P U L M O N A RY R E H A B I L I TAT I O N

Contractile Fatigue of the Quadriceps Muscle Predicts Improvement in Exercise Performance After Pulmonary Rehabilitation M. Jeffery Mador, MD; Mohammed Mogri, MD; Anil Patel, MD

■ RATIONALE: We hypothesized that among patients with chronic obstructive pulmonary disease, those who develop quadriceps contractile fatigue (QCF) after exhaustive submaximal cycle exercise would have a greater response to exercise training than those who do not develop QCF (NQCF).

K E Y

■ METHODS: Patients (N = 132) had measurement of QCF at baseline. Sixminute walk distance (6MWD), maximal incremental cycle exercise testing, and quality of life measured by the Chronic Respiratory Questionnaire were obtained before and after pulmonary rehabilitation (PR).

exercise performance

■ RESULTS: Eighty of the 132 patients (60.6%) developed QCF following constant workload exhaustive cycle exercise. Patients who developed QCF had a significantly greater improvement in 6MWD following PR (45.3 ± 45.2 m) than those who did not (27.5 ± 45.7 m; P = .032). When baseline differences between patients who developed QCF and NQCF were accounted for, the difference in 6MWD remained significant. Patients who developed QCF were not more likely to identify leg fatigue as the factor limiting exercise (56.2% of QCF group stated that leg fatigue was the limiting factor compared with 47.9% in the NQCF group; P = .46). When baseline differences were accounted for, the symptom causing exercise termination was not a predictor of the response to PR. ■ CONCLUSION: Patients who were capable of developing QCF had a significantly greater improvement in 6MWD after PR compared to NQCF. Symptoms causing exercise termination could not be used to predict the development of contractile fatigue or the response to PR.

Pulmonary rehabilitation (PR) is a highly effective treatment option that improves exercise tolerance and quality of life in patients with chronic obstructive pulmonary disease (COPD).1,2 The improvement in exercise performance after PR can be highly variable in individual patients. In order for exercise to result in physiologic changes consistent with training, the exercise must be above a minimum critical intensity.3

W O R D S

contractile fatigue of muscle COPD

pulmonary rehabilitation

Author Affiliations: Veteran Affairs Western New York Healthcare System (Dr Mador), and Division of Pulmonary, Critical Care and Sleep Medicine, State University of New York at Buffalo (Drs Mador, Mogri, and Patel), Buffalo, New York. The authors declare no conflicts of interest. Correspondence: M. Jeffery Mador, MD, Division of Pulmonary, Critical Care and Sleep Medicine, Section 111S, 3495 Bailey Ave, Buffalo, NY 14215 (mador@ buffalo.edu). DOI: 10.1097/HCR.0000000000000023

While this minimum intensity has not been precisely characterized, it is quite easy to exercise above this level in normal healthy subjects. However, it may be harder in patients with COPD, as they develop intolerable symptoms at much lower exercise intensities. In healthy subjects, cardiac and peripheral muscles reach their functional limits during maximal exercise. In patients with COPD, because of deranged lung

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mechanics, patients develop greater dyspnea at any given workload, causing the patient to stop exercise before cardiac and peripheral muscles have reached their physiologic limits. Thus, it is more difficult to train patients with COPD. In addition, these patients also have deranged peripheral muscle function. Because of this impairment, many patients with COPD develop contractile fatigue of the exercising muscle during exhaustive submaximal exercise (particularly during cycling exercise as opposed to walking)4,5 despite their increased dyspnea. Fatigue of the exercising muscle indicates an excessive load to the muscle and suggests that exercise intensity is very likely to be above this minimum critical intensity. It is a basic exercise training principle that the intensity of training has to be sufficient to stress the muscle to obtain physiologic adaptations to muscle training. This is the principle of muscle overload. Thus, the ability to develop contractile fatigue of the exercising muscle after exhaustive exercise may be a predictor of an adequate training stimulus and, thus, predict the response to training in patients with COPD. In support of this hypothesis, a recent study found that those subjects who developed quadriceps contractile fatigue (QCF) after an exercise training session had a larger improvement in functional exercise capacity and quality of life following an exercise training program.6 We hypothesized that patients who develop QCF after exhaustive submaximal cycle exercise would have a greater response to exercise training than those who do not develop QCF (NQCF). We reasoned that if patients did not develop QCF following exhaustive cycle exercise, they would be highly unlikely to develop QCF after a PR session. In contrast, we reasoned that patients who develop QCF during such exercise would have the potential to develop QCF during a PR session, depending on its structure. Accordingly, we identified all patients at our institution who had measurements of QCF, 6-minute walk distance (6MWD), maximal exercise capacity, and quality of life, before and after PR, to determine whether the development of QCF predicted an enhanced response to training.

METHODS All graduates of our PR program who had undergone measurements of QCF were included in this study. Most patients included in this study had been described in previous work.7-10 All patients were enrolled in the Veterans Affairs Western New York Healthcare System. This study was approved by the Veterans Affairs Institutional Review Board. www.jcrpjournal.com

Diagnosis of COPD was made by clinical history consistent with chronic bronchitis and/or emphysema, a long history of cigarette smoking, and pulmonary function tests revealing fixed airflow obstruction. All patients had quit smoking for at least 3 months before enrollment into PR.

Pulmonary Function Testing Spirometry was performed in accordance with American Thoracic Society/European Respiratory Society recommendations.11 Lung volumes by body plethysmography and single-breath diffusing capacity were also measured. Predicted normal values were those of Hankinson et al12 and Crapo et al.13,14

Exercise Testing (V˙ O2 Measurements) An incremental symptom-limited exercise test was performed on an electronically braked cycle ergometer to determine maximal work capacity. Workload was increased in a ramp fashion by 10 W every minute until the subject could no longer continue. After a 30- to 40-minute rest period or on a separate day, constant workload exercise (endurance test) was performed at approximately 70% of maximal work capacity (Wmax) to volitional exhaustion. Patients who were on oxygen during exercise breathed from a 200-L reservoir bag containing 35% oxygen. After PR was complete, exercise tests were repeated. After PR, subjects were allowed to stop after 40 minutes of endurance exercise even if they could continue exercising. Patients on oxygen therapy were excluded from the final V˙O2 analysis, as the variance in this measurement was greater in those on oxygen than in those who were not on oxygen. Subjects were asked whether leg fatigue, dyspnea, or some other factor was the symptom that caused them to stop exercising. 6-Minute walk distance tests were administered before (the best of 3 tests) and after completion of the PR program (the best of 3 tests) as a test of functional exercise capacity. Participants were given standardized instructions to cover the greatest distance possible in 6 minutes. A difference of 26 m (∼85 ft) between the pre- and post-rehabilitation values was considered to be the minimal important difference (MCID).15

Skeletal Muscle Strength and Quadriceps Fatigability Quadriceps contractile fatigue was assessed by measuring quadriceps twitch force during supramaximal magnetic stimulation of the femoral nerve16 before and after endurance constant workload cycle exercise to the limits of tolerance. Quadriceps twitch force was measured as previously described.7-10 Following a Contractile Fatigue of Muscle in PR / 55

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vigorous voluntary contraction, the subsequent twitch is significantly increased in size (twitch potentiation).17 Prior studies have suggested that the potentiated twitch (TwQp) is more sensitive at detecting fatigue than the unpotentiated twitch (TwQu), particularly when the amount of fatigue is small.18 Accordingly, we measured the TwQp twitch before and 10 minutes after exercise. Potentiated twitch was measured as previously described.7-10 Quadriceps fatigue in individual participants was defined as a greater than 15% fall in TwQp 10 minutes after exercise.7-10 Maximum voluntary contraction of the quadriceps was measured during an isometric contraction, as previously described.10

Health-Related Quality of Life Health-related quality of life was measured using the Chronic Respiratory Disease Questionnaire (CRQ),19,20 which was administered by a trained interviewer before and after PR.

PR Program Thirty-five of 52 NQCF patients (67.31%) and 53 of 80 QCF patients (66.25%) underwent our standard PR protocol. We included patients who underwent nonstandard PR because previous work7-9 showed that these interventions did not alter the extent of improvement in health-related quality of life or exercise performance compared with standard PR alone. During PR, patients exercised 3 times per week, as previously described.9 Nonstandard PR included additional strength or hyperpnea training, or interval training substituted for continuous training. Detailed descriptions of strength, hyperpnea, and interval training have been described previously.7-9 Missed sessions were made up at the end of the 8 weeks to ensure that all patients completed a total of 24 sessions. Compliance with PR was excellent with subjects missing, on average, 2 sessions (range, 0-8).

Statistical Analysis Data are expressed as mean ± SD. Changes in variables over time within groups were analyzed using a paired t test and between groups were analyzed by unpaired t test. Baseline values for the 2 groups were compared by unpaired t test. A P value of ≤.05 was considered to be significant. We also reanalyzed the results after excluding the patients who did not undergo standard PR. Because the QCF and NQCF groups were different at baseline, the presence of fatigue and other physiologic variables at baseline were entered into a multiple linear regression model to determine whether any differences between QCF and NQCF remained after differences in other physiologic

variables were accounted for. Differences in symptoms limiting exercise between QCF and NQCF were compared by χ2 analysis.

RESULTS Baseline characteristics of patients are shown in Table 1. Patients with NQCF had more severe COPD and lower exercise performance but similar quality of life compared with QCF patients. However, there was no significant difference in the V˙E/MVV ratio (a measure of ventilatory limitation) between groups.

Response to PR As expected, both groups showed significant improvement in exercise performance and quality of life. Comparisons of the extent of responses to PR are shown in Tables 2 and 3.

Impact of Quadriceps Fatigue Following PR, improvement was significantly greater for the 6MWD, total CRQ scores, and mastery in the QCF group than in the NQCF group (Table 2). When only those patients who underwent the standard PR program were included, similar results were found (Table 3); improvements in exercise endurance time and dyspnea were also significantly greater in the QCF group.

Role of Fatigue as a Predictor of Response to PR Since QCF patients had better pulmonary function and better exercise performance at baseline, this could have accounted for the difference in the extent of improvement after PR between groups. However, using multiple linear regression, the only significant baseline predictors of the extent of improvement in 6MWD after PR were endurance time during constant workload cycle exercise (P = .013) and presence or absence of QCF (P = .038). There were no baseline predictors of the extent of improvement in total CRQ or in the mastery or dyspnea domains of the CRQ. When a distance of 85 ft (∼26 m) was considered to be the MCID in 6MWD, 54.9% of the NQCF group and 67.9% of the QCF group had an improvement in the 6MWD (P = .25). When a distance of 115 ft (∼35 m) was considered to be the MCID, 37.3% of the NQCF group and 55.3% of the QCF group had an improvement in the 6MWD (P = .07). If a cutoff of 164 ft (∼50 m) was considered as the MCID, then 20.0% of the NQCF group and 38.2% of the QCF group had an improvement in the 6MWD (P = .054).

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T a b l e 1 • Baseline Characteristics of Patients With and Without Quadriceps Contractile Fatigue QCF (n = 80) Gender, % males Age, y 2

BMI, kg/m

NQCF (n = 52)

P Value

96.25

98.08

71.5 ± 7.9

69.5 ± 7.3

.133

28.0 ± 5.8

28.9 ± 6.2

.386

1.000

1.5 ± 0.5

1.3 ± 0.5

.006

FEV1, % predicted

46.7 ± 15.1

38.1 ± 14.6

.002

FVC, % predicted

67.2 ± 15.2

59.2 ± 14.6

.003

FEV1/FVC ratio

51.3 ± 11.8

47.4 ± 13.1

.083

FEV1, L

Total lung capacity, % predicted

102.1 ± 25.6

99.4 ± 24.2

.578

Residual volume, % predicted

166.2 ± 67.0

169.3 ± 65.8

.808 .004

57.7 ± 23.8

43.3 ± 17.0

415.2 ± 108.3

385.3 ± 102.1

Maximal workload, % predicted

42.3 ± 17.4

27.8 ± 13.5

Contractile fatigue of the quadriceps muscle predicts improvement in exercise performance after pulmonary rehabilitation.

We hypothesized that among patients with chronic obstructive pulmonary disease, those who develop quadriceps contractile fatigue (QCF) after exhaustiv...
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