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* From the Rehabilitation Clinical Trials Center, Harbor-UCLA Research and Education Institute, Torrance, CA.
Correspondence to: Richard Casaburi, PhD, MD, FCCP, Division of Respiratory and Critical Care Physiology and Medicine, Harbor-UCLA Research and Education Institute, Building RB2, 1124 W Carson St, Torrance, CA 90502; e-mail: casaburi{at}ucla.edu
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Abstract |
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 TOP Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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O2) kinetics observed in COPD patients
is a manifestation of skeletal muscle dysfunction of multifactorial
origin. We determined whether oxygen supplementation during exercise
makes the dynamic O2 response faster and
reduces transient lactate increase.
Design: Ten
patients with severe COPD (ie, mean [± SD]
FEV1, 31 ± 10% predicted) and 7 healthy subjects of
similar age performed four repetitions of the transition between rest
and 10 min of moderate-intensity, constant-work rate exercise
while breathing air or 40% oxygen in random order. Minute ventilation
(E), gas exchange, and heart rate (HR) were
recorded breath-by-breath, and arterialized venous pH,
PCO2, and lactate levels were measured
serially.
Results: Compared to healthy subjects, the
time constants (
) for O2, HR, carbon
dioxide output (CO2), and
E kinetic responses were significantly slower in
COPD patients than in healthy subjects (70 ± 8 vs 44 ± 3 s,
98 ± 14 vs 44 ± 8 s, 86 ± 8 vs 61 ± 4 s, and 81 ± 7 vs
62 ± 4 s, respectively; p < 0.05). Hyperoxia decreased
end-exercise E in the COPD group but not the healthy
group. Hyperoxia did not increase the speed of
O2 kinetics but significantly slowed
CO2 and E response
dynamics in both groups. Only small increases in lactate occurred with
exercise, and this increase did not correlate with the for
O2.
Conclusion: In nonhypoxemic COPD patients performing moderate exercise, the lower ventilatory requirement induced by oxygen supplementation is not related to improved muscle function but likely stems from direct chemoreceptor inhibition.
Key Words: COPD • exercise • gas exchange kinetics • lactate • muscle dysfunction • oxygen
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Introduction |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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However, the benefits of oxygen are multifactorial. We can conceive of three beneficial effects of oxygen therapy that potentially might increase exercise tolerance: (1) pulmonary vasodilation, which might allow increased cardiac output; (2) increased oxyhemoglobin saturation, which would increase arterial oxygen content; and (3) increased arterial PO2, which could inhibit carotid chemoreceptor discharge. The first two mechanisms would succeed in decreasing the ventilatory requirement for exercise only if oxygen delivery to the exercising muscles was thereby increased and aerobic metabolism was facilitated. COPD patients have been found to have dysfunctional muscles, and one manifestation of this dysfunction is the onset of lactic acidosis at low work rates.3 4 5 6 7 Improved muscle oxygen delivery has the potential to ameliorate lactic acidosis and, thereby, to reduce ventilatory stimulation. Furthermore, muscle fatigue, in itself, may be a contributing factor to exercise limitation in COPD patients,8 9 so it is plausible that improved muscle oxygen delivery may directly alter muscle acidosis and the perception of fatigue.
A key piece of evidence suggesting that the muscles of ambulation of
patients with COPD do not function normally is the slowness of oxygen
uptake (O2) kinetics following
the onset of moderate exercise.5
10
11
Morphologic studies
have revealed a reduction in the proportion of oxidative (type I)
fibers accompanied by an increase of glycolytic (type II) fibers of the
vastus lateralis muscle in COPD patients.12
The lower
number of capillary contacts for types I and IIa fibers12
and the reduced myoglobin level,13
along with the abnormal
oxidative capacity of skeletal muscles14
15
also suggests
inefficient oxygen utilization. These factors likely contribute to slow
O2 kinetics, resulting in an
increased oxygen deficit. Such an oxygen deficit would be expected to
elicit transient reliance on anaerobic energy sources; this has been
shown to be associated with an "early lactate" response
(ie, a transient elevation in lactate level even for
exercise below the anaerobic threshold).16
17
Information relevant to determining whether supplemental oxygen therapy
improves the aerobic function of the exercising muscles was obtained by
Palange et al.10
They found that, in COPD patients with
only mild desaturation, breathing 30% oxygen speeded the
O2 response to moderate
exercise onset considerably, resulting in a smaller oxygen deficit.
This finding implies, first, that oxygen breathing increases muscle
oxygen delivery. That is, the vasoconstrictor effect of oxygen on the
microvasculature of skeletal muscle18
is overbalanced by
the higher oxygen content in the arterial blood. Second, this
finding implies that muscle oxygen metabolism early in exercise is
oxygen flow-limited and that higher oxygen supply ameliorates the
transient reliance on anaerobic energy sources, thus reducing oxygen
debt.
To better define the consequences of oxygen supplementation on muscle
metabolism at the onset of moderate-intensity exercise in COPD
patients, we compared O2
kinetics while subjects breathed air or 40% oxygen. We sampled blood
at frequent intervals during the transition in order to define the
kinetic response of blood lactate, hypothesizing that any increase in
the speed of O2 kinetics
produced by oxygen supplementation would be accompanied by a reduced
transient rise in blood lactate level. These responses were compared to
those of healthy subjects of similar ages.
We also wished to examine the acid-base changes that occur at the onset
of exercise in these patients. We, and others, have observed that both
carbon dioxide output (CO2)
and minute ventilation (E) kinetics are slow
in COPD patients performing moderate exercise5
10
11
and
that these kinetics are slowed further by breathing
oxygen.10
11
We reasoned that the transient behavior of
PCO2 and pH in the arterialized
venous blood of COPD patients, in comparison to that observed in
healthy subjects, would help to explain the physiologic mechanisms
underlying these observations.
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Materials and Methods |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Pulmonary Function Testing
Before exercise testing, subjects underwent pulmonary function
testing (Vmax 229 and Autobox 6200; SensorMedics; Yorba Linda, CA)
including spirometry, lung volumes determined by plethysmography, and
single-breath carbon monoxide diffusing capacity. The normal values
were those given in the work of Knudson et al,19
Goldman
and Becklake,20
and Crapo and Morris,21
respectively. Albuterol, 200 µg, was administered to the patients
from a metered-dose inhaler 30 min before testing.
Exercise Testing
A symptom-limited incremental exercise test was conducted with
the subject breathing room air on an electronically braked cycle
ergometer (Ergoline-800; SensorMedics). After 3 min of rest and 3 min
of unloaded pedaling, the work rate was increased continuously
(ramp pattern) by 5 or 10 W/min for the patients and 15 or 20
W/min for the healthy subjects. The peak
O2 was determined as the
average O2 over the last
30 s of exercise. Constant-work rate tests at a work rate equal to
80% of the LAT were performed on the same ergometer. LAT was
determined by the modified V-slope method.22
The pedaling
rate was kept constant between 55 and 65 revolutions per minute.
Compressed air and oxygen were blended (air-oxygen blender;
SensorMedics) from gas cylinders into a 200-L meteorological balloon to
be inspired during exercise. Subjects breathed through a mouthpiece
attached to a low-resistance, two-way, nonrebreathing valve (dead
space, 80 mL) [Hans-Rudolph; Kansas City, MO] with a nose clip in
place. Respiratory flow rates were measured with a calibrated mass flow
sensor (SensorMedics). E,
O2, and
CO2 were measured
breath-by-breath with a metabolic cart (Vmax 29c; SensorMedics). Each
test consisted of 3 min of motionless rest followed by 10 min of the
assigned constant work rate. To eliminate the initial inertia of the
ergometer, 10 s before the beginning of exercise a laboratory
staff member manually turned the pedals at 60 revolutions per minute.
Equipment was calibrated immediately before each test with a 3-L
syringe and two precision gas mixtures. A metabolic pump calibrator,
which simulated known levels of E,
O2, and
CO2, was also
employed.23
Biological calibration by healthy individuals
chosen from among the laboratory personnel with repeated bouts
of moderate constant-work rate exercise with 40% oxygen and air
breathing revealed (mean ± SD) 8.0 ± 1.7% higher values for
O2 during
O2 breathing compared to air breathing but no
significant differences for
CO2 or E
(-2.6 ± 4.3% and 1.3 ± 3.8%, respectively). The
O2 difference was presumed to
be related to nonlinearities in the oxygen analyzer at higher fraction
of inspired oxygen. O2 values
during oxygen breathing were corrected for this error. Heart rate (HR)
and oxygen saturation were recorded with continuous ECG (Cardiosoft;
SensorMedics) and pulse oximetric (N-200 pulse oximeter; Nellcor;
Hayward, CA) monitoring.
On one of the experimental days, before the constant-work rate exercise tests were performed, a 21-gauge butterfly catheter was placed in a vein in the dorsum of the hand. The catheter was flushed intermittently with heparinized saline solution. A heat lamp was used to warm the hand and thereby to arterialize the venous samples. This procedure yielded PCO2, pH, and lactate levels that approximated arterial values.24 Samples were taken within 60 s before the onset of exercise and at 20, 40, 60, 80, 100, and 120 s and 3, 4, 5, 7, and 10 min after the onset of exercise. Blood samples were taken anaerobically in heparinized syringes and were iced immediately. Each sample was analyzed within 30 min after exercise for pH and PCO2 levels (model 1640; Instrumentation Laboratories; Lexington, MA) and, after centrifugation, for plasma lactate (model 2300; Yellow Springs Instruments; Yellow Springs, OH).
Analysis of Response Kinetics
Before the start of exercise, a sufficient time (10 to 15 min)
was allowed for the subjects to accommodate to the mouthpiece and
equilibrate gas stores with the respired air. Further, subjects with
COPD were encouraged to take deep breaths intermittently during the
initial 7 to 10 min of oxygen breathing in order to equilibrate poorly
ventilated airspace. In preliminary studies, we found that achieving
the complete equilibrium of lung gas stores was of utmost importance
because, otherwise, the deep breathing that occurred at the onset of
exercise would tend to wash out the nitrogen in poorly ventilated
areas, falsely elevating the
O2 level and yielding an
appearance of more rapid O2
kinetics. An example of this phenomenon is shown in Figure 1
.
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E,
O2,
CO2, and HR were fitted by
iteration using the following nonlinear regression
analysis26
to a three-parameter, first-order exponential
model:
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is the response time
constant.
Data Analysis
Comparison between the responses breathing air and oxygen and
between COPD patients and healthy subjects were made by paired and
unpaired t tests. The correlation among variables was
determined by calculating the Pearson product-moment correlation
coefficient. Significance was accepted at the p < 0.05 level.
Dispersion about the mean values is expressed as ± SD, unless
otherwise specified.
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Results |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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O2 levels were threefold
and twofold higher in the healthy subjects, respectively. As gauged by
the breathing reserve (ie, the difference between maximum
voluntary ventilation [estimated as FEV1 times
40] and peak exercise ventilation in the incremental test), the COPD
patients but not the healthy subjects reached a ventilatory limitation
(3.4 ± 1.8 and 41.7 ± 9.2 L/min, respectively). The exercise
level for the constant-work rate tests averaged 21 ± 2 W
(41 ± 2% of the peak work rate) for the COPD patients and 48 ± 6
W (35 ± 3% of the peak work rate) for the healthy subjects. The
variables characterizing gas-exchange and cardiorespiratory response
kinetics (which were determined by fitting the response data to our
equation) are shown in Table 2
. Apart from the mildly higher resting HR values in COPD patients
(during both air and oxygen breathing), all preexercise values were
similar in the two groups and did not differ significantly between the
two inhalations.
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O2 and
CO2 were significantly higher
in the healthy subjects than in the COPD patients. The tendency toward
a higher HR amplitude failed to achieve statistical significance. In
contrast, E amplitudes were similar in the two
groups, which likely was a result of higher dead space ventilation in
the COPD patients.
O2 time constants were
substantially longer in the COPD group, and oxygen supplementation did
not result in acceleration of the kinetic response in either group.
This finding is reinforced in Figure 2
, which shows the grand average of the time courses of responses from
all subjects. The O2 time
courses are essentially identical for air and oxygen breathing in the
two groups. Oxygen breathing yielded a mild acceleration in HR kinetics
in the COPD group, which failed to achieve statistical significance.
The values for CO2 and
E were significantly greater in the COPD patients.
Oxygen breathing resulted in a significant prolongation of these
kinetic responses in both groups.
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E/CO2),
blood gas composition, and blood lactate level are shown in Figures 3
and 4
. The most obvious effect of oxygen was manifested in the pulmonary
ventilation and breathing pattern responses. Breathing 40% oxygen
resulted in a slower rise in ventilation, tidal volume, and breathing
frequency in the COPD patients, but not in the healthy subjects. The
end-exercise E level was significantly lower during
hyperoxia than during normoxia in the COPD patients
(25.6 ± 1.9 vs 23.9 ± 1.8 L/min, respectively; p < 0.05) but
did not differ significantly in the control subjects. The partial
pressure of end-tidal CO2 at rest was
significantly lower in the COPD patients than in the healthy subjects
both while breathing air (34.6 ± 0.7 vs 40.2 ± 0.8 mm Hg,
respectively; p < 0.001) and breathing oxygen (34.1 ± 1.8 vs
38.5 ± 1.1 mm Hg, respectively; p < 0.001). Compared to air
breathing, oxygen breathing resulted in a significantly greater
increase in partial pressure of end-tidal CO2 by
the end of exercise both in the COPD group (5.4 ± 0.9 vs
3.3 ± 0.4 mm Hg, respectively; p < 0.001) and in healthy
individuals (4.5 ± 0.5 vs 3.0 ± 0.4 mm Hg, respectively;
p < 0.001); the magnitude of this elevation during oxygen breathing
was significantly (p < 0.001) greater in the COPD patients. The
E/CO2 at
rest was higher in the COPD group than in the healthy group both while
breathing room air (48.7 ± 2.2 vs 38.0 ± 1.5, respectively;
p < 0.001) and breathing 40% oxygen (47.1 ± 1.4 vs
39.1 ± 2.3, respectively; p < 0.001). The magnitude of decrease
in E/CO2
with exercise (rest to steady-state) was not statistically different
between the two groups for a given inhalation.
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O2 time constant with either
inhalation in either group. |
Discussion |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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E and CO2
kinetics without an acceleration of
O2 and HR kinetics in both
groups. The slow O2 dynamics
seen in the COPD patients were not accompanied by large transient
changes in arterialized venous lactate concentration. Our observations
suggest that the improved exercise tolerance observed in nonhypoxemic
COPD patients who breathe supplemental oxygen1
is likely
not related to improved peripheral muscle function. Gas exchange responses following the start of moderate-intensity, constant-work rate exercise are characterized by three temporal phases.27 Phase I lasts about 15 to 20 s and represents the immediate increase in gas exchange, the majority of which is accounted for by the abrupt increase of pulmonary blood flow at the start of exercise.28 Phase II is the slower, approximately exponential increase in the kinetic variables resulting from the increased cellular respiration in the working muscles and the further increase in cardiac output. Phase III is the steady state, starting at 3 to 4 min after the onset of exercise when the work rate is moderate. At work rates associated with sustained levels of lactic acidosis, phase III features a further increase in response, thus yielding a slower overall kinetic response.
The factors determining the speed of
O2 kinetics remain unclear.
While some posit that sluggish oxygen delivery to the muscle can slow
O2 kinetics, others believe
that the determining factors are intrinsic to the muscle
(eg, inadequate capillarity12
and suboptimal
oxidative enzyme performance14
15
). Therefore, the finding
of Palange et al10
that the speed of
O2 kinetics can be
increased appreciably by modest increases in arterial oxygen content
assumes considerable importance. First of all, it implies that
increasing the fraction of inspired oxygen improves oxygen delivery to
the exercising muscle. This is not necessarily so, as oxygen is a
vasoconstrictor in peripheral vascular beds.18
In both
healthy subjects29
and in COPD patients30
at
a given level of exercise, oxygen breathing results in both a reduced
muscle blood flow and an increased oxygen content, resulting in a net
blunting or elimination of oxygen delivery increase. This possibility
is given credence by a report of Simon et al,31
who
studied patients similar to those studied here, in which femoral vein
catheterization allowed the direct measurement of oxygen delivery.
During moderate-intensity exercise, oxygen delivery to the leg was not
higher when the inhaled oxygen concentration was increased. Second,
even if oxygen can be delivered to the muscle at a more rapid rate, the
muscle may be unable to utilize it at an accelerated
rate.32
33
34
In contrast, endurance exercise training, an
intervention that alters muscle structure and biochemistry, has been
clearly shown to speed
O2 kinetics
following the onset of moderate exercise in both healthy subjects and
COPD patients.5
35
We cannot with certainty explain the difference between our
results and those of Palange et al10
who found that
supplemental oxygen substantially increased the speed of
O2 kinetics. They employed a
mixing-chamber system to evaluate kinetics and observed only a single
exercise transition for each inhalation. Furthermore, since the
end-exercise oxygen saturation was not stated and the lactate level
was not measured, it is conceivable that either exercise-induced
desaturation while breathing air was marked or that the work rate was
considerably above the LAT, although these were not the authors’
intention. An additional possibility, the one that we favor, is that a
technical difficulty with measuring
O2 in the presence of elevated
inhaled oxygen could have resulted in a falsely increased speed of
O2 kinetics. When oxygen
breathing commences, the wash-in of oxygen into the lung and body
oxygen stores occurs rapidly (ie, within several minutes) in
subjects with normal lungs. However, the lung of the COPD
patient may contain poorly ventilated areas that wash out very slowly,
or not at all, during quiet breathing. Taking periodic deep breaths may
succeed in equilibrating these areas and, thus, may avoid the sudden
washout of these airspaces with low oxygen content. Figure 1
presents
an extreme example in which the apparent
O2 kinetics are much
faster when equilibration with the higher oxygen inhalation is not
complete.
Although the mechanisms linking muscle hypoxia to lactate
production are controversial, in a variety of situations interventions
that increase muscle oxygen supply lower lactate levels in the blood.
We therefore postulated that improvements in oxidative metabolism
leading to more rapid O2
kinetics would be associated by an attenuation of the transient
increase in lactate in the arterialized venous blood. In fact, as shown
in Figure 4
, only small increases in lactate level were observed in the
COPD patients, and oxygen supplementation resulted in no alteration in
lactate levels or time course. Furthermore, in the healthy subjects,
despite transitioning to a considerably higher work rate, the lactate
time course was nearly identical. These data do not support the
contention of Cerretelli et al36
that slower
O2 kinetics are associated
with an accentuated transient increase in blood lactate ("early
lactate").
Reinforcing the findings of previous studies,37
38
we found that the dynamics of E track
closely those of CO2 in both
experimental conditions in both groups. Both
CO2 and E
kinetics were considerably slower in the COPD patients than in the
healthy subjects. In part, this is related to the slower
O2 kinetics, but a primary
role for sluggish ventilatory response kinetics is likely as
well.39
In both healthy subjects and COPD patients, oxygen
supplementation slowed CO2 and
E kinetics. This has been tied to the inhibition of
the carotid bodies, delaying the ventilatory response to metabolic
transients.37
In the case of the hyperoxic transition to
moderate-work rate exercise in the COPD patients, the rise in
arterialized venous PCO2 (Fig 4)
would be expected to contribute to the wash-in of the body’s
CO2 stores, with a consequent slowing of
CO2 kinetics.
The observation that end-exercise ventilation was lower in the COPD patients when oxygen was respired, but that the lactate level was not lower, sheds light on the mechanism of oxygen’s ability to improve exercise tolerance during constant-work rate exercise. It seems unlikely that either pulmonary vasodilation or higher arterial oxygen content play a predominant role, otherwise we would have observed signs of improved muscle function in these studies. Rather, we may speculate that carotid body inhibition by hyperoxia directly inhibits ventilation, allowing for decreased hyperinflation and the forestalling of ventilatory muscle fatigue.
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Footnotes |
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CO2 = carbon dioxide
output; E = minute ventilation;
E/CO2 = ventilatory
equivalent for CO2;
O2 = oxygen uptake Dr. Somfay is a visiting scientist from the Department of Pulmonology, Albert Szent-Györgyi Medical University, Szeged, Hungary, and is partly supported by the Hungarian SOROS Foundation (Budapest, Hungary), the Foundation for Hungarian Pulmonology (Budapest, Hungary), and the Foundation for Quality Care of Patients with Lung and Heart Diseases (Deszk, Hungary). Dr. Pórszász is a visiting scientist from the National Institute of Occupational Hygiene and Health (Budapest, Hungary). Dr. Lee is a visiting scientist from the Department of Internal Medicine, Eulji Medical College, (Seoul, Korea) and is the recipient of a World Health Organization fellowship. Dr. Casaburi occupies the Alvin Grancell-Mary Burns Chair in the Rehabilitative Sciences.
Received for publication May 7, 2001. Accepted for publication August 8, 2001.
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References |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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O2 kinetics during exercise in obstructive pulmonary disease. J Appl Physiol 78,2228-2234O2 on-response and early blood lactate. J Appl Physiol 47,761-769O2 on-kinetics in isolated in situ canine muscle. J Appl Physiol 85,1394-1403This article has been cited by other articles:
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  M M Peters, K A Webb, and D E O'Donnell Combined physiological effects of bronchodilators and hyperoxia on exertional dyspnoea in normoxic COPD Thorax, July 1, 2006; 61(7): 559 - 567. [Abstract] [Full Text] [PDF]
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 P. M. A. Calverley Dynamic Hyperinflation: Is It Worth Measuring? Proceedings of the ATS, May 1, 2006; 3(3): 239 - 244. [Abstract] [Full Text] [PDF]
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T. Troosters, R. Casaburi, R. Gosselink, and M. Decramer Pulmonary Rehabilitation in Chronic Obstructive Pulmonary Disease Am. J. Respir. Crit. Care Med., July 1, 2005; 172(1): 19 - 38. [Full Text] [PDF]
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 J. P Mattson and J. C Martin Emphysema-induced reductions in locomotory skeletal muscle contractile function Exp Physiol, July 1, 2005; 90(4): 519 - 525. [Abstract] [Full Text] [PDF]
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 N. Ambrosino and S. Strambi New strategies to improve exercise tolerance in chronic obstructive pulmonary disease Eur. Respir. J., August 1, 2004; 24(2): 313 - 322. [Abstract] [Full Text] [PDF]
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 T. A. Bauer, E. P. Brass, M. Nehler, T. J. Barstow, and W. R. Hiatt Pulmonary VO2 dynamics during treadmill and arm exercise in peripheral arterial disease J Appl Physiol, August 1, 2004; 97(2): 627 - 634. [Abstract] [Full Text] [PDF]
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M. Emtner, J. Porszasz, M. Burns, A. Somfay, and R. Casaburi Benefits of Supplemental Oxygen in Exercise Training in Nonhypoxemic Chronic Obstructive Pulmonary Disease Patients Am. J. Respir. Crit. Care Med., November 1, 2003; 168(9): 1034 - 1042. [Abstract] [Full Text] [PDF]
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 G. L. Snider Enhancement of Exercise Performance in COPD Patients by Hyperoxia: A Call for Research Chest, November 1, 2002; 122(5): 1830 - 1836. [Abstract] [Full Text] [PDF]
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