Improving Outcomes in Cardiac Arrest/CPR with Inhaled Nitric Oxide

描述(由申请人提供)：心脏骤停(CA)是全球主要的死亡原因之一。尽管心肺复苏(CPR)方法取得了进展，但这些逮捕中有60%-80%会导致立即死亡，而在其余的人中，只有大约5%的人成功复苏，恢复正常生活。CA术后早期恢复自主循环(ROSC)的患者预后不良可归因于CA后综合征。虽然治疗性低温(TH)已在临床研究中被证明是有效的，但目前还没有可用的药物来改善CA的预后。大量研究表明，一氧化氮(NO)在缺血再灌注(IR)损伤中具有保护作用。尽管最初被开发为一种选择性肺血管扩张剂，但吸入NO在各种临床前和临床研究中已被证明具有全身效应，而不会引起全身血管扩张。在作为这项研究建议的基础的初步研究中，我们发现，在CPR成功23小时后开始呼吸低浓度的NO显著改善短期(长达10天)的神经和心脏结果，以及在7.5分钟的CA和CPR之后小鼠的存活。值得注意的是，吸入NO对CA/CPR后10天存活的有益影响在缺乏NO受体的可溶性鸟苷环化酶(SGC)小鼠中被取消。基于这些令人兴奋的新观察，我们假设，CA心肺复苏成功后呼吸NO可通过sGC依赖的信号机制改善长期预后。为了解决这一假设，我们建议确定吸入NO对CA/CPR(目标1)后长期结果(最长4周)的影响，探讨sGC在吸入NO对CA/CPR(目标2)结果保护作用中的作用，并阐明吸入NO对CA/CPR(目标3)长期结果的保护作用的细胞机制。由于吸入NO不会导致全身低血压，与全身NO供体相比，它特别适合于治疗CA术后血压经常不稳定的患者。在小型哺乳动物上成功完成拟议的研究将为大型动物研究吸入NO在CA/CPR中的影响提供机制基础。鉴于吸入NO的安全性已经确立，我们相信拟议的研究将使这一新的非侵入性治疗策略能够快速转化，以改善患有突发性CA和CA后综合征的患者的预后。

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.