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1 Unité de Recherche en
Pneumologie, Premature lactic
acidosis during exercise in patients with chronic obstructive pulmonary
disease (COPD) may play a role in exercise intolerance. In this study,
we evaluated whether the early exercise-induced lactic acidosis in
these individuals can be explained by changes in peripheral
O2 delivery
(
chronic obstructive pulmonary disease; metabolism; skeletal muscle; leg blood flow
THE CAUSES OF EXERCISE intolerance in patients with
chronic obstructive pulmonary disease (COPD) are traditionally focused on limitations in ventilation and gas exchange. Consequently, dyspnea,
hypoxemia, and hypercapnia during exercise are the most common factors
addressed. Recent studies have clearly shown that peripheral skeletal
muscles are compromised in COPD (11, 22). Decreases in skeletal muscle
mass, strength, and mitochondrial enzyme activities have been described
in this disease and may play an important role in exercise limitation
in COPD (11, 22).
It is still unclear whether there are changes in the metabolism and
acid-base status during exercise of the contracting muscles in patients
with COPD. In fact, it is commonly believed that, because
of ventilatory limitation, the vast majority of COPD patients are
unable to exercise sufficiently to produce significant amounts of
lactic acid (2). On the contrary, recent studies have shown early
lactic acidosis during exercise in COPD (5, 22).
31P-NMR studies have demonstrated
a greater than normal decrease in muscle pH and in the ratio of
phosphocreatine/Pi [PCr/(PCr + Pi)] in COPD patients
during small muscle group contractions, consistent with an impaired
energetic metabolism with a shift toward anaerobic glycolysis (18, 24).
Because reduction in muscle pH is a contributory factor to muscle
fatigue (13, 20), premature muscle acidosis may be another mechanism
that contributes to exercise intolerance in COPD patients. In these
patients, an impaired energy metabolism could be caused by several
factors, including poor peripheral
O2 delivery
( The specific objectives of this study were to address the following
questions. 1) In COPD patients, is
there any reduction in blood flow to peripheral contracting skeletal
muscles during cycle exercise? 2) Is
lactate release from the peripheral muscles excessive in
patients with COPD compared with lactate release in
age-matched normal subjects? 3) Do
changes in peripheral
Patient Population
ABSTRACT
Top
Abstract
Introduction
Methods
Results
Discussion
References
O2).
Measurements of leg blood flow by thermodilution and of arterial and
femoral venous blood gases, pH, and lactate were obtained during a
standard incremental exercise test to capacity in eight patients with
severe COPD and in eight age-matched controls. No significant
difference was found between the two groups in leg blood flow at rest
or during exercise at the same power outputs. Blood lactate
concentrations and lactate release from the lower limb were greater in
COPD patients at all submaximal exercise levels (all
P < 0.05). Leg
O2
at a given power output was not significantly different between the two
groups, and no significant correlation was found between this parameter
and blood lactate concentrations. COPD patients had lower arterial and
venous pH at submaximal exercise, and there was a significant positive
correlation between venous pH at 40 W and the peak
O2 uptake
(r = 0.91, P < 0.0001). The correlation between
venous pH and peak O2 uptake
suggests that early muscle acidosis may be involved in early exercise
termination in COPD patients. The early lactate release from the lower
limb during exercise could not be accounted for by changes in
peripheral
O2. The present results point to skeletal muscle dysfunction as being responsible for the early onset of lactic acidosis in
COPD.
INTRODUCTION
Top
Abstract
Introduction
Methods
Results
Discussion
References
O2)
or less-efficient oxidative metabolism. Although a decrease in
activities of skeletal muscle oxidative enzymes has been reported (22),
the possible influence of peripheral
O2
has not been evaluated in patients with COPD.
O2 have any influence on blood lactate concentration?
4) Do femoral venous gases and
acid-base status, a reflection of intramuscular values, reach similar
values at peak exercise in COPD patients compared with normal
subjects? To address these issues, arterial and femoral venous blood
was sampled and leg blood flow (
leg) was
measured during leg-cycle exercise in patients with COPD and in
age-matched normal subjects.
METHODS
Top
Abstract
Introduction
Methods
Results
Discussion
References
Protocol
Catheter placements and leg measurements.
leg of a single leg was measured with a
thermodilution catheter (model 93 A-105-5F; Edwards Laboratory,
Santa Ana, CA) as previously described (32, 34). On this catheter, the
injectate port and the thermistor are located 10 and 1.5 cm,
respectively, from the tip. After the subject's right groin was
shaved, disinfected, and anesthetized with lidocaine, the catheter was
inserted into the femoral vein 2 cm below the inguinal ligament, with
the distal thermistor tip positioned 10-12 cm above the inguinal
ligament in the external iliac vein. The catheter was interfaced with a model SP 1435 cardiac-output computer (Gould Statham, Oxnard, CA), and
boluses of 1-5 ml iced or room temperature saline were injected to
obtain two to four flow measurements at rest and during exercise.
Thermodilution curves were displayed on the Gould recorder to ensure a
monophasic curve with an exponential decay. The validity and the
reproducibility of this technique have been confirmed in previous
studies by Sullivan et al. (32, 34). To sample venous blood, we also
inserted a 10-cm indwelling catheter in the right femoral vein, 1 cm
below the thermodilution catheter, with its tip located in the external
iliac vein. Finally, a cannula was placed in a radial artery.
Exercise test.
Subjects were seated on an electrically braked ergocycle and connected
to the exercise circuit through a mouthpiece. The exercise circuit
consisted of a pneumotachograph,
O2 and
CO2 analyzers, and a mixing
chamber (Quinton Qplex, A. H. Robins, Seattle, WA). After subjects
rested for 5 min, a progressive, stepwise exercise test was performed
up to the individual's maximum capacity. Five-breath averages of
minute ventilation (
E),
O2 uptake
(O2), and
CO2 excretion
(CO2) were measured at rest
and during exercise. Each exercise step lasted 3 min, and increments of
20 W were used. leg measurements were obtained
during the second minute of each exercise step, whereas the arterial
and femoral blood were sampled during the last minute. During the last
minute of each exercise step, subjects were asked to rate their dyspnea
and perception of leg fatigue on a modified Borg scale (3). Blood
samples were placed on ice until the end of the exercise test; then
they were rapidly processed. Arterial and venous
PO2,
PCO2, and pH were measured with a
blood-gas machine (AVL 995; AVL Scientific, Roswell, GA), and oxygen
saturation (SaO2) was
measured with a CO-oximeter (OSM2 Hemoximeter; Radiometer, Copenhagen,
Denmark). The standard HCO
3 values
were derived from the Siggard-Andersen nomogram. After
blood was centrifuged at room temperature, lactate concentrations in
plasma were determined with an enzymatic technique (lactate kit,
Boehringer-Mannheim, Mannheim, Germany).
Statistical analysis.
Results are expressed as means ± SE. The maximal voluntary
ventilation was estimated by multiplying the
FEV1 by 35 (6). The predicted
values for spirometry, lung volume, and
DLCO are those of Knudson et al. (17), Goldman and Becklake (10), and Cotes and
Hall (7), respectively. Blood O2
and CO2 content were calculated
from standard formulas with appropriate modification for Hb
concentration, SaO2, and pH (8).
Single-leg O2 and CO2
(O2 leg
and
CO2 leg,
respectively) were derived by using the Fick principle. The lactate
release from the lower limb was computed from the
leg and venous-arterial (v-a) lactate difference product, and the single-leg O2
delivery
(O2 leg)
was computed from the leg and arterial
O2 content product. The
time-course changes of study parameters with exercise in both groups
were compared with two approaches.
1) Changes of each parameter during exercise in normal subjects and in COPD patients were compared by using
profile analysis, which allowed us to evaluate and to compare the time
course of different variables between two groups (28).
2) The values at rest and at each
exercise level were compared between both groups by using two-way ANOVA
(group, exercise work rate) with repeated measures for the second
factor (exercise work rate). A value of
P < 0.05 was considered
statistically significant.
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RESULTS |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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The characteristics of the experimental and control groups are given in
Table 1. Age, height, weight, body mass
index, and Hb were comparable in the two groups. The experimental group
had severe airflow obstruction, with an
FEV1 of 37 ± 3% predicted normal values. All subjects completed the incremental exercise test to
their maximal subjective capacity (Table
2). The peak power output achieved in the
COPD group was 63 ± 5 W, with a peak O2
(O2 peak) of 1.1 ± 0.1 l/min. The peak power output of the control group was significantly
greater at 168 ± 15 W, with a
O2 peak of 2.8 ± 0.2 l/min (P < 0.001). As
expected, peak heart rate and E
were also lower in COPD (P < 0.001).
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Peripheral Blood Flow to Peripheral Muscles During Exercise
Lower limb hemodynamic responses to incremental exercise are presented in Table 3. Restingleg
was similar in both groups (0.43 ± 0.06 and 0.44 ± 0.04 l/min,
in normal subjects and in COPD patients, respectively;
P > 0.05). The increase in
leg during exercise was similar for the two groups,
although it tended to be lower in COPD patients (at 60 W: 3.08 ± 0.19 vs. 2.72 ± 0.23 l/min in normal subjects and COPD patients,
respectively).
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Lactate Release in Lower Limb During Exercise
Resting values for arterial and venous lactate were similar for both groups (Fig. 1). The increase in these parameters was steeper in COPD patients, as indicated by the higher values obtained in these patients for each submaximal exercise work rate (P < 0.005). The change in v-a lactate difference and lactate release during exercise paralleled that of the arterial and venous concentrations. In addition, v-a lactate and lactate release, for each submaximal-exercise level, were greater in COPD patients compared with normal subjects (for P values see Fig. 1, C and D). Because of the greater peak work rate achieved in normal subjects, values of arterial and venous lactate concentrations at peak exercise capacity were greater in these individuals than in individuals with COPD (P < 0.001 and P < 0.01, respectively). At peak exercise, the v-a lactate was greater in COPD patients than in normal subjects (P < 0.01), whereas lactate release was similar for both groups.
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Peripheral
O2,
Lower-Limb Metabolism, and Blood-Lactate Concentration During Exercise
O2 leg,
O2leg,
CO2leg,
and single-leg respiratory quotient (RQleg) are shown in
Table 3. Resting and exercise values for PaO2 and
SaO2 were significantly lower in COPD
patients than in normal subjects (all
P < 0.001), whereas
PvO2 and
SvO2 were
similar in both groups during submaximal exercise. In both groups, the beginning of exercise was accompanied by a reduction in
PvO2, which
remained stable afterward. In contrast,
SvO2 decreased
progressively during exercise and reached nadir values of 24 ± 3 and 28 ± 3% at peak exercise in normal subjects and in COPD
patients, respectively (P > 0.05).
As a result of lower SaO2, the
O2 leg
tended to be smaller in COPD patients during submaximal level (all
P > 0.11). In contrast, O2 leg
was markedly lower in COPD patients compared with normal subjects at
peak exercise (P < 0.0001).
C(a-v)O2 was preserved in COPD patients, as
indicated by the small and nonsignificant differences in
C(a-v)O2 between both groups during submaximal exercise.
O2 leg
was no different at rest in the two groups and tended to be smaller in
COPD patients during submaximal exercise (at 60 W: 408 ± 87 vs.
333 ± 86 ml/min in normal and in COPD patients, respectively; P = 0.14). Because the
CO2 leg
was almost identical for both groups, the leg respiratory coefficient
(RQleg) was greater in COPD patients than in normal
subjects during submaximal exercise, although this difference reached
statistical significance only at 60 W (1.21 ± 0.05 vs. 1.04 ± 0.06, respectively; P < 0.05). As a
reflection of a higher exercise work rate achieved in normal subjects,
leg,
O2 leg,
and
CO2 leg
were greater in these individuals at maximal exercise
(P < 0.005).
The relationship between the individual values of
O2 leg
and venous lactate concentration obtained at an identical work rate (40 W) is depicted in Fig. 2. This exercise
level was chosen because it was the highest achieved by all
participants. For a given
O2 leg,
venous lactate concentration varied considerably among subjects.
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Femoral Venous Blood Gases and Acid-Base Status During Exercise
The time course of changes in arterial and venous values for pH, PCO2, and standard HCO3 during exercise is shown in Fig.
3. The decline in arterial and venous pH is
faster in COPD patients than in normal subjects
(P < 0.0005), with lower pH at each
submaximal exercise level (P < 0.05 at 20 W, and P < 0.001 at 40 and 60 W). This was caused by CO2
accumulation and metabolic acidosis, as indicated by a faster increase
in PCO2 and a steeper decrease in
standard HCO3 in arterial and femoral
blood in COPD patients compared with normal subjects (P < 0.005). At end of exercise,
arterial and venous pH were similar in both groups, averaging 7.31 ± 0.02 and 7.27 ± 0.01, and 7.16 ± 0.02 and 7.14 ± 0.01 in normal subjects and in COPD patients, respectively
(P > 0.05), despite a much lower
peak-exercise work rate achieved in the latter group. The relationship
between venous pH at 40 W and the
O2 peak is
shown in Fig. 4. A significant positive
correlation was found between these two parameters
(r = 0.91, P < 0.0001). Not shown in Fig. 4 is
a similar observation made at 20 W (r = 0.84, P < 0.0001).
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DISCUSSION |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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In this study, we evaluated energy metabolism of the lower limb and
hemodynamics responses during leg-cycle exercise in patients with
severe COPD and in age-matched normal subjects. There were striking
differences in metabolism and acid-base status of the blood draining
the active peripheral muscles in the COPD group compared with the
normal control group. These differences could not be explained by
changes in peripheral
O2.
Despite a much lower maximal-exercise capacity in COPD patients,
similarities between end-exercise RQleg, lactate release,
and venous pH in both groups indicate a maximal or near-maximal
peripheral muscle activation in COPD patients. This finding contrasts
the traditional view regarding exercise physiology in patients with
severe COPD. That view states that these individuals cannot tolerate
sufficient exercise intensity to activate their peripheral muscles (2).
Peripheral Perfusion and
O2
leg and
O2 leg
were preserved in COPD patients compared with normal subjects, although
the values tended to be smaller in the former group. This
difference, however, did not reach statistical significance, possibly
because of the relatively small number of subjects included in this
study. The finding that the rise in peripheral blood flow is normal or slightly reduced in these patients is consistent with previous studies
on central hemodynamics during exercise in COPD patients. These studies
have shown a normal cardiac
output/O2 relationship (9).
It also indicates that, in COPD, the increase in cardiac output during
cycle exercise is appropriately directed to the lower limbs. It is
possible, however, that, in some patients with clinically evident cor
pulmonale or in those who develop right ventricular dysfunction during
exercise (23), inadequate increase in cardiac output and consequently
in leg during exercise may be important in limiting
exercise in those individuals.
Lactate Release and Metabolism in Lower Limb During Exercise in Patients with COPD
Excessive arterial blood lactate accumulation during exercise in COPD patients was related to an increased lactate release in the lower limb. This indicates that the decrease in lactate degradation by organs, such as the liver or noncontracting skeletal muscles, is not the primary mechanism accounting for the increase in lactate concentration in COPD. The increased lactate release probably reflects an accelerated lactate production, although reduced lactate uptake by the muscles of the lower limb (30) may have contributed to the increase in lactate release.The increase in lactate release and the higher venous
PCO2 and RQleg found at
submaximal exercise in COPD patients suggest that the energy sources
for muscle contraction are different in these patients compared with
normal subjects; i.e., there is a higher glycolytic activity in the
former. These results are in line with previous studies that used
31P-NMR to demonstrate greater
decline in intracellular pH and in PCr/(PCr + Pi) ratio during exercise in
patients with COPD (18, 24). These data and the present study
indicate an impaired oxidative phosphorylation and ATP
resynthesis, with early activation of anerobic glycolysis within the
contracting muscles in patients with COPD. A number of factors may
contribute to this altered muscle metabolic activity, including a
decreased
O2
and a less-efficient oxidative metabolism. Similarities in
leg, O2
extraction, and PvO2 for a
given exercise level, and the large variability of blood lactate
concentrations for a given
O2 leg
(Fig. 2) suggest that the altered energy metabolism in COPD cannot be
accounted for by poor perfusion and oxygenation of the contracting
muscles. Because these metabolic abnormalities are not explained by a
reduction in
O2
and extraction, a possible explanation for this finding is an intrinsic
muscle abnormality or an altered metabolic regulation of muscle in COPD
(26). This contention is further supported by a study indicating poor
skeletal muscle oxidative capacity in these patients (22), and by the
relationship described between the increase in arterial lactate during
exercise and skeletal muscle oxidative capacity in normal subjects
(14), patients with COPD (22) and those with chronic heart failure
(33). A shift toward a more pronounced anerobic glycolysis can also occur in a state of heightened 
-adrenergic stimulation (29); this
was not evaluated herein.
Another explanation that should be considered for the altered
muscle-energy metabolism is chronic intracellular hypoxia. There is
evidence, both in normal subjects exposed to environment with low
PO2 (12) and in COPD patients (24),
that chronic hypoxia could modify significantly the cellular oxidative
metabolism. In our patients, this explanation is less likely, because
their resting PaO2 was not markedly
reduced, ranging between 62 and 97 Torr, and their
leg and
O2
were preserved at rest and during exercise. However, normal or slightly
decreased daytime PaO2 and peripheral
O2
at rest or during exercise do not completely rule out chronic
intracellular hypoxia. Oxygen desaturation may occur repeatedly during
sleep in patients with severe COPD, and the degree of cellular hypoxia
may be underestimated from the resting daytime
PaO2. leg and
O2 can also be directed toward
nonmuscular tissue and not to the contracting muscle. This is unlikely,
because it has been shown that the rise in leg during
exercise is closely related to skeletal muscle blood flow (27).
Intracellular hypoxia could also result from a mismatch between
O2
and the metabolic requirements within the contracting muscle (36). This
would occur if the vasoregulation were abnormal during exercise in
COPD, although the preserved O2
extraction does not support this contention. Finally, a block to
O2 diffusion from the
extracellular space to the mitochondria could explain intracellular
hypoxia despite preserved
O2
and O2 extraction. These issues could not be
resolved by the present study, and in this regard monitoring of
intramuscular PO2 would be helpful.
Femoral Venous Blood Gases and Acid-Base Status During Exercise
The venous blood pH and PCO2 at rest and during exercise were used to estimate the corresponding end-capillary values and to provide some indication of the metabolic milieu to which the muscle cells are exposed (31). Because of greater PCO2 and lactic acidosis, the decline in venous pH was much faster in COPD patients than in normal subjects. Considering the level of exercise, this acidosis is definitely abnormal and may be involved in further worsening of skeletal muscle function during exercise. Studies have indicated that intracellular acidosis may adversely influence muscle contractility and be involved in the development of muscle fatigue and, consequently, may be involved in exercise tolerance (13, 20). The correlation between venous pH at 40 W and theO2 peak is in
accordance with these notions, and it can be hypothesized that early
muscle acidosis may be involved in exercise termination. However, the
relationship between venous pH and
O2 peak must be
interpreted cautiously. Previous studies have indicated that changes in
muscle pH may be dissociated from those of
O2 peak (19).
This suggests that the link between these two variables is more complex
than a one-to-one causal relationship.
Methodological Considerations
In the present investigation,leg was measured with
the bolus injection method. This technique has been used successfully by several investigators, and the present results obtained are remarkably similar to those reported after using paired electromagnetic flow probes or the dye-dilution technique (16, 35, 37). Resting and
exercise values for leg and
O2 leg
obtained in our normal subjects are comparable to those reported in
previous studies; therefore, we are confident about their validity (16, 35, 37). However, because leg and blood-gas
measurements were not simultaneous and were probably obtained before
reaching a steady state, a small error in
O2 leg
calculation can be expected. The magnitude of this error can be
estimated by looking at the changes in total body
O2 that occurred between
minutes 2 and 3 of the exercise step, assuming that
most of the changes in O2 during this period originated in the lower limbs and
that C(a-v)O2 was relatively stable.
At 60 W, the increase in total body
O2 from
minute 2 to
3, averaged 23 ml/min in normal
subjects and 54 ml/min in COPD patients. At this exercise level, this
amounts to an underestimation in
O2 leg
of 3 and 8% in normal subjects and COPD patients, respectively.
Because the magnitude of this error is greater in COPD patients, the
actual differences in
O2 leg values for a given exercise work rate between the two groups would be
even smaller than those reported in this study.
Clinical Implications
The present results point to skeletal muscle dysfunction as being responsible for the early lactic acidosis onset in COPD. However, the discussion regarding the causes of the muscle abnormalities can only be speculative. Several muscle changes found in COPD, including reductions in muscle mass, in strength, and in mitochondrial enzyme activities, and the excessive lactic acidosis during exercise are consistent with the effects of chronic inactivity and the resulting muscle deconditioning (4). The improvement in skeletal muscle oxidative capacity in COPD patients that occurs with 12 wk of endurance training is also consistent with this interpretation (21). In that study, however, the decreases in enzyme activities were not completely corrected. This suggests that the training duration was not sufficiently long or that other contributing factors, such as malnutrition or chronic hypoxia (even if mild), may have played a role in altering the skeletal muscle function in COPD patients.Accordingly, the observed differences in muscle metabolism between COPD
patients and normal subjects can probably be explained largely by the
different fitness level of the two groups. Although the fitness level
of the control group could be considered normal, with a mean
O2 peak within 1 SD of
the reported mean value for normally active men of this age group (25),
it was above the average value for individuals of this age group
[O2 peak of 
30% above the predicted value of Jones (15)]. Despite this limitation of the present study, we believe that differences in lactate
response would have persisted, even if a group of less-fit subjects
(i.e.,
O2 peak 100% predicted value) had been used for comparison.
1) The difference in lactate
concentration in the blood draining the active muscles between normal
subjects and COPD patients was substantial.
2) There was no overlap of blood
lactate concentration between the two groups at submaximal exercise
level despite the fact that one normal subject had a O2 peak value 102% of
that predicted.
In COPD patients, the end-exercise
E was greater than the calculated maximal
voluntary ventilation, whereas the peak heart rate was smaller than the
maximal predicted value. In addition, oxygen desaturation and
CO2 retention occurred during
exercise in these individuals. Despite these evidences of limitations
in ventilation and gas exchange, the profound degree of acidosis and
the high RQleg and lactate release achieved at peak
exercise suggest that their skeletal muscle was nearly or
maximally activated. Although it is conceivable that these
abnormalities may be involved in early exercise termination, it is also
possible that they may be only markers of peripheral muscle
deconditioning associated with chronic inactivity. Further studies are
needed to clarify the role of excessive lower-limb lactate release and
acidosis as independent factors limiting exercise in COPD.
In summary, these results provide new insight into skeletal muscle function during exercise in patients with COPD. In this study, marked differences between COPD patients and normal subjects in lactate release, in venous blood pH, in venous CO2 accumulation, and in RQleg at submaximal exercise could not be attributed to differences in peripheral DO2. This finding suggests an intrinsic muscle abnormality. Despite evidences of ventilation limitation in the COPD group, femoral venous gases and acid-base status reached common limiting constraints during exercise both in COPD patients and in normal subjects.
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ACKNOWLEDGEMENTS |
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The authors thank Serge Simard for statistical assistance. The authors are grateful to the respirologists of the Centre de Pneumologie de l'Hôpital Laval for supporting F. Maltais in this research.
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FOOTNOTES |
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Address for reprint requests: F. Maltais, Centre de Pneumologie, Hôpital Laval, 2725 Chemin Ste-Foy, Ste-Foy, Quebec, Canada G1V 4G5 (E-mail: medfma{at}hermes.ulaval.ca).
Received 5 September 1997; accepted in final form 7 January 1998.
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Abstract
Introduction
Methods
Results
Discussion
References
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, 
) and in
normal subjects (
, 
). Peak exercise values represent average of
all peak values obtained in each subject in both groups. In contrast to
submaximal values, peak values were not obtained at an identical work
rate. Although arterial and venous lactate concentrations at maximal
exercise were greater in normal subjects than in COPD patients because
of greater exercise workload achieved, the increase in these parameters
was steeper in the latter group.
* P < 0.05;
P < 0.001;
P < 0.01.
