Reperfusion Injury Protection During Cardiac Arrest: A Novel CPR Method

描述(由申请人提供)：平均而言，90%的心脏骤停患者死亡。几乎所有人都意外死于这一主要死亡原因，部分原因是标准心肺复苏(S-CPR)的基本组成部分：以每分钟100英寸的速度进行手动胸部按压，深度1至1.5英寸，以及正压通风，本质上是一种效率低下的方法 这一过程，为心脏和大脑提供了不到25%的正常血流量。尽管进行了密集的研究，但半个多世纪以来，几乎没有观察到结果有所改善。这一应用建立在我们对CPR过程中如何优化流向心脏和大脑的血液并保护这些器官免受再灌注损伤的新理解之上。它有望为遭受心脏性猝死的患者带来新的希望。这项拟议的研究旨在证明，通过缺血后处理(PC)减少或预防再灌注损伤对于显著提高心脏骤停后的存活率和良好的神经功能是可行的，也是关键的。基于最近在治疗脑和心脏缺血方面取得的重大进展，控制再灌注已被证明能显著减少脑血管事件和心肌梗死患者的中风和梗塞范围，最近，我们在一个长期未治疗的心脏骤停猪模型上暂时限制了CPR前三分钟的血流。结果令人震惊：在未经治疗的室颤15分钟后，在循环的前三分钟内进行多次明确和可控的停顿的CPR，并在CPR期间优化流向心脏和大脑的血液流动的方法，使大脑和心脏功能在心跳骤停24小时后恢复正常。这些令人兴奋的观察结果与之前认为不可能的事情相矛盾：在长期没有血液流动和严重新陈代谢紊乱的情况下恢复完整的生命。虽然与目前的做法相反，但这种显著减少再灌注损伤并在某些情况下防止再灌注损伤的新方法可能会导致一种新的、临床上重要的CPR方法，该方法易于EMS人员和家庭实施。它基于合理的生理学原则和概念，提供了显著改善迄今为止从未可能复苏的患者的神经完整存活率的前景。在本申请中，我们建议进一步探索这些发现。在目前的应用中，我们建议a)验证循环和复苏率的预期改善可以转化为心脏骤停动物模型中神经学上完整的存活率，以及b)设计和原型一个工具来帮助在PC上执行CPR。如果成功，这种疗法每年将挽救10,000多名美国人的院外心脏骤停，以及类似数量的住院幸存者，因为在心肺复苏期间，PC具有优越的血流和保护大脑和心脏免受再灌注损伤的能力。 公共卫生相关性：基于多种新发现的在心肺复苏期间增强循环的机制的组合，在当前的应用中，我们建议a)验证在长期未经治疗的心脏骤停后，通过 在心脏骤停的动物模型中，后处理(受控CPR暂停)结合更优越的血液动力学方法可以转化为更高的神经完整存活率，以及b)开发一种CPR设备，该设备可提供持续的用户对CPR质量的反馈，并引导用户执行新型CPR，这是在心脏骤停期间改善脑和心脏血流的关键，目的是提高神经完整的存活率。这项技术是必要的，因为高质量的STD CPR为心脏提供了不到20%的正常血流量，而向大脑提供的血流量几乎没有增加。即使在最有效的紧急医疗系统中，所有院外心脏骤停的患者中，只有不到20%的人出院时神经功能完好。值得注意的是，几十年来，全国出院心脏骤停患者的平均存活率一直不到5%。这种复杂的疾病状态仍然是美国的头号杀手，仅在美国，每天就有1000多人死于医院外，1000人死于医院里。在心肺复苏期间改善大脑和其他重要器官的循环，特别是当结合以系统为基础的整体方法进行复苏前和复苏后护理时，有可能显著降低心脏骤停的发病率和死亡率。

DESCRIPTION (provided by applicant): On average, >90% of patients who suffer from a cardiac arrest die. Nearly all die unexpectedly from this leading cause of death, in part, because the essential components of standard CPR (S-CPR): manual chest compressions at a rate of 100/min, 1 to 1.5 inches in depth and positive pressure ventilations, are an inherently inefficient process, providing less than 25% of normal blood flow to the heart and brain. Despite intensive research, little or no improvement in outcomes has been observed for over half a century. This application builds upon our new understanding of ways to optimize blood flow to the heart and brain during CPR and protect these organs from reperfusion injury. It promises to provide new hope for patients who suffer from sudden cardiac death. The proposed research is focused on demonstrating proof of concept that reducing or preventing reperfusion injury by ischemic postconditioning (PC) is both feasible and critical to markedly enhancing survival with favorable neurological function after cardiac arrest. Building upon recent and significant advances in the treatment of cerebral and cardiac ischemia, where controlled reperfusion has been shown to strikingly reduce stroke and infarct size in patients with cerebral vascular events and myocardial infarction, we have recently temporarily restricted blood flow during the first three minutes of CPR in a pig model of prolonged untreated cardiac arrest. The results have been striking: after 15 minutes of untreated ventricular fibrillation, performing CPR with a number of defined and controlled pauses during the first three minutes of circulation in conjunction with a means to optimize blood flow to the heart and brain during CPR has normalized brain and heart function < 24-hours after arrest. These exciting observations contradict what was previously thought impossible; to restore full life in the setting of prolonged absence of flow and severe metabolic derangement. While antithetical to current practice, this novel approach that significantly reduces and in some cases prevents reperfusion injury may result in a novel and clinically important method of CPR that is easy to implement by EMS personnel and in the home. It provides the promise, based upon sound physiological principles and concepts, to markedly improve neurologically intact survival in patients that have heretofore never been possible to resuscitate. In this application we propose to further explore these findings. In the current application we propose to a) verify that the anticipated improvement in circulation and resuscitation rates can be translated into neurologically intact survival in animal models of cardiac arrest, and b) design and prototype a tool to help perform CPR with PC. If successful, this therapy will result in saving >10,000 more Americans each year from out of hospital cardiac arrest and a similar number of in-hospital survivors based upon the superior blood flow and the ability afforded by PC to protect the brain and heart from reperfusion injury during CPR. PUBLIC HEALTH RELEVANCE: Based upon a combination of multiple newly discovered mechanisms to enhance circulation during CPR, in the current application we propose to a) verify that after prolonged untreated cardiac arrest, controlled re-introduction of blood flow with postconditioning (controlled CPR pauses) combined with a superior hemodynamic method of CPR can be translated into higher rates of neurologically intact survival in animal models of cardiac arrest, and b) develop a CPR device that provides continuous user feedback on quality of CPR and guides the user to perform a novel type of CPR which is key to improving brain and heart blood flow during cardiac arrest with the goal of improving neurologically intact survival. This technology is needed because high quality STD CPR provides less than 20% of normal blood flow to the heart and little more to the brain. Even in the most efficient emergency medical systems, less than 20% of all patients with an out-of-hospital cardiac arrest are discharged from the hospital with intact neurological function. Strikingly, the average national survival to hospitl discharge after out-of-hospital cardiac arrest has remained less than 5% for decades. This complex disease state remains the nation's #1 killer, claiming more than 1000 lives outside the hospital and 1000 lives inside the hospital each day in the United States alone. Improved circulation to the brain and other vital organs during CPR, especially when combined in an overall systems-based approach to pre and post-resuscitation care, has the potential to significantly reduce morbidity and mortality from cardiac arrest.