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.

项目概要/摘要麻醉师将数百万患者置于可逆的昏迷状态以挽救生命每年进行手术的麻醉护理的基本目标是可靠地消除患者的意识。手术持续时间和术后快速使患者恢复到基线认知状态两者都不是。然而，今天这些目标可以可靠地实现，一些患者在手术过程中恢复了意识。目前的术中脑电图监测无法可靠地检测到意识发作，并且可以导致创伤后应激障碍和焦虑症，相比之下，其他患者需要很长时间才能恢复。正常认知。这可能表现为术后谵妄和认知紊乱。谵妄影响着数百万患者，每年造成 340 亿美元的损失，而且它本身就可能是认知功能障碍的先兆。手术后这种持续的认知功能下降可能会持续数月。尚不清楚为什么有些患者会出现围麻醉期并发症，而其他患者则接受看似相同的麻醉剂在围手术期的过程并不均匀。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人的小鼠麻醉反应的测量使用这些方法揭示了传统方法的效果。基于人群的药理学概念（例如药物效力）不足以描述个体我们确定了两个独立的衡量标准，可以反映个人反应的范围：对状态转换的敏感性和抵抗力（Rst）敏感性描述了个体清醒或清醒的频率。以麻醉剂量麻醉，而 Rst 描述了这两者之间发生转变的频率我们还证明了敏感性和 Rst 可以通过药理学进行差异调节。证明了唤醒途径（蓝斑）的化学遗传学激活会降低 Rst，而无需由于 Rst 在基于人群的药理学研究中完全被掩盖，我们追求 Rst 是“隐藏变量”，可能有助于解释为什么有些患者会经历围麻醉期并发症，而其他则没有。我们建议研究蓝斑减少 Rst 的机制。药理学和遗传学方法，我们将确定该基因座使用的神经递质系统蓝斑调节 Rst。我们将分别确定蓝斑对神经生理学的影响。使用我们实验室开发的高密度脑电图系统来检测状态变化，包括行为第一的相关性。最后，我们将转向确定蓝斑调节的神经通路首先，拟议的研究路线将阐明蓝斑的活动如何影响个体化。麻醉反应，这将是实现个性化麻醉的重要一步。