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Centre de Recherche, Hpital Laval, Institut Universitaire de Cardiologie et de Pneumologie de l'Universite Laval, Ste-Foy, Quebec, Canada
ABSTRACT
Rationale: There is no consensus regarding which exercise test to use to evaluate the functional impact of bronchodilators in patients with chronic obstructive pulmonary disease.
Objective and Methods: Bronchodilator-induced changes in endurance time were evaluated during cycling and walking in 17 patients with chronic obstructive pulmonary disease who completed two cycle endurance tests and two endurance shuttle walks at 80% of peak capacity. Each endurance test was preceded by the nebulization of a placebo or 500 μg of ipratropium bromide using a randomized, double-blind, crossover design. Quadriceps twitch force was measured with magnetic stimulation of the femoral nerve before and after each endurance test.
Results: Cycling endurance time did not improve significantly after bronchodilation despite a significant increase in FEV1 (endurance time ipratropium bromide – placebo: 51 ± 255 s, p = 0.42). A similar change in FEV1 was associated with a significant improvement in walking endurance time (endurance time ipratropium bromide – placebo: 164 ± 177 s, p < 0.01). A 22 ± 17% fall in quadriceps twitch force was observed after cycling, whereas no significant change was seen after walking.
Conclusion: The endurance shuttle walk is a sensitive test to detect changes in exercise tolerance after bronchodilation. Differences in the occurrence of quadriceps muscle fatigue may explain, in part, the different responsiveness to change between cycling and walking.
Key Words: bronchodilation chronic obstructive pulmonary disease cycling exercise test muscle fatigue shuttle walk
Exercise testing is frequently used in the clinical evaluation of patients with chronic obstructive pulmonary disease (COPD) to evaluate the functional impact of a treatment (1). There is, however, no consensus regarding which exercise testing protocol should be used for this application. Although maximal progressive cycle ergometry remains the most frequently used test in clinical practice (1), endurance tests are gaining popularity because they have demonstrated their ability to detect improvements in exercise tolerance after several interventions (2–5).
Recently, Oga and colleagues (6) reported that the cycle endurance test was more responsive to the acute effects of bronchodilation than the 6-min walking test. They found a 19% improvement in cycle endurance time after bronchodilation compared with a 1% increase in the 6-min walking distance, suggesting that walking was less sensitive than cycling to evaluate the functional impact of bronchodilation in patients with COPD. The physiologic mechanisms underlying this finding were unexplored in this study because gas exchange parameters were not measured during the 6-min walking test.
The present study was therefore undertaken to further investigate this intriguing notion that walking is not a sensitive modality to evaluate the functional impact of bronchodilation in patients with COPD. In fact, a number of physiologic observations suggest that walking should be responsive to bronchodilation. Previous reports have demonstrated that the peak ventilatory demand (7) and dyspnea levels (7, 8) were higher during shuttle walking than during cycle ergometry. On the basis of these observations, walking performance would be expected to improve more than cycling performance after bronchodilation. In addition, given that leg fatigue occurs more frequently after cycling than after walking (8), and given that the presence of leg fatigue has been shown to prevent bronchodilation from translating into better exercise tolerance (9), walking tests would be expected to be more responsive to bronchodilation than cycling tests.
The poor sensitivity to change of walking reported by Oga and colleagues (6) may have been related to the methodologic properties of the 6-min walking test, a self-paced test during which patients determine their own walking speed, and thus their workload. We therefore hypothesized that walking, if performed at an externally paced constant load as in the endurance shuttle walk, would be a sensitive modality to capture the improvement in exercise tolerance after acute bronchodilation in COPD.
Specifically, the study objectives were as follows: (1) to evaluate, in patients with COPD, the bronchodilator-induced changes in endurance time during the cycle endurance test and the endurance shuttle walk, and (2) to examine the cardiorespiratory response and the degree of quadriceps muscle fatigue elicited by both endurance tests to provide a physiologic understanding of each modality's responsiveness to change. Some of the results of this study have been reported previously in the form of an abstract (10).
METHODS
Subjects
Nineteen patients with stable COPD volunteered to participate in this study. Two patients failed to complete the protocol: one because of time constraints and the other because of a COPD exacerbation. Thus, 17 patients constituted the study group. Inclusion criteria were as follows: (1) moderate to severe COPD according to the Global Initiative for Chronic Obstructive Lung Disease guidelines (11), (2) age older than 50 yr, (3) smoking history of more than 10 pack-yr, (4) no exacerbation of airflow limitation within the preceding 4 wk, (5) no history of asthma, (6) no need for supplemental oxygen during exercise, and (7) no other active condition that could influence exercise tolerance. Patients on tiotropium bromide were also excluded from the study. The research protocol was approved by the institutional ethics committee, and a signed, informed consent was obtained from each subject.
Study Design
After baseline assessment of pulmonary function, peak cycling, and walking capacity, subjects entered a crossover design where they each completed two cycle endurance tests and two endurance shuttle walks. Each test was preceded by the nebulization of either a placebo or 500 μg of ipratropium bromide. The order of the testing modalities was determined randomly and the medication was administered in a randomized and double-blind fashion. The study visits were separated by at least 48 h and no more than 1 wk. A figure summarizing the experimental design is provided in the online supplement. The sponsor was not involved in the study design, data collection, and analysis. The sponsor had the opportunity to read the manuscript before submission with no obligation for the authors to incorporate any comments.
Pulmonary Function Testing
Spirometry and lung volumes were measured according to recommended techniques (12). Results were compared with predicted normal values from the European Community for Coal and Steel/European Respiratory Society (13).
Incremental Exercise Tests
Peak cycling and walking capacity were determined with progressive cycle ergometry and incremental shuttle walking (14), respectively. More details about these tests can be found in the online supplement.
Endurance Exercise Tests
The cycle endurance test was performed on an electromagnetically braked cycle ergometer (Quinton Corival 400; A-H Robins, Seattle, WA). After 2 min of unloaded pedaling, the workload was set at 80% of peak workload achieved during progressive cycle ergometry. The endurance shuttle walk was performed in an enclosed corridor on a flat 10-m-long course, as previously described by Revill and colleagues (15). After 2 min of warm-up, walking speed was set at the speed corresponding to 80% of V·O2 peak, as predicted from incremental shuttle walking. Before each endurance test, patients were asked to walk or cycle for as long as possible. No encouragement was provided during the tests to avoid any potential confounding effect on exercise performance (16).
Physiologic Measures
Gas exchange parameters (V·O2, V·CO2,V·E) and heart rate were monitored breath by breath with a portable telemetric system (K4b2; Cosmed, Rome, Italy). More details about this system are available in the online supplement. Oxygen saturation (SpO2) was measured at rest and at end-exercise by pulse oximetry (OSM2 Hemoximeter; Radiometer, Copenhagen, Denmark).
Quadriceps twitch force (TwQ) was measured before and immediately after each endurance test using magnetic stimulation of the femoral nerve as previously described by Saey and colleagues (9). Contractile muscle fatigue was defined as a postexercise reduction in TwQ of more than 15% from the resting value (9). Further details on this methodology are available in the online supplement.
Subjective Measures
Dyspnea and perception of leg fatigue were evaluated at end-exercise using the modified 10-point Borg scale (17). Patients were also asked to identify the main reason for which they stopped the test.
Statistical Analyses
Results are reported as mean ± SD. The endurance time was defined as the duration of pedaling or walking at 80% maximum capacity, excluding the 2-min warm-up period. The extent to which the two exercise modalities were able to capture changes in endurance time after bronchodilation was first examined by the ability of the two exercise modalities to detect statistically significant changes using a paired t test. In addition, the standardized response mean was computed for the two exercise modalities. This parameter was obtained by dividing the difference in the endurance time between ipratropium bromide and placebo by the SD of the change in endurance time of the corresponding exercise modality (18). The end-exercise values for the measured variables obtained during placebo and ipratropium bromide were compared using paired t tests. The time course of V·O2, V·E, heart rate, and respiratory rate was compared between the two modalities using repeated-measures analysis of variance. The proportion of fatiguers (subjects who developed quadriceps muscle fatigue) and nonfatiguers, and the locus of symptom limitation, were compared between the two modalities using a Wilcoxon signed-rank test. Pearson correlations were performed to examine the association between various baseline characteristics (baseline endurance time, body mass index, FEV1, FVC, inspiratory capacity, baseline TwQ) and the gain in endurance time after bronchodilation for each exercise modality. The level of statistical significance was set at p < 0.05. All statistical analyses were performed using SPSS statistical software, version 10.0 (SPSS, Inc., Chicago, IL).
RESULTS
Subjects
Characteristics of the study group are presented in Table 1. The sample included patients with mild to severe airflow obstruction, as indicated by the wide range of FEV1 values. The physiologic response to incremental cycling and walking is shown in Table 2. Patients reached a significantly higher V·O2 peak during the incremental shuttle walk than during progressive cycle ergometry. In contrast, heart rate, V·E, and perception of leg fatigue were significantly higher for progressive cycle ergometry than for incremental shuttle walking. The absence of ventilatory reserve at peak exercise (V·E/maximal voluntary ventilation > 100%) and the level of exercise-induced symptoms suggest that maximum exercise capacity was reached by the patients on both incremental tests.
Pulmonary Function
Pre- and postnebulization FEV1 values are shown for the two walking and two cycling tests in Figure 1. As illustrated, FEV1 remained stable under the two placebo conditions, whereas a significant and similar increase was observed under the two ipratropium bromide conditions. The pre- versus postnebulization changes in FEV1 were similar between cycling (0.18 ± 0.13 L, p < 0.001) and walking (0.19 ± 0.16 L, p < 0.001).
Endurance Time
Individual data and group mean values for the endurance time across the four exercises tests are presented in Figure 2. Cycling endurance time did not increase significantly with ipratropium bromide (endurance time ipratropium bromide – placebo: 51 ± 255 s, p = 0.42), whereas a significant improvement in walking endurance time was found with bronchodilation (endurance time ipratropium bromide – placebo: 164 ± 177 s, p = 0.0015). As illustrated by the individual data, the response to bronchodilation was more homogeneous for the endurance shuttle walk than for the cycling endurance test, with 14 of the 17 patients (82%) showing an improvement in walking performance after bronchodilation, compared with 8 of 17 (47%) for cycling. The standardized response mean (magnitude of change/SD of change) was larger for walking than cycling (0.93 and 0.20, respectively). A larger standardized response mean indicates a greater responsiveness to change. Significant correlations were found between baseline TwQ and the improvement in cycling endurance time (r = 0.60, p = 0.01), and between baseline inspiratory capacity and the improvement in walking endurance time (r = 0.65, p = 0.005).
Physiologic Response
The time course of V·O2, heart rate, V·E, and respiratory rate during the cycling endurance test and the endurance shuttle walk under the placebo conditions is depicted in Figure 3. The initial response tended to be faster during the endurance shuttle walk than during the cycling endurance test for each of these parameters, but thereafter the drift tended to be more pronounced during cycling than during walking, such that similar end-exercise values were reached for both tests. Despite these subtle differences, there was no statistically significant interaction between the testing modality and the time for all four parameters, suggesting that the V·O2, heart rate, V·E, and respiratory rate kinetics were similar during both tests.
Significant differences in the occurrence of quadriceps muscle fatigue were noted between the two testing modalities. As shown in Figure 4A, a 22 ± 17% fall in TwQ was observed after the cycling endurance test (p < 0.01), whereas no significant change in TwQ was seen after the endurance shuttle walk (+ 3 ± 23%). In addition, the proportion of patients who developed quadriceps muscle fatigue (postexercise fall in TwQ > 15% from resting value) was significantly higher for the cycling endurance test than for the endurance shuttle walk (63 vs. 19%, respectively; p < 0.01).
Subjective Response
The perception of leg fatigue was significantly higher at end-exercise for the cycling endurance test than for the endurance shuttle walk (p < 0.01). In addition, the locus of symptom limitation was significantly different between the two testing modalities (Figure 4B; p < 0.01). For the cycling endurance test (placebo condition), seven patients (41%) cited dyspnea as the main limiting factor, whereas six (35%) cited leg fatigue and four (24%) cited the combination of both symptoms. The corresponding patient numbers for the endurance shuttle walk were 12 (70%), three (18%), and two (12%).
DISCUSSION
The main objective of this study was to evaluate, in patients with COPD, the bronchodilator-induced changes in endurance time for the cycle endurance test and the endurance shuttle walk. Similar gains in pulmonary function after bronchodilation resulted in more consistent and greater improvement in endurance time during walking compared with cycling. This finding may have important implications in the design of future clinical trials evaluating the functional impact of various therapeutic interventions in COPD.
Previous investigations have shown a significant acute improvement in cycling endurance time after bronchodilation (3, 6, 19–22). The improvement in cycling endurance time obtained after acute bronchodilation in the present study is consistent in magnitude with the values previously reported (3, 6). Given that those studies were conducted among larger samples, it is possible that statistical significance was not reached in the present study because of a type II error. Differences observed in the response to bronchodilation during cycling in various studies may also be related to variation in the entry criteria. In previous investigations (19, 20, 22), patients were recruited on the basis of the presence of resting hyperinflation or dyspnea as the main complaint to exercise intolerance, whereas no such criteria were mandatory in the present study. Thus, previous investigators have selected patients who were most likely limited by breathlessness regardless of the exercise modality. In comparison, in the present study, the sample was composed of patients with a wide range of disease severity, hyperinflation, and exercise-limiting symptoms. This likely resulted in a more heterogeneous response to bronchodilation, especially during cycling, because of the contribution of leg fatigue.
In two recent large clinical trials evaluating the impact of bronchodilation on cycling capacity in patients with COPD (20, 21), two full cycling endurance tests were performed before randomization to familiarize the patients with the study procedure. In comparison, in the present study, only a few minutes of constant-work-rate cycling exercise were performed during the familiarization. This likely resulted in more variability in the exercise response during cycling. The requirement of two full familiarization procedures for cycling may be seen as a disadvantage in the implementation of this exercise modality as a practical evaluative tool in clinical practice. Interestingly, a significant improvement in exercise performance could be detected with walking because its response to bronchodilation was more homogeneous than with cycling. Using the standardized response mean (18), we also found that the ability to capture changes in endurance time was greater for walking than for cycling. This parameter estimates the signal-to-noise ratio and therefore the responsiveness of a measuring tool (18). Also, it has direct implication in the determination of sample size for clinical trials; the larger the standardized response mean, the smaller the sample size to demonstrate a treatment effect. If confirmed in larger studies, this would imply that clinical trials could be designed with smaller sample sizes when using the endurance shuttle walk instead of the cycle endurance test as the functional outcome variable.
Two physiologic mechanisms were explored as an attempt to understand the different responsiveness to change between cycling and walking: the cardiorespiratory response and the degree of quadriceps muscle fatigue elicited by both endurance tests. Despite subtle differences in the V·O2, heart rate, V·E, and respiratory rate profiles between the cycle endurance test and the endurance shuttle walk, the cardiorespiratory response was very similar during both tests. To our knowledge, this study is the first to compare ventilatory adaptations to constant-load cycling and endurance shuttle walking. It has previously been proposed that the ventilatory responses during cycling and walking were driven by different mechanisms (7, 8, 23, 24). During cycling, the ventilatory response is believed to be modulated by an important contribution of nonaerobic metabolism (7, 25, 26), resulting from the predominant solicitation of the quadriceps muscle and the overwhelming demand on its oxidative machinery. Conversely, during walking, the contribution of nonaerobic metabolism is minimal (27), probably because several muscle groups are involved, but the activation of arm and trunk muscles is believed to be a potential source of increased afferent input to the respiratory centers (24).
Our data regarding the degree of quadriceps muscle fatigue elicited by both exercise modalities support the concept that quadriceps muscles are recruited more extensively during cycling than during walking. Indeed, as reported by Man and coworkers (8), quadriceps muscle fatigue was more frequent and more pronounced after cycling than after walking. In a previous study, we reported that the occurrence of quadriceps muscle fatigue during cycling exercise could prevent acute bronchodilation with ipratropium bromide from translating into better exercise tolerance (9). Thus, in patients predominantly limited by quadriceps muscle fatigue during exercise, the administration of a bronchodilator may not necessarily translate into improvements in exercise tolerance. This may be one potential explanation for the rather heterogeneous response to bronchodilation of the cycling endurance test despite the fact that its reliability has been well documented (3, 28).
Subjective information obtained from the patients was consistent with our physiologic findings. In fact, the locus of symptom limitation was markedly different between cycling and walking, with a greater proportion of patients reporting leg fatigue as the limiting symptom during cycling compared with walking. The impact of leg fatigue on the exercise response to bronchodilation was further emphasized in a secondary analysis of two large clinical trials (20, 21) evaluating the effects of tiotropium on the endurance during constant-work-rate cycling exercise (29). This analysis clearly indicated that the impact of bronchodilation on constant-work-rate endurance time was considerably lessened when leg fatigue was the main exercise-limiting symptom.
One interesting question is why walking, as performed in the endurance shuttle walk, was sensitive to detect bronchodilator-induced changes in exercise capacity, whereas the 6-min walking test does not seem to share the same responsiveness to change (6). Although we can only speculate on this issue, one likely explanation lies in the designs of the two walking tests, which are intrinsically different. Although the endurance shuttle walk is externally paced, the 6-min walking test has been designed to be self-paced. It can be argued that the capacity of a walking test to detect changes could be compromised when the patient is allowed to choose a convenient walking rhythm. Another possibility may be linked to the fixed and relatively short duration of the test, which may mask any impact of bronchodilation occurring beyond its predetermined 6-min duration. Although no clear physiologic explanation can be provided, the current literature (6, 30–32) is consistent with the notion that the 6-min walking test is not an appropriate evaluative tool to quantify the impact of acute bronchodilation on the functional status in COPD. This should not be interpreted as a suggestion to abandon the 6-min walking test. This test may be a useful prognostic indicator in COPD (33) and it may be helpful to quantify the impact of pulmonary rehabilitation (34). Therefore, the endurance shuttle walk and the 6-min walking test should be viewed as complementary in the evaluation of patients with COPD.
In comparison to cycling, some potential limitations of the walking tests are worth mentioning. It is, for instance, more difficult to inquire about the perception of dyspnea and leg fatigue on a regular basis when the patient is not stationary. This is why, in the present investigation, we inquired about these symptoms only at the end of the walking exercises. Any possible differences in the degree of dynamic hyperinflation during walking and cycling could influence their response to bronchodilation. This was not addressed in the present investigation because inspiratory capacity could not be measured during exercise with the telemetric cardiopulmonary exercise system that was used. There is, however, indirect evidence suggesting that the degree of dynamic hyperinflation would not be much different between walking and cycling. First, the similarity in ventilation and respiratory rate during walking and cycling (Figure 3) would argue against any major variation in the degree of dynamic hyperinflation between the two exercise modalities. Second, the degree of dynamic hyperinflation occurring during a 6-min walk was previously quantified in one study in which inspiratory capacity was spirometrically determined before and after walking (35). Despite some underestimation of the degree of dynamic hyperinflation due to a time lag between the end of the walking exercise and the determination of the inspiratory capacity, the fall in inspiratory capacity after walking was of similar magnitude to what was reported during constant cycling exercise (20). Direct comparison of the effects of walking and cycling on dynamic hyperinflation will soon become possible with newer versions of the telemetric exercise system.
Conclusions
In summary, this study indicates that walking, as performed in the endurance shuttle walk, is sensitive to detect changes in exercise performance after bronchodilation. In fact, on the basis of the similar cardiorespiratory responses during cycling and walking and on the finding that quadriceps muscle fatigue is more frequent and more pronounced after cycling than after walking, it could be argued that the endurance shuttle walk is a particularly well designed evaluative tool. This may be especially true when testing patients with COPD with a wide range of disease severity, hyperinflation, and exercise-limiting symptoms. Overall, these findings may have important clinical implications for the evaluation of the functional impact of bronchodilation in patients with COPD in future clinical trials.
Acknowledgments
The authors thank Marthe Belanger, Marie-Josee Breton, Brigitte Jean, and Josee Picard for their help in accomplishing this study. They also thank Drs. Alan Hamilton and Yves Lacasse for helpful insight in the discussion of the data.
FOOTNOTES
Supported by the Fondation de l'Hpital du Sacre-Cur de Montreal (V.P.); a Ph.D. training award from Fonds de la Recherche en Sante du Quebec to D.S.; and an unrestricted educational grant from Boehringer Ingelheim (Canada) Ltd./Pfizer Canada, Inc. F.M. is a research scholar for the Fonds de la Recherche en Sante du Quebec.
This article has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org
Originally Published in Press as DOI: 10.1164/rccm.200507-1037OC on September 15, 2005
Conflict of Interest Statement: V.P. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. D.S. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. F.W. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. P.L. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. F.M. received $12,000 in 2003 and $12,000 in 2004 for speaking at conferences sponsored by Boehringer Ingelheim, Pfizer, and GlaxoSmithKline (GSK). He received $6,000 in 2004 for serving on an advisory board for GSK and Altana Pharma. He received $250,000 in 2003 and 2004 from GSK, Boehringer Ingelheim, Altana Pharma, and Merck as research grants for participating in multicenter trials. He has been reimbursed by AstraZeneca for attending one conference, and has received an unrestricted research grant of $40,000/yr from Boehringer Ingelheim.
REFERENCES
American Thoracic Society/American College of Chest Physicians. ATS/ACCP Statement on cardiopulmonary exercise testing. Am J Respir Crit Care Med2003;167:211–277.
O'Donnell DE, Sanii R, Younes M. Improvement in exercise endurance in patients with chronic airflow limitation using continuous positive airway pressure. Am Rev Respir Dis1988;138:1510–1514.
O'Donnell DE, Lam M, Webb KA. Measurement of symptoms, lung hyperinflation, and endurance during exercise in chronic obstructive pulmonary disease. Am J Respir Crit Care Med1998;158:1557–1565.
Solway S, Brooks D, Lacasse Y, Thomas S. A qualitative systematic overview of the measurement properties of functional walk tests used in the cardiorespiratory domain. Chest2001;119:256–270.
Cambach W, Chadwick-Straver RVM, Wagenaar RC, van Keimpema ARJ, Kemper HCG. The effects of a community-based pulmonary rehabilitation programme on exercise tolerance and quality of life: a randomized controlled trial. Eur Respir J1997;10:104–113.
Oga T, Nishimura K, Tsukino M, Hajiro T, Ikeda A, Izumi T. The effects of oxitropium bromide on exercise performance in patients with stable chronic obstructive pulmonary disease: a comparison of three different exercise tests. Am J Respir Crit Care Med2000;161:1897–1901.
Palange P, Forte S, Onorati P, Manfredi F, Serra P, Carlone S. Ventilatory and metabolic adaptations to walking and cycling in patients with COPD. J Appl Physiol2000;88:1715–1720.
Man WD, Soliman MG, Gearing J, Radford SG, Rafferty GF, Gray BJ, Polkey MI, Moxham J. Symptoms and quadriceps fatigability after walking and cycling in chronic obstructive pulmonary disease. Am J Respir Crit Care Med2003;168:562–567.
Saey D, Debigare R, LeBlanc P, Mador MJ, Cte CH, Jobin J, Maltais F. Contractile leg fatigue after cycle exercise: a factor limiting exercise in patients with COPD. Am J Respir Crit Care Med2003;168:425–430.
Pepin V, Whittom F, Saey D, LeBlanc P, Maltais F. How to detect bronchodilator-induced improvements in exercise tolerance in COPD: should patients walk or cycle Am J Respir Crit Care Med2005;171:A315.
Pauwels RA, Buist AS, Calverley PM, Jenkins CR, Hurd SS. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease (GOLD) workshop summary. Am J Respir Crit Care Med2001;163:1256–1276.
American Thoracic Society. Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease (COPD) and asthma. Am Rev Respir Dis1987;136:225–244.
Quanjer PH, Tammeling GJ, Cotes JE, Pedersen OF, Peslin R, Yernault JC. Lung volumes and forced ventilatory flows. Work Group on Standardization of Lung Function Tests, European Community for Steel and Coal. Official Statement of the European Respiratory Society. Eur Respir J Suppl1993;16:5–40.
Singh SJ, Morgan MD, Scott S, Walters D, Hardman AE. Development of a shuttle walking test of disability in patients with chronic airways obstruction. Thorax1992;47:1019–1024.
Revill SM, Morgan MD, Singh SJ, Williams J, Hardman AE. The endurance shuttle walk: a new field test for the assessment of endurance capacity in chronic obstructive pulmonary disease. Thorax1999;54: 213–222.
Guyatt GH, Pugsley S, Sullivan MJ, Thompson PJ, Berman L, Jones NL, Fallen EL, Taylor DW. Effect of encouragement on walking test performance. Thorax1984;39:818–822.
Borg G. Psychophysical bases of perceived exertion. Med Sci Sports Exerc1982;14:377–381.
Liang MH. Longitudinal construct validity: establishment of clinical meaning in patient evaluative instruments. Med Care2001;38:84–90.
O'Donnell DE, Voduc N, Fitzpatrick M, Webb KA. Effect of salmeterol on the ventilatory response to exercise in chronic obstructive pulmonary disease. Eur Respir J2004;24:86–94.
O'Donnell DE, Fluge T, Gerken F, Hamilton A, Webb K, Aguilaniu B, Make B, Magnussen H. Effects of tiotropium on lung hyperinflation, dyspnoea and exercise tolerance in COPD. Eur Respir J2004;23:832–840.
Maltais F, Hamilton A, Marciniuck D, Hernandez P, Sciurba F, Richter K, Kesten S, O'Donnell DE. Improvements in symptom-limited exercise performance over eight hours with once-daily tiotropium in patients with COPD. Chest2005;128:1168–1178.
Mahler DA, Fierro-Carrion G, Mejia-Alfaro R, Ward J, Baird JC. Responsiveness of continuous ratings of dyspnea during exercise in patients with COPD. Med Sci Sports Exerc2005;37:529–535.
Delgado HR, Braun SR, Skatrud JB, Reddan WG, Pegelow DF. Chest wall and abdominal motion during exercise in patients with chronic obstructive pulmonary disease. Am Rev Respir Dis1982;126:200–205.
Celli BR, Rassulo J, Make BJ. Dyssynchronous breathing during arm but not leg exercise in patients with chronic airflow obstruction. N Engl J Med1986;314:1485–1490.
Mathur RS, Revill SM, Vara DD, Walton R, Morgan MD. Comparison of peak oxygen consumption during cycle and treadmill exercise in severe chronic obstructive pulmonary disease. Thorax1995;50:829–833.
Troosters T, Vilaro J, Rabinovich R, Casas A, Barbera JA, Rodriguez-Roisin R, Roca J. Physiological responses to the 6-min walk test in patients with chronic obstructive pulmonary disease. Eur Respir J2002;20:564–569.
Onorati P, Antonucci R, Valli G, Berton E, De Marco F, Serra P, Palange P. Non-invasive evaluation of gas exchange during a shuttle walking test vs. a 6-min walking test to assess exercise tolerance in COPD patients. Eur J Appl Physiol2003;89:331–336.
van't Hul A, Gosselink R, Kwakkel G. Constant-load cycle endurance performance: test-retest reliability and validity in patients with COPD. J Cardiopulm Rehabil2003;23:143–150.
O'Donnell DE, Hamilton A, Kesten S. Influence of the exercise-limiting symptom on the relationship between lung hyperinflation and endurance time in COPD patients treated with tiotropium . Am J Respir Crit Care Med2005;171:A314.
Grove A, Lipworth BJ, Reid P, Smith RP, Ramage L, Ingram CG, Jenkins RJ, Winter JH, Dhillon DP. Effects of regular salmeterol on lung function and exercise capacity in patients with chronic obstructive airways disease. Thorax1996;51:689–693.
Boyd G, Morice AH, Pounsford JC, Siebert M, Peslis N, Crawford C. An evaluation of salmeterol in the treatment of chronic obstructive pulmonary disease (COPD). Eur Respir J1997;10:815–821.
Mahler DA, Donohue JF, Barbee RA, Goldman MD, Gross NJ, Wisniewski ME, Yancey SW, Zakes BA, Rickard KA, Anderson WH. Efficacy of salmeterol xinafoate in the treatment of COPD. Chest1999;115:957–965.
Celli BR, Cote CG, Marin JM, Casanova C, Montes de Oca M, Mendez RA, Pinto Plata V, Cabral HJ. The body-mass index, airflow obstruction, dyspnea, and exercise capacity index in chronic obstructive pulmonary disease. N Engl J Med2004;350:1005–1012.
Lacasse Y, Wong E, Guyatt GH, King D, Cook DJ, Goldstein RS. Meta-analysis of respiratory rehabilitation in chronic obstructive pulmonary disease. Lancet1996;348:1115–1119.
Marin JM, Carrizo SJ, Gascon M, Sanchez A, Gallego B, Celli BR. Inspiratory capacity, dynamic hyperinflation, breathlessness, and exercise performance during the 6-minute-walk test in chronic obstructive pulmonary disease. Am J Respir Crit Care Med2001;163:1395–1399.