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-肾上腺素能受体的作用机制及治疗 体外循环(CPB)中的(β-AR)脱敏。在 在此背景下，本研究试图测试以下两个 假设：1)体外循环期间急性心肌AR脱敏 定位于AR部分本身，是受体的结果 磷酸化。2)静脉注射美托洛尔干预 CPB开始可防止心肌β-AR脱敏 体外循环，临床效果较好。目前唯一存在的 急性心肌β-AR脱敏的临床模型(3h时间 帧)发生在CPB期间。预防心肌β-AR脱敏 在心脏手术期间应导致心肌功能增强 离开CPB的时间，可能是由于使用较少的 正性肌力药和改善患者预后。我们研究了心肌 右房活检(CPB前后)患者的β-AR功能 接受择期冠状动脉搭桥术(CABG)。尽管 恒定的β-AR密度，急性心肌β-AR脱敏 发生的证据是ISO刺激的AC活性下降了20%。这个 最初的GCRC方案#759研究-肾上腺素能受体 体外循环患者体外循环期间的脱敏反应 冠状动脉搭桥术(CABG)。在这项研究中，300例冠状动脉搭桥术 患者以双盲安慰剂对照的方式入选。 接受10毫克美托洛尔或安慰剂。对肾上腺素能受体的影响 活动是要评估的。此外，另一个次要假设是 美托洛尔预防脱敏效果显著 临床结果。1997年2月，首批50名患者接受了10次 美托洛尔mg。结果发现，10毫克的美托洛尔不起作用 防止脱敏。因此，调查员获得了来自 IRB和GCRC将进行一项不盲目的小剂量研究，将剂量增加到20 在20名患者中使用mg，然后在另外20名患者中使用30 mg以确定 两种剂量的美托洛尔是否都会使受体脱敏。在……里面 1997年7月，注意到起搏的发生率增加了。 患者在脱离体外循环时需要接受治疗 在30毫克剂量下。因此，调查人员获得了IRB的批准 和GCRC取代半衰期较短的艾司洛尔 在狗身上被证明是有效的。两次静脉注射艾司洛尔(小剂量： 1 mg/kg，然后100g/kg/min输注，高剂量：3 mg/kg，然后 300g/kg/min)将被研究(每组n=20)以确定是否 可防止脱敏。如果防止了脱敏，那么 这种新药将再次开始随机双盲试验。

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.