Neuromuscular Blockade in Post-Cardiac Arrest

 描述（由申请人提供）：在美国，每年有超过20万例患者发生院外心脏骤停（OHCA），估计死亡率超过90%。美国心脏协会（AHA）的指南不仅强调了优化停搏期间治疗的重要性，还强调了停搏后患者的管理。直到最近，神经肌肉阻滞（NMB）被认为是潜在的有害的危重病，与几个较老的病例系列表明与肌肉无力的发展。这些担忧导致目前AHA建议限制NMB的使用。然而，最近的一项急性呼吸窘迫综合征（ARDS）随机试验的数据挑战了这一范式。在这项试验中，ARDS患者随机接受NMB治疗与常规治疗相比，生存率提高。我们在一项对成人院外心脏骤停患者进行的多中心观察性研究中检查了肌松，发现与未接受肌松的患者相比，接受早期持续肌松的患者生存率提高，乳酸盐下降更快。肌松可通过多种机制改善结局，包括减少全身耗氧量、预防患者-呼吸机不同步、减少代谢需求、减少炎症或其他未识别的途径。鉴于此，我们假设为CA后患者提供NMB将导致死亡率降低。我们认为，评估这一假设的第一步是进行一项初步随机试验，以确定这种干预的可行性，探索潜在的机制，并获得必要的数据，以设计一项III期研究，评估对死亡率的影响。因此，我们正在进行一项II期、多中心、随机试验，以确定NMB是否降低CA后患者的乳酸水平。这项试验（由美国心脏协会资助）形成了当前拨款提案的母研究，其双重目标是推进复苏科学和初级研究人员进入复苏科学领域并取得进展。为此，我们提出了三个额外的科学目标，其中两个将表征NMB组与安慰剂组患者之间的耗氧量和炎症反应。我们的最终目标将包括一项调查和大型数据登记查询，该调查和查询将评估整个美国NMB的使用模式以及NMB使用的潜在持续时间相关差异及其与死亡率的相关性。这些额外的科学目标将支持该项目的教育/指导目标，即提高复苏科学领域研究人员的质量和数量。为此，这笔赠款将支持一位既定的导师（Michael Donnino博士），因为他继续为致力于复苏科学的大型转化研究小组的初级研究人员提供指导和结构 （Beth Israel Deaconess Medical Center）这项提案的科学部分的实验范围（临床试验[沿着涉及总体耗氧量的临床子研究]、与患者相关的基于实验室的工作[血液生物标志物和细胞耗氧量测量]、调查的创建和分发，和大型数据注册表查询）沿着该小组正在进行的工作，将为旨在增加初级调查员的知识和专长的全面培训方案提供背景。复苏科学中心有多个正在进行的临床试验和观察性研究，从而为支持下一代复苏研究者提供了良好的基础设施。目前的建议将加强资源，以提供必要的保护时间和项目支持，以执行一个优秀的科学和复苏研究培训计划。

 DESCRIPTION (provided by applicant): Out-of-hospital cardiac arrest (OHCA) occurs in more than 200,000 patients in the United States each year with an estimated mortality of greater than 90%. Guidelines from the American Heart Association (AHA) emphasize not only the importance of optimizing intra-arrest treatment, but also the management of patients during the post-arrest period. Until recently, neuromuscular blockade (NMB) was considered potentially detrimental in the critically ill, with several older case series suggesting an association with th development of muscle weakness. These concerns lead to the current AHA recommendation to limit NMB use. However, recent data from a randomized trial in acute respiratory distress syndrome (ARDS) challenged this paradigm. In this trial, patients with ARDS had improved survival when randomized to NMB therapy versus usual care. We examined NMB in a multicenter observational investigation of adult out-of-hospital cardiac arrest patients and found that patients who received early, sustained NMB had improved survival as well as a more rapid decrease in lactate compared to patients who did not receive NMB. NMB may improve outcome through a number of mechanisms including the reduction of global oxygen consumption, prevention of patient-ventilator dyssynchrony, reduction of metabolic demand, reduction of inflammation, or other unidentified pathways. Given this, we hypothesize that provision of NMB to post-CA patients will result in improved mortality. We believe the first step in the evaluation f this hypothesis is a pilot randomized trial to determine the feasibility of this intervention, explre potential mechanisms and obtain the necessary data with which to design a Phase III investigation evaluating the effect on mortality. Thus, we are performing a Phase II, multicenter, randomized trial to determine if NMB decreases lactate levels in post-CA patients. This trial (funded by the American Heart Association) forms the parent study of the current grant proposal which has the dual Aim of advancing the science of resuscitation and the pool of junior investigators entering and advancing in the field of resuscitation science. To that end, we propose three additional scientific Aims, two of which will characterize the oxygen consumption and inflammatory response between patients in the NMB arm versus placebo. Our final Aim will include a survey and large data registry query which will evaluate both the usage patterns of NMB throughout the United States as well as the potential duration-related differences in NMB usage and their association with mortality. These additional scientific Aims will support the education/mentoring objective of the project which is to increase the quality and quantity of investigators in the field of resuscitation science. To that end, this grant will support an established mentor (Dr. Michael Donnino) as he continues to provide mentoring and structure for junior investigators in a large translational research group dedicated to resuscitation science (Center of Resuscitation Science at Beth Israel Deaconess Medical Center). The breadth of experiments in the scientific portion of this proposal (clinical trial [along with clinical sub-stuy involving global oxygen consumption], patient-related laboratory-based work [blood biomarkers and measurement of cellular oxygen consumption], creation and distribution of a survey, and a large data registry query) along with ongoing work by the group will provide the background for a comprehensive training program aimed at increasing the knowledge and expertise of junior investigators. The Center for Resuscitation Science has multiple ongoing clinical trials and observational studies thus providing excellent infrastructure for supporting the next generation of resuscitation investigators. This current proposal will bolster the resources in order to provid the necessary protected time and project support to execute an outstanding scientific and resuscitation research training program.