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Departments of 1 Medicine and 2 Pathology, University of California San Diego, La Jolla, California 92093-0623
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ABSTRACT |
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Top
Abstract
Introduction
References
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Increased ventilation-perfusion
(
A/
)
inequality is observed in ~50% of humans during heavy exercise and
contributes to the widening of the alveolar-arterial
O2 difference
(A-aDO2). Despite extensive investigation, the cause remains unknown. As a first
step to more direct examination of this problem, we developed an animal
model. Eight Yucatan miniswine were studied at rest and during
treadmill exercise at ~30, 50, and 85% of maximal
O2 consumption
(O2 max). Multiple
inert-gas, blood-gas, and metabolic data were obtained. The
A-aDO2
increased from 0 ± 3 (SE) Torr at rest to 14 ± 2 Torr during
the heaviest exercise level, but arterial
PO2
(PaO2) remained at resting levels during exercise. There was normal
A/
inequality [log SD of the perfusion distribution
(log
) = 0.42 ± 0.04] at rest, and moderate increases
(log = 0.68 ± 0.04, P < 0.0001) were
observed with exercise. This result was reproducible on a separate day.
The
A/
inequality changes are similar to those reported in highly trained
humans. However, in swine, unlike in humans, there was no inert gas
evidence for pulmonary end-capillary diffusion limitation during heavy
exercise; there was no systematic difference in the measured
PaO2 and the PaO2 as predicted from the inert
gases. These data suggest that the pig animal model is
well suited for studying the mechanism of exercise-induced
A/ inequality.
swine; animal model; ventilation-perfusion inequality; pulmonary diffusion limitation; interstitial pulmonary edema
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INTRODUCTION |
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Top
Abstract
Introduction
References
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IT IS WELL ESTABLISHED (7, 15, 26) that
ventilation-perfusion
(A/) inequality
increases with exercise and increasing exercise intensity. In
endurance-trained athletes,
A/
inequality is responsible for >60% of the alveolar-arterial
O2 difference (A-aDO2) (15)
during exercise intensities approaching maximal O2 consumption
(O2 max). Increased
A/
inequality with exercise is accentuated in humans by hypoxia (32), is
reduced by breathing 100% O2 (7),
and persists into the recovery period from heavy exercise, after
ventilation and cardiac output have returned to normal (26).
Consequently, interstitial pulmonary edema is an attractive possible
mechanism. Interstitial edema, resulting from rapid transcapillary
fluid flux in excess of the lymphatic drainage capacity of the lung,
would be expected to cause increased
A/ inequality by means of mechanical effects that reduce the compliance of
alveoli and by compression of small airways and blood vessels, resulting in nonuniform air flow and blood flow distribution in the lung.
There is considerable indirect evidence that humans may develop
interstitial pulmonary edema with exercise. There are case reports of
the development of frank pulmonary edema after strenuous exercise (20,
33). Postexercise, there is also an increase in transthoracic
electrical impedance (2), a decrease in vital capacity, and an increase
in residual volume (2, 3, 23). This suggests early airway closure
secondary to subclinical pulmonary edema. Subjects who have a history
of high- altitude pulmonary edema (HAPE) have an increase in
exercise-induced
A/
inequality compared with normal subjects who have been to high altitude
without developing HAPE (22). Recently, we have shown (13) in healthy athletes exercising for 1 h at 65% of
O2 max that
A/
inequality increases with increasing exercise duration. This suggests
that the duration of exposure of the lungs to high blood flow
and pulmonary vascular pressures is important in the development of
increased A/
inequality with exercise. It is difficult to establish a direct
relationship between exercise-induced increases in
A/ inequality and interstitial edema in humans, because any edema is
likely to be subtle and transient in nature. Attempts to image pulmonary edema by using computerized tomography scanning have not been
conclusive. This is because of the difficulty in distinguishing an
increase in intravascular lung water, secondary to increased pulmonary
blood flow postexercise, from extravascular fluid accumulation that
results in interstitial pulmonary edema (4). Thus, as a first step in
investigating this problem, we sought to develop an animal model. Pigs
were chosen because they have been previously shown to have an increase
in the A-aDO2
with exercise that is similar to that observed in humans (10).
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METHODS |
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This experiment was approved by the Animal Subjects Committee of the
University of California, San Diego. Eight male Yucatan miniswine
[weight, 26.1 ± 8.5 (SD) kg] were trained to run on a
treadmill (model Q65; Quinton, Seattle WA). During the week before the
experiment, the
O2 max of each animal
was determined twice by using previously described methods (21). The
results of these tests were used to select workloads that elicited
~30, 50, and 90% of
O2 max.
Surgical Preparation
Surgical anesthesia was induced with ketamine (33 mg/kg im) plus atropine (0.05 mg/kg im) and thiopental sodium (10 mg/kg iv) and was then maintained with a combination of 1-2% halothane and O2. Under sterile conditions, Silastic catheters were placed in the right carotid artery, the right external jugular vein, and the left internal jugular vein. These catheters were exteriorized on the back of the animal and adjacent to the spine. The catheter sites were cleaned, and the catheters were flushed with heparin (1,00 U/ml, 3 times/wk) to maintain patency.On the day of the experiment, a no. 7-Fr triple-lumen Swan-Ganz catheter was inserted into the lumen of the right external jugular cannula and was advanced via the external jugular vein into the pulmonary artery by using direct pressure monitoring. This catheter was used for sampling of mixed venous blood and measurement of pulmonary arterial pressure and blood temperature.
The experiments took place in a temperature-controlled (21-23°C), ventilated room, and the animal was cooled during the exercise portion of the study by using a 21-in. electric fan and by frequently spraying the animal with water. Data were collected at rest and during the last 2 min of each of the 5-min exercise levels. Postexercise data were collected at 15-min intervals for 2 h. Each set of measurements included pulmonary arterial pressure measurements and sampling of pulmonary mixed venous blood, arterial blood, and mixed expired gases for the multiple inert-gas analyses, blood-gas analyses, cardiac output calculations, and metabolic rate measurements.
Ventilation and Metabolic Rate Measurements
A valveless face mask was strapped to the animal's head, and room air was drawn through the mask at a rate of 75 l/min at rest and 300-350 l/min during exercise. This face mask consisted of a soft rubber mask that was attached to the animal by using padded Velcro straps. Room air was drawn around the animal's face and then into a heated mixing chamber by using standard respiratory fittings. Total flow (i.e., bias and expired gas) was measured by using a pneumotachometer (Fleisch no. 3) that was integrated to obtain volume. Gas temperature and relative humidity were measured in the gas stream adjacent to the pneumotachometer. The expired concentrations of O2 and CO2 (model 1100 mass spectrometer; Perkin-Elmer, Pomona, CA) were measured during each inert-gas sample-collection period, and O2 consumption (O2) and
CO2 production
(CO2) were calculated. In
preliminary exercise studies in five animals, with the use of the same
workloads as in the inert-gas study, arterial blood gases were not
different with or without the mask.
Multiple Inert-Gas Measurements
The multiple inert-gas technique was applied in the usual manner. The inert-gas solution was prepared in 5% dextrose (7) and infused for ~20 min before collection of the samples at rest and during the course of the study at a rate (in milliliters per minute) of ~10% of the bias flow rate (in liters per minute). For example, an infusion rate of 10 ml/min was matched to a bias flow of 100 l/min. This infusion rate provides sufficient signal-to-noise ratio for all six inert gases (SF6, ethane, cyclopropane, enflurane, ether, and acetone) at all exercise levels. The total volume of fluid infused during the study was 1 liter over a period of ~3-4 h.Quadruplicate 15-ml samples of mixed expired gas and duplicate 6-ml
samples of pulmonary and systemic arterial blood were obtained in
gas-tight syringes at rest and during exercise for measurement of the
steady-state concentrations of the six inert gases by using a gas
chromatograph (model 5890A; Hewlett-Packard, Wilmington, DE) (30).
During the recovery period, duplicate mixed expired gas and single
pulmonary mixed venous and arterial blood samples were obtained.
A/
distributions were calculated by using the multiple
inert-gas-elimination technique in the usual fashion. Solubilities,
retentions [(R) equal to the ratio of arterial to mixed venous
partial pressure] and excretions [(E) equal to the 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 (30, 31). The
second moment of the perfusion distribution, exclusive of
intrapulmonary shunt
(log), and the
second moment of the ventilation distribution, exclusive of dead space
(log
), were
used as indicators of the degree of
A/
inequality (i.e., the greater the
log or the
log, the
greater the
A/
inequality). The residual sum of squares (RSS) was used as
an indicator of the adequacy of fit of the data to the 50-compartment
model of the lung (31).
Hemodynamic Measurements
The pressure transducers (Statham P23 ID, Oxnard, CA) were zeroed to the level of the right atrium, and calibration was checked before each measurement. Mean arterial, pulmonary arterial, and pulmonary arterial wedge pressures were recorded on a strip-chart recorder (Gould, model 200, Valleyview, OH) immediately before each set of inert-gas measurements. Cardiac output () was calculated from
the mixed venous, arterial blood-gas, and mixed expired inert-gas concentrations by using the Fick equation.
Blood-Gas Measurements
Arterial and mixed venous samples (2 ml each) were collected immediately after each inert-gas arterial and mixed venous blood sample and were maintained on ice until analyzed for PO2, PCO2, and pH with the use of an IL1306 (Instrumentation Laboratories, Lexington, MA) blood-gas analyzer. Hemoglobin and O2 saturation were measured from each sample by using an IL282 CO-oximeter (Instrumentation Laboratories), and hematocrit was determined. The blood gases were corrected to pulmonary arterial blood temperature.Statistical Analyses
Data are presented as means ± SE. Repeated-measures analysis of variance (SuperANOVA 1.11, Abacus Concepts, Berkeley, CA) was used to statistically test changes in the dependent variables from rest, over the duration of exercise, and during recovery. Significance was accepted at P < 0.05, two tailed. Preplanned contrasts were performed to statistically test the changes in the major dependent variables from the end of exercise to the first recovery measurement.| |
RESULTS |
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All animals tolerated the study well. The treadmill speeds during
exercise averaged 2.0 miles/h (mph) and 0% grade, 2.7 mph and 5%
grade, and 3.25 mph and 15% grade for the 30, 50, and 90% of
O2 max workloads, respectively.
Exercise
Metabolic rate and hemodynamic data.
Metabolic and hemodynamic data are given in Fig.
1 and are summarized for the heaviest
workload in Table 1.
O2 was 22.5 ± 1.3 ml · kg
1 · min1
(33% of O2 max) during
light exercise, 35.5 ± 1.5 ml · kg1 · min1
(53% of
O2 max)
during moderate exercise, and 57.4 ± 3.0 ml · kg1 · min1
(85% of O2 max) during
heavy exercise. Cardiac output was 4.8 ± 0.3 l/min at rest and
increased to 14.8 ± 0.7 1/min during heavy exercise. Pulmonary
arterial pressures averaged 14.7 ± 1.2 mmHg at rest and increased
progressively with each exercise increment to 33.0 ± 2.0 mmHg
during heavy exercise (P < 0.0001).
There was a corresponding increase in pulmonary arterial wedge
pressure, which increased from 4 ± 1 mmHg at rest to 13 ± 1 mmHg during heavy exercise (P < 0.05).
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Pulmonary gas exchange. Arterial blood-gas data are given in Fig. 2. Arterial PO2 (PaO2) averaged 104 ± 3 Torr at rest, and there were no systematic changes with exercise. There was an increase in the A-aDO2 from 0 ± 3 Torr at rest to 14 ± 2 Torr during heavy exercise (P < 0.0005). Arterial PCO2 (PaCO2) decreased significantly across exercise levels from 43 ± 2 Torr at rest to 38 ± 2 Torr during heavy exercise (P < 0.005); this suggests increased alveolar ventilation in relationship to metabolic rate.
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A/.
Acetone allows the discrimination of areas of
A/ 
100 from dead space. Without acetone, the next soluble gas
(ether; blood/gas partition coefficient 10) allows the separation of
areas of
A/
10 from dead space. However, all of the recovered distributions in
these animals were within the range spanned by the five gases used, and
the effect of the elimination of acetone on the recovered
A/
distribution is minimal. Averaged over all the data sets, the mean RSS
was 3.4, which is <50th percentile expectation of the sum of squares for n = 5 gases. This indicates
excellent technical quality of the data and good fit of the data to the
50-compartment model.
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increased significantly during exercise from 0.41 ± 0.04 at rest to
0.68 ± 0.04 during heavy exercise
(P < 0.0001), indicating an increase
in
A/ inequality with exercise. This was a consistent finding, as all animals
showed an increase in the
log with
exercise. There was also a corresponding increase in the log
(P < 0.05). The multiple inert-gas-elimination technique allows an analysis of alveolar-end capillary diffusion limitation by computing the
PaO2 that would be
expected from the recovered
A/
distribution, assuming alveolar-end capillary diffusion equilibrium and
comparing it with measured values of
PaO2 (28). Because the inert gases are
essentially invulnerable to alveolar-end capillary diffusion
limitation, when a measured PaO2 value
is less than that predicted from the inert-gas exchange, this is
consistent with alveolar-end capillary diffusion limitation or
extrapulmonary shunting. There were no significant differences between
the measured and predicted values for
PaO2 during either preexercise rest or
exercise; this indicates absence of pulmonary-end capillary diffusion
limitation for O2 in the pig. Thus
all of the increase in the
A-aDO2 with
exercise can be accounted for by
A/
inequality in these animals.
Recovery
Metabolic rate and hemodynamic data (Fig.
3).
O2 and
CO2 decreased rapidly
postexercise and were not different from the preexercise values by the
first recovery measurement (15 min postexercise). At this time,
postexercise pulmonary arterial pressure was also reduced to 18.5 ± 1.6 mmHg, slightly elevated from the preexercise resting value, and
there were no significant changes during the 2-h recovery period.
Pulmonary arterial wedge pressure was also reduced by 15 min
postexercise to 5.5 ± 1 mmHg and did not change significantly
during recovery.
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Pulmonary gas exchange (Figs. 3 and 4,
Table 3).
During the recovery from exercise, the
log and
logSD
decreased rapidly and were not different from the preexercise resting values at
the first recovery measurement. There were no significant differences in log or log
throughout the
remainder of the postexercise period.
PaO2 averaged 107 Torr over the recovery
period. At 105 min of recovery, there was a significant
(P < 0.005) reduction in
PaO2 to 100 ± 4 Torr, which was
reversed by 120 min postexercise. This was associated with a
corresponding increase (P < 0.05) in
the
A-aDO2
from 2 Torr (averaged over the entire recovery period) to 8 ± 4 Torr at 105 min. There was a small, yet statistically significant
(P < 0.05), difference between the
PaO2 predicted from the inert gases and
the measured PaO2 at this time point
only, consistent with either alveolar-end capillary diffusion
limitation or extrapulmonary shunting.
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DISCUSSION |
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Animal Model
We have shown that the pig develops increasedA/
inequality without the development of alveolar-end capillary diffusion limitation during heavy exercise. We chose the pig as an animal model
for a variety of reasons. First, we wanted an animal which developed a
gas-exchange impairment with exercise. Pigs are known to decrease their
PaO2 with exercise (10); this is not
true of other possible animal models. For example, dogs do not
develop a significant difference in
A-aDO2,
even during heavy exercise (27). Horses, although they
develop hypoxemia during exercise and a wide
A-aDO2,
have minimal increases in
A/
inequality (12, 29). Horses are also remarkable in that, even
during prolonged exercise, the increase in
A/
inequality is to the level of most other mammals and humans at rest
(12). Second, pigs are easily trained to exercise, and they are large
enough so that repeated measures of
A/
inequality can be made without hemodynamic compromise. Finally, the
relatively large size of pigs and their cardiovascular system that is
similar to that of humans (21) facilitate hemodynamic measurements.
Pulmonary Gas Exchange During Exercise
Our animals maintained PaO2 with exercise, associated with an increase in A-aDO2 of 14 Torr, which was completely accounted for by increasedA/
inequality. There was no evidence for pulmonary diffusion limitation
during exercise in these animals. Moderately active or untrained humans
generally show either an increase or a small decrease in
PaO2 during heavy exercise (8, 28) that
is associated with an
A-aDO2 of ~20
Torr, which is also accounted for by increased
A/
inequality (7). Athletes, on the other hand, may develop a decrease in
PaO2 of >20 Torr from resting
values and an
A-aDO2 of >40
Torr (6, 14) with significant pulmonary diffusion limitation (9, 15).
Thus our findings in pigs are very similar to those observed in
nonathletic humans. Our animals were habituated to running on the
treadmill, with 8-10 exercise sessions of ~12-min duration
spread out over a 2-wk period. The remainder of the time, the animals
were kept in indoor pens; thus it is unlikely that any significant
training effect occurred. It is possible that these animals may develop a greater gas-exchange impairment with heavy exercise after exercise training, but this hypothesis remains to be tested.
A/
Inequality With Exercise
A/
inequality with exercise. This is in contrast to the human studies in
moderately trained individuals, where it occurs in ~50% of subjects
(26). The reason for the differences between humans and pigs is
unknown. One possible explanation may relate to species differences in
lung structure. Pigs differ from humans more in airway structure than
in pulmonary vascular structure. In both humans and the pig, the
airways and arteries branch together, and growth is by elongation and
branching of the alveolar ducts, combined with an increase in the
number and size of the alveoli (11). More of the pig airways contain
cartilage, and the acinus is separated from the cartilage-containing
structure by about three generations of broncheoli in the pig, compared
with 10 generations in humans (11). Pigs also lack collateral
ventilation (1), compared with the dog, which has extensive collateral
channels. It is likely that human lungs are a structural intermediate
between pigs and dogs.
Pigs have thick-walled muscular pulmonary arteries and a brisk
pulmonary vasoconstrictor response to hypoxia; this response may be
related to lack of collateral ventilation (17). Species that have
extensive collateral ventilation, such as the sheep and the dog, have
thin-walled pulmonary arteries (17) and a less brisk hypoxic pulmonary
vasoconstrictor response (humans are intermediate between the pig and
the dog in this respect). At rest, hypoxic pulmonary vasoconstriction
is the major means of
A/
matching in the pig (16). The presence of collateral ventilation may
possibly act to reduce
A/
inequality via collateral gas transport, optimizing gas exchange (16).
The mechanism of increased
A/
inequality with exercise in any species is unknown. In humans,
A/
inequality is exaggerated in extreme hypobaric hypoxia (32) and
improves with 100% O2 breathing.
It is worse during exercise at sea level in subjects who have
previously suffered from HAPE, compared with normal controls who have
been to altitude without developing HAPE (22), and
A/
inequality is correlated with pulmonary arterial pressure and pulmonary
arterial wedge pressure. Exercise-induced increases in
A/
inequality are worsened by prolonged exercise in humans (13). This
information suggests that the severity and duration of high pulmonary
vascular pressures are important factors in the development of
exercise-induced increases in
A/
inequality. Interstitial pulmonary edema, resulting from rapid
transcapillary fluid flux in excess of the lymphatic drainage capacity
of the lung, is a possible mechanism in the pig, and perivascular edema
has been observed in pigs that have been exercised for 6-7 min at
maximal levels (25). Clearly, the next step in directly examining any
potential relationship between exercise-induced increases in
A/
inequality and interstitial pulmonary edema in these animals will be
measurements of
A/ inequality and then lung histology in the same animals.
Recovery From Heavy Exercise
The animals recovered rapidly from exercise, and by 15 min postexercise, pulmonary gas exchange had returned to preexercise resting levels. This included a very rapid resolution of the increasedA/
inequality that occurred with exercise. In humans, the log decreases
immediately postexercise, but to a significantly lesser extent in those
subjects who develop increased
A/
inequality during exercise (26) compared with controls who do not. In
both groups of subjects, during recovery, the
log was never
significantly greater than baseline values, which is consistent with
the present data. Because all of our animals developed increased
A/
inequality with exercise, we cannot perform a similar type of analysis.
At a single point in the recovery period (105 min), we found a small
and transient decrease in PaO2
associated with an increase in the
A-aDO2 and a
significant discrepancy between measured
PaO2 and that predicted from the inert
gases. This is compatible with either alveolar-end capillary diffusion
limitation or extrapulmonary shunts. Alternatively, this may simply be
a false positive result. We cannot choose between these possibilities
on the basis of the available data. Some authors have observed a small
reduction in the lung diffusing capacity for carbon monoxide after
exercise (18, 19, 24) and suggest that this reflects an alteration in
the structure of the blood-gas barrier and alveolar-end capillary diffusion limitation (4, 5, 18, 19). They have hypothesized that this
may be related to the development of interstitial pulmonary edema. Our findings of a reduction of
PaO2, with a significantly lower
measured PaO2 than predicted
PaO2 at 105 min of recovery, could be compatible with this hypothesis. However, resting alveolar-end capillary pulmonary diffusion limitation of
O2 transport would be very
unlikely, especially because none was observed even at 85% of
O2 max, and
it is difficult to imagine interstitial pulmonary edema of sufficient
magnitude to affect the diffusion of
O2 across the blood-gas barrier
without also having an effect on
A/ inequality.
Another possible explanation for these findings is extrapulmonary shunting, via either the bronchial circulation or the thebesian veins. The difference between measured and predicted PaO2 in the present study can be explained by an extrapulmonary shunt of ~1-2%. It is conceivable that the bronchial blood flow could be increased postexercise to this extent, although why it would be increased only at this time point is unclear.
Summary
With exercise, the pig develops impaired pulmonary gas exchange and a widened A-aDO2. This increase in the A-aDO2, which is similar to that seen in untrained human subjects, is entirely due toA/
inequality and not to any alveolar-end capillary diffusion limitation.
However, the
A/
inequality resolves rapidly postexercise and is restored to preexercise
resting levels by 15 min postexercise. The pig model will allow
investigation of the mechanism of increased
A/
inequality with exercise and the use of techniques, such as direct
examination of lung tissue, that are not possible in humans.
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ACKNOWLEDGEMENTS |
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The technical assistance of Nick Busan, Jeff Struthers, Julia Janas, and Molly Rice is gratefully acknowledged.
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FOOTNOTES |
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This work was supported by National Institutes of Health Grants HL-17731, HL-07212, M01-RR-00827, and HL-32670.
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 8 May 1998; accepted in final form 2 September 1998.
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Top
Abstract
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) and pulmonary arterial wedge pressure (
)
(middle), and ventilation-perfusion
inequality, as measured by the log standard deviation of the perfusion
distribution
(log
