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Benefits of home-based endurance training in lung transplant recipients
Respiratory Physiology & Neurobiology 177 (2011) 189–198
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Benefits of home-based endurance training in lung transplant recipients Isabelle Vivodtzev a,h , Christophe Pison b,c , Karen Guerrero b,d , Paulette Mezin e , Elisabeth Maclet c , Jean-Christian Borel a , Phillipe Chaffanjon f , Rachid Hacini g , Olivier Chavanon g , Dominique Blin g , Bernard Wuyam a,h,∗ a
Inserm U1042, HP2 Laboratory, Joseph Fourier University, 38043 Grenoble, France Inserm U884, Université Joseph Fourier, Laboratoire de Bioénergétique Fondamentale et Appliquée, 2280 rue de La Piscine, 38400 Saint-Martin d’Hères, France CHU de Grenoble, Clinique de Pneumologie, BP217, 38043, Grenoble, France d Inserm U803 - CHU de Grenoble, Centre d’Investigation Clinique – Innovation Technologique, France e CHU de Grenoble, Département d’Anatomie et de Cytologie Pathologique, BP217, 38043, Grenoble, France f CHU de Grenoble, Clinique de Chirurgie Thoracique et Vasculaire, BP217, 38043, Grenoble, France g CHU de Grenoble, Clinique de Chirurgie Cardiaque, BP217, 38043, Grenoble, France h CHU de Grenoble, Pole Physiologie Rééducation, Clinique de Physiologie, Sommeil & Exercice, BP217, 38043, Grenoble, France b c
a r t i c l e
i n f o
Article history: Accepted 11 February 2011 Keywords: Lung transplant recipients Cystic fibrosis Pulmonary rehabilitation
a b s t r a c t Background: To investigate the effect of home-based exercise training on exercise tolerance, muscle function and quality of life in lung transplant recipients (LTR). Methods: Twelve LTR and 7 age-matched healthy subjects underwent exercise training (ET, 12-wk, 3×/wk, 40 min). Peak aerobic capacity (V˙ O2peak ), endurance time (Tend ), minute ventilation (V˙ E) quadriceps strength, percentage of type I fiber (%Ifb), fiber diameters and chronic respiratory questionnaire were assessed before and after ET. A positive response to ET was defined as an improvement in Tend at least comparable to the mean change observed in healthy subjects. Results: Training significantly improved Tend (+12 ± 11 min), isowatt during exercise (−5.5 ± 2.6 L/min), muscle strength (+4.6 ± 2.6 kg) and dyspnea score (+0.6 ± 0.9) in LTR (p < 0.05), leading to recovery of Tend and muscle strength up to healthy subjects’ values. In responders (n = 6), V˙ O2peak , %Ifb and fatigue score were improved after training (p < 0.05). Non-responders had lower %Ifb and greater delay between surgery and the beginning of the study than responders (56 [21–106] vs. 8 [2–59] months respectively, p = 0.03). Conclusions: Home-based ET was effective to improve exercise tolerance, muscle strength and quality of life in LTR but more successful in patients with moderate muscle dysfunction and in the first years after transplantation. Multicenter and controlled-studies are needed to confirm the benefits and optimal modalities of home training in LTR. © 2011 Published by Elsevier B.V.
1. Introduction Lung transplantation is a recognized treatment for end-stage cardiopulmonary diseases, since it has been shown to be viable (Christie et al., 2009), to enhance survival (Hosenpud et al., 1998) and to improve quality of life (Vermuelen et al., 2007). However, despite the significant improvement in lung function, exercise capacity is still limited in these patients (Williams et al., 1990, 1992).
∗ Corresponding author at: Laboratoire REx-S, Université Joseph Fourier & Laboratoire EFCR, CHU de Grenoble, Avenue de Kimberley BP 185, 38042 Grenoble-Cedex 09, France. Tel.: +33 04 76 76 22 90; fax: +33 04 76 76 56 17. E-mail address: [email protected] (B. Wuyam). 1569-9048/$ – see front matter © 2011 Published by Elsevier B.V. doi:10.1016/j.resp.2011.02.005
Peripheral muscular deconditioning may be responsible for the low exercise tolerance in lung transplant recipients (LTR) (Miyoshi et al., 1990; Orens et al., 1995; Tirdel et al., 1998; Lands et al., 1999; Pantoja et al., 1999; Pinet et al., 2004). Although the benefits of exercise training to enhance exercise tolerance and quality of life have been clearly established in chronic heart and lung diseases (Lacasse et al., 2006; van Tol et al., 2006), pulmonary rehabilitation has been poorly investigated in LTR. To our knowledge, two previous studies have shown that supervised endurance training could enhance functional capacity, muscle strength and quality of life in the first months following the surgery (Maury et al., 2008; Munro et al., 2009). Yet, in numerous patients, exercise tolerance remains abnormally low even years after transplantation (Orens et al., 1995; Lands et al., 1999). Only one study has shown that exercise training could improve exercise capacity and ventilatory response within 6–18 months after surgery in LTR (Stiebellehner et al., 1998). The
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paucity of the literature on rehabilitation in this population may be a sign of troubles to design a controlled study on rehabilitation in the context of post transplant care and follow-up. There is however a clear interest on pulmonary rehabilitation after transplantation in LTR (Rochester, 2008). In chronic obstructive pulmonary disease (COPD) patients, Maltais et al. suggested that home-based training is an equivalent alternative to outpatient rehabilitation in patients with COPD. The authors reported similar improvements in exercise tolerance and quality of life after outpatient and home-based exercise training (Maltais et al., 2008). We thus wonder whether home-based exercise training could be a strategy to increase access to rehabilitation in LTR. In this study, we aimed at investigate the benefits of 3-month home-based endurance training in LTR. We hypothesized that, even performed at home, exercise training may improve exercise tolerance, muscle strength and quality of life in LTR. We further hypothesized that not all the patients would be able to benefit from unsupervised training at home. In a secondary objective, we thus aimed at identifying the patients who are either responders or non-responders to home-based exercise training. We distinguished the patients depending on their ability to improve exercise tolerance after training. To do that, endurance time was measured and compared to the mean change observed in a group of aged-matched healthy subjects. Differences at baseline between responders and non-responders to exercise training were studied.
patients for whom the surgery was far away from the inclusion date, we observed great variability between patients in the change in body weight during the training period (from −6 to +5 kg).
2. Methods and materials
2.3. Measurements
2.1. Subjects
2.3.1. Body composition Fat-free mass (FFM) was measured with bioelectrical impedance analysis at 50 kHz and equation from Kyle et al. was used (Kyle et al., 2003).
Procedures were approved by our institutional review board and all participants gave informed consent. Twelve lung transplant recipients (LTR) and 7 age-matched healthy subjects were recruited. All LTR had performed a 4-week inpatient rehabilitation program immediately after transplantation but none of them had performed home-based exercise training later on. Healthy subjects were included when their spontaneous physical activity did not exceed 2 h per week in the last 2 months before inclusion in the protocol. The score of physical activity as assessed by the Voorrips questionnaire tended to be lower in LTR as compared with healthy subjects (Table 2, Voorrips et al., 1991). 2.1.1. Subject characteristics The characteristics of the LTR are reported in Table 1. Three patients presented a chronic rejection before inclusion in the training program, as assessed by the presence of a bronchiolitis obliterans syndrome of grade 2, 3 and 1 in the patients with number 5, 10 and 11 respectively (Belperio et al., 2009). However, all the patients were stable at least 2 months before inclusion. The anti-rejection treatment included tacrolimus (4.2 ± 2.6 mg/day), mycophenolate mofetil (1.3 ± 0.4 g/day) and prednisone (7.7 ± 2.1 mg/day). Most patients received anti-hypertensive treatments such as calcium blockers or angiotensin converting enzyme inhibitors. No change in medications occurred over the training period. 2.1.2. Nutritional support In cystic fibrosis, the nutritional support was based on routine care, mainly including gastro-protected pancreatic extract in cases of exocrine pancreatic insufficiency and insulin therapy in cases of endocrine pancreatic failure. Furthermore, all patients received diet advices to increase energy intake to reach a minimal BMI of 19. In patients for whom the surgery was performed few months before the inclusion in the study, the body weight spontaneously increased thanks to correction of mechanical disadvantage and resolution of chronic infection and inflammation after the surgery. Inversely, in
2.2. Study design Measurements of exercise capacity and muscle function were done before and after training in all subjects. Health-related quality-of-life was also assessed in LTR using the Chronic Respiratory Questionnaire (CRQ) (Bourbeau et al., 2004). Training consisted of 3-month endurance training at home on a cycloergometer (Ergometer 900PC, Ergoline), 3 times a week for 12 weeks. Exercise consisted of cycling at 50% and progressively increasing up to 80% of previously determined peak workload (Wpeak ) for 10 min followed by 5 min at 30% Wpeak , three times per session in all subjects. The patients were directly supervised for the first sessions by a physiotherapist at home and via phone each subsequent week. For security reasons and control purposes, subjects had a cardiofrequency meter (S610i, Polar, Kempele, Finland) with memory. Every month, these monitors were downloaded to a personal computer to check that planned exercise sessions were achieved. Results after training were compared between LTR and healthy subjects and also between responders and non-responders to exercise training (ET). A positive response to ET was defined as an improvement in endurance time at least comparable to the mean change observed in healthy subjects.
2.3.2. Pulmonary function Spirometry and thoracic gas volumes were measured using Pitot pneumotachograph and pressure plethysmograph (Medical Graphics Corporation, St Paul, MN, USA), according to ATS/ERS recommendations (Miller et al., 2005). Reference values were those of Quanjer et al. (1993). 2.3.3. Skeletal muscle biopsy and muscle fibers Biopsy of Vastus Lateralis was obtained as previously described (Guerrero et al., 2005). Fibers were visually counted to determine the percentage and the mean diameter of each fiber type (Dubowitz and Brookes, 1985). Morphometric measurements were performed with Histo Biocom software (Les Ullis, France). 2.3.4. Quadriceps twitch tension measurement (Twq) Twq was performed using magnetic stimulation of the femoral nerve as previously described in our laboratory (Vivodtzev et al., 2005). Muscle strength was measured with a strain gauge tensiometer (GLOBUS, Dempo Technologies, Trevisio, Italy). Twq was accepted as the mean of 5 consecutive and reproducible trials. 2.3.5. Incremental exercise All subjects performed a progressive stepwise exercise test on a cycloergometer with breathing room, 12-lead ECG, and pulse oximetry (Vmax system 229, SensorMedics, Yorba Linda, CA, USA). After a 2-min warm-up, each exercise step lasted 1 min and workload increments of 5 and 15 W/min were used in LTR and Healthy subjects, respectively, up to the individual’s maximal capacity. The peak workload (Wpeak ) was defined as the highest exercise workload tolerated for at least 30 s. Heart rate, oxygen consumption (V˙ O2 ) and minute ventilation (V˙ E) were measured at peak exercise and at the highest equivalent exercise workload (i.e., isowatt for
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Table 1 Characteristics of the LTR. Patient
Gender
Age (years)
1 2 3 4 5 6 7 8 9 10 11 12
M M M F M F M M M M M M
37 40 47 45 47 58 38 20 70 49 57 60
Mean 10/2 SD
47 13
22 3
BMI (kg/m2 )
Diagnostic
Transplant
20 20 22 22 21 17 21 21 26 21 23 27
CF CF Histiocitosis Emphysema Emphysema PAH Emphysema CF Emphysema CF COPD IPF
DLT DLT DLT DLT DLT DLT DLT DLT SLT DLT HLT SLT
Month (post LT) 5 25 10 59 4 2 61 22 21 106 68 51
36 33
2.2 (74) 1.0 (24)
FEV1 (L, % pred.) 3.59 (100) 2.77 (73) 3.53 (91) 2.16 (100) 2.04 (58) 1.90 (75) 3.72 (100) 4.20 (104) 1.36 (51) 0.94 (25) 2.27 (71) 1.63 (54) 3.2 9.5
FVC (L) 3.7 3.7 4.0 2.8 3.2 2.0 4.3 5.0 2.0 2.5 2.9 2.3
FEV1 /FVC (%) 96 74 88 79 63 95 87 84 70 37 77 70
77 16
Abbreviations: BMI, body mass index; CF, cystic fibrosis; COPD, chronic obstructive pulmonary disease; PAH, pulmonary arterial hypertension; IPF, idiopathic pulmonary fibrosis; DLT, double lung transplantation; SLT, single lung transplantation; HLT, heart lung transplantation; FEV1 , forced expiratory volume in 1 s; FVC, forced vital capacity. Table 2 Anthropometric characteristics, exercise capacity and muscle function of all the subjects at baseline.
Anthropometric Male/female sex, No Age (years) BMI (kg/m2 ) FFM (kg) FFMindex Voorrips Score (physical activity) Exercise capacity Wpeak V˙ O2peak , L (% predicted) V˙ O2 peak
V˙ Epeak (L/min) V˙ Epeak (% MVV) Dyspnea score Leg fatigue score Endurance time 65% Wpeak (min) V˙ ECET (end of test), % MVV V˙ ECET (end of test), %V˙ Epeak Muscle function Muscle force (Twq, kg) Muscle fatigue (Fall in Twq after CET, % baseline) Type I Fiber (%) Type II Fiber (%) Type I Fiber diameter (m) Type II Fiber diameter (m)
Healthyn = 7
LTR n = 12
p
7/0 44 ± 11 25 ± 3 56 ± 6 31 ± 4 13.8 ± 2.3
10/2 47 ± 13 22 ± 3* 46 ± 6* 27 ± 3* 11.7 ± 2.3
0.27 0.57 0.05 0.005 0.05 0.07
195 ± 32 2.5 ± 0.4
85 ± 43* 1.2 ± 0.5*
<0.0001 <0.0001
94 ± 12
63 ± 20*
0.001
87.7 ± 18.3 58 ± 10 5.6 ± 1.0 6.0 ± 1.8 27 ± 9 23 ± 16 92 ± 7
55.4 ± 19.9* 66 ± 19 5.8 ± 2.7 7.0 ± 1.3 18 ± 10 43 ± 27 85 ± 15
0.002 0.35 0.79 0.20 0.08 0.07 0.31
10.5 ± 4.6 86 ± 27 34 ± 12 66 ± 12 60.6 ± 7.3 60.4 ± 5.8
5.4 ± 3.2* 110 ± 58 16 ± 6* 84 ± 6* 60.5 ± 12.9 58.3 ± 14.6
0.02 0.33 0.0006 0.001 0.99 0.71
Data are mean ± SD. Abbreviations: BMI, body mass index; FFM, fat free mass. Wpeak , peak workload; V˙ O2peak , peak oxygen consumption; CET, constant-workload exercise test; V˙ E, minute ventilation, MVV, maximal voluntary ventilation; Twq, quadriceps twitch tension. The score of physical activity was assessed using the Voorrips questionnaire. End-of-test dyspnea and leg fatigue were assessed using a visual analogic scale (ranging from 0 = minimal score to 10 = maximal score). * Significantly different from healthy.
each patient) (V˙ Eisowatt ). Dyspnea and leg discomfort were assessed using modified Borg scales graduated from 0 (no leg discomfort or dyspnea) to 10 (maximal dyspnea or leg discomfort) (Borg, 1982). 2.3.6. Constant-workload exercise test (CET) Patients performed a constant-workload exercise test (CET) at 65% Wpeak and 60–70 rpm speed up to exhaustion (endurance time). Heart rate, oxygen consumption and minute ventilation (V˙ ECET ) were measured all along the test. 2.4. Statistical analysis All data are expressed as mean ± SD (standard deviation). The level of significance for all tests was set at p < 0.05. The normality was checked with the omnibus test. To assess the effect of training in LTR, the pre-training values were compared to the post-training
values using paired Student’s t-test for all the variables of exercise capacity, muscle function and quality of life. Differences at baseline or after training between LTR and healthy subjects were assessed using unpaired Student’s t-test. Changes in ventilation during CET were analyzed using a two-way ANOVA with repeated-measures for the two groups. Correlations between continuous variables and changes after training were made using simple regressions with Pearson’s correlation coefficient. Correcting factors were applied using stepwise and multiple regression analysis. The comparison of the subgroups of LTR (responders vs. non-responders) was done at baseline and after training using unpaired Student’s t-test for all the variables of anthropometry, the number of months between surgery and initial testing, exercise capacity, muscle function and quality of life. The comparison in muscle strength and percentage of type I fiber between healthy subjects, responders and nonresponders was done using one-way ANOVA analysis (Statview 5.0).
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3. Results 3.1. Patients studied
3.2. Effect of training All the patients have completed the training program. The monitor of cardiofrequency meter reported that patients have completed 39 ± 10 sessions of 33 ± 10 min with a mean intensity of 68 ± .29% of the initial maximal workload during 3 months. Intensity corresponded to a mean HR of 83 ± .10% of maximal HR achieved during initial incremental exercise test. There was no significant difference between the 2 subgroups of LTR patients in any of these parameters. After training, no significant change was observed in pulmonary function or FFM in LTR. 3.2.1. Exercise capacity Exercise capacity and endurance time to constant-workload exercise test (CET) are reported on Fig. 1. After exercise training (ET), peak oxygen consumption (V˙ O2peak ) was significantly improved in healthy subjects and a trend to improvement was observed in LTR (+0.13 ± 0.22, p = 0.059, Fig. 1A). Endurance time was improved after ET in LTR to the same extent than in healthy subjects but with greater variability between patients (+9 ± 12 min vs. +8 ± 6 min in LTR and healthy subjects, respectively, Fig. 1B). 3.2.2. Ventilatory response to exercise Resting V˙ E and V˙ Epeak did not change after ET in both groups but there was a significant reduction in V˙ Eisowatt when expressed as % peak value in LTR (81 ± 15% vs. 94 ± 8% V˙ Epeak , after vs. before ET, respectively, p = 0.02), similarly to the change observed in healthy subjects (Fig. 2A). During CET, V˙ ECET was significantly reduced after ET in LTR (35.7 ± 4.6 L/min vs. 41.2 ± 7.1 L/min, after v. before training, respectively, p = 0.04) as well as in healthy subjects (51.2 ± 9.3 L/min vs. 65.3 ± 11.4 L/min, after vs. before training, respectively, p = 0.03, Fig. 2B). Furthermore, isowatt and endurance VCO2 were significantly reduced after training in LTR (−0.13 ± 0.16
VO2peak (L/min)
.
†
A *
3.5 3.0 2.5
p = 0.06
2.0 1.5 1.0 0.5 0.0
Healthy
LTR
Before training After training 50
Endurance time to CET (min)
Anthropometrics and pulmonary function in LTR are shown in Table 1. FEV1 forced expiratory volume in 1 s was under normal value at 74 ± 24% of predicted value. Two patients (patients 9 and 12) had a single lung transplantation and showed moderate obstruction after transplantation. Two double lung transplant patients (patients 5 and 10), one HLT (patient 11) showed also moderate to severe obstruction pattern because of chronic dysfunction. A comparison of LTR and healthy subjects in anthropometrics, exercise capacity and muscle function at baseline is presented in Table 2. Body mass index (BMI) fat free mass (FFM) and FFM index were lower in LTR than in healthy (p < 0.05). As expected, Wpeak , V˙ O2peak , muscle strength (Twq) and the percentage of type I fiber were lower in LTR than healthy subjects. However, the endurance time only tended to be lower in LTR than healthy and the diameter of quadriceps fibers were similar in the two groups. Although V˙ Epeak in raw value was lower in LTR than healthy, it was not significantly different when expressed in %MVV (maximal voluntary ventilation). Furthermore, as assessed by V˙ Epeak when expressed in %MVV and by V˙ ECET when expressed in % V˙ Epeak , maximal ventilatory capacity was not reached during maximal and endurance tests suggesting that there were no ventilatory limits during exercise in both groups. Finally, using the Voorrips’ questionnaire for assessment of physical activity, we reported a trend to significant lower daily physical activity in LTR as compared with healthy subjects. More precise assessment using accelerometer would probably help to better discriminate those 2 groups.
4.0
Before training After training
p = 0.08
B
*
*
40
30
20
10
0
Healthy
LTR
Fig. 1. Effect of exercise training on peak oxygen consumption (V˙ O2peak ) (A) and endurance time during constant-workload exercise test (CET) at 65% Wpeak (B), in healthy and LTR. *Significantly different from baseline (p < 0.05). † Significantly different from healthy (p ≤ 0.02).
and −0.15 ± 0.15 mL, respectively, p < 0.05) although FE CO2 was unchanged during both tests. 3.2.3. Muscle function After training, muscle strength (Twq) was significantly improved in LTR to the same extent than healthy subjects (+4.6 ± 2.6 kg in LTR, p = 0.001 and +3.1 ± 3.6 kg in healthy, p = 0.047, Fig. 3A), leading to a recovery of muscle strength as compared with initial healthy subjects’ value. Concerning quadriceps muscle fibers, we observed trends to significant changes in the percentage of type
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Before training After training
*
A
25
*
Before training After training
†
A
*
.
20
Twq (kg)
.
VE isowatt (%VEpeak)
100
80
60
* 15
10
5
40
Healthy
LTR
B
*
Healthy
.
LTR
Healthy VEpeak
80
.
LTR VEpeak
60
Type I fiber before training Type I fiber after training Type II fiber before training Type II fiber after training
100
B 40
Healthy-pre ET Healthy post ET LTR-pre ET LTR-post ET
20
* 0 0
5
10
15
20
25
30
35
Time (min) Fig. 2. Effect of exercise training on minute ventilation at identical workload (V˙ Eisowatt ) during incremental cycle exercise when expressed in percentage of V˙ Epeak , in healthy and LTR (A) and on V˙ E as a function of time during CET (B), in healthy and LTR. Comparisons of ventilation measurements were made from 1 to 25 min in healthy and from 1 to 15 min in LTR, in order to have the maximal number of subjects in the analysis. Dashed lines correspond to maximal ventilation achieved during incremental exercise, in LTR (bottom line) and healthy subjects (top line). *Significantly different from baseline (p < 0.05).
Percentage of fiber type
.
VE during CET at 65% Wpeak (L/min)
0 100
*
80 p = 0.10
60
40
20
0
Healthy
LTR
Fig. 3. Effect of exercise training on quadriceps twitch tension (Twq) (A) and on the distribution of quadriceps muscle fiber type (B) in healthy and LTR. After training, Twq was significantly improved in both groups. *Significantly different from baseline (p < 0.05). † Significantly different from healthy (p < 0.02).
I fiber (+7% from −9 to +44%, p = 0.10, Fig. 3B) and the type II fiber diameter (−3 from −14 to +3 m, p = 0.10), in LTR. 3.2.4. Health-related quality of life After ET, a statistically and clinically (Bourbeau et al., 2004) significant improvement was observed in the dyspnea score in LTR (+0.6 ± 0.9 points, p = 0.03, Table 3). No significant changes were observed after ET in other domains but a trend to improvement in the fatigue domain (+0.5 ± 1.0 points, p = 0.07). 3.2.5. Factors of change in endurance time to CET in LTR Correlation coefficients between changes in endurance time and changes in independent variables in LTR are reported in Table 4 (univariate analysis). Using multiple regression analysis including all variables that significantly correlated with changes in endurance time in univariate analyses, changes in V˙ Eisowatt and changes in type II fiber diameter were independent factors of changes in endurance time (r = 0.93, p = 0.0003). 3.3. Responder vs. non responders to ET Responders and non-responders to ET were distinguished depending on their improvement in endurance time after ET. Six
patients improved endurance time to the same extent or even higher than healthy subjects and were considered as responders to ET as displayed in Fig. 4. After ET, responders had higher improvements than non-responders in V˙ O2peak (+0.25 ± 0.19 L/min vs. −0.01 ± 0.17 L/min, p = 0.04), V˙ Eisowatt (−27 ± 13% vs. +1 ± 17% V˙ Epeak , p = 0.009) and in type II fiber diameter (+0.8 ± 1.7 m vs.
−8.2 ± 5.8 m, p = 0.005), in responders vs. non-responders, respectively. Furthermore, within-group improvements were observed in responders in the percentage of type I fiber (+8 ± 10%, p = 0.02) and in the fatigue domain of CRQ with clinical significance (+0.8 ± 0.5 points, p = 0.01). Differences at baseline between responders and nonresponders, as well as adherence to the training program in both groups are presented in Table 5. Pulmonary function, exercise capacity and muscle strength were similar in both groups, despite differences in lung transplantation procedures used within patients. The medication doses and the number of acute rejections were also quite similar although in both groups a trend to significant higher 2nd year prednisone dose in non-responders vs. responders to training (7.6 ± 0.2 mg/day vs. 6.4 ± 1.8 mg/day, respectively, p = 0.10). Patients had similar exercise capacity and
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Table 3 Chronic Respiratory Questionnaire domain score differences from baseline to post training* . Variable
Baseline
Dyspnea Mastery Fatigue Emotion
3.6 4.4 4.5 5.6
± ± ± ±
After training
1.5 1.3 1.4 1.2
4.2 4.9 4.8 5.7
± ± ± ±
1.2 1.5 1.2 1.2
Differences from baseline (95% CI)
p-Value
+0.6 ± (−1.6 to 1.8)† +0.3 (−1.3 to 1.9) +0.5 (−1.8 to 2.0) +0.3 (−2.0 to 6.0)
0.03 0.22 0.07 0.65
* Data are means and 95% CIs. A positive difference is interpreted as an improvement. For each of the 4 Chronic Respiratory Questionnaire domains (dyspnea, mastery, fatigue, and emotion), the scores represent changes in mean score per question on a 4 to 7-point scale. A difference greater than 0.5 (improvement) or less than −0.5 (deterioration) is considered clinically important. † Significantly different from baseline.
Table 4 Correlation coefficients of changes in endurance time and changes in independent variables in LTR (univariate analysis). Variables Pulmonary function FEV1 (L) Aerobic capacity Wpeak (W) V˙ O2peak (L) HRpeak (bpm) V˙ Epeak (L/min) V˙ Eisowatt (% V˙ Epeak ) Limb muscle function Type I fiber (%) Type II fiber diameter Type II fiber diameter Twq (kg)
r
after training in LTR (r = 0.64, p = 0.02, n = 12) and this relation was even stronger in the subgroup of non-responders (r = 0.90, p = 0.01, n = 6).
p 0.16
0.71* 0.64* 0.37 0.54 −0.83* 0.09 0.09 0.76* 0.24
0.60 0.008 0.02 0.23 0.06 0.0008 0.78 0.78 0.005 0.55
Abbreviations: FEV1 , forced expiratory volume in one second; Wpeak , peak workload; V˙ O2peak , peak oxygen consumption; HR, heart rate; V˙ E, minute ventilation; Twq, quadriceps twitch tension. * Significantly related to changes in endurance time.
4. Discussion The main result of this study is that 3-month endurance training could improve endurance time, muscle strength and quality of life in LTR in a home based setting. Changes in endurance time were independently associated with a decrease in minute ventilation during exercise and an increase in type II fibers diameter. Furthermore, half of the patients improved endurance time to the same absolute extent than age-matched healthy subjects after training, and they significantly improved peak oxygen consumption and percentage of type I fiber after training. LTR with moderate muscle dysfunction and in early post-transplantation period (<2 years after transplantation) appear as good responders to home-based endurance training. 4.1. Benefits of training
Fig. 4. Individuals and mean values of endurance time to CET measured before and after training in healthy subjects (left of the panel) and in LTR (right of the panel). When distinguished as responders and non-responders to ET (improvement in endurance time > 40% of initial value). Significantly different from baseline (p < 0.03).
endurance and they trained with a similar regularity. HR measured during the training sessions was lower in non-responders as compared with responders when expressed in raw data. However, HR during training was not significantly different between groups when reported in percentage of the peak HR achieved during incremental test, suggesting that the all patients trained at similar relative intensity of training. On the contrary, non-responders had greater delay between surgery and the beginning of the study. Furthermore, as can be seen in Fig. 5, the muscle strength and the percentage of quadriceps type I fiber were significantly different between healthy subjects, responders and non-responders. Non-responders had lower muscle strength and percentage of type I fiber than responders. Finally, changes after training in body mass index was significantly related to those in endurance time
We observed significant and similar improvements in endurance time during constant-workload exercise test (CET) in both LTR and age-matched healthy subjects. Interestingly, we could show that patients regained comparable values of endurance time after training to controls (Fig. 1B). Previous studies have shown that a rehabilitation program completed immediately following transplantation could improve exercise tolerance in LTR (Maury et al., 2008; Munro et al., 2009). In addition, when performing within 6–18 months of surgery and supervised by a physician at least 3 out of the 6 weeks of training. endurance training could improve submaximal and peak exercise performance in LTR and reduce ventilation during exercise (Stiebellehner et al., 1998). In the present study, we also found a trend to significant improvement in peak aerobic capacity in LTR, although we found great variability between patients (+16 ± 25%, p = 0.059, Fig. 1A). Furthermore, minute ventilation was reduced at maximal level during incremental exercise (V˙ Eisowatt ), and at submaximal level during CET (V˙ ECET , Fig. 2). Changes in V˙ Eisowatt were independently related to the changes in endurance time (Table 4), suggesting that the reduction in ventilation during exercise may be one possible mechanism of improvement in endurance time in spite of the alleviation of the mechanical constraints to breathing after transplantation. Furthermore, as suggested by the reduction in isowatt and endurance VCO2 in LTR associated with a stable FE CO2 , the lower ventilation measured during exercise may result from lower metabolic production during exercise after training and probably due to lower use of glycolytic pathway (Wasserman et al., 1967) and a better oxidative phosphorylation (Guerrero et al., 2005). Thus, the present study suggested that even entirely performed at home, ET may improve exercise tolerance and probably in association with an improvement in ventilation requirement during exercise.
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Table 5 Characteristics of responders and non-responders to ET at baseline.
Preoperative diagnosis Emphysema Cystic fibrosis Pulmonary hypertension Histiocytose X Interstitial pulmonary Fibrosis Type of procedure Double lung Single lung Heart and lung Time from transplant to initial assessment Acute rejections before inclusion Medication Tacrolimus 1st year dose (mg/day/kg body weight) Tacrolimus 2nd year dose (mg/day/kg body weight) Mycophenolate mofetil 1st year dose (g/day) Mycophenolate mofetil 2nd year dose (g/day) Prednisone 1st year dose (mg/day) Prednisone 2nd year dose (mg/day) Anthropometric Male/Female sex, No Age (years) BMI (kg/m2 ) FFM (kg) Pulmonary function FEV1 (L) FEV1 (% predicted) FVC (% predicted) FEV1 /FVC (%) Exercise capacity Wpeak (W) V˙ O2peak (% pred) HR peak (% pred) RR Endurance time at 65% Wpeak V˙ Epeak (L/min) Muscle function Muscle force (Twq, kg) Type I fiber (%) Type I fiber diameter (m) Type II fiber diameter (m) Training parameters Number of sessions Mean duration of session (min) Mean intensity of cycling (W) Mean intensity of cycling (% Wpeak ) Mean HR during cycling (HR) Mean HR during cycling (% HRpeak )
Respondersn = 6
Non respondersn = 6
p
2 2 1 1 0
3 2 0 0 1
6 0 0 18 ± 22 0.3 ± 0.4
3 2 1 55 ± 32* 0.5 ± 0.4
0.03 0.51
0.11 ± 0.02 0.11 ± 0.02 4.0 ± 1.0 2.0 ± 1.4 1.6 ± 0.3 1.25 ± 0.35
0.15 ± 0.06 0.12 ± 0.01 5.4 ± 3.4 4.8 ± 3.4 2.0 ± 0.6 1.6 ± 0.4
0.38 0.55 0.52 0.33 0.41 0.35
4/2 46 ± 7 20 ± 2 45 ± 8
6/0 49 ± 18 23 ± 3* 48 ± 2
0.68 0.05 0.36
2.7 ± 0.7 80 ± 15 3.2 ± 0.8 82 ± 11
2.4 ± 1.3 68 ± 31 3.2 ± 1.2 70 ± 18
0.62 0.39 0.90 0.22
85 ± 40 66 ± 14 80 ± 11 1.11 ± 0.9 19 ± 10 54 ± 16
86 ± 50 60 ± 27 73 ± 9 1.10 ± 0.1 18 ± 10 57 ± 25
0.97 0.63 0.31 0.79 0.94 0.77
6.6 ± 2.5 20 ± 6 57 ± 12 49 ± 6
3.2 ± 3.4 12 ± 4* 64 ± 14 69 ± 14*
0.15 0.02 0.39 0.01
38 ± 6 33 ± 4 54 ± 18 73 ± 38 121 ± 10 85 ± 9
41 ± 13 33 ± 15 48 ± 21 62 ± 19 104 ± 10* 81 ± 14
0.67 0.89 0.61 0.54 0.02 0.62
Data are mean ± SD. Abbreviations: BMI, body mass index; FFM, fat free mass; FEV1 , forced expiratory volume in one second; FVC, forced vital capacity. Wpeak , peak workload; V˙ O2peak , peak oxygen consumption; HR, heart rate; RR, respiratory ratio; CET, constant-workload exercise test; V˙ E, minute ventilation; Twq, quadriceps twitch tension. *
Significantly different from responders.
An important factor of exercise intolerance in LTR is muscle dysfunction, mainly due to acquired deconditioning before transplantation (Lands et al., 1999; Pantoja et al., 1999; Pinet et al., 2004) as well as inactivity associated with the perioperative period (Rochester, 2008). The improvement in twitch tension measured in this study suggest that ET could improve muscle strength in LTR (nearly twice the initial value), regaining normal value of muscle strength as compared with sedentary age-matched healthy subjects (Fig. 3A), confirming the previous observation of Maury et al. (2008) when rehabilitation was completed immediately after surgery in LTR. Such an improvement in muscle strength without significant improvement in FFM may be a surprising result however. A first explanation of this result is that FFM is a global measure and a selective measurement of mid-thigh cross sectional area would have probably been more sensible to training (Bernard et al., 1999). Nevertheless changes in FFM was not correlated to those in twitch tension suggesting that, in this study, changes in twitch tension were maybe mainly associated to neuromuscular adaptation
such as excitation contraction coupling (Millet and Lepers, 2004) rather than hypertrophy. Moreover, we found trends to significant change in percentage of type I fiber (Fig. 3B) and in type II fiber diameter in LTR. However, muscle typology and morphology did not change in healthy subjects either, suggesting that great modifications in fiber size or in the number of fibers could not be expected in LTR. Nevertheless, the changes in type II fiber diameter were positively and independently associated with changes in endurance time (Table 4), suggesting that changes at the peripheral level (muscle function) could have influenced changes at general level (exercise tolerance) in LTR. The understanding of the mechanism may be debated however, considering that we did not distinguished the type IIa from the type IIx fiber. We could only hypothesize that training had induced an improvement in type IIa diameter in certain patients in whom endurance time was also increased after training (Andersen and Henriksson, 1977), although it deserves to be confirmed. Alternatively, we have shown previously that, besides muscle fibers
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Healthy subjects LTR - Responders LTR - Non-responders
Healthy subjects LTR - Responders LTR - Non-responders 16
*
50
14
*
*
40
12
30
%
Kg
10 8
20 6 4
10
2
0
0
Twq
Type I fiber
Fig. 5. Mean value of quadriceps twitch tension (Twq) and percentage of type I fiber at baseline in healthy subjects, responders LTR and non-responders LTR. Twq and percentage type I fiber were significantly different between the 3 groups (ANOVA p = 0.04 and p = 0.001, respectively). *Significantly different from healthy subjects (p ≤ 0.01).
typology, ET could result in changes in the system cellular level properties within the Intra Cellular Energy Units resulting in a better functional coupling between adenine nucleotide translocase and mitochondrial creatine kinases (Guerrero et al., 2005). Mechanisms behind the interplays between control on ventilation and skeletal muscles changes after ET remain to be unraveled in a systems biology approach. In spite of increasing survival after transplantation, exercise tolerance is still reduced in LTR (Hosenpud et al., 1998; Orens et al., 1995) and the quality of life is another important question in these patients. As assessed by the chronic respiratory questionnaire, ET could significantly reduce dyspnea in daily tasks and had a tendency to reduce fatigue in LTR (Table 3). Munro et al. (2009) have already shown that ET could improve all the domains of the SF36 questionnaire in the months following surgery. We thus suggested that ET could help in improving quality of life even years after transplantation.
abnormal nutritional status associated with body loss are likely less responder to home-based ET. Previous studies have shown that mycophenolate mofetil could influence muscle mass regulation (Hopkins and McNeil, 2008). Whether longer duration of medication intake such as corticoid, tacrolimus or also mycophenolate mofetil may be responsible for higher muscular alteration in those long-term LTR deserves to be investigated. New active behaviors early after transplantation should additionally be promoted to a greater extent. Finally, it cannot be excluded that a 10% lower training intensity had contributed to induce lower physiological benefit after training in non-responders (Maltais et al., 1997) (Table 5). Whether incentre rehabilitation programs prior to home-based training could be a useful strategy to increase to potential of training at higher intensity in certain patients deserve to be investigated.
4.2. Responders vs. non responders to ET
The present study is the first study to investigate the effect of home-based exercise training on exercise tolerance, muscle function and quality in lung transplant recipients. One strength of this study is the concomitant investigation of exercise tolerance (during incremental exercise and CET) and muscle function (as assessed by muscle strength and muscle typology and morphometry) with possible comparisons with sedentary age-matched healthy subjects. We nevertheless acknowledge that the sample size is small that we did not include a LTR control group without rehabilitation. We concede that LTR patient profile was wide and that co morbidities could have impacted on the high variability of the data. However, we did not report significant differences between groups when comparing the benefit of training in subgroup of patients with CF, emphysema and cystic fibrosis. Furthermore, the benefits of exercise training vs. normal daily activity have already been demonstrated in LTR (Stiebellehner et al., 1998). In this study, we wished to emphasize the comparison between LTR and healthy subjects in muscle function in atypical design study (muscle strengths measured using magnetic stimulation of femoral nerve and expected changes in typology and morphometry of quadriceps fibers after intermittent endurance training). One other possible limitation of this study is that we had included 3 patients < 6 month after transplantation which may have positively influenced the effect of training, due to natural
The second objective of this study was to investigate whether all the patients had actually benefited from home-based ET. Although there was no significant difference between the 2 subgroups in the adherence of training (Table 5), six out of the 12 patients had improved endurance time to the same extent than healthy subjects that was +39% of baseline value (Fig. 1) and were considered as responder to ET (Fig. 4). Responders significantly improved peak oxygen consumption and percentage of type I fiber after training, although both remained lower than baseline healthy values. Inversely, non-responders did not improve any of the parameters of exercise tolerance. Non-responders had initially a greater delay between surgery and initial testing than responders (Table 5) with significant lower muscle strength and percentage of type I fiber as compared with responders and healthy subjects (Fig. 5). Furthermore, the correlation between changes in body mass index and those in endurance time after training would suggest that maintain of body weight is a condition of well response to endurance training in LTR. On the contrary, a loss of body weight which is more often observed several years after transplantation can be an obstacle in progressing during exercise training in these patients. Those results suggested that very weak patients, those with lower type I fibers and/or long time after transplantation and/or patients with
4.3. Study limitations
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recovery after transplantation (Williams et al., 1990). However, it is doubtful that it would have constituted a bias in this study because there were no differences in the subgroup of responders between the patients including in the study <6 month vs. patients including >6 month after transplantation in peak exercise, ventilation during exercise, muscles strength or percentage of type I fiber and fiber diameter. Furthermore, there was no significant relation between baseline FEV1 or change in FEV1 after training and changes in ventilation during exercise in LTR. 4.4. Conclusion and clinical relevance Home-based cycle endurance training may be an useful alternative of in-setting pulmonary rehabilitation to improve exercise tolerance, muscle strength and quality of life in LTR. LTR with moderate muscle dysfunction are better responders to home-based programs than patients with very weak muscle function. Considering its direct impact on daily habits, home-based training may be an interesting avenue to improve the access of rehabilitation by offering different rehabilitation settings than hospital-based ones and probably in the first years after transplantation. Further multicenter and controlled-studies are necessary to confirm the safety and the benefit of home-based exercise training in LTR. Funding Grants from Conseil Scientifique of Association Nationale de Traitement à Domicile Innovation et Recherche, Conseil Scientifique of AGIR-à-dom, «Délégation à la Recherche Clinique du Centre Hospitalier Universitaire de Grenoble», awarded to Dr Bernard Wuyam. Centre d’Investigation Clinique, Inserm, CHU Grenoble, and, «Programme Interdisciplinaire Complexité du Vivant et Action STIC-Inserm» awarded to Pr Christophe Pison, Bourse «André Dion» (ATRIR) awarded to Dr Isabelle Vivodtzev. Conflict of interest statement Mrs Isabelle Vivodtzev has no conflict of interest to disclose. Pr Christophe Pison has conflicts of interest to disclose: he received honorarium from Astellas, Novartis and Roche companies. The study sponsors had no involvement in the collection, analysis and interpretation of data, in the writing of the manuscript and in the decision to submit the manuscript for publication. The authors Karen Guerrero, Paulette Mezin, Elisabeth Maclet, Jean-Christian Borel, Phillipe Chaffanjon, Rachid Hacini, Olivier Chavanon, Dominique Blin, and Bernard Wuyam have no conflict of interest to disclose. Acknowledgements The authors are grateful to the scientific council of AGIR-à-dom (Meylan, France) for its financial support to this study and for the management of the rehabilitation program. The authors are also grateful to Mr Patrice Flore for scientific advices and to Mrs Chrystèle Deschaux for statistical advices. References Andersen, P., Henriksson, J., 1977. Training induced changes in the subgroups of human type II skeletal muscle fibres. Acta Physiol. Scand. 99, 123–125. Belperio, J.A., Weigt, S.S., Fishbein, M.C., Lynch, J.P., 2009. Chronic lung allograft rejection: mechanisms and therapy. Proc. Am. Thorac. Soc. 6, 108–121. Bernard, S., Whittom, F., Leblanc, P., Jobin, J., Belleau, R., Berube, C., Carrier, G., Maltais, F., 1999. Aerobic and strength training in patients with chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 159, 896–901. Borg, G.A., 1982. Psychophysical bases of perceived exertion. Med. Sci. Sports Exerc. 14, 377–381.
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Bourbeau, J., Maltais, F., Rouleau, M., Guimont, C., 2004. French-Canadian version of the Chronic Respiratory and St George’s Respiratory questionnaires: an assessment of their psychometric properties in patients with chronic obstructive pulmonary disease. Can. Resp. J. 11, 480–486. Christie, J.D., Edwards, L.B., Aurora, P., Dobbels, F., Kirk, R., Rahmel, A.O., Stehlik, J., Taylor, D.O., Kucheryavaya, A.Y., Hertz, M.I., 2009. The registry of the international society for heart and lung transplantation: twenty-sixth official adult lung and heart-lung transplantation Report-2009. J. Heart Lung Transpl. 28, 1031–1049. Dubowitz, V., Brookes, G., 1985. Muscle Biopsy: A Practical Approach, 2nd ed. Bailliere Tindall, London. Guerrero, K., Wuyam, B., Mezin, P., Vivodtzev, I., Vendelin, M., Borel, J.C., Hacini, R., Chavanon, O., Imbeaud, S., Saks, V., Pison, C., 2005. 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Maury, G., Langer, D., Verleden, G., Dupont, L., Gosselink, R., Decramer, M., Troosters, T., 2008. Skeletal muscle force and functional exercise tolerance before and after lung transplantation: a cohort study. Am. J. Transpl. 8, 1275–1281. Miller, M.R., Crapo, R., Hankinson, J., Brusasco, V., Burgos, F., Casaburi, R., Coates, A., Enright, P., van der Grinten, C.P., Gustafsson, P., Jensen, R., Johnson, D.C., MacIntyre, N., McKay, R., Navajas, D., Pedersen, O.F., Pellegrino, R., Viegi, G., Wanger, J., 2005. General considerations for lung function testing. Eur. Respir. J. 26, 153–161. Millet, G.Y., Lepers, R., 2004. Alterations of neuromuscular function after prolonged running, cycling and skiing exercises. Sports Med. 34, 105–116. Miyoshi, S., Trulock, E.P., Schaefers, H.J., Hsieh, C.M., Patterson, G.A., Cooper, J.D., 1990. Cardiopulmonary exercise testing after single and double lung transplantation. Chest 97, 1130–1136. Munro, P.E., Holland, A.E., Bailey, M., Button, B.M., Snell, G.I., 2009. Pulmonary rehabilitation following lung transplantation. Transpl. Proc. 41, 292–295. Orens, J.B., Becker, F.S., Lynch 3rd, J.P., Christensen, P.J., Deeb, G.M., Martinez, F.J., 1995. Cardiopulmonary exercise testing following allogeneic lung transplantation for different underlying disease states. Chest 107, 144–149. Pantoja, J.G., Andrade, F.H., Stoki, D.S., Frost, A.E., Eschenbacher, W.L., Reid, M.B., 1999. Respiratory and limb muscle function in lung allograft recipients. Am. J. Respir. Crit. Care Med. 160, 1205–1211. Pinet, C., Scillia, P., Cassart, M., Lamotte, M., Knoop, C., Melot, C., Estenne, M., 2004. Preferential reduction of quadriceps over respiratory muscle strength and bulk after lung transplantation for cystic fibrosis. Thorax 59, 783–789. Quanjer, P.H., Tammeling, G.J., Cotes, J.E., Pedersen, O.F., Peslin, R., Yernault, J.C., 1993. Lung volumes and forced ventilatory flows. 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Benefits of home-based endurance training in lung transplant recipients Isabelle Vivodtzev a,h , Christophe Pison b,c , Karen Guerrero b,d , Paulette Mezin e , Elisabeth Maclet c , Jean-Christian Borel a , Phillipe Chaffanjon f , Rachid Hacini g , Olivier Chavanon g , Dominique Blin g , Bernard Wuyam a,h,∗ a
Inserm U1042, HP2 Laboratory, Joseph Fourier University, 38043 Grenoble, France Inserm U884, Université Joseph Fourier, Laboratoire de Bioénergétique Fondamentale et Appliquée, 2280 rue de La Piscine, 38400 Saint-Martin d’Hères, France CHU de Grenoble, Clinique de Pneumologie, BP217, 38043, Grenoble, France d Inserm U803 - CHU de Grenoble, Centre d’Investigation Clinique – Innovation Technologique, France e CHU de Grenoble, Département d’Anatomie et de Cytologie Pathologique, BP217, 38043, Grenoble, France f CHU de Grenoble, Clinique de Chirurgie Thoracique et Vasculaire, BP217, 38043, Grenoble, France g CHU de Grenoble, Clinique de Chirurgie Cardiaque, BP217, 38043, Grenoble, France h CHU de Grenoble, Pole Physiologie Rééducation, Clinique de Physiologie, Sommeil & Exercice, BP217, 38043, Grenoble, France b c
a r t i c l e
i n f o
Article history: Accepted 11 February 2011 Keywords: Lung transplant recipients Cystic fibrosis Pulmonary rehabilitation
a b s t r a c t Background: To investigate the effect of home-based exercise training on exercise tolerance, muscle function and quality of life in lung transplant recipients (LTR). Methods: Twelve LTR and 7 age-matched healthy subjects underwent exercise training (ET, 12-wk, 3×/wk, 40 min). Peak aerobic capacity (V˙ O2peak ), endurance time (Tend ), minute ventilation (V˙ E) quadriceps strength, percentage of type I fiber (%Ifb), fiber diameters and chronic respiratory questionnaire were assessed before and after ET. A positive response to ET was defined as an improvement in Tend at least comparable to the mean change observed in healthy subjects. Results: Training significantly improved Tend (+12 ± 11 min), isowatt during exercise (−5.5 ± 2.6 L/min), muscle strength (+4.6 ± 2.6 kg) and dyspnea score (+0.6 ± 0.9) in LTR (p < 0.05), leading to recovery of Tend and muscle strength up to healthy subjects’ values. In responders (n = 6), V˙ O2peak , %Ifb and fatigue score were improved after training (p < 0.05). Non-responders had lower %Ifb and greater delay between surgery and the beginning of the study than responders (56 [21–106] vs. 8 [2–59] months respectively, p = 0.03). Conclusions: Home-based ET was effective to improve exercise tolerance, muscle strength and quality of life in LTR but more successful in patients with moderate muscle dysfunction and in the first years after transplantation. Multicenter and controlled-studies are needed to confirm the benefits and optimal modalities of home training in LTR. © 2011 Published by Elsevier B.V.
1. Introduction Lung transplantation is a recognized treatment for end-stage cardiopulmonary diseases, since it has been shown to be viable (Christie et al., 2009), to enhance survival (Hosenpud et al., 1998) and to improve quality of life (Vermuelen et al., 2007). However, despite the significant improvement in lung function, exercise capacity is still limited in these patients (Williams et al., 1990, 1992).
∗ Corresponding author at: Laboratoire REx-S, Université Joseph Fourier & Laboratoire EFCR, CHU de Grenoble, Avenue de Kimberley BP 185, 38042 Grenoble-Cedex 09, France. Tel.: +33 04 76 76 22 90; fax: +33 04 76 76 56 17. E-mail address: [email protected] (B. Wuyam). 1569-9048/$ – see front matter © 2011 Published by Elsevier B.V. doi:10.1016/j.resp.2011.02.005
Peripheral muscular deconditioning may be responsible for the low exercise tolerance in lung transplant recipients (LTR) (Miyoshi et al., 1990; Orens et al., 1995; Tirdel et al., 1998; Lands et al., 1999; Pantoja et al., 1999; Pinet et al., 2004). Although the benefits of exercise training to enhance exercise tolerance and quality of life have been clearly established in chronic heart and lung diseases (Lacasse et al., 2006; van Tol et al., 2006), pulmonary rehabilitation has been poorly investigated in LTR. To our knowledge, two previous studies have shown that supervised endurance training could enhance functional capacity, muscle strength and quality of life in the first months following the surgery (Maury et al., 2008; Munro et al., 2009). Yet, in numerous patients, exercise tolerance remains abnormally low even years after transplantation (Orens et al., 1995; Lands et al., 1999). Only one study has shown that exercise training could improve exercise capacity and ventilatory response within 6–18 months after surgery in LTR (Stiebellehner et al., 1998). The
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paucity of the literature on rehabilitation in this population may be a sign of troubles to design a controlled study on rehabilitation in the context of post transplant care and follow-up. There is however a clear interest on pulmonary rehabilitation after transplantation in LTR (Rochester, 2008). In chronic obstructive pulmonary disease (COPD) patients, Maltais et al. suggested that home-based training is an equivalent alternative to outpatient rehabilitation in patients with COPD. The authors reported similar improvements in exercise tolerance and quality of life after outpatient and home-based exercise training (Maltais et al., 2008). We thus wonder whether home-based exercise training could be a strategy to increase access to rehabilitation in LTR. In this study, we aimed at investigate the benefits of 3-month home-based endurance training in LTR. We hypothesized that, even performed at home, exercise training may improve exercise tolerance, muscle strength and quality of life in LTR. We further hypothesized that not all the patients would be able to benefit from unsupervised training at home. In a secondary objective, we thus aimed at identifying the patients who are either responders or non-responders to home-based exercise training. We distinguished the patients depending on their ability to improve exercise tolerance after training. To do that, endurance time was measured and compared to the mean change observed in a group of aged-matched healthy subjects. Differences at baseline between responders and non-responders to exercise training were studied.
patients for whom the surgery was far away from the inclusion date, we observed great variability between patients in the change in body weight during the training period (from −6 to +5 kg).
2. Methods and materials
2.3. Measurements
2.1. Subjects
2.3.1. Body composition Fat-free mass (FFM) was measured with bioelectrical impedance analysis at 50 kHz and equation from Kyle et al. was used (Kyle et al., 2003).
Procedures were approved by our institutional review board and all participants gave informed consent. Twelve lung transplant recipients (LTR) and 7 age-matched healthy subjects were recruited. All LTR had performed a 4-week inpatient rehabilitation program immediately after transplantation but none of them had performed home-based exercise training later on. Healthy subjects were included when their spontaneous physical activity did not exceed 2 h per week in the last 2 months before inclusion in the protocol. The score of physical activity as assessed by the Voorrips questionnaire tended to be lower in LTR as compared with healthy subjects (Table 2, Voorrips et al., 1991). 2.1.1. Subject characteristics The characteristics of the LTR are reported in Table 1. Three patients presented a chronic rejection before inclusion in the training program, as assessed by the presence of a bronchiolitis obliterans syndrome of grade 2, 3 and 1 in the patients with number 5, 10 and 11 respectively (Belperio et al., 2009). However, all the patients were stable at least 2 months before inclusion. The anti-rejection treatment included tacrolimus (4.2 ± 2.6 mg/day), mycophenolate mofetil (1.3 ± 0.4 g/day) and prednisone (7.7 ± 2.1 mg/day). Most patients received anti-hypertensive treatments such as calcium blockers or angiotensin converting enzyme inhibitors. No change in medications occurred over the training period. 2.1.2. Nutritional support In cystic fibrosis, the nutritional support was based on routine care, mainly including gastro-protected pancreatic extract in cases of exocrine pancreatic insufficiency and insulin therapy in cases of endocrine pancreatic failure. Furthermore, all patients received diet advices to increase energy intake to reach a minimal BMI of 19. In patients for whom the surgery was performed few months before the inclusion in the study, the body weight spontaneously increased thanks to correction of mechanical disadvantage and resolution of chronic infection and inflammation after the surgery. Inversely, in
2.2. Study design Measurements of exercise capacity and muscle function were done before and after training in all subjects. Health-related quality-of-life was also assessed in LTR using the Chronic Respiratory Questionnaire (CRQ) (Bourbeau et al., 2004). Training consisted of 3-month endurance training at home on a cycloergometer (Ergometer 900PC, Ergoline), 3 times a week for 12 weeks. Exercise consisted of cycling at 50% and progressively increasing up to 80% of previously determined peak workload (Wpeak ) for 10 min followed by 5 min at 30% Wpeak , three times per session in all subjects. The patients were directly supervised for the first sessions by a physiotherapist at home and via phone each subsequent week. For security reasons and control purposes, subjects had a cardiofrequency meter (S610i, Polar, Kempele, Finland) with memory. Every month, these monitors were downloaded to a personal computer to check that planned exercise sessions were achieved. Results after training were compared between LTR and healthy subjects and also between responders and non-responders to exercise training (ET). A positive response to ET was defined as an improvement in endurance time at least comparable to the mean change observed in healthy subjects.
2.3.2. Pulmonary function Spirometry and thoracic gas volumes were measured using Pitot pneumotachograph and pressure plethysmograph (Medical Graphics Corporation, St Paul, MN, USA), according to ATS/ERS recommendations (Miller et al., 2005). Reference values were those of Quanjer et al. (1993). 2.3.3. Skeletal muscle biopsy and muscle fibers Biopsy of Vastus Lateralis was obtained as previously described (Guerrero et al., 2005). Fibers were visually counted to determine the percentage and the mean diameter of each fiber type (Dubowitz and Brookes, 1985). Morphometric measurements were performed with Histo Biocom software (Les Ullis, France). 2.3.4. Quadriceps twitch tension measurement (Twq) Twq was performed using magnetic stimulation of the femoral nerve as previously described in our laboratory (Vivodtzev et al., 2005). Muscle strength was measured with a strain gauge tensiometer (GLOBUS, Dempo Technologies, Trevisio, Italy). Twq was accepted as the mean of 5 consecutive and reproducible trials. 2.3.5. Incremental exercise All subjects performed a progressive stepwise exercise test on a cycloergometer with breathing room, 12-lead ECG, and pulse oximetry (Vmax system 229, SensorMedics, Yorba Linda, CA, USA). After a 2-min warm-up, each exercise step lasted 1 min and workload increments of 5 and 15 W/min were used in LTR and Healthy subjects, respectively, up to the individual’s maximal capacity. The peak workload (Wpeak ) was defined as the highest exercise workload tolerated for at least 30 s. Heart rate, oxygen consumption (V˙ O2 ) and minute ventilation (V˙ E) were measured at peak exercise and at the highest equivalent exercise workload (i.e., isowatt for
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Table 1 Characteristics of the LTR. Patient
Gender
Age (years)
1 2 3 4 5 6 7 8 9 10 11 12
M M M F M F M M M M M M
37 40 47 45 47 58 38 20 70 49 57 60
Mean 10/2 SD
47 13
22 3
BMI (kg/m2 )
Diagnostic
Transplant
20 20 22 22 21 17 21 21 26 21 23 27
CF CF Histiocitosis Emphysema Emphysema PAH Emphysema CF Emphysema CF COPD IPF
DLT DLT DLT DLT DLT DLT DLT DLT SLT DLT HLT SLT
Month (post LT) 5 25 10 59 4 2 61 22 21 106 68 51
36 33
2.2 (74) 1.0 (24)
FEV1 (L, % pred.) 3.59 (100) 2.77 (73) 3.53 (91) 2.16 (100) 2.04 (58) 1.90 (75) 3.72 (100) 4.20 (104) 1.36 (51) 0.94 (25) 2.27 (71) 1.63 (54) 3.2 9.5
FVC (L) 3.7 3.7 4.0 2.8 3.2 2.0 4.3 5.0 2.0 2.5 2.9 2.3
FEV1 /FVC (%) 96 74 88 79 63 95 87 84 70 37 77 70
77 16
Abbreviations: BMI, body mass index; CF, cystic fibrosis; COPD, chronic obstructive pulmonary disease; PAH, pulmonary arterial hypertension; IPF, idiopathic pulmonary fibrosis; DLT, double lung transplantation; SLT, single lung transplantation; HLT, heart lung transplantation; FEV1 , forced expiratory volume in 1 s; FVC, forced vital capacity. Table 2 Anthropometric characteristics, exercise capacity and muscle function of all the subjects at baseline.
Anthropometric Male/female sex, No Age (years) BMI (kg/m2 ) FFM (kg) FFMindex Voorrips Score (physical activity) Exercise capacity Wpeak V˙ O2peak , L (% predicted) V˙ O2 peak
V˙ Epeak (L/min) V˙ Epeak (% MVV) Dyspnea score Leg fatigue score Endurance time 65% Wpeak (min) V˙ ECET (end of test), % MVV V˙ ECET (end of test), %V˙ Epeak Muscle function Muscle force (Twq, kg) Muscle fatigue (Fall in Twq after CET, % baseline) Type I Fiber (%) Type II Fiber (%) Type I Fiber diameter (m) Type II Fiber diameter (m)
Healthyn = 7
LTR n = 12
p
7/0 44 ± 11 25 ± 3 56 ± 6 31 ± 4 13.8 ± 2.3
10/2 47 ± 13 22 ± 3* 46 ± 6* 27 ± 3* 11.7 ± 2.3
0.27 0.57 0.05 0.005 0.05 0.07
195 ± 32 2.5 ± 0.4
85 ± 43* 1.2 ± 0.5*
<0.0001 <0.0001
94 ± 12
63 ± 20*
0.001
87.7 ± 18.3 58 ± 10 5.6 ± 1.0 6.0 ± 1.8 27 ± 9 23 ± 16 92 ± 7
55.4 ± 19.9* 66 ± 19 5.8 ± 2.7 7.0 ± 1.3 18 ± 10 43 ± 27 85 ± 15
0.002 0.35 0.79 0.20 0.08 0.07 0.31
10.5 ± 4.6 86 ± 27 34 ± 12 66 ± 12 60.6 ± 7.3 60.4 ± 5.8
5.4 ± 3.2* 110 ± 58 16 ± 6* 84 ± 6* 60.5 ± 12.9 58.3 ± 14.6
0.02 0.33 0.0006 0.001 0.99 0.71
Data are mean ± SD. Abbreviations: BMI, body mass index; FFM, fat free mass. Wpeak , peak workload; V˙ O2peak , peak oxygen consumption; CET, constant-workload exercise test; V˙ E, minute ventilation, MVV, maximal voluntary ventilation; Twq, quadriceps twitch tension. The score of physical activity was assessed using the Voorrips questionnaire. End-of-test dyspnea and leg fatigue were assessed using a visual analogic scale (ranging from 0 = minimal score to 10 = maximal score). * Significantly different from healthy.
each patient) (V˙ Eisowatt ). Dyspnea and leg discomfort were assessed using modified Borg scales graduated from 0 (no leg discomfort or dyspnea) to 10 (maximal dyspnea or leg discomfort) (Borg, 1982). 2.3.6. Constant-workload exercise test (CET) Patients performed a constant-workload exercise test (CET) at 65% Wpeak and 60–70 rpm speed up to exhaustion (endurance time). Heart rate, oxygen consumption and minute ventilation (V˙ ECET ) were measured all along the test. 2.4. Statistical analysis All data are expressed as mean ± SD (standard deviation). The level of significance for all tests was set at p < 0.05. The normality was checked with the omnibus test. To assess the effect of training in LTR, the pre-training values were compared to the post-training
values using paired Student’s t-test for all the variables of exercise capacity, muscle function and quality of life. Differences at baseline or after training between LTR and healthy subjects were assessed using unpaired Student’s t-test. Changes in ventilation during CET were analyzed using a two-way ANOVA with repeated-measures for the two groups. Correlations between continuous variables and changes after training were made using simple regressions with Pearson’s correlation coefficient. Correcting factors were applied using stepwise and multiple regression analysis. The comparison of the subgroups of LTR (responders vs. non-responders) was done at baseline and after training using unpaired Student’s t-test for all the variables of anthropometry, the number of months between surgery and initial testing, exercise capacity, muscle function and quality of life. The comparison in muscle strength and percentage of type I fiber between healthy subjects, responders and nonresponders was done using one-way ANOVA analysis (Statview 5.0).
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3. Results 3.1. Patients studied
3.2. Effect of training All the patients have completed the training program. The monitor of cardiofrequency meter reported that patients have completed 39 ± 10 sessions of 33 ± 10 min with a mean intensity of 68 ± .29% of the initial maximal workload during 3 months. Intensity corresponded to a mean HR of 83 ± .10% of maximal HR achieved during initial incremental exercise test. There was no significant difference between the 2 subgroups of LTR patients in any of these parameters. After training, no significant change was observed in pulmonary function or FFM in LTR. 3.2.1. Exercise capacity Exercise capacity and endurance time to constant-workload exercise test (CET) are reported on Fig. 1. After exercise training (ET), peak oxygen consumption (V˙ O2peak ) was significantly improved in healthy subjects and a trend to improvement was observed in LTR (+0.13 ± 0.22, p = 0.059, Fig. 1A). Endurance time was improved after ET in LTR to the same extent than in healthy subjects but with greater variability between patients (+9 ± 12 min vs. +8 ± 6 min in LTR and healthy subjects, respectively, Fig. 1B). 3.2.2. Ventilatory response to exercise Resting V˙ E and V˙ Epeak did not change after ET in both groups but there was a significant reduction in V˙ Eisowatt when expressed as % peak value in LTR (81 ± 15% vs. 94 ± 8% V˙ Epeak , after vs. before ET, respectively, p = 0.02), similarly to the change observed in healthy subjects (Fig. 2A). During CET, V˙ ECET was significantly reduced after ET in LTR (35.7 ± 4.6 L/min vs. 41.2 ± 7.1 L/min, after v. before training, respectively, p = 0.04) as well as in healthy subjects (51.2 ± 9.3 L/min vs. 65.3 ± 11.4 L/min, after vs. before training, respectively, p = 0.03, Fig. 2B). Furthermore, isowatt and endurance VCO2 were significantly reduced after training in LTR (−0.13 ± 0.16
VO2peak (L/min)
.
†
A *
3.5 3.0 2.5
p = 0.06
2.0 1.5 1.0 0.5 0.0
Healthy
LTR
Before training After training 50
Endurance time to CET (min)
Anthropometrics and pulmonary function in LTR are shown in Table 1. FEV1 forced expiratory volume in 1 s was under normal value at 74 ± 24% of predicted value. Two patients (patients 9 and 12) had a single lung transplantation and showed moderate obstruction after transplantation. Two double lung transplant patients (patients 5 and 10), one HLT (patient 11) showed also moderate to severe obstruction pattern because of chronic dysfunction. A comparison of LTR and healthy subjects in anthropometrics, exercise capacity and muscle function at baseline is presented in Table 2. Body mass index (BMI) fat free mass (FFM) and FFM index were lower in LTR than in healthy (p < 0.05). As expected, Wpeak , V˙ O2peak , muscle strength (Twq) and the percentage of type I fiber were lower in LTR than healthy subjects. However, the endurance time only tended to be lower in LTR than healthy and the diameter of quadriceps fibers were similar in the two groups. Although V˙ Epeak in raw value was lower in LTR than healthy, it was not significantly different when expressed in %MVV (maximal voluntary ventilation). Furthermore, as assessed by V˙ Epeak when expressed in %MVV and by V˙ ECET when expressed in % V˙ Epeak , maximal ventilatory capacity was not reached during maximal and endurance tests suggesting that there were no ventilatory limits during exercise in both groups. Finally, using the Voorrips’ questionnaire for assessment of physical activity, we reported a trend to significant lower daily physical activity in LTR as compared with healthy subjects. More precise assessment using accelerometer would probably help to better discriminate those 2 groups.
4.0
Before training After training
p = 0.08
B
*
*
40
30
20
10
0
Healthy
LTR
Fig. 1. Effect of exercise training on peak oxygen consumption (V˙ O2peak ) (A) and endurance time during constant-workload exercise test (CET) at 65% Wpeak (B), in healthy and LTR. *Significantly different from baseline (p < 0.05). † Significantly different from healthy (p ≤ 0.02).
and −0.15 ± 0.15 mL, respectively, p < 0.05) although FE CO2 was unchanged during both tests. 3.2.3. Muscle function After training, muscle strength (Twq) was significantly improved in LTR to the same extent than healthy subjects (+4.6 ± 2.6 kg in LTR, p = 0.001 and +3.1 ± 3.6 kg in healthy, p = 0.047, Fig. 3A), leading to a recovery of muscle strength as compared with initial healthy subjects’ value. Concerning quadriceps muscle fibers, we observed trends to significant changes in the percentage of type
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193
Before training After training
*
A
25
*
Before training After training
†
A
*
.
20
Twq (kg)
.
VE isowatt (%VEpeak)
100
80
60
* 15
10
5
40
Healthy
LTR
B
*
Healthy
.
LTR
Healthy VEpeak
80
.
LTR VEpeak
60
Type I fiber before training Type I fiber after training Type II fiber before training Type II fiber after training
100
B 40
Healthy-pre ET Healthy post ET LTR-pre ET LTR-post ET
20
* 0 0
5
10
15
20
25
30
35
Time (min) Fig. 2. Effect of exercise training on minute ventilation at identical workload (V˙ Eisowatt ) during incremental cycle exercise when expressed in percentage of V˙ Epeak , in healthy and LTR (A) and on V˙ E as a function of time during CET (B), in healthy and LTR. Comparisons of ventilation measurements were made from 1 to 25 min in healthy and from 1 to 15 min in LTR, in order to have the maximal number of subjects in the analysis. Dashed lines correspond to maximal ventilation achieved during incremental exercise, in LTR (bottom line) and healthy subjects (top line). *Significantly different from baseline (p < 0.05).
Percentage of fiber type
.
VE during CET at 65% Wpeak (L/min)
0 100
*
80 p = 0.10
60
40
20
0
Healthy
LTR
Fig. 3. Effect of exercise training on quadriceps twitch tension (Twq) (A) and on the distribution of quadriceps muscle fiber type (B) in healthy and LTR. After training, Twq was significantly improved in both groups. *Significantly different from baseline (p < 0.05). † Significantly different from healthy (p < 0.02).
I fiber (+7% from −9 to +44%, p = 0.10, Fig. 3B) and the type II fiber diameter (−3 from −14 to +3 m, p = 0.10), in LTR. 3.2.4. Health-related quality of life After ET, a statistically and clinically (Bourbeau et al., 2004) significant improvement was observed in the dyspnea score in LTR (+0.6 ± 0.9 points, p = 0.03, Table 3). No significant changes were observed after ET in other domains but a trend to improvement in the fatigue domain (+0.5 ± 1.0 points, p = 0.07). 3.2.5. Factors of change in endurance time to CET in LTR Correlation coefficients between changes in endurance time and changes in independent variables in LTR are reported in Table 4 (univariate analysis). Using multiple regression analysis including all variables that significantly correlated with changes in endurance time in univariate analyses, changes in V˙ Eisowatt and changes in type II fiber diameter were independent factors of changes in endurance time (r = 0.93, p = 0.0003). 3.3. Responder vs. non responders to ET Responders and non-responders to ET were distinguished depending on their improvement in endurance time after ET. Six
patients improved endurance time to the same extent or even higher than healthy subjects and were considered as responders to ET as displayed in Fig. 4. After ET, responders had higher improvements than non-responders in V˙ O2peak (+0.25 ± 0.19 L/min vs. −0.01 ± 0.17 L/min, p = 0.04), V˙ Eisowatt (−27 ± 13% vs. +1 ± 17% V˙ Epeak , p = 0.009) and in type II fiber diameter (+0.8 ± 1.7 m vs.
−8.2 ± 5.8 m, p = 0.005), in responders vs. non-responders, respectively. Furthermore, within-group improvements were observed in responders in the percentage of type I fiber (+8 ± 10%, p = 0.02) and in the fatigue domain of CRQ with clinical significance (+0.8 ± 0.5 points, p = 0.01). Differences at baseline between responders and nonresponders, as well as adherence to the training program in both groups are presented in Table 5. Pulmonary function, exercise capacity and muscle strength were similar in both groups, despite differences in lung transplantation procedures used within patients. The medication doses and the number of acute rejections were also quite similar although in both groups a trend to significant higher 2nd year prednisone dose in non-responders vs. responders to training (7.6 ± 0.2 mg/day vs. 6.4 ± 1.8 mg/day, respectively, p = 0.10). Patients had similar exercise capacity and
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Table 3 Chronic Respiratory Questionnaire domain score differences from baseline to post training* . Variable
Baseline
Dyspnea Mastery Fatigue Emotion
3.6 4.4 4.5 5.6
± ± ± ±
After training
1.5 1.3 1.4 1.2
4.2 4.9 4.8 5.7
± ± ± ±
1.2 1.5 1.2 1.2
Differences from baseline (95% CI)
p-Value
+0.6 ± (−1.6 to 1.8)† +0.3 (−1.3 to 1.9) +0.5 (−1.8 to 2.0) +0.3 (−2.0 to 6.0)
0.03 0.22 0.07 0.65
* Data are means and 95% CIs. A positive difference is interpreted as an improvement. For each of the 4 Chronic Respiratory Questionnaire domains (dyspnea, mastery, fatigue, and emotion), the scores represent changes in mean score per question on a 4 to 7-point scale. A difference greater than 0.5 (improvement) or less than −0.5 (deterioration) is considered clinically important. † Significantly different from baseline.
Table 4 Correlation coefficients of changes in endurance time and changes in independent variables in LTR (univariate analysis). Variables Pulmonary function FEV1 (L) Aerobic capacity Wpeak (W) V˙ O2peak (L) HRpeak (bpm) V˙ Epeak (L/min) V˙ Eisowatt (% V˙ Epeak ) Limb muscle function Type I fiber (%) Type II fiber diameter Type II fiber diameter Twq (kg)
r
after training in LTR (r = 0.64, p = 0.02, n = 12) and this relation was even stronger in the subgroup of non-responders (r = 0.90, p = 0.01, n = 6).
p 0.16
0.71* 0.64* 0.37 0.54 −0.83* 0.09 0.09 0.76* 0.24
0.60 0.008 0.02 0.23 0.06 0.0008 0.78 0.78 0.005 0.55
Abbreviations: FEV1 , forced expiratory volume in one second; Wpeak , peak workload; V˙ O2peak , peak oxygen consumption; HR, heart rate; V˙ E, minute ventilation; Twq, quadriceps twitch tension. * Significantly related to changes in endurance time.
4. Discussion The main result of this study is that 3-month endurance training could improve endurance time, muscle strength and quality of life in LTR in a home based setting. Changes in endurance time were independently associated with a decrease in minute ventilation during exercise and an increase in type II fibers diameter. Furthermore, half of the patients improved endurance time to the same absolute extent than age-matched healthy subjects after training, and they significantly improved peak oxygen consumption and percentage of type I fiber after training. LTR with moderate muscle dysfunction and in early post-transplantation period (<2 years after transplantation) appear as good responders to home-based endurance training. 4.1. Benefits of training
Fig. 4. Individuals and mean values of endurance time to CET measured before and after training in healthy subjects (left of the panel) and in LTR (right of the panel). When distinguished as responders and non-responders to ET (improvement in endurance time > 40% of initial value). Significantly different from baseline (p < 0.03).
endurance and they trained with a similar regularity. HR measured during the training sessions was lower in non-responders as compared with responders when expressed in raw data. However, HR during training was not significantly different between groups when reported in percentage of the peak HR achieved during incremental test, suggesting that the all patients trained at similar relative intensity of training. On the contrary, non-responders had greater delay between surgery and the beginning of the study. Furthermore, as can be seen in Fig. 5, the muscle strength and the percentage of quadriceps type I fiber were significantly different between healthy subjects, responders and non-responders. Non-responders had lower muscle strength and percentage of type I fiber than responders. Finally, changes after training in body mass index was significantly related to those in endurance time
We observed significant and similar improvements in endurance time during constant-workload exercise test (CET) in both LTR and age-matched healthy subjects. Interestingly, we could show that patients regained comparable values of endurance time after training to controls (Fig. 1B). Previous studies have shown that a rehabilitation program completed immediately following transplantation could improve exercise tolerance in LTR (Maury et al., 2008; Munro et al., 2009). In addition, when performing within 6–18 months of surgery and supervised by a physician at least 3 out of the 6 weeks of training. endurance training could improve submaximal and peak exercise performance in LTR and reduce ventilation during exercise (Stiebellehner et al., 1998). In the present study, we also found a trend to significant improvement in peak aerobic capacity in LTR, although we found great variability between patients (+16 ± 25%, p = 0.059, Fig. 1A). Furthermore, minute ventilation was reduced at maximal level during incremental exercise (V˙ Eisowatt ), and at submaximal level during CET (V˙ ECET , Fig. 2). Changes in V˙ Eisowatt were independently related to the changes in endurance time (Table 4), suggesting that the reduction in ventilation during exercise may be one possible mechanism of improvement in endurance time in spite of the alleviation of the mechanical constraints to breathing after transplantation. Furthermore, as suggested by the reduction in isowatt and endurance VCO2 in LTR associated with a stable FE CO2 , the lower ventilation measured during exercise may result from lower metabolic production during exercise after training and probably due to lower use of glycolytic pathway (Wasserman et al., 1967) and a better oxidative phosphorylation (Guerrero et al., 2005). Thus, the present study suggested that even entirely performed at home, ET may improve exercise tolerance and probably in association with an improvement in ventilation requirement during exercise.
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Table 5 Characteristics of responders and non-responders to ET at baseline.
Preoperative diagnosis Emphysema Cystic fibrosis Pulmonary hypertension Histiocytose X Interstitial pulmonary Fibrosis Type of procedure Double lung Single lung Heart and lung Time from transplant to initial assessment Acute rejections before inclusion Medication Tacrolimus 1st year dose (mg/day/kg body weight) Tacrolimus 2nd year dose (mg/day/kg body weight) Mycophenolate mofetil 1st year dose (g/day) Mycophenolate mofetil 2nd year dose (g/day) Prednisone 1st year dose (mg/day) Prednisone 2nd year dose (mg/day) Anthropometric Male/Female sex, No Age (years) BMI (kg/m2 ) FFM (kg) Pulmonary function FEV1 (L) FEV1 (% predicted) FVC (% predicted) FEV1 /FVC (%) Exercise capacity Wpeak (W) V˙ O2peak (% pred) HR peak (% pred) RR Endurance time at 65% Wpeak V˙ Epeak (L/min) Muscle function Muscle force (Twq, kg) Type I fiber (%) Type I fiber diameter (m) Type II fiber diameter (m) Training parameters Number of sessions Mean duration of session (min) Mean intensity of cycling (W) Mean intensity of cycling (% Wpeak ) Mean HR during cycling (HR) Mean HR during cycling (% HRpeak )
Respondersn = 6
Non respondersn = 6
p
2 2 1 1 0
3 2 0 0 1
6 0 0 18 ± 22 0.3 ± 0.4
3 2 1 55 ± 32* 0.5 ± 0.4
0.03 0.51
0.11 ± 0.02 0.11 ± 0.02 4.0 ± 1.0 2.0 ± 1.4 1.6 ± 0.3 1.25 ± 0.35
0.15 ± 0.06 0.12 ± 0.01 5.4 ± 3.4 4.8 ± 3.4 2.0 ± 0.6 1.6 ± 0.4
0.38 0.55 0.52 0.33 0.41 0.35
4/2 46 ± 7 20 ± 2 45 ± 8
6/0 49 ± 18 23 ± 3* 48 ± 2
0.68 0.05 0.36
2.7 ± 0.7 80 ± 15 3.2 ± 0.8 82 ± 11
2.4 ± 1.3 68 ± 31 3.2 ± 1.2 70 ± 18
0.62 0.39 0.90 0.22
85 ± 40 66 ± 14 80 ± 11 1.11 ± 0.9 19 ± 10 54 ± 16
86 ± 50 60 ± 27 73 ± 9 1.10 ± 0.1 18 ± 10 57 ± 25
0.97 0.63 0.31 0.79 0.94 0.77
6.6 ± 2.5 20 ± 6 57 ± 12 49 ± 6
3.2 ± 3.4 12 ± 4* 64 ± 14 69 ± 14*
0.15 0.02 0.39 0.01
38 ± 6 33 ± 4 54 ± 18 73 ± 38 121 ± 10 85 ± 9
41 ± 13 33 ± 15 48 ± 21 62 ± 19 104 ± 10* 81 ± 14
0.67 0.89 0.61 0.54 0.02 0.62
Data are mean ± SD. Abbreviations: BMI, body mass index; FFM, fat free mass; FEV1 , forced expiratory volume in one second; FVC, forced vital capacity. Wpeak , peak workload; V˙ O2peak , peak oxygen consumption; HR, heart rate; RR, respiratory ratio; CET, constant-workload exercise test; V˙ E, minute ventilation; Twq, quadriceps twitch tension. *
Significantly different from responders.
An important factor of exercise intolerance in LTR is muscle dysfunction, mainly due to acquired deconditioning before transplantation (Lands et al., 1999; Pantoja et al., 1999; Pinet et al., 2004) as well as inactivity associated with the perioperative period (Rochester, 2008). The improvement in twitch tension measured in this study suggest that ET could improve muscle strength in LTR (nearly twice the initial value), regaining normal value of muscle strength as compared with sedentary age-matched healthy subjects (Fig. 3A), confirming the previous observation of Maury et al. (2008) when rehabilitation was completed immediately after surgery in LTR. Such an improvement in muscle strength without significant improvement in FFM may be a surprising result however. A first explanation of this result is that FFM is a global measure and a selective measurement of mid-thigh cross sectional area would have probably been more sensible to training (Bernard et al., 1999). Nevertheless changes in FFM was not correlated to those in twitch tension suggesting that, in this study, changes in twitch tension were maybe mainly associated to neuromuscular adaptation
such as excitation contraction coupling (Millet and Lepers, 2004) rather than hypertrophy. Moreover, we found trends to significant change in percentage of type I fiber (Fig. 3B) and in type II fiber diameter in LTR. However, muscle typology and morphology did not change in healthy subjects either, suggesting that great modifications in fiber size or in the number of fibers could not be expected in LTR. Nevertheless, the changes in type II fiber diameter were positively and independently associated with changes in endurance time (Table 4), suggesting that changes at the peripheral level (muscle function) could have influenced changes at general level (exercise tolerance) in LTR. The understanding of the mechanism may be debated however, considering that we did not distinguished the type IIa from the type IIx fiber. We could only hypothesize that training had induced an improvement in type IIa diameter in certain patients in whom endurance time was also increased after training (Andersen and Henriksson, 1977), although it deserves to be confirmed. Alternatively, we have shown previously that, besides muscle fibers
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Healthy subjects LTR - Responders LTR - Non-responders
Healthy subjects LTR - Responders LTR - Non-responders 16
*
50
14
*
*
40
12
30
%
Kg
10 8
20 6 4
10
2
0
0
Twq
Type I fiber
Fig. 5. Mean value of quadriceps twitch tension (Twq) and percentage of type I fiber at baseline in healthy subjects, responders LTR and non-responders LTR. Twq and percentage type I fiber were significantly different between the 3 groups (ANOVA p = 0.04 and p = 0.001, respectively). *Significantly different from healthy subjects (p ≤ 0.01).
typology, ET could result in changes in the system cellular level properties within the Intra Cellular Energy Units resulting in a better functional coupling between adenine nucleotide translocase and mitochondrial creatine kinases (Guerrero et al., 2005). Mechanisms behind the interplays between control on ventilation and skeletal muscles changes after ET remain to be unraveled in a systems biology approach. In spite of increasing survival after transplantation, exercise tolerance is still reduced in LTR (Hosenpud et al., 1998; Orens et al., 1995) and the quality of life is another important question in these patients. As assessed by the chronic respiratory questionnaire, ET could significantly reduce dyspnea in daily tasks and had a tendency to reduce fatigue in LTR (Table 3). Munro et al. (2009) have already shown that ET could improve all the domains of the SF36 questionnaire in the months following surgery. We thus suggested that ET could help in improving quality of life even years after transplantation.
abnormal nutritional status associated with body loss are likely less responder to home-based ET. Previous studies have shown that mycophenolate mofetil could influence muscle mass regulation (Hopkins and McNeil, 2008). Whether longer duration of medication intake such as corticoid, tacrolimus or also mycophenolate mofetil may be responsible for higher muscular alteration in those long-term LTR deserves to be investigated. New active behaviors early after transplantation should additionally be promoted to a greater extent. Finally, it cannot be excluded that a 10% lower training intensity had contributed to induce lower physiological benefit after training in non-responders (Maltais et al., 1997) (Table 5). Whether incentre rehabilitation programs prior to home-based training could be a useful strategy to increase to potential of training at higher intensity in certain patients deserve to be investigated.
4.2. Responders vs. non responders to ET
The present study is the first study to investigate the effect of home-based exercise training on exercise tolerance, muscle function and quality in lung transplant recipients. One strength of this study is the concomitant investigation of exercise tolerance (during incremental exercise and CET) and muscle function (as assessed by muscle strength and muscle typology and morphometry) with possible comparisons with sedentary age-matched healthy subjects. We nevertheless acknowledge that the sample size is small that we did not include a LTR control group without rehabilitation. We concede that LTR patient profile was wide and that co morbidities could have impacted on the high variability of the data. However, we did not report significant differences between groups when comparing the benefit of training in subgroup of patients with CF, emphysema and cystic fibrosis. Furthermore, the benefits of exercise training vs. normal daily activity have already been demonstrated in LTR (Stiebellehner et al., 1998). In this study, we wished to emphasize the comparison between LTR and healthy subjects in muscle function in atypical design study (muscle strengths measured using magnetic stimulation of femoral nerve and expected changes in typology and morphometry of quadriceps fibers after intermittent endurance training). One other possible limitation of this study is that we had included 3 patients < 6 month after transplantation which may have positively influenced the effect of training, due to natural
The second objective of this study was to investigate whether all the patients had actually benefited from home-based ET. Although there was no significant difference between the 2 subgroups in the adherence of training (Table 5), six out of the 12 patients had improved endurance time to the same extent than healthy subjects that was +39% of baseline value (Fig. 1) and were considered as responder to ET (Fig. 4). Responders significantly improved peak oxygen consumption and percentage of type I fiber after training, although both remained lower than baseline healthy values. Inversely, non-responders did not improve any of the parameters of exercise tolerance. Non-responders had initially a greater delay between surgery and initial testing than responders (Table 5) with significant lower muscle strength and percentage of type I fiber as compared with responders and healthy subjects (Fig. 5). Furthermore, the correlation between changes in body mass index and those in endurance time after training would suggest that maintain of body weight is a condition of well response to endurance training in LTR. On the contrary, a loss of body weight which is more often observed several years after transplantation can be an obstacle in progressing during exercise training in these patients. Those results suggested that very weak patients, those with lower type I fibers and/or long time after transplantation and/or patients with
4.3. Study limitations
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recovery after transplantation (Williams et al., 1990). However, it is doubtful that it would have constituted a bias in this study because there were no differences in the subgroup of responders between the patients including in the study <6 month vs. patients including >6 month after transplantation in peak exercise, ventilation during exercise, muscles strength or percentage of type I fiber and fiber diameter. Furthermore, there was no significant relation between baseline FEV1 or change in FEV1 after training and changes in ventilation during exercise in LTR. 4.4. Conclusion and clinical relevance Home-based cycle endurance training may be an useful alternative of in-setting pulmonary rehabilitation to improve exercise tolerance, muscle strength and quality of life in LTR. LTR with moderate muscle dysfunction are better responders to home-based programs than patients with very weak muscle function. Considering its direct impact on daily habits, home-based training may be an interesting avenue to improve the access of rehabilitation by offering different rehabilitation settings than hospital-based ones and probably in the first years after transplantation. Further multicenter and controlled-studies are necessary to confirm the safety and the benefit of home-based exercise training in LTR. Funding Grants from Conseil Scientifique of Association Nationale de Traitement à Domicile Innovation et Recherche, Conseil Scientifique of AGIR-à-dom, «Délégation à la Recherche Clinique du Centre Hospitalier Universitaire de Grenoble», awarded to Dr Bernard Wuyam. Centre d’Investigation Clinique, Inserm, CHU Grenoble, and, «Programme Interdisciplinaire Complexité du Vivant et Action STIC-Inserm» awarded to Pr Christophe Pison, Bourse «André Dion» (ATRIR) awarded to Dr Isabelle Vivodtzev. Conflict of interest statement Mrs Isabelle Vivodtzev has no conflict of interest to disclose. Pr Christophe Pison has conflicts of interest to disclose: he received honorarium from Astellas, Novartis and Roche companies. The study sponsors had no involvement in the collection, analysis and interpretation of data, in the writing of the manuscript and in the decision to submit the manuscript for publication. The authors Karen Guerrero, Paulette Mezin, Elisabeth Maclet, Jean-Christian Borel, Phillipe Chaffanjon, Rachid Hacini, Olivier Chavanon, Dominique Blin, and Bernard Wuyam have no conflict of interest to disclose. Acknowledgements The authors are grateful to the scientific council of AGIR-à-dom (Meylan, France) for its financial support to this study and for the management of the rehabilitation program. The authors are also grateful to Mr Patrice Flore for scientific advices and to Mrs Chrystèle Deschaux for statistical advices. References Andersen, P., Henriksson, J., 1977. Training induced changes in the subgroups of human type II skeletal muscle fibres. Acta Physiol. Scand. 99, 123–125. Belperio, J.A., Weigt, S.S., Fishbein, M.C., Lynch, J.P., 2009. Chronic lung allograft rejection: mechanisms and therapy. Proc. Am. Thorac. Soc. 6, 108–121. Bernard, S., Whittom, F., Leblanc, P., Jobin, J., Belleau, R., Berube, C., Carrier, G., Maltais, F., 1999. Aerobic and strength training in patients with chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 159, 896–901. Borg, G.A., 1982. Psychophysical bases of perceived exertion. Med. Sci. Sports Exerc. 14, 377–381.
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