Personalized Anesthetic Pharmacology Across the Lifespan

抽象的。 有关麻醉剂剂量的决定通常依赖于基于人群的药物效力衡量标准。 然而，相似的麻醉剂剂量对不同的个体有明显不同的影响。虽然有些病人 顺利从麻醉中恢复，在其他情况下，恢复复杂于术后精神错乱和 认知功能障碍。这种并发症在老年人中非常普遍。目前尚不清楚 为什么一些老年患者会出现这些令人虚弱和昂贵的并发症。为了回答这个问题, 必须制定基于个人而不是基于总体的药物效果衡量标准。我们创造了这样的 对小鼠的麻醉药进行检测。初步数据表明，基于人口的标准衡量标准 麻醉效力，如半数有效浓度(EC50)，不足以解释麻醉。 每个人的反应。这是因为在固定的麻醉剂浓度下， 每个人都有波动。虽然觉醒状态的波动是自发发生的，但有一个惯性 每种动物都有抵抗状态转换的倾向。因此，每个人的反应不仅取决于 取决于麻醉浓度，也取决于个体先前的唤醒状态。标准药品 效力指标未能解释这种对历史的依赖。因此，要充分量化以个人为基础的 对于麻醉药的反应，我们开发了两个独立的测量方法：个性化的药物敏感性和耐药性 到状态转换。我们假设，对状态转换的抵抗导致延迟恢复 麻醉后的认知功能。我们首先研究了抵抗状态转换的年龄依赖性。 一种纵向研究(目标1)。为了研究抵抗状态转换的神经生物学基础，我们 通过化学激活食欲素能神经元来选择性地减少对状态转换的抵抗 与稳定睡眠和清醒密切相关(目标2)。以确定是否对 状态转换与认知的恢复有因果关系，我们使用持续注意力的行为测试 (Sa)麻醉后苏醒时立即进行。我们发表的结果表明，SA是 在人类志愿者从麻醉中恢复后被戏剧性地破坏。我们确定是否增加了 对状态转换的抵触与出现后SA表现的更大损害有关 老鼠。我们尝试通过调整状态转换的阻力来恢复正常的SA性能 食欲素能神经元的化学激活(目标3)。总而言之，我们开发了一种质量上新颖的测量方法 个性化的麻醉反应，而不是基于群体的麻醉反应：对状态转换的抵抗。我们 确定抵抗状态转换的神经生物学基础，并研究其与 随后的认知恢复。因此，我们向开发真正个性化的产品迈出了关键的第一步。 麻醉和描述导致意识恢复延迟的因素。

Abstract. Decisions concerning anesthetic dosing typically rely on population-based measures of drug potency. However, similar anesthetic doses have markedly different effects on distinct individuals. While some patients recover from anesthesia uneventfully, in others, recovery is complicated by postoperative delirium and cognitive dysfunction. Such complications are disproportionally prevalent in the elderly. It is presently unclear why some elderly patients exhibit these debilitating and costly complications. To answer this question, individual-based rather than population-based measures of drug effects must be developed. We create such measures for anesthetics in mice. Preliminary data indicate that standard population-based measures of anesthetic potency, such as half-maximal effective concentration (EC50), are insufficient to explain anesthetic responses in each individual. This is because at a fixed anesthetic concentration, the level of consciousness in each individual fluctuates. While fluctuations in the state of arousal occur spontaneously, there is an inertial tendency in each animal to resist state transitions. Hence, the response in each individual depends not just upon the anesthetic concentration, but also upon the individual’s previous state of arousal. Standard drug potency measures fail to account for this history-dependence. Thus, to adequately quantify individual-based responses to anesthetics, we develop two independent measures: personalized drug sensitivity and resistance to state transitions. We hypothesize that resistance to state transitions contributes to delayed restoration of cognitive function after anesthesia. We investigate age-dependence of resistance to state transitions in a first of a kind longitudinal study (Aim 1). To investigate a neurobiological basis of resistance to state transitions, we selectively decrease resistance to state transitions using chemogenetic activation of orexinergic neurons that are critically involved in stabilization of sleep and wakefulness (Aim 2). To determine whether resistance to state transitions is causally linked to restoration of cognition, we use a behavioral test of sustained attention (SA) performed immediately upon recovery after anesthesia. Our published results indicate that SA is dramatically disrupted after recovery from anesthesia in human volunteers. We determine if increased resistance to state transitions is associated with greater impairment on SA performance after emergence in mice. We attempt to restore normal SA performance by modulating resistance to state transitions using chemogenetic activation of orexinergic neurons (Aim 3). In summary, we develop a qualitatively novel measure of personalized, rather than population-based anesthetic responses: resistance to state transitions. We determine the neurobiological underpinnings of resistance to state transitions, and investigate its relationship to subsequent cognitive recovery. Thus, we offer a critical first step towards developing truly personalized anesthesia and delineate factors underlying delayed restoration of consciousness.