Download Studies of Cardiopulmonary Blood Volume

Studies of Cardiopulmonary Blood Volume
Measurement of Total Cardiopulmonary Blood Volume
in Normal Human Subjects at Rest
and during Exercise
By GILBERT E. LEVINSON, M.D., ALBERT D. PACIFICO, M.D.,
AND
MARTIN J. FRANK, M.D.
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SEVERAL of the fundamental variables
of hemodynamics, namely pressure, flow,
resistance, and pulse rate, have received
intensive and systematic study. Until recently,
volume had not been accorded comparable
study, in part because of inability to obtain
valid and accurate measurements of anatomically meaningful circulatory compartments, and
perhaps in part because of a tendency to regard volumes as static, passive, virtually structural aspects of the circulatory system. At present, an intensive and systematic study of the
circulatory volumes is both possible and important, in view of the development of safer
technics of catheterization of individual cardiac
chambers, technical and conceptual advances
in methods of measuring chamber volumes in
vivo, and theoretical and experimental grounds
for regarding volumes as dynamic factors, exerting active or permissive roles in circulatory
adjustments.
For these reasons, we have undertaken an
investigation of the cardiopulmonary blood
volume and its components. Indicator dilution
has been used to measure volumes because of
its versatility and applicability to all compart-
ments. Although this technic has been the basis
for estimates of a variety of "central" blood
volumes, measurements of the true cardiopulmonary blood volume in man have not previously been reported. This paper is a report of
the technics employed and the results obtained
in measuring total cardiopulmonary blood volume in a group of normal human subjects.
Methods
Eighty-one measurements of the volume of
blood between right atrium and aortic root
(hereafter referred to as cardiopulmonary blood
volume) were obtained in 11 male and 4 female
subjects, ranging in age from 14 to 54 years.
In six subjects soft ejection systolic murmurs
and possible pulmonary plethora on chest roentgenograms led to diagnostic cardiac catheterization, including oxygen sampling series, selective cinefluorography, and indicator dilution
studies, with entirely normal results. The other
nine subjects were volunteers.
All subjects were studied in the fasting state,
under mild barbiturate sedation, in the supine
position. In the volunteer subjects, polyethylene
catheters (internal diameter, 1.13 mm; length,
70 cm) were introduced percutaneously, under
local procaine analgesia, into the right brachial
artery and median antecubital vein, and advanced
into left ventricle and right atrium. Under pressure and fluoroscopic guidance, the left ventricular catheter was withdrawn into the aortic
root immediately distal to the aortic valve, and
the right atrial catheter was placed at the
junction of the superior vena cava and the right
atrium. In the subjects undergoing diagnostic
catheterizations, the right heart catheter was an
NIH or Goodale-Lubin catheter, introduced by
brachial or saphenous venotomy and placed at
the junction of superior vena cava and right
atrium on completion of the diagnostic procedures. In some of the subjects undergoing diagnostic catheterization, the aortic catheter was
From the Division of Cardiovascular Diseases, Department of Medicine, New Jersey College of Medicine, and the Thomas J. White Cardiopulmonary
Institute, B. S. Pollak Hospital for Chest Diseases,
Jersey City, New Jersey.
Supported in part by Grant HE-08581 and Program Project Grant HE-06376 from the National
Heart Institute, U. S. Public Health Service, and in
part by the Union County Heart Association.
Work done while Dr. Pacifico was a Student Research Fellow under U. S. Public Health Service
Graduate Training Grant HE-5510.
Circulation, Volume XXXIII, March 1966
347
LEVINSON ET AL.
348
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an NIH type which, after being used for the
recording of left ventricular pressures and for
selective left ventricular injections of indocyaninegreen dye, was withdrawn into the aortic root
for the sampling of dilution curves.
At a pre-arranged signal, 6.6 mg of indocyanine-green dye in 1 ml of diluent, and a
saline flush were injected rapidly into the right
atrium from a calibrated pipette.' The duration
of injection of dye and flush were recorded,
and the midpoint of injection of the dye was
obtained from a knowledge of the volumes of
catheter, dye injectate, and saline flush. This
midpoint was taken as zero time. By means of
Harvard infusion-withdrawal pumps, blood was
withdrawn from the aorta through a Gilford
densitometer at a constant rate of 0.8 to 2.0 ml
per second into an air-free heparinized syringe.
The output of the densitometer was recorded
on a photographic recorder (Electronics for Medicine). The 90% response time of the sampling
system,2 including catheter and densitometer
cuvette, ranged from 0.56 to 0.7 sec. Calibration
was by the integrated sample technic.3 Except
for the small volumes required for calibration,
all blood sampled was returned to the subject
immediately after inscription of each dilution
curve. This permitted the recording of two or
more dilution curves for each subject, in each
of several states, with negligible blood loss.
Representative curves are shown in figure 1.
Each subject was studied at rest, a total of
38 measurements being obtained on the 15 subjects. In eight subjects, measurements were repeated during the last 6 minutes of a 13- to 26minute period of leg elevation to the pedals
of a bicycle ergometer, and again during a 13- to
26-minute period of leg exercise. A total of 17
u
44
A
0% ,
Figure
000,
1
Dilution curves at rest (left) and during exercise
(right) in patient E. S. Paper speed was 5 mm/sec
with time lines at 1-sec intervals. The interruption
of the horizontal line at top signaled the injection.
measurements was obtained during passive leg
elevation, and 26 measurements during exercise.
Oxygen consumption was measured at rest and 3
minutes prior to the final dilution curve during
exercise by an open-circuit respiratory system
using the Beckman oxygen analyzer for the analysis of expired air.
Curves were plotted semilogarithmically and
extrapolated to 1% of peak concentration. Cardiac
output and mean transit time were calculated
for each dilution curve by the usual StewartHamilton formulas.4' 5 The mean transit time was
corrected for the delay introduced by the sampling system. The cardiopulmonary blood volume
was calculated as the product of cardiac output
and mean transit time. All calculations were
performed on an IBM 1620 computer programmed
for the digitized data after the semilogarithmic
replotting of the primary data.
The results of the study were analyzed by
conventional statistical technics for small samples.
Correlations were evaluated by the product-moment correlation coefficient (r).
Results
The results of the study are listed in tables
1 and 2.
Cardiac Output, Heart Rate, and
Stroke Volume at Rest
Cardiac output ranged from 2.19 to 5.29,
with a mean value of 3.39 ± 0.84 L/min/m.2
The cardiac index was slightly (3.48 versus
3.37 L/min/m2) and insignificantly (P>0.9)
higher in the female subjects. Reproducibility
of the measurements was excellent: the maximum and mean discrepancies between successive replications were 0.43 and 0.11 L/min
/m2, respectively, and the mean coefficient of
variation for measurements of output was 3.4%.
Heart rate ranged from 45 to 131, with a
mean value of 81 + 21 beats per minute, and
stroke volume from 34 to 55, with a mean of
42 + 6 ml/beat/M.2 Exclusion from the series
of the patients with extreme values for heart
rate (mean rate of 45 per minute in an athletic
male youth and mean rate of 131 per minute
in an anxious adolescent girl) results in a
change of 1 beat per minute in mean heart rate
for the group and a change of less than 1% in
mean values for cardiac output and cardiopulmonary blood volume. Heart rate was
higher, by an average of 10 beats per minute,
in the female subjects than in the male, and
Circulation, Volume XXXIII, March 1966
CARDIOPULMONARY BLOOD VOLUME
349
stroke volume index was less by 3 ml per beat,
but these differences were not statistically
significant (P > 0.4). Rhythm was regular sinus in all instances.
ume in the male subjects significantly exceeded
that in the female subjects (means = 447 and
352 ml/m2, respectively, P < 0.05). Reproducibility of measurements was good. In the 13
patients with two or more measurements, the
mean discrepancy between suiccessive replications was 25 ml/m2 and the mean coefficient
of variation was 3.7%.
Cardiopulmonary Blood Volume at Rest
The cardiopulmonary blood volume in individual subjects ranged from 301 to 546 ml/m2,
with a mean for the group of 422 ± 76 ml/m2.
If 2.5 to 3.0 L/m2 is the average total blood
volume in normal subjects,6 7 the cardiopulmonary blood volume represents 15.3% of total blood volume. Cardiopulmonary blood vol-
Relations Between Cardiopulmonary Blood
Volume and Cardiac Output or Stroke
Volume at Rest
There was, as can be seen from figure 2, no
correlation (r =0.07) between cardiac output
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Table
Data at Rest
Cardiac
index,
L/min/m2
BSA (m2) Mean
S.D.
Age,
sex
Patient
F.J.
L.P.
W.R.
B.S.
G.B.
C.P.
E.W.
R.M.
M.U.
J.W.
J.c.
J.R.
E.S.
C.R.
S.M.
50
42
17
20
29
34
19
44
15
19
14
14
57
22
34
M
M
M
F
M
M
M
M
M
M
F
M
F
M
F
2.14
1.58
1.78
1.95
1.79
2.30
1.80
1.80
1.63
1.70
1.40
1.45
1.64
2.06
1.89
2.78
2.95
2.19
3.11
2.81
2.88
3.22
3.53
5.30
3.94
4.71
4.46
2.94
2.98
3.13
0.12
0.08
0.15
0.05
0.25
0.01
0.11
0.06
0.18
0.12
0.04
0.02
0.03
0.07
0.31
3.39
0.84
Mean
Heart
rate,
beats min
Mean
S.D.
68
86
Mean
transit
Cardiopulmonary
blood volume,
time,
sec
ml/m2
Mean
S.D.
Mean
S.D.
Stroke
volume,
ml /beats /m2
Mean S.D.
45
77
57
76
87
70
97
84
131
113
81
82
66
1
2
1
1
3
2
1
2
2
8
1
4
3
0
3
41
34
49
41
49
38
37
50
55
47
36
39
36
36
47
2
1
3
1
2
1
1
1
2
3
1
1
1
1
3
10.2
8.4
13.4
7.2
10.9
8.5
7.6
8.9
6.2
7.0
4.2
5.1
7.0
6.0
7.0
0.2
0.2
0.3
0.6
0.9
0.3
0.1
0.0
0.0
0.1
0.2
0.2
0.1
0.2
0.9
471
416
491
374
512
410
409
527
546
458
330
343
301
364
11
4
34
25
46
11
15
8
20
4
16
10
4
4
27
81
21
42
6
7.9
2.3
422
76
379
Table 2
Efects of Leg Elevation and Exercise
Patient
R
F.J.
W.R.
B.S.
G.B.
C.P.
J.C.
E.S.
C.R.
Mean
Cardiac index,
L/min/m2
L
E
R
2.78
2.20
3.30
68
3.12
2.81
2.89
3.45
2.85
3.18
4.71
2.95
2.99
4.65
2.97
3.04
4.76
5.28
5.31
4.54
4.70
5.44
4.92
4.95
3.06
3.20
4.99
2.15
Stroke volume,
ml beat m2
E
R
L
Cardiopulmonary
blood volume,
R
ml /m2
L
E
476
497
388
492
458
390
358
328
514
449
338
548
493
412
417
322
423
436
47
45
47
52
100
147
118
116
41
49
41
49
38
36
36
36
43
51
40
36
38
39
43
59
47
37
42
43
471
491
374
512
410
330
343
301
111
41
42
46
404
102
102
77
57
76
131
81
82
70
48
81
56
79
130
79
78
77
78
45
R = rest. L = leg elevation. E = exercise.
Circulation, Volume XXXIII, March 1966
Heart rate,
beats /min
L
E
124
78
LEVINSON ET AL.
350
and cardiopulmonary blood volume. However,
good correlation (r = 0.79, P < 0.0001 ) is evident (fig. 3) between cardiopulmonary blood
volume and stroke volume. That this correlation is not merely a reflection of the bimodal
distributions related to sex difference, that is,
of the lower stroke volume and cardiopulmonary blood volume prevailing in the female
subjects, is evidenced by the high correlation
(r = 0.85, P < 0.001) between stroke volume
and total cardiopulmonary blood volume for
the 11 male subjects.
w
-J
D
0
500
0
0
-
0
0
0
0
-4 N
o
i%
400-
*0
0.
90
E
z
0
2
300
-
0
a-
0
*
Effects of Leg Elevation and Exercise
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With elevation of the legs, there were no
significant changes in cardiac output, heart
rate, or stroke volume. In all but one subject,
however, the cardiopulmonary blood volume
rose. The mean increase in the seven in whom
increases occurred was 25 + 8 ml/m2, or 6.4%
of the resting volume of 389 ml in these patients,
and was statistically significant (P < 0.01).
The mean change for the entire group of
eight was an increase of 19 ±9 ml/m2; this
change is not quite significant statistically
(0.05 < P < 0.10) if a two-tailed t test is employed, but a one-tailed test, on the assumption that leg elevation is expected to produce
a centripetal volume shift, leads to the conclusion that the change is not attributable to
chance (P < 0.05).
With exercise, no further significant change
w
.
-3
500-
0
0
a
0
a"
:r
400-
E
z
0
E
.
300-
a.I
0
<
U.
200 -f
!.O
I
3.0
CARDIAC INDEX
I
X
0
X
4'0
5'0
(L./min./M.2)
Figure 2
Relationship of cardiopulmonary blood volume
cardiac output.
50
30
40
4
STROKE VOLUME INDEX (ml. /M.2)
Figure 3
Relationship of cardiopulmonary blood volume to
stroke volume.
in cardiopulmonary blood volume occurred
despite significant increases in oxygen consumption, cardiac output, heart rate, and
stroke volume of 138, 56, 43, and 9%, respectively, of the values during passive leg elevation (P < 0.005). The response of cardiopulmonary blood volume ranged from 13% fall to 16%
rise, a fall occurring in three subjects and a rise
in five. The mean change was a statistically insignificant (P > 0.4) increase of 13 + 15 ml/m2
or 3% of the value obtained during passive leg
elevation.
That the subjects were in a steady state is
indicated by the fact that the coefficients of
variation for measurements of flow and volume were essentially the same during exercise
and at rest: for the eight subjects, the coefficient of variation for output measurements was
3.2% at rest and 3.9% during exercise, and the
coefficient of variation for volume measurements was 4.0% at rest and 4.8% during exercise. There were no differences in response
based on duration of exercise and no significant differences between the values measured
early in exercise and those measured later.
No significant correlations existed between
changes in cardiopulmonary blood volume and
changes in either cardiac ouput or stroke volume with exercise.
Circulation, Volume XXXIII, March 1966
CARDIOPULMONARY BLOOD VOLUME
Discussion
Cardiac Output, Stroke Volume, and Heart Rate
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The mean cardiac output, stroke volume, and
heart rate in this study are in agreement with
values reported by other authors, using the
oxygen Fick method, Evans blue or indocyanine-green dilution, or radiocardiography
with precordial counting. Survey of the reports
of cardiac output in normal subjects or "hospital normals" reveals the following ranges
for the mean values: from 3.22 to 3.79 L/min
/M2 by the oxygen Fick method;8 '9 from 3.2
to 3.76 L/min/m2 by dye dilution with arterial
sampling;0"11 and from 3.47 to 3.64 L/min/
m2 by radiocardiography.'12 '3 In the series
of Bickelmann and associates,14 which is most
comparable to our own in material (15 thoroughly normal subjects aged 20 to 46 years)
and methods (indocyanine-green dye, arterial
sampling, Gilford cuvette densitometers), the
results were almost identical with those of the
present study: cardiac index 3.39 + 0.76 L/min
/m2, stroke volume index 44+6 ml/beat/m2,
and heart rate 76 ± 12 beats per minute. The
agreement between cardiac output values for
normal men and women has also been reported
by Huff and co-workers'2 and Campione and
co-workers.15
The range of individual values for heart rate
in resting subjects extends from 50/min in the
series of Braunwald and Kelly'6 to 120/min in
one of the subjects of Cournand and associates.'7 With the exception of the groups reported by Lagerlof and Werkd18 and by Donald and associates19 in whom the mean values
exceeded 50 ml, the mean stroke volume index
in the reported studies has ranged from 40 to
49 ml/beat/m.2 The means and ranges for output, stroke volume, and heart rate obtained in
the present study constitute reassuring criteria
as to the representative normality of our group
of subjects.
Reproducibility of Measurements
The mean coefficient of variation for measurement of output in the present study (3.4%)
is almost identical in magnitude with the error
referred to as "measurement error" by Sleeper
and co-workers.20 In their considerably more
extensive series, measurement error was deCirculation, Volume XXXIII, March 1966
351
fined by comparison of simultaneous measurements obtained from the same needle; the
standard deviation of the difference was 3%
of the mean cardiac output. A larger variation
(standard deviation = 10% of mean cardiac
output) resulted when the simultaneous measurements were from the brachial and femoral
arteries, and intermediate values when the simultaneous measurements were from the radial
and brachial arteries of the same arm. That
the discrepancies between paired measurements from different arteries were due to nonuniform distribution of dye was indicated by
an increase in such discrepancies when peripheral flow alterations were induced. Sleeper
and associates suggested that sampling from
the root of the aorta would obviate these differences provided that the sampling technic
could compensate for the necessarily increased
length of the sampling tube. Their suggestion
is confirmed by the present results in which
the reproducibility of duplicate successive determinations was superior to that found in their
series for brachial or femoral sampling. This
finding indicates that aortic root sampling
offers advantages in the accuracy of measurement of cardiac output.
The calculation of mean transit time is based
on the same deflection readings used for calculating output. However, slurring of the curve
will result in proportionally larger error in calculation of mean transit time than in measurement of area. The comparability of variation
in measurement of flow and volume in the
present study (coefficients of variation=3.4
and 3.7%, respectively) demonstrates the adequacy of the technics used for sampling and
for zero-time inscription.
Cardiopulmonary Blood Volume
Numerous investigators have used the Stew-
art-Hamilton principle in estimating mean transit time-volumes, variously labeled "pulmonary," "cardiopulmonary," "central," and
"intrathoracic" blood volumes. The values for
such volumes, which were reviewed and discussed in a previous communication from this
laboratory,21 range from 436 to more than
1,300 ml/m.2 Clearly, because of the temporal
boundaries involved, none of the volumes
LEVINSON ET AL.
352
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obtained by various methods and investigators'0' 22-29 represents true cardiopulmonary
blood volume.
It is possible that the volumes measured in
the present study are also inaccurate, with a
systematic underestimate arising from incompleteness of mixing in the right atrium. If mixing in the right atrium is poor, and injection
was into the flow stream selectively sampled
by the right ventricle, then part or all of the
right atrial volume will be excluded. The measured volume would then be anatomically imperfect but physiologically quite meaningful,
since it consists of the volumes of the two circulatory pumps plus the segment of vasculature (pulmonary circulation and left atrium)
interposed between them. The circulatory compartment between the two pumps, which may
be referred to as interventricular volume, is
probably what was measured by Milnor,30 and
Dock and their associates,31 and ourselves21 and
labeled by all three groups as pulmonary
blood volume. It follows that the cardiopulmonary blood volume measured in the present study should exceed the pulmonary blood
volume as measured by the above authors by
a quantity approximating the sum of the volumes of the two ventricles. The normal subjects in the series of Dock and associates31
had a mean volume of 246 ml/m.2 In six normal subjects studied in this laboratory, the
mean interventricular volume was 254 ml/m.2
If interventricular blood volume is, therefore,
approximately 250 ml/m2, and the volume
measured in the present study (422 ml/m2)
represents the sum of ventricular and interventricular volumes, then the combined volume of the two ventricles should be about 170
ml/m2 in the normal subject. The latter figure
is in excellent agreement with the sum of right
ventricular end-diastolic volume (79 ml/m2)
measured by Evans blue dye dilution32 and
left ventricular end-diastolic volume measured
by radiocardiography (89 ml/m2),33 thermodilution (97 mI/M2),34 and indocyanine-green
dye dilution (88 mI/M2).35 If, moreover, the
weight of the normal heart muscle (300 g or
170 mI/M2 )36 iS subtracted from the mean
value for total cardiac volume (muscle plus
blood content) measured by teleroentgenography (372 ml/m2 ),37 38 the resultant volume
(approximately 200 mI/M2) exceeds the intracardiac volume estimated in the present series
(approximately 170 ml/m2 ) by the reported anatomic capacity of the right atrium (approximately 30 ml/m2).39
These considerations support the conclusion
that the volume measured in this investigation
approximates the sum of the ventricular and
interventricular blood volumes. Blumgart and
Weiss,40 in their classic studies of circulation
time measured with radium C, predicted, on
the basis of experiment plus physiologic reasoning, that the transit time through right ventricle, pulmonary circulation, and left heart,
which they could not measure directly, would
be 7.5 sec. The cardiopulmonary blood volume
estimate corresponding to that transit time
(14.6% of total blood volume) is insignificantly
different from the value (15.3% of total blood
volume) calculated in the present study.
Relations Between Cardiopulmonary Blood
Volume and Cardiac Output or Stroke Volume
In previous studies, stroke volume has been
shown by Milnor and co-workers30 and by ourselves,21 to be related to pulmonary or interventricular volume and, by Doyle and coworkers,'0 to a central blood volume measured
from pulmonary artery to a peripheral artery.
In Milnor's report, a weaker relationship also
existed between the volume measured and
cardiac output, but such a relationship was not
described by Doyle and associates and, in the
previous report from this laboratory, the relationship between volume and output per minute was, at best, equivocal. The results of the
present study seem to confirm our previous
conclusion that the cardiopulmonary volume
plays a role in the regulation of stroke volume.
Effects of Exercise
Previous workers have concluded that,
with exercise, the central blood volume is increased,'6' 41A3 decreased28 44 or unchanged.29
45-4 These disparate conclusions resulted from
use of volume estimates based on different
concepts and technics. In one of the studies44
volumes were estimated by the slope-volume
Circulation, Volume XXXIII, March 1966
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CARDIOPULMONARY BLOOD VOLUME
353
principle of Newman and associates.47 The increased volumes were obtained from mean
transit times involving, by reason of peripheral
venous injection, peripheral arterial sampling
or both, indefinite temporal boundaries.16' 4143
Wang and associates,48 from studies performed
in animals, and Marshall and Shepherd,49 from
studies performed in human subjects, have
offered evidence that, with peripheral injection
or peripheral collection, the slope volume does
not, either quantitatively or qualitatively, reflect changes in pulmonary blood volume, because it is affected by linear dispersal of
indicator in peripheral vessels. Moreover, with
venous injection or arterial sampling, the peripheral vascular redistribution of flow with
exercise may give spuriously elevated mean
transit times for calculation of central blood
volume.50 51 When volumes of narrower boundaries and better anatomical definition are
studied, as with the precordial counting of
isotopic indicators28' 29 and with pulmonary
artery-to-aortic root dilution curves46 the central volumes have been decreased28 or unchanged29 46 with exercise. The small increase
reported by Giuntini and associates52 in pulmonary blood volume measured by radiocardiography may reflect the effect of leg elevation, since the resting measurements were not
made with the legs elevated.
The conclusion that exercise does not appreciably alter the total cardiopulmonary blood
volume should not be construed to mean that
important redistributions within this volume
do not take place. Indeed, available evidence
makes it seem most likely that such redistributions do occur. Rushmer and associates53
have reported that left ventricular diameters
usually decrease in dogs during treadmill exercise. In human subjects, studies employing
orthodiagraphy,37 54 55 cinefluorography,56 indicator dilution,57 and radiopaque clips sutured
to myocardial surfaces58 also indicate that
a decrease in ventricular dimensions is usually
associated with muscular effort. If the right
and left ventricular components of total cardiopulmonary blood volume diminish with muscular exercise, then constancy of the total
cardiopulmonary blood volume, as demonstrat-
ed in the present study, conceals an increase
in the interventricular (or pulmonary) component. The radiographic measurements reported by Cournand and associates57 indicate
such an increase in pulmonary blood volume
both in active subjects and in subjects leading
sedentary lives. In the former, the increase in
pulmonary blood volume was accompanied by
a decrease in the volumes of the ventricles, so
Circulation, Volume XXXIII, March 1966
that the total cardiopulmonary blood volume
remained unchanged. Moreover, increase in
the volume of blood within the capillary bed of
the lungs during exertion is indicated by the
data of Lewis and co-workers59 and of Johnson and co-workers.60 Nevertheless, it is clear
from the present study that the magnitude of
the total cardiopulmonary blood volume in
normal man is not significantly affected by
muscular exercise.
Summary
The volume of blood in the heart and lungs
can be measured, by the Stewart-Hamilton
principle, as the product of cardiac output and
the mean transit time from right atrium to the
aortic root. Although previous investigators
have estimated a variety of central blood volumes, measurements of the true cardiopulmonary blood volume in man have not previously
been reported.
Eighty-one measurements of the total cardiopulmonary blood volume were obtained in
15 normal human subjects. At rest, total cardiopulmonary blood volume ranged from 301
to 546 ml/m2, with a mean of 422 ml/m2, and
it represented 15% of estimated total blood
volume. Cardiopulmonary blood volume was
significantly larger in the male subjects than in
the female. Reproducibility of measurements
was good: the mean discrepancy between successive replications was 25 ml/m2 and the
mean coefficient of variation 3.7%. There was
no correlation between cardiac output and
cardiopulmonary blood volume but a significant correlation (r = 0.79, P < 0.0001) was
evident between cardiopulmonary blood volume and stroke volume.
With elevation of the legs to the pedals of a
bicycle ergometer, a small but statistically
354
LEVINSON ET AL.
significant increase occurred in cardiopulmonary blood volume, but no significant changes
occurred in cardiac output, heart rate, or stroke
volume. With exercise, no further significant
change in cardiopulmonary blood volume occurred, despite significant increases in output,
rate, and stroke volume.
Analysis of cardiac output measurements,
both at rest and during exercise, indicates that
aortic root sampling is characterized by an
appreciably higher reproducibility than that
reported for peripheral arterial sampling.
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Acknowledgment
We are pleased to acknowledge the assistance in
the catheterization laboratory of Miss Sandra Weltner, R. N., Miss Gloria Salge, R. N., and Miss
Georgina Abich, and the technical assistance of
Mr. Henry Oldewurtel and Miss Sharon Malone, and
to thank Miss Christine Berlane for the preparation
of the manuscript.
References
1. ROBINSON, C. V., Li, T. H.,
2.
3.
4.
5.
6.
7.
AND
ETSTEN, B. E.:
Improved injection pipettes for determination
of cardiac output by dye method. J Lab Clin
Med 42: 773, 1953.
Fox, I. J., SUTTERER, W. F., AND WooD, E. H.:
Dynamic response characteristics of systems
for continuous recording of concentration
changes in a flowing liquid (for example,
indicator-dilution curves). J Appl Physiol 11:
390, 1957.
McNEELEY, W. F., AND GRAVELLESE, M. A.:
Measurement of cardiac output by dye dilution technic: Use of an "integrated" sample
collection in calibration of the photometric
instrument. J Appl Physiol 7: 55, 1954.
STEWART, G. N.: Researches on the circulation
time and on the influences which affect it:
IV. The output of the heart. J Physiol (London) 22: 159, 1897.
HAMILTON, W. F., MooRE, J. W., KINSMAN, J.
M., AND SPURLING, R. G.: Studies on the
circulation. IV. Further analysis of the injection method, and of changes in hemodynamics under physiological and pathological
conditions. Amer J Physiol 99: 534, 1932.
GIBSON, J. G., II., AND EVANS, W. A., JR.: Clinical studies of the blood volume: I. Clinical
application of a method employing the azo
dye "Evans blue" and the spectrophotometer.
J Clin Invest 16: 301, 1937.
GrIBSON, J. G., II., AND EVANS, W. A., JR.: Clinical
studies of the blood volume: II. The relation
of plasma and total blood volume to venous
pressure, blood velocity rate, physical measurements, age and sex in ninety normal humans. J Clin Invest 16: 317, 1937.
8. REGAN, T. J., TIMMIS, G., GRAY, M., BINAK, K.,
AND HELLEMS, H. K.: Myocardial oxygen consumption during exercise in fasting and
lipemic subjects. J Clin Invest 40: 624, 1961.
9. DEXTER, L., WHITTENBERGER, J. L., HAYNES,
F. W., GOODALE, W. T., GORLIN, R., AND
SAWYER, C. G.: Effect of exercise on circulatory dynamics of normal individuals. J Appl
Physiol 3: 439, 1951.
10. DOYLE, J. T., WILSON, J. S., LEPINE, C., AND
WARREN, J. V.: Evaluation of the measurement of the cardiac output and of the so-called
pulmonary blood volume by the dye-dilution
method. J Lab Clin Med 41: 29, 1953.
11. KOWALSKI, H. J., AND ABELMANN, W. H.: Car-
diac output at rest in Laennec's cirrhosis. J
Clin Invest 32: 1025, 1953.
12. HUFF, R. L., FELLER, D. D., JUDD, 0. J., AND
BOGARDUS, G. M.: Cardiac output of men
and dogs measured by in vivo analysis of Iodinated (1131) human serum albumin. Circulalation Research 3: 564, 1955.
13. ZIPF, R. E., McGunRE, T. F., WEBBER, J. M.,
GROVE, G. R.: Determination of cardiac output by means of external monitoring of radioisotope injected intravenously. Amer J Clin
Path 28: 134, 1957.
14. BICKELMANN, A. G., LIPPSCHUT1z, E. J., AND
WEINSTEIN, L.: Response of the normal and
abnormal heart to exercise: Functional evaluation. Circulation 28: 238, 1963.
15. CAMPIONE, K. M., ANDAY, I. J., SERRATTO, M.,
AND EARLE, D. P.: Cardiac index in ambulatory patients estimated by precordial dilution
curves. Amer J Cardiol 7: 779, 1961.
16. BRAUNWALD, E., AND KELLY, E. R.: Effects of
exercise on central blood volume in man.
J Clin Invest 39: 413, 1960.
17. COURNAND, A., RILEY, R. L., BREED, E. S., BALDWIN, E. DEF., AND RICHARDS, D. W.: Measurement of cardiac output in man using the
technique of catheterization of the right
auricle or ventricle. J Clin Invest 24: 106,
1945.
18. LAGER6F, H., AND WERK6, L.: Studies on the
circulation in man: II. Normal values for cardiac output and pressure in the right auricle,
right ventricle and pulmonary artery. Acta
Physiol Scand 16: 75, 1948.
19. DONALD, K. W., BISHOP, J. M., CUMMING, G.,
AND WADE, 0. L.: Effect of exercise on the
cardiac output and circulatory dynamics of
normal subjects. Clin Sci 14: 37, 1955.
20. SLEEPER, J. C., THOMPSON, H. K. JR., MCINTOSH, H. D., AND ELSTON, R. C.: Reproducibility of results with indicator-dilution techCirculation, Volume XXXIII, March 1966
CARDIOPULMONARY BLOOD VOLUME
nique for estimating cardiac output in
Circulation Research 11: 712, 1962.
man.
21. LEVINSON, G. E., FRANK, M. J., AND HELLEMS,
H. K.: Pulmonary vascular volume in man.
Measurement from atrial dilution curves.
Amer Heart J 67: 734, 1964.
22. EIcH, R. H., CHAFFEE, W. R., AND CHODOS,
R. B.: Measurement of central blood volume
by external monitoring. Circulation 20: 689,
Downloaded from http://circ.ahajournals.org/ by guest on April 29, 2017
1959.
23. ETSTEN, B., AND Li, T. H.: Hemodynamic
changes during thipental anesthesia in humans: Cardiac output, stroke volume, total
peripheral resistance, and intrathoracic blood
volume. J Clin Invest 34: 500, 1955.
24. KOPELMAN, H., AND LEE, G. DEJ.: The intrathoracic blood volume in mitral stenosis and
left ventricular failure. Clin Sci 10: 383, 1951.
25. BALL, J. D., KOPELMAN, H., AND WITHAM, A. C.:
Circulatory changes in mitral stenosis at rest
and on exercise. Brit Heart J 14: 363, 1952.
26. MONGE, C. C., CAZORIA, A. T., WHITrEMBURY,
G. M., SAKATA, Y. B., AND RIzO-PATRON, C.:
Description of the circulatory dynamics in the
heart and lungs of people at sea level and at
high altitude by means of the dye dilution
technique. Acta Physiol Lat Amer 5: 198,
1955.
27. MELLs, H., AND KATTUS, A. A., JR.: Comparison
of volumes calculated from medial circulation
time and from slope of human dye dilution
curves. J Lab Clin Med 48: 413, 1956.
28. LAMMERANT, J.: Le volume sanguin des poumons chez l'homme. Bruxelles, Editions Arscia, 1957.
29. Mom, T. W., AND GOTT, F. S.: Central circulating blood volume in normal subjects and
patients with mitral stenosis. Amer Heart J
61: 740, 1961.
30. MILNOR, W. R., JosE, A. D., AND McGAFF, C.
J.: Pulmonary vascular volume, resistance,
and compliance in man. Circulation 22: 130,
1960.
31. DOCK, D. S., KRAus, W. L., McGuiRE, L. B.,
HYLAND, J. W., HAYNES, F. W., AND DEXTER,
L.: Pulmonary blood volume in man. J Clin
Invest 40: 317, 1961.
32. FREis, E. D., RIVARA, G. L., AND GILMORE, B.
L.: Estimation of residual and end-diastolic
volumes of the right ventricle of men without
heart disease, using the dye-dilution method.
Amer Heart J 60: 898, 1960.
33. FOLSE, R., AND BRAUNWALD, E.: Determination
of fraction of left ventricular volume ejected
per beat and of ventricular end-diastolic and
residual volumes. Experimental and clinical
observations with a precordial dilution technic.
Circulation 25: 674, 1962.
Circulation, Volume XXXIII,
March 1966
355
34. BmRSTOW, J. D., FARREHI, C., LEWIS, R. P., AND
GRISWOLD, H. E.: Left ventricular volume
studies in man by thermodilution. Clin Res
12: 76, 1964.
35. LEviNsON, G. E., NADIMI, M., BRAUNSTEIN, M.,
AND FRANK, M. J.: Measurement of the volume of the normal human left ventricle by
dye-dilution. Fed Proc 23: 302, 1964.
36. ANDERSON, W. A. D.: Pathology. St. Louis, C.
V. Mosby. 1948, p. 533.
37. NYLIN, G.: On the amount of, and changes in,
the residual blood of the heart. Amer Heart
J 25: 598, 1943.
38. LILJESTRAND, G., LYSHOLM, E., NYLIN, G., AND
ZACHRISSON, C. G.: The normal heart volume in
man. Amer Heart J 17: 406, 1939.
39. GRAY, H.: Anatomy of the Human Body. ed.
25. Philadelphia, Lea & Febiger, 1948, p. 533.
40. BLUMGART, H. L., AND WEISS, S.: Studies on
the velocity of blood flow: VII. The pulmonary circulation time in normal resting individuals. J Clin Invest 4: 399, 1927.
41. MANKIN, H. T., AND SWAN, H. J. C.: Arterial
dilution curves of T-1824 during rest and
exercise. Fed Proc 12: 93, 1953.
42. MITCHELL, J. H., SPROULE, B. J., AND CHAPMAN, C. B.: The physiological meaning of
the maximal oxygen intake test. J Clin Invest
37: 538, 1958.
43. MITCHELL, J. H., SPROULE, B. J., AND CHAPMAN, C. B.: Factors influencing respiration
during heavy exercise. J Clin Invest 37: 1693,
1958.
44. KATTUS, A. A., JR., MILLS, H., KLUG, A. B.,
AND PEARCE, M. L.: Slope volume in normal
subjects and in valvulotomy patients before
and after exercise. Circulation 12: 728, 1955.
45. VON NOWY, H., KIKODSE, K., AND ZOLLNER, N.:
Vber Bestimmungen des Herzminuten Volumens und zentralen Blut Volumens in Ruhe
und bei korperlicher Arbeit mit Hilfe der
Farbstroff-methode. Z Kreislaufforsch 46:
382, 1957.
46. SEMLER, H. J., SHEPHERD, J. T., AND MARSHALL,
R. J.: Pressure-flow-volume relationship in the
pulmonary circulation of the exercising dog.
Fed Proc 18: 141, 1959.
47. NEWMAN, E. V., MERRELL, M., GENECIN, A.,
MONGE, C., MILNOR, W. R., AND MCKEEVER,
W. P.: The dye dilution method for describing
the central circulation: Analysis of factors
shaping the time-concentration curves. Circulation 4: 735, 1951.
48. WANG, Y., SHEPHERD, J. T., AND MARSHALL,
R. J.: Evaluation of the slope-volume method
as an index of pulmonary blood volume. J
Clin Invest 39: 466, 1960.
49. MARSHALL, R. J., AND SHEPHERD, J. T.: Interpretation of changes in "central" blood vol-
356
50.
51.
52.
53.
54.
Downloaded from http://circ.ahajournals.org/ by guest on April 29, 2017
55.
56.
LEVINSON ET AL.
ume and slope volume during exercise in
man. J Clin Invest 40: 375, 1961.
GLEASON, W. L., BACOS, J. M., MILLER, D. E.,
AND MCINroSH, H. D.: A major pitfall in
the interpretation of the central blood volume. Clin Res 7: 227, 1959.
MARSHALL, R. J.: Significance of changes in
"central" blood volume in man during exercise. Fed Proc 19: 118, 1960.
GrUNTINI, C., LEWIS, M. L., LEWIS, A. S., AND
HARVEY, R. M.: A study of the pulmonary
blood volume in man by quantitative radiocardiography. J Clin Invest 42: 1589, 1963.
RUSHMER, R. F., SMITH, O., AND FRANKLIN,
D.: Mechanisms of cardiac control in exercise. Circulation Research 7: 602, 1959.
JORGENSEN, G.: Experimental Investigations of
the Venous Pressure; with Special Reference
to the Regulation of the Circulation. Copenhagen, Danish Science Press, Ltd., 1954.
RuoSUNOJA, R., LINKO, E., LIND, J., AND SOLLBERGER, A.: Heart volume changes at rest
and during exercise. Acta Med Scand 162:
263, 1958.
CHAPMAN, C. B., BAKER, O., AND MITCHELL,
57.
58.
59.
60.
J. H.: Left ventricular function at rest and
during exercise. J Clin Invest 38: 1202, 1959.
COURNAND, A., ET AL.: Separate performance of
both ventricles in man during the early phase
of exercise, as analyzed by the method of
selective radiocardiography. Trans Ass Amer
Physicians 73: 283, 1960.
HARRISON, D. C., GOLDBLATT, A., BRAUNWALD,
E., GLICK, G., AND MASON, D. T.: Studies
on cardiac dimensions in intact, unanesthetized
man: I. Description of techniques and their
validation: II. Effects of respiration: III.
Effects of muscular exercise. Circulation Research 13: 448, 1963.
LEwIS, B. M., LIN, T. H., NOE, F. E., AND
KOMISARTuK, R.: Measurement of pulmonary
capillary blood volume and pulmonary membrane diffusing capacity in normal subjects:
Effects of exercise and position. J Clin Invest 37: 1061, 1958.
JOHNSON, R. L., SPICER, W. S., BISHOP, J. M.,
AND FORSTER, R. E.: Transients of pulmonary
capillary blood flow and diffusing capacity
after starting and stopping exercise. Clin Res
6: 158, 1958.
The Danger of Technical Language
Technical expressions are a danger for every system of philosophy, whether Indian or
European. For they may become formulae which hinder the natural development of
thought in the same way as ruts in a road hinder traffic. So to find out what are its
real contents it is reasonable to test a system of thought by setting aside the expressions which it has coined for its own use and compelling it to speak in ordinary
comprehensible language.-ALBERT SCHWEITZER: Indian Thought and Its Development.
New York, Henry Holt and Company, 1936, p. IX.
Circulation, Volume XXXIII, March 1966
Studies of Cardiopulmonary Blood Volume: Measurement of Total
Cardiopulmonary Blood Volume in Normal Human Subjects at Rest and during
Exercise
GILBERT E. LEVINSON, ALBERT D. PACIFICO and MARTIN J. FRANK
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Circulation. 1966;33:347-356
doi: 10.1161/01.CIR.33.3.347
Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
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