Download Global muscle dysfunction as a risk factor of readmission to hospital

Respiratory Medicine (2010) 104, 1896e1902
available at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/rmed
Global muscle dysfunction as a risk factor of
readmission to hospital due to COPD exacerbations
Jordi Vilaró a,g, Alba Ramirez-Sarmiento b,g,
Juana Ma Martı́nez-Llorens b, Teresa Mendoza c, Miguel Alvarez d,
Natalia Sánchez-Cayado e, Ángeles Vega e, Elena Gimeno f, Carlos Coronell b,
Joaquim Gea b, Josep Roca f, Mauricio Orozco-Levi b,*
a
FCS Blanquerna, Universitat Ramon Llull, Barcelona, Spain
Grupo de Investigación en Lesión, Respuesta Inmune y Función Pulmonar (LIF), Instituto Municipal de Investigación Médica
(IMIM), Servei de Pneumologia, Hospital del Mar; CIBER of Respiratory Diseases (CIBERES), ISCIII, Barcelona, Spain
c
Servicio de Rehabilitación Hospital Insular, Las Palmas de Gran Canaria, Spain
d
Hospital General de la Defensa, Madrid, Spain
e
Instituto Nacional de Silicosis, Oviedo, Spain
f
Servei de Pneumologia i Al.lergia Respiratòria (CIBERESP), Hospital Clı´nic i Provincial, Barcelona, Spain
b
Received 2 February 2010; accepted 3 May 2010
Available online 11 June 2010
KEYWORDS
Respiratory and
peripheral muscles;
Muscle weakness;
Nutrition;
Exacerbation;
Hospitalisation
Summary
Exacerbations of chronic obstructive pulmonary disease (COPD) are associated with several
modifiable (sedentary life-style, smoking, malnutrition, hypoxemia) and non-modifiable
(age, co-morbidities, severity of pulmonary function, respiratory infections) risk factors. We
hypothesise that most of these risk factors may have a converging and deleterious effects
on both respiratory and peripheral muscle function in COPD patients.
Methods: A multicentre study was carried out in 121 COPD patients (92% males, 63 11 yr, FEV1,
49 17%pred). Assessments included anthropometrics, lung function, body composition using
bioelectrical impedance analysis (BIA), and global muscle function (peripheral muscle (dominant
and non-dominant hand grip strength, HGS), inspiratory (PImax), and expiratory (PEmax) muscle
strength). GOLD stage, clinical status (stable vs. non-stable) and both current and past hospital
admissions due to COPD exacerbations were included as covariates in the analyses.
Results: Respiratory and peripheral muscle weakness were observed in all subsets of patients.
Muscle weakness, was significantly associated with both current and past hospitalisations.
Patients with history of multiple admissions showed increased global muscle weakness after
* Corresponding author at: Servei de Pneumologia, Hospital del Mar, Passeig Marı́tim 25-29, E-08003 Barcelona, Spain. Tel.: þ34
932483138; fax: þ34 932213237.
E-mail address: [email protected] (M. Orozco-Levi).
g
For authorship purposes, J. Vilaro and A. Ramirez-Sarmiento contributed equally to this project and share the rank of first author.
0954-6111/$ - see front matter ª 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.rmed.2010.05.001
Muscle dysfunction and risk of exacerbation in COPD
1897
adjusting by FEV1 (PEmax, OR Z 6.8, p < 0.01; PImax, OR Z 2.9, p < 0.05; HGSd, OR Z 2.4, and
HGSnd, OR Z 2.6, p Z 0.05). Moreover, a significant increase in both respiratory and peripheral
muscle weakness, after adjusting by FEV1, was associated with current acute exacerbations.
Conclusions: Muscle dysfunction, adjusted by GOLD stage, is associated with an increased risk of
hospital admissions due to acute episodes of exacerbation of the disease. Current exacerbations
further deteriorate muscle dysfunction
ª 2010 Elsevier Ltd. All rights reserved.
Introduction
Chronic obstructive pulmonary disease (COPD) is a relevant
health problem in most developed countries due to its high
prevalence and enormous costs, both direct and indirect,
which generate a tremendous burden on healthcare
systems.1 In Spain, COPD affects about 9% of the adult
population (40e70 years old) and is the fourth largest cause
of hospital admission and death in this age group.1,2
The natural history of COPD implies a series of respiratory symptoms and periods of clinical exacerbation that
decrease not only the quality of life but also life expectancy.3 Exacerbation is clinically defined by worsened
dyspnoea, worsened sputum volume and/or change in its
colour, and new or worsened cough.2 There is limited
information describing the clinicalephysiological changes
in patients admitted to hospital with an exacerbation of
COPD. Although several groups of authors have studied the
risk factors of exacerbation in relation to hospital readmission for COPD patients, no study has specifically focused
on muscle dysfunction.
One of the frequent extrapulmonary manifestations of
COPD is skeletal muscle dysfunction and wasting.4 With
increasing severity of disease, patients with COPD loose
muscle bulk, especially in their thighs and upper arms. Over
time, exercise endurance decreases in these patients and
they complain of dyspnoea and leg discomfort with mild to
moderate workload increases.5 These symptoms curtail
exercise capacity and compromise cardiac fitness, which
further limits exercise tolerance, creating a vicious downward spiral that can eventually lead to generalised debility
and immobility.6 Skeletal muscle dysfunction contributes to
reduce health status of patients with COPD and substantially increases the risk of mortality, independent of
traditional markers of COPD mortality such as baseline lung
function, age, and cigarette smoking.7,8 Encouragingly,
early interventions with exercise programmes may restore
some of the lost health status related to muscle dysfunction
and increase patients’ exercise tolerance and stamina.9
It is clearly recognised that, whereas one group of COPD
patients may rarely need hospital admission during exacerbations, other groups of patients are prone to multiple
admissions.2 There are a few of studies suggesting that
inspiratory and expiratory muscle dysfunction could act as
a modifiable risk factor of hospital admission in patients
with COPD. Martı́nez-Llorens et al.10 using a case-control
study design showed that exacerbations of COPD associates
with pronounced deleterious changes in skeletal muscle
function in association with acute loss of muscle mass. In
other setting, González et al.11 clearly identified that
respiratory muscle overload (defined as a high pressuretime index of the inspiratory muscles) as a risk factor of
hospital readmission in a 1-year follow-up of a cohort of
patients with moderate-to-severe COPD. We hypothesised
that patients with higher risk for severe exacerbations have
a limited ventilatory reserve and that respiratory muscle
dysfunction underlies and negatively affects the balance
between functional reserve and acute loading imposed by
exacerbation.12 We thus considered that (1) a greater
respiratory muscle dysfunction can be present even at the
stable clinical conditions in patients with greater risk for
hospital admission, and (2) that global muscle involvement
could be captured by measuring inspiratory, expiratory and
peripheral muscle strength. To test these hypotheses,
a multicentre study was performed in two subsets of COPD
patients defined by their clinical stability (present or
absent). In a post-hoc analysis, the history of hospital
admissions (none, current, or multiple hospitalisations) was
taken in account in the analyses.
Methods
This was a multicentre, cross-sectional study carried out
over two consecutive years. The principles of the Declaration of Helsinki13 were applied and all patients gave written
informed consent to participate. The study was approved
by the Ethics Committees at all the centres participating in
the study.
Candidates were all patients with COPD assigned to two
cohorts: 1) patients admitted to the hospital due to exacerbations of COPD, and 2) stable COPD patients that
currently go to the hospital for their regular follow-up.
Those subsets of patients were defined by their clinical
stability (present or absent). In a post-hoc analysis, the
history of hospital admissions (none, current, or multiple
hospitalisations) was taken into account for the definition
of study groups. Group 1 was composed of patients who
attended regular hospital follow-up but had never required
hospital admission. Group 2 included clinically stable COPD
patients defined as three or more months from the last
exacerbation with a history of multiple (three or more)
hospital admissions during the last year. Group 3 was
composed of patients admitted to hospital for the very first
time with a physician diagnosis of an acute exacerbation of
COPD. Finally, Group 4 included patients with acute
exacerbation but admitted to the hospital on multiple
(three or more) occasions. Only patients requiring level II
admission that is hospitalisation in a medical ward but not
in the ICU14 were included in the study. In the latter two
groups (3 and 4), a respiratory physiotherapist performed
an early (<48 hours of admission) assessment that included:
1) body weight; 2) inspiratory and expiratory muscle
strength (expressed as maximal expiratory and inspiratory
mouth pressures, respectively); 3) peripheral muscle
1898
strength (measured by hand dynamometry) and 4) body
composition (bioelectrical impedance analysis, expressed
in both absolute and relative values). Conventional blood
and biochemical analyses were also taken for all patients
and all prescribed drugs were systematically recorded.
Exclusion criteria were as follows: pneumonia, infection
from any other organ, left heart failure, previous myocardial infarction, previous or present pulmonary embolism,
asthma or the need for ventilatory support. In addition,
patients were excluded if they had chronic respiratory
failure and relevant comorbidity. These were defined as the
presence or suspicion of recent orthopaedic, medical, or
surgical diseases that could affect muscle structure and
function and introduce confusion factors into the analysis.
Peripheral oedema, suspicion of ascites, hormonal therapy
for causes other than hyperglycaemia associated with
steroid therapy during admission, and history of chronic
systemic steroid therapy were considered additional
exclusion criteria Current smoking was not considered an
exclusion criterion.
Measurements
Body weight (in kilograms) was assessed using officially
approved floor scales (SECA, Berlin, Germany). Patients
were weighed in light clothing, barefoot and with an empty
bladder. Values were rounded to nearest 100 g. Height (in
m) was measured using a wall-mounted stadiometer. Body
mass index (BMI) was calculated with the formula weight/
height2 (kg/m2). To assess body compartments, bioelectrical impedance analysis (BIA) was performed using
portable equipment (BODYSTAT 1500, Bodystat LTD, Isle
of Man, British Isles). Fat, muscle mass and total body water
were determined and expressed as relative values to total
body weight. Arterial blood was taken following conventional techniques. Gas analyses were performed (Beckman
Coulter, Synchron Cx9Po, Germany). Forced spirometry
(Sibel, Barcelona, Spain), static lung volumes, airway
resistance, and carbon monoxide diffusing capacity (Masterlab, Jaeger, Würzburg, Germany) were assessed in all
patients.15e17 Inspiratory and expiratory muscle strength
were assessed by determining maximal respiratory mouth
pressures during voluntary manoeuvres. Patients were
instructed to carry out maximal respiratory efforts with
occluded airway.18 Maximal inspiratory pressure (PImax) was
measured from pulmonary residual volume (RV), and
maximal expiratory pressure (PEmax) from total lung
capacity (TLC). The best value of three reproducible
manoeuvres (difference <5%) was included in the analysis.
(Pmax Morgan Medical, Gillingham, Kent, UK). PImax and
PEmax values were assessed both in absolute (cmH2O) and
relative pressure values according to reference values
reported by Morales and colleagues.19
A hand dynamometer (JAMAR dynamometer; Preston,
Jackson, MI, USA) was used to record maximal voluntary
hand grip strength (HGS, in kg) of the finger flexors in both
the dominant and non-dominant hand (HGSd and HGSnd
respectively) during three consecutive manoeuvres separated by a 3-minute rest. The maximal value of the
reproducible manoeuvres was used for the analysis. Absolute and relative values were analysed in relation to
reference values.20
J. Vilaró et al.
Statistical analysis
All numerical values are expressed as the mean SD. As
a case control study the characteristics analysis was conducted using the t test (for quantitative variables of normal
distribution), the KruskaleWallis test (for quantitative
variables of non-normal distribution) or c2 (for qualitative
variables). Normal distribution was tested using a ShapiroeWilk test. The variables corresponding to muscle function and body composition were included in the analyses as
dependent variables. Age and lung function tests were
analysed as independent variables. An unconditioned
multivariate logistic regression model was used to obtain
the association between muscle weakness and exacerbation, after adjusting for potential confounders.21 A p value
of <0.05 was deemed to be significant.
Results
A total of 121 former or currently smoking patients (92%
males) were included in the study. As part of the usual
outpatient treatment, all patients received some inhaled
bronchodilator therapy (formoterol, salmeterol, albuterol,
tiotropium, ipratropium), 5% received oral theophylline,
and 15% received inhaled steroids. No patient received
systemic steroid therapy on a regular basis. At baseline, no
patient presented chronic respiratory failure (defined as
PaO2 <60 mmHg), and none of them qualified for long-term
oxygen therapy. Ten patients, however, showed PaCO2
above 45 mmHg.
General characteristics of the study groups are summarised in Table 1. Seventy-seven patients were at stable
clinical conditions, whereas 44 patients were admitted to
the hospital due to acute exacerbation of COPD. Differences in body composition were associated with history of
multiple hospital admissions whereas patients under first
hospital admission showed fat and fat-free mass comparable to the stable non admitted COPD group. Collectively,
there were differences between the four groups in some
principal pulmonary function variables. Patients with
history of multiple admissions and present acute exacerbation, disclosed greater air trapping (%RV) and lower
diffusing capacity for CO (both TLCO and KCO) compared to
the COPD patients without admissions (p < 0.05 each).
Table 2 shows that muscle weakness was strongly associated with the past and current exacerbations of COPD.
Fig. 1 shows a significant decrease of both respiratory and
peripheral muscle strength in all patient groups. After
adjusting by GOLD stage (FEV1), muscle weakness showed
a significant association with two covariates: number of
past admissions and current hospital admission, as indicated in Tables 2e4.
Discussion
The present study confirms that dysfunction of both respiratory and peripheral muscles is highly prevalent in patients
with COPD, even during stable clinical conditions. This is
probably the first report identifying an association between
risk for hospital admission due to exacerbations and baseline muscle function, irrespective of body weight and BMI.
Muscle dysfunction and risk of exacerbation in COPD
Table 1
1899
General characteristics of the study population.
Stable COPD
Patients
n (%)
Age
Yrs
Anthropometrics
Weight
Kg
BMI
kg/m2
TBW
%
FM
%
FFM
%
Pulmonary function
% pred
FEV1
FVC
% pred
TLC
% pred
RV
% pred
TLco
% pred
Kco
% pred
PaO2
mmHg
PaCO2
mmHg
Smoking exposure
Smoking, %
Current/former
Pack-year
Acute exacerbation of COPD
No previous
admissions
With multiple
admissionsa
No previous
admissionsa
With multiple
admissionsa
50 (41)
667
27 (22)
687
17 (14)
678
27 (22)
659
7513
274
544
289
203
7616
275
573a
183b
201
718
253
573a
276
184
7817
285
554
226a
226a
4917
7213
11020
16255
6323
7521
7412
395
4215
6815
10816
10816
5419
7226
7110
415
3716
6223
11223
17869
6011
6320
649
4210
3713
5919
11021
20965b
4721a
5825a
6316
436
34/66
2920
4/96
348
44/56
4942a
33/67
309
Abbreviations: (BMI): body mass index; (TBW): Total body water; (FM); fat mass; (FFM): fat-free mass; (FEV1): forced expiratory volume
in the 1st second; (FVC): forced vital capacity; (TLC) total lung capacity; (RV): residual volume; (Tlco, Kco): transfer capacity for CO.
a
p<0.05 ; p values correspond to comparisons with the stable COPD with no previous hospital admission group.
b
p<0.01; p values correspond to comparisons with the stable COPD with no previous hospital admission group.
This association between muscle weakness and risk of
hospitalisation remained significantly increased after
adjustment by the degree of airflow obstruction.
Muscle dysfunction in patients with COPD is not merely
a cosmetic description. Muscle function is relevant from the
clinical point of view as it is associated with increased
symptoms (dyspnoea and discomfort in legs), impaired
physical performance (e.g., decrease in exercise capacity),
reduced health status, and increased risk of mortality,2
independent of traditional markers of COPD mortality
such as baseline lung function, age, and cigarette
smoking.6,7 Surprisingly, we identified one study analysing
the potential role of muscle dysfunction as a risk factor of
severe exacerbations of COPD and hospital admissions.11
Our results reported so far suggested a previously
unrecognised association in which muscle dysfunction is not
only present in stable clinical conditions but associated
with the risk of hospital admissions.
Table 2 Function of peripheral and respiratory muscles as assessed by maximal voluntary contraction manoeuvres according
to both clinical status and history of hospital admissions.
Stable COPD
Patients,
Peripheral muscles
Dominant HGS
Non-dominant HGS
Expiratory muscles
PEmax
Inspiratory muscles
PImax
Acute exacerbation of COPD
No previous
admissions
With multiple
admissionsa
First
admissiona
With multiple
admissionsa
n (%)
50 (41)
27 (22)
17 (14)
27 (22)
%pred (%n)
%pred (%n)
7313 (31)
7112 (50)
6412b (58)
6211b (58)
5222c (70)
5319b (67)
5818c (68)
5518b (82)
%pred
7721
8321
5618b
5226b
%pred
8524
7118a
5319c
6328b
Abbreviations: (HGS): hand grip strength, dominant and non-dominant; (PImax): Maximal inspiratory pressure measured at the mouth
(Müller manoeuvre); (PEmax): maximal expiratory pressure measured at the mouth (Valsalva manoeuvre). Values correspond to the
percentage of predicted values and in (), the patients incidence of muscle dysfunction, under 70% of predicted, for each study group.
a
p<0.05; p values correspond to comparisons with the stable COPD with no previous hospital admission group.
b
p<0.01; p values correspond to comparisons with the stable COPD with no previous hospital admission group.
c
p<0.001; p values correspond to comparisons with the stable COPD with no previous hospital admission group.
1900
J. Vilaró et al.
Prevalence of muscle dysfunction
(values <70% pred)
100
90
80
70
Dominant hand
Non-dominant hand
Expiratory muscles
Inspiratory muscles
60
50
40
30
20
10
0
Stable COPD
without history of
admissions
Stable COPD with
history of multiple
admissions
First admission due
to exacerbation of
COPD
Exacerbated COPD
with multiple
admissions
Figure 1 The graph represents the proportion of patients suffering muscle dysfunction determined by a decrease under 70% of
the predicted values. The prevalence of respiratory muscle dysfunction is higher in exacerbated patients but for peripheral
muscles, the prevalence is more notorious in hospital multiple admitted patients.
The present multicentre study offers novel information,
including a particular selection and group assignment of the
patients. We analysed former smokers with COPD who
showed a preserved body weight and were without
comorbidity (known or detected during the clinical assessment processes), regular use of alcohol or sedatives, and
domiciliary oxygen therapy. These selection criteria allow
us to summarise the results in three main concepts, as
follows. The first concept is that patients with stable COPD
without hospital admissions had a high prevalence of
respiratory and peripheral muscle dysfunction as assessed
by strength of inspiratory, expiratory and peripheral
muscles (Table 2). These data confirm previous knowledge
that skeletal muscle dysfunction is among the frequent
extrapulmonary manifestations even in stable COPD.4 The
second concept derived from our study is that, acute
exacerbation of COPD associates with an increase in both
prevalence and severity of global muscle dysfunction (Table
4). It is reasonable to postulate that this additional
impairment in muscle function is associated with the
inflammatory burst and therapy of exacerbations. In fact,
we recently showed that COPD patients who require
admission for exacerbation suffer a global, progressive and
linear deterioration of muscle function.10 The third
concept deals with the evidence that prevalence and
severity of respiratory and peripheral muscle dysfunction
remain elevated even while recovering clinical stability
(Table 3). These data are consistent with the study from
other cohort by Gonzalez et al.,11 who were able to
demonstrate that at hospital discharge, noninvasively
measured respiratory muscle overload were associated with
an increased risk of hospital readmission for exacerbation
in patients with moderate-to-severe COPD. Despite these
information, the ultimate cause of muscle dysfunction has
not yet been determined in either stable or exacerbated
COPD, but our study clearly demonstrates that muscle
weakness strongly associates with the risk for hospitalisation due to exacerbation, as discussed below.
Exacerbation of COPD represents not only a worsening of
airflow obstruction but also increased respiratory and
systemic demand in a host receiving treatment and with
limited ventilatory reserve.22 With regards to inspiratory
Table 3 Crude and adjusted associations between muscle dysfunction and risk for severe exacerbations in stable COPD
patients without hospital admissions vs. stable patients with multiple admissions.
Peripheral muscle weakness
Dominant HGS
Lower
Non-dominant HGS
Lower
Expiratory muscle weakness
PEmax
Lower
Inspiratory muscle weakness
PImax
Lower
Univariate logistic regression
Multivariate logistic regressiona
Crude OR (95% CI)
p
Adjusted OR (95% CI)
P
than 70%pred
than 70%pred
5.4 (2.0e14.4)
2.1 (1.2e8.3)
<0.001
0.12
6.0 (2.0e17.9)
1.7 (0.6e4.7)
<0.001
0.30
than 70%pred
0.88 (0.3e2.5)
0.81
0.6 (0.2e2.2)
0.55
than 70%pred
3.6 (1.4e9.4)
<0.01
3.2 (1.1e9.0)
<0.05
Abbreviations: (HGS): hand grip strength; (PImax): Maximal inspiratory pressure measured at the mouth (Müller manoeuvre); (PEmax):
maximal expiratory pressure measured at the mouth (Valsalva manoeuvre).
a
Adjusted by FEV1.
Muscle dysfunction and risk of exacerbation in COPD
1901
Table 4 Crude associations between muscle dysfunction and risk for severe exacerbations in stable COPD patients vs. Patients
with acute exacerbation.
Peripheral muscle weakness
Dominant HGS
Lower
Non-dominant HGS
Lower
Expiratory muscle weakness
PEmax
Lower
Inspiratory muscle weakness
Lower
PImax
Univariate logistic regression
Multivariate logistic regressiona
Crude OR (95% CI)
p
Adjusted OR (95% CI)
P
than 70%pred
than 70%pred
2.8 (1.2e6.7)
3.1 (1.2e8.3)
0.023
0.017
2.4 (1.0e6.0)
2.6 (1.0e6.9)
0.052
0.051
than 70%pred
7.3 (2.4-21.9)
<0.001
6.8 (2.1e21.3)
<0.01
than 70%pred
3.3 (1.5e7.6)
0.004
2.9 (1.2e6.9)
<0.05
(HGS): hand grip strength; (PImax): Maximal inspiratory pressure measured at the mouth (Müller manoeuvre); (PEmax): maximal expiratory
pressure measured at the mouth (Valsalva manoeuvre).
a
Adjusted by FEV1.
muscles, one of the factors related to functional deterioration during exacerbation is the progressive increase in
functional residual capacity due to dynamic air trapping.2
However, our study also demonstrates that the patients
prone to hospitalisation showed a greater dysfunction of
expiratory muscles (assessed as PEmax) and peripheral
muscles (HGS), which cannot be explained by geometrical
changes in the thorax. In addition, systemic inflammation is
associated with reduced muscle strength, exercise tolerance, and health status in COPD patients23; exacerbations
have been associated with an inflammatory burst as
assessed by increases in inflammatory mediators in both
sputum and plasma.4
A systemic (global) muscle involvement was captured in
the present study by detecting both peripheral muscle
weakness and modified fat free mass index in patients with
higher risk of exacerbation. Peripheral muscle function
(strength and endurance) is closely related to the absolute
quantity of muscle mass, which is reduced with aging.24e27
Consistent with a previous study,30 however, and intrinsic
to our selection criteria, we were unable to demonstrate
a relationship between age, body weight or BMI, and
susceptibility to multiple exacerbations. Prior retrospective
studies have stated that a significant proportion of patients
with COPD suffer from progressive weight loss in relation to
exacerbation of their disease.28 Other transversal studies in
this field, such as one by Pascual and colleagues,29 have
shown that deterioration of pulmonary function has
a correlation with some anthropometric variables in COPD
patients. We should point out that our patients are from the
Mediterranean area, whereas the study by Vermeeren and
colleagues28 included patients from the north of Europe.
Consequently, we cannot exclude the possibility that there
are differences in the impact of exacerbation of the disease
on patients living in different geographical regions or
having a different ethnic origin.30 Similar differences have
recently been described in cardiovascular disease with
a multifactorial origin.31 In summary, the present study
adds a piece of information demonstrating that peripheral
muscle function may be clinically useful as an additional
marker of risk of exacerbation in patients with COPD,
normal weight, and normal BMI.
One of the limitations of this study is that a crosssectional design does not allow us to identify causative
relationships between muscle function and exacerbation or
treatment. Previous studies reported that COPD exacerbation was associated with a progressive loss of water and
muscle body mass that reached minimum values on the day
of hospital discharge.28 Other possible limitations could be
related to the absence of functional assessments of lower
limb muscles such as histological correlates, muscle or fat
tissue biopsies and adipometric techniques. As for the
physical exercise tests or limb muscle measurements,
a practical and ethical limitation has made us restrict
assessments to those that, in our opinion, would not involve
a significant increase in metabolic waste. For similar
reasons, we did not carry out biopsies of muscle or fat.
Finally, we did not perform adipometric assessments or
compartmental anthropometry. This limits us when defining
whether the changes assessed with BIA had a peripheral,
centripetal, or global distribution.
Conclusion
Collectively, the present results extend the concept of
susceptibility to multiple exacerbations of COPD beyond
the pulmonary system to the muscle compartments. We
provide a clinical and epidemiological rationale linking
inspiratory and expiratory muscle dysfunction with
susceptibility to multiple exacerbations of COPD. Our study
shows that muscle function may be clinically useful as
a marker of exacerbation risk in patients with COPD.
These data support the possibility of using respiratory
and peripheral muscle training as an additional treatment
to mitigate the increased susceptibility to exacerbations.
Acknowledgements
The authors are grateful to all the Respiratory Departments
and the staff of the lung function laboratories of the
following institutions: Hospital del Mar, Barcelona; Hospital
Clı́nic, Barcelona, Hospital Materno-Infantil, Las Palmas de
Gran Canaria; Hospital General de la Defensa, Madrid and
Instituto Nacional de Silicosis, Ovideo, all of them in Spain
for their collaboration in the study.
Sources of support: Supported in part by grants from
“SEPAR-Area de Enfermerı́a y Fisioterapia” and BAE06/
90061. CIBERES (Instituto de Salud Carlos III, Ministerio de
Sanidad, Spain).
1902
Conflict of interest
None declared.
References
1. Peña VS, Miravitlles M, Gabriel R, Jimenez-Ruiz CA,
Villasante C, Masa JF, Viejo JL, Fernandez-Fau L. Geographic
variations in prevalence and underdiagnosis of COPD. Results
of the IBERCOP multicentre epidemiological study. Chest 2000;
118:981e9.
2. Global Initiative for Chronic Obstructive Lung Disease. Global
strategy for the diagnosis management and prevention Chronic
Obstructive Lung Disease. NHLB e WHO Workshop Report; 2002.
3. Connors AF, Dawson NV, Thomas C, Harel Jr FE, Desbiens N,
Wj Fulkerson, Kussin P, Bellamy P, Goldman L, Knaus WA.
Outcomes following acute exacerbation of severe chronic
obstructive lung disease. Am J Respir Crit Care Med 1996;154:
959e67.
4. Wouters EF. Chronic obstructive pulmonary disease. 5:
systemic effects of COPD. Thorax 2002;57:70e1067.
5. Sin DD, Jones RL, Mannino DM, et al. Forced expiratory volume
in 1 second and physical activity in the general population. Am
J Med 2004;117:3e270.
6. Montes de Oca M, Rassulo J, Celli BR. Respiratory muscle and
cardiopulmonary function during exercise in very severe COPD.
Am J Respir Crit Care Med 1996;154:9e1284.
7. Schols AM, Broekhuizen R, Weling-Scheepers CA, et al. Body
composition and mortality in chronic obstructive pulmonary
disease. Am J Clin Nutr 2005;82:9e53.
8. Marquis K, Debigare R, Lacasse Y, et al. Midthigh muscle crosssectional area is a better predictor of mortality than body mass
index in patients with chronic obstructive pulmonary disease.
Am J Respir Crit Care Med 2002;166:13e809.
9. Sin DD, McAlister FA, Man SF, et al. Contemporary management
of chronic obstructive pulmonary disease: scientific review.
JAMA 2003;290:12e2301.
10. Martinez-Llorens JM, Orozco-Levi M, Masdeu MJ, Coronell C,
Ramirez-Sarmiento A, Sanjuas C, Broquetas JM, Gea J. Global
muscle dysfunction and exacerbation of COPD: a cohort study.
Med Clin 2004;122:521e7.
11. González C, Servera E, Marı́n J. Importance of noninvasively
measured respiratory muscle overload among the causes of
hospital readmission of COPD patients. Chest 2008;133:941e7.
12. Orozco-Levi M. Structure and function of the respiratory
muscles in patients with COPD: impairment or adaptation? Eur
Respir J Suppl 2003;46:41se51s.
13. World Medical Association. Declaration of Helsinki: Ethical
Principles for Medical Research Involving Human Subjects, as
amended by the 52nd WMA Assembly, Edinburgh, Scotland,
October 2000; Note of Clarification in Paragraph 29 added by
the WMA General Assembly, Washington, DC; 2002.
14. Celli BR, MacNee W. Standard for the diagnosis and treatment
of patients with COPD: a summary of the ATS/ERS position
paper. Eur Respir J 2004;23:932e46.
J. Vilaró et al.
15. Roca J, Burgos F, Sunyer J, Saez M, Chinn S, Anto JM, Rodriguez-Roisin R, Quanjer PH, Nowak D, Burney P. References
values for forced spirometry. Group of the European Community Respiratory Health Survey. Eur Respir J 1998;11:62e1354.
16. Roca J, Burgos F, Barbera JA, Sunyer J, Rodriguez-Roisin R,
Castellsague J, Sanchis J, Antó JM, Casan P, Clausen JL.
Prediction equations for plethysmographic lung volumes.
Respir Med 1998;92:60e454.
17. Roca J, Rodriguez-Roisin R, Cobo E, Burgos F, Perez J,
Clausen JL. Single-breath carbon monoxide diffusing capacity
prediction equations from a Mediterranean population. Am Rev
Respir Dis 1990 Apr;141(4 Pt 1):32e1026.
18. Black LF, Hyatt RE. Maximal respiratory pressures: normal
values and relationship to age and sex. Am Rev Respir Dis 1969;
99:696e702.
19. Morales P, Sanchis J, Cordero PJ, Dies JL. Maximum static
respiratory pressures in adults. The reference values for
a Mediterranean Caucasian population. Arch Bronconeumol
1997;33:9e213.
20. Mathiowetz V, Dove M, Kashman N, Rogers S. Grip and pinch
strength: normative data for adults. Arch Phys Med Rehabil
1985;66:69e72.
21. Schelesselman J. Case-control studies: design, conduct and
analysis. New York: Oxford University Press; 1982.
22. Pinto-Plata VM, Livnat G, Girish M, Cabral H, Masdin P,
Linacre P, Dew R, Kenney L, Celli BR. Systemic cytokines,
clinical and physiological changes in patients hospitalized for
exacerbation of COPD. Chest 2007;131:37e43.
23. Sin DD, Man SF. Skeletal muscle weakness, reduced exercise
tolerance, and COPD: is systemic inflammation the missing
link? Thorax 2006;61:1e3.
24. Newman AB, Haggerty CL, Goodpaster B, et al. Strength and
muscle quality in a cohort of well-functioning older adults: the
health aging and body composition study. J Am Geriatr Soc
2003;51:323e30.
25. Metier EJ, Lynch N, Conwit R, Lindle R, Tobin J, Hurley B.
Muscle quality and age: cross-sectional and longitudinal
comparisons. J Gerontol A Biol Sci Med Sci 1999;54(5):
B207eB218.
26. Baumgartner RN. Body composition in healthy aging. Ann N Y
Acad Sci 2000;904:437e48.
27. Gallagher D, Visser M, De Meersman RE, et al. Appendicular
skeletal mass: effects of age, gender, and ethnicity. J Appl
Phys 1997;83:229e39.
28. Vermeeren MAP, Schols AMWJ, Wouters EFM. Effects of an
acute exacerbation on nutritional and metabolic profile of
patients with COPD. Eur Respir J 1997;10:2264e9.
29. Pascual JM, Carrion F, Sanchez C, Sanchez B, Gonzalez C.
Nutritional changes in patients with advanced chronic
obstructive pulmonary disease. Med Clin 1996;107:486e9.
30. Coronell C, Orozco-Levi M, Gea J. COPD and body weight in
a Mediterranean population. Clin Nutr 2002;21(3).
31. Schroder H, Marrugat J, Elosua R, Covas MI. Tobacco and
alcohol consumption: impact on other cardiovascular and
cancer risk factors in a southern European Mediterranean
population. Br J Nutr 2002;88:273e81.