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。尽管在心肺复苏（CPR）方面做出了最大的努力，但每年仍有超过35万名患者死亡或患有严重的神经功能障碍。尽管成功的复苏和结果与OHCA持续时间成反比，但我们有理由相信，在初始CPR期间由血流重新引入引起的突然分子和代谢变化比缺血本身造成的损伤更有害。因此，为了这个具有竞争性的变革研究奖，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：缺血后适应（IPC），即通过间歇性停止胸部按压来控制血液流动的暂停，以及在心肺复苏的前3分钟通过肺部给予吸入剂（IAPC），如七氟烷或氦。尽管目前的标准CPR似乎是相互矛盾和挑战的，但我们认为，这些针对RI的保护性技术的机制、安全性和有效性的拟议研究可以从根本上改变传统的临床范例。为了实现我们的总体目标，即提高每年数千名OHCA患者的神经系统完整生存率，我们提出的项目的目标是测试不同的后适应策略（IPC， IAPC）及其组合，表征它们随时间的器官保护发展，并阐明它们的细胞内信号传导机制。基于初步结果，我们假设与标准CPR相比，IPC和/IAPC复苏时动物一氧化氮生成增加和线粒体通透性过渡孔开放延迟是导致显著改善的原因。在三个交错的具体目标中，我们将在已建立的猪模型中，通过将早期和延迟IPC和IAPC整合到延长心室颤动后的CPR中，来评估心脏、大脑、肾脏和肝脏的保护作用。结果将与目前治疗性低温的金标准进行比较。最先进的血液动力学测量、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为每个系统中观察到的保护提供全面的定量和定性评估。令人信服的初步证据，加上来自三个不同学术机构的研究人员的丰富专业知识，使这成为一种最有前途的、创新的和独特的方法，其结果具有非凡的潜力，将在未来几年影响复苏领域的研究和临床护理。

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.