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Assessment of Prospectively Randomized Patients Receiving Propranolol Therapy before Coronary Bypass Operation
Assessment of Prospectivelv Randomized Patients Receiving hopran6101 Therapy before Coronary Bypass Operation Andrew S. Wechsler, M.D. ABSTRACT Fifty patients receiving propranolol were randomized into two groups of 25 patients each. One group received the last dose of propranolol within 4 hours of operation and were on a regimen of 160 mg daily. The second group had propranolol discontinued 24 to 48 hours prior to operation. Two nonrandomized control groups consisted of 25 patients who had never had propranolol and 15 patients who were on a regimen of 160 mg or more and who were operated on for unstable angina. Blood levels of propranolol were obtained just prior to incision. Several hemodynamic variables were assessed prior to anesthetic induction, at peak response during the early anesthetic period, and at the termination of cardiopulmonary bypass. Strict criteria were enforced for the administration of inotropic agents and the incidence of myocardial injury in the various groups was tabulated. Significant differences were present in the form of lower pressure-rate products in the patients maintained on propranolol therapy. The incidence of inotropic support, however, was also higher within the subgroups of patients who had propranolol immediately prior to operation. When examined further, increased inotropic requirements existed in patients having 320 to 480 mg of propranolol just before operation; this finding correlated with serum propranolol levels measured at the time of operation. This tightly controlled study supports the maintenance of propranolol for From the Departments of Surgery, Duke University Medical Center and the Veterans Administration Medical Center, Durham, NC.
I express my appreciation to Ayerst Laboratories for making this study possible, specifically to Dr. Ezra Lamdin for his encouragement, and for the performance of the propranolol assays. Appreciation is also expressed to Mrs. Edna Ferrell and Mrs. Ruby Griffin for secretarial assistance and to the anesthesia, operating room, and intensive care support personnel at the Durham Veterans Administration Hospital. Presented at the Sixteenth Annual Meeting of The Society of Thoracic Surgeons, Jan 21-23, 1980, Atlanta, GA. Address reprint requests to Dr. Wechsler, Associate Professor of Surgery, PO Box 3174, Duke University Medical Center, Durham, NC 27710.
its beneficial perioperative hemodynamic effects but suggests that maintenance of doses of 320 to 480 mg per day are associated with a greater duration and extent of action that may transiently affect early postoperative hemodynamic performance.
The use of propranolol as part of the immediate preoperative pharmaceutical program for patients undergoing aortocoronary bypass grafting has been controversial. Despite early warnings relating preoperative beta blockade to high operative risks, most investigators have discerned little difference in patients receiving propranolol preoperatively compared with patients in whom the medication was discontinued. As summarized in Table 1, most information has been gleaned from reports of successive cohorts of patients and only one prior investigation used a clinical study in which propranolol maintenance or withdrawal was prospectively randomized. Moreover, most comparisons were made between groups of patients maintained on propranolol to within 36 to 48 hours of operation compared with groups of patients in whom propranolol was discontinued several days in advance of the operative procedure. This study compares patients maintained on substantial doses of propranolol in the immediate preoperative period with a group of patients in whom the medication was discontinued 24 to 48 hours prior to operation.
Material and Methods Ninety patients were included in the study. Informed consent was obtained from all patients who participated in the study, and the entire investigational protocol was approved by the Human Experimental Investigation Committee. Fifty patients receiving long-term propranolol therapy who were admitted for elective aortocoronary bypass operation were randomly assigned to one of two groups of 25 patients
128 0003-4975/80/080128-09$01.25 @ 1980 by The Society of Thoracic Surgeons
129 Wechsler: Prospectively Randomized Patients Receiving Propranolol
Table 1. Previous Investigators Reporting on the Use of Propranolol in the Immediate Perioperative Period Patients on Propranolol
Author
Year
Type Study
Viljoen et a1 [141 Caralps et a1 [21 Moran et a1 [lo] Kaplan et al [71 Jones et a1 [61
1972 1974 1974
Case reports
5
25 52
1976
Retrospective Retrospective Retrospective Retrospective
Kirsh et a1 [8]”
1978
Prospective
1978
randomized Retrospective
Boudoulas et a1 [l]
1975
Patients off Propranolol 0 75
251
143 113 14
26
30
50
72
13
“This study represents the only other investigation in which a prospectively randomized format for propranolol management was used.
each. One group had propranolol discontinued 24 to 48 hours prior to operation. Regardless of the dose taken on admission, these patients were maintained on 160 mg of propranolol daily prior to cessation of therapy. Eighteen patients were on a regimen of 160 mg of propranolol daily and 7, 320 to 480 mg daily. The second group of 25 patients were maintained on propranolol and received the last dose 4 hours prior to operation. Patients receiving more than 160 mg of propranolol daily were reduced to 160 mg daily 24 to 48 hours prior to operation. Of this group, 16 patients were on a regimen of 160 mg daily and 9, 320 to 480 mg daily. A third group of patients, in whom therapy was not randomized, consisted of 25 successive patients admitted for elective aortocoronary bypass operation. These patients were not receiving propranolol. A fourth group consisted of 15 patients who underwent operation for unstable angina pectoris and who were receiving propranolol u p to 4 hours prior to operation. These patients did not have the propranolol dosage reduced regardless of the admission dosage program. Statistical comparisons were made only between the two groups of patients in whom drug therapy was prospectively randomized. All patients were men, and computer analysis of patient variables among the four groups was used to assess multiple descriptors by analysis of covariance to determine the comparability of the groups. This analysis included the incidence of left main coronary disease of greater
than 70% obstruction, resting ejection fraction, presence or absence of mitral valve regurgitation, presence or absence of congestive heart failure, presence or absence of resting S-T segment and T wave changes, patient age, history of prior myocardial infarction, arterial venous oxygen saturation difference, number of diseased vessels, evidence of ventricular dysfunction on cineangiogram, and the presence or absence of cardiomegaly on chest roentgenogram. For these descriptors, patients operated on for unstable angina (not randomized) had a higher incidence of left main coronary artery disease, as indicated in Table 2, but were otherwise indistinguishable. In addition to the patient risk descriptors just described, the perioperative pressure-heart rate product was calculated on arrival in the operating room, at the peak response during anesthetic induction, and 30 minutes following termination of cardiopulmonary bypass. The incidence of myocardial infarction was determined from the presence of new Q waves on the postoperative electrocardiogram and a myocardial damage index was calculated for the patients having prospective randomization of their propranolol programs by determining the area under a CPK-MB duration curve level with samples being drawn at 6-hour intervals for the first 72 hours after operation. Requirements for inotropic support were recorded both for patients who required such support to terminate cardiopulmonary bypass and for patients who required initiation of such support within the first 24 hours after opera-
130 The Annals of Thoracic Surgery Vol 30 No 2 August 1980
Table 2 . Critical Variables for the Patient Groups Studied Variable Left main coronary disease > 70% Resting ejection fraction (%) No. of grafts Cross-clamp time (min)
(YO)
or
P
16 43 f 5.2 2.6 f 0.14 36 k 4.1
16 44 k 4.6 2.9 f 0.19 34 3.7
'p
*
20 47 ? 5.1 2.8 f 0.15 37 f 2.9
P(NR) 33 a 41 f 3.9 2.9 k 0.23 37 f 4.3
" p < 0.01. This was significantly different from all the other groups. OF = patients never receiving propranolol; 1' = patients receiving the last dose of propranolol4 hours prior to operation;% patients receiving long-term propranolol therapy, discontinued 24 to 48 hours prior to operation; P(NR) = patients with unstable angina who received the last propranolol dose 4 hours prior to operation. =
tion. The incidence of hypertension requiring nitroprusside therapy was noted as was documentation of arrhythmias. Propranolol serum levels were obtained in each patient at the time the skin incision was made. The Student t test for unpaired data was used to calculate differences between the randomized groups.
Basic Operative Techniques A standardized method of operation was used for all patients in the study. This included anesthetic induction with diazepam (Valium) and morphine and maintenance with morphine, nitrous oxide, and pancuronium. Hernodilution techniques were employed; however, the hematocrit was not allowed to fall below 20% during the period of cardiopulmonary bypass. Systemic temperatures were maintained at 30°C and operations were performed using hyperkalemic, crystalloid cardioplegia (5°C) with a potassium concentration of 24 mEq per liter. Proximal anastomoses were performed prior to distal anastomoses and following an initial cardioplegic infusion of approximately 500 ml per square meter of body surface area. Supplements of cardioplegic solution were infused after the completion of each distal anastomosis (usually 150 to 200 ml). Left ventricular venting was not employed, and reperfusion was greater than or equal to half the aortic cross-clamp time. Strict criteria for inotropic support were employed. Inotropic agents were used to terminate cardiopulmonary bypass when the patient was unable to maintain a blood pressure greater than 110 mg Hg systolic or when the systolic pressure was less than 20% below control levels, and when the pulmonary artery diastolic pressure, pulmonary capillary wedge pressure,
or left atrial mean pressure was greater than 15 mm Hg. A decision to employ inotropic support following termination of cardiopulmonary bypass was made for a cardiac index less than 2 or when the pulmonary artery diastolic pressure, pulmonary capillary wedge pressure, or left atrial mean pressure was greater than 15 mm Hg. If isolated hypotension was present with cardiac indices greater than 2 Llminlm', alpha agonists were employed.
Results Table 2 summarizes the salient intraoperative features for the four study groups. No significant differences among the groups in the number of grafts or the aortic cross-clamp times existed. Table 3 lists the principal comparisons made among the groups. In addition to these, the incidence of important arrhythmias was not different for the two groups. Significant differences between the two groups in which propranolol therapy had been randomly managed were confined to the pressure-rate product determined at all three measurement points as well as in the requirement for inotropic support, particularly within the first 24 hours. The increment in inotropic support between that required to terminate cardiopulmonary bypass and that initiated within the first 24 hours for all patients occurred within 6 hours of return to the intensive care unit. The mean propranolol serum level was also higher in the group in which propranolol had been maintained compared with the group in which it had been discontinued. These differences are examined in more detail in Figures 1, 2, and 3. As illustrated in Figure 1, significant differences existed in the basal pressure-rate product among patients maintained on propranolol and
131 Wechsler: Prospectively Randomized Patients Receiving Propranolol
Table 3 . Chief Variables Compared in S t u d y Variable
or
P
P
P("
Arrival pressure-rate product Peak pressure-rate product
11,242 f 722 17,400 k 902 12,146 f 513 2125 2125 15/25 1125 2/25 0
6,960 rt 421" 10,800 k 629" 9,422 f 622" 1/25 7/25" 12/25 1/25 3125 16.4"
11,480 ?c 803 18,100 k 1151 13,114 rt 877 2/25 1/25 16125 0/25 1125 3.1
6,640 k 501 11,200 ?c 781 9,017 k 536 2/15 4/15 8115 1/15 2115 20.2
P o s t p u m p pressure-rate product Pump inotropic support 24-hr inotropic s u p p o r t Required nitroprussideb Acute myocardial infarction" Myocardial d a m a g e i n d e x > 200 Propranolol level
" p < 0.01 when compared with randomized patients in whom propranolol was discontinued 24 to 48 hours prior to operation. bFigures represent the absolute number of patients in each group requiring nitroprusside administration for control of postoperative hypertension. 'As defined by the appearance of new Q waves. OP = patients never receiving propranolol; P = randomized patients receiving the last dose of propranolol4 hours prior to operation; P = randomized patients in whom propranolol was discontinued 24 to 48 hours prior to operation; P(NR) = patients with unstable angina who received the last propranolol dose 4 hours prior to operation.
100 r
140
100 Ly
I 60
20
P
OP
P
'R
PINR)
Fig 1 . (Top) Pressure-rate product (P X HR) XlO-' on arrival in the operating room and at peak response during anesthetic induction for each of the four study groups. (Bottom) Heart rate (HR) determined at the same times as the pressure-rate product. (OP = patients never receiving propranolol; P = patients receiving the last dose of propranolol4 hours prior to operation; R = patients receiving long-term propranolol therapy discontinued 24 to 48 hours prior to operation; P(NR) = patients with unstable angina w h o received the last propranolol dose 4 hours prior to operation; * = p < 0.01 when compared with the randomized group in which propranolol was discontinued 24 to 48 hours prior to operation.)
PNRI
Fig 2 . (Top) Percentage of patients in each of the subgroups requiring inotropic support either to terminate cardiopulmonary bypass or within the first 24 hours after cardiopulmonary bypass. There was a significant difference (p < 0.05) between the two groups of patients in the randomized treatment protocol as there was between the patients maintained on propranolol who had unstable angina compared with those not receiving propranolol or in whom propranolol had been discontinued. (Bottom) Comparison of patients maintained on propranolol and having inotropic support requirements as a function of propranolol dosage. (OP = patients never receiving propranolol; P = patients receiving the last dose of propran01014 hours prior to operation; YP = patients who had long-term propranolol therapy discontinued 24 to 48 hours prior to operation; P(NR) = patients with unstable angina who received the last propranolol dose 4 hours prior to operation.)
132 The Annals of Thoracic Surgery
w
Vol 30 No 2 August 1980
m >320mg/d
rn
rn rn 0
P
P
P(NR)
lnotropic Support Patients
Fig 3 . Relationship between serum propranolol levels and the dosage of propranolol in patients requiring inotropic support anytime within the perioperative period. (P= patients who had long-term propranolol therapy discontinued 24 to 48 hours prior to operation; P = patients receiving the last dose of propranolol4 hours prior to operation; P(NR) = patients with unstable angina who received the last propranolol dose 4 hours prior to operation.)
tained on propranolol, which paralleled the incidence of inotropic support in patients operated on for unstable angina who continued propranolol treatment. In the upper half of the figure, almost 30% of patients maintained on high-dose propranolol therapy required inotropic support using the criteria described in the Methods section. Further breakdown of the patient subgroups is shown in the lower portion of the figure where the percentage of inotropic support for patients receiving continued propranolol therapy is shown. An increased incidence of inotropic support was noted only in patients receiving more than 320 mg of propranolol daily and approached 60% of that population. On the other hand, patients being maintained on propranolol but in doses of less than 320 mg had an incidence of inotropic support requirement no greater than patients either not receiving propranolol or in whom propranolol was discontinued 24 to 48 hours prior to operation. The relationship between the dosage of propranolol maintained and the serum propranolol level in the patients requiring inotropic support is illustrated in Figure 3. Only 2 patients receiving less than 320 mg per day of propranolol required inotropic support. Both these patients were in the randomized group in which propranolol had been discontinued 24 to 48 hours prior to operation, and both these patients had no detectable serum levels of propranolol. All the patients in the randomized group that had propranolol discontinued 24 to 48 hours prior to operation had no detectable serum levels of propranolol as was true for the group of patients never receiving propranolol therapy. Of the patients requiring inotropic support in the groups maintained on propranolol until the time of operation, 7 patients had 20 ng per milliliter or greater concentration of propranolol, while 4 had concentrations below that level. No propranolol levels greater than 10 ng per milliliter were found in patients in either of the groups maintained on propranolol who did not require inotropic support.
those in whom the drug was discontinued. Similarly, there was suppression of the elevation in pressure-rate product that accompanied induction of anesthesia in this group as well. These observations paralleled closely the comparison among nonrandomized patients not receiving propranolol compared with patients not randomized and operated on for unstable angina who were maintained on propranolol. In both the randomized and nonrandomized groups, maintenance of propranolol therapy was associated with significantly lower pressure-rate products on arrival in the operating room and during the anesthetic induction period. Separate analyses of heart rate as shown in the lower half of the figure showed parallel significant suppression of heart rate response to anesthetic induction in both propranololtreated groups. Moreover, the heart rate differences appear primarily responsible for the decreased pressure-rate products in the group of patients maintained on propranolol therapy. A more detailed analysis of patients requiring inotropic support is presented in Figure 2. Patients who underwent randomization of propranolol therapy with withdrawal of drug 24 to 48 hours prior to operation had an incidence of inotropic support requirement that paralleled closely the group of patients never receiving propranolol treatment. A significantly greater Comment percentage of patients required inotropic sup- The data presented in this study generally support in the group of patients randomly main- port the notion that continuance of propranolol
133 Wechsler: Prospectively Randomized Patients Receiving Propranolol
therapy to the time of operation is safe and potentially beneficial. The reduced pressure-rate product in patients maintained on propranolol in the absence of untoward anesthetic events appears to be a highly desirable benefit of such therapy, particularly for the suppression of the heightened pressure-rate product that generally accompanied the process of intubation in patients not receiving propranolol or in whom propranolol had been discontinued 24 to 48 hours prior to operation. The finding of substantial levels of propranolol in the serum of patients maintained to the time of operation is not inconsistent with prior reports on the half-life of serum propranolol. Thirty-six to 48 hours following discontinuation of propranolol therapy, most investigators have shown no serum propranolol present, absent propranolol from atrial tissue excised at operation, and a normal response to pharmacological beta stimulation [2-5, 11, 121. The propranolol levels in patients maintained on the drug to the time of operation were significantly higher than in patients in whom the drug had been discontinued. In patients requiring inotropic intervention, the daily dosage of propranolol was invariably 320 mg or more, even though reduced to 160 mg 24 to 48 hours prior to operation in the group of patients who underwent randomization of the therapeutic programs. It was interesting to note that more patients in the group requiring inotropic support evidenced their need for such support within several hours of operation than did those requiring inotropic intervention to terminate cardiopulmonary bypass. It is possible that intense levels of neurogenic and humoral catecholamine stimulation in the period immediately after pump removal allowed adequate maintenance of beta function to support systemic hemodynamics. With some withdrawal of this intense stimulation, and in the presence of significant propranolol levels or betablocking hepatic metabolites of propranolol (not measured in this study), a dependence on exogenous beta stimulation may have resulted. In all patients, beta agonists could be withdrawn within 24 hours of operation, perhaps suggesting the dislodgment of beta blockers and subsequent metabolic degradation of these
rather than intrinsic myocardial injury and depression. This study differs from previous investigations in several respects. It utilized a tightly controlled patient population under the care of a single surgeon. A primary comparison was possible between two groups of patients in whom propranolol therapy could be managed in a randomly allocated fashion. The issue addressed was related more to the relative safety of maintaining propranolol in significant doses immediately prior to the time of operation compared with following the more recommended protocol of discontinuing propranolol 24 to 48 hours prior to operation. Most previous investigations were concerned primarily with the question of discontinuing propranolol several days in advance of the procedure or maintaining it to within 24 to 48 hours of operation. In our population of patients studied in whom propranolol was discontinued 24 to 48 hours prior to operation, there was no evidence of a ”propranolol rebound phenomenon,” confirming the safety of this conservative approach to management of propranolol dosage [9, 131. As a result of this investigation and after consideration of prior reports appearing in the literature, it appears beneficial to maintain propranolol in patients with unstable angina or those with unusually severe angina by history at outpatient levels immediately prior to the time of operation because of the desirable perioperative hemodynamic effects. The surgeon should anticipate that patients so maintained, who are receiving doses of propranolol in excess of 320 mg daily, may require inotropic support transiently in the perioperative period. But such support will be temporary and does not appear to correlate with demonstrable myocardial injury.
References 1. Boudoulas H, Snyder GL, Lewis RE’, et al: Safety and rationale for continuation of propranolol therapy during coronary bypass operation. Ann Thorac Surg 261222,1978 2. Caralps JM, Mulet J, Wienke R, et al: Results of coronary artery surgery in patients receiving
propranolol. J Thorac Cardiovasc Surg 67:526, 1974 3. Coltart DJ, Cayen MN, Stinson EB, et al: Investi-
134 The Annals of Thoracic Surgery Vol 30 No 2 August 1980
gation of the safe withdrawal period for propranolol in patients scheduled for open heart surgery. Br Heart J 37:1228, 1975 4. Coltart DJ, Shand DG: Plasma propranolol levels in the quantitative assessment of P-adrenergic blockade in man. Br Med J 3:731, 1970 5. Faulkner SL, Hopkins JT, Boerth RC, et al: Time required for complete recovery from chronic propranolol therapy. N Engl J Med 289:607, 1973 6. Jones EL, Kaplan JA, Dorney ER, et al: Propranolol therapy in patients undergoing myocardial revascularization. Am J Cardiol38:696, 1976 7. Kaplan JA, Dundar RW, Bland JW Jr, et al: Propranolol and cardiac surgery: a problem for the anesthesiologist? Anesth Analg (Cleve) 54:571, 1975 8. Kirsh MM, Behrendt DM, Jackson AP, et al: Myocardial revascularization in patients receiving long-term propranolol therapy. Ann Thorac Surg 25:117, 1978 9. Miller RR, Olson HG, Amsterdam EA, et al: Propranolol withdrawal rebound phenomenon: exacerbation of coronary events after abrupt cessation of antianginal therapy. N Engl J Med 293:416, 1975 10. Moran JM, Mulet J, Caralps JM, et al: Coronary revascularization in patients receiving propranolol. Circulation 49, 5O:II-116, 1974 11. Parker JO, West 0, Digiorgi S: Hemodynamic effects of propranolol in coronary heart disease. Am J Cardiol 21:11, 1968 12. Romagnoli A, Keats AS: Plasma and atrial propranolol after preoperative withdrawal. Circulation 52:1123, 1975 13. Shand DG, Wood AJJ: Propranolol withdrawal syndrome: why? (editorial.) Circulation 58:202, 1978 14. Viljoen JF, Estafanous FG, Kellner GA: Propranolol and cardiac surgery. J Thorac Cardiovasc Surg 64:826, 1972
Discussion D R . ELLIS L. JONES (Atlanta, GA): I congratulate' Dr. Wechsler for a very well conceived and well executed clinical study, which is so characteristic of the work from Duke. Our initial experience dates back to 1975 when my colleagues and I reviewed the records of 185 consecutive patients having myocardial revascularization. We looked at the preoperative administration of propranolol and the intraoperative or postoperative complications. The 185 patients were arbitrarily divided into four groups. Group 1 patients had propranolol continued to within 10 hours of induction of anesthesia. In Group 2, propranolol was discontinued 24 to 48 hours before operation. In Group 3, propranolol was discontinued more than 48 hours before operation, and Group 4 patients never were administered the
drug at all. For the most part, the dosages were in the low and intermediate ranges, although a few patients were at the higher l e v e l s 3 2 0 to 480 mg a day. The incidence of complications, e.g., hypotension, bradycardia, hypertension, and tachycardia, prior to cardiopulmonary bypass was no greater in patients on a regimen of propranolol up until the time of operation than in patients who had the drug discontinued in advance or had never received the drug. It was very interesting that the incidence of hypertension and tachycardia, the factors that control ratepressure product and myocardial oxygen consumption, was no greater and probably a little less in those patients administered propranolol the night before operation. Postoperatively there was no greater incidence of hypertension requiring inotropic support or balloon pumping and no greater mortality in Groups 1and 2 (recently on a regimen of propranolol) compared with those in Group 3 or 4. The time of our study was 1975, when patients on a regimen of beta-blocking drugs were routinely withdrawn from the drug seven days prior to revascularization. We measured the serum levels of propranolol and, as Dr. Wechsler mentioned, found a difference in levels for the different groups of patients. Those on low and intermediate doses of propranolol had no significantly detectable serum levels by the end of cardiopulmonary bypass. However, for those patients given very large doses of the drug, serum levels were still present at the conclusion of the operation. Since adopting the policy of continuing propranolol until the night prior to operation, we have found the incidence of inotropic requirement has decreased over the years, and the incidence of intraaortic balloon pumping is about 1%. Hospital mortality in our last 3,040 patients has been 0.8% (25 deaths). We, therefore, believe our present philosophy regarding propranolol has not influenced our clinical results adversely. In conclusion, data are very scanty for patients on a regimen of extremely large doses of beta-blocking agents. Their numbers in our practice are very small. Our cardiologists appear to have gone through a transition in their thinking. If patients fail to respond to the low and intermediate doses, they are recommended for operation and are not carried to the extremes of medical management. I have one question for Dr. Wechsler. Have you employed test doses of isoproterenol in patients who receive large doses of propranolol after bypass to see if there is residual beta blockade? DR. CHARLES w. PEARCE (New Orleans, LA): It has been my privilege in New Orleans to do cardiac surgical procedures in three different hospitals and thus to work with three different cardiology groups. One of these groups typically uses quite large doses of pro-
135 Wechsler: Prospectively Randomized Patients Receiving Propranolol
pranolol in patients. It is quite common for the patients to receive doses of 320 to 480 mg of propranolol right up through the evening prior to operation. Another group tends to use propranolol in moderate dosage and the third, in quite low dosage. During the past year we have operated on 392 consecutive patients. There has been no hospital mortality. However, those of us operating on the patients whose cardiologists typically use large doses of propranolol, 320 to 480 mg, have made these observations: prolonged pump support is often necessary before these patients can be weaned from the pump, and additional inotropic support is necessary at that point and in the early period following operation. These observations, I think, support Dr. Wechsler’s general observation that a propranolol dosage of high magnitude does indeed have some definite effect on myocardial function in the operative and the early postoperative period. (Pelham, NY): We have also been interested in the effect of propranolol withdrawal on perioperative hemodynamics. Some of our data were presented at the recent American Heart Association meeting in Anaheim. We studied four groups of patients, each containing 17 to 20 patients. Group 1 never received propranolol; in Group 2, propranolol was discontinued 48 hours preoperatively; in Group 3, it was discontinued 10 hours preoperatively; and in Group 4, it was continued throughout the operation and restarted postoperatively in small intravenously administered doses. We also looked at rate-pressure products and found no differences in the responses when propranolol was discontinued 48 hours preoperatively (Group 2) or 10 hours preoperatively (Group 3). Both groups demonstrated huge increases in rate-pressure products on induction of anesthesia. By contrast, there was a marked blunting of this effect in patients in whom propranolol was continued throughout the operation (Group 4). In addition to blunting the increases in rate-pressure product, we found that maintenance of propranolol resulted in a marked decrease in postoperative atrial arrhythmias compared with those groups in whom propranolol was discontinued. I will remind you that a large percentage of perioperative infarctions are initiated in the prebypass phase of the operation. Maintenance of beta blockade prior to revascularization should minimize the potential for perioperative infarction. I thank Dr. Wechsler for providing me with a copy of his manuscript. I agree that maintenance of propranolol is not only safe but is often beneficial, and we continue to use it aggressively and to reinstitute propranolol as soon as the patient returns to the intensive care unit. I have one question for Dr. Wechsler. I noticed that
DR. RONALD M . BECKER
his group uses morphine anesthesia. I consider this a poor choice for patients having a coronary operation since morphine does not block cortical responses to stress. Perhaps Dr. Wechsler could comment on his choice of anesthetic agent. DR.RICHARD D. WEISEL (Toronto, Ontario, Canada): A randomized trial of intravenously administered propranolol was performed in 100 patients undergoing elective coronary bypass operation at the Toronto General Hospital under the direction of Drs. Dosch and Teasdale. In 50 control patients, propranolol was discontinued 8 hours preoperatively and in 50 patients it was continued by an infusion of 0.04 mg per kilogram of body weight per hour intraoperatively and for 36 hours postoperatively. Serum propranolol levels revealed that only control patients receiving more than 160 mg per day had measurable propranolol levels during anesthesia induction. This information supports Dr. Jones’s findings. The propranolol group had a lower rate-pressure product during anesthesia induction and a lower incidence of postoperative arrhythmias. Did Dr. Wechsler also find fewer postoperative arrhythmias? A subgroup of 20 patients randomly allocated to a group to receive intravenously administered proyranolol or to a control group, had serial measurements of postoperative myocardial performance and metabolism. The propranolol group had depressed performance compared with the control group but responded to atrial pacing by lactate extraction whereas control patients produced lactate in response to atrial pacing in the immediate postoperative period (2 to 6 hours). An infusion of propranolol perioperatively may protect the ischemic myocardium, but renders the patient very sensitive to hypervolemia or hypovolemia. Therefore, it must be used with caution. DR. WECHSLER: I thank Dr. Jones, Dr. Pearce, Dr. Becker, and Dr. Weisel for their comments. Dr. Jones, we did not do isoproterenol testing. I think it would have been a good maneuver to look for residual physiological effects of the propranolol. Regarding the use of morphine sulfate, the anesthesiologists at the time of the study used that method exclusively. In answer to your question, I think the trend has been to revert to inhalation anesthetics, and currently the large doses of morphine are not used. We did not find that there was a decrease in the incidence of atrial arrhythmias in those patients in whom the propranolol had been maintained to the time of operation. Dr. Weisel, perhaps your study differs from ours in that you maintain the drug through the operative period. Dr. Becker, I can’t explain why we didn‘t make this observation and you did. I have a final comment. This study provides a bit of
136 The Annals of Thoracic Surgery Vol 30 No 2 August 1980
a caveat. Initially there was concern that patients could not be continued on propranolol to the immediate operative time, and most studies analyzed the effect of withdrawal of the drug several days before operation as compared with 24 to 48 hours prior to operation. There have only been one or two studies in which the drug was continued right to the time of operation in significant doses. Using doses of 320 to 480 mg, such as our high-dose patients were receiving, has not been documented before except in a few
of the patients in Group 1of Dr. Jones’s study. In this subgroup of patients, there clearly are high serum levels present at the time of operation. Moreover, metabolites become present during operation as the result of hepatic detoxification. Some of these metabolites are beta blockers that do not show in serum propranolol assays but which do have a pharmacological effect. Of course, the beta block can be reversed simply by the use of beta agonists in the perioperative period if necessary.
Notice from the American Board of Thoracic Surgery
The American Board of Thoracic Surgery will give a voluntary recertification examination in the fall of 1981. Diplomates interested in participating in this examination should maintain a documented list of their cardiothoracic operations performed two years prior to application for recertification. They should also keep a record of their attendance at thoracic surgical meetings and other continuing medical education activities for the two years prior to application for recertification.
Some time during the summer, a Recertification Brochure will be mailed to all diplomates outlining the rules and requirements established for recertification in thoracic surgery. This brochure will also contain information about applying for the voluntary recertification examination. Please address all communications to the American Board of Thoracic Surgery, 14640 E Seven Mile Rd, Detroit, MI 48205.
I express my appreciation to Ayerst Laboratories for making this study possible, specifically to Dr. Ezra Lamdin for his encouragement, and for the performance of the propranolol assays. Appreciation is also expressed to Mrs. Edna Ferrell and Mrs. Ruby Griffin for secretarial assistance and to the anesthesia, operating room, and intensive care support personnel at the Durham Veterans Administration Hospital. Presented at the Sixteenth Annual Meeting of The Society of Thoracic Surgeons, Jan 21-23, 1980, Atlanta, GA. Address reprint requests to Dr. Wechsler, Associate Professor of Surgery, PO Box 3174, Duke University Medical Center, Durham, NC 27710.
its beneficial perioperative hemodynamic effects but suggests that maintenance of doses of 320 to 480 mg per day are associated with a greater duration and extent of action that may transiently affect early postoperative hemodynamic performance.
The use of propranolol as part of the immediate preoperative pharmaceutical program for patients undergoing aortocoronary bypass grafting has been controversial. Despite early warnings relating preoperative beta blockade to high operative risks, most investigators have discerned little difference in patients receiving propranolol preoperatively compared with patients in whom the medication was discontinued. As summarized in Table 1, most information has been gleaned from reports of successive cohorts of patients and only one prior investigation used a clinical study in which propranolol maintenance or withdrawal was prospectively randomized. Moreover, most comparisons were made between groups of patients maintained on propranolol to within 36 to 48 hours of operation compared with groups of patients in whom propranolol was discontinued several days in advance of the operative procedure. This study compares patients maintained on substantial doses of propranolol in the immediate preoperative period with a group of patients in whom the medication was discontinued 24 to 48 hours prior to operation.
Material and Methods Ninety patients were included in the study. Informed consent was obtained from all patients who participated in the study, and the entire investigational protocol was approved by the Human Experimental Investigation Committee. Fifty patients receiving long-term propranolol therapy who were admitted for elective aortocoronary bypass operation were randomly assigned to one of two groups of 25 patients
128 0003-4975/80/080128-09$01.25 @ 1980 by The Society of Thoracic Surgeons
129 Wechsler: Prospectively Randomized Patients Receiving Propranolol
Table 1. Previous Investigators Reporting on the Use of Propranolol in the Immediate Perioperative Period Patients on Propranolol
Author
Year
Type Study
Viljoen et a1 [141 Caralps et a1 [21 Moran et a1 [lo] Kaplan et al [71 Jones et a1 [61
1972 1974 1974
Case reports
5
25 52
1976
Retrospective Retrospective Retrospective Retrospective
Kirsh et a1 [8]”
1978
Prospective
1978
randomized Retrospective
Boudoulas et a1 [l]
1975
Patients off Propranolol 0 75
251
143 113 14
26
30
50
72
13
“This study represents the only other investigation in which a prospectively randomized format for propranolol management was used.
each. One group had propranolol discontinued 24 to 48 hours prior to operation. Regardless of the dose taken on admission, these patients were maintained on 160 mg of propranolol daily prior to cessation of therapy. Eighteen patients were on a regimen of 160 mg of propranolol daily and 7, 320 to 480 mg daily. The second group of 25 patients were maintained on propranolol and received the last dose 4 hours prior to operation. Patients receiving more than 160 mg of propranolol daily were reduced to 160 mg daily 24 to 48 hours prior to operation. Of this group, 16 patients were on a regimen of 160 mg daily and 9, 320 to 480 mg daily. A third group of patients, in whom therapy was not randomized, consisted of 25 successive patients admitted for elective aortocoronary bypass operation. These patients were not receiving propranolol. A fourth group consisted of 15 patients who underwent operation for unstable angina pectoris and who were receiving propranolol u p to 4 hours prior to operation. These patients did not have the propranolol dosage reduced regardless of the admission dosage program. Statistical comparisons were made only between the two groups of patients in whom drug therapy was prospectively randomized. All patients were men, and computer analysis of patient variables among the four groups was used to assess multiple descriptors by analysis of covariance to determine the comparability of the groups. This analysis included the incidence of left main coronary disease of greater
than 70% obstruction, resting ejection fraction, presence or absence of mitral valve regurgitation, presence or absence of congestive heart failure, presence or absence of resting S-T segment and T wave changes, patient age, history of prior myocardial infarction, arterial venous oxygen saturation difference, number of diseased vessels, evidence of ventricular dysfunction on cineangiogram, and the presence or absence of cardiomegaly on chest roentgenogram. For these descriptors, patients operated on for unstable angina (not randomized) had a higher incidence of left main coronary artery disease, as indicated in Table 2, but were otherwise indistinguishable. In addition to the patient risk descriptors just described, the perioperative pressure-heart rate product was calculated on arrival in the operating room, at the peak response during anesthetic induction, and 30 minutes following termination of cardiopulmonary bypass. The incidence of myocardial infarction was determined from the presence of new Q waves on the postoperative electrocardiogram and a myocardial damage index was calculated for the patients having prospective randomization of their propranolol programs by determining the area under a CPK-MB duration curve level with samples being drawn at 6-hour intervals for the first 72 hours after operation. Requirements for inotropic support were recorded both for patients who required such support to terminate cardiopulmonary bypass and for patients who required initiation of such support within the first 24 hours after opera-
130 The Annals of Thoracic Surgery Vol 30 No 2 August 1980
Table 2 . Critical Variables for the Patient Groups Studied Variable Left main coronary disease > 70% Resting ejection fraction (%) No. of grafts Cross-clamp time (min)
(YO)
or
P
16 43 f 5.2 2.6 f 0.14 36 k 4.1
16 44 k 4.6 2.9 f 0.19 34 3.7
'p
*
20 47 ? 5.1 2.8 f 0.15 37 f 2.9
P(NR) 33 a 41 f 3.9 2.9 k 0.23 37 f 4.3
" p < 0.01. This was significantly different from all the other groups. OF = patients never receiving propranolol; 1' = patients receiving the last dose of propranolol4 hours prior to operation;% patients receiving long-term propranolol therapy, discontinued 24 to 48 hours prior to operation; P(NR) = patients with unstable angina who received the last propranolol dose 4 hours prior to operation. =
tion. The incidence of hypertension requiring nitroprusside therapy was noted as was documentation of arrhythmias. Propranolol serum levels were obtained in each patient at the time the skin incision was made. The Student t test for unpaired data was used to calculate differences between the randomized groups.
Basic Operative Techniques A standardized method of operation was used for all patients in the study. This included anesthetic induction with diazepam (Valium) and morphine and maintenance with morphine, nitrous oxide, and pancuronium. Hernodilution techniques were employed; however, the hematocrit was not allowed to fall below 20% during the period of cardiopulmonary bypass. Systemic temperatures were maintained at 30°C and operations were performed using hyperkalemic, crystalloid cardioplegia (5°C) with a potassium concentration of 24 mEq per liter. Proximal anastomoses were performed prior to distal anastomoses and following an initial cardioplegic infusion of approximately 500 ml per square meter of body surface area. Supplements of cardioplegic solution were infused after the completion of each distal anastomosis (usually 150 to 200 ml). Left ventricular venting was not employed, and reperfusion was greater than or equal to half the aortic cross-clamp time. Strict criteria for inotropic support were employed. Inotropic agents were used to terminate cardiopulmonary bypass when the patient was unable to maintain a blood pressure greater than 110 mg Hg systolic or when the systolic pressure was less than 20% below control levels, and when the pulmonary artery diastolic pressure, pulmonary capillary wedge pressure,
or left atrial mean pressure was greater than 15 mm Hg. A decision to employ inotropic support following termination of cardiopulmonary bypass was made for a cardiac index less than 2 or when the pulmonary artery diastolic pressure, pulmonary capillary wedge pressure, or left atrial mean pressure was greater than 15 mm Hg. If isolated hypotension was present with cardiac indices greater than 2 Llminlm', alpha agonists were employed.
Results Table 2 summarizes the salient intraoperative features for the four study groups. No significant differences among the groups in the number of grafts or the aortic cross-clamp times existed. Table 3 lists the principal comparisons made among the groups. In addition to these, the incidence of important arrhythmias was not different for the two groups. Significant differences between the two groups in which propranolol therapy had been randomly managed were confined to the pressure-rate product determined at all three measurement points as well as in the requirement for inotropic support, particularly within the first 24 hours. The increment in inotropic support between that required to terminate cardiopulmonary bypass and that initiated within the first 24 hours for all patients occurred within 6 hours of return to the intensive care unit. The mean propranolol serum level was also higher in the group in which propranolol had been maintained compared with the group in which it had been discontinued. These differences are examined in more detail in Figures 1, 2, and 3. As illustrated in Figure 1, significant differences existed in the basal pressure-rate product among patients maintained on propranolol and
131 Wechsler: Prospectively Randomized Patients Receiving Propranolol
Table 3 . Chief Variables Compared in S t u d y Variable
or
P
P
P("
Arrival pressure-rate product Peak pressure-rate product
11,242 f 722 17,400 k 902 12,146 f 513 2125 2125 15/25 1125 2/25 0
6,960 rt 421" 10,800 k 629" 9,422 f 622" 1/25 7/25" 12/25 1/25 3125 16.4"
11,480 ?c 803 18,100 k 1151 13,114 rt 877 2/25 1/25 16125 0/25 1125 3.1
6,640 k 501 11,200 ?c 781 9,017 k 536 2/15 4/15 8115 1/15 2115 20.2
P o s t p u m p pressure-rate product Pump inotropic support 24-hr inotropic s u p p o r t Required nitroprussideb Acute myocardial infarction" Myocardial d a m a g e i n d e x > 200 Propranolol level
" p < 0.01 when compared with randomized patients in whom propranolol was discontinued 24 to 48 hours prior to operation. bFigures represent the absolute number of patients in each group requiring nitroprusside administration for control of postoperative hypertension. 'As defined by the appearance of new Q waves. OP = patients never receiving propranolol; P = randomized patients receiving the last dose of propranolol4 hours prior to operation; P = randomized patients in whom propranolol was discontinued 24 to 48 hours prior to operation; P(NR) = patients with unstable angina who received the last propranolol dose 4 hours prior to operation.
100 r
140
100 Ly
I 60
20
P
OP
P
'R
PINR)
Fig 1 . (Top) Pressure-rate product (P X HR) XlO-' on arrival in the operating room and at peak response during anesthetic induction for each of the four study groups. (Bottom) Heart rate (HR) determined at the same times as the pressure-rate product. (OP = patients never receiving propranolol; P = patients receiving the last dose of propranolol4 hours prior to operation; R = patients receiving long-term propranolol therapy discontinued 24 to 48 hours prior to operation; P(NR) = patients with unstable angina w h o received the last propranolol dose 4 hours prior to operation; * = p < 0.01 when compared with the randomized group in which propranolol was discontinued 24 to 48 hours prior to operation.)
PNRI
Fig 2 . (Top) Percentage of patients in each of the subgroups requiring inotropic support either to terminate cardiopulmonary bypass or within the first 24 hours after cardiopulmonary bypass. There was a significant difference (p < 0.05) between the two groups of patients in the randomized treatment protocol as there was between the patients maintained on propranolol who had unstable angina compared with those not receiving propranolol or in whom propranolol had been discontinued. (Bottom) Comparison of patients maintained on propranolol and having inotropic support requirements as a function of propranolol dosage. (OP = patients never receiving propranolol; P = patients receiving the last dose of propran01014 hours prior to operation; YP = patients who had long-term propranolol therapy discontinued 24 to 48 hours prior to operation; P(NR) = patients with unstable angina who received the last propranolol dose 4 hours prior to operation.)
132 The Annals of Thoracic Surgery
w
Vol 30 No 2 August 1980
m >320mg/d
rn
rn rn 0
P
P
P(NR)
lnotropic Support Patients
Fig 3 . Relationship between serum propranolol levels and the dosage of propranolol in patients requiring inotropic support anytime within the perioperative period. (P= patients who had long-term propranolol therapy discontinued 24 to 48 hours prior to operation; P = patients receiving the last dose of propranolol4 hours prior to operation; P(NR) = patients with unstable angina who received the last propranolol dose 4 hours prior to operation.)
tained on propranolol, which paralleled the incidence of inotropic support in patients operated on for unstable angina who continued propranolol treatment. In the upper half of the figure, almost 30% of patients maintained on high-dose propranolol therapy required inotropic support using the criteria described in the Methods section. Further breakdown of the patient subgroups is shown in the lower portion of the figure where the percentage of inotropic support for patients receiving continued propranolol therapy is shown. An increased incidence of inotropic support was noted only in patients receiving more than 320 mg of propranolol daily and approached 60% of that population. On the other hand, patients being maintained on propranolol but in doses of less than 320 mg had an incidence of inotropic support requirement no greater than patients either not receiving propranolol or in whom propranolol was discontinued 24 to 48 hours prior to operation. The relationship between the dosage of propranolol maintained and the serum propranolol level in the patients requiring inotropic support is illustrated in Figure 3. Only 2 patients receiving less than 320 mg per day of propranolol required inotropic support. Both these patients were in the randomized group in which propranolol had been discontinued 24 to 48 hours prior to operation, and both these patients had no detectable serum levels of propranolol. All the patients in the randomized group that had propranolol discontinued 24 to 48 hours prior to operation had no detectable serum levels of propranolol as was true for the group of patients never receiving propranolol therapy. Of the patients requiring inotropic support in the groups maintained on propranolol until the time of operation, 7 patients had 20 ng per milliliter or greater concentration of propranolol, while 4 had concentrations below that level. No propranolol levels greater than 10 ng per milliliter were found in patients in either of the groups maintained on propranolol who did not require inotropic support.
those in whom the drug was discontinued. Similarly, there was suppression of the elevation in pressure-rate product that accompanied induction of anesthesia in this group as well. These observations paralleled closely the comparison among nonrandomized patients not receiving propranolol compared with patients not randomized and operated on for unstable angina who were maintained on propranolol. In both the randomized and nonrandomized groups, maintenance of propranolol therapy was associated with significantly lower pressure-rate products on arrival in the operating room and during the anesthetic induction period. Separate analyses of heart rate as shown in the lower half of the figure showed parallel significant suppression of heart rate response to anesthetic induction in both propranololtreated groups. Moreover, the heart rate differences appear primarily responsible for the decreased pressure-rate products in the group of patients maintained on propranolol therapy. A more detailed analysis of patients requiring inotropic support is presented in Figure 2. Patients who underwent randomization of propranolol therapy with withdrawal of drug 24 to 48 hours prior to operation had an incidence of inotropic support requirement that paralleled closely the group of patients never receiving propranolol treatment. A significantly greater Comment percentage of patients required inotropic sup- The data presented in this study generally support in the group of patients randomly main- port the notion that continuance of propranolol
133 Wechsler: Prospectively Randomized Patients Receiving Propranolol
therapy to the time of operation is safe and potentially beneficial. The reduced pressure-rate product in patients maintained on propranolol in the absence of untoward anesthetic events appears to be a highly desirable benefit of such therapy, particularly for the suppression of the heightened pressure-rate product that generally accompanied the process of intubation in patients not receiving propranolol or in whom propranolol had been discontinued 24 to 48 hours prior to operation. The finding of substantial levels of propranolol in the serum of patients maintained to the time of operation is not inconsistent with prior reports on the half-life of serum propranolol. Thirty-six to 48 hours following discontinuation of propranolol therapy, most investigators have shown no serum propranolol present, absent propranolol from atrial tissue excised at operation, and a normal response to pharmacological beta stimulation [2-5, 11, 121. The propranolol levels in patients maintained on the drug to the time of operation were significantly higher than in patients in whom the drug had been discontinued. In patients requiring inotropic intervention, the daily dosage of propranolol was invariably 320 mg or more, even though reduced to 160 mg 24 to 48 hours prior to operation in the group of patients who underwent randomization of the therapeutic programs. It was interesting to note that more patients in the group requiring inotropic support evidenced their need for such support within several hours of operation than did those requiring inotropic intervention to terminate cardiopulmonary bypass. It is possible that intense levels of neurogenic and humoral catecholamine stimulation in the period immediately after pump removal allowed adequate maintenance of beta function to support systemic hemodynamics. With some withdrawal of this intense stimulation, and in the presence of significant propranolol levels or betablocking hepatic metabolites of propranolol (not measured in this study), a dependence on exogenous beta stimulation may have resulted. In all patients, beta agonists could be withdrawn within 24 hours of operation, perhaps suggesting the dislodgment of beta blockers and subsequent metabolic degradation of these
rather than intrinsic myocardial injury and depression. This study differs from previous investigations in several respects. It utilized a tightly controlled patient population under the care of a single surgeon. A primary comparison was possible between two groups of patients in whom propranolol therapy could be managed in a randomly allocated fashion. The issue addressed was related more to the relative safety of maintaining propranolol in significant doses immediately prior to the time of operation compared with following the more recommended protocol of discontinuing propranolol 24 to 48 hours prior to operation. Most previous investigations were concerned primarily with the question of discontinuing propranolol several days in advance of the procedure or maintaining it to within 24 to 48 hours of operation. In our population of patients studied in whom propranolol was discontinued 24 to 48 hours prior to operation, there was no evidence of a ”propranolol rebound phenomenon,” confirming the safety of this conservative approach to management of propranolol dosage [9, 131. As a result of this investigation and after consideration of prior reports appearing in the literature, it appears beneficial to maintain propranolol in patients with unstable angina or those with unusually severe angina by history at outpatient levels immediately prior to the time of operation because of the desirable perioperative hemodynamic effects. The surgeon should anticipate that patients so maintained, who are receiving doses of propranolol in excess of 320 mg daily, may require inotropic support transiently in the perioperative period. But such support will be temporary and does not appear to correlate with demonstrable myocardial injury.
References 1. Boudoulas H, Snyder GL, Lewis RE’, et al: Safety and rationale for continuation of propranolol therapy during coronary bypass operation. Ann Thorac Surg 261222,1978 2. Caralps JM, Mulet J, Wienke R, et al: Results of coronary artery surgery in patients receiving
propranolol. J Thorac Cardiovasc Surg 67:526, 1974 3. Coltart DJ, Cayen MN, Stinson EB, et al: Investi-
134 The Annals of Thoracic Surgery Vol 30 No 2 August 1980
gation of the safe withdrawal period for propranolol in patients scheduled for open heart surgery. Br Heart J 37:1228, 1975 4. Coltart DJ, Shand DG: Plasma propranolol levels in the quantitative assessment of P-adrenergic blockade in man. Br Med J 3:731, 1970 5. Faulkner SL, Hopkins JT, Boerth RC, et al: Time required for complete recovery from chronic propranolol therapy. N Engl J Med 289:607, 1973 6. Jones EL, Kaplan JA, Dorney ER, et al: Propranolol therapy in patients undergoing myocardial revascularization. Am J Cardiol38:696, 1976 7. Kaplan JA, Dundar RW, Bland JW Jr, et al: Propranolol and cardiac surgery: a problem for the anesthesiologist? Anesth Analg (Cleve) 54:571, 1975 8. Kirsh MM, Behrendt DM, Jackson AP, et al: Myocardial revascularization in patients receiving long-term propranolol therapy. Ann Thorac Surg 25:117, 1978 9. Miller RR, Olson HG, Amsterdam EA, et al: Propranolol withdrawal rebound phenomenon: exacerbation of coronary events after abrupt cessation of antianginal therapy. N Engl J Med 293:416, 1975 10. Moran JM, Mulet J, Caralps JM, et al: Coronary revascularization in patients receiving propranolol. Circulation 49, 5O:II-116, 1974 11. Parker JO, West 0, Digiorgi S: Hemodynamic effects of propranolol in coronary heart disease. Am J Cardiol 21:11, 1968 12. Romagnoli A, Keats AS: Plasma and atrial propranolol after preoperative withdrawal. Circulation 52:1123, 1975 13. Shand DG, Wood AJJ: Propranolol withdrawal syndrome: why? (editorial.) Circulation 58:202, 1978 14. Viljoen JF, Estafanous FG, Kellner GA: Propranolol and cardiac surgery. J Thorac Cardiovasc Surg 64:826, 1972
Discussion D R . ELLIS L. JONES (Atlanta, GA): I congratulate' Dr. Wechsler for a very well conceived and well executed clinical study, which is so characteristic of the work from Duke. Our initial experience dates back to 1975 when my colleagues and I reviewed the records of 185 consecutive patients having myocardial revascularization. We looked at the preoperative administration of propranolol and the intraoperative or postoperative complications. The 185 patients were arbitrarily divided into four groups. Group 1 patients had propranolol continued to within 10 hours of induction of anesthesia. In Group 2, propranolol was discontinued 24 to 48 hours before operation. In Group 3, propranolol was discontinued more than 48 hours before operation, and Group 4 patients never were administered the
drug at all. For the most part, the dosages were in the low and intermediate ranges, although a few patients were at the higher l e v e l s 3 2 0 to 480 mg a day. The incidence of complications, e.g., hypotension, bradycardia, hypertension, and tachycardia, prior to cardiopulmonary bypass was no greater in patients on a regimen of propranolol up until the time of operation than in patients who had the drug discontinued in advance or had never received the drug. It was very interesting that the incidence of hypertension and tachycardia, the factors that control ratepressure product and myocardial oxygen consumption, was no greater and probably a little less in those patients administered propranolol the night before operation. Postoperatively there was no greater incidence of hypertension requiring inotropic support or balloon pumping and no greater mortality in Groups 1and 2 (recently on a regimen of propranolol) compared with those in Group 3 or 4. The time of our study was 1975, when patients on a regimen of beta-blocking drugs were routinely withdrawn from the drug seven days prior to revascularization. We measured the serum levels of propranolol and, as Dr. Wechsler mentioned, found a difference in levels for the different groups of patients. Those on low and intermediate doses of propranolol had no significantly detectable serum levels by the end of cardiopulmonary bypass. However, for those patients given very large doses of the drug, serum levels were still present at the conclusion of the operation. Since adopting the policy of continuing propranolol until the night prior to operation, we have found the incidence of inotropic requirement has decreased over the years, and the incidence of intraaortic balloon pumping is about 1%. Hospital mortality in our last 3,040 patients has been 0.8% (25 deaths). We, therefore, believe our present philosophy regarding propranolol has not influenced our clinical results adversely. In conclusion, data are very scanty for patients on a regimen of extremely large doses of beta-blocking agents. Their numbers in our practice are very small. Our cardiologists appear to have gone through a transition in their thinking. If patients fail to respond to the low and intermediate doses, they are recommended for operation and are not carried to the extremes of medical management. I have one question for Dr. Wechsler. Have you employed test doses of isoproterenol in patients who receive large doses of propranolol after bypass to see if there is residual beta blockade? DR. CHARLES w. PEARCE (New Orleans, LA): It has been my privilege in New Orleans to do cardiac surgical procedures in three different hospitals and thus to work with three different cardiology groups. One of these groups typically uses quite large doses of pro-
135 Wechsler: Prospectively Randomized Patients Receiving Propranolol
pranolol in patients. It is quite common for the patients to receive doses of 320 to 480 mg of propranolol right up through the evening prior to operation. Another group tends to use propranolol in moderate dosage and the third, in quite low dosage. During the past year we have operated on 392 consecutive patients. There has been no hospital mortality. However, those of us operating on the patients whose cardiologists typically use large doses of propranolol, 320 to 480 mg, have made these observations: prolonged pump support is often necessary before these patients can be weaned from the pump, and additional inotropic support is necessary at that point and in the early period following operation. These observations, I think, support Dr. Wechsler’s general observation that a propranolol dosage of high magnitude does indeed have some definite effect on myocardial function in the operative and the early postoperative period. (Pelham, NY): We have also been interested in the effect of propranolol withdrawal on perioperative hemodynamics. Some of our data were presented at the recent American Heart Association meeting in Anaheim. We studied four groups of patients, each containing 17 to 20 patients. Group 1 never received propranolol; in Group 2, propranolol was discontinued 48 hours preoperatively; in Group 3, it was discontinued 10 hours preoperatively; and in Group 4, it was continued throughout the operation and restarted postoperatively in small intravenously administered doses. We also looked at rate-pressure products and found no differences in the responses when propranolol was discontinued 48 hours preoperatively (Group 2) or 10 hours preoperatively (Group 3). Both groups demonstrated huge increases in rate-pressure products on induction of anesthesia. By contrast, there was a marked blunting of this effect in patients in whom propranolol was continued throughout the operation (Group 4). In addition to blunting the increases in rate-pressure product, we found that maintenance of propranolol resulted in a marked decrease in postoperative atrial arrhythmias compared with those groups in whom propranolol was discontinued. I will remind you that a large percentage of perioperative infarctions are initiated in the prebypass phase of the operation. Maintenance of beta blockade prior to revascularization should minimize the potential for perioperative infarction. I thank Dr. Wechsler for providing me with a copy of his manuscript. I agree that maintenance of propranolol is not only safe but is often beneficial, and we continue to use it aggressively and to reinstitute propranolol as soon as the patient returns to the intensive care unit. I have one question for Dr. Wechsler. I noticed that
DR. RONALD M . BECKER
his group uses morphine anesthesia. I consider this a poor choice for patients having a coronary operation since morphine does not block cortical responses to stress. Perhaps Dr. Wechsler could comment on his choice of anesthetic agent. DR.RICHARD D. WEISEL (Toronto, Ontario, Canada): A randomized trial of intravenously administered propranolol was performed in 100 patients undergoing elective coronary bypass operation at the Toronto General Hospital under the direction of Drs. Dosch and Teasdale. In 50 control patients, propranolol was discontinued 8 hours preoperatively and in 50 patients it was continued by an infusion of 0.04 mg per kilogram of body weight per hour intraoperatively and for 36 hours postoperatively. Serum propranolol levels revealed that only control patients receiving more than 160 mg per day had measurable propranolol levels during anesthesia induction. This information supports Dr. Jones’s findings. The propranolol group had a lower rate-pressure product during anesthesia induction and a lower incidence of postoperative arrhythmias. Did Dr. Wechsler also find fewer postoperative arrhythmias? A subgroup of 20 patients randomly allocated to a group to receive intravenously administered proyranolol or to a control group, had serial measurements of postoperative myocardial performance and metabolism. The propranolol group had depressed performance compared with the control group but responded to atrial pacing by lactate extraction whereas control patients produced lactate in response to atrial pacing in the immediate postoperative period (2 to 6 hours). An infusion of propranolol perioperatively may protect the ischemic myocardium, but renders the patient very sensitive to hypervolemia or hypovolemia. Therefore, it must be used with caution. DR. WECHSLER: I thank Dr. Jones, Dr. Pearce, Dr. Becker, and Dr. Weisel for their comments. Dr. Jones, we did not do isoproterenol testing. I think it would have been a good maneuver to look for residual physiological effects of the propranolol. Regarding the use of morphine sulfate, the anesthesiologists at the time of the study used that method exclusively. In answer to your question, I think the trend has been to revert to inhalation anesthetics, and currently the large doses of morphine are not used. We did not find that there was a decrease in the incidence of atrial arrhythmias in those patients in whom the propranolol had been maintained to the time of operation. Dr. Weisel, perhaps your study differs from ours in that you maintain the drug through the operative period. Dr. Becker, I can’t explain why we didn‘t make this observation and you did. I have a final comment. This study provides a bit of
136 The Annals of Thoracic Surgery Vol 30 No 2 August 1980
a caveat. Initially there was concern that patients could not be continued on propranolol to the immediate operative time, and most studies analyzed the effect of withdrawal of the drug several days before operation as compared with 24 to 48 hours prior to operation. There have only been one or two studies in which the drug was continued right to the time of operation in significant doses. Using doses of 320 to 480 mg, such as our high-dose patients were receiving, has not been documented before except in a few
of the patients in Group 1of Dr. Jones’s study. In this subgroup of patients, there clearly are high serum levels present at the time of operation. Moreover, metabolites become present during operation as the result of hepatic detoxification. Some of these metabolites are beta blockers that do not show in serum propranolol assays but which do have a pharmacological effect. Of course, the beta block can be reversed simply by the use of beta agonists in the perioperative period if necessary.
Notice from the American Board of Thoracic Surgery
The American Board of Thoracic Surgery will give a voluntary recertification examination in the fall of 1981. Diplomates interested in participating in this examination should maintain a documented list of their cardiothoracic operations performed two years prior to application for recertification. They should also keep a record of their attendance at thoracic surgical meetings and other continuing medical education activities for the two years prior to application for recertification.
Some time during the summer, a Recertification Brochure will be mailed to all diplomates outlining the rules and requirements established for recertification in thoracic surgery. This brochure will also contain information about applying for the voluntary recertification examination. Please address all communications to the American Board of Thoracic Surgery, 14640 E Seven Mile Rd, Detroit, MI 48205.