Effect of Sodium Nitroprusside during the Payback Period of Cardiopulmonary Bypass on the Incidence of Postoperative Arrhythmias

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1 Effect of Sodium Nitroprusside during the Payback Period of Cardiopulmonary Bypass on the Incidence of Postoperative Arrhythmias Kit V. Arom, M.D., David M. Angaran, M.S., William G. Lindsay, M.D., William F. Northrup, M.D., and Demetre M. Nicoloff, M.D. ABSTRACT This study was designed to determine whether a sodium nitroprusside infusion during the reperfusion (payback) period of cardiopulmonary bypass would minimize arrhythmias during the early postoperative period of coronary artery bypass surgery. A double-blind randomized study was carried out in 38 patients with no previous history of ventricular arrhythmias. Seventeen received 5% dextrose in water (D5W) and 21 received sodium nitroprusside at the rate of 2 pg per kilogram per minute during the payback period. The pump flow was kept constant at 2.2 liters per square meter per minute, and mean pressure was maintained at > 50 mm Hg. There was a statistically significant difference between the two groups in the number of patients who developed ventricular arrhythmias (13 of 17, or 76%, in the D5W group versus 6 of 21, or 29%, in the sodium nitroprusside group; p < 0.005). Twelve of the 13 patients in the D5W group experienced arrhythmias (6 ventricular tachycardia and 6 ventricular premature depolarization) within the first 24 hours, compared to 5 of 12 patients in the nitroprusside group (3 ventricular tachycardia and 2 ventricular premature depolarization). Only 1 patient in each group developed ventricular arrhythmia after the first postoperative day. One patient in each group experienced atrial arrhythmia during the first 24 hours. After 24 hours, atrial arrhythmias developed in 5 patients in the D5W group (35%) and 3 patients in the sodium nitroprusside group (17O/0) (p > 0.05). The arterial ph ranged from 7.35 to 7.55, with a Po, greater than 70 torr and a serum potassium of 3.7 k 0.36 meq per liter in the D5W group and 3.4 k 0.34 From the Minneapolis Heart Institute, Minneapolis, MN, and United Hospitals, St. Paul, MN. Presented at the Twenty-eighth Annual Meeting of the Southern Thoracic Surgical Association, Nov 5-7, 1981, Palm Beach, FL. Address reprint requests to Dr. Arom, Minneapolis Heart Institute, 2545 Chicago Ave S, Minneapolis, MN meq per liter in the nitroprusside group during the period of arrhythmias. Sodium nitroprusside given during the payback period of cardiopulmonary bypass appears to minimize ventricular arrhythmias in the early postoperative period of coronary artery bypass surgery. Coronary artery bypass surgery has become an important therapeutic modality in the management of coronary artery disease. Recent technical advances and improved perioperative care have reduced the operative mortality to 1 to 3% among experienced surgeons. However, because postoperative arrhythmias are common, recent attention has been directed toward techniques to decrease these potentially serious complications. New atrial arrhythmias appear with almost equal frequency after valvular and coronary artery bypass operations and are most likely related to the mechanical effects of cardiopulmonary bypass. Ventricular arrhythmias, however, are detected more frequently after coronary artery bypass surgery than after valve procedures and appear to be related to underlying ischemia and scar in the left ventricle [l-31. Arrhythmias usually are well tolerated and do not greatly complicate the postoperative management. However, recurring arrhythmias sometimes will produce hemodynamic instability which can, in turn, produce renal, cerebral, and pulmonary complications and even death. Recently, sodium nitroprusside has been shown clinically to have antiarrhythmic properties during acute myocardial ischemia [4]. Our study attempted to determine whether intravenous sodium nitroprusside given during the reperfusion (payback) period of cardiopulmonary bypass could minimize arrhythmias during the early postoperative period in patients undergoing coronary artery bypass surgery by The Society of Thoracic Surgeons

2 308 The Annals of Thoracic Surgery Vol34 No 3 September 1982 Materials and Methods A double-blind randomized study was carried out in 38 patients undergoing saphenous vein coronary bypass surgery. None of these patients had a history of ventricular arrhythmias or electrocardiographic abnormality during a l-month period prior to operation. Twentynine men and 9 women, ranging in age from 33 to 81 years, were operated on in one hospital by one group of surgeons, using similar anesthetic and surgical techniques. Extracorporeal circulation was carried out using the Bentley BOS-10 oxygenator and Sarns Modular System roller pump, priming with Plasmalyte solution at 20 to 25 ml per kilogram. During cardiopulmonary bypass, the body temperature was lowered to 28 C and diastolic arrest was obtained with a cold potassium cardioplegic solution (5% dextrose in 0.25% normal saline plus 30 meqll potassium chloride plus 5 meqll sodium bicarbonate). The myocardial temperature was kept below 20 C (12.8" f 1.8"C to 18.9" f 9 C in the group receiving 5% dextrose in water and 13.2" f 2.O"C to 18.4" f 1.2"C in the sodium nitroprusside group; p > 0.05) by intermittently infusing 500 f 100 mi of cardioplegic solution every 20 iz 3 minutes. A solution containing either sodium nitroprusside or 5% dextrose in water (D5W) was prepared each morning of surgery by a pharmacist who alone knew its contents. The solution was infused intravenously into each patient at the beginning of the rewarming period at a rate of 2 pg per kilogram per minute until the rectal temperature reached 35 C (myocardial temperature of 36.5" f 0.5"C in the D5W group, and 36.5" f 0.8"C in the nitroprusside group; p > 0.05). During this time, the pump flow was kept at 2.2 liters per minute per square meter. Perfusion pressure was maintained above 50 mm Hg with intermittent intravenous injections (0.1 mg) of phenylephrine hydrochloride (Neo- Synephrine). The patients were divided into two groups according to the solution which they received during the rewarming period. Seventeen patients received D5W and 21 patients received sodium nitroprusside. These patients were comparable in weight and age (Table 1). As previously stated, none of them Table 1. Comparison of Age and Weight of the Two Test Groups Sodium Nitroprusside Patient D5W Group Group Characteristic (N = 17) (N = 21) Age (yr) 56.9 f f 18.9 Weight (kg) 70.5 f f 21.2 D5W = 5% dextrose in water. had a prior history of ventricular or atrial arrhythmias, except for 1 patient in the nitroprusside group who demonstrated one episode of atrial premature depolarizations after admission. Preoperatively, 16 of the 17 patients in the D5W group and 18 of the 21 in the nitroprusside group received propranolol hydrochloride (Inderal) in a comparable ( p > 0.05) dose of 121 f 98 mg per day and 157 f 97 mg per day, respectively. A history of previous myocardial infarction was present in 9 of the 17 patients in the D5W group and 18 of 21 in the nitroprusside group. The ejection fraction was less than 55% in only 2 patients in the D5W group and 5 patients in the nitroprusside group. There were no statistically significant differences in the number of grafts, total cross-clamp time or reperfusion time, pressure, and pump flow rate between these two groups (Table 2). Each patient was monitored directly in the intensive care unit and again with telemetry during the first 10 postoperative days. All arrhythmias during this period were automatically recorded on a multichannel recorder. Any of the following abnormal cardiac patterns were considered significant arrhythmias: Atrial in Origin 1. Atrial fibrillation or atrial flutter, whether sustained or paroxysmal 2. Reentrant or automatic paroxysmal supraventricular tachycardia 3. Frequent atrial premature depolarization (APD) 2 5 per minute Ventricular in Origin 1. Unifocal ventricular premature depolarization (VPD) 3 30 per hour

3 309 Arom et al: Effect of Nitroprusside during Payback Period of CPB Table 2. Comparison of Clinical Data in the Two Test Groups Sodium Nitroprusside Groupa Clinical Data D5W Groupa (N = 17) (N = 21) No. of grafts 3.1 f f 1.2 Cross-clamp time (min) 36 iz 6 33 f 4 Reperfusion time (min) 36 f k 7.5 Reperfusion flow (Limin/m2) Reperfusion pressure (mm Hg) 67.3 f f 10 astatistical significance: p > D5W = 5% dextrose in water. 2. Ventricular couplets 3. Ventricular tachycardia (2 3 consecutive VPDs) 4. Multiform VPDs Propranolol was given to 16 of the 17 patients in the D5W group and 18 of the 21 patients in the nitroprusside group during and beyond the study period (1 mg intravenously every 6 hours for 4 doses, then 20 mg orally every 12 hours). During all episodes of abnormal cardiac rhythm, any factors that could affect the arrhythmia also were recorded, including the systemic blood pressure, serum potassium level, arterial blood ph, and PaO,. These variables are listed in Table 3; they did not differ significantly between the two groups. Intermittent injections of Neo-Synephrine were necessary in 5 of the 17 patients in the D5W group (average, 0.22 mg per patient) and 9 of the 21 patients in the nitroprusside group (average, 0.29 mg per patient), in order to maintain the perfusion pressure above 50 mm Hg according to the protocol. All the data were analyzed for statistical significance of difference by paired Student t test and were expressed as mean plus or minus standard error of the mean. Results A patient was considered to have a new atrial or ventricular arrhythmia only if none of the arrhythmias had ever occurred preoperatively. Since hemodynamic instability and arrhythmias occurred more frequently during the first 24 hours than during the remainder of the postoperative period, all data were analyzed in two parts (Table 4): arrhythmias that occurred in the first 24 postoperative hours and those that occurred after 24 hours but before 10 days. Arrhythmias Occurring During the First 24 Hours During the first 24 hours postoperatively, ventricular arrhythmias were more common than arrhythmias of atrial origin. Frequent APDs occurred in only 1 patient of each group, whereas ventricular tachycardia occurred in 6 patients in the D5W group and only 3 patients in the nitroprusside group ( p < 0.005). Also, 6 patients in the D5W group experienced significant VPDs during this same period, compared to only 2 patients in the nitroprusside group ( p < 0.005). Table 3. Comparison of Potential Arrhythmia-affecting Factors in the Two Test Groups Sodium Nitroprusside Groupa Factor D5W Group" (N = 17) (N = 21) Systolic blood pressure (mm Hg) 118 f f 11 Serum potassium (meqll) 3.7 f * 0.34 Arterial ph 7.39 f f 0.6 Arterial POz (tom) 84 f f 9 'Statistical significance: p > D5W = 5% dextrose in water.

4 310 The Annals of Thoracic Surgery Vol34 No 3 September 1982 Table 4. Numbers of Patients Developing Arrhythmias during the Postoperative Perioda Sodium Nitroprusside Group Abnormal Rhythm D5W Group (N = 17) (N = 21) Atrial arrhythmias <24 hr >24 hr Ventricular arrhythmias <24 hr >24 hr anumbers in parentheses indicate total of arrhythmias. Statistical significance: "p < 0.005; 'p < (1) APDs 3 (5) F&F, 2 (2) APDs 6 (8) VT,b 6 (9) WDsC 1 (1) VT 1 (1) APDs 2 (4) F&F, 1 (2) APDs 3 (4) 2 (4) VPDsC 1 (1) VPDs D5W = 5% dextrose in water; APDs = atrial premature depolarizations; VPDs = ventricular premature depolarizations; F&F = fibrillation and flutter; VT = ventricular tachycardia. Arrhythmias Occurring after the First 24 Hours and before 10 Days After the first 24 hours postoperatively and before 10 days had elapsed, atrial arrhythmias occurred in 5 patients in the D5W group, compared to 3 patients in the nitroprusside group. These differences were not statistically significant. Atrial fibrillation and flutter dominated the arrhythmias in both groups (3 of 5 patients in the D5W group and 2 of 3 patients in the nitroprusside group). The remaining 3 atrial arrhythmias were APDs. Ventricular tachycardia occurred on the second postoperative day in 1 patient in the D5W group, and 1 VPD occurred on the seventh postoperative day in 1 patient in the nitroprusside group. There was no statistically significant difference between the myocardial temperature among these two groups during cardioplegic arrest or the rewarming period ( p > 0.05). Also, no statistical significance could be obtained between the dosages or the number of patients who required Neo-Synephrine during the rewarming period (p > 0.05). Comment The fact that patients are prone to have cardiac arrhythmias after open-heart operations is well documented. The incidence of arrhythmias generally ranges from 25 to 65%, although an incidence as high as 74% has been reported in a series of patients undergoing cardiac valve replacement [l-3, Another series reported a 39% incidence of arrhythmias in 75 patients undergoing coronary artery bypass surgery [91. However, these patients were not evaluated for arrhythmia frequency preoperatively. Therefore, the incidence of new arrhythmias was not known. Recently, Michelson and colleagues [21 reported arrhythmias in 32 of 50 patients undergoing coronary artery bypass surgery. Twenty-six (52%) of these patients had newly developed arrhythmias. The incidence of atrial and ventricular arrhythmias in this group was almost identical (38% atrial and 36% ventricular). From these reports, it also is clear that ventricular arrhythmias occurred more frequently after coronary artery bypass surgery than usually is seen following valve procedures. Presumably, this was related to underlying ischemia of the left ventricle. Nuclear imaging and other techniques may shed light on whether these arrhythmias are attributable to reperfusion of reversibly ischemic myocardium or to changes of chronic ischemia and scar plus the effect of discontinuing preoperative medication. Digitalis has been advocated for the prevention of postoperative arrhythmias. In one report [lo], 120 patients undergoing coronary artery bypass surgery were randomly selected to serve as controls or to undergo preoperative digitalization. There was a 25% incidence of atrial arrhythmias in the control group and a 5% incidence in the group that received digitalis. The incidence of ventricular arrhythmias, however,

5 311 Arom et al: Effect of Nitroprusside during Payback Period of CPB was similar in both groups [lo]. In another randomized study, patients were digitalized with ouabain immediately after coronary bypass surgery. Atrial arrhythmias occurred in 9 of the 18 patients in the control group but in none of the 15 patients who had received ouabain [lll. Tyras and co-workers [12] reported a study of 140 patients having coronary bypass surgery and randomized to either control or digitalis groups. The incidence of postoperative arrhythmias actually was higher in the group receiving digitalis (27.8% versus 11.4%). However, these authors noted a striking reduction in postoperative arrhythmias in patients in whom propranolol therapy was resumed 1 to 2 days following the operation. The ability of sodium nitroprusside to lower blood pressure is reported to have been known by Claude Bernard [13]. The potential therapeutic merit of nitroprusside in the treatment of hypertension, particularly in a crisis, was suggested by Johnson in 1928 [14]. However, it was not until 1951 that this potential was clinically realized, when Page described its extensive use in hypertensive emergencies including encephalopathy [15]. By 1959, nitroprusside was recognized as an effective drug for use in the management of malignant hypertension. Remarkably, it was not until 1974 that an approved preparation of this inexpensive chemical was made available commercially in the United States. Sodium nitroprusside recently has come into widespread use, not only for the treatment of severe hypertension, but also for intraoperative induction of arterial hypotension during operations and for reduction of afterload by peripheral vasodilatation in patients with acute myocardial infarction or severe congestive heart failure. It has recently been shown that sodium nitroprusside therapy is effective in the treatment of hypertensive patients with recurring resting chest pain and ventricular arrhythmias [51. Rowe and Henderson [7] studied the systemic and coronary hemodynamic effects of sodium nitroprusside in dogs. A dose of the drug that decreased mean arterial pressure only 8% produced a 53% increase in coronary flow and a 30% increase in coronary sinus oxygen content and cardiac output. The increases in coronary blood flow and coronary sinus oxygen content were interpreted as evidence of improved myocardial perfusion and oxygenation. In our study, atrial arrhythmias were less common in patients receiving sodium nitroprusside (17%) than in those receiving D5W (35%) during the payback period of cardiopulmonary bypass. This difference, however, does not reach any statistical significance. The incidence of these atrial arrhythmias in both groups was within the range of new supraventricular arrhythmias reported in other series [l-3, 5, 61. It is assumed that these atrial arrhythmias usually are related to direct mechanical injury from surgery, pericardial inflammation, atelectasis, and other minor pulmonary complications. Ventricular arrhythmias developed in 76% of the patients not given nitroprusside during the payback period of cardiopulmonary bypass. This occurrence is slightly more frequent than was reportedly seen in other series and is credited to the extended postoperative monitoring in our study. Only 29% of the patients treated with nitroprusside developed ventricular arrhythmias. This incidence is much lower than that usually seen in previously reported series and is significantly lower than the incidence of similar arrhythmias in the group of patients in our study who received D5W during the same payback period. The lower incidence of ventricular arrhythmias in the group treated with nitroprusside probably is related to the vasodilator effect of sodium nitroprusside on the coronary arteries. The improvement in coronary artery blood supply increases global myocardial perfusion, the result of which is a more uniform warming and oxygenation of the ischemic myocardium. This effect alone could perhaps significantly decrease the oxygen debt during the payback period. The effects of nitroprusside on afterload reduction and on altering the endocardiauepicardia1 flow ratio may or may not affect myocardial oxygenation in our setup, since the heart remained in the empty, nonworking state during the reperfusion period. It is not known whether sodium nitroprusside has any direct antiarrhythmic properties. There was no correlation between the incidence of arrhythmias and the number of

6 312 The Annals of Thoracic Surgery Vol34 No 3 September 1982 grafts, total cross-clamp time, and completeness of revascularization in each group. It has been our routine practice, unless there is an absolute contraindication, to place all postoperative patients on Inderal therapy until 3 months after surgery. In our experience, paroxysmal supraventricular tachyarrhythmias often were not well tolerated. Hemodynamically, this is not surprising [16, 171. However, in some patients these tachyarrhythmias produced no symptoms and would not have been detected without extended electrocardiographic monitoring. Although arrhythmias were frequent, their occurrence did not necessarily contribute substantially to other complications in the immediate postoperative period. Therefore, the decision to treat arrhythmias was made on an individual basis. Further follow-up may determine whether any of these arrhythmias contribute to sudden death or to other complications after hospital discharge. References Installe E, Schoevaerdts JC, Gadisseux PH, et al: Intravenous amiodarone in the treatment of various arrhythmias following cardiac operations. J Thorac Cardiovasc Surg 81:302, 1981 Michelson EL, Morganroth J, MacVaugh H: Postoperative arrhythmias after coronary artery and cardiac valvular surgery detected by longterm electrocardiographic monitoring. Am Heart J 97:442, 1979 Stephenson LW, McVaugh H, Tomasello DN, et al: Propranolol for prevention of postoperative cardiac arrhythmias: a randomized study. Ann Thorac Surg 29:113, 1980 Mukherjee D, Feldman MS, Helfant RH: Nitroprusside therapy: treatment of hypertensive patients with recurrent resting chest pain, ST- segment elevation, and ventricular arrhythmias. JAMA 235:2406, Mohr R, Smolinsky A, Goor DA: Prevention of supraventricular tachyarrhythmia with low-dose propranolol after coronary bypass. J Thorac Cardiovasc Surg 81:840, Roffman JA, Fieldman A: Digoxin and propranolol in the prophylaxis of supraventricular tachydysrhythmias after coronary artery bypass surgery. Ann Thorac Surg 31:496, Rowe GG, Henderson RH: Systemic and coronary hemodynamic effects of sodium nitroprusside. Am Heart J 87233, Smith R, Grossman W, Johnson L, et al: Arrhythmias following cardiac valve replacement. Circulation 45:1018, Angelini P, Feldman M, Lufshanowcki R, et al: Cardiac arrhythmias during and after heart surgery: diagnosis and management. Prog Cardiovasc Dis 16:469, Johnson LW, Dickstein RA, Fruehan CT, et al: Prophylactic digitalization for coronary artery bypass surgery. Circulation , O Kane H, Grela A, Bane A, et al: Prophylactic digitalization in aortocoronary bypass patients. Circulation 45, 46:Suppl 2:199, Tyras DH, Stothert JC, Kaiser GC, et al: Supraventricular tachyarrhythmias after myocardial revascularization: a randomized trial of prophylactic digitalization. J Thorac Cardiovasc Surg 77:310, Schiffmann H, Fuchs P: Controlled hypotension effected by sodium nitroprusside. Acta Anaesthesiol Scand [Suppl] 23:704, Johnson CC: Mechanism of actions and toxicity of nitroprusside. Proc SOC Exp Biol Med 26:102, Page IH: Treatment of essential and malignant hypertension. JAMA 147:1311, Goldreyer BN, Kastor JA, Kershbaum KL: The hemodynamic effects of induced supraventricular tachycardia in man. Circulation 54:783, McIntosh HD, Yihong K, Morris J: Hemodynamic effects of supraventricular arrhythmias. Am J Med 37:712, 1964