JOURNAL OF SURGICAL RESEARCH, 13, 182-187 (1972)

HEMODYNAMIC EFFECTS OF SODIUM PENTOBARBITAL IN THE BOVINE

FRED L. ANDERSON, M.D., ALEX C. KRALIOS, M.D., THEOFILOS J.

TSAGARIS, M.D., AND HIROSHI KUIDA, M.D.*

SODIUM PENTOBARBITAL (SP) IS A WIDELY USED anesthetic agent that has a number and variety of effects upon the circu- lation [4, 6, 7, 121. The observation in our lab- oratory that normal calves (Bos tourus) as well as calves with high altitude brisket dis- ease (BD) anesthetized with SP occasionally develop acute pulmonary hypertension and sometimes pulmonary edema prompted a study to determine the hemodynamic effects of this agent in the bovine species. This study is deemed especially pertinent in view of the in- creasing use of the bovine as a suitable species for cardiopulmonary research, especially that related to circulatory and cardiac assist de- vices [13].

METHODS

Thirty-four normal Hereford calves (aver- age weight 101 kg) obtained randomly at auc- tion were studied 39 times. In addition, seven calves with BD obtained from high altitude enzootic ranges, and of similar age and weight were each studied once. Each calf was studied

Cardiovascular Division, Veterans Administration Hospital and the University of Utah College of Medi- cine, Salt Lake City, Utah 84112.

This study was supported by the U.S. Public Health Service (Grants No. HE-07618 and HE 250) and the Utah Heart Association.

The authors are grateful to Dr. R. F. Marshall, Veterinary Consultants, Inc., Des Moines, Iowa for a generous supply of propylene glycol, alcohol and water. The technical assistance of Mr. Don Anton and Filimon Ukradyha, Ph.D. is greatly appreciated.

Submitted for publication March 24, 1972. * USPHS Research Career Development Awardee

(HE-4530).

lying on its side without premeditation or general anesthesia. The external jugular vein, common carotid artery and a branch of the femoral artery and vein were surgically ex- posed under local lidocaine anesthesia. Two no. 8 Cournand catheters were introduced into the external jugular vein and under fluoro- scopic guidance one was advanced to the pul- monary artery (PA) and the other to the pul- monary artery wedge (PAW) position, An- other no. 8 Cournand catheter was introduced into the common carotid artery and advanced to the left ventricle (LV). A Teflon cannula (no. 18 gauge), 15 cm in length, was inserted into a branch of the femoral artery (FA) and advanced proximally. These catheters and cannula were connected to P23Db pressure transducers.

After placement of catheters the trachea was intubated with a large cuffed endotracheal tube. Each animal was given heparin (200 mg) intravenously to prevent formation of blood clots in catheters and cannula. Cardiac output (CO) was measured by the dye-dilu- tion technique. Indocyanine green dye (5.0-7.5 mg) was injected into the PA and sampled from the FA through a densitometer (Gilson Medical Electronics, Middleton, WI) using a constant rate withdrawal pump (Harvard Ap- paratus Co., Dover, MA). Pressures, the elec- trocardiogram and the dye curves were re- corded on an oscillographic recorder (Minnea- polis Honeywell, Denver, CO). Analysis of ar- terial blood for pH, COZ tension and O2 ten- sion was carried out using the Astrup appara- tus.

Cardiac output, PA, PAW, LV and FA pres-

182 Copyright 0 1972 by Academic Press, Inc. All rights of reproduction in any form reserved.

ANDERSON ET AL.: HEllIODYNAMIC EFFECTS PENTOBARBITAL 183

sures were measured during a control period with the animal breathing spontaneously. A bolus of SP (Diabutal, Diamond Laboratories, Inc.), average dose 3.6 mg/kg, was injected into the femoral vein or PA. Except for inter- ruption of PA pressures during the injection PA, PAW and FA pressures were recorded continuously. Cardiac output determination was carried out and arterial blood samples ob- tained for gas analysis at peak pulmonary hy- pertensive response to SP. Injections of SP were carried out while the animal breathed room air spontaneously and during artificial positive pressure breathing with 100% Oz. Pos- itive pressure breathing was performed using a Medtronic pressure regulated respirator.

The vehicle in which SP is dissolved con- sists of a mixture of 2 parts propylene glycol, 1 part ethanol and 7 parts water (PG) . In order to determine the effect of PG on pulmonary and systemic hemodynamics, injections of PG (av 6.1 ml) were made into the PA in 24 calves using a protocol similar to that for the SP injections.

RESULTS

Data obtained from these experiments were divided into four groups. Group 1: Normal calves, spontaneous respiration. Group 2 : Nor- mal calves, positive pressure respiration breathing 100% 02. Group 3: Brisket calves,

spontaneous respiration [4], positive pressure respiration breathing room air [3]. Group 4: Normal calves, spontaneous respiration given PG.

The results of a typical experiment from a Group 1 calf are shown in Fig. 1. Mean hemo- dynamic dat,a for Groups l-4 are shown in Table 1 and Fig. 2.

Groups 1 and 6. Data comprise 39 injections of SP in 32 calves in Group 1 and 12 injections in 8 calves in Group 2. The response to SP was similar in both groups. There was an increase in PA pressure, a fall in FA pressure followed by a delayed rise above control levels, an in- crease in heart rate and no change in CO or PAW pressure.

Group S. Data comprise eight injections in seven brisket calves. Control PA and PAW pressures were greater than in Groups 1, 2 or 3 consistent with the characteristic hemody- namic disturbance seen in brisket disease. The response to SP differed from that in Groups 1 or 2 in that PA pressure did not rise and FA pressure did not fall. There was a late rise in FA pressure, similar to that observed in Groups 1 and 2. Heart rate increased. Cardiac output did not change.

Group 4. Data comprise 40 injections of PG in 24 calves. PA pressure increased in 6 calves and did not change in 18. There was no change in FA or PAW pressure, CO or HR.

b----I I---,

/’ ,a----,4

,’ I

0 r------- 20 set 5rnlrl IOmln

Fig. 1. Results of a typical experiment in a normal calf after the injection of sodium pentobarbital into the femoral vein. FAP is the femoral artery pressure. PAP is the pulmonary artery pressure. PAW is the pulmonary artery wedge pressure.

184 JOURNAL OF SURGICAL RESEARCH, VOL. 13, NO. 4, OCTOBER 1972

Table 1. Hemodynamic Dataa

PAP FAP PAW co HR

c P c P L c P C P c P

Group 1

n 39 39 39 39 36 21 20 18 18 23 22 iiE 2.3 29 4.1 41 2.2 139 3.0 126 2.9 163 2.9 6 1.1 6 78 81 99 122

3.9 4.1 6.0 4.1 P < .Ol < .Ol < .Ol N.S. N.S. < .Ol

Group 2

n 12 12 12 12 12 11 11 12 11 12 12 5 31 46 127 103 137 13 14 57 59 95 102 SE 2.7 4.0 6.4 7.2 6.5 1.7 2.4 4.6 3.6 3.6 4.8 P < .Ol < .Ol < .05 N.S. N.S. < .05

Group 3

n 8 8 9 7 7 6 6 9 9 9 9

:E 6.1 65 6.5 62 5.9 103 12.4 106 8.5 136 4.9 24 5.5 26 55 63 112 10.7 15.7 6.9 120 .4 .5 P N.S. N.S. < .05 N.S. N.S. < .05

Group 4

n 40 40 40 40 - 9 9 9 9 9 9 5 26 31 140 141 - 3 4 76 82 82 82 SE 1.4 2.6 2.4 2.2 - 0.7 1.0 4.4 5.7 8.3 9.2 P < .Ol N.S. N.S. N.S. N.S.

a Hemodynamic data obtained during control period (C) and after sodium pentobarbital at time of peak pul- monary hypertension (P). Femoral artery pressure (FAP) shown also during late (L) rise which occurred after the initial fall. Group l-normal calves, spontaneous respiration. Group 2-normal calves, positive pressure respiration breathing 100% 02. Group 3-brisket calves. Group 4-normal calves given propylene glycol, ethanol and water. PAP is the mean pulmonary artery pressure. PAW is the mean pulmonary artery wedge pressure. CO is the cardiac output. HR is the heart rate. f is the mean value. SE is one standard error. n is the number of njections. N.S. is not significant.

Arterial blood gas and pH measurements were obtained in 7 Group 2 calves. Mean POz was 248 and 223 mm Hg, respectively, before and after SP. Mean PCO:! was 24 mm Hg and pH was 7.56 before and after SP.

The individual response to SP and PG in relationship to the change in PA pressure for Group 1 and 4 calves is shown in Fig. 3. It is significant that in several calves in which SP provoked pulmonary hypertension, control PA pressure was increased.

When PG and SP were given in sequence variable results were obtained. In 12 calves no response was elicited by either agent. In seven calves PG elicited no response while SP pro- duced pulmonary hypertension. In one calf the opposite effect was observed wherein PG elicited pulmonary hypertension with no re- sponse to SP. Lastly, in four calves both agents produced pulmonary hypertension.

In 9 Group 1 calves given SP systemic vas- cular resistance was calculated and found to be 2.07 mm Hg/ml/min/kg during the late rise in FA pressure as compared to 1.81 Hg/ml/ min/kg during the control period (P < .05). A comparable change in systemic vascular resist- ance did not occur after PG.

DISCUSSION

These data indicate that a relatively small dose (by canine standards) of SP may exert a transient but significant effect on the pulmo- nary and systemic circulations of the bovine. Since CO did not change significantly we infer that the pressor response of the pulmonary cir- culation in the normal calves was probably due to a local vasoconstrictor effect of SP on resistance vessels. Assessment of changes in CO is difficult in this situation because of the

AKDERSON ET AL.: HEMODYNAMIC EFFECTS I’ENTOBARBITAL 185

PAP GROUP

co mmHg ml/mm/Kg GROUP

75, 1 2 _3 4 100, 1 2 3 4

50-

++ 25.

O-25; FAP

60-

Fig. 2. Mean values 2 1 SE obtained during con- trol period (closed circles) and after sodium pento- barbital at time of peak pulmonary hypertension (closed triangles). Mean femoral artery pressure (FAP) shown also during late rise which occurred after the initial fall (closed squares). PAP is the mean pulmonary artery pressure. CO is the cardiac output. PAWP is the pulmonary artery wedge pres- sure. HR is the heart rate. Group identification same as Table 1.

transient effect. Since it is not known whether a steady state was reached during this period of peak response dye CO measurement may be subject to error. Since pulmonary hypertension developed during artificially controlled respir- ation with an elevated arterial PO2 alveolar hypoventilation and/or hypoxia did not seem to play a major role. The absence of a pulmo- nary pressor effect in the BD calves is proba- bly due to the fact that severe pulmonary vas- oconstriction known to be present in BD ob- scures any additional effect of SP on resistance vessels.

The fact that PAW pressure remained con- stant indicates that the increase in PA pres- sure was not secondary to an increase in left atria1 pressure. It should be emphasized, how- ever, that under certain conditions PAW pres-

sure in the bovine can be quite labile and may not reflect left atria1 pressure. Injections of small volumes (l-5 ml) of solutions contain- ing either dextrose in water, normal saline, or blood may result in transient but significant elevations of this pressure [l, 31. To obviate this difficulty, the PAW catheter was not flushed once it had been positioned by fluoros- copy in a suitable site and had recorded a pressure comparable to that obtained simulta- neously from the LV during diastole. We re- peatedly compared the PAW pressure with the LV diastolic pressure throughout each experi- ment.

That the effect of SP can occur independent of its vehicle is evident from the fact that 7 of 24 calves developed pulmonary hypertension

PAP mmHg

120 1 4 IOO-

80-

60-

40-

20-

PAP mmHg

100

1 60

Fig. 5. Average individual change in pulmonary artery pressure (PAP) for 32 Group 1 calves given sodium pentobarbital (A) and 24 Group 4 calves given propylene glycol (B). Open circles are the con- trol pulmonary artery pressure. Open triangles are the peak pulmonary artery pressure.

186 JOURNAL OF SURGICAL RESEARCH, VOL. 13, NO. 4, OCTOBER 1972

with SP when a comparable dose of PG given immediately beforehand failed to elicit any re- sponse. However, it is apparent that in some calves PG may also elicit pulmonary hyper- tension in that five calves developed increased PA pressure with PG alone. Thus in any given calf given Diabutal a pulmonary hypertensive response may be due to SP or PG or both. Changes in FAP were not seen with PG. Whether or not the rise in PAP following PG is related to the PG alone or the ethanol can- not be determined from our data since the ef- fect of ethanol alone was not tested.

In contrast to its pulmonary pressor effect in the bovine, SP seems to have no effect on the resistance vessels of the canine pulmonary circulation [4, lo]. However, these observa- tions are consistent with other studies in the bovine which have shown increased pulmonary vascular reactivity to a variety of agents in- cluding hypoxia, endotoxin, ATP, ADP and mucin from fetal fluids [2, 5, 9, 111.

The effects of SP on the systemic circulation of the bovine appear to be of diverse etiology. Tachycardia occurred consistently. This has been observed in other species and is thought to represent the vagolytic effect of SP [6, 7, 8, 121. The transient systemic hypotension that occurred in the normal calves early after injection of SP has been reported in dogs [7]. If our assumption of little or no change in CO is correct the response suggests momentary systemic vasodilation. Whether this is due to a direct effect or a reflex mediated by pulmonary hypertension it is not possible to say. It should be noted that. calves with BD experienced nei- ther transient pulmonary hypertension nor systemic hypotension. The late rise in sys- temic vascular resistance above the control level in both the normal and BD calves is an observation that has also been made in other species [4, 71. The etiology is unclear but in the normal calves reflex vasoconstriction sec- ondary to baroreceptor stimulation by the pe- riod of hypotension is a distinct possibility.

The significance of these observations re- lates to the frequency with which SP is used as an anesthetic agent in laboratory animals as well as to the increasing use of the bovine in cardiovascular research. The occasional and unpredictable reactivity of the bovine pulmo- nary vessels to agents not having this effect in

other commonly used laboratory species is once again emphasized by this study.

SUMMARY

The effects of intravenous sodium pentobar- bital (SP) were studied in 34 normal and in 7 calves with brisket disease (BD). Average in- crease in pulmonary artery pressure was 12 mm Hg for normal calves with no significant change in BD calves. Average increase in fem- oral artery pressure after a transient decrease was 24 mm Hg in normal calves and 33 mm Hg in BD calves. Pulmonary artery wedge pressure and cardiac output did not change significantly in either normal or BD calves. Heart rate increased in both groups. When the diluent for SP, propylene glycol, ethanol and water (PG) was tested variable results were observed. In seven calves PG elicited no re- sponse while SP produced pulmonary hyper- tension. In five calves however, pulmonary hy- pertension occurred due to PG alone. The ef- fect of SP on pulmonary artery pressure is probably due to a direct pressor effect on pul- monary vessels whereas the basis for the effect on the systemic circulation is unclear.

1.

2.

3.

4.

5.

6.

7.

8.

REFERENCES

Anderson, F. L., Wray, R. B., Tsagaris, T. J., and Kuida, H. Pulmonary artery wedge pressure labil- ity in the bovine. Fed Proc. 31:307, March-April 1972. Daoud, F., Eastin, C., and Reeves, J. T. Pulmo- nary hypertensive properties of a mucin-like ma- terial from the fetal fluids of the calf. Fed. Proc. 29527, 1970. Droszcz, W. A., Latorre, F., and Reeves, J. T. Lability of the pulmonary wedge pressure in the calf. J. Appl. Physiol. 24:640-644, 1968. Goldberg, S. J., Linde, L. M., Gaal, P. G., Momma, K., Takahaski, M., and Sarna, G. Effects of barbiturates on pulmonary and systemic hae- modynamics. Cardiovnsc. Res. 2:137-142, 196% Kuida, H., Brown, A. M., Thorne, J. L., Lange, R. L., and Hecht, H. H. Pulmonary vascular response to acute hypoxia in normal unanesthetized calves. Amer. J. Physiol. 203:391396, 1962. Nash, C. B., Davis, F., and Woodbury, R. A. Cardiovascular effects of anesthetic doses of pen- tobarbital sodium. Amer. J. Physiol. 185:107-112, 1956. Olmsted, F., and Page, I. H. Hemodynamic changes in dogs caused by sodium pentobarbital anesthesia. Amer. J. Physiol. 210:817-820, 1966. Page, I. H., and McCubbin, J. W. Autonomic reg-

ANDERSON ET AL.: HEMODTN~4RIIC EFFECTS PENTOBARBITAL 187

ulation of arterial pressure responses. Arch. Int. Pharmacodyn. 157:152-165, 1965.

9. Reeves, J. T., Jolrl, P., Mcrida, J., and Leathers, J. E. Pulmonary vascular obstruction following ad- ministration of high-energy nuclcotides. J. Appl. Physiol. 22 :475-479, 1967.

10. Rudolph, A. M., and Scarpelli, E. M. Drug action on pulmonary circulation of unanesthetized dogs. Amer. J. Physiol. 206:1201-1206,1964.

11. T&off, G., Kuida, H., and Chiga, M. Hemody-

namic cffrcts of cndotosin in calves. Amer. J. Phpsiol. 210 :847-853, 1966.

12. Van Cittrrs. 1~. J,.! Franklin, D. L. and Rushmer, R. F. Left ventricular dynamics in dogs during anesthesia with alpha-chloralose and sodium pen- tobarbital. Amer. J. Cardiol. 13 :349354, 1964.

13. Weber, K. T.: Dennison, B. H., Fugua, J. M., Speaker, D. M., and Hastings, F. W. Hemody- namic measurements in unanesthetized calves. J. Swg. lies. 11:383-389. 1971.