ROLE OF B ADRENERGIC RECEPTOR ANTAGONISTS IN CARDIAC SURGERY PATIENTS

这项研究的长期目标是确定潜在的 急性心肌β-肾上腺素能受体的机制和治疗 （β- AR）脱敏。 内 在这种情况下，本研究试图测试以下两个 假设：1）CPB期间急性心肌AR脱敏， 定位于AR部分本身并由受体 磷酸化和2）静脉内美托洛尔干预， CPB的启动将防止心肌β-AR脱敏， CPB并导致更好的临床结局。目前唯一存在的 急性心肌β-AR脱敏的临床模型（3小时时间 帧）在CPB期间发生。预防心肌β-AR脱敏 在心脏手术期间， 从CPB分离的时间，并可能使用更少的 正性肌力药和改善的患者结果。 我们研究了心肌 患者右心房活检（CPB前后）中的β-AR功能 接受择期冠状动脉旁路移植术（CABG）。尽管 恒定β-AR密度，急性心肌β-AR脱敏 如ISO刺激的AC活性降低20%所证明的。 的 原始GCRC方案#759研究-肾上腺素能受体 心肺转流术中的脱敏 冠状动脉旁路移植术（CABG）。 在这项研究中，300名CABG患者 患者将以双盲安慰剂对照的方式入组 接受10 mg美托洛尔或安慰剂。 对肾上腺素能受体的影响 活动进行了评估。此外，一个次要假设是， 试验表明，美托洛尔预防脱敏的效果会改善 临床结果。1997年2月，第一批50名接受10名 mg美托洛尔。发现10 mg美托洛尔没有 防止脱敏。因此，研究人员得到了 IRB和GCRC进行一项小型非盲剂量递增研究， 20例患者接受30 mg，然后另20例患者接受30 mg，以确定 美托洛尔的剂量是否会使受体脱敏。 在 1997年7月，注意到起搏发生率增加， 在患者与心肺转流分离时需要 30 mg剂量。 因此，研究者获得了IRB的批准 和GCRC替代艾司洛尔，艾司洛尔的半衰期较短， 在狗身上被证明是有效的 两剂IV艾司洛尔（低剂量： 1 mg/kg，随后100 g/kg/min输注，高剂量：3 mg/kg，随后 300 g/kg/min）（每组n=20），以确定 防止了脱敏。 如果脱敏被阻止， 随机双盲试验将开始再次与这种新药。

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.