RehabilitaPulmonarexacerbacionesEPOC

Pulmonary Rehabilitation-2009- Moving Forward -

Richard Casaburi, Ph.D.,M.D.Los Angeles Biomedical Research

Institute at Harbor-UCLA Medical Center

Torrance, California, USA

Disclosures: Grants/Consultation for Boehringer-Ingelheim, Forest, Astra Zeneca, Novartis, Inogen, Pfizer, GlaxoSmithKline, Osiris, Roche

Pulmonary Rehabilitation

…the standard of care for COPD

patients debilitated by their disease

Chest 2007, 131:4S-42S

38 pages of EVIDENCE!

Evidence Based Rehabilitation Guidelines

Evidence Grades:1,2 - Strength of Recommendation

based on balance of risks and benefits

A,B,C - Strength of Evidencebased on supporting evidence

Evidence Based Rehabilitation Guidelines for COPD

Pulmonary rehabilitation:• Both low- and high-intensity exercise

training produce clinical benefits- 1A • improves the symptom of dyspnea - 1A• improves health-related quality of life - 1A

These benefits are generally of greater magnitude than for any

other COPD therapy


Pulmonary rehabilitation:• reduces the number of hospital days

and other measures of health care utilization - 2B

• induces psychosocial benefits - 2B

Chest 2007, 131:4S-42S

Rehabilitation in COPD

Why is rehabilitation poorly funded…and therefore poorly available?

• Inadequate lobbying• Inadequate evidence of benefit

2008 - A Good Year for Pulmonary Rehabilitation

in the United States• Pulmonary Rehabilitation achieves

Assembly status in the ATS• Federal legislation establishing

pulmonary rehabilitation as a covered service under Medicare is passed

Details of coverage decision being worked

out by CMS -implementation in January 1, 2010

Rehabilitation in COPD

Why is rehabilitation poorly funded…and therefore poorly available?

• Inadequate lobbying• Inadequate evidence of benefit

Pulmonary Rehabilitation- Moving Forward -

• Can rehabilitation be administered at home?• Is activity level increased by rehabilitation?• Can the benefits of rehabilitation be

maintained?• Can we make the exercise training component

more effective?• Can we demonstrate a survival benefit?

Ann Int Med, 2008

Ann Int Med, 2008

Change in CRQ

Dyspnea at 3 months

Ann Int Med, 2008-6

4

14

24

34

44

54

Home-Based Center-Based

Change in 6MWD at 3 months

Respir Med, 2007

Respir Med, 2007

Respir Med, 2007





Better Exercise Tolerance

Better Long-Term

Outcomes (e.g., survival)


Better Long-Term


More Active During Daily

Life


Better Long-Term



Life


Better Long-Term



Life

?

?

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

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• Ringbaek et al., Clin Rehabil, 2005

– 226 Danish LTOT patients completed activity questionnaire

– Followed for mean of 8 years for mortality

Are self-ratings of activity reliable?

No long-term studies of influence of objectively assessed activity on

prognosis in COPD

Is activity level increased by rehabilitation?

• Sewell et al., Chest - 2005• Walker et al., Thorax -2008• Steele et al. JCR -2008• Pitta et al. Chest -2008


• Sewell et al., Chest - 2005 YES• Walker et al., Thorax -2008 YES• Steele et al. JCR -2008 NO• Pitta et al. Chest -2008 MAYBE

Pitta et al., Chest, 2008


• Sewell et al., Chest - 2005• Walker et al., Thorax -2008• Steele et al. JCR -2008• Pitta et al. Chest -2008

Differences in Activity Monitoring Technology and Duration May Explain Differences in Results


• Sewell et al., Chest - 2005 2 days• Walker et al., Thorax -2008 2 days• Steele et al. JCR -2008 6 days• Pitta et al. Chest -2008 5 days

Differences in Activity Monitoring Technology and Duration May Explain Differences in Results





• 209 completed rehabilitation program

• 18 died in one-year follow-up period

• 49 failed to continue through 1-year evaluation (non-completers)

Number Needed to Treat to Improve SGRQ by a Clinically Important

Amount for 1 Year ~ 1.6

N=142Completers

N=49Non-

completers





Adjuncts to High Intensity Rehabilitative Exercise in COPD

• Bronchodilators• Supplemental

oxygen• Anabolic steroids• Electrical muscle

stimulation• Ventilation feedback

• Interval training• Creatine • Heliox breathing• Non-invasive ventilation• One-legged exercise• Nutritional

supplementation• Inspiratory muscle

training







training







training

Promising Approaches

n=93







training


Combined Effects of Exercise Training and 30% Oxygen Breathing in Non-hypoxemic COPD

0

5

10

15

20

25

30

Tim

e (m

in)

Oxygen Training Air Training

Air-preOxygen-preAir-postOxygen-post

Before After Before After

** **

**

** *

Emtner et al., AJRCCCM, 2003

Increase in Constant Work Rate Test Endurance after Exercise Training

02468

10121416

Tim

e (m

in)

Oxygentraining group

Air traininggroup

air and oxygenbreathing tests

* 38% greater gain in endurance







training


Anabolic steroidsCasaburi R, Bhasin S Cosentino L. et al. Effects of testosterone

replacement and resistance training in men with COPD. Am. J. Respir.Crit. Care Med. 170:870-878,2004.

P+NE T+NE P+E T+E-0.5

0.0

0.5

1.0

1.5

2.0mean ± SE

*

*

∆ L

eg L

ean

Bod

y M

ass

(kg)

*

P+NE T+NE P+E T+E0

20

40

60

80

100

120

140

160

180mean ± SE

*

*

∆ L

eg P

ress

(lb)

*

∆Leg Muscle Mass (kg) ∆Leg Muscle Strength (lb)

N=47

• Fiber hypertrophy documented for both resistance training and testosterone

• Mediators of muscle anabolism increased

• Fiber hypertrophy documented for both resistance training and testosterone

• Mediators of muscle anabolism increased

Wide use of testosterone unlikely because of potential side effects:

• virulization in women

• prostate stimulation in men

Selective androgen receptor modulators (SARMs), now entering clinical trials, are likely to overcome these problems







training


• Surface electrodes stimulate a motor nerve to induce repeated muscle contractions

• All studies small (n=15 to 18)• Two of three studies showed

increases in muscle strength and endurance vs. control group

• One study showed muscle stimulation, when added to exercise training, yielded additional strength, but not endurance, improvement

Electrical Muscle Stimulation

• Surface electrodes stimulate a motor nerve to induce repeated muscle contractions

• All studies small (n=15 to 18)• Two of three studies showed

increases in muscle strength and endurance vs. control group

• One study showed muscle stimulation, when added to exercise training, yielded additional strength, but not endurance, improvement

Electrical Muscle Stimulation

Larger studies needed to define benefits and refine techniques







training


In ventilation feedback training, a computerized system encourages slower-deeper breathing pattern

33 patients completed VF training vs training alone

Less dynamic hyperinflation and trend for better exercise tolerance in VF group





• Interval training• Creatine• Heliox breathing• Non-invasive ventilation• One-legged exercise• Nutritional


training

Evidence of Lack of Benefit

Interval training

• Varga J, Porszasz J, Boda K, et al. Supervised high intensity continuous and interval training vs. self-paced training in COPD. Respir Med 2007; 101:2297-2304 (n=71)

• Arnardottir RH, Boman G, Larsson K, et al. Interval training compared with continuous training in patients with COPD. Respir Med 2007; 101:1196-1204 (n=60)

• Puhan MA, Busching G, Schunemann HJ, et al. Interval versus continuous high-intensity exercise in chronic obstructive pulmonary disease: a randomized trial. Ann Intern Med 2006; 145:816-825 (n=98)

• Mador MJ, Krawza M, Alhajhusain A et al. Interval training versus continuous training in patients with COPD. J Cardiopulm Rehabil 2009; 29:126-132. (n=21)

• Nasis IG, Vogiatzis I, Stratakos G, et al. Effects of interval-load versus constant-load training on the BODE index in COPD patients. Respir Med 2009 (in press) (n=42)

Recent COPD Studies

Interval training

• Varga J, Porszasz J, Boda K, et al. Supervised high intensity continuous and interval training vs. self-paced training in COPD. Respir Med 2007; 101:2297-2304 (n=71)

• Arnardottir RH, Boman G, Larsson K, et al. Interval training compared with continuous training in patients with COPD. Respir Med 2007; 101:1196-1204 (n=60)

• Puhan MA, Busching G, Schunemann HJ, et al. Interval versus continuous high-intensity exercise in chronic obstructive pulmonary disease: a randomized trial. Ann Intern Med 2006; 145:816-825 (n=98)

• Mador MJ, Krawza M, Alhajhusain A et al. Interval training versus continuous training in patients with COPD. J Cardiopulm Rehabil 2009; 29:126-132. (n=21)

• Nasis IG, Vogiatzis I, Stratakos G, et al. Effects of interval-load versus constant-load training on the BODE index in COPD patients. Respir Med 2009 (in press) (n=42)

Recent COPD Studies

Decent sized studies!

Interval training not found superior to constant work rate training in any

of them.


• Bronchodilators• Supplemental oxygen• Anabolic steroids• Electrical muscle


• Interval training• Creatine• Heliox breathing• Non-invasive ventilation• One-legged exercise• Nutritional


trainingEvidence of Lack of Benefit

Creatine Supplementation

• Fuld JP, Kilduff LP, Neder JA, et al. Creatine supplementation during pulmonary rehabilitation in chronic obstructive pulmonary disease. Thorax 2005; 60:531-537 (n=38)

• Faager G, Soderlund K, Skold CM, et al. Creatine supplementation and physical training in patients with COPD: a double blind, placebo-controlled study. Int J Chron Obstruct Pulmon Dis 2006; 1:445-453 (n=23)

• Deacon SJ, Vincent EE, Greenhaff PL, et al. Randomised controlled trial of dietary creatine as an adjunct therapy to physical training in COPD. Am J Respir Crit Care Med 2008 (n=100)

- During Pulmonary Rehabilitation -

No evidence for additive effects on exercise endurance to date







training

Likely Impractical for Routine

Use







training

82 COPD patients performed 4 endurance shuttle walk tests breathing

•21% O2, 79% N2

•28% O2, 72% N2

•21% O2, 79% He

•28% O2, 72% HeAJRCCM, 2006

82 COPD patients performed 4 endurance shuttle walk tests breathing

•21% O2, 79% N2

•28% O2, 72% N2

•21% O2, 79% He

•28% O2, 72% HeAJRCCM, 2006

Problem with Heliox in rehabilitation: must provide entire respired volume of

Heliox gas






trainingLikely Impractical for Routine Use

Eur Respir J, 2006n=29

Eur Respir J, 2006

Pressure support training:

-requires 1:1 patient-to-therapist ratio

-is uncomfortable for the patient

n=29






training

Likely Impractical for Routine Use

One-legged exercise• Dolmage TE, Goldstein RS. Effects of

one-legged exercise training of patients with COPD. Chest 2008; 133:370-376(n=18)

• Half trained with both legs for 30 minutes, half for 15 minutes with each leg; intensity increased as tolerated.

• One-legged exercise group demonstrated better performance in incremental, but not constant work rate, exercise testing, than two-legged group

One-legged exercise• Dolmage TE, Goldstein RS. Effects of

one-legged exercise training of patients with COPD. Chest 2008; 133:370-376(n=18)

• Half trained with both legs for 30 minutes, half for 15 minutes with each leg; intensity increased as tolerated.

• One-legged exercise group demonstrated better performance in incremental, but not constant work rate, exercise testing, than two-legged group

Solid physiologic rationale…but awkward

Larger studies, perhaps with both intensity and session duration increased

as tolerated, would be of interest







trainingResearch Needed for Use in Special

Populations

Nutritional SupplementationCan optimizing nutritional support improve the benefits of

rehabilitative exercise training?Steiner MC, Barton RL, Singh SJ, et al. Nutritional

enhancement of exercise performance in chronic obstructive pulmonary disease: a randomised controlled trial. Thorax 2003; 58:745-751

• 85 COPD patients participating in a 7 week rehabilitation program were assigned to carbohydrate supplement vs. placebo

• Supplemented patients gained more fat weight, but did not have greater exercise tolerance gains

More targeted nutritional interventions might yield better results






trainingResearch Needed for Use in Special

Populations

• 8 weeks endurance training • ± hyperpnea training via a rebreathing circuit• In hyperpnea training group

– Respiratory muscle strength & endurance increased– No difference in exercise endurance between groups

Limit study to those with respiratory muscle weakness?







training





Survival: the missing piece of the puzzle

Question: Why does the US spend ~ $3 billion annually to provide COPD

patients with long-term oxygen therapy?

Answer: Because LTOT delivers an unequivocal

survival benefit

Evidence considered conclusive despite:

•No confirmation since 1981

•Based on a total of < 300 patients


“There is insufficient evidence to determine whether pulmonary rehabilitation improves survival. No recommendation is provided.”

Evidence-Based PulmonaryRehabilitation, Chest, 2007

Does pulmonary rehabilitation improve survival?

Ries, A. L. et. al. Ann Intern Med 1995;122:823-832

Pulmonary Rehabilitation’s Mortality Trial

“Experts” believe patients participating in rehabilitation live longer, but this possibility has never received an adequate test in a clinical trial. Therapies that improve survival have a high priority. We think that a clinical trial is practical and we are working to get it underway.

PRIMOPulmonaryRehabilitationImpactsMortalityOutcomes

PRIMO• a ~ 10 center study,• ~ 800 patients discharged from the

hospital following a COPD exacerbation,

• patient accrual over ~ two years,• rehab vs. no-rehab, follow-up ~ 3 years• multiple outcomes, with mortality as

primary outcome

A Revised Application to NIH is Being Composed





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RehabilitaPulmonarexacerbacionesEPOC