ROLE OF B ADRENERGIC RECEPTOR ANTAGONISTS IN CARDIAC SURGERY PATIENTS

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The long term object of this research is to determine underlying mechanisms of, and therapy for, acute myocardial beta-adrenergic receptor (Beta- AR) desensitization during cardiopulmonary bypass (CPB). Within this context, the present study seeks to test the following two hypotheses: 1) Acute myocardial AR desensitization during CPB is localized to the AR moiety itself and results from receptor phosphorylation. and 2) Intervention with intravenous metoprolol upon initiation of CPB will prevent myocardial beta-AR desensitization during CPB and result in better clinical outcome. The only currently existing clinical model of acute myocardial beta-AR desensitization (3 hour time frame) occurs during CPB. Prevention of myocardial beta-AR desensitization during cardiac surgery should lead to enhanced myocardial performance at the time of separation from CPB, and possibly to the use of fewer inotropic agents and improved patient outcome. We studied myocardial beta-AR function in right atrial biopsies (pre and post-CPB) from patients undergoing elective coronary artery bypass graft (CABG) surgery. In spite of constant beta-AR density, acute myocardial beta-AR desensitization occurs as evidenced by a 20% decrease in ISO-stimulated AC activity. The original GCRC protocol #759 investigates-adrenergic receptor desensitization during cardiopulmonary bypass in patients undergoing coronary artery bypass grafting (CABG). In the study, 300 CABG patients were to be enrolled in a double blind placebo controlled fashion to receive 10 mg metoprolol or placebo. The effect on adrenergic receptor activity was to be assessed. In addition, a secondary hypothesis was being tested that prevention of desensitization by metoprolol would improve clinical outcome. In February of 1997, the first 50 patients receiving 10 mg metoprolol were analyzed. It was found that 10 mg of metoprolol did not prevent desensitization. Thus, the investigator received permission from the IRB and GCRC to conduct a small unblinded dose escalation study to 20 mg in 20 patients and then 30 mg in another 20 patients to determine whether either dose of metoprolol would desensitize the receptors. In July of 1997, it was noted that there was an increased incidence of pacing being required upon separation from cardiopulmonary bypass in the patients at the 30 mg dose. Thus, the investigators obtained approval from the IRB and GCRC to substitute esmolol which has a shorter half life and which had been proven efficacious in dogs. Two doses of IV esmolol (low dose: 1mg/kg followed by 100 g/kg/min infusion and high dose: 3mg/kg followed by 300 g/kg/min) will be studied (n=20 in each group) to determine if desensitization is prevented. If desensitization is prevented then the randomized double blind trial will begin again with this new drug.