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1 Department of Medicine, University of California, San Diego, La Jolla, California 92093; and 2 Department of Thoracic Medicine, Royal Adelaide Hospital, Adelaide, South Australia, Australia
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Noninvasive measurement of cardiac output
(
T) is problematic during
heavy exercise. We report a new approach that avoids unpleasant
rebreathing and resultant changes in alveolar
PO2 or
PCO2 by measuring short-term
acetylene
(C2H2)
uptake by an open-circuit technique, with application of mass balance for the calculation of
T. The
method assumes that alveolar and arterial
C2H2
pressures are the same, and we account for
C2H2 recirculation by extrapolating end-tidal
C2H2
back to breath 1 of the maneuver. We
correct for incomplete gas mixing by using He in the inspired mixture.
The maneuver involves switching the subject to air containing trace
amounts of
C2H2
and He; ventilation and pressures of He,
C2H2,
and CO2 are measured continuously
(the latter by mass spectrometer) for 20-25 breaths. Data from
three subjects for whom multiple Fick
O2 measurements of
T were
available showed that measurement of
T by the
Fick method and by the
C2H2 technique was statistically similar from rest to 90% of maximal O2 consumption
(
O2 max). Data from
12 active women and 12 elite male athletes at rest and 90% of
O2 max fell on a
single linear relationship, with
O2 consumption
(O2) predicting
T values of 9.13, 15.9, 22.6, and 29.4 l/min at
O2 of 1, 2, 3, and 4 l/min.
Mixed venous PO2 predicted from
C2H2-determined T, measured
O2, and arterial
O2 concentration was ~20-25
Torr at 90% of
O2 max during air
breathing and 10-15 Torr during 13%
O2 breathing. This modification of
previous gas uptake methods, to avoid rebreathing, produces reasonable
data from rest to heavy exercise in normal subjects.
maximal exercise; new methodology; inert gas
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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THE USE OF INSPIRED GASES to noninvasively measure
pulmonary capillary blood flow, which then serves as an index of
cardiac output
(T), has
advantages over other techniques. Currently used invasive techniques
include direct Fick O2 measurement
(15), thermodilution, and dye dilution. Although such methods remain the gold standard of
T measurement
in the clinical setting, the research setting has benefited from the
application of noninvasive techniques. In particular, noninvasive
techniques do not require a central venous or peripheral arterial catheter.
Several authors have introduced methodological variations of an
acetylene
(C2H2)
or CO2 gas-rebreathing or
single-breath technique to measure
T (4-6,
13, 16, 19, 21). These methods have been used in resting and exercising
humans and animals. A method using a
C2H2-rebreathing
technique and mass spectrometry for continuous measurement of
C2H2
in resting and exercising human subjects gave results that were not
significantly different from those measured by dye-dilution techniques
(19, 21). Furthermore,
C2H2-rebreathing and Fick measurement of
T at rest and
levels of work up to 90% of maximal
O2 consumption
(O2 max) were not found
to be statistically different (16).
A nonrebreathing variation of the above techniques would be desirable
in exercise studies, especially at altitude, inasmuch as it does not
involve potential increases in arterial
PCO2 (PaCO2) or changes in arterial
PO2
(PaO2) that may occur with rebreathing
and themselves change
T. Moreover,
such a method would be better accepted by subjects, because
PaO2 and
PaCO2 would remain unaffected. Becklake
et al. (3) used such a method based on
N2O in 1962, but it appears not to
be in general use. In this investigation, we developed and report a
C2H2-nonrebreathing
technique that involves breathing a
C2H2
gas mixture in an open-circuit system and measuring
C2H2
uptake in a short-term, quasi-steady state. In particular, it
acknowledges the problem caused by rapid recirculation of
C2H2
back to the lungs in venous blood and allows for this in the
calculations. Becklake et al. found that at lighter levels of exercise
the recirculation of
C2H2
was nonproblematic and, therefore, did not correct for this, but since
we specifically wish to use this approach during maximal exercise, we
believed that it was necessary to reexamine the issue of recirculation.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Subjects
This study was approved by the Human Subjects Committee of the University of California, San Diego, and the University of Adelaide. Twelve nonsmoking healthy female athletes and 15 nonsmoking healthy highly trained male athletes with no prior history of respiratory or cardiac disease were included as subjects. After subjects gave written informed consent, a history was obtained, and a physical examination was performed to exclude cardiopulmonary abnormality. All subjects were then screened for pulmonary disease with standard pulmonary function tests (static and dynamic lung volumes) and single-breath carbon monoxide diffusing capacity. There were three study groups: highly trained male athletes studied with C2H2 and direct Fick methods (n = 3, group 1), female athletes studied with the C2H2 method only (n = 12, group 2), and elite male athletes studied with the C2H2 method only (n = 12, group 3). Their anthropometric data are summarized in Table 1.
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Procedure
Group 1 (well-trained competitive cyclists).
To first establish maximal exercise capacity, exercise was performed 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
nonrebreathing valve (model 2700, Hans Rudolph, Kansas City, MO), with
a dead space of 100 ml. Expired gas was sampled continuously from a
heated mixing chamber, and O2 and CO2 concentrations were measured
with a mass spectrometer (model 1100, Perkin-Elmer, Pomona, CA).
Expired gas flow was measured using a pneumotach (no. 3 Fleisch) and a
differential pressure transducer (model DP45-14, Validyne, Northridge,
CA), and the electrical signals from the mass spectrometer and the
pneumotach were logged at 100 Hz with use of a 12-bit analog-to-digital
converter. Ventilation
(E),
O2 consumption
(O2), and
CO2 production
(CO2) were calculated using
a commercially available software package (Consentius Technologies,
Salt Lake, UT).
O2 max was considered to be the average of the four highest consecutive 15-s measures of
O2.
T, the
subjects returned to the laboratory on the following morning after
ingesting a liquid-only breakfast. A 20-gauge arterial cannula was
placed in the radial artery of the nondominant hand for blood sampling. A 5-F Swan-Ganz catheter was introduced percutaneously into the basilic
vein and manipulated into the pulmonary artery for sampling of mixed
venous blood. All catheters were placed using sterile technique 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. Two-milliliter arterial and mixed venous
samples were collected at rest and after 4 min of exercise at each of
30, 60, and 90% of the previously determined
O2 max and maintained
on ice until analyzed for Hb and
O2 saturation measured using a
CO-oximeter (model IL 282, Instrumentation Laboratories, Lexington,
MA). T was
calculated using the Fick principle. These studies were a component of
a more extensive exercise protocol (10).
Several weeks later the subjects returned to the laboratory and the
O2 max testing was
repeated as described above.
T was
measured at several workloads during the
O2 max test by the
C2H2
technique (see below).
Group 2 (female recreational athletes).
O2 max was determined
on an electronically braked cycle ergometer (Excaliber, Quinton
Instruments). After warm-up at 50 W, subjects performed a progressive
exercise test with work intensity ramped at 25 W/min until subjects
were no longer able to continue. E,
O2,
CO2, and heart rate were
measured in the manner described above for group
1.
O2 max were
calculated. Thirty minutes after the initial
O2 max determination, subjects were studied at rest and at the above calculated workloads for
5 min at each level. O2,
E, and
CO2 were measured as previously described;
T was
measured by the
C2H2 technique.
One week after the cycle ergometer protocol, subjects returned for a
similar exercise test on a treadmill (Landice 8700 Sprint 3, Randolph,
NJ) in which ramp speed was increased from a warm-up speed of 2.5 mph
to a speed previously chosen by the subject. Ramp grade was then
increased by 2%/min until the subject could no longer continue.
Workloads (speed and grade) corresponding to 30, 60, and 90% of
O2 max were
calculated. Thirty minutes after the initial O2 max determination,
subjects were studied at rest and at the above calculated workloads for
5 min at each level.
E,
O2, and
CO2 were measured on a
breath-by-breath basis;
T was
measured by the
C2H2 technique.
Group 3.
Twelve elite male cyclists performed a protocol similar to that
performed by group 2 on the cycle
ergometer in normoxia and hypoxia (fraction of inspired
O2 = 0.13) at rest and at 30, 60, and 90% of the previously determined normoxic and hypoxic
O2 max. The details
of the O2 max
determination differed slightly from groups
1 and 2 and have been
reported elsewhere (18). The order of the two tests was randomized with
~1 h between tests. Group 3 did not
perform the treadmill protocol.
T Measurement
by Short-Term
C2H2 Uptake
T was
measured in all three study groups by a nonrebreathing
C2H2
technique. Just as for the rebreathing approach, this is based on the
principle of mass balance: the rate of alveolar-capillary transfer of a
soluble gas is proportional to pulmonary capillary blood flow, which
equals T in
normal subjects. Subjects breathe through a one-way valve from a
gas mixture containing known concentrations of
C2H2
(1%), He (5%), O2 (20.9%), and
N2 (73%). Concentrations of
C2H2
and He are then measured continuously for 20-25 breaths by mass
spectrometer (model MGA-1100, Perkin-Elmer; Fig.
1A). End-tidal [alveolar
(PACO2)] and mixed
expired
(PECO2) PCO2 are also measured, along with
E, as
described above.
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End-tidal
C2H2
concentrations (corrected for mixing with the ratio of inspired He to
end-tidal He) are calculated for each breath, and this corrected
end-tidal
C2H2
concentration is then extrapolated back to breath
1 to account for
C2H2
recirculation (Fig. 1B).
T (l/min) is
then calculated according to the following mass conservation equation
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E is expired
ventilation (l/min BTPS),
PECO2
is mixed expired PCO2,
PACO2 is end-tidal
(alveolar) PCO2,
PIC2H2
is inspired
C2H2
partial pressure, PAC2H2
is He-corrected end-tidal (alveolar)
C2H2
partial pressure extrapolated back to breath
1 of the procedure, and 
is
C2H2
blood-gas partition coefficient
(BTPS).
The for
C2H2
was measured directly on each subject in duplicate by use of gas
chromatography (23).
Data Analysis
Paired parameters (O2 and
T) were
compared by standard linear regression analysis. Pearson product moment
correlations were calculated for each regression analysis. Statistical
analysis was performed using the paired
t-test, with
P < 0.05 (2-tailed) considered significant.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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General Data
Descriptive information for groups 1-3 is available in Table 1. Summary metabolic data for groups 1, 2, and 3 are shown in Tables 2, 3, and 4, respectively. Resting heart rates tended to be somewhat elevated. This was due to the stresses of having just been catheterized (arterial line) and the anticipation of heavy exercise.
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Group 1
T as measured
by the Fick principle for O2
ranged from 5.4 to 26.3 l/min (Table 2). There was a linear
relationship between T and
O2:
T = 4.71 O2 + 5.63, r = 0.94 (Fig.
2A). To
determine the appropriate methodology for calculation of
T by use of
the C2H2
technique,
C2H2-determined
T was
calculated using different breath numbers for backextrapolation and
then, for each choice, compared with the Fick method (Fig.
2B). Extrapolation to
breath 1 minimized the difference
between Fick measurements and the
C2H2 measurements (Fig. 2C). With use of
breath 1,
T, as measured by the
C2H2
technique, ranged from 6.0 to 26.4 l/min. There was a linear
relationship between
C2H2-measured
T and
O2:
T = 4.71 O2 + 5.60, r = 0.93 (Fig.
2A). There was no statistically significant difference between
T measurement
by Fick and
C2H2-nonrebreathing methods.
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Group 2
T measured by
C2H2
at rest and at 30, 60, and 90% of
O2 max ranged from 2.1 to 28.6 l/min, and there was again a linear relationship to
O2:
T = 7.13 O2 + 2.35, r = 0.96 (Fig.
3, Table 3). Mixed venous
PO2 predicted from
C2H2-measured T, measured
O2, and arterial
O2 concentration was 35-40
Torr at rest and 20-25 Torr at 90% of
O2 max, further
indicating that the method produces reasonable results.
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Group 3
In normoxic conditions,T measured by
C2H2
at rest and at 30, 60, and 90% of
O2 max ranged from 3.8 to 40.2 l/min, and there was a linear relationship to
O2:
T = 6.67 O2 + 2.38, r = 0.97 (Table 4). In hypoxic
conditions the range of measured T was
5.1-40.1 l/min, and there was a linear relationship of T to
O2:
T = 7.80 O2 + 2.92, r = 0.97 (Fig.
4). Mixed venous
PO2 predicted from
T, measured
O2, and arterial O2 concentration was 20-25
Torr at 90% of O2 max
(normoxia) and 10-15 Torr during 13%
O2 breathing.
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Data from female and male subjects at rest and at 90% of
O2 max gave a single
linear relationship:
T = 6.75 O2 + 2.38, r = 0.96 (Fig.
5).
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C2H2 Solubility Measurements
To determine its effect on the calculation ofT, was
measured in all subjects. The equation for
C2H2-determined
T given in
METHODS shows that errors in produce equivalent (but opposite) percent errors in
T, so this
aspect of the measurement of
T is important
to consider. Analysis of measurements showed a mean of 0.830 ± 0.017 in 12 female subjects and 0.684 ± 0.065 in 12 male subjects.
Repeated measurements in the same 12 female subjects at two different
times 1 wk apart showed no significant difference in
C2H2
solubility (P = 0.48).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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This study has proposed and demonstrated the reasonableness of a
nonrebreathing,
C2H2
uptake approach to
T measurement
in exercising normal human subjects.
Assumptions
Our methodology involves certain key assumptions that are necessary forT to be
measured accurately. These are the same as the assumptions required in
the rebreathing method for
T measurement.
First, we assume that alveolar and arterial
C2H2 partial pressures are equal during the measurement of
T. Hlastala and Robertson (9) showed that in a normal lung with minor degrees of
ventilation-perfusion
(A/)
mismatch the alveolar-arterial difference for an inert gas of this
solubility is minimal. This is particularly likely to be nonproblematic
during exercise, when overall
A/
is high. In addition, on a theoretical basis, inert gases, such as
C2H2,
are not diffusion limited. As such, in a subject with normal pulmonary
function tests, the assumption is reasonable. However, the assumption
that alveolar and arterial C2H2
are equal implies that the technique we have described cannot be used
reliably for measurement of
T in subjects
with significant A/ inequality.
Second, in the calculation of
T, we assume
that mixed venous
C2H2
concentration is zero. Although this is not true for the 25 breaths we
use, we extrapolate the difference between inspired and alveolar
C2H2
back to the breath at which venous
C2H2
can be assumed to be zero. Inasmuch as our study was noninvasive, we
were not able to directly measure the time necessary for recirculation when venous
C2H2
would no longer be zero. Other studies in the literature have estimated
this time period to be ~15 s (21). However, we used our measurement
of T by the
direct Fick method compared with the
C2H2
method (group 1) to estimate the breath at
which our assumption would be valid. We determined alveolar C2H2
for different choices of breath numbers to which to extrapolate and
then calculated the resultant
T. We then
compared the regression of the relationship between
O2 and
T from the
direct Fick method with the regression from the
C2H2
method using different breath numbers (Fig. 2). The breath number that
minimized the difference between the two methods was determined to be
the appropriate choice for backextrapolation, and this was
breath 1. In the backextrapolation to
breath 1, the first four breaths are
generally excluded in the regression analysis, as evident from Fig.
1B, where the first breath included is
breath 5. This is because very rapid
lung kinetics govern the washin of
C2H2
during the first few breaths, whereas the much slower kinetics of body
tissue
C2H2
uptake and its effects on recirculation of
C2H2
dictate the remaining breaths. Indeed, the first four breaths usually
do not lie on the regression line that fits the remaining 20-25
breaths because of the different lung and tissue kinetics. Typical
values of E
and T during heavy exercise and of body tissue volumes indicate that four half times, or 94% of the transient response, take 4-8 s for lung
equilibration; for the tissues the corresponding calculations show 94%
response time in ~3 min. Because we are addressing the effects of
recirculation by backextrapolation, discarding the first four breaths
has an appropriate rationale.
Third, an important aspect to our methodology is that the for
C2H2
is not assumed but, rather, is measured directly. The range of (0.596-0.910) between subjects (Fig.
6) is such that T could be
considerably in error when extreme values of occur. For example, if
we used the overall mean value of 0.757 (n = 27), T in the
subject with the lowest measured solubility would have been 27% too
low; similarly, in the subject with the highest measured solubility,
T would have
been 13% too high. Reported values of
C2H2
solubility range from 0.740 to 0.843 (5, 6, 20, 23). Jibelian et al.
(12) showed that solubility varies directly with hematocrit and
indirectly with temperature. However, our data show very weak
correlation to Hb
(r2 = 0.10) and
hematocrit (r2 = 0.05), so an assumed value of correcting for the Hb level is not
likely to be a good replacement for the actual value. As such, direct
measurement in each individual at body temperature gives the most
appropriate estimate of and is particularly important if
individually accurate
T values are
desired. However, if group mean
T values are
desired, then individual values may be less important. Figure 6
shows the distribution of values for
C2H2 in this study and supports the contention that this variable should be
measured.
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Finally, there was a delay of several weeks between
C2H2
and Fick T
measurement in the three subjects of group
1. A maximum of 2 mo occurred between measurements.
However, the subjects were competitive cyclists who maintained their
fitness between studies and objectively had similar
O2 max on each occasion
and at similar power outputs (Table 2). As such, we believe that the
time lag is not of significance, and therefore the two methods can be compared.
Advantages of the Nonrebreathing Technique
Our nonrebreathing method of measuringT by
C2H2
uptake was designed principally to improve on previous rebreathing
methods (4, 13, 16, 19, 21). Inasmuch as nonrebreathing and rebreathing
involve uptake of an inert gas to measure pulmonary capillary blood
flow and thus
T, the
assumptions of the two techniques are identical. Nonrebreathing is
preferable, especially at maximal exercise, for multiple reasons.
First, nonrebreathing is favored by subjects, inasmuch as it is more
comfortable, because there is no change in
PAO2 or
PACO2. At high work rates
and at high altitudes, where inspired
PO2 is already low, decreasing
PAO2 or increasing
PACO2 becomes even more
intolerable. In addition, a fall in
PAO2, as may occur with
rebreathing, can serve as a stimulus for rapid changes in
T and
E via
chemoreceptors, thus potentially causing a physiological alteration in
T. In our
method, such changes are avoided, thus increasing the accuracy of the
T measurement.
Comparison with the Literature
Other methodologies for measuringT have been
published in the literature. Regression equations from the literature
for the Fick method, the dye-dilution technique, and
C2H2
rebreathing are presented in Table 5. We
have compared our findings from groups
1 and 3 with studies
performed on men and have compared findings from group
2 with the limited number of studies on women in the
literature. Our method compares well with those previously measured
and, in particular, with the standard for
T measurement, the Fick method.
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The method of Becklake et al. (3) published in 1962 uses
N2O rather than
C2H2
but is similar in principle. The major difference is that Becklake et
al. argued that recirculation of
C2H2
into the mixed venous blood was inconsequential; clearly, our data are
in disagreement with their data (Fig. 1). Thus end-tidal
C2H2 levels progressively rise throughout the entire data collection period
because of such recirculation. This suggests that the assumptions of
Becklake et al. on this matter are not always adequate, and this led us
to develop the backextrapolation procedure to overcome the problem. The
other difference from the work of Becklake et al. is that our data
extend to extremely high
T values,
essentially double those described by Becklake et al., as a result of
studying elite athletes at maximal exercise.
Alveolar Ventilation
OurT
calculation relies on the use of alveolar ventilation and not total
ventilation. This is represented in our equation as
E * (PECO2/PACO2).
By convention,
E and alveolar ventilation are reported at body temperature saturated
with water vapor at ambient pressure, i.e.,
BTPS. We therefore measure for
C2H2
at BTPS conditions. Although it would
also be acceptable to express alveolar ventilation as
CO2/PaCO2,
CO2 must be converted to
BTPS units rather than remain at
STPD. This is to remain compatible
with how is measured. Conversion to
BTPS is particularly important at
altitude, inasmuch as the difference between
STPD and
BTPS values is greater in those conditions.
In summary, we have devised a nonrebreathing methodology based on
short-term quasi-steady-state
C2H2
uptake for the calculation of
T in
exercising human subjects with normal lungs. The results are comparable
to previously reported
T
measurements. We believe this approach will be of particular value at
heavy exercise and especially at altitude, where rebreathing methods
may alter arterial PO2 and
PCO2 and are also quite uncomfortable.
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ACKNOWLEDGEMENTS |
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This study was funded by National Institutes of Health Grants HL-17731, M01 RR-00827, and HL-09624 and by the American Physiological Society Science Teacher Research Program.
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FOOTNOTES |
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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 and other correspondence: P. D. Wagner, Div. of Physiology, University of California, San Diego, 9500 Gilman Dr., MC 0623A, La Jolla, CA 92093-0623 (E-mail: pdwagner{at}ucsd.edu).
Received 22 March 1999; accepted in final form 7 June 1999.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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,
Value, backextrapolated to breath 1 of washin,
used for cardiac output
(
