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1 Division of Physiology, Department of Medicine, University of California, San Diego, La Jolla, California 92093; 2 Department of Thoracic Medicine, University of Crete, Heraklion 711 10 Crete, Greece; and 3 Department of Physiology and Pharmacology, Loma Linda University, Loma Linda, California 92354
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ABSTRACT |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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During maximal
exercise, ventilation-perfusion inequality increases, especially in
athletes. The mechanism remains speculative. We
hypothesized that, if interstitial pulmonary edema is involved, prolonged exercise would result in increasing ventilation-perfusion inequality over time by exposing the pulmonary vascular bed to high
pressures for a long duration. The response to short-term exercise was
first characterized in six male athletes [maximal O2 uptake
(
O2 max) = 63 ml · kg
1 · min1] by using 5 min
of cycling exercise at 30, 65, and 90%
O2 max. Multiple inert-gas, blood-gas, hemodynamic, metabolic rate, and ventilatory data were obtained. Resting log SD of the perfusion distribution (log
SD
) was normal [0.50 ± 0.03 (SE)] and increased with exercise (log
SD = 0.65 ± 0.04, P < 0.005), alveolar-arterial
O2 difference increased (to 24 ± 3 Torr), and end-capillary pulmonary diffusion limitation occurred at 90%
O2 max. The subjects
recovered for 30 min, then, after resting measurements were taken,
exercised for 60 min at ~65%
O2 max.
O2 uptake, ventilation, cardiac
output, and alveolar-arterial O2
difference were unchanged after the first 5 min of this test, but log
SD increased from
0.59 ± 0.03 at 5 min to 0.66 ± 0.05 at 60 min
(P < 0.05), without pulmonary diffusion limitation. Log
SD was negatively
related to total lung capacity normalized for body surface area
(r = 
0.97,
P < 0.005 at 60 min). These data are compatible with interstitial edema as a mechanism and suggest that lung
size is an important determinant of the efficiency of gas exchange
during exercise.
multiple inert-gas elimination technique; interstitial pulmonary edema
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INTRODUCTION |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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HUMANS, particularly athletes, experience pulmonary
limitations to gas exchange during heavy exercise (3, 14) manifested by
an increase in the alveolar-arterial difference for
O2
(A-aDO2) and arterial hypoxemia (3, 9, 19). Ventilation-perfusion (A/) inequality
increases during short-term (~5 min) maximal exercise (5, 9) and
contributes to as much as 60% of the A-aDO2 (9).
The cause of worsening
A/ relationships with
exercise is unknown, but interstitial pulmonary edema resulting from
high pressures in the pulmonary vascular bed is the most attractive explanation. Evidence that interstitial pulmonary edema develops during
exercise includes the observation of a significant reduction in lung
diffusing capacity for carbon monoxide
(DLCO)
(15) and vital capacity after exercise, without a corresponding
reduction in expiratory flow rates (17). Additionally, pig lungs show an increase in perivascular edema on histological examination (16) in
exercised animals, compared with resting controls. Interstitial pulmonary edema would be expected to affect gas exchange in the lung by
reducing the compliance of alveoli and by compressing small blood
vessels, resulting in nonuniform air-flow and blood-flow distribution
in the lung. In support of this idea,
A/ inequality persists
into recovery from heavy exercise, even after ventilation and cardiac
output have returned to normal (17), and subjects who have previously
suffered from high-altitude pulmonary edema (HAPE) have both higher
pulmonary arterial pressures (PAPs) and greater
A/ inequality during
sea-level exercise than do control subjects (4, 13). However, direct
evidence of interstitial edema in humans with exercise-induced
increases in A/
inequality remains to be demonstrated.
We hypothesized that, if interstitial pulmonary edema is the cause of
A/ inequality with
exercise, then prolonged submaximal exercise, by increasing the
duration of the pulmonary vascular bed exposure to high pressures,
would likely result in greater A/ inequality than that
observed with ~5 min of exercise at the same intensity. We therefore
compared, in well-trained athletes, the effects on pulmonary
gas exchange of 5 min of exercise at ~65% of maximal
O2 uptake
(O2 max) to effects of
15, 30, 45, and 60 min of exercise at the same intensity, using the
multiple inert-gas elimination technique.
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METHODS |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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This study was approved by the Human Subjects Committee of the University of California, San Diego. Six men were recruited by advertisement and agreed to further study, after giving informed consent. All were healthy, nonsmoking competitive cyclists or triathletes, with a negative medical history.
Preliminary Screening
Screening history and physical examination were performed, and the subjects were screened for cardiovascular (12-lead electrocardiogram), pulmonary (chest X-ray, spirometry, DLCO), and hematological (complete blood count) abnormalities. To determine the appropriate workloads for the exercise tests,O2 max was determined
on an electronically braked cycle ergometer (Excaliber, Quinton
Instruments, Gronigen, the Netherlands) equipped with a racing saddle
and the subject's own pedals. After a 10- to 15-min warm-up at a
self-selected workload and a 5-min warm-up at 150 W, the subjects rode
a progressive exercise test (30 W/min) until they were unable to
continue. Heart rate was monitored by cardiac monitor (Lifepak 6, Physio-control, Redmond, WA). The subjects breathed through a
non-rebreathing valve (2700, Hans-Rudolph, Kansas City, MO). Expired
gas was sampled continuously from a heated mixing chamber, and
O2 and
CO2 concentrations were measured
(mass spectrometer 1100, Perkin-Elmer, Pomona, CA). Expired gas flow
was measured by using a pneumotach (no. 3, Fleisch) and differential
pressure transducer (DP45-14, Validyne, Northridge, CA), and the
electrical signals from the mass spectrometer and the pneumotach were
logged at 100 Hz by using a 12-bit analog-to-digital converter. Minute
ventilation (E),
O2 consumption
(O2), and CO2 production were calculated by
using a commercially available software package (Consentius
Technologies, Salt Lake City, UT). O2 max was considered
to be the average of the four highest consecutive 15-s measurements of
O2. These results were used to calculate workloads that represented ~30, 65, and 90% of the subject's O2 max.
Subject Preparation
The next morning the subjects returned to the laboratory for further study. The subjects were instructed to ingest a liquid-only breakfast before insertion of the catheters. All catheters were placed by using a sterile technique with the subject under local anesthesia, and the subject was monitored by electrocardiogram by a physician who directed his attention exclusively to the subject. Cardiopulmonary resuscitation drugs and intubation equipment were available at all times. The standard catheter arrangement used by our laboratory for inert-gas studies has been described previously (4). A 20-gauge arterial cannula was placed in the radial artery of the nondominant hand for blood sampling and arterial pressure. A sterile rapid-response (<0.1 s) thermistor (18T, Physitemp Instruments, Clifton, NJ) was placed, by using a sterile technique, through the injection hub into the lumen of a small-volume (0.6 ml) extension set T (Abbott Hospitals, North Chicago, IL), which was flushed with saline and connected to the arterial cannula. This placed the thermistor into the flowing bloodstream when arterial blood was sampled, and the peak deflection of the temperature was used as the arterial blood temperature. This allowed us to use a smaller (5-F) Swan-Ganz catheter during the study, because a thermodilution catheter was not required. The catheter was introduced percutaneously into the basilic vein and manipulated into the pulmonary artery for sampling mixed venous blood and measuring PAP and pulmonary arterial occlusion pressure (PAOP). An 18-gauge intravenous catheter was placed in a vein of the dominant forearm for infusion of the inert-gas mixture.Exercise and Data-Collection Protocol
The study took place in two parts. In the first part (short protocol), the hemodynamic and pulmonary gas-exchange responses to exercise were characterized by using the usual exercise protocol from our laboratory (13, 17). In the second part (long protocol), we measured the hemodynamic and pulmonary gas-exchange responses to 1 h of submaximal exercise targeted at a workload designed to elicit a constantO2 of ~65%
O2 max. However, in
most subjects, minor (~20 W) reductions in workload were required
during the initial 10 min to ensure a constant
O2 and completion of the 60 min of exercise. Each set of measurements (described below) consisted
of arterial and pulmonary arterial blood gases, arterial and mixed
expired inert gases, and metabolic and hemodynamic measurements. The
subject was seated on the bicycle for 20 min and breathed through the
mouthpiece for 10 min before the start of the resting measurements.
After these were obtained, the short exercise protocol was begun. This
protocol consisted of 5 min at workloads producing ~30, 65, and 90%
O2 max. Data were
collected in the last 2 min at each exercise level. The subject was
allowed to recover for at least 30 min and then was again seated on the
bicycle before a second set of resting measurements was taken, as
described above. Then the long exercise protocol was initiated. The
subject was exercised at the power output that elicited ~65%
O2 max
during the O2 max
testing. Data were collected at 5, 15, 30, 45, and 60 min of exercise.
Multiple Inert-Gas Measurements
The multiple inert-gas technique was applied in the usual manner (5). The inert-gas solution was prepared in 5% dextrose and infused for ~20 min before collection of the resting samples in both exercise protocols. During the short exercise protocol, the rate of the infusion was increased at the onset of each new workload to a rate (in ml/min) equal to one-fourth of the expectedE
(l/min). Because of the relatively long duration of the long protocol
(60 min) and the high infusate flow rate (20 ml/min) required to match
the high ventilation during exercise, the inert-gas infusion was turned
on 5 min before the collection of each exercise sample (see below) and
turned off immediately afterward to minimize the fluid load to the
subject. Because the pulmonary blood flow and ventilation are both
extremely high, even during submaximal exercise, 5 min of infusion are
sufficient to ensure steady-state conditions during exercise (see
DISCUSSION). The total volume of
fluid infused during the course of the study was ~1 liter over ~2.5
h, which is hemodynamically insignificant for athletes exercising to
this extent.
Quadruplicate 15-ml samples of mixed expired gas and duplicate 6-ml
samples of arterial blood were obtained in gas-tight syringes at each
sampling time for measurement of the steady-state concentrations of the
six inert gases (sulfur hexafluoride, ethane, cyclopropane, enflurane,
ether, and acetone) by using a gas chromatograph (5890A, Hewlett-Packard, Wilmington, DE) (22). Mixed venous concentrations of
the inert gases were calculated from the measured cardiac output (see
below) and arterial and mixed expired concentrations by using the Fick
principle. A/
distributions were obtained by using the multiple inert-gas elimination
technique in the usual fashion: namely, solubilities, retentions
(R = ratio of arterial to mixed venous partial pressure), and
excretions (E = ratio of mixed expired to mixed venous partial
pressure) for the inert gases were determined and corrected for body
temperature, and A/
distributions were calculated from the inert-gas data (22, 23). The
second moment of the perfusion distribution, exclusive of
intrapulmonary shunt [log SD of the perfusion distribution (log
SD)], and
the second moment of the ventilation distribution, exclusive of dead
space [log SD of the ventilation distribution (log
SD)] are
used as indicators of the degree of
A/ inequality
(i.e., the greater the log
SD or the log SD, the greater
the A/ inequality). The residual sum of squares was used as an indicator of the adequacy of
fit of the data to the 50-compartment model of the lung (21).
Hemodynamic Measurements
The pressure transducers (P23 ID, Statham, Oxnard, CA) were zeroed to the level of the right atrium, and calibration was checked before each measurement. Mean arterial pressure, PAP, and PAOP were recorded on a strip-chart recorder (model 200, Gould, Valleyview, OH) immediately before each set of inert-gas measurements. Cardiac output was calculated from the mixed venous and arterial blood contents and measuredO2 by using the
Fick principle.
Blood-Gas Measurements
Two milliliters of arterial and mixed venous samples were collected immediately after each inert-gas arterial sample and maintained on ice until they were analyzed for PO2, PCO2, and pH by using an IL1306 (Instrumentation Laboratories, Lexington, MA) blood-gas analyzer. In each sample, hemoglobin and O2 saturation were measured by using an IL282 CO-oximeter (Instrumentation Laboratories), and hematocrit was determined. The blood gases were corrected to blood temperature.Immediately after the end of the second exercise test, the catheters were removed, and pulmonary function tests were repeated (mean time to onset of repeat pulmonary function testing = 34 ± 2.5 min). These involved measurement of static lung volumes, a flow-volume curve, and DLCO.
Statistical Analyses
ANOVA for repeated measures (SuperANOVA version 1.11, Abacus Concepts, Berkeley, CA) was used to statistically test changes in the dependent variables over the duration of the exercise tests. For the 1-h test, preplanned contrasts were used to compare the changes in the major dependent variables during the course of the exercise test. Significance was accepted at P < 0.05, two tailed. Data are presented as means ± SE throughout.| |
RESULTS |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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General Data
All subjects tolerated the study well. The subjects averaged 27.1 ± 1.7 yr of age, 177.7 ± 2.3 cm in height, and 74.7 ± 3.2 kg in weight. The subjects were well-trained aerobic athletes, as evidenced by theirO2 max, which
averaged 63 ± 7 ml · kg1 · min1,
and peak power output (415 ± 5 W). Pulmonary function data are given in Table 1. All the
pulmonary function data were within normal limits. After exercise,
there was a small (6%) but significant (P < 0.05) decrease in the
DLCO,
without any other change in pulmonary function.
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Short Protocol
Metabolic rate and hemodynamic data.
O2, cardiac output, and PAP
data are given in Fig. 1. Cardiac output
and ventilation are given in Table 2.
During the short protocol, the exercise intensities produced were
38% (light exercise), 63% (moderate exercise), and 92% (heavy
exercise) of O2 max, close to the targets of 30, 65, and 90%, respectively. PAP rose significantly from rest (14.0 ± 1.3 mmHg) to light exercise (23.4 ± 3.8 mmHg) but did not change significantly with increasing
workload thereafter (24.8 ± 5.6 mmHg during heavy exercise). We
were able to obtain a complete set of PAOP measurements on three of our subjects. PAOP increased significantly
(P < 0.0001) with increasing exercise intensity, from 7.5 ± 1.4 mmHg at rest to 20.3 ± 3.1 mmHg at the end of heavy exercise. In these three
subjects, PAP increased from 15 ± 0.6 to 32 ± 6.1 mmHg at the
same times. Calculated pulmonary vascular resistance was reduced from
88 to 40 dyn · s · cm5
during heavy exercise; this change was not significant
(P = 0.07), likely because of the
small number of subjects (n = 3) with
complete data.
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Pulmonary gas exchange.
Arterial blood gases during the short protocol are given in Fig.
2, and inert-gas data are given in Fig.
3 and Table 2. There was a significant drop
in arterial PO2
(PaO2) with increasing exercise
intensity (P < 0.05), from 105 ± 5 Torr at rest to 91 ± 3 Torr during heavy exercise. There was no
evidence of exercise-induced hypoxemia, as hemoglobin saturations were
>93% at all times during the test. The
A-aDO2
widened progressively with increasing exercise intensity and reached 24 ± 3 Torr during heavy exercise. There was a significant increase in
A/
inequality (as measured by the log
SD and log
SD) with
increasing exercise intensity (P < 0.005 and P < 0.05, respectively). The log SD
increased from 0.50 ± 0.03 at rest to 0.65 ± 0.04 at the end of
heavy exercise. This was a consistent observation among individuals,
and all subjects had an increase in log
SD equal to 1 SD
of the group mean value above their initial resting value. The log
SD was negatively
related to total lung capacity normalized for body size at rest
(r = 0.77, P = 0.07) and during light
(r = 0.74,
P = 0.09), moderate
(r = 0.85,
P < 0.05), and heavy exercise
(r = 0.90,
P < 0.05; see Fig.
4). The log
SD was not
significantly correlated with ventilation
(r = 0.16, 0.11, 0.50, and 0.10 at rest and during light, moderate, and heavy exercise, respectively; all
P > 0.05), ventilation normalized
for body size, or arterial PCO2
(PaCO2)
(r = 0.63, 0.47, 0.43, and 0.71 at
rest and during light, moderate, and heavy exercise, respectively; all
P > 0.05) at any single exercise
intensity. The log
SD was also not
significantly correlated with cardiac index or PAP.
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A/ distribution and
intrapulmonary shunt and assuming diffusion equilibrium (19). During
heavy exercise, the measured
A-aDO2 was
significantly greater (by 9 ± 3 Torr) than that predicted from the
inert gases, suggesting pulmonary diffusion limitation (although
extrapulmonary shunt cannot be excluded).
Long Protocol
Metabolic rate and hemodynamic data.
Before the onset of the 1-h protocol, heart rate was elevated from 62 ± 5 beats/min (resting heart rate before any exercise) to 87 ± 5 beats/min. However, there were no significant differences in
O2, cardiac output, or PAP
compared with the resting measurements obtained before the short
protocol. The average exercise intensity sustained during the long
protocol produced a O2 of 3.0 l/min, which was 65%
O2 max.
O2, cardiac output, PAP and
PAOP during the 1-h protocol are given in Fig.
5. Cardiac output and ventilation are
given in Table 3. There were no significant
changes in O2, ventilation,
or cardiac output during the exercise test. However, the small (17 W)
reduction in power output required to maintain a constant
O2 over the course of the
exercise test was statistically significant
(P < 0.0001). Heart rate increased
significantly from 155 ± 4 beats/min at 5 min to 168 ± 4 beats/min at the end of 60 min of exercise
(P < 0.0001), with a corresponding
decrease in stroke volume (P < 0.05). PAP increased from 14.0 ± 1.1 mmHg at rest to 30.6 ± 3.2 mmHg at 5 min of exercise. There was a subsequent decrease in PAP to
26.1 ± 4 mmHg by 15 min of exercise
(P < 0.05) and no significant change
thereafter. There were corresponding changes in PAOP
(n = 3). PAOP increased from rest (8.3 ± 1.8 mmHg) to exercise (P < 0.005) with a peak at 5 min (18.3 ± 2.6 mmHg). There was a
significant decrease from 5 to 15 min to 15.3 ± 2.4 mmHg
(P < 0.05) and no significant change
thereafter. Pulmonary vascular resistance was 96 dyn · s · cm5
at rest; there were no systematic changes with exercise, and the
pulmonary vascular resistance ranged from 56 to 72 dyn · s · cm5
throughout the duration of the exercise test.
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Pulmonary gas exchange.
Arterial blood gases during the 1-h test are given in Fig.
6, and inert-gas data are given in Fig.
7 and Table 3. At rest, PaO2 and
PaCO2 were not significantly different
from the resting values obtained before the short exercise protocol.
PAP and the log
SD and log
SD were also not
different from the first resting measurements. There was a small but
significant decrease in PaO2 from rest
to exercise, and then a progressive increase throughout the 1-h test,
with a decrease in PaCO2 indicating
increasing alveolar ventilation. The
A-aDO2 was
increased to 10 ± 3 Torr by the first 5 min of the prolonged
exercise test and did not change further as the test continued.
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A/ inequality from rest
to the first 5 min of exercise (P < 0.005), and the log
SD continued to
increase as the exercise test continued; log
SD and log
SD were
significantly greater at the end of 60 min of exercise than after 5 min
(P < 0.05). However, log
SD and log
SD were less at
the 30-min time point than at any other time during exercise
(P < 0.05 and
P < 0.005, respectively). The log
SD at the end of
1 h of exercise was closely correlated with the log
SD during
exercise at 90% O2 max (r = 0.93, P < 0.01). The log
SD was
significantly negatively related to total lung capacity normalized for
body size at rest (r = 0.90,
P < 0.05) and at 5 min
(r = 0.93,
P < 0.01), 45 min
(r = 0.94,
P < 0.005), and 60 min
(r = 0.97,
P < 0.005; see Fig.
8). The log
SD was not
significantly correlated with ventilation
(r = 0.67, 0.29, 0.47, 0.61, and 0.31 for 5, 15, 30, 45, and 60 min of exercise, respectively; all
P > 0.05), ventilation normalized
for body size, or PaCO2
(r = 0.70, 0.33, 0.18, 0.36, and 0.38 for 5, 15, 30, 45, and 60 min of exercise, respectively; all
P > 0.05) at any time
point. The log
SD was not significantly correlated with cardiac index or PAP. There was no
evidence for the development of intrapulmonary shunting, areas of low
A/ ratio, or
end-capillary pulmonary diffusion limitation at any point during the
prolonged exercise test. Thus the increase in log
SD reflected a
slight broadening of the
A/ distribution and not
the development of lung units with extremely low or high
A/ ratios.
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DISCUSSION |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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This study shows that
A/ inequality increases
slightly but significantly with increasing exercise duration during
prolonged submaximal exercise in athletes. To our knowledge, this is
the first study to measure in humans the effects of prolonged
submaximal exercise on pulmonary gas exchange by using the multiple
inert-gas elimination technique. The increase in
A/ inequality occurs despite constant O2, cardiac
output, and slightly decreasing PAPs. We did not find evidence for the
development of end-capillary pulmonary diffusion limitation over the 1 h of the prolonged exercise test.
A/ Inequality and
Exercise
A/ inequality with both
exercise tests in all six subjects. This is in keeping with data
previously obtained in a similar group of athletes (9) and in contrast to the lower incidence found in subjects who are less aerobically fit
(6, 17). We observed an increase in the log
SD and the log
SD with
increasing exercise duration without a corresponding increase in the
A-aDO2. This is because of the overall shift in mean
A/ ratio with increasing exercise duration toward a higher
A/ ratio, as alveolar
ventilation increased slightly while cardiac output was constant.
Therefore, although the overall
A/ distributions are
broader, the perfusion of relatively low
A/ areas is not increased and the overall
A-aDO2 is
not changed.
The cause of increased
A/ inequality with
exercise is presently unknown. Interstitial pulmonary edema, resulting
from rapid transcapillary fluid flux in excess of the lymphatic
drainage capacity of the lung, is the most attractive possibility
because 1)
A/ inequality is
exaggerated in extreme hypobaric hypoxia (24);
2) it is improved with 100%
O2 breathing (6), which would be
expected to decrease both PAP and driving pressure for fluid flux; and
3) there is no evidence of
bronchoconstriction, despite moderately severe
A/
inequality. Also
A/ inequality persists after exercise, even after ventilation and cardiac output have
returned to normal (17). Possible alternate mechanisms include
heterogeneity of hypoxic pulmonary vasoconstriction (10), reduction of
gas mixing in large airways (20), or heterogeneity because of increased
ventilation alone. The data in the present study do not allow any
direct examination of the first possibility. However, the data do not
support reduction in gas mixing or increased ventilation as a
cause of the increased
A/ inequality, because there was no correlation between ventilation, ventilation normalized for lung size, or PaCO2 and the log
SD at any
exercise level.
We hypothesized that, if interstitial pulmonary edema were the
cause of the increased
A/ inequality with
exercise, prolonged exercise might exacerbate the
A/ inequality, by
increasing the duration of the exposure of the pulmonary vascular bed
to increased pulmonary vascular pressures. This, in turn, could lead to
increased filtration of fluid across the capillary endothelium in
excess of the capacity of lymphatic drainage, resulting in interstitial
pulmonary edema. The results of this study lend support to this
possible mechanism but, of course, are not proof of this hypothesis.
The log SD at the
end of prolonged submaximal exercise was closely correlated with the
log SD during
heavy exercise (between subjects). Thus susceptible individuals can
develop an increase in
A/ inequality with
exercise, either by exposure to short-term, very heavy exercise or by
prolonged exercise at a lower intensity. The extent of the increased
A/ inequality is very
similar within individuals, regardless of which of these two types of exercise is used. The log
SD at the end of
the prolonged test was not greater than that observed during heavy
exercise. Such a comparison does not allow for the effect (if any) of
previous exercise on A/
matching, because the order of these two types of exercise was not
randomized. The log
SD was
significantly (P < 0.05) lower after
the first 5 min of the prolonged exercise test than it was after 5 min
at the same intensity in the first (short) exercise test.
Total Lung Capacity and
A/ Inequality
at
rest and during both types of exercise. Although the sample size in our
study is small, this relationship merits discussion because it is so
striking. The correlation between lung size and
A/ inequality is
present at rest and becomes more marked during exercise. Under both
exercising conditions, the slope of the relationship is accentuated,
compared with rest, suggesting that exercise per se may have an
additional effect on the relationship between lung size and
A/ inequality. Although
we can only speculate as to the reason for this finding, it may
indicate intrinsic differences in the lungs of those individuals
susceptible to increased
A/ inequality with
exercise. Possibly, individuals with a smaller relative lung size may
also have smaller airways and blood vessels. If this were the case, any
small regional inhomogeneity in the distribution of air flow and blood
flow could be accentuated in these individuals, both at rest and during
exercise. Recent studies of HAPE-susceptible subjects and normal
controls (4, 13) found both a greater forced vital capacity and less
A/ inequality with sea
level exercise in control subjects compared with HAPE-susceptible individuals, suggesting that this finding is not limited to the present
study.
Alveolar-End-Capillary Diffusion Limitation
During the short-term exercise test, our subjects had a greater A-aDO2 than predicted from the inert gases at 90 but not at 60 or 30%O2 max. This suggests
pulmonary diffusion limitation (19) at 90%
O2 max. Extrapulmonary
shunts (bronchial circulation, thebesian veins) cannot be completely
excluded but are unlikely (19). We did not find evidence of
alveolar-end-capillary diffusion limitation in our subjects during the
prolonged exercise test. This is not surprising, because significant
alveolar-end-capillary diffusion limitation in humans during normobaric
normoxic exercise has been shown to occur only during short-term,
near-maximal exercise (6, 9) and is most likely related to rapid
pulmonary transit times (8). As mentioned previously, we did not see
evidence for alveolar-end-capillary diffusion limitation at the same
O2 (65%
O2 max) during
short-term exercise.
Some authors have suggested that the potential effect of interstitial
pulmonary edema on pulmonary gas exchange would be an alteration in the
structure of the blood-gas barrier, resulting in alveolar-end-capillary
diffusion limitation and an increase in the
A-aDO2 (1,
2, 11, 12). The main evidence cited in support of this idea has been
the observation of a small reduction in
DLCO after
exercise of varying duration and intensities (11, 12, 15). In the
present study, we observed both an increase in
A/ inequality during
prolonged exercise and a reduction in the
DLCO after
exercise but, as previously stated, no associated increase in the
alveolar-end-capillary diffusion limitation as measured by the inert
gases. Thus all of the increase in
A-aDO2 during prolonged exercise is explained by
A/ inequality.
Therefore, we think it is unlikely that interstitial pulmonary edema,
if it exists, is of sufficient magnitude to affect the diffusion of
O2 across the blood-gas barrier.
In situations in which interstitial edema does occur, it appears as a
cuff around medium-sized airways and blood vessels (16). This would not
affect the alveolar-capillary diffusion distance, and the
intra-alveolar distance has not been shown to increase (18). More
likely, we feel, the effect of any interstitial pulmonary edema on gas
exchange would result in increased
A/ inequality.
Interstitial edema fluid would be expected to distort the surrounding
architecture of the alveoli and capillary network. Altered airway and
blood vessel diameter resulting from the presence of cuffing would
affect distribution of air flow and blood flow in the lung.
Additionally, alveolar interstitial fluid may alter alveolar compliance
with additional impairment of air-flow distribution in the lung.
Recently, Hanel et al. (7) have shown that the reduction in
DLCO
1-2 h after exercise is related to a decrease in pulmonary blood
volume and a redistribution of central blood flow; this also argues
against pulmonary edema per se causing the fall in DLCO. We
did not measure inert gases and blood gases simultaneously with our
DLCO
measurements. However, previous data suggest that, although
A/ inequality persists
into recovery, it is resolved by 20 min (17) and that there is minimal
effect on the
A-aDO2. Also, there is no associated increase in alveolar-end-capillary diffusion limitation for O2 as
measured by the inert gases (17) after the cessation of exercise. Taken
together, this information suggests that any interstitial pulmonary
edema, if present, is likely to be transient in nature.
Effect of Experimental Design on Study Data
One factor that needs to be addressed is the effect of high fluid-infusion rates necessary for the inert-gas analysis onA/ inequality and our
results. To obtain adequate peak detection of the inert gases in blood
and expired air, the inert-gas mixture infusion rate (in ml/min) is
~0.25 of E (in l/min). During the long
exercise protocol, the infusion rate was 20 ml/min. That infusion rate,
if continuously run, would result in the administration of ~1,300 ml
of fluid over the prolonged test and 2,000 ml total for the study. By
turning the infusion on and off during the prolonged test, we were able
to reduce the amount of intravenous fluid to 1,000 ml for the entire
study. Given that the subjects exercised for a total of 75 min and were
sweating profusely throughout, this amount of fluid is hemodynamically
insignificant. In fact, despite the ad libitum consumption of water
between protocols and during the prolonged exercise test, there was
evidence that our subjects were unable to maintain their central blood
volume. Although cardiac output was unchanged, heart rate was increased with increasing exercise time, indicating a reduction in stroke volume
over the duration of the prolonged exercise test. Mean arterial
pressure was reduced with increasing test duration, consistent with
peripheral vasodilation and cardiovascular drift. Thus we feel that it
is highly unlikely that the observed increase in A/ inequality could be
caused by fluid overload.
A second point worth discussing is the effects on our results of the
intermittent inert-gas infusion during the prolonged exercise test. The
inert-gas analysis assumes pulmonary steady-state equilibrium for the
inert gases. The time constant for attainment of pulmonary steady state
is a function of the ratio of lung gas conductance
(A + 
T) to
alveolar gas and tissue capacitance (FRC + Vti), where
A is alveolar
ventilation, is the blood-gas partition coefficient,
T is total
blood flow, FRC is functional residual capacity, and Vti is lung tissue
volume. With the use of blood flow and ventilation data from Fig. 1 and
the measured FRC, and assuming Vti in humans is ~600 ml, the time to
95% equilibrium is <2 min at rest and <30 s during exercise. Thus
20 min of equilibration at rest and 5 min during exercise are ample for
the attainment of pulmonary steady state. In keeping with our
calculation, the residual sum of squares averaged <5 at all times,
indicating excellent fit of the data to the inert-gas model and the
absence of any unexpected errors in data collection.
Pulmonary Hemodynamics
Although PAP was elevated above resting levels throughout the duration of the prolonged exercise test, the highest values occurred during the first 5 min of the prolonged exercise test, with a subsequent significant decrease thereafter (Fig. 5). Thus we observed increasingA/ inequality during a
time when PAP, although elevated above resting levels, was slightly but
steadily decreasing. The mean PAP decreased by 8 mmHg between the first 5 and 60 min of prolonged exercise, without a change in cardiac output.
We were able to obtain PAOPs on three of the five subjects who underwent pulmonary arterial catheterization. Particularly with the small (5-Fr) catheters used in this study, it is a difficult balance between having the catheter sufficiently distal to allow PAOP measurement to be obtained and sufficiently proximal to allow blood to be drawn for the cardiac output determinations. There was also a significant decrease in PAOP over the duration of the 1-h test; consequently, the pulmonary vascular resistance was unchanged. The decrease in PAOP was associated with a decrease in mean arterial pressure. Taken together, this suggests that, as the duration of exercise continued, mean arterial pressure decreased from peripheral vasodilation. As a consequence, left ventricular filling pressure was likely decreased with a subsequent reduction in both PAOP and PAP.
This study demonstrates that, in athletic subjects who develop
A/ inequality with
exercise, the extent of
A/ inequality is
increased with increasing exercise duration up to 1 h. This time course
in the face of constant cardiac output and elevated (albeit declining)
PAP supports, but does not prove, the hypothesis that interstitial
pulmonary edema may be the underlying cause of increasing
A/ inequality with
exercise.
| |
ACKNOWLEDGEMENTS |
|---|
We thank our subjects for their enthusiastic participation. The technical assistance of Nick Busan and Jeff Struthers is gratefully acknowledged. We also thank CeCe Echon and the nurses of the University of California, San Diego General Clinical Research Center.
| |
FOOTNOTES |
|---|
This work was supported by National Institutes of Health Grants HL-17731, HL-07212, and M01-RR-00827. T. P. Gavin was supported in part by National Research Service Award HL-09624.
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests: S. R. Hopkins, Dept. of Medicine 0623, Univ. of California, San Diego, 9500 Gilman Dr., La Jolla, CA 92093-0623 (E-mail: shopkins{at}ucsd.edu).
Received 28 January 1998; accepted in final form 2 June 1998.
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Top
Abstract
Introduction
Methods
Results
Discussion
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) and
A-aDO2
predicted from inert gases (
)
(top) and arterial
blood gases [arterial
PO2
(PaO2;
middle) and
PCO2
(PaCO2;
bottom)] at rest and during 5 min of exercise at 30, 65, and 90%
