Improving Outcomes in Cardiac Arrest/CPR with Inhaled Nitric Oxide

描述（由申请人提供）：心脏骤停（CA）是世界范围内死亡的主要原因之一。尽管心肺复苏（CPR）方法取得了进步，但这些骤停中有60-80%导致立即死亡，而剩下的人中，只有约5%成功复苏，恢复了有生产力的生活。患者在CA后最初实现自然循环恢复（ROSC）的不良预后归因于CA后综合征。虽然治疗性低温（TH）在临床研究中被证明是有效的，但没有药物可以改善CA的结果。许多研究表明，一氧化氮（no）在缺血和再灌注（IR）损伤中具有保护作用。虽然最初是作为选择性肺血管扩张剂开发的，但在各种临床前和临床研究中，吸入一氧化氮已被证明具有全身性作用，而不会引起全身性血管舒张。在作为本研究计划基础的初步研究中，我们发现，在心肺复苏术成功后1小时开始呼吸低浓度NO，持续23小时，可显著改善小鼠在心肺复苏术后7.5分钟的短期（长达10天）神经和心脏预后和生存率。值得注意的是，在缺乏可溶性鸟苷酸环化酶（sGC）（一种NO受体）的小鼠中，吸入NO对CA/CPR后10天存活的有益作用被消除。基于这些令人兴奋的新观察结果，我们假设通过sgc依赖的信号机制，CA成功CPR后呼吸NO可改善长期预后。为了解决这一假设，我们建议确定吸入NO对CA/CPR后长期结果（长达4周）的影响（目的1），检查sGC在吸入NO对CA/CPR后结果的保护作用中的作用（目的2），并阐明吸入NO对CA/CPR后长期结果的保护作用的细胞机制（目的3）。与全身NO供体相比，吸入NO不会引起全身性低血压，因此它特别适合治疗血压经常不稳定的ca后患者。在小型哺乳动物中成功完成拟议的研究将为大型动物研究检查CA/CPR中吸入NO的影响提供机制基础。鉴于吸入一氧化氮已确立的安全性，我们相信所提出的研究将使这种新颖的非侵入性治疗策略能够快速转化，以改善突发CA和CA后综合征患者的预后。

DESCRIPTION (provided by applicant): Sudden cardiac arrest (CA) is one of the leading causes of death worldwide. Despite advances in cardiopulmonary resuscitation (CPR) methods, 60-80% of these arrests result in immediate death, and of the remaining, only about 5 percent are successfully resuscitated to the extent that they are returned to productive lives. The poor outcomes of patients, who initially achieve return of spontaneous circulation (ROSC) after CA are attributed to the post-CA syndrome. While therapeutic hypothermia (TH) has proven effective in clinical studies, no pharmacological agent is available to improve outcome from CA. A protective role for nitric oxide (NO) in ischemia and reperfusion (IR) injury has been suggested by a number of studies. Although originally developed as a selective pulmonary vasodilator, inhaled NO has been shown to have systemic effects in a variety of pre-clinical and clinical studies without causing systemic vasodilation. In preliminary studies that serve as the foundation of this research proposal, we found that breathing a low concentration of NO starting 1h after successful CPR for 23h markedly improves short-term (up to 10 days) neurological and cardiac outcomes and survival in mice after 7.5 min of CA followed by CPR. Of note, the salutary effect of inhaled NO on 10-day survival after CA/CPR was abolished in mice deficient in soluble guanylate cyclase (sGC), a NO receptor. Based on these exciting new observations, we hypothesize that breathing NO after successful CPR from CA improves long-term outcome via sGC-dependent signaling mechanisms. To address this hypothesis, we propose to determine the impact of NO inhalation on the long-term outcome (up to 4 weeks) after CA/CPR (Aim 1), to examine the role of sGC in the protective effects of inhaled NO on outcomes of CA/CPR (Aim 2), and to elucidate the cellular mechanisms responsible for the protective effects of inhaled NO on the long-term outcomes after CA/CPR (Aim 3). Because inhaled NO does not cause systemic hypotension, in contrast to systemic NO-donors, it is uniquely suited for the treatment of post-CA patients in whom blood pressure is often unstable. Successful completion of the proposed studies in small mammals would provide the mechanisms foundation for large animal studies examining the effects of inhaled NO in CA/CPR. Given the established safety profile of inhaled NO, we believe the proposed studies will enable rapid translation of this novel and non- invasive therapeutic strategy to improve outcomes in patients suffering from sudden CA and the post-CA syndrome. PUBLIC HEALTH RELEVANCE: Despite advances in resuscitation techniques, fewer than 8% of the 300,000 adults who experience cardiac arrest (CA; also called sudden cardiac death) in the US each year survive to hospital discharge, and up to 60% of survivors have long lasting neurological deficits. Using a mouse model of CA and successful resuscitation, the principle investigators recently discovered that breathing low concentrations nitric oxide (NO) can markedly improve survival and reduce brain injury in mice. With insights gained during the course of the proposed studies, together with the proven safety of NO breathing (used to treat babies with low oxygen levels-"blue babies"), it is anticipated that this novel therapy will be rapidly applied to help patients who experience sudden cardiac death.