Nonlinear exercise training in advanced COPD is superior to traditional exercise

Transcription

1 Online data supplement Nonlinear exercise training in advanced COPD is superior to traditional exercise training: a randomized trial. Peter Klijn, PhD, Anton van Keimpema, MD, PhD, Monique Legemaat, RN, Rik Gosselink, PhD, PT, and Henk van Stel, PhD.

2 Methods - additional information: Study subjects Consecutive patients with stage III-IV COPD Global Initiative for Chronic Obstructive Lung Diseases (GOLD) (post-bronchodilator forced expiratory volume in one second (FEV ) %predicted < 0%; FEV /forced vital capacity (FVC) <0%;) (E), referred between May 008 and May 0 to the inpatient PR program of Merem Asthma Center Heideheuvel (Hilversum, The Netherlands) and being able to comply with the training protocol were included. General inclusion and exclusion (e.g., severe cardiological disease, psychiatric disorders, neurological disease and musculo-skeletal disease that preclude participation in our PR program) criteria for inpatient PR were applied (E, E). The study goal and procedures were explained during the diagnostic period. Study design During the -day diagnostic period preceding our pulmonary rehabilitation (PR) program peak work rate (Wmax) was assessed with a cardiopulmonary exercise test. Assessments should follow each phase to assess the effects for an adequate subsequent training prescription (E). Depleted NLPE patients only performed RT during the first training period and consecutive cycling and RT during the second training period. Therefore, in the depleted groups additional assessments (constant work rate test, isotonic muscle strength, healthrelated quality of life) were included at the end of the first training period. 0 Assessments Cardiopulmonary exercise testing An incremental symptom-limited exercise test on an electromagnetically braked cycle ergometer (Lode Excalibur 0-; Lode, Groningen, The Netherlands) was performed during the -day diagnostic period under supervision of a chest physician (E). The maximal workload (Wmax) was defined as the workload a subject was able to complete

3 for 0 seconds. Wmax and maximum cardiac frequency were expressed as predicted normal values (E) Constant work rate test (CWT) On day or of the rehabilitation period and again in week (depleted patients only) and, constant work rate exercise (CWT) (E) was performed at % Wmax (E) to volitional exhaustion (with a maximum of 0 minutes) on the same cycle ergometer as used for cardiopulmonary exercise testing. Sitting on the ergometer, the subjects were allowed a minute acclimatization period. Thereafter, a minute warm-up period started at 0 W before initiating exercise at % of Wmax. Heart rate and percutaneous oxygen saturation (SpO ) were continuously monitored. Dyspnea and leg fatigue were assessed at the end of the CWT with the modified 0-point Borg scale (E8) Isotonic strength testing Maximal dynamic isotonic strength was evaluated at baseline, weeks (depleted patients only), and weeks to determine maximal lower body (leg press and leg extension) and upper body (chest press and pull down) strength via an one-repetition maximum (-RM: the maximal amount of weight lifted only once, at a controlled pace throughout the complete range of motion, determined in the unloaded position) using standard equipment (Biometrics Europe, Almere, The Netherlands). Patients were instructed on how to properly perform the lifts. Measurements were made with identical equipment positioning. Dynamic muscular strength was primarily assessed to prescribe training intensity (% -RM). All strength tests were conducted with paying special attention to consistency with seat adjustment, body position, amount of stabilization, and level of vocal encouragement to motivate the patients to

4 give maximal effort. All exercises were performed bilaterally and were executed with correct breathing, avoiding Valsalva maneuver. A familiarization protocol was used before attempting an -RM. In short, subjects performed repetitions with a relatively light load (approximately 0-0% estimated -RM), and again repetitions with approximately 0% of the estimated -RM. For the next single repetition the load was increased; chest press to kg, pull down and leg extension to kg, leg press to 0 kg. If this weight was lifted with the proper form, the patient attempted another repetition with an additional load. The increments in resistance between attempts were adjusted to minimize the total number of attempts required before the true -RM was obtained and to keep the number of attempts similar before and after training. Increases in resistance were dependent on the effort required and the form shown performing the exercise. To determine -RM with great precision increments became progressively smaller as the subject approached the -RM. At that stage every successful attempt was followed by - minutes rest. The test ended when on two sequential attempts separated with a -minute rest the full range of motion was not achieved. The maximum load was normally determined within attempts and was used to set the load for training. The new -RM at week in the depleted groups was used to set the load in the remaining training sessions. Health-related quality of life Health-related quality of life was assessed with the Dutch version of the Chronic Respiratory Questionnaire (CRQ) (E9). The four CRQ-domains (Dyspnea, Fatigue, Emotion, Mastery) each range from (most severe impairment) to (no impairment), with higher scores indicating better health-related quality of life.

5 Pulmonary function Spirometry, lung volumes, and diffusion capacity (TL, CO ) (Masterscreen PFT, Jaeger/CareFusion) were determined, according to previously described recommendations (E0) and related to predicted normal values (E) Bio-impedance analysis Anthropometric measurements were performed during the -day diagnostic period, on PR program admission and in week. Body weight was measured using a platform beam balance (Seca, Germany) with an accuracy of 0.0 kg. Height was measured with a stadiometer (Holtain, Crymich, UK) with an accuracy of 0. cm. Body mass index (BMI: body weight/height ) was determined. Fat-free mass (FFM) and FFM-index (FFMi: (kg FFM)/height ) were determined in the morning after an overnight fast by bioelectrical impedance analysis (Equip b.v., Gouda, The Netherlands, Model BIA 0/S) (E) Exercise training Exercise training was part of a comprehensive, standardized, multidisciplinary in-patient PR program which included among others (on a weekly basis): education on understanding of pulmonary pathophysiology, and the mechanisms of breathlessness, breathing retraining, methods of clearance of pulmonary secretions, education of inhalation technique, skilloriented self-management, energy conserving techniques and psychosocial support sessions relating to chronic disability, and physical and exercise therapy. The multidisciplinary treatment team consist of a pulmonologist, respiratory nurse, psychologist, exercise physiologist, physical therapist, Cesar practice therapist, occupational therapist, exercise therapist, dietician, social worker, and recreation therapist. Endurance training (ET) was performed on a calibrated cycle ergometer (Lode Examiner, The

6 Netherlands) and treadmill (EPR groups only) (Biometrics Europe BV, Almere, The Netherlands). RT on standard isotonic strength equipment (Biometrics Europe BV, Almere, The Netherlands); leg press, bilateral leg extension, pull down and chest press. Patients did not take part in other forms of endurance or resistance exercises than the training program. Throughout the study all patients were reminded not to alter their regular daily activities for the duration of the study when they went home during the weekends Monitoring All training sessions were supervised by exercise therapists (physical education teachers) and Cesar practice therapists. Training sessions were twice weekly supervised by a clinical exercise physiologist (PK) to ensure that all essential program characteristics were strictly enforced. Most important, to ensure progression of training loads with optimal adaptations the therapists in the study were responsible for supervising endurance duration, repetition range, loads and rest periods. Evaluation of exercise-induced dyspnea, exercise-induced fatigue and sense of effort with the category-ratio Borg scale was included immediately following exercise completion during the rest phases between sets and exercises (E8). Symptom ratings were primarily used to guide adjustment of exercise, taking into account the affective component of symptoms (i.e., the amount of threat imposed by the symptoms) and not just the sensory aspects (E). During exercise SpO % and heart rate were monitored on a regular basis with non-invasive pulsoximetry (Nellcor Incorp., Hayward, USA). Resistance training For RT prescription, the specific component variables that determine physiological adaptation are the intensity, repetition-volume (i.e., the product of the number of sets and repetitions),

7 rest interval between sets, training frequency, the sequence of exercise performance, workout structure (e.g., the number of muscle groups trained) and movement velocity (E). During the RT-segment, leg press was executed first in order to present a superior stimulus to the muscles involved in the multi-joint exercise with the other three acting as assistance exercises (E). For the leg press patients were sitting in upright position with both feet 0 cm apart against an upright plate (at a 0-º angle) and their knees in 90º flexion. Patients were instructed to extend their knees to 0º (to prevent locking at the knee joint) during exhalation, then, during another exhalation return to 90º flexion. Due to recurring decreased shoulder mobility in our population, pull down and chest press are frequently excluded from individual training sessions. Repetitions were executed with proper breathing technique. The rhythm of breathing was in harmony with the rhythm of movement: inhalation during the rest phase, and exhalation during movement. In general, contraction duration was ~- s for the concentric and ~- s for the eccentric phase of the lift, interspersed with a ~ s pause (i.e., inhalation) for leg press and chest press and to avoid Valsalva maneuver, no pause for leg extension and pull down. Upper and lower extremity exercise was alternated. In order to prevent the utilization of stretch-shortening cycles, subjects were asked to pause momentarily ( s) between lifts (E). Patients were instructed to relax the muscles previously used during the rest interval between sets by putting the training equipment in the unloaded position to ensure unrestricted blood flow. Relaxing during the rest interval enhances the resynthesis of ATP, resupplying the working muscles with the necessary fuel (E). In order to achieve a progressive overload, increments of -0% (lower percent for smaller muscle mass exercise; higher percent increase for large muscle mass exercise), depending on the absolute training load were used (E).

8 8 9 0 Endurance and progressive resistance training Treadmill walking speed in the first week was set at 0% of the average speed obtained from the baseline six-minute walking test (MWT speed ) for 0 minutes, and was increased thereafter with the aim to reach minutes (E) with % MWT speed in training week 0. EPR-patients who were unable to complete their assigned cycle duration in a single bout were allowed to break exercise duration in two parts; duration of rest periods was determined by the duration of the work phase. The criteria used to increase or decrease the intensity of training were those described by Maltais and colleagues (E8). In short, dyspnea Borg scores were used to prescribe exercise intensity (%W max, walking speed). Intensity was increased with a score <, remained unchanged with a score between and, and was decreased with a score. During RT, EPR patients initially performed two sets of 8 to 0 repetitions (0% -RM) for each of the exercises (E9). Thereafter, standard principles of progressive RT were applied (E) with sets per exercise and the load gradually increasing to 0-80% -RM (E, E9- E) Nonlinear periodized exercise training Pre-induced quadriceps fatigue has been shown to reduce cycle performance (E). Therefore, RT was placed at the end of a combined training session and addressed the same energy system (aerobic or anaerobic) as cycling to optimize physiological adaptation (E, E). Aerobic cycle training was combined with high-volume, (very-) low-intensity RT and anaerobic cycling with low-volume, moderate-high intensity RT (Table E). [Table E: Combined cycle and resistance training in nonlinear periodized exercise training.]

9 8 Results Enrolment and baseline characteristics Figure E displays the patients flow for the depleted and non-depleted groups. Table E shows the baseline characteristics of the 0 randomized patients meeting the inclusion criteria Attendance rate and training characteristics Supplemental oxygen was used during training: Depleted EPR (n=), depleted NLPE (n=8), non-depleted EPR (n=), non-depleted NLPE (n=). The attendance rate was comparable between groups. Depleted: first training period, EPR 8.9±.% versus NLPE 8.8±.%, p=0.; second training period, EPR 80.±8.% versus NLPE 9.±.8%, p=0.9. Non-depleted: EPR 8.±8.% versus NLPE 8.±9.%, p= Cycle training Depleted: EPR and NLPE trained with comparable mean %Wmax, ±% versus ±%, (p=0.). Non-depleted: EPR patients trained at slightly lower mean %Wmax compared to NLPE patients, ±% versus ±% (p<0.0). Cycle work phase duration was significantly longer in EPR compared to NLPE; depleted 8±s versus 0±s; non-depleted 8±9s versus 8±s, respectively, (all p<0.00). 9 0 Resistance training Examples of RT protocols in EPR and in NLPE are shown in Figure E. Depleted: During the first and second training period EPR patients trained with significantly lower mean repetitions and higher mean -RM% compared to NLPE. First period: 9± reps versus ± reps and ±%-RM versus ±%-RM, respectively. Second period: 9±

10 9 reps versus 8± reps and ±%-RM versus 9±%-RM, respectively, (all p<0.00). Non-depleted: During the training program, EPR patients also trained with less mean repetitions and higher mean -RM% compared to NLPE patients, 0± reps versus 0±9 reps and ±8%-RM versus 8±8% -RM, respectively, (all p<0.00). 8 9 [Figure E: Examples of EPR resistance training protocol and NLPE resistance training protocol.] As shown in Table E, cycle training and resistance training in EPR resulted in significantly higher symptom scores compared to NLPE. 0 Cycle endurance Mean values of cycle endurance (with 9% confidence limits) are presented in Table E and Figure E. Endurance in the depleted group increased in both EPR and NLPE after the first and second training period, with significantly larger improvements for the NLPE group compared to the EPR group. Cycle endurance in the non-depleted group improved in both groups but with significantly larger improvements in NLPE [Table E. Improvements in cycle endurance and leg press strength in EPR and NLPE groups after the first and second training period.] [Figure E. Change in cycle endurance in depleted and non-depleted groups.] At the end of the first training period % (n=) of depleted EPR and % (n=) of depleted NLPE patients reached the 0 minute CWT-ceiling. This increased to % (n=) and ~% (n=), respectively at the end of the training program. In the non-depleted groups ~% (n=; EPR) and ~% (n=; NLPE) reached the 0 minute limit at the end of 0 weeks

11 0 exercise training. All improvements in cycle endurance were above the threshold for a minimal clinically important difference of 0 sec (E). 8 9 Isotonic leg muscle strength Table E shows that after the first training period a significant larger improvement in -RM isotonic leg press was found in depleted NLPE patients compared depleted EPR patients. Although the difference was the same, it was not significant anymore at the end of the 0- week training period (p=0.). In the non-depleted group, NLPE patients also showed a nonsignificantly larger improvement compared to EPR patients (p=0.) FFMi and BMI Depleted: After the 0-week training period FFMi showed a small non-significant change in EPR patients (from.9± to.0±., p=0.08) and increased significantly in NLPE patients from.± to ±. (p<0.0). BMI increased significantly in both depleted groups: EPR from.±. to.±. (p<0.0); NLPE from ±. to.±.9 (p<0.0). Changes in FFMi and BMI were not significantly different in depleted groups: FFMi 0. (9% CI to 0.), BMI 0. (9% CI -0. to 0.). Non-depleted: FFMi and BMI did not change significantly, EPR patients.±. to.±. and 8.±. to 8.8±., respectively and NLPE patients from 8.±. to 8.±. and 0.9±. to.±., respectively (all p>0.0). Health-related quality of life As shown in Table E, there were large effects of both training interventions on the dyspnea, fatigue, and emotion dimension of the CRQ. In the depleted group, a substantial part of the

12 improvement was already obtained during the first training period, with only domains from the EPR group below the threshold for clinically important difference of 0. unit. At the end of the 0-week training program, all domains from all groups showed improvement above the threshold. Both in the depleted and in the non-depleted group, NLPE patients had a significantly greater improvement in all CRQ-domains compared to EPR patients [Table E. Improvements in health-related quality of life depleted and non-depleted patients.] The change in the domains of the CRQ are also shown graphically in figures E and E, panels A to D contain mean and 9% CI s from the depleted patients and non-depleted patients, respectively. The values were derived from the raw data, not from the mixed effects model (as this model does not give a 9% CI for the baseline value). The scores may therefore differ somewhat from the estimates derived from the mixed effects model [Figure E: CRQ scores in depleted patients. A: dyspnea scores in depleted patients; B: fatigue scores in depleted patients; C: emotions scores in depleted patients; D: mastery scores in depleted patients] [Figure E: CRQ scores in non-depleted patients. A: dyspnea scores in non-depleted patients; B: fatigue scores in non-depleted patients; C: emotions scores in non-depleted patients; D: mastery scores in non-depleted patients]

13 Table E: Combined cycle and resistance training in nonlinear periodized exercise training. Cycle training Resistance training repetition zones Goal Repetition range Goal Aerobic 0 Muscular endurance - Anaerobic Muscular strength

14 Table E. Baseline characteristics of the depleted and non-depleted study population. depleted EPR depleted NLPE non-depleted EPR non-depleted NLPE Gender, f/m 8 / 0 / 8 / / Age, yr ± 0 ± ± ± FEV, % predicted ± 0 ± 0 ± 9 ± 9 FEV /FVC % predicted ± 9 9 ± 9 ± 8 9 ± TL, CO, % predicted * ± 0 0 ± 9 ± 0 ± 0 LTOT 8 9 Smoking (packyears) ± 9 ± ± ± Long-acting beta-agonists, % Long-acting anticholinergic, % Inhaled corticosteroid, % Oral corticosteroid mg/day, % Exacerbation frequency /year, % BMI, kg/m ± ± 9 ± ± FFMi, (kg FFM)/m ± ± ± 8 ± Wmax, watts % predicted 9 ± ± 9 ± ± ± 0 ± 9 ± 9 ± Peak HR, bt/min % predicted ± ± 0 ± 8 ± ± 8 ± 9 ± ± 0 CWT Time, sec SpO, % HR, bt/min Dyspnea (Borg scale) Leg fatigue (Borg scale) 9 ± 9 ± ± ± ± 99 ± 0 90 ± 0 ± 8 ± ± ± 0 90 ± ± ± ± ± 8 9 ± 0 ± 8 ± ± Leg press, kg kg/ kg FFM CRQ (score) Dyspnea Fatigue Emotion Mastery 0 ± ±. ±.0. ±..0 ±.0. ±. ± ±. ±..8 ±.. ±.. ±. 9 ± ±.8 ±..8 ±.. ±.. ±. 8 ± 0 ±.8 ± 0.9. ±..0 ± 0.9. ±.

15 8 EPR = endurance and progressive resistance training; NLPE = nonlinear periodized exercise training; FEV = forced expiratory volume in one second; FVC = forced vital capacity; TL, CO = transfer factor of the lung for carbon monoxide; LTOT = long-term oxygen therapy; BMI = body mass index; FFMi = fat-free mass index; Wmax = maximum work rate attained during incremental cardiopulmonary exercise test; HR = heart rate; CWT = constant work rate test; S P O = transcutaneous oxygen saturation; CRQ = Chronic Respiratory Questionnaire. Data are presented as mean (sd). * Data missing for patients ( in depleted EPR, in depleted NLPE, in non-depleted EPR, in non-depleted NLPE).

16 Table E. Mean end of exercise symptom Borg scores during cycling and leg press strength exercise in EPR and NLPE training. Cycling exercise Leg press Dyspnea Fatigue Exertion Dyspnea Fatigue Exertion Total EPR NLPE.0 ± 0..9 ±0.9.8 ± 0.. ± 0.9. ± 0.8. ± 0.9. ± 0.9. ± 0.9 *. ± 0.9. ± 0.8. ± 0.9. ± 0. * Depleted Second period First period EPR NLPE EPR NLPE. ±.0 n.a.. ± 0.9. ±.. ± 0.9 n.a..0 ± 0.8. ± 0.8. ±.0 n.a..0 ±.. ±.0. ±.. ±.0. ± 0.9. ± 0.9. ±.. ±.0. ±.0. ±.0. ±..9 ± 0.8. ±.0. ± 0. Non-depleted EPR NLPE.±0..±0..9±0..9±0..9±0..0±0..±0.9.0±0.8 **.±0.8.9±0..±0..±0. **

17 EPR = endurance and progressive resistance training; NLPE = nonlinear periodized exercise training; na = not applicable. Total: * p<0.0; p<0.00, EPR versus NLPE. Depleted: p<0.0; p<0.0; p<0.00, EPR versus NLPE. Non-depleted: ** p<0.0; p<0.0; p<0.00, EPR versus NLPE.

18 Table E. Improvements in cycle endurance and leg press strength in EPR and NLPE groups after the first and second exercise training period. CWT Leg press strength Depleted group First training period EPR +s NLPE +s Difference in change 0s (9-s) * 0. kg (0. to 0. kg) Total training period EPR +s NLPE +9s Difference in change 0s (-s) 0. kg (-. to kg) Non-depleted group EPR +98s NLPE +8s Difference in change 9s (8-s). kg (-9. to. kg) 8 9 EPR = endurance and progressive resistance training; NLPE = nonlinear periodized exercise training. Values derived from mixed effects model. Improvement: mean; difference in change: mean (9%CI). Baseline values: depleted group 98s, non-depleted group 8s. Depleted: first training period * p<0.00; total training period p<0.00, EPR versus NLPE. Non-depleted: p<0.00, EPR versus NLPE.

19 8 Table E. Improvement in health-related quality of life after NLPE and EPR training in depleted and non-depleted patients. Chronic Respiratory Questionnaire (Score) Dyspnea Fatigue Emotions Mastery Depleted group -week versus baseline EPR NLPE week versus baseline EPR NLPE Difference in change (0..9) ( ) (0.0 0.) ( ) Non-depleted group -week versus baseline EPR NLPE Difference in change (0..) (0.9.) (0..) (0.0.) EPR = endurance and progressive resistance training; NLPE = nonlinear periodized exercise training. Values derived from mixed effects model. Improvement: mean; difference in change: mean (9%CI).

20 9 Figure legends Figure E. Flow diagram of the study design. EPR = endurance and progressive resistance training; NLPE = nonlinear periodized exercise training; FFMi = fat-free mass index Figure E. Example non-varied resistance training protocol for leg press in depleted endurance and progressive resistance (EPR) training group with halfway assessments (A), and non-depleted EPR group (B): -times/week, sets, 8-0 repetitions and progressive intensity 0% -RM. Example resistance training protocol for leg press in depleted nonlinear periodized exercise (NLPE) training group with halfway assessments and taper halfway and at completion of the training program (C), and non-depleted NLPE with taper at completion of the training program (D): -times/week, - sets. Both (C and D) with varying repetition zones with corresponding RT intensity and relative emphasis on muscular endurance. Performance adaptations are stimulated by shifting the relative emphasis on intensity and volume (i.e., product of number of sets and repetitions) in training (E, E).

21 0 Figure E. Baseline cycle endurance and change in cycle endurance in depleted groups at and weeks (A) and non-depleted groups at weeks (B). Solid line (A and B): endurance and progressive resistance training (EPR); Dotted line (A and B): nonlinear periodized exercise training (NLPE). Mean values of cycle endurance with 9% confidence limits. The values were derived from the raw data, not from the mixed effects model (as this model does not give a 9% CI for the baseline value). The scores may therefore differ somewhat from the estimates derived from the mixed effects model. Depleted: at weeks * p<0.00; at weeks p<0.00, EPR versus NLPE. Non-depleted: p<0.00, EPR versus NLPE Figure E. Baseline and change score in the Chronic Respiratory Questionnaire (CRQ) at and weeks in depleted patients: Dyspnea (A), Fatigue (B), Emotions (C), Mastery (D). Solid line (A - D): endurance and progressive resistance training (EPR); Dotted line (A - D): nonlinear periodized exercise training (NLPE). Mean values of cycle endurance with 9% confidence limits. at weeks * p<0.0; p<0.00; at weeks p<0.0; p<0.00, EPR versus NLPE.

22 Figure E. Baseline and change score in the Chronic Respiratory Questionnaire (CRQ) at weeks in non-depleted patients: Dyspnea (A), Fatigue (B), Emotions (C), Mastery (D). Solid line (A - D): endurance and progressive resistance training (EPR); Dotted line (A - D): nonlinear periodized exercise training (NLPE). Mean values of cycle endurance with 9% confidence limits. p<0.0; ** p<0.0, EPR versus NLPE.

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26 Figure E. Eligible patients N= Patients failed to reach randomization for a number of reasons N= Participation in other research or treatment program (n=) Hospitalization (n=0) Died (n=) Other reasons (n=) Stratification N=0 Week baseline assessment Week Depleted EPR N= Randomisation depleted N= Female: FFMi < (kg FFM)/m Male: FFMi < (kg FFM)/m Depleted NLPE N= Randomisation non-depleted N= Female: FFMi (kg FFM)/m Male: FFMi (kg FFM)/m Non-depleted EPR N= Non-depleted NLPE N= Week Exercise training week measurement N= week measurement N= No week measurement due to exacerbation but continued participation: n= Week outcome assessment Final measurement N=9 No final measuremen N= -early discharge (n=) - died (n=) Final measurement N=8 No final measurement N= - early discharge (n=) - worsening condition (n=) Final measurement N= - at weeks (n =9) - at weeks (n=) - at 8 weeks (n=) Final measurement N= - at weeks (n=0) - at 0 weeks (n=) - at 8 weeks (n=) Patients included in the analysis of change N= Patients included in the analysis of change N= Patients included in the analysis of change N= Patients included in the analysis of change N=

27 Figure E A: depleted EPR C: depleted NLPE One repetition maximum leg press (%) One repetition maximum leg press (%) number of training sessions number of training sessions B: non-depleted EPR D: non-depleted NLPE One repetition maximum leg press (%) One repetition maximum leg press (%) number of training sessions number of training sessions

28 Figure E. A. 00 Cycle endurance (seconds) * 0 Baseline weeks weeks Measurement B.

29 Figure E. A: dyspnea scores in depleted patients B: fatigue scores in depleted patients Dyspnea score Fatigue score * Baseline weeks weeks Measurement Baseline weeks weeks Measurement

30 Figure E. C: emotion scores in depleted patients D: mastery scores in depleted patients Emotions score * Mastery score * Baseline weeks weeks Measurement Baseline weeks weeks Measurement

31 Figure E. A: dyspnea scores in non-depleted patients B: fatigue scores in non-depleted patients Dyspnea score ** Fatigue score ** Baseline Measurement weeks Baseline Measurement weeks

32 Figure E. C: emotions scores in non-depleted patients D: mastery scores in non-depleted patients Emotions score Mastery score Baseline Measurement weeks Baseline Measurement weeks