Peripheral Muscle Dysfunction

in Patients With COPD

Comparing Apples to Apples?
O
ur understanding of the mechanisms of diseases
that result in impaired functional capacity, and
impair an individuals ability to work, recreate, and
perform activities of daily living, has evolved in a
remarkable and surprising manner. In the past, we
knew that a patient with heart failure had dyspnea
and fatigue because the heart pumped insufficient
blood and the lungs became congested. Similarly, we
knew that lung disease limited patients because their
ability to increase ventilation was inadequate to meet
the increased metabolic demands of work. Of course,
newer explanations have challenged many of these
ideas, largely because reduced function of the pri-
marily involved organ frequently fails to account for
the magnitude of reduction in overall capacity (eg,
decreased maximum oxygen uptake [V

o
2
]). De-
creased left ventricular ejection fraction, cardiac
output, and stroke volume in patients with chronic
heart failure, for example, do not entirely explain
reduced exercise capacity and poorer prognosis.
Accordingly, other contributing factors have been
sought and identified, including abnormalities of the
peripheral circulation, muscles of ambulation, lungs,
and the pulmonary circulation.
In patients with COPD, the severity of airway ob-
struction must play a major role in determining impair-
ment. Reduced FEV
1
, however, is poorly predictive of
the reduction in exercise capacity,
13
indicating that
other factors must play a role. Candidates include
abnormalities of the pulmonary circulation, impaired
lung gas exchange, decreased performance of respira-
tory muscles, differences in the degree of hyperinfla-
tion, abnormal left and right ventricular performance,
familial and other differences in ventilatory response,
reduced oxygen-carrying capacity of the blood, and
dysfunction of skeletal muscles other than the respira-
tory muscles (ie, the peripheral muscles).
The significance of peripheral skeletal muscle
disease as a limiting factor in patients with COPD
has been emphasized.
1,46
In fact, some investigators
have concluded that muscle dysfunction is seen in a
considerable proportion of COPD patients and have
suggested inactivity, acidosis, hypoxemia, chronic
inflammation, malnutrition, coexisting heart disease,
severe deconditioning, and medications (especially
corticosteroids) as some of the proposed mecha-
nisms. Controversy remains as to whether or not
COPD is associated with a specific myopathic con-
dition or whether peripheral muscle disorders are
secondary to the consequences of COPD, resulting
in malnutrition, chronic inflammation, or disuse.
How often and how much peripheral muscle disor-
ders affect function in COPD is a very important
question. This is because we want to know whether
the treatment of COPD should be directed only at
the lungs, using bronchodilators, corticosteroids, ox-
ygen, and smoking cessation, or whether therapy
with exercise training, nutritional interventions, and
anabolic agents would be of benefit. Furthermore,
some investigators
7
have found an association be-
tween reduced muscle mass and survival in COPD
patients, independent of a reduction of FEV
1
.
Two studies described in this issue of CHEST (see
page 83 and page 75) focus on skeletal muscle abnor-
malities in patients with COPD. One study, by
Debigare et al, begins with the assumption that muscle
wasting is a not uncommon finding in COPD patients
and seeks correlative data in an attempt to infer its
cause. The other study, by Heijdra and colleagues,
evaluated a group of outpatients with COPD to deter-
mine how often and to what degree evidence of
peripheral muscle dysfunction could be identified.
Interestingly, these different approaches yielded results
that seemcontradictory. Yet, it is likely that the findings
might lead us to distinguish subsets of patients who
may benefit from more tailored therapy.
Debigare and colleagues reported data collected
from 45 men with COPD in stable condition who
had no evidence of current inflammatory disease
and had participated in a prior study of muscle mass
and survival. To estimate the degree of peripheral
skeletal muscle abnormality, they looked at mid-
thigh muscle cross-sectional area (CSA) by CT scan,
choosing a cutoff value for abnormal based on the
findings of a previous study of clinical outcome
7
in
patients with COPD. Because the 45 men were
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selected from a population of those with a known
proportion of abnormally low muscle CSA, and were
not chosen at random or sequentially, it is not
possible to extrapolate the prevalence of low mid-
thigh muscle CSA to the COPD population in
general. In this study, 18 of 45 patients had a CSA of
70 cm
2
, and this subset was compared to 27
COPD patients with CSA of 70 cm
2
and to 16
healthy nonsmoking men of similar age. These in-
vestigators looked primarily at markers of catabolism
(ie, interleukin [IL]-6 and cortisol) and anabolism (ie,
bioavailable testosterone, dehydroepiandrosterone
sulfate [DHEAS], and insulin-like growth factor-1),
hypothesizing that peripheral muscle loss would be
associated with a shift toward patterns of greater
catabolism and lesser anabolism. COPD patients
with a mid-thigh CSA of 70 cm
2
had significantly
higher ratios of cortisol/DHEAS and IL-6/DHEAS
compared to those with mid-thigh CSA of 70 cm
2
,
as well as higher ratios compared to control subjects.
While not drawing a conclusion about causality, the
authors suggested that these data indicated a shift
toward catabolism that may contribute to the devel-
opment of decreased peripheral skeletal muscle
mass. One point that deserves emphasis, however, is
that loss of muscle mass may or may not be associ-
ated with an ongoing loss of muscle mass. For
example, if the inflammatory or catabolic mechanism
is interrupted after muscle mass is lost, the correla-
tion between the two may be weakened. Similarly,
some patients simply have always had low muscle
mass rather than having lost muscle mass secondary
to COPD.
Heijdra and colleagues asked how often evidence
for a peripheral muscle disorder could be identified
in a set of stable COPD patients attending an
outpatient clinic. They surmised that peripheral
muscle dysfunction might be important in those with
malnutrition, a recognized cocondition in COPD
patients, but they suggested that evidence of a
systemic myopathy might be uncommon in this
population of COPD patients. That is, Heijdra et al
hypothesized that stable COPD patients with normal
fat-free mass (FFM) would not have evidence of
clinically significant peripheral muscle dysfunction.
In COPD patients and control subjects, they com-
pared anthropomorphic evaluation and skeletal mus-
cle strength (ie, maximal inspiratory and expiratory
pressures for respiratory muscles and handgrip
for peripheral muscles). Because the slow kinetics
of V

o
2
has been attributed to factors intrinsic to
the peripheral muscles rather than to impaired oxy-
gen delivery
810
to the muscles, they also looked
at the time constant for V

o
2
during low-level,
constant-work exercise. Their subjects were 32 stable
patients with severe COPD (mean [ SD] FEV
1
,
0.97 0.29 L) who had been recruited from an
outpatient clinic and 36 control subjects of similar
age. Importantly, they estimated FFM by bioelectri-
cal impedance, and all 36 control subjects and 31 of
32 COPD patients had a FFM index (FFMI) at or
above normal (defined as 16 kg/m
2
for men and
15 kg/m
2
for women). These investigators found
that the mean handgrip force, the maximal expira-
tory pressure, and the time constant for V

o
2
(COPD
patients, 72 34 s; control subjects, 78 37 s) were
not different between COPD patients and control
subjects. They concluded that COPD patients who
had been identified from a clinic population, had
been stable for at least 6 months, and had a normal
FFMI showed no evidence of peripheral muscle
dysfunction in the group as a whole. Because the
multiple regression analysis of Heijdra and col-
leagues showed that FFMI accounted for 42% of the
variance in peak V

o
2
, they suggested that those
patients with decreased muscle mass could be iden-
tified and perhaps targeted for specific therapy.
Therefore, Debigare and colleagues demonstrated
that COPD patients with decreased mid-thigh mus-
cle mass had findings in the blood suggesting a
catabolic state, while Heijdra et al found that their
COPD patients had little evidence of a clinically
significant peripheral muscle dysfunction. Are these
results in conflict? If so, what might be the reasons
for these differences?
The most evident differences are in the study
populations. The patients in the study by Debigare et
al were chosen to compare a subset of patients with
decreased mid-thigh CSA to a group of COPD
patients with a CSA 70 cm
2
(ie, below normal but
previously associated with better prognosis). On the
other hand, almost all of the patients recruited by
Heijdra et al had a normal FFMI value. In a study by
Bernard et al,
11
skeletal muscle weakness was related
to peripheral muscle atrophy as estimated by thigh
muscle CSA. Although quadriceps strength was re-
duced in COPD patients compared to healthy sub-
jects, the ratio of quadriceps strength to muscle CSA
was not different. Therefore, reduced muscle mass
correlated with decreased muscle strength. Similarly,
Engelen et al
12
used dual-energy radiograph absorp-
tiometry to estimate the whole-body and upper
extremity FFM and compared these values to hand-
grip strength in COPD and control subjects. Re-
duced handgrip strength was seen in COPD patients
(in both those patients with chronic bronchitis and
those with emphysema), but the ratio of handgrip
strength to FFM was not different from that of
control subjects, and patients whole-body FFM
strongly correlated with extremity FFM. Again,
these data suggest that reduced strength (ie, hand-
grip strength) is seen if and only if there is reduced
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FFM, due presumably to reduced muscle mass.
Thus, one explanation of the difference between the
two studies being discussed is that the patients in the
study of Heijdra et al had normal or near-normal
FFM, meaning that they had normal upper extrem-
ity muscle mass and subsequently normal handgrip
strength, and normal lower extremity muscle mass,
resulting in no difference in V

o
2
kinetics during
steady-state exercise. Perhaps these patients, who
had been selected from an outpatient clinic but had
not been enrolled in a pulmonary rehabilitation
program, were better nourished or less decondi-
tioned than were other COPD patients.
A second way of comparing the two studies also
helps to reconcile the results. Whole-muscle atrophy
might be assumed to be due to the atrophy of
individual muscle fibers (ie, if the number of muscle
fibers remains constant). Gosker et al
13
showed a
strong correlation between FFM determined by
bioelectrical impedance and mean fiber CSA (deter-
mined from a biopsy specimen of the lateral part of
the quadriceps femoris) in COPD patients. Extrap-
olating from data of Gosker et al, the mean FFM of
the COPD patients presented by Heijdra et al would
translate into a mean muscle fiber CSA that would
be well into the normal range. Similarly, the data
supplied by Debigare and colleagues showed that
the mean mid-thigh CSA for their group of COPD
patients with a CSA of 70 cm
2
was 60% of the
values of control subjects (58 vs 96 cm
2
, respectively).
Thus, the patients in the study by Debigare et al
matched well with the COPD patients presented by
Gosker et al, who had a mean fiber CSA that was
62% of that of the control subjects (3,839 vs 4,647
m
2
, respectively). Again, this analysis supports the
idea that different subsets of COPD patients are
being contrasted in the two studies being compared.
Finally, the study by Schols and colleagues
14
sheds
some additional light on potential differences. They
reported data from 30 patients with COPD and 26
healthy age-matched control subjects. Eight of 30
COPD patients had elevated C-reactive protein
(CRP) levels, and in those 8 patients the levels of
IL-8 and two soluble tumor necrosis factor receptors
were increased. In addition, the patients with ele-
vated CRP levels had lower FFM, as determined by
bioelectrical impedance. Thus, patients having mark-
ers of inflammation or acute-phase reactants were
those with lower FFM. The patients in the study by
Heijdra et al had normal FFM, so they would not
have been expected to have these markers associated
with inflammation. The patients in the study by
Debigare et al with low mid-thigh CSA, on the other
hand, might be similar to the subset of patients in the
study by Schols et al who had low FFM and elevated
CRP levels.
What should we conclude about the role of pe-
ripheral muscle dysfunction in COPD patients? The
therapy for COPD is quite limited, with a focus on
bronchodilators, corticosteroids, oxygen, and smok-
ing cessation. But, if peripheral muscle dysfunction
is important, then therapy with, for instance, exercise
training, nutritional intervention, and anabolic hor-
mones may be beneficial. For example, exercise
training during a rehabilitation program has been
shown to lessen ventilatory requirements and in-
crease exercise performance independent of the
degree of airflow obstruction,
15
and pulmonary re-
habilitation is effective in reducing symptoms.
16
Im-
portantly, it appears that much of the improvement
with exercise training is due to its effect on periph-
eral skeletal muscle function.
8,9
Could measures of
peripheral muscle size or function help to determine
which COPD patients would profit additionally from
therapies such as anabolic hormones, growth factors,
or nutritional intervention?
At a minimum, we need to understand better the
frequency, severity, and mechanisms of peripheral
muscle dysfunction in COPD patients. If not all
patients have clinically evident peripheral muscle
dysfunction, then investigators studying COPD ther-
apy must describe their patients in sufficient detail to
allow us to understand the state of the peripheral
muscles, if relevant. In particular, studies of exercise
training and pharmacologic intervention that are
directed at the peripheral muscles, whether positive
or negative, need to describe whether the patients
studied had normal or reduced muscle mass and
need to provide other information about the baseline
function and subsequent function of the skeletal
muscles.
Darryl Y. Sue, MD, FCCP
Torrance, CA
Dr. Sue is affiliated with the Division of Respiratory and Critical
Care Physiology and Medicine, Department of Medicine, Har-
bor-UCLA Medical Center, and is Professor of Clinical Medi-
cine, David Geffen School of Medicine, University of California
at Los Angeles.
Reproduction of this article is prohibited without written permis-
sion from the American College of Chest Physicians (e-mail:
permissions@chestnet.org).
Correspondence to: Darryl Y. Sue, MD, FCCP, Department of
Medicine, Box 400, Harbor-UCLA Medical Center, 1000 W
Carson St, Torrance, CA 90509-2910; e-mail: dsue@ucla.edu
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date Software, 2003
Simple Mediastinal Cysts
Resect Them All?
I
recall the first case that I scrubbed on as an
eager medical student in 1973 at a Boston teach-
ing hospital was that of a man of about 70 years who
presented with a cough. Then, patients were hospi-
talized for workup and buffing up in advance of
the operation. The medical student was first to
interact with the patient: take the history and per-
form the physical examination, type or write the
findings on the chart, order tests that the residents
wanted, and report the results on morning rounds
(very early morning rounds; 5:30 am, to be exact). In
this case, the chest radiograph showed a left mid-
lung field opacity. Linear tomograms may have been
performed, but CT scanning was not available. Be-
cause of the possibility of cancer, the patient under-
went a full posterolateral thoracotomy and was found
to have a pseudotumor (ie, fluid in the interlobar
fissure). The surgical team was pleased that there
was no cancer and related the good news to the
patient, who also was pleased, and he was discharged
from the hospital about 10 days later. The surgeons
acted in the best interests of the patient based on the
information available. I do not know whether his
cough was relieved by surgical intervention, but I
suspect not.
Fortunately, much has changed. Thoracotomy for
benign lesions, which accounted for 60% of oper-
ations in the 1960s and 1970s, especially in endemic
fungal regions, is now rare. In addition, nonresective
thoracotomy for lung cancer currently occurs in
5% of cases. There are two reasons for this
improvement. First and foremost are the dramatic
advances in imaging that have occurred in the last 2
decades and that continue to evolve exponentially.
Second, procedures such as needle biopsy and tho-
racoscopy have markedly reduced the need for tho-
racotomy. Although still occasionally required and
associated with low risk, open surgery, including
minimal thoracotomy, that yields a benign diagnosis
invariably induces this thoracic surgeon to retrace
the pathway that led to the operating room to
determine whether other options might have been
preferable. What these musings have to do with
mediastinal cysts is that, like the pseudotumor, these
cysts are benign, can be diagnosed with certainty by
imaging, and are mostly asymptomatic. If doubt
remains or if symptoms are thought to be related to
the cyst, procedures other than open operation,
some nonsurgical, may be applicable.
In this issue of CHEST (see page 125) Takeda and
associates report on a half-century institutional expe-
rience with mediastinal cysts. Unfortunately, the
present report suffers from the problems of most
discussions of this subject. The literature consists of
small series. Conclusions are further confounded by
the inclusion in most reports of only surgical cases
and, perhaps in order to achieve a presentable
number of patients, combine cysts of various etiolo-
gies. In addition, symptomatic cysts in infants and
children are clinically different from those discov-
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