Combined Therapy With Digoxin and Nitroprusside in Heart Failure Complicating Acute Myocardial Infarction

DANIEL S. RAABE, Jr., MD, FACC Burlington, Vermont

From the Department of Medicine, Division of Cardiology, University of Vermont College of Medicine, Burlington, Vermont. Manuscript received October 2, 1978; revised manuscript received December 1, 1978, accepted December 7, 1978. Address for reprints: Daniel S. Raabe Jr., MD, Cardiology Unit, kkal Center Hospital of Vermont, Mary Fletcher Unit, Burlington, Vermont 05401.

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The hemodynamic effects of digoxin plus nitroprusside were compared with those of nitroprusside alone in 11 patients with congestive heart failure complicating acute myocardiai infarction. Hemodynamic measurements were made using a Swan-Ganx thermodiiution catheter and a bedside thermodiiution cardiac output computer. Patients received increasing doses of nitroprusside until mean arterial pressure decreased to 70 mm Hg or pulmonary arterial wedge pressure decreased to 16 mm Hg. The infusion rate of nitroprusside was then held constant for 120 minutes. After 30 minutes of constant nitroprusside infusion, 0.5 mg of digoxin was given intravenously. Hemodynamic measurements were obtained before treatment with nitroprusside and immediately before and 30, 60 and 90 minutes after the administration of digoxin. Nitroprusside produced a significant decrease in pulmonary arterial wedge pressure (24 to 18 mm Hg), mean arterial pressure (92 to 85 mm Hg and systemic vascular resistance (1,816 to 1,480 dynes set cmB5) and a significant increase in cardiac index (2.19 to 2.5 1 IitersImin per m*). Ninety minutes after the administration of digoxin, cardiac index was further increased (2.51 to 28.2 iiters/min per m*, P = 0.03) and systemic vascular resistance was lower (1,480 to 1,320 dynes set cms5, P = 0.03). Pulmonary arterial wedge pressure was not further decreased by the addition of digoxin. Thus, the addition of digoxin further increases cardiac output in patients with congestive heart failure complicating myocardiai infarction who are receiving nitroprusside but does not produce any further decrease in pulmonary arterial wedge pressure.

The use of vasodilating agents in the treatment of congestive heart failure complicating acute myocardial infarction results in improved left ventricular function1-5 and increased survival.4,5 The vasodilator used most frequently in this situation is nitroprusside,6 an agent that produces balanced dilatation in both the venous and arteriolar beds with a resultant decrease in pulmonary capillary wedge pressure and an increase in cardiac output.7 However, in some patients, the level of cardiac output may remain low or pulmonary capillary wedge pressure high despite maximal vasodilator treatment. Because nitroprusside has no inotropic effect,s the addition of a positive inotropic agent should result in a further improvement in cardiac function in these patients. Digitalis is the inotropic agent most commonly used to treat chronic congestive heart failure, but its role in the treatment of congestive heart failure complicating acute myocardial infarction remains controversial.g However, the weight of the available evidence suggests that digitalis improves ventricular performance in patients with acute myocardial infarction, particularly if sensitive measures of left ventricular function are used to detect this change.lO The present study was undertaken to determine whether the combination of a vasodilator (nitroprusside) and a positive inotropic agent (digoxin) would improve cardiac performance more than treatment with

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Results

a vasodilator alone in platients with congestive heart failure complicating acute myocardial infarction.

The average dose of nitroprusside was 120 pglmin (range 50 to 280), and the average time from the onset of infarction to initiation of therapy was 9 hours (range 3 to 29). No.patient had ventricular arrhythmias that required treatment after digoxin therapy. Hemodynamic measurements (Table I): Before treatment, all patients had an elevated pulmonary capillary wedge pressure (mean 24 f 3 mm Hg, range 21 to 30). The cardiac index was less than 2.5 liters/min per m2 in 10 patients and in the 11th patient, it was in the low normal range (2.61 liters/min per m2). Systemic vascular resistance was elevated in all patients (mean 1,860, dyne-cm/sec5, range 1,520 to 2,320 dynes set cmM5). At maximal nitroprusside infusion, there was a significant decrease in mean arterial pressure, pulmonary capillary wedge pressure and systemic vascular resistance and a significant increase in cardiac index and stroke index. Stroke work index increased from 23 to 25 g-m/m2, but the change was not significant (P = 0.08). Heart rate did not change. After digoxin administration, there was no further change in heart rate, mean arterial pressure, or pulmonary capillary wedge pressure. Cardiac index continued to rise, and 90 minutes after digoxin administration it was greater than with nitroprusside alone (2.51 versus 2.82 liters/min per m2) (P = 0.03). Although nitroprusside alone did not result in a significant increase in stroke work index, 30 and 90 minutes after digoxin this variable was increased over control values (23 versus 27 g-m/m2) (I’ = 0.05) but was not different from the stroke work index after nitroprusside alone (25 versus 27 g-m/m2) (P = 0.1). Systemic vascular resistance, which decreased with nitroprusside therapy, continued to decline after digoxin administration, and 90 minutes after digoxin it was lower than with nitroprusside alone (1,480 versus 1,320 dynes set crne5) (I’ = 0.03). Analysis of hemodynamic changes (Fig. 1): Nitroprusside administration produced a decrease in pulmonary capillary wedge pressure and systemic vascular resistance in all patients. Ninety minutes after digoxin administration, pulmonary capillary wedge

Methods Patients: The study population

consisted of 11 patients with acute myocardial infarction, In all patients, myocardial infarction was documented by a history consistent with infarction, the development of pathologic Q waves in the electrocardiogram and an increase in serum creatine kinase with the appearance of the myocardial fraction of creatine kinase (CK MB) on electrophoresis. There were eight men and three women with a mean age of 57 years (range 36 to 68 years). The location of the infarction was anterior in eight patients and inferior in three. None of t.he 11 patients had ever taken digitalis or a vasodilator before this study. All were in Killip class II or III at the time of study. Continuous electrocardiographic monitoring in the coronary care unit was carried out on all patients during the period of this study.

Protocol: After informed consent had been obtained, a Swan-Ganz triple lumen thermodilution catheter was positioned in the pulmonary artery. Cardiac output was determined using 10 cc of iced saline solution and an Edwards Laboratories cardiac output computer, model 9510A. Each cardiac output was determined in triplicate. Arterial pressure was obtained directly via a radial artery cannula. All pressures were measured with Hew:lett Packard model 1290C pressure transducers and model 78205B pressure modules. Mean pressures were obtained hy electronic damping. After baseline hemodynamic measurements were obtained, an infusion of nitroprusside was begun at 50 pg/min. The infusion rate was increased by 17 pg/min every 10 minutes until the mean arterial pressure was less than 70 mm Hg or the pulmonary capillary wedge pressure decreased to 16 mm Hg. The infusion rate was then held constant for the remainder of the study. After the infusion rate had been stabilized for 30 minutes, hemodynamic measurements were repeated. Digoxin, 0.5 mg, was then given intravenously over 30 seconds and the hemodynamic measurements were repeated 30,60 and 90 minutes after administration of digoxin. No patient received any other hemodynamically active agent during this study. Only patients who completed the entire study within 48 hours of the onset of infarction are included in this report. Hemodynamic variab’les were calculated using standard formulas. Statistical analysis was performed using a paired t test for small samples.

TABLE I Hemodynamic Data MAP

HR

Cl

PCWP

C

94 f 20

92f

24 f 3

N D30 D60 D90

95 f 94f 93f 98f

85 86 84 83

:;$$ 17 f 5+ 17 f 3+

17 18 16 19

11 f 11’ f 11’ f 12’ f 13’

2.19 2.51 2.63 2.60 2.82

f f f f f

SWI 0.33 0.57’ 0.55t 0.57+ 0.72+§

23 f 25 f 27 f 26 f 2759’

SVR i 7 8‘ 6

1816 1480 1432 1424 1320

f f f f f

264 376+ 296+ 368+ 320’5

Probability (P) < 0.05 versus control. + P < 0.001 versus control. s P < 0.01 versus control. 5 P < 0.05 versus nitroprusside. Values are mean f 1 standard deviation. C = control data; Cl = cardiac index (literslmin per m*); D30, D60 and D90 = data 30.60 and 90 minutes, respectively, after 0.5 mg of digoxin; HR = heart rate (beats/min): MAP = mean arterial pressure (mm Hg); N = data during constant nitroprusside infusion; PCWP = pulmonary capillary wedge pressure (mm Hg); SVR = systemic vascular resistance (dynes set cmd5); SWI = stroke work index (g-m/m2). l

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PCWP

CI

SVR

SW1 2CtQ.

!500-

IW-

m-

0

1 p 0.05); p = probability.

pressure decreased. These results are consistent with those of previous studies on the use of nitroprusside in congestive heart failure after acute myocardial infarction.1-5 Digitalis in congestive heart failure complicating acute myocardial infarction: Because nitroprusside has no intrinsic inotropic properties, the combination of nitroprusside and a positive inotropic agent might be expected to improve cardiac function more than either agent alone. In chronic congestive heart failure, the use of nitroprusside plus dopamine produces a larger increase in cardiac index than either agent individually.17J8 However, the usefulness of a positive inotropic agent, especially digitalis, in congestive heart failure complicating acute myocardial infarction remains controversialgJO Numerous experimenta11g~20 and clinica121-23 studies have failed to show any increase in cardiac output or reduction in pulmonary capillary wedge pressure after the administration of digitalis in the presence of acute myocardial infarction. In part, these results are explained by the fact that in some of these studies little clinical or hemodynamic evidence of congestive heart failure was present before digitalization.21,22 Because digitalis is known to have little or no effect on cardiac output or pulmonary capillary wedge pressure in the absence of congestive heart failure,24 these results are not surprising. In the absence of congestive heart failure, the direct peripheral vasoconstrictor effects of digitalis may predominate, and the subsequent increase in ventricular afterload may actually cause a decrease in cardiac output and an increase in pulmonary capillary wedge pressure.24J5 In patients with congestive heart failure complicating acute myocardial infarction, digitalis can produce an increase in cardiac index and a decrease in pulmonary capillary wedge pressure,25-28 although these beneficial effects may not occur in all patients with congestive heart failure.23 Rahimtoola et a1.28showed that even in the absence of an increase in cardiac index or a decrease in pulmonary arterial wedge pressure, digitalis improves left ventricular function in patients with congestive heart failure after acute myocardial infarction. In this study the first derivative of left ventricular pressure (dP/dt) was significantly increased and the ratio of preejection period to left ventricular ejection time (PEP/LVET) significantly decreased after the admin-

DIGOXIN AND NITROFWJSSIDE IN MYOCARDIAL INFARCTION--RAAgE

istration of ouabain to patients with acute myocardial infarction and congestive heart failure. Digoxin plus nitroprusside: Whatever the effects of digitalis alone in acute myocardial infarction, our study demonstrates that digoxin given to patients with heart failure who were already receiving nitroprusside produced a significant increase in cardiac index and stroke work index. This increase in cardiac index occurred whether or not the cardiac index had been normalized by nitroprusside therapy. Concomitant with this increase in cardiac index, systemic vascular resistance fell significantly from the level achieved with nitroprusside alone. Presumably, withdrawal of sympathetic tone occurred as cardiac output increased with a resultant decrease in systemic vascular resistance.24 Although it is unlikely that such changes in cardiac index and systemic vascular resistance were spontaneous and unrelated to the administration of digoxin, this possibility cannot be excluded. However, in our experience patients receiving nitroprusside tend to have a stable hemodynamic pattern as long as the rate of infusion of the drug is kept constant. Digitalis and cardiac output: The mechanism responsible for the increase in cardiac output after the administration of digitalis remains open to question. Maroko and Braunwald2g have shown that an area of infarction is surrounded by a “border zone” of ischemic tissue, which in turn is surrounded by normally perfused myocardium. In experimental infarction Banka et a1.30 concluded that digitalis preparations retain a positive inotropic effect on both the normal and border zones but have no effect on the central zone of infarction. In that study both the total tension developed and the rate of tension development in the normal and border zones were increased by the administration of digoxin. Previously, Sarnoff et a1.31demonstrated that digitalis increased myocardial contractility in the isolated heart preparation even when coronary flow was reduced to 30 percent of control values. Thus, the increase in cardiac output in our patients could be due to the positive inotropic effect of digitalis. However, another explanation is possible. When given to dogs with acute myocardial infarction and congestive heart failure, intravenous digitalis increased coronary collateral blood flow to ischemic zones.32 This increase in coronary flow was accompanied by a marked decrease in ischemic S-T segment elevation. Similar changes in coronary flow to ischemic zones and electrocardiographic signs of ischemit injury were demonstrated by Vatner et a1.33They also showed that these changes in coronary blood flow are accompanied by an improvement in overall left

ventricular function and in contraction characteristics of the ischemic zone. Finally, when given to patients with acute myocardial infarction and congestive heart failure, digitalis decreased final infarct size as measured by serum creatine kinase accumulation.34 These data suggest that digitalis may improve left ventricular function in acute myocardial infarction by decreasing myocardial ischemia with a resultant improvement in the contraction characteristics of the ischemic zone rather than by its positive inotropic effect. Digitalis and pulmonary capillary wedge pressure: Nitroprusside produced a significant decrease in pulmonary capillary wedge pressure from 24 to 17 mm Hg, but the addition of digoxin did not result in any further decrease in this pressure. The reasons for this failure of digoxin to decrease pulmonary capillary wedge pressure further are not clear. Both digitalis and nitroprusside decrease ventricular filling pressures by increasing venous capacitance and decreasing venous return to the heart. In the case of nitroprusside, this is a direct effect of the drug,8 whereas with digitalis, venous relaxation is due to a decrease in sympathetic tone consequent to an increase in cardiac output.24 The decrease in systemic vascular resistance in our patients after the administmtion of digoxin suggests that sympathetic withdrawal did occur. It may be that in the presence of the direct venous dilating effects of nitroprusside, a further decrease in venous tone could not occur despite decreased sympathetic stimulation and, therefore, pulmonary capillary wedge pressure did not decrease after treatment with digitalis. It is also possible that the change in cardiac volume produced by digoxin was too small to produce a decrease in left ventricular end-diastolic pressure because it is known that in the postinfarction state, ventricular compliance may be greatly altered.s5 Clinical implications: The combination of nitroprusside and digoxin produced a greater increase in cardiac index and stroke work index and a greater fall in systemic vascular resistance than were produced by nitroprusside alone when given to patients with congestive heart failure in the early stages of acute myocardial infarction. This further increase in cardiac index occurred whether or not cardiac index had been normalized by nitroprusside. Treatment with nitroprusside plus digoxin did not result in any greater decrease in pulmonary capillary wedge pressure than treatment with nitroprusside alone. Therefore, this combination of a positive inotropic agent and a vasodilator may be useful in the treatment of congestive heart failure complicating acute myocardial infarction.

References 1. Franclosa JA, Gulha NH, Lima8 CJ, Rodriguera E, Cohn JN: Improved ventricular function during nitroprusside infusion in acute myocardial infarction. Lancet 1:650-658, 1972 2. odd HK, Leinba& RC, &Mars CA: Use of sublingualnib-oglycerin in congestive failure following acute myocardial infarction. Circulation 48:839-845, 1972 3. Chattertee K, Parmley WW, Ganz W, Forrester J, Wallnsky P,

Crexells C, Swan HJC: Hemodynamic and metabolic responses to vasodilator therapy in acute myocardial infarction. Circulation 48:1183-1193,1973 4. Chaiterjee K, Swan HJC, Kaushlk VS, Jobin G, Magnusson P, Forrester J: Effects of vasodilator therapy for severe pump failure in acute myocardial infarction on short-term and late prognosis. Circulation 53:797-802. 1976

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DS: Predictions of survival in patients treated with nitroprusside for pump failure following acute myocardial infarction (abstr). Clin Res 26:605A. 1976 Cohn JN, Franclosa JA: Vasodilator therapy of cardiac failure. N Engl J Med 297:27-31,254-256, 1977 Mliler RR, Vlsmara LA, Williams 00, Amsterdam EA. Mason DT: Pharmacological mechanisms for left ventricular unloading in clinical congestive heart failure. Circ Res 39:127-133, 1976 Palmer RF, Lasseter KC: Sodium nitroprusside. N Engl J Med 292:294-296, 1975 Kariiner JS, Braunwaid E: Present status of digitalis treatment of acute myocardial infarction. Circulation 45691-902, 1972 Rahimtooia SH, Gunnar RY: Digitalis in acute myocardial infarction: help or hazard? Ann Intern Med 82(2):234-240, 1975 Braunwaid E: Determinants and assessment of cardiac function. N Engl J Med 296:66-89, 1977 Patterson SW, Starling EH: On the mechanical factors which determine the output of the ventricles. J Physiol 48357-379, 1914 Majid PA, Sharma B, Taylor SH: Phentolamine for vasodilator treatment of severe heart failure. Lancet 2:7 19-724, 197 1 Chatterjee K, Parmley WWr The role of vasodilator therapy in heart failure. Prog Cardiovasc Dis 19:301-325, 1977 Awan NA, Miller RR, Demarla AN, Maxwell KS, Neumann A, Mason DT: Efficacy of ambulatory systemic vasodilator therapy with oral prazosin in chronic refractory heart failure. Circulation 56~346-354, 1977 Yassie B, Chatterjee K, Werner J, Greenberg B, Hart R, Parmley WW: Hemodynamic advantage of combined administration of hydralazine orally and nitrates nonparentally in the vasodilator therapy of chronic heart failure. Am J Cardiol 40:794-801. 1977 Stempie DR, Kleiman JH, Harrison DC: Combined nitroprussidedopamine therapy in severe chronic congestive heart failure. Am J Cardiol 42:267-275. 1978 Miller RR, Awan NA, Joye JA, Maxwell KS, Demarla AN, Amsterdam EA, Mason Df: Combined dopamine and nitroprusside therapy in congestive heart failure. Circulation 55:861-884. 1977 Hood WB, McCarthy B, Lown B: Myocardial infarction following coronary ligation in dogs. Circ Res 21:191-199, 1967 Kumar R, Hood WB, Jolson J, Gllmour DP, Norman xi, Abefmann WH: Experimental myocardial infarction: efficacy and toxicity of digitalis in acute and healing phase in intact conscious dogs. J Clin Invest 49:358-363, 1970 Balcon R, Hoy J, Sowton E: Haemodynamic effects of rapid digitalization following acute myocardial infarction. Br Heart J 30: 373-376, 1968

5. Reebe

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6. 9. 10. 11. 12.

13. 14. 15.

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22. Hodges M, Frlesinger GC, R&Ins RCK, Dagenals GR: Effects of intravenously administered digoxin on mild left ventricular failure in acute myocardial infarction in man. Am J Cardiol29:749-756, 1972 23. Forrester J. Bezdek W, ChatterMe K, Levln P, Parmtey WW, Swan HJC: Hemodynamic effects of digitalis in acute myocardial infarction (abstr). Ann Intern Med 76:863-864, 1972 24. Mason DT, Braunwald E: Studies on digitalis. X. Effects of ouabain on forearm vascular resistance and venous tone in normal subjects and in patients in heart failure. J Clin Invest 43:532-543. 1964 25. Cohn JN, TrIstani FE, Khatri IM Cardiac and peripheral vascular effects of digitalis in cardiogenic shock. Am Heart J 78:318-330, 1969 26. Ratshin RA, Russell RO, Kaymacalan S, Rackley CE: The effects of digoxin on left ventricular performance in myocardial infarction and cardiogenic shock (abstr). Clin Res 19:335, 1971 27. Lipp H, Denes P, Gambetta M, Resnekov L: Hemodynamic response to acute intravenous digoxin in patients with recent myocardial infarction and coronary insufficiency with and without heart failure. Chest 63:862-867, 1972 28. Rahimtooia SH, Sinno MZ, Chuquimia R, Loeb HS, Rosen KM, Gunnar RM: Effects of ouabain on impaired left ventricular function in acute myocardial infarction. N Engl J Med 287:527-531, 1972 29. Maroko PR, Braunwaid E: Modification of myocardial infarction size after coronary occlusion. Ann Intern Med 79:720-733, 1973 30. Banka VS. Chadda KD, Bodenheimer MM, H&ant RH: Digitalis in experimental acute myocardial infarction. Am J Cardiol 35: 801-808, 1975 31. Samoff SJ, Giimore JP, Wallace AG, Sklnner NS Jr, Mitchell JH, Daggett WM: Effect of acetylstrophanthidin therapy on cardiac dynamics. oxygen consumption and efficiency in the isolated heart with and without hypoxia. Am J Med 37:3-13, 1964 32. Kirk ES, -Nelson OR, Sonnenbllck EH: Digitalis: mechanism of action in ischemic heart failure (abstr). Circulation 52:Suppl ll:ll-24, 1975 33. Vatner SF, Baig H, Menders WT, Murray PA: Effects of a cardiac glycoside in combination with propranolol on the ischemic heart of conscious dogs. Circulation 57:568-575, 1978 34. Pizrarelio A, Reduto L, Geiier K, Gulotta S, Morrlson J: Protection of the ischemic myocardium in man by digitalis (abstr). Circulation 52:Suppl ll:ll-226, 1975 35. Dlamond 0, Forrester JS: Effect of coronary artery disease and acute myocardial infarction on left ventricular compliance in man. Circulation 45:11-19, 1972

Volume 43

Combined therapy with digoxin and nitroprusside in heart failure complicating acute myocardial infarction.

Combined Therapy With Digoxin and Nitroprusside in Heart Failure Complicating Acute Myocardial Infarction DANIEL S. RAABE, Jr., MD, FACC Burlington,...
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