Reperfusion Injury Protection Strategies During Basic Life Support

描述（由申请人提供）：院外心脏骤停（OHCA）在美国仍然是一个严重的健康问题。每年有超过350，000名患者死亡或患有严重的神经功能缺损，尽管心肺复苏术（CPR）已尽了最大努力。虽然成功的复苏和结果与OHCA的持续时间成反比，但我们有理由相信，在初始CPR期间重新引入血流导致的突然分子和代谢变化比缺血本身引起的损伤更有害。因此，对于这个具有竞争力的变革性研究奖，我们提出了几种新颖且易于应用的策略来减轻再灌注损伤（RI）的发展：缺血后处理（IPC），即，通过间歇性停止胸部按压控制血流暂停，以及在CPR的前3分钟期间通过肺部给予吸入剂（IAPC）如七氟醚或氦的药理学后处理。尽管目前的标准心肺复苏术看似矛盾和具有挑战性，但我们认为，对这些预防RI的技术的机制、安全性和有效性的拟议研究可能从根本上改变传统的临床范式。在追求我们的总体目标，以提高神经系统完整的生存OHCA为成千上万的患者，每年，我们提出的项目的目标是测试不同的后处理策略（IPC，IAPC）和它们的组合，表征他们的器官保护发展随着时间的推移，并阐明他们的细胞内信号传导机制。基于初步结果，我们假设，增加一氧化氮的生产和延迟线粒体通透性转换孔开放是负责动物与IPC和/IAPC相比，标准CPR复苏时的显着改善。在三个交错的具体目标，我们将评估心脏，大脑，肾脏和肝脏的保护，通过整合早期和延迟IPC和IAPC到心肺复苏术后，长期心室颤动在一个既定的猪模型。研究结果将与目前的低温治疗金标准进行比较。最先进的血流动力学测量、器官特异性生物标志物、组织组织学、线粒体研究和神经学测试将对每个系统中观察到的保护进行全面的定量和定性评估。令人信服的初步证据以及来自三个不同学术机构的研究人员的丰富专业知识使其成为最有前途，创新和独特的方法，其结果提供了影响未来几年复苏领域研究和临床护理的特殊潜力。

DESCRIPTION (provided by applicant): Out-of-hospital cardiac arrest (OHCA) remains a severe health problem in the United States. More than 350,000 patients die or have severe neurological deficits each year despite best efforts in cardiopulmonary resuscitation (CPR). Although successful resuscitation and outcome are inversely proportional to the duration of OHCA, we have reason to believe that the abrupt molecular and metabolic changes resulting from reintroduction of blood flow during initial CPR are more harmful than the injury caused by the ischemia itself. Accordingly, for this competitive Transformative Research Award we propose several novel and readily applicable strategies to mitigate the development of reperfusion injury (RI): ischemic postconditioning (IPC), i.e., controlled pauses of blood flow by intermittently stopping chest compressions, and pharmacological postconditioning with inhaled agents (IAPC) such as sevoflurane or helium administered through the lungs during the first 3 min of CPR. Though seemingly contradictory and challenging current standard-of-care CPR, we submit, however, that the proposed study of mechanisms, safety, and efficacy of these protective techniques against RI could fundamentally change traditional clinical paradigms. In pursuit of our overall goal to improve neurologically intact survival for OHCA for thousands of patients each year, the objectives of our proposed project are to test different postconditioning strategies (IPC, IAPC) and their combination, to characterize their organ-protective development over time, and to elucidate their intracellular signaling mechanisms. Based on preliminary results, we hypothesize that increased nitric oxide production and delayed mitochondrial permeability transition pore opening are responsible for the dramatic improvement in animals when resuscitated with IPC and/IAPC compared to standard CPR. In three staggered specific aims we will assess cardiac, cerebral, renal and hepatic protection by integrating early and delayed IPC and IAPC into CPR following prolonged ventricular fibrillation in an established pig model. Results will be compared with the current gold-standard of therapeutic hypothermia. State- of-the-art hemodynamic measurements, organ-specific biomarkers, tissue histology, mitochondrial studies and neurological testing will provide a comprehensive quantitative and qualitative assessment of the observed protection in each system. Convincing preliminary evidence together with the wealth of expertise of researchers from three different academic institutions make this a most promising, innovative and unique approach whose results offer exceptional potential to influence research and clinical care in the field of resuscitation for yeas to come.