Effectiveness of Pulmonary Rehabilitation in Exercise Capacity and Quality of Life in Chronic Obstructive Pulmonary Disease Patients With and Without Global Fat-Free Mass Depletion
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Published Online: February 18, 2013
Abstract
Objective
To investigate the effectiveness of pulmonary rehabilitation (PR) in exercise capacity and quality of life in patients with chronic obstructive pulmonary disease (COPD) with and without global fat-free mass (FFM) depletion.
Design
Retrospective case-control.
Setting
Outpatient clinic, university center.
Participants
COPD patients (N=102) that completed PR were initially evaluated.
Intervention
PR including whole-body and weight training for 12 weeks, 3 times per week.
Main Outcome Measures
St. George Respiratory Questionnaire (SGRQ), 6-minute walk distance (6MWD), and FFM evaluation applied before and after PR.
Results
Patients were stratified according to their FFM status measured by bioelectric impedance. They were considered depleted if the FFM index was ≤15kg/m2 in women and ≤16kg/m2 in men. From the initial sample, all depleted patients (n=31) composed the FFM depleted group. It was composed predominantly by women (68%) with a mean age ± SD of 64.4±7.3 years and a forced expiratory volume in 1 second of 33.6%=−13.2% predicted. Paired for sex and age, 31 nondepleted patients were selected from the initial sample to compose the nondepleted group. Improvement in the 6MWD was similar in these 2 groups after PR. Both groups improved SGRQ scores, although the observed power was small and did not allow adequate comparison between depleted and nondepleted patients. There was no difference between groups in weight change, whereas FFM tended to be greater in depleted patients. This increase had no correlation with the 6MWD or the SGRQ.
Conclusions
Benefits of PR to exercise capacity were similar comparing FFM depleted and nondepleted COPD patients. Although FFM change tended to be greater in depleted patients, this increase had no definite relation with clinical outcomes.
List of abbreviations:
BMI (body mass index), COPD (chronic obstructive pulmonary disease), FEV1 (forced expiratory volume in 1 second),FFM (fat-free mass), FVC (forced vital capacity), HRQOL (health-related quality of life), MANOVA (multiple analysis of variance), MRC (Medical Research Council), PR (pulmonary rehabilitation), RM (repetition maximum), SGRQ (St. George Respiratory Questionnaire), 6MWD (6-minute walk distance)
The cardinal symptoms in most patients with chronic obstructive pulmonary disease (COPD) are dyspnea and exercise intolerance, resulting in decreased health status.1 Extra-pulmonary manifestations often include profound peripheral muscle deconditioning and sarcopenia. Peripheral muscle weakness and an altered muscle energy metabolism have been recognized as contributing factors to impaired exercise capacity,2, 3 and these associations are related to depletion of muscle mass.4 Loss of muscle mass causes significant impact on muscle function5 and on survival.6, 7, 8, 9 No current treatment strategy could reverse the loss of lung function in these patients.1 Nonetheless, improvements in skeletal muscle function after exercise training result in gains in exercise capacity despite the absence of changes in lung function.10
Improving peripheral skeletal muscle mass and function is, therefore, an important goal of pulmonary rehabilitation (PR) programs. PR is currently considered standard care for patients with chronic lung diseases and is associated with improvement in important clinical outcomes, such as exercise capacity, health-related quality of life (HRQOL), and dyspnea.11 Unfortunately, poor adherence is common in daily practice of PR, because many COPD patients fail to attend programs and others drop out.12 Some studies have shown that low fat-free mass (FFM)13 and reduced quadriceps strength14 are major conditions associated with PR absenteeism and drop out, respectively.
Additionally, exercise can induce increased systemic inflammatory and oxidative responses in muscle-wasted COPD patients15 and can alter amino acid intermediary metabolism in patients with COPD, regardless of muscle depletion.16Increasing evidence associates systemic inflammation and oxidative stress with muscle wasting and muscle dysfunction in COPD.17, 18 FFM depleted COPD patients may represent, therefore, a group less likely to improve in PR programs.
Despite these findings, we believe that FFM depleted patients can achieve the same clinical benefits after PR as nondepleted patients. Previous studies evaluating depleted COPD inpatients showed an increase in FFM after rehabilitation, mainly when combining rigorous nutritional supplementation with or without androgenic steroid administration.19, 20 More recently, a community-based rehabilitation plus nutritional support program demonstrated that wasted patients improved FFM and weight, a finding not observed in nonwasted patients.21 However, these studies did not primarily compare depleted and nondepleted COPD patients regarding improvement in exercise capacity, HRQOL, and the relation of these clinical outcomes with FFM changes after PR.
The aim of the current study is to evaluate the effects of an outpatient PR program on improvements in exercise capacity, HRQOL, and FFM, contrasting FFM depleted and nondepleted patients with moderate-to-severe COPD. The relations between changes in FFM and clinical outcomes after PR were also evaluated. We hypothesized that FFM depleted patients could achieve similar clinical benefits as nondepleted COPD patients from an outpatient PR program.
Methods
Participants
Pulmonary function, dyspnea, body composition, exercise capacity, and disease-specific health status have been assessed prospectively in 129 consecutive pulmonary disease patients before and after a specialized PR program. Subjects with clinical and functional diagnosis of COPD (n=102) according to the global strategy for the diagnosis, management, and prevention of COPD guidelines1 (irreversible airflow limitation defined as forced expiratory volume in 1s [FEV1]/forced vital capacity [FVC] <.70) and FEV1 <80% of predicted normal values were initially selected. Thereafter, all FFM depleted patients with complete data for main outcome analysis (n=31) and nondepleted patients matched for age and sex to depleted patients (n=31) were included in the study analyses (fig 1). Patients also had disease stability indicated by no change in medication dosage or exacerbation of symptoms in the preceding 4 weeks.
Fig 1
Flowchart of study groups' formation.
The study was approved by the local ethics committee, and all subjects gave written informed consent to participate in the PR program.
Design
This was a single-center, retrospective case-control study of participants in a 12-week PR program. Exercise capacity (6-minute walk distance), HRQOL using the St. George Respiratory Questionnaire (SGRQ), and nutritional status were evaluated at baseline and after completion of PR (last day up to the following week). Effects of PR were analyzed according to patients' FFM status, as measured by bioelectric impedance analysis. They were considered depleted if FFM index was ≤15kg/m2 in women and ≤16kg/m2 in men.4
Pulmonary rehabilitation
Subjects participated in a standard comprehensive outpatient rehabilitation program comprising endurance training and individually prescribed resistance training for 36 sessions over 12 weeks.
Aerobic exercise training was performed on a treadmill aiming to achieve the maximum tolerated exercise intensity for at least 20 minutes. Speed was anchored to perceived effort ranked from moderate to intense, according to the Borg scale.22Thus, at the beginning of each week, new increased speed was set in order to maintain moderate to intense effort perception.
Resistance training involved gym equipmenta and free weights. Before being tested for 1 repetition maximum (RM), subjects performed 3 series of 15 light-weight repetitions for the muscle group to be tested. Loads were initially set at 50% to 60% of 1 RM during the first 2 weeks, and then they were gradually increased each week, as tolerated, toward 85% of 1 RM.23 Thereafter, the training workload was increased when more than 12 repetitions per set could be performed. Resistance training was performed after aerobic training consisting of 2 sets per muscle group, each of 8 to 12 repetitions.10 Exercises to strengthen the upper body included bench press (pectoralis), chest cross (horizontal flexion of the shoulder joint), shoulder press (trapezius), pull downs (latissimus dorsi), biceps flexion, triceps extensions, and exercises for abdominal muscles (sit-ups). Lower-body exercises included knee extension, knee flexion, and plantar flexion.
Dietary intake was advised based on 3-day food diaries, 24-hour recall dietetic analysis, and nutritional status, as evaluated by body mass index (BMI). Subjects were managed according to their needs and nutritional status. Low-weight patients (BMI <22kg/m²) or those considered to ingest insufficient food received specific instruction to fulfill minimum daily energetic needs according to the total energetic value method,24 aiming to consume 55% of carbohydrates, 30% lipids, and 15% to 20% proteins. Total energetic value was estimated through the basal metabolic rate multiplied by an activity factor (1.5) for light to moderately active subjects. After initial nutritional orientation, if caloric ingestion was judged inadequate, a daily polysaccharide supplementation (oral maltodextrin powder) was recommended to make up to 15% of daily carbohydrate needs.
Measurements
Spirometry
Spirometric tests were performed using the spirometer,b according to published standard.25 Subjects completed at least 3 acceptable maximal forced expiratory maneuvers before and 20 minutes after 400μg inhaled salbutamol. The intraclass correlation coefficient was described in a previous article26 as .99 and .95 for FVC and FEV1, respectively.
Dyspnea
Dyspnea was evaluated by the modified Medical Research Council (MRC) scale, a 5-point scale that considers certain activities that provoke breathlessness.27 Patients had to grade their self-perceived dyspnea by using predefined statements (eg, 0: “I only get breathless with strenuous exercise”; 1: “I get short of breath when hurrying on the level or up a slight hill”; 2: “I walk slower than people of the same age on the level because of breathlessness or have to stop for breath when walking at my own pace on the level”; 3: “I stop for breath after walking 90 to 100 meters (100yd) or after a few minutes on the level”; and 4: “I am too breathless to leave the house or breathless when dressing or undressing”). Patients were asked about their perceived breathlessness according to descriptive statements and classified into MRC dyspnea grades. Interobserver agreement in ratings of dyspnea using the MRC scale evaluated by weighted kappa was .92.28
Body composition
Body composition was measured noninvasively using whole-body bioelectric impedance.c FFM was estimated using a specific regression equation described for patients with COPD.29 During the measurement, patients lay in a supine position, clothed but without shoes or socks. Any metal object attached to the body was removed. Two electrodes were positioned on the dorsal surface of the right hand, and 2 additional electrodes were positioned on the dorsal surface of the right foot. The skin under the electrodes was cleaned with alcohol, and a thin layer of electrolyte gel was applied to each electrode before application. Measurements were made after 6 hours of fasting and within 30 minutes after voiding. Patients were instructed to neither exercise nor ingest fatty foods 24 hours beforehand. Alcoholic beverages were forbidden at least 48 hours beforehand. Reliability of bioelectric impedance analysis indicates an intraclass correlation coefficient of .98 in patients with COPD.30
Quality of life assessment
The SGRQ measures disease-specific health status, and a local language validated version was used.31 The answers to its 50 items can be grouped into an overall score and 3 subscores for symptoms, activity, and impact. The number of reply options per question varies from 2 to 5. Replies are weighted and scores are calculated by dividing the summed weights by the maximum possible weight and expressing the result as a percentage, 0% being the best possible score and 100% the worst. The self-report questionnaires were completed with supervision by a research assistant. The minimum clinically important response to treatment is defined as an improvement of 4% on the separate domains and the overall score.32The intraclass correlation coefficient of the translated version of the SGRQ is .79.31
Exercise capacity
Exercise capacity was evaluated by the 6-minute walk distance (6MWD), obtained by partially following specific guidelines33 in an indoor 50-m corridor. The turnaround points were marked with a cone. The tests were performed under quiet conditions, with distractions and corridor traffic kept to a minimum. Subjects were requested to cover as much ground as possible during the test period, stopping only if they felt too tired or breathless to continue, and to resume walking as soon as they were able to do so. Encouragement was given with standardized phrases every minute. Dyspnea was assessed using the Borg scale.22 A respiratory therapist walked behind the patients and continuously monitored oxygen saturation by pulse oximetry.d Oxygen was provided to patients whose oxygen saturation decreased to <88%, aiming to maintain figures around 90%. The minimum clinically important response to interventions is usually considered as an improvement of 54m (95% confidence interval, 37–71m).32, 34 Reliability of the 6MWD, as estimated by the intraclass correlation coefficient, is .88.35
Statistical analysis
Change in the 6MWD was used to estimate the sample size needed to achieve adequate statistical power for the current investigation. We assumed a minimum important difference between groups of 54±52m in the 6MWD32, 34 after PR. Thus, at α=.05 and power=.90, a sample size of 21 patients per group was calculated.
Data are expressed as mean ± SD, unless otherwise indicated. Distribution of the variables was assessed with a Shapiro-Wilk test. Those with normal distribution were evaluated with parametric tests, and the remaining variables were evaluated with nonparametric tests. Characteristics at baseline between groups were compared with an unpaired t test, Mann Whitney U test, or a chi-square test (Fisher exact test), as appropriate. Multiple comparisons between subjects (according to FFM status) and within subjects (post-pre change after PR) were performed using repeated-measures multiple analysis of variance (MANOVA). Pearson product-moment coefficients assessed linear association. The probability of a type I error was set at 5% (P<.05). Data were analyzed using SPSS, version 18.0 for Windows.e
Results
One hundred and two patients (65 men; 64%) were referred from their physician to a university PR center with COPD (seefig 1). Mean age ± SD was 64.2±8.7 years, with the disease being moderate to very severe.1 Thirty-two (30%) of the 102 patients were considered muscle depleted; of these, 18 patients (56.3%) had a BMI ≥21. In a different point of view, of the 87 patients with BMI ≥21, 20.7% were muscle depleted, whereas 3 (20%) of the 15 patients with BMI <21 were not.
From this initial population, we formed depleted and nondepleted groups, as previously mentioned (see fig 1). Baseline characteristics of these groups are presented in table 1.
NOTE. Data presented as mean ± SD or as otherwise indicated.
∗Comparison between groups: P<.05.
†n=16 in each group.
As expected from the group composition strategy, the groups were well balanced with regard to sex and age distribution. Similarly, no difference was found between baseline 6MWD, absolute values of resting lung function, and in all domains of the SGRQ (symptom, activity, impact, and total score). On the other hand, the group of depleted patients had lower values of weight, FFM, BMI, and FFM index.
The 6MWD (fig 2) and the SGRQ overall score and individual domains (fig 3, see table 2) significantly improved after PR in both groups without differences between groups. However, a power of only 52% was observed in the MANOVA for the interaction between FFM status and SGRQ improvement (considering the 4 domains) after PR.
Fig 2
Similar improvement in 6MWD changes after PR in patients with (black) and without (white) FFM depletion. Data are shown as mean ± SE. *P<.05 comparing before and after PR within group.
Fig 3
SGRQ changes after PR contrasting patients with (black) and without (white) FFM mass depletion. Data are shown as mean ± SE. *P<.05 comparing before and after PR within group.
NOTE. Data presented as mean ± SD.
∗Comparison pre- and postrehabilitation within subjects; P<.05.
FFM change after PR tended to be greater in depleted patients (mean ± SE, 1.00±.37 vs −.31±.41kg; interaction P=.069), while weight change was similar (mean ± SE, .14±.50 vs −.78±.44kg; interaction P=.36) (Table 3, Table 4). A power of 44% was observed in the MANOVA for the interaction between FFM status and FFM increase after PR.
NOTE. Data presented as mean ± SD. No difference was found in comparison pre- and postrehabilitation within group.
∗Comparison between depleted and nondepleted subjects in a given moment (before or after PR); P<.05.
| Variables | Between Subjects | Within Subjects | Interaction |
|---|---|---|---|
| Anthropometrics | .000 | .499 | .034 |
| Weight | .000 | .374 | .200 |
| BMI | .000 | .290 | .095 |
| FFM | .000 | .497 | .069 |
| FFM index | .000 | .577 | .096 |
| SGRQ | .489 | .000 | .137 |
| Symptom | .313 | .000 | .194 |
| Activity | .330 | .000 | .009 |
| Impact | .150 | .000 | .480 |
| Total | .085 | .000 | .271 |
| 6MWD | .305 | .000 | .805 |
After PR, 8 (26%) of the 31 depleted patients had improvement in FFM and FFM index and were no longer considered depleted, while 4 (12%) of the 32 nondepleted patients became depleted.
Considering only the depleted patients, FFM improvement showed a tendency to correlate with improvements in SGRQ total score (r=.44; P=.051), and FFM index increase was significantly correlated with SGRQ total score (r=.37; P=.04). No other association was observed between improvement in FFM or FFM index and any other clinical outcome. Among nondepleted patients, no correlation was found between measured outcomes.
Characteristics of the depleted patients that became nondepleted after PR
Depleted patients that improved their nutritional status after PR had greater weight (62.6±7.6 vs 52.6±14.4; P=.02), BMI, and FFM index (15.1±1.3 vs 13.5±1.4; P<.03), as expected. Other baseline characteristics were similar. Compared with those that remained depleted after PR, improvements in the 6MWD, SGRQ scores, and weight were the same.
Discussion
This study demonstrated that clinical improvement in exercise capacity and HRQOL after PR were achieved independently of the nutritional status by patients with COPD. However, the present data had a small observed power to detect significant differences between groups in HRQOL changes. Nonetheless, both groups had improvements in HRQOL greater than the minimum considered clinically important. Also, FFM gain tended to be greater in patients with FFM depletion (see tables 3 and 4). This change in body composition had marginal association with HRQOL (SGRQ overall score) improvement in depleted patients (r=.44; P=.051), while it was not associated with any other clinical improvements in any group.
Improvement in the 6MWD and HRQOL are known benefits by PR in COPD patients.10, 11 Our data corroborate that these benefits could be achieved in COPD patients independently of FFM status. Improvement in exercise capacity was unequivocally similar in both groups. Although none of the groups exhibited the traditional clinically meaningful mean improvement (>54m), both achieved an updated value of minimum important difference for the 6MWD of 25m.36 Despite the absence of statistical significance, final values of all domains (see table 2) and change after PR of symptom and activity scores (see fig 3) of the SGRQ seem to be worse in depleted patients.
The majority of previous studies that investigated improvement in the muscle mass of FFM depleted COPD patients in the context of PR employed generous specific caloric19 or pharmacologic anabolic37, 38 supplementation associated with exercise training and did not directly compare them with nondepleted COPD patients. All these studies consistently demonstrated improvement in FFM with different associated exercise training modalities (ie, strength38 or aerobic19, 37). Furthermore, when analyzing only patients who performed exercise training and did not receive anabolic supplementation, like our data, the parameter of exercise capacity improved, whereas the parameter of HRQOL showed conflicting results.19, 37 On the other hand, 1 study20 stratified depleted and nondepleted COPD patients, comparing aerobic training isolated or combined with nutritional supplementation alone or associated with androgenic administration. Both supplemented arms showed a significant and similar improvement in FFM (around 1.9±2.5kg), while no significant increase was observed in the arm that used only exercise. In that study,20 the exercise training plus nutritional supplementation arm had a greater FFM improvement in depleted compared with nondepleted patients, and this finding had no influence on exercise capacity increase after PR. The main difference with regard to our study is that the former study was conducted in an inpatient rehabilitation center allowing strict control over daily caloric intake.
In contrast with our results, Franssen et al,39 studying only nondepleted COPD patients, were able to induce FFM increase through an intensive inpatient exercise training program. In that study,39 changes in FFM correlated weakly with changes in maximal oxygen consumption (r=.36; P<.05) but did not correlate with changes in peak work rate or quadriceps strength. Again, these discrepant findings compared with our study could be attributed in part to the greater control in an inpatient program.
The strength exercise protocol used in the present study was almost the same as previously reported in another study to increase FFM in COPD patients.40 What can be inferred from the present and all other previously cited studies19, 20, 37, 38,39 is that strength training can increase FFM in COPD patients with or without depletion. The fundamental condition for this to occur is to provide an adequate nutritional support. Although dietary intake was not rigidly controlled in the present study, only depleted patients received nutritional orientation and recommendations for caloric supplementation, as necessary (see Methods section). Therefore, we speculate that nutritional counseling was the differential factor, which, associated with strength exercise training, could result in a tendency to greater FFM gains in depleted patients.
Increase in estimated muscle mass had no significant association with improvement in exercise capacity both in depleted20 and nondepleted patients.39 This suggests that effects on cellular energy and intermediary metabolism should be considered to explain the main benefits of exercise training independently of muscle mass. Bernard et al,40 aiming to investigate the effects of additional strength training on aerobic exercise in COPD patients, showed that strength training is effective in increasing muscle mass. This change, however, did not translate into further improvement in exercise tolerance or quality of life. Besides FFM gain, an increase in muscle function would also contribute to an improvement in HRQOL. Therefore, we believe that this is the reason why the association between increase in FFM and HRQOL was only marginal.
The present study corroborates literature evidence that, despite muscle depletion (and probably dysfunction) in some COPD patients, a comprehensive rehabilitation program is able to promote important clinical improvements in muscle depleted41 and underweight COPD patients.42, 43 Furthermore, depleted patients tended to achieve significant gains in FFM. Therefore, exercise training is indicated for FFM depleted patients with COPD.
Study limitations
Our study is underpowered to detect differences in HRQOL change after PR between depleted and nondepleted patients. Nonetheless, FFM depleted patients could improve HRQOL in a clinically (4 units reduction) and statistically significant way after PR (see table 2 and fig 3).
FFM increase had practically no association with clinical improvements in depleted patients. Skeletal appendicular muscle strength, respiratory muscle pressures, and local measures of muscle mass were not evaluated. These measurements would be worth doing with the aim of assessing the whole benefit of PR when comparing depleted and nondepleted COPD patients and might provide deeper insights regarding functional versus anatomical improvements in muscle performance. Such investigation could corroborate the inference that improved muscle function should occur independently of muscle mass. Better muscles might result in increased exercise capacity and reduced symptoms, which could be translated into improved HRQOL. We did not assess exercise dyspnea and limitation with a cardiopulmonary exercise test; however, it could represent a valuable method for evaluating maximal exercise constraints before and after PR.
Finally, the possibility of bias introduced by the way the cases and controls were selected is a limitation inherent of the study design.
Conclusions
FFM depleted COPD patients participating in a comprehensive outpatient rehabilitation program obtained the same clinical gains in exercise capacity as FFM nondepleted patients. Additionally, both groups achieved important clinical improvement in HRQOL. The increment in FFM tended to be greater in depleted patients, and this had no relation with clinical outcomes.
Suppliers
- a.Aston; Sportmania, Avenida Victor Hugo Kunz, 2295, Novo Hamburgo, Brazil.
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- c.Bodystat 1500; Nutrição Total Ltda. Rua Maestro Cardim, 1175. São Paulo, Brazil.
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- e.SPSS, 233 S Wacker Dr, 11th Fl, Chicago, IL 60606.
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