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(Received in original form August 6, 2009; accepted in final form February 3, 2010)
* These authors contributed equally to this article.
Supported by Research Foundation Flanders grants KAN 1.5.139.06N and
G.0386.05N.
Correspondence and requests for reprints should be addressed to Thierry
Troosters, P.T., Ph.D., Respiratory Rehabilitation and Respiratory Division, UZ
Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium. E-mail: thierry.troosters@
med.kuleuven.be
This article has an online supplement, which is accessible from this issues table of
contents at www.atsjournals.org
Am J Respir Crit Care Med Vol 181. pp 10721077, 2010
Originally Published in Press as DOI: 10.1164/rccm.200908-1203OC on February 4, 2010
Internet address: www.atsjournals.org
AT A GLANCE COMMENTARY
Scientific Knowledge on the Subject
exacerbations of COPD. It is unclear, however, whether traininginduced acute inflammation could result in deleterious effects in
patients already suffering from systemic inflammation. Hence,
feasibility and safety need to be further investigated in the context
of acute exacerbations.
We speculated that resistance training is able to counteract
the deleterious effects of acute exacerbations on skeletal muscle
force. A randomized controlled trial set out to investigate the
feasibility and safety of such a training program during a hospital
admission for an acute exacerbation of COPD. The primary
outcome of the study was skeletal muscle force after resistance
training or usual care. Skeletal muscle biopsies were obtained
after the training or control period to confirm the impact of the
resistance training on anabolic and catabolic markers in skeletal
muscle.
METHODS
A detailed description of the methods used in the present study is
available in the online supplement. The trial has been submitted to
www.clinicaltrials.gov with identification number NCT00877084. Preliminary data were presented in abstract form (11, 12).
Methods
Maximal voluntary quadriceps force (QF) was assessed on Day 2, Day 8,
and at follow-up (1 mo after discharge). Functional exercise tolerance
and lung function were assessed at discharge and after 1 mo. Details on
these assessments can be found in the online supplement. Symptoms of
dyspnea were assessed using the Medical Research Council dyspnea
scale on Day 1 and at 1 month after discharge (14).
A morning venous blood sample was taken on Days 1, 3, 8, and
1 month after discharge. Circulating levels of C-reactive protein,
testosterone, and insulinlike growth factor-I (IGF-1) were assessed in
serum and plasma, respectively.
In 20 patients willing to undergo the procedures, a percutaneous
Bergstrom needle muscle biopsy (103 6 51 mg) of the m. vastus lateralis
was obtained on the day of discharge. Baseline characteristics of these
representative patients are given in the online data supplement. Quantitative real-time polymerase chain reaction assay with Sybr Green was
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Interventions
During the hospital admission, patients in the control group received
usual care according to a strict clinical pathway (2). Patients received
standard doses of oral corticosteroids to treat the exacerbation.
In principle, patients received 32 mgday21 oral methylprednisolone
for 1 week, followed by 16 mgday21 for 4 days and a subsequent
decrease of 4 mgweek21. However, steroids were given and tapered as
judged possible by the treating chest physician. Physiotherapy was
limited to mucous secretion clearance techniques and breathing
exercises. Patients were not restricted in their physical activities but
no formal exercise therapy was offered. The training group received
usual care and in addition performed daily quadriceps resistance
training for 7 days on a knee-extension chair (Gymna, Bilsen,
Belgium). The initial load was set at 70% of the 1RM (one repetition
maximum: the maximum load that can be moved only once over the
full range of motion without compensatory movements). Patients
performed three sets of eight repetitions and adjustments in the load
were made based on symptoms (Borg scores of dyspnea and fatigue;
see online supplement for further details and picture). The individual
training sessions were supervised by two physiotherapist-researchers
(V.S.P. and T.T.).
Statistical Analysis
Statistical analysis was performed using the Statistical Analysis System
v9.2 (SAS Institute, Cary, NC). Results were described as mean 6 SD
unless specified otherwise. All patients who had their outcome
measures assessed were included in the analysis, regardless of the
number of sessions they successfully completed. No imputations were
made for missing data. To minimize baseline differences, QF was
expressed as a percentage of the value obtained at Day 2. A two-way
analysis of variance was performed to analyze the effect of the
intervention. In addition, the effect of the intervention during the
hospital admission was analyzed using an unpaired t test. Differences
in mRNA expression were analyzed using nonparametric testing.
We speculated that myostatin, MAFbx, MURF-1, and NEDD4 would
be up-regulated in the control group as these molecules are
up-regulated with unloading. By contrast, we speculated that MGF
and IGF-I would be up-regulated with resistance training. These
hypotheses were tested with one-tailed nonparametric testing. The
relative anaboliccatabolic balance was obtained by calculating
the relative mRNA expression as a value from 0 to 100 with 0 being
the lowest expression and 100 the highest expression observed in the
available biopsies from patients in both groups. The mean expression
of the anabolic (MGF, IGF-I, MyoD, and myogenin) and the catabolic
(myostatin, MAFbx, MURF-1, and NEDD4) were subtracted. A value
greater than zero would indicate a balance in favor of anabolism, and a
value less than zero would indicate a balance in favor of catabolism.
For all analyses the level of significance for all comparisons was set
at P < 0.05.
RESULTS
Thirty-six patients were assessed at the end of the hospital
discharge. Their characteristics are displayed in Table 1. There
was a trend for a better FEV1 in the control group. No other
differences were seen between the groups. A similar number of
patients in the control and training groups (53% vs. 76%) had
received steroids before admission to the hospital by their general
practitioner. The cumulative dose of methylprednisolone over
the exacerbation tended to be lower in control subjects (157 6
54 mg) compared with those in the training group (185 6 27 mg;
P 5 0.06).
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2010
Gender, f/m
Age, yr
Hospital stay, d
Methylpred before, % (mg)
BMI, kgm22
FEV1, % predicted
FRC, % predicted
TL,co, % predicted
PaO2, mm Hg
PaCO2, mm Hg
MRC, points
Smoking, pack-years
6-Min walking distance, m
Current smokers, no.
Control Group
(n 5 19)
Training Group
(n 5 17)
5/14
69 6 7
8 (814)
53% (80 6 107)
24 6 6
50 6 18
142 6 34
54 6 23
63 6 12
44 6 4
2.3 6 1.1
48 6 22
380 6 117
8
4/13
67 6 8
8 (89)
76%* (103 6 108)
25 6 6
40 6 12
151 6 36
50 6 21
70 6 10
44 6 3
2.2 6 1.1
43 6 12
330 6 137
5
The resistance training program had no impact on the readmission rate of patients. After 6 months, nine patients from the
training group and eight control subjects were readmitted to the
hospital.
DISCUSSION
This randomized controlled trial shows that resistance training
can be applied during a hospital admission for a severe exacerbation of COPD. Resistance training has favorable effects on
quadriceps muscle force likely through a favorable impact on
the anaboliccatabolic balance. In particular it counteracts the
up-regulation of myostatin. We did not observe increased
systemic inflammation induced by the resistance training.
Quadriceps muscle weakness is an important systemic consequence of severe acute exacerbations. Our group previously
showed an acute reduction in quadriceps strength (1, 2).
Hospital admissions for COPD exacerbations may lead to
skeletal muscle dysfunction. Several factors, including bed rest
combined with the administration of high doses of oral gluco-
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TABLE 2. SERUM LEVELS OF INFLAMMATION AND
ANABOLIC FACTORS
ER
CRP, mgml21
WBCneutro, 103 cells/ml
Testtot, ngdl21
IGF-I, ngml21
CT
TR
CT
TR
CT
TR
CT
TR
53 6 77*
56 6 65*
10.7 6 3.82*
9.90 6 5.69*
98 6 97
100 6 114
108 6 37
135 6 51
Day 3
16
24
8.14
6.70
109
107
125
127
6
6
6
6
6
6
6
6
21
38
2.85
2.92
103
127
44
42
Day 8
8 6 12
10 6 19
7.76 6 2.47
6.75 6 2.68
157 6 122
141 6 132
148 6 45
149 6 62
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physical activity levels (2), this was unfortunately not done in the
present study. Six-minute walking and skeletal muscle force are
related to physical activity in patients with COPD (26).
In addition, muscle strength and 6-minute walking distance have
been shown to be related to self-efficacy for functional tasks in
patients with arthritis (27). It is tempting to speculate that patients
who are discharged from hospital with less impaired muscle
strength have more confidence to take up activities of daily living.
This clearly needs further investigation, however. It should be
mentioned that even the patients who followed resistance training during the hospital admission would likely have benefited
from further pulmonary rehabilitation after discharge (28, 29).
The present study may provide an effective bridge to such a
rehabilitation program. Several studies showed the effectiveness
of rehabilitation in patients who were recently discharged from
hospital after an exacerbation (29). The proposed intervention
alone, however, does not prevent readmission to hospital.
The present study has some limitations. First, the study was
powered to investigate the feasibility of resistance training and
its effectiveness in enhancing skeletal muscle function during
acute exacerbations. Other analysis should be regarded as
secondary. Larger studies are needed to investigate the impact
of this intervention on longer-term outcomes. Second, we
assessed maximal voluntary quadriceps strength. Although our
research group has extensive experience with this technique,
less effort-dependent measurements would be preferred. This is
why we obtained muscle biopsy samples in a subset of patients.
From these biopsies we conclude that indeed anabolism was
initiated in these patients. Third, patients in the control group
did not follow sham training. This was a considered choice
because no studies were performed to identify the minimal dose
of muscle activity in these patients to block the catabolism seen
during exacerbations.
The mechanisms by which resistance training enhances
muscle function in the context of an acute exacerbation remain
to be explored. Serial biopsies are needed to investigate the
series of events initiated by repeated bouts of exercise training.
In addition, expression of genes does not necessarily mean that
changes at the protein level are initiated or that the activity of
proteins is altered. Unfortunately, the small biopsy size did not
allow carrying out analyses at the protein level. Hence, the
present study cannot go much further than to suggest that the
catabolic mechanisms initiated by the inactivity seen during
exacerbations are at least to some extent counterbalanced by
the resistance training.
We conclude that resistance training during acute exacerbations of COPD is a safe and effective strategy to counterbalance
loss of skeletal muscle function. Resistance training does
generate a protective stimulus to the skeletal muscle and may
facilitate functional recovery after an acute exacerbation.
Conflict of Interest Statement: T.T. has received advisory board fees from Bl-Pfizer
and AZ ($1,001$5,000) and has received lecture fees from Bl-Pfizer and Chiesi
($1,001$5,000). V.S.P. does not have a financial relationship with a commercial
entity that has an interest in the subject of this manuscript. T.C. does not have
a financial relationship with a commercial entity that has an interest in the subject
of this manuscript. F.P. does not have a financial relationship with a commercial
entity that has an interest in the subject of this manuscript. G.G.R. does not have
a financial relationship with a commercial entity that has an interest in the subject
of this manuscript. M.D. has received consultancy fees from Dompe ($5,001
$10,000); fees for serving on an advisory board from Boehringer, GlaxoSmithKline,
and Nycomed ($5,001$10,000); lecture fees from Pfizer ($5,001$10,001); and
an industry-sponsored grant from AstraZeneca ($5,001$10,000). R.G. does not
have a financial relationship with a commercial entity that has an interest in the
subject of this manuscript.
Acknowledgment: The authors thank Drs. M. Van Vliet and G. Maury for taking
the muscle biopsies in the present study and F. Vanderhoydonck for his help with
the RT-PCR. They also thank the clinical teams of the respiratory division
(particularly Unit 650 and 651 and the pulmonary rehabilitation department)
for assisting with the logistics of the study.
1077
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