University of Groningen. Physical activity and fitness in patients with COPD Altenburg, Wytske Agatha

University of Groningen Physical activity and fitness in patients with COPD Altenburg, Wytske Agatha DOI: 10.1016/j.rmed.2014.10.020 10.1016/j.rmed.2011.11.008 10.1016/j.rmed.2013.06.002 IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record Publication date: 2015 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): Altenburg, W. A. (2015). Physical activity and fitness in patients with COPD: Making a change. [Groningen]: University of Groningen. https://doi.org/10.1016/j.rmed.2014.10.020, https://doi.org/10.1016/j.rmed.2011.11.008, https://doi.org/10.1016/j.rmed.2013.06.002 Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons). Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum. Download date: 14-04-2019

CHAPTER 5 A better response in exercise capacity after pulmonary rehabilitation in more severe COPD patients Wytske A. Altenburg, Mathieu H.G. de Greef, Nick H. T. ten Hacken, Johan B. Wempe Respiratory Medicine 2012 May; 106(5): 694-700

Chapter 5 Abstract Purpose: Pulmonary rehabilitation (PR) has positive effects on exercise capacity in Chronic Obstructive Pulmonary Disease (COPD). However, not all COPD patients benefit from PR to the same extent. We investigated whether there is a patient profile, which is associated with the improvement in endurance exercise capacity. Methods: In this observational study, we included 102 COPD patients who followed PR (age 60 ± 10 (mean ± SD) years, %predicted 44±6 %, 54 men). Lung function, maximal incremental cycle testing (Wpeak, VO 2 peak, Δlactate), quadriceps force and incremental and endurance shuttle walk test (ISWT/ESWT) were performed at the start of PR. The ESWT was repeated after 7 weeks of PR. Results: Mean change in ESWT (ΔESWT) was 100±154 %. Four variables showed a statistically significant negative correlation with ΔESWT: %pred. (ρ=-0.20), Wpeak (ρ=-0.24), Δlactate (ρ=-0.33) and incremental shuttle walk test (ISWT) (ρ=-0.31). A cluster analysis identified two patient profiles: A profile with high ΔESWT, TLC and RV and low, VO 2 peak, quadriceps force, Δlactate, HR peak % pred. and ISWT distance and a profile with low ΔESWT, TLC and RV and high, VO 2 peak, quadriceps force, Δlactate, HR peak % pred. and ISWT distance. Conclusions: Single variables from lung function or exercise testing at baseline have limited predictive value for response to exercise training. However, patients with worse disease status (i.e. a combination of lower, more hyperinflation, lower exercise capacity and worse quadriceps force) improve more in endurance exercise capacity. 90

Predictors of pulmonary rehabilitation outcome Introduction In patients with COPD strength and endurance exercise capacity are impaired. 1-4 Exercise capacity may be affected by many factors such as ventilatory limitation, dynamic hyperinflation and diminished oxygen uptake in the lung. 5 In addition, impaired exercise capacity could be caused by factors outside the lung, such as early lactate production 2,6-8, muscle dysfunction 1 and cardiovascular deconditioning (e.g. higher heart rate and lower stroke volume during exercise) 9,10, which may at least be partially induced by sedentary lifestyle due to dyspnea. 11 Pulmonary rehabilitation (PR) has beneficial effects on exercise-induced dyspnea, exercise capacity and daily physical activity level in COPD. 12-16 In addition, it is known in healthy subjects that exercise training can reverse the process of deconditioning and delays the anaerobic threshold during exercise. 17 Not all COPD patients benefit from PR to the same extent, as is shown in several studies. 18-22 The limiting factor in exercise may play a role in the response to PR. For instance, the presence of a marked ventilatory reserve is associated with improvement in exercise capacity after PR in two studies. 20,22 Besides that, the presence of cardiovascular limitation is associated with improvement in exercise capacity after PR as well. 19,20 Finally, reduced muscle strength is found to be associated with improvement in exercise capacity after PR. 18,20 These studies are, however, quite difficult to compare as they show differences in patient selection, rehabilitation program, outcome measures and statistical methods used. 18-22 In a well defined patient group we investigated whether a patient profile exists with a combination of variables instead of a single variable, which may predict the degree of improvement in endurance exercise capacity after PR. To reveal this profile, the cluster analysis technique was used. We hypothesized that patients with better lung function combined with more signs of deconditioning, e.g. high lactate production during maximal exercise testing and low peak exercise capacity show the largest improvement in endurance exercise capacity after PR. 5 Methods Design A post-hoc analysis was performed on data from patients participating in a PR program in a PR center. At baseline, standardized pulmonary function testing, maximal incremental cycle testing, and incremental and endurance shuttle walk tests (ISWT and ESWT) were performed. After seven weeks of exercise training the ESWT was repeated. Subjects In this study 102 COPD patients, who participated in the PR program of the Center for Rehabilitation of the University Medical Center Groningen, were included. Inclusion criteria were a diagnosis of COPD according to the GOLD guidelines and the capability of following an endurance exercise program and filling out questionnaires. Patients were free of exacerbations for at least six weeks. Excluded were patients with musculoskeletal disorders and malignant diseases which would interfere with exercise training. Both outpatients and inpatients were included. 91

Chapter 5 If necessary, patients were assigned to the inpatient PR program based on criteria such as travel distance, dependence in activities of daily life and nutritional status, in accordance with the ATS/ERS statement. 23 All patients consented to the scientific use of data from tests they performed. Pulmonary function testing Spirometry to determine and FVC was performed in the sitting position using a spirometer (Masterlab, Viasys Healthcare), and static lung volumes were determined with a bodyplethysmograph (Masterlab, Viasys Healthcare). Tests were performed following accepted standards. 24 Exercise testing Subjects performed a symptom-limited incremental cycle test (1-min increments of 5 or 10 W) to the limit of tolerance on an electromagnetically braked cycle ergometer (OxyconPro, Viasys Healthcare) after a 5-minute rest, followed by 1 min of unloaded pedaling. Peak work rate was defined as the highest work level reached and maintained at a pedaling frequency of 60 revolutions per minute for at least 30 s. Pulmonary oxygen uptake, pulmonary carbon dioxide output and minute ventilation were recorded using a mixing chamber. Heart rate was determined using the R-R interval from a 12-lead on-line electrocardiogram. Arterial blood was drawn from a line in the radial or brachial artery for the analysis of arterial oxygen tension, carbon dioxide tension and lactate, at rest, every 2 minutes during the test and 2 minutes after stopping (Rapidlab, Siemens). The change in lactate concentration from rest to the highest level, either at maximal work load or 2 minutes after stopping the test (Δlactate), was used for further analyses. Endurance exercise capacity was measured at the start of and after PR, using the endurance shuttle walk test (ESWT). The ESWT was developed as a standardized field test to assess endurance capacity using constant walking speeds and external regulation of pace. 25 This test is based on the incremental shuttle walk test (ISWT), which uses a 10m course and the walking speed is externally controlled by acoustic signals. 26 The patient is instructed to walk for as long as possible. Patients have to reach the end of the course in time before the audio signal; when they fail to do so, or when they indicate they are exhausted, the test is ended. This test was performed once at the start of PR. VO 2 peak can be predicted by the performance on ISWT with the equation: VO 2 peak (ml/min/kg) = 4.19 + 0.025 (distance in meters). 27 For the ESWT a speed was used that corresponded with 85% of the VO 2 peak. The ESWT speed was read from a graph which related shuttle walking speeds to predicted VO 2 peak. 25 While the ISWT measures maximal exercise capacity in COPD patients, the ESWT is considered to better reflect the endurance exercise capacity. 25,27 The ESWT appears to be responsive to change after an intervention, perhaps even more than the ISWT and the six minute walking distance. 25,28 Quadriceps strength was measured with a handheld dynamometer (microfet), with the patient in sitting position, the knee at 90, and the leg vertical. 29 Pulmonary rehabilitation The exercise sessions in the PR program aimed at improving endurance exercise capacity. Training forms used to achieve increased endurance capacity were cycling, walking, swimming 92

Predictors of pulmonary rehabilitation outcome and sports, 3 sessions per week, 1-2 hours. All patients participated in all these exercise training modalities. The target of each training session was to achieve a training stimulus of 30 minutes at 60 to 70% of the peak work load achieved on maximal incremental cycle testing. In cycling, training intensity was based on work load, whereas in other training modalities the intensity was based on heart rate or Borg scores. The progression of the training load during the exercise program was individually tailored. In addition, subjects followed educational courses and received psychological and/or nutritional support if necessary. The program meets the criteria of the ACSM and ATS/ERS. 23,30,31 Statistical analysis Statistical analysis was performed using SPSS version 16.0. A p-value below 0.05 (two-sided) was considered statistically significant. Means and standard deviations (SD) were calculated if the outcome variables were normally distributed. Normality was tested with the Kolmogorov- Smirnov or Shapiro-Wilks tests. Spearman s ρ was calculated because the primary outcome measure, percentage change in endurance shuttle walk test (ΔESWT), was not normally distributed. Discriminant analysis, method enter (meaning that all variables are taken into the model whether they contribute significantly or not) was performed to find predictors of improved endurance exercise capacity. The outcome variable ΔESWT was divided in two groups using the median. A K-means cluster analysis was used to find homogeneous groups with characteristic profiles showing different response to rehabilitation, measured with the ESWT. Cluster analysis is a data mining technique, in which all subjects are assigned to a predetermined number of relatively homogeneous subgroups. These groups are formed by comparing Euclidean distances between each subject, and each cluster centre in an interactive process. Within these groups the consistency of the variables is high. In this analysis we used the highest and lowest tertile of ΔESWT scores, because we opted for finding patient profiles which were associated with high or low improvement in endurance exercise capacity. 5 93

Chapter 5 Results In this study 102 COPD patients were included: 5 GOLD I, 28 GOLD II, 50 GOLD III and 19 GOLD IV patients. Characteristics of the total group are shown in Table 1. Table 1. Baseline patient characteristics (N= 102) Demographics Age (y) 60.2 ±10.4 Female / Male 48 / 54 BMI (kg/m 2 ) 27.3 ± 6.1 Pulmonary function (l) 1.27 ± 0.59 (% pred) 44.2 ± 15.9 TLC (% pred) 117.9 ± 19.7 RV%TLC (%) 54.8 ± 10.3 Exercise tests ISWT (m) 233 ± 131 ESWT (m) 409 ± 350 ESWT (sec) 390 ± 274 Quadriceps force (N) 292 ± 82 Maximal incremental exercise testing Rest Peak exercise VO 2 peak (% pred) 54.5 ± 16.3 Wpeak (%pred) 41.5 ± 22.1 Wpeak (W) 53.8 ± 36.3 VO 2 (ml/min) 278.7 ± 100.6 971.0 ± 371.2 HR (b/min) 88 ± 16 119 ± 22 VE (l) 11.8 ± 4.0 35.8 ± 15.2 PaCO 2 (kpa) 5.27 ± 0.67 5.70 ± 1.02 PaO 2 (kpa) 9.38 ± 1.25 8.58 ± 1.72 Lactate (mmol/l) 1.62 ± 0.88 4.90 ± 2.50 Peak Borg score dyspnea 1 (0-3) 7 (5-9) Peak Borg score fatigue 0.5 (0-2) 7 (5-9) Values given as a mean ± sd or median (IQR) BMI: body mass index; : forced expiratory volume in one second; TLC: total lung capacity; RV: residual volume; ISWT: incremental shuttle walk test; ESWT: endurance shuttle walk test; VO 2: : oxygen uptake; Wpeak: peak work rate; HR: heart rate; VE: minute ventilation; PaCO 2 : carbon dioxide tension; PaO 2 : arterial oxygen tension 94

Predictors of pulmonary rehabilitation outcome The mean age of the patients was 60 ± 10 (mean ± SD) years, and the male/female ratio was almost equal. The number of missed exercise sessions was < 8%. Maximal exercise capacity was below normal values as shown by the decreased predicted peak workload (41.5% ± 22.1%) and predicted peak oxygen uptake (54.5% ± 16.3%). After 7 weeks of PR mean ΔESWT was 100% ± 154%, corresponding with an absolute ESWT distance improvement of 188 ± 446 meters and an improvement in ESWT time of 216 ± 418 seconds. Of all patients 24% improved between 10% and 50%, whereas 52% improved more than 50%. The correlations between various physiological factors and the ΔESWT are shown in Table 2. Four variables showed a weak but significant negative correlation with the ΔESWT: lactate, %pred, ISWT distance and Wpeak. Table 2. Correlations of initial measures with ΔESWT (Spearman s ρ ) Age (y) BMI (kg/m 2 ) (l) ΔESWT (%) (%pred) ρ = -0.20 * TLC (% pred) RV% TLC (%) ISWT (m) ρ = -0.31 * Quadriceps force (N) V O 2 peak (ml/min) Wpeak (W) ρ = -0.24 * HR peak% predicted (%) Δlactate (mmol/l) ρ = -0.33 * * p<.05, n.s.: non significant correlation BMI: body mass index; : forced expiratory volume in one second; TLC: total lung capacity; RV: residual volume; ISWT: incremental shuttle walk test; VO 2 peak: peak oxygen uptake; Wpeak: peak work rate; HR: heart rate; Δlactate: Change in lactate concentration before and after maximal incremental exercise testing n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. 5 Discriminant analysis (method enter) was used to further explore predictive factors for ΔESWT and we included the variables in the model which are currently known or suggested as predictors. In our final model Δlactate appeared to be the strongest contributing factor in the equation explaining 33% of the variance (Table 3). However, the model was not statistically significant (Wilk s Lambda = 0.888, p= 0.372) although 65.3 % of the patients were classified correctly. 95

Chapter 5 Table 3. Discriminant Analysis: Structure Matrix Canonical discriminant function coefficient Δlactate (mmol/) 0.374 Wpeak (W) 0.312 Quadriceps force (N) 0.283 BMI (kg/m 2 ) -0.276 (% pred) 0.271 RV%TLC (%) -0.258 TLC (%pred) 0.231 Age (y) 0.185 VO 2 peak (ml/min) -0.159 HRpeak%predicted (%) 0.031 Canonical correlation=.335, Wilks Lambda= 0.888, p=0.372 Patients classified correctly=65,3% Δlactate: Change in lactate concentration before and after maximal incremental exercise testing, Wpeak: peak work rate; BMI: body mass index; : forced expiratory volume in one second; RV: residual volume; TLC: total lung capacity; VO 2 peak: peak oxygen uptake; HR: heart rate. The K-means cluster analysis revealed the presence of two homogeneous groups, which were significantly different on several variables i.e. ΔESWT, %pred., TLC%pred., RV%TLC, Wpeak, quadriceps force, VO 2 peak, Δlactate, HRpeak%pred. and ISWT distance (Table 4). A high ΔESWT was associated with a patient profile with high TLC and RV%TLC and low %pred., Wpeak, VO 2 peak, HRpeak%pred., quadriceps strength, ISWT distance. A low ΔESWT was associated with a patient profile with low TLC and RV%TLC and high %pred, Wpeak, VO 2 peak, HRpeak%pred, quadriceps strength, ISWT distance. The clusters showed no significant differences for age and BMI. Discussion This study shows that four variables measured at the start of a PR program are correlated with the change in endurance exercise capacity after 7 weeks of exercise training in COPD: %pred., Wpeak, Δlactate and ISWT distance. As we expected, patients with lower Wpeak and ISWT distance improved more. However, opposite to what we expected, it appeared that lower values of and Δlactate correlate with a larger improvement in endurance exercise capacity after PR. In addition to this univariate analysis, the cluster analysis, used to detect patient profiles, shows that two homogeneous groups can be formed: a patient profile with a combination of worse lung function and exercise capacity, showing a larger improvement in endurance exercise capacity, and a patient profile with a combination of better lung function and exercise capacity, showing a substantially smaller improvement. 96

Predictors of pulmonary rehabilitation outcome Table 4. K-means cluster analysis: Cluster profile Final Cluster Centers ANOVA 1 (n=17) 2 (n=48) F p ΔESWT (%) 40.2 141.3 4.281 0.043 (% pred) 57.9 39.1 23.133 <0.001 TLC (% pred) 108.1 122.8 7.203 0.009 RV%TLC (%) 45.9 60.0 30.219 <0.001 Wpeak (W) 100.0 41.0 55.937 <0.001 Quadriceps force (N) 337 269 9.171 0.004 VO 2 peak (ml/min) 1530.2 801.7 101.686 <0.001 Δlactate (mmol/l) 5.19 2.74 16.547 <0.001 HR peak (%predicted) 83 72 12.439 0.001 ISWT (m) 364 199 28.491 <0.001 Age (y) 60 60 0.011 0.919 BMI (kg/m 2 ) 29.8 26.5 3.325 0.073 ΔESWT: Change in endurance shuttle walk test percentage, before and after pulmonary rehabilitation; : forced expiratory volume in one second; TLC: total lung capacity; RV: residual volume; Wpeak: peak work rate; VO 2 peak: peak oxygen uptake; Δlactate: Change in lactate concentration before and after maximal incremental exercise testing; HR: heart rate; ISWT: incremental shuttle walk test; BMI: body mass index. A number of other investigators have examined whether the change in exercise capacity can be predicted. 18-22 Their results are equivocal and difficult to interpret. The differences in results may be due to differences in patient selection, outcome measures, intervention and statistical methods used to analyze the data. Garrod et al. studied a very heterogeneous group of COPD patients from primary and secondary care, who followed either outpatient or, for the most severe patients, home-based PR, for 7 weeks, twice a week for 1 h. 18 The 6MWD was the primary outcome measure for exercise capacity, and the minimal clinically important difference was used to determine if a patient was a responder. A logistic regression analysis was used and no predictors for the observed change in exercise capacity were found. 5 Plankeel et al. included non-oxygen dependent COPD patients following a 4-week PR program and found that the nature of limitation on maximal incremental exercise testing, whether it was cardiovasculary, ventilatory, both or none, did not predict the increase in endurance exercise capacity, measured with the 6MWD. 19 Interestingly, this study showed that the increase in VO 2 peak after PR was highest in subjects with no ventilatory limitation. Recently, Vagaggini et al. studied moderate to severe COPD patients who followed an 8-week outpatient PR program. 21 The effect of the PR program was measured with the 6MWD. Using a logistic regression analysis, they found that patients with BMI > 25 kg/m 2 and patients with PO 2 < 8 Kpa (60 mmhg) improved more in exercise capacity after PR. 97

Chapter 5 Troosters et al. studied moderate to severe COPD patients following a 12 week outpatient PR program. 20 They used a discriminant analysis to distinguish between responders and nonresponders. Responders were defined by having a 15% increase in maximal workload and/ or 25% increase in 6MWD. They found that responders had more ventilatory reserve and lower inspiratory and peripheral muscle strength. Zu Wallack et al studied pulmonary patients, of which 80% had a primary diagnosis of COPD, after a 6-week PR program. 22 The effect of the program was measured with the 12MWD. Using a regression analysis they showed that a combination of higher and low initial walking distance on 12MWD predicted improvement in exercise capacity. Together the above described results suggest that a worse functional status may be related to a larger improvement in endurance exercise capacity after exercise training. Our study adds to previous results by including a heterogeneous group of patients and using a different statistical approach, the cluster analysis. Besides that we think that the outcome measure in our study, the ESWT, is a sensitive measurement tool to assess changes in endurance capacity after PR, as it has shown to be responsive to change after an intervention. 28 We found a lower to be associated with a higher improvement in exercise capacity in contrast to some studies 19,20,22, which showed that patients with some ventilatory reserve improved the most after PR. However, the negative association we found between improvement in exercise capacity after PR and initial exercise testing is in line with other studies. 19,22 An explanation for the larger improvement of the patients with low initial exercise capacity in our study may be that these patients have entered a downward spiral of dyspnea, avoidance of physical activity, deconditioning and demotivation. 9 These deconditioned and demotivated patients may have a larger capacity for improvement than patients with more preserved exercise capacity and thus may show larger improvement after exercise training. The finding that patients with a lower lactate production improve more than patients with higher lactate production is confusing. The literature until now states that high lactate at maximal exercise testing is a reflection of poor (reversible) muscle and/or cardiac function thus possibly predicting a positive response to PR. 2,6,19 The maximal incremental cycle test in our study was symptom limited, and we believe that patients really reached their maximal value, reflected by high Borg scores on dyspnea and/or fatigue. That is why we expected higher lactate levels at low exercise levels, which reflect deconditioning, to be associated with larger improvement in endurance exercise capacity. However, it may be possible that in these severe COPD patients other aspects than aerobic capacity determine maximal work load or the change in walking distance. For instance, neuromuscular efficiency and psychological factors such as desensitization and self confidence may play a role. There are some limitations to our study. In contrast with many other studies, a considerable part of our patients followed an inpatient PR program in a specialized rehabilitation centre, thus including more severe patients, even those who are oxygen-dependent. This may limit the extrapolation of our results to less severe COPD patients. In our study we used data of a maximal incremental cycle test to characterize patients at the start of our PR program, and used an endurance walking test as a primary outcome measure of change in endurance capacity. The advantage of using a maximal incremental cycle test at the beginning of PR is 98

Predictors of pulmonary rehabilitation outcome that more variables can be measured, such as blood gases and lactate concentrations, and that EKG-recordings can easily be made to assess exercise safety. In addition, it is shown that the peak exercise response is not different for VO 2, tidal volume, respiratory frequency and heart rate between an incremental shuttle walking test and a maximal incremental cycle test. 32 Finally, we focused on endurance capacity as an outcome measure because we believe this is important for functioning in daily life. However, to be able to select patients that benefit from PR, changes in health related quality of life and healthcare utilization after PR should be investigated as well. In our opinion, the results of the current study are clinically relevant. Single variables from lung function or maximal incremental exercise testing at entry of PR are of limited value in predicting the response to exercise training. However, the cluster analysis shows that the more severe COPD patients, i.e. patients with worse lung function combined with worse exercise capacity seem to benefit more from PR, which provides a strong argument not to exclude these severely disabled patients from PR programs. We hypothesize that in these patients a downward spiral of dyspnea, avoidance of physical activity, deconditioning and demotivation exists. Therefore, we suggest that the role of lifestyle and psychological factors such as low activity pattern, demoralization and demotivation may particularly be important in these patients and should be investigated. In conclusion, COPD patients with worse disease status, i.e. lower, more signs of hyperinflation, lower exercise capacity and worse quadriceps force improve more in endurance exercise capacity after PR and should not be excluded for treatment with PR. Acknowledgements The authors would like to acknowledge Wim P. Krijnen ( Hanze University, Institute for Life Science and Technology, Groningen, The Netherlands) for his contribution to the statistical analyses. 5 99

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