JOURNAL
OF SURGICAL
Circulatory
RESEARCH
l&181-184
(1975)
Effects of Propranolol
and Cardiopulmonary
Bypass
G. FRANK 0. TYERS, M.D., F.R.C.S.(C), F.A.C.S. AND HOWARD C. HUGHES, JR., V.M.D. Departments of Surgery und Comparative Medicine, College of Medicine. The Milton S. Hershey Medical Center of The Pennsylvania State University, Hershey, Pennsylvania 17033 Received November 8, 1974
Clinical experience has indicated a high operative risk due to depressed ventricular function in certain patients receiving chronic oral propranolol therapy for control of the symptoms of obstructive coronary artery disease.This has led to the recommendation that propranolol be discontinued 2 wk prior to elective coronary bypass surgery [5]. However, the half-life of propranolol in man is less than 6 hr [3] and other workers have reported no significant difference in mortality rates when comparing coronary artery bypass graft patients who had chronic propranolol therapy discontinued 36-48 hr prior to surgery with graft patients who had never received propranolol[4]. Because of the large number of angina patients receiving propranolol, the increasing performance of emergency coronary artery bypass surgery, and the occasional occurrence of acute myocardial infarction after propranolol withdrawal [l] the residual effects of chronic propranolol therapy on cardiac function after induction of anesthesia and after cardiopulmonary bypass were further investigated. METHODS Three groups of adult mongrel dogs were prepared for cardiopulmonary bypass. Six animals received no drugs prior to surgery. Twelve dogs were given 40 mg of propranolol orally twice daily for a minimum of 3 and a maximum of 5 wk. Six of these animals underwent 1 hr of cardiopulmonary bypass approximately 8 hr after the last oral dose of propranolol had been administered. Six had cardiopulmonary
bypass initiated 48 hr after the last dose of propranolol. Prior to bypass, peak systolic pressure, and heart rate were recorded at central venous pressures of 5, 10, and 15 mmHg. After bypass, the animals were allowed to recover for 30 min and cardiac function determinations were repeated at the same preloads. Pre- and postbypass comparisons of cardiac function were made in each of the three groups of animals using the paired t test. For determination of the significance of the differences between the control, propranolol 4% and propranolol 8hr groups the Student t test was used. RESULTS Controls
Cardiac function (means f SE) before and after cardiopulmonary bypass in control animals at central venous pressures of 5, 10, and 15 mmHg are shown in Table 1. As the filling pressure was increased, cardiac output, left ventricular end diastolic pressure, and peak systolic pressure rose both prior to and after bypass. Postbypass parameters were, in general, slightly lower than prebypass values for all functions studied. OfPropranolol48
181 Copyright D 1975 by Academic Press, Inc. All rights of reproduction in any form reserved.
hr
The results of the same cardiac function studies performed approximately 48 hr after the last oral dose of propranolol are shown in Table 2. At a central venous pressure of 5 mmHg, there was no difference between the controls and the experimental animals and there was
182
JOURNAL OF SURGICAL
RESEARCH VOL. 18, NO. 2, FEBRUARY
1975
TABLE 1 Cardiac Function Before and After 1 Hr of Cardiopulmonary Bypass Control Bypass Central venous pressure (mmHg) Cardiac output (ml/min/kg) Left ventricular end diastolic pressure (mmHg) Peak systolic pressure (mmHg) Heart rate (beats/mh)
Pre
Post
Pre
Post
Pre
Post
5 95* 11
5 92* 15
10 195 + 23
10 176 + 24
15 309 f 24
15 2622 25
3*2 7’3 + 18 152 f 16
2+ 1 65* 9 156 f 13
5*2 104 f 10 163 * 12
6+1 102 f 5 163 + 13
11 f 1 121 f 13 149 f 12
9t2 115 f 6 145% 7
_
no difference between pre- and postbypass receiving propranolol until approximately 8 function in the animals off propranolol48 hr. hr prior to cardiopulmonary bypass are At a central venous pressure of 10 mmHg, given in Table 3. there were again no significant differences At a central venous pressure of 5 mmHg, between controls and animals off the only variation from the controls was the propranolol 48 hr, although the experi- postbypass elevation of peak systolic mental group showed a slight reduction in pressure by 49 mmHg (P < 0.05). cardiac output prior to bypass. Both prior to When the central venous pressure was eleand after bypass a slight elevation in sys- vated to 10 mmHg, a number of differences temic pressure was present. However, when were noted. Prior to bypass, cardiac output pre- and postbypass propranolol parameters was 95 ml/min/kg (P < 0.05) lower and left were compared, cardiac output was found to ventricular end diastolic pressure 4 mmHg have risen significantly (P < 0.05 paried t) higher in the propranolol dogs than in the after cardiopulmonary bypass. controls. After cardiopulmonary bypass At a central venous pressure of 15 mmHg, peak systolic pressure was again elevated (57 cardiac output was reduced and peak sys- mmHg, P < 0.05) over control levels, while tolic pressure elevated (both P < 0.05) prior cardiac output rose to control levels (P < to bypass but there were no postbypass 0.05 paried t ). Prior to bypass, when the central venous differences when the 48-hr propranolol and pressure was elevated to 15 mmHg, cardiac control animals were compared. However, output was significantly reduced (147 ml/ when pre- and postbypass data were compared in the animals off propranolol 48 hr, min/kg, P < 0.01) and peak systolic the postbypass left ventricular end diastolic pressure was elevated (44 mmHg, P < 0.05) pressure was noted to have fallen when the animals off propranolol 8 hr were compared with the controls. Postbypass significantly (P < 0.05 paried t ). peak systolic pressure remained elevated (P Of Propranolol8 hr < 0.05) while cardiac output rose to within The results of cardiac function studies the normal range (P < 0.05 paired t). There were no significant differences in prior to and 30 min after surgery in animals TABLE 2 Cardiac Function Before and After 1 Hr of Cardiopulmonary Bypass Chronic Propranolol Discontinued 48 Hr Bypass
Pre
Post
Pre
Post
Pre
Post
Central venous pressure (mmHg) Cardiac output (ml/min/kg) Left ventricular end diastolic pressure (mmHg) Peak systolic pressure (mmHg) Heart rate (beats/min)
5 99 f 23
5 90 f 15
10 159 * 28
10 230 f 43
15 199 f 30
15 261 f 38
2*1 86 f 13 146 f 11
6*1 118 f 20 147 f 12
6*2 116 f 7 144 f 8
16 f 2 159 f 15 133 f 13
9*1 133 f 6 134 f 3
3*1 61 f 8 145 * 9
TYERS AND HUGHES: PROPRANOLOL
AND CARDIOPULMONARY
BYPASS
183
TABLE 3 Cardiac Function Before and After 1 HI of Cardiopulmonary Bypass Chronic Prop~auolol Discontinued 8 HI Bypass Central venous pressure (mmHg) Cardiac output (ml/min/kg) Left ventricular end diastolic pressure (mmHg) Peak systolic pressure (mmHg) Heart rate (beatslmin)
Post
Pre
Post
Pre
Post
5 71* 12
5 100 f 20
10 112 f 20
10 194 t 30
15 162* 17
15 229 t 41
3t2 83t 17 160 * 7
2*1 114 f 17 173 f 7
9+3 119 f 19 162* 11
5*2 159 f 19 163 f 6
14 ?r5 165 f 14 159 * 8
8*2 163 + 13 163 f 3
Pre
administration of propranolol was used [4]. The same report indicated an early return of human cardiac function to normal after the withdrawal of propranolol therapy [4]. Isolated atria1 strips nourished by diffusion were used and a significant bulk of tissue was probably ischemic rendering interpretation of results difficult. In addition, the extrapolation of results from isolated atria1 strips to the intact ventricle is questionable. While the same authors reported no “significant” difference in the operative mortality rate when comparing patients who DISCUSSION had recently received propranolol and After the withdrawal of chronic oral patients never on propranolol [4], a careful propranolol therapy, the induction of study of their data reveals that 2 of 21 anesthesia is associated with a reduction in propranolol patients died (10%) compared cardiac output and elevations of systemic with 2 of 40 nonpropranolol patients (5%). pressure and left ventricular end diastolic The lack of a significant difference may be pressure. These abnormalities of cardiac due more to the small sample than the unfunction are minimal when the preload is low questioned safety of operating while the but become highly significant when the heart effects of propranolol persist. Tests to detect is volume loaded. As the interval between propranolol based on rate must be viewed the last dose of propranolol and the initia- with caution as the present study and a pretion of surgery was increased, the magnitude vious report [5] both indicate the transient of the circulatory changes was reduced, but nature of propranolol’s bradycardic effect significant abnormalities persisted at 48 hr. once the drug is stopped. After an hour of cardiopulmonary bypass, When the combined effects of ischemic the deleterious effects of propranolol were heart disease and propranolol therapy, the ameliorated, with cardiac output and left altered metabolic and hemodynamic effects ventricular end diastolic pressure returning of different routes of drug administration toward normal, although peak systolic and the varying durations of cardiopressure elevation remained. pulmonary bypass are taken into The difference in accumulation of active consideration, some of the discrepancies bemetabolites of propranolol after chronic tween previously reported clinical and exoral administration as compared with perimental findings regarding the duration of parenteral administration [2] makes ques- residual propranolol effects can be undertionable the clinical applicability of previous stood. The clinical course is usually benign in animal studies in which intraperitoneal patients who, without specific indication, heart rate noted when pre- and postbypass results were compared in the controls and in the two groups of animals that had been receiving propranolol. When control rates were compared with rates in the propranolol animals again no differences were noted. However, while oral propranolol was being administered, a marked difference in heart rate between control (195.83h2.01 beats/ min) and treated animals (95.33h5.26 beats/min) was present and P-R interval increased moderately.
184
JOURNAL OF SURGICAL
RESEARCH VOL. 18, NO. 2, FEBRUARY
have received propranolol to within a few hours of surgery. However, the clinical course may be complicated when the drug is continued until just prior to surgery because of patient dependence on it for pain or arrhythmia control. Propranolol dependence indicates severe or diffuse myocardial ischemia and an increased risk on that basis. The effects of atherosclerotic coronary artery disease and propranolol may be additive as both reduce coronary flow, while peripheral vascular disease and propranolol both increase peripheral resistance. When combined with the marked reduction in tolerance to volume loading after chronic propranolol therapy, these additive effects may leave the angina patient with severe coronary artery disease little reserve with which to respond to the stresses of anesthesia and surgery. in patients demonstrating propranolol dependence, we now recommend intraaortic balloon counterpulsation followed by gradual drug withdrawal
1975
prior to surgery. Elective coronary bypass surgery can then be undertaken several days after the last dose of propranolol. REFERENCES ,, Diaz, R. G., Somberg, J. C., Freeman, E., and Levitt, B. Withdrawal of propranolol and myocardial infarction. Lancer 1:1068(1973). 2. Evans, G. H., and Sband, D. G. The disposition of propranolol V. Drug accumulation and steady-state concentration during chronic oral administration in man. Clin. Pharmacol. Ther. 14:487(1973). 3 Evans, G. H., and Shand, D. G. The disposition of ’ propranolol VI. Independent variations in steadystate circulating drug concentrations and half-life as a result of plasma drug binding in man. Clin. Pharmacol. Ther. 14:494(1973). 4. Faulkner, S. L., Hopkins, J. T., Boerth, R. C., Young, J. L., Jr., Jellett, L. B., Nies, A. S., Bender, H. W., and Sband, D. G. Time required for complete recovery from chronic propranolol therapy. N. Engl. J. Med. 289:607-609 (1973). s, Viljoen, J. F., Estafanous, F. G., and Kellner, G. A. Propranolol and cardiac surgery. J. Thorac Cardiovast. Surg. 64:826-830 (1972).
OF SURGICAL
Circulatory
RESEARCH
l&181-184
(1975)
Effects of Propranolol
and Cardiopulmonary
Bypass
G. FRANK 0. TYERS, M.D., F.R.C.S.(C), F.A.C.S. AND HOWARD C. HUGHES, JR., V.M.D. Departments of Surgery und Comparative Medicine, College of Medicine. The Milton S. Hershey Medical Center of The Pennsylvania State University, Hershey, Pennsylvania 17033 Received November 8, 1974
Clinical experience has indicated a high operative risk due to depressed ventricular function in certain patients receiving chronic oral propranolol therapy for control of the symptoms of obstructive coronary artery disease.This has led to the recommendation that propranolol be discontinued 2 wk prior to elective coronary bypass surgery [5]. However, the half-life of propranolol in man is less than 6 hr [3] and other workers have reported no significant difference in mortality rates when comparing coronary artery bypass graft patients who had chronic propranolol therapy discontinued 36-48 hr prior to surgery with graft patients who had never received propranolol[4]. Because of the large number of angina patients receiving propranolol, the increasing performance of emergency coronary artery bypass surgery, and the occasional occurrence of acute myocardial infarction after propranolol withdrawal [l] the residual effects of chronic propranolol therapy on cardiac function after induction of anesthesia and after cardiopulmonary bypass were further investigated. METHODS Three groups of adult mongrel dogs were prepared for cardiopulmonary bypass. Six animals received no drugs prior to surgery. Twelve dogs were given 40 mg of propranolol orally twice daily for a minimum of 3 and a maximum of 5 wk. Six of these animals underwent 1 hr of cardiopulmonary bypass approximately 8 hr after the last oral dose of propranolol had been administered. Six had cardiopulmonary
bypass initiated 48 hr after the last dose of propranolol. Prior to bypass, peak systolic pressure, and heart rate were recorded at central venous pressures of 5, 10, and 15 mmHg. After bypass, the animals were allowed to recover for 30 min and cardiac function determinations were repeated at the same preloads. Pre- and postbypass comparisons of cardiac function were made in each of the three groups of animals using the paired t test. For determination of the significance of the differences between the control, propranolol 4% and propranolol 8hr groups the Student t test was used. RESULTS Controls
Cardiac function (means f SE) before and after cardiopulmonary bypass in control animals at central venous pressures of 5, 10, and 15 mmHg are shown in Table 1. As the filling pressure was increased, cardiac output, left ventricular end diastolic pressure, and peak systolic pressure rose both prior to and after bypass. Postbypass parameters were, in general, slightly lower than prebypass values for all functions studied. OfPropranolol48
181 Copyright D 1975 by Academic Press, Inc. All rights of reproduction in any form reserved.
hr
The results of the same cardiac function studies performed approximately 48 hr after the last oral dose of propranolol are shown in Table 2. At a central venous pressure of 5 mmHg, there was no difference between the controls and the experimental animals and there was
182
JOURNAL OF SURGICAL
RESEARCH VOL. 18, NO. 2, FEBRUARY
1975
TABLE 1 Cardiac Function Before and After 1 Hr of Cardiopulmonary Bypass Control Bypass Central venous pressure (mmHg) Cardiac output (ml/min/kg) Left ventricular end diastolic pressure (mmHg) Peak systolic pressure (mmHg) Heart rate (beats/mh)
Pre
Post
Pre
Post
Pre
Post
5 95* 11
5 92* 15
10 195 + 23
10 176 + 24
15 309 f 24
15 2622 25
3*2 7’3 + 18 152 f 16
2+ 1 65* 9 156 f 13
5*2 104 f 10 163 * 12
6+1 102 f 5 163 + 13
11 f 1 121 f 13 149 f 12
9t2 115 f 6 145% 7
_
no difference between pre- and postbypass receiving propranolol until approximately 8 function in the animals off propranolol48 hr. hr prior to cardiopulmonary bypass are At a central venous pressure of 10 mmHg, given in Table 3. there were again no significant differences At a central venous pressure of 5 mmHg, between controls and animals off the only variation from the controls was the propranolol 48 hr, although the experi- postbypass elevation of peak systolic mental group showed a slight reduction in pressure by 49 mmHg (P < 0.05). cardiac output prior to bypass. Both prior to When the central venous pressure was eleand after bypass a slight elevation in sys- vated to 10 mmHg, a number of differences temic pressure was present. However, when were noted. Prior to bypass, cardiac output pre- and postbypass propranolol parameters was 95 ml/min/kg (P < 0.05) lower and left were compared, cardiac output was found to ventricular end diastolic pressure 4 mmHg have risen significantly (P < 0.05 paried t) higher in the propranolol dogs than in the after cardiopulmonary bypass. controls. After cardiopulmonary bypass At a central venous pressure of 15 mmHg, peak systolic pressure was again elevated (57 cardiac output was reduced and peak sys- mmHg, P < 0.05) over control levels, while tolic pressure elevated (both P < 0.05) prior cardiac output rose to control levels (P < to bypass but there were no postbypass 0.05 paried t ). Prior to bypass, when the central venous differences when the 48-hr propranolol and pressure was elevated to 15 mmHg, cardiac control animals were compared. However, output was significantly reduced (147 ml/ when pre- and postbypass data were compared in the animals off propranolol 48 hr, min/kg, P < 0.01) and peak systolic the postbypass left ventricular end diastolic pressure was elevated (44 mmHg, P < 0.05) pressure was noted to have fallen when the animals off propranolol 8 hr were compared with the controls. Postbypass significantly (P < 0.05 paried t ). peak systolic pressure remained elevated (P Of Propranolol8 hr < 0.05) while cardiac output rose to within The results of cardiac function studies the normal range (P < 0.05 paired t). There were no significant differences in prior to and 30 min after surgery in animals TABLE 2 Cardiac Function Before and After 1 Hr of Cardiopulmonary Bypass Chronic Propranolol Discontinued 48 Hr Bypass
Pre
Post
Pre
Post
Pre
Post
Central venous pressure (mmHg) Cardiac output (ml/min/kg) Left ventricular end diastolic pressure (mmHg) Peak systolic pressure (mmHg) Heart rate (beats/min)
5 99 f 23
5 90 f 15
10 159 * 28
10 230 f 43
15 199 f 30
15 261 f 38
2*1 86 f 13 146 f 11
6*1 118 f 20 147 f 12
6*2 116 f 7 144 f 8
16 f 2 159 f 15 133 f 13
9*1 133 f 6 134 f 3
3*1 61 f 8 145 * 9
TYERS AND HUGHES: PROPRANOLOL
AND CARDIOPULMONARY
BYPASS
183
TABLE 3 Cardiac Function Before and After 1 HI of Cardiopulmonary Bypass Chronic Prop~auolol Discontinued 8 HI Bypass Central venous pressure (mmHg) Cardiac output (ml/min/kg) Left ventricular end diastolic pressure (mmHg) Peak systolic pressure (mmHg) Heart rate (beatslmin)
Post
Pre
Post
Pre
Post
5 71* 12
5 100 f 20
10 112 f 20
10 194 t 30
15 162* 17
15 229 t 41
3t2 83t 17 160 * 7
2*1 114 f 17 173 f 7
9+3 119 f 19 162* 11
5*2 159 f 19 163 f 6
14 ?r5 165 f 14 159 * 8
8*2 163 + 13 163 f 3
Pre
administration of propranolol was used [4]. The same report indicated an early return of human cardiac function to normal after the withdrawal of propranolol therapy [4]. Isolated atria1 strips nourished by diffusion were used and a significant bulk of tissue was probably ischemic rendering interpretation of results difficult. In addition, the extrapolation of results from isolated atria1 strips to the intact ventricle is questionable. While the same authors reported no “significant” difference in the operative mortality rate when comparing patients who DISCUSSION had recently received propranolol and After the withdrawal of chronic oral patients never on propranolol [4], a careful propranolol therapy, the induction of study of their data reveals that 2 of 21 anesthesia is associated with a reduction in propranolol patients died (10%) compared cardiac output and elevations of systemic with 2 of 40 nonpropranolol patients (5%). pressure and left ventricular end diastolic The lack of a significant difference may be pressure. These abnormalities of cardiac due more to the small sample than the unfunction are minimal when the preload is low questioned safety of operating while the but become highly significant when the heart effects of propranolol persist. Tests to detect is volume loaded. As the interval between propranolol based on rate must be viewed the last dose of propranolol and the initia- with caution as the present study and a pretion of surgery was increased, the magnitude vious report [5] both indicate the transient of the circulatory changes was reduced, but nature of propranolol’s bradycardic effect significant abnormalities persisted at 48 hr. once the drug is stopped. After an hour of cardiopulmonary bypass, When the combined effects of ischemic the deleterious effects of propranolol were heart disease and propranolol therapy, the ameliorated, with cardiac output and left altered metabolic and hemodynamic effects ventricular end diastolic pressure returning of different routes of drug administration toward normal, although peak systolic and the varying durations of cardiopressure elevation remained. pulmonary bypass are taken into The difference in accumulation of active consideration, some of the discrepancies bemetabolites of propranolol after chronic tween previously reported clinical and exoral administration as compared with perimental findings regarding the duration of parenteral administration [2] makes ques- residual propranolol effects can be undertionable the clinical applicability of previous stood. The clinical course is usually benign in animal studies in which intraperitoneal patients who, without specific indication, heart rate noted when pre- and postbypass results were compared in the controls and in the two groups of animals that had been receiving propranolol. When control rates were compared with rates in the propranolol animals again no differences were noted. However, while oral propranolol was being administered, a marked difference in heart rate between control (195.83h2.01 beats/ min) and treated animals (95.33h5.26 beats/min) was present and P-R interval increased moderately.
184
JOURNAL OF SURGICAL
RESEARCH VOL. 18, NO. 2, FEBRUARY
have received propranolol to within a few hours of surgery. However, the clinical course may be complicated when the drug is continued until just prior to surgery because of patient dependence on it for pain or arrhythmia control. Propranolol dependence indicates severe or diffuse myocardial ischemia and an increased risk on that basis. The effects of atherosclerotic coronary artery disease and propranolol may be additive as both reduce coronary flow, while peripheral vascular disease and propranolol both increase peripheral resistance. When combined with the marked reduction in tolerance to volume loading after chronic propranolol therapy, these additive effects may leave the angina patient with severe coronary artery disease little reserve with which to respond to the stresses of anesthesia and surgery. in patients demonstrating propranolol dependence, we now recommend intraaortic balloon counterpulsation followed by gradual drug withdrawal
1975
prior to surgery. Elective coronary bypass surgery can then be undertaken several days after the last dose of propranolol. REFERENCES ,, Diaz, R. G., Somberg, J. C., Freeman, E., and Levitt, B. Withdrawal of propranolol and myocardial infarction. Lancer 1:1068(1973). 2. Evans, G. H., and Sband, D. G. The disposition of propranolol V. Drug accumulation and steady-state concentration during chronic oral administration in man. Clin. Pharmacol. Ther. 14:487(1973). 3 Evans, G. H., and Shand, D. G. The disposition of ’ propranolol VI. Independent variations in steadystate circulating drug concentrations and half-life as a result of plasma drug binding in man. Clin. Pharmacol. Ther. 14:494(1973). 4. Faulkner, S. L., Hopkins, J. T., Boerth, R. C., Young, J. L., Jr., Jellett, L. B., Nies, A. S., Bender, H. W., and Sband, D. G. Time required for complete recovery from chronic propranolol therapy. N. Engl. J. Med. 289:607-609 (1973). s, Viljoen, J. F., Estafanous, F. G., and Kellner, G. A. Propranolol and cardiac surgery. J. Thorac Cardiovast. Surg. 64:826-830 (1972).
