Preoperative Therapy for Prevention of Postoperative Low Cardiac Output Syndrome

描述（由申请人提供）： 心肌功能不全和由此导致的低心排血量综合征（LCOS）是小儿心脏手术后发病率和死亡率的重要因素。尽管在诊断准确性和术中心肌保护策略方面取得了重大进展，但LCOS仍然是一个重要的临床问题，在接受心肺转流术的婴儿中估计发生率约为25%。本申请提出了一项多中心、随机、双盲、安慰剂对照的临床试验，以研究术前给予糖皮质激素（甲基强的松龙、类固醇）和/或促红细胞生成素（EPO）是否会保护接受心肺转流术的婴儿免受缺血-再灌注损伤，从而降低LCOS的发生率。此外，尽管这两种药物之间存在重要的相互作用，但主要信号传导途径不同;因此，联合使用可能会导致协同降低LCOS的发生率。将有四个术前治疗组：1）安慰剂; 2）类固醇; 3）EPO;和4）类固醇和EPO联合。研究设计假设将在术中给予类固醇。 这一假设是基于最近发表的一项调查，该调查将其记录为儿科中心的常见做法，以及我们自己的调查，这些调查证明了术前和术中使用类固醇的获益改善。本研究的主要目的是比较术前类固醇和/或EPO与安慰剂对心肺转流术后前48小时内LCOS发生率的影响。有待验证的假设包括：1）术前类固醇保护缺血再灌注损伤，以提高术后心肌性能，从而降低LCOS的发生率。2)术前EPO在缺血-再灌注期间保护心肌细胞，导致术后心肌性能改善，随后降低LCOS的发生率。3)术前激素和EPO联合应用对降低PCOS的发生率有协同作用。主要结果是LCOS。LCOS的诊断将基于临床体征和症状、生化标志物以及对额外肌力/机械支持的需求的复合。五个次要目的将评估治疗对死亡率和发病率临床指标、术后心肌性能、心脏手术前后心肌功能障碍的炎症和非炎症介质、心肺转流术前后心肌细胞保护和凋亡以及心肺转流术后48小时内肾损伤发生率的影响。这些研究的完成将极大地提高我们对缺血再灌注损伤和治疗的理解，以预防婴幼儿心肺转流手术后的LCOS。(End摘要）

DESCRIPTION (provided by applicant): Myocardial dysfunction and resulting low cardiac output syndrome (LCOS) contribute significantly to postoperative morbidity and mortality in pediatric heart surgery. Despite major advances in diagnostic accuracy and intra-operative myocardial protection strategies, LCOS remains an important clinical problem with an estimated incidence of ~25% in infants undergoing cardiopulmonary bypass. This application proposes a multi-center, randomized, double blind, placebo-controlled clinical trial, to investigate whether preoperative administration of glucocorticoids (methylprednisolone, steroids) and/or erythropoietin (EPO) will afford protection from ischemia-reperfusion injury and thereby reduce the incidence of LCOS for infants undergoing cardiopulmonary bypass. Furthermore, although there are important interactions between these two agents, the primary signaling pathways are distinct; hence, combined use may result in a synergistic reduction in the incidence of LCOS. There will be four preoperative treatment arms: 1) placebo; 2) steroids; 3) EPO; and 4) steroids and EPO combined. The study design assumes that intra-operative steroids will be administered. This assumption is based on a recent published survey documenting this as common practice in pediatric centers, and our own investigations that demonstrate an improved benefit from pre- and intraoperative steroid use. The Primary Aim of the proposed study is to compare the effect of preoperative steroids and/or EPO with placebo on LCOS incidence through the first 48 hours following cardiopulmonary bypass surgery. Hypotheses to be tested include: 1) Preoperative steroids protect against ischemia-reperfusion injury to enhance myocardial performance postoperatively, resulting in a lower incidence of LCOS. 2) Preoperative EPO protects cardiomyocytes during ischemia-reperfusion, resulting in improved myocardial performance postoperatively with a subsequent reduction in the incidence of LCOS. 3) Concurrent administration of preoperative steroids and EPO will have a synergistic effect to reduce the incidence of LCOS. The Primary Outcome is LCOS. The diagnosis of LCOS will be based on a composite of clinical signs and symptoms, biochemical markers, and the need for additional inotropic/mechanical support. Five Secondary Aims will assess treatment effects on mortality and clinical measures of morbidity, postoperative myocardial performance, inflammatory and non-inflammatory mediators of myocardial dysfunction pre- and post-heart surgery, cardiomyocyte protection and apoptosis pre- and post-cardiopulmonary bypass surgery and the incidence of renal injury within 48 hours after cardiopulmonary bypass surgery. Completion of the proposed studies should greatly improve our understanding of ischemia-reperfusion injury and therapies to prevent LCOS following surgery with cardiopulmonary bypass in infants. (End of Abstract)