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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.

项目总结/摘要为了挽救生命，麻醉师将数百万患者置于可逆的昏迷状态每年的手术。麻醉护理的基本目标是可靠地熄灭意识，手术后，患者迅速恢复到基线认知状态。俩都不然而，这些目标今天可以可靠地实现。有些病人在手术过程中会恢复知觉。目前基于脑电图的术中监测不能可靠地检测到意识的发作，导致创伤后压力和焦虑症。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障碍。术后谵妄影响数百万患者，每年花费340亿美元，并且本身可以是认知障碍的先兆。手术后的抑郁症这种认知功能的持续衰退可以持续数月。目前据不清楚为什么有些患者会出现围麻醉期并发症，而另一些患者接受看起来相同的麻醉剂具有无事件的围手术期过程。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人的测量小鼠的麻醉反应。这些方法的使用表明，基于人群的药理学概念（如药物效力）不足以描述个体应答我们确定了两个独立的衡量标准，它们确实反映了个体反应的范围：灵敏度和状态转换电阻（Rst）。敏感度描述了一个人清醒或在麻醉剂量下麻醉，而Rst描述了这两者之间发生转换的频率 states.我们证明了灵敏度和Rst可以被差分调制。我们也表明化学激活唤醒途径-蓝斑-降低Rst，而没有药物敏感性的变化。由于Rst在基于人群的药理学研究中完全模糊，我们假设Rst是“隐藏变量”，这可能有助于解释为什么有些患者会出现麻醉期并发症，而其他人没有。我们建议通过蓝斑降低Rst的机制进行调查。使用药理学和遗传学的方法，我们将确定神经递质系统所使用的基因座蓝斑调节Rst.另外，我们将确定蓝斑对神经生理的影响，状态变化，包括行为Rst的相关性，使用我们实验室开发的高密度EEG系统。最后，我们将转向确定蓝斑通过哪些神经元通路来调节 Rst.建议的调查路线将澄清蓝斑的活动如何影响个体化麻醉反应，并将是向提供个性化麻醉的重要一步。