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Pathophysiology and treatment of myocardial ischemia
Pathophysiology and Treatment of Myocardial Ischemia Keith D. Knopes, MD, John B. Leslie. MD. and Martin J. London, MD
ECENT CLINICAL investigations have pointed to the impact of perioperative myocardial ischemia on postoperative morbidity in patients with ischemic heart disease.' The added awareness that silent myocardial ischemia (8MI) contributes to the patient's total ischemic burden has focused the anesthesiologist's attention on the peri operative management of these patients. The purpose of this review is to outline the effects of the adrenergic stress response on hemodynamic changes that may precipitate myocardial ischemia, and to propose a strategy for anesthetic management of patients with ischemic heart disease.
R
PATHOPHYSIOLOGY OF MYOCARDIAL ISCHEMIA
Ischemic episodes, both symptomatic and silent, are frequently observed during daily activity in patients with coronary artery disease (CAD)Y There is interest in the effect of 8MI on the prognosis and management of these patients in that it contributes to the overall ischemic burden as CAD progresses to infarction (Fig 1). Investigations have shown that 8MI is associated with a significant deleterious impact on the outcome of patients with ischemic heart disease .v' Knight et al 6 found that most perioperative ischemic events in patients undergoing coronary artery bypass grafting were asymptomatic. This indicates that perioperative risk attributable to myocardial ischemia may be substantially underestimated. Myocardial oxygen balance is influenced by supply and demand factors, as shown in Fig 2. The goal of the anesthetic plan is to maximize myocardial oxygen supply and minimize demand. Heart rate is one important determinant of myocardial oxygen consumption. It is also a primary regulator of myocardial oxygen supply because it determines the duration of coronary diastolic filling time during which oxygen may be supplied to the myocardium. Therefore, an anesthetic anti-ischemic strategy should have the control of heart rate as a primary attribute. Increases in wall tension (preload and afterload) cause increases in myocardial oxygen demand. Systolic blood pressure, the major contrib-
utor to afterload, can increase significantly during adrenergic stress periods, resulting in an increase in myocardial oxygen demand that can be detrimental in the ischemic-prone myocardium. Effort should be made to lower systolic pressure while avoiding significant reductions in diastolic blood pressure or coronary perfusion pressure. MYOCARDIAL ISCHEMIA AND ,B-BLOCKADE
The targeting of specific agents to specific functions is a polypharmacological alterna tive to the quest for a single ideal anesthetic agent. ,B-Adrenergic blockade has a well-established role in the management of patients with ischemic heart disease," The potential mechanisms by which ,B-blockers may reduce the risk of myocardial ischemia in injury include (I) the reduction of myocardial oxygen consumption by blockade of ,B-adrenergic receptors; (2) reduction of lipolysis and myocardial free fatty acid uptake with shifting of myocardial substrate utilization to glucose; (3) redistribution of coronary flow toward ischemic subendocardium; (4) direct membrane-stabilizing effects; (5) alteration of platelet function; and (6) reduction of microvascular damage." Animal studies have shown that ,B-blockade will decrease myocardial infarct size, possibly due to the decrease in heart rate and contractility that result in a diminution of myocardial oxygen consumption.S'? Data from several clinical studies suggest that ,B-blockers may reduce mortality following myocardial infarction. 8,11. 13 Studies of the effects of ,B-blockade on the cardiovascular response to anesthesia and surgery now extend over two decades." Many of these studies have focused on the antihypcrten-
From the Department oj Anesthesiology, Virginia Mason Clinic and the University oj Washington, Seattle, WA; the Cardiac Anesthesia Division. Department ojAnesthesia, Duke University Medical Center. Durham, NC; and the Department ofAnesthesia. University ofCalifomia, San Francisco, CA. Address reprint requests to Keith D. Knopes, MD. Department of Anesthesiology B2-AN. Virginia Mason Clinic, 1100 Ninth A ve. Seattle, WA 98111. e 1990 by W.B. Saunders Company. 0888-6296/90/0405-2011$03.00/0
JoumalofCardiothoracicAnesthesia, Vol 4, No 5. Suppl2 (October), 1990: pp 51-54
51
52
KNOPES, LESLIE, AND LONDON
,
8MI I
8MI I
~ 8MI--.-CAD ---I.~ Angina ---i.~ Unstable ----t.~lnfarction
I_ _ _ _t Angina
+
I
8MI Fig 1.
8MI
Schematic representation of the contribution of silent myocardial ischemia ISM" to total ischemic burden.
sive effects of {J-blockade in patients with preexisting hypertension. More recently, attention has turned to the anti-ischemic properties of P-blockade in the surgical patient. Stone and colleagues have published two reports on the use of perioperative {J-blockade in patients prone to myocardial ischemia, the results of which suggest that treatment with {J-adrenergic blocking agents is effective in preventing myocardial ischemia due to adrenergic stress. 14•15 One study used a single small preoperative oral dose of a {J-blocker in patients with mild hypertension who were not receiving other antihypertensive medication.'! A 28% incidence of myocardial ischemia occurred in the control group (no (J-blockade) compared with a 2% incidence in the (J-blocker-treated group. There are few outcome data on the use of {J-blockers during anesthesia for the prevention of postoperative complications. Pasternack et al 16
Supply Heart Rate Preload
+
+
Diastolic Pressure Hemoglobin
+
Oxygenation
+
t
studied 32 patients undergoing elective abdominal aortic aneurysm surgery with metoprolol administered in the perioperative period. The hemodynamic response and postoperative myocardial infarction rates were compared with historic (non-ji-blocked) controls. Results showed a significant difference in the myocardial infarction rate between the two groups, suggesting that perioperative tJ-blockade has a positive effect on outcome in this patient population (Fig 3). These data are consistent with other reports showing the efficacy of tJ-blockers for preventing ischemia and limiting infarction size. The safety and efficacy of esmolol in patients with acute myocardial ischemia or infarction have been demonstrated by several investigators. 18•19 In a group of patients with acute myocardial infarction, postinfarction angina, or acute unstable angina, esmolol infusion (titrated to a maximum dose of 300 Ilgjkgjmin) significantly reduced ventricu-
I'
Demand Heart Rate Preload Systolic Pressure Contractility
+ + + +
Fig 2. Myocardial oxy_ gen balance-factors that decrease O2 demand and increase O2 supply.
TREATMENT OF MYOCARDIAL ISCHEMIA
53
f3 -Blockade
No f3 -Blockade
(n = 32)
A
Fig 3. Clinical outcome in patients undergoing abdominalaortlc aneurysm repair with P-blockade. (Reprinted with permission.'11
(n
= 51)
A
Periop MI
No Periop MI
Periop MI
No Periop MI
1 (3.1%)
31
9 (17.6%)
42
lar rate (92 to 77 beats/min), systolic blood pressure (120 to 97 mm Hg), and cardiac index (2.8 to 2.2 L/min/m2) Y There were no significant changes in pulmonary capillary wedge pressure or PR interval; none of the patients developed atrioventricular conduction delay, initiation or exacerbation of congestive heart failure, or bronchospasm. After discontinuation of esmolol infusion, arterial pressure quickly returned toward baseline levels. In a study of 18 patients with ischemic heart disease, esmolol reduced heart rate and systolic blood pressure but did not decrease ventricular ejection fraction or the Doppler flow velocity integral.i? When doses of csmolol and propranolol were titrated to produce similar reductions in rate-pressure product, the investigators concluded that both drugs had similar efficacy in the management of unstable angina. However, esmolol's shorter duration of action was cited as an additional advantage in the event of an adverse cardiac reaction that might necessitate treatment withdrawal." Lower doses of esmolol may be used to produce beneficial effects in patients having significant left ventricular dysfunction without the development of clinically significant hemodynamic changes. The results of these studies point to the safety and efficacy of esmolol in the treatment of critically ill patients. However, it should be noted that esmolol should be avoided in patients with congestive heart failure or shock (Table 1).
Careful titration of anesthetic drugs should be balanced with other needed pharmacological agents to optimize hemodynamics. Excessive doses of anesthetic drugs may provide the desired reductions in oxygen demands on the myocardium, but a management strategy must be formulated to control the anesthetic emergent state. Despite adequate anesthetic levels, patients with significant CAD may respond to perioperative stimuli with tachycardia and hypertension. This response creates an increase in myocardial oxygen demand that may lead to myocardial ischemia.ri-Blockers are safe, effective, and easily administered, and provide sympatholysis by modification of the perioperative adrenergic stress response. Esmolol potentially provides a unique and effective therapeutic intervention for the management of ischemia, heart rate, and blood pressure, and may improve outcome in patients with ischemic heart disease undergoing the stress of anesthesia and surgery. Table 1. Relative Contraindications to p.Blockade Hypotension Hypovolemia Heart block Sick sinus syndrome Congestive heart failure Non-a-blocked pheochromocytoma Pregnancy Bronchospasm (relative contra indicat ionsl Fixed cardiac output state (tamponade, etcl
REFERENCES 1. Slogolf S. Keats AS: Does perioperative myocardial ischemia lead to postoperative myocardial infarction? Anesthesiology 62:I07-114, 1985
2. Schang Sl, Pepine Cl: Transient asymptomatic ST segment depression during daily activity. Am 1 Cardiol 39:396·402,1977 3. Deanfield lE, Shea M, Ribiero P; et al: Transient
ST segment depression: A marker of myocardial ischemia during daily life. Am 1 CardioI54:1195·1200, 1984 4. Gottlieb SO, Weisfeldt ML, Ouyang P, et a1: Silent ischemia as a marker for early unfavorable outcomes in patients with unstable angina. N Engl 1 Med 314:1214· 1219,1986 5. Assey ME, Walters GL, Hendrixs GH , et al: Incidents of acute myocardial infarction in patients with
54
exercise-induced silent myocardial ischemia. Am J Cardiol 59:497-500,1987 6. Knight AA, Hollenberg M, London MJ: Perioperative myocardial ischemia: Importance of the perioperative ischemic pattern. Anesthesiology 68:681-688,1988 7. Braunwald E. Muller JE , Kloner RA. et al: Role of fJ-adrenergicblockade in the therapy of patients with myocardial infarction. Am J Med 74:113·123,1983 8. Rasmussen MM, Reimer KA, Kloner RA, et al: Infarct size reduction by propranolol before and after coronary ligation in dogs. Circulation 56:794-798, 1977 9. Miura M, Thomas R. Ganz W, et al: The effect of delay in propranolol administration on reduction of myocardial infarct size after experimental coronary artery occlusion in dogs. Circulation 59:1158-1159, 1979 10. Norwegian Multicenter Study Group : Timolol induced reduction in mortality and reinfarction in patients survivingacute myocardial infarction. N Engl J Med 304:801807.1981 II . Hjalmarson A. Herlitz J, Holmberg S, et al: The Goteborg metoprolol trial: Effects on mortality and morbidity in acute myocardial infarction. Circulation 67:26·32, 1983 (suppll) 12. P-Blocker Heart Attack Trial Research Group: A randomized trial of propranolol in patients with acute myocardial infarction. I. Mortality results. JAMA 247:1707-1713, 1982 13. Prys-Roberts C. Foex P, Biro GP. et al: Studies of anaesthesia in relation to hypertension. V: Adrenergic p-receptor blockade. Br J Anesth 45:671-680,1973
KNOPES. LESLIE. AND LONDON
14. Stone JG, Foex P, Sear JW. et al: Risk of myocardial ischaemia dur ing anaesthesia in treated and untreated hypertensive patients. Br J Anesth 61:675-679. 1988 IS. Stone JG. Foex P, Sear JW, et al: Myocardial ischemia in untreated hypertensive patients: Effect of a single small oral dose of a p-adrenergic blocking agent. Anesthesiology 68:495·500. 1988 16. Pasternack PF, Imparato AM. Baumann FG, et al: The hemodynamics of fJ-blockade in patients undergoing abdominal aortic aneurysm repair. Circulation 76:1-7. 1987 (suppI3) . 17. Lange R, Kloner RA. Braunwald E: First ultrashort-acting p-adrenergic blocking agent : Its effect on size and segmental wall dynamics of repcrfused myocardial infarcts in dogs. Am J Cardiol 51:1759-1767, 1983 18. Kirshenbaum JM, Antman EM, McGowan N: Use of esmolol in patients with acute myocardial ischemia and contraindications to fJ-blockade.J Am Coli Cardiol 9:24, 1987 19. Smith MD, Allin 0, Hua T: Effects of esmolol in ventricular function in patients with ischemic heart disease. X World Congress Meeting, Washing ton, DC, June 1988. 793:139 20. Wallis DE, Pope CM. Littman WJ, et al: Esmolol vs propranolol in the management of unstable angina. Clin Res 34:904, 1986 . 21. Iskandrian AS, Bemis CE, Hakki AH. et al: Effects of esmolol on patient with left ventricular dysfunction. J Am Call Cardiol 8:225-231. 1986
ECENT CLINICAL investigations have pointed to the impact of perioperative myocardial ischemia on postoperative morbidity in patients with ischemic heart disease.' The added awareness that silent myocardial ischemia (8MI) contributes to the patient's total ischemic burden has focused the anesthesiologist's attention on the peri operative management of these patients. The purpose of this review is to outline the effects of the adrenergic stress response on hemodynamic changes that may precipitate myocardial ischemia, and to propose a strategy for anesthetic management of patients with ischemic heart disease.
R
PATHOPHYSIOLOGY OF MYOCARDIAL ISCHEMIA
Ischemic episodes, both symptomatic and silent, are frequently observed during daily activity in patients with coronary artery disease (CAD)Y There is interest in the effect of 8MI on the prognosis and management of these patients in that it contributes to the overall ischemic burden as CAD progresses to infarction (Fig 1). Investigations have shown that 8MI is associated with a significant deleterious impact on the outcome of patients with ischemic heart disease .v' Knight et al 6 found that most perioperative ischemic events in patients undergoing coronary artery bypass grafting were asymptomatic. This indicates that perioperative risk attributable to myocardial ischemia may be substantially underestimated. Myocardial oxygen balance is influenced by supply and demand factors, as shown in Fig 2. The goal of the anesthetic plan is to maximize myocardial oxygen supply and minimize demand. Heart rate is one important determinant of myocardial oxygen consumption. It is also a primary regulator of myocardial oxygen supply because it determines the duration of coronary diastolic filling time during which oxygen may be supplied to the myocardium. Therefore, an anesthetic anti-ischemic strategy should have the control of heart rate as a primary attribute. Increases in wall tension (preload and afterload) cause increases in myocardial oxygen demand. Systolic blood pressure, the major contrib-
utor to afterload, can increase significantly during adrenergic stress periods, resulting in an increase in myocardial oxygen demand that can be detrimental in the ischemic-prone myocardium. Effort should be made to lower systolic pressure while avoiding significant reductions in diastolic blood pressure or coronary perfusion pressure. MYOCARDIAL ISCHEMIA AND ,B-BLOCKADE
The targeting of specific agents to specific functions is a polypharmacological alterna tive to the quest for a single ideal anesthetic agent. ,B-Adrenergic blockade has a well-established role in the management of patients with ischemic heart disease," The potential mechanisms by which ,B-blockers may reduce the risk of myocardial ischemia in injury include (I) the reduction of myocardial oxygen consumption by blockade of ,B-adrenergic receptors; (2) reduction of lipolysis and myocardial free fatty acid uptake with shifting of myocardial substrate utilization to glucose; (3) redistribution of coronary flow toward ischemic subendocardium; (4) direct membrane-stabilizing effects; (5) alteration of platelet function; and (6) reduction of microvascular damage." Animal studies have shown that ,B-blockade will decrease myocardial infarct size, possibly due to the decrease in heart rate and contractility that result in a diminution of myocardial oxygen consumption.S'? Data from several clinical studies suggest that ,B-blockers may reduce mortality following myocardial infarction. 8,11. 13 Studies of the effects of ,B-blockade on the cardiovascular response to anesthesia and surgery now extend over two decades." Many of these studies have focused on the antihypcrten-
From the Department oj Anesthesiology, Virginia Mason Clinic and the University oj Washington, Seattle, WA; the Cardiac Anesthesia Division. Department ojAnesthesia, Duke University Medical Center. Durham, NC; and the Department ofAnesthesia. University ofCalifomia, San Francisco, CA. Address reprint requests to Keith D. Knopes, MD. Department of Anesthesiology B2-AN. Virginia Mason Clinic, 1100 Ninth A ve. Seattle, WA 98111. e 1990 by W.B. Saunders Company. 0888-6296/90/0405-2011$03.00/0
JoumalofCardiothoracicAnesthesia, Vol 4, No 5. Suppl2 (October), 1990: pp 51-54
51
52
KNOPES, LESLIE, AND LONDON
,
8MI I
8MI I
~ 8MI--.-CAD ---I.~ Angina ---i.~ Unstable ----t.~lnfarction
I_ _ _ _t Angina
+
I
8MI Fig 1.
8MI
Schematic representation of the contribution of silent myocardial ischemia ISM" to total ischemic burden.
sive effects of {J-blockade in patients with preexisting hypertension. More recently, attention has turned to the anti-ischemic properties of P-blockade in the surgical patient. Stone and colleagues have published two reports on the use of perioperative {J-blockade in patients prone to myocardial ischemia, the results of which suggest that treatment with {J-adrenergic blocking agents is effective in preventing myocardial ischemia due to adrenergic stress. 14•15 One study used a single small preoperative oral dose of a {J-blocker in patients with mild hypertension who were not receiving other antihypertensive medication.'! A 28% incidence of myocardial ischemia occurred in the control group (no (J-blockade) compared with a 2% incidence in the (J-blocker-treated group. There are few outcome data on the use of {J-blockers during anesthesia for the prevention of postoperative complications. Pasternack et al 16
Supply Heart Rate Preload
+
+
Diastolic Pressure Hemoglobin
+
Oxygenation
+
t
studied 32 patients undergoing elective abdominal aortic aneurysm surgery with metoprolol administered in the perioperative period. The hemodynamic response and postoperative myocardial infarction rates were compared with historic (non-ji-blocked) controls. Results showed a significant difference in the myocardial infarction rate between the two groups, suggesting that perioperative tJ-blockade has a positive effect on outcome in this patient population (Fig 3). These data are consistent with other reports showing the efficacy of tJ-blockers for preventing ischemia and limiting infarction size. The safety and efficacy of esmolol in patients with acute myocardial ischemia or infarction have been demonstrated by several investigators. 18•19 In a group of patients with acute myocardial infarction, postinfarction angina, or acute unstable angina, esmolol infusion (titrated to a maximum dose of 300 Ilgjkgjmin) significantly reduced ventricu-
I'
Demand Heart Rate Preload Systolic Pressure Contractility
+ + + +
Fig 2. Myocardial oxy_ gen balance-factors that decrease O2 demand and increase O2 supply.
TREATMENT OF MYOCARDIAL ISCHEMIA
53
f3 -Blockade
No f3 -Blockade
(n = 32)
A
Fig 3. Clinical outcome in patients undergoing abdominalaortlc aneurysm repair with P-blockade. (Reprinted with permission.'11
(n
= 51)
A
Periop MI
No Periop MI
Periop MI
No Periop MI
1 (3.1%)
31
9 (17.6%)
42
lar rate (92 to 77 beats/min), systolic blood pressure (120 to 97 mm Hg), and cardiac index (2.8 to 2.2 L/min/m2) Y There were no significant changes in pulmonary capillary wedge pressure or PR interval; none of the patients developed atrioventricular conduction delay, initiation or exacerbation of congestive heart failure, or bronchospasm. After discontinuation of esmolol infusion, arterial pressure quickly returned toward baseline levels. In a study of 18 patients with ischemic heart disease, esmolol reduced heart rate and systolic blood pressure but did not decrease ventricular ejection fraction or the Doppler flow velocity integral.i? When doses of csmolol and propranolol were titrated to produce similar reductions in rate-pressure product, the investigators concluded that both drugs had similar efficacy in the management of unstable angina. However, esmolol's shorter duration of action was cited as an additional advantage in the event of an adverse cardiac reaction that might necessitate treatment withdrawal." Lower doses of esmolol may be used to produce beneficial effects in patients having significant left ventricular dysfunction without the development of clinically significant hemodynamic changes. The results of these studies point to the safety and efficacy of esmolol in the treatment of critically ill patients. However, it should be noted that esmolol should be avoided in patients with congestive heart failure or shock (Table 1).
Careful titration of anesthetic drugs should be balanced with other needed pharmacological agents to optimize hemodynamics. Excessive doses of anesthetic drugs may provide the desired reductions in oxygen demands on the myocardium, but a management strategy must be formulated to control the anesthetic emergent state. Despite adequate anesthetic levels, patients with significant CAD may respond to perioperative stimuli with tachycardia and hypertension. This response creates an increase in myocardial oxygen demand that may lead to myocardial ischemia.ri-Blockers are safe, effective, and easily administered, and provide sympatholysis by modification of the perioperative adrenergic stress response. Esmolol potentially provides a unique and effective therapeutic intervention for the management of ischemia, heart rate, and blood pressure, and may improve outcome in patients with ischemic heart disease undergoing the stress of anesthesia and surgery. Table 1. Relative Contraindications to p.Blockade Hypotension Hypovolemia Heart block Sick sinus syndrome Congestive heart failure Non-a-blocked pheochromocytoma Pregnancy Bronchospasm (relative contra indicat ionsl Fixed cardiac output state (tamponade, etcl
REFERENCES 1. Slogolf S. Keats AS: Does perioperative myocardial ischemia lead to postoperative myocardial infarction? Anesthesiology 62:I07-114, 1985
2. Schang Sl, Pepine Cl: Transient asymptomatic ST segment depression during daily activity. Am 1 Cardiol 39:396·402,1977 3. Deanfield lE, Shea M, Ribiero P; et al: Transient
ST segment depression: A marker of myocardial ischemia during daily life. Am 1 CardioI54:1195·1200, 1984 4. Gottlieb SO, Weisfeldt ML, Ouyang P, et a1: Silent ischemia as a marker for early unfavorable outcomes in patients with unstable angina. N Engl 1 Med 314:1214· 1219,1986 5. Assey ME, Walters GL, Hendrixs GH , et al: Incidents of acute myocardial infarction in patients with
54
exercise-induced silent myocardial ischemia. Am J Cardiol 59:497-500,1987 6. Knight AA, Hollenberg M, London MJ: Perioperative myocardial ischemia: Importance of the perioperative ischemic pattern. Anesthesiology 68:681-688,1988 7. Braunwald E. Muller JE , Kloner RA. et al: Role of fJ-adrenergicblockade in the therapy of patients with myocardial infarction. Am J Med 74:113·123,1983 8. Rasmussen MM, Reimer KA, Kloner RA, et al: Infarct size reduction by propranolol before and after coronary ligation in dogs. Circulation 56:794-798, 1977 9. Miura M, Thomas R. Ganz W, et al: The effect of delay in propranolol administration on reduction of myocardial infarct size after experimental coronary artery occlusion in dogs. Circulation 59:1158-1159, 1979 10. Norwegian Multicenter Study Group : Timolol induced reduction in mortality and reinfarction in patients survivingacute myocardial infarction. N Engl J Med 304:801807.1981 II . Hjalmarson A. Herlitz J, Holmberg S, et al: The Goteborg metoprolol trial: Effects on mortality and morbidity in acute myocardial infarction. Circulation 67:26·32, 1983 (suppll) 12. P-Blocker Heart Attack Trial Research Group: A randomized trial of propranolol in patients with acute myocardial infarction. I. Mortality results. JAMA 247:1707-1713, 1982 13. Prys-Roberts C. Foex P, Biro GP. et al: Studies of anaesthesia in relation to hypertension. V: Adrenergic p-receptor blockade. Br J Anesth 45:671-680,1973
KNOPES. LESLIE. AND LONDON
14. Stone JG, Foex P, Sear JW. et al: Risk of myocardial ischaemia dur ing anaesthesia in treated and untreated hypertensive patients. Br J Anesth 61:675-679. 1988 IS. Stone JG. Foex P, Sear JW, et al: Myocardial ischemia in untreated hypertensive patients: Effect of a single small oral dose of a p-adrenergic blocking agent. Anesthesiology 68:495·500. 1988 16. Pasternack PF, Imparato AM. Baumann FG, et al: The hemodynamics of fJ-blockade in patients undergoing abdominal aortic aneurysm repair. Circulation 76:1-7. 1987 (suppI3) . 17. Lange R, Kloner RA. Braunwald E: First ultrashort-acting p-adrenergic blocking agent : Its effect on size and segmental wall dynamics of repcrfused myocardial infarcts in dogs. Am J Cardiol 51:1759-1767, 1983 18. Kirshenbaum JM, Antman EM, McGowan N: Use of esmolol in patients with acute myocardial ischemia and contraindications to fJ-blockade.J Am Coli Cardiol 9:24, 1987 19. Smith MD, Allin 0, Hua T: Effects of esmolol in ventricular function in patients with ischemic heart disease. X World Congress Meeting, Washing ton, DC, June 1988. 793:139 20. Wallis DE, Pope CM. Littman WJ, et al: Esmolol vs propranolol in the management of unstable angina. Clin Res 34:904, 1986 . 21. Iskandrian AS, Bemis CE, Hakki AH. et al: Effects of esmolol on patient with left ventricular dysfunction. J Am Call Cardiol 8:225-231. 1986