Reperfusion Injury Protection Strategies During Basic Life Support

基本生命支持期间的再灌注损伤保护策略

• 批准号: 8875751
• 负责人: Demetris Yannopoulos
• 金额: $ 99.71万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-20 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8875751
• 关键词: 911 call; Anesthetics; Animal Model; Animals; Award; Basic Life Support; Biological Markers; Blood flow; Breathing; Cardiac; Cardiology; Cardiopulmonary Resuscitation; Caring; Cerebrum; Chest; Clinical; Clinical Research; Complement; Data; Development; Effectiveness; Environmental air flow; Evaluation; Evolution; Family suidae; Goals; Gold; Health; Heart Arrest; Helium; Hepatic; Histology; Hospitals; Individual; Injury; Institution; Ischemia; Kidney; Knowledge; Light; Literature; Lung; Measurement; Metabolic; Methods; Minority; Mitochondria; Modeling; Molecular; Myocardial; Myocardial dysfunction; Neurologic; Neurology; Nitric Oxide; Organ; Outcome; Oxidative Stress; Paramedical Personnel; Patients; Physiological; Police; Production; Provider; Public Health; Quality of life; Reperfusion Injury; Reperfusion Therapy; Research; Research Personnel; Research Project Grants; Resuscitation; Role; Safety; Scientist; Signal Transduction; Structure; System; Techniques; Technology; Testing; Therapeutic; Time; Tissues; Training; Transplantation; United States; Ventricular Fibrillation; Western World; base; body system; clinical care; clinically relevant; emergency service responder; hemodynamics; improved; improved functioning; innovation; mitochondrial permeability transition pore; natural hypothermia; novel; novel therapeutic intervention; protective effect; protective efficacy; sevoflurane; therapeutic target

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.

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。尽管尽了最大努力进行心肺复苏 (CPR)，但每年仍有超过 350,000 名患者死亡或患有严重的神经功能缺损。尽管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，在初始心肺复苏期间重新引入血流所导致的分子和代谢突变比缺血本身造成的损伤更有害。因此，对于这一竞争性的变革性研究奖，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外按压来控制血流暂停，以及药物后处理在 CPR 的前 3 分钟内通过肺部吸入七氟烷或氦气等吸入剂 (IAPC)。尽管看似矛盾且具有挑战性的当前护理标准心肺复苏，但我们认为，拟议的针对 RI 保护技术的机制、安全性和有效性的研究可能会从根本上改变传统的临床范式。为了实现每年提高数千名 OHCA 患者的神经完整生存率的总体目标，我们提出的项目的目标是测试不同的后处理策略（IPC、IAPC）及其组合，以表征其器官保护随时间的发展。 ，并阐明其细胞内信号传导机制。根据初步结果，我们推测，与标准 CPR 相比，使用 IPC 和/IAPC 进行复苏时，一氧化氮生成增加和线粒体通透性转变孔开放延迟是动物显着改善的原因。在三个交错的具体目标中，我们将通过在已建立的猪模型中发生长期心室颤动后将早期和延迟的 IPC 和 IAPC 整合到 CPR 中来评估心脏、大脑、肾脏和肝脏的保护。结果将与当前低温治疗的金标准进行比较。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，使这是一种最有前途、创新和独特的方法，其结果为影响未来复苏领域的研究和临床护理提供了非凡的潜力。