Vascular and uterine responses to dobutamine and dopamine in the gravid ewe

Vascular and uterine responses to dobutamine and dopamine in the gravid ewe J. I. FISHBURNE, M.D. P. J. MEIS, M.D. R. B. URBAN, M.D. F. C. GREISS, M.D. A. S. WHEELER, M.D. F. M. JAMES, M.D. M. F. SWAIN, R.N. A. L. RHYNE, PH.D. Winston-Salem, North Carolina Dopamine, a naturally occurring catecholamine precursor of norepinephrine, has been used in the treatment of cardiogenic shock. Following intravenous administration it increases cardiac output, blood pressure, and renal blood flow. Dobutamine is a directly acting inotropic agent which increases myocardial contractility without significantly changing blood pressure. This study was devised to compare the effects of these two drugs on uterine blood flow (UBF), uterine tonus (UT), mean arterial blood pressure (MAP), and heart rate (HR). Chronically instrumented pregnant ewes near term were infused with different concentrations of dopamine and dobutamine while HR, MAP, UT, and UBF were recorded continuously. Dopamine produced a decrease in UBF and an increase in MAP and UT while the HR response was variable. Dobutamine administration resulted in a marked increase in HR and a decrease in UBF, while MAP and UT remained essentially unchanged. Uterine vascular resistance increased with both drugs during high-dosage administration, but the rise was most pronounced folloWing dopamine infusion. Since dobutamine exhibits less ex-adrenergic activity than dopamine this drug would seem to be preferred when an inotropic agent is required for treatment of the pregnant patient. (AM. J. OesTET. GYNECOL. 137:944, 1980.)

DoBUTAMINE is a newly developed inotropic agent derived by modification of the isoproterenol molecule. It is purported to have /3 1-agonist activity similar to that of epinephrine, with only slight a- and /32-activity.I In From tlu! Departments of Obstetrics and Gynecology and Anesthesiology, Bowman Gray School of Medicine of Wake Forest University. This research was supported by United States Public Health Service Grant No. HD 11339-19Al frmn the National Institute of Child Health and Human Development. Presented as Official Guest at the Forty-second Annual Meeting of the South Atlantic Association of Obstetricians and Gynecologists, Atlanta, Georgia, February 3-6, 1980. Reprint requests: john /. Fishburne, M.D., Department of Obstetrics and Gynecology, Bowman Gray School of Medicine of Wake Forest University, 300 S. Hawthorne Road, Winston-Salem, North Carolina 27103.

944

humans, the inotropic effect predominates over the chronotropic effect and there is little tendency to arrhythmia at the lower dosage levels. 2 - 5 Blood pressure remains essentially unchanged while cardiac output increases, signaling a decrease in systemic vascular resistance.6 These features suggest that dobutamine would be a valuable drug for treatment of the patient with cardiogenic shock. 5 Dopamine, a naturally occurring catecholamine, is a precursor of norepinephrine. Its actions in the human include increased cardiac output due to an inotropic effect on the myocardium, elevation of the mean arterial blood pressure (MAP), and a variable effect on heart rate (HR). 7 Renal· and splanchnic blood flow is augmented, while How to peripheral vascular beds may be diminished. 8- 10 Total peripheral resistance at low doses is usually unchanged but tends to increase at 0002-9378/80/160944+09$00.90/0

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1980 The C. V. Mosby Co.

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Responses to dobutamine and dopamme

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Fig. l. Original tracing of typical responses to dobutamine infusion in a gravid ewe. Note that MAP and UT were essentially constant, while HR increased and UBF decreased. higher dosage levels secondary to the release of endogenous norepinephrine. 9 • 11 Although these drugs are being used primarily in the treatment of cardiogenic shock in patients suffering myocardial infarction, they may also prove useful in treating the reduced cardiac output associated with conditions such as severe pre-eclampsia and peripartal cardiomyopathy. Effects of intravenously administered dopamine on ovine uterine blood flow (UBF) have been previously reported . 11 - 16 Review of these studies reveals a dichotomy with respect to the action of dopamine on UBF. The present study in the pregnant ewe was undertaken to evaluate uterine and vascular responses to dobutamine and to provide further evidence in the controversv regarding the effects of dopamine on UBF.

Methods Seven ewes between 100 and 132 days of gestation were anesthetized with intravenous ketamine (4 mg/kg loading dose, 7.2 mg/min maintenance dose) and surgically prepared. Catheters were placed in the distal aorta and inferior vena cava via the left mammary artery a nd vein, respectively. A saline-filled, balloontipped catheter was placed extra-amhiotically · in the nonpregnant uterine horn . An electromagnetic flow probe was situated around the left middle uterine ar-

Table I. Numbers of observations tor each parameter at each dosage for copamine and dobutamine DOS I' Drug

Dopamine

Measurement

HR

MAP lJT

UBF Total Dobutamine

HR

MAP UT UBF Total

2

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8 120

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19

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78

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tery and an occlusion loop was placed around the distal aorta. These devices permitted measurement of mean arterial blood pressure (MAP), HR, uterine tonus (UT), and UBF. Details of these procedures have been published previously. 17 • tB. 19 The ewes were studied twice during the week following recovery from surgery, one day with each of the test drugs . The animals were maintained during testing in a small mobile cart in a quiet isolated environment. After all parameters had been allowed to stabilize. one of the test drugs was infused intravenouslv at a con-

946

Fishburne et al.

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stant rate of 4, 8, 20, or 40 ~-tglkg/min for dopamine and 2, 4, 8, 20, or 40 ~-tglkg/min for dobutamine. Each concentration was infused for a 2-minute period one to four times on each of the study days. Test infusions were preceded and followed by infusions of 0.9% saline.

Recorded parameters were observed and calculated at 12-second intervals for the I minute preceding each test infusion and at the same intervals during and following infusion until the noted effects had dissipated. Control values were considered to be the average of the five 12-second observation s preceding each infusion .

Volume l:l7 N umber 8

Responses to dobutamine and dopamine

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HR, MAP, UT, and UBF means and standard errors of the mean were calculated for each drug and dose as a function of time . Uterine vascular resistance (UVR) was estimated by the formula UVR =

~~; . Dose-re-

sponse curves for the two drugs were derived from regression analysis by computer program and were calculated from the mean value of each parameter immediately following each infusion.

Results One hundred ninety-three drug infusions were carried out on seven ewes between 105 and 138 days of

gestation . The numbers of observations of each parameter, dosage and drug are depicted in Table I. Typical responses of HR. MAP, UT, and UBF are shown at different concentrations of infused dobutamine (Fig. I) and dopamine (Fig. 2). The variable response of HR to dopamine is illustrated. Fig. 3 depicts the average magnitude of change occurring in HR, MAP, UT, and UBF in response to the intravenous infusion of dopamine. In general, maximal changes occur shortly following the drug infusion and are dose dependent. The effects of dobutamine infusion on HR and UBF are illustrated in Fig. 4. Minimal changes in MAP and UT were noted.

Volume 137 "'umher 8

Responses to dobutamine and dopamine

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ewes. The two drugs act similarly only in their effects on UBF.

Effects on HR. MAP, UT, and UBF after 2 minutes of infusion are summarized for the two drugs at varying concentrations in Fig. 5. Dopamine exerts a minimal effect on HR (Fig. 5, A) in the lower doses and produces slight bradycardia (p < 0.01) at the highest dosage level. Dobutamine, on the other hand, causes significant tachycardia at all dosages (p < 0.0 1) with the HR more than doubled at 40 Mg/kg/min. MAP (Fig. 5, B) is unaffected by dobutamine infusion. Dop~mine infusion significantly (p < 0.01) decreases MAP at low dosage (4 and 8 ~J.g/kg/min) but increases it (p < 0.01) when infused at the rate of 40 ~J.g/kg/min. UT (Fig. 5, C) is similarly unaffected by dobutamine except for a slight decrease at high dosage (p < 0.05). It rises significantly, however, in response to the infusion of dopamine at 20 ~J.g/kg/min (p < 0.05) and 40 ~J.g/kg/min (p < 0.01). The effects of dopamine and dobutamine on UBF are shown in Fig. 5, D. Both drugs produce

significant reductions in UBF at all dosage levels tested (p < 0.05 at 2 ~J.g/kg/min and p < 0.01 at 4 to 40 ~J.g/kg/min). Dose-response curves are illustrated in Fig. 6. Changes in UVR were calculated from the average UBF and MAP and are shown in Fig. 7 for each drug at each infused concentration. Significant increases in UVR occur with both drugs at the higher dosages (p < 0.01). The magnitude of these changes is greater for dopamine than for dobutamine (p < 0.0 I at the 40 ~J.g/kg/min infusion rate).

Comment The inotropic agents dopamine and dobutamine have found clinical usage in the treatment of cardiogenic shock accompanying myocardial infarction, severe sepsis, cardiomyopathy, chronic cardiac disease, and cardiac surgery. Since many of these conditions

950

Fishburne et al.

.-\ugust I c>. 19HO Am . .J . Ohst~L. (;rnecol.

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may coexist with pregnancy it seemed appropriate to evaluate and compare cardiovascular and uterine effects of these two agents in the pregnant ewe. Previous studies with dopamine reported divergent effects on UBF. Blanchard and assoCiates, 12 using an electromagnetic flow probe on the common internal iliac artery in pregnant sheep, demonstrated significant increases in UBF in response to infusion of dopamine at increasing concentrations. Callender and associates, 11 on the other hand, applied an electromagnetic flow probe to a branch of the uterine artery arid recorded decreased UBF, particularly at the higher concentrations of 20 to 40 p.g/kg/min. Our present work supports that of the latter group. Recent evidence by Tabsh and associates 16 lends additional support. These authors demonstrated that different vascular responses are measured by these two techniques, suggesting that a flow probe on the common internal iliac artery measures more than the uterine vascular bed alone. One may, therefore, conclude that the correct values are recorded from the middle uterine artery and that the

true dopamine response in ovine pregnane) is one ot decreased UBF. This phenomenon prohahh- res11lts from increased UVR associated with elevation of UT and vasospasm due to the release of endogenous norepinephrine by this agent. In this study the chronotropic effects of dobutamine were striking and paralleled the reduction of U BF produced by this drug. Dopamine, however, caused a marked reduction of UBF without a concomitant change in HR. Since dobutamine has been shown t.o produce a powerful inotropic effect with little increase in HR in humans, one may surmise that a significant increase in myocardial contractility will occur at low dosage (< 4 p.g/ kg/ min) while the CBF is only sli ght ly compromised. Furthermore , if these ovine data may be extrapolated to the human, one should be able to judge UBF reduction by observation of the maternal HR. In this manner fetal stress could be minimized while cardiac output is augmented. Clinical reduction of UBF by dopamine should prove more difficult to predict. Furthermore, this agent has been shown to raise blood pressure, thus increasing cardiac afterload and consequently cardiac work. In addition, UT in the human may be more sensitive to the effects of dopamine than our ovine model would suggest, and in this event the fetus might experience further stress secondary to the use of this agent. Studies by Rolbin and associates 1" using the ovine model indicated that dopamine is not a useful drug for treatment of spinal anesthesia-induced hypotension. Since dobutamine does not influence blood pressure but reduces UBF, it appears that this drug would also prove ineffective in the management of this condition. We conclude that both of these agents reduce UBF in a dose-related manner. However, because dobutamine seems. to exhibit less a-adrenergic activity than dopamine, it would appear to be the preferable agent for treatment of cardiogenic shock occurring in the pregnant patient.

REFERENCES

J.: Development of a new catecholamine to selectively increase cardiac contractility, Circ. Res. 36:185, 1975. · 2. Meyer, S. L., Curry, G. C., Donsky, M. S. , Twieg, D. B., Parkey, R. W., and Willerson, ]. T.: Influence of dobutamine on he!llodynamics and coronary blood flow in patients with and without coronary artery disease, Am. ]. Cardiol. 38: 103, 1976. 3. Beregovich, J., Bianchi, C., D'Angelo, R., Diaz, R., and Rubler, S.: Hemodynamic stuqies with dobutamine, a new inotropic agent, Circulation (Suppl. 4) 48:144, 1973. 4. Jewitt, D., Mitchell, A., Birkhead,]., and Dollery, C.: ClinI. Tuttle, R. R. , and Mills,

5.

6. 7. 8.

ical cardiovascular pharmacology of dobutamine : A selective inotropic catecholamine, Lancet 1:363, 1974. Tinker, J. H ., Tarhim, S., White, R. D., Pluth,]. R., and Barnhorst, D. A. : Dobutamine for inotropic support during emergence from cardiopulmonary bypass, Anesthesiology 44:281, 1976. Robie, N. W., and Goldberg, L. I.: Comparative systemic and regional hemodyna!llic effects of dopamine and dobutamine, Am. Heart]. 90:340, 1975. · Horwitz, D., Fox, S. M., and Goldberg, L. I.: Effects of dopamine in man, Circ. Res. 10:237, 1962. McDonald, R. H., Goldberg, L. I., McNay,]. L., and Tut-

Volume Ui :-.iumber H

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10. 1 I.

12.

13. 14.

tie, E. P.: Effects of dopamine in man: Augmentation of sodium excretion, glomerular filtration rate, and renal plasma flow.]. Clin. Invest. 43:1116, 1964. Hollenberg, N. K., Adams, D. F., Mendell, P., Abrams, H. L., and Merrill, J. P.: Renal vascular responses to dopamine: Haemodynamic and angiographic observations in normal man, Clin. Sci. 45:733, 1973. McNay, J. L., McDonald. R. H., and Goldberg, L. 1.: Direct renal vasodilatation produced by dopamine in the dog. Circ. Res. 16:510, 1965. Callender, K.. Levinson, G., Shnider, S. M., Feduska, N. ]., Biehl, D. R., and Ring, G.: Dopamine administration in the normotensive pregnant ewe, Obstet. Gynecol. 51:586, 1978. Blanchard. K., Dandavino. A .. Nuwayhid, B., Brinkman, C. R., and Assali, ~. S.: Systemic and uterine hemodynamic responses to dopamine in pregnant and nonpregnant sheep, AM. J. 0BSTET. GY:.ECO!.. 130:669, 1978. Blanchard. K., Brinkman, C. R., Dandavino, A., Clark, K. E., and Assali, N. S.: Reactivitv of uterine vasculature to dopamine, Gynecol. Invest. 8:56, 1977. Cabalum. T .. Zugaib, M., Lieh. S.. Nuwayhid, B.. Brink-

Dlacusslon DR. DoNALD CATON, Gainesville, Florida (By invitation). Dr. Fishburne and his colleagues have made some interesting observations on the effects of a relatively new group of sympathomimetic drugs that are becoming more and more important in the clinic. The authors observed, as have others, that the drugs may support the maternal circulation, but only at the expense of UBF. It is precisely this point which is important to those of us who care for obstetric patients. This study raises a general question which often confronts us clinically: Given the fact that a drug may decrease UBF, how can we decide if the decrease is clinically significant? The sympathetic nervous system functions to help the individual deal with acute stress. One way this occurs is by the diversion of the flow of blood from nonessential areas of the body to those more critical. During pregnancy, 10% to 20% of cardiac output goes to the uterus; there are mechanisms which will divert this flow to those areas necessary to the fight-or-flight response. Also exogenous sympathomimetic amines, whether their activity is primarily a- or ,8-adrenergic, can have a similar effect. Those of us who measure UBF of pregnant experimental animals see changes of the magnitude described by Dr. Fishburne even when animals are only mildly excited. In fact, changes of this sort may occur from one day of pregnancy to the next or within a single day as part of a normal biorhythm and not any overt stress.L 2 We assume that similar changes in UBF occur in our obstetric patients. I shudder to think of the uterine vascular changes of a woman taking off or landing in a plane at the airport in Atlanta, Georgia. What we would like to know, both in the laboratory and in the clinic, is the extent to which the UBF may

Responses to dobutamine and dopamine

15.

16.

17.

18. 19.

951

man, C. R., and Assali, N. S.: Effect of dopamine on hypotension induced by spinal anesthesia, A~r .J. OssTET. GYNECOL. 133:630, 1979. Rolbin, S. H., Levinson, G., Shnider, S. M .. Biehl. D. R., and Wright, R. G.: Dopamine treatment of spinal hypotension decreases uterine blood How in rhe pregnant ewe, Anesthesiology 51:36, 1979. Tabsh, K. M., Nuwayhid, B., Zugaih. M .. Lieb, S., Brinkman, C. R .. III, and Assali, N. S.: Differential reactivity of the uterine vascular bed, in Scientific Abstracts, Twenty-sixth Annual Meeting, Society for (;ynecologic Investigation, San Diego. California, March 21-2ct. 1979. (Abst. 248.) Fishburne,]. I., Griess, F. C., Hopkinson, R ... md Rhyne, A. L.: Responses of the gravid uterine vasculature to arterial levels of local anesthetic agents. A:-t. J. OasTET. GYNECOL. 133:753, 1979. Greiss, F. C.: The uterine vascular bed: Effen of adrenergic stimulation, Obstet. Gynecol. 21:295, I H6:~. Griess, F. C.: A mechanical zero reference l(w implanted flowmeter systems.]. Appl. Physiol. 17: l7i. I9fi2.

decrease before harm comes to the fetus: vVe need an estimate of a margin of safety. This may vary considerably among individuals. For example, even among a group as homogeneous as a flock of sheep, the rate of blood flow to the uterus during various stages of pregnancy may vary as much as threefold. 1 This has no relationship to the weight of the fetus, that is to say, the small fetus may be served by as high a rate of uterine blood flow as a large one. But what happens in times of stress, as in cardiogenic shock or in other clinical situations which call for the administration of a vasopressor? In these circumstances, the fetus with a high margin of safety, that is, the small fetus receiving a high rate of blood flow, may have a distinct advantage. To put the matter another way, for the fetus whose margin of safety is small, the selection and the use of the vasopressor may be critical. Dr. Fishburne's experiments may help us to identify some of these subtle differences in effects of drugs. This brings me to some related questions for Dr. Fishburne. How does the magnitude of the change in UBF you induced compare to that of the spontaneous changes which occur normally in animals? Did you observe individual differences in the capacities of the fetuses to deal with the drug infusion? For example, how many went on to term? If any aborted, could you relate this to any peculiarity of that animal's response to the drugs? REFERENCES I. Caton, D., Crenshaw, C., Wilcox, D.]., and Barron, D. H.: 0 2 delivery to the pregnant uterus: its relationship to Oz consumption, Am. J. Physiol. 237:R52, 1979. 2. Lanz, E., Caton, D., Schlereth, H., and Barron, D. H.: Die Wirkung von Lokalanesthetika auf Durchblutung und 0 2 Verbrauch des Uterus von schwangeren Schafen, Anaesthesist 26:403, 1977.

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Fishburne et al. Am.

DR. FISHBURNE (Closing). We also have observed these wide swings in UBF when we monitor these animals on a long-term basis. We attempt to get around that for the study purpose by achieving a baseline and then infusing the drug and studying the effects in relation to the baseline. The possible use in cardiogenic shock or the preference of one drug over another is entirely speculative. For one thing, we are relating sheep to people. I am not sure we can make such a generalization as that one. The animals were close to

J.

August 15, 198ll Obstet. G~necol.

term when the experiments were carried out. Becau~e of the need to obtain as many studies as possible from the animals that we prepare, we had several different experiments going on. These animals were stressed far more significantly by other experiments with the use of norepinephrine than they were by this experiment. We did, however, have some animals that delivered spontaneously within a few days of the study. The of[~pring were normal. One or two of them did have stillbirths, but again they were severely insulted.

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