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）：在美国，院外心脏骤停（OHCA）仍然是一个严重的健康问题。尽管心肺复苏（CPR）竭尽全力，但每年有35万多名患者死亡或患有严重的神经系统缺陷。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CPR期间重新引入血流而导致的突然的分子和代谢变化比由缺血本身造成的损害更有害。因此，对于这一竞争性变革性研究奖，我们提出了几种新颖且容易适用的策略，以减轻再灌注损伤的发展（RI）：缺血性术后（IPC），即通过间歇性停止胸部压缩和在疾病中与疾病的治疗（例如，疾病）（例如，疾病）（例如，iapc）（iapc）进行治疗，以控制血液流量的暂停（IPC）。 CPR的前3分钟。尽管看似矛盾且挑战目前的护理标准心肺复苏术，但我们认为，对这些保护性RI的机制，安全性和功效的拟议研究可能会从根本上改变传统的临床范式。为了实现我们每年为数千名患者改善OHCA神经系统完整生存的总体目标，我们拟议的项目的目标是测试不同的论术后策略（IPC，IAPC）及其组合，以表征其随着时间的流逝，并阐明其细胞内信号机制。基于初步结果，我们假设一氧化氮产生增加并延迟的线粒体通透性过渡孔口开口是与标准CPR相比，用IPC和/IAPC复活时，动物的急剧改善是急剧改善。在三个交错的特定目标中，我们将通过在既定的猪模型中长时间的心室纤维化后，将IPC和IAPC的早期和延迟IPC和IAPC整合到CPR中，以评估心脏，脑，肾脏和肝脏保护。结果将与当前治​​疗性体温过低的金标准进行比较。状态血流动力学测量，器官特异性生物标志物，组织学，线粒体研究和神经系统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这成为最有前途，创新和独特的方法，其结果具有出色的潜力，可以影响到即将到来的YEE的复苏领域的研究和临床护理。