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Keywords:

  • Activities of daily living;
  • exercise;
  • lung transplantation;
  • rehabilitation

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgments
  9. Disclosure
  10. References
  11. Supporting Information

The effects of exercise training after lung transplantation have not been studied in a randomized controlled trial so far. We investigated whether 3 months of supervised training, initiated immediately after hospital discharge, improve functional recovery and cardiovascular morbidity of patients up to 1 year after lung transplantation. Patients older than 40 years, who experienced an uncomplicated postoperative period, were eligible for this single blind, parallel group study. Sealed envelopes were used to randomly allocate patients to 3 months of exercise training (n = 21) or a control intervention (n = 19). Minutes of daily walking time (primary outcome), physical fitness, quality of life and cardiovascular morbidity were compared between groups adjusting for baseline assessments in a mixed models analysis. After 1 year daily walking time in the treated patients (n = 18) was 85 ± 27 min and in the control group (n = 16) 54 ± 30 min (adjusted difference 26 min [95%CI 8–45 min, p = 0.006]). Quadriceps force (p = 0.001), 6-minute walking distance (p = 0.002) and self-reported physical functioning (p = 0.039) were significantly higher in the intervention group. Average 24 h ambulatory blood pressures were significantly lower in the treated patients (p ≤ 0.01). Based on these results patients should be strongly encouraged to participate in an exercise training intervention after lung transplantation.


Abbreviations: 
6MWD

six-minute walking distance

BE

bronchiectasis

BMI

body mass index

CI

confidence interval

COPD

chronic obstructive pulmonary disease

FEV1

forced expiratory volume in the first second

ICU

intensive care unit

MET

metabolic equivalent

PF

pulmonary fibrosis

QF

quadriceps force

RCT

randomized controlled trial

SSLTx

bilateral lung transplantation

VO2

max, peak oxygen consumption

Wmax

peak work rate

Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgments
  9. Disclosure
  10. References
  11. Supporting Information

Lung transplantation is a treatment option for patients with end-stage lung disease (1). During the last two decades, considerable advances in organ preservation, surgical techniques, immunosuppressant and antibiotic therapy have contributed to improvement in postoperative survival (2). Despite the overall success of the procedure, participation in daily activities, physical fitness and aspects of health-related quality of life related to physical functioning remain impaired following transplantation (3). Improving these functional limitations might be possible with exercise training interventions. Around 30–50% of patients develop comorbid conditions such as osteoporosis, hyperlipidemia and diabetes in the years after transplantation (4). The prevalence of hypertension in 5-year survivors of lung transplantation has even been shown to be around 90% (4). It is known that these morbidities can be prevented by a physically active lifestyle (5,6).

Limitations in maximal exercise capacity in the range of 40–60% of predicted normal values are typically observed after lung transplantation (7–9). These persisting limitations are mostly unrelated to ventilatory or cardiovascular factors (4,7,9). A major determinant of the reduced exercise capacity after lung transplantation is limb muscle dysfunction (muscle atrophy, muscle weakness and changes in muscle composition and metabolism) (8–10). A sedentary lifestyle both before and after the transplantation contributes to this limb muscle dysfunction (3,11–17). Hospitalizations due to infections or acute rejections and the use of immunosuppressive medication further impact on muscle function in lung recipients (18). Participation in a supervised exercise training program might help to improve this limb muscle dysfunction. This should enable more participation in daily physical activity which in turn should help to reduce the risk of developing some frequently observed comorbid conditions after transplantation.

Pre- and posttransplant rehabilitation programs are widely recognized as part of best practice management and have been reported to be offered on a mandatory basis in 80–85% of centers in Canada (19). The intervention can however not be regarded to be evidence based due to the lack of randomized controlled studies (20). Insight in the potential added value of an exercise training intervention is important as the prescription of exercise training has important consequences for the postoperative management of these patients and should be based on evidence. Only a randomized controlled trial can show whether an exercise training intervention is superior to improvements observed due to the natural recovery of patients after transplantation. We therefore conducted a randomized controlled trial that investigated the effects of a 3-month supervised exercise training program initiated immediately after hospital discharge following lung transplantation on participation in daily physical activities, physical fitness, quality of life and the incidence of frequently observed comorbidities in the first year after hospital discharge.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgments
  9. Disclosure
  10. References
  11. Supporting Information

The study was performed as a single-center parallel group randomized controlled trial (RCT) with equal allocation ratio between intervention and control group. The trial was approved by the University Hospital Leuven's Institutional Review Board (Approval Number ML3782) and was carried out in accordance with the ethical guidelines as defined in the Belgian law relating to experiments in humans dated May 7, 2004. All patients gave written informed consent after the trial was explained by the treating pulmonologist. Interventions started immediately upon hospital discharge and were evaluated after 3 months (immediately following the exercise training intervention), and after 12 months following hospital discharge (9 months follow-up period). Patients were also assessed while being on the lung transplant waiting list to account for possible differences between groups prior to surgery.

All patients between 40 and 65 years who experienced an uncomplicated postoperative period (hospital stay ≤6 weeks) after single or double lung transplantation were eligible to participate in the study. During hospitalization all patients received a standardized mobilization program consisting of daily exercises (walking, cycling, stair climbing and resistance exercises). Systematic differences in treatment between groups are very unlikely since patients were not randomized at this moment and therapists were thus completely blinded to group allocation. Patients with a prolonged hospital stay resulting in severe weakness were prescribed rehabilitation by default in our center.

Patients in the intervention group exercised three times weekly during 3 months following hospital discharge. The exercise training included cycling, walking, stair climbing and resistance exercises using leg press equipment. Each session lasted for about 90 min. Initial training intensity was set at 60% of the baseline maximal workload for ergometry cycling and 75% of the average walking speed during the baseline 6-minute walking distance (6MWD) test for treadmill walking. The workload increased each week, guided by Borg-symptom scores. To improve lower extremity muscle force, patients performed three times eight repetitions using leg press equipment, with the initial load set at 70% of the One-Repetition Maximum. A Borg score of 4–6 for perceived symptoms of dyspnea or perceived effort was set as target intensity for all exercises on a modified Borg scale. Patients in the control group did not participate in a supervised exercise training program. To provide them with a minimal intervention all patients (both intervention and control group) did receive instructions to increase their participation in daily physical activity during individual counseling sessions. During the first 6 months following hospital discharge patients participated in six individual counseling sessions, each lasting 15–30 min.

Daily walking time (objectively assessed with activity monitors) was a priori defined as the primary outcome. Time spent in different postures, daily steps, movement intensity and time spent in moderate intense activities were secondary outcomes reflecting participation in daily physical activity. Standing is a weight-bearing activity and is therefore presented separately from postures reflecting sedentary behavior (sitting and lying). Measurements were performed with an accelerometer-based activity monitor (DynaPort activity monitor, McRoberts BV, The Hague, the Netherlands). Assessment of physical activity was done on five consecutive days during at least 12 waking hours a day. Patients were asked to keep their normal daily activities unaltered during the measurement. The SenseWear Pro Armband (SenseWear, BodyMedia Inc., Pittsburg, PA, USA) was worn simultaneously with the DynaPort during these assessments and was also used for feedback and intermediate evaluation of physical activity and energy expenditure during the activity counseling interventions. More detailed information on the activity counseling intervention and measurements of physical activity is provided in the Supporting Information. Functional and peak exercise capacity, peripheral muscle force, pulmonary function, health-related quality of life and mood status were additional secondary outcomes. Incidence of cardiovascular morbidity (hypertension, hyperlipidemia and diabetes) and osteoporosis was also registered.

A sample size of 23 patients for each group was initially calculated to detect an absolute difference in the increment in daily walking time (pre–post transplantation) of 15 min (40 min in the intervention group vs. 25 min in the control group), assuming a standard deviation of 20 min, with a statistical power of 80% and the risk for a type I error (α) <5%. Taking into account an expected dropout rate of 30% it was initially aimed to include 30 patients in each group between November 2006 and October 2009. Sequentially numbered, opaque sealed envelopes were used for randomization and allocation concealment (21). It was not possible to blind patients in any form to the treatment they received. Care providers and assessors of outcomes were however blinded to the assigned interventions. All statistical analyses were performed in SAS, release 9.2. Primary and secondary outcomes between groups were compared with a mixed models analysis. Time and group (Control/Intervention) and the interaction between them were considered as fixed effects. Since all measurements were clustered within a patient the latter was considered as a random effect. The progression of outcomes appeared to be different in the two parts of the study (intervention period and follow-up period). Therefore, the progression of the outcomes between groups in the intervention period (from hospital discharge until 3 months after discharge) and in the follow-up period (from 3 months until 12 months after hospital discharge) were compared by using a “broken line” regression with a breakpoint at 3 months (immediately following the intervention period).

The analyses of all variables were corrected for the measurements that had been carried out before and immediately after the transplantation with exception for the responses from the maximal cardiopulmonary exercise test. This test was not performed in all patients on the waiting list for transplantation. An alpha of less than 0.05 was taken as the threshold for statistical significance. Data are presented as means ± SD throughout the manuscript unless indicated otherwise. Additional detail on treatments, measurement methods, sample size calculation, randomization and statistical analysis is provided in the Supporting Information.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgments
  9. Disclosure
  10. References
  11. Supporting Information

Forty patients were randomized after hospital discharge between September 2006 and October 2009 (21 patients in the training group and 19 patients in the control group) and then followed until 1 year after hospital discharge. A diagram summarizing the flow through the study is presented in Figure 1. One year after hospital discharge 18 patients in the intervention group and 16 patients in the control group were analyzed for the primary and secondary outcomes. Inclusion was terminated in October 2009 to finish the study at the scheduled completion date of November 2010. Baseline characteristics of participants are presented in Table 1. Anthropometric characteristics, the prevalence of underlying diagnoses, the moment of pretransplant assessments, the duration of hospital stay, the types of surgery performed and the presence of early acute rejection before hospital discharge were comparable between groups. Additional information on immunosuppressive drug regimens during the first year following transplantation is provided in Table S1.

image

Figure 1. Diagram showing the flow of participants through each stage of the randomized trial.

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Table 1.  Baseline characteristics
 InterventionControl group
 group n = 18Control group n = 16
  1. Data are means (SD) or numbers (%).

  2. BMI = body mass index; COPD = chronic obstructive pulmonary disease; PF = pulmonary fibrosis; BE = bronchiectasis; Time to LTX = days from pretransplant assessment to surgery; Hospital stay = days spent in hospital after surgery; ICU days = days spent in the intensive care unit; SSLTx = bilateral lung transplantation.

Age (years)59 (4)59 (6)
Height (cm)165 (7)166 (7)
Weight (kg)61 (15)58 (13)
BMI (kg/m2)22.1 (4.7)20.9 (4.2)
Sex (female)9 (50%)9 (56%)
Diagnosis (COPD/PF/BE)15 (83%) / 2 / 114 (88%) / 2 / 0
Time to LTx (days)174 (118)152 (154)
Hospital stay (days)27 (7)28 (7)
ICU days5 (2)5 (3)
Transplant type (SSLTx)15 (83%)14 (88%)
Early acute rejection (present)6 (33%)5 (31%)

At least four full days of activity monitor data were collected for all patients during the four measurements (Pre-LTX, Baseline, 3 months and 1 year after hospital discharge). Severe limitations in daily physical activity, physical fitness and quality of life were observed before transplantation (Tables 2, 3 and S5). Immediately following the exercise training intervention (3 months after hospital discharge) statistically significant differences between groups in daily walking time, movement intensity during walking and daily steps (Table 2) and in physical fitness (6-minute walking distance and quadriceps force [Table 3]) were observed. No statistically significant differences in handgrip force, respiratory muscle force, quality of life and mood status were observed at this stage (Tables S2, S5 and S7). Nine months later (12 months following hospital discharge) statistically significant differences were maintained. In addition, time spent in moderate intense (≥3METS) physical activity (Table 2), peak work rate during an incremental exercise test on a cycle ergometer (Table 3) and two items of the SF-36 health status questionnaire (physical functioning and role limitations due to physical functioning, Table S5) were significantly different between groups. No differences in mood status (Table S2) or any of the other parameters of participation in daily physical activity, physical fitness and quality of life were observed. Results of the broken line regression revealed that the evolution of quadriceps force was different during the two phases of the study. While the slopes were significantly different in favor of the intervention group during the first 3 months (intervention period; difference in slopes: β= 4.9, p = 0.001) this was not the case (difference in slopes: β=−0.2, p = 0.663) during the follow-up period (Figure 2). The slopes of daily walking time (Figure 2) were also significantly different in the first 3 months (β= 4.2, p = 0.011) and showed a trend to be different during the follow-up period (β= 1.5, p = 0.085). No significantly different slopes in either intervention or follow-up period were detected for other variables that showed statistically significant differences between groups at either 3-month or 12-month follow-up (e.g. 6MWD, Figure 2).

Table 2.  Participation in daily physical activity before transplantation (Pre-LTx), upon hospital discharge (Baseline), 3 months and 1 year after hospital discharge
 Intervention (mean ± SD)Control (mean ± SD)Adjusted difference1 (95% CI)p-Value
  1. 1Comparisons adjusted for baseline value.

  2. 2Measured with the DynaPort activity monitor.3Measured with the SenseWear activity monitor.

  3. CI = confidence interval; Sedentary = time spent lying and sitting; MI = movement intensity; METs = metabolic equivalents; Time > 3 METs = time spent in physical activity of at least moderate intensity.

Sedentary (min/day)2    
 Pre-LTx497 ± 94504 ± 113  
 Baseline508 ± 90525 ± 106  
 3 months435 ± 108495 ± 99−51 (−118 to 17)0.133
 1 year402 ± 106459 ± 108−48 (−114 to 17)0.147
Standing (min/day)2    
 Pre-LTx182 ± 75181 ± 101  
 Baseline167 ± 19149 ± 22  
 3 months216 ± 100176 ± 8228 (−28 to 86)0.313
 1 year225 ± 103193 ± 8523 (−40 to 85)0.465
Walking (min/day)2    
 Pre-LTx36 ± 2129 ± 21  
 Baseline36 ± 1632 ± 26  
 3 months56 ± 2438 ± 2314 (4 to 24)0.008
 1 year85 ± 2754 ± 3026 (8 to 45)0.006
MI walking (m/s2)2    
 Pre-LTx1.85 ± 0.221.71 ± 0.17  
 Baseline1.85 ± 0.251.66 ± 0.28  
 3 months2.13 ± 0.071.89 ± 0.150.18 (0.01 to 0.35)0.044
 1 year2.23 ± 0.181.91 ± 0.160.27 (0.14 to 0.39)0.001
Daily steps2    
 Pre-LTx3225 ± 20392426 ± 1747  
 Baseline3094 ± 14582701 ± 2216  
 3 months5194 ± 15863451 ± 21751376 (481 to 2269)0.004
 1 year7406 ± 25744462 ± 25183017 (1185 to 4849)0.002
Time > 3 METs (min/day)3    
 Pre-LTx20 ± 2120 ± 26  
 Baseline24 ± 2417 ± 25  
 3 months69 ± 4538 ± 5818 (−2 to 38)0.077
 1 year98 ± 6758 ± 7027 (1 to 54)0.047
Table 3.  Levels of pulmonary function and physical fitness before transplantation (Pre-LTx), upon hospital discharge (Baseline), 3 months and 1 year after hospital discharge
 InterventionControlAdjusted difference1 
 (mean ± SD)(mean ± SD)(95% CI)p-Value
  1. 1Comparisons adjusted for baseline value.

  2. CI = confidence interval; pred = predicted; FEV1= forced expiratory volume in the first second; QF = quadriceps force; 6MWD = 6-minute walking distance; Wmax= peak workload; VO2,max= peak oxygen uptake.

FEV1 (%pred)    
 Pre-LTx33 ± 2026 ± 10  
 Baseline79 ± 1869 ± 17  
 3 months89 ± 1880 ± 221 (−9 to 11)0.888
 1 year92 ± 2089 ± 25−3 (−16 to 10)0.615
QF (%pred)    
 Pre-LTx78 ± 2275 ± 25  
 Baseline63 ± 1656 ± 22  
 3 months82 ± 2060 ± 1817 (9 to 24)0.001
 1 year92 ± 2171 ± 2016 (7 to 25)0.001
6MWD (%pred)    
 Pre-LTx53 ± 1150 ± 16  
 Baseline56 ± 1051 ± 14  
 3 months79 ± 870 ± 109 (3 to 15)0.008
 1 year86 ± 774 ± 1112 (5 to 19)0.002
Wmax (%pred)    
 Baseline47 ± 1539 ± 14  
 3 months63 ± 2350 ± 2213 (−2 to 29)0.093
 1 year69 ± 2053 ± 2316 (1 to 31)0.042
VO2,max (%pred)    
 Baseline55 ± 1547 ± 14  
 3 months71 ± 2659 ± 2112 (−5 to 28)0.149
 1 year78 ± 2763 ± 2415 (−2 to 33)0.082
image

Figure 2. Progression of quadriceps force, 6-minute walking distance (6MWD) and daily walking time during the intervention period (Baseline to 3 months) and during the follow-up period (3 months to 1 year).*, significant difference between groups; #, significant difference in slopes between groups.

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Significantly lower values for both average 24 h ambulatory diastolic and systolic blood pressure measurements were observed in the intervention group 1 year after hospital discharge (Table S6). More antihypertensive medication had to be prescribed in the control group (Table S3) and a lower incidence of patients that had to be treated for diabetes in the intervention group (1/18 [6%]) in comparison with the control group (4/16 [25%]) was observed. Due to the small sample size this clinically meaningful difference did however not reach statistical significance (Table S6). No differences in weight gain, blood lipid profiles and bone mineral density were observed between groups (Tables S4 and S6).

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgments
  9. Disclosure
  10. References
  11. Supporting Information

Three months of supervised exercise training, initiated immediately following hospital discharge, improved functional recovery and reduced cardiovascular morbidity during the first year after transplantation in lung recipients who had experienced an uncomplicated postoperative period. The treated patients engaged in more daily physical activity in the first year following hospital discharge which in turn resulted in favorable health outcomes. They achieved better physical fitness (quadriceps force, functional exercise capacity and peak work rate achieved during a maximal incremental exercise test on a cycle ergometer) and reported better physical functioning than patients in the control group. Average 24 h ambulatory diastolic and systolic blood pressure of the treated patients was lower than in the control group.

Strengths of the study design

This study is the first randomized controlled trial in lung recipients to show that exercise training results in improvements in participation in daily physical activities, functional exercise capacity, peripheral muscle function, health-related quality of life and cardiovascular morbidity. None of the previous studies that looked into the effects of exercise training on endurance capacity had been designed as a randomized controlled trial (20). The importance of comparing the improvements in the treated patients with a control group is illustrated by the average improvement of 132 m in the 6-minute walking distance in the control group during the first 3 months after hospital discharge in comparison with pretransplant values. The intervention group achieved an improvement of 177 m. This 45 m difference between groups would be considered a clinically relevant improvement in patients with moderate-to-severe chronic obstructive pulmonary disease (COPD) (22). Moreover we assessed patients prior to transplantation and were able to show that functional limitations due to chronic lung disease were comparable between groups prior to transplantation. Limitations observed in daily physical activity, physical fitness, quality of life and mood status before transplantation were consistent with previous findings (12,23).

Effects of the intervention on participation in daily physical activity

Improvements in physical fitness and especially muscle force that were induced by the exercise training intervention probably facilitated participation in daily activities in the first year following transplantation. It might be that treated patients engaged in more daily activities because they could perform them at a lower relative workload than patients in the control group. Exercise training might also have increased the effectiveness of the activity counseling intervention. It has been described previously that participation in exercise training programs contributes to increasing self-efficacy (i.e. the confidence of being able to perform a certain behavior) for regular participation in physical activity (24).

Effects of the intervention on leg muscle function

The average loss in quadriceps force after hospitalization in comparison with values before transplantation was 15–20% in both the treated patients and the control group. This was comparable with losses in quadriceps force observed in a similar cohort that had previously been studied in our center (15). Leg muscle dysfunction has been identified as the factor that mainly contributes to persisting exercise limitations in most patients after lung transplantation (9). The deterioration in skeletal muscle function in the immediate postoperative period therefore needs to be addressed during rehabilitative treatments after lung transplantation. This study shows that exercise training is capable of improving leg muscle function in lung recipients. While both groups reported symptoms of leg effort to be the main limiting symptom during the maximal incremental exercise test on a cycle ergometer the intervention group was able to complete a significantly higher amount of work during this test. Patients in the intervention group increased their quadriceps force during the intervention period to values that were slightly exceeding those that had been observed before the transplantation. The force of patients in the control group 3 months after hospital discharge was still clearly lower than before the transplantation. Performing only light-to-moderate intense daily activities, as it was done by patients in the control group, seems therefore not sufficient to restore leg muscle force. Specific resistance exercises at high training intensities, like they were only performed by patients in the treatment group, seem necessary to restore leg muscle force in the first months following hospital discharge. This is also supported by the fact that the evolution in quadriceps force was only significantly different between groups during the intervention period but not during the follow-up period when neither of the two groups engaged in supervised exercise training including specific resistance exercises.

Effects on self-perceived health status

Despite the large differences in physical fitness and physical activity between groups after the 3-month treatment period no differences in self-perceived health status were observed at this stage. This is most likely related to the large improvements that all patients experienced in the first 3 months following hospital discharge in comparison with their pretransplant status. This is also a possible explanation why none of the patients in the control group wanted to participate in an exercise training intervention 3 months after hospital discharge. Measures of physical fitness of these patients remained however well below the normal values for their age and the improvements in these measures were much more pronounced in the intervention group. It was only 9 months later that these differences between groups did also translate into self-perceived changes in health status. These differences were limited to two of the physical component subscales of the SF-36 questionnaire. This is not surprising since most limitations in health-related quality of life both before and after transplantation are observed in these subscales and the effects of exercise training are theoretically most closely linked to these subscales (3,12,25).

Effects of the intervention on the incidence of morbidities

This study was initially not powered to detect differences in the incidence of cardiovascular morbidity. Still some clinically relevant differences in the occurrence of hypertension and diabetes were detected. The prevalence of these morbidities is known to increase dramatically within the first 5 years following lung transplantation (4). This study provides the first data indicating that the incidence of these morbidities in the years following transplantation might be prevented by interventions that increase the participation in regular physical activity. Several studies have described physiological mechanisms relating to antihypertensive benefits of physical activity. An immediate (acute) reduction in blood pressure following exercise has been termed “postexercise hypotension” and is agreed to be caused by reductions in vascular resistance (26). The mechanisms associated with the chronic adaptations to blood pressure are more complex. A meta-analysis supports this chronic role being partially explained by a decreased systemic vascular resistance in which the autonomic nervous system and renin–angiotensin system are most likely the underlying regulatory mechanisms (27). It was remarkable to observe that the higher values in average blood pressure in the control group were mainly caused by several very sedentary subjects who in turn developed severe symptoms of hypertension. It is therefore tempting to speculate that avoiding very sedentary behavior is of key importance to prevent the incidence of hypertension following lung transplantation.

The effects on the incidence of bronchiolitis obliterance syndrome could not be studied since none of the patients had developed signs of chronic rejection after 1 year following hospital discharge. Larger studies with a longer follow-up would be necessary to specifically investigate the effects of exercise training interventions on the incidence of frequently observed morbidities in the years after lung transplantation.

Limitations

A limitation of the study is that almost 40% of eligible candidates refused to participate. Due to the randomization procedure this should not have caused any systematic bias. It indicates however that it is not easy to motivate patients to attend an outpatient exercise training program after transplantation. Large travel distances that have to be covered to reach the transplant centers and the perception of large spontaneous improvements by patients and caregivers are probably at the root of this low participation rate. This is reflected in the small number of patients that have so far been included in exercise training studies after lung transplantation despite a growing interest into improving functional recovery in lung recipients (20,28). Based on the findings of this study patients should be strongly encouraged to participate in an exercise training program including leg resistance exercises in a center specialized in pulmonary rehabilitation immediately after hospital discharge. An alternative approach for patients living very far from these specialized centers would be to offer a (partly supervised) home-based exercise training program. This has recently been applied in a small group of patients after transplantation with encouraging results (29). A multicenter study on a larger group of patients and a longer follow-up period would have allowed to better study the long-term effects of the intervention on the incidence of frequently observed morbidities, including chronic rejection, in the years after transplantation.

External validity

The strict selection criteria had the advantage of reducing variability within the sample but were at the same time impacting on the external validity of the findings. Strictly speaking the current findings are only applicable to patients between 40 and 65 years who experienced an uncomplicated postoperative period. Patients who went through a more complicated postoperative period usually present themselves with even more pronounced reductions in leg muscle force (15). These patients were prescribed rehabilitation by default in our center and it is very likely that the intervention is at least equally effective in these patients. A separate randomized study in this population would therefore seem unethical. The current findings can however probably not be extrapolated to patients younger than 40 years. These patients probably experience a different spontaneous postoperative recovery due to a less sedentary lifestyle both before and after the transplantation. Muscle abnormalities in younger lung recipients with cystic fibrosis have however also been observed (30). This makes it likely that exercise training could also have beneficial effects in these patients. A randomized controlled trial of an exercise training intervention in these younger patients would be necessary to clarify this.

Conclusion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgments
  9. Disclosure
  10. References
  11. Supporting Information

In conclusion the results of this study show that supervised exercise training initiated immediately following hospital discharge improve functional recovery after lung transplantation in patients who experienced an uncomplicated postoperative period. Participation in daily physical activities, physical fitness (quadriceps force and functional exercise capacity) and health-related quality of life in the training group showed clinically relevant improvements on top of the natural recovery observed in the control group up to 1 year following hospital discharge. Favorable effects on cardiovascular morbidity were also observed. Elderly lung recipients, even those who experience an uncomplicated postoperative course after transplantation, should therefore be strongly encouraged to participate in an outpatient exercise training program in a specialized center after hospital discharge.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgments
  9. Disclosure
  10. References
  11. Supporting Information

Trial registration: clinicaltrials.gov Identifier: NCT00395889—the authors would like to thank the lung recipients who were treated and followed up on this protocol and wish to acknowledge the following persons for their complementary support:

Respiratory Rehabilitation Unit: V. Barbier, I. Coosemans, I. Muylaert and A. Cattaert; Graduate students physiotherapy: L. Schepers, A. Dierckx, P. Van Elst, K. Aerts and M. A. Cebrià i Iranzo; Lung Transplant Unit Outpatient Clinic: C. Jans and C. Rosseel; Lung Transplant Research Unit: S. Verleden, R. Vos and B. Vanaudenaerde; Department of Thoracic Surgery: D. Van Raemdonck, W. Coosemans, H. Decaluwé, P. De Leyn, P. Nafteux and T. Lerut.

Funding source: Research Foundation—Flanders project G0523.06.

Authors’ contributions: D.L. contributed to study design, patient accrual, data collection and writing of the report. C.B. and L.S. contributed to study design, data collection and revised the final report. A.I. performed the statistical analysis and revised the final report. G.V., M.D., T.T. and R.G. contributed to study design and revised the final report. D.L. had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Disclosure

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgments
  9. Disclosure
  10. References
  11. Supporting Information

The funding source did not interfere with the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the paper for publication. D.L. is a postdoctoral fellow and C.B. is a doctoral fellow of Research Foundation-Flanders. None of the authors has any conflict of interest as described by the American Journal of Transplantation.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgments
  9. Disclosure
  10. References
  11. Supporting Information
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Supporting Information

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgments
  9. Disclosure
  10. References
  11. Supporting Information

Table S1: Immunosuppressive regimens

Table S2: Levels of anxiety and depression (Hospital Anxiety and Depression scale)

Table S3: Frequencies of prescribed antihypertensive drugs

Table S4: Bone mineral density of patients

Table S5: Levels of health-related quality of life (SF-36 health status questionnaire)

Table S6: Cardiovascular comorbidity

Table S7: Handgrip force and respiratory muscle force

FilenameFormatSizeDescription
AJT_4000_sm_suppmet.doc228KSupporting info item

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