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输出量综合征(LCOS)是导致小儿心脏手术术后并发症和死亡率的重要原因。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，LCOS仍然是一个重要的临床问题，据估计，在接受体外循环的婴儿中，LCOS的发生率约为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，以调查术前应用糖皮质激素(甲基强的松龙、类固醇)和/或促红细胞生成素(EPO)是否对缺血再灌注损伤起到保护作用，从而减少接受体外循环的婴儿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，但主要的信号通路是不同的；因此，联合使用可能会协同减少LCOS的发生率。将有四种术前治疗手段：1)安慰剂；2)类固醇；3)促红细胞生成素；以及4)类固醇和促红细胞生成素联合使用。研究设计假设在术中使用类固醇。这一假设是基于最近发表的一项调查，该调查记录了这是儿科中心的常见做法，以及我们自己的研究，证明了术前和术中使用类固醇的好处有所改善。这项拟议研究的主要目的是比较术前类固醇和/或促红细胞生成素与安慰剂对体外循环手术后48小时内LCOS发生率的影响。有待检验的假说包括：1)术前激素对缺血再灌注损伤有保护作用，以提高术后心肌功能，从而降低LCOS的发生率。2)术前促红细胞生成素对缺血再灌注心肌细胞具有保护作用，可改善术后心肌功能，降低LCOS的发生率。3)术前同时应用激素和促红细胞生成素对减少LCOS的发生有协同作用。主要结果是LCOS。LCOS的诊断将基于临床体征和症状、生化标记物以及是否需要额外的肌力/机械支持。五个二级目标将评估对死亡率的治疗效果和临床措施，包括发病率、术后心肌功能、心脏手术前后心肌功能障碍的炎性和非炎性介质、体外循环手术前后的心肌细胞保护和细胞凋亡，以及体外循环手术后48小时内的肾脏损伤发生率。建议研究的完成将极大地提高我们对缺血-再灌注损伤和预防婴幼儿体外循环手术后LCOS的治疗方法的了解。(摘要结束)

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)