Role of Sedation in the Post-Cardiac Arrest Neurological Recovery

心脏骤停（CA）是导致死亡的主要原因。尽管心肺复苏取得了进展 (CPR)方法，只有10-20%的成年CA受害者存活到出院。神经损伤是主要的 最初恢复自主循环的患者的死亡原因和停止治疗的原因 （ROSC）在CA之后。虽然亚低温已被广泛采用，以改善神经恢复后， ROSC最近的证据反驳了它的疗效，导致一个新的指南，不建议低温 再也没有了因为大多数昏迷的CA后患者无论温度管理如何都是镇静的， 镇静对CA后神经功能恢复的确切影响尚不清楚。排除CA后患者的研究 这表明镇静剂提供非常差的睡眠质量，导致ICU中镇静剂最小化的重大推动。 另一方面，CA后镇静可发挥神经保护作用。脑血管失调是一种 CA后脑病的共同特征，并与不良结局相关。镇静剂可以正常化 同时调节CA后的能量需求和脑血流量（CBF），从而改善脑代谢。进一步 需要研究来阐明镇静对CA后神经恢复的作用。定量 脑电图（EEG）被广泛用于CA后神经监测。最近的研究表明， 在ROSC后早期使用丙泊酚诱导EEG上的慢波活动与良好的神经功能相关 CA后患者的结局。下丘脑的麻醉激活神经元（AAN）被多种 产生慢δ振荡的麻醉剂种类。然而，慢波的生理作用 振荡，特别是在缺血后的脑中，是未知的。在最近发表的与这一建议有关的研究中， 我们评估了镇静对低温（33°C）处理的小鼠CA后结果的影响。我们观察到 与CA后无镇静的低温相比， 异丙酚或右美托咪定（DEX）可减轻脑充血， 在ROSC后，改善了雄性和雌性小鼠的神经学结果和存活率。在新的初步 研究中，CA后氯胺酮镇静输注未能改善生存率，而化学发生激活 ROSC后的AAN诱导慢波睡眠，并倾向于提高小鼠的存活率。基于这些结果， 我们假设CA后低温期间的镇静通过促进CA后的神经恢复而改善CA后的神经恢复。 电生理恢复和预防脑血管功能和代谢失调。到 为了解决这一假设，我们特别建议确定CA后丙泊酚镇静的效果， 在常温期间，右美托咪定，以表征CA后氯胺酮镇静对 神经学结果，并阐明慢波振荡在CA后神经保护作用中的作用 镇静剂虽然大多数CA后患者使用镇静剂，但镇静剂如何改变神经功能结局在很大程度上仍然是未知的。 未知拟议的研究将填补知识空白，并寻求优化CA后护理中的镇静。

Sudden cardiac arrest (CA) is a leading cause of death. Despite advances in cardiopulmonary resuscitation (CPR) methods, only 10-20% of adult CA victims survive to hospital discharge. Neurologic injury is the main cause of death and reason to withdraw care in patients who initially achieve return of spontaneous circulation (ROSC) after CA. Although mild hypothermia has been widely adopted to improve neurologic recovery after ROSC, recent evidence refuted its efficacy leading to a new guideline that does not recommend hypothermia any longer. Because majority of comatose post-CA patients are sedated regardless of temperature management, precise impact of sedation on post-CA neurologic recovery is unknown. Studies excluding post-CA patients suggest that sedation provides very poor sleep quality, leading to a significant push to minimize sedation in ICU. On the other hand, post-CA sedation may exert neuroprotective effects. Cerebrovascular dysregulation is a common feature of post-CA encephalopathy and associated with poor outcomes. Sedation may normalize cerebral metabolism by concurrently modulating energy demand and cerebral blood flow (CBF) after CA. Further studies are needed to elucidate the role of sedation on neurologic recovery after CA. Quantitative electroencephalogram (EEG) is widely used for post-CA neuroprognostication. Recent studies showed that induction of slow-wave activities on EEG by propofol early after ROSC is associated with favorable neurologic outcomes in post-CA patients. Anesthesia-activated neurons (AANs) in hypothalamus are activated by diverse classes of anesthetic agents to produce slow-delta oscillations. However, physiological role of slow-wave oscillation, especially in post-ischemic brain, is unknown. In recently published studies related to this proposal, we evaluated the effects of sedation on outcomes after CA in hypothermia (33°C)-treated mice. We observed that, compared to hypothermia without sedation after CA, hypothermia with sedation with an intravenous infusion of propofol or dexmedetomidine (DEX) attenuated cerebral hyperemia, induced higher slow wave EEG power after ROSC, and improved neurological outcomes and survival in male and female mice. In new preliminary studies, post-CA sedation with ketamine infusion failed to improve survival, whereas chemogenetic activation of AANs after ROSC induced slow wave sleep and tended to improve survival rates in mice. Based on these results, we hypothesize that post-CA sedation during hypothermia improves neurological recovery after CA by promoting electrophysiological recovery and preventing dysregulation of cerebrovascular function and metabolism. To address this hypothesis, specifically, we propose to determine the effects of post-CA sedation with propofol or dexmedetomidine during normothermia, to characterize the effects of post-CA sedation with ketamine on neurologic outcomes, and to elucidate the role of slow-wave oscillation in the neuroprotective effects of post-CA sedation. While most post-CA patients are sedated, how sedation alters neurologic outcomes remains largely unknown. The proposed studies will fill the knowledge gap and seek to optimize sedation in post-CA care.