Personalized Anesthesia: The Role of the Locus Coeruleus in Individual Anesthetic Responses

个性化麻醉：蓝斑在个体麻醉反应中的作用

基本信息

批准号：
10799159
负责人：
Andrew Rich McKinstry-Wu
金额：
$ 13万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2026-07-31
项目状态：
未结题

项目摘要

PROJECT SUMMARY/ABSTRACT Millions of patients are placed into a reversible state of unconsciousness by anesthesiologists for life saving surgeries every year. The basic goals of anesthetic care are to reliably extinguish consciousness for the duration of surgery and afterwards swiftly return the patient to their baseline cognitive state. Neither one of these goals can be reliably achieved today, however. Some patients regain consciousness during surgery. Episodes of consciousness are not reliably detected by current intraoperative EEG-based monitoring and can result in post-traumatic stress and anxiety disorders. In contrast, other patients take a long time to resume normal cognition. This can manifest as postoperative delirium and cognitive derangements. Postoperative delirium affects millions of patients, costs 34 billion dollars annually, and can itself be a harbinger of cognitive dcline after surgery. Such persistent decrements in cognitive function can last for many months. It is presently unclear why some patients experience peri-anesthetic complications while other patients that receive seemingly identical anesthetics have an uneventful perioperative course. To address this, we propose to study individual-based anesthetic pharmacology rather than previously used population-based measures. We have recently developed experimental and computational methods to quantify individual-based measures of anesthetic responses in mice. The use of these methods revealed that conventional population-based pharmacological concepts such as drug potency are not sufficient to describe individual responses. We identified two independent measures that do capture the range of individual responses: sensitivity and resistance to state transitions (Rst). Sensitivity describes how often an individual is awake or anesthetized at an anesthetic dose, while Rst describes how frequently transitions happen between those two states. We demonstrated that sensitivity and Rst can be differentially pharmacologically modulated. We also demonstrated that chemogenetic activation of an arousal pathway – locus coeruleus – decreases Rst without a change in drug sensitivity. Because Rst is completely obscured in population-based pharmacological studies, we hypothesize that Rst is the “hidden variable” that may help explain why some patients experience peri-anesthetic complications while others do not. We propose to investigate the mechanisms through which the locus coeruleus decreases Rst. Using pharmacologic and genetic approaches, we will identify the neurotransmitter systems used by the locus coeruleus to modulate Rst. Separately, we will identify the effects of the locus coeruleus on neurophysiologic state change, including correlates of behavioral Rst, using a high-density EEG system developed by our lab. Finally, we will turn towards identifying the neuronal pathways through which locus coeruleus acts to modulate Rst. The proposed lines of investigation will clarify how activity of the locus coeruleus influences individualized anesthetic responses, and will be an important step towards delivering personalized anesthesia.

项目摘要/摘要麻醉师为挽救生命而将数百万患者置于可逆的无意识状态每年的手术。麻醉护理的基本目标是可靠地消除意识手术持续时间，然后迅速将患者归还其基线认知状态。两个都不是但是，今天可以可靠地实现这些目标。一些患者在手术期间继续意识。当前基于脑电图的监测目前无法检测到意识发作，无法可靠，并且可以导致创伤后压力和焦虑症。相反，其他患者需要很长时间才能恢复正常认知。这可以表现为术后del妄和认知演变。术后 ir妄影响数百万患者，每年成本为340亿美元，并且本身可以成为认知的预兆手术后的DCLINE。这种认知功能的持续减少可以持续数月。现在是尚不清楚某些患者为什么会经历麻醉周期并发症，而其他接受的患者看似相同的麻醉剂具有平稳的周期性课程。为了解决这个问题，我们建议研究基于个体的麻醉药理学，而不是以前使用的基于人群的措施。我们最近开发了实验和计算方法来量化基于个体的基于个体的方法小鼠麻醉反应的度量。这些方法的使用表明传统基于人群的药物概念（例如药物效力）不足以描述个体回答。我们确定了确实捕获个体响应范围的两种独立措施：敏感性和对状态过渡（RST）的抵抗力。敏感性描述了一个人醒的频率或在麻醉剂量上进行麻醉，而RST描述了这两个之间发生过渡的频率国家。我们证明了敏感性和RST可以差异化。我们也是证明唤醒途径的化学发生激活 - 层基因座 - 在没有a的情况下下降药物敏感性的变化。由于RST在基于人群的药物研究中完全掩盖了我们假设RST是“隐藏变量”，它可能有助于解释某些患者体验的原因骨检查并发症而其他并没有。我们建议研究核基因座降低的机制。使用药理学和遗传方法，我们将确定该基因座使用的神经递质系统凝结以调节rst。另外，我们将确定层层基因座对神经生理学的影响使用我们实验室开发的高密度EEG系统，包括行为rST的相关性，包括行为rst的相关性。最后，我们将转向识别神经元途径，该途径通过该途径进行调节第拟议的投资线将阐明基因座的活动如何影响个性化麻醉反应，将是提供个性化麻醉的重要一步。