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Blood gas cardiopulmonary and urine electrolyte reference values in the pregnant yellow baboon (Papio cynocephalus).

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American Journal of Primatology 11:277-284 (1986)
Blood Gas, Cardiopulmonary, and Urine Electrolyte
Reference Values in the Pregnant Yellow Baboon
(Papio cynocephalus)
JOHN H. CISSIK', GARY D. HANKINS', JOHN C. HAUTH3, AND THOMAS J. KUEHL4
'Clinical Investigation Facility, 'Obstetrics Service, and 3Department of Obstetrics and
Gynecology, Wilford Hall USAF Medical Center, Lackland AFB, Texas; 4Perinatal Biology
Program, Department of Physiology and Medicine, Southwest Foundation for Biomedical
Research, San Antonio, Texas
We measured urine sodium and potassium; respiratory rate, lung water,
and arterial and mixed venous blood gases; adult and fetal heart rates;
hematocrit, plasma sodium and potassium; cardiac output; and arterial,
pulmonary artery, central venous, and pulmonary wedge pressures in 13
clinically normal, pregnant yellow baboons (pupio cynocephulus). Arithmetic
means, standard deviations, and coefficients of variation were calculated to
develop reference values; in addition, the 95% confidence limits for ranges
were established and regression analyses were performed to determine
relationships between parameters. Comparison of derived data with those
from published values for nonpregnant baboons indicated differences similar to those seen when examining pregnant and nonpregnant humans.
Key words: animal pregnancy, hemodynamics
INTRODUCTION
Historically, nonhuman primates have been extremely important as laboratory
animal models for research on organ transplantation [DeKlerk et al, 1969; Haglin
& Armer, 1969; Van Zyl et al, 19681. More recently, the advantages of using nonhuman primates to resolve basic uncertainties in the field of reproductive physiology,
particularly in endocrinology and pharmacology related to reproduction, are becoming increasingly evident [Horie, 19833.
As more and more sophisticated questions are asked, the establishment of
reference values for those laboratory animals used in human-related research has
become more important. That is, it is necessary to be able to reference standard
normal values if the changes seen in physiologic data during research protocols are
to be properly interpreted. In addition, knowing the reference values may actually
reduce the number of animals used in a study by eliminating the need to obtain as
much baseline data. Finally, the existence of detailed normal values could provide
information needed for better care of colony animals and for diagnosis of diseases.
The effects of age, sex, species, husbandry techniques, and environmental conditions on several categories of reference values in the baboon have been documented
Received March 20, 1986; revision accepted June 9, 1986
Address reprint requests to Lt Col John H. Cissik, WHMCBGS, Lackland AFB, TX 78236-5300.
0 1986 Alan R. Liss, Inc.
278 I Cissik et a1
[Altman & Dittmer, 1971; Melby & Altman, 1976; Vagtborg, 1965, 19671. However,
we are aware of only one study specifically evaluating the pregnant baboon [Berchelmann et al, 19711.
Therefore, in conjunction with a n ongoing obsterical research protocol, we used
the opportunity to compile reference values and intervals for several appropriate
parameters in pregnant baboons.
MATERIALS AND METHODS
Thirteen clinically normal, pregnant Savannah bellow) baboons (Papio cynocephalus), 9-15 years of age, were used in this study. These multiparous female
baboons had a n average body weight of 15.98kg and a n average body surface area
of 0.71 m2. The body surface areas were calculated using standard human equations
[Consolazio et al, 19631. Conception dates were estimated to within f 2 days from
daily perineal sex skin observations. The mean gestational age of 130.34 f 22.34
days (range = 71-163 days; term = 182 days) was the mean equivalent to a 26-week
human gestation. Each study was begun a t 8 am in order to preclude major circadian
variations. Although allowed water, the baboons were not fed for 12 hours prior to
the studies.
Anesthesia was initiated by a bolus intramuscular injection of ketamine hydrochloride (300-550 mg; mean, 362 mg). Following a l-mg intramuscular injection of
atropine, endotracheal intubation was performed; clear lung fields were verified by
auscultation and chest radiography. A light level of anesthesia was maintained with
intravenous pentobarbital (25-100 mg). Light anesthesia was defined as a level such
that spontaneous respirations were maintained by the animal but spontaneous
movements and cough were not. Before the baseline physiologic measurements were
obtained, the animals were allowed a minimum of one undisturbed hour after
instrumentation to return to a basal steady-state condition.
A 5-F lung water catheter (American Edwards Laboratories, Santa Ana, CA)
and 6-FCordis (Cordis Corp., Miami, FL) introducer was placed in the femoral artery
and vein after surgically isolating the vessels. A 5-F flow-directed pulmonary artery
catheter was then positioned in the pulmonary artery by waveform. Bentley pressure transducers (Bentley Laboratories, Irvine, CAI, a Mennen Greatback fourchannel monitor (Mennen Medical Inc., Clarence, NY) strip chart recorder, and a
solo hemodynamic computer were used for data collection and storage.
The American Edwards lung water computer system was used to determine
cardiac output and extravascular lung water as described by Lewis and associates
[Lewis & Elings, 1978; Lewis et al, 19791. All measurements were performed in
triplicate and with the animal in a supine position. Fetal heart rate was visualized
using realtime ultrasonography. Blood gases were determined in duplicate on a n IL
813 pWBlood Gas Analyzer (Instrumentation Laboratories, Lexington, MA). The
means of three arterial blood hematocrits were determined by centrifugation for 5
minutes with the Adams Micro-Hematocrit Centrifuge (Clay-Adams, Inc., New York,
NY). Sodium and potassium concentrations in serum and urine were obtained using
the IL Model 443 Flame Photometer (Instrumentation Laboratories, Lexington,
MA). All equipment was calibrated and quality controlled according to manufacturer
and standard literature specifications.
Due to the large number of animals that would have been required to establish
a valid statistical relationship between the gestation time and the physiologic
parameters (eg, fetal heart rate), we elected at this time only to develop standard
reference tables. The means, standard deviations, coefficients of variation, and
regression analyses used to create these tables were determined using a standard
statistical computer software package (BMDP Simple Data Description and Data
Pregnant Baboon Reference Values I 279
TABLE I. Reference Hematocrit and Serum and Urine Electrolyte Values in 13 Pregnant
Baboons*
Parameter (units)
Body weight (kg)
Body surface
area (m2)
Hematocrit (%)
Serum sodium
(mEqA)
Serum potassium
(mEqA)
Urine sodium
(mEq/l)
Urine potassium
(mEqA)
Mean
( kSD)
cv
Rangea
15.98
0.71
(1.22)
(0.06)
0.08
0.09
35.12
137.08
(2.03)
(2.29)
0.06
0.06
32.0-38.0
133.0-140.0
3.15
(0.32)
0.10
2.7-3.8
69.15
(10.36)
0.15
5 1.O-82 .O
29.37
(8.85)
0.30
15.0-44.0
*SD, standard deviation; CV, coefficient of variation.
aNormal range of values at 95%confidence limits.
TABLE 11. Measured Pulmonary Reference Values in 13 Pregnant Baboons*
Parameter (units)
Mean
27.39
Respiratory rate
(breaths per minute)
Lung water (mVkg)
7.14
Arterial pH
7.39
PaOa (torr)
82.23
PaC02 (torr)
39.69
HC03- (mEqA)
23.29
Base excess
-0.70
% Saturation
96.11
Mixed venous pH
7.38
PvOz (torr)
50.15
PvCOz (torr)
40.92
HC03- (mEq/l)
23.19
Base excess
-0.80
% Saturation
74.32
*SD,standard deviation; CV, coefficient of variation.
*SD)
cv
Rangea
(7.93)
0.29
16.0-40.0
(1.15)
(0.03)
(8.42)
(3.86)
(2.79)
(2.32)
(0.75)
(0.03)
(4.24)
(4.13)
(2.24)
(2.41)
(3.52)
0.09
0.01
0.10
0.10
0.12
0.35
0.04
0.01
0.09
0.10
0.10
0.39
0.04
4.0-9.0
7.31-7.43
70.0-96.0
35.0-48.0
21.1-32.0
- 3.O-5.8
94.0-97.5
7.31-7.44
45.0-57.0
36.0-50.0
20.4-29.3
-3.9-5.8
69.0-82.0
(
'Normal range of values at 95%confidence limits.
Management Package, Department of Biomathematics, University of California,
Los Angeles). The regression line (Y = ax b) of best fit to the data points was
determined by the method of the sum of least squares. Correlation coefficients (r)for
the parameters were calculated from the fitted lines.
+
RESULTS
Table I lists the means f 1 standard deviation (SD) for the body weight and
body surface area (BSA) of the baboon study propulation. In addition, the means,
SDs, coefficients of variation (CVs), and ranges for the hematocrit and serum and
urine electrolyte reference values are listed. All ranges are calculated at the 95%
confidence limits.
280 I Cissik et a1
TABLE 111. Measured Referenee Hemodynamie Values in 13 Pregnant Baboons*
Parameter (units)
Mean
( k SD)
CV
Heart rate (beats per
minute)
Systolic arterial pressure
(mmHg)
Diastolic arterial pressure
(mmHg)
Mean arterial pressure
(mmHg)
Systolic pulmonary artery
pressure (mmHg)
Diastolic pulmonary artery
pressure (mmHg)
Mean pulmonary artery
pressure (mmHg)
Central venous pressure
(mmHg)
Pulmonary wedge pressure
(mmHg)
Cardiac output
(Vmin)
Fetal heart rate
(beats per minute)
150.08
(18.02)
0.14
128.0-192.0
131.25
(20.21)
0.19
103.0-169.0
84.54
(18.66)
0.20
60.0-114.0
100.11
(10.30)
0.24
84.0-125.0
18.69
(7.78)
0.42
10.0-31.0
8.23
(5.31)
0.65
2.0-20.0
11.54
(5.20)
0.17
5.0-26.0
1.39
(2.53)
0.70
0.0-8.0
5.68
(2.86)
0.51
2.5-12.7
2.39
(0.38)
0.16
1.8-3.0
134.46
(18.06)
0.13
108.0-164.0
Rangea
“SD, standard deviation; CV, coefficient of variation.
aNormal range of values at 95% confidence limits.
Table I1 shows the means, SDs, CVs, and ranges for the measured pulmonary
parameters, while Table I11 indicates the measured hemodynamic values. Calculated hemodynamic and cardiopulmonary reference variables are denoted in Tables
IV and V, respectively. All ranges are calculated at the 95% confidence limits.
The significant relations (P < 0.05) between BSA and hemodynamic and respiratory parameters, as determined by regression analysis, are denoted in Table VI.
DISCUSSION
Because the baboon has proved a most satisfactory model for many reproductive
studies, this research was undertaken to document specific hematologic, pulmonary,
and urine parameters in the pregnant baboon. In order for this study to provide
significant information to other researchers, it is necessary to determine what
physiologic alterations have been caused by pregnancy in the female baboon and to
compare these changes with those that develop in humans during pregnancy. Where
available, the observed data are compared with previously published reference
baboon normals. In those cases where the reference values for baboons are not
available, data from other species are used. When comparisons are made, however,
it is important to remember that reference data in humans were developed without
anesthesia. The physiologic data from other species (including the pregnant baboons
reported on here) were developed using various levels and classes of anesthesia.
In examining the values from Table I, the hematocrit was comparable to the
nonpregnant female baboon mean reference value of 38%. The serum sodium and
potassium means were reduced compared to the female baboon means of 151 mEq/l
and 4.3 mEq/l, respectively [Hack & Gleiser, 19821. The mean urine sodium and
Pregnant Baboon Reference Values I 281
TABLE IV. Calculated Reference Hemodynamic Values in 13 Pregnant Baboons*
Parameter (units)
Cardiac index
(Vmidm)
Stroke volume
(mlheat)
Stroke index
(mIheat/m2)
Stroke work
(gm-&eat)
Stroke work index
(gm-m/beat/m2)
Pulmonary arteriolar
resistance (dyne sec cm-5)
Total pulmonary
resistance (dyne sec cm-5)
Total systemic
resistance (dyne sec cm-5)
(+SD)
cv
Rangea
3.35
(0.42)
0.13
2.3-3.9
15.90
(3.65)
0.19
9.5-22.0
22.44
(4.53)
0.26
13.0-3 1.5
28.54
(7.53)
0.26
21.0-50.0
40.08
(8.36)
0.21
34.0-64.0
203.46
(68.49)
0.39
72.0-340.5
390.39
(125.63)
0.46
138.5-660.0
3,281.08
(722.33)
0.23
2,292.0-5,144.0
Mean
*SD, standard deviation; CV, coefficient of variation.
aNormalrange of values at 95%confidence limits.
TABLE V. Calculated CardiopulmonaryReference Values in 13 Pregnant Baboons*
Parameter (units)
Alveolar-arterial oxygen
difference (mmHg)
Arterial oxygen content
(mV100 ml)
Venous oxygen content
(m1/100 ml)
Arterial-venous oxygen content
difference (vol %)
Oxygen delivery
(mVmin/m2)
Oxygen consumption
(mVmin/m2)
Oxygen extraction ratio
Mean
(+SD)
cv
Rangea
16.85
(2.15)
0.07
10.0-19.0
16.69
(0.21)
0.03
16.0-17.0
12.51
(0.51)
0.05
11.4-13.5
4.06
(0.33)
0.03
3.5-5.0
555.55
(65.32)
0.25
342.0-604.5
139.46
(31.09)
0.09
72.0-198.5
24.58
(2.06)
0.15
15.5-24.0
13.70
(1.75)
0.06
11.5-19.0
(%)
Venous-arterial shunt
(%)
*SD,standard deviation; CV, coefficient of variation.
aNormalrange of values at 95% confidence limits.
potassium levels in the pregnant baboon fell at the lower end of the human normal
ranges of 30-280 and 25-120 mEq/l, respectively [Henry, 19791.
The mean respiratory rate in this study population, shown in Table 11, was 4
breaths per minute higher than the reference for nonpregnant baboons [Melby &
Altman, 19761. The mean extravascular lung water in the pregnant baboon fell at
the upper end of the normal range of 5.5-7.2 mlkg found in the dog [Lewis et al,
282 I Cissik et a1
TABLE VI. Variation in Hemodynamic and Respiratory Parameters in
Relation to Body Surface Area (BSA)*
Y
Heart rate
(beatslminute)
Cardiac output
(Vmin)
Stroke work
(ml/beat/m2)
Hematocrit (S)
Respiratory
rate (breathdminute)
Pulmonary capillary
wedge pressure
(mmHg)
a
b
r
85.91
69.01
0.807
3.08
0.19
0.773
70.72
-21.73
0.785
16.86
0.53
25.25
27.01
0.821
0.701
10.49
-1.87
0.791
*r = correlation coefficient; for all “r,” P < 0.05. Regression analysis: y = ax
where x = BSA.
+ b;
19791. Arterial pH in the pregnant baboon was essentially unchanged in comparison
with that of the nonpregnant baboon [Altman & Dittmer, 19711, while the remainder
of the arterial values and the mixed venous parameters were all within normal
human limits [Shapiro et al, 19771.
The mean heart rate, as listed in Table 111, was 3 beats per minute higher than
the reference nonpregnant baboon mean [Melby & Altman, 19761. The mean systolic
and diastolic arterial blood pressures, while right at the upper end of the normal
human values of 100-140160-90 mmHg, respectively [Willerson & Sanders, 19771,
were lower than the mean values of 159/127 mmHg found in rhesus monkeys
[Altman & Dittmer, 19711. The mean pulmonary artery pressure, central venous
pressure, and pulmonary capillary wedge pressure all fell within the normal human
limits of 10-20 mmHg, -2-+5 mmHg, and 0-12 mmHg, respectively [Willerson &
Sanders, 19771. The cardiac output was below the normal human range of 4.0-8.0 1/
min [Willerson & Sanders, 19771, while the mean fetal heart rate fell just below the
140-170 beats per minute range of values for the rhesus monkey [Altman & Dittmer,
19711.
The mean cardiac index, as denoted in Table IV,fell within the normal human
limits of 2.5-4.0 llminlm2 [Willerson & Sanders, 19771. The pulmonary arteriolar
resistance, total pulmonary resistance, and total systemic resistance were all higher
than the normal human values of 45-120, 150-250, and 900-1,400 dyne sec cm-5,
respectively [Hurst et al, 19781.
As listed in Table V, the alveolar-arterial oxygen difference was slightly higher
than the published human range of 5-15 mmHg, while the arterial-venous oxygen
content difference was slightly below the normal human limits of 4.5-6.0 vol percent
[Lough et al, 19851. The oxygen delivery, oxygen consumption, and oxygen extraction ratio all fell within the normal human limits of 520-720 ml/min/m2, 100-180
ml/min/m2,and 22-30%, respectively [Lough et al, 19851. The venous-arterial shunt,
however, slightly exceeded the normal human value of 2-5% [Lough et al, 19851.
In general, comparison of the observed data in this study with the available
published baboon reference values indicates changes similar in direction to those
seen in pregnant humans [Hytten & Chamberlain, 19801. Specifically, the mean
heart reate in this group of pregnant baboons was slightly elevated in relation to
Pregnant Baboon Reference Values I 283
reference nonpregnant baboon values; the hematocrit was comparable to reference
values; and the pH was unchanged. In comparison with human values, the pulmonary artery pressure, central venous pressure, and pulmonary wedge pressure were
all normal; the alveolar-arterial oxygen difference was increased; and the arterialvenous oxygen difference was decreased. The data in this investigation complement
those reported by Berchelmann and associates [1971], who found many blood changes
in pregnant baboons similar in direction to changes seen in the pregnant human.
Finally, regression analysis of the data showed that statistically significant
relationships (P<O.O5) existed only between body surface area and heart rate,
cardiac output, stroke work, hematocrit, respiratory rate, and pulmonary capillary
wedge pressure (see Table VI). All other possible relationships between various
paramaters were nonsignificant (P> 0.05).
These reference values are meant to be used as a guideline for investigators
using pregnant baboons, both to provide a baseline for research and for health care
of colonies of animals. We find it particularly interesting and encouraging that the
referenced changes in pregnant baboons mimic changes in pregnant humans.
CONCLUSIONS
1. Reference values and 95% confidence limit ranges were established for selected blood gas, cardiopulmonary, and urine parameters in pregnant baboons.
2. Comparison of these values with those published for nonpregnant baboons
indicates changes similar in direction to those seen in pregnant humans.
3. These findings encourage the use of the pregnant baboon as a model for
human pregnancy.
ACKNOWLEDGMENTS
We would like to thank Dr. Wayne Pierson for his assistance with the statistical
analysis of the derived data.
The views expressed herein are those of the authors and do not necessarily
reflect the views of the United States Air Force or the Department of Defense. All
animals were humanely used and cared for in compliance with DOD Directives and
NIH Publications.
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