PG-11

NEW SCIENCE IN THE COMPREHENSIVE
MANAGEMENT OF THE CHRONIC OBSTRUCTIVE

PULMONARY DISEASE PATIENT
Postgraduate Course 11
Friday, May 18, 2012

8:00 am – 4:00 pm
Room 2005, West Building (Level 2)

Moscone Center
San Francisco, California
This session and the International Conference are supported by an educational grant from
Pfizer, Inc.
The grant has no influence on the content, quality and scientific integrity of this CME activity, which is
developed by the American Thoracic Society. All CME sessions are free of the control of commercial
interests.
New Science In The Comprehensive Management Of The Chronic May 18, 2012
Obstructive Pulmonary Disease Patient
COURSE DESCRIPTION
COPD often has clinically-important systemic manifestations that contribute to its morbidity. Its optimal treatment, which
usually requires combining pharmacologic with non-pharmacologic therapies, has changed substantially over the past
few years. This course will present this new science interactively using an audience response system. Areas will
include the potential usefulness of phenotyping, concept of disease modification, the importance of addressing co-
morbidity, recognizing and treating physical inactivity, identifying cognitive issues, preventing and treating the
exacerbation, promoting self-efficacy, effective dyspnea management, widening the application of pulmonary
rehabilitation to the post-hospitalization period and to less-severe disease, and the use of palliative care in severe
disease.
OBJECTIVES
At the conclusion of this course, the participant will be able to:
 recognize the importance of addressing and treating the systemic manifestations of COPD;
 apply the new knowledge presented to improve patients' health status;
 recognize the need to individualize care to the unique needs of the patient.
CME ACCREDITATION & DESIGNATION
The American Thoracic Society is accredited by the Accreditation Council for Continuing Medical Education to provide
continuing medical education for physicians.
The American Thoracic Society designates this educational activity for a maximum of 6.5 AMA PRA Category 1
Credit(s)™. Physicians should only claim credit commensurate with the extent of their participation in the activity.
Please note that International Physicians are eligible to receive AMA PRA Category 1 Credit™ for ATS
International Conference participation. Awarding of AMA PRA Category 1 Credit is not limited to U.S. licensed
physicians.
COURSE DIRECTORS: Carolyn L. Rochester, MD

Brian W. Carlin, MD
Claudio Donner, MD
PROGRAM:
Time Title
Introduction: New Developments In The Assessment And Treatment Of

Chronic Obstructive Pulmonary Disease
8:00 am - 8:25 am Claudio Donner, MD
New Insights Into Chronic Obstructive Pulmonary Disease Phenotypes

8:25 am - 8:50 am Bartolome R. Celli, MD
Addressing Co-Morbidity In Chronic Obstructive Pulmonary Disease

8:50 am - 9:15 am Carolyn L. Rochester, MD
Advances In The Science Of Exercise Training For Chronic Obstructive

Pulmonary Disease Patients
9:15 am - 9:40 am Francois Maltais, MD
Physical Inactivity In Chronic Obstructive Pulmonary Disease Patients

9:40 am - 10:05 am Richard Casaburi, MD, PhD
10:05 am - 10:35 am Break
Addressing Psychological, Behavioral And Cognitive Issues In Chronic

Obstructive Pulmonary Disease
10:35 am - 11:00 am Jan Vercoulen, PhD
Measuring Exercise Performance In Chronic Obstructive Pulmonary

Disease
11:00 am - 11:25 am Anne E. Holland, PhD
New Pharmacologic Treatments On The Horizon

11:25 am - 11:50 am Nicola A. Hanania, MD, MS
Dyspnea Management For Advanced Lung Disease

11:50 am - 12:15 pm Paula M. Meek, RN, PhD
12:15 pm - 12:45 pm Lunch
Targeting The Chronic Obstructive Pulmonary Disease Exacerbation

12:45 pm - 1:10 pm Jadwiga A. Wedzicha, MD
Let's Talk Disease Modification

1:10 pm - 1:35 pm Stephen I. Rennard, MD
Palliative Care And Pulmonary Rehabilitation

1:35 pm - 2:00 pm Daisy Janssen, MD
2:00 pm - 2:30 pm Break
Widening The Application Of Pulmonary Rehabilitation

2:30 pm - 2:55 pm Fritz Franssen, MD
Transition Of Care Of The Chronic Obstructive Pulmonary Disease Patient

From Hospital To Home
2:55 pm - 3:20 pm Brian W. Carlin, MD
3:20 pm - 4:00 pm Questions And Answers

COURSE DIRECTORS
Carolyn L. Rochester, MD Brian W. Carlin, MD

Yale University School of Medicine Integrated Pulmonary Physicians Ltd.
Pulmonary and Critical Care Pulmonology
New Haven, Connecticut Pittsburgh, Pennsylvania
Claudio Donner, MD
Mondo Medico
Rehabilitation Outpatient Clinic
Borgomanero, Italy
FACULTY
Richard Casaburi, MD, PhD Francois Maltais, MD

Los Angeles Biomedical Research Institute at Institute of Cardiology and Pneumology
Harbor – UCLA Medical Center Pneumology
Torrance, California Quebec, Canada
Bartolome R. Celli, MD Paula M. Meek, RN, PhD

Brigham and Women's Hospital University of Colorado College of Nursing
Pulmonary and Critical Care Adult and Gerontological
Boston, Massachusetts Denver, Colorado
Frits Franssen, MD Stephen I. Rennard, MD

CIRO University of Nebraska Medical Center
Centre of Expertise For Chronic Organ Failure Pulmonary and Critical Care Medicine
Horn, Netherlands Omaha, Nebraska
Nicola A. Hanania, MD, MS Jan Vercoulen, PhD

Baylor College of Medicine Universitair Medisch Centrum St. Radboud
Pulmonary and Critical Care Medicine Psychology
Houston, Texas Groesbeek, Netherlands
Anne E. Holland, PhD Jadwiga A. Wedzicha, MD

La Trobe University University College London
Physiotherapy Center for Respiratory Research, Medicine
Melbourne, Australia London, United Kingdom
Daisy Janssen, MD
CIRO
Program Development Centre
Horn, Netherlands
Introduction: New Developments In The
Assessment And Treatment Of Chronic
Claudio Donner, MD
8:00 am - 8:25 am
New developments in the assessment and treatment of COPD
Claudio F. Donner
Mondo Medico, Multidisciplinary and Rehabilitation Outpatient Clinic

Borgomanero (NO), Italy
Summary
A number of genes in conjunction with environmental factors are likely to influence the
development of airway inflammation and parenchymal destruction, in other words, the
susceptibility to COPD. At present, most of the genes that contribute to the genetic component
to COPD remain undetermined. However, the genes that are implicated in the pathogenesis of
COPD are divided into three categories based on their functions: antiproteolysis, xenobiotic
metabolism of the toxic substances in the cigarette smoke, and inflammatory response to
cigarette smoke.
Concerning antiproteolysis, the imbalance in relative amounts of proteases and antiproteases is
thought to play a major role in the pathogenesis of COPD, especially emphysema. Deficiencies
or abnormalities in anti-proteases could lead to enhanced lung parenchymal destruction. Among
the genes, alpha-1 anti-trypsin deficiency has proved to be an important risk factor.
Concerning xenobiotic metabolising enzymes, cigarette smoke contains many toxic and highly
reactive compounds that can cause injury to the tissues and inflammation. Any change in the
enzyme systems designed to detoxify reactive substances may contribute to an increased risk of
development of COPD in smokers. Microsomal epoxide hydrolase (mEH) is a xenobiotic
metabolising enzyme that converts reactive epoxides into more soluble dihydrodiol derivatives
that are easily eliminated from the body. mEH plays an important role in the metabolism of
different highly reactive compounds found in cigarette smoke. Low levels of mEH make the
lung vulnerable to damage by epoxides. Glutathion S-transferases (GSTs) play an important role
in detoxifying different aromatic hydrocarbons found in cigarette smoke. They conjugate
electrophilic substrates with glutathione and facilitate further metabolism and elimination. The
GST-M1 is expressed in the bronchiolar epithelium, alveolar macrophages, and type-1 and type-
2 pneumocytes. Homozygous deficiency for GST-M1 results in emphysema and severe chronic
bronchitis in heavy smokers.
Inflammatory mediators play a very important role in the pathogenesis of COPD. Genetic
polymorphisms may either augment inflammation or impair antiinflammatory pathways and
contribute to individual variability in their susceptibility to cigarette smoke. In the alveoli,
interstitium and alveolar capillaries, there is an accumulation of macrophages, neutrophils and
CD8+ lymphocytes in COPD. These cells release the mediators such as tumour necrosis factor-
alpha (TNF-α), leucotriene (LT)-B4, and the potent neutrophil chemoattractant interleukin (IL)-
8. Unlike COPD, asthma is associated with accumulation of activated eosinophils, mast cells
and TH2 CD4+ lymphocytes and there is release of entirely different mediators, such as IL-4,
IL-5 and IL-13. The line of distinction gets faded when COPD and bronchial asthma co-exist.
Long-standing cases of severe asthma may exhibit airway remodeling resulting in fixed airflow
limitation. Patients with COPD may exhibit asthmatic element with reversibility of airflow
limitation. These characteristics may cause difficulty to differentiate between an asthmatic
episode and an acute exacerbation of COPD. TNF-α is produced by macrophages. It not only
induces the release of neutrophils from the bone marrow, but also stimulates other cells such as
monocytes, epithelial cells and smooth muscle cells in the airway that are also involved in the
production of IL-8. IL-8 in addition to being a neutrophil chemo-attractant, acts as an activator
of neutrophils. In COPD there is an increased protease activity and action of free radicals,
cytokines and chemokines in the inflammatory infiltrate to result in narrowing of airways and
loss of alveolar tethering. Neutrophils and macrophages are involved in the synthesis and
secretion of proteinases such as neutrophil elastase and macrophage-derived tryptases, and other
metalloproteinases. These digest lung tissue and cause fibrosis. These are involved in airway
remodeling and stimulate excess production of mucus. The CD8+ cells are likely to be involved
in apoptosis of epithelial cells in the alveolar walls. The action of perforins and TNF-α leads to
the development of emphysema. There are goblet cell hyperplasia, squamous metaplasia and
minimal smooth muscle hypertrophy. There is destruction of lung parenchyma. The focal
damage is evident in central areas of acinus (centriacinar emphysema). There can be a uniform
destruction of walls of airspaces distal to the terminal bronchioles (panacinar emphysema).
There is loss of elastic recoil of the lung to result in hyperinflation, a premature collapse of
airways and air trapping. Unike asthma, the inflammatory process in COPD is not associated
with accumulation of an increased number of activated eosinophils in the lungs. This is the
reason for ineffectiveness of corticosteroids in COPD. They are indicated only when there is an
exacerbation of the disease or in the presence of concomitant asthma, wherein there is a
significant accumulation of activated eosinophils in the lungs. Eosinophils get activated only
during exacerbation of the disease. The glucocorticosteroid-sensitive TH2 pathway is not active
in COPD in contrast to asthma. All these basic abnormalities make steroids ineffective during
stable COPD. The study of bronchoalveolar lavage (BAL) fluid and sputum samples from
patients with COPD has revealed presence of large number of neutrophils and macrophages.
Sputum also shows a greater amount of IL-8 and TNF-α.
Another important aspect in assessing the COPD patient is the definition of correct outcome
measures. Understanding the merits and limitations of current methods for assessing
physiological and clinical outcomes of COPD is crucial for the interpretation and design of
clinical trials. Unfortunately, in contrast to monitoring lung function, there is no gold standard
for measuring symptoms such as dyspnea, health status, exercise capacity, physical activity, or
exacerbations, since none of the available methods is optimal in all regards. Accordingly, no
single outcome measure can be recommended for the assessment of treatment response in
COPD. More research is needed to improve and simplify questionnaire-based markers or
technologies to assess outcomes such as physical activity or health status, in order to enable
wider use in clinical trials as well as in primary care. A further step in that direction may be the
recent development of a COPD assessment test. Implementation of minimal importance
differences (MIDs) may also help to assess which changes of outcome markers can be
considered clinically relevant. However, MIDs hardly reflect the heterogeneity, variability, and
severity of COPD, as well as the numerous confounding factors contributing to the clinical
presentation of the disease. Further, no biomarkers have been established yet to reflect the
inflammatory and destructive process in the lung or to indicate responsiveness to treatment.
However, further research in this area is important as pulmonary biomarkers - whether
physiological or biochemical - are urgently needed if clinical trials are to be shorter and more
discriminating than at present. Finally, comorbid conditions such as cardiovascular disease,
anxiety and depressive disorders, lung cancer and osteoporosis are often observed in COPD
patients and are likely to affect COPD outcomes. The impact of these conditions together with
the influences of concomitant medication on COPD are variable and for many of them still
uncertain; nevertheless, they may alter COPD phenotype, disease progression and survival, and
responses to treatment. A systematic evaluation of comorbidities and co-medication should be
considered as part of COPD management as they may influence the results of clinical outcome
measures.
Recently there has been an important debate on the content and the role played by guidelines
and statements on COPD according to the new approach to the assessment and treatment of the
disease. The statement recently published in a joint document by ACP, ACCP, ATS, and ERS
well expresses the innovations that have emerged in this area. The main recommendations are as
follows:
Recommendation 1: spirometry should be obtained to diagnose airflow obstruction in patients

with respiratory symptoms (Grade: strong recommendation, moderate-quality evidence). It
should not be used to screen for airflow obstruction in individuals without respiratory symptoms
(Grade: strong recommendation, moderate-quality evidence).
Recommendation 2: for stable COPD patients with respiratory symptoms and FEV1 between
60% and 80% predicted, treatment with inhaled bronchodilators may be used (Grade: weak
recommendation, low-quality evidence).
Recommendation 3: in stable COPD patients with respiratory symptoms and FEV1<60%

predicted, treatment with inhaled bronchodilators is recommended (Grade: strong
recommendation, moderate-quality evidence).
Recommendation 4: clinicians should prescribe monotherapy using either long-acting inhaled

anticholinergics or long-acting inhaled β2-agonists for symptomatic patients with COPD and
FEV1 <60% predicted (Grade: strong recommendation, moderate-quality evidence). The choice
of monotherapy should be based on patient preference, cost, and adverse effect profile.
Recommendation 5: combination inhaled therapies (long-acting inhaled anticholinergics, long-

acting inhaled β2-agonists, or inhaled corticosteroids) may be administered for symptomatic
patients with stable COPD and FEV1 < 60% predicted (Grade: weak recommendation,
moderate-quality evidence).
Recommendation 6: pulmonary rehabilitation should be prescribed for symptomatic patients

with FEV1 <50% predicted (Grade: strong recommendation, moderate-quality evidence).
It may be considered for symptomatic or exercise-limited patients with FEV1 >50% predicted.
(Grade: weak recommendation, moderate-quality evidence).
Recommendation 7: continuous oxygen therapy should be prescribed in patients with COPD

who have severe resting hypoxemia (Pa O2≤ 55 mm Hg or SpO 2 ≤ 88%) (Grade: strong
Reference list of sources for the presentation
1. Jones PW, Agusti AGN. Outcomes and markers in the assessment of chronic obstructive
pulmonary disease. Eur Respir J 2006; 27: 822–832. DOI: 10.1183/09031936.06.00145104
2. Qaseem A, Wilt TJ, Weinberger SE, Hanania NA, Criner G, van der Molen T, Marciniuk DD,
Denberg T, Schünemann H, Wedzicha W, MacDonald R, Shekelle P, for the American College
of Physicians, the American College of Chest Physicians, the American Thoracic Society, and
the European Respiratory Society. Diagnosis and Management of Stable Chronic Obstructive
Pulmonary Disease: A Clinical Practice Guideline Update from the American ollege of
Physicians, American College of Chest Physicians, merican Thoracic Society, and European
Respiratory Society Ann Intern Med. 2011;155:179-191.
3. Glaab T, Vogelmeier C, Buhl R. Outcome measures in chronic obstructive pulmonary disease
(COPD): strengths and limitations. Respiratory Research 2010, 11:79 http://respiratory-
research.com/content/11/1/79 doi: 10.1186/1465-9921-11-79
4. Han MK, Agustí A, Calverley PM, Celli BR, Criner G, Curtis JL, Fabbri LM, Goldin JG, Jones
PW, Macnee W, Make BJ, Rabe KF, Rennard SI, Sciurba FC, Silverman EK, Vestbo J, Washko
GR, Wouters EF, Martinez FJ. Chronic obstructive pulmonary disease phenotypes. The future
of COPD. Am J Respir Crit Care Med 2010; 182: 598-604.
5. Wardlaw AJ, Silverman M, Siva R, Pavord ID, Green R. Multi-dimensional phenotyping:
towards a new taxonomy for airway disease. Clin Exp Allergy 2005; 35: 1254-1262.
6. Gibson PG, Simpson JL. The overlap syndrome of asthma and COPD: what are its features and
how important is it? Thorax 2009; 64:728-735
7. Hardin M, Silverman EK, Barr RG, Hansel NH, Schroeder, Make BJ, Crapo JD, Hersh CP for
the COPDGene Investigators. The clinical features of overlap between COPD and asthma.
Respir Res 2011; 12: 127.
8. Soriano JB, Davis KJ, Coleman B, Visick G, Mannino D, Pride NB. The proportional Venn
diagram of obstructive lung disease. Chest 2003; 124:474-481.
9. Criner GJ, Belt P, Sternberg AL, Mosenifar Z, Make BJ, Utz JP, Sciurba F: National
Emphysema Treatment Trial Research Group. Effects of lung volume reduction surgery on gas
exchange and breathing pattern during maximum exercise. Chest 2009, 135:1268-79.
10. Cazzola M, MacNee W, Martinez FJ, Rabe KF, Franciosi LG, Barnes PJ, Brusasco V, Burge PS,
Calverley PMA, Celli BR, Jones PW, Mahler DA, Make B, Miravitlles M, Page CP, Palange P,
Parr D, Pistolesi M, Rennard SI, Ruttenvan Mölken MP, Stockley R, Sullivan SD, Wedzicha JA,
Wouters EF, American Thoracic Society/European Respiratory Society Task Force on
outcomes of COPD. Outcomes for COPD pharmacological trials: from lung function to
biomarkers. Eur Respir J 2008, 31:416-469.
11. Watz H, Waschki B, Meyer T, Magnussen H. Physical activity in patients with COPD. Eur
Respir J 2009, 33:262-272.
12. Puhan MA, Garcia-Aymerich J, Frey M, ter Riet G, Antó JM, Agustí AG, Gómez FP,
Rodríguez-Roisín R, Moons KGM, Kessels AG, Held U. Expansion of the prognostic
assessment of patients with chronic obstructive pulmonary disease: the updated BODE index
and the ADO index. Lancet 2009, 374:704-711.
Glossary
mEH = microsomal epoxide hydrolase

GSTs = glutathion S-transferases
TNF-α = tumour necrosis factor-alpha
IL = interleukin
MIDs = minimal importance differences
FEV1 = forced expiratory volume in 1 second
PaO2 = partial pressure of arterial oxygen
SpO2 = oxygen saturation measured by pulse oximetry
New developments in the assessment and
treatment of COPD
Claudio F. Donner
Mondo Medico
Multidisciplinary and Rehabilitation Outpatient Clinic, Borgomanero (NO) - Italy
• COPD is characterised by a fall in expiratory flow and lung

hyperinflation. These changes are due to loss of lung elasticity and
inflammatory narrowing of the small airways of the lung.
• A number of genes in conjunction with environmental factors are

likely to influence the development of airway inflammation and
parenchymal destruction, in other words, the susceptibility to COPD.
• At present, most of the genes that contribute to the genetic

component to COPD remain undetermined. However, the genes that
are implicated in the pathogenesis of COPD are divided into three
categories based on their functions:
1. antiproteolysis
2. xenobiotic metabolism of the toxic substances in cigarette
smoke, and
3. inflammatory response to cigarette smoke.
Antiproteolysis
• Imbalance in relative amounts of proteases and

antiproteases are thought to play a major role in the
pathogenesis of COPD, especially emphysema.
• Deficiencies or abnormalities in anti-proteases could

lead to enhanced lung parenchymal destruction. Among
the genes, those involved in alpha-1 anti-trypsin
deficiency have proved to be an important risk factor.
Page 1
1
Xenobiotic Metabolising Enzymes
Cigarette smoke contains many toxic and highly reactive compounds that
can cause tissue injury and inflammation. Any change in the enzyme
systems designed to detoxify reactive substances may lead to an
increased risk of development of COPD in smokers.
1. Microsomal epoxide hydrolase (mEH) is a xenobiotic metabolising

enzyme that converts reactive epoxides into more soluble dihydrodiol
derivatives that are easily eliminated from the body. It plays an important
role in the metabolism of diverse highly reactive compounds found in
cigarette smoke. Low levels of mEH make the lung vulnerable to damage
by epoxides.
2. Glutathion S-transferases (GSTs) play an important role in detoxifying

different aromatic hydrocarbons found in cigarette smoke. They
conjugate electrophilic substrates with glutathione and facilitate further
metabolism and elimination. GST-M1 is expressed in the bronchiolar
epithelium, alveolar macrophages, and type-1 and type-2 pneumocytes.
Homozygous deficiency for GST-M1 results in emphysema and severe
chronic bronchitis in heavy smokers.
The overlap phenotype: the link between asthma and

COPD
Interest in the clinical phenotypes of COPD and their definition and characterisation is
growing. Among these phenotypes, the so-called overlap of syndromes with airflow
obstruction is usually poorly considered.
The asthma-COPD overlap phenotype has been described as: symptoms of increased
variability of airflow in association with an incompletely reversible airflow obstruction.
From a clinical point of view it usually corresponds to individuals diagnosed with
asthma before the age of 40 who, at an older age, fulfil the criteria for COPD. Recent
estimations of its prevalence report that about 13-20% of COPD subjects have the
overlap phenotype, with an increasing trend in the elderly population (up to 50% in the
over 70 age group).
COPD patients with the overlap phenotype may have some degree of eosinophilic
inflammation which is more responsive to corticosteroids and has a somewhat better
prognosis than patients with irreversible airway obstruction.
Han MK, et al. Am J Respir Crit Care Med 2010; Wardlaw AJ, et al. Clin Exp Allergy 2005;
Gibson PG, et al. Thorax 2009; Hardin M, et al. Respir Res 2011; Soriano JB, et al. Chest 2003.
P. S. Shankar,2008
Page 2
2
Inflammatory Mediators (I)
• Inflammatory mediators play a very important role in the pathogenesis of COPD. Genetic
polymorphisms may either augment inflammation or impair antiinflammatory pathways and
contribute to individual variability in their susceptibility to cigarette smoke. In the alveoli,
interstitium and alveolar capillaries, there is an accumulation of macrophages, neutrophils
and CD8+ lymphocytes in COPD. These cells release the mediators such as tumour
necrosis factor-alpha (TNF-α), leukotriene (LT)-B4, and the potent neutrophil
chemoattractant interleukin (IL)-8.
• Unlike COPD, asthma is associated with accumulation of activated eosinophils, mast cells
and TH2 CD4+ lymphocytes and release of entirely different mediators, e.g. IL-4, IL-5 and
IL-13.
• The line of distinction fades when COPD and bronchial asthma co-exist. Chronic severe
asthma may exhibit airway remodeling resulting in fixed airflow limitation. COPD patients
may exhibit asthmatic element with reversibility of airflow limitation. These characteristics
may cause difficulty to differentiate between an asthmatic episode and an acute
exacerbation of COPD.
• TNF-α is produced by macrophages. It not only induces the release of neutrophils from the
bone marrow, but also stimulates other cells such as monocytes, epithelial cells and
smooth muscle cells in the airway that are also involved in the production of IL-8. IL-8, in
addition to being a neutrophil chemoattractant, acts as an activator of neutrophils.
Inflammatory Mediators (II)

• In COPD there is an increased protease activity and action of free radicals, cytokines and
chemokines in the inflammatory infiltrate to result in narrowing of airways and loss of alveolar
tethering. Neutrophils and macrophages are involved in the synthesis and secretion of
proteinases such as neutrophil elastase and macrophage-derived tryptases, and other
metalloproteinases. These digest lung tissue and cause fibrosis. These are involved in airway
remodeling and stimulate excess production of mucus.
• The CD8+ cells are likely to be involved in apoptosis of epithelial cells in the alveolar walls.
The action of perforins and TNF-α leads to the development of emphysema.
• There are goblet cell hyperplasia, squamous metaplasia and minimal smooth muscle
hypertrophy.
• There is destruction of lung parenchyma. The focal damage is evident in central areas of
acinus (centriacinar emphysema). There can be a uniform destruction of walls of airspaces
distal to the terminal bronchioles (panacinar emphysema).
• There is loss of elastic recoil of the lung to result in hyperinflation, a premature collapse of
airways and air trapping.
Inflammatory Mediators (III)
• Unike asthma, the inflammatory process in COPD is not associated with

accumulation of an increased number of activated eosinophils in the lungs. This
is the reason for ineffectiveness of corticosteroids in COPD. They are indicated
only when there is an exacerbation of the disease or in the presence of
concomitant asthma, wherein there is a significant accumulation of activated
eosinophils in the lungs.
• Eosinophils get activated only during exacerbation of the disease. The

glucocorticosteroid-sensitive TH2 pathway is not active in COPD in contrast to
asthma. All these basic abnormalities make steroids ineffective during stable
COPD.
• The study of bronchoalveolar lavage (BAL) fluid and sputum samples from
patients with COPD has revealed presence of large number of neutrophils and
macrophages. Sputum also shows a greater amount of IL-8 and TNF-α.
Page 3
3
P.W. Jones* and A.G.N. Agusti .Eur. Respir. J 2006
#
P.W. Jones* and A.G.N. Agusti .Eur. Respir. J 2006
Outcome measures relevant Airflow limitation

for the evaluation of COPD and hyperinflation
management.
Dyspnea
Exacerbations
Reduced physical activity

and exercise capacity
Impaired health status
Disease progression
Mortality
Glaab et al. Respiratory Research 2010 11:79
Page 4
4
Outcome measures in COPD:
strengths and limitations (I)
Understanding the merits and limitations of current methods for assessing
physiological and clinical outcomes of COPD is crucial for the interpretation
and design of clinical trials.
Unfortunately, in contrast to lung function monitoring, there is no gold

standard for measuring symptoms such as
dyspnea,
health status,
exercise capacity,
physical activity, or
exacerbations,
since none of the available methods is optimal in all regards.
Accordingly, no single outcome measure can be recommended for the

assessment of treatment response in COPD.

strengths and limitations (II)
More research is needed to improve and simplify questionnaire-based

markers or technologies to assess outcomes such as physical activity
or health status, in order to enable wider use in clinical trials as well
as in primary care. A further step in that direction may be the recent
development of a COPD assessment test.
Implementation of minimal importance differences (MIDs) may also

help to assess which changes of outcome markers can be considered
clinically relevant. However, MIDs hardly reflect the heterogeneity,
variability, and severity of COPD, as well as the numerous
confounding factors contributing to the clinical presentation of the
disease.

strengths and limitations (III)
No biomarkers have yet been established to reflect the inflammatory and
destructive process in the lung or to indicate responsiveness to treatment.
Further research in this area is important as pulmonary biomarkers - whether
physiological or biochemical - are urgently needed if clinical trials are to be
shorter and more discriminating than at present.
Finally, comorbid conditions (cardiovascular disease, anxiety and depressive

disorders, lung cancer and osteoporosis) are often observed in COPD patients
and are likely to affect COPD outcomes.
The impact of these conditions together with the influences of concomitant

medication on COPD are variable and for many of them still uncertain; they
may alter COPD phenotype, disease progression and survival, and responses
to treatment. A systematic evaluation of comorbidities and co-medication
should be considered as part of COPD management as they may influence the
results of clinical outcome measures.
Page 5
5
Recommendation 1:
ACP, ACCP, ATS, and ERS recommend that spirometry should be

obtained to diagnose airflow obstruction in patients with respiratory
symptoms
Spirometry should not be used to screen for airflow obstruction in

individuals without respiratory symptoms
Ann Intern Med. 2011;155:179-191.
• Recommendation 2: For stable COPD patients with respiratory

symptoms and FEV1 between 60% and 80% predicted, ACP,
ACCP, ATS, and ERS suggest that treatment with inhaled
bronchodilators may be used
(Grade: weak recommendation, low-quality evidence).
• Recommendation 3: For stable COPD patients with respiratory

symptoms and FEV1< 60% predicted, ACP, ACCP, ATS, and ERS
recommend treatment with inhaled bronchodilators
Ann Intern Med. 2011;155:179-191.
Recommendation 4: ACP, ACCP, ATS, and ERS recommend that

clinicians prescribe monotherapy using either long-acting inhaled
anticholinergics or long-acting inhaled β2-agonists for symptomatic
patients with COPD and FEV1 <60% predicted.
Clinicians should base the choice of specific monotherapy on patient
preference, cost, and adverse effect profile.
Recommendation 5: ACP, ACCP, ATS, and ERS suggest that clinicians

may administer combination inhaled therapies (long-acting inhaled
anticholinergics, long-acting inhaled β2-agonists, or inhaled
corticosteroids) for symptomatic patients with stable COPD and FEV1 <
60% predicted (Grade: weak recommendation, moderate-quality
evidence).
Ann Intern Med. 2011;155:179-191.
Page 6
6
Recommendation 6: ACP, ACCP, ATS, and ERS recommend that clinicians
should prescribe pulmonary rehabilitation for symptomatic patients with an
FEV1 <50% predicted.
Clinicians may consider pulmonary rehabilitation for symptomatic or
exercise-limited patients with an FEV1 >50% predicted. (Grade: weak
Recommendation 7: ACP, ACCP, ATS, and ERS recommend that clinicians

should prescribe continuous oxygen therapy in patients with COPD who
have severe resting hypoxemia (Pa O2≤ 55 mm Hg or SpO 2 ≤ 88%)
Ann Intern Med. 2011;155:179-191.
Page 7
7
Addressing Co‐Morbidity In Chronic
Carolyn L. Rochester, MD
8:50 am - 9:15 am
Addressing Comorbidities of COPD
Carolyn L. Rochester, M.D.
Friday May 18th, 2012
Summary of Presentation:
COPD is commonly associated with one or more medical co‐morbidities that may
have components of shared pathogenesis with the structural and functional changes
in the lungs. Medical co‐morbidities commonly associated with COPD include
cardiovascular disease (hypertension, coronary artery disease, peripheral vascular
disease, systolic and/or diastolic heart failure, arrhythmias, stroke), metabolic
disturbances (diabetes, osteoporosis and osteoarthritis), skeletal muscle
dysfunction, obstructive sleep apnea, renal insufficiency, anemia, infections, lung
cancer, psychological disturbances (anxiety and depression), and cognitive
dysfunction. Most patients have one or more of these co‐morbid conditions,
especially as airflow obstruction becomes moderate to severe. Medical co‐
morbidities have substantial impact on both patients and society. They worsen
symptoms, disability and quality of life, as well as increase mortality. Co‐
morbidities also increase healthcare utilization and healthcare costs. Awareness of
these co‐morbidities is therefore needed to optimize management of COPD.
Healthcare providers should ask COPD patients about symptoms relevant to the
common co‐morbidities, and must consider a broader base of diagnostic testing
beyond pulmonary function to enable their recognition. The presence of medical co‐
morbidities has implications for patients’ pharmacologic and non‐pharmacologic
therapy. Early intervention may have the potential to alter the course of the disease.
Addressing Co‐morbidities of COPD
Reference List
1. Barnes PJ, Celli BR, Systemic manifestations and comorbidities of COPD, Eur
Respir J 2009; 33:1165‐85.
2. Decramer M, Rennard S, Troosters T et al., COPD as a lung disease with
systemic consequences—clinical impact, mechanisms, and potential for early
intervention, COPD: Journal of COPD 2008; 5:235‐56.
3. Nussbaumer‐Oschner Y, Systemic manifestations of COPD, Chest 2011;
139:165‐73.
4. Fabbri LM, Luppi F, Beghe B et al., Complex chronic comorbidities of COPD,
Eur Respir J 2008; 31:204‐12.
5. Cazzola M, Bettoncelli G, Sessa E, et al., Prevalence of comorbidities in
patients with chronic obstructive pulmonary disease, Respiration 2010; 80:
112‐9.
6. Sin DD, Man SF, Why are patients with chronic obstructive pulmonary
disease at increased risk of cardiovascular diseases? The potential role
systemic inflammation in chronic obstructive pulmonary disease, Circulation
2003; 107:1514‐9.
7. Sin DD, Wu L, Man SF, The relationship between reduced lung function and
cardiovascular mortality: a population based study and systematic review of
the literature, Chest 2005; 127:1952‐9.
8. Soriano JB, Visick GT, Muellerova H et al., Patterns of comorbidities in newly
diagnosed COPD and asthma in primary care, Chest 2005; 128(4)2099‐107.
9. Van der Molen T, Co‐morbidities of COPD in primary care: frequency, relation
to COPD and treatment consequences, Prim Care Respir J 2010; 19(4)326‐34.
10. Lee R, McNicholas WT, Obstructive sleep apnea in chronic obstructive
pulmonary disease patients, Curr Opin Pulm Med 2011; 17:79‐83.
11. Antonelli‐Incalzi R, Corsonello A, Pedone C et al., Chronic renal failure: a
neglected comorbidity of COPD, Chest 2010; 137:831‐7.
12. Hanania NA, Muellerova H, Locantore NW et al., Determinants of depression
in the ECLIPSE chronic obstructive pulmonary disease cohort, Am J Respir
Crit Care Med 2011; 183:604‐11.
13. Maurer J, Rebbapragada V, Borson S et al., Anxiety and depression in COPD:
Current understanding, unanswered questions and research needs, Chest
2008; 134:43S‐56S.
14. Terada K, Muro S, Ohara T et al., Abnormal swallowing reflex and COPD
exacerbations, Chest 2010; 137:326‐32.
15. Biskobing DM, COPD and osteoporosis, Chest 2002; 121:609‐20.
16. Cote C, Zilberberg MD, Mody SH et al., Haemoglobin level and its clinical
impact in a cohort of patients with COPD, Eur Respir J 2007; 29:932‐9.
17. Dodd JW, Getov SV, Jones PW, Cognitive function in COPD, Eur Respir J 2010;
35:913‐22.
18. Simon‐Tuval T, Scharf SM, Maimon N et al., Determinants of elevated
healthcare utilization in patients with COPD, Respir Res 2011; 12:7.
19. Barr RG, Celli BR, Mannino DM et al., Comorbidities, patient knowledge, and
disease management in a national sample of patients with COPD, Am J Med
2009; 122:3448‐55.
20. Schneider KM, O’Donnell BE, Dean D, Prevalence of multiple chronic
conditions in the United States Medicare Population, Health and Qual of Lie
Outcomes 2009; 7:82.
21. Boyd CM, Darer J, Boult C et al., Clinical practice guidelines and quality of care
for older patients with multiple co‐morbid diseases: implications for pay for
performance, JAMA 2005; 294:716‐24.
22. Lash TL, Johansen MB, Christensen S et al., Hospitalization rates and survival
associated with COPD: a nationwide Danish cohort study, Lung 2011; 189:27‐
35.
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Chest 2009; 136:734‐43.
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by statins, angiotensin‐converting enzyme inhibitors and angiotensin
receptor blockers in patients with chronic obstructive pulmonary disease, J
Am Coll Cardiol 2006; 47:2554‐60.
25. Troosters T, van Remoortel H, Pulmonary rehabilitation and cardiovascular
disease, Semin Resp Crit Care Med 2009; 30:675‐83.
Addressing Co‐Morbidities of COPD
Key Terms
Co‐morbidity
Systemic inflammation
Mortality
Cardiovascular disease
Skeletal muscle dysfunction
Osteoporosis
Metabolic disease: diabetes
Obstructive sleep apnea
Anemia
Psychological disturbances (anxiety, depression)
Cognitive impairment
Patient assessment
Rehabilitation
4/4/2012
Addressing Co‐morbidities in COPD

Yale University School of Medicine
VA Connecticut Healthcare System
No conflicts of interest to disclose in regard to this presentation
Talk Outline
• Statement of the problem

• What co‐morbidities and how common?
• Is there a pathogenic link?
• Impact of co‐morbidities
• Patient
• Society
• Assessing co‐morbidities
• Implications for COPD management
• Pharmacologic
• Physical activity and rehabilitation
“COPD is a preventable and treatable disease with

some significant extra-pulmonary effects that may
contribute to the severity in individual patients. Its
pulmonary component is characterized by airflow
limitation that is not fully reversible. The airflow limitation
is usually progressive and associated with an
abnormal inflammatory response of the lung to
noxious particles or gases”
Global Initiative for Chronic Obstructive Pulmonary Disease

NHLBI/WHO Workshop report, www.goldcopd.com, 2009
1
4/4/2012
Anemia: 15‐30% Osteoporosis: 35‐60%
Skeletal Muscle Dysfunction: ~30%
Common Co‐morbidities of COPD

Lung Cancer Infections
Cardiac disease: 23‐56%

• CHF 5‐8%
Anxiety: 10‐20% • MI 2‐ Depression: 10‐42%
22%
• A fib 4.7%
• VT/VF 0.8%
Other co‐morbidities: often under‐recognized
• Obstructive sleep apnea

• Chronic renal insufficiency
• Swallowing dysfunction/GERD
• Diabetes/metabolic syndrome
• Cognitive dysfunction
Multiple Co‐morbidities May Co‐exist

• Analysis of 2005 FFS Medicare claims:
Prevalence, utilization and Medicare program
costs for common chronic medical conditions:
Schneider, Health and QOL Outcomes ’09; 7:82
• 50% of beneficiaries received care for ≥ 1
condition; 11% got care for COPD
• Of the COPD patients:
• 28.3% had only COPD
• 32.7% had 1 other condition
• 39% had ≥ 2 other conditions
• COPD Patients had a median of 9 co‐morbidities !
• Barr RG, Am J Med 2009;122:348‐55
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Is There a Pathogenesis Link?

Age
Inactivity
Oxidant Stress
Tissue Injury
“Spill over” Acute phase proteins

CRP
Surfactant protein D
Systemic inflammation Serum amyloid A
lL‐1, Il‐6, TNF‐
Modified from: Barnes & Celli, Eur Respir J ’09; 33: 1165-85; Googleimages.com
Impact Of Co‐morbidities For The Patient
Worse Increased
symptoms Mortality
Increased Worse
Morbidity Quality
Worse
of Life
Disability
Co‐morbidities Impact Mortality

• People often die WITH COPD, not necessarily FROM COPD
• National Health & Nutrition Examination Survey (NHANES): < 30% pts with severe
COPD had COPD listed as cause of death (Mannino, Thorax ’03; 58:388‐93)
• Lung Health Study: major causes of death in mild COPD: 33% lung cancer, 22% CV
disease, 8% resp. disease (Anthonisen, Ann Intern Med ’05; 142:233‐9)
• TORCH Study: 35% respiratory deaths, 27% cardiac, 21% cancer (Calverley, NEJM ’07; 356:775‐89)
• Co‐morbidities of DM, HTN, CV disease are associated with increased risk of
hospitalization and mortality (Mannino, ERJ ’08; 32:962‐7)
• Overall mortality and deaths from non‐respiratory causes are

increasing over time (Ekstrom, Am J Respir Crit Care Med ‘11; 183:1032‐6)
• Co‐morbidities increase mortality of patients hospitalized for COPD
exacerbation
• Patients hospitalized for AECOPD with co‐morbidities are ~ 2 X as likely to die
(Almagro, Chest ’02; 121:1441‐8)
• Co‐morbidities increase 180 day mortality of 1st hospitalization for COPD
(Lash, Lung ‘11; 189:27‐35)
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Cardiovascular Disease and COPD
Structural changes in lungs: impact Suspected link with systemic inflammation

of airflow limitation and hyperinflation --endothelial dysfunction and atherosclerosis
--pulmonary artery hypertension --heart failure: systolic and/or diastolic
-remodeling of PA --other: HTN, stroke, peripheral vascular
-loss of intact vessels disease
-hypoxic vasoconstriction
--Increased intrathoracic pressure
Barnes & Celli, ERJ ’09; 33:1165
-increased RV afterload MacNee, Proc Am Thorac Soc ’08; 5:824
-compromised LV filling Funk, Chest ’08; 133: 1354;
Watz, AJRCCM ’08; 177:743
Sabit, AJRCCM ’07; 175:1259
McAllister, AJRCCM ’07; 176:1208
Atherosclerotic Changes in Vessels Begin Early in COPD and Correlate

with Severity of Airflow Obstruction
Correlation between FEV1% pred. and

intimal-medial thickness of carotid
Iwamoto, AJRCCM ’09;179:35-40

% of carotid plaque
Increased Severity of Atherosclerosis in COPD
COPD Controls p value
Mean # affected CA: 2.5 ± .6 2.1 ± .7 .004
Mean extent score: 37 ± 16 23 ± 11 .001
Gensini Score: 10.9 ± 6 6.6 ± 4 .01
Topsakal, Heart Vessels ’09; 24:164-8
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COPD and Cardiovascular Disease

• 2002 National Health Interview Survey, 18,342 pts > age 40:1
• 56.5% prevalence of CV dis. for COPD pts. vs. 25.6% for non‐COPD (p < .0001)
• Patients with COPD have 2‐3 fold increased risk of CV conditions 1,2
• Ischemic ht dis., stroke, HTN, heart failure, arrythmia
• CV disease is leading cause of mortality for patients with mild‐
moderate COPD 2,3
• Lung Health Study: > 5800 smokers, FEV1 55‐90% pred.
• CV disease accounted for ~ 50% hospital admissions and ~ 25% deaths 1
• Increased risk of death from MI independent of age, gender,
smoking status 4,5
• Heart failure is strong independent predictor of all‐cause mortality
in patients with COPD 6
1. Finkelstein, Int J COPD ’09; 4:337; 2. Sin, Chest ’09; 136:329

3. Sin & Man, Can J Physiol Pharm ’05; 83:8; 4. Barnes & Celli, ERJ ’09; 33:1165
5. Sin, Chest ’05; 127:1952; 6. Boudestein, Eur J Ht Failure ’09; 11:1182
COPD Increases Mortality for Patients with

Ischemic Heart Disease
• Longitudinal f/u (42.8 mo) of 9877 pts with hx of CABG or

PCI, 30 institutions
• COPD associated with increased:
• All cause mortality (p < .0001)
• Cardiovascular death ( p < .0002)
• Cardiac death ( p = .0001)
• Fewer patients with COPD and CAD were on standard Rx
for ischemic heart disease eg., ASA, beta‐blocker, statin
Nishiyama, Int J Cardiol ‘10;143:178-83
Diabetes and COPD

• Increased prevalence among COPD patients (RR 1.5‐2.0)
• Metabolic syndrome more common in COPD
• Increased insulin resistance related to IL‐6, TNF‐, NFkB and
oxidative stress
• DM is independently associated with worse lung function
• Can affect respiratory muscles, drive, mechanics, infection risk
• Peripheral neuropathy and claudication (microvascular disease)
can affect functional status, eg. walking
• Increased risk for cardiovascular disease
Bolton, J COPD ’07; 4:121-6, Tiengo, Diabetes Metab ’08; 34:447-54, Laghl, ERJ ’09;
34:975-96, Mannino, ERJ ’08; 32:962-7, McNicholas, AJRCCM ’09; 180:692-700,
Barnes & Celli, ERJ ’09; 33: 1165-85, Nussbaumer-Ochsner, Chest ‘11; 139:165-7
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Obstructive Sleep Apnea & COPD:

“Overlap Syndrome”
• ~10‐20% of COPD patients have OSA
• “overlap syndrome” affects ~ 1 % adults
• More severe hypercarbia & (nocturnal) hypoxemia
(c/w COPD pts w/out OSA matched for GOLD stage)
• More severe pulmonary hypertension, cor pulmonale;
increased CV morbidity and mortality
• Affects mood, cognitive function, energy level
• Those not Rx with CPAP have:
• Increased risk of severe COPD exac. requiring hospitalization (RR 1.7)
• Increased mortality (RR 1.79)
Lee, Curr Opin Pulm Med 2011; 17:79-85
Toraldo, Sleep Breath ‘10; 14:115-23
Machado, Eur Respir J ‘10; 35:132-7
Osteoporosis
• 35‐72% osteopenia, 36‐60% osteoporosis

• Prevalence increases with disease severity
• 29% prevalence of vertebral Fx among COPD pts awaiting transplant
(Shane E, Am J Med ‘96;101:262‐9)
• Osteoporotic fracture:
• Increased risk of subsequent Fx
• May worsen lung function/ respiratory failure
• Decreased mobility
• Hip Fx: 20% mortality in first year in elderly
• Osteoarthritis contributes commonly to activity limitation and
impaired ADL performance
Van der Molen, Prim Care Resp J ‘10; 19:326‐34; Biskobing,
Chest ‘02; 121:609‐20; Jorgensen, Curr Opin Pulm Med ‘08;
14:122‐7; Leech JA, ARRD ‘90;141:68‐77;
Walker‐Bone K, Rev Contemp Pharmacother ‘98
Several Factors Contribute to

Osteoporosis in COPD
• Smoking: increased bone mineral loss

• Corticosteroids
• Reduced skeletal muscle mass/strength
• Altered body composition/decreased BMI
• Hypogonadism
• Decreased IgF1
• Chronic inflammation
• Increased ETOH intake
• Low vitamin D levels
• Genetic factors
Ionescu A, Eur Respir J ‘03;22 Suppl 46; 64S‐75S
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4/4/2012
COPD and Anemia
• Normochromic, normocytic anemia common in

chronic disease, inflammatory states
• 15‐30% prevalence in COPD
• Hgb independently associated with dyspnea,
exercise capacity, impaired QOL and mortality
• Resistance to erythropoietin postulated
John, Int J Cardiol ’06; 111:365-70

Cote, Eur Respir J ’07; 29:923-9
Shorr, Curr Med Res Opin ’08; 24:1123-30
Krishnan, BMC Pulm Med ’06;6:23
John, Chest ’05; 127:825-9
COPD and Renal Insufficiency

• 356 COPD pts > age 65 and 290 age‐matched controls:
• Overt CRI: 22.2% COPD, 13.4% controls (OR 1.94)
• BMI (OR 1.78), DM (OR 2.25) CV disease (OR 2.12) were
significant correlates
• Occult CRI: 20.8% COPD, 10% controls (OR 2.19)
• DM (OR 1.96), albumin < 3.5 (OR 2.83), musculoskel. dis
(OR 1.78) were significant correlates
• CRI may play a role in anemia in COPD:

• Among pts with COPD, anemia in 19.2% w/out CRI, 23% w/
occult CRI, 39.2% w/ overt CRI (p < .001)
Antonelli-Incalzi, Chest ‘10; 137:831-7
Depression and COPD
• 10‐42% prevalence in COPD

• Impacts symptoms, energy, functional capacity,
executive functioning, quality of life
• Associated with increased exacerbations, HC use,
mortality
• ECLIPSE Study:
• 2118 COPD (26% D), 335 Smoker w/out COPD (12% D), 243 Nonsmoker (7% D)
• Higher prevalence in women, current smokers, severe disease
• Multivariate analysis: fatigue, age, hx of CVD, higher SGRQ score, lower 6MWD, higher MRC
score also associated with depression
Hanania, Am J Respir Crit Care Med ‘11; 183:604‐11

De Voogd, Chest ‘09; 135(3)619‐23
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4/4/2012
Cognitive Impairment and COPD

• Present in up to 77% COPD with hypoxemia
• Neuron damage
• Altered neurotransmitter production
• Inflammation
• smoking
• MRI evidence of altered cerebral metabolism in non‐hypoxic
severe COPD
• Global, or selected domains:
(memory, processing, motor function, attention, executive function)
• Associated with other co‐morbidities, disability and mortality
• Impairs daily function (including ADL, social, occupational)
Dodd , Eur Respir J ‘10; 35:913-22
Co‐morbidities Increase Healthcare Utilization and Costs

• 389 COPD pts vs. age‐, gender‐, area of residence‐matched
controls; computerized database, single payer healthcare
system (Simon‐Tuval, Respir Res ‘11; 12:7)
• 3.4 X greater HC utilization in COPD c/w controls (p < .001)
• The top 25% “most costly” pts (98) contributed 63% of all costs
• Independent risks for being in “most‐costly” group:
• Age‐adjusted Charlson Co‐morbidity index (OR 1.09)
• Hx of MI (OR 2.87)
• CHF (OR 3.52)
• Liver disease (OR 3.83)
• Diabetes: (OR 2.02)
• Analysis of 2005 FFS Medicare Claims:
(Schneider, Health and QOL Outcomes ’09; 7:82)
• Annual per‐beneficiary payments:
• 1 condition: $7,172
• 2 conditions: $14,931
• ≥ 3 conditions: $32,498
Assessing Co‐morbidities in the COPD Patient

• Symptom Assessment:
• Chest pain, exertional dizziness, palpitations, claudication, TIA
• Joint pain, impaired mobility/activity limitation, compression Fx
• Weight gain or weight loss
• Muscle weakness, gait or balance disturbance, falls
• Anxiety, depression, fear, isolation, memory impairment
• Fatigue, daytime sleepiness, disrupted sleep, snoring, witnessed apnea
• Testing to Consider:
• CBC, chemistry (Bun/Cr, glucose), GFR, albumin
• BMI, 6MWT, dyspnea assessment (eg. MRC), muscle strength testing
• EKG, echo, stress, CPET
• DEXA scanning
• BECK, HAD, CES‐D, MMSE
• nocturnal oximetry, PSG
• Pts > age 40, > 10 pack/year smoking, pulmonary function test c/w
COPD ‐‐‐> assess for co‐morbidities ! (Fabbri, Lancet ‘07; 370:797‐9)
8
4/4/2012
Practical Implications for Patient Management
• Treating COPD can have beneficial effects on

co‐morbidities
• Treating co‐morbidities can have beneficial
effect on COPD
• Early intervention may influence the course of
disease
• Symptoms, function, complications, exacerbations,
hospitalizations, health status, costs of care, survival
Looking at Existing COPD Therapies in New Ways:

Possible Impact on Systemic Effects of Disease
• Bronchodilators
• ? Possible anti‐inflammatory effects
 ‐agonists can improve muscle mass
• Bronchodilation may alter mechanical forces  reduce strain on
structural cells  reduce inflammation and remodeling
• Awareness of and monitoring for potential adverse CV effects
• Inhaled Corticosteroids
• Possible benefits for systemic inflammation
• Reduced lung cancer risk reported in some studies
• Decreased risk of MI
Barnes & Celli, ERJ ’09; 33:1165-85

Huiart, ERJ ’05; 25:634-9
• Smoking Cessation
• all cause mortality
• risk of myocardial events
• risk of cancer
• bone mineral density
• may slow progression of renal failure
• Oxygen Therapy
• Decreased mortality in hypoxemic COPD
• Reduce dyspnea, sleep disturbance, nocturnal arrythmias,
neuropsychiatric symptoms, stabilize PA pressure, improve
exercise tolerance
Luppi, Proc Am Thorac Soc ‘08; 5:848-56

Nussbaumer-Ochsner, Chest ‘11; 139:165-73
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4/4/2012
Statins and COPD

• Reduce inflammation and prevent
experimental emphysema in mice
• In humans:
‐‐reduce exacerbations
‐‐improve pulmonary function
‐‐exercise capacity
‐‐reduce COPD‐ and all cause‐ mortality
Barnes & Celli, ERJ ’09; 33:1165
Janda, Chest ’09; 136:734-43
ACE Inhibitors and COPD

• Polymorphisms for ACE linked to COPD susceptibility and quadriceps strength
• Potential for anti‐inflammatory effects
• Reduced exacerbations and mortality in COPD
Andreas, ERJ ’06; 27:972-9
Mancini, J Am Coll Cardiol ’06; 47:2554-60
Busquets, Int J COPD ’07; 2:329-34
Hopkinson, AJRCCM ’04; 170:395-9
Statins, ACE Inhibitors and COPD
van Gestel, Am J Cardiol ‘08; 102:192 Mancini, J Am Coll Cardiol ‘06; 47:2554
Beta‐blockers and COPD
• Do not adversely affect FEV1 or induce bronchospasm

• Do not diminish FEV1 response to inhaled bronchodilator
• May reduce risk of exacerbations and improve survival
• Should be used in patients with cardiac indications!!!!
Salpeter, Cochrane Database Syst Rev ‘05; 19:CD003566

Rutten, Arch Intern Med ‘10; 170:880-7
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Physical Activity and Pulmonary Rehabilitation
• Physical Activity
• Associated with slower loss of lung function
• Garcia‐Aymerich, AJRCCM ’07; 175:458‐63
• Reduced markers for systemic inflammation

• Watz, Chest ‘09; 136:1039‐46
• Recommended for COPD, cardiovascular disease,

musculoskeletal disease, obesity, diabetes
• Consider pulmonary rehabilitation
Considerations in Pulmonary Rehabilitation
• Formulation of the exercise training plan:

• Consider orthopedic and/or cardiovascular limitations
• Avoid activities that exacerbate joint/back pain
• Consider specific safety issues
• Consult with primary and/or specialty care providers regarding exercise
limitation parameters where appropriate
• Consider formal CPET in selected patients
• Consider specialty equipment needs
• Broad‐based self‐management education
• Formulate realistic goals to meet patients’ daily life needs
Lung/Airway Disease
Muscle Disease Cardiovascular Disease
Skeletal Disease COPD
Psychologic Disease
Metabolic Disease
Systemic Inflammatory Disease
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4/4/2012
Going Forward Into the Future

Avoid Confining Thoughts Novel approaches
to Our Tower of Expertise to medical therapy
• Further look at effects
of existing therapies
• Treating systemic
inflammation
• Understanding
pathogenetic
mechanisms may lead
to new therapeutic
targets
• Enhanced role for
pulmonary
rehabilitation
12
Advances In The Science Of Exercise
Training For Chronic Obstructive
Francois Maltais, MD
9:15 am - 9:40 am
PG course‐ATS 2012
New Science in the Comprehensive Management of the COPD Patient
Advances in the science of exercise training for COPD patients
François Maltais, MD FRCPC
Summary
Although exercise training has been used for years inpatients with COPD1,
a solid scientific rationale for this intervention has emerged over the last
20 years of research in this area. In 1991, Casaburi and colleagues
published a landmark paper showing that high intensity aerobic training
was associated with reduced lactic acidosis and ventilation during
exercise in patients with COPD2. This study was important because it
refuted the common belief that patients with COPD were too dyspneic to
gain benefits from exercise training. It also laid the foundation for
subsequent physiological investigations in this field thathave clearly
confirmed that skeletal muscle adaptation can occur with aerobic
exercises, even in patients with advanced COPD2-5. At the same time,
muscle strength and mass can be improved by strengthening exercises in
these individuals6-8.
Simultaneously to those physiological studies, epidemiological studies

have confirmed the ability of exercise training to improve dyspnea,
quality of life and exercise capacity9. More recently, it has been suggested
that being active and undertaking pulmonary rehabilitation can prevent
or slow down the deterioration in lung function10,11. These exciting
observations will need to be confirmed in subsequent studies but
nevertheless they raise the possibility that pulmonary rehabilitation may
impact on the course of the disease.
Despite the solid epidemiological and physiological foundation of

exercise training, it has to be appreciated that the exercise response may
be suboptimal and that up to 30% of patients do not exhibit the expected
1
improvement following exercise training12. This so‐called “non‐response”
to exercise training can be attributed to several mechanisms. On one
hand, it could be considered a normal phenomenon, as the training
response to aerobic exercises is also highly variable, even in healthy
individuals13. It could also be related to insufficient training volume and
to poor observance to the exercise prescription. An emerging finding is
that the muscle response to exercise training appears to differ between
patients with COPD and healthy subjects, with different responses,
notable found at the oxidative metabolism, oxidative stress, and protein
degradation levels14,15,16. It is too early to tell about the clinical significance
of these biochemical findings, but this topic will be interesting to follow
in the upcoming years.
Considering the observation that the response to exercise training may

be suboptimal in COPD, a number of investigators have evaluated
differentexercise training adjuncts and strategies with the hope that they
will be able to allow patients to derive more benefit from pulmonary
rehabilitation. Among these, anabolic drugs17, interval training oxygen
therapy5, one‐legged cycling exercises18, oxygen alone19 or in mixture with
helium20, non‐invasive ventilation21 and eccentric exercise22 have all been
proposed to enhance the tolerance to exercise training in COPD.
Despite all the positive findings about pulmonary rehabilitation, it

remains that only a small portions of patient undertake this therapeutic
modality. One important challenge will be to ensure that a larger fraction
of the COPD population actually accesses it. One way to do this is to bring
pulmonary rehabilitation closer to the community or even the home.
Recent published experience suggests that, in a structured setting,
pulmonary rehabilitation performed in the home can be as effective as
the traditional outpatient rehabilitation program23.
In conclusion, the scientific foundations of exercise training in COPD have

been laid out24. Exercise training is the best approach to improve
2
functional status and dyspnea in patients with COPD. Remaining
challenges include finding ways to improve the response to exercise
training in this population and to improve accessibility.
References
1. Petty TL, Nett LM, Finigan MM, Brink GA, Corsello PR. A
comprehensive care program for chronic airway obstruction.
Methods and preliminary evaluation of symtomatic and functional
improvement. Ann Intern Med 1969;70:1109‐1120.
2. Casaburi R, Patessio A, Ioli F, Zanaboni S, Donner CF, Wasserman K.
Reductions in exercise lactic acidosis and ventilation as a result of
exercise training in patients with obstructive lung disease. American
Review of Respiratory Disease 1991;143:9‐18.
3. Maltais F, Leblanc P, Simard C, Jobin J, Bérubé C, Bruneau J, Carrier L,
Belleau R. Skeletal muscle adaptation to endurance training in
patients with chronic obstructive pulmonary disease. American
Journal of Respiratory and Critical Care Medicine 1996;154:442‐447.
4. Sala E, Roca J, Marrades RM, Alonso J, Gonzalez de Suso JM, Moreno A,
Barbera JA, Nadal J, de Jover L, Rodriguez‐Roisin R, Wagner PD.
Effects of endurance training on skeletal muscle bioenergetics in
chronic obstructive pulmonary disease. American Journal of
Respiratory and Critical Care Medicine 1999;159:1726‐1734.
5. Vogiatzis I, Terzis G, Nanas S, Stratakos G, Simoes DC, Georgiadou O,
Zakynthinos S, Roussos C. Skeletal muscle adaptations to interval
training in patients with advanced copd. Chest 2005;128:3838‐3845.
6. Bernard S, Whittom F, Leblanc P, Jobin J, Belleau R, Bérubé C, Carrier
G, Maltais F. Aerobic and strength training in patients with copd.
American Journal of Respiratory and Critical Care Medicine
1999;159:896‐901.
7. Mador MJ, Bozkanat E, Aggarwal A, Shaffer M, Kufel TJ. Endurance
and strength training in patients with copd. Chest 2004;125:2036‐
2045.
8. Ortega F, Toral J, Cejudo P, Villagomez R, S†nchez H, Castillo J,
Montemayor T. Comparison of effects of strength and endurance
training in patients with chronic obstructive pulmonary disease.
American Journal of Respiratory and Critical Care Medicine 2002;166
669‐674.
9. Lacasse Y, Goldstein R, Lasserson TJ, Martin S. Pulmonary
rehabilitation for chronic obstructive pulmonary disease. Cochrane
Database Syst Rev 2006:CD003793.
10. Garcia‐Aymerich J, Lange P, Benet M, Schnohr P, Anto JM. Regular
physical activity modifies smoking‐related lung function decline and
reduces risk of chronic obstructive pulmonary disease: A population‐
based cohort study. American journal of respiratory and critical care
medicine 2007;175:458‐463.
3
11. Stav D, Raz M, Shpirer I. Three years of pulmonary rehabilitation:
Inhibit the decline in airflow obstruction, improves exercise
endurance time, and body‐mass index, in chronic obstructive
pulmonary disease. BMC pulmonary medicine 2009;9:26.
12. Troosters T, Gosselink R, Decramer M. Exercise training in copd:
How to distinguish responders from nonresponders. J Cardiopulm
Rehabil 2001;21:10‐17.
13. Bouchard C, An P, Rice T, Skinner JS, Wilmore JH, Gagnon J, Perusse L,
Leon AS, Rao DC. Familial aggregation of vo(2max) response to
exercise training: Results from the heritage family study. Journal of
applied physiology 1999;87:1003‐1008.
14. Rabinovich RA, Ardite E, Troosters T, Carbo N, Alonso J, Gonzalez de
Suso JM, Vilaro J, Barbera JA, Polo MF, Argiles JM, Fernandez‐Checa JC,
Roca J. Reduced muscle redox capacity after endurance training in
patients with chronic obstructive pulmonary disease. Am J Respir Crit
Care Med 2001;164:1114‐1118.
15. Rabinovich RA, Ardite E, Mayer AM, Polo MF, Vilaro J, Argiles JM,
Roca J. Training depletes muscle glutathione in patients with chronic
obstructive pulmonary disease and low body mass index. Respiration
2006;73:757‐761.
16. Radom‐Aizik S, Kaminski N, Hayek S, Halkin H, Cooper DM, Ben‐Dov I.
Effects of exercise training on quadriceps muscle gene expression in
chronic obstructive pulmonary disease. J Appl Physiol
2007;102:1976‐1984.
17. Casaburi R, Bhasin S, Cosentino L, Porszasz J, Somfay A, Lewis MI,
Fournier M, Storer TW. Effects of testosterone and resistance
training in men with chronic obstructive pulmonary disease.
American Journal of Respiratory and Critical Care Medicine 2004;170
870‐878.
18. Dolmage TE, Goldstein RS. Effects of one‐legged exercise training of
patients with copd. Chest 2008;133:370‐376.
19. Emtner M, Porszasz J, Burns M, Somfay A, Casaburi R. Benefits of
supplemental oxygen in exercise training in nonhypoxemic chronic
obstructive pulmonary disease patients. American Journal of
Respiratory and Critical Care Medicine 2003;168 1034‐1042.
20. Eves ND, Sandmeyer LC, Wong EY, Jones LW, MacDonald GF, Ford GT,
Petersen SR, Bibeau MD, Jones RL. Helium‐hyperoxia: A novel
intervention to improve the benefits of pulmonary rehabilitation for
patients with copd. Chest 2009;135:609‐618.
21. Ambrosino N, Strambi S. New strategies to improve exercise
tolerance in chronic obstructive pulmonary disease. European
Respiratory Journal 2004;24:313‐322.
22. Rocha Vieira DS, Baril J, Richard R, Perrault H, Bourbeau J, Taivassalo
T. Eccentric cycle exercise in severe copd: Feasibility of application.
COPD 2011;8:270‐274.
4
23. Maltais F, Bourbeau J, Shapiro S, Lacasse Y, Perrault H, Baltzan M,
Hernandez P, Rouleau M, Julien M, Parenteau S, Paradis B, Levy RD,
Camp P, Lecours R, Audet R, Hutton B, Penrod JR, Picard D, Bernard S.
Effects of home‐based pulmonary rehabilitation in patients with
chronic obstructive pulmonary disease: A randomized trial. Ann
Intern Med 2008;149:869‐878.
24. Casaburi R, ZuWallack R. Pulmonary rehabilitation for management
of chronic obstructive pulmonary disease. N Engl J Med
2009;360:1329‐1335.
5
ATS 2012- San Francisco
New science in the comprehensive
management of the COPD patient
Advances in the science of exercise

training for COPD patients
François Maltais
Centre de Pneumologie
IUCPQ
Québec, Canada
Disclosure
 Personal financial relationships with commercial
interests relevant to medicine, within past 3 years:
 Personal financial support from a non-commercial
source relevant to medicine, within past 3 years:
 Personal relationships with tobacco industry entities
within the past 3 years:
No relationships to disclose in relation to

this presentation.
Objectives
 Review the mechanisms of action of

exercise training in COPD.
 Discuss physiological and clinical benefits
of exercise training in COPD.
 Discuss the adjuncts to exercise training
modalities in COPD.
1
How can an intervention that does not
improve pulmonary function enhance
exercise tolerance in COPD?
Mechanisms of action
Casaburi and Zuwallack NEJM 2009;360:1329-1335.
Locus of symptom limitation
43%
Leg fatigue
Dyspnea and 31%
leg fatigue
Dyspnea
26%
Killian et al. ARRD 1992; 146: 935-940.
2
Susceptibility to fatigue
110
Unpotentiated Twitch Force
100
(Percentage of Baeline)
90
80
*
70 * *†
60
50 Healthy elderly
COPD
0
Baseline10 min 30 min 60 min
Post Exercise
Mador et al. Chest 2003;123:1104-1111.
Metabolic stress during cycling
Saey, Lemire et al. JAP 2011;110:116-124.
Muscle fatigue during cycling
COPD CONTROLS COPD CONTROLS

0 0
-5 -5
-10 -10
-15
% fall MVC
-15
% fall MVC
-20 -20
-25 -25
-30 -30
-35 -35
-40 -40
COPD are athletes in their daily life!

Saey, Lemire et al. JAP 2011;110:116-124.
3
Fiber-typing
Normal COPD
I I
100 m 100  m
Whittom et al. MSSE 1998; 30 1467-1474.
Poor oxidative capacity

CS HADH
60 10
50 8
(µmol/min/g)
40 6
30 4
*
*
20 2
10 0
N COPD N COPD * p < 0,0005
Maltais et al. AJRCCM 1996; 154: 442-7.
Muscle weakness in COPD

COPD
Strength (kg)
Controls
* *
100
*
80
60
40
20
Quadriceps Pectoralis Latissimus

major dorsi
Bernard et al. AJRCCM 1998; 158: 629-634.
4
10
9
8 Very strong
Leg fatigue 7
(Borg) Very weak
6
5
4
3
2
1 Controls
0.5 Pulmonary
0
0 400 800 1200 1600
Work (kpm/min)
Hamilton et al. AJRCCM 1995; 152: 2021-2031.
Reductions in Exercise Lactic Acidosis and Ventilation

as a Result of Exercise Training in Patients with
Obstructive Pulmonary Disease1-3
RICHARD CASABURI, ANTONIO PATESSIO, FRANCO IOLI, SYLVIO ZANABONI,

CLAUDIO F. DONNER, KARLMAN WASSERMAN
American Review of Respiratory Disease 1991;143: 9-18.
High intensity Low intensity

Heart Rate
Heart Rate
Lactate
Lactate
VE/VO2
VE/VO2
. .
VCO2
VCO2
VO2
VO2
% Change . . . . .
VE
VE
. . .
0 0
-10 -10
-20 -20
-30 -30
Casaburi et al. ARRD 1991;143:9-18.
5
Muscle adaptation to exercise
CS HADH
35 12
10
30
8
*
(µmol/min/g)
*
25 6
4
20
2
* p < 0.05 * p < 0.01

15 0
PRE POST PRE POST
Maltais et al. AJRCCM 1996; 154: 442-7.
Anabolic effects of exercise training
A IGF-1 B MGF-1 C MyoD

5 5 5
MGF-1 / GAPDH mRNA expression
MyoD / GAPDH mRNA expression

IGF-1 / GAPDH mRNA expression
4 4 4
3 3 3
*
2
* 2 2
*
1 1 1
0 0 0
Pre Post Pre Post Pre Post

training training training training training training
Vogiatzis et al. Thorax 2007; 62: 950-956.
Muscle adaptation across disease

severity
Vogiatzis et al. Chest 2011; 140: 744-752.
6
Muscle adaptation to exercise
15
30 Endurance
Endurance + strength
% change with training
*
* 25
10 20 *
15
5 10
0 0
Mid-thigh CSA Quadriceps Pectoralis Latissimus
major dorsi
Bernard et al. AJRCCM 1999;159: 896-901.
Exercise to treat muscle impairment
100
Twitch force (% baseline)
*
*
90 *
80
70
60
Pre rehabilitation
50
Post rehabilitation
Baseline10 min 30 min 60 min

Post exercise
Mador et al. AJRCCM 2001;163:930-935.
Exercise to reduce ventilatory

requirements
Better muscle function Ventilatory

limitation
Ventilation
↓ lactate
less acidosis
Ventilatory
 requirements
↓ ventilation
Activity level
Casaburi. Principles and practice of pulmonary rehabilitation, 1993.
7
Exercise to treat dynamic hyperinflation
IC at standardized WR
4
3 *
0
Pre Post
Gigliotti et al. Chest 2003;123:1794-1802.
Reduced symptom perception
6 6
Breathlessness (Borg)
Pre-EXT
Pre-EXT
Leg Effort (Borg)
5 5
4 4
3 3
Post-EXT
2 2
Post-EXT
1 1
0 0
0 20 40 60 80 100 0 20 40 60 80 100
.
VO2 (%predicted)
O'Donnell et al. AJRCCM 1995; 152: 2005-2013.
Other potential benefits of exercise

training
8
Activity level, hospitalisation and mortality
1.00
hospitalized
Not being
0.75 High
Moderate
0.50 Low
Very low
0.25
0.00
0 5 10 15 20
1.00
Surviving
0.75
0.50
High
Moderate
0.25 Low
Very low
0.00
0 5 10 15 20
Years
Garcia-Aymerich et al. Thorax 2006;61:772-778.
Exercise training and daily activity

#
60
% change in walking
50
time in daily life
40
30
20
10
0
3 months 6 months
Pitta et al. Chest 2008;134: 273-280.
Excercise and mortality

Cumulative survival probability
1.0
Superior tercile
Physical activity
0.5
+ 10 ml/yr of FEV1
0.0
20 25 30 35
Years of follow-up Pelkonen et al. AJRCCM 2003;168:494-499.
9
Exercise and FEV1 decline
21 ml/yr between
low and high
physical activity
levels
Garcia-Aymerich et al. AJRCCM 2007;175:458-463.
Pulmonary rehabilitation and decline

in FEV1
1500
1300
FEV1 ml
1100
900
700
0 6 12 18 24 30 36
Months
Stav D et al. BMC Pulm Med 2009;9:26.
Can/should we do better?
10
« Responders » versus « non-responders »
Response: 6 MWD 25% or  IET 10 watts Troosters et al. JCR 2001;21:10-17.
Non-response to rehabilitation
 It may be a normal phenomenon,

unrelated to COPD.
 Insufficient training volume.
 Poor observance.
 Deleterious effects of training?
Possible deleterious effects of training
GSH (nmol/mg prot) GSSG (nmol/mg prot)

12 3.0 p = 0.05
p = 0.01 2.5
10 2.0
8 1.5
6 1.0
4 0.5
2 0.0
Pre- Post- Pre- Post- Pre- Post- Pre- Post-
training training training training training training training training
COPD Healthy COPD Healthy
GSSG/GSH  N  in COPD
Rabinovich et al. AJRCCM 2001; 164: 1114-1118.
11
Possible deleterious effects of training
*
*
∆GSH post-pre training
5
(nmol/mg protein)
7
BMIL BMIN Controls
Rabinovich et al. Respiration 2006; 73: 757-761.
The response to exercise training is

different in COPD
 Expression in both groups
 Expression in both groups
 Expression only in healthy controls
 Expression only in COPD
Oxidative stress
Uquitination
COX
Radom-Aizik et al. JAP 2007; 102: 1976-1984.
Fatigue and training response
Burtin et al. ERJ 2011. In press.
12
Tools to increase the response rate
 Anabolic drugs
 Interval training
 One-legged training
 Oxygen/Heliox
 NIV
 Eccentric exercises
Anabolic treatment
‡ *
Lean leg
Mass kg
1 ‡
2.3 3.3
0
Lean body
4 *
Mass kg
3 *
2
1
0
No training Strength training
Casaburi et al. AJRCCM 2004;170:870-878.
Interval training
160 120
peak))
(%peak
100
peak))
(%peak
120
Dyspnea (%
80
WR (%
60
80
40
40 20
peak))
(%peak
120
110
100
Leg discomfort (%
peak))
100
(%peak
80
ƒc (%
90
60
80 40
70 20
0 5 10 15 20 25 30 0 5 10 15 20 25 30
Training sessions Training sessions
Vogiatzis et al. Chest 2005;128:3838-3845.
13
Interval training
2.00
*
to--fiber ratio
1.50 *
Capillary--to
1.00
Capillary
Pre Post Pre Post

0.50
0.00
Interval training Constant-load exercise
Vogiatzis et al. Chest 2005;128:38383845.
One-legged cycling exercise training
Domage et al. Chest 2008;129:370-376.
Oxygen supplementation during training
70
60
Work Rate (Watt)
50
40
30
20
0 5 10 15 20
Training Sessions
Emtner et al. AJRCCM 2003;168:1034-1042.
14
Heliox and exercise in COPD
Eves et al. Chest 2009;135:609-618.
Oxidative stress and endurance
60
40
20
20
40
0 100 200 300 400 500 600
Quadriceps endurance time (seconds)
Couillard et al. AJRCCM 2003;167:1664-1669.
Oxidative stress and endurance
* ..
Time limit (seconds)
350
300
250 .. ..
200
150
100
.. .
50
0
Placebo NAC
Koechlin et al. AJRCCM 2004;169:1022-1027.
15
Conclusions
 A solid physiological rationale for the
use of exercise training in COPD has
been established.
 Exercise training may positively impact
of important predictors of mortality in
COPD.
 Works is currently undergoing to further
optimize these already positive effects
of exercise training in COPD.
16
Physical Inactivity In Chronic Obstructive
Richard Casaburi, MD, PhD
9:40 am - 10:05 am
Physical Inactivity in Chronic Obstructive Pulmonary Disease
Richard Casaburi, PhD, MD
Updated from: Casaburi, R. Activity promotion: a paradigm shift for COPD therapeutics.
Proc. Amer. Thoracic Soc. 8:334-337,2011.
When we evaluate the effectiveness of current chronic obstructive pulmonary

disease (COPD) therapies, it is helpful to look at the progress that has been made in
recent years. From the point of view of the GOLD guidelines(1) for the goals of COPD
therapies, we may consider the glass to be half full or half empty. Half full because our
currently available pharmacologic therapies have been clearly shown to decrease
dyspnea, improve exercise tolerance, decrease exacerbations and improve quality of life.
The past decade has seen great advances in documenting these benefits. We can take
justifiable pride in demonstrating these benefits; they yield appreciable relief of the
suffering that COPD patients endure.
But the glass certainly can be considered half empty. Specifically, little progress
has been made in demonstrating that our therapies modify disease time course or
decrease mortality. For the vast majority of COPD patients, only smoking cessation has
been conclusively proven to yield these benefits(2). Where might we expect our next
breakthrough in COPD therapeutics? While we all wish for a cure, no therapy on the
near horizon seems to promise this. Among the plausible possibilities for more modest
but potentially important benefit:
 An improved bronchodilator
 A novel anti-inflammatory
 A new way to reduce exacerbations
 An alveolar growth factor
 Stem cell therapy
Although these are all attractive approaches (and are all worth pursuing), it may require a
paradigm change to identify our next major focus of therapy.
Consider our current conception of the pathway by which the basic

pathophysiologic feature of expiratory airflow limitation translates into major morbidity
and mortality in COPD. Expiratory airflow limitation’s major consequence is its
propensity to induce dynamic hyperinflation during activity. This yields increased elastic
work of breathing; chest wall deformation induces neural discharge that results in
dyspnea on exertion(3). Quite naturally, discomfort associated with exertion leads to
reluctance to perform such activities. Exacerbations have been shown to lead to
worsening of airflow obstruction and dyspnea and to result in long-lasting activity
reduction(4). Further, a downward spiral has been conceptualized in which inactivity
leads to disuse atrophy of the muscles of ambulation, yielding substantial muscle
dysfunction that further exacerbates the tendency for exertion to cause dyspnea. These
changes reduce the ability of COPD patients to perform everyday activities leading to a
reduced quality of life and are felt to lead to substantial long-term morbidity and
mortality.
A number of our therapeutic interventions can be seen to be aimed at
interrupting this downward spiral. Bronchodilators reduce dynamic hyperinflation and
thereby enhance exercise tolerance(5). A range of strategies capable of reducing COPD
exacerbation frequency has been identified(6). Pulmonary rehabilitation has been shown
to appreciably reduce dysfunction of the muscles of ambulation, rendering them more fit
for both endurance and strength activities(7).
Documentation of the prevalence and degree of inactivity in COPD patients has

started to emerge. Troosters et al. used activity monitoring to document that, compared
to an age matched control group, stage I COPD patients spend only half the time and
stage IV patients spent only a quarter of the time being moderate active(8). Watz et al.
reported qualitatively similar results(9). The finding that activity levels are reduced in
conjunction with mild airflow limitation, a level that would not be predicted to lead to
ventilatory limitation to exercise in most patients(10), is especially intriguing: are COPD
patients inactive for reasons other than their lung disease?
That COPD patients are inactive may have serious prognostic consequences.
Inactivity has been associated with higher mortality in non-COPD groups; data on COPD
patients has started to emerge. For example, a study of 225 patients with peripheral
arterial disease showed that, based on activity monitoring, the hazard ratio for 5-year
mortality was over threefold greater in those in the lowest activity level quartile
compared to the highest quartile(11). Among 302 high-functioning older adults (average
age of 75 years), energy expenditure determined by doubly-labeled water was strongly
predictive of 6 year mortality(12). In COPD, studies have yet to appear in which
sophisticated methods of determining activity have been used in long-term studies of
prognosis. Two studies, both in Danish cohorts, in which simple activity questionnaires
were employed, are of interest. Garcia-Aymerich et al. found that 10-year survival was
roughly 75% among COPD patients who rated their activity level as high, as compared
with 45% among those who rated their activity level as very low(13). Ringbaek et al.
reported that COPD patients receiving long-term oxygen therapy had a 4-year survival of
35% if they reported regular outdoor activity but a dismal survival of 18% if they had no
regular outdoor activity(14). Most recently, a prospective study of a cohort of 170 COPD
patients has employed activity monitoring to demonstrate that physical activity level
showed the best discriminative properties for 4-year survival (14a)
For many years it has been appreciated that, in cross-sectional studies, subjects
with better exercise tolerance have better long-term outcomes(15). As a result,
improving exercise tolerance has been seen as an important goal although we generally
have lacked long-term interventional studies that prove that increasing exercise tolerance
improves prognosis. Clearly, better exercise tolerance correlates with better long-term
outcomes. But, the data cited above demonstrates that higher activity levels also
correlate with better long-term outcomes. Since those with higher exercise tolerance also
tend to have higher activity levels, cross-sectional studies cannot determine which of the
two variables is causative. A study that provides some insight into these interrelations is
a post-hoc analysis of the results of the National Emphysema Treatment Trial
(NETT)(16). In 597 emphysema subjects not assigned to volume-reduction surgery,
2
exercise tolerance was assessed by both 6 minute walk and peak work rate in an
incremental test, activity level was assessed by a questionnaire and the long-term
outcome was exacerbation hospitalization rate. Interestingly, exercise tolerance was not
significantly correlated to activity level (r=0.02), allowing separation of the influence of
activity level and exercise tolerance. In this cohort, activity level was a significant
predictor of hospitalization exacerbation (p<0.01) while exercise tolerance was not.
Why would exercise tolerance not be closely linked to activities of everyday

living? Clearly a good exercise tolerance is permissive of activity, but it does not
mandate higher activity levels. Troosters has pointed out that, besides exercise capacity,
activity level is determined by a complex set of factors including health beliefs,
personality characteristics, exercise-associated symptoms, mood, past behaviors, and
social and cultural factors (personal communication). In other words, activity level has a
strong behavioral component.
The first step in evaluating the determinants of activity level in COPD patients is
developing robust methods of activity assessment.
 Questionnaires have been developed to assess activity, but subjects have been found
to report overestimates of actual activity levels.(17)
 Energy expenditure methods yield estimates of metabolic costs of activity and are,
therefore, highly relevant. Doubly-labeled water yields an estimate of CO2 output
over a period of 1-2 weeks but the methodology is rather expensive and temporal
resolution is limited(18). Portable metabolic measurement systems are capable of
accurate assessment of metabolic rate(19), but the requirement that the subject
breathe through a mouthpiece or facemask makes long-term monitoring impractical.
 Over the first decade of this century, instruments to assess activity have advanced
from mechanical step counters to fully computerized data recorders. Current day
activity monitors generally rely on accelerometry to record “vibrations” associated
with movement(20), although multi-sensor monitors integrate other measurements as
well(21). A number of these monitors are capable of minute-by-minute recordings
over a period of several weeks. Although the goal of having monitors of this sort
provide accurate assessment of the metabolic cost of the full range of everyday
activity is probably unachievable(22), these monitors have proven to be quite useful
in both cross-sectional and interventional studies of activity level.
Do we have evidence that current therapies for COPD increase activity levels? There
is good evidence that, in appropriately selected patients, bronchodilator therapy(23),
supplemental oxygen(24) and pulmonary rehabilitation(7) are all capable of increasing
exercise tolerance. The measures of improvement in exercise tolerance have generally
included both measures of maximal exercise tolerance (e.g., incremental
cardiopulmonary exercise testing, incremental shuttle walk) and endurance exercise
capacity (e.g., constant work rate cardiopulmonary exercise testing, endurance shuttle
walk). Fractional improvement in endurance measures is often greater(25) and may be
more relevant to activities of daily living. But demonstrating that activity in everyday
life is increased by these therapies has yielded less unequivocal evidence of benefit.
3
 Only one report of a placebo-controlled trial of the effect of bronchodilators on
activity level have been published (no effect was detected)(25a). In a placebo
controlled trial of tiotropium given in conjunction with pulmonary rehabilitation,
self-reported participation in physical activities (utilizing a non-validated
questionnaire) tended to increase more in the tiotropium group than in the placebo
group(26).
 For COPD patients who exhibit activity-induced desaturation provision of
lightweight oxygen supplies might be expected to increase frequency and duration
of out-of-door activities. However, two trials utilizing accelerometer activity
monitors failed to demonstrate this(27,27a).
 The effect of pulmonary rehabilitation on activity levels, assessed by activity
monitors, has been reported in nine publications to date(28-36), all in the past
decade (Table 1). It can be seen that some of these studies have features that
might be suboptimal: several studies have small sample sizes; several have
periods of activity monitoring that are less than the 7 days hypothesized to be
necessary for accurate assessment(37). It might be considered disappointing that
a consistent message does not emerge from these studies: 4 have demonstrated
significant increases in activity level after pulmonary rehabilitation; 5 have not.
None of the study characteristics listed in the Table seem to explain these
differences.
It is notable that the studies of interventions designed to increase activity levels in

COPD have not featured long-term follow-up. Durability of activity improvement
resulting from physical activity interventions has been hard to achieve in older adults(38).
Especially in the case of pulmonary rehabilitation, there is reason to question whether
short-term increases in activity levels will persist in most participants unless the program
features a formal long-term component.
If activity promotion is to be a major goal for COPD patients, a major rethinking of

our therapeutic strategies will be required. Pulmonary rehabilitation seems like a good
place to start: behavior modification has always been at least an informal part of such
programs. Activity promotion might be seen as a co-primary goal along with exercise
capacity enhancement. Scientifically-based strategies for activity promotion might be
incorporated, much as they are for exercise capacity enhancement. It seems entirely
plausible that the exercise tolerance enhancing potential of bronchodilators or of
ambulatory oxygen therapy will not translate into increased activity in everyday life in
the majority of COPD patients. In particular, it might be considered that, if a goal of
ambulatory long-term oxygen therapy is to promote activity, it might be considered
worthwhile only if delivered in conjunction with an activity enhancement intervention.
Whether pulmonary rehabilitation programs could be adapted to this purpose requires
investigation.
4
Physical Inactivity in Chronic Obstructive Pulmonary Disease
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16. Benzo RP, Chang CC, Farrell MH, Kaplan R, Ries A, Martinez FJ, Wise R, Make
B, Sciurba F. Physical activity, health status and risk of hospitalization in patients with
severe chronic obstructive pulmonary disease. Respiration 2010;80:10-18.
17. Pitta F, Troosters T, Probst VS, Spruit MA, Decramer M, Gosselink R.
Quantifying physical activity in daily life with questionnaires and motion sensors in
copd. Eur Respir J 2006;27:1040-1055.
18. Speakman JR. The history and theory of the doubly labeled water technique. Am J
Clin Nutr 1998;68:932S-938S.
19. Meyer T, Davison RC, Kindermann W. Ambulatory gas exchange measurements-
-current status and future options. Int J Sports Med 2005;26 Suppl 1:S19-27.
20. Chen KY, Bassett DR, Jr. The technology of accelerometry-based activity
monitors: Current and future. Med Sci Sports Exerc 2005;37:S490-500.
21. Hill K, Dolmage TE, Woon L, Goldstein R, Brooks D. Measurement properties of
the sensewear armband in adults with chronic obstructive pulmonary disease.
Thorax;65:486-491.
22. Kozey SL, Lyden K, Howe CA, Staudenmayer JW, Freedson PS. Accelerometer
output and met values of common physical activities. Med Sci Sports Exerc
2010;42:1776-1784.
23. Aguilaniu B. Impact of bronchodilator therapy on exercise tolerance in COPD. Int
J Chron Obstruct Pulmon Dis;5:57-71.
24. Bradley JM, Lasserson T, Elborn S, Macmahon J, O'Neill B. A systematic review
of randomized controlled trials examining the short-term benefit of ambulatory oxygen in
COPD. Chest 2007;131:278-285.
25. Oga T, Nishimura K, Tsukino M, Hajiro T, Ikeda A, Izumi T. The effects of
oxitropium bromide on exercise performance in patients with stable chronic obstructive
pulmonary disease. A comparison of three different exercise tests. Am J Respir Crit Care
Med 2000;161:1897-1901.
25a. O’Donnell DE, Casaburi R, Vincken W, Puente-Maestu L, Swales J, Lawrence
D, Kramer B on behalf of the INABLE 1 study investigators. Effect of indacaterol on
exercise endurance and lung hyperinflation in COPD. Respir. Med. 2011;105:1030-
1036.
26. Kesten S, Casaburi R, Kukafka D, Cooper CB. Improvement in self-reported
exercise participation with the combination of tiotropium and rehabilitative exercise
training in COPD patients. Int J Chron Obstruct Pulmon Dis 2008;3:127-136.
27. Sandland CJ, Morgan MD, Singh SJ. Patterns of domestic activity and ambulatory
oxygen usage in COPD. Chest 2008;134:753-760.
27a. Casaburi R, Porszasz J, Hecht A, Tiep B, et al. for the COPD Clinical Research
Network. Influence of lightweight ambulatory oxygen on oxygen use and activity
patterns of COPD patients receiving long-term oxygen therapy. J. COPD 2012;9:3-11.
2
28. Coronado M, Janssens JP, de Muralt B, Terrier P, Schutz Y, Fitting JW. Walking
activity measured by accelerometry during respiratory rehabilitation. J Cardiopulm
Rehabil 2003;23:357-364.
29. Steele BG, Belza B, Hunziker J, Holt L, Legro M, Coppersmith J, Buchner D,
Lakshminaryan S. Monitoring daily activity during pulmonary rehabilitation using a
triaxial accelerometer. J Cardiopulm Rehabil 2003;23:139-142.
30. Sewell L, Singh SJ, Williams JE, Collier R, Morgan MD. Can individualized
rehabilitation improve functional independence in elderly patients with COPD? Chest
2005;128:1194-1200.
31. Mercken EM, Hageman GJ, Schols AM, Akkermans MA, Bast A, Wouters EF.
Rehabilitation decreases exercise-induced oxidative stress in chronic obstructive
pulmonary disease. Am J Respir Crit Care Med 2005;172:994-1001.
32. Pitta F, Troosters T, Probst VS, Langer D, Decramer M, Gosselink R. Are
patients with COPD more active after pulmonary rehabilitation? Chest 2008;134:273-
280.
33. Walker PP, Burnett A, Flavahan PW, Calverley PM. Lower limb activity and its
determinants in COPD. Thorax 2008;63:683-689.
34. Steele BG, Belza B, Cain KC, Coppersmith J, Lakshminarayan S, Howard J,
Haselkorn JK. A randomized clinical trial of an activity and exercise adherence
intervention in chronic pulmonary disease. Arch Phys Med Rehabil 2008;89:404-412.
35. Dallas MI, McCusker C, Haggerty MC, Rochester CL, Zuwallack R. Using
pedometers to monitor walking activity in outcome assessment for pulmonary
rehabilitation. Chron Respir Dis 2009;6:217-224.
36. Mador MJ, Patel AN, Nadler J. Effects of pulmonary rehabilitation on activity
levels in patients with chronic obstructive pulmonary disease. J Cardiopulm Rehabil Prev
2010.
37. Hecht A, Ma S, Porszasz J, Casaburi R. Methodology for using long-term
accelerometry monitoring to describe daily activity patterns in COPD. COPD
2009;6:121-129.
38. van der Bij AK, Laurant MG, Wensing M. Effectiveness of physical activity
interventions for older adults: A review. Am J Prev Med 2002;22:120-133.
39. Pitta F, Troosters T, Spruit MA, Decramer M, Gosselink R. Activity monitoring
for assessment of physical activities in daily life in patients with chronic obstructive
pulmonary disease. Arch Phys Med Rehabil 2005;86:1979-1985.
3
4/4/2012
Physical Inactivity in COPD

Los Angeles Biomedical Research
Institute at Harbor-UCLA Medical Center
Torrance, California, USA
Physical Inactivity in COPD

Los Angeles Biomedical Research
Institute at Harbor-UCLA Medical Center
Torrance, California, USA
No Conflicts of Interest to Declare
Clinical Course of COPD

COPD
COPD
Expiratory Flow Limitation
Air Trapping
Exacerbations Hyperinflation
Breathlessness
Deconditioning Inactivity
Reduced Exercise
Capacity
Poor Health-Related Quality of Life
Disability Disease progression Death
1
4/4/2012

COPD
COPD
Air Trapping
Breathlessness
Reduced Exercise
Capacity

COPD
COPD
Air Trapping
Breathlessness
Reduced Exercise
Capacity
Skeletal Muscle Dysfunction in

COPD
Lactate Increase
• Low muscle mass During Exercise
• Poor capillarity
• Low muscle oxidative enzyme
activity
• Low fraction of type I fibers
• Muscle inflammation
• Corticosteroid myopathy
• Low levels of anabolic
hormones Thorax, 2010
• Vasoregulatory abnormalities VO2 (L/min)
Maltais F, et al. Am J Respir Crit Care Med. 1996;153:288-293.
2
4/4/2012
Skeletal Muscle Dysfunction in

COPD
Lactate Increase
• Low muscle mass During Exercise
• Poor capillarity
• Low muscle oxidative enzyme
activity
• Low fraction of type I fibers
• Muscle inflammation
• Corticosteroid myopathy
• Low levels of anabolic
hormones Thorax, 2010
• Vasoregulatory abnormalities VO2 (L/min)
Maltais F, et al. Am J Respir Crit Care Med. 1996;153:288-293.

COPD
COPD
Air Trapping
Breathlessness
Reduced Exercise
Capacity

COPD
COPD
Air Trapping
Breathlessness
Reduced Exercise
Capacity
3
4/4/2012
COPD Patients are Inactive

Physical inactivity in patients with COPD, a
controlled multi-center pilot-study
Troosters T, F Sciurba, S Battaglia, D Langer, S Rao Valluri, L
Martino, R Benzo, D Andre, I Weisman,M Decramer
70 COPD and 30 normal subjects

wore a Sensewear Armband activity
monitor continuously for 6-8 days
Respir Med, 2010

Physical inactivity in patients with COPD, a controlled
multi-center pilot-study
N=100
Troosters et al., Respir. Med., 2010

Physical activity in patients with COPD
H. Watz, B. Waschki, T. Meyer, H. Magnussen
200 smokers, 30 with normal spirometry

and 170 with GOLD I-IV COPD wore a
Sensewear Armband activity monitor
continuously for 8 days
ERJ, 2009
4
4/4/2012


“Stage 0” ERJ, 2009


“Stage 0” ERJ, 2009
Do more active COPD

patients survive longer?
• Garcia-Aymerich et al. Thorax, 2006

– 2386 Danish COPD patients completed
activity questionnaire
– Followed for 12.0±5.9 years for mortality
and other outcomes
5
4/4/2012
Do more active COPD

patients survive longer?
• Ringbaek et al., Clin Rehabil, 2005
– 226 Danish LTOT patients completed
activity questionnaire
– Followed for mean of 8 years for mortality
6
4/4/2012
2011
•170 COPD patients: age 64 y, FEV1=56%predicted

•Activity level recorded by Armband device over 5-6 days
•Median follow-up 4 years; all cause mortality=15.4%
•Predictors of mortality were sought
7
4/4/2012
Significant Predictors of
Mortality
Survivors (143) Non-survivors (26)
FEV1 (%predicted) 58.8 41.4
IC/TLC 34.5 25.2
6 minute walk (m) 450 317
BMI (kg/m2) 26.7 23.5
MMRC dyspnea 2 3
SGRQ 43 54
BODE 2 4
Step count (per day) 6424 3006
Physical activity level 1.55 1.27
Mortality
IC/TLC 34.5 25.2
BMI (kg/m2) 26.7 23.5
MMRC dyspnea 2
Highest 3
SGRQ Independent
43 54
BODE Predictive
2 Value 4
Mortality
IC/TLC 34.5 25.2
BMI (kg/m2) 26.7 23.5
MMRC dyspnea 2
Highest 3
SGRQ Independent
43 54
BODE Predictive
2 Value 4
8
4/4/2012
For many years we’ve

focused on improving
exercise tolerance as an
outcome.
Is it time to shift to activity
promotion?
Better Exercise
Tolerance
Better Long-
Term
Outcomes
(e.g., survival)
Better Exercise
Tolerance
Better Long-
Term
More Active Outcomes
During Daily (e.g., survival)
Life
9
4/4/2012
Better Exercise
Tolerance
Better Long-
Term
Life
Better Exercise
Tolerance ?
Better Long-
Term
More Active ? Outcomes
Life
Better Exercise
Tolerance ?
Better Long-
Term
Life
10
4/4/2012
Better Exercise
Tolerance ?
Is it higher activity level rather
than higher exerciseBetter Long-
tolerance
Term
that yields better long-term
outcomes?
Life
Analysis of the NETT study: one year follow-up

in the non-surgical group
Better Exercise N=597

Tolerance
Better Long-
Term
Life
Benzo et al. Respiration, 2009

6 minute
Better walk
Exercise N=597
Tolerance
Peak work rate
Better Long-
Hospitalization
Term
Activity
During Daily (e.g.,Risk
survival)
Questionnaire
Life
11
4/4/2012

6 minute
Better walk
Exercise N=597
Tolerance
Peak work rate
N.S.
R=0.02 Better Long-

Hospitalization
Term
More Active P<0.01 Outcomes
Activity
survival)
Questionnaire
Life

6 minute
Better walk
Exercise N=597
Tolerance
Peak work rate
Why is activity
N.S. level
Better
from Long-
dissociatedHospitalization
R=0.02
Term
exercise tolerance?
More Active P<0.01 Outcomes
Activity
survival)
Questionnaire
Life
Determinants of physical activity

Pharmacotherapy
Airflow obstruction 'Fear'

personality)
Mood
Dynamic hyperinflation
Pulmonary gas exchange
Respiratory muscles
Symptoms
Body composition Symptoms

Exercise Distress HRQoL
Peripheral muscle tolerance
function Amount of PA
Cardio -vascular Health

function beliefs Self
efficacy
Past
behavior
Socio -cultural
factors
Courtesy of T Troosters
12
4/4/2012

Pharmacotherapy

personality)
Mood
Respiratory muscles
Symptoms
Body composition Symptoms

Exercise Distress HRQoL
Peripheral muscle tolerance
function Amount of PA

function beliefs Self
efficacy
Past
behavior
Socio -cultural
factors

Pharmacotherapy

personality)
Mood
Improved Exercise
Respiratory muscles
Symptoms
Tolerance is Only
Body composition
Exercise
Symptoms
Distress HRQoL
Permissive of Higher
Peripheral muscle
function
tolerance
Amount of PA

function
Acitivity Level beliefs
Past
Self
efficacy
behavior
Socio -cultural
factors
The Paradigm Shift
Focus on strategies to
improve activity levels
in COPD patients
The initial task: develop methods to
accurately assess activity levels
13
4/4/2012
Methods for Activity Assessment

• Questionnaires
• Energy expenditure measures
– Doubly labeled water
– Portable metabolic measurement systems
• Activity monitors
– Pedometers
– Heart rate monitors
– Accelerometers
– Integrated multi-sensor monitors

• Questionnaires -little validation in COPD;
often overestimate activity levels
– Pedometers
– Accelerometers

• Questionnaires
– Pedometers
– Accelerometers
14
4/4/2012

• Questionnaires
– Pedometers
– Accelerometers
Activity Monitoring
Potential Technologic Challenges
• Accelerometers yield a poor reflection of
metabolic cost of activities
• Long duration of monitoring required for accurate
assessment
• Compliance with wearing the monitor affects
activity measures
• The location of the monitor influences readings
• Variability among monitor units can be
appreciable
• Motor vehicle travel influences activity
assessments
15
4/4/2012
Activity Monitoring
Accelerometers are poorly reflective of
• Accelerometers are basically vibration
sensors.
• Accelerometer-based units often calculate
calorie equivalent of activity counts; such
relationships are necessarily unreliable.
• Consider that walking up a slope and walking
on the level yield similar activity counts, but
engender greatly different metabolic costs.
Activity Monitoring
assessment
activity measures
appreciable
assessments
Activity Monitoring
Long duration of monitoring required for
accurate assessment
• Activity varies day to day
• Activity varies within a day
• Weekend activity may be systematically
different from weekday activity
• Knowledge that activity is being
monitored may affect activity level
16
4/4/2012
Activity Monitoring
accurate assessment
• Weekend activity may be systematically
different from weekday activity
Activity Monitoring
accurate assessment
•
1-2 weeks of wearing required
Weekend activity may be systematically
for adequate
different from weekdayassessment
activity
Activity Monitoring
assessment
activity measures
appreciable
assessments
17
4/4/2012
Activity Monitoring
assessment
activity measures
appreciable
assessments
Activity Monitoring
Advances in technology may be
assessment
able to overcome some of these
activity measures
challenges
appreciable
assessments
Activity Monitoring
-How to express outcome?-
• Steps
• Vector Magnitude Unit
• Energy expenditure
• Time spent in activities
• Intensity of activities
18
4/4/2012
Do Current Therapies for COPD

Increase Activity Level?
• Bronchodilators and Anti-
Inflammatory Drugs
• Supplemental Oxygen
• Pulmonary Rehabilitation
Each of These Interventions

Improves Exercise Tolerance

Inflammatory Drugs – only one
published study to date
•90 COPD patients (FEV1=61% pred) were

studied during two 3 week periods in which
they received indacaterol or placebo in
randomized blinded order
•The Armband activity monitor was worn
during the last 5 days of each of the two
periods
Respiratory Medicine, 2011
19
4/4/2012
•90 COPD patients (FEV1=61% pred) were

studied during two 3 week periods in which
they received indacaterol or placebo in
randomized blinded order
•The Armband activity monitor was worn
during the last 5 days of each of the two
periods
Respiratory Medicine, 2011

• Supplemental Oxygen - do
lightweight ambulatory oxygen
supplies improve activity levels?
A Project of the COPD Clinical

Research Network of the NHLBI
J COPD, 2012
20
4/4/2012
Benefits of Ambulatory
Oxygen
While it is supposed that lightweight
oxygen supplies promote activity
and compliance, this has never been
confirmed
Goal: Determine benefits of
lightweight ambulatory oxygen
supplies in COPD patients with
hypoxemia at rest and during
exertion
Project required development of

devices and data analysis for
continuous monitoring of oxygen
use and activity
Oxygen
-Study Plan-
• LTOT patients currently receiving E-cylinders as their
portable oxygen source were recruited
• After a 2-week assessment period, they were
randomized to either continue with E-cylinder use or to
use a lightweight portable supply
• Subjects were monitored over the 6 months following
randomization
– 6 month-long assessments of ambulatory and stationary
oxygen use
– 3 weeks of activity monitoring at 3 and 6 months post-
randomization
21
4/4/2012
Oxygen
-Study Plan-
Lightweight Oxygen
• LTOT patients currently receiving E-cylinders as their
portable
M06D oxygen
carbon source were recruited
fiber
• wrapped aluminum
After a 2-week assessment period, they were
randomized
cylinder - withto either continue with E-cylinder use or to
use a lightweight
regulator = 4 lbs portable supply
• Subjects were monitored over the 6 months following
randomization
– 6 month-long assessments of ambulatory and stationary
oxygen use
– 3 weeks of activity monitoring at 3 and 6 months post-
randomization
Oxygen
-Key Inclusion Criteria-
• Receiving LTOT with E-cylinder
• COPD with FEV1  60% predicted
• Ambulatory
• PaO2  60 torr at screening
After 9 months, only 22 patients had been randomized

out of target of 100; study stopped
Oxygen
-Study Population-
Age BMI FEV1% PaO2

(years) (kg/m2) pred (torr)
COPD 66.8 30.1 33.6 51.7

(n=22) ±8.9 ±9.7 ±11 ±6.4
14 men
22
4/4/2012
Oxygen
• Oxygen Use
• Activity Monitoring
Baseline
Average Minutes
of Oxygen Used
per Hour over
the Course of a
Day in 22 COPD
Patients
-14 day average-
Baseline
19.7 hours total Average Minutes
of Oxygen Used
per Hour over
17.2 hours stationary the Course of a
Day in 22 COPD
Patients
2.5 hours ambulatory -14 day average-
23
4/4/2012
Daily Hours of
Oxygen Use at
Baseline and
Over the 6
Months Post-
randomization
in COPD
Patients
Receiving LTOT
Oxygen
• Oxygen Use
• Activity Monitoring
Lightweight O2 E-cylinder O2
Baseline and
Post-
Intervention
Activity Time
Course
(VMU/min) and
Use of Activity
Monitor
(min/hour)
-14 day average-
24
4/4/2012
Oxygen in Hypoxemic COPD
Patients
• In this small sample, provision of
lightweight oxygen supplies was not
associated with significantly increased
activity level or use of ambulatory
oxygen

Inflammatory Drugs
• Supplemental Oxygen
• Pulmonary Rehabilitation
Is activity level increased by

rehabilitation?
Author Year # subjects monitoring device
Coronado 2003 15 1 day uniaxial
Steele 2003 41 5 days triaxial
Sewell 2005 120 2 days uniaxial
Mercken 2005 11 9 days uniaxial
Pitta 2008 29 2-5 days Dynaport
Walker 2008 33 2-3 days uniaxial
Dallas 2009 45 7 days pedometer
Mador 2010 24 7 days triaxial
Breyer 2010 60 3 days Dynaport
25
4/4/2012

rehabilitation?

rehabilitation? Yes No
Activity Promotion in COPD

- Future Directions -
• Further develop and validate activity
monitoring techniques
– Questionnaires
– Devices
26
4/4/2012
PROactive COPD
Public-Private partnership
Courtesy T. Troosters
Confidential T Troosters
PROactive COPD
General Aim :
To develop a patient reported outcome that
captures relevant dimensions of physical
activity and is sensitive to change with
interventions including pharmacotherapy.
PROactive will develop a single PRO that

captures ‘Physical Activity’ much like
other tools capture ‘Quality of life’.
Courtesy T. Troosters
Activity Promotion in COPD

- Future Directions -
• Further develop and validate activity
monitoring techniques
– Questionnaires
– Devices
• Rethink COPD therapeutics
…especially pulmonary rehabilitation…
to optimally promote and maintain
activity
27
Measuring Exercise Performance In
Anne E. Holland, PhD
11:00 am - 11:25 am
Measuring Exercise Performance In
Anne Holland PhD
Why should we measure exercise capacity in COPD?

Reduced exercise performance is a cardinal feature of chronic obstructive pulmonary disease
(COPD). People with COPD frequently present for health care due to breathlessness on
exertion, and the effect of dyspnoea on daily activities is discussed in almost all
consultations. A reduction in peak oxygen uptake (VO2peak) is evident as early as GOLD
stage 2 [1] and exercise performance continues to decline across the stages of disease [2].
People with COPD can detect changes in their exercise performance [3], probably because
reductions in exercise capacity are associated with reduced daily life activity [4]. Measures of
exercise capacity therefore provide important information regarding the impact of COPD on
individuals and their daily lives.
Several authors have shown that exercise performance may be a more sensitive marker of
COPD progression than measures of respiratory function, particularly in those with advanced
disease. In individuals with moderate to very severe COPD who were followed for five years,
the changes in VO2 measured by cardiopulmonary exercise testing were larger than the
decline in FEV1 [5]. Similarly, a five year study found that the rate of decline in 6-minute
walk distance (6MWD) for patients with GOLD stage 4 disease was 15 metres per year,
however the FEV1 did not change significantly over time in this group [6].
Exercise capacity may be particularly sensitive to changes in clinical status because it is a

global assessment that reflects the multi-system nature of COPD. Recently a large study if
1795 individuals with COPD has investigated the determinants of 6MWD [2]. Pulmonary
factors have an influence on functional walking capacity, with significant relationships shown
between 6MWD and a range of pulmonary markers including GOLD stage, extent of
emphysema and the degree of pulmonary hyperinflation. However non-pulmonary factors
were also important, particularly the presence of depression [2]. Other authors report that the
presence of quadriceps weakness is associated with a mean reduction in 6MWD of 30 metres
(95% CI 8-53m), independent of impairment in pulmonary function [7]. Reductions in body
mass index and fat free mass have also been associated with lower 6MWD [8] along with
impaired vitamin D status [9].
Exercise capacity provides a unique insight into prognosis for people with COPD. As the
6MWD decreases there is a clear increase in both hospital admissions related to
exacerbations and death from any cause [10]. A 6MWD threshold of 350 metres appears
clinically useful for predicting both increased risk of mortality and hospitalisation [10, 11].
The five year survival for those with a 6MWD<350 meters has been reported as 39% [11],
dropping to 15% for those with a 6MWD less than 100 meters [12].
Fortunately, there are a number of treatments available that improve exercise capacity for
people with COPD [13]. Both pulmonary rehabilitation [14] and lung volume reduction
surgery [15] result in clinically important improvements in functional exercised capacity.
Exercise endurance improves with chronic administration of tiotropium [16], acute
administration of oxygen [17] and six months of treatment with inhaled corticosteroids [18].
The impact of impaired exercise tolerance on the wellbeing of people with COPD, along with
the capacity of current treatments to modify exercise capacity, provides a strong rationale for
measurement of exercise performance in clinical practice.
How can we measure exercise capacity in COPD?

A number of tests are available to quantify exercise performance in people with COPD. In
this presentation we will consider both laboratory tests (cardiopulmonary exercise testing and
constant work rate tests) and field tests of exercise capacity, particularly the 6-minute walk
test, the incremental shuttle walk test and the endurance shuttle walk test.
Cardiopulmonary exercise test

The cardiopulmonary exercise test (CPET) provides very detailed information about both
exercise capacity and the nature of exercise limitation. It is a maximum, symptom-limited
incremental exercise test, with breath-by-breath monitoring of exhaled gases. The CPET is
most commonly performed on a cycle ergometer, which allows direct measurement of the
amount of work (in Watts) performed during the test. However, a CPET may also be
performed on a treadmill, which may elicit greater oxhaemoglobin desaturation than a cycle
test [19]. This difference may be important if a purpose of the test is to establish the need for
ambulatory oxygen prescription.
The detailed information obtained from a CPET is useful to evaluate the mechanisms of
exercise intolerance [20]. Analysis of physiological responses to exercise may assist in
determining whether exercise is primarily limited by ventilation, or whether cardiac and gas
exchange abnormalities also play a role. Although peripheral muscle is not directly evaluated
during a CPET, recording the symptoms associated with cessation of exercise may provide
some indication of the importance of muscular dysfunction. The peak work rate achieved on
a CPET is very useful for exercise prescription, with current guidelines recommending a
training intensity of 60% of peak work (Wpeak) in order to achieve a physiological training
effect [21]. A CPET also allows the evaluation of detailed physiological responses to
exercise, such as reduction in dynamic hyperinflation with inhaled therapies [22].
It is recommended that the work rate increment for a CPET is selected carefully such that the
duration of exercise is between 8 and 12 minutes [23]. Work rate increments are generally
between 5 and 25 Watts. The choice of work rate increment will influence results of the test,
as greater increments result in a higher Wpeak [24, 25]. However the increment size will not
affect VO2peak, suggesting that this might be a more appropriate measure of exercise
tolerance to follow over time. When the aim of testing is to prescribe exercise intensity for
training based on a percentage of Wpeak, or to evaluate the effects of intervention on work
capacity, a standard work rate increment should be selected.
Although the CPET is still generally considered the ‘gold standard’ test of exercise capacity
in COPD, due to the wealth of information that is generated, there are some limitations to this
test. Firstly, the CPET requires a laboratory with sophisticated equipment and highly trained
staff; these resources may not be available in all settings. It may not be possible to perform a
CPET in some patients with very advanced disease, because of inability to tolerate
incremental exercise, inability to use the cycle ergometer or a baseline oxyhaemoglobin
saturation that is too low to perform the test [23]. It has also been suggested that the usual
outcomes of the CPET (VO2peak, Wpeak) may not be sensitive to change following many
common treatments in COPD, a feature that has led to exploration of other methods to
evaluate changes following clinical interventions.
Constant work rate tests

Constant work rate tests are increasingly utilised to document change in exercise capacity
following treatment in people with COPD. During a constant work rate test, a patient cycles
for as long as possible at 75-85% of the Wpeak they have achieved on a CPET. An exercise
duration of 4 -7 minutes (pre-intervention) is recommended in order to ensure that change can
be demonstrated following treatment [26]. It has previously been shown that administration
of bronchodilator improves endurance time on a constant work rate test by 19% in people
with COPD, despite an absence of significant improvement in VO2peak measured on a CPET
[27]. Endurance time also improves significantly with pulmonary rehabilitation [28] and
acute administration of oxygen [17].
To understand why the constant work rate test is sensitive to change requires an
understanding of the relationship between power output and endurance time, a relationship
that has been explained eloquently elsewhere [20, 26]. Briefly, during a constant work rate
test there is a hyperbolic relationship between power output and endurance time, such that the
higher the work rate, the shorter the endurance time. Treatment results in an upwards shift of
the power-endurance time curve, and the shape of this curve means that only a small shift in
the curve can result in highly significant changes in endurance time.
A key concept is the critical power, which is the highest work rate that can be sustained
indefinitely, as blood lactate reaches a steady state [29]. If the chosen work rate is at or below
the critical power, patients with COPD can continue to exercise indefinitely. If the chosen
work rate is too high, patients can only exercise for a short period and have limited capacity
to improve at followup, as responses fall on the steep portion of the curve. It has been
suggested that work rates of 85% of Wpeak will most reliably deliver the 4-7 minutes of
exercise that is required for a baseline test [26].
The constant work rate test requires that patients undergo a CPET in order to set the
appropriate workload. An interval of at least one hour has been recommended between these
tests if they are performed on the same day [23]. Although the constant work rate test is
sensitive to change, the minimal important difference has not been fully explored. A
difference in endurance time of 1.75 minutes between testing occasions may be clinically
important within an individual [26].
6-minute walk test
The 6-minute walk test is a commonly used exercise test for people with COPD. It is easy to
perform in a clinical setting, requires little equipment and can be tolerated across the clinical
spectrum of disease. Although the 6-minute walk test is a test of functional exercise capacity,
in COPD it has been shown to elicit a peak VO2 similar to that seen on a CPET [30]. The
main outcome is the 6-minute walk distance (6MWD), however other information gained
from this test includes desaturation, duration of continuous walking, symptoms limiting
exercise, and need for walking aids such as a rollator.
The 6-minute walk test requires patients to walk as far as possible in six minutes, along a 30
meter track. Standard operating procedures for the test have been documented [31]. Age, sex,
height, weight, FEV1 and ethnicity are important determinants of an individual’s 6MWD. However,
the published reference equations for the 6-minute walk vary considerably in the predicted distance,
suggesting that reference values may be population-specific.
A number of factors have been shown to influence the 6MWD, including:

 Repeat testing – an increase of 27 meters on subsequent days [32]
 Track shape – 34 meters further on a continuous track compared to a straight track
[33]
 Gait aids – 14 meters further with a rollator (pooled mean difference of 4 studies)
 Treadmill - 102 meters less on a treadmill compared to walking in a hallway [34]
 Supplemental oxygen – 35 meters further when using supplemental oxygen (pooled
mean difference of 7 studies)
These data underscore the importance of standardising the administration of the 6-minute
walk test, including performance of two tests at baseline to control for a learning effect;
consistent track length and layout; consistent use of walking aids and supplemental oxygen;
and ensuring that the best effort has been made by checking the limiting symptoms with the
patient at the conclusion of the test.
It was previously thought that a change in 6MWD of 54 meters was required in order to be
confident that clinical change had occurred [35]. However, more recent estimates of the
minimal important difference are considerably shorter, in the range of 25 – 35 metres [3, 36].
Incremental shuttle walk test

The incremental shuttle walk test (ISWT) is a field test of exercise capacity that is externally
paced, incremental and symptom limited. Patients walk back and forth around two markers at
speeds that are set by a recording and the number of shuttles (10 meters each) is recorded.
The ISWT is a valid measure of exercise capacity in COPD [37]. It is a high intensity test,
eliciting a VO2peak similar to CPET [38]. The ISWT is a strong predictor of survival in
patients who are undergoing pulmonary rehabilitation [39].
Because it is externally paced, the ISWT is thought to be less affected by patient motivation
than the 6-minute walk test. However there is a learning effect on the ISWT, such that two
tests are required at each time point to be confident that the best value has been obtained [40].
One of the great advantages of the ISWT is that it may avoid the ceiling effect seen in self-
paced walking tests and thus may be more responsive to change in patients with better
preserved exercise capacity. The ISWT is therefore suitable for patients across the spectrum
of disease in COPD. Reference values for the ISWT have recently become available [41].
The ISWT is most frequently used as an outcome measure for pulmonary rehabilitation and
guidelines for exercise prescription from the ISWT are available. Clinically important
changes in ISWT for patients undertaking a pulmonary rehabilitation program have been
established. The minimal important difference is 47.5 meters, with a distance of 78.7 meters
representing a more significant benefit [42].
Endurance shuttle walk test

The endurance shuttle walk test (ESWT) involves walking at a speed equivalent to 85% of
predicted VO2 peak, estimated from the ISWT. Patients walk for as long as possible, with
walking distance and time recorded. The ESWT may be more sensitive to change following
pulmonary rehabilitation than the ISWT [43] and is also sensitive to change with
pharmacotherapy [44] and supplemental oxygen [45]. The minimal important difference for
the ESWT following administration of a bronchodilator has been reported as 65 seconds
(95% CI 45-85 seconds) or 95 meters (95% CI 60 – 115 meters).
Unlike the ISWT, a practice test is not required for the ESWT [40]. However, in order to set
an accurate walking speed for the ESWT, two ISWTs must be performed first.
Which exercise test should be used in COPD?

The choice of an exercise test for an individual with COPD will depend on the aims of
testing, as well as local resources and skills.
Detailed examination of the physiological limitations to exercise can only be undertaken with
a CPET, which also provides more monitoring if there are safety concerns. A CPET allows
accurate prescription of exercise training workloads as a percentage of Wpeak. However the
CPET may not be responsive to changes with commonly used therapies in COPD. An
endurance cycle test may be more appropriate for assessing response to treatment, although
patient tolerance to undertaking both CPET and constant work rate testing should be
considered.
The 6-minute walk test is easy to perform and is strongly related to prognosis in COPD, both
of which contribute to its popularity in clinical practice. However, it has significant space
requirements as a 30-meter corridor is required. It appears moderately responsive to
commonly used interventions. However, there are many factors related to both the tester and
the environment that may influence the 6MWD, so strict adherence to a standardised protocol
is required.
Because it is externally paced, the ISWT is less likely to be influenced by either patient
motivation or factors related to the tester. Growing data on its relationship to prognosis and
new definitions of clinically important change suggest that use of the ISWT will continue to
grow. The ESWT provides a very sensitive measure of change following intervention in
COPD, however requires multiple tests in order to establish a workload, which may not be
feasible in some settings.
Conclusions
Measurement of exercise capacity is critical to our understanding of the multi-faceted impact
of COPD on individuals, as well as providing estimation of likely prognosis and documenting
response to therapies. We are fortunate that there are several tests of exercise capacity for
people with COPD that are valid, reliable and responsive to change. Choice of an exercise
test requires careful consideration of the aims of testing.
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Glossary of Terms
6MWD 6-minute walk distance

95% CI 95% confidence interval
COPD chronic obstructive pulmonary disease
CPET cardiopulmonary exercise test
ESWT endurance shuttle walk test
FEV1 forced expiratory volume in one second
ISWT incremental shuttle walk test
VCO2 carbon dioxide production
VE minute ventilation
VO2 oxygen uptake
VO2peak peak oxygen uptake
Wpeak peak workload achieved on a cardiopulmonary exercise test
4/04/2012
Measuring Exercise
Performance in COPD
Anne Holland
Overview
• Why measure exercise
performance?
• Tests of exercise
performance
• Which test should we
choose?
Why measure exercise

performance in COPD?
1. Exercise limitation is a cardinal feature
of COPD
1
4/04/2012
Peak VO2 is reduced as early as

GOLD stage 2
Pinto-Plata et al 2007
Change in exercise capacity

matters to individuals
Holland 2010
Reduced 6MWD reflects decreased

walking time in daily life
Pitta 2005
2
4/04/2012

of COPD
2. Exercise performance is sensitive to
changes in disease state
Decrease in peak VO2 over 5 years

despite stable FEV1
Oga 2005
6MWD may be more sensitive

than FEV1 in severe disease
Casanova 2007
3
4/04/2012

of COPD
3. Exercise capacity reflects the multi-system
nature of COPD
Predictors of lower 6MWD

• Pulmonary
– higher GOLD stage, more emphysema on HRCT
– hyperinflation Spruit 2010
• Non-pulmonary
– quadriceps weakness Seymour 2010
– lower body mass index, fat free mass Rambod 2011
– lower vitamin D Forli 2009
– depression Spruit 2010

of COPD
nature of COPD
4. Exercise capacity predicts prognosis
4
4/04/2012
6-minute walk distance (6MWD)

• 6MWD<350m
– 5 year survival 39% Cote 2008
– Increased likelihood of moderate to severe
exacerbation in the year following rehab Carr 2007
• 6MWD<200m
– Poor outcome following LVRS Szekely 1997
• 6MWD<100m
– 1 year survival 15% Pinto Plata 2004
Mortality and hospitalisation

increase as the 6MWD decreases
Spruit 2012 JAMDA

of COPD
nature of COPD
4. Exercise capacity predicts prognosis
5. Exercise performance changes with therapy
5
4/04/2012
Change in 6MWD with treatment in

randomised controlled trials
Rasekaba 2009
Tests of exercise performance

in COPD
• Cardiopulmonary exercise test
• Constant work rate test
• 6-minute walk test
• Incremental shuttle walk test
• Endurance shuttle walk test
• (Other tests...)

• Maximum, symptom-limited incremental
exercise test
• Most commonly on cycle ergometer
– may use treadmill – more desaturation Hsia 2009
• breath-by-breath monitoring of
cardiopulmonary variables
• evaluate mechanisms of exercise intolerance
• ventilation vs cardiac vs gas exchange vs other
Ferrazza 2009
6
4/04/2012

• Advantages:
– Detailed physiological information obtained
• VO2, VCO2, VE
• peak oxygen uptake (VO2peak)
– Very useful for exercise prescription
• direct measure of peak work (Wpeak)
– Detects physiological response to therapy
• eg decreased hyperinflation with inhaled therapies
– Highly standardised protocols

• Considerations:
– Requires a laboratory, sophisticated equipment
and highly trained staff
– May not be possible in some patients Epstein 1997
– Choice of increment is important
• affects Wpeak, but not VO2 peak Debigare 2000
– Usual outcomes (VO2peak, Wpeak) may not be
responsive to common therapies
Constant work rate test

• Work rate 75-85% of peak on CPET
• Patient cycles for as long as possible (Tlim)
– pre-intervention
duration of
4-7 minutes
is desirable
7
4/04/2012
Constant work rate test –

small changes in peak exercise capacity
can give rise to large changes in Tlim
post
pre
Ferazza 2009
Constant work rate test

• Considerations:
– More responsive to change following
intervention than incremental test
– Minimal important difference (MID)
• ?1.75 minutes Casaburi 2005
– Requires incremental test first, to set workload
– Choice of workload is important in order to show
change Casaburi 2009
6-minute walk test

• Commonly used test in COPD
• Easy to perform in the clinic
– no specialised equipment
• Predicts prognosis
• Main outcome: 6-minute walk distance
• Other information obtained:
– desaturation, duration of continuous walking,
symptoms limiting exercise, need for rollator
8
4/04/2012
6-minute walk test

• Self-paced walking along a 30 meter track
• Aim to walk as far as possible in 6 minutes
• Standard Operating Procedures ATS 2002
• Many and varied

reference values
– population specific
Factors influencing the 6MWD

Repeat testing ↑ 27 meters
Continuous track ↑ 34 meters
Outdoors No difference
Rollator ↑ 14 meters
Treadmill ↓ 102 meters
Supplemental O2 ↑ 35 meters
Standardisation of testing
procedure is important
Standardising the 6MWT

• Standardised instructions
• Two tests at baseline
– best distance recorded
• Consistent use of walking aids and
supplemental oxygen on repeat tests
• Consistent track length and layout
• Ensure best effort – check symptom
limiting test with RPE / Borg
9
4/04/2012
Interpreting change in 6MWD
• Minimum important difference:

– Previously thought a change of 54 m required
Redelmeier 1997
– New estimates considerably shorter:

• Group: 35 metres (95% CI 30–42 meters) Puhan 2008
• Individual: 25 metres (95% CI 20-61 meters) Holland 2010
Incremental shuttle walk test (ISWT)

• Externally paced and incremental
• Symptom limited
• The number of shuttles (10m) is recorded
• ISWT distance related to VO2peakSingh 1994
• Reference values available Probst 2011
Standardising the ISWT

• Two tests needed for reliability McKeough 2011
– Best distance recorded
• Use only standardised instructions on the CD
• No encouragement
• Standardised prompts:
– Each time the beep sounds: "Increase your speed now.”
– If the patient is less than 0.5 m away from the cone when
the beep sounds: “You’re not going fast enough; try to
make up the speed this time.”
10
4/04/2012
Interpreting change in ISWT
Better - 79 meters
Slightly better – 47.5 meters’
No change
Singh 2008’

• Walking speed equivalent to 85% of
predicted VO2peak, estimated from ISWT
• Walking distance and time are recorded
• Minimal important difference following
bronchodilator:
– Time: 65 seconds (95% CI 45-85 sec)
– Distance: 95 meters (95% CI 60–115m)
Pepin 2011

• More sensitive than ISWT to change
following pulmonary rehabilitation Revill 1999
• Sensitive to change with pharmacotherapy
and supplemental oxygen Pepin 2005, Revill 2010
• Does not require a practice test McKeough 2011
– BUT two ISWTs must be performed first, to set
the walking speed
11
4/04/2012
Which exercise test?

Reason 6MWT ISWT ESWT CPET CWR
for test
Diagnosis - - - + -
Safety Ax + + - +++ -
ExRx ++ ++ ++ +++ ++
Responsive ++ ++ +++ + ++++
Cost + + ++ +++ ++++
Medical - - - + -
supervison
Space +++ + + + +
Conclusions
• Measurement of exercise capacity is crucial
to fully understand:
– the multi-faceted impact of COPD on individuals
– likely prognosis
– response to therapy
• Several valid, reliable and responsive tests
– choice depends primarily on aims of testing
– also consider local resources
12
Dyspnea Management For Advanced
Lung Disease
Paula M. Meek, RN, PhD
11:50 am - 12:15 pm
Management Dyspnea in Advanced COPD 2012
Bausewein, C., S. Booth, et al. (2008). "Non-pharmacological interventions for breathlessness in

advanced stages of malignant and non-malignant diseases." Cochrane Database Syst Rev(2):
CD005623.
BACKGROUND: Breathlessness is a common and distressing symptom in the advanced stages
of malignant and non-malignant diseases. Appropriate management requires both pharmacological and
non-pharmacological interventions. OBJECTIVES: The primary objective was to determine the
effectiveness of non-pharmacological and non-invasive interventions to relieve breathlessness in
participants suffering from the five most common conditions causing breathlessness in advanced disease.
SEARCH STRATEGY: We searched the following databases: The Cochrane Central Register of
Controlled Trials, MEDLINE, EMBASE, CINAHL, British Nursing Index, PsycINFO, Science Citation Index
Expanded, AMED, The Cochrane Pain, Palliative and Supportive Care Trials Register, The Cochrane
Database of Systematic Reviews, and Database of Abstracts of Reviews of Effectiveness in June 2007.
We also searched various websites and reference lists of relevant articles and textbooks. SELECTION
CRITERIA: We included randomised controlled and controlled clinical trials assessing the effects of non-
pharmacological and non-invasive interventions to relieve breathlessness in participants described as
suffering from breathlessness due to advanced stages of cancer, chronic obstructive pulmonary disease
(COPD), interstitial lung disease, chronic heart failure or motor neurone disease. DATA COLLECTION
AND ANALYSIS: Two review authors independently assessed relevant studies for inclusion. Data
extraction and quality assessment was performed by three review authors and checked by two other
review authors. Meta-analysis was not attempted due to heterogeneity of studies. MAIN RESULTS: Forty-
seven studies were included (2532 participants) and categorised as follows: single component
interventions with subcategories of walking aids (n = 7), distractive auditory stimuli (music) (n = 6), chest
wall vibration (CWV, n = 5), acupuncture/acupressure (n = 5), relaxation (n = 4), neuro-electrical muscle
stimulation (NMES, n = 3) and fan (n = 2). Multi-component interventions were categorised in to
counselling and support (n = 5), breathing training (n = 3), counselling and support with breathing-
relaxation training (n = 2), case management (n = 2) and psychotherapy (n = 2). There was a high
strength of evidence that NMES and CWV could relieve breathlessness and moderate strength for the
use of walking aids and breathing training. There is a low strength of evidence that
acupuncture/acupressure is helpful. There is not enough data to judge the evidence for distractive
auditory stimuli (music), relaxation, fan, counselling and support, counselling and support with breathing-
relaxation training, case management and psychotherapy. Most studies have been conducted in COPD
patients, only a few studies included participants with other conditions. AUTHORS' CONCLUSIONS:
Breathing training, walking aids, NMES and CWV appear to be effective non-pharmacological
interventions for relieving breathlessness in advanced stages of disease.
Bausewein, C., M. Farquhar, et al. (2007). "Measurement of breathlessness in advanced disease: a

systematic review." Respir Med 101(3): 399-410.
BACKGROUND: There is a plethora of assessment tools available to measure breathlessness,
the most common and disabling symptom of advanced cardio-respiratory disease. The aim of this
systematic review was to identify all measures available via standard search techniques and review their
usefulness for patients with advanced disease. METHODS: A systematic literature search was performed
in Medline. All studies focusing on the development or evaluation of tools for measuring breathlessness in
chronic respiratory disease, cardiac disease, cancer, or MND were identified. Their characteristics with
regard to validity, reliability, appropriateness and responsiveness to change were described. The tools
were then examined for their usefulness in measuring significant aspects of breathlessness in advanced
disease. RESULTS: Thirty-five tools were initially identified, two were excluded. Twenty-nine were
multidimensional of which 11 were breathlessness-specific and 18 disease-specific. Four tools were
unidimensional, measuring the severity of breathlessness. The majority of disease-specific scales were
validated for chronic obstructive pulmonary disease (COPD), few were applicable in other conditions. No
one tool assessed all the dimensions of this complex symptom, which affects the psychology and social
functioning of the affected individual and their family--most focused on physical activity. CONCLUSION:
As yet there is no one scale that can accurately reflect the far-reaching effects of breathlessness on the
patient with advanced disease and their family. Therefore, at present, we would recommend combining a
unidimensional scale (e.g. VAS) with a disease-specific scale (where available) or a multidimensional
1
scale in conjunction with other methods (such as qualitative techniques) to gauge psychosocial and carer
distress for the assessment of breathlessness in advanced disease.
Bertog, S. C., C. Kolmer, et al. (2012). "Percutaneous femoral arteriovenous shunt creation for
advanced chronic obstructive pulmonary disease: a single-center safety and efficacy study." Circ
Cardiovasc Interv 5(1): 118-126.
BACKGROUND: Advanced chronic obstructive pulmonary disease causes a significant reduction
in functional capacity because of dyspnea and fatigue, partially related to hypoxemia and compromised
oxygen delivery. Percutaneous creation of an arteriovenous shunt may increase oxygen delivery and,
hence, improve patients' functional capacity. METHODS AND RESULTS: This is a prospective, single-
center, proof-of-concept pilot study. Patients with advanced chronic obstructive pulmonary disease
underwent percutaneous arteriovenous shunt creation. End points were the change in 6-minute walking
distance; quality of life, measured by St George's Respiratory Questionnaire; and physiological
parameters at 12-week follow-up. Fifteen patients underwent percutaneous arteriovenous shunt creation.
Cardiac output and oxygen delivery increased significantly from 4.1 L/min at baseline to 5.9 L/min at 12
weeks (P<0.01) and from 751 mL/min at baseline to 972 mL/min at 12 weeks (P<0.01), respectively;
however, there was a trend toward a significant decrease in the 6-minute walking distance between
baseline (338 m) and 12-week follow-up (294 m) (P=0.07). There was no significant difference in the St
George's Respiratory Questionnaire score, oxygen saturation, or lung function tests. Lower extremity
edema, venous stenosis, right heart failure, and deep venous thrombosis occurred in 10, 7, 4, and 4
patients, respectively. CONCLUSIONS: Though it causes a significant increase in cardiac output and
oxygen delivery , the creation of an arteriovenous shunt in the setting of severe chronic obstructive
pulmonary disease did not improve functional capacity or quality of life. A significant number of adverse
events occurred. This concept cannot be recommended for routine clinical use in unselected patients with
advanced chronic obstructive pulmonary disease.
Blinderman, C. D., P. Homel, et al. (2009). "Symptom distress and quality of life in patients with
advanced chronic obstructive pulmonary disease." J Pain Symptom Manage 38(1): 115-123.
Although chronic obstructive pulmonary disease (COPD) is a highly prevalent and disabling
illness, few empirical studies have evaluated the impact of the disease on symptom distress, functional
status, and quality of life. These outcomes were explored in a prospective survey of 100 patients with
advanced COPD. Patients were recruited from two academic centers. The mean forced expiratory volume
in 1 second (FEV1) was 24.4% (standard deviation=3.9). Validated instruments were used to assess
symptom distress (Memorial Symptom Assessment Scale [MSAS]), mental health (Mental Health
Inventory [MHI]-5), functional status (Sickness Impact Profile [SIP]), quality of life (Multidimensional Index
of Life Quality [MILQ]), spirituality (Functional Assessment of Chronic Illness Therapy [FACIT] Spirituality
Scale), and comorbid conditions (Charlson Comorbidity Index). The most prevalent symptoms were
dyspnea (94%), fatigue (71%), xerostomia (60%), coughing (56%), and anxiety (51%). Other symptoms
with high prevalence were drowsiness (47%), irritability (42%), feeling nervous (40%), and wheezing
(40%). Significant pain was reported in about one-third of patients. Patients reported relatively high levels
of overall functional impairment (SIP median=24.0) and modest impairment in overall quality of life (MILQ
median=52). Overall, psychological well-being was relatively unimpaired (median=24.5), and the comfort
derived from faith was intact (FACIT median=2.5). Impairment in quality of life was strongly associated
with symptom distress (MSAS-GDI; r=-0.74, P<0.001), functional impairment (SIP total; r=-0.59,
P<0.001), female sex (r=-0.26, P=0.01), and poor psychological well-being (MHI-5; r=0.68, P<0.001). In
multivariate analyses, poor quality of life was strongly correlated with higher total symptom distress,
sickness-related dysfunction, and lower levels of psychological well-being (R(2)=0.66). In addition, two
specific psychological symptoms-worrying and feeling irritable-were independently predictive of poor
quality of life. Patients with advanced COPD have multiple distressing symptoms and a high prevalence
of disturbances in mood, functional status, and quality of life. A focus on ameliorating prevalent physical
symptoms and psychological distress may lead to an improvement in the overall quality of life in this
patient population.
2
Currow, D. C. and A. P. Abernethy (2007). "Pharmacological management of dyspnoea." Curr Opin

Support Palliat Care 1(2): 96-101.
PURPOSE OF REVIEW: This paper reviews the current evidence for the pharmacological
treatment of refractory symptomatic breathlessness in people with advanced life-limiting illnesses. The
paper does not explore changes in function. RECENT FINDINGS: Oral and parenteral opioids reduce
dyspnoea, and data continue to add to this indication for these drugs. Optimal dosing of opioids is being
refined. Interest in other medications continues to be explored - benzodiazepines, nebulised frusemide,
and selective serotonin reuptake inhibitors - but their role in day-to-day clinical practice is not defined.
SUMMARY: Low-dose regular opioids, especially sustained-release preparations, have a key role in the
pharmacological management of dyspnoea when titrated for effect, and may be used regularly across a
range of underlying pathophysiologies. Key research questions for all the current symptomatic
pharmacological agents used in refractory dyspnoea remain.
Ek, K., E. Sahlberg-Blom, et al. (2011). "Struggling to retain living space: patients' stories about
living with advanced chronic obstructive pulmonary disease." J Adv Nurs 67(7): 1480-1490.
AIM: This paper is a report of a study of the experience of living with advanced chronic
obstructive pulmonary disease and long-term oxygen therapy when living alone. BACKGROUND: Chronic
obstructive pulmonary disease affects an increasing number of people. Breathlessness, fatigue and
dejection are common symptoms during the last years of life. METHOD: Repeated qualitative interviews
with four participants were conducted over an 8-month period in 2008. The data comprised 17 interviews,
15 telephone conversations and various field notes. A phenomenological hermeneutical method was
used to interpret the text. FINDINGS: The analysis resulted in two main themes and five sub-themes. The
first main theme, Being subordinated to the sick body, implies that the body, assistive devices and
entrusting oneself to the hands of others can both extend and restrict the living space. The second main
theme, Protecting significant values of identity, encompasses both the struggle to maintain self-image and
the awareness of one's own death. CONCLUSION: Living alone with advanced chronic obstructive
pulmonary disease is a challenging and complex phenomenon. The everyday life was characterized by a
struggle to keep autonomy during a time of increasing dependency and need for help. A person-centred
nursing care, built upon peoples' own experiences, may be one way to promote identity and dignity in
patients even when they are close to death.
Eskander, A., T. K. Waddell, et al. (2011). "BODE index and quality of life in advanced chronic
obstructive pulmonary disease before and after lung transplantation." J Heart Lung Transplant
30(12): 1334-1341.
BACKGROUND: The BODE index (Body mass index, Obstruction, Dyspnea, Exercise), predicts
the risk of death in patients with chronic obstructive pulmonary disease (COPD), and is used to identify
candidates for lung transplantation. We hypothesized that a higher BODE index would be associated with
worse health-related quality of life (HRQL) in advanced COPD, and with larger improvements in HRQL
after transplantation. METHODS: In this cohort study (n = 112), we administered the St. George's
Respiratory Questionnaire (SGRQ), 36-Item Short Form (SF-36), Visual Analog Scale, Standard Gamble
and EuroQol Group 5-Dimension (EQ-5D) index to otherwise healthy COPD patients with a FEV(1) <50%
predicted. We compared mean HRQL values across BODE score groups, and tested for linear trends. In
patients who received lung transplants during the study period, we compared SGRQ scores before and
early (mean 4 months) after transplantation. RESULTS: BODE was directly associated with SGRQ and
inversely related to all other HRQL measures (p < 0.05). Early post-transplant improvements in HRQL
were also seen across the spectrum of BODE scores from 5 to 10. CONCLUSIONS: The BODE score is
a significant predictor of HRQL in patients with severe COPD. We noted dramatic improvements in HRQL
after transplantation, which appeared similar in magnitude for patients with pre-transplant BODE scores
of 5 or 6 and 7 to 10, despite the difference in expected survival between these two groups. The
association of the BODE score with HRQL further supports its use in identifying potential candidates for
lung transplantation.
3
Gardiner, C., M. Gott, et al. (2009). "Living with advanced chronic obstructive pulmonary disease:
patients concerns regarding death and dying." Palliat Med 23(8): 691-697.
Prognosis in COPD is poor and many patients perceive shortcomings in the education they
receive about aspects of their condition. This study explores the experiences of patients with COPD,
particularly fears surrounding death and dying. Semi-structured interviews were conducted with 21
patients with moderate or severe COPD. Findings revealed that patient understanding of COPD was
poor, most patients were unaware of the progressive nature of the condition, and few were aware they
could die of COPD. Despite this, patients often expressed concerns that their condition might deteriorate.
Patients had particular concerns regarding the manner of their death; the overriding fear was dying of
breathlessness or suffocation. None of the patients' had discussed these fears with a health care
professional. Improved patient education is needed in order to improve patients understanding of their
condition and prognosis. Open communication regarding death, as advocated in a palliative care
approach, is also appropriate to alleviate patients fears and to allow them to make decisions regarding
the management of their care at the end of life.
Ginsburg, M. E., B. M. Thomashow, et al. (2011). "Lung volume reduction surgery using the NETT
selection criteria." Ann Thorac Surg 91(5): 1556-1560; discussion 1561.
BACKGROUND: The National Emphysema Treatment Trial (NETT) proved that lung volume
reduction surgery (LVRS) was safe and effective in patients with certain clinical characteristics and using
defined inclusion-exclusion criteria. Based on the selection criteria developed in that trial, we performed
bilateral LVRS on 49 patients during the period of February 2004 until May 2009. METHODS: Forty-nine
patients underwent lung volume reduction by either median sternotomy (10) or video-assisted
thoracoscopic surgery (39) selected according to NETT described parameters. Preoperative
characteristics were the following: mean (+/-SD) age 62.5+/-6.6 years, preoperative FEV1 (forced
expiratory volume in the first second of expiration) 691 cc (+/-159), % of predicted FEV1 25.3 (+/-6.2),
preoperative Dlco (diffusing capacity of lung for carbon monoxide) 7.6 (+/-2.7), and % of predicted DLCO
27% (+/-7.3). All patients had upper lobe predominant disease and either low exercise capacity (n=23) or
high exercise capacity (n=26) as defined by the NETT. RESULTS: There was no operative or 90-day
mortality. Median length of stay was 8 days (interquartile range=6 to 10). Two patients required
reintubation and tracheostomy but were decannulated prior to discharge. The BODE index (body mass
index, airflow obstruction, dyspnea, and exercise capacity), a multidimensional predictor of survival in
chronic obstructive pulmonary disease, improved -2.3 (+/-1.5, p<0.0001) (missing data: 5 of 42, 11.9%)
and the FEV1 improved 286 cc (+/-221, p<0.0001), both 1 year after surgery. Probability of survival was
0.98 (95% CI [confidence interval]=0.94 to 1) at 1 year, and 0.95 (95% CI=0.88 to 1) at 3 years.
CONCLUSIONS: Surgical lung volume reduction for emphysema can be performed in patients using
selection criteria developed by the NETT with very low surgical risk and excellent midterm results.
Surgical LVRS is the standard against which other nonsurgical treatments for advanced emphysema
should be judged.
Goodridge, D., W. Duggleby, et al. (2008). "Caring for critically ill patients with advanced COPD at
the end of life: a qualitative study." Intensive Crit Care Nurs 24(3): 162-170.
Providing expert critical care for the high acuity patient with a diagnosis of COPD at the end of life
is both complex and challenging. The purpose of this descriptive study was to examine intensive care unit
(ICU) clinicians' perspectives on the obstacles to providing quality care for individuals with COPD who die
within the critical care environment. Transcripts of three focus groups of ICU clinicians were analyzed
using thematic analysis. The three themes of "managing difficult symptoms", "questioning the
appropriateness of life-sustaining care" and "conflicting care priorities" were noted to be significant
challenges in providing high quality end of life care to this population. Difficulties in palliating dyspnea and
anxiety were associated with caregiver feelings of helplessness, empathy and fears about "killing the
patient". A sense of futility, concerns about "torturing the patient" and questions about the patient/family's
understanding of treatment pervaded much of the discourse about caring for people with advanced
COPD in the ICU. The need to prioritize care to the most unstable ICU patients meant that patients with
COPD did not always receive the attention clinicians felt they should ideally have. Organizational support
must be made available for critical care clinicians to effectively deal with these issues.
4
Guenette, J. A., K. A. Webb, et al. (2011). "Does dynamic hyperinflation contribute to dyspnoea
during exercise in patients with COPD?" Eur Respir J.
Dynamic hyperinflation (DH) during exercise occurs in most but not all patients with advanced
COPD. It is not known whether the presence or absence of DH has implications for dyspnoea and
exercise tolerance. Therefore, we compared detailed ventilatory and sensory responses to exercise in
hyperinflators and non-hyperinflators with moderate to severe COPD.Non-hyperinflators (n=65) were
retrospectively identified from a sample of 427 patients and case-matched to a group of hyperinflators
(n=65) based on sex, age, body mass index and %predicted forced expiratory volume in 1 second.
Resting pulmonary function and constant work rate cycle exercise responses were
compared.Hyperinflators decreased inspiratory capacity (IC) from rest to peak exercise by 0.46+/-0.24 L
whereas the non-hyperinflators increased IC by 0.10+/-0.15 L (P<0.0001). There were no significant
group differences in endurance time (9.11+/-5.98 vs. 8.87+/-5.24 min) or dyspnoea intensity for any given
time or ventilation. An inflection in tidal volume versus ventilation occurred in the majority of non-
hyperinflators (n=61) and hyperinflators (n=62) at a similar time and ventilation. Mechanical constraints on
tidal volume expansion and the attendant rise in dyspnoea intensity were similar in both groups.Dyspnoea
intensity during exercise was associated with progressive mechanical constraints on tidal volume
expansion regardless of the presence of DH.
Herth, F. J., D. Gompelmann, et al. (2011). "Treatment of advanced emphysema with

emphysematous lung sealant (AeriSeal(R))." Respiration 82(1): 36-45.
BACKGROUND: This report summarizes initial tests of an emphysematous lung synthetic
polymer sealant (ELS) designed to reduce lung volume in patients with advanced emphysema.
OBJECTIVES: The primary study objective was to define a therapeutic strategy to optimize treatment
safety and effectiveness. METHODS: ELS therapy was administered bronchoscopically to 25 patients
with heterogeneous emphysema in an open-label, noncontrolled study at 6 centers in Germany.
Treatment was performed initially at 2-4 subsegments. After 12 weeks, patients were eligible for repeat
therapy to a total of 6 sites. Safety and efficacy were assessed after 6 months. Responses were
evaluated in terms of changes from baseline in lung physiology, functional capacity, and health-related
quality of life. Follow-up is available for 21 of 25 patients. RESULTS: Treatment was well tolerated. There
were no treatment-related deaths (i.e., within 90 days of treatment), and an acceptable short- and long-
term safety profile. Physiological and clinical benefits were observed at 24 weeks. Efficacy responses
were better among Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage III patients [n =
14; change in residual volume/total lung capacity (DeltaRV/TLC) = -7.4 +/- 10.3%; Delta forced expiratory
volume in 1 s (DeltaFEV(1)) = +15.9 +/- 22.6%; change in forced vital capacity (DeltaFVC) = +24.1 +/-
22.7%; change in carbon monoxide lung diffusion capacity (DeltaDLCO) = +19.3 +/- 34.8%; change in 6-
min walk test (Delta6MWD) = +28.7 +/- 59.6 m; change in Medical Research Council Dyspnea
(DeltaMRCD) score = -1.0 +/- 1.04 units; change in St. George's Respiratory Questionnaire (DeltaSGRQ)
score = -9.9 +/- 15.3 units] than for GOLD stage IV patients (n = 7; DeltaRV/TLC = -0.5 +/- 6.4%;
DeltaFEV(1) = +2.3 +/- 12.3%; DeltaFVC = +2.6 +/- 21.1%; DeltaDLCO = -2.8 +/- 17.2%; Delta6MWD =
+28.3 +/- 58.4 m; DeltaMRCD = 0.3 +/- 0.81 units; DeltaSGRQ = -6.7 +/- 7.0 units). CONCLUSIONS: ELS
therapy shows promise for treating patients with advanced heterogeneous emphysema. Additional
studies to assess responses in a larger cohort with a longer follow-up are warranted.
Janssen, D. J., M. A. Spruit, et al. (2011). "Symptoms, comorbidities, and health care in advanced
chronic obstructive pulmonary disease or chronic heart failure." J Palliat Med 14(6): 735-743.
BACKGROUND: Patients with advanced chronic obstructive pulmonary disease (COPD) or
chronic heart failure (CHF) may experience significant symptom distress. For development of palliative
care programs that adequately address symptoms of patients with COPD or CHF, it is necessary to know
severity of symptom distress and to gain insight in comorbidities and current provision of health care.
Objective of the present cross-sectional observational study was to assess severity of symptoms,
presence of comorbidities, and current provision of health care in outpatients with advanced COPD or
CHF. METHODS: A total of 105 outpatients with clinically stable but advanced COPD (Global initiative for
chronic Obstructive Lung Disease [GOLD] stage III or IV) and 80 patients with advanced CHF (New York
Heart Association [NYHA] class III or IV) were assessed for demographics, clinical characteristics, self-
5
reported comorbidities, and severity of symptoms using visual analogue scales. In addition, current health
care and symptom-related interventions have been assessed. RESULTS: Comorbidities were reported by
96.3% of the CHF patients and 61.9% of the COPD patients. Patients suffered from multiple symptoms,
like dyspnea, fatigue, muscle weakness, coughing, low mood, sleeplessness, and frequent micturition.
For most symptoms, only the minority of patients had received symptom-related treatment. Involvement of
allied health care professionals was low. The majority of COPD and CHF patients had received home
adaptation and medical aids. CONCLUSIONS: Patients with advanced COPD or CHF experience
comorbidities and suffer from multiple symptoms, which are often under treated. Further development and
implementation of palliative care programs, consisting of regular assessment of the patients'
comorbidities and symptoms as well as the provision of patient-tailored interventions is needed.
Jensen, D., K. Amjadi, et al. (2008). "Mechanisms of dyspnoea relief and improved exercise
endurance after furosemide inhalation in COPD." Thorax 63(7): 606-613.
BACKGROUND: This study examined the effects of inhaled furosemide on the ventilatory and
perceptual response to high-intensity constant-load cycle exercise in chronic obstructive pulmonary
disease (COPD). METHODS: In a randomised, double-blind, placebo-controlled, crossover study, 20
patients with COPD (mean (SD) forced expiratory volume in 1 s 45 (15)% predicted) received either
nebulised furosemide 40 mg or placebo on two separate days. Thirty minutes after each treatment,
patients performed pulmonary function tests and a symptom-limited cycle exercise test at 75% of their
maximum incremental work rate. Changes in spirometry, plethysmographic lung volumes, dynamic
operating lung volumes, ventilation, breathing pattern, cardiovascular function, dyspnoea intensity and
exercise endurance time were compared between treatments. RESULTS: Compared with placebo,
treatment with furosemide resulted in a mean (SD) decrease in dyspnoea intensity at the highest
equivalent exercise time (ie, isotime for each patient) of 0.9 (1.0) Borg units (p<0.01) and an increase in
exercise endurance time of 1.65 (0.63) min (p<0.05). These improvements were associated with
increases in dynamic inspiratory capacity, tidal volume and mean tidal expiratory flow rates at isotime
(p<0.01). The eight patients whose exercise endurance time improved by >1 min had greater changes in
operating lung volumes (p<0.05), submaximal oxygen pulse (p<0.05) and oxygen uptake (p = 0.05) than
those in whom exercise endurance time did not improve. CONCLUSION: Alleviation of exertional
dyspnoea after single-dose furosemide inhalation in COPD is multifactorial but improvements in dynamic
ventilatory mechanics are contributory in some individuals.
Mahler, D. A. (2011). "Understanding mechanisms and documenting plausibility of palliative

interventions for dyspnea." Curr Opin Support Palliat Care 5(2): 71-76.
PURPOSE OF REVIEW: To review the mechanisms for the perception of dyspnea and to
consider the plausibility of interventions that palliate dyspnea after optimal treatment of the underlying
disease. RECENT FINDINGS: Activation of sensory receptors by blood gas abnormalities, mechanical
respiratory loads, and hyperinflation provides afferent information to the central nervous system for
integration and processing. It has been proposed that a discriminative pathway processes afferent
impulses to the somatosensory cortex that reflects the intensity of dyspnea, whereas an affective pathway
projects afferent impulses to structures of the limbic system that reflects the unpleasantness of dyspnea.
In one study, patients with chronic obstructive pulmonary disease reported consistently higher ratings of
breathlessness after administration of naloxone, an opioid receptor antagonist, compared with
physiological saline during high-intensity treadmill exercise. This finding supports the role of endogenous
opioids in modulating dyspnea. Nebulized furosemide, anti-inflammatory therapy, and chest wall vibration
are potential approaches for modulating lung and chest wall receptors to relieve dyspnea. SUMMARY:
Targets for palliating dyspnea in patients with advanced disease include sensory receptors within the
lung/chest wall and the central nervous system. The opioid system plays an important role in palliating
dyspnea. Both endogenous (beta-endorphins) and exogenous (morphine) opioids modulate
breathlessness.
6
Mahler, D. A., J. A. Murray, et al. (2009). "Endogenous opioids modify dyspnoea during treadmill
exercise in patients with COPD." Eur Respir J 33(4): 771-777.
Exogenous opioid drugs, such as morphine, relieve breathlessness. The present study
hypothesis was that endogenous opioids, released during the stress of exercise, modify dyspnoea in
patients with chronic obstructive pulmonary disease. After familiarisation, patients performed an
incremental treadmill exercise test followed by constant work on the treadmill for 10 min. At subsequent
visits (2 to 3 days apart), patients received two puffs of albuterol, had a catheter placed in an arm vein for
removal of blood to measure beta-endorphin immunoreactivity, received normal saline or 10 mg of
naloxone intravenously in randomised order, and then performed high-intensity constant work rate
exercise on the treadmill. The mean+/-sd age of the 17 patients (eight females and nine males) was 63+/-
7 yrs, and post-bronchodilator forced expiratory volume in one second was 50+/-17% predicted. In both
conditions, beta-endorphin levels increased three-fold from rest to end-exercise. The regression slope of
breathlessness as a function of oxygen consumption (primary outcome), mean ratings of breathlessness
throughout exercise and peak ratings of breathlessness were significantly higher with naloxone than
normal saline. There were no differences in physiological responses throughout exercise between
conditions. In conclusion, endogenous opioids modify dyspnoea during treadmill exercise in patients with
chronic obstructive pulmonary disease by apparent alteration of central perception.
Make, B., S. Krachman, et al. (2010). "Oxygen therapy in advanced COPD: in whom does it work?"
Semin Respir Crit Care Med 31(3): 334-342.
Supplemental oxygen therapy is commonly used in patients with advanced chronic obstructive
pulmonary disease (COPD) and severe hypoxemia at rest. Use of oxygen in these patients is justified by
studies showing a mortality benefit. However, the use of oxygen in other patients with advanced COPD
has not clearly been established. Long-term studies assessing not only mortality but also other outcomes
that are important to patients and physicians such as dyspnea, health status, and exercise capacity are
lacking. This article reviews the available studies of the use of supplemental oxygen in patients with less
severe hypoxemia at rest during the day, hypoxemia occurring only at night, and hypoxemia occurring
only with exercise. With the knowledge that studies in patients with advanced COPD and less severe
hypoxemia are limited, recommendations are provided on oxygen use in these groups of patients.
Marciniuk, D. D., D. Goodridge, et al. (2011). "Managing dyspnea in patients with advanced chronic
obstructive pulmonary disease: a Canadian Thoracic Society clinical practice guideline." Can
Respir J 18(2): 69-78.
Dyspnea is a cardinal symptom of chronic obstructive pulmonary disease (COPD), and its
severity and magnitude increases as the disease progresses, leading to significant disability and a
negative effect on quality of life. Refractory dyspnea is a common and difficult symptom to treat in
patients with advanced COPD. There are many questions concerning optimal management and,
specifically, whether various therapies are effective in this setting. The present document was compiled to
address these important clinical issues using an evidence-based systematic review process led by a
representative interprofessional panel of experts. The evidence supports the benefits of oral opioids,
neuromuscular electrical stimulation, chest wall vibration, walking aids and pursed-lip breathing in the
management of dyspnea in the individual patient with advanced COPD. Oxygen is recommended for
COPD patients with resting hypoxemia, but its use for the targeted management of dyspnea in this setting
should be reserved for patients who receive symptomatic benefit. There is insufficient evidence to support
the routine use of anxiolytic medications, nebulized opioids, acupuncture, acupressure, distractive
auditory stimuli (music), relaxation, handheld fans, counselling programs or psychotherapy. There is also
no evidence to support the use of supplemental oxygen to reduce dyspnea in nonhypoxemic patients with
advanced COPD. Recognizing the current unfamiliarity with prescribing and dosing of opioid therapy in
this setting, a potential approach for their use is illustrated. The role of opioid and other effective therapies
in the comprehensive management of refractory dyspnea in patients with advanced COPD is discussed.
7
Martinez, F. J., J. L. Curtis, et al. (2007). "Sex differences in severe pulmonary emphysema." Am J
Respir Crit Care Med 176(3): 243-252.
RATIONALE: Limited data on sex differences in advanced COPD are available. OBJECTIVES:
To compare male and female emphysema patients with severe disease. METHODS: One thousand fifty-
three patients (38.8% female) evaluated for lung volume reduction surgery as part of the National
Emphysema Treatment Trial were analyzed. MEASUREMENTS AND MAIN RESULTS: Detailed clinical,
physiological, and radiological assessment, including quantitation of emphysema severity and distribution
from helical chest computed tomography, was completed. In a subgroup (n = 101), airway size and
thickness was determined by histological analyses of resected tissue. Women were younger and
exhibited a lower body mass index (BMI), shorter smoking history, less severe airflow obstruction, lower
Dl(co) and arterial Po(2), higher arterial Pco(2), shorter six-minute walk distance, and lower maximal
wattage during oxygen-supplemented cycle ergometry. For a given FEV(1)% predicted, age, number of
pack-years, and proportion of emphysema, women experienced greater dyspnea, higher modified BODE,
more depression, lower SF-36 mental component score, and lower quality of well-being. Overall
emphysema was less severe in women, with the difference from men most evident in the outer peel of the
lung. Females had thicker small airway walls relative to luminal perimeters. CONCLUSIONS: In patients
with severe COPD, women, relative to men, exhibit anatomically smaller airway lumens with
disproportionately thicker airway walls, and emphysema that is less extensive and characterized by
smaller hole size and less peripheral involvement.
Mohan, A., C. Mohan, et al. (2007). "Impact of chronic obstructive pulmonary disease on
respiratory status and quality of life in newly diagnosed patients with lung cancer." Respirology
12(2): 240-247.
OBJECTIVE AND BACKGROUND: A significant proportion of patients with lung cancer have
associated COPD, which is considered an independent risk factor and cause of morbidity and mortality.
However, the effect of COPD on respiratory status and quality of life in lung cancer has not been
evaluated. METHODS: Newly diagnosed patients with lung cancer were assessed at diagnosis before
starting treatment, for detailed respiratory status, spirometry and World Health Organization-Bref Quality
of Life questionnaire in Hindi (WHOQOL-Bref Hindi). RESULTS: One hundred and sixty patients were
studied. Spirometry was abnormal in 92.7% patients, 42% had COPD, and the majority (88.6%) had
advanced disease (stage III and IV). Patients scored poorly in all QOL domains, with social domain faring
worst. Karnofsky Performance status (KPS) correlated significantly with all QOL domains. No significant
differences were found in clinical profile, KPS, or QOL scores between patients with and without COPD.
Chest pain and dyspnoea severity (assessed by Medical Research Council) grading and visual analogue
scale correlated with physical QOL domain. CONCLUSION: Patients with lung cancer have a poor QOL
that is affected by the severity of respiratory profile and KPS. The presence of COPD does not
significantly affect QOL in lung cancer patients.
Neder, J. A., J. P. Fuld, et al. (2007). "Effects of formoterol on exercise tolerance in severely
disabled patients with COPD." Respir Med 101(10): 2056-2064.
OBJECTIVE: We wished to evaluate the effects of inhaled formoterol, a long-acting beta(2)-
adrenergic agonist, on exercise tolerance and dynamic hyperinflation (DH) in severely disabled chronic
obstructive pulmonary disease (COPD) patients. DESIGN: In a two-period, crossover study, 21 patients
with advanced COPD (FEV(1)=38.8+/-11.7% predicted, 16 patients GOLD stages III-IV) were randomly
allocated to receive inhaled formoterol fumarate 12 microg twice daily for 14 days followed by placebo for
14 days, or vice versa. Patients performed constant work-rate cardiopulmonary exercise tests to the limit
of tolerance (Tlim) on a cycle ergometer: inspiratory capacity (IC) was obtained at rest and each minute
during exercise. Baseline and transitional dyspnoea indices (BDI and TDI) were also recorded.
RESULTS: Eighteen patients completed both treatment periods. Formoterol treatment was associated
with an estimated increase of 130 s in Tlim compared with placebo (P=0.052): this corresponded to a
37.8% improvement over placebo (P=0.012). Enhanced exercise tolerance after bronchodilator was
associated with diminished DH marked by higher inspiratory reserve and tidal volumes at isotime and
exercise cessation (P<0.05). There was no significant difference between formoterol and placebo on
exercise dyspnoea ratings; however, all domains of the TDI improved (P<or=0.02) following formoterol,
8
compared with placebo. CONCLUSION: Inhaled formoterol 12 microg twice daily is effective in
ameliorating DH, daily dyspnoea and exercise intolerance even in patients with advanced COPD.
O'Donnell, D. E., C. D'Arsigny, et al. (2001). "Effects of hyperoxia on ventilatory limitation during
exercise in advanced chronic obstructive pulmonary disease." Am J Respir Crit Care Med 163(4):
892-898.
We studied interrelationships between exercise endurance, ventilatory demand, operational lung
volumes, and dyspnea during acute hyperoxia in ventilatory-limited patients with advanced chronic
obstructive pulmonary disease (COPD). Eleven patients with COPD (FEV(1.0) = 31 +/- 3% predicted,
mean +/- SEM) and chronic respiratory failure (Pa(O(2)) 52 +/- 2 mm Hg, Pa(CO(2 ))48 +/- 2 mm Hg)
breathed room air (RA) or 60% O(2) during two cycle exercise tests at 50% of their maximal exercise
capacity, in randomized order. Endurance time (T(lim)), dyspnea intensity (Borg Scale), ventilation (V E),
breathing pattern, dynamic inspiratory capacity (IC(dyn)), and gas exchange were compared. Pa(O(2)) at
end-exercise was 46 +/- 3 and 245 +/- 10 mm Hg during RA and O(2), respectively. During O(2), T(lim)
increased 4.7 +/- 1.4 min (p < 0.001); slopes of Borg, V E, V CO(2), and lactate over time fell (p < 0.05);
slopes of Borg-V E, V E-V CO(2), V E-lactate were unchanged. At a standardized time near end-exercise,
O(2) reduced dyspnea 2.0 +/- 0.5 Borg units, V CO(2) 0.06 +/- 0.03 L/min, V E 2.8 +/- 1.0 L/min, and
breathing frequency 4.4 +/- 1.1 breaths/min (p < 0.05 each). IC(dyn) and inspiratory reserve volume (IRV)
increased throughout exercise with O(2) (p < 0.05). Increased IC(dyn) was explained by the combination
of increased resting IRV and decreased exercise breathing frequency (r(2) = 0.83, p < 0.0005). In
conclusion, improved exercise endurance during hyperoxia was explained, in part, by a combination of
reduced ventilatory demand, improved operational lung volumes, and dyspnea alleviation.
Ohar, J. A. and J. F. Donohue (2010). "Mono- and combination therapy of long-acting

bronchodilators and inhaled corticosteroids in advanced COPD." Semin Respir Crit Care Med
31(3): 321-333.
Beta-2 adrenergic agonists are sympathomimetic agents that stimulate bronchodilation by
activation of adenyl cyclase to produce cyclic 3'5' adenosine monophosphate (AMP). Short-acting beta-
agonists (SABAs) have a 3- to 6-hour duration of action, and the duration of action of long-acting beta-
agonists (LABAs) exceeds 12 hours. Because of their rapid onset of action, SABAs are effective for
rescue from symptoms of chronic obstructive pulmonary disease (COPD). LABAs-salmeterol and
formoterol-have been shown to significantly improve lung function, health status, and symptom reduction,
compared with ipratropium. Despite safety concerns over the use of LABAs as monotherapy in asthma
the use of these medications in COPD has generally been described as safe. Novel bronchodilators for
COPD in late-stage development include the beta-agonists indacterol and carmoterol. Parasympathetic
activity in the large and medium-size airways is mediated through the muscarinic receptors and results in
airway smooth-muscle contraction, mucus secretion, and possibly increased ciliary activity. Although
short-acting ipratropium has been used as monotherapy or in combination with albuterol the use of long-
acting antimuscarinics is superior in improving health outcomes. The use of tiotropium results in improved
health status, dyspnea, and exercise capacity, and reduced hyperinflation and COPD exacerbation rate in
patients with moderate to severe COPD. Analysis of prospective clinical trial data shows a mortality
reduction in subjects treated with tiotropium, despite retrospective review of insurance claims that show
an enhanced mortality. Theophylline is a nonselective phosphodiesterase inhibitor that acts as both a
weak bronchodilator and a respiratory stimulant. Novel approaches include using the inhalation route to
reduce side effects and combination with inhaled corticosteroids (ICS). However, because of its potential
adverse effects and narrow therapeutic index, it should only be used when symptoms persist despite
optimal bronchodilator therapy. Current guidelines highlight that for COPD patients uncontrolled by
bronchodilator monotherapy, combination therapy is recommended. These include LABA/ICS and
LAMA/LABA combinations. Bronchodilators and their combination with ICS are central to the
management of COPD. The choice of agents is based primarily on disease stage, individual response,
cost, side effect profile, and availability.
9
Pasqua, F., G. Biscione, et al. (2010). "Combining triple therapy and pulmonary rehabilitation in
patients with advanced COPD: a pilot study." Respir Med 104(3): 412-417.
BACKGROUND: The synergistic interactions between pharmacotherapy and pulmonary
rehabilitation has been provided, but it remains to be established whether this may also apply to more
severe patients. OBJECTIVES: We have examined whether tiotropium enhances the effects of exercise
training in patients with advanced COPD (FEV(1)</=60% predicted, hypoxemia at rest corrected with
oxygen supplementation, and limitations of physical activity). METHODS: We enrolled 22 patients that
were randomised to tiotropium 18mug or placebo inhalation capsules taken once daily. Both groups (11
patients in each group) underwent an in patient pulmonary rehabilitation program and were under regular
treatment with salmeterol/fluticasone twice daily. Each rehabilitation session was held 5 days per week
(3h/day) for a total of 4 weeks. RESULTS: Compared to placebo, tiotropium had larger impact on
pulmonary function (FEV(1)+0.164L, FVC +0.112L, RV -0.544L after tiotropium, FEV(1)+0.084L, FVC -
0.039L, RV -0.036L after placebo). The addition of tiotropium allowed a longer distance walked in 6min
(82.3m vs. 67.7m after placebo) and reduced dyspnoea (Borg score) (-0.4 vs. +0.18 after placebo) when
compared with baseline (pre pulmonary rehabilitation program). The changes in SGRQ from baseline to
the end of treatment were: total score -28.3U, activity -27.8U, impact -14.5U, and symptoms -33.4U in the
placebo group; and total score -19.1U, activity -18.9U, impact -16.4U, and symptoms -33.8U in the
tiotropium group. CONCLUSIONS: Our study clearly indicates that there is an advantage in combining
pulmonary rehabilitation with an aggressive drug therapy in more severe patients.
Patel, K., D. J. Janssen, et al. (2012). "Advance care planning in COPD." Respirology 17(1): 72-78.
The review aims to discuss current concepts in advance care planning (ACP) for patients with
COPD, and to provide a narrative review of recent trends in ACP and end-of-life care for patients with
COPD. ACP, which involves patient-clinician communication about end-of-life care, can improve
outcomes for patients and their families, and may be especially relevant for patients with COPD. Effective
patient-clinician communication is needed to inform and prepare patients about their diagnosis, treatment,
prognosis and what dying might be like. It is important for clinicians to understand patients' values and
preferences for life-sustaining treatments as well for their site of terminal care. Unfortunately, discussions
about ACP and end-of-life care in current practice are scarce, and their quality is often poor. ACP can
improve outcomes for patients and their relatives. The challenge remains in the practical implementation
of ACP in the clinical setting, especially for patients with COPD. ACP should be implemented alongside
curative-restorative care for patients with advanced COPD. The disease course of COPD is such that
there will rarely be a clear transition point predicting the timing of the need for initiation of end-of-life care.
Future studies should focus on interventions that facilitate concurrent ACP and prepare patients for
making in-the-moment decisions, with the goal of improving the quality of end-of-life care.
Rabe, K. F., S. Hurd, et al. (2007). "Global strategy for the diagnosis, management, and prevention
of chronic obstructive pulmonary disease: GOLD executive summary." Am J Respir Crit Care Med
176(6): 532-555.
Chronic obstructive pulmonary disease (COPD) remains a major public health problem. It is the
fourth leading cause of chronic morbidity and mortality in the United States, and is projected to rank fifth
in 2020 in burden of disease worldwide, according to a study published by the World Bank/World Health
Organization. Yet, COPD remains relatively unknown or ignored by the public as well as public health and
government officials. In 1998, in an effort to bring more attention to COPD, its management, and its
prevention, a committed group of scientists encouraged the U.S. National Heart, Lung, and Blood Institute
and the World Health Organization to form the Global Initiative for Chronic Obstructive Lung Disease
(GOLD). Among the important objectives of GOLD are to increase awareness of COPD and to help the
millions of people who suffer from this disease and die prematurely of it or its complications. The first step
in the GOLD program was to prepare a consensus report, Global Strategy for the Diagnosis,
Management, and Prevention of COPD, published in 2001. The present, newly revised document follows
the same format as the original consensus report, but has been updated to reflect the many publications
on COPD that have appeared. GOLD national leaders, a network of international experts, have initiated
investigations of the causes and prevalence of COPD in their countries, and developed innovative
approaches for the dissemination and implementation of COPD management guidelines. We appreciate
10
the enormous amount of work the GOLD national leaders have done on behalf of their patients with
COPD. Despite the achievements in the 5 years since the GOLD report was originally published,
considerable additional work is ahead of us if we are to control this major public health problem. The
GOLD initiative will continue to bring COPD to the attention of governments, public health officials, health
care workers, and the general public, but a concerted effort by all involved in health care will be
necessary.
Raghavan, N., K. Webb, et al. (2011). "Recent advances in pharmacotherapy for dyspnea in
COPD." Curr Opin Pharmacol 11(3): 204-210.
Dyspnea is the most distressing symptom experienced by those suffering from advanced stages
of chronic obstructive pulmonary disease (COPD). Activity-related dyspnea in COPD is multifactorial but
is associated with increased central neural drive, impaired dynamic respiratory mechanics and abnormal
respiratory muscle function. Each of these components can potentially be targeted for pharmacotherapy.
Recent advances in the pharmacotherapy of COPD include the development of new long-acting
bronchodilators which, when combined, provide sustained improvements in dyspnea. Additionally, novel
applications of older therapies such as opiates, furosemide, helium-oxygen, and statins show early
promise as dyspnea-relieving interventions in COPD. Effective pharmacological manipulation of the
affective dimension of dyspnea remains an important challenge. In this review of the recent literature in
this field, we highlight the main advances that have been achieved.
Rocha Vieira, D. S., J. Baril, et al. (2011). "Eccentric cycle exercise in severe COPD: feasibility of
application." COPD 8(4): 270-274.
Eccentric cycling may present an interesting alternative to traditional exercise rehabilitation for
patients with advanced COPD, because of the low ventilatory cost associated with lengthening muscle
actions. However, due to muscle damage and soreness typically associated with eccentric exercise, there
has been reluctance in using this modality in clinical populations. This study assessed the feasibility of
applying an eccentric cycling protocol, based on progressive muscle overload, in six severe COPD
patients with the aim of minimizing side effects and maximizing compliance. Over 5 weeks, eccentric
cycling power was progressively increased in all patients from a minimal 10-Watt workload to a target
intensity of 60% peak oxygen consumption (attained in a concentric modality). By 5 weeks, patients were
able to cycle on average at a 7-fold higher power output relative to baseline, with heart rate being
maintained at approximately 85% of peak. All patients complied with the protocol and presented tolerable
dyspnea and leg fatigue throughout the study; muscle soreness was minimal and did not compromise
increases in power; creatine kinase remained within normal range or was slightly elevated; and most
patients showed a breathing reserve > 15 L.min(-1). At the target intensity, ventilation and breathing
frequency during eccentric cycling were similar to concentric cycling while power was approximately five
times higher (p = 0.02). This study showed that an eccentric cycling protocol based on progressive
increases in workload is feasible in severe COPD, with no side effects and high compliance, thus
warranting further study into its efficacy as a training intervention.
Rocker, G., R. Horton, et al. (2009). "Palliation of dyspnoea in advanced COPD: revisiting a role for
opioids." Thorax 64(10): 910-915.
Chronic obstructive pulmonary disease (COPD) will be the third leading cause of death worldwide
by 2020. The burdens of this increasingly prevalent illness borne by patients, their family caregivers and
the healthcare system are substantial. Dyspnoea as the predominant symptom becomes increasingly
difficult to palliate as COPD progresses through advanced stages and, for 50% of patients, can become
refractory to conventional treatment. This narrative review focuses on the potential role for carefully
initiated and titrated opioids in the management of dyspnoea for patients with advanced COPD who are
not yet in a terminal stage, yet struggle with symptoms that reflect underlying mechanisms of dyspnoea
that lend themselves to this approach. The many barriers that currently exist to the provision of opioids in
this setting are addressed, and recommendations are provided for an approach that should engender
confidence among patients, their caregivers and the physicians who treat them.
11
Simon, S. T., I. J. Higginson, et al. (2010). "Benzodiazepines for the relief of breathlessness in
advanced malignant and non-malignant diseases in adults." Cochrane Database Syst Rev(1):
CD007354.
BACKGROUND: Breathlessness is one of the most common symptoms experienced in the
advanced stages of malignant and non-malignant disease. Benzodiazepines are widely used for the relief
of breathlessness in advanced diseases and are regularly recommended in the literature. However, the
evidence for their use for this symptom is unclear. OBJECTIVES: To determine the efficacy of
benzodiazepines for the relief of breathlessness in patients with advanced disease. SEARCH
STRATEGY: We searched 14 electronic databases up to September 2009. We checked the reference
lists of all relevant studies, key textbooks, reviews, and websites. We contacted investigators and
specialists in palliative care for unpublished data. SELECTION CRITERIA: We included randomised
controlled trials (RCTs) and controlled clinical trials (CCTs) assessing the effect of benzodiazepines in
relieving breathlessness in patients with advanced stages of cancer, chronic obstructive pulmonary
disease (COPD), chronic heart failure (CHF), motor neurone disease (MND), and idiopathic pulmonary
fibrosis (IPF). DATA COLLECTION AND ANALYSIS: Two review authors independently assessed
identified titles and abstracts. Three independent review authors performed assessment of all potentially
relevant studies (full text), data extraction, and assessment of methodological quality. We carried out
meta-analysis where appropriate. MAIN RESULTS: Seven studies were identified, including 200 analysed
participants with advanced cancer and COPD. Analysis of all seven studies (including a meta-analysis of
six out of seven studies) did not show a beneficial effect of benzodiazepines for the relief of
breathlessness in patients with advanced cancer and COPD. Furthermore, no significant effect could be
observed in the prevention of breakthrough dyspnoea in cancer patients. Sensitivity analysis
demonstrated no significant differences regarding type of benzodiazepine, dose, route and frequency of
delivery, duration of treatment, or type of control. AUTHORS' CONCLUSIONS: There is no evidence for a
beneficial effect of benzodiazepines for the relief of breathlessness in patients with advanced cancer and
COPD. There is a slight but non-significant trend towards a beneficial effect but the overall effect size is
small. Benzodiazepines caused more drowsiness as an adverse effect compared to placebo, but less
compared to morphine. These results justify considering benzodiazepines as a second or third-line
treatment within an individual therapeutic trial, when opioids and non-pharmacological measures have
failed to control breathlessness. Although a few good quality studies were included in this review, there is
still a further need for well-conducted and adequately powered studies.
van Wetering, C. R., M. Hoogendoorn, et al. (2010). "Short- and long-term efficacy of a community-
based COPD management programme in less advanced COPD: a randomised controlled trial."
Thorax 65(1): 7-13.
BACKGROUND: The effectiveness of pulmonary rehabilitation in advanced COPD is well
established, but few data are available in less advanced disease. METHODS: In a 2 year randomised
controlled trial, 199 patients with an average moderate airflow obstruction but impaired exercise capacity
(mean (SD) forced expiratory volume in 1 s (FEV(1)) 60 (16)%, peak work load (Wmax) <70%) were
randomised to the INTERdisciplinary COMmunity-based COPD management programme (INTERCOM)
or usual care. Intervention consisted of 4 months multidisciplinary rehabilitation followed by a 20-month
maintenance phase. Outcomes (4, 12, 24 months): health-related quality of life (St George's Respiratory
Questionnaire (SGRQ)), exacerbation frequency, MRC dyspnoea score, cycle endurance time (CET), 6-
minute walking distance (6MWD), skeletal muscle strength and patients' and caregivers' perceived
effectiveness. RESULTS: Between-group comparison after 4 months revealed the following mean (SE)
significant differences in favour of INTERCOM: SGRQ total score 4.06 (1.39), p = 0.004; activity and
impact subscores, p<0.01; MRC score 0.33 (0.13), p = 0.01; Wmax 6.0 (2.3) Watt, p = 0.02; CET 221
(104) s, p = 0.04; 6MWD 13 (6) m, p = 0.02; hand grip force 4.3 (1.5) lb, p<0.01; and fat-free mass index
0.34 (0.13) kg/m(2), p = 0.01. Between-group differences over 2 years were as follows: SGRQ 2.60 (1.3),
p = 0.04; MRC score 0.21 (0.10), p = 0.048; CET 253 (104) s, p = 0.0156; 6MWD 18 (8) m, p = 0.0155.
Exacerbation frequency was not different (RR 1.29 (95% CI 0.89 to 1.87)). Patients' and caregivers'
perceived effectiveness significantly favoured the INTERCOM programme (p<0.01). CONCLUSIONS:
This study shows that a multidisciplinary community-based disease management programme is also
effective in patients with COPD with exercise impairment but less advanced airflow obstruction.
12
White, P., S. White, et al. (2011). "Palliative care or end-of-life care in advanced chronic obstructive
pulmonary disease: a prospective community survey." Br J Gen Pract 61(587): e362-370.
BACKGROUND: Calls for better end-of-life care for advanced chronic obstructive pulmonary
disease (COPD) reflect the large number who die from the disease and their considerable unmet needs.
AIM: To determine palliative care needs in advanced COPD. DESIGN: Cross-sectional interview study in
patients' homes using structured questionnaires generated from 44 south London general practices.
METHOD: One hundred and sixty-three (61% response) patients were interviewed, mean age 72 years,
50% female, with diagnosis of COPD and at least two of: forced expiratory volume in the first second
(FEV(1)) <40% predicted, hospital admissions or acute severe exacerbations with COPD, long-term
oxygen therapy, cor pulmonale, use of oral steroids, and being housebound. Patients with advanced
cancer, severe alcohol-related or mental health problems, or learning difficulties, were excluded; 145
patients were included in the analysis. RESULTS: One hundred and twenty-eight (88%) participants
reported shortness of breath most days/every day, 45% were housebound, 75% had a carer. Medical
records indicated that participants were at least as severe as non-participants. Eighty-two (57%) had
severe breathlessness; 134 (92%) said breathlessness was their most important problem; 31 (21%) were
on suboptimal treatment; 42 (30%) who were severely affected had not been admitted to hospital in the
previous 2 years; 86 of 102 who had been admitted would want admission again if unwell to the same
extent. None expressed existential concerns and few discussed need in terms of end-of-life care, despite
severe breathlessness and impairment. CONCLUSION: Needs in advanced COPD were considerable,
with many reporting severe intractable breathlessness. Palliation of breathlessness was a priority, but
discussion of need was seldom in terms of 'end-of-life care'.
Yohannes, A. M. (2007). "Palliative care provision for patients with chronic obstructive pulmonary
disease." Health Qual Life Outcomes 5: 17.
Chronic obstructive pulmonary disease (COPD) is a major cause of disability, morbidity and
mortality in old age. Patients with advanced stage COPD are most likely to be admitted three to four times
per year with acute exacerbations of COPD (AECOPD) which are costly to manage. The adverse events
of AECOPD are associated with poor quality of life, severe physical disability, loneliness, and depression
and anxiety symptoms. Currently there is a lack of palliative care provision for patients with advanced
stage COPD compared with cancer patients despite having poor prognosis, intolerable dyspnoea, lower
levels of self efficacy, greater disability, poor quality of life and higher levels of anxiety and depression.
These symptoms affect patients' quality of life and can be a source of concern for family and carers as
most patients are likely to be housebound and may be in need of continuous support and care. Evidence
of palliative care provision for cancer patients indicate that it improves quality of life and reduces health
care costs. The reasons why COPD patients do not receive palliative care are complex. This partly may
relate to prognostic accuracy of patients' survival which poses a challenge for healthcare professionals,
including general practitioners for patients with advanced stage COPD, as they are less likely to engage
in end-of-life care planning in contrast with terminal disease like cancer. Furthermore there is a lack of
resources which constraints for the wider availability of the palliative care programmes in the health care
system. Potential barriers may include unwillingness of patients to discuss advance care planning and
end-of-life care with their general practitioners, lack of time, increased workload, and fear of uncertainty of
the information to provide about the prognosis of the disease and also lack of appropriate tools to guide
general practitioners when to refer patients for palliative care. COPD is a chronic incurable disease; those
in an advanced stage of the disease pursuing intensive medical treatment may also benefit from the
simultaneous holistic care approach of palliative care services, medical services and social services to
improve quality of end of life care.
13
4/4/2012
Dyspnea Management For

Advanced Lung Disease
Paula M. Meek PhD, RN
Professor
University of Colorado College of Nursing
Conflict of Interest
 None to declare
1
4/4/2012
Overview
 Advance COPD
 Latest Understanding of Mechanism associated
with dyspnea
 Measurement of dyspnea
 Interventions
 Summary
Advanced COPD
Advanced COPD
 GOLD Criteria
• Rabe, K. F., S. Hurd, et
al. (2007). Am J Respir BODE
Crit Care Med 176(6): Quartile
532-555.
GOLD Classification Classification
 BODE I Mild FEV1 80% Q1: 0-2
• Celli, B. R., C. G. Cote, et II Moderate FEV1 50%<80% Q2: 3-4
al. (2004). N Engl J Med
III Severe FEV1 30%<50% Q3: 5-6
350(10): 1005-1012.
III Very Severe FEV1 <30% Q4: 7-10
2
4/4/2012
Advanced COPD
 Health Status
• Amorós, M.M., Mas-Tous, C., et al. Chronic
Respir Dis 2009; 6: 75–80
NHP BODE
SGRQ Imp GOLD
SGRQ Act
SGRQ Sym
SGRQ Tot
-0.25 0 0.25 0.5 0.75

Correlation
3
4/4/2012
Issues in Advanced COPD

 Depression
 Anxiety
 Increase Dyspnea
• Other symptoms - fatigue
 Activity Limitations
 Social limitations- isolation
 Frequent Health Care
• Urgent care
• Hospitalizations
Mechanism associated with

dyspnea
ATS Statement on dyspnea 2012
Dyspnea
“dyspnea is a term used to
characterize a subjective
experience of breathing
discomfort that is comprised of
qualitatively distinct sensations
that vary in intensity.”
ATS, 1999, 2012
4
4/4/2012
Key differences 1999-2012

1. Distinct Mechanisms and afferent
pathways are reliably associated with
different sensory qualities
• Work/Effort
• Tightness
• Air hunger/unsatisfied inspiration
2. Distinct sensations most often do not
occur in isolation
3. Dyspnea sensation vary in unpleasantness
Possible Afferent Sources

for Respiratory Sensations
Possible Afferent Sources

for Respiratory Sensations
5
4/4/2012
Measurement
Domains of Dyspnea Measurement

 Sensory-perceptual experience-what the breathing
feels like
• Single items (VAS, Borg)
• Descriptors of sensations (MDP,dyspnea-12)
 Affective distress- how distressing

• Single items (VAS, Borg)
 Symptom impact or burden- affects on functional

ability or health status.
• Unidimensional rating of disability or activity limitation (MRC)
• Unidimensional multi-rating functional ability (PFSDQ)
• Multidimensional quality of life/health status (CRQ, SGRQ)
6
4/4/2012
Systematic Issues
General measurement properties
Dyspnea Typical purpose Question Scaling

Measures Timeframe
VAS Both Currently 0 to 100
BDI/TDI Discriminative Current 0 to 12
Evaluative change from -9 to +9
BDI
CRQ Both Last 2 wks 1 to 7
PFSDQ-M Discriminative Currently, 0 to 10
Today, Most
days,
Mechanisms and
Measuring Change
Timeframe of Improvement
Mechanism Rapid Intermediate Prolonged
Reduce resistive load
Rx Therapy
Improve Inspiratory Muscle
Function
Inspiratory muscle
training
Alter Central Perception
Education
BODE-MRC
7
4/4/2012
MRC Scale
 Grade1- are you ever troubled by breathlessness
except on strenuous exertion?
 Grade 2- if yes: are you short of breath when
hurrying on the level or walking up a slight hill?
 Grade 3- if yes: do you have to walk slower than
most people on the level? Do you have to stop
after a mile or so (30min) on the level at your own
pace?
 Grade4- if yes to either: do you have to stop for
breath after walking about 100 yards (or a few
minutes) on the level?
 Grade5- if yes: are you to breathless to leave the
house, or breathless after undressing?
Effort and Distress
Effort is the amount of Greatest Greatest
work or energy you

possible possible
distress effort
feel is associated with

your breathing
Distress is the amount
of upset associated
with your breathing
effort
No distress No effort
Interventions
8
4/4/2012
9
4/4/2012
Muscle fatigue Dyspnea

5
4.5
4
3.5
3
Borg
2.5
2
1.5
1
0.5
0
1 2 3 4 5
Week
10
4/4/2012
Summary
Approach to Dyspnea in
Advanced COPD
Self- Management
Dealing with Anxiety, Managing Depression
11
Targeting The Chronic Obstructive
Pulmonary Disease Exacerbation
Jadwiga A. Wedzicha, MD
12:45 pm - 1:10 pm
TARGETING THE COPD EXACERBATION
Jadwiga A Wedzicha
Centre for Respiratory Medicine
University College London
London, UK
w.wedzicha@ucl.ac.uk
SUMMARY
Exacerbations of chronic obstructive pulmonary disease are associated with

considerable morbidity and mortality and cost to health care services. Exacerbations
also contribute to disease progression in COPD and thus prevention of exacerbations
is important in improving prognosis. COPD exacerbations are complex events with a
variety of triggers, inflammatory processes at exacerbation onset and recovery and
require an integrated approach with the following components:
• Coordinated patient centred services

• Patient education about nature of exacerbation symptoms and interventions
available
• Early/prompt presentation for therapy with exacerbation and contact with
health care professionals
• Assessment of COPD severity, exacerbation risk and differential diagnosis
• Appropriate exacerbation management and prevention
• Self-management for suitable patients
• Follow up of the exacerbation
COPD exacerbations are often associated with infective triggers such as respiratory
viruses and airway bacteria and this leads to increase in airway and systemic
inflammation and the major symptoms of exacerbations such as increased shortness of
breath, cough, increased sputum volume and purulence. COPD exacerbations
generally increase in frequency and severity as COPD progresses but it is now clear
that even in moderate COPD (FEV1 between 50 and 80% predicted) some patients
are susceptible to COPD exacerbations and these are known as frequent exacerbators
(exacerbation frequency at 2 or more exacerbations per year). The best marker of a
patient’s exacerbation frequency is the number of exacerbations in the previous year
and this was shown in both the ECLIPSE cohort and in the London COPD cohort. It
has been recently suggested that intervention in moderate Stage 2 GOLD disease to
prevent COPD exacerbations may have a greater effect on disease progression and
mortality than treating later in the natural history of the disease.
Patient education is key in the integrated management of the exacerbation and

patients must be aware of the triggers of exacerbations and the key symptoms to
enable self-management or to present to health care professionals for therapy. It has
been estimated that in the region of 30 to 50% of COPD exacerbations are not
reported to healthcare professionals for treatment or are not self-managed. Patients
with a history of under reporting of exacerbations are more likely to have worse
health status and an increased chance of hospital admissions.
In addition to presentation for therapy, patients need to be treated as soon as possible

after the onset of their exacerbations and data from the London COPD cohort showed
some time ago that the longer the delay between onset of symptoms and therapy, the
lomger the exacerbation and this was confirmed in a study of hospital admission by
Chandra et al 2009. The benefit of early intervention was shown in an
epidemiological study of antibiotic therapy in patients hospitalized for COPD and
patients were more likely to show improved outcomes with prompt onset of therapy.
Another intervention that requires prompt use is noninvasive ventilation that reduces
mortality in exacerbations associated with respiratory failure. A hospital admission
may also be an important “opportunity” to educate the patient, review their COPD,
address cigarette smoking, enroll them into pulmonary rehabilitation programmes,
assess any psychosocial needs, co-morbidities and helping them to understand
exacerbation symptoms.
Studies have shown high readmission rates after hospital admissions for COPD
exacerbations and this may be due to delayed initial therapy but also may be due to
the fact that once a patient develops one exacerbation they are more prone to
develop another one in the next 8 weeks (clustering). Patients with a history of
frequent exacerbations are more likely to show exacerbation clustering. Thus follow
up of the patient in the period after a hospital admission or a severe exacerbation is
important to ensure recovery.
A number of studies have shown that patients develop fatigue and muscle weakness
during exacerbations. There has been much interest in the concept of intervention
with pulmonary rehabilitation early during exacerbation recovery. There have been a
number of small mainly positive studies showing benefit but one large well designed
study from New Zealand where the programme was started in hospital and transferred
to primary recovery showed no significant difference between the active and placebo
groups in main outcomes. Participation in the programme overall was not optimal
and thus there is a need to develop strategies to enable patients to improve adherence.
There have been a number of hospital at home and self-management programmes

described though results have been variable and generally the best outcomes are seen
in programmes from specialist centres. Some programmes have reduced hospital
admissions though the increased contact with health care professionals can lead to
more physician visits. Thus there is a need to tailor particular programme and their
intensity to the specific population according to the needs of the patient. Over the last
few years, there has already been considerable improvement and advances in the
management of COPD exacerbations and by using an integrative approach we can
enhance the outcome of exacerbations further and improve the our COPD patients
quality of life.
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prevention. Lancet. 2007;370:786-96.
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Time course and recovery of exacerbations in patients with chronic obstructive
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Seemungal TAR, Harper-Owen R , Bhowmik A, Moric I, Sanderson G, Message

S, MacCallum P, Meade TW, Jeffries DJ , Johnston SL,, Wedzicha JA
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Eur Respir J. 2010 501-7
Hurst JR, Vestbo J, Anzueto A, Locantore N, Müllerova H, Tal-Singer R, Miller B,

Lomas DA, Agusti A, MacNee W, Calverley P, Rennard S, Wouters EFM, Wedzicha
JA, Susceptibility to Exacerbation in Chronic Obstructive Pulmonary Disease.
N Engl J Med. 2010; 63: 128-1138
Michael B. Rothberg, Penelope S. Pekow, Maureen Lahti, Oren Brody, Daniel J.

Skiest, Peter K. Lindenauer. Antibiotic Therapy and Treatment Failure in Patients
Hospitalized for Acute Exacerbations of Chronic Obstructive Pulmonary Disease
JAMA. 2010;303(20):2035-2042.
Lightowler JVJ, Wedzicha JA, Elliott MW, Ram FSF. Non-invasive positive pressure
ventilation for the treatment of respiratory failure due to exacerbations of chronic
obstructive pulmonary disease: a Cochrane systematic review and meta-analysis.
BMJ 2003; 326:185-7
Hurst JR, Donaldson GC, Quint JK, Goldring JJP, Baghai-Ravary B, Wedzicha JA.
Temporal Clustering of Exacerbations in Chronic Obstructive Pulmonary Disease
Am. J. Respir. Crit. Care Med. 2009; 179: 369-374.
Baghai R. Quint JK, Goldring J, Donaldson GC, Hurst J, Wedzicha JA Determinants

and impact of fatigue in chronic obstructive pulmonary disease. Respiratory Medicine
2009; 103:216-23
Man WD, Polkey MI, Donaldson N, et almCommunity pulmonary rehabilitation after

hospitalisation for acute exacerbations of chronic obstructive pulmonary disease:
randomised controlled study. BMJ 2004;329:1209.↵
Puhan M, Scharplatz M, Troosters T, et al Pulmonary rehabilitation following

exacerbations of chronic obstructive pulmonary disease. Cochrane Database Syst Rev
2009:CD005305.
Outpatient pulmonary rehabilitation following acute exacerbations of COPD

John M Seymour, Lauren Moore, Caroline J Jolley, Katie Ward, Jackie Creasey, Joerg S
Steier, Bernard Yung, William D-C Man, Nicholas Hart, Michael I Polkey, John Moxham
Outpatient pulmonary rehabilitation following acute exacerbations of COPD
Thorax 2010;65:423-428
Tam EATON1, Pam YOUNG1, Wendy FERGUSSON1, Lisa MOODIE1, Irene

ZENG1, Fiona O'KANE1, Nichola GOOD1, Leanne RHODES1, Phillippa POOLE2,
John KOLBE1,2 Does early pulmonary rehabilitation reduce acute health-care
utilization in COPD patients admitted with an exacerbation? A randomized controlled
study DOI: 10.1111/j.1440-1843.2008.01418.x
Taylor SJC, Candy B, Bryar RM, Ramsay J, Vrijhoef HJM, Esmond G, Wedzicha
JA, Griffiths CJ. Effectiveness of nursing and nurse-led chronic disease management
innovations for patients with chronic obstructive pulmonary disease: systematic
review of evidence. BMJ 2005: 331: 485
Bourbeau J, Julien M, Maltais F, et al Reduction of hospital utilization in patients

with chronic obstructive pulmonary disease: a disease-specific self-management
intervention. Arch Intern Med 2003;163:585–91.
Effing T, Kerstjens H, van der Valk P, Zielhuis G, van der Palen J. Cost-effectiveness
of self-treatment of exacerbations on the severity of exacerbations in patients with
COPD: the COPE II studyThorax. 2009 Nov;64(11):956-62.
Jaap C A Trappenburg, Evelyn M Monninkhof, Jean Bourbeau, Thierry Troosters,

Augustinus J P Schrijvers, Theo J M Verheij, Jan-Willem J Lammers Effect of an
action plan with ongoing support by a case manager on exacerbation-
related outcome in patients with COPD: a multicentre randomised controlled trial
Thorax 2011;66:977-984
Bischoff EW, Hamd DH, Sedeno M, Benedetti A, Schermer TR, Bernard S, Maltais
F, Bourbeau J. Effects of written action plan adherence on COPD exacerbation
recovery. Thorax. 2011 Jan; 66(1):26-31.
TARGETING THE COPD
EXACERBATION
Professor Wisia Wedzicha

UCKL Medical School
University College London, UK
SURVIVAL OF COPD PATIENTS AFTER HOSPITAL

DISCHARGE IN 2 COHORTS –
1996-1997AND 2003-2004
Almagro P et al. Thorax 2010;65:298-302
INTEGARTED CARE OF THE

EXACERBATION
• Coordinated patient centred services

• Education about nature of exacerbation symptoms
and interventions available
• Early/prompt presentation for therapy with
exacerbation and contact with health care
professionals
• Assessment of COPD severity, exacerbation risk
and differential diagnosis
• Appropriate exacerbation management
• Self-management for suitable patients
• Follow up of the exacerbation
1
EXACERBATIONS AND DISEASE SEVERITY
DATA FORM LARGE TRIALS
ISOLDE – oral steroids or antibiotics

CCLS – more cough and phlegm
EUROSCOP - therapy
Burge, Wedzicha
ERJ 2003
ECLIPSE DATA
ASSOCIATION OF DISEASE SEVERITY WITH THE
FREQUENCY AND SEVERITY OF EXACERBATIONS
Hurst JR et al. N Engl J Med 2010;363:1128-1138
ECLIPSE DATA
ASSOCIATION OF DISEASE SEVERITY WITH THE
FREQUENCY AND SEVERITY OF EXACERBATIONS
71% OF FREQUENT EXACERBATORS IN YEAR 1 AND

YEAR 2 WERE FREQUENT EXACERBATORS
IN YEAR 3
Hurst JR et al. N Engl J Med 2010;363:1128-1138
2
PATIENT RECALLED EXACERBATION
FREQUENCY AND ACTUAL EXACERATION
FREQUENCY
87.1% 86.8%
Data from London COPD
cohort
%
patients % Recalling themselves to be IE
by
% Recalling themselves to be FE
recall
infrequent frequent
exacerbators exacerbators Quint et al ERJ In press
Classified by diary cards
TORCH DATA – ANALYSIS BY DISEASE SEVERITY

Jenkins et al Respiratory Research 2009
EXACERBATIONS
UPLIFT Mild* COPD subgroup: Exacerbations

*FEV > 50%
Decramer et al Lancet 2009
Hazard
Tiotropium Control
Ratio P-value
n = 1384 n = 1355
(95% CI)
Time to first
exacerbation 23.1 (21.0, 17.5 (15.9, 0.82 (0.75, <0.0001
(month) 26.3) 19.7) 0.90)* *
Mean number of
exacerbations/pt yr 0.56 (0.52, 0.70 (0.65, 0.80 (0.72,
<0.0001†
(95% CI) 0.60) 0.75) 0.88)†
3
SELF MANAGEMENT SCHEMES AT COPD
EXACERBATIONS
• Recognition of nature of stable and

exacerbation symptoms (differential diagnosis)
• Understanding the triggers of exacerbation
• How to alter medication
• Contact person
• Recognition of worsening and life threatening
symptoms
• Preventative strategies
from Bourbeau et al in Chronic Obstructive Pulmonary Disease Exacerbations,

Lung Biology in Health and Disease ed Wedzicha, Martinez 2008
From Wedzicha, JA, Seemungal T

Lancet 2007
EXACERBATIONS: REPORTED AND

UNREPORTED
200
50% not reported to study team
180 (UNREPORTED EXACERBATIONS)
160
140
120
100
80
60
40
20
0
Total Rep Unrep
Seemungal et al AJRCCM 1998

Seemungal et al AJRCCM 1998
4
IMPORTANCE OF UNREPORTED EXACERBATIONS
Wilkinson et all AJRCCM 2004
Rho = -0.22, p = 0.018

=
SGRQ
Total
< 25% > 75%

% Exacerbations Treated
RELATION BETWEEN EXACERBATION

THERAPY AND HOSPITALISATION
P<0.04
Wilkinson et al AJRCCM 2004
SIGNIFICANCE OF TREATMENT DELAY

Figure 1
AND RECOVERY TIME
Wilkinson et al AJRCCM 2004
Total Recovery Time
Treatment
Treated Recovery Time
Prodrome Delay
Exacerbation Initiation of
Onset Treatment
5
SYMPTOM ONSET AND EARLY
START OFTHERAPY
24
Symptom recovery time (days)
P<0.001
18
12
0
0 7 14
Delay between onset and treatment (days)
Patients who receive prompt therapy after symptom onset are likely to
recover more rapidly than are patients whose treatment is delayed
Wilkinson et al. Am J Respir Crit Care Med. 2004;169:1298-1303.
DELAY IN PRESENTATION AMD RISK OF HOSPITAL ADMISSION

Chandra et al COPD 2009
Late presenters had more symptoms

Presentation > 24 hours increased risk of hospital admission
(OR 2.2; 95%CI 1.1-4.8)
6
UNADJUSTED OUTCOMES BY ANTIBIOTIC EXPOSURE
Rothberg et al
JAMA 2010
Rothberg, M. B. et al. JAMA 2010;303:2035-2042.
BENEFITS OF NONINVASIVE VENTILATION

ON MORTALITY
Lightowler et al BMJ 2003
7
READMISSION AFTER COPD
EXACERBATION
UK NATIONAL COPD AUDIT
Thorax 2006
234 Acute Hospitals identified 40 consecutive

admissions
Readmission rate 31.4% at 90 days
Mortality 15.3% (inpatient at 7.4%)
“OPPORTUNITY” OF THE
HOSPITAL ADMISSION
• Review of COPD severity – smoking status
• Assess psychosocial needs
• Adherence to therapy
• Exacerbation symptoms – who to contact?
• Co-morbidities
• Dietary review
• Access to rehabilitation
• Assessment for home oxygen, home NIV if
required
CRP AND EXACERBATION RECOVERY
P=0.03
Perera et al ERJ 2007
8
CRP at DAY 14 AND RECURRENT EXACERBATION
AT 50 DAYS Perera et al ERJ2007 P<0.01
EXACERBATION CLUSTERING
Hurst et al AJRCCM 2009
633 Exacerbations occurred between 3 and

2189 Exacerbations 8 weeks, 103 (19.4%) more than that
1923 Exacerbation intervals predicted by the exponential function
(p=0.040).
EXACERBATIONS AND OUTDOOR ACTIVITY

Donaldson et al AJRCCM 2005
50 3
OPEN CIRCLES
CLOSED CIRCLES
45
Symptom count
2
% of patients
Housebound
40
1
35
30 0
-14 -7 0 7 14 21 28 35
Days
9
FATIGUE ASSOCIATED WITH COPD EXACERBATIONS
Baghai et al Resp Med 2009
Puhan et al Cochrane Review 2009
EARLY REHABILITATION AT
EXACERBATION
Eaton et al Respirology 2009
• Study spanned in-patient and out-patient

admission
• Only 57% of patients satisfied eligibility
criteria, significant number refused
• Intervention started mean 2.6 days from
admission
• 40% attended 75% of the session –
“attendees”
• No effect on hospital admissions
10
EARLY PULMONARY REHABILITATION
Eaton et al Respirology 2009
PRIMARY OUTCOME – TIME TO FIRST COPD – RELATED ADMISSION
P=0.32
EARLY REHAB
USUAL CARE
USUAL CARE (N=30) POST EX PR (N=30) P VALUE
Hospital admission 10 (33%) 2(7%) 0.02

For exacerbation
ED attendance 7(23%) 6 (27%) 0.52
Hospital or
ED attendance 17 (57%) 8 (27%) 0.02
Thorax 2010 Seymour et al
CHANGE IN QUADRICEPS MAXIMUM VOLUNTARY

CONTRACTION (QMVC) AND CHANGE IN
INCREMENTAL SHUTTLE WALKING TEST (ISW).
P<0.01
Seymour J M et al. Thorax 2010
11
ISSUES IN PERFORMING STUDIES OF
REHABILITATION AT
HOSPITALADMISSION/ EXACERBATION
• Eligible groups will be relatively small
• Co-morbidity complicates
• Usual care will vary
• Hospital admission should not be prolonged
• Patients need careful follow up of their
exacerbation and further therapy if
required
• Exercise training should be a feature of all
exacerbations
No Caption Found
UPPER LOBE
EMPHYSEMA
Hunsaker, A. R. et al. N Engl J Med

2003;348:2091
EFFECT OF LUNG VOLUME REDUCTION ON EXACERBATIONS

Washko et al AJRCCM2008
12
NOVEL MODELS OF CARE FROM COPD
EXACERBATIONS
from Partridge M in Chronic Obstructive Pulmonary Disease Exacerbations,
Lung Biology in Health and Disease ed Wedzicha, Martinez 2008
• Nurse led care

• Hospital at home schemes,
• Admission avoidance schemes
• Early (or assisted) discharge schemes
• Case management
Effects of nurse led management interventions for COPD on mortality

(from trials of long term or intensive interventions)
Taylor, S. J C et al. BMJ 2005;331:485
EDUCATION AND SUPPORT

Bourbeau, J. et al. Arch Intern Med 2003;163:585-591
13
“INTEGRATED CARE” PREVENTS HOSPITALISATIONS
Casas et al ERJ 2006
155 patients in Barcelona and Leuven recruited after hospital discharge

•Patient assessment at discharge
•Self- management education
•Individually tailored programme agreed with nurse case manager and primary care
•E Health approach used for communication
Lower hospitalisation rates with IC
Integrated Care Less readmissions
No differences in mortality
Usual care
Thorax 2008
Treatment Control
FLOW DIAGRAM OF PROGRESS OF SUBJECTS THROUGH THE COPE

II STUDY.
Effing T et al. Thorax 2009;64:956-962
14
NUMBER OF EXACERBATION DAYS PER YEAR FOR PATIENTS IN
THE INTERVENTION AND CONTROL GROUPS
Effing T et al. Thorax 2009;64:956-962
“HOSPITAL AT HOME SCHEMES”

RELATIVE RISK FOR READMISSION TO HOSPITAL
Ram F et al. BMJ 2004;329:315
PATIENTS NOT SUITABLE FOR

“HOSPITAL AT HOME” PROGRAMMES
BTS Statement on Intermediate Care Thorax 2007
• Those with impaired level of consciousness

• Those with acute confusion
• Respiratory acidosis (pH < 7.35)
• Those with acute changes on a chest radiograph
• Those in whom co-morbidity necessitates
hospitalisation
• Patients with insufficient social support or lack of
access to a telephone or long distance from
hospital
• Those with apparently new onset hypoxemia (Sp02
equal to or less than 90%)
• If oxygen can not be provided at home.
15
CONCLUSIONS
• Exacerbation management and

prevention require a number of
coordinated interventions
• Integrated care can be organised and
needs involvement of both primary
and secondary care
16
Palliative Care And Pulmonary
Rehabilitation
Daisy Janssen, MD
1:35 pm - 2:00 pm
Summary Postgraduate Course 11
Palliative care and Pulmonary rehabilitation by D.J.A. Janssen
COPD is a major course of mortality worldwide. Symptom burden of patients with advanced
COPD is comparable with symptom burden of patients with cancer. The last years, the need
for palliative care of patients with advanced chronic lung disease has been recognized.
Palliative care aims to improve quality of life by early identification and treatment of
physical, psychological, social and spiritual problems. Palliative care should not be limited to
terminal care, but should be offered early in the course of the disease. An important aspect
of early palliative care is advance care planning. Advance care planning can be defined as
“planning for and about preference sensitive decisions often arising at the end‐of‐life and
implemented usually by means of effective patient‐provider communication and education”.
Advance care planning can be effective in changing outcomes for patients and their loved
ones. However, in patients with COPD advance care planning occurs rarely, despite the fact
that these patients are able to indicate their preferences for life‐sustaining treatments and
end‐of‐life care. Pulmonary rehabilitation may be an opportunity for introduction of advance
care planning. Indeed, education is a core component of pulmonary rehabilitation. Patients
with COPD have indicated that they need education about prognosis, dying, and advance
care planning. Nevertheless, most pulmonary rehabilitation programs do not offer education
about advance care planning. An education workshop about advance directives and end‐of‐
life topics during pulmonary rehabilitation was able to increase the proportion of patients
that completed a living, as well as the proportion of patients that discussed advance
directives with their physician, and the proportion of patients that expected their physician
to understand their wishes for life‐support. Therefore, pulmonary rehabilitation provides the
opportunity to facilitate advance care and directive education by creating a venue that
encourages increased completion of living wills and durable powers of attorney for health
care, patient‐physician discussions about advance directives, and discussions about options
for life support.
Reference list Postgraduate Course 11
1. Curtis, J.R., Palliative and end‐of‐life care for patients with severe COPD. Eur Respir J.
2008;32(3):796‐803.
2. Edmonds, P., S. Karlsen, S. Khan, and J. Addington‐Hall, A comparison of the palliative
care needs of patients dying from chronic respiratory diseases and lung cancer.
Palliat Med. 2001;15(4):287‐95.
3. Gore, J.M., C.J. Brophy, and M.A. Greenstone, How well do we care for patients with
end stage chronic obstructive pulmonary disease (COPD)? A comparison of palliative
care and quality of life in COPD and lung cancer. Thorax. 2000;55(12):1000‐6.
4. World Health Organisation. WHO definition of palliative care.
http://www.who.int/cancer/palliative/definition/en Accessed 12/01/2011.
5. Claessens, M.T., J. Lynn, Z. Zhong, et al., Dying with lung cancer or chronic obstructive
pulmonary disease: insights from SUPPORT. Study to Understand Prognoses and
Preferences for Outcomes and Risks of Treatments. J Am Geriatr Soc. 2000;48(5
Suppl):S146‐53.
6. Lanken, P.N., P.B. Terry, H.M. Delisser, et al., An official American Thoracic Society
clinical policy statement: palliative care for patients with respiratory diseases and
critical illnesses. Am J Respir Crit Care Med. 2008;177(8):912‐27.
7. Lorenz, K.A., L.R. Shugarman, and J. Lynn, Health care policy issues in end‐of‐life care.
J Palliat Med. 2006;9(3):731‐48.
8. Patel, K., D.J. Janssen, and J.R. Curtis, Advance care planning in COPD. Respirology.
2012;17(1):72‐8.
9. Janssen, D.J., M.A. Spruit, J.M. Schols, et al., Predicting changes in preferences for
life‐sustaining treatment among patients with advanced chronic organ failure. Chest.
2011 Published online ahead of print. DOI: 10.1378/chest.11‐1472.
10. Janssen, D.J., M.A. Spruit, J.M. Schols, and E.F. Wouters, A call for high‐quality
advance care planning in outpatients with severe COPD or chronic heart failure.
Chest. 2011;139(5):1081‐88.
11. Gardiner, C., M. Gott, N. Small, et al., Living with advanced chronic obstructive
pulmonary disease: patients concerns regarding death and dying. Palliat Med.
2009;23(8):691‐7.
12. Nici, L., C. Donner, E. Wouters, et al., American Thoracic Society/European
Respiratory Society statement on pulmonary rehabilitation. Am J Respir Crit Care
Med. 2006;173(12):1390‐413.
13. Curtis, J.R., M.D. Wenrich, J.D. Carline, et al., Patients' perspectives on physician skill
in end‐of‐life care: differences between patients with COPD, cancer, and AIDS. Chest.
2002;122(1):356‐62.
14. Heffner, J.E., B. Fahy, and C. Barbieri, Advance directive education during pulmonary
rehabilitation. Chest. 1996;109(2):373‐9.
15. Heffner, J.E., B. Fahy, L. Hilling, and C. Barbieri, Attitudes regarding advance directives
among patients in pulmonary rehabilitation. Am J Respir Crit Care Med. 1996;154(6 Pt
1):1735‐40.
16. Heffner, J.E., B. Fahy, L. Hilling, and C. Barbieri, Outcomes of advance directive
education of pulmonary rehabilitation patients. Am J Respir Crit Care Med.
1997;155(3):1055‐9.
17. Silveira, M.J., S.Y. Kim, and K.M. Langa, Advance directives and outcomes of
surrogate decision making before death. N Engl J Med. 2010;362(13):1211‐8.
Glossary Postgraduate Course 11
Advance care planning=

Planning for and about preference sensitive decisions often arising at the end‐of‐life and
implemented usually by means of effective patient‐provider communication and education.
Palliative care=
Palliative care is an approach that improves the quality of life of patients and their families
facing the problem associated with life‐threatening illness, through the prevention and relief
of suffering by means of early identification and impeccable assessment and treatment of
pain and other problems, physical, psychosocial and spiritual.
Palliative care and
Pulmonary
Rehabilitation
Daisy J.A. Janssen, MD PhD

ATS conference 2012
Presenter disclosures
Daisy J.A. Janssen
• Personal financial relationships with commercial interests

relevant to medicine, within past 3 years:
No relationships to disclose
• Personal financial support from a non-commercial source

relevant to medicine, within past 3 years:
• Personal relationships with tobacco industry entities within

the past 3 years:
1
Outline
• Palliative care needs
• Disease trajectory COPD
• Palliative care model
• Advance care planning and

Pulmonary rehabilitation
Introduction
• COPD is a major cause of

mortality worldwide
• Symptom burden and

quality of life comparable
with cancer patients
• Need for palliative care
Edmonds et al. Palliat Med 2001 Gore et al. Thorax 2000
‘Palliative care is an approach that improves the

quality of life of patients and their families
facing the problem associated with life-
threatening illness, through the prevention and
relief of suffering by means of early identification
and impeccable assessment and treatment of
pain and other problems, physical, psychosocial
and spiritual’.
2
Psychological Social
Physical Spiritual
Quality
of Life
Symp-
toms
Commu- Care
nication needs
Palliative
care needs
Treat-
ment
Family
prefe-
rences
Health
status
Disease trajectory
3
Lorenz et al. J Palliat Med 2006
6-month survival estimate

before death
0.6
0.5
0.4
0.3
0.2
Lung cancer
0.1
0
7 6 5 4 3 2 1
Days to Death
Claessens et al. JAGS 2000

before death
0.6
0.5
0.4
0.3
0.2 Lung cancer
0.1
COPD
0
7 6 5 4 3 2 1
Days to Death
Claessens et al. JAGS 2000
4
Predicting appropriate
timing of palliative care?
Palliative care model
Lanken et al. AJRCCM 2008
5
Palliative care
End
of life
Care
Curtis et al. ERJ 2008
6
Advance care planning
“Planning for and about preference

sensitive decisions often arising at the
end-of-life and implemented usually by
means of effective patient-provider
communication and education.”
Patel et al. Respirology 2011
• Discussions regarding goals of care

• Resuscitation and life support
• Palliative care options
• Surrogate decision making
• Living wills and medical directives
7
ATS principles palliative care
“Palliative care includes identification of,
and respect for, the preferences of
patients and families.
This should be done through careful

assessment of their values, goals, and
priorities, as well as their cultural context
and spiritual needs.”
Health and Retirement study
42.5% 70.3%
3746 subjects required lacked
≥ 60 years decision- capacity to
Making make
decisions
Silveira et al. NEJM 2010
Health and Retirement study
• patients who had prepared advance directives

received care that was strongly associated
with their preferences
• patients with a living will were more likely to

receive comfort care before dying than
patients without a living will
Silveira et al. NEJM 2010
8
Preferences for CPR
2%
28%
yes
70% no
don't know
n=105 Janssen et al. Chest 2011

According to physician
25
According to physician and patient
% patients with ACP
20
20%
15
16%
10
5
6%
4%
0
COPD CHF
Janssen et al. Chest 2011
9
Stability of preferences for CPR
13%
11%
no change
decreased willingness
increased willingness
variable preference
14% 62%
Predictors of changes
Changes over time in:
 generic health status

 Mobility
 symptoms of anxiety and depression
 marital status
COPD patients concerns

regarding death and dying
• Poor understanding of COPD
• Unaware of progressive nature
• Few aware they could die of COPD
• Concerns that their condition might
deteriorate
• Concerns regarding manner of their death
• Fear of breathlessness or suffocation
• None had discussed these fears with health
care professional
Gardiner et al. Palliat Med 2009
10
Quality of communication:
general
p>0.05
10
QOC score (points)
0
COPD CHF
Quality of communication:
end-of-life care
p>0.05
10
QOC score (points)
0
COPD CHF
Items not addressed
• talking about how long you have to live (88.6%)

• talking about what dying might be like (88.6%)
• asking about spiritual or religious beliefs (93.4%)
• involving you in treatment discussions about your
care (84.9%)
• asking you about important things in life (83.2%)
11
Barriers to advance care
planning
• Assumptions that clinicians will initiate ACP
discussions when they are needed
• Lack of education regarding COPD and its course
and prognosis
• Not being informed about having a life-limiting
disease
• Avoidance of ACP discussions out of fear of
abandonment
PR: Opportunity to
advance care planning?
Curative
care
Palliative
care
Education=
Core component of
Pulmonary Rehabilitation
Nici et al. AJRCCM 2006
12
Educational needs
• Diagnosis
• Disease process
• Treatment
• Prognosis
• What dying might be like
• Advance care planning
Curtis et al. Chest 2002
Provided AD education during PR
AD education materials 42
AD education 33
Recording AD 17
33
Discussing AD
Prognostic information 82
0 20 40 60 80 100
% PR programs
Heffner et al. Chest 1996
Need for AD education during PR
Need information LS 69
Need information AD 89
Completed AD 42
94
Opinions CPR
Health worries 94
0 20 40 60 80 100
% patients
Heffner et al. AJRCCM 1996
13
Need for AD education during PR
Feeling physician 14
understood wishes
19
Had ACP
99
Wanted ACP
0 20 40 60 80 100
% patients
AD education intervention
Education
PR site 1 workshop Living wills
AD
End-of-life topics AD discussed
Impression physician
understood wish
PR site 2 Usual care group
Living will
80
72
70 *
60
% patients
52
50 Education
44
* Control
40
30
30
20
Baseline Follow-up
* p<0.05 compared with baseline, between groups

p>0.05 between group comparisons Heffner et al. AJRCCM 1997
14
AD discussed
60 58 *
50 #
40 44 *
% patients
30 Education
22
Control
20
19
10
0
Baseline Follow-up

# p<0.05 between group comparisons Heffner et al. AJRCCM 1997
Understanding with
physician about life-support
60
50 44
40
*
% patients
30 # Education
Control
20 14 19
10
9
0
Baseline Follow-up

# p<0.05 between group comparisons Heffner et al. AJRCCM 1997
Conclusions
• Need for palliative care for patients with

advanced COPD
• Need for advance care planning
• Lack of advance care planning
• Pulmonary rehabilitation: opportunity for
advance care planning education
15
16
Widening The Application Of Pulmonary
Rehabilitation
Frits Franssen, MD
2:30 pm - 2:55 pm
‘Widening the application of pulmonary rehabilitation’
Frits Franssen, MD, PhD
Summary:
In the updated ATS/ERS statement on pulmonary rehabilitation (PR) 2012, PR is defined as

a comprehensive intervention based on a thorough patient assessment followed by patient-
tailored therapies, which include, but are not limited to, exercise training, education and
behavior change, designed to improve the physical and emotional condition of people with
chronic respiratory disease and to promote the long-term adherence of health-enhancing
behaviors. The purpose of PR is to minimize symptoms, maximize exercise performance,
promote autonomy, increase participation in everyday activities, improve the overall quality of
life, improve long-term health-enhancing behavior, and provide tools to elicit behavior change
in physical activity and symptom management in people with chronic respiratory disease.
Traditionally, pulmonary rehabilitation programs enrolled patients with severe to very severe
COPD. Nevertheless, the correlation between the degree of airflow limitation and daily
symptoms of dyspnea, health status (1) and exercise performance is weak and extra-
pulmonary features and co-morbidities of COPD also occur in patients with a mild to
moderate degree of airflow limitation (2). Therefore, pulmonary rehabilitation should be
considered in COPD patients, irrespective of the degree of lung function impairment. In fact,
the revised GOLD guidelines 2011 state that PR should be offered to all patients who get
short of breath when walking on their own pace on level ground (mMRC ≥2). Indeed, a
community-based pulmonary rehabilitation program showed to be effective in improving
exercise tolerance, muscle function and health status patients with moderate COPD but with
an impaired exercise performance at baseline (3).
Exacerbations represent a major health burden for patients with COPD and are responsible
for a large proportion of health care costs attributable to this disease (4). They are associated
with increased morbidity and mortality (5), as well as substantial decline in functional status
(6), muscle function (7), health related quality of life (8) and psychological distress (9). Given
the positive effects of PR on these outcomes in patients with stable disease, it appears
logical to consider the effects of pulmonary rehabilitation in the acute setting. Indeed, a
systematic Cochrane review of nine randomized trials comparing outcomes of PR versus
usual care after an exacerbation showed a significant reduction in hospital readmission in the
PR groups (10). Post-hospitalisation PR also resulted in lower mortality and improved health
status and functional performance compared to usual care (10). Thus the current body of
evidence suggests that pulmonary rehabilitation is an effective and safe intervention in
COPD patients after exacerbation. At this time, some questions are unanswered. The
minimal duration of post-hospitalization PR, the duration of benefit and the optimal setting
are currently unknown. Also, the effect of PR after exacerbations of other respiratory
diseases have not been investigated.
Few studies investigated the effects of training during hospitalization for an COPD
exacerbation. Significant improvements in walking distance (11) and muscle strength (12)
were shown. In COPD patients with very severe disease and high dyspnea burden,
neuromuscular electrostimulation during exacerbation may provide an alternative for active
training (13).
In summary, PR is considered a cornerstone in the management of patients with stable

COPD. In addition, the is convincing evidence showing that post-exacerbation PR is safe and
effective in COPD. Also during exacerbation, training of hospitalized patients appears to be
beneficial. Finally, it has become clear that PR should not be restricted to patients with
severe or end-stage disease.
References:
1. Agusti A, Calverley PM, Celli B, Coxson HO, Edwards LD, Lomas DA, MacNee W,
Miller BE, Rennard S, Silverman EK, et al. Characterisation of COPD heterogeneity in
the eclipse cohort. Respir Res 2010;11:122.
2. Fabbri LM, Luppi F, Beghe B, Rabe KF. Complex chronic comorbidities of COPD. Eur
Respir J 2008;31:204-212.
3. van Wetering CR, Hoogendoorn M, Mol SJ, Rutten-van Molken MP, Schols AM.
Short- and long-term efficacy of a community-based COPD management programme
in less advanced COPD: A randomised controlled trial. Thorax 2009;65:7-13.
4. Jansson SA, Andersson F, Borg S, Ericsson A, Jonsson E, Lundback B. Costs of
COPD in sweden according to disease severity. Chest 2002;122:1994-2002.
5. Groenewegen KH, Schols AM, Wouters EF. Mortality and mortality-related factors
after hospitalization for acute exacerbation of COPD. Chest 2003;124:459-467.
7. Spruit MA, Gosselink R, Troosters T, Kasran A, Gayan-Ramirez G, Bogaerts P,
Bouillon R, Decramer M. Muscle force during an acute exacerbation in hospitalised
patients with COPD and its relationship with cxcl8 and igf-i. Thorax 2003;58:752-756.
8. Seemungal TA, Donaldson GC, Paul EA, Bestall JC, Jeffries DJ, Wedzicha JA. Effect
of exacerbation on quality of life in patients with chronic obstructive pulmonary
disease. Am J Respir Crit Care Med 1998;157:1418-1422.
9. Dahlen I, Janson C. Anxiety and depression are related to the outcome of emergency
treatment in patients with obstructive pulmonary disease. Chest 2002;122:1633-1637.
10. Puhan MA, Gimeno-Santos E, Scharplatz M, Troosters T, Walters EH, Steurer J.
Pulmonary rehabilitation following exacerbations of chronic obstructive pulmonary
disease. Cochrane Database Syst Rev 2011
11. Nava S. Rehabilitation of patients admitted to a respiratory intensive care unit. Arch
Phys Med Rehabil 1998;79:849-854.
12. Troosters T, Probst VS, Crul T, Pitta F, Gayan-Ramirez G, Decramer M, Gosselink R.
Resistance training prevents deterioration in quadriceps muscle function during acute
exacerbations of chronic obstructive pulmonary disease. Am J Respir Crit Care Med
2010;181:1072-1077.
13. Abdellaoui A, Prefaut C, Gouzi F, Couillard A, Coisy-Quivy M, Hugon G, Molinari N,
Lafontaine T, Jonquet O, Laoudj-Chenivesse D, et al. Skeletal muscle effects of
electrostimulation after COPD exacerbation: A pilot study. Eur Respir J 2011;38:781-
788.
References:
1. Nici L, Donner C, Wouters E, Zuwallack R, Ambrosino N, Bourbeau J, Carone M,

Celli B, Engelen M, Fahy B, et al. American Thoracic Society/European Respiratory
society statement on pulmonary rehabilitation. Am J Respir Crit Care Med
2006;173:1390-1413.
2. Lacasse Y, Goldstein R, Lasserson TJ, Martin S. Pulmonary rehabilitation for chronic
obstructive pulmonary disease. Cochrane Database Syst Rev 2006:CD003793.
3. Jansson SA, Andersson F, Borg S, Ericsson A, Jonsson E, Lundback B. Costs of
COPD in Sweden according to disease severity. Chest 2002;122:1994-2002.
4. Groenewegen KH, Schols AM, Wouters EF. Mortality and mortality-related factors
after hospitalization for acute exacerbation of COPD. Chest 2003;124:459-467.
5. Dahlen I, Janson C. Anxiety and depression are related to the outcome of emergency
treatment in patients with obstructive pulmonary disease. Chest 2002;122:1633-1637.
6. Seemungal TA, Donaldson GC, Paul EA, Bestall JC, Jeffries DJ, Wedzicha JA. Effect
of exacerbation on quality of life in patients with chronic obstructive pulmonary
disease. Am J Respir Crit Care Med 1998;157:1418-1422.
7. Spruit MA, Gosselink R, Troosters T, Kasran A, Gayan-Ramirez G, Bogaerts P,
Bouillon R, Decramer M. Muscle force during an acute exacerbation in hospitalised
patients with COPD and its relationship with cxcl8 and igf-i. Thorax 2003;58:752-756.
9. Pitta F, Troosters T, Spruit MA, Probst VS, Decramer M, Gosselink R. Characteristics
of physical activities in daily life in chronic obstructive pulmonary disease. Am J
Respir Crit Care Med 2005;171:972-977.
10. Kirsten DK, Taube C, Lehnigk B, Jorres RA, Magnussen H. Exercise training
improves recovery in patients with COPD after an acute exacerbation. Respir Med
1998;92:1191-1198.
11. Man WD, Polkey MI, Donaldson N, Gray BJ, Moxham J. Community pulmonary
rehabilitation after hospitalisation for acute exacerbations of chronic obstructive
pulmonary disease: Randomised controlled study. BMJ 2004;329:1209.
12. Seymour JM, Moore L, Jolley CJ, Ward K, Creasey J, Steier JS, Yung B, Man WD,
Hart N, Polkey MI, et al. Outpatient pulmonary rehabilitation following acute
exacerbations of COPD. Thorax 2010;65:423-428.
13. Puhan MA, Gimeno-Santos E, Scharplatz M, Troosters T, Walters EH, Steurer J.
Pulmonary rehabilitation following exacerbations of chronic obstructive pulmonary
disease. Cochrane Database Syst Rev 2011
14. Nava S. Rehabilitation of patients admitted to a respiratory intensive care unit. Arch
Phys Med Rehabil 1998;79:849-854.
15. Troosters T, Probst VS, Crul T, Pitta F, Gayan-Ramirez G, Decramer M, Gosselink R.
Resistance training prevents deterioration in quadriceps muscle function during acute
exacerbations of chronic obstructive pulmonary disease. Am J Respir Crit Care Med
2010;181:1072-1077.
16. Abdellaoui A, Prefaut C, Gouzi F, Couillard A, Coisy-Quivy M, Hugon G, Molinari
N, Lafontaine T, Jonquet O, Laoudj-Chenivesse D, et al. Skeletal muscle effects of
electrostimulation after COPD exacerbation: A pilot study. Eur Respir J 2011;38:781-
788.
17. Puhan MA, Spaar A, Frey M, Turk A, Brandli O, Ritscher D, Achermann E, Kaelin R,
Karrer W. Early versus late pulmonary rehabilitation in chronic obstructive pulmonary
disease patients with acute exacerbations: A randomized trial. Respiration 2011.
18. van Wetering CR, Hoogendoorn M, Mol SJ, Rutten-van Molken MP, Schols AM.
Short- and long-term efficacy of a community-based COPD management programme
in less advanced COPD: A randomised controlled trial. Thorax 2009;65:7-13.
Glossary:
COPD: chronic obstructive pulmonary disease. This is a chronic and progressive respiratory
disease, characterized by persistent airflow limitation with limited reversibility. It is caused by
chronic exposure to cigarette smoke and other noxious gases.
Exacerbation: an acute increase in symptoms beyond normal day-to-day variation. This

generally includes an acute increase in one or more of the following cardinal symptoms:
cough increases in frequency and severity, sputum production increases in volume and/or
changes character, dyspnea increases
Pulmonary rehabilitation: a comprehensive intervention based on a thorough patient

assessment followed by patient-tailored therapies, which include, but are not limited to,
exercise training, education and behavior change, designed to improve the physical and
emotional condition of people with chronic respiratory disease and to promote the long-term
adherence of health-enhancing behaviors
4/4/2012
Widening The Application Of Pulmonary Rehabilitation
Frits M.E. Franssen, MD, PhD

CIRO+, center of expertise for chronic organ failure
Horn, The Netherlands
Conflict of interest disclosure

Widening The Application Of
I have no, real or perceived, conflicts of

interest that relate to this presentation
Agenda
1) Updated definition of pulmonary rehabilitation
2) Post-hospitalisation pulmonary rehabilitation
3) In-hospital exercise training
4) Effects of pulmonary rehabilitation in less advanced

COPD
5) Unanswered questions
5) Summary and discussion

4/4/2012
American Thoracic Society / European Respiratory

Society new definition of pulmonary rehabilitation 2012
‘Pulmonary rehabilitation is a comprehensive

intervention based on a thorough patient assessment
followed by patient-tailored therapies, which include,
but are not limited to, exercise training, education and
behavior change, designed to improve the physical
and emotional condition of people with chronic
respiratory disease and to promote the long-term
adherence of health-enhancing behaviors’

Society goals of pulmonary rehabilitation 2012
‘The purpose of pulmonary rehabilitation is to minimize

symptoms, maximize exercise performance, promote
autonomy, increase participation in everyday activities,
improve the overall quality of life, improve long-term
health-enhancing behavior, and provide tools to elicit
behavior change in physical activity and symptom
management in people with chronic respiratory disease’

Society positioning of pulmonary rehabilitation 2012
‘Pulmonary rehabilitation should be integrated

throughout the clinical course of a patient’s disease
and modified to the complexity of disease phenotypes
including unique co-morbidities’
4/4/2012
Therapy at each stage of COPD
GOLD COPD 2010
Therapy at each stage of COPD
GOLD COPD 2010
Can we widen the application of pulmonary

rehabilitation?
4/4/2012
Exacerbations and hospitalisations in COPD

Exacerbations represent a major health burden for patients with COPD
and are responsible for a large proportion of health care costs attributable
to this disease
Jansson et al., Chest 2002
Re-hospitalisation following acute exacerbations of COPD
Hospital readmissions frequently occur following hospital discharge
Groenewegen et al., Chest 2003
Psychological factors predict outcome after exacerbation
COPD patients with anxiety and depression have a doubled risk of short-
term hospital re-admission after emergency treatment
Dahlen et al., Chest 2002

4/4/2012
Effect of exacerbations on health status in COPD

Health status in COPD patients with frequent exacerbations is more impaired
than in patients without frequent exacerbations
Seemungal et al., Am J Respir Crit Care Med 1998
Effect of exacerbations on muscle strength in COPD

Quadriceps muscle strength is reduced during exacerbations, declines even
further during hospitalisation and recovery is poor
Spruit et al., Thorax 2003
Effect of exacerbations on physical activity in COPD

Level of daily physical activity is severely comprimised during and after
exacerbations of COPD
Pitta et al., Chest 2006 & Am J Respir Crit Care Med 2005
4/4/2012
Rationale for post-hospitalisation pulmonary rehabilitation
Given the impact of exacerbations on health status, muscle function

and exercise tolerance, the negative effects of anxiety and depression
and the high risk of re-hospitalisation and mortality, pulmonary
rehabilitation could play an important role in the management of
COPD patients with (repeated) exacerbations
Pulmonary rehabilitation following exacerbations of COPD
n = 15 n = 14
Inpatient exercise training significantly improves exercise capacity in

patients with severe COPD after an acute exacerbation
Kirsten et al., Respir Med 1998
At identical work load, exercise training results is significant reductions in minute

ventilation, oxygen consumption, arterial pCO2, dyspnea and lactic acid production
Kirsten et al., Respir Med 1998

4/4/2012
Community PR results in significant improvements in exercise capacity

and health status after hospitalisation for acute exacerbation of COPD
Man et al., BMJ 2004
Pulmonary rehabilitation following exacerbations of COPD:

health care utilization
Readmission were 30% lower in the rehabilitation group (ns) and the
percentage of patients with emergency visits was significantly lower in this
group, compared to the usual care group
Man et al., BMJ 2004
Pulmonary rehabilitation following exacerbations of COPD:

health care utilization
Eight weeks of outpatient PR following hospitalisation resulted in fewer

hospital admissions, compared to usual care
Seymour et al., Thorax 2010

4/4/2012
Compared to usual care, eight weeks of outpatient PR following

hospitalisation resulted increased quadriceps strength and exercise capacity
Post-exacerbation pulmonary rehabilitation improves health status
Cochrane review: pulmonary rehabilitation

following exacerbations of COPD
Primary outcome: hospital admissions
Puhan et al., Cochrane Database Syst Rev 2011

4/4/2012

Mortality
6MWD

Health status
Rehabilitation during acute exacerbation?

4/4/2012
Rehabilitation of patients at respiratory intensive care unit
Rehabilitation (n=60) Control (n=20)
Six minute walking distance improved significantly in patients receiving

rehabilitation in RICU, compared to patients with standard medical therapy
Nava, Arch Phys Med Rehabil 1998
Rehabilitation of patients at respiratory intensive care unit
Rehabilitation (n=60) Control (n=20)
Dyspnea scores improved in both groups, but improvement was more marked
in patients receiving rehabilitation.
Rehabilitation did not reduce total length of RICU stay or short-term mortality
Nava, Arch Phys Med Rehabil 1998
Strength training during hospitalisation for exacerbation

In-hospital resistance training resulted in increased quadriceps force at
discharge and after one month, compared to usual care
Resistance training counter-acted the up-regulation of myostatin, probably

resulting in favorable impact on anabolic-catabolic balance
Troosters et al., Am J Respir Crit Care Med 2010

4/4/2012
Neuromuscular electrostimulation after ICU

hospitalisation for exacerbation
In patients with very severe COPD and dysnea at rest six weeks of NMES for
five days per week resulted in significant improvements in muscle strength and
walking distance compared to sham treatment
Abdellaoui et al., Eur Respir J 2011
Early versus late pulmonary rehabilitation after

exacerbation
Timing of pulmonary rehabilitation after exacerbation did not affect

exacerbation rate during 18 months follow-up
Puhan et al., Respiration 2011
Unanswered questions
1) Minimal duration of post-hospitalisation PR?
2) Duration of effects?
3) Effects of post-exacerbation PR in other respiratory

diseases?
4) Optimal setting for non-stable COPD PR?

4/4/2012
Rehabilitation in less advanced disease?
Pulmonary rehabilitation in less advanced COPD

INTERCOM trial: 4 months pulmonary rehabilitation, 20 months maintenance
Van Wetering et al., Thorax 2010
Four months of pulmonary rehabilitation resulted in significant improvements in

health status and exercise performance compared to usual care
During the follow up period, differences between treatment groups

remained significant

4/4/2012
Community-based pulmonary rehabilitation is feasible and effective in

patients with less advanced airflow obstruction
GOLD COPD Revision 2012
4
Exacerbation frequency (/y)
(C) (D) ≥2
GOLD classification
2 1
(A) (B)
11 0
mMRC < 2 mMRC ≥ 2

CAT < 10 CAT ≥ 10
Symptoms
GOLD COPD 2012
GOLD COPD Revision 2012
4
Exacerbation frequency (/y)
(C) (D) ≥2
GOLD classification
2 1
(A) (B)
11 0
mMRC < 2 mMRC ≥ 2

CAT < 10 CAT ≥ 10
Symptoms
GOLD COPD 2012
4/4/2012
Summary
1) Pulmonary rehabilitation is a cornerstone in the
management of patients with COPD
2) In addition to stable disease, there is convincing

evidence that post-hospitalisation pulmonary
rehabilitation is safe and effective
3) In-hospital training of exacerbating patients increases

muscle function
4) Pulmonary rehabilitation should not be reserved for

patients with late or end-stage disease
fritsfranssen@ciro-horn.nl

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NEW SCIENCE IN THE COMPREHENSIVE

MANAGEMENT OF THE CHRONIC OBSTRUCTIVE

Friday, May 18, 2012

Room 2005, West Building (Level 2)

At the conclusion of this course, the participant will be able to:

 apply the new knowledge presented to improve patients' health status;

CME ACCREDITATION & DESIGNATION

COURSE DIRECTORS: Carolyn L. Rochester, MD

Introduction: New Developments In The Assessment And Treatment Of

New Insights Into Chronic Obstructive Pulmonary Disease Phenotypes

Addressing Co-Morbidity In Chronic Obstructive Pulmonary Disease

Advances In The Science Of Exercise Training For Chronic Obstructive

Physical Inactivity In Chronic Obstructive Pulmonary Disease Patients

10:05 am - 10:35 am Break

Addressing Psychological, Behavioral And Cognitive Issues In Chronic

Measuring Exercise Performance In Chronic Obstructive Pulmonary

New Pharmacologic Treatments On The Horizon

Dyspnea Management For Advanced Lung Disease

12:15 pm - 12:45 pm Lunch

Targeting The Chronic Obstructive Pulmonary Disease Exacerbation

Let's Talk Disease Modification

Palliative Care And Pulmonary Rehabilitation

2:00 pm - 2:30 pm Break

Widening The Application Of Pulmonary Rehabilitation

Transition Of Care Of The Chronic Obstructive Pulmonary Disease Patient

3:20 pm - 4:00 pm Questions And Answers

Carolyn L. Rochester, MD Brian W. Carlin, MD

Richard Casaburi, MD, PhD Francois Maltais, MD

Bartolome R. Celli, MD Paula M. Meek, RN, PhD

Frits Franssen, MD Stephen I. Rennard, MD

Nicola A. Hanania, MD, MS Jan Vercoulen, PhD

Anne E. Holland, PhD Jadwiga A. Wedzicha, MD

Mondo Medico, Multidisciplinary and Rehabilitation Outpatient Clinic

Recommendation 1: spirometry should be obtained to diagnose airflow obstruction in patients

Recommendation 3: in stable COPD patients with respiratory symptoms and FEV1<60%

Recommendation 4: clinicians should prescribe monotherapy using either long-acting inhaled

Recommendation 5: combination inhaled therapies (long-acting inhaled anticholinergics, long-

Recommendation 6: pulmonary rehabilitation should be prescribed for symptomatic patients

Recommendation 7: continuous oxygen therapy should be prescribed in patients with COPD

mEH = microsomal epoxide hydrolase

• COPD is characterised by a fall in expiratory flow and lung

• A number of genes in conjunction with environmental factors are

• At present, most of the genes that contribute to the genetic

• Imbalance in relative amounts of proteases and

• Deficiencies or abnormalities in anti-proteases could

1. Microsomal epoxide hydrolase (mEH) is a xenobiotic metabolising

2. Glutathion S-transferases (GSTs) play an important role in detoxifying

The overlap phenotype: the link between asthma and

Inflammatory Mediators (II)

Inflammatory Mediators (III)

• Unike asthma, the inflammatory process in COPD is not associated with

• Eosinophils get activated only during exacerbation of the disease. The

P.W. Jones* and A.G.N. Agusti .Eur. Respir. J 2006

Outcome measures relevant Airflow limitation

Reduced physical activity

Impaired health status

Unfortunately, in contrast to lung function monitoring, there is no gold

Accordingly, no single outcome measure can be recommended for the

Glaab et al. Respiratory Research 2010 11:79

Outcome measures in COPD: