2007 - CHEST - Pulmonary Rehabilitation (Supplement)

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Pulmonary Rehabilitation*Joint ACCP/AACVPR Evidence-Based ClinicalPractice Guidelines

Andrew L. Ries, MD, MPH, FCCP (Chair);Gerene S. Bauldoff, RN, PhD, FCCP; Brian W. Carlin, MD, FCCP;Richard Casaburi, PhD, MD, FCCP; Charles F. Emery, PhD;Donald A. Mahler, MD, FCCP; Barry Make, MD, FCCP;Carolyn L. Rochester, MD; Richard ZuWallack, MD, FCCP; andCarla Herrerias, MPH

Background:Pulmonary rehabilitation has become a standard of care for patients with chronic lung diseases. This

document provides a systematic, evidence-based review of the pulmonary rehabilitation literature that updates the

1997 guidelines published by the American College of Chest Physicians (ACCP) and the American Association of

Cardiovascular and Pulmonary Rehabilitation.

Methods: The guideline panel reviewed evidence tables, which were prepared by the ACCP Clinical Research

Analyst, that were based on a systematic review of published literature from 1996 to 2004. This guideline

updates the previous recommendations and also examines new areas of research relevant to pulmonary

rehabilitation. Recommendations were developed by consensus and rated according to the ACCP guideline

grading system.

Results: The new evidence strengthens the previous recommendations supporting the benefits of lower and upper

extremity exercise training and improvements in dyspnea and health-related quality-of-life outcomes of pulmonaryrehabilitation. Additional evidence supports improvements in health-care utilization and psychosocial outcomes. There

are few additional data about survival. Some new evidence indicates that longer term rehabilitation, maintenance

strategies following rehabilitation, and the incorporation of education and strength training in pulmonary rehabilitation

are beneficial. Current evidence does not support the routine use of inspiratory muscle training, anabolic drugs, or

nutritional supplementation in pulmonaryrehabilitation. Evidence does support the use of supplemental oxygen therapy

for patients with severe hypoxemia at rest or with exercise. Noninvasive ventilation may be helpful for selected patients

with advanced COPD. Finally, pulmonary rehabilitation appears to benefit patients with chronic lung diseases other

than COPD.

Conclusions: There is substantial new evidence that pulmonary rehabilitation is beneficial for patients with COPD and

other chronic lung diseases. Several areas of research provide opportunities for future research that can advance the

field and make rehabilitative treatment available to many more eligible patients in need.

(CHEST 2007; 131:4S42S)

Key words:COPD; dyspnea; exercise training; guidelines; pulmonary rehabilitation; quality of life

Abbreviations: AACVPR American Association of Cardiovascular and Pulmonary Rehabilitation; ACCP AmericanCollege of Chest Physicians; ADL activity of daily living; CRDQChronic Respiratory Disease Questionnaire;DAS distractive auditory stimuli; DEXA dual-energy x-ray absoptiometry; ESM education and stress management;HR heart rate; HRQOL health-related quality of life; IMT inspiratory muscle training; MRCMedical ResearchCouncil; NETTNational Emphysema Treatment Trial; NPPV noninvasive positive-pressure ventilation;PAV proportional assist ventilation; Pimaxmaximal inspiratory pressure; RCT randomized controlled trial;Sao2 arterial oxygen saturation; TCEMS transcutaneous electrical stimulation of the peripheral muscles; V eminute

ventilation; V o2 oxygen uptake

CHEST SupplementPULMONARY REHABILITATION: JOINT ACCP/AACVPR EVIDENCE-BASED CLINICAL PRACTICE GUIDELINES

4S Pulmonary Rehabilitation: Joint ACCP/AACVPR Evidence-Based Clinical Practice Guidelines

wnloaded From: http://journal.publications.chestnet.org/ on 07/01/2014


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Pulmonary diseases are increasingly importantcauses of morbidity and mortality in the modern

world. The COPDs are the most common chroniclung diseases, and are a major cause of lung-relateddeath and disability.1 Pulmonary rehabilitation hasemerged as a recommended standard of care forpatients with chronic lung disease based on a grow-ing body of scientific evidence. A previous set2,3 ofevidence-based guidelines was published in 1997 asa joint effort of the American College of ChestPhysicians (ACCP) and the American Association ofCardiovascular and Pulmonary Rehabilitation

(AACVPR). Since then, the published literature inpulmonary rehabilitation has increased substantially,and other organizations have published importantstatements about pulmonary rehabilitation (eg, theAmerican Thoracic Society and the European Respi-ratory Society4). The purpose of this document is toupdate the previous ACCP/AACVPR document witha systematic, evidence-based review of the literature

published since then.

Epidemiology of COPD

In the United States, COPD accounted for119,054 deaths in 2000, ranking as the fourth leadingcause of death and the only major disease among thetop 10 in which mortality continues to increase.58 Inpersons 55 to 74 years of age, COPD ranks third inmen and fourth in women as cause of death.9

However, mortality data underestimate the impact of

COPD because it is more likely to be listed as acontributory cause of death rather than the underly-ing cause of death, and it is often not listed at all.10,11

Death rates from COPD have continued to increasemore in women than in men.5 Between 1980 and2000, death rates for COPD increased 282% forwomen compared to only 13% for men. Also, in2000, for the first time, the number of women dyingfrom COPD exceeded the number of men.5

Morbidity from COPD is also substantial.5,12

COPD develops insidiously over decades and be-cause of the large reserve in lung function there is a

long preclinical period. Affected individuals have fewsymptoms and are undiagnosed until a relativelyadvanced stage of disease. In a population survey inTucson, AZ, Burrows13 reported that only 34% ofpersons with COPD had ever consulted a physician,36% denied having any respiratory symptoms, and30% denied dyspnea on exertion, which is the pri-mary symptom. National Health and Nutrition Ex-amination Study III data estimate that 24 million USadults have impaired lung function, while only 10million report a physician diagnosis of COPD.5

There are approximately 14 million cases of chronic

bronchitis reported each year, and 2 million cases ofemphysema.14 The National Center for Health Sta-tistics for 1996 reported prevalence rates of chronicbronchitis and emphysema in older adults (eg, per-sons 65 years of age) of 82 per 1,000 men and 106per 1,000 women.15 In 2000, COPD was responsiblefor 8 million physician office visits, 1.5 millionemergency department visits, and 726,000 hospital-izations.5 COPD accounts for 5% of physicianoffice visits and 13% of hospitalizations.16 NationalHealth and Nutrition Examination Study III datafrom 1988 to 1994 indicated an overall prevalence of

*From the University of California, San Diego, School of Medi-cine (Dr. Ries, Chair, representing both groups), San Diego, CA;The Ohio State University College of Nursing (Dr. Bauldoff,representing the AACVPR, and Dr. Emery, representing theAACVPR), Columbus, OH; Allegheny General Hospital (Dr.Carlin, ACCP Health and Science Policy Liaison, representingboth groups), Pittsburgh, PA; the Los Angeles Biomedical Re-search Institute (Dr. Casaburi, representing the ACCP), Harbor-

UCLA Medical Center, Los Angeles, CA; the Department ofPulmonary and Critical Care Medicine (Dr. Mahler, representingthe ACCP), Dartmouth-Hitchcock Medical Center, Lebanon,NH; the Department of Pulmonary Rehabilitation and Emphy-sema (Dr. Make, representing the ACCP), National JewishResearch and Medical Center, Denver, CO; the Section ofPulmonary and Critical Care (Dr. Rochester, representing theACCP), Yale University School of Medicine, New Haven, CT; thePulmonary Disease Section (Dr. ZuWallack, representing theAACVPR), St. Francis Hospital, Hartford, CT; and the AmericanCollege of Chest Physicians (Ms. Herrerias), Northbrook, IL.The evidence-based practice guidelines published by The Amer-ican College of Chest Physicians (ACCP) incorporate data ob-tained from a comprehensive literature review of the most recentstudies then available. Guidelines are intended for generalinformation only, are not medical advice, and do not replace

professional medical care and physician advice, which alwaysshould be sought for any specific condition. Furthermore, guide-lines may not be complete or accurate because new studies thatmay have become available late in the process of guidelinedevelopment may not be incorporated into any particular guide-line before it is disseminated. The ACCP and its officers, regents,governors, executive committee, members, and employees (the

ACCP Parties) disclaim all liability for the accuracy or complete-ness of a guideline, and disclaim all warranties, express orimplied. Guideline users always are urged to seek out newerinformation that might impact the diagnostic and treatmentrecommendations contained within a guideline. The ACCPParties further disclaim all liability for any damages whatsoever(including, without limitation, direct, indirect, incidental, puni-tive, or consequential damages) arising out of the use, inability touse, or the results of use of a guideline, any references used in a

guideline, or the materials, information, or procedures containedin a guideline, based on any legal theory whatsoever and whetheror not there was advice of the possibility of such damages.The authors have reported to the ACCP that no significantconflicts of interest exist with any companies/organizations whoseproducts or services may be discussed in this article.Manuscript received October 2, 2006; revision accepted Febru-ary 2, 2007.Reproduction of this article is prohibited without written permissionfrom the American College of Chest Physicians (www.chestjournal.org/misc/reprints.shtml).Correspondence to: Andrew L. Ries, MD, MPH, FCCP, Univer-

sity of California, San Diego, Department of Pulmonary andCritical Care Medicine, UCSD Medical Center, 200 West ArborDr, San Diego, CA 92103-8377; e-mail: [email protected]: 10.1378/chest.06-2418

www.chestjournal.org CHEST / 131 / 5 / MAY, 2007 SUPPLEMENT 5S



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COPD of 8.6% among 12,436 adults (average age forentire cohort, 37.9 years).17 In the United States,COPD is second only to coronary heart disease as areason for Social Security disability payments.

Worldwide, the burden of COPD is projected toincrease substantially, paralleling the rise in tobaccouse, particularly in developing countries. An analysisby the World Bank and World Health Organization

ranked COPD 12th in 1990 in disease burden, asreflected in disability-adjusted years of life lost.10

Severity of COPD

For consistency throughout the document, thepanel used the description of severity of COPD asrecommended by the Global Initiative for ChronicObstructive Lung Disease18 and the American Tho-racic Society/European Respiratory Society Guide-lines19 based on FEV1, as follows: stage I (mild),

FEV1 80% predicted; stage II (moderate), FEV150 to 80% predicted; stage III (severe), FEV130 to50% predicted; and stage IV (very severe), FEV1 30% predicted.

Pulmonary Rehabilitation

Rehabilitation programs for patients with chroniclung diseases are well-established as a means ofenhancing standard therapy in order to control andalleviate symptoms and optimize functional capaci-

ty.2,4,14,20 The primary goal is to restore the patient tothe highest possible level of independent function.This goal is accomplished by helping patients be-come more physically active, and to learn moreabout their disease, treatment options, and how tocope. Patients are encouraged to become activelyinvolved in providing their own health care, moreindependent in daily activities, and less dependenton health professionals and expensive medical re-sources. Rather than focusing solely on reversing thedisease process, rehabilitation attempts to reducesymptoms and reduce disability from the disease.

Many rehabilitation strategies have been devel-oped for patients with disabling COPD. Programstypically include components such as patient assess-ment, exercise training, education, nutritional inter-vention, and psychosocial support. Pulmonary reha-bilitation has also been applied successfully topatients with other chronic lung conditions such asinterstitial diseases, cystic fibrosis, bronchiectasis,and thoracic cage abnormalities.21 In addition, it hasbeen used successfully as part of the evaluation andpreparation for surgical treatments such as lungtransplantation and lung volume reduction sur-

gery.2226 Pulmonary rehabilitation is appropriate forany stable patient with a chronic lung disease who isdisabled by respiratory symptoms. Patients with ad-vanced disease can benefit if they are selectedappropriately and if realistic goals are set. Althoughpulmonary rehabilitation programs have been devel-oped in both outpatient and inpatient settings, mostprograms, and most of the studies reviewed in this

document, pertain to outpatient programs for ambu-latory patients.

Definition

The American Thoracic Society and the EuropeanRespiratory Society have recently adopted the fol-lowing definition of pulmonary rehabilitation: Pul-monary rehabilitation is an evidence-based, multidis-ciplinary, and comprehensive intervention forpatients with chronic respiratory diseases who are

symptomatic and often have decreased daily lifeactivities. Integrated into the individualized treat-ment of the patient, pulmonary rehabilitation isdesigned to reduce symptoms, optimize functionalstatus, increase participation, and reduce health-carecosts through stabilizing or reversing systemic man-ifestations of the disease. Comprehensive pulmonaryrehabilitation programs include patient assessment,exercise training, education, and psychosocial sup-port.4

This definition focuses on three important featuresof successful rehabilitation:

1. Multidisciplinary: Pulmonary rehabilitationprograms utilize expertise from various health-care disciplines that is integrated into a com-prehensive, cohesive program tailored to theneeds of each patient.

2. Individual: Patients with disabling lung diseaserequire individual assessment of needs, individ-ual attention, and a program designed to meetrealistic individual goals.

3. Attention to physical and social function: To besuccessful, pulmonary rehabilitation pays atten-

tion to psychological, emotional, and socialproblems as well as physical disability, andhelps to optimize medical therapy to improvelung function and exercise tolerance.

The interdisciplinary team of health-care profes-sionals in pulmonary rehabilitation may include phy-sicians; nurses; respiratory, physical, and occupa-tional therapists; psychologists; exercise specialists;and/or others with appropriate expertise. The spe-cific team make-up depends on the resources andexpertise available, but usually includes at least onefull-time staff member.27




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Methodology and Grading of the

Evidence for Pulmonary Rehabilitation

In 1997, the ACCP and the AACVPR released anevidence-based clinical practice guideline entitledPulmonary Rehabilitation: Joint ACCP/AACVPREvidence-Based Guidelines.2,3 Following the ap-proved process for the review and revision of clinical

practice guidelines, in 2002 the ACCP Health andScience Committee determined that there was aneed for reassessment of the current literature andan update of the original practice guideline. Thisnew guideline is intended to update the recommen-dations from the 1997 document and to provide newrecommendations based on a comprehensive litera-ture review. The literature review and developmentof evidence tables were conducted by Carla Herre-rias, MPH, the ACCP Clinical Research Analyst. Thejoint ACCP/AACVPR expert panel used the evi-dence to develop graded recommendations.

Expert Panel Composition

The guideline panel was organized under the jointsponsorship of the ACCP and the AACVPR. AndrewRies, MD, MPH, FCCP, Chair of the 1997 panel,served as Chair of the new panel. Panel members wereevenly distributed between and selected by the twoorganizations with a goal of making the panel multidis-ciplinary and geographically diverse. Drs. Casaburi,Mahler, Make, and Rochester represented the ACCP,and Drs. Bauldoff, Carlin, Emery, and ZuWallackrepresented the AACVPR. Five panel members (Drs.

Carlin, Casaburi, Emery, Mahler, and Make) hadserved on the previous guideline panel. In addition toseveral conference calls, the panel met for one 2-daymeeting to review the evidence tables and becomefamiliar with the process of grading recommendations.Writing assignments were determined by membersknown expertise in specific areas of pulmonary rehabil-itation. Each section of the guideline was assigned toone primary author and at least one secondary author.Sections were reviewed by relevant panel memberswhen topics overlapped.

Conflict of InterestAt several stages during the guideline develop-

ment period, panel members were asked to discloseany conflict of interest. These occurred at the timethe panel was nominated, at the first face-to-facemeeting, the final conference call, and prior topublication. Written forms were completed and areon file at the ACCP.

Scope of Work

The 1997 practice guideline on pulmonary reha-bilitation focused on program component areas of

lower and upper extremity training, ventilatory mus-cle training, and various outcomes of comprehensivepulmonary rehabilitation programs, including dys-pnea, quality of life, health-care utilization, andsurvival. Psychosocial and educational aspects ofrehabilitation were examined both as program com-ponents and as outcomes.

For this review, the panel decided to focus on studies

that had been published since the previous review,again concentrating on stable patients with COPD.Since there have been many advances and new areas ofinvestigation since the previous document was written,the panel decided to expand the scope of this reviewrather than just update the previous one. Topics cov-ered in this document include the following:

Outcomes of comprehensive pulmonary rehabili-tation programs: lower extremity exercise training;dyspnea; health-related quality of life (HRQOL);health-care utilization and economic analysis; sur-

vival; psychosocial outcomes; and long-term ben-efits from pulmonary rehabilitation; Duration of pulmonary rehabilitation; Postrehabilitation maintenance strategies; Intensity of aerobic exercise training; Strength training in pulmonary rehabilitation; Anabolic drugs; Upper extremity training; Inspiratory muscle training (IMT); Education; Psychosocial and behavioral components of pul-

monary rehabilitation;

Oxygen supplementation as an adjunct to pulmo-nary rehabilitation; Noninvasive ventilation; Nutritional supplementation in pulmonary reha-

bilitation; Pulmonary rehabilitation for patients with disor-

ders other than COPD; and Summary and recommendations for future research.

Review of Evidence

The literature review was based on the scope of thework as outlined in the previous section. The literature

search was conducted through a comprehensive MED-LINE search from 1996 through 2004, and was sup-plemented by articles supplied by the guideline panelas well as by a review of bibliographies and referencelists from review articles and other existing systematicreviews. The literature search was limited to articlespublished in peer-reviewed journals only in the Englishlanguage, and on human subjects. Inclusion criteriaprimarily included a population of persons with adiagnosis of COPD determined either by physicalexamination or by existing diagnostic criteria; however,those with other pulmonary conditions (eg, asthma or




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interstitial lung disease) were also included. The searchincluded randomized controlled trials (RCTs), meta-analyses, systematic reviews, and observational studies.The search strategy linked pulmonary rehabilitation ora pulmonary rehabilitation program with each keysubcomponent, as listed in section on Scope of Work.To locate studies other than RCTs, such as systematicreviews and metaanalyses, those key words were usedin searching MEDLINE and the Cochrane databases.Informal review articles were included only for handsearching additional references. For the purpose of thisreview, pulmonary rehabilitation was defined opera-tionally as studies involving exercise training plus atleast one additional component. Associated outcomesacross all components were dyspnea, exercise toler-ance, quality of life and activities of daily life, andhealth-care utilization. An initial review of 928 abstractswas conducted by the ACCP Clinical Research Analystand the Research Specialist. Full articles (a total of 202)were formally reviewed and abstracted by the ClinicalResearch Analyst, and a total of 81 clinical trials wereincluded in all evidence tables. RCTs were scored usinga simplified system that was based on methods ofrandomization, blinding, and documentation of with-drawals/loss to follow-up. This system follows a methodthat is based on a 3-point scale, which rates random-ization (and appropriateness), blinding (and appropri-ateness), and tracking of withdrawals and loss to follow-up. Studies were graded on a scale of 0 to 5.28 Noformal quantitative analysis was performed due to thewide variation in methodologies reported in studies.Given the length of time required to prepare the finalmanuscript after the conclusion of the systematic liter-ature review in December 2004, from which the tableswere constructed, the committee was allowed to in-clude reference to selected articles published in 2005and 2006 in the text if the additional informationprovided by the newer publications was felt to beimportant.

Strength of Evidence and Grading ofRecommendations

The ACCP system for grading guideline recom-

mendations is based on the relationship between thestrength of the evidence and the balance of benefitsto risk and burden (Table 1).29 Simply stated, rec-ommendations can be grouped on the following twolevels: strong (grade 1); and weak (grade 2). If thereis certainty that the benefits do (or do not) outweighrisk, the recommendation is strong. If there is lesscertainty or the benefits and risks are more equallybalanced, the recommendation is weaker. Severalimportant issues must be considered when classify-ing recommendations. These include the quality ofthe evidence that supports estimates of benefit, risks,

and costs; the importance of the outcomes of theintervention; the magnitude and the precision ofestimate of the treatment effect; the risks and bur-

dens of an intended therapy; the risk of the targetevent; and varying patient values.The strength of evidence is classified, based on the

quality of the data, into the following three catego-ries: high (grade A); moderate (grade B); and low(grade C). The strongest evidence comes from well-designed RCTs yielding consistent and directly ap-plicable results. In some circumstances, high-qualityevidence can be the result of overwhelming evidencefrom observational studies. Moderate-quality evi-dence is based on RCTs with limitations that mayinclude methodological flaws or inconsistent results.

Studies other than RCTs that may yield strongresults are also included in the moderate-qualitycategory. The weakest type of evidence is that fromother types of observational studies. It should benoted that the ACCP Health and Science PolicyCommittee has endorsed the principle that mostrelevant clinical studies provide evidence, eventhough the quality of that evidence is varied. There-fore, the reasons for excluding studies should bedocumented.

Table 2 describes the balance of benefits to riskand burden, and the level of certainty based on this

balance. As stated above, the more certain the

Table 2Description of Balance of Benefits to Risks/Burdens Scale

Benefits clearly outweigh the risksand burdens

Certainty of imbalance

Risks and burdens clearlyoutweigh the benefits

Certainty of imbalance

The risks/burdens and benefitsare closely balanced

Less certainty

The balance of benefits to risksand burdens is uncertain

Uncertainty

Table 1Relationship of Strength of the SupportingEvidence to the Balance of Benefits to Risks and

Burdens*

Strength ofEvidence

Balance of Benefits to Risks and Burdens

BenefitsOutweigh

Risks/Burdens

Risks/BurdensOutweighBenefits

EvenlyBalanced Uncertain

High 1A 1A 2AModerate 1B 1B 2BLow or very

low1C 1C 2C 2C

*1A strong recommendation; 1B strong recommendation;1C strong recommendation; 2Aweak recommendation;2B weak recommendation; 2C weak recommendation.




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balance, or lack thereof, the stronger the recommen-dation. Patient and community values are importantconsiderations in clinical decision making and arefactored into the grading process. In situations inwhich the benefits clearly do or do not outweigh therisks, it is assumed that nearly all patients would havethe same preferences. For weaker recommenda-tions, however, there may not be consistency inpatient preferences.

In addition to recommendations, the committeeincluded several statements when it thought thatthere was insufficient evidence to make a specificrecommendation. These statements are includedalong with the recommendations but are not graded.

Outcomes of Comprehensive Pulmonary

Rehabilitation Programs

As currently practiced, pulmonary rehabilitation typ-

ically includes several different components, includingexercise training, education, instruction in various re-spiratory and chest physiotherapy techniques, and psy-chosocial support. For this review,comprehensive pul-monary rehabilitationwas defined as an interventionthat includes one or more of these components beyondjust exercise training, which is considered to be anessential, mandatory component.

In addition to the clinical trials reviewed in theevidence tables in this document, several systematicreviews and metaanalyses have been published

within the past decade that support the beneficialeffects from comprehensive pulmonary rehabilita-tion programs. In a Cochrane Review published in2006, Lacasse30 analyzed 31 RCTs in patients withCOPD and concluded that rehabilitation forms animportant component of the management of COPD.They reported statistically and clinically significantimprovements in important domains of quality of life(i.e., dyspnea, fatigue, emotions, and patient controlover disease). Improvement in measures of exercisecapacity were slightly below the threshold for clinicalsignificance. Similarly, after a systematic review,

Cambach and colleagues31 identified 18 articlesfor inclusion in a metaanalysis of outcome mea-sures of exercise capacity and HRQOL in patientswith COPD. They found significant improvementsfor exercise measures of maximal exercise capac-ity, endurance time, and walking distance, and forHRQOL measures in all dimensions of theChronic Respiratory Disease Questionnaire(CRDQ) [ie, dyspnea, fatigue, emotion, and mas-tery]. Improvements in maximal exercise capacityand walking distance were sustained for up to 9months after rehabilitation.

Lower Extremity Exercise Training

Dyspnea: In the previous evidence-based reviewdocument2,3 the 1997 guidelines panel concludedthat the highest strength of evidence (A) supportedthe recommendation for including lower extremityexercise training as a key component of pulmonaryrehabilitation for patients with COPD. In addition,

the panel concluded that there was high-grade evi-dence (A) that pulmonary rehabilitation improvesthe symptom of dyspnea in patients with COPD.This panel concluded that the evidence presented inTable 3 in this document further strengthens thoseconclusions and recommendations.

Recommendations

1. A program of exercise training of the mus-cles of ambulation is recommended as a man-datory component of pulmonary rehabilitation

for patients with COPD. Grade of recommenda-tion, 1A2. Pulmonary rehabilitation improves the

symptom of dyspnea in patients with COPD:Grade of recommendation, 1A

HRQOL

Regarding changes in HRQOL, the previous panelconcluded that there was B level strength of evi-dence supporting the recommendation that pulmo-nary rehabilitation improves health-related quality oflife in patients with COPD. Based on the current

review, this panel believes that the additional pub-lished literature now available strengthens supportfor this conclusion and upgrades the evidence tograde A. In this document, the termHRQOLwill beused interchangeably with the term health status.

In one of the larger RCTs reported (200 patients),Griffiths and colleagues32 reported significant im-provements in HRQOL 1 year after a 6-week pul-monary rehabilitation program. Troosters and col-leagues33 reported sustained improvement inHRQOL over 18 months after patients participatedin a 6-month outpatient pulmonary rehabilitation

program compared with the decline observed in thecontrol group. The study reported by Green andcolleagues34 reported improvement in HRQOL afterpulmonary rehabilitation and found that improve-ments after a 7-week intervention were greater thanthose after 4 weeks of pulmonary rehabilitation.Strijbos and colleagues35 reported significant im-provement in reported well-being after pulmonaryrehabilitation that was maintained over 18 months inrehabilitation-treated subjects, while most patientsin the control group felt unchanged or worse. Foglioand colleagues36 reported sustained improvements




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in HRQOL up to 2 years after pulmonary rehabili-tation. In a study of early pulmonary rehabilitationafter hospital discharge for an exacerbation ofCOPD, Man and colleagues reported significantimprovements in HRQOL measures. Finnerty andcolleagues37 reported marked improvements inHRQOL after pulmonary rehabilitation that persistedfor 6 months. Similar findings were reported by Bend-

strup and colleagues.38 In the study reported byWedzicha and colleagues,39 which stratified patientsaccording to baseline dyspnea, improvement inHRQOL after pulmonary rehabilitation was observedin patients with moderate dyspnea (Medical ResearchCouncil [MRC] score, 3 or 4) but not in controlsubjects or patients with severe baseline dyspnea(MRC score, 5). The study by Ries and colleagues40

evaluated a maintenance program after pulmonaryrehabilitation. However, observational results after pul-monary rehabilitation that had been administered to allpatients before randomization demonstrated consistent

improvements in several different measures of bothgeneral and disease-specific measures of HRQOL.Guell and colleagues41 reported significant improve-ment in HRQOL that persisted, although diminished,for up to 2 years of follow-up after the pulmonaryrehabilitation intervention.

Of the studies reported in Table 3, only one smallstudy by White and colleagues42 reported only mod-est improvements in measured HRQOL that did notconsistently reach statistically or clinically significantlevels. In addition to the studies reported in Table 3,which generally were performed in single specialized

centers, two observational studies43,44 provide strongevidence of the effectiveness of pulmonary rehabil-itation as routinely practiced in clinical centers.Although neither of these studies43,44 was an RCT,they provide important information regarding thegeneralizability of the practice of pulmonary rehabil-itation beyond specialized centers and as currentlypracticed in the general medical community in theUnited States. A multicenter evaluation of pulmo-nary rehabilitation in 522 patients in nine centersthroughout California43 reported consistent im-provements in symptoms of dyspnea and HRQOL

after pulmonary rehabilitation. Similar findings werereported in a multicenter observational study inConnecticut.44 In this study, significant improve-ment was reported in the pulmonary functionalstatus scale in 164 patients in 10 centers and in theCRDQ in 60 patients in 3 centers. Also, in theNational Emphysema Treatment Trial (NETT),26 arandomized study that evaluated lung volume reduc-tion surgery in 1,218 patients with severe emphy-sema, all subjects were required to complete a pulmo-nary rehabilitation program as part of the eligibilityrequirements before randomization. Pulmonary reha-

bilitation was conducted at the 17 NETT centers aswell as at 539 satellite centers throughout the UnitedStates. Observational results demonstrated significantimprovements in measures of exercise tolerance, dys-pnea, and HRQOL after rehabilitation that were quitecomparable among the specialized NETT centers andthe largely community-based satellite centers.

Recommendation

3. Pulmonary rehabilitation improves HRQOLin patients with COPD. Grade of recommenda-tion, 1A

Health-Care Utilization and Economic Analysis

Regarding changes in health-care utilization re-sulting from pulmonary rehabilitation, the previouspanel concluded that there was B level strength ofevidence supporting the recommendation that pul-monary rehabilitation has reduced the number of

hospitalizations and the number of days of hospital-ization for patients with COPD.

In the current review, some additional informationis available about changes in health-care utilizationafter pulmonary rehabilitation. In the study by Grif-fiths and colleagues,32 over 1 year of follow-up thenumber of patients admitted to the hospital wassimilar in both the pulmonary rehabilitation groupand the control group (40 of 99 vs 41 of 101patients); however, the number of days spent in thehospital was significantly lower in the rehabilitationpatients (10.4 vs 21.0 days, respectively). In a subse-

quent cost-utility economic analysis of the results inthis pulmonary rehabilitation trial, Griffiths and col-leagues45 found that the cost per quality-adjustedlife-years indicated that pulmonary rehabilitationwas, in fact, cost-effective and would likely result infinancial benefits to the health-care system (quality-adjusted life-year is a measure of effectiveness that iscommonly used in cost-effectiveness analyses, re-flecting survival adjusted for quality of life, or thevalue that individuals place on expected years of life).In the trial reported by Foglio and colleagues,36

results indicated a significant decrease in yearly

hospitalizations and exacerbations 2 years afterpulmonary rehabilitation.

Goldstein and colleagues46 conducted a cost anal-ysis that was associated with an RCT of a 2-monthinpatient pulmonary rehabilitation program (fol-lowed by 4 months of outpatient supervision) thatproduced statistically and clinically significant im-provements in measures of HRQOL and exercisecapacity. Although the cost analysis in this study wasdriven largely by the inpatient phase of the programand, as such, is not applicable to the large majority ofoutpatients programs, the authors found cost-effective-




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ness ratios for the CRDQ component measures torange from $19,011 to $35,142 (in Canadian dollars)per unit difference. Even with the added costs associ-ated with the inpatient program, these cost/benefitratios are within a range that has been typically consid-ered to represent reasonable cost-effectiveness forother widely advocated health-care programs.47

In a small randomized trial of early pulmonary

rehabilitation after hospitalization for acute exacerba-tion, Man and colleagues48 reported a significant re-duction in emergency department visits and a trendtoward reduced numbers of hospital admissions anddays spent in the hospital over the 3 months afterhospital discharge in the pulmonary rehabilitationgroup compared to the usual-care group. Also, in amulticenter randomized trial of a self-managementprogram of patients with severe COPD, Bourbeau andcolleagues49 reported a significant reduction in thenumbers of hospital admissions and days spent in thehospital in the year following the intervention com-

pared to the usual-care control group.In a multicenter, observational evaluation43 of the

effectiveness of pulmonary rehabilitation in centersthroughout California (not included in Table 3),self-reported measures of health-care utilizationwere found to decrease substantially over 18 monthsof observation after the rehabilitation intervention.In the 3-month period prior to pulmonary rehabili-tation, 522 patients reported 1,357 hospital days (2.4per patient), 209 urgent care visits (0.4 per patient),2,297 physician office visits (4.4 per patient), and1,514 telephone calls to physicians (2.7 per patient).

Over the 18 months after rehabilitation, the averageper patient reported health-care utilization (in thepast 3 months) was reduced approximately 60% forhospital days, 40% for urgent care visits, 25% forphysician office visits, and 30% for telephone calls. Itshould be recognized that the results of an observa-tional, noncontrolled study like this may be influ-enced by the selection of patients for pulmonaryrehabilitation shortly after an exacerbation or epi-sode of increased health-care utilization.

Recommendations

4. Pulmonary rehabilitation reduces thenumber of hospital days and other measures ofhealth-care utilization in patients with COPD.Grade of recommendation, 2B

5. Pulmonary rehabilitation is cost-effective inpatients with COPD. Grade of recommendation, 2C

Survival

The previous panel concluded that there was littleevidence (strength of evidence, C) regarding survivalafter pulmonary rehabilitation and made the recom-

mendation that pulmonary rehabilitation may im-prove survival in patients with COPD. Only oneRCT50 of pulmonary rehabilitation was included inthe previous review. In that study of 119 patients,Ries and colleagues50 reported 11% higher survivalover 6 years after comprehensive pulmonary reha-bilitation (67%) compared with an education controlgroup (56%). This difference was not statistically

significant. Other evidence for improved survival wasderived from nonrandomized and observationalstudies. This lack of evidence does not necessarilyindicate that pulmonary rehabilitation has no effecton survival, but in order to be reasonably powered todetect an effect of this magnitude the sample sizewould have to be a magnitude larger than thosefound in existing studies. The timed walk distanceand MRC-rated dyspnea do improve with pulmonaryrehabilitation, and these variables are correlated withsurvival in patients with COPD.

In the current review, few additional data were

found regarding the effect of pulmonary rehabilita-tion on survival. Similar to previous published stud-ies, the trial reported by Griffiths and colleagues32

that followed 200 patients over 1 year found fewerdeaths in the rehabilitation group (6 of 99 patients)compared with the control group (12 of 101 pa-tients).

Recommendation

6. There is insufficient evidence to deter-mine whether pulmonary rehabilitation im-

proves survival in patients with COPD. No rec-ommendation is provided.

Psychosocial Outcomes

Regarding psychosocial outcomes of pulmonaryrehabilitation, the previous panel concluded thatscientific evidence was lacking (strength of evi-dence, C). Reviews of the research literature per-taining to psychosocial outcomes of pulmonary reha-bilitation programs indicate that comprehensivepulmonary rehabilitation is generally associated withenhanced psychological well-being (ie, reduced dis-

tress) and improved quality of life.51,52 In addition, ithas been found that increased self-efficacy associ-ated with exercise may mediate the effect of exerciserehabilitation on quality of life.53 Other positivepsychosocial outcomes of exercise rehabilitation in-clude improved cognitive function,5456 reducedsymptoms of anxiety32,55 and depression,32 and im-proved patient perceptions of positive consequencesof the illness.57

In the current review of randomized studies,Griffiths and colleagues32 reported reduced symp-toms of anxiety and depression following a 6-week




10/39

pulmonary rehabilitation program, with symptoms ofdepression remaining significantly reduced at the12-month follow-up. Emery and colleagues55 foundreduced anxiety and improved cognitive functionfollowing a 10-week pulmonary rehabilitation inter-vention. In a study of 164 patients participating inpulmonary rehabilitation prior to being randomlyassigned to a long-term follow-up intervention, Ries

and colleagues40 observed significant improvementsin measures of depression and self-efficacy for walk-ing immediately following the 8-week pulmonaryrehabilitation program.

Recommendation

7. There are psychosocial benefits from com-prehensive pulmonary rehabilitation programsin patients with COPD. Grade of recommenda-tion, 2B

Long-term Benefits From Pulmonary RehabilitationThe formal component of most pulmonary reha-

bilitation programs is of relatively short duration,usually ranging from 6 to 12 weeks. Regarding theissue of long-term benefits following the short-termintervention, the previous panel did not specificallyaddress this topic but recommended it as an impor-tant area for future research. Since that time, addi-tional important studies have addressed this topic.The next section discusses the issue of the durationof pulmonary rehabilitation treatment (ie, beyond 12weeks).

Several clinical trials of 6 to 12 weeks of compre-hensive pulmonary rehabilitation that have followedpatients over a longer term have found that benefitstypically persist for about 12 to 18 months after theintervention but gradually wane thereafter. In manyways, this is surprising given the severity of illness formany of these patients with chronic lung disease andthe complex set of behaviors incorporated into pul-monary rehabilitation (eg, exercise training, breath-ing control techniques, complex treatment regimenswith medications, use of supplemental oxygen, andrelaxation or panic control techniques). More recent

clinical trials substantiate these findings (Table 4).Griffiths and colleagues32 reported improvements

in measures of exercise tolerance, HRQOL, anxiety,and depression after pulmonary rehabilitation thatremained significant but declined gradually over 1year of follow-up. The study reported by Wijkstraand colleagues58 evaluated the effects of weekly vsmonthly follow-up over the 18 months after pulmo-nary rehabilitation in a small sample of patients withCOPD (n 36). They reported no long-term im-provement in exercise tolerance in the two experi-mental groups, although this was better than the

decline observed in the control group. There were,however, more sustained improvements in dyspnea.Engstrom and colleagues59 reported sustained im-provement in exercise tolerance at 12 months afterpulmonary rehabilitation with minimal improve-ments in either a general or disease-specific measureof HRQOL (although there was a trend for worsen-ing HRQOL in the control group). Strijbos and

colleagues35 reported significant improvement inreported well-being after pulmonary rehabilitationthat was maintained over 18 months (compared tomost control subjects who reported being unchangedor worse). The study reported by Guell and col-leagues41 also found persistent, but diminished, ben-efits in measures of exercise tolerance, dyspnea, andHRQOL over the 2 years of follow-up after pulmo-nary rehabilitation.

The study reported by Ries and colleagues40 ex-amined the effects of a telephone-based mainte-nance program for 1 year after a short-term rehabil-

itation intervention. The experimental effects of themaintenance program are discussed in a subsequentsection on postrehabilitation maintenance. However,as an observational study, it is notable that thecontrol group (without postprogram maintenance)demonstrated a progressive decline in benefits over2 years of follow-up. Another multicenter observa-tional evaluation of the effectiveness of pulmonaryrehabilitation in centers throughout California (notincluded in Table 3)43 found that improvements insymptoms of dyspnea, HRQOL, and indexes ofhealth-care utilization declined over 18 months but

still remained above baseline levels.

Recommendation

8. Six to twelve weeks of pulmonary rehabil-itation produces benefits in several outcomesthat decline gradually over 12 to 18 months.Grade of recommendation, 1A. Some benefits,such as HRQOL, remain above control levels at12 to 18 months.Grade of recommendation, 1C

Duration of Pulmonary RehabilitationThere is no consensus of opinion regarding the

optimal duration of the pulmonary rehabilitationintervention. From the patients perspective, theoptimal duration should be that which producesmaximal effects in the individual without becomingburdensome. Significant gains in exercise tolerance,dyspnea, and HRQOL have been observed followinginpatient pulmonary rehabilitation programs as shortas 10 days60 and after outpatient programs as long as18 months.61 Shorter program duration has thepotential to reduce the cost per patient served and to




11/39

spread limited resources.62 On the other hand,longer program duration may produce greater gainsand improved maintenance of benefits. This sectionwill examine longer term pulmonary rehabilitationinterventions (ie, beyond 12 weeks of treatment).

Successful pulmonary rehabilitation requires com-plex behavioral changes for which the patients com-petence and adherence may be facilitated by longerexposure to treatment interventions and interactionswith staff who provide reinforcement, encourage-

Table 4Long-term Effects of Pulmonary Rehabilitation*

Study/Year Study Type Country/Setting Patients, Total No. Outcomes Results

Wijkstra et al58/1996

RCT: home PRP vs controlgroup

Netherlands/home

45 Lung fx; endurance;6MWD; IM strengthand endurance

FEV1improved in group B(p 0.05 to baseline);Wmax decreased (p 0.05for control subjects); PIP/endurance significantincrease in group A only

Engstrom etal59/1999 RCT: single blind; long-termvs conventional care Sweden/OP 50 Lung fx and otherphysiologic factors;QOL

Walk distance/tolerancesignificantly increased in txgroup

Sickness impact profile:decreased in control group

Griffiths et al32/2000

RCT: single blind: 6-wk PRPvs conventional care

UnitedKingdom/OP

200 Exercise capacity;general health status;HRQL

Shuttle walk, SGRQ, SF-36,HAD statistically significantvs control group (6 wk)

Shuttle walk, SGRQ, CRDQ,SF-36, and HAD statisticallysignificant vs control group(12 wk)

Guell et al41/2000

RCT: single-blind; long-termvs standard care

Spain/OP 60 Dyspnea, exercise,HRQL, hospitalutilization

Treatment effects: FVC(p 0.04); 10MWT(p 0.0001); dyspnea

(p 0.0001); MRC scales(p 0.0001); CRDQ scorein all domains

Exacerbations: control group,207; tx group, 111(p 0.0001);hospitalization: controlgroup, 39; tx group, 18

Foglio et al36/2001

RCT: single-blind; repeat PRPvs no repeat

Italy/OP 61 Lung fx; symptoms;dyspnea; HRQL;health-care utilization

Lung fx/inspiratory muscle fx:NS; exercise tolerance:increased in tx group, notsustained; dyspnea/leg pain,NS; POD, short-termimprovement (NS);utilization: hospitalization

decreasedBrooks et al71/

2002RCT: enhanced follow-up after

PRP vs standard careCanada/OP 109 Functional exercise

capacity; HRQL6MWD: distance, NS; time

(p 0.001); time groupinteraction (p 0.03);distance at 12 mo decreased(p 0.001); HRQL:significant differences overtime

Ries et al40/2003

RCT: 12-mo maintenance vsstandard care

United States/OP

172 PFT, exercise tolerance,psychosocialmeasures, health-careutilization

At 12 mo, exercise tolerance/health status significantlyimproved in tx vs controlgroup; 6MWT decreasedboth groups

AT 24 mo, levels for all

parameters were slightlyhigher than pre-PRP;utilization decreased in txgroup

*10MWT 10-min walk test; MRC Medical Research Council; PIP peak inspiratory mouth pressure; 6 MWT 6-min walk test; PFT pulmonary function test; POD perception of dyspnea. See Table 3 for abbreviations not used in the text.




12/39

ment, and coaching. These changes include incorpo-rating regular exercise into the patients lifestyle; theuse of breathing techniques, pacing and energyconservation strategies; and the use of medicationsand equipment, supplemental oxygen, and psychos-ocial adaptations. A number of external factors alsoinfluence program duration including health-caresystems and reimbursement policies, access to pro-

grams, level of functional disability, health-care pro-vider referral patterns, and the ability of individualpatients to make progress toward treatment goals.

Few clinical trials have focused on the impact ofprogram duration on rehabilitation outcomes, butexisting data suggest that gains in exercise tolerancemay be greater following longer programs (Table 5).For example, two other randomized trials compared3 vs 18 months of low-intensity exercise training inpulmonary rehabilitation.63,64 Berry and colleagues63

demonstrated that the longer intervention led to a6% increase in the 6-min walk distance, a 12%

reduction in self-reported disability, and faster com-pletion of stair climbing and overhead tasks. Foy andcolleagues64 showed that only male patients achievedgreater gains in CRDQ scores following the 18-month program (compared to the 3-month pro-gram). In a 2005 published prospective trial involv-ing seven outpatient programs (not in Table 5),Verrill and colleagues65 demonstrated that patientsachieved significant gains in exercise tolerance (6-min walk distance), dyspnea (University of Califor-nia, San Diego Shortness of Breath Questionnaire),and health status (Medical Outcomes Study 36-item

Short Form and the quality-of-life index) after 12weeks of pulmonary rehabilitation. Following anadditional 12 weeks of rehabilitation, exercise toler-ance but not health status or dyspnea outcomesimproved further, suggesting that program durationmay not impact all outcomes equally.

Also in support of longer term exercise training,Troosters and colleagues33 demonstrated that a6-month outpatient pulmonary rehabilitation pro-gram composed of moderate-to-high-intensity aero-bic and strength exercise training led to significantimprovements in exercise performance and quality

of life. Although this study did not compare the6-month program with a shorter one, the benefitsgained following the 6-month training program per-sisted 18 months after the completion of rehabilita-tion. This contrasts with the results of other stud-ies35,50,66 of pulmonary rehabilitation of shorter than6 months duration in which benefits tended todecline progressively over the year following reha-bilitation. Likewise, in the study by Guell and col-leagues41 (Table 4) a 12-month intervention (6months of daily rehabilitation followed by 6 monthsof weekly supervision) led to gains in exercise toler-

Table5Du

rationofPulmonaryRehabilitation

*

Study/Year

StudyType

Country/Setting

Patients,TotalNo.

Outcome

s

Results

Troostersetal33/

2000

RCT:6vs18movsusual

care

Belgium/OP

100

Pulmonaryfx;exercisecapacity;

musclestrength;QOL

Walkingdistance(p

0.0

5);exercisecapacity

(p

0.02);nosignificanteffectsoftraining

programonPFmeasuresvsusualcare;improved

quadricepsstrength(p

0.05)andQOL

(p

0.001)

Foyetal64/2001

RCT:short-vslong-term

PRP

UnitedStates/OP

140

FourdomainsofCR

Q

Significantchangesinsho

rtvslongterminall

domains

Greenetal34/

2001

RCT:single-blind;short-

vslong-termPRP

UnitedKingdom/OP

44

Endurance;HRQL

CRDQ(p

0.011);dyspn

ea(p

0.021),emotion

(p

0.003),mastery(p

0.027)

Berryetal63/

2003

RCT:single-blind;short-

vslong-termPRP

UnitedStates/OP

140

Physicalfunctionanddisability;

pulmonaryfunctio

n

Disability:p

0.016long-vsshort-term

Physicalfx:increasedw

alkdistance(p

0.03long-

term);stairclimbtime

(p

0.05)

Pulmonaryfx:NS

*SeeTable3forabbreviationsnotusedinthetext.




13/39

ance, dyspnea, and health status that persisted overthe 1 year after rehabilitation, although even thesebenefits tended to decline gradually over the secondyear of follow-up.

Green and colleagues34 also demonstrated thatpatients with severe COPD achieved greater im-provements in treadmill endurance, incrementalshuttle walk distance, and quality of life following a

7-week outpatient pulmonary rehabilitation programcompared with an identical program of only 4 weeksduration. However, patients who underwent the4-week program were not reassessed at the 7-weektime point to enable the direct comparison of out-comes.

A more recent trial (not in Table 5) readdressedthis issue in a larger cohort of patients. Sewell andcolleagues67 randomized 100 patients with moder-ate-to-severe COPD (mean FEV1, 1.13 L) to receive4 vs 7 weeks of outpatient rehabilitation. All patientswere assessed at baseline, at the end of the rehabil-

itation intervention, and 6 months later. Patients inthe 4-week training group were also evaluated at 7weeks. Patients in both groups had significant im-provements in exercise tolerance and health status.This study contrasts with the results of other pub-lished studies mentioned above in that it showed thatthe shorter 4-week intervention produced gains inexercise tolerance at both the 7-week and 6-monthfollow-up time periods that were comparable tothose following the longer 7-week program. Finally,in an older trial Wijkstra and colleagues61 showedthat patients who underwent 18 months of home-

based rehabilitation had greater sustained improve-ments in quality of life compared with patients whoreceived twice-weekly rehabilitation over a 3-monthperiod, but no difference was noted between groupsin the magnitude of gains in the 6-min walk distance.

Overall, although some studies suggest that theduration of the pulmonary rehabilitation programimpacts exercise tolerance improvement, it is lessclear that other outcomes such as health status ordyspnea are similarly affected by program duration.Other studies60,67 have demonstrated that even pro-grams of short duration (ie, 10 days to 4 weeks) can

produce significant benefits as well. Moreover, theeffect of program duration on patient abilities toperform activities of daily living (ADLs) is uncertain.The clinical benefits of pulmonary rehabilitation maydepend as much on program site and content as onduration.62 Thus, given the variations in types ofrehabilitation programs and differences in clinicalstudy design, patient populations, health systems indifferent countries, program location, and programcontent, it is not possible at this time to draw firmconclusions regarding the optimal duration of pul-monary rehabilitation treatment.

Recommendation

9. Longer pulmonary rehabilitation pro-grams (beyond 12 weeks) produce greater sus-tained benefits than shorter programs.Grade ofrecommendation, 2C

Postrehabilitation MaintenanceStrategies

Although the benefits of pulmonary rehabilitationhave been demonstrated up to 2 years following ashort-term intervention,41 most studies suggest thatthe clinical benefits of pulmonary rehabilitation tendto wane gradually over time. This is underscored in12-month follow-up data from a cohort of patientswith COPD who had completed a 10-week compre-hensive pulmonary rehabilitation program.68 At theend of the 10-week program, participants were givena structured home exercise program to follow. At the

follow-up evaluation 1 year later, participants whohad continued with the prescribed exercise routinemaintained the gains that had been achieved inphysical endurance, psychological functioning, andcognitive functioning during the initial intervention.However, participants who did not maintain theexercise routine exhibited significant declines in allareas of functioning, including exercise endurance,psychological functioning, and cognitive functioning.

Interest has thus arisen in strategies to maintainthe benefits of pulmonary rehabilitation over time,such as repeated courses of rehabilitation treatment

or maintenance interventions. In the study by Foglioand colleagues,36 although repeated pulmonary re-habilitation interventions spaced 1 year apart led tosignificant short-term gains similar to those seenfollowing an initial 8-week outpatient program, noadditive, long-term physiologic benefits were noted.A study by Ries and colleagues40 demonstrated thata 12-month maintenance intervention (consisting ofmonthly supervised exercise and educational rein-forcement sessions and weekly telephone contacts)following an initial 8-week outpatient pulmonaryrehabilitation program led to modest improvements

in the maintenance of walking endurance, healthstatus, and health-care utilization compared withusual care following pulmonary rehabilitation over a1-year follow-up period. However, a gradual declinein these outcomes was noted over time in bothpatient groups, and the initial benefits of the main-tenance intervention were no longer evident at 24months of follow-up. In a separate study by Puente-Maestu and colleagues,69 a 13-month maintenanceprogram (consisting of patient self-governed walking4 km per day at least 4 days per week with supervisedsessions every 3 months) led to small gains in




14/39

tolerance of high-intensity constant-work-rate exer-cise and quality of life after an initial 8 weeks oflower extremity training (two different regimens),but the effects of the maintenance program on theability to perform lower intensity exercise or ADLswere not tested. Grosbois and colleagues70 showedthat 18 months of both self-managed, home-based,and center-based supervised exercise maintenancewere beneficial in maintaining the benefits in maxi-mal exercise tolerance following a 7-week outpatientpulmonary rehabilitation program. In this study,center-based exercise maintenance afforded no ben-efits over the patient self-managed, home-basedapproach. Other studies71 have failed to demonstrateany benefit of maintenance programs following theshort-term rehabilitation intervention. Althoughmost studies have not yet assessed how maintenanceprograms truly impact patients ability to performdaily activities outside of the program setting, par-

ticipation after pulmonary rehabilitation in regularexercise such as walking has been associated with aslower decline in HRQOL and dyspnea duringADLs.72

Thus, the role of maintenance pulmonary rehabil-itation interventions following initial structured pro-grams remains uncertain at this time, and the bene-fits of such interventions studied to date are modest,at best. Additional research is needed to clarify therelative impact of the many factors that can impactduration benefits from short-term pulmonary reha-bilitation, such as the maintenance program struc-ture, content, and location; exacerbations of respira-tory disease; complications of other medicalcomorbidities; and the absence of reimbursementfor continued patient participation. An additionalimportant topic that must be addressed in the futureis that of long-term patient participation. A relativelysmall number of patients who are offered a commu-nity-based exercise maintenance program will acceptit and adhere to it.73 Moreover, among those personswho do enroll in maintenance programs, attrition isproblematic, resulting from factors such as diseaseexacerbations, loss of interest and/or motivation,transportation barriers, depression, program costs,and other personal issues affecting patients lives.Additional work is needed to evaluate the optimalmethods to incorporate short-term rehabilitationstrategies into long-term disease management pro-grams for patients with chronic lung disease.

Recommendation

10. Maintenance strategies following pulmo-nary rehabilitation have a modest effect on long-term outcomes.Grade of recommendation, 2C

Intensity of Aerobic Exercise Training

Exercise training is one of the key components ofpulmonary rehabilitation. The exercise prescriptionfor the training program is guided by the followingthree parameters: intensity; frequency; and duration.The characteristics of exercise programs in pulmo-nary rehabilitation for patients with COPD have not

been extensively investigated.As noted by the previous panel and a 2005 re-

view,74 for most patients with COPD with limitedmaximum exercise tolerance, training intensities athigher percentages of maximum (ie, peak exercise)are well-tolerated, and physiologic training effects(eg, increase in aerobic capacity and anaerobicthreshold with reduced ventilatory demand) havebeen documented as a result of (relatively) high-intensity aerobic training. Although it has not beenconclusively demonstrated in patients with COPD,higher intensity training may result in better physi-

ologic training effects, including reduced minuteventilation (V e) and heart rate (HR), and, thus, lessdyspnea at submaximal exercise. In this context, thetermhigh-intensity trainingfor patients with COPDrefers to patients exercising close to individual peaklevels and is relative to the markedly reduced peakexercise levels in these patients. In previous studies,high-intensity training targetshave been operation-ally defined to be at least 60 to 80% of the peak workrate achieved in an incremental maximum exercisetest.75,76 This should not be interpreted to representtraining at high absolute work levels.

There have only been two randomized studies77,78published since the previous panel report that haveevaluated the intensity of exercise during pulmonaryrehabilitation in patients with COPD. Gimenez andcolleagues77 randomized 13 patients to high-intensityor moderate-intensity lower extremity exercise train-ing daily for a period of 6 weeks. High-intensityexercise was performed on a cycle ergometer using aprotocol of 1-min periods at peak oxygen uptake(V o2) followed by 4-min periods at 40 to 45% of peakV o2. The moderate-intensity exercise group pushedan oxygen cart for a similar duration of 45 min per

session. High-intensity training resulted in greaterphysiologic improvements (eg, improvement in max-imum V o2). High-intensity exercise, but not low-intensity exercise, also resulted in decreased dyspneaat rest and during submaximal exercise, and in-creased the 12-min walk distance. Vallet and col-leagues78 randomized 24 subjects to exercise at anHR achieved at the anaerobic or gas exchangethreshold (high intensity) or at an HR of 50% ofmaximal cardiac frequency reserve (low intensity).Stationary cycle ergometry was performed for 45min 5 days per week for 4 weeks. Subjects who




15/39

trained at the higher gas exchange threshold inten-sity exhibited improvement in maximum exerciseV o2and a greater decrease in V ecompared to thosewho trained with low-intensity exercise.

The physiologic benefits of higher intensity exer-cise training with the associated reduction in V e atsimilar workloads may be expected to result in betteroutcomes from pulmonary rehabilitation. The few

small controlled randomized studies77,78 availableconfirm these expectations. However, the effects ofhigh-intensity training on other key patient-centeredoutcomes such as quality of life, shortness of breath,and ability to perform ADLs have not been investi-gated rigorously.

Moreover, the impact of exercise intensity on theimportant outcome of maintenance of exercise train-ing has not been evaluated. As in other populations,it is possible that lower intensity exercise trainingmay be associated with better long-term adherencethan higher intensity training.

Recommendations

11. Lower extremity exercise training athigher exercise intensity produces greaterphysiologic benefits than lower intensity train-ing in patients with COPD.Grade of recommen-dation, 1B

12. Both low-intensity and high-intensity ex-ercise training produce clinical benefits for pa-tients with COPD.Grade of recommendation, 1A

Strength Training in Pulmonary

Rehabilitation

Although always recognized as important, improv-ing the function of the muscles of the arms and legshas recently become a central focus of pulmonaryrehabilitation. In the course of everyday activities,these muscles are asked to perform two categories oftasks. Endurance tasks require repetitive actionsover an extended period of time; walking, cycling,and swimming are examples. Strength tasks requireexplosive performance over short time periods;

sprinting, jumping, and lifting weights are examples.For individuals whose muscles are weak, another cat-egory of strength-related tasks may become relevant,such as maintaining balance while standing, rising froma chair, or hoisting objects above head level.

Different characteristics of skeletal muscle enablethe performance of endurance and strength tasks.Endurance is facilitated by having machinery capa-ble of the aerobic metabolism of nutrients. Predom-inance of type I fibers, dense capillarity, high con-centrations of enzymes subserving oxidativemetabolism, and high mitochondrial density all pro-

mote muscle endurance. In contrast, strength isfacilitated in muscles, the fibers of which are high innumber and large in cross-section, with high frac-tions of type II fibers.

Some work7981 has shown that the skeletal mus-cles of patients with COPD are, in general, dysfunc-tional. Some structural and biochemical abnormali-ties would predict poor aerobic function (eg, poor

capillarization and type II fiber predominance).However, compared to age-matched healthy sub-jects, patients with COPD also have low musclemass,82,83 especially in the muscles of ambulation;this predicts poor muscle strength.8385

In healthy subjects, strength-training programs, inwhich progressive resistance methods are used toincrease the ability to exert or resist force,86 arecapable of profoundly altering muscle structure andbiochemistry, even in older subjects.8790 An impor-tant principle of training specificity dictates thattraining programs featuring endurance activities (eg,

treadmill walking and bicycle riding) yield musclechanges that improve endurance, while training pro-grams that feature tasks requiring strength (eg, ma-chine weights, free weights, elastic resistance, andlifting the body against gravity) yield muscle changesimproving strength. However, more recent work91,92

has shown that the muscles of elderly subjects mayalso show improvements in aerobic characteristicsafter a program of strength training.

In patients with COPD, there is a strong scientificbasis for implementing endurance-training programsin regard to both design and benefits. In comparison,

programs of strength training have been explored inclinical trials only in more recent years. Since the lastreview, eight randomized clinical trials relevant tostrength training have been published (Table 6),which is a considerable advance on the one studypublished prior to 1997. This older study (Simpsonand colleagues93) was not included in the previousreview and so has been included in the currentanalysis. These nine studies93101 can be separatedinto those that allow comparison between a controlgroup (ie, either no exercise or endurance exer-cise)9398 and a strength-trained group, and those

that allow comparison between an endurance-trained group and a group receiving a combinedendurance-training and strength-training interven-tion.97,99101 The latter comparison is especially rel-evant to rehabilitative practice in which the questionis whether the addition of strength training to anendurance-training program produces additionalbenefits.

The six randomized clinical trials9398 examiningthe responses of patients with COPD to a program ofstrength training have sufficient commonality to beexamined as a group. With one exception,95 the




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Ta

ble6StrengthTraining*

Study/Year

StudyType

Country/Setting

Patients,TotalNo.

Outcomes

Results

Bernardetal99/

1999

RCT:notblinded;

aerobictraining

vsaerobic/strength

Canada/OP

45

Musclefunction,PF,exercise

capacity,QOL

Musclefunction:sign

ificantincreasesinstrength

group

Workrate:increaseinstrengthgroup

6MWD:improved(p

0.0005bothgroups)

HRQL:improved(p

0.05bothgroups)

Clarketal95/2000

RCT:trainingvscontrol

UnitedKingdom/OP

43

Musclestrength;endurance

Maximumweightlifted(p

0.001vscontrol;

fouroffiveexercises)

Endurance:increased

(p

0.001vscontrol

subjects)

Spruitetal98/2002

RCT:resistancevs

endurance

Belgium/OP

48

PF;exercisecapacity;endurance;

HRQL

Significantimprovem

entinalloutcomesin

exercisetraininggroup

Ortegaetal97/2002

RCT:endurancev

sstrengthvs

combinedvscontrol

Spain/OP

72

PF;peakexercisep

arameters;

capacity;muscle

strength;HRQL

PF:changesNS

Endurance:significan

tincreaseallgroups

Strength:significantincreaseinallgroups;

HRQL:improvedfatigueandemotion

Pantonetal101/

2004

RCT:resistancevs

aerobic

UnitedStates/OP

18

PF;bloodmeasures;strength;

12MWT;ADL

Upperandlowerbod

ystrengthincreasedintx

group

HR,Sao2,RPE,RPD

:nochange

12MWT:increasein

txgroup

ADL:improvements

intxgroup

Kongsgaardetal96/

2004

RCT:resistancevs

control

Denmark/OP

18

Bodymeasurement

s;dynamic

strength;maximu

mlegextension

power;normal/m

aximumgait

speed;stairclimb;ADL

Anthropometricparameters:nochange;decrease

inFEV1

NSincon

trolgroup

Significantrelationshipsamongchangesin

strength,physicalf

unction,power;CSA,

MVC,kneeextensiontrunkflex,power

(p

0.05resistance);5RM

(kg),N-gait

(p

0.001resistan

ce)

ADL:improvement(

p

0.05)intxgroup

Madoretal100/

2004

RCT:endurancev

scombined

training

UnitedStates/OP

32

PF,exercisetesting

,QOL,muscle

measurements

Musclestrength:incr

easesincombinedvs

enduranceonly

QOL:improvements

inbothgroups

Exerciseperformance:NSinbothgroups

Exerciseendurance:significantincreaseinboth

groups

Casaburietal94/

2004

RCT:blinded;placebovs

resistance

UnitedStates/OP

47

Bodycomposition;

musclestrength,

endurance,PF,b

loodmeasures,

safetymeasures

Bodycomposition:weightgain:NSinplacebo

groups;increasein

txgroups;leanmass

increasesignificant

intxgroups

Endurance:significan

tincreaseintxgroups

PeakO2

update,peakworkrate,lacticacid:

significantchanges

intxgroup

*12MWT

12-minwalktime;CSAcr

oss-sectionalarea;MVC

maximumisometricextension;RPE

rateofpreceivede

xertion;RPD

rateofperceiveddyspnea;RM

rangeofmovement;

N-gait

normalgait.SeeTable3forabbreviationsnotusedinthetext.




17/39

average disease severity was moderately severe(FEV1range, 38 to 48% predicted). The exception isthe study of Clark and colleagues95 in which patientswith very mild COPD were studied (average FEV1,77% predicted). Collectively, the total number ofpatients studied was moderate, with the strength-trained group in the various studies comprising 6 to26 subjects (total, 99 subjects). The training appara-

tus, exercise repetition, and intensity progressionvaried among studies (see Storer102 for a review ofsuitable strength-training strategies). Program lengthranged from 8 to 12 weeks; sessions were held two orthree times per week, and session length (whenstated) ranged from 40 to 90 min. These programcharacteristics are similar to those known to beeffective in healthy subjects.103

The recorded outcomes of these studies includechanges in strength, endurance, muscle mass, anddisease-specific HRQOL. All six studies9398 re-ported improvements in strength. A variety of

testing apparatuses were used, and it should bestressed that the measures of strength used inthese studies were effort, motivation, and practicedependent. In all studies but one,96 the change inexercise endurance was also assessed. Results weremixed. The peak exercise level in an incrementalcycle ergometer test showed a statistically signifi-cant increase in only one of five studies98; theduration of a constant-work-rate task increased inthree of five studies93,95,97; and the 6-min walkdistance increased in one of the two studies in which itwas assessed.98 In two studies in which it was mea-

sured, muscle mass (assessed by MRI of a quadricepscross-section96 or dual-energy x-ray absorptiometry[DEXA] scan of lean leg mass94) increased significantly(by 4% and 3%, respectively).

Four studies97,99101 allowed a comparison of ben-efits to COPD patients between a combinedstrength-training and endurance-training programand an endurance-training program alone. Thesestudies examined patients with, on average, moder-ately severe to severe disease (mean FEV1range, 33to 45% predicted). The number of patients includedin the strength-training-plus-endurance-training

group ranged from 9 to 21 (total, 55 patients).Training programs were 8 to 12 weeks in duration;sessions were held two or three times per week; theduration of strength training per session was gener-ally not stated (it was 45 min in the study by Bernardand colleagues99). Strength-training exercises wereincluded for both the arms and the legs.

In all four studies, improvement in measures ofmuscle strength was superior in the group receiv-ing a strength-training component to that seenamong those receiving endurance training alone.In one study,101 measures of ADLs improved more

in the combined-training group. However, mea-sures of the increase in exercise endurance werecomparable in the two groups (with the exceptionof the study by Panton and colleagues,101 whofound a superior increase in the 12-min walkdistance in the combined-training group). Twostudies99,101 assessed muscle mass changes; neitherdetected significant changes in subjects perform-ing endurance training alone, while both showedincreases in the groups in whom a strength-training program was added (8% increase in thighcross-section by CT scan99 and 5% increase inwhole-body lean mass by DEXA scan101).

These data can be interpreted to indicate that well-designed strength-training programs increase musclestrength and mass in patients with moderate-to-severeCOPD. Strength training, when delivered as an iso-lated intervention may improve disease-specific qualityof life but does not seem to produce additional gains

when added to a program of endurance training.Strength training does not produce endurance benefitsas consistently as does specific endurance training.

It should be emphasized that, to date, all citedtrials featuring combined programs have added astrength-training component to an endurance-train-ing program (ie, essentially doubling the time spenttraining) rather than substituting part of the endur-ance-training program with an endurance compo-nent. Therefore, whether it is wise for rehabilitationpractitioners to include a strength-training compo-nent in a session of fixed duration by reducing thetime spent in endurance activities cannot be assessedat this time. Importantly, no serious adverse effectsof strength training have been reported; these pre-liminary data suggest that strength training is safe inpatients without obvious contraindications (eg, se-vere osteoporosis). Little information is available onthe long-term benefits of strength training in thepulmonary rehabilitation patient. Whether strengthgains persist and whether adverse consequences ofweakness occur (eg, decreased mobility or injuries dueto falls) cannot be determined. Larger, longer termtrials are required to resolve these issues. Finally,muscle biopsy studies of the cellular and biochemicaladjustments following strength training have yet to bereported; such studies should help to determine theextent to which strength training ameliorates the mus-cle dysfunction seen in COPD patients.

Recommendation

13. The addition of a strength-training com-ponent to a program of pulmonary rehabilita-tion increases muscle strength and musclemass.Strength of evidence, 1A




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Anabolic Drugs

Since exercise-training interventions are a corner-stone in pulmonary rehabilitation and yield benefits,at least in part, by improving the function of theexercising muscles, it seems reasonable to hypothe-size that pharmaceutical agents that improve musclefunction in similar ways might be useful adjuncts to

rehabilitative therapy. However, the list of drugs thatmight be suitable for clinical trials is quite limited. Inparticular, no agent that is capable of directly im-proving the aerobic characteristics of muscle hasbeen studied in a clinical trial. It is plausible thaterythropoietin might be of use in anemic patientswith COPD; increasing muscle oxygen deliverymight increase exercise endurance as it has in otherpatient groups,104,105 but this has not been tested ina clinical trial.

Drugs that produce muscle hypertrophy havebeen identified and studied to determine whether

they elicit improvements in muscle strength. Growthhormone, generally administered by daily injection,has been shown to induce modest increases inmuscle mass. However, improved functionality hasbeen difficult to demonstrate.106,107 In the only studyin COPD, Burdet and colleagues108 studied 16 un-derweight patients with COPD who received dailygrowth hormone injections for 3 weeks. Lean bodymass (assessed by DEXA scan) increased 2.3 kg inthe growth-hormone group compared with 1.1 kg inthe placebo group. No differences in maximuminspiratory pressure, handgrip strength, or incre-

mental cycle ergometer exercise capacity were de-tected between groups. The 6-min walk distancedecreased significantly in the growth-hormonegroup. Clearly, growth hormone cannot be recom-mended as an adjunct therapy for pulmonary reha-bilitation at this time.

In men, therapy with testosterone and its analogshas been shown to increase muscle mass, decreasefat mass, and improve muscle strength. Well-con-trolled trials of testosterone supplementation inhealthy young men109,110 and older men111 havedemonstrated that muscle mass and strength in-

crease with a linear dose-response relationship; anappreciable hypertrophic response is seen within thephysiologic range of circulating testosterone levels.Further, hypogonadal men show increases in musclemass and strength in response to physiologic doses oftestosterone.112 The side effects of testosterone ad-ministration are of concern; lipid abnormalities,polycythemia, and liver function abnormalities havebeen reported.113 In older men who may harborsubclinical foci of prostate cancer, testosterone ad-ministration may enhance the growth of these fo-ci.114 More recent experience suggests that substan-

tially supraphysiologic doses of testosterone shouldbe avoided in older men.111 A number of formula-tions of testosterone are available; it can be admin-istered by injection, transdermal patch, transdermalgel, and orally.115 Oral administration, however, hasoften been associated with elevations in liver func-tion test results. There have also been some prelim-inary studies116 of testosterone administration in

women. Circulating levels of testosterone in womenare roughly 10-fold lower than those in men, andhigh testosterone doses are inevitably associated withvirulization.117 Whether lower doses that are notassociated with virulization will have substantial an-abolic effects on muscle remains to be seen.

A rationale for testosterone supplementation in menwith COPD is that circulating levels have been shownto be lower than those seen in healthy young men andare often lower than those in age-matched controlsubjects.94,118,119 Since the publication of the previousrehabilitation guidelines, five RCTs94,120123 have ap-

peared in which testosterone or its analogs (collectivelyknown asanabolic steroids) have been administered topatients with COPD. These trials are similar, in thatpatients with moderately severe COPD were studied(mean FEV1range, 34 to 49% predicted). All studieswere limited to men, except for the study of Schols andcolleagues,122 in which women received half the drugdose that men received. In three of the studies,120122

all participants received a rehabilitation-type program.All studies used relatively low doses, and no cleardrug-related adverse reactions (with the exception of amodest increase in hematocrit94) have been reported.

Schols and colleagues122 administered nandrolonedecanoate or placebo by injection every 2 weeks for8 weeks to approximately 130 patients who alsoreceived nutritional supplementation. Although nodifferences in body weight change were observedbetween these groups, in the nandrolone groupweight gain was predominantly in lean mass, whereasin the placebo group weight gain was predominantlyfat. No difference in changes in the 6-min walkdistance or peak inspiratory pressure was detected.

Ferreira and colleagues121 administered oralstanozolol or placebo daily for 27 weeks to 23

underweight patients with COPD. DEXA scan-ning revealed an increase in lean mass of approx-imately 2 kg and a 5% increase in thigh circum-ference, which are changes that were not seen inthe control group. No differences were detected in6-min walk distance or incremental cycle ergome-ter testing results.

Creutzberg and colleagues120 administered nan-drolone decanoate or placebo by IM injection every2 weeks for 8 weeks to 63 men with COPD. Fat-freemass increased by 1.7 kg in the nandrolone groupcompared to 0.3 kg in the placebo group. No signif-




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icant differences were seen between groups in incre-mental cycle ergometer exercise capacity orHRQOL. Muscle strength was assessed, but nodifferences were detected in handgrip strength orisokinetic leg strength testing results.

Svartberg and colleagues123 administered testos-terone enanthate or placebo by injection every 4weeks for 26 weeks to 29 men with COPD. DEXA

scanning revealed a 1.1-kg increase in lean mass and a1.5-kg decrease in fat mass in the testosterone group.No exercise outcomes were assessed. No difference inquality of life, as assessed by the St. George respiratoryquestionnaire was detected, but better sexual quality oflife and erectile function was noted.

Casaburi and colleagues94 studied 47 men withCOPD and low testosterone levels (mean total tes-tosterone level, 320 ng/dL). Subjects received 100mg of testosterone enanthate or placebo by IMinjection for 10 weeks. Half of the group receivingtestosterone also underwent a strength-training pro-

gram. Testosterone therapy yielded a 2.2-kg increasein lean body mass; the group receiving both testos-terone and strength training experienced a 3.3-kgincrease in lean mass. Average leg press strengthincreased by 12% in the testosterone group and by22% in the group receiving testosterone therapy plusstrength training. No improvements in incrementalor constant-work-rate cycle ergometer exercise tol-erance were demonstrated.

In summary, anabolic steroid administration hasconsistently been shown to increase lean (presum-ably muscle) body mass in men with moderate-to-

severe COPD. As expected on theoretical grounds,no improvement in endurance exercise capacitywas detected. In one study,94 but not in another,120

an increase in the strength of the muscles of ambula-tion was detected. No evidence for improvements inquality of life has been obtained. It is premature tosuggest that the administration of anabolic steroids beincorporated into rehabilitative programs f

2007 - CHEST - Pulmonary Rehabilitation (Supplement)

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