Exercise Training After Lung Transplantation Improves Participation in Daily Activity: A Randomized Controlled Trial

Article (PDF Available)inAmerican Journal of Transplantation 12(6):1584-92 · March 2012with83 Reads
DOI: 10.1111/j.1600-6143.2012.04000.x · Source: PubMed
Abstract
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.
American Journal of Transplantation 2012; 12: 1584–1592
Wiley Periodicals Inc.
C
Copyright 2012 The American Society of Transplantation
and the American Society of Transplant Surgeons
doi: 10.1111/j.1600-6143.2012.04000.x
Exercise Training After Lung Transplantation Improves
Participation in Daily Activity: A Randomized
Controlled Trial
D. Langer
a,b
, C. Burtin
a,b
,L.Schepers
a
,
A. Ivanova
c
,G.Verleden
b
, M. Decramer
b
,
T. Tr o o s t e r s
a,b
and R. Gosselink
a,b,
*
a
Faculty of Kinesiology and Rehabilitation Sciences,
KULeuven, Tervuursevest, Heverlee, Belgium
b
Respiratory Rehabilitation and Respiratory Division,
University Hospitals KULeuven, Herestraat, Leuven,
Belgium
c
Leuven Statistics Research Centre, KULeuven,
Celestijnenlaan, Heverlee, Belgium
*
Corresponding author: Rik Gosselink,
rik.gosselink@faber.kuleuven.be
The effects of exercise training after lung transplan-
tation have not been studied in a randomized con-
trolled trial so far. We investigated whether 3 months
of supervised training, initiated immediately after hos-
pital discharge, improve functional recovery and car-
diovascular 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 pa-
tients 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 sig-
nificantly higher in the intervention group. Average 24
h ambulatory blood pressures were significantly lower
in the treated patients (p 0.01). Based on these re-
sults patients should be strongly encouraged to par-
ticipate in an exercise training intervention after lung
transplantation.
Key words: Activities of daily living, exercise, lung
transplantation, rehabilitation
Abbreviations: 6MWD, six-minute walking distance;
BE, bronchiectasis; BMI, body mass index; CI, confi-
dence interval; COPD, chronic obstructive pulmonary
disease; FEV1, forced expiratory volume in the first
second; ICU, intensive care unit; MET, metabolic equiv-
alent; PF, pulmonary fibrosis; QF, quadriceps force;
RCT, randomized controlled trial; SSLTx, bilateral lung
transplantation; VO2, max, peak oxygen consumption;
Wmax, peak work rate.
Received 16 November 2011, revised 29 December
2011 and accepted for publication 13 January 2012
Introduction
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 tech-
niques, immunosuppressant and antibiotic therapy have
contributed to improvement in postoperative sur vival (2).
Despite the overall success of the procedure, participa-
tion in daily activities, physical fitness and aspects of
health-related quality of life related to physical function-
ing remain impaired following transplantation (3). Improv-
ing these functional limitations might be possible with ex-
ercise training interventions. Around 30–50% of patients
develop comorbid conditions such as osteoporosis, hyper-
lipidemia 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 ventilator y or cardiovascular factors
(4,7,9). A major determinant of the reduced exercise ca-
pacity 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 immunosup-
pressive 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
1584
Exercise Training After Lung Transplantation
of developing some frequently observed comorbid condi-
tions 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 how-
ever not be regarded to be evidence based due to the lack
of randomized controlled studies (20). Insight in the po-
tential added value of an exercise training intervention is
important as the prescription of exercise training has im-
portant 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 transplanta-
tion. We therefore conducted a randomized controlled trial
that investigated the effects of a 3-month supervised ex-
ercise 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
The study was performed as a single-center parallel group randomized con-
trolled trial (RCT) with equal allocation ratio between intervention and con-
trol group. The trial was approved by the University Hospital Leuven’s In-
stitutional 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 pul-
monologist. 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 hospitaliza-
tion 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). Measure-
ments were performed with an accelerometer-based activity monitor (Dy-
naPort activity monitor, McRoberts BV, The Hague, the Netherlands). As-
sessment 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 feed-
back 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 ca-
pacity, 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 de-
tect 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 (a) <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 num-
bered, 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” regres-
sion 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 ex-
ception for the responses from the maximal cardiopulmonary exercise test.
This test was not performed in all patients on the waiting list for transplan-
tation. 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
American Journal of Transplantation 2012; 12: 1584–1592 1585
Langeretal.
Figure 1: Diagram showing the flow of participants through each stage of the randomized trial.
methods, sample size calculation, randomization and statistical analysis is
provided in the Supporting Information.
Results
Forty patients were randomized after hospital discharge be-
tween 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 dia-
gram 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. In-
clusion was terminated in October 2009 to finish the study
at the scheduled completion date of November 2010. Base-
line characteristics of participants are presented in Table 1.
Anthropometric characteristics, the prevalence of underly-
ing diagnoses, the moment of pretransplant assessments,
the duration of hospital stay, the t ypes of surgery per-
formed and the presence of early acute rejection before
hospital discharge were comparable between groups. Ad-
ditional information on immunosuppressive drug regimens
Ta b l e 1 : Baseline characteristics
Intervention Control group
group n = 18 Control group n = 16
Age (years) 59 (4) 59 (6)
Height (cm) 165 (7) 166 (7)
Weight (kg) 61 (15) 58 (13)
BMI (kg/m
2
) 22.1 (4.7) 20.9 (4.2)
Sex (female) 9 (50%) 9 (56%)
Diagnosis
(COPD/PF/BE)
15 (83%) / 2 / 1 14 (88%) / 2 / 0
Time to LTx (days) 174 (118) 152 (154)
Hospital stay (days) 27 (7) 28 (7)
ICUdays 5(2) 5(3)
Transplant type
(SSLTx)
15 (83%) 14 (88%)
Early acute rejection
(present)
6 (33%) 5 (31%)
Data are means (SD) or numbers (%).
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.
1586 American Journal of Transplantation 2012; 12: 1584–1592
Exercise Training After Lung Transplantation
during the first year following transplantation is provided in
Table S1.
At least four full days of activity monitor data were col-
lected for all patients during the four measurements (Pre-
LTX, Baseline, 3 months and 1 year after hospital dis-
charge). Severe limitations in daily physical activity, physical
fitness and quality of life were observed before transplan-
tation (Tables 2, 3 and S5). Immediately following the ex-
ercise training intervention (3 months after hospital dis-
charge) 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 ob-
served. 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 incre-
mental exercise test on a cycle ergometer (Table 3) and
two items of the SF-36 health status questionnaire (physi-
cal functioning and role limitations due to physical function-
ing, 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 (in-
tervention period; difference in slopes: b = 4.9, p = 0.001)
this was not the case (difference in slopes: b =−0.2,
p = 0.663) during the follow-up period (Figure 2). The
slopes of daily walking time (Figure 2) were also sig-
nificantly different in the first 3 months (b = 4.2, p =
0.011) and showed a trend to be different during the
follow-up period (b = 1.5, p = 0.085). No significantly
different slopes in either intervention or follow-up pe-
riod 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).
Significantly lower values for both average 24 h ambula-
tory diastolic and systolic blood pressure measurements
were observed in the intervention group 1 year after hospi-
tal 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 dia-
betes 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
Three months of supervised exercise training, initiated
immediately following hospital discharge, improved func-
tional recovery and reduced cardiovascular morbidity dur-
ing the first year after transplantation in lung recipients
who had experienced an uncomplicated postoperative pe-
riod. The treated patients engaged in more daily physi-
cal activity in the first year following hospit al discharge
which in turn resulted in favorable health outcomes. They
achieved better physical fitness (quadriceps force, func-
tional 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 im-
provements in participation in daily physical activities, func-
tional exercise capacity, peripheral muscle function, health-
related quality of life and cardiovascular morbidity. None of
the previous studies that looked into the effects of exer-
cise training on endurance capacity had been designed as
a randomized controlled trial (20). The importance of com-
paring 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 m onths after hospital discharge in com-
parison 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 fit-
ness, 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 interven-
tion 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 counsel-
ing intervention. It has been described previously that par-
ticipation in exercise training programs contributes to in-
creasing self-efficacy (i.e. the confidence of being able to
perform a certain behavior) for regular participation in phys-
ical activity (24).
American Journal of Transplantation 2012; 12: 1584–1592 1587
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Ta b l e 2 : Participation in daily physical activity before transplantation (Pre-LTx), upon hospital discharge (Baseline), 3 months and 1 year
after hospital discharge
Intervention Control Adjusted difference
1
(mean + SD) (mean + SD) (95% CI) p-Value
Sedentary (min/day)
2
Pre-LTx 497 ± 94 504 ± 113
Baseline 508 ± 90 525 ± 106
3 months 435 ± 108 495 ± 99 51 (118 to 17) 0.133
1 year 402 ± 106 459 ± 108 48 (114 to 17) 0.147
Standing (min/day)
2
Pre-LTx 182 ± 75 181 ± 101
Baseline 167 ± 19 149 ± 22
3 months 216 ± 100 176 ± 82 28 (28 to 86) 0.313
1 year 225 ± 103 193 ± 85 23 (40 to 85) 0.465
Walking (min/day)
2
Pre-LTx 36 ± 21 29 ± 21
Baseline 36 ± 16 32 ± 26
3 months 56 ± 24 38 ± 23 14 (4 to 24) 0.008
1year 85± 27 54 ± 30 26 (8 to 45) 0.006
MI walking (m/s
2
)
2
Pre-LTx 1.85 ± 0.22 1.71 ± 0.17
Baseline 1.85 ± 0.25 1.66 ± 0.28
3 months 2.13 ± 0.07 1.89 ± 0.15 0.18 (0.01 to 0.35) 0.044
1year 2.23 ± 0.18 1. 91 ± 0.16 0.27 (0.14 to 0.39) 0.001
Daily steps
2
Pre-LTx 3225 ± 2039 2426 ± 1747
Baseline 3094 ± 1458 2701 ± 2216
3 months 5194 ± 1586 3451 ± 2175 1376 (481 to 2269) 0.004
1 year 7406 ± 2574 4462 ± 2518 3017 (1185 to 4849) 0.002
Time > 3 METs (min/day)
3
Pre-LTx 20 ± 21 20 ± 26
Baseline 24 ± 24 17 ± 25
3 months 69 ± 45 38 ± 58 18 (2 to 38) 0.077
1year 98± 67 58 ± 70 27 (1 to 54) 0.047
1
Comparisons adjusted for baseline value.
2
Measured with the DynaPort activity monitor.
3
Measured with the SenseWear activity monitor.
CI = confidence interval; Sedentary = time spent lying and sitting; MI = movement intensity; METs = metabolic equivalents;
Time > 3METs= time spent in physical activity of at least moderate intensity.
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
Baseline 3 months 1 year
50
60
70
80
90
100
Interv ention
Control
*
*
#
Quadriceps Force
(%pred)
Baseline 3 months 1 year
50
60
70
80
90
100
*
*
6MWD (%pred)
Baseline 3 months 1 year
0
25
50
75
100
*
*
#
Daily Walking (min)
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.
1588 American Journal of Transplantation 2012; 12: 1584–1592
Exercise Training After Lung Transplantation
Ta b l e 3 : Levels of pulmonary function and physical fitness before transplantation (Pre-LTx), upon hospital discharge (Baseline), 3 months
and 1 year after hospital discharge
Intervention Control Adjusted difference
1
(mean ± SD) (mean ± SD) (95% CI) p-Value
FEV
1
(%pred)
Pre-LTx 33 ± 20 26 ± 10
Baseline 79 ± 18 69 ± 17
3 months 89 ± 18 80 ± 22 1 (9 to 11) 0.888
1year 92± 20 89 ± 25 3(16 to 10) 0.615
QF (%pred)
Pre-LTx 78 ± 22 75 ± 25
Baseline 63 ± 16 56 ± 22
3 months 82 ± 20 60 ± 18 17 (9 to 24) 0.001
1year 92± 21 71 ± 20 16 (7 to 25) 0.001
6MWD (%pred)
Pre-LTx 53 ± 11 50 ± 16
Baseline 56 ± 10 51 ± 14
3 months 79 ± 870± 10 9 (3 to 15) 0.008
1year 86± 774± 11 12 (5 to 19) 0.002
Wmax (%pred)
Baseline 47 ± 15 39 ± 14
3 months 63 ± 23 50 ± 22 13 (2 to 29) 0.093
1year 69± 20 53 ± 23 16 (1 to 31) 0.042
VO
2,max
(%pred)
Baseline 55 ± 15 47 ± 14
3 months 71 ± 26 59 ± 21 12 (5 to 28) 0.149
1year 78± 27 63 ± 24 15 (2 to 33) 0.082
1
Comparisons adjusted for baseline value.
CI = confidence interval; pred = predicted; FEV
1
= forced expiratory volume in the first second; QF = quadriceps force; 6MWD =
6-minute walking distance; W
max
= peak workload; VO
2,max
= peak oxygen uptake.
limitations in most patients after lung transplantation (9).
The deterioration in skeletal muscle function in the immedi-
ate postoperative period therefore needs to be addressed
during rehabilitative treatments after lung transplant ation.
This study shows that exercise training is capable of im-
proving leg muscle function in lung recipients. While both
groups reported symptoms of leg effort to be the main
limiting symptom during the maximal incremental exer-
cise test on a cycle ergometer the intervention group was
able to complete a significantly higher amount of work dur-
ing 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 m onths after hospit al discharge was
still clearly lower than before the transplant ation. Perform-
ing 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 resis-
tance 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 sig-
nificantly 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 phys-
ical 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 compari-
son with their pretransplant status. This is also a possi-
ble explanation why none of the patients in the control
group wanted to participate in an exercise training inter-
vention 3 months after hospital discharge. Measures of
physical fitness of these patients remained however well
below the normal values for their age and the improve-
ments 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).
American Journal of Transplantation 2012; 12: 1584–1592 1589
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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 clini-
cally relevant differences in the occurrence of hypertension
and diabetes were detected. The prevalence of these mor-
bidities is known to increase dramatically within the first
5 years following lung transplantation (4). This study pro-
vides 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 ben-
efits of physical activity. An immediate (acute) reduction in
blood pressure following exercise has been termed “pos-
texercise hypotension and is agreed to be caused by re-
ductions in vascular resistance (26). The mechanisms as-
sociated with the chronic adaptations to blood pressure
are more complex. A meta-analysis supports this chronic
role being partially explained by a decreased systemic vas-
cular resist ance in which the autonomic nervous system
and renin–angiotensin system are most likely the under-
lying 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 symp-
toms 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 fol-
lowing hospital discharge. Larger studies with a longer
follow-up would be necessary to specifically investigate
the effects of exercise training interventions on the inci-
dence 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 randomiza-
tion 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 percep-
tion 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 improv-
ing 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 hospit al dis-
charge. 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 multicen-
ter 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 uncompli-
cated 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 dif-
ferent spontaneous postoperative recovery due to a less
sedentary lifestyle both before and after the transplanta-
tion. Muscle abnormalities in younger lung recipients with
cystic fibrosis have however also been observed (30). This
makes it likely that exercise training could also h ave ben-
eficial effects in these patients. A randomized controlled
trial of an exercise training intervention in these younger
patients would be necessary to clarify this.
Conclusion
In conclusion the results of this study show that supervised
exercise training initiated immediately following hospit al
discharge improve functional recovery after lung transplan-
tation in patients who experienced an uncomplicated post-
operative 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 there-
fore be strongly encouraged to participate in an outpatient
exercise training program in a specialized center after hos-
pital discharge.
1590 American Journal of Transplantation 2012; 12: 1584–1592
Exercise Training After Lung Transplantation
Acknowledgments
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. Cebri
`
a i Iranzo; Lung Transplant Unit Out-
patient 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. Decaluw
´
e, P. De Leyn, P. Nafteux and
T. L e r u t .
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 statis-
tical 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
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.
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Supporting Information
Additional Supporting Information may be found in the on-
line version of this article:
Expanded methods section
Ta b l e S 1 : Immunosuppressive regimens
Ta b l e S 2 : Levels of anxiety and depression (Hospit al Anxi-
ety and Depression scale)
Ta b l e S 3 : Frequencies of prescribed antihypertensive
drugs
Ta b l e S 4 : Bone mineral density of patients
Ta b l e S 5 : Levels of health-related quality of life (SF-36
health status questionnaire)
Ta b l e S 6 : Cardiovascular comorbidity
Ta b l e S 7 : Handgrip force and respiratory muscle force
Please note: Wiley-Blackwell is not responsible for the con-
tent or functionality of any supporting materials supplied
by the authors. Any queries (other than missing material)
should be directed to the corresponding author for the
article.
1592 American Journal of Transplantation 2012; 12: 1584–1592
    • "Based on the results of a randomized control trial studying exercise training after lung transplantation, patients should be strongly encouraged to participate in an exercise training intervention. These patients exhibited improved functional recovery and increased participation in daily physical activities (Langer et al. 2012). "
    [Show abstract] [Hide abstract] ABSTRACT: Aims: The aims of this study were two fold. a)to develop the concept analysis by Allvin et al. from lung recipients' perspective of their post-transplant recovery process and b)to identify the recovery trajectories including critical junctions in the post-transplant recovery process after lung transplantation. Background: Lung transplantation is an established treatment for patients with end-stage lung disease. The recovery process after lung transplantation is very demanding. Today, patients are expected to play an active role in their own recovery but require on-going support during the process. Design: A deductive, retrospective interview study using directed content analysis and Allvin's recovery concept analysis. Method: Fifteen adult lung transplant recipients who were due their 12-month follow-up were consecutively included and interviewed during 2015. Patients who were medically unstable or had difficulties speaking Swedish were excluded from this multi-centre study. Findings: Allvin's concept analysis is partly applicable to the context of lung transplantation. The recipients' experience of the post-transplant recovery process could be confirmed in the main dimensions of the concept analysis, while several sub-dimensions were contradictory and were excluded. Six new sub-dimensions emerged; symptom management, adjusting to physical restraints, achieving an optimum level of psychological well-being, emotional transition, social adaptation and reconstructing daily occupation. Conclusion: The concept analysis by Allvin et al. was possible to expand to fit the lung transplantation context and a new contextual definition of post-transplant recovery after solid organ transplantation was developed. Recovery and health were viewed as two different things. This article is protected by copyright. All rights reserved.
    Full-text · Article · Jun 2016
    • "Calcineurin inhibitors reduce the excretion of cholesterol to the bile and the peripheral LDL-cholesterol receptors, thereby raising circulating levels of cholesterol [11]. The link between exercise and improved physical condition has been well established in patients after different types of transplantation [12]. Exercise training can improve exercise capacity, body composition, and muscle strength following different types of transplantation [13] [14] [15]. "
    [Show abstract] [Hide abstract] ABSTRACT: Background: As long-term survival improves after liver transplantation, metabolic syndrome, including dyslipidemia, hypertension, diabetes, obesity and sarcopenia is emerging as a major cause of late morbidity and mortality. Aim: The aim of this work was to evaluate the efficacy of exercise training program as a type of physical therapy approach in treatment of sarcopenic obesity and dyslipidemia after liver transplantation. Subjects and methods: Thirty patients with liver transplantation since six months had participated in this study. The patients were randomly divided into two groups of equal numbers. The exercise group received aerobic and resisted exercise in addition to receive the traditional medical intervention. The control group received only the traditional medical intervention. Measurements of fat mass, muscle mass, cholesterol level and triglycerides level (by bioelectrical impedance and lipid profile) were collected before treatment and after three months of treatment. Results: Comparison between exercise and control groups post treatment revealed a significant decrease in fat mass, cholesterol and triglyceride levels in the exercise group compared to the control group (p
    Full-text · Article · Jan 2015
    • "The relationships between prognostic factors and the behavioural outcome can be automatically inferred from participants with known prognostic factors and outcomes on entirely mathematical criteria [8] (a-classifier obtained from data mining). The relationships can also be theorized by an expert committee and validated on participants with known prognostic factors and outcomes [7] (b-man-made model). Our proposed system relies on asking participants about the relationships rather than the prognostic factors in isolation (c-Fuzzy Cognitive Map). "
    [Show abstract] [Hide abstract] ABSTRACT: Controlling bias is key to successful randomized controlled trials for behaviour change. Bias can be generated at multiple points during a study, for example, when participants are allocated to different groups. Several methods of allocations exist to randomly distribute participants over the groups such that their prognostic factors (e.g., socio-demographic variables) are similar, in an effort to keep participants' outcomes comparable at baseline. Since it is challenging to create such groups when all prognostic factors are taken together, these factors are often balanced in isolation or only the ones deemed most relevant are balanced. However, the complex interactions among prognostic factors may lead to a poor estimate of behaviour, causing unbalanced groups at baseline, which may introduce accidental bias. We present a novel computational approach for allocating participants to different groups. Our approach automatically uses participants' experiences to model (the interactions among) their prognostic factors and infer how their behaviour is expected to change under a given intervention. Participants are then allocated based on their inferred behaviour rather than on selected prognostic factors. In order to assess the potential of our approach, we collected two datasets regarding the behaviour of participants (n = 430 and n = 187). The potential of the approach on larger sample sizes was examined using synthetic data. All three datasets highlighted that our approach could lead to groups with similar expected behavioural changes. The computational approach proposed here can complement existing statistical approaches when behaviours involve numerous complex relationships, and quantitative data is not readily available to model these relationships. The software implementing our approach and commonly used alternatives is provided at no charge to assist practitioners in the design of their own studies and to compare participants' allocations.
    Full-text · Article · Dec 2014
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