Blood gas cardiopulmonary and urine electrolyte reference values in the pregnant yellow baboon (Papio cynocephalus).код для вставкиСкачать
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 , 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. REFERENCES Altman, P.L., Dittmer, D.S., eds. BIOLOGICAL HANDBOOKS: RESPIRATION AND CIRCULATION. Bethesda, MD, Federation of American Societies for Experimental Biology, 1971. Berchelmann, M.L., Vice, T.E., Kalter, S.S. Peripheral blood changes in the pregnant (Kenya) baboon Papio cynocephalus. LABORATORY ANIMAL SCIENCE 21~613620,1971. Consolazio, C.F., Johnson, R.E., Pecora, L J. PHYSIOLOGICAL MEASUREMENTS OF METABOLIC FUNCTIONS IN MAN. New York, McGraw-Hill Book Company, 1963. DeKlerk, J.N., Murphy, G.P., Van Zyl, J.J.W., Van Zyl, J.A., Weber, H.W., Brede, H.D. Scott, W.W. New methods of treatment for renal allotransplants using the baboon as a primate experimental model. JOURNAL OF UROLOGY 102532-540,1969. Hack, C.A., Gleiser, C.A. Hematologic and serum chemical reference values for adult and juvenile baboons (Papio sp. LABORATORY ANIMAL SCIENCE 32(5):502-505, 1982. Haglin, J.J., Armer, D. Lung transplantation in the baboon. ANNALS OF THE NEW YORK ACADEMY OF SCIENCE 162:404411, 1969. Henry, J.B., ed. Todd, Sanford, Davidson’s CLINICAL DIAGNOSIS AND MANAGEMENT BY LABORATORY METHODS, VOLUME I, (16th Ed.). Philadelphia, W.B. Saunders Company, 1979. Horie. K. Baboon as a n animal model for research of human reproduction. JAPANESE JOURNAL OF MEDICINE. SCIENCE, AND BIOLOGY 36(4):244-248, 1983. Hurst, J.W., Logue, R.B., Schlant, R.C., Wenger, N.K. eds. THE HEART, 4th Ed. New York, McGraw-Hill Book Company, 1978. Hytten, F.E., Chamberlain G. CLINICAL PHYSIOLOGY IN OBSTERICS. London. 284 I Cissik et a1 Blackwell Scientific Publications, 1980. Lewis, F.R., Elings, V.I. Microprocessor determination of lung water using thermalgreen dye double Gdicator dilution. SURGICAL FORUM 29:182-189.1978. Lewis, F.R., Elings, V.B., Johannes, A.S. Bedside measurement of lung water. JOURNAL OF SURGICAL RESEARCH 27250261. 1979. Lough, M.D., Chatburn, R, Schrock, W.A. HANDBOOK OF RESPIRATORY CARE. Chicago; Year Book Medical Publishers, Inc., 1985. Melby, E.C., Jr., Altman, N.H., eds. CRC HANDBOOK OF LABORATORY ANIMAL SCIENCE VOLUME 111. Cleveland, OH, CRC Press, Inc., 1976. Shapiro, B.A., Harrison, R.A., Walton, J.R. CLINICAL APPLICATION OF BLOOD GASES, 2nd Ed. Chicago, Year Book Medical Publishers, Inc., 1977. Vagtborg, H., ed. THE BABOON IN MEDICAL RESERACH, VOLUME I. Austin, Texas, University of Texas Press, 1965. Vagtborg, H., ed. THE BABOON IN MEDICAL RESEARCH, VOLUME 11. Austin, Texas, University of Texas Press, 1967. Van Zyl, J.J.W., DeKlerk, J.N., Murphy, G.P. Baboons in organs transplant research. Special Supplement to SOUTH AFRICAN MEDICAL JOURNAL 17~1-105,1968. Willerson J.T., Sanders, C.A. eds. CLINICAL CARDIOLOGY. New York, Grune and Stratton, 1977.