis, hypocarbia, decreased 2,3-DPG, and hypothermia shift the curve to the left. Abnormal forms
of hemoglobin may have a normal, increased, or decreased affinity for oxygen. The absolute clinical significance
of each of these influences is not known.
Physiology of Chronic Anemia

Chronic anemia, or reduction in the volume of circulating red blood cells, tends to develop gradually and permit
compensation. These compensatory mechanisms include an increase in the plasma volume to maintain a
euvolemic or even a hypervolemic state, an increase in the heart rate and stroke volume, and a passive (but
real) increase in the cardiac output as a result of decreased viscosity. In healthy humans, this process occurs
with little or no increase in myocardial oxygen extraction (16). Another compensatory mechanism is increased
oxygen extraction by tissues, often associated with a decrease in the affinity of hemoglobin for oxygen (produced
by an increase in the 2,3-DPG level in the red blood cells). This mechanism is not usually operative at
hemoglobin levels that continuously exceed 7 g/dL (16).
Reduction in physical activity with a subsequent decrease in oxygen consumption is an important additional
mechanism. Chronically anemic patients whose anemia is well compensated may be compromised if metabolic
demands are increased (e.g., by enhanced physical activity, fever, or an intrinsic or acquired heart disease that
renders the heart unable to increase its output). In this context, anesthetized patients will have improved
tolerance to anemia because of reduced total body oxygen consumption (overall, ˜15%) and, especially, a
reduced myocardial oxygen demand (28). Hypothermia is an important physiologic method for reducing oxygen
utilization by tissues and has a greater or lesser role to play, depending on the clinical circumstances. Again,
anesthesia has a significant role, because the compensatory mechanisms that maintain normothermia, such as
shivering, are blocked by anesthesia and muscle relaxation.
The acute anemia produced by hemodilution coupled with lower-than-normal flow rates at CPB initiation must
also be associated with operative compensatory mechanisms to permit adequate oxygen delivery. These include
general anesthesia and muscle relaxation, normovolemia, improved microcirculatory perfusion as a consequence
of decreased viscosity, and, often, induced hypothermia.
Whereas chronic anemia is generally well tolerated in most patients, as discussed below, this and acute anemia
of some degree are associated with less favorable outcomes that affect specific organ systems and increase the
risk of death. The exact physiologic reasons for this association are yet to be determined and may involve more
subtle factors than just inadequate oxygen transport (29).
Hemodilution and Complications of Cardiopulmonary Bypass

Despite the early success of open-heart operations in which CPB was used, a high rate of complications was
common. Specifically, CPB was associated with postoperative neurologic, pulmonary, and renal dysfunction, all
of which occurred at both high and low flow rates; each of these complications was attributed to a variety of
physiologic or clinical factors.
Neurologic dysfunction was thought to be associated with low perfusion pressures. Stockard et al. (30)
mathematically related an increased incidence of neurologic complications to the degree and duration of
hypotension. Pulmonary
P.426
complications (postperfusion pulmonary insufficiency, or “pump lung”) were attributed to parenchymal hypoxia,
pulmonary venous distension, the oxygenator itself, or other mechanical factors (31). Renal failure was primarily
related to a low perfusion pressure and, secondarily, to a low urine output during CPB (32). In reporting their first
100 cases involving hemodilution with dextrose and water prime, Cooley et al. (6) anecdotally noted a reduction
in postoperative cerebral, pulmonary, and renal complications. Hemodilution may have been instrumental in the
reduction of CPB-related morbidity for each of these organ systems.
The uncoupling of flow and pressure with hemodilution, as discussed earlier, modifies the relationship between
perfusion pressure and neurologic complications. In all the patients described by Stockard et al. (30), blood
prime was used for CPB. The relationship between perfusion pressure and the incidence of neurologic
complications disappeared once hemodilution began to be universally adopted (33,34). Govier et al. (35) and
Prough et al. (36) also described the maintenance of cerebral autoregulation in patients undergoing hemodilution
at varying flow, temperature, and PCO2 levels.
Similar differences in reports of renal dysfunction with and without blood priming are also revealing. Bhat et al.
(32) found that bypass time, low perfusion pressure, volume of urine formed during CPB, and hemoglobinemia
were factors for postoperative dysfunction when blood prime was employed. In 1976, Abel et al. (37) found none
of these factors to be predictive when hemodilution was used. However, at that time, it appeared that in the
absence of low cardiac output before or after CPB, or in the absence of excessive perioperative transfusion,
preoperative renal dysfunction was the only predictor of postoperative dysfunction (34). More recent evidence
has made this point debatable (38).
Postperfusion respiratory failure still occurs for multiple reasons, but these are often related to extrapulmonary
factors (39). Since the 1960s, “pump lung” has markedly decreased in incidence, at least partly because of
hemodilution techniques (6,40).
Another problem, referred to as homologous blood syndrome, was blamed for both intraoperative and
postoperative bleeding diatheses and also for contributing to postoperative cerebral, pulmonary, and renal
dysfunction (41). The syndrome was sometimes thought to result from incompatibility or cross-reactions between
the patient and one or more of the multiple units of donor blood used in the prime. More likely, with correct donor-
patient cross-matching, homologous blood syndrome was a reaction that occurred when units of homologous
blood from different donors were mixed together in the CPB circuit before bypass. Whatever the exact
mechanism, this complication, too, disappeared with the introduction of crystalloid priming.
Hemodilution is not solely responsible for the reduction in complications associated with CPB. Other factors,
such as more accurate initial diagnoses, improved anesthetic methods, better CPB equipment, and quicker
recognition and treatment of ventricular failure, have all contributed. Specifically, blood filtering helps decrease
pulmonary complications (42), and reduced suctioning of the operative field helps reduce hemolysis, thereby
decreasing the incidence of renal dysfunction.
PRIMING SOLUTIONS
Crystalloid Primes
Currently, the use of a crystalloid priming solution is the norm during CPB. There is probably as much
institutional variation in specific primes and components as there is in cardioplegic solutions, because both of
those elements have developed in an empiric manner. In general, all modern priming solutions have a similar
electrolyte-to-plasma content and a similar osmolarity. A balanced salt solution, such as lactated Ringers, with or
without glucose, is a common, basic prime. Many clinicians believe that the addition of colloid may be justified in
longer-than-normal perfusion procedures to prevent the development of excessive edema. In addition to
institutional variations in the types of priming fluids used, differences in the volume are also common, as a
consequence of the differences in priming requirements for the variety of oxygenators, connective tubes, and
arterial filters employed. Some institutions have a “standard” prime volume that is used for all adult patients,
whereas other institutions vary the volume, depending on the patient’s weight or body surface area. There has
been a relatively recent movement to decrease circuit volumes in an attempt to limit the degree of hemodilution.
This is probably especially important in smaller or anemic patients. Each specific oxygenator-tubing system will
obviously have a minimum “safe” priming volume—that is, one that will allow the initiation of CPB without an
undue risk of air embolism and will permit adequate flow rates. Adequate flow should never be compromised, and
an air embolism remains a major potential complication of CPB.
The degree of hemodilution can be predicted on the basis of the patient’s weight and hematocrit, the amount of
intravenous fluids administered before CPB, and the oxygenator priming volume. The blood volume of adults can
be approximately calculated by multiplying the weight of the patient in kilograms by 7% (for women) or 7.5% (for
men) (Table 16.2). If use of the intended prime volume causes unacceptable hemodilution, packed red blood
cells can be added to the CPB circuit to compensate for this occurrence.
Children, especially infants, present a special challenge, because pediatric CPB circuits, even with efforts at
miniaturization, have a minimum priming volume that is often larger than an infant’s blood volume; therefore,
blood must usually be added empirically to the prime to achieve an appropriate hemodilution in most institutional
protocols. The acceptable range for the hematocrit is essentially the same for children and adults, but in many
institutions this range has changed, because there is evidence that higher hematocrits in children
P.427
under certain conditions lead to fewer complications (as discussed below and in Chapter 28).
TABLE 16.2. Prediction of initial hematocrit during cardiopulmonary bypass
• One unit of RBCs or whole blood equals approximately 150 mL of RBC volume.
• Estimated blood volume is equal to the patient’s weight × 0.08-0.085 for infants, 0.075 for children and
men, and 0.07 for women.
CPB, cardiopulmonary bypass; Hct, hematocrit; RBC, red blood cell.
Allowable Hemodilution
The degree of allowable hemodilution is an important consideration in the composition of the initial prime. There
are large institutional variations in the range of “acceptable” hemodilution. In general, because hemodilution has
a salutary effect on perfusion and because there is a theoretical decrease in microcirculatory flow with a
hematocrit above 30% (16), many centers try to achieve a hematocrit below 30% during CPB. With priming
volumes in the range of 1,400 to 2,000 mL, this goal is easily achieved in most adults. Patients with large blood
volumes, high hematocrits, or both, may require a prepump phlebotomy or additional dilution while undergoing
CPB (Table 16.2). Although not a new technique, performing an immediate prepump phlebotomy in
hemodynamically stable patients has become more popular in recent years at many centers; whereas the goal is
to promote blood conservation and perhaps improve the patient’s postpump coagulation status, direct evidence
for this effect is lacking. However, withdrawing blood into standard transfusion bags in a sterile manner,
preserving it in the operating room, and transfusing it immediately after protamine administration is generally
regarded as a benign technique with few risks and some possible benefits.
The reverse technique, a concept called retrograde autologous priming, is used at some institutions. In this
approach, a combination of positioning and vasoconstriction is used to “prime” the venous tubing of the heart-
lung machine before the initiation of bypass, thereby decreasing the degree of hemodilution. This technique has
not been well studied in terms of complications and has not been found to appreciably decrease the incidence of
transfusion (43).
Hypothermia also influences the acceptable hematocrit range, but guidelines are again institutional. Because of
the viscosity-flow relationship and the influence of hypothermia, it is appropriate to target a hematocrit of less
than 30% if the temperature is reduced to 30°C; lower hematocrits, generally below 25%, are preferred at some
institutions if temperatures are to be reduced below 25°C, though there is little direct evidence for this practice.
Experimental evidence suggests that a hematocrit below 20% may be associated with an abnormal distribution of
flow to the organs (44,45). However, if it is of short duration, a hematocrit below this level appears to be well
tolerated clinically by most patients, and values in the range of 15% to 18% are commonly seen during the initial
stages of CPB. Physiologic compensatory mechanisms may be involved in addition to the benefits of anesthesia
and hypothermia. Even extreme hemodilution to a hematocrit below 15%, as used by some centers for
hypothermic circulatory arrest or as sometimes seen in Jehovah’s Witness patients (11), appears to be clinically
well tolerated (46). This concept has been challenged, however, at least for pediatric hypothermic circulatory
arrest, by researchers who observed that cerebral recovery was improved in animal experiments in which the
hematocrit was maintained at 30% (47) and that outcomes were improved in infants maintained at higher
hematocrit levels (48,49).
When considering CPB management of patients whose hematocrit levels are below an institutional minimum—
specifically when considering whether transfusion should be used—the reasons for the low hematocrit values
must be evaluated before transfusion is initiated. Table 16.3 lists multiple factors that affect the hematocrit value
during CPB. Obviously, efforts to limit their influence, including establishing
P.428
meticulous initial hemostasis, conserving prepump intravenous fluids, and minimizing the priming volume (if
possible), can affect each patient differently. Also, the timing of blood sampling may have an influence. A sample
taken shortly after the initiation of CPB may show more apparent hemodilution than would a sample drawn later
with no other intervention, when greater equilibration has been achieved between the prime and the patient’s red
blood cell volume. The initial sample, even if timed appropriately, usually has the lowest hematocrit of all the
samples obtained in routine CPB cases, because both equilibration and fluid loss to the interstitial space tend to
cause hemoconcentration as bypass progresses. In general, transfusion decisions should not be based on the
first hematocrit reading, unless the clinician is convinced that the patient is hypovolemic, that treating the
hypovolemia with crystalloid or another nonblood fluid will reduce the hematocrit further, and/or that the value is
far outside institutional norms. During CPB, hemoconcentration (ultrafiltration) devices in the circuit may be used
as an alternative to transfusion, if patients are anemic and have a very large circulating volume. However, when
using hemoconcentration techniques, one should be aware that patients with large hearts may require large
volumes to fill the cardiac chambers when CPB is discontinued.
TABLE 16.3. Factors that affect hematocrit during cardiopulmonary bypass (CPB)
Patient’s weight: Blood volume depends on weight, so the hemodilution effect is greater in large patients
and lesser in small patients.
Sex: Female patients are generally smaller, with smaller blood volumes and lower starting hematocrits.
Preoperative anemia/polycythemia.
Preoperative hypovolemia/hypervolemia.
CPB circuit volume: In many cases, it may be possible to reduce this variable by adjusting the size and
length of tubing.
CPB prime volume: There is a minimum priming volume for each circuit.
Pre-CPB blood loss.
Pre-CPB volume administration.

Crystalloid cardioplegia volume: This factor has additional dilutional effects.
Added crystalloid or colloid prime is needed to maintain normal flow rates.
Over the last several years, questions have been raised concerning hematocrit levels during CPB and their
association with outcome. Several separate reports concerning adult patients have described an association
between the nadir hematocrit during CPB and an increased incidence of postoperative complications
(38,50,51,52,53,54), including neurologic, myocardial (low-output syndrome), pulmonary, and renal problems,
longer hospital stays, and increased mortality. Most studies show the strongest association between the nadir
hematocrit during CPB and renal complications. However, other studies have shown different hematocrit levels
that appeared important, ranging from 14% to 25%. All the authors of these studies advocate keeping hematocrit
levels above a certain value by limiting hemodilution in various ways, and none of the authors promote
intraoperative transfusion itself as a method of compensating for lower hematocrit levels. In terms of gender, a
recent large retrospective study suggested that female cardiac surgical patients had a higher overall mortality
rate than male patients and similar susceptibility to renal injury and mortality with greater hemodilution during
CPB. However, among patients with severe hemodilution (i.e., lowest hematocrit ≤22%), women’s rate of renal
injury was no higher than men’s, and men had a higher mortality rate (55). Some of these authors, as well as
others (56,57), have also shown that patients who require transfusion have an increased rate of complications
other than the common ones of infectious disease and transfusion reactions. It is easy to assume that “sick,”
high-risk patients with multiple comorbidities will also have lower initial hematocrit levels, require more
transfusions, and have more perioperative complications associated with their degree of illness, anemia being
only a marker for their high risk. The Society of Thoracic Surgeons and Society of Cardiovascular
Anesthesiologists clinical practice guidelines also admit that there is a lack of hard data regarding CPB
transfusion triggers, and these guidelines are mostly based on expert opinion. In general, they recommend
transfusion for “healthy” patients who have hemoglobin levels of 6 g/dL or less and transfusion for patients who
have compromised organ systems, with hemoglobin levels of 7 g/dL or lower (58,59). The question of transfusion
efficacy during CPB and transfusion’s absolute effect on outcome remains unresolved (60).
Another consideration regarding allowable hemodilution levels is an acceptable hematocrit for weaning from
CPB. Here too, there are many institutional variants and few specific data. Because maldistribution of coronary
flow away from the subendocardium occurs experimentally with a hematocrit at or below 15% (45,61), especially
if the coronary circulation is compromised, it would seem prudent to separate patients from bypass only if they
have a hematocrit above this level. Evidence of myocardial ischemia would be a further reason to transfuse.
Many clinicians will choose to transfuse if they know or strongly suspect that cardiac output will be compromised
when the patient emerges from bypass. Again, no absolute levels are associated with an improved outcome in
this subset of patients. An argument against maintaining a higher hematocrit (≥34%) is that it has been
associated with a greater risk of Q-wave myocardial infarction, worsened left ventricular function, and mortality
after coronary artery bypass grafting (62).
The safety of hemodilution, especially with crystalloid solutions, was initially questioned because of fear of
increased postoperative bleeding secondary to dilutional coagulopathy. These fears proved unfounded in
general, even with extreme hemodilution (63). In polycythemic patients with congenital heart disease, adequate
hemodilution (hematocrit <30%) has been associated with a decreased incidence of postoperative
coagulopathies (64).
Use of Glucose
For the last several years, there has been considerable debate over intraoperative glucose management (65)
and intraoperative use of glucose-containing fluids in general. Originally, data from a series of noncardiac
surgical cases showed an association between a worsened neurologic outcome and hyperglycemia (66). These
data subsequently affected the management of the CPB prime because the use of glucose-containing fluids was
widespread. However, more recent data regarding management of intraoperative glucose have shown improved
outcomes, particularly in patients with wound infections, when the blood glucose concentration is tightly
controlled than when hyperglycemia is treated in a less rigid manner. A focus on more rigid control of glucose
levels in critically ill patients in the intensive care unit has led to efforts by many clinicians
P.429
to maintain glucose levels during CPB that are lower than some arbitrary value by using insulin infusions and
removing glucose from crystalloid priming solutions (67).
In contrast, Metz and Keats (68) have shown that the addition of glucose to priming solutions raises the osmotic
pressure of the prime and significantly reduces perioperative fluid requirements and postoperative fluid retention.
Also, use of insulin infusions in patients undergoing CPB has been associated with postoperative hypoglycemia,
which is another risk factor for neurologic complications (69). The seeming lack of complications in the use of
glucose during CPB for many years may relate to the putative mechanism of injury, because both animal and
human data suggest that central-nervous-system damage associated with hyperglycemia occurs when either a
global or a focal injury is followed by immediate reperfusion of the ischemic area (70). In the absence of a low
cardiac output, cerebral injury after CPB is almost always embolic in origin, and affected areas would not be
expected to be reperfused immediately. Nevertheless, efforts at intraoperative glucose control—specifically
during CPB—are very appealing, despite the demonstrable beneficial effects with regard to fluid requirements.
Because attempts to maintain rigid control of glucose have been associated with an increased incidence of
hypoglycemia and worsened outcomes, many physicians do not maintain such control and, instead, accept
values of around 200 mg/dL.
The use of glucose may be advocated for patients in whom the maintenance of high osmotic pressure in the
CPB prime is important and for whom use of blood-derived colloidal solutions may be restricted (such as
members of the Jehovah’s Witness faith).
Colloidal Prime
A consequence of hemodilution in CPB is the decrease in the plasma colloidal oncotic pressure secondary to
dilution of the circulating plasma proteins. This may result, especially in the absence of glucose, in increased
movement of fluid out of the vascular space and into the interstitial and intracellular spaces, which can lead to
postoperative edema, as well as lung or other organ dysfunction. In an effort to attenuate these changes, the
addition of colloidal particles to a crystalloid prime, or even the use of a colloidal solution as the principal priming
fluid, has been advocated. Solutions that have been used include 5% and 25% albumin, low- and high-
molecular-weight dextran, 5% plasma protein fraction, 6% hydroxyethyl starch (now removed by the Food and
Drug Administration from clinical use in the United States due to associated complications (71)), and human
plasma. These solutions have been compared, in various combinations, with a crystalloid prime alone or with
each other. Differences in lung water or total body water are reported between groups, most notably immediately
after bypass, but these differences tend to diminish quickly in the immediate postoperative period (72,73). The
relative importance of colloid in short-term CPB is therefore hard to judge, and individual decisions can be made
on the basis of availability and cost. No significant harm seems associated with synthetic or heat-treated colloid,
but there is an increased economic cost. Human plasma should not be used without a specific indication, usually
a clinically apparent and laboratory-documented bleeding diathesis. Patients undergoing cardiac transplantation
or implantation of a left ventricular assist device are examples of those who may present for surgery with a
significant coagulopathy due to a low cardiac output, liver dysfunction, or pharmacologic therapy; in these
patients, there is little chance of resolving the coagulopathy issues before CPB, and addition of plasma may be a
method for attenuating postpump coagulopathy.
Other Additives
Table 16.4 lists additional components that have been used for varying reasons in primes, with the rationale for
the use of each one. Much institutional variation exists here as well.
Experimental Priming Solutions

The use of oxygen-carrying solutions in CPB has paralleled their experimental use as blood substitutes in
noncardiac surgery and has been confined to four types: perfluorocarbons, cross-linked hemoglobin,
polymerized hemoglobin, and conjugated hemoglobin. The evaluation of these liquids, which can carry relatively
large amounts of dissolved oxygen in comparison with untreated human plasma, has been under way for several
years. Benefits of their use include the ability to permit oxygen delivery even in the face of profound native
anemia.
TABLE 16.4. Additional components for cardiopulmonary bypass priming solutions
Component Amount Rationale
Heparin 10-25 mg Provides an additional safety factor if systemic heparinization is

(1,000-2,500 inadequate
U)/L of priming
volume
Calcium 200 mg/L of Prevents chelation of circulating calcium if citrated blood is added
priming volume to the prime; may be especially important in pediatric patients
because of frequent use of blood in the prime
Mannitol 25-50 g Helps prevent tissue edema and induce an osmotic diuresis
Corticosteroids Variable Prevents or attenuates activation of inflammatory processes by

P.430
Because they are insoluble in blood, perfluorocarbons (also known as fluorocarbons) must be emulsified before
use. They are nearly chemically inert substances with a high natural solubility for oxygen. Their oxygen solubility
is linear, unlike that of hemoglobin, so they are able to release oxygen in environments that have a very low
partial pressure of oxygen (74). The release of oxygen by perfluorocarbons is not related to pH or temperature
(75). Perfluorocarbon particles are small (0.118 μm), and their viscosity is roughly half that of blood; these
characteristics allow them to bypass stiffened red blood cells readily and to perfuse distal capillary beds (74).
However, when perfluorocarbons were used in Jehovah’s Witness patients who were profoundly anemic, their
survival rate did not increase (76).
Substitution of a hemoglobin-containing solution for the transfusion of red blood cells would seem ideal because
of hemoglobin’s natural oxygen-carrying capacity and osmotic activity in solution. Hemoglobin solutions have a
number of benefits over banked blood: they are readily available and have a long shelf life, and they do not
require blood typing or cross-matching (77). Although hemoglobin solutions have generally been thought to be
free of infectious contamination, this assumption has been questioned (78). They do not cause
immunosuppression, as blood can. The viscosity of hemoglobin-based substitutes, like that of perfluorocarbons,
is low. Bovine hemoglobin, chemically cross-linked to prevent its filtration by the kidneys, has a low oxygen
affinity, similar to that of human hemoglobin in erythrocytes (79).
Despite promising theoretical advantages and a great deal of effort by many researchers and organizations over
the last two decades, hemoglobin-based blood substitutes are not used clinically in the United States. This is
mainly because of safety concerns, including adverse physiologic effects, such as vasoconstriction, which may
occur because of modulations these compounds make in the nitric-oxide levels and the microcirculation (80).
Thus, blood substitutes remain at various stages of evaluation, and though some are used in other countries,
none appears close to release for use in the United States (81).
ASSESSING ADEQUACY OF PERFUSION WITH HEMODILUTION

As stated earlier, the most notable effect of the use of modern asanguinous priming solutions is a marked
decrease in perfusion pressure on institution of CPB. In almost all instances, this decrease is secondary to the
resulting hemodilution and the corresponding decrease in viscosity, not to dilution of circulating catecholamines
or vasodilation (Fig. 16.2). Because hemodilution results in uncoupling of the relationship between perfusion
pressure and blood flow, the adequacy of perfusion must be assessed by means other than blood pressure
measurement. Standard flow rates of 50 mL/kg/min or 2 L/m2/min are a tested reference, although they may be
modified by age, weight, or temperature.
Monitoring of organ perfusion is probably the most reliable method of determining adequate perfusion during
CPB with hemodilution; however, clinical methods of monitoring are most often indirect and may be inadequate.
Global cerebral function can be monitored by electroencephalography, blood flow velocity by transcranial
Doppler, and oxygen saturation by near-infrared spectroscopy (NIRS), but whether such monitoring confers the
ability to detect and modify an impending central-nervous-system adverse event is open to question. Further
study, especially with NIRS, is ongoing and encouraging. Because some degree of anemia may contribute to
significantly lowered NIRS values, one of several possible clinical responses to such values is transfusion,
though presently no specific hematocrit level triggers correlated with NIRS values are known (82). The obvious
parameter of renal function, urinary output, is easily and virtually uniformly measured, but clinical studies have
shown that the volume of urine produced during CPB has little or no bearing on postoperative renal function.
Measurement of arterial blood gases will monitor oxygenator function, and measurement of mixed venous oxygen
tension may detect inadequate perfusion. However, normal mixed venous oxygen tension does not ensure
adequate regional perfusion, because it may not reflect local organ conditions.
SUMMARY
In summary, hemodilution probably represents the most significant advance in CPB technique after the
development of the pump oxygenator itself. Hemodilution permits the maintenance of organ homeostasis
under what would otherwise often be inadequate circumstances, thereby decreasing complications and
conserving blood resources. Despite all that has been learned during more than 60 years of CPB use, the
absolute limits of hemodilution are still largely uncertain.
KEY Points
Hemodilution
Advantages of hemodilution include:
Decreased blood viscosity.
Improved regional blood flow.
Improved oxygen delivery to tissues.
Decreased exposure to homologous blood products.
Improved blood flow at lower perfusion pressure (lower shear stress), especially during
hypothermic perfusion.
Hemodilution affects the pharmacokinetic and pharmacodynamic properties of drugs used during
CPB, predominantly by changing protein binding through dilution of plasma proteins.
Hemodilution decreases bypass-related complications (neurologic, renal, and pulmonary), but there
appears to be an association between a hematocrit below a certain level and increased
complications.
P.431
CPB Priming Solutions
Crystalloid priming solutions are the norm in the present-day practice of CPB.
The most commonly used solutions are “balanced salt” or “physiologic saline” types.
The use of 5% dextrose was once common, but complications associated with hyperglycemia have
led to its withdrawal in most practices.
Hyperglycemia during and after CPB may predispose the patient to neurologic damage and
infectious complications, but rigid control efforts can have adverse consequences.
Colloidal solutions (e.g., albumin, hydroxyethyl starch) are widely used empirically as priming
components, though whether they have clear benefits is questionable.
Oxygen-carrying colloidal solutions of perfluorocarbons or hemoglobin have much promise, but
unanticipated problems with efficacy and safety have significantly delayed their clinical use in the
United States.
REFERENCES
1. Gibbon JH Jr. Application of a mechanical heart and lung apparatus to cardiac surgery. Minn Med
1954;37:171-185; passim.
2. Kirklin JW, Donald DE, Harshbarger HG, et al. Studies in extracorporeal circulation. I. Applicability of
Gibbon-type pump-oxygenator to human intracardiac surgery: 40 cases. Ann Surg 1956;144:2-8.
3. Lillehei CW, Cohen M, Warden HE, et al. The results of direct vision closure of ventricular septal defects
in eight patients by means of controlled cross circulation. Surg Gynecol Obstet 1955;101:446-4660.
4. Dewall RA, Lillehei RC, Sellers RD. Hemodilution perfusions for open-heart surgery. Use of five per cent
dextrose in water for the priming volume. N Engl J Med 1962;266:1078-1084.
5. Cohen M, Lillehei CW. A quantitative study of the azygos factor during vena caval occlusion in the dog.
Surg Gynecol Obstet 1954;98:225-232.
6. Cooley DA, Beall AC Jr, Grondin P. Open-heart operations with disposable oxygenators, 5 per cent
dextrose prime, and normothermia. Surgery 1962;52:713-719.
7. Greer AE, Carey JM, Zuhdi N. Hemodilution principle of hypothermic perfusion. A concept obviating blood
priming. J Thorac Cardiovasc Surg 1962;43:640-648.
8. Long DM Jr, Sanchez L, Varco RL, et al. The use of low molecular weight dextran and serum albumin as
plasma expanders in extracorporeal circulation. Surgery 1961;50:12-28.
9. Panico FG, Neptune WB. A mechanism to eliminate the donor blood prime from the pump-oxygenator.
Surg Forum 1960;10:605-609.
10. Burnett CM, Duncan JM, Vega JD, et al. Heart transplantation in Jehovah’s Witnesses. An initial
experience and follow-up. Arch Surg 1990;125:1430-1433.
11. Cooper JR Jr. Perioperative considerations in Jehovah’s Witnesses. Int Anesthesiol Clin 1990;28:210-
215.
12. Gordon RJ, Ravin M, Rawitscher RE, et al. Changes in arterial pressure, viscosity and resistance during
13. Nichols WW, O’Rourke MF. The nature of flow of a liquid. In: Nichols WW, O’Rourke MF, eds.
McDonald’s blood flow in arteries. 4th ed. New York, NY: Oxford University Press, 1998:11-53.
14. Chein S. Present state of blood rheology. In: Messmer K, Schmid-Schoenbein H, eds. Hemodilution:
theoretical basis and clinical application. Basel: Karger, 1972:1-45.
15. Priebe HJ. Hemodilution and oxygenation. Int Anesthesiol Clin 1981;19:237-255.
16. Messmer K. Hemodilution. Surg Clin North Am 1975;55:659-678.
17. Laver MB, Buckley MJ. Extreme hemodilution in the surgical patient. In: Messmer K, Schmid-Schoenbein
H, eds. Hemodilution: theoretical basis and clinical application. Basel: Karger, 1972:215-222.
18. Guyton AC, Richardson TQ. Effect of hematocrit on venous return. Circ Res 1961;9:157-164.
19. Rand PW, Lacombe E, Hunt HE, et al. Viscosity of normal human blood under normothermic and
hypothermic conditions. J Appl Physiol 1964;19:117-122.
20. Lundar T, Froysaker T, Lindegaard KF, et al. Some observations on cerebral perfusion during
21. Lundar T, Lindegaard KF, Froysaker T, et al. Cerebral perfusion during nonpulsatile cardiopulmonary
22. Brass LM, Pavlakis SG, DeVivo D, et al. Transcranial Doppler measurements of the middle cerebral
artery. Effect of hematocrit. Stroke 1988;19:1466-1469.
23. Reves JG, Greeley WJ. Cerebral blood flow during cardiopulmonary bypass: some new answers to old
questions. Ann Thorac Surg 1989;48:752-754.
24. Levy JH, Hug CC Jr. Use of cardiopulmonary bypass in studies of the circulation. Br J Anaesth
1988;60:35S-37S.
25. Okutani R, Philbin DM, Rosow CE, et al. Effect of hypothermic hemodilutional cardiopulmonary bypass
on plasma sufentanil and catecholamine concentrations in humans. Anesth Analg 1988;67:667-670.
26. LeVeen HH, Ip M, Ahmed N, et al. Lowering blood viscosity to overcome vascular resistance. Surg
Gynecol Obstet 1980;150:139-149.
27. Carson JL, Poses RM, Spence RK, et al. Severity of anaemia and operative mortality and morbidity.
Lancet 1988;1:727-729.
28. Theye RA, Michenfelder JD. Individual organ contributions to the decrease in whole-body Vo2 with
isoflurane. Anesthesiology 1975;42:35-40.
29. Hare GM, Freedman J, David Mazer C. Review article: risks of anemia and related management
strategies: can perioperative blood management improve patient safety? Can J Anaesth 2013;60:168-175.
30. Stockard JJ, Bickford RG, Schauble JF. Pressure-dependent cerebral ischemia during cardiopulmonary
bypass. Neurology 1973;23:521-529.
31. Tilney NL, Hester WJ. Physiologic and histologic changes in the lungs of patients dying after prolonged
cardiopulmonary bypass: an inquiry into the nature of post-perfusion lung. Ann Surg 1967;166:759-766.
32. Bhat JG, Gluck MC, Lowenstein J, et al. Renal failure after open heart surgery. Ann Intern Med
1976;84:677-682.
33. Slogoff S, Girgis KZ, Keats AS. Etiologic factors in neuropsychiatric complications associated with
34. Slogoff S, Reul GJ, Keats AS, et al. Role of perfusion pressure and flow in major organ dysfunction after
tension during hypothermic cardiopulmonary bypass. Anesthesiology 1986;64:576-581.
37. Abel RM, Buckley MJ, Austen WG, et al. Acute postoperative renal failure in cardiac surgical patients. J
Surg Res 1976;20:341-348.
38. Karkouti K, Beattie WS, Wijeysundera DN, et al. Hemodilution during cardiopulmonary bypass is an
independent risk factor for acute renal failure in adult cardiac surgery. J Thorac Cardiovasc Surg
2005;129:391-400.
39. Matthay MA, Wiener-Kronish JP. Respiratory management after cardiac surgery. Chest 1989;95:424-
434.
40. Hepps SA, Roe BB, Wright RR, et al. Amelioration of the pulmonary postperfusion syndrome with
hemodilution and low molecular weight dextran. Surgery 1963;54:232-243.
41. Gadboys HL, Slonim R, Litwak RS. Homologous blood syndrome. I. Preliminary observations on its
relationship to clinical cardiopulmonary bypass. Ann Surg 1962;156:793-804.
42. Solis RT, Gibbs MB. Filtration of the microaggregates in stored blood. Transfusion 1972;12:245-250.
43. Murphy GS, Szokol JW, Nitsun M, et al. The failure of retrograde autologous priming of the
cardiopulmonary bypass circuit to reduce blood use after cardiac surgical procedures. Anesth Analg
2004;98:1201-1207.
P.432
44. Brazier J, Cooper N, Buckberg G. The adequacy of subendocardial oxygen delivery: the interaction of
determinants of flow, arterial oxygen content and myocardial oxygen need. Circulation 1974;49:968-977.
45. Race D, Dedichen H, Schenk WG Jr. Regional blood flow during dextran-induced normovolemic
hemodilution in the dog. J Thorac Cardiovasc Surg 1967;53:578-586.
46. Laver MB, Buckley MJ, Austen WG. Extreme hemodilution with profound hypothermia and circulatory
arrest. Bibl Haematol 1975;41:225-238.
47. Duebener LF, Sakamoto T, Hatsuoka S, et al. Effects of hematocrit on cerebral microcirculation and
tissue oxygenation during deep hypothermic bypass. Circulation 2001:104:I260-I264.
48. Jonas RA, Wypij D, Roth SJ, et al. The influence of hemodilution on outcome after hypothermic
cardiopulmonary bypass: results of a randomized trial in infants. J Thorac Cardiovasc Surg 2003;126:1765-
1774.
49. Wypij D, Jonas RA, Bellinger DC, et al. The effect of hematocrit during hypothermic cardiopulmonary
bypass in infant heart surgery: results from the combined Boston hematocrit trials. J Thorac Cardiovasc Surg
2008;135:355-360.
50. DeFoe GR, Ross CS, Olmstead EM, et al. Lowest hematocrit on bypass and adverse outcomes
associated with coronary artery bypass grafting. Northern New England Cardiovascular Disease Study
Group. Ann Thorac Surg 2001;71:769-776.
51. Habib RH, Zacharias A, Schwann TA, et al. Adverse effects of low hematocrit during cardiopulmonary
bypass in the adult: should current practice be changed? J Thorac Cardiovasc Surg 2003;125:1438-1450.
52. Ranucci M, Biagioli B, Scolletta S, et al. Lowest hematocrit on cardiopulmonary bypass impairs the
outcome in coronary surgery: an Italian multicenter study from the National Cardioanesthesia Database. Tex
Heart Inst J 2006;33:300-305.
53. Ranucci M, Pavesi M, Mazza E, et al. Risk factors for renal dysfunction after coronary surgery: the role of
cardiopulmonary bypass technique. Perfusion 1994;9:319-326.
54. Swaminathan M, Phillips-Bute BG, Conlon PJ, et al. The association of lowest hematocrit during
cardiopulmonary bypass with acute renal injury after coronary artery bypass surgery. Ann Thorac Surg
2003;76:784-791; discussion 792.
55. Mehta RH, Castelvecchio S, Ballotta A, et al. Association of gender and lowest hematocrit on
cardiopulmonary bypass with acute kidney injury and operative mortality in patients undergoing cardiac
56. Fransen E, Maessen J, Dentener M, et al. Impact of blood transfusions on inflammatory mediator release
in patients undergoing cardiac surgery. Chest 1999;116:1233-1239.
57. Surgenor SD, DeFoe GR, Fillinger MP, et al. Intraoperative red blood cell transfusion during coronary
artery bypass graft surgery increases the risk of postoperative low-output heart failure. Circulation
2006;114:I43-I48.
58. Society of Thoracic Surgeons Blood Conservation Guideline Task Force; Ferraris VA, Brown JR,
Despotis GJ, et al. 2011 update to the Society of Thoracic Surgeons and the Society of Cardiovascular
Anesthesiologists blood conservation clinical practice guidelines. Ann Thorac Surg 2011;91:944-982.
59. Society of Thoracic Surgeons Blood Conservation Guideline Task Force; Ferraris VA, Ferraris SP, Saha
SP, et al. Perioperative blood transfusion and blood conservation in cardiac surgery: the Society of Thoracic
Surgeons and The Society of Cardiovascular Anesthesiologists clinical practice guideline. Ann Thorac Surg
2007;83:S27-S86.
60. Spiess BD. Choose one: damned if you do/damned if you don’t! Crit Care Med 2005;33:1871-1874.
61. Hagl S, Heimisch W, Meisner H, et al. The effect of hemodilution on regional myocardial function in the
presence of coronary stenosis. Basic Res Cardiol 1977;72:344-364.
62. Spiess BD, Ley C, Body SC, et al. Hematocrit value on intensive care unit entry influences the frequency
of Q-wave myocardial infarction after coronary artery bypass grafting. The Institutions of the Multicenter
Study of Perioperative Ischemia (McSPI) Research Group. J Thorac Cardiovasc Surg 1998;116:460-467.
63. Niinikoski J, Laato M, Laaksonen V, et al. Effects of extreme haemodilution on the immediate post-
operative course of coronary artery bypass patients. Eur Surg Res 1983;15:1-10.
64. Milam JD, Austin SF, Nihill MR, et al. Use of sufficient hemodilution to prevent coagulopathies following
surgical correction of cyanotic heart disease. J Thorac Cardiovasc Surg 1985;89:623-629.
65. Sieber FE, Smith DS, Traystman RJ, et al. Glucose: a reevaluation of its intraoperative use.
66. Pulsinelli WA, Levy DE, Sigsbee B, et al. Increased damage after ischemic stroke in patients with
hyperglycemia with or without established diabetes mellitus. Am J Med 1983;74:540-544.
67. Doenst T, Wijeysundera D, Karkouti K, et al. Hyperglycemia during cardiopulmonary bypass is an

independent risk factor for mortality in patients undergoing cardiac surgery. J Thorac Cardiovasc Surg
2005;130: 1144.
68. Metz S, Keats AS. Benefits of a glucose-containing priming solution for cardiopulmonary bypass. Anesth
Analg 1991;72:428-434.
69. Chaney MA, Nikolov MP, Blakeman BP, et al. Attempting to maintain normoglycemia during
cardiopulmonary bypass with insulin may initiate postoperative hypoglycemia. Anesth Analg 1999;89:1091-
1095.
70. Lanier WL, Stangland KJ, Scheithauer BW, et al. The effects of dextrose infusion and head position on
neurologic outcome after complete cerebral ischemia in primates: examination of a model. Anesthesiology
1987;66: 39-48.
71. Zarychanski R, Abou-Setta AM, Turgeon AF, et al. Association of hydroxyethyl starch administration with
mortality and acute kidney injury in critically ill patients requiring volume resuscitation: a systematic review
and meta-analysis. JAMA 2013;309:678-688.
72. Lumb PD. A comparison between 25% albumin and 6% hydroxyethyl starch solutions on lung water
accumulation during and immediately after cardiopulmonary bypass. Ann Surg 1987;206:210-213.
73. Marelli D, Paul A, Samson R, et al. Does the addition of albumin to the prime solution in cardiopulmonary
bypass affect clinical outcome? A prospective randomized study. J Thorac Cardiovasc Surg 1989;98:751-
756.
74. Fennema M, Erdmann W, Faithful NS. Myocardial oxygen supply under critical conditions, the effects of
hemodilution and fluorocarbons. In: Erdmann W, Bruley DF, eds. Oxygen transport to tissue XIV. New York,
NY: Plenum Publishing, 1992:527-544.
75. Holman WL, Spruell RD, Ferguson ER, et al. Tissue oxygenation with graded dissolved oxygen delivery
during cardiopulmonary bypass. J Thorac Cardiovasc Surg 1995;110:774-785.
76. Gould SA, Rosen AL, Sehgal LR, et al. Fluosol-DA as a red-cell substitute in acute anemia. N Engl J Med
1986;314:1653-1656.
77. Cohn SM. The current status of haemoglobin-based blood substitutes. Ann Med 1997;29:371-376.
78. Dietz NM, Joyner MJ, Warner MA. Blood substitutes: fluids, drugs, or miracle solutions? Anesth Analg
1996;82:390-405.
79. Bunn HF. The role of hemoglobin based blood substitutes in transfusion medicine. Transfus Clin Biol
1995;2:433-439.
80. Cabrales P, Intaglietta M. Blood substitutes: evolution from noncarrying to oxygen- and gas-carrying
fluids. ASAIO J 2013;59:337-354.
81. Alayash AI. Blood substitutes: why haven’t we been more successful? Trends Biotechnol 2014;32:177-
185.
82. Hampton DA, Schreiber MA. Near infrared spectroscopy: clinical and research uses. Transfusion
2013;53(Suppl 1):52S-58S.
Chapter 17
Hematologic Effects and Coagulopathy
Andreas Pape
Kai Zacharowski
Circulating blood is the transport medium of oxygen, nutrients, carbon dioxide, and cellular and soluble factors of
the immune and coagulation systems (i.e., white blood cells, immunoglobulins, platelets, and coagulation
factors). Hematorheologic properties including blood viscosity and viscoelasticity are essential for the transport
of these substrates, in particular at the site of the microcirculation. Additionally, a sophisticated balance between
pro- and anticoagulant factors maintains blood fluidity, on the one hand, while providing hemostatic potential to
seal off a microvascular bleeding at any time, on the other hand.
Cardiopulmonary bypass (CPB) imposes extremes on hematorheology and on hemostasis, for example, by
hemodilution, hypothermia, hemolysis, and heparinization. Moreover, the CPB surface is perceived as a foreign
body by circulating blood elements, which attempt to “clot it off” by activating hemostasis and simultaneously to
“reject it” by mounting an inflammatory attack. As a consequence, coagulation gets activated, resulting in
consumptive coagulopathy and platelet dysfunction.
Both proinflammatory mediators and activated clotting factors enter into the patient’s circulation, thereby
promoting mechanisms of organ dysfunction. In addition, the impairment of hemostasis results in increased
bleeding and transfusion requirements, which additionally increase perioperative morbidity and mortality.
This chapter will present the pathophysiologic principles of hematologic and coagulatory disorders provoked by
CPB on cellular and soluble components and the cross talk between these single factors.
CELLULAR COMPONENTS
Red Blood Cells
Red blood cells (RBCs) represent about 99% of cellular blood constituents and are therefore the major
determinant of hematocrit (Hct). Hct, defined as the percentage of packed cell volume in whole blood, is the key
determinant of oxygen transport capacity, on the one hand, and of blood viscosity and thus hemorheologic
properties, on the other hand. During CPB, oxygen transport and hemorheology become impaired by
hemodilution, hypothermia, and hemolysis.
Priming the CPB circuit with acellular fluids results in a dilution of the cell mass within the vascular system, that
is, in acute anemia with a corresponding decrease of hematocrit and oxygen transport capacity. Depending on
the type of the CPB circuit and the patient’s circulating blood volume, the degree of hemodilution ranges
between 25% and 35% (1) (for more details, see Chapter 16). Physiologically, acute anemia is compensated by
increases in cardiac output and arteriovenous oxygen extraction (2). However, during CPB, the possibility to
increase cardiac output is limited, so that increasing oxygen extraction becomes the predominant compensatory
mechanism in this setting. Thus, a sustained decrease of mixed venous oxygen saturation might indicate a
critical limitation of oxygen transport capacity (3).
Hemodilution exerts effects on coagulation beyond the dilution of coagulatory factors, since RBCs contribute to
hemostasis: first, RBCs are integrated into the red thrombus like bricks, thereby contributing to clot stability in a
passive manner; second, RBCs expose pro-coagulatory factors like phosphatidylserine on their surface, which
directly contribute to thrombin generation (4); third, the laminar blood flow of RBCs directs platelets and
coagulation toward the endothelium (“radial dispersion”) where they are needed for hemostasis (5). Due to
different shear rates within the arterial and the venous circulations (see below), the latter effect plays a
predominant role in arterial blood vessels.
To decrease total body oxygen demand, CPB is usually performed under hypothermia (see Chapter 9). The
consequence is a left shift of the oxygen dissociation curve with impaired oxygen offloading from hemoglobin to
the tissues. Moreover, blood temperature influences blood viscosity. It has long been known that rheologic
properties of blood are impaired by increased blood viscosity during hypothermia (6), so that hypothermia alters
both oxygen transport and hematorheologic properties.
Another frequently observed consequence of CPB is hemolysis, which is principally caused by mechanical shear
stress and turbulences within the roller pump and the circuit (i.e., tubes, connectors, cannula, reservoirs, and
oxygenator) (7). Damaging mechanisms include the contact of circulating blood with air and nonendothelial
surfaces, wall impact
P.434
forces, pressure gradients to assist venous drainage, and the use of cardiotomy suction (8).
While some RBCs disintegrate immediately, a considerable quantity of erythrocytes suffer “sublethal” damage,
resulting in cellular lysis at a later time point. However, the deformability of these RBCs is altered, leading to an
impaired blood rheology. As a result of disintegration of erythrocytes, hemoglobin and heme molecules are
released into the circulation. The degree of hemolysis seems to correlate with the duration of CPB (8) and is
reflected by increased plasma levels of free hemoglobin and lactate dehydrogenase (LDH) and by decreased
levels of haptoglobin. As RBCs suffering a “sublethal” damage may break down at a later time point, the release
of intracellular constituents into the circulation can be sustained over a long period of time and free hemoglobin
levels may even increase after the cessation of CPB (9).
Free hemoglobin is a potent scavenger of nitric oxide (NO), the most important endogenous vasodilator.
Reduced bioavailability of NO exerts vasoconstriction, which has proven harmful for microcirculatory function and
thus tissue oxygenation (10). Moreover, free heme reacts with endogenous hydrogen peroxide, resulting in the
formation of radical oxygen species and thus in the induction of oxidative damage (11).
A direct consequence of vascular dysfunction is an impairment of organ perfusion, so that the role of hemolysis
in the development of organ dysfunction after surgery with CPB has gained increasing interest (8). To decrease
morbidity and mortality, therapeutic targets address the modification of CPB circuit systems and scavengers of
free hemoglobin molecules (12,13).
Circulating blood behaves like a non-Newtonian fluid, as the viscosity of flowing blood varies with shear rates.
Aside from hematocrit, blood viscosity is determined by RBC deformability, RBC aggregation, and plasma
viscosity (14). Within an arterial blood vessel, laminar blood flow can be modeled as concentric rings of fluid
moving at different velocities (see Fig. 17.1). The central core of fluid moves at the highest velocity. Sheathing
this central, fastest-moving fluid core is a ring whose velocity is slightly slower. Immediately outside that ring is
another that moves still more slowly, as does each successive ring of blood all the way out to the vessel wall.
The shear rate, γ, is a measure of how rapidly these adjacent fluid layers slide past each other, and is expressed
in inverse seconds (s-1)10. The shear rate at a radial point, r (measured from the vessel center), can be
calculated according to the following equation:
γ = dvz/dr = 4(vz) r/R2
where vz is the mass average velocity and R is the vessel radius. Accordingly, the shear rate is greatest at the
vessel wall (γwall = 4(vz)/R) and zero at the center of the vessel. Given that wall shear rates are inversely
proportional to the vessel radius, R, wall shear is greatest in arterioles, in the order of 5,000 s-1, and decreases
in progressively larger arteries, reaching a still-forceful nadir of approximately 500 s-1 in the major arteries.
Contrasting this, the velocity of blood flow, vz, is low enough in the venous system that shear force is virtually
negligible in the venous circulation (15).
FIGURE 17.1. Rheology of fluid flow through a cylinder. Schematic of fluid flowing as concentric rings of a
Newtonian fluid moving at different velocities within a cylinder. The velocity is greatest at the center and
decreases with radial distance from the center, with VZ = the mass average velocity. The shear is greatest at the
wall and approaches zero at the center. (Adapted from Rinder CS. Hematologic effects and coagulopathy. In:
Gravlee GP, Davis RF, Stammers AH, et al., eds. Cardiopulmonary bypass—principles and practice. 3rd ed.
Philadelphia, PA: Lippincott Williams & Wilkins, 2008:439-458.)
The differing shear rates within the arterial and venous circulation also affect the coagulant effects within these
different vascular regions. In the “pressurized” arterial system, a relatively small vascular disruption can rapidly
result in significant blood loss and hematoma formation, creating the need for a system that can speedily and
securely seal off
P.435
bleeding sites. Platelets dominate this “rapid response team,” initially containing blood loss, then providing a
surface on which to localize and accelerate the fibrin formation that ultimately consolidates hemostasis. In the
venous circulation, by contrast, the more leisurely flow rates diminish the need for speed, making platelets less
critical, and indeed, thrombin generation constitutes the pivotal reaction controlling the balance of venous
hemostasis. It is critical to understand how venous and arterial hemostasis operate in part through common
pathways, and how the two differ, to fully appreciate the manifestations of different CPB-induced coagulation
defects.
White Blood Cells

Contrasting RBCs, white blood cells (WBCs) make up approximately 1% of whole blood volume under
physiologic conditions. As cells of the immune system, WBCs serve the purpose to defend the organism against
infections and foreign materials. Basically, WBCs can be divided into granulocytes (including neutrophils,
basophils, and eosinophils) and agranulocytes (lymphocytes, monocytes, and macrophages).
The contact of circulating blood with the nonendothelial surface of the CPB circuit initiates a marked activation of
circulating WBCs—predominantly neutrophils and monocytes—resulting in a proinflammatory response. In detail,
mechanisms of CPB-associated inflammation are described in Chapter 13.
During CPB, WBCs get activated by mediators of the contact and complement systems (predominantly by
kallikrein and C5a), by elevated plasma levels of heparin, histamine, thrombin, and FXIIa, and by proinflammatory
cytokines (16,17). C5a induces neutrophil chemotaxis, superoxide generation, and degranulation (18).
Activated neutrophils release cytotoxic enzymes (neutrophil elastase, cathepsin G, lysozymes, myeloperoxidase)
triggering the formation of oxygen free radicals and hydrogen peroxide. Moreover, activated neutrophils interact
with endothelial cells upon expression of their adhesion factor (CD11b/CD18), thereby promoting leukocyte
rolling and sticking, clumping, microvascular occlusion, and finally end-organ ischemia (19). Following
transmigration into extravascular tissues, cytotoxic effects of activated neutrophils and the formation of tissue
edema result in the deterioration of cellular function (20,21,22).
Compared with neutrophils, the activation of monocytes during CPB happens more slowly, as peak levels of
monocyte activity have been observed with a certain delay (19). The mechanism leading to the activation of
monocytes during CPB has not been fully elucidated. However, the alternative pathway of complement activation
may be involved, but interactions with soluble tissue factor and endotoxin are additionally discussed (23).
Activated monocytes release proinflammatory cytokines such as TNF-α, IL-1β, IL-6, and IL-8 (24), thereby
reinforcing the inflammatory response to CPB. By expression of tissue factor, activated monocytes also promote
the generation of thrombin and thus the activation of the coagulation system (25). Contrasting this, a newly
discussed anti-inflammatory effect of monocytes is mediated by the CD163 receptor. Elevated levels of CD163
expression were observed on activated monocytes after endocytosis of hemoglobin-haptoglobin complexes,
which elicits a marked release of anti-inflammatory IL-10 (26).
Activated leukocytes contribute significantly to hemostatic disorders during CPB (16), in particular by expressing
tissue factor on their surfaces (27), thereby activating factor VII and initiating the plasmatic coagulation system
(see below). Additionally, activated monocytes have been reported to conjugate with platelets via the granule
membrane protein-140 receptor, thereby contributing to thrombopenia and coagulopathy (28,29).
Anticoagulant responses mediated by leukocytes include the release of elastase and cathepsin G as well as the
upregulation of the adhesion receptors CD11b/CD18, the latter facilitating the adhesion to fibrin (30).
Additionally, lysosomal enzymes such as elastase and cathepsin G are capable of degrading fibrin (31,32),
thereby contributing to the destabilization of clots.
Platelets
Structure and Function of Platelets
Platelets are anucleate cell fragments derived from megakaryocytes of the bone marrow. Within the circulation,
the life span of platelets is approximately 7 to 10 days. The abundance ratio of platelets to RBCs is 1:10 to 1:20.
Resting platelets are biconvex discoid structures measuring 2 to 3 μm in diameter. The cellular membrane
possesses invaginations known as the open canalicular system, which permits small molecules to enter into the
network of internal membranes. Inside the cells are two types of granules, the α- and dense granules, which
store molecular platelet activators (15). The more prevalent a-granules mainly contain adhesive ligands and
growth factors (e.g., GPIIb/IIIa, fibrinogen, von Willebrand factor [vWF]), while dense granules contain calcium,
serotonin, and adenosine diphosphate (ADP) (33).
In the case of bleeding, platelets initiate primary hemostasis by adhesion to the endothelial defect. Initial platelet
adhesion is driven by interactions between the GPIbα receptor and subendothelial compounds like vWF and
collagen, which is exposed due to the disruption of the endothelial cell layer.
Essential to the adhesion of platelets to the endothelium is vWF, a large multimeric glycoprotein (20,000 kDa)
composed of base units (polypeptides of 2,813 amino acids) which are produced by endothelial cells,
megakaryocytes, and in the subendothelial tissue (34). Primarily, platelet adhesion to the endothelium is
supported by two domains of the vWF multimer: the α1 domain, which binds to the platelet GPIbα receptor and
the α3 domain binding to subendothelial collagen.
In the plasma, vWF circulates as a loosely coiled molecule with an apparent diameter of 200 to 300 nm. As the α1
P.436
domain remains cryptic in that state, circulating vWF usually shows no affinity for cocirculating platelets.
However, under the influence of the high shear present along the vessel wall (a threshold value of 1,000 s-1 is
required), vWF uncoils to lengths as great as 1,300 nm and the α1 domain becomes apparent, thereby enabling
the interaction with the platelet surface receptor GPIbα (34).
The coupling of this vWF domain to GPIbα is characterized by a high rate of bond formation. This “fast-on”
binding tethers the platelet to the exposed subendothelium in the face of the high-velocity blood flow that would
otherwise sweep the platelet past the bleeding site. The relatively weak strength of this adhesive tethering is
soon overcome by the local shear force, and the platelet moves on, albeit now traveling at a slower velocity but
still in proximity to the vessel wall (15). In addition to slowing the platelet’s velocity, this brief vWF-GPIbα
interaction stimulates platelet activation with a conformational change in the GPIIb/IIIa receptor, which allows it to
interact with fibrinogen and bind to a different vWF domain (RGD sequence). Unlike the initial vWF-GPIbα
interaction, however, the binding of GPIIb/IIIa to vWF has sufficient strength to resist the local shear forces, such
that the platelet is firmly arrested on the surface of this tethered ligand (33). If the vWF multimer is of sufficient
size, both steps can occur on a single vWF molecule; therefore, the better hemostatic efficiency is of the largest
multimers. Accordingly, the initial interaction of GPIbα with vWF has a dual role, one of slowing the platelet and
another of inducing the conformational changes that allow it to be cemented to the subendothelial matrix. (15).
FIGURE 17.2. Platelet adhesion to von Willebrand factor (vWF) at the site of an arterial vessel injury. Schematic
representation of the sequence of events in response to platelet adhesion to subendothelium under conditions of
high shear stress. The first contact tethers the platelet to an immobilized vWF multimer through the platelet
receptor, GPIb. This bond must be formed rapidly, but does not have the strength to hold fast against the high
shear present at the vessel wall. The shear rips the platelet free, creating a rolling movement, but the transient
binding is sufficient to cause the platelet to become activated. This activation results in a conformational change
in a second platelet receptor, GPIIb/IIIa, which allows this receptor to bind to a distinct site on vWF, producing
stable, irreversible adhesion to the subendothelium; EC, endothelial cells. (Adapted from Rinder CS.
Hematologic effects and coagulopathy. In: Gravlee GP, Davis RF, Stammers AH, et al., eds. Cardiopulmonary
bypass-principles and practice. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2008:439-458.)
Binding of ligands to the GP receptors causes platelets to change their shape, that is, to transform from discoid
to spherical, while building lateral finger-like extensions (pseudopods). Simultaneously, platelet fibrinogen
receptors (GPIIb/IIIa) are expressed and activated via a conformational change (35), thereby allowing further
binding of vWF or fibrinogen as ligands and the formation of a platelet-ligand-platelet matrix.
Moreover, activated platelets release agonists like ADP and serotonin from their granules and thromboxane A2
from their cytosol. Degranulation exerts chemotaxis and stimulation of passing thrombocytes, thereby recruiting
them for the amplification of the initial platelet response. The resulting platelet plug built up at the site of
endothelial defect is also known as “white thrombus” (33) (Fig. 17.2).
However, the white thrombus generated during primary hemostasis is rather unstable. Crucial for the formation of
a stable blood clot is an interaction of activated platelets with the soluble coagulation system (see below). During
platelet activation, membrane phospholipids become negatively charged, thereby facilitating the activation of
several coagulation factors (predominantly FV and FVIII), binding of the prothrombin complex to the platelet
membrane, and finally converting prothrombin to thrombin (33). Thrombin converts fibrinogen to fibrin, which is in
turn a potent platelet
P.437
activator. Therefore, the activation of further platelets and the simultaneous formation of the fibrin network lead
to the formation of the so-called red-thrombus and to strengthening of the blood clot (36).
Platelet Defects during CPB

Qualitative and quantitative platelet defects are typically witnessed during CPB, both having the potential to
cause significant bleeding (18). During CPB, platelet counts usually decrease by 30% to 50%. Occasionally, this
can result in dips below 50,000/ μL, which is an accepted transfusion trigger for platelet concentrates in surgical
patients (37). However, functional platelet defects elicited by CPB may produce bleeding that requires platelet
transfusion despite seemingly adequate platelet counts (15). Additionally, platelet function is frequently restricted
by antiplatelet medication.
While hemodilution with acellular priming solutions generally appears to be a plausible explanation for decreases
in platelet counts, some further mechanisms deserve consideration in this context. One mechanism most likely to
decrease the number of circulating thrombocytes is their adhesion to the circuit surfaces, which are coated with
adsorbed fibrinogen, vWF, and fibronectin. Upon activation, platelets express their GPIIb/IIIa receptors (see
above), which allows them to adhere to fibrinogen and vWF (19). Further physical factors contributing to CPB-
associated thrombopenia include mechanical disruption, shear stress, hypothermia, and sequestration in
pulmonary and splenic tissues (38). Moreover, consumptive coagulopathy (19,39) and the formation of platelet
conjugates (i.e., platelet-monocyte or platelet-neutrophil) also contribute to decreasing platelet counts (28). While
platelet levels drop, a few new platelets enter the circulation either by outpouring from the bone marrow or by
recruitment from the spleen. Extracorporeal circulation thus has a profound effect on platelet population, which
can become highly heterogenous during CPB (19).
Several alterations in platelet function can occur in the peri-CPB patient, with no single functional defect
accounting for the preponderance of bleeding. In general, platelet response to stimulation by agonists gets
blunted. Accordingly, higher concentrations of ADP, collagen, thrombin, and other platelet agonists are required
to achieve irreversible platelet aggregation. Moreover, the ability to adhere in the presence of high shear is
decreased (15).
The emergence of platelet dysfunction appears to be multifactorial with platelet activation being the leading
cause. Platelet activation becomes measurable by release of granular contents and essentially results from
direct contact with the synthetic material of the CPB circuit. Most likely, this process is mediated by the GPIIb/IIIa
receptor (40,41). Within the circuit as well as in the pericardial wound, low concentrations of thrombin—a potent
platelet activator—are generated. Most likely, this effect is mediated by activation of protein-C-kinase and the
upregulation of P-selectin and interactions with the GPIb receptor (38). In the further course of surgery, platelets
also become activated by complement factors (C5b-9), leukotrienes, plasmin, platelet-activating factor (PAF),
and different collagenases (19). Hypothermia, heparin dosing, and antagonization of heparin with protamine also
contribute to the alterations of platelet counts and function (19). Heparin (which is used as an anticoagulant for
CPB) binds to the surface of platelets, thereby causing degranulation of the a-granules (38). Moreover, heparin
has been observed to bind to vWF at a site critical for binding to platelet GPIb (42). The neutralization of heparin
with protamine leads to a transient decrease of platelet count, which is associated with activation of platelets via
the classic pathway of the complement system and the formation of transient aggregates, which are sequestered
in the lungs (43).
The activation of the complement system and the release of proinflammatory cytokines such as IL-6 and IL-8
represent endogenous mechanisms of platelet activation, both having the potential to activate platelets via P-
selectin (44). Complement activation comprises the anaphylatoxins C3a and C5a, the opsonin C3b, and the
membrane attack complex C5b-9. Platelet activation leading to P-selectin expression occurs in response to C5b-
9 complex (45). In an in vitro study simulating extracorporeal circulation, monoclonal antibodies preventing the
generation of C5a and C5b-9 have been shown to abolish the expression of platelet P-selectin, thereby blocking
the formation of leukocyte-platelet aggregates (46).
As a consequence of activation, molecules residing on the surface of platelets change their expression patterns,
thereby modulating their hemostatic and inflammatory effects (38). In particular, the levels of GPIb and GPIIb/IIIa
are reduced, while the GPIV receptor is upregulated (47), the latter appears to be relevant for the platelet-
collagen adhesion (48) and is involved in the thrombospondin-mediated stabilization of platelet aggregates (49).
In vitro studies have demonstrated that stimulated platelets become refractory to repeated stimulation by the
same agonist. It is possible that the CPB-induced activation might produce a pool of granule-depleted platelets
incapable of contributing their granule contents to the platelet plug. Indeed, electron microscopic examination of
platelets during CPB demonstrates a heterogeneous mixture of discoid and shapechanged platelets, in addition
to partially and completely degranulated platelets (50). Several attempts have been sought to prevent CPB-
associated platelet dysfunction. These include the reduction of platelet shear originating from cardiotomy suction
(aspiration of air along with blood and shear forces are reduced when cardiotomy suction is performed gently) as
well as from the pump unit. While the use of centrifugal pumps instead of roller pumps is advocated by some
authors (51), no significant differences between these pump types were detected regarding the extent of platelet
activation (52). Contrasting this, coating of CPB units seems to be associated with a lower degree of platelet
activation (53). Pharmacologic
P.438
strategies to inhibit platelet activation consist in the administration of reversible platelet inhibitors like
prostacyclin, iloprost, or nitric oxide. Although transient platelet inhibition was associated with preserved platelet
function and slightly reduced chest tube drainage after CPB, these findings did not result in a reduction of
perioperative transfusion rates (54). Finally, a strategy to prevent the exposure of platelets to CPB exists in
preoperative platelet pheresis, harvesting 20% or more of the patient’s platelet population for retransfusion after
CPB (38). While this technique has been demonstrated to reduce postoperative blood loss and transfusion
requirements in two studies (55,56), robust data to advocate the routine use of platelet pheresis prior to on-pump
surgery are lacking (38).
Endothelial Cells
Endothelial cells line the interior surface of the vascular wall, thereby forming an interface between the
circulating blood and the vessel wall. The biologic functions of endothelial cells include a barrier function
between the intravascular lumen and the surrounding tissue, angiogenesis, regulation of vascular tone, and they
modulate inflammation and hemostasis. Endothelial cells share common features with platelets, as both cell
types are derived from a common progenitor cell originating from the bone marrow. Endothelial cells and
platelets feature similar expression programs including vWF, multimerin, and P-selectin and both of them store
their bioactive materials in cytoplasmatic granules (33). During CPB, endothelial cells are activated by several
agonists. Activated endothelial cells forfeit many of their biologic functions; in particular, their capability to
modulate inflammation and hemostasis gets significantly altered by CPB (57).
To this effect, platelets and neutrophils previously activated by CPB interact with endothelial cells. Activated
neutrophils with expressed CD11b/18 adhesion factor directly activate endothelial cells. Endothelial cells express
the adhesion molecule CD40, which interacts with a ligand expressed on the surface of activated platelets
(complement binding molecule, CD40L), which stimulates endothelial cells to secrete IL-8 and MCP-1 as
cytokines with chemotactic effects on neutrophils and monocytes (58).
Aside from cells activated by CPB, activation of endothelial cells during CPB is also elicited by thrombin, C5a,
and the cytokines IL-1β and TNF-α (18). During CPB, endothelial cells produce a variety of anticoagulants:
heparin, antithrombin, protein S, and thrombomodulin, the latter exerting its anticoagulant effects by amplifying
the activation of protein C (59). Moreover, endothelial cells secrete tissue factor pathway inhibitor (TFPI), a
single-chain polypeptide that reversibly inhibits factor Xa and indirectly inhibits the factor VIIa-TF complex and
tissue plasminogen activator (tPA) as a fibrinolytic agonist (19).
All in all, endothelial cells contribute to CPB-associated coagulopathy by upregulation of anticoagulant and
fibrinolytic pathways (see Regulation and Remodeling of Vascular Clots). In a clinical study investigating the
activation of fibrinolytic pathway before, during, and after CPB, t-PA levels increased 6-fold already 5 minutes
after initiation of CPB, with t-PA secretion continued into the post-CPB period (60). As a result, plasmin
generation increased over 100-fold and D-dimer generation increased 200-fold within 5 minutes of CPB initiation
(61).
Fibrinolysis occurring simultaneously with thrombin generation and formation of fibrin may trigger consumptive
coagulopathy and increase perioperative bleeding. Therefore, an adequate antifibrinolytic management strategy
is warranted during CPB (62).
SOLUBLE COMPONENTS
The Contact System
The contact system (also referred to as kinin-kallikrein system) consists of four primary plasma proteins: FXII,
FXI, prekallikrein, and high-molecular-weight kininogen (HMWK). During CPB, due to the contact of blood with
the negatively charged nonendothelial surface of the circuit, FXII gets activated. As a consequence, FXIIa
activates FXI, thereby promoting the intrinsic coagulation pathway. Further effects of FXIIa are the formations of
bradykinin from HMWK and kallikrein from pre-kallikrein. Kallikrein is a potent activator of neutrophils and
fibrinolysis by activating plasminogen to plasmin (18). By means of a positive feedback loop, kallikrein also exerts
further activation on FXII and thus amplifies its effects on inflammation and hemostasis (19). Aside from activating
neutrophils and the intrinsic coagulation pathway, FXIIa also activates platelets, the fibrinolytic system, the
complement cascade, and endothelial cells (63) (Fig. 17.3).
Complement System
The complement system is an innate cytotoxic immune defense system composed of approximately 35
interacting plasma- and membrane-associated proteins which contribute to host defense by initiating and
amplifying the inflammatory response (18). Complement activation occurs via three major pathways: (1) the
classic pathway, which is antibody-dependent (i.e., activated by immune complexes), (2) the alternative pathway,
which is activated by direct contact with the specific pathogen, and (3) the mannose-binding lectin (MBL)
pathway, which is activated by a plasma lectin that binds to mannose residues found on microbes. Hence, the
alternative and MBL pathways are—in contrast to the classic pathway—independent of the formation of
antibodies and are therefore nonspecific. During CPB, the complement system is thought to be activated
predominantly by the alternative pathway. However, the formation of heparin-protamine complexes after reversal
of heparin at the end of CPB may additionally activate the classic pathway (64).
All three pathways lead to the generation of C3 convertase, which activates and cleaves C3 into C3a and C3b
and causes
P.439
a cascade of further cleavage and activation events (Fig. 17.4) (19). Following the alternative pathway, C3b
binds to plasma protein factor B, which, in the presence of factor D, is cleaved into Ba and Bb. While Ba is
released into the surrounding medium, Bb and C3b form C3bBb. C3bBb cleaves further C3 proteins into C3a
and C3b, thereby creating C3bBbC3b. C3bBbc3b functions as C5 convertase, activating C5 to C5a and C5b.
While C5a directly activates neutrophils, C5b initiates the formation of the membrane attack complex (MAC). As
the endpoint of the complement cascade, MAC produces a transmembrane channel capable of producing
osmotic cell lysis and death (19).
FIGURE 17.3. Activation of the contact system. FXII is activated by contact with the nonendothelial circuit. FXIIa
cleaves FXI to FXIa, which ends in the intrinsic pathway of the coagulation cascade. Moreover, FXIIa converts
high-molecular-weight kininogen (HMWK) to bradykinin and prekallikrein to kallikrein, the latter activating
plasminogen to plasmin. In terms of a feedback loop, kallikrein exerts further activation of FXII.
FIGURE 17.4. Activation of the alternative (i.e., antigen-, antibody-independent) pathway of the complement
system.
Moreover, MAC is a potent platelet activator, inducing a-granule release, formation of procoagulant
microparticles, and surface exposure of the negatively charged phosphatidylserine residues essential to the
coagulation cascade (65). In vitro, platelets activated by MAC are unable to bind fibrinogen to their GPIIb/IIIa
receptors, so that an aggregation defect similar to that induced in vivo by CPB is created (66). Consequently,
complement-borne platelet activation may contribute to the CPB-associated coagulopathy and platelet defect.
Plasmatic Coagulation
Cascade Model and Cell-Based Model of Coagulation
Fifty years ago, plasmatic coagulation was described for the first time as a “waterfall” (67) or as a “cascade”
model (68). As displayed in Fig. 17.5, this model is based on the assumption that the overall structure of the
coagulation process is a series of proteolytic reactions, culminating in the formation of a fibrin clot (69).
Screening coagulation laboratory tests such as activated partial thromboplastin time (aPTT) and prothrombin
time (PT) represent the intrinsic and extrinsic pathways, into which the cascade model is dovetailed.
The intrinsic pathway is initiated by the exposure of circulating blood to collagen or to foreign surfaces such as
the
P.440
CPB circuit. As a result, FXII gets activated to FXIIa, which is further amplified by plasma kallikrein via a positive
feedback loop. FXIIa cleaves FXI to FXIa, resulting in the subsequent activation of FIX to FIXa and FX to FXa, the
latter converting prothrombin to thrombin. The initial stimulus of the extrinsic pathway is the contact of circulating
blood with TF, which is exposed after disruption of the endothelial layer. Circulating FVIIa creates a complex with
TF, which activates FX to FXa. Once FXa is generated, the remainder of the cascade is similar to the intrinsic
pathway (18).
FIGURE 17.5. The cascade or waterfall model of coagulation. The intrinsic pathway consists of zymogens,
factors XII, XI, IX, and VIII. The extrinsic pathway consists of tissue factor (TF) and factor VII, and the common
pathway, factors X, V, prothrombin, and fibrinogen, culminating in the generation of thrombin and fibrin. The
activated form of these factors is indicated by adding the letter “a” as a suffix.
FIGURE 17.6. Cell-based model of hemostasis. The three phases of coagulation occur on different cell surfaces:
Initiation on the tissue factor-bearing cell, amplification on the platelet as it becomes activated, and propagation
on the activated platelet surface. (Modified according to Hoffman M, Monroe DM III. A cell-based model of
hemostasis. Thromb Haemost 2001;85:958-965.)
Actually, PT and aPTT (and, in addition, the corresponding elastomeric assays; see Chapter 18) are still the gold
standard for assessment of plasmatic coagulation. Although the cascade model is very workable for explanation
of hemostatic pathologies, it has several shortcomings delimiting its potential to represent the function of
hemostasis in vivo. It is evident that in vivo coagulation is initiated by contact of blood with tissue factor (TF),
which is exposed at the site of endothelial defects. Moreover, the cascade model does not consider the
contribution of cells, particularly platelets, to hemostasis, as it implies that the primary role of cells is to provide
anionic phospholipids for coagulation complex assembly (70).
Cell-Based Model of Hemostasis

A current model of hemostasis integrating the dynamic function of platelets with the plasmatic coagulation system
is based on the assumption that thrombin generation occurs in three phases: (1) the initiation phase, which
occurs on TF-bearing cells, (2) the amplification phase, in which platelets and cofactors get activated, and (3)
the propagation phase, in which large amounts of thrombin are generated (see Fig. 17.6) (69). The amount of
thrombin generated in the propagation phase is sufficient to convert fibrinogen to fibrin.
The initiation phase of coagulation is promoted by TF, which is exposed at the site of the endothelial defect (e.g.,
by fibroblasts). Under physiologic conditions, picomolar amounts of FVIIa are present in the circulation at all
times. The formation of TF-FVIIa complexes effectively hallmarks the initiation of coagulation, as the TF-FVIIa
complex catalyzes the conversion of factor IX to IXa and X to Xa. Within the circulation, FXa is rapidly inhibited by
tissue factor pathway inhibitor (TFPI) and antithrombin (AT). However, FXa
P.441
remaining on the cell surface generates nanomolar amounts of thrombin, which plays an important role in the
subsequent amplification phase.
During the amplification phase, the large-scale production of thrombin is prepared by activating platelets, which
causes them to release FV, which is activated by FXa and thrombin. Furthermore, thrombin activates FV to FVa
and FVIII to FVIIIa after releasing it from vWF. FVa and FVIIIa remain bound to the surface, thereby localizing the
subsequent thrombin burst to the site of endothelial defect.
The propagation phase begins with the assembly of the so-called tenase (FVIIIa-FIXa) complex on the platelet
surface, when FIXa diffuses into a specific binding site. The formation of FIXa is reinforced by FXIa, leading to an
extensive complexation of FVIIIa. Finally, the tenase complex activates FX to FXa, which builds the
“prothrombinase” complex after binding to its cofactor FVa. The high prevalence of prothrombinase complexes
enables the large-scale production of thrombin by cleaving prothrombin (“thrombin-burst”), which is necessary to
form a hemostatic fibrin clot (69).
Aside from activating platelets and stimulating endothelial cells to produce vWF, the principal actions of thrombin
are to convert fibrinogen to fibrin and to activate FXIII (71).
The formation of a fibrin clot begins with the cleavage of fibrinogen to fibrin, which results in the formation of
soluble fibrin strands. For further stabilization, fibrin strands are cross-linked by FXIII, which circulates in the
plasma and is also contained in the platelet. About 50% of the total fibrin-stabilizing activity in blood resides in
the platelets released at sites of bleeding following platelet activation. In the plasma, factor XIII is a tetrameric
molecule consisting of two α subunits, containing the active site of the enzyme, and two β subunits, which serve
to increase the plasma halflife of the zymogen but must be dissociated for full enzyme activity. Platelet factor XIII,
by contrast, is a dimer that contains only the two α subunits. Thrombin-activated factor XIIIa binds to fibrin and
forms cross-links between the fibrin units, thereby stabilizing them and rendering them less permeable and less
lysis-prone. Perhaps even more critical to protection from fibrinolysis is the ability of FXIIIa to crosslink the major
plasmin inhibitor, α2 antiplasmin, directly to the a chain of fibrin, positing it for expeditious neutralization of any
invading plasmin. A number of factors within the microenvironment of the developing clot importantly influence
clot architecture. As might be expected for a biochemical reaction, local concentrations of thrombin and
fibrinogen (i.e., enzyme and substrate) dominantly impact fibrin strand formation. In a thrombin-rich environment,
fibrin clots that form are generally constructed from thinner, more tightly cross-linked fibers, making them virtually
impermeable to lytic enzymes. In contradistinction, clots that form in the presence of low thrombin concentrations
exhibit thicker and more porous fibrin strands that are vulnerable to thrombolysis. Similarly, when high fibrinogen
concentrations are present, large thrombi form with a tight and rigid meshwork, making the fibrin clot less
deformable and more resistant to lysis. Low fibrinogen concentrations, by contrast, produce a less compact clot
that is highly lysis-prone (15).
Plasmatic Coagulopathy during CPB

During CPB, the plasmatic coagulation system gets challenged. Underlying mechanisms include fibrinogen
depletion, activation of coagulation with consumptive coagulopathy, and heparinization.
The depletion of fibrinogen is due to binding to extracorporeal surfaces within minutes of blood passage through
the CPB circuit. This bound fibrinogen is conformationally altered such that it is capable of binding to the resting
GPIIb/IIIa receptor on platelets (72), and the resulting tethering of platelets is one likely explanation for the excess
thrombocytopenia associated with CPB. Moreover, clot strength is impaired following CPB, and this change has
been correlated with increased chest tube drainage (73). Clot strength derives in part from factor XIIIa-mediated
cross-linking, and because 50% of factor XIII levels are platelet-derived, it is not surprising that platelet count,
factor XIII levels, and clot strength all correlate with each other and with postoperative bleeding (Fig. 17.7) (15).
As described earlier, plasmatic coagulation gets activated by the contact system. In the presence of HMWK,
FXIIa cleaves FXI to FXIa, which is reinforced by the simultaneous formation of kallikrein. The activation of FXI by
FXIIa represents the initial step of the intrinsic pathway and finally results in additional formation of thrombin. This
pathway is the predominant route activating coagulation during all applications of extracorporeal circulation (19).
Additionally, the extrinsic pathway becomes activated by “blood-borne TF,” that is, TF either located on
stimulated mononuclear cells or circulating as soluble procoagulant TF fragments (74,75). The TF-FVIIa complex
activates FX, ending in thrombin generation. Therefore, both pathways of the coagulation cascade get activated
by CPB.
To prevent clot formation within the bypass circuit, anticoagulation is usually performed with heparin, which
potentiates the activity of antithrombin and thereby accelerates thrombin inactivation 1,000-fold (76). Of note, this
effect primarily addresses the end of the coagulation cascade, so that clot formation is prevented, although the
coagulation system is still activated during CPB. Moreover, a relevant risk inherent in systemic heparinization is
platelet activation with heparin-induced thrombocytopenia (HIT), which occasionally requires alternative
techniques of anticoagulation (77,78). In patients undergoing cardiac surgery with CPB, it was demonstrated that
molecular markers of thrombin generation such as thrombin-antithrombin complex (TAT) and prothrombin
fragment (PF1C2) were still elevated despite systemic heparinization (79). As the coagulation cascade remains
activated, thrombin generation occurs progressively, in particular within the
P.442
pericardial wound (80), which produces a consumptive coagulopathy responsible for thromboembolic as well as
bleeding complications associated with CPB (19).
FIGURE 17.7. Correlations between (A) platelet count (r = -0.4, p < 0.025), (B) clot strength (r = -0.38, p < 0.04),
and (C) factor XIII antigen levels (r = -0.4, p < 0.025), versus cumulative chest tube output at 2, 4, and 8 hours
after surgery. Open circles, chest tube output at 2 hours; x, chest tube output at 4 hours; filled circles, chest tube
output at 8 hours. (Reprinted from Chandler WL, Patel MA, Gravelle L, et al. Factor XIIIa and clot strength after
cardiopulmonary bypass. Blood Coagul Fibrinolysis 2001;12:101-108, with permission.)
Another factor contributing to postoperative bleeding is residual heparin effect. Although heparin is neutralized by
protamine at the end of CPB, a fraction of heparin may be unavailable for protamine reversal because of protein
binding or endothelial sequestration. The release of this fraction is also known as heparin rebound (15).
In addition to consumptive coagulopathy and heparin rebound, plasmatic coagulation is also impaired by
hypothermia. As a cascade of enzymatic reactions, the plasmatic coagulation system has an optimum physiologic
temperature of 37°C. While moderate hypothermia (i.e., 33°C) may predominantly impair platelet-based
hemostasis, severe hypothermia below 33°C additionally impairs plasmatic coagulation (81). Hypothermia-
induced changes are reversible upon rewarming; however, this effect may impair postoperative coagulation in
patients who are inadequately rewarmed or recooled after leaving the operating room (OR) suite (15).
Anticoagulant Pathways and Fibrinolysis

Regulation and Remodeling of Vascular Clots
To avoid excessive clot formation resulting in thrombosis and obstruction of microvessels, hemostasis is well
balanced by anticoagulant mechanisms counteracting coagulation. These
P.443
mechanisms serve to limit the extent of clot formation and to localize it to the site of tissue or vessel injury. They
can be divided into endogenous anticoagulants and into the fibrinolytic system. These clot containment systems
are supplied by healthy endothelial cells (EC) serving as a renewable source of anticoagulant mediators and
providing an extracellular matrix to localize them at the vessel wall (15).
Endogenous anticoagulants include antithrombin (AT), tissue factor pathway inhibitor (TFPI), and activated
protein C (APC). Under circumstances of normal hemostasis, AT is present at more than twice the concentration
(3.2 μmol/L) of the highest local thrombin concentration reached during clotting (1.4 μmol/L), and its activity
against thrombin is potentiated approximately 1,000-fold by endogenous EC-associated heparan sulfate
proteoglycans. The platelet surface membrane and platelet-released platelet factor 4 protect thrombin from
inactivation at the site of clot formation. However, in the absence of the protection conferred by the platelet
membrane, any circulating thrombin is inhibited by plasma levels of AT with a reaction time constant that is less
than 1 minute, and in the microenvironment of healthy endothelial cells where approximately 60,000 molecules of
AT bind per cell, thrombin is neutralized almost instantaneously (15). TFPI is synthesized in endothelial cells and
inactivates FXa and the TF-FVIIa complex, thereby inhibiting thrombin generation. A proposed mechanism is that
TFPI binds to FXa dissociated from its activating TF-FVIIa complex. The TFPI-FXa complex then reassociates
with TF-FVIIa binding to the active site of FVIIa (82). TFPI requires some basal coagulation activation to fully
exert its anticoagulant activity. APC is an endogenous protein whose combined anticoagulant, anti-inflammatory,
and profibrinolytic properties make it an important regulator in situations where both thrombosis and inflammation
are prominent (83). Like TFPI, the protein C system becomes activated only after coagulation is partly under
way. Formed thrombin binds to thrombomodulin, a proteoglycan associated with endothelial and monocyte cell
surfaces. Once bound, thrombin loses its ability to activate platelets and instead activates protein C. APC slows
down the procoagulant process by inactivating factors VIIIa and Va, critical components of the tenase and
prothrombinase complexes, respectively, in a reaction that is also enhanced by endothelial cell receptor (EPCR)
and protein S. In addition to its effects on thrombin generation, APC neutralizes plasminogen activator inhibitor-1
(PAI-1), and thereby enhances clot remodeling (15).
The fibrinolytic system operates to preserve blood fluidity and to prevent clot formation within noninjured vessels.
The key player of the fibrinolytic system is plasmin, which degrades fibrin into soluble fibrin degradation products
and inactivates FVa and FVIIIa. Plasmin comes into action when plasminogen is cleaved by specific activators,
that is, by tPA and/or the urokinase-type plasminogen activator (u-PA). Both plasminogen activators are
synthesized and stored in endothelial cells. Their release from unaffected endothelial cells is triggered by FXa,
thrombin, kallikrein, and HMWK (see Fig. 17.8). tPA mediates intravascular plasminogen activation and is
primarily involved in the dissolution of fibrin in the circulation, while u-PA binds to specific cellular receptors,
resulting in enhanced activation of cell-bound plasminogen, and is primarily involved in tissue remodeling and
repair (84). Under physiologic conditions, the concentrations of tPA and u-PA are the key determinants of
plasmin formation, as plasminogen exists in vast excess in the plasma (15).
The fibrinolytic system is well regulated by inhibitory pathways. A direct inhibition of plasmin is elicited by α2-
antiplasmin, while an indirect inhibition of the fibrinolytic system consists in the type I and II plasminogen activator
inhibitors (PAI-1 and PAI-2), which are released from endothelial cells to block tPA and u-PA. Although the
formation of complexes and inactivation of circulating plasmin represent a direct target of α2-antiplasmin, a
relevant part of plasmin is bound to fibrin and is thereby protected from α2-antiplasmin. Hence, fibrinolysis may
occur despite physiologic levels of α2-antiplasmin. To avoid premature lysis of clots on the other hand, PAI-1 is
present in several-fold molar excess in the plasma and is also released by activated platelets (85).
Another mediator that limits fibrinolysis principally in the vicinity of the clot is thrombin activator fibrinolysis
inhibitor (TAFI) (86). TAFI is synthesized in an inactive form by the liver, and circulates in the plasma, possibly in
a complex with plasminogen. TAFI requires either plasmin or thrombin for activation, although thrombin-mediated
TAFI activation requires extraordinarily large and relatively unphysiologic amounts of free thrombin. By contrast,
thrombomodulin potentiates thrombin-induced TAFI activation 1,250-fold,
P.444
making this an essential cofactor and one that is predominantly available at the blood-vessel interface (15).
FIGURE 17.8. The fibrinolytic system. tPA, tissue-type plasminogen activator; u-PA, urokinase-type plasminogen
activator; PAI-1, plasminogen activator inhibitor I; PAI-II, plasminogen activator inhibitor II; HMWK, high-
molecular-weight kininogen; TAFI, thrombin activatable fibrinolysis inhibitor. (Modified according to Mahdy AM,
Webster NR. Perioperative systemic haemostatic agents. Br J Anaesth 2004;93:842-858.)
Hyperfibrinolysis during CPB

During CPB, fibrinolytic activity is typically increased with pro-fibrinolytic activity being virtually unopposed by
endogenous antifibrinolytic agents. As mentioned earlier, endothelial cells get activated by contact of circulating
blood with the nonendothelial circuit surface. Following activation of endothelial cells, tPA is released, resulting in
a 100-fold increase of plasmin generation already a few minutes after initiation of CPB (61). As a consequence,
D-dimer levels increase 200-fold indicating the degradation of fibrin, and additionally, platelet adhesion and
aggregation have been observed to be altered in the context of CPB-associated fibrinolysis (87).
While hyperfibrinolysis per se is associated with an increased bleeding tendency, also the architecture of the
fibrin clot has an influence on the vulnerability of newly formed clots to fibrinolysis. The lysis resistance of fibrin
strands mainly depends on the availability of fibrinogen and thrombin: aside from converting fibrinogen to fibrin,
thrombin also activates FXIII and thereby empowers the fibrin clot to gain stability by cross-linking the fibrin
monomers to insoluble fibrin polymers. Of note, thrombin exerts a lysis-protective effect to the clot by activating
TAFI.
The aforementioned antiplatelet action of plasmin may contribute to the dysfunction demonstrable in freely
circulating platelets during CPB, although active tPA principally localizes onto formed fibrin. Tranexamic acid
preserves platelet granule content on CPB, possibly by preventing partial platelet activation. Such an effect of
this small-molecule antifibrinolytic may be much more specific than the multiplicity of actions of aprotinin in
preserving platelet number and function following CPB (88,89).
Plasmin has been demonstrated to elicit a redistribution of GPIb and GPIIb/IIIa receptors on platelets, thereby
impairing primary hemostasis (87). On average, CPB is associated with a modest decrease, in the range of 20%
to 30%, in platelet GPIb, and aprotinin has been shown to preserve platelet GPIb levels. GPIb-dependent
adhesion also depends on the presence of high-molecular-weight polymers of vWF for optimal activity, as
discussed earlier. The plasma levels of these larger polymers are regulated by low-level proteolysis, allowing for
a prompt but not pathologic response to arterial injury. CPB causes a modest increase in vWF proteolysis that is
proportional to CPB duration, reducing the proportion of the larger vWF multimers that are most hemostatically
effective (90). It is possible that, in concert with other multiple defects induced by CPB, this decrease might be a
factor in suboptimal postoperative platelet performance (15).
SUMMARY
Circulating blood maintains pro- and antithrombotic factors that are carefully balanced in number and
function to preserve blood fluidity, and yet this balance can transform instantly to seal off a site of bleeding.
However, during CPB this balance is profoundly challenged.
CPB alters hematorheologic properties of circulating blood and activates cellular and soluble blood
constituents. RBCs have functions beyond oxygen transport, such as contributing to clot formation and
being the driving force of blood rheology. Hematocrit is the key determinant of rheologic properties, which
play an important role in hemostasis by driving the radial dispersion of platelets and plasmatic factors
toward the endothelial lesion. However, CPB impairs the function and number of RBCs via hemodilution,
hemolysis, and hypothermia.
Moreover, CPB exerts a proinflammatory response arising from activation of leukocytes and endothelial
cells via the contact and complement systems. Within these systems, kallikrein, high-molecular-weight
kininogen, and thrombin are the mediators responsible for the activation for the coagulatory system.
Endothelial cells become also activated by stimulated neutrophils and monocytes. The expression of tissue
factor on the surface of activated leukocytes is another mechanism essential in the initiation of consumptive
coagulopathy. Moreover, activated endothelial cells release anticoagulant agents such as AT and APC and
activate the fibrinolytic system. Taken together, the cross talk between CPB-induced inflammation and
coagulation results in impairment of hemostasis and increased perioperative blood loss and the need for
allogeneic blood transfusions.
CPB is typically associated with qualitative and quantitative platelet defects. Thrombocytopenia can be
caused by heparin (heparin-induced thrombopenia [HIT]), by platelet adhesion to the circuit surface,
mechanical disruption, and sequestration in the spleen. Moreover, platelets get activated during the
inflammatory response and their number decreases in line with consumptive coagulopathy. Platelet
dysfunction is frequently witnessed during CPB. While platelet aggregation is the pharmacologic target of
antiplatelet drugs like aspirin or clopidogrel, CPB routinely impairs platelet adhesion and aggregation.
Platelets become activated, resulting in degranulation and a lack of responsibility to agonists like
epinephrine, collagen, ADP, and thrombin. Moreover, the number of GPIb- and GPIIb/IIIa-receptors
decreases, resulting in an impairment of primary hemostasis.
Aside from thrombocytopenia and platelet dysfunction, the post-CPB bleeding tendency after cardiac
surgery is also attributable to nonplatelet-related causes such as hyperfibrinolysis, heparin or protamine
excess, loss of plasmatic coagulation factors and thus reduced thrombin potential and weakness of the
fibrin clot itself (reduced activity of FXIIIa). Hemodilution and hypothermia also contribute to malfunction of
the plasmatic coagulation system and thereby to post-CPB bleeding. Fibrinogen depletion is predominantly
due to adhesion to the circuit surface. Despite anticoagulation with heparin, the plasmatic coagulation
cascade is still activated leading to thrombin generation and consumption of coagulation factors. Of note, a
fraction of heparin is sequestered in the endothelium and may be released after circulating heparin
P.445
has been neutralized with protamine and this so-called heparin rebound also contributes to post-CPB
bleeding tendency.
Another factor compromising hemostasis is the activation of the fibrinolytic system. Elevated plasmin levels
may result in excessive clot lysis, while low fibrin and thrombin levels render clots more prone to lysis. In
addition, the fibrinolytic system impairs platelet function due to redistribution of membrane receptors.
The chance that a clot can successfully form and arrest bleeding mainly depends on the availability of
fibrinogen and the efficiency of thrombin generation, on the one hand, and on the protection of the
developing clot against fibrinolysis, on the other hand. Frequently, surgery by itself challenges the
hematologic systems involved in these processes. Perhaps more than any other event, extracorporeal
circulation in conjunction with surgery impairs the hemostatic system in ways that are still incompletely
understood. However, the cross talk between inflammation and coagulation seems to play a key role in this
context.
Ideally, both coagulation and inflammatory systems could be arrested until the need for the CPB circuit has
ended; then separation from CPB would be accompanied by the full return of coagulation and immunologic
function. In reality, the coagulation “arrest” achieved by current anticoagulation is partial at best, and
subsequent restoration of coagulation is frequently suboptimal. Occasionally it is profoundly impaired,
resulting in excessive blood loss and the need for transfusion. Likewise, stimulation of the immune system
by the bypass circuit produces an inflammatory response persisting into the post-CPB period, possibly with
its own adverse hemostatic effects. In view of these complex alterations observed during CPB, hemostatic
management remains a major challenge during any form of extracorporeal circulation.
KEY Points
Cardiopulmonary bypass (CPB) imposes extremes on hematorheology and on hemostasis by
affecting cellular and soluble blood constituents. The underlying mechanisms include hemodilution,
hypothermia, hemolysis, heparinization, and activation of the coagulation system.
RBCs have functions beyond oxygen transport, such as contributing to clot formation and being the
driving force of blood rheology. Hematocrit is the key determinant of rheologic properties, which play
an important role in hemostasis by driving the radial dispersion of platelets and plasmatic factors
toward the endothelial lesion.
CPB is typically associated with qualitative and quantitative platelet defects. Thrombocytopenia can
be caused by heparin (heparin-induced thrombopenia, HIT), by platelet-adhesion to the circuit
surface, mechanical disruption, and sequestration in the spleen. Moreover, platelet activation results
in degranulation and a lack of responsiveness to agonists like epinephrine, collagen, ADP, and
thrombin.
During CPB, fibrinogen depletion predominantly derives from adhesion to the circuit surface.
Despite anticoagulation with heparin, the plasmatic coagulation cascade is still activated, leading to
thrombin generation and consumption of coagulation factors.
Although heparin is neutralized by protamine at the end of CPB, a fraction of heparin may be
unavailable for protamine reversal because of protein binding or endothelial sequestration.
Moreover, activation of the fibrinolytic system impairs hemostasis. Elevated plasmin levels may
result in excessive clot lysis, while low fibrin and thrombin levels render clots more prone to lysis. In
addition, fibrinolytic system activation impairs platelets via redistribution of membrane receptors.
CPB exerts a proinflammatory response arising from activation of leukocytes and endothelial cells
via the contact and complement systems. The cross talk between CPB-induced inflammation and
coagulation impairs hemostasis and increases perioperative blood loss and transfusion
requirements.
Both blood transfusion and organ dysfunction promoted by proinflammatory mediators and activated
clotting factors increase perioperative morbidity.
REFERENCES
1. Chandler WL. Effects of hemodilution, blood loss, and consumption on hemostatic factor levels during
2. Habler OP, Messmer KF. The physiology of oxygen transport. Transfus Sci 1997;18:425-435.
3. Lequeux PY, Bouckaert Y, Sekkat H, et al. Continuous mixed venous and central venous oxygen
saturation in cardiac surgery with cardiopulmonary bypass. Eur J Anaesthesiol 2010;27:295-299.
4. Whelihan MF, Mann KG. The role of the red cell membrane in thrombin generation. Thromb Res
2013;131:377-382.
5. Peyrou V, Lormeau JC, Herault JP, et al. Contribution of erythrocytes to thrombin generation in whole
blood. Thromb Haemost 1999;81:400-406.
6. Rittenhouse EA, Mori H, Dillard DH, et al. Deep hypothermia in cardiovascular surgery. Ann Thorac Surg
1974;17:63-98.
7. Wright G. Haemolysis during cardiopulmonary bypass: update. Perfusion 2001;16:345-351.
P.446
8. Vermeulen Windsant IC, Hanssen SJ, Buurman WA, et al. Cardiovascular surgery and organ damage: time
to reconsider the role of hemolysis. J Thorac Cardiovasc Surg 2011;142:1-11.
9. Svenmarker S, Jansson E, Stenlund H, et al. Red blood cell trauma during cardiopulmonary bypass:
narrow pore filterability versus free haemoglobin. Perfusion 2000;15:33-40.
10. Intaglietta M. Microcirculatory basis for the design of artificial blood. Microcirculation 1999;6:247-258.
11. Kristiansen M, Graversen JH, Jacobsen C, et al. Identification of the haemoglobin scavenger receptor.
Nature 2001;409:198-201.
12. Anastasiadis K, Asteriou C, Deliopoulos A, et al. Haematological effects of minimized compared to

conventional extracorporeal circulation after coronary revascularization procedures. Perfusion 2010;25:197-
203.
13. Schaer DJ, Buehler PW, Alayash AI, et al. Hemolysis and free hemoglobin revisited: exploring
hemoglobin and hemin scavengers as a novel class of therapeutic proteins. Blood 2013;121:1276-1284.
14. Messmer K, Sunder-Plassmann L. Hemodilution. Prog Surg 1974;13:208-245.

15. Rinder CS. Hematologic effects and coagulopathy. In: Gravlee GP, Davis RF, Stammers AH, et al., eds.
Cardiopulmonary bypass—principles and practice. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins,
2008:439-458.
16. Jennewein C, Paulus P, Zacharowski K. Linking inflammation and coagulation: novel drug targets to treat
organ ischemia. Curr Opin Anaesthesiol 2011;24:375-380.
17. Rossaint J, Berger C, Van AH, et al. Cardiopulmonary bypass during cardiac surgery modulates systemic
inflammation by affecting different steps of the leukocyte recruitment cascade. PLoS One 2012;7:e45738.
18. Day JR, Taylor KM. The systemic inflammatory response syndrome and cardiopulmonary bypass. Int J
Surg 2005;3:129-140.
19. Warren OJ, Smith AJ, Alexiou C, et al. The inflammatory response to cardiopulmonary bypass, Part 1:
mechanisms of pathogenesis. J Cardiothorac Vasc Anesth 2009;23:223-231.
20. Belhaj A. Actual knowledge of systemic inflammation reaction during cardiopulmonary bypass. Recent
Pat Cardiovasc Drug Discov 2012;7: 165-169.
21. Hanssen SJ, Derikx JP, Vermeulen Windsant IC, et al. Visceral injury and systemic inflammation in
patients undergoing extracorporeal circulation during aortic surgery. Ann Surg 2008;248:117-125.
22. Rosner MH, Portilla D, Okusa MD. Cardiac surgery as a cause of acute kidney injury: pathogenesis and
potential therapies. J Intensive Care Med 2008;23:3-18.
23. Hattori T, Khan MM, Colman RW, et al. Plasma tissue factor plus activated peripheral mononuclear cells
activate factors VII and X in cardiac surgical wounds. J Am Coll Cardiol 2005;46:707-713.
24. Zimmermann AK, Simon P, Seeburger J, et al. Cytokine gene expression in monocytes of patients
undergoing cardiopulmonary bypass surgery evaluated by real-time PCR. J Cell Mol Med 2003;7:146-156.
25. Shibamiya A, Tabuchi N, Chung J, et al. Formation of tissue factor-bearing leukocytes during and after
cardiopulmonary bypass. Thromb Haemost 2004;92:124-131.
26. Philippidis P, Mason JC, Evans BJ, et al. Hemoglobin scavenger receptor CD163 mediates interleukin-10
release and heme oxygenase-1 synthesis: antiinflammatory monocyte-macrophage responses in vitro, in
resolving skin blisters in vivo, and after cardiopulmonary bypass surgery. Circ Res 2004;94:119-126.
27. Maugeri N, Brambilla M, Camera M, et al. Human polymorphonuclear leukocytes produce and express
functional tissue factor upon stimulation. J Thromb Haemost 2006;4:1323-1330.
28. Rinder CS, Bonan JL, Rinder HM, et al. Cardiopulmonary bypass induces leukocyte-platelet adhesion.
Blood 1992;79:1201-1205.
29. Weerasinghe A, Athanasiou T, Philippidis P, et al. Platelet-monocyte pro-coagulant interactions in on-
pump coronary surgery. Eur J Cardiothorac Surg 2006;29:312-318.
30. Loscalzo J. The macrophage and fibrinolysis. Semin Thromb Hemost 1996;22:503-506.
31. Machovich R, Owen WG. The elastase-mediated pathway of fibrinolysis. Blood Coagul Fibrinolysis
1990;1:79-90.
32. Kolev K, Machovich R. Molecular and cellular modulation of fibrinolysis. Thromb Haemost 2003;89:610-
621.
33. Ghoshal K, Bhattacharyya M. Overview of platelet physiology: its hemostatic and nonhemostatic role in
disease pathogenesis. ScientificWorldJournal 2014;2014:781857.
34. de Wit TR, van Mourik JA. Biosynthesis, processing and secretion of von Willebrand factor: biological
implications. Best Pract Res Clin Haematol 2001;14:241-255.
35. Bennett JS, Berger BW, Billings PC. The structure and function of platelet integrins. J Thromb Haemost
2009;7(Suppl 1):200-205.
36. Munnix IC, Cosemans JM, Auger JM, et al. Platelet response heterogeneity in thrombus formation.
Thromb Haemost 2009;102:1149-1156.
37. American Society of Anesthesiologists Task Force on Perioperative Blood Transfusion and Adjuvant
Therapies. Practice guidelines for perioperative blood transfusion and adjuvant therapies: an updated report
by the American Society of Anesthesiologists Task Force on Perioperative Blood Transfusion and Adjuvant
Therapies. Anesthesiology 2006;105:198-208.
38. Weerasinghe A, Taylor KM. The platelet in cardiopulmonary bypass. Ann Thorac Surg 1998;66:2145-
2152.
39. Addonizio VP, Colman RW. Platelets and extracorporeal circulation. Biomaterials 1982;3:9-15.
40. Gemmell CH, Ramirez SM, Yeo EL, et al. Platelet activation in whole blood by artificial surfaces:
identification of platelet-derived microparticles and activated platelet binding to leukocytes as material-
induced activation events. J Lab Clin Med 1995;125:276-287.
41. Paparella D, Yau TM, Young E. Cardiopulmonary bypass induced inflammation: pathophysiology and
treatment. An update. Eur J Cardiothorac Surg 2002;21:232-244.
42. Sobel M, McNeill PM, Carlson PL, et al. Heparin inhibition of von Willebrand factor-dependent platelet
function in vitro and in vivo. J Clin Invest 1991;87:1787-1793.
43. Hofmann B, Bushnaq H, Kraus FB, et al. Immediate effects of individualized heparin and protamine
management on hemostatic activation and platelet function in adult patients undergoing cardiac surgery with
tranexamic acid antifibrinolytic therapy. Perfusion 2013;28:412-418.
44. Lumadue JA, Lanzkron SM, Kennedy SD, et al. Cytokine induction of platelet activation. Am J Clin Pathol
1996;106:795-798.
45. Rinder HM, Tracey JL, Rinder CS, et al. Neutrophil but not monocyte activation inhibits P-selectin-
mediated platelet adhesion. Thromb Haemost 1994;72:750-756.
46. Rinder CS, Smith MJ, Rinder HM, et al. Leukocyte effects of C5a-receptor blockade during simulated
extracorporeal circulation. Ann Thorac Surg 2007;83:146-152.
47. Rinder CS, Mathew JP, Rinder HM, et al. Modulation of platelet surface adhesion receptors during
48. Tandon NN, Kralisz U, Jamieson GA. Identification of glycoprotein IV (CD36) as a primary receptor for
platelet-collagen adhesion. J Biol Chem 1989;264:7576-7583.
49. Tuszynski GP, Rothman VL, Murphy A, et al. Thrombospondin promotes platelet aggregation. Blood
1988;72:109-115.
50. Zilla P, Fasol R, Groscurth P, et al. Blood platelets in cardiopulmonary bypass operations. Recovery
occurs after initial stimulation, rather than continual activation. J Thorac Cardiovasc Surg 1989;97:379-388.
51. Saczkowski R, Maklin M, Mesana T, et al. Centrifugal pump and roller pump in adult cardiac surgery: a
meta-analysis of randomized controlled trials. Artif Organs 2012;36:668-676.
52. Yoshikai M, Hamada M, Takarabe K, et al. Clinical use of centrifugal pumps and the roller pump in open
heart surgery: a comparative evaluation. Artif Organs 1996;20:704-706.
53. Lindholm L, Westerberg M, Bengtsson A, et al. A closed perfusion system with heparin coating and
centrifugal pump improves cardiopulmonary bypass biocompatibility in elderly patients. Ann Thorac Surg
2004;78:2131-2138.
54. Chung A, Wildhirt SM, Wang S, et al. Combined administration of nitric oxide gas and iloprost during
cardiopulmonary bypass reduces platelet dysfunction: a pilot clinical study. J Thorac Cardiovasc Surg
2005;129:782-790.
55. Christenson JT, Reuse J, Badel P, et al. Plateletpheresis before redo CABG diminishes excessive blood
transfusion. Ann Thorac Surg 1996;62:1373-1378.
56. DelRossi AJ, Cernaianu AC, Vertrees RA, et al. Platelet-rich plasma reduces postoperative blood loss
after cardiopulmonary bypass. J Thorac Cardiovasc Surg 1990;100:281-286.
57. Ranucci M. The endothelial function in cardiac surgery. Minerva Anestesiol 2006;72:503-506.
58. Henn V, Slupsky JR, Grafe M, et al. CD40 ligand on activated platelets triggers an inflammatory reaction
of endothelial cells. Nature 1998;391:591-594.
59. Cardigan RA, Mackie IJ, Machin SJ. Hemostatic-endothelial interactions: a potential anticoagulant role of
the endothelium in the pulmonary circulation during cardiac surgery. J Cardiothorac Vasc Anesth
1997;11:329-336.
P.447
60. Chandler WL, Velan T. Secretion of tissue plasminogen activator and plasminogen activator inhibitor 1
during cardiopulmonary bypass. Thromb Res 2003;112:185-192.
61. Chandler WL, Velan T. Plasmin generation and D-dimer formation during cardiopulmonary bypass. Blood
62. Edmunds LH Jr. Managing fibrinolysis without aprotinin. Ann Thorac Surg 2010;89:324-331.
63. Sainz IM, Pixley RA, Colman RW. Fifty years of research on the plasma kallikrein-kinin system: from
protein structure and function to cell biology and in-vivo pathophysiology. Thromb Haemost 2007;98:77-83.
64. Carr JA, Silverman N. The heparin-protamine interaction. A review. J Cardiovasc Surg (Torino)
1999;40:659-666.
65. Wiedmer T, Esmon CT, Sims PJ. Complement proteins C5b-9 stimulate procoagulant activity through
platelet prothrombinase. Blood 1986;68:875-880.
66. Ando B, Wiedmer T, Sims PJ. The secretory release reaction initiated by complement proteins C5b-9
occurs without platelet aggregation through glycoprotein IIb-IIIa. Blood 1989;73:462-467.
67. Davie EW, Ratnoff OD. Waterfall sequence for intrinsic blood clotting. Science 1964;145:1310-1312.
68. McFarlane RG. An enzyme cascade in the blood clotting mechanism, and its function as a biochemical
amplifier. Nature 1964;202:498-499.
69. Hoffman M, Monroe DM III. A cell-based model of hemostasis. Thromb Haemost 2001;85:958-965.
70. Hoffman M. Remodeling the blood coagulation cascade. J Thromb Thrombolysis 2003;16:17-20.
71. Ariens RA, Lai TS, Weisel JW, et al. Role of factor XIII in fibrin clot formation and effects of genetic
polymorphisms. Blood 2002;100:743-754.
72. Musial J, Niewiarowski S, Hershock D, et al. Loss of fibrinogen receptors from the platelet surface during
simulated extracorporeal circulation. J Lab Clin Med 1985;105:514-522.
73. Chandler WL, Patel MA, Gravelle L, et al. Factor XIIIA and clot strength after cardiopulmonary bypass.
Blood Coagul Fibrinolysis 2001;12:101-108.
74. Khan MM, Hattori T, Niewiarowski S, et al. Truncated and microparticle-free soluble tissue factor bound
to peripheral monocytes preferentially activate factor VII. Thromb Haemost 2006;95:462-468.
75. Engelmann B. Initiation of coagulation by tissue factor carriers in blood. Blood Cells Mol Dis
2006;36:188-190.
76. Griffith MJ. Kinetics of the heparin-enhanced antithrombin III/thrombin reaction. Evidence for a template
model for the mechanism of action of heparin. J Biol Chem 1982;257:7360-7365.
77. Follis F, Filippone G, Montalbano G, et al. Argatroban as a substitute of heparin during cardiopulmonary
bypass: a safe alternative? Interact Cardiovasc Thorac Surg 2010;10:592-596.
78. Warkentin TE, Greinacher A, Koster A. Bivalirudin. Thromb Haemost 2008;99:830-839.
operations. Ann Thorac Surg 1998;65: 712-718.
80. Philippou H, Adami A, Davidson SJ, et al. Tissue factor is rapidly elevated in plasma collected from the
pericardial cavity during cardiopulmonary bypass. Thromb Haemost 2000;84:124-128.
81. Wolberg AS, Meng ZH, Monroe DM III, et al. A systematic evaluation of the effect of temperature on
coagulation enzyme activity and platelet function. J Trauma 2004;56:1221-1228.
82. Crawley JT, Lane DA. The haemostatic role of tissue factor pathway inhibitor. Arterioscler Thromb Vasc
Biol 2008;28:233-242.
83. Esmon CT. Protein C anticoagulant pathway and its role in controlling microvascular thrombosis and
inflammation. Crit Care Med 2001;29: S48-S51.
84. Mahdy AM, Webster NR. Perioperative systemic haemostatic agents. Br J Anaesth 2004;93:842-858.
85. Dellas C, Loskutoff DJ. Historical analysis of PAI-1 from its discovery to its potential role in cell motility
and disease. Thromb Haemost 2005;93: 631-640.
86. Nesheim M. Thrombin and fibrinolysis. Chest 2003;124:33S-39S.
87. Cramer EM, Lu H, Caen JP, et al. Differential redistribution of platelet glycoproteins Ib and IIb-IIIa after
plasmin stimulation. Blood 1991;77: 694-699.
88. Mojcik CF, Levy JH. Aprotinin and the systemic inflammatory response after cardiopulmonary bypass.
89. McCormack PL. Tranexamic acid: a review of its use in the treatment of hyperfibrinolysis. Drugs
2012;72:585-617.
90. Perutelli P. Proteolysis of von Willebrand factor is increased during cardiopulmonary bypass. Thromb
Res 2001;102:467-473.
Chapter 18
Coagulation Testing
Jay C. Horrow
Josef Nile Mueksch
Nicholas Weber
Michael S. Green
No coagulation test can duplicate the complex milieu present at an injured vessel. Merely placing a needle or a
catheter in a vessel initiates a multitude of hemostatic responses that alter measurements on the blood sample
that has been removed. Surface activation of the clotting cascade begins when blood leaves the protective
environment of the endothelial cells and enters into collection tubes. For these reasons, coagulation tests must
be viewed as an approximation of actual events. This chapter examines the role of coagulation tests performed
at central laboratory facilities and the changing landscape brought about by point-of-care testing.
CENTRALIZED COAGULATION LABORATORY TESTS

Devices using formation of a clot as an endpoint usually employ electrical or optical detection methods. The
classic instrument, the Fibrometer (BBL Microbiological Systems, Cockeysville, MD), places a stationary and a
moving probe in the sample. When fibrin strands bridge the two electrodes, conductivity increases causing a
timer to halt (1). Laboratory prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen, and
thrombin time determinations use this technology.
Prothrombin Time and Activated Partial Thromboplastin Time

Figure 18.1 illustrates the steps in performing these tests. Each test involves centrifuging a citrated specimen of
blood. Citrate complexes calcium, a necessary cofactor in the coagulation cascade, thereby preventing
coagulation factor activation. The supernatant obtained by centrifugation, plasma, is incubated for 3 minutes with
an additive that differs for the two tests. After addition of excess calcium with respect to citrate, the time to
formation of gel is measured.
The PT, better called a complete thromboplastin time, incubates plasma with tissue extract (thromboplastin). As
a tissue product, thromboplastin supplies its own phospholipid plus tissue factor. If the plasma sample contains
sufficient factor VII and factors in the common pathway, it will gel in approximately 12 seconds. Variations in the
potency and quality of thromboplastin reagents require simultaneous determination of a control sample and
comparison of the patient’s result with the control result. Each batch of thromboplastin reagent is graded in
potency. The international normalized ratio (INR) calculation allows for comparison of PT results from different
commercial thromboplastin reagents: INR = PCRISI, where PCR is the ratio of patient sample to control sample
PT results and ISI is the international sensitivity index, a measure of responsiveness to decreased
concentrations of vitamin K-dependent factors. The higher the ISI of a thromboplastin, the less responsive the
clotting time to changes in coagulation factors when using that thromboplastin. Therefore, a less responsive
thromboplastin, which yields a smaller PCR, carries a larger ISI, yielding a similar calculated INR.
P.450
Thromboplastin reagent manufacturers determine the ISI by comparing the reactivity of each specific lot of
thromboplastin with an international reference preparation (2).
FIGURE 18.1. Steps in performing the prothrombin time (PT, left side) and the activated partial thromboplastin
time (aPTT, right side). See text for details.
The partial thromboplastin time (PTT) incubates plasma with an extract of thromboplastin that contains the
phospholipid but not the tissue factor, thereby preventing activation of extrinsic factor VII. Now entirely dependent
on surface activation alone, the gel forms slowly (73 ± 11 [SD] seconds) (3). The aPTT uses a surface activation
accelerator such as kaolin, ellagic acid, silica, bentonite, or celite, which allows gel formation to then occur in
approximately 32 seconds (1). As with the PT, simultaneous controls are required, with abnormal results at 1.5 or
more times the control.
Warfarin therapy, which inhibits carboxylation of the vitamin K-dependent clotting factors, prolongs the PT
because factor VII production is most vulnerable to lack of vitamin K. Heparin primarily affects the aPTT but not
the PT because the potent procoagulant action of the thromboplastin reagent in the PT test easily overwhelms
any inhibition of factors Xa and thrombin from the moderate doses of heparin used to treat venous thrombosis or
acute coronary syndrome. The less potent partial thromboplastin reagent in the aPTT test, however, is sensitive
enough to demonstrate heparin’s anticoagulant effects. Large doses of heparin will prolong the PT also.
Thrombin Time
Adding thrombin to a plasma sample will form fibrin within 10 seconds if functionally active fibrinogen is present,
heparin is absent, and fibrin degradation products (FDPs) are absent. Sensitivity of the thrombin time to small
amounts of heparin occurs because small amounts of thrombin are added. The traditional thrombin time is
relatively insensitive to fibrinogen deficiency and to FDPs: detectable prolongation requires less than 0.75 g/L
fibrinogen (4) or more than 200 mg/mL FDPs. Sensitivity to FDPs increases if fibrinogen concentrations are low.
Also, diluted plasma increases sensitivity of the thrombin test to fibrinogen deficiency. Amyloidosis prolongs the
thrombin time by inhibiting conversion of fibrinogen to fibrin (5).
Reptilase Time
The Reptilase time measures the interval between addition to plasma of venom from the South American pit viper
Bothrops jararaca and formation of fibrin: it is like a thrombin time, but uses the venom instead of thrombin to
form fibrin. A prolonged Reptilase time implicates reduced or dysfunctional fibrinogen or high concentrations of
FDPs as the cause of a prolonged thrombin time. Neither heparin nor direct thrombin inhibitors prolong the
Reptilase time (6). It is several-fold more insensitive to FDPs than the thrombin time. Amyloidosis also prolongs
the Reptilase time.
Fibrinogen
Most laboratories use the Clauss method for fibrinogen determination, in which a thrombin time is performed on
diluted plasma. With diluted samples, fibrinogen becomes the factor limiting clot formation, so that the clotting
time varies inversely with fibrinogen activity (1). The Ellis method employs undiluted plasma, smaller amounts of
thrombin, and a spectrophotometric measure of turbidity. A PT-based method adds thromboplastin to undiluted
plasma, thereby using endogenously generated thrombin. Antibody-based tests for fibrinogen can distinguish
among the dysfibrinogenemias. Decreased fibrinogen concentration occurs in end-stage hepatic failure,
consumptive coagulopathy, and uncontrolled fibrinolysis leading to fibrinogenolysis, extreme hemodilution, and
massive transfusion.
Fibrin Degradation Products

Immunologic tests provide a semiquantitative determination of the various fragments resulting from fibrin and
fibrinogen degradation. The most common test for FDPs uses latex agglutination of serum. Note that serum, not
plasma, is used. It provides results as either negative (<10 μg/mL) or positive (>10 μg/mL) for antigens, which
are the breakdown products of either fibrin or fibrinogen. Serial dilutions of plasma yield more specific information
when the undiluted sample is positive. More expensive quantitative analysis reveals normal serum levels of 2.1
to 2.7 μg/mL for FDPs in the absence of exercise or stress (1). This test does not differentiate the breakdown
products of fibrinogen from those of fibrin.
D-Dimer
Molecules of two linked “D” domains, shown in Figure 18.2, a specific degradation product of cross-linked fibrin,
can be detected either semiquantitatively with a latex agglutination technique or in a fully quantitative manner
with an enzyme-linked immunosorbent assay (ELISA). Many hospital coagulation laboratories offer this test on a
batched basis. The D-dimer is more specific for secondary fibrinolysis than the FDP test. Like the FDP test, D-
dimer results appear as fibrinogen equivalent units (i.e., the quantity of fibrinogen initially present that leads to
the observed level of breakdown product). Normally, D-dimer is less than 0.5 μg/mL (fibrinogen equivalent units).
Antibody-based tests use plasma, rather than serum, because the specificity afforded by the antibody method
prevents fibrinogen in plasma from confounding the results.
Platelet Count
The central role of platelets in coagulation and the impact of bypass on platelet function augment the importance
of monitoring platelets during surgery. Because bypass affects both platelet function and count, measurement of
platelet count is necessary but not sufficient to assess platelet role in coagulation. Although cell counters can
and have been made mobile (7), measurement of platelet count has remained a central laboratory function at
nearly all centers.
P.451
FIGURE 18.2. Formation of fibrin degradation products from cross-linked fibrin. Plasmin cleaves fibrin between
its D and E domains at the dashed lines to yield D-dimer (DD), fragment Y (DE), fragment X (DED), and larger
combinations (DY, YY, DXD, and others not shown). D-Dimer serves as a specific marker for lysis of cross-linked
fibrin. (From Francis CW, Marder VJ. Physiologic regulation and pathologic disorders of fibrinolysis. In: Colman
RW, Hirsh J, Marder VJ, et al., eds. Hemostasis and thrombosis. 3rd ed. Philadelphia, PA: JB Lippincott Co,
1994:1076-1103, with permission.)
FIGURE 18.3. The dose-response curve of ecarin clotting time (ECT) to in vitro titration in six patients before
cardiac surgery, with each solid dot representing results from one patient. (From Nuttall GA, Oliver WC Jr.
Patients with a history of type II heparin-induced thrombocytopenia with thrombosis requiring cardiac surgery
with cardiopulmonary bypass: a prospective observational case series. Anesth Analg 2003;96(2):344-350.)
Platelet Aggregometry
Platelet aggregometry utilizes a photo-optical instrument to measure light transmittance through a platelet-rich
plasma sample (8). Upon exposure to a platelet agonist, the initially turbid sample shows increased light
transmittance as platelets adhere to surfaces and one another. Impaired aggregation correlates poorly with
clinical bleeding (8,9). Agonist agents include collagen, epinephrine, and adenosine diphosphate (ADP). Owing
to the technical expertise often required to perform aggregometry, it finds application in research more often than
in routine clinical care.
Ecarin Clotting Time

The injectable direct thrombin inhibitors hirudin, bivalirudin (Angiomax), and argatroban are alternatives to
heparin available to patients with heparin-induced thrombocytopenia (HIT) (see Chapter 19). The ecarin clotting
time (ECT) monitors the extent of anticoagulation from direct thrombin inhibitors. It is based on the conversion of
thrombin to meizothrombin by ecarin, venom from the snake Echis carinatus (10). Less procoagulant than
thrombin, meizothrombin binds to direct thrombin inhibitors in equimolar concentrations creating a linear
correlation between ECT prolongation and thrombin inhibitor concentration (Fig. 18.3). With a point-of-care ECT
test (11,12,13,14) no longer available, each hospital laboratory must create its own standardized version,
thereby making the ECT extremely difficult to apply to the operative care of patients with HIT. Clinicians report
successful cardiopulmonary bypass (CPB) using individual calibration curves for each patient (15). An alternative
anticoagulation management scheme for patients with HIT takes the functional approach using either the
activated clotting time (ACT) or aPTT,
P.452
as opposed to targeting specific blood concentrations using the ECT. Only case reports exist regarding
monitoring failure or success (16,17,18,19,20,21).
POINT-OF-CARE COAGULATION TESTS

For clinicians, the ability to obtain coagulation results in a timely manner critically impacts the diagnosis and
treatment of specific hemostatic derangements: results must be timely as well as accurate. Prompt turnaround
potentially saves time, which translates into financial savings. The desire for accurate and prompt coagulation
information has created an interest in point-of-care testing (22).
Point-of-care, also designated as “near-patient,” “on-site,” “alternate site,” or “bedside,” tests utilize whole-blood
samples in close proximity to the patient, compared with a laboratory test performed on a serum or plasma
sample at a hospital location remote from the patient. Figure 18.4 represents a typical point-of-care device.
Transport of the sample to the coagulation laboratory, centrifugation of the sample, extraction of plasma or
serum, and batch testing add time and expense to the testing procedure (22).
Point-of-care tests clearly provide results faster than laboratory tests: PT, INR, aPTT results average 2.23
minutes (range 20-418 seconds) compared with 90 minutes for laboratory versions. In one study, the quickest
laboratory coagulation result (21 minutes) was three times longer than the tardiest one by point of care (6.97
minutes) (22).
Point-of-care tests, however, have limited scope, are usually performed by personnel without formal laboratory
training, and are expensive. Cost:benefit ratios remain unanalyzed for these tests. Also, point-of-care testing in
the United States must fulfill the same requirements that laboratory tests meet of the Clinical Laboratory
Improvement Amendment, College of American Pathologists, Health Care Finance Administration, and the Joint
Commission on Accreditation of Healthcare Organizations (23).
FIGURE 18.4. The Hemochron Signature Elite point-of-care coagulation analyzer measures ACT, aPTT, PT,
and INR. A whole-blood droplet is placed onto a preinserted cuvette yielding results. (From
http://www.itcmed.com/products/hemochron-signature-elite-whole-blood-microcoagulation-system. Accessed 18-
July-2015.)
The real-time endpoints for some point-of-care tests differ from the values reported because of adjustment
algorithms accounting for the difference in methodology. For example, point-of-care aPTT endpoints take slightly
longer than those of the traditional laboratory-based aPTT. The Hemochron Jr. ACT does not report actual
elapsed time, but rather calculates the ACT determined by previous Hemochron devices from an algorithm (see
subsequent text). These discrepancies can confuse caregivers unaware of the scientific foundation of the test
procedures.
In addition, point-of-care tests usually do not utilize a coincident control sample. Therefore, periodic quality
control assumes great importance to provide accurate reproducible tests; these administrative and regulatory
burdens fall on the caregivers by the patient’s bedside or in the operating room. Because near-patient testing
technology undergoes rapid development, the reader should seek additional current information when
implementing it in the operating room. With these strengths and limitations in mind, this chapter now presents
information on several point-of-care tests for evaluating the coagulation status of patients during and after CPB.
Heparin Monitoring
Laboratory testing for heparin falls into two categories: clotting function and measurements of blood- or plasma
heparin concentration. Advocates of clotting time cite the importance of assessing the clinical effect of heparin,
suggesting that measuring concentration alone fails to detect patients resistant to anticoagulation effects of
heparin (24). Proponents of concentration assays note the changing relation between ACT and blood heparin
concentration induced by CPB, especially during hypothermia (25). Desirable characteristics of a heparin monitor
include low cost, the use of whole blood, point-of-care availability with minimal equipment and operator attention,
precise and accurate results that are quickly available, and the use of shelf-stable reagents (26).
Activated Clotting Time

Introduced in 1966 by Hattersley (27), the ACT remains the primary workhorse for monitoring anticoagulation
during CPB. Clinicians may now choose from a variety of devices and reagents; the specific ones chosen will
affect the degree of automation and the normal and therapeutic ranges of the test (28,29). Originally described
using diatomaceous earth (celite) as an activator, the operator placed whole blood into a prewarmed tube
submersed in a water bath or placed on a heating block, and measured the time for clot to form (27). Variation in
operator adherence to detail led to high variability in results, often explaining the differences from one institution
to another in ACT requirements for initiation of CPB (30).
The original manually performed ACT has been replaced by automated versions that minimize distraction from
the patient
P.453
during CPB. Options available concurrent with publication appear in Table 18.1, with discussion immediately
following.
The first automated ACT utilized tubes containing celite activator and a small cylindrical magnet (Hemochron
ACT; International Technidyne Corp., Edison, NJ) (1). The clinician starts a timer upon placing 2 mL of blood in
the tube, mixes the contents, and places it in an angled detector well, providing slow rotation. The magnet stays
in the most dependent portion of the tube, despite tube rotation, as long as the blood is liquid. When clot forms,
the magnet, encased in the clot, rotates away from the detector, which then halts the timer and activates an
audible signal. Variability using this method remains between 4% and 8%, the higher values occurring with
heparin doses for bypass (31). Updated versions of the original Hemochron machine now perform many point-of-
care tests, using tubes with different reagents (described later). Simultaneous measurement of duplicate ACTs
reduces occasional inappropriate clinical management decisions that would occur when relying on a single test
result (32).
Another automated version of Hattersley’s manual test, the HemoTec (Medtronic, Englewood, CO) utilizes a
smaller volume of whole blood placed in a cuvette containing kaolin activator and a plastic stirring plunger that is
lifted up in the cuvette approximately every 2 seconds (3). When the blood thickens sufficiently, fall of the
plunger by gravity is slowed. Optics detects this slower descent of the plunger and a timer is signaled. The kaolin
activator yields ACT values that are shorter than the celite-based Hemochron device (33). Its variability is
approximately 9.2% (34).
TABLE 18.1. Current available devices
Vendor Device Name Method End point
Accriva Hemochron ACT, Heparin response, Protamine Magnet rotation ceases

Diagnostics Response response, Protamine dose assay
Hemochron ACT, PT, aPTT Optical interference

Signature Elite
Verify Now Platelet reactivity Change in turbidity
Medtronic HMS Plus Heparin response Tardy descent of raised

flag, optically detected
ACT Plus ACT Electromechanical

disruption
Haemoscope TEG analyzer Thromboelastography Clot formation and

retraction
Hemodyne Hemostasis Platelet viscoelasticity Clot formation and

analysis retraction
system
Tem ROTEM Thromboelastometry Clot formation and

Innovations retraction
Sienco Sonoclot Impedance to rapidly vibrating probe Clot formation and

retraction
ACT, activated clotting time, PT, prothrombin time, aPTT, activated partial thromboplastin time.
The Hemochron Signature Elite device moves 0.015 mL from a drop of whole blood into a test channel (4). The
sample picks up reagent (celite or kaolin for ACT tests, depending on the card chosen) as it moves through the
card. Motion ceases when clot forms. The device detects a mechanical endpoint for clotting by optical means.
The displayed result is not true elapsed time; rather, it shows an equivalent ACT from correlation analysis based
on a device algorithm derived from thousands of samples. Since its introduction (35), the small sample volume
and easy portability have made this a popular option.
Choice of Activator for Activated Clotting Time

Heparin prolongs the celite-activated ACT more than the kaolin-activated ACT. Aprotinin artificially prolongs the
ACT substantially with celite activator, but only minimally with kaolin activator (36,37,38). This is due to binding
of kaolin to aprotinin, eliminating aprotinin’s effect on the ACT (39). The synthetic antifibrinolytic drugs
aminocaproic acid and tranexamic acid do not affect ACT measurement with either activator.
Hypothermia, Hemodilution, and Thrombocytopenia
Table 18.2 lists factors affecting the ACT. A heparin-like inhibitor of factor Xa is released in induced hypothermia,
as determined in canines (40). Still, ACT prolongation may be
P.454
an artifact due to a large, cold sample volume. It does not occur in microliter sample ACT tests such as the
Hemochron Signature Elite.
TABLE 18.2. Clinical conditions influencing activated clotting time (ACT)
Condition Effect on ACT
Hypothermia Increase (40)
Hemodilution Increase or NE (41)
Thrombocytopenia Increase or NE (42,43,44)
Inhibition of platelet function Increase (43,44)
Lysed platelets Decrease (44)
Protamine Increase (45,46)
Aprotinin Increase (40,41)
Surgical incision Decrease (30)
NE, no effect.
TABLE 18.3. Heparin concentration measurement techniques
Protamine titration (manual or automated)
Hexadimethrine (Polybrene) titration
Factor Xa inhibition
Chromogenic assay (manual or automated)
Fluorogenic assay
Colorimetric assay (azure A or toluidine blue)

Hemodilution prolongs the ACT. However, the effect is small within the range of hematocrit values typically
experienced during CPB, and does not occur even within that range unless heparin is present. (41).
Thrombocytopenia prolongs the ACT. This effect occurs only with extreme thrombocytopenia (<20,000/μL) (42).
Functional thrombocytopenia with severe platelet impairment induced by prostacyclin or by platelet activation
increased mean ACT by 50% to 60%. At very high levels of heparinization (>4 units/mL), further ACT increases
depend almost entirely on platelet functional impairment (43). In unheparinized samples, GPIIb/IIIa platelet
membrane inhibitors do not prolong the ACT, but in the presence of heparin, GPIIb/IIIa inhibitors do prolong ACT
in a synergistic manner (44).
Activated Clotting Time Prolongation by Protamine

Gross excess of protamine in relation to heparin or protamine alone prolongs the ACT. The stresses of
anesthesia and surgery independently decrease the ACT.
Monitoring of Heparin Concentration

Because CPB changes the sensitivity of ACT to heparin, some have advocated monitoring heparin concentration
directly. Table 18.3 lists several laboratory techniques that measure whole-blood- or plasma heparin
concentration.
The most often utilized point-of-care heparin concentration monitors are the HMS Plus (Medtronic HemoTec Inc.,
Parker, CO) and the Hemochron Response (Accriva Diagnostics, Piscataway, NJ). Protamine titrations measure
heparin concentration by identifying the reagent (protamine) concentration that optimally neutralizes heparin in
the test sample, as judged by the fastest clot formation (47,48,49,50). Because an excess of protamine ex vivo
inhibits clot formation, the cartridge with the shortest clotting time represents the closest match between heparin
and its neutralizing agent. These titrations are performed on whole blood, which offers a practical advantage
over most other nonclotting-time heparin assays. HMS Plus offers automated techniques that greatly simplify the
bedside measurement of blood heparin concentration and have therefore become second in popularity only to
ACT measurement in heparin monitoring. A management plan for anticoagulation during CPB that maintains
stable heparin concentration, as compared with stable ACT, usually results in larger doses of heparin. This
occurs because hemodilution and hypothermia during CPB prolong both the celite and the kaolin (to a smaller
degree) ACT, but the heparin concentration remains unchanged or lower (33). Automated protamine titration
more closely correlates with measurements of antifactor Xa activity than with ACT during CPB (51), although the
reproducibility of these devices has not been systematically confirmed (Fig. 18.5).
During hemofiltration, volume removal increases not only hematocrit, but also heparin activity (Units/mL), by both
anti-IIa and anti-Xa assays. Hepcon measurements reflect this increased activity (52). Frequent monitoring of
blood heparin concentration during hemofiltration may obviate the need to administer additional heparin doses.
Fluorogenic Assay
In a fluorogenic heparin assay, plasma or diluted whole blood is mixed with pooled normal plasma, then
incubated for a fixed period with a known amount of thrombin (53,54,55,56,57,58). This mixture is then added to
a fibrin analog that is cleaved predictably by any residual thrombin (i.e., thrombin not bound by heparin or AT III)
to form a quantifiably fluorescent product. Most
P.455
applications of this technique require plasma, which makes the procedure impractical for the bedside. The
current level of clinical evidence does not support utilizing heparin concentration alone as the standard of care to
predict postoperative bleeding. In certain situations, for example, during deep hypothermia, where ACT
monitoring alone could lead to inadequate heparin therapy, heparin concentration monitoring is indicated.
FIGURE 18.5. A correlation exists between whole-blood heparin concentration (WBHC), measured by the
Hepcon (Medtronic HemoTec) protamine titration assay and plasma anti-Xa heparin activity (Xa Units/mL) as
measured from the start of cardiopulmonary bypass (CPB) (time 0). Values for whole-blood heparin
concentration were corrected for the hematocrit. The Xa heparin concentration was measured in plasma with a
substrate assay. Note the poor relation between activated clotting time (ACT) and anti-Xa heparin activity due to
the resultant hemodilution causing a decrement of heparin concentration, suggesting that ACT measurements
plotted above in 100s of seconds are not reflective of heparin concentration. HC, Hemochron (celite activator);
HT, HemoTec (kaolin activator). (From Despotis GJ, Summerfield AL, Joist JH. Comparison of activated
coagulation time and whole blood heparin measurements with laboratory plasma anti-Xa heparin concentration in
patients having cardiac operations. J Thorac Cardiovasc Surg 1994;108:1076-1082, with permission.)
FIGURE 18.6. Response of three coagulation tests to heparin. Data are the mean of results from 30 volunteers.
□, Hemochron-activated coagulation time (ACT); ˆ, Hemochron whole-blood activated partial thromboplastin time
(aPTT); •, plasma aPTT. The plasma aPTT becomes unmeasurable with heparin concentrations >0.4 units/mL.
Note that whole-blood aPTT is linear up to ≈1.0 units/mL and the ACT linear up to ≈3 units/mL. Heparin
concentrations are estimated from dose administered and estimated blood volume. (Data from LaDuca F, PhD,
and International Technidyne Corporation.)
Prothrombin Time and Activated Partial Thromboplastin Time

Point-of-care PT and aPTT tests use whole blood rather than plasma. Although platelets remain and provide
phospholipid, a phospholipid reagent is added to ensure an excess. The Hemochron-based tests (Accriva
Diagnostics, Piscataway, NJ) use 2 mL of whole blood. Figure 18.6 demonstrates heparin sensitivity of the ACT,
bedside aPTT, and laboratory aPTT tests. Note that the whole-blood aPTT lies intermediate in sensitivity
between the laboratory aPTT and the ACT. Medtronic HemoTec, Inc. (Englewood, CO) also supplies cartridges
for bedside determination of PT and aPTT using a stir bar-based monitor.
The Hemochron Signature Elite cuvette system features cards for aPTT or PT determination (48). All
Hemochron aPTT and PT products are available for use with fresh whole blood or citrated whole blood. The PT
cuvette uses a highly sensitive lyophilized preparation of rabbit brain thromboplastin. The aPTT cuvette uses a
lyophilized activator plus a phospholipid derived from either brain or lung tissue. Other manufacturers of point-of-
care devices that previously supported both PT and aPTT measurement have recently focused solely on home
PT and INR measurement, and will not be discussed further here. Phospholipid and activator preparations for all
aPTT tests vary considerably between manufacturers and even between lots from the same manufacturer;
hence, one cannot interpret whole blood or plasma aPTT values appropriately unless one knows the
standardized in vitro sensitivity of that particular aPTT test to an anticoagulant such as heparin (48).
Thromboelastography
This viscoelastic test on whole blood rotates a specimen in a cuvette through a small arc (9.5°) every 10
seconds. A central piston, positioned to provide a 1-mm rim of blood (0.35 mL) between it and the cuvette,
remains immobile (R time) until fibrin strands couple it to the rotatory motion of the cuvette (K time). At this time,
fibrin strands begin to build up and cross-link (a angle) building to the maximum amplitude said to symbolize clot
strength (59,60). Fibrinolysis is measured by calculating the time it takes to decrease from the maximum
amplitude. While all this is occurring, torsion on the piston results in movement of a recording heat stylus across
sensitive paper advancing at 2 mm/min. The width of
P.456
the resultant tracing relates to the shear modulus (elasticity) of the specimen (61).
FIGURE 18.7. Idealized thromboelastogram with commonly measured parameters. See text and Table 18.4 for
definition and normal ranges of these measurements. (From Spiess BD, Tuman RJ, McCarthy RJ, et al.
Thromboelastography as an indicator of post cardiopulmonary bypass coagulopathies. J Clin Monit 1987;3:25-
30, with permission.)
FIGURE 18.8. Thromboelastometry (ROTEM) with commonly measured parameters. (Modified from
http://www.practical-haemostasis.com/Miscellaneous/Miscellaneous%20 Tests/teg.html. Accessed 1 July 2015.)
Figure 18.7 and Table 18.4 display the measurements obtained from the TEG and their normal ranges.
Appreciation of the overall shape of the TEG purportedly provides more information than these component
measures. For example, a teardrop shape caused by loss of clot strength may denote high fibrinolytic activity
(62,63). In fact, TEG tracings cannot diagnose one specific hematologic abnormality as a distinct entity because
the overall goal of the TEG is to reflect the global physical property of clot formation. The TEG parameters
correlate poorly with routine laboratory coagulation tests (64,65,66). An abnormal TEG tracing does, however,
suggest further investigation. Association of abnormal TEG parameters with transfusion need and/or clinical
bleeding varies among different centers but may find application in transfusion algorithms (67,68,69).
Rotational Thromboelastometry
Similar to thromboelastography, rotational thromboelastometry (ROTEM) is a POC viscoelastic test performed on
citrated whole blood. In contrast to TEG, the cuvette containing the patient blood sample is held stationary. A
central pin encased by a sleeve is submerged into the sample. The sleeve rotates clockwise, then
counterclockwise 4.75° repeatedly. The central pin does not make contact with the sleeve, and remains
stationary until clot bridges the 1-mm gap between the sleeve and the pin. An LED light source refracts off the
pin to a detector, thus measuring central pin motion. The manufacturer claims that this mechanism is much more
sensitive than the counterforce spring used in the TEG, and that extraneous vibrations affect the stationary
sample of the ROTEM less than the oscillating sample of the TEG. Also, the TEG device requires a level
surface, whereas ROTEM does not (70). ROTEM may produce data describing coagulation factor function in 10
minutes and platelet and fibrinogen function within 23 minutes of a sample being drawn, two to five times more
rapidly than results from hospital laboratories (71). Measurements of fibrinolysis take up to 40 minutes. The
teardrop-shaped graphic produced by ROTEM resembles that produced by TEG (Fig. 18.8). Although each
system uses unique nomenclature to describe the graphics, some results are interchangeable, such as MA and
MCF, while others are not, such as K and CFT (72,73,74) (Table 18.5).
Thromboelastography or thromboelastometry can probe the causes of coagulation disturbances by employing a
number of channels or instruments run simultaneously, and adding specific reagents to selected samples, for
example, heparinase, tissue factor, thromboplastin, and aprotinin.
The use of intraoperative ACT monitoring during cardiac surgery decreased the incidence of transfusion of fresh
frozen plasma, platelets, and packed red blood cells (80). Mixed evidence exists regarding transfusion reduction
with viscoelastic POC use. Algorithms utilizing TEG or ROTEM testing have been developed to guide transfusion
and coagulation management in specific patient populations. This has been associated with reduced allogeneic
blood transfusion requirements (81).
P.457
A large meta-analysis shows no statistical difference in utilization of packed red blood cells, fresh frozen plasma,
platelets, or cryoprecipitate (82). ROTEM has not outperformed laboratory coagulation tests as a predictor of
chest tube output after cardiac surgery (83). While ROTEM offers a unique method of illustrating hemostasis,
clinical utility beyond laboratory testing has yet to be defined.
TABLE 18.4. Parameters measured by thromboelastogram
Normal Significance of
Name Definition rangea abnormal values References
R (reaction Time from sample collection 7.5-15 Hypercoagulability? Nielsen et
time) until pen deviation from min Factor deficiency? al. (59)
midline Nielsen et
al. (60)
K time) Time from initial pen 3-6 min ? ?

(coagulation deviation from midline to
amplitude of 20 mm
α (speed of Angle formed by midline and 45°-55° Hypofibrinogenemia? Nielsen et

clot tangent of amplitude tracing Dysfibrinogenemia? al. (60)
formation) upslope ?
MA Maximum amplitude 50-60 Hypofibrinogenemia, Howland et

(maximum mm platelet dysfunction, al. (63)
amplitude) thrombocytopenia Zuckerman
Hypercoagulability? et al. (64)
A60 Tracing amplitude 60 min ≥(MA - Fibrinolysis or uremia Howland et

(amplitude) after MA 5) mm al. (63)
von Kaulla
et al. (65)
?, lack of published scientific evidence for the claimed significance.
aNormal values from Spiess BD, Tuman RJ, McCarthy RJ, et al. Thromboelastography as an indicator
of post cardiopulmonary bypass coagulopathies. J Clin Monit 1987;3:25-30.
FIGURE 18.9. A Sonoclot signature in a patient before (dashed line) and after (solid line) receiving four doses of
325 mg aspirin over 2 days. The initial flat portion (SonAct) is normally 60 to 130 seconds. R1, R2, and R3,
slopes of the curves, measure the rate of change in viscosity of the sample. TI, time to the first inflection point;
TP, time to peak viscosity. Normally, R1 is 15% to 30%/min and TP 5 to 10 minutes. The vertical axis, called
percent, lacks calibration against a standard. (From Samra SK, Harrison RL, Bee DE, et al. A study of aspirin
induced changes in bleeding time, platelet aggregation, and Sonoclot coagulation analysis in humans. Ann Clin
Lab Sci 1991;21: 315-327, with permission.)
Sonoclot
Another test designed to examine the entire clotting process is the Sonoclot (Sienco Inc., Morrison, CO). It
attempts to provide information regarding coagulation, fibrin gel formation, clot retraction, and hyperfibrinolysis
(84).
This viscoelastic test performed on whole blood uses a probe vibrating in a small sample (0.4 mL) of whole blood
at 200 Hz. Although the TEG displays clot shear modulus, the Sonoclot charts impedance to probe motion, which
increases as coagulation events proceed. This outcome variable is not calibrated in physical units, appearing
instead in units of “percent.” The curve obtained divides into several parts, termed waves, based on the rate of
increase of impedance with time (84). The manufacturer identifies a component analogous to the ACT (“SonAct”)
and certain curve shapes reflecting platelet dysfunction, thrombocytopenia, and “hypercoagulability.” No
independent data verify these associations. In one unblinded
P.458
study, the Sonoclot predicted that platelet transfusion would correct postbypass bleeding in 21 of 25 patients
(85). Figure 18.9 displays Sonoclot signatures before and after aspirin administration to 1 of 22 volunteers. The
Sonoclot failed to reflect the prolongation in bleeding time associated with aspirin (86). Although interesting in
concept, hematopathologists view skeptically the TEG, ROTEM, and Sonoclot for diagnostic purposes, perhaps
because of insufficient data linking test results with independently confirmed pathology.
TABLE 18.5. Parameters measured in rotational thromboelastometry
Name Definition Contributing factors References
CT (clotting Latency from sample placement to Coagulation factor Coelho et al.

time) gaining 2 mm of clot firmness concentrations; presence of (75)
heparin
CFT Time between 2 mm and 20 mm of Primarily platelet count and Engstrom et

(coagulation amplitude function, with fibrinogen and al. (76)
time) coagulation factors contributing
α angle Angle of tangent at 2 mm Primarily platelet count and Trelinski et

amplitude function, with fibrinogen and al. (77)
coagulation factors contributing
MCF Largest vertical amplitude Influenced by platelets and Greene et.

(maximum fibrin, platelet block substance al. (78)
clot
firmness)
ML Decrease in amplitude at set time Fibrinolysis Nilsson et

(maximum points reflective of decrement of al. (79)
lysis) clot stability (30 and 60 minutes)
Platelet Function Tests
Point-of-care technologies using whole blood can also evaluate platelet function by agonist-activated platelet-
mediated hemostasis. The Platelet Function Analyzer (PFA 100, Dade-Behring Inc., Miami, FL), formerly known
as Thrombostat 4000, performs the equivalent of a bleeding time in vitro. The Rapid Platelet Function Analyzer,
or Ultegra (RPFA, Accumetrics Inc., San Diego, CA) performs a computerized whole-blood platelet aggregation
test (87,88,89). The Clot Signature Analyzer (Xylum Corp., Scarsdale, NY), formerly known as the
Hemostatometer, measures platelet function through shear-induced activation and aggregation in a physiologic
flow environment (90). The Hemodyne (Hemodyne Inc., Richmond, VA) provides a measure of platelet-mediated
force transduction, which relates to quantitative and qualitative platelet function. The above whole-blood point-of-
care platelet tests await widespread clinical validation. The reader is directed to the website
www.labtestsonline.org/understanding/analytes/platelet-function/glance.html for noncommercial educational
information.
SOPHISTICATED HEMATOLOGY TESTS

Research laboratories and a few clinical centers specializing in hemostasis and thrombosis offer a host of
specialized coagulation tests. Chromogenic technology, in which a color-absorbing molecule is linked to a
component of the reaction to be measured, permits quantitation of the activity of many hemostatic elements, such
as antithrombin, tissue plasminogen activator (tPA), heparin, and anti-IIa, and anti-Xa activities. Tests based on
antibody technology include quantitation of fibrinopeptides A and B, the latter available for the fibrinogen split
product Bβ1-42 and for the fibrin split product Bβ15-42; tPA antigen; thrombin-antithrombin complex; plasmin-
antiplasmin complex; plasminogen activator inhibitor (PAI 1); and tPA-PAI complex.
PREDICTIVE VALUE OF LABORATORY TESTS FOR BLEEDING

The literature yields conflicting results regarding the absolute and relative abilities of various coagulation tests to
predict hemostasis after CPB. Routine laboratory tests succeed in some studies (91,92,93) and fail in others
(94,95). Likewise, the TEG predicts postbypass hemorrhage in one study (91), demonstrates superiority to
laboratory tests in three others (62,92,96) and to the HemoSTATUS (93), yet fails to identify patients at risk in a
different investigation (92). More sophisticated tests such as D-dimer concentration and glycoprotein Ib
expression correlate with blood loss after surgery but are cumbersome and expensive to measure (97). Single
reports
P.459
each tout the usefulness of specific devices, namely, the Hemostatometer (98) and the Hemodyne (99).
When evaluating the literature on coagulation test utility, clinicians must temper enthusiasm for new technologies
with the need for properly designed and properly analyzed comparisons with available tests. Large variation in
patient populations and in blood loss after bypass even in well-defined populations can further complicate these
judgments.
KEY Points
A variety of laboratory tests are available to evaluate the functional integrity of the coagulation cascade.
These tests can be performed in a centralized location or at the point-of-care setting. Common
centralized tests include PT, aPTT, thrombin time, fibrinogen, fibrinogen degradation products, D-dimer,
platelet count, and platelet aggregometry. Bedside or point-of-care tests include PT, aPTT, thrombin time
and its variants, ACT, TEG, Sonoclot, and some platelet function tests. Although many of these tests can
effectively diagnose specific blood clotting deficits and thereby facilitate therapy (with point-of-care
testing expediting this process), overall the ability of coagulation testing to predict post-CPB clotting
disorders has been disappointing.
Anticoagulation with heparin for CPB can be monitored by measuring clotting times or whole-blood
heparin concentrations. Of the many tests available, those most commonly used for CPB are the ACT
and heparin concentration as determined by an automated protamine titration method. The ACT shows
that anticoagulation has occurred, but it is imprecise, results vary among different commonly used ACT
techniques, and it is prolonged by hypothermia and hemodilution. Automated heparin concentrations
generally remain stable with hypothermia and hemodilution but do not measure functional
anticoagulation.
Clinical outcome studies do not clearly demonstrate the superiority of any specific heparin monitoring
technique, but they do show that anticoagulation with heparin is incomplete (as judged by markers of
thrombin activity) regardless of dose.
In the event of heparin sensitivity or heparin-induced thrombocytopenia, CPB anticoagulation can be
achieved through the use of direct thrombin inhibitors. The ECT may be the test of choice for monitoring
anticoagulation with these novel agents. Of note, no currently available drug reverses the anticoagulant
effects of these medications.
The majority of coagulation tests attempt to analyze only certain portions of the entire clotting cascade.
The TEG, ROTEM, Platelet Function Analyzer, and the Sonoclot attempt to overcome these limitations
by analyzing the coagulation cascade in its entirety. Currently, evidence does not support the routine use
of these monitors for patients undergoing CPB.
REFERENCES
1. Koepke JA. Coagulation testing systems. In: Koepke JA, ed. Laboratory hematology. New York, NY:
Churchill Livingstone, 1984:1113-1140.
2. van Rijn JLML, Schmidt NA, Rutten WPF. Correction of instrument and reagent based differences in
determination of the international normalized ratio (INR) for monitoring anticoagulant therapy. Clin Chem
1989;35:840-843.
3. Miale JB. Hematology. 4th ed. St. Louis, MO: Mosby, 1972:1280.
4. Schmaier AH. Diagnosis and therapy of disseminated intravascular coagulation and activated coagulation.
In: Koepke JA, ed. Laboratory hematology. New York, NY: Churchill Livingstone, 1984:631-658.
5. Van Cott EM, Laposata M. Coagulation. In: Jacobs DS, Oxley DK, DeMott WR, eds. The laboratory test
handbook. 5th ed. Cleveland, OH: Lexi-Comp, 2001:327-358.
6. Bell WR. Defibrinogenating enzymes. In: Colman RW, Hirsh J, Marder VJ, et al., eds. Hemostasis and
thrombosis. 3rd ed. Philadelphia, PA: JB Lippincott Co, 1994:886-900.
7. Despotis GJ, Santoro SA, Spitznagel E, et al. Prospective evaluation and clinical utility of on site
monitoring of coagulation in patients undergoing cardiac operation. J Thorac Cardiovasc Surg 1994;107:271-
279.
8. Shore-Lesserson L. Evidence based coagulation monitors: heparin monitoring, thromboelastography, and
platelet function. Semin Cardiothorac Vasc Anesth 2005;9:41-52.
9. Ray MJ, Hawson GA, Just SJ, et al. Relationship of platelet aggregation to bleeding after cardiopulmonary
10. Nowak G, Bucha E. Prothrombin conversion intermediate effectively neutralizes toxic levels of hirudin.
Thromb Res 1995;80:317-325.
11. Koster A, Loebe M, Hansen R, et al. A quick assay for monitoring recombinant hirudin during
cardiopulmonary bypass in patients with heparin-induced thrombocytopenia type II: adaptation of the ecarin
clotting time to the ACT II device. J Thorac Cardiovasc Surg 2000;119:1278-1283.
12. Oberhardt BJ, Dermott SC, Taylor M, et al. Dry reagent technology for rapid, convenient measurements
of blood coagulation and fibrinolysis. Clin Chem 1991;37:520-526.
13. Hoffmann JJ, Janssen WC. Comparison of three methods for measuring PEG-hirudin in blood. Blood
14. Koster A, Chew D, Gründel M, et al. Bivalirudin monitored with the ecarin clotting time for anticoagulation
during cardiopulmonary bypass. Anesth Analg 2003;96:383-386.
15. Nuttall GA, Oliver WC Jr. Patients with a history of type II heparin-induced thrombocytopenia with
thrombosis requiring cardiac surgery with cardiopulmonary bypass: a prospective observational case series.
Anesth Analg 2003;96(2):344-350.
16. Koster A, Spiess B. Effectiveness of bivalirudin as a replacement for heparin during cardiopulmonary
bypass in patients undergoing coronary artery bypass grafting. Am J Cardiol 2004;93(3):356-359.
17. Despotis GJ, Hogue CW. The relationship between hirudin and activated clotting time: implications for
patients with heparin-induced thrombocytopenia undergoing cardiac surgery. Anesth Analg 2001;93(1):28-
32.
18. Merry AF, Raudkivi PJ. Bivalirudin versus heparin and protamine in offpump coronary artery bypass
19. Edwards JT, Hamby JK. Successful use of argatroban as a heparin substitute during cardiopulmonary
bypass: heparin-induced thrombocytopenia in a high-risk cardiac surgical patient. Ann Thorac Surg
2003;75(5):1622-1624.
20. Cannon MA, Butterworth J. Failure of argatroban anticoagulation during offpump coronary artery bypass
21. Hallman SE, Hebbar L. The use of argatroban for carotid endarterectomy in heparin-induced
thrombocytopenia. Anesth Analg 2005;100(4):946-948.
22. Fitch JCK, Mirto GP, Geary KLB, et al. Point of care and standard laboratory coagulation testing during
cardiovascular surgery. Balancing reliability and timeliness. J Clin Monit Comput 1999;15:197-204.
23. Gilbert HC, Vender JS. The current status of point of care monitoring. Int Anesthesiol Clin 1996;34:243-
261.
24. Esposito RA, Culliford AT, Colvin SB, et al. Heparin resistance during cardiopulmonary bypass. The role
of heparin pretreatment. J Thorac Cardiovasc Surg 1983;85:346-353.
25. Umlas J, Gauvin G, Taff R. Heparin monitoring and neutralization during cardiopulmonary bypass using a
rapid plasma separator and a fluorometric assay. Ann Thorac Surg 1984;37:301-303.
26. Jobes DR, Schwartz AJ, Ellison N, et al. Monitoring heparin anticoagulation and its neutralization. Ann
Thorac Surg 1981;31:161-166.
P.460
27. Hattersley PG. Activated coagulation time of whole blood. JAMA 1966;196:436-440.
28. Jaberi M, Bell WR, Benson DW. Control of heparin therapy in open heart surgery. J Thorac Cardiovasc
Surg 1974;67:133-141.
29. Bjornsson TD, Nash PV. Variability in heparin sensitivity of APTT reagents. Am J Clin Pathol
1986;86:199-204.
30. Gravlee GP, Whitaker CL, Mark LJ, et al. Baseline activated coagulation time should be measured after
surgical incision. Anesth Analg 1990;71:549-553.
31. Gravlee GP, Case LD, Angert KC, et al. Variability of the activated coagulation time. Anesth Analg
1988;67:469-472.
32. Bennett JA, Horrow JC. Activated coagulation time: one tube or two? J Cardiothorac Vasc Anesth
1996;10:471-473.
33. Despotis GJ, Alsoufiev AL, Spitznagel E, et al. Response of kaolin ACT to heparin: evaluation with an
automated assay and higher heparin doses. Ann Thorac Surg 1996;61:795-799.
34. Green TP, Isham Schopf B, Steinhorn RH, et al. Whole blood activated clotting time in infants during
extracorporeal membrane oxygenation. Crit Care Med 1990;18:494-498.
35. Pan C-M, Van Riper DF, Horrow JC, et al. A modified microsample ACT test for heparin monitoring. J
36. Wang JS, Lin CY, Hung WT, et al. Monitoring of heparin induced anticoagulation with kaolin activated
clotting time in cardiac surgical patients treated with aprotinin. Anesthesiology 1992;77:1080-1084.
37. Dietrich W, Jochum M. Effect of celite and kaolin on activated clotting time in the presence of aprotinin:
activated clotting time is reduced by binding of aprotinin to kaolin [brief correspondence]. J Thorac
38. Huyzen RJ, Harder MP, Huet RCGG, et al. Alternative perioperative anticoagulation monitoring during
cardiopulmonary bypass in aprotinin treated patients. J Cardiothorac Vasc Anesth 1994;8:153-156.
39. Dietrich W, Jochum M. Effect of celite and kaolin on activated clotting time in the presence of
aprotinin:activated clotting time is reduced by binding of aprotinin to kaolin. J Thorac Cardiovasc Surg
1995;109:177-178.
40. Paul J, Cornillon B, Baguet J, et al. In vivo release of a heparin like factor in dogs during profound
hypothermia. J Thorac Cardiovasc Surg 1981;82:45-48.
41. Culliford AT, Gitel SN, Starr N, et al. Lack of correlation between activated clotting time and plasma
heparin during cardiopulmonary bypass. Ann Surg 1981;193:105-111.
42. Ammar T, Fisher CF, Sarier K, et al. The effects of thrombocytopenia on the activated coagulation time.
Anesth Analg 1996;83:1185-1188.
43. Moorehead MT, Westengard JC, Bull BS. Platelet involvement in the activated coagulation time of
heparinized blood. Anesth Analg 1984;63:394-398.
44. Ammar T, Scudder LE, Coller BS. In vitro effects of the platelet glycoprotein IIb/IIIa receptor antagonist
c7E3 Fab on the activated clotting time. Circulation 1997;95:614-617.
45. Kresowik TF, Wakefield TW, Fessler RD II, et al. Anticoagulant effects of protamine sulfate in a canine
model. J Surg Res 1988;45:8-14.
46. Dutton DA, Hothersall AP, McLaren AD, et al. Protamine titration after cardiopulmonary bypass.
Anesthesia 1983;38:264-268.
47. Bull MH, Huse WM, Bull BS. Evaluation of tests used to monitor heparin therapy during extra corporeal
circulation. Anesthesiology 1975;43: 346-353.
48. Gomperts ED, Bethlehem B, Hockley J. The monitoring of heparin activity during extracorporeal
circulation. S Afr Med J 1977;51:973-976.
49. Baugh RF. Detection of whole blood coagulation. Am Clin Products Rev 1984;45:38-45.
50. Despotis GJ, Joist JH, Hogue CW Jr, et al. More effective suppression of hemostatic system activation in
patients undergoing cardiac surgery by heparin dosing based on heparin blood concentrations rather than
ACT. Thromb Haemost 1996;76:902-908.
51. Despotis GJ, Summerfield AL, Joist JH. Comparison of activated coagulation time and whole blood
heparin measurements with laboratory plasma anti Xa heparin concentration in patients having cardiac
52. Despotis GJ, Levine V, Filos KS, et al. Hemofiltration during cardiopulmonary bypass: the effect on anti
Xa and anti IIa heparin activity. Anesth Analg 1997;84:479-483.
53. Anido G, Freeman DJ. Heparin assay and protamine titration. Am J Clin Pathol 1981;76:410-415.
54. Choo IHF, Didisheim P, Doerge ML, et al. Evaluation of a heparin assay method using a fluorogenic
synthetic peptide substrate for thrombin. Thromb Res 1982;25:115-123.
55. Gauvin G, Umlas J, Chin N. Measurement of plasma heparin levels using a fluorometric assay. Med
Instrum 1983;17:165-168.
56. Savidge GF, Kesteven PJ, Al Hasani SF, et al. Rapid quantitation of plasma heparin and antithrombin III
levels for cardiopulmonary bypass monitoring, using fluorometric substrate assays. Thromb Haemost
1983;50:745-748.
57. Huyzen RJ, Harder MP, Gallandat HRCG, et al. Alternative perioperative anticoagulation monitoring
during cardiopulmonary bypass in aprotinin treated patients. J Cardiothorac Vasc Anesth 1994;8:153-156.
58. Reich DL, Yanakakis MJ, Vela Cantos FP, et al. Comparison of bedside coagulation monitoring tests with
standard laboratory tests in patients after cardiac surgery. Anesth Analg 1993;77:673-679.
59. Nielsen VG, Lyerly RT, Gurley WQ. The effect of dilution on plasma coagulation kinetics determined by
thrombelastography is dependent on antithrombin activity and mode of activation. Anesth Analg 2004;99:
1587-1592.
60. Nielsen VG, Cohen BM, Cohen E. Effects of coagulation factor deficiency on plasma coagulation kinetics
determined via thrombelastography: critical roles of fibrinogen and factors II, VII, X and XII. Acta Anaesthesiol
Scand 2005;49:222-231.
61. Bjoraker DG. The thromboelastograph D coagulation analyzer. Anesthesiol Rev 1991;18:34-40.
62. Spiess BD, Tuman RJ, McCarthy RJ, et al. Thromboelastography as an indicator of post
cardiopulmonary bypass coagulopathies. J Clin Monit 1987;3:25-30.
63. Howland WS, Schweizer O, Goulp P. Comparison of intraoperative measurements of coagulation. Anesth
Analg 1974;53:657-663.
64. Zuckerman L, Cohen E, Vagher JP, et al. Comparison of thromboelastography with common coagulation
tests. Thromb Haemost 1981;46:752-756.
65. von Kaulla K, von Kaulla E, Wasantapruck S, et al. Blood coagulation in uremic patients before and after
hemodialysis and transplantation of the kidney. Arch Surg 1966;92:184-191.
66. Nutall GA, Oliver WC, Ereth MH, et al. Coagulation tests predict bleeding after cardiopulmonary bypass.
J Cardiothorac Vasc Anesth 1997;11: 815-823.
67. Nuttall GA, Oliver WC, Santrach PJ, et al. Efficacy of a simple intraoperative transfusion algorithm for
nonerythrocyte component utilization after cardiopulmonary bypass. Anesthesiology 2001;94:773-781.
68. Royston D, von Kier S. Reduced haemostatic factor transfusion using heparinase-modified
thrombelastography during cardiopulmonary bypass. Br J Anaesth 2001;86:575-578.
69. Shore-Lesserson L, Manspeizer HE, DePerio M, et al. Thromboelastography-guided transfusion

algorithm reduces transfusions in complex cardiac surgery. Anesth Analg 1999;88:312-319.
70. http://www.rotem.de/en/methodology/thromboelastometry/. Accessed 5 June 2014.
71. Haas T, Spielmann N, Mauch J, et al. Comparison of thromboelastometry (ROTEMs) with standard
plasmatic coagulation testing in pediatric surgery. Br J Anaesth 2012;108:36-41.
72. Venema LF, Post WJ, Hendriks HG, et al. An assessment of clinical interchangeability of TEG and
ROTEM thromboelastographic variables in cardiac surgical patients. Anesth Analg 2010;111:339-344.
73. Lang T, Bauters A, Braun SL, et al. Multicenter investigation on reference ranges for ROTEM
thromboelastometry. Blood Coagul Fibrinolysis 2005;16:301-310.
74. Sankarankutty A, Nascimento B, Luz LT, et al. TEG® and ROTEM® in trauma: similar test but different
results? World J Emerg Surg 2012;7(Suppl 1):S3.
75. Coelho MCA, Neto LV, Kasuki L, et al. Rotation thromboelastometry and the hypercoagulable state in
Cushing’s syndrome. Clin Endocrinol (Oxf) 2014;81(5):657-664.
76. Engstro M, Rundgren M, Schott U. An evaluation of monitoring possibilities of argatroban using rotational
thromboelastometry and activated partial thromboplastin time. Acta Anaesthesiol Scand 2010;54:86-91.
77. Treliński J, Misiewicz M, Robak M, et al. Assessment of rotation thromboelastometry (ROTEM)

parameters in patients with multiple myeloma at diagnosis. Thromb Res 2014;133:667-670.
78. Greene LA, Chen S, Seery C, et al. Beyond the platelet count: immature platelet fraction and
thromboelastometry correlate with bleeding in patients with immune thrombocytopenia. Br J Haematol
2014;166(4):592-600.
P.461
79. Nilsson CU, Tynngard N, Reinstrup P, et al. Monitoring fibrinolysis in whole blood by viscoelastic
instruments: a comparison of ROTEM and ReoRox. Scand J Clin Lab Invest 2013;73:457-465.
80. Despotis GJ, Santoro SA, Spitznagel E, et al. Prospective evaluation and clinical utility of on-site
monitoring of coagulation in patients undergoing cardiac operation. J Thorac Cardiovasc Surg 1994;107:271-
279.
81. Görlinger K, Shore-Lesserson L, Dirkmann D, et al. Management of hemorrhage in cardiothoracic

surgery. J Cardiothorac Vasc Anesth 2013;27:S20-S34.
82. Wikkelsoe AJ, Afshari A, Wetterslev J, et al. Monitoring patients at risk of massive transfusion with
thrombelastography or thromboelastometry: a systematic review. Acta Anaesthesiol Scand 2011;55:1174-
1189.
83. Lee GC, Kicza AM, Liu KY, et al. Does rotational thromboelastometry (ROTEM) improve prediction of
bleeding after cardiac surgery? Anesth Analg 2012;115:499-506.
84. Shenaq SA, Saleem A. Viscoelastic measurement of clot formation: the Sonoclot. In: Ellison E, Jobes DR,
eds. Effective hemostasis in cardiac surgery. Philadelphia, PA: WB Saunders, 1988:183-193.
85. Saleem A, Blifeld C, Saleh SA, et al. Viscoelastic measurement of clot formation: a new test of platelet
function. Ann Clin Lab Sci 1983;13:115-124.
86. Samra SK, Harrison RL, Bee DE, et al. A study of aspirin induced changes in bleeding time, platelet
aggregation, and Sonoclot coagulation analysis in humans. Ann Clin Lab Sci 1991;21:315-327.
87. Smith JW, Steinhubl SR, Lincoff AM, et al. Rapid platelet function assay: automated and quantitative
cartridge-based method. Circulation 1999;99:620-625.
88. Coller BS, Folts JD, Scudder LE, et al. Antithrombotic effect of a monoclonal antibody to the platelet
glycoprotein IIb/IIIa receptor in an experimental animal model. Blood 1986;68:783-786.
89. Coller BS, Lang D, Scudder LE. Rapid and simple platelet function assay to assess glycoprotein IIb/IIIa
receptor blockade. Circulation 1997;95:860-867.
90. Griffin MJ, Rinder HM, Smith BR, et al. The effects of heparin, protamine, and heparin/protamine reversal
on platelet function under conditions of arterial shear stress. Anesth Analg 2001;93:20-27.
91. Wang JS, Lin CY, Hung WT, et al. Thromboelastogram fails to predict postoperative hemorrhage in
cardiac patients. Ann Thorac Surg 1992;53:435-439.
92. Dorman BH, Spinale FG, Bailey MK, et al. Identification of patients at risk for excessive blood loss during
coronary artery bypass surgery. Thromboelastography versus coagulation screen. Anesth Analg
1993;76:694-700.
93. Ereth MH, Nutall GA, Santrach PJ, et al. The relationship between the platelet activated clotting test
(HemoSTATUS) and blood loss after cardiopulmonary bypass. Anesthesiology 1998;88:962-969.
94. Ramsey G, Arvan DA, Stewart S, et al. Do preoperative laboratory tests predict blood transfusion needs
in cardiac operations? J Thorac Cardiovasc Surg 1983;85:564-569.
95. Gravlee GP, Arora S, Lavendar SW, et al. Predictive value of blood clotting tests in cardiac surgical
patients. Ann Thorac Surg 1994;58:216-221.
96. Tuman KJ, Spiess BD, McCarthy RJ, et al. Comparison of viscoelastic measures of coagulation after
97. Wahba A, Rothe G, Lodes H, et al. Predictors of blood loss after coronary artery bypass grafting. J
98. Ratnatunga CP, Rees GM, Kovacs IB. Preoperative hemostatic activity and excessive bleeding after
99. Greilich PE, Carr ME, Carr SL, et al. Reductions in platelet force development by cardiopulmonary
bypass are associated with hemorrhage. Anesth Analg 1995;80:459-465.
Chapter 19
Anticoagulation for Cardiopulmonary Bypass
Linda Shore-Lesserson
Alan Finley
Glenn S. Murphy
Glenn P. Gravlee
HISTORY
Numerous events led to the first performance of surgical procedures with cardiopulmonary bypass (CPB) in Philadelphia
in 1953 (1). Development of an effective and reversible method to prevent blood clotting in an extracorporeal circuit
impeded this development. Heparin was discovered accidentally in 1916 by an ambitious young medical student named
Jay McLean, who had been assigned to experiment with cephalin, a thromboplastic substance. McLean investigated
extracts of the heart and liver to determine if the thromboplastic substance found in the brain extracts might be
something other than cephalin. Using similar extraction procedures, he discovered an extract that retarded plasma
coagulation from both the heart (named cuorin) and the liver (named heparphosphatide initially, then changed to
heparin) (2,3). Although McLean had made an important scientific discovery at a young age, he subsequently selected a
clinically oriented career that apparently precluded his participation in the development of heparin as a drug (4).
The purification of heparin proceeded in the 1920s, and a fairly crude preparation was first used to anticoagulate blood
for transfusion in 1924. Febrile reactions curbed this application, and it took another 12 years to attain a heparin
preparation that appeared safe for intravenous administration. During that interval, the discovery that heparin could be
obtained from bovine lung less expensively than from bovine liver proved practical in the commercial development of
heparin. Clinical trials in thrombotic disorders were initiated in 1935, and it was evident even then that heparin could
prevent clot formation or extension, although it possessed minimal ability to dissolve existing clots. Chargaff and Olson
(5) discovered in 1937 that the peptide protamine dramatically neutralizes the anticoagulant effects of heparin. Gibbon
(6) reported heparin-induced anticoagulation for CPB in animals in 1939. These events led to the selection of heparin
for anticoagulation and protamine for its subsequent neutralization in the first human operation in which CPB was used,
in 1953. Although most other aspects of CPB practice have changed markedly since that time, the use of heparin and
protamine has continued for over 60 years. This longevity serves as a testimonial to the astute judgment of Gibbon and
his colleagues at Jefferson Medical College. Consequently, this chapter primarily discusses the pharmacology and
clinical use of heparin for this purpose. Strategies for monitoring the anticoagulant effects of heparin and of heparin
alternatives are also presented. The final portion of the chapter is devoted to discussion of heparin-induced
thrombocytopenia (HIT) and heparin-induced thrombocytopenia with thrombosis (HITT) syndromes.
HEPARIN PHARMACOLOGY
Structural Characteristics and Biologic Function
Heparin, more specifically described as a glycosaminoglycan, is a polysaccharide that resides almost exclusively in mast
cells. Its physiologic purpose, however, remains uncertain, although roles in neovascularization and in the inflammatory
response appear likely. Clearly, endogenous heparin plays no significant role in maintaining the fluidity of circulating blood.
Heparan, a related glycosaminoglycan having a substantially lower sulfur content, dangles tantalizingly from endothelial cell
membranes to attract circulating antithrombin III (ATIII) irresistibly and potentiate thrombin inhibition. Physiologic
anticoagulation at the blood-tissue interface thereby derives not from heparin but from heparan. The primary physiologic
purpose of heparin may be to participate in nonimmunologic defense against bacterial infections, with other roles likely in
capillary angiogenesis and lipid metabolism.
Most heparin preparations can be described as unfractionated, which means that the heparin compound isolated from animal
tissues contains heparin molecules of various lengths, with molecular weights ranging from 3,000 to more than 40,000 Da.
The mean molecular mass approximates 15,000 Da (7,8) (Fig. 19.1). The molecular weight distribution varies somewhat with
the tissue source, animal source, and method of purification (9,10). This variability has some clinical relevance because the
spectrum of clinical actions of heparin derives in part from the molecular weight distribution of a heparin compound (11). As a
result, each unfractionated commercial heparin preparation might best be described as a family of drugs with actions and
potency that may vary from batch to batch (12,13,14).
P.464
FIGURE 19.1. Molecular weight distribution pattern of a typical commercial preparation of unfractionated heparin. (From
Stiekema JCJ. Heparin and its biocompatibility. Clin Nephrol 1986;26(Suppl 1):S3-S8, with permission.)
Heparin can be distinguished from other polysaccharides by its acid nature. It is the strongest macromolecular acid in the
body, a characteristic that derives from abundant sulfation of its saccharide units. The basic subunit consists of a repeating
disaccharide that contains a uronic acid residue linked to a glucosamine residue (Fig. 19.2). Both the uronic acid and
glucosamine residues can assume many different forms based on the side groups attached to these hexose units. Sulfate
groups may attach to the hexose ring through an oxygen, amino, aminoacetyl, or methane link. The result is a large molecule
that bears a highly negative charge within the physiologic pH range, and that therefore attracts positively charged molecules.
Specific saccharide sequences along the heparin chain determine binding sites to other macromolecules for which it has high
affinity, such as ATIII, thrombin, and lipoprotein lipase. In the case of ATIII, a specific pentasaccharide sequence binds
consistently to a specific amino acid sequence on the ATIII molecule (15).
Tissue Source and Commercial Preparation

Heparin can be purified from several tissues and from several mammalian species. Although the name heparin was selected
because the substance was originally isolated from liver extracts, intestinal mucosa and lung tissue represent the most
common commercial sources. Mucosal heparin tends to have a lower mean molecular weight, a more cross-linked
polysaccharide structure, and a lower cost than lung heparin (12). Differences in the tissue source from which heparin is
extracted influence molecular structure and activity more than differences in the animal source (16,17). However, nuclear
magnetic resonance spectroscopy has enabled the identification of differences between porcine and bovine mucosal heparin
in sulfation of various subunits. Nuclear magnetic resonance spectroscopy has also demonstrated a higher content of 3- O-
sulfated glucosamine units (active site for ATIII binding) in porcine than in bovine mucosal heparin (18). Heparin
manufacturers most often extracted mucosal heparin from pigs (porcine mucosal heparin) and lung heparin from cattle
(bovine lung heparin).
Both porcine mucosal heparin and bovine lung heparin had been widely used as anticoagulants for CPB. Both provide
effective anticoagulation and prevent thrombosis in experimental models (19) and in adult volunteers (20). Investigating
standardized needle punctures in exposed carotid arteries in dogs, Abbott et al. (21) found a higher incidence of delayed
hemorrhage in animals anticoagulated with mucosal heparin than with lung heparin. This difference remained significant even
when the anticoagulation was neutralized with protamine. Two studies prospectively compared mucosal and lung heparin for
CPB in humans. Stewart and Gaich (22) found that higher doses of mucosal heparin than of lung heparin were needed to
reach the desired prolongation of the activated clotting time (ACT), a finding that might be attributable to batch variability. In a
dialysis study comparing mucosal with lung heparin at standard patient doses of heparin, a lower anticoagulant activity was
noted in International Units/mL with bovine heparin, despite higher weight-based drug levels. Both preparations resulted in
anticoagulant effects and plasma levels within the recommended safe range (23). Fiser et al. (24) observed greater
postoperative blood loss in patients randomly assigned to receive mucosal heparin than in those who received lung heparin.
Both animal and human studies indicate that mucosal heparin can be neutralized with 25% to 30% less protamine than can
lung heparin, a consequence of the lesser anti-IIa activity of mucosal heparin than bovine (17,25). These studies used
standard tests of plasma coagulation such as clotting time and activated partial thromboplastin time (aPTT), which might not
detect residual unneutralized inhibition of factor Xa. Because of its lower mean molecular weight, mucosal heparin, in concert
with ATIII, more effectively inhibits factor Xa than does lung heparin (26), and protamine only partially neutralizes this effect.
The higher mean molecular weight of lung heparin enables this molecule to inhibit factor IIa more effectively through ATIII.
The anti-IIa activity is more susceptible to protamine antagonism, which may explain the greater propensity for delayed
bleeding found after anticoagulation with mucosal heparin (20,22) and the requirement for lower doses of protamine for
neutralization. Fairly limited prospective comparisons and some theoretic considerations therefore suggest a slight advantage
of lung heparin for CPB anticoagulation, but many hospitals have ceased to utilize lung heparin because of its greater
propensity for HIT. In the mid-1990s, bovine heparin production and commercialization ceased in the United States and many
European countries due to fears of potential transmission of bovine spongiform encephalopathy. Porcine heparin became the
exclusive heparin product used in medicine, hemodialysis, and cardiac surgery. Porcine heparin is primarily derived from
Chinese production sources, and the reliance on a single source of drug is very limiting and increases the risk of drug
shortage. This became evident in 2008
P.465
when the heparin produced in China was found to be contaminated with oversulfated chondroitin sulfate, and was
responsible for catastrophic hypotensive events in cardiac surgery and hemodialysis patients. A serious heparin shortage
ensued as there were no other manufacturers making heparin in the quantities being produced by China. In addition, current
detection methods for transmissible BSE agents are superior now compared with those during the mid-1990s (when mad cow
disease reached crisis numbers), and some believe that a reintroduction of bovine heparin into the US commercial market is
in order. Both clinical studies and practice demonstrate that for CPB anticoagulation, clearly both mucosal and lung heparin
are effective and safe.
FIGURE 19.2. Molecular structure of different parts of the heparin polysaccharide chain. The top row demonstrates a
common repeating disaccharide subunit consisting of L-iduronic acid 2-sulfate (I2S) and N-sulfo-α-D-glucosamine 6-sulfate
(ANS,6S), which represents up to 90% of beef lung heparin and 70% of porcine mucosal heparin. In the middle row, the five
saccharide units between the vertical dotted lines comprise the pentasaccharide sequence required for binding antithrombin
III (ANA,6S substitutes an N-acetyl for the N-sulfo group on ANS,6S, G represents β-D-glucuronic acid, and I represents β-L-
iduronic acid). This sequence occurs in approximately 33% of the chains of mucosal heparin and approximately 20% of the
chains of lung heparin. The circled sulfate groups are believed essential for high-affinity binding. The bottom row shows the
typical terminal sequence of a heparin molecule (Gal, galactose; Xyl, xylose) linking to a serine amino acid residue. (From
Casu B. Methods of structural analysis. In: Lane DA, Lindahl U, eds. Heparin. Chemical and biological properties, clinical
applications. Boca Raton, FL: CRC Press, 1989:25-49, with permission.)
Because of the acid nature of heparin, a ligand must be bound to it when the compound is prepared for commercial use.
Sodium and calcium have been used for this purpose. The two salts are indistinguishable with intravenous heparin
administration, but the calcium salt retards the uptake of subcutaneously administered heparin (9,27) and may reduce local
hematoma formation with subcutaneously administered heparin.
Potency Standardization
Four assays have been used in recent years to determine the potency of unfractionated heparin (UH) (19,28), including
International, United States, British, and European standards. The International Standard represents the mean of the
pharmacopoeial methods, which results in some variation in potency between international units (IU) and United States
Pharmacopoeia (USP) units. The USP assay defines 1 USP unit as the amount of heparin that maintains the fluidity of 1 mL
of citrated sheep plasma for 1 hour after recalcification. The
P.466
British Pharmacopoeia (BP) method uses sulfated ox blood activated with thromboplastin. The BP method has been
superseded by a European Pharmacopoeia (EP) method, which recalcifies sheep plasma in the presence of kaolin and
cephalin incubated for 2 minutes, thereby constituting an aPTT for sheep plasma. The EP method rigorously standardizes
the collection of sheep plasma, which might diminish the assay variability previously reported between batches of sheep
plasma substrate (16). Although speculation exists about the clinical significance of batch-to-batch variability in heparin
potency, it seems more likely that pharmacodynamic differences account for most of the observed variations in the clinical
anticoagulation response to heparin (see subsequent section on Heparin Resistance). Because the relation between mass
(milligrams) and potency (units) varies among heparin preparations, it appears more sensible to record heparin doses in units
than in milligrams.
Pharmacokinetics
Because heparin administration for CPB is exclusively intravenous, this discussion is limited to that route of administration.
After central venous injection of a heparin bolus, the onset of maximal ACT prolongation in the radial artery occurs within 1
minute. A previous study (29) suggested that heparin action peaks 10 to 20 minutes after administration in cardiac surgical
patients, but this finding probably was an artifact representing prolongation of the ACT by other factors, such as hemodilution
and hypothermia. Controlling for these factors, another study clearly demonstrated that the onset of action of heparin is much
faster, and maximal ACT prolongation probably occurs in less than 5 minutes (30). A rapid redistribution effect probably
accounts for a modest reduction in the anticoagulant effect of heparin that occurs 3 to 13 minutes after the peak effect (Fig.
19.3). It remains possible that the onset of action would be slightly delayed in states of low cardiac output or with peripheral
venous injection.
Distribution
Heparin is macromolecular and highly polarized, so one would expect minimal distribution beyond the bloodstream. These
principles and the results of bioassay studies of heparin kinetics were the basis for the former belief that the distribution of
heparin is virtually confined to the plasma compartment of the bloodstream (31,32). Substantial in vitro evidence now points
to the redistribution of heparin into the endothelial cells (33,34,35,36), although this redistribution appears small in
comparison with that of most other drugs. Uptake into extracellular fluid, alveolar macrophages, splenic and hepatic
reticuloendothelial cells, and vascular smooth muscle also occurs (37,38,39). Some or all of these tissues create a relatively
small reservoir for heparin that probably contributes to the delayed recurrence of heparin-induced anticoagulation (heparin
rebound) after protamine neutralization of the heparin residing in the bloodstream. Defining an apparent volume of distribution
for heparin remains elusive because pharmacokinetic studies in humans have used some measure of heparin effect (i.e., a
bioassay) rather than direct measurement of plasma heparin concentration. Bioassays represent the most practical approach
to the clinical evaluation of heparin pharmacodynamics, but these assays can only indirectly and crudely assess
pharmacokinetics.
FIGURE 19.3. The activated clotting time (ACT) measured through radial artery blood sampling at five different intervals after
the injection of 300 units of heparin per kilogram into the right atrium. Maximum ACT prolongation occurred within 2 minutes
in most patients, with subsequent moderate ACT reduction, likely reflecting a rapid redistribution effect. (From Gravlee GP,
Angert KC, Tucker WY, et al. Early anticoagulation peak and rapid distribution after intravenous heparin. Anesthesiology
Elimination and Excretion

Heparin elimination has been studied by using various clotting times as bioassays, so the available information largely
defines the time course of its clinical activity. The clotting times differ in their sensitivities to heparin, so differences reported
in heparin “elimination” kinetics under similar conditions are not necessarily inconsistent. Despite these unavoidable
limitations, several aspects of heparin pharmacokinetics can be explained by existing studies. Very small doses of heparin
produce minimal or no effect, suggesting a rapid initial clearance, possibly the result of the affinity of heparin for endothelial
membranes (40). The doses used for CPB anticoagulation are very large, and the biologic elimination half-life of heparin is
dose-dependent (41,42). In the only volunteer study in which doses sufficient for CPB were used, Olsson et al. (41) found a
half-life of 126 ± 24 minutes with a heparin dose of 400 units/kg. The half-lives for doses onefourth and one-half that large
were 61 ± 9 and 93 ± 6 minutes, respectively. Because CPB distorts the bioassay methods
P.467
through hypothermia and hemodilution, attempts to define heparin pharmacokinetics in patients undergoing CPB are largely
impractical. Hypothermia delays heparin elimination, with virtually constant heparin concentrations shown during 40 to 100
minutes of CPB at 25°C (43). Wright et al. (44) found a progressive decline in heparin concentrations at all temperatures, but
the rate of decline was delayed in proportion to the hypothermia. Bull et al. (45) found a small decrease in the rate of ACT
decline at 30°C (in comparison with normothermia), although the independent prolongation of ACT by hypothermia had not
been discovered at the time of that study. Mabry et al. (46) found the consumption of heparin to vary from 0.01 to 3.86
units/kg/min during CPB. In addition, there is little correlation between the initial ACTbased sensitivity to heparin and the rate
of heparin decay (47). In children, the variability in ACT response is greater than that in adults and is highly dependent on the
test mechanism and activators used (48) (Fig. 19.4).
Severe renal impairment may also prolong heparin action, although available studies yield conflicting results. Liver disease
apparently has little effect on heparin elimination. The primary mechanism for heparin elimination remains uncertain, but
metabolism in the reticuloendothelial system and renal elimination both occur (37,39,40).
Pharmacodynamics
Inhibition of Fibrin Formation
Heparin induces anticoagulation primarily by potentiating the activity of ATIII (or “antithrombin”), a plasma glycoprotein (GP)
with a molecular weight of 58,000 Da. Heparin attaches to a lysine residue on ATIII, thereby altering the ATIII configuration
and rendering it much more attractive to thrombin (15,49). Heparin therefore increases the thrombin-inhibitory potency of
circulating ATIII by a factor of 1,000 or more. In addition to converting fibrinogen to fibrin enzymatically, thrombin activates
cofactors VIII and V, thereby greatly increasing the rate of fibrin clot formation through the intrinsic and common pathways,
respectively. Figure 19.5 shows the plasma coagulation cascade, which can be somewhat crudely divided into intrinsic,
extrinsic, and common pathways. ATIII also inhibits factors IXa, Xa, XIa, and XIIa (50) kallikrein, and plasmin. Plasma
coagulation factors vary in their sensitivity to ATIII and to different chain lengths of heparin. UH inhibits thrombin most quickly,
then inactivates Xa, IXa, XIa, and XIIa with progressively decreasing rate constants (50). Thrombin inhibition involves
transient simultaneous heparin binding to ATIII and to thrombin, which requires a relatively long oligosaccharide chain. This is
why shorter heparin chains are relatively ineffective in thrombin inhibition, even if they contain the pentasaccharide sequence
required for ATIII binding (Fig. 19.6). Factor Xa inhibition involves heparin binding to ATIII, which in turn binds to factor Xa
molecules that need not bind separately to heparin, as depicted in Figure 19.6. Two-thirds or more of the heparin molecules
present in commercially available preparations have no anticoagulant effect (11), which probably results from an absence of
the specific pentasaccharide sequence that binds to ATIII.
FIGURE 19.4. The Hemochron and HemoTec (Hepcon) activated clotting time (ACT) values in 22 pediatric patients at six
time-points during cardiopulmonary bypass (CPB). Hemochron ACT was significantly higher than HemoTec ACT at five time-
points, and HemoTec ACT was below the threshold value of 400 seconds at all time-points. *p < 0.01. (Modified from Horkay
F, Martin P, Rajah M, et al. Response to heparinization in adults and children undergoing cardiac operations. Ann Thorac
Surg 1992;53:822-826, with permission.)
Heparin also binds to cofactor II, a GP of 65,000 Da that inactivates thrombin independently of ATIII (51). This reaction
occurs more slowly and requires higher heparin concentrations than does thrombin inhibition through the heparin-ATIII
complex. The thrombin-heparin-cofactor II interaction is significantly catalyzed in vitro by plasma heparin concentrations
between 0.1 and 0.4 units/mL, which is well below the heparin concentrations used for CPB. This mechanism might therefore
contribute routinely to the anticoagulant effect of heparin during CPB, and might assume particular importance in patients
with ATIII deficiency.
Variability of Patient Response

Whether heparin concentration or a clotting time is measured, the response to a fixed-dose heparin bolus varies substantially
from patient to patient (29,45,52,53,54,55,56,57,58,59). The variability of clotting time responses usually exceeds the
variability of blood- or plasma heparin concentrations observed, as demonstrated by Monkhouse et al. (52) as early as 1953
(53,54,60). Bull et al. (45,61) showed a 3-fold variation in ACT response to a heparin bolus of 200 units/kg, and Esposito et
al. (53) found a 4-fold ACT range (62-267 seconds) at that dose and a 6-fold range (128-755 seconds) after an intravenous
bolus of 400 units/kg. Bull et al. (45,61) reported equally impressive ranges of heparin elimination rates during CPB when
using ACT as an indirect heparin assay.
P.468
FIGURE 19.5. Schematic diagram of the plasma coagulation pathway, divided into intrinsic, extrinsic, and common
component pathways. F, factor; roman numerals, different coagulation factors by number; a, activated coagulation factor;
Ca2+, ionized calcium; HMWK, high-molecular-weight kininogen; PF3, platelet factor 3; FSP, fibrin split products.
FIGURE 19.6. Schematic representation of the interaction between heparin (H) and activated factors X (FXa) and II
(thrombin, FIIa). Inhibition of factor IIa requires a heparin chain containing at least 18 saccharide units (shown in B and C) in
addition to the critical pentasaccharide sequence for antithrombin III (ATIII) binding (shown as the framed portion of H bound
to AT). This occurs because the heparin molecule must simultaneously bind ATIII and thrombin. Factor Xa inhibition is also
accomplished with polysaccharide chains long enough to inhibit factor IIa (shown in B), but shorter chains can also inhibit
factor Xa (shown in A with an octasaccharide chain) because simultaneous binding of heparin, ATIII, and factor Xa is not
required for Xa inhibition. (From Holmer E. Low-molecular-weight heparin. In: Lane DA, Lindahl U, eds. Heparin. Chemical
and biological properties, clinical applications. Boca Raton, FL: CRC Press, 1989:575-595, with permission).
Side Effects
Plasma coagulation, the formation of a platelet plug, and fibrinolysis constitute the three major components of blood clot
formation and dissolution. The therapeutic effects of heparin derive primarily from its effects on plasma coagulation,
described in the preceding text, but heparin also affects the other two components.
Heparin-induced activation of fibrinolysis has been identified in a primate model (62). During simulated CPB in a
P.469
baboon model, heparin administration led to activation of fibrinolysis as measured by plasmin activity, immunoreactive
plasmin light chain, and immunoreactive fibrinogen fragment E (63). The mechanism whereby heparin facilitates fibrinolysis
may involve the direct stimulation of plasminogen activator release from endothelial cells and monocytes. Additional modes of
activation include indirect stimulation of plasminogen activator by release of protein C, inhibition of fibrin polymerization (64),
modulation of antiplasmin effects, and enhancement of the effects of tissue factor pathway inhibitor (TFPI). Activation of the
fibrinolytic pathway does occur during anticoagulation associated with CPB, so heparin might participate in this activation.
Heparin also has numerous effects on platelets, many of which occur acutely, and these would therefore be relevant in
patients undergoing CPB. Table 19.1 lists the aggregatory effects of heparin on platelets, which most often represent
laboratory findings obtained in human platelet-rich plasma. The clinical significance of these findings is uncertain, but clearly
heparin binds avidly to platelets. With the use of specific chemical and enzymatic treatments to produce heparin-derived
glycosaminoglycans, the platelet-binding properties of heparin have been elucidated (77). Although specific receptors for
heparin on the platelet surface have not been identified, heparin binding relates directly to molecular weight and sulfation and
is unrelated to ATIII affinity (77,78,79,80,81). Heparin binding decreases with the decreasing size of the heparin fragment and
is therefore clinically negligible in the low-molecular-weight heparin (LMWH) preparations. Small quantities of heparin may
bind to the GPIIb/IIIa platelet receptor, but this is not the major locus for heparin binding. At clinical doses, heparin induces a
platelet release reaction characterized by release of platelet factor 4 (PF4), GPIIb/IIIa activation, P-selectin expression, and
increased aggregation that is not seen with LMWH derivatives (75,82). At plasma levels as high as 100 units/mL, heparin
suppresses degranulation and P-selectin expression, a finding that indicates the future possibility of separation of the
anticoagulant and the antiplatelet properties of heparin (76,83). Moderate prolongation of bleeding time and transient
decreases in platelet count have been present in some investigations and absent in others (80). Both predictable and
idiosyncratic effects of heparin on platelets have been reviewed by Warkentin and Kelton (80). The idiosyncratic syndrome of
HIT is discussed later in a separate section (see Heparin-Induced Thrombocytopenia).
TABLE 19.1. Acute effects of heparin on platelets
Action
Serotonin release (65)
Increased adenosine diphosphate-induced aggregation (66,67,68)
Decreased thrombin-induced aggregation (69)
Opposes prostacyclin-mediated platelet inhibition (70,71)
Increased collagen-induced aggregation (68)
Dose-dependent increase in bleeding time (72,73)
Increased platelet factor 4 release (68)
Increased epinephrine-induced platelet aggregation (66)
Decreased platelet count (74)
P-selectin expression (75)
Suppresses a-granule release (high-dose heparin only) (76)
In clinical settings other than CPB, bleeding complications comprise the most common side effect of heparin, with reported
incidences varying from 1% to 37% (84,85,86,87). The profound anticoagulation present during CPB probably increases
surgical bleeding, but blood salvage through the cardiotomy suction usually renders this unimportant. Large doses of heparin
induce fibrinolysis and activate platelet activation to contribute to abnormalities of hemostasis (88). Conversely, insufficient
heparin anticoagulation during CPB causes consumption of coagulation factors, which may also result in a bleeding diathesis
(89). Excessive postoperative bleeding from residual unneutralized heparin or from heparin rebound can occur after CPB and
should be closely monitored (see Chapter 20).
The intravenous heparin bolus dose administered before CPB decreases arterial pressure and systemic vascular resistance
approximately 10% to 20% without affecting cardiac output or heart rate (90,91). Urban et al. (91) related this change to a
decrease in ionized calcium levels, and they were able to prevent them by prophylactically administering 125 mg of calcium
chloride.
Heparin can induce a variety of metabolic and immunologic effects (92) that might contribute to the array of abnormalities
known to occur in those systems during CPB. Heparin dramatically increases plasma levels of lipoprotein lipase by releasing
this enzyme from vascular endothelium. This activity bears no relation to ATIII affinity, and it results in triglyceride degradation
and increased circulating levels of free fatty acids. Although the clinical significance of these effects remains unclear, they
could potentially affect myocardial metabolism and the plasma-free fraction of lipid-soluble drugs.
Rare acute reactions attributed to heparin include anaphylaxis, pulmonary edema (93,94,95,96,97,98,99), and disseminated
intravascular coagulation (100). Some of these reactions have been traced to the preservatives chlorocresol and chlorbutol
(95,96). Harada et al. (93) reported the uneventful use of bovine lung heparin for CPB in a child who had previously
experienced anaphylaxis from porcine mucosal heparin, and
P.470
Schey (101) reported resolution of a localized skin reaction to subcutaneous heparin injections when LMWH was substituted
for UH. Interactions with antibiotics have also been reported, notably with gentamicin and erythromycin (102,103), although
these appear unlikely to have clinical significance. Administration of heparin for weeks to months has been associated with
osteoporosis, alopecia, hyperaldosteronism, and benign elevation of serum glutamic oxaloacetic transaminase levels
(104,105,106).
HEPARIN DOSING
During the first two decades of cardiac surgery with CPB, heparin dosing was accomplished empirically, with initial doses
usually ranging from 200 to 400 units/kg and maintenance doses of 50 to 100 units/kg given as often as every 30 minutes or
as infrequently as every 2 hours (51). The priming fluid used for the extracorporeal circuit usually contained 10,000 to 20,000
units of heparin. Heparin monitoring, defined as laboratory testing for the adequacy of blood heparin concentration or of a
heparin-induced anticoagulant effect, was limited by the absence of an easily applicable test. This situation changed with the
introduction of two coagulation tests that could be performed practically at the bedside on whole blood. The activated
coagulation time (more appropriately called the activated clotting time [ACT] in later publications) was introduced by
Hattersley (107), and the blood-activated recalcification time (BART), also termed the recalcified whole-blood partial
thromboplastin time, was introduced by Blakely (108). Both of these tests were first reported for CPB heparin monitoring in
1974, BART for cardiac surgery and ACT for longterm respiratory support (56,109). The two classic papers by Bull et al.
(45,61) pointed out the apparent inadequacy of empiric heparin and protamine dosing protocols and recommended a
structured approach using the ACT. This served as a turning point for heparin management during CPB, and the application
of ACT monitoring to CPB evolved from virtually nonexistent to widespread during the ensuing 5 years. Laboratory tests for
heparin monitoring are covered in Chapter 18.
Clinical Assessments and Comparisons of Heparin Dosing and Monitoring Techniques

Once Bull et al. (45) had outlined the potential problems in heparin management during CPB with the use of standardized
dosing schemes that varied widely among institutions, numerous investigators followed up on their work by comparing clinical
outcomes of ACT monitoring with those of standardized unmonitored heparin management (Table 19.2). Blood loss, blood
transfusion comparisons, or both were compared in the clinical investigations shown in Table 19.2. Six of ten studies showed
decreased blood loss with ACT monitoring, and five of seven showed decreased allogeneic blood transfusion requirements.
Unfortunately, only one of these studies appeared to be completely prospective (110), and that study did not specify the
method of patient assignment to the two study groups, nor was statistical analysis performed on the observed differences.
Ottesen et al. (111) found no difference in postoperative blood loss between two groups that differed only in precise versus
crude application of the Bull protocol for determining maintenance doses of heparin during CPB. The studies comparing
transfusion requirements did not list the criteria for blood transfusion, which can vary substantially among physicians and
institutions (112). From these studies, it appears likely that ACT-based CPB heparin management does not increase
postoperative bleeding or transfusion requirement; therefore, its effect on these parameters is either neutral or favorable.
Furthermore, Metz and Keats (113) found no relation between lower CPB ACTs and postoperative bleeding when empiric
heparin management was used. Although limitations in experimental designs, notably the use of historical control groups,
preclude a more ambitious conclusion favoring ACT, unmonitored heparin management is rarely practiced. Because
protamine dosing can also influence postoperative bleeding (114), differences in protamine dosing might also have
influenced the results of most of these studies.
Table 19.2 lists clinical outcome studies comparing ACT monitoring with heparin concentration monitoring. One of two
studies shows that heparin concentration monitoring decreases blood loss in comparison with no monitoring (124). This study
appears to be prospective and randomized, although the method of randomization was not specified and the unmonitored
(control) group may have been historical. Three published studies have compared ACT monitoring with heparin concentration
monitoring (Table 19.2). The two studies by Gravlee et al. (125,127) showed conflicting results with regard to postoperative
blood loss (see below). This discrepancy might be explained by aggressive diagnosis and treatment of heparin rebound in
the second study. Despotis et al. (128) prospectively compared heparin concentration monitoring with ACT monitoring in
conjunction with a point of care transfusion algorithm for post-CPB bleeding. In the course of maintaining a threshold heparin
concentration, determined before CPB for each patient, the authors’ study group received nearly twice the dose of heparin of
the ACT group. In addition, the study group had a small reduction in the volume of mediastinal tube drainage and received
significantly fewer transfusions of non-red blood cell allogeneic blood products. The transfusion-sparing result was attributed
to better suppression of intravascular coagulation during CPB.
Is there an optimal range for ACT or heparin concentration during CPB? Bull et al. (45) reported clinical experience that a clot
does not form in the oxygenator circuit with an ACT exceeding 300 seconds. Those authors further stated the opinions that
(1) ACTs below 180 seconds should be considered so inadequate as to be life threatening, (2) ACTs between 180 and 300
seconds should be considered highly questionable, and (3) maintaining ACTs exceeding 600 seconds would seem unwise.
They noted that a minimum ACT of 180 seconds had
P.471
P.472
been suggested for patients undergoing long-term extracorporeal oxygenation for pulmonary support, and that the higher
minimum ACT recommended for cardiac surgery requiring CPB was needed because of the greater amounts of tissue fluid
gaining access to the circulation in that setting. Although this hypothesis holds some appeal, it remains unproven. Bull et al.
also recommended attaining an ACT of 480 seconds before initiating CPB, suggesting that this particular ACT value provides
a safety margin over the believed minimum safe ACT of 300 seconds. It appears that many practitioners have misinterpreted
their recommendation by assuming that an ACT of 480 seconds represents the minimum safe level for CPB anticoagulation,
when the authors were simply offering a suggestion without scientific validation. Young et al. (130) raised the minimum
recommended ACT level of Bull et al. (300 seconds) by demonstrating fibrin formation and depletion of clotting factors, ATIII,
and platelets in monkeys sustaining ACTs below 400 seconds during CPB. They then applied this information to five
pediatric patients undergoing CPB, finding no untoward events when ACTs above 400 seconds were maintained. They did
not, however, investigate the possibility that ACTs below 400 seconds might also be safe in humans. At least six studies have
reported ACT values below 400 seconds for CPB without complications (60,113,123,125,131,132). Five of these studies
reported some CPB maintenance ACTs below 300 seconds (60,113,123,125,131,132) reported a mean ACT of 296 ± 51
seconds (range, 230-437 seconds) after rewarming during CPB in 22 adults.
TABLE 19.2. Clinical outcome comparison of different types of heparin monitoring for
Number of Blood Experimental

Investigators and year patients loss Transfusion method
ACT vs. no monitoring
Babka et al., 1977 (110) 20 ACT < NE Prospective,

NMa randomized?
Verska, 1977 (115) 114 ACT < ACT < NM Historical control group
NM
Roth et al., 1979 (116) 56 ND ND Historical control group
Akl et al., 1980 (58) 120 ND ACT < NM Historical control group
Papaconstantinou and Raådegran, 126 ACT < ACT < NMb Historical control group
1981 (117) NMb
Jumean and Sudah, 1983 (118) 77c ACT < NE Historical control group
NM
Dearing et al., 1983 (119) 648 ACT < ACT < NM Retrospective,
NM sequential grouping
Niinikoski et al., 1984 (120) 100 ACT < ND Retrospective,

NM sequential grouping
Lefemine and Lewis, 1985 (121) 61 ND NE Not specifiedd
Preiss et al., 1985 (122) 350 ND ACT < NM Retrospective, not

randomized
Heparin concentration vs. no monitoring
Jobes et al., 1981 (123) 46 ND NE Prospective,

randomized
Bowie and Kemna, 1985 (124) 150 HC<NMa HC<NMa Prospective,

randomized
ACT vs. heparin concentration monitoring
Gravlee et al., 1990 (125) 21 ACT<HCe NE Prospective,

randomized
Urban et al., 1991 (126) 38 ND ND Prospective,

randomized
Gravlee et al., 1992 (127) 163 NDf ND Prospective,

randomized
Despotis et al., 1995 (128) 254 ND HC<ACT Prospective,

randomized
Koster et al., 2002 (129) 200 ND ND Prospective,

randomized
aNo statistical analysis.

bIntraoperative only, no difference in postoperative period.
cPediatric patients.
dForty-three ACT patients, 18 NM patients.
eNo systematic assessment of heparin rebound postoperatively.
fHeparin rebound systematically assessed and treated. HC > ACT for incidence of heparin rebound.
ACT, activated clotting time; HC, heparin concentration; ND, no difference; NE, not evaluated; NM, no monitoring.
Metz and Keats (113) assessed the utility of ACT monitoring by administering heparin (300 units/kg) to 193 patients
undergoing CPB, then blindly measuring ACT at predetermined intervals. Fifty-one of their patients had ACTs below 400
seconds during CPB, with four patients having ACT values below 300 seconds. No clots were visible in the extracorporeal
circuits during or after CPB, and no relation was found between lower CPB ACTs and postoperative bleeding. Cardoso et al.
(133) reported no differences in coagulation factors, platelet counts, or membrane oxygenator performance between two
groups of six pigs assigned to an ACT range of 250 to 300 seconds or of more than 450 seconds for 2 hours of hypothermic
CPB.
Several reports suggest the safety of ACTs either in the 170- to 250-second range or twice normal for prolonged respiratory
support with extracorporeal membrane oxygenators (109,134,135,136,137,138). Defining ideal anticoagulation in that clinical
setting proves difficult, however, because the patients’ disease processes predispose to both thromboembolic events and
disseminated intravascular coagulation, and even the relatively modest level of anticoagulation used appears to increase
bleeding complications (134,135,136).
Two studies measuring plasma levels of fibrinopeptide A (FpA), a sensitive marker of fibrin formation, found higher-than-
normal levels during CPB for cardiac surgery, but these levels were still considerably lower than those measured after
surgical incision alone. Davies et al. (139) noted that 54 of their 73 CPB ACT measurements in 15 patients were below 400
seconds, and they concluded (without assessing a clinical outcome) that the anticoagulation of these patients had been
inadequate. Investigating 21 patients with two different heparin-monitoring protocols, Gravlee et al. (125) found that higher
heparin concentrations better suppressed FpA levels early in CPB, but that this difference was not sustained during
rewarming (Fig. 19.7). Those authors found no correlation between CPB FpA levels and postoperative bleeding, although
five patients exhibited CPB FpA levels more than ten times the upper limit of normal. It therefore appears that plasma FpA
levels are not reliable indicators of inadequate CPB anticoagulation in humans unless the threshold for morbidity exceeds the
levels reported thus far.
Maintenance of ACT alone during CPB support can lead to an overestimation of heparin effect specifically during conditions
of hemodilution and hypothermia. In a controlled, nonrandomized sample of 42 patients, Machin et al. (140) demonstrated
prolongation of ACT values during hypothermic CPB when compared to normothermic CPB. Leyvi et al. (141) reported similar
significant differences in a prospective trial of 27 patients when comparing multiple ACT technologies to plasma anti-factor Xa
heparin level activity under conditions of both hypothermia and hemodilution. These known sensitivity limitations in ACT
monitoring should be considered when using ACT to guide anticoagulation for CPB.
Routine redosing of heparin can also occur at fixed intervals when heparin concentration assays are not available or can
occur via a heparin infusion (142). In a prospective trial of 100 patients presenting for cardiac surgery, one-third of the initial
heparin bolus was administered at the 90-minute point of CPB, with repeat doses every 60 minutes thereafter (143). This
strategy maintained adequate anticoagulation during the entire period of hypothermic CPB. Despotis compared standard
heparin concentration-based heparin dosing by bolus with that of a patient-specific weight-adjusted infusion of heparin. Mean
heparin concentrations were slightly lower using the infusion technique, but both were therapeutic (142). Despite these
reported benefits of higher heparin dosing or a continuous infusion, higher doses of heparin have not yet demonstrated
improved long-term clinical outcomes.
Is there a maximum safe level of anticoagulation for CPB? Exaggerating the hemorrhagic diathesis during CPB poses little
difficulty so long as the blood losses are scavenged effectively into the extracorporeal circuit. One study suggests that higher
blood heparin concentrations (>4 units/mL) and ACTs (>600 seconds) during CPB predispose to increased postoperative
blood loss (134), although a follow-up study from the same group of investigators failed to confirm this (136). In the latter
study, higher CPB heparin concentrations predisposed to postoperative heparin rebound, which required treatment with
protamine. In addition to the need for higher initial protamine doses and a higher incidence of heparin
P.473
rebound, heparin doses exceeding the presumed minimum safe requirement for CPB may be associated with a greater
degree of platelet dysfunction as measured by aggregometry (144). It remains unclear whether large doses of heparin are
detrimental as a result of the aforementioned complications, or whether they confer an advantage by better suppression of
coagulation activity. The maintenance of stable heparin concentrations does suppress coagulant activity during CPB, as
evidenced by lower levels of FpA and lower levels of D-dimers in the period before protamine (89). Another study showed
that higher heparin concentrations during CPB (i.e., heparin dosing based on heparin concentrations rather than on ACT)
reduced thrombin generation, D-dimers, and neutrophil elastase; the latter finding suggests better suppression of the
inflammatory response with higher heparin concentrations (129). That study found no differences in post-CPB clotting
function or blood loss, however. After protamine administration, markers of fibrin formation and thrombin activation increase in
all patients and are likely to be indistinguishable between patients who have experienced ACT monitoring and those who
have undergone heparin concentration monitoring. There is no consistent substantiation for the hypothesis that lower levels
of fibrin formation or thrombin activation predict improved clinical outcomes; however, it would seem prudent to suppress
thrombin activation as much as possible. Despotis advocates doing so by administering larger doses of heparin (89).
Because heparin does not inhibit clot-bound thrombin, total inhibition is not possible. Ideally, further thrombin inhibition could
be achieved through the use of a direct thrombin inhibitor or through the use of an anticoagulant that works at a different
point in the coagulation cascade (i.e., extrinsic pathway).
FIGURE 19.7. Fibrinopeptide A (FpA) levels in three groups of patients during cardiac surgery. Patients in groups 1 and 2
received an initial heparin dose of 200 or 300 units/kg and additional heparin during cardiopulmonary bypass (CPB)
whenever the activated clotting time was below 400 seconds. Group 3 patients received an initial heparin dose of 400
units/kg and additional heparin whenever the whole-blood heparin concentration was below 4.0 units/kg. The FpA levels
peaked before heparin and after protamine and were significantly different between the groups during hypothermic bypass
(group 3 vs. group 1 only). (From Gravlee GP, Haddon WS, Rothberger HK, et al. Heparin dosing and monitoring for
cardiopulmonary bypass. A comparison of techniques with measurement of subclinical plasma coagulation. J Thorac
Cardiovasc Surg 1990;99:518-527, with permission.)
More studies purport to evaluate safe ACT levels for CPB than safe blood or plasma heparin concentrations. Jobes et al.
(123) found no adverse effects with whole-blood heparin concentrations exceeding 2 units/mL. The findings of Kesteven
(132) were similar, except that he measured plasma heparin concentrations, which should be higher than whole-blood
heparin concentrations in proportion to the relative volumes of the two compartments. Possibly, Kesteven corrected his
heparin concentrations to represent whole-blood levels because his patients otherwise would have sustained CPB whole-
blood heparin concentrations between 1.0 and 1.5 units/mL, which would likely represent inadequate anticoagulation.
The most consistent predictable response to heparin administration is the wide variability in responsiveness due to many
pharmacodynamic factors. Na et al. (145) reported large variations in heparin responsiveness in an observational study in
patients with treated endocarditis. In a large single-center retrospective study, Garvin and colleagues demonstrated great
variability in the response to a single bolus of heparin (146). Grima proposed that small graded doses of heparin (100
International Units/kg × doses) were more effective in maintaining adequate ACT levels during CPB than was a single-bolus
dose.
P.474
Grima’s work also suggests that intermittent pre-CPB heparin dosing was associated with lower mean decreases in factor
VIII, fibrinogen, ATIII, and platelet count (147). In a prospective nonrandomized trial performed by Neema et al. (143), 6 of the
100 patients who received 300 International Units/kg of heparin prior to CPB had a resultant post-heparin ACT <350
seconds. The variability in heparin potency and the recent change in heparin formulations since the China heparin-
contamination crisis have led investigators and clinicians to consider larger doses of heparin (350-400 International Units/kg)
as prudent for the initiation of CPB.
In summary, the optimal ACT or heparin concentration range for CPB has not been definitively established. The ACT
minimum of 300 seconds originally recommended by Bull et al. (45) has withstood the test of time, but it appears that lower
ACTs may also be acceptable with heparin-coated circuits (148,149,150). It has not been clearly established whether it is
better to monitor heparin concentration or heparin effect, but Nielsen et al. (151) reported one case of clots in both the
surgical field and the extracorporeal circuit despite maintenance of whole-blood heparin concentrations of 4.0 units/mL or
higher. The ACTs were not reported for that patient, who had a previously undiagnosed familial deficiency of ATIII. It seems
likely that this clinical scenario could have been avoided by monitoring heparin effect (i.e., ACT) rather than heparin
concentration, as there have been no reports of clots (although the authors have received verbal reports from colleagues) in
the extracorporeal circuit with ACTs above 300 seconds.
Because there is no apparent advantage to maintaining ACTs below 400 seconds, the simplest clinical guideline is to exceed
that value during CPB for cardiac surgery. Metz and Keats (113) appropriately questioned the need for any heparin
monitoring, although the rare occurrences of marked heparin resistance (151) or accidental injection of a substance other
than heparin suggest some virtue in doing so. There is no proven need to compensate for hypothermia-induced ACT
prolongation by maintaining the blood heparin concentration that was present before hypothermia so long as one anticipates
the expected decrease in ACT on rewarming (152). However, some suggest that the ACT may prove inadequate as a sole
heparin monitor with deeper levels of hypothermia (<24°C) and with profound hemodilution (as often occurs with neonates
and infants). Others suggest that the ACT should be used in conjunction with heparin concentration monitoring during
moderate levels of hypothermia or with CPB of prolonged duration (153). In most situations, the authors see no clinical
advantage to heparin concentration monitoring and have selected the following CPB heparin management protocol for adults,
although they recognize that other protocols may be equally acceptable:
Administer 350 to 400 units of heparin per kilogram intravenously.

Draw an arterial sample for ACT in 2 to 5 minutes.
Give additional heparin as needed to achieve an ACT above 400 seconds before initiating CPB and to maintain an ACT
above 400 seconds during normothermic CPB and above 480 seconds during hypothermia between 24°C and 30°C.
Prime the extracorporeal circuit with approximately 5 units of heparin per milliliter (e.g., 5,000 units for a 1,000-mL clear
priming solution).
Monitor the ACT every 30 minutes during CPB, or more frequently if the patient proves resistant to heparin-induced
prolongation of the ACT.
Although some prefer to select supplemental heparin doses precisely with the aid of a manual or computer-generated graphic
plot, as recommended by Bull et al. (45), the authors believe that the relative imprecision of the ACT, the unpredictability and
likely nonlinearity of the ACT-to-heparin dose-response relationship, and the lack of any proven benefit to a narrowly defined
ACT endpoint render such maneuvers unnecessary. If ACT decreases below the desired minimum value, supplemental
heparin doses of 50 to 100 units/kg most often prolong the ACT sufficiently without the aid of precise calculations.
In vitro techniques have been introduced that measure individual patient dose-response relation between heparin and either
blood heparin concentration (HemoTec, Englewood, CO) or ACT (International Technidyne, Edison, NJ) (154,155). These
assays are patient-specific in that they measure a patient’s heparin sensitivity and incorporate the patient’s estimated blood
volume into a formula that calculates the heparin dose required to achieve a target ACT or heparin concentration. The
Hemochron RxDx (International Technidyne) system is an ACT-based heparin dose-response assay. The heparin response
test is an ACT with a known quantity of in vitro heparin (3 International Units/mL); along with a baseline ACT, it allows
generation of a dose-response curve that enables calculation of the heparin dose required to attain the target ACT. The
RxDx system also provides a protamine response test. This is an ACT with one of two specific quantities of protamine,
depending on the amount of circulating heparin suspected (2 or 3 units/mL). By using the patient’s heparinized ACT, the
protamine response test, and an estimate of the patient’s blood volume, the protamine dose needed to return the ACT to
baseline can be calculated based on a protamine-response curve. Jobes et al. (156) randomly assigned patients to receive
standard ACT-based management or individualized heparin management with the RxDx system. They were able to lower
their protamine doses significantly by using the protamine titration assay, and they reported significantly reduced transfusions
and chest tube drainage in the group that received individualized dosing. A follow-up study, however, was unable to confirm
that transfusions or chest tube drainage is significantly affected by the RxDx intervention (157). Both studies revealed that
the RxDx system results in administration of a reduced protamine dose, but differences in transfusion
P.475
outcomes may have resulted from different total heparin doses or different management strategies for heparin rebound.
Another in vitro individualized heparin dose-response assay is the Hepcon (Medtronic) heparin dose-response (HDR), which
constructs a three-point dose-response curve based on baseline, 1.5-, and 2.5-U/mL concentrations of heparin. This is an
individualized heparin dose-response curve. From this curve, extrapolation to the desired ACT or heparin concentration
yields the predicted dose of heparin required to achieve the desired ACT. The database review by Garvin et al. (146)
showed that the in vitro heparin dose-response relationship calculated by the HDR had a poor correlation with the actual
dose-response curve generated by the baseline ACT and the patient’s ACT after the administration of heparin.
If a true emergency dictates the need to institute immediate CPB, it would seem reasonable to administer a large systemic
dose of heparin (400 units/kg) because there may be insufficient time to confirm the effect of heparin with an ACT. Under
these circumstances, it also seems reasonable to place a larger-than-usual heparin dose in the extracorporeal circuit (e.g.,
10,000 units for a usual adult priming volume of 1,000 mL).
HEPARIN RESISTANCE
Heparin resistance can be loosely defined as the need for higher-than-normal heparin doses to induce sufficient
anticoagulation for the safe conduct of CPB. Unfortunately, no universal definition exists for heparin resistance. The chief
concern when heparin resistance is encountered is inadequate anticoagulation. At best, subtherapeutic anticoagulation will
result in activation of the coagulation cascade on CPB and potentially the development of a consumptive coagulopathy. At
worst, subtherapeutic anticoagulation will result in thrombus formation in the CPB circuit. Despite years of use, the ideal
target ACT and the minimum ACT to maintain sufficient anticoagulation remain unknown. Because of this, clinicians often
choose a target ACT that provides an acceptable margin of safety in order to prevent complications related to subtherapeutic
anticoagulation.
Mechanism Related to ATIII Deficiency

Many factors have been reported to alter the anticoagulation response to heparin (Table 19.3). Usually, these effects are
clinically insignificant (188), but they may cumulatively account for the consistent demonstration of marked interpatient
variability in the anticoagulation response to a fixed heparin dose (expressed in units per kilogram). ATIII deficiency has long
been thought to be the primary mechanism of heparin resistance as heparin’s anticoagulant effect is mediated indirectly
through ATIII, a natural anticoagulant. In point of fact, the incidence of heparin resistance has been shown to be higher in
patients with ATIII deficiency compared to those with normal ATIII levels (189,190,191). Additionally, low ATIII levels have
been shown to correlate with increased coagulation activation during cardiac surgery (192,193).
ATIII deficiency can be either congenital or acquired. Congenital ATIII deficiency follows an autosomal-dominant transmission
pattern and has an estimated prevalence of 1 in every 2,000 to 20,000 people (194,195). A reduced amount of normal ATIII
constitutes the most common form (195). Affected persons are at increased risk of developing thrombotic complications as
they usually have ATIII levels below 50% of normal. Factors precipitating this occurrence include pregnancy, infection, and
surgery, so the primary clinical presentation may be either thrombosis after surgery or difficulty achieving adequate
anticoagulation for CPB (159,194,195,196,197). Newborns and infants normally have low ATIII levels averaging 60% to 80%
of adult level, and reach or exceed 90% of adult levels at approximately 3 months of age (198). Despite the low AT levels,
newborns do not exhibit the thrombotic events that adults do at these levels.
In the cardiac surgical patient population, acquired ATIII deficiency is much more common than congenital ATIII deficiency.
The multiple conditions associated with acquired ATIII deficiency are listed in Table 19.4 (199,200,201,202,203,204). Certain
other conditions, listed in Table 19.3, may also be related to acquired ATIII deficiency (e.g., septicemia, endocarditis,
hypercoagulable states). Among the etiologies of acquired deficiency, preoperative heparin treatment deserves special
discussion, as heparin infusions are commonly administered in the preoperative period. Heparin infusions have been
reported to decrease ATIII levels approximately 5% to 7% per day (203,205), but the decrease usually plateaus at levels
exceeding 60%. The mechanism for this decline relates to the rapid clearance of the thrombin/ATIII complex by the
reticuloendothelial system after this complex has dissociated from heparin. However, the moderate heparin resistance
observed in patients receiving preoperative heparin therapy has not consistently been associated with decreased ATIII levels
(53,206,207,208,209). In one study that did demonstrate lower AT levels with heparin pretreatment, the small difference (ATIII
activity of 80.9% vs. 92.6%) is unlikely to be clinically significant (208). Despite the exact mechanism of heparin resistance
remaining unclear in the setting of heparin pretreatment, heparin responsiveness has been demonstrated to be lower in this
patient population.
Regardless of the etiology of ATIII deficiency, heparin responsiveness should be expected to correlate with ATIII levels if ATIII
levels are the primary determinant of heparin responsiveness. In vitro, heparin responsiveness does correlate with ATIII
levels, especially at ATIII levels <60% (210). However, the correlation between ATIII levels and heparin responsiveness is
poor in patients undergoing cardiac surgery (191,210,211). Furthermore, AT supplementation does not restore heparin
responsiveness in all patients with heparin resistance (212,213). For these reasons, an alternative, AT-independent
mechanism of heparin resistance must exist.
P.476
TABLE 19.3. Factors reported to decrease the anticoagulant response to heparin
Animal or in vitro
Factor Human studies Case reports models
ATIII deficiency Nielsen et al., 1987 (151)
Familial Soloway and Christiansen,

1980 (158)
Marciniak, 1974 (159)
Acquired Chung et al., 1981 (160) Reuter, 1978 (161)
Platelets
Thrombocytosis Gravlee et al., 1987 Wilds et al., 1982 (162) Conley et al., 1948
(154) (163)
Heparin-induced Olinger et al., 1984 (164)

thrombocytopenia
Age
Pediatrics/newborns Doty et al., 1979 (54)
Dauchot et al., 1983 (131)

Increased adult age Gravlee et al., 1987
(154)
Circadian rhythm Schved et al., 1985

(165)
Decousus et al., 1985

(166)
Decousus et al., 1985

(166)
Hemoglobin concentration
Decreased Kase and Dearing,

1985 (167)
Increased Whitfield and Levy,

1980 (168)
Preheparin ACT or PTT
Decreased Esposito et al., 1983 Bjornsson and Nash, 1986

(53) (169)
Increased Whitfield and Levy,

1980 (168)
Drugs
Several medications Nelson et al., 1958

(170)
Ongoing heparin therapy Esposito et al., 1983 Hicks, 1983 (171)

(53)
Dietrich et al., 1991

(172)
Cloyd et al., 1986

(190)
Nitroglycerin Habbab and Haft,

1987 (173)
Becker et al., 1990

(174)
Reich, 1992 (175)

Amin, 1990 (176)
pH and protein effects
Increased acid Godal, 1961 (177)

glycoprotein
Decreased pH Kase and Dearing, Jaques, 1967 (178)

1985 (167)
Antiheparin Glueck et al., 1972 (179) Jordan et al., 1987

immunoglobulin (181)
Neutrophil elastase Pogliani et al., 1975 (180)
Increased lipoprotein Bleyl et al., 1975 (182)

levels
Increased HRG Lijnen et al., 1983

(183)
Protein binding Young et al., 1992

(184)
Pregnancy Whitfield et al., 1983

(185)
Hypereosinophilic syndrome Hanowell et al., 1981 (186)
Sepsis/endocarditis Mabry et al., 1979 (46)
Chung et al., 1981 (160)
Autologous blood withdrawal Mummaneni et al.,

1983 (187)
Hypercoagulable states de Takats, 1943 (59) Reuter, 1978 (174)
Male sex Whitfield and Levy,

1980 (168)
ATIII, antithrombin III; ACT, activated clotting time; PTT, partial thromboplastin time; HRG, histidine-rich glycoprotein.
P.477
TABLE 19.4. Conditions associated with acquired antithrombin deficiency
Decreased synthesis from liver cirrhosis
Drug induced
L-Asparaginase
Estrogens
Heparin
Increased excretion
Protein-losing enteropathy
Inflammatory bowel disease
Nephrotic syndrome
Accelerated consumption
Disseminated intravascular coagulation
Surgery
Dilutional
Cardiopulmonary bypass
Autologous blood withdrawal
AT-Independent Mechanisms of Heparin Resistance

Multiple alternative hypotheses exist for the mechanism of heparin resistance, but many of these remain poorly defined.
Heparin-binding proteins are believed to be one of the main AT-independent mechanisms and have been shown to modulate
heparin’s anticoagulant activity to a degree that may be clinically relevant (183,214). The list of heparin binding proteins is
extensive and a complete discussion on each protein as well as the disease states in which they are higher is beyond the
scope of this chapter.
Other potential AT-independent mechanisms for heparin resistance include extreme thrombocytosis (platelet count
>700,000/μL) (162), septicemia (46,160), hypereosinophilic syndrome (186), and nitroglycerin (173,174). Specifically related
to nitroglycerin’s effect on heparin responsiveness, Reich et al. (175) could not confirm a reduction in heparin
responsiveness in the cardiac surgical setting, and Amin and Horrow (176) did not find a significant in vitro interaction.
Heparin Resistance Treatment

When an ACT fails to reach the intended target, clinicians have four options to choose from when deciding how to proceed.
P.478
These include the administration of additional heparin, ATIII supplementation with fresh frozen plasma (FFP), ATIII
supplementation with AT concentrate, or proceeding with CPB without any additional treatment. The first option,
administering additional heparin, is often chosen to account for the potential presence of higher than normal amounts of
heparin binding proteins. When administering additional heparin, there appears to be a ceiling effect in regard to the
anticoagulation effect of high doses of heparin and raising the heparin concentration above 4 units/mL is unlikely to increase
the ACT (215). Ideally, point-of-care whole-blood heparin concentrations should be used to monitor heparin concentrations to
minimize the empiric administration of additional heparin, but this technology is not uniformly available. If higher than normal
doses have been administered, clinicians should be aware that protein-bound heparin persists after protamine neutralization
of heparin (216). The dissociation of protein-heparin complexes after CPB may contribute to the phenomenon known as
heparin rebound and will potentially increase chest tube drainage. Very high doses of heparin must be given with caution
because of the concern for heparin rebound and should trigger clinicians to monitor for heparin rebound in the postoperative
period and treat with additional protamine if necessary.
Treatment of heparin resistance with ATIII supplementation has historically been performed using 2 units of FFP. FFP
contains a concentration of approximately 1 International Unit of ATIII per 1 mL of FFP (217). Therefore, 2 units of FFP (˜500
mL) result in an ATIII dose of approximately 500 International Units. Heparin resistance has been shown both in vivo and in
vitro to respond to FFP (158,161,207,218,219,220,221). However, this literature consists of one in vitro study and case
reports. No literature exists supporting a reduction in coagulation activation while on CPB or a reduction in postoperative
bleeding complications. Moreover, in a randomized, controlled trial evaluating AT concentrates, Avidan et al. (212)
demonstrated that 2 units of FFP failed to improve heparin responsiveness in the vast majority of patients. Concerns also
exist in regard to the time delay to thaw FFP and the safety concerns with transfusions, making FFP a less appealing option.
Lastly, the FDA only recommends the use of FFP to treat single-factor deficiencies when no factor concentrate is available.
Despite ATIII concentrates being readily available in the United States, many clinicians do not have them readily available on
a hospital’s formulary for cost concerns.
ATIII concentrates represent a more targeted approach to treating ATIII deficiency. Compared to FFP, ATIII concentrates use
a much lower volume, have a much lower rate of viral transmission, and have a much lower rate of other transfusion related
complications (i.e., transfusion-related acute lung injury). ATIII concentrate is a stable, lyophilized product that is heat treated
at 60°C ± 0.5°C for at least 10 hours to eliminate infectious agents. ATIII concentrate can be either recombinant or human
purified and the key differences are highlighted in Table 19.5. Before choosing between the two AT concentrates,
consideration must be given to the expected duration of therapy and their differing pharmacokinetics.
TABLE 19.5. Comparison of Antithrombin Preparations
Recombinant AT (Atryn)a Human purified AT (Thrombate)b
Supplied Sterile, lyophilized powder Sterile, lyophilized powder
Standardization WHO International Standard WHO International Standard
Source Goat milk Human plasma
Contraindications Goat milk hypersensitivity None
T½ 11.6 hr 3.8 d
Affinity 4-Fold higher
Supplied ˜1,750 International Unit vials ˜500 International Unit vials
Cost ? ?
AT - antithrombin, WHO - World Health Organization, T1/2 - elimination half time
aManufactured by rEVO Biologics.
bManufactured by Grifols.
The use of ATIII therapy during heparinization for extracorporeal circulation enhances anticoagulation as demonstrated by
numerous studies showing an increase in heparin responsiveness as determined by the ACT
(191,212,213,215,222,223,224,225,226). Furthermore, studies have also demonstrated a reduction in hemostatic activation
during cardiac surgical procedures. Hashimoto et al. (192) evaluated the effect of ATIII on markers of thrombin activity in
adults and children. Although this was a descriptive study, the authors reported the use of lower heparin doses in patients
receiving ATIII. ATIII therapy resulted in unchanged FpA levels during and after CPB, which suggests a reduction in thrombin
activity, whereas control patients had large increases in FpA levels. Additionally, both Avidan et al. (213) and Koster et al.
(222) demonstrated a reduction in coagulation activation in heparin resistant patients treated with ATIII. However, both
Avidan and Koster used significantly larger doses of ATIII concentrate (50-75 units/kg or 3,500-5,250 units for a 70-kg
patient) than the commonly used 500 to 1,000 units for heparin resistance. Such high doses raise the concern that the
reduction in coagulation activation seen in these studies may be secondary to an alternative mechanism than the treatment of
heparin resistance. Levy et al. (227) were able to demonstrate a reduction in coagulation activation with ATIII concentrate
doses of 50 to 75 units/kg in non-heparin-resistant patients. Despite the consistent increase seen with
P.479
the ACT and the potentially improved preservation of the coagulation system, no studies show a reduction in bleeding related
complications in heparin resistant patients treated with ATIII concentrates. Furthermore, ACT prolongation after administration
of ATIII or FFP does not establish that ATIII deficiency caused the heparin resistance, because increasing plasma ATIII levels
should increase heparin-induced anticoagulation whether or not initial ATIII levels are inadequate (207,228).
The last option, accepting the current ACT and commencing CPB without further intervention, is often not chosen for fear of
subtherapeutic anticoagulation. However, the magnitude of the increased heparin dose and the necessity for other
interventions (i.e., ATIII supplementation) may be exaggerated by misconceptions about the safe minimum ACT required for
CPB (158,160,196). Even though the safe minimum ACT remains unknown, the fact remains that many institutions use target
ACTs much higher than levels successfully used at other institutions (229). As many institutions use target ACTs <400
seconds without reported issues, it is feasible that institutions with a higher target ACT are obtaining a higher margin of
safety than is necessary for safe conduct of CPB. In these centers, some patients should not need additional interventions,
but rather should proceed with CPB.
Decisions about managing heparin resistance are often empirically made. FFP is rarely chosen as treatment due to its
potential risks (193) and the widespread availability of ATIII. If a high heparin concentration has been achieved (> 4.0 U/ml),
or > 600 IU/kg of unfractionated heparin has been given, and ACT is still <400 seconds, additional heparin is unlikely to be of
benefit and may increase the risk of heparin rebound. In this instance, a presumptive diagnosis of ATIII deficiency is made
and a dose of 500-1000 Units ATIII may be given. ATIII levels can be measured preoperatively, although the target ideal level
is unknown. Measuring the ATIII level helps greatly in the dosing the patient to achieve ATIII activity at 80-100%. Patients
with a near-normal ATIII level whose ACT fails to exceed 400 seconds after a high dose of heparin (e.g., >500 IU/kg) are
likely to have a different etiology for heparin resistance. In this case, an alternative anticoagulant (i.e., direct thrombin
inhibitor) should be considered.
ALTERNATIVES TO UNFRACTIONATED HEPARIN

Clinical situations that might call for avoidance of heparin include protamine allergy, HIT, or heparin allergy. Until recently, no
viable alternatives existed, but at least three intravenous alternatives to UH are currently available. None of these drugs has
yet been approved by the US Food and Drug Administration (FDA) for use in cardiac surgery in the United States.
Low-Molecular-Weight Heparin and Heparinoids

The discovery that different components of UH possess differing affinities for platelets and for ATIII suggested a potential
advantage to fractionating heparin into different compounds to be used for different indications (230,231). These heparin
fractions are produced by either chemical or enzymatic depolymerization of conventional heparins or by de novo synthesis
(232,233). At least six commercially prepared LMWH compounds have been studied for their ability to reduce venous
thrombosis. These include enoxaparin sodium (Lovenox, Sanofi-Aventis); dalteparin sodium (Fragmin, Pharmacia & Upjohn);
fraxiparin (Sanofi); tinzaparin (Logiparin, Innohep [Pharmion]); ardeparin (Normiflo, St. John Health); and danaparoid sodium
(Lomoparan, Orgaran, manufactured by Organon). Each of these drugs has been approved by the FDA for prophylaxis
and/or treatment against deep vein thrombosis. Methods used to depolymerize UH include nitrous acid (fraxiparin,
dalteparin), peroxidative depolymerization (ardeparin), alkaline depolymerization (enoxaparin), gamma irradiation, and
heparinase digestion (Innohep). Danaparoid sodium is a synthetic heparinoid compound prepared from a porcine intestinal
source and consists of heparan sulfate (84%), dermatan sulfate (12%), and chondroitin sulfate (4%).
Synthetic pentasaccharide formulations are currently available for use as anticoagulants and for prophylaxis for deep vein
thrombosis. Fondaparinux (Arixtra) is a recently introduced pentasaccharide whose antithrombotic potential has been
explored in the perioperative arena. The saccharide composition in fondaparinux constitutes the active site at which most
heparin and LMWH molecules bind antithrombin. The pentasaccharide molecule has profound anti-Xa properties relative to
weak anti-IIa properties, yet its thrombotic efficacy is excellent and bleeding complications are rare.
Shorter heparin chains have a lower affinity for platelets, bind less avidly to plasma proteins (234), and do not bind at all to
endothelial cells in culture (235). The reduced protein binding may enhance the bioavailability of LMWH molecules and allow
a more consistent dose-response relation in comparison to that for UH. Protein binding facilitates heparin’s enzymatic
breakdown, elimination from plasma, and neutralization of its anticoagulant effects. Therefore, LMWH has a longer plasma
half-life than UH. With intravenous administration, the half-lives of the different compounds range from 110 to 200 minutes
(except for danaparoid and fondaparinux), and renal excretion is the principal route of elimination. As a result of their small
size, LMWHs have a reduced ability to inhibit thrombin (factor IIa) but are potent inhibitors of factor Xa (236). Typically, only
25% to 50% of LMWH molecules contain the longer chain length necessary for binding factor IIa. The anti-Xa to anti-IIa ratios
of LMWHs range from 2:1 to 4:1, with mean molecular weights of 4,000 to 6,500 Da (237); however, the distribution of
molecular weights may differ among preparations, rendering mean molecular weight an inaccurate way to assess anti-IIa
efficacy (238). The anti-Xa to anti-IIa ratio for the heparinoid danaparoid is 28:1. Moderate inhibition of factor Xa appears to
inhibit thrombus formation
P.480
without impairing hemostasis as intensely as simultaneous inhibition of Xa and IIa; therefore, effective prophylaxis against
deep vein thrombosis might occur with a lower incidence of bleeding complications than with UH (239). This potential benefit
has fueled the development of many different LMWH compounds. Some evidence supports the antithrombotic efficacy of Xa
inhibition, but other reports support the need for IIa inhibition to achieve the same goal (240,241,242).
The lower platelet binding capacity of LMWHs provides potential benefit in a number of clinical scenarios. LMWHs are less
likely to cause HIT because they elicit less immune response than does UH (243). When platelet activity is measured with
hemostatometry, LMWH minimally reduces the force of platelet retraction, whereas UH dramatically reduces it (244). When
flow cytometric techniques are used to identify P-selectin, a marker for platelet activation, LMWH induces less platelet
activation than does UH (76) (Fig. 19.8). In an in vitro study designed to test the proinflammatory and antiinflammatory
responses to 2.5 units of UH/mL versus LMWH, the addition of these drugs to monocyte cell cultures induced similar
increases in cytokine levels. Increases in interleukin-1b levels reached statistical significance only with UH (245).
LMWH therapy complicates heparin monitoring because aPTT (and presumably ACT) are much less sensitive to Xa inhibition
than to IIa (thrombin) inhibition (246). Factor Xa inhibition can be measured, but not with a simple bedside test (247,248,249).
The difficulties of measuring Xa inhibition have complicated the potency standardization of LMWH compounds. The recent
development of a standard based on potency of Xa inhibition should assist future comparisons of different LMWH
compounds.
Intravenously administered LMWH has a half-life at least twice as long as that of UH, and the half-life of some LMWH
compounds is possibly several times as long (230,250). The half-life poses a potential problem with LMWH use for CPB
because Xa inhibition is much less responsive to protamine neutralization than is IIa inhibition, and the hemodynamic toxicity
of protamine is still evident (251,252).
Some experience with LMWH for CPB has accrued. In 1983, Gouault-Heilmann et al. (253) reported LMWH use for a
pulmonary embolectomy in a 66-year-old man suffering from HITT. Apparently no attempt was made to neutralize the LMWH
after CPB, and postoperative blood loss figures were not reported. This patient survived in a situation in which, in theory, the
administration of a large dose of UH might have induced severe morbidity through further intravascular clotting. After
determining that LMWH could be used safely to anticoagulate sheep for CPB, Massonnet-Castel et al. (254) used LMWH to
anticoagulate six adults undergoing elective procedures requiring CPB, decreasing the dose with each successive patient.
Although no clots developed in the extracorporeal circuit, all patients bled excessively in the 6 hours following CPB. Although
protamine was initially avoided, its use was deemed necessary in five patients, and the authors viewed heparin neutralization
as only partially effective. Three of the six patients required reoperation for bleeding. One patient died 3 days later of a
myocardial infarction, and autopsy revealed several “spots of subperitoneal hemorrhage.” The same group
P.481
subsequently reported anticoagulation in 15 patients undergoing CPB with LMWH doses smaller than the lowest dose
administered in the previous report (255). Protamine was successfully avoided in nine patients, although three of those
patients bled excessively. Three different patients received protamine as treatment for excessive bleeding, and this was
again considered only partially effective because bleeding in two of these patients through their mediastinal tubes amounted
to more than 2,000 mL in the first 24 hours. In vitro evidence supports a possible role for aminocaproic acid in this situation
(251,244). Three patients received protamine prophylactically, and they did not bleed excessively despite the lack of effective
reduction in anti-Xa activity by protamine. Touchot et al. (256) successfully anticoagulated nine dogs (one died of
postoperative hemorrhage) and four patients with LMWH. No clots were seen during CPB, but no postoperative data were
provided. Subsequently, a randomized prospective study of an extracorporeal CPB model in dogs compared UH (250
International Units/kg) with the LMWH enoxaparin (250 anti-Xa U/kg) and measured hematologic variables up to 24 hours
postoperatively. Protamine was used to reverse anticoagulation in both groups. These authors found no differences between
the groups in postoperative blood loss or fibrin deposition on the arterial filters of the circuits, and they suggest that this
anticoagulation regimen may be safe (257). Prospective randomized clinical studies in humans are still lacking.
FIGURE 19.8. Relative platelet reactivity of unfractionated heparin (A), low-molecular-weight heparin (LMWH) (B), and
hirudin (C), measured by hemostatometry, which yields values inversely related to platelet function. HR is the ratio of the
hemostatometry measurement with anticoagulant to a baseline measurement with no anticoagulant. HR values of less than 1
indicate enhanced platelet reactivity, values between 1 and 10 indicate mild to moderate platelet inhibition, and values
greater than 10 indicate severe platelet inhibition. Note that a significantly greater proportion of samples exposed to LMWH
had preservation of platelet reactivity and a smaller number had platelet inhibition in comparison with samples exposed to
unfractionated heparin. (From John LCH, Rees GM, Kovacs IB. Different anticoagulants and platelet reactivity in cardiac
surgical patients. Ann Thorac Surg 1993;56:899-902, with permission.)
Two glycosaminoglycans with heparin-like properties are available for clinical use: dermatan sulfate and danaparoid
(Lomoparan). These glycosaminoglycans are also referred to as heparinoids because they represent a class of synthetic or
naturally occurring heparin analogs. Henny et al. (258) compared UH with danaparoid (a natural composite of heparan
sulfate, dermatan sulfate, and chondroitin sulfates) for CPB in dogs and found that both produced satisfactory
anticoagulation. The group receiving danaparoid experienced less postoperative bleeding despite the absence of protamine,
which was administered to the dogs receiving heparin. Danaparoid has been shown to have a lower cross-reactivity with HIT
antibodies than does LMWH (10%-18%) and has been used successfully to anticoagulate patients with HIT for CPB.
Monitoring the plasma level and the anti-Xa activity is strongly recommended because there is no known antidote for
danaparoid excess, and bleeding complications have been demonstrated (259). Danaparoid was used successfully for CPB
in one patient with HIT in whom a therapeutic aPTT was maintained; however, macroscopic clots were noted in the circuit
filters after CPB (250). Typically, danaparoid levels are maintained by a bolus dose aimed at achieving a plasma level of 1.0
to 1.5 units/mL. As expected, plasma danaparoid levels correlate poorly with ACT and aPTT (260). Many questions remain
unanswered about LMWH and heparinoids for CPB, so this therapy must currently be viewed as experimental. Emergency
CPB in a patient experiencing HIT is the only appealing indication, and other options are preferred even in that setting. The
combination of long half-life, potentially inadequate thrombin (IIa) inhibition, and ineffective neutralization by protamine render
anticoagulation for CPB using LMWH and heparinoids highly questionable.
Defibrinogenating Agents
Zulys et al. (261) prospectively reported the successful use of ancrod for CPB anticoagulation in 20 patients. Derived from
Malayan pit viper venom, this agent lyses fibrinogen in a manner that precludes the formation of fibrin polymers. The unstable
fibrin formed is removed from the circulation by fibrinolysis and reticuloendothelial sequestration. Ancrod also stimulates the
release of tissue plasminogen activator (t-PA) from the vascular endothelium. The rapid elimination half-life of ancrod is 3 to 5
hours; however, achieving a sufficient fibrinogen depletion for safe CPB anticoagulation (plasma fibrinogen concentration of
0.4-0.8 g/L made aPTT and ACT infinite) takes at least 12 hours. Restoration of plasma coagulation after CPB requires FFP
and cryoprecipitate. When compared with 20 control patients receiving heparin-induced anticoagulation, the ancrod patients
experienced no difference in blood loss but received more packed red blood cells, FFP, and cryoprecipitate. A case report
describes the successful use of ancrod anticoagulation in a patient in whom HITT was diagnosed and in whom LMWH failed
to prevent the formation of thrombi in the extracorporeal circuit (262). Another patient in whom HIT was diagnosed underwent
successful CPB anticoagulation with the combination of ancrod and danaparoid sodium (Orgaran). In this case, ancrod alone
was ineffective in suppressing thrombin formation for CPB, but the combination allowed for safe CPB (263). The delayed
onset and the increased need for allogeneic blood products represent clear disadvantages to the clinical use of ancrod. An
antivenom is available, but it would not assist in the regeneration of fibrinogen, which is determined by the synthetic capacity
of the liver.
Defibrinogenation can also be achieved with thrombolytic agents such as streptokinase and its derivatives urokinase and
recombinant t-PA (264). This would be at the expense of increased plasmin formation and commensurate hyperfibrinolysis,
which would set the stage for a potentially severe post-CPB coagulopathy. Consequently, thrombolytic agents would serve
as undesirable heparin substitutes and probably should not be considered except in an emergency when heparin is relatively
contraindicated (e.g., ongoing HITT) and other heparin substitutes are unavailable.
Direct Thrombin Inhibitors

Unlike heparin compounds of any molecular size from any tissue source, direct thrombin inhibitors do not require cofactors
such as ATIII or heparin cofactor II to inhibit thrombin. This provides them with some advantages over heparin, but there
P.482
are disadvantages as well. Direct thrombin inhibitors fall into two categories, which are hirudin-like agents and argatroban.
Hirudin and Congeners
Hirudin
A coagulation inhibitor isolated from the salivary glands of the medicinal leech (Hirudo medicinalis), hirudin is a potent
inhibitor of thrombin that, unlike heparin, acts independently of ATIII and inhibits clot-bound thrombin in addition to fluid-phase
thrombin (265,266). Currently available through recombinant genetics, this substance is a polypeptide (molecular weight of
approximately 7,000 Da) that has been used in patients with chronic disseminated intravascular coagulation (265).
Pharmacokinetic studies in healthy volunteers show a plasma elimination half-life of approximately 1 hour and a urinary
excretion half-life of 2½ hours (266). After an intravenous bolus, the aPTT is prolonged markedly but transiently, returning to
normal in 15 minutes, whereas the thrombin time (TT) remains markedly prolonged for 2 to 3 hours. The aPTT prolongation
correlates well with plasma hirudin concentrations but does not correlate well with chromogenic antifactor II levels. For this
reason, a surrogate aPTT using the snake venom ecarin for activation has been described. This whole-blood test yields
excellent linear correlation with in vitro hirudin concentrations between 0.5 and 4 μg/mL, with coefficients of variation from 2%
to 5% (267). Walenga et al. (268) prospectively compared two hirudin dosing protocols with traditional heparin
anticoagulation in 30 dogs and found that hirudin induced satisfactory anticoagulation that appears measurable with ACT.
The relatively short-lived effect of a single intravenous bolus suggests the advisability of bolus administration followed by a
continuous infusion. The authors report that all clotting times returned to normal within 30 minutes of hirudin discontinuation,
but one of their figures suggests moderate ACT prolongation for as much as 2 hours. The hirudin groups displayed a trend
toward increased blood loss in the 150-minute observation period after CPB, but this did not reach statistical significance. In
a pig model, heparin (400 International Units/kg) was compared with hirudin (1 mg/kg) during 60 minutes of extracorporeal
circulation. There were no gross thrombotic episodes noted in either group. Moreover, pigs in the heparin group exhibited a
higher incidence of fibrin deposition on the arterial line filters, detected by electron microscopy, and a higher incidence of
tissue bleeding. Platelet aggregation was also better preserved in the hirudin group than in the heparin group (269).
Hirudin may demonstrate benefit as an anticoagulant for CPB in that it has been shown to inhibit the platelet activation
induced by nonionic contrast media (270). The mechanism of this has not been investigated; however, one could speculate
that hirudin inhibits platelet activation induced by CPB. Hirudin does not activate platelets nearly as much as UH does. This
property of direct thrombin inhibitors makes them more “biofriendly” than UH. Using direct thrombin inhibitors preserves
platelet activity and reduces release of platelet activation markers as compared with UH (Fig. 19.8).
There are some data examining the use of recombinant hirudin (r-hirudin) in humans. Koster et al. (271) performed a
retrospective analysis of 57 patients with HIT who underwent cardiac surgical procedures with CPB. r-Hirudin concentrations
were maintained between 3 and 4 μg/mL using the ecarin clotting time (see below). Elimination of r-hirudin was enhanced at
the end of CPB using modified ultrafiltration and diuresis. Blood loss over 24 hours ranged from 50 to 2,200 mL, and four
patients with impaired renal function had excessive bleeding and required surgical re-exploration. Fifty-four of the patients
fully recovered. In a small clinical trial, 20 patients were randomized to receive either r-hirudin or heparin (272). A bolus dose
of r-hirudin was administered (0.25 mg/kg with 0.2 mg/kg added to the CPB prime) and additional drug (5 mg) administered
on the basis of the ecarin clotting time. Blood loss in the first 36 hours was higher in the r-hirudin group (1,226) compared to
the heparin group (869 mL), and one patient in the r-hirudin group developed a pulmonary embolus. The limitations of hirudin
use during CPB include a relatively long half-life and increased risk of bleeding, particularly in the setting of renal
insufficiency. This indicates that in the setting of heparin avoidance, agents with a shorter half-life and less reliance on renal
elimination would be preferable.
Bivalirudin
Bivalirudin is a synthetic peptide formerly known as Hirulog and currently marketed as Angiomax (The Medicines Company).
A bivalent thrombin inhibitor, bivalirudin consists of one moiety that binds thrombin on its active-site cleft, and a second
hirudin-like C-terminal region that binds thrombin at its positively charged surface groove known as the anion-binding
exosite. Bivalirudin is a synthetic derivative of hirudin and therefore acts as a direct thrombin inhibitor. Bivalirudin offers
advantages over hirudin in both safety and potential efficacy. Bivalirudin appears to have a wider therapeutic window,
possibly because it only transiently inhibits the active site of thrombin. This broader safety margin for bivalirudin permits
administration of higher doses, which probably gives it an efficacy advantage over hirudin as well. Hirudin prevents thrombin
from activating protein C, thereby suppressing an anticoagulant pathway. In contrast, bivalirudin may promote protein C
activation by transiently inhibiting thrombin until it can be bound by thrombomodulin, a small (20-amino acid) molecule with a
plasma half-life of 24 minutes. Bivalirudin binds to both of its thrombin binding sites in both fluid phase and clot-bound
thrombin. Thrombin itself cleaves the part of the bivalirudin molecule that binds to it, so bivalirudin activity elimination is
independent of specific organ metabolism. This presents another advantage over hirudin, which requires renal elimination for
drug metabolism and dissipation of anticoagulant effect. Bivalirudin has been used successfully as an anticoagulant in
interventional cardiology procedures as a
P.483
replacement for heparin. In fact, in interventional cardiology, bivalirudin has been associated with less bleeding and
equivalent ischemic outcomes when compared with heparin plus a platelet inhibitor (273). This may result from the capacity
of bivalirudin to inhibit fluid-phase thrombin anticoagulant and platelet-bound thrombin (274). At lower bivalirudin plasma
concentrations, the anticoagulant effects will dissipate whereas antiplatelet effects continue. Bivalirudin anticoagulation
induces less P-selectin expression than do either UH or LMWH, indicating less platelet reactivity and possibly platelet
protection (274,275). In patients undergoing coronary angioplasty, bivalirudin demonstrated anti-ischemic and side effect
profiles that were superior to those of heparin as early as 1995 (276,277). Bivalirudin’s half-life of aPTT prolongation is
approximately 40 minutes, and reductions in FpA formation provide evidence of thrombin inhibition and fibrinogen
preservation. Careful monitoring should be employed because there may be a rebound prothrombotic state after cessation of
therapy, which could lead to recurrence of anginal symptoms.
Of the alternative agents to heparin for cardiac surgery, bivalirudin has been the most extensively studied in clinical trials
(retrospective, observational, and randomized). On the basis of case reports describing the successful use of bivalirudin in
both on- and off-pump cardiac cases, Merry et al. (278) performed the first randomized clinical trial using this agent in
2004. One hundred patients undergoing off-pump (OPCAB) surgery were randomized to receive bivalirudin (0.75 mg/kg
followed by a 1.75-mg/kg/hr infusion) or heparin. Blood loss 12 hours after surgery did not differ between groups. During
coronary angiography three months following surgery, patients in the bivalirudin group had higher median graft flow rates, as
well as more patients with full flow in at least one graft. Four randomized clinical trials were performed in patients with
(CHOOSE-ON and CHOOSE-OFF) and without (EVOLUTION-ON and EVOLUTION-OFF) HIT (279,280,281,282). The
primary outcome measure in all of the investigations was in-hospital procedural success, defined as freedom from death, Q-
wave myocardial infarction, stroke, or repeat vascularization. In the EVOLUTION-ON study, patients were randomized to
receive bivalirudin ( n = 101) or heparin (279). Dosing of bivalirudin was standardized (1.0 mg/kg bolus followed by a 2.5-
mg/kg/hr infusion), with additional boluses provided to maintain the ACT 2.5 times baseline. There were no differences
between groups in the primary endpoint (procedural success) up to 12 weeks following surgery. In addition, the two groups
did not differ in 24-hour blood loss or transfusion requirements. Similar results were observed in the EVOLUTION-OFF study
(105 patients randomized to receive bivalirudin and 52 to heparin) (280). Bivalirudin was administered as a 0.75-mg/kg bolus
and a 1.75-mg/kg/hr infusion, with adjustments to the infusion to maintain the ACT >300 seconds. Procedural success rates
(93%) were identical in the two groups, and blood loss and transfusions did not differ between groups. In both the CHOOSE-
ON and CHOOSE-OFF trials, 50 patients with confirmed or suspected HIT or positive HIT antibodies were given bivalirudin
for on- or off-CPB surgery (281,282). Dosing and monitoring of bivalirudin was identical to the EVOLUTION studies. In the
CHOOSE-ON trial, procedural success at 7 days was achieved in 94% of patients. Mean 24-hour blood loss was 998 mL,
with a mean of 5.6 units of red blood cells transfused by 7 days. Similarly, procedural success was achieved in 92% of
patients in the CHOOSE-OFF trial. Chest tube output at 24 hours was 936 mL, and 25% of patients received a red blood cell
transfusion. The safety of bivalirudin was further demonstrated in two large database studies. Koster et al. (283) reported
clinical outcomes in 141 patients receiving bivalirudin for on- and off-CPB surgery. Procedural success rates of 99% were
noted, with 30% (off-pump) and 56% (on-pump) of patients receiving a transfusion. Palmer et al. (284) examined data on 243
consecutive OPCAB patients who received bivalirudin for anticoagulation. Overall rates of morbidity and mortality (0.4%)
were low. These studies suggest that bivalirudin is a safe and effective alternative anticoagulant for cardiac surgical
procedures when it is used by experienced clinicians.
When bivalirudin is administered, surgical and perfusion techniques must be altered to reduce the risk of clot formation in the
CPB circuit or in saphenous vein or internal mammary artery grafts. Care should be exercised to ensure the absence of
stasis in the CPB circuit, and a recirculation limb should be incorporated into the extracorporeal circuit if periods of stasis are
expected. This need ensues from thrombin’s aforementioned capacity to metabolize bivalirudin even as it remains bound to
and inhibits thrombin-induced anticoagulation, so bivalirudin will be consumed in static blood if drug is not continuously
infused. Similarly, care must be taken to be sure that saphenous vein grafts that have been flushed with anticoagulated blood
are perfused regularly with anticoagulant, and that there is no static blood in internal mammary artery grafts between arterial
harvest and anastomosis.
Case reports confirm the safety of bivalirudin use for CPB anticoagulation while monitoring anticoagulant activity using the
ecarin clotting time (285,286,287). Ecarin cleaves prothrombin to meizothrombin, an intermediate compound that is
specifically antagonized by hirudin or bivalirudin. For this reason, ecarin clotting time more specifically measures thrombin
inhibition by these drugs than does the standard ACT (288). The ecarin clotting time better correlates with anti-IIa activity and
plasma drug concentrations than does the ACT (288,289). Unfortunately, the ecarin clotting time is currently not clinically
available because the platform is not currently supported by any company, but it may become available again in the future.
Until a specific test for thrombin inhibition using meizothrombin can be developed, modified ACT (1 to 1 dilution of patient
blood with FFP) has been used to monitor the effectiveness of bivalirudin and other thrombin inhibitors and this approach
appears to be safe (290,291). The standard ACT has also been used safely to monitor the anticoagulant
P.484
effects of bivalirudin. Since the direct thrombin inhibitors do not rely on a catalyst such as ATIII to exert their effects, the
pharmacokinetics of these drugs are much more predictable than those of heparin. In recent clinical trials using bivalirudin to
anticoagulate patients during CPB, an ACT of 2.5 times the baseline value was accepted as therapeutic (279). This minimum
ACT level was maintained during the clinical trials without adverse consequence. It is important to recognize that the target of
2.5 times baseline ACT is a minimum acceptable level that clinical trials to date would not support reducing bivalirudin
infusion rates to below 2.5 mg/kg/hr to achieve that level. The current recommendation is to maintain the bivalirudin infusion
rate at 2.5 mg/kg/hr, or higher if the target minimum ACT has not been met. The anticoagulant effects of the thrombin
antagonists can be monitored using the ACT, aPTT, or the thrombin time when lower doses of inhibitor are used such as
occurs in the catheterization laboratory or vascular surgical operating rooms. In a canine CPB model, dogs receiving a
synthetic thrombin inhibitor had less postoperative blood loss and higher platelet counts than those receiving heparin;
however, those who received a large dose of the thrombin inhibitor still had ACT elevations at 2 hours after CPB (292). The
safest approach is probably to continue the maintenance bivalirudin infusion rate at 2.5 mg/kg/hr or higher until the
conclusion of CPB, although the duration of its residual effect and the absence of a reversal agent lend some appeal to
reducing or discontinuing the infusion 15 to 30 minutes before discontinuing CPB, especially if the ACT exceeds the minimum
threshold by a substantial margin. The problem with stasis in the extracorporeal circuit does not end at the discontinuation of
CPB, so care must be taken to recirculate the residual CPB circuit after CPB as long as one wishes to either transfuse from
the circuit or preserve the potential opportunity to resume CPB. It is also important to add bivalirudin (50 mg bolus, 50 mg/hr
infusion) to the circulation of the closed circuit to prevent clotting until it is determined that CPB does not have to be
reestablished.
Argatroban
Argatroban (MW 527 Da) is a synthetic derivative of arginine that inhibits thrombin by binding only to its catalytic site. It is
approved for use as an alternative anticoagulant to heparin for patients with HIT. Like hirudin and bivalirudin (and unlike
heparin), argatroban inhibits both circulating and fibrin-bound thrombin. The plasma elimination half-life is approximately 40
minutes, and the agent is metabolized by the liver with biliary elimination. Therefore, argatroban offers appeal in patients with
severe renal insufficiency or renal failure. Argatroban anticoagulation for CPB is initiated (with or without a loading dose) with
a bolus of 0.1 to 0.2 mg/kg followed by an intravenous infusion at 5 to 10 μg/kg/min (less if there is hepatic insufficiency), and
the dose is then adjusted to maintain the aPTT 1.5 to 3 times normal. The ACT may also be used to guide therapy, in which
case the optimal ACT level appears to be 300 to 400 seconds (293,294).
Although the principal indication for argatroban is for patients with HIT, its use has also been well-described in non-HIT
patients undergoing interventional cardiology procedures and investigationally as an elective heparin alternative for patients
with acute coronary syndromes (295,296), unstable angina, and thromboembolic stroke (297). In general, such investigations
have found a similar efficacy as heparin, although some have reported a tendency to fewer bleeding complications.
Argatroban has been used safely as a heparin substitute for CPB; however, many bleeding complications have been
reported (298). A 2007 review reported on 21 cases of argatroban use during cardiac surgery (299). Three intraoperative
thrombi occurred during off-pump surgery, and one clot was noted in the CPB circuit during on-pump surgery. All of the
reported on-pump cases required large volumes of blood products, and half developed a severe coagulopathy. Argatroban
has also been used successfully for anticoagulation during pediatric cardiac surgery with CPB and for extracorporeal
membrane oxygenation (300,301,302). Although argatroban’s theoretic appeal as a CPB anticoagulant for chronic dialysis
patients is compelling, scattered anecdotal clinical experiences to date suggest the possibility that either bivalirudin alone or
UH in combination with a potent platelet inhibitor such as eptifibatide or a prostaglandin derivative may be preferred over
argatroban. Problems with both bleeding and clotting (even in the same patient) have been reported, so the drug may be
unsatisfactory for CPB, or alternatively the optimal dosing and monitoring may have not yet been determined.
Platelet Inhibitors
Pharmacologic platelet inhibition has been used to supplement or replace heparin for CPB anticoagulation. This technique is
discussed below with HIT.
Coated Surfaces
This topic is discussed in Chapter 2.
Factor Inhibitors
The development of factor IXa inhibitor (factor IXai) represents a novel approach to designing the optimal anticoagulant for
CPB. This molecule was developed by modifying the active site of the enzyme. Factor IXai competitively blocks active factor
IX and replaces it in the intrinsic coagulation cascade, thereby preventing activation of factor X and thrombin formation
through this pathway. It leaves the extrinsic coagulation pathway intact, allowing for normal coagulation in response to tissue
factor release. Twenty mongrel dogs undergoing CPB were studied, 15 receiving factor IXai (300-600 μg/kg) and 5 receiving
standard heparin and protamine. The group receiving IXai experienced no fibrin deposition in the circuit and less bleeding
than did the heparin group (303). A case is described in which a patient on ventricular assist device received factor IXai, with
subsequent reductions in markers of thrombin activation and activity; however, these results
P.485
are difficult to interpret, as the patient died from a massive hemorrhage (304). Trials using a specific factor Xa inhibitor have
not demonstrated reduced thrombin formation and in fact have shown increased fibrin formation in comparison to heparin and
LMWH anticoagulation (305).
HEPARIN-INDUCED THROMBOCYTOPENIA
The syndrome known as HIT develops in anywhere from 5% to 28% of patients receiving heparin, and is commonly divided
into two subtypes. Type I HIT, characterized by a mild decrease in platelet count, results from the proaggregatory effects of
heparin on platelets (81). Type II HIT is considerably more severe, most often occurs after more than 5 days of heparin
administration (average onset time of 9 days), and is most likely immune mediated. Heparin exposure results in the formation
of antibodies, primarily of the IgG type. It is now known that the Fc portion of the antibody binds to the complex formed
between heparin and PF4 on the platelet surface. The Fab portion of the antibody then causes platelet activation and
hyperaggregability (306,307,308). Therefore, the heparin-PF4 complex acts as an antigenic stimulus (309,310). Antibody
binding also results in generation of procoagulant, platelet derived microparticles. The end result of these processes is the
generation of thrombin and subsequent arterial and venous thrombosis. Heparin-PF4 complexes can also exist on the
surface of platelets or can bind to endothelial cells, which become activated when the antibody binds. Associated immune-
mediated endothelial injury and complement activation may set the stage for the activated platelets to adhere, aggregate, and
form platelet clots (311,312). When carried to an extreme, this syndrome can cause severe morbidity or fatal intravascular
thromboembolic phenomena (313,314). Among the patients in whom HIT develops, the incidence of thrombotic complications
(HIT type II) approximates 20%, which in turn may carry a mortality rate as high as 35%. Both of these figures may be
overestimated as a result of reporting bias, although some prospective investigations support the 20% incidence of
thrombosis (80). Although venous thrombotic events (deep vein thrombosis or pulmonary embolus) are more common in
medical patients, the majority of HIT-related thrombotic events in cardiac surgical patients are arterial. Additionally, HIT II can
be a subclinical syndrome masquerading as other more frequent entities until devastating thrombosis occurs. The most
important step toward diagnosis is the need to consider HIT as the cause of a decrease in platelet count in patients receiving
heparin.
Heparin-induced thrombocytopenia is a clinicopathologic syndrome; identification of HIT is based upon both a clinical
diagnosis and positive laboratory testing (antigen assay or functional assay [see below]). Clinicians should consider a
possible diagnosis of HIT whenever thrombocytopenia develops in the postoperative period. The thrombocytopenia typically
observed in a patient with HIT (90%-95% of patients) is a reduction in platelet count to less than 150 × 109/L or a 30% to
50% decrease in platelet number, even if the platelet count remains >150 × 109/L (315). Most commonly, the fall in platelet
count occurs 5 to 10 days after the initial dose of heparin was administered (typical-onset HIT). However, a rapid reduction in
platelet count can occur within 24 hours if circulating HIT antibodies are present due to recent heparin exposure (rapid-onset
HIT). On occasion, the drop in platelet number can occur up to 3 weeks after heparin exposure was discontinued (delay-
onset HIT). Clinical diagnosis of HIT is often difficult in the postoperative period. In a postoperative patient with a decrease in
platelet count, the use of a clinical probability scoring system, in addition to laboratory testing, can increase the likelihood of
determining whether HIT is present. The “4T” scoring system is the most commonly used clinical prediction tool (316). The
four “T”s assessed in this system are Thrombocytopenia, Timing (of platelet count fall or thrombosis), Thrombosis (or other
clinical sequelae, and oTher causes of thrombocytopenia. A score of 0 to 2 is assigned to each category, and a total score
determined. Patients with a low 4T score have a low probability of HIT (0%-3%), whereas up to 61% of patients with high 4T
scores may not actually have HIT (315). Therefore, laboratory testing is essential in the diagnosis of HIT.
Two categories of laboratory testing are available; antigen assays that detect the presence of HIT antibodies and functional
assays that demonstrate platelet activation by HIT antibodies in the presence of heparin. Functional assays (demonstration
of heparin-induced aggregation of platelets) are used to confirm the diagnosis of HIT type II (317). This can be accomplished
with a heparin-induced serotonin release assay (318) or a specific heparin-induced platelet activation assay (319). However,
these tests are difficult to perform and are available at only a small number of medical centers. Most hospitals perform
antigen assays to help confirm a clinical diagnosis of HIT. A highly specific enzyme-linked immunosorbent assay (ELISA) for
the heparin-PF4 complex has been developed and used to delineate the course of immunoglobulin G and immunoglobulin M
antibody responses in patients exposed to UH during cardiac surgery (320). Many centers use the ELISA as the sole
confirmatory evidence of a HIT II diagnosis. However, the antibody is present in many patients who receive heparin and who
never develop thrombocytopenia or thrombosis (321,322,323). When unfractionated heparin is used perioperatively, 25% to
50% of cardiac surgical patients will demonstrate HIT antibodies on ELISA testing, but only 1% to 3% of these patients will
develop actual HIT (324). Therefore, the presence of antibody as judged by the ELISA assay is very sensitive to yet
nonspecific for HIT. In fact, antibody has been detected in patients who lacked any exposure to heparin (301). Antibody titers
may be helpful in that high titers appear to be more predictive of thrombocytopenia or thrombosis (307).
P.486
The currently accepted threshold for HIT at many centers is an optical density (OD) of 0.40 units (optical density reflects the
strength of the ELISA reaction). Specificity of the ELISA test may be increased by raising the OD threshold. In a database
study of 1,958 patients, changing the cutoff for a diagnosis of HIT from an OD of 0.40 units to an OD of 0.80 units reduced
the false-positive rate for HIT from 31% to 6%. Retrospective data suggests that raising the ELISA threshold to an OD of 1.0
or greater, combined with an intermediate or high 4T score, may be as accurate in diagnosing clinical HIT as functional
assays (315). However, confirmatory diagnostic testing with a functional test for platelet hyperaggregability is recommended
before embarking on a treatment course with an alternative anticoagulant, since this testing remains the “gold standard” in
the diagnosis of HIT. Management decisions may be made in the absence of functional testing if such testing is unavailable,
or if delays in treatment may place the patient at high risk for adverse outcomes (the rate of thrombosis is 5% per day prior to
treatment with alternative anticoagulants) (315,325).
The mere presence of heparin-PF4 antibody has been associated with adverse outcomes after cardiac surgery (326) (Table
19.6). The presence of antibody serves as a marker of exposure to a heparin compound. It is not clear that the presence of
antibody portends an adverse outcome or predicts it by signaling the potential for microembolic phenomena (334). It is also
very likely that the presence of antibody marks a patient who has had a complex medical course and who is already known to
be at risk for adverse outcomes. Some clarification on the association between preoperative HIT antibodies in cardiac
surgical patients not suspected to have HIT and adverse postoperative outcomes was provided in a systematic review by
Yusuf et al. (332). Five studies involving 2,332 patients were reviewed. Preoperative anti-PF4/heparin antibodies were
detected in 5% to 22% of patients. The authors concluded that preformed antibodies did not predict postoperative
thromboembolic complications or death, although an association with nonthrombotic complications was likely.
Diagnosis of HIT in cardiac surgical patients is further complicated by the observation that a decrease in platelet count is
frequently observed postoperatively in patients without HIT. In the majority of cardiac surgical patients, platelet count
decreases by approximately 40% to 50% due to hemodilution and platelet consumption during CPB (315). For the first 1 to 2
postoperative days, platelet counts will continue to decline, before increasing to (or above) preoperative levels beginning on
postoperative day three. A diagnosis of HIT should be suspected when a fall in platelet count ≥50% from this peak
postoperative value occurs within 5 to 10 days of surgery, or if thrombocytopenia persists for more than four postoperative
days.
HIT differs from other immune-mediated, drug-induced thrombocytopenias in the following ways: (1) The antibodies
associated with HIT often become undetectable several weeks after the drug is discontinued, (2) the clinical syndrome does
not always recur on reexposure to the drug and sometimes resolves despite continued drug therapy, (3) the in vitro platelet
aggregation reaction is sometimes patient-specific, and (4) intravascular thrombosis develops only in some patients (80).
Most studies have found a 5-fold higher incidence with bovine lung heparin than with porcine mucosal heparin
(80,81,335,336,337,338).
Patients with cardiovascular disease frequently receive heparin, because this reduces the incidence of thrombotic
complications of anterior myocardial infarction, of recurrent thrombosis after percutaneous transluminal coronary angioplasty
for acute coronary thrombosis, and of myocardial infarction in patients with unstable angina pectoris (86,339,340,341).
Because some of these patients may need subsequent surgical myocardial revascularization, the possibility exists that
patients with unrecognized HIT could present for urgent surgery.
At the present time there are no alternative anticoagulants that are approved for use during on- or off-pump cardiac surgery.
This necessitates the off-label use of these agents under exceptional circumstances. As HIT is a relatively uncommon
complication of heparin treatment, it is unlikely that a definitive treatment strategy will be clearly defined by large-scale
randomized trials. However, some recommendations about therapeutic options in the patient with HIT are provided in
guidelines published by the American College of Chest Physicians (315). Patients with HIT type I can receive heparin safely
for cardiac surgery. Patients with a history of HIT type II whose antibody levels have dropped to undetectable concentrations
and who have not received heparin for 90 or more days can receive heparin for CPB and they will probably not mount an
antibody response to this dose (342). All other heparin must be carefully avoided in the preoperative period. If postoperative
anticoagulation is needed, consideration must be given to selecting a different anticoagulant such as a direct thrombin
inhibitor. Olinger et al. (164) reported three patients in whom discontinuation of heparin for 4 to 8 weeks resolved the
antiplatelet antibody reaction. Those patients then tolerated the brief period of heparinization for CPB without complication
and without development of thrombocytopenia beyond that expected from hemodilution. Although evidence is limited using
this strategy, the risks associated with non-heparin anticoagulants during CPB are likely greater than the small possibility of
developing clinical HIT.
There are two possible management strategies for patients with a history of HIT type II in whom HIT antibodies are still
present (Table 19.7). If cardiac surgery is not urgent, it is recommended that surgery should be delayed if possible until HIT
antibodies are no longer detectable. Heparin can then be administered intraoperatively (but carefully avoided pre- and
postoperatively). If surgery cannot be delayed, anticoagulation should be achieved with an alternative anticoagulant for CPB
or with a combination of heparin and a profound platelet-inhibiting drug such as tirofiban, eptifibatide, or prostaglandin
congeners possessing these properties (e.g., iloprost, prostacyclin, prostaglandin E1) (271,289,343). Success with UH plus
tirofiban has been reported (343).
P.487
TABLE 19.6. Preoperative anti-PF4/heparin antibodies and adverse postoperative outcomes following
cardiac surgery
Authors Date No. of Study type % Patients Clinical outcomes Association

patients with assessed between anti-PF4
preoperative antibodies and
anti- adverse outcomes
PF4/Heparin
antibodies
Visentin 1996 51 Prospective 22 Thrombocytopenia, None: clinically

et al. observational clinically significant significant
(320) thrombosis thrombosis did not
develop in any
patient
Bauer et 1997 111 Prospective 19 Thrombocytopenia, None: no difference

al. (327) observational thromboembolic in prevalence of
events thrombocytopenia or
thrombo-embolic
events
Bennett- 2005 466 Prospective 13 Major Presence of
Guerrero observational complications antibodies before
et al. (Death or surgery is an
(326) postoperative independent
hospitalization >10 predictor for death
d) and/or prolonged
hospital stay
Everett et 2007 299 Prospective 4.3 Clinical thrombosis None: no

al. (328) observational association between
antibody and
thromboembolic
events
Kress et 2007 1,114 Retrospective 5.4 Clinical recovery Patients with

al. (329) and adverse preoperative
events antibodies had
increased risk of
prolonged
ventilation, acute
limb ischemia, and
renal/gastrointestinal
complications
Gluckman 2009 368 Prospective 3 % of saphenous None: antibody not

et al. observational vein grafts predictive of vein
(330) occluded, clinical graft occlusion or
outcomes outcomes
Selleng et 2010 591 Prospective 21.7 Postoperative IgG and IgA

al. (331) observational complications, antibodies not
frequency of HIT or associated with
thrombotic increased risk for
complications, adverse events; IgM
prolonged antibodies
inhospital stay, 30- associated with
day mortality increased risk of
non-thrombotic
complications and
longer hospital stay
Yusuf et 2012 2,332 Systematic 5-22 Postoperative Preoperative

al. (332) (total review thromboembolic antibodies do not
from 5 outcomes, predict
studies) nonthromboembolic postoperative
outcomes, hospital thromboembolic
length of stay, complications or
mortality death; there may be
an association
between antibodies
and non-
thromboembolic
adverse events, but
a causal relationship
is unlikely
Chen et 2013 54 Prospective 13 Frequency of HIT None: no patients

al. (333) observational developed clinical
HIT or thrombosis
P.488
Hirudin and bivalirudin offer specific advantages in patients with HIT because, unlike heparin, these direct thrombin inhibitors
do not require a cofactor, are capable of inhibiting “clot-bound” thrombin, are not susceptible to neutralization by PF4, and do
not activate platelets. In a prospective study, r-hirudin was given successfully for CPB as a bolus of 0.25 mg/kg, followed by
administration of a 5-mg bolus whenever the hirudin concentration fell below 2,500 ng/mL, determined by the ecarin clotting
time (344). This study also treated noncardiac surgical patients experiencing HIT or HIT II with r-hirudin and compared their
outcomes with those of a historical control group. They found that patients treated with r-hirudin sustained increases in their
platelet counts and maintained stable hemoglobin levels with very few bleeding complications. Median plasma hirudin
concentrations in the noncardiac surgical patients with thrombosis ranged from 1,149 to 1,698 ng/mL. The incidence of
death, new limb amputations, or thromboembolic complications was lower in the hirudin group, with a risk-adjusted hazard
ratio of 0.508 (95% confidence interval [CI], 0.290-0.892; p = 0.014). Because of a shorter half-life and a reduced need for
normal renal function for complete elimination, bivalirudin has replaced hirudin for the treatment of patients with HIT II
requiring CPB. The CHOOSE and EVOLUTION clinical trials (see above) have demonstrated that this agent can be used
successfully and safely in cardiac surgery and that it compares well with UH for this purpose (279,280,281,282). At the
present time, no randomized clinical trials have directly compared outcomes between patients receiving different nonheparin
anticoagulation agents in the setting of cardiac surgery. In patients with HIT antibodies requiring urgent cardiac surgery, the
highest level of evidence supports the use of bivalirudin (for both on- and off-CPB procedures). When cardiac surgery cannot
be delayed until HIT antibodies are negative, recent evidence-based guidelines recommend the use of bivalirudin over other
alternative anticoagulant agents (including heparin plus antiplatelet agents) (315). However, the choice of agent may be
impacted by other factors, which include drug availability, cost, and monitoring capability at each clinical center. In the
CHOOSE-ON and EVOLUTION-ON clinical trials, the ACT was used to monitor the anticoagulant effect of bivalirudin during
CPB (279,281). Anticoagulation was considered adequate if a 2.5-fold or greater prolongation of the baseline ACT value was
achieved. In the CHOOSE-OFF and EVOLUTION-OFF, an ACT of 300 seconds or greater was the target for acceptable
anticoagulation during off-pump cardiac surgery (280,282). However, the ACCP guidelines state that the ecarin clotting time
(ECT) is the preferred assay to monitor anticoagulation during CPB, if available (see preceding section on the ecarin clotting
time) (315).
In clinical settings other than CPB, initiating therapeutic heparin doses in patients with unrecognized HIT has been
associated with life-threatening complications (80). A report of two cases documents HIT in which the sole exposure to
heparin was intermittent flushing of a single intra-arterial catheter used only for intraoperative monitoring. One of these cases
proved fatal (345). Would the larger heparin doses administered for CPB induce profound thrombocytopenia or acute
intravascular thrombosis in patients with unrecognized or incipient HIT? Reports of such events could not be found, but
thrombocytopenia disproportionate to hemodilution has been reported in such situations, even in the protective presence of
antiplatelet drugs (346,347). It is also possible that some of the reports of total intravascular thrombosis seen as a
complication of cardiac surgery are actually instances of undiagnosed HIT type II (348). Many of these thrombotic events
have been reported (349,350,351,352). They are usually attributed to antifibrinolytic therapy and they are often fatal (353).
Other hypercoagulable states have also been attributed to these events. Heparin resistance commonly occurs in patients
receiving heparin infusions in whom thrombocytopenia has not developed, but it has also been temporally associated with
HIT (80,164,354). Consequently, unrecognized HIT should be considered in the differential diagnosis of intraoperative
heparin resistance in patients receiving preoperative heparin therapy.
TABLE 19.7. Recommendations from the American College of Chest Physicians on the treatment and
prevention of heparininduced thrombocytopenia
1. In patients with a history of HIT in whom heparin antibodies have been shown to be absent who require
cardiac surgery, we suggest the use of heparin (short-term use only) over nonheparin anticoagulants (Grade
2C).
2. In patients with a history of HIT in whom heparin antibodies are still present who require cardiac surgery, we
suggest the use of nonheparin anticoagulants over heparin or LMWH (Grade 2C).
3. In patients with acute HIT (thrombocytopenic, HIT antibody positive) or subacute HIT (platelets recovered, but
still HIT antibody positive) who require urgent cardiac surgery, we suggest the use of bivalirudin over other
nonheparin anticoagulants and over heparin plus antiplatelet agents (Grade 2C).
4. In patients with acute HIT who require nonurgent cardiac surgery, we recommend delaying the surgery (if
possible) until HIT has resolved and HIT antibodies are negative (Grade 2C).
Remarks: Other factors not covered by our analysis, such as drug availability, cost, and ability to monitor the
anticoagulant effect may influence the choice of agent.
Grade 2C: Weak recommendation, low or very low quality of evidence.
From Linkins LA, Dans AL, Moores LK, et al. Treatment and prevention of heparininduced thrombocytopenia:
antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based
Clinical Practice Guidelines. Chest 2012;141(2, Suppl):e495S-e530S.
P.489
Changing the tissue source of heparin has been shown to circumvent the reaction (355), although cross-reactivity often
exists, so this approach is not recommended. It should be taken only if it can be proved safe by testing the patient’s platelet-
rich plasma in vitro with the alternative heparin. The risk of developing HIT antibodies after cardiac surgery can also be
influenced by the tissue source of heparin. In a study of 207 patients undergoing firsttime CABG surgery, seroconversion
(positive HIT antibodies) was observed significantly more frequently in patients given bovine heparin (44.4%) compared to
those administered porcine heparin (30.6%) (356). Some types of LMWH have proved effective in HIT (see preceding text),
but their use presents another set of problems, and nonreactivity with the patient’s platelets should be confirmed in vitro
before this option is selected (357). Although case reports have described the use of LMWH for CPB (see preceding text),
use of these agents is not recommended due to a risk of excessive bleeding, difficulties in monitoring, and lack of an effective
neutralizing agent. Low-molecular-weight heparinoids (like danaparoid) appear safer than LMWHs in this setting (358).
However, the use of danaparoid in cardiac surgery has been associated with excessive bleeding and transfusion
requirements due to the drugs long half-life and lack of a reversal agent. Furthermore, dosing requirements have not been
established and specialized monitoring is required (see preceding text). Past treatment with heparin administration and
pharmacologic platelet inhibition through prostacyclin, iloprost, tirofiban, aspirin, or aspirin and dipyridamole has been
reported (346,347,359,360), all with favorable outcomes. The use of iloprost titrated to a documented level of platelet
functional suppression permitted heparin use without undue thrombocytopenia (359,360), whereas aspirin or aspirin plus
dipyridamole may less consistently protect against thrombocytopenia (346,347). It seems logical that prostaglandin E1 would
also serve effectively in this role (361,362), although this agent shares the vasodilator side effect of prostacyclin.
Plasmapheresis acutely reduced heparin-induced platelet aggregation in two cases (363,364).
CONCLUSION
Advances in our understanding of coagulation and our ability to monitor for appropriate levels of anticoagulation during
CPB allow us to employ extracorporeal circulation safely in a variety of clinical settings. Inhibition of microvascular
coagulation is important for minimization of the inflammatory response to CPB, and reversal of this effect is important in
postoperative hemostasis. The aforementioned devices, tests, and pharmaceuticals are important components in the
blood conservation armamentarium for patients undergoing cardiac surgery.
KEY Points
Heparin is a heterogeneous, heavily sulfated polysaccharide compound derived from pig intestinal mucosa or bovine
lung. Some of the polysaccharide chains possess a specific pentasaccharide sequence that binds ATIII, profoundly
facilitating its native ability to inhibit plasma coagulation, most prominently through inhibition of factors IIa (thrombin)
and Xa. Longer polysaccharide chains effectively inhibit IIa and Xa, whereas shorter chains preferentially inhibit Xa.
Heparin offers the advantages of a rapid onset of action, clinical efficacy as an anticoagulant for CPB, and rapid
neutralization by protamine.
Common or routine side effects of heparin include facilitation of fibrinolysis, stimulation of TFPI, platelet binding and
activation, activation of lipoprotein lipase, and a decrease in systemic vascular resistance. HITT represents an
immune and potentially life-threatening reaction that occurs in 5% to 28% of patients, who most often have been
receiving heparin for a period of several days. Heparin administration has rarely been associated with immediate
anaphylaxis or pulmonary edema.
Anticoagulation with heparin for CPB can be monitored by measuring clotting times or whole-blood heparin
concentrations. Of the many tests available, those most commonly used for CPB are the ACT and heparin
concentration as determined by an automated protamine titration method. The ACT shows that anticoagulation has
occurred, but it is imprecise, results vary among different commonly used ACT techniques, and it is prolonged by
hypothermia and hemodilution. Automated heparin concentrations generally remain stable with hypothermia and
hemodilution but do not measure the degree of anticoagulation. Newer clotting tests showing some promise for
heparin monitoring include the heparin management test and the high-dose thrombin time.
Clinical outcome studies do not clearly demonstrate the superiority of any specific heparin-monitoring or dosing
technique, but they do show that anticoagulation with heparin is incomplete (as judged by markers of thrombin
activity) regardless of dose. For most clinical situations requiring CPB, the authors recommend monitoring ACT and
maintaining levels above 400 seconds. Some exceptions (e.g., aprotinin use) are detailed in the text.
Heparin resistance, defined as the need for higher-than-normal doses of heparin to achieve the desired level of
anticoagulation for CPB, has a variety of potential causes and may be multifactorial in any specific patient. When
excessive doses of heparin are required to achieve a desired ACT, the authors recommend administering an ATIII
concentrate, although FFP will also suffice.
P.490
Several alternatives to heparin have undergone investigation in animal models, humans, or both. LMWHs and low-
molecular-weight heparinoids appear unsatisfactory for CPB because of limited thrombin inhibition, long clinical half-
lives, difficulty in monitoring anticoagulation, and incomplete neutralization with protamine. Other possibilities include
ancrod, hirudin and its congeners, and factor IXa inhibitor.
When patients with HIT present for cardiac surgery requiring CPB, several clinical approaches have been used
successfully. The approach may vary according to the presence or absence of active disease (as judged by
diagnostic assays), the severity of disease, and the urgency of surgery. If possible, surgery should be delayed until
HIT has resolved and HIT antibodies are negative. Heparin can then be used intraoperatively (but avoided
preoperatively and postoperatively). If urgent surgery is required, evidence supports the use of bivalirudin over other
nonheparin anticoagulants and over heparin plus antiplatelet agents. However, other factors such as drug cost and
availability, familiarity of the cardiac team with various agents, and availability of appropriate monitoring should be
considered. Other alternative anticoagulant strategies in the patient with HIT requiring cardiac surgery include use of
other direct thrombin inhibitors (lepirudin, argatroban), administration of low-molecularweight heparinoids such as
danaparoid, or preoperative pharmacologic inactivation of platelets in preparation for intraoperative anticoagulation
with heparin.
REFERENCES
1. Gibbon JH Jr. Application of a mechanical heart and lung apparatus to cardiac surgery. Minn Med 1954;37(3):171-
185; passim.
2. Mc LJ. The discovery of heparin. Circulation 1959;19(1):75-78.
3. Howell WH, Holt E. Two new factors in blood coagulation—heparin and pro-antithrombin. Am J Physiol 1918;47:328-
341.
4. Best CH. Preparation of heparin and its use in the first clinical cases. Circulation 1959;19(1):79-86.
5. Chargaff E, Olson KB. Studies on the chemistry of blood coagulation. VI. Studies on the action of heparin and other
anti-coagulants. The influence of protamine on the anticoagulant effect in vivo. J Biol Chem 1938;125: 671-676.
6. Gibbon JH Jr. The maintenance of life during experimental occlusion of the pulmonary artery followed by survival. Surg
Gynecol Obstet 1939;69:602-614.
7. Stiekema JC. Heparin and its biocompatibility. Clin Nephrol 1986; 26(Suppl 1):S3-S8.
8. Hirsh J. Heparin. N Engl J Med 1991;324(22):1565-1574.
9. Thomas DP, Barrowcliffe TW, Johnson EA. The influence of tissue source, salt and molecular weight and heparin
activity. Scand J Haematol Suppl 1980;36:40-49.
10. Walton PL, Ricketts CR, Bangham DR. Heterogeneity of heparin. Br J Haematol 1966;12(3):310-325.
11. Jaques LB, McDuffie NM. The chemical and anticoagulant nature of heparin. Semin Thromb Hemost 1978;4(4):277-
297.
12. Rodriguez HJ, Vanderwielen AJ. Molecular weight determination of commercial heparin sodium USP and its sterile
solutions. J Pharm Sci 1979;68(5):588-591.
13. Lasker SE. The heterogeneity of heparins. Fed Proc 1977;36(1):92-97.
14. Eika C. The platelet aggregating effect of eight commercial heparins. Scand J Haematol 1972;9(5):480-482.
15. Rosenberg RD. Biochemistry of heparin antithrombin interactions, and the physiologic role of this natural
anticoagulant mechanism. Am J Med 1989;87(3B):2S-9S.
16. Bangham DR, Woodward PM. A collaborative study of heparins from different sources. Bull World Health Organ
1970;42(1):129-149.
17. Novak E, Sekhar NC, Dunham NW. A comparative study of the effect of lung and gut heparins on platelet aggregation
and protamine neutralization in man. Clin Med 1972;79:22-27.
18. Casu B, Guerrini M, Naggi A. Characterization of sulfation patterns of beef and pig mucosal heparins by nuclear
magnetic resonance spectroscopy. Arzneimittelforschung 1996;46:472-477.
19. Silverglade A. Biological equivalence of beef lung and hog musosal heparins. Curr Ther Res Clin Exp 1975;18(1, Part
1):91-103.
20. Baltes BJ, Diamond S, D’Agostino RJ. Comparison of anticoagulant activity of two preparations of purified heparin.
Clin Pharmacol Ther 1973;14(2):287-290.
21. Abbott WM, Warnock DF, Austen WG. The relationship of heparin source to the incidence of delayed hemorrhage. J
Surg Res 1977;22(6):593-597.
22. Stewart SR, Gaich PA. Clinical comparison of two brands of heparin for use in cardiopulmonary bypass. J Extra
23. Tovar AM, Teixeira LA, Rembold SM, et al. Bovine and porcine heparins: different drugs with similar effects on human
haemodialysis. BMC Res Notes 2013;6:230.
24. Fiser WP, Read RC, Wright FE, Vecchio TJ. A randomized study of beef lung and pork mucosal heparin in cardiac
surgery. Ann Thorac Surg 1983;35(6): 615-620.
25. Lowary LR, Smith FA, Coyne E, Dunham NW. Comparative neutralization of lung- and mucosal-derived heparin by
protamine sulfate using in vitro and in vivo methods. J Pharm Sci 1971;60(4):638-640.
26. Barrowcliffe TW, Johnson EA, Eggleton CA, Thomas DP. Anticoagulant activities of lung and mucous heparins.
Thromb Res 1978;12(1):27-36.
27. Thomas DP, Sagar S, Stamatakis JD, et al. Plasma heparin levels after administration of calcium and sodium salts of
heparin. Thromb Res 1976;9(3): 241-248.
28. Merton RE, Curtis AD, Thomas DP. A comparison of heparin potency estimates obtained by activated partial
thromboplastin time and british pharmacopoeial assays. Thromb Haemost 1985;53(1):116-117.
29. Effeney DJ, Goldstone J, Chin D, et al. Intraoperative anticoagulation in cardiovascular surgery. Surgery
1981;90(6):1068-1074.
30. Gravlee GP, Angert KC, Tucker WY, et al. Early anticoagulation peak and rapid distribution after intravenous heparin.
Anesthesiology 1988;68(1): 126-129.
31. Estes JW. The fate of heparin in the body. Curr Ther Res Clin Exp 1975; 18(1, Part1):45-57.
32. Estes JW. Clinical pharmacokinetics of heparin. Clin Pharmacokinet 1980;5(3):204-220.
33. Hiebert LM, Jaques LB. The observation of heparin on endothelium after injection. Thromb Res 1976;8(2):195-204.
34. Glimelius B, Busch C, Hook M. Binding of heparin on the surface of cultured human endothelial cells. Thromb Res
1978;12(5):773-782.
35. Barzu T, Molho P, Tobelem G, et al. Binding and endocytosis of heparin by human endothelial cells in culture.
Biochim Biophys Acta 1985;845(2):196-203.
36. Mahadoo J, Heibert L, Jaques LB. Vascular sequestration of heparin. Thromb Res 1978;12(1):79-90.
37. Jaques LB, Mahadoo J. Pharmacodynamics and clinical effectiveness of heparin. Semin Thromb Hemost
1978;4(4):298-325.
38. Castellot JJ Jr, Wong K, Herman B, et al. Binding and internalization of heparin by vascular smooth muscle cells. J
Cell Physiol 1985;124(1):13-20.
39. Dawes J, Papper DS. Catabolism of low-dose heparin in man. Thromb Res 1979;14(6):845-860.
40. de Swart CA, Nijmeyer B, Roelofs JM, Sixma JJ. Kinetics of intravenously administered heparin in normal humans.
Blood 1982;60(6):1251-1258.
41. Olsson P, Lagergren H, Ek S. The elimination from plasma of intravenous heparin. An experimental study on dogs
and humans. Acta Med Scand 1963;173:619-630.
42. Bjornsson TD, Wolfram KM, Kitchell BB. Heparin kinetics determined by three assay methods. Clin Pharmacol Ther
1982;31(1):104-113.
43. Cohen JA, Frederickson EL, Kaplan JA. Plasma heparin activity and antagonism during cardiopulmonary bypass with
hypothermia. Anesth Analg 1977;56(4):564-570.
44. Wright JS, Osborn JJ, Perkins HA, Gerbode F. Heparin levels during and after hypothermic perfusion. J Cardiovasc
Surg (Torino) 1964;5:244-250.
45. Bull BS, Korpman RA, Huse WM, Briggs BD. Heparin therapy during extracorporeal circulation. I. Problems inherent
in existing heparin protocols. J Thorac Cardiovasc Surg 1975;69(5):674-684.
P.491
46. Mabry CD, Read RC, Thompson BW, et al. Identification of heparin resistance during cardiac and vascular surgery.
Arch Surg 1979;114(2):129-134.
47. Estes JW. Kinetics of the anticoagulant effect of heparin. JAMA 1970;212(9):1492-1495.
48. Horkay F, Martin P, Rajah SM, Walker DR. Response to heparinization in adults and children undergoing cardiac
operations. Ann Thorac Surg 1992; 3(5):822-826.
49. Villaneuva GB, Danishefsky I. Evidence for a heparin-induced conformational change on antithrombin III. Biochem
Biophys Res Commun 1977;74(2):803-809.
50. Pixley RA, Schapira M, Colman RW. Effect of heparin on the inactivation rate of human activated factor XII by
antithrombin III. Blood 1985;66(1):198-203.
51. Ofosu FA, Fernandez F, Gauthier D, Buchanan MR. Heparin cofactor II and other endogenous factors in the
mediation of the antithrombotic and anticoagulant effects of heparin and dermatan sulfate. Semin Thromb Hemost
1985;11(2):133-137.
52. Monkhouse FC, Macmillan RL, Brown KW. The relation between heparin blood levels and blood coagulation times. J
Lab Clin Med 1953;42(1):92-97.
53. Esposito RA, Culliford AT, Colvin SB, et al. Heparin resistance during cardiopulmonary bypass. The role of heparin
pretreatment. J Thorac Cardiovasc Surg 1983;85(3):346-353.
54. Doty DB, Knott HW, Hoyt JL, Koepke JA. Heparin dose for accurate anticoagulation in cardiac surgery. J Cardiovasc
Surg (Torino) 1979;20(6):597-604.
55. Stenbjerg S, Berg E, Albrechtsen OK. Heparin levels and activated clotting time (ACT) during open heart surgery.
Scand J Haematol 1981;26(4):281-284.
56. Jaberi M, Bell WR, Benson DW. Control of heparin therapy in open-heart surgery. J Thorac Cardiovasc Surg
1974;67(1):133-141.
57. Friesen RH, Clement AJ. Individual responses to heparinization for extracorporeal circulation. J Thorac Cardiovasc
Surg 1976;72(6):875-879.
58. Akl BF, Vargas GM, Neal J, et al. Clinical experience with the activated clotting time for the control of heparin and
protamine therapy during cardiopulmonary bypass. J Thorac Cardiovasc Surg 1980;79(1):97-102.
59. De Takats G. Heparin tolerance. A test of the clotting mechanism. Surg Gynecol Obstet 1943;77:31-39.
60. Culliford AT, Gitel SN, Starr N, et al. Lack of correlation between activated clotting time and plasma heparin during
cardiopulmonary bypass. Ann Surg 1981;193(1):105-111.
61. Bull BS, Huse WM, Brauer FS, Korpman RA. Heparin therapy during extracorporeal circulation. II. The use of a dose-
response curve to individualize heparin and protamine dosage. J Thorac Cardiovasc Surg 1975;69(5):685-689.
62. Fareed J, Walenga JM, Hoppensteadt DA, Messmore HL. Studies on the profibrinolytic actions of heparin and its
fractions. Semin Thromb Hemost 1985;11(2):199-207.
63. Upchurch GR, Valeri CR, Khuri SF, et al. Effect of heparin on fibrinolytic activity and platelet function in vivo. Am J
Physiol 1996;271(2, Part 2): H528-H534.
64. Carr ME Jr, Carr SL, Greilich PE. Heparin ablates force development during platelet mediated clot retraction. Thromb
Haemost 1996;75(4):674-678.
65. Zucker MB. Effect of heparin on platelet function. Thromb Diath Haemorrh 1975;33(1):63-65.
66. Thomson C, Forbes CD, Prentice CR. The potentiation of platelet aggregation and adhesion by heparin in vitro and in
vivo. Clin Sci Mol Med 1973;45(4):485-494.
67. Abela M, McArdle B, Qureshi M. Heparin-enhanced ADP-induced platelet aggregation in patients undergoing
cardiopulmonary bypass surgery. Perfusion 1986;1(3):175-178.
68. Cella G, Menardo A, Girolami A. Effect of heparin on in vivo platelet factor 4 (PF4) release and platelet aggregation
after aspirin administration. Clin Lab Haematol 1980;2(4):333-338.
69. Michalski R, Lane DA, Kakkar VV. Comparison of heparin and a semi-synthetic heparin analogue, A73025. II. Some
effects on platelet function. Br J Haematol 1977;37(2):247-256.
70. Bertele V, Roncaglioni MC, Donati MB, de Gaetano G. Heparin counteracts the antiaggregating effect of prostacyclin
by potentiating platelet aggregation. Thromb Haemost 1983;49(2):81-83.
71. Eldor A, Weksler BB. Heparin and dextran sulfate antagonize PGI2 inhibition of platelet aggregation. Thromb Res
1979;16(5/6):617-628.
72. Heiden D, Mielke CH Jr, Rodvien R. Impairment by heparin of primary haemostasis and platelet [14C]5-
hydroxytryptamine release. Br J Haematol 1977;36(3):427-436.
73. O’Brien JR. Heparin and platelets. Curr Ther Res Clin Exp 1975;18(1, Part1):79-90.
74. Davey MG, Lander H. Effect of injected heparin on platelet levels in man. J Clin Pathol 1968;21(1):55-59.
75. Xiao Z, Theroux P. Platelet activation with unfractionated heparin at therapeutic concentrations and comparisons with
a low-molecular-weight heparin and with a direct thrombin inhibitor. Circulation 1998;97(3):251-256.
76. Rohrer MJ, Kestin AS, Ellis PA, et al. High-dose heparin suppresses platelet alpha granule secretion. J Vasc Surg
1992;15(6):1000-1008; discussion 1008-1009.
77. Suda Y, Marques D, Kermode JC, et al. Structural characterization of heparin’s binding domain for human platelets.
Thromb Res 1993;69(6):501-508.
78. Holmer E, Lindahl U, Backstrom G, et al. Anticoagulant activities and effects on platelets of a heparin fragment with
high affinity for antithrombin. Thromb Res 1980;18(6): 861-869.
79. Cella G, Scattolo N, Luzzatto G, Girolami A. Effects of low-molecular-weight heparin on platelets as compared with
commercial heparin. Res Exp Med (Berl) 1984;184(4):227-229.
80. Warkentin TE, Kelton JG. Heparin and platelets. Hematol Oncol Clin North Am 1990;4(1):243-264.
81. Salzman EW, Rosenberg RD, Smith MH, et al. Effect of heparin and heparin fractions on platelet aggregation. J Clin
Invest 1980;65(1):64-73.
82. Bode AP, Castellani WJ, Hodges ED, Yelverton S. The effect of lysed platelets on neutralization of heparin in vitro
with protamine as measured by the activated coagulation time (ACT). Thromb Haemost 1991;66(2):213-217.
83. Carr ME Jr, Carr SL. At high heparin concentrations, protamine concentrations which reverse heparin anticoagulant
effects are insufficient to reverse heparin anti-platelet effects. Thromb Res 1994;75(6):617-630.
84. Cines DB. Heparin: do we understand its antithrombotic actions? Chest 1986;89(3):420-426.
85. Hyers TM, Hull RD, Weg JG. Antithrombotic therapy for venous thromboembolic disease. Chest 1986;89(2
Suppl):26S-35S.
86. Kaplan K. Prophylactic anticoagulation following acute myocardial infarction. Arch Intern Med 1986;146(3):593-597.
87. Levine MN. Nonhemorrhagic complications of anticoagulant therapy. Semin Thromb Hemost 1986;12(1):63-66.
88. Khuri SF, Valeri CR, Loscalzo J, et al. Heparin causes platelet dysfunction and induces fibrinolysis before
cardiopulmonary bypass. Ann Thorac Surg 1995;60(4):1008-1014.
89. Despotis GJ, Joist JH, Hogue CW Jr, et al. More effective suppression of hemostatic system activation in patients
undergoing cardiac surgery by heparin dosing based on heparin blood concentrations rather than ACT. Thromb Haemost
1996;76(6):902-908.
90. Seltzer JL, Gerson JI. Decrease in arterial pressure following heparin injection prior to cardiopulmonary bypass. Acta
Anaesthesiol Scand 1979;23(6): 575-578.
91. Urban P, Scheidegger D, Buchmann B, Skarvan K. The hemodynamic effects of heparin and their relation to ionized
calcium levels. J Thorac Cardiovasc Surg 1986;91(2):303-306.
92. Jaques LB. Heparin: an old drug with a new paradigm. Current discoveries are establishing the nature, action, and
biological significance of this valuable drug. Science 1979;206:528-533.
93. Harada A, Tatsuno K, Kikuchi T, et al. Use of bovine lung heparin to obviate anaphylactic shock caused by porcine
gut heparin. Ann Thorac Surg 1990; 49(5):826-827.
94. Ahmed SS, Nussbaum M. Development of pulmonary edema related to heparin administration. J Clin Pharmacol
1981;21(2):126-128.
95. Dux S, Pitlik S, Perry G, Rosenfeld JB. Hypersensitivity reaction to chlorbutol-preserved heparin. Lancet
1981;1(8212):149.
96. Hancock BW, Naysmith A. Hypersensitivity to chlorocresol-preserved heparin. Br Med J 1975;3(5986):746-747.
97. Ansell JE, Clark WP Jr, Compton CC. Fatal reactions associated with intravenous heparin. Drug Intell Clin Pharm
1986;20(1):74-75.
98. Rosenzweig P, Gary NE, Gocke DJ, et al. Heparin allergy accompanying acute renal failure. Artif Organs
1979;3(1):78-79.
99. Bernstein IL. Anaphylaxis to heparin sodium; report of a case, with immunologic studies. J Am Med Assoc
1956;161(14):1379-1381.
100. Klein HG, Bell WR. Disseminated intravascular coagulation during heparin therapy. Ann Intern Med 1974;80(4):477-
481.
101. Schey SA. Hypersensitivity reactions to heparin and the use of new low molecular weight heparins. Eur J Haematol
1989;42(1):107.
102. Yourassowsky E, DeBroe ME, Wieme RJ. Effect of heparin on gentamicin concentration in blood. Clin Chim Acta
1972;42(1):189-191.
103. Colburn WA. Pharmacologic implications of heparin interactions with other drugs. Drug Metab Rev 1976;5(2):281-
293.
P.492
104. Levine MN, Hirsh J. Hemorrhagic complications of anticoagulant therapy. Semin Thromb Hemost 1986;12(1):39-57.
105. Leehey D, Gantt C, Lim V. Heparin-induced hypoaldosteronism. Report of a case. JAMA 1981;246(19):2189-2190.
106. Salomon F, Schmid M. Heparin [Letter]. N Engl J Med 1991;325:1585.
107. Hattersley PG. Activated coagulation time of whole blood. JAMA 1966;196(5):436-440.
108. Blakely JA. A rapid bedside method for the control of heparin therapy. Can Med Assoc J 1968;99(22):1072-1076.
109. Hill JD, Dontigny L, De Leval M, Mielke CH Jr. A simple method of heparin management during prolonged
extracorporeal circulation. Ann Thorac Surg 1974;17(2):129-134.
110. Babka R, Colby C, El-Etr A, Pifarre R. Monitoring of intraoperative heparinization and blood loss following
cardiopulmonary bypass surgery. J Thorac Cardiovasc Surg 1977;73(5):780-782.
111. Ottesen S, Stormorken H, Hatteland K. The value of activated coagulation time in monitoring heparin therapy during
extracorporeal circulation. Scand J Thorac Cardiovasc Surg 1984;18(2):123-128.
112. Goodnough LT, Johnston MF, Toy PT. The variability of transfusion practice in coronary artery bypass surgery.
Transfusion Medicine Academic Award Group. JAMA 1991;265(1):86-90.
113. Metz S, Keats AS. Low activated coagulation time during cardiopulmonary bypass does not increase postoperative
bleeding. Ann Thorac Surg 1990;49(3):440-444.
114. Guffin AV, Dunbar RW, Kaplan JA, Bland JW Jr. Successful use of a reduced dose of protamine after
cardiopulmonary bypass. Anesth Analg 1976; 55(1):110-113.
115. Verska JJ. Control of heparinization by activated clotting time during bypass with improved postoperative
hemostasis. Ann Thorac Surg 1977;24(2):170-173.
116. Roth JA, Cukingnan RA, Scott CR. Use of activated coagulation time to monitor heparin during cardiac surgery. Ann
Thorac Surg 1979;28(1):69-72.
117. Papaconstantinou C, Radegran K. Use of the activated coagulation time in cardiac surgery. Effects on heparin-
protamine dosages and bleeding. Scand J Thorac Cardiovasc Surg 1981;15(2):213-215.
118. Jumean HG, Sudah F. Monitoring of anticoagulant therapy during openheart surgery in children with congenital
heart disease. Acta Haematol 1983;70(6):392-395.
119. Dearing JP, Bartles DM, Stroud MR. Activated clotting times versus protocol anticoagulation management. J Extra
120. Niinikoski J, Laato M, Laaksonen V, et al. Use of activated clotting time to monitor anticoagulation during cardiac
surgery. Scand J Thorac Cardiovasc Surg 1984;18(1):57-61.
121. Lefemine AA, Lewis M. Activated clotting time for control of anticoagulation during surgery. Am Surg 1985;51(5):274-
278.
122. Preiss DU, Schmidt-Bleibtreu H, Berguson P, Metz G. Blood transfusion requirements in coronary artery surgery
with and without the activated clotting time (ACT) technique. Klin Wochenschr 1985;63(6):252-256.
123. Jobes DR, Schwartz AJ, Ellison N, et al. Monitoring heparin anticoagulation and its neutralization. Ann Thorac Surg
1981;31(2):161-166.
124. Bowie JE, Kemma GD. Automated management of heparin anticoagulation in cardiovascular surgery. Proc Am Acad
125. Gravlee GP, Haddon WS, Rothberger HK, et al. Heparin dosing and monitoring for cardiopulmonary bypass. A
comparison of techniques with measurement of subclinical plasma coagulation. J Thorac Cardiovasc Surg 1990;
99(3):518-527.
126. Urban MK, Gordon M, Farrell DT. The management of anticoagulation during cardiopulmonary bypass (CPB)
[abstract]. Anesthesiology 1991;75(Suppl 3A):A437.
127. Gravlee GP, Rogers AT, Dudas LM, et al. Heparin management protocol for cardiopulmonary bypass influences
postoperative heparin rebound but not bleeding. Anesthesiology 1992;76(3):393-401.
128. Despotis GJ, Joist JH, Hogue CW Jr, et al. The impact of heparin concentration and activated clotting time
monitoring on blood conservation. A prospective, randomized evaluation in patients undergoing cardiac operation. J
129. Koster A, Fischer T, Praus M, et al. Hemostatic activation and inflammatory response during cardiopulmonary
bypass: impact of heparin management. Anesthesiology 2002;97(4):837-841.
130. Young JA, Kisker CT, Doty DB. Adequate anticoagulation during cardiopulmonary bypass determined by activated
clotting time and the appearance of fibrin monomer. Ann Thorac Surg 1978;26(3):231-240.
131. Dauchot PJ, Berzina-Moettus L, Rabinovitch A, Ankeney JL. Activated coagulation and activated partial
thromboplastin times in assessment and reversal of heparin-induced anticoagulation for cardiopulmonary bypass. Anesth
Analg 1983;62(8):710-719.
132. Kesteven PJL. Blood coagulation studies during open-heart surgery. London, UK: St. Thomas’ Hospital, 1985.
133. Cardoso PF, Yamazaki F, Keshavjee S, et al. A reevaluation of heparin requirements for cardiopulmonary bypass. J
Thorac Cardiovasc Surg 1991;101(1): 153-160.
134. Hickling KG. Extracorporeal CO2 removal in severe adult respiratory distress syndrome. Anaesth Intensive Care
1986;14(1):46-53.
135. Kanter KR, Pennington G, Weber TR, et al. Extracorporeal membrane oxygenation for postoperative cardiac support
in children. J Thorac Cardiovasc Surg 1987;93(1):27-35.
136. Uziel L, Agostoni A, Pirovano E, et al. Hematologic survey during low frequency positive pressure ventilation with
extracorporeal CO2 removal. Trans Am Soc Artif Intern Organs 1982;28:359-364.
137. Heiden D, Mielke CH Jr, Rodvien R, Hill JD. Platelets, hemostasis, thromboembolism during treatment of acute
respiratory insufficiency with extracorporeal membrane oxygenation. J Thorac Cardiovasc Surg 1975;70(4):644-655.
138. Uziel L, Cugno M, Fabrizi I, et al. Physiopathology and management of coagulation during long-term extracorporeal
respiratory assistance. Int J Artif Organs 1990;13(5):280-287.
139. Davies GC, Sobel M, Salzman EW. Elevated plasma fibrinopeptide A and thromboxane B2 levels during
cardiopulmonary bypass. Circulation 1980;61(4):808-814.
140. Machin D, Devine P. The effect of temperature and aprotinin during cardiopulmonary bypass on three different
methods of activated clotting time measurement. J Extra Corpor Technol 2005;37(3):265-271.
141. Leyvi G, Shore-Lesserson L, Harrington D, et al. An investigation of a new activated clotting time “MAX-ACT” in
patients undergoing extracorporeal circulation. Anesth Analg 2001;92(3):578-583.
142. Despotis GJ, Levine V, Joiner-Maier D, Joist JH. A comparison between continuous infusion versus standard bolus
administration of heparin based on monitoring in cardiac surgery. Blood Coagul Fibrinolysis 1997;8(7):419-430.
143. Neema PK, Sinha PK, Rathod RC. Activated clotting time during cardiopulmonary bypass: is repetition necessary
during open heart surgery? Asian Cardiovasc Thorac Ann 2004;12(1):47-52.
144. Boldt J, Schindler E, Osmer C, et al. Influence of different anticoagulation regimens on platelet function during
cardiac surgery. Br J Anaesth 1994; 73(5):639-644.
145. Na S. Stabilized infective endocarditis and altered heparin responsiveness during cardiopulmonary bypass. World J
Surg 2009;33(9):1862-1867.
146. Garvin S, Fitzgerald DC, Despotis G, et al. Heparin concentration-based anticoagulation for cardiac surgery fails to
reliably predict heparin bolus dose requirements. Anesth Analg 2010;111(4):849-855.
147. Grima C. The effects of intermittent prebypass heparin dosing in patients undergoing coronary artery bypass
grafting. Perfusion 2003;18(5):283-289.
148. Ovrum E, Holen EA, Tangen G, et al. Completely heparinized cardiopulmonary bypass and reduced systemic
heparin: clinical and hemostatic effects. Ann Thorac Surg 1995;60(2):365-371.
149. Aldea GS, Doursounian M, O’Gara P, et al. Heparin-bonded circuits with a reduced anticoagulation protocol in
primary CABG: a prospective, randomized study. Ann Thorac Surg 1996;62(2):410-417; discussion 417-418.
150. von Segesser LK, Weiss BM, Pasic M, et al. Risk and benefit of low systemic heparinization during open heart
operations. Ann Thorac Surg 1994; 58(2):391-397; discussion 398.
151. Nielsen LE, Bell WR, Borkon AM, Neill CA. Extensive thrombus formation with heparin resistance during
extracorporeal circulation. A new presentation of familial antithrombin III deficiency. Arch Intern Med 1987;147(1): 149-
152.
152. Cohen JA. Activated coagulation time method for control of heparin is reliable during cardiopulmonary bypass.
153. Jobes DR. Safety issues in heparin and protamine administration for extracorporeal circulation. J Cardiothorac Vasc
Anesth 1998;12(2, Suppl 1):17-20.
154. Gravlee GP, Brauer SD, Roy RC, et al. Predicting the pharmacodynamics of heparin: a clinical evaluation of the
Hepcon System 4. J Cardiothorac Anesth 1987;1(5):379-387.
155. Cipolle RJ, Uden DL, Gruber SA, et al. Evaluation of a rapid monitoring system to study heparin pharmacokinetics
and pharmacodynamics. Pharmacotherapy 1990;10(6):367-372.
156. Jobes DR, Aitken GL, Shaffer GW. Increased accuracy and precision of heparin and protamine dosing reduces
blood loss and transfusion in patients undergoing primary cardiac operations. J Thorac Cardiovasc Surg 1995;110(1):36-
45.
157. Shore-Lesserson L, Reich DL, DePerio M. Individual heparin and protamine dose titration does not improve
haemostasis parameters in cardiac surgical patients. Can J Anaesth 1998;45:10-18.
P.493
158. Soloway HB, Christiansen TW. Heparin anticoagulation during cardiopulmonary bypass in an antithrombin-III
deficient patient. Implications relative to the etiology of heparin rebound. Am J Clin Pathol 1980;73(5):723-725.
159. Marciniak E, Farley CH, DeSimone PA. Familial thrombosis due to antithrombin 3 deficiency. Blood 1974;43(2):219-
231.
160. Chung F, David TE, Watt J. Excessive requirement for heparin during cardiac surgery. Can Anaesth Soc J
1981;28(3):280-282.
161. Reuter NF. Heparin insensitivity responding to fresh frozen plasma. Minn Med 1978;61(2):79-81.
162. Wilds SL, Camerlengo LJ, Dearing JP. Activated clotting time and cardiopulmonary bypass. III. Effect of high platelet
count on heparin management. J Extra Corpor Technol 1982;14:322-324.
163. Conley CL, Hartmann RC, Lalley JS. The relationship of heparin activity to platelet concentration. Proc Soc Exp Biol
Med 1948;69(2):284-287.
164. Olinger GN, Hussey CV, Olive JA, Malik MI. Cardiopulmonary bypass for patients with previously documented
heparin-induced platelet aggregation. J Thorac Cardiovasc Surg 1984;87(5):673-677.
165. Schved JF, Gris JC, Eledjam JJ. Circadian changes in anticoagulant effect of heparin infused at a constant rate. Br
Med J (Clin Res Ed) 1985;290(6477):1286.
166. Decousus M, Gremillet E, Decousus H, et al. Nycthemeral variations of 99Tcm-labelled heparin pharmacokinetic
parameters. Nucl Med Commun 1985;6(10):633-640.
167. Kase PB. Factors affecting the activated clotting time. J Extra Corpor Technol 1985;17:27-30.
168. Whitfield LR, Levy G. Relationship between concentration and anticoagulant effect of heparin in plasma of normal
subjects: magnitude and predictability of interindividual differences. Clin Pharmacol Ther 1980;28(4):509-516.
169. Bjornsson TD, Nash PV. Variability in heparin sensitivity of APTT reagents. Am J Clin Pathol 1986;86(2):199-204.
170. Nelson RM, Frank CG, Mason JO. The antiheparin properties of the antihistamines, tranquilizers, and certain
antibiotics. Surg Forum 1958;9:146-150.
171. Hicks GL Jr. Heparin resistance during cardiopulmonary bypass. J Thorac Cardiovasc Surg 1983;86(4):633.
172. Dietrich W, Spannagl M, Schramm W, et al. The influence of preoperative anticoagulation on heparin response
during cardiopulmonary bypass. J Thorac Cardiovasc Surg 1991;102(4):505-514.
173. Habbab MA, Haft JI. Heparin resistance induced by intravenous nitroglycerin. A word of caution when both drugs are
used concomitantly. Arch Intern Med 1987;147(5):857-860.
174. Becker RC, Corrao JM, Bovill EG, et al. Intravenous nitroglycerin-induced heparin resistance: a qualitative
antithrombin III abnormality. Am Heart J 1990;119(6):1254-1261.
175. Reich DL, Hammerschlag BC, Rand JH, et al. Modest doses of nitroglycerin do not interfere with beef lung heparin
anticoagulation in patients taking nitrates. J Cardiothorac Vasc Anesth 1992;6(6):677-679.
176. Amin, F, Horrow J. Nitroglycerin antagonism of heparin. Anesthesiology 1990;73(1):193-194.
177. Godal HC. Heparin tolerance and the plasma proteins. Scand J Clin Lab Invest 1961;13:314-325.
178. Jaques LB. The pharmacology of heparin and heparinoids. Prog Med Chem 1967;5:139-198.
179. Glueck HI, MacKenzie MR, Glueck CJ. Crystalline IgG protein in multiple myeloma: identification effects on
coagulation and on lipoprotein metabolism. J Lab Clin Med 1972;79(5):731-744.
180. Pogliani E, Cofrancesco E, Praga C. Anti-heparin activity of a macroglobulin from a patient with breast
adenocarcinoma. Acta Haematol 1975;53(4):249-255.
181. Jordan RE, Kilpatrick J, Nelson RM. Heparin promotes the inactivation of antithrombin by neutrophil elastase.
Science 1987;237(4816):777-779.
182. Bleyl H, Addo, O, Roka L. Proceedings: Heparin neutralizing effect of lipoproteins. Thromb Diath Haemorrh
1975;34(2):549.
183. Lijnen HR, van Hoef B, Collen D. Interaction of heparin with histidine-rich glycoprotein and with antithrombin III.
Thromb Haemost 1983;50(2): 560-562.
184. Young E, Prins M, Levine MN, Hirsh J. Heparin binding to plasma proteins, an important mechanism for heparin
resistance. Thromb Haemost 1992; 67(6):639-643.
185. Whitfield LR, Lele AS, Levy G. Effect of pregnancy on the relationship between concentration and anticoagulant
action of heparin. Clin Pharmacol Ther 1983;34(1):23-28.
186. Hanowell ST, Kim YD, Rattan V, MacNamara TE. Increased heparin requirement with hypereosinophilic syndrome.
187. Mummaneni N, Istanbouli M, Pifarre R, El-Etr AA. Increased heparin requirements with autotransfusion. J Thorac
188. Hodby ED, Hirsh J, Adeniyi-Jones C. The influence of drugs upon the anticoagulant activity of heparin. Can Med
Assoc J 1972;106(5):562-564.
189. Dietrich W, Braun S, Spannagl M, Richter JA. Low preoperative antithrombin activity causes reduced response to
heparin in adult but not in infant cardiac-surgical patients. Anesth Analg 2001;92(1):66-71.
190. Ranucci M, Isgro G, Cazzaniga A, et al. Predictors for heparin resistance in patients undergoing coronary artery
bypass grafting. Perfusion 1999;14(6): 437-442.
191. Lemmer JH Jr, DesOtis GJ. Antithrombin III concentrate to treat heparin resistance in patients undergoing cardiac
192. Hashimoto K, Yamagishi M, Sasaki T, et al. Heparin and antithrombin III levels during cardiopulmonary bypass:
correlation with subclinical plasma coagulation. Ann Thorac Surg 1994;58(3):799-804; discussion 804-805.
193. Practice Guidelines for blood component therapy: a report by the American Society of Anesthesiologists Task Force
on Blood Component Therapy. Anesthesiology 1996;84(3):732-747.
194. Hirsh J, Piovella F, Pini M. Congenital antithrombin III deficiency. Incidence and clinical features. Am J Med
1989;87(3B):34S-38S.
195. Thaler E, Lechner K. Antithrombin III deficiency and thromboembolism. Clin Haematol 1981;10(2):369-390.
196. Anderson EF. Heparin resistance prior to cardiopulmonary bypass. Anesthesiology 1986;64(4):504-507.
197. Towne JB, Bernhard VM, Hussey C, Garancis JC. Antithrombin deficiency—a cause of unexplained thrombosis in
vascular surgery. Surgery 1981; 89(6):735-742.
198. Andrew M, Paes B, Milner R, et al. Development of the human coagulation system in the full-term infant. Blood
1987;70(1):165-172.
199. Buller HR, ten Cate JW. Acquired antithrombin III deficiency: laboratory diagnosis, incidence, clinical implications,
and treatment with antithrombin III concentrate. Am J Med 1989;87(3B):44S-48S.
200. Arai H, Miyakawa T, Ozaki K, Sakuragawa N. Changes of the levels of antithrombin III in patients with
cerebrovascular diseases. Thromb Res 1983; 31(2):197-202.
201. Duckert F. Behaviour of antithrombin 3 in liver disease. Scand J Gastroenterol Suppl 1973;19:109-112.
202. Bick RL, Bick MD, Fekete LF. Antithrombin III patterns in disseminated intravascular coagulation. Am J Clin Pathol
1980;73(4):577-583.
203. Marciniak E, Gockerman JP. Heparin-induced decrease in circulating antithrombin-III. Lancet 1977;2(8038):581-584.
204. Pickering NJ, Brody JI, Fink GB, et al. The behavior of antithrombin III, alpha 2 macroglobulin, and alpha 1
antitrypsin during cardiopulmonary bypass. Am J Clin Pathol 1983;80(4):459-464.
205. Matthai WH Jr, Kurnik PB, Groh WC, et al. Antithrombin activity during the period of percutaneous coronary
revascularization: relation to heparin use, thrombotic complications and restenosis. J Am Coll Cardiol 1999; 33(5):1248-
1256.
206. von Blohn G, Hellstern P, Kohler M, et al. Clinical aspects of acquired antithrombin III deficiency [in German].
Behring Inst Mitt 1986;79:200-215.
207. Barnette RE, Shupak RC, Pontius J, Rao AK. In vitro effect of fresh frozen plasma on the activated coagulation time
in patients undergoing cardiopulmonary bypass. Anesth Analg 1988;67(1):57-60.
208. Linden MD, Schneider M, Baker S, Erber WN. Decreased concentration of antithrombin after preoperative
therapeutic heparin does not cause heparin resistance during cardiopulmonary bypass. J Cardiothorac Vasc Anesth
2004;18(2):131-135.
209. Nicholson SC, Keeling DM, Sinclair ME, Evans RD. Heparin pretreatment does not alter heparin requirements
during cardiopulmonary bypass. Br J Anaesth 2001;87(6):844-847.
210. Despotis GJ, Levine V, Joist JH, et al. Antithrombin III during cardiac surgery: effect on response of activated clotting
time to heparin and relationship to markers of hemostatic activation. Anesth Analg 1997;85(3):498-506.
211. Garvin S, Fitzgerald D, Muehlschlegel JD, et al. Heparin dose response is independent of preoperative antithrombin
activity in patients undergoing coronary artery bypass graft surgery using low heparin concentrations. Anesth Analg
2010;111(4):856-861.
212. Avidan MS, et al. A phase III, double-blind, placebo-controlled, multicenter study on the efficacy of recombinant
human antithrombin in heparin-resistant patients scheduled to undergo cardiac surgery necessitating cardiopulmonary
bypass. Anesthesiology 2005;102(2):276-284.
213. Avidan MS, Levy JH, Scholz J, et al. Recombinant human antithrombin III restores heparin responsiveness and
decreases activation of coagulation in heparin-resistant patients during cardiopulmonary bypass. J Thorac Cardiovasc
Surg 2005;130(1):107-113.
P.494
214. Lijnen HR, Van Hoef B, Collen D. Histidine-rich glycoprotein modulates the anticoagulant activity of heparin in
human plasma. Thromb Haemost 1984;51(2):266-268.
215. Levy JH, Montes F, Szlam F, Hillyer CD. The in vitro effects of antithrombin III on the activated coagulation time in
patients on heparin therapy. Anesth Analg 2000;90(5):1076-1079.
216. Teoh KH, Young E, Bradley CA, Hirsch J. Heparin binding proteins. Contribution to heparin rebound after
cardiopulmonary bypass. Circulation 1993; 88(5, Part 2):II420-II425.
217. Mintz PD, Blatt PM, Kuhns WJ, Roberts HR. Antithrombin III in fresh frozen plasma, cryoprecipitate, and
cryoprecipitate-depleted plasma. Transfusion 1979;19(5):597-598.
218. Sabbagh AH, Chung GK, Shuttleworth P, et al. Fresh frozen plasma: a solution to heparin resistance during
cardiopulmonary bypass. Ann Thorac Surg 1984;37(6):466-468.
219. Heller EL, Paul L. Anticoagulation management in a patient with an acquired antithrombin III deficiency. J Extra
Corpor Technol 2001;33(4):245-248.
220. Leong CK, Ong BC. A case report of heparin resistance due to acquired antithrombin III deficiency. Ann Acad Med
Singapore 1998;27(6):877-879.
221. Despotis GJ, Levine V, Alsoufliev A, et al. Recurrent thrombosis of biventricular-support devices associated with
accelerated intravascular coagulation and increased heparin requirements. J Thorac Cardiovasc Surg 1996;112(2): 538-
540.
222. Koster A, Fischer T, Gruendel M, et al. Management of heparin resistance during cardiopulmonary bypass: the
effect of five different anticoagulation strategies on hemostatic activation. J Cardiothorac Vasc Anesth 2003; 17(2):171-
175.
223. Williams MR, D’Ambra AB, Beck JR, et al. A randomized trial of antithrombin concentrate for treatment of heparin
resistance. Ann Thorac Surg 2000; 70(3):873-877.
224. Kanbak M. The treatment of heparin resistance with antithrombin III in cardiac surgery. Can J Anaesth
1999;46(6):581-585.
225. Van Norman GA, Gernsheimer T, Chandler WL, et al. Indicators of fibrinolysis during cardiopulmonary bypass after
exogenous antithrombin-III administration for acquired antithrombin III deficiency. J Cardiothorac Vasc Anesth
1997;11(6):760-763.
226. Conley JC, Plunkett PF. Antithrombin III in cardiac surgery: an outcome study. J Extra Corpor Technol
1998;30(4):178-183.
227. Levy JH, Despotis GJ, Szlam F, et al. Recombinant human transgenic antithrombin in cardiac surgery: a dose-
finding study. Anesthesiology 2002;96(5): 1095-1102.
228. Dietrich W, Schroll A, Gob E, et al. Antithrombin III substitution for optimization of the heparin effect during
extracorporeal circulation in heart surgery [in German]. Anaesthesist 1984;33(9):422-427.
229. Lobato RL, Despotis GJ, Levy JH, et al. Anticoagulation management during cardiopulmonary bypass: a survey of
54 North American institutions. J Thorac Cardiovasc Surg 2010;139(6):1665-1666.
230. Horner AA. The nature of two components of pig mucosal heparin, separated by electrophoresis in agarose gel. Can
J Biochem 1967;45(7):1015-1020.
231. Jordan RE, Oosta GM, Gardner WT, Rosenberg RD. The kinetics of hemostatic enzyme-antithrombin interactions in
the presence of low molecular weight heparin. J Biol Chem 1980;255(21):10081-10090.
232. Fareed J, et al. A primate model (Macaca mulatta) to study the pharmacokinetics of heparin and its fractions. Semin
Thromb Hemost 1985;11(2):138-154.
233. Jordan RE, Favreau LV, Braswell EH, Rosenberg RD. Heparin with two binding sites for antithrombin or platelet
factor 4. J Biol Chem 1982;257(1): 400-406.
234. Lane DA, Pejler G, Flynn AM, et al. Neutralization of heparin-related saccharides by histidine-rich glycoprotein and
platelet factor 4. J Biol Chem 1986; 261(9):3980-3986.
235. Barzu T, Van Rijn JL, Petitou M, et al. Endothelial binding sites for heparin. Specificity and role in heparin
neutralization. Biochem J 1986;238(3):847-854.
236. Hirsh J, Ofosu F, Buchanan M. Rationale behind the development of low molecular weight heparin derivatives.
Semin Thromb Hemost 1985;11(1):13-16.
237. Darien BJ, Fareed J, Centgraf KS, et al. Low molecular weight heparin prevents the pulmonary hemodynamic and
pathomorphologic effects of endotoxin in a porcine acute lung injury model. Shock 1998;9(4):274-281.
238. Lane DA, Ryan K. The importance of anti-factor Xa and antithrombin activities of low molecular weight heparins. J
Lab Clin Med 1990;116(2):269-270.
239. Salzman EW. Low-molecular-weight heparin: is small beautiful? N Engl J Med 1986;315(15):957-959.
240. Messmore HL. Clinical efficacy of heparin fractions: issues and answers. Crit Rev Clin Lab Sci 1986;23(2):77-94.
241. Ofosu FA, Blajchman MA, Modi GJ, et al. The importance of thrombin inhibition for the expression of the
anticoagulant activities of heparin, dermatan sulphate, low molecular weight heparin and pentosan polysulphate. Br J
Haematol 1985;60(4):695-704.
242. Turpie AG, Levine MN, Hirsh J, et al. A randomized controlled trial of a low-molecular-weight heparin (enoxaparin) to
prevent deep-vein thrombosis in patients undergoing elective hip surgery. N Engl J Med 1986;315(15): 925-929.
243. Warkentin TE, Levine MN, Hirsh J, et al. Heparin-induced thrombocytopenia in patients treated with low-molecular-
weight heparin or unfractionated heparin. N Engl J Med 1995;332(20):1330-1335.
244. John LC, Rees GM, Kovacs IB. Different anticoagulants and platelet reactivity in cardiac surgical patients. Ann
Thorac Surg 1993;56(4):899-902.
245. McBride WT, Armstrong MA, McMurray TJ. An investigation of the effects of heparin, low molecular weight heparin,
protamine, and fentanyl on the balance of pro- and anti-inflammatory cytokines in in-vitro monocyte cultures. Anaesthesia
1996;51(7):634-640.
246. Gitlin SD, Deeb GM, Yann C, Schmaier AH. et al. Intraoperative monitoring of danaparoid sodium anticoagulation
during cardiovascular operations. J Vasc Surg 1998;27(3):568-575.
247. Abildgaard U, Norrheim L, Larsen AE, et al. Monitoring therapy with LMW heparin: a comparison of three
chromogenic substrate assays and the Heptest clotting assay. Haemostasis 1990;20(4):193-203.
248. Mammen EF. Why low molecular weight heparin? Semin Thromb Hemost 1990;16(Suppl):1-4.
249. Bara L, Billaud E, Kher A, Samama M. Increased anti-Xa bioavailability for a low molecular weight heparin (PK
10169) compared with unfractionated heparin. Semin Thromb Hemost 1985;11(3):316-317.
250. Marshall LR, Cannell PK, Herrmann RP. Successful use of the APTT in monitoring of the anti-factor Xa activity of
the heparinoid organon 10172 in a case of HITS requiring open heart surgery. Thromb Haemost 1992;67(5):587.
251. Fareed J. Development of heparin fractions: some overlooked considerations. Semin Thromb Hemost
1985;11(2):227-236.
252. Racanelli A, Fareed J, Walenga JM, Coyne E. Biochemical and pharmacologic studies on the protamine interactions
with heparin, its fractions and fragments. Semin Thromb Hemost 1985;11(2):176-189.
253. Gouault-Heilmann M, Huet Y, Contant G, et al. Cardiopulmonary bypass with a low-molecular-weight heparin
fraction. Lancet 1983;2(8363):1374.
254. Massonnet-Castel S, Pelissier E, Dreyfus G, et al. Low-molecular-weight heparin in extracorporeal circulation.

Lancet 1984;1(8387):1182-1183.
255. Massonnet-Castel S, Pelissier E, Bara L, et al. Partial reversal of low molecular weight heparin (PK 10169) anti-Xa
activity by protamine sulfate: in vitro and in vivo study during cardiac surgery with extracorporeal circulation. Haemostasis
1986;16(2):139-146.
256. Touchot B, Laborde F, Dum F. Use of low molecular weight heparin CY 222 during cardiopulmonary bypass.
Experimental study and clinical application. Perfusion 1986;1:99-102.
257. Koza MJ, Messmore HL, Wallock ME, et al. Evaluation of a low molecular weight heparin as an anticoagulant in a
model of cardiopulmonary bypass surgery. Thromb Res 1993;70(1):67-76.
258. Henny CP, Ten Cate H, Ten Cate JW, et al. A randomized blind study comparing standard heparin and a new low
molecular weight heparinoid in cardiopulmonary bypass surgery in dogs. J Lab Clin Med 1985;106(2):187-196.
259. Doherty DC, Ortel TL, de Bruijn N, et al. “Heparin-free” cardiopulmonary bypass: first reported use of heparinoid
(Org 10172) to provide anticoagulation for cardiopulmonary bypass. Anesthesiology 1990;73(3):562-565.
260. Wilhelm MJ, Schmid C, Kececioglu D, et al. Cardiopulmonary bypass in patients with heparin-induced
thrombocytopenia using Org 10172. Ann Thorac Surg 1996;61(3):920-924.
261. Zulys VJ, Teasdale SJ, Michel ER, et al. Ancrod (Arvin) as an alternative to heparin anticoagulation for
cardiopulmonary bypass. Anesthesiology 1989; 71(6):870-877.
262. Teasdale SJ, Zulys VJ, Mycyk T, et al. Ancrod anticoagulation for cardiopulmonary bypass in heparin-induced
thrombocytopenia and thrombosis. Ann Thorac Surg 1989;48(5):712-713.
263. Kanagasabay RR, Unsworth-White MJ, Robinson G, et al. Cardiopulmonary bypass with danaparoid sodium and
ancrod in heparin-induced thrombocytopenia. Ann Thorac Surg 1998;66(2):567-569.
264. Marder VJ. Comparison of thrombolytic agents: selected hematologic, vascular and clinical events. Am J Cardiol
1989;64(2):2A-7A; discussion 24A-26A.
265. Markwardt F. Pharmacology of selective thrombin inhibitors. Nouv Rev Fr Hematol 1988;30(3):161-165.
P.495
266. Bichler J, Fichtl B, Siebeck M, Fritz H. Pharmacokinetics and pharmacodynamics of hirudin in man after single
subcutaneous and intravenous bolus administration. Arzneimittelforschung 1988;38(5):704-710.
267. Potzsch B, Madlener K, Seelig C, et al. Monitoring of r-hirudin anticoagulation during cardiopulmonary bypass—
assessment of the whole blood ecarin clotting time. Thromb Haemost 1997;77(5):920-925.
268. Walenga JM, Bakhos M, Messmore HL, et al. Potential use of recombinant hirudin as an anticoagulant in a
cardiopulmonary bypass model. Ann Thorac Surg 1991;51(2):271-277.
269. Riess FC, Potzsch B, Behr I, et al. Recombinant hirudin as an anticoagulant during cardiac operations: experiments
in a pig model. Eur J Cardiothorac Surg 1997;11(4):739-745.
270. Koza MJ, Shankey TC, Walenga JM, et al. Flow cytometric evaluation of platelet activation by ionic or nonionic
contrast media and modulation by heparin and recombinant hirudin. Invest Radiol 1995;30(2):90-97.
271. Koster A, Hansen R, Kuppe H, et al. Recombinant hirudin as an alternative for anticoagulation during
cardiopulmonary bypass in patients with heparin-induced thrombocytopenia type II: a 1-year experience in 57 patients. J
272. Riess FC, Poetzsch B, Madlener K, et al. Recombinant hirudin for cardiopulmonary bypass anticoagulation: a
randomized, prospective, and heparin-controlled pilot study. Thorac Cardiovasc Surg 2007;55(4):233-238.
273. Maroo A, Lincoff AM. Bivalirudin in PCI: an overview of the REPLACE-2 trial. Semin Thromb Hemost
2004;30(3):329-336.
274. Aggarwal A, Sobel BE, Schneider DJ. Decreased platelet reactivity in blood anticoagulated with bivalirudin or
enoxaparin compared with unfractionated heparin: implications for coronary intervention. J Thromb Thrombolysis
2002;13(3):161-165.
275. Aggarwal A. The vulnerable endothelium: priming the vascular endothelium for thrombosis with unfractionated
heparin: biologic plausibility for observations from the Superior Yield of the New Strategy of Enoxaparin,
Revascularization and Glycoprotein IIb/IIIa Inhibitors (SYNERGY) trial (Am J Heart 2005;150:189-92). Am Heart J
2006;151(5):e2.
276. Bittl JA. Comparative safety profiles of hirulog and heparin in patients undergoing coronary angioplasty. The Hirulog
Angioplasty Study Investigators. Am Heart J 1995;130(3, Part 2):658-665.
277. Bittl JA, Strony J, Brinker JA, et al. Treatment with bivalirudin (Hirulog) as compared with heparin during coronary
angioplasty for unstable or postinfarction angina. Hirulog Angioplasty Study Investigators. N Engl J Med 1995;
333(12):764-769.
278. Merry AF. Bivalirudin, blood loss, and graft patency in coronary artery bypass surgery. Semin Thromb Hemost
2004;30(3):337-346.
279. Dyke CM, Smedira NG, Koster A, et al. A comparison of bivalirudin to heparin with protamine reversal in patients
undergoing cardiac surgery with cardiopulmonary bypass: the EVOLUTION-ON study. J Thorac Cardiovasc Surg
2006;131(3):533-539.
280. Smedira NG, Dyke CM, Koster A, et al. Anticoagulation with bivalirudin for off-pump coronary artery bypass grafting:
the results of the EVOLUTION-OFF study. J Thorac Cardiovasc Surg 2006;131(3):686-692.
281. Koster A, Dyke CM, Aldea G, et al. Bivalirudin during cardiopulmonary bypass in patients with previous or acute
heparin-induced thrombocytopenia and heparin antibodies: results of the CHOOSE-ON trial. Ann Thorac Surg
2007;83(2): 572-577.
282. Dyke CM, Aldea G, Koster A, et al. Off-pump coronary artery bypass with bivalirudin for patients with heparin-
induced thrombocytopenia or antiplatelet factor four/heparin antibodies. Ann Thorac Surg 2007;84(3):836-839.
283. Koster A, Buz S, Krabatsch T, et al. Bivalirudin anticoagulation during cardiac surgery: a single-center experience in
141 patients. Perfusion 2009;24(1): 7-11.
284. Palmer GJ, Sankaran IS, Sparkman GM, et al. Routine use of the direct thrombin inhibitor bivalirudin for off-pump
coronary artery bypass grafting is safe and effective. Heart Surg Forum 2008;11(1):E24-E29.
285. Davis Z, Anderson R, Short D, et al. Favorable outcome with bivalirudin anticoagulation during cardiopulmonary
bypass. Ann Thorac Surg 2003;75(1): 264-265.
286. Chuter TA, Pak LK, Gordon RL, et al. Heparin-induced thrombocytopenia and graft thrombosis following
endovascular aneurysm repair. J Endovasc Ther 2003;10(6): 1087-1090.
287. Vasquez JC, Vichiendilokkul A, Mahmood S, Baciewicz FA Jr. Anticoagulation with bivalirudin during
cardiopulmonary bypass in cardiac surgery. Ann Thorac Surg 2002;74(6):2177-2179.
288. Koster A, Spiess B, Chew DP, et al. Effectiveness of bivalirudin as a replacement for heparin during
cardiopulmonary bypass in patients undergoing coronary artery bypass grafting. Am J Cardiol 2004;93(3):356-359.
289. Koster A, Chew D, Grundel M, et al. Bivalirudin monitored with the ecarin clotting time for anticoagulation during
cardiopulmonary bypass. Anesth Analg 2003;96(2):383-386, table of contents.
290. Zucker ML, Koster A, Prats J, Laduca FM. Sensitivity of a modified ACT test to levels of bivalirudin used during
cardiac surgery. J Extra Corpor Technol 2005;37(4):364-368.
291. Koster A, Despotis G, Gruendel M, et al. The plasma supplemented modified activated clotting time for monitoring of
heparinization during cardiopulmonary bypass: a pilot investigation. Anesth Analg 2002;95(1):26-30, table of contents.
292. Chomiak PN, Walenga JM, Koza MJ, et al. Investigation of a thrombin inhibitor peptide as an alternative to heparin
in cardiopulmonary bypass surgery. Circulation 1993;88(5, Part 2):II407-II412.
293. Shrager JB, Kaiser LR. Argatroban as a heparin substitute in cases of heparin-induced thrombocytopenia. Ann
Thorac Surg 2004;78(6):2208; author reply 2208-2209.
294. Warkentin TE. An overview of the heparin-induced thrombocytopenia syndrome. Semin Thromb Hemost
2004;30(3):273-283.
295. Lewis BE, Walenga JM. Argatroban in HIT type II and acute coronary syndrome. Pathophysiol Haemost Thromb
2002;32(Suppl 3):46-55.
296. Lewis BE, Matthai WH Jr, Cohen M, et al. Argatroban anticoagulation during percutaneous coronary intervention in
patients with heparin-induced thrombocytopenia. Catheter Cardiovasc Interv 2002;57(2):177-184.
297. Hiatt BK, Lentz SR. Prothrombotic states that predispose to stroke. Curr Treat Options Neurol 2002;4(6):417-425.
298. Gasparovic H, Nathan NS, Fitzgerald D, Aranki SF. Severe argatroban-induced coagulopathy in a patient with a
history of heparin-induced thrombocytopenia. Ann Thorac Surg 2004;78(6):e89-e91.
299. Martin ME, Kloecker GH, Laber DA. Argatroban for anticoagulation during cardiac surgery. Eur J Haematol
2007;78(2):161-166.
300. Hursting MJ, Dubb J, Verme-Gibboney CN. Argatroban anticoagulation in pediatric patients: a literature analysis. J
Pediatr Hematol Oncol 2006;28(1): 4-10.
301. Dyke PC II, Russo P, Mureebe L, et al. Argatroban for anticoagulation during cardiopulmonary bypass in an infant.
Paediatr Anaesth 2005;15(4):328-333.
302. Mejak B, Giacomuzzi C, Heller E, et al. Argatroban usage for anticoagulation for ECMO on a post-cardiac patient
with heparin-induced thrombocytopenia. J Extra Corpor Technol 2004;36(2):178-181.
303. Spanier TB, Oz MC, Minanov OP, et al. Heparinless cardiopulmonary bypass with active-site blocked factor IXa: a
preliminary study on the dog. J Thorac Cardiovasc Surg 1998;115(5):1179-1188.
304. Smith CR. Management of bleeding complications in redo cardiac operations. Ann Thorac Surg 1998;65(4,
Suppl):S2-S8; discussion S27-S28.
305. Gikakis N, Khan MM, Hiramatsu Y, et al. Effect of factor Xa inhibitors on thrombin formation and complement and
neutrophil activation during in vitro extracorporeal circulation. Circulation 1996;94(9, Suppl):II341-II346.
306. Spiess BD. Update on heparin-induced thrombocytopenia and cardiovascular interventions. Semin Hematol
2005;42(3, Suppl 3):S22-S27.
307. Warkentin TE, Greinacher A. Heparin-induced thrombocytopenia: recognition, treatment, and prevention: the
Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004;126(3, Suppl):311S-337S.
308. DeBois WJ, Liu J, Lee LY, et al. Diagnosis and treatment of heparin-induced thrombocytopenia. Perfusion
2003;18(1):47-53.
309. Visentin GP, Ford SE, Scott JP, Aster RH. Antibodies from patients with heparin-induced
thrombocytopenia/thrombosis are specific for platelet factor 4 complexed with heparin or bound to endothelial cells. J Clin
Invest 1994; 93(1):81-88.
310. Greinacher A, Potzsch B, Amiral J, et al. Heparin-associated thrombocytopenia: isolation of the antibody and
characterization of a multimolecular PF4-heparin complex as the major antigen. Thromb Haemost 1994;71(2): 247-251.
311. Cines DB, Kaywin P, Bina M, et al. Heparin-associated thrombocytopenia. N Engl J Med 1980;303(14):788-795.
312. Cines DB, Tomaski A, Tannenbaum S. Immune endothelial-cell injury in heparin-associated thrombocytopenia. N
Engl J Med 1987;316(10): 581-589.
313. White PW, Sadd JR, Nensel RE. Thrombotic complications of heparin therapy: including six cases of heparin—
induced skin necrosis. Ann Surg 1979;190(5):595-608.
314. Kappa JR, Fisher CA, Berkowitz HD, et al. Heparin-induced platelet activation in sixteen surgical patients: diagnosis
and management. J Vasc Surg 1987;5(1):101-109.
315. Linkins LA, Dans AL, Moores LK, et al. Treatment and prevention of heparin-induced thrombocytopenia:
antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based
Clinical Practice Guidelines. Chest 2012;141(2, Suppl):e495S-e530S.
P.496
316. Linkins LA, Warkentin TE. The approach to heparin-induced thrombocytopenia. Semin Respir Crit Care Med
2008;29(1):66-74.
317. Chong BH, Burgess J, Ismail F. The clinical usefulness of the platelet aggregation test for the diagnosis of heparin-
induced thrombocytopenia. Thromb Haemost 1993;69(4):344-350.
318. Sheridan D, Carter C, Kelton JG. A diagnostic test for heparin-induced thrombocytopenia. Blood 1986;67(1):27-30.
319. Greinacher A, Michels I, Kiefel V, Mueller-Eckhardt C. A rapid and sensitive test for diagnosing heparin-associated
thrombocytopenia. Thromb Haemost 1991;66(6):734-736.
320. Visentin GP, Malik M, Cyganiak KA, Aster RH. Patients treated with unfractionated heparin during open heart
surgery are at high risk to form antibodies reactive with heparin:platelet factor 4 complexes. J Lab Clin Med 1996;
128(4):376-383.
321. Warkentin TE. Heparin-induced thrombocytopenia and the anesthesiologist. Can J Anaesth 2002;49(6):S36-S49.
322. Warkentin TE, Cook RJ, Marder VJ, et al. Anti-platelet factor 4/heparin antibodies in orthopedic surgery patients
receiving antithrombotic prophylaxis with fondaparinux or enoxaparin. Blood 2005;106(12):3791-3796.
323. Warkentin TE, Greinacher A. Heparin-induced thrombocytopenia and cardiac surgery. Ann Thorac Surg
2003;76(2):638-648.
324. Warkentin TE, Greinacher A. Heparin-induced thrombocytopenia and cardiac surgery. Ann Thorac Surg
2003;76(6):2121-2131; (Ref. 323 corrected and republished).
325. Lubenow N, Eichler P, Lietz T, et al. Lepirudin in patients with heparin-induced thrombocytopenia—results of the
third prospective study (HAT-3) and a combined analysis of HAT-1, HAT-2, and HAT-3. J Thromb Haemost
2005;3(11):2428-2436.
326. Bennett-Guerrero E, Slaughter TF, White WD, et al. Preoperative anti-PF4/heparin antibody level predicts adverse
outcome after cardiac surgery. J Thorac Cardiovasc Surg 2005;130(6):1567-1572.
327. Bauer TL, Arepally G, Konkle BA, et al. Prevalence of heparin-associated antibodies without thrombosis in patients
undergoing cardiopulmonary bypass surgery. Circulation 1997;95:1242-1246.
328. Everett BM, Yeh R, Foo S, et al. Prevalence of heparin/platelet factor 4 antibodies before and after cardiac surgery.
Ann Thorac Surg 2007;83: 592-597.
329. Kress DC, Aronson S, McDonald ML, et al. Positive heparin-platelet factor 4 antibody complex and cardiac surgical
outcomes. Ann Thorac Surg 2007;83:1737-1743.
330. Gluckman TJ, Segal JB, Schulman SP, et al. Effect of anti-platelet factor-4/heparin antibody induction on early
saphenous vein graft occlusion after coronary artery bypass surgery. J Thromb Haemost 2009;7:1457-1464.
331. Selleng S, Malowsky B, Itterman T, et al. Incidence and clinical relevance of anti-platelet factor 4/heparin antibodies
before cardiac surgery. Am Heart J 2010;160:362-369.
332. Yusuf AM, Warkentin TE, Arsenault KA, et al. Prognostic importance of preoperative anti-PF4/heparin antibodies in
patients undergoing cardiac surgery. Thromb Haemost 2012;107:8-14.
333. Chen YC, Lin CY, Tsai CS. The frequency of heparin-induced thrombocytopenia in Taiwanese patients undergoing
cardiopulmonary bypass surgery. J Formos Med Assoc 2013. doi:10.1016/j.jfma.2013.11.003.
334. Chilver-Stainer L, Lammle B, Alberio L. Titre of anti-heparin/PF4-antibodies and extent of in vivo activation of the
coagulation and fibrinolytic systems. Thromb Haemost 2004;91(2):276-282.
335. Cipolle RJ, Rodvold KA, Seifert R, et al. Heparin-associated thrombocytopenia: a prospective evaluation of 211
patients. Ther Drug Monit 1983;5(2): 205-211.
336. Ansell J, et al. Heparin induced thrombocytopenia: a prospective study. Thromb Haemost 1980;43(1):61-65.
337. Bell WR, Royall RM. Heparin-associated thrombocytopenia: a comparison of three heparin preparations. N Engl J
Med 1980;303(16):902-907.
338. Bailey RT Jr, Ursick JA, Heim KL, et al. Heparin-associated thrombocytopenia: a prospective comparison of bovine
lung heparin, manufactured by a new process, and porcine intestinal heparin. Drug Intell Clin Pharm 1986; 20(5):374-
378.
339. Laskey MA, Deutsch E, Hirshfeld JW Jr, et al. Influence of heparin therapy on percutaneous transluminal coronary
angioplasty outcome in patients with coronary arterial thrombus. Am J Cardiol 1990;65(3):179-182.
340. Resnekov L, Chediak J, Hirsh J, Lewis D. Antithrombotic agents in coronary artery disease. Chest 1986;89(2,
Suppl):54S-67S.
341. Kander NH, Holland KJ, Pitt B, Topol EJ. A randomized pilot trial of brief versus prolonged heparin after successful
reperfusion in acute myocardial infarction. Am J Cardiol 1990;65(3):139-142.
342. Warkentin TE, Kelton JG. Temporal aspects of heparin-induced thrombocytopenia. N Engl J Med
2001;344(17):1286-1292.
343. Koster A, Loebe M, Mertzlufft F, et al. Cardiopulmonary bypass in a patient with heparin-induced thrombocytopenia II
and impaired renal function using heparin and the platelet GP IIb/IIIa inhibitor tirofiban as anticoagulant. Ann Thorac Surg
2000;70(6):2160-2161.
344. Greinacher A, Volpel H, Janssens U, et al. Recombinant hirudin (lepirudin) provides safe and effective
anticoagulation in patients with heparin-induced thrombocytopenia: a prospective study. Circulation 1999;99(1):73-80.
345. Ling E, Warkentin TE. Intraoperative heparin flushes and subsequent acute heparin-induced thrombocytopenia.
Anesthesiology 1998;89(6):1567-1569.
346. Makhoul RG, McCann RL, Austin EH, et al. Management of patients with heparin-associated thrombocytopenia and
thrombosis requiring cardiac surgery. Ann Thorac Surg 1987;43(6):617-621.
347. Smith JP, Walls JT, Muscato MS, et al. Extracorporeal circulation in a patient with heparin-induced
thrombocytopenia. Anesthesiology 1985;62(3): 363-365.
348. Augoustides JG, Lin J, Gambone AJ, Cheung AT. Fatal thrombosis in an adult after thoracoabdominal aneurysm
repair with aprotinin and deep hypothermic circulatory arrest. Anesthesiology 2005;103(1):215-216.
349. Cetta F, Graham LC, Wrona LL, et al. Argatroban use during pediatric interventional cardiac catheterization.
Catheter Cardiovasc Interv 2004;61(1): 147-149.
350. Coon PD, Rychik J, Novello RT, et al. Thrombus formation after the Fontan operation. Ann Thorac Surg
2001;71(6):1990-1994.
351. Gruber EM, Shukla AC, Reid RW, et al. Synthetic antifibrinolytics are not associated with an increased incidence of
baffle fenestration closure after the modified Fontan procedure. J Cardiothorac Vasc Anesth 2000;14(3):257-259.
352. Quinones JA, Deleon SY, Bell TJ, et al. Fenestrated Fontan procedure: evolution of technique and occurrence of
paradoxical embolism. Pediatr Cardiol 1997;18(3):218-221.
353. Shore-Lesserson L, Reich DL. A case of severe diffuse venous thromboembolism associated with aprotinin and
hypothermic circulatory arrest in a cardiac surgical patient with factor V Leiden. Anesthesiology 2006;105(1):219-221.
354. Rhodes GR, Dixon RH, Silver D. Heparin induced thrombocytopenia: eight cases with thrombotic-hemorrhagic
complications. Ann Surg 1977;186(6):752-758.
355. Guay DR, Richard A. Heparin-induced thrombocytopenia—association with a platelet aggregating factor and cross-
sensitivity to bovine and porcine heparin. Drug Intell Clin Pharm 1984;18(5):398-401.
356. Francis JL, Palmer GJ 3rd, Moroose R, Drexler A. Comparison of bovine and porcine heparin in heparin antibody
formation after cardiac surgery. Ann Thorac Surg 2003;75(1):17-22.
357. Horellou MH, Conard J, Lecrubier C, et al. Persistent heparin induced thrombocytopenia despite therapy with low
molecular weight heparin. Thromb Haemost 1984;51(1):134.
358. Harenberg J, Harenberg J, Zimmerman R, Schwarz F, Kubler W. Treatment of heparin-induced thrombocytopenia

with thrombosis by new heparinoid. Lancet 1983;1(8331):986-987.
359. Kappa JR, Horn MK 3rd, Fisher CA, et al. Efficacy of iloprost (ZK36374) versus aspirin in preventing heparin-
induced platelet activation during cardiac operations. J Thorac Cardiovasc Surg 1987;94(3):405-413.
360. Kraenzler EJ, Starr NJ, Miller ML, Schiavone WA. Heparin-associated thrombocytopenia: management of patients
for open heart surgery. Case reports describing the use of iloprost. Anesthesiology 1988;69(6):964-967.
361. Addonizio VP Jr, Macarak EJ, Niewiarowski S, et al. Preservation of human platelets with prostaglandin E1 during in
vitro simulation of cardiopulmonary bypass. Circ Res 1979;44(3):350-357.
362. Kappa JR, Musial J, Fisher CA, Addonizio VP Jr. Quantitation of platelet preservation with prostanoids during
simulated bypass. J Surg Res 1987; 42(1):10-18.
363. Vender JS, Matthew EB, Silverman IM, et al. Heparin-associated thrombocytopenia: alternative managements.
Anesth Analg 1986;65(5):520-522.
364. Brady J, Riccio JA, Yumen OH, et al. Plasmapheresis. A therapeutic option in the management of heparin-
associated thrombocytopenia with thrombosis. Am J Clin Pathol 1991;96(3):394-397.
Chapter 20
Heparin Neutralization
Justin Horricks
Mark E. Comunale
Heparin remains the anticoagulant of choice for cardiopulmonary bypass (CPB). The action of heparin is well understood,
and one of its principal advantages is the ease with which it can be neutralized. Protamine remains the mainstay of this
process.
This chapter discusses the process of protamine neutralization of heparin-induced anticoagulation and its side effects,
including life-threatening and sometimes fatal reactions. In addition, we present recent work examining alternatives to
protamine.
CHEMISTRY OF PROTAMINE
Heparin acts by enhancing the activity of antithrombin III (ATIII), a circulating proteinase inhibitor that acts on serine
proteases. ATIII inhibits activated factors XIIa, XIa, IXa, Xa, thrombin (IIa), and XIIIa. Heparin-modified ATIII especially
accelerates inactivation of factors Xa and thrombin (1).
Protamine, a polycationic protein derived from salmon sperm, is strongly alkaline secondary to its amino acid composition
being 67% arginine. The protein has a high affinity for negatively charged sulfated glycosaminoglycans, such as heparin.
However, like heparin, it also possesses some anticoagulant activity, albeit much less significant. Heparin binds to
protamine ionically, producing a stable salt, which results in the loss of anticoagulant activity for both drugs. This protamine-
heparin complex is subsequently cleared by the reticuloendothelial system (2).
Other clinical uses of protamine include complexing it with insulin to produce neutral protamine Hagedorn (NPH) insulin.
This renders insulin relatively insoluble at neutral pH, extending the duration of action to approximately 24 hours. Similarly,
complexing protamine with zinc forms protamine-zinc insulin, which has a duration of 36 hours. Protamine also inhibits
angiogenesis (3), a property which led to its previously unsuccessful evaluation as an antineoplastic agent (4).
The anticoagulant effect of protamine was first demonstrated in 1937 (5). Many studies have since verified that protamine
exerts a dose-dependent anticoagulant effect (6,7,8,9,10,11,12,13,14,15,16). However, debate exists as to whether this
effect is clinically important and at what doses it occurs. It has been suggested that the anticoagulant effect of protamine
becomes important only at doses approximately three times those required for neutralization of residual heparin (17). More
recently, McLaughlin and Dunning (18) did a literature review to answer the question of whether high doses of protamine
cause increased bleeding in cardiac surgery patients. They concluded that high doses of protamine can cause increased
bleeding and impaired platelet function but these effects are not shown to be significant below a protamine-to-heparin dose
ratio of 2.6:1 (Fig. 20.1). This relatively large therapeutic window for protamine is reassuring, but the potential for disruption
of the coagulation system from protamine overdose during heparin reversal still remains. Mochizuki et al. (6) found that
excess protamine prolonged the activated clotting time (ACT) and altered platelet function following CPB. A recent pilot
study looked at the impact of protamine overdose following CPB, and noted that there was a trend toward an increased
need for transfusion of PRBCs, FFP, and plasma coagulation factors in the group receiving excess protamine, although it
was not
P.498
found to be statistically significant for the small cohort of subjects enrolled (16).
FIGURE 20.1. Effects of incremental ratios of protamine on reversal of heparin from blood samples obtained after
cardiopulmonary bypass. Activated clotting time (ACT) values are expressed as mean ± SD. The maximal reduction of ACT
values for each experiment (max) is shown. Heparin anticoagulation was maximally reversed at a protamine-to-heparin dose
ratio of 1.3:1. Each increment in protamine concentration (i.e., in excess of a calculated protamine-to-heparin dose ratio of
1.3:1) resulted in a larger ACT value that was statistically significant at dose ratios >2.6:1. (From Mochizuki T, Olson PJ,
Szlam F, et al. Protamine reversal of heparin affects platelet aggregation and activated clotting time after cardiopulmonary
bypass. Anesth Analg 1998;87(4):781-785, with permission.)
Many studies have looked at the mechanism by which protamine exerts its anticoagulant effect. Some have suggested that
the anticoagulant effect of protamine may be attributed to the inhibition of platelet-induced aggregation. Ellison et al. (19)
showed a decrease in in vitro platelet sensitivity to adenosine diphosphate (ADP) and collagen in the presence of the
heparin-protamine complex. Mammen et al. (20) showed decreased platelet aggregation in response to ADP and ristocetin
when protamine was administered to patients at the conclusion of CPB. They also demonstrated a decrease in platelet
volume and suggested that a change in platelet surface membranes could be responsible for this altered platelet function.
More recently, studies have shown that protamine mediates its anticoagulant activity through the downregulation of
thrombin generation (11,14), specifically by inhibiting the activation of factor V (13).
A variety of dosing regimens have been described as appropriate for clinical administration of protamine for heparin
reversal. In 1976, a human trial that compared administration of protamine equal to the total heparin dose versus protamine
at a reduced dose based on a heparin half-life of 2 hours resulted in markedly decreased chest tube drainage, higher
platelet counts, and postoperative clotting times closer to control values in those patients receiving the smaller protamine
doses (21). Dutton et al. (22) showed that smaller protamine doses (derived by protamine titration just before the
discontinuation of CPB) resulted in acceptable values for ACT at the conclusion of bypass with no subsequent evidence of
heparin rebound. The previous studies indicate that most patients will tolerate an excess protamine dose of 1 to 2 mg/kg
without significant adverse effects on hemostasis. However, the clinician should be aware that the greater the amount of
excess protamine administered, the more likely it is that coagulation disturbances will be experienced. Therefore, a top
priority should be to provide the most suitable dose of protamine for heparin reversal. The following section will examine
various methods used for calculating an appropriate protamine dosage.
ASSESSMENT OF REVERSAL OF ANTICOAGULATION

Monitoring the level of anticoagulation during and following CPB is a widely accepted practice. Tests evaluating
anticoagulation should yield quick results and be easily performed in the operating room. ACT, a variation of the whole-
blood clotting time, has been the test most commonly utilized for this purpose and is described in detail in Chapter 18.
Calculation of Protamine Dose

The anticoagulant effects of a given dose of heparin vary considerably between patients. Bull et al. (23) demonstrated that
simple weight-based dosing without monitoring of the anticoagulant effects can lead to underdosing or overdosing in some
patients (Fig. 20.2). Accurate calculation of the protamine dose is therefore important because unneutralized heparin can
increase postoperative bleeding. Several inherent problems in calculating protamine dosage have been pointed out by Hurt
et al. (24). These include the following: (1) the dose of protamine necessary to neutralize heparin is not the same in vivo as
in vitro; (2) heparin and protamine preparations vary in their potency; and (3) because heparin undergoes continuous
metabolism or excretion, the dose of protamine needed decreases with time.
FIGURE 20.2. Before the initiation of cardiopulmonary bypass, a heparin dose of 300 units/kg was given, with 100 units/kg
given after 2 hours and each hour thereafter. Neutralization was accomplished with protamine at 1.5 times the total dose of
heparin. For each procedure, (A) shows patients (darkened triangles and open circles) who had the least sensitivity to
heparin and the shortest half-life of heparin (closed diamonds and open squares); (B) shows the course of anticoagulant
therapy for patients who were the most sensitive to heparin (open diamonds and closed circles) and patients who had the
longest half-life of heparin (darkened squares and x). Solid lines depict the coagulation times during bypass, and broken
lines indicate the institution and termination of anticoagulation. (From Bull BS, Korpman RA, Huse WM, et al. Heparin
therapy during extracorporeal circulation. I. Problems inherent in existing heparin protocols. J Thorac Cardiovasc Surg
P.499
Many different dose regimens for protamine neutralization of heparin anticoagulation are employed. Inappropriate protamine
dosage may result in inadequate reversal, protamine anticoagulation, or adverse side effects. Table 20.1 highlights the
advantages and disadvantages of the different techniques.
Fixed Protamine Dose Regimen

The easiest method for calculating a protamine dose is a fixeddose ratio of protamine to heparin. This method involves
giving 1.0 to 1.3 mg of protamine for each 100 units of heparin. Either the total dose of heparin administered for the case or
the heparin dose given initially defines the amount of heparin to be neutralized (25,26). Simplicity constitutes the main
advantage of this method, as no assays are required at the end of bypass and there is no need to measure the ACT. The
disadvantage is the considerable variability in the half-life of heparin, which makes it difficult to predict the status of the
coagulation system immediately preceding heparin neutralization (25).
TABLE 20.1. Comparison of methods for calculating protamine dosage
Method Advantages Disadvantages

Fixed dose Simple Inadequate or excessive protamine
Not reliant on ACT Potential for elevated coagulation

times with standard doses
ACT/heparin dose-response Rapid, easy to use in the operating room No correlation between ACT and
curves heparin concentrations
More accurate protamine administration Relies on ACT
Decreased blood product requirements Dependence on plasma volume

compared to fixeddose regimen estimate
Heparin Less protamine given Dependence on plasma volume

concentration/protamine estimate
titration (HEPCON)
Not reliant on ACT Not a functional test
Reasonably rapid bedside test
Decreased postoperative bleeding

(suggested by some studies)
ACT, activated clotting time.
Heparin-Activated Clotting Time Dose-Response Curves

This technique uses the method described by Bull et al. (27) and involves determining three ACT values and plotting them
on a graph versus the heparin dose (Figs. 20.3, 20.4). The calculated amount of heparin is then neutralized by giving 1.3
mg of protamine per 100 units of heparin at the conclusion of CPB. This method is rapid and easy to use. Other advantages
of this method include the following: (1) the protamine dose can be calculated more accurately than with the fixed regimen;
(2) a reduced quantity of protamine is administered; and (3) infusion of blood, platelets, and fresh frozen plasma is possibly
decreased (28). One disadvantage is the reliance on the ACT, which is affected by numerous factors. Culliford et al. (29)
demonstrated that CPB distorts the relation between ACT and heparin levels, with the ACT becoming prolonged beyond
what could be explained by the plasma-heparin concentration. The authors also noted that protamine doses calculated by
this method exceeded those calculated by measuring plasma-heparin concentration, and the amount calculated by
measuring plasma-heparin concentration was usually sufficient to neutralize heparin-induced anticoagulation.
Heparin Concentration and Protamine Titration

Precise determination of the plasma-heparin concentration remaining at the conclusion of bypass is a technique used by
many centers. One method, which has been used as a verification test for research studies, incubates the plasma to be
analyzed for heparin with factor Xa in the presence of an excess of its inhibitor (Xai). Heparin accelerates factor Xa
inhibition, and residual factor X remaining after 2 minutes is measured and converted to a heparin concentration, expressed
in units per milliliter (30). Culliford et al. (29) demonstrated the use of decreased protamine doses after calculation by this
method as opposed to heparin-ACT dose-response curves. However, the major disadvantage of this method is the delayed
acquisition of test results. Therefore, the values may not be accurate when received because the patient’s heparin
concentration decreases at an unknown rate while the blood specimen is being analyzed. Furthermore, the conversion of
plasma heparin concentrations into a protamine dose requires an estimation of plasma volume, which is difficult to assess
at the completion of bypass (27).
Calculation of protamine dose by protamine titration was initially described by Allen et al. (31), and several variations of this
method have been described (22,23,32). All methods employ tubes with several dilutions of a standard protamine
P.500
solution, to which a fixed volume of whole heparinized blood is added. The lowest protamine concentration resulting in the
shortest clotting time represents the optimal neutralization of heparin. The protamine dose is then calculated based on an
assumed neutralization ratio (e.g., 1 mg of protamine per 100 units of heparin) and on estimated blood volume. Therefore,
this method actually constitutes an indirect way of estimating heparin concentrations. Advantages claimed for this method
include administration of a lower protamine dose than with a fixed-dose regimen (23), absence of excessive postoperative
bleeding response (23), and absence of heparin rebound despite reduced protamine doses (22). However, this method can
be time consuming and cumbersome because of the multiple steps involved which does not lend itself well to the cardiac
surgery environment.
FIGURE 20.3. (A) and (B) depict a computerized monitoring simulation of the patients shown in Figure 1. The activated
coagulation time was raised to 8 minutes initially and was returned to that level every 60 minutes during the surgery.
Protamine was administered in a ratio of 1.3 mg for every 100 units of heparin remaining in the circulation at the conclusion
of bypass. Solid lines depict the calculated coagulation times during CPB. Broken lines depict successful neutralization of
anticoagulation with protamine. (From Bull BS, Korpman RA, Huse WM, et al. Heparin therapy during extracorporeal
circulation. I. Problems inherent in existing heparin protocols. J Thorac Cardiovasc Surg 1975;69:674-684, with permission.)
This paradigm changed with the introduction of automated point-of-care coagulation monitors. The Hepcon system by
Medtronic has become the most well-known and utilized. The device works by using disposable cartridges that automate
the protamine titration process, thereby providing a current heparin concentration along with a calculated protamine
reversal dose using the patient’s height and weight. Multiple studies have looked at the Hepcon system with regard to
bleeding and blood product usage with overall positive, but varying results (33,34,35,36,37,38). Dunning et al. (39)
published guidelines for anticoagulation management in cardiac surgery after reviewing the evidence in 2008, and found
that Hepcon monitoring is associated with a lower protamine doses and may decrease postoperative bleeding and blood
product requirement. They concluded that routine use is reasonable but acknowledged that further studies are necessary.
Recently, Noui et al. (40) found that protamine titration with the Hepcon device during cardiac surgery could predict a lower
protamine dose and lower postoperative bleeding, along with lower perioperative red blood cell transfusion and shorter
chest closure times.
OTHER DRUGS USED TO NEUTRALIZE HEPARIN

The reported incidence of severe reactions to protamine, including respiratory compromise, hypotension, and shock, varies
from 0.2% to 3% in the general population to as high as 27% in patients who are allergic to fish or have received NPH
insulin (41). This has led to an ongoing search for alternative agents to neutralize heparin-induced anticoagulation and also
alternatives to heparin. Most of these substitutes have had limited success.
Platelet Factor 4
The α-granules of human platelets contain platelet factor 4 (PF4), which binds and neutralizes heparin when released
during platelet aggregation (1). PF4 is released at the site of vascular injury, binding heparin and facilitating thrombin
accumulation and clot formation (31).
Recombinant PF4 (rPF4) cloned in Escherichia coli neutralizes heparin as effectively as protamine in vitro (Fig. 20.5).
P.501
rPF4 and protamine both neutralize heparin inhibition of factor Xa and thrombin. rPF4 restored factor Xa levels more
effectively than protamine (by approximately 50%-60%) and was equipotent with human PF4 (31) (Fig. 20.6). In a rat model,
rPF4 was as effective as protamine in reversing heparin anticoagulation. The PF4 injection produced normal platelet counts
in this model (42).
FIGURE 20.4. Procedure for the construction and use of the dose-response curve. ACT, activated clotting time. (From Bull
BS, Huse WM, Brauer FS, et al. Heparin therapy during extracorporeal circulation. II. The use of a dose-response curve to
individualize heparin and protamine dosage. J Thorac Cardiovasc Surg 1975;69:685-689, with permission.)
Human or rPF4 administered to Sprague-Dawley rats after heparinization had no effect on white blood cell count, platelet
count, or complement levels (43) (Fig. 20.7). In contrast, protamine administered after heparin (0.1 mg/100 g) caused
decreases of these same parameters. Furthermore, heparin neutralization by recombinant or human PF4 caused no
decrease in mean arterial blood pressure or pathologic pulmonary changes, whereas protamine neutralization produced
these adverse effects (44).
Dehmer et al. (45) compared PF4 with protamine in a prospective, double-blind study in patients undergoing cardiac
catheterization. In this study, the administration of PF4 to patients was both safe and effective in the doses used. In
addition, PF4 had the advantage of rapid administration, within 2 minutes, in comparison with 10 minutes for protamine. The
P.502
number of patients was small and clinical experience in humans is limited. PF4 is expensive, and its cost-effectiveness
remains to be established. The advantages of rapid administration and lack of serious side effects merit a larger study in
patients undergoing CPB.
Kurrek et al. (46) showed that PF4 produces acute pulmonary hypertension in lambs. The magnitude of pulmonary
hypertension was similar to that seen with protamine. However, PF4 did not cause hypoxemia and neutropenia, indicating
that complement was not activated by PF4. In contrast, Cook et al. (44) studied reversal of heparin anticoagulation with PF4
in the rat and concluded that PF4 is both effective and devoid of serious side effects. Similarly, Bernabei et al.
P.503
(47) demonstrated the safety and efficacy of PF4 in baboons. The effectiveness of PF4 has been established in vitro;
heparinized blood obtained from patients undergoing CPB was reversed with PF4.
FIGURE 20.5. Neutralization of heparin elongation of activated partial thromboplastin time (APTT). rPF4, recombinant PF4.
(From Hunt AJ, Gray GS, Myers JA, et al. Heparin neutralization by recombinant human PF4 in vitro [abstract]. FASEB J
1990;4:A1991, with permission.)
FIGURE 20.6. Neutralization of heparin by protamine and recombinant PF4 (rPF4). A: With factor Xa, rPF4 and protamine
were both effective, although 1 μM of rPF4 could restore factor Xa activity to higher levels than could protamine. B: Both
rPF4 and protamine were equally effective (on a molar basis) in preventing inhibition of thrombin. (From Hunt AJ, Gray GS,
Myers JA, et al. Heparin neutralization by recombinant human PF4 in vitro [abstract]. FASEB J 1990;4:A1991, with
permission.)
FIGURE 20.7. Effect of injection of protamine sulfate or recombinant PF4 (rPF4) on the number of circulating white blood
cells (A) and platelets (B). Number of experiments in parentheses. *p < 0.01, significantly different from platelet or WBC
count before heparin. The values correspond to the mean ± standard error of the mean. (From Cook JJ, Niewiarowski S,
Yan Z, et al. Platelet factor 4 efficiently reverses heparin anticoagulation in the rat without adverse effects of heparin-
protamine complexes. Circulation 1992;85:1102-1109, with permission.)
Mixon et al. (48) performed the first open-label, phase 1 human study using rPF4. Patients received rPF4 in doses of 0.5,
1.0, 2.5, or 5.0 mg/kg over 3 minutes to reverse heparin anticoagulation after diagnostic cardiac catheterization. There were
no important hemodynamic changes and the rPF4 was highly effective in neutralizing heparin. Serial measurements of rPF4
levels showed a monophasic elimination pattern with a serum half-life of 25.5 ± 13.5 minutes that was independent of dose
administered. A randomized and blinded trial comparing rPF4 to protamine confirmed the safety and effectiveness of rPF4.
One potential drawback to the use of rPF4 is the occasional need to emergently return CPB. In this instance, there may be
a significant amount of rPF4 in circulation for as much as 2 hours (although more commonly 30-60 minutes), making
reheparinization difficult.
Although rPF4 was initially being evaluated as a clinical alternative to protamine, it is not currently being developed for
general clinical use. However, a recent publication revisited data from a case series that had been performed in 1995 to
1996 on patients undergoing CPB. The study involved 21 patients: 16 patients who received rPF4 for heparin reversal and
5 who received the standard protamine. This case series demonstrated that heparin anticoagulation was effectively
reversed with rPF4 without serious complications and indicated that further examination of rPF4 as an alternative to
protamine may be something to reconsider (49).
Protamine Variants
Wakefield et al. (50) have been working on a protamine variant, a so-called designer protamine, to neutralize the
anticoagulant effect of heparin. Two such variants are currently under investigation. The first, +18BE (standard protamine
being +21), has a +18 charge with acetyl and amide groups on the ends and glutamic acid replacing prolene in the
background structure. The second molecule has a side group, arginine-glycine-aspartate (RGD), that is a known
recognition site for platelet adhesion protein.
In a dog model (51), the reversal of anticoagulation (measured by the reversal of antifactor Xa activity) achieved with the
RGD compound was superior to that achieved with standard protamine. Side effects as measured by changes in oxygen
consumption, blood pressure, and cardiac output, were significantly reduced by the RGD variant. Platelet clumping and
prolongation of bleeding times were also not observed with the RGD variant.
Okajima et al. (52) described the mechanism of heparin neutralization and suggested that protamine competes with ATIII for
binding to heparin. Owing to a stronger affinity to heparin, protamine dissociates ATIII from the heparin-ATIII complex
thereby reversing the anticoagulant function of heparin. Although protamine binds heparin through an electrostatic
interaction, heparin binds ATIII through a small pentasaccharide sequence. Sela et al. (53) also described that small
peptides in the range of 1,500 Da or below are usually either weakly immunogenic or completely devoid of immunogenicity,
as compared with the much stronger immunogenicity of unfractionated protamine.
Byun et al. (54) suggested that effective binding of protamine to the pentasaccharide sequence in heparin to displace the
complexed ATIII through an ionic interaction may not require the whole protamine molecule for favorable electrostatic
interaction but rather, a small fragment encompassing an intact arginine-rich sequence called low-molecular-weight
protamine (LMWP). However, the LMWP required to neutralize the heparin was twice the amount of unfractionated
protamine. Although there were only a small number of animals in the study, there was no evidence of antigenicity or cross-
reactivity in mice that were previously exposed to protamine. Initial studies suggest that LMWP dosing for heparin
neutralization is between one and four times the amount of heparin given by weight, assuming a heparin concentration of
100 units/mg administered. This area of research holds exciting prospects for decreasing the toxicity of protamine.
Heparinase
Heparinase, derived from the bacterium Flavobacterium heparinum, neutralizes heparin by enzymatic cleavage of α-
glycoside linkages at the ATIII binding site. Heparinase is an effective antagonist of heparin as measured by ACT and
heparin concentrations. Michelson et al. (55) found that heparinase did not produce any significant hemodynamic changes
when administered as an intravenous bolus to heparinized dogs under anesthesia. In an in vitro study of the blood of
healthy volunteers, Ammar and Fisher (8) demonstrated that heparinase has minimal effects on platelets, whereas
protamine markedly inhibits platelet responsiveness. In these studies, heparinase was as effective as protamine in
neutralizing heparin-induced anticoagulation, and it appears to be a promising potential alternative to protamine. Heres et
al. (56) demonstrated that Heparinase-I (Neutralase) successfully restored ACT with no adverse hemodynamic events in
patients undergoing coronary artery surgery with CPB in an open-label dose-determining trial. Stafford-Smith et al. (57)
concluded that heparinase-I reverses heparin anticoagulation after coronary artery bypass surgery but possesses inferior
neutralizing capacity as compared with protamine, possibly as a result of heparinase lysing circulating unfractionated
heparin into a functional equivalent of low-molecular-weight heparin. Human trials have been discontinued. Similar to rPF4,
a potential drawback to heparinase is the occasional need to emergently return to CPB. Prior use of Heparinase-I may
require large doses of heparin in order to achieve rapid reheparinization for 36 minutes or more, due to the possibility of
having a significant amount of heparinase-I still in circulation.
P.504
Heparin-Removal Devices
The use of immobilized protamine during extracorporeal circulation has been reported by Yang et al. (58). Their method
utilizes a “protamine bioreactor” in the bypass circuit that is composed of protamine bonded to the cellulose fibers of a
hemodialyzer. This protamine bioreactor is placed directly into the bypass circuit to remove and neutralize heparin in vitro.
Because heparin-bonded tubing is used downstream from these devices, clot formation and embolic phenomena do not
appear to be a concern. Use of this device was associated with decreased complement activation in comparison with the
systemic administration of protamine.
A separate extracorporeal circuit called a heparin-removal device can be used at the end of CPB to remove heparin from
the blood. The principle of plasmapheresis is applied in the heparin-removal device system to expose heparinized plasma
from the patient to poly-L-lysine. The negatively-charged heparin molecules bind irreversibly with the positively-charged
poly-L-lysine and are removed from plasma. Hendrikx et al. (59) used this system to neutralize heparin-induced
anticoagulation in dogs undergoing CPB and concluded that the heparin-removal device was as efficient as systemic
administration of protamine. Thrombocytopenia and complement activation were less than with protamine.
Zwischenberger et al. (60) also examined this poly-L-lysine device in the adult swine model, and came to similar
conclusions. Although this method is unique, simple, and effective, the time taken to reverse heparin activity (30 minutes or
longer) is currently unacceptable for routine clinical practice. It is also not as cost effective as simple protamine
administration. However, this device could be considered in patients who have known severe reactions to protamine.
PROTAMINE REACTIONS
Adverse cardiopulmonary responses to protamine have been observed during the entire history of clinical cardiac surgery.
The complexity of the clinical situation has made this adverse drug reaction very difficult to define. In 1983, a specific
clinical syndrome of catastrophic pulmonary vasoconstriction was described. Within 1 month, Lowenstein et al. (61)
observed three severe protamine reactions, and in another 3 months they had collected a total of five such incidents. They
observed profound increases in pulmonary arterial and central venous pressures with concurrent dramatic decreases in left
atrial and systemic arterial pressures. These five patients shared certain characteristics: valvular heart disease, bolus
administration of protamine, low total dose of protamine (<0.5 mg/kg), tolerance to further protamine infusions without
adverse effects, and no adverse sequelae. Since then, substantial clinical and basic science investigation has led to the
recognition of three mechanisms producing adverse protamine reactions (Table 20.2).
It now appears that catastrophic pulmonary vasoconstriction after protamine occurs in approximately 0.6% of adult cardiac
surgical patients or fewer (62,63). Numerous risk factors have been suggested, including valvular heart disease, preexisting
pulmonary hypertension, bolus protamine administration, infusion rates greater than 50 mg/min, diabetes with prior NPH
insulin exposure, specific brands of protamine, sterilization through ligation of the vas deferens, site of administration, and
rate of administration. To date, none of these predisposing risk factors has been verified, but some deserve mention and
are discussed here (see Pulmonary Vasoconstrictive Reactions) (64).
TABLE 20.2. Classification of protamine reactions
Type Horrow Moorman, Zapol, Lowenstein
I Hypotension resulting from Pharmacologic histamine release

rapid administration
IIa Anaphylactic reactions True anaphylaxis (IgE-mediated)
IIb Immediate anaphylactoid

reactions
IIc Delayed anaphylactoid Anaphylactoid reactions Pulmonary vasoconstriction (IgG/complement-

reactions mediated) Noncardiogenic pulmonary edema
III Catastrophic pulmonary

vasoconstriction
Classification of Protamine Reactions

Two classifications of protamine reactions have been proposed (Table 20.2). The classification of Horrow (65)
differentiates protamine reactions into types I, II, and III. Type I reactions result in transient systemic hypotension secondary
to rapid administration. Type II reactions consist of anaphylactic and anaphylactoid reactions, which are further divided into
types IIa, IIb, and IIc. Type IIa comprises true anaphylactic reactions. Immediate anaphylactoid reactions characterize type
IIb, and delayed anaphylactoid reactions (e.g., noncardiogenic pulmonary edema) are considered type IIc reactions. Type III
reactions consist of catastrophic pulmonary vasoconstriction (66).
We propose an alternative classification, as follows: (1) pharmacologic histamine release, (2) true anaphylaxis mediated by
a specific antiprotamine immunoglobulin E (IgE) antibody, and (3) anaphylactoid thromboxane release leading to pulmonary
P.505
vasoconstriction and bronchoconstriction. Therefore, Horrow type I reactions, which are characterized by systemic
hypotension secondary to rapid administration, correspond in our classification to pharmacologic histamine release.
Although Horrow includes true anaphylactic and anaphylactoid reactions in his type II, we consider them as two different
types because true anaphylaxis is mediated by a specific antiprotamine IgE antibody that can be produced by protamine in
the absence of heparin. The role of antiprotamine IgG antibodies is not clear. The anaphylactoid reaction is independent of
a specific IgE antibody, is associated with the heparin-protamine complex, and does not occur in the absence of heparin.
Catastrophic pulmonary vasoconstriction is the most common example of the anaphylactoid reaction in our categorization,
whereas Horrow classifies it separately. The rare occurrences of delayed pulmonary edema and adult respiratory distress
syndrome appear to represent different manifestations of anaphylactoid responses, so we classify them that way. In this
chapter, we employ the latter classification system.
Pharmacologic Release
Alkaline drugs, such as morphine sulfate and d-tubocurarine, cause histamine release with rapid infusion (61). Protamine,
also a basic (alkaline) drug, was believed to induce hypotension by this mechanism, and it was demonstrated to release
histamine by degranulating isolated mast cells (67). We classify protamine-induced hypotension resulting from this
mechanism as pharmacologic release. Pharmacologic release of histamine does not depend on the formation of heparin-
protamine complexes, but it can occur after the infusion of protamine alone. Its occurrence appears to depend on the rate of
infusion (68).
Stoelting et al. (68) demonstrated that the rapid administration of 4.7 mg of protamine per kilogram within 5 minutes in
heparinized humans and 4.5 mg/kg at the same rate in unheparinized dogs did not change hemodynamics or histamine
levels at the conclusion of CPB. The administration of 4.5 mg of protamine per kilogram (1) as a rapid infusion caused
decreases in blood pressure with parallel increases of histamine levels in unheparinized dogs (66).
Parsons and Mohandas (69) gave 1 mg of protamine per 1 mg of remaining heparin at a rate of 2.5 mg/s to patients
pretreated with histamine 1 (10 mg of chlorpheniramine) and histamine 2 (400 mg of cimetidine) receptor blockers. These
patients experienced a 23% decrease in mean arterial pressure, versus a 34% decrease in patients not given pretreatment.
This data again suggests a possible role of histamine in this type of reaction (69).
A greater degree of hypotension and greater increases in plasma histamine levels have been observed after rapid
rightsided protamine injections than after rapid left-sided administration in humans (64). These same observations have
been made in animal models, which suggest a pulmonary source of the histamine released in this response (55).
Some human studies have demonstrated only a very mild and transient decrease of blood pressure and systemic vascular
resistance after rapid protamine administration (70), but clinical experience has demonstrated that rapid protamine
administration can result in hypotension in humans. The variable degree of hypotension produced in many of these studies
may also reflect the variability of myocardial contractile reserve. Perhaps patients with good myocardial reserve can
compensate for the decreased systemic vascular resistance with a sufficient increase of cardiac index to avoid a major
decline in blood pressure (68).
A direct myocardial depressant effect of protamine has been proposed as being partially responsible for this hypotension
(71,72). It is difficult to determine whether depressed myocardial function is the consequence of a reduced reserve or direct
effect of the drug on the heart (69,73). The data on myocardial depression are far from conclusive because others have
shown no changes in global myocardial metabolism or hemodynamic parameters (including cardiac index) in patients with
normal left ventricular function after rapid protamine administration (74).
In summary, it appears that protamine can induce hypotension independently of the heparin-protamine complex in a manner
dependent on the rate of administration. Therefore, hypotension appears to be partly mediated by histamine release. The
degree of histamine release may be greater when a rightsided injection route is utilized, possibly reflecting pulmonary
histamine release, although this is controversial. This type of protamine-induced hypotension is accompanied by elevated
histamine concentrations, whereas increased plasma thromboxane and C5a levels and pulmonary hypertension are absent.
True Anaphylactic Protamine Reactions

True anaphylaxis to protamine (Horrow type IIa) does not require the heparin-protamine complex and is mediated by a
specific antiprotamine IgE antibody. This reaction is perhaps the most dreaded adverse effect of protamine. True
anaphylaxis requires prior protamine exposure to sensitize and produce IgE antibodies, which then bind to mast cells on
reexposure to the challenging antigen, protamine. These reactions, although uncommon, have to date been convincingly
documented exclusively in diabetic patients receiving NPH or protamine-zinc insulin. Patients with prior protamine exposure,
or patients with a fish allergy, have been suspected as candidates for these reactions, but documentation is lacking.
Physiologically, they are characterized by decreased systemic arterial, pulmonary arterial, left atrial, and right atrial
pressures; bronchospasm is variably present.
Using an enzyme-linked immunosorbent assay (ELISA), Sharath et al. (75) showed that 53% of diabetic patients taking
NPH insulin had elevated protamine-specific IgE antibodies. They also noted that IgE levels were highest in patients taking
protamine for long periods and in those who had begun protamine before age 20. Nondiabetic patients and diabetic
patients not using a protamine-containing form of insulin had no IgE reacting with protamine. Levy et al. (76) prospectively
studied
P.506
blood samples from 50 diabetic patients taking NPH insulin. They found only one sample that demonstrated an in vitro
leukocyte histamine release in response to protamine challenge.
Weiss et al. (77), in a case-control study, examined 27 diabetic and nondiabetic patients who had adverse protamine
reactions. Of these 27 patients, only diabetic patients who received protamine-containing insulin preparations had
antiprotamine IgE antibodies (Fig. 20.8). Their reactions were characterized primarily by a decreased blood pressure, with
the variable occurrence of bronchospasm. Some diabetic patients receiving protamine-containing insulin injections had
adverse drug reactions but lacked this IgE antibody. These patients exhibited a different clinical picture, characterized by
increased pulmonary artery pressures, decreased systemic arterial pressure, and often by the presence of antiprotamine
IgG antibody. Patients not receiving protamine insulin had reactions characterized by pulmonary vasoconstriction. These
differing clinical presentations suggest two different mechanisms, one being anaphylactic and mediated by IgE antibody and
the other being anaphylactoid and associated with IgG antibody. Patients may not exhibit positive skin test reactions to
dilute protamine insulin preparations because of desensitization; therefore, the absence of a positive skin test reaction does
not reliably exclude an IgE- or IgG-mediated protamine reaction.
FIGURE 20.8. The immunoglobulin E (IgE) antibody to protamine. Serum levels of IgE antibody to protamine were
measured with the use of the radioallergosorbent test in five patient populations. Normal subjects (Group A) had never
been exposed to protamine in any form and included three atopic subjects with total serum IgE levels of more than 1,000
ng/mL. Group B consisted of diabetic patients who had not received subcutaneous protamine insulin injections but who had
received intravenous protamine after coronary artery bypass surgery without a reaction. Group C consisted of diabetic
patients who were receiving daily subcutaneous injections of protamine and insulin and who had no reaction to intravenous
protamine after bypass surgery. Group D consisted of 13 nondiabetic patients and one diabetic patient who had adverse
reactions to intravenous protamine but had no previous exposure to protamine insulin preparations. Group E was
composed of diabetic patients receiving daily subcutaneous injections of protamine and insulin who had adverse reactions
when given intravenous protamine. The response was reported as a binding ratio (counts per minute of an unknown serum
sample per counts per minute of a negative serum sample). A ratio of 2.5 or higher indicated a positive response. Nine of
the 13 patients in Group E had IgE antibodies to protamine, in comparison with none of the 70 patients in the other four
groups. Soluble protamine inhibited the binding of IgE antibody to the protamine-agarose complex in all nine positive serum
samples. The inhibition of direct binding ranged from 60.7% to 99.5% (mean, 85.8%; data not shown). (From Weiss ME,
Nyhan D, Peng Z, et al. Association of protamine IgE and IgG antibodies with life-threatening reactions to intravenous
protamine. N Engl J Med 1989;320:886-892, with permission.)
There have been three reports of patients with true fish allergies experiencing adverse cardiopulmonary protamine
reactions, including one patient who experienced cardiovascular collapse following protamine administration at the
conclusion of CPB (78). This patient was subsequently shown to have elevated levels of IgE antibody specific for codfish
antigen, peripheral eosinophilia, and a positive protamine skin test reaction, as well as IgG-, IgM-, and IgE-specific
antibodies directed against protamine sulfate. Vertebrate fish protamines exhibit a similar nucleoprotein structure to that
found in humans, and it has been suggested that patients with a true fish allergy have antibodies that can cross-react with
the protamine derived from salmon sperm, or with antigenic contaminants accompanying the protamine (79). Because
shellfish and true fish are phylogenetically different, a shellfish allergy should not predispose a patient to a protamine
reaction.
Vasectomized men have been suggested to have an increased risk for protamine reactions because of the development of
antisperm antibodies and antibodies to protamine (80). Men with a positive complement fixation test to human protamine
also fix complement in the presence of salmon protamine. It has been speculated that cross-reactivity could cause problems
on exposure to protamine (81). Because human and fish protamines are similar, some cross-reactivity is possible. This
possibility remains only theoretical, however, because to date there is no documentation that protamine reactions occur
more frequently in vasectomized men. Levy et al. (62) prospectively observed cardiac surgical patients with prior
vasectomies and fish allergies and also retrospectively evaluated a cohort of 3,245 consecutive cardiac surgical patients
requiring CPB in search of adverse reactions to protamine. There were no adverse reactions to protamine in 6 patients with
fish allergies nor in 16 patients with vasectomies. Recognizing that their study did not have sufficient power to exclude fish
allergy and vasectomy as risk factors for protamine allergy, they appropriately concluded that a history of fish allergy or
prior vasectomy does not contraindicate protamine administration.
Anaphylactoid Reactions
Anaphylactoid reactions include those classified as types IIb, IIc, and III by Horrow. Mediators of anaphylaxis can be
liberated by pathways other than classic antigen-antibody
P.507
interactions (Fig. 20.9). Certain types of adverse responses to protamine are believed to be anaphylactoid in nature and
mediated by complement activation with secondary release of histamine, thromboxane, or other vasoactive substances
(82).
Protamine is itself incapable of activating complement. However, the interaction of heparin with protamine has been shown
to deplete plasma C1, suggesting classic activation of the complement cascade, as in the depletion produced by antibody-
antigen interactions (83).
Complement activation by the alternate pathway with increased C3a levels has been demonstrated following CPB in
humans (84,85). A second peak in C3a and C4a levels, indicating activation of the classic pathway, has also been
demonstrated following protamine neutralization of heparin. The anaphylatoxins C3a and C5a can produce systemic
inflammatory-type reactions with histamine release, increased capillary permeability, leukosequestration, and hemodynamic
derangements (86) manifesting as edema of the skin and mucosa, decreased systemic vascular resistance, bronchospasm,
and flushing (64). Protamine has been shown to inhibit human plasma carboxypeptidase semicompetitively in vitro. This
enzyme is responsible for the inactivation of anaphylatoxins and kinins. Therefore, it appears that protamine can cause
activation of the complement cascade and then block the hydrolysis of the various mediators produced by that process (87).
It is believed that certain types of adverse protamine reactions are caused by these mechanisms.
FIGURE 20.9. Both true anaphylactic and anaphylactoid reactions can cause similar pathophysiologic responses, including
the release of many of the same mediators and end-organ responses. The only reliable way of differentiating mechanisms
is by measuring specific antibody levels. The presence of immunoglobulin G (IgG) antibody is not specific. SRS-A, slow
release substance of anaphylaxis; ECF-A, eosinophil chemotactic factor A. (Modified from Levy JH. Anaphylactic reactions
in anesthesia and intensive care. Boston, MA: Butterworth-Heinemann, 1986:40, with permission.)
Adverse reactions to protamine in nondiabetic patients with prior protamine exposure have not been proven to be mediated
by IgE antibodies. Data suggest that these reactions are anaphylactoid in nature. Levy et al. (76) reported a 2% incidence
of protamine reactions in a series of more than 1,500 nondiabetic patients undergoing cardiac surgery with CPB, but
subsequent studies show an incidence of less than 1% (63). The mediator profile and antigen or antibody status of these
patients were not defined. Presumably, most of these patients had previously received protamine following cardiac
catheterization.
Stewart et al. (88), in a series of 866 patients undergoing cardiac catheterization, noted two major reactions in patients with
prior protamine exposure as the only apparent risk factor. Again, their antibody status was undefined. Weiss et al. (77)
showed that patients with antiprotamine IgG antibody had an increased risk for protamine reactions and speculated that this
was a consequence of prior exposure during cardiac catheterization. The ability of IgG antibodies to cause anaphylactoid
reactions to protamine was suspected by others (89).
Pulmonary Vasoconstrictive Reactions

The most extensively studied protamine reactions are anaphylactoid in nature and manifested by intense pulmonary
vasoconstriction. Since most types of protamine reactions are heralded by the onset of systemic hypotension, it was only
when the widespread use of pulmonary artery catheters was
P.508
adopted that this type of protamine reaction was recognized. As the name implies, pulmonary vasoconstrictive protamine
reactions are characterized by an increased pulmonary artery pressure secondary to pulmonary vasoconstriction, which
leads in turn to right ventricular failure, systemic hypotension, and decreased left atrial pressures during protamine
administration (Fig. 20.10). This syndrome has occurred after small doses of protamine, often less than 0.5 mg/kg and as
little as 0.14 mg/kg (90).
FIGURE 20.10. An example of a pulmonary vasoconstrictive (anaphylactoid) protamine reaction. LAP, left atrial pressure;
RAP, right atrial pressure; PAP, mean pulmonary artery pressure; SAP, systemic arterial pressure; HR, heart rate. The two
spikes on the right atrial pressure trace represent artifact from central venous sampling. MGH, Massachusetts General
Hospital number; DM, diabetes mellitus; NPH, neutral protamine Hagedorn; AVR, aortic valve replacement.
Heparin-protamine interactions have been extensively studied in animal models to elucidate the possible mechanisms in
humans. Much research has focused on anaphylactoid reactions, which can be catastrophic and are considered
idiosyncratic and therefore unpredictable. Compounding the idiosyncratic nature of anaphylactoid reactions is a lack of
clear risk factors. This makes pulmonary vasoconstrictive reactions especially frustrating to the clinician.
The expression of heparin-protamine reactions in animals has been very species-dependent (Table 20.3). However,
multiple studies have established their presence in an increasing number of mammals. The sheep model has been most
extensively utilized because the ovine pulmonary vasculature is very prone to vasoconstriction. Morel et al. (91) consistently
elicited pulmonary hypertension accompanied by an increased pulmonary vascular resistance, pulmonary capillary
occlusion pressure, and thromboxane B2 levels and a decreased cardiac output and stroke volume in awake sheep given
200 units of heparin per kilogram as a bolus followed by 2 mg of protamine per kilogram administered during 10 seconds
through the right atrial catheter. This response was not seen in animals given protamine without prior heparin, nor was it
observed in animals pretreated with indomethacin (a cyclooxygenase inhibitor) or a thromboxane synthetase inhibitor.
Animals pretreated with dimethylsulfoxide (a hydroxide scavenger) experienced increased pulmonary artery pressures,
whereas dimethylthiourea (a hydrogen peroxide scavenger) pretreatment prevented the response (Fig. 20.11). Sheep were
also found to have a profound leukopenia with the heparin-protamine interaction. Analysis of complement and histamine
concentrations revealed a consistent increase in C3a levels but no change in plasma histamine levels during heparin-
protamine interactions (91). Montalescot et al. (92) were able to prevent this reaction by pretreatment with a thromboxane
receptor blocker despite unchanged levels of the plasma thromboxane metabolite. Leukopenia was not prevented by
pretreatment with this agent. In pigs, the heparin-protamine complex consistently induced pulmonary hypertension with
increased thromboxane B2 levels (93,94,95,96).
Degges et al. (96) showed that increased thromboxane B2 release and pulmonary hypertension could be blocked by
pretreating pigs with aspirin but not antihistamines. They also demonstrated the pulmonary vasoconstrictor response in
isolated lungs by using an acellular dextran perfusion medium. Therefore, platelet aggregation, leukocyte sequestration,
and plasma complement activation are not required. In a prospective, randomized study involving 1,501 patients, Comunale
et al. (63) reported that none of the 10 patients who had pulmonary hypertension were taking aspirin preoperatively.
Preoperative use of aspirin seems to confer protection against pulmonary hypertension during protamine neutralization of
heparin. Additionally, it may explain Lowenstein’s early observations that such reactions seem to be more common in
patients undergoing valve surgery, as such patients are less likely to be on aspirin (i.e., no coronary disease).
Thromboxane A2, a short-lived vasoconstrictor, is rapidly hydrolyzed to thromboxane B2, which is inactive and longlived.
Thromboxane A2 is known to be a potent pulmonary vasoconstrictor. Pretreatment with thromboxane antagonists would
seem to offer one solution to pulmonary vasoconstrictive reactions, at least in the animal model. However, thromboxane
receptor antagonists can cause platelet dysfunction, which could lead to increased hemorrhage following CPB. Therefore,
an extremely short-acting antagonist would be required for clinical utility.
P.509
TABLE 20.3. Heparin-protamine interactions in animal models
TX
Author Species Hemodynamics Levels Antagonist Reaction Coagulation
Morel, 1988 Sheep PAP, PVR, SVR, Increased TX synthetase Attenuated Not studied
(91) PW increased
CO, SV Indomethacin Blocked

decreased
BP, HR no DMTU Blocked

change
DMSO Present
Montalescot, Sheep PAP increased Increased TXA2 receptor Blocked BT no

1990 (92) change
CO, SV no
change
Degges, Pigs PAP increased Increased Diphenhydramine Present Not studied

1987 (96)
Cromolyn sodium Present
ASA Blocked
Schumacher, Pigs PAP, PVR TX receptor Blocked Not studied

1988 (95) increased
Conzen, Pigs PAP, PVR Increased TX receptor Blocked Not studied

1989 (94) increased
MABP Indomethacin Blocked

decreased
HR no change
Nuttall, 1991 Pigs PAP increased Increased TXA2 receptor Decreased BT

(93) (given 2 min after duration increased in
protamine) 50%, platelet
aggregation
inhibited
TX, thromboxane; PAP, pulmonary artery pressure; PVR, pulmonary vascular resistance; PW, pulmonary capillary
wedge pressure; SVR, systemic vascular resistance; SV, stroke volume; CO, cardiac output; MABP, mean arterial
blood pressure; HR, heart rate; BP, blood pressure; ASA, aspirin (acetylsalicylic acid); BT, bleeding time; DMTU,
dimethylthiourea; DMSO, dimethylsulfoxide; TXA2, thromboxane A2.
Some thromboxane receptor antagonists are known to inhibit platelet aggregation to collagen and arachidonic acid
stimulation and cause a brief prolongation of bleeding times (93,97), whereas other antagonists cause no increase in
bleeding times, even at the highest dosages used (92). Nuttall et al. (93) showed that thromboxane A2 receptor blockade
initiated 2 minutes after protamine administration shortened the duration of the pulmonary hypertensive response in pigs
despite similar elevations in pulmonary artery pressures and plasma thromboxane B2 levels (Fig. 20.12).
Although thromboxane release appears to be a central factor in pulmonary vasoconstriction induced by heparin-protamine,
the source of thromboxane is unclear. A blood source seems doubtful, as the reaction can be produced in isolated lungs
perfused with acellular media (94) and in platelet-depleted animals (98). Endothelial cells or pulmonary intravascular
macrophages (PIMs) may be the source of the thromboxane.
It has been speculated that PIMs may be the source of the thromboxane generated in pulmonary vasoconstrictive reactions
(99). These lung macrophages have been described in sheep (100) and pigs (101) and occur less commonly in rats
(102,103) and dogs (104). They are five times more numerous than neutrophils in sheep lung (105) and occupy 15% of
intracapillary volume (98). These macrophages respond to the infusion of various foreign particles by releasing vasoactive
eicosanoids, particularly thromboxane (106). Infusion of radioactively labeled protamine into rats and sheep showed uptake
primarily by the lungs in sheep with rapid development of pulmonary vasoconstriction, in comparison with uptake primarily
by the liver in rats. On the basis of these data, it has been hypothesized that the uptake of heparin-protamine
P.510
complexes by PIMs causes the release of mediators, namely thromboxane, with resultant pulmonary vasoconstriction.
Humans have a lesser population of these macrophages than do sheep, which may partially explain the variable
development of this syndrome in humans (97).
FIGURE 20.11. Effect of bolus injection of protamine (arrow) on mean pulmonary arterial pressure (Ppa), pulmonary
capillary wedge pressure (Pw), and pulmonary vascular resistance (PVR) in the six treatment groups. Heparinized controls,
n = 4; unheparinized controls (no heparin), n = 10 (except for times +1 and +2 minutes for PVR values, where n = 6 and n =
7, respectively); indomethacin-pretreated heparinized sheep, n = 3; UK 38-485-pretreated heparinized sheep, n = 5;
DMSO-pretreated heparinized sheep, n = 4; DMTU-pretreated heparinized sheep, n = 6. Values are the mean ± standard
error of the mean. *p = 0.05 value differs from before protamine injection. DMSO, dimethylsulfoxide hydroxide scavenger;
DMTU, dimethylthiourea hydrogen peroxide scavenger; UK 38-485, thromboxane synthetase inhibitor. (From Morel DR,
Lowenstein E, Nguyenduy T, et al. Acute pulmonary vasoconstriction and thromboxane release during protamine reversal
of heparin anticoagulation in awake sheep. Circ Res 1988;62:905-915, with permission.)
Platelet-depleted sheep still exhibit increased thromboxane B2 levels, increased pulmonary vascular resistance, and
leukopenia when protamine is administered after heparin (96). These studies suggest that platelets do not cause this
adverse response.
Rate of Administration
Morel et al. (107) determined the rate of protamine administration to be an important factor leading to pulmonary
vasoconstriction in sheep. In their study, sheep given protamine during 3 seconds consistently demonstrated thromboxane
release, pulmonary vasoconstriction, increased pulmonary artery pressure, increased systemic vascular resistance, and
decreased cardiac output, whereas those given protamine over 30 minutes exhibited no change. The intermediate infusion
rates were associated with variable and attenuated reactions.
Site of Administration
The site of protamine administration has been considered and studied as a triggering factor for protamine reactions. Canine
studies (72,108) suggest that detrimental vasoactive substances are released on exposure of the pulmonary vasculature to
protamine. Giving the drug on the left side of the circulation or through a peripheral vein with subsequent dilution was
hypothesized to limit the first-pass pulmonary exposure. Casthely et al. (108) confirmed this hypothesis in a canine model in
which protamine delivered during 4 minutes through a peripheral vein or the left atrium proved benign, whereas delivery
through central venous injection decreased systemic blood pressure and systemic vascular resistance and increased
pulmonary vascular resistance and pulmonary artery pressure. These results were not confirmed by others (109,110).
Frater et al. (110) demonstrated decreased systolic blood pressure and increased plasma histamine levels in patients given
protamine through the right atrium, changes that were not observed when protamine was administered through the left
atrium. However, most human studies to date have not demonstrated any advantage to left-sided versus right-sided
protamine administration (111,112). The rate of infusion, and not the infusion site, appears to be the more important
variable to control. Lastly, because of the risk for air embolization when a left atrial or aortic route is used, protamine is
probably best administered on the right side of the circulation.
P.511
FIGURE 20.12. The increase in mean pulmonary vascular resistance (PVR) and mean pulmonary arterial pressure (PAP)
after protamine administration at time t = 0 for control and antagonist-treated pigs. The thromboxane receptor antagonist (L-
670596) was administered 2 minutes after protamine administration. Data plotted as mean ± standard error of the mean. At
lower PAP and PVR, error bars are hidden by figure points. *p ≤ 0.05, compared to time 0. (From Nuttall GA, Murray MJ,
Bowie JW. Protamine-heparin-induced pulmonary hypertension in pigs; effects of treatment with a thromboxane receptor
antagonist on hemodynamics and coagulation. Anesthesiology 1991;74:1-145, with permission.)
Summary of Pulmonary Vasoconstrictive Reactions

In summary, pulmonary vasoconstrictive protamine reactions in certain animal models result from uptake or activation in the
lung, perhaps by PIMs, of the heparin-protamine complex. This interaction causes nonimmunologic activation of the classic
complement pathway with increased levels of C3a and C5a, which can release vasoconstrictor substances, most
importantly thromboxane. The question of whether complement activation is merely associated with the formation of
heparin-protamine complexes or is a prerequisite for thromboxane generation remains unsettled. Leukocytes do not appear
to play a crucial role, as evidenced by the work with acellular perfusates. Histamine and platelets also do not appear to be
involved. Certain drugs can block the development of this syndrome at various points of the reaction, but because of
interference with coagulation or other problems, these agents are not yet feasible for clinical use after CPB.
Patients in whom pulmonary vasoconstriction and bronchoconstriction developed following protamine administration at the
conclusion of CPB had markedly elevated levels of plasma thromboxane B2 and C5a in comparison with control patients in
whom adverse responses to protamine administration did not develop. The time of peak thromboxane B2 levels
corresponded to the maximum pulmonary artery pressures. These data suggest that the activation of complement fraction
C5a is associated with thromboxane generation. Consistent with the animal model, the same authors also documented that
leukopenia and increased C3a and C4a plasma concentrations were universal after protamine administration, although only
patients in whom pulmonary vasoconstrictive reactions developed had elevated concentrations of thromboxane and C5a
(113).
One difference between the animal and human studies has been that catastrophic pulmonary vasoconstriction is
demonstrated consistently in animal models, whereas the incidence in humans is relatively low (1%-2%). This fact suggests
that different factors may play a role in humans. Hobbhahn et al. (114) examined the effects of protamine neutralization of
heparin in 14 noncardiac surgical patients undergoing transurethral surgery. Nine of these 14 (64%) patients responded
with increases in mean pulmonary artery pressures, mean arterial pressure, pulmonary vascular resistance, and increased
thromboxane B2 and C3a levels. This work confirms the relevance of the animal model to the human reaction.
Diagnosis
Diagnosis of the type of protamine reaction in a patient experiencing one is based on the clinical hemodynamic
presentation, the mediators that are present, and the presence or absence of specific IgE or IgG antibodies. Screening
for antibodies in insulin-dependent diabetics may be a way to identify patients at risk for anaphylaxis to protamine.
Skin testing is available but requires a strict protocol to yield reproducible results, is unreliable in diabetic patients, and
can cause an adverse systemic response when an antigen is reintroduced (115). Additionally, the absence of a
positive skin test reaction does not ensure the lack of an IgE-mediated protamine reaction. The leukocyte histamine
response is an in vitro test that has been used to detect protamine allergy in NPH insulin-dependent diabetic patients
and protect them from adverse reactions (74). A positive response to this standard technique in in vitro allergy study
indicates specific IgE antibodies (116). However, little evidence supports the usefulness of this test in screening
patients at risk for adverse protamine reactions. Serum levels of IgG or complement can be measured but are
nonspecific indicators of a potential allergic reaction. They are also difficult to interpret post hoc because of
consumption during the reaction and dilution by volume therapy during an adverse reaction (111).
Prevention and Therapy

Prevention of the heparin-protamine reaction would be the best strategy. Until a reliable screening test for antiprotamine
antibodies becomes available, a history of a proven anaphylactic reaction can be helpful. Protamine should be administered
P.512
slowly. The protamine package insert suggests that infusion should not be faster than 5 mg/min, although in practice, a rate
of 15 mg/min seems to be well tolerated. Administration should be terminated at the first sign of any adverse reaction. It is
difficult to strictly define a safe upper limit for the rate of protamine administration, because some patients tolerate
administration rates as high as 50 mg/min with only mild vasodilatory responses, whereas others may experience profound
hypotension at rates as low as 5 to 10 mg/min. Pharmacologic release reactions are rate-dependent, so that slow
administration prevents them. Protamine anaphylaxis is treated like any classic anaphylactic reaction with oxygen, fluids,
and epinephrine/norepinephrine. Excessive protamine doses should be avoided because protamine has been shown to
inhibit the enzyme responsible for the inactivation of anaphylatoxins and kinins, as mentioned earlier in this chapter. Also,
because protamine does not inhibit angiotensin I, which can also break down these compounds, patients on angiotensin-
converting enzyme inhibitors may be at some increased risk for pulmonary hypertensive reactions to protamine (85).
Prophylactic histamine 1 and histamine 2 blockers and corticosteroids have not been shown to reduce the incidence of
pulmonary vasoconstrictor reactions. Histamine blockers are known to decrease the severity of hypotension with rapid
protamine administration (77), which suggests the potential for benefit in IgE-mediated reactions as well, but there is no
evidence to support their routine use for this purpose. Therefore, we do not recommend routine prophylaxis with histamine
blockers.
Various supportive strategies have been used to treat acute pulmonary vasoconstriction and hypotension, including such
pulmonary vasodilators as nitroglycerin and isoproterenol and virtually all vasoactive/inotropic drugs. The comparative
efficacy of different regimens for these short-lived reactions has not been documented. Reinstitution of CPB may be
required. It is crucial to heparinize effectively before the reinstitution of bypass to avoid gross clotting and the
consumption of components of coagulation, which can lead to disseminated intravascular coagulation. Case reports
suggest that the reinstitution of bypass with heparin administration causes the reaction to abate (117); however, it is likely
that this represents merely the conclusion of a transient reaction.
Inhaled nitric oxide has recently been reported as a therapy for the pulmonary vasoconstrictor reactions induced by
heparin-protamine complexes in lambs (118). Nitric oxide selectively produces profound relaxation of the pulmonary
vascular smooth muscle without systemic vasodilation. In this animal model, breathing nitric oxide at 180 parts per million
has been shown to attenuate the pulmonary vasoconstrictor response markedly following heparin neutralization by
protamine. Nitric oxide is short-lived, easily administered, and effective for treating certain types of reversible pulmonary
hypertension. There are recent case reports of the use of inhaled nitric oxide to treat protamine-induced pulmonary
vasoconstriction in patients.
The initial pulmonary vasoconstrictive episode usually abates after a few minutes (3). Once this occurs, continued inotropic
infusion can result in a hyperdynamic heart, so these agents may then need to be withdrawn. Protamine administration may
be reinstituted at a rate of 5 mg/min following resolution of the episode and after resumption of hemodynamic stability.
However, recent studies have shown that even though these protamine reactions are usually transient, patients that
experience any type hemodynamic disruption as a result of protamine administration have an increased mortality risk
(119,120). Therefore, strategies that avoid or attenuate these reactions should be a top priority.
FUTURE MANAGEMENT
To date, there is no well-proven substitute for heparin anticoagulation and its reversal with protamine for the management
of CPB. Research is ongoing in areas such as total elimination of systemic heparinization through the use of heparin-
bonded bypass circuitry (121). Heparin alternatives such as bivalirudin are available and used in specific patients where
heparin is contraindicated, although they have no reversal agent. Research into the reversal of heparin by PF4 and by
heparinase, agents which showed considerable initial promise, has slowed because of various combinations of efficacy
limitations, side effects, high projected cost-to-benefit ratio, and funding insufficiency for further studies. However, research
in other protamine alternatives such as LMWPs and engineered virus-like nanoparticles continues (122).
KEY Points
Protamine, a strongly alkaline polycationic protein, attracts the polyanionic heparin sufficiently to separate it from its
binding site on ATIII and reverse its anticoagulant effect.
Inhibition of plasma coagulation and platelet function is one of the side effects of protamine, so it appears prudent
to avoid administering protamine doses beyond the amount needed to neutralize heparin.
Methods for calculating the protamine dose include the following:
Use a fixed ratio of protamine to the total or initial dose of heparin.
Use the heparin-ACT dose-response to determine the amount of circulating heparin, and then assume a
protamine-to-heparin neutralization ratio of approximately 1.1-1.3 mg to 100 units of heparin.
Measure whole-blood- or plasma-heparin concentration, assume a protamine-to-heparin neutralization ratio, and
estimate blood or plasma volume.
None of these approaches has shown clear superiority over the others, other than the general concept that using
the minimum dose necessary to neutralize heparin has reduced post-CPB bleeding in most comparisons.
P.513
A variety of methods exist for methods 2 and 3, some of which are automated (Hepcon system). Each method has
advantages and disadvantages, and there is no widely accepted “gold standard” for calculating the protamine dose.
Aside from commercially available protamine, other possible approaches to heparin neutralization include the
administration of PF4, heparinase, or protamine variants (“designer protamine”), and the use of heparin-removal
devices. Although some of these alternative methods are under investigation, none are currently available for
routine use.
Protamine reactions can be classified as pharmacologic histamine release, true anaphylaxis, and anaphylactoid
reactions.
Pharmacologic histamine release is principally related to overly rapid administration of protamine and can result
in vasodilation and possibly myocardial depression.
True anaphylaxis requires previous exposure to protamine, which has been conclusively demonstrated only in
diabetic patients taking intermediate-duration insulin preparations that contain protamine. Even in this group of
patients, the incidence of anaphylaxis after protamine administration is low (<3% in most studies).
The interaction of protamine with heparin activates complement, which has been associated with the release of
thromboxane A2. Thromboxane A2 (in sufficient amounts) causes intense pulmonary vasoconstriction. Factors
predisposing some patients to the development of this rare, life-threatening reaction, which is predictable in some
animal species, remain ill-defined.
The treatment of protamine reactions is largely supportive. It is possible that inhaled nitric oxide can rapidly and
effectively terminate a life-threatening pulmonary hypertensive response.
REFERENCES
1. Hunt AJ, Gray GS, Myers JA, et al. Heparin neutralization by recombinant human PF4 in vitro [abstract]. FASEB J
1990;4:A1991.
2. Carr JA, Silverman N. The heparin-protamine interaction. A review. J Cardiovasc Surg 1999;40:659-666.
3. Taylor S, Folkman J. Protamine as an inhibitor of angiogenesis. Nature 1982;297:307-312.
4. Wright JE. Clinical trial of protamine in the treatment of malignant diseases. Br J Cancer 1968;22:415-421.
5. Chargaff E, Olson KB. Studies on the chemistry of blood coagulation. J Biol Chem 1937;122:153-167.
6. Mochizuki T, Olson PJ, Szlam F, et al. Protamine reversal of heparin affects platelet aggregation and activated
clotting time after cardiopulmonary bypass. Anesth Analg 1998;87:781-785.
7. Chu AJ, Wang ZG, Raicu M, et al. Protamine inhibits tissue factor-initiated extrinsic coagulation. Br J Haematol
2001;115:392-399.
8. Ammar T, Fisher CF. The effects of heparinase 1 and protamine on platelet reactivity. Anesthesiology 1997;86:1382-
1386.
9. Kresowik TF, Wakefield TW, Fessler RD, et al. Anticoagulant effects of protamine sulfate in the canine model. J Surg
Res 1988;45:8-14.
10. Eslin DE, Zhang C, Samuels KJ, et al. Transgenic mice studies demonstrate a role for platelet factor 4 inthrombosis:
dissociation between anticoagulant and antithrombotic effect of heparin. Blood 2004;104:3173-180.
11. Nielsen VG. Protamine enhances fibrinolysis by decreasing clot strength: role of tissue factor-initiated thrombin
generation. Ann Thorac Surg 2006;81:1720-1727.
12. Brecher AS, Roland AR. Protamine inhibits formation of the covalent factor IXa-antithrombin complex. Blood Coagul
Fibrinolysis 2008;19:591-596.
13. Ainle FN, Preston RJ, Jenkins PV, et al. Protamine sulfate down-regulates thrombin generation by inhibiting factor V
activation. Blood 2009;114:1658-1665.
14. Bollinger D, Szlam F, Azran M, et al. The anticoagulant effect of protamine sulfate is attenuated in the presence of
platelets or elevated factor VIII concentrations. Anesth Analg 2010;111(3):601-608.
15. Inagaki M, Goto K, Katayama H, et al. Activated partial thromboplastin time-protamine dose in the presence and
absence of heparin. J Cardiothorac Anesth 1989;3:734-736.
16. Koster A, Borgermann J, Gummert J, et al. Protamine overdose and its impact on coagulation, bleeding, and
transfusions after cardiopulmonary bypass: results of a randomized double-blind controlled pilot study. Clin Appl
Thromb Hemost 2014;20(3):290-295.
17. Perkins HA, Osborn JJ, Hurt R, et al. Neutralization of heparin in vivo with protamine: a simple method of estimating
the required dose. J Lab Clin Med 1956;48:223-226.
18. McLaughlin KE, Dunning J. In patients post-cardiac surgery, do high doses of protamine cause increased bleeding?
Interact Cardiovasc Thorac Surg 2003;2:424-426.
19. Ellison N, Edmunds LH, Colman RW. Platelet aggregation following heparin and protamine administration.
20. Mammen EF, Koets MH, Washington BC, et al. Hemostasis changes during cardiopulmonary bypass surgery.
Semin Thromb Hemost 1985;11:281-292.
21. Guffin AV, Dunbar RW, Kaplan JA, et al. Successful use of a reduced dose of protamine after cardiopulmonary
bypass. Anesth Analg 1976;55:110-113.
22. Dutton DA, Hothersall AP, McLaren AD, et al. Protamine titration after cardiopulmonary bypass. Anesthesiology
1983;38:264-268.
23. Bull BS, Korpman RA, Huse WM, et al. Heparin therapy during extracorporeal circulation. I. Problems inherent in
existing heparin protocols. J Thorac Cardiovasc Surg 1975;69:674-684.
24. Hurt R, Perkins HA, Osborn JJ, et al. The neutralization of heparin by protamine in extracorporeal circulation. J
Thorac Surg 1956;32:612-619.
25. Hattersley PG. Activated coagulation time of whole blood. JAMA 1966;196:150-154.
26. Akl BF, Vargas GM, Neal J, et al. Clinical experience with the activated clotting time for the control of heparin and
protamine therapy during cardiopulmonary bypass. J Thorac Cardiovasc Surg 1980;79:97-102.
27. Bull BS, Huse WM, Brauer FS, et al. Heparin therapy during extracorporeal circulation. II. The use of a dose-
response curve to individualize heparin and protamine dosage. J Thorac Cardiovasc Surg 1975;69:685-689.
28. Ellison N, Beatty CP, Blake DR, et al. Heparin rebound, studies in patients and volunteers. J Thorac Cardiovasc
Surg 1974;67:723-729.
29. Culliford AT, Gitel SN, Starr N, et al. Lack of correlation between activated clotting time and plasma heparin during
cardiopulmonary bypass. Ann Surg 1981;193:105-111.
30. Yin ET, Wessler S, Butler JV. Plasma heparin: a unique, practical, submicrogram-sensitive assay. J Lab Clin Med
1973;81:298-310.
31. Allen JG, Moulder PV, Elghammer RM, et al. A protamine titration as an indication of a clotting defect in certain
hemorrhagic states. J Lab Clin Med 1949;34:473-476.
32. Hawksley M. De-heparinisation of blood after cardiopulmonary bypass. Lancet 1966;1:563-565.
33. Murray DJ, Brosnahan WJ, Pennell B, et al. Heparin detection by the activated coagulation time: a comparison of
the sensitivity of coagulation tests and heparin assays. J Cardiothorac Vasc Anesth 1997;11:24-28.
34. Shigeta O, Kojima H, Hiramatsu Y, et al. Low-dose protamine based on heparin-protamine titration method reduces
platelet dysfunction after cardiopulmonary bypass. J Thorac Cardiovasc Surg 1999;118:354-360.
35. Despotis GJ, Joist JH, Hogue CW Jr, et al. The impact of heparin concentration and activated clotting time
monitoring on blood conservation. A prospective, randomized evaluation in patients undergoing cardiac operation. J
P.514
36. Beholz S, Grubitzsch H, Bergmann B, et al. Haemostatis management by use of the Hepcon HMS: increased
bleeding without increased need for blood transfusion. Thorac Cardiovasc Surg 1999;47:322-327.
37. Koster A, Fischer T, Praus M, et al. Hemostatic activation and inflammatory response during cardiopulmonary
bypass: impact of heparin management. Anesthesiology 2002;97:837-841.
38. Shore-Lesserson L, Reich DL, DePerio M. Heparin and protamine titration do not improve hemostasis in cardiac
surgical patients. Can J Anaesth 1998;45:10-18.
39. Dunning J, Versteegh M, Fabbri A, et al. Guideline on antiplatelet and anticoagulation management in cardiac
40. Noui N, Zogheib E, Walczak K, et al. Anticoagulation monitoring during extracorporeal circulation with the
Hepcon/HMS device. Perfusion 2012;27:214-220.
41. Kanbak M, Kahraman S, Celebioglu B, et al. Prophylactic administration of histamine 1 and/or histamine 2 receptor
blockers in the prevention of heparin-and protamine-related hemodynamic effects. Anaesth Intensive Care
1996;15:559-563.
42. Cook JJ, Niewiarowski S, Yan Z, et al. Platelet factor 4 efficiently reverses heparin anticoagulation in the rat without
the adverse effects of heparin-protamine complexes. Circulation 1992;85:1102-1109.
43. Walker WS, Reid KG, Hider CF, et al. Successful cardiopulmonary bypass in diabetics with anaphylactoid reactions
to protamine. Br Heart J 1984;52:112-114.
44. Cook JJ, Schaffer LH, Niewiarowski S, et al. Heparin neutralization by protamine and platelet factor 4 in the rat
[abstract]. FASEB J 1990;4:A1234.
45. Dehmer GJ, Lange RA, Tate DA, et al. Randomized trial of recombinant platelet factor 4 versus protamine for the
reversal of heparin anticoagulation in humans. Circulation 1996;94(9, Suppl):II347-II352.
46. Kurrek M, Winkler M, Robinson DR, et al. Platelet factor 4 injection produces acute pulmonary hypertension in the
awake lamb. Anesthesiology 1995;82:183-188.
47. Bernabei A, Gikakis N, Maione TE, et al. Reversal of heparin anticoagulation by recombinant platelet factor 4 and
protamine sulfate in baboons during cardiopulmonary bypass. J Thorac Cardiovasc Surg 1995;109:765-771.
48. Mixon TA, Dehmer GJ. Recombinant platelet factor 4 for heparin neutralization. Semin Thromb Hemost
2004;30(3):369-377.
49. Demma L, Levy J. A case series of recombinant platelet factor 4 for heparin reversal after cardiopulmonary bypass.
Anesth Analg 2012;115:1273-1278.
50. Wakefield TW, Andrews PC, Wrobleski SK, et al. Effective and less toxic reversal of low-molecular-weight heparin
anticoagulation by a designer variant of protamine. J Vasc Surg 1995;21:839-849.
51. Wakefield TW, Andrews PC, Wrobleski SK, et al. A [+ 18RGD] protamine variant for nontoxic and effective reversal
of conventional heparin and low-molecular-weight heparin anticoagulation. J Surg Res 1996;63:280-286.
52. Okajima Y, Kanayama S, Maeda Y, et al. Studies on the neutralizing mechanism of anti-thrombin activity of
protamine. Thromb Res 1981;24:21-29.
53. Sela M. Antigenicity: some molecular aspects. Science 1969;166:1365-1374.
54. Byun Y, Singh VK, Yang VC. Low molecular weight protamine: a potential nontoxic heparin antagonist. Thromb Res
1999;94:53-61.
55. Michelson LG, Kikura M, Levy JH, et al. Heparinase I (neutralase) reversal of systemic anticoagulation.
56. Heres EK, Horrow JC, Gravlee GP, et al. A dose-determining trial of heparinase-I for heparin neutralization in
coronary artery surgery. Anesth Analg 2001;93(6):1446-1452.
57. Stafford-Smith M, Lefrak EA, Qazi AG, et al; Members of the Global Perioperative Research Organization. Efficacy
and safety of heparinase I versus protamine in patients undergoing coronary artery bypass grafting with and without
58. Yang VC, Port FK, Kim JS, et al. The use of immobilized protamine in removing heparin and preventing protamine-
induced complications during extracorporeal blood circulation. Anesthesiology 1991;75:288-297.
59. Hendrikx M, Leuvens V, Vandezarde E, et al. The use of heparin removal devices: a valid alternative to protamine.
Int J Artif Organs 1997;20:166-174.
60. Zwischenberger J, Weike T, Deyo D, et al. Safety and efficacy of a heparin removal device: a prospective
randomized preclinical outcomes study. Ann Thorac Surg 2001;71:270-277.
61. Lowenstein E, Johnston WE, Lappas DG, et al. Catastrophic pulmonary vasoconstriction associated with protamine
reversal of heparin. Anesthesiology 1983;59:470-473.
62. Levy JH, Schwieger IM, Zaidan JR, et al. Evaluation of patients at risk for protamine reactions. J Thorac Cardiovasc
Surg 1989;98:200-220.
63. Comunale ME, Haering JM, Robertson LK, et al. Aspirin prevents protamine-induced pulmonary hypertension.
Anesth Analg 1997;84:S66.
64. Schapira M, Christman BW. Neutralization of heparin by protamine, time for a change? Circulation 1990;82:1887-
1879.
65. Horrow JC. Protamine allergy. J Cardiothorac Anesth 1988;2:225-252.

66. Rosow CE, Moss J, Philbin DM, et al. Histamine release during morphine and fentanyl anesthesia. Anesthesiology
1982;56:93-96.
67. Keller R. Interrelation between different types of cells. II. Histamine release for the mast cells of various species by
cationic polypeptides of polymorphonuclear leukocytes, lysosomes and other cationic compounds. Int Arch Allergy Appl
Immunol 1968;34:139-144.
68. Stoelting RK, Henry DP, Verbur KM, et al. Haemodynamic changes and circulating histamine concentrations
following protamine administration to patients and dogs. Can Anaesth Soc J 1984;31:534-540.
69. Parsons RS, Mohandas K. The effect of histamine-receptor blockade on the hemodynamic responses to protamine.
J Cardiothorac Anesth 1989;3:37-43.
70. Shapira N, Schaff HV, Piehler JM, et al. Cardiovascular effects of protamine sulfate in man. J Thorac Cardiovasc
Surg 1982;84:505-514.
71. Sethna D, Gray R, Bussell J, et al. Further studies on the myocardial metabolic effect of protamine sulfate following
72. Goldman BS, Joison J, Austen WG. Cardiovascular effects of protamine sulfate. Ann Thorac Surg 1969;7:459-471.
73. Michaels IAL, Barash PG. Hemodynamic changes during protamine administration. Anesth Analg 1983;62:831-835.
74. Sethna DH, Moffitt E, Gray RJ, et al. Effects of protamine sulfate on myocardial oxygen supply and demand in
patients following cardiopulmonary bypass. Anesth Analg 1982;61:157-251.
75. Sharath MD, Metzger WJ, Richerson HB, et al. Protamine-induced fatal anaphylaxis, prevalence of antiprotamine
immunoglobin E antibody. J Thorac Cardiovasc Surg 1985;90:86-90.
76. Levy JH, Zaidan JR, Faraj B. Prospective evaluation of risk of protamine reactions in patients with NPH insulin-
dependent diabetes. Anesth Analg 1986;65:739-742.
77. Weiss ME, Nyhan D, Peng Z, et al. Association of protamine IgE and IgG antibodies with life-threatening reactions
to intravenous protamine. N Engl J Med 1989;320:886-892.
78. Knape JTA, Schuller JL, De Haan P, et al. An anaphylactic reaction to protamine in a patient allergic to fish.
79. Caplan SN, Berkman EM. Protamine sulfate and fish allergy [Letter]. N Engl J Med 1976;295:172.
80. Samuel T, Kolk AHJ, Rumke P, et al. Auto-immunity to sperm antigens in vasectomized men. Clin Exp Immunol
1975;21:65-74.
81. Samuel T, Kolk A. Auto-antigenicity of human protamines. In: Lepow IH, Crozier R, eds. Vasectomy: immunological
and pathophysiologic effect in animal and man. New York, NY: Academic Press, 1979:203-220.
82. Best N, Teisner B, Grudzinkas JG, et al. Classical pathway activation during an adverse response to protamine
sulfate. Br J Anaesth 1983;55:1149-1153.
83. Rent R, Ertel N, Eisenstein R, et al. Complement activation by interaction of polyanions and polycations. I. Heparin-
protamine induced consumption of complement. J Immunol 1975;114:120-115.
84. Kirklin JK, Chenoweth DE, Naftel DC, et al. Effects of protamine administration after cardiopulmonary bypass on
complement, blood elements, and the hemodynamic state. Ann Thorac Surg 1986;41:193-199.
85. Cavarocchi NC, Schaff HV, Orszulak TA, et al. Evidence for complement activation by protamine-heparin interaction
after cardiopulmonary bypass. Surgery 1985;98:525-530.
86. Grant JA, Dupree E, Goldman AS, et al. Complement-mediated release of histamine from human leukocytes. J
Immunol 1975;114:1101-1106.
87. Tan F, Jackman H, Skidgel RA, et al. Protamine inhibits plasma carboxypeptidase N, the inactivator of
anaphylatoxins and kinins. Anesthesiology 1989;70:267-275.
88. Stewart WJ, McSweeney SM, Kellett MA, et al. Increased risk of severe protamine reactions in NPH insulin-
dependent diabetics undergoing cardiac catheterization. Circulation 1984;5:788-792.
89. Lakin JD, Blocker TJ, Strong DM, et al. Anaphylaxis to protamine sulfate mediated by a complement-dependent IgG
antibody. J Allergy Clin Immunol 1978;61:102-107.
90. Lowenstein E. Lessons from studying an infrequent event: adverse hemodynamic responses associated with
protamine reversal of heparin anticoagulation. J Cardiothorac Anesth 1989;3:99-107.
91. Morel DR, Lowenstein E, Nguyenduy T, et al. Acute pulmonary vasoconstriction and thromboxane release during
protamine reversal of heparin anticoagulation in awake sheep. Circ Res 1988;62:905-915.
P.515
92. Montalescot G, Lowenstein E, Ogletree ML, et al. Thromboxane receptor blockade prevents pulmonary
hypertension induced by heparin-protamine reactions in awake sheep. Circulation 1990;82:1765-1777.
93. Nuttall GA, Murray MJ, Bowie JW. Protamine-heparin-induced pulmonary hypertension in pigs: effects of treatment
with a thromboxane receptor antagonist on hemodynamics and coagulation. Anesthesiology 1991;74:1-145.
94. Conzen PF, Habazettl H, Gutman R, et al. Thromboxane mediation of pulmonary hemodynamic responses after
neutralization of heparin by protamine in pigs. Anesth Analg 1989;68:25-31.
95. Schumacher WA, Heran CL, Ogletree ML. Effect of thromboxane receptor antagonism on pulmonary hypertension
caused by protamine-heparin interaction in pigs. Circulation 1988;78(Suppl):II-207.
96. Degges RD, Foster ME, Dang AQ, et al. Pulmonary hypertensive effect of heparin and protamine interaction:
evidence for thromboxane B2 release from the lung. Am J Surg 1987;154:696-699.
97. Friedhoff LT, Manning J, Funke PT, et al. Quantitation of drug levels and platelet receptor blockade caused by a
thromboxane antagonist. Clin Pharmacol Ther 1986;40:634-642.
98. Montalescot G, Kreil E, Lynch K, et al. Effect of platelet depletion on lung vasoconstriction in heparin-protamine
reactions. J Appl Physiol 1989;66:2344-2350.
99. Kreil E, Montalescot G, Robinson DR, et al. Adverse heparin-protamine neutralization interactions and the lung. In:
Zapol WM, Lemarie F, eds. Adult respiratory distress syndrome. New York, NY: Marcel Dekker Inc, 1991:451-490.
100. Warner AE, Barry BE, Brain JD. Pulmonary intravascular macrophages in sheep: morphology and function of a
novel constituent of the mononuclear phagocyte system. Lab Invest 1986;55:276-288.
101. Bertram TA, Overby LH, Danilowicz R, et al. Pulmonary intravascular macrophages metabolize arachidonic acid in
vitro. Am Rev Respir Dis 1988;1:936-944.
102. Warner AE, DeCamp MM, Molina RM, et al. Pulmonary removal of circulating endotoxin results in acute lung injury
in sheep. Lab Invest 1988;59:219-230.
103. Warner A, Molina A, Brain JD. Uptake of blood-borne bacteria by pulmonary intravascular macrophages and
consequent inflammatory responses in sheep. Am Rev Respir Dis 1987;136:683-690.
104. Crocker SH, Eddy DO, Obenauf RN, et al. Bacteremia: host-specific lung clearance and pulmonary failure. J
Trauma 1981;21:215-220.
105. Albertine KH, Decker SA, Schultz EL, et al. Clearance of monastral blue by intravascular macrophages in
pulmonary microvessels of sheep, goat, and pig [abstract]. Anat Rec 1987;218:6A.
106. Bertram TA, Thigpen J, Eling TE, et al. Bacterial phagocytosis and consequent arachidonic acid metabolism by
pulmonary intravascular and alveolar macrophages in vitro. Am Rev Respir Dis 1989;139:A159.
107. Morel DR, Costabella PM, Pittet JF. Adverse cardiopulmonary effects and increased thromboxane concentrations
following the neutralization of heparin with protamine in awake sheep are infusion rate-dependent. Anesthesiology
1990;73:415-424.
108. Casthely PA, Goodman K, Fryman PN, et al. Hemodynamic changes after the administration of protamine. Anesth
Analg 1986;65:78-80.
109. Taylor RL, Little WC, Freeman GL, et al. Comparison of the cardiovascular effects of intravenous and intraaortic
protamine in the conscious and anesthetized dog. Ann Thorac Surg 1986;42:22-26.
110. Frater RWM, Oka Y, Hong Y, et al. Protamine-induced circulatory changes. J Thorac Cardiovasc Surg
1984;87:687-692.
111. Milne B, Rogers K, Cervenko F, et al. The hemodynamic effects of intaaortic versus intravenous administration of
protamine for reversal of heparin in man. Can Anaesth Soc J 1983;30:347-351.
112. Cherry DA, Chiu CJ, Wynands JE, et al. Intraaortic vs. intravenous administration of protamine: a prospective
randomized clinical study. Surg Forum 1985;36:2-250.
113. Morel DR, Zapol WM, Thomas SJ, et al. C5a and thromboxane generation associated with pulmonary vaso-and
bronchoconstriction during protamine reversal of heparin. Anesthesiology 1987;66:597-604.
114. Hobbhahn J, Conzen P, Habazettl H, et al. Heparin reversal by protamine in humans—complement,

prostaglandins, leukocytes, platelets, and hemodynamics. J Appl Physiol 1991;71:1415-1421.
115. Fisher M. Intradermal testing after anaphylactoid reaction to anaesthetic drugs: practical aspects of performance
and interpretation. Anaesth Intensive Care 1984;12:115-120.
116. May CD, Lyman M, Alberto R, et al. Procedures for immunochemical study of histamine release from leukocytes
with small volumes of blood. J Allergy 1970;46:12-20.
117. Loch R, Hessel EA. Probable reversal of protamine reactions by heparin administration. J Cardiothorac Anesth
1990;4:604-608.
118. Fratacci MD, Frostell CG, Chen TY, et al. Inhaled nitric oxide. A selective pulmonary vasodilator of heparin
protamine vasoconstriction in sheep. Anesthesiology 1991;75:990-999.
119. Welsby I, Newman M, Phillips-Bute B, et al. Hemodynamic changes after protamine administration: Association
with mortality after coronary artery bypass surgery. Anesthesiology 2005;102:308-314.
120. Kimmel S, Sekeres M, Berlin J, et al. Mortality and adverse events after protamine administration in patients
undergoing cardiopulmonary bypass. Anesth Analg 2002;94:1402-1408.
121. Von Segesser LK, Turina M. Cardiopulmonary bypass without systemic heparinization. J Thorac Cardiovasc Surg
1989;98:6-396.
122. Gale A, Elias D, Averell P, et al. Engineered virus-like nanoparticles reverse heparin anticoagulation more
consistently than protamine in plasma from heparin-treated patients. Thromb Res 2011;128(4):9-13.
Chapter 21
Pharmacologic Prophylaxis for Post-cardiopulmonary Bypass
Bleeding
Niamh A. McAuliffe
Deepak Hanumanthaiah
C. David Mazer
INTRODUCTION
Blood transfusion in cardiac surgery patients has warranted and generated much investigation and discussion.
Significant perioperative blood loss requiring transfusion of blood products has been associated with increased
morbidity and mortality in cardiac surgery (1). In the quest for reducing the inherent risks and significant costs of
transfusion, many aspects of the perioperative course have been examined. Factors which contribute to the
requirement for blood transfusion in the perioperative period include preoperative antiplatelet medication, the
nature of the surgery, hemolysis by extracorporeal circuits, hemodilution, and heparin use. Up to 50% of patients
undergoing cardiac procedures receive no blood transfusion (2). However, there is a subset of “high risk”
patients who require substantial perioperative blood transfusion. One review suggested an overall blood
transfusion rate of 57% in patients with a packed red blood cell (RBC) transfusion rate of 49% and a non-RBC
component transfusion rate of 27% (3). An audit by the European Association for Cardio-thoracic Surgery
estimated that cardiac surgery accounted for 5% of blood donated in the United Kingdom (4). Perioperative
transfusion of packed RBCs has been associated with increased risk for a broad spectrum of postoperative
morbidity after cardiac surgery, including renal failure, prolonged ventilation, infection, neurologic events, and
mortality (1). Karkouti et al. (5) demonstrated that massive blood loss after cardiac surgery resulted in an 8-fold
increase in mortality. Blood transfusion of even minimal amounts has been associated with increased morbidity
and mortality for on-pump coronary artery bypass surgeries (6). Studies have linked perioperative blood
transfusion during cardiac surgeries with mediastinitis leading to increased cost and mortality (7). Increased risk
of delirium in the postoperative period has been linked to duration of storage of packed RBCs (8). A review of 42
studies showed an association between intraoperative blood transfusion and wound infection in cardiac surgical
patients (9). In a large prospective study, Horvath et al. (10) identified pneumonia and bloodstream infections as
the most common manifestations of infection and the incremental risk associated with each unit of packed RBCs
was 29%. Since the early 1990s, antifibrinolytic drugs have played a major role in blood conservation strategies
in cardiac surgery. Perioperative blood conservation strategies play an important role in the reduction of blood
transfusion. This chapter will focus on the key prophylactic role played by antifibrinolytic drugs in reducing blood
loss and transfusion.
FIBRINOLYSIS AND ANTIFIBRINOLYTIC MECHANISMS

Hemostasis is the process of clot formation at the exposure site of subendothelial collagen in a blood vessel. The
hemostatic system consists of four components: coagulation system, endothelium and regulatory proteins,
platelets, and fibrinolysis (11). Nonendothelial surfaces in the cardiopulmonary bypass (CPB) circuit initiate
contact activation of the intrinsic coagulation pathway resulting in nonhemostatic thrombin generation (12).
Under normal hemostatic conditions, soluble fibrin accounts for 1% of total fibrin formation. CPB leads to
dysregulation of fibrin resulting in an increase in soluble fibrin of up to 35% (13). Thrombin generation and
soluble fibrin formation increase at initiation of CPB, at CPB cessation, and after protamine administration (14).
High-dose unfractionated heparin, via antithrombin III, decreases thrombin activity and fibrin generation, thereby
preventing clot formation within the extracorporeal circuit (15). However, thrombin has also been widely
recognized as a key amplifier protein of inflammation, coagulation, and fibrinolysis. Thrombin causes the release
of tissue plasminogen activator (tPA) from endothelium which promotes plasminogen conversion to plasmin, an
enzyme that proteolytically degrades fibrin (16). The plasminogen molecule contains specific lysine-binding sites
that interact with both fibrin and the major inhibitor, α2-antiplasmin. Urinary plasminogen activator (uPA) and tPA
are the two main serine protease activators (17). Vascular endothelial cells secrete tPA, while uPA is secreted by
a variety of cell types including nonvascular cells. Bradykinin has been shown to play an important role
stimulating the release of tPA via β2 receptors (18). Activators convert plasminogen to plasmin, generating
soluble degradation products and exposing carboxy-terminal lysine residues (19).
Other factors contribute to the initiation of fibrinolytic activity during cardiac surgery. Surgical trauma, such as
sternotomy alone, can activate fibrinolysis. There is contact activation of fibrinolysis by the CPB circuit, resulting
in a 5-fold increase
P.518
in tPA activity (14). Peak tPA levels occur early during CPB within 30 to 60 minutes. Increased soluble fibrin is a
powerful stimulator of tPA (12). Unfractionated heparin in itself is also a mild stimulator of vascular plasminogen
activators, thereby contributing to fibrinolytic augmentation (20). This hyperfibrinolytic state consumes fibrinogen,
thereby impairing coagulation postoperatively. In addition to fibrin, plasmin cleaves fibrinogen and a variety of
plasma proteins. The breakdown of fibrin strands by plasmin results in the release of fibrin degradation products
that include D-dimers. D-Dimer levels have been used as indicators of fibrinolysis in many studies.
FIGURE 21.1. Site of action of antifibrinolytics. Fibrin is polymerized by thrombin and activated Factor XIII at the
site of vascular injury. Thrombin-activated fibrinolysis inhibitor (TAFI) helps stabilize the clot against the activity
of plasmin. Broken lines indicate inhibitory action of the protease inhibitors. (Reused from Ide M, Bolliger D,
Taketomi T, Tanaka KA. Lessons from the aprotonin saga: Current perspective on antifibrinolytic therapy in
cardiac surgery. J Anesth 2010;24(1):96-106).α-2 AP-α-2 antiplasmin; tPA- tissue plasminogen activator; TAFIa-
activated TAFI; Plgn-plasminogen; PC- Protein C; APC- Activated Protein C; AT- Antithrombin; PAR- Protease-
activated Receptor1.
Plasmin activity is regulated both by plasminogen activators and inhibitors. Inhibitors of plasminogen activation
are plasminogen activator inhibitor-1 (PAI-1), α2-antiplasmin, and thrombin-activated fibrinolysis inhibitor (TAFI).
PAI-1 is a member of the serine protease inhibitor family. It is produced by vascular endothelial and smooth
muscle cells and is the primary physiologic regulator of uPA and tPA activity (21). PAI-1 is an acute phase
reactant and levels are increased following surgery (14). α2-antiplasmin is manufactured in the liver and is the
major inhibitor of plasmin in plasma. TAFI is activated by thrombin and removes carboxy-terminal lysine residues,
thereby attenuating plasmin generation. The resultant overall hyperfibrinolytic state consumes fibrinogen
impairing coagulation postoperatively, and increasing postoperative hemorrhagic complications and blood
transfusion requirements (22). When antifibrinolytic agents are prophylactically administered during CPB, they
reduce the susceptibility of fibrin clots to plasmin-mediated degradation.
Plasmin and plasminogen bind at lysine-binding sites onto fibrinogen. The lysine analogs e-aminocaproic acid
(ACA) and tranexamic acid (TXA) competitively inhibit the fibrin-binding site on plasminogen and prevent the
degradation of fibrin and the dissolution of clot (Fig. 21.1, Table 21.1).
Tranexamic Acid
TXA is an isomer of 4-aminomethylcyclohexane carboxylic acid which competitively inhibits plasminogen. TXA
binds to both strong and weak lysine-binding sites on plasminogen and has poor affinity for other plasma
proteins. Saturation of the lysine-binding sites of plasminogen with TXA displaces plasminogen from the fibrin
surface. At a concentration of 10 μg/mL, 80% of plasminogen was inhibited; with higher doses, 100% of
plasminogen activity was inhibited with a plasma concentration of 100 μg/mL (23). At higher concentrations, it is
also a noncompetitive inhibitor of plasmin (24). Another proposed mechanism of TXA action is that it increases
collagen synthesis, thus increasing the tensile strength of the clot (25). The reduction in D-dimers following TXA
use has been used as an indicator of reduced fibrinolysis (26).
The molecular formula of TXA is C8H15NO2. It is a weak acid (pKa ˜4.3), which does not bind to plasma proteins
and is nonlipophilic. Administration can be via oral, intravenous, or topical routes (27). Absorption after oral
ingestion is approximately 50% and the half-life is approximately 80 minutes (28). A two-compartment model best
describes the distribution of TXA (29). The following pharmacokinetic properties for a 70-kg adult were
documented by Grassin-Delyle et al. (30): peripheral volume of distribution = 10.8 L, volume of central
compartment = 6.6 L, clearance = 4.8 L/hr, diffusional clearance = 32.2 L/hr. Two covariates (body weight and
creatinine clearance) are known to affect drug levels. Although CPB was previously thought to affect TXA
pharmacokinetics, recent research suggests that modern CPB techniques do not have a significant effect
(30,31,32). Up to 95% of TXA is excreted unchanged in the urine, with the remainder metabolized by
biotransformation involving acetylation and deamination. As renal excretion of TXA is directly related to creatinine
clearance, renal failure may prolong its half-life and
P.519
thus potentially lead to increased serum concentrations when TXA is administered by continuous infusion.
Various suggestions for reduction in TXA infusion rates in the setting of renal dysfunction are shown in Table
21.2.
TABLE 21.1. Comparison of antifibrinolytic drugs
Aminocaproic
Aprotinin acid Tranexamic acid
Structure
Chemical C284H432N84O79S7 C6H13NO2 C8H15NO2
formula
Molecular 6,512 131 157

weight
Plasma level 4.2 60 3.3

(mg/dL)
Ki values
(Mol.)
Plasmin 7 × 10-11 3.2 × 10-1 1.6 × 10-2
Kallikrein 3.6 × 10-8 NS NS
Thrombin 6.1 × 10-5 NS NS
FXIa 1.1 × 10-6 NS NS
APC 1.1 × 10-6 NS NS
NS, not significant; Ki, inhibition coefficient; FXIa, activated Factor XI; APC, activated Protein C.
It has been suggested that the optimal benefits from TXA use are derived when administration is initiated at
commencement of surgery and maintained throughout by continuous infusion (33). However, others have
reported beneficial effects with bolus dosing only. In addition, the timing of drug initiation varies from immediately
after induction of anesthesia to after heparin administration. Advocates of the former approach suggest that
fibrinolysis begins as early as surgical incision, whereas advocates of the latter approach suggest that heparin
may protect against potential thrombotic effects of antifibrinolytic agents. Fiechtner et al. (34) demonstrated that
inhibition of fibrinolysis could be achieved with a bolus of 10 mg/kg followed by an infusion of 1 mg/kg/hr, which
results in a plasma concentration of 25 to 40 μg/mL, whereas Dowd et al. suggested that higher doses (30 mg/kg
bolus, 2 mg/kg added to CPB prime and 16 mg/kg/hr; the “Blood Conservation Using Antifibrinolytics in
Randomized Trial [BART] dose”) were required to maintain TXA concentrations greater than 800 μmol/L (29).
Many dosing regimens have been studied (Table 21.3), however the optimal dose has not been established.
Although some advocate lower TXA dosing regimens to avoid the potential side effects (i.e., seizure activity), two
recent randomized, controlled studies have demonstrated significantly reduced bleeding and/or transfusion with
the high-dose (BART) regimen (35,36). In both of these studies, there was no significant difference in the
incidence of seizures with the BART regimen compared with lower-dose regimens.
Another area of interest is the topical use of antifibrinolytics to reduce postoperative bleeding. Topical use of
TXA,
P.520
aminocaproic acid, and aprotinin have all been described. For TXA, the dosing regimens have consisted of
administration of 1 to 2.5 g in 100 to 250 mL into the pericardial cavity at the time of surgery, either alone or
combined with systemic administration. The theoretical advantage of topical administration is targeted local effect
with avoidance of any systemic absorption and systemic side effects (37). Some small individual studies have
shown a trend toward decreased bleeding and transfusion requirements (38,39,40,41); meta-analysis suggests
significant reduction in chest tube losses and transfusion rates (42,43).
TABLE 21.2. Suggested reduction in tranexamic acid maintenance infusion rates in renal
disease
Serum creatinine % of usual % of normal creatinine % of usual

(mg/dL)a maintenance dosea clearanceb maintenance doseb
1.6-3.3 75 75 75
3.3-6.6 50 50 37.5
>6.6 25 25 31.3
10 10
1 1
aGrassin-Delyle S, Tremey B, Abe E, et al. Population pharmacokinetics of tranexamic acid in adults

undergoing cardiac surgery with cardiopulmonary bypass. Br J Anaesth 2013;111:916-924; Fiechtner
BK, Nuttall GA, Johnson ME, et al. Plasma tranexamic acid concentrations during cardiopulmonary
bYang Q, Jerath A, Bies RR, et al. Pharmacokinetic modeling of tranexamic acid for patients undergoing
cardiac surgery with normal renal function and model simulations for patients with renal impairment.
Biopharm Drug Dis 2015. doi:10.1002/bdd.1941.
TABLE 21.3. Reported dosing regimens for tranexamic during cardiac surgery
Study name or Journal name and CPB Infusion Serum TXA
first author year Bolus dose dose rate concentration
BART (81) N Engl J Med, 2008 30 mg/kg 2 16 >100 μg/mL

Anaesthesia, 2012 mg/kg mg/kg/hr
Grassin-Delyle Br J Anaesth, 2013 46 mg/kg - 9-11 150 μg/mL

(30) mg/kg/hr
Bokesch (35) J Thorac Cardiovasc 1g 500 400 >600 μmol/L

Surg, 2012 mg mg/hr
Fiechtner (34) Anesth Analg, 2001 10 mg/kg - 1 20-70 μg/mL

mg/kg/hr
Karski (112) J Cardiothorac Vasc 50-150 - - -

Anesth, 1998 mg/kg
Dietrich (113) Anesth Analg, 2008 2g 2g 1 g/hr
Karski (114) J Thorac Cardiovasc 10 g - 2 g/hr -

Surg, 1995 (for 5 hr)
Horrow (115) Anesthesiology, 1995 10-40 - 1-4 -

mg/kg mg/kg/hr
Abrishami (42) Can J Anesth, 2009 1-2.5 g - -

(topical
route)
CPB, cardiopulmonary bypass; TXA, tranexamic acid.
A potential adverse effect associated with the use of TXA in cardiac surgery is convulsive seizures. The
incidence varies but has been reported up to 7.6% following various open cardiac or open aortic procedures
(44). The description of these abnormal involuntary movements, which usually manifest early in the
postoperative period has included grand mal seizure, focal seizure, and intermittent myoclonic jerks (45). TXA-
associated seizures are short, lasting only seconds to minutes and are usually self-terminating. If necessary,
benzodiazepines or propofol can be given to terminate the seizures and if recurrent, phenytoin can be
considered to prevent further seizures. Numerous risk factors for postoperative seizure have been identified
including TXA administration, age, complex (noncoronary artery bypass grafting [non-CABG]) surgery, CPB
P.521
cross-clamp time, renal dysfunction, and preexisting neurologic disease (44,45,46,47,48,49). Postoperative
seizures in general cause concern since they can be associated with delirium, prolonged length of stay, and
mortality, especially if they are related to structural brain injury such as stroke. However, in the absence of brain
injury, it is unlikely that an isolated TXA-associated seizure leads to adverse outcome.
TXA-associated seizures are thought to be mediated by TXA blockade of inhibitory receptors in the brain, which
would enhance excitatory neurotransmission to cause seizures. It has been postulated that TXA and ACA are
structural analogs of glycine, which is an important central nervous system (CNS) neurotransmission inhibitor.
Lecker et al. (50) demonstrated a temporal relationship between peak TXA concentration in CSF and onset of
seizure activity. Another postulated mechanism for seizure is TXA-induced inhibition of g-aminobutyric acid A
(GABAA) receptors in the amygdala, thereby increasing excitatory neurotransmission (51,52). Glycine receptors
appear to be more sensitive to TXA than GABAA receptors, which may be important given the low levels of TXA
measured in the CSF of patients to date (50,53).
ε - Aminocaproic Acid
ACA is a synthetic inhibitor of both plasminogen and plasmin (54). The main difference between TXA and ACA
lies in the binding affinity to plasminogen. TXA binds 10 times more avidly than ACA, and is therefore more
potent than ACA (55).
ACA can be administered intravenously, orally or tropically, and has a half-life of 2 hours in plasma. ACA is
excreted unchanged in urine (28). One suggested dose to maintain stable plasma concentration is a bolus of 50
mg/kg followed by a maintenance dose of 25 mg/kg/hr (56). ACA has also been used topically but a significant
reduction in transfusion rate has not been demonstrated using that route (57).
In the 1960s, questions were raised about the effect of ACA on renal function in the perioperative period (58,59).
Stafford-Smith et al. (60) reviewed 1,502 patients who received ACA perioperatively and no statistically
significant decrease in creatinine clearance was found. Neurologic deficits relative to ACA use were reviewed by
Bennett-Guerrero et al. (61). They found that, with the usual post-CABG cerebrovascular event rate of 1.5%,
there was no evidence for an independent contribution of ACA to those events. In addition, since ACA (like TXA)
is a structural analog of glycine, which interacts with GABAA receptors, it theoretically could also be associated
with postoperative seizures. However, this has not been observed clinically, perhaps because of relatively lower
dosing and lesser potency of ACA.
Despite being widely used as an antifibrinolytic agent, there is relatively little published about ACA use in cardiac
surgery compared to either TXA or aprotinin. Nonetheless, the medical literature does support the efficacy and
safety of this agent. Indeed, a recent network meta-analysis of randomized controlled trials (RCTs) and
observational trials showed a lower mortality with ACA compared to aprotinin (62). In this, and other meta-
analyses, ACA was found to be similar to TXA in terms of other clinical outcomes such as bleeding, reoperation,
myocardial infarction (MI), and renal dysfunction (63). Despite having similar neuronal inhibitory receptor
blockade properties as TXA, there are fewer reports of seizures associated with ACA than TXA.
Aprotinin
Aprotinin is a nonspecific serine protease inhibitor derived from bovine lung. It inhibits fibrinolysis, thrombin
generation, and inflammatory responses. The active site of aprotinin contains a single lysine, which is the
binding site for the serine proteases. Unlike the lysine analogs, aprotinin inhibits a broad spectrum of other
proteins involved in coagulation including kallikrein, activated protein C, and thrombin (64). Through its activity
as an inhibitor of kallikrein and serine protease inhibition, aprotinin inhibits contact activation of the coagulation
system during cardiac surgery. Aprotinin and the lysine analogs have different modes and scopes of action, but
ultimately inhibit fibrinolysis by limiting the action of plasmin.
Aprotinin was previously widely used in cardiac surgery to reduce blood loss and transfusion requirements (65).
A Cochrane review combined the data from 61 studies and found a 30% reduction in blood transfusion, less
blood drainage, and a significantly lower incidence of reoperation due to bleeding (2).
The “High-dose aprotinin” regimen consists of a 2-million kallikrein-inhibiting units (KIU) IV loading dose, 2-million
KIU pump-priming dose, and 0.5-million KIU IV/hr maintenance dose. Plasma half-life for aprotinin with this dose
regimen is approximately 5 hours. Aprotinin is excreted mainly via the kidneys, although the effect on half-life of
decreased glomerular filtration rate is unclear. The high-dose aprotinin regimen has been shown to reduce blood
loss by 40% to 80% in cardiac surgical procedures (66,67). High-dose aprotinin has been shown to reduce total
blood loss during cardiac surgery to a greater extent than TXA and ACA (68). Lower-dose regimens have also
been proven effective at reducing blood loss and transfusion requirement (69). Low-dose aprotinin consists of a
1-million KIU IV loading dose, 1-million KIU pump-priming dose, and 0.25-million KIU IV/h maintenance dose.
Aprotinin is derived from bovine lung and thus has potential antigenic properties. The incidence of
hypersensitivity to aprotinin is reported to be 1% to 3% (70), although some studies have quoted figures as low
as 0.09% for primary exposure to aprotinin (71). However, repeated exposure especially in a short time frame
can significantly increase the risk of anaphylactic reaction with a peak risk occurring 4 days after previous
administration. Controversies regarding aprotinin use, optimal heparin dose, and activated clotting time (ACT)
levels came to the fore in the 1990s. It was noted that highdose aprotinin led to an increase in the ACT during
CPB. Further studies established that the elevated ACT was only noted when celite was used as the surface
activator and that this rise
P.522
in ACT was a measurement artifact as opposed to an increased anticoagulant effect of aprotinin (72). Any
decrease in heparin dose to compensate for ACT elevation therefore would put patients at risk of inadequate
anticoagulation on bypass (73). It is thus important that kaolin be used as the surface activator in ACT
measurement when aprotinin is in use and that the clinician be cognizant of this potential source of error (74).
The International Multicenter Aprotinin Graft Patency Experience (IMAGE) trial raised the question whether graft
occlusion was linked to perioperative aprotinin use. A higher occlusion rate in saphenous vein grafts in the
overall study population was noted, but it was suggested that this was related to local surgical factors (75). A
meta-analysis concluded that there was a small but significant increase in the odds ratio for vein graft occlusion
to 1.52 (95% confidence interval [CI] 1.13-2.03) in patients receiving aprotinin during CABG (76). To date, no
evidence supports an increased risk for arterial (e.g., internal mammary artery) graft occlusion (77).
The overall safety of aprotinin relative to other antifibrinolytics was called into question in 2006 when Mangano
and colleagues (78) observed that aprotinin was associated with an increased risk of renal failure, MI, heart
failure, stroke, encephalopathy, and an increased mortality in a prospective observational study of 4,374
patients. A dose-response effect was suggested, with poorer outcomes associated with higher aprotinin doses.
Karkouti et al. (79), in a second observational study, also reported an association between aprotinin and renal
dysfunction. In 2007, Mangano et al. (80) published a further analysis of the same dataset as in the 2006 paper
and reported that aprotinin use was an independent predictor of higher 5-year mortality. In the 2007 guidelines
from the Society of Thoracic Surgeons (STS), the use of high-dose aprotinin to reduce blood transfusion, blood
loss and to limit reexploration was recommended in high-risk patients undergoing cardiac operations. They
advised that benefits of use be balanced against the increased risk for renal dysfunction (2), and advised
consideration of low-dose aprotinin, as this approach would still reduce the number of patients requiring blood
transfusion and the total blood loss. In 2008, a large randomized, controlled trial, The BART study, found that
while aprotinin was associated with a lower incidence of massive bleeding compared with TXA and ACA, it also
was associated with a significant increase in mortality (81). The trial was terminated early because of increased
mortality. The BART study was the first large-scale head-to-head randomized, controlled trial comparing
aprotinin with lysine analogs, reporting a significant increased risk of 30-day mortality among patients randomly
assigned to aprotinin as compared to lysine analogs (relative risk 1.53; 95% CI 1.06-2.22). Based on this
evidence, the drug regulatory bodies in Europe and North America temporarily suspended the marketing
authority for aprotinin. The license in the United Kingdom (UK) allowed administration of the drug but the overall
use of aprotinin dropped dramatically (82). Other observational studies supported the finding that patients who
received aprotinin had a higher mortality rate and larger increases in serum creatinine levels than those who
received lysine analogs or no antifibrinolytic agent (83,84). In 2011, the STS guidelines reflected this change and
acknowledged that while both high- and low-dose aprotinin reduced the number of adult patients requiring blood
transfusion, total blood loss, and reexploration in patients undergoing cardiac surgery, they recommended that
aprotinin should not be used for routine blood conservation because the risks outweighed the benefits (85).
The response to the marketing suspension of aprotinin has been variable. Some reports have suggested that
withdrawal of aprotinin impacted negatively on bleeding, transfusion practice, and clinical outcome, although
many practitioners have implemented blood management programs and find the lysine analogs to be effective
and safe alternatives to aprotinin (86,87,88). Using the STS database, Bennett-Guerrero et al. (89) reported no
difference in transfusion practice after publication of the Mangano articles or suspension of aprotinin. Although
aprotinin is established as an effective antifibrinolytic agent, the debate over whether aprotinin is associated with
increased mortality or not continues, with some reports confirming the BART finding while others report no
association of aprotinin with mortality (62,63,90,91,92). However, some have also suggested that the question is
not whether aprotinin increases mortality, but rather whether there is good evidence that it decreases mortality
compared to active comparators. If it does not decrease mortality, this begs the question of whether the drug
should be used and/or whether there is something wrong with the hypothesis that decreasing bleeding and
transfusion saves lives. In addition, aprotinin was approved for use only in CABG surgery, but it is specifically in
the high-risk non-CABG surgery patients that there is a strong perceived need for a better drug than lysine
analogs.
Health Canada lifted the temporary marketing suspension of aprotinin in September 2011, and the European
Medicines Agency (EMA) also recommended lifting the suspension of aprotinin in February 2012. These
recommendations were based on a review of the data related to aprotinin and the BART study. They suggested
that the study was not primarily designed to determine the risk of death and that “the increased number of deaths
in Trasylol (TXA) patients could have been due to chance,” a comment that could apply to most research
studies. The two regulatory agencies also had three primary criticisms of the BART study, specifically related to
the reclassification of the primary outcome, exclusion from the primary analysis of 137 patients once randomized,
and potential imbalances at baseline and with anticoagulation. A response to these issues has recently been
published, clarifying the true reclassification of primary outcomes to be 1.6%, providing sensitivity analyses
documenting consistency of results over time and with multiple analyses either including or excluding the 137
patients, and documenting similar weight- and time-adjusted doses of heparin between groups (93), with no
significant change in observed outcomes. In addition, the transparency of EMA decisions related to aprotinin has
also been questioned (94). Large peer-reviewed academic trials with active controls yield
P.523
important findings but they may complicate safety evaluations undertaken by regulatory agencies, especially
when using active comparators not licensed for the clinical indication instead of placebo. Pragmatic trials with
usual care conditions, such as the BART study, are different from the tightly controlled studies usually needed
for drug approval. While many factors can influence regulatory decision making, a more prudent approach and
regulatory standard might have been to mandate a second large trial comparing aprotinin to an active agent so
that the BART trial results could properly be either confirmed or refuted.
OTHER AGENTS
Desmopressin
Desmopressin (DDAVP) is a synthetic analog of vasopressin (95). Initially used to treat diabetes insipidus, the
clinical spectrum of its use has now broadened to include bleeding disorders, mainly factor VIII deficiency and
von Willebrand’s disease (96,97).
DDAVP increases von Willebrand factor, Factor VIII, and plasminogen activator levels, all of which result in a
decrease in activated prothrombin time and bleeding time (98).While the exact mechanism of action of DDAVP is
unknown, it is hypothesized that DDAVP acts on Vasopressin type 2 (V2) receptors resulting in exocytosis of the
above coagulation factors (99). DDAVP can be administered via intravenous, intramuscular, sublingual, or oral
routes (100). Desmopressin has a systemic vasodilatory rather than vasopressor effect (101). The response to
DDAVP can vary among patients, and it has been recommended that a basal factor VIII level should be done and
a test dose of DDAVP given to assess the response (102). Being a synthetic medication, DDAVP could reduce
the risk of transfusion-related infections.
The use of DDAVP as bleeding prophylaxis in cardiac surgery patients has been widely studied with varying
results. Carless et al. (103) reported a meta-analysis which included 18 double-blinded, randomized, controlled
trials and which did not show a significant reduction in blood loss with DDAVP prophylaxis. On the other hand, a
more recent review by Wademan et al. (104) found that DDAVP reduced postoperative bleeding in patients who
were on aspirin within 7 days preoperatively, in patients with prolonged CPB time, and in patients with platelet
dysfunction.
There is also controversy about the safety of DDAVP in cardiac surgery. A meta-analysis by Levi et al. (105) of
eight trials using DDAVP for pharmacologic prophylaxis to prevent bleeding in cardiac cases found an increased
incidence (Odds ratio 2.4, 95% CI 1.02-5.6) of perioperative MI. One explanation put forward was that DDAVP
causes a prothrombotic effect and hemodynamic changes, which predisposed to myocardial ischemia.
In a meta-analysis of 12 trials reporting post-DDAVP MI, the overall incidence was 5.25% (103). Out of the 876
patients in the trials, 441 patients received DDAVP. Twenty-eight (6.3%) patients in the DDAVP group developed
MI, and 18 (4.14%) patients did so in the non-DDAVP group. There was no statistical significance between the
DDAVP and placebo groups for MI with 95% confidence limits for the relative risk between 0.77 and 2.5. Of note,
this study included both cardiac and noncardiac cases. Dosing of DDAVP in most studies is typically either 0.3
μg/kg or a fixed dose of 20 μg.
Kallikrein Inhibitors
There has also been recent interest in the potential use of kallikrein inhibitors to prevent bleeding in cardiac
surgery. Kallikrein activation is directly linked to bradykinin and several other key mediators of the clotting,
fibrinolytic, and inflammatory cascades. Thus, kallikrein inhibition has been investigated as a way to reduce the
blood loss and inflammation associated with cardiac surgery and CPB.
Ecallantide
Ecallantide is a recombinant human peptide which inhibits plasma kallikrein and the tissue factor pathway of
coagulation and which has been approved by the FDA for the treatment of hereditary angioedema (Kalbitor®).
Compared to aprotinin, ecallantide is more specific and a less potent plasmin inhibitor (Table 21.4). Based on its
effects on clotting, fibrinolytic, and inflammatory cascades, an international randomized, double-blind trial of
ecallantide versus TXA was conducted in cardiac surgery patients with a high risk of bleeding. However, this
study was stopped prior to target enrollment because of a significantly higher mortality rate in the ecallantide
group compared to the TXA group (35). In addition, patients receiving ecallantide received more transfused
packed RBCs, fresh frozen plasma, and platelets than patients receiving TXA. Interestingly, this study also found
that high-dose TXA (similar to the BART dose) was significantly more effective than a lower dose, which was the
approved dose in Germany. In addition, the only seizures observed were in the lower-dose group.
MD2010
Another synthetic small peptide molecule with plasmin and kallikrein inhibitor properties (Table 21.4) has been
investigated as a possible alternative to aprotinin for bleeding prophylaxis in cardiac surgery. This agent (known
as MDCO-2010 or CU-2010) also inhibits thrombin generation, which is thought to mediate some of the adverse
effects of CPB. Preclinical studies confirmed its antifibrinolytic and anticoagulant properties and animal studies
with CPB demonstrated reduced bleeding with suppression of inflammation, improved myocardial function, and
salutary effects on coronary blood flow (106,107,108).
In a Phase IIa double-blind, placebo-controlled dose escalation study of 32 patients undergoing elective, primary
CABG surgery, chest tube drainage and incidence of transfusion were lower in patients receiving MDCO-2010
compared to placebo (109). Dosage-dependent drug levels and antifibrinolytic effects were observed as
expected. There were no significant differences in adverse events; one MDCO-2010 patient developed HIT and
a late postoperative stroke and MI, and another developed intraoperative vein graft thrombosis that was
considered possibly related to the study drug.
P.524
TABLE 21.4. Comparative inihibitory concentrations of kallikrein inhibitors (nM)
Enzyme Aprotinin Ecallantide (DX88) MDCO-2010 (CU-2010)
Plasmin 4 20 2
Plasma kallikrein 31 0.04 0.04
Factor Xa 200,000 - 51
Factor XIa 2,700 10 26
Thrombin 164,000 20,000 1,400
Similar to aprotinin, this drug prolonged ACT, regardless of the ACT activator or device used (110). However,
despite the promising preclinical and initial human study, clinical development of this compound was halted in
2012 after a subsequent Phase 2b trial of MDCO-2010 in patients undergoing primary cardiac surgery was
stopped after 44 of 90 patients were enrolled because of “serious unexpected patient safety issues” (111).
CONCLUSIONS
Prophylactic administration of antifibrinolytic drugs is well established to decrease bleeding and transfusion
in patients undergoing cardiac surgery. Several guidelines assign class 1 levels of evidence to the use of
TXA and ACA. Further research is necessary to confirm the optimal drug and respective doses to be
administered.
KEY Points
Perioperative blood transfusion has been associated with increased postoperative morbidity and mortality
after cardiac surgery.
Multiple factors contribute to the hyperfibrinolytic state that exists during cardiac surgery.
Antifibrinolytic agents are frequently administered prophylactically during cardiac surgery to improve the
stability of fibrin clots against plasmin-mediated degradation. Both systemic and topical administration of
antifibrinolytic drugs has been reported to decrease bleeding and transfusion.
Tranexamic acid (TXA) is a lysine analogue with antifibrinolytic properties. Multiple dosing regimens have
been described but there is no consensus on optimal dose. Early postoperative seizures have been
described with higher TXA dosing regimens.
Aminocaproic acid is a lysine analogue which is 10 times less potent than TXA. There are relatively fewer
studies of aminocaproic acid in cardiac surgery than either TXA or aprotinin, but those that have been
published suggest efficacy and safety without increased postoperative seizure activity.
Aprotinin is a nonspecific serine protease inhibitor which was previously widely used in cardiac surgery.
Marketing of aprotinin was temporarily suspended after the BART trial and other observational studies
reported a higher mortality and larger creatinine increase associated with aprotinin when compared to
lysine analogues. Aprotinin use in cardiac surgery is a subject of ongoing debate.
DDAVP and some new investigational drugs have also been evaluated for use in cardiac surgery.
Prophylactic use of DDAVP after CPB has not been proven beneficial except possibly in patients who
have taken aspirin within 7 days preoperatively. It may also be beneficial for patients with documented
platelet dysfunction following CPB.
REFERENCES
1. Koch CG, Li L, Duncan AI, et al. Morbidity and mortality risk associated with red blood cell and blood-
component transfusion in isolated coronary artery bypass grafting. Crit Care Med 2006;34:1608-1616.
2. Society of Thoracic Surgeons Blood Conservation Guideline Task Force; Society of Cardiovascular
Anesthesiologists Special Task Force on Blood Transfusion. Perioperative blood transfusion and blood
conservation in cardiac surgery: the Society of Thoracic Surgeons and The Society of Cardiovascular
Anesthesiologists clinical practice guideline. Ann Thorac Surg 2007;83:S27-S86.
3. Daly DJ, Myles PS, Smith JA, et al. Anticoagulation, bleeding and blood transfusion practices in
Australasian cardiac surgical practice. Anaesth Intensive Care 2007;35:760-768.
4. Dunning J, Versteegh M, Fabbri A, et al. Guideline on antiplatelet and anticoagulation management in

cardiac surgery. Eur J Cardiothorac Surg 2008;34:73-92.
5. Karkouti K, Wijeysundera DN, Yau TM, et al. The independent association of massive blood loss with
mortality in cardiac surgery. Transfusion 2004;44:1453-1462.
6. Paone G, Likosky DS, Brewer R, et al; Membership of the Michigan Society of Thoracic and
Cardiovascular Surgeons. Transfusion of 1 and 2 units of red blood cells is associated with increased
morbidity and mortality. Ann Thorac Surg 2014;97:87-93; discussion 93-94.
7. Ang LB, Veloria EN, Evanina EY, et al. Mediastinitis and blood transfusion in cardiac surgery: a systematic
review. Heart Lung 2012;41:255-263.
8. Brown CH IV, Grega M, Selnes OA, et al. Length of red cell unit storage and risk for delirium after cardiac
surgery. Anesth Analg 2014;119:242-250.
9. Bryan CS, Yarbrough WM. Preventing deep wound infection after coronary artery bypass grafting: a
review. Tex Heart Inst J 2013;40:125-139.
10. Horvath KA, Acker MA, Chang H, et al. Blood transfusion and infection after cardiac surgery. Ann Thorac
Surg 2013;95:2194-2201.
11. Sniecinski RM, Chandler WL. Activation of the hemostatic system during cardiopulmonary bypass.
Anesth Analg 2011;113:1319-1333.
12. de Haan J, van Oeveren W. Platelets and soluble fibrin promote plasminogen activation causing down-
regulation of platelet glycoprotein Ib/IX complexes: protection by aprotinin. Thromb Res 1998;92:171-179.
13. Chandler WL, Velan T. Plasmin generation and D-dimer formation during cardiopulmonary bypass. Blood
14. Chandler WL, Velan T. Secretion of tissue plasminogen activator and plasminogen activator inhibitor 1
during cardiopulmonary bypass. Thromb Res 2003;112:185-192.
P.525
16. Tanaka K, Takao M, Yada I, et al. Alterations in coagulation and fibrinolysis associated with
cardiopulmonary bypass during open heart surgery. J Cardiothorac Anesth 1989;3:181-188.
17. Horrevoets AJ. Plasminogen activator inhibitor 1 (PAI-1): in vitro activities and clinical relevance. Br J
Haematol 2004;125:12-23.
18. Pretorius M, Scholl FG, McFarlane JA, et al. A pilot study indicating that bradykinin B2 receptor
antagonism attenuates protamine-related hypotension after cardiopulmonary bypass. Clin Pharmacol Ther
2005;78:477-485.
19. Cesarman-Maus G, Hajjar KA. Molecular mechanisms of fibrinolysis. Br J Haematol 2005;129:307-321.
20. Day JR, Landis RC, Taylor KM. Heparin is much more than just an anticoagulant. J Cardiothorac Vasc
Anesth 2004;18:93-100.
21. Iwaki T, Urano T, Umemura K. PAI-1, progress in understanding the clinical problem and its aetiology. Br
J Haematol 2012;157:291-298.
22. Henry DA, Carless PA, Moxey AJ, et al. Anti-fibrinolytic use for minimising perioperative allogeneic blood
transfusion. Cochrane Database Syst Rev 2011;(3):CD001886.
23. Andersson L, Eriksson O, Hedlund PO, et al. Special considerations with regard to the dosage of
tranexamic acid in patients with chronic renal diseases. Urol Res 1978;6:83-88.
24. Laupacis A, Fergusson D. Drugs to minimize perioperative blood loss in cardiac surgery: meta-analyses
using perioperative blood transfusion as the outcome. The International Study of Peri-operative Transfusion
(ISPOT) Investigators. Anesth Analg 1997;85:1258-1267.
25. Hosgor I, Yarat A, Yilmazer S, et al. Collagen deposition in myocardium after inhibition of fibrinolytic
activity. Blood Coagul Fibrinolysis 2005;16:25-30.
26. Faraoni D, Cacheux C, Van Aelbrouck C, et al. Effect of two doses of tranexamic acid on fibrinolysis
evaluated by thromboelastography during cardiac surgery: a randomised, controlled study. Eur J
Anaesthesiol 2014;31:491-498.
27. Alshryda S, Sukeik M, Sarda P, et al. A systematic review and meta-analysis of the topical administration
of tranexamic acid in total hip and knee replacement. Bone Joint J 2014;96-B:1005-1015.
28. Verstraete M. Clinical application of inhibitors of fibrinolysis. Drugs 1985;29: 236-261.
29. Dowd NP, Karski JM, Cheng DC, et al. Pharmacokinetics of tranexamic acid during cardiopulmonary
bypass. Anesthesiology 2002;97:390-399.
30. Grassin-Delyle S, Tremey B, Abe E, et al. Population pharmacokinetics of tranexamic acid in adults
undergoing cardiac surgery with cardiopulmonary bypass. Br J Anaesth 2013;111:916-924.
31. Sharma V, Fan J, Jerath A, et al. Pharmacokinetics of tranexamic acid in patients undergoing cardiac
surgery with use of cardiopulmonary bypass. Anaesthesia 2012;67:1242-1250.
32. Yang Q, Jerath A, Bies RR, et al. Pharmacokinetic modeling of tranexamic acid for patients undergoing
cardiac surgery with normal renal function and model simulations for patients with renal impairment.
Biopharm Drug Dis 2015. doi:10.1002/bdd.1941.
33. Sperzel M, Huetter J. Evaluation of aprotinin and tranexamic acid in different in vitro and in vivo models of
fibrinolysis, coagulation and thrombus formation. J Thromb Haemost 2007;5:2113-2118.
34. Fiechtner BK, Nuttall GA, Johnson ME, et al. Plasma tranexamic acid concentrations during
35. Bokesch PM, Szabo G, Wojdyga R, et al. A phase 2 prospective, randomized, double-blind trial
comparing the effects of tranexamic acid with ecallantide on blood loss from high-risk cardiac surgery with
cardiopulmonary bypass (CONSERV-2 Trial). J Thorac Cardiovasc Surg 2012;143:1022-1029.
36. Sigaut S, Tremey B, Ouattara A, et al. Comparison of two doses of tranexamic acid in adults undergoing
cardiac surgery with cardiopulmonary bypass. Anesthesiology 2014;120:590-600.
37. De Bonis M, Cavaliere F, Alessandrini F, et al. Topical use of tranexamic acid in coronary artery bypass
operations: a double-blind, prospective, randomized, placebo-controlled study. J Thorac Cardiovasc Surg
2000;119:575-580.
38. Yasim A, Asik R, Atahan E. Effects of topical applications of aprotinin and tranexamic acid on blood loss
after open heart surgery [in Turkish]. Anadolu Kardiyol Derg 2005;5:36-40.
39. Baric D, Biocina B, Unic D, et al. Topical use of antifibrinolytic agents reduces postoperative bleeding: a
double-blind, prospective, randomized study. Eur J Cardiothorac Surg 2007;31:366-371; discussion 371.
40. Fawzy H, Elmistekawy E, Bonneau D, et al. Can local application of tranexamic acid reduce post-
coronary bypass surgery blood loss? A randomized controlled trial. J Cardiothorac Surg 2009;4:25.
41. Spegar J, Vanek T, Snircova J, et al. Local and systemic application of tranexamic acid in heart valve
surgery: a prospective, randomized, double blind LOST study. J Thromb Thrombolysis 2011;32:303-310.
42. Abrishami A, Chung F, Wong J. Topical application of antifibrinolytic drugs for on-pump cardiac surgery:
a systematic review and meta-analysis. Can J Anaesth 2009;56:202-212.
43. Ipema HJ, Tanzi MG. Use of topical tranexamic acid or aminocaproic acid to prevent bleeding after major
surgical procedures. Ann Pharmacother 2012;46:97-107.
44. Martin K, Knorr J, Breuer T, et al. Seizures after open heart surgery: comparison of epsilon-aminocaproic
acid and tranexamic acid. J Cardiothorac Vasc Anesth 2011;25:20-25.
45. Sharma V, Katznelson R, Jerath A, et al. The association between tranexamic acid and convulsive
seizures after cardiac surgery: a multivariate analysis in 11 529 patients. Anaesthesia 2014;69:124-130.
46. Goldstone AB, Bronster DJ, Anyanwu AC, et al. Predictors and outcomes of seizures after cardiac
surgery: a multivariable analysis of 2,578 patients. Ann Thorac Surg 2011;91:514-518.
47. Manji RA, Grocott HP, Leake J, et al. Seizures following cardiac surgery: the impact of tranexamic acid
and other risk factors. Can J Anaesth 2012;59:6-13.
48. Montes FR, Pardo DF, Carreno M, et al. Risk factors associated with postoperative seizures in patients
undergoing cardiac surgery who received tranexamic acid: a case-control study. Ann Card Anaesth
2012;15:6-12.
49. Koster A, Borgermann J, Zittermann A, et al. Moderate dosage of tranexamic acid during cardiac surgery
with cardiopulmonary bypass and convulsive seizures: incidence and clinical outcome. Br J Anaesth
2013;110:34-40.
50. Lecker I, Wang DS, Romaschin AD, et al. Tranexamic acid concentrations associated with human
seizures inhibit glycine receptors. J Clin Invest 2012;122:4654-4666.
51. Furtmuller R, Schlag MG, Berger M, et al. Tranexamic acid, a widely used antifibrinolytic agent, causes
convulsions by a gamma-aminobutyric acid(A) receptor antagonistic effect. J Pharmacol Exp Ther
2002;301:168-173.
52. Kratzer S, Irl H, Mattusch C, et al. Tranexamic acid impairs gamma-aminobutyric acid receptor type A-
mediated synaptic transmission in the murine amygdala: a potential mechanism for drug-induced seizures?
53. Abou-Diwan C, Sniecinski RM, Szlam F, et al. Plasma and cerebral spinal fluid tranexamic acid
quantitation in cardiopulmonary bypass patients. J Chromatogr B Analyt Technol Biomed Life Sci
2011;879:553-556.
54. Griffin JD, Ellman L. Epsilon-aminocaproic acid (EACA). Semin Thromb Hemost 1978;5:27-40.
55. Tzortzopoulou A, Cepeda MS, Schumann R, et al. Antifibrinolytic agents for reducing blood loss in
scoliosis surgery in children. Cochrane Database Syst Rev 2008;(3):CD006883.
56. Butterworth J, James RL, Lin Y, et al. Pharmacokinetics of epsilon-aminocaproic acid in patients
undergoing aortocoronary bypass surgery. Anesthesiology 1999;90:1624-1635.
57. Gurian DB, Meneghini A, Abreu LC, et al. A randomized trial of the topical effect of antifibrinolytic epsilon
aminocaproic acid on coronary artery bypass surgery without cardiopulmonary bypass. Clin Appl Thromb
Hemost 2014;20:615-620.
58. Cooksey MW, Knapp MS. Aminocaproic acid and “proteinuria”. Br Med J 1968;1:769.
59. Biswas CK, Milligan DA, Agte SD, et al. Acute renal failure and myopathy after treatment with
aminocaproic acid. Br Med J 1980;281:115-116.
60. Stafford-Smith M, Phillips-Bute B, Reddan DN, et al. The association of epsilon-aminocaproic acid with
postoperative decrease in creatinine clearance in 1502 coronary bypass patients. Anesth Analg
2000;91:1085-1090.
61. Bennett-Guerrero E, Spillane WF, White WD, et al. Epsilon-aminocaproic acid administration and stroke
following coronary artery bypass graft surgery. Ann Thorac Surg 1999;67:1283-1287.
62. Hutton B, Joseph L, Fergusson D, et al. Risks of harms using antifibrinolytics in cardiac surgery:
systematic review and network meta-analysis of randomised and observational studies. BMJ
2012;345:e5798.
63. Howell N, Senanayake E, Freemantle N, et al. Putting the record straight on aprotinin as safe and
effective: results from a mixed treatment meta-analysis of trials of aprotinin. J Thorac Cardiovasc Surg
2013;145:234-240.
64. Levy JH, Sypniewski E. Aprotinin: a pharmacologic overview. Orthopedics 2004;27:s653-s658.
65. Royston D, Bidstrup BP, Taylor KM, et al. Effect of aprotinin on need for blood transfusion after repeat
open-heart surgery. Lancet 1987;2:1289-1291.
66. Dietrich W, Barankay A, Dilthey G, et al. Reduction of homologous blood requirement in cardiac surgery
by intraoperative aprotinin application—clinical experience in 152 cardiac surgical patients. Thorac
67. Dietrich W, Barankay A, Hahnel C, et al. High-dose aprotinin in cardiac surgery: three years’ experience
in 1,784 patients. J Cardiothorac Vasc Anesth 1992;6:324-327.
P.526
68. Brown JR, Birkmeyer NJ, O’Connor GT. Meta-analysis comparing the effectiveness and adverse
outcomes of antifibrinolytic agents in cardiac surgery. Circulation 2007;115:2801-2813.
69. Schonberger JP, Everts PA, Ercan H, et al. Low-dose aprotinin in internal mammary artery bypass
operations contributes to important blood saving. Ann Thorac Surg 1992;54:1172-1176.
70. Siehr S, Stuth E, Tweddell J, et al. Hypersensitivity reactions to aprotinin re-exposure in paediatric
71. Dietrich W, Ebell A, Busley R, et al. Aprotinin and anaphylaxis: analysis of 12,403 exposures to aprotinin
in cardiac surgery. Ann Thorac Surg 2007;84:1144-1150.
72. Despotis GJ, Filos KS, Levine V, et al. Aprotinin prolongs activated and nonactivated whole blood clotting
time and potentiates the effect of heparin in vitro. Anesth Analg 1996;82:1126-1131.
73. Hunt BJ, Segal H, Yacoub M. Aprotinin and heparin monitoring during cardiopulmonary bypass.
Circulation 1992;86:II410-II412.
74. Wang JS, Lin CY, Hung WT, et al. Monitoring of heparin-induced anticoagulation with kaolin-activated
clotting time in cardiac surgical patients treated with aprotinin. Anesthesiology 1992;77:1080-1084.
75. Alderman EL, Levy JH, Rich JB, et al. Analyses of coronary graft patency after aprotinin use: results from
the International Multicenter Aprotinin Graft Patency Experience (IMAGE) trial. J Thorac Cardiovasc Surg
1998;116:716-730.
76. Kalkat M, Levine A, Dunning J. Does use of aprotinin in coronary artery bypass graft surgery affect graft
patency? Interact Cardiovasc Thorac Surg 2004;3:124-128.
77. Jegaden O, Vedrinne C, Rossi R. Aprotinin does not compromise arterial graft patency in coronary
bypass operations. J Thorac Cardiovasc Surg 1993;106:180-181.
78. Mangano DT, Tudor IC, Dietzel C; Multicenter Study of Perioperative Ischemia Research Group;
Ischemia Research and Education Foundation. The risk associated with aprotinin in cardiac surgery. N Engl
J Med 2006;354:353-365.
79. Karkouti K, Beattie WS, Dattilo KM, et al. A propensity score case-control comparison of aprotinin and
tranexamic acid in high-transfusion-risk cardiac surgery. Transfusion 2006;46:327-338.
80. Mangano DT, Miao Y, Vuylsteke A, et al.; Investigators of The Multicenter Study of Perioperative
Ischemia Research Group; Ischemia Research and Education Foundation. Mortality associated with aprotinin
during 5 years following coronary artery bypass graft surgery. JAMA 2007;297:471-479.
81. Fergusson DA, Hebert PC, Mazer CD, et al. A comparison of aprotinin and lysine analogues in high-risk
cardiac surgery. N Engl J Med 2008;358:2319-2331.
82. McMullan V, Alston RP. The effect of the suspension of the license for aprotinin on the care of patients
undergoing cardiac surgery: a survey of cardiac anesthesiologists’ and surgeons’ opinions in the United
Kingdom. J Cardiothorac Vasc Anesth 2010;24:418-421.
83. Schneeweiss S, Seeger JD, Landon J, et al. Aprotinin during coronary-artery bypass grafting and risk of
death. N Engl J Med 2008;358:771-783.
84. Shaw AD, Stafford-Smith M, White WD, et al. The effect of aprotinin on outcome after coronary-artery
bypass grafting. N Engl J Med 2008;358:784-793.
85. Society of Thoracic Surgeons Blood Conservation Guideline Task Force; Society of Cardiovascular
Anesthesiologists Special Task Force on Blood Transfusion; International Consortium for Evidence Based
Perfusion. 2011 update to the Society of Thoracic Surgeons and the Society of Cardiovascular
Anesthesiologists blood conservation clinical practice guidelines. Ann Thorac Surg 2011;91:944-982.
86. Wang X, Zheng Z, Ao H, et al. A comparison before and after aprotinin was suspended in cardiac
surgery: different results in the real world from a single cardiac center in China. J Thorac Cardiovasc Surg
2009;138:897-903.
87. Beckerman Z, Shopen Y, Alon H, et al. Coronary artery bypass grafting after aprotinin: are we doing
better? J Thorac Cardiovasc Surg 2013;145:243-248.
88. Walkden GJ, Verheyden V, Goudie R, et al. Increased perioperative mortality following aprotinin
withdrawal: a real-world analysis of blood management strategies in adult cardiac surgery. Intensive Care
Med 2013;39:1808-1817.
89. Bennett-Guerrero E, Song HK, Zhao Y, et al. Temporal changes in the use of blood products for
coronary artery bypass graft surgery in North America: an analysis of the Society of Thoracic Surgeons Adult
Cardiac Database. J Cardiothorac Vasc Anesth 2010;24:814-816.
90. Pagano D, Howell NJ, Freemantle N, et al. Bleeding in cardiac surgery: the use of aprotinin does not
affect survival. J Thorac Cardiovasc Surg 2008;135:495-502.
91. Karkouti K, Wijeysundera DN, Yau TM, et al. The risk-benefit profile of aprotinin versus tranexamic acid
in cardiac surgery. Anesth Analg 2010;110: 21-29.
92. Meybohm P, Herrmann E, Nierhoff J, et al. Aprotinin may increase mortality in low and intermediate risk
but not in high risk cardiac surgical patients compared to tranexamic acid and epsilon-aminocaproic acid—a
meta-analysis of randomised and observational trials of over 30,000 patients. PLoS One 2013;8:e58009.
93. Hebert PC, Fergusson DA, Hutton B, et al. Regulatory decisions pertaining to aprotinin may be putting
patients at risk. CMAJ 2014;186:1379-1386.
94. Rosen M. EMA, transparency, and decision-making process. Lancet 2013;382:26-27.
95. Mannucci PM. Desmopressin (DDAVP) in the treatment of bleeding disorders: the first twenty years.
Haemophilia 2000;6(Suppl 1):60-67.
96. Rodeghiero F, Castaman G, Mannucci PM. Clinical indications for desmopressin (DDAVP) in congenital
and acquired von Willebrand disease. Blood Rev 1991;5:155-161.
97. Franchini M, Favaloro EJ, Lippi G. Mild hemophilia A. J Thromb Haemost 2010;8:421-432.
98. Mannucci PM. Hemostatic drugs. N Engl J Med 1998;339:245-253.
99. Kaufmann JE, Vischer UM. Cellular mechanisms of the hemostatic effects of desmopressin (DDAVP). J
Thromb Haemost 2003;1:682-689.
100. de la Fuente B, Kasper CK, Rickles FR, et al. Response of patients with mild and moderate hemophilia
A and von Willebrand’s disease to treatment with desmopressin. Ann Intern Med 1985;103:6-14.
101. Mannucci PM, Remuzzi G, Pusineri F, et al. Deamino-8-D-arginine vasopressin shortens the bleeding
time in uremia. N Engl J Med 1983;308:8-12.
102. Nolan B, White B, Smith J, et al. Desmopressin: therapeutic limitations in children and adults with
inherited coagulation disorders. Br J Haematol 2000;109:865-869.
103. Carless PA, Henry DA, Moxey AJ, et al. Desmopressin for minimising perioperative allogeneic blood
transfusion. Cochrane Database Syst Rev 2004;(1):CD001884.
104. Wademan BH, Galvin SD. Desmopressin for reducing postoperative blood loss and transfusion
requirements following cardiac surgery in adults. Interact Cardiovasc Thorac Surg 2014;18:360-370.
105. Levi M, Cromheecke ME, de Jonge E, et al. Pharmacological strategies to decrease excessive blood
loss in cardiac surgery: a meta-analysis of clinically relevant endpoints. Lancet 1999;354:1940-1947.
106. Dietrich W, Nicklisch S, Koster A, et al. CU-2010—a novel small molecule protease inhibitor with
antifibrinolytic and anticoagulant properties. Anesthesiology 2009;110:123-130.
107. Szabo G, Veres G, Radovits T, et al. Effects of novel synthetic serine protease inhibitors on
postoperative blood loss, coagulation parameters, and vascular relaxation after cardiac surgery. J Thorac
Cardiovasc Surg 2010;139:181-188; discussion 188.
108. Szabo G, Veres G, Radovits T, et al. The novel synthetic serine protease inhibitor CU-2010 dose-
dependently reduces postoperative blood loss and improves postischemic recovery after cardiac surgery in a
canine model. J Thorac Cardiovasc Surg 2010;139:732-740.
109. Englberger L, Dietrich W, Eberle B, et al. A novel blood-sparing agent in cardiac surgery? First in-
patient experience with the synthetic serine protease inhibitor MDCO-2010: a phase II, randomized, double-
blind, placebo-controlled study in patients undergoing coronary artery bypass grafting with cardiopulmonary
110. Kim H, Szlam F, Tanaka KA, et al. The effects of MDCO-2010, a serine protease inhibitor, on activated
clotting time in blood obtained from volunteers and cardiac surgical patients. Anesth Analg 2012;115:244-
252.
111. The Medicines Company Discontinues Phase 2b Trial of MDCO-2010. Available at

http://ir.themedicinescompany.com/phoenix.zhtml?c=122204&p=irol-news Article&ID=1741990. Accessed 8
April 2015.
112. Karski JM, Dowd NP, Joiner R, Carroll J, Peniston C, Bailey K, Glynn MF, Teasdale SJ, Cheng DC.
The effect of three different doses of tranexamic acid on blood loss after cardiac surgery with mild systemic
hypothermia (32 degrees C). J Cardiothorac Vasc Anesth. 1998 Dec;12(6):642-6.
113. Dietrich W, Spannagl M, Boehm J, Hauner K, Braun S, Schuster T, Busley R. Tranexamic acid and
aprotinin in primary cardiac operations: an analysis of 220 cardiac surgical patients treated with tranexamic
acid or aprotinin. Anesth Analg. 2008 Nov;107(5):1469-78.
114. Karski JM, Teasdale SJ, Norman P, Carroll J, VanKessel K, Wong P, Glynn MF. Prevention of bleeding
after cardiopulmonary bypass with high-dose tranexamic acid. Double-blind, randomized clinical trial. J
Thorac Cardiovasc Surg. 1995 Sep;110(3):835-42.
115. Horrow JC, Van Riper DF, Strong MD, Grunewald KE, Parmet JL. The dose-response relationship of
tranexamic acid. Anesthesiology. 1995 Feb; 82(2):383-92.
Chapter 22
Conduct of Cardiopulmonary Bypass
Mark Kurusz
Vincent R. Conti
Richard F. Davis
Total body perfusion represents a most exciting hemodynamic experiment, since it offers the unique possibility
of controlling blood flows, intravascular pressures, and circulating blood volume at will. Because these
parameters are interrelated in ways still not fully understood, total body perfusion also presents a difficult
challenge to those who attempt it (1, p. 194).
The thoughts in the preceding text appeared in 1962 when cardiopulmonary bypass (CPB) was still considered
by some to be experimental. Although that era and belief have long passed, CPB still represents a challenge
because there are aspects primarily involving subtle patient physiologic reactions, and, to a lesser degree,
methods of management that are still not fully understood. As a clinical modality practiced many thousands of
times daily worldwide, basic principles and practices for the safe conduct of CPB have been mostly empirically
determined and refined over the last 50 years, even though a large body of published literature now exists, with
several hundred articles appearing each year.
Perfusion as a field of study and practice by professionals has emerged during the last five decades. In the
1950s and early 1960s, physicians who had experimented and trained with the technology in the animal research
laboratory often performed CPB. Much of the equipment used during that era was fabricated within the
institution. Disposable devices were unheard of and polished stainless steel, glass, industrial-grade plastic, and
rubber tubing comprised the CPB circuitry.
Currently, formal perfusion educational programs teach clinical applications of extracorporeal technology for
medical situations where it is necessary to support or temporarily replace a patient’s circulatory or respiratory
function (2). These programs have evolved from diploma programs emphasizing intensive clinical experience to
baccalaureate or advanced degree programs with didactic courses in the basic sciences (3). The animal
laboratory, which was an important training environment decades ago, has been replaced by high-fidelity
perfusion simulators (4). The perfusionist is knowledgeable regarding applications of the technology for patients
with varying degrees of pathophysiologic conditions and is educated to conduct CPB safely. There is a wide
variety of cardiopulmonary equipment and supplies available, and there are many different ways in which these
components can be assembled and used. In the last three decades, increased awareness of abnormal events (or
the rare perfusion mishap) resulting in adverse clinical outcome has further helped define safe practices and
codify institutional protocols and national practice guidelines.
As noted in Galletti and Brecher’s classic text (1, p. 251), “Cardiopulmonary bypass is such a formidable
intrusion into the mechanisms of homeostasis that monitoring of a few key parameters is necessary for
maintenance of viable conditions.” Besides monitoring basic physiologic functions and CPB device and circuit
performance, safe conduct also entails activities before and after bypass, including selection of appropriate
equipment, assembly and priming of the system, completion of checklists, resumption of normal cardiopulmonary
function, disposition of residual perfusate, and initiation and reversal of systemic anticoagulation.
The conduct of CPB involves personnel from different disciplines and backgrounds who must function together
as a team (5, p. 23). These disciplines are surgery, anesthesiology, perfusion, and nursing, none of which
individually holds substantially greater importance during CPB. Activities of any team member can affect the
performance of other team members, so effective communication is important for successful outcome. The
importance of these team members functioning skillfully and in concert during CPB may be without equal in the
practice of medicine (6).
This chapter reviews the conduct of CPB, including initiation, performance and monitoring, and physiologic
response. Generic institutional checklists and protocols are discussed, and guidelines and standards that have
been promulgated by professional organizations are reviewed and summarized.
CIRCUIT
Chart Review and Selection of Equipment
Before assembling the perfusion circuit, information from the patient’s chart is reviewed regarding the proposed
surgical procedure and relevant history. Equipment is then selected that is appropriate to surgical and patient
needs. The circuit consists of reusable equipment and disposable components
P.530
available from commercial sources. For most adult cardiac surgical procedures, the circuit is standardized, but for
pediatric cases, smaller adults, and for special or infrequently performed procedures such as thoracic aortic
surgery, the circuitry is often modified to accommodate patient size or surgical needs specific to the procedure.
Disposable components are supplied sterile and individually wrapped. In a few settings, reusable devices such
as stainless steel connectors or suction tips may be used. Reusable equipment such as the CPB console,
cooler-heater, or point-of-care blood testing devices are cleaned after each case and maintained in good working
order with regularly scheduled preventive maintenance (7). Hospital biomedical personnel or equipment
manufacturer representatives can perform this preventive maintenance (8).
Assembly
After confirming sterile packaging for integrity, the perfusionist assembles the circuit, usually while the patient is
prepared for surgery by nursing and anesthesia personnel. In some hospitals, a generic circuit is assembled (but
not primed with fluid) and kept available at all times in the event CPB is needed urgently. These circuits must be
kept in a secure area with sealed ports and vents to maintain sterility of the blood-contacting surfaces. Such
preassembled circuits may be used for regularly scheduled procedures so that an extended period of time does
not elapse before the circuit is used (9). Having such preassembled CPB circuits on site and ready to prime
enhances the surgical team’s ability to respond rapidly to urgent situations. In some instances, an assembled
and preprimed circuit may be used when emergency institution of CPB may be required. If these circuits are
maintained sterile, they may be used within an institutionally-determined period of time for elective cases.
The exact sequence of circuit assembly varies among perfusionists but should be done in a consistent manner to
facilitate the occasional need for urgent circuit assembly. Components routinely include the oxygenator (with or
without integral venous and/or cardiotomy reservoir) and arterial filter and may also include an external
cardiotomy reservoir, centrifugal pump head, cardioplegia delivery set, and a filter for hemoconcentration. Some
recently introduced membrane oxygenators have an integral arterial filter. The selected components are
connected together with precut sterile tubing most commonly supplied in an institution-specific customized tubing
pack. The tubing or device manufacturer may supply some components preconnected for more rapid assembly
and convenience. In the rare instance when tubing must be cut to size at the time of assembly, careful attention
to sterile technique is necessary to avoid potential contamination of the blood-contacting surfaces.
Once the connected devices are mounted on the CPB console, the water source to the heat exchanger and
cardioplegia delivery system should be turned on and tested to verify adequate flow over ranges of expected
temperatures. These components are then observed for integrity and absence of water leaks into the blood-
contacting sections. The CPB circuit may be briefly flushed with filtered 100% carbon dioxide to displace room
air. This technique was originally used as an aid for arterial filter priming (10) but is also advantageous for de-
airing membrane oxygenators (11) because carbon dioxide is approximately 30 times more soluble than the
nitrogen in room air (12), which greatly facilitates the removal of gas bubbles from the circuit when it is primed
with fluid. For most effective displacement of room air, tubing clamps should be placed in a manner that directs
carbon dioxide flow through all the CPB blood-contacting components.
Priming
Balanced electrolyte solution and additives, excluding blood products, are then added to the CPB circuit (usually
through the cardiotomy or venous reservoir) and recirculated through a prebypass filter (0.2-5 μm pore size). The
prebypass filter is often positioned as a connection between the arterial and venous lines and is part of the
sterile tubing placed on the surgical field or enclosed in sterile wrapping material. Its purpose is to remove any
potential small debris that may be present from the manufacture or assembly of devices or tubing (13). After an
appropriate period of recirculation, the prebypass filter is removed, most often when separating the arterial and
venous lines just before cannulation, in a way that avoids reintroduction of any captured debris into the circuit.
Except for patients with a low blood volume (smaller adults and some pediatric patients), and patients with a low
starting hematocrit, the use of homologous packed red blood cells as a component of the prime fluid is
infrequently necessary. If blood is deemed necessary in the prime before initiating CPB, it should be added after
removal of the prebypass filter and recirculated to ensure adequate mixing with the crystalloid solution and any
drug additives. Recirculation of perfusate also allows the circuit to be “stressed” at flows and pressures at or
exceeding those expected to be used during CPB to ensure circuit integrity. Recirculation also allows for
adjustment of the perfusate pH, Pco2, Po2, and electrolyte composition.
Setting Occlusion and Verifying Accuracy of Pump Flow

To ensure accurate delivery of systemic blood flow when a roller pump is being used, the occlusion should be
set before bypass after verifying proper blood flow direction by tracing the tubing from the operative field to the
CPB circuit and back to ensure proper tubing assembly. A small gap should exist between the tubing and the
roller pump backing plate, and the tubing should be aligned so that it does not ride up or down within the pump
housing with normal rotation of the rollers. When it is properly assembled the roller pump tubing resembles a “U”
shape, which is maintained by securing the tubing at the inlet and outlet with correctly sized tubing inserts or
holders.
P.531
The traditional method for setting occlusion is to allow a 30- to 40-inch vertical column of fluid in the outlet side of
the tubing to drop slightly (at a rate less than 1 inch/min) by adjusting roller occlusion against the backing plate
(14, p. 376). The occlusion should be set by moving the rollers toward the pump backing plate to accommodate
any free play in the occlusion adjustment mechanism; if the occlusion is set by moving the rollers away from the
backing plate, underocclusion may result when the pump is operating. Each roller should be checked in three
positions (typically, at 8, 6, and 4 o’clock where 11 and 1 o’clock approximate the positions of the inlet and outlet,
respectively). In the event the two rollers in the pump head do not yield the same rate of fluid drop, the occlusion
should be set to the roller that is most occlusive.
A second method for setting roller pump occlusion (15) is to fill the systemic flow tubing (or line) with priming fluid
and then pressurize the line by applying a tubing clamp beyond a pressure monitoring port and slightly
advancing and then stopping the roller pump. The degree of pump head occlusion is then assessed by
observing a slow decline in the line pressure.
A third method (16) for setting roller pump head occlusion is the so-called dynamic method whereby the
occlusion is adjusted while the roller pump rotates. A pressure monitor is required, as is a pressure-activated,
valved shunt between the outlet and inlet tubing to prevent overpressurization. Like the second method, a tubing
clamp is applied to the fluid-filled arterial line downstream of the pump head. With the pump rotating at 6 to 10
revolutions per minute (rpm), the occlusion is adjusted to maintain a pressure above that anticipated during CPB.
Using this method, fluid displaced will flow across the valved shunt while the desired pressure is maintained.
Because the flow output of a centrifugal pump is afterload-sensitive and functions differently from a roller pump,
occlusion setting is not required. However, like the roller pump, the inlet and outlet lines must be correctly
identified and connected to ensure proper direction of flow. When a centrifugal pump is used for systemic blood
flow, a flow probe (either inline or clamp-on type) must also be calibrated and zeroed before CPB to ensure
accurate flow readings. Centrifugal pumps are not used for suction or venting because possible air entrainment
will effectively deprime the pump and stop its suction effect and forward flow.
The occlusion of suction and vent roller pumps is set when the tubing is fluid free by clamping the inlet tubing,
starting the roller pump at moderate rpm and adjusting the degree of occlusion until the tubing in the roller pump
just collapses. This is assessed visually or by hearing a “smacking” sound as the tubing in the pump repeatedly
collapses as negative pressure is created and then released with rotation of the rollers. After setting the
occlusion but before removing the inlet clamp, each roller should be stopped at three positions to verify that the
tubing remains collapsed, thereby ensuring adequate occlusion. The response will depend on tubing wall
thickness and type (polyvinyl chloride or silicone rubber). Suction pumps should then also be tested with water to
confirm they are aspirating fluid instead of blowing air, which indicates that the suction pump has been either
assembled incorrectly (inlet and outlet reversed) or the pump is rotating in reverse of its intended operation; a
reversed suction or vent pump carries the serious risk of air embolism. If a suction or vent pump is nonocclusive,
there is also a risk of air embolism should the cardiotomy reservoir become pressurized (17).
A conventional blood cardioplegia delivery pump contains two segments of tubing, one for blood and the other
for the crystalloid component of the cardioplegia solution. Because these tubes often have different diameters,
setting the proper occlusion for this pump must ensure that both segments are occlusive. The two segments of
tubing are typically joined with a Y-connection after the roller pump to deliver the mixed cardioplegia solution in
the appropriate ratio (typically 4:1 blood to crystalloid). A shunt connecting both sets of tubing may be located
before the pump to allow delivery of blood alone. Setting the appropriate occlusion can be accomplished by
observing a slow drop and then cessation of fluid drop from a spiked bag of crystalloid solution when the delivery
system is initially primed. This should be performed while recirculating fluid through the arterial/venous loop with
the systemic flow pump so that the cardioplegia pump is operated under pressure. Like the method outlined
earlier, each roller should be checked in three positions. As an alternative, the cardioplegia pump occlusion can
be set observing the pressure decline after pressurizing the delivery system by placing a tubing clamp on the
outlet tubing. If the occlusion is properly set, there will be no decline in pressure measured between the pump
assembly and clamp.
Regardless of how the occlusion is set on the cardioplegia pump, a second way to assess proper occlusion is to
verify that no fluid leaks past the roller pump and begins to fill the crystalloid bag when the systemic pump is
rotating and the cardioplegia pump is stopped. When two tubing segments are placed in a single roller pump, it is
important that both segments are approximately equal in length to avoid kinking, excessive stretching, or
overriding of one segment upon the other, all of which can interfere with effective pump function. There are
dedicated, stand-alone cardioplegia delivery systems, such as the myocardial protection system (MPS)
manufactured by Quest Medical, Inc. (Allen, TX), which employs precisely metered small volume electrolyte
concentrations and blood composition together with temperature control; this has largely obviated much of the
difficulty with previously employed roller pump cardioplegia delivery systems.
Positioning the Pump and Arrangement of Lines

When the surgeon is ready to begin CPB, the heart-lung machine console is positioned near the operating table.
Some surgeons prefer that the pump is placed opposite them, most often parallel to the table and on the patient’s
left side, whereas
P.532
others prefer to have the pump positioned on the patient’s right side directly behind the primary surgeon.
Depending on other equipment in the room or institutional preference, the pump may also be positioned at an
angle to the patient or at the foot of the table. Whatever the chosen position, the pump should be placed in such
a manner to minimize tubing lengths to the cannulation sites so as to decrease the required crystalloid priming
volume and its commensurate hemodilution upon initiation of bypass.
Sterile pump lines may be passed from the sterile surgical field to the perfusionist for connection to the CPB
circuit, but alternatively the use of sterile prepackaged tubing kits allows the perfusionist to pass the sterile lines
to personnel at the operative field. The console position and line arrangement also should permit easy line
identification and visualization using colored tapes pre-affixed to the tubing and allow for surgical personnel
mobility during the procedure without compromising operative field sterility or kinking the CPB lines. Sufficient
lengths of tubing should be provided between the oxygenator, venous reservoir, and systemic blood pump to
enable CPB component change-out or hand-cranking if they are required.
Pre-CPB Checklist
Between the times of pump assembly and cannulation for CPB, the primary perfusionist should complete a
prebypass checklist to verify proper assembly and function of all CPB equipment (18). Checklist formats include
memorized, written, and automated types (19). The written type is most common and consists of items that are
checked off a list sequentially. This exercise can be conducted as a “do-list” format in which the checklist item
triggers a response as a series of tasks are performed or as a “done-list” whereby the task is either verified to
have been completed or it is repeated. The redundancy incorporated into the second method increases the
chance of the task being completed. The checklist procedure may be conducted either “silent,” in which one
person performs both the checklist and tasks, or it may be carried out as a “challenge and response” where
either two people, or one person and a computer prompt, then record task performance. By analogy to cockpit
checklists, which are mandated in commercial aviation, the “challenge and response” methodology is the most
robust, but it does require two individuals to participate.
Checklists can be abbreviated or all inclusive. All-inclusive checklists tend to be long and are subject to misuse
because of the demands of checking each item on a long list. Checklists are most effective if they contain only
those items, which if omitted, would have a direct and adverse effect on the safe conduct of CPB. In aviation
checklists, such items are referred to as “killer” items. Examples of such items in perfusion practice would be
failure to securely connect the ventilating gas delivery line to the oxygenator, failure to properly set the occlusion
on a roller pump, or assembly of vent tubing in a roller pump in the incorrect direction. Generic checklists have
been promoted by the American Society of Extracorporeal Technology (AmSECT) (20) but in practice checklists
are most often customized for specific hospital or surgeon protocol. Whatever system is used, the pre-CPB
checklist should be in the “always and never” category of activities, that is “always” done and “never” omitted.
The sections of a checklist should include items related to: patient and procedure; sterility of CPB components;
proper pump assembly and function; adequacy of electrical connections; operational readiness of cardioplegia
delivery system including proper solutions; adequacy of oxygenator ventilating gas supply; arrangement and
integrity of CPB lines; testing and engagement of alarms; use of positive and negative pressure relief valves and
operational vacuum regulator if assisted venous return is used; calibration and placement of monitors and
probes; documentation of adequate anticoagulation; operational capacity of water supply system; verification of
anticoagulation; and availability of backup supplies and equipment. In addition, the checklist may contain a
termination of CPB section addressing confirmation that if vacuum-assisted venous drainage (VAVD) has been
used, the vacuum source is disabled and reservoirs are vented to atmosphere, and shunts and vents are either
clamped or removed. The post-CPB checklist calls for announcement by the perfusionist that CPB has been
terminated; other items addressed in a post-CPB checklist include clamping the arterial and venous tubing and
confirming with those at the surgical field that the arterial circuit and aortic cannula are bubble-free in the event
residual perfusate needs to be transfused from the CPB circuit. In the event CPB must be restarted emergently,
a checklist should be used to confirm adequate anticoagulation in the event it has been reversed, all components
are debubbled, gas flow to the oxygenator is reestablished, and alarms that may have been disengaged are
reactivated.
INITIATION OF BYPASS
Connection of Patient to Circuit
After administration of systemic heparin and verification that the patient is adequately anticoagulated, the
perfusate is recirculated through the CPB circuit one final time while the lines are tapped and inspected by the
surgeon or an assistant to verify absence of any visible gas bubbles. Recirculation is stopped and the arterial
and venous lines are then clamped at the pump and table. The perfusionist must ensure any stopcocks or tubing
shunts between the systemic pump and arterial tubing at the field are also closed to avoid draining perfusate
retrograde when the tubing clamp is removed at the field. The surgeon or assistant divides the arterial/venous
recirculation loop. Most often, the surgeon connects the CPB systemic tubing to the arterial cannula first after
securing it in the ascending aorta with purse-string sutures. After the cannula is filled retrograde with the
patient’s blood, an air-free connection is made between the CPB arterial flow line and the arterial cannula.
Having the perfusionist advance the perfusate by slowly activating
P.533
the systemic flow pump (the so-called “bump the pump” maneuver) will facilitate an air-free connection;
alternatively, an assistant can add sterile fluid from a syringe as the CPB line and cannula are joined. If the latter
technique is used, the systemic flow line must be identified and distinguished from the venous drainage line to
avoid the risk of reversed lines. This is particularly a risk if the tubing diameter for both the systemic and venous
tubing is identical; color-coding the tubing so each can be correctly identified will lessen the risk of a
misconnection leading to reversed lines.
After removal of the arterial line clamp at the field, the perfusionist should manually palpate or observe pulsation
on an arterial flow line pressure monitor. The pressure transmitted from the aortic cannula through the arterial
flow line will reasonably ensure that the cannula has been placed in the lumen of the aorta (or other arterial site).
Absence of adequate pulsation may indicate malposition of the cannula or its insertion into the vessel wall, which
could lead to arterial wall hematoma or dissection upon initiation of CPB. Some protocols call for the perfusionist
to administer a 100-mL bolus of perfusate before starting bypass by briefly activating the systemic pump to
further ensure patency between the CPB tubing and patient’s systemic circulation. If transesophageal
echocardiography (TEE) is being used, the tip of the aortic canula may be imaged during this bolus to further
verify cannula tip position and flow direction.
Fluid Balance and Circuit Priming Volume

It is often prudent to obtain an estimation of the patient’s fluid balance from the time of arrival in the operating
room (OR) by checking and recording the estimated blood loss, urinary output, and volume of fluids administered
by anesthesia personnel. Knowing the patient’s estimated blood volume, hematocrit, and circuit priming volume
allows calculation of an estimated hematocrit after initiation of CPB. This will give the perfusionist and
anesthesiologist some indication of CPB fluid or blood requirements.
To reduce circuit priming volume and the resultant hemodilution upon starting CPB, a technique called
retrograde autologous priming may be used (21). After connecting the arterial line and cannula but before
starting bypass, priming fluid can be removed from the circuit through a stopcock on the arterial filter or arterial
sampling manifold by allowing the patient’s arterial blood to displace the crystalloid priming solution. This
procedure can be accomplished relatively quickly while carefully monitoring the patient’s hemodynamics. The
volume of priming solution displaced in this manner typically ranges between 200 and 600 mL. Retrograde
autologous priming techniques must be carefully employed to avoid pre-CPB hemodynamic instability during the
withdrawal and/or at the onset of CPB due to insufficient reservoir volume to sustain full pump flows. Further,
there are little published data in adults showing improved fluid balance or transfusion sparing associated with
this technique.
Another method for reducing priming volume relies on VAVD (22). After final pre-CPB recirculation, priming fluid
in the venous line can be discarded or sequestered in a sterile intravenous bag for later administration on CPB,
leaving the venous line devoid of fluid and containing only room air. When this technique is used, a clamp must
remain in place on the venous cannula until immediately before starting bypass. Because the technique of VAVD
does not totally rely on gravity siphon drainage but instead uses regulated vacuum applied to a hardshell venous
reservoir, removal of the venous line clamp will allow the negative pressure created in the reservoir to actively
withdraw venous blood from the patient upon initiation of CPB. This approach may eliminate 400 to 1,000 mL of
priming solution but carries the risk of generating gaseous microemboli from the room air in venous tubing that
will traverse the oxygenator and arterial filter upon initiation of CPB (23).
The anticipated result of these circuit prime reduction techniques is a higher hematocrit during CPB and a
possible reduced need for administration of homologous blood either during or after bypass (24). This exercise
will fail to achieve this goal if the patient’s blood volume is marginal before CPB, because ultimately this will
manifest as a reduced blood level in the venous reservoir to maintain appropriate systemic flows, thus mandating
the addition of crystalloid or blood. Reduction of the hyperdynamic response often seen after CPB has been
reported when using minimal CPB priming volumes (25). The gradual adoption of so-called mini-bypass systems
are also aimed at reduced hemodilution and improved clinical outcomes when CPB is used, and manufacturers
have developed systems but their role is yet to be determined in most centers (26).
Establishing Extracorporeal Blood Flow

Upon instruction from the surgeon, CPB begins by removing the clamp(s) on the arterial line and activating the
systemic pump speed control. If a centrifugal pump is used, the pump speed control should be increased to
sufficient rpm to avoid retrograde flow before unclamping the arterial line because such retrograde flow has been
associated with air entry into the systemic tubing from the aortic cannulation site (27).
The rationale for starting flow in the systemic pump before releasing the venous line clamp is to avoid
exsanguinating the patient into the CPB circuit in the event of a pump malfunction. As the volume of perfusate in
the CPB reservoir begins to decrease, the venous line clamp or occluder is released (partially or totally
depending on whether the surgeon wishes to maintain some cardiac ejection or have the heart immediately
decompressed), allowing venous blood to drain into the CPB reservoir. Full CPB flow can be established in most
cases within 15 to 20 seconds. Systemic flow is most often indexed to the patient body surface area (in m2) or
weight (in kg). Generally accepted indices are 2.2 to 2.4 L/min/m2 or 50 to 65 mL/kg when normothermic or when
cooling. Higher indices are often used in pediatric patients or when rewarming the adult patient. Once the patient
is hypothermic, these indices
P.534
may be reduced proportionate to the degree of hypothermia because of decreased oxygen consumption (28).
The arterial filter purge line stopcock is opened to provide a low-pressure vent for removal of any potential gas
emboli in the systemic flow line. For oxygenators containing an integral arterial filter the purge function still
requires it to be opened once full blood flow is established and then clamped off or closed by means of a
stopcock when CPB is stopped. The volume of arterial blood shunted back into the venous reservoir or
cardiotomy reservoir through an active purge is generally 150 to 300 mL/min but can be greater than 500 mL/min
depending on purge line diameter and length and the arterial line pressure. By connecting a non-integrated
purge line to the cardiotomy reservoir, the volume flow per minute can be measured by clamping the cardiotomy
drain line for 10 seconds, noting the volume rise in the reservoir, and then multiplying by 6 to get mL/min shunt
flow. Although the effect of this shunt volume is generally insignificant in adults, it can be clinically important
during pediatric cases, potentially leading to hypoperfusion (29). Consequently, in the latter clinical scenario, the
purge line is kept closed or only partially open with brief intermittent periods of unrestricted flow for purging.
If VAVD is being used, regulated vacuum less than -100 mm Hg is applied to the venous reservoir only after
establishing full CPB flow. It is recommended to use the least degree of vacuum necessary to achieve adequate
venous drainage. Excessive levels of vacuum may cause hemolysis (30) or even vascular collapse in the
patient’s large veins. It is extremely important that the cardiotomy/venous reservoir should not be closed to
atmosphere before establishing CPB and after CPB is stopped because operational suction pumps may cause
pressurization that can lead to retrograde air embolism (31). Use of positive pressure relief valves are designed
to prevent this complication and should be incorporated into the circuit whenever VAVD is used.
Management of Gas Flow

Oxygenators from various manufacturers have different operating characteristics and the instructions for use
should be followed for initial gas settings. The ventilating gas flow to the oxygenator is started just before or
simultaneously with initiation of CPB. Once adequate oxygenation is verified by observing bright red blood or
satisfactory in-line arterial Po2 or Svo2 values, adjustments in gas flow and mixture are made. A useful technique
for managing and assessing oxygenator ventilating gas (sweep) flow settings is to express it in a ratio to the
systemic blood flow. Typical gas-toblood flow ratios with current membrane oxygenators are in the range of 0.5
to 1.0:1, depending on patient size and temperature, Svo2, and desired arterial Pco2 values.
Inhalational anesthetics are often delivered to the patient through the oxygenator ventilating gas with a vaporizer
mounted on the CPB console and placed in-line with the oxygenator ventilating gas. This modality can greatly
facilitate systemic blood pressure control in addition to maintaining anesthesia during CPB. It is important to
mount vaporizers in a location away from disposable circuit components because spilled volatile anesthetic fluid
can structurally degrade plastics (32,33,34). Incorporation of a vaporizer in the oxygenator ventilating gas line
requires additional tubing connections, so the integrity of the entire gas line should be verified before starting
bypass. Adequate gas flow may be verified by simply disconnecting the distal end of the gas delivery tubing from
the gas inlet on the oxygenator to confirm gas flow. Alternatively, a more complicated method has been
described (35) whereby clamping the gas line just proximal to its junction with the oxygenator and running a gas
flow sufficient to generate a measured gas line pressure of 40 cm H2O, thereby ensuring that this pressure can
be maintained at minimal (e.g., <200 mL/min) gas flow. Note that such pressurizing of the gas flow line is not
advisable if a vaporizer is connected in-line because the back pressure on the vaporizer chamber would likely
render its metered output inaccurate. If anesthetic vapors are used during CPB, then it is prudent to arrange
some mechanism for directing the exhaust gas from the oxygenator to a gas evacuation system if at all possible;
failure to do so results in trace concentrations of anesthetic vapors escaping into the OR environment. The
controversial issue of blood gas management techniques (α-stat and pH-stat) during hypothermia is more fully
discussed elsewhere in the text.
Placement and Use of Vents

The site of placement and use of vents is discussed more thoroughly elsewhere. As noted earlier, all vents
should be tested before use by briefly immersing the tip of the vent in a basin of saline or pool of blood at the
operative site to verify its suctioning effect (Fig. 22.1). It is important to avoid excessive negative pressures when
operating vents, which can cause hemolysis. This may be accomplished by use of a one-way negative pressure
P.535
relief valve in the vent line. The one-way valve may be placed on the vent tubing either near the pump or at the
sterile field. Regardless of its location, the perfusionist or personnel at the operative field must verify the proper
direction of flow for correct placement of such valves. Sometimes, a small-gauge needle is inserted in the vent
line by the surgeon to relieve pressure in the vent tubing; the necessity for placement of the needle in the proper
(vent) line is extremely important.
FIGURE 22.1. Method for testing the vent before use. Alternatively, the vent tip may be placed in a pool of blood
by the surgeon or assistant to verify proper suctioning before its insertion in the heart or vessels.
Ideally, the perfusionist should be notified when vents are placed, and the surgeon should announce when they
are needed for use. This is particularly important if the vent is placed in a nonroutine manner. Discontinuation
and/or removal of the vent(s) should also be communicated to the perfusionist, because a significant portion of
blood return to the CPB reservoir may be through a vent; therefore, its removal may be accompanied by an
abrupt decrease in the CPB reservoir level.
Operator Safety
Health risks to all open-heart surgical team members include percutaneous needle sticks, blade cuts or other
exposures to blood, and back injuries. Of these, exposure to blood-borne pathogens represents the most serious
risk. Cardiac surgery and CPB pose a high risk of blood exposure, and so-called universal precautions have
been developed and promulgated (36) to decrease the risk of acquiring human immunodeficiency virus (HIV) and
hepatitis B and C viruses. However, healthcare worker awareness and compliance with such precautions appear
to be highly variable (37,38,39,40,41). According to a multicenter study involving surgeons (42), the lifetime risk
of acquiring hepatitis B or C is far greater than that of acquiring HIV (30%-40% vs. 0.5%). The HIV
seroconversion rate from a percutaneous needle stick is 0.2% to 0.5% (43). Because preoperative universal
testing of patients is controversial and more expensive than practicing universal precautions (44), it is prudent for
all who have patient contact during an open-heart surgical procedure to adhere to universal precautions (45).
These include the use of personal protective equipment (gloves, gowns, face masks, and eyeshields), avoidance
of procedures such as recapping used needles or by using blunt-tipped needles, and proper disposal or cleaning
of blood contaminated equipment after the CPB procedure.
MONITORING DURING BYPASS
Physiologic Variables
Because the CPB circuit and the patient’s circulation are contiguous during bypass, circuit performance must be
monitored and managed continuously to maintain adequate perfusion and organ system viability. Kouchoukos
and coauthors (46, p. 81) distinguished between those physiologic variables under direct external control and
other variables determined primarily by patient response. The first types include total systemic blood flow; input
pressure waveform; systemic venous pressure; hematocrit and composition of priming fluid; arterial blood
oxygen, carbon dioxide, and nitrogen levels; and temperature of the perfusate and patient. The patient
determines other variables, some of which are still, in part, determined by external control: systemic vascular
resistance; total body oxygen consumption; mixed venous blood oxygen levels; lactic acidemia and pH; regional
and organ blood flow; and organ function.
Monitoring physiologic function during CPB differs little in principle from normal intraoperative monitoring
practices for surgical procedures of similar magnitude without CPB. Because CPB occupies only a portion of the
total operative interval, management of patients for surgical procedures requiring CPB must include physiologic
monitoring appropriate to the patient’s condition in addition to the routine monitoring associated with all
anesthetic procedures. For example, the pre- and post-CPB course for a patient undergoing a second
aortocoronary bypass surgery with a left ventricular aneurysmectomy would be expected to be more complex
than that for an otherwise healthy child undergoing closure of a secundum atrial septal defect. Accordingly, the
intensity of physiologic monitoring should be based on patient condition, procedural requirements, and potential
problems.
From a practical standpoint, in addition to monitoring patient intravascular pressures (including central venous
pressure [CVP], pulmonary artery [PA], and/or left atrial [LA]) and temperatures (including myocardium), the
perfusionist and anesthesiologist should monitor the electrocardiogram (ECG) and, if used, the
electroencephalogram (EEG). Both can warn of abnormal or unexpected conditions. For example, the
development of cardiac electrical activity manifested by a slow but regular wide QRS waveform may indicate
myocardial rewarming due to inadequate cardioplegia and the need for another infusion of cardioplegia solution.
Urinary output should be monitored periodically during bypass as a relative indication of adequate perfusion.
Blood coagulation status is also monitored throughout bypass. Most often a simple activated coagulation time
(ACT) is performed periodically, the timing of which depends on previous test results, patient temperature, or
elapsed time. Some teams use a whole blood heparin concentration device, the Heparin Monitoring System
(HMS, Medtronic, Inc., Minneapolis, MN) in place of, or in addition to, the traditional ACT (47). It should be noted
that the HMS does not actually measure heparin concentration in blood. Rather it measures the degree of
anticoagulation (basically an ACT) in response to varying known heparin concentrations for the predicted patient
heparin dose, and the degree of reversal of anticoagulation in patient blood in response to varying known doses
of protamine to calculate effective heparin concentration and, at the end of CPB, a predicted protamine
concentration. One purported advantage of measuring this “heparin concentration” is that a more precise
protamine dose may be automatically calculated for post-CPB reversal of anticoagulation.
Continuous assessment of anesthetic depth and degree of muscle relaxant effects during CPB are typically
supplanted by somewhat arbitrary drug dosing schedules—for example, half of the intubating dose of relaxant at
the onset of CPB, continuous use of the vaporizer throughout CPB, and “refreshing” the doses of opioids and
sedatives at the point of rewarming.
P.536
Decreasing Svo2 or overt patient movement may indicate that additional anesthetic drugs are required.
Circuit Variables
Circuit parameters that should be continuously monitored by the perfusionist include the systemic blood flow by
calibrated roller pump or by electronic flowmeter when using a centrifugal or a nonocclusive type of displacement
pump. Venous blood drainage to the CPB circuit is assessed indirectly by monitoring the volume of perfusate in
the reservoir. The perfusionist should always be aware whether this blood volume is increasing (indicating
venous or other blood return in excess of systemic blood flow), decreasing (indicating the reverse situation), or
relatively stable. Awareness of the rate of rise or fall of volume in the reservoir is required so that appropriate
changes in systemic blood flow can be made in a timely manner before a dangerously low volume situation
occurs. It has been suggested that the venous reservoir volume should be equal to 25% of the systemic blood
flow (L/min) to allow for a 15-second reaction time (5, p. 23). Recommendations from device manufacturers on
minimum blood levels for safe operation to avoid entrainment of air should be considered as well. Figure 22.2
shows reaction times for various reservoir blood volumes at different blood flow rates.
The perfusionist should try to anticipate the surgeon’s needs during bypass (14, p. 376) not only by being aware
of CPB circuit function and the various monitored patient parameters, but also by the progression of the
operation and activity and movements of personnel at the sterile field. It is useful to establish a pattern of
continuous scanning of CPB functions and monitors and the activities of other personnel in the OR. Distractions
and interruptions extraneous to patient management during CPB can lead to errors. In this regard, the
perfusionist would be well advised to adopt a “curious and suspicious” attitude any time CPB is being used. This
is a philosophy practiced by many airplane pilots to anticipate and avoid potential problems (48).
FIGURE 22.2. Reaction times with various cardiopulmonary bypass (CPB) reservoir volumes. Each curve
depicts decreasing reservoir volume plotted as a function of flow rate and time (in seconds) in the event there is
a cessation in venous drainage. As the flow rate is increased, the perfusionist’s time to make an appropriate
reduction in CPB systemic flow is reduced. The dashed horizontal line shows the flow rate that should not be
exceeded for a given reservoir volume to maintain a 15-second reaction time.
The perfusionist adjusts the flow and composition of ventilating gas to the oxygenator in response to changing
patient temperature and blood gas results. This gas flow is monitored by an in-line flowmeter and oxygen
monitor, which should have adjustable upper and lower alarm settings. Inhalational anesthetics, if used, should
be scavenged through suction from the oxygenator exhaust port, and the degree of suction applied must be
regulated to avoid problems with oxygenator gas transfer (49,50) or air embolism (51). Pressure transducers on
the systemic blood flow line can warn of arterial cannula malposition or kinks in the arterial line. Most CPB
consoles can be servoregulated to stop designated roller pumps if a preset line pressure is exceeded. Measuring
oxygenator line pressures both proximal and distal to the membrane allows calculation of pressure drop and may
warn of oxygenator failure (52).
Control over patient cooling and warming rates requires the perfusionist to monitor a variety of temperatures,
including arterial blood, venous blood, and water sources for the oxygenator and cardioplegia delivery system.
Induction and reversal of hypothermia should be guided by maintenance of an 8°C to 12°C gradient between the
arterial blood and patient temperature when cooling and between the venous blood and heat exchanger water
source when rewarming to avoid the potential for free gas to come out of solution (53). It is advisable to monitor
at least two patient temperatures (e.g., bladder, nasopharyngeal, tympanic, rectal, or esophageal) in the event
there is a probe failure or malposition (54). There should also be some periodic assessment of the adequacy of
water flow to the oxygenator’s heat exchanger and cardioplegia delivery system, which can be assessed by a
built-in flow meter on the water source or by listening to the flow and monitoring the water temperature. Cerebral
hyperthermia (55,56,57) should be avoided by careful monitoring of patient and blood temperatures and by not
allowing the perfusate temperature to exceed 37.5°C because organs with high blood flow to tissue mass ratios
(e.g., the brain) will more quickly equilibrate with perfusate temperature than the measured “core” temperature.
Once the heart has recovered its function, some circulating volume may be translocated from the CPB circuit to
the patient to provide left heart ejection so that cooler blood from the venous return is mixed with warm blood
from the arterial line. Perfusing the brain with unmixed perfusate at temperatures greater than 38°C may be
causally related to neurologic dysfunction after the operation and therefore should be avoided.
Suction pump speed should be regulated to achieve adequate blood and/or air removal without excessive pump
speed that can cause the lines to “chatter” when obstructed, potentially resulting in hemolysis. Likewise, when a
roller pump is used for a vent, its speed must be regulated to prevent possible air embolism, which can occur
with high negative pulmonary venous pressures that can pull air across the alveolar membranes (17).
P.537
PHYSIOLOGIC RESPONSE
Cardiovascular Monitoring
Systemic Blood Flow and Perfusion Pressure
Maintenance of cardiovascular stability during CPB requires the obvious interplay of machine (CPB) function for
blood flow and patient factors such as systemic vascular resistance and venous compliance. Yet despite the
ease of blood flow control and the sophisticated pharmacologic agents available for manipulation of vascular
smooth muscle tone, there is no uniformly accepted standard for either CPB systemic blood flow rate or
perfusion pressure. Any discussion of optimum flow rates and perfusion pressure during CPB should be based
on an understanding of oxygen consumption, blood flow distribution, and intrinsic autoregulatory capability of
specific vascular beds.
Fortunately, in some of these areas, a reasonable body of knowledge has developed in the more-than-60-year
history of clinical CPB. Unfortunately, there are large gaps in the data. For example, clinically the regional
distribution of blood flow during hypothermic CPB and the regional vascular autoregulatory capability remain
relatively poorly understood, with some notable exceptions as discussed in subsequent text.
Oxygen Consumption
Minute oxygen consumption (Vo2) is the major determinant of blood flow requirement normally and during CPB.
The well-known Fick equation describes Vo2 in the readily understandable and clinically measurable terms of
cardiac output and arteriovenous oxygen content difference.
Vo2 = Q(Ca-v)o2
where (C(a-v))o2 = (1.34) (Hb) + (P(a-v))o2) (0.0031); Vo2 = minute oxygen consumption (mL/min); Q = cardiac
output (L/min); Hb is the hemoglobin concentration (g/L), 1.34 = hemoglobin oxygen content (mL O2/g) at 100%
saturation (mL/g); (S(a-v))o2 = arteriovenous hemoglobin oxygen saturation difference (mL/L); (P(a-v))o2 =
arteriovenous oxygen partial pressure difference (mm Hg); and 0.0031 = solubility of oxygen in blood (mL O2/mm
Hg/100 mL blood, at 37°C) increased by hypothermia.*,†
Therefore, knowledge of Vo2 allows reasonable prediction of effective blood flow requirement during CPB for any
given level of hemoglobin concentration (hemodilution) and arteriovenous oxygen content difference (oxygen
extraction). Two important caveats apply to this simplistic approach. First, there is a requirement for accurate
knowledge of Vo2 and second, the key phrase is “effective flow.”
Determinants of Vo2
Total systemic Vo2 is primarily a function of age, size (body surface area or lean body mass), and temperature. In
the newborn infant, Vo2 in proportion to body weight is approximately twice that of the average adult (8 vs. 4
mL/kg/min). This proportion rises over the first 2 months of life to a peak of 9 to 10 mL/kg/min. Thereafter, there
is an exponential decline in Vo2 per unit mass, as age increases, which parallels the change in cardiac index with
age. The relation between Vo2 and size is similar to that for Vo2 and age in that as body mass increases (beyond
an age of approximately 6 months), the Vo2 per unit mass actually decreases. The influence of temperature on
Vo2 is fully discussed elsewhere. In the present context, it is important to remember that the relationship is
nonlinear and Vo2 approaches a minimum of 10% to 15% of the normothermic value at approximately 15°C (Fig.
22.3). Importantly, however, this decline in Vo2 with decreasing temperature may not be the same in all organs.
For example, the duration of “safe” circulatory arrest time at 18°C is 45 to 60 minutes regarding neurological
outcome, yet for renal function at 18°C the safe limit is significantly longer. The transplantation literature would
suggest even longer “circulatory arrest” times for transplanted organs (4-5 hours for the heart, 24 or more hours
for the kidney and the liver), recognizing of course that graft organs are stored at more profound levels of
hypothermia (<4°C) than are clinically applied in CPB. However, factors other than decreased Vo2, for example,
variable, tissue-specific tolerance for hypoxia, may also contribute to the variability of safe arrest time in different
organs maintained at the same temperature.
Effective Flow
During CPB, effective blood flow is blood flow from the oxygenator that actually results in tissue perfusion. It must
be understood that arterial blood aspirated from the surgical field represents a loss of effective flow from total
CPB flow. In this context, all physiologic and anatomic shunting of arterialized blood around capillary beds to the
venous circulation also detracts from effective perfusion. For example, bronchial blood flow, which is normally the
major component of “physiologic” right-to-left shunting of blood (accounting for 2%-4% of cardiac output), may
be significantly increased in certain congenital lesions associated with decreased pulmonary arterial blood flow
and correspondingly increased pulmonary collateral blood flow. In adults with significant chronic obstructive lung
disease, bronchial blood flow may also be significantly
P.538
increased. At a total flow rate of 4 to 5 L/min during CPB, this physiologic shunting may normally be 250 to 500
mL/min that is lost from effective systemic perfusion and pathologic increases in bronchial or pulmonary collateral
flow may substantially increase that amount of lost effective blood flow.
FIGURE 22.3. Relation between oxygen consumption (Vo2), as a percent of the control value at 37°C, and body
temperature. The dotted lines show the 70% confidence limits. (From Kouchoukos NT, Blackstone EH, Doty DB,
et al. Kirklin/Barratt-Boyes cardiac surgery, Vol. 1. 3rd ed. Philadelphia, PA: Churchill Livingstone, 2003:70, with
permission.)
Left atrial, left ventricular, or aortic root vents are another common source of loss of effective flow. Blood
returned to the oxygenator from these vent lines is lost from effective systemic perfusion. Parenthetically, the
requirement for such vents is largely created by the existence of physiologic and anatomic shunts. Finally, if the
microcirculation is not homogenously perfused—for example, because of an increased interstitial fluid
compartment either locally or systemically, then the net result is an increased effective diffusion distance for
oxygen from the capillaries to the cells that results in a loss of effective perfusion. Therefore, determination of
effective blood flow is not altogether straightforward, and the volume of effective physiologic blood flow may be
at times significantly less than total CPB systemic output.
Organ Autoregulation
Autoregulation of blood flow to various organ vascular beds during CPB obviously pertains to any discussion of
blood flow rate and perfusion pressure requirements during CPB. Physiologically, autoregulation of blood flow
refers to the ability of organ vasculature, through neural, chemical, and direct smooth muscle effects, to regulate
local resistance to maintain relatively constant flow despite significant changes in perfusion pressure (59, p.
234). This capability is preserved in some organ vascular beds during CPB despite the superimposition of a
nonpulsatile flow pattern, hemodilution, and hypothermia. For example, Govier et al. (64), Prough et al. (65), and
Murkin et al. (66) independently examined cerebral blood flow (CBF) responsiveness to changed perfusion
pressure and carbon dioxide tension during CPB. The conclusion from these studies was that CO2
responsiveness of the cerebral vasculature is maintained during CPB even at 20°C. Also, autoregulation of CBF
to changes in perfusion pressure is preserved during CPB and the response curve may even be shifted to the
left, indicating a decrease of the autoregulatory pressure threshold from the normal of approximately 50 mm Hg
to approximately 30 mm Hg. As discussed by Thomson (67), this lowering of the pressure threshold for
autoregulation is linked to the decreased cerebral metabolic rate for oxygen produced by hypothermia. The
cerebral perfusion pressure (CPP) intercept with the maximal vasodilation blood flow line would be expected to
be lower as temperature decreases if blood flow and metabolic rate remain coupled during hypothermia, as has
been shown by Murkin et al. (66) for a-stat pH management (Fig. 22.4). Others have shown in animal studies
that CBF during moderate hypothermia is primarily regulated by arterial pressure and not CPB systemic flow rate
(68).
The effect of CPB on autoregulation in other organs is clinically less well documented. Likewise, the effect of
CPB on distribution of blood flow to (and within) specific organs requires further study in humans despite nearly
60 years of clinical experience and many millions of cases with CPB, as well as a substantial experimental
database. Experimentally,
P.539
with systemic blood flow in the range of 2.0 to 2.5 L/min/m2, systemic blood flow distribution remains essentially
normal (69). Experimentally, hypothermia during CPB is associated with altered local Vo2, and the associated
change in vascular resistance tends to promote regional blood flow distribution in proportion to the local Vo2
produced by hypothermia.
FIGURE 22.4. Theoretic effect of hypothermic bypass on the autoregulatory threshold. The solid line is the
pressure flow relation for the maximally vasodilated state. The autoregulatory threshold is the point where the
autoregulatory plateau (represented by the dashed lines) intersects the maximal vasodilation pressure flow
relation. Given maintained coupling between cerebral metabolic rate and blood flow, a decreased metabolic rate
such as that produced by hypothermia will effectively produce a leftward shift of the autoregulatory threshold
(lower dashed line, solid line intersection). CBF, cerebral blood flow; CMRo2, cerebral metabolic rate of oxygen
consumption; Hct, hematocrit; CPP, cerebral perfusion pressure. (From Murkin JM, Farrar JK, Tweed A, et al.
Cerebral autoregulation and flow/metabolism coupling during cardiopulmonary bypass: the influence of carbon
dioxide. Anesth Analg 1987;61:825, with permission.)
Monitoring Perfusion Adequacy

Systemic measurements that may indicate the adequacy of total blood flow relative to total Vo2 during CPB
include Svo2, pH, and lactate concentration. The latter two are closely linked because accumulation of lactic acid
in blood leads to hydrogen ion accumulation through dissociation (CH3CHOHCOOH ↔ CH3CHOHCOO-+ H+).
However, there are other sources of hydrogen ion production during oxygen (blood flow) deprivation such as
ongoing glycolysis (anaerobic glucose metabolism) and continued adenosine triphosphate hydrolysis, both of
which produce a net accumulation of hydrogen ion.
Measurement of hemoglobin oxygen saturation in the venous blood (or venous oxygen partial pressure) during
CPB has the same significance as the corresponding PA (mixed venous) measurement during normal circulation.
Given steadystate conditions of hemoglobin concentration, P50 (primarily a function of 2,3-diphosphoglyceric
acid concentration, temperature, and pH), and arterial oxygenation then Svo2 will change in direct proportion to
systemic blood flow at constant Vo2. Unfortunately, the inverse relation between Svo2 and Vo2 (predictable from
the Fick equation) confounds the simple interpretation of Svo2 data. For example, if blood flow and arterial
oxygen content are held constant, then Svo2 will increase as Vo2 decreases (70). In the case of a capillary bed
that is hypoperfused relative to the local level of Vo2, the contribution to the systemic Svo2 (or pH or lactic acid
concentration, for that matter) is a function of the ratio between systemic blood flow volume and the local area
blood flow volume. Importantly, an intense hypoxic insult in a focal area of considerable clinical importance (e.g.,
brain, heart, kidney, gut) may well not produce a major change in Svo2. Accordingly, although monitoring Svo2
during CPB is a common practice, a normal or increased Svo2 value during CPB does not ensure that the CPB
systemic blood flow is necessarily meeting regional oxygen delivery (Do2) requirements. However, a low Svo2
during CPB does indicate a problem with systemic Do2 that may be due to insufficient blood flow, hemoglobin
function or concentration, arterial oxygenation, or excessive oxygen consumption due to inadequate anesthesia
or hyperthermia.
P.540
FIGURE 22.5. Relation of oxygen consumption (Vo2) to perfusion flow rate and temperature. The small xs
represent commonly clinically used flow rates at the various temperatures. (From Kouchoukos NT, Blackstone
EH, Doty DB, et al. Kirklin/Barratt-Boyes Cardiac Surgery, Vol. 1. 3rd ed. Philadelphia, PA: Churchill
Livingstone, 2003:87, with permission.)
Relation between Perfusion and Oxygen Consumption

One method for individualizing blood flow volume relative to Vo2 during CPB was termed oxygen consumption
plateauing by its original describers, Mandl and Motley (71). Using this method, Vo2 is calculated during CPB
and the perfusion is increased until there is no further increase in Vo2, the Vo2 plateau. Perfusion is then
maintained at this level until an intervention occurs that would be expected to alter Vo2, for example rewarming,
at which point the plateau must be reestablished. One theoretic advantage to this technique is that it calls
attention to variables other than flow that have an effect on Vo2. For example, pharmacologic manipulation of
perfusion pressure, if excessive vasoconstriction or vasodilation exists, may improve Vo2, presumably by
improving perfusion to previously underperfused areas. The concept then becomes one of Vo2 optimization.
The chief difficulty of the technique is the lack of a wellaccepted standard against which to compare any given
clinical Vo2 calculation during CPB. The steady-state awake or anesthetized prebypass value may be calculated
and used as the baseline for CPB, when corrected for the expected temperature effect, but using the
uncorrected awake Vo2 as the baseline would yield excess perfusion during CPB. The anesthetized, paralyzed,
mechanically ventilated patient has a substantially lower Vo2 than the awake patient. Another difficulty is that
clinically there is not as clear a plateau to Vo2 as would be theoretically predicted. Parolari et al. (72) have
further studied Vo2 and the influence of hemodynamics during CPB in 101 patients managed with conventional
systemic flow indices (2.4 L/min/m2 during cooling and rewarming and 2.0 L/min/m2 when hypothermic at 28°C-
30°C). There was a direct relation between Do2 and Vo2 during the three phases of bypass. During cooling,
there was no relation between Vo2 and either mean arterial pressure or peripheral vascular resistance, but
during warming these parameters were inversely related; hence, lower mean arterial pressure and peripheral
vascular resistance values were associated with higher Vo2. This may be attributable to the natural tendency for
patients to vasodilate as they rewarm. These authors could not demonstrate a plateau effect in any patient but
acknowledged that only a narrow range of CPB flows and deliveries was used. They recommended higher CPB
systemic flows during all phases of CPB but particularly during rewarming to achieve an optimal whole body
oxygen metabolism. Optimization of Vo2 during CPB may provide the best means of assessing adequacy of
perfusion during CPB; however, this represents an untested hypothesis, at least as measured against the
standard of clinical outcome.
Flow Recommendations
What then are reasonable flow recommendations for CPB? In adults at normothermia, progressive acidosis and
increased lactate production are seen with total flows <1.6 L/min/m2 or 50 mL/kg/min (73,74). Clinical and
experimental data support a total flow of 1.8 L/min/m2 as predictive of the Vo2 plateau in normothermic adults
(75,76). Kouchoukos and coauthors (46, p. 87) recommended a flow of 2.2 L/min/m2 in adults 28°C or warmer. In
patients greater than 2 m2, a systemic flow of 1.8 to 2 L/min/m2 is recommended to avoid excessively high flows
through the CPB circuit that can increase blood damage and lessen the perfusionist’s reaction time. During
hypothermia, various nomograms have been proposed (Fig. 22.5) that predominantly rely on the
P.541
plateauing of Vo2 to indicate overall adequacy of perfusion for any given temperature. The recommended flow in
infants and children is higher at 2.5 L/min/m2. Kern et al. (77) delineated minimum flow rates of 30 mL/kg/min at
18°C and 30 to 35 mL/kg/min at 27°C to 28°C in pediatric patients for maintenance of adequate CBF and
unaltered cerebral oxygen consumption using xenon 133 clearance methods.
FIGURE 22.6. Changes in viscosity of human blood measured in vitro with varying temperatures and hematocrit
(Hct). (From Robicsek F, Masters TN, Niesluchowski W, et al. Vasomotor activity during cardiopulmonary
bypass. In: Utley JR, ed. Pathophysiology and techniques of cardiopulmonary bypass. Baltimore, MD: Williams
& Wilkins, 1983:6, with permission.)
Perfusion Pressure and Vascular Resistance

Perfusion (arterial) pressure during CPB, like blood flow, remains a topic of some controversy in the
management of CPB. In general, blood flow probably outweighs perfusion pressure as a guide to adequacy of
perfusion during CPB, especially with hemodilution, but solid data supporting this contention are lacking. In a
prospective randomized study (albeit relatively small patient numbers) investigating outcomes, Gold et al. (78)
reported that maintenance of higher perfusion pressures in the range 80 to 100 mm Hg (actually achieving a
mean perfusion pressure of 70 mm Hg) using flow indices of 1.9 to 2.3 L/min/m2 and vasoactive drugs was
associated with a reduced combined incidence of cardiac and neurologic complications when compared with
patients whose pressures were maintained at 50 to 60 mm Hg. Perfusion pressure is determined by the
interaction of blood flow and overall arterial impedance. Impedance, in this case, is primarily related to actual
friction resistance because the steady-state nonpulsatile nature of most CPB circuits largely negates the
elastance, inertial, and reflection components that influence aortic input impedance during pulsatile flow. Friction
resistance is primarily a function of the vasomotor tone (cross-sectional area of the arterial system) and blood
viscosity. Viscosity, in turn, is a function of temperature and the degree of hemodilution. The interaction of
temperature and hematocrit with regard to viscosity is depicted graphically in Figure 22.6.
For any given level of hematocrit, the viscosity (and therefore resistance to blood flow) increases substantially as
temperature decreases. Normal viscosity at 37°C and a hematocrit of 40% approximates that seen at 25°C with
hematocrit of 25%. This relationship indicates the importance of hemodilution in CPB, especially with
hypothermia. With the onset of CPB, using an asanguineous prime solution there is an immediate fall in systemic
vascular resistance that is not seen with a blood prime (Fig. 22.7). This drop in resistance with the onset of CPB
is primarily due to the acute decrease in viscosity produced by the hemodilution from the prime solution (79).
Fortunately, this usually transient hypotension appears to have little clinical effect.
A more complex phenomenon pertaining to perfusion pressure during CPB is the increasing vascular resistance
seen over time. Because of the third space equilibration of crystalloid prime solutions and the hemoconcentrating
effect of the diuresis commonly seen during CPB, the initial drop in viscosity is corrected as the excess
crystalloid is removed from the vasculature. Add to this the physical increase in viscosity produced by even
moderate hypothermia (Fig. 22.6) and it would seem attractive to accept that viscosity change accounts for both
the precipitous drop in vascular resistance with the onset of CPB and the steady increase of resistance over time
during CPB. However, even if temperature and blood composition (viscosity) are held constant during CPB,
calculated vascular resistance still increases with time (79).
P.542
FIGURE 22.7. Changes in circulatory resistance comparing data from 15 patients undergoing normothermic
bypass with a crystalloid prime (solid line) to 8 patients undergoing normothermic bypass with a blood prime. RL,
Ringer’s lactate solution. (From Robicsek F, Masters TN, Niesluchowski W, et al. Vasomotor activity during
cardiopulmonary bypass. In: Utley JR, ed. Pathophysiology and techniques of cardiopulmonary bypass.
Baltimore, MD: Williams & Wilkins, 1983:4, with permission.)
The increase in circulating catecholamines that occurs during CPB is well documented and is to some extent
modifiable by the type and depth of the anesthetic, but there remains in most clinical circumstances a significant
increase in plasma catecholamines during CPB (80,81). This catecholamine release is but one manifestation of a
major stress response elicited by CPB. It is likely that the additive vasomotor effects of circulating
catecholamines and other vasoactive mediators of the stress response are responsible for the increased
vascular resistance found during and after CPB. Indirect evidence that reflex sympathetic neural activation may
also play a role in this response is provided by the observation that unilateral stellate ganglion blockade
ameliorates the hypertensive response after CPB (82).
Arterial Pressure Measurement Artifacts

Another practical point regarding perfusion pressure during and immediately after CPB is the relatively common
occurrence of significant measurement artifacts. Especially when hypothermia has been used during CPB, a
significant underestimation of central aortic pressure is seen in measured radial artery pressures, sometimes by
as much as 30% to 40%. This is counter to the normal state where actual radial artery systolic pressure exceeds
central aortic pressure by 10% to 15% or more, largely due to the amplification of effects of pressure waves
reflected from the periphery (83).
This artifact is associated with rewarming at the end of CPB and often continues for 30 minutes or more into the
post-CPB interval. The physiologic cause of the artifact is not completely understood. In the past, persistent
vasoconstriction was often stated to be the cause. However, sufficient proximal conductance vessel constriction
to dampen the radial pressure is unlikely, and the effect of distal constriction should be an enhancement of the
normal gradient rather than a dampening of the radial arterial pressure waveform. A more likely explanation is
that rewarming initiates uneven vasodilation and intense skeletal muscle vasodilation in the forearm and hand
may have the effect of a large arteriovenous shunt, thereby decreasing the actual arterial pressure measured at
the radial artery (84). The final solution to this interesting puzzle remains. But the important clinical message is
that apparent hypotension, as measured at the radial artery, at the conclusion of CPB should be confirmed,
preferably by a central aortic or femoral arterial pressure measurement, before instituting inotropic or
vasoconstrictor therapy. This is easily accomplished using an 18 or 20 gauge needle with pressure tubing
connected to a transducer. One should not be misled into escalating pharmacologic support for a patient with
apparent radial arterial hypotension at a time when the directly measured proximal aorta pressure could be
significantly higher.
Other common causes of low-pressure artifact from the radial artery measurement include surgical retraction and
patient size. Significantly obese patients positioned with their arms tucked to the sides will frequently have
enough tissue compression of the axillary artery to cause dampening of the radial artery waveform. Even with
nonobese patients, this positioning coupled with aggressive use of a sternal retractor for internal mammary artery
dissection can lead to axillary artery compression and radial artery waveform dampening. For completeness, the
potential disaster of aortic dissection must be mentioned. A sudden precipitous drop of radial artery pressure
(either left or right, but more classically left) coincident with the onset of CPB should at least raise the question of
aortic dissection caused by aortic cannula malposition at the onset of perfusion. Fortunately, the associated
findings of a tensely distended aorta with obvious intramural hematoma formation are sufficiently pronounced to
make the diagnosis of the problem relatively straightforward. Given the high frequency of use of intraoperative
echocardiography during cardiac surgical procedures, the diagnosis of this uncommon catastrophe is more
easily confirmed now than it was previously. Unfortunately, the treatment of the problem is still complex.
Less common, but of equal or greater importance, is the artifact of radial artery pressure measurement during
CPB caused by inappropriate aortic perfusion cannula placement so that the flow of blood out of the cannula is
directed
P.543
preferentially into one of the great vessels of the aortic arch. The artifact produced is a high and very pulsatile
radial arterial pressure when the radial catheter is ipsilateral to the inadvertent cannulation in the case of either
the innominate or left subclavian artery (Fig. 22.8). Another clinical sign of this same complication is lateralized
blanching of the face with the onset of CPB in the case of the left carotid artery perfusion (85). The clinical
problem presented is one of gross hyperperfusion of the cerebral arterial system leading to cerebral edema or
frank neurologic injury and also the probability of significant systemic hypoperfusion. Awareness of the potential
problem by perfusionists, surgeons, and anesthesiologists coupled with vigilance for these signs is the key to
preventing this potential disaster.
FIGURE 22.8. Left radial artery pressure waveform during cardiopulmonary bypass. The high pulsatile pressure
is due to the arterial cannula inadvertently directed into the left subclavian system. At the arrow, the cannula was
redirected into the aortic lumen. (From McCleskey CH, Cheney FW. A correctable complication of
cardiopulmonary bypass. Anesthesiology 1982;36:214-216, with permission.)
Pulmonary Artery and Left Atrial Pressure Monitoring

Both PA and, and the less frequently used LA, pressure monitoring have roles in clinical care decisions in
cardiac surgical patients. The most important components occur in the pre- and post-CPB intervals, and both
measurements feature prominently in decisions regarding weaning from CPB. However, both monitoring sites
can be useful during CPB. In recent years, the role of the PA catheter in the perioperative management of
cardiac surgical patients has been questioned. It is difficult to document outcome improvement from the routine
use of PA catheters, and some studies actually show a higher frequency of adverse events among patients that
had PA catheters placed as compared to similar patients managed without these catheters. However, data from
both monitoring sites can be useful during CPB. Given the difficulties of making accurate estimates of cardiac
chamber volume from measurement of chamber pressure due largely to complicated and variable pressure-
volume relationships, these data must be very cautiously interpreted. Fortunately, the common utilization of
intraoperative echocardiography provides a much more direct method of assessing cardiac chamber volume.
As with radial artery catheter pressure measurement, one must be aware of measurement artifacts during CPB in
PA and LA pressures. Both PA and LA catheters can be inadvertently kinked or obstructed; LA catheters are
more vulnerable to inadvertent dislodgment than are PA catheters, but this complication may occur with both.
There is a tendency during CPB for a PA catheter that has been properly positioned in the prebypass period to
migrate distally into the PA by 3 to 5 cm or more as blood volume is taken from the right ventricle into the venous
reservoir and the heart empties with initiation of CPB. This can produce a “permanent wedge” phenomenon that
has been implicated in PA rupture or pulmonary infarction. Often this malposition is indicated by a distinct
increase in the PA pressure reading or the Svo2 measurement in the case of an oximeter PA catheter. This
malposition is sufficiently predictable that it is clinically prudent to routinely and arbitrarily withdraw the PA
catheter by 3 to 5 cm at the commencement of CPB. The routine use of a catheter introducer and a sterile
protective sheath allows sterile repositioning of the PA catheter at the end of CPB. Some experienced clinicians
recommend withdrawal of the PA catheter further, into the superior vena cava (SVC), during CPB. However,
refloating the PA catheter at the end of CPB is not always easily accomplished, and hemodynamic management
difficulty is most likely to occur at this time. Despite the seemingly sound arguments for withdrawing the PA
catheter during CPB, it has not been conclusively shown that this practice decreases the already small incidence
of PA catheter-induced PA rupture. Another important point regarding PA catheters during CPB is that they are
vulnerable to being inadvertently snared by sutures placed for closure of the atriotomy (especially) during mitral
or tricuspid surgery and during the atrial purse string placement for the venous cannulas or for the retrograde
cardioplegia catheter. Such a trapped PA catheter may require repeat surgery and even occasionally CPB for
removal, and removal is reported to be accompanied by significant morbidity and even mortality (86).
Accordingly, it is prudent to be sure that the PA catheter is free (e.g., by moving it several centimeters) after the
end of CPB and completion of decannulation.
Central venous pressure measurement may also be helpful in guiding clinical decisions during CPB. As with PA
and LA pressures, the expectation is that pressure in the vena cavae (both SVC and inferior vena cava [IVC])
should be at or near zero or even slightly negative during CPB when the heart is arrested and when unrestricted
venous drainage is intended. In contrast to PA and LA pressure increases, an increased SVC or IVC pressure is
not usually associated with cardiac distension. Rather, the increased CVP may indicate impaired venous
P.544
drainage to the venous reservoir due to venous cannulas of insufficient size, malpositioned venous cannulas,
venous cannula or drainage line obstruction, insufficient height differential between the heart and the venous
reservoir to promote an adequate siphon effect, or insufficient vacuum applied to the venous reservoir if VAVD is
being used.
The major adverse physiologic effect of elevated venous pressure during CPB is a reduction in effective
perfusion pressure for critical organs such as the brain, kidneys, and abdominal viscera and an enhanced
tendency for edema production. For example, if the mean arterial pressure is 60 mm Hg during CPB and if SVC
and IVC pressures are near zero, then the brain, the kidneys, and the splanchnic arterial bed have an effective
perfusion pressure of 60 mm Hg. However, if SVC or IVC pressure is elevated to 20 mm Hg, then the net
perfusion pressure in these same areas is only 40 mm Hg and the increased back pressure will promote
accumulation of edema. From this perspective, the liver is theoretically particularly vulnerable because
approximately 75% of hepatic blood flow occurs at venous pressure through the portal vein. An elevated venous
outflow pressure (i.e., IVC pressure) could theoretically have a major adverse effect on hepatic blood flow during
bypass.
It is important to recognize that SVC and IVC pressures are not necessarily equal during CPB even with a single
twostage venous drainage cannula. Moreover, there is little visible evidence of IVC engorgement with a median
sternotomy incision, even with the use of intraoperative echo. Especially with cardiac retraction and a single two-
stage venous cannula, it is common to have venous drainage impairment and an increased measured CVP.
Venous pressure measurement is also subject to significant artifact during bypass. For example, during total CPB
(bicaval cannulation with tourniquets around the cavae), the venous catheter may become entrapped in the
tourniquet. If the venous catheter is occluded, the constant flush infusion device on the transducer will rapidly
overpressurize the transducer. On the other hand, if the catheter remains patent and passes beyond the
tourniquet, then, with the heart open, an artifactually low venous pressure will be measured. In this situation,
SVC and IVC pressure can each vary independently. A further CVP measurement artifact, not specific for CPB, is
produced when the pressure port of a PA catheter remains within the lumen of the introducer sheath. In this
case, an infusion into the sheath through the sidearm can produce a pressure inside the sheath in excess of
SVC pressure, which will be measured as CVP from the right atrial port of the PA catheter (Fig. 22.9) (87).
The Svo2, as measured from a PA catheter, loses most of its clinical utility during CPB because of the diversion
of venous return into the venous reservoir. However, as previously mentioned, a very high PA catheter Svo2 can
be an indicator of a catheter in “wedged” position during CPB. The value of Svo2 measurement of venous blood
drained into the venous reservoir is considerable, having much the same significance as the corresponding PA
catheter measurement off bypass. As described in the section on blood flow and perfusion pressure
requirements during CPB, if one is aware of the major determinants of the Svo2 value (hemoglobin
concentration, blood flow, hemoglobin P50, arterial oxygenation, and systemic oxygen consumption), then the
Svo2 can be used as a reasonable guide to adequacy of oxygen delivery during CPB.
Other Cardiovascular Monitors

Another increasingly commonly used clinical cardiovascular monitor is TEE. Unfortunately, a substantial portion
of TEE utility is lost during CPB with cardioplegia. Blood loss from the cardiac chambers obscures the
ultrasonographic definition of the chambers because there is little or no cavity and therefore little or no
ultrasonographic contrast to define cardiac structures. Likewise, during CPB there is little or no intracardiac
blood flow, so Doppler information on blood flow velocity and direction and on valvular function is largely not
available. However, as the heart is filled near the conclusion of CPB, TEE regains its ability to visually display
intracardiac structures, wall motion, and blood flow direction and velocity and can also be a useful guide to
effective air evacuation from the cardiac chambers.
Electrocardiographic monitoring must be continued during CPB. During periods of cardioplegic arrest, it is
important to verify that the ECG is isoelectric. After surgical repair, the ECG should return to the baseline state
before weaning from CPB. Abrupt changes of the ST-segment deviation from isoelectric should raise the
immediate question of intracoronary embolization of air (particularly to the right coronary artery as typically
reflected in leads II, III, and aVF) or particulates. Persistent ST-segment deviation should raise the question of
ongoing ischemia that should be investigated and corrected before terminating CPB. One should not overlook
the value of direct observation of the heart as an adjunct to ECG diagnosis, especially in patients with
dysrhythmias.
Neurologic Monitoring
Neurologic monitoring during CPB is directed primarily toward the myoneural junction to confirm adequacy of
muscle paralysis and toward the central nervous system (CNS) to detect functional abnormalities developing
during CPB. The former is straightforward and needs little attention here except to note that unnecessary oxygen
consumption and CO2 production during moderate hypothermic CPB are decreased when a complete level of
skeletal muscle paralysis is maintained. This, coupled with the decreased effective concentration of
neuromuscular blocking agents produced by the blood volume expansion from the CPB priming volume, explains
the common clinical recommendation to redose relaxants with approximately one-half of an expected “intubating
dose” at the time of initiating CPB.
Central nervous system monitoring has traditionally relied on electrophysiologic measurement of neurologic
activity measured from the body surface and exemplified by the EEG.
P.545
An enhancement of this passive measurement is the evoked potential. Typically, an evoked potential is
measured as the surface electrophysiologic manifestation of the transmission of a stimulus along a given neural
pathway. Other nonelectrophysiologic CNS monitoring includes transcranial Doppler and reflectance
spectrometry. Transcranial Doppler ultrasonography measures blood flow velocity in major arterial segments in
the brain and can detect transient artifacts in the velocity signal attributable to particulate or gas emboli.
Reflectance spectrometry developments now allow measurement of the signal produced by the mean oxygen
hemoglobin saturation at discrete loci in the brain. Although the CNS monitoring capabilities applicable to
patients undergoing CPB are significant, their clinical use is relatively small compared with the total scope of
CPB monitoring. Also, the ability of more intensive CNS monitoring to decrease the frequency of adverse
neurologic outcome after CPB remains largely untested. Recording of a full standard EEG electrode montage on
a strip chart with an experienced EEG analyst observing the signals may be the ideal method for EEG
monitoring. The value of this approach intraoperatively has been debated for certain procedures such as carotid
endarterectomy; however, application of such a technique to CPB is rarely seen outside of specific focused
clinical investigation. The processed EEG, either compressed spectral array or density modulated spectral array,
provides a smaller volume of data than the raw EEG. However, the data are presented in a more user-friendly
format, which allows clinicians to detect lateralized (or global) change in both the dominant frequency and the
power of the EEG, even with intermittent observation of the record. Excellent comprehensive reviews of this
subject are readily available (88,89,90,91).
FIGURE 22.9. Right atrial pressure (RAP) is increased at the onset of the venous infusion port infusion (solid
arrow) and returns to the preinfusion level when the infusion stops. ECG, electrocardiogram, AP, arterial
pressure; PAP, pulmonary artery pressure; CABG, coronary artery bypass graft. (From Davis RF. Yet another
CVP artifact. Anesthesiology 1984;60:262, with permission.)
The process of CPB presents many physiologic changes that markedly complicate the interpretation of the EEG.
The primary changes in the EEG indicating hypoperfusion or
P.546
hypoxia are slowing of the dominant frequency and loss of power in the signal, and similar changes can be
produced by hemodilution, hypothermia, anesthetics, CPB systemic flow changes, and pulsatility changes, in
addition to any imputed hypoxic CNS insult (92). For example, anesthetics have wellknown EEG effects,
including the ability to produce burst suppression or an isoelectric pattern with barbiturates and with the volatile
anesthetic isoflurane. Mild hypothermia itself produces slowing of the EEG, which proceeds through burst
suppression to an isoelectric pattern as temperature is further decreased. However, comparing temperature-
related EEG changes to hypoxia, there are differences that may become clinically useful (93). Significant hypoxia
is marked by a rapid decrease in high-frequency EEG activity. Also, although the burst suppression pattern of
hypothermia tends to be regular, that seen with hypoxia is more irregular. Perhaps the situation is analogous to
ST-segment depression in the ECG. Here, the unproved but hopeful hypothesis is that discrete EEG patterns
exist, detectable during CPB and distinguishable from other effects, which reliably indicate CNS hypoxia at a
treatable point before frank cytologic injury.
Currently, the use of evoked potentials during CPB is largely limited to surgery involving the descending thoracic
aorta, generally repair of aortic coarctation, aortic dissection, and aortic aneurysm repair. Because of the
anatomy of the major blood supply to the spinal cord (the anterior spinal artery and the communicating artery of
Adamkewicz) (Fig. 22.10), the spinal cord is at risk of ischemic injury when the descending thoracic aorta is
clamped to permit surgical repair. By monitoring the progress of an evoked signal at several sites from the
periphery to the cerebral cortex, one can monitor the function of each component of the transmission sequence
from peripheral nerve through the spinal cord to the cerebral cortex. Theoretically, observation of increased
latency or decreased amplitude of the evoked potential signal at any site along the path would allow intervention
before neurologic injury. In aortic coarctation, for example, observation of an abnormal evoked potential after
application of the aortic clamp could then trigger removal and replacement of the clamp or some other
(pharmacologic) maneuver to increase perfusion pressure or cardiac output in an attempt to improve spinal cord
blood flow before the repair is undertaken. Unfortunately, the caveats regarding the interaction of CPB,
hypothermia, anesthesia, hemodilution, and the EEG also apply to evoked potentials. The predominant type of
evoked potential used clinically is currently the sensory evoked potential. In the case of the somatosensory
evoked potential, the motor component of the spinal cord is relatively silent. Cases exist of dense motor
paraplegia after thoracic aortic surgery despite persistently normal somatosensory evoked potentials throughout
the aortic cross-clamp interval (92).
Within the past decade near infrared spectroscopy (NIRS) technology has been developed to provide
commercially available monitors capable of measuring and displaying tissue hemoglobin oxygen saturation data
in near real-time. Pertinent to the present discussion of CNS monitoring during CPB, NIRS technology has been
applied to measurement of cerebral tissue oxygen saturation. The technique is well described elsewhere (88),
but briefly it is done by passing specific wavelengths of infrared light through the frontal cortex bilaterally. Signal
processing allows “focusing” of the reflectance data so that only cerebral tissue is sampled, canceling the
reflectance signals from the scalp, skull and meninges. The resulting data display allows clinicians to monitor
bilateral frontal cortical oxygen saturation in close to real-time, which provides the opportunity to detect
desaturation events sufficiently early to be able to undertake interventions intended to prevent or ameliorate
actual tissue damage. Examples of such interventions to improve cerebral oxygenation include increasing
cerebral perfusion pressure, increasing systemic blood oxygen content (both Pao2 and hemoglobin
concentration), and normalization of cerebral vascular resistance by Paco2 manipulation. Several published
clinical studies have documented the utility of cerebral oximetry data to guide such interventions to decrease the
severity and duration of desaturation events during cardiac surgery. One study in particular (88), a prospective
randomized trial of the use of cerebral oximetry during coronary bypass surgery observed a decreased incidence
of both cardiac and cerebral adverse events in the monitored group of patients. Although the technique is not
universally accepted, it has the inherent advantages of ease of use and interpretation,
P.547
relatively low cost (at least in the cardiac surgery context) and documented efficacy.
FIGURE 22.10. Variation in blood supply to the spinal cord. The variation diagrammed on the right presents a
higher risk for spinal cord ischemia with descending aortic surgery. (From Dembitsky WP. Central nervous
system injury during surgery of the descending aorta. In: Utley JR, ed. Pathophysiology and techniques of
cardiopulmonary bypass, Vol. 1. Baltimore, MD: Williams & Wilkins, 1982:80, with permission.)
FIGURE 22.11. Relations of temperatures measured at various sites over time during cooling and rewarming
from cardiopulmonary bypass. (From Stefaniszyn HJ, Novick RJ, Keith FM, et al. Is the brain adequately cooled
during deep hypothermic cardiopulmonary bypass? Curr Surg 1983;40:294-297, with permission.)
Temperature Monitoring
Because of the integral relation between temperature control (manipulation) and CPB, temperature measurement
is a core physiologic monitor during CPB. A major difficulty, however, is the simple definition of “core”
temperature. The technology available for temperature measurement during CPB is nothing less than abundant.
The problem is not how to measure; the technologic capability exceeds the clinical need for accuracy or
adaptability. Measurement of nasopharyngeal, esophageal, tracheal, mixed venous blood, arterial blood, bladder
urine, rectal, tympanic membrane, and even great toe temperature are readily available for clinical use. In many
cardiac surgical units, measurement of two or more of these patient temperatures is common practice. But what
is core temperature? The concept of a single core body temperature is just that—a concept rather than a reality.
Figure 22.11 is instructive in this regard. The expectation is that especially during cooling or rewarming,
temperature is site specific and the variability from site to site is significant. Besides these patient temperatures
there are CPB temperatures such as water bath(s) for the oxygenator and cardioplegia delivery system as well
as perfusate and venous blood temperatures that are routinely used to guide cooling and rewarming rates.
Temperatures are measured during cooling to ensure that the organs believed most vulnerable to potential
hypoperfusion actually receive the benefit of the desired degree of hypothermia. In this regard, the brain is
usually the target, and nasopharyngeal (not airway), tympanic membrane, or esophageal (below tracheal
bifurcation) are the usually accepted best estimates of brain temperature. Tympanic membrane temperature
monitoring is less popular because of the occurrence of probe-related tympanic membrane injury. Mixed venous
temperature in the extracorporeal circuit is a reasonable indicator of average body temperature directly
analogous to
P.548
an Svo2 measurement. If a jugular vein bulb catheter is used, concurrent measurement of Sjvo2 and the
associated blood temperature may be a more accurate assessment of global (hemispheric) brain temperature.
During rewarming, the target, obviously, is a uniformly normothermic patient at the end of CPB. Success is both
time and temperature dependent. For example, the total caloric loss in a series of adult patients cooled to 30°C
for 130 minutes on CPB was calculated at 238 kcal (94). The net return during rewarming was approximately 160
kcal, leaving a heat debt of 78 kcal or approximately the equivalent of 1.5 hours of the basal metabolic heat
output. This deficit is likely the explanation for the common clinical observation of rebound hypothermia,
sometimes termed afterdrop, after termination of CPB. In this regard, the use of vasodilators, such as
nitroprusside or nitroglycerin, to force a vasodilation during the rewarming period theoretically promotes a more
uniform rewarming and has been clinically shown to decrease the incidence and severity of rebound hypothermia
after CPB (95). However, this practice may not be feasible due to the decreased vascular resistance commonly
seen toward the end of CPB. Important considerations for temperature measurement during rewarming are
prevention of liberation of free gas bubbles and blood damage. Because of the inverse relation between gas
solubility in blood (or any liquid) and temperature, dissolved gases tend to come out of solution as a fluid is
warmed. If this happens clinically, the consequences of gaseous embolization (even microemboli) can be
significant. In general, maintenance of a temperature gradient from the heat exchanger to the venous blood of
not more than approximately 8°C to 10°C will prevent significant microbubble formation. Although heat
exchangers are highly efficient, there is a temperature gradient produced within the heat exchanger. A boundary
layer forms immediately adjacent to the heat exchanger in which blood temperature will equal heat exchanger
water temperature, whereas blood farther away from the exchange surface will not fully equilibrate with water
temperature. Because blood damage (both cellular elements and protein denaturation) increases with
temperatures greater than 42°C, this temperature forms the practical upper limit to water temperature within the
heat exchanger (46, p. 89). But, as previously mentioned, the minimum exchanger water temperature
(approximately 4°C) appears not to damage blood. It is very important to avoid hyperthermia, especially of the
CNS, so that heater/cooler temperatures above 37°C or 38°C should not be used.
Urinary Volume and Renal Function
A detailed discussion of the effect of CPB on renal function is found elsewhere in the text. Most cardiac surgical
teams closely follow the urinary output of patients during CPB as an indicator of normal renal function. Although
a brisk flow of urine during CPB may be comforting and may, in fact, facilitate fluid management during CPB,
existing clinical data do not support a close relationship between urine flow while on bypass and postoperative
renal function. In the mid-1970s, Abel et al. (96) examined a large number of patients for factors predictive of
postoperative renal failure. Two major factors emerged as significant correlates of postoperative renal failure:
time on bypass and preexisting renal failure. Other factors, including urinary volume produced on bypass, were
not significantly related to postoperative renal failure.
What is the place of diuretic medications, either osmotic (i.e., mannitol) or loop (i.e., furosemide and congeners),
in the management of the oliguric patient during CPB? Several considerations are pertinent. The first is to
ensure Foley catheter patency. This may seem simplistic, but clinical experience indicates that the bladder is
remarkably compliant and that pharmacologic diuresis will rarely fill it to a pressure sufficient to overcome an
obstructed catheter. In general, a physiologic urinary volume of 0.5 to 1.0 mL/kg/hr requires no treatment.
Oliguric or anuric patients may or may not benefit from diuretic therapy. Again, available clinical data do not
relate urine volume during CPB to postoperative renal dysfunction. However, oliguria or even normal urine flow
in the face of hyperkalemia, hemoglobinemia (presumed hemolysis), or suspected volume overload (excessive
hemodilution) are indications for diuresis. Theoretically, in the case of hyperkalemia, loop diuretics would provide
the greatest potassium loss. In the case of hemoglobinuria, a large volume of alkaline urine is desired, so either
loop or osmotic diuretics (or both) may be useful.
Coagulation Status
Coagulation monitoring is an obviously major area of patient monitoring during CPB. A detailed review of all
relevant aspects of coagulation and CPB is in a separate section of the text.
Laboratory Data
The frequency and type of laboratory data monitored during CPB are relatively institution specific, but laboratory
support should minimally include blood gas and pH measurement and rapid access to electrolytes, especially
potassium and calcium, and glucose and perhaps lactate. Whether these data are available from a satellite
laboratory in close proximity to the OR, from in-line or in-room monitors, or from the main hospital laboratory is
less important than the rapid availability of data. The rapidity and magnitude of intraoperative changes in these
parameters in cardiac surgical patients makes their rapid (5-10 minutes) availability a virtual requirement for safe
cardiac surgery.
A common area of controversy in blood gas data interpretation during CPB is the management of Paco2 and pH
during hypothermia. The discussion of a-stat versus pH-stat management schemes is well presented elsewhere
in the text and does not need to be recapitulated here. The use of potassium-based cardioplegia solutions
mandates the capability for rapid and accurate assessment of serum potassium concentration. The metabolic
consequences of CPB, especially those involving
P.549
glucose utilization create the requirement for frequent glucose (and optimally lactate) measurement during and
after CPB.
Technologies for in-line, online, point-of-care, or local laboratory measurements include cartridge-based
electrode systems and intravascular, usually fluorochrome, catheter-based technology. The latter generally
couples intensity of fluorescence of the fluorochrome when stimulated by light at a specific wavelength to
fiberoptic technology for transmission of the emitted fluorescent light to an analytic instrument. The intensity of
fluorescence is proportional to the concentration of the parameter being measured (e.g., oxygen, carbon dioxide,
or hydrogen ion). Current capabilities in this area include systems that will pass through a 20-gauge catheter, are
capable of giving near-continuous Pao2, Paco2, and pH data at ambient patient temperature, and still permit
pressure measurement through the same catheter. Depending on institutional practices regarding frequency of
blood gas analysis and cost of the testing, this approach may prove to be cost effective, but the clinical value
(despite widespread use) of continuous measurement of blood gas data as opposed to intermittent sampling
remains to be established.
The cartridge electrode systems are more conventional in that electrochemical reactions form the basis for
measurement. The advantage is that the cartridge is a self-contained unit with electrodes and calibration
solutions capable of making a defined number of measurements over a defined time span. For institutions
capable of using the full capacity of the cartridge within its lifespan, the result is also often cost effective.
Cartridge-based systems are often small enough to be physically attached to the CPB circuit and may be
equipped with automatic sampling capability. Although this is not actually a continuous measurement, the
sampling frequency is programmable and limited only by the time required for the actual electrode measurement.
These instruments may also provide quality management functions such as documentation of quality control
testing and control over instrument use by uncertified or untrained individuals, in addition to providing needed
laboratory data.
EQUIPMENT MONITORING DURING CPB

Oxygenator Function
Arguably, the single most important item of equipment in the CPB setup is the oxygenator. Oxygenators in
current use are manufactured as single-use disposable items subject to stringent quality control. Problems do
occur nevertheless, although rarely. The immediate life-sustaining function of the oxygenator is oxygenation of
the blood; ventilation follows closely behind. Therefore, the single best monitor of oxygenator function is
oxygenation. As just discussed, a variety of instrumentation is available for blood gas (Pao2, in this case)
analysis ranging from laboratory benchmark instruments to in-line CPB sensors or catheter-based systems. The
point is that the adequacy of oxygenation must be reliably determined both early and throughout the CPB course.
The emphasis on laboratory determination does not discount clinical observation. For example, a cyanotic
surgical field should be noticed quickly. Having established adequate initial oxygenator function, it is prudent to
reassess blood gases at regular intervals throughout CPB or whenever changes are made in oxygenator gas
flow or composition or CPB systemic blood flow. Also, recalling the earlier discussion of the value of Svo2
measurement to guide perfusion adequacy, CPB venous blood oximetry is a useful monitor used by most
perfusionists currently.
What then is an appropriate level for Pao2 during CPB? Two studies have suggested hyperoxia (defined as
arterial Po2 >185 mm Hg) might be deleterious during normothermic and hypothermic CPB (97,98). With the
current availability, accuracy, and reliability of in-line blood gas sensors, it is relatively easy to maintain the Pao2
in the 140 to 180 mm Hg range. Although it is acknowledged that these values are not normoxemic, maintaining
blood gas values in this range with in-line sensors displaying contemporary data will provide a margin of safety
during CPB, particularly when the aortic cross-clamp is removed and during reversal of hypothermia when the
patient’s oxygen needs increase.
Cardioplegia Delivery
When cardioplegia solution is delivered by the perfusionist, the flow, pressure, and temperature should be
monitored. Depending on the pressure drop through the delivery system and cannula, the aortic root pressure
can be monitored and regulated to appropriate levels by adjusting the flow rate. It is particularly important to
monitor pressures when cardioplegia solution is delivered directly into coronary ostia or retrograde into the
coronary sinus to avoid tissue damage from excessively high pressures and to ensure proper cannula placement
(99). Some cardioplegia cannulas provide for direct measurement of infusion pressure through a second
pressure monitoring line or lumen (100). If aortic infusion pressure is not measured directly, the aortic root
pressure can be estimated by subtracting the pressure drop of the delivery system from the cardioplegia line
pressure. Monitoring the temperatures of both the cardioplegia solution and myocardium can reasonably ensure
adequate cardioplegia and guide intervals for reinfusion.
Fluid Management
Fluid administration during CPB in response to decreased circulating volume usually consists of crystalloid
solution added directly into the circuit. Extravascular loss of blood at the operative field, fluid shifts within the
patient’s tissues and organs, and urinary output can contribute to the need for supplemental fluid administration.
Depending on the patient’s recent hematocrit, packed red blood cells may be added per protocol or surgeon or
anesthesiologist order. Alternatively, packed
P.550
washed cells recovered from a cell salvage device may be administered during CPB to raise the hematocrit. The
choice of type of fluid administration (crystalloid or blood products) may be governed by stage of the operation,
patient condition, or protocol. For example, if the patient has good diuresis and patient weaning from CPB is
expected shortly, blood products may be withheld to avoid donor blood exposure. In other cases such as the
elderly, children, or those patients with reduced cardiac function, the threshold for administration of bank blood
may be lower. All blood administered should be double-checked against the patient’s name and identification
number before administration, with the time of administration recorded on the perfusion record.
When a hemoconcentrator, or modified ultrafiltration (MUF), is used during bypass, the volume of plasma water
removed should be monitored to avoid excessive fluid removal with concomitant decreases in circulating volume
(101). So-called Z-BUF, or zero-balance ultrafiltration, using normal saline as a replacement fluid may be used to
lower potassium values while maintaining steady state blood volumes in the CPB circuit (102,103). In some
settings, a cell salvage device is used in conjunction with CPB to wash shed blood instead of using conventional
pump suction. However, the time and volume required for such blood processing must be taken into account
during CPB because blood being processed may not be immediately available for administration. With
hemoconcentration, plasma proteins and platelets are preserved, and use of this device is technically simpler
and more cost effective than routine cell salvage during CPB (104,105).
Circuit Alarms
Most CPB circuits have alarms to warn of potentially dangerous conditions such as low reservoir volume or high
systemic line pressure. An air bubble detector placed on the arterial line will automatically alarm and shut off the
systemic roller pump in the event a bolus of air inadvertently enters the line proximal to the sensor. The location
of the air bubble detector within the circuit can vary (106), but for most prompt air detection, the sensor should be
placed between the CPB reservoir and systemic pump. Manufacturer recommendations and some practitioners
place the sensor after all devices on the arterial flow line, including the arterial line filter. This configuration has
the advantage of detecting large bubbles that may inadvertently enter this line after all CPB components but the
disadvantage of having to remove all air from the arterial line filter before restarting CPB, which can be difficult.
Some CPB consoles today have the capability of placing more than one air bubble detector on the circuit such
as on the cardioplegia delivery system tubing. Low-level reservoir alarms have a long history of use, and they
can be used to warn of low reservoir volume conditions or automatically shut off the systemic blood flow pump if
the CPB reservoir volume is too low. However, the use of the alarm is not a substitute for an alert perfusionist
monitoring the reservoir level.
Perfusion Record
Record keeping provides permanent documentation of the patient’s hemodynamics and metabolic parameters
during the period of CPB support. The perfusion record, whether hand-written on a preprinted form or electronic,
should contain at least the following information: health care personnel; patient diagnosis and preoperative risk
factors; procedure(s); equipment used, including disposables and non-disposables; patient physiological
parameters, including blood gas and anticoagulation monitoring results; and time of administration of drugs,
fluids, and blood products. According to AmSECT (107), the goals for a perfusion record are that it should serve
to increase awareness and safety; be an accurate representation of service delivered; allow for internal
review/risk management; serve as a basis for medico-legal defense; and meet compliance, benchmarking, or
Joint Commission for Accreditation of Healthcare Organizations requirements. Importantly, the perfusion record
may also provide information for other healthcare personnel responsible for the patient after surgery. As such,
the perfusion record contains information that may become part of a larger database or serve as documentation
for further medical study. Perhaps one of the most important functions of the perfusion record is to prompt the
perfusionist to make observations and in some cases document patient physiologic variables and circuit
performance. Verbal orders from physicians to the perfusionist should be documented, and ideally, the perfusion
record should include the signature of the physician(s) providing oversight. In essence, the perfusion record can
be viewed as an ongoing checklist during CPB.
The format of the perfusion record varies and may be of the commonly used random time and entry or chart type
where data regarding systemic blood flow, patient and circuit blood pressure(s), temperature(s), oxygenator
ventilating gas flow and composition, rpm when using a centrifugal pump, and results of laboratory tests such as
hemoglobin, arterial and venous blood gases, and electrolytes are recorded at fixed (predetermined) time
intervals.
A second less frequently used perfusion record is the combination flow with time and entry type, which is similar
to an anesthesia record. This record also contains information on patient physiologic parameters, but because
notations are made at fixed intervals on a grid, it is conceptually easier to determine trends and view in its
entirety what occurred during the period of bypass. In practice, the timing of entries should occur every 15
minutes or less in either a random entry or a timed entry record. Systems for automated recordkeeping now exist
wherein more frequent data points are collected and stored electronically for later review as needed.
During CPB, an entry should also be made every time a major change is made by the perfusionist in any of the
perfusion controls or parameters or any time one of the monitored values change. Use of 24-hour time entries
(“military time”) is recommended and can clarify the time of day or night for the various entries. Blood gas and
other laboratory values should be recorded
P.551
on the perfusion record at the time they were drawn and not when the results were received. Blood gas samples
should be drawn shortly after making a change in systemic blood flow or if there is a major change in patient
temperature. Likewise, tests for electrolyte levels should be done after administration of solutions or drugs that
can affect values such as potassium chloride, glucose, or insulin. The use of in-line monitors for arterial and
venous blood gas and/or chemistry values may decrease the need for more frequent sampling and
documentation. However, the in-line monitor should be calibrated according to the manufacturer’s instruction and
against a sample using standard laboratory measurements to verify its accuracy.
All fluids added to the CPB circuit should be recorded at the time they are added. These notations, when
combined with estimated blood loss and urinary output on bypass, will allow calculation of an estimated fluid
balance at the conclusion of bypass and may guide patient management decisions after CPB. Medications
added by the perfusionist, whether by protocol or on direction from the surgeon or other physician, should be
noted along with who ordered it or whether it was given according to protocol.
COMMUNICATION
It should be apparent from the preceding sections that any medical procedure as invasive, life-sustaining and
complex in execution as CPB depends on close coordination of activities by all team members. Essential and
effective communication provides a means to facilitate such coordination. Effective teamwork is critical and does
not occur spontaneously; see the chapter, Primum Non Nocere: Patient Safety in CPB.
Instructions or announcements from the surgeon to the perfusionist or anesthesia personnel are necessary
during conduct of the operation because CPB is being used to facilitate a surgical procedure in a patient under
anesthesia. Instructions from the anesthesiologist to the perfusionist also occur often during the period of CPB.
All instructions or announcements should be followed by an acknowledgment from the person to whom it was
directed. In this manner, errors of omission will be minimized and the surgical procedure can proceed
expeditiously. If acknowledgment does not occur, the communication should be repeated until a response is
heard, most often by the intended recipient repeating the instruction to avoid possible errors in interpretation.
The perfusionist should communicate to the surgeon activities that are performed according to protocol or
according to surgeon preference. Likewise, the anesthesiologist should communicate activities to the perfusionist
that can also affect the conduct of CPB and vice versa. An example would be administration of a vasodilator that
can alter the circulating volume of blood and CPB reservoir level. Fluid additions to the CPB circuit should be
communicated from the perfusionist to the anesthesiologist because of implications for fluid management after
CPB.
Both perfusionist and anesthesiologist, and indeed any other operating room personnel, are obligated to
communicate to the surgeon any significant abnormal conditions they observe. Much of the surgeon’s attention
may be focused on the surgical procedure, and the perfusionist and anesthesiologist are better able to monitor
the key parameters outlined earlier.
Some conditions can occur unexpectedly that may potentially jeopardize patient well-being, including increased
CPB arterial line pressure; sustained decreased venous drainage; nonfunctioning vent or sucker; sustained
elevated or low patient arterial blood pressure; elevated CVP, PA, or LA pressures; elevated delivery pressure
and/or lower-than-expected flow during cardioplegia administration; and any potentially life-threatening
equipment malfunction or failure. In such instances, immediate communication is required.
Often abnormal situations can occur that are less acute but potentially damaging, including: elevated serum
potassium; lower than expected hemoglobin or hematocrit (with or without the expected need for blood
transfusion that should be authorized by a physician); higher than expected fluid volume requirements; higher
than expected use of vasopressors or need for increased systemic blood flow for decreased systemic vascular
resistance; lower than expected mixed Svo2; resumption of cardiac electrical or mechanical activity during
cardioplegic arrest; and air entrainment in the venous line. If deep hypothermia and low flow or elective
circulatory arrest is required, the surgeon should be notified of the duration of cooling, patient temperature(s),
and elapsed times of low flow or circulatory arrest. The frequency for such notification should be communicated
to the perfusionist before the procedure or at the time of initiation of low flow or circulatory arrest.
Surgical manipulations of the heart or major vessels may affect CPB. For example, retraction of the heart for
surgical exposure may restrict venous drainage or allow air to enter the venous line at the venous cannulation
site(s) or through side holes in the cannula inadvertently exposed to atmosphere if the cannula becomes
displaced. Such retraction may also distort the aortic valve, causing aortic incompetence with possible left
ventricular distention from flow exiting the arterial cannula. Retraction of the heart may increase or decrease vent
return. These conditions should be communicated to the surgeon when they occur, and surgeons should alert
the perfusionist when they are displacing the unarrested heart such as when a circumflex coronary artery graft
anastomosis is checked for bleeding. Collateral blood flow may partially obstruct the surgical field, necessitating
a decrease in CPB systemic flow. Application of the aortic cross-clamp is usually preceded by instruction from
the surgeon to the perfusionist to momentarily decrease the systemic blood flow to lower pressure in the aorta.
The perfusionist should communicate all changes in systemic blood flow, whether in response to direct
instruction or by protocol.
POST-CPB ACTIVITIES
The perfusionist should be prepared to transfuse residual perfusate through the arterial cannula as required and
instructed by the surgeon or anesthesiologist. It is important to check
P.552
the arterial cannula for any residual air bubbles that may have been liberated from cardiac chambers or vessels
since stopping bypass before using the cannula for transfusions (Fig. 22.12). Often, the arterial cannulation site
is in the uppermost position in the aorta and will become the site of lodgment of residual air due to buoyancy
effects.
FIGURE 22.12. Common site of air lodgment in arterial cannula immediately after cardiopulmonary bypass
(arrow). The venous cannula(s), which are still in place in the right atrium and/or vena cavae, are not shown for
illustrative purposes.
It is important that the pump sucker(s) or vent(s) not be used if fibrin glue or coagulation-inducing drugs are
being used in the operative field (108,109). Aspiration of blood containing hemostatic drugs or materials, even if
in a liquid state, can cause coagulation in the cardiotomy reservoir, venous reservoir, or oxygenator with or
without stasis, thereby compromising use of the circuit in the event CPB must be restarted. Similarly, the pump
sucker(s) should be turned off when protamine administration begins, to avoid similar problems.
After the arterial cannula has been removed, residual perfusate in the CPB circuit can be salvaged by transfer
into a completely de-aired sterile intravenous bag for possible transfusion by anesthesia personnel. Bags
containing residual perfusate should be labeled with the patient’s name, hospital identification number, and time
and date of collection. In practice, residual perfusate is most often administered in the immediate postbypass
period. Alternatively, a cell salvage device may be used to process the residual perfusate and increase the red
blood cell concentration. A hemoconcentrator can also be used to process residual perfusate before collection. It
is important that supplemental protamine sulfate is given after any such transfusion of unwashed residual
perfusate to counteract heparin contained in the salvaged perfusate.
The time of administration of protamine sulfate has been temporally related to hemodynamic deterioration in
some patients. The perfusionist should continue to observe patient hemodynamics at this time and maintain the
CPB circuit in a functionally usable state if it is necessary to urgently restart bypass. If the patient must be placed
back on CPB, then the protamine must be stopped and a full loading dose of heparin (300-400 units/kg) should
be given before restarting bypass to adequately anticoagulate the patient. Sometimes, the readministration of
heparin will neutralize the heparin-protamine complex and the previously observed hemodynamic deterioration
will resolve (110,111). Circuit disassembly and recovery or processing of residual perfusate should not be
undertaken until it is reasonably certain that the patient will maintain adequate hemodynamics.
PERFUSION PROTOCOLS, GUIDELINES, AND STANDARDS

Protocols, guidelines, and standards are no substitute for common sense and experience. However, they have
been useful in promoting safe conduct of CPB. Perhaps in its simplest form, an institutional protocol outlines the
selection of circuit components and required priming volumes (with constituents) according to patient size or
diagnosis. These protocols are often determined after review of manufacturer product data and then further
developed and updated after a period of use. Such protocols provide some consistency on a case-by-case basis
regardless of perfusion personnel involved. Basic institutional protocols may be customized to a specific surgeon
or for specific procedures or patient conditions.
A second type of protocol, which is particularly applicable for pediatric cases or specialty situations, outlines
recommended or preferred cannula size and type. Flow charts can be created by performing benchtop
measurements or can be provided by manufacturers, showing pressure drops at different flows for arterial
cannulas. Similarly, venous cannulas are most often classified by a range of flows with height differentials
typically used for gravity siphon drainage.
More detailed protocols may be used to describe various aspects of conduct of CPB and ancillary or more rarely
performed procedures such as performing hemodialysis during bypass. Such protocols are usually unique to the
institution and sometimes contain specific protocols according to surgeon preference. An example might be
desired range of arterial blood pressure while on bypass or treatment regimens for abnormal laboratory results.
Detailed protocols may also list in outline form specific steps for circuit assembly, priming, and management
during certain less frequently performed procedures such as cardiac transplantation, left heart bypass for repair
of the descending thoracic aorta, or retrograde or antegrade cerebral perfusion. Protocols should be developed
with input from all team members and should be periodically reviewed and updated so that they remain
contemporary with current clinical practice. Protocols are especially useful when orienting new personnel who
may bring preconceived methods of CPB conduct learned in an educational program or previous job experience.
Although it is generally agreed that CPB can be
P.553
conducted in many ways with acceptable patient outcome, safe conduct of CPB on a case-by-case basis is
facilitated by use of mutually-agreed-on protocols that clarify personnel roles and expectations and specific
patient management issues.
The first national standard of perfusion practice formulated by a professional society appeared in 1978 (112) and
contained basic items that were considered important for inclusion on a perfusion record such as names of the
surgeon, perfusionist, and anesthesiologist. Also to be recorded were timed entries for specific parameters such
as CPB systemic blood flow, patient temperatures and pressures, and blood gas results. In 1987, a second
standard of practice document was published by the American Academy of Cardiovascular Perfusion (113). It
acknowledged that although the primary responsibility for care of the patient undergoing CPB rested with the
surgeon or physician in charge, it was considered the responsibility of the perfusionist to assist the surgeon in
any way possible in care of the patient and particularly within the defined area of expertise of the perfusionist. It
further emphasized the necessity for a written perfusion record; choice of equipment including cost containment
and use of available safety devices; personnel (two qualified perfusionists or a qualified assistant for the primary
perfusionist per case was deemed preferable); mandatory use of a prebypass checklist; and conduct of
perfusion. The standard addressed issues such as maintenance of a safe volume at all times in the CPB
reservoir, the volume of which would allow 15 seconds for reaction time in the event of interrupted venous
drainage. It specified that systemic blood flow rates should be maintained at such a level that inadequate tissue
perfusion not develop, examples of which were development of increasing metabolic acidosis, mixed venous
oxygen desaturation, or EEG changes. Specific pressure ranges were not defined in the standard, but the
standard did state that the systemic blood pressure “must be maintained at an adequate level so that organ
preservation and function are not compromised or impaired function detected.” Anticoagulation assessment
should be performed on a routine basis and should be adequate to prevent clotting in the extracorporeal circuit
and consumption of blood clotting factors. This document has been updated several times, and the most recent
version appeared in 2008 (114).
AmSECT also developed essentials for perfusion practice that were endorsed by their membership (115). In the
preamble, the standard reiterated a statement that appeared in an earlier scope of practice (116):
“Extracorporeal circulation shall be conducted according to established procedures and protocols in accordance
with hospital policy and upon prescription by a physician.” Tenets of the standard included: “an accurate
perfusion record must be maintained; the perfusionist should use a checklist(s); extracorporeal circulation should
be conducted by a knowledgeable and competent perfusionist; anticoagulation should be monitored; appropriate
gas exchange, blood flow, pressures, and volumes should be maintained; appropriate safety and monitoring
devices should be used; the perfusionist should make a reasonable effort to contain costs; and the perfusionist
must ensure proper maintenance of equipment.” Those essential statements dealing with actual conduct of
perfusion were qualified by the phrase “according to the established protocol” to permit variations in individual
team practice. The intent of these standards was to provide guidance for safe perfusion practice rather than
mandating specific practice.
In 1995, AmSECT published specific guidelines for perfusion practice (117) to augment the earlier essentials
document (115). The basis for this document was a national survey on perfusion practice conducted by the
organization in 1993 (118). Recently, these practice guidelines have been extensively revised (119) with input
from the International Consortium for Evidence-Based Perfusion (120). As with most guidelines and standards
documents, statements are phrased using the words “shall” indicating a mandatory requirement or “should”
indicating a recommendation. The development of institutionally-based protocols is encouraged based on the
published practice guidelines.
CONCLUSIONS
CPB, as noted by Kouchoukos and coauthors (46, p. 79), is conceptually simple and equipment is now
available to accomplish it with ease. In the 1960s, when CPB was just beginning to be practiced routinely in
major medical centers, Galletti and Brecher (1, p. 251) made a plea that it be kept simple, particularly
considering the multitude of parameters that could be monitored. The capability for monitoring CPB in many
different ways has not diminished decades later. Although CPB was not ideal in 1962, nor is it at the current
time, it is an established procedure that is well tolerated in most patients who make uneventful recoveries
after their cardiac surgery. Until an alternative method is developed to provide the surgeon a motionless
blood-free operative field and safely protect vital organs, CPB will likely continue to be used at current
levels of several hundred thousand procedures annually worldwide.
As stated previously, the actual conduct of perfusion practice may vary according to surgeon/perfusionist
preference and institutional or even regional practice. However, national consensus on what constitutes
adequate and safe conduct of CPB has been delineated and promulgated by professional organizations in
the last three decades. Such guidelines, standards, and protocols are important to consider in the context of
individual practice, but they must be used in perspective. They cannot anticipate every contingency or
emergency that might arise during CPB. Further, guidelines, standards and protocols cannot govern all
activities of all team members. All personnel involved in the conduct of CPB must rely on experience and
deductive reasoning to solve problems or avoid a perfusion crisis. Guidelines, standards, and protocols are
derived from experience. Experience includes mistakes, accidents, and failures. Guidelines, standards, and
protocols are meant to eliminate these life-threatening events but should not be totally relied on without
constant awareness of the individual patient being supported by CPB and constant vigilance to detect early
any abnormal behavior on bypass that could compromise patient safety.
P.554
KEY Points
The patient’s chart should be reviewed before CPB to obtain information regarding the proposed surgical
procedure and patient history.
Assembly of the CPB circuit should be performed in a consistent manner on a day-to-day basis.
Roller pump occlusion on all pumps should be set before use for each case.
Centrifugal pump flow probes must be calibrated and zeroed before use for accurate CPB systemic flow
measurement.
Completion of a prebypass checklist will greatly ensure the odds of proper CPB assembly and function.
Minimizing circuit prime volume will result in a higher mixed patient/circuit hematocrit and possibly reduce
the need for homologous blood transfusion.
CPB should be established by activating the systemic pump first (before release of the venous line
clamp) to avoid patient exsanguination in the event of a malfunction of the CPB systemic pump.
Vents should be tested before use to verify proper suctioning effect.
The CPB reservoir volume should be continuously monitored so that appropriate changes in systemic
blood flow can be made in the event of decreased venous drainage.
Cooling and warming rates should not exceed an approximate 8°C to 10°C gradient (arterial blood and
patient temperature when cooling; venous blood and heat exchanger water source when rewarming).
Measuring Svo2 does not ensure that CPB systemic flow is meeting regional Do2 requirements; however,
a low Svo2 does indicate a problem with systemic Do2.
A CPB systemic flow index of 2.2 L/min/m2 is recommended when normothermic for adequate perfusion;
in children, the corresponding flow index should be at least 2.5 L/min/m2.
Hypothermia allows proportionate reductions in CPB systemic flow guided by nomograms that rely on
plateauing of Vo2.
Viscosity (and resistance to blood flow) increases substantially with hypothermia, indicating the
importance of hemodilution with CPB.
Pressure measurement artifacts are frequently seen during CPB and result from effects of hypothermia,
uneven vasodilation with rewarming, mechanical tissue/vessel compression, or aortic cannula tip
malposition.
Central venous, PA, and LA pressures should be at or near zero during CPB when the heart is arrested
and when unrestricted venous drainage is intended; an increase in any one of these parameters is a
matter for concern requiring assessment of venous cannula(s) position and confirmation of an
unrestricted venous drainage line.
During rewarming with a beating heart after recovery from the arrest period, a filling pressure adequate to
create ejection is frequently beneficial.
An elevated CVP will reduce the effective perfusion pressure to organs (e.g., brain, kidney, liver) and
tissue beds (e.g., gut).
Changes in the EEG may be induced by hemodilution, hypothermia, anesthetics, CPB systemic flow and
pulsatility changes, and hypoxia, making interpretation and diagnosis of CNS insult difficult.
“Core temperature” is conceptually simple, but in reality brain temperature during CPB is best
approximated by measuring the nasopharyngeal, tympanic, or esophageal temperature.
Use of continuous reading in-line blood gas sensors allows precise management of Pao2 and Paco2 in
the perfusate and provides a margin of safety during CPB.
The flow, pressure, and temperature of cardioplegic solution and temperature of the myocardium should
be monitored to reasonably ensure adequate cardioplegia.
Use of circuit alarms (e.g., level sensor, air bubble detector) can decrease the risk of air embolism during
CPB.
REFERENCES
1. Galletti PM, Brecher GA. Heart-lung bypass, principles and techniques of extracorporeal circulation. New
York, NY: Grune & Stratton, 1962.
2. Commission on Accreditation of Allied Health Education Programs. Standards and guidelines for the
accreditation of educational programs in perfusion. Available at www.caahep.org/. Accessed 4 September
2014.
3. Toomasian JM, Searles B, Kurusz, M. The evolution of perfusion education in America. Perfusion
2003;18:257-265.
4. Sistino JJ, Michaud NM, Sievert AN, et al. Incorporating high fidelity simulation into perfusion education.
Perfusion 2011;26:390-394.
5. Reed CC, Kurusz M, Lawrence AE Jr. Safety and techniques in perfusion. Stafford, TX: Quali-Med
Publishers, 1988.
6. Davis RF, Dobbs JL, Casson H. Conduct and monitoring of cardiopulmonary bypass. In: Gravlee GP,
Davis RF, Utley JR, eds. Cardiopulmonary bypass, principles and practice, Baltimore, MD: Williams &
Wilkins, 1993:579.
7. Emergency Care Research Institute. Inspection and preventive maintenance of cardiopulmonary perfusion
equipment and an overview of problems. Health Devices 1980;9:70-80.
P.555
8. Kurusz M, Crane TN, Speer D. Preventive maintenance of heart-lung machines. Proc Am Acad
Cardiovasc Perfusion 1985;6:34-37.
9. Young WV, Heemsoth CH, Georgiafandis G, et al. Extracorporeal circuit sterility after 168 hours. J Extra
10. Wellons HA, Nolan SP. Prevention of air embolism due to trapped air in filters used in extracorporeal
circuits. J Thorac Cardiovasc Surg 1973;65:476-478.
11. Hargrove M, McCarthy AP, Fitzpatrick GJ. Carbon dioxide flushing prior to priming the bypass circuit, an
experimental derivation of the optimal flow rate and duration of the flushing process. Perfusion 1987;2:177-
180.
12. Altman PL, Dittmer DS, eds. Respiration and circulation. In: Biological handbooks. Bethesda, MD:
Federation of American Societies for Experimental Biology, 1971:16-18.
13. Reed CC, Romagnoli A, Taylor DE, et al. Particulate matter in bubble oxygenators. J Thorac Cardiovasc
Surg 1974;68:971-974.
14. Reed CC, Stafford TB. Cardiopulmonary bypass. 2nd ed. Houston, TX: Texas Medical Press, 1985.
15. Rath T, Sutton R, Ploessel J. A comparison of static occlusion setting methods: fluid drop rate and
pressure drop. J Extra Corpor Technol 1996;28:21-26.
16. Lee-Sensiba K, Azzaretto N, Carolina C, et al. New roller pump disposable provides safety and simplifies
occlusion setting. J Extra Corpor Technol 1997;29:19-24.
17. Mills NL, Ochsner JL. Massive air embolism during cardiopulmonary bypass; causes, prevention and
management. J Thorac Cardiovasc Surg 1980;80:707-717.
18. Crane TN, Keen WR Jr, Spiller CE, et al. A prebypass checklist—why aren’t you using one? Proc Am
Acad Cardiovasc Perfusion 1986;7:98-100.
19. Kurusz M, Harshaw RC. The contribution of checklists to perfusion safety: lessons from aviation. In:
Steenbrink J, Wijers-Hille MJ, deJong DS, eds. Fourth European congress on extracorpeal circulation
technology. Utrecht, Netherlands: Foundation European Congress on Extracorporeal Circulation, 1995:177-
185.
20. American Society of Extracorporeal Technology. Perfusion checklist. Available at

http://amsect.org/sections/practice/practice-articles/article1.iphtml. Accessed 3 September 2014.
21. Rosengart TR, DeBois WJ, O’Hara M, et al. Retrograde autologous priming for cardiopulmonary bypass:
a safe and effective means of decreasing hemodilution and transfusion requirements. J Thorac Cardiovasc
Surg 1998;115:426-439.
22. Darling E, Kaemer D, Lawson S, et al. Experimental use of an ultra-low prime neonatal cardiopulmonary
bypass circuit utilizing vacuum-assisted venous drainage. J Extra Corpor Technol 1998;30:184-189.
23. Willcox TW, Mitchell SJ, Gorman DF. Venous air in the bypass circuit: a source of arterial line emboli
exacerbated by vacuum-assisted drainage. Ann Thorac Surg 1999;68:1285-1289.
24. Petry AF, Jost T, Sievers H. Reduction of homologous blood requirements by blood-pooling at the onset
of cardiopulmonary bypass. J Thorac Cardiovasc Surg 1994;107:1210-1214.
25. Jansen PGM, te Velthuis H, Bulder ER, et al. Reduction in prime volume attenuates the hyperdynamic
response after cardiopulmonary bypass. Ann Thorac Surg 1995;60:544-550.
26. Gourlay T, Gunaydin S, eds. Minimized cardiopulmonary bypass techniques and technologies.
Sawston, Cambridge, UK: Woodhead Publishing, 2012.
27. Kolff J, McClurken JB, Alpern JB. Beware centrifugal pumps; not a oneway street, but a potentially
dangerous “syphon” [Letter]. Ann Thorac Surg 1990;50:512.
28. Fox LS, Blackstone EH, Kirklin JW, et al. Relationship of whole body oxygen consumption to perfusion
flow rate during hypothermic cardiopulmonary bypass. J Thorac Cardiovasc Surg 1982; 83:239-248.
29. Lee-Sensiba K, Azzaretto N, Carolina C, et al. Errors in flow and pressure related to the arterial filter
purge line. J Extra Corpor Technol 1998;30:77-82.
30. Pedersen TH, Videm V, Svennevig JL, et al. Extracorporeal membrane oxygenation using a centrifugal
pump and a servo regulator to prevent negative inlet pressure. Ann Thorac Surg 1997;63:1333-1339.
31. Davila RM, Rawles T, Mack MJ. Venoarterial air embolus: a complication of vacuum-assisted venous
drainage. Ann Thorac Surg 2001;71:1369-1371.
32. Jones L, Knight PG, Alley R, et al. Adverse effects of Forane, Ethrane, and Halothane of the William
Harvey H-1700 bubble oxygenator. Proc Am Acad Cardiovasc Perfusion 1987;8:178-181.
33. Maltry DE, Eggers GWN Jr. Isoflurane-induced failure of the Bentley-10 oxygenator [Correspondence].
34. Walls JT, Curtis JJ, McClatchey BJ, et al. Adverse effects of anesthetic agents on polycarbonate plastic
oxygenators [Letter]. J Thorac Cardiovasc Surg 1988;96:667-668.
35. Gravlee GP, Wong AB, Charles DJ. Hypoxemia during cardiopulmonary bypass from leaks in the gas
supply system [Letter]. Anesth Analg 1985;64:649-650.
36. Centers for Disease Control. Recommendations for prevention of HIV transmission in health care
settings. MMWR Morb Mortal Wkly Rep 1989;36:1S-18S.
37. Courington KR, Patterson SL, Howard RJ. Universal precautions are not universally followed. Arch Surg
1991;126:93-96.
38. Shelley GA, Howard RJ. A national survey of surgeons’ attitudes about patients with human
immunodeficiency virus infections and acquired immunodeficiency syndrome. Arch Surg 1992;127:206-212.
39. Gershon RRM, Vlahov D, Felknor SA, et al. Compliance with universal precautions among health care
workers at three regional hospitals. Am J Infect Control 1995;23:225-236.
40. Megan J, Patterson M, Novak CB, et al. Surgeons’ concern and practices of protection against
bloodborne pathogens. Ann Surg 1998;228:266-272.
41. Akduman D, Kim LE, Parks RL, et al. Use of personal protective equipment and operating room
behaviors in four surgical subspecialties: personal protective equipment and behaviors in surgery. Infect
Control Hosp Epidemiol 1999;20:110-114.
42. Pietrabissa A, Merigliano S, Montorsi M, et al. Reducing the occupational risk of infections for the
surgeon: multicentric national survey on more than 15,000 surgical procedures. World J Surg 1997;21:573-
578.
43. Flum DR, Wallack MK. The surgeon’s database for AIDS: a collective review. J Am Coll Surg
1997;184:403-412.
44. Lawrence VA, Gafni A, Kroenke K. Preoperative HIV testing: is it less expensive than universal
precautions? J Clin Epidemiol 1993;46:1219-1227.
45. Klatt EC. Surgery and human immunodeficiency virus infection: indications, pathologic findings, risks, and
risk prevention. Int Surg 1994;79:1-5.
46. Kouchoukos NT, Blackstone EH, Doty DB, et al. Kirklin/Barratt-Boyes Cardiac surgery, Vol. 1. 3rd ed.
Philadelphia, PA: Churchill Livingstone, 2003.
47. Noui N, Zogheib E, Walczak K, et al. Anticoagulation monitoring during extracorporeal circulation with the
Hepcon/HMS device. Perfusion 2012;27:214-220.
48. Collins RL. Air crashes, what went wrong, why, and what can be done about it. New York, NY:
Macmillan, 1986:17.
49. Jerabek CF, Walton HG, Doerfler S. The effect of gas scavenging on hollow fiber membrane oxygenator
performance. In: Proceedings of the 27th international conference American Society of Extra-Corporeal
Technology, 10-14 March 1989:24-29.
50. Kurusz M, Andrews JJ, Arens JF, et al. Monitoring oxygen concentration prevents potential adverse
patient outcome caused by a scavenging malfunction: case report. Proc Am Acad Cardiovasc Perfusion
1991;12:162-165.
51. Emergency Care Research Institute. Hazard, scavenging gas from membrane oxygenators. Health
Devices 1987;16:343-344.
52. Blomback M, Kronlund P, Aberg B, et al. Pathologic fibrin formation and cold-induced clotting of
membrane oxygenators during cardiopulmonary bypass. J Cardiothorac Vasc Anesth 1995;9:34-43.
53. Donald DE, Fellows JL. Physical factors relating to gas embolism in blood. J Thorac Cardiovasc Surg
1961;42:110-118.
54. Stone JG, Young WL, Smith CR, et al. Do standard monitoring sites reflect true brain temperature when
profound hypothermia is rapidly induced and reversed? Anesthesiology 1995;82:344-351.
55. Cook DJ, Orszulak TA, Daly RC, et al. Cerebral hyperthermia during cardiopulmonary bypass. J Thorac
56. Nussmeier NA, Cheng W, Marino MR, et al. Temperature during cardiopulmonary bypass: the
discrepancies between monitored sites. Anesth Analg 2006;103:1373-1379.
57. Buss MI, McLean RF, Wong BI, et al. Cardiopulmonary bypass, rewarming, and central nervous system
dysfunction. Ann Thorac Surg 1996;61:1423-1427.
58. Leigh JM. Oxygen therapy at ambient pressure. In: Scurr C, Feldman S, eds. Scientific foundations of
anaesthesia. 2nd ed. Chicago, IL: Medical Yearbook, 1974:254.
59. Guyton AC. Textbook of medical physiology. 7th ed. Philadelphia, PA: WB Saunders, 1986.
60. Gregory IC. The oxygen and carbon monoxide capacities of fetal and adult blood. J Physiol
1974;236:625-634.
61. Brandfonbrenner M, Landowne M, Shock NW. Changes in cardiac output with age. Circulation
1955;12:557-566.
62. Gerstenblith G, Renlund DG, Lakatta EG. Cardiovascular response to exercise in younger and older
men. Fed Proc 1987;46:1834-1839.
63. Rodenheffer RJ, Gerstenblith G, Becker LC, et al. Exercise cardiac output is maintained with advancing
age in healthy human subjects: cardiac dilatation and increased stroke volume compensate for a diminished
heart rate. Circulation 1984;69:203-213.
P.556
tension during hypothermic cardiopulmonary bypass. Anesthesiology 1986;64:576-581.
66. Murkin JM, Farrar JK, Tweed A, et al. Cerebral autoregulation and flow/metabolism coupling during
cardiopulmonary bypass: the influence of carbon dioxide. Anesth Analg 1987;66:825-832.
67. Thomson IR. The influence of cardiopulmonary bypass on cerebral physiology and function. In: Tinker
JH, ed. Cardiopulmonary bypass, current concepts and controversies. Philadelphia, PA: WB Saunders,
1989:21-40.
68. Schwartz AE, Sandhu AA, Kaplon RJ, et al. Cerebral blood flow is determined by arterial pressure and
not cardiopulmonary bypass flow rate. Ann Thorac Surg 1995;60:165-170.
69. Rudy LW, Heymann MA, Edmunds H. Distribution of systemic blood flow during cardiopulmonary bypass.
J Appl Physiol 1973;34:194-200.
70. Harris EA, Seelye ER, Barratt-Boyes BG. On the availability of oxygen to the body during
cardiopulmonary bypass in man. Br J Anaesth 1974;46:425-431.
71. Mandl JP, Motley JR. Oxygen consumption plateauing: a better method of achieving optimum perfusion. J
72. Parolari A, Alamanni F, Gherli T, et al. Cardiopulmonary bypass and oxygen consumption: oxygen
delivery and hemodynamics. Ann Thorac Surg 1999;67:1320-1327.
73. Clowes GHA, Neville WE, Sabga G, et al. The relationship of oxygen consumption, perfusion rate, and
temperature to acidosis associated with cardiopulmonary bypass. Surgery 1958;44:220-225.
74. Diesh G, Flynn PJ, Marable SA, et al. Comparison of low (azygous) flow and high flow principles of
extracorporeal circulation employing a bubble oxygenator. Surgery 1957;42:67-72.
75. Moffitt EA, Kirklin JW. Physiologic studies during whole-body perfusion in tetralogy of Fallot. J Thorac
76. Levin MB, Theye RA, Fowler WS, et al. Performance of the stationary vertical-screen oxygenator (Mayo-
Gibbon). J Thorac Cardiovasc Surg 1960;39:417-426.
77. Kern FH, Ungerleider RM, Reves JG, et al. Effect of altering pump flow rate on cerebral blood flow and
metabolism in infants and children. Ann Thorac Surg 1993;56:1366-1372.
78. Gold JP, Charlson ME, Williams-Russo P, et al. Improvement of outcomes after coronary artery bypass; a
randomized trial comparing intraoperative high versus low mean arterial pressure. J Thorac Cardiovasc Surg
1995;110:1302-1314.
79. Robicsek F, Masters TN, Niesluchowski W, et al. Vasomotor activity during cardiopulmonary bypass. In:
Utley JR, ed. Pathophysiology and techniques of cardiopulmonary bypass, Vol II. Baltimore, MD: Williams &
Wilkins, 1983:1-12.
80. Hine IP, Wood WG, Mainwaring-Buton RW, et al. The adrenergic response to surgery involving
cardiopulmonary bypass, as measured by plasma and catecholamine concentrations. Br J Anaesth
1976;48:355-363.
81. Wallach R, Karp RB, Reves JG, et al. Pathogenesis of paroxysmal hypertension developing during and
after coronary artery bypass surgery: a study of hemodynamic and humoral factors. Am J Cardiol
1980;46:559-565.
82. Fouad FM, Estafanous FG, Bravo EL. Possible role of cardioaortic reflexes in post-coronary bypass
hypertension. Am J Cardiol 1979;44:866-872.
83. Murgo JP, Westerhof N. Arterial reflections and pressure waveforms in humans. In: Yin FCP, ed.
Ventricular vascular coupling. Berlin, Germany: Springer-Verlag, 1987:144-146.
84. Stern DH, Gerson JI, Allen FB, et al. Can we trust the radial artery pressure immediately after
cardiopulmonary bypass? Anesthesiology 1985;62:557-561.
85. Chapin JW, Nance P. Facial paleness. Anesth Analg 1982;61:475.
86. Jacobsohn E, Fessler DA, Rosemeier F, et al. Morbidity and mortality associated with accidentally
entrapped pulmonary artery catheters during cardiac surgery: a case series. J Cardiothorac Vasc Anesth
2006;20:371-375.
87. Davis RF. Yet another CVP artifact. Anesthesiology 1984;60:262.
88. Murkin JM, Arango M. Near-infrared spectroscopy as an index of brain and tissue oxygenation. Br J
Anaesth 2009;103(Suppl 1):i3-i13.
89. Apostolidou I, Morrisette G, Sarwar MF, et al. Cerebral oximetry during cardiac surgery: the association
between cerebral oxygen saturation and perioperative patient variables. J Cardiothorac Vasc Anesth
2012;26:1015-1021.
90. Grocott HP, Davie SN. Future uncertainties in the development of clinical cerebral oximetry. Front
Physiol 2013;4:1-3.
91. Zheng F, Sheinberg R, Yee M-S, et al. Cerebral near-infrared spectroscopy monitoring and neurologic
outcomes in adult cardiac surgery patients: a systematic review. Anesth Analg 2013;116:663-676.
92. Ginsburg HH, Shetler AG, Raudzeus PA. Postoperative paraplegia with preserved intraoperative
somatosensory evoked potentials. J Neurosurg 1985;63:296-300.
93. Levy WJ. Quantitative analysis of EEG changes during hypothermia. Anesthesiology 1984;60:291-297.
94. Davis FM, Parimelazhagan KN, Harris EA. Thermal balance during cardiopulmonary bypass with
hypothermia in man. Br J Anaesth 1977;49:1127-1132.
95. Noback CR, Tinker JH. Hypothermia after cardiopulmonary bypass in man. Anesthesiology 1980;53:277-
280.
96. Abel RM, Buckley MJ, Austen WG, et al. Etiology, incidence and prognosis of renal failure following
cardiac operations. Results of a prospective analysis of 500 consecutive patients. J Thorac Cardiovasc Surg
1976;71:323-333.
97. Joachimsson P-O, Sjoberg F, Forsman M, et al. Adverse effect of hyperoxemia during cardiopulmonary
bypass. J Thorac Cardiovasc Surg 1996;112: 812-819.
98. Ihnken K, Winkler A, Schlensak C, et al. Normoxic cardiopulmonary bypass reduces oxidative myocardial
damage and nitric oxide during cardiac operations in the adult. J Thorac Cardiovasc Surg 1998;116:327-334.
99. Kurusz M, Girouard MK, Brown PS Jr. Coronary sinus rupture with retrograde cardioplegia. Perfusion
2002;17:77-90.
100. Sievertsen WA, Hankins TD, Lazar HL, et al. A new technique for measuring aortic root pressure during
infusion of cardioplegic solution. Ann Thorac Surg 1986;41:675-677.
101. Faulkner SC, Kurusz M, Manning JV Jr, et al. Clinical experience with the Amicon Diafilter during
cardiopulmonary bypass. Proc Am Acad Cardiovasc Perfusion 1987;8:66-69.
102. Darling E, Searles B, Nasrallah F, et al. High-volume, zero balanced ultrafiltration improves pulmonary
function in a model of post-pump syndrome. J Extra Corpor Technol 2002;34:254-259.
103. de Baar M, Diephuis JC, Moons KG, et al. The effect of zero-balanced ultrafiltration during
cardiopulmonary bypass on S100b release and cognitive function. Perfusion 2004;18:9-14.
104. Nakamura Y, Masuda M, Toshima Y, et al. Comparative study of cell saver and ultrafiltration
nontransfusion in cardiac surgery. Ann Thorac Surg 1990;49:973-978.
105. Boldt J, Zickmann B, Fedderson B, et al. Six different hemofiltration devices for blood conservation in
cardiac surgery. Ann Thorac Surg 1990;51: 747-753.
106. Sarns/3M Health Care. Four out of five regularly use bubble detectors. Heart-to-Heart Newsletter
1993;8:5.
107. American Society of Extracorporeal Technology. Pump templates. Available at

http://amsect.org/sections/practice/practice-articles/article3.iphtml. Accessed 3 September 2014.
108. Lupinetti FM, Stoney WS, Alford WC Jr, et al. Cryoprecipitate-topical glue, initial experience in patients
undergoing cardiac operation. J Thorac Cardiovasc Surg 1985;90:502-505.
109. Robicsek F, Duncan GD, Born GVR, et al. Inherent dangers of simultaneous application of microfibrillar
collagen hemostat and blood-saving devices. J Thorac Cardiovasc Surg 1986;92:766-770.
110. Utley JR, Bhatt MA, Stephens DB, et al. Reversal of protamine reaction with heparin. Perfusion
1986;1:63-64.
111. Lock R, Hessel EA II. Probable reversal of protamine reactions by heparin administration. J
Cardiothorac Anesth 1990;4:604-608.
112. American Society of Extracorporeal Technology. Standards of practice: recommended minimum

standards, permanent perfusion records. J Extra Corpor Technol 1978;10:46.
113. American Academy of Cardiovascular Perfusion. Standards of practice. Proc Am Acad Cardiovasc
Perfusion 1987;8:272-274.
114. American Academy of Cardiovascular Perfusion. Standards of practice. Available at

http://www.theaacp.com/. Accessed 4 September 2014.
115. American Society of Extracorporeal Technology. Essentials for perfusion practice; clinical function:
conduct of extracorporeal circulation. Perfusion Life 1992;9:37.
116. American Society of Extracorporeal Technology. Perfusion scope of practice. Perfusion Life 1991;8:25.
117. American Society of Extracorporeal Technology. Guidelines for perfusion practice. Perfusion Life
1995;12:20-22.
118. American Society of Extracorporeal Technology. Perfusion practice survey, September 1993. Perfusion
Life 1994;11:42-45.
119. American Society of Extracorporeal Technology. Practice guidelines.

http://amsect.org/sections/practice/. Accessed 4 September 2014.
120. Baker RA, Bronson SL, Dickinson TA, et al. Report from AmSECT’s International Consortium for
Evidence-Based Perfusion: American Society of Extracorporeal Technology Standards and Guidelines for
Perfusion Practice: 2013. J Extra Corpor Technol 2013;45:156-166.
Chapter 23
Primum Non Nocere: Patient Safety in Cardiopulmonary Bypass
Izumi Harukuni
Valerie Sera
TO ERR IS HUMAN
Perfusion safety is a problem that encompasses a broad range of topics for which there is no one solution. Since the first successful clinical use of
cardiopulmonary bypass (CPB) by the pioneering cardiac surgeon John Gibbon in 1953, numerous positive changes in the engineering and manufacturing of
equipment, surgical and anesthetic techniques, education of perfusionists, and the management of perfusion have made CPB safer. Separating patient safety
during CPB and clinical outcome specifically related to CPB from the complex milieu of the perioperative course of cardiac surgery is a difficult task. For
example, a study reported by Healey in 2002 identified an overall adverse event rate of 26.9% and a mortality rate of 3.34% among 1,438 cardiac surgical
patients, including 1,596 individual procedures (1). As assessed by a rigorous peer review process, 49.5% of the 182 minor complications, 38.7% of the 181
major complications, and 25.0% of the 48 deaths in this study were categorized as avoidable. Although CPB was not specifically cited in this report, “equipment
failure” was tabulated and had a zero occurrence rate for both complication categories and for mortality as well. Nevertheless, CPB-related adverse events do
occur, are often avoidable, and can produce significant adverse events including fatalities.
Perfusion safety does not refer only to the incorporation of safety devices in the equipment and supplies used during CPB, rather it includes everything about
safe conduct of CPB such as the heart-lung machines, circuit design, ancillary equipment, perfusion practices, surgical and anesthetic techniques, and perhaps
most importantly, the training and education of perfusionists with emphasis on vigilance and communication with the other members of the team in the operating
room. The literature contains a multitude of reports describing oxygenator failure (2,3,4,5), mechanical failure (6), electrical failure (7,8,9,10), massive air
embolization (11,12), and preventative maintenance (13,14). There are accident surveys (15,16,17,18,19,20,21), comparisons of those surveys (22,23), reviews
of the risks and hazards of CPB (24,25,26,27,28), review of safety devices (29,30), and other aspects of safe CPB (31,32). Defining the problem of perfusion
safety requires identifying the types of incidents and their frequency through a quantitative approach (33).
Patient safety during CPB has been a prime concern since its earliest clinical history. In the earliest perfusion circuits and equipment, there were complex safety
feedback loops and devices incorporated into the design. The first heart-lung machines had fail-safe mechanisms such as oxygenator blood level sensors, level
floats, and pressure sensors, many of which were described in the classic perfusion textbook by Pierre Galletti in 1962, Heart-lung bypass; principles and
techniques of extracorporeal circulation (34). Although the clinical roots of CPB are in the operative repair of congenital cardiac anomalies and valvular heart
disease, arguably it was the rapid increase in the numbers of coronary artery bypass procedures, which followed the 1968 publication by Favaloro (35), that
produced an explosive increase in the numbers of cardiac surgical procedures and the further development of CPB equipment, processes, and training
programs. The need for the development of simple, reliable systems became a necessity. Disposable components for the bypass machines have largely
replaced earlier reusable components. Oxygenator design has moved from large, clumsy film oxygenators through hard-shell bubble oxygenators and to the
current disposable, single-use, self-contained membrane oxygenators most commonly used (in the USA) today. Improved electromagnetically coupled
centrifugal pumps replaced the early roller pumps. Problems associated with air embolization and anticoagulation have been heavily investigated. More recently,
reperfusion injury and the systemic inflammatory response elicited by the blood to foreign surface exposure inherent in current CPB have received substantial
attention. Over the last six decades, there have been many improvements in the equipment and circuits used, but in the end, it is still difficult to mimic the
anatomy and physiology of the heart and lungs. And in the attempt to do so, adverse events do occur. Examination of these occurrences with the intent of
reducing their frequency is the focus of this chapter.
There is abundant literature regarding CPB with particular attention paid to CPB techniques and the equipment. The actual number of articles written
specifically addressing perfusion safety is small in comparison, although an underlying theme of safety is inferred. Palanzo searched a proprietary
P.558
database (PerfSearch, property of American Academy of Cardiovascular Perfusion, and limited to use by its members) that specifically encompasses CPB-
related manuscripts that appear in journals from cardiac surgery, anesthesiology, cardiology, perfusion, and biomedical engineering (33). Of more than 12,000
published manuscripts, the percentage that was dedicated to perfusion safety was only 1.4%, a total of 165 articles. Many of those 165 articles were case
reports or small series that described air embolism. Others were reviews that included air accidents. Only 0.45% (54 of the total) reported on safety devices or
issues different from gaseous emboli. Some of the earliest articles addressed the prevention of air embolization (36,37). The era of the late 1950s and 1960s,
articles that discussed flow meters (38), safety devices for CPB (39), mechanical failure during CPB and a left ventricular vent valve (40) were published. The
1970s showed a decrease in the number of articles about perfusion safety, but popular topics during that time described aortic vents to prevent air embolization
(41), retrograde dissection of the aorta during CPB (42), and run away pump head (43). The next decade witnessed an increase in the number of safety reports
secondary to a large increase in the number of cardiac surgeons and training programs. Christman and Kurusz (29) published a review of safety devices
available for preventing massive gas embolization. The safety devices were divided into four categories: devices attached to oxygenators, those devices that
used proximal and distal to the pump head, and a device that functioned as a blood pump. There are reports of power failures (7,8) and reviews on the risks of
CPB (25,26,27). Other topics reported were about preventive maintenance (13), oxygenator failure (2), safety devices for blood level regulation (44) and for
pressure measurement (45,46). In 1988, the American Academy of Cardiovascular Perfusion devoted an entire issue in its journal Perfusion to the many aspects
of perfusion safety. The 1990s focused on a different aspect of perfusion safety. Reports on risk management (32) and quality assurance (47) made their debut,
and remain important aspects of CPB safety.
KNOWLEDGE FROM THE PAST

In the first 30 years of CPB, there was constant attention paid to promoting safety in perfusion as is illustrated by the previous accounting of reports describing
all of the various safety devices that were engineered and manufactured. But, it was not until 1980 when the first hints appeared regarding the frequency of
adverse incidents occurring during CPB. Table 23.1 is a summary of surveys documenting the types and frequency of incidents. The Stoney report was a
survey of 349 cardiac surgeons between 1972 and 1977 in the United States and Canada to estimate the frequency of patients injured by accidental arterial line
air embolism (15). It was the first comprehensive effort to determine the incidence of perfusion-related adverse events (AEs). The questionnaire asked several
questions about accidents concerning the pump oxygenators, that is, episodes of arterial line air embolism, mechanical failure of the pump, electrical failure of
the pump, disseminated intravascular coagulation (DIC) during or after bypass, and oxygenator failure. There were a total of 1,419 accidents that resulted in 100
permanent injuries and 264 deaths (Fig. 23.1).
Air embolism in the arterial line was responsible for 92 deaths, and DIC was responsible for 163 deaths. Mechanical, electrical, or oxygenator failures were
responsible for nine deaths. Another common cause of accidents was the reversal of the tubing connected to the ventricular sump, causing air to be pumped
into the left ventricle. When asked about the usage of low-level alarms, only 42% of the responders used them and only 20% used an alarm system that was
equipped with an automatic pump shut-off. When asked about the use of an activated clotting time (ACT) during bypass only 37% did not, but interestingly,
those using the ACT reported 313 episodes of DIC and those who did not use the ACT reported only 57 episodes of DIC. This is likely a nice example of the
underreporting of adverse events that occur when surveillance for the occurrence is limited or absent. The authors concluded that most of the accidents caused
by arterial line air embolism were a result of human error, but could be eliminated by consistent usage of low-level alarm systems and automatic shutoff devices.
Additionally, the deaths and injuries secondary to DIC during CPB might be avoided by consistent use of ACTs or heparin titration. A possible disadvantage in
the methodology of the survey was that the information gathered by the questionnaire relied on the memories of the cardiac surgeons and was not a review of
past experience. It should be expected that this methodology could have produced an underestimation of the true incidence of accidents during CPB.
In 1981, Wheeldon published results from two surveys akin to the Stoney report (16,17). They were both retrospective surveys sent to perfusionists in the
United Kingdom covering the years 1974 to 1979 for the first and 1979 to 1980 for the second. The results from the first survey were similar to the results from
the Stoney report, with accidents occurring 1 in every 300 perfusions and permanent injury or death occurring 1 in every 1,500 perfusions. In the second survey,
published in 1980, there was a reported increase in incidents (1 in 140 perfusions) but a decrease in permanent injury or death (1 in 1,800 perfusions). In both
surveys, the major incidents were arterial line embolism and consumptive coagulopathies. The most frequent occurrences had to do with inadequate
oxygenation while on CPB secondary to inadequate oxygenator performance or impaired perfusion.
In 1986, Kurusz et al. (18) published results of another survey of clinical perfusionists in North America. Its purpose was to update results from previous surveys
and to assess the current perfusion technique and determine state-of-the-art perfusion practice. The Perfusion Accident questionnaires ( n = 1,366), 10 pages
long with questions divided into sections (hematology, hemodynamics, pharmacology, gas
P.559
P.560
embolism, myocardial protection, equipment, perfusion technique, and miscellaneous), were mailed to perfusionists in the United States and Canada for the
years between 1982 and 1985. Figure 23.2 summarizes the types and frequency of perfusion accidents and their associated morbidity and mortalities. In this
survey, the permanent injury and death numbers were combined to calculate morbidity/mortality.
TABLE 23.1. Summary of published perfusion safety surveys
Number of
Number pump- Most Permanent
Type of Time Response of related common injury or
Study survey period Recipients Responses rate (%) cases accidents accidents death
Stoney et Retrospective 1972- Cardiac 349 21 374,819 1/300 Arterial line 1/1,000
al., 1980 questionnaire 1977 surgeons Procedures embolism DIC Procedures
(15) Electrical
failure
Oxygenator
failure
Wheeldon, Retrospective 1974- Perfusionists 608 78 43,262 1/400 Air embolism 1/1,500
1981 (16) questionnaire 1979 Procedures DIC Procedures
Inadequate
perfusion
Wheeldon, Retrospective 1980 Perfusionists 146 70 9,013 1/140 Air embolism 1/1,800
1981 (17) questionnaire Procedures DIC Procedures
Inadequate
perfusion
Kurusz et Retrospective 1982- Perfusionists 524 44 573,785 1/100 Protamine 1/1,000

al., 1986 questionnaire 1985 Procedures reaction Procedures
(18) Hypoperfusion
gas embolism
Jenkins et Retrospective Jan Perfusionists 101 69 27,048 1/135 Heater/cooler 1/1,300

al., 1997 questionnaire 1994- Procedures failure Urgent Procedures
(19) June return to CPB
1995 Air embolism
in circuit
Hospital
power failure
Oxygenator
membrane
leak
Mejak et Retrospective 1996- Chief 552 52 653,621 1/138 Protamine 1/1,453
al., 2000 questionnaire 1998 perfusionists Procedures reactions Procedures
(20) (1/783)
Coagulopathy
(1/771)
Heater/cooler
failure
(1/1,809)
DIC, disseminated intravascular coagulation; CPB, cardiopulmonary bypass.
FIGURE 23.1. Results of a survey of cardiopulmonary bypass (CPB)-related occurrences that resulted in permanent injury or death. (Adapted from data
presented in Stoney WS, Alford WC Jr, Burrus GR, et al. Air embolism and other accidents using pump oxygenators. Ann Thorac Surg 1980;29:336-340.)
Answers from the hematology section of questions revealed that almost 32% of the respondents witnessed visibly evident clotting in the circuit while on bypass.
Of 354 cases, 31 patients suffered permanent injury or death. The most common hematologic manifestation was postoperative hemorrhage. But a life-
threatening consumptive coagulopathy, observed by 4.8% of respondents, resulting directly from a CPB mishap, was thought to be responsible for 29
permanent injuries or death of 119 cases. Transfusion reactions, resulting in 5 permanent injuries and 33 deaths were witnessed by 25% of the respondents in
a total of 319 cases. Twenty-eight percent of the respondents observed life-threatening hypotension in 548 cases secondary to inadequate blood flow during
CPB. Eightyseven patients suffered permanent injury or death. There were 281 cases of separation of the extracorporeal lines; this occurrence was one-and-a-
half times more common on the arterial side than on the venous, and resulted in five patient deaths. A drug administration error by any member of the cardiac
team while on CPB occurred in 469 cases and resulted in 48 instances of permanent injury or death. The most common type of error was improper dosing of a
vasoconstrictor or vasodilator. Protamine administration during CPB occurred in 65 cases and heparin overdose occurred in 58 cases. Almost 72% of the
respondents observed a “protamine reaction,” which was responsible for 133 deaths, 21 permanent injuries, and overall the greatest number of AEs. CPB had
to be reinstated urgently 830 times.
Arterial line embolism occurred in 200 cases, resulting in permanent injury or death in 33 of the cases. The cause of over half of these cases was thought to be
due to inattention to the reservoir level most often while using a bubble oxygenator. Other causes of embolism were reported in 258 cases; attributed to aortic
root air in the cardioplegia lines, unexpected ejection of the heart, reversed left ventricular vent lines, or pressurized craniotomy reservoirs. Permanent injury or
death was seen in 36 patients.
At the time of this survey (1982-1985), potassium cardioplegia was being used routinely by 98.4% of the perfusionists surveyed. Crystalloid cardioplegia was
used twice as often of blood cardioplegia and one-third of the perfusionists used both types. The intra-aortic balloon pump (IABP) was used less than 2% of the
time to assist in weaning from CPB. Mechanical failure of the CPB equipment occurred in 170 cases, resulting in three permanent injuries and one death; roller
pump stoppage was the most common form of mechanical failure. Loss of hospital power accounted for 326 cases of electrical failure. Profoundly inadequate
oxygenation, observed by 31% of the respondents during 506 cases, was responsible for 10 permanent injuries and 32 deaths. A switch from one oxygenator to
another was made in 365 cases, with an outcome of permanent injury or death in 27 patients. When surveyed as to the type of oxygenators used, bubble and
membrane oxygenators were used almost equally.
Several questions in this survey addressed the use of measures for the prevention of accidents on CPB. Most of the
P.561
perfusionists who were surveyed (81%) used arterial line filters, almost 70% used low-level alarms but only one-third would use the device in the automatic
pump shut-off mode, less than 50% used air bubble detectors, and 35% used oneway pressure relief valves in the left ventricular vent line. Less than 3%
admitted to not using any safety devices whatsoever. Those surveyed were given the opportunity to submit their opinions regarding the effect of the use of
safety devices on vigilance, and almost 70% noted that the use of safety devices did not lessen their vigilance, while 30% thought that vigilance was decreased
by the use of such devices. When asked to comment on the effectiveness of safety devices during a CPB accident, most felt that an arterial line filter or an air
bubble detector was functional and effective, a low-level alarm system was effective only approximately 50% of the time, and the one-way pressure relief valve
in the left ventricular vent line failed more often. Fortunately, greater than 95% of those surveyed would have backup equipment available while on bypass such
as pump hand cranks, extra tubing, IABP, and spare oxygenators. Slightly more than half did not use a written perfusion protocol. A prebypass checklist was
used by 70% but most went through the list in their minds as opposed to looking at a written list or using the two-person state and response system common in
aviation. Table 23.2 displays a list of activities that the perfusionists felt lowered the risk of perfusion accidents. Most perfusionists (72.3%) felt that, despite the
implementation of safety devices, human error was responsible for causing accidents as opposed to CPB equipment safety device failure.
FIGURE 23.2. Types of perfusion accidents with associated morbidity and mortality. (Adapted from data presented in Kurusz M, Conti VR, Arens JF, et al.
Perfusion accident survey. Proc Am Acad Cardiovasc Perfusion 1986;7:57-65.)
TABLE 23.2. Activities that are believed to decrease risk of perfusion accidents
1. Discussions with colleagues
2. Laboratory experience with new devices
3. “Hands on” workshops
4. Reading the perfusion literature
5. Technical support from manufacturers
6. Attendance at perfusion meetings
7. Perfusionist certification
8. Accreditation of training programs
9. Product alerts
10. Written protocols
11. FDA-device experience network
From Kurusz M, Wheeldon DR. Risk containment during cardiopulmonary bypass. Semin Thorac Cardiovasc Surg 1990;2:400-409.
The last set of questions asked about the current practice among perfusionists. For the most part, the perfusionists controlled venous return to the pump by
tubing clamps or another occlusion mechanism on the CPB venous return line; following CPB, the perfusionist would be responsible for clamping the venous
and arterial line more than half the time. Pressures monitored by perfusion included radial artery, central venous, and pulmonary artery. Most perfusionists
administered drugs in addition to heparin and buffers directly into the CPB lines. Answers to questions regarding the management of blood gas
P.562
values showed no consensus of practice. Choice of equipment used was made jointly by the surgeons and perfusionists most of the time. The majority of
perfusionists were not carrying individual liability insurance but instead were covered by a blanket policy.
The purpose of this study (18) was to determine if new innovations and techniques, along with the recommendations by previous authors, had made any
beneficial impact on the frequency of AEs while on CPB. Because the sampled population was considered good, a secondary benefit resulted in documentation
of “state-of-the-art” levels of practice. In this study, with regard to specific types of accidents, the most frequent complication was the so-called “protamine
reaction” seen immediately following bypass by more than two-thirds of perfusionists surveyed. Arguably, in the immediate postbypass period, hemodynamic
instability can occur for reasons other than a protamine reaction, but a temporal relation between administration of protamine and unstable hemodynamics could
not be dismissed. DIC was seen much less frequently than in earlier studies most likely due to an increase in heparin monitoring, and gas embolization
incidence fell to 1 in every 8,000 cases, perhaps due to more perfusionists using a low-level alarm and the availability of a secondary anti-air embolism device
that when activated shuts the pump down instantaneously. Air bubble detectors, with an arterial line filter and one-way pressure relief valves in the left
ventricular vent, considered redundant safety devices, also contributed to the decrease of catastrophic events. The overall incidence rate of permanent injury or
death from all accidents had fallen to 1 in every 1,000 cases.
Between 1986 and 1997, there was a paucity of formal surveys of perfusion safety despite the very rapid advancement in CPB technology and education since
the introduction of CPB. The literature during that interval focused on the current trends in perfusion practices, specifically the current perfusion practices in
North America, the United Kingdom, and Australia (48,49,50,51).
In 1995, a survey conducted by Jenkins was sent to all members of record of the three Australian perfusion societies (19). It was a seven-page survey
consisting of a list of incidents seen and a list of safety procedures. Respondents were asked to note the numbers of times they witnessed the occurrence of
specific incidents and the use of certain safety procedures within an 18-month period while personally operating the CPB apparatus. The overall response rate
was 69% representing all states of Australia and New Zealand. In the category of equipment failure, the most frequent incident involved the heat exchanger
occurring 86 times necessitating changing to a backup system, seen by 43% of the respondents, followed by hospital electrical power failure seen 40 times by
26% of the respondents. Fortunately, in anticipation of the high frequency rate, there were backup heating/cooling devices immediately available for 97% of the
respondents. Failure of electrical power occurred less frequently, but surprisingly, only between 29% and 36% of the respondents had backup emergency
power systems in place. Incidents related to oxygenators; 36 membrane leaks and the need for replacement before or during CPB on 35 occasions, were seen
by 25% of those surveyed. There were 55 incidents of air visualized in the circuit, but not reaching the patient. For incidents where air was entrained, but did
reach the patient, 11 of those occurred through the cardioplegia line and 23 through the main circuit, including 2 incidents of massive air embolism. The most
common incident related to coagulation was the inability to maintain an ACT above 400 seconds during CPB despite giving additional heparin. This occurred 56
times and was seen by 29% of respondents. Although ACTs were being monitored by most of the perfusionists, an alarmingly high percentage of those
surveyed (18%) admitted to only sometimes using ACT monitoring while on bypass and 27% admitted to not routinely checking for an adequately prolonged
ACT before initiating CPB. After separation from CPB, protamine-induced clotting of the circuit occurred 39 times, resulting in the need for an urgent re-setup of
a new circuit on four occasions. Other incidents that were not under the direct control of the perfusionists occurred fairly frequently, such as cannula
displacement, vessel dissection, gas supply failures, flow meter or vaporizer problems, and those related to drugs (wrong drug, wrong dose), fluids, and blood
(wrong type, transfusion reactions). Figure 23.3 illustrates the number of consequential serious patient injuries and deaths.
Serious patient injuries were defined as those that significantly complicated patient recovery or that persisted following hospital discharge. The total number of
serious injuries was 11 and total deaths were 10 in 27,048 cases, giving a rate of serious injury or death of 1 in every 1,288 perfusions. Of the incidents found to
be responsible for serious injury or death, the category of Urgent circuit re-setup after circuit disposal accounted for a higher frequency than of all the others
that were reported, but ultimately may not have been caused by perfusion-related factors, rather they were more likely poor ventricular function. If these
particular incidents are excluded, then the rate of injury or death in this study drops to 1 in 2,459 perfusions.
Earlier studies compared injury rate data for five specific events; air embolism, electrical failure, mechanical failure, oxygenator failure, and DIC
(15,18,32,51,52). For this group of five events in the Jenkins study (19), the rate of occurrence was 1 in 27,000. Perhaps the largest difference between the two
previously mentioned studies are the larger number of events the respondents were asked to comment on in the Jenkins study. The rate of reporting of
incidents per 1,000 perfusions in the Jenkins study was 1 in 35 perfusions (95% CI 1:33-1:38), considerably more than the rates of 1:98 and 1:264 in previous
surveys. Although more incidents were reported in the Jenkins study, the rate of serious injury or death per reported incident was significantly less. There was
careful avoidance of some survey methodologic shortcomings present
P.563
in previous studies. Only those engaged as primary perfusionists were surveyed, as opposed to surveying surgeons or other perfusion department members or
heads that responded on behalf of others. Fortunately, in Australia and New Zealand, the perfusion community is small and easily identified yielding a response
rate of 69%. Finally, the reporting period was truncated at 18 months to minimize the problem of poor recall of event details.
FIGURE 23.3. Reported frequency of types of perfusion accidents with associated morbidity and mortality. (Adapted from data presented in Jenkins OF, Morris
R, Simpson JM. Australasian perfusion incident survey. Perfusion 1997;12:279-288.)
In this survey (19), at least 80% of perfusionists used important safety devices (blood level alarms with or without pump shut-off, high-pressure alarms, arterial
line filters, oxygenators gas filter, ACT monitoring during CPB, prebypass checklist, backup arterial pump head, backup heater/cooler, emergency oxygen
supply). Alarmingly, the flip side is that as high as 20% of perfusionists were not using important safety devices or procedures. Admittedly, the authors could not
demonstrate a statistical association between the number of incidents and the use of safety devices due to such a small number of reported incidents. This is
not to imply that such an association does not exist.
In summary, this survey reiterated conclusions found by previous surveys. Human error is still at the root of the majority of accidents (70%-85%). Improving
perfusion education would have the most impact on minimizing the number of incidents due to human error. In response, American, European, Australian, and
New Zealand perfusion boards ensure that perfusionist education, practice, experience, training, certification, and accreditation of training centers meet a
minimum standard.
In 2000, Mejak et al. (20) published the results of a survey sent to centers performing cardiac surgery in the United States. Its purpose was to identify current
perfusion incident rates and safety devices used during CPB. It consisted of a four-page questionnaire mailed to 1,030 chief perfusionists at all cardiac centers
identified by Billian’s Hospital Blue Book and were asked to comment on procedures done between July 1, 1996, and June 30, 1998. Eighty questions were
divided into four categories: “Perfusion information,” “Hospital information,” “Equipment information,” and perfusion incidents during CPB, or as a direct result.
Categorization of the incidents were “no injury,” “serious injury,” or “death.” Serious injury was defined as an incident that caused the patient an extended stay
in hospital. There were 524 responses representing 797 hospitals, 2,385 perfusionists, 360 perfusion assistants, and 671,290 open-heart procedures. Figure
23.4 summarizes the frequencies of the most common types of perfusion incidents and those with death rates greater than 2%. The rate of occurrence of
perfusion incidents during CPB was one incident for every 138 procedures, higher than the Kurusz or Stoney surveys, but less than the Australian survey. The
most common types of perfusion incidents were protamine reactions, coagulopathy after CPB, arterial dissection, clot in the circuit while on CPB, and
transfusion reactions. The most common types of safety devices used were hand cranks, arterial line filters, cardioplegia line pressure manometers, and gas
line filters.
COMPARISON OF SURVEYS
The one commonality in all of the surveys, among the many differences, is that all were retrospective questionnaires. The target responder populations varied
between surveys. Cardiac surgeons, as well as perfusionists and chief perfusionists were asked to answer as individuals or as a representative of a perfusion
group. The number and type of questions also varied. The older surveys asked about very specific types of
P.564
incidents, whereas the newer surveys included questions over a very broad scope of incidents. This may be the explanation for the increase in perfusion
incidents seen in the more recent surveys (Fig. 23.5). The more detailed the questions concerning the various incidents, the higher the rate of incidents
reported. Palanzo (33) showed a direct correlation between the CPB-associated incident rates and the number of questions/categories on the survey.
Comparison of the first national survey of CPB-related complications done by Stoney in 1980 to the most recent survey done by Mejak in 2000 suggests that the
incidence of permanent injury or death over the span of 20 years may have decreased (Fig. 23.6). Despite the differences in results, there are themes that have
carried through time in these surveys. Protamine reactions and coagulopathies were prevalent in the first survey and continue to be frequently reported
problems now. Although the overall incidence has decreased, the morbidity and mortality from protamine reactions and coagulopathies are between 2% and
10%. Massive air embolism still occurs albeit at a very low rate but still carries with it mortality as high as 34%. The increased
P.565
use of arterial line filters and air bubble detectors may have had some impact on the very low occurrence of a very devastating event (53).
FIGURE 23.4. The most common types of perfusion incidents with death rates greater than 2%. CPB, cardiopulmonary bypass. (Adapted from data presented in
Mejak BL, Stammers A, Rauch E, et al. A retrospective study on perfusion incidents and safety devices. Perfusion 2000;15:51-61.)
FIGURE 23.5. A summary of reported perfusion incident rates from 1980 to 2000.
FIGURE 23.6. Illustration of the reported decrease of perfusion incidents over time.
NEW INITIATIVES
Following the era of collecting data through surveys, efforts in the last three decades have been focused particularly on the safety of cardiopulmonary bypass. In
the 1970s, the American Society of Extra-Corporeal Technology (AmSECT) published standards for the content of the perfusion record (54) and a subsequent
guideline (55) addressed the perfusion checklist. This guideline underwent several updates to include newer CPB techniques, equipment, and more importantly,
the distinction between the items considered to be most important and less critical items. The rational for this distinction was to provide perfusionists with an
expedited checklist in the event of an emergency. This has critical importance in the setting of rapid advancement of interventional cardiology.
In parallel to the development of a standard of practice for perfusion, there was also standardization of the accreditation of training programs and certification of
perfusionists. An accreditation and certification process was established by the European Board of Cardiovascular Perfusion (EBCP) and by the American
Board of Cardiovascular Perfusion (ABCP). Other organizations such as the Association of the Advancement of Medical Instrumentation (AAMI), American
National Standards Institute (ANSI), and International Organization for Standardization (ISO) also contribute by overseeing these efforts.
In the early 2000s, efforts to adopt a systems approach and to apply Quality Assurance and Quality Improvement (QA/QI) to perfusion practice have been
reported. These processes have been incorporated into the updated practice guidelines (56). In earlier years, six physiologic parameters (pH, base excess,
Paco2, Pao2, ACT, and esophageal temperature) were evaluated if they were associated with postoperative outcomes as the assessment of perfusion
performance (57). Later, these parameters were expanded to ten parameters (in addition to the aforementioned six parameters, fluid balance, blood transfused,
hematocrit, and potassium) to develop the perioperative perfusion score system (PerfSCORE) that is reported to be an independent predictor of morbidity (58).
The use of the electronic perfusion record allows electronic data collection that contributes to the automated generation of a QI report resulting in improved
adherence to practice guidelines (59).
As the clinical practice guidelines in medicine were moving toward evidence-based practice, the same methodologies were employed to generate guidelines in
perfusion practice. In 2006, the International Consortium for Evidence-Based Perfusion was formed to develop evidence-based guidelines, to translate that
evidence into clinical practice, and to evaluate improvements in patient care. This Consortium is currently in the process of setting up an international registry
based on the evidence collected for improved patient safety.
Another development that significantly contributed to perfusion safety is the improvement in perfusion education as well as maintenance of core skills. Use of
simulation was shown to improve crisis management skill (60). Recent developments in communication technology contribute to the dissemination of the
knowledge and information that improve education in perfusion (61).
NEW CHALLENGES
Newer technical challenges are emerging with newer surgical and interventional techniques. Not only does this advancement require the development of newer
equipment, up-todate protocols, and collaboration with multidisciplinary team, it forces the re-distribution of resources in perfusion practice. In recent years,
transcatheter aortic valve replacement (TAVR) has expanded the options for the treatment of severe aortic stenosis in high-surgical-risk patients and studies
have shown
P.566
good early and mid-term survivals similar to surgical aortic valve replacement (AVR) (62). However, the TAVR procedure carries risks of complications resulting
in hemodynamic collapse due to severe paravalvular leak, coronary occlusion, valve embolization, aortic rupture or dissection, and bleeding from the left
ventricular apex. The reported incidence of the expeditious use of CPB is 1.2% to 6% in high-volume institutions (63). Successful rescue is dependent on the
preparedness of the multidisciplinary team including cardiologists, cardiothoracic surgeons, cardiac anesthesiologists, nurses, and perfusionists. During the
preprocedure huddle, all of the team members should agree on the rescue plan, understand individual roles, and confirm the availability of necessary
equipment. Developing a written safety checklist and protocol that includes a “Time Out” is critical for successful rescue CPB initiation (64). TAVR is best
performed in a hybrid operating room that can accommodate all of the necessary equipment and personnel, and allows the access to the resources. When a
hybrid room is not available, TAVR can be done in the cardiac catheterization laboratory. There are numerous challenges when the need to convert to a rescue
open-heart procedure that occurs in the catheterization lab arises. It includes gathering and transporting all the possibly necessary equipment for any
emergencies, as well as working in an unfamiliar environment and limited space. Operating room sterility and electrical standards may not be met in the
catheterization lab. Securing power and gas sources for both anesthesia and perfusion equipment and adequate lighting for the conversion to surgical AVR may
not be possible.
Similar conditions exist when managing patients on extracorporeal membrane oxygenation (ECMO) in the intensive care unit (ICU). ECMO has been used to
treat severe pulmonary or cardiopulmonary failure over the past two decades in the neonatal population. Since the outbreak of influenza A (H1N1) resulting in
severe acute respiratory distress syndrome (ARDS), there have been significant increases in the need for this technique in the adult population (65). A
multidisciplinary-team approach is needed for well-rounded care and the role of perfusionists who are well trained and qualified to perform critical components of
care for patients on ECMO cannot be overstated.
Not only are there the challenges in newly emerging technologies, the rapid growth in the number and the urgent nature of the cardiothoracic surgeries are
exhausting perfusion resources resulting in the overwork of perfusionists. In 2010, Trew et al. (66) conducted a survey that consisted of 35 questions regarding
the work experience and the opinions and attitudes on extended work hours and fatigue. The survey was posted on the Internet perfusion forums. Four hundred
and forty-five perfusionists from a wide range of age, experience, and practice responded to the survey. The survey indicated that over 65% of the responders
reported performing CPB during a period greater than or equal to 23 hours of wakefulness and over three-fourths of responding perfusionists affirm that they
have been concerned about their own abilities to operate a heart-lung machine due to fatigue. Two-thirds of responders believe that they have made an error
while performing CPB under such fatigued conditions. A serious perfusion accident, which the reporters believed to be directly related to fatigue, occurred to
6.7% of these perfusionists. The authors acknowledged that prescriptive hours of service remedies to prevent fatigue due to sleep deprivation appear to be
difficult to comply with because of the lack of manpower. However, the need for hours of service guidelines for perfusion safety seems to be clear.
KEY Points
The patient undergoing a procedure requiring CPB is safer now than 30 years ago.
Safety of CPB has increased as a result of improved technology, the creation of practice guidelines, and the improvement of perfusion education.
There has been a decrease in the overall rate of perfusion-related incidents and a significant decrease in the types of events that have catastrophic
results.
Regardless, human error still remains a factor that cannot be completely eliminated by using the highest technology and adhering to the strictest of
guidelines.
REFERENCES
1. Healey MA, Shackford SR, Osler TM, et al. Complications in surgical patients. Arch Surg 2002;137:611-618.
2. Tyndal CM Jr, Berryessa RG, Hydrick DR, et al. Is your oxygenator failing? Diagnosis and suggested treatment. J Extra Corpor Technol 1987;19:330-
337.
3. Fisher AR. The incidence and cause of emergency oxygenator changeovers. Perfusion 1999;14:207-212.
4. Svenmarker S, Haggmark S, Jansson E, et al. The relative safety of an oxygenator. Perfusion 1997;12:289-292.
5. Palanzo DA, Manley NJ, Montesano RM, et al. Potential problem when using the new lower-prime hollow-fiber membrane oxygenators with uncoated
stainless steel heat exchangers. Perfusion 1996;11:481-485.
6. Kreel I, Kavee DJ, Zaroff LL, et al. Mechanical failure during extracorporeal circulation: a method for prevention. Surgery 1959;45:645-647.
7. Underwood S, Widmer S, Butler B, et al. Power failure and the pump: how effective is manual operation? J Extra Corpor Technol 1987;19:365-368.
8. O’Brien D, Aherne T, Hargrove M. Failure of electrical mains and backup generator supply during cardiopulmonary bypass. J Extra Corpor Technol
1989;21:28-29.
9. Troianos CA. Complete electrical failure during cardiopulmonary bypass. Anesthesiology 1995;82:298-302.
10. Lochab SS, Kiran S. Total electricity failure during cardiopulmonary bypass. Ann Card Anaesth 2002;5:88-89.
11. Mills NL, Ochsner JL. Massive air embolism during cardiopulmonary bypass. Causes, prevention, and management. J Thorac Cardiovasc Surg
1980;80:708-717.
12. Suehiro S, Shibata T, Minamimura H, et al. Case of massive air embolism during cardiopulmonary bypass. Nippon Kyobu Geka Gakkai Zasshi
1995;43:1059-1062.
13. Berkowitz DE. Inspection and preventive maintenance of cardiopulmonary perfusion equipment and an overview of problems. J Extra Corpor Technol
1980;12:68-70.
P.567
14. Crane TN, Speer D, Kurusz M. Preventive maintenance of heart-lung machines. Proc Am Acad Cardiovasc Perfusion 1985;6:34-37.
15. Stoney WS, Alford WC Jr, Burrus GR, et al. Air embolism and other accidents using pump oxygenators. Ann Thorac Surg 1980;29:336-340.
16. Wheeldon DR. Can cardiopulmonary bypass be a safe procedure? In: Longmore DB, ed. Towards safer cardiac surgery. Lancaster, England: MTP
Press, 1981:427-446.
17. Wheeldon DR. Safety during cardiopulmonary bypass. London, UK: Franklin Scientific Projects, 1981:27-29.
18. Kurusz M, Conti VR, Arens JF, et al. Perfusion accident survey. Proc Am Acad Cardiovasc Perfusion 1986;7:57-65.
20. Mejak BL, Stammers A, Rauch E, et al. A retrospective study on perfusion incidents and safety devices. Perfusion 2000;15:51-61.
21. Wheeldon DR, Kurusz M. Perfusion safety. Perfusion 1988;3:97-112.
22. Kurusz M. Lessons from perfusion surveys. Perfusion 1997;12:221-227.
23. Palanzo DA. Perfusion safety: past, present, and future. J Cardiothorac Vasc Anesth 1997;11:383-390.
24. Mortensen JD, Yates WG, Schenberg AA, et al. Final report: cardiopulmonary bypass systems: a study of safety and performance. Salt Lake City, Utah:
University of Utah Research Institute, 1981.
25. Mortensen JD. Potential methods for controlling risks and hazards of CPB devices. Proc Am Acad Cardiovasc Perfusion 1981;2:57-68.
26. Stofer RC. The hidden hazards of perfusion. Proc Am Acad Cardiovasc Perfusion 1982;3:46-48.
27. Schabel RK, Berryessa RG, Justison GA, et al. Ten common perfusion problems: prevention and treatment protocols. J Extra Corpor Technol
1987;19:392-398.
28. Boothman BR. Dangers of cardiopulmonary operations. Br Med J 1989;298:254-255.
29. Christman EW, Kurusz M. Preventing massive air embolism during cardiopulmonary bypass: a review of safety devices. J Extra Corpor Technol
1980;12:115-119.
30. Hill AG. Cardiopulmonary bypass safety devices and techniques. Perfusion 1985;8:38-42.
31. Kriewall TJ. Safety systems in perfusion: practices, philosophy and products. Perfusion Life 1994;11:18-23.
32. Kurusz M, Wheeldon DR. Risk containment during cardiopulmonary bypass. Semin Thorac Cardiovasc Surg 1990;2:400-409.
33. Palanzo DA. Perfusion safety: defining the problem. Perfusion 2005;20:195-203.
34. Galletti PM, Brecher GA. Heart-lung bypass; principles and techniques of extracorporeal circulation. New York, NY: Grune & Stratton, 1962.
35. Favaloro RG. Saphenous vein autograft replacement of severe segmental coronary artery occlusion: operative technique. Ann Thorac Surg. 1968;5:334-
339.
36. Senning A. Ventricular fibrillation during extracorporeal circulation used as a method to prevent air-embolisms and to facilitate intracardiac operations.
Acta Chir Scand Suppl 1952;171:1-79.
37. Glenn WW, Sewell WH Jr. Experimental cardiac surgery. IV. The prevention of air embolism in open heart surgery; repair of interauricular septal defects.
Surgery 1953;34:195-206.
38. Nixon PG. A simple flow-meter and safety device for the extracorporeal circulation. Lancet 1959;2:830.
39. Olmstead F, Kolff WJ, Effler DB. Three safety devices for the heart-lung machine. Cleve Clin Q 1958;25:169-176.
40. Jones RD, Cross FS. A vent valve to minimize air embolism during openheart surgery. J Thorac Cardiovasc Surg 1964;48:310-313.
41. Brenner WI, Wallsh E, Spencer FC. Efficiency of aortic vents in the prevention of air embolism. Surg Forum 1970;21:139-142.
42. Burgess FM. Retrograde dissection during cardiopulmonary bypass. J Extra Corpor Technol 1974;6:86-90.
43. Kurusz M, Shaffer CW, Christman EW, et al. Runaway pump head: new cause of gas embolism during cardiopulmonary bypass. J Thorac Cardiovasc
Surg 1979;77:792-795.
44. Frazier TM. The automatic level regulator as a low-level safety device and volume regulator. Proc Am Acad Cardiovasc Perfusion 1984;5:73-75.
45. Vinansky RP. Pressure measurement and safety with a self-contained device. Proc Am Acad Cardiovasc Perfusion 1986;7:101-104.
46. Snyder EJ. A negative pressure alarm for use in neonatal extracorporeal membrane oxygenation. J Extra Corpor Technol 1988;20:63-66.
47. Eagle CJ, Davies JM, McCloskey B. An introduction to quality assurance with an application for perfusionists. J Extra Corpor Technol 1991;23:22-25.
48. Elliott M, Rao PV, Hampton M. Current paediatric perfusion practice in the UK. Perfusion 1993;8:7-25.
49. Groom RC, Hill AG, Kurusz M, et al. Paediatric perfusion practice in North America: an update. Perfusion 1995;10:393-401.
50. Hill AG, Groom RC, Akl BF, et al. Current paediatric perfusion practice in North America. Perfusion 1993;8:27-38.
51. Wajon PR, Walsh RG, Symons NL. A survey of cardiopulmonary bypass perfusion practices in Australia in 1992. Anaesth Intensive Care 1993;21:814-
821.
52. Reed CC. Safety and techniques in perfusion. Anaesth Intensive Care 1988;21:814-821.
53. Kurusz M, Butler B, Katz J, et al. Air embolism during cardiopulmonary bypass. Perfusion 1995;10:361-391.
54. American Society of Extra-Corporeal Technology. Standards of practice: recommended minimum standards, permanent perfusion records. J Extra
Corpor Technol 1978;10:46.
55. Kurusz M. Standards update on perfusion equipment and practice. Perfusion 2005;20:205-208.
56. American Society of Extra-Corporeal Technology. Standards and guidelines for perfusion practice. American Society of Extra-Corporeal Technology
website (2014). Available at http://www.amsect.org. Accessed 9 July 2015.
57. Jegger D, Ruchat P, Horisberger J, et al. A cardiopulmonary bypass score system to assess quality of perfusion performance. Perfusion 2001;16:183-
188.
58. Jegger D, Revelly JP, Horisberger J, et al. Establishing an association between a peri-operative perfusion score system (PerfSCORE) and post-
operative patient morbidity/mortality during CPB cardiac surgery. Perfusion 2007;22:311-316.
59. Baker RA, Newland RF. Continuous quality improvement of perfusion practice: the role of electronic data collection and statistical control charts.
Perfusion 2008;23:7-16.
60. Fernandez A. Simulation in perfusion: where do we go from here? Perfusion 2010;25:17-20.
61. Kurusz M. Perfusion safety: new initiatives and enduring principles. Perfusion 2010;26:6-14.
62. Svensson LG, Tuzcu M, Kapadia S, et al. A complihensive review of the PARTNER trial. J Thorac Cardiovasc Surg 2013;145:S11-S16.
63. Roselli EE, Idrees J, Mick S, et al. Emergency use of cardiopulmonary bypass in complicated transcatheter aortic valve rreplacement: importance of a
heart team approach. J Thorac Cardiovasc Surg 2014;148:1413-1416.
64. Fernandes P, Cleland A, Bainbridge D, et al. Development of our TAVI protocol for emergency initiation of cardiopulmonary bypass. Perfusion
2015;30:34-39.
65. Mongero LB, Beck JR, Charette KA. Managing the extracorporeal membrane oxygenation (ECMO) circuit integrity and safety utilizing the perfusionist as
the “ECMO Specialist.” Perfusion 2013;28:552-555.
66. Trew A, Searles B, Smith T, et al. Fatigue and extended work hours among cardiovascular perfusioninsts: 2010 Survery. Perfusion 2011;26:361-370.
Chapter 24
Management of Unusual Problems Encountered during
Procedures that Require the Use of Cardiopulmonary Bypass
Mark Kurusz
Noel L. Mills
Richard F. Davis
Some uncommon preexisting clinical conditions and similarly infrequently occurring problems with the operation
and/or function of the cardiopulmonary bypass (CPB) circuit can jeopardize patient safety during CPB, and may
lead to adverse clinical outcomes. Given that many such occurrences present with relatively low frequency, the
clinical experience of any single surgical team member or even the combined clinical experiences of several team
members may be inadequate to rapidly implement an appropriate plan of management for such problems. This
chapter examines several such clinical conditions and occurrences. Admittedly, some of these may stretch the
definition of “unusual” and, while not representative of the day-to-day “routine” practice, should be expected to
occur with a moderate frequency depending on the nature of one’s clinical practice. Some of these conditions
may be encountered preoperatively, allowing time to develop a carefully considered management strategy. In
contrast, some of these events may occur unexpectedly during a procedure, which demands rapid
implementation of predetermined management strategies by one or more team members to prevent potentially
significant morbidity or even mortality. Suggested management strategies are derived from the published
literature and are referenced as appropriate, and some of the suggested strategies are derived from the authors’
collective clinical experiences.
CONDITIONS IDENTIFIABLE BEFORE CARDIOPULMONARY BYPASS

Severe Ascending Aortic Atherosclerosis
The severely atherosclerotic ascending aorta can present problems during cannulation for CPB, application of
clamps, delivery of cardioplegia, construction of proximal anastomoses for coronary artery bypass grafts, or valve
replacement or repair. A large multicenter study identified the presence of proximal aortic atherosclerosis as the
strongest predictor of perioperative stroke (1), which is consistent with embolization of atherosclerotic debris
liberated by surgical manipulation of the aorta as being perhaps the most common cause of strokes after CPB.
Risk factors for ascending aortic atherosclerosis include: significant carotid, abdominal aortic, and left main
coronary artery atherosclerosis; aortic wall irregularity on ascending aortic angiogram; adhesions between the
ascending aorta and its adventitia; pale appearance of the ascending aorta; and minimal bleeding of an aortic
stab wound (2). The presence of severe ascending aortic calcific atherosclerosis will most likely be known from
preoperative imaging studies such as chest computed tomography (CT) or magnetic resonance imaging (MRI)
scans, angiography or ultrasound, so that an appropriate surgical management strategy can be developed in
advance of the procedure. In recent years, the use of intraoperative ultrasound, transesophageal
echocardiography (TEE), or epiaortic scans has become almost universal in major cardiac surgical centers.
These two techniques are complementary because of the frequent inability to visualize the upper ascending
aorta with TEE due to the interposition of the tracheobronchial structures (air) between the TEE probe in the
esophagus and the ascending aorta. This problem is avoided with epiaortic scanning. Visualization of Grade 4 or
5 plaques in or closely adjacent to normal aortotomy sites should prompt the use of alternative sites or surgical
techniques. Cannulations via the innominate artery, the femoral artery, or the lesser curvature of the aortic arch
are examples of use of alternative sites. Surgical techniques designed to minimize or avoid aortic clamping
should be considered.
Careful surgical palpation of the aorta prior to selecting cannulation and other aortotomy sites may facilitate
identification of less diseased sites for insertion of the arterial perfusion cannula or proximal anastomoses. Such
palpation may be facilitated before CPB by inducing a brief period of hypotension with venous inflow occlusion,
that is, briefly occluding the superior and inferior venae cavae to rapidly decrease cardiac ejection and arterial
pressure. With lower pressure in the aorta, gentle palpation can be used to assess the quality of the aortic wall
to determine the location of less diseased sites for cannulation and placement of the aortic cross-clamp. Despite
these techniques, numerous reports published over the last two decades have consistently found intraoperative
ultrasound imaging to be more sensitive than manual palpation for identification of atherosclerotic plaques.
In severely diseased aortas, application of an aortic crossclamp may not be deemed feasible because of
increased risk
P.570
of dislodgment of atherosclerotic debris or aortic dissection (Fig. 24.1). The so-called no-touch technique has
evolved to better manage these patients (2). It relies on the internal mammary artery or gastroepiploic artery as
conduits for coronary bypass grafts. In some patients requiring extensive revascularization, saphenous vein
grafts can be anastomosed to the internal mammary artery. In no-touch cases, a femoral artery, axillary artery, or
the underside of the distal aortic arch is used as the arterial cannulation site (2,3,4). Alternatively, either a long-
arch cannula can be inserted distal to the left subclavian artery or a diffusion-tipped cannula can be used (5) to
better disperse the flow jet at the CPB cannula tip. However, these cannulation techniques still present some risk
of stroke hazard from insertion of the cannula in the severely diseased aorta. Cannulating from the left ventricular
apex with the cannula advanced through the aortic valve has also been described (6).
Rather than using conventional approaches to cardioplegia delivery, the surgeon may instead rely on electrical
fibrillation or administration of a β-adrenergic blocker such as esmolol to slow the heart during distal
anastomoses. In these cases, left ventricular venting may be avoided. However, if significant aortic insufficiency
is present, conventional venting methods should be used, which then requires needle vent placement in the
ascending aorta for de-airing before weaning from CPB and which carries some degree of hazard in the
diseased aorta. An endoaortic clamp, as designed for minimally invasive cardiac surgery, may be used to isolate
the heart from CPB systemic flow, deliver cardioplegic solution, and vent the aortic root (7). However, in the
presence of severe atherosclerosis, this approach does not necessarily decrease the risk of dislodging
atherosclerotic debris. An aortic filtration system (8) that uses an umbrella screen inserted through a modified
24F arterial cannula before aortic cross-clamp removal has been shown to capture particulate debris that
presumably would have otherwise embolized systemically.
FIGURE 24.1. Type 1, type II, and type III ascending aortic atherosclerosis. No clamp is safe on these types of
ascending aortic disease. Type I: Circumferential ascending aortic calcification, which may be easily diagnosed
preoperatively on the angiogram. Palpation of the ascending aorta at operation reveals firm calcification.
Embolization or aortic injury that may be difficult to repair may result if the aorta is clamped. Type II: This pattern
may be diagnosed preoperatively by noting an irregularity of the normally smooth lining of the ascending aorta on
the left ventricular angiogram or aortic root injection. Visualization of the ascending aorta is now considered a
mandatory part of workup before coronary artery bypass graft. Type III: Intraluminal liquid debris is the most
elusive of the three patterns to diagnose before clamping the aorta. A pale appearance of the aorta or adherence
of the adventitia to the ascending aorta may be the only diagnostic clues. Operative echocardiography will reveal
a thickened ascending aorta that will liberate liquid debris if a cross-clamp or partial occlusion clamp is applied.
(From Mills NL, Everson CT. Atherosclerosis of the ascending aorta and coronary artery bypass: pathology,
clinical correlates, and operative management. J Thorac Cardiovasc Surg 1991;102:546-553, with permission.)
In summary, cannulation of the severely diseased ascending aorta may be associated with significant morbidity
after CPB. Modification of conventional CPB cannulation, cardioplegia, and venting techniques may reduce the
incidence of stroke in this challenging patient population. Newer diagnostic measurements such as release of S-
100b, a marker of cerebral ischemia (9), and novel perfusion cannulation techniques under development may
lead to further reductions in neurologic injury in the patient with diffuse atherosclerosis needing cardiac surgery.
Hematologic Problems
Cryoproteins
Cold agglutinins are serum antibodies that become active at decreased blood temperature and produce
agglutination of red blood cells. In some cases, blood cell agglutination may involve complement fixation and lead
to significant hemolysis. These antibodies are most commonly directed against antigens on the red blood cells
but can also be nonspecific. One very important and most clinically relevant characteristic of cold agglutinins is
termed the thermal amplitude, which is the temperature below which the antibodies become activated. As
temperature drops below this threshold, antibody activity increases exponentially. In general, this activity
reverses as rewarming occurs (10). Another important parameter of cold agglutinins is termed the titer, which is
the concentration of the cold agglutinin expressed as the dilution factor beyond which the agglutination does not
occur. A 1:1 titer indicated a relatively low concentration of the cold agglutinin because a 1:1 dilution is sufficient
to eliminate the agglutination, while a 1:128 titer indicated a much higher concentration of the cold agglutinin.
Clearly, higher cold agglutinin titers (concentrations) are more clinically significant than low titers. There is no
widely accepted definition for high versus low titer; however, Lee et al. (11) suggested titers less than 1:32 as
being low and those greater than 1:128 as being high.
The complement system is activated during CPB, especially so during rewarming from hypothermia. Red blood
cells agglutinated by cold agglutinins may fix activated complement and
P.571
undergo hemolysis, which can be severe, depending largely on the thermal amplitude and titer of the cold
agglutinin. For hemolysis to occur, the cold agglutinin and complement activities must overlap. That is, the
temperature must be low enough for the cold agglutinins to activate but warm enough for a complement fixation
to occur.
Aside from during hypothermic bypass, cold agglutinins seldom produce symptoms because activation most often
occurs at temperatures well below the usual range of body temperature. With cold exposure, clinical signs may
include acrocyanosis of digits, tip of the nose, or ears from agglutination-induced ischemia. Most commonly,
immediate warming of the affected areas reverses the agglutination and thus the ischemia. A patient with
prolonged hypothermic CPB would be at risk for multi-organ damage from prolonged vascular occlusion (12).
This is an uncommon but potentially catastrophic consequence of failure to recognize and treat the presence of
cold agglutinins.
When patients undergo screening for cold agglutinins, a diagnosis can be easily made based on laboratory test
results. If screening at 4 °C is negative, no further screening is needed. If the screen is positive at 4°C, the
thermal amplitude should be determined and the titer determined for each temperature at which the screen was
positive. This will give more precise information for dealing with the cold agglutinin antibodies.
In patients who are not initially screened for cold agglutinins, a diagnosis may be made by astute observation.
During hypothermic CPB, agglutination within the vessels may be noted, particularly if the surgeon is wearing
magnifying loops. Hemolysis manifested by hemoglobinuria is most often recognized by pink or red-tinged urine.
The latter observation, however, still sometimes occurs even in the absence of cryoagglutination. If blood
cardioplegia is used, the perfusionist may note agglutination in the cardioplegia delivery system as the blood is
cooled (13,14). In addition, immediate agglutination of blood in a syringe during phlebotomy may indicate the
presence of cold agglutinins. Agglutination also can be confirmed visually by immersing a test tube of blood into
an ice slush solution and observing cell clumping on the side of the test tube that often disappears when the tube
is warmed. Many cold agglutinins will present during a routine crossmatch done at room temperature. Any of the
above findings suggests the presence of clinically significant cold agglutinins, and steps should be taken to
prevent adverse reactions during CPB (13,15,16).
Both monoclonal and polyclonal cold agglutinins exist. The monoclonal types usually associated with
lymphoreticular neoplasms are generally irreversible. The polyclonal antibodies are often associated with acute
infectious diseases such as mycoplasma, infectious mononucleosis, or cytomegalovirus (12). Production of
polyclonal cold agglutinins is typically transient and may remit spontaneously in weeks, but when present it may
be associated with acute life-threatening intravascular hemolysis (12). Leach et al. (15) developed a comparison
of clinically significant and insignificant cold agglutinins (Table 24.1). An important point in assessing the need to
screen for cold agglutinins is that a failure to screen may lead to an adverse outcome, such as myocardial
infarction, stroke, or acute renal failure. Without knowledge of the presence of cold agglutinins, these adverse
outcomes may be attributed to another cause. For example, hemolysis may be attributed to mechanical trauma to
blood from CPB (17). However, mechanical trauma to blood may be a more important source of clinically
significant hemolysis than cold-reacting autoantibodies when the thermal amplitude is less than 22°C.
TABLE 24.1. Characteristics of cold agglutinins
Clinically significanta Clinically insignificantb
1. Lytic (cause hemolysis) 1. Nonlytic (reversible red blood cell agglutination)

2. Active in saline at 20°C 2. Peak activity 0°C-4°C
3. Almost always IgM antibodies 3. Seldom IgM antibodies (IgG, IgA, or non-Ig)
4. Wide thermal range (4°C-32°C) 4. Low thermal range 0°C-6°C
5. Bind complement 5. Seldom bind complement
6. Agglutination irreversible 6. Agglutination reversible
7. ↑ agglutination in albumin (30°C) 7. No enhanced agglutination in albumin
aThese are commonly associated with chronic cold hemagglutinin disease, neoplasm of lymphoid origin,
and mycoplasma pneumonia.
bThese are commonly associated with viral infections (e.g., cytomegalovirus infections and
mononucleosis).
Adapted from Leach AB, Van Hasset GL, Edwards JC. Cold agglutinins and deep hypothermia.
Anaesthesia 1983;38:140-143.
Treatment of cold agglutinin disease during CPB essentially consists of prevention of complement activation and
ultimately of agglutination or hemolysis. Treatment is based on the etiology and the severity of the problem. In a
mild case of cold agglutinins (i.e., a case in which there is a very low thermal amplitude, such as 4°C) and/or a
low titer of antibodies, minor or no changes in surgical or CPB techniques and, in some cases, treatment with
corticosteroids to avoid hemolysis have been advised (18). For patients with low-titer nonspecific antibodies (and
only these patients), Moore et al. (10) concluded that hypothermic CPB can be performed on these patients
without increased risks of hemolytic or agglutination crises; further, minor degrees of hemolysis occur in all
patients during hypothermic bypass, especially during the rewarming phase, whether or not cold agglutinins are
present.
In a case with clinically significant cold agglutinins (i.e., high thermal amplitude, high titer, or clinical symptoms), a
number of changes in surgical technique have resulted in successful surgery using CPB. In the case of clinically
significant cold agglutinins caused by acute infection (e.g., a recent viral illness), elective cardiac surgery should
be postponed for
P.572
several weeks, by which time the antibody may have disappeared (17). If the urgency of surgery precludes that
approach, the most sensible approach is to use either normothermia or mild hypothermia using blood
temperatures continuously maintained above the thermal amplitude to avoid the active temperature range of
agglutination (17,19,20,21,22,23). Hence, the presence of cryoagglutinins with high titer or high thermal
amplitude may represent a reasonable indication for the use of warm cardioplegia myocardial protection
techniques while maintaining normothermic systemic temperatures.
In patients with clinically significant cold agglutinins, if it is deemed necessary to use cold cardioplegia, the
patient’s blood should be initially flushed out of the coronary circulation with warm crystalloid cardioplegic
solution followed by cold cardioplegic solution. Just before removal of the aortic cross-clamp, warm cardioplegic
solution should be used to prevent agglutination from blood exposed to a cold heart. Refinements of this latter
technique consist of bicaval cannulation with tightening of caval tapes to avoid cooling large amounts of blood in
the cardiac and pulmonary circulation. A sump catheter may be placed in the right atrium to retrieve cardioplegic
solution until the coronary sinus effluent is clear. In addition, lower-than-normal CPB systemic flows may be used
to decrease the noncoronary collateral flow and subsequent cooling of this blood.
If it is uncertain whether this noncoronary collateral flow will cause problems, the heart may be maintained at a
temperature above the thermal amplitude (24). Venting the left ventricle will avoid cooling and stagnation of blood
in the left ventricular cavity. Crystalloid cardioplegia has been used rather than blood cardioplegia to avoid
agglutination of the cells in the solution when delivered at low temperature (25). Adjuncts may include a
myocardial insulation pad to prevent cooling of blood in structures adjacent to the heart. Using a septal
temperature probe in the myocardium to keep the temperature greater than the thermal amplitude may prevent
significant activation of cold agglutinins. However, once the red blood cells are flushed out of the coronary
circulation, the heart can be cooled to provide myocardial protection provided the above adjuncts are used. In
addition, all fluids, blood, plasma, inspired gases, and bolus injections should be warmed (17) in the periods
before and after bypass, especially if the cryoagglutinin has high thermal amplitude.
The literature contains descriptions of successful cardiac surgery after plasmapheresis (23,26) or total exchange
transfusions in patients with high-titer, high-thermal-amplitude cold agglutinins. There is some evidence that the
patient’s own red blood cells may be protected from hemolysis, and if transfusions are required, autologous
packed red blood cells may be advantageous (17). In the case of unexpected agglutination encountered at the
time of surgery, several techniques may be useful: verification by the blood bank that cold agglutination is
present rather than an unrecognized alloantibody; the use of crystalloid cardioplegic solution to dilute the
antibody in the coronary circulation; use of noncardioplegic techniques (e.g., electrical fibrillation); and
maintenance of systemic temperatures greater than 28°C to 30°C at which significant amounts of agglutination
are unlikely to occur. In addition, the CPB circuit and blood cardioplegia delivery system should be monitored
carefully throughout bypass for presence of cell aggregates, and CPB arterial line filters should be used in all
cases.
Several cases of fibrin formation and clotting of membrane oxygenators during hypothermic CPB have been
reported (27). Although cold agglutination was initially suspected, none of these patients exhibited agglutinin
formation either during preoperative screening or postoperative hematologic workup. No abnormalities in blood
coagulation factors VII and VIII or von Willebrand factor were demonstrated in blood samples tested
postoperatively, nor were there significant differences between the affected patients’ blood samples and control
patients’ blood. However, rapid CPB cooling in conjunction with use of efficient oxygenator heat exchangers
having small blood pathways was associated with excessive premembrane CPB line pressure buildup that
usually resolved with more moderate cooling strategies or by warming the perfusate.
In summary, all patients undergoing hypothermic CPB should be screened preoperatively for cold agglutinins
(19,20,21,23,28). If an initial screen is positive, the cold agglutinins should be characterized as to thermal
amplitude and titer. Clinical symptoms should also be sought. A patient with low titer, low thermal amplitude, and
clinically asymptomatic can tolerate CPB with moderate hypothermia at very low risk with little or no alteration in
technique. For clinically significant cold agglutinins with high thermal amplitude and/or titer, if due to a transient
viral illness, elective surgery may be postponed for several weeks in the hope that this will decrease cold
agglutinins to insignificant levels. However, in severe cases in which the high-titer, high-thermal-amplitude cold
agglutinins are not transient, precautions should be taken as outlined above to prevent an agglutination or
hemolytic crisis (Fig. 24.2).
Hemoglobinopathy and Erythrocyte Disorders
Sickle Cell Trait and Disease

In the normal adult, hemoglobin A comprises 96% to 97% of all hemoglobin. Hemoglobin A is a tetramer
composed of two α- and two β-globin chains each associated with one oxygen carrying heme moiety. Sickle cell
hemoglobinopathy (hemoglobin S) is a single-gene recessive abnormality in which the amino acid valine is
substituted for the normally occurring glutamic acid at position 6 in the beta chain. It is thought that this single
nucleotide polymorphism arose in central Africa primarily because the heterozygous form (sickle cell trait) confers
some resistance to malaria, which is particularly endemic in that region. Sickle cell disease is the homozygous
form of this hemoglobinopathy. There are a variety of subtypes of the condition. The percentage of hemoglobin S
and hemoglobin A
P.573
varies with the individual, but sickle cell disease patients typically have predominantly hemoglobin S. This
homozygous state is found in 0.15% of African-Americans and is associated with severe hemolytic anemia and
vaso-occlusive phenomena, resulting from the increased blood viscosity that occurs when red blood cells
aggregate and individually typically assume a sickle shape (29). Sickled cells have a very limited capacity to load
and unload oxygen.
FIGURE 24.2. Algorithm for management of cold agglutinins in cardiopulmonary bypass.
In contrast, patients with the sickle cell trait have a lower percentage of hemoglobin S, accounting for 20% to
45% of their total hemoglobin. Approximately 8% of African-Americans carry the heterozygous recessive trait.
These individuals have few clinical problems, and except for severe or provoked conditions, they rarely
experience sickle cell crises. Red blood cell sickling results from deoxyhemoglobin formation. The tendency
toward sickling increases with hypoxemia, acidosis, increased concentrations of 2,3-diphosphoglyceric acid,
infection, hypothermia, and capillary stagnation. A hypertonic environment that may lead to crenation of normal
red blood cells also will lead to sickling. Hemoglobin S demonstrates increased osmotic and mechanical fragility,
making hemolysis more likely. A hypotonic environment will lyse red blood cells with increased osmotic fragility.
In patients with sickle cell disease, some sickling begins to appear at 85% hemoglobin oxygen saturation, and
sickling of red blood cells is complete at 38% hemoglobin oxygen saturation. In patients with sickle cell trait,
sickling begins at hemoglobin oxygen saturations of approximately 40%. Sickling is reversible to a degree, but if
it is repeated, the sickled cells become permanently damaged, resulting in markedly increased fragility and a
shortened cell lifespan. In addition to increased blood viscosity potentially causing vascular occlusion, sickling
can cause endothelial cell injury in the microvasculature. This may activate the intrinsic clotting system and
exacerbate the vaso-occlusive phenomenon (29,30,31,32).
The operative strategy in sickle cell patients is to prevent sickling and thereby prevent hemolysis or vaso-
occlusive phenomena intraoperatively and postoperatively. Because sickling results from decreased hemoglobin
oxygen saturation, maintaining adequate arterial oxygen tension assumes paramount importance. Adequate
capillary perfusion with short capillary transit times and avoidance of low output states (to prevent low mixed
venous hemoglobin oxygen saturations) are also important (33,34,35). Continuous measurement of arterial and
mixed venous hemoglobin oxygen saturations help to maintain adequate oxygen saturations. Because sickle
crises are frequent when high concentrations of hemoglobin S are present (i.e., homozygous patients), marked
reduction of sickling can be achieved by relative dilution of hemoglobin S with respect to hemoglobin A. This can
be accomplished by using preoperative or intraoperative exchange transfusions.
Preoperative exchange transfusions, particularly applicable in patients who are already anemic, not only
increase the prevalence of hemoglobin A relative to hemoglobin S but also suppress the production of
hemoglobin S. This therapy improves the oxygen-carrying capacity of the blood by correcting the anemia and
deficiency of hemoglobin A. In nonanemic patients, exchange transfusion may be accomplished intraoperatively.
This type of transfusion is usually performed by sequestering the initial CPB venous drainage from the patient
after priming the extracorporeal circuit with whole blood containing hemoglobin A (29,35). The goal of exchange
transfusion is to achieve a hemoglobin A fraction of 60% to 70%, which is also the level sought when treating a
major sickle cell crisis (34).
Acidosis shifts the oxyhemoglobin dissociation curve to the right, which increases the tendency toward sickling.
This holds true particularly in venous blood, where sickling is most often initiated. Arterial and mixed venous
blood gases should be measured frequently and any developing acidosis aggressively treated with sodium
bicarbonate (34,35). Hypoperfusion may result from hypothermia, administration of cardioplegia, diminished
intravascular volume, poor patient positioning, tourniquets, low CPB systemic flows, or low cardiac output states.
It is important to avoid hypoperfusion because of the tendency of blood to desaturate during the capillary and
venous phase of circulation, resulting in low hemoglobin oxygen saturation and red blood cell sickling.
Hypoperfusion can usually be prevented by maintaining adequate systemic CPB
P.574
flows and avoiding low cardiac output states both before and after bypass.
Localized sickling may occur in the heart during aortic cross-clamping because of the absence of coronary blood
flow. This phenomenon may be avoided by flushing hemoglobin S out of the coronary arteries using either
crystalloid cardioplegia or blood cardioplegia with a high fraction of hemoglobin A. Because mechanical
prosthetic valves may predispose the patient to increased hemolysis, such valves are not recommended in these
patients (35). Other means of avoiding mechanical blood trauma include minimizing the use of cardiotomy suction
and venting. In patients with sickle cell disease, it appears advisable to minimize or avoid hypothermia during
CPB. Despite the risks involved, numerous patients with homozygous sickle cell disease have successfully
undergone CPB using the techniques described above (36,37,38,39,40,41,42,43,44,45). Successful cases have
been described even using deep hypothermia with circulatory arrest (46).
Hereditary Spherocytosis
Hereditary spherocytosis, an autosomal dominant defect in red blood cell membranes, results in spherically
shaped red blood cells that have increased osmotic and mechanical fragility. The usual treatment for hereditary
spherocytosis resulting in hemolysis is splenectomy, which corrects the hemolysis and increases the shortened
lifespan of the red blood cells to normal, although the cells retain their abnormal properties. Information
describing CPB in these patients is limited. One case report describes a nonsplenectomized patient undergoing
bypass with no apparent increase in blood destruction or in osmotic fragility over the baseline level (47). In
addition, in a patient who had previously undergone splenectomy, no increase in hemolysis was noted during or
after CPB, despite triple valve replacement using Bjork-Shiley mechanical valves (48). Other patients have had
porcine valves inserted to minimize mechanically induced hemolysis. One study reported uneventful closure of
an atrial septal defect in a 31-year-old with hereditary spherocytosis and suggested that a short CPB time was
important in avoiding complications (49). Hereditary elliptocytosis is a condition thought to be similar to hereditary
spherocytosis; there is infrequent hemolysis and anemia, and no specific precautions are recommended in these
patients (50).
Thalassemia and G-6PD Deficiency

Thalassemia minor patients exhibit no increase in red blood cell fragility, and therefore one would expect no
hemolysis. Anemia in these patients is treated with transfusions. Hemolysis has been induced by a number of
drugs in patients with glucose-6-phosphate dehydrogenase deficiency (50). This gender-linked inherited
deficiency is present in 10% to 15% of African-American males. Susceptible individuals may develop explosive
hemolysis when they receive drugs such as antimalarials, quinidine, phenacetin, or sulfonamides. These drugs
should be avoided in susceptible patients undergoing surgery, including those undergoing CPB.
Methemoglobin
Acute methemoglobinemia may result from increased production of methemoglobin to levels far exceeding the
usual amount, which is less than 1% of total circulating hemoglobin (51). Secondary or acquired
methemoglobinemia is almost always caused by poisoning with chemicals or drugs classified either as direct
oxidants such as nitrites or indirect oxidants such as benzocaine. Other such medications include highdose
methylene blue (52), nitroglycerin (53,54,55,56), nitroprusside, prilocaine, silver nitrate, sodium nitrate, flutamide
(56), and sulfonamides.
The diagnosis of methemoglobinemia is made when cyanosis or oxygen desaturation occurs in the presence of
an adequate arterial oxygen tension and is supported by a chocolate-brown color of blood rather than the usual
dark blue of cyanosis (57). The diagnosis can be confirmed by spectrophotometry (58).
Treatment at times may need to precede definitive diagnosis. First, all probable offending drugs should be
withdrawn. Next, maximal oxygen concentrations should be delivered to the oxygenator. If cyanosis or oxygen
desaturation persists in the presence of high oxygen tension, pharmacologic treatment should begin. The drug of
choice is methylene blue, 1 to 3 mg/kg administered in a 1% solution, which converts methemoglobin to active
hemoglobin. The response to methylene blue is usually immediate and excellent, and because the treatment is
relatively innocuous, its use should not be delayed. However, methylene blue may cause methemoglobinemia
when a dose greater than 7 mg/kg is administered (59). If the patient fails to respond to methylene blue, the next
line of treatment consists of high-dose vitamin C and, if necessary, exchange transfusion (53).
Polycythemia
Polycythemia is defined as increased red blood cell mass. It occurs with cyanotic congenital cardiac defects as
compensation for reduced oxygen delivery to tissues. The preoperative hematocrit in severe cases may exceed
70%, at which level blood viscosity is sufficiently high to compromise blood flow. Hemostatic abnormalities
consistent with consumptive coagulopathy can occur (increased prothrombin and activated partial thromboplastin
times, increased fibrin degradation products, thrombocytopenia, factor deficiencies, etc.) (60,61,62).
Hemodilution beyond that normally used to prime the CPB circuit may better preserve the patient’s coagulation
status, so this may be an ideal situation for withdrawal of autologous blood before CPB. The degree of
hemodilution needed to achieve a desired patient/pump hematocrit can be calculated using a formula shown in
Figure 24.3 (60). Polycythemia vera is a hematologic disease that carries an increased risk of myocardial
infarction.
Religious Objections to Blood Transfusion

Avoidance of homologous blood transfusion is a desirable goal whenever CPB is used; with patients of the
Jehovah’s Witness
P.575
faith it is mandatory because of their strict interpretation of the bible (63). More than 50 years ago, Cooley et al.
(64) first reported the feasibility of open-heart surgery in this patient population. In 1977, Ott and Cooley (65)
reported additional results in a large series of Jehovah’s Witness patients in whom no blood was transfused.
However, there was a 10.7% mortality in those undergoing CPB ( n = 39), with preoperative or postoperative
anemia a contributing factor in 12 deaths.
FIGURE 24.3. Calculation of volume of crystalloid solution (cardiopulmonary bypass prime volume) necessary for
hemodiluting to a desired hematocrit. EBV, estimated blood volume; CPB, cardiopulmonary bypass. aFactor
(EBV/kg) is assumed to be 80 mL/kg for <10 kg body weight; 75 mL/kg for 10 to 20 kg of body weight; 70 mL/kg
for >20 kg of body weight. The example addresses the polycythemic adult, but this condition is more prevalent in
cyanotic pediatric patients with smaller required CPB circuit prime volumes. (From Milam JD, Austin SF, Nihill
MR, et al. Use of sufficient hemodilution to prevent coagulopathies following surgical correction of cyanotic heart
disease. J Thorac Cardiovasc Surg 1985;89:623-629, with permission.)
Using current low-prime membrane oxygenator circuits, intraoperative cell salvage, and reinfusion of shed
mediastinal blood, CPB can be performed relatively safely, even in pediatric patients (63,66,67), reoperations, or
those with complex anatomy (68). The lowest safe hematocrit on CPB is not known, but values of approximately
15% have been used successfully provided CPB systemic flows are maintained at levels to prevent development
of metabolic acidosis.
Most of these patients (but not all) who will accept the use of CPB will also accept the return of cell salvage
products provided that continuity between removed blood and the patient’s vascular system has been maintained
when cell salvage is used (69). Figure 24.4 shows how this can be accomplished pre- and post-bypass. We
recommend having and documenting this specific discussion preoperatively. Some authors have further
advocated use of heparin-bonded CPB circuits and lower levels of heparinization (activated clotting time [ACT]
>280 seconds) with favorable results (70). Use of erythropoietin preoperatively to promote red blood cell
production and antifibrinolytics perioperatively also have been advocated (71,72). Van Son et al. (67)
enumerated management strategies to minimize blood loss in these patients (Table 24.2). Lee and Martin (73)
wrote an excellent review of CPB management in this patient population.
Reoperative Surgery
Patients undergoing repeat cardiac surgery often present problems because of adhesions that make a second
sternotomy and vascular access for CPB cannulation technically difficult. There is also an increased risk of
encountering major bleeding during dissection because cardiac structures or vessels may be adherent to the
chest wall, particularly if the pericardium has not been closed during the initial operation (74). Normal anatomic
landmarks are often obliterated, prolonging adequate surgical exposure and CPB times. Because of adhesions
necessitating sharp dissection, these patients tend to bleed more and have higher transfusion rates than first
time cases (75). The surgeon should dissect as little as possible during reoperative surgery to minimize large
disrupted tissue surface areas that will bleed. Use of an argon beam coagulator in these cases may also
minimize bleeding problems associated with extensive dissection.
In some cases, groin cannulation of the femoral or iliac artery and femoral vein must be used to establish CPB.
Placing an adequately sized femoral arterial cannula can usually be accomplished easily, but placement of an
adequately sized venous cannula may be more difficult. New long, thin-walled, kink-resistant femoral venous
cannulas are commercially available to permit positioning the cannula tip near the cavoatrial junction (76).
However, because of their length, standard gravity siphonage may be inadequate to permit full CPB systemic
flow. If maximizing the height differential between the patient’s heart and the CPB venous reservoir or
repositioning the cannula does not improve venous drainage, flow may be augmented with a centrifugal pump
placed in the venous line (77,78). Activation of the centrifugal pump will exert additional negative pressure
beyond that obtainable by height differential alone with a concomitant modest increase in venous line flow.
Alternatively, a hard-shell venous reservoir may have regulated vacuum applied to its interior to effect additional
venous line flow using the same principles (79).
Both methods of augmented venous drainage require careful monitoring of venous line pressure so that
excessive levels of vacuum are not created (80). Excessive vacuum can collapse vascular walls into the venous
cannula openings, thus impeding or stopping venous line flow (81). Excessive
P.576
vacuum may be manifested by intermittent or staccato flow; in severe situations, the venous line may rhythmically
jerk and relax as flow stops and is then reestablished with systemic venous return in the patient’s cavae or right
atrium. Levels of hemolysis will also quickly rise if excessive vacuum is exerted in the venous line (82).
FIGURE 24.4. Schematic drawing of cardiopulmonary bypass (CPB) circuit for collection, processing, and
reinfusion of blood after bypass while maintaining continuity with the patient’s circulation. The reinfusion bag (top
left) should initially be back-filled with patient’s blood from an intravenous site to establish continuity with cell
salvaged blood (from collection bag) before CPB. Cardiotomy suction can be used after bypass until protamine is
administered with collected blood processed in the cell salvage system. Residual perfusate in the CPB circuit
should be transferred to the cardiotomy reservoir and also processed by the cell-salvage system to minimize
blood loss. A second cardiotomy reservoir (not shown) is used during CPB for conventional collection of
suctioned and vent blood, which is drained into the venous reservoir. (Modified from Milan TP Jr, Whitmore J,
Maddi R. Reoperative cardiac surgery in a Jehovah’s Witness: role of continuous cell salvage and in-line
reinfusion. J Cardiothorac Anesth 1989;3:211-214, with permission.)
Establishing CPB via the groin vessels will afford the surgeon more control if massive bleeding in the chest is
encountered. Alternatively, if the arterial cannula has been placed, CPB may be established using the pump
suckers and a vent as a source of venous return (so-called sucker bypass). This will allow surgical control of
bleeding and provide adequate decompression of the heart and preserve patient hemodynamics until the
surgeon can place a conventional venous cannula in the right atrium or right atrium/inferior vena cava. The
perfusionist should be prepared with additional cannulas, connectors, and tubing if CPB must be established
emergently during reoperations (83). It must be recognized that the risk of aortic dissection is much greater when
femoral arterial cannulation is used, which is discussed later in this chapter.
In summary, the number of patients presenting for reoperation is increasing. Increased surgical experience, use
of antifibrinolytic drugs, and newer CPB technology can reduce the risk of morbidity and mortality associated with
these procedures to levels approaching primary cardiac operation (84,85). Augmented venous drainage
techniques have also been applied during minimally invasive cardiac surgery (86) and are discussed in greater
detail subsequently.
Cardiopulmonary Bypass after Pneumonectomy

CPB techniques for patients who have undergone prior pneumonectomy have been addressed in the literature
(87,88). The technical aspects of conducting CPB in such patients are not significantly different from those in
patients who have had lobectomy or no pulmonary resection.
Hemodilution for CPB has been associated with a decrease in postoperative pulmonary problems theoretically
from dilution of noxious blood elements or from avoidance of noxious elements (e.g., microaggregates present in
homologous
P.577
blood). However, excessive hemodilution may predispose to pulmonary edema, which might be addressed by
limiting hemodilution to a hematocrit fraction of more than 20% in postpneumonectomy patients.
TABLE 24.2. Perioperative measures to minimize blood loss in the Jehovah’s Witness
patient
1. Pretreat patient with synthetic erythropoietin if hematocrit <38%.
2. Avoid cardiac catheterization, if possible.
3. Administer antifibrinolytics perioperatively.
4. Use low-energy electrocautery in chest wall, pericardial, and great vessel dissections.
5. Use cell salvage system.
6. Minimize pre-CPB fluid administration.

7. Reduce CPB circuit priming volume.
8. Use moderate CPB systemic flow rates and gentle cardiotomy suction.
9. Use hemoconcentration to remove excess plasma water.
10. Avoid deep levels of hypothermia if possible.
11. Delay heparin neutralization until all bleeding sites have been secured (this will allow continued
use of cardiotomy suction).
12. Gradually return entire volume of residual perfusate to patient (after processing by cell salvage
system).
13. Administer postoperative iron supplements in patients with depleted red blood cell mass.
CPB, Cardiopulmonary bypass.
Derived from Von Son Jam, Hovaguimian H, Rao IM, et al. Strategies for repair of congenital heart
defects in infants without the use of blood. Ann Thorac Surg 1995;59:384-388.
Blood transfusions should be avoided not only because of potential infections or transfusion reactions but also
because of possible pulmonary damage from such elements as platelets and white blood cells. Washed packed
red blood cells appear more appropriate when transfusion is indicated; return of shed blood should be avoided.
When platelet transfusion is indicated, steroids and diphenhydramine should be used as pretreatment and
leukocyte-depleted platelet concentrate should be used. Leukocyte reduction of all transfused residual perfusate
will lessen the potential for pulmonary injury (89).
Technically, the position of the heart may be distorted because of contracted fibrothorax and/or hyperinflation of
the remaining lung. This may lead to technical difficulty in gaining exposure, especially after left pneumonectomy.
Remote cannulation from the femoral vessels has been helpful in some patients. Monitoring of pulmonary artery
or left atrial pressure, with possible left ventricular venting, is important because strict control of the level of
pulmonary capillary hydrostatic pressure is critical both intraoperatively and postoperatively to prevent pulmonary
edema. Air emboli in the pulmonary circuit would seemingly be less well tolerated, and this is addressed by
standard de-airing techniques. Time on CPB directly correlates with postoperative lung water; therefore, at
times, a less complete coronary revascularization may be preferable to incurring a long CPB time. For coronary
bypass surgery, the proximal anastomoses may be performed off pump or with low-flow partial CPB.
Minimally Invasive Surgery

A full discussion of the use of CPB in support of all minimally invasive cardiac surgery, such as port access and
robot-assisted procedures, is beyond the intended scope of this chapter. More detailed discussion of these
techniques may be found in Chapter 7. However, two features commonly used with CPB support for these
minimally invasive approaches, namely cannulation of femoral vessels and management of venous drainage
warrant specific consideration here.
Femoral arterial cannulation is recognized to have a somewhat different risk profile than ascending aortic
cannulation. Specifically there may be a higher occurrence of aortic dissection and other complications
associated with the more traditional blind insertion of a relatively short femoral artery cannula. Although
published literature is sparse a more reasonable approach is the use of a modified Seldinger technique with a
guidewire and sequential dilation of the vessel to the point where it will accept the appropriate cannula size
capable of delivering expected required flow rates within acceptable circuit pressure ranges. Visualization of the
initial guidewire in the distal thoracic aorta using intraoperative TEE is helpful in assuring that the cannula will be
located within the aortic lumen.
Femoral vein cannulation typically utilizes a long cannula that is passed to the point of the superior vena
cava/right atrial junction. This position may be approximated by surface measurements but correct positioning is
greatly assisted by direct visualization of first the guide wire and subsequently the venous cannula using
intraoperative TEE. Because of the length and relatively small diameter of these cannulas, the conventional
siphon pressure gradient may not be sufficient to generate adequate venous drainage blood flow. If this occurs,
then venous flow may be augmented significantly by application of vacuum to the (hard shell) venous reservoir.
Use of the minimum vacuum pressure necessary to produce the necessary increment in venous drainage is
recommended. Higher venous vacuum can produce air entrainment if vascular openings to the ambient
environment are present. Hemodynamic monitoring catheters, unrecognized intracardiac defects, cannula
misplacement, and other iatrogenic causes have been implicated. Air entrainment can be sufficient to worsen (or
totally obstruct) venous drainage, or in a worst-case scenario air can pass from the venous circuitry into the
systemic perfusion side of the circuit with potentially disastrous results. Further discussion of air embolization
may be found in a subsequent section of this chapter. Despite the apparent logic of further increasing the venous
vacuum to increase venous drainage when air entrainment occurs to accelerate passage
P.578
of the air and improve flow, the logic is flawed. Greater negative pressure will only serve to increase air
entrainment and worsen the issues. The preferred approach would be to identify the source of the air
entrainment and prevent further entrainment.
INITIATION OF CARDIOPULMONARY BYPASS

The initiation of bypass is discussed in detail in Chapter 19. To briefly recapitulate a key issue, patency and
continuity between the patient’s vascular system (venous and arterial) and the CPB circuit must be assured for
uncomplicated initiation of CPB. Cannula malposition, kinks in the CPB tubing, or clamps inadvertently left in
place on cannulas or CPB tubing (venous or arterial) can prevent a smooth transition to full CPB flow. The
absence of air bubbles in the CPB systemic line or arterial cannula must be visually verified to avoid systemic air
embolism when CPB is started. Presence of abnormal anatomy (e.g., persistent left superior vena cava) or
patient pathophysiology (e.g., aortic valve insufficiency) may compromise decompression of the heart during
CPB. Presence of anatomic shunts may further obscure the surgical site, requiring placement of vents. Problems
related to CPB cannulation and venting are discussed thoroughly in Chapter 2.
Acute dissection of the aorta is a serious and often devastating problem that can occur with initiation of CPB. It is
associated with a high mortality rate and, when recognized, inevitably leads to modification of the original
surgical procedure. Fortunately, the incidence of acute dissection with ascending aortic cannulation is much less
than when the femoral artery is used for the CPB systemic flow connection. Dissection may be delayed and not
recognized until the postoperative period. This most often occurs in patients undergoing coronary artery bypass
surgery who have a history of hypertension and severe atherosclerosis (90).
A triad of observations may aid recognition of acute aortic dissection. First and foremost is an unexpectedly
increased CPB arterial line pressure as the systemic pump is activated. This often coincides with profoundly
decreased systemic pressure measured by the indwelling arterial catheter. Third, the perfusionist may
experience decreased venous drainage to the CPB circuit. At the surgical field, a hematoma may develop near
the arterial cannulation site or there may be bleeding around the purse-string sutures.
If aortic dissection is suspected, the perfusionist should immediately stop CPB and notify the surgeon. The
perfusionist and surgeon must confirm there are no kinks or clamps on the arterial line responsible for the
increased CPB line pressure and/or decreased systemic pressure. The surgeon should palpate the aorta; if it is
flaccid, this often indicates a major problem and acute dissection should be strongly suspected. It is important to
clamp the venous line in this emergency situation to avoid exsanguinating the patient into the CPB reservoir. If
dissection is confirmed, the arterial cannula is removed and reinserted in a different location so that CPB can be
resumed. The dissection must be surgically repaired, which may involve replacement of the ascending aorta,
quite possibly with deep hypothermia and circulatory arrest.
The risk of acute aortic dissection may be decreased by the surgeon observing a brisk backflow of blood at the
time of insertion of the arterial cannula into the aorta. Once the CPB systemic flow line and cannula are joined,
the perfusionist should observe and manually palpate pulsation in the CPB line that corresponds with the
patient’s pulse before starting bypass. Unrestricted administration of a bolus of 100 cc of CPB perfusate also
reasonably assures patency between the arterial cannula and the lumen of the aorta or other cannulation site.
Direct continuous measurement of arterial line pressure by aneroid gauge or electronic transducer allows
observation of the CPB systemic line pressure during initiation and throughout the course of bypass.
Massive air embolism may occur during aortotomy for cannulation if an intraaortic balloon is in place (91,92).
Briefly turning off the balloon pump whenever the aorta is opened, for instance, when placing cannulas (arterial
or cardioplegia) or vents, will prevent aspirating room air into the aorta with intraaortic balloon deflation (93).
MAINTENANCE OF CARDIOPULMONARY BYPASS

There are two basic requirements during CPB: adequate blood volume to maintain appropriate blood flow and
adequate gas flow (in the correct composition) to maintain appropriate gas exchange. Because of the invasive
nature of cardiac surgery and CPB, a third requirement is avoidance of air embolism at all stages of the
procedure. Myriad threats exist in accomplishing these objectives. Miscellaneous problems that may jeopardize
patient well-being include errors in drug administration, contamination of the circuit or patient, and transfusion
reactions or administration of mismatched blood products. Because of the patient’s dependence on the CPB
circuit and ancillary monitoring devices, equipment malfunction or failure is always a potential concern.
Fortunately, the incidence of perfusion accidents is low, and the incidence of adverse patient outcome (defined
as injury requiring prolonged hospitalization, permanent injury, or death) is rare.
Publication of case reports and national surveys examining CPB experience has further heightened practitioner
awareness of errors and malfunctions associated with CPB. Surveys by Stoney et al. (94), Kurusz et al. (95), and
Mejak et al. (96) have elucidated incidence rates in the United States for a variety of perfusion mishaps occurring
in the 1970s, 1980s, and 1990s, respectively. Other broad-based surveys by Wheeldon (97), Jenkins et al. (98),
Charrière et al. (99), and Groenenberg et al. (100) have reported experiences in
P.579
the United Kingdom, Australasia, and Europe. The following discussion addresses the more common perfusion
incidents based on these survey reports and the authors’ experience (101,102). Although direct comparison of
results among different respondents during different survey time frames may be challenged, some sense of
trends in the major reported CPB incidents may be discerned. Because of these and other subtle differences
among the wording of questions (see the legend for Fig. 24.5) it is difficult to make meaningful direct
comparisons or conclusions. However, with these caveats, it appears that overall incidence rates, and more
important, the incidence for an adverse patient outcome have declined to zero or negligible levels in most
categories as shown in Figure 24.5, A and B. The two most recent surveys indicate that the so-called protamine
reaction remains a relatively common occurrence followed in frequency by coagulation problems and aortic
dissection at the CPB cannulation site. However, it is important to know that in spite of these mishaps, a
permanent injury or patient death directly attributable to CPB is exceedingly rare in current practice.
Inadequate Blood Flow

Acute aortic dissection can be a cause for inadequate blood flow during CPB and was discussed in the previous
section because it most often is manifested at the time of initiation of CPB. Other causes of inadequate blood
flow include low circulating volume that may result from a variety of causes. With the emphasis on reduced
priming volumes for the CPB circuit and limited pre-CPB fluid administration by anesthesia personnel, there may
be insufficient volume in the reservoir to maintain appropriate CPB systemic flow. Administration of vasodilators
can drastically reduce CPB reservoir levels. Undetected blood leaks either from the CPB circuit or, more
commonly, in the operative field or under surgical drapes will also reduce circulating blood volume. A particularly
insidious blood leak may occur from Swan-Ganz catheter-induced pulmonary artery perforation, which carries a
high risk of mortality (103,104). Hypothermia causes the catheter tip to stiffen and may predispose it to perforate
the pulmonary artery (105). Because pulmonary blood volume usually decreases at the onset of CPB and
because the pulmonary artery catheter is typically fixed at the insertion site, the resulting tendency is for the
catheter to migrate distally further into the pulmonary artery during CPB, an occurrence that has been implicated
in pulmonary artery perforation by the catheter. Because of this, deflating the balloon and withdrawing the
catheter approximately 3 to 5 cm before or at the onset of CPB is a reasonable approach to lessen the risk of this
complication (103).
Inappropriate cannula size can reduce venous drainage, as will partial occlusion on the venous line. The venous
or arterial cannulas may become malpositioned within the vasculature or inadvertently kinked or clamped,
leading to reduced CPB blood flow (106,107,108,109,110). Rarely, the venous cannula may have a
manufacturing defect that compromises the available cross-sectional area of its lumen, thus preventing normal
venous drainage. Therefore, all cannulas should be inspected before use not only for proper size selection but
also to confirm the absence of structural defects. A partially obstructed arterial cannula or oxygenator is
manifested by elevated CPB systemic flow line pressures and lower than expected patient arterial pressures
(111) or, if a centrifugal pump is being used, higher than expected revolutions per minute to maintain the desired
flow. Another problem with centrifugal pumps is inaccurate flowmeter readings, which can arise when the flow
probe is miscalibrated. With roller pumps, false displays of CPB pump output will result if the flow rate indicator
on the CPB console is not set to match the tubing size (111), or if the occlusion of the tubing within the roller
pump head was not properly adjusted.
Small quantities of entrained venous line air are rarely problematical in leading to a decrease in CPB systemic
blood flow. However, if the entire venous line becomes filled with air, the gravity siphon effect will be lost
(commonly referred to as air lock). This usually requires slowing or momentarily stopping CPB by clamping the
venous line at the pump to allow personnel at the surgical field to refill the venous line with fluid and then
“walking” any remaining air down the venous line into the venous reservoir to reestablish effective siphon
drainage.
The CPB pump may fail, causing inadequate blood flow. Centrifugal pumps may decouple, meaning that the
magnetic force to effectively rotate the pump has been lost between the pump console and base of the
disposable pump head. This incident is often manifested by a high-pitched whining sound as the centrifugal
pump motor accelerates to very high revolutions per minute; the in-line blood flowmeter also will show decreased
flow that can progress to zero forward flow (and even retrograde flow) if not promptly corrected. An in-line valve
in the CPB systemic flow line may prevent retrograde flow from the patient’s aorta under these conditions (112).
Underocclusion of a roller pump may lead to inadequate blood flow; this condition may be more difficult to detect
than a centrifugal pump malfunction because in-line flowmeters are rarely used with roller pumps. Manifestations
might include lower-than-expected CPB line or patient arterial pressures and decreased mixed venous
hemoglobin oxygen saturation or Pvo2 with developing acidosis.
Inadequate Gas Exchange

Although there are fundamental physiologic issues related to whole body oxygen consumption and delivery
during CPB (discussed in Chapter 19), mechanical problems related to inadequate gas exchange by the
oxygenator include oxygenator failure and gas delivery system failures. Oxygenator failure is diagnosed by
observing dark-colored blood exiting the oxygenator that cannot be corrected by increasing the concentration of
oxygen in the ventilating gas. Blood gas analysis
P.580
P.581
P.582
or in-line blood gas sensors can confirm visual assessment of inadequate oxygenation. Causes may include loss
of gas supply to the CPB oxygen/air blender or flowmeter or, more rarely, failure of the blender. Leaks or
obstructions in the gas delivery system have been reported (113,114,115). Use of an in-line oxygen analyzer,
which is considered standard on anesthesia machines, should be incorporated into the oxygenator gas delivery
line to monitor delivery of appropriate concentrations and warn of abnormally low oxygen flow. The optimal
position of the sensor is to place it nearest the oxygenator (116). Kirson and Goldman (117) reviewed oxygenator
gas delivery problems in detail and proposed a system consisting of an aspirating oxygen sensor and
pneumotachograph for more accurate detection of such problems. Problems with gas scavenging systems
causing inadequate gas transfer in the oxygenator have been reported (118). The patient who is too lightly
anesthetized may have higher oxygen consumption that can lead to decreased mixed venous hemoglobin oxygen
saturation and decreased arterial Po2 if left uncorrected. Likewise, mild-to-moderate hypothermia is a frequent
component of CPB and it is known to increase skeletal muscle tension even in the absence of overt shivering,
which increases oxygen consumption. For these reasons, it is commonly recommended to increase the “depth”
of anesthesia and administer additional muscle relaxant at the onset of CPB. Also, the CPB fresh gas in-flow line
should be equipped with a vaporizer for an appropriate volatile anesthetic agent to allow its continued
administration during the course of CPB.
FIGURE 24.5. (A) and (B) Specific incidents are compared from the major cardiopulmonary bypass (CPB)
perfusion incident surveys in the last five decades. The total caseload experience represented in each survey
was as follows: Stoney, 373,819; Wheeldon, ˜33,000; Kurusz, 573,785; Jenkins, 27,048; Mejak, 653,621;
Charrière, 34,496; Groenenberg, 23,500. Total numbers of incidents per 1,000 cases are plotted in pink bars
and reported adverse patient outcomes (defined as permanent injury, significantly complicated patient recovery,
prolonged hospital stay, or death) are plotted (again as occurrences per 1,000 cases) to the right in blue bars.
aPatient outcome for reversed left ventricular vent incidents was not reported in the Stoney survey; Charrière did
not report any information on this specific incident, while Groenenberg reported four cases of “air embolus due to
reversed vent/sucker tubing” with none resulting in an adverse patient outcome. bJenkins reported “coagulation
problems”, Mejak reported “coagulation problems following bypass”, while Charrière and Groenenberg reported
“coagulation of the circuit” and “clot-induced obstruction in circuit during CPB,” respectively. These incidents are
distinct from “disseminated intravascular coagulopathy” or “consumption coagulopathy” as was used by Stoney,
Wheeldon, and Kurusz; such differences in survey question wording could have accounted for the higher
incident rates reported by Jenkins and Mejak, and are not directly comparable in the more recent surveys.
cCharrière reported etiologies of
gas embolism two ways: from the CPB circuit and from the cardioplegia line, but
the total number of cases represented by each etiology differed, so the incidence rate for gas embolism from the
CPB circuit is only shown on the graph; neither type of gas embolism (Continued)
FIGURE 24.5. (Continued) resulted in any adverse patient outcomes. cGroenenberg reported a variety of
etiologies associated with CPB described as “air embolus,” the majority of which did not reach the patient (n =
29); the second most frequent category was “due to air in the cardioplegia line” (n = 17), but an adverse patient
outcome from all causes was extremely low. dStoney asked about “failure of delivery of oxygen to pump,”
whereas Kurusz asked about “oxygenator failure”; Jenkins asked about several specific types of “oxygenator
failures” and “gas supply failures,” the most common being membrane leak; there were 35 cases reported in his
survey, for which the oxygenator required replacement before or during CPB. Charrière reported “hypoxemia
caused by oxygenator failure” and Groenenberg included failures to exchange gas as well as leaks as
oxygenator failures. Of note, this type of incident resulted in the need to replace the oxygenator either prior to or
during CPB 29 times by respondents on Groenenberg’s survey, but there were no adverse patient outcomes
reported on either recent survey. eLike the Jenkins and Mejak reports, mechanical and electrical failures were
combined on the Charrière survey (n = 19, 13, and 140), respectively, and resulted in no adverse patient
outcomes in all but one report (Mejak). Groenenberg reported mechanical and electrical failures as occurring
either prior to or during CPB; electrical failures occurred more frequently than mechanical failures, but were
extremely rare and in no instance resulted in an adverse patient outcome.
Inadequate anticoagulation leading to clotting in the oxygenator can cause inadequate gas transfer. The use of
propofol anesthetic administered directly into the membrane oxygenator can potentially affect gas transfer,
presumably by blocking pores or otherwise interfering with the membrane surface in the blood-contacting
compartment of a microporous membrane. Therefore, propofol should be administered peripherally to permit de-
emulsification before it reaches the membrane oxygenator (119,120).
Fisher (121) provided data from the United Kingdom on the incidence of oxygenator failures requiring change-
out. Two time periods were surveyed (1990-1992 and 1994-1996) during which the incidence was approximately
0.25 per thousand CPB procedures (1:4,000). Major causes for the change-outs differed between the two time
periods. In the earlier survey, clotting in the oxygenator, particularly when aprotinin was being used, was the
most frequently cited reason. In the latter survey, development of a high transoxygenator pressure gradient or a
blood leak in the oxygenator was the major reason for change-out. Table 24.3 outlines steps for oxygenator
change-out during CPB. Hart et al. (122) also described a technique for membrane oxygenator change-out that
does not require stopping CPB. Earlier techniques with bubble oxygenator change-out required short periods (˜2-
3 min) of circulatory arrest (123,124).
TABLE 24.3. Emergency replacement of membrane oxygenator
1. Notify surgeon and anesthesiologist of problem; seek qualified assistance (second perfusionist
preferable).
2. Turn off water flow to heat exchanger; clamp and disconnect water lines.
3. Turn off gas flow and remove oxygen delivery line.
4. Clamp venous line, turn off stopcock venting arterial line filter, and stop systemic blood flow
pump.
5. Remove monitoring/sample line from oxygenator outlet.
6. Double clamp recirculation line (leaving 3-inch between clamps while squeezing tubing between
clamps to decrease pressure), oxygenator inlet and outlet lines; cut midway between clamps,
leaving adequate lengths of tubing for reconnection.
7. Detach oxygenator from bracket; detach oxygenator from hard-shell venous reservoir (if
attached).
8. Attach replacement oxygenator to hard-shell venous reservoir (if present) and mount in bracket.
9. Reconnect oxygenator inlet, outlet, and recirculation lines (trace connections to verify proper
direction of flow) and band all new connections.
10. Connect water lines to heat exchanger, turn on water source, and inspect for leaks.
11. Connect oxygen line and set blender to deliver 100% oxygen.
12. Remove clamps from recirculation and oxygenator inlet tubing lines (do not unclamp arterial
outlet line or venous drainage line).
13. After verifying sufficient volume in venous reservoir, turn on systemic flow pump slowly to fill the
oxygenator.
14. Recirculate at 4-5 L/min to debubble oxygenator.
15. Stop recirculation and clamp recirculation line.
16. Visually inspect entire system to ensure system is free of leaks and gas bubbles.
17. Notify surgeon that CPB is ready to be restarted.
18. Remove all clamps from arterial and venous lines, open arterial purge line stopcock, turn on gas
flow, and restart CPB.
CPB, cardiopulmonary bypass.
Electrical Problems
Minor and major electrical problems are relatively common during CPB but only rarely cause adverse patient
outcome. The entire CPB console or individual components can fail to operate as a result of wall power or
electrical cord failures. Most hospitals have backup emergency generators to supply the operating room with
electricity in the event of power outage. Sometimes these backup generators can fail to come on in a timely
manner, making it prudent to have alternative electrical backup such as an uninterruptible power supply in the
operating room and in line with the CPB console for dealing with power failures. Some CPB consoles have
battery power built in to provide continuous function in the event of electrical failure. All CPB systemic pumps
should have provision for manual hand cranking readily available in the event backup
P.583
electrical sources fail. The CPB console can be sabotaged, either by inappropriate conduct by untrained
personnel or by malicious actions by those with more sinister intentions. In either situation, performance of a
thorough pre-bypass checklist by the primary perfusionist at the time of setup should uncover potential
malfunctions before placing the patient on bypass.
Electronic components within the console can fail, leading to erratic operation or cessation of function of
individual components. Runaway pumps have been reported (125,126), as have electrical fires that can lead to
loss of function of CPB components (127). Power surges or brownouts can lead to inaccurate readings on the
CPB console or physiologic monitors. Piezo-electric or static charges created by roller pump rotation can
interfere with the electrocardiogram (ECG) (128). This may be prevented by grounding the CPB console to a
metal-jacketed temperature port in the oxygenator (129). Skin ECG electrodes, lead wires, and cables should be
intact to also avoid ECG “noise” when the patient is on CPB (130). Transducers may “drift” over the course of
several hours, leading to inaccurate readings. It is therefore prudent to re-zero transducers before weaning from
bypass to ensure accuracy of measured parameters that can influence management decisions (131).
Temperature probes may become disconnected or malpositioned, leading to improper displays. It is therefore
advisable to place at least two patient temperature probes for redundancy. In-line blood gas monitors or
oximeters may display erroneous values unless calibrated against standard laboratory samples. The
electrocautery can interfere with monitor displays; use of a shielded ECG cable will minimize such interference.
There are a variety of alarms used on anesthesia, perfusion, and ancillary equipment in the cardiac surgical
operating room. Often, similar sounding high-pitched signals can make rapid identification of the source of the
alarm difficult. Cases of misinterpreted alarms (e.g., intraaortic balloon and low-level alarm on CPB reservoir)
have distracted the perfusionist with serious patient consequences (132). Alarms may be obtrusive, and there
may be a tendency among some practitioners to disable alarms that are designed to give early warning or
automatically respond if user-set thresholds are exceeded when potentially hazardous patient conditions are met
(133,134).
Perfusionists, anesthesiologists, and nurses must know how to troubleshoot equipment used during CPB.
Performing team drills for the unexpected perfusion crisis such as oxygenator change-out, hand cranking for
electrical failure, or dealing with massive air embolism can be life-saving during these rare events. Cooper et al.
(135) cited lack of familiarity with equipment as one major factor in operating room mishaps, and Gaba (136)
provided an excellent review of human error during conduct of anesthesia that has applicability to performance of
CPB.
Air Embolism
Concern over air embolism during CPB has been a constant focus of all involved in the perioperative care of the
cardiac surgical patient. Air embolism (venous or arterial) may occur not only from CPB (pump air) but during a
variety of surgical procedures (surgical air) or at the head of the table from actions or inaction by anesthesia
personnel (anesthetic air) (137). The pathophysiology of air embolism has been extensively studied in laboratory
experiments, many of which predated the clinical use of CPB. Case reports detailing mechanisms of air embolism
have appeared periodically in the literature. The next sections review the more common etiologies, followed by a
discussion of treatment strategies for this complication.
Surgical (Operative) Air

In 1914, the danger of air embolism during cardiac surgery was reported by Carrel (138), who wrote, “The
opening of the ventricles or of the pulmonary artery and the aorta is always followed by entrance of air into the
heart.” Support for his statement was the observation of ventricular fibrillation and death in animals after
coronary artery air embolism.
Air embolism on the left side of the heart was well known to thoracic surgeons before the advent of open-heart
surgery. Reyer and Kohl (139) reported 10 cases of venous or arterial air embolism, five of which resulted in the
patients’ deaths, during a variety of surgical or diagnostic procedures. Kent and Blades (140) further warned that
the two major hazards of thoracic surgery were infection and embolic phenomena. In their animal experiments, air
embolism was found to be well tolerated on the venous side, in the absence of a patent foramen ovale, but fatal
with small injections of air into the pulmonary veins.
Geoghegan and Lam (141) reported that the mechanism of death due to air embolism in dogs (0.25-2.0 mL/kg)
was either coronary (immediate death) or cerebral (severe brain damage). Benjamin et al. (142) further sought to
define the mechanisms of air embolism by injecting varying amounts of air (0.5-8.0 mL/kg) into the left atrium, left
ventricle, aortic root, common carotid, or descending aorta of dogs. Left atrial air embolism was fatal 100% of the
time, whereas the same volumes of air injected into the left ventricle caused death in 83% of the animals. Aortic
root and carotid air embolism were better tolerated, and large volumes of air (up to 10 mL/kg) were required to
cause death when given into the descending aorta. They, like other investigators
(143,144,145,146,147,148,149,150,151), noted the dangers of left heart air but concluded that small amounts of
air in the systemic circulation were generally well tolerated during surgical procedures if appropriate resuscitative
maneuvers were undertaken when required.
Many retrospective reviews of early clinical experience with CPB have been published. Callaghan et al. (152)
analyzed 60 deaths in 250 CPB patients operated on between 1956 and 1961. A variety of causes described
included seven cases of cerebral damage, four of which were from air embolism. Ehrenhaft et al. (153) reported
19 of 244 (7.7%) patients undergoing open-heart surgery suffered cerebral damage. Systemic air embolism was
the suspected etiology because many
P.584
operations involved closure of septal defects. Like Carrel nearly 50 years earlier, they warned of air entrance to
the left side of the heart or aorta with subsequent embolization when the normal circulation was restored. Allen
(154) reported cerebral damage in 18 of 500 (3.6%) patients undergoing repair of valvular or congenital cardiac
defects and warned of the propensity of air to collect in the left atrium near the right superior pulmonary vein.
Sloan et al. (155) reported 78 of 600 (13%) patients died after CPB; air trapped in the left ventricle was identified
as the source of the air and was believed responsible for 49 deaths. Nicks (156) reported systemic air embolism
in 40 of 340 (11.7%) patients undergoing congenital or valvular procedures; 10 patients died. Fishman et al.
(157) later confirmed the left atrium and pulmonary veins as locations of trapped air whenever the left heart was
opened. Anderson et al. (158) and Lin (159) also warned of the risks of pulmonary hypertension due to right-
sided air embolism.
The preference of cannulation of the ascending aorta for CPB, although much safer than the femoral artery site,
increased the risk of cerebral air embolism. Gomes et al. (160) found that air embolism via the femoral artery was
five times less likely to involve the cerebral vessels if the air originated from the CPB arterial line. Beckman et al.
(161) determined the optimum method of placement of the ascending aortic cannula to lessen the risk of air
entry. Direct insertion of the cannula without the use of a side-biting clamp, which tended to trap a small amount
of air, was found to be the safest.
In the landmark article by Mills and Ochsner (101) on mechanisms of air embolism, two additional surgical
sources were described: unexpected resumption of the heart beat and inadequate steps to remove air after
cardiotomy. Coronary air embolism with cardioplegia techniques was reported in 1981 (162) and 1986 (95).
Although air embolism was generally thought not to occur during coronary bypass operations, Hughes (163)
reported the possibility of intraventricular air with right superior pulmonary vein venting that could draw air in via
coronary arteriotomy, especially when the left anterior descending coronary artery was opened. Robicsek and
Duncan (164) and Lee (165) subsequently confirmed this mechanism. Air also can be drawn retrograde through
an opened coronary artery if an aortic root vent is used and placed under significant negative pressure.
Cardiopulmonary Bypass (Pump) Air

Air embolism originating from the CPB circuit may enter the patient’s vascular system either from the arterial line
or by other mechanisms, many of which are discussed in other chapters. Reed et al. (166) reviewed the many
mechanisms for air embolism from the CPB circuit, some of which have been reported in the literature and others
learned through direct or anecdotal experience.
Arterial line air embolism due to emptying of the CPB reservoir, as occurred during Dennis’ early case (167) has
been a common cause. The current popular use of membrane oxygenators in which the blood is drawn from a
venous reservoir and then pumped through the oxygenator may have decreased the incidence of arterial line air
embolism that was much more prevalent when bubble oxygenators were widely used (95). However, inattention
to the reservoir level can still cause air to be transmitted to the CPB systemic flow line, regardless of oxygenator
type. The importance of maintaining an adequate volume in the CPB reservoir was reported in 1958 (168) and
has been one of the fundamental safety principles taught in perfusion educational programs since their inception.
High pump flows in conjunction with vertical CPB reservoir outlets may cause vortexing of air into the systemic
flow line. Newer model reservoirs with angled or horizontal outlets are less prone to this condition.
The arterial roller pump head tubing may rupture, causing arterial air embolism. Cases of electrical malfunction of
the arterial pump (roller and centrifugal) were previously mentioned; in some circumstances the malfunctioning
pump can spontaneously accelerate to a high speed, drawing air into the CPB systemic flow line. Less dramatic,
but just as dangerous, the arterial roller pump may rotate slowly before or after CPB and may be unnoticed by
the perfusionist, leading to emptying of the reservoir and subsequent air embolism. If the arterial pump is not
operating, a second roller pump for blood cardioplegia can draw air into both the cardioplegia delivery circuit and
the arterial line.
Accidental disconnects, punctures, cuts, or openings, such as stopcocks left open to atmosphere, in the arterial
line can cause air embolism depending on flow conditions. Generally, such disruptions will cause blood loss from
the circuit, but under low CPB systemic flow conditions air may enter the arterial line (169,170). Centrifugal
pumps, when connected directly to the patient’s venous system, can draw air into the CPB circuit if intravenous
lines are open to atmosphere. Breaks in the integrity of the CPB arterial line are especially favorable for air entry
if they occur on the negative (inlet) side of the pump. Strictures in the arterial line on the positive side from kinks,
application of clamps, or excessive flows through small-diameter connectors or cannulas can produce air
embolism from cavitation effects (171).
The oxygenator or venous or cardiotomy reservoir may become pressurized and transmit air into blood lines
connected to the patient if ports designed to vent them to atmosphere become occluded (172,173). The current
popularity of vacuum-assisted venous return has the potential for pressurizing the cardiotomy reservoir if vacuum
is not maintained and the pump suction or vent pumps continue to operate. Vacuum-assisted venous drainage
also has the potential to deprime the arterial line filter or oxygenator if vacuum is applied before establishing
CPB. A pressurized cardiotomy reservoir may transmit air retrograde to the patient’s heart via the vent line or to
the arterial filter if the purge line is connected to the reservoir and a one-way valve is not incorporated into
P.585
the purge line. Retrograde venous air embolism from bubble oxygenators due to blockage of the gas scavenging
line was described by Wells and Stiles (174) and confirmed by others (175,176). Alternatively, if the gas phase of
either a silicone rubber or microporous membrane oxygenator becomes pressurized above blood phase
pressure, ventilating gas can enter the arterial line through the membrane material.
Anesthetic Air
The risk of air embolism in the course of anesthetic management of patients undergoing open-heart surgery most
commonly occurs with intravenous or monitoring lines. Despite controversy regarding the risk of small quantities
of venous air, cases of fatal air embolism during neurosurgical procedures with patients in the sitting position
were reported as early as 1902 (175). During animal experiments, Goodridge (177) sought to dispel the earlier
report by Hare (178) that venous air embolism was innocuous. He concluded (177) “I would say that I believe the
statement, ‘that large quantities of air may be introduced into the veins without unfavorable results’ to be
pernicious teaching and not supported by fact.”
Inappropriate ventilation of the patient during insertion of CPB cannulas or a left atrial monitoring line can cause
air embolism. Expanding the lungs fully to displace pulmonary venous air is an important adjunct to surgical de-
airing maneuvers; if not performed properly, air may be retained and later embolize to the systemic circulation.
The risk of greater than 50% nitrous oxide ventilation in promoting bubble growth has been reported by several
authors (179,180,181,182) and was reviewed by Munson (183). Wells et al. (184) found increased cerebrospinal
fluid markers indicative of cerebral ischemia when nitrous oxide anesthesia was used in conjunction with bubble
oxygenation. Conventional wisdom is that nitrous oxide should be avoided from the time of cannulation for CPB
until emergence from CPB. Many would also advise its avoidance after CPB, because the likelihood of some
intravascular air is relatively high, especially in procedures where the heart has been opened.
Treatment of Air Embolism

Peirce (185) wrote that treatment of iatrogenic air embolism has not kept pace with other medical knowledge,
perhaps because it is a rare and frequently unrecognized complication. Intraoperative treatment for air embolism
in open-heart surgical patients is unique when compared with other medical procedures where air embolism may
occur. If coronary air embolism results in myocardial dysfunction, the circulatory needs of the patient can be met
by the CPB circuit. Systemic heparinization, a requisite for CPB, has been shown to be of benefit in reducing
interactions of bubbles with blood but may be deleterious if brain infarction has occurred (186). Hemodilution to
levels commonly used during CPB will reduce blood viscosity and improve tissue perfusion when air embolism
occurs. With the chest open, the surgeon is able to aspirate air directly from the heart chambers or vessels.
Venting, induction of hypothermia (187,188), retrograde coronary sinus (189,190) or cerebral perfusion, or direct
cardiac massage are all useful if air embolism occurs during the open-heart operation. If right coronary artery air
embolism is suspected (isolated acute ST segment elevation in the inferior ECG leads is highly suggestive), the
surgeon can transiently raise the pressure in the proximal aorta by gently pinching the aorta distal to the arterial
cannula with the left hand while using the index finger of the other hand to assess proximal aortic pressure. The
transiently increased aortic pressure will push intracoronary air bubbles through the coronary circulation, which
often can be seen if significant right coronary air embolism has occurred. This maneuver should be tried in all
patients before implementing intraaortic balloon counterpulsation when there is difficulty encountered in weaning
from CPB.
Drug or fluid therapy by the anesthesiologist also may be instituted immediately via the CPB circuit. Packing the
patient’s head in ice will decrease cerebral metabolism and may be beneficial (191). Ventilating the patient with
100% oxygen favors bubble resolution and can limit cerebral ischemia (192). If air embolism occurs before or
after CPB, conventional means of treatment can immediately be used such as positioning the patient head-down
and turning the patient into the left lateral recumbent position (193,194) or instituting cardiopulmonary
resuscitation (195).
The source of air must be determined and promptly interrupted to prevent further transmission of air into the
patient. If the source of air is the CPB systemic flow line, then CPB should be stopped immediately (196). The
arterial and venous lines should be clamped to prevent additional embolization or exsanguination. After
confirming sufficient volume in the CPB reservoir, air in the arterial line should be purged out by aspirating with a
large syringe or refilling the line using the systemic pump. If a pressurized reservoir or CPB component is the
source, the pressure should be relieved before releasing clamps on lines directly connected to the patient.
If air has filled the aorta, the arterial line can be disconnected from the arterial cannula. After clamping the
venous cannula(s) and disconnecting the venous line, the arterial line and venous line are joined so perfusate
can be quickly recirculated back to the CPB reservoir to remove the air. Once cleared of air, the lines are
reconnected to the appropriate cannulas and CPB may be resumed. If air has not reached the arterial line filter, it
can be vented out the purge line by slowly advancing flow with the systemic pump. Air can be removed from a
centrifugal pump by detaching it from the console and positioning the pump head outlet uppermost to take
advantage of buoyancy effects; with the pump head de-aired, recirculation or resumption of CPB can then be
accomplished. Air may be removed from the membrane oxygenator by recirculating at high flow via the
membrane recirculation line. Tapping and inverting components, as is performed during initial priming,
P.586
may be required to effectively remove CPB air. If the arterial filter has been filled with air, it may be necessary to
clamp the filter out of the circuit and use an arterial filter bypass line to quickly reestablish CPB blood flow.
Alarms to detect air embolism often must be turned off to reestablish CPB systemic flow but then should be
reengaged after the patient is safely back on bypass.
Placing the patient in the Trendelenburg position after air embolism is common practice but may not aid in bubble
removal from cerebral vessels deep within the brain. Butler et al. (197) studied the distribution of carotid artery
injections of air (0.5-1.0 mL) in dogs placed in 0° to 30° Trendelenburg position. They concluded that regardless
of the position, if the heart was ejecting blood, bubbles would not be retarded in their distribution into the brain. In
additional in vitro studies in the same report using a simulated carotid artery, the authors verified that the
buoyant properties of the bubbles were not sufficient to prevent the blood from carrying bubbles in the direction
of flow. They did suggest, however, that in conditions of circulatory arrest or extremely low flow, bubbles would
have a propensity to rise in stagnated blood.
Mehlhorn et al. (198) studied the effects of body repositioning on the hemodynamic response to large infusions
of venous air (2.5 mL/kg at a rate of 5 mL/sec) in dogs. Testing the supine, left lateral recumbent (Durant’s
maneuver), left lateral recumbent with 10° head-down, or right lateral recumbent positions, they found no
significant differences among the various body positions in terms of heart rate, blood pressure, pulmonary artery,
central venous, or left ventricular end-diastolic pressures, or cardiac output. There also were no significant
differences in recovery times regardless of body position.
If large quantities of air are suspected of having entered the cerebral vessels, retrograde cerebral perfusion, as
first described by Mills and Ochsner (101), may be used with remarkable results. There are a number of case
reports now in the literature (199,200,201,202,203,204,205,206,207) confirming the benefit of this technique, as
well as anecdotal information from survey respondents. The fact that retrograde cerebral perfusion has been
used electively during aortic arch surgery may facilitate implementation of this method under emergency
condition. Table 24.4 outlines steps to perform retrograde cerebral perfusion for massive air embolism.
Drug therapy for arterial air embolism is aimed first at raising the arterial blood pressure to force bubbles through
tissue vasculature to the venous side of the circulation (208). Corticosteroids, diuretics, antiplatelet agents,
anticonvulsants, and barbiturates have been advocated to decrease cerebral manifestations of ischemic injury
due to air embolism. Lidocaine pretreatment has been shown to be beneficial in an experimental setting (209).
Surface tension-reducing agents have been proposed (210,211,212). The use of perfluorocarbons to enhance
oxygen delivery has also been suggested for treatment of air embolism (213); however, it apparently has not
been used clinically for treatment of air embolism (214). Such agents may also reduce the surface tension at the
bubble-blood interface and would aid in absorption and dissolution of the bubbles (215,216). Speiss et al.
(217,218) studied the protective effects of prophylactically administered perfluorocarbon solutions in
experimental coronary and cerebral air embolism in the laboratory. Treated animals had significantly fewer
dysrhythmias and less decrease in myocardial function when pretreated.
TABLE 24.4. Steps to perform retrograde cerebral perfusion for treatment of massive air
embolism
1. Perfusionist: Stop CPB.
2. Anesthesiologist: Place patient in steep head-down position.
3. Surgeon: Remove aortic cannula from ascending aorta.
4. After purging air and refilling CPB systemic flow line, insert arterial cannula in the SVC above a
point where a vascular clamp can be placed; if bicaval cannulation has been used, the arterial
cannula may be connected to the snared SVC cannula.
5. Begin retrograde perfusion with hypothermia (20°C) at a flow of 1-2 L/min for 1-3 min or until no
more air or froth is seen exiting the opened aorta.
6. Anesthesiologist: Temporarily compress the carotids during the later phase to purge air retrograde
through the vertebral system.
CPB, cardiopulmonary bypass; SVC, superior vena cava.
The patient with known or suspected air embolism should be ventilated with 100% oxygen (219). Ventilation with
nitrous oxide, if it is being used, should be discontinued to decrease the possibility for bubble expansion
(220,221). Hlastala and Van Liew (222) showed that a 2-mm bubble will disappear in approximately 1 hour if the
patient is breathing oxygen; if the patient is not being ventilated and is breathing room air, the same-size bubble
will persist for 9 hours.
Regardless of when air embolism occurs during the intraoperative period, most authors have recommended that
the surgical procedure should be completed. An air embolism incident in the course of an open-heart surgical
procedure can create confusion on the part of various team members. Having a predetermined treatment plan
(196,223) for dealing with this event can be life-saving. Tovar et al. (224) published an excellent review of
management of air embolism. A proposed algorithm from their article is shown in Figure 24.6.
The most effective postoperative treatment for air embolism is compression in a hyperbaric chamber and
ventilation with 100% oxygen (225,226,227,228,229,230,231,232,233,234,235). Although the logistics of moving
a critically ill patient on a ventilator and with invasive monitoring and multiple intravenous lines can be daunting,
treatment in such a facility has been credited for many complete recoveries. Recoveries have been reported
even if such treatment is delayed (236,237). However, it must be recognized that access to a multiplace
hyperbaric chamber may be limited.
P.587
There are only approximately 100 such facilities in the United States, most of which are located on the coastlines
or near large bodies of water and therefore are at great distances from many hospitals performing open-heart
surgery. The patient with suspected air embolism should not be transported by air because reduced air pressure
during flight will cause intravascular bubbles to expand. Brenner (196) suggested that treatment regimens for air
embolism should be continued unless the patient expires or is diagnosed as brain dead. Table 24.5 outlines
management strategies for treatment of air embolism.
FIGURE 24.6. Algorithm for postoperative management of air embolism. (From Tovar EA, DelCampo C, Borsari
A, et al. Postoperative management of cerebral air embolism: gas physiology for surgeons. Ann Thorac Surg
1995;60:1138-1142, with permission.)
Miscellaneous Problems
The CPB circuit or its components may become contaminated by inattention to detail during setup or operation.
The obvious risk of bacterial contamination via the patient’s bloodstream necessitates observing sterile
technique at all stages of use of CPB. Infection after cardiac surgery is an uncommon but serious complication
leading to prolonged duration of mechanical ventilation and intensive care unit stay. One-third of these patients
may die of causes related to infection (238).
The practice of dry preassembly of the CPB circuit is not without risk. The Centers for Disease Control and
Prevention recently reported an investigation into an outbreak of gram-negative bacteremia in nine cardiac
surgery patients at one hospital (239). The source of the infections was found to be caused by housekeeping
personnel inadvertently contaminating uncovered preassembled disposable pressure transducers on the CPB
console with sprayed cleaning water. This complication can be prevented by ensuring that all blood-contacting
surfaces and devices on the CPB circuit are kept covered until time of use. Alternatively, the entire CPB circuit
can be set up just before use to minimize risk of contamination. Hospital-prepared cardioplegic solution may be
the source of contamination by Enterobacter cloacae (240,241) due to defective equipment used by
manufacturing pharmacy personnel. Thus, meticulous attention to quality control, including batch sterility testing
of the cardioplegic solution, will minimize this risk. Alternatively, commercially prepared cardioplegic solutions are
usually subject to more stringent quality controls.
Drug errors by any cardiac surgical team member are relatively common and can lead to adverse outcomes. The
most commonly cited drug-related problem in one survey (95) was overdosage of either a vasodilator or
vasoconstrictor. Although these types of errors may be short-lived and of no clinical consequence, drug errors
related to anticoagulation can be fatal. Protamine administration during CPB can effectively render the
oxygenator, reservoir, and arterial line filter unusable due to development of gross clot. A case of inadvertent
protamine administration instead of heparin has been reported (242). The patient survived, but a massive clot
was found in the oxygenator, a smaller clot in the arterial filter, and
P.588
fibrin strands in the cardiotomy suction tubing. No activated clotting time or heparin assay testing was performed.
The hospital changed their policy to no longer store protamine in the operating room; it is now reportedly not
drawn up until the surgeon requests that protamine be administered.
TABLE 24.5. Intraoperative and postoperative management strategies for treatment of air
embolism
1. Perfusionist: Stop CPB immediately, clamp arterial and venous lines, and notify surgeon and
anesthesiologist.
2. Locate and confirm source of air; if due to pressurized CPB component, isolate component from
patient before relieving pressure.
3. Perfusionist: Purge air from CPB systemic flow line and refill with fluid.
4. Surgeon: Aspirate air (if present) from arterial cannula; if possible, initiate cardiac massage until
CPB is restarted.
5. Anesthesiologist: Place patient in steep head-down position; be prepared to temporarily occlude

carotid arteries.
6. Confirm sufficient volume in CPB reservoir and resume CPB with active aortic root venting.
7. Administer vasopressors to raise perfusion pressure.
8. If suspected cerebral air embolism, cool patient on CPB and consider instituting retrograde
cerebral perfusion; consider packing patient’s head in ice.
9. Anesthesiologist: Ventilate lungs vigorously with 100% oxygen; administer corticosteroids (2-4 g
methylprednisolone and/or 20 mg dexamethasone, and continue for 72-96 hr postoperatively).
10. Administer 25 g mannitol and maintain for 48 hr postoperatively.
11. Aim for early patient arousal and assess for return of normal mentation.
12. Consult a neurologist if central nervous system damage is suspected.
13. Consider computed tomography or magnetic resonance imaging if patient fails to awaken or
develops delayed mental deterioration.
14. Consider hyperbaric oxygen treatment (6 ATA using recommended U.S. Navy dive tables) and
make necessary ground transportation arrangements; repeat hyperbaric therapy as necessary.
15. Do not give up resuscitative efforts unless patient expires or is diagnosed to be brain dead.
CPB, cardiopulmonary bypass; ATA, atmospheres of absolute pressure.
Another serious complication is transfusion of ABO-incompatible bank blood. The manifestation is an acute
hemolytic reaction that can damage the kidneys. Prevention lies in adherence to strict double checking of blood
units against the patient’s identification wristband. Maintenance of urinary output with diuretics, intravenous fluid
support, and administering corticosteroids and cardiotonic drugs has been used with success (243).
The common use of blood surface-treated tubing, which may render the lumen lubricious when compared to
untreated tubing, may predispose accidental disconnects at connector sites on the CPB circuit. Therefore, it is
important to confirm all such connections are secure. Use of tie-bands on high-pressure connections is prudent
to avoid this complication that can lead to blood loss and/or air entry into the CPB circuit.
PATIENT PATHOPHYSIOLOGY
Pregnancy
Although the rate of cardiovascular disease in pregnancy has steadily declined over the past several decades, it
remains a topic of interest because of the high rate of fetal mortality when an operation requiring CPB is needed.
The incidence of all maternal cardiovascular disease during pregnancy is currently about 1.5% (244). The most
frequently performed procedures include closed mitral commissurotomy, open mitral commissurotomy, mitral
valve replacement, and aortic valve replacement. Credit for the first case using CPB in a pregnant patient has
been attributed to Leyse et al. (245) in 1958, with three more cases reported subsequently (246,247). Other
cardiac problems associated with pregnancy in which operation may be necessary are atrial septal defect, patent
ductus arteriosus, ventricular septal defect, and idiopathic hypertrophic subaortic stenosis (248). Because of the
high (and increasing) prevalence of intravenous drug abuse, infectious endocarditis is becoming increasingly
common among cardiovascular diseases in pregnancy.
A number of fundamentals in the physiology of pregnancy affect the timing and use of CPB in the pregnant
patient. The first trimester is the trimester of organogenesis. Therefore, any injury to the developing fetus during
this period may result in teratogenesis. This is particularly true of drugs. An important example is warfarin, a well-
known teratogen. Because of the small size of the warfarin molecule, it can cross the placenta. The neonatal
morbidity and mortality for patients taking warfarin throughout their pregnancy may be 40% or greater. For this
reason, patients undergoing warfarin therapy are often changed to heparin when pregnancy is confirmed. The
large heparin molecule cannot cross the uteroplacental barrier (249). However, the rate of spontaneous abortion
increases with heparin. During the second trimester of pregnancy, the period of organogenesis is finished;
therefore, teratogenesis is not seen. Also, the risk of premature labor is much less than in the third trimester,
when the risk rises significantly. The hypervolemia and anemia of pregnancy also are less in the second
trimester than in the third trimester, as are the hemodynamic demands because of the smaller size of the fetus
and lesser uterine blood flow. These factors may indicate that timing of a schedulable cardiac surgery that
requires CPB, the second trimester of pregnancy may be the preferred time.
Numerous physiologic changes occur during pregnancy. Because there is no autoregulation of uterine blood
flow, nonpulsatile flow during CPB may compromise fetal blood supply. After the 28th to 32nd week of gestation,
the patient’s blood volume increases by 30% to 50%. Heart rate increases
P.589
10% to 15% and stroke volume increases 30% to 35% with an associated 15% decrease in systemic vascular
resistance. During pregnancy, uterine blood flow represents 10% to 15% of the cardiac output, as compared with
only 1% in a nonpregnant female (248).
The lowest risk for CPB surgery is believed to occur during the second trimester, with reported maternal mortality
risk during this time varying from 1.5% to 5% (250,251,252,253). In particular, a survey (244) regarding bypass
surgery on pregnant women revealed only one maternal death in 68 cases. In general, the maternal risk is
probably not increased over that in a nonpregnant patient. Fetal risk, however, is quite high, ranging from 10% to
50% (248,251,252,253,254,255,256,257,258,259). The previously cited survey (244) revealed a 20% fetal
mortality in the same 68 CPB cases.
A closer examination of the causes of fetal risk reveals multiple factors. There are numerous possible causes for
fetal hypoxia. Low CPB systemic flows or hypotension during bypass can result in fetal hypoxia because of the
lack of autoregulation of the uterine blood flow. Low hemoglobin oxygen saturation and possibly the lack of
pulsatile flow, uterine arteriovenous shunts, or uterine arterial spasm may contribute to fetal hypoxia. Hypoxia
may result from particulate or bubble embolization to the uteroplacental bed (258,260). Uterine blood flow also
may be compromised by venous obstruction of the inferior vena cava resulting from improper cannula placement
(261).
Hypoxia is best diagnosed by noting fetal heart rate (FHR) decelerations. The normal FHR is between 120 and
160 beats/min. The FHR may decrease to 80 to 100 beats/min with hypothermia, but an FHR less than 60
beats/min suggests a high probability of life-threatening fetal distress. Acidosis may contribute to fetal
bradycardia. Fetal bradycardia, defined as FHR less than 120 beats/min at normothermia and FHR less than 80
beats/min at hypothermia, may be treated by increasing the CPB systemic flow rate, which usually increases the
heart rate toward normal (257,262,263). However, one problem that may occur is a temporary increase in the
heart rate followed by a heart rate reduction that does not respond to increased flow. For this reason, time on
CPB is a significant factor and should be minimized (252).
The unintended initiation of uterine contractions is a frequent cause of fetal death during CPB (251,252). The
dilution of progesterone during CPB secondary to hemodilution may predispose to the onset of uterine
contractions (257), which can be detected by a tachodynamometer. When the FHR is monitored simultaneously,
the FHR pattern may show late decelerations with each uterine contraction, indicating hypoxia. This usually
indicates that blood flow across the myometrium stops as uterine contraction pressure increases to exceed the
uteroplacental arteriolar pressure. Most uterine contractions resolve after the termination of CPB. Risk of
initiation of uterine contractions does not end, however, with termination of CPB; therefore, it is recommended
that tocodynamometry and FHR monitoring continue for 72 hours postoperatively (256). The rewarming cycle
during bypass is associated with the onset of uterine contractions (256). Uterine contractions are treated with
tocolytic agents (see below). Progesterone may also be useful.
Perfusion problems constitute a potential source of fetal complications. These include nonpulsatile perfusion,
inadequate perfusion pressure, inadequate systemic blood flow, embolic phenomena to uteroplacental
circulation, or alterations in placental blood flow secondary to cannulation. Meffert and Stansel (249) noted an
increase in fetal mortality when mitral valve replacement was performed, as compared with that resulting from
mitral commissurotomy. Those authors believed that this difference resulted from the longer CPB times required
for mitral valve replacement. Fetal mortality rate has been noted to increase with an increase in CPB time in
some reviews (252), yet Weiss et al. (253) could find no correlation between time on CPB and neonatal outcome
in their survey of the literature.
A number of strategies have evolved to avoid complications, and techniques have been devised to reduce the
rate of fetal complications. Because of the marked increase in cardiac output during pregnancy, normal cardiac
output during the third trimester of pregnancy may be 6 L/min; therefore, a perfusion flow of 4 L/min represents
only two-thirds that of the normal flow and could result in fetal hypoperfusion. Using a membrane oxygenator and
an arterial line filter in the CPB circuit minimizes particulate and gaseous emboli. FHR can be adequately
maintained by perfusion at either normothermia or mild hypothermia. In pregnant patients, most authors
recommend systemic pressures ranging from 60 to 75 mm Hg, preferably accomplished with high perfusion flows
rather than with α-adrenergic agonists. FHR monitoring should be used to detect the decreases in heart rate
associated with poor fetal perfusion. Because FHR is correlated with CPB systemic flow, fetal bradycardia
should be treated with an increase in CPB flow rate. Both FHR and uterine activity monitoring should be
maintained for 48 to 72 hours postoperatively. Table 24.6 outlines management strategies for the pregnant
patient.
In the third trimester of pregnancy, particularly because of the increased rate of premature labor, expectant
management of the patient allowing the fetus to stay in utero as long as possible plays an increasing role.
Options may include expectant management of the mother with delivery or cesarean section followed by
maternal cardiac surgery, maternal surgery with the fetus remaining in utero, or simultaneous cesarean section
and maternal cardiac surgery. The approach selected should balance the maturity of the fetus with the severity
of maternal cardiac disease and the risk of labor and delivery with uncorrected cardiac disease. If uteroplacental
insufficiency is present (suggested by fetal bradycardia), delivery of the fetus before CPB should be considered.
Although the exact role is not known, avoidance of CPB altogether by using a closed procedure such as closed
mitral commissurotomy or balloon
P.590
valvuloplasty may be an option in patients at particularly high risk for undergoing CPB.
TABLE 24.6. Management strategies for the pregnant patient
1. If possible, postpone surgery until patient is postpartum.
2. Position patient in left uterine displacement position if gestational age of fetus >20 wk.
3. Monitor fetal heart rate (FHR).
4. Monitor uterine contractile activity.
5. Prime CPB circuit with bank blood if expected mixed patient/circuit hematocrit is <22%-25%.
6. Use CPB systemic flow index of 2.5-3.0 L/min/m2 and be prepared to increase flow if FHR
decreases.
7. Maintain minimum mean arterial pressure 60 mm Hg.
8. Use normothermia or mild hypothermia (32°C); use deep hypothermia and circulatory arrest only
if surgical conditions necessitate.
9. Do not use potassium-based cardioplegia.
10. Be prepared to administer progesterone, β-agonist, or intravenous alcohol if uterine contractions

occur.
11. Minimize CPB time consistent with surgical objective.

12. Have an obstetrician and neonatologist on standby in case cesarean section is required
(gestational age >28 wk).
CPB, cardiopulmonary bypass.
Fetal complications could also be theoretically attributed to nonpulsatile perfusion, hyperoxygenation, or

anticoagulation with heparin. At present, none of these factors has been clearly identified as the cause of fetal
problems. Hypothermia also causes FHR decelerations; therefore, normothermia or mild hypothermia (32°C) is
generally used. However, Buffolo et al. (264) reported use of deep hypothermia with circulatory arrest for aortic
arch surgery with survival of the mother and fetus. Others (258,265) also reported successful cases in which
hypothermia with a period of circulatory arrest was required. Most sources believe that a hematocrit exceeding
22% should be maintained as well as a CPB systemic flow index of 3.0 L/min/m2. To avert the potential effects of
aortocaval compression by the gravid uterus, central cannulation is preferable to femoral arterial or venous
cannulation. Late in pregnancy, the right flank should be elevated to prevent aortocaval compression (249).
When necessary, tocolytic agents are used. At term, the uterus is more responsive to tocolytic agents than it is
earlier in pregnancy (256). A number of tocolytic agents are available. The agent should be chosen because of
its effectiveness and its lack of side effects. A number of tocolytic agents may have cardiovascular side effects,
particularly β-adrenergic agonists such as terbutaline (248,257,266). Ritodrine and magnesium sulfate have
been proven most effective in clinical trials (255). Other approaches include ethanol or a combination of a β-
adrenergic agonist and progesterone (257). Because of limited side effects, magnesium sulfate may be the best
tocolytic agent for pregnant patients undergoing CPB associated with diabetes mellitus or hypertension.
If measures to avoid or treat fetal complications fail and fetal distress occurs, measures must be taken to correct
this problem. If fetal distress can be prevented, fetal mortality will decline. Metabolic acidosis, when present, is
treated with sodium bicarbonate. Glucose is given to replenish decreased fetal glycogen stores, and reduced
arterial or venous hemoglobin oxygen saturations are promptly corrected by increasing oxygenator gas flow,
CPB systemic flow, or hemoglobin concentration as indicated (262). Inotropic or vasopressor agents should be
avoided when other treatments may be substituted. For example, if the patient has lost blood and needs volume
replacement, transfusion would be preferred over vasopressor agents. Epinephrine has been recommended
because of its rapid onset, brief duration, and minimal unwanted side effects at moderate doses. At high doses,
epinephrine predominantly manifests α-adrenergic effects. Because blood flow to the gravid uterus is primarily
under α-adrenergic control, α-adrenergic agonists will decrease uterine blood flow in normotensive pregnant
patients. Drugs that exhibit a combination of α- and β-adrenergic activity are most useful because they increase
maternal blood pressure without reducing uterine blood flow (260,267). Examples of such drugs are ephedrine
and moderate-dose epinephrine. A reduction in uterine blood flow has been seen in animal studies in which
hypotension was treated with dopamine or hypertension was treated with nitroprusside. In addition, nitroprusside
crosses the placenta in animals and may liberate free cyanide ions and cause metabolic acidosis. Large doses of
nitroprusside in gravid ewes uniformly result in maternal and fetal death (250,268).
In summary, CPB during pregnancy is associated with a low rate of maternal complications but a high risk to the
fetus. If possible, bypass surgery should be avoided during pregnancy. If the disease process dictates that
surgery is necessary, the first and third trimester are best avoided to minimize teratogenesis or premature
initiation of uterine contractions and labor, respectively. It appears likely that fetal distress and complications can
be avoided by maintaining a high mean arterial pressure, high CPB systemic flows, normothermia, or mild
hypothermia, by the use of fetal monitoring, and by early treatment of FHR decelerations and uterine
contractions. If fetal distress does become apparent, corrective measures must be taken.
Renal Failure
The effects of CPB on renal function are discussed fully in Chapter 15. However, in patients with preexisting
renal disease, cardiac surgery and CPB present difficulties primarily related to their inability to excrete potassium
and tendency to become fluid overloaded during the perioperative period.
P.591
Secondary problems involve anemia, acidosis, platelet dysfunction, and hypofibrinogenemia, all of which may be
exacerbated by conventional CPB. The patient on chronic hemodialysis may also present with sepsis, bleeding
tendencies, malnutrition, and glucose intolerance.
Hemodialysis can be performed concurrently with CPB and offers benefits over either scavenging hyperkalemic
cardioplegic solution (269) or using conventional hemoconcentration, which is not as effective in removing
potassium. The first case of hemodialysis during CPB has been attributed to Soffer et al. (270) in 1979. The
patient was a 55-year-old with congestive heart failure from aortic insufficiency secondary to infective
endocarditis. The patient had been on maintenance hemodialysis for 10 months before admission for aortic valve
replacement. The CPB circuit was primed with two units of packed red blood cells, fresh frozen plasma (900 mL),
and balanced electrolyte solution (300 mL), which resulted in an initial hematocrit of 30% on CPB. A conventional
hemodialysis machine was connected to the CPB circuit, drawing blood from the venous line and returning it to
the cardiotomy reservoir (flow rate 180 mL/min); the dialysate flow rate was 500 mL/min. Serum potassium
values ranged from 3.2 to 4.3 mEq/L, and the patient did not require hemodialysis again until postoperative day
3.
In 1984, Geronemus and Schneider (271) reported continuous arteriovenous hemodialysis using a hollow-fiber
hemoconcentrator to treat acute renal failure in 10 critically ill patients. Peritoneal dialysis fluid was slowly
pumped (15-20 mL/min) countercurrent to blood flow that relied on the patient’s arterial blood pressure as the
driving force. Because of these low flow rates, the continuous arteriovenous hemodialysis was maintained for
between 23 and 108 hours. They found that advantages included simplicity of the extracorporeal circuit,
hemodynamic stability during treatment, and excellent urea and creatinine clearance. The technique was less
effective in treatment of volume overload with fluid removal rates between 25 and 100 mL/hr.
In 1985, Hakim et al. (272) reported on a series of 26 patients undergoing cardiac surgery, including cardiac
transplantation, who had impaired or absent renal function preoperatively. In five cases, a conventional
hemodialysis machine was used in the operating room by accessing the patient’s circulation via the CPB circuit.
The other 21 had hemodialysis performed using continuous arteriovenous hemodialysis via a shunt in parallel
with the CPB circuit (blood flow 200-300 mL/min). Benefits described were no fluid retention after CPB, no
increase in the serum potassium (average 4.5 mEq/L) or blood urea nitrogen, unlimited ability to use potassium
cardioplegia, and no need for increased heparin dosages to maintain anticoagulation. Murkin et al. (273) also
reported intraoperative hemodialysis in 12 patients with renal failure. All patients underwent conventional
hemodialysis the evening before surgery and had a portable dialysis machine connected to the CPB circuit.
Blood flow was between 150 and 300 mL/min and dialysate flow was 500 mL/min to maintain the serum
potassium at 4.0 mEq/L. Benefits included simplicity and intraoperative control of metabolic changes when other
methods would have been ineffective.
Wheeldon and Bethune (274) published an excellent review of the principles of hemofiltration
(hemoconcentration) and hemodialysis during CPB, including available equipment and suggested circuitry.
Besides providing safe intraoperative management of patients in renal failure, they concluded that hemodialysis
or hemoconcentration was a simple, efficient, and inexpensive method for control of patient blood volume and
blood conservation during CPB. Sutton (275) also reviewed CPB management for patients with renal failure and
provided a useful table listing sieving coefficients of drugs and ions (Table 24.7).
TABLE 24.7. Sieving coefficients for selected drugs and ions
PB (%) PC S
Ions
Ca2+ 45 5.0 mEq/L 0.55
K+ 0 4.4 mEq/L 1.0
Mg2+ 0 2.0 mEq/L 1.0
Drugs
Aprotinin 0 250 KIU/mL 1.0
Bretylium 6 0.63 mg/L 0.94
Digoxin 25 0.0005 mg/L 0.75
Diltiazem 83 0.215 mg/L 0.17
Dobutamine 0 0.025 mg/L 1.0
Fentanyl 71 0.016 mg/L 0.28
Furosemide 95 6.14 mg/L 0.05
Heparin 80 4,821.25 units/L 0.20
Lidocaine 63 1.63 mg/L 0.37
Midazolam 95 0.18 mg/L 0.06
Pancuronium 87 0.20 mg/L 0.13
Vecuronium 70 0.38 mg/L 0.30
Verapamil 90 0.19 mg/L 0.10
The higher the sieving coefficient (S), the more readily ions or drugs will diffuse across the
hemoconcentrator or dialyzer membrane. For an S value of 1.0, solute will freely diffuse across the
membrane. Other factors affecting sieving coefficients include the percent of the ion or drug that is
protein bound, drug membrane interaction, drug charge, molecular size, patient protein concentration,
membrane material, membrane design, and blood flow.
PB, protein bound; PC, plasma concentration; Ca2+, calcium; K+, potassium; Mg2+, magnesium.
From Sutton RG. Renal considerations, dialysis, and ultrafiltration during cardiopulmonary bypass. Int
Anesthesiol Clin 1996;34:165-176, as modified from Clar A, Larson DF. Hemofiltration: determinants of
drug loss and concentration. J Extra Corpor Technol 1995;27:158-163, with permission.
P.592
Other authors (276,277,278,279) reported the benefits of intraoperative hemodialysis when compared with
routine hemodialysis before and after CPB (usually postoperative day 1) to control serum potassium and reverse
fluid overload. A primary benefit appears to be delay of reinstitution of conventional hemodialysis with systemic
heparinization until postoperative day 2 or 3. Hamilton et al. (277) described the use of a hollow-fiber
hemoconcentrator to perform hemodialysis during CPB. They relied on regulated gravity flow of peritoneal
dialysis fluid matched to blood flow (300-500 mL/min) through the hemoconcentrator. For increased removal of
solutes, the dialysate flow can be increased. However, if the serum potassium is low, dialysate flow can be
stopped while maintaining hemoconcentration. If the serum glucose becomes elevated, they recommended using
normal saline as the dialysate. They also noted the importance of careful monitoring of the blood pH and Hco3
values, with sodium bicarbonate administration as necessary. A diagram of hemodialysis using two roller pumps
to control dialysate flow in and out of the hemoconcentrator is shown in Figure 24.7.
FIGURE. 24.7. Circuit for performing hemodialysis with a hollow-fiber hemoconcentrator during cardiopulmonary
bypass. Blood and fluid flow is in direction of arrows, and bold Xs represent placement of tubing clamps. The
arterial filter purge line (top right) is used as a source of blood (estimated flow 150-300 mL/min) through the
hemoconcentrator and is returned to the venous reservoir. Dialysate fluid is drawn from large bag by roller pump
#1 and pumped through the outer chamber of the hemoconcentrator while simultaneously being drawn (roller
pump #2) from the hemoconcentrator effluent port where it is discarded into a collection canister (lower left). The
speed of pump #1 must always be less than the speed of pump #2 to prevent dialysate from crossing hollow
fibers in the hemoconcentrator and entering the bloodstream. For most effective solute removal, blood flow and
dialysate flow should be countercurrent. Increasing the flow of dialysate will increase the rate of removal of
solutes. Frequent laboratory measurements of serum electrolytes, acid-base status, and whole-blood activated
clotting time should be performed when using intraoperative hemodialysis. If hemodialysis is not required,
hemoconcentration alone can be accomplished by stopping pump #1 and using pump #2 to exert a slight
negative pressure in the hemoconcentrator. The volume of fluid collected in excess of that removed by pump #1
from the dialysate bag represents plasma water removed from the patient’s circulation. The volume of removed
fluid or collected dialysate should be monitored continuously when using this technique. If both hemodialysis and
hemoconcentration are not required, both pumps are turned off and blood is simply allowed to shunt through the
hemoconcentrator to avoid stasis.
In summary, the leading cause of death in patients undergoing chronic renal dialysis is cardiovascular disease
(278), and it is estimated that there are in excess of 180,000 patients on hemodialysis for end-stage renal
disease in the United States (280). The risk of morbidity or mortality after coronary artery bypass surgery is only
slightly increased in this patient population (281), and it is likely that more patients with renal failure will require
open-heart surgery in the future. Hemodialysis
P.593
concurrent with CPB can be performed safely using equipment and techniques familiar to perfusionists. Attention
to maintenance of adequate hematocrit, electrolyte and fluid balance, and control of hemodynamics during
hemodialysis on CPB are important for successful patient outcome.
Malignant Hyperthermia
Malignant hyperthermia is a syndrome of acute hyperthermia (core temperatures may exceed 42°C) and/or
myotonic reactions initiated by a hypermetabolic state of skeletal muscle. This syndrome can be triggered by
administration of potent inhalation anesthetics (e.g., halothane, sevoflurane, and isoflurane) and depolarizing
skeletal muscle relaxants such as succinylcholine. The syndrome was originally described in 1962 (282). The
incidence is approximately 1 in 15,000 children and 1 in 50,000 adults. Early on, management of patients with
malignant hyperthermia consisted of copious amounts of chilled intravenous Ringer’s lactate solution, lavage of
stomach and bladder with iced solutions, and large doses of procainamide or procaine (283). Currently,
dantrolene sodium from 1 to 10 mg/kg is the treatment of choice, along with some of the active cooling measures
listed above. Unlike previous pharmacologic measures (e.g., procainamide), dantrolene specifically addresses
the causative mechanism, which is impaired reuptake of ionized calcium from the cytosol into storage sites
located in the sarcoplasmic reticulum of skeletal muscle myocytes. Before the introduction of dantrolene,
mortality was greater than 60% (284). Before dantrolene was available, CPB had been used unsuccessfully and
later successfully as a method of controlled cooling in the treatment of malignant hyperthermia (285).
Byrick et al. (286) described the anesthetic management of a patient with biopsy-proven malignant hyperthermia
who underwent coronary artery bypass grafting. Measures included pretreatment with dantrolene, removal of the
halothane vaporizer from the oxygenator-inspired gas pathway, and the use of high-dose fentanyl for anesthesia
and pancuronium for muscle relaxation. Cold potassium (10 mEq/L) cardioplegia was used; inotropic agents and
calcium (possible trigger agent) were avoided. The patient continued to receive dantrolene every 6 hours for 24
hours after the operation. No evidence of malignant hyperthermia was encountered. Other authors (287) used
similar management strategies with success, the common theme of which is avoidance of trigger agents.
Pretreatment with dantrolene is no longer recommended.
The diagnosis of malignant hyperthermia may be complicated or delayed by the coincidental use of CPB and
may require an increased index of suspicion. Cases in which malignant hyperthermia occurred while on CPB
have been reported (288,289). Both patients were successfully treated with a single dose of dantrolene (1
mg/kg). Early recognition and treatment of malignant hyperthermia is important because the marked
hypermetabolism may exceed the oxygen delivery capacity of the oxygenator, especially at normothermia. During
CPB, unexpected hyperthermia or temperature rises and unexplained metabolic and respiratory acidosis would
provide the most likely clues to the diagnosis. When suspected, it appears sensible to induce or maintain CPB
hypothermia while awaiting dantrolene-induced resolution of the clinical syndrome. Repeated doses of
dantrolene may be required. Dantrolene is known to cause skeletal muscle weakness and causes myocardial
depression in animals; caution is advised in its use in cardiac patients (286,287). Schwartz and Hensley (290)
presented two cases and reviewed the physiologic basis and clinical diagnosis of this rare complication.
Advanced Age
There is no specific contraindication for CPB in the elderly patient, and several reports demonstrated successful
outcomes for coronary artery bypass surgery in octogenarians (291,292,293). Coronary bypass surgery has
even been performed in a 100-year-old patient for unstable angina with favorable outcome for 3 years after
surgery. Others reported a low incidence of cardiac-related mortality in patients after coronary bypass or valve
replacement surgery (294). However, the risk of morbidity or mortality is increased in the elderly patient
population (295).
Rady et al. (296) statistically determined perioperative predictors of morbidity and mortality in elderly patients
(defined as age older than 75 years) having surgery with CPB. They reviewed the records of 1,157 patients who
had cardiac surgery within a 30-month period at one hospital (14% of total caseload during the same time frame)
and found that predictors of postoperative morbidity were: preoperative intraaortic balloon; preoperative serum
bilirubin of more than 1.0 mg/dL; blood transfusion with more than 10 units of packed red blood cells; CPB time
more than 120 minutes (aortic cross-clamp time greater than 80 minutes); return to operating room for surgical
exploration; heart rate more than 120 beats/min; use of inotropes or vasopressors after CPB and upon admission
to the intensive care unit; and anemia beyond postoperative day 2. Predictors of mortality ( n = 90/1,157 or 8%)
were similar and included: preoperative cardiogenic shock; serum albumin less than 4.0 g/dL; systemic oxygen
delivery less than 320 mL/min/m2 before surgery; blood transfusion more than 10 units; CPB time more than 140
minutes (aortic cross-clamp time more than 120 minutes); return to operating room for surgical exploration; mean
arterial pressure less than 60 mm Hg; heart rate more than 120 beats/min; central venous pressure more than 15
mm Hg; stroke volume index less than 30 mL/min/m2; requirement for inotropes; arterial bicarbonate less than 20
mmol/L; plasma glucose more than 300 mg/dL after surgery; and anemia beyond postoperative day 2.
The decision to operate on the elderly patient should consider these findings. Maintenance of higher-than-
normal CPB perfusion pressure (e.g., minimum 70 mm Hg), having a lower target threshold for administration of
blood products, and minimizing CPB time may address several of the risk
P.594
factors outlined above. In addition, the carotid arteries of all patients over 75 years of age should be checked
preoperatively by noninvasive examination. For the cachectic patient, an immunologist can perform an anergy
skin test battery (tetanus toxoid, diphtheria toxoid, Streptococcus, old tuberculin, Candida, Trichophyton, and
Proteus), which can be used to screen those patients who would benefit from nutritional therapy before their
surgery (297). Those patients determined to be anergic will have a high incidence of morbidity and mortality
associated with open-heart surgery.
Morbid Obesity
The obese patient may be at a slightly increased risk of superficial wound complications or atrial dysrhythmias,
but obesity per se is not a risk factor for adverse outcome after cardiac surgery (298). The standard criteria for
CPB systemic flow indices based on body surface area may be safely lowered to 1.8 to 2.0 L/min/m2 to avoid
very high CPB flows (299), provided acceptable metabolic parameters are maintained. Occasionally, there may
be difficulties in achieving adequate venous drainage in the obese patient (300); these problems can be
overcome by use of assisted venous drainage methods (see Chapter 19). In the occasional morbidly obese
patient, perhaps especially one who is also quite tall, the gas exchange capacity of the oxygenator may prove
marginal at normothermia. If this problem develops, possible approaches include deepening anesthesia, cooling
the patient, and using two oxygenators in parallel.
Cirrhosis
Klemperer et al. (301) showed that patients with noncardiac liver cirrhosis (Child class A) tolerate CPB and
cardiac surgery with only minor morbidity. However, with moderate-to-advanced cirrhosis, morbidity and mortality
are markedly high (80% mortality). All patients in their series ( n = 13) had chest tube drainage and requirement
for blood transfusion at a rate three times higher than patients without liver disease. Because the liver produces
most coagulation factors but also clears activated factors and fibrinolytic components from the circulation (302),
bleeding after CPB is the major concern in this patient population. Patients with liver disease also frequently
have reduced platelet numbers and function (303) and increased fibrinolysis secondary to low-grade
disseminated intravascular coagulopathy (304), which may be aggravated by the hematologic derangement
inherent with CPB. Because of the high risk of morbidity in the patient presenting for cardiac surgery with chronic
active hepatitis, a liver biopsy should be performed. If white blood cells are found, elective surgery should be
postponed until the infection is controlled.
CONCLUSIONS
An unanticipated perfusion mishap or the unusual or unappreciated patient condition can turn a routine CPB
case into a challenge that will tax even the most experienced practitioners. Although statistically the current
risk of patient serious injury or death directly related to CPB has been reduced to levels of a fraction of 1%
and are certainly less than the risk of untreated heart disease in most cases, perfusion safety should
continue to be a guiding principle whenever CPB is used (305,306). For the team that experiences an
adverse patient outcome, reexamination of practices can yield rewards for future patients. A systematic
approach to how CPB is performed may eliminate inherent potential errors that will occur, no matter how
diligent the team is.
Newer CPB technology will undoubtedly continue to evolve. If device or equipment failure or fluids
administered to the patient on CPB are suspected as contributory to an adverse patient outcome, they
should be sequestered in a secure area for later examination. Like other endeavors that rely on complex
tightly coupled technologies (307), CPB accidents more often result from operator error than from device
failure. This chapter was written in the hope that awareness and communication of past failures will educate
dedicated clinicians in avoiding their repetition.
KEY Points
To reduce the incidence of stroke after CPB in the patients with severe atherosclerosis of the ascending
aorta, transesophageal echocardiographic visualization of the aortic lumen, alternative cannulation sites
and techniques, bilateral proximal carotid compression during surgical manipulation of the aorta, electrical
fibrillation or β-adrenergic blockers for myocardial protection, and no-touch techniques should be
considered.
All patients undergoing hypothermic CPB should be screened for cold agglutinins.
Patients found to exhibit low titer (e.g., less than 1:32), low thermal amplitude (e.g., <22°C), or cold
agglutinins and who are clinically asymptomatic can tolerate CPB with moderate hypothermia.
Patients with high thermal amplitude and/or titer (e.g., more than 1:128) with clinical symptoms of cold
agglutinins require that the temperature be maintained above the thermal amplitude; additionally, warm
crystalloid cardioplegia (followed by cold with insulation of the heart from adjacent structures) may
prevent activation of cold agglutinins.
Sickle cell disease is a homozygous gene recessive abnormality characterized by a predominance of
hemoglobin S; sickled cells have a limited capacity to load and unload oxygen, exhibit increased osmotic
and mechanical fragility, increase blood viscosity, and can cause vascular occlusion.
P.595
Sickle cell trait is a heterozygous recessive abnormality in which hemoglobin S comprises 20% to 40% of
the total hemoglobin.
Tendency for sickling occurs with hypoperfusion, hypoxemia, acidosis, increased concentrations of 2,3-
diphosphoglyceric acid, infection, hypothermia, and capillary stagnation.
Exchange transfusion before or with the initiation of CPB should raise the hemoglobin A fraction more
than 60% to decrease the risk of sickling, which will minimize hemolysis and prevent vaso-occlusive
phenomenon.
Acute methemoglobinemia is most often induced by chemicals or drugs and is diagnosed when cyanosis
or oxygen desaturation (chocolate-brown-colored blood) occurs despite an adequate arterial oxygen
tension.
The most effective treatment of methemoglobinemia consists of methylene blue administration (1-2.5
mg/kg); additionally, the oxygenator should be ventilated with 100% oxygen and high CPB systemic flows
should be used.
Patients with polycythemia may be hemodiluted to normal CPB levels by either removal of blood before
bypass or using larger volumes of crystalloid solution in the CPB prime.
Jehovah’s Witness patients may safely undergo CPB by minimizing circuit prime and fluid administration,
use of cell salvage and hemoconcentration, and return of residual perfusate after bypass while
maintaining continuity between removed blood and the patient to accommodate the patient’s religious
beliefs.
Reoperative patients may require alternative cannulation sites and augmented venous drainage
techniques to adequately establish CPB.
Acute aortic dissection should be suspected if the CPB arterial line pressure unexpectedly increases and
there is a simultaneous decrease in systemic pressure and/or venous drainage.
Venous or arterial air embolism may occur from improper operation of CPB, surgical technique, or
through intravenous lines.
Systemic air embolism carries a greater risk than venous air embolism because of the potential for
cerebral involvement.
Air embolism originating from CPB may enter the patient’s systemic circulation from the arterial line or by
other mechanisms such as improperly operated vents, cardioplegia delivery, or vacuum-assisted venous
drainage or from pressurized CPB components.
Improperly de-aired intravenous lines or inappropriate ventilation of the patient during insertion of
cannulas or vents or during surgical de-airing maneuvers can result in air embolism.
If massive air embolism from the CPB circuit occurs, bypass should be stopped immediately, the source
of air determined, and efforts made to remove the air from the circuit and patient’s vasculature.
Retrograde cerebral perfusion may be an effective treatment if significant air is suspected to have
entered the patient’s cerebral circulation.
The sterility of preassembled CPB circuits must be maintained by ensuring that all blood-contacting
surfaces and components are kept secure and covered until time of use.
CPB in the pregnant patient is associated with a low risk of maternal complications but a high risk to the
fetus, particularly during the first and third trimesters when teratogenesis or premature initiation of uterine
contractions may occur.
Maintenance of mean arterial pressures more than 60 mm Hg, CPB flow indices of 2.5 to 3.0 L/min/m2,
normothermia or mild hypothermia, avoidance of potassium-based cardioplegia, use of FHR monitoring,
and prompt treatment of uterine contractions with tocolytic agents can minimize complications in the
mother and fetus.
Hemodialysis during CPB for patients with renal failure can be performed using a hemoconcentrator to
lower elevated serum potassium, remove excess fluid, and delay reinstitution of maintenance
hemodialysis until postoperative day 2 or 3.
Malignant hyperthermia may be suspected during CPB in the patient who exhibits unexpected
temperature rises and unexplained metabolic and respiratory acidosis; it is treated with dantrolene (1-2.5
mg/kg).
REFERENCES
1. Roach GW, Kanchuger M, Mangano CM, et al. Adverse cerebral outcomes after coronary bypass surgery.
N Engl J Med 1996;335:1857-1863.
2. Mills NL, Everson CT. Atherosclerosis of the ascending aorta and coronary artery bypass: pathology,
clinical correlates, and operative management. J Thorac Cardiovasc Surg 1991;102:546-553.
3. Olearchyk AS. Case report: calcified ascending aorta and coronary artery disease. Ann Thorac Surg
1994;59:1013-1015.
4. Sabik JF, Lytle BW, McCarthy PM, et al. Axillary artery: an alternative site of arterial cannulation for
patients with extensive aortic and peripheral vascular disease. J Thorac Cardiovasc Surg 1995;109:885-891.
P.596
5. Groom RC, Hill AG, Kuban B, et al. Aortic cannula velocimetry. Perfusion 1995;10:183-188.
6. Tanaka T, Kawamura T, Ohara K, et al. Transapical aortic perfusion with a double-barreled cannula. Ann
Thorac Surg 1978;25:209-214.
7. Liddicoat JR, Doty JR, Stuart RS. Case report: management of the atherosclerotic ascending aorta with
endoaortic occlusion. Ann Thorac Surg 1998;65:1133-1135.
8. Reichenspurner HH, Navia J, Berry G, et al. Particulate embolic capture by an intra-aortic filter device
during cardiac surgery. J Thorac Cardiovasc Surg 2000;119:233-241.
9. Kumar P, Dhital K, Hossein-Nia M, et al. S-100 protein release in a range of cardiothoracic surgical
procedures. J Thorac Cardiovasc Surg 1997;113:953-954.
10. Moore RA, Geller EA, Mathews ES, et al. The effect of hypothermic cardiopulmonary bypass on patients
with low-titer, nonspecific cold agglutinins. Ann Thorac Surg 1984;37:233-238.
11. Lee M-C, Chang C-H, Hsieh M-J. Use of a total wash-out method in an openheart operation. Ann Thorac
Surg 1989;47:57-58.
12. Pruzanski W, Shumak KH. Biologic activity of cold-reacting autoantibodies, Part 2. N Engl J Med
1977;297:583-589.
13. Dake SB, Johnston MFM, Brueggeman P, et al. Detection of cold hemagglutination in a blood
cardioplegia unit before systemic cooling of a patient with unsuspected cold agglutinin disease. Ann Thorac
Surg 1989;47: 314-315.
14. Fischer GD, Claypoole V, Collard CD. Increased line pressures in the retrograde blood cardioplegia line:
an unusual presentation of cold agglutinins during cardiopulmonary bypass. Anesth Analg 1997;84:454-456.
15. Leach AB, Van Hasselt GL, Edwards JC. Cold agglutinins and deep hypothermia. Anaesthesia
1983;38:140-143.
16. Pruzanski W, Shumak KH. Biologic activity of cold-reacting autoantibodies, Part 1. N Engl J Med
1977;297:538-542.
17. Shahian DM, Wallach SR, Bern MM. Open-heart surgery in patients with cold-reactive proteins. Surg
Clin North Am 1985;65:315-322.
18. Schreiber AD, Herskovitz BS, Goldwein M. Low-titer cold-hemagglutinin disease: mechanism of
hemolysis and response to corticosteroids. N Engl J Med 1977;296:1490-1494.
19. Berreklouw E, Moulijin AC, Pegels JG, et al. Myocardial protection with cold cardioplegia in a patient with
cold autoagglutinins and hemolysins. Ann Thorac Surg 1982;33:521-522.
20. Klein HG, Faltz LL, McIntosh CL, et al. Surgical hypothermia in a patient with a cold agglutinin.
Transfusion 1980;20:354-357.
21. Williams AC. Cold agglutinins: cause for concern? Anaesthesia 1980;35: 887-889.
22. Diaz JH, Cooper ES, Ochsner JL. Cardiac surgery in patients with cold autoimmune diseases. Anesth
Analg 1984;63:349-352.
23. Agarwal SK, Ghosh PK, Gupta D. Collective review: cardiac surgery and cold-reactive proteins. Ann
Thorac Surg 1995;60:1143-1150.
24. Landymore R, Isom W, Barlam B. Management of patients with cold agglutinins who require open-heart
surgery. Can J Surg 1983;26:79-80.
25. Holman WL, Smith SH, Edwards R, et al. Agglutination of blood cardioplegia by cold-reacting
autoantibodies. Ann Thorac Surg 1991;51:833-836.
26. Paccagnella A, Simini G, Nieri A, et al. Cardiopulmonary bypass and cold agglutinin [Letter]. J Thorac
Cardiovasc Surg 1988;95:543.
27. Blomback M, Kronlund P, Aberg B, et al. Pathologic fibrin formation and cold-induced clotting of
membrane oxygenators during cardiopulmonary bypass. J Cardiothorac Vasc Anesth 1995;9:34-43.
28. Dove SK, Raskin SA, Lawson DS. Cold agglutinins and hypothermic cardiopulmonary bypass. Perfusion
1992;7:3-6.
29. Szentpetery S, Robertson L, Lower RR. Complete repair of tetralogy associated with sickle cell anemia
and G-6-PD deficiency. J Thorac Cardiovasc Surg 1976;72:276-279.
30. Hebbel RP. Beyond hemoglobin polymerization: the red blood cell membrane and sickle disease
pathophysiology [Review]. Blood 1991;77:214-237.
31. Ballas SK, Mahandas N. Pathophysiology of vaso-occlusion. Hematol Oncol Clin North Am
1996;10:1221-1239.
32. Setty BNY, Stuart MJ. Vascular cell adhesion molecule-1 is involved in mediating hypoxia-induced sickle
red blood cell adherence to endothelium: potential role in sickle cell disease. Blood 1996;88:2311-2320.
33. Chun PKC, Flannery EP, Bowen TE. Open-heart surgery in patients with hematologic disorders. Am
Heart J 1983;105:835-842.
34. Fox MA, Abbott TR. Hypothermic cardiopulmonary bypass in a patient with sickle-cell trait. Anaesthesia
1984;39:1121-1123.
35. Ingram CT, Floyd JB, Santora AH. Aortic and mitral valve replacement after sickle cell crisis [Letter].
Anesth Analg 1982;61:802-803.
36. Yacoub MH, Baron J, Et-Etr A, et al. Aortic homograft replacement of the mitral valve in sickle cell trait. J
37. Craenen J, Kilman J, Hosier DM, et al. Mitral valve replacement in a child with sickle cell anemia. J
38. Heiner M, Teasdale SJ, David T, et al. Aortocoronary bypass in a patient with sickle cell trait. Can
Anaesth Soc J 1979;26:428-434.
39. Riethmuller R, Grundy EM, Radley-Smith R. Open heart surgery in a patient with homozygous sickle cell
disease. Anaesthesia 1982;37:324-327.
40. Baxter MRN, Bevan JC, Esseltine DW, et al. The management of two pediatric patients with sickle cell
trait and sickle cell disease during cardiopulmonary bypass. J Cardiothorac Anesth 1989;3:477-480.
41. Balasundaram MS, Duran CG, Al-Halees Z, et al. Cardiopulmonary bypass in sickle cell anaemia: report
of five cases. J Cardiovasc Surg 1991;32:271-274.
42. Pagani FD, Polito RJ, Bolling SF. Case report: mitral valve reconstruction in sickle cell disease. Ann
Thorac Surg 1996;61:1841-1843.
43. Kingsley CP, Chronister T, Cohen DJ, et al. Case conference. Case 2-1996, anesthetic management of a
patient with hemoglobin SS disease and mitral insufficiency for mitral valve repair. J Cardiothorac Vasc
Anesth 1996;10:419-424.
44. Shulman G, McQuitty C, Vertrees RA, et al. Case report: acute normovolemic red cell exchange for
cardiopulmonary bypass in sickle cell disease. Ann Thorac Surg 1998;65:1444-1446.
45. Yung GL, Channick RN, Fedullo PF, et al. Successful pulmonary thromboendarterectomy in two patients
with sickle cell disease. Am J Respir Crit Care Med 1998;157:1690-1693.
46. Longenecker VW, Hartley MB, Dingmann M, et al. Cardiopulmonary bypass in the sickle cell anemia
patient using profound hypothermia and circulatory arrest: a case report. J Extra Corpor Technol
1998;30:135-139.
47. Moyes DG, Holloway AM, Hutton WS. Correction of Fallot’s tetralogy in a patient suffering from
hereditary spherocytosis. S Afr Med J 1974;48: 1535-1536.
48. Gayyed NL, Bouboulis N, Holden MP. Open heart operation in patients suffering from hereditary
spherocytocis. Ann Thorac Surg 1993;55:1497-1500.
49. Dal A, Kumar RS. Open heart surgery in presence of hereditary spherocytosis. J Cardiovasc Surg
1995;36:447-448.
50. deLeval MR, Taswell HF, Bowie EJW, et al. Open heart surgery in patients with inherited
hemoglobinopathies, red cell dyscrasias and coagulopathies. Arch Surg 1974;109:618-622.
51. Mansouri A. Methemoglobinemia [Review]. Am J Med Sci 1985;289:200-209.
52. Hedlund KD, Sanford DM, Coyne DP. Methemoglobinemia during cardiopulmonary bypass? A case
report and review. Proc Am Acad Cardiovasc Perfus 1987;8:232-235.
53. Robicsek F. Acute methemoglobinemia during cardiopulmonary bypass caused by intravenous
nitroglycerin infusion. J Thorac Cardiovasc Surg 1985;90:931-933.
54. Bojar RM, Rastegar H, Payne DD, et al. Methemoglobinemia from intravenous nitroglycerin: a word of
caution. Ann Thorac Surg 1987;43:332-334.
55. Zurick AM, Wagner RH, Starr NJ, et al. Intravenous nitroglycerin, methemoglobinemia, and respiratory
distress in a postoperative cardiac surgical patient. Anesthesiology 1984;61:464-466.
56. Jackson SH, Barker SJ. Case reports: methemoglobinemia in a patient receiving flutamide.
57. Cooper JR, Keats AS. Methemoglobinemia diagnosed as a consequence of cardiopulmonary bypass.
Tex Heart Inst J 1985;12:103-106.
58. Armstrong D, Schmalfuss V, Reed CC, et al. A case study: methemoglobinemia during cardiopulmonary
bypass. Proc Am Acad Cardiovasc Perfus 1985;6:179-181.
59. Kastrup EK. Antidotes. In: Kastrup EK, ed. Drug facts and comparisons. St. Louis, MO: J.B. Lippincott,
1986:2012-2013.
60. Milam JD, Austin SF, Nihill MR, et al. Use of sufficient hemodilution to prevent coagulopathies following
surgical correction of cyanotic heart disease. J Thorac Cardiovasc Surg 1985;89:623-629.
61. Ware JA, Reaves WH, Horak JK, et al. Defective platelet aggregation in patients undergoing surgical
repair of cyanotic congenital heart disease. Ann Thorac Surg 1983;36:289-294.
62. Dyke C, Sobel M. The management of coagulation problems in the surgical patient. Adv Surg
1991;24:229-257.
63. Stein JI, Gombotz H, Rigler B, et al. Open heart surgery in children of Jehovah’s Witness: extreme
hemodilution on cardiopulmonary bypass. Pediatr Cardiol 1991;12:170-174.
P.597
64. Cooley DA, Crawford ES, Howell JF, et al. Open heart surgery in Jehovah’s Witnesses. Am J Cardiol
1964;13:779-781.
65. Ott DA, Cooley DA. Cardiovascular surgery in Jehovah’s Witnesses: report of 542 operations without
blood transfusion. JAMA 1977;238:1256-1258.
66. Tsang VT, Mullaly RJ, Ragg PG, et al. Bloodless open-heart surgery in infants and children. Perfusion
1994;9:257-263.
67. Van Son JAM, Hovaguimian H, Rao IM, et al. Strategies for repair of congenital heart defects in infants
without the use of blood. Ann Thorac Surg 1995;59:384-388.
68. St. Rammos K, Bakas AJ, Panagopoulos FG. Mitral valve replacement in a Jehovah’s Witness with
dextrocardia and situs solitus. J Heart Valve Dis 1996;5:673-674.
69. Malan TP Jr, Whitmore J, Maddi R. Reoperative cardiac surgery in a Jehovah’s Witness: role of
continuous cell salvage and in-line reinfusion. J Cardiothorac Anesth 1989;3:211-214.
70. Aldea GS, Shapira OM, Treanor PR, et al. Effective use of heparin-bonded circuits and lower
anticoagulation for coronary artery bypass grafting in Jehovah’s Witnesses. J Card Surg 1996;11:12-17.
71. Rosengart TK, Helm RE, Klemperer J, et al. Combined aprotinin and erythropoietin use for blood
conservation: results with Jehovah’s Witnesses. Ann Thorac Surg 1994;58:1397-1403.
72. Chikada M, Furuse A, Kotsuka Y, et al. Open-heart surgery in Jehovah’s Witness patients. Cardiovasc
Surg 1996;4:311-314.
73. Lee RB, Martin TD. Religious objections to blood transfusion. In: Mora CT, ed. Cardiopulmonary bypass,
principles and techniques of extracorporeal circulation. New York, NY: Springer-Verlag, 1995:473-480.
74. Dobell ARC, Jain AK. Catastrophic hemorrhage during redo sternotomy. Ann Thorac Surg 1984;37:273-
278.
75. Bracey AW, Radovancevic R, Radovancevic B, et al. Blood use in patients undergoing repeat coronary
artery bypass graft procedures: multivariate analysis. Transfusion 1995;35:850-854.
76. Jones RE, Fitzgeral D, Cohn LH. Reoperative cardiac surgery using a new femoral venous right atrial
cannula. J Card Surg 1990;5:170-173.
77. Praeger PI, Pooley RW, Moggio RA, et al. Simplified method for reoperation on the mitral valve. Ann
Thorac Surg 1989;48:835-837.
78. Solomon L, Sutter FP, Goldman SM, et al. Augmented femoral venous return. Ann Thorac Surg
1993;55:1262-1263.
79. Darling E, Kaemer D, Lawson S, et al. Experimental use of an ultra-low prime neonatal cardiopulmonary
bypass circuit utilizing vacuum-assisted venous drainage. J Extra Corpor Technol 1998;30:184-189.
80. Toomasian JM, McCarthy JP. Total extrathoracic cardiopulmonary support with kinetic assisted venous
drainage: experience in 50 patients. Perfusion 1998;13:137-143.
81. Kurusz M, Deyo DJ, Sholar AD, et al. Laboratory testing of femoral venous cannulae: effect of size,
position and negative pressure on flow. Perfusion 1999;14:379-387.
82. Pedersen TH, Videm V, Svennevig JL, et al. Extracorporeal membrane oxygenation using a centrifugal
pump and a servo regulator to prevent negative inlet pressure. Ann Thorac Surg 1997;63:1333-1339.
83. Reed CC, Kurusz M, Lawrence AE Jr. Effects of surgical technique on cardiopulmonary bypass. In:
Safety and techniques in perfusion. Stafford, TX: Quali-Med, 1988:187-189.
84. Antunes MJ. Techniques of valvular reoperation. Eur J Cardiothorac Surg 1992;6(Suppl I):S54-S58.
85. Watanabe G, Haverich A, Speier R. Third-time coronary artery revascularization. Thorac Cardiovasc
Surg 1993;41:163-166.
86. Toomasian JM, Peters WS, Siegal LC. Extracorporeal circulation for port-access cardiac surgery.
Perfusion 1997;12:83-91.
87. Berrizbeitia LD, Anderson WA, Laub GW, et al. Case report: coronary artery bypass grafting after
pneumonectomy. Ann Thorac Surg 1994;58:1538-1540.
88. Soltanian H, Sanders JH Jr, Robb JC, et al. Case report: hybrid myocardial revascularization after
previous left pneumonectomy. Ann Thorac Surg 1998;65:259-260.
89. Gu YJ, Obster R, Haan J, et al. Biocompatibility of leukocyte removal filters during leukocyte filtration of
cardiopulmonary bypass perfusate. Artif Organ 1993;17:660-665.
90. Murphy DA, Craver JM, Jones EL, et al. Recognition and management of ascending aortic dissection
complicating cardiac surgical operations. J Thorac Cardiovasc Surg 1983;85:247-256.
91. Mills NL, Morris JM. Air embolism associated with cardiopulmonary bypass. In: Waldhausen JA, Orringer
MB, eds. Complications in cardiothoracic surgery. St. Louis, MO: Mosby, 1991:60-67.
92. Coughlan DWS, Diehl JT, Rice TW, et al. Ascending aortic insertion of the intra-aortic balloon catheter:
the potential for air embolism. Proc Am Acad Cardiovasc Perfus 1986;7:161-162.
93. Kurusz M, Lick SD, Conti VR. Air embolism with intraaortic balloon counterpulsation during
cardiopulmonary bypass [Letter]. J Thorac Cardiovasc Surg 1998;115:1393.
94. Stoney WS, Alford WC Jr, Burrus GR, et al. Air embolism and other accidents using pump oxygenators.
95. Kurusz M, Conti VR, Arens JF, et al. Perfusion accident survey. Proc Am Acad Cardiovasc Perfus
1986;7:57-65.
96. Mejak BL, Stammers A, Rauch E, et al. A retrospective study on perfusion accidents and safety devices.
Perfusion 2000;15:51-61.
97. Wheeldon DR. Can cardiopulmonary bypass be a safe procedure? In: Longmore DB, ed. Towards safer
cardiac surgery. Lancaster, UK: MTP, 1981:427-446.
99. Charrière JM, Pélisse J, Verd C, et al. Survey: retrospective survey of monitoring/safety devices and
incidents of cardiopulmonary bypass for cardiac surgery in France. J Extra Corpor Technol 2007;39:142-157.
100. Groenenberg I, Weerwind PW, Everts PAM, et al. Dutch perfusion incident survey. Perfusion
2010;25:329-336.
101. Mills NL, Ochsner JL. Massive air embolism during cardiopulmonary bypass-causes, prevention, and
management. J Thorac Cardiovasc Surg 1980;80:708-717.
102. Kurusz M, Wheeldon DR. Risk containment during cardiopulmonary bypass. Semin Thorac Cardiovasc
Surg 1990;2:400-409.
103. Fleisher AG, Tyers GFO, Manning GT, et al. Management of massive hemoptysis secondary to
catheter-induced perforation of the pulmonary artery during cardiopulmonary bypass. Chest 1989;95:1340-
1341.
104. Thrush DN, Jeffries D. Pulmonary hemorrhage during cardiac surgery. J Cardiothorac Vasc Anesth
1991;5:377-378.
105. Cohen JA, Blackshear RH, Gravenstein N, et al. Increased pulmonary artery perforating potential of
pulmonary artery catheters during hypothermia. J Cardiothorac Vasc Anesth 1991;5:234-236.
106. Kulkarni MG. A complication of aortic cannulation. J Cardiovasc Surg 1968;9:207-208.
107. Krous HF, Mansfield PB, Sauvage LR. Carotid artery hyperperfusion during open-heart surgery. J
108. Ross WT, Lake CL, Wellons HA. Cardiopulmonary bypass complicated by inadvertent carotid
cannulation. Anesthesiology 1981;54:85-86.
109. McLeskey CH, Cheney FW. A correctable complication of cardiopulmonary bypass. Anesthesiology
1982;56:214-216.
110. Sudhaman DA. Accidental hyperperfusion of the left carotid artery during CPB [Letter]. J Cardiothorac
Vasc Anesth 1991;5:100-101.
111. Tempe D, Khanna SK. Accidental hyperperfusion during cardiopulmonary bypass: suggested safety
features [Letter]. Ann Thorac Surg 1998;65:306.
112. Springer MA, Korth DC, Guiterrez PJ, et al. An in vitro analysis of a one-way arterial check valve. J
113. Gravlee GP, Wong AB, Charles DJ. Hypoxemia during cardiopulmonary bypass from leaks in the gas
supply system [Letter]. Anesth Analg 1985;64:646-653.
114. Roth JV, Fried DW. Catastrophic cardiopulmonary bypass accident [Letter]. J Cardiothorac Vasc Anesth
1993;7:253-254.
115. Robblee JA, Crosby E, Keon WJ. Hypoxemia after intraluminal oxygen line obstruction during
116. Kurusz M, Andrews JJ, Arens JF, et al. Monitoring oxygen concentration prevents potential adverse
patient outcome caused by a scavenging malfunction: case report. Proc Am Acad Cardiovasc Perfus
1991;12:162-165.
117. Kirson LE, Goldman JM. A system for monitoring the delivery of ventilating gas to the oxygenator during
118. Jerabek CF, Walton HG, Doerfler S. The effect of gas scavenging on hollow fiber membrane oxygenator
performance. In: Proceedings 27th international conference of the American Society of Extracorporeal
Technology, 10-14 March 1989:24-29.
119. Nader-Djalal, Khadra WZ, Spaulding W, et al. Correspondence: Does propofol alter the gas exchange
in membrane oxygenators? Ann Thorac Surg 1998;66:298-299.
120. Tarr TJ, Kent AP. Sequestration of propofol in an extracorporeal circuit. J Cardiothorac Anesth
1989;3(Suppl 1):75.
P.598
121. Fisher AR. The incidence and cause of emergency oxygenator changeovers. Perfusion 1999;14:207-
212.
122. Hart MA, Abshier DA, Pacheco SL, et al. A technique for the change-out of a malfunctioning membrane
oxygenator without terminating cardiopulmonary bypass. Proc Am Acad Cardiovasc Perfus 1988;9:105-113.
123. McMillan J, Smith BF, Cooper E, et al. Case report: emergency changing of an oxygenator during total
cardiopulmonary bypass. Anaesth Intensive Care 1979;7:271-272.
124. Reed CC, Stafford TB. Cardiopulmonary bypass. 2nd ed. Houston, TX: Texas Medical Press,
1985:408.
125. Kurusz M, Shaffer CW, Christman EW, et al. Runaway pump head: new cause of gas embolism during
126. Ballard S, Biggan DE. Runaway pumphead. In: Stafford TB, Toomasian JM, Kurusz M, eds. Case
reports. I. Clinical studies in extracorporeal circulation. Houston, TX: PREF Press, 1994:94-99.
127. Kurusz M. Fire in the heart-lung machine during mitral valve replacement. In: Stafford TB, Toomasian
JM, Kurusz M, eds. Case reports. I. Clinical studies in extracorporeal circulation. Houston, TX: PREF Press,
1994:85-93.
128. Khambatta HJ, Stone JG, Wald A, et al. Electrocardiographic artifacts during cardiopulmonary bypass.
Anesth Analg 1990;71:88-91.
129. Metz S. ECG artifacts during cardiopulmonary bypass and alternative method [Letter]. Anesth Analg
1991;72:715-716.
130. Emergency Care Research Institute. ECG artifact in the OR. Health Devices 1991;20:140-141.
131. Hug CC Jr. The anesthesiologist’s response to a low-output state after cardiopulmonary bypass:
etiologies and remedies. J Card Surg 1990;5:259-262.
132. Kurusz M, Faulkner SC. Anecdotes and case reports from the perfusion accident survey. Proc Am Acad
133. Quinn ML. Semipractical alarms: a parable. J Clin Monit 1989;5:196-200.
134. Beneken JEW, van der Aa JJ. Alarms and their limits in monitoring. J Clin Monit 1989;5:205-210.
135. Cooper JB, Newbower RS, Kitz RJ. An analysis of major errors and equipment failures in anesthesia
practice—considerations for prevention and detection. Anesthesiology 1984;60:34-42.
136. Gaba DM. Human error in anesthetic mishaps. Int Anesthesiol Clin 1989;27:137-147.
137. Kurusz M, Butler BD, Katz J, et al. Air embolism during cardiopulmonary bypass. Perfusion
1995;10:361-391.
138. Carrel A. Experimental operations on the orifices of the heart. Ann Surg 1914;60:1-6.
139. Reyer GW, Kohl HW. Air embolism complicating thoracic surgery. JAMA 1926;87:1626-1630.
140. Kent EM, Blades B. Experimental observations upon certain intracranial complications of particular
interest to the thoracic surgeon. J Thorac Cardiovasc Surg 1942;11:434-445.
141. Geoghegan T, Lam CR. The mechanism of death from intracardiac air and its reversibility. Ann Surg
1953;139:351-359.
142. Benjamin RB, Turbak CE, Lewis FJ. The effects of air embolism in the systemic circulation and its
prevention during open cardiac surgery. J Thorac Cardiovasc Surg 1957;34:548-552.
143. Clowes GHA Jr. Experimental procedures for entry into the left heart to expose the mitral valve. Ann
Surg 1951;134:957-968.
144. Potts WJ, Riker WL, de Bord R, et al. Maintenance of life by homologous lungs and mechanical
circulation. Surgery 1952;31:161-166.
145. Helmsworth JA, Clark LC, Kaplan S, et al. Artificial oxygenation and circulation during complete by-pass
of the heart. J Thorac Cardiovasc Surg 1952;24:117-133.
146. Lewis FJ, Taufic M. Closure of atrial septal defects with the aid of hypothermia. Surgery 1953;33:52-59.
147. Miller BJ, Gibbon JH Jr, Greco VF, et al. The production and repair of interatrial septal defects under
direct vision with the assistance of an extracorporeal pump-oxygenator circuit. J Thorac Surg 1953;26:598-
616.
148. Eguchi S, Bosher LH Jr. Myocardial dysfunction resulting from coronary air embolism. Surgery
1962;51:103-111.
149. Goldfarb D, Bahnson HT. Early and late effects on the heart of small amounts of air in the coronary
circulation. J Thorac Cardiovasc Surg 1963;46:368-378.
150. Taber RE, Maraan BM, Tomatis L. Prevention of air embolism during openheart surgery: a study of the
role of trapped air in the left ventricle. Surgery 1970;68:685-691.
151. Justice C, Leach J, Edwards WS. The harmful effects and treatment of coronary air embolism during
open-heart surgery. Ann Thorac Surg 1972;14:47-53.
152. Callaghan JC, Despres JP, Benvenuto R. A study of the causes of 60 deaths following total
153. Ehrenhaft JL, Claman MA, Layton JM, et al. Cerebral complications of open-heart surgery: further
observations. J Thorac Cardiovasc Surg 1961;42:514-526.
154. Allen P. Central nervous system emboli in open heart surgery. Can J Surg 1963;6:332-337.
155. Sloan H, Morris JD, Mackenzie J, et al. Open heart surgery: results in 600 cases. Thorax 1962;17:128-
138.
156. Nicks R. Arterial air embolism. Thorax 1967;22:320-326.
157. Fishman NH, Carlsson E, Roe BB. The importance of the pulmonary veins in systemic air embolism
following open-heart surgery. Surgery 1969;66:655-662.
158. Anderson RM, Fritz JM, O’Hae JE. Pulmonary air emboli during cardiac surgery. J Thorac Cardiovasc
Surg 1965;49:440-449.
159. Lin C-Y. Pulmonary air embolism: reappraisal of the importance in openheart surgery. Nagoya J Med
Sci 1967;30:365-372.
160. Gomes OM, Pereira SN, Castagna RC, et al. The importance of the different sites of air injection in the
tolerance of arterial air embolism. J Thorac Cardiovasc Surg 1973;65:563-568.
161. Beckman CR, Hurley F, Mammana R, et al. Risk factors for air embolization during cannulation of the
ascending aorta. J Thorac Cardiovasc Surg 1980;80:302-307.
162. Sturm J. Air embolism during mitral valve replacement [Letter]. J Thorac Cardiovasc Surg 1981;81:804-
805.
163. Hughes D. Air embolism during cardiopulmonary bypass [Letter]. J Thorac Cardiovasc Surg
1981;82:639.
164. Robicsek F, Duncan GD. Retrograde air embolization in coronary operations. J Thorac Cardiovasc Surg
1987;94:110-114.
165. Lee ME. Air embolism in coronary bypass operations [Letter]. J Thorac Cardiovasc Surg 1988;95:543.
166. Reed CC, Kurusz M, Lawrence AE Jr. Air embolism. In: Safety and techniques in perfusion. Stafford,
TX: Quali-Med, 1988:239-246.
167. Dennis C. Perspective in review: one group’s struggle with development of a pump-oxygenator. Trans
Am Soc Artif Intern Organ 1985;31:1-11.
168. Milnes RF, vanderWoude R, Morris JD, et al. Problems related to a bubble oxygenator system. Surgery
1958;42:986-992.
169. Baird RJ, Miyagishima RT. The danger of air embolism through a pressure-perfusion cannula. J Thorac
170. Kumar AS, Jayalakshmi TS, Kale SC, et al. Management of massive air embolism during open heart
surgery. Int J Cardiol 1985;9:413-416.
171. Tanasawa I, Wotton DR, Yang W-J, et al. Experimental study of air bubbles in a simulated
cardiopulmonary bypass system with flow constriction. J Biomech 1970;3:417-424.
172. Comer TP, Saxena NC, Hamel NC. Full recovery of a patient after oxygenator replacement during open-
heart surgery. Cardiovasc Dis Bull Tex Heart Inst 1980;7:165-168.
173. Pfefferkorn RO, Rose MW, Pfefferkorn SP. An unreported pathway for the introduction of air embolism
from and unvented hardshell cardiotomy reservoir: a case report. In: Proceedings First World Congress on
open heart technology, Brighton UK 1981. London, UK: Franklin Scientific Projects, 1982:78-79.
174. Wells WJ, Stiles QR. Massive venous air embolism during cardiopulmonary bypass. Ann Thorac Surg
1981;31:86-89.
175. Pickard LR. Venous air embolism [Letter]. Ann Thorac Surg 1982;33:102-103.
176. Emergency Care Research Institute. Hazard: scavenging gas from membrane oxygenators. Health Dev
1987;16:343-344.
177. Goodridge M. Entrance of air into the veins, and its treatment. Am J Med Sci 1902;124:461-476.
178. Hare HA. The effect of the entrance of air into the circulation. Therap Gazette 1889;5:606-610.
179. Tisovec L, Hamilton WK. Newer considerations in air embolism during operation. JAMA 1967;201:376-
377.
180. Munson ES. Transfer of nitrous oxide into body air cavities. Br J Anaesth 1974;46:202-209.
181. Garcia C, Albin MS, Bunegin L. Effect of nitrous oxide on air bubble volume in arterial air embolism
[Letter]. Crit Care Med 1989;17:1236.
182. Losasso TJ, Black S, Muzzi DA, et al. Detection and hemodynamic consequences of venous air
embolism. Does nitrous oxide make a difference? Anesthesiology 1992;77:148-152.
183. Munson ES. Pathophysiology and treatment of venous air embolism: a review. Middle East J
Anesthesiol 1988;9:315-325.
P.599
184. Wells DG, Podolakin W, Mohr M, et al. Nitrous oxide and cerebrospinal fluid markers of ischemia
following cardiopulmonary bypass. Anaesth Intensive Care 1987;15:431-435.
185. Peirce EC II. Cerebral gas embolism (arterial) with special reference to iatrogenic accidents. HBO Rev
1980;1:161-188.
186. Dutka AJ. A review of the pathophysiology and potential application of experimental therapies for
cerebral ischemia to the treatment of cerebral arterial gas embolism. Undersea Biomed Res 1985;12:403-
421.
187. Spampinato N, Stassano P, Gagliardi C, et al. Massive air embolism during cardiopulmonary bypass:
successful treatment with immediate hypothermia and circulatory support. Ann Thorac Surg 1981;32:602-
603.
188. Steward D, Williams WG, Freedom R. Hypothermia in conjunction with hyperbaric oxygenation in the
treatment of massive air embolism during cardiopulmonary bypass. Ann Thorac Surg 1977;24:591-593.
189. Fundaro P, Santoil C. Massive coronary gas embolism managed by retrograde coronary sinus
perfusion. Tex Heart Inst J 1984;11:172-174.
190. Sandhu AA, Spotnitz HM, Dickstein ML, et al. Retrograde cardioplegia preserves myocardial function
after induced coronary air embolism. J Thorac Cardiovasc Surg 1997;113:917-922.
191. Bauer RO, Campbell M, Goodman R, et al. Aeroembolism treated by hypothermia: report of a case.
Aerospace Med 1965;36:671-675.
192. Fine J, Fischmann J. An experimental study of the treatment of air embolism. N Engl J Med
1940;223:1054-1057.
193. Alvaran SB, Toung JK, Graff TE, et al. Venous air embolism: comparative merits of external cardiac
massage, intracardiac aspiration, and left lateral decubitus position. Anesth Analg 1978;57:166-170.
194. Musgrove JE, MacQuigg RE. Successful treatment of air embolism. JAMA 1952;150:28.
195. Ericsson JA, Gottlieb JD, Sweet RB. Closed-chest cardiac massage in the treatment of venous air
embolism. N Engl J Med 1964;270:1353-1354.
196. Brenner WI. A battle plan in the event of massive air embolism during open heart surgery. J Extra-Corp
Technol 1985;17:133-137.
197. Butler BD, Laine GA, Leiman BC, et al. Effect of Trendelenburg position on the distribution of arterial air
emboli in dogs. Ann Thorac Surg 1988;45:198-202.
198. Mehlhorn U, Burke EJ, Butler BD, et al. Body position does not affect the hemodynamic response to
venous air embolism in dogs. Anesth Analg 1994; 79:734-739.
199. Watanabe T, Shimasaki T, Kuraoka S, et al. Retrograde cerebral perfusion against massive air
embolism during cardiopulmonary bypass [Letter]. J Thorac Cardiovasc Surg 1992;104;532-533.
200. Brown JW, Dierdorf SF, Moorthy SS, et al. Venoarterial cerebral perfusion for treatment of massive
arterial air embolism. Anesth Analg 1987;66:673-674.
201. Diethrich EB, Koopot R, Maze A, et al. Successful reversal of brain damage from iatrogenic air
embolism. Surg Gynecol Obstet 1982;154:572-575.
202. Ghosh PK, Kaplan O, Barak J, et al. Massive arterial air embolism during cardiopulmonary bypass. J
203. Hendricks FFA, Bogers AJJC, de la Riviere AB, et al. The effectiveness of venoarterial perfusion in
treatment of arterial air embolism during cardiopulmonary bypass. Ann Thorac Surg 1983;36:433-436.
204. Noritake S, Kitayama H, Matsuno S, et al. Massive air embolism during cardiopulmonary bypass: a case
report of successful management by temporary retrograde perfusion through the superior vena cava. Kyobu
Geka 1985;38:274-277.
205. Stark J, Hough J. Air in the aorta: treatment by reversed perfusion. Ann Thorac Surg 1986;41:337-338.
206. Toscano M, Chiavarelli R, Ruvolo G, et al. Management of massive air embolism during open-heart
surgery with retrograde perfusion of the cerebral vessels and hyperbaric oxygenation. Thorac Cardiovasc
Surg 1983;31:183-184.
207. Rozanski J, Szufladowicz M. Successful treatment of massive air embolism. J Card Surg 1994;9:430-
432.
208. Goldstone J, Towan HJ, Ellis RJ. Rationale for use of vasopressors in treatment of coronary air
embolism. Surg Forum 1978;29:237-239.
209. Evans DE, Kobrine AI, LeGrys DC, et al. Protective effect of lidocaine in acute cerebral ischemia
induced by air embolism. J Neurosurg 1984;60:257-263.
210. Padula RT, Eisenstat TE, Bronstein MH, et al. Intracardiac air following cardiotomy: location, causative
factors, and a method for removal. J Thorac Cardiovasc Surg 1971;62:736-742.
211. Eiseman B, Baxter BJ, Prachuabmoh K. Surface tension reducing substances in the management of
coronary air embolism. Ann Surg 1959;149:374-380.
212. Malette WG, Fitzgerald JB, Eiseman B. Aeroembolus: a protective substance. Surg Forum 1960;11:155-
156.
213. Menasche P, Pinard E, Desroches A-M, et al. Fluorocarbons: a potential treatment of cerebral air
embolism in open-heart surgery. Ann Thorac Surg 1985;40:494-497.
214. Menasche P, Fleury J-P, Piwnica A. Update: fluorocarbons: a potential treatment of cerebral air
embolism in open-heart surgery. Ann Thorac Surg 1992;54:392-393.
215. Butler BD, Kurusz M. Fluorocarbon treatment for cerebral air embolism [Letter]. Ann Thorac Surg
1986;42:350-351.
216. Speiss BD, McCarthy RJ, Tuman KJ, et al. Perfluorocarbon emulsions and air embolism [Letter]. Ann
Thorac Surg 1987;44:223.
217. Speiss BD, McCarthy RJ, Ivankovich AD. Protection from coronary air embolism by a perfluorocarbon
emulsion (FC-43). J Cardiothorac Anesth 1987;1:210-215.
218. Speiss BD, Braverman B, Woronowicz AW, et al. Protection from cerebral air emboli with
perfluorocarbons in rabbits. Stroke 1986;17:1146-1149.
219. Annane D, Troche G, Delisle F, et al. Effects of mechanical ventilation with normobaric oxygen therapy
on the rate of air removal from cerebral arteries. Crit Care Med 1994;22:851-857.
220. Presson RG Jr, Kirk KR, Haselby KA, et al. Effect of ventilation with soluble and diffusible gases on the
size of air emboli. J Appl Physiol 1991;70:1068-1074.
221. Tuman KJ, McCarthy RJ, Speiss BD, et al. Effects of nitrous oxide on coronary perfusion after coronary
air embolism. Anesthesiology 1987;67:952-959.
222. Hlastala MP, Van Liew HD. Absorption of in vivo inert gas bubbles. Respir Physiol 1975;24:147-158.
223. Schabel RK, Berryessa RG, Justison GA, et al. Ten common perfusion problems: prevention and
treatment protocols. J Extra Corpor Technol 1987;19:392-398.
224. Tovar EA, Del Campo C, Bosari A, et al. Postoperative management of cerebral air embolism: gas
physiology for surgeons. Ann Thorac Surg 1995;60:1138-1142.
225. Armon C, Deschamps C, Adkinison C, et al. Hyperbaric treatment of cerebral air embolism sustained
during an open-heart surgical procedure. Mayo Clin Proc 1991;66:565-570.
226. Bove AA, Clark JM, Simon AJ, et al. Successful therapy of cerebral air embolism with hyperbaric oxygen
at 2.8 ATA. Undersea Biomed Res 1982;9:75-79.
227. Halliday P, Anderson DN, Davidson AI, et al. Management of cerebral air embolism secondary to a
disconnected central venous catheter. Br J Surg 1994;81:71.
228. Hart GB. Treatment of decompression illness and air embolism with hyperbaric oxygen. Aerospace Med
1974;45:1190-1193.
229. Kindwall EP. Massive surgical air embolism treated with brief recompression to six atmospheres
followed by hyperbaric oxygen. Aerospace Med 1973;44:663-666.
230. Lar LW, Lai LC, Ren LW. Massive arterial air embolism during cardiac operation: successful treatment
in hyperbaric chamber under 3 ATA [Letter]. J Thorac Cardiovasc Surg 1990;100:928-930.
231. Meijne NG, Schoemaker G, Bulterijs AB. The treatment of cerebral gas embolism in a high pressure
chamber: and experimental study. J Cardiovasc Surg 1963;4:757-763.
232. Menkin M, Schwartzman RJ. Cerebral air embolism: report of five cases and review of the literature.
Arch Neurol 1977;34:168-170.
233. Murphy BP, Harford FJ, Cramer FS. Cerebral air embolism resulting form invasive medical procedures:
treatment with hyperbaric oxygen. Ann Surg 1985;201:242-245.
234. Peirce EC II. Specific therapy for arterial air embolism [Editorial]. Ann Thorac Surg 1980;29:300-303.
235. Takita H, Olszewski W, Schimert G, et al. Hyperbaric treatment of cerebral air embolism as a result of
open-heart surgery: report of a case. J Thorac Cardiovasc Surg 1968;55:682-85.
236. Mader JT, Hulet WH. Delayed hyperbaric treatment of cerebral air embolism: report of a case. Arch
Neurol 1979;36:504-505.
237. Bitterman H, Melamed Y. Delayed hyperbaric treatment of cerebral air embolism. Israel J Med Sci
1993;29:22-26.
238. Ryan T, McCarthy JF, Rady MY, et al. Early bloodstream infection after cardiopulmonary bypass:
frequency rate, risk factors, and implications. Crit Care Med 1997;25:2009-2014.
239. Rudnick JR, Beck-Sague CM, Anderson RL, et al. Gram-negative bacteremia in open-heart-surgery
patients traced to probable tap-water contamination of pressure-monitoring equipment. Infect Control Hosp
Epidemiol 1996;17:281-285.
240. Hughes CF, Grant AF, Leckie BD, et al. Cardioplegic solution: a contamination crisis. J Thorac
P.600
241. Talbot GH. Contamination of cardioplegic solution [Letter]. J Thorac Cardiovasc Surg 1986;92:966.
242. Metz S. Administration of protamine rather than heparin in a patient undergoing normothermic
243. Ti LK. Survival after large ABO-incompatible blood transfusion. Can J Anaesth 1998;45:916.
244. Becker RM. Intracardiac surgery in pregnant women. Ann Thorac Surg 1983;36:453-458.
245. Leyse R, Ofstun M, Dillard DH, et al. Congenital aortic stenosis in pregnancy, corrected by
extracorporeal circulation: offering a viable male infant at term but with anomalies eventuating in his death at
four months of age—report of a case. JAMA 1961;176:1009-1012.
246. Dubourg G, Broustet P, Bricaud H, et al. Correction complete d’une triade de Fallot en circulation extra-
corporelle chez une femme enceinte. Arch Mal Coeur 1959;52:1389-1391.
247. Kay CF, Smith K. Surgery in the pregnant cardiac patient. Am J Cardiol 1963;12:293-295.
248. Werch A, Lambert HM, Cooley D, et al. Fetal monitoring and maternal open heart surgery [Letter]. South
Med J 1977;70:1024.
249. Meffert WG, Stansel HC Jr. Open heart surgery during pregnancy. Am J Obstet Gynecol
1968;102:1116-1120.
250. Pedersen H, Finster M. Anesthetic risk in the pregnant surgical patient. Anesthesiology 1979;51:439-
451.
251. Parry AJ, Westaby S. Cardiopulmonary bypass during pregnancy. Ann Thorac Surg 1996;61:1865-
1869.
252. Pomini F, Mercogliano D, Cavalletti C, et al. Cardiopulmonary bypass in pregnancy. Ann Thorac Surg
1996;61:259-268.
253. Weiss BM, von Segesser LK, Seifert B, et al. Outcome of cardiovascular surgery and pregnancy: a
systematic review of the period 1984-1996. Am J Obstet Gynecol 1998;179:1643-1653.
254. Izquierdo LA, Kushnir O, Knieriem K, et al. Effect of mitral valve prosthetic surgery on the outcome of a
growth-retarded fetus. A case report. Am J Obstet Gynecol 1990;163:584-586.
255. Caritis SN, Edelstone DI, Mueller-Heubach E. Pharmacologic inhibition of premature labor. Am J Obstet
Gynecol 1979;133:557-578.
256. Lamb MP, Ross K, Johnstone AM, et al. Fetal heart rate monitoring during open heart surgery. Br J
Obstet Gynecol 1983;88:669-674.
257. Korsten HHM, Van Zundert AAJ, Mooij PNM, et al. Emergency aortic valve replacement in the 24th
week of pregnancy. Acta Anaesth Belg 1989;40:201-205.
258. Strickland RA, Oliver WC Jr, Chantigian RC, et al. Anesthesia, cardiopulmonary bypass, and the
pregnant patient. Mayo Clin Proc 1991;66: 411-429.
259. Chambers CE, Clark SL. Cardiac surgery during pregnancy. Clin Obstet Gynecol 1994;37:316-323.
260. Conroy JM, Bailey MK, Hollon MF, et al. Anesthesia for open heart surgery in the pregnant patient.
South Med J 1989;82:492-495.
261. Harrison EC, Roschke EJ. Pregnancy in patients with cardiac valve prostheses. Clin Obstet Gynecol
1975;18:107-123.
262. Koh KS, Friesen RM, Livingstone RA, et al. Fetal monitoring during maternal cardiac surgery with
cardiopulmonary bypass. Can Med Assoc J 1975;112:1102-1104.
263. Reisner LS. Cardiac dysfunction: special considerations during pregnancy. In: Utley JR, ed.
Pathophysiology and techniques of cardiopulmonary bypass, Vol. III. Baltimore, MD: Williams & Wilkins,
1985:15-29.
264. Buffolo E, Palma JH, Gomes WJ, et al. Case report: successful use of deep hypothermic circulatory
arrest in pregnancy. Ann Thorac Surg 1994;58:1532-1534.
265. Daley R, Harrison GK, McMillan IKR. Direct-vision pulmonary valvotomy during pregnancy. Lancet
1957;273:875-876.
266. Ravindran R, Viegas OJ, Padilla LM, et al. Anesthetic considerations in pregnant patients receiving
terbutylline treatment. Anesth Analg 1980;59:391-392.
267. Rolbin SH, Levinson G, Shnider SM, et al. Dopamine treatment of spinal hypotension decreases uterine
blood flow in the pregnant ewe. Anesthesiology 1979;51:37-40.
268. Naulty JS, Cefalo RC, Lewis P. Fetal toxicity of nitroprusside in the pregnant ewe. Am J Obstet Gynecol
1980;139:708-711.
269. Kopman EA. Scavenging of potassium cardioplegic solution to prevent hyperkalemia in hemodialysis-
dependent patients. Anesth Analg 1983;62:780-782.
270. Soffer O, MacDonell C Jr, Finlayson DC, et al. Intraoperative hemodialysis during cardiopulmonary
bypass in chronic renal failure. J Thorac Cardiovasc Surg 1979;77:789-791.
271. Geronemus R, Schneider N. Continuous arteriovenous hemodialysis: a new modality for treatment of
acute renal failure. Trans Am Soc Artif Intern Organs 1984;30:610-613.
272. Hakim M, Wheeldon D, Bethune DW, et al. Haemodialysis and haemofiltration on cardiopulmonary
bypass. Thorax 1985;40:101-106.
273. Murkin JM, Murphy DA, Finlayson DC, et al. Hemodialysis during cardiopulmonary bypass: report of
twelve cases. Anesth Analg 1987;66: 899-901.
274. Wheeldon D, Bethune D. Haemofiltration during cardiopulmonary bypass. Perfusion 1990;5(Suppl):39-

51.
275. Sutton RG. Renal considerations, dialysis, and ultrafiltration during cardiopulmonary bypass. Int
Anesthesiol Clin 1996;34:165-176.
276. Ilson BE, Bland PS, Jorkasky DK, et al. Intraoperative versus routine hemodialysis in end-stage renal
disease patients undergoing open-heart surgery. Nephron 1992;61:170-175.
277. Hamilton CC, Harwood SJ, Deemar KA, et al. Haemodialysis during cardiopulmonary bypass using a
haemofilter. Perfusion 1994;9: 135-139.
278. Koyangi T, Nishida, Endo M, et al. Coronary artery bypass grafting in chronic renal dialysis patients:
intensive perioperative dialysis and extensive usage of arterial grafts. Eur J Cardiothorac Surg 1994;8:505-
507.
279. Garrido P, Bobadilla JF, Albertos J, et al. Cardiac surgery in patients under chronic hemodialysis. Eur J
280. United States Health Care Financing Administration. End stage renal disease program highlights (Fact
sheet). August 1997.
281. Marshall WG Jr, Rossi NP, Meng RL, et al. Coronary artery bypass grafting in dialysis patients. Ann
Thorac Surg 1986;42(Suppl):S12-S15.
282. Denborough MA, Foster VFA, Lovell RRH, et al. Anaesthetic deaths in a family. Br J Anaesth
1962;34:395-396.
283. Ryan JF, Kerr WS Jr. Malignant hyperthermia: a catastrophic complication. J Urol 1973;109:879-883.
284. Britt BA, Kalow W. Malignant hyperthermia, a statistical review. Can Anaesth Soc J 1970;17:293-301.
285. Ryan JF, Donlon JV, Malt RA, et al. Cardiopulmonary bypass in the treatment of malignant
hyperthermia. N Engl J Med 1974;290:1121-1122.
286. Byrick RJ, Rose DK, Ranganathan N. Management of a malignant hyperthermia patient during
287. Bahret PM, Larach DR, Williams DR, et al. Malignant hyperthermia: a case report. Proc Am Acad
288. MacGillivray RG, Jann H, Vanker E, et al. Development of malignant hyperthermia obscured by
289. Quinn RD, Pae WE Jr, McGary SA, et al. Development of malignant hyperthermia during mitral valve
replacement. Ann Thorac Surg 1992;53: 1114-1116.
290. Schwartz AJ, Hensley FA Jr. Case conference 3, 1990. J Cardiothorac Anesth 1990;4:385-399.
291. Utley JR, Leyland SA. Coronary artery bypass grafting in the octogenarian. J Thorac Cardiovasc Surg
1991;101:866-870.
292. Tsai T-P, Nessim S, Kass RM, et al. Morbidity and mortality after coronary artery bypass in
octogenarians. Ann Thorac Surg 1991;51:983-986.
293. Ko W, Kreiger KH, Lazenby D, et al. Isolated coronary artery bypass grafting in one hundred
consecutive octogenarian patients. J Thorac Cardiovasc Surg 1991;102:532-538.
294. Ranger WR, Glover JL, Shannon FL, et al. Coronary artery bypass and valve replacement in
octogenarians. Am Surg 1996;62:941-946.
295. Cane ME, Chen C, Bailery BM, et al. CABG in octogenarians: early and late events and actuarial
survival in comparison with a matched population. Ann Thorac Surg 1995;60:1033-1037.
296. Rady MY, Ryan T, Starr NJ. Perioperative determinants of morbidity and mortality in elderly patients
undergoing cardiac surgery. Crit Care Med 1998;26:225-235.
297. Johnson WC, Lurich F, Meguid MM, et al. Role of delayed hypersensitivity in predicting postoperative
morbidity and mortality. Am J Surg 1979;137:536-542.
298. Moulton MJ, Creswell LL, Mackey ME, et al. Obesity is not a risk factor for significant adverse outcome
after cardiac surgery. Circulation 1996; 94(Suppl II):II-87-II-92.
P.601
299. Kouchoukos NT, Blackstone EH, Doty DB, et al., eds. Kirklin/Barratt-Boyes Cardiac Surgery, Vol. 1. 3rd
ed. Philadelphia, PA: Churchill Livingston, 2003:87.
300. Babka RM, Caviness ML, Howell J, et al. The effects of obesity on cardiopulmonary bypass using the
Bentley BOS-10 oxygenator. Proc Am Acad Cardiovasc Perfus 1982;3:60-63.
301. Klemperer JD, Ko W, Kreiger K, et al. Cardiac operations in patients with cirrhosis. Ann Thorac Surg
1998;65:85-87.
302. Humphries JE. Transfusion therapy in acquired coagulopathies. Hematol Oncol Clin North Am
1994;8:1181-1201.
303. Joist JH. Hemostatic abnormalities in liver disease. In: Colman RW, Hirsh J, Marder VJ, eds.
Hemostasis and thrombosis: basic principles and clinical practice. Philadelphia, PA: J.B. Lippincott,
1994:906.
304. Rastogi P, Gupta SC, Bisht D. Coagulation studies in patients with cirrhosis of liver: bleeders vs. non-
bleeders. Indian J Pathol Microbiol 1990;33:323-327.
305. Kurusz M, Wheeldon DR. Perfusion safety. Perfusion 1988;3:97-112.
306. Kurusz M. Perfusion safety: new initiatives and enduring principles. Perfusion 2011;26 (Suppl 1):6-14.
307. Perrow C. Normal accidents, living with high-risk technologies. New York, NY: Basic Books, 1984.
Chapter 25
Termination of Cardiopulmonary Bypass
Roger L. Royster
Adair Q. Locke
Jeffrey C. Gardner
Cardiopulmonary bypass (CPB) is required for many cardiac surgical procedures. CPB results in major physiologic abnormalities, including
nonpulsatile flow, hypothermia, hemodilution, profound anticoagulation, electrolyte and neuroendocrine disturbances, an inflammatory response, and
ischemia/reperfusion injury. Restoration of the normal cardiopulmonary circulation after CPB requires reversing many of these pathophysiologic
problems. The cardiothoracic anesthesiologist facilitates this safe transition for the patient by thorough planning and preparation as shown in Table
25.1, but termination of bypass is a team effort requiring clear communication among anesthesiologist, surgeon, and perfusionist.
SEPARATION FROM CARDIOPULMONARY BYPASS: PREPARATION

Rewarming
The patient must be rewarmed if hypothermia is used for organ protection (1). Mild hypothermia (33°C-35°C) is used for shorter cases with warm
intermittent or continuous cardioplegia. Moderate hypothermia (25°C-30°C) is often used to slow myocardial rewarming after cold cardioplegia. Deep
hypothermia (18°C-22°C) with circulatory arrest is occasionally needed for repairs of certain congenital defects or for aortic arch reconstruction.
Rewarming with the heat exchanger in the bypass circuit is initiated to restore normothermia by the completion of the surgical procedure.
Temperature measurement of the arterial and venous blood is necessary to keep the arteriovenous gradient less than 6°C to prevent bubble
formation, as the blood warms and gaseous solubility decreases (2). The temperature required for complete rewarming is usually a nasopharyngeal
or esophageal temperature of 37°C or a bladder or rectal temperature of 35°C to 36°C. Palpation of the patient’s head and shoulders can be helpful
in assessing the degree of rewarming. However, the high blood flow-totissue mass ratio of the head and neck region may result in underestimation of
the completeness of rewarming in other vascular beds. Therefore, sweating of the forehead during rewarming in CPB does not necessarily mean that
the patient is “lightly anesthetized” but suggests a normal thermoregulatory response to rewarming (3).
Inadequate rewarming after discontinuation of CPB can result in rebound hypothermia. This problem is often compounded by further convective heat
loss from the patient into the cool operating room environment. Pharmacologic-induced vasodilation during CPB may facilitate rewarming and
decrease the postbypass fall in temperature (4). However, the use of this technique may require more intravascular volume expansion to maintain
adequate perfusion pressure, which worsens hemodilution and tissue edema. Inadequate rewarming while on CPB can result in a considerable (2°C-
3°C) drop in patient temperature from the end of CPB until arrival in the intensive care unit. This fall in temperature can result in shivering, which
increases oxygen consumption, carbon dioxide production, and peripheral vascular resistance. Subclinical shivering in a patient who is partially
paralyzed during CPB results in hypercarbia and the need for muscle relaxation. Shivering should be anticipated when systemic temperature is less
than 35°C. It should be aggressively treated with active rewarming measures.
Metabolic Abnormalities
Nonpulsatile flow results in vasoconstriction during CPB and a low perfusion state especially during prolonged cases that can cause metabolic
problems. Acidemia, from respiratory or metabolic causes, should be corrected because of its depressant effects on myocardial function, its
interference with the action of inotropic drugs, and its ability to increase pulmonary vascular tone (5,6,7). Acidemia and administration of cardioplegic
solutions frequently result in hyperkalemia, which has pronounced deleterious effects on cardiac conduction, including atrioventricular conduction
block (8). Atrial depolarization is especially sensitive to hyperkalemia and failure to capture either the atria or ventricle with pacing can result.
Hyperkalemia can be treated with insulin, calcium, and bicarbonate. It is usually unnecessary to treat mild hyperkalemia (<6.0 mEq/L) in the presence
of normal renal function, because serum potassium usually falls after CPB due to rewarming and increased glucose utilization, renal losses from a
diuresis that develops from the hemodilution, and increased
P.604
catecholamine and β2 receptor stimulation from the stress of CPB, all of which move potassium intracellularly. If hypokalemia develops after bypass,
it should be treated promptly, because ventricular and atrial arrhythmias are likely to develop.
TABLE 25.1. Checklist before termination of cardiopulmonary bypass (CPB)
Metabolic data Heart rate and rhythm
Arterial blood gases Electrocardiogram assessment
Mixed venous oxygen saturation Rhythm
Serum Na+, K+, ionized Ca2+, Mg, glucose Conduction abnormalities

Hemoglobin/Hematocrit Ischemia—review all available leads
Activated clotting time, heparin concentration, thromboelastogram Atrial and/or ventricular pacing leads
Temperature (36°C-37°C nasopharyngeal or esophageal, 35°C-36°C rectal or bladder, 37°C Rate—pacing

arterial blood) capability/thresholds/sensing
Anesthesia/oxygenation/ventilation/perfusion Organ function assessment
Analgesia—supplemental opioid Cardiac function—contractility, size
Amnesia—benzodiazepines Ventricular filling
Muscle relaxation—if needed Air removed—TEE
Airway and functional oxygen delivery system on Vent removed
Anesthesia machine on Assessment of surgical repair
Vaporizer off-on pump Ventilator on
Blood flow on pump Inflation/Deflation both lungs
Pump Reservoir Volume Lung compliance
Safety monitors—oxygen analyzer, circuit pressure alarm, spirometer Suctioning of secretions if necessary
Adequate oxygen supply Pulse oximeter Bladder catheter—urine output
Capnometer/mass spectrometer
Hemodynamic monitors Cardiac support
Invasive blood pressure monitors—zeroed and calibrated Pharmacologic
Arterial catheter—radial, femoral, or aortic Inotropes
Pulmonary artery catheter Vasodilators
Central venous (right atrial) catheter Vasoconstrictors
Left atrial catheter Antiarrhythmics
Transesophageal echocardiogram Intraaortic balloon counterpulsation
Atrial and/or ventricular pacing
Left and/or right ventricular assist

device
Hypocalcemia results from hemodilution and transfusion of albumin or citrate-containing blood products. Hypocalcemia during CPB should not be
treated, because normocalcemia usually occurs by the end of rewarming due to the normal response of increased parathyroid hormone (9). If ionized
hypocalcemia is present (<0.8 mg/dL) after rewarming is complete, then it should be corrected with calcium chloride (5 mg/kg) to improve myocardial
contractility and peripheral vascular resistance. Otherwise, calcium should not be administered, because it can worsen the reperfusion injury that
occurs after cardioplegic arrest. Hypomagnesemia also results from hemodilution, but magnesium has no counterregulatory hormone to increase
magnesium levels. Magnesium should be administered during CPB to provide vasodilation of coronary arteries, to attenuate post-CPB hypertension,
and to prevent arrhythmias (10). Hyperglycemia is common during the hypothermic period of CPB and usually returns to normal shortly after
termination of CPB in the nondiabetic patient. However, persistent hyperglycemia after CPB in any patient should be treated with insulin. In diabetic
patients, insulin infusions are often needed during CPB and postoperatively for hyperglycemic control. Even
P.605
mild hyperglycemia (>150 mg/dL) has significant adverse effects in terms of increasing the risk of postoperative infection, wound healing, and
increased mortality (11). More severe hyperglycemia increases serum osmolarity and can cause osmotic diuresis and central nervous system
dysfunction and may increase the susceptibility of the brain to hypoxic damage.
Pump priming with crystalloid solutions results in hemodilution. Hemodilution reduces blood viscosity and improves microcirculatory flow; however,
hemodilution decreases serum protein levels, which decreases plasma colloid osmotic pressure and increases the movement of fluid from the
intravascular to the extravascular compartments to cause tissue edema. Hemodilution reduces hemoglobin and hematocrit concentrations. The
optimal hemoglobin concentration during CPB is usually accepted as being ≥ 7 g/dL, although there is no proven minimum safe level. However, Hgb
<8 g/dL has been associated with worsened outcomes, yet treatment with blood transfusion makes outcomes even worse (12). Healthy adult patients
rarely need homologous blood transfusion with appropriate blood conservation measures if they are not anemic preoperatively. Blood transfusion
increases the risk of renal failure and infection; so the benefits of blood transfusion in terms of increased oxygen transport should be weighed against
its risks.
Heparin-induced anticoagulation should be carefully monitored during rewarming because of the increased metabolism of heparin at higher body
temperatures and the dangerous consequences of inadequate anticoagulation. In addition to reducing electrolyte levels and hematocrit, hemodilution
reduces platelet levels by about 40% and dilutes coagulation factor levels (13). Protamine should be available to reverse heparin following
termination of bypass but some recommend protamine not be drawn into a syringe until needed to avoid the possibility of administration while on
cardiopulmonary bypass (CPB). Plasma, cryoprecipitate, or prothrombin complex concentrates should be available for treating documented factor
deficiencies or coagulopathy. DDAVP may improve platelet function in patients with aortic stenosis or a ventricular assist device who develop an
acquired von Willebrand factor deficiency (14). Platelet transfusions are occasionally required, especially in patients who have significant
thrombocytopenia (<50 K), chronic renal failure, or who are receiving antiplatelet drugs. Postoperative bleeding is usually due to inadequate surgical
hemostasis, inadequate heparin reversal, or mild coagulopathy.
Anesthesia, Oxygenation, and Ventilation

The requirements for anesthetics and muscle relaxants are reduced during CPB in approximate proportion to the level of hypothermia because of
anesthetic effects of hypothermia and decreased metabolism of most drugs (15). Changes in intravenous anesthetic drug distribution and elimination
also contribute to reduced anesthetic requirements. However, rewarming reverses much of this effect, and hence adequate anesthetic depth and
muscle relaxation to prevent patient awareness and shivering becomes a concern. As a result, benzodiazepines, narcotics, and muscle relaxants may
be needed during rewarming in anticipation of volatile agents being discontinued before termination of CPB to avoid their circulatory and myocardial
depressant effects (16,17). Administration of volatile anesthetic agents during the weaning process can contribute to failure to wean from CPB
because of cardiodepressant effects. However, volatile anesthetic agents also induce vasodilation and facilitate rewarming and may be continued
during rewarming, but most often should be discontinued approximately 10 minutes before termination of bypass.
Oxygenation and ventilation must begin before discontinuation of bypass. The lungs should be manually reinflated and visually inspected to
document bilateral reinflation and elimination of atelectasis. Unilateral reinflation suggests malposition of the endotracheal tube or possibly mucus
plug or blood clot in a mainstem bronchus, which may require therapeutic bronchoscopy. Suctioning should be done carefully in the anticoagulated
patient to avoid mucosal trauma and bleeding. Occasionally, a pneumothorax or blood accumulation in the pleural space may impede reinflation, both
of which are easily corrected by the surgeon. Mechanical ventilation with 100% oxygen and a sufficient minute ventilatory volume to produce an
arterial P PCO2 of 30 to 35 mmHg should be initiated before beginning the weaning process. Minute ventilation should be higher than pre-CPB
because of the increased carbon dioxide production during rewarming, which extends into the post-CPB period. Mild hyperventilation prevents
hypercapnia and respiratory acidosis, which could result in elevated pulmonary artery pressures (PAPs) (18,19). Patients with chronic lung disease
may sometimes require positive end-expiratory pressure (PEEP), pressure controlled ventilation, or bronchodilators.
Most CPB consoles include an in-line monitor of mixed venous blood hemoglobin oxygen saturation. Changes in this parameter may reflect the
adequacy of systemic perfusion and oxygen delivery or increases in oxygen consumption (e.g., shivering) while on CPB. Before terminating CPB, the
venous saturation and pump flow should be checked. A low saturation may indicate the need for additional muscle relaxant, red blood cell
transfusion, or vasodilator therapy before weaning from bypass. Substantial reduction in extracorporeal circuit venous oxygen saturation during the
weaning process strongly suggests inadequate cardiac output for successful separation from CPB.
Hemodynamic Monitors
All routine monitors need to be returned to their full operating mode before terminating CPB. Pulse oximeter probes placed on the extremities often do
not function while the patient is cold and pulseless on CPB. Assessment of their function must wait until partial bypass is instituted. Pressure
transducers
P.606
should be re-zeroed. Frequently, the radial arterial pressure does not reflect the central aortic pressure after CPB (20,21,22). If there appears to be a
discrepancy between the transduced radial arterial pressure and the aortic pressure estimated by palpation or the blood pressure cuff, the aortic
pressure can be transduced from the antegrade cardioplegia line or stopcock on the aortic cannula once bypass is discontinued. Documenting an
adequate central aortic pressure compared to an inadequate radial pressure can prevent the administration of unnecessary vasoactive drugs.
Alternatively, a femoral arterial catheter, which will more closely reflect the central aortic pressure, can be placed. Central and peripheral arterial
pressures usually equilibrate shortly after CPB is discontinued.
Pulmonary artery catheters frequently migrate distally during manipulation of the heart during cardiac surgery (23). If the PA waveform reflects
pulmonary artery occlusion pressure, the catheter should be pulled back while on partial bypass until the phasic PAP waveform reappears. A left
atrial (LA) catheter can be a useful monitor of left ventricular preload if a pulmonary artery catheter is not present and transesophageal
echocardiography (TEE) is not being used. An LA catheter can also be used as a route for administration of inotropic drugs, especially those with
significant α-adrenergic agonist properties in the context of excessive pulmonary vasoconstriction (see subsequent text). The central venous
pressure (CVP) should be measured, especially in those patients with pulmonary hypertension or right ventricular failure. Appropriate right/left
ventricular function balance is an important variable in successful weaning.
Urine output is routinely monitored during CPB but low urine output during CPB is not independently predictive of postoperative renal dysfunction
(24). Nevertheless, for patients with preoperative renal dysfunction or low urine output during CPB higher perfusion pressures during CPB should be
considered (e.g., mean arterial pressure [MAP] >60 mmHg). Some cardiac surgical centers may have protocols for renal protection, which include
volume loading when possible to establish good urine output pre-CPB, bicarbonate infusions, or additional mannitol; no renal protection protocol has
been proven to protect renal function during CPB. After resumption of pulsatile blood flow, many patients exhibit a marked diuresis due to the
hemodilution, particularly if mannitol has been administered.
TEE provides information that can be very useful during termination of CPB. While on partial CPB, TEE provides an excellent assessment of residual
air in the heart after open procedures and allows de-airing maneuvers which can prevent a coronary air embolus post-CPB. The left ventricular short-
axis view provides a useful indicator of left ventricular size and filling. Regional wall motion abnormalities may provide an important indicator of
myocardial ischemia and inadequate flow through a specific coronary artery bypass graft (CABG). However, regional wall motion abnormalities may
also be due to residual effects of cardioplegia, inhomogeneous myocardial temperature, or preexisting abnormalities. One of the most useful
applications of TEE before and after the termination of CPB is in evaluating valvular function after valve replacement or repair (25). Epicardial
echocardiography and TEE have been proven useful in evaluating the repair of complex congenital heart defects (26,27). Also, in contrast to routine
intracardiac pressure measurements, which do not accurately reflect cardiac chamber volumes, TEE provides the capability to accurately assess
biventricular filling volumes (28,29). Direct observation of the right ventricle (RV) on the anterior surface of the heart is a useful monitor for guiding
volume infusions from the pump and can prevent the right heart from becoming overdistended.
Heart Rate and Rhythm

After the aortic cross-clamp is released and coronary reperfusion commences, cardiac electrical activity returns. This may be in the form of
ventricular fibrillation, which is likely a reperfusion arrhythmia due to calcium overload of ischemic myocardium. Lidocaine is often given before the
cross-clamp is released or in the cardioplegia and is effective at preventing ventricular fibrillation. Ventricular fibrillation during CPB may result in
ventricular distension and irreversible myocardial damage. The heart should be electrically defibrillated as soon as possible. Electrolytes should be
treated if abnormal. Recurrent ventricular fibrillation should be treated with amiodarone and repeat defibrillation. β-Adrenergic blockers are also
remarkably effective for facilitating defibrillation in resistant cases.
More commonly after hyperkalemic cardioplegic arrest, the return of cardiac electrical activity is in the form of a junctional bradycardia or sinus
bradycardia with atrioventricular conduction block. Sinus bradycardia is easily treated with atrial pacing when normal A-V conduction is present.
Sequential atrioventricular pacing is indicated for atrioventricular conduction block or significant first-degree heart block. This preserves the atrial
contribution to ventricular filling, which is a significant advantage in the presence of a noncompliant hypertrophied ventricle (hypertension, aortic
stenosis) or enlarged ventricle (aortic or mitral regurgitation). Ventricular pacing should be used only when atrial or atrioventricular pacing is not
feasible (e.g., atrial fibrillation or flutter with a very slow ventricular response) or in a backup demand mode when the patient is in sinus rhythm. In
patients with low ejection fraction and preoperative conduction system abnormalities, temporary biventricular pacing may improve postoperative
hemodynamics and prevent left ventricular dyssynchrony (30).
In the absence of TEE, all available electrocardiogram (ECG) leads should be examined and compared with a preoperative tracing before terminating
CPB to detect evidence of acute myocardial ischemia. Temporary pacing can be momentarily discontinued to make this evaluation. Transient ST-
segment elevation is common during emergence from CPB
P.607
but usually resolves shortly thereafter (31). Persistent ST-segment abnormalities suggest myocardial ischemia, which may require surgical treatment
(i.e., revision of a graft or placement of an additional graft). Intracoronary air embolism usually involves the right coronary artery, which should
resolve after a short period of increased perfusion pressure. Coronary artery or internal mammary artery spasm also produces a similar clinical
picture and often responds favorably to treatment with intravenous nitroglycerin or to elevation of the perfusion pressure.
Tachycardia before termination of CPB is more difficult to manage. Heart rate often slows with ventricular filling and increased arterial pressure;
therefore termination of CPB may slow sinus tachycardia. It is important to consider and treat other common causes of tachycardia, including
hypoxemia, hypercapnia, anemia, inadequate anesthesia, and inotropic drugs. Once these causes are eliminated and myocardial function is
determined to be adequate, the abnormal rate can be reduced with appropriate doses of β-adrenergic receptor or calcium channel blocking drugs.
The b receptor antagonist esmolol is especially useful because of its short duration of action if adverse effects develop. Refractory supraventricular
tachycardia, atrial fibrillation, or flutter is best treated with electrical cardioversion.
Ventricular Function and Prophylactic Inotropic Support

The ischemia imposed by aortic cross-clamping can result in considerable myocardial stunning, which is prolonged reversible acute postischemic
ventricular dysfunction of viable myocardium that follows reperfusion (32). In the case of chronic myocardial ischemia, successful myocardial
revascularization may improve ventricular function by restoring perfusion. However, improvements in ventricular function can be delayed for hours to
days because of myocardial stunning (33). Improved ventricular function is usually obtained after aortic valve replacement for aortic stenosis where
the compensatory response to chronic pressure overload is concentric hypertrophy of the ventricular wall that tends to normalize wall stress (34). In
contrast, myocardial dysfunction is frequently present after valve replacement in the patient with mitral regurgitation where removing the low-pressure
ejection of blood into the left atrium increases left ventricular afterload (34,35). The degree of postoperative dysfunction is less predictable in patients
with mitral stenosis or aortic regurgitation, but myocardial depression may exist because of the cardiomyopathy of rheumatic heart disease or
eccentric ventricular hypertrophy, respectively. Previous myocardial infarction is an obvious cause for irreversible myocardial dysfunction
postoperatively. Procedures requiring a left ventriculotomy may have a profound impact on postoperative ventricular function because of transection
of important coronary artery branches, resection of viable myocardium, or reduced ventricular compliance produced by left ventricular resection.
Prediction of the need for pharmacologic support after CPB is usually assessed by reviewing preoperative and pre-CPB hemodynamic data and the
intraoperative course. Information such as the preoperative ejection fraction, left ventricular filling pressures before and after contrast injection during
the catheterization, history of heart failure, pre-CPB cardiac index, the effectiveness of intraoperative myocardial protection, the length of time on
CPB, and the adequacy of surgical repair all can affect the decision to start inotropic drugs prophylactically. The goal of prophylactic administration is
to allow smooth separation from CPB without causing cardiac distension, hypotension, and reinstitution of bypass.
In a Canadian study of 12,471 patients undergoing CABG surgery, preoperative left ventricular function was important in predicting outcome. In
patients with a left ventricular ejection fraction greater than 40%, the predictors of postoperative mortality were emergency surgery, female gender,
reoperation, type of myocardial protection (blood-based cardioplegia appeared to offer greater protection than crystalloid cardioplegia), and age. The
presence of left main coronary artery disease was a predictor of death in patients with an ejection fraction greater than 40%. The type of myocardial
protection used remained correlated with mortality in patients with ejection fraction between 20% and 40% (36). In patients with an ejection fraction
less than 20%, emergency surgery was the only predictor of death (Table 25.2).
Relatively few studies have been conducted to help predict which patients will require pharmacologic support during and immediately after CPB. In a
retrospective analysis of patients who underwent CABG surgery, predictors of the need for inotropic support were essentially the same as those
identified for major morbidity and mortality (37). Preexisting low ejection fraction, a dilated left ventricle, an elevated left ventricular end-diastolic
pressure (LVEDP), longer duration of aortic cross-clamp (or total bypass) time, age, and
P.608
female gender were predictors of the need for postoperative inotropic support. Interestingly, in patients with normal preoperative ejection fractions
(EF > 55%), the presence of wall motion abnormalities and an LVEDP greater than 10 mmHg indicated a higher risk for needing inotropic support
similar to patients with lower ejection fractions (37). In another study, left ventricular dysfunction, defined as an ejection fraction less than 40%,
LVEDP more than 15 mmHg, and abnormal systolic and diastolic left ventricular volumes, correlated with the need for postoperative hemodynamic
support, either pharmacologic or with an intra-aortic balloon pump (IABP) (38) (Fig. 25.1).
TABLE 25.2. Predictors of mortality following coronary bypass surgery
N = 12,471 patients
1. Ejection Fraction (EF) >40%, n = 9,445, mortality predictors: emergency surgery, female gender, left main coronary artery disease,
reoperation, age
2. EF = 20%-40% n = 2,539, mortality predictors: emergency surgery, female gender, age, reoperation, myocardial protection (crystalloid vs.
blood)
3. EF <20%, n = 487 mortality predictors: emergency surgery only
Adapted from Christakis GT, Weisel RD, Frerres SE, et al. Coronary artery bypass grafting in patients with poor ventricular function. J
Thorac Cardiovasc Surg 1992;103(6):1083-1092, with permission.
FIGURE 25.1. Conceptualized time course of ventricular function change that occurs after cardiopulmonary bypass (CPB). (From Royster RL.
Myocardial dysfunction after cardiopulmonary bypass: recovery patterns, predictors of inotropic need, theoretical concepts of inotropic administration.
J Cardiothorac Vasc Anesth 1993;7(Suppl 2):19-25, with permission.)
Several factors, including microemboli, reperfusion injury, chest closure, incomplete rewarming, and hemodilution, may explain the observed
postoperative decline in cardiac function. One study evaluated patterns of left ventricular functional recovery after cardiac surgery. Patients with
normal preoperative ventricular function recovered completely within 24 hours while reaching a peak depression in ventricular function at 4 to 6 hours
after surgery (39). In a second group of patients with reduced preoperative left ventricular function, postoperative recovery required 24 hours or
more. A review summarized data from multiple studies and found that a decline in ventricular function occurs immediately after CPB as compared to
preoperative ventricular function, with consistent early post-CPB improvement reaching the preoperative level 1 to 2 hours after CPB (40). A decline
in function follows that, which reaches a nadir 4 to 6 hours after CPB with subsequent improvement over the next 12 to 18 hours (Fig. 25.1).
Therefore, the intuitive predictors of needing inotropic therapy after CPB are supported by clinical data, and preoperative left ventricular dysfunction
strongly predicts a requirement for postoperative inotropic support.
SEPARATION FROM CARDIOPULMONARY BYPASS: TECHNIQUE
Routine Termination of Cardiopulmonary Bypass
Separation from bypass restores the normal circulation to the heart and the lungs. The duration of the transitional period of partial bypass is
determined by the ability of the left and right ventricle (RV) to sustain the entire cardiac output. Reduced left ventricular function mandates a period of
partial bypass while ventricular loading conditions are carefully adjusted by manipulations of venous return and vascular resistance and contractility
is improved by judicious selection of positive inotropic drug therapy if necessary. During separation, ventricular distension should be avoided and
coronary perfusion pressure must be maintained.
A general approach to the termination of CPB is shown in Figure 25.2. Separation is accomplished by gradual occlusion of the venous cannula,
which decreases flow to the pump and allows more blood to pass through the heart and lungs. Arterial inflow from the pump is then gradually
reduced. Hemodynamics and ventricular function are assessed by visual inspection of the heart and by TEE. Venous cannula clamping can be
increased, arterial inflow decreased, and hemodynamics reassessed. This process is repeated until separation from CPB is complete. Hemodynamic
management for every patient focuses on regulating four primary determinants of cardiac function: rate and rhythm, arterial pressure, preload or
ventricular volume (ventricular filling pressure), and contractility (stroke volume). An algorithm for the diagnosis and treatment of hemodynamic
abnormalities at the termination of CPB is shown in Figure 25.3.
After CPB, the clinical management goal is to have a systolic arterial pressure of 90 to 100 mmHg, a normal cardiac index (>2.0 L/min/m2), and a
normal or low ventricular preload, as judged by TEE or by filling pressures of 10 to 15 mmHg. Additional volume can be infused directly from the
pump through the aortic cannula until the cannula is removed after protamine reversal. The need for additional volume infusion can be judged by
evaluating the arterial pressure and filling pressure responses. Adequate filling of the heart is assessed by direct inspection of the RV, hemodynamic
measurements, and TEE. The pulmonary artery occluded (PAO) or pulmonary artery diastolic (PAD) pressure is frequently used to guide volume
infusion at the conclusion of CPB. A pulmonary artery diastolic pressure of 10 to 15 mmHg is almost always adequate in patients after isolated
coronary artery bypass surgery. Higher pressures may be required in patients with valvular disease or pulmonary hypertension.
However, PAO or PAD pressure correlates poorly with left ventricular end-diastolic volume after coronary artery bypass surgery secondary to acute
decreases in left ventricular compliance (28). TEE clearly provides the best available clinical
P.609
intraoperative estimate of ventricular volumes (29). For example, during mild hypotension with elevated filling pressures shortly after termination of
bypass, a TEE will often reveal an underfilled ventricle. These patients can be temporarily supported with phenylephrine to raise the coronary
perfusion pressure and nitroglycerin to decrease the filling pressures. If the filling pressures decrease appropriately, additional volume may then be
administered to maintain systemic pressure and cardiac index. Often, ventricular compliance improves dramatically during the first 30 minutes of
CPB, as manifested by a spontaneous increase in coronary perfusion pressure with a simultaneous decrease in filling pressures.
FIGURE 25.2. General approach to the termination of cardiopulmonary bypass. BP, blood pressure. (From Amado WJ, Thomas SJ. Cardiac surgery:
intraoperative management. In: Thomas SJ, ed. Manual of cardiac anesthesia. 2nd ed. New York, NY: Churchill Livingstone, 1993, with permission.)
FIGURE 25.3. Algorithm for the diagnosis and treatment of hemodynamic abnormalities at the termination of cardiopulmonary bypass (CPB). BP,
blood pressure; VFP, ventricular filling pressure; SV, stroke volume; Dx, diagnosis; SVR, systemic vascular resistance; CVP, central venous
pressure; LAP, left atrial pressure; Rx, treatment; PA, pulmonary artery; IABP, intra-aortic balloon pump; PGE1, prostaglandin E1; NO, nitric oxide;
LVAD, left ventricular assist device; RVAD, right ventricular assist device; RV, right ventricle. (From Amado WJ, Thomas SJ. Cardiac surgery:
intraoperative management. In: Thomas SJ, ed. Manual of cardiac anesthesia. 2nd ed. New York, NY: Churchill Livingstone, 1993, with permission.)
Systemic vascular resistance progressively decreases with rewarming and continues to decrease during the period after CPB. Pronounced
vasodilation at the termination of CPB can be related to the duration of rewarming, comorbid diseases which can cause peripheral neuropathy such
as diabetes, chronic drug therapy such as angiotensin-converting enzyme (ACE) inhibitors, vasoplegia associated with left ventricular assist device
(LVAD) placement, or septicemia in cases of infective endocarditis. This condition is manifested by hypotension with low filling pressures, a normal-
to-high cardiac index and good ventricular function on TEE (other than with LVAD). Vasoconstrictors such as phenylephrine are effective treatment
because they stimulate a-adrenergic receptors which increase arterial blood pressure by increasing systemic vascular resistance (afterload) and by
venoconstriction which increases venous return (increasing preload). If refractory
P.610
arterial vasodilation is present or if vasodilation is combined with mildly reduced left ventricular function, norepinephrine may be appropriate to
counteract the vasodilation while providing some degree of inotropic support to meet the increased afterload. In septic patients or patients receiving
ACE inhibitors who are refractory to phenylephrine and/or norepinephrine, vasopressin should be considered. Some studies have shown reduced
endogenous vasopressin in these patients and a dramatic response to exogenously administered vasopressin.
Pure α-adrenergic receptor agonists are useful for hypotension in patients with good ventricular function. The beneficial increase in coronary
perfusion pressure usually outweighs the negative effects of decreased cardiac output and increased filling pressures in the patient with coronary
artery disease or ventricular hypertrophy. In general, pure α-adrenergic agonists to increase arterial blood pressure in patients with poor ventricular
function or pulmonary hypertension are best avoided because increased afterload without a compensatory increase in contractility decreases stroke
volume.
SEPARATION FROM CARDIOPULMONARY BYPASS: DIFFICULT SITUATIONS

Left Ventricular Failure
Ventricular failure or dysfunction can be defined as inadequate cardiac pump performance despite appropriate adjustments of rate, rhythm, preload,
and afterload to allow separation from bypass. This may derive from a decrease in myocardial contractility that can be either acute from ischemic or
reperfusion injury or chronic from preexisting cardiac dysfunction. If acute ischemia is suspected, as in incomplete revascularization, nitroglycerin can
be administered to maximize coronary blood flow and improve diastolic relaxation while coronary perfusion pressure is controlled. Supplemental
calcium should ideally be avoided with myocardial stunning. If prophylactic inotropes were administered for preexisting cardiac dysfunction, and the
hemodynamics do not improve rapidly, additional support may be required. If additional inotropes and vasoactive drugs are not effective, partial or full
cardiopulmonary bypass should be reinstituted while therapy is optimized. This will allow the heart to recover from a period of hypotension and
cardiac distension while additional therapy takes effect. Additional time on partial CPB will allow more time for the postischemic recovery of
ventricular function (41).
Initial therapy of left ventricular dysfunction is usually achieved with positive inotropic drugs, of which there are several clinically useful categories. A
comparison of mild ventricular dysfunction after separation from CPB and the result of inotropic treatment can be analyzed by pressure-volume loops
(Fig. 25.4). Calcium chloride or calcium gluconate (Table 25.3) has a positive inotropic effect in the presence of hyperkalemia or hypocalcemia but
are ineffective at augmenting contractility in the presence of normal ionized calcium concentrations and may actually be harmful because of
vasoconstriction and of the detrimental effects of elevated intracellular Ca2+ in ischemic cells after reperfusion (42).
FIGURE 25.4. A: Idealized pressure-volume loop with corresponding events of the cardiac cycle under normal conditions. A, mitral valve opens and
ventricular filling begins; B, mitral valve closes: end-diastolic volume (EDV) and end-diastolic pressure (EDP); C, aortic valve opens after isovolumic
contraction; D, aortic valve closes: end-systolic volume (ESV) and end-systolic pressure (ESP). The stroke volume (SV) is EDV-ESV. B: Pressure-
volume loop demonstrating mild ventricular dysfunction after separation from cardiopulmonary bypass. Loop A shows an increase in end-diastolic
volume, a reduced end-systolic pressure-volume relation (ESPVR) and reduced stroke volume. Inotropic therapy will usually increase contractility as
illustrated by the shift from ESPVR (A) to ESPVR (B). Stroke volume increases, end-systolic and end-diastolic volumes decrease. (From Amado WJ,
Thomas SJ. Cardiac surgery: intraoperative management. In: Thomas SJ, ed. Manual of cardiac anesthesia. 2nd ed. New York, NY: Churchill
Livingstone, 1993, with permission.)
β-Adrenergic receptor agonists are the most potent and widely used inotropes. Myocardial activation of the β1 receptor leads to modulation of the G-
protein system which activates adenyl cyclase. This enzyme leads to the formation of cyclic 3′,5′-adenosine monophosphate (AMP) from adenosine
triphosphate (ATP). Increased intracellular concentrations of
P.611
P.612
cyclic AMP lead to increased availability of Ca2+ to the contractile apparatus in the sarcomere, which increases the speed and force of contraction
(Fig. 25.5). In addition to increasing the force of contraction (a positive inotropic effect), β-adrenergic receptor activation leads to an increase in the
slope of diastolic depolarization and heart rate (positive chronotropic effect), in the speed of conduction of the electrical impulse throughout the
myocardium (a positive dromotropic effect), and in the speed of relaxation of the myocardium during diastole (a positive lusitropic effect). Because of
these widespread cardiac effects, β-adrenergic agonists have been at the core of the “therapeutic armamentarium” for treating acute ventricular
dysfunction after CPB. A number of different β-adrenergic agonists are available (Table 25.3). These drugs have varying actions at β1, β2, and a-
adrenergic receptors. Typically, a specific drug is best selected based on the specific hemodynamic abnormality being treated and the drug’s relative
actions at each receptor type.
TABLE 25.3. Inotropes used in the termination of cardiopulmonary bypass (CPB)
Adverse
Drug Dose Mechanism Actions Indications Contraindications effects
Calcium 2-10 mg/kg IV ↑ Ca2+i Inotrope if Hypocalcemia (from Hypercalcemia Coronary artery
chloride bolus Effects hypocalcemic CPB, albumin, Pancreatitis spasm
Calcium last 10-20 min Vasopressor if citrate) Digitalis toxicity Pancreatitis
gluconate normocalcemic Hyperkalemia
Hypotension (e.g.,
secondary to
protamine)
Myocardial
depression (e.g.,
secondary to
residual
cardioplegia or
hypocalcemia)
Calcium channel
blocker overdose
Epinephrine Low-dose α1-Receptor Inotrope: β1- Ventricular HOCM(relative) Vasoconstriction

infusion 1-4 (↑ Ca2+i) effect dysfunction Tetralogy of Fallot (splanchnic,
μg/min (0.02- Vasopressor: Vasodilation (with RV outflow renal)
β1-Receptor
0.06 μg/kg/min), α1-effect at Anaphylaxis tract obstruction, Arrhythmias
primarily β (↑ cAMP) Bronchoconstriction relative)
higher doses
Moderate dose β2-Receptor
Vasodilator: β2-
infusion 4-10 (↑ cAMP)
effect primarily
μg/min (0.06- in muscle
0.15 μg/kg/min), Chronotrope:
mixed α and β β1-effect
High-dose
Bronchodilation:
infusion 10-20
β2-effect
μg/min (0.15-
0.3 μg/kg/min),
primarily
a;potent
vasoconstriction
2-8 μg IV bolus
Norepinephrine 4-20 μg/min β1-Receptor Inotrope: β1- Ventricular See epinephrine Vasoconstriction
(0.05-0.3 (↑ cAMP) effect dysfunction (splanchnic,
μg/kg/min) α1-Receptor Vasopressor: Vasodilation renal)
α1-effect Anaphylactic Shock Arrhythmias
(↑ Ca2+i)
Chronotrope:
β1-effect
Dopamine 0.5-2 μg/kg/min α1-Receptor Inotrope: β1- Ventricular See epinephrine Tachycardia
(activation of effect dysfunction Peripheral
(↑ Ca2+i)
DA1 receptors) Vasopressor: Vasodilation vasoconstriction
β1-Receptor Renal Arrhythmias
>2 μg/kg/min α1-effect
(activation of β1 (↑ cAMP) dysfunction/oliguria
Renal
DA1-
receptors) vasodilator and
>5 μg/kg/min Receptor (↑ natriuretic: DA1
(activation of α1 cAMP)
effect
receptors) Chronotrope:
β1-effect
Dobutamine 2-20 μg/kg/min β1-Receptor Inotrope: β1- Vasoconstriction See epinephrine Tachycardia
(↑ cAMP) effect Ventricular
α1-Receptor Vasodilator: β2- dysfunction
effect Transplantation
(↑ Ca2+i)
Chronotrope:
β1-effect
Isoproterenol 1-5 μg/min β1-Receptor Inotrope: β1- Ventricular See epinephrine Tachycardia
(0.02-0.07 (↑ cAMP) effect dysfunction, Vasodilation ↑
μg/kg/min) β2-Receptor Vasodilator: β2- especially RV MVo2
(↑ cAMP) effect Bronchoconstriction
Bronchodilation: Bradycardia:
β2-effect profound β-
blockade, AV block,
Chronotrope:
Cardiac transplant
β1-effect
Pulmonary
hypertension:
primary, secondary
Milrinone 0.05 mg/kg IV PDE III Ventricular Vasodilation

bolus (slow), inhibition (↑ dysfunction
0.5 μg/kg/min cAMP) (↑
infusion Ca2+i)
Inotrope:
due to ↑
cAMP
Vasodilator:
due to ↑
cAMP
Ephedrine 5-10 mg IV α1-Effect (↑ Vasopressor: Ventricular See epinephrine Tachycardia

bolus Ca2+i) α1-effect dysfunction
Inotrope: β1- Vasodilation
β1-Effect (↑
cAMP) effect ↓ Venous
capacitance
Ca2+, intracellular ionized calcium; cAMP, cyclic adenosine monophosphate; RV, right ventricular; DA, dopamine; MV MVo2, myocardial O2
consumption; AV, atrioventricular; PDE, phosphodiesterase; HOCM, hypertrophic obstructive cardiomyopathy; CPB, cardiopulmonary
bypass.
Epinephrine and norepinephrine are useful when ventricular dysfunction is accompanied by peripheral vasodilation, because they are also potent a-
receptor agonists. The vasopressor effect of norepinephrine is greater than that of epinephrine because of the greater potency of epinephrine at the
β2 receptors, which produce considerable vasodilation in skeletal muscle and other major vascular beds. Dobutamine and dopamine are useful when
minimal or mild inotropic support is desired, although the wisdom of selecting a drug with less adrenergic agonist potency (i.e., dopamine or
dobutamine) as opposed to careful titration of a more potent drug (i.e., epinephrine) is very debatable. Dobutamine is a β1, β2 receptor agonist with
only minimal a-receptor activity and may therefore be useful when further vasoconstriction is undesirable. Dopamine is unique in that it stimulates
renal dopamine receptors and causes an increase in both renal blood flow and sodium excretion (43,44); however, the use of dopamine increases
morbidity in septic shock patients and there is an increased risk of infection when it is used chronically. Dopamine as an inotrope at higher doses
(>8-10 μg/kg/min) is complicated by its increasing activity at a-adrenergic receptors, which may produce undesirable increases in systemic and
pulmonary vascular resistance. The partial dependence of the inotropic effects of dopamine on the release of endogenous
P.613
catecholamines (i.e., indirect effect) may also limit its efficacy in patients with chronic heart failure after CPB. At high doses, both dobutamine and
dopamine tend to induce tachycardia and atrial arrhythmias (45,46). At equally effective inotropic doses, dobutamine and dopamine both appear to
have stronger arrhythmogenic potency than does epinephrine (45).
FIGURE 25.5. Cyclic adenosine monophosphate (AMP)-mediated intracellular pathways for inotropic stimulation. Cascade of cyclic AMP effects
leading to increased inotropy. PDE, phosphodiesterase, ATP, adenosine triphosphate.
Isoproterenol is a nonselective β-adrenergic receptor agonist that is a potent inotrope (β1 effect) and peripheral vasodilator (β2 effect) which is more
potent than dobutamine. The potent chronotropic effect of isoproterenol (β1 effect) is not compensated for by the baroreceptor-mediated reflex
bradycardia that occurs with β-adrenergic receptor agonists that also possess intrinsic α-adrenergic receptor activity like norepinephrine. Either
isoproterenol or dobutamine may be useful in patients with severe pulmonary hypertension and right ventricular failure, because of the lack of α-
adrenergic receptor stimulation, which has a potent pulmonary arterial vasoconstrictive effect. Isoproterenol and dobutamine are also useful for the
treatment of slow ventricular rates or atrioventricular conduction disturbances when other methods have failed because of the positive chronotropic
and dromotropic effects of β-adrenergic stimulation. These effects are also clinically useful in cardiac transplantation when dealing with the acutely
denervated transplanted heart.
In general, epinephrine appears to be the most useful adrenergic drug for inotropic stimulation for adult cardiac surgical patients after CPB, perhaps
because of its combined β1, β2, and a-adrenergic actions. Dopamine and isoproterenol are often favored in the pediatric population because of
advantages of a higher heart rate. However, patterns of inotrope use show significant institutional variation, and the literature describing comparative
effects of the drugs in patients requiring inotropic support, especially larger-scale well-designed clinical trials, is sparse. One well-designed trial
documented the increased efficacy of epinephrine as compared with calcium chloride for increasing cardiac performance after CPB (47). In this
study, epinephrine had superior hemodynamic effects as compared with calcium. And calcium, when given to normocalcemic patients, had no
predictable effect on cardiac output but did increase mean arterial pressure. The use of dopamine or epinephrine as an inotrope in severe left
ventricular dysfunction is limited by dose-dependent increases in afterload
P.614
and preload. These undesirable side effects are the basis for the frequent clinical use of combined inotropic stimulation and afterload reduction with
direct-acting vasodilators such as nitroprusside or nitroglycerin (48).
Another class of positive inotropic drugs, the phosphodiesterase (PDE) enzyme inhibitors, has contributed greatly to the ability to treat myocardial
failure after CPB. Although these drugs also increase the intracellular concentration of cyclic AMP, they produce this effect by an entirely different
mechanism, inhibiting the metabolic breakdown of intracellular cyclic AMP. Several classes of drugs have the property of PDE inhibition (Table 25.4).
Benzylisoquinolines (e.g., papaverine) and methylxanthines (e.g., aminophylline) are examples of nonspecific inhibitors of PDE. The PDE enzymes
have several isoforms, of which type III predominates in the myocardium and in vascular smooth muscle. The selective type III PDE inhibitor used
most often clinically is the bipyridine derivative milrinone. In vascular smooth muscle, milrinone increases concentrations of cyclic AMP and
guanosine monophosphate (GMP), which produces significant vasodilation. Clinically, these drugs produce mild to moderate improvement in cardiac
contraction that is often overshadowed by the more marked improvement in cardiac pump performance produced by the combined inotropic,
lusitropic, and peripheral vasodilation effects. The inotropic activity of the PDE III inhibitors is synergistic with that of β-adrenergic agents (Fig. 25.6)
and may not be associated with increased myocardial oxygen consumption; these properties have made this combination therapy with epinephrine or
norepinephrine particularly useful in patients with severe left ventricular dysfunction (49,50). Because of the significant vasodilation that occurs with
milrinone, an a-adrenergic vasoconstrictor, usually phenylephrine or norepinephrine, may be required to maintain coronary perfusion pressure
(51,52). Alternatively, vasopressin may fulfill this need. Some advocate administration of milrinone before weaning is attempted so that the flow from
the pump can counteract the vasodilation that occurs during loading.
Milrinone’s inotropic effect is independent of β-adrenergic receptor activation. This confers an advantage to PDE III inhibitors in patients with
downregulation of the β-adrenergic receptors as in chronic heart failure. This downregulation may also occur in the more acute immediate
postoperative period. The desensitization of β-adrenergic receptors that occurs in congestive heart failure limits the efficacy of β-adrenergic agonists.
Combined therapy with PDE III inhibitors enhances the inotropic effect of β-adrenergic receptor agonists by potentiating the rise in intracellular cyclic
AMP. Such combined therapy may also permit use of a lower dose of the β-adrenergic agonist, thereby avoiding possible adverse side effects such
as arrhythmias.
TABLE 25.4. Phosphodiesterase inhibitors
Nonspecific
Benzylisoquinolines (e.g., papaverine)

Methylxanthines (e.g., aminophylline)
Fraction III specific
Bipyridines (e.g., milrinone, amrinone)

Imidazolones (e.g., enoximone)
FIGURE 25.6. Change in stroke volume (SV) for the control (C), epinephrine (E), amrinone (A), and amrinone plus epinephrine (A + E) groups. The
change in stroke volume for the A + E group is at least additive to the change in A and E alone (clear area).*p < 0.05 compared to baseline and †p <
0.05 compared to C and E. (From Royster RL, Butterworth JF, Prielipp RC, et al. Combined inotropic effects of amrinone and epinephrine after
cardiopulmonary bypass in humans. Anesth Analg 1993;77:662-672, with permission.)
If ventricular function remains inadequate despite appropriate inotropic therapy, the addition of mechanical support may be required to allow
termination of CPB (53). An intra-aortic balloon pump (IABP) should be considered in a patient with poor preoperative ventricular function and
postoperative low cardiac output syndrome (54). If difficulty or failure is encountered when terminating CPB despite maximal pharmacologic therapy,
the IABP should be inserted while still on bypass to prevent ventricular distension. If terminating bypass continues to be a problem despite maximum
pharmacologic therapy plus an IABP, then a ventricular assist device (VAD) should be considered.
Right Ventricular Failure

Acute right ventricular (RV) failure has been reported to occur in 0.04% to 0.1% of cardiac surgery patients. The incidence increases dramatically
following heart transplantation and placement of left ventricular assist devices (55). Refractory acute RV failure is associated with higher long-term
mortality when compared to those suffering from isolated LV failure (56). Cardiac surgery patients may present with varying degrees of right
ventricular dysfunction as a result of preexisting medical
P.615
disease and/or underlying cardiac pathology. When combined with the acute insult of ischemia and reperfusion of the heart, postoperative right
ventricular failure becomes more likely.
Unlike the robust, relatively thick cone-shaped left ventricle, the right ventricle is anatomically designed to maximize its efficiency as a thinner,
compliant, low-pressure pump. The RV lacks circumferentially oriented myofibers, which results in a more longitudinal contractile motion and
peristaltic intracavitary flow (57). The geometry of the normal right ventricle also takes advantage of the simultaneous LV septal contraction, which
facilitates forward flow even in the absence of right ventricular depolarization (58). Not surprisingly, both RV dilation and ventricular dyssynchrony via
bundle branch blocks or RV pacing reduce right ventricular performance.
The right ventricle is uniquely susceptible to intraprocedureal injury due to the anterior (uppermost coronary artery in supine position) position of the
right coronary artery and its propensity to receive air emboli, the relative lack of robust right coronary artery collaterals, and the anterior position of
the RV itself within the mediastinum. This front and center location promotes ventricular warming from the ambient environment making
cryoprotection more difficult to sustain.
Intraoperative events that may worsen postoperative RV function include inadequate myocardial protection, right intracoronary air, thrombus or
embolic phenomena, right coronary artery damage or occlusion, chronic pulmonary hypertension, acute increases in pulmonary arterial pressure from
inadequate ventilation/oxygenation, drug interactions, light anesthesia, and aggressive volume loading (resulting in acute RV distention and
worsening tricuspid insufficiency) (59) (Fig. 25.7). Early recognition and timely management of these triggers may avoid fulminant RV failure and a
need for emergent return to CPB.
FIGURE 25.7. Right ventricular failure post-cardiopulmonary bypass. RV, right ventricular; TR, tricuspid regurgitation; TEE, transesophageal
echocardiography; PA, pulmonary artery; CVP, central venous pressure; LA, left atrial; RVAD, right ventricular assist device.
Evaluation should include intraoperative TEE to assess for RV enlargement, moderate or severe tricuspid regurgitation (TR), evidence of volume or
pressure overload, and global ventricular function. Increased pulmonary artery pressures and/or CVPs, decreased arterial pressure and cardiac
output, and a bulging RV usually characterize right ventricular failure. Pulmonary artery occlusion (or LA) pressure and left ventricular volume
assessed by TEE will be low or normal if right ventricular failure is associated with normal left ventricular function. However, these measurements will
be abnormal if right ventricular and left ventricular dysfunctions coexist.
The therapeutic goals in treating right ventricular dysfunction are similar to those in treating left ventricular dysfunction: increase ventricular
contractility and decrease afterload (PAP) while maintaining adequate preload (CVP) and coronary perfusion pressure. It is more difficult to achieve
these objectives due to the pulmonary vasoconstriction induced by most adrenergic positive inotropes with a-receptor agonist effects. It is critical to
maintain adequate systemic arterial pressure in the presence of right ventricular failure to provide adequate coronary perfusion pressure to the
distended RV, which will typically have an elevated diastolic pressure resisting perfusion. Because of the relatively thin wall of the RV,
intramyocardial wall tension is higher for any given level of intracavitary pressure than is the case for the left ventricle, as predicted by the Laplace
relationship. This increases oxygen consumption and compromises coronary blood flow.
These hemodynamic effects may be best achieved by inhaled pulmonary vasodilators combined with inotropic/
P.616
vasopressor drugs administered prior to separation from bypass (Table 25.5). Unlike other vasodilators, inhaled nitric oxide is very selective for the
pulmonary circulation because it is largely taken up by hemoglobin before reaching the systemic circulation and causing systemic vasodilation. The
inhaled prostacyclin analogs, epoprostenol, and iloprost, also have the advantage over intravenous drugs in that their effects are limited to the
pulmonary circulation. Inhaled iloprost has been shown to be an effective pulmonary vasodilator in severe pulmonary hypertension and is very useful
in the treatment of pulmonary hypertension and right ventricular failure after CPB (60). In refractory cases of RV failure, NO and inhaled prostanoids
may be used in combination to provide an additive effect given their different mechanisms of action (61). Continuation of pre-CPB inhaled
epoprostenol while on CPB should be avoided, as it has been associated with markedly increased post-CPB bleeding (62).
Inotropic drugs like isoproterenol or dobutamine can be infused into the right atrium and are useful for increasing right ventricular contractility without
significantly increasing PAP (afterload), although problems with tachycardia and arrhythmias may occur. The PDE III inhibitors are highly useful in
treating right ventricular dysfunction and pulmonary hypertension after CPB because of their ability to increase right ventricular contractility and
reduce pulmonary vascular resistance, although systemic hypotension often occurs and vasoconstrictors may be necessary to maintain coronary
perfusion pressure (63). Vasopressin has little direct effect on the pulmonary vasculature due to the relative lack of V1a receptors in the lungs. In
practice, both an adrenergic agonist such as norepinephrine and a low-dose infusion of vasopressin can be used to achieve acceptable systemic
pressures without creating intolerable increases in PVR. Selective infusion of pulmonary vasodilators into the right atrium and vasopressors into the
left atrium through a left atrial catheter is another method to achieve the desired goals. This has been demonstrated by infusing prostaglandin E1
(30-50 mg/kg/min) into the right atrium and norepinephrine into the left atrium in patients with refractory right heart failure after mitral valve
replacement (64). Alternatively, nitroglycerin can be infused into the right atrium as the pulmonary vasodilator.
TABLE 25.5. Pharmacologic therapy for the treatment of right ventricular failure with pulmonary hypertension
Drug Dose Class Mechanism of action T½ Comments
Milrinone Load: 50 μg/kg Bipyridine Phosphodiesterase 3 inhibitor 30-60 min Inodilator.

(consider 12.5-25 (healthy Inhibition of
μg/kg to attenuate volunteers) vascular smooth
hypotension) 2.5-hr muscle.
0.375-0.75 average Reduces both
μg/kg/min (CHF PVR and SVR.
continuous IV patient) 90% renally
infusion eliminated
Levosimendan 6-24 μg/kg IV over Pyridazinone- Ca sensitizer/PDE-3 inhibition Parent Active

10 min; 0.1 dinitrile drug (1 hr) metabolites
μg/kg/min derivative Active primarily renally
thereafter metabolite eliminated.
OR 1896 Caution if GFR
(80 hr) <30 mL/min
Nitric Oxide 5-40 ppm inhaled EDRF Promotes cGMP formation within VSM 0.05-1.8 Rebound pHTN
resulting in decreased Ca entry, K ms in may occur with
hyperpolarization, and increased myosin human rapid
light-chain phosphatase activity plasma discontinuation
Epoprostenol 20,000 ng/mL Prostaglandin Promotes cAMP formation within VSM 6 min Rebound pHTN
continuous resulting in inhibition of myosin light-chain may occur with
nebulization kinase activity rapid
discontinuation
Iloprost 2.5-5 μg Prostaglandin As above 20-30 min

nebulization q 2-4
hr. Max 9 doses in
24 hr
IV, intravenous; EDRF,endothelium-derived relaxing factor; cGMP, cyclic guanosine monophosphate; VSM, vascular smooth muscle; Ca,
calcium; PDE-3, phosphodiesterase 3; GFR, glomerular filtration rate; K, potassium; pHTN, pulmonary hypertension; ms, milliseconds;
cAMP, cyclic adenosine monophosphate; μg, micrograms; ng, nanograms; q, every; ppm, parts per million.
Other manipulations to decrease pulmonary vascular resistance include hyperventilation to induce hypocapnia, a reduction in tidal volume and
inspiratory time, and avoidance of hypoxemia and acidemia. If these measures fail, mechanical support may be required either in the form of an IABP
or a right VAD. IABP improves RV failure by maintaining coronary perfusion to an overdistended right ventricle.
Vasoplegic Syndrome
Vasoplegic syndrome (VS) is a known complication of cardiac surgery that may complicate weaning from cardiopulmonary bypass and contribute to
significant complications in the postoperative period. Specific hemodynamic criteria vary,
P.617
but the vasoplegic syndrome is generally characterized as a distributive shock state with severe hypotension, decreased systemic vascular
resistance (SVR), normal-to-high cardiac output, low filling pressures, and poor response to intravascular volume and vasopressors. This syndrome
occurs in 5% to 20% of adult patients after cardiopulmonary bypass, but may be greater than 40% in patients undergoing placement of a left-
ventricular assist device. VS is associated with prolonged ICU and hospital stays and poor clinical outcomes (65). It can lead to multiorgan
hypoperfusion and subsequent multisystem organ failure with mortality as high as 25% if it persists beyond 36 to 48 hours postoperatively (66).
The etiology of VS is not completely understood and is likely multifactorial. Systemic activation of vasodilator mechanisms, as well as resistance to
vasopressors, contributes to the overall picture. Multiple studies have identified the preoperative use of heparin, angiotensin-converting enzyme
inhibitors, β-blockers, and calcium channel blockers as well as the postoperative use of amiodarone and phosphodiesterase inhibitors as
pharmacologic risk factors. Patient and surgical risk factors include preoperative EF <35%, higher additive EuroSCORE, pre-CPB hemodynamic
instability, and the duration of CPB (38% increased risk for every additional 30-minute interval) (65,67,68).
Identification of the underlying mechanisms for the decreased vascular tone and potential treatment remain areas of active research and debate.
Several mechanisms have been proposed to contribute to vasoplegic syndrome including the activation of ATP-sensitive potassium channels (Katp
channels) in vascular smooth muscle, the activation of the inducible form of nitric oxide synthase, and a relative deficiency of vasopressin (69).
Despite the high incidence of this syndrome, high-quality data to help guide appropriate selection of vasopressor therapy are lacking.
Norepinephrine, phenylephrine, vasopressin, and high-dose dopamine are all common selections for the treatment of decreased vascular tone.
When the target MAP cannot be achieved with one of these agents, the addition of another agent with an alternative mechanism of action can allow
restoration of organ perfusion. In studies comparing norepinephrine combined with vasopressin to norepinephrine alone, the combination of the two
resulted in significantly higher MAP and decreased norepinephrine requirements without significant adverse effects. Prophylactic therapy with
vasopressin infusions in at-risk patients starting before CPB has also been employed, resulting in reduced postoperative hypotension and
vasopressor requirements (70,71).
Methylene blue has also emerged as a potential therapy for vasoplegic syndrome, though its use remains mostly investigational. Methylene blue
inhibits nitric oxide synthesis and scavenges nitric oxide. It also inhibits soluble guanylate cyclase, which may otherwise be activated by substances
like interleukins and oxygen free radicals. All of these actions ultimately reduce the production of cyclic GMP, thereby improving vascular smooth
muscle contractility (70). Methylene blue shows promise in both prophylactic and rescue therapy for vasoplegia with few reported adverse effects,
although the data supporting its use remain confined to small sample sizes (66,72,73,74). Furthermore, optimal dosing regimens have not been
clearly defined. Methylene blue is contraindicated with severe renal impairment and should be used with great caution in patients taking serotonergic
medications since it is a potent monoamine oxidase inhibitor. Other transient adverse reactions are cardiac arrhythmias, coronary vasoconstriction,
decreased cardiac output and renal blood flow, increased pulmonary vascular resistance, and worsened gas exchange at high doses (67). Future
studies may help guide standardized dosing and optimal timing of administration.
In patients undergoing heart transplantation, independent risk factors for vasoplegia include thyroid disease and ventricular assist devices (75).
Other notable associated risk factors included the degree of heart failure, CPB and ischemic time, previous sternotomy, platelet transfusion, aspirin,
and larger body mass. Refractory cases of vasoplegia in cardiac transplantation may respond to plasmapheresis, which has been successfully used
in the authors’ institution in a nontransplant heart failure patient following cardiac surgery.
Delayed Acute Hemodynamic Deterioration

Sudden hemodynamic collapse can result from cardiac arrhythmias, graft or valve malfunction, air embolus to the right coronary artery, reactions to
medications (often to protamine), or to the adverse hemodynamic effects of closure of the pericardium or the sternum. The latter can result in
compression of the heart producing a tamponade effect, which may improve with volume infusion or inotropic support as the heart adjusts to the
altered loading conditions. The pericardium may need to be reopened. In severe cases, the sternum may have to be left open for closure at a later
date. Acute myocardial ischemia produced by kinking, clotting, or embolization of a coronary artery graft may require surgical revision. This is usually
associated with acute changes in the ECG, often with ST-segment elevation and occasionally with arrhythmias. Coronary (or mammary graft)
vasospasm or delayed coronary air is another cause of acute ischemia after CPB. Treatment of coronary spasm includes nitroglycerin or calcium
channel blockers. Intracoronary air can be treated with an increased coronary perfusion pressure (phenylephrine) and coronary vasodilation
(nitroglycerin). Other causes of acute hemodynamic deterioration include arrhythmias, which may be secondary to new myocardial ischemia; other
metabolic or electrolyte abnormalities; to atrial decannulation; and to surgical manipulation of the heart. In this situation, TEE can provide vital
diagnostic information about new regional wall motion abnormalities, valve function, and ventricular filling to help determine the most appropriate
therapy. Occasionally, acute hemodynamic deterioration from any cause may result in ventricular tachycardia or fibrillation. Patients will need
electrical defibrillation of the heart and sometimes emergency reinstitution of CPB if hemodynamic instability continues after defibrillation.
P.618
Postbypass Hypertension
Because it is common to turn off inhalational agents before separating from CPB, light anesthesia often contributes to post-CPB hypertension. If
inadequate anesthesia is suspected, inhalational agents can be administered, but some prefer to administer bolus doses of a short-acting vasodilator
(e.g., nitroglycerin, nicardipine) and await completion of protamine administration before resuming inhalational agents. Additional narcotics or
benzodiazepines can be administered judiciously based on whether the patient is a candidate for “fast-track” extubation. Intravenous bridging
medications such as propofol or dexmedetomidine, which are more commonly used for unconscious sedation during transport from the operating
room until extubation, might be beneficial as well.
Although positive inotropes are useful in improving the contractile state of the failing ventricle, sometimes they can contribute to postbypass
hypertension in patients with reduced compliance of their vascular system. Systemic vascular resistance and ventricular afterload then increase,
which could be detrimental to myocardial function in a failing heart. Vasodilators can not only treat postbypass hypertension, but can improve
ventricular function by optimizing loading conditions (76). Nitroglycerin is often administered during coronary artery bypass surgery to prevent
myocardial ischemia or arterial conduit vasospasm. Nitroglycerin can reduce afterload as well as preload and treat hypertension, especially at higher
doses. Esmolol can be effective in reducing hypertension and tachycardia with careful titration in patients requiring inotropes, although intuitively it
seems more appropriate to reduce inotropic support in that scenario. However, low serum levels of β-adrenergic receptor blockers reduce heart rate
without inducing significant negative inotropic effects. Other classes of vasodilating drugs such as calcium channel blockers (e.g., nicardipine),
dopaminergic agonists (e.g., fenoldopam), and natriuretic peptides (e.g., nesiritide) have been used to treat hypertension (77,78,79). Occasionally, in
refractory cases, the obsolescent drug sodium nitroprusside may still be used, as it remains highly effective in managing these more difficult cases of
postbypass hypertension.
Hypoxemia
Hypoxemia can be a serious problem in the immediate post-CPB period if not quickly recognized and treated. A frequent etiology is atelectasis, which
can be largely corrected by vigorous lung reexpansion and the addition of positive end-expired pressure (PEEP). Visualization of expansion of both
lungs is necessary prior to emergence from CPB. Bronchospasm may be caused by preexisting pulmonary disease, light anesthesia, a systemic
inflammatory response to CPB, or protamine administration. It is often recognized by high peak inspiratory pressures, poor lung deflation, and a
shallow slope on the expiratory phase of the capnogram. Clinically significant bronchospasm is best treated with aerosolized β2-adrenergic agonists,
volatile anesthetic agents if ventricular function and MAP are satisfactory, methylxanthines, or intravenous epinephrine or isoproterenol.
Right-to-left intracardiac shunt, which may occur with congenital heart disease or in patients with a patent foramen ovale and elevated right atrial
pressure, may require mechanical correction. Early intraoperative diagnosis is made possible by TEE. Low cardiac output may be associated with
hypoxemia, especially when accompanied by right-to-left intrapulmonary shunting, high oxygen consumption, and/or low oxygen delivery (anemia).
Intravenous nitrates and milrinone increase intrapulmonary shunting due to inhibition of hypoxic pulmonary vasoconstriction.
Pulmonary edema prior to institution of bypass can present problems post-CPB. Patients with pulmonary edema should have frequent suctioning of
the lungs before going on CPB because hypothermia may cause the edema fluid to become more viscous and more difficult to remove after CPB.
Noncardiogenic pulmonary edema is usually caused by allergic reactions to drugs or blood products. Pneumothorax, hemothorax, or hydrothorax is
usually clinically evident, as distended pleurae are visible in the surgical field, and TEE usually facilitates diagnosis. Many other causes of hypoxemia
after CPB are not specific to cardiac surgery, including inadequate ventilation, anesthesia circuit disconnect, endobronchial intubation, endotracheal
tube kinking, or obstruction of the endotracheal tube with a mucus plug or clot. Occasionally diagnostic or therapeutic bronchoscopy is required.
Despite assessment of adequate oxygen saturation using pulse oximetry and ventilation using end-tidal CO2, arterial blood gases should be checked
soon after the termination of CPB to assess the adequacy of ventilation and oxygenation.
SEPARATION FROM CARDIOPULMONARY BYPASS: CONTROVERSIAL ISSUES

Calcium Administration
Routine administration of calcium salts at the end of CPB is not beneficial and may be harmful. Exceptions include patients with evidence of
hypocalcemia or hyperkalemia. The incidence of hypocalcemia during CPB is relatively high, but ionized calcium usually approaches normal values
immediately before termination of bypass due to an increase in parathyroid hormone (9). Moreover, considerable evidence suggests that elevated
intracellular Ca2+ is correlated with increased cell death and injury during ischemia and reperfusion, as occurs frequently during cardiac surgery (42).
One study suggests that calcium chloride administration during emergence from CPB in patients with good ventricular function has no significant
effect on cardiac index (47) (Fig. 25.8). Use of calcium salts at the conclusion of CPB should be guided by serum ionized calcium levels. Improved
ventricular function is produced experimentally by Ca2+ administration in the presence of ionized hypocalcemia (80). Calcium salts should
P.619
not be routinely administered to patients with good ventricular function in the absence of hypocalcemia or hyperkalemia because of the potential
detrimental effects of iatrogenic hypercalcemia, especially in a calcium-overloaded reperfused/ischemic myocardium.
FIGURE 25.8. Cardiac index during the first phase of the study comparing calcium (n = 20) (circles) and placebo (n = 20) (triangles) groups. The
asterisk denotes a significant increase in cardiac index in both groups compared to time 0 (p < 0.05). However, there was no difference between
groups, indicating that an improvement in cardiac function occurs during the first few minutes after discontinuation of cardiopulmonary bypass despite
calcium administration. (From Royster RL, Butterworth JF, Prielipp RC, et al. A randomized, blinded, placebo-controlled evaluation of calcium chloride
and epinephrine for inotropic support after emergence from cardiopulmonary bypass. Anesth Analg 1992;74:3-13, with permission.)
Use of Inotropes
Although these drugs are necessary to separate from CPB in many patients, routine use may be detrimental. Concern exists that inotropic stimulation
of the myocardium may have deleterious effects because of increased energy consumption (81). This may be particularly relevant after cardiac
surgery with ischemic cardiac arrest, especially in the presence of residual myocardial ischemia caused by disproportionate increases in myocardial
oxygen consumption relative to supply (82). Animal data suggest that catecholamines should be avoided in the reperfusion period immediately after
release of the aortic cross-clamp to facilitate metabolic recovery of the myocardium (83). Exogenous positive inotropic agents may also potentiate
damage because of the already high endogenous catecholamine levels during cardiac surgery (84). Inotropic agents are clearly useful in
discontinuing CPB and may even expedite the recovery of stunned myocardium (85). Given their potential to increase myocardial damage, however,
their use should probably be delayed until the heart has had a chance to recover from the ischemia immediately after aortic cross-clamp release.
Animal data suggest that, in the presence of ventricular dysfunction, the potentially deleterious effects of inotropic stimulation on oxygen consumption
may be reduced by afterload-reducing agents (86). More recently, a clinical study of cardiac surgery patients ( n = 6,005) compared a group that did
not require inotropic therapy ( n = 1,170) to a propensity-matched cohort of patients who did receive inotropes ( n = 1,170) (87). In the matched
cohort, there was an increased incidence of myocardial infarction, stroke and renal replacement therapy, and increased 1-year mortality (Fig. 25.9).
This strongly advocates the use of inotropic therapy following cardiac surgery only when indicated by clinical need and hemodynamic criteria.
FIGURE 25.9. Cumulative 1-year mortality risk by treatment status comparing patients not receiving inotropes to a matched cohort treated with
inotropes. Log-rank p < 0.00001. (From Nielsen DV, Hansen MK, Johnsen SP, et al. Health outcomes with and without use of inotropic therapy in
cardiac surgery: results of a propensity score-matched analysis. Anesthesiology 2014;120:1098-1108, with permission.)
KEY Points
Systematic preparation for separation from CPB is critical.
Metabolic data, anesthesia/oxygenation/ventilation, hemodynamic monitors, heart rate and rhythm, organ function assessment, and the
need for cardiac support.
Large-scale studies include age, emergency surgery, female gender, preoperative ventricular function, left main coronary disease, and
reoperation as risk factors for left ventricular dysfunction after CPB.
There is a biphasic postoperative course for ventricular function: early (1-2 hours) improvement relative to the end of CPB, nadir of
ventricular function 4 to 6 hours after CPB, and improvement over next 12 to 18 hours.
P.620
Support for ventricular function after CPB includes optimizing patient physiologic status; preparing before initiating the weaning process;
anticipation of requirements; pharmacologic support with positive inotropic drugs (e.g., catecholamines, PDE III inhibitors, calcium);
vasoconstrictors (e.g., phenylephrine, norepinephrine); vasodilators (e.g., nitroprusside, nitroglycerin, PDE III inhibitors, prostaglandin E1,
nitric oxide); and mechanical support with IABP or VAD.
Causes for right ventricular failure include right coronary insufficiency, poor right ventricular (RV) protection, and pulmonary hypertension.
Principal findings in right ventricular failure include elevated PAP, high CVP, decreased arterial pressure, decreased cardiac output, RV
distension, and high RV wall tension.
Treatment for right ventricular failure includes elevation of perfusion pressure (e.g., LA infusion of vasoconstrictors) and pulmonary artery
vasodilation (nitric oxide, prostaglandin E1, nitrovasodilators, PDE III inhibitors).
Common cardiorespiratory problems during and shortly after separation from CPB include vasodilation, low cardiac output, hypertension,
acute hemodynamic deterioration (following initially satisfactory hemodynamics), bronchospasm, and hypoxemia.
Controversies include appropriate use of inotropes and calcium salts. Neither drug should be used routinely, because the potential for harm
exceeds the benefit in the absence of a clear indication.
REFERENCES
1. Nussmeier NA. Management of temperature during and after cardiac surgery. Tex Heart Inst J 2005;32:472-476.
2. Geissler HJ, Allen SJ, Mehlhorm U. Cooling gradients and formation of gaseous microemboli with cardiopulmonary bypass: an
echocardiographic study. Ann Thorac Surg 1997;64:100-104.
3. Sladen RN, Berend JZ, Sessler DI. Rewarming and sweating during cardiopulmonary bypass. J Cardiothorac Vasc Anesth 1994;8(1):45-50.
4. Novack CR, Tinker JH. Hypothermia after cardiopulmonary bypass in man. Anesthesiology 1980;53:277-280.
5. Cingolani HE, Faulkner SL, Mattiazzi AR, et al. Depression of human myocardial contractility with “respiratory” and “metabolic” acidosis.
Surgery 1975;77:427-432.
6. Houle DB, Weil MH, Brown EB, et al. Influence of respiratory acidosis on ECG and pressor responses to epinephrine, norepinephrine and
metaraminol. Proc Soc Exp Biol Med 1957;94:561-564.
7. Rudolph AM, Yuan S. Response of the pulmonary vasculature to hypoxia and H + ion concentration changes. J Clin Invest 1966;45:399-441.
8. Ettinger PO, Regan TJ, Oldewurtel HA. Hyperkalemia, cardiac conduction, and the electrocardiogram: a review. Am Heart J 1974;88:360-371.
9. Robertie PG, Butterworth JB, Royster RL, et al. Normal parathyroid hormone responses to hypocalcemia during cardiopulmonary bypass.
10. Prielipp RC, Zaloga GP, Butterworth JB, et al. Magnesium inhibits the hypertensive but not the cardiotonic actions of low dose epinephrine.
11. Zerr KJ, Furnary AP, Grunkemeier GL, et al. Glucose control lowers the risk of wound infection in diabetes after open heart operations. Ann
Thorac Surg 1997;63:356-361.
12. Surgenor SD, DeFoe GR, Fillinger MP, et al. Intraoperative red blood cell transfusion during coronary artery bypass graft surgery increases
the risk of postoperative low-output heart failure. Circulation 2006; 114(1, Suppl):I43-I48.
13. 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;56:824-834.
14. Vincentelli A, Susen S, Le Tourneau T, et al. Acquired von Willebrand syndrome in aortic stenosis. N Engl J Med 2003;349:343-349.
15. Buylaert WA, Herrengods LL, Mortier EP, et al. Cardiopulmonary bypass and the pharmacokinetics of drugs: an update. Clin Pharmacokinet
1989;7:234-251.
16. Price SL, Brown DL, Carpenter RL. Isoflurane elimination via a bubble oxygenator during extracorporeal circulation. J Cardiothorac Anesth
1988;2:41-44.
17. Nussmeier NA, Lambert ML, Moskowitz GJ, et al. Wash-in and wash-out of isoflurane administered via bubble oxygenators during
18. Bermudez J, Lichtiger M. Increases in arterial to end-tidal CO2 tension differences after cardiopulmonary bypass. Anesth Analg 1987;66:690-
692.
19. Salmenpera M, Heinonen J. Pulmonary vascular responses to moderate changes in Pa PaCO2 after cardiopulmonary bypass.
20. Stern DH, Gerson JI, Allen FB, et al. Can we trust the direct radial artery pressure immediately after cardiopulmonary bypass?
Anesthesiology 1985;62: 557-571.
21. Mohr R, Lavee J, Goor DA. Inaccuracy of radial artery pressure measurement after cardiac operations. J Thorac Cardiovasc Surg
1987;94:286-290.
22. Gallagher JD, Moore RA, McNicholas KW, et al. Comparison of radial and femoral arterial blood pressure in children after cardiopulmonary
bypass. J Clin Monit 1985;1:168-171.
23. Johnston WE, Royster RL, Choplin RH, et al. Pulmonary artery catheter migration during cardiac surgery. Anesthesiology 1986;64:258-262.
24. Abel RM, Buckley MJ, Austen WG, et al. Etiology, incidence and prognosis of renal failure after cardiac operations: results of a prospective
analysis of 500 consecutive patients. J Thorac Cardiovasc Surg 1976;71:323-333.
25. Cahalan MK, Litt L, Botvinick EH, et al. Advances in noninvasive cardiovascular imaging: implications for the anesthesiologist.
26. Ungerleider RM, Greeley WJ, Sheikh KH, et al. Routine use of intraoperative epicardial echocardiography and Doppler color flow imaging to
guide and evaluate repair of congenital heart lesions. A prospective study. J Thorac Cardiovasc Surg 1990;100:297-309.
27. Greeley WJ, Ungerleider RM. Echocardiography during surgery for congenital heart disease. In: DeBruijn NP, Clements FM, eds.
Intraoperative use of echocardiography. Philadelphia, PA: JB Lippincott Co., 1991:129-175.
28. Hansen RM, Viguerat CE, Matthay MA, et al. Poor correlation between pulmonary arterial wedge pressure and left ventricular end-diastolic
volume after coronary artery bypass graft surgery. Anesthesiology 1986;64:764-770.
29. Cheung AT, Savino JS, Weiss SJ, et al. Echocardiographic and hemodynamic indexes of left ventricular preload in patients with normal and
abnormal ventricular function. Anesthesiology 1994;81:376-387.
30. Berberian G, Quinn TA, Kanter JP, et al. Optimized biventricular pacing in atrioventricular block after cardiac surgery. Ann Thorac Surg
2005;80: 870-875.
31. Thomson IR, Rosenbloom M, Cannon JE, et al. Electrocardiographic ST-segment elevation after myocardial reperfusion during coronary
artery surgery. Anesth Analg 1987;66:1183-1186.
32. Braunwald E, Kloner RA. The stunned myocardium: prolonged, post-ischemic ventricular dysfunction. Circulation 1982;66:1146-1149.
33. Rahimtoola SH. The hibernating myocardium. Am Heart J 1989;117:211-221.
34. Ross J Jr. Afterload mismatch in aortic and mitral valve disease: implications for surgical therapy. J Am Coll Cardiol 1985;5:811-826.
35. Ross J Jr. Left ventricular function and the timing of surgical treatment in valvular heart disease. Ann Intern Med 1981;94:498-504.
36. Christakis GT, Weisel RD, Fremes SE, et al. Coronary artery bypass grafting in patients with poor ventricular function. J Thorac Cardiovasc
Surg 1992;103:1083-1092.
P.621
37. Royster RL, Butterworth JF, Prough DS, et al. Preoperative and intraoperative predictors of inotropic support and long-term outcome in
patients having coronary artery bypass grafting. Anesth Analg 1991;72:729-736.
38. Goenen M, Jacquemart JL, Galvez S, et al. Preoperative left ventricular dysfunction and operative risks in coronary bypass surgery. Chest
1987;92:804-806.
39. Mangano DT. Biventricular function after myocardial revascularization in humans: deterioration and recovery patterns in the first 24 hours.
40. Royster RL. Myocardial dysfunction after cardiopulmonary bypass: recovery patterns, predictors of inotropic need, theoretical concepts of
inotropic administration. J Cardiothorac Vasc Anesth 1993;7(Suppl 2):19-25.
41. Takeishi Y, Tono-Oka I, Kubota I, et al. Functional recovery of hibernating myocardium after coronary bypass surgery: does it coincide with
improvement in perfusion? Am Heart J 1991;122:665-670.
42. Elz JS, Panagiotopoulos S, Nayler WG. Reperfusion-induced calcium gain after ischemia. Am J Cardiol 1989;63:7E-13E.
43. Davis RF, Lappas DG, Kirklin JK, et al. Acute oliguria after cardiopulmonary bypass: renal functional improvement with low dose dopamine
infusion. Crit Care Med 1982;10:852-856.
44. Hilberman M, Moseda J, Stinson EB, et al. The diuretic properties of dopamine in patients after open-heart operation. Anesthesiology
1984;61:489-494.
45. Steen PA, Tinker JH, Pluth JR, et al. Efficacy of dopamine, dobutamine, and epinephrine during emergence from cardiopulmonary bypass in
man. Circulation 1978;57:378-384.
46. Salomon NW, Plachetka JR, Copeland JG. Comparison of dopamine and dobutamine after coronary artery bypass grafting. Ann Thorac Surg
1982;33:48-54.
47. Royster RL, Butterworth JF, Prielipp RC, et al. A randomized, blinded, placebo-controlled evaluation of calcium chloride and epinephrine for
inotropic support after emergence from cardiopulmonary bypass. Anesth Analg 1992;74:3-13.
48. Hess W, Klein W, Muller-Busch C, et al. Haemodynamic effects of dopamine and dopamine combined with nitroglycerin in patients subjected
to coronary bypass surgery. Br J Anaesth 1979;51:1063-1068.
49. Royster RL, Butterworth JF, Prielipp RC, et al. Combined inotropic effects of amrinone and epinephrine following cardiopulmonary bypass in
man. Anesth Analg 1993;77:662-672.
50. Benotti JR, Grossman W, Braunwald E, et al. Effects of amrinone on myocardial energy metabolism and hemodynamics in patients with
severe congestive heart failure due to coronary artery disease. Circulation 1980;62:28-34.
51. Robinson RJS, Tchervenkow C. Treatment of low cardiac output after aortocoronary bypass surgery using a combination of norepinephrine
and amrinone. J Cardiothorac Anesth 1987;1:229-233.
52. Lathi KG, Shulman MS, Diehl JT, et al. The use of amrinone and norepinephrine for inotropic support during emergence from
cardiopulmonary bypass. J Cardiothorac Anesth 1991;5:250-254.
53. Sturm JT, Fuhrman TM, Sterling R, et al. Combined use of dopamine and nitroprusside therapy in conjunction with intra-aortic balloon
pumping for the treatment of postcardiotomy low-output syndrome. J Thorac Cardiovasc Surg 1981;82:13-17.
54. Feola M, Weiner L, Walinsky P, et al. Improved survival after coronary artery bypass surgery in patients with poor left ventricular function: role
of intraaortic balloon counterpulsation. Am J Cardiol 1977;39:1021-1026.
55. Kaul TK, Fields BL. Postoperative acute refractory right ventricular failure: incidence, pathogenesis, management and prognosis. Cardiovasc
Surg 2000;8:1-9.
56. Haddad F, Doyle R, Murphy DJ, et al. Right ventricular function in cardiovascular disease, Part II: pathophysiology, clinical importance, and
management of right ventricular failure. Circulation 2008;117:1717-1731.
57. Itagaki S, Hosseinian L, Varghese R. Right ventricular failure after cardiac surgery: management strategies. Semin Thorac Cardiovasc Surg
2012;24(3):188-194.
58. Sheehan F, Redington A. The right ventricle: anatomy, physiology and clinical imaging. Heart 2008;94:1510-1515.
59. Damiano RJ Jr, La Follette P Jr, Cox JL, et al. Significant left ventricular contribution to right ventricular systolic function. Am J Physiol
1991;261:H1514-H1524.
60. Olschewski H, Simonneau G, Galie N, et al. Inhaled iloprost for sever pumonary hypertension. N Engl J Med 2002;347:322-329.
61. Lahm T, McCaslin CA, Wozniak TC, et al. Medical and surgical treatment of acute right ventricular failure. J Am Coll Cardiol 2010;56:1435-
1446.
62. Groves DS, Blum FE, Huffmyer JL, et al. Effects of early inhaled epoprostenol therapy on pulmonary artery pressure and blood loss during
LVAD placement. J Cardiothorac Vasc Anesth 2014;28:652-660.
63. Hess W, Arnold B, Veit S. The haemodynamic effects of amrinone in patients with mitral stenosis and pulmonary hypertension. Eur Heart J
1986;7:800-807.
64. D’Ambra MN, LaRaia PJ, Philbin DM, et al. Prostaglandin E1: a new therapy for refractory right heart failure and pulmonary hypertension
after mitral valve replacement. J Thorac Cardiovasc Surg 1985;89:567-572.
65. Mekontso-Dessap A, Houël R, Soustelle C, et al. Risk factors for post-cardiopulmonary bypass vasoplegia in patients with preserved left
ventricular function. Ann Thorac Surg 2001 May;71:1428-1432.
66. Levin RL, Degrange MA, Bruno GF, et al. Methylene blue reduces mortality and morbidity in vasoplegic patients after cardiac surgery. Ann
Thorac Surg 2004;77:496-499.
67. Andritsos MJ. Con: methylene blue should not be used routinely for vasoplegia perioperatively. J Cardiothorac Vasc Anesth 2011;25:739-
743.
68. Fischer GW, Levin MA. Vasoplegia during cardiac surgery: current concepts and management. Semin Thorac Cardiovasc Surg
2010;22(2):140-144.
69. Levin MA, Lin HM, Castillo JG, et al. Early on-cardiopulmonary bypass hypotension and other factors associated with vasoplegic syndrome.
Circulation 2009;120:1664-1671.
70. Riha H, Augoustides JG. Pro: methylene blue as a rescue therapy for vasoplegia after cardiac surgery. J Cardiothorac Vasc Anesth
2011;25:736-738.
71. Egi M, Bellomo R, Langenberg C, et al. Selecting a vasopressor drug for vasoplegic shock after adult cardiac surgery: a systematic literature
review. Ann Thorac Surg 2007;83:715-723.
72. Ozal E, Kuralay E, Yildirim V, et al. Preoperative methylene blue administration in patients at high risk for vasoplegic syndrome during cardiac
73. Leyh RG, Kofidis T, Strüber M, et al. Methylene blue: the drug of choice for catecholamine-refractory vasoplegia after cardiopulmonary
bypass? J Thorac Cardiovasc Surg 2003;125:1426-1431.
74. Maslow AD, Stearns G, Butala P, et al. The hemodynamic effects of methylene blue when administered at the onset of cardiopulmonary
75. Patarroyo M, Simbaqueba C, Shrestha K, et al. Pre-operative risk factors and clinical outcomes associated with vasoplegia in recipients of
orthotopic heart transplantation in the contemporary era. J Heart Lung Transplant 2012;31:282-287.
76. LeJemtel TH, Sonnenblick EH. Should the failing heart be stimulated? N Engl J Med 1984;310:1384-1385.
77. David D, DuBois C, Loria Y. Comparison of nicardipine and sodium nitroprusside in the treatment of paroxysmal hypertension after
aortocoronary bypass surgery. J Cardiothorac Vasc Anesth 1991;5:357-361.
78. Goldberg ME, Cantillo J, Nemiroff MS, et al. Fenoldepam infusion for the treatment of postoperative hypertension. J Clin Anesth 1993;5:386-
391.
79. Mills RM, LeJemtel TH, Horton D, et al. Sustained hemodynamic effects of an infusion of nesritide (human β-type natriuretic peptide) in heart
failure: a randomized, double-blind, placebo-controlled clinical trial. J Am Coll Cardiol 1999;34:155-162.
80. Drop LJ, Geffin GA, O’Keefe DD, et al. Relation between ionized calcium concentration and ventricular pump performance in the dog under
hemodynamically controlled conditions. Am J Cardiol 1981;47:1041-1051.
81. Katz AM. Potential deleterious effects of inotropic agents in the therapy of chronic heart failure. Circulation 1986;73(Suppl 3):184-190.
82. Lazar HL, Buckberg GD, Foglia RP, et al. Detrimental effects of premature use of inotropic drugs to discontinue cardiopulmonary bypass. J
83. Ward HB, Einzig S, Wang T, et al. Comparison of catecholamine effects on canine myocardial metabolism and regional blood flow during and
after cardiopulmonary bypass. J Thorac Cardiovasc Surg 1987;87:452-465.
84. Reves JG, Buttner E, Karp RB, et al. Elevated catecholamines during cardiac surgery: consequences of reperfusion of the post-arrested
heart. Am J Cardiol 1984;53:722-728.
85. Ellis SG, Wynne J, Braunwald E, et al. Response of reperfusion-salvaged, shinned myocardium to inotropic stimulation. Am Heart J
1984;107:13-19.
86. Dyke CM, Lee KF, Parmor J, et al. Inotropic stimulation and oxygen consumption in a canine model of dilated cardiomyopathy. Ann Thorac
Surg 1991;52:750-758.
87. Nielsen DV, Hansen MK, Johnsen SP, et al. Health Outcomes with and without use of inotropic therapy in cardiac surgery. Anesthesiology
2014; 120: 1098-1108.
Chapter 26
ECMO for Respiratory Support in Adults
Darryl Abrams
Daniel Brodie
INTRODUCTION
The role of extracorporeal membrane oxygenation (ECMO) for adults with respiratory failure has been evolving
over the last several decades, most prominently in the context of the acute respiratory distress syndrome
(ARDS). However, early versions of the technology, with their high rates of complications, had significantly
limited the applicability of ECMO. More recent advances in technology, along with improved management
strategies, have favorably impacted both the risk-benefit profile and the consequent survival rates in patients
with severe forms of respiratory failure. However, there remains a lack of randomized controlled trials definitively
demonstrating the benefit of ECMO over conventional standard-of-care ventilator management. Less severe
forms of respiratory failure may likewise benefit from ECMO through the use of smaller cannulae and lower blood
flow rates than those typically required for severe ARDS. However, these applications also require more rigorous
study before they can be recommended. This chapter reviews both the existing role and the future potential for
ECMO in acute and chronic respiratory failure.
CONFIGURATION APPROACHES
ECMO refers to an extracorporeal circuit that directly delivers oxygen to and removes carbon dioxide from the
blood via an oxygenator, a gas exchange device with a semipermeable membrane, that selectively permits
diffusion of gas into and out of the blood. Deoxygenated blood is drained from a central vein via an external
pump, passes through the oxygenator, and is returned to the patient through a reinfusion cannula. When blood is
returned to a central vein, referred to as venovenous ECMO, the device only provides respiratory support. When
blood is returned to an artery, referred to as venoarterial ECMO, the circuit may provide both respiratory and
circulatory support. ECMO, in contrast to cardiopulmonary bypass, most often provides partial cardiopulmonary
support.
Oxygenation is primarily determined by the amount of circuit blood flow, the fraction of oxygen delivered through
the oxygenator (FDO2), the amount of recirculation, and native lung function. Carbon dioxide removal is
principally determined by the rate of gas flow through the oxygenator, known as the sweep gas flow rate, by the
extracorporeal circuit blood flow rate, and by native lung function (1). Because extracorporeal circuits are very
efficient at removing carbon dioxide and can usually do so at lower blood flow rates than those needed to
achieve adequate oxygenation (2,3), smaller cannulae can be used for the purpose of extracorporeal carbon
dioxide removal (ECCO2R). These smaller cannulae offer the advantage of being easier and safer to insert (4,5),
thus potentially improving the risk profile of ECCO2R over ECMO. ECCO2R may be implemented to correct
derangements in carbon dioxide and pH in the setting of acute or chronic hypercapnic respiratory failure (5).
Alternatively, it may be useful in eliminating carbon dioxide in the setting of hypoxemic respiratory failure when
lung-protective ventilatory strategies result in severe respiratory acidosis. However, ECCO2R delivers very little
oxygen to the bloodstream.
Venovenous ECMO traditionally involves cannulation of two distinct venous access points for drainage and
reinfusion of blood (1), including cannulation of a femoral vein (Fig. 26.1). When the drainage and reinfusion
ports are in close proximity, reinfused oxygenated blood may be taken back up into the circuit, a phenomenon
known as recirculation (6). Recirculated blood, which does not contribute to systemic oxygenation, may
compromise the circuit’s efficiency. With the advent of bicaval dual-lumen cannulae, venovenous ECMO can be
performed through a single venous access site (Fig. 26.2). When performed via the internal jugular vein, for
instance, this avoids the need for femoral access and potentially reduces the amount of recirculation when
properly positioned (6,7,8,9). Placement is best accomplished under imaging guidance (10), potentially limiting
the utility of such a strategy in emergency situations when transesophageal echocardiography or fluoroscopy is
unavailable. However, for patients in whom mobilization is anticipated, a cannulation strategy that avoids femoral
cannulation is often preferable. The choice of cannula size is based on the patient’s physiologic needs.
Particular consideration should be given to the patient’s estimated cardiac output. For a given extracorporeal
blood flow, changes in cardiac output will alter the percentage of the
P.624
patient’s blood volume passing through the oxygenator, which will have a direct impact on systemic oxygenation.
FIGURE 26.1. Two-site venovenous ECMO. Venous blood is drained from a central vein via a drainage cannula,
pumped through an oxygenator, and returned to a central vein through a separate reinfusion cannula. Inset:
Some reinfused blood may be taken back up by the drainage cannula (purple arrow) without passing through the
systemic circulation, which is referred to as recirculation. (From Abrams D, Brodie D. Extracorporeal circulatory
approaches to treat ARDS. Clin Chest Med 2014;35(4):765-779, with permission.)
A less commonly employed configuration, used primarily for carbon dioxide removal, is arteriovenous ECCO2R,
which is a pumpless circuit that uses the patient’s native cardiac output to generate blood flow through an
oxygenator (11,12). The potential for complications associated with arterial cannulation, along with an inability to
control circuit blood flow, makes arteriovenous ECCO2R less desirable than venovenous cannulation for most
ECCO2R clinical scenarios (13). Additionally, because the partial pressure of carbon dioxide in arterial blood is
lower than that in venous blood, arteriovenous ECCO2R is inherently less efficient than venovenous ECCO2R.
In patients with impaired gas exchange and significant cardiac dysfunction, a venoarterial configuration may be
appropriate to provide both respiratory and circulatory support. Traditionally, venoarterial ECMO involves
femoral venous drainage and femoral arterial reinfusion. However, the reinfusion flow in that configuration travels
retrograde up the aorta and may meet resistance from antegrade flow generated by the left ventricle, potentially
compromising oxygen delivery to the aortic arch if native gas exchange is significantly impaired (Fig. 26.3). In
such circumstances, an additional reinfusion cannula may be added to the circuit via a connection of the femoral
arterial reinfusion cannula that is inserted into an internal jugular vein (14), thereby taking advantage of the
native cardiac output to circulate reinfused oxygenated blood into the right heart and on to the ascending aorta
(Fig. 26.4). Of note, some patients with severe respiratory failure may have concomitant right ventricular
dysfunction, in which case, it is theoretically possible that
P.625
this approach could induce or exacerbate right ventricular volume overload in a subset of these patients. This
combination of venous drainage and arterial and venous reinfusion is referred to as venoarterial-venous ECMO.
Combining internal jugular venous drainage and subclavian arterial reinfusion (via an end-to-side graft)
constitutes an alternative venoarterial cannulation strategy that optimizes upper-body oxygenation (15), although
this configuration requires an open-surgical approach in an operating room and would not be appropriate for
emergent bedside cannulation (16).
FIGURE 26.2. Single-site venovenous ECMO. Dual-lumen cannula insertion allows for venovenous ECMO
through a single venous access point and may minimize recirculation when properly positioned. (From Abrams D,
Brodie D. Extracorporeal circulatory approaches to treat ARDS. Clin Chest Med 2014;35(4):765-779, with
permission.)
Venovenous ECMO alone often provides adequate gas exchange support for patients with respiratory failure,
because improved oxygenation often decreases pulmonary vascular resistance and increases coronary
perfusion and right ventricular function (17). However, in patients with pulmonary hypertension independent of
hypoxemic vasoconstriction, venoarterial support may be necessary.
POTENTIAL INDICATIONS FOR ECMO
Acute Respiratory Distress Syndrome
ARDS is the indication for which ECMO has been most rigorously studied (1) (Table 26.1). When ARDS is
severe enough to require invasive mechanical ventilation (IMV), positive pressure ventilation perpetuates the
underlying lung injury (18). Strategies that minimize tidal volumes and airway pressures have been proven to
reduce mortality in ARDS (19). These strategies allow for so-called permissive hypercapnia and its attendant
respiratory acidosis. However, severe reductions in respiratory system compliance may limit the ability to apply
lung-protective ventilation because of the development of unacceptably severe respiratory acidosis (20,21).
ECMO, by removing carbon dioxide, potentially facilitates lung-protective ventilation by correcting unsustainable
levels of respiratory acidosis that may accompany low tidal volume
P.626
ventilation (4,22). Additionally, ECMO may be used as a rescue therapy for patients with refractory hypoxemia
despite maximal ventilatory support (1). Potential indications for ECMO use in ARDS have been proposed (1,23),
although there are no universally accepted criteria.
FIGURE 26.3. Femoral venoarterial ECMO in the setting of impaired gas exchange. Reinfused oxygenated blood
flows retrograde up the aorta (red arrow), and may meet resistance from antegrade flow from the native cardiac
output (purple arrow), which, in the context of impaired native gas exchange, may lead to poor upper-body
oxygenation. (From Abrams D, Brodie D. Novel uses of extracorporeal membrane oxygenation in adults. Clin
Chest Med 2015. doi:10.1016/j.ccm.2015.05.014, with permission.)
Despite the potential for ECMO to alter outcomes in ARDS, early randomized trials failed to demonstrate an
effect of ECMO on mortality in severe ARDS, owing in part to high rates of device-related complications (24,25).
In the most recent randomized controlled trial involving ECMO for ARDS (Conventional Ventilation or ECMO for
Severe Adult Respiratory Failure, CESAR), 180 subjects with the equivalent of severe ARDS were randomly
assigned to referral to a specialized center for consideration of ECMO or to ongoing conventional mechanical
ventilation, primarily at the originating hospital (26). Those referred for consideration of ECMO had a significantly
lower rate of the combined endpoint of death or severe disability at 6 months (37% vs. 53%, relative risk 0.69, p
= 0.03). Because this study was pragmatic in design, there are significant limitations to the interpretation of these
results, including the fact that only 70% of the control group received a lung-protective ventilation strategy at any
time during the study. Additionally, 24% of those in the ECMO-referred group were managed without ECMO,
making it difficult to evaluate the effect of ECMO itself on survival. Other nonrandomized observational studies,
particularly during the influenza A (H1N1) pandemic in 2009, have shown conflicting results of the impact of
ECMO on survival in severe ARDS (27,28). Such discrepancies call attention to the need for prospective
randomized data evaluating the effect of ECMO on survival in severe ARDS. The ongoing ECMO to rescue lung
injury in severe ARDS (EOLIA) trial prospectively randomizes
P.627
patients with severe, refractory ARDS to either ECMO or to optimal conventional management, including the use
of neuromuscular blockade and prone positioning (29). Risk stratification models have been proposed to help
identify ARDS patients who will derive the greatest benefit from venovenous extracorporeal support
(30,31,32,33). Data regarding the neurocognitive, psychiatric, and functional sequelae for those who recover
from ARDS after having received ECMO are limited (28,34,35). Results from EOLIA and other prospective
randomized trials should clarify these outcomes.
FIGURE 26.4. Venoarterial venous ECMO. Inadequate upper-body oxygenation due to a combination of femoral
venoarterial ECMO and impaired native gas exchange may be partially overcome by the addition of a second
reinfusion limb into an internal jugular vein. (From Abrams D, Brodie D. Novel uses of extracorporeal membrane
oxygenation in adults. Clin Chest Med 2015. doi:10.1016/j.ccm.2015.05.014, with permission.)
Other forms of refractory hypoxemic respiratory failure that can mimic ARDS, such as pulmonary vasculitis with
alveolar hemorrhage, may likewise benefit from gas exchange support with ECMO (36,37). Although the inability
to tolerate anticoagulation is traditionally considered a relative contraindication to ECMO, patients with alveolar
hemorrhage have been successfully managed with judicious systemic anticoagulation (36).
In addition to its ability to facilitate standard-of-care lung-protective ventilation, ECMO may further reduce lung
injury by permitting the use of very low tidal volume airway pressures and respiratory rates (38,39,40). This
approach has been proven feasible (38,40), and is already practiced at many ECMO centers, although more
data are needed to best understand its clinical impact (41,42). If this approach proves effective, it may extend to
less severe cases of ARDS through the use of ECCO2R, which offers the advantage of lower blood flow rates
than those traditionally needed for oxygenation. In a trial comparing ECCO2R-assisted very low tidal volume
ventilation (3 mL/kg predicted body weight) to standard-of-care low tidal volume ventilation (6 mL/kg) in patients
with moderate-to-severe ARDS, a post hoc subgroup analysis of
P.628
those with more severe hypoxemia demonstrated more ventilator-free days in the ECCO2R group (40.9 vs. 28.2,
p = 0.033) (40). The optimal role of ECCO2R in less severe cases of ARDS remains to be defined, and that is
the focus of upcoming randomized controlled trials.
TABLE 26.1. Current and emerging indications for ECMO in respiratory failure
Configuration
Current potential indications
Severe ARDS Venovenous ECMO
Pulmonary hypertension with right Venoarterial ECMO

ventricular failure Or
Bicaval dual-lumen venovenous ECMO in the presence of an
inter-atrial septal defect
Bridge to lung transplantation Venovenous ECMO or ECCO2R
Primary graft dysfunction after lung Venovenous ECMO

transplantation
Status asthmaticus Venovenous ECCO2R or ECMO
Emerging potential indications
Less severe ARDS Venovenous ECCO2R
Acute exacerbations of COPD Venovenous ECCO2R or ECMO
Destination therapy To be determined
ARDS, acute respiratory distress syndrome; ECMO, extracorporeal membrane oxygenation; ECCO2R,
extracorporeal carbon dioxide removal; COPD, chronic obstructive pulmonary disease.
Pulmonary Hypertension
With advances in technology and cannulation strategies, ECMO is increasingly being recognized as a feasible
management strategy in decompensated pulmonary hypertension with right ventricular failure. ECMO may
stabilize gas exchange and hemodynamics while acutely reversible processes are treated, medical management
is optimized, or the patient is evaluated for lung transplantation (43). Venoarterial configurations are typically
necessary to decompress the right ventricle and overcome the high resistance of the pulmonary vascular bed.
The previously mentioned upper-body venoarterial configuration provides an alternative to traditional femoral
venoarterial cannulation (15). Additionally, for those either with preexisting interatrial septal defects or who have
undergone atrial septostomy, a dual-lumen cannula may be introduced with the reinfusion jet directed across the
defect, thereby decompressing the right ventricle while creating an oxygenated right-to-left shunt, avoiding
arterial cannulation altogether (44,45,46). Alternative open-surgical approaches include pumpless arteriovenous
ECMO between the pulmonary artery and the left atrium (47). Endotracheal intubation and general anesthesia
pose a significant risk of cardiovascular collapse in the setting of decompensated pulmonary hypertension. A
strategy to initiate upper-body venoarterial ECMO without intubation or general anesthesia has recently been
described (48). In patients with potentially reversible causes of decompensation, ECMO can facilitate up-titration
and optimization of pulmonary vasodilators (43). Conversely, for those with endstage pulmonary hypertension
who are supported with ECMO as a bridge to lung transplantation, pulmonary vasodilators may be weaned,
preferentially shunting blood through the extracorporeal circuit, thereby optimizing systemic oxygenation (49).
ECMO as Bridge to Transplantation for End-Stage Lung Disease

ECMO has historically been associated with poor outcomes when used as a bridge to lung transplantation,
owing in large part to high complication rates and the late use of ECMO as salvage therapy (50). With decreased
complication rates and earlier implementation, recent studies have reported improved posttransplant outcomes
for patients supported with ECMO, with better results coming from higher-volume centers (51,52). Although
ECMO has traditionally been employed as a supplement to the ventilator, select patients may be supportable
with ECMO alone, thereby avoiding ventilator-associated complications (52,53,54). The addition of active
physical therapy (e.g., ambulation) may further optimize outcomes (54,55,56). Despite all of these advances,
ECMO currently requires continuous ICUlevel care, so there is no current destination ECMO device. As a result,
ECMO should not be offered to patients with end-stage lung disease who will not be transplant candidates
(23,57).
Primary Graft Dysfunction after Lung Transplantation

Similar to its role in ARDS, ECMO can be used to support gas exchange in severe cases of primary graft
dysfunction (PGD), a form of acute lung injury that is the leading cause of early death after lung transplantation
(58). Similar survival has been reported between ECMO-supported severe PGD and less severe PGD not
supported by ECMO (59). However, no beneficial effect on long-term allograft function has been demonstrated.
EMERGING POTENTIAL INDICATIONS

Acute Hypercapnic Respiratory failure
With the ability to efficiently manage hypercapnia with low blood flow rates and small cannulae, ECCO2R has
considerable potential to manage acute hypercapnic respiratory failure without the need for IMV (5). Positive
pressure ventilation is associated with multiple complications, particularly in obstructive lung diseases, including
dynamic hyperinflation and increased
P.629
intrinsic PEEP, ventilator-associated pneumonia, and impaired delivery of aerosolized medications (60,61).
Several studies have demonstrated the ability of ECCO2R to facilitate weaning from the ventilator or avoiding
intubation in acute exacerbations of COPD (62,63,64,65,66). In some case series, ECCO2R was found to
facilitate early mobilization by improving dyspnea and work of breathing (64,66). Prospective randomized trials
are needed to better define the risk-benefit ratio of ECCO2R, the optimal patient population in which it should be
used, and its economic impact before it can be recommended clinically. Even in the absence of randomized data,
refractory status asthmaticus with severe hypercapnic respiratory failure is a situation in which ECCO2R should
be considered, particularly when positive pressure ventilation is contributing to dynamic hyperinflation and
impaired ventilation (67,68).
Destination Therapy for Respiratory Failure

ECMO for respiratory failure has no destination device equivalent, and can only serve as a bridging therapy to
recovery or lung transplantation. However, ongoing advances in technology, including smaller circuit
components, more efficient oxygenators, and increasingly biocompatible materials are helping the field progress
toward a portable extracorporeal gas exchange device with the potential to dramatically alter the management of
both acute and chronic respiratory failure.
COMPLICATIONS
Complication rates vary by institutional experience, patient selection, and the configurations and devices
used. Thrombotic and hemorrhagic complications are commonly reported (Table 26.2) (69). Anticoagulation,
which is required to maintain circuit patency and minimize thrombotic complications, inherently increases the
risk of bleeding. Traditionally, therapeutic levels of anticoagulation similar to those used for
cardiopulmonary bypass had been used for ECMO. Recently, many centers have adopted lower
anticoagulation targets, which have helped to reduce clinically significant bleeding events without
increasing the rate of thrombosis or negatively impacting survival (70). Reported rates of infectious
complications vary greatly, with some studies suggesting a correlation between infections and longer
durations of mechanical ventilation, ECMO support, and hospital stays, although it remains unclear whether
or not these infectious complications are circuit-related (69,71). Limb ischemia and compartment syndrome
have been reported with femoral arterial cannulation and can have catastrophic consequences (13). It is
important to consider vessel caliber and the physiologic needs of the patient when choosing cannula sizes.
Smaller cannulae may mitigate the risk of both limb ischemia and bleeding while still providing adequate gas
exchange and hemodynamic support (72). If the risk of limb ischemia is thought to be high, insertion of a
distal reperfusion cannula into the superficial femoral artery or end-to-side grafting of the cannula to the
femoral artery may be considered (15,73,74). Other complications including hemolysis, thrombocytopenia,
acquired von Willebrand syndrome, disseminated intravascular coagulopathy, and air embolism occur with
varying frequency and should be monitored for as clinically appropriate (69).
TABLE 26.2. ECMO-associated complications
Complication Rate (%) (69)
Thrombosis (circuit) 25.2
Infection (culture proven) 10.4

Hemorrhage
Cannulation site 13.5
Surgical site 10.6
Gastrointestinal 7.2
Intrapulmonary 5.7
Intracerebral 2.5
Hemolysis 6.8
Disseminated intravascular coagulopathy 2.0
Limb ischemia 1.0
Compartment syndrome 0.2
CONCLUSION
The use of ECMO for respiratory failure is increasing rapidly, but this usage continues to outpace the
evidence. The most extensive, albeit flawed, data favoring ECMO are in the setting of severe ARDS, with a
large randomized controlled trial currently ongoing. The potential for ECMO and ECCO2R to be applied to a
much broader patient population is substantial. However, more data are needed before extracorporeal
support should be routinely used for these emerging indications.
KEY Points
In cases of severe ARDS, ECMO has the ability to both correct profound hypoxemia and facilitate
adherence to lung-protective ventilation.
The use of ECCO2R has the potential to further reduce ventilator-associated lung injury in ARDS by
permitting the application of very low tidal volume ventilation, though this has yet to be demonstrated in
randomized clinical trials.
Beyond ARDS, ECMO has an expanding role in the management of end-stage lung disease and
pulmonary hypertension. However, the lack of a destination device limits this application.
P.630
REFERENCES
1. Brodie D, Bacchetta M. Extracorporeal membrane oxygenation for ARDS in adults. N Engl J Med
2011;365:1905-1914.
2. Schmidt M, Tachon G, Devilliers C, et al. Blood oxygenation and decarboxylation determinants during
venovenous ECMO for respiratory failure in adults. Intensive Care Med 2013;39:838-846.
3. Gattinoni L, Kolobow T, Damia G, et al. Extracorporeal carbon dioxide removal (ECCO2R): a new form of
respiratory assistance. Int J Artif Organs 1979;2:183-185.
4. Abrams D, Brodie D. Emerging indications for extracorporeal membrane oxygenation in adults with
respiratory failure. Ann Am Thorac Soc 2013;10:371-377.
5. Abrams D, Roncon-Albuquerque R Jr, Brodie D. What’s new in extracorporeal carbon dioxide removal for
COPD? Intensive Care Med 2015;41:906-908.
6. Abrams D, Bacchetta M, Brodie D. Recirculation in venovenous extracorporeal membrane oxygenation.

ASAIO J 2015;61:115-121.
7. Wang D, Zhou X, Liu X, et al. Wang-Zwische double lumen cannula-toward a percutaneous and
ambulatory paracorporeal artificial lung. ASAIO J 2008;54:606-611.
8. Javidfar J, Brodie D, Wang D, et al. Use of bicaval dual-lumen catheter for adult venovenous
extracorporeal membrane oxygenation. Ann Thorac Surg 2011;91:1763-1768; discussion 1769.
9. Abrams D, Brodie D, Javidfar J, et al. Insertion of bicaval dual-lumen cannula via the left internal jugular
vein for extracorporeal membrane oxygenation. ASAIO J 2012;58:636-637.
10. Javidfar J, Wang D, Zwischenberger JB, et al. Insertion of bicaval dual lumen extracorporeal membrane
oxygenation catheter with image guidance. ASAIO J 2011;57:203-205.
11. Bein T, Weber F, Philipp A, et al. A new pumpless extracorporeal interventional lung assist in critical
hypoxemia/hypercapnia. Crit Care Med 2006;34:1372-1377.
12. 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.
13. Aziz F, Brehm CE, El-Banyosy A, et al. Arterial complications in patients undergoing extracorporeal
membrane oxygenation via femoral cannulation. Ann Vasc Surg 2013;28(1):178-183.
14. Biscotti M, Lee A, Basner RC et al. Hybrid configurations via percutaneous access for extracorporeal
membrane oxygenation: a single-center experience. ASAIO J 2014;60:635-642.
15. Javidfar J, Brodie D, Costa J, et al. Subclavian artery cannulation for venoarterial extracorporeal
membrane oxygenation. ASAIO J 2012;58:494-498.
16. Biscotti M, Bacchetta M. The “sport model”: extracorporeal membrane oxygenation using the subclavian
artery. Ann Thorac Surg 2014;98:1487-1489.
17. Reis Miranda D, van Thiel R, Brodie D, et al. Right ventricular unloading after initiation of venovenous
extracorporeal membrane oxygenation. Am J Respir Crit Care Med 2015;191:346-348.
18. Anonymous. International consensus conferences in intensive care medicine: ventilator-associated lung
injury in ARDS. This official conference report was cosponsored by the American Thoracic Society, The
European Society of Intensive Care Medicine, and The Societe de Reanimation de Langue Francaise, and
was approved by the ATS Board of Directors, July 1999. Am J Respir Crit Care Med 1999;160:2118-2124.
19. 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;342:1301-1308.
20. Rubenfeld GD, Cooper C, Carter G, et al. Barriers to providing lung-protective ventilation to patients with
acute lung injury. Crit Care Med 2004;32:1289-1293.
21. Mikkelsen ME, Dedhiya PM, Kalhan R, et al. Potential reasons why physicians underuse lung-protective
ventilation: a retrospective cohort study using physician documentation. Respir Care 2008;53:455-461.
22. Combes A, Brechot N, Luyt CE, et al. What is the niche for extracorporeal membrane oxygenation in
severe acute respiratory distress syndrome? Curr Opin Crit Care 2012;18:527-532.
23. Abrams D, Brodie D. Extracorporeal circulatory approaches to treat acute respiratory distress syndrome.
Clin Chest Med 2014;35:765-779.
failure. A randomized prospective study. JAMA 1979;242:2193-216.
25. 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.
26. Peek GJ, Mugford M, Tiruvoipati R, et al. Efficacy and economic assessment of conventional ventilatory
support versus extracorporeal membrane oxygenation for severe adult respiratory failure (CESAR): a
multicentre randomised controlled trial. Lancet 2009;374:1351-1363.
27. Noah MA, Peek GJ, Finney SJ, et al. Referral to an extracorporeal membrane oxygenation center and
mortality among patients with severe 2009 influenza A(H1N1). JAMA 2011;306:1659-1668.
28. Pham T, Combes A, Roze H, et al. Extracorporeal membrane oxygenation for pandemic influenza
A(H1N1)-induced acute respiratory distress syndrome: a cohort study and propensity-matched analysis. Am
J Respir Crit Care Med 2013;187:276-285.
29. Assistance Publique—Hôpitaux de Paris. Extracorporeal Membrane Oxygenation for Severe Acute
Respiratory Distress Syndrome (EOLIA). In: ClinicalTrials.gov [Internet]. Bethesda, MD: National Library of
Medicine (US), 2000 [cited 2012 Jul 1]. Available at http://clinicaltrials.gov/ct2/show/NCT01470703.NLM
Identifier: NCT01470703.
30. Schmidt M, Zogheib E, Roze H, et al. The PRESERVE mortality risk score and analysis of long-term
outcomes after extracorporeal membrane oxygenation for severe acute respiratory distress syndrome.
Intensive Care Med 2013;39:1704-1713.
31. Pappalardo F, Pieri M, Greco T, et al. Predicting mortality risk in patients undergoing venovenous ECMO
for ARDS due to influenza A (H1N1) pneumonia: the ECMOnet score. Intensive Care Med 2013;39:275-281.
32. Schmidt M, Bailey M, Sheldrake J et al. Predicting survival after extracorporeal membrane oxygenation
for severe acute respiratory failure. The Respiratory Extracorporeal Membrane Oxygenation Survival
Prediction (RESP) score. Am J Respir Crit Care Med 2014;189:1374-1382.
33. Klinzing S, Wenger U, Steiger P, et al. External validation of scores proposed for estimation of survival
probability of patients with severe adult respiratory distress syndrome undergoing extracorporeal membrane
oxygenation therapy: a retrospective study. Crit Care 2015;19:142.
34. Hodgson CL, Hayes K, Everard T, et al. Long-term quality of life in patients with acute respiratory
distress syndrome requiring extracorporeal membrane oxygenation for refractory hypoxaemia. Crit Care
2012;16:R202.
35. Abrams D, Brodie D, Combes A. What is new in extracorporeal membrane oxygenation for ARDS in
adults? Intensive Care Med 2013;39:2028-2030.
36. Abrams D, Agerstrand CL, Biscotti M, et al. Extracorporeal membrane oxygenation in the management of
diffuse alveolar hemorrhage. ASAIO J 2015;61:216-218.
37. Patel JJ, Lipchik RJ. Systemic lupus-induced diffuse alveolar hemorrhage treated with extracorporeal
membrane oxygenation: a case report and review of the literature. J Intensive Care Med 2014;29:104-109.
38. Gattinoni L, Pesenti A, Mascheroni D, et al. Low-frequency positive-pressure ventilation with

extracorporeal CO2 removal in severe acute respiratory failure. JAMA 1986;256:881-886.
39. Hager DN, Krishnan JA, Hayden DL, et al. Tidal volume reduction in patients with acute lung injury when
plateau pressures are not high. Am J Respir Crit Care Med 2005;172:1241-1245.
40. Terragni PP, Del Sorbo L, Mascia L, et al. Tidal volume lower than 6 ml/kg enhances lung protection: role
of extracorporeal carbon dioxide removal. Anesthesiology 2009;111:826-835.
41. Combes A, Bacchetta M, Brodie D, et al. Extracorporeal membrane oxygenation for respiratory failure in
adults. Curr Opin Crit Care 2012;18:99-104.
42. Terragni P, Faggiano C, Ranieri VM. Extracorporeal membrane oxygenation in adult patients with acute
respiratory distress syndrome. Curr Opin Crit Care 2014;20:86-91.
43. Abrams DC, Brodie D, Rosenzweig EB, et al. Upper-body extracorporeal membrane oxygenation as a
strategy in decompensated pulmonary arterial hypertension. Pulm Circ 2013;3:432-435.
44. Javidfar J, Brodie D, Sonett J, et al. Venovenous extracorporeal membrane oxygenation using a single
cannula in patients with pulmonary hypertension and atrial septal defects. J Thorac Cardiovasc Surg
2012;143:982-984.
45. Camboni D, Akay B, Sassalos P, et al. Use of venovenous extracorporeal membrane oxygenation and an
atrial septostomy for pulmonary and right ventricular failure. Ann Thorac Surg 2011;91:144-149.
P.631
46. Hoopes CW, Gurley JC, Zwischenberger JB, et al. Mechanical support for pulmonary veno-occlusive
disease: combined atrial septostomy and venovenous extracorporeal membrane oxygenation. Semin Thorac
47. 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.
48. Biscotti M, Vail E, Cook KE, et al. Extracorporeal membrane oxygenation with subclavian artery
cannulation in awake patients with pulmonary hypertension. ASAIO J 2014;60:748-750.
49. Rosenzweig E, Brodie D, Abrams D, et al. Extracorporeal membrane oxygenation as a novel bridging
strategy for the management of acute right heart failure in Group 1 PAH. ASAIO J 2014;60(1):129-133.
50. Maurer JR, Frost AE, Estenne M, et al. International guidelines for the selection of lung transplant
candidates. The International Society for Heart and Lung Transplantation, the American Thoracic Society,
the American Society of Transplant Physicians, the European Respiratory Society. Transplantation
1998;66:951-956.
51. George TJ, Beaty CA, Kilic A, et al. Outcomes and temporal trends among high-risk patients after lung
transplantation in the United States. J Heart Lung Transplant 2012;31:1182-1191.
52. Javidfar J, Brodie D, Iribarne A, et al. Extracorporeal membrane oxygenation as a bridge to lung
transplantation and recovery. J Thorac Cardiovasc Surg 2012;144:716-721.
53. Mason DP, Thuita L, Nowicki ER, et al. Should lung transplantation be performed for patients on
mechanical respiratory support? The US experience. J Thorac Cardiovasc Surg 2010;139:765-773.e1.
54. Abrams D, Javidfar J, Farrand E, et al. Early mobilization of patients receiving extracorporeal membrane
oxygenation: a retrospective cohort study. Crit Care 2014;18:R38.
55. 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.
56. 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.
57. Abrams DC, Prager K, Blinderman CD, et al. Ethical dilemmas encountered with the use of extracorporeal
membrane oxygenation in adults. Chest 2014;145:876-882.
58. Christie JD, Edwards LB, Kucheryavaya AY, et al. The Registry of the International Society for Heart and
Lung Transplantation: 29th adult lung and heart-lung transplant report-2012. J Heart Lung Transplant
2012;31: 1073-1086.
59. Hartwig MG, Appel JZ III, Cantu E III, et al. Improved results treating lung allograft failure with venovenous
extracorporeal membrane oxygenation. Ann Thorac Surg 2005;80:1872-1879; discussion 1879-1880.
60. Ai-Ping C, Lee KH, Lim TK. In-hospital and 5-year mortality of patients treated in the ICU for acute
exacerbation of COPD: a retrospective study. Chest 2005;128:518-524.
61. Bekaert M, Timsit JF, Vansteelandt S, et al. Attributable mortality of ventilator-associated pneumonia: a
reappraisal using causal analysis. Am J Respir Crit Care Med 2011;184:1133-1139.
62. Kluge S, Braune SA, Engel M, et al. Avoiding invasive mechanical ventilation by extracorporeal carbon
dioxide removal in patients failing noninvasive ventilation. Intensive Care Med 2012;38:1632-1639.
63. Burki NK, Mani RK, Herth FJ, et al. A novel extracorporeal CO2 removal system: results of a pilot study of
hypercapnic respiratory failure in patients with COPD. Chest 2013;143:678-686.
64. Abrams DC, Brenner K, Burkart KM, et al. Pilot study of extracorporeal carbon dioxide removal to
facilitate extubation and ambulation in exacerbations of chronic obstructive pulmonary disease. Ann Am
Thorac Soc 2013;10:307-314.
65. Del Sorbo L, Pisani L, Filippini C, et al. Extracorporeal CO2 removal in hypercapnic patients at risk of
noninvasive ventilation failure: a matched cohort study with historical control. Crit Care Med 2014;43(1):120-
127.
66. Roncon-Albuquerque R Jr, Carona G, Neves A, et al. Venovenous extracorporeal CO2 removal for early
extubation in COPD exacerbations requiring invasive mechanical ventilation. Intensive Care Med
2014;40:1969-1970.
67. Brenner K, Abrams D, Agerstrand C, et al. Extracorporeal carbon dioxide removal for refractory status
asthmaticus: experience in distinct exacerbation phenotypes. Perfusion 2014;29(1):26-28.
68. Mikkelsen ME, Woo YJ, Sager JS, et al. Outcomes using extracorporeal life support for adult respiratory
failure due to status asthmaticus. ASAIO J 2009;55:47-52.
69. Extracorporeal Life Support Organization Registry Report. US Complications January 2014. 17 May
2015.
70. Agerstrand CL, Burkart KM, Abrams DC, et al. Blood conservation in extracorporeal membrane
oxygenation for acute respiratory distress syndrome. Ann Thorac Surg 2015;99:590-595.
71. Schmidt M, Brechot N, Hariri S, et al. Nosocomial infections in adult cardiogenic shock patients
supported by venoarterial extracorporeal membrane oxygenation. Clin Infect Dis 2012;55:1633-1641.
72. Takayama H, Landes E, Truby L, et al. Feasibility of smaller arterial cannulas in venoarterial
extracorporeal membrane oxygenation. J Thorac Cardiovasc Surg 2015;149(5):1428-1433.
73. Haley MJ, Fisher JC, Ruiz-Elizalde AR, et al. Percutaneous distal perfusion of the lower extremity after
femoral cannulation for venoarterial extracorporeal membrane oxygenation in a small child. J Pediatr Surg
2009;44:437-440.
74. Jackson KW, Timpa J, McIlwain RB, et al. Side-arm grafts for femoral extracorporeal membrane
oxygenation cannulation. Ann Thorac Surg 2012;94:e111-e112.
Chapter 27
Perfusion for Thoracic Aortic Surgery
Scott A. LeMaire
Joseph S. Coselli
Steven A. Raskin
Terry N. Crane
Eric Jenkins
Murphy Rayle
Victoria Vasileiadou
Kim I. de la Cruz
Surgical repair of thoracic aortic aneurysm and dissection has been an active field of innovation and
investigation for more than 50 years. Although outcomes have greatly improved over the past few decades,
operative mortality and neurologic complications remain the greatest challenges associated with open aortic
repair. The diversity of surgical approaches across institutions is a testament to the complexity of these
procedures and the lack of evidence regarding the efficacy of many technical details (1).
Because of the risks related to open repair, hybrid and purely endovascular approaches to treating disease of
the thoracic aorta have recently been developed as less invasive alternatives for high-risk patients (1,2). The
main pitfalls of procedures involving endovascular techniques include the risks of embolic stroke and repair
failure due to stent migration or endoleak. Although the feasibility of hybrid and endovascular techniques has
been demonstrated, long-term durability and survival data are yet to be collected, and once they are, they must
be evaluated against data from contemporary series of open surgical repairs (1,3). Extending hybrid and purely
endovascular techniques to low-risk surgical candidates with extensive thoracic aortic disease would be
premature at this point, and although the indications for these approaches will no doubt continue to expand,
there will remain a need for open repair and the associated perfusion techniques for many years to come.
Thoracic aortic aneurysms require individualized treatment. The specific challenges of each case must be
considered, and decisions should be based on the aneurysm’s extent, rate of progression, and cause, as well as
the patient’s overall health. Careful attention to imaging studies and preoperative planning are imperative for
devising optimal surgical strategies. In these complex operations, protecting critical organs—including the brain,
heart, spinal cord, kidneys, and other viscera—must be a primary goal, because periods of ischemia often
determine the degree of injury and the eventual outcome.
Since the last edition of this book was published, there have been several important changes in the methods,
equipment, and techniques used in thoracic aortic aneurysm surgery. The goal of perfusion in aneurysm
operations is to enable the required repairs while minimizing ischemic injury, especially to the central nervous
system. Many different strategies are needed, in part because each approach must be suited to the section of
the aorta that is being treated.
The aorta can be thought of as having three major segments:
1. The ascending aorta. The ascending aorta begins at the aortic valve annulus and ends just proximal to the
origin of the innominate artery.
2. The transverse aortic arch. The transverse aortic arch is the segment from which the three brachiocephalic
branches arise, extending from the origin of the innominate artery to the origin of the left subclavian artery
(LSCA).
3. The descending thoracic/thoracoabdominal aorta. The descending thoracic/thoracoabdominal aorta extends
from just beyond the LSCA to the aortoiliac bifurcation.
Thoracic aortic aneurysms and dissections do not respect distinct boundaries; so the surgical and perfusion
techniques used in their treatment must be adaptable for use in different segments. Because the perfusion
techniques used in operations on the ascending and transverse sections often overlap, they are discussed
together in the following section covering proximal aortic operations. Perfusion techniques used during repair of
descending thoracic aortic aneurysm (DTAA) and thoracoabdominal aortic aneurysm (TAAA) are described in the
subsequent section regarding distal aortic operations.
PROXIMAL AORTIC OPERATIONS

Proximal aortic operations are approached most commonly by median sternotomy. For nonemergent operations
limited to the ascending aortic segment, we use cardiopulmonary bypass (CPB), whereas in cases of aneurysm
rupture or acute dissection, we use hypothermic circulatory arrest (HCA) with selective antegrade cerebral
perfusion (ACP). Although acute proximal aortic dissection can be repaired without HCA, using this technique
eliminates the need for aortic clamping. The “open” distal anastomosis technique—originally advocated by
Cooley and Livesay in 1981 (4)—avoids clamp injury of the fragile dissecting membrane, allows identification of
tears within the transverse arch, and facilitates assessment of
P.634
aortic arch diameter. We also use HCA with ACP during graft replacement of the transverse aortic arch (5).
Options for Cannulation

Disease that is limited to the aortic root or ascending aorta is approached with CPB. The arterial cannula can be
often placed in the ascending aorta or transverse aortic arch, with the aortic cross-clamp applied proximal to the
innominate artery. For patients in whom aortic cannulation is not feasible—such as those with disease extending
into the aortic arch—one alternative for cannulation is the femoral artery, a particularly useful cannulation site in
emergency situations with hemodynamically unstable patients. However, delivering CPB inflow from the femoral
artery has several disadvantages in patients with extensive aortic disease (6). Most notably, retrograde flow
through the diseased atheromatous distal aorta can potentially cause stroke and other complications by plaque
embolization (7). Moreover, in cases of aortic dissection, blood flow may preferentially pressurize the false
lumen, causing cerebral malperfusion.
The problems related to femoral artery cannulation can be avoided by using the right axillary artery for CPB
inflow (Fig. 27.1) (8). The axillary artery is rarely involved in aneurysmal disease or dissection, which makes it a
better site for establishing inflow. Furthermore, the right axillary artery provides a direct route to the right common
carotid artery for ACP (as described in the section regarding adjuncts for cerebral protection).
FIGURE 27.1. Right axillary artery perfusion is delivered through a graft sutured to the anterior aspect of the
artery. The axillary vein and the cords of the brachial plexus are immediately adjacent to the artery. (Used with
permission of Baylor College of Medicine.)
Several groups, including ours, have reported that innominate cannulation is a safe and effective alternative for
arterial inflow in proximal aortic surgery (Fig. 27.2) (9). We continue to use right axillary cannulation in selected
redo operations when reentry is difficult or the innominate artery appears poorly suited for cannulation. We
generally reserve femoral artery cannulation for patients who present in extremis and are hemodynamically
unstable. When the right axillary and innominate arteries are unusable, alternative proximal options include the
left axillary and carotid arteries.
When an arterial cannula is used, the size of the cannula is chosen to minimize the pressure gradient across the
cannula at the patient’s calculated flow rate, which is based on a standard cardiac index of 2.2 to 2.4 L/min2 for
adults at normothermic temperatures. The cannula should be large enough to provide the calculated flow rate
with a gradient of less than 100 mm Hg. After the cannula is inserted into the vessel, it is connected to the circuit
tubing during a forward pump roll to facilitate air removal at the connection. If a femoral arterial cannula is used, it
is inserted percutaneously over a guidewire, de-aired, and attached to the arterial side of the circuit as fluid is
slowly run forward in order to create a wet connection
P.635
during a forward pump roll. After the cannula is placed, reverse flow is briefly allowed to ensure that a false
lumen has not been cannulated accidentally. Poor arterial return into the cannula during this maneuver may
indicate proximal arterial obstruction, which necessitates repositioning the cannula or changing to an alternative
cannulation site. A forward roll is then commenced to confirm good access (5).
FIGURE 27.2. Innominate artery perfusion is delivered through a graft sutured to the anterior aspect of the
artery. (Used with permission of Baylor College of Medicine.)
Venous cannulation is accomplished with a right atrial dual-stage cannula, bicaval cannulas, or a long femoral
venous cannula that extends up the inferior vena cava and into the base of the right atrium. This long cannula
sometimes requires vacuum or kinetic assistance for drainage. Like femoral arterial cannulation, femoral venous
cannulation is routinely used in hemodynamically unstable patients who require pump support before sternotomy.
It is particularly useful in patients who are at risk of aortic injury during sternotomy, including patients undergoing
reoperation and those with large ascending aortic aneurysms abutting the sternum. In such patients, the femoral
cannula is placed before sternotomy is performed.
A left ventricular sump cannula is inserted through a purse-string suture placed at the junction of the right
superior pulmonary vein and the left atrium. The sump minimizes preload, prevents ventricular distention,
reduces myocardial rewarming, prevents ejection of air, and facilitates exposure of the aortic valve. An in-line
pressure-relief valve is located between the sump cannula and a roller pump, which returns the vented blood to
the bypass circuit either through the cardiotomy reservoir or directly into the venous reservoir. The degree of
sump suction is constantly regulated, because too little suction allows ventricular distension, and too much can
cause ventricular collapse and injury.
Myocardial protection is achieved by using systemic hypothermia and a combination of antegrade and retrograde
cardioplegia, which facilitates adequate delivery of cardioplegia to all areas of the heart. We use a one-pass
circuit to deliver 4°C blood-crystalloid (4:1) cardioplegia solution. The retrograde cardioplegia cannula is inserted
into the coronary sinus after venous cannulation so that the coronary sinus cannula will not be dislodged when
the venous cannula is positioned in the inferior vena cava. The initial bolus of antegrade cardioplegia is
delivered either into the aortic root through an aortic needle placed proximal to the aortic cross-clamp, or directly
into the coronary ostia through a cannula held by forceps after the aorta is opened. Then, additional boluses of
cardioplegia solution are delivered directly into each coronary ostium at a rate of 250 mL/min approximately
every 6 minutes in the amount specified at the time by the surgeon.
Hypothermic Circulatory Arrest and Cerebral Perfusion Adjunct
Improvements in aortic arch surgery outcomes have been partly attributed to better cerebral protection
techniques. When DeBakey et al (10) first successfully replaced the aortic arch in the 1950s, they directly
perfused the brachiocephalic branches during the operation. Since that first arch-replacement procedure, and
since the first application of hypothermia to aortic surgery by Griepp and colleagues in 1975 (11) by inducing
deep HCA at a body temperature of 18°C, the two main methods of brain protection have been inducing different
degrees of hypothermia and using adjuncts for cerebral perfusion (12).
Soon after Griepp’s report was published, Crawford and Saleh (13) adopted the HCA technique and reported its
efficacy in reducing morbidity and mortality. The protective limits of HCA were defined in 1993 by Svensson et al.
(14), who reported Crawford’s experience with 656 patients who underwent HCA during proximal aortic surgery.
The overall rates of transient stroke, permanent stroke, and early mortality were low, but the incidence of
perioperative neurologic complications rose sharply when the HCA time exceeded 40 minutes,
P.636
and mortality increased dramatically when HCA time exceeded 65 minutes. The limitations of using HCA alone
(i.e., without perfusion adjuncts) are now well recognized. During arch repairs that only necessitate short periods
of HCA (i.e., less than 30 minutes, such as in elective hemiarch replacement), HCA alone provides satisfactory
brain protection. However, during more complex repairs (e.g., total arch replacement) that necessitate
substantially longer HCA times, the use of HCA alone is associated with a high risk of stroke and death (14).
In the late 1980s, we adopted the use of retrograde cerebral perfusion (RCP) as an adjunct to HCA (Fig. 27.3)
(15,16,17). Electroencephalographic (EEG) monitoring was used to guide the induction of deep or profound
hypothermia (<20°C); cooling was stopped when EEG silence was achieved. To enhance brain protection,
dexamethasone was given 3 minutes before HCA was initiated. Once HCA was started, RCP was used to direct
oxygenated blood from the CPB circuit into the head through the snared superior vena caval cannula. The RCP
flow was delivered through a connection between the arterial inflow line and the superior vena caval cannula line
(16).
FIGURE 27.3. Retrograde cerebral perfusion is delivered via tubing that bridges the arterial inflow line and the
superior vena caval cannula. This technique provides retrograde flow of cold, oxygenated blood into the head via
the superior vena cava during hypothermic circulatory arrest. (Used with permission of Baylor College of
Medicine.)
Although RCP became a widely used adjunct in the 1990s, the expanding experimental and clinical data did not
consistently support the efficacy of RCP for cerebral protection (18,19,20,21,22,23). There were questions as to
whether RCP produces sufficient flow to meet the metabolic demands of the brain or even whether RCP
provides any flow through the cerebral
P.637
microvasculature. Experimental data increasingly suggested that RCP does not effectively deliver blood to the
brain; rather, the benefits of RCP seemed to be chiefly related to maintaining regional hypothermia and to
flushing air and debris out of the cerebral circulation.
We used RCP during HCA for many years; however, as evidence mounted for the benefits of ACP, in the last
decade, we have shifted to using HCA and selective ACP almost exclusively when repairing acute ascending
aortic dissection or aortic arch aneurysm (5). Our initial approach to ACP involved placing balloon-tipped
catheters in the origins of the innominate artery and the left common carotid artery (LCCA) to deliver ACP during
the HCA period (Fig. 27.4). Subsequently, the shift from using RCP to using ACP was further facilitated by a
second major change in technique: the introduction of right axillary artery perfusion (Figs. 27.1 and 27.5A) (8).
Once systemic HCA has begun, ACP is initiated by reducing axillary inflow to 10 mL/kg/min and occluding the
innominate artery by using either a Rumel tourniquet or a vascular clamp. Because most patients have a
complete circle of Willis, right-sided ACP generally provides adequate left-sided cerebral protection. When direct
left-sided ACP is indicated, it can be delivered through the LCCA by inserting a balloon-tipped catheter that has
been connected to a Y-limb from the arterial CPB line (Fig. 27.5) (16).
FIGURE 27.4. During hypothermic circulatory arrest, antegrade cerebral perfusion can be delivered directly into
the arch branches via separate balloon perfusion catheters. (Used with permission of Baylor College of
Medicine.)
Multiple studies (16,24,25) have shown that ACP extends the safe duration of arch intervention beyond what
HCA alone provides, especially when the distal arch repair time exceeds
P.638
P.639
30 minutes. However, the ideal core temperature for HCA with ACP has yet to be determined (1). We found that
temperature below 20°C is associated with a 9-fold increase in hospital death, as well as significant increases in
the 30-day mortality rate and CPB time and a nonsignificant increase in the incidence of stroke (12). Our current
routine approach to open repair of the aortic arch features either right axillary artery or innominate artery CPB
inflow and moderate HCA (23°C-25°C) with ACP. We use this approach for all openarch replacement
procedures, including hemiarch replacements, total arch replacements, elephant trunk procedures, aortic
dissection repairs, as well as repairs of aortic aneurysm without dissection.
FIGURE 27.5. Occluding the proximal innominate artery with a snare during (A) axillary artery or (B) innominate
artery inflow enables delivery of antegrade cerebral perfusion during hypothermic circulatory arrest. When
necessary, antegrade perfusion can also be delivered to the left common carotid artery through a separate
balloon perfusion catheter. (Used with permission of Baylor College of Medicine.)
The Trifurcated Graft Technique for Arch Replacement

When performing total arch replacement, we currently use the trifurcated graft technique (Fig. 27.6), which we
incorporated into our practice in 2006 (26). This technique employs a single- or double-Y-graft that can be
constructed to suit the patient’s anatomy and the planned reconstruction. Alternatively, an appropriately sized,
prefabricated Y-graft can be used. In either case, the trifurcated graft is used to enable continuous delivery of
ACP during the HCA period and to attach the brachiocephalic branches to the main aortic graft. This technique
enables the use of bilateral ACP for cerebral protection, permits a shorter duration of cerebral HCA, and isolates
the brachiocephalic vessels from the often-diseased atheromatous aorta near their origins. It provides continuous
brain protection and allows great versatility of the Y-graft to accommodate arch anomalies or to modify the
sequence of anastomoses according to intraoperative findings. Further, the trifurcated graft can be precisely
tailored to the patient’s anatomy, so the potential for kinking is lower than it is with the use of prefabricated four-
branched arch grafts, in which the position of the branches is fixed.
Technical Details of Aortic Arch Repair Procedures
Before general anesthesia is induced, we begin bilateral cerebral near-infrared spectroscopy with an INVOS
Cerebral Somatic Oximeter (Covidien, Mansfield, MA). Noninvasive sensors are placed on the forehead, over the
frontal lobes, to monitor brain oxygenation throughout the procedure. General anesthesia is then induced with
etomidate, midazolam, fentanyl, and isoflurane. Before incision, patients receive either aminocaproic acid or
tranexamic acid as an antifibrinolytic (27). Whenever possible, we collect one to three autologous units of blood
before heparinization to achieve a hematocrit of 23% to 25%; this is mainly done in patients whose baseline
hematocrit is less than 20%. The autologous units are then administered after protamine administration and
surgical hemostasis. To enhance cerebral protection during HCA, we add 25 g of mannitol to the pump prime
and administer an intravenous dose of dexamethasone (100 mg) before initiating CPB, although the supporting
evidence for this practice is equivocal.
Performing HCA safely requires the careful monitoring of several temperatures throughout the procedure,
including the patient’s nasopharyngeal temperature. Also monitored in the perfusion circuit are the temperatures
of the arterial blood at the oxygenator outlet, the venous blood about to enter the venous reservoir, and the water
for the heat exchanger unit. Other possible temperatures to monitor are those of the patient’s bladder, arterial
perfusate, venous perfusate, and cardioplegia solution.
Our arterial cannulation strategy has shifted from femoral and direct aortic cannulation to right axillary and, more
recently, innominate artery cannulation (8,9). Unlike femoral cannulation, both right axillary and innominate artery
cannulation prevent malperfusion and retrograde cerebral atheroembolism, and facilitate delivery of ACP
throughout the HCA period (Fig. 27.5). The axillary artery is approached through a 4- to 6-cm incision made at
the right deltopectoral groove (Fig. 27.1). After the fibers of the pectoralis major muscle are separated, the
underlying pectoralis minor is divided to expose the fat pad immediately posterior to the muscle. The brachial
plexus lies beneath the fat pad, so care must be taken to avoid causing direct trauma or electrical injury to it
during cautery. The axillary vein is usually retracted inferiorly to expose the artery. A short segment of the artery
is then mobilized and encircled with a vessel loop. After the artery is exposed, the sternum is opened and, once
sternal and mediastinal hemostasis has been achieved, a 3-mg (300 International Units/kg) bolus of heparin is
administered. A partial occluding clamp is then applied to achieve proximal and distal control. An 8-mm polyester
graft is anastomosed to the axillary artery in end-to-side manner with running 6-0 polypropylene suture. After the
graft is carefully flushed and de-aired, it is secured to the inflow, or arterial, arm of the CPB circuit with a ⅜- to ¼-
inch reducer connector, a plastic band, and heavy silk ligature. Alternatively, the axillary artery can be
cannulated directly. During cooling, the innominate artery is exposed, posterior and superior to the innominate
vein, and encircled with an umbilical tape passed through a tourniquet.
Innominate artery cannulation has several advantages over axillary artery cannulation. First, there is no need for
an additional incision; thus, the operative time is potentially shorter. Second, because the cannulation site
remains under the surgeon’s direct vision at all times, additional blood loss and possible kinking of the inflow
graft can be avoided. Third, the innominate artery is technically easier to cannulate in obese patients than the
axillary artery. Fourth, the risk of brachial plexus injury and arm ischemia or claudication is eliminated.
The innominate artery is exposed to its bifurcation and encircled with an umbilical tape (Fig. 27.2). Three minutes
after 1 mg/kg of heparin is given, a partial occluding clamp
P.640
is applied to the distal innominate artery. An 8-mm polyester graft is then sewn to the artery in an end-to-side
manner. The graft is de-aired and connected to the arterial line with a ⅜- to ¼-inch reducer connector. After the
innominate artery is cannulated, a full dose of heparin is given (3 mg/kg or 300 International Units/kg); the target
activated clotting time is 480 seconds (9). The proximal aspect of the innominate artery is encircled with an
umbilical tape passed through a tourniquet.
FIGURE 27.6. The Y-graft technique with antegrade cerebral perfusion for elephant trunk repair of an extensive
aneurysm involving the ascending, arch, and descending thoracic aorta. The proximal portions (A) of the
brachiocephalic arteries are exposed. The first two branches of the graft (B) are sewn to the transected left
subclavian and left common carotid arteries, and the residual proximal ends of the arteries are ligated. A balloon-
tipped perfusion cannula (C) is placed inside the double Y-graft and used to deliver antegrade cerebral
perfusion. After initiation of systemic circulatory arrest, the innominate artery is clamped, transected, and sewn to
the distal end of the main graft. The proximal aspect of the Y-graft is then clamped (D). This directs flow from the
axillary artery to all three brachiocephalic arteries. The arch is then replaced (E) with a collared elephant trunk
graft. The distal anastomosis between the elephant trunk graft and the aorta is created between the innominate
and left common carotid arteries rather than the anatomic origins of the left subclavian artery. The collared graft
accommodates any discrepancy in aortic diameter. The aortic graft is clamped (F), and a second limb from the
arterial inflow tubing of the cardiopulmonary bypass circuit is used to deliver distal perfusion through a side-
branch of the arch graft while the proximal portion of the ascending aorta is replaced. Once the proximal aortic
anastomosis is completed, the main trunk of the double Y-graft is cut to an appropriate length. The beveled end
is then sewn to an oval opening created in ascending aortic graft, which completes the repair (G). (Adapted with
permission from LeMaire SA, Price MD, Parenti JL, et al. Early outcomes after aortic arch replacement by using
the Y-graft technique. Ann Thorac Surg 2011;91:700-708, copyright The Society of Thoracic Surgeons, Fig. 2A-
G.)
The femoral artery can serve as an alternative cannulation site in emergent cases. When femoral artery
cannulation is used in patients with aortic dissection, careful attention is
P.641
required to ensure cannulation of the true lumen. Because the false lumen usually progresses down the left iliac
artery, cannulating the right femoral artery is preferable in dissection cases. Poor backflow into the arterial
cannula during a brief reverse flow test may indicate cannulation of the false lumen; to prevent retrograde
malperfusion, the cannula should be repositioned or placed in a different vessel before CPB is initiated.
Venous cannulation is established through the right atrium, both venae cavae, or the femoral vein, depending on
need and accessibility as previously discussed. CPB is initiated, and the adequacy of perfusion is assessed; this
is particularly important when the femoral artery has been cannulated in a patient with aortic dissection. A
retrograde cardioplegia catheter is placed in the coronary sinus, and a left ventricular sump catheter is placed
through the right superior pulmonary vein. The sump is especially important in patients who are prone to
ventricular distention, such as those with aortic valve regurgitation. Ventricular distention can also result from
fibrillation caused by systemic hypothermia; to prevent this complication, the sump is generally placed before
systemic cooling begins.
Once systemic cooling has begun, 100 mg lidocaine, 100 mg esmolol, 150 mg amiodarone, and 2 mg magnesium
are administered through the central line. Each 10°C decrease in body temperature reduces the rate of oxygen
consumption by approximately 50%. As the temperature and metabolic rate decrease, pump flows are reduced to
1.6 to 1.8 L/min/m2. In addition, for every 10°C decrease in core temperature, there is a 20% to 25% increase in
blood viscosity (28,29). In the past, before the use of hemodilution, hypothermia-induced hyperviscosity caused
substantial morbidity (e.g., stroke and visceral infarction) and mortality. Currently, patients’ blood is routinely
hemodiluted to a hematocrit of less than 25% until the aortic reconstruction is completed, at which time
rewarming and hemoconcentration are initiated. Although hemodilution decreases oxygen-carrying capacity,
overall oxygen delivery is improved because the decreased blood viscosity enhances microcirculatory flow.
As the cooling takes place, 4:1 blood cardioplegia solution (10-15 mL/kg) is delivered retrograde into the
coronary sinus. Despite the absence of a cross-clamp on the aorta, this induces diastolic arrest that is
maintained by the deepening hypothermia. If the patient has significant aortic valve regurgitation, it is important
to cross-clamp the ascending aorta if possible to prevent ventricular distension and enable the delivery of
cardioplegia directly into the coronary ostia while maintaining systemic flow and cooling through the innominate
or axillary artery. Then, after the initial bolus of cardioplegia has been delivered, intermittent cardioplegia
(retrograde, antegrade, or both) is used to protect the heart throughout the procedure.
Previously, we used EEG to guide rapid cooling, which would be stopped when the EEG showed electrocerebral
silence. EEG silence typically occurs after 20 to 25 minutes of cooling and corresponds to a brain temperature of
18°C to 20°C (30,31). Although we did not cool patients to a prescribed temperature, we did not actively cool
them to less than 15°C. When EEG was not available, we cooled patients for at least 25 minutes to a target core
temperature of 18°C to 20°C. Currently, we cool patients to a moderate level of hypothermia, with a target
temperature of 23°C to 25°C, before inducing circulatory arrest (12).
The choice of approach to aortic arch reconstruction depends on the extent of repair needed. For most patients
with acute ascending aortic dissection, or with aneurysm that only extends into the proximal arch, we perform
hemiarch replacement, in which a beveled graft is sutured end-to-end to the arch during HCA and ACP so that
the graft replaces the lesser curvature (Fig. 27.7). In cases in which the entire arch must be replaced, HCA and
ACP are used during branch-vessel reconstruction and the distal aortic anastomosis; the remainder of this
section describes the techniques for this type of procedure in detail.
In total aortic arch replacement, reconstruction of the brachiocephalic vessels begins during the cooling phase.
When the patient’s anatomy allows, the LSCA is ligated proximally and transected (Fig. 27.6A), and the first
branch of an independent, prefabricated, trifurcated graft (i.e., a Y-graft) is sutured end-to-end to the vessel.
Then, the mid-portion of the LCCA is clamped, its base is ligated, and the artery is divided and sutured end-to-
end to the middle branch of the trifurcated graft (Fig. 27.6B). The LSCA and LCCA anastomoses can be
performed during CPB at full flow. In some cases, it is easier to approach the LSCA after decompressing the arch
aneurysm; in such cases, we generally address the LCCA first and attach the LSCA later.
Once the target temperature is achieved, pentobarbital is given intravenously at a dose of 500 to 1,000 mg and
allowed to circulate for 3 minutes. Ice packs are placed around the patient’s head to assist the surface cooling of
the brain, and the patient is placed in the Trendelenburg position. CPB flow is then temporarily discontinued so
that the innominate artery can be safely clamped or snared with a tourniquet. Flow is resumed at a rate of 10 to
15 mL/kg/min with a target pressure of 50 to 70 mm Hg, thereby providing ACP through the innominate artery
and into the right common carotid artery. If there is concern about left cerebral malperfusion, we do not hesitate
to augment ACP through a balloon-tipped perfusion cannula that is connected to a Y-limb from the inflow tubing
and placed in the proximal aspect of the trifurcated graft (Fig. 27.6C). This is important when near-infrared
spectroscopy indicates a substantial decline in left brain oxygenation during ACP through the right common
carotid artery and in cases in which the femoral artery was the initial cannulation site.
The aorta is then opened, and a weighted cardiotomy suction catheter is placed in the distal arch to enable
adequate visualization. The innominate artery is transected at its base and sutured end-to-end to the appropriate
limb of the Y-graft (Fig. 27.6C). After this anastomosis is completed, the graft is de-aired, the innominate artery
snare is released, and the main
P.642
P.643
body of the graft is clamped to enable ACP delivery to all three of the attached vessels (Fig. 27.6D).
FIGURE 27.7. The hemiarch technique using antegrade cerebral perfusion for limited aortic arch repair in cases
of acute aortic dissection. This repair requires a median sternotomy (A) and cardiopulmonary bypass. The
ascending aorta is opened during hypothermic circulatory arrest, and antegrade cerebral perfusion is delivered
via a conduit graft attached to the axillary artery. The dissecting membrane is removed (B) to expose the true
lumen. Surgical adhesive is used to obliterate the false lumen (C) and strengthen the aorta for the distal
anastomosis. A 30-mL balloon catheter is used to compress the false lumen by expanding the true lumen; this
helps to prevent distal embolization of the adhesive through reentry sites by keeping the adhesive in the proximal
false lumen. An open distal anastomosis (D) prevents any potential clamp injury of fragile tissue and permits
inspection of the arch lumen. A balloon perfusion catheter in the left common carotid artery ensures antegrade
perfusion of the left cerebral circulation. If the origin of the dissection does not extensively involve the greater
curvature of the aortic arch, and if there is no evidence of a preexisting arch aneurysm, a beveled hemiarch
repair is carried out, preserving most of the greater curvature of the arch. The aorta is transected, beginning at
the greater curvature immediately proximal to the origin of the innominate artery and extending distally toward the
lesser curvature to the level of the left subclavian artery. In this manner, most of the transverse artic arch, except
for the dorsal segment containing the brachiocephalic arteries, is removed. An appropriately sized Dacron graft is
used, and the beveled distal anastomosis is made with continuous suture. After the anastomosis is covered with
additional adhesive (E) and cardiopulmonary bypass is resumed, the aortic valve is assessed; as possible, the
valve may be resuspended to restore valvular competence with pledgeted mattress sutures at disrupted
commissures. The aorta is generally transected at the sinotubular junction (F), and adhesive is used to obliterate
the false lumen within the proximal aortic stump. When surgical adhesive is applied to the aortic root, it is
important to turn the sump off for a few minutes to prevent aspiration of adhesive into the left ventricular outflow
tract and subsequent valve dysfunction or embolization. A moist gauze sponge is placed within the true lumen to
prevent the adhesive from injuring the aortic valve leaflets or entering the coronary artery ostia. After the
adhesive has set (G), the proximal anastomosis is carried out at the sinotubular junction and incorporates the
distal margin of the commissures. (Used with permission from Creager MA, Dzau VS, Loscalzo J, eds. Vascular
Medicine. Philadelphia, PA: WB Saunders; 2006. Copyright Elsevier, 2006, Fig. 35-3A-G.)
Attention is then directed to aortic reconstruction with a separate tube graft. Although traditionally the graft is
sutured end-to-end to the proximal descending thoracic aorta, the position of the distal anastomosis is flexible
with the trifurcated graft approach; it is often made at some level proximal to the LSCA, which potentially reduces
the risk of inadvertent nerve injury and allows better control of any hemorrhage that may occur at the distal
anastomosis (32,33). If the aneurysm extends into the descending thoracic aorta, an elephant trunk repair is
performed, leaving approximately 10 cm of the graft suspended within the aneurysmal distal aortic segment (Fig.
27.6D, E). In either case, after the distal anastomosis is completed, a Y-limb of the arterial perfusion line is
inserted into the graft or attached to a side branch (Fig. 27.6F), the graft is thoroughly de-aired, and a clamp is
applied to the graft so that systemic circulation is reestablished.
The next portion of the procedure is focused on the proximal aspects of the aortic reconstruction, which may
include repair or replacement of the aortic valve, replacement of the aortic root, or just replacement of the
ascending aorta. During the proximal repair, we slowly rewarm the patient to 36.5°C, making sure not to exceed
a gradient of 10°C between the arterial blood and nasopharyngeal temperatures (34). Once the proximal portion
of the repair has been completed, an oval opening is made in the right anterolateral aspect of the ascending
graft, and the proximal end of the Y-graft is anastomosed to the opening (Fig. 27.6F), which completes the aortic
reconstruction (Fig. 27.6G). The aorta and heart are then de-aired through a venting needle placed in the aortic
graft. The aorta is unclamped, the retrograde cardioplegia cannula is removed, epicardial pacing wires are
attached, and the patient is weaned from CPB. Before the patient is separated from the pump, the aortic venting
needle and left ventricular sump are removed when the echocardiogram shows that the heart is free of air. The
venous cannula is removed, protamine is administered, and pump blood is returned to the patient. The graft to
the innominate or axillary artery is then clamped and cut. A silk ligature is tied approximately 5 mm above the
anastomosis so as not to place excessive tension on the suture line or narrow the vessel, and the free end of the
graft is oversewn or ligated with polypropylene suture.
DISTAL AORTIC OPERATIONS

Surgical techniques and perfusion practices for the distal aortic segment have evolved tremendously in recent
years, and their use varies according to the extent of each patient’s aortic disease. The extent of graft
replacement in the distal segment ranges from a few centimeters of the descending thoracic aorta to the entire
thoracoabdominal aorta, that is, from the LSCA to the aortoiliac bifurcation. For operative planning and risk
assessment, it is important to distinguish DTAAs from TAAAs. Whereas DTAAs can involve any portion of the
aorta between the LSCA and the diaphragm, TAAAs are characterized by dilatation of the aorta within the
diaphragmatic hiatus—the boundary that separates the descending thoracic and abdominal aortic segments—
with varying degrees of extension in the chest and abdomen. Crawford’s classification system (Fig. 27.8), which
further defines the extent of aortic replacement, is used to plan the operative procedure, select perfusion
techniques (Table 27.1), and estimate surgical risks.
Ischemic injuries can involve the spinal cord, kidneys, and other abdominal viscera and often have catastrophic
consequences. Perfusion techniques play a central role in our group’s current multimodal approach to preventing
ischemic complications (35). The mainstay of perfusion in extent I and II TAAAs is left heart bypass (LHB) with
selective visceral artery perfusion. LHB is also used in selected high-risk patients undergoing repair of DTAA, or
of less extensive TAAA. Cold renal perfusion is also used during nearly all TAAA repairs. Other important
adjuncts include moderate heparinization (1 mg/kg), permissive mild hypothermia (nasopharyngeal temperature,
32°C-34°C), cerebrospinal fluid drainage (36),
P.644
sequential aortic clamping, and aggressive reattachment of segmental intercostal and lumbar arteries.
FIGURE 27.8. Illustration of the Crawford classification of thoracoabdominal aortic aneurysm repair based on the
extent of aortic replacement. Extent I repair involves most or all of the descending thoracic aorta and the upper
abdominal aorta. Extent II repair involves most or all of the descending thoracic aorta and extends into the
infrarenal abdominal aorta. Extent III repair involves the distal half or less of the descending thoracic aorta and
varying portions of the abdominal aorta. Extent IV repair involves most or all of the abdominal aorta. (Used with
TABLE 27.1. Current perfusion strategies for spinal cord and visceral protection during
descending thoracic and thoracoabdominal aortic repairs
Descending thoracic aortic repairs
Left heart bypass for high-risk patients (i.e., those with acute dissection, rupture, or prior abdominal
aortic aneurysm repair) (Fig. 27.9)
Extent I and II thoracoabdominal repairs

Cerebrospinal fluid drainage
Left heart bypass during proximal anastomosis (Fig. 27.10A)
Selective perfusion of celiac axis and superior mesenteric artery during intercostal and visceral
anastomoses (Fig. 27.10B)
Perfusion of renal arteries with 4°C crystalloid solution (Fig. 27.10B)
Extent III and IV thoracoabdominal repairs
Perfusion of renal arteries with 4°C crystalloid solution
The abovementioned multimodal strategy is applicable to most patients undergoing surgical repair of DTAA or
TAAA (37,38,39). Particular perfusion techniques and other adjuncts are chosen according to each patient’s
individual risk factors, especially the planned extent of aortic replacement. Additional factors that increase the
risk of ischemic complications are also important considerations in operative planning; these factors include
acute dissection and preexisting renal insufficiency. Likewise, selection of the surgical approach is based on
several important technical considerations, most notably the ability to safely clamp the aorta; if the aorta cannot
be clamped because of proximal disease extension into the arch or the presence of rupture, severe calcification,
or thrombus, CPB with HCA is necessary.
Left Heart Bypass

The rationale for using LHB is to provide distal aortic perfusion while the aorta is cross-clamped, thereby
decreasing the
P.645
ischemic times for distal organs, particularly the spinal cord (Figs. 27.9 and 27.10A). It is established during the
proximal portion of the aortic repair by instituting a temporary bypass from the left atrium to either the distal
descending thoracic aorta or the femoral artery (usually the left) with a closed circuit with an inline centrifugal
pump. Although LHB is most commonly used during extent I and II TAAA repair, this adjunct is also used in less
extensive repairs if patients have acute aortic dissection, previous infrarenal aortic replacement, or other risk
factors for ischemic complications. Because LHB unloads the heart, it is also useful in patients who have a
suboptimal cardiac reserve.
Several studies (40,41,42,43,44,45) support using LHB to minimize spinal cord ischemia during TAAA repair;
however, because these studies involved many types of aneurysms, patient risk factors, and additional surgical
adjuncts, it is difficult to draw firm conclusions from them. Nonetheless, LHB appears to provide the greatest
benefit to patients undergoing the more extensive repairs. Our own retrospective review of 1,250 consecutive
extent I or II TAAA repairs showed that LHB, which was used in 666 cases, was associated with a reduced
incidence of spinal cord deficits in patients who underwent extent II repairs (46). By contrast, in an analysis of
data from 387 patients who underwent DTAA repair, we found no effect of LHB on postoperative paraplegia and
paraparesis rates (37). Data from series in which LHB and cerebrospinal fluid drainage were used together
suggest that combining these adjuncts may provide better spinal cord protection than using either adjunct alone
(47,48).
FIGURE 27.9. Graft repair of a descending thoracic aortic aneurysm with left heart bypass. Distal aortic
perfusion is provided by pumping blood from the left atrium to the distal descending thoracic aorta during the
proximal portion of the repair.
Selective Visceral Perfusion and Cold Renal Perfusion

Potential complications of TAAA repair include liver dysfunction, coagulopathy, and bowel ischemia. After distal
aortic perfusion is discontinued, the abdominal viscera become vulnerable to ischemia. Selective visceral
perfusion is meant to reduce ischemic time and potentially prevent ischemic complications (49). Selective
visceral perfusion is delivered from the
P.646
P.647
LHB circuit through a Y-limb of the return line and into individual balloon perfusion catheters placed in the celiac
axis and superior mesenteric arteries (Fig. 27.10B), thereby providing oxygenated blood to the abdominal viscera
while the intercostal and visceral branches are reattached to the graft. Previously, we used the LHB circuit to
selectively perfuse the celiac, superior mesenteric, and renal arteries with isothermic blood (50). Now, however,
we selectively perfuse only the celiac and superior mesenteric arteries while intermittently infusing cold
crystalloid solution into the renal arteries (Fig. 27.10B) (51). This practice is based on the results of a
randomized trial of cold lactated Ringer’s solution versus isothermic blood from the LHB circuit for renal perfusion
in patients undergoing Crawford extent II TAAA repair (51). This trial showed that cold crystalloid solution
provided superior renal protection. A subsequent trial did not support our hypothesis that cold blood would
provide even better renal protection than cold crystalloid fluid, but it did confirm that using cold renal perfusion
during TAAA repair provides effective protection from renal injury (52).
FIGURE 27.10. Perfusion strategies used during extensive thoracoabdominal aortic repair include (A) left heart
bypass during the proximal portion of the repair followed by (B) selective visceral perfusion with isothermic blood
and cold crystalloid renal perfusion while intercostal and visceral arteries are reattached. (Used with permission
of Baylor College of Medicine.)
Hypothermic Circulatory Arrest

CPB and HCA are used for DTAA and TAAA repair when aortic disease at the distal arch and proximal
descending thoracic aorta precludes clamping (Fig. 27.11). For example, aortic aneurysms that extend into the
transverse arch may necessitate an open proximal anastomosis. Enormous aneurysms, rupture, or severe
atherosclerosis in this segment can also prevent safe aortic manipulation or clamping.
Some surgeons use HCA preferentially for DTAA and TAAA repair because of the known protective effects of
hypothermia on the central nervous system (53,54,55). Although outcomes with HCA use in this type of repair
have improved, we do not routinely use HCA in such cases because of concerns about intrapulmonary bleeding,
adult respiratory distress syndrome, and coagulopathy (56,57).
Technical Details of Thoracoabdominal Aortic Repair Procedures

Our current approach includes the selective use of LHB, cerebrospinal fluid drainage, selective visceral
perfusion, and cold renal perfusion. For each case, the selection of techniques is largely guided by the planned
extent of aortic replacement, which is categorized according to the Crawford classification (Fig. 27.8).
Because of the extensive degree of aortic replacement during TAAA repair, a large amount of blood may be lost,
especially when the aorta is being opened. To mitigate blood loss, a “rapid reinfusion” approach may be used to
return shed, unwashed blood into the patient. During this procedure, we use a cell saver with one simple
modification: as heparin is administered, we convert the cell saver into a rapid-return suction device (Fig. 27.12).
The cell saver is set up and assembled for normal use. However, a Y-connector is inserted into the cell saver
line just distal to the collection reservoir, which provides microaggregate filtration (20 μm) to remove blood
component materials, clots and other debris. A ¼-inch line is extended from the Y through a roller head and is
connected to a Belmont Rapid Infuser (Belmont Instrument Corporation, Billerica, MA). Once heparin has been
administered, the clamp on the rapid-return line just below the cell saver cardiotomy is moved to the cell saver
side below the cardiotomy. This diverts the now heparinized, suctioned blood into the roller pump and back to
the infuser. The amount of reinfused shed blood is computed by subtracting the volume listed on the infuser from
the volume delivered after use of the rapid-return line.
We use LHB during most Crawford extent I and II repairs (Fig. 27.10A) and occasionally during extent III repairs.
The LHB circuit comprises an inflow and an outflow cannula, ⅜-inch polyvinylchloride tubing, a centrifugal pump,
a flow probe, and a ⅜ × ⅜-inch luer connector with a three-way, large-bore, high-flow stopcock attached just
distal to the pump. For selective visceral perfusion, we use two irrigation occlusion catheters (Pruitt, Model 9F-
10-EP; LeMaitre Vascular, Inc., Burlington, MA), which have a 9F balloon and dual-lumen architecture that
provide intraluminal occlusion plus irrigation; these catheters are connected to the return line via the stopcock
and to the cardioplegia table line by a Y-type perfusion adapter. No reservoir or heat exchanger is incorporated
into the circuit. Although intravenous heparin is not necessary when a centrifugal pump is used for LHB, we
routinely administer 1 mg/kg of heparin to prevent thrombosis of the small intercostal and spinal arteries. The
patient’s core temperature is allowed to fall 3°C to 4°C below normal to achieve passive mild hypothermia. A heat
exchanger is not used to maintain normothermia or to rewarm the patient.
Proximal cannulation for LHB is usually done in the left inferior pulmonary vein. Alternatively, the cannula can be
placed in the left superior pulmonary vein or inserted directly into the left atrial appendage. In either location, a 3-
0 polypropylene mattress suture with Teflon felt pledgets and a Rumel tourniquet are used to secure a 24F right-
angled cannula in position, with its tip in the left atrium. For distal cannulation, we prefer to cannulate the
descending thoracic aorta directly, usually at the level of the diaphragm. This eliminates the need for a groin
incision and provides reliable inflow. Alternative cannulation sites include the left femoral artery and the
abdominal aorta. To prevent embolic complications, preoperative computed tomography or magnetic resonance
imaging data are used to select a cannulation site without extensive mural thrombus. A 3-0 polypropylene suture
with Teflon felt pledgets is placed at the selected location, and a 20- to 24F right-angled cannula is inserted into
the aorta. To prevent retrograde flow into the left atrium on initiation of LHB, the pump is started at 1,000 rpm,
and the clamp on the perfusion loop is slowly removed. Pump flow is maintained near 500 mL/min until the aorta
is clamped.
P.648
FIGURE 27.11. Repair of a descending thoracic aortic aneurysm involving the distal aortic arch by using
profound hypothermic circulatory arrest (HCA). Cardiopulmonary bypass is initiated (A), and a long femoral
venous cannula is advanced into the right atrium. Drainage is augmented by cannulating the left atrium through
the left inferior pulmonary vein. After the patient has been cooled sufficiently to moderate hypothermia,
circulatory arrest is initiated. The aneurysm is opened (B) and the proximal anastomosis is constructed. A Y-limb
from the arterial line is connected (C) to a side branch of the graft, after the proximal anastomosis is completed.
The completion repair (D) is shown. (Used with permission of Baylor College of Medicine.)
The proximal aortic cross-clamp is placed on the aortic arch distal to the left carotid artery or on the descending
thoracic aorta distal to the LSCA if the anatomy of the aneurysm permits (Fig. 27.10A). The distal aortic clamp is
placed on the midthoracic aorta, usually between T4 and T7. This isolates the proximal portion of the aneurysm
for repair while the LHB circuit delivers distal aortic perfusion. Distal aortic perfusion flow is increased to 1.5 to
2.5 L/min; the mean proximal aortic pressure is carefully maintained at approximately 70 mm Hg, and the mean
pulmonary artery pressure is maintained near 20 mm Hg by changing the flow rates, infusing anesthetic
medications, or both. Proximal blood pressure, cardiac hemodynamic values, and peripheral vascular resistance
are maintained at optimal levels by administering sodium nitroprusside, nitroglycerin, or both, and by replacing
lost fluid and blood with the aid of a cell-saving device and a rapid-infusion system. To prevent acidosis, a
sodium bicarbonate solution is continuously infused at 2 to 3 mEq/kg/hr while the aorta is clamped.
P.649
FIGURE 27.12. Illustration of a modified cell saver system to enable rapid reinfusion of shed blood. (Used with
The isolated proximal segment of the aneurysm is opened, and the upper intercostal arteries are oversewn.
Usually, a 22- or 24-mm Gelweave graft (Vascutek Terumo) is used for aortic replacement. After the proximal
anastomosis is completed, either the distal clamp is sequentially moved down the aorta or LHB is discontinued
entirely and the distal clamp is removed. The aortic cannula is removed, and the perfusion circuit is clamped
distal to the stopcock to allow subsequent selective visceral perfusion. The aneurysm is opened to its distal
extent (Fig. 27.10B). For patients with extensive TAAAs, selective visceral perfusion is delivered during
intercostal, visceral, and renal artery reattachment. Selective visceral perfusion is achieved by opening the
stopcock to divert blood flow through the cardioplegia table line to the 9F Pruitt irrigation perfusion catheters,
which are connected to a bifurcated manifold that leads into the ostia of the celiac and superior mesenteric
arteries.
Whenever the extent of repair affords access to the renal artery ostia, we deliver intermittent cold crystalloid
renal perfusion to protect against ischemic renal injury (58,59). Cold renal perfusion is provided by a cardioplegia
administration set and a roller pump connected to set of hanging premedicated bags of lactated Ringer’s solution
(Fig. 27.10). To every liter of lactated Ringer’s solution, we add 12.5 g of mannitol and 125 mg of
methylprednisolone. The bags are then connected to the cardioplegia circuit via a ¼-inch tube connected to a
roller-head pump. The solution is constantly infused through an iced cardioplegia chamber to maintain a
perfusate temperature of 4°C and is delivered by additional 9F Pruitt irrigation catheters placed in the ostia of the
renal arteries and connected to a bifurcated manifold. Although the rates of perfusion delivered to the individual
mesenteric vessels are not controlled independently, a total of 200 mL/min delivered through both branches is
effective in preventing critical ischemic damage. Crystalloid renal perfusion is initially provided as a 400- to 600-
mL bolus. Additional intermittent infusions of 200 to 300 mL are given every 6 to 10 minutes, with care to avoid
excessive systemic hypothermia or fluid overload.
Selected patent intercostal arteries between T8 and L1 are anastomosed to an opening in the graft (Fig.
27.10B). In extent I repairs, the reattached visceral arteries are often incorporated into a beveled distal
anastomosis; in extent II and III repairs, however, the visceral artery origins are reattached to one or more oval
openings in the graft. In 30% to 40% of cases, the left renal artery is substantially displaced away from the other
three vessels and therefore is attached either to a separate opening in the graft or to an interposition graft.
Alternatively, a prefabricated multi-branched aortic graft can be used to reattach the visceral arteries separately,
thereby minimizing residual native aortic tissue (2). In most extent II, III, and IV repairs, the distal anastomosis is
performed at the level of the aortoiliac bifurcation. After the aortic reconstruction has been completed, the aorta
is unclamped, protamine sulfate is administered to reverse the effects of heparin, and the operative field is
irrigated with warm water to reverse the cooling trend. It is imperative that adequate hemostasis be achieved at
all suture lines. The renal, visceral, and peripheral circulations are assessed to assure satisfactory restoration of
perfusion.
In cases requiring HCA, CPB is initiated through the femoral artery and vein (Fig. 27.11A). A long femoral venous
cannula is advanced into the right atrium, and its position is verified with transesophageal echocardiography. A
cannula connected to a Y-limb of the venous line is placed in the left atrium through the left inferior pulmonary
vein to augment drainage. After the patient has been cooled sufficiently to achieve deep hypothermia, circulatory
arrest is initiated. A clamp can often be placed across the mid-descending thoracic aorta to enable distal aortic
perfusion via the femoral cannula during the proximal anastomosis. The aneurysm is opened, and the proximal
anastomosis is constructed (Fig. 27.11B);
P.650
if necessary, the repair is extended into the transverse arch. After the proximal anastomosis is completed, a Y-
limb from the arterial line is connected to a side branch of the graft (Fig. 27.11C). The graft is de-aired and
clamped, pump flow to the upper body is resumed, and the remainder of the aortic repair is performed (Fig.
27.11D).
SUMMARY
Open repair of aneurysms and dissections involving the thoracic aorta has traditionally been associated
with high morbidity and mortality rates, largely because of complications related to interrupting normal blood
flow to critical organs. Experimental and clinical research has contributed to the understanding of the
pathophysiology of organ ischemia and has had an enormous effect on thoracic aortic surgery. Specifically,
advancements in cannulation techniques, neurologic protection, and advanced grafting techniques have
revolutionized this field and simplified the conduct of the operation. Aortic surgeons are continuing to
develop and adopt innovative tools that facilitate safe and effective open repair of the thoracic aorta (1).
Over the past 20 years, our approach to these operations has gradually evolved with the introduction of
various techniques aimed at reducing the risk of neurologic complications, improving hemostasis, and
eliminating residual aortic tissue. For aortic arch repairs, these changes include converting from retrograde
to ACP, introducing cannulation of the axillary artery and then of the innominate artery, and switching from
the patch technique to the Y-graft technique for reattaching the brachiocephalic branches. For
thoracoabdominal aortic repairs, we have incorporated cerebrospinal fluid drainage, refined techniques for
LHB and renal perfusion, and developed new grafting strategies. By using these techniques in combination
during thoracic aortic operations, surgical teams can obtain excellent early outcomes.
KEY Points
Thoracic aortic aneurysms require individualized treatment. Decisions are generally based on the
location and cause of aneurysm, rate of disease progression, and proposed extent of repair, as well
as any patient-specific comorbidities.
Segment-specific surgical strategies are generally based on the extent of repair and the location of
branching arteries.
There are several potential sites for arterial cannulation. The approach to cannulation is based on
patient-specific factors (such as dissection extending into the branching vessels, or a heavy
atherosclerotic burden) and surgeon preference.
The development of surgical adjuncts for open-aortic repair has reduced postoperative
complications in contemporary patients who undergo complex repair. Many centers use antegrade
cerebral perfusion with hypothermic circulatory arrest during aortic arch repair and cerebrospinal
fluid drainage during thoracoabdominal aortic repair.
Hypothermic circulatory arrest alone offers satisfactory cerebral protection for relatively short
procedures, but when repair time exceeds 30 minutes, antegrade cerebral perfusion is a useful
addition.
Although the ideal core temperature for hypothermic circulatory arrest with antegrade cerebral
perfusion has yet to be determined, many centers now use moderate (20.1°C-28°C) or mild (28.1°C-
34°C) temperature targets rather than a profound temperature target (≤14°C).
Regarding cannulation sites for aortic arch repair, innominate artery cannulation has several
advantages over axillary artery cannulation. These include potentially shorter operative times, a
decreased likelihood of kinking the inflow graft because it remains under the surgeon’s direct vision
at all times, ease of implementation in obese patients, a greatly decreased risk of arm ischemia or
claudication, and no risk of brachial plexus injury.
A multimodal strategy is used in distal aortic repair: adjuncts, techniques, and perfusion practices
vary by the extent of repair. Graft replacement in the distal aorta ranges from a few centimeters of
the descending thoracic aorta to the entire thoracoabdominal aorta.
In distal aortic repair, the rationale for using left heart bypass is to provide downstream aortic
perfusion while the proximal portion of the descending thoracic aorta is cross-clamped. This
decreases the ischemic times for distal organs, particularly for the spinal cord.
ACKNOWLEDGMENTS
The authors thank Stephen N. Palmer, PhD, ELS, Virginia Fairchild, BA, and Susan Y. Green, MPH, for editorial
support; Scott A. Weldon, MA, CMI, and Carol P. Larson, CMI, for creating the medical illustrations; and Joseph
Huh, MD, and John Bozinovski, MD, for their substantial contributions to the chapter published in the 3rd edition
of the textbook, on which this updated chapter was based.
REFERENCES
1. Ouzounian M, LeMaire SA, Coselli JS. Open aortic arch repair: state-of-theart and future perspectives.
Semin Thorac Cardiovasc Surg 2013;25:107-115.
2. Coselli JS. Update on repairs of the thoracoabdominal aorta. Tex Heart Inst J 2013;40:572-574.
P.651
3. Benedetto U, Melina G, Angeloni E, et al. Current results of open total arch replacement versus hybrid
thoracic endovascular aortic repair for aortic arch aneurysm: a meta-analysis of comparative studies. J
4. Cooley DA, Livesay JJ. Technique of “open” distal anastomosis for ascending and transverse arch
resection. Cardiovasc Dis 1981;8:421-426.
5. Huh J, LeMaire SA, Bozinovski J, et al. Perfusion for thoracic surgery. In: Gravlee GP, Davis RF,
Stammers AH, et al, eds. Cardiopulmonary bypass: principles and practice. 3rd ed. Philadelphia, PA:
Lippincott Williams & Wilkins, 2008:647-661.
6. Sabik JF, Lytle BW, McCarthy PM, et al. Axillary artery: an alternative site of arterial cannulation for
patients with extensive aortic and peripheral vascular disease. J Thorac Cardiovasc Surg 1995;109:885-890;
discussion 890-891.
7. Goldstein LJ, Davies RR, Rizzo JA, et al. Stroke in surgery of the thoracic aorta: incidence, impact,
etiology, and prevention. J Thorac Cardiovasc Surg 2001;122:935-945.
8. Wong DR, Coselli JS, Palmero L, et al. Axillary artery cannulation in surgery for acute or subacute
ascending aortic dissections. Ann Thorac Surg 2010;90:731-737.
9. Preventza O, Bakaeen FG, Stephens EH, et al. Innominate artery cannulation: an alternative to femoral or
axillary cannulation for arterial inflow in proximal aortic surgery. J Thorac Cardiovasc Surg 2013;145:S191-
S196.
10. DeBakey ME, Crawford ES, Cooley DA, et al. Successful resection of fusiform aneurysm of aortic arch
with replacement by homograft. Surg Gynecol Obstet 1957;105:657-664.
11. Griepp RB, Stinson EB, Hollingsworth JF, et al. Prosthetic replacement of the aortic arch. J Thorac
12. Tsai JY, Pan W, LeMaire SA, et al. Moderate hypothermia during aortic arch surgery is associated with
reduced risk of early mortality. J Thorac Cardiovasc Surg 2013;146:662-667.
13. Crawford ES, Saleh SA. Transverse aortic arch aneurysm: improved results of treatment employing new
modifications of aortic reconstruction and hypothermic cerebral circulatory arrest. Ann Surg 1981;194:180-
188.
14. Svensson LG, Crawford ES, Hess KR, et al. Deep hypothermia with circulatory arrest: determinants of
stroke and early mortality in 656 patients. J Thorac Cardiovasc Surg 1993;106:19-28.
15. Coselli JS. Retrograde cerebral perfusion via a superior vena caval cannula for aortic arch aneurysm
16. de la Cruz KI, Coselli JS, LeMaire SA. Open aortic arch replacement: a technical odyssey. J Extra Corpor
Technol 2012;44:P42-P47.
17. Raskin SA, Fuselier VW, Reeves-Viets JL, et al. Deep hypothermic circulatory arrest with and without
retrograde cerebral perfusion. Int Anesthesiol Clin 1996;34:177-193.
18. Boeckxstaens CJ, Flameng WJ. Retrograde cerebral perfusion does not perfuse the brain in nonhuman
primates. Ann Thorac Surg 1995;60:319-327; discussion 327-328.
19. Harrington DK, Bonser M, Moss A, et al. Neuropsychometric outcome following aortic arch surgery: a
prospective randomized trial of retrograde cerebral perfusion. J Thorac Cardiovasc Surg 2003;126:638-644.
20. Moon MR, Sundt TM III. Influence of retrograde cerebral perfusion during aortic arch procedures. Ann
Thorac Surg 2002;74:426-431; discussion 431.
21. Reich DL, Uysal S, Ergin MA, et al. Retrograde cerebral perfusion as a method of neuroprotection during
thoracic aortic surgery. Ann Thorac Surg 2001;72:1774-1782.
22. Sakurada T, Kazui T, Tanaka H, et al. Comparative experimental study of cerebral protection during
aortic arch reconstruction. Ann Thorac Surg 1996;61:1348-1354.
23. Ye J, Yang L, Del Bigio MR, et al. Neuronal damage after hypothermic circulatory arrest and retrograde
cerebral perfusion in the pig. Ann Thorac Surg 1996;61:1316-1322.
24. Krüger T, Weigang E, Hoffmann I, et al. Cerebral protection during surgery for acute aortic dissection
type A: results of the German Registry for Acute Aortic Dissection Type A (GERAADA). Circulation
2011;124:434-443.
25. Shihata M, Mittal R, Senthilselvan A, et al. Selective antegrade cerebral perfusion during aortic arch
surgery confers survival and neuroprotective advantages. J Thorac Cardiovasc Surg 2011;141:948-952.
26. LeMaire SA, Price MD, Parenti JL, et al. Early outcomes after aortic arch replacement by using the Y-
graft technique. Ann Thorac Surg 2011;91:700-708.
27. LeMaire SA, Weldon SA, Coselli JS. Total aortic arch replacement: current approach using the trifurcated
graft technique. Ann Cardiothorac Surg 2013;2:347-352.
28. Cooper JR, Slogoff S. Hemodilution and priming solutions for cardiopulmonary bypass. In: Hensley FA,
Martin DE, eds. A practical approach to cardiac anesthesia. Boston, MA: Little, Brown and Company,
1995:124-137.
29. Rand PW, Lacombe E, Hunt HE, et al. Viscosity of normal human blood under normothermic and
hypothermic conditions. J Appl Physiol 1964;19:117-122.
30. Coselli JS, Crawford ES, Beall AC Jr, et al. Determination of brain temperatures for safe circulatory arrest
during cardiovascular operation. Ann Thorac Surg 1988;45:638-642.
31. Mizrahi EM, Patel VM, Crawford ES, et al. Hypothermic-induced electrocerebral silence, prolonged
circulatory arrest, and cerebral protection during cardiovascular surgery. Electroencephalogr Clin
Neurophysiol 1989;72:81-85.
32. Kazui T, Washiyama N, Muhammad BA, et al. Total arch replacement using aortic arch branched grafts
with the aid of antegrade selective cerebral perfusion. Ann Thorac Surg 2000;70:3-8; discussion 8-9.
33. Spielvogel D, Strauch JT, Minanov OP, et al. Aortic arch replacement using a trifurcated graft and
selective cerebral antegrade perfusion. Ann Thorac Surg 2002;74:S1810-S1814; discussion S1825-S1832.
34. Coselli JS, LeMaire SA. Temperature management after hypothermic circulatory arrest. J Thorac
35. MacArthur RG, Carter SA, Coselli JS, et al. Organ protection during thoracoabdominal aortic surgery:
rationale for a multimodality approach. Semin Cardiothorac Vasc Anesth 2005;9:143-149.
36. Coselli JS, LeMaire SA, Koksoy C, et al. Cerebrospinal fluid drainage reduces paraplegia after
thoracoabdominal aortic aneurysm repair: results of a randomized clinical trial. J Vasc Surg 2002;35:631-639.
37. Coselli JS, LeMaire SA, Conklin LD, et al. Left heart bypass during descending thoracic aortic aneurysm
repair does not reduce the incidence of paraplegia. Ann Thorac Surg 2004;77:1298-1303; discussion 1303.
38. Coselli JS, LeMaire SA, Miller CC III, et al. Mortality and paraplegia after thoracoabdominal aortic
aneurysm repair: a risk factor analysis. Ann Thorac Surg 2000;69:409-414.
39. LeMaire SA, Miller CC III, Conklin LD, et al. A new predictive model for adverse outcomes after elective
thoracoabdominal aortic aneurysm repair. Ann Thorac Surg 2001;71:1233-1238.
40. Bavaria JE, Woo YJ, Hall RA, et al. Retrograde cerebral and distal aortic perfusion during ascending and
thoracoabdominal aortic operations. Ann Thorac Surg 1995;60:345-352; discussion 352-353.
41. Frank SM, Parker SD, Rock P, et al. Moderate hypothermia, with partial bypass and segmental
sequential repair for thoracoabdominal aortic aneurysm. J Vasc Surg 1994;19:687-697.
42. Hessmann M, Dossche K, Wellens F, et al. Surgical treatment of thoracic aneurysm: a 5-year experience.
43. Kitamura M, Hashimoto A, Tagusari O, et al. Operation for type B aortic dissection: introduction of left
heart bypass. Ann Thorac Surg 1995;59:1200-1203.
44. Safi HJ, Campbell MP, Miller CC III, et al. Cerebral spinal fluid drainage and distal aortic perfusion
decrease the incidence of neurological deficit: the results of 343 descending and thoracoabdominal aortic
aneurysm repairs. Eur J Vasc Endovasc Surg 1997;14:118-124.
45. Schepens MA, Defauw JJ, Hamerlijnck RP, et al. Use of left heart bypass in the surgical repair of
thoracoabdominal aortic aneurysms. Ann Vasc Surg 1995;9:327-338.
46. Coselli JS. The use of left heart bypass in the repair of thoracoabdominal aortic aneurysms: current
techniques and results. Semin Thorac Cardiovasc Surg 2003;15:326-332.
47. Safi HJ, Estrera AL, Miller CC, et al. Evolution of risk for neurologic deficit after descending and
thoracoabdominal aortic repair. Ann Thorac Surg 2005;80:2173-2179; discussion 2179.
48. Safi HJ, Miller CC III, Huynh TT, et al. Distal aortic perfusion and cerebrospinal fluid drainage for
thoracoabdominal and descending thoracic aortic repair: ten years of organ protection. Ann Surg
2003;238:372-380; discussion 380-381.
49. Safi HJ, Miller CC III, Yawn DH, et al. Impact of distal aortic and visceral perfusion on liver function during
thoracoabdominal and descending thoracic aortic repair. J Vasc Surg 1998;27:145-152; discussion 152-153.
50. Jacobs MJ, van Eps RG, de Jong DS, et al. Prevention of renal failure in patients undergoing
thoracoabdominal aortic aneurysm repair. J Vasc Surg 2004;40:1067-1073; discussion 1073.
51. Koksoy C, LeMaire SA, Curling PE, et al. Renal perfusion during thoracoabdominal aortic operations:
cold crystalloid is superior to normothermic blood. Ann Thorac Surg 2002;73:730-738.
P.652
52. LeMaire SA, Jones MM, Conklin LD, et al. Randomized comparison of cold blood and cold crystalloid
renal perfusion for renal protection during thoracoabdominal aortic aneurysm repair. J Vasc Surg
2009;49:11-19.
53. Carrel TP, Berdat PA, Robe J, et al. Outcome of thoracoabdominal aortic operations using deep
hypothermia and distal exsanguination. Ann Thorac Surg 2000;69:692-695.
54. Kouchoukos NT, Masetti P, Murphy SF. Hypothermic cardiopulmonary bypass and circulatory arrest in
the management of extensive thoracic and thoracoabdominal aortic aneurysms. Semin Thorac Cardiovasc
Surg 2003;15:333-339.
55. Patel HJ, Shillingford MS, Mihalik S, et al. Resection of the descending thoracic aorta: outcomes after
use of hypothermic circulatory arrest. Ann Thorac Surg 2006;82:90-95; discussion 95-96.
56. Crawford ES, Coselli JS, Safi HJ. Partial cardiopulmonary bypass, hypothermic circulatory arrest, and
posterolateral exposure for thoracic aortic aneurysm operation. J Thorac Cardiovasc Surg 1987;94:824-827.
57. Safi HJ, Miller CC, 3rd, Subramaniam MH, et al. Thoracic and thoracoabdominal aortic aneurysm repair
using cardiopulmonary bypass, profound hypothermia, and circulatory arrest via left side of the chest
incision. J Vasc Surg 1998;28:591-598.
58. Coselli JS. Strategies for renal and visceral protection in thoracoabdominal aortic surgery. J Thorac
Cardiovasc Surg 2010;140:S147-S149; discussion S185-S190.
59. LeMaire SA, Price MD, Green SY, et al. Results of open thoracoabdominal aortic aneurysm repair. Ann
Chapter 28
Pediatric Cardiopulmonary Bypass
Gregory S. Matte
James A. DiNardo
INTRODUCTION
Cardiopulmonary bypass for adult acquired cardiac disease commonly has limited variation in the equipment required for each perfusion setup. One or two oxygenator options and
one or two custom tubing packs are frequently sufficient to handle the patient population within an adult perfusion practice. Pediatric perfusion is quite different. It is not uncommon
for a pediatric perfusion group to utilize three to five different-sized oxygenators along with four or five different custom tubing packs. This array of equipment is required in order to
appropriately size major circuit components to a wide range of patients who vary not only in size, but in cardiac defect, flow requirements, and expected cardiotomy suction flow from
field suction and the left ventricular vent. An appropriately-sized selection of equipment minimizes hemodilution and limits transfusion requirements during bypass for the wide variety
of patients encountered. Table 28.1 lists notable differences between adult and pediatric cardiopulmonary bypass.
THE CARDIOPULMONARY BYPASS CIRCUIT

The cardiopulmonary bypass (CPB) circuit is intended to isolate the cardiopulmonary system so that optimal surgical exposure can be obtained for operations on the heart, lungs
and great vessels. For this isolation to be effective, the CPB circuit must be able to perform the functions of the intact cardiopulmonary system for a finite period. At a minimum, the
circuit must be capable of adding oxygen and removing carbon dioxide from blood and of providing adequate perfusion of all organs with this blood. In addition, the circuit must be
able to fulfill these requirements without doing permanent damage to the cardiopulmonary system, the blood, or any of the patient’s end organs.
The major components for consideration in a pediatric bypass circuit are the arterial pump, oxygenator, venous reservoir and cardiotomy system, heat exchanger, arterial line filter
(ALF), tubing, cannulas, and hemofilter (Fig. 28.1). A cell saver can be regarded as accessory equipment.
TABLE 28.1. Notable differences between adult and pediatric cardiopulmonary bypass
Parameter Adult Pediatric
Minimum CPB temperature Rarely <28°C Frequently 18°C-28°C
Use of DHCA or RCP Rarely Frequently
Pump prime
Dilution of blood volume 20-30% 50-150%
WB or PRBC added Rarely Commonly
Perfusion pressure 50-80 mm Hg 20-50 mm Hg
pH-stat management Rarely Usually at or below 30°C
Glucose management
Hyperglycemia Frequently, requires insulin Occasionally
Hypoglycemia Rarely Occasionally
DHCA, deep hypothermic circulatory arrest; RCP, regional cerebral perfusion; WB, whole blood; PRBC, packed red blood cells.
Arterial Pump
The arterial pump system is the “heart” of the heart-lung machine, being the driving force to the “lung” of the heart-lung machine. Arterial pump head systems are classified as either
roller head or centrifugal head. Most pediatric perfusion practices utilize a roller head for the arterial pump (1).
Roller Head Pump

The roller head pump, shown in Figure 28.2A, consists of a raceway where two roller spindles oriented 180° from each other rotate around a central axis and compress the raceway
tubing. This raceway tubing is also referred to as the “boot line.” The double-headed roller pump is a positive volume displacement pump. Sequential compression of the boot line
propels the blood forward. The amount of compression of the tubing is set in a manner to ensure forward flow without
P.656
P.657
being over- or underocclusive, otherwise known as the minimally nonocclusive setting. This compression setting is simply referred to as the “occlusion” and is set during priming of
the circuit. Proper occlusion is commonly set at a level that allows for the fluid level in the arterial limb to fall at a rate of 1 cm/min when held 75 cm above the venous reservoir fluid
level. An overocclusive setting risks damaging the formed elements of the blood as well as increasing the risk of rupturing the boot line. An underocclusive setting risks damaging
blood elements by allowing for sloshing in the raceway and compromises effective forward flow. This becomes an important safety issue if flow is not being monitored with an arterial
line flow probe. Roller head pumps in modern heart-lung machines have the advantage of very low primes, since it is common for the arterial head to be positioned close to the
venous reservoir and oxygenator. These pump heads also operate independently of vascular and system resistance, thereby allowing precise low-flow management, which is
especially important in pediatric perfusion. To prevent circuit disruptions with load-independent roller head pumps, it is standard practice to incorporate servoregulating pressure
monitoring to prevent excess system pressures. Circuit system pressure normally ranges between 100 and 250 mm Hg, but with kinked tubing or a misplaced line clamp can
instantly spike to >500 mm Hg. Servoregulation adjusts arterial pump flow automatically to prevent pressures which could cause circuit connections to fail with subsequent loss of
cardiopulmonary support.
FIGURE 28.1. Perfusionist views from the front and side of a setup heart-lung machine. A, arterial head pump and its controller A1; B, cardioplegia head pump and its controller B1;
C, vent head pump and its controller C1; D, field sucker pump and its controller D1; E, electronic venous occluder controller, F, master display tower; G, sterile custom tubing pack;
H, custom cardioplegia tubing set; I, cardiotomy venous reservoir, J, oxygenator with integrated heat exchanger and arterial line filter; K, hemofilter; L, tubing for hot and cold water
from heater-cooler unit; M, custom tubing pack. (Images courtesy of Robert J. Howe, CCP, LP, FPP.)
FIGURE 28.2. Roller and centrifugal pumps. A: Roller head pump shown with clear safety cover removed. Pump may rotate in either direction. The head depicted here has a
counterclockwise rotation, as indicated by the directional arrows. B: Centrifugal pump head oriented with the arterial outlet at the low position. The inlet is always at the center of the
device with the outlet at a point along its circumference.
Centrifugal Head Pump

The centrifugal head pump, shown in Figure 28.2B, operates on the principle of a constrained vortex. Impellers or vanes on a spinning disc within plastic housing create negative
pressure at the pump’s central axis inlet and positive displacement at the pump’s normally singular outlet, positioned at its outer circumference. As with roller head systems, a
centrifugal head system is positioned in the bypass circuit to aspirate blood from the venous reservoir and to then pump it into the oxygenator. Centrifugal heads have the theoretical
advantage of creating less trauma to the formed elements of the blood (2,3). However, a best-evidence review in patients undergoing elective coronary artery bypass grafting failed
to find a significant difference in this regard as compared to roller head pumps (4). Centrifugal heads are afterload-sensitive. An afterload-sensitive system greatly reduces the
chances of overpressurizing a pump circuit that can lead to component and system failure, otherwise referred to as “blowing up a circuit” (5). This benefit comes at the expense of
less-constant pump flow when system resistance varies (changing systemic vascular resistance, pressure on the arterial limb of the circuit by the surgical team, cannula position
change, etc.). Centrifugal heads also reduce the risk of massive arterial air embolism in the case of an emptied venous reservoir, because forward flow is stopped if large amounts of
air enter the constrained vortex. Disadvantages of centrifugal systems relative to roller systems for pediatric perfusion include cost and increased prime volume. As with roller head
pumps, it is standard practice to incorporate servoregulating arterial circuit pressure monitoring. Additionally, centrifugal systems commonly incorporate a one-way valve in the
arterial limb of the bypass circuit to prevent retrograde flow back through the device which could occur during low-flow and no-flow conditions. Automated pump arterial line clamps
which activate to prevent retrograde flow may also be used.
Oxygenators
Oxygenators perform the gas exchange functions of the lung and are thus the “lung” of the heart-lung machine. In modern systems, the oxygenator is integrated with several
additional components, including the gas exchange membrane, venous reservoir and cardiotomy filter, and heat exchanger (Fig. 28.3). Some oxygenators on the market are also
integrated with an
P.658
ALF. Despite the fact that oxygenators are incorporated in a system in which blood is pumped under pressure, all gas exchange occurs at atmospheric pressure because the
oxygenators are vented to the atmosphere.
FIGURE 28.3. Terumo CAPIOX FX15 oxygenator with integrated arterial filter. (Image courtesy of Terumo Cardiovascular Systems Corporation, Ann Arbor, MI, All rights reserved.)
Design
There are two distinct types of oxygenators: bubble oxygenators and membrane oxygenators. Bubble oxygenators will not be discussed here, because essentially only membrane
oxygenators are currently used in the care of pediatric cardiac surgical patients (6,7).
Membrane oxygenators can be classified as either microporous or true membrane. The gas exchange membrane for pediatric CPB is nearly universally of the microporous type.
Microporous membranes are made of 200 to 300 μm diameter polypropylene tubes with hydrophobic pores 0.03 to 0.07 μm in diameter. These pores cover at least 50% of the
membrane surface. Blood flow is normally on the outside of the tubes, while countercurrent gas flow is through the inside of the tubes. This is referred to as extraluminal blood flow
and is preferred over intraluminal flow, which has a higher risk of membrane clots and shunts which could quickly decrease device performance. Upon exposure to blood, the
micropores are designed to become covered with a thin proteinaceous layer through which gas exchange occurs without blood and gas coming in direct contact.
The other type of membrane oxygenator is referred to as a true membrane or a solid membrane type because an intact membrane separates the gas and blood. Solid membranes
are constructed of methyl silicon rubber that is thin enough (<25 μm) to permit diffusion of gas, with CO2 diffusing across the membrane five times as easily as O2. These
membranes are more limiting to diffusion than microporous systems, and therefore require a greater gas exchange surface area. Hence, the priming volume to provide comparable
gas exchange is larger. They also do not share the important advantage of microair removal from the blood flow path that microporous-type systems have. A major advantage of true
membranes is that they have a useful life measured in days. For this reason, true membranes are still used in the setting of extracorporeal membrane oxygenation (ECMO), although
their use in this setting is decreasing as advances in microporous systems have increased their useful life.
Gas Exchange
While modern membranes themselves offer little impedance to gas diffusion, there are other characteristics of membrane oxygenators that limit gas exchange. The primary
determinants of O2 and CO2 exchange across a membrane are the solubility and diffusability of each in blood and the partial pressure gradient across the membrane. Because O2 is
less soluble and diffusible in blood than CO2 (ratio of 1:25), the thickness of the blood film has a greater influence on oxygen exchange. Approximately 90% of the resistance to
diffusion in a membrane oxygenator system is diffusion of O2 into blood (8). The pressure gradient for O2 can be increased by increasing the O2 concentration in the fresh gas flow.
However, because of the lower diffusability of O2, a thick blood film or boundary layer will result in poor O2 delivery to the erythrocytes most distant from the gas exchange pores,
even when the pressure gradient for O2 is high. Modern membranes have design features to induce eddy currents, which serve to limit the boundary layer and maximize red blood
cell exposure to the micropores. As CO2 is more soluble and diffusible than O2, CO2 exchange is mainly dependent on the pressure gradient for CO2 across the membrane. The rate
of CO2 removal can be increased by increasing the oxygenator’s sweep flow rate of ventilating gas, which is analogous to increasing alveolar ventilation. The rate of CO2 removal
can also be enhanced by decreasing the CO2 content of the sweep gas. Most adult oxygenator systems do not contain CO2 in the sweep gas but pediatric programs utilizing pH-stat
blood gas management commonly do, and therefore CO2 content of the ventilating gas becomes an important consideration.
Capabilities and Sizing

The properties of O2 transfer into and CO2 removal from the blood are defining characteristics of the different oxygenators. The manufacturing techniques for oxygenator bundle
wrapping, the overall oxygenator membrane surface area, and the blood flow path through the device will primarily determine the gas transfer capabilities and maximum
recommended blood flow rate which can be handled by the device. To note, over the course of several hours of use, the gas exchange capacity of microporous membranes
deteriorates as a protein layer coats the micropores. The designed useful life for gas exchange in microporous oxygenators, as stated by their manufacturers, is normally 6 hours.
Pediatric perfusion systems must appropriately size the oxygenator to meet the anticipated individual patient needs for gas exchange and blood flow.
Air Embolism
Microporous systems have been proven to be immensely effective. Because their efficient gas exchange properties and microair removal are difficult to match, they have lead the
marketplace for cardiac surgery for more than two decades. A disadvantage of microporous membranes is that air can be drawn across the micropores into the blood flow path
under unique negative pressure situations. Negative pressure in the oxygenator can occur at any time but practically speaking this can occur during or after bypass. On bypass, if
there is an abrupt stoppage of blood flow, the fluid momentum in the oxygenator has the potential to pull ventilating gas into the blood flow path. Excessive suction while drawing
blood samples, especially with low flow rates or regional perfusion, can draw ventilating gas into the blood flow path. After bypass, air can be drawn into the blood flow path during
traditional
P.659
arteriovenous modified ultrafiltration (MUF). Postoxygenator ALFs are therefore extremely important safety devices.
Venous Reservoir and Cardiotomy System

The venous reservoir and cardiotomy system are other components integrated into modern oxygenator systems (Fig. 28.4). Integration of the venous and cardiotomy systems
decreases prime volume and overall system surface area by eliminating separate connections between the two devices.
Venous Reservoir
The venous reservoir has blood flow into it directly from the bypass circuit venous line as well as from the cardiotomy filter. Venous return from the patient has its own dedicated
filtration system to process the relatively clean venous blood. Venous reservoirs may be open or sealed. Open reservoirs are open to the atmosphere so that air is automatically
purged. Sealed reservoirs have a single venting port which may be easily sealed for use with vacuum-assisted venous drainage (VAVD). VAVD requires the use of a sealed
reservoir.
Cardiotomy System
Cardiotomy suction serves as an important source of blood conservation. Most systems use a roller pump to provide cardiotomy suction, with the collected blood directed to a
cardiotomy filter that then drains into the venous reservoir. As the cardiotomy suction is frequently used during cannula placement before initiation of CPB, it is essential that
adequate heparinization be achieved before use of cardiotomy suction so that clot does not form in the cardiotomy filter or venous reservoir.
FIGURE 28.4. Schematic of CAPIOX FX05 oxygenator with integrated arterial filter. (Image courtesy of Terumo Cardiovascular Systems Corporation, Ann Arbor, MI, All rights
reserved.)
The cardiotomy filter is normally located higher than and behind the venous reservoir. This superior arrangement allows the cardiotomy filter, which may have more dynamic volume
hold up during filtering, the time necessary to work before blood drains into the circulating volume of the venous reservoir. Placing the cardiotomy filter posteriorly in the venous
reservoir allows the perfusionist to visualize and focus on the forward facing venous reservoir level to constantly ensure a safe operating level.
The cardiotomy filter has a higher filtration capacity than the venous return filter to handle blood from the field suction devices and ventricular vent line. Cardiotomy blood always has
air mixed in and may also contain particulate contaminants which necessitate increased filtering capacity. While cardiotomy suction has its disadvantages, most clinicians consider it
obligate, especially in pediatric cardiac surgery, because of the volume of blood lost to the field with collateral circulations and general bleeding during the course of surgery. If
cardiotomy suction was not used in these situations, there would be a regular need for homologous blood transfusion simply to maintain a sufficient volume within the CPB system.
And, the loss of plasma via cell saver salvage may also be unacceptable.
Blood from the pericardial well collected by cardiotomy suction during bypass and returned to the venous reservoir is known to activate the extrinsic coagulation pathway (9). This
aspirated pericardial well blood contaminated by tissue contact is the most significant activator of the coagulation system
P.660
during bypass (10). Pericardial aspirate is rich in tissue factor (TF) and procoagulant cellular (primarily platelet) derived microparticles (10,11,12). It has also been demonstrated that
elimination of cardiotomy suction return to the venous reservoir or washing of pericardial cardiotomy blood prior to return reduces inflammatory mediator generation and thrombin,
neutrophil, and platelet activation (13). Cardiotomy suction is the major source of blood trauma and hemolysis during CPB due to the unavoidable aspiration of air and blood (10,14).
In addition to cardiotomy suction, bypass circuits utilize a roller head pump to provide ventricular venting. The vent line collects blood from the ventricular vent and normally returns it
to the cardiotomy filter.
HEAT EXCHANGER
Cardiopulmonary bypass commonly utilizes hypothermia to reduce systemic, especially cerebral, oxygen consumption and to aid in maintaining myocardial hypothermia during
cardioplegic arrest. Heat exchangers are necessary to produce the active cooling and rewarming of the patient’s blood required for hypothermic bypass. Integration of the heat
exchanger into the oxygenator system is a common way to reduce prime volume.
The oxygenator heat exchanger has a stainless steel or plastic barrier separating countercurrent flow of water and blood. A folded flat sheet design increases the surface area for
heat transfer. The water temperature is controlled by a thermocirculator which is commonly referred to as a heater-cooler. The perfusionist sets the temperature of the water to effect
the target patient temperature for various phases of bypass. This water temperature is set within certain limits outlined by the manufacturer. The temperature gradient between the
venous blood inlet and the water inlet is normally kept less than 10°C. This maximum gradient helps evenly cool and warm the blood and patient while preventing gas from coming
out of solution. Excessive gradients during warming or cooling can allow gas to come out of solution to form microemboli in the blood of the patient and bypass circuit. In other words,
if cold blood with its higher gas solubility enters a warmer area of the patient or circuit with lower gas solubility, gaseous microemboli (GME) can form. The integrated heat exchanger
is normally rated for performance based on the achieved heat transfer divided by the potential heat transfer. This performance factor can be quantified with the following equation:
The performance factor will vary at different blood flow rates since the heat exchange surface area is fixed and heat exchange improves with time allowed for transfer. The adequacy
of heat exchange performance is ideally considered at the maximum expected blood flow rate for a given cardiopulmonary bypass case. Of note, the water inlet temperature should
never reach 40°C, as at 42°C protein denaturation and damage to the blood may result. Also, aggressive rewarming should be avoided since hyperthermic perfusate temperatures
have been linked to greater neuropsychologic dysfunction after cardiac surgery (15), and an oxygenator outlet temperature greater than 37°C has been correlated with acute kidney
injury (16). These potential complications must be considered in light of the fact that oxygenator temperature systems at normothermia may under report outlet values by 0.5°C or
more (17).
A variety of heater-cooler systems are available, and include the 3T Heater-Cooler System (Sorin Group, Milan, Italy), Hemotherm CE (Cincinnati Sub-Zero Medical, Cincinnati, OH),
and heater-cooler unit HCU 40 (Maquet Getinge Group, Göteborg, Sweden). Circuits can supply temperature-controlled water to the oxygenator heat exchanger, the cardioplegia
heat exchanger, and warming/cooling blankets. Some centers have used hot and cold water from institutional sources (“wall water”) which are then passed through a mixing valve to
control CPB temperatures. Such systems are costly and rarely used in light of the efficient and more cost-effective heater-cooler systems available today.
Arterial Line Filter

The ALF may be a separate (nonintegrated) component positioned distal to the oxygenator or less commonly integrated into the oxygenator.
Nonintegrated ALFs consist of a screen filter, usually made of polyester, which may be a flat sheet or folded and layered to increase contact surface area (Fig. 28.5). This screen
filter commonly has a pore size of 20 to 40 μm which traps particulate matter and air larger than its pore size. There is usually a low-flow purge of blood at the top of the device which
returns blood, and any air, to the cardiotomy filter.
Integration of the ALF into the oxygenator is of particular benefit in pediatric cardiac surgery since a significant reduction in prime volume can be achieved. The integrated ALF is
primarily wrapped around the oxygenator membrane, but can be integrated into the oxygenator bundle itself with unique bundle weaving technology. Neither of these designs
requires a purge line to the cardiotomy filter. Wrapping the filter medium around the oxygenator bundle has the advantage of creating back pressure which can purge microair into
the gas flow path of the microporous oxygenator. The other method for integrating the ALF with the oxygenator is by constructing the oxygenator bundle fibers such that the space
between the membrane fibers before the blood exits the device is a maximum of 25 to 40 μm. There is currently only one oxygenator on the US market which is approved with this
technology (Affinity Fusion Oxygenation System, Medtronic, Minneapolis, MN), and it is unclear if this technology will become more prevalent in future devices. Studies comparing
the effectiveness of GME removal by available external ALFs to integrated filters wrapped around the oxygenator bundle and filtration provided by unique bundle
P.661
wrapping technology are warranted to validate these relatively new technologies.
FIGURE 28.5. Dideco Kids D130 arterial line filter. (Image courtesy of Sorin Group, Mirandola, Italy, All rights reserved.)
Tubing
Custom tubing packs are an essential item for pediatric perfusion practice. The overall goals for tubing selection are to minimize sizes and requisite prime volume while assuring
reasonable system pressure so as not to damage the blood or increase the risk of tubing disconnect while on bypass. Tubing packs can be customized to accommodate an
institution’s selection of heart-lung machine and arterial head systems, oxygenators, ALFs, and the positioning of these components relative to the surgical field.
Tubing Sizes
Tubing sizes for congenital heart surgery range in internal diameter sizes from ⅛ to ½ inches, and will vary within each custom set-up. Prime volumes for different size tubing are
shown in Table 28.2.
TABLE 28.2. Prime volume for cardiopulmonary bypass circuit tubing
Internal tubing diameter (inches) 1/8 3/16 1/4 5/16 3/8 1/2
Milliliters per foot 2.4 5.0 9.7 15.5 21.7 38.6
TABLE 28.3. Example of tubing size and maximum achievable flow rates
Tubing size (inches) Boot line with standard pump head (mL/min) Arterial line (mL/min) Venous line with gravity siphon drainage (mL/min)
3/16 1,200 1,500 600

1/4 2,100 3,150 1,800
3/8 4,400 >3,150 3,750
1/2 >4,400 NA >3,750
Institutions generally have accepted maximum values for system pressure and achievable flow rates for the different tubing sizes. Tubing packs are then defined based on
anticipated pump flow and line lengths required within a CPB setup. For example, a program may start with 3/16-inch tubing for the major tubing components (arterial and venous
limbs, boot line) for patients with an expected maximum bypass flow rate of 600 mL/min. As patient weight and expected flow rates increase, the different tubing components are then
upsized. The venous limb size is normally increased first, followed by the boot line, and finally the arterial limb until adult bypass circuit sizes are achieved. An adult circuit commonly
has a ⅜-inch arterial limb with ½-inch venous and boot lines. The venous limb tends to be the largest tubing prime component, but can be reduced in size with augmented venous
return (kinetic and vacuum assisted drainage) techniques. Table 28.3 provides an example of tubing selection based on its position and maximum recommended pump flow rate.
The left ventricular and other vent lines and the field suction lines are other primary components of a custom tubing pack. They are not normally primed before bypass and so their
volumes have less impact on the system. However, their sizing is particularly important for small patients because they can be intermittently primed with blood during bypass.
Generally, these lines are primed at various times during bypass, but are free of blood during the weaning phase of bypass. For example, an aortic root vent line may be primed with
aortic root blood after aortic cross-clamping and during rewarming to aid in de-airing. This line is then either disconnected or
P.662
allowed to deprime to the bypass circuit before separation from bypass.
Surface Modification
Treatment of the bypass circuit tubing, cannulas, and oxygenators with heparin and other surface-modifying agents (SMAs) has been undertaken by manufacturers in an effort to
increase the circuit’s biocompatibility (18,19,20). In theory, use of SMAs should result in decreased activation of platelets and attenuation of the inflammatory response induced by
contact activation (21). However, solid evidence linking use of SMAs to meaningful improvements in important clinical outcomes such as reduced blood loss, reduced incidence of
renal dysfunction, or shorter duration of ventilatory support in either children or adults undergoing cardiac surgery with CPB is lacking (21,22). Despite this, SMAs are clearly in
widespread use in pediatric cardiac surgery programs; a 2011 review of international pediatric perfusion practice reported that 85% of programs were using CPB circuits that
incorporated SMAs (1,7).
Cannulas
Once the circuit components for bypass are selected and assembled, and the circuit primed, attention shifts to cannulation. Assuring proper arterial inflow and venous outflow with
appropriate gas exchange are important first assessments when placing a patient on CPB. This includes not only the type and size of the arterial and venous cannulas, but also the
site for cannulation.
Arterial Cannulas
Arterial inflow is provided most often with a single arterial cannula placed in the ascending aorta proximal to the innominate artery. Alternative arterial inflow strategies include
femoral arterial cannulation for reoperations, double arterial cannulation for interrupted aortic arches, and ductus arteriosus/pulmonary artery cannulation for ascending aorta and
aortic arch hypoplasia. The surgeon must be cognizant of the arterial cannulation strategy required and its potential effects on systemic perfusion, operative strategy and blood
pressure monitoring sites.
Sizing of arterial cannulas is by their outer diameter. The lumen must be large enough to allow for anticipated pump flow rates while not creating excessively high system pressures.
If a cannula is too large, it can obstruct native heart output, particularly in the ascending aortic position as this output is critical during cannulation and the initiation and weaning
phases of bypass. An arterial cannula that is too small, in addition to limiting flow, leads to high pressures, increased flow velocities, jetting against the arterial wall, and high shear
forces which may damage the formed elements of the blood (23,24). The pressure drop across an arterial cannula is normally limited to 100 mm Hg. Arterial cannulas come in a
variety of styles and sizes to meet the varied needs of congenital cardiac patients (Fig. 28.6). The outer diameter for arterial cannulas ranges from 6 to 24F to accommodate
neonates to older adults. Arterial cannulas commonly have wire-wound bodies to resist kinking. Additionally, arterial cannulas should not become too rigid during hypothermia since
this can put undue stress on the aortic wall.
FIGURE 28.6. Pediatric arterial cannulas. A: Biomedicus 8F arterial cannula. B: Medtronic DLP 6F arterial cannula.
Venous Cannulas
The venous limb of the bypass circuit connects to the venous cannulas. The majority of adult cardiac procedures are extra-cardiac in nature (coronary artery bypass grafts and
aortic valve replacements) and may be performed with only a single right atrial cannula for venous drainage. In contrast, most congenital heart operations are intra-cardiac. Venous
drainage is typically provided with bicaval cannulation, which allows for total CPB. Venous cannulas are normally rated for achievable flow based on the pressure drop across their
length in the setting of gravity siphon drainage (GSD). A pressure drop less than 35-40 mm Hg is commonly used as a limit. Venous cannulas ideally have an internal lumen that is
large enough to handle the expected portion of the bypass flow diverted to it while not having an external diameter that completely occludes the vessel. Venous cannulas commonly
have side port holes, in addition to the tip hole, which importantly affect flow performance. Blocking these side ports by inserting too large a cannula can diminish flow performance
and desired flow rates (Fig. 28.7). It follows that a maximized internal-to-outer (IO) ratio of cannula diameter is advantageous. For this reason, metal- and hard plastic-tipped venous
cannulas are commonly used in pediatric settings. These materials lend
P.663
themselves to more favorable IO ratios than standard cannula materials such as polyvinylchloride.
FIGURE 28.7. Pediatric venous cannulas. A: Biomedicus 14F venous cannula. B: Medtronic DLP right angle venous cannula. C: Magnified image of a Medtronic DLP right angle
metal venous cannula tip. (Images courtesy of Medtronic Inc., Minneapolis, MN, All rights reserved.)
Hemofilters
Hemofilters are devices commonly added to the CPB circuit to filter blood by removing water, low molecular weight solutes (potassium, glucose, heparin, citrate, lactate), and
inflammatory mediators (25,26). The removal of water results in hemoconcentration and an increase in the hematocrit. These devices produce the ultrafiltrate as a result of a
hydrostatic pressure gradient across a semipermeable membrane, and are the same devices used for hemodialysis. When hemofilters are used in conjunction with CPB, they are
commonly called hemoconcentrators. Use of the term “ultrafilter” is commonly used without distinction.
Hemofilters consist of a core of microporous hollow fibers made of polysulfone, polyethersulfone, polyamide, or polyacrylonitrile material arranged in a bundle. The pore size in
hemofilters generally allows molecules less than 60,000 to 70,000 Da to pass. Due to the pressure drop across the device, blood inflow can either be passively obtained from the
arterial side of the CPB circuit or actively provided with the use of a roller head pump. Hemoconcentrator outflow is normally diverted to the cardiotomy venous reservoir. The
ultrafiltrate is collected in a container, commonly connected to a regulated vacuum source, and discarded.
The ultrafiltrate has the composition of glomerular filtrate, and the rate at which it is produced is dependent on the transmembrane pressure (TMP). TMP is determined by the
arterial inlet pressure (Pa), the venous outlet pressure (Pv), the absolute value of applied suction at the outlet (Pn), the oncotic pressure at the inlet (Pi), and the oncotic pressure at
the outlet (Po), as follows:
Using the regulated vacuum source connected to the outlet of the device increases or decreases Pn. For most hemofilters, the TMP should not exceed 500 mm Hg.
The techniques and potential benefits and risks of ultrafiltration are discussed later in the chapter in the section relating to the conduct of CPB.
CARDIOPULMONARY BYPASS CIRCUIT PRIME

The prime volume of the bypass circuit is a simple function of adding the prime volume of the various components utilized. Normally, the lowest volume circuit components available
which can safely provide the anticipated maximum flow rates and gas exchange, with some performance reserve, are chosen. The circuit is commonly flushed with CO2 and then
primed with a crystalloid solution. This process helps ensure that the components of the circuit and their connections are not leaking and are visually free of air. Thereafter, the
degree of hemodilution (dilutional hematocrit, %) is calculated using the following formula:
where EBV = the patient’s estimated blood volume (mL) and PV = circuit prime volume (mL). The patient’s EBV is the product of weight and blood volume. Because blood volume
changes with weight/age, EBV is calculated using the values shown in Table 28.4. If the dilutional hematocrit is deemed acceptable, the prime can be buffered and the patient can
be placed on CPB with a clear prime. If the dilutional hematocrit is deemed too low, red blood cells may be added to the circuit to achieve the desired dilutional hematocrit. The
amount of blood required (mL) in the circuit prime can be calculated with the following equation:
P.664
TABLE 28.4. Estimated blood volume according to patient weight
Patient weight (kg) Blood volume (mL/kg)
<10 85
10 to <20 80
20 to <30 75
30 to <40 70
≥40 65
Institutional practice varies with respect to the type of blood used (packed red blood cells with or without plasma added) for priming the circuit and the lowest acceptable dilutional
hematocrit. While most centers use packed red blood cells, the use of whole blood or packed red blood cells reconstituted with plasma may reduce untoward dilution of clotting
factors during bypass (27). A safe dilutional hematocrit for CPB has yet to be defined for the numerous cardiac defects seen in pediatric cardiac surgery. Analysis of the Boston
hemodilution trials found that in neonates and infants undergoing biventricular repair without arch reconstruction, a hematocrit greater than approximately 24% on bypass was
associated with improved neurodevelopmental outcomes (28). While there has been great interest in transfusion-free bypass for congenital heart surgery, studies are needed to
demonstrate that lower hematocrit strategies have comparable neurologic outcomes as compared to protocols maintaining a hematocrit greater than 24% during CPB in pediatric
cardiac surgery patients. The current practice at Boston Children’s Hospital is a dilutional hematocrit at the onset of bypass of 24% to 35% in neonates, infants, and children and
depends on the underlying diagnosis and intended operation.
CONDUCT OF CARDIOPULMONARY BYPASS

Initiation of Bypass
In clinical practice, the perfusionist initiates bypass by releasing the circuit arterial limb clamp and increasing pump flow to the arterial cannula. It is imperative that the circuit system
pressure is within acceptable and expected limits as flow is increased toward the target rate. An excessively high pressure indicates a problem ranging from a simple failure to
remove the arterial limb clamp or a kinked arterial limb to a malpositioned cannula or ascending aortic dissection. The surgeon and perfusionist must be familiar with how to deal with
these events. The circuit venous limb clamp is released after the arterial limb clamp but it is held near the venous line until proper venous drainage and arterial inflow are reasonably
assured. Reapplication of the venous clamp may be necessary to prevent exsanguination if the arterial cannula inadvertently comes out or if arterial inflow is interrupted in some
other way during this critical phase of bypass. Preventing exsanguination significantly decreases emergent interventions required when arterial inflow is compromised and being
rectified during the initiation of bypass.
The assessment of venous drainage at the initiation of bypass is critical and is nearly simultaneous with assessment of arterial inflow. Proper drainage with the given venous
cannulas normally equates to arterial inflow at its target rate with a sufficient and stable venous reservoir volume. If this is not the case, several considerations must be made
including adjustment of cannula position and/or size and verification of bypass circuit venous limb patency. Initiation of bypass is almost always with GSD, commonly referred to as
“gravity.” Gravity drainage for bypass is dependent on venous cannula size, the relative height of the patient above the venous reservoir, the length and diameters of the venous
tubing, maintenance of a continuous fluid column, characteristics of the venous reservoir, and patient volume status (29). These requirements can be limiting with the small cannulas
and bypass tubing used in pediatrics and a problem when significant collateral or other unique circulations flood the surgical field preventing adequate visualization for the surgeon.
These concerns and the desire to decrease prime volume have led to an increased use of augmented venous return strategies for pediatric CPB.
Most commonly in pediatric perfusion, augmented venous return is via vacuum-assisted venous drainage (VAVD). The vacuum technique has the perfusionist apply negative
pressure from a regulated vacuum source to a sealed hard-shell venous reservoir. This vacuum pressure gets transmitted to the venous limb of the bypass circuit. The requirements
of gravity drainage described above become less important with use of VAVD. Vacuum can improve drainage and visualization at the field. Vacuum assisted drainage is not without
risk. Vacuum increases air entrainment into the venous limb of the circuit that, even with arterial line filtration, has been shown to increase arterial line GME transmission to the
patient (30,31,32,33). It is unclear what level of GME becomes associated with adverse neurologic outcomes, but even the proper application of vacuum assist has been associated
with a devastating outcome (34). VAVD also carries an increased risk of massive air embolism via the venous limb of the bypass circuit due to the venous reservoir being sealed and
the presence of a nonfunctioning high-pressure relief valve (35,36,37). Vacuum drainage can greatly aid the surgeon and decrease circuit prime volume and decrease transfusion
requirements for bypass (38). Proper clinical application of VAVD has the potential to prevent untoward outcomes (39) but much research is needed to qualify the effect of increased
GME load on clinical outcome in congenital cardiac surgery. An alternative technique to VAVD is kinetic-assisted venous drainage (KAVD). With KAVD, a kinetic pump applies
suction to the venous drainage
P.665
line rather than to the reservoir. A centrifugal pump is used for control of the negative pressure (24).
Once proper arterial inflow and venous drainage are assured, bypass parameters are adjusted to achieve target flow rates, mean arterial pressure, depth of hypothermia, and blood
gas values.
Partial versus Total Bypass

The initial phase of bypass is usually partial CPB. With partial CPB, only a portion of the systemic venous return to the heart drains into the bypass circuit, with the remaining portion
passing to the right atrium (RA). Ideally, right atrial return passes to the right ventricle (RV) and pulmonary vasculature, where gas exchange occurs. The blood then returns to the
left atrium (LA) and left ventricle (LV), from which it is ejected into the systemic circulation. During partial CPB, the patient’s systemic blood flow is therefore provided in part by the
CPB circuit and in part by the patient’s heart. There are two essential requirements for partial bypass to be effective: the heart must be beating and ejecting and the lungs must be
ventilated. If ejection is ineffective or nonexistent, distention of the heart will occur and systemic blood flow will be inadequate. In the absence of ventilation, pulmonary venous blood
returning to the LA will ultimately reach the systemic circulation without having undergone gas exchange; this can result in hypoxemia and hypercarbia. The patient’s arterial Po2,
Pco2, and pH are thus a reflection of the quantity and effectiveness of gas exchange in the two sources of systemic blood flow. Therefore, during partial CPB, samples for blood gas
analysis must be drawn from the patient and not from the CPB circuit in order to accurately reflect in vivo conditions.
Cases with single venous cannulation of the right atrium effectively have the patient on partial bypass. In contrast, if nearly all of the venous return is diverted to the CPB circuit, the
patient is said to be on total CPB. Total bypass is normally achieved with bicaval cannulation and caval snares, which prevent blood from circumventing the caval cannulas. Caval
snares also prevent air from entering the bypass circuit once the right heart is opened. Total bypass is preferred for intra-cardiac repairs to aid in visualization at the surgical field.
Capturing all venous return to provide true total bypass in congenital cardiac patients can be problematic. Patients may have a persistent left superior vena cava (SVC) with
drainage to the coronary sinus, an interrupted inferior vena cava (IVC) with drainage of hepatic veins directly to the RA or azygous continuation to a left-sided SVC, which may not
be easily accessed or cannulated. These situations usually require increased use of field suction in the pericardial well or in the heart itself.
Flow Rates and Temperature

Flow rates during CPB are chosen to provide adequate systemic oxygen delivery. Systemic hypothermia is routinely employed during pediatric CPB, with many operations performed
at temperatures of 28°C to 32°C. Systemic hypothermia reduces whole-body and cerebral oxygen consumption 5% to 7% for each 1°C decrease in body temperature (40). Flows of
1.8 to 2.5 L/min/m2 are commonly used for infants, children, and adults during mild-to-moderate systemic hypothermia. Due to age-related differences in the relationship of weight to
body surface area, when these flow rates are expressed in mL/kg/min, they will be substantially higher in the neonate than in the adult. Low-flow CPB in neonates and infants is
conducted at temperatures of 18°C to 22°C and flow rates of 50 to 75 mL/kg/min or approximately 0.7 to 1.2 L/min/m2. The arterial pump head output is decreased from the full flow
value in a temperature appropriate fashion. Table 28.5 lists common index flows used in pediatric CPB relative to patient temperature. These listed flows are general estimates only
as flow rates vary with surgical and patient needs. Near infrared spectroscopy (NIRS) monitoring of regional cerebral tissue oxygen saturation is used by clinicians as an adjunct to
real-time arterial and venous blood gas values in an attempt to provide safer blood flow rates during CPB (41,42,43).
Blood Gas Management

Blood gas management during hypothermic CPB is a confusing and poorly understood topic for many clinicians new to cardiac surgery, and has been reviewed in detail by Jonas
(44). The best way to approach this subject is to understand 1) the change in pH of water and blood when cooled; 2) how blood gas analyzers function with respect to temperature;
3) the difference between the a-stat and pH-stat strategies with respect to how arterial blood gases are interpreted and whether CO2 is added to the circuit ventilating gas; 4)
cerebral autoregulation and the interaction with temperature
P.666
and pH; and finally (5) α-stat and pH-stat in relation to the dominant mechanism of cerebral injury in pediatric cardiac surgery.
TABLE 28.5. Cardiopulmonary bypass flow rates relative to patient temperature
Patient temperature (°C) Flow rate (L/min/m2)
≥35 ≥2.5
32 2.2
30 2.0
28 1.8
26 1.6
24 1.4
22 1.2
20 1.0
18 0.7
Change in pH of Water and Blood with Cooling

Electrochemical neutrality occurs when there are equal concentrations of hydrogen (H+) and hydroxyl (OH-) ions. Electrochemical neutrality is important for maintenance of a
constant transcellular H+ gradient necessary for many cellular processes and optimal protein and enzyme function. In humans, electrochemical neutrality (ratio of H+:OH- = 1) occurs
at an intracellular pH of 7.1, which is close to the pH of neutrality of water (7.0). Buffer systems maintain the extracellular pH at 7.4 and the intracellular pH at 7.1. The imidazole
group of the amino acid histidine is present in many cellular and plasma proteins, including hemoglobin. Together with phosphate (mainly intracellular) and bicarbonate, these
buffers maintain an equal concentration of H+ and OH- ions, and thereby electrochemical neutrality.
When water (and blood) is cooled, the dissociation constant (pK) decreases, resulting in an equal reduction in the concentration of H+ and OH- ions. As pH is the inverse logarithm
of the H+ concentration, and because the H+ concentration decreases with cooling, the pH of the water (and blood) will increase. For each 1°C decrease in temperature, the pH of
water will increase by 0.017 and the pH of blood will increase by 0.0147 (45).
Changes in cellular pH during hypothermia are mediated through Paco2 homeostasis. As temperature decreases, the solubility of CO2 in blood increases. If the total CO2 content of
blood is held constant, this increase in CO2 solubility will result in a reduction in Pco2. For example, if the total CO2 content is held constant and the measured Pco2 at 37°C is 40
mm Hg, then the measured Pco2 at 20°C will be 16 mm Hg. This causes pH to increase as temperature decreases and electrochemical neutrality is maintained.
TABLE 28.6. Arterial blood gas uncorrected and corrected values for α-stat and pH-stat blood gas management
Temperature uncorrected (reported at 37°C) Temperature corrected (reported at patient temperature)
Patient temp. (°C) α-Stat pH pH-stat pH α-Stat Pco2 pH-stat Pco2 α-Stat pH pH-stat pH α-Stat Pco2 pH-stat Pco2
37 7.40 7.40 40 40 7.40 7.40 40 40
33 7.40 7.34 40 47 7.44 7.40 35 40
30 7.40 7.30 40 54 7.50 7.40 29 40
27 7.40 7.26 40 62 7.55 7.40 26 40
23 7.40 7.21 40 74 7.60 7.40 22 40
20 7.40 7.18 40 84 7.65 7.40 19 40
17 7.40 7.14 40 96 7.69 7.40 17 40
Blood Gas Analyzers and Temperature

Blood gas analyzers evaluate samples at a temperature of 37°C. If a blood sample is lower than 37°C, the analyzer will warm the sample to 37°C and then measure the various
parameters. Therefore, when a blood gas sample is drawn from a hypothermic patient and sent to the blood gas laboratory, the sample is warmed to 37°C before measurement. The
values obtained at 37°C are called the temperature-uncorrected values. These values are then converted to temperature-corrected values at the patient’s temperature using a
nomogram. The nomogram accounts for temperature-induced changes in pH, O2 solubility, and CO2 solubility in a closed-blood system. When pH and Paco2 are measured at 37°C
and then corrected to a lower temperature, the electrochemically neutral pH will be higher and the corrected Paco2 will be lower than the values at 37°C. Temperature correction of
blood gas values is independent of whatever blood gas strategy is being used to manage the patient and is only accounting for the physiochemical changes of temperature on pH
and solubility of CO2 and O2.
α-Stat and pH-Stat

α-Stat and pH-stat are methods of acid-base management and directly influence blood flow to the brain and other organs.
In α-stat regulation, electrochemical neutrality is maintained at whatever temperature the patient is at. This is achieved by allowing the pH to increase as the patient is cooled. The
pH will be alkalotic and the Paco2 decreased in the temperature-corrected blood gas and normal in the temperature-uncorrected blood gas. For example, when a blood gas is taken
from a patient at 27°C, the temperature uncorrected (at 37°C) pH and Paco2 will be 7.4 and 40 mm Hg, respectively, while the temperature corrected (27°C) pH and Paco2 will be
7.55 and 26 mm Hg, respectively (Table 28.6). With a-stat management, the total CO2 content of the patient and bypass circuit is held constant.
P.667
With pH-stat regulation, electrochemical neutrality is lost in that the pH is maintained at 7.4 and the Paco2 at 40 mm Hg at whatever colder temperature the patient is at, that is,
normal values on the temperature-corrected blood gas. As shown in Table 28.6, at temperature-uncorrected values the pH will be acidotic and the Paco2 higher than normal. A pH-
stat strategy is achieved by adding CO2 to the ventilating gas during hypothermic CPB to increase Paco2 and decrease the pH. In contrast to a-stat regulation, in which total CO2
content is kept constant, pH stat regulation results in an increase in total CO2 content.
It is important to point out that at a patient temperature above 30°C there is essentially no difference between a-stat and pH-stat management. The difference between these
strategies becomes more marked as temperature progressively decreases and is not clinically relevant until patient temperature is below 30°C. For practical purposes, it is easier to
use uncorrected blood gases aiming for a pH of 7.4 and a Paco2 of 40 mm Hg at 37°C during a-stat management and blood gases corrected for patient temperature aiming for a pH
of 7.4 and a Paco2 of 40 mm Hg during pH-stat management.
Cerebral Autoregulation, Temperature, and Metabolism

Landmark studies by Greeley and colleagues found that when a-stat regulation is used, pressure-flow autoregulation is preserved during moderate hypothermic (25°C-32°C)
bypass, but is lost or attenuated during deep hypothermic (18°C-22°C) bypass (46,47). Cerebral blood flow (CBF) and cerebral O2 consumption (CMRo2) are appropriately coupled
with a-stat regulation. In contrast, the addition of CO2 during pH-stat management produces loss of autoregulation and uncoupling of CBF and CMRo2 (48). As a result, CBF varies
linearly with arterial blood pressure and luxuriant cerebral blood flow exists with CBF far in excess of that dictated by cerebral metabolic rate. This hyper-perfusion state is the result
of reduced CMRo2 induced by hypothermia and cerebral vasodilation resulting from a disproportionately high Paco2 for the degree of hypothermia present. Cerebral metabolism is
exponentially related to temperature, and the temperature coefficient in neonates, infants, and children is 3.65 versus 2.4 in adults (49,50).
pH-Stat for Pediatric Bypass

The etiology of brain injury during CPB is a major consideration in the decision to use an α-stat or pH-stat strategy. Because of atherosclerotic disease, adults are more susceptible
than children to brain injury resulting from macro- and microembolism of atherosclerotic debris. By linking CBF with CMRo2 and thereby avoiding the cerebral hyperperfusion
associated with pH-stat, α-stat regulation is most commonly used for adult cardiac surgery. Global and regional hypoperfusion is a bigger concern in the pediatric population.
Additionally, lower temperatures, with shift of the oxyhemoglobin dissociation curve to the left, are more frequently required in children. Consequently, pediatric CPB more frequently
uses the pH-stat strategy. Additional benefits of pH-stat include suppression of CMRo2, which may prolong oxygen availability during periods of circulatory arrest, and more efficient
brain cooling (51). The acidosis associated with pH-stat increases the pulmonary vascular resistance and thereby decreases pulmonary blood flow, which has the benefit of
reducing the steal of blood from the systemic and hence cerebral circulation in patients with significant aortopulmonary collaterals (52). For an extensive review supporting the use of
pH-stat in pediatric cardiac surgery, the reader is referred to reference (44).
Oxygenation Strategy
Ischemia-reperfusion injury is associated with the generation of reactive oxygen species (oxygen free radicals) which cause cellular injury by lipid peroxidation. The immature heart
and lungs exposed to chronic hypoxemia are more susceptible to an oxygen-mediated injury when hypoxemia is reversed (53,54,55). Accordingly, some centers advocate the use of
normoxia rather than hyperoxia during pediatric CPB. Boston Children’s Hospital and other centers routinely use hyperoxic management on bypass (44). Studies in piglets
comparing normoxia to hyperoxia found that a normoxic strategy was associated with higher embolus counts (nitrogen is less soluble than oxygen) and significantly increased
histologic evidence of brain injury (56). Findings on near-infrared spectroscopy suggested that the mechanism was hypoxia.
Ventricular Venting
Ventricular venting is intended to prevent blood from collecting in the systemic ventricle during bypass, which can lead to ventricular distension and unintended warming of the heart.
Distension causes mechanical damage to the heart from subendocardial compression. Left ventricular blood flow compromises surgical exposure during the repair. The risk of
distension is greatest when the blood return to the right or left heart is high and the ventricles are no longer effectively ejecting blood. As CPB commences, bradycardia, ventricular
fibrillation, or asystole may occur and prevent effective ventricular ejection. Warm blood collecting in the ventricles compromises myocardial protection during the cross clamp period
by affecting myocardial temperature.
Blood flow to the right heart during CPB is usually the result of coronary blood flow from the coronary arteries and their collaterals. A small portion of right heart return comes from
noncoronary collaterals, usually of pericardial and mediastinal origin (57). Coronary venous blood returns to the coronary sinus, which is located near the junction of the IVC and the
right atrium (RA). Coronary sinus return can be captured by a properly positioned single cannula or with separate IVC and SVC cannulas with the caval tapes loosened. For
procedures in which the right heart is opened, coronary sinus blood can be captured with cardiotomy suction. Coronary arterial and sinus blood flow (except that contributed by
noncoronary collaterals) will cease when an aortic cross-clamp is applied.
P.668
Blood flow to the left heart during bypass may be from the thebesian veins, bronchial veins, extra-cardiac left-to-right shunts, and aortic valve incompetence. Thebesian veins drain a
small portion of the myocardium into mostly the right atrium, with a few emptying into the ventricles. Thebesian flow will cease when the aortic cross-clamp terminates coronary blood
flow. The bronchial veins drain into the pulmonary veins and subsequently into the left atrium and ventricle. The bronchial circulation can be very large in patients with cyanotic heart
disease. With extra-cardiac left-to-right shunts, a large portion of pulmonary blood flow may be supplied by anatomic (patent ductus arteriosus, aortopulmonary collaterals) or
surgical systemic-to-pulmonary artery communications (Blalock-Taussig, Sano, Waterston, Potts, and central shunts). If these communications are not ligated or controlled before or
shortly after institution of CPB, the blood return to the pulmonary artery, and subsequently to the left atrium and left ventricle, may be very large. In this circumstance venting will
relieve left heart distention, but unless CPB flow rate is increased by an amount equal to the vented blood, systemic oxygen delivery (especially cerebral) will be compromised. Aortic
valve incompetence results in retrograde filling of the left ventricle with blood from the aortic cannula until the aortic cross-clamp is applied.
Right ventricular venting is usually unnecessary because coronary sinus flow can be captured with a drop sucker or the venous cannulas depending on cannulation strategy.
Several sites are available for left ventricular venting. The junction of the left atrium and the right superior pulmonary vein provides relatively easy access to the left atrium. The vent
can then be easily placed across the mitral valve into the left ventricle. The insertion site can be used subsequently for placement of a transthoracic left atrial pressure line. Direct
venting of the left ventricular apex is possible, but this route requires careful repair and may result in damage to the left ventricle. Direct venting via the left atrium is also possible.
The pulmonary artery can be used to vent both the right heart and the left heart. However, a competent mitral valve will limit effective venting of the left ventricle via this route.
Close communication between surgeon and perfusionist are necessary during bypass to ensure proper venting of the heart during the appropriate time intervals. It is common for the
team to announce when vent flow is terminated during rewarming and before separation from bypass. This prevents unintentional over-filling of the heart which can occur when
arterial inflow is unchanged while return to the pump is suddenly decreased.
Ultrafiltration
Techniques
Various methods of ultrafiltration are used during CPB in the pediatric population. Common techniques are prebypass ultrafiltration (PBUF), zero balance ultrafiltration (ZBUF),
conventional ultrafiltration (CUF), and MUF. All techniques can be utilized for a bypass case with the same ultrafilter.
Prebypass Ultrafiltration
Pediatric bypass patients more commonly receive blood primes in the circuit. Abnormal values of electrolytes and other molecules in blood primes may be harmful and could cause
arrhythmias and hypotension with volume infusion from the circuit before bypass and upon initiation of bypass. These values can be made more physiologic by passing the blood
prime solution through an ultrafilter before bypass while adding a balanced electrolyte solution in equal amounts to the ultrafiltrate removed. The electrolyte values approach those in
the solution added to filter the prime. PBUF can effectively correct for levels of lactate, potassium, and glucose out of normal physiologic ranges (58).
Zero Balance Ultrafiltration

ZBUF, also referred to as dilutional ultrafiltration (DUF), is a technique used during CPB to effect changes much like PBUF. The perfusionist adds a crystalloid solution such as
Plasma-Lyte A 7.4 (Baxter Healthcare, Deerfield, IL) in amounts equal to what is being removed by the ultrafilter. The net effect on fluid balance is zero, but electrolyte abnormalities
can be corrected and mediators of inflammation removed with circuit values approaching those in the crystalloid solution (59). ZBUF is particularly useful when there is not excessive
venous reservoir volume to filter and remove.
Conventional Ultrafiltration
CUF is utilized in nearly all pediatric bypass cases and involves removal of excess volume in the venous reservoir during bypass. Excess venous reservoir volume can be caused by
the crystalloid component of cardioplegia, valve testing solution, or simply when a patient has an elevated circulating blood volume. CUF removes excess volume by passing blood,
either passively or actively with a roller head, through the ultrafilter. With CUF, the ultrafiltrate is sometimes referred to as “free water.” The removal of free water increases the
hematocrit and can remove mediators of inflammation.
Modified Ultrafiltration
MUF allows ultrafiltration to continue after weaning from CPB. MUF allows the bypass circuit to remain primed while both the patient’s blood volume and the bypass circuit volumes
are hemoconcentrated. MUF may be performed utilizing either an arteriovenous or venoarterial system. In the arteriovenous system, first described by Naik et al. (60), inflow to the
ultrafilter is drawn with a roller pump directly from the aortic cannula. Outflow from the ultrafilter is directed to the right atrium. In the venoarterial system, the right atrium provides
inflow to the ultrafilter with the aid of a roller pump while outflow from the ultrafilter is returned to the aortic cannula (61). With both systems, blood volume is kept constant as
ultrafiltrate is lost by replacing the ultrafiltrate with blood from the CPB circuit. The end-point for termination of MUF following CPB varies from institution to institution and may
depend on a set time interval (10-15 minutes), a set target hematocrit (40%), or a
P.669
set volume removed (750 mL/m2). Heparin anticoagulation must be maintained during MUF with protamine reversal only initiated after termination of MUF.
The major advantage of MUF over CUF is that by allowing hemoconcentration to continue after CPB, MUF normally allows for a greater degree of hemoconcentration than can be
obtained with CUF alone, especially in small children. Some institutions utilize both CUF and MUF, as the techniques are not mutually exclusive. However, when a standardized
volume of fluid is removed there is no difference in clinical outcome or hemoconcentration between CUF and MUF (62).
Benefits and Risks

Ultrafiltration before, during, and after CPB in pediatric cardiac surgery greatly enhances fluid management (63). While prebypass and bypass ultrafiltration can be used on all
patients, postbypass MUF is usually reserved for patients less than 15 kg in weight. The rationale is that the greater prime volumes and blood volumes above 15 kg require an
unacceptably long time to process since MUF circuit flow cannot be increased proportionately because of limitations of the tubing and connectors commonly used in such systems.
The use of MUF has been reported to decrease circulating inflammatory mediators, myocardial edema, myocardial systolic and diastolic function, hypotension, inotrope
requirements, coagulopathy, and A-a O2 gradient (25,60,64,65,66,67,68,69). However , all these studies with neonates utilized a CPB technique that consisted of a very large
asanguinous pump prime (400-900 mL) with packed red blood cells added to achieve a dilutional hematocrit of 15% to 20%. This is precisely the subset of patients who would
require and benefit from aggressive hemofiltration and hemoconcentration.
A number of studies have compared ultrafiltration techniques alone or in combination. ZBUF in conjunction with MUF was more effective than MUF alone in reducing inflammatory
mediator concentrations immediately following filtration and associated with lower blood loss, shorter duration of postoperative ventilatory support, and a more favorable 24-hour A-a
O2 gradient (70). ZBUF in combination with MUF was more effective than CUF alone in reducing postbypass plasma endothelin 1 and thromboxane B2 levels and attenuating
postoperative pulmonary hypertension, and decreasing the duration of postoperative ventilatory support and transfusion requirements (71,72,73,74). In contrast, other investigators
found no difference in postoperative course when comparing ZBUF plus MUF to CUF (75,76).
While most ultrafiltration techniques are easily and safely incorporated into practice, MUF in particular has been associated with significant safety concerns. MUF has been
implicated with cavitation of air into the bypass circuit and increased risk of iatrogenic air embolism, increased plasma heparin concentrations which may require reevaluation of the
protamine dose, reduced plasma opioid and benzodiazepine levels, and hypothermia if the system is not modified to warm the MUF circuit return flow (77,78,79,80,81,82).
Low-Flow Cardiopulmonary Bypass

Reduced flow rates and low-flow CPB are commonly used in pediatric cardiac surgery. The main advantage is improved surgical exposure, but other benefits are a reduction in the
inflammatory response to bypass and decreased embolic load (44). Minimal acceptable flow rates for pediatric CPB are not clearly defined and importantly will vary with the
conditions (blood gas management, temperature, degree of hemodilution, oxygenation strategy) of bypass (83).
CBF and O2 delivery are maintained with flow rates as low as 1.0 L/min/m2 and perhaps as low as 0.5 L/min/m2 with moderate hypothermic CPB and α-stat regulation (84). There
seems to be a preferential distribution of blood flow to the brain when low bypass flows are used, but cerebral oxygen delivery at these flows is maintained at the expense of
increased cerebral O2 extraction and resultant decreased jugular venous oxygen saturation. Despite the fact that somatosensory neural transmission remains intact when moderate
systemic hypothermia is used and flow rate is reduced to 0.5 L/min/m2, significant cerebral lactate accumulation develops after 15 minutes (85). When conventional flow rates (150
mL/kg/min for neonates and 100 mL/kg/min for infants and children) are reduced 35% to 45% at moderate hypothermia (26°C-29°C) and deep hypothermia (18°C-22°C) with a-stat
acid-base management, CBF, cerebral metabolism, and cerebral oxygen extraction are unaffected (86). When conventional flow rates are reduced by 45% to 70% at moderate
hypothermia (26°C-29°C), there is a reduction in CBF and a reduction in the cerebral metabolic rate despite a compensatory increase in cerebral oxygen extraction. However, similar
flow reductions during deep hypothermia (18°C-22°C) reduce CBF and CMRo2 but do not produce increased oxygen extraction, suggesting that at deep hypothermic temperatures
CBF and O2 delivery exceed metabolic needs. Cerebral cellular O2 debt seems to occur at 5 to 30 mL/kg/min at 18°C and at 30 to 35 mL/kg/min at 28°C (86). In a group of 28
neonates cooled to 18°C, cerebral blood was detectable in the middle cerebral artery by transcranial Doppler as long as CPB flow rate was at least 30 mL/kg/min (87).
The relationship between CPB perfusion variables and oxygen delivery to organs other than the brain has not been systematically investigated in children. It has been suggested
that whole-blood lactate-level increases may be a surrogate marker for regional oxygen supply-demand imbalance during CPB. An increase in whole-blood lactate >3 mmol/L during
CPB has high sensitivity and specificity, but low positive predictive value, for mortality; the lactate increase correlated with duration of CPB and circulatory arrest (88). Renal
dysfunction following pediatric cardiac surgical procedures is not uncommon and is associated with significant morbidity and mortality. The incidence of acute renal insufficiency
following
P.670
pediatric cardiac surgery in one large series was 17%, with 14% of those ultimately requiring peritoneal dialysis (89). Additionally, children who developed acute renal insufficiency
had a five times higher mortality rate. Nonetheless, the CPB perfusion variables associated with development of postoperative renal dysfunction in children undergoing cardiac
surgery are multifactorial and have not been adequately investigated.
Deep Hypothermic Circulatory Arrest

Deep hypothermic circulatory arrest (DHCA) most often involves cooling a patient on bypass to a core body temperature of less than 20°C, ceasing arterial pump flow, and
exsanguinating the patient’s blood volume into the bypass venous reservoir. This technique allows for ideal visualization for the surgeon during complex aortic arch repairs,
correction of anomalous pulmonary venous drainage, or when the patient’s size and/or anatomy would prevent adequate venous drainage during surgical repair. The use of DHCA
is much more limited today than in years past, mostly due to use of continuous low-flow bypass or regional cerebral perfusion (RCP) as an alternative to DHCA. Circulatory arrest
periods greater than 33 to 41 minutes have been associated with unfavorable neurodevelopmental outcomes (90). In the Boston Circulatory Arrest cohort, continuous low-flow
bypass was associated with better neurodevelopmental outcome than DHCA at 16 years of age (91).
Regional Cerebral Perfusion

RCP, also referred to as selective or antegrade cerebral perfusion, is a bypass strategy which can oftentimes limit or even eliminate the need for DHCA. RCP refers to the technique
of diverting pump arterial blood flow, commonly through the innominate artery, solely to the right subclavian and right common carotid arteries. Most of the body essentially
undergoes circulatory arrest, though some collateral circulation has been reported (92). An RCP flow rate of 20 to 40 mL/kg/min has been shown to adequately perfuse the cerebral
circulation and is commonly utilized, although some centers use higher flow rates (mean 56-63 mL/kg/min) (92,93). This flow may be adjusted based on the use of NIRS and
transcranial Doppler, though it is common for the regional cerebral oxygen saturation reading to be at the device’s maximum value (94). RCP is used by many surgeons to allow
more time and less pressure to complete a repair than that deemed reasonable with circulatory arrest.
Most studies reported to date had small sample sizes and found no difference in neurodevelopmental outcome between DHCA and RCP, although one study found RCP to be
advantageous (95,96,97,98).
Systemic Inflammatory Response in Children

Cardiopulmonary bypass is a potent stimulus for initiation of the systemic inflammatory response syndrome (SIRS) and is discussed in detail in Chapter 14. The magnitude and
intensity of this response is enhanced in neonates, infants, and small children, in part due to the higher circuit surface area-to-blood volume ratio as compared to adults (99). In
children, the intensity of the inflammatory response as measured by proinflammatory mediator levels has been linked to the likelihood of developing organ dysfunction (myocardial,
pulmonary, renal, hepatic) and sepsis in the perioperative period (100). Evidence suggests that SIRS and postoperative sepsis is more likely in infants and children who have
reduced monocyte human lymphocyte antigen DR (HLA-DR) expression (101).
Efforts to mitigate SIRS and its sequelae in children and adults have been reviewed (102,103). The use of MUF, CUF, and ZBUF has been discussed above. Administration of C1-
esterase inhibitor to a small group of neonates undergoing the arterial switch operation resulted in less postoperative weight gain than in infants receiving placebo, but in an animal
model was associated with impaired isovolumic relaxation (104,105). Heparin-bonded circuits which potentially improve biocompatibility and reduce complement activation have
been investigated to a limited extent in children. Early postoperative improvements in urine output and a reduction in the A-a O2 gradient have been seen but with no substantial
improvement in morbidity or mortality (106). A subsequent study found decreased postoperative blood product use, improved postoperative lung function, and a reduction in ICU
length of stay (107). Glucocorticoids reduce inflammation via a number of mechanisms, including inhibition of nuclear factor kappa B (main transcription factor of genes for
inflammatory proteins) and increasing the transcription of many anti-inflammatory proteins such as interleukin 10 and interleukin 1 receptor antagonist. In addition, glucocorticoids
decrease endotoxin release and leukocyte adhesion molecule (CD 11b) expression (100). A 2007 Cochrane Review was unable to determine the effect on all-cause mortality, but
found weak evidence for reducing peak core temperature, duration of mechanical ventilation, and intensive care length of stay (108). Enthusiasm for use of steroids in both neonates
and children in conjunction with CPB must be tempered by evidence from a large database that steroid administration does not afford any mortality or length-of-stay benefit and may
be associated with increased infection in low-risk surgical subsets (109,110). The optimal timing of administration, specific glucocorticoid, dose, and influence on clinical outcome
are still uncertain.
ANTICOAGULATION
Heparin
It is essential that adequate anticoagulation be obtained before use of cardiotomy suction, cannulation, and commencement of bypass. Unfractionated heparin (UFH) is the most
common
P.671
anticoagulant used for CPB. It is generally accepted that an activated clotting time (ACT) in excess of 400 seconds is necessary to ensure adequate anticoagulation and anti-Xa
suppression for the safe conduct of CPB.
While there is a large heparin anticoagulation monitoring literature in adults, that for children is significantly less. The ACT, which is most commonly used to assess CPB
anticoagulation, is also prolonged by hypothermia, hemodilution, platelet dysfunction, and low coagulation factor levels (111,112). Because of the decreased fibrinogen levels
associated with hemodilution, the ACT in children will overestimate the anti-factor IIa and Xa effects of heparin (113,114). It has been suggested that the Hepcon Hemostasis
Management System (Hepcon HMS, Medtronic Inc., Minneapolis, MN), which is less dependent than the ACT on variations in dilutional hypofibrinogenemia, is a better assessment
of anticoagulation in children (115). With the Hepcon HMS, the heparin dose-response test (HDR) determines a patient’s ACT responsiveness to heparin and using an estimate of
patient blood volume determines a heparin dose necessary to reach the target heparin concentration (THC) which will result in an ACT ≥480 seconds. Using the HDR, it has been
observed that the heparin dose necessary to obtain a therapeutic heparin concentration for CPB in infants and young children (<5 years) is greater than that necessary in older
children (>5 years) and adults (>14 years) (107). In addition, the THC needed for young children (1-5 years) is significantly greater than that needed in the infant, older child, and
adult groups (116). This was interpreted to be consistent with reduced heparin sensitivity in this age group (111). The ability of a standardized dose of 400 units/kg of UFH to
adequately suppress thrombin formation in neonates has been questioned as well (117).
The Hepcon also performs a heparin protamine titration by measuring clotting times enhanced by addition of thromboplastin in several channels that contain varying quantities of
protamine. The first channel to clot is the channel in which the protamine-to-heparin neutralization ratio is closest to one. The absolute clotting time is not important; only the
determination of the channel with the appropriate ratio. Therefore, the determination should be independent of nonheparin factors that prolong the ACT. Assuming a protamine-to-
heparin neutralization ratio of 1:1, this method allows determination of the whole-blood heparin level. Whole-blood heparin concentrations as measured by this method and plasma
heparin concentrations as measured by anti-Xa chromogenic substrate assay correlate well in children (118).
These and future studies must be interpreted in light of the following:
1. For a given THC, the initial dose of heparin in units/kg or mg/kg would be expected to be higher in neonates/infants and young children than in older children and adults because
of the greater blood volume-to-total mass ratio in the youngest children.
2. Children exhibit increased clearance of heparin and increased binding of UFH to acute phase proteins as compared to adults (119,120).
3. Thrombin generation in newborns is inhibited at substantially lower concentrations of UFH than in children and adults (121).
4. Neonatal thrombin generation is only 30% to 50% of peak adult thrombin generation and thrombin generation remains reduced by 25% throughout childhood (122,123). This is
the direct result of reduced plasma levels of prothrombin. The hemostatic system remains in balance despite this because in conjunction with a reduced ability to generate
thrombin there are concomitant reductions in the levels of the anticoagulants AT-III, tissue factor pathway inhibitor (TFPI), and protein C (123,124). An age-dependent increase in
both pro- and anticoagulant activity allows the hemostatic system to remain in balance as the child matures.
5. Low levels of AT-III are present in neonates/infants and AT-III does not reach adult levels until 3 to 6 months of age. It has been demonstrated that despite low AT-III levels in
infants, heparin has a more pronounced anticoagulant effect as compared to adults (125). This observation is in keeping with the concept that it is the balance between
procoagulant and anticoagulant factors that is important and not the absolute level of any one factor.
Most institutions use an age- or weight-based protocol to administer the initial pre-CPB dose of heparin and add heparin to the CPB prime as the prime volume would be expected to
decrease plasma heparin levels with initiation of CPB (126,127). Typical doses are 300 to 400 units/kg to achieve an ACT >480 seconds pre-CPB. The CPB circuit commonly
contains 3U of heparin for each mL of prime volume. Recent evidence suggests that this approach results in inferior clinical outcomes as compared to use of the Hepcon HMS with a
protocol modified for use in infants (128). Heparin should always be given via a central venous line from which blood return can be easily demonstrated or, as is common in
infants/neonates, directly into the heart (usually the right atrium) by the surgeon. This is necessary to ensure that the heparin dose has reached the central circulation. An ACT can
be drawn within minutes of heparin administration as peak arterial ACT prolongation occurs within 30 seconds and peak venous ACT prolongation within 60 seconds (129).
Protamine Reversal of Heparin

Dosing
Protamine is a polyvalent cation derived from salmon sperm that is used to neutralize systemic heparinization. Protamine is normally given after bypass once stable hemodynamics is
exhibited and the surgeon is satisfied with the repair. Protamine should not be administered until the likelihood that having to reinstitute CPB is minimal. After protamine
P.672
neutralization of heparin begins, the cardiotomy suction should not be used. This practice ensures the usefulness of the bypass circuit should reinstitution of bypass be required.
The venous cannulae are usually removed before protamine administration. The arterial cannula remains until adequate hemostasis is achieved and circuit blood is no longer
required.
There are several approaches to the neutralization of heparin with protamine, all with reportedly good clinical results (130). Some centers use a ratio of 1.0 to 1.3 mg of protamine
for each 100 units (1 mg) of heparin determined to exist at the termination of CPB. This ratio is based on the in vitro protamine-to-heparin neutralization ratio of 1.3:1.0. The amount
of heparin present is determined by obtaining an ACT when CPB terminates and using reverse extrapolation of the patient’s heparin dose-response curve to correlate ACT and
heparin dose. This method has been criticized because the ACT obtained at the termination of CPB is prolonged by factors other than heparin, such as CPB-induced
thrombocytopenia, platelet dysfunction, and hemodilution of coagulation factors. This may result in an overestimation of the amount of heparin present at the termination of CPB and
a larger than necessary protamine dose.
Some centers simply administer a fixed dose of protamine based on the patient’s weight (3-4 mg/kg) regardless of the heparin dose administered, whereas others administer 1.0 to
1.3 mg of protamine for each 100 units of heparin administered. Obviously, these methods do not rely on any post-CPB assessment of residual heparin effect, such as the ACT, to
determine the protamine dose. Nonetheless, these methods have been shown to result in adequate heparin reversal. In the case of the fixed-dose regimen, heparin reversal is
obtained at much lower protamine doses than predicted by the reverse extrapolation method.
Some centers use heparin assays and then calculate the protamine dose based on the patient’s blood volume and a protamine-to-heparin neutralization ratio ranging from 1:1 to
1.3:1. Despite the fact that not all heparin present in blood exerts an anticoagulant effect and need to be neutralized, this method has been shown to provide adequate heparin
reversal with low doses of protamine. Other centers use Hepcon automated heparin protamine titration as previously described. In theory, this method should allow determination of
the appropriate dose of protamine independent of the nonheparin parameters that prolong ACT. It has recently been demonstrated that this method allows low-dose administration of
protamine and better preservation of platelet function than a fixed-dose regimen (131).
The ACT should be checked after administration of the selected protamine dose keeping in mind that, particularly in infants, ACT prolongation may be due to factors other than the
presence of residual UFH (118). Comparison of a heparinase or protamine dose assay-orange (PDA-O) ACT (International Technidyne Corporation, Edison, NJ) and native ACT will
allow UFH effect to be isolated from these other causes. Excess protamine is clearly detrimental to platelet function by nature of its inhibitory effects on the platelet receptor
GPIb/IX/V interaction with von Willebrand factor (vWF), which is a critical component of platelet adhesion and aggregation (132,133,134). In addition, the anticoagulant effect of
protamine is exacerbated by thrombocytopenia and low FVIII levels (135). Administration of additional protamine is not benign and tends to delay detection and treatment of
thrombocytopenia, platelet dysfunction, and coagulation factor deficiencies by the surgical team.
Protamine Reactions
The incidence of protamine reactions in children following cardiac surgery is substantially lower than that in adults. A retrospective analysis of 1,249 children revealed the incidence
of hypotension (at least 25% decrease in mean arterial pressure) following protamine administration to be 1.76% to 2.88% depending on the stringency of criteria linking the episode
to protamine administration (136). In this series, no episodes of pulmonary hypertension or right ventricular dysfunction were noted. There is a report of pulmonary hypertension and
cardiovascular collapse in a 6-week-old infant following protamine administration (137). Clinical experience indicates that pulmonary hypertensive episodes in children following
protamine administration are rare but can happen. The management of protamine reactions is described in Chapter 21.
Routine administration of calcium in conjunction with protamine cannot be advocated in pediatric patients, given the low incidence of hypotensive responses and the questionable
efficacy of calcium in attenuating these episodes. Calcium chloride administered as a bolus prior to protamine administration offered no hemodynamic advantage (blood pressure
and heart rate changes) over calcium chloride administered in conjunction with protamine in a group of 151 pediatric patients (138). The absence of a placebo group in this study
leaves unanswered the question as to whether calcium chloride administration offers any advantage over placebo during the administration of protamine in children.
Heparin-Induced Thrombocytopenia
Management of children who require anticoagulation for CPB in the presence of acute or subacute heparin-induced thrombocytopenia associated with the presence of anti-platelet
factor 4 antibodies is, as in adults, problematic (139). A number of different approaches have been used: delaying surgery if possible until antibodies titers have disappeared (140),
use of UFH in conjunction with high doses of intravenous epoprostenol to suppress platelet function (141), and use of the direct thrombin inhibitors argatroban and bivalirudin as an
alternative to UFH (142,143,144,145,146,147,148,149,150). Use of epoprostenol requires simultaneous infusion of norepinephrine to counteract the vasodilating effects of the drug.
Neither of the direct thrombin inhibitors have an antidote but in vivo metabolism of bivalirudin makes it preferable to
P.673
argatroban, the elimination of which is dependent on hepatic metabolism. Caution must be taken to avoid stasis of blood in every component of the CPB circuit (cardiotomy/venous
reservoir, hemoconcentrator, tubing), the chest cavity, the pericardial well, and in all vascular conduits when bivalirudin is utilized as thrombosis will occur. Additionally, use of CPB
circuit components coated with heparin, such as tubing and in-line blood gas monitoring cuvettes, are contraindicated. Finally, cell saver devices must utilize an alternate
anticoagulant such as citrate.
MANAGEMENT OF POST CARDIOPULMONARY BYPASS BLEEDING

Hemostasis following termination of CPB and protamine administration can be problematic for a number of reasons. Many of the surgical procedures involve long suture lines in
vessels with systemic pressures. In addition, portions of the suture line such as the posterior aortic wall may be concealed or difficult to reach, making detection and control of the
bleeding site challenging. Apart from the well-known effects of CPB on the coagulation system, many patients have preexisting coagulation and fibrinolytic defects.
Preexisting Coagulation Defects

Cyanosis
Cyanosis has been implicated in the genesis of coagulation and fibrinolytic defects, particularly when secondary erythrocytosis produces a hematocrit greater than 60%. Defects
include thrombocytopenia (decreased production and survival time), platelet dysfunction (decreased response to mediators of aggregation, deficient GPIb/IX/V receptors), and
coagulation factor abnormalities (low levels of fibrinogen and factors II, VII, IX, X, XI, and XII) (146,147,149,150,151). Coagulation factor abnormalities appear to occur with lower
frequency than platelet defects, but the full extent of coagulation factor abnormalities is unknown because this issue has been incompletely studied. Although chronic disseminated
intravascular coagulation (DIC) has been proposed as a mechanism leading to a coagulopathic state in cyanotic heart disease (152), more recent data do not substantiate the
presence of chronic DIC (153). Poor cardiac output rather than cyanosis per se may be a risk factor for DIC.
On the procoagulant side, evidence documents the overproduction of platelet microparticles in erythrocytotic patients (hematocrit >60%) with CHD (137). Microparticles are cellular
fragments that are the result of exocytotic budding and which contain both cytoplasmic and membrane components. These microparticles express FVa and FXa and are highly
procoagulant. Microparticle formation occurs as a result of the high microvascular shear forces which accompany erythrocytosis and can be reduced via hematocrit reduction with
therapeutic phlebotomy (154).
Hypofibrinogenemia and Dysfunctional Fibrinogen

Hypofibrinogenemia is known to exist in a substantial number of neonates pre-CPB (155). In neonates, fibrinogen is present in a fetal form that has a higher sialic acid content than
adult fibrinogen (156), and a recent TEG study demonstrated that the fibrinogen of neonates and infants undergoing cardiac surgery is dysfunctional as compared to older children
and adults (157).
von Willebrand Factor

Neonatal platelet adhesion under shear conditions is enhanced as compared to adults due to the presence of larger, more adhesive vWF multimers (158). Loss of the highest-
molecular-weight multimers of vWF has been identified in children with CHD and is associated with prolonged bleeding times (159,160). Loss of these multimers appears to occur
with greater frequency with cyanosis although this association has not been rigorously investigated (160).
Platelet Dysfunction
In addition to the functional platelet defects induced by CPB, platelet defects inherent to normal infants and to those with CHD are present. Platelets undergo an age-dependent
maturation process. Specifically, the platelets of preterm and term infants have fewer pseudopods, smaller glycogen deposits, less visible microtubular structures, and markedly less
a-granules than platelets of children and adults (161). Associated with these morphologic deficiencies is diminished reactivity to thrombin (a very potent platelet agonist),
epinephrine/ADP, collagen, and thromboxane A2 (151). These defects are more prominent in low birth weight (LBW) and premature infants, a subset of patients commonly seen in
high-volume pediatric cardiac centers (148).
Bypass-Induced Coagulopathy
The extent to which dilution of platelets and coagulation factors occur depends on the size of the patient, the extent of preexisting thrombocytopenia and factor deficiencies, and the
volume and composition of the bypass circuit prime.
In small patients, platelet functional defects induced by CPB are overshadowed by the presence of bypass-induced dilutional thrombocytopenia. Dilutional thrombocytopenia is a
problem in neonates and infants given the relatively large CPB prime volumes and the absence of platelets in all prime solutions except fresh, unrefrigerated whole blood. Whole
blood stored for more than 48 hours at 4°C using ACD or CPD is devoid of platelets.
At our institution, where reconstituted whole blood (<7 days old) is used for the pump prime, we have consistently found a 50% to 80% immediate post-CPB reduction in
preoperative platelet count. Obviously, the largest reductions are seen in the smallest patients undergoing the longest procedures (159).
In the past, with a large (750 mL) aged whole-blood prime, initiation of CPB in neonates was associated with a 70%
P.674
reduction in platelet count and a 50% reduction in levels of coagulation factors and anti-thrombin III (155). Dilution of coagulation factors in neonates/infants is less likely if the pump
prime consists of whole blood or reconstituted whole blood (packed red blood cells and fresh frozen plasma) (162). However, even in the current era, in neonates with a small-
volume prime (340-465 mL) with nonfresh or reconstituted whole blood to reach a dilutional hematocrit of 30%, there is a clinically significant dilutional thrombocytopenia (˜60% at
initiation of CPB and 70%-80% just prior to termination of bypass) and a less significant reduction in Factors II, V, VII, IX, X, plasminogen and anti-thrombin III (163). Significant
dilution of coagulation factors is more likely if an asanguinous prime is used. Dilution of coagulation factors and red blood cells can be mitigated by use of conventional or MUF.
Blood Component Therapy

As fresh whole blood with functional platelets is rarely available, therapy for treatment of post-CPB coagulopathies requires component therapy such as packed red blood cells
(PRBCs) in conjunction with platelets and cryoprecipitate. This strategy allows efficient correction of coagulopathies and anemia using small volumes. This is particularly important in
small patients where transfusion volume is constrained and dilutional anemia can accompany component therapy.
Platelets
Platelet transfusions of 0.5 to 1.0 units/kg may be necessary to normalize the post-CPB platelet count (250-600 K/μL) in neonates/infants. Thrombocytopenia just prior to termination
of CPB or following protamine administration has been consistently demonstrated to correlate with excessive postoperative blood loss in children (164,165,166). Since platelets are
suspended in fresh frozen plasma (FFP), platelet transfusions in these patients also provide a substantial FFP transfusion. The minimum volume of FFP suspension for 1 unit of
platelets is 20 mL (concentrated platelets), while the usual volume of a platelet unit is 40 mL. As such, a 2-unit platelet transfusion would provide a 4-kg patient with a 10- to 20-
mL/kg FFP transfusion.
Fresh Frozen Plasma

It has been observed in children that FFP transfusion following platelet transfusion is not effective in restoring hemostasis (and may in fact exacerbate bleeding), but cryoprecipitate
transfusion following platelet transfusion is effective in restoring hemostasis (164). This may be due to the fact that the deficiencies that exist after platelet transfusion are not
addressed by FFP because FFP has already been given as part of the platelet transfusion and additional FFP in neonates/infants and small children will likely also induce a
dilutional thrombocytopenia. Additionally, transfusion of FFP in neonates does not reliably increase thrombin generation (167).
Cryoprecipitate
Cryoprecipitate contains fibrinogen, factor VIII/vWF, and factor XIII. One unit of cryoprecipitate (20-30 mL) contains 150 mg of fibrinogen and 80 to 120 units of Factor VIII/vWF. This
quantity of fibrinogen is comparable to what would be found in 75 mL of FFP, and this quantity of factor VIII/vWF is comparable to what would be found in 80 to 120 mL of FFP. In
small patients where volume constraints limit transfusion volumes, cryoprecipitate is therefore a much more efficient source of fibrinogen and factor VIII/vWF. Cryoprecipitate, 0.5 to
1.0 units/kg, is transfused for bleeding that persists following normalization of the platelet count. Transfusion of cryoprecipitate will correct the hypofibrinogenemia that exists
following termination of CPB; hypofibrinogenemia is correlated with postoperative blood loss (164). Cryoprecipitate transfusion may offer an additional benefit as well. Unpublished
data from our institution demonstrates that hypofibrinogenemia following platelet transfusion is uncommon given a reconstituted whole-blood (PRBCs with plasma) CPB prime and
the FFP transfusion that accompanies platelet transfusion. The clinical effectiveness of cryoprecipitate may be related to the transfusion of factor VIII/vWF. It is now appreciated that
surgical hemostasis is dependent on, and initiated by, formation of an initial platelet thrombus in a severed arteriole. This process involves platelets, vascular endothelium, integrin
and nonintegrin adhesion receptors and their ligands. Wall shear rates in severed arterioles are high (1,700/seconds) and tethering, translocation, and stable arrest of platelets
leading to platelet adhesion and aggregation in arterioles require at least four platelet receptors (GPVI, GPIb/IX/V, GPIa/IIa, GPIIb/IIIa) and three ligands (vWF, collagen, fibrinogen)
(168).
Antifibrinolytic Agents
The continued generation of thrombin during CPB despite heparinization is largely responsible for induction of ongoing fibrinolysis. Adjuvant therapy to improve hemostasis post-
CPB is directed toward use of antifibrinolytic agents. Plasminogen contains 5 lysine-binding domains or kringles that allow it to bind to the lysine residues on fibrin. Fibrinbound
plasminogen is subsequently cleaved to plasmin by tissue plasminogen activator (tPA). Plasmin is the activated form of plasminogen and is a serine protease. Sequential cleavage
of fibrin by plasmin is responsible for fibrinolysis. tPA also contains lysine-binding domains that allow binding to fibrin. Free tPA is capable of converting fibrin-bound plasminogen to
plasmin, but tPA bound to fibrin stimulates activation of plasminogen to plasmin by two orders of magnitude.
The lysine analogs e-aminocaproic acid (EACA) and tranexamic acid (TXA) inhibit fibrinolysis by (1) binding to plasminogen, thus rendering it incapable of binding to the lysine
residues on fibrin, and (2) reducing the rate of conversion of plasminogen to plasmin by tPA. TXA is 6 to 10 times
P.675
more potent than EACA. The reduction in plasmin generation is also beneficial in that plasmin is a potent platelet activator (169). Subsequent to plasmin-induced platelet activation,
the platelet adhesion molecule GPIb/IX/V undergoes proteolysis or translocation away from the platelet surface.
In adults, the pharmacokinetics of both TXA and EACA (as well as aprotinin) has been elucidated and dose regimens to establish desired plasma levels determined (170,171,172). In
children, such determinations are more complicated given the large variability in patient size, type of operative procedure, age-related distribution and elimination kinetics, bypass
prime volume, and the use of ultrafiltration. There are anecdotal reports of adverse thrombotic events such as shunt thrombosis and premature fenestration closure associated with
use of lysine analogs and aprotinin in children. However, to date, there exists little objective evidence to accurately quantify the risk of such events with use of these agents. One
study has demonstrated that perioperative use of TXA or EACA is not a risk factor in the genesis of premature fenestration closure in Fontan patients (173).
ε-Aminocaproic Acid
The pharmacokinetics of EACA in children undergoing repair of CHD has been studied in a group of eight patients ranging in age from 5 months to 4 years, in weight from 7.2 to
18.9 kg, and with CPB prime volumes of 650 to 850 mL (174). The authors concluded that a bolus of 75 mg/kg over 10 minutes followed by a continuous infusion of 75 mg/kg/hr and
75 mg/kg added to the CPB prime would maintain a constant therapeutic plasma concentration (>130 μg/mL). In adults, an EACA loading dose of 50 mg/kg by infusion over 20
minutes and a maintenance infusion of 25 mg/kg/hr would be needed to maintain the same target concentration (170). Two large studies have demonstrated the effectiveness of
EACA, administered as a 100-mg/kg patient bolus, 100 mg/kg added to the CPB prime, and 33 mg/kg/hr for 3 hours following termination of CPB, in reducing the time to sternal
closure, 24-hour blood loss, use of homologous blood, and the surgical reexploration rate as compared to placebo in primary and reoperative pediatric cardiac surgical patients
(175,176). In a group of 140 cyanotic and acyanotic children (average age 7-8 years) undergoing reoperation, EACA was administered as a 150-mg/kg patient bolus with a
continuous intraoperative infusion of 30 mg/kg/hr. Compared to placebo, EACA reduced intraoperative blood loss and the surgical reexploration rate but was not effective in reducing
mediastinal drainage or homologous transfusion requirements (177).
TABLE 28.7. Dosing schedules required to reach low-, intermediate-, and high-plasma concentrations of tranexamic acid according to patient ag
Age Low (20 μg/mL) Intermediate (60 μg/mL) High (150 μg/mL)
0-2 mo
Loading 15 mg/kg 50 mg/kg 120 mg/kg

dose
Infusion 2.5 mg/kg/hr 7 mg/kg/hr 17 mg/kg/hr
CPB 20 μg/mL of 60 μg/mL of prime volume 150 μg/mL of prime volume

Prime prime volume
dose
2-12
mo
Loading 9 26 65
dose (6,7,8,9,10,11,12) (20,21,22,23,24,25,26,27,28,29,30) (45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77
mg/kg mg/kg mg/kg
Infusion 2 mg/kg/hr 6 mg/kg/hr 14 mg/kg/hr

prime prime volume
dose
>12 mo
and
≤20 kg
Loading 4 mg/kg 13 mg/kg 31 mg/kg

dose
Infusion 2 mg/kg/hr 5.5 mg/kg/hr 14 mg/kg/hr

prime prime volume
dose
Tranexamic Acid
In a dose-finding study, Chauhan et al. (178) found an effective dosing regimen to be 10 mg/kg patient bolus, 10 mg/kg in the CPB prime, and 10 mg/kg after protamine
administration. Tranexamic acid in a single dose of 50 mg/kg prior to skin incision has been shown in two studies at one institution to be either marginally effective or ineffective in
reducing blood loss and homologous transfusion requirements in pediatric cardiac surgical patients (153,179). In children undergoing reoperative procedures, TXA in a dose of 100
mg/kg patient bolus over 30 minutes, a continuous intraoperative infusion of 10 mg/kg/hr and 100 mg/kg in the CPB prime, was found to be superior to placebo in reducing blood
loss, total transfusion requirements, and total donor unit exposure (180,181). The plasma TXA concentrations in the aforementioned studies were not measured. Recently,
pharmacokinetic modeling in children aged 1 to 12 years demonstrated that a
P.676
bolus dose of 6.4 mg/kg followed by a weight-adjusted infusion of 2.0 to 3.1 mg/kg/hr was necessary to achieve an as-yet clinically unsubstantiated target plasma concentration of
20 μg/mL (181).
A more recent population pharmacokinetic analysis has been conducted of TXA in neonates, infants, and young children undergoing cardiac surgery where the routine clinical
practices of hypothermia, DHCA, CUF, and MUF were used (182). The dosing schedules required to reach low-, intermediate-, and high-plasma concentrations of TXA are shown in
Table 28.7.
CONCLUSION
Cardiopulmonary bypass for neonates, infants, and children undergoing surgery for congenital heart disease has unique characteristics when compared to correction of
acquired heart disease in adults (183). Patients differ widely in age, size, type of lesion, and vulnerability to physiologic trespass. Acid-base management and ultrafiltration
techniques are different, and strategies for bypass vary amongst surgeons. For more detailed information on pediatric perfusion the reader is referred to reference 183.
KEY Points
Pediatric perfusion necessitates a greater size selection of cardiopulmonary bypass (CPB) circuit components than adult perfusion. Limitation of prime volume is central in
the design of pediatric bypass circuits.
The arterial pump may be roller head or centrifugal head. Roller heads have the advantage of low prime volumes and precise control of flow rates, but because they
operate independently of vascular and system resistance have a higher risk for circuit disruption. Centrifugal heads theoretically cause less damage to the formed
elements of blood and carry a lower risk of massive air embolism, but because they are afterloadsensitive there is less control of flow rate with changes in vascular or
system resistance; additionally, they have increased prime volumes and are more expensive.
Oxygenators in modern systems are integrated with the venous reservoir and cardiotomy system, the heat exchanger, and at times the ALF. Membrane oxygenators made
up of microporous polypropylene tubes (200-300 μm diameter with 0.03-0.07 μm hydrophobic pores) with countercurrent flow are used nearly universally for pediatric
CPB. The gas transfer capabilities for oxygen and the maximum recommended blood flow rate determine the size of oxygenator used for a particular child. Negative
pressure in the oxygenator can lead to air embolism by the drawing of air across the microporous membrane.
The venous reservoir may be open to the atmosphere or sealed, and although integrated with the cardiotomy system, it has a dedicated filter to process venous return
from the patient. Cardiotomy suction is an important source of blood conservation, with the collected blood passing through a higher-capacity dedicated filter into the
venous reservoir. Roller head pumps are used for cardiotomy suction and ventricular venting.
Heat exchangers are necessary for active cooling and rewarming and are integrated into the oxygenator system to reduce prime volume. A stainless steel or plastic barrier
separates the counter-current flow of water and blood. The temperature gradient between the venous blood and water inlet is normally kept below 10°C to prevent gas
coming out of solution.
ALFs consist of a screen filter with a pore size of 20 to 40 μm to trap particulate matter and air, and are most commonly positioned distal to the oxygenator rather than
integrated with it.
Tubing sizes must include diameters from ⅛ to ½ inches. Custom tubing packs are essential for minimizing size and prime volume while assuring reasonable system
pressure so as not to damage the blood or increase the risk of tubing disconnect. Tubing packs are determined by anticipated pump flow and line lengths required within a
CPB setup.
Surface modification of tubing, cannulas, and oxygenators with heparin or other agents is widely used despite a lack of solid evidence relating this practice to improved
clinical outcomes.
Arterial cannulas are sized by outer diameter, ranging from 6 to 24F, and commonly have wire-bound bodies to resist kinking. Venous cannulas commonly have side port
holes in addition to tip holes and are rated for achievable flow based on a maximum pressure drop with GSD of 35-40 mm Hg across their length. Venous drainage is
typically provided by bicaval cannulation.
Hemofilters are commonly added to the circuit to filter blood by removing water, low-molecular-weight solutes, and inflammatory mediators. Hemofilters consist of a core of
microporous hollow fibers with the pore sizes allowing molecules of 60,000 to 70,000 Da to pass through.
Prime volume of a CPB circuit is a simple function of adding the prime volume of the various components utilized. The lowest volume components that can safely provide the
anticipated maximum flow rates and gas exchange, with some performance reserve, are chosen.
The circuit is commonly flushed with CO2 and then primed with a crystalloid solution, a process that helps ensure that the components and their connections are not
leaking and visually free of air.
The degree of hemodilution, the dilutional hematocrit, is calculated as follows:
P.677
Many institutions maintain a minimum hematocrit of 24% at the onset of bypass and a target of 24% to 35% during bypass.
Cardiopulmonary bypass is initiated by release of the circuit arterial limb clamp and increasing pump flow to the arterial cannula, followed by assessment of venous drainage.
The limitations of small venous cannulas and bypass tubing, with the desire for small prime volumes, have led to increased use of augmented venous return with VAVD or
KAVD.
The initial phase of CPB is partial in that only a portion of the systemic venous return to the heart drains into the bypass circuit. Two requirements for effective partial
bypass are a beating and ejecting heart and lung ventilation.
Total CPB occurs when nearly all of the venous return to the heart is diverted to the bypass circuit. Total CPB requires bicaval cannulation and caval snares.
Flow rates during CPB are chosen to provide adequate systemic oxygen delivery at the patient’s temperature. Full-flow rates are 150-200 mL/kg/min for neonates and 100-
150 mL/kg/min for infants and children. Systemic hypothermia is routinely employed during pediatric bypass although it is being used less in the current surgical era.
Global and regional cerebral hypoperfusion is a bigger concern in the pediatric population than macro- and microembolism of atherosclerotic debris. Together with the use of
lower temperatures and the leftward shift of the oxyhemoglobin curve, and the decrease in pulmonary vascular resistance caused by alkalosis, most pediatric centers use a
pH-stat strategy for blood gas management.
Some centers advocate the use of normoxia during CPB to limit the ischemia-reperfusion injury associated with generation of reactive oxygen species, while others use
hyperoxia as animal studies have shown increased brain injury with a normoxic strategy.
Ultrafiltration enhances fluid management by removing excess water and solutes to increase hematocrit and to decrease circulating inflammatory mediators, leading to
improved myocardial and respiratory function postbypass. Techniques, which may be used alone or in combination, include PBUF, ZBUF, CUF, and MUF.
Low-flow CPB is a technique that involves reducing flow rates at moderate-to-deep hypothermia to improve surgical exposure and avoid DHCA.
DHCA involves cooling the patient to a core body temperature less than 18°C, ceasing arterial pump flow, and exsanguinating the patient’s blood volume into the bypass
venous reservoir. Although it allows for ideal visualization by the surgeon, arrest periods greater than 33 to 41 minutes are associated with adverse neurodevelopmental
outcomes. Consequently, its use today is more limited owing to the use of continuous lowflow bypass and RCP.
RCP is the technique of diverting pump arterial flow, commonly through the innominate artery, solely to the right subclavian and right common carotid arteries. Recommended
flow rates vary from about 20 to 70 mL/kg/min. Significant differences in neurodevelopmental outcome between DHCA and RCP have yet to be shown.
The magnitude and intensity of the systemic inflammatory response in neonates, infants, and small children is enhanced compared to adults, in part due to the higher circuit
surface area-to-blood volume ratio.
The management of heparin anticoagulation in neonates, infants, and young children is made more complex by the greater blood volume-to-total mass ratio, greater degree
of hemodilution, increased heparin clearance, decreased thrombin generation and its response to heparin, and lower levels of anti-thrombin III. The incidence of protamine
reactions in children is substantially lower than in adults, but severe pulmonary hypertension and cardiovascular collapse can occur.
Hypothermia, thrombocytopenia, platelet dysfunction, and low coagulation factor levels may cause a prolonged ACT following administration of protamine, in addition to
residual heparin.
Postbypass bleeding can be problematic for a number of reasons.
Long suture lines in vessels with systemic pressures, and concealed or difficult-to-reach suture lines.
Bypass-induced coagulopathy from dilutional thrombocytopenia, platelet dysfunction, and dilution of coagulation factors (especially fibrinogen and Factor VIII/vWF).
Preexisting coagulation defects in cyanotic congenital heart disease (CHD) include thrombocytopenia, platelet dysfunction, and coagulation factor abnormalities.
Hypofibrinogenemia and dysfunctional fibrinogen can exist in some neonates pre-CPB.
Loss of the highest molecular weight multimers of vWF in children with CHD is associated with decreased platelet adhesion.
Immaturity of platelet function in infants in addition to the functional defects induced by CPB.
P.678
Blood component therapy with packed red blood cells, platelets, and cryoprecipitate allows efficient correction of coagulopathies and anemia using small volumes.
Platelet transfusion of 0.5 to 1 units/kg may be necessary to normalize post-CPB platelet count in neonates and small infants.
A unit of cryoprecipitate (20-30 mL) contains 150 mg of fibrinogen and 80 to 120 units of Factor VIII/vWF. Cryoprecipitate, 0.5 to 1 units/kg, is transfused for bleeding that
persists following normalization of platelet count.
The pharmacokinetics of tranexamic acid and e-aminocaproic acid are more complicated than in adults, given the age-related distribution and elimination kinetics, large
variability in patient size, type of operative procedure, bypass prime volume, and the use of ultrafiltration.
REFERENCES
1. Harvey B, Shann KG, Fitzgerald D, et al. International pediatric perfusion practice: 2011 survey results. J Extra Corpor Technol 2012;44(4): 186-193.
2. Hoerr HR, Kraemer MF, Williams JL. In vitro comparison of the blood handling by the constrained vortex and twin roller pumps. J Extra Corpor Technol 1987;19:316-321.
3. Jakob H, Hafner G, Iversen S, et al. Reoperation and the centrifugal pump? Eur J Cardiothorac Surg 1992;6(Suppl 1):S59-S63.
4. Asante-Siaw J, Tyrrell J, Hoschtitzky A, et al. Does the use of a centrifugal pump offer any additional benefit for patients having open heart surgery? Interact Cardiovasc
Thorac Surg 2006;5(2):128-134.
5. Trocchio CR, Sketel JO. Mechanical pumps for extracorporeal circulation. In: Mora CT, ed. Cardiopulmonary bypass: principles and techniques of extracorporeal circulation.
New York, NY: Springer-Verlag, 1995:220-228.
6. Cecere G, Groom R, Forest R, et al. A 10-year review of pediatric perfusion practice in North America. Perfusion 2002;17(2):83-89.
7. Itoh H, Sano S, Pouard P. Pediatric perfusion in Japan: 2010 practice survey. Perfusion 2012;27(1):72-77.
8. Stammers AH, Trowbridge CC. Principles of oxygenator function: gas exchange, heat transfer, and operation. In: Gravlee GP, Davis RF, Stammers AH, et al. eds.
Cardiopulmonary bypass: principles and practice. 3rd ed. Philadelphia, PA: Wolters Kluwer Health/Lippincott Williams & Wilkins, 2008: 47-62.
9. Chung JH, Gikakis N, Rao AK, et al. Pericardial blood activates the extrinsic coagulation pathway during clinical cardiopulmonary bypass. Circulation 1996;93(11):2014-2018.
10. De Somer F, Van Belleghem Y, Caes F, et al. Tissue factor as the main activator of the coagulation system during cardiopulmonary bypass. J Thorac Cardiovasc Surg
2002;123(5):951-958.
11. Nieuwland R, Berckmans RJ, Rotteveel-Eijkman RC, et al. Cell-derived microparticles generated in patients during cardiopulmonary bypass are highly procoagulant.
Circulation 1997;96(10):3534-3541.
12. Philippou H, Adami A, Davidson SJ, et al. Tissue factor is rapidly elevated in plasma collected from the pericardial cavity during cardiopulmonary bypass. Thromb Haemost
2000;84(1):124-128.
13. Aldea GS, Soltow LO, Chandler WL, et al. Limitation of thrombin generation, platelet activation, and inflammation by elimination of cardiotomy suction in patients undergoing
coronary artery bypass grafting treated with heparin-bonded circuits. J Thorac Cardiovasc Surg 2002;123(4): 742-755.
14. Vermeulen Windsant IC, Hanssen SJ, Buurman WA, et al. Cardiovascular surgery and organ damage: time to reconsider the role of hemolysis. J Thorac Cardiovasc Surg
2011;142(1):1-11.
15. Sahu B, Chauhan S, Kiran U, et al. Neuropsychological function in children with cyanotic heart disease undergoing corrective cardiac surgery: effect of two different
rewarming strategies. Eur J Cardiothorac Surg 2009;35(3):505-510.
16. Newland RF, Tully PJ, Baker RA. Hyperthermic perfusion during cardiopulmonary bypass and postoperative temperature are independent predictors of acute kidney injury
following cardiac surgery. Perfusion 2013;28(3):223-231.
17. Newland RF, Baker RA, Sanderson AJ, et al. Oxygenator safety evaluation: a focus on connection grip strength and arterial temperature measurement accuracy. J Extra
Corpor Technol 2012;44(2):53-59.
18. Jensen E, Andreasson S, Bengtsson A, et al. Changes in hemostasis during pediatric heart surgery: impact of a biocompatible heparin-coated perfusion system. Ann Thorac
Surg 2004;77(3):962-967.
19. Ozawa T, Yoshihara K, Koyama N, et al. Superior biocompatibility of heparin-bonded circuits in pediatric cardiopulmonary bypass. Jpn J Thorac Cardiovasc Surg
1999;47(12):592-599.
20. Gunaydin S. Emerging technologies in biocompatible surface modifying additives: quest for physiologic cardiopulmonary bypass. Curr Med Chem Cardiovasc Hematol
Agents 2004;2(4):295-302.
21. Sniecinski RM, Chandler WL. Activation of the hemostatic system during cardiopulmonary bypass. Anesth Analg 2011;113(6):1319-1333.
22. Landis RC, Brown JR, Fitzgerald D, et al. Attenuating the systemic inflammatory response to adult cardiopulmonary bypass: a critical review of the evidence base. J
Extracorpor Technol 2014;46:197-211.
23. Groom RC, Hill AG, Kuban B, et al. Aortic cannula velocimetry. Perfusion 1995;10(3):183-188.
24. Stammers AH, Brindisi N, Kurusz M, et al. Cardiopulmonary bypass circuits: design and use. In: Hensley FA, Martin DE, Gravlee GP, eds. A practical approach to cardiac
anesthesia. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2008:528-556.
25. Journois D, Pouard P, Greeley WJ, et al. Hemofiltration during cardiopulmonary bypass in pediatric cardiac surgery. Effects on hemostasis, cytokines, and complement
components. Anesthesiology 1994;81(5):1181-1189; discussion 26A-27A.
26. McRobb CM, Mejak BL, Ellis WC, et al. Recent advances in pediatric cardiopulmonary bypass. Semin Cardiothorac Vasc Anesth 2014;18(2): 153-160.
27. Lee JW, Yoo YC, Park HK, et al. Fresh frozen plasma in pump priming for congenital heart surgery: evaluation of effects on postoperative coagulation profiles using a
fibrinogen assay and rotational thromboelastometry. Yonsei Med J 2013;54(3):752-762.
28. Wypij D, Jonas RA, Bellinger DC, et al. The effect of hematocrit during hypothermic cardiopulmonary bypass in infant heart surgery: results from the combined Boston
hematocrit trials. J Thorac Cardiovasc Surg 2008;135(2):355-360.
29. Beck JR, Park DY, Mongero LB. Cannulation and clinical concerns for cardiopulmonary bypass access. In: Mongero LB, Beck JR, eds. On bypass: advanced perfusion
techniques. Current cardiac surgery. Totowa, NJ: Humana Press; 2008:171-192.
30. Lapietra A, Grossi EA, Pua BB, et al. Assisted venous drainage presents the risk of undetected air microembolism. J Thorac Cardiovasc Surg 2000;120(5):856-862.
31. Lou S, Ji B, Liu J, et al. Generation, detection and prevention of gaseous microemboli during cardiopulmonary bypass procedure. Int J Artif Organs 2011;34(11):1039-1051.
32. Willcox TW. Vacuum-assisted venous drainage: to air or not to air, that is the question. Has the bubble burst? J Extra Corpor Technol 2002;34(1): 24-28.
33. Willcox TW, Mitchell SJ, Gorman DF. Venous air in the bypass circuit: a source of arterial line emboli exacerbated by vacuum-assisted drainage. Ann Thorac Surg
1999;68(4):1285-1289.
34. Jahangiri M, Rayner A, Keogh B, et al. Cerebrovascular accident after vacuum-assisted venous drainage in a Fontan patient: a cautionary tale. Ann Thorac Surg
2001;72(5):1727-1728.
35. Burch TM, Locke AQ. Air lock and embolism upon attempted initiation of cardiopulmonary bypass while using vacuum-assisted venous drainage. J Cardiothorac Vasc Anesth
2012;26(3):468-470.
36. Fiorucci A, Gerometta PS, DeVecchi M, et al. In vitro assessment of the vacuum-assisted venous drainage (VAVD) system: risks and benefits. Perfusion 2004;19(2):113-117.
37. Matte GS, Kussman BD, Wagner JW, et al. Massive air embolism in a Fontan patient. J Extra Corpor Technol 2011;43(2):79-83.
P.679
38. Wang S, Undar A. Vacuum-assisted venous drainage and gaseous microemboli in cardiopulmonary bypass. J Extra Corpor Technol 2008;40(4): 249-256.
39. Durandy Y. Vacuum-assisted venous drainage, angel or demon: PRO? J Extra Corpor Technol 2013;45(2):122-127.
40. Rosomoff HL, Holaday DA. Cerebral blood flow and cerebral oxygen consumption during hypothermia. Am J Physiol 1954;179(1):85-88.
41. Andropoulos DB, Stayer SA, Diaz LK, et al. Neurological monitoring for congenital heart surgery. Anesth Analg 2004;99(5):1365-1375.
42. Kussman BD, Wypij D, DiNardo JA, et al. Cerebral oximetry during infant cardiac surgery: evaluation and relationship to early postoperative outcome. Anesth Analg
2009;108(4):1122-1131.
43. Murkin JM, Arango M. Near-infrared spectroscopy as an index of brain and tissue oxygenation. Br J Anaesth 2009;103(Suppl 1):i3-i13.
44. Jonas RA. Conduct of cardiopulmonary bypass. In: Comprehensive surgical management of congenital heart disease. 2nd ed. Boca Raton, FL: CRC Press, 2014:181-206.
45. Swan H. The importance of acid-base management for cardiac and cerebral preservation during open heart operations. Surg Gynecol Obstet 1984;158(4):391-414.
46. Greeley WJ, Ungerleider RM, Kern FH, et al. Effects of cardiopulmonary bypass on cerebral blood flow in neonates, infants, and children. Circulation 1989;80(3, Part
1):I209-I215.
47. Kern FH, Ungerleider RM, Quill TJ, et al. Cerebral blood flow response to changes in arterial carbon dioxide tension during hypothermic cardiopulmonary bypass in children.
J Thorac Cardiovasc Surg 1991;101(4):618-622.
48. Hindman BJ, Dexter F, Cutkomp J, et al. pH-stat management reduces the cerebral metabolic rate for oxygen during profound hypothermia (17 degrees C). A study during
cardiopulmonary bypass in rabbits. Anesthesiology 1995;82(4):983-995; discussion 24A.
49. Greeley WJ, Kern FH, Ungerleider RM, et al. The effect of hypothermic cardiopulmonary bypass and total circulatory arrest on cerebral metabolism in neonates, infants, and
children. J Thorac Cardiovasc Surg 1991;101(5):783-794.
50. Woodcock TE, Murkin JM, Farrar JK, et al. Pharmacologic EEG suppression during cardiopulmonary bypass: cerebral hemodynamic and metabolic effects of thiopental or
isoflurane during hypothermia and normothermia. Anesthesiology 1987;67(2):218-224.
51. Kurth CD, O'Rourke MM, O'Hara IB, et al. Brain cooling efficiency with pH-stat and alpha-stat cardiopulmonary bypass in newborn pigs. Circulation 1997;96(9, Suppl):II-358-
II-363.
52. Kirshbom PM, Skaryak LR, DiBernardo LR, et al. pH-stat cooling improves cerebral metabolic recovery after circulatory arrest in a piglet model of aortopulmonary collaterals.
J Thorac Cardiovasc Surg 1996;111(1):147-155; discussion 56-57.
53. Allen BS, Rahman S, Ilbawi MN, et al. Detrimental effects of cardiopulmonary bypass in cyanotic infants: preventing the reoxygenation injury. Ann Thorac Surg
1997;64(5):1381-1387; discussion 7-8.
54. Caputo M, Mokhtari A, Rogers CA, et al. The effects of normoxic versus hyperoxic cardiopulmonary bypass on oxidative stress and inflammatory response in cyanotic
pediatric patients undergoing open cardiac surgery: a randomized controlled trial. J Thorac Cardiovasc Surg 2009;138(1):206-214.
55. Ihnken K, Morita K, Buckberg GD, et al. Studies of hypoxemic/reoxygenation injury: without aortic clamping. II. Evidence for reoxygenation damage. J Thorac Cardiovasc
Surg 1995;110(4, Part 2):1171-1181.
56. Nollert G, Jonas RA, Reichart B. Optimizing cerebral oxygenation during cardiac surgery: a review of experimental and clinical investigations with near infrared
spectrophotometry. Thorac Cardiovasc Surg 2000;48(4):247-253.
57. Picichè M, Fadel E, Kingma JG Jr, et al. Blood flow to the heart from noncoronary arteries: an intriguing but challenging research field. Cardiovasc Revasc Med
2012;13(1):25-29.
58. Osthaus WA, Sievers J, Breymann T, et al. Bicarbonate buffered ultrafiltration leads to a physiologic priming solution in pediatric cardiac surgery. Interact Cardiovasc Thorac
Surg 2008;7(6):969-972.
59. Sever K, Tansel T, Basaran M, et al. The benefits of continuous ultrafiltration in pediatric cardiac surgery. Scand Cardiovasc J 2004;38(5):307-311.
60. Naik SK, Knight A, Elliott MJ. A successful modification of ultrafiltration for cardiopulmonary bypass in children. Perfusion 1991;6(1):41-50.
61. Myers GJ, Leadon RB, Mitchell LB, et al. Simple modified ultrafiltration. Perfusion 2000;15(5):447-452.
62. Thompson LD, McElhinney DB, Findlay P, et al. A prospective randomized study comparing volume-standardized modified and conventional ultrafiltration in pediatric cardiac
63. Ungerleider RM, Shen I. Optimizing response of the neonate and infant to cardiopulmonary bypass. Semin Thorac Cardiovasc Surg Pediatr Card Surg Annu 2003;6:140-
146.
64. Davies MJ, Nguyen K, Gaynor JW, et al. Modified ultrafiltration improves left ventricular systolic function in infants after cardiopulmonary bypass. J Thorac Cardiovasc Surg
1998;115(2):361-369; discussion 9-70.
65. Gaynor JW. The effect of modified ultrafiltration on the postoperative course in patients with congenital heart disease. Semin Thorac Cardiovasc Surg Pediatr Card Surg
Annu 2003;6:128-139.
66. Kameyama T, Ando F, Okamoto F, et al. The effect of modified ultrafiltration in pediatric open heart surgery. Ann Thorac Cardiovasc Surg 2000;6(1):19-26.
67. Mahmoud AB, Burhani MS, Hannef AA, et al. Effect of modified ultrafiltration on pulmonary function after cardiopulmonary bypass. Chest 2005;128(5):3447-3453.
68. Rivera ES, Kimball TR, Bailey WW, et al. Effect of veno-venous ultrafiltration on myocardial performance immediately after cardiac surgery in children. A prospective
randomized study. J Am Coll Cardiol 1998;32(3):766-772.
69. Williams GD, Ramamoorthy C, Chu L, et al. Modified and conventional ultrafiltration during pediatric cardiac surgery: clinical outcomes compared. J Thorac Cardiovasc Surg
2006;132(6):1291-1298.
70. Journois D, Israel-Biet D, Pouard P, et al. High-volume, zero-balanced hemofiltration to reduce delayed inflammatory response to cardiopulmonary bypass in children.
71. Bando K, Turrentine MW, Vijay P, et al. Effect of modified ultrafiltration in high-risk patients undergoing operations for congenital heart disease. Ann Thorac Surg
1998;66(3):821-827; discussion 828.
72. Bando K, Vijay P, Turrentine MW, et al. Dilutional and modified ultrafiltration reduces pulmonary hypertension after operations for congenital heart disease: a prospective
randomized study. J Thorac Cardiovasc Surg 1998;115(3):517-525; discussion 25-27.
73. Chaturvedi RR, Shore DF, White PA, et al. Modified ultrafiltration improves global left ventricular systolic function after open-heart surgery in infants and children. Eur J
Cardiothorac Surg 1999;15(6):742-746.
74. Hiramatsu T, Imai Y, Kurosawa H, et al. Effects of dilutional and modified ultrafiltration in plasma endothelin-1 and pulmonary vascular resistance after the Fontan procedure.
Ann Thorac Surg 2002;73(3):861-865.
75. Maluf MA. Modified ultrafiltration in surgical correction of congenital heart disease with cardiopulmonary bypass. Perfusion 2003;18(Suppl 1): 61-68.
76. Maluf MA, Mangia C, Silva C, et al. Conventional and conventional plus modified ultrafiltration during cardiac surgery in high-risk congenital heart disease. J Cardiovasc
Surg (Torino) 2001;42(4):465-473.
77. Darling E, Nanry K, Shearer I, et al. Techniques of paediatric modified ultrafiltration: 1996 survey results. Perfusion 1998;13(2):93-103.
78. Deptula J, Gaynor JW, Groneck J, et al. Alleviating heat loss associated with modified ultrafiltration. J Extra Corpor Technol 2002;34(2):88-91.
79. Despotis GJ, Levine V, Filos KS, et al. Hemofiltration during cardiopulmonary bypass: the effect on anti-Xa and anti-IIa heparin activity. Anesth Analg 1997;84(3):479-483.
80. Hodges UM, Berg S, Naik SK, et al. Filtration of fentanyl is not the cause of the elevation of arterial blood pressure associated with post-bypass ultrafiltration in children. J
81. Ramamoorthy C, Lynn AM. Con: the use of modified ultrafiltration during pediatric cardiovascular surgery is not a benefit. J Cardiothorac Vasc Anesth 1998;12(4):483-485.
82. Williams GD, Ramamoorthy C, Totzek FR, et al. Comparison of the effects of red cell separation and ultrafiltration on heparin concentration during pediatric cardiac surgery.
J Cardiothorac Vasc Anesth 1997;11(7): 840-844.
83. Anttila V, Hagino I, Zurakowski D, et al. Specific bypass conditions determine safe minimum flow rate. Ann Thorac Surg 2005;80(4):1460-1467.
84. Fox LS, Blackstone EH, Kirklin JW, et al. Relationship of whole body oxygen consumption to perfusion flow rate during hypothermic cardiopulmonary bypass. J Thorac
85. Rebeyka IM, Coles JG, Wilson GJ, et al. The effect of low-flow cardiopulmonary bypass on cerebral function: an experimental and clinical study. Ann Thorac Surg
1987;43(4):391-396.
86. Kern FH, Ungerleider RM, Reves JG, et al. Effect of altering pump flow rate on cerebral blood flow and metabolism in infants and children. Ann Thorac Surg
1993;56(6):1366-1372.
P.680
87. Zimmerman AA, Burrows FA, Jonas RA, et al. The limits of detectable cerebral perfusion by transcranial Doppler sonography in neonates undergoing deep hypothermic low-
flow cardiopulmonary bypass. J Thorac Cardiovasc Surg 1997;114(4):594-600.
88. Munoz R, Laussen PC, Palacio G, et al. Changes in whole blood lactate levels during cardiopulmonary bypass for surgery for congenital cardiac disease: an early indicator
of morbidity and mortality. J Thorac Cardiovasc Surg 2000;119(1):155-162.
89. Kist-van Holthe tot Echten JE, Goedvolk CA, Doornaar MB, et al. Acute renal insufficiency and renal replacement therapy after pediatric cardiopulmonary bypass surgery.
Pediatr Cardiol 2001;22(4):321-326.
90. Forbess JM, Visconti KJ, Hancock-Friesen C, et al. Neurodevelopmental outcome after congenital heart surgery: results from an institutional registry. Circulation
2002;106(12, Suppl 1):I95-I102.
91. Bellinger DC, Wypij D, Rivkin MJ, et al. Adolescents with d-transposition of the great arteries corrected with the arterial switch procedure/clinical perspective. Circulation
2011;124(12):1361-1369.
92. Pigula FA, Nemoto EM, Griffith BP, et al. Regional low-flow perfusion provides cerebral circulatory support during neonatal aortic arch reconstruction. J Thorac Cardiovasc
Surg 2000;119(2):331-339.
93. Andropoulos DB, Hunter JV, Nelson DP, et al. Brain immaturity is associated with brain injury before and after neonatal cardiac surgery with highflow bypass and cerebral
oxygenation monitoring. J Thorac Cardiovasc Surg 2010;139(3):543-556.
94. Andropoulos DB, Stayer SA, McKenzie ED, et al. Novel cerebral physiologic monitoring to guide low-flow cerebral perfusion during neonatal aortic arch reconstruction. J
95. Algra SO, Jansen NJ, van der Tweel I, et al. Neurological injury after neonatal cardiac surgery: a randomized, controlled trial of 2 perfusion techniques. Circulation
2014;129(2):224-233.
96. Andropoulos DB, Easley RB, Brady K, et al. Neurodevelopmental outcomes after regional cerebral perfusion with neuromonitoring for neonatal aortic arch reconstruction.
Ann Thorac Surg 2013;95(2):648-654; discussion 54-55.
97. Goldberg CS, Bove EL, Devaney EJ, et al. A randomized clinical trial of regional cerebral perfusion versus deep hypothermic circulatory arrest: outcomes for infants with
functional single ventricle. J Thorac Cardiovasc Surg 2007;133(4):880-887.
98. Guo Z, Hu RJ, Zhu DM, et al. Usefulness of deep hypothermic circulatory arrest and regional cerebral perfusion in children. Ther Hypothermia Temp Manag 2013;3(3):126-
131.
99. Brix-Christensen V. The systemic inflammatory response after cardiac surgery with cardiopulmonary bypass in children. Acta Anaesthesiol Scand 2001;45(6):671-679.
100. Seghaye MC. The clinical implications of the systemic inflammatory reaction related to cardiac operations in children. Cardiol Young 2003;13(3):228-239.
101. Allen ML, Peters MJ, Goldman A, et al. Early postoperative monocyte deactivation predicts systemic inflammation and prolonged stay in pediatric cardiac intensive care. Crit
Care Med 2002;30(5):1140-1145.
102. Ben-Abraham R, Weinbroum AA, Dekel B, et al. Chemokines and the inflammatory response following cardiopulmonary bypass—a new target for therapeutic intervention?
—a review. Paediatr Anaesth 2003;13(8):655-661.
103. Warren OJ, Watret AL, de Wit KL, et al. The inflammatory response to cardiopulmonary bypass, Part 2: anti-inflammatory therapeutic strategies. J Cardiothorac Vasc
Anesth 2009;23(3):384-393.
104. Baig K, Nassar R, Craig DM, et al. Complement factor 1 inhibitor improves cardiopulmonary function in neonatal cardiopulmonary bypass. Ann Thorac Surg
2007;83(4):1477-1482; discussion 83.
105. Tassani P, Kunkel R, Richter JA, et al. Effect of C1-esterase-inhibitor on capillary leak and inflammatory response syndrome during arterial switch operations in neonates. J
106. Miyaji K, Hannan RL, Ojito J, et al. Heparin-coated cardiopulmonary bypass circuit: clinical effects in pediatric cardiac surgery. J Card Surg 2000;15(3):194-198.
107. Deptula J, Glogowski K, Merrigan K, et al. Evaluation of biocompatible cardiopulmonary bypass circuit use during pediatric open heart surgery. J Extra Corpor Technol
2006;38(1):22-26.
108. Robertson-Malt S, Afrane B, El Barbary M. Prophylactic steroids for pediatric open heart surgery. Cochrane Database Syst Rev 2007(4):CD005550.
109. Pasquali SK, Hall M, Li JS, et al. Corticosteroids and outcome in children undergoing congenital heart surgery: analysis of the Pediatric Health Information Systems
database. Circulation 2010;122(21):2123-2130.
110. Pasquali SK, Li JS, He X, et al. Perioperative methylprednisolone and outcome in neonates undergoing heart surgery. Pediatrics 2012;129(2): e385-e391.
111. Chan AK, Leaker M, Burrows FA, et al. Coagulation and fibrinolytic profile of paediatric patients undergoing cardiopulmonary bypass. Thromb Haemost 1997;77(2):270-
277.
112. Huyzen RJ, van Oeveren W, Wei F, et al. In vitro effect of hemodilution on activated clotting time and high-dose thrombin time during cardiopulmonary bypass. Ann Thorac
Surg 1996;62(2):533-537.
113. Martindale SJ, Shayevitz JR, D'Errico C. The activated coagulation time: suitability for monitoring heparin effect and neutralization during pediatric cardiac surgery. J
114. Owings JT, Pollock ME, Gosselin RC, et al. Anticoagulation of children undergoing cardiopulmonary bypass is overestimated by current monitoring techniques. Arch Surg
2000;135(9):1042-1047.
115. Guzzetta NA, Bajaj T, Fazlollah T, et al. A comparison of heparin management strategies in infants undergoing cardiopulmonary bypass. Anesth Analg 2008;106(2):419-
425.
116. D'Errico C, Shayevitz JR, Martindale SJ. Age-related differences in heparin sensitivity and heparin-protamine interactions in cardiac surgery patients. J Cardiothorac Vasc
Anesth 1996;10(4):451-457.
117. Guzzetta NA, Miller BE, Todd K, et al. An evaluation of the effects of a standard heparin dose on thrombin inhibition during cardiopulmonary bypass in neonates. Anesth
Analg 2005;100(5):1276-1282.
118. Guzzetta NA, Monitz HG, Fernandez JD, et al. Correlations between activated clotting time values and heparin concentration measurements in young infants undergoing
cardiopulmonary bypass. Anesth Analg 2010;111(1): 173-179.
119. Monagle P, Michelson AD, Bovill E, et al. Antithrombotic therapy in children. Chest 2001;119(1, Suppl):344S-370S.
120. Revel-Vilk S, Chan AK. Anticoagulation therapy in children. Semin Thromb Hemost 2003;29(4):425-432.
121. Chan AK, Berry LR, Monagle PT, et al. Decreased concentrations of heparinoids are required to inhibit thrombin generation in plasma from newborns and children
compared to plasma from adults due to reduced thrombin potential. Thromb Haemost 2002;87(4):606-613.
122. Andrew M, Schmidt B, Mitchell L, et al. Thrombin generation in newborn plasma is critically dependent on the concentration of prothrombin. Thromb Haemost
1990;63(1):27-30.
123. Andrew M, Vegh P, Johnston M, et al. Maturation of the hemostatic system during childhood. Blood 1992;80(8):1998-2005.
124. Cvirn G, Gallistl S, Leschnik B, et al. Low tissue factor pathway inhibitor (TFPI) together with low antithrombin allows sufficient thrombin generation in neonates. J Thromb
Haemost 2003;1(2):263-268.
125. Dietrich W, Braun S, Spannagl M, et al. Low preoperative antithrombin activity causes reduced response to heparin in adult but not in infant cardiac-surgical patients.
Anesth Analg 2001;92(1):66-71.
126. Andrew M, MacIntyre B, MacMillan J, et al. Heparin therapy during cardiopulmonary bypass in children requires ongoing quality control. Thromb Haemost 1993;70(6):937-
941.
127. Turner-Gomes SO, Nitschmann EP, Norman GR, et al. Effect of heparin loading during congenital heart operation on thrombin generation and blood loss. Ann Thorac Surg
1997;63(2):482-488.
128. Gruenwald CE, Manlhiot C, Chan AK, et al. Randomized, controlled trial of individualized heparin and protamine management in infants undergoing cardiac surgery with
cardiopulmonary bypass. J Am Coll Cardiol 2010;56(22):1794-1802.
129. Heres EK, Speight K, Benckart D, et al. The clinical onset of heparin is rapid. Anesth Analg 2001;92(6):1391-1395.
130. Despotis GJ, Gravlee G, Filos K, et al. Anticoagulation monitoring during cardiac surgery: a review of current and emerging techniques. Anesthesiology 1999;91(4):1122-
1151.
131. Shigeta O, Kojima H, Hiramatsu Y, et al. Low-dose protamine based on heparin-protamine titration method reduces platelet dysfunction after cardiopulmonary bypass. J
132. Barstad RM, Stephens RW, Hamers MJ, et al. Protamine sulphate inhibits platelet membrane glycoprotein Ib-von Willebrand factor activity. Thromb Haemost
2000;83(2):334-337.
133. Carr ME Jr, Carr SL. At high heparin concentrations, protamine concentrations which reverse heparin anticoagulant effects are insufficient to reverse heparin anti-platelet
effects. Thromb Res 1994;75(6):617-630.
P.681
134. Mochizuki T, Olson PJ, Szlam F, et al. Protamine reversal of heparin affects platelet aggregation and activated clotting time after cardiopulmonary bypass. Anesth Analg
1998;87(4):781-785.
135. Bolliger D, Szlam F, Azran M, et al. The anticoagulant effect of protamine sulfate is attenuated in the presence of platelets or elevated factor VIII concentrations. Anesth
Analg 2010;111(3):601-608.
136. Seifert HA, Jobes DR, Ten Have T, et al. Adverse events after protamine administration following cardiopulmonary bypass in infants and children. Anesth Analg
2003;97(2):383-389.
137. Boigner H, Lechner E, Brock H, et al. Life threatening cardiopulmonary failure in an infant following protamine reversal of heparin after cardiopulmonary bypass. Paediatr
Anaesth 2001;11(6):729-732.
138. Muangmingsuk V, Tremback TF, Muangmingsuk S, et al. The effect on the hemodynamic stability of varying calcium chloride administration during protamine infusion in
pediatric open-heart patients. Anesth Analg 2001;93(1):92-95.
139. Warkentin TE, Greinacher A. Heparin-induced thrombocytopenia and cardiac surgery. Ann Thorac Surg 2003;76(6):2121-2131.
140. Schreiber C, Dietrich W, Braun S, et al. Use of heparin upon reoperation in a pediatric patient with heparin-induced thrombocytopenia after disappearance of antibodies.
Clin Res Cardiol 2006;95(7):379-382.
141. von Heymann C, Hagemeyer E, Kastrup M, et al. Heparin-induced thrombocytopenia type II in an infant with a congenital heart defect—anticoagulation during
cardiopulmonary bypass with epoprostenol sodium and heparin. Pediatr Crit Care Med 2006;7(4):383-385.
142. Almond CS, Harrington J, Thiagarajan R, et al. Successful use of bivalirudin for cardiac transplantation in a child with heparin-induced thrombocytopenia. J Heart Lung
Transplant 2006;25(11):1376-1379.
143. Argueta-Morales IR, Olsen MC, DeCampli WM, et al. Alternative anticoagulation during cardiovascular procedures in pediatric patients with heparin-induced
thrombocytopenia. J Extra Corpor Technol 2012;44(2):69-74.
144. Dragomer D, Chalfant A, Biniwale R, et al. Novel techniques in the use of bivalirudin for cardiopulmonary bypass anticoagulation in a child with heparin-induced
thrombocytopenia. Perfusion 2011;26(6):516-518.
145. Dyke PC II, Russo P, Mureebe L, et al. Argatroban for anticoagulation during cardiopulmonary bypass in an infant. Paediatr Anaesth 2005;15(4):328-333.
146. Odegard KC, Zurakowski D, DiNardo JA, et al. Prospective longitudinal study of coagulation profiles in children with hypoplastic left heart syndrome from stage I through
Fontan completion. J Thorac Cardiovasc Surg 2009;137(4):934-941.
147. Odegard KC, Zurakowski D, Hornykewycz S, et al. Evaluation of the coagulation system in children with two-ventricle congenital heart disease. Ann Thorac Surg
2007;83(5):1797-1803.
148. Rajasekhar D, Barnard MR, Bednarek FJ, et al. Platelet hyporeactivity in very low birth weight neonates. Thromb Haemost 1997;77(5):1002-1007.
149. Ware JA, Reaves WH, Horak JK, et al. Defective platelet aggregation in patients undergoing surgical repair of cyanotic congenital heart disease. Ann Thorac Surg
1983;36(3):289-294.
150. Wedemeyer AL, Edson JR, Krivit W. Coagulation in cyanotic congenital heart disease. Am J Dis Child 1972;124(5):656-660.
151. Rajasekhar D, Kestin AS, Bednarek FJ, et al. Neonatal platelets are less reactive than adult platelets to physiological agonists in whole blood. Thromb Haemost
1994;72(6):957-963.
152. Ihenacho HN, Fletcher DJ, Breeze GR, et al. Consumption coagulopathy in congenital heart-disease. Lancet 1973;1(7797):231-234.
153. Levin E, Wu J, Devine DV, et al. Hemostatic parameters and platelet activation marker expression in cyanotic and acyanotic pediatric patients undergoing cardiac surgery in
the presence of tranexamic acid. Thromb Haemost 2000;83(1):54-59.
154. Horigome H, Hiramatsu Y, Shigeta O, et al. Overproduction of platelet microparticles in cyanotic congenital heart disease with polycythemia. J Am Coll Cardiol
2002;39(6):1072-1077.
155. Kern FH, Morana NJ, Sears JJ, et al. Coagulation defects in neonates during cardiopulmonary bypass. Ann Thorac Surg 1992;54(3):541-546.
156. Kuhle S, Male C, Mitchell L. Developmental hemostasis: pro- and anticoagulant systems during childhood. Semin Thromb Hemost 2003;29(4):329-338.
157. Miller BE, Tosone SR, Guzzetta NA, et al. Fibrinogen in children undergoing cardiac surgery: is it effective? Anesth Analg 2004;99(5):1341-1346.
158. Israels SJ, Rand ML, Michelson AD. Neonatal platelet function. Semin Thromb Hemost 2003;29(4):363-372.
159. Gill JC, Wilson AD, Endres-Brooks J, et al. Loss of the largest von Willebrand factor multimers from the plasma of patients with congenital cardiac defects. Blood
1986;67(3):758-761.
160. Turner-Gomes SO, Andrew M, Coles J, et al. Abnormalities in von Willebrand factor and antithrombin III after cardiopulmonary bypass operations for congenital heart
disease. J Thorac Cardiovasc Surg 1992;103(1): 87-97.
161. Michelson AD. Platelet function in the newborn. Semin Thromb Hemost 1998;24(6):507-512.
162. Manno CS, Hedberg KW, Kim HC, et al. Comparison of the hemostatic effects of fresh whole blood, stored whole blood, and components after open heart surgery in
children. Blood 1991;77(5):930-936.
163. Hornykewycz S, Odegard KC, Castro RA, et al. Hemostatic consequences of a non-fresh or reconstituted whole blood small volume cardiopulmonary bypass prime in
neonates and infants. Paediatr Anaesth 2009;19(9):854-861.
164. Miller BE, Mochizuki T, Levy JH, et al. Predicting and treating coagulopathies after cardiopulmonary bypass in children. Anesth Analg 1997;85(6):1196-1202.
165. Williams GD, Bratton SL, Ramamoorthy C. Factors associated with blood loss and blood product transfusions: a multivariate analysis in children after open-heart surgery.
Anesth Analg 1999;89(1):57-64.
166. Williams GD, Bratton SL, Riley EC, et al. Coagulation tests during cardiopulmonary bypass correlate with blood loss in children undergoing cardiac surgery. J Cardiothorac
Vasc Anesth 1999;13(4):398-404.
167. Hyytiainen S, Syrjala M, Fellman V, et al. Fresh frozen plasma reduces thrombin formation in newborn infants. J Thromb Haemost 2003;1(6):1189-1194.
168. Tabuchi N, Tigchelaar I, van Oeveren W. Shear-induced pathway of platelet function in cardiac surgery. Semin Thromb Hemost 1995;21(Suppl 2):66-70.
169. Ervin AL, Peerschke EI. Platelet activation by sustained exposure to low-dose plasmin. Blood Coagul Fibrinolysis 2001;12(6):415-425.
170. Butterworth J, James RL, Lin Y, et al. Pharmacokinetics of epsilon-aminocaproic acid in patients undergoing aortocoronary bypass surgery. Anesthesiology
1999;90(6):1624-1635.
171. Dowd NP, Karski JM, Cheng DC, et al. Pharmacokinetics of tranexamic acid during cardiopulmonary bypass. Anesthesiology 2002;97(2):390-399.
172. Nuttall GA, Fass DN, Oyen LJ, et al. A study of a weight-adjusted aprotinin dosing schedule during cardiac surgery. Anesth Analg 2002;94(2):283-289.
173. Gruber EM, Shukla AC, Reid RW, et al. Synthetic antifibrinolytics are not associated with an increased incidence of baffle fenestration closure after the modified Fontan
procedure. J Cardiothorac Vasc Anesth 2000;14(3): 257-259.
174. Ririe DG, James RL, O'Brien JJ, et al. The pharmacokinetics of epsilon-aminocaproic acid in children undergoing surgical repair of congenital heart defects. Anesth Analg
2002;94(1):44-49.
175. Chauhan S, Kumar BA, Rao BH, et al. Efficacy of aprotinin, epsilon aminocaproic acid, or combination in cyanotic heart disease. Ann Thorac Surg 2000;70(4):1308-1312.
176. Rao BH, Saxena N, Chauhan S, et al. Epsilon aminocaproic acid in paediatric cardiac surgery to reduce postoperative blood loss. Indian J Med Res 2000;111:57-61.
177. Williams GD, Bratton SL, Riley EC, et al. Efficacy of epsilon-aminocaproic acid in children undergoing cardiac surgery. J Cardiothorac Vasc Anesth 1999;13(3):304-308.
178. Chauhan S, Bisoi A, Kumar N, et al. Dose comparison of tranexamic acid in pediatric cardiac surgery. Asian Cardiovasc Thorac Ann 2004;12(2):121-124.
179. Zonis Z, Seear M, Reichert C, et al. The effect of preoperative tranexamic acid on blood loss after cardiac operations in children. J Thorac Cardiovasc Surg
1996;111(5):982-987.
180. Reid RW, Zimmerman AA, Laussen PC, et al. The efficacy of tranexamic acid versus placebo in decreasing blood loss in pediatric patients undergoing repeat cardiac
surgery. Anesth Analg 1997;84(5):990-996.
181. Grassin-Delyle S, Couturier R, Abe E, et al. A practical tranexamic acid dosing scheme based on population pharmacokinetics in children undergoing cardiac surgery.
182. Wesley MC, Pereira LM, Scharp LA, et al. Pharmacokinetics of tranexamic acid in neonates, infants, and children undergoing cardiac surgery with cardiopulmonary bypass.
183. Matte GS. Perfusion for congenital heart surgery: notes on cardiopulmonary bypass for a complex patient population. Hoboken, NJ: John Wiley & Sons, 2015:224.
Chapter 29
Myocardial Protection for Neonates and Infants
Paul J. Chai
Barry D. Kussman
INTRODUCTION
The goal of myocardial protection in pediatric cardiac surgery is to allow for a technically perfect repair without
cardiac injury. Essentially all intracardiac repairs in neonates and infants require a period of ischemia to provide
an immobile and bloodless field (1). Whatever technique is used, the principle is to maintain a favorable balance
between myocardial oxygen supply and demand. It is important to be aware that myocardial protection is not
limited to the period of ischemia during cardiopulmonary bypass (CPB), and includes optimum management of
the patient preoperatively, intraoperatively before and after any myocardial ischemia, and in the postoperative
period. Multiple factors in addition to myocardial preservation influence postoperative cardiac output and
outcome.
Pediatric myocardial protection differs from that of adults in a number of significant ways. The immature heart
has differences in structure and function, and as the myocardium matures, fundamental changes occur that
directly influence the ability of the heart to withstand periods of ischemia and injury. Although coronary artery
occlusion is rare, many congenital cardiac anomalies are associated with impaired myocardial function
(“stressed” myocardium) before reparative surgery. Myocardial protection techniques must be tailored to the age
of the patient, the cardiac physiology, and the complexity of the surgical procedure in order to achieve the best
outcomes.
BIOLOGY OF MYOCARDIAL INJURY AND PROTECTION

Factors to consider with respect to the biology of myocardial injury and protection are listed in Table 29.1.
Physiologic Differences between Immature and Mature Myocardium

The precise age of crossover from the immature myocardium of the neonate and infant to the mature
myocardium of the child and adult is not well defined (1). Differences in structure and function between immature
and mature hearts have implications for myocardial protection during ischemia. The normal neonatal myocardium
is generally considered to be more resistant to ischemia than mature myocardium (2,3,4,5). However, the
“stressed” myocardium is thought to be more sensitive to ischemia. The physiologic differences allowing
immature myocardium greater tolerance to ischemia have been reviewed by Doenst et al. and are considered
below (6) (Table 29.2).
TABLE 29.1. Biology of myocardial protection
Immature vs. mature myocardium
Energy substrate
Calcium metabolism
Enzyme activity
Catecholamine sensitivity
Ischemic preconditioning
Normal vs. stressed heart
Hypoxia and cyanosis
Heart failure
Ventricular hypertrophy (pressure and volume overload)
Ischemia-reperfusion injury
Coronary vascular dysfunction
Nonischemic causes of myocardial injury
Ventricular distension
Retraction injury
Myocardial edema
Ventriculotomy
Coronary artery injury
Energy Substrate
Myocardium derives its energy production, adenosine triphosphate (ATP), from various sources that include free
fatty acids, glucose, glycogen, lactate, pyruvate, ketones, and amino acids. In the adult heart under aerobic
conditions, 95% of energy production is from oxidation of long-chain fatty acids (7). In contrast, glucose is the
main substrate for the neonatal heart, and is supplemented by oxidation of fatty acids, lactate, ketones, and
amino acids (8). The timing of the shift in substrate preference from glucose to fatty acids varies
P.684
between species and is thought to be due to upregulation of 5′-adenosine monophosphate-activated protein
kinase (9). During this period of development, the neonatal myocardium shows a progressive decline in glucose
uptake which can be stimulated by insulin, that is, insulin resistance and a much greater capacity to store
glycogen (10). The greater ability of the immature myocardium to utilize anaerobic glycolysis may partially
account for the greater tolerance to ischemia. Laboratory and clinical studies in adults have found that enhanced
glucose uptake and oxidation is associated with enhanced functional myocardial recovery, despite normalization
of fatty acid oxidation (6).
TABLE 29.2. Physiologic differences between pediatric and adult myocardium and the
potential impact of these differences on ischemia tolerance of the pediatric heart
Potential impact on ischemia

Pediatric Adult tolerance in the pediatric heart
Preferred substrate for adenosine Glucose Fatty Increase

triphosphate production acids
Glycogen content High Low Increase
Insulin sensitivity Impaired Normal a
Calcium handling (intracellular) Impaired Normal a
Calcium sensitivity Increased Normal Decreasea
Antioxidant defense Low High Decrease
5′ nucleotidase Low High Increase
Catecholamine sensitivity Low Normal a
Ischemic preconditioning Absent Present a
aPotential effect unknown.
Reprinted from Doenst T, Schlensak C, Beyersdorf F. Cardioplegia in pediatric cardiac surgery: do we

believe in magic? Ann Thorac Surg 2003;75: 1668-77, with permission.
Calcium Metabolism
Immature myocardium is significantly more sensitive to and dependent on extracellular calcium than adult
myocardium (Fig. 29.1). The sarcoplasmic reticulum in immature myocardium is less well developed and the
sarcoplasmic reticular Ca2+-ATPase activity is also reduced. The result is a reduced storage capacity for
calcium, reduced calcium uptake into the sarcoplasmic reticulum, and decreased calcium release following
ryanodine receptor activation. Therefore, there is greater dependence on movement of calcium from the
extracellular to the intracellular space (11,12,13,14). The decreased capacity for calcium sequestration may
explain why the immature myocardium is susceptible to postischemic calcium overload. Several studies have
found adverse effects with cardioplegia solutions containing normal or high concentrations of calcium (15,16).
Most cardioplegia solutions in use currently contain very low levels of calcium (17,18,19,20,21).
Enzyme Activity
Two enzyme systems seem to be important for myocardial protection during periods of ischemia: the antioxidant
system and 5′ nucleotidase. The antioxidant system includes superoxide dismutase, catalase, and glutathione
reductase and is responsible for scavenging the oxygen-derived free radicals generated during reperfusion.
Reactive oxygen species (ROS), which comprise superoxide, hydrogen peroxide, hydroxyl radical, and lipid
peroxides, cause peroxidation of phospholipids in cell membranes leading to loss of cellular integrity and
function. In addition to enzyme depletion during long periods of ischemia, the activity of this enzyme system is
reduced in immature myocardium (22). Another study, however, found significantly increased baseline catalase
activity and reduced xanthine oxidase activity in newborn rat heart (23). Neonates with tetralogy of Fallot have a
significant reduction in the activity of antioxidant enzymes (24), and may be at even greater risk.
The enzyme 5′ nucleotidase catalyzes the conversion of adenosine monophosphate (AMP) to adenosine. While
AMP is unable to pass through the cell membrane, adenosine passes easily and is rapidly lost to the extracellular
space, thereby depleting the adenine nucleotide pool (AMP, ADP, and ATP). The size of this adenine nucleotide
pool is important for, though not predictive of, postischemic recovery of the myocardium (25,26,27). The 5′
nucleotidase system is reduced in immature myocardium and may be an additional explanation as to why
immature myocardium is more tolerant to ischemia (28). If the pool is depleted more than 50%, immediate full
recovery of contractile function is not possible (27,29,30).
P.685
FIGURE 29.1. Sources of calcium regulation. Calcium entry via the L-type Ca2+ channel causes Ca2+ release
from the sarcoplasmic reticulum (SR) via the ryanodine receptor (Ca-induced Ca release) and activation of
contraction. Calcium is pumped back into the SR by SR Ca2+-ATPase and extruded from the cell by activating
the Na+-Ca2+-exchanger to allow relaxation. Calcium can also enter mitochondria via a Ca2+ uniporter.
(Reprinted from Levitsky S, McCully JD. Myocardial protection. In: Sellke FW, del Nido PJ, Swanson SJ, eds.
Sabiston & Spencer surgery of the chest. 8th ed. Philadelphia, PA: Saunders Elsevier, 2010:977-998, Figure 63-
4 (p. 980), with permission.)
Catecholamine Sensitivity
The sensitivity to catecholamines is decreased in immature hearts. An in vitro study found evidence to suggest
that this is due to functionally incomplete coupling of myocardial β-adrenergic receptors to adenylate cyclase at
birth (31). In contrast, the kinetics of cyclic AMP hydrolysis and the inhibitory potential of phosphodiesterase
inhibitors were not affected by age. Whether this decreased catecholamine sensitivity plays a role in tolerance to
ischemia is uncertain.
Ischemic Preconditioning
Ischemic preconditioning can be defined as the adaptive mechanism induced by a brief period of reversible
ischemia increasing the heart’s resistance to a subsequent longer period of ischemia (32). Although protective
for older age groups, ischemic preconditioning was not found to be effective in the newborn rat heart (33).
Conversely, chronic hypoxia is associated with reduced tolerance to myocardial ischemia.
Normal versus Stressed Myocardium

Although normal neonatal myocardium may be more tolerant to an ischemic insult than adult myocardium, this
tolerance does not seem to be present in hearts that have been stressed by exposure to severe hypoxemia,
chronic cyanosis, ventricular hypertrophy, or refractory heart failure (15,34,35,36,37,38,39). These myocardial
stressors are frequently present in neonates and infants and are associated with depletion of high-energy
phosphates, glycogen, and Kreb’s cycle intermediates (40). Volume and pressure loading increase myocardial
oxygen demand, and ventricular hypertrophy can result in relative hypoperfusion of the subendocardium.
Cyanotic lesions with decreased pulmonary blood flow tend to have aortopulmonary collaterals that during CPB
increase left heart return, rewarm the heart, and washout cardioplegia. Stressed myocardium translates into
greater depression of systolic and diastolic function following ischemia and reperfusion injury. As myocardial
energy stores in normal piglet hearts have been found to differ between individuals, some unstressed hearts may
be more susceptible to ischemia (41).
Ischemia-Reperfusion Injury
The heart is an obligate aerobic organ with injury to the myocardium occurring during both ischemia and
reperfusion. Oxygen and the production of ATP are necessary for the external mechanical work of contraction
and basal metabolism (unloaded contraction) (42). Myosin ATPase is required for the development of wall
tension, sarcoplasmic Ca2+-ATPase for the sequestration of calcium, and Na+-K+-ATPase for the maintenance of
the membrane potential. Experimentally, myocardial oxygen consumption (MVo2) in different states in the
neonate differs somewhat from what studies in adult hearts have shown. MVo2 (expressed in mL of O2 per 100 g
of ventricular
P.686
tissue per minute) averaged 6.7 mL in the working state (adult 8 mL), 3.2 mL in the empty beating state (adult 5.6
mL), 1.3 mL in the potassium-arrested heart at 37°C (adult 1.1 mL), 0.37 mL in the hypothermic (15°C) heart, and
0.32 mL in the hypothermic (15°C) potassium-arrested heart (43,44).
Ischemia-reperfusion injury involves multiple cellular and extracellular processes and is reviewed in detail
elsewhere (18). Briefly, ischemia and reperfusion are associated with the depletion of ATP, intracellular acidosis,
intracellular calcium overload, inflammation, myocardial edema, generation of ROS, and endothelial dysfunction.
Reversible ischemia-reperfusion injury may occur as “stunning” (contractile dysfunction persisting after normal or
near-normal reperfusion in the absence of cell damage) or “hibernation” (reversible chronically reduced
contractile function) .
Putative mechanisms involved in ischemia-reperfusion injury are shown in Figure 29.2. The calcium hypothesis
is based on the inability of the myocyte to regulate intracellular and intraorganellular calcium concentration such
that increased calcium activates a cascade of events resulting in cell dysfunction, cell injury, and/or cell death.
The free-radical hypothesis suggests that accumulation of ROS during the early stages of reperfusion causes
myocyte injury through peroxidation of the cellular phospholipid layers. The lethal reperfusion injury hypothesis
has been described in adults in the setting of acute coronary occlusion and refers to the death of myocardial
cells that were viable immediately before reperfusion (45). It presupposes that during reperfusion the biochemical
and metabolic changes compound the changes produced during the period of ischemia and interact with each
other to mediate cardiomyocyte death through the opening of the mitochondrial permeability transition pore
(PTP) and the induction of cardiomyocyte hypercontracture (46). The mitochondrial PTP is a nonselective
channel of the inner mitochondrial membrane whereby channel opening minimizes the mitochondrial membrane
potential leading to uncoupling of oxidative phosphorylation, ATP depletion, and cell death (47).
FIGURE 29.2. Mechanisms of ischemia-reperfusion injury. Putative mechanisms of the calcium and free-radical
hypotheses and inflammation in the generation of ischemia-reperfusion injury. ROS, reactive oxygen species.
(Reprinted from Levitsky S, McCully JD. Myocardial protection. In: Sellke FW, del Nido PJ, Swanson SJ, eds.
Sabiston & Spencer surgery of the chest. 8th ed. Philadelphia, PA: Saunders Elsevier, 2010:977-998, Figure 63-
3 (p. 980), with permission.)
Coronary Vascular Dysfunction

Endothelial cells regulate microcirculatory vascular tone by promoting vascular relaxation and inhibiting platelet
function (48). Ischemia-reperfusion and the systemic inflammatory response to CPB are associated with
endothelial injury and impaired release of nitric oxide (NO), prostacyclin, and adenosine. NO is a potent smooth
muscle relaxant and inhibitor of platelet and neutrophil adhesion, and is thought to be an important component in
the recovery of myocardial
P.687
(and pulmonary) function as a result of ischemia-reperfusion injury and the associated endothelial dysfunction
(49). In neonatal lambs, the addition of L-arginine (NO precursor) or nitroglycerine (NO donor) during reperfusion
resulted in significantly higher preload recruitable stroke work and cardiac index (50). A clinical practice at
Boston Children’s Hospital is to start a nitroglycerine infusion (1 μg/kg/min) 5 to 10 minutes before removal of the
aortic cross-clamp and continue it until the end of rewarming.
Nonischemic Causes of Myocardial Injury

Ventricular Distension
There is a general feeling among pediatric cardiac surgeons that immature myocardium is significantly more
vulnerable to stretch injury. Stretch injury typically occurs with overdistension of the left heart and excessive
retraction on myocardial tissues, causing ventricular injury and contractile dysfunction. It can also lead to
distension of the left atrium and pulmonary veins, resulting in elevated pulmonary transcapillary pressure and
development of significant pulmonary edema and pulmonary dysfunction. Ventricular distension can occur with
aortic valve insufficiency prior to cross-clamping the aorta. Excessive pulmonary venous return in the setting of
reduced heart rate and myocardial function, ventricular fibrillation during cooling, or multiple aortopulmonary
collaterals can also cause distension of the left ventricle.
The cardiac surgeon needs to be acutely aware of instances when distension of the left heart can occur. Slow
cooling with maintenance of ventricular ejection until application of the aortic cross-clamp is important in the
setting of aortic insufficiency. Inspection and palpation of the main pulmonary artery and left ventricle, as well as
massage of the left ventricle, are important. Left heart venting should be performed either through the right
superior pulmonary vein or through an atrial septal defect to keep left atrial and ventricular pressures low. The
safest time to insert a left atrial vent is after the aortic cross-clamp is applied in order to prevent entrainment of
air into the left ventricle and ejection into the systemic circulation. Depending on the etiology, pulmonary venous
return can be reduced by preoperative coil occlusion of collaterals, shunt, or PDA ligation after commencement
of CPB, or opening of the pulmonary artery on CPB. An instant measure to reduce left ventricular distension is
having the perfusionist quickly drop the flow rate and perfusion pressure until the issue is resolved. Removal of
the left heart vent can also result in entrainment of air, and so should only occur when the heart is contracting
and the patient is on partial bypass with the left heart filled with blood above atmospheric pressure.
Retraction Injury
Excessive retraction to improve exposure can injure the myocardium and conduction system. Retraction force of
assistants needs to be monitored and adjusted as necessary.
Myocardial Edema
Myocardial edema can result from ischemia and reperfusion injury, delivery pressure of cardioplegia,
cardioplegia osmolarity and chemical composition, excessive hemodilution, the inflammatory response to CPB,
impaired myocardial lymphatic drainage, and handling of the myocardium (18,51). Myocardial edema causes
impaired diastolic function.
Ventriculotomy
A ventriculotomy is a component of some surgical repairs and may cause direct myocardial injury and
dysfunction. Typical operations include repair of tetralogy of Fallot, some ventricular septal defects, and
placement of a right ventricle-to-pulmonary artery conduit.
Coronary Artery Injury

Injury to the coronary arteries may occur during reimplantation (arterial switch operation, aortic root/ascending
aorta surgery), incisions in the anterior wall of the right ventricle (some cases of tetralogy of Fallot), or mitral
valve surgery. Reoperations also pose a risk of coronary artery injury.
TECHNIQUES FOR MYOCARDIAL PROTECTION

There is no clear consensus concerning the optimal strategy for myocardial protection in the neonate and infant.
Although strategies and composition of cardioplegia vary significantly from center to center, hypothermia for
reduction of metabolic activity and cardioplegia for electrical and contractile arrest is the mainstay. Published
studies often demonstrate conflicting results, which make it difficult to recommend a “best” method for myocardial
protection.
Preischemic Management
Patients who are well resuscitated before surgically-induced ischemia generally have a better outcome (1). This
is particularly relevant for the neonate or infant with a “stressed” heart. The goal is achievement of a normal
metabolic state with reversal of tissue ischemia as manifested by hemodynamic stability, normal renal and
hepatic function, and appropriate blood pH and lactate levels. Apart from newborns with obstructed total
anomalous pulmonary venous connection, this can be accomplished by administration of a prostaglandin E1
infusion (alprostadil 0.01-0.05 μg/kg/min) to maintain or reestablish ductal patency, endotracheal intubation and
mechanical ventilation, fluid administration, and inotropic support.
Maintenance of blood pressure and myocardial blood flow in the operating room is also important. When the
pulmonary and systemic circulations are connected, lowering of the pulmonary vascular resistance by general
anesthesia and mechanical ventilation leads to diastolic runoff, systemic hypotension, and decreased myocardial
blood flow (1). This can occur with truncus arteriosus, aortopulmonary window, large ventricular
P.688
septal defects, single-ventricle lesions, patent ductus arteriosus, aortopulmonary collaterals, or surgical
systemic-to-pulmonary artery shunt. In addition to fluid and inotropic agent administration, systemic pressure can
be restored by temporarily occluding (“snaring”) the right pulmonary artery. This may necessitate increasing the
inspired oxygen concentration.
Hypothermia
Hypothermia alone can provide a significant amount of myocardial protection and may be the single most
important factor concerning myocardial protection in the neonate and infant. A synopsis of laboratory and clinical
studies from 1984 to 2001 examining the efficacy of systemic hypothermia and cardioplegia was reviewed by
Doenst et al. (6). In the past, some authors have questioned the role of cardioplegia, with a number of studies
showing equivalent or better myocardial protection using hypothermia alone compared to the use of hypothermia
with the addition of cardioplegia (52,53,54,55,56). These studies were performed at very low systemic
temperatures (≤15° C) and other studies performed at similarly low temperatures showed cardioplegia to be
beneficial (57,58,59,60). Studies at higher temperatures consistently demonstrate additional myocardial
protection with the addition of cardioplegia (5,6,61,62).
Cooling of the human body to 32°C reduces whole-body oxygen consumption by 45% (63). At temperatures
below 12°C, MVo2 is <1% of normal with cessation of contractile function (64). In the early days of pediatric
cardiac surgery, successful repairs were performed under deep hypothermic circulatory arrest (DHCA) (patient
packed in crushed ice) with limited or no CPB (65). Rapid cooling contracture (cold contracture) of the neonatal
myocardium prior to mechanical arrest is associated with poorer recovery of function than if the heart was kept
warm up to the time of ischemia (66). The proposed mechanism was cytosolic calcium loading as cold
contracture is not seen when the calcium concentration of the perfusate is low.
The maintenance of satisfactory myocardial hypothermia is of critical importance in the clinical setting, but can
sometimes be difficult to maintain. Multiple strategies are therefore necessary and incorporate systemic
hypothermia, topical cooling with chilled slush, cold irrigating solutions, cold ambient temperatures (13°C-14°C),
reduced intensity of lighting over the operative field, and intermittent reinfusion of cold cardioplegia (67).
Although the arterial switch operation in neonates and repair of two-ventricle defects in older children can be
performed using continuous normothermic CPB with intermittent (every 15 minutes after the induction dose)
warm blood cardioplegia, the additional safety margin provided by hypothermia to especially the heart and brain
is not present (68,69,70). As stated by de Leval: “Redundancy is one of the characteristics of high-reliability
organizations and systems and this is probably applicable to neonatal cardiac surgery” (68).
Cardioplegia
Diastolic (electromechanical) arrest is a mainstay of myocardial protection for procedures requiring cross-
clamping of the aorta. The reduction of MVo2 by hypothermia and arrest of the contractile apparatus and
electrical activity of the myocytes by administration of cardioplegia are widely accepted for prolongation of
myocardial tolerance to ischemia (6).
The aim of cardioplegia is to preserve myocardial function during the arrest period and limit reperfusion injury.
Mechanisms to achieve this include the modality of electromechanical arrest, cardioplegia temperature, mode of
delivery, and composition with respect to prevention of intracellular Ca2+ accumulation, buffering of acidosis,
prevention of myocardial edema, scavenging of oxygen-derived free radicals, and substrate enhancement to
improve energy production during rewarming and reperfusion. Although many studies attempt to address these
issues, the findings are contradictory (5,15,71,72,73). The composition and mode of delivery vary significantly
between institutions, with over 150 cardioplegia solutions having been used clinically for cardiac transplantation
in the United States (74). In addition to composition, there are varying protocols for administration of
cardioplegia.
Depolarization versus Polarization Arrest

Cardioplegia targets various points in the excitation-contraction coupling pathway to induce depolarized arrest,
polarized arrest, or promotion of arrest by influencing calcium mechanisms (Fig. 29.3) (75).
The method used most frequently to achieve rapid diastolic arrest is a depolarized arrest caused by increasing
the concentration of potassium ions in the extracellular space (19). As reviewed by Chambers, hyperkalemia
depolarizes the myocardial cell resting membrane potential ( Em) so that when the potential is approximately -65
mV there is inactivation of the voltage-dependent fast sodium channels producing the action potential spike (75).
However, depolarization to about -40 mV by administration of too much potassium will activate the slow Ca2+
channel and promote intracellular calcium overload. Although depolarization arrest is simple and has a rapid
onset and reliable recovery, myocardial recovery is poor because of decreased ATP, intracellular acidosis,
intracellular accumulation of sodium and calcium, and washout of the potassium-containing solution (19,76).
Energy-dependent processes such as the sarcolemmal and sarcoplasmic reticular Ca2+-ATPase pumps and the
Na+/K+-ATPase pump remain active. Sodium influx occurs via the Na+/H+-exchanger, which activates the
Na+/Ca2+-exchanger.
Polarized arrest in which the Em remains close to the resting Em limits ionic movement, thereby slowing down the
rate of ATP utilization and intracellular Ca2+ accumulation (75). Polarizing agents include lidocaine, procaine,
magnesium, adenosine, and potassium channel openers. Polarizing arrest in rabbits with a K+-ATP channel
opener found better functional recovery than K+ depolarization arrest (77). In
P.689
the current era, sodium channel blockade with lidocaine and Ca2+-competing ions like magnesium are used to
counteract the negative effects of hyperkalemic depolarized arrest by polarizing the cell to some degree and
reducing intracellular accumulation of Na+ and Ca2+ (19,78).
FIGURE 29.3. Excitation-contraction coupling in depolarized and polarized arrest. Excitation-contraction coupling
and the targets within this pathway that are inhibited or activated by agents that induce depolarized arrest,
polarized arrest, or arrest by influencing calcium mechanisms. SR, sarcoplasmic reticulum; BDM, 2,3-
butanedione monoxime; TTX, tetrodotoxin. (Reprinted from Chambers DJ. Mechanisms and alternative methods
of achieving cardiac arrest. Ann Thorac Surg 2003;75:S661-S666, Figure 1 (p. S662), with permission.)
Blood versus Crystalloid Cardioplegia

The relative advantage of blood cardioplegia compared to crystalloid cardioplegia is still the subject of debate.
Blood cardioplegia offers several theoretical advantages such as the ability to carry oxygen, excellent buffering
capacity, a more similar electrolyte and osmotic composition, and the potential to scavenge free radicals to
minimize oxidative damage to the heart. The precise mechanism by which blood and red blood cells provide
myocardial protection is still controversial (19).
In spite of these theoretical advantages, it has been difficult to demonstrate a clinical superiority of blood
cardioplegia over crystalloid cardioplegia in pediatric cardiac surgery. There are only a few clinical investigations
comparing blood and crystalloid cardioplegia (79,80,81,82). While one study demonstrated better preservation of
myocardial metabolism and ventricular function in infants receiving blood cardioplegia (79), another found no
significant differences in clinical outcomes between the two cardioplegia solutions (81). The literature remains
inconclusive and crystalloid cardioplegia remains in use at some centers (67).
Mode of Delivery
Route
Antegrade administration of cardioplegia results in excellent distribution for the majority of pediatric procedures.
With severe aortic insufficiency, direct coronary ostial administration or retrograde administration is also
frequently used. Coronary artery occlusion is uncommon in the pediatric population, but other situations in which
retrograde cardioplegia could be used include marked ventricular or septal hypertrophy, and during coronary
artery transfers when anterograde administration is not possible. Retrograde cardioplegia is problematic with a
persistent left-sided superior vena cava draining into the coronary sinus.
Perfusion Pressure
The ideal cardioplegia infusion pressure has not been determined. Low perfusion pressure can limit distribution,
while excessively high pressures with the associated shear forces may cause capillary damage and myocardial
edema, especially in hypoxic hearts (83). Some surgeons measure aortic root pressure during administration,
while others use the system pressure and monitor the aortic root for distension (19). During infusion of
retrograde cardioplegia, flow through the retrograde cannula is adjusted to result in a cardioplegia perfusion
pressure no higher than 50 mm Hg.
Timing and Temperature

Delivery of cardioplegia can be divided into three phases, namely induction, maintenance, and reperfusion (40).
In stressed hearts (coronary occlusion, hypoxemia, pressure overload, volume overload) with substrate and
energy depletion, a brief 3- to 5-minute infusion of warm amino-acid (aspartate and glutamate)-enriched blood
cardioplegia ( warm induction) at 37°C prior to aortic cross-clamping was shown
P.690
to improve aerobic metabolism and enhance ventricular function (26,84). Induction temperature was felt to be
much less important in normal hearts. In contrast, other laboratory and clinical studies found no advantage to
enrichment of the perfusate with aspartate and glutamate before or after ischemia (21,85,86).
Dosing Strategy
Clinical techniques vary from surgeons who advocate the use of single-dose cold cardioplegia to those who
favor a more conventional multi-dose approach adapted from adult cardiac surgery. A retrospective pediatric
study comparing single (del Nido solution) with multiple dose (modified adult solution) administration for arrest
times exceeding 90 minutes found no significant difference in postoperative complications (87). The rationale for
a multidose strategy is that noncoronary collateral washout of cardioplegia solution is counteracted (40). A large
retrospective study comparing intermittent (every 15 minutes after initial injection) warm blood cardioplegia
(IWBC) with intermittent cold blood cardioplegia found that IWBC also provided safe and effective myocardial
protection (69). A small prospective randomized trial comparing normothermic bypass with IWBC to mildly
hypothermic (32°C) bypass with intermittent cold crystalloid cardioplegia also found that normothermic bypass
with IWBC was not deleterious when compared with more conventional approaches (20). In neonates
undergoing the arterial switch operation, Custodiol was associated with a larger troponin release when
compared to repeated oxygenated warm blood cardioplegia, but was not associated with any difference in 30-
day mortality (88). Terminal warm hyperkalemic blood cardioplegia prior to removal of the aortic crossclamp,
termed a “hot shot,” was shown to improve metabolic and functional recovery in adult hearts, and subsequently
in pediatric hearts (81,89).
Additives
The roles of potassium chloride and lidocaine are discussed under depolarized and polarized arrest,
respectively. As stated above, the benefits of amino-acid-enriched cardioplegia have not translated into clinical
practice.
Mannitol
Myocardial edema leads to a decrease in ventricular compliance and diastolic dysfunction. Mannitol has been
shown to reduce myocardial cell swelling, vascular resistance, and necrosis (90). It is also an oxygen-derived
free-radical scavenger, providing myocardial protection independent of its hyperosmolar properties (91).
Magnesium Sulfate
Magnesium has been found to improve ventricular recovery and reduce the incidence of postoperative
arrhythmias (40). Possible mechanisms are inhibition of cellular calcium entry during ischemia, ischemia-induced
magnesium loss, and the prevention of sodium influx during reperfusion (92).
Sodium Bicarbonate
Accumulation of lactate and hydrogen ions during ischemia inhibits anaerobic glycolysis and ATP production
(93). Buffering by sodium bicarbonate reduces hydrogen ion concentration (94). An important role for blood
cardioplegia may be the buffering by red blood cells.
Steroids
Prophylactic administration of corticosteroids to attenuate the systemic inflammatory response associated with
cardiac surgery and CPB is a common practice (95). A Cochrane Review in 2007 was unable to determine the
effect on all-cause mortality, but found weak evidence for reducing peak core temperature, duration of
mechanical ventilation, and intensive care unit length-of-stay (96). Studies performed subsequent to this review,
both prospective randomized double-blind trials and retrospective reviews, have similarly yielded mixed results
(97,98,99,100,101). The optimal timing of administration, specific glucocorticoid, dose, and influence on clinical
outcome are still uncertain.
Empty-Beating Heart and Fibrillatory Arrest

Neonatal MVo2 differs between empty-beating hearts and fibrillating hearts. In a piglet study, MVo2 (expressed in
milliliters of O2 per 100 g of ventricular tissue per minute; mean ± standard deviation) was 6.69 ± 1.91 for
working hearts, 3.19 ± 1.08 for empty-beating hearts, 3.72 ± 0.84 for fibrillating hearts, 1.30 ± 0.34 for potassium-
arrested hearts at 37°C, and 0.32 ± 0.10 for potassium-arrested hearts at 15°C (44). Hypothermia decreases
MVo2 under all conditions. However, in beating hearts, there is the inotropic effect of hypothermia which is less
forceful in fibrillating hearts but associated with a higher myocardial wall tension (43). With fibrillating hearts it is
essential to vent the heart.
Surgeons vary in their practices. In patients with no intracardiac communications, some surgeons will perform or
complete procedures on the right side of the heart with an empty beating heart. Others may use fibrillatory arrest
prior to placing an aortic cross-clamp.
CLINICAL TECHNIQUES
Practice Patterns
Pediatric perfusion and cardioplegia practice vary widely across the world. North American and International
surveys report that the majority (68%) of centers use a high-potassium depolarizing cardioplegia solution with
induction and maintenance dosing (17,102) (Table 29.3). Approximately one-third of centers in North America
use the modified depolarizing del Nido solution (Compass; Baxter Healthcare Inc., Edison, NJ). The Custodiol
HTK hyperpolarizing solution (Dr. Franz Köhler Chemie GmbH, Alsbach-Hähnlein, Germany) is more prevalent in
Europe and used by about one-third of centers. Customized solutions are usually used with a dilution ratio of 4
parts blood to 1 part crystalloid, the del Nido solution with
P.691
1 part blood to 4 parts crystalloid, and no dilution with Custodiol. Customized solutions with multiple-dose
administration adapted from adult cardiac surgery are used by many centers.
TABLE 29.3. Cardioplegia solutions used in 2010 by region
NA (n = CSA (n = Asia (n = OA (n = EU (n = Total (n =

89) (%) 14) (%) 10) (%) 5) (%) 28) (%) 146) (%)
Hyperpolarizing
(Custodiol HTK)a 4 23 0 0 31 10
Depolarizing (high
potassium) 64 77 89 100 62 68
Modified
depolarizing (del
Nido)b 32 0 11 0 8 22
n = number of centers responding to the survey (response rate 51%).
aCustodiol HTK Solution (Dr. Franz Köhler Chemie GmbH, Alsbach-Hähnlein, Germany).
bOriginal patent, University of Pittsburgh, now expired.
NA, North America; CSA, Central and South America; OA, Oceana; EU, European Union.
Reprinted from Harvey B, Shann KG, Fitzgerald D, et al. International pediatric perfusion practice: 2011
survey results. J Extra Corpor Technol 2012;44:186-193, with permission.
Single-Dose Cardioplegia
The del Nido and Custodiol solutions are designed to increase the safe ischemic time with fewer interruptions
and are usually administered as a single-antegrade dose. The use of these solutions can also greatly simplify an
operation as they can eliminate the need for retrograde or direct ostial administration in certain procedures.
Custodiol cardioplegia solution, also referred to as Bretschneider’s histidine-tryptophan-ketoglutarate (HTK)
solution, is an intracellular crystalloid solution used for myocardial protection and transplant organ preservation
(Table 29.4). It is classified as intracellular because of its low Na+ and Ca2+ content (103). The low Na+
concentration arrests the heart in diastole by causing sodium depletion of the extracellular space. Histidine acts
as a buffer against intracellular acidosis, tryptophan stabilizes the cell membrane, and ketoglutarate (precursor
for nicotinamide dinucleotide phosphate) improves ATP production during reperfusion. The manufacturer’s
guidelines for administration for small hearts are cooling of the solution to 5°C to 8°C, a perfusion rate of 1
mL/min/g-estimated-heart-weight (infants 0.6% of body weight) at a perfusion pressure of 40 to 50 mm Hg, and a
perfusion time of not less than 6 to 8 minutes to ensure homogeneous equilibration (104). The heart should
tolerate a cold ischemic time of up to 4 hours per the manufacturer. There are conflicting results in studies
comparing Custodiol with conventional cardioplegia techniques (88,105,106).
The del Nido cardioplegia solution is the result of modifications to the original formulation for myocardial
protection developed at the University of Pittsburgh in the early 1990s. This solution is used for all patients of
any age at Boston Children’s Hospital and Columbia University Medical Center. The protocol has been
described in detail by Matte and del Nido (19). The base solution is Plasma-Lyte A to which mannitol,
magnesium sulfate, sodium bicarbonate, potassium chloride, and lidocaine are added (Table 29.5). The
cardioplegia solution is mixed with the patient’s blood as 4 parts crystalloid to 1 part blood and is generally given
as a single 20 mL/kg dose at a delivery temperature of 8°C to 12°C. The dose is reduced to 10 mL/kg for
procedures requiring a crossclamp time less than 30 minutes. Additional volume may be given to patients with
hypertrophied hearts, aortic insufficiency, or coronary artery disease based on the effectiveness
P.692
of the initial dose and surgeon preference. A subsequent dose is only given if there is electrical activity (rare) or
for crossclamp times greater than 3 hours at the surgeon’s discretion. In rat cardiomyocytes, the del Nido
solution was associated with lower intracellular calcium during arrest and reperfusion, more complete arrest, and
reduced troponin-T release compared with adult cardioplegia (modified Buckberg) (78). A single-surgeon small
retrospective study comparing the del Nido solution with modified adult multi-dose solution found no difference in
postoperative complications but lower perioperative glucose levels with the del Nido solution (87). The del Nido
cardioplegia solution is also being used to protect the mature myocardium. In isolated aged rat hearts, the del
Nido solution provided superior functional recovery and lower troponin release than intermittent standard cold
cardioplegia (107).
TABLE 29.4. Custodiol (Bretschneider’s HTK-solution)
Pharmacologically active ingredient mmol/1,000 mL
Sodium chloride 15
Potassium chloride 9
Calcium chloride · 2H2O 0.015
Magnesium chloride · 6H2O 4
Sodium Bicarbonate 0
Histidine hydrochloride · H2O 18
Histidine 180
Tryptophan 2
Ketoglutarate 1
Mannitol 30
Potassium hydrogen 2-oxopentandioate 1
pH at 25°C 7.02-7.20
Osmolality 310 mOsmol/kg
CUSTODIOL® [package insert]. Ewing, NJ: Essential Pharmaceuticals, LLC; 2009.

TABLE 29.5. Crystalloid component of del Nido cardioplegia solution
Plasma-Lyte A 1,000 mL
Mannitol 20% 16.3 mL
Magnesium sulfate 50% 4 mL
Sodium bicarbonate 8.4% 13 mL
Potassium chloride (2 mEq/mL) 13 mL
Lidocaine 1% 13 mL
Reprinted from Matte GS, del Nido PJ. History and use of del Nido cardioplegia solution at Boston
Children’s Hospital. J Extra Corpor Technol 2012;44:98-103, with permission.
CONCLUSION
Myocardial protection is only one of the many factors affecting outcome in pediatric cardiac surgery.
Postoperative myocardial dysfunction remains problematic, especially in neonates and cyanotic lesions.
Despite numerous laboratory and clinical studies over the past 50 years or so, myocardial protection
techniques still vary significantly between congenital heart surgeons (17,102). Species differences, age-
related differences, underlying pathophysiology, surgical technique, cardioplegia protocols, and study
methodology preclude recommendation of a best strategy for pediatric (and adult) myocardial protection. A
large prospective randomized study comparing well-defined protocols of CPB with consideration of the
many variables (age, cardiac lesion, preoperative clinical condition, conduct of bypass, quality of repair,
anesthetic management, postoperative management) influencing postischemic myocardial function and
selection of meaningful markers of post-CBP morbidity is still necessary to improve outcomes further (68).
KEY Points
Myocardial protection is not limited to the period of ischemia during aortic cross-clamping, and includes
optimal management of the patient preoperatively, intraoperatively, and postoperatively.
The normal neonatal myocardium is more resistant to ischemia but the “ stressed” neonatal myocardium is
more sensitive to ischemia. Stressors include severe hypoxemia, chronic cyanosis, ventricular
hypertrophy, and refractory heart failure.
The precise age of crossover from immature to mature (adult) myocardium is not well defined, but
thought to be complete by 12 months of age. The immature myocardium has structural and functional
differences as follows:
Glucose is the main energy substrate, likely due to upregulation of 5′-AMP-activated protein kinase,
and with larger glycogen stores allows for increased anaerobic glycolysis.
Greater dependence on extracellular Ca2+ for contraction and more susceptible to intracellular Ca2+
overload during ischemia.
Reduced activity of 5′ nucleotidase and antioxidant enzymes predisposes to decreased loss of
intracellular adenosine during ischemia and free-radical damage during reperfusion, respectively.
Sensitivity to catecholamines is decreased, but the kinetics of cAMP hydrolysis is not affected by age.
Ischemic preconditioning has not been shown to be effective in immature hearts.
More vulnerable to stretch injury.
Hypothermia and contractile (diastolic) arrest reduce MVo2 and prolong myocardial tolerance to ischemia.
Cardioplegia aims to preserve myocardial function during the arrest period and to limit reperfusion injury.
Mechanisms to achieve this include the modality of electromechanical arrest, cardioplegia temperature,
mode of delivery, and composition with respect to prevention of intracellular Ca2+ accumulation, buffering
of acidosis, prevention of myocardial edema, scavenging of oxygen-derived free radicals, and substrate
enhancement to improve energy production during rewarming and reperfusion.
Blood may be added to cardioplegia solutions, but the precise mechanism by which blood and red blood
cells provide myocardial protection and the relative advantage of blood cardioplegia are still
undetermined.
P.693
The depolarizing del Nido solution (Compass; Baxter Healthcare Inc., Edison, NJ) and the Custodiol HTK
hyperpolarizing solution (Dr. Franz Köhler Chemie GmbH, Alsbach-Hähnlein, Germany) are designed to
increase the safe ischemic time with fewer interruptions and are usually administered as a cold single-
antegrade dose. Customized solutions with multiple-dose administration adapted from adult cardiac
surgery are used by many centers.
Strategies for myocardial protection during CPB vary significantly between congenital heart surgeons and
centers, and there is no universal consensus on the optimal strategy.
REFERENCES
1. Castaneda AR, Jonas RA, Mayer JE, et al. Myocardial preservation in the immature heart. In: Cardiac
surgery of the neonate and infant. Philadelphia, PA: Saunders; 1994:41-54.
2. Bove EL, Gallagher KP, Drake DH, et al. The effect of hypothermic ischemia on recovery of left ventricular
function and preload reserve in the neonatal heart. J Thorac Cardiovasc Surg 1988;95(5):814-818.
3. Grice WN, Konishi T, Apstein CS. Resistance of neonatal myocardium to injury during normothermic and
hypothermic ischemic arrest and reperfusion. Circulation 1987;76(5, Part 2):V150-V155.
4. Hammon JW Jr. Myocardial protection in the immature heart. Ann Thorac Surg 1995;60(3):839-842.
5. Julia P, Young HH, Buckberg GD, et al. Studies of myocardial protection in the immature heart. IV.
Improved tolerance of immature myocardium to hypoxia and ischemia by intravenous metabolic support. J
6. Doenst T, Schlensak C, Beyersdorf F. Cardioplegia in pediatric cardiac surgery: do we believe in magic?

Ann Thorac Surg 2003;75(5):1668-1677.
7. Goodwin GW, Ahmad F, Doenst T, et al. Energy provision from glycogen, glucose, and fatty acids on
adrenergic stimulation of isolated working rat hearts. Am J Physiol 1998;274(4, Part 2):H1239-H1247.
8. Lopaschuk GD, Spafford MA, Marsh DR. Glycolysis is predominant source of myocardial ATP production
immediately after birth. Am J Physiol 1991;261(6, Part 2):H1698-H1705.
9. Makinde AO, Gamble J, Lopaschuk GD. Upregulation of 5′-AMP-activated protein kinase is responsible for
the increase in myocardial fatty acid oxidation rates following birth in the newborn rabbit. Circ Res
1997;80(4):482-489.
10. Clark CM Jr. Characterization of glucose metabolism in the isolated rat heart during fetal and early
neonatal development. Diabetes 1973;22(1):41-49.
11. Boland R, Martonosi A, Tillack TW. Developmental changes in the composition and function of
sarcoplasmic reticulum. J Biol Chem 1974;249(2):612-623.
12. Jarmakani JM, Nakanishi T, George BL, et al. Effect of extracellular calcium on myocardial mechanical
function in the neonatal rabbit. Dev Pharmacol Ther 1982;5(1-2):1-13.
13. Klitzner TS. Maturational changes in excitation-contraction coupling in mammalian myocardium. J Am

Coll Cardiol 1991;17(1):218-225.
14. Nakanishi T, Jarmakani JM. Developmental changes in myocardial mechanical function and subcellular
organelles. Am J Physiol 1984;246(4, Part 2):H615-H625.
15. Bolling K, Kronon M, Allen BS, et al. Myocardial protection in normal and hypoxically stressed neonatal
hearts: the superiority of hypocalcemic versus normocalcemic blood cardioplegia. J Thorac Cardiovasc Surg
1996;112(5):1193-1200; discussion 200-201.
16. Kronon MT, Allen BS, Hernan J, et al. Superiority of magnesium cardioplegia in neonatal myocardial
protection. Ann Thorac Surg 1999;68(6):2285-2291; discussion 91-92.
17. Kotani Y, Tweddell J, Gruber P, et al. Current cardioplegia practice in pediatric cardiac surgery: a North
American multiinstitutional survey. Ann Thorac Surg 2013;96(3):923-929.
18. Levitsky S, McCully JD. Myocardial protection. In: Sellke F, del Nido PJ, Swanson S, eds. Sabiston and
Spencer’s surgery of the chest. I. 8th ed. Philadelphia, PA: Saunders; 2010:977-998.
19. Matte GS, del Nido PJ. History and use of del Nido cardioplegia solution at Boston Children’s Hospital. J
Extra Corpor Technol 2012;44(3):98-103.
20. Poncelet AJ, van Steenberghe M, Moniotte S, et al. Cardiac and neurological assessment of
normothermia/warm blood cardioplegia vs hypothermia/cold crystalloid cardioplegia in pediatric cardiac
surgery: insight from a prospective randomized trial. Eur J Cardiothorac Surg 2011;40(6): 1384-1390.
21. Suominen PK, Keski-Nisula J, Tynkkynen P, et al. The effect of tepid amino acid-enriched induction
cardioplegia on the outcome of infants undergoing cardiac surgery. Perfusion 2012;27(4):338-344.
22. Teoh KH, Mickle DA, Weisel RD, et al. Effect of oxygen tension and cardiovascular operations on the
myocardial antioxidant enzyme activities in patients with tetralogy of Fallot and aorta-coronary bypass. J
23. Rowland RT, Meng X, Ao L, et al. Mechanisms of immature myocardial tolerance to ischemia: phenotypic
differences in antioxidants, stress proteins, and oxidases. Surgery 1995;118(2):446-452.
24. del Nido PJ, Mickle DA, Wilson GJ, et al. Evidence of myocardial free radical injury during elective repair
of tetralogy of Fallot. Circulation 1987;76(5, Part 2):V174-V179.
25. Rosenkranz ER, Okamoto F, Buckberg GD, et al. Biochemical studies: failure of tissue adenosine
triphosphate levels to predict recovery of contractile function after controlled reperfusion. J Thorac
Cardiovasc Surg 1986;92(3, Part 2):488-501.
26. Rosenkranz ER, Vinten-Johansen J, Buckberg GD, et al. Benefits of normothermic induction of blood
cardioplegia in energy-depleted hearts, with maintenance of arrest by multidose cold blood cardioplegic
infusions. J Thorac Cardiovasc Surg 1982;84(5):667-677.
27. Taegtmeyer H, Goodwin GW, Doenst T, et al. Substrate metabolism as a determinant for postischemic
functional recovery of the heart. Am J Cardiol 1997;80(3A):3A-10A.
28. Bolling SF, Olszanski DA, Bove EL, et al. Enhanced myocardial protection during global ischemia with 5′-
nucleotidase inhibitors. J Thorac Cardiovasc Surg 1992;103(1):73-77.
29. Hammon JW Jr, Graham TP Jr, Boucek RJ Jr, et al. Myocardial adenosine triphosphate content as a
measure of metabolic and functional myocardial protection in children undergoing cardiac operation. Ann
Thorac Surg 1987;44(5):467-470.
30. Path G, Robitaille PM, Merkle H, et al. Correlation between transmural high energy phosphate levels and
myocardial blood flow in the presence of graded coronary stenosis. Circ Res 1990;67(3):660-673.
31. Artman M, Kithas PA, Wike JS, et al. Inotropic responses change during postnatal maturation in rabbit.
Am J Physiol 1988;255(2, Part 2):H335-H342.
32. Perrault LP, Menasche P. Preconditioning: can nature’s shield be raised against surgical ischemic-
reperfusion injury? Ann Thorac Surg 1999;68(5):1988-1994.
33. Awad WI, Shattock MJ, Chambers DJ. Ischemic preconditioning in immature myocardium. Circulation
1998;98(19, Suppl):II206-II213.
34. del Nido PJ, Mickle DA, Wilson GJ, et al. Inadequate myocardial protection with cold cardioplegic arrest
during repair of tetralogy of Fallot. J Thorac Cardiovasc Surg. 1988;95(2):223-229.
35. Imura H, Caputo M, Parry A, et al. Age-dependent and hypoxia-related differences in myocardial
protection during pediatric open heart surgery. Circulation 2001;103(11):1551-1556.
36. Julia PL, Kofsky ER, Buckberg GD, et al. Studies of myocardial protection in the immature heart. I.
Enhanced tolerance of immature versus adult myocardium to global ischemia with reference to metabolic
differences. J Thorac Cardiovasc Surg 1990;100(6):879-887.
37. Lupinetti FM, Wareing TH, Huddleston CB, et al. Pathophysiology of chronic cyanosis in a canine model.
Functional and metabolic response to global ischemia. J Thorac Cardiovasc Surg 1985;90(2):291-296.
38. Najm HK, Wallen WJ, Belanger MP, et al. Does the degree of cyanosis affect myocardial adenosine
triphosphate levels and function in children undergoing surgical procedures for congenital heart disease? J
39. Silverman NA, Kohler J, Levitsky S, et al. Chronic hypoxemia depresses global ventricular function and
predisposes to the depletion of high-energy phosphates during cardioplegic arrest: implications for surgical
repair of cyanotic congenital heart defects. Ann Thorac Surg 1984;37(4):304-308.
P.694
40. Allen BS. Pediatric myocardial protection: a cardioplegic strategy is the “solution”. Semin Thorac
Cardiovasc Surg Pediatr Card Surg Annu 2004;7:141-154.
41. Wittnich C, Maitland A, Vincente W, et al. Not all neonatal hearts are equally protected from ischemic
damage during hypothermia. Ann Thorac Surg 1991;52(4):1000-1004.
42. Krukenkamp IB, Silverman NA, Levitsky S. The effect of cardioplegic oxygenation on the correlation
between the linearized Frank-Starling relationship and myocardial energetics in the ejecting postischemic
heart. Circulation 1987;76(5, Part 2):V122-V128.
43. Buckberg GD, Brazier JR, Nelson RL, et al. Studies of the effects of hypothermia on regional myocardial
blood flow and metabolism during cardiopulmonary bypass. I. The adequately perfused beating, fibrillating,
and arrested heart. J Thorac Cardiovasc Surg 1977;73(1):87-94.
44. Jessen ME, Abd-Elfattah AS, Wechsler AS. Neonatal myocardial oxygen consumption during ventricular
fibrillation, hypothermia, and potassium arrest. Ann Thorac Surg 1996;61(1):82-87.
45. Piper HM, Garcia-Dorado D, Ovize M. A fresh look at reperfusion injury. Cardiovasc Res 1998;38(2):291-
300.
46. Yellon DM, Hausenloy DJ. Myocardial reperfusion injury. N Engl J Med 2007;357(11):1121-1135.
47. Hausenloy DJ, Yellon DM. The mitochondrial permeability transition pore: its fundamental role in
mediating cell death during ischaemia and reperfusion. J Mol Cell Cardiol 2003;35(4):339-341.
48. Sellke FW, Boyle EM Jr, Verrier ED. Endothelial cell injury in cardiovascular surgery: the pathophysiology
of vasomotor dysfunction. Ann Thorac Surg 1996;62(4):1222-1228.
49. Hiramatsu T, Forbess JM, Miura T, et al. Effects of L-arginine and L-nitro-arginine methyl ester on
recovery of neonatal lamb hearts after cold ischemia. Evidence for an important role of endothelial production
of nitric oxide. J Thorac Cardiovasc Surg 1995;109(1):81-86; discussion 87.
50. Hatsuoka S, Sakamoto T, Stock UA, et al. Effect of L-arginine or nitroglycerine during deep hypothermic
circulatory arrest in neonatal lambs. Ann Thorac Surg 2003;75(1):197-203; discussion 203.
51. Starr JP, Jia CX, Amirhamzeh MM, et al. Coronary perfusate composition influences diastolic properties,
myocardial water content, and histologic characteristics of the rat left ventricle. Ann Thorac Surg
1999;68(3):925-930.
52. Baker JE, Boerboom LE, Olinger GN. Cardioplegia-induced damage to ischemic immature myocardium is
independent of oxygen availability. Ann Thorac Surg 1990;50(6):934-949.
53. Baker JE, Boerboom LE, Olinger GN. Age and protection of the ischemic myocardium: is alkaline
cardioplegia appropriate? Ann Thorac Surg 1993;55(3):747-755.
54. Bull C, Cooper J, Stark J. Cardioplegic protection of the child’s heart. J Thorac Cardiovasc Surg
1984;88(2):287-293.
55. Hosseinzadeh T, Tchervenkov CI, Quantz M, et al. Adverse effect of prearrest hypothermia in immature
hearts: rate versus duration of cooling. Ann Thorac Surg 1992;53(3):464-471.
56. Magovern JA, Pae WE Jr, Waldhausen JA. Protection of the immature myocardium. An experimental
evaluation of topical cooling, single-dose, and multiple-dose administration of St. Thomas’ Hospital
cardioplegic solution. J Thorac Cardiovasc Surg 1988;96(3):408-413.
57. Corno AF, Bethencourt DM, Laks H, et al. Myocardial protection in the neonatal heart. A comparison of
topical hypothermia and crystalloid and blood cardioplegic solutions. J Thorac Cardiovasc Surg
1987;93(2):163-172.
58. Diaco M, DiSesa VJ, Sun SC, et al. Cardioplegia for the immature myocardium. A comparative study in
the neonatal rabbit. J Thorac Cardiovasc Surg 1990;100(6):910-913.
59. Ganzel BL, Katzmark SL, Mavroudis C. Myocardial preservation in the neonate. Beneficial effects of
cardioplegia and systemic hypothermia on piglets undergoing cardiopulmonary bypass and myocardial
ischemia. J Thorac Cardiovasc Surg 1988;96(3):414-422.
60. Konishi T, Apstein CS. Comparison of three cardioplegic solutions during hypothermic ischemic arrest in
neonatal blood-perfused rabbit hearts. J Thorac Cardiovasc Surg 1989;98(6):1132-1137.
61. Avkiran M, Hearse DJ. Protection of the myocardium during global ischemia. Is crystalloid cardioplegia
effective in the immature myocardium? J Thorac Cardiovasc Surg 1989;97(2):220-228.
62. Bove EL, Stammers AH, Gallagher KP. Protection of the neonatal myocardium during hypothermic
ischemia. Effect of cardioplegia on left ventricular function in the rabbit. J Thorac Cardiovasc Surg
1987;94(1):115-123.
63. Bigelow WG, Lindsay WK, et al. Oxygen transport and utilization in dogs at low body temperatures. Am J
Physiol 1950;160(1):125-137.
64. Niazi SA, Lewis FJ. The effect of carbon dioxide on ventricular fibrillation and heart block during
hypothermia in rats and dogs. Surg Forum 1955;5:106-109.
65. Barratt-Boyes BG, Simpson M, Neutze JM. Intracardiac surgery in neonates and infants using deep
hypothermia with surface cooling and limited cardiopulmonary bypass. Circulation 1971;43(5, Suppl):I25-I30.
66. Rebeyka IM, Hanan SA, Borges MR, et al. Rapid cooling contracture of the myocardium. The adverse
effect of prearrest cardiac hypothermia. J Thorac Cardiovasc Surg 1990;100(2):240-249.
67. Sinha P. Myocardial protection. In: Jonas RA, ed. Comprehensive surgical management of congenital
heart disease. 2nd ed. Boca Raton, FL: CRC Press, 2014:207-218.
68. de Leval MR. ‘Because we can, should we…?’. Eur J Cardiothorac Surg 2006;30(5):693-694.
69. Durandy Y, Hulin S. Intermittent warm blood cardioplegia in the surgical treatment of congenital heart
disease: clinical experience with 1400 cases. J Thorac Cardiovasc Surg 2007;133(1):241-246.
70. Pouard P, Mauriat P, Ek F, et al. Normothermic cardiopulmonary bypass and myocardial cardioplegic
protection for neonatal arterial switch operation. Eur J Cardiothorac Surg 2006;30(5):695-699.
71. Bove EL, Stammers AH. Recovery of left ventricular function after hypothermic global ischemia. Age-
related differences in the isolated working rabbit heart. J Thorac Cardiovasc Surg 1986;91(1):115-122.
72. Karck M, Ziemer G, Haverich A. Myocardial protection in chronic volume-overload hypertrophy of

immature rat hearts. Eur J Cardiothorac Surg 1996;10(8):690-698.
73. Pearl JM, Laks H, Drinkwater DC, et al. Normocalcemic blood or crystalloid cardioplegia provides better
neonatal myocardial protection than does low-calcium cardioplegia. J Thorac Cardiovasc Surg
1993;105(2):201-206.
74. Demmy TL, Biddle JS, Bennett LE, et al. Organ preservation solutions in heart transplantation—patterns
of usage and related survival. Transplantation 1997;63(2):262-269.
75. Chambers DJ. Mechanisms and alternative methods of achieving cardiac arrest. Ann Thorac Surg
2003;75(2):S661-S666.
76. Dobson GP, Jones MW. Adenosine and lidocaine: a new concept in nondepolarizing surgical myocardial
arrest, protection, and preservation. J Thorac Cardiovasc Surg 2004;127(3):794-805.
77. Cohen NM, Wise RM, Wechsler AS, et al. Elective cardiac arrest with a hyperpolarizing adenosine
triphosphate-sensitive potassium channel opener. A novel form of myocardial protection? J Thorac
Cardiovasc Surg 1993;106(2):317-328.
78. O’Brien JD, Howlett SE, Burton HJ, et al. Pediatric cardioplegia strategy results in enhanced calcium
metabolism and lower serum troponin T. Ann Thorac Surg 2009;87(5):1517-1523.
79. Amark K, Berggren H, Bjork K, et al. Blood cardioplegia provides superior protection in infant cardiac
surgery. Ann Thorac Surg 2005;80(3): 989-994.
80. Caputo M, Modi P, Imura H, et al. Cold blood versus cold crystalloid cardioplegia for repair of ventricular
septal defects in pediatric heart surgery: a randomized controlled trial. Ann Thorac Surg 2002;74(2):530-534;
discussion 535.
81. Modi P, Suleiman MS, Reeves B, et al. Myocardial metabolic changes during pediatric cardiac surgery: a
randomized study of 3 cardioplegic techniques. J Thorac Cardiovasc Surg 2004;128(1):67-75.
82. Young JN, Choy IO, Silva NK, et al. Antegrade cold blood cardioplegia is not demonstrably advantageous
over cold crystalloid cardioplegia in surgery for congenital heart disease. J Thorac Cardiovasc Surg
1997;114(6):1002-1008; discussion 8-9.
83. Kronon M, Bolling KS, Allen BS, et al. The importance of cardioplegic infusion pressure in neonatal
myocardial protection. Ann Thorac Surg 1998;66(4):1358-1364.
84. Kronon MT, Allen BS, Bolling KS, et al. The role of cardioplegia induction temperature and amino acid
enrichment in neonatal myocardial protection. Ann Thorac Surg 2000;70(3):756-764.
85. Ghomeshi HR, Sun J, Tian G, et al. Can stunned hearts be resuscitated? Evaluation of
aspartate/glutamate secondary blood cardioplegia using magnetic resonance spectroscopy. Interact
Cardiovasc Thorac Surg 2009. Sep 24. [Epub ahead of print].
86. Ghomeshi HR, Tian G, Ye J, et al. Aspartate/glutamate-enriched blood does not improve myocardial
energy metabolism during ischemia-reperfusion: a 31P magnetic resonance spectroscopic study in isolated
pig hearts. J Thorac Cardiovasc Surg 1997;113(6):1068-1077; discussion 77-80.
P.695
87. Charette K, Gerrah R, Quaegebeur J, et al. Single dose myocardial protection technique utilizing del Nido
cardioplegia solution during congenital heart surgery procedures. Perfusion 2012;27(2):98-103.
88. Bojan M, Peperstraete H, Lilot M, et al. Cold histidine-tryptophan-ketoglutarate solution and repeated
oxygenated warm blood cardioplegia in neonates with arterial switch operation. Ann Thorac Surg
2013;95(4):1390-1396.
89. Toyoda Y, Yamaguchi M, Yoshimura N, et al. Cardioprotective effects and the mechanisms of terminal
warm blood cardioplegia in pediatric cardiac surgery. J Thorac Cardiovasc Surg 2003;125(6):1242-1251.
90. Powell WJ Jr, DiBona DR, Flores J, et al. The protective effect of hyperosmotic mannitol in myocardial
ischemia and necrosis. Circulation 1976;54(4): 603-615.
91. Ouriel K, Ginsburg ME, Patti CS, et al. Preservation of myocardial function with mannitol reperfusate.
Circulation 1985;72(3, Part 2):II254-II258.
92. Lareau S, Boyle AJ, Stewart LC, et al. The role of magnesium in myocardial preservation. Magnes Res
1995;8(1):85-97.
93. del Nido PJ, Wilson GJ, Mickle DA, et al. The role of cardioplegic solution buffering in myocardial
protection. A biochemical and histopathological assessment. J Thorac Cardiovasc Surg 1985;89(5):689-699.
94. Rovetto MJ, Lamberton WF, Neely JR. Mechanisms of glycolytic inhibition in ischemic rat hearts. Circ
Res 1975;37(6):742-751.
95. Checchia PA, Bronicki RA, Costello JM, et al. Steroid use before pediatric cardiac operations using
cardiopulmonary bypass: an international survey of 36 centers. Pediatr Crit Care Med 2005;6(4):441-444.
96. Robertson-Malt S, Afrane B, El Barbary M. Prophylactic steroids for pediatric open heart surgery.
Cochrane Database Syst Rev 2007;(4):CD005550.
97. Clarizia NA, Manlhiot C, Schwartz SM, et al. Improved outcomes associated with intraoperative steroid
use in high-risk pediatric cardiac surgery. Ann Thorac Surg 2011;91(4):1222-1227.
98. Graham EM, Atz AM, Butts RJ, et al. Standardized preoperative corticosteroid treatment in neonates
undergoing cardiac surgery: results from a randomized trial. J Thorac Cardiovasc Surg 2011;142(6):1523-
1529.
99. Heying R, Wehage E, Schumacher K, et al. Dexamethasone pretreatment provides antiinflammatory and
myocardial protection in neonatal arterial switch operation. Ann Thorac Surg 2012;93(3):869-876.
100. Keski-Nisula J, Pesonen E, Olkkola KT, et al. Methylprednisolone in neonatal cardiac surgery: reduced
inflammation without improved clinical outcome. Ann Thorac Surg 2013;95(6):2126-2132.
101. Mastropietro CW, Barrett R, Davalos MC, et al. Cumulative corticosteroid exposure and infection risk
after complex pediatric cardiac surgery. Ann Thorac Surg 2013;95(6):2133-2139.
102. Harvey B, Shann KG, Fitzgerald D, et al. International pediatric perfusion practice: 2011 survey results.
J Extra Corpor Technol 2012;44(4):186-193.
103. Edelman JJ, Seco M, Dunne B, et al. Custodiol for myocardial protection and preservation: a systematic
review. Ann Cardiothorac Surg 2013;2(6): 717-728.
104. CUSTODIOL® [package insert]. Ewing, NJ: Essential Pharmaceuticals, LLC; 2009.
105. Liu J, Feng Z, Zhao J, Li B, et al. The myocardial protection of HTK cardioplegic solution on the long-
term ischemic period in pediatric heart surgery. ASAIO J 2008;54(5):470-473.
106. Scrascia G, Guida P, Rotunno C, et al. Myocardial protection during aortic surgery: comparison
between Bretschneider-HTK and cold blood cardioplegia. Perfusion 2011;26(5):427-433.
107. Govindapillai A, Hua R, Rose R, et al. Protecting the aged heart during cardiac surgery: use of del Nido
cardioplegia provides superior functional recovery in isolated hearts. J Thorac Cardiovasc Surg 2013;146(4):
940-948.
Chapter 30
Brain Injury and Neuroprotective Strategies in Pediatric Cardiac
Surgery
Christopher E. Mascio
J. William Gaynor
INTRODUCTION
Brain injury is the most common and potentially disabling complication following congenital heart surgery. With
improved survival, the focus has shifted to optimizing functional outcomes. An important goal of therapy for every
congenital heart surgical patient is to reduce the risk of brain injury as much as possible. Along with updated
perfusion, anesthetic, and surgical strategies, techniques for neuromonitoring have been refined and adopted by
many centers performing pediatric cardiothoracic surgery. We review neurodevelopmental outcomes,
intraoperative neuromonitoring, and current published data concerning neuromonitoring.
NEURODEVELOPMENTAL OUTCOMES
Survival after congenital heart surgery has improved, and the focus has shifted to also optimizing
neurodevelopmental outcomes. Survivors of repair of congenital heart disease (CHD) in the neonatal period
demonstrate cognitive, motor, speech, visual, and learning abnormalities (1). Determining causation in abnormal
neurodevelopment and the occurrence of neurodevelopmental disability is a challenging endeavor. There are
both nonmodifiable and modifiable factors associated with adverse neurodevelopmental outcomes (Table 30.1).
Genetic predisposition and many other nonmodifiable patient factors, including prematurity, socioeconomic
status, and maternal education, have been shown to be risk factors for worse neurodevelopmental outcomes.
Additionally, there is increasing evidence that CHD is associated with altered fetal brain growth and
development. Modifiable perioperative management factors have also been implicated in altering
neurodevelopmental outcome. Over the last few decades, there have been refinements in perioperative care,
anesthetic management, and surgical techniques.
Nonmodifiable Factors
Fetal Brain Development
Beginning in the third trimester of fetal life, patients with CHD are known to have smaller gestational age- and
weight-adjusted brain volumes with impaired neuroaxonal development and metabolism (2). These abnormalities
are most pronounced with more complex types of heart defects, including hypoplastic left heart syndrome
(HLHS) and transposition of the great arteries (TGA).
TABLE 30.1. Factors associated with adverse neurodevelopmental outcomes
Nonmodifiable factors Modifiable factors
Fetal brain development Preoperative and postoperative management factors
Preoperative brain abnormalities Hypoxemia and acidosis

Prematurity Hypotension and cardiac arrest
Socioeconomic factors
Genetic syndromes and polymorphisms Intraoperative management factors
Other patient factors Temperature
Circulatory arrest vs. continuous low-flow bypass
Circulatory arrest vs. regional cerebral perfusion
Blood gas management
Hematocrit
Glucose
Preoperative Brain Abnormalities

Structural malformations of the brain occur at a much higher rate than in the general population (3).
Microcephaly, microencephaly, and other malformations, including agenesis of the corpus callosum and an
immature cortical mantle, have been documented in necropsy series of patients with HLHS (4). Neonates with
CHD can have altered cerebral hemodynamics, often with lower-than-normal cerebral blood flow (CBF) and/or
oxygen delivery. One study of neonates with complex CHD used preoperative pulsed arterial spin-label perfusion
magnetic resonance imaging (MRI) to quantitate CBF (5). More than half of the cohort had developmental or
acquired lesions, and the CBF was less than half of that reported in
P.698
normal, term neonates (6). There was evidence of delayed white matter development, which may lead to an
increased risk of white matter injury (WMI), typically periventricular leukomalacia (PVL), and microcephaly. The
same study also examined cerebrovascular responsiveness to CO2, and found that PVL was associated with
decreased CO2 responsiveness. Abnormal cerebrovascular reactivity to CO2 has been associated with
increased mortality and worse neurodevelopmental outcomes (7,8). WMI characterized by PVL is the most
common pattern of injury (9). The mechanism of this injury is thought to be due to the effects of hypoxia and/or
ischemia on vulnerable premyelinating oligodendrocyte precursors during their most vulnerable time of 24 to 34
weeks’ gestation (10). Up to 40% of neonates with CHD have PVL on preoperative MRI, and PVL has been
shown to be associated with poor neurodevelopmental outcomes (5,11,12) (Fig. 30.1). The incidence of PVL is
highest in neonates undergoing cardiopulmonary bypass (CPB). A study by Galli et al. (13) found a 54%
incidence of PVL in neonates compared to 4% in infants. PVL is the neurologic lesion associated with cerebral
palsy in infants born prematurely (14). This pattern of brain injury is seen not only in preterm newborns but also
in term neonates with CHD (15). A comparison of term newborns with CHD to a control cohort without heart
defects revealed that almost one-third of those with CHD had WMI, while no WMI was seen in those without
heart defects (16).
FIGURE 30.1. Periventricular leukomalacia shown by (A) contrast-enhanced T1 weighted multiplanar
reconstruction (MPR), and (B) diffusion weighted imaging (DWI). (Images courtesy of Daniel J. Licht, MD.)
Prematurity
Preterm birth, even in infants without CHD, is a powerful predictor of worse neurodevelopmental outcome. Along
with low birth weight, prematurity has been associated with longterm behavioral and learning issues. In a study of
125 very low birth weight preterm infants who were evaluated with the Bayley Scales of Infant and Toddler
Development III (BSID-III) at 24 months, later gestational age was associated with better neurodevelopmental
outcome (17).
Socioeconomic Factors
Other nonmodifiable patient factors that adversely affect neurodevelopmental outcomes are socioeconomic
status and maternal education. Follow-up of the Boston Circulatory Arrest Study (BCAS) cohort at 16 years of
age found that family social class and parental IQ were significant predictors of neurodevelopmental outcome
(18). In a study of neurodevelopmental outcome after repair of total anomalous pulmonary venous connection,
lower socioeconomic status was predictive of lower scores on the Mental Developmental Index (MDI) of the
Bayley Scales of Infant Development II (BSID-II) (19). The Single Ventricle Reconstruction trial is the randomized,
prospective trial comparing shunt types in the Norwood procedure (20). Evaluation of this cohort at 14 months
demonstrated that lower maternal education, in addition to the presence of genetic syndromes or other
anomalies and lower birth weight, was associated with lower BSID-II MDI scores (21).
Genetic Syndromes and Polymorphisms

There are many genetic syndromes associated with CHD, and include Down syndrome, Noonan syndrome,
Williams syndrome, and DiGeorge syndrome (22q11.2 microdeletion) (22,23,24,25). These syndromes are
associated with developmental delay and assigning causation of neurodevelopmental delay can be challenging.
For example, those with DiGeorge syndrome have a mean IQ in the 70s, a predisposition to psychiatric
disorders, and an increased incidence of white matter abnormalities (26,27,28).
There is also evidence that genetic variants which modify the brain’s response to injury and subsequent
recovery may also be important determinants of neurodevelopmental outcomes. The first genetic polymorphism
studied in relation to CHD and surgery was apolipoprotein E (APOE) (1). APOE regulates cholesterol metabolism
and is the primary lipid transport vehicle in the central nervous system. There is evidence that APOE is important
for neuronal repair. There are three APOE alleles (ε2, ε3, ε4) on chromosome 19 that vary by a single amino acid.
Investigators at the Children’s Hospital of Philadelphia evaluated the association of APOE genotype and
postoperative neurodevelopmental outcome at age 1 year
P.699
(1). On the BSID-II, the APOE ε2 allele was associated with a significantly lower Psychomotor Developmental
Index (PDI) score after adjustment for perioperative covariates including gestational age, age at operation, sex,
race, socioeconomic status, cardiac defect, and the use of circulatory arrest. Further analysis of this group
revealed that patient-specific factors, namely the presence of a genetic syndrome, low birth weight, and the
APOE ε2 allele, significantly predicted neurodevelopmental outcomes at age 1 year (29). Neurobehavioral
outcomes evaluated in the cohort between 4 and 5 years of age revealed that those with the APOE ε2 allele had
increased behavioral problems, restricted behavior patterns, and impaired social skills (30). The entire cohort
had a significantly higher proportion of patients considered either at-risk or in the clinically significant range for
neurodevelopmental problems. Further evaluation of the cohort by a genome-wide association study with
adjustment for the effects of APOE identified single nucleotide polymorphisms (SNP) as being associated with
neurobehavioral abnormalities (31). Ten SNPs reached a threshold for suggested significant associations with
neurobehavioral phenotypes.
Other Patient Factors

A study comparing the relative contribution of other patient factors (gestational age, genetic syndrome, birth
weight, gender, etc.) to management factors during neonatal and infant cardiac surgery on neurodevelopmental
outcomes at 1 year of age showed that patient factors explained more of the variability in the PDI (21% vs. 8%)
and MDI (13% vs. 5%) scores on the BSID-II than management factors (29). Accordingly, factors such as gender,
birth weight, and presence of a genetic syndrome had a more significant impact on neurodevelopmental
outcomes than CPB time, circulatory arrest time, and hematocrit. Not all patients with CHD enter the operating
room with the same neurodevelopmental prognosis. Interindividual variation of many nonmodifiable patient
factors significantly contributes to widely disparate neurodevelopmental outcomes of different patients with the
same cardiac diagnosis.
Modifiable Factors
Many studies have examined the impact of different management strategies before and during congenital heart
operations on neurodevelopmental outcomes. Studies have found that both preoperative and postoperative
management can have a profound impact on neurologic outcome.
Preoperative and Postoperative Management Factors
Hypoxemia and Acidosis

Ductal-dependent cardiac lesions put patients at risk of hypoxemia, acidosis, and cardiovascular collapse if the
diagnosis is not known and ductal closure occurs (4,32). Prenatal diagnosis of congenital heart lesions has
increased in recent years. This often results in delivery in centers equipped to care for newborns with severe
forms of CHD, thereby permitting immediate or early infusion of prostaglandin to maintain ductal patency
(33,34,35). Preoperative hypoxemia has been shown to be associated with abnormal neurodevelopmental
outcomes. Neurodevelopmental testing on a cohort of patients 5 to 10 years after repair of tetralogy of Fallot or
ventricular septal defect in infancy demonstrated more speech and language dysfunction in the group with
preoperative hypoxemia and cyanosis (36).
Postoperative systemic oxygen delivery can affect neurodevelopmental outcomes. Prolonged low postoperative
cerebral oxygen saturation (<45% for >180 minutes) following the Norwood operation for HLHS was associated
with the development of new or worsened ischemia on postoperative brain MRI (37). In a small study of neonates
with HLHS who underwent the Norwood procedure, low systemic venous oxygen saturation and hypotension
was associated with adverse neurodevelopmental outcomes (38). A study of neonates and infants undergoing
biventricular repair without aortic arch reconstruction found that lower Sto2 in the postbypass and early
postoperative period was associated with lower PDI scores (BSID-II) and brain hemosiderin on MRI (39).
Hypotension and Cardiac Arrest

In neonates undergoing congenital heart surgery, new postoperative WMI was found to be specifically
associated with low mean blood pressure during the first postoperative day (40).
Cardiac arrest places all organs at risk until circulation, either spontaneous or mechanical, is restored. A review
of pediatric cardiac extracorporeal membrane oxygenation (ECMO) and extracorporeal cardiopulmonary
resuscitation (ECPR) in children with cardiac disease identified 10 studies that examined survival and neurologic
outcomes after ECPR (41). Overall survival of ECPR was 49% (range 33%-79%). In the nine studies describing
Pediatric Cerebral Performance Category (PCPC) score (an early test of neurologic function), 79% of the
survivors had a PCPC score of ≤2, indicating normal or mild neurologic impairment. There is no data describing
long-term neurodevelopmental outcomes after cardiac arrest and ECPR.
Intraoperative Management Factors
Temperature
Hypothermia was first used in congenital heart surgery in 1953 to aid in atrial septal defect closure (42). As
discussed in detail in Chapter 8, the rationale for hypothermia is protection against ischemic damage by
decreasing the metabolic rate. Different levels of hypothermia may be used: moderate (25°C-32°C), deep (18°C-
20°C), and deep hypothermic circulatory arrest (DHCA) (16°C-18°C). In the pediatric population, the Q10 (ratio of
metabolic rate at two temperatures separated by 10°C) is higher (3.65) than that in adults (2.4-2.8) (43).
Hypothermia permits reduced CPB flow rates (or zero flow if employing DHCA) and provides a margin of safety
should a disastrous event occur during CPB (44). Hypothermia also reduces the
P.700
inflammatory response to CPB and cools tissues that are in contact with the myocardium (45).
Hypothermia is neuroprotective and the BCAS suggested that a duration of DHCA ≤41 minutes (95% 1-sided
lower confidence limit of 32 minutes) is safe (46,47). It should be noted that the equipment, blood gas
management (a-stat), and degree of hemodilution (hematocrit of 20%) used in the BCAS are outdated and have
been modified (pH-stat, hematocrit no lower than 25%-30%) at most centers.
The frequency of use of hypothermia is surgeon-specific and there has been increasing utilization of
normothermic bypass (48). Some surgeons will use normothermia or mild hypothermia for most of their cases,
only using hypothermia during circulatory arrest. When not employing hypothermia, full-flow CPB (150
mL/kg/min) is recommended. Although the feasibility of neonatal cardiac surgery with normothermic bypass has
been shown, there is still no convincing evidence of its superiority over hypothermic CPB for brain protection
(49,50,51). What is known is that cerebral hyperthermia during rewarming is associated with neurocognitive
dysfunction in both adults and children (52,53,54).
Deep Hypothermic Circulatory Arrest versus Continuous Low-Flow Bypass

A prospective, randomized trial performed at Boston Children’s Hospital between 1988 and 1992 assigned
infants with D-transposition of the great arteries undergoing the arterial switch operation to a method of support
consisting predominantly of DHCA or continuous low-flow CPB (55). This study is frequently referred to as the
BCAS. Developmental and neurologic evaluation and brain MRI were performed at 1 year of age. Patients
randomized to circulatory arrest had a significantly lower mean PDI score on the BSID-II. The PDI score was
inversely related to the duration of DHCA, with a longer duration arrest also associated with an increased risk of
neurologic abnormalities. The authors were unable to determine a safe threshold for duration of DHCA but noted
that a period shorter than 41 minutes had minimal effect on the PDI score and that significant deficits were more
prevalent in those infants that had a circulatory arrest period greater than 45 minutes. At 4- and 8-year follow-up,
the BCAS found worse motor and speech function in the circulatory arrest group (56,57). However, measures of
behavior were worse in subjects randomized to continuous low-flow CPB. At the 16-year evaluations, fewer
significant treatment group differences were found but the scores of both groups tended to be lower than
normative test populations (18). The circulatory arrest cohort scored lower on tests of executive function and
visual spatial skills. Postoperative seizures were the medical variable most commonly related to worse outcomes.
Socioeconomic status explained more test variation than did treatment group assignment.
The effect of DHCA as a modifier of neurodevelopmental outcomes was evaluated at 4 years of age in the
prospective observational study of APOE polymorphisms and infant cardiac surgery without aortic arch
obstruction (58). There were no differences in unadjusted outcomes between those infants that received
circulatory arrest (mean duration 36 minutes) and those that did not. However, consistent with previously
published data, nonmodifiable patient factors were significantly associated with neurodevelopmental outcomes.
Presence of a genetic anomaly, lower socioeconomic status and maternal education, and younger gestational
age were all associated with worse outcomes.
Deep Hypothermic Circulatory Arrest versus Regional Cerebral Perfusion

There has been increasing interest in regional cerebral perfusion (RCP) to avoid or minimize use of DHCA. A
study from the University of Michigan randomized 77 neonates to receive either DHCA or RCP during the
Norwood operation (59). Neurodevelopmental testing was performed before the second stage operation and at
age 1 year using BSID-II. The entire cohort demonstrated delayed neurodevelopment with the PDI scores being
lower than the MDI scores. There was no statistically significant difference in PDI or MDI scores between the two
groups, although the point estimates were consistently lower for the RCP group.
Another study of 57 neonates examined pre- and postoperative MRI and 1-year neurodevelopmental outcomes
with use of RCP during aortic arch reconstruction (60). The mean RCP time was 71 minutes and the mean RCP
flow rate was 57 mL/kg/min. New postoperative brain injury on MRI was seen in 40% of patients, which is
comparable to that of other studies. Cognitive outcomes (BSID-III) at age 1 year were at reference population
norms, while language and motor outcomes were lower than reference population norms.
A recent study from the Netherlands randomized neonates to either DHCA or antegrade cerebral perfusion (61).
MRI was done preoperatively and 1 week postoperatively. Preoperatively, 51% of the cohort had cerebral injury
with WMI affecting 49% of all patients. No difference was found between the circulatory arrest and antegrade
perfusion cohorts in terms of new cerebral injury (78% vs. 72% respectively, p = 0.66). The most common type of
injury was ischemic WMI, but infarctions of the thalamus, basal ganglia, or internal capsule were seen only after
antegrade cerebral perfusion. Motor and cognitive testing performed at 24 months showed no difference
between the two groups.
Blood Gas Management

Blood gas management (pH strategy) is an important part of the operative management of patients during
hypothermic CPB. The two commonly utilized methods are a-stat and pH-stat. While laboratory studies found
improved cerebral energetics and tissue oxygenation during deep hypothermic bypass and after circulatory
arrest with a pH-stat strategy, this has not translated into improved outcomes in humans (62,63). A prospective,
randomized study comparing these
P.701
two strategies demonstrated significantly earlier return of electroencephalogram (EEG) activity and a tendency to
fewer EEG seizures in patients randomized to pH-stat management (64). However, neurodevelopmental testing
at 1 year of age was not consistently associated with improved or impaired outcome with either strategy (65).
Despite this, most clinical and animal data favors the use of pH-stat blood gas management during hypothermia
as more uniform cerebral cooling has been demonstrated (66,67,68,69). One possible explanation for the lack of
difference with either strategy in congenital heart surgery is the multiplicity of nonmodifiable factors.
Hematocrit
Hematocrit is a modifiable, operative management variable that has been shown to affect neurodevelopmental
outcomes. A prospective, randomized study at Boston Children’s Hospital assigned infants to undergo
hemodilution to a hematocrit level of either 20% or 30% (70). At age 1 year, the lower hematocrit group had
significantly lower PDI scores, with the PDI scores of both groups significantly lower than population norms. A
second prospective, randomized study by the same group compared bypass hematocrits of 25% and 35% (71).
There were no differences between the groups on tests of neurodevelopment at 1 year of age. Similarly,
developmental outcomes of both groups were below population norms. Analysis of the combined Boston
hematocrit trials demonstrated that PDI scores at 1 year of age varied nonlinearly with scores increasing up to
23.5% hematocrit with a plateau effect beyond 23.5% (72). Based largely on these studies, most centers have
chosen 25% as the lowest acceptable hematocrit while on CPB.
Glucose
In contrast to the first reported study of intensive insulin therapy in critically ill adults, a more recent large
international randomized trial of tight glycemic control in critically ill adults found that tight glucose control
increased mortality (73,74). A single-center study of glycemic control in a mixed medical and surgical (including
cardiac surgery) pediatric intensive care unit compared tight glycemic control to standard management (75). The
cohort receiving tight glycemic control had a lower mortality, but experienced much higher rates of hypoglycemia
(25% vs. 1%). Hypoglycemia is potentially dangerous to the developing brain. A more recent two-center
prospective randomized trial enrolled 980 children 10 to 36 months of age undergoing congenital heart surgery
with CPB to receive either tight glycemic control or standard glucose management postoperatively (76). There
was no difference between the groups in infection rate, mortality, length of stay, or measures of organ failure.
Continuous glucose monitoring was used, and although the tight glycemic group had a low rate (3%) of severe
hypoglycemia (blood glucose <40 mg/dL), with no obvious benefits it seems unnecessary to institute tight
glycemic control and risk deleterious effects of episodes of hypoglycemia on the developing brain.
INTRAOPERATIVE NEUROMONITORING
The history of intraoperative neurophysiologic monitoring has been reviewed by Nuwer and is as follows (77).
Intraoperative neurophysiologic monitoring was first reported in 1937 by Penfield and Boldrey who used direct
cortical stimulation during surgery for epilepsy. Recording an EEG directly from exposed cerebral cortex, also for
epilepsy surgery, was first reported in 1949 by Jasper and Marshall and Walker (78,79). Routine scalp EEG,
utilized first during carotid endarterectomy, was introduced in the late 1960s. Doppler ultrasound evaluation of
the extracranial cerebral arteries was first reported in 1965 by Miyazaki and Kato (80). Transcranial Doppler
(TCD) sonography was reported by Aaslid in 1982 after measuring the flow of the middle cerebral artery with a
probe placed on the scalp over the temporal bone (81). Near-infrared spectroscopy (NIRS) was introduced
clinically in 1985 for monitoring of cerebral oxygenation in preterm infants (82). Spinal intraoperative monitoring,
specifically somatosensory evoked potentials (SEP), was developed in the 1970s (77,53) The first intraoperative
neuromonitoring clinical service was established at the University of California at Los Angeles in 1979, and
commercial neurophysiologic monitoring equipment became available in the early 1980s (77).
Many institutions have adopted intraoperative neuromonitoring as a potential mechanism to minimize brain injury
in congenital heart surgery. It can be as simple as having the anesthesiologist monitor NIRS or as complex as
using four modalities with a certified neuromonitoring professional in the operating room providing feedback
during each case. The most common modalities employed are NIRS, electroencephalography (EEG), and TCD.
Intraoperative NIRS is used at most congenital heart centers for all CPB cases. Somatosensory evoked
potentials (SSEP or SEP) are used very little in congenital heart surgery (83).
Near-Infrared Spectroscopy
NIRS is a noninvasive optical technology that relies on the relative transparency of biological tissues to near-
infrared light. Spectroscopic separation results from the different absorption spectra of oxyhemoglobin (HbO) and
deoxyhemoglobin (HbR) (84). Commercial NIRS monitors use continuous wave, spatially-resolved spectroscopy
to measure the ratio of HbO to total hemoglobin (HbO + HbR) and provide an estimate of cerebral tissue oxygen
saturation (Sto2). The measurement is from a mixture of arterioles, capillaries and venules, with the venous
compartment representing approximately 70% of the signal (venous-weighted) (85). It is important to note that
inferences on global cerebral oxygen balance are being made from a regional measurement(s). NIRS is the only
modality capable of monitoring the brain during circulatory arrest as the EEG is typically flat and TCD will
indicate no flow. Cooling and increasing levels of anesthetics will decrease cerebral oxygen metabolism (CMRo2)
P.702
and increase an individual patient’s Sto2 value. The decrease in CMRo2 with cooling is greater than the
decrease in CBF with both a-stat and pH-stat strategies (86). It is unknown what thresholds and time at or below
those thresholds are important in the pediatric cardiac surgery patient. As there are no established guidelines in
pediatric patients, some centers use parameters derived from adult studies (a decrease in Sto2 below 50%
[absolute] and/or a drop >20% [relative] from baseline). Many centers follow trends rather than absolute values
of Sto2, particularly as there is significant interindividual variation. Additionally, as values for Sto2 in children with
CHD are more variable than in adult cardiac surgery patients, and with some values close to or below 50% at
“baseline,” it is probably more appropriate to consider threshold values derived from laboratory studies (87,88).
Electroencephalography
Intraoperative EEG can be used to detect ischemia during congenital heart surgery. To monitor the EEG, cup
electrodes are placed on the scalp and shaving hair is not required. A 4-channel EEG (four electrodes over each
hemisphere and a ground in the middle) will measure the anterior and posterior circulations of both hemispheres.
EEG recordings demonstrate significant variability between individuals and proper analysis requires skill and
experience at pattern recognition (89).
In patients under anesthesia, EEG slowing can be associated with increasing depth of anesthesia and/or
cerebral hypoxiaischemia and/or hypothermia. As the most important monitoring change associated with cerebral
hypoxia-ischemia is EEG slowing, the multifactorial etiology of EEG slowing is a significant limitation of EEG
monitoring (90). In general, patients under anesthesia with adequate cerebral oxygen delivery will demonstrate
high-amplitude, low-frequency waves (theta and delta) on the EEG (91). Ischemia is represented by slowing with
preservation of voltage (mild-to-moderate ischemia) or loss of voltage (severe ischemia), burst suppression, or a
flat EEG.
Slowing is usually not focal or asymmetric unless there is a previous cortical injury or abnormality, or there is
new, acute injury. Fast-frequency frontal beta waves are seen with lower levels of anesthetics, and can be
difficult to distinguish from epileptiform waves (89). As with slowing, focal disparities are a sign of previous injury
or new, acute ischemia or injury. New epileptiform or epileptic activity indicates cortical dysfunction usually due
to ischemia. Distinguishing concerning changes from artifact can be a challenge and requires significant
experience. Artifact can be due to pulsation (near a pulsatile vessel), electrocardiogram (EKG) interference,
electrical interference (such as a headlight, operating room bed, or lower-extremity compression devices), or a
loose electrode (92). Comparing the EEG abnormalities to the QRS complexes on the EKG often helps resolve
cases of suspected pulsation and EKG artifact. Temporarily interrupting other electrical sources in the operating
room can help determine if electrical interference is present. Securing electrodes and checking them will help
prevent artifact due to loose electrodes.
There are times during congenital heart operations with CPB that changes in the EEG can be expected (90).
Slowing is often seen during cannulation (arterial and/or venous) of smaller patients. It is thought that the larger
cannula to vessel ratio in small patients may cause obstruction to flow. There is a transient depression in the
EEG at the onset of CPB, likely due to hemodilution and relative oxygen deficiency. Finally, hypotension after the
release of the aortic cross clamp can cause EEG slowing. DHCA causes slowing and eventually an isoelectric
(flat) EEG. When combined with other neuromonitoring modalities, the cause of the slowing can be better
delineated (93).
Processed EEG monitors use parameters derived from power analysis and/or bispectral analysis of the raw
EEG, and are technically easier to use. The Bispectral Index (BIS) monitor was approved by the Food and Drug
administration in 1996 as an EEG-based monitor of anesthetic effect (94). The BIS is an easy-to-use, quickly
applied, 1-channel processed EEG. It describes the continuous, varying signal of the EEG in a nonlinear scale
ranging from 100 (awake) to 0 (complete cortical suppression). The BIS Bilateral System can also display up to 4
channels of EEG and can be used as a marker of cortical silence during DHCA. The hypothesized benefits and
limitations of BIS and frontal channel EEG monitoring in the cardiac surgical population has been reviewed by
Kertai et al. (91).
Transcranial Doppler Sonography

TCD sonography measures the velocity of red blood cells in the intracranial cerebral arteries (81). TCD can
determine both the presence and direction of blood flow. The probe is commonly positioned over the temporal
bone above the zygomatic arch to monitor flow in the middle cerebral artery. Peak systolic velocity and mean
velocity are markers of cerebral inflow while end-diastolic velocity is inversely related to cerebrovascular
resistance. Inflow obstruction will result in a decrease in the peak and mean systolic velocities. If accompanied
by EEG slowing, an ischemic process is likely evolving (90). Outflow obstruction, for example with venous
cannula malposition, will increase the cerebrovascular resistance and decrease the end-diastolic velocity. High-
intensity transient signals (HITS) represent the presence of gaseous or particulate emboli within the insonated
blood vessel. Data from adult studies indicate that an increasing number of HITS may predict postoperative
neurobehavioral and pulmonary complications (83,95). TCD is currently unable to fully differentiate between
gaseous and particulate emboli. Factors limiting widespread use of TCD in the pediatric population include the
challenge of maintaining a stable probe position without patient injury or dislodgment by the surgeon, the
relatively long learning curve to become proficient in TCD monitoring, and widely varying ranges of intra- and
interindividual velocities.
P.703
Biomarkers
Various serum biomarkers have been found to be associated with neurodevelopmental outcome. In a study of
infants less than 6 weeks of age undergoing intracardiac surgery, postoperative lactic acid level correlated with
survival and neurodevelopmental outcome (96). Survivors had lower lactate levels than nonsurvivors, and those
survivors with suboptimal neurodevelopmental outcomes had a longer time to plasma lactate normalization (≤2
mmol/L) when compared to those with normal neurodevelopmental outcomes.
Brain type natriuretic peptide (BNP) is a serum marker of heart failure that is elevated when there are increased
right or left heart pressures. A study of single-ventricle patients in the enalapril trial examined the association of
BNP and height with neurodevelopmental outcomes (97). The investigators discovered that patients with high
BNP values and poor growth had worse MDI scores on the BSID-II at 14 months.
CURRENT DATA
Optimizing long-term functional outcome for every patient is a major focus of congenital heart surgery. The
landmark study reporting the benefit of multimodality neurophysiologic monitoring in pediatric cardiac surgery
was reported by Austin et al. in 1997 (93). An interventional algorithm was developed in a cohort of 250 patients.
The main finding was neurologic sequelae in 7% of patients without noteworthy changes on neuromonitoring, in
6% of patients with interventions in response to noteworthy changes, and in 26% of patients with a noteworthy
change but no intervention. Limitations of this study were its retrospective analysis, nonrandomized design, and
changing clinical practice in response to neuromonitoring over the time period of the study. As mentioned above,
many institutions now employ one or more modalities of intraoperative neuromonitoring. Although there are many
single-institution case-control, observational, and retrospective studies (see appendix material of cited reference
for list of studies), there is a paucity of randomized, prospective trials so that there remains considerable debate
about the benefit, if any, that intraoperative neuromonitoring provides (98).
More recently, one report describes an institution’s attempts to decrease the risk of neurologic injury to neonates
undergoing cardiac surgery through the use of intraoperative neuromonitoring (99). They review their high-flow
and increased oxygen delivery strategy for neonatal CPB and discuss their use of bilateral NIRS and TCD to
guide antegrade cerebral perfusion (ACP) to minimize duration or eliminate DHCA during aortic arch
reconstruction. In spite of this strategy, 36% of neonates had new postoperative WMI, infarction, or hemorrhage
on brain MRI (100). Neurodevelopmental testing (BSID-III) at age 1 year found no significant difference in
cognitive, language, and motor outcomes with the normative reference population (60). In neonates undergoing
the arterial switch operation (without ACP), these authors also found that neurodevelopmental outcome means
were within population ranges, concluding that larger, prospective observational trials were necessary to
corroborate these findings (101).
Another group discussed their approach to multimodality monitoring and reviewed the available evidence (98).
They utilize NIRS, TCD, EEG, and SEP. Raw and processed EEG is monitored continuously with real-time
neurologist oversight after placement of the electrodes by a neurophysiologist. The authors intervene when Sto2
decreases more than 20% from the postinduction baseline. However, they admit that this threshold is derived
from adult studies and that a pediatric threshold has not been defined. Their use of TCD is similar to previous
reports, namely detection of alterations in CBF and emboli. The authors also describe their preference for 4-
channel EEG in those less than age 2 years (8-channel for those older), and their routine use of SEP in those
older than 2 years. This group has not yet reported the influence of interventions on the rate of adverse events
and neurodevelopmental outcome. As stated above, review of the available neuromonitoring data by these
authors concluded that evidence is limited to show that intraoperative neuromonitoring is associated with
improved neurologic outcome.
A systematic review of neuromonitoring and neuroprotective strategies during CPB was performed by another
group that included pediatric cardiac surgeons, a pediatric neurologist, and a pediatric anesthesiologist (102).
The literature review encompassed 20 years (1990-2010) and initially identified 527 manuscripts. Review by this
group of abstracts resulted in 187 potential manuscripts based on the inclusion and exclusion criteria. Another
review generated the final list of 162 manuscripts. The primary outcome was evidence of structural brain injury or
functional disability and was demonstrated in only 43% of the manuscripts analyzed. Only 13% of the studies
were randomized prospective trials. Manuscript categories analyzed included blood gas management,
hematocrit, EEG, cooling, glycemic control, S100b, TCD, NIRS, and DHCA/low flow CPB/RCP. The largest
group of manuscripts were those pertaining to DHCA, low-flow CPB, and RCP ( n = 44 manuscripts), followed by
NIRS ( n = 35). As with the aforementioned study, these authors also concluded that data supporting the use of
current neuromonitoring and neuroprotective techniques are limited. Only two studies (1.3%) were graded as
procedures or treatments that are recommended as the benefits clearly outweigh the risks (American College of
Cardiology/American Heart Association level of evidence grade class I, level B). These two studies evaluated the
effect of hemodilution on neurodevelopmental outcomes and suggest that severe hemodilution (probably ≤24%)
is associated with adverse neurodevelopmental outcomes (70,72). No category reached class I, level A—
demonstration of a clear benefit and recommended as effective. No studies reported a benefit to use of
perioperative medications including phenobarbital, erythropoietin,
P.704
allopurinol, aprotinin, tranexamic acid, and steroids. Since this systematic review, there have not been many
manuscripts added to the literature on the subject of intraoperative neuromonitoring.
Most centers have adopted protocols for neuroprotection and neuromonitoring that they feel are safe and work
best at their institution. At The Children’s Hospital of Philadelphia, the neuromonitoring and neuroprotection
strategy for CPB currently includes the following: The CPB pump setup contains a bubble detector and
continuous arterial blood gas and venous saturation monitors. The goal hematocrit for patients under 1 year of
age is >30%. For those over 1 year of age, the goal hematocrit is >25%. While on CPB, the goal mean arterial
pressure is 25 to 55 mm Hg, the lower range being for neonates or infants weighing 5 kg or less. This increases
to 60 to 80 mm Hg for those aged 11 years and older and weighing over 40 kg. α-Stat is used at normothermia
and when rewarming, while pH-stat is used during cooling and maintenance of hypothermia. The arterial-to-
patient temperature gradient is maintained between 8°C and 10°C when cooling. Cooling is performed for at
least 15 minutes prior to circulatory arrest and the arterial temperature is maintained above 15°C. Warming is
also done with the arterial-to-patient temperature gradient maintained at 8°C to 10°C.
CONCLUSION
There are still many questions to be answered in regard to brain injury, neuroprotective strategies,
neuromonitoring, and neurodevelopmental outcomes in the pediatric cardiac surgical population. It is clear
now that many patients have preoperative cerebral abnormalities, and that some with a structurally and
functionally normal brain are at higher risk of brain injury during congenital heart surgery because of a
genetic predisposition. Longer-term follow-up will continue to help plan future strategies to optimize
neurodevelopmental outcomes. CPB circuitry and techniques continue to evolve and there is still no
consensus as to whether DHCA or RCP is superior during aortic arch reconstruction. Over the past 10 to 15
years, and apart from the debate over regional perfusion and circulatory arrest, research to improve
neurologic outcomes in congenital heart surgery has shifted from the intraoperative period and techniques
of CPB to the fetal, preoperative, and early postoperative periods. Whether intraoperative neuromonitoring
techniques prevent brain injury remains to be proven. A prospective, randomized study with longer-term
neurodevelopmental outcomes has not been performed and may never be accomplished as many centers
have already adopted these technologies as a standard of care without proof of benefit. Perhaps
neuromonitoring in pediatric cardiac surgery should be viewed in a similar light to that of pulse oximetry. In
spite of widespread acceptance and use, a Cochrane Review of pulse oximetry for perioperative monitoring
concluded that although pulse oximetry can detect hypoxemia and related events, there was no evidence
that it affected outcome of anesthesia (103). As stated by Pollard in 1996 following FDA approval of the first
commercial cerebral oximeter, “It is a trend monitor of greatest value in situations in which intracranial
hemoglobin saturation could dangerously change and in which changes in systemic hemodynamics and
oxygenation would not predict that change” (104). The best outcomes in such a heterogeneous field as
congenital heart surgery are often achieved by doing what is comfortable and safe for an individual
surgeon, team, and institution.
KEY Points
Survivors of repair of CHD in the neonatal period demonstrate cognitive, motor, speech, visual, and
learning abnormalities.
Adverse neurodevelopmental outcome is associated with both nonmodifiable and modifiable factors.
Nonmodifiable factors include abnormal fetal brain development, altered cerebral hemodynamics,
preoperative WMI, prematurity, low socioeconomic status and parental IQ, genetic syndromes and
polymorphisms, and low birth weight.
Modifiable factors include perioperative hypoxemia, hypotension, acidosis, and cardiac arrest. CPB
factors include temperature, perfusion strategy (low-flow bypass, DHCA, and RCP), blood gas
management, hematocrit, and glucose.
In the current era, nonmodifiable factors have a greater impact on neurodevelopmental outcomes than
modifiable factors.
Intraoperative neuromonitoring has been adopted by many institutions as a potential mechanism to
minimize brain injury.
NIRS for measurement of cerebral tissue oxygen saturation is the most widely used modality. However,
threshold values and time at or below those thresholds associated with brain injury in the pediatric
cardiac surgical population have yet to be determined.
EEG with a limited montage and raw or processed EEG is used by some centers. Without it being part
of a multimodality neuromonitoring technique, it can be difficult to distinguish EEG changes due to
cerebral hypoxia-ischemia from those caused by anesthetic drugs or hypothermia.
P.705
TCD sonography can determine the presence, magnitude, and direction of blood flow, as well as
detect emboli in the insonated vessel. Widespread use in the pediatric population is limited by the
challenge of maintaining a stable probe position without patient injury or dislodgment by the surgical
team, a relatively long learning curve to become proficient, and wide inter- and intraindividual variability
in velocities.
Multimodality neuromonitoring and intervention algorithms have been developed, but whether
intraoperative neuromonitoring prevents brain injury remains to be proven.
Postoperative lactic acid level in neonates and young infants correlates with survival and
neurodevelopmental outcome. Survivors had lower lactate levels than nonsurvivors, and those survivors
with suboptimal neurodevelopmental outcomes had a longer time to plasma lactate normalization.
REFERENCES
1. Gaynor JW, Gerdes M, Zackai EH, et al. Apolipoprotein E genotype and neurodevelopmental sequelae of
infant cardiac surgery. J Thorac Cardiovasc Surg 2003;126(6):1736-1745.
2. Limperopoulos C, Tworetzky W, McElhinney DB, et al. Brain volume and metabolism in fetuses with
congenital heart disease: evaluation with quantitative magnetic resonance imaging and spectroscopy.
Circulation 2010;121(1):26-33.
3. Mahle WT, Wernovsky G. Neurodevelopmental outcomes in hypoplastic left heart syndrome. Semin
Thorac Cardiovasc Surg Pediatr Card Surg Annu 2004;7:39-47.
4. Glauser TA, Rorke LB, Weinberg PM, et al. Congenital brain anomalies associated with the hypoplastic
left heart syndrome. Pediatrics 1990;85(6):984-990.
5. Licht DJ, Wang J, Silvestre DW, et al. Preoperative cerebral blood flow is diminished in neonates with
severe congenital heart defects. J Thorac Cardiovasc Surg 2004;128(6):841-849.
6. Chiron C, Raynaud C, Mazière B, et al. Changes in regional cerebral blood flow during brain maturation in
children and adolescents. J Nucl Med 1992;33(5):696-703.
7. Ashwal S, Perkin RM, Thompson JR, et al. CBF and CBF/Pco2 reactivity in childhood strangulation.
Pediatr Neurol 1991;7(5):369-374.
8. Ashwal S, Stringer W, Tomasi L, et al. Cerebral blood flow and carbon dioxide reactivity in children with
bacterial meningitis. J Pediatr 1990;117(4):523-530.
9. Kinney HC, Panigrahy A, Newburger JW, et al. Hypoxic-ischemic brain injury in infants with congenital
heart disease dying after cardiac surgery. Acta Neuropathol 2005;110(6):563-578.
10. Licht DJ, Shera DM, Clancy RR, et al. Brain maturation is delayed in infants with complex congenital
heart defects. J Thorac Cardiovasc Surg 2009;137(3):529-536; discussion 536-537.
11. Mahle WT, Tavani F, Zimmerman RA, et al. An MRI study of neurological injury before and after
congenital heart surgery. Circulation 2002;106(12, Suppl 1):I109-I114.
12. Miller SP, Ferriero DM, Leonard C, et al. Early brain injury in premature newborns detected with magnetic
resonance imaging is associated with adverse early neurodevelopmental outcome. J Pediatr
2005;147(5):609-616.
13. Galli KK, Zimmerman RA, Jarvik GP, et al. Periventricular leukomalacia is common after neonatal cardiac
14. Folkerth RD. Periventricular leukomalacia: overview and recent findings. Pediatr Dev Pathol 2006;9(1):3-
13.
15. Dimitropoulos A, McQuillen PS, Sethi V, et al. Brain injury and development in newborns with critical
congenital heart disease. Neurology 2013;81(3):241-248.
16. Miller SP, McQuillen PS, Hamrick S, et al. Abnormal brain development in newborns with congenital heart
disease. N Engl J Med 2007;357(19):1928-1938.
17. Filipouski GR, Silveira RC, Procianoy RS. Influence of perinatal nutrition and gestational age on
neurodevelopment of very low-birth-weight preterm infants. Am J Perinatol 2013;30(8):673-680.
18. Bellinger DC, Wypij D, Rivkin MJ, et al. Adolescents with D-transposition of the great arteries corrected
with the arterial switch procedure/clinical perspective. Circulation 2011;124(12):1361-1369.
19. Alton GY, Robertson CM, Sauve R, et al. Early childhood health, growth, and neurodevelopmental
outcomes after complete repair of total anomalous pulmonary venous connection at 6 weeks or younger. J
20. Ohye RG, Sleeper LA, Mahony L, et al. Comparison of shunt types in the Norwood procedure for single-
ventricle lesions. N Engl J Med 2010;362(21):1980-1992.
21. Newburger JW, Sleeper LA, Bellinger DC, et al. Early developmental outcome in children with hypoplastic
left heart syndrome and related anomalies: the single ventricle reconstruction trial. Circulation
2012;25(17):2081-2091.
22. Franceschini P, Guala A, Vardeu MP, et al. The Williams syndrome: an Italian collaborative study.
Minerva Pediatr 1996;48(10):421-428.
23. Swillen A, Vogels A, Devriendt K, et al. Chromosome 22q11 deletion syndrome: update and review of the
clinical features, cognitive-behavioral spectrum, and psychiatric complications. Am J Med Genet
2000;97(2):128-135.
24. Wälti U. Intelligence profile in children with trisomy 21. Helv Paediatr Acta 1973;30(Suppl):38-39.
25. Wood A, Massarano A, Super M, et al. Behavioural aspects and psychiatric findings in Noonan’s
syndrome. Arch Dis Child 1995;72(2):153-155.
26. Barnea-Goraly N, Menon V, Krasnow B, et al. Investigation of white matter structure in velocardiofacial
syndrome: a diffusion tensor imaging study. Am J Psychiatry 2003;160(10):1863-1869.
27. Moss EM, Batshaw ML, Solot CB, et al. Psychoeducational profile of the 22q11.2 microdeletion: a
complex pattern. J Pediatr 1999;134(2):193-198.
28. van Amelsvoort T, Henry J, Morris R, et al. Cognitive deficits associated with schizophrenia in velo-
cardio-facial syndrome. Schizophr Res 2004;70(2/3):223-232.
29. Gaynor JW, Wernovsky G, Jarvik GP, et al. Patient characteristics are important determinants of
neurodevelopmental outcome at one year of age after neonatal and infant cardiac surgery. J Thorac
Cardiovasc Surg 2007;133(5):1344-1353, 53.e1-53.e3.
30. Gaynor JW, Nord AS, Wernovsky G, et al. Apolipoprotein E genotype modifies the risk of behavior
problems after infant cardiac surgery. Pediatrics 2009;124(1):241-250.
31. Kim DS, Stanaway IB, Rajagopalan R, et al. Results of genome-wide analyses on neurodevelopmental
phenotypes at four-year follow-up following cardiac surgery in infancy. PLoS One 2012;7(9):e45936.
32. Miller G, Eggli KD, Contant C, et al. Postoperative neurologic complications after open heart surgery on
young infants. Arch Pediatr Adolesc Med 1995;149(7):764-768.
33. Mahle WT, Clancy RR, McGaurn SP, et al. Impact of prenatal diagnosis on survival and early neurologic
morbidity in neonates with the hypoplastic left heart syndrome. Pediatrics 2001;107(6):1277-1282.
34. Satomi G, Yasukochi S, Shimizu T, et al. Has fetal echocardiography improved the prognosis of
congenital heart disease? Comparison of patients with hypoplastic left heart syndrome with and without
prenatal diagnosis. Pediatr Int 1999;41(6):728-732.
35. Tworetzky W, McElhinney DB, Reddy VM, et al. Improved surgical outcome after fetal diagnosis of
hypoplastic left heart syndrome. Circulation 2001;103(9):1269-1273.
36. Hövels-Gurich HH, Bauer SB, Schnitker R, et al. Long-term outcome of speech and language in children
after corrective surgery for cyanotic or acyanotic cardiac defects in infancy. Eur J Paediatr Neurol
2008;12(5):378-386.
37. Dent CL, Spaeth JP, Jones BV, et al. Brain magnetic resonance imaging abnormalities after the Norwood
procedure using regional cerebral perfusion. J Thorac Cardiovasc Surg 2005;130(1):1523-1530.
38. Hoffman GM, Mussatto KA, Brosig CL, et al. Systemic venous oxygen saturation after the Norwood
procedure and childhood neurodevelopmental outcome. J Thorac Cardiovasc Surg 2005;130(4):1094-1100.
P.706
39. Kussman BD, Wypij D, Laussen PC, et al. Relationship of intraoperative cerebral oxygen saturation to
neurodevelopmental outcome and brain magnetic resonance imaging at 1 year of age in infants undergoing
biventricular repair. Circulation 2010;122(3):245-254.
40. McQuillen PS, Barkovich AJ, Hamrick SE, et al. Temporal and anatomic risk profile of brain injury with
neonatal repair of congenital heart defects. Stroke 2007;38(2, Suppl):736-741.
41. Joffe AR, Lequier L, Robertson CM. Pediatric outcomes after extracorporeal membrane oxygenation for
cardiac disease and for cardiac arrest: a review. ASAIO J 2012;58(4):297-310.
42. Lewis FJ, Taufic M. Closure of atrial septal defects with the aid of hypothermia; experimental
accomplishments and the report of one successful case. Surgery 1953;33(1):52-59.
43. Greeley WJ, Kern FH, Ungerleider RM, et al. The effect of hypothermic cardiopulmonary bypass and
total circulatory arrest on cerebral metabolism in neonates, infants, and children. J Thorac Cardiovasc Surg
1991;101(5):783-794.
44. Bering EA Jr, Bernhard WF, Schwarz HF, et al. Vascular resistance and oxygen utilization of the brain,
heart, and whole body in profound hypothermia. Surg Forum 1961;12:411-412.
45. Bel A, Elleuch N, Florens E, et al. Temperature and inflammatory response on cardiopulmonary bypass.
Cardiovasc Eng 2001;5(3):230-233.
46. Newburger JW, Jonas RA, Wernovsky G, et al. A comparison of the perioperative neurologic effects of
hypothermic circulatory arrest versus low-flow cardiopulmonary bypass in infant heart surgery. N Engl J Med
1993;329(15):1057-1064.
47. Wypij D, Newburger JW, Rappaport LA, et al. The effect of duration of deep hypothermic circulatory
arrest in infant heart surgery on late neurodevelopment: the Boston Circulatory Arrest Trial. J Thorac
Cardiovasc Surg 2003;126(5):1397-1403.
48. Durandy Y. Warm pediatric cardiac surgery: European experience. Asian Cardiovasc Thorac Ann
2010;18(4):386-395.
49. de Leval MR. ‘Because we can, should we…?’. Eur J Cardiothorac Surg 2006;30(5):693-694.
50. Pouard P, Mauriat P, Ek F, et al. Normothermic cardiopulmonary bypass and myocardial cardioplegic
protection for neonatal arterial switch operation. Eur J Cardiothorac Surg 2006;30(5):695-699.
51. Poncelet AJ, van Steenberghe M, Moniotte S, et al. Cardiac and neurological assessment of
normothermia/warm blood cardioplegia vs hypothermia/cold crystalloid cardioplegia in pediatric cardiac
surgery: insight from a prospective randomized trial. Eur J Cardiothorac Surg 2011;40(6):1384-1390.
52. Arrowsmith JE, Grocott HP, Reves JG, et al. Central nervous system complications of cardiac surgery. Br
J Anaesth 2000;84(3):378-393.
53. Bar-Yosef S, Mathew JP, Newman MF, et al. Prevention of cerebral hyperthermia during cardiac surgery
by limiting on-bypass rewarming in combination with post-bypass body surface warming: a feasibility study.
Anesth Analg 2004;99(3):641-646.
54. Sahu B, Chauhan S, Kiran U, et al. Neuropsychological function in children with cyanotic heart disease
undergoing corrective cardiac surgery: effect of two different rewarming strategies. Eur J Cardiothorac Surg
2009;35(3):505-510.
55. Bellinger DC, Jonas RA, Rappaport LA, et al. Developmental and neurologic status of children after heart
surgery with hypothermic circulatory arrest or low-flow cardiopulmonary bypass. N Engl J Med
1995;332(9):549-555.
56. Bellinger DC, Wypij D, duDuplessis AJ, et al. Neurodevelopmental status at eight years in children with
dextro-transposition of the great arteries: the Boston Circulatory Arrest Trial. J Thorac Cardiovasc Surg
2003;126(5):1385-1396.
57. Bellinger DC, Wypij D, Kuban KC, et al. Developmental and neurological status of children at 4 years of
age after heart surgery with hypothermic circulatory arrest or low-flow cardiopulmonary bypass. Circulation
1999;100(5):526-532.
58. Fuller S, Rajagopalan R, Jarvik GP, et al. J. Maxwell Chamberlain Memorial Paper for congenital heart
surgery. Deep hypothermic circulatory arrest does not impair neurodevelopmental outcome in school-age
children after infant cardiac surgery. Ann Thorac Surg 2010;90(6):1985-1994; discussion 1994-1995.
59. Goldberg CS, Bove EL, Devaney EJ, et al. A randomized clinical trial of regional cerebral perfusion
versus deep hypothermic circulatory arrest: outcomes for infants with functional single ventricle. J Thorac
Cardiovasc Surg 2007;133(4):880-887.
60. Andropoulos DB, Easley RB, Brady K, et al. Neurodevelopmental outcomes after regional cerebral
perfusion with neuromonitoring for neonatal aortic arch reconstruction. Ann Thorac Surg 2013;95(2):648-654;
discussion 654-655.
61. Algra SO, Jansen NJ, van der Tweel I, et al. Neurological injury after neonatal cardiac surgery: a
randomized, controlled trial of 2 perfusion techniques. Circulation 2014;129(2):224-233.
62. Duebener LF, Hagino I, Sakamoto T, et al. Effects of pH management during deep hypothermic bypass
on cerebral microcirculation: alpha-stat versus pH-stat. Circulation 2002;106(12, Suppl 1):I103-I108.
63. Hindman BJ, Dexter F, Cutkomp J, et al. pH-stat management reduces the cerebral metabolic rate for
oxygen during profound hypothermia (17 degrees C). A study during cardiopulmonary bypass in rabbits.
Anesthesiology 1995;82(4):983-995; discussion 24A.
64. du Plessis AJ, Jonas RA, Wypij D, et al. Perioperative effects of alpha-stat versus pH-stat strategies for
deep hypothermic cardiopulmonary bypass in infants. J Thorac Cardiovasc Surg 1997;114(6):991-1000;
discussion 1000-1001.
65. Bellinger DC, Wypij D, du Plessis AJ, et al. Developmental and neurologic effects of alpha-stat versus
pH-stat strategies for deep hypothermic cardiopulmonary bypass in infants. J Thorac Cardiovasc Surg
2001;121(2):374-383.
66. Jonas RA. Optimal pH strategy for hypothermic circulatory arrest. J Thorac Cardiovasc Surg
2001;121(2):204-205.
67. Jonas RA, Bellinger DC, Rappaport LA, et al. Relation of pH strategy and developmental outcome after
hypothermic circulatory arrest. J Thorac Cardiovasc Surg 1993;106(2):362-368.
68. Kurth CD, O’Rourke MM, O’Hara IB. Comparison of pH-stat and alpha-stat cardiopulmonary bypass on
cerebral oxygenation and blood flow in relation to hypothermic circulatory arrest in piglets. Anesthesiology
1998;89(1):110-118.
69. Priestley MA, Golden JA, O’Hara IB, et al. Comparison of neurologic outcome after deep hypothermic
circulatory arrest with alpha-stat and pHstat cardiopulmonary bypass in newborn pigs. J Thorac Cardiovasc
Surg 2001;121(2):336-343.
70. Jonas RA, Wypij D, Roth SJ, et al. The influence of hemodilution on outcome after hypothermic
cardiopulmonary bypass: results of a randomized trial in infants. J Thorac Cardiovasc Surg
2003;126(6):1765-1774.
71. Newburger JW, Jonas RA, Soul J, et al. Randomized trial of hematocrit 25% versus 35% during
hypothermic cardiopulmonary bypass in infant heart surgery. J Thorac Cardiovasc Surg 2008;135(2):347-
354, e1-e4.
72. Wypij D, Jonas RA, Bellinger DC, et al. The effect of hematocrit during hypothermic cardiopulmonary
bypass in infant heart surgery: results from the combined Boston hematocrit trials. J Thorac Cardiovasc Surg
2008;135(2):355-360.
73. Finfer S, Chittock DR, Su SY, et al. Intensive versus conventional glucose control in critically ill patients.
N Engl J Med 2009;360(13):1283-1297.
74. van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in the critically ill patients. N
Engl J Med 2001;345(19):1359-1367.
75. Vlasselaers D, Milants I, Desmet L, et al. Intensive insulin therapy for patients in paediatric intensive care:
a prospective, randomised controlled study. Lancet 2009;373(9663):547-556.
76. Agus MS, Steil GM, Wypij D, et al. Tight glycemic control versus standard care after pediatric cardiac
surgery. N Engl J Med 2012;367(13): 1208-1219.
77. Nuwer MR. Introduction, history, and staffing for intraoperative monitoring. In: Galloway GM, Nuwer MR,
Lopez JR, et al., eds. Intraoperative neurophysiologic monitoring. Cambridge, MA: Cambridge University
Press, 2010: 1-9.
78. Jasper HH. Electroencephalography in child neurology and psychiatry. Pediatrics 1949;3(6):783-800.
79. Marshall C, Walker AE. Electrocorticography. Bull Johns Hopkins Hosp 1949;85(5):344-359.
80. Miyazaki M, Kato K. Measurement of cerebral blood flow by ultrasonic Doppler technique. Jpn Circ J
1965;29:375-382.
81. Aaslid R, Markwalder TM, Nornes H. Noninvasive transcranial Doppler ultrasound recording of flow
velocity in basal cerebral arteries. J Neurosurg 1982;57(6):769-774.
82. Brazy JE, Lewis DV, Mitnick MH, et al. Noninvasive monitoring of cerebral oxygenation in preterm infants:
preliminary observations. Pediatrics 1985;75(2):217-225.
83. Clark RE, Brillman J, Davis DA, et al. Microemboli during coronary artery bypass grafting. Genesis and
effect on outcome. J Thorac Cardiovasc Surg 1995;109(2):249-257; discussion 257-258.
P.707
84. Ferrari M, Mottola L, Quaresima V. Principles, techniques, and limitations of near infrared spectroscopy.
Can J Appl Physiol 2004;29(4):463-487.
85. Ito H, Kanno I, Iida H, et al. Arterial fraction of cerebral blood volume in humans measured by positron
emission tomography. Ann Nucl Med 2001;15(2):111-116.
86. Murkin JM, Farrar JK, Tweed WA, et al. Cerebral autoregulation and flow/metabolism coupling during
cardiopulmonary bypass: the influence of Paco2. Anesth Analg 1987;66(9):825-832.
87. Kurth CD, Levy WJ, McCann J. Near-infrared spectroscopy cerebral oxygen saturation thresholds for
hypoxia-ischemia in piglets. J Cereb Blood Flow Metab 2002;22(3):335-341.
88. Kurth CD, Steven JL, Montenegro LM, et al. Cerebral oxygen saturation before congenital heart surgery.
Ann Thorac Surg 2001;72(1):187-192.
89. Simon MV. Neurophysiologic tests used in the operating room. In: Simon MV, ed. Intraoperative
neurophysiology: a comprehensive guide to monitoring and mapping. New York, NY: Demos Medical
Publishing, 2010:1-46.
90. Edmonds HL Jr, Rodriguez RA, Audenaert SM, et al. The role of neuromonitoring in cardiovascular
surgery. J Cardiothorac Vasc Anesth 1996;10(1): 15-23.
91. Kertai MD, Whitlock EL, Avidan MS. Brain monitoring with electroencephalography and the
electroencephalogram-derived bispectral index during cardiac surgery. Anesth Analg 2012;114(3):533-546.
92. Simon MV, Gerrard JL, Eskandar EN. Electrocorticography. In: Simon MV, ed. Intraoperative
neurophysiology: a comprehensive guide to monitoring and mapping. New York, NY: Demos Medical
Publishing, 2010:95-130.
93. Austin EH III, Edmonds HL Jr, Auden SM, et al. Benefit of neurophysiologic monitoring for pediatric
cardiac surgery. J Thorac Cardiovasc Surg 1997;114(5):707-115, 717; discussion 715-716.
94. Johansen JW, Sebel PS. Development and clinical application of electroencephalographic bispectrum
monitoring. Anesthesiology 2000;93(5): 1336-1344.
95. Motallebzadeh R, Bland JM, Markus HS, et al. Neurocognitive function and cerebral emboli: randomized
study of on-pump versus off-pump coronary artery bypass surgery. Ann Thorac Surg 2007;83(2):475-482.
96. Cheung PY, Chui N, Joffe AR, et al. Postoperative lactate concentrations predict the outcome of infants
aged 6 weeks or less after intracardiac surgery: a cohort follow-up to 18 months. J Thorac Cardiovasc Surg
2005;130(3):837-843.
97. Ravishankar C, Zak V, Williams IA, et al. Association of impaired linear growth and worse
neurodevelopmental outcome in infants with single ventricle physiology: a report from the pediatric heart
network infant single ventricle trial. J Pediatr 2013;162(2):250-256.
98. Clark JB, Barnes ML, Undar A, et al. Multimodality neuromonitoring for pediatric cardiac surgery: our
approach and a critical appraisal of the available evidence. World J Pediatr Congenit Heart Surg
2012;3(1):87-95.
99. Khan MS, Fraser CD. Neonatal brain protection in cardiac surgery and the role of intraoperative
neuromonitoring. World J Pediatr Congenit Heart Surg 2012;3(1):114-119.
100. Andropoulos DB, Hunter JV, Nelson DP, et al. Brain immaturity is associated with brain injury before
and after neonatal cardiac surgery with highflow bypass and cerebral oxygenation monitoring. J Thorac
Cardiovasc Surg 2010;139(3):543-556.
101. Andropoulos DB, Easley RB, Brady K, et al. Changing expectations for neurological outcomes after the
neonatal arterial switch operation. Ann Thorac Surg 2012;94:1250-1256.
102. Hirsch JC, Jacobs ML, Andropoulos D, et al. Protecting the infant brain during cardiac surgery: a
systematic review. Ann Thorac Surg 2012;94(4): 1365-1373; discussion 1373.
103. Pedersen T, Moller AM, Hovhannisyan K. Pulse oximetry for perioperative monitoring. Cochrane
Database Syst Rev 2009;(4):CD002013.
104. Pollard V, Prough DS. Cerebral near-infrared spectroscopy: a plea for modest expectations. Anesth
Analg 1996;83(4):673-674.
Chapter 31
Extracorporeal Membrane Oxygenation in Infants and Children
Ravi R. Thiagarajan
INTRODUCTION
Extracorporeal membrane oxygenation (ECMO) is used to provide mechanical cardiopulmonary support to
patients with refractory cardiac or pulmonary failure unresponsive to conventional medical therapies (1,2). The
clinical use of ECMO as a mechanical support modality for cardiac and respiratory failure was propelled by the
development of the artificial lung (oxygenator), innovation in cardiopulmonary bypass techniques, and cardiac
surgery. In 1972, Hill et al. (3) reported the first successful use of ECMO in an adult with acute respiratory failure
due to posttraumatic acute respiratory distress syndrome (ARDS). Bartlett et al. (4,5) reported successful use of
ECMO to support a child with congenital heart disease after cardiac surgery in 1972, and subsequently a
neonate with respiratory failure due to meconium aspiration syndrome in 1975.
Early randomized controlled trials (RCTs) conducted in adults with severe ARDS comparing ECMO support to
conventional mechanical ventilation by Zapol et al. (6) and Morris et al. (7) showed no improvement in survival
for those supported with ECMO. Subsequently, the use of ECMO to support adults with refractory
cardiorespiratory failure decreased (8). In contrast, RCT conducted in neonates by Bartlett et al. (9) and
O’Rourke et al. (10) for neonatal respiratory failure showed superior outcomes in those supported with ECMO
compared to those supported with conventional mechanical ventilation. These studies established a role for the
use of ECMO in the neonatal population. ECMO was then extended to infants and older children, and for other
indications such as support of cardiac failure.
There has been a resurgence in ECMO use to support adults with severe ARDS following publication of the
CESAR trial (conventional ventilatory support vs. ECMO for severe adult respiratory failure) in 2009 that showed
improved survival for adults managed with ECMO compared to conventional mechanical ventilation (11). In
addition, reports of successful ECMO use in respiratory failure associated with the 2009 Influenza A (H1N1)
epidemic have helped reestablish a role for ECMO in adults with respiratory failure (12). ECMO to support
infants and children has continued to grow, and ECMO use has become common in many tertiary-level neonatal
and pediatric intensive care units (13). Healthcare providers caring for critically ill infants, children, and adults in
these units should be familiar with ECMO indications, technology, patient management on ECMO, and
outcomes.
MODES OF ECMO SUPPORT

The typical ECMO circuit consists of tubing, a mechanical blood pump, membrane lung (oxygenator), cannulas
for blood drainage (venous) and return (arterial), reservoir (bladder), heat exchanger, and pressure, flow, and
oxygen saturation monitors (1,14). Figure 31.1 is an illustration of a typical ECMO circuit, with the circuit
components discussed in detail later in the chapter. To provide cardiorespiratory support, blood is drained from
the venous circulation into the ECMO circuit. A pump then propels blood through the membrane oxygenator for
gas exchange. The oxygenated blood is warmed to the desired body temperature and returned to the patient via
the arterial cannula.
ECMO is used in two distinct support modes: venoarterial ECMO (VA ECMO) and veno-venous ECMO (VV
ECMO) (1,2,15,16). The differences between the two modes are listed in Table 31.1 and discussed below in
detail.
Veno-Arterial ECMO
In this mode, blood from the venous circulation is drained into the ECMO circuit, pumped through the oxygenator
for gas exchange, and the oxygenated blood from the circuit is returned to the arterial circulation (1,2,15,16). In
this configuration, ECMO provides both cardiac and respiratory support (Figs. 31.1, 31.2).
Preload to the heart is decreased during VA ECMO because blood is drained from the venous circulation into the
ECMO circuit (17,18,19). Decreased preload reduces myocardial contractility, left ventricular stroke volume, and
pulse pressure. When the venous circulation is completely drained into the ECMO circuit, nonpulsatile flow
ensues. However, in myocardial disease, decreased myocardial contractility and loss of pulsatile flow can occur
prior to complete venous drainage, as injured or diseased myocardium may require higher
P.710
P.711
end-diastolic pressure and volume for myocardial contractility. When myocardial injury or disease improves,
myocardial contractility returns, left ventricular ejection increases, and pulsatile flow resumes. Because
decreased preload reduces contractile function of the ventricle, status of myocardial preload should be taken into
account when evaluating myocardial contractility during ECMO.
FIGURE 31.1. ECMO circuit in veno-arterial support mode.
TABLE 31.1. Differences between veno-arterial and veno-venous ECMO modes

VA ECMO VV ECMO
Support type Cardiac and pulmonary Pulmonary only
Cardiac support Partial or complete None
Cannulation sites Venous and arterial sites Venous sites
Cardiac preload Decreased Unchanged
Cardiac afterload Increased Unchanged
Pulmonary blood flow Decreased Unchanged
Pulse pressure May decrease Unchanged
Coronary blood flow LV ejection or ECMO LV ejection
Recirculation None Common
VA ECMO, veno-arterial ECMO; VV ECMO, veno-venous ECMO; LV, left ventricle.
FIGURE 31.2. Veno-venous (VV) and veno-arterial (VA) ECMO. SVC, superior vena cava; IVC, inferior vena
cava.
Afterload to the left ventricle (LV) is increased during ECMO support (17,20,21). Increased afterload may be due
to systemic vasoconstriction from sympathetic activation and the stress response to critical illness, use of
inotrope and vasoconstrictor infusions, and arterial flow from the ECMO circuit into the aorta. Increased afterload
increases LV end-diastolic pressure (LV-EDP), LV wall stress, and left atrial (LA) pressure (22,23,24,25,26). The
manifestation of LA hypertension during VA ECMO is severe pulmonary edema, pulmonary hemorrhage, and
“white-out” of the lung fields on chest X-ray (Fig. 31.3). Furthermore, increased LV-EDP and wall stress can
impair myocardial recovery. Because the LV is not directly drained during VA ECMO, left heart decompression
may be required in some patients supported with VA ECMO to lower LA pressure and reduce pulmonary edema
and hemorrhage. Left heart decompression may also reduce LV wall stress and thereby promote myocardial
recovery. Left heart decompression can be achieved in the interventional cardiac catheterization laboratory by
creating an atrial communication (balloon atrial septostomy), or by draining the LA into the venous limb of the
ECMO circuit using a drainage cannula (LA venting cannula).
Cardiac output during VA ECMO is a combination of the ECMO flow and native cardiac ejection. ECMO flow and
systemic vascular resistance (SVR) determine mean arterial blood pressure (MAP) (18). In VA ECMO without
native LV ejection, oxygenated blood from ECMO arterial return flows retrograde in the ascending aorta and
aortic arch to provide coronary blood flow. However, in those patients with native LV ejection, coronary blood
flow is antegrade from native LV ejection. Native LV ejection contains blood that is not drained into the ECMO
circuit from the right atrium (RA) but ejected into the pulmonary circulation by the right ventricle and returned to
the left heart. Mechanical ventilation with appropriate inspired oxygen concentration (Fio2) is required to
oxygenate the blood transiting the pulmonary circulation and returning to the left heart in order to deliver oxygen
to the myocardium. In an animal model of VA ECMO, Shen et al. (27) have shown that myocardial perfusion with
oxygenated blood, provided by mechanical ventilation with an appropriate Fio2, was associated with improved
myocardial recovery.
FIGURE 31.3. Pulmonary edema due to left atrial hypertension during veno-arterial ECMO. A: Pulmonary edema
soon after ECMO cannulation; B: Resolution of pulmonary edema after balloon atrial septostomy.
Veno-Venous ECMO
In VV ECMO, venous blood is drained from the venous circulation into the ECMO circuit, pumped through the
oxygenator, and returned to the RA (Fig. 31.2) (1,15,16,28). Oxygenated blood returned to the RA from the
ECMO circuit enters the RV through the tricuspid valve (TV) and is ejected into the pulmonary circulation (Fig.
31.4). The oxygenated blood transits the pulmonary circulation to the left heart and is ejected by the LV into the
systemic circulation. Thus, VV ECMO does not provide cardiac support and depends on native cardiac function
to maintain cardiac output.
Systemic oxygen saturation (Sao2) depends on the proportion of oxygenated blood entering the right ventricle
(RV)
P.712
(28,29). Therefore, positioning the return limb of the venous cannula such that oxygenated blood from the ECMO
circuit returning to the RA is directed toward the TV is crucial (Fig. 31.4). Recirculation of some oxygenated
blood returned to the RA back into the venous drainage is common. However, recirculation of significant amounts
of oxygenated blood results in reduced Sao2. Recirculation can be assessed by comparing the partial pressure
of oxygen in the arterial (Pao2) and venous (Pvo2) limbs of the VV ECMO circuit. A Pvo2 <20% of the Pao2 is
acceptable and does not impair the efficiency of VV ECMO (30). Decreased Sao2 during VV ECMO should
prompt the evaluation of cannula position to ensure that oxygenated blood returned to the RA is directed toward
the TV. Other causes of low Sao2 during VV ECMO include hypovolemia, RV dysfunction, increased pulmonary
vascular resistance (PVR), and developing oxygenator failure. These issues should be promptly investigated and
treated.
FIGURE 31.4. Cannula position for veno-venous ECMO. SVC, superior vena cava; IVC, inferior vena cava; TV,
tricuspid valve; RV, right ventricle; LV, left ventricle; Ao, aorta; PA, pulmonary artery.
Choosing an ECMO Mode

Patients with severe cardiac dysfunction due either to primary cardiac disease or secondary to other diseases
(e.g., sepsis) require VA ECMO (1,14). VV ECMO is used to support children with respiratory failure with
adequate cardiac function and output. Children with heart disease presenting with pure respiratory failure can be
successfully managed with VV ECMO (31,32). Some patients with hypoxemic respiratory failure may have
cardiac dysfunction secondary to hypoxemia. Restoration of systemic oxygenation with VV ECMO in these
patients can improve cardiac function by correcting respiratory acidosis, reducing PVR, and enhancing
myocardial oxygenation. In these patients, an initial trial of VV ECMO can help avoid the need for VA ECMO.
INDICATIONS FOR ECMO

Cardiac or respiratory failure unresponsive to conventional medical therapies is the usual indication for ECMO
(Table 31.2) (1,14,33). ECMO has been used successfully to support neonatal respiratory failure due to
persistent pulmonary hypertension and meconium aspiration syndrome. In children, respiratory failure due to
pulmonary infection (bacterial, viral, or other pathogens) is a common indication for ECMO support. Cardiac
indications for ECMO support include management of refractory cardiac dysfunction following cardiac surgery for
congenital heart disease, and nonsurgical cardiac dysfunction due to myocarditis or cardiomyopathy (33). The
availability of inhaled nitric oxide and high-frequency ventilation has reduced the need for ECMO in neonates
with respiratory failure. Recent trends
P.713
indicate that ECMO is being increasingly used to support neonates and children with postoperative cardiac
failure following surgery for congenital heart disease (34).
TABLE 31.2. Indications for ECMO
Indications
1. Refractory hypoxemic or hypercapnic respiratory failure
2. Refractory cardiogenic shock
Acute myocarditis
Cardiomyopathy
Severe sepsis
3. Postoperative refractory cardiac failure
Postoperative low cardiac output syndrome
Failure to wean from cardiopulmonary bypass
Refractory arrhythmias
Pulmonary hypertension
4. Cardiac arrest refractory to conventional cardiopulmonary resuscitation
5. Procedural support
6. Bridge to lung or heart transplantation or ventricular assist device
Relative contraindications
1. End-stage primary disease with poor prognosis
2. Severe neurologic injury or intracranial bleeding
3. Uncontrolled visceral bleeding
4. Prematurity (<34 wk gestation)

5. Low weight (<2 kg)
6. Family or patient directive limiting ECMO use
ECMO is being increasingly used to support children with cardiac arrest failing to respond to conventional
cardiopulmonary resuscitation (ECPR) (35,36). In these patients, ECMO provides circulatory and respiratory
support while the etiology for cardiac arrest is being investigated and treated. ECMO can also be used to
support cardiac and respiratory function when undertaking surgical and cardiac catheterization procedures in
critically ill patients whose risk of cardiac arrest while undergoing the procedure is deemed to be high (37,38).
When considering ECMO support, it is important to note that ECMO is only a support modality and does not treat
the primary disease causing cardio-respiratory dysfunction. Thus, ECMO is most useful for those patients whose
primary disease is reversible or can be successfully treated and associated with good prognosis. ECMO is
generally considered short-term support (days to ˜2 weeks) as a bridge to recovery. However, some patients
supported with ECMO for cardiac or respiratory failure fail to recover and wean off ECMO. In these patients,
ECMO can be used as a bridge to heart or lung transplantation if the patient is deemed to be suitable for
transplantation (39,40). The use of ECMO as a bridge to cardiac transplantation has been largely replaced with
ventricular assist devices (VAD) as these devices provide mechanical support for longer duration (41,42). In
some patients presenting with cardiogenic shock, ECMO can be used initially to resuscitate patients from shock
prior to VAD implantation (bridge to VAD). ECMO remains an important mechanical support modality to bridge
patients to lung transplantation.
Contraindications for ECMO support are relative and vary widely between institutions (Table 31.2) (33). ECMO
is not useful when prognosis for the primary condition causing cardiac or respiratory failure is poor (irreversible
or inoperable) or end-stage. Critically ill children with advanced multi-organ failure and those with severe
neurologic injury may not benefit from ECMO. Anticoagulation used for ECMO support can exacerbate
preexisting intracranial bleeding and bleeding in major organs, and thus ECMO may be deleterious for these
situations. The risk of neurologic injury and intracranial hemorrhage is high in premature infants (<34 weeks
gestation). Small-sized neonates (<2 kg) may pose technical challenges to ECMO cannulation and support.
Finally, patient and family directives may limit the use of ECMO support in some patients.
EQUIPMENT FOR ECMO

Circuit Tubing and Prime
ECMO circuit tubing is made from a polyvinylchloride-based plastic compound (43). Blood contact with the
prosthetic surface of the ECMO circuit tubing activates the coagulation cascade and platelets to form clot (44).
The inflammatory cascade is also activated, resulting in a systemic inflammatory response and capillary leak
syndrome. Biocompatible circuit-lining materials (e.g., Carmeda BioActive Surface [CBAS] uses heparin coating;
Carmeda, Stockholm, Sweden) that reduce blood contact activation have been used in ECMO circuits to reduce
clotting (45,46). Release of plasticizer (di-2-ethylhexyl phthalate [DEHP]) has been a concern with the use of
polyvinyl tubing (47). Exposure to DEHP has shown to be associated with infertility, reduced sperm production,
and ovarian dysfunction in animal studies (48). However, a study of adolescents exposed to DEHP during
neonatal ECMO support by Rais-Bahrami et al. (47,49) showed no effects on physical growth and pubertal
maturity.
ECMO circuits can be primed with either blood or crystalloid (e.g., Plasma-Lyte, Abbott Laboratories, Abbott
Park, IL) solution. Blood-primed ECMO circuits are generally used when ECMO is deployed semi-electively,
whereas crystalloid-primed circuits are commonly used for urgent ECMO support such as in patients cannulated
for ECMO during cardiopulmonary resuscitation (CPR) (33,36).
Blood Pump
The function of the blood pump is to propel blood through the oxygenator and ECMO circuit (43,50). Ideally, an
ECMO pump should be able to provide a wide range of flows (75-200 mL/kg/min) without exerting excessive
shear stress on red blood cells and causing hemolysis. Currently available ECMO pump technology can be
categorized into two major types: roller and centrifugal . Comparisons between the two pump types are listed in
Table 31.3.
Roller pumps are positive displacement pumps that use a rotating roller head to sequentially compress linear
tubing against a back plate, thereby forcing the column of blood in the tubing forward (Fig. 31.5) (43,50). The
portion of the ECMO tubing within the pump is called the “raceway” and is
P.714
made of reinforced material (e.g., Tygon S-95-E; Tygon, Saint-Gobain Corp., Courbevoie, France) to help
withstand the shear stress imposed by the roller heads (51). Pump output is a function of pump speed
(revolutions per minute; RPM), raceway tubing diameter, and degree of occlusion (43,50). To avoid direct
suction to the venous catheter in roller pump ECMO circuits, a reservoir called the “bladder” is placed between
the pump and the venous drainage tubing (52). Venous blood from the patient is drained passively by gravity into
the bladder, limiting the direct application of negative suction pressure to the venous inflow and preventing injury
to vascular structures and endothelium. A servo-control mechanism contained in the bladder regulates pump flow
by decreasing pump speed when the bladder has reduced volume or is empty. This servo-control mechanism
prevents cavitation and hemolysis from excessive negative pressure resulting from continued pump function
when pump venous inflow is reduced or occluded and is thus an important safety feature for roller-pump ECMO
circuits (53).
TABLE 31.3. Comparison of roller and centrifugal pumps
Roller pump Centrifugal pump
Pump mechanism Positive displacement Centrifugal force
Pump inflow Passive drainage Active drainage
Pump occlusion Occlusive Nonocclusive
Retrograde flow Not possible Possible
Pump flow More precise More variable
Factors affecting pump flow Pump RPM Displacement Pump RPM, Preload and
volume afterload
Risk of tubing rupture with outflow Present Extremely rare

obstruction
Hemolysis Present Present

RPM, revolutions per minute.
FIGURE 31.5. Schematic diagram of roller and centrifugal pumps.
Pump outlet pressure is a function of pump speed and resistance in the tubing, oxygenator, cannula, and SVR
(43,50). In roller pumps, when the ECMO circuit (i.e., tubing, oxygenator, or arterial cannula) beyond the pump
outlet is obstructed, the pump will continue to flow resulting in high outlet pressure proximal to the obstruction
which can result in circuit tubing rupture. Thus, a high outlet pressure alarm is essential and should prompt
careful evaluation for ECMO circuit outflow obstruction.
Centrifugal pumps contain a spinning rotor in a rigid conical housing that creates a constrained vortex to draw
blood into the pump and uses centrifugal force to eject blood from the pump (Fig. 31.5) (43,50). Sub-atmospheric
pressure is created at the center of the vortex and pump inlet, resulting in active drainage of blood from the
patient into the pump. Positive pressure created at the edge of the vortex results in passive ejection of blood
through the pump outlet creating pump flow. Centrifugal pumps are nonocclusive systems and create continuous
nonpulsatile flow. The centrifugal pump rotary mechanism will continue to spin when venous inflow becomes
obstructed resulting in increased negative pump inlet pressure causing hemolysis and rarely cavitation. These
issues can be overcome with reducing pump speed at times of decreased venous return or incorporating a
bladder to automatically regulate pump speed based on pump inflow. Because ejection of blood from the
centrifugal pump is passive, pump flow for a given pump speed is dependent on resistance applied to pump
outflow from the ECMO circuit and SVR. Increased outflow resistance can decrease pump flow. Circuit rupture
with outflow occlusion is extremely rare because pump flow is reduced or absent with increased resistance.
Because centrifugal pumps are nonocclusive systems, retrograde flow from the outlet into the pump is possible
at low pump rotational speeds.
Other potential problems with centrifugal pumps relate to issues of blood stagnation and heat generation in the
pump (43,50). These issues can result in thrombus formation within the pump and hemolysis. Newer generation
centrifugal pump designs have reduced stagnation, heat generation, and shear stress to blood cells and have
helped minimize these complications. Even though centrifugal pumps are becoming increasingly used in ECMO
circuits, reports comparing complications and patient outcomes with roller pumps have shown mixed results.
Some studies have shown increased hemolysis with roller pumps, and others show no difference in pump-related
complications and patient outcomes (54,55,56,57).
Membrane Oxygenator
The membrane oxygenator is the “lung” of the ECMO circuit and provides for blood oxygenation and removal of
carbon dioxide (CO2) (43,50). In these devices, blood and gas circulate on the opposite sides of the membrane,
in a countercurrent direction, and gas exchange occurs because of diffusion gradients for oxygen (O2) and CO2
across the membrane. The Kolobow silicone membrane oxygenator containing a silicone rubber membrane
sheet wrapped around a wire mesh coil was the standard oxygenator used in ECMO circuits for many years
(52,58). Higher resistance to blood flow, difficulty with de-airing, and longer time needed to prime these
oxygenators have resulted in these oxygenators being replaced by lower resistance, efficient, and easier to
prime hollow-fiber membrane oxygenators.
Microporous hollow-fiber oxygenators contain fibers made of hydrophobic polymers (polypropylene) with
micropores (0.2-0.7 μm) (Fig. 31.1) (43,50,59,60,61). In these oxygenators, gas flows within the fibers and blood
outside the fibers in a countercurrent direction. Gas circulated through the fibers occupies the micropores and
forms a gas-liquid interface for gas exchange. Long-term use of early hollow-fiber oxygenators was limited by
plasma leak into the micropores that occurred within 8 to 16 hours of oxygenator use and resulted in impaired
gas exchange. Polymethylpentene (PMP) coated
P.715
fibers in the newer generation hollow-fiber oxygenators (e.g., QUADROX-D, QUADROX-iD, and QUADROX PLS,
Maquet Cardiovascular LLC, Wayne, NJ) has reduced plasma leak and resulted in more durable oxygenators
suitable for longer ECMO support times. Hollow-fiber oxygenators have a shorter path for blood flowing from the
inlet to the outlet, thus resulting in low resistance to blood flow through the oxygenator. The membrane fibers
provide a large surface area for gas exchange resulting in superior efficiency compared to solid membrane
oxygenators.
Because the solubility and diffusion capacity of O2 in blood is lower than that of CO2 (1:25), oxygenation
depends on the duration of blood transit through the oxygenator. Thus, membrane oxygenators are limited in
their capacity to oxygenate but not so for removal of CO2 (62). The standard employed for comparing efficiency
of membrane oxygenators is called “Rated Flow.” Rated flow is the blood flow rate required to increase oxygen
saturation of venous blood, with hemoglobin of 12 g/dL, from a saturation of 75% to 95%.
Gas circulated through the membrane oxygenator for gas exchange is called “sweep gas.” Sweep gas in most
instances contains 100% O2; however, the amount of O2 in sweep gas can be regulated using an oxygen-
nitrogen blender and based on the patient’s Sao2. Carbon dioxide clearance in the membrane oxygenator is
related to the sweep gas flow rate and sweep CO2 concentration. A higher sweep gas flow rate increases CO2
clearance in the membrane oxygenator. Gas-toblood flow rate in the oxygenator is usually 1:1. The sweep gas
flow rate can be adjusted based on the partial pressure of carbon dioxide (Pco2) in the blood. In some instances,
5% CO2 can be added into the sweep gas to maintain Pco2 and prevent hypocapnia.
Venous and Arterial Cannulas

Arterial and venous cannulas are required to provide ECMO support, and are made from biocompatible
polyurethane material (14,43,63). The cannula walls are reinforced with wire mesh to prevent luminal collapse
and their internal surfaces are coated with heparin polymers to prevent thrombus formation. Single lumen end-
hole cannulas can be used to provide arterial access, whereas venous cannulas have multiple fenestrations at
the tip. Right angle metal tip cannulas are used for open chest cannulation of the RA and are similar to those
used for cardiopulmonary bypass. Double lumen cannulas where blood can be drained though ports in one
lumen and returned through a port in the other lumen can be used to provide single-site VV ECMO via the neck
veins (Fig. 31.4).
Resistance to flow through the ECMO cannula is influenced by length and internal diameter, so that shorter and
larger diameter cannulas provide the least resistance to ECMO flow. The “M” number is a summary index of
cannula pressure-flow characteristics based on flow, blood viscosity, cannula diameter and pressure gradient,
and can be used to compare pressure-flow characteristics of ECMO cannulas for purposes of cannula selection
(63). Several patient factors including size, site of cannulation, vessel size, and indication for ECMO also
influence choice of ECMO cannula used.
Although a surgical approach is commonly used for ECMO cannulation, percutaneous ECMO cannulation is
increasingly utilized in adults and older children especially for VV ECMO. Commonly used venous cannulation
sites include the internal jugular vein (IJV), femoral veins (FV), and the RA. Commonly used arterial sites include
the carotid artery (CA), femoral arteries (FA), and aorta (Ao). Central cannulation of RA and Ao via sternotomy is
often preferred for children placed on ECMO after recent cardiac surgery. In patients with septic shock requiring
ECMO support, central cannulation of the RA and Ao can provide more ECMO flow and has been shown to be
associated with improved survival (64). When the FA is cannulated, a reperfusion catheter is often used to
maintain perfusion to the leg distal to the cannula (65).
Following ECMO cannulation, the position of the venous and arterial cannulas should be confirmed. Chest X-ray
is the most commonly used radiological modality. For patients cannulated using the IJV and CA, ideal cannula
position is with the tip of the venous cannula in the mid-RA and end of the arterial cannula in the aortic arch at
the entrance to the innominate artery (Fig. 31.6). In one study, echocardiography was found to be superior to
chest radiographic assessment for evaluation of ECMO cannula position (66,67).
Heat Exchanger, Hemofiltration System, Bridge, and Vascular Access Ports

Many centers customize their circuits based on the type of pump used and intended population for ECMO
support.
P.716
Heat exchangers warm the blood returning to the patient to the desired body temperature. Heat exchangers are
generally placed distal to the oxygenator and prior to arterial return to the patient (50,52). Blood is warmed by
circulation of warm water in the silicone tubes of the heat exchanger in a countercurrent direction to blood flow. A
heater unit provides the oxygenator-water supply for maintaining patient temperatures between 33°C and 39°C.
The newer generation of hollow-fiber oxygenators, for example, QUADROX iD, incorporates a heat exchanger
within the oxygenator (68).
FIGURE 31.6. Cannula position following cannulation via the right internal jugular vein and right common carotid
artery for veno-arterial ECMO. The portion of the venous cannula between the superior vena cava and the tip is
radiolucent.
Some centers incorporate a hemofiltration system in their ECMO circuits for patient fluid management (69).
Hemofilters produce an ultrafiltrate as a result of a hydrostatic pressure gradient across a semipermeable
membrane, and are the same devices used for hemodialysis. Inflow into the hemofiltration system is obtained
postpump, and blood drained into the hemofiltration system is usually returned to the circuit at the level of the
bladder or prepump. Hemofiltration can be used to augment fluid removal from a patient and for
hemoconcentration when a crystalloid solution is used to prime the ECMO circuit (69,70,71).
Some centers include a bridge between the arterial and venous limbs of the circuit to allow circuit maintenance
during a clamping trial (Fig. 31.1). The bridge can be left open, occluded with a clamp and opened every 30
minutes to prevent clotting in the bridge, or left closed. Because the bridge can cause flow turbulence, circuit
clots, and reduce systemic and cerebral blood flow when opened, some centers do not incorporate a bridge in
their ECMO circuit or leave the bridge completely closed and only use the bridge during a clamping trial
(72,73,74,75). During a clamping trial for patients on VA ECMO, clamps are applied to the arterial and venous
limbs near the patient and the bridge is opened to maintain flow through the ECMO circuit to preserve it while
candidacy for ECMO decannulation is being evaluated.
ECMO circuits have many vascular access ports for monitoring circuit pressures, administration of medications,
and for laboratory monitoring (14). These sites create potential for turbulent blood flow and stasis and can result
in circuit clots. Frequent entry into these ports increases the risk of infection and air embolism. Thus, limiting the
number of vascular access ports in ECMO circuits is essential to reduce these risks.
TABLE 31.4. ECMO circuit pressures and troubleshooting the circuit
Bladder or pump inflow Premembrane Postmembrane

pressure pressure pressure Possible etiology
↓ No change No change ↓ Venous return

1. Hypovolemia
2. Tamponade
3. Venous cannula
malposition, clamp
No change ↑ ↓ Clots/obstruction in
oxygenator
No change ↑ ↑ 1. Circuit arterial limb

obstruction
2. Arterial Cannula
malposition
Circuit Monitors
Circuit pressure and flow monitors help ensure safe functioning of the ECMO circuit and help troubleshoot circuit
alarms (Table 31.4) (14,33,50). Use and location of circuit monitors vary widely between institutions.
Pressure monitors are generally placed at the level of the bladder, venous inflow of centrifugal pumps, and pre-
and postmembrane oxygenator. As previously mentioned, bladder pressure and venous inflow pressure monitors
act as servo regulators to slow the ECMO pump down when venous drainage decreases. Monitoring inflow
pressures can also help avoid generating excessive suction pressure and hemolysis. Causes of reduced venous
drainage include hypovolemia, obstruction to right atrial filling (e.g., cardiac tamponade), or obstruction to venous
drainage from the patient (e.g., cannula malposition). Pressure monitors pre- and postoxygenator help evaluate
resistance to flow and the “health” of the membrane oxygenator. The baseline pressure gradient across the
oxygenator at initiation of ECMO is typically 10 to 20 mm Hg. An increasing gradient, particularly approaching 40
mm Hg with the QUADROX iD, implies imminent oxygenator failure.
Flow monitors use ultrasound technology to estimate flow in the circuit. Most ECMO pumps have an integrated
flow monitor at the pump outlet to measure flow generated by the pump. Flow monitors on the distal arterial limb
beyond the oxygenator can measure actual flow delivered to the patient. Other monitors commonly used in
ECMO circuits include oxygen saturation and hemoglobin monitors, and are generally placed on the venous limb
of the ECMO circuit for measurement of mixed venous oxygen saturation (S o2) and hemoglobin concentration.
Bubble detectors are used by some centers to reduce risk of air embolism to the patient. These detectors are
placed on the arterial limb and shut the pump off when air bubbles are detected.
P.717
Equipment Storage
ECMO equipment, including an assembled circuit, surgical instruments for use during cannulation, and ECMO
cannulas and connectors should be stored in an easily accessible location. A mobile ECMO cannulation cart that
contains a wide range of cannulas and connectors of all sizes and can be brought to the bedside at the time of
ECMO deployment can be very useful. An example of a cannulation cart and assembled circuit used at Boston
Children’s Hospital is shown in Figure 31.7. Table 31.5 is a list of equipment stored in the cart.
PATIENT MANAGEMENT ON ECMO

Guidelines and policies should be developed in each institution to guide and standardize management of ECMO
patients (1,14,33). Physicians, nurses, and other healthcare providers managing a patient on ECMO should be
well trained on all aspects of ECMO care, including the ECMO circuit and patient management (76). ECMO
management requires a large interdisciplinary team of providers and therefore excellent teamwork and proper
communication is required for successful conduct of ECMO.
ECMO Deployment
Timing of Deployment
Timing of ECMO initiation varies widely within and between ECMO centers and there is no clear consensus
about when ECMO should be initiated. The oxygenation index (OI = Fio2* mean airway pressure/Pao2) has been
used to guide timing of ECMO initiation in neonates with respiratory failure. An OI >40 is used as a threshold for
initiating ECMO in these patients (1). Similar criteria are not available for older children with respiratory failure
and neonates, infants, and children with cardiac failure. In children with respiratory failure, the presence of
severe impairment of oxygenation (Pao2/Fio2 ratio <100) or the need for significant inflation pressure (e.g., mean
airway pressure >25 cm H2O) should prompt consideration of ECMO support. Similarly, children with cardiac
failure who have progressive worsening of cardiac function, end-organ dysfunction, and tissue oxygen deficit
evidenced by lactic acidosis despite aggressive cardiac failure management and increasing inotrope support
should prompt consideration of ECMO support (77,78,79,80). Although there are no data to support improved
survival following early ECMO deployment in critically ill patients, ECMO is only beneficial when deployed before
the onset of irreversible end-organ injury. As with any other therapy, consideration of ECMO support requires
careful evaluation of risks of mortality or severe morbidity from continuing conventional therapy weighed against
risks arising from ECMO complications. Because of time constraints with respect to establishing ECMO during
CPR, the need for ECMO should be considered early when the likelihood of restoration of spontaneous
circulation with CPR is low.
FIGURE 31.7. ECMO equipment storage. A: ECMO equipment cart; B: Assembled ECMO circuits in the
intensive care unit ready for use.
P.718
TABLE 31.5. Boston Children’s Hospital ECMO cannula cart equipment list
ECMO cannula guide
Size Flowa Weight

Cannula/characteristics (Fr) (L/min) (kg)
Bio-Medicus pediatric arterial (length = 10 cm) 6

Neck or chest
3/16″ connector—step-up: 3/16″ tubing + 3/16 × 1/4″
connector
Radiopaque to 0.5 cm b/f tip
Bio-Medicus pediatric arterial (length = 10 cm) 8 0.7 <4.5

Neck, chest, or femoral 10 1.3 4.5-10
1/4″ connector 12 2.1 10-14
Radiopaque to 0.5 cm b/f tip 14 2.8 14-28
Bio-Medicus pediatric venous (length = 10 cm) 8 0.47 <3

Neck or femoral 10 0.9 3-6
Side holes—1/4″ connector 12 1.45 6-8
Radiopaque to 4 cm b/f tip + dot at tip 14 2.0 8-12
Bio-Medicus percutaneous kit (length = 18 cm) 15 3.0 28-40

Neck or femoral—arterial 17 4.0 40-55
Side holes—3/8″ connector 19 5.3 55-75
Radiopaque to 4 cm b/f tip 21 6.5 >75
Bio-Medicus percutaneous kit (length = 50 cm) 15 1.3 12-16

Femoral—venous 17 1.8 16-22
3/8″ connector 19 2.5 22-30
Radiopaque to 4 cm b/f tip 21 3.2 30-34
Bio-Medicus + introducer (length = 50 cm) 23 4.0 34-46

Femoral—venous only 25 4.7 46-58
1/2″ connector—step-down: 1/2″ tubing + 1/2″ × 3/8″ 27 5.8 58-75
Radiopaque to 4 cm b/f tip 29 6.5 >75
Single DLP angled venous (length = 37-38 cm) 12 0.8 <5

Chest—venous 14 1.6 5-12
Radiopaque throughout 16 1.9 12-18
ADD connector 18 2.6 18-26
▪ 1/4″ for 12-18 20 3.0 26-55
▪ 1/4″ or 3/8″ for 20, 22 22 4.5 >55
▪ 3/8″ for 24, 28 24 5.5
28
Origen VV-dual lumen (PCTA introducer kit available) Size × tip length
1/4″ connector 13 Fr × 9 cm
Radiopaque throughout 16 Fr × 11 cm
19 Fr × 15 cm
Avalon VV Bi-caval dual lumen Size × insertable length

1/4″ connector: 13, 16, 19 13 Fr × 11 cm
3/8″ connector: 20, 23, 27, 31 16 Fr × 14 cm
Radiopaque throughout 19 Fr × 21 cm
Vascular access kit needed 20, 23, 27, 31 Fr × 31 cm
Mark drainage & re-infusion hubs w/blue & red vessel
loops
Foley strap to secure lines
aWater flow measurement.
P.719
Cannulation
Cannulation for ECMO is often done at the patient’s bedside. Noninvasive and invasive patient monitoring,
inotrope, and ventilator support should continue and cardio-respiratory function should be carefully monitored
during ECMO cannulation. Vascular access for administration of volume expanders, blood products, and
medications should be established prior to cannulation. The ECMO circuit, cannulation equipment, and surgical
instruments should be brought to the site of cannulation and be readily accessible. Cannulation sites (venous
sites for VV ECMO and arterial and venous sites for VA ECMO), cannula size and type, and a cannulation plan
should be decided ahead of the procedure (81). The patient must be properly positioned, and sedation,
analgesia, and neuromuscular paralysis should be provided. The ECMO circuit can be primed and ready to
deploy. For ECPR deployment, a crystalloid primed circuit is often used. When the circuit is blood primed,
potassium and ionized calcium levels and blood pH should be checked. Sodium bicarbonate should be
administered into the circuit to correct low-circuit blood pH and intravenous calcium may be needed to treat
hypocalcaemia or hyperkalemia prior to ECMO deployment. Vascular access for ECMO can be accomplished
surgically through peripheral vessels (usually the right common carotid artery and internal jugular vein), via the
chest in patients who have undergone recent sternotomy, or using percutaneous vascular access techniques
(Seldinger technique) (1,14,81).
An intravenous bolus dose of heparin (50-100 units/kg) is administered just prior to placement of ECMO
cannulas in the vessels. Once cannulation has been completed, the cannulas are attached to the ECMO circuit
and flow is commenced, initially at a low rate, and then increased in steps over several minutes to the target flow
required for full ECMO support.
Initial Stabilization
VA ECMO
The goal of VA ECMO is to provide adequate flow to match the patient’s metabolic demand (1,2,14,33). Optimal
ECMO flow should provide adequate end-organ perfusion without causing turbulence and excessive pressure
gradients in the ECMO circuit. ECMO flows of 100 to 150 mL/kg/min are usually required to provide adequate
ECMO support. Assessing adequacy of ECMO support is of paramount importance and should begin soon after
ECMO deployment. This can be done clinically with assessment of peripheral perfusion, capillary refill time, and
urine output. MAP >45 to 50 mm Hg in neonates and infants, and >60 to 70 mm Hg in children should be
targeted to ensure adequate perfusion pressure. These targets can also be used to wean inotropic support or
initiate vasodilator therapy to manage high MAP. Finally, adequacy of tissue oxygen delivery can be assessed
using S o2 and arterial blood lactate levels. If ECMO flow is inadequate, as evidenced by continued poor
perfusion, oliguria, hypotension, and/or increasing arterial blood lactate levels, then ECMO flows should be
increased. Inability to increase ECMO flows, or inadequate ECMO support despite achieving usual ECMO flows
should prompt evaluation of the ECMO circuit, including the cannulas, and the patient. Investigation of
inadequate ECMO flows or support is shown in Table 31.6.
As previously mentioned, the left heart is not drained during VA ECMO so that initial stabilization of children with
heart disease should include assessment of the need for LA decompression (22,23,24,25,26). Presence of
pulmonary edema on chest X-ray, pink frothy secretions suctioned from the endotracheal tube, and LA distension
on echocardiography suggest the presence of LA hypertension. LA decompression can be performed in the
cardiac catheterization laboratory, with resultant decrease in pulmonary edema and lung injury, left ventricular
wall stress, and myocardial injury. In post-cardiac-surgical patients supported with cannulation of the RA and
aorta, a surgical vent can be placed in the LA to decompress the left heart. LA hypertension can also occur in the
setting of LV distension from aortic insufficiency, particularly with improper carotid artery or aortic cannula
positioning so that ECMO flow is directed toward the aortic valve. In these situations, the cannula should be
repositioned directing flow away from the aortic valve (67). In patients with severe pre-ECMO aortic regurgitation,
LV decompression may result in recirculation of arterial return from the ECMO cannula back into the ECMO
circuit, resulting in inadequate ECMO support. Thus, in patients with severe aortic regurgitation, ECMO may not
be beneficial (82,83,84).
TABLE 31.6. Investigation of inadequate ECMO support during VA ECMO
Inadequate ECMO
support Possible etiology Management
ECMO flow low Hypovolemia Volume expansion

(servo pressure ↓)a Bleeding Correct coagulopathy, surgical
Venous cannula malposition or exploration
obstruction Correct cannula position
Small venous cannula Consider upsizing or adding an
Cardiac tamponade additional venous cannula
Tension pneumothorax Pericardiocentesis or surgical
LA hypertension exploration
Chest drain
Consider LA decompression
ECMO flow normal High metabolic demand MAP ↓, Consider increasing ECMO flow
patient warm and vasodilated Consider adding vasopressors
aServo pressure signifies bladder

(roller pumps) or inlet pressure (centrifugal pumps). CVP, central
venous pressure; MAP, mean arterial blood pressure; LA, left atrium.
P.720
VV ECMO
The goal of VV ECMO is to provide adequate oxygenation and CO2 removal for the patient (1,14). In addition to
monitoring gas exchange, cardiovascular function similar to VA ECMO patients should be carefully evaluated. A
Sao2 of 85% to 92% is the usual goal in VV ECMO. Causes of low oxygen saturation include inadequate ECMO
flow or recirculation (28,29,30). Recirculation should be suspected in a VV ECMO patient with low Sao2.
Increased recirculation may be suspected when the color of blood in the venous drainage limb looks similar to
the color of blood in the reinfusion (arterial) limb, and can be confirmed by measuring Po2 in the venous and
arterial limbs of the ECMO circuit. The commonest reason for recirculation is malposition of the cannula such
that the reinfusion port is not aligned with the TV to facilitate streaming of highly saturated blood into the RV.
Rarely, RV dysfunction and increased PVR can increase recirculation. Management of recirculation should
include prompt investigation and correction of these issues.
Anticoagulation with heparin should be started as soon after ECMO deployment as possible and the heparin
titrated based on anticoagulation testing (1,14). Initial evaluation of all ECMO patients should include
assessment for bleeding at surgical and cannulation sites. Excessive bleeding may require interruption or
modification of the heparin infusion, correction of coagulopathy, and surgical exploration. If not known at the time
of ECMO deployment, investigation and treatment of the primary etiology resulting in cardio-respiratory failure
should be undertaken as soon as possible. Residual structural lesions following repair of congenital heart
disease may present as refractory cardiac failure in the postoperative period and require ECMO support. To
optimize ECMO survival, residual lesions should be diagnosed and intervened upon as soon as the patient is
stable on ECMO (78,85,86). Echocardiography and cardiac catheterization may be required for the diagnosis.
Correction of residual heart disease may require interventional cardiac catheterization or repeat cardiac surgery.
Daily ECMO Management

Daily ECMO management requires careful attention to patient care, technical aspects of the ECMO circuit,
adequacy of ECMO support, and assessment for recovery of cardiac and respiratory function (1,14,33).
Patient Care
Hemodynamic support should be tailored to the patient’s condition. To help reduce myocardial oxygen
consumption and promote recovery, where possible, inotropes and vasopressors should be weaned to low
doses. Similarly, ventilator support should be reduced to prevent ventilator-induced lung injury by minimizing
cyclic sheer stress alveolar overdistension. Typically, lung rest settings include a positive end-expiratory
pressure (PEEP) of 10 to 15 cm H2O, tidal volume of 4 to 6 mL/kg, and a low rate of 6 to 10 breaths/min. In
patients supported with VA ECMO where native ejection is present, oxygenating blood passing through the
lungs, by increasing the ventilator Fio2, is necessary to provide oxygen delivery to the myocardium.
Fluid retention is common in ECMO patients and careful attention to fluid balance is important for recovery and
weaning from ECMO (87). Administration of diuretics and use of hemofiltration when indicated to augment fluid
clearance can help maintain appropriate fluid balance (70,71). Sedation and analgesia should be provided for
management of pain and discomfort (33). Morphine (0.05-0.1 mg/kg/hr) and Midazolam (0.05-0.1 mg/kg/hr)
infusions are commonly used to provide analgesia and sedation, titrating the dosages as necessary.
Neuromuscular blockade is commonly used in ECMO patients. Neuromuscular blockade may be required when
excessive patient movement increases the risk of accidental dislodgment of ECMO cannula, and postcardiac
surgery when the chest is left open. Parenteral or enteral nutrition should be provided according to the patient’s
nutritional requirements (88). Proton pump inhibitors and H2-receptor antagonists are commonly used for
prophylaxis against acid gastritis.
Nosocomial infections are common during ECMO support (89). Meticulous attention to hand hygiene and
adherence to hospital infection-prevention bundles are essential to reduce the risk of infection. Although there is
no data to support the notion that antibiotic prophylaxis beyond the peri-cannulation period (24-48 hours
postcannulation) reduces risk of infections acquired during ECMO, antibiotics are commonly used to provide
infection prophylaxis in many ECMO programs (90). Commonly used antibiotics for infection prophylaxis are
Cefazolin and Vancomycin. Rarely, antifungal agents are used as part of antibiotic prophylaxis (90,91). Use of
aminoglycoside antibiotics for infection prophylaxis has been shown to be associated with increased incidence of
sensorineural deafness in ECMO survivors and should be avoided when possible (92). Skin care to prevent
pressure ulcers and preserving mobility of joints are important aspects of ECMO patient care (93).
Neurologic injury can occur during ECMO support and thus careful neurologic surveillance is very important
(33,94,95,96,97). Physical examination has limited value because patients on ECMO are heavily sedated and
muscle relaxed. A planned period of awakening or complete discontinuation of neuromuscular blockade, when
possible, can help provide neurologic assessment and monitoring. Head ultrasound scanning is commonly used
in neonates and young children with an open anterior fontanelle for evaluation of intracranial bleeding or
infarction. In older children, computerized tomography scan (CT scan) can be used to evaluate clinical suspicion
of neurologic complications. The availability of portable CT Scanners in many ICUs has improved evaluation for
neurologic complications in older children supported with ECMO (98). Confirmation of clinical suspicion of
seizures requires bedside video electroencephalography (EEG). Many ECMO programs have
P.721
protocols that include a pediatric neurologist to routinely follow patients supported with ECMO so that neurologic
complications can be diagnosed and managed expertly (33).
There is increasing recognition that routine intensive care including the use of sedative and neuromuscular
blockading agents, parental nutrition, and mechanical ventilation may contribute to poor outcomes and morbidity
in ECMO patients. Thus, in some centers, patients supported with VV ECMO are weaned and extubated from
mechanical ventilation (99,100). Extubation reduces the need for long-term sedation, allows enteral nutrition,
physical therapy and rehabilitation, and may improve ECMO outcomes. For patients supported with ECMO in
whom extubation is desired, ECMO cannula should be secured carefully to prevent accidental dislodgment.
Circuit Care
Daily evaluation of the ECMO patient also includes daily assessment of the ECMO circuit with respect to the
tubing, pressure monitors, function of the membrane oxygenator, and assessment of the circuit for the presence
of visible thrombus (101). These issues are closely monitored by the beside ECMO specialist. Oxygenator
dysfunction, leakage, or significant thrombi in the circuit may require circuit or oxygenator change. As described
above, an increasing pressure gradient across the oxygenator implies obstruction as a result of thrombosis and
warrants consideration of changing out the oxygenator before it fails.
Anticoagulation and Blood Product Replacement

Anticoagulation is essential to prevent circuit thrombosis and systemic thromboembolism, and is started at the
time of cannulation and continued throughout the course of ECMO (102,103). Anticoagulation for ECMO should
balance the risks of circuit or systemic thrombosis with bleeding. Heparin is the most commonly used
anticoagulant (102,103,104). A bolus dose of heparin (50-100 units/kg) is administered at the time of cannulation
and anticoagulation is maintained with an infusion of heparin. There is wide variability on laboratory tests used to
titrate heparin. Activated clotting time (ACT) is the most commonly used test; however, a small number of
programs use anti-Xa activity (heparin levels) and Thromboelastography (TEG). Because the anticoagulation
effect of heparin is mediated through Antithrombin III (AT-III), AT-III levels should be maintained within the normal
range (50%-100%). Fresh frozen plasma or AT-III concentrate can be used to replace AT-III. An institutional
protocol for providing safe anticoagulation for ECMO is required and can help reduce ECMO bleeding and
clotting complications. Heparin-induced thrombocytopenia (HIT) has been described in pediatric patients
supported with ECMO (102,103,105). If a diagnosis of HIT is confirmed, heparin should be discontinued and
anticoagulation should be provided by a direct thrombin inhibitor such as Argatroban or Bivalirudin
(106,107,108,109). ECMO bleeding and management of bleeding is discussed under ECMO complications.
Weaning and Decannulation

Weaning from ECMO should be attempted after recovery of cardiac or respiratory function (1,2,14,33). For
patients supported with VA ECMO for cardiac dysfunction, increasing pulse pressure and end-tidal CO2
suggests recovery of ventricular function. In VV ECMO patients, improved lung compliance on mechanical
ventilation and improved lung pathology on serial chest X-rays suggest readiness for a weaning trial.
In VA ECMO, ECMO flow is gradually decreased to allow ventricular loading and ejection. Mechanical ventilation
is optimized and inotropes and/or inodilators may be commenced prior to weaning. An ECMO flow rate of 200
mL/min for ¼-or ⅜-inch-diameter tubing and 500 mL/min for ½-inch tubing are generally considered minimal
ECMO flows. Once tolerance to low-flow ECMO has been demonstrated, the arterial and venous cannulas are
occluded by clamps between the patient and the bridge. The ECMO circuit is maintained by increasing flow
through the bridge while the patient is being evaluated for decannulation. Echocardiography, urine output, gas
exchange, blood lactate levels, and S o2 if available, are monitored closely to assess readiness for
decannulation. ECMO cannulas are flushed every 5 to 10 minutes during a clamping trial to maintain their
patency. Intravascular volume and vasoactive support should be optimized during weaning. Because low flows
during weaning risk circuit thrombosis, anticoagulation should be increased for the period of weaning and
clamping trials. Patients who fail a weaning or clamping trial are placed back on ECMO support, and the reason
for failure should be evaluated and corrected prior to further weaning trials.
Weaning in VV ECMO is simpler than VA ECMO. In these patients, ECMO flows are decreased to reduce the
contribution of ECMO to gas exchange. Mechanical ventilation is increased prior to weaning and optimized after
weaning. Once on low ECMO flows, the membrane sweep gas is discontinued. If gas exchange is maintained on
reasonable ventilator settings (e.g., peak inflation pressure <30 cm H2O, PEEP <10 cm H2O, Fio2 <60%), the
patient can be decannulated.
Decannulation from ECMO is usually done at the bedside and requires a surgical team, surgical equipment,
sedation and analgesia, and patient monitoring similar to ECMO cannulation. Vessels used for ECMO
cannulation are generally reconstructed and systemic anticoagulation is continued to help maintain vessel
patency (110,111,112). A 2007 study using Magnetic Resonance Imaging (MRI) of reconstructed right common
carotid artery (RCCA) after ECMO cannulation found a high rate of occlusion at 2 years post-ECMO (112).
Unsuccessful reconstruction of the RCCA was not associated with poorer neurologic outcomes, questioning the
usefulness of RCCA reconstruction following ECMO.
P.722
Duration and Recovery
The duration of ECMO support needed for recovery of cardiac or respiratory dysfunction is variable. The
average duration of ECMO required for cardiac recovery when ECMO is used to support cardiac dysfunction in
the postoperative period after cardiac surgery is 5 to 7 days (78,113). The duration of support required from
nonsurgical cardiac dysfunction (e.g., acute fulminant myocarditis) is generally longer and in the range of 7 to 10
days (114,115,116). Patients with respiratory failure supported with ECMO often need longer durations of
support, usually in the range of 2 weeks (117,118). Recent evaluation of survival for patients supported with
ECMO for respiratory failure for >21 days showed a 38% survival, suggesting that some patients may recover
with longer duration of ECMO support (117). Thus, decisions regarding usefulness of continuing ECMO in
patients showing delayed recovery should be individualized, and include prognosis of the primary diagnosis,
presence of serious ECMO complications, multi-organ failure, and transplant candidacy.
COMPLICATIONS OF ECMO
Mechanical circuit and patient complications are common during ECMO support. Prevention of complications
requires vigilance and knowledge of ECMO circuit and patient management. The common complications during
ECMO support are listed in Table 31.7 and described as follows.
Mechanical Complications
Mechanical complications include oxygenator and pump failure, air embolism, and circuit tubing rupture (119).
Mechanical complications occur in about 15% of ECMO runs and the incidence increases with longer ECMO
duration. Oxygenator failure (7% of ECMO runs) and air embolism (4% of ECMO runs) are the most common
mechanical complications during ECMO. Thrombosis within the oxygenator can result in oxygenator failure and
can be detected by monitoring and pre- and postoxygenator pressures. Air embolism is a rare event and can
occur from dislodgment of venous cannula and accessing the circuit via stopcocks for medication administration.
Ultrasonic bubble detectors that stop the ECMO pump on detection of air bubbles can be incorporated into the
ECMO circuit to reduce the risk of air embolism to the patient.
TABLE 31.7. Complications of ECMO
Mechanical complications—oxygenator failure, air embolism, circuit tubing rupture
Circuit thrombosis and thromboembolism
Bleeding
Infection
Hemolysis
Neurologic injury
Circuit Thrombosis and Thromboembolism

Fibrin and platelet deposits in the ECMO circuit are common because the clotting cascade is activated by
interaction of the blood and the artificial surface of the circuit. These may progress to thrombus formation, which
can lead to circuit occlusion and/or thromboembolism. Clot formation is common in areas of blood stasis within
the circuit, typically in areas where connectors are used (14). Although small clots are common, meticulous
adherence to anticoagulation protocols can prevent progression to large clots. Large clots that interfere with the
function of the circuit components (e.g., membrane oxygenator) may necessitate circuit or component
replacement.
Bleeding
Bleeding is common during ECMO and occurs in the cannulation and surgical sites, and viscera (14). Bleeding is
exacerbated by anticoagulation, consumptive coagulopathy, and the fibrinolysis that occurs during ECMO. Mild
local bleeding, such as bleeding at the cannulation site, can be controlled with blood products, local measures,
and reducing the level of anticoagulation. Massive bleeding, however, requires blood product administration to
correct coagulopathy, reducing or even stopping heparin infusion, and administration of anti-fibrinolytics (e.g., ε-
aminocaproic acid) (120,121). The use of recombinant Factor VIIa to control bleeding on ECMO has been
reported from some centers (122,123). A fresh primed ECMO circuit should be readily available when ECMO
bleeding management requires stopping anticoagulation and administration of prothrombotic agents.
Infection
Infection acquired during ECMO occurs in 12% of ECMO cases and is more common in older children, longer
duration of ECMO, and preexisting conditions that cause reduced immunity (89,124). Infections on ECMO are
associated with increased risk of mortality. Coagulase negative staphylococci, candida, and pseudomonas
species are the most commonly isolated pathogens. Meticulous hand hygiene, adherence to current healthcare-
associated infection-prevention bundles, and sterile precautions when accessing the ECMO circuit may help
reduce infection acquired during ECMO. As previously mentioned, antibiotic prophylaxis beyond the peri-
cannulation period does not reduce nosocomial infection during ECMO. Because patient temperature is often
controlled during ECMO, the detection of infection during
P.723
ECMO is not always straightforward and requires a high index of suspicion.
Hemolysis
Hemolysis is common in ECMO circuits and is caused by shear stress exerted on red blood cells by the ECMO
pump and areas of turbulent flow (connectors, ports; same as areas of thrombosis) within circuit. In one study,
use of higher pump speed, higher negative pump inlet pressures, and oxygenator type were associated with
increased hemolysis (125). Hemolysis can cause renal dysfunction. A plasma-free hemoglobin level >1 g/L was
shown to be associated with increased mortality. Massive hemolysis may require ECMO circuit change.
Neurologic Injury
Neurologic complications including cerebral infarction and hemorrhage are major ECMO complications that result
in mortality and long-term disability in survivors (94,96,97,126). The incidence of neurologic complications is 20%
in neonates and 12.9% in infants and children. Neurologic injury can occur because of thromboembolism,
severity of illness, cardiac arrest prior to ECMO deployment, carotid artery cannulation, and anticoagulation.
Radiologic imaging including head ultrasound or CT scans should be used to diagnose and manage neurologic
complications during ECMO. Expert consultation from a pediatric neurologist or neurosurgeon may be required to
adequately manage neurologic complications.
ECMO OUTCOMES
The Extracorporeal Life Support Organization (ELSO) was founded in 1989 and collects data from 230 US and
international centers on ECMO use for patients of all ages and indications (34,127,128). Outcomes for children
supported with ECMO as reported by ELSO, January 2014 are shown in Table 31.8. Overall survival to hospital
discharge for all uses of ECMO is about 60%. Survival to hospital discharge for neonates with respiratory failure
is the highest, whereas children with heart disease and those who are supported with ECPR have much poorer
outcomes. These outcomes can be considered for making clinical decisions regarding efficacy of ECMO and for
providing advice to patient and families on ECMO outcomes. Only limited data on neurodevelopmental,
functional, and quality-of-life outcomes for ECMO survivors are available (34,129,130). Currently available data
suggest that neurodevelopmental deficits (cognitive and behavioral deficits), reduced physical functioning and
quality of life, and sensorineural deafness may be present in ECMO survivors. Consequently,
neurodevelopmental and long-term follow-up for ECMO survivors should be strongly encouraged so that these
deficits can be identified early for intervention.
The ELSO website (www.elsonet.org) is an excellent resource for both novice and experienced ECMO programs
and contains information on ECMO circuit and patient management, anticoagulation, guidelines for new ECMO
program, and ECMO specialist education. ELSO and its ECMO registry have been pivotal in improving our
understanding of ECMO outcomes in the pediatric population.
TABLE 31.8. Outcomes following ECMO use from the international summary of the
Extracorporeal Life Support Organization (ELSO), January 2014
Number of patients Survived ECLS Survived to hospital discharge
Neonatal
Respiratory 27,007 22,782 (84%) 20,093 (74%)
Cardiac 5,425 3,339 (62%) 2,206 (41%)

ECPR 980 626 (64%) 388 (40%)
Pediatric
Respiratory 6,149 4,034 (66%) 3,496 (57%)
Cardiac 6,784 4,443 (65%) 3,388 (50%)
ECPR 2,071 1,123 (54%) 840 (41%)
Adult
Respiratory 5,146 3,317 (64%) 2,905 (56%)
Cardiac 4,042 2,255 (56%) 1,636 (40%)
ECPR 1,238 476 (38%) 355 (29%)
Total 58,842 42,395 (72%) 35,307 (60%)
ECLS, extracorporeal life support; ECPR, ECMO to support cardiopulmonary resuscitation.
SUMMARY
ECMO can provide support for children with cardiac or respiratory failure failing to respond to conventional
therapies. As ECMO is a support modality that does not treat the primary illness, success from ECMO use
is closely related to the prognosis of the primary disease. Providing safe care to ECMO patients requires
specialized equipment, an ECMO team well versed in management of the ECMO circuit and patient
emergencies, coordination of services from many specialties, and post-ECMO care. ECMO support can be
associated with significant ECMO-related mortality and morbidity. Maintaining an ECMO program and
providing ECMO support to patients is expensive, so that ECMO should be used judiciously with clear goals
in mind, by a well-coordinated team of ECMO experts.
ACKNOWLEDGMENT
Ms. Emily Harris, Department of Cardiology, Boston Children’s Hospital created all the figures.
P.724
KEY Points
ECMO is used to provide mechanical cardiopulmonary support to patients with refractory cardiac and/or
pulmonary failure unresponsive to conventional medical therapies.
Indications for ECMO include refractory respiratory failure, cardiogenic shock, postoperative cardiac
failure, cardiac arrest refractory to conventional cardiopulmonary resuscitation (ECPR), procedural
support, and as a bridge to transplantation (lung or heart) or a ventricular assist device.
ECMO is used in two distinct support modes: VA ECMO and VV ECMO.
VA ECMO provides both cardiac and respiratory support:
Arterial and venous cannulation is required. Blood from the venous circulation is drained into the
ECMO circuit, pumped through the oxygenator for gas exchange, and returned to the arterial
circulation.
Cardiac output is a combination of the ECMO flow and native cardiac ejection.
With native ejection, mechanical ventilation with an appropriate Fio2 is necessary to oxygenate blood
transiting the pulmonary circulation in order to deliver oxygen to the myocardium.
VV ECMO provides respiratory support only:
Only venous cannulation is required. Venous blood is drained from the circulation into the ECMO
circuit, pumped through the oxygenator for gas exchange, and returned to the RA.
Maintenance of cardiac output is dependent on native cardiac function.
As systemic oxygen saturation depends on the proportion of blood entering the right ventricle,
positioning of the return limb of the cannula so that the opening is directed toward the TV is crucial to
limit recirculation.
The typical ECMO circuit consists of arterial and venous or just venous cannulas, tubing, a mechanical
blood pump, membrane oxygenator, a reservoir, heat exchanger, vascular access ports, and pressure,
flow, and oxygen saturation monitors.
Circuit tubing is made from a polyvinylchloridebased plastic and is often coated with biocompatible
materials to reduce blood contact activation.
Crystalloid-primed circuits are commonly used for urgent ECMO support whereas blood-primed circuits
are generally used when ECMO is deployed semi-electively.
Blood pumps may be roller head or centrifugal and should be able to provide a wide range of flows
(75-200 mL/kg/min) without exerting excessive shear stress on red blood cells.
A reservoir, called the “bladder,” is placed between the pump and the venous drainage tubing in roller
pump circuits to avoid direct suction to the venous catheter.
A membrane oxygenator provides for blood oxygenation and CO2 removal. These are made up of
microporous hollow fibers, with gas flowing within the fibers and blood outside the fibers in a
countercurrent direction.
Cannulation for ECMO may be surgical or percutaneous, with the internal jugular, femoral or RA
commonly used for venous cannulation and the internal carotid, femoral or aorta used for arterial
cannulation.
A heat exchanger warms the blood returning to the patient to the desired temperature.
A hemofiltration system may be incorporated for hemoconcentration and fluid management.
A bridge between the arterial and venous limbs of the circuit allows circuit maintenance during a
clamping trial.
Pressure monitors, apart from the obvious, can also be used as servo regulators for pump flow and for
evaluation of the “health” of the oxygenator. Flow monitors use ultrasound to measure flow and can be
placed at the pump outlet and the distal arterial limb. Hemoglobin, arterial and mixed venous oxygen
saturation monitors are also used.
An assembled ECMO circuit, surgical instruments for cannulation, and cannulas and connectors
should be stored in an easily accessible location.
Patient management requires a large interdisciplinary team of providers with excellent communication
and teamwork for success.
There is no clear consensus about when ECMO should be initiated, with the exception of an
oxygenation index >40 for neonates with respiratory failure.
Heparin (50-100 units/kg) is administered as an intravenous bolus just prior to placement of ECMO
cannulas in the vessels. A heparin infusion is started as soon as possible after deployment and titrated
based on anticoagulation testing.
Optimal ECMO flow should provide adequate endorgan perfusion without causing turbulence and
excessive pressure gradients in the circuit. Flows of 100 to 150 mL/kg/min are usually required for full
support during VA ECMO. With VV ECMO, a Sao2 of 85% to 92% is the usual goal.
Left heart decompression may be required to lower LA pressure and reduce pulmonary edema and
hemorrhage, and also to reduce left ventricular wall stress and thereby promote myocardial recovery.
Daily ECMO management requires careful attention to patient care, technical aspects of the ECMO
circuit with respect to the tubing, pressure monitors, function of the membrane oxygenator, and
assessment of the circuit for the presence of visible thrombus, the adequacy of ECMO support, and
assessment for recovery of cardiac and respiratory function.
P.725
For patients supported with VA ECMO for cardiac dysfunction, increasing pulse pressure and endtidal
CO2 suggests recovery of ventricular function. In VV ECMO patients, improved lung compliance on
mechanical ventilation and improved lung pathology on serial chest X-rays suggest readiness for a
weaning trial.
Decannulation from ECMO is usually done at the bedside and requires a surgical team, surgical
equipment, sedation and analgesia, and patient monitoring similar to ECMO cannulation.
The duration of ECMO support needed for recovery of cardiac or respiratory dysfunction is variable.
Decisions regarding continuation of ECMO in patients showing delayed recovery (>2 weeks) should
be individualized, and include prognosis of the primary diagnosis, presence of serious ECMO
complications, multi-organ failure, and transplant candidacy.
Complications of ECMO include mechanical complications (oxygenator failure, air embolism, and circuit
tubing rupture), circuit thrombosis and thromboembolism, bleeding, infection, hemolysis, and
neurologic injury.
Outcomes for children supported with ECMO vary with age and whether the indication is cardiac,
respiratory, or ECPR. Neurodevelopmental deficits (cognitive and behavioral), reduced physical
functioning and quality of life, and sensorineural deafness may be present in ECMO survivors.
The Extracorporeal Life Support Organization (ELSO) website (www.elsonet.org) is an excellent
resource.
REFERENCES
1. Conrad SA, Dalton HJ. Extracorporeal life support. In: Nichols DG, ed. Roger’s textbook of pediatric
intensive care. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2008:544-562.
2. Karl TR, Kirshbom PM, Horton SB. Mechanical circulatory support in infants and children. In: Nichols DG,
Ungerleider RM, Spevak PJ, et al., eds. Critical heart disease in infants and children. 2nd ed. Philadelphia,
PA: Elsevier, 2006:529-544.
3. Hill JD, O’Brien TG, Murray JJ, et al. Prolonged extracorporeal oxygenation for acute post-traumatic
respiratory failure (shock-lung syndrome). Use of the Bramson membrane lung. N Engl J Med
1972;286(12):629-634.
4. Bartlett RH, Gazzaniga AB, Fong SW, et al. Extracorporeal membrane oxygenator support for
cardiopulmonary failure. Experience in 28 cases. J Thorac Cardiovasc Surg 1977;73(3):375-386.
5. Bartlett RH. Esperanza. Presidential address. Trans Am Soc Artif Intern Organs 1985;31:723-726.
failure. A randomized prospective study. JAMA 1979;242(20):2193-2196.
7. 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(2, Part 1):295-305.
8. Zapol WM. What future for ECMO? Int J Artif Organs 1979;2(5):231-232.
9. Bartlett RH, Roloff DW, Cornell RG, et al. Extracorporeal circulation in neonatal respiratory failure: a
prospective randomized study. Pediatrics 1985;76(4):479-487.
10. O’Rourke PP, Crone RK, Vacanti JP, et al. Extracorporeal membrane oxygenation and conventional
medical therapy in neonates with persistent pulmonary hypertension of the newborn: a prospective
randomized study. Pediatrics 1989;84(6):957-963.
11. Peek GJ, Mugford M, Tiruvoipati R, et al. Efficacy and economic assessment of conventional ventilatory
support versus extracorporeal membrane oxygenation for severe adult respiratory failure (CESAR): a
multicentre randomised controlled trial. Lancet 2009;374(9698):1351-1363.
12. Australia and New Zealand Extracorporeal Membrane Oxygenation Influenza Investigators; Davies A,
Jones D, Bailey M, et al. Extracorporeal membrane oxygenation for 2009 influenza A(H1N1) acute respiratory
distress syndrome. JAMA 2009;302(17):1888-1895.
13. Paden ML, Conrad SA, Rycus PT, et al.; ELSO Registry. Extracorporeal Life Support Organization
Registry Report 2012. ASAIO J 2013;59(3):202-210.
14. Butt W, Heard M, Peek GJ. Clinical management of the extracorporeal membrane oxygenation circuit.
Pediatr Crit Care Med 2013;14(5, Suppl 1): S13-S19.
15. Gaffney AM, Wildhirt SM, Griffin MJ, et al. Extracorporeal life support. BMJ 2010;341:c5317.
16. Ventetuolo CE, Muratore CS. Extracorporeal life support in critically ill adults. Am J Respir Crit Care Med
2014;190(5):497-508.
17. Martin GR, Short BL. Doppler echocardiographic evaluation of cardiac performance in infants on
prolonged extracorporeal membrane oxygenation. Am J Cardiol 1988;62(13):929-934.
18. Thiagarajan RR, Yarlagadda V, Bratton SL. Cardiac failure: principles and physiology. In: Annich GM,
Lynch WR, MacLaren G, et al., eds. ECMO: extracorporeal cardiopulmonary support in critical care. 4th ed.
Ann Arbor, MI: Extracorporeal Life Support, 2012:33-39.
19. Shen I, Levy FH, Vocelka CR, et al. Effect of extracorporeal membrane oxygenation on left ventricular
function of swine. Ann Thorac Surg 2001;71(3):862-867.
20. Fuhrman BP, Hernan LJ, Rotta AT, et al. Pathophysiology of cardiac extracorporeal membrane
oxygenation. Artif Organs 1999;23(11):966-969.
21. Martin GR, Chauvin L, Short BL. Effects of hydralazine on cardiac performance in infants receiving
extracorporeal membrane oxygenation. J Pediatr 1991;118(6):944-948.
22. Eastaugh LJ, Thiagarajan RR, Darst JR, et al. Percutaneous left atrial decompression in patients
supported with extracorporeal membrane oxygenation for cardiac disease. Pediatr Crit Care Med
2015;16(1):59-65.
23. Cheung MM, Goldman AP, Shekerdemian LS, et al. Percutaneous left ventricular “vent” insertion for left
heart decompression during extracorporeal membrane oxygenation. Pediatr Crit Care Med 2003;4(4):447-
449.
24. Thiagarajan RR, Salvin JW. Cardiac catheterization procedures for ECMO patients. In: Annich GM,
Ann Arbor, MI: Extracorporeal Life Support Organization, 2012:425-431.
25. Aiyagari RM, Rocchini AP, Remenapp RT, et al. Decompression of the left atrium during extracorporeal
membrane oxygenation using a transseptal cannula incorporated into the circuit. Crit Care Med 2006;34(10):
2603-2606.
26. Koenig PR, Ralston MA, Kimball TR, et al. Balloon atrial septostomy for left ventricular decompression in
patients receiving extracorporeal membrane oxygenation for myocardial failure. J Pediatr 1993;122(6):S95-
S99.
27. Shen I, Levy FH, Benak AM, et al. Left ventricular dysfunction during extracorporeal membrane
oxygenation in a hypoxemic swine model. Ann Thorac Surg 2001;71(3):868-871.
28. Brodie D, Bacchetta M. Extracorporeal membrane oxygenation for ARDS in adults. N Engl J Med
2011;365(20):1905-1914.
29. Abrams D, Bacchetta M, Brodie D. Recirculation in venovenous extracorporeal membrane oxygenation.

ASAIO J 2015;61(2):115-121.
30. Locker GJ, Losert H, Schellongowski P, et al. Bedside exclusion of clinically significant recirculation
volume during venovenous ECMO using conventional blood gas analyses. J Clin Anesth 2003;15(6):441-
445.
31. Kim K, Mazor RL, Rycus PT, et al. Use of venovenous extracorporeal life support in pediatric patients for
cardiac indications: a review of the Extracorporeal Life Support Organization registry. Pediatr Crit Care Med
2012;13(3):285-289.
32. Imamura M, Schmitz ML, Watkins B, et al. Venovenous extracorporeal membrane oxygenation for
cyanotic congenital heart disease. Ann Thorac Surg 2004;78(5):1723-1727.
P.726
33. Wessel DL, Almodovar MC, Laussen PC. Intensive care management of cardiac patients on
extracorporeal membrane oxygenation. In: Duncan BW, ed. Mechanical support for cardiac and respiratory
failure in pedaitric patients. 1st ed. New York, NY: Marcel Dekker; 2001:75-112.
34. Brown KL, Ichord R, Marino BS, et al. Outcomes following extracorporeal membrane oxygenation in
children with cardiac disease. Pediatr Crit Care Med 2013;14(5, Suppl 1):S73-S83.
35. Thiagarajan RR, Laussen PC, Rycus PT, et al. Extracorporeal membrane oxygenation to aid
cardiopulmonary resuscitation in infants and children. Circulation 2007;116(15):1693-700.
36. Kane DA, Thiagarajan RR, Wypij D, et al. Rapid-response extracorporeal membrane oxygenation to
support cardiopulmonary resuscitation in children with cardiac disease. Circulation 2010;122(11,
Suppl):S241-S248.
37. Carmichael TB, Walsh EP, Roth SJ. Anticipatory use of venoarterial extracorporeal membrane
oxygenation for a high-risk interventional cardiac procedure. Respir Care 2002;47(9):1002-1006.
38. Booth KL, Roth SJ, Perry SB, et al. Cardiac catheterization of patients supported by extracorporeal
membrane oxygenation. J Am Coll Cardiol 2002;40(9):1681-1686.
39. Biscotti M, Sonett J, Bacchetta M. ECMO as bridge to lung transplant. Thorac Surg Clin 2015;25(1):17-
25.
40. Almond CS, Singh TP, Gauvreau K, et al. Extracorporeal membrane oxygenation for bridge to heart
transplantation among children in the United States: analysis of data from the Organ Procurement and
Transplant Network and Extracorporeal Life Support Organization Registry. Circulation 2011;123(25):2975-
2984.
41. Almond CS, Morales DL, Blackstone EH, et al. Berlin Heart EXCOR pediatric ventricular assist device for
bridge to heart transplantation in US children. Circulation 2013;127(16):1702-1711.
42. Fraser CD Jr, Jaquiss RD, Rosenthal DN, et al. Prospective trial of a pediatric ventricular assist device. N
Engl J Med 2012;367(6):532-541.
43. Lequier L, Horton SB, McMullan DM, et al. Extracorporeal membrane oxygenation circuitry. Pediatr Crit
Care Med 2013;14(5, Suppl 1):S7-S12.
44. Annich GM, Cornell TT, Massicotte MP, et al. Blood biomaterial surface interaction during ECLS. In:
Annich GM, Lynch WR, MacLaren G, et al., eds. ECMO: extracorporeal cardiopulmonary support in critical
care. 4th ed. Ann Arbor, MI: Extracorporeal Life Support Organization, 2012:75-86.
45. Larm O, Larsson R, Olsson P. A new non-thrombogenic surface prepared by selective covalent binding
of heparin via a modified reducing terminal residue. Biomater Med Devices Artif Organs 1983;11(2/3):161-
173.
46. Muehrcke DD, McCarthy PM, Kottke-Marchant K, et al. Biocompatibility of heparin-coated extracorporeal
bypass circuits: a randomized, masked clinical trial. J Thorac Cardiovasc Surg 1996;112(2):472-483.
47. Rais-Bahrami K, Nunez S, Revenis ME, et al. Adolescents exposed to DEHP in plastic tubing as
neonates: research briefs. Pediatr Nurs 2004;30(5):406, 433.
48. Park JD, Habeebu SS, Klaassen CD. Testicular toxicity of di-(2-ethylhexyl) phthalate in young Sprague-
Dawley rats. Toxicology 2002;171(2/3):105-115.
49. Rais-Bahrami K, Nunez S, Revenis ME, et al. Follow-up study of adolescents exposed to di(2-ethylhexyl)
phthalate (DEHP) as neonates on extracorporeal membrane oxygenation (ECMO) support. Environ Health
Perspect 2004;112(13):1339-1340.
50. Toomasian JM, Lawson DS, Harris WE. The circuit. In: Annich GM, Lynch WR, MacLaren G, et al., eds.
ECMO: extracorporeal cardiopulmonary support in critical care. 4th ed. Ann Arbor, MI: Extracorporeal Life
Support Organization, 2012:107-32.
51. Snyder EJ, McElwee DL, Harb HM, et al. Investigation of fatigue failure of S-65-HL “Super Tygon” roller
pump tubing. J Extra Corpor Technol 1996;28(2):79-87.
52. Lawson DS, Walczak R, Lawson AF, et al. North American neonatal extracorporeal membrane
oxygenation (ECMO) devices: 2002 survey results. J Extra Corpor Technol 2004;36(1):16-21.
53. Bass RM, Longmore DB. Cerebral damage during open heart surgery. Nature 1969;222(5188):30-33.
54. Byrnes J, McKamie W, Swearingen C, et al. Hemolysis during cardiac extracorporeal membrane
oxygenation: a case-control comparison of roller pumps and centrifugal pumps in a pediatric population.
ASAIO J 2011;57(5):456-461.
55. Barrett CS, Jaggers JJ, Cook EF, et al. Outcomes of neonates undergoing extracorporeal membrane
oxygenation support using centrifugal versus roller blood pumps. Ann Thorac Surg 2012;94(5):1635-1641.
56. Barrett CS, Jaggers JJ, Cook EF, et al. Pediatric ECMO outcomes: comparison of centrifugal versus
roller blood pumps using propensity score matching. ASAIO J 2013;59(2):145-151.
57. Barrett CS, Thiagarajan RR. Centrifugal pump circuits for neonatal extracorporeal membrane
oxygenation. Pediatr Crit Care Med 2012;13(4):492-493.
58. Kolobow T, Bowman RL. Construction and evaluation of an alveolar membrane artificial heart-lung. Trans
Am Soc Artif Intern Organs 1963;9: 238-243.
59. Kawahito S, Maeda T, Motomura T, et al. Feasibility of a new hollow fiber silicone membrane oxygenator
for long-term ECMO application. J Med Invest 2002;49(3/4):156-162.
60. Kawahito S, Maeda T, Motomura T, et al. Development of a new hollow fiber silicone membrane
oxygenator: in vitro study. Artif Organs 2001;25(6):494-498.
61. Kawahito S, Maeda T, Takano T, et al. Gas transfer performance of a hollow fiber silicone membrane
oxygenator: ex vivo study. Artif Organs 2001;25(6):498-502.
62. Galletti PM, Richardson PD, Snider MT, et al. A standardized method for defining the overall gas transfer
performance of artificial lungs. Trans Am Soc Artif Intern Organs 1972;18(0):359-368, 374.
63. Bartlett RH. Physiology of extracorporeal life support. In: Annich GM, Lynch WR, MacLaren G, et al.
ECMO: extracorporeal cardiopulmonary support in critical care. 4th ed. Ann Arbor, MI: Extracorporeal Life
Support Organization, 2012:11-31.
64. MacLaren G, Butt W, Best D, et al. Central extracorporeal membrane oxygenation for refractory pediatric
septic shock. Pediatr Crit Care Med 2011;12(2):133-136.
65. Kasirajan V, Simmons I, King J, et al. Technique to prevent limb ischemia during peripheral cannulation
for extracorporeal membrane oxygenation. Perfusion 2002;17(6):427-428.
66. Irish MS, O’Toole SJ, Kapur P, et al. Cervical ECMO cannula placement in infants and children:
recommendations for assessment of adequate positioning and function. J Pediatr Surg 1998;33(6):929-931.
67. Thomas TH, Price R, Ramaciotti C, et al. Echocardiography, not chest radiography, for evaluation of
cannula placement during pediatric extracorporeal membrane oxygenation. Pediatr Crit Care Med
2009;10(1):56-59.
68. Horton S, Thuys C, Bennett M, et al. Experience with the Jostra Rotaflow and QuadroxD oxygenator for
ECMO. Perfusion 2004;19(1):17-23.
69. Fleming GM, Brophy PD. Renal function and renal supportive therapy during ECMO. In: Annich GM,
Ann Arbor, MI: Extracorporeal Life Support Organization, 2012:189-204.
70. Heiss KF, Pettit B, Hirschl RB, et al. Renal insufficiency and volume overload in neonatal ECMO
managed by continuous ultrafiltration. ASAIO J 1987;33(3):557-560.
71. Foland JA, Fortenberry JD, Warshaw BL, et al. Fluid overload before continuous hemofiltration and
survival in critically ill children: a retrospective analysis. Crit Care Med 2004;32(8):1771-1776.
72. Van Heijst A, Liem D, Van Der Staak F, et al. Hemodynamic changes during opening of the bridge in
venoarterial extracorporeal membrane oxygenation. Pediatr Crit Care Med 2001;2(3):265-270.
73. Liem KD, Kollee LA, Klaessens JH, et al. Disturbance of cerebral oxygenation and hemodynamics related
to the opening of the bypass bridge during veno-arterial extracorporeal membrane oxygenation. Pediatr Res
1995;38(1):124-129.
74. Totapally BR, Sussmane JB, Hultquist K, et al. Variability in systemic arterial pressure during closed- and
open-bridge extracorporeal life support: an in vitro evaluation. Crit Care Med 2000;28(6):2076-2080.
75. Ejike JC, Schenkman KA, Seidel K, et al. Cerebral oxygenation in neonatal and pediatric patients during
veno-arterial extracorporeal life support. Pediatr Crit Care Med 2006;7(2):154-158.
76. Combes A, Brodie D, Bartlett R, et al. Position paper for the organization of extracorporeal membrane
oxygenation programs for acute respiratory failure in adult patients. Am J Respir Crit Care Med
2014;190(5):488-496.
77. Trittenwein G, Pansi H, Graf B, et al. Proposed entry criteria for postoperative cardiac extracorporeal
membrane oxygenation after pediatric open heart surgery. Artif Organs 1999;23(11):1010-1014.
78. Chaturvedi RR, Macrae D, Brown KL, et al. Cardiac ECMO for biventricular hearts after paediatric open
heart surgery. Heart 2004;90(5):545-551.
79. Tsui SS, Schultz JM, Shen I, et al. Postoperative hypoxemia exacerbates potential brain injury after deep
hypothermic circulatory arrest. Ann Thorac Surg 2004;78(1):188-196; discussion 188-196.
80. Ungerleider RM, Shen I, Yeh T, et al. Routine mechanical ventricular assist following the Norwood
procedure—improved neurologic outcome and excellent hospital survival. Ann Thorac Surg 2004;77(1):18-
22.
P.727
81. Pranikoff T, Hines MH. Vascular access for extracorporeal support. In: Annich GM, Lynch W, MacLaren
G, et al., eds. ECMO: extracorporeal cardiopulmonary support in critical care. 4th ed. Ann Arbor, MI:
Extracorporeal Life Support Organization, 2013:133-47.
82. Rastan AJ, Dege A, Mohr M, et al. Early and late outcomes of 517 consecutive adult patients treated with
extracorporeal membrane oxygenation for refractory postcardiotomy cardiogenic shock. J Thorac Cardiovasc
Surg 2010;139(2):302-311.
83. Sidebotham D, Allen S, McGeorge A, et al. Catastrophic left heart distension following initiation of
venoarterial extracorporeal membrane oxygenation in a patient with mild aortic regurgitation. Anaesth
Intensive Care 2012;40(3):568-569.
84. Gandy KL, Mitchell ME, Pelech AN, et al. Aortic exclusion: a method of handling aortic insufficiency in the
pediatric population needing mechanical circulatory support. Pediatr Cardiol 2011;32(8):1231-1233.
85. Black MD, Coles JG, Williams WG, et al. Determinants of success in pediatric cardiac patients
undergoing extracorporeal membrane oxygenation. Ann Thorac Surg 1995;60(1):133-138.
86. Agarwal HS, Hardison DC, Saville BR, et al. Residual lesions in postoperative pediatric cardiac surgery
patients receiving extracorporeal membrane oxygenation support. J Thorac Cardiovasc Surg
2014;147(1):434-441.
87. Selewski DT, Cornell TT, Blatt NB, et al. Fluid overload and fluid removal in pediatric patients on
extracorporeal membrane oxygenation requiring continuous renal replacement therapy. Crit Care Med
2012;40(9):2694-2699.
88. Hanekamp MN, Spoel M, Sharman-Koendjbiharie I, et al. Routine enteral nutrition in neonates on
extracorporeal membrane oxygenation. Pediatr Crit Care Med 2005;6(3):275-279.
89. Bizzarro MJ, Conrad SA, Kaufman DA, et al.; Extracorporeal Life Support Organization Task Force on
Infections; Extracorporeal Membrane Oxygenation. Infections acquired during extracorporeal membrane
oxygenation in neonates, children, and adults. Pediatr Crit Care Med 2011;12(3): 277-281.
90. Kao LS, Fleming GM, Escamilla RJ, et al. Antimicrobial prophylaxis and infection surveillance in
extracorporeal membrane oxygenation patients: a multi-institutional survey of practice patterns. ASAIO J
2011;57(3): 231-238.
91. Gardner AH, Prodhan P, Stovall SH, et al. Fungal infections and antifungal prophylaxis in pediatric
cardiac extracorporeal life support. J Thorac Cardiovasc Surg 2012;143(3):689-695.
92. Fligor BJ, Neault MW, Mullen CH, et al. Factors associated with sensorineural hearing loss among
survivors of extracorporeal membrane oxygenation therapy. Pediatrics 2005;115(6):1519-1528.
93. Thiagarajan RR, Teele SA, Teele KP, et al. Physical therapy and rehabilitation issues for patients
supported with extracorporeal membrane oxygenation. J Pediatr Rehab Med 2012;5(1):47-52.
94. Cengiz P, Seidel K, Rycus PT, et al. Central nervous system complications during pediatric
extracorporeal life support: incidence and risk factors. Crit Care Med 2005;33(12):2817-2824.
95. Polito A, Barrett CS, Rycus PT, et al. Neurologic injury in neonates with congenital heart disease during
extracorporeal membrane oxygenation: an analysis of ELSO registry data. ASAIO J 2015;61(1):43-48.
96. Polito A, Barrett CS, Wypij D, et al. Neurologic complications in neonates supported with extracorporeal
membrane oxygenation. An analysis of ELSO registry data. Intensive Care Med 2013;39(9):1594-1601.
97. Barrett CS, Bratton SL, Salvin JW, et al. Neurological injury after extracorporeal membrane oxygenation
use to aid pediatric cardiopulmonary resuscitation. Pediatr Crit Care Med 2009;10(4):445-451.
98. LaRovere KL, Brett MS, Tasker RC, et al.; Pediatric Critical Nervous System Program. Head computed
tomography scanning during pediatric neurocritical care: diagnostic yield and the utility of portable studies.
Neurocrit Care 2012;16(2):251-257.
99. 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(12): 2593-2598.
100. Anton-Martin P, Thompson MT, Sheeran PD, et al. Extubation during pediatric extracorporeal
membrane oxygenation: a single-center experience. Pediatr Crit Care Med 2014;15(9):861-869.
101. Bower LK. Management of the extracorporeal membrane oxygenator circuit for children with cardiac
disease. In: Duncan BW, ed. Mechanical support for cardiac and respiratory failure in pedaitric patients. 1st
ed. Phildelphia, PA: Marcel Dekker, 2001:139-57.
102. Annich G, Adachi I. Anticoagulation for pediatric mechanical circulatory support. Pediatr Crit Care Med
2013;14(5, Suppl 1):S37-S42.
103. Extracorporeal Life Support Organization. ELSO Anticoagulation Task Force anticoagulation guideline.
Available at https://www.elso.org/Portals/0/Files/elsoanticoagulationguideline8-2014-table-contents.pdf,
published 2014. Accessed 19 December 2014.
104. Bembea MM, Annich G, Rycus P, et al. Variability in anticoagulation management of patients on
extracorporeal membrane oxygenation: an international survey. Pediatr Crit Care Med 2013;14(2):e77-e84.
105. Welp H, Ellger B, Scherer M, et al. Heparin-induced thrombocytopenia during extracorporeal membrane
oxygenation. J Cardiothorac Vasc Anesth 2014;28(2):342-344.
106. Mejak B, Giacomuzzi C, Heller E, et al. Argatroban usage for anticoagulation for ECMO on a post-
cardiac patient with heparin-induced thrombocytopenia. J Extra Corpor Technol 2004;36(2):178-181.
107. Almond CS, Harrington J, Thiagarajan R, et al. Successful use of bivalirudin for cardiac transplantation
in a child with heparin-induced thrombocytopenia. J Heart Lung Transplant 2006;25(11):1376-1379.
108. Nagle EL, Dager WE, Duby JJ, et al. Bivalirudin in pediatric patients maintained on extracorporeal life
support. Pediatr Crit Care Med 2013;14(4): e182-e188.
109. Beiderlinden M, Treschan T, Gorlinger K, et al. Argatroban in extracorporeal membrane oxygenation.

Artif Organs 2007;31(6):461-465.
110. Desai SA, Stanley C, Gringlas M, et al. Five-year follow-up of neonates with reconstructed right
common carotid arteries after extracorporeal membrane oxygenation. J Pediatr 1999;134(4):428-433.
111. Cheung PY, Vickar DB, Hallgren RA, et al. Carotid artery reconstruction in neonates receiving
extracorporeal membrane oxygenation: a 4-year follow-up study. Western Canadian ECMO Follow-Up
Group. J Pediatr Surg 1997;32(4):560-564.
112. Buesing KA, Kilian AK, Schaible T, et al. Extracorporeal membrane oxygenation in infants with
congenital diaphragmatic hernia: follow-up MRI evaluating carotid artery reocclusion and neurologic
outcome. Am J Roentgenol 2007;188(6):1636-1642.
113. Duncan BW, Hraska V, Jonas RA, et al. Mechanical circulatory support in children with cardiac disease.
J Thorac Cardiovasc Surg 1999;117(3): 529-542.
114. Duncan BW, Bohn DJ, Atz AM, et al. Mechanical circulatory support for the treatment of children with
acute fulminant myocarditis. J Thorac Cardiovasc Surg 2001;122(3):440-448.
115. Rajagopal SK, Almond CS, Laussen PC, et al. Extracorporeal membrane oxygenation for the support of
infants, children, and young adults with acute myocarditis: a review of the Extracorporeal Life Support
Organization registry. Crit Care Med 2010;38(2):382-387.
116. Teele SA, Allan CK, Laussen PC, et al. Management and outcomes in pediatric patients presenting with
acute fulminant myocarditis. J Pediatr 2011;158(4):638-643.
117. Brogan TV, Zabrocki L, Thiagarajan RR, et al. Prolonged extracorporeal membrane oxygenation for
children with respiratory failure. Pediatr Crit Care Med 2012;13(4):e249-e254.
118. Green TP, Moler FW, Goodman DM. Probability of survival after prolonged extracorporeal membrane
oxygenation in pediatric patients with acute respiratory failure. Extracorporeal Life Support Organization. Crit
Care Med 1995;23(6):1132-1139.
119. Fleming GM, Gurney JG, Donohue JE, et al. Mechanical component failures in 28,171 neonatal and
pediatric extracorporeal membrane oxygenation courses from 1987 to 2006. Pediatr Crit Care Med
2009;10(4):439-444.
120. Downard CD, Betit P, Chang RW, et al. Impact of AMICAR on hemorrhagic complications of ECMO: a
ten-year review. J Pediatr Surg 2003;38(8):1212-1216.
121. Wilson JM, Bower LK, Fackler JC, et al. Aminocaproic acid decreases the incidence of intracranial
hemorrhage and other hemorrhagic complications of ECMO. J Pediatr Surg 1993;28(4):536-540; discussion
540-541.
122. Niebler RA, Punzalan RC, Marchan M, et al. Activated recombinant factor VII for refractory bleeding
during extracorporeal membrane oxygenation. Pediatr Crit Care Med 2010;11(1):98-102.
123. Long MT, Wagner D, Maslach-Hubbard A, et al. Safety and efficacy of recombinant activated factor VII
for refractory hemorrhage in pediatric patients on extracorporeal membrane oxygenation: a single center
review. Perfusion 2014;29(2):163-170.
P.728
124. Extacorporeal Life Support Organization. ELSO Infectious Disease Task Force recommendation
summary. Available at https://www.elso.org/Portals/0/Files/ ELSO-ID-Task-Force-Recommendations-
Summary.pdf, 2012. Accessed 12 January 2015.
125. Lou S, MacLaren G, Best D, et al. Hemolysis in pediatric patients receiving centrifugal-pump
extracorporeal membrane oxygenation: prevalence, risk factors, and outcomes. Crit Care Med
2014;42(5):1213-1220.
126. Teele SA, Salvin JW, Barrett CS, et al. The association of carotid artery cannulation and neurologic
injury in pediatric patients supported with venoarterial extracorporeal membrane oxygenation*. Pediatr Crit
Care Med 2014;15(4):355-361.
127. Conrad SA, Rycus PT. The regsitry of the Extracorporeal Life Support Organization. In: Annich GM,
Ann Arbot, MI: Extracorporeal Life Support Organization, 2012:87-104.
128. Joffe AR, Lequier L, Robertson CM. Pediatric outcomes after extracorporeal membrane oxygenation for
cardiac disease and for cardiac arrest: a review. ASAIO J 2012;58(4):297-310.
129. Iguchi A, Ridout DA, Galan S, et al. Long-term survival outcomes and causes of late death in neonates,
infants, and children treated with extracorporeal life support. Pediatr Crit Care Med 2013;14(6):580-586.
130. Costello JM, O’Brien M, Wypij D, et al. Quality of life of pediatric cardiac patients who previously
required extracorporeal membrane oxygenation. Pediatr Crit Care Med 2012;13(4):428-434.
Chapter 32
Ventricular Assist Devices for Infants and Children: State of the
Art and Future
Iki Adachi
Charles D. Fraser Jr.
INTRODUCTION
The last decade has witnessed significant advancements in ventricular assist devices (VADs) for the adult
population. Continued refinement of device technology as well as clinical management has led to improved
outcomes of VAD support, resulting in a rapid increase in the number of patients supported with VADs (1). In
stark contrast to the adult population, options for mechanical circulatory support (MCS) in children, particularly
infants and small children, are limited by a paucity of devices designed for pediatric use (2). In fact,
extracorporeal membrane oxygenation (ECMO) used to be the only MCS option in this group of patients. This
frustrating reality, however, is starting to change. Owing to widespread acceptance of the Berlin Heart EXCOR
(Berlin Heart, The Woodland, TX), which is equipped with a variety of pump and cannula sizes, even infants can
now benefit from longterm VAD support. In addition, the Infant Jarvik 2000 (Jarvik Heart Inc., New York, NY), an
implantable, continuous-flow VAD for small children, will be analyzed for safety and efficacy in its first randomized
trial (3). Finally, the era of pediatric MCS has begun. In this chapter, we will review VAD devices available for the
pediatric population.
RECENT DRAMATIC CHANGES IN HEART FAILURE MANAGEMENT

In recent years, VADs have become an integral component of the standard of care provided to adults with end-
stage heart failure. The most significant change to impact patient management strategy is the emergence of
implantable, continuous-flow VADs such as the HeartMate II (Thoratec Corporation, Pleasanton, CA) and the
HeartWare HVAD (HeartWare Inc., Framingham, MA). The efficiency of these devices, coupled with low-
morbidity profiles, has contributed to a change in indications for device placement. Early utilization of such a
device is now considered a reasonable option in preference to escalating medical management. Nowadays,
VADs are being used not only for bridging the patient to heart transplantation (bridge to transplant, BTT) but also
as destination therapy (DT), which is currently offered only to those candidates deemed unsuitable for
transplantation. In fact, the number of patients who undergo VAD placement for DT has increased, now
accounting for about 41% of all adult VAD implantations (1). It is suggested that with continuing evolution of VAD
therapy, the medical community is approaching the point where VADs may be considered the primary alternative
to cardiac transplantation (4,5).
Although the pediatric population has not yet experienced this shift in the MCS paradigm, there has been a
growing interest in pediatric MCS in recent years for the following reasons: First, the number of children with
endstage heart failure far exceeds the availability of suitable pediatric cardiac donors. The number of pediatric
heart transplants worldwide has been stagnant at approximately 300 to 400 per year (6,7). By analyzing 15
million pediatric hospitalizations using the Healthcare Cost and Utilization Project Kids Inpatient Database,
Rossano et al. have shown that heart failure-related hospitalizations occur in 11,000 to 14,000 children annually
in the United States, with an overall mortality of 7% (8). It is important to note that admissions did not greatly
increase over the 10-year study period (1997-2006), but the total mean length of stay increased from 13.8 to
19.4 days. This data possibly indicates a temporal increase in the proportion of sicker children. Secondly, an
increment in the number of children listed for heart transplantation would support this view, which has inevitably
resulted in prolongation of wait times on the heart transplant list in the setting of unchanged organ supply (6).
While ECMO has traditionally been used for bridging the patient to transplantation, the outcome of such an
intervention is generally poor. Inherently temporary, ECMO support cannot be instituted indefinitely until a
suitable organ is found. This limitation has gained greater significance in recent years where waitlist duration has
been steadily increasing. Using the ELSO Registry, Almond and associates (9) found that a third of pediatric
heart transplant recipients on ECMO support as a BTT die during the same admission. Five- and ten-year
posttransplantation survival is also worse in patients on ECMO prior to transplant than in patients who were on a
VAD or not on MCS (10).
P.730
INDICATIONS FOR VENTRICULAR ASSIST DEVICES
At present, there is no universal consensus with regard to indications for instituting VAD support. In general, VAD
therapy for any patient is considered when the proposed benefits of VAD outweigh the risks. Traditionally, VAD
support is indicated when severity of heart failure extends beyond the capability of maximal medical
management. As with all interventions, a practitioner’s individual threshold in deciding whether to provide or
withhold a therapy is influenced by the degree of confidence in that modality to consistently produce positive
outcomes. Since the risk-to-benefit ratio is largely determined by the patient’s clinical status, institutional
experience, and type of devices available, the decision needs to be made on a case-by-case basis by an
experienced multidisciplinary team. The Fifth Interagency Registry for Mechanically Assisted Circulatory Support
(INTERMACS) report found that preoperative clinical status of a VAD candidate has an appreciable impact on
postimplant outcomes (5). There are ongoing discussions about extending partial VAD support to include
patients with INTERMACS profile 4 to 7 (1 being worst, 7 being best) who may derive some benefit (11,12). The
trend of early VAD institution has so far resulted in considerably improved outcomes after VAD implantation (1).
Pediatric physicians, contrary to adult physicians, tend to be more judicious when evaluating indications for VAD
use in children. Globally, most pediatric heart centers have less experience with such devices as compared with
adult centers. This is particularly true for small children, who can only be supported with pulsatile, extracorporeal
VADs (e.g., Berlin Heart EXCOR) that are associated with significantly higher risk profiles than implantable,
continuous-flow devices (13). Devices such as these present a challenge to clinicians with respect to
determining the optimum timeframe within which to commence therapy, as waiting too long to implant the EXCOR
sharply increases the risk of mortality, while initiating EXCOR support too soon increases the risk of device-
related morbidities. The ideal timeframe for implanting the device is, unfortunately, debatable and dependent on
several variables (14). Further complicating matters, there are several contraindications to VAD support in
children including, but not limited to, extreme prematurity, low body weight (<2.0 kg), preexisting neurologic
injury, and congenital anomalies or major chromosomal aberrations with poor prognosis. In addition, multisystem
end-organ injury presents a relative contraindication, but does not necessarily preclude patients from
consideration of VAD support if end-organ recovery is predicted with improved cardiac output. Again, individual
assessment of patient risk profile is of critical importance.
At Texas Children’s Hospital (TCH), the application of the Berlin Heart EXCOR is limited to critically ill children
with cardiogenic shock or end-organ injury (INTERMACS profile 1 or 2) (15). The reality is that the vast majority
of these patients who undergo Berlin EXCOR implantation are already on ECMO support or mechanically
ventilated. In older children who can accommodate an adult-sized implantable device (e.g., HeartMate II or
HeartWare HVAD), TCH initiates VAD support sooner, typically at INTERMACS profile 2 or 3. Lower risk profiles
of these implantable devices, compared to an extracorporeal pulsatile VAD, justify such an early initiation.
Certain clinical circumstances have to be carefully considered before VADs are implanted in children:
Congenitally malformed hearts have anatomic variations, such as abnormal size and location of the aorta or
unusual location or shape of the ventricle, that pose technical challenges, specifically with regards to placement
of inflow and outflow cannulas. In addition, previous surgical palliation may jeopardize the provision of MCS due
to further anatomic and circulatory physiologic disorder, such as systemic-to-pulmonary artery shunts or
disconnected vena cava and pulmonary artery after the Glenn or Fontan operations. Furthermore, unique
pathophysiologic features of heart failure must be taken into account when considering VAD support for patients
with single-ventricle physiology. For instance, device selection for the failing Fontan circulation requires careful
assessment of the etiology, which can be multifactorial. If systemic ventricular dysfunction is the primary
impediment to the Fontan circulation, placement of a VAD to support the failing systemic ventricle would suffice
(16). A total artificial heart may be necessary, however, when the Fontan circulation is restricted at multiple levels
(e.g., ventricular dysfunction, atrioventricular valve insufficiency, and high pulmonary vascular resistance) (17). In
addition, psychosocial and family counseling should be offered, particularly if the possibility of home discharge
with an implantable VAD arises, to optimize outpatient management.
CHOOSING THE MOST APPROPRIATE MODE OF SUPPORT

ECMO versus Ventricular Assist Device
ECMO is the initial support of choice for patients unable to be weaned off cardiopulmonary bypass (CPB) or
failure of return of spontaneous circulation after cardiac arrest (extracorporeal cardiopulmonary resuscitation,
ECPR) (18). Beyond this, there are two major elements that factor in to deciding what type of MCS is required.
These are the anticipated duration of support and whether the support should be univentricular or biventricular.
The anticipated duration of support is largely dependent on the etiology of the heart failure, and whether it is
acute (e.g., viral myocarditis), or chronic (e.g., dilated cardiomyopathy). Short-term support is offered to patients
with acute-type or unknown etiologies, or if transplant candidacy is uncertain. The objective is hemodynamic
optimization, thereby allowing for further investigation to assist in decision making (bridge-to-decision). If, at this
point, longterm support is deemed necessary in order to bridge to transplant, or until possible cardiac recovery,
temporary MCS can
P.731
be transitioned to long-term VAD (bridge-to-bridge). The second determinant is deciding whether left ventricular
support (LVAD), right ventricular support (RVAD), or both, biventricular support (BiVAD), are needed. Table 32.1
lists the modes of support and the devices currently available for use in the pediatric population.
TABLE 32.1. Modes of support and devices currently available for use in children
Extracorporeal membrane oxygenation
Short-term ventricular assist devices
Central cannulation
CentriMag (centrifugal)
PediMag (centrifugal)
Rotaflow (centrifugal)
Peripheral cannulation
TandemHeart (centrifugal)
Impella (axial)
Long-term ventricular assist devices
Pulsatile
Berlin Heart EXCOR
Continuous flow
HeartMate II (axial)
HeartWare HVAD (centrifugal)
Since acutely decompensated heart failure often results in pulmonary dysfunction, affected patients may need
additional pulmonary support by way of ECMO. Although many pediatric heart centers around the world promote
the use of ECMO as the first-line MCS strategy, intact pulmonary function notwithstanding, TCH reserves ECMO
support for when pulmonary support is clearly needed. Due to the presence of an oxygenator, we believe that
application of ECMO is appropriate and should be limited to patients in whom pulmonary support is needed.
ECPR, as stated above, is a typical situation necessitating its use. Other potential applications include severe
pulmonary edema secondary to ventricular dysfunction, pulmonary hypertension, hemodynamic instability due to
septic shock, or all situations where pulmonary function is or may become threatened (19,20). For purely
circulatory support, the use of a VAD is favored. As ECMO is described in detail in Chapter 31, the rest of this
chapter will be dedicated to discussing VADs.
Short-Term Ventricular Assist Device

It warrants repeating, in our opinion, that short-term VAD support is the quintessential MCS option for acute
causes of heart failure where recovery of cardiac function is expected in a relatively short period of time (i.e., 2
weeks or less). A compelling reason for this preference over ECMO is direct decompression of the left heart,
providing both the myocardium and the lungs with the best chance for recovery. Comparatively, ECMO requires
placing a venous inflow cannula in the right side of the heart which has indirect, and hence limited, effects on the
decompression of a failing left ventricle. In patients with an intact atrial septum, a left atrial cannula may need to
be placed to adequately decompress the left ventricle and lower left atrial pressures.
Central Cannulation
The basic components of an extracorporeal short-term VAD system include a pump head and console, circuit
tubing, and inflow and outflow cannulas (Fig. 32.1). Several centers use a centrifugal pump, such as the
CentriMag (flow range up to 10 L/min) or PediMag (flow range 0.4-1.7 L/min) (Thoratec, Pleasanton, CA; Fig.
32.2A) or Rotaflow (Maquet, Germany; Fig. 32.2B). Although LV apical cannulation is an acceptable alternative
(21), our preferred approach is placing the inflow cannula in the left atrium, either from Waterston’s groove or the
left atrial appendage, in an effort to avoid further aggravating an already damaged left ventricle. We have found
that left atrial cannulation provides very stable inflow function. We have fortunately not experienced the serious
potential complication of left ventricular thrombus formation with left atrial cannulation. Although some would
consider sternotomy a significant disadvantage of short-term VAD support as compared to ECMO, this central
access provides unparalleled advantages of employing larger cannulas for direct drainage of the left heart that
will result in superior pulmonary protection. This is particularly useful in conditions with increased cardiac return
(e.g., systemic-to-pulmonary artery collaterals) that is often encountered in the pediatric population. The same
degree of decompression cannot be achieved with peripheral ECMO where a smaller-sized inflow cannula is
inserted into the right-sided cardiac chamber. The outflow cannula is typically inserted into the ascending aorta.
If there is a possibility that the short-term VAD may need to be converted to a long-term VAD (bridge-tobridge),
the outflow cannula for the short-term VAD should be inserted in the distal ascending aorta or even in the
proximal arch so that there is sufficient space in the proximal ascending aorta for a long-term VAD outflow
cannula.
Peripheral Cannulation
Peripheral cannulation is an alternative approach to central cannulation via sternotomy for short-term VAD
support. The use of peripheral cannulation requires an inflow venous cannula to be inserted via the femoral vein
and advanced into the left atrium across the interatrial septum (22). A distinct advantage of peripheral
cannulation is the ability to establish VAD support quickly by negating sternal access, which is particularly helpful
in cases of hemodynamically unstable children who have had a previous sternotomy.
P.732
FIGURE 32.1. Circuit configurations for extracorporeal membrane oxygenation (ECMO) and short-term
ventricular assist device (VAD). The major differences are the location of the inflow cannula and the presence (or
absence) of an oxygenator.
The TandemHeart (CardiacAssist Inc., Pittsburgh, PA; Fig. 32.3) is one currently available short-term VAD
system allowing peripheral cannulation. This system uses a centrifugal hydrodynamic pump and a 21Fr
transseptal venous cannula (62 or 72 cm in length). Due to the relatively large size of this venous cannula, its
application in the pediatric population is limited to older children and adolescents (approximately >40 kg in
weight). Another potential problem with transseptal venous cannulation is the risk of cannula dislodgment. The
patient will become severely hypoxic if the cannula dislodges into the right atrium. This risk is increased in
children where the left atrium is much smaller than in adults. Arterial cannulation is with a 17Fr cannula placed in
the femoral artery.
Another minimally invasive, catheter-based VAD that can also be placed percutaneously is the Impella (Abiomed,
Inc., Danvers, MA; Fig. 32.4). This device has an axial flow pump and is available in a variety of sizes. The
smallest pump of this family, the Impella 2.5 (specifications: flow rate up to 2.5 L/min, 9Fr catheter, 12Fr pump
motor) has been used successfully in the pediatric population (23). Although cannulation is usually femoral,
insertion via the right common carotid artery has been reported in an animal model (24). The company has a
pediatric initiative and is currently developing a pediatric-specific line of products (25).
Initiation of Short-Term VAD Support

Once LVAD support has been initiated, inotropic support should be reduced appropriately, but not discontinued
because the right ventricle requires pharmacologic support. Inhaled nitric oxide can be used in an attempt to
reduce pulmonary vascular resistance. Initiation of vasodilator drugs may be necessary to modulate systemic
vascular resistance and control hypertension. Once the ideal VAD flow is achieved, and systemic arterial
pressure optimized, adequate systemic perfusion is confirmed by clinical and laboratory parameters. Adjustment
of ventilator settings to maintain low pulmonary vascular resistance is essential to maximizing right-sided cardiac
output, which will ultimately determine the filling status of the LVAD pump. Temperature control can be
problematic, particularly in small children with an open chest. Unlike an ECMO circuit, the short-term VAD circuit
does not have a heat exchanger. In such circumstances, an overhead radiant infant heater or an external
convective warmer may be used. Serial assessment of cardiac function is used as a guide to weaning
P.733
mechanical support. In our experience with the use of shortterm VADs, the majority of patients with acute
etiologies (17 out of 20, 85%) were successfully weaned off VAD support (26). Although all patients with acute
myocarditis ( n = 11) in this cohort recovered, the incidence of cardiac recovery with ECMO for acute myocarditis
has been reported to be 60% to 85% (27,28,29). Although most children with acute myocarditis can be supported
reasonably well with ECMO, the difference in left heart decompression may make a difference in the most severe
end of the spectrum. The superior outcome with our approach to using short-term VAD support may be attributed
to the capability of saving this subset of the sickest children who would not have survived without perfect
decompression of the left heart.
FIGURE 32.2. Short-term ventricular assist devices. A: CentriMag pump (Image courtesy of Thoratec
Corporation, Pleasanton, CA). B: Rotaflow pump (Image courtesy of Maquet, Germany).
FIGURE 32.3. TandemHeart (Image courtesy of CardiacAssist Inc., Pittsburgh, PA).
The scope of using short-term VAD in chronic heart failure differs from acute failure in the knowledge that
appreciable recovery of myocardial function in the former is unlikely, ultimately requiring transition to more
durable, long-term VAD support. Temporary VAD support is used primarily as a “rescue option,” to mitigate
sustained decompensation with concomitant evidence of end-organ injury (INTERMACS 1 profile), granting the
patient time to recover to be a better candidate for a subsequent more invasive surgical procedure.
P.734
FIGURE 32.4. Impella 2.5 (Image courtesy of Abiomed Inc., Danvers, MA).
Right Heart Short-Term VAD Support

Although a short-term VAD is typically used to support the systemic circulation (i.e., as an LVAD), there are
certain situations where temporary RVAD support may be indicated. Heart transplantation in patients with high
pulmonary vascular resistance is an example. It is our experience that the failing RV of a transplanted heart
improves relatively quickly and that RVAD support can be discontinued within a few days. By weaning the RVAD
flow gradually, the clinicians can slowly manipulate the loading conditions of the RV. This allows accurate
assessment of how much support the RV is still requiring. Right ventricular failure immediately after long-term
LVAD placement is another indication for temporary RVAD support. If the etiology of RV failure is deemed
transitory, it would be a reasonable approach to use a short-term RVAD to determine the potential for RV
recovery.
Long-Term Ventricular Assist Device

Selection of Device
In the setting of chronic heart disease with relatively stable hemodynamic parameters, a long-term VAD should
be considered as a first-line device therapy. The selection of this device is primarily dependent on the patient’s
body surface area (BSA). At TCH, the Berlin Heart EXCOR (Fig. 32.5A) is the device of choice in children with a
BSA ≤0.7 m2 (26). Implantable, continuous-flow devices are preferred in larger children. While the HeartMate II
(Fig. 32.5B) is used in patients with a BSA ≥1.3 m2, the HeartWare HVAD (Fig. 32.5C) is an excellent option for
children in the intermediate range with a BSA of 0.7 to 1.3 m2 (30). It is our experience that most children with
severe heart failure can be satisfactorily supported with LVAD only. This is despite the fact that the right
ventricular function almost always appears to be severely depressed on echocardiography prior to VAD
implantation. Once the LV is decompressed with LVAD, the pulmonary artery pressure falls, subsequently
reducing afterload on the right ventricle. In other words, LVAD alone should be adequate if right ventricular
failure is “secondary” to left ventricular failure. Addition of RVAD support may be needed if the right ventricular
myocardium is inherently compromised (i.e., arrhythmogenic right ventricular dysplasia). Also, when pulmonary
vascular resistance is severely elevated, as seen in restrictive cardiomyopathy, BiVAD support may be
necessary (31). Since previous studies have consistently shown BiVAD support to be associated with worse
outcomes compared to that with LVAD alone, it stands to reason that BiVAD should be used sparingly and only in
carefully selected cases.
Management
In patients with isolated LVAD support, the focus of postoperative care is directed at enhancing right ventricular
cardiac output. It is the native right ventricle that determines overall systemic cardiac output. The basic principle
of preventing right heart failure on LVAD is to minimize pulmonary vascular resistance, yet maintain adequate
preload to the right heart. Although echocardiography is a useful tool to assess right ventricular function, its
findings alone are unreliable. The fundamental question is whether an LVAD is filling adequately or not: If the
filling of the LVAD is adequate, performance of the right ventricle is sufficient. In our experience, it is not
uncommon to see decent filling of the LVAD in the face of echocardiographic evidence of severe right ventricular
dysfunction. With an extracorporeal, pulsatile pump, such as the Berlin Heart EXCOR, direct visual assessment
of the pump’s filling status is the most straightforward indicator of right heart cardiac output, sine qua non
absence of aortic insufficiency or intracardiac shunting.
Technical Considerations
Accurate placement of the inflow cannula is crucial to ensuring successful long-term VAD support. In this regard,
placement of a VAD in a comparatively smaller ventricular chamber is technically more challenging. Even adult
hearts with a smaller ventricular chamber, such as occurs with restrictive cardiomyopathy, possess limited
tolerance for minor technical
P.735
imperfections (32). This is particularly true if adult-sized implantable devices are used in children, creating an
inherent “device-patient” mismatch with respect to inflow cannula and ventricular intracavitary volume. In the
interest of avoiding inflow-related issues such as pump suctioning against the ventricular septum or thrombus,
the inflow cannula should be placed paying particular attention to its angle relative to the ventricular septum.
Based on extensive experience with the HeartMate II, a positive correlation was found between the axis of the
inflow cannula relative to the interventricular septum, and the incidence of pump thrombus formation (33). Ideally,
the axis of the inflow cannula should lie parallel to the septum rather than perpendicularly. Because of differing
device technology and configuration, a specific technique which has previously proved successful with one
device, may not necessarily be applicable to others. Be that as it may, we believe this basic principle of inflow
cannula angle holds true regardless of device type. Owing to its miniaturized design,
P.736
the HeartWare HVAD (HeartWare Inc.) is now increasingly being used in the pediatric population (34). The angle
of the inflow cannula with HVAD has not received as much attention as the HeartMate II. Interestingly, the HVAD
inflow cannula was often found to spontaneously situate itself perpendicularly to the interventricular septum
when implanted intrapericardially (Fig. 32.6A), as recommended by the manufacturer. Some adult surgeons have
recognized this occurrence and have advocated modifying the implantation technique by inserting the inflow
cannula through the diaphragmatic surface of the left ventricle instead of the apex, the latter being typically done
with almost all devices (35). At TCH, we use the left ventricular apex as an insertion point but immediately gently
and purposefully relocate the LV apex medially
P.737
and caudally by placing the HVAD pump housing in a small pocket created on the left hemidiaphragm (36). With
this maneuver, the tip of the inflow cannula points toward the mitral valve, satisfying the requirement that it
virtually lie parallel to the interventricular septum (Fig. 32.6B). The important commonality between these
modified techniques is securing near-vertical orientation of the inflow cannula. Although there is not yet scientific
data to support such spatial configuration, anecdotal evidence and experiential wisdom may warrant this extra
effort, especially when using HVAD in pediatric hearts. Ostensibly, the manufacturer has recently become aware
of this design flaw and is in the process of updating the subsequent device (HeartWare MVAD) to allow
adjustment of the inflow cannula angle (37).
FIGURE 32.5. Long-term ventricular assist devices. A: Berlin Heart EXCOR (Image courtesy of Berlin Heart, The
Woodland, TX). B: HeartMate II (Image courtesy of Thoratec Corporation, Pleasanton, CA). C: HeartWare HVAD
(Image courtesy of HeartWare Inc., Framingham, MA).
FIGURE 32.6. Techniques for placement of implantable devices. A: Postimplant chest X-rays with the standard
intrapericardial technique (left) and with the infradiaphragmatic technique (right). The dotted line represents an
imaginary line of the interventricular septum. There is a notable difference between the two techniques in terms
of the relationship of the inflow axis relative to the septum. With the infradiaphragmatic technique, the inflow axis
lies more parallel to the septum. In addition, left lower lobe atelectasis can be avoided with the
infradiaphragmatic technique since the device does not occupy the space in the pleural cavity. B: Ideal
configuration of the HeartWare HVAD placement.
ANTICOAGULATION STRATEGIES
Anticoagulation strategies differ between devices and institutions. What we describe here is just an overview of
our own strategy at TCH. Temporary devices (i.e., short-term VAD and ECMO) are managed with a continuous
infusion of heparin. We mainly rely on the activated clotting time (ACT: 160-180 seconds for short-term VAD and
180-200 seconds for ECMO), though we also routinely monitor heparin assay as well as activated partial
thromboplastin time (APTT). As these numbers fluctuate considerably and are not always consistent with each
other, it is of utmost importance not to focus on just a single marker. Rather, the clinician should look at the entire
picture. Direct assessment of the patient and the MCS circuit is even more critical than laboratory tests. If the
circuit is clean and the patient is not bleeding, anticoagulation should be considered appropriate regardless of
laboratory values. We maintain the antithrombin III level at 80% or higher. We also try to maintain a fibrinogen
level within the normal range. The very basic principle of anticoagulation for VAD is maintenance of underlying
coagulation profiles as normal as possible. Thromboelastography with and without heparinase is a useful tool to
evaluate the underlying coagulation status.
Long-term devices require more chronic forms of anticoagulation such as warfarin or low-molecular-weight
heparin in addition to an antiplatelet agent; a heparin-bridge is often necessary. The Berlin Heart EXCOR is
more challenging than other implantable devices in terms of anticoagulation because of its higher tendency for
fibrin/thrombus formation. Although the standard anticoagulation protocol for the Berlin EXCOR (so-called
Edmonton protocol) involves the use of low-molecular-weight heparin in infants (<12 months old), it is our
preference to administer warfarin for all age groups. With this device, the clinicians are often placed in a dilemma
of two mutually related complications, namely bleeding and thrombosis. Since the safety margin between the two
complications is slim, the clinical team often has to err on the side of one complication over the other, depending
on the clinical scenario. Balancing the risks of complications is even more difficult when the patient has
significant systemic inflammation, typically manifested by high levels of fibrinogen and/or C-reactive protein.
Since systemic inflammatory status is often associated with hypercoagulability, there is an increased risk of
thrombotic complications. At the same time, bleeding risk is also increased since a hypercoagulable state often
requires extremely high doses of anticoagulants (e.g., heparin infusion >50 units/kg/hr) in order to achieve a
therapeutic level of anticoagulation. In such circumstances, administration of a steroid may be a useful adjuvant
to suppress inflammation (38). When therapeutic levels cannot be achieved without an excessive degree of
anticoagulation, the clinician may have to accept a sub-therapeutic level to avoid bleeding complications while
being aware of the possible development of pump fibrin/thrombus, which may require pump exchange. Such a
“permissive under-anticoagulation” strategy is particularly important in the early postoperative period where
bleeding risks outweigh the risk of thrombotic complications (39).
TIMING OF REACTIVATION ON THE HEART TRANSPLANT LIST

The average waiting time for heart transplant is shorter in children with VAD support than their adult counterparts
(6). This can potentially be explained by differences in United Network for Organ Sharing (UNOS) listing criteria,
as it applies to each cohort. Adult patients are given 1A status (the highest priority on the basis of medical
urgency) for 30 days after VAD implantation. Following the 30-day “grace” period, their status is downgraded to
1B, unless VAD-related complications occur. Pediatric patients with ongoing VAD support, on the other hand,
maintain 1A status until transplantation. In the Berlin Heart IDE trial, the average duration of VAD support was
approximately 1 month (28 days in smaller children (BSA ≤0.7 m2) and 43 days in larger children) (13). A
patient’s poor clinical status prior to institution of VAD support may preclude listing for transplant as “active.”
Given the high incidence of device-related complications with extracorporeal pulsatile VAD, namely stroke (29%
and 29% for BSA <0.7 m2 and 0.7 to <1.5 m2, respectively), major bleeding (42% and 50%, respectively), or
infection (63% and 50%, respectively), it is essential to revert patient status on the UNOS transplant waitlist to
“active” as soon as clinically feasible subsequent to VAD placement for transplantation to occur before
complications occur. In comparison, the quest to determine an ideal timeframe for status re-activation
postimplantable, continuous-flow VAD may need different consideration. A distinct advantage of implantable
devices is greater mobility and ability for outpatient management, providing an opportunity for physical
rehabilitation prior to undergoing a physiologically demanding transplant procedure. Given the lower risks of
device-related complications with an
P.738
implantable VAD, it may be reasonable to maintain patient’s status on the transplant list as “inactive” for a certain
period of time after VAD placement. In addition to rehabilitation, this buys clinicians some time to assess the
possibility of native cardiac function recovery. It is TCH’s routine practice to closely observe the patient for 3
months postoperatively before considering reactivating their wait-list status.
Although an extracorporeal, pulsatile-flow VAD such as the Berlin Heart EXCOR is associated with a higher risk
of device-related complications, pulsatile VADs have been found to have a higher potential for cardiac recovery
(40). This viewpoint is based on observations of more frequent cardiac recovery in the “old era,” when pulsatile
VADs were predominantly used in adult patients. Although there is a paucity of data regarding pediatric
myocardial recovery, seeking treatment strategies to achieve cardiac recovery in children is thought to have
significant clinical potential. Pediatric myocardium promises theoretical advantages for recovery over adult
myocardium due to its greater abundance of cardiac progenitor cells (41).
Reviewing the available literature on pediatric VAD support, a percentage of patients (ranging from 5% to 73%)
in each series recovered enough cardiac function to allow weaning off VAD support (42,43,44,45,46,47,48,49). In
a report published by the German Heart Institute, Hetzer et al. observed this phenomenon in 15% of their
pediatric VAD patients (9 out of 62). Zimmerman et al. and Ihnat et al. report a substantially higher incidence of
recovery, 73% (8 out of 11 patients) and 62% (8 out of 13 patients), respectively, than other studies. It must be
taken into context that the support durations in these two studies were very short (mean <2 weeks). Cautious
interpretation is necessary, therefore, to determine whether or not these series represent true myocardial
recovery as a consequence of reverse remodeling of failing myocardium (50). In this regard, a recent article from
Freeman Hospital in the United Kingdom, one of the busiest centers with pediatric VAD services, offers some
framework. Irving et al. reviewed their experience with Berlin Heart EXCOR, specifically focusing on patients
whose cardiac function had recovered (51). Ten of 53 patients with EXCOR (19%) showed signs of sufficient
recovery to undergo VAD explantation, with a median support time of 36 days (range 7-120 days). Despite the
fact that three of these recovered patients (30%) had relapse of heart failure, requiring subsequent VAD support
and eventual heart transplantation, their data highlight the fact that myocardial recovery with pediatric VAD is
certainly achievable. Further research into reverse remodeling, specifically in pediatric myocardium, is needed to
improve clinical strategies for bridge-to-recovery in children.
THE FUTURE
Destination Therapy
In adult centers, long-term VAD support is increasingly being used as DT. Ventricular assist device implantation
with destination indication now accounts for approximately 40% of total implants (1). DT is currently not a widely
accepted strategy in the pediatric population, but may gradually gain more significance in the management of
pediatric heart failure. An example of diseases that could potentially benefit from DT is Duchenne muscular
dystrophy (DMD), an X-linked recessive disorder characterized by progressive skeletal muscle weakness (52).
These patients often develop severe congestive heart failure secondary to dilated cardiomyopathy. Long-term
VAD support as DT in adolescents and young adults with this disorder has recently been reported (53). Although
it is not clear if this intervention will considerably redirect the natural history of patients with this devastating
disorder, it is hoped that it may alter their clinical trajectories by alleviating crippling symptoms of heart failure
(54). It remains to be seen if this type of therapy gains wider acceptance by the pediatric medical community.
Long-Term Outcomes
Previously, success of pediatric VAD support was indicated primarily by clinical parameters such as survival, time
to explantation or transplantation, or complications occurring during support. As surgical methodologies are
perfected, clinicians need to shift focus from the aforementioned shorter-term outcomes to include the possibility
of lasting effects on patient outcomes beyond the transplant.
A persistent dilemma regarding pediatric VAD support is human leukocyte antigen (HLA) sensitization. Data from
adult series have suggested that VAD support is associated with higher risk of HLA sensitization (55,56).
Although children may have different immunologic responses to human tissue exposure (e.g., blood transfusion,
homograft patch for cardiac reconstruction) compared to that of adults, it is reasonable to infer a high likelihood
of similar HLA sensitization in children. Currently available pediatric single-center studies have reported the
incidence of sensitization of children with VAD, or ECMO, support to be 18% to 35% (57,58,59). A recent study
using the Organ Procurement and Transplantation Network database supports these findings in that the use of
VADs for bridge-to-transplant in children with dilated cardiomyopathy was associated with a 3-fold increase in
HLA sensitization, a 2-fold increase in the risk of a positive crossmatch at transplant, and a higher incidence of
rejection after transplant (60). Another study using data from the multi-institutional Pediatric Heart Transplant
Study Group showed higher waitlist mortality as well as lower posttransplant survival with allosensitization (61).
Better understanding of the basic mechanisms of HLA sensitization in children undergoing VAD support is
warranted so as to develop strategies to prevent, or at least minimize, HLA sensitization in this patient
population.
An equally important facet of care is quality-of-life outcomes in patients. Using a validated generic measure, the
P.739
Pediatric Quality of Life Inventory, designed to assess quality of life in pediatric heart transplant recipients, two
studies found that quality of life of pediatric heart transplant recipients with MCS bridge is not inferior to that of
children who did not receive MCS (62,63). Neurologic complication during MCS support is associated with worse
quality of life (5). Needless to say, finding avenues to minimize complications while on prolonged VAD support
fulfills the very definition of successful therapy.
FIGURE 32.7. Devices in development. A: Infant Jarvik 2000 (Image courtesy of Jarvik Heart Inc., New York,
NY). B: HeartMate III (Image courtesy of Thoratec Corporation, Pleasanton, CA). C: HeartWare MVAD (Image
courtesy of HeartWare Inc., Framingham, MA).
Devices in Development
The pressing need for pediatric-specific VADs, particularly for small children, has long been recognized. In 2004,
the US government, through the National Heart, Lung, and Blood Institute (NHLBI), awarded 5-year contracts
totaling $23 million to five groups developing pediatric-specific MCS devices (64). In 2010, the NHLBI launched
the Pumps for Kids, Infants, and Neonates program (so-called PumpKIN program) to continue work on some of
the most promising devices with the goal of translation to clinical use (65). The only device currently under
development within this program is the Infant Jarvik 2000 (Jarvik Heart Inc., New York, NY; Fig. 32.7A) that is
designed for children weighing 8 to 15 kg. This device is currently being tested in animal models and its clinical
trial is on the horizon (3).
There are several adult devices that would have significant potential for pediatric application. These include the
Thoratec HeartMate III (Fig. 32.7B) and the HeartWare miniaturized VAD (MVAD Pump; Fig. 32.7C). The
HeartMate III has a magnetically-levitated rotor in a housing. This feature is expected to result in less mechanical
stress to the rotor as well as to blood. The HeartMate III is also equipped with another unique technology in that
the device can generate an “artificial pulse.” This could impact a reduction in clinical adverse events such as
gastrointestinal bleeding. The HeartMate III has already been tested in the CE Mark clinical trial and its US trial
has just begun. The HeartWare MVAD pump may also have the potential to drastically change the outlook of the
pediatric VAD field. Owing to its significantly smaller design, the MVAD pump may become the first implantable
VAD that gains widespread acceptance for small children. Clinical trials of the MVAD are expected to begin in
2015 in Europe and the United States.
SUMMARY
The number of children with severe heart failure is increasing, in the midst of a limited organ supply
destined for pediatric heart transplantation. Pediatric MCS will continue to gain clinical importance over time
in a true effort to bridge this gap. Appropriate selection and application of MCS devices in the pediatric
population is indispensable to maximizing chances of survival for children with end-stage heart failure.
P.740
KEY Points
VAD support is indicated when the severity of heart failure extends beyond the capability of maximal
medical management.
VADs can be used as a bridge to recovery, bridge to transplant, bridge to another device, or as DT.
The ideal time for VAD implantation is debatable and dependent on multiple variables so that
individual assessment of a patient’s risk profile is critically important. The trend to earlier VAD
implantation before significant clinical deterioration has resulted in considerably improved outcomes.
Apart from size considerations, anatomic and physiologic variations have to be considered before
implantation in children with congenital heart disease.
ECMO is the initial support of choice for patients unable to be weaned off CPB or failure of return of
spontaneous circulation after cardiac arrest (ECPR).
Beyond ECMO, factors influencing the choice of VAD are the anticipated duration of support and
whether the support should be univentricular or biventricular. Institutions vary in their first-line
strategy for mechanical circulatory support, with ECMO used when pulmonary support is also
necessary.
Short-term VAD support is indicated for acute causes of heart failure where recovery of cardiac
function is expected in a relatively short period of time (i.e., about 2 weeks or less).
Cannulation may be central or peripheral.
Central cannulation requires a sternotomy. Basic components of the circuit include a pump head
and console, circuit tubing, and inflow (venous) and outflow (arterial) cannulas. The inflow
cannula may be placed in the left atrium or apex of the left ventricle and the outflow cannula is
placed in the ascending aorta.
Peripheral cannulation requires an inflow venous cannula to be inserted via the femoral vein and
advanced into the left atrium across the interatrial septum. An advantage of peripheral
cannulation is the ability to establish VAD support quickly by negating sternal access, which is
particularly helpful in cases of hemodynamically unstable children who have had a previous
sternotomy.
Clinical management includes supporting the right ventricle (inotropes) and lowering the
pulmonary vascular resistance (ventilator settings, nitric oxide), as right-sided cardiac output
ultimately determines the filling status of the LVAD pump. Vasodilators to modulate systemic
vascular resistance and control hypertension may be necessary.
Short-term VAD support in chronic heart failure is used with the knowledge that appreciable
recovery of myocardial function is unlikely. It is used primarily as a “rescue option” to mitigate
sustained decompensation with concomitant evidence of end-organ injury, granting the patient
time to recover to be a better candidate for transition to long-term VAD support or transplantation.
Long-term VAD support can be used as LVAD in the majority of children with severe heart failure,
particularly if right ventricular failure is “secondary” to left ventricular failure. RVAD becomes
necessary if the right ventricular myocardium is inherently compromised.
Device selection is primarily dependent on the patient’s BSA. At Texas Children’s Hospital, the
Berlin Heart EXCOR is the device of choice in children with a BSA ≤0.7 m2. Implantable,
continuous-flow devices are preferred in larger children, with the HeartMate II used in patients
with a BSA ≥1.3 m2, and the HeartWare HVAD for children in the intermediate range with a BSA
of 0.7 to 1.3 m2.
Accurate placement of the inflow cannula is crucial to avoid pump suctioning against the
ventricular septum or thrombus formation. Ideally, the axis of the inflow cannula should lie parallel
to the septum.
With LVAD, the focus of postimplantation management is support of the right ventricle as
described above.
The commonest complications, particularly for ECMO, short-term VAD and pulsatile devices, are
major bleeding, thrombosis, and infection. Devastating stroke can result.
Anticoagulation strategies differ between devices and institutions, with balancing of the risks of
bleeding and thrombosis. Generally, a heparin bolus followed by an infusion is used for ECMO and
short-term VAD support. Long-term devices require chronic anticoagulation with warfarin or low-
molecular-weight heparin in addition to an antiplatelet agent; a heparin-bridge is often necessary.
Poor clinical status prior to institution of VAD support may preclude listing for transplant as “active,”
and because of a high incidence of device-related complications (as described above), it is essential
to revert patient status on the UNOS transplant waitlist to “active” as soon as clinically feasible.
Long-term implantable devices have lower risks of complications, allowing time for rehabilitation and
the possibility of cardiac recovery before listing as “active.”
Although long-term VAD support is increasingly being used as DT in adults, DT is currently not a
widely accepted strategy in the pediatric population.
P.741
Success of VAD support is indicated by survival, complications, and time to recovery or
transplantation. Long-term outcomes now being studied include human leukocyte antigen
sensitization and quality of life.
A device under development specifically for children is the Jarvik 2000 for children weighing 8 to 15
kg. Adult devices with potential for pediatric application include the Thoratec HeartMate III and the
HeartWare MVAD pump.
REFERENCES
1. Kirklin JK, Naftel DC, Pagani FD, et al. Sixth INTERMACS annual report: a 10,000-patient database. J
Heart Lung Transplant 2014;33(6):555-564.
2. Adachi I, Fraser CD Jr. Mechanical circulatory support for infants and small children. Semin Thorac
Cardiovasc Surg Pediatr Card Surg Annu 2011;14(1): 38-44.
3. Wei X, Li T, Li S, et al. Pre-clinical evaluation of the infant Jarvik 2000 heart in a neonate piglet model. J
Heart Lung Transplant 2013;32(1):112-119.
4. Birks EJ. The comparative use of ventricular assist devices: differences between Europe and the United
States. Tex Heart Inst J 2010;37(5):565-567.
5. Kirklin JK, Naftel DC, Kormos RL, et al. Fifth INTERMACS annual report: risk factor analysis from more
than 6,000 mechanical circulatory support patients. J Heart Lung Transplant 2013;32(2):141-156.
6. Colvin-Adams M, Smithy JM, Heubner BM, et al. OPTN/SRTR 2012 annual data report: heart. Am J
Transplant 2014;14(Suppl 1):113-138.
7. Kirk R, Edwards LB, Aurora P, et al. Registry of the International Society for Heart and Lung
Transplantation: eleventh official pediatric heart transplantation report—2008. J Heart Lung Transplant
2008;27(9):970-977.
8. Rossano JW, Kim JJ, Decker JA, et al. Prevalence, morbidity, and mortality of heart failure-related
hospitalizations in children in the United States: a population-based study. J Card Fail 2012;18(6):459-470.
9. Almond CS, Singh TP, Gauvreau K, et al. Extracorporeal membrane oxygenation for bridge to heart
transplantation among children in the United States: analysis of data from the Organ Procurement and
Transplant Network and Extracorporeal Life Support Organization Registry. Circulation 2011;123(25):2975-
2984.
10. Davies RR, Russo MJ, Hong KN, et al. The use of mechanical circulatory support as a bridge to
transplantation in pediatric patients: an analysis of the United Network for Organ Sharing database. J Thorac
Cardiovasc Surg 2008;135(2):421-427.
11. Barbone A, Pini D, Rega F, et al. Circulatory support in elderly chronic heart failure patients using the
CircuLite® Synergy® system. Eur J Cardiothorac Surg 2013;44(2):207-212; discussion 212.
12. Meyns B, Klotz S, Simon A, et al. Proof of concept: hemodynamic response to long-term partial
ventricular support with the synergy pocket micro-pump. J Am Coll Cardiol 2009;54(1):79-86.
13. Fraser CD Jr, Jaquiss RD, Rosenthal DN, et al. Prospective trial of a pediatric ventricular assist device. N
Engl J Med 2012;367(6):532-541.
14. Adachi I, Fraser CD Jr. Berlin Heart EXCOR Food and Drug Administration Investigational Device
Exemption Trial. Semin Thorac Cardiovasc Surg 2013;25(2):100-106.
15. Stevenson LW, Pagani FD, Young JB, et al. INTERMACS profiles of advanced heart failure: the current
picture. J Heart Lung Transplant 2009;28(6):535-541.
16. Morales DL, Adachi I, Heinle JS, et al. A new era: use of an intracorporeal systemic ventricular assist
device to support a patient with a failing Fontan circulation. J Thorac Cardiovasc Surg 2011;142(3):e138-
e140.
17. Rossano JW, Goldberg DJ, Fuller S, et al. Successful use of the total artificial heart in the failing Fontan
circulation. Ann Thorac Surg 2014;97(4): 1438-1440.
18. Fagnoul D, Combes A, De Backer D. Extracorporeal cardiopulmonary resuscitation. Curr Opin Crit Care
2014;20(3):259-265.
19. Horton S, d’Udekem Y, Shann F, et al. Extracorporeal membrane oxygenation via sternotomy for
circulatory shock. J Thorac Cardiovasc Surg 2010;139(2):e12-e13.
20. MacLaren G, Butt W, Best D, et al. Central extracorporeal membrane oxygenation for refractory pediatric
septic shock. Pediatr Crit Care Med 2011;12(2):133-136.
21. Takayama H, Chen JM, Jorde UP, et al. Implantation technique of the CentriMag biventricular assist
device allowing ambulatory rehabilitation. Interact Cardiovasc Thorac Surg 2011;12(2):110-111.
22. Pavie A, Leger P, Nzomvuama A, et al. Left centrifugal pump cardiac assist with transseptal
percutaneous left atrial cannula. Artif Organs 1998;22(6):502-507.
23. Dimas VV, Murthy R, Guleserian KJ. Utilization of the Impella 2.5 micro-axial pump in children for acute
circulatory support. Catheter Cardiovasc Interv 2014;83(2):261-262.
24. Webb MK, Wang J, Guleserian KJ, et al. TCT-452 feasibility of carotid artery placement of the novel
impella pediatric prototype. J Am Coll Cardiol 2014;64(11_S). doi:10.1016/j.jacc.2014.07.503
25. Webb MK, Lutts ER, Price DT, et al. A porcine survival model for the novel impella pediatric prototype.
Washington, DC: American Society for Artificial Internal Organs, June 18-21, 2014:91.
26. Adachi I, Heinle JS, McKenzie ED, et al. The use of short-term ventricular assist devices in children. J
Heart Lung Transplant 2012;31:S119.
27. Duncan BW, Bohn DJ, Atz AM, et al. Mechanical circulatory support for the treatment of children with
acute fulminant myocarditis. J Thorac Cardiovasc Surg 2001;122(3):440-448.
28. Haines NM, Rycus PT, Zwischenberger JB, et al. Extracorporeal Life Support Registry Report 2008:
neonatal and pediatric cardiac cases. ASAIO J 2009;55(1):111-116.
29. Teele SA, Allan CK, Laussen PC, et al. Management and outcomes in pediatric patients presenting with
acute fulminant myocarditis. J Pediatr 2011;158(4):638-643.
30. Stiller B, Adachi I, Fraser CD Jr. Pediatric ventricular assist devices. Pediatr Crit Care Med 2013;14(5,
Suppl 1):S20-S26.
31. Kimberling MT, Balzer DT, Hirsch R, et al. Cardiac transplantation for pediatric restrictive
cardiomyopathy: presentation, evaluation, and short-term outcome. J Heart Lung Transplant 2002;21(4):455-
459.
32. Kirklin JK, Naftel DC, Kormos RL, et al. Interagency Registry for Mechanically Assisted Circulatory
Support (INTERMACS) analysis of pump thrombosis in the HeartMate II left ventricular assist device. J Heart
Lung Transplant 2014;33(1):12-22.
33. Taghavi S, Ward C, Jayarajan SN, et al. Surgical technique influences HeartMate II left ventricular assist
device thrombosis. Ann Thorac Surg 2013;96(4):1259-1265.
34. Miera O, Potapov EV, Redlin M, et al. First experiences with the HeartWare ventricular assist system in
children. Ann Thorac Surg 2011;91(4):1256-1260.
35. Gregoric ID, Cohn WE, Frazier OH. Diaphragmatic implantation of the Heart-Ware ventricular assist
device. J Heart Lung Transplant 2011;30(4):467-470.
36. Adachi I, Guzman-Pruneda FA, Jeewa A, et al. A modified implantation technique of the HeartWare
ventricular assist device for pediatric patients. J Heart Lung Transplant 2015;34(1):134-136.
37. McGee E Jr, Chorpenning K, Brown MC, et al. In vivo evaluation of the HeartWare MVAD Pump. J Heart
38. Byrnes JW, Prodhan P, Williams BA, et al. Incremental reduction in the incidence of stroke in children
supported with the Berlin EXCOR ventricular assist device. Ann Thorac Surg 2013;96(5):1727-1733.
39. Byrnes JW, Frazier E, Tang X, et al. Hemorrhage requiring surgical intervention among children on
pulsatile ventricular assist device support. Pediatr Transplant 2014;18(4):385-392.
40. Kato TS, Chokshi A, Singh P, et al. Effects of continuous-flow versus pulsatile-flow left ventricular assist
devices on myocardial unloading and remodeling. Circ Heart Fail 2011;4(5):546-553.
41. Mishra R, Vijayan K, Colletti EJ, et al. Characterization and functionality of cardiac progenitor cells in
congenital heart patients. Circulation 2011;123(4):364-373.
42. Blume ED, Naftel DC, Bastardi HJ, et al. Outcomes of children bridged to heart transplantation with
ventricular assist devices: a multi-institutional study. Circulation 2006;113(19):2313-2319.
43. Fan Y, Weng YG, Xiao YB, et al. Outcomes of ventricular assist device support in young patients with
small body surface area. Eur J Cardiothorac Surg 2011;39(5):699-704.
44. Hetzer R, Potapov EV, Stiller B, et al. Improvement in survival after mechanical circulatory support with
pneumatic pulsatile ventricular assist devices in pediatric patients. Ann Thorac Surg 2006;82(3):917-924;
discussion 924-925.
P.742
45. Ihnat CL, Zimmerman H, Copeland JG, et al. Left ventricular assist device support as a bridge to recovery
in young children. Congenit Heart Dis 2011;6(3):234-240.
46. Imamura M, Dossey AM, Prodhan P, et al. Bridge to cardiac transplant in children: Berlin Heart versus
extracorporeal membrane oxygenation. Ann Thorac Surg 2009;87(6):1894-1901; discussion 1901.
47. Morales DL, Almond CS, Jaquiss RD, et al. Bridging children of all sizes to cardiac transplantation: the
initial multicenter North American experience with the Berlin Heart EXCOR ventricular assist device. J Heart
48. Reinhartz O, Keith FM, El-Banayosy A, et al. Multicenter experience with the thoratec ventricular assist
device in children and adolescents. J Heart Lung Transplant 2001;20(4):439-448.
49. Zimmerman H, Covington D, Smith R, et al. Recovery of dilated cardiomyopathies in infants and children
using left ventricular assist devices. ASAIO J 2010;56(4):364-368.
50. Weia B, Adachi I, Jacot JG. Clinical and molecular comparison of pediatric and adult reverse remodeling
with ventricular assist devices Artif Organs 2015;39(8):691-700.
51. Irving CA, Crossland DS, Haynes S, et al. Evolving experience with explanation from Berlin Heart EXCOR
ventricular assist device support in children. J Heart Lung Transplant 2014;33(2):211-213.
52. Manzur AY, Kinali M, Muntoni F. Update on the management of Duchenne muscular dystrophy. Arch Dis
Child 2008;93(11):986-990.
53. Ryan TD, Jefferies JL, Sawnani H, et al. Implantation of the HeartMate II and HeartWare left ventricular
assist devices in patients with Duchenne muscular dystrophy: lessons learned from the first applications.
ASAIO J 2014;60(2):246-248.
54. Amodeo A, Adorisio R. Left ventricular assist device in Duchenne cardiomyopathy: can we change the
natural history of cardiac disease? Int J Cardiol 2012;161(3):e43.
55. John R, Lietz K, Schuster M, et al. Immunologic sensitization in recipients of left ventricular assist
devices. J Thorac Cardiovasc Surg 2003;125(3):578-591.
56. Massad MG, Cook DJ, Schmitt SK, et al. Factors influencing HLA sensitization in implantable LVAD
recipients. Ann Thorac Surg 1997;64(4):1120-1125.
57. Hong BJ, Delaney M, Guynes A, et al. Human leukocyte antigen sensitization in pediatric patients
exposed to mechanical circulatory support. ASAIO J 2014;60(3):317-321.
58. O’Connor MJ, Menteer J, Chrisant MR, et al. Ventricular assist device-associated anti-human leukocyte
antigen antibody sensitization in pediatric patients bridged to heart transplantation. J Heart Lung Transplant
2010; 29(1):109-116.
59. Yang J, Schall C, Smith D, et al. HLA sensitization in pediatric pre-transplant cardiac patients supported
by mechanical assist devices: the utility of Luminex. J Heart Lung Transplant 2009;28(2):123-129.
60. Almond CS, Daly KP, Singh TP, et al. Effect of VAD use on HLA sensitization and risk of rejection post-
heart transplant in US children with dilated cardiomyopathy. J Heart Lung Transplant 2013;32(4):S108.
61. Mahle WT, Tresler MA, Edens RE, et al. Allosensitization and outcomes in pediatric heart transplantation.
J Heart Lung Transplant 2011;30(11):1221-1227.
62. Ezon DS, Khan MS, Adachi I, et al. Pediatric ventricular assist device use as a bridge to transplantation
does not affect long-term quality of life. J Thorac Cardiovasc Surg 2014;147(4):1334-1343.
63. Wray J, Lunnon-Wood T, Smith L, et al. Perceived quality of life of children after successful bridging to
heart transplantation. J Heart Lung Transplant 2012;31(4):381-386.
64. Baldwin JT, Borovetz HS, Duncan BW, et al. The National Heart, Lung, and Blood Institute Pediatric
Circulatory Support Program. Circulation 2006;113(1):147-155.
65. Baldwin JT, Borovetz HS, Duncan BW, et al. The National Heart, Lung, and Blood Institute Pediatric
Circulatory Support Program: a summary of the 5-year experience. Circulation 2011;123(11):1233-1240.

Cardiopulmonay Bypass 1

Uploaded by

Copyright:

Available Formats

Cardiopulmonay Bypass 1

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

Cardiopulmonay Bypass 1

Uploaded by

Copyright:

Available Formats

Editors

Richard F. Davis MD, MBA

Barry D. Kussman MBBCh, FFA(SA)

Frank A. Baciewicz Jr., MD

John F. Butterworth IV, MD

W. Randolph Chitwood Jr., MD, FACS, FRCS (England)

Joseph C. Cleveland Jr., MD

Vincent R. Conti, MD, FACS

John R. Cooper Jr., MD

Terry N. Crane, BS, CCP, LP

Richard F. Davis, MD, MBA

Alan Finley, MD, FASE

Charles D. Fraser Jr., MD

Deepak Hanumanthaiah, MD, FCARCSI, FRCPC

Eugene A. Hessel II, MD, FACS

Michael H. Hines, MD, FACS

Eric Jenkins, CCT, CCP, FPP

Mark Kurusz, CCP (Emeritus)

Barry D. Kussman, MBBCh, FFA(SA)

Alan P. Kypson, MD, FACS

Gregory S. Matte, CCP, LP, FPP

C. David Mazer, MD, FRCPC

Niamh A. McAuliffe, MBBCh, FCARCSI, FRCPC

Josef Nile Mueksch, MD, MBA

Mark T. Nelson, MD, Med

Priv. Doz. Dr. med. Andreas Pape

Steven A. Raskin, CCP

Murphy Rayle, BA, CCP, LP

David M. Rothenberg, MD, FCCM

Roger L. Royster, MD, FACC

Derek A. Sanderson Jr., BS, CCP, LP

Valerie Sera, MD, DDS

Kenneth G. Shann, CCP

Robert N. Sladen, MBChB, FCCM

Robin G. Sutton, MS, CCP

Ravi R. Thiagarajan, MBBS, MPH

Kai Zacharowski, MD, PhD, FRCA

Mustafa Zakkar, PhD, MRCS

THE DEVELOPMENT OF CARDIOPULMONARY BYPASS FOR HEART

JOHN GIBBON’S EARLY RESEARCH

GIBBON’S RESEARCH CONTINUES

Kirklin (47) goes on to say:

Kirklin (47) goes on to state:

Kirklin (47) continued:

Blood Heat Exchanger

A BUMPY ROAD DURING THE EARLY'50s

1952 February (1952 or 1953, John Gibbon; see February 1953)

EXTRACORPOREAL LIFE SUPPORT

16. McLean J. The discovery of heparin. Circulation 1959;19:75-78.

54. Centrifugal pump. Wikipedia May 5, 2015:1-11.

58. Lim MW. The history of extracorporeal oxygenators. Anaesthesia 2006;61:984-995.

GENERAL SURVEY OF THE CIRCUIT

CANNULATION TO THE PATIENT

Types and Sizes of Cannulas

TABLE 2.1. Right atrial two-stage cannula, estimated flow rates

BSA (m2) Size (F) Max flow (L/min) Model Manufacturer

≤1.8 29/37 4.5 Thin-Flex Edwards Life Science

>1.8 to <2.5 32/40 6.0 MC2 Medtronic

≥2.5 36/46 8.0 MC2 Medtronic

Connection to the Patient (Sites for Venous Cannulation)