Pulmonary Rehabilitation* Joint ACCP/AACVPR Evidence-Based Clinical Practice 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; Carla Herrerias, MPH

Disclosures

CHEST. 2007;131(5):4S-42S. 

In This Article

Anabolic Drugs

Since exercise-training interventions are a cornerstone in pulmonary rehabilitation and yield benefits, at least in part, by improving the function of the exercising muscles, it seems reasonable to hypothesize that pharmaceutical agents that improve muscle function in similar ways might be useful adjuncts to rehabilitative therapy. However, the list of drugs that might be suitable for clinical trials is quite limited. In particular, no agent that is capable of directly improving the aerobic characteristics of muscle has been studied in a clinical trial. It is plausible that erythropoietin might be of use in anemic patients with COPD; increasing muscle oxygen delivery might increase exercise endurance as it has in other patient groups,[104,105] but this has not been tested in a clinical trial.

Drugs that produce muscle hypertrophy have been identified and studied to determine whether they elicit improvements in muscle strength. Growth hormone, generally administered by daily injection, has been shown to induce modest increases in muscle mass. However, improved functionality has been difficult to demonstrate.[106,107] In the only study in COPD, Burdet and colleagues[108] studied 16 underweight patients with COPD who received daily growth hormone injections for 3 weeks. Lean body mass (assessed by DEXA scan) increased 2.3 kg in the growth-hormone group compared with 1.1 kg in the placebo group. No differences in maximum inspiratory pressure, handgrip strength, or incremental cycle ergometer exercise capacity were detected between groups. The 6-min walk distance decreased significantly in the growth-hormone group. Clearly, growth hormone cannot be recommended as an adjunct therapy for pulmonary rehabilitation at this time.

In men, therapy with testosterone and its analogs has been shown to increase muscle mass, decrease fat mass, and improve muscle strength. Well-controlled trials of testosterone supplementation in healthy young men[109,110] and older men[111] have demonstrated that muscle mass and strength increase with a linear dose-response relationship; an appreciable hypertrophic response is seen within the physiologic range of circulating testosterone levels. Further, hypogonadal men show increases in muscle mass and strength in response to physiologic doses of testosterone.[112] The side effects of testosterone administration are of concern; lipid abnormalities, polycythemia, and liver function abnormalities have been reported.[113] In older men who may harbor subclinical foci of prostate cancer, testosterone administration may enhance the growth of these foci.[114] More recent experience suggests that substantially supraphysiologic doses of testosterone should be avoided in older men.[111] A number of formulations of testosterone are available; it can be administered by injection, transdermal patch, transdermal gel, and orally.[115] Oral administration, however, has often been associated with elevations in liver function test results. There have also been some preliminary studies[116] of testosterone administration in women. Circulating levels of testosterone in women are roughly 10-fold lower than those in men, and high testosterone doses are inevitably associated with virulization.[117] Whether lower doses that are not associated with virulization will have substantial anabolic effects on muscle remains to be seen.

A rationale for testosterone supplementation in men with COPD is that circulating levels have been shown to be lower than those seen in healthy young men and are often lower than those in age-matched control subjects.[94,118,119] Since the publication of the previous rehabilitation guidelines, five RCTs[94] have appeared in which testosterone or its analogs (collectively known as anabolic steroids) have been administered to patients with COPD. These trials are similar, in that patients with moderately severe COPD were studied (mean FEV1 range, 34 to 49% predicted). All studies were limited to men, except for the study of Schols and colleagues,[122] in which women received half the drug dose that men received. In three of the studies,[120,121,122] all participants received a rehabilitation-type program. All studies used relatively low doses, and no clear drug-related adverse reactions (with the exception of a modest increase in hematocrit[94]) have been reported.

Schols and colleagues[122] administered nandrolone decanoate or placebo by injection every 2 weeks for 8 weeks to approximately 130 patients who also received nutritional supplementation. Although no differences in body weight change were observed between these groups, in the nandrolone group weight gain was predominantly in lean mass, whereas in the placebo group weight gain was predominantly fat. No difference in changes in the 6-min walk distance or peak inspiratory pressure was detected.

Ferreira and colleagues[121] administered oral stanozolol or placebo daily for 27 weeks to 23 underweight patients with COPD. DEXA scanning revealed an increase in lean mass of approximately 2 kg and a 5% increase in thigh circumference, which are changes that were not seen in the control group. No differences were detected in 6-min walk distance or incremental cycle ergometer testing results.

Creutzberg and colleagues[120] administered nandrolone decanoate or placebo by IM injection every 2 weeks for 8 weeks to 63 men with COPD. Fat-free mass increased by 1.7 kg in the nandrolone group compared to 0.3 kg in the placebo group. No significant differences were seen between groups in incremental cycle ergometer exercise capacity or HRQOL. Muscle strength was assessed, but no differences were detected in handgrip strength or isokinetic leg strength testing results.

Svartberg and colleagues[123] administered testosterone enanthate or placebo by injection every 4 weeks for 26 weeks to 29 men with COPD. DEXA scanning revealed a 1.1-kg increase in lean mass and a 1.5-kg decrease in fat mass in the testosterone group. No exercise outcomes were assessed. No difference in quality of life, as assessed by the St. George respiratory questionnaire was detected, but better sexual quality of life and erectile function was noted.

Casaburi and colleagues[94] studied 47 men with COPD and low testosterone levels (mean total testosterone level, 320 ng/dL). Subjects received 100 mg of testosterone enanthate or placebo by IM injection for 10 weeks. Half of the group receiving testosterone also underwent a strength-training program. Testosterone therapy yielded a 2.2-kg increase in lean body mass; the group receiving both testosterone and strength training experienced a 3.3-kg increase in lean mass. Average leg press strength increased by 12% in the testosterone group and by 22% in the group receiving testosterone therapy plus strength training. No improvements in incremental or constant-work-rate cycle ergometer exercise tolerance were demonstrated.

In summary, anabolic steroid administration has consistently been shown to increase lean (presumably muscle) body mass in men with moderate-to-severe COPD. As expected on theoretical grounds, no improvement in endurance exercise capacity was detected. In one study,[94] but not in another,[120] an increase in the strength of the muscles of ambulation was detected. No evidence for improvements in quality of life has been obtained. It is premature to suggest that the administration of anabolic steroids be incorporated into rehabilitative programs for patients with COPD. Only roughly 150 patients have received this intervention and only with relatively short-term exposures; whether the benefits outweigh the risks in the long term cannot be determined at this time.

14. Current scientific evidence does not support the routine use of anabolic agents in pulmonary rehabilitation for patients with COPD. Grade of recommendation, 2C

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