The Hemodwamic Response to Dopamine. Artery Bypass (Fontan Procedure) and Nitroprkside Follubing Right ktrium-pulmonary

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1 The Hemodwamic Response to Dopamine and Nitroprkside Follubing Right ktrium-pulmonary Artery Bypass (Fontan Procedure) Donald B. Williams, M.D., Paul D. Kiernan, M.D., Hartzell V. Schaff, M.D., H. Michael Marsh, M.B., and Gordon K. Danielson, M.D. ABSTRACT Cardiac output is critically dependent upon pulmonary vascular resistance after right atrium-pulmonary artery bypass (Fontan procedure), since there is no pulmonary ventricle in the circulation. Inotropic agents, including dopamine, may increase pulmonary vascular resistance and, therefore, might have an adverse effect on cardiac output. The present study determined the hemodynamic responses to dopamine and nitroprusside of 9 patients following right atrium-pulmonary artery bypass. Particular attention was given to effects on cardiac output (CI), pulmonary vascular resistance, and right atrial pressure (RAP). Baseline hemodynamic data were measured without drugs, with dopamine at 7.5 pglkglmin, with sodium nitroprusside up to 5.0 pglkglmin, and with a combination of dopamine, 7.5 pgkglmin, and sodium nitroprusside, 1.0 pglkglmin. Right and left atrial pressures (LAP), mean arterial blood pressure (el, heart rate (HR), and CI were measured. Stroke volume index and pulmonary arteriolar resistance index were calculated. The increase in CI from baseline (1.98 f 0.86 liters per minute) was significant for infusions of dopamine (2.75 f 1.05,~ < 0.001), sodium nitroprusside (2.57 f 0.78, p < 0.001), and both drugs (2.74 f 0.84, p < 0.001). The increased CI was achieved primarily by a significant increase in HR with dopamine and by an increase in stroke volume index with sodium nitroprusside. With a similar increment in CI, the RAP was significantly decreased from baseline (21 k 4 tom) with sodium nitroprusside (15 f 3, p < 0.001) but was unchanged with dopamine. Pulmonary arteriolar resistance index From the Mayo Clinic and Mayo Foundation, Rochester, MN. Presented at the Eighteenth Annual Meeting of The Society of Thoracic Surgeons, New Orleans, LA, Jan 11-13, Address reprint requests to Dr. Danielson, Mayo Clinic, Rochester, MN decreased significantly from baseline (375 f 230 dynes sec cm-s/mp) with sodium nitroprusside (169 f 132, p < 0.001), and, interestingly, with dopamine as well (273 f 165, p < 0.05). Both dopamine and sodium nitroprusside in these dosages have favorable effects on CI and pulmonary arteriolar resistance index in patients after right atrium-pulmonary artery bypass. Whenever feasible, sodium nitroprusside is preferred for increasing CI after such a bypass procedure, since lower RAP decreases the severity of fluid retention, ascites, and chest tube drainage. Dopamine (3,4-dihydroxyphenethylamine) has proved useful for augmenting myocardial performance in both children and adults after cardiac operation [l-41. It is often the inotropic agent of choice because it has less tendency to produce an unfavorable chronotropic effect than such agents as isoproterenol[5-71, and because it has the unique ability among sympathomimetic amines to selectively increase renal blood flow [8]. Dopamine also appears to have less peripheral vasoconstrictive effect than either epinephrine or norepinephrine [5, 61. Sodium nitroprusside, a potent vasodilator, has been shown to improve cardiac performance by decreasing left ventricular afterload in both children and adults after cardiac operation [2-41. Vasodilation with sodium nitroprusside may be used to treat low cardiac output with increased systemic vascular resistance, and restoration of preload by expansion of blood volume has been shown to further improve cardiac function [41. In 1971, Fontan and Baudet 191 reported successful right atrium-pulmonary artery bypass for the "correction" of tricuspid atresia. Since then, right atrium-pulmonary artery bypass has gained increasing acceptance in the surgical treatment of that anomaly, as well as in the treatment of certain types of univentricular by The Society of Thoracic Surgeons

2 52 The Annals of Thoracic Surgery Vol34 No 1 July 1982 heart and other complex cardiac anomalies [lo] involving an absent or hypoplastic pulmonary ventricle. This procedure results in physiological correction of the congenital defect by directing all desaturated systemic venous blood to the lungs and all oxygenated pulmonary venous blood to the systemic arterial circulation. Cardiac output is critically dependent on pulmonary vascular resistance in patients who have undergone right atrium-pulmonary artery bypass, because of the absence of a pulmonary ventricle in the circulation. Although the hemodynamic effects of dopamine and sodium nitroprusside have been studied in children and adults after cardiac operation [l-41, the precise response to their infusion in patients after right atrium-pulmonary artery bypass has not been reported. In order to clarify the use of these agents in treating low cardiac output following such a bypass procedure, the hemodynamic responses to dopamine and sodium nitroprusside were studied in each patient; particular attention was paid to effects on cardiac output, pulmonary vascular resistance, and right atrial pressure (RAP). Materials and Methods Nine patients were studied from July, 1980, to January, 1981, one to three days after having undergone right atrium-pulmonary artery bypass. This procedure, in our institution, essentially entails creating a wide conduit between the right atrium and either the rudimentary right ventricle (outlet chamber) or pulmonary artery, usually using a flap of right atrial appendage as the floor of the conduit and autologous pericardium as the roof [lo]. There were 4 male and 5 female patients with a mean age of 13.9 years (range, 8 to 23 years). Four patients had univentricular heart, 4 had tricuspid atresia, and 1 had double-outlet right ventricle with dextrocardia. All 9 patients were shown to have normal-sized pulmonary arteries for their height and weight, as well as a normal pulmonary vascular resistance at preoperative cardiac catheterization. Four patients had a previous systemic-pulmonary artery shunt that was closed as part of the right atrium-pulmonary artery bypass repair. In 1 patient, operated on elsewhere, a stricture developed in a prosthetic Dacron conduit placed between the right atrium and the pulmonary artery. This conduit was removed and a right atrium-pulmonary artery bypass was performed as just described. All patients were studied in the early postoperative period after they had been weaned from inotropic and ventilator support. Baseline hemodynamic data were measured without drugs, including RAP and left atrial pressure (LAP), mean arterial blood pressure (E), heart rate (HR), and cardiac index (CI). Cardiac index was measured using standard dye dilution techniques with indocyanine green injected into a left atrial catheter and sampled from a peripheral arterial catheter, and was taken as the average of three consecutive measurements. Patients were transfused with a volume of blood equal to that removed during CI measurements to maintain a relatively stable circulating blood volume. Stroke volume index (SVI), systemic vascular resistance index (SVRI), and pulmonary arteriolar resistance index (SVRI), and pulmonary arteriolar resistance index (PARI) were calculated according to the following formulas: SVI (ml/beatlm*) = (CIIHR) x 1,000 SVRI (dynes sec ~ m-~/m~) = [(m- RA)/CI] X 80 PARI (dynes sec ~m-~/m~) = [(RA - LA)/CI] X 80 After these baseline hemodynamic indices had been recorded, an infusion of dopamine was begun into a central venous catheter. The drug was increased to 7.5 pglkglmin as tolerated, and after 20 minutes, hemodynamic measurements were repeated. The dopamine infusion was discontinued, and an infusion of sodium nitroprusside begun at 1.0 pglkglmin and increased cautiously until the BP had fallen to approximately 70 torr or until a maximum of 5.0 pglkglmin had been reached. Hemodynamic data were again recorded after 20 minutes. The sodium nitroprusside infusion was decreased to 1.0 pglkglmin, and the dopamine infusion restarted at 7.5 pglkglmin. After 20 minutes, hemodynamic data were again recorded. Statistical analyses performed with Student s t test were used to assess differences in the same hemodynamic indices for infusions of

3 53 Williams et al: Hemodynamic Response to Dopamine and Nitroprusside Hemodynamic Indices for 9 Patients after Right Atrium-Pulmonary Artery Bypass Dopamine + Dopamine Nitroprusside Nitroprusside Hemodynamic Baseline (7.5 pglkgimin) (4.5 pglkglmin) ( pglkglmin) RAP (torr) 21 f 4 21 f 3 15 f 3' 19 f 3" LAP (torr) 12 f 5 10 f 5" 9 * 4" 10 * 5" MBP (torr) 89 f k f 12' 84 iz 13 HR (beatslmin) 91 f f 35" 95 f * 36" CI (Llminlm2) 1.98 f f 1.05' 2.57 f 0.78" 2.74 f 0.84' SVI (mllbeatlm*) 22 * 5 25 f f 9;' 25 f 10 SVRI dynes sec ~rn-~/rn* 3174 f f f 687" 2058 f 663" PARI dynes sec ~rn-~lrn~ 375 f k 165" 169 f 132" 279 f 163" "p < 0.05 versus baseline. hp < 0.01 versus baseline. "p < versus baseline. RAP = right atrial pressure; LAP = left atrial pressure; BP = mean blood pressure; HR = heart rate; CI = cardiac index; SVI = stroke volume index; SVRI = systemic vascular resistance index; PARI = pulmonary arteriolar resistance index. dopamine, sodium nitroprusside, and the combination of dopamine and nitroprusside compared with baseline data without drugs. Results The Table summarizes the mean hemodynamic indices for the 9 patients measured at baseline without drugs, with dopamine at 7.5 pglkgl min, with sodium nitroprusside up to 5.0 pgl kglmin, and with a combination of dopamine at 7.5 pglkglmin and sodium nitroprusside at 1.0 pglkglmin. The Figure demonstrates changes in the mean RAP, HR, CI, and pulmonary arteriolar resistance index during the study. All patients tolerated the dopamine infusion, although sinus tachycardia of 150, 157, and 165 beats per minute developed in 3 of them. No other arrhythmias were noted during drug infusions. A maximum dose of sodium nitroprusside of 5.0 pglkglmin was achieved in 5 patients, 3 patients tolerated a maximum of 4.0 pglkglmin, and 1 patient tolerated only 1.04 pglkglmin because of a fall in BP to 65 torr. The mean dose of sodium nitroprusside for the 9 patients was 4.6 pglkglmin. Seven patients were in normal sinus rhythm, 1 patient was atrially paced, and 1 had a stable nodal rhythm during the study period. The increase in, CI from baseline was significant for dopamine, sodium nitroprusside, and both drugs together. The HR was sig- nificantly increased from baseline for dopamine and both drugs, but was essentially unchanged during infusion of sodium nitroprusside. The stroke volume index increased significantly with sodium nitroprusside; the smaller increase with dopamine or both drugs was not statistically significant. With essentially similar increments in CI for dopamine and for sodium nitroprusside, the RAP was significantly decreased with the latter, but was unchanged with the former. The addition of a comparatively small dose of sodium nitroprusside to dopamine caused a significant decrease in RAP, although the change was less marked than with sodium nitroprusside alone. Left atrial pressure was significantly decreased for infusions of each drug alone, and both combined. Pulmonary arteriolar resistance index was significantly decreased for all three drug infusions, although the change in this index was more pronounced with sodium nitroprusside than for either dopamine or both drugs combined. Systemic vascular resistance index was significantly decreased with sodium nitroprusside and with this drug plus dopamine, while there was no significant change in this index with dopamine alone. Comment Although there are no data on the hemodynamic effects of either dopamine or sodium

4 54 The Annals of Thoracic Surgery Vol34 No 1 July 1982 RAP torr HR beats,rnin CI L rnin m2 PAR1 Dynes-sec-m2 crn5 j B D N D+N 160 ~ I 100 B D N D+N B D N D;N Right atrial pressure (RAP), heart rate (HR), cardiac index (CI), and pulmonary arteriolar resistance index (PARI) for 9 patients after right atrium-pulmonary arfey bypass. Mean data are shown at baseline with no drugs (B), with dopamine at 7.5 pglkglmin (D), with sodium nitroprusside up to 5.0 pglkglmin (N), and with a combination of dopamine at 7.5 pglkglmin and sodium nitroprusside at 1.0 pglkglmin (D + N). nitroprusside in patients after right atriumpulmonary artery bypass, there have been several studies related to the effects of these drugs in patients in shock or after cardiac operation. Stephenson and co-workers [21 studied 28 children early after open-heart operation with infusions of dopamine at 8 pglkgl min and found that CI and HR increased significantly with the infusion, while systemic vascular resistance index and pulmonary vascular resistance index did not change greatly. When patients with pulmonary hypertension were excluded, there was no significant dif- ference in response among subgroups of patients based on the type of disease treated surgically. Lang and associates [l] studied 5 infants less than 2 years of age after cardiac operation and found that CI, E, and HR increased significantly at doses of dopamine greater than 10 pglkglmin. However, there was no change noted in atrial pressure, pulmonary vascular resistance index, systemic vascular resistance index, or stroke volume index. Despite significant increases in HR associated with dopamine infusion reported in these studies, others have noted no such increase with infusions of dopamine up to 30 pglkglmin [ll Miller and co-workers [4] found a significant increase in CI in adult patients after cardiopulmonary bypass with low-dose dopamine (approximately 2.5 pglkglmin); this was associated with a decrease in systemic vascular resistance index but no change in LAP (preload). Our data suggest that early after right atrium-pulmonary artery bypass, both CI and HR will increase significantly without a change in RAP during infusion of dopamine. Since stroke volume index did not significantly increase with dopamine, the change in CI would seem to be mediated predominantly by an increase in HR. The fact that RAP did not change with infusion of dopamine is not surprising, since dopamine does not predictably reduce right-sided filling pressures, due to its variable vasoconstrictive effects on the venous capacitance bed [141. Although there is some evidence that dopamine increases pulmonary artery pressure [15-181, our data suggest that calculated pulmonary arteriolar resistance index will fall significantly with infusion of dopamine at 7.5 pglkglmin after right atrium-pulmonary artery bypass. The mechanism by which the pulmonary vascular resistance is lowered with dopamine in patients after this procedure is unclear. It cannot be determined from our data whether the tone of the pulmonary vasculature is altered directly or reflexly by dopamine or whether the increase in cardiac output causes a recruitment of additional pulmonary vascular beds to accommodate the increased flow. Previous work has shown that in patients without

5 55 Williams et al: Hemodynamic Response to Dopamine and Nitroprusside pulmonary hypertension, dopamine infusion at 5 to 10 pglkglmin will not alter pulmonary resistance substantially [2, 193. However, in children with pulmonary hypertension, dopamine in this dose range has caused an increase in pulmonary vascular resistance [2]. Systemic vascular resistance has been shown by some to decrease [3, 18-20] and by others to be unchanged [l, 21 during infusion of dopamine up to as much as 25 pglkglmin. Systemic vascular resistance index decreased during infusion of dopamine in our patients after right atrium-pulmonary artery bypass, but the drop was not statistically significant. The patients studied in this report represent a carefully selected group with regard to pulmonary vascular resistance. Relatively stringent criteria for operability are necessary in considering patients for right atrium-pulmonary artery bypass; these criteria include normal pulmonary vascular resistance and angiographically normal-sized pulmonary arteries according to height and weight. Hence, it is difficult to compare these data from patients after right atrium-pulmonary artery bypass with other data in the literature derived from more heterogeneous patient groups, especially those with elevated pulmonary vascular resistances. Infusion of sodium nitroprusside resulted in a significant increase in CI and a significant decrease in RAP, LAP, BP, pulmonary arteriolar resistance index, and systemic vascular resistance index in our patients. There was no change in HR during infusion of sodium nitroprusside; hence the increase in CI primarily reflected a significant improvement in stroke volume index. Stephenson and co-workers [2] found no significant change in CI with greater than 3 pglkglmin of sodium nitroprusside in children with normal baseline hemodynamics, although pulmonary and systemic vascular resistances decreased. The greatest drop in pulmonary vascular resistance was seen in patients who had baseline elevations in this resistance. The authors thought that the lack of improvement with sodium nitroprusside could be related to the fact that the patients were not volume loaded and did not have severely depressed cardiac function. In contrast, Appelbaum and co-workers [31 studied 16 infants less than 18 months of age with depressed cardiac function early after operation and noted a significant improvement in CI with infusion of sodium nitroprusside. Eight of our 9 patients studied after bypass operation had severely depressed cardiac function, with 6 having a CI of less than 2.0 L/minlm2. In all 8 of these patients, CI increased with infusion of sodium nitroprusside. One patient in our series had had a previous right atrium-pulmonary artery bypass procedure with a Dacron conduit and was reoperated on for conduit stenosis. His CI early postoperatively was normal with a very low pulmonary arteriolar resistance index. Infusion of sodium nitroprusside (up to 5 pglkglmin) failed to change the CI, although the RAP decreased from 21 to 17 torr. The data in this report suggest that sodium nitroprusside will considerably improve hemodynamics in patients early after right atrium-pulmonary artery bypass; this effect may be more dramatic in those patients with depressed cardiac function than in those with more normal function. Restoration of intravascular volume during infusion of sodium nitroprusside has been shown to result in further increments in cardiac output [3,41. Although the patients after bypass had improved cardiac function with significantly lower atrial pressures during infusion of sodium nitroprusside, we did not evaluate restoration of preload to its baseline levels during this study. We prefer sodium nitroprusside after right atrium-pulmonary artery bypass, since it lowers RAP and thereby decreases the severity of fluid retention, hepatic congestion, ascites, and chest tube drainage. Preload restoration to baseline RAP during infusion of sodium nitroprusside may further improve CI. In those individuals with severely depressed cardiac function, dopamine infusion is added to nitroprusside and preload restoration. It has become our policy to maintain patients after right artrium-pulmonary artery bypass on sodium nitroprusside for 24 to 48 hours to maximize cardiac function at lower RAP, and then to convert to oral vasodilating agents such as prazosin or hydralazine. It has been our observation that aggressive use of vasodilators in both the early postoperative period and the long term may decrease the sever-

6 56 The Annals of Thoracic Surgery Vol34 No 1 July 1982 ity of right heart failure and other problems associated with high RAP. We acknowledge with appreciation the contribution of Mr. Ken Offord, Division of Medical Research Statistics, Mayo Clinic, in performing the statistical analyses and Ms. Peggy Aspen in preparing the manuscript. References 1. Lang P, Williams RG, Norwood WI, Castaneda AR: The hemodynamic effects of dopamine in infants after corrective cardiac surgery. J Pediatr 96:630, Stephenson LW, Edmunds LH Jr, Raphaely R, et al: Effects of nitroprusside and dopamine on pulmonary arterial vasculature in children after cardiac surgery. Circulation 60: Suppl2:104, Applebaum A, Blackstone EH, Kouchoukos NT, Kirklin JW: Afterload reduction and cardiac output in infants early after intracardiac surgery. Am J Cardiol39:445, Miller DC, Stinson EB, Oyer PE, et al: Postoperative enhancement of left ventricular performance by combined inotropic-vasodilator therapy with preload control. Surgery 88:108, Goldberg LI: Dopamine: clinical uses of an endogenous catecholamine. N Engl J Med 291:707, Goldberg LI: Cardiovascular and renal actions of dopamine: potential clinical applications. Pharmacol Rev 24:1, Halloway EL, Schultz CS, Stinson EB, Harrison DC: Comparison of circulatory effects of dopamine and isoproterenol immediately following cardiac surgery. Circulation 48:Suppl 4:177, Dopamine for treatment of shock. Med Lett Drugs Ther 17:13, Fontan F, Baudet E: Surgical repair of tricuspid atresia. Thorax 26:240, Gale AW, Danielson GK, McGoon DC, Mair DD: Modified Fontan operation for univentricular heart and complicated congenital lesions. J Thorac Cardiovasc Surg 78:831, Crexells C, Bourassa MG, Buron P: Effects of dopamine on myocardial metabolism in patients with ischemic heart disease. Cardiovasc Res 7:438, Holloway EL, Stinson EB, Derby GC, Harrison DC: Action of drugs in patients early after cardiac surgery: I. Comparison of isoproterenol and dopamine. Am J Cardiol 35:656, Holzer J, Karliner JS, O Rourke RA, et al: Effectiveness of dopamine in patients with cardiogenic shock. Am J Cardiol 32:79, Mark AL, Iizuka T, Wendling MG, Eckstein JW: Responses of saphenous and mesenteric veins to administration of dopamine. J Clin Invest 49:259, Harrison DC, Puages S, Robison S, Wintroub B: The pulmonary and systemic circulatory response to dopamine infusion. Br J Pharmacol 37:618, Holloway EL, Polumbo RA, Harrison DC: Acute circulatory effects of dopamine in patients with pulmonary hypertension. Br Heart J 37:482, Mentzer RM Jr, Alegre CA, Nolan SP: The effects of dopamine and isoproterenol on the pulmonary circulation. J Thorac Cardiovasc Surg 71:807, Loeb HS, Bredakis J, Gunnar RM: Superiority of dobutamine over dopamine for augmentation of cardiac output in patients with chronic low output cardiac failure. Circulation 55:375, Driscoll DJ, Gillette PC, Duff DF, McNamara DG: The hemodynamic effect of dopamine in children. J Thorac Cardiovasc Surg 78:765, Truccone N, Farouki Z, Green E, et al: Cardiocirculatory effects of dopamine in infants and children with low cardiac output after open-heart surgery. Presented at the Annual Meeting of the American Academy of Pediatrics, New York, NY, Nov, 1977 Discussion DR. WOLFGANG BIRCKS (Dusseldorf, West Germany): I have one question for Dr. Williams: do you believe nitroprusside works directly on the resistance of the pulmonary artery tree, or does it only act to decrease the left atrial pressure? DR. WATTS R. WEBB (New Orleans, LA): Our preference generally has been to administer dopamine and dobutamine at a level that would not increase the heart rate quite this much, and perhaps add more nitroglycerin or nitroprusside. I wonder if the authors considered using additional nitroprusside to get a result more comparable to that achieved when the maximum nitroprusside dose of 5 pg was used. DR. ROBERT M. SADE (Charleston, SC): We routinely use both dopamine and nitroprusside in our patients who have right heart bypass, and titrate both drugs to the optimal level. It seems to me that this study was flawed by reduction of the nitroprusside dosage from 5 to 1 pg/kg/min at just the crucial moment, when the authors could have demonstrated a strong additive effect of the two drugs used together. I would like to ask why the nitroprusside dosage was dropped substantially at that point. DR. WILLIAMS: I thank the discussants for their comments. With regard to the first question, I do not have an answer to how nitroprusside works. I would

7 57 Williams et al: Hemodynamic Response to Dopamine and Nitroprusside like to think that it probably has a combination effect of acting on the pulmonary circulation and decreasing the left atrial pressure. With regard to Dr. Webb s comment, I think he is correct when he says that perhaps more nitroprusside and less dopamine is a more efficacious way to treat this patient population. The present study was born out of our inability to clearly define the effects of these drugs on this very select group of patients. Dr. Sade is absolutely correct in pointing out that, in retrospect, obtaining data at a dopamine dosage of 7.5 pglkglmin and the maximum nitroprusside dose would have been desirable. What we did was to follow a planned protocol to see if we could alter the effect of dopamine with a very small dose of nitroprusside. Dr. Sade s comment about titration of these drugs is probably the key issue; that is, one uses nitroprusside and dopamine in a combination that will work effectively in a given clinical setting.