Comparison of Dopamine and Dobutamine Follaking CoronG Artery Bypass Grafting

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1 Comparison of Dopamine and Dobutamine Follaking CoronG Artery Bypass Grafting Neal W. Salomon, M.D., John R. Plachetka, Pharm.D., and Jack G. Copeland, M.D. ABSTRACT A prospective, randomized comparison of the hemodynamic effects of dopamine and dobutamine was performed in 20 patients following coronary artery bypass grafting. Approximately 6 hours postoperatively, when patients were hemodynamically stable, either dopamine or dobutamine was administered at 2.5, 5.0, and 7.5 pg per kilogram of body weight per minute. At 5.0 pglkg, both drugs increased cardiac index without changing heart rate, mean arterial pressure, pulmonary capillary wedge pressure, or peripheral vascular resistance. At 7.5 pglkg, dobutamine caused a further increase in cardiac index without changing the other variables. In contrast, increasing dopamine from 5.0 to 7.5 pglkglmin caused significant increases in mean arterial pressure, pulmonary capillary wedge pressure, and pulmonary vascular resistance but no further increase in cardiac index. We conclude that dobutamine is preferable to dopamine in patients following coronary artery bypass grafting, since it produces consistent, dose-related increases in cardiac index without increases in heart rate, mean arterial pressure, pulmonary capillary wedge pressure, or pulmonary vascular resistance. Coronary artery bypass operation often is performed without the need for postoperative inotropic support. However, because of differences in intraoperative myocardial protection and the extent of both the coronary disease and the status of the myocardium, it is not uncommon to require the temporary use of inotropic or vasopressor agents. Two of the most often used inotropic agents are dopamine (Intropin) and a From the Surgery Department, University of Arizona Health Sciences Center, Tucson, AZ. Presented at the Seventeenth Annual Meeting of The Society of Thoracic Surgeons, Jan 26-28,1981, Los Angeles, CA. Address reprint requests to Dr. Copeland, Surgery Department, University of Arizona Health Sciences Center, 1501 N Campbell Ave, Tucson, AZ relatively new cardioselective agent, dobutamine (Dobutrex). Although previous studies have attempted to examine the hemodynamic effects of these two drugs using a crossover design, they were performed for very short time spans intraoperatively or in the immediate perioperative period [l-31. During these times, substantial non-drug-related hemodynamic changes may occur, especially alterations in peripheral vascular resistance, which can cause confusion about the actual effects of the drug. In the present analysis, patients were studied in the postoperative period when hemodynamic stability was assured and when they had obtained a temperature of 37 C. Material and Methods We studied 20 male patients, 42 to 69 years old (mean, 56 years), each of whom had been maintained on orally administered propranolol for at least one month prior to operation. None had any evidence of chronic congestive heart failure, bronchospasm, or heart block. The day before operation, patients gave written, informed consent to participate in this study, which was approved by the University of Arizona Human Subjects Committee. They were then randomly assigned to receive either dopamine (n = 10) or dobutamine (n = 10) postoperatively. Randomization was carried out by assigning patients a number from a table of random numbers. Then a correspondingly numbered envelope was opened to reveal which treatment the patient would receive. Because of the possibility of time-dependent, non-drug-related hemodynamic changes, a crossover study design was not used. Patients had the last oral dose of propranolo1 8 to 12 hours before operation [4-61. The preoperative daily maintenance dose of propranolol in the dopamine group (213 & mg by The Society of Thoracic Surgeons

2 49 Salomon, Plachetka, and Copeland: Comparison of Dopamine and Dobutamine per kilogram of body weight) did not differ significantly from that of the dobutamine group (177 f 80.3 mg). There were also no differences between groups regarding age, left ventricular performance (ejection fraction), left ventricular filling pressure, cardiac index, number of grafts placed, or general preoperative risk factors (history of previous myocardial infarction, arrhythmias, hypertension, obesity, smoking). The drug administration studies were begun approximately 6 to 8 hours postoperatively when wedge pressure was greater than 10 mm Hg, rectal temperature was 37 C or greater, heart rate was less than 110 beats per minute, and mean arterial pressure was less than 90 mm Hg. No patient received nitroprusside or other vasoactive drugs other than dopamine or dobutamine during the control study periods. Solutions of dopamine and dobutamine for intravenous administration were prepared in identical concentrations and labeled only as Inotropic drug-400 mg in 500 ml D,W [5% dextrose in water] by a hospital pharmacist. The person monitoring and measuring the hemodynamic variables was blinded as to which drug was being administered to the patient. All drug solutions were infused with a constant infusion pump. Following baseline control measurements, either dopamine or dobutamine was administered at incremental doses of 2.5, 5.0, 7.5, or 10.0 pg per kilogram of body weight per minute. A twenty-minute stabilization period was allowed before hemodynamic evaluation. A second set of control data were obtained thirty minutes following discontinuation of the final dose. All doses were given as indicated unless heart rate increased to more than 25% of control, mean arterial pressure increased to more than 25 mm Hg, cardiac index increased to twice the control value, serious life-threatening arrhythmias occurred, or if there was electrocardiographic or clinical evidence of myocardial ischemia. The following variables were used to evaluate the hemodynamic effects of the two drugs: heart rate; mean, diastolic, and systolic arterial pressures; pulmonary artery systolic, diastolic, and wedge pressures; cardiac index; stroke volume index; and calculated peripheral vascular resistance in resistance units (mean arterial pressurelcardiac index). Left ventricular stroke work index was also calculated but since it completely paralleled the data for stroke volume index, it was omitted. Unless otherwise specified, data are expressed as f 1 standard deviation. Differences between groups were evaluated for statistical significance using a two-tailed Student s t test for unpaired samples. Comparisons within groups were evaluated for statistical significance with a two-tailed Student s t test for paired samples. Results were considered statistically significant when p < Results The results of the study are presented in the Table. At a dose of 2.5 pglkglmin, there were no significant changes from control in any of the variables measured in either group. At 5.0 pglkglmin, both drugs caused a significant increase in cardiac index with no change in the other variables. At 7.5 pglkglmin, both groups demonstrated significant increases from control in mean arterial pressure and cardiac index (Fig 1). However, patients receiving dobutamine had a 26% mean increase in cardiac index compared with a 17% mean increase in the patients receiving dopamine. The increase in cardiac index noted in the dobutamine group was also significantly increased from the previous dose, whereas no significant increase in cardiac index occurred in the dopamine group between the 5.0 and 7.5 pglkg dosages. At comparable heart rates, the increase in cardiac index in both groups was achieved largely by an increase in stroke volume index. This increase in the stroke volume index, however, only reached statistical significance at 7.5 pglkglmin in the dobutamine group, when it increased 20% above control (Fig 2). Patients receiving dobutamine had no changes in the pulmonary capillary wedge pressure within the dosage range examined (Fig 3A). However, at 7.5 pglkglmin of dopamine, there was a significant increase in the wedge pressure. Concomitantly, a significant increase in calculated peripheral vascular resistance was noted at this dose (Fig 3B). There were no significant changes in peripheral vas-

3 50 The Annals of Thoracic Surgery Vol 33 No 1 January 1982 Summary of Hemodynarnic Data for All Patientsa Dose (pglkglmin) Variable Control DOBUTAMINE (N = 10) HR (beatslmin) 87.6 f f f f 17.5 MAP (mm Hg) 79.4 f f k f 15.3 PCWP (mm Hg) 13.0 f f f f 3.7 CI (Llminlm') 2.7 f f f 0.6b 3.4 f 0.8b.C SVI (mllmin/m2) 31.6 f f k f 11.4b PVR (resistance units) 30.7 f f f f 7.2 DOPAMINE (N = 10) HR (beatslmin) 96.3 f f f f 15.1 MAP (mm Hg) 80.4 f f f f 12.1b PCWP (mm Hg) 13.0 f f It f 5.4b CI (Llmidm') 2.8 f f f 0.6b 3.3 f l.bb SVI (ml/min/m2) 29.7 f f f f 10.1 PVR (resistance units) 29.4 f f f k 6.8" adata shown as group mean? 1 standard deviation. "p < 0.05 vs control. 'p < 0.05 vs previous dose. HR = heart rate; MAP = mean arterial pressure; PCWP = pulmonary capillary wedge pressure; CI = cardiac index; SVI = stroke volume index; PVR = peripheral vascular resistance (resistance units = MAPICI). cular resistance seen at any of the doses of dobutamine tested. Because of the stringent exclusion criteria and guidelines for termination of the drug administration study, only a limited number of patients tolerated either drug at the 10 pglkglmin dose. In 7 of the 10 receiving dopamine the infu- Fig 1. Changes in (A) mean arterial pressure and (B) cardiac index with different doses of dobutamine and dopamine. sion was stopped because of hypertension, and in 2 because of tachycardia. Of the patients receiving dobutamine, hypertension in 4 and tachycardia in 3 necessitated the termination of the infusion. No arrhythmias were noted with either drug. Comment Dopamine and dobutamine are considered potent inotropic agents with less chronotropic and arrhythmogenic effects than other cate T m-l I" g A Dobutamine Dopamine B Dobutamine '1 T Dopamine

4 51 Salomon, Plachetka, and Copeland: Comparison of Dopamine and Dobutamine n E e E J T Dobutamine Dopamine Fig 2. Changes in stroke volume index with different doses of dobutamine and dopamine. A B 20 22$ T Dobutamine Dopamine w Dobutamine Dopamine Fig 3. Changes in (A) pulmonary capillary wedge pressure (PCWP) and (B) peripheral vascular resistance (PVR) with differing doses of dobutamine and dopamine. (RU = resistance units; MAP = mean arterial pressure; CI = cardiac index.) cholamines, but each has unique effects on the peripheral vasculature. At doses of less than 5.0 pglkglmin, dopamine causes vasodilation of renal, mesenteric, and splanchnic vascular beds, all of which contain dopaminergic receptors. Cardiac output may also increase at these low doses, although usually doses greater than 5.0 pglkglmin are required for this effect. Dopamine has minimal effects on P,-adrenergic receptors in the peripheral circulation. However, significant alpha-receptor stimulation, which causes vasoconstriction, usually occurs when doses exceed 10 pglkglmin [7, 81. There is evidence in the English-language literature that dopamine may also increase pulmonary capillary wedge pressure at these high doses 19-12]. Dobutamine, a synthetic catecholamine, was designed specifically to be a potent inotropic agent with little effect on either heart rate or the peripheral vasculature. Its inotropic potency is almost equal to that of isoproterenol and is due to direct stimulation of myocardial beta receptors [13]. Increases in cardiac output are usually achieved without significant increases in heart rate until the dose exceeds 8 pglkglmin [8, Dobutamine s inotropic effects, however, may be apparent at doses as low as 2 to 3 pgl kglmin. Unlike dopamine, increases in leftsided filling pressures are rarely seen [17]. The peripheral vascular effects of dobutamine are also somewhat different from those of dopamine [12, 181. At doses of less than 7.5 pglkglmin, there is a slight stimulation of alpha receptors. At doses of more than 7.5 pglkglmin, its predominant vascular effect is vasodilation mediated by stimulation of p,-adrenergic receptors. Blood pressure changes are usually minor with dobutamine and, as is also true with dopamine, reflect the increase in cardiac output as well as the changes in systemic vascular resistance [12, 181. Therefore, in normovolemic patients, as the dosage of dobutamine is increased, blood pressure remains unchanged or is raised only slightly because increases in cardiac output are accompanied by a fall in systemic vascular resistance [19]. Under similar conditions, dopamine would be expected to raise blood pressure, since systemic vascular resistance increases with increasing doses. It might be reasoned that the presence of clinically significant beta-adrenergic blockade in these patients modified the physiological effects of the two drugs tested. However, this study was designed to examine both the hemodynamic effects of each drug in the presence of beta blockade as well as the phar-

5 52 The Annals of Thoracic Surgery Vol 33 No 1 January 1982 macological efficacy under existing clinical situations. Although no control group in the absence of beta-adrenergic blockade was available, the results are not discordant with those that might be predicted for patients without beta blockade. Indeed, the degree of clinical beta blockade is extremely difficult to ascertain. The patient group, however, represents a standard clinical situation of patients undergoing coronary artery bypass operation on therapeutic doses of propranolol [4-61. Direct comparison of these results with previous studies in postoperative cardiac surgical patients is difficult because of variations in experimental protocols. There are no previous data on the use of the inotropic agents in patients with therapeutic beta-adrenergic blockade. Steen and co-workers [3] compared the hemodynamic effects of dobutamine and dopamine immediately following discontinuation of cardiopulmonary bypass in a mixed population of patients (valve replacement, coronary artery bypass grafting, or both). They demonstrated increases in cardiac index for patients receiving dobutamine that were similar to those observed in the present study. However, they noted a much greater increase in cardiac index with dopamine than we found. Possibly, the effect of dopamine on cardiac output is more significantly attenuated in the presence of beta-adrenergic blockade than is that of dobutamine. However, our study confirms the general trend for patients receiving dobutamine noted by previous workers; i.e., an incremental rise in cardiac index with minimal increases or even decreases in peripheral vascular resistance and filling pressures [2, 33. Dobutamine has been introduced as an agent specifically applicable to clinical situations of low cardiac output and adequate or increased left-sided filling pressures. Our results indicate that dobutamine may be preferable to dopamine for use after coronary artery bypass surgery, since it produces consistent doserelated increases in stroke volume index without concomitant increases in heart rate, pulmonary capillary wedge pressure, or peripheral vascular resistance. Unnecessary rises in myocardial oxygen consumption, which would i2 ii i4 $5 is PCWP (mm Hg) Fig 4. Modified left ventricular function curves for each drug plotting pulmonary capillary wedge pressure (PCWP) and stroke volume index. (DB = dobutamine; DP = dopamine.) otherwise be associated with both chronotropic stimulation and increased afterload, are thus minimized. Dopamine, on the other hand, increased cardiac index less reliably at high doses, but also augmented wedge pressure, mean arterial pressure, and peripheral vascular resistance. A summary of the hemodynamic effects of dobutamine and dopamine in patients with beta-adrenergic blockade follows Dobutamine acts as a true inotropic agent providing incremental rises in cardiac index primarily by augmenting stroke volume index. In the dose range tested, no significant pulmonary or peripheral vascular effects were noted. Dopamine showed less of an incremental effect on cardiac index and no significant change in stroke volume index, and was associated with increases in pulmonary capillary wedge pressure and calculated peripheral vascular resistance. Frank-Starling left ventricular function curves were constructed for both drugs (Fig 4) by plotting pulmonary capillary wedge pressure and stroke volume index for the doses tested. This allows a graphic comparison of the inotropic effects of each drug and demonstrates the capacity of dobutamine to significantly increase stroke volume index with minimal elevations in pulmonary capillary wedge pressure.

6 53 Salomon, Plachetka, and Copeland: Comparison of Dopamine and Dobutamine We wish to thank Marianne Sherman, R.N., for assistance in gathering data during this study. References Lewis GRJ, Poole Wilson PA, Angerpointer TA, et al: Measurement of the circulatory effects of dobutamine, a new inotropic agent, in patients following cardiac surgery. Am Heart J 95:301, 1978 Sakamoto T, Yamada T: Hemodynamic effects of dobutamine in patients following open heart surgery. Circulation 55:525, 1977 Steen PA, Tinker JH, Pluth JR, et al: Efficacy of dopamine, dobutamine, and epinephrine during emergence from cardiopulmonary bypass in man. Circulation 57:378, 1978 Jones EL, Kaplan JA, Dorney ER, et al: Propranolol therapy in patients undergoing myocardial revascularization. Am J Cardiol38:696, 1976 Slogoff S, Keats AS, Ott E: Preoperative propranolol therapy and aortocoronary bypass operation. JAMA 240:1487, 1978 Wechsler AS: Assessment of prospectively randomized patients receiving propranolol therapy before coronary bypass operation. Ann Thorac Surg 30:128, 1980 Goldberg LI: Dopamine: clinical uses of an endogenous catecholamine. N Engl J Med 291:707, 1974 Andy JJ, Curry CL, Ali N: Cardiovascular effects of dobutamine in severe congestive heart failure. Am Heart J 94:175, 1977 Hess W, Klein W, Mueller Busch C, et al: Hemodynamic effects of dopamine and dopamine combined with nitroglycerine in patients subjected to coronary artery bypass surgery. Br J Anaesth 51:1063, 1979 Holloway EL, Polumbo RA, Harrison DC: Acute circulatory effects of dopamine in patients with pulmonary hypertension. Br Heart J 37:482, 1975 Leier CV, Heban PT, Huss P, et al: Comparative systemic and regional hemodynamic effects of dopamine and dobutamine in patients with cardiomyopathic heart failure. Circulation 58:466, 1978 Loeb HS, Bredakis J, Gunnar RM: Superiority of dobutamine over dopamine for augmentation of cardiac output in patients with chronic low output failure. Circulation 55:375, 1977 Tuttle RR, Mills J: Dobutamine: development of a new catecholamine to selectively increase cardiac contractility. Circ Res 36:185, 1975 Akthar N, Mikulic E, Cohn JN: Hemodynamic effect of dobutamine in patients with severe heart failure. Am J Cardiol 36:202, 1975 Loeb HS, Mushtaq K, Klodnylky ML: Hemo- dynamic effects of dobutamine in man. Circ Shock 2:29, Stoner JD, Bolen JL, Harrison DC: Comparison of dobutamine and dopamine in treatment of severe heart failure. Br Heart J 39:536, Goldberg LI: Cardiovascular and renal actions of dopamine: potential clinical applications. Pharmacol Rev 24:1, Robie NW, Goldberg LI: Comparative systemic and regional hemodynamic effects of dopamine and dobutamine. Am Heart J 90:340, Leier CV, Webel J, Bush CA: The cardiovascular effects of the continuous infusion of dobutamine in patients with severe cardiac failure. Circulation 56:468, 1977 Discussion DR. WILLARD M. DAGGETT (Boston, MA): I am pleased to have the opportunity to discuss this interesting study on the hemodynamic effects of these two important agents for cardiac support. Our own studies on dobutamine have produced results similar to those reported by Dr. Salomon and his co-workers. Of particular interest, I think, is the observation that dopamine and dobutamine produced comparable effects on heart rate, cardiac output, blood pressure, filling pressures, and vascular resistance up to a dose of 7.5 pglkglmin, which is a delivered dose of 350 pglmin for a 50 kg patient. It is also clear from their data that at the highest doses, a greater cardiac effect was evident for dobutamine. However, I question how useful these higher doses may be with the attendant increments in myocardial oxygen consumption that occur, even when heart rate is not increased. In the patient who shows a requirement for increasingly high doses of catecholamines, we have been inclined to turn to mechanical support and thus minimize energy utilization. It would appear that the divergent effects of the two agents at the highest doses may be as much a consequence of alpha-receptor stimulation by dopamine as a greater inotropic effect of dobutamine. I think both of these agents are valuable for postoperative cardiac support, and each has some unique features that may make it preferable in a given situation. I have one small criticism to make. Only the effects of the drug on mean aortic pressure are reported. I think it important to report their effects on diastolic aortic pressure as well. I have one question for Dr. Salomon. The design of your study specified that the drugs be given to patients with normal hemodynamics. To what degree, then, can the data be extrapolated to patients in left ventricular failure or a low cardiac output state? DR. JAMES R. SKINNER (Charlottesville, VA): I have one question for Dr. Salomon. As I interpret his data,

7 54 The Annals of Thoracic Surgery Vol 33 No 1 January 1982 if the control level of either drug is increased to 7.5 pg, there appears to be no significance in the effects produced, and so the only difference is found when the dose is increased from 5 to 7.5 pg. Conversely, if low doses of these particular drugs are being used, might not dopamine be the better drug to employ when going from 0 to 5 pg? DR. SALOMON: I thank Dr. Daggett for critically evaluating the manuscript. Clearly, each drug has its own unique effects, and we as surgeons involved with the everyday postoperative care of critically ill patients need to be cognizant of the ways to use either drug. If we want to stimulate the urine output, for example, the dopaminergic effects of dopamine are very useful. In fact, we occasionally have patients on a regimen of both dobutamine and dopamine, if necessary. For example, patients may be on a regimen of up to 5 pglkglmin of dopamine for its renal effects and dobutamine or another drug for its inotropic effects. I am glad Dr. Daggett brought up the question of study design. The study was performed in this way because of the necessary constraints of a clinical prospective study. In fact, it might have been more useful in a broad sense to do this study in patients undergoing valve replacement or combined procedures. But I thought that in order to be able to manipulate the drug dosages freely, I wanted to use only patients who were not dependent on the drug; and, therefore, it could be changed with some degree of safety. With regard to the comment concerning which drug to use, it is just a question of using each drug in its own unique way. If the filling pressures are elevated or even normal, I think dobytamine is the drug to use. However, if the aim is to raise the pressure in a hypovolemic patient, dobutamine would not be the drug to use. It is not a vasopressor. In fact, as shown in the data, as the dosage of dobutamine is increased up to 10 pglkg in a hypovolemic patient, the patient would probably become more hypotensive secondary to peripheral vasodilatation.