Personalized Anesthetic Pharmacology Across the Lifespan

抽象的。 关于麻醉剂剂量的决定通常依赖于基于人群的药物效力测量。 然而，相似的麻醉剂量对不同的个体有明显不同的影响。虽然一些患者 从麻醉中顺利恢复，在其他情况下，恢复并发术后谵妄， 认知功能障碍这种并发症在老年人中非常普遍。目前还不清楚 为什么一些老年患者会出现这些使人衰弱和昂贵的并发症。为了回答这个问题， 必须制定以个人而不是以人口为基础的药物效果衡量标准。我们创造这样的 用于小鼠麻醉剂的测量。初步数据表明，基于人口的标准措施， 麻醉效力，如半数最大有效浓度（EC 50），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， 每个人都在波动。虽然觉醒状态的波动是自发发生的，但存在一种惯性， 每只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 麻醉剂浓度，以及个体先前的觉醒状态。标准药物 效力测量不能解释这种历史依赖性。因此，为了充分量化基于个人的 对麻醉药的反应，我们开发了两个独立的措施：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有助于延迟恢复。 麻醉后的认知功能我们研究了年龄依赖性的电阻状态转换在第一个 一种纵向研究（目标1）。为了研究状态转换抵抗的神经生物学基础，我们 使用化学发生激活食欲素能神经元选择性地降低对状态转换的抗性， 在睡眠和觉醒的稳定中起关键作用（目标2）。为了确定是否抵抗 状态转换与认知恢复有因果关系，我们使用持续注意力的行为测试 (SA)麻醉后恢复后立即进行。我们公布的结果表明，SA是 在人类志愿者从麻醉中恢复后急剧中断。我们确定是否增加 对状态转换的抵抗与出现后SA性能的更大损害相关， 小鼠我们试图通过调节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发生激活（Aim 3）。总之，我们开发了一个定性的新措施， 个性化的，而不是基于人群的麻醉反应：对状态转换的抵抗。我们 确定对状态转换的抵抗的神经生物学基础，并研究其与 随后的认知恢复。因此，我们为开发真正个性化的产品迈出了关键的第一步。 麻醉和描述延迟恢复意识的潜在因素。

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.