Personalized Anesthetic Pharmacology Across the Lifespan

整个生命周期的个性化麻醉药理学

• 批准号: 10684036
• 负责人: Max Kelz
• 金额: $ 50.67万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-21 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10684036
• 关键词: Address; Adult; Affect; Age; Age Months; Aging; Anesthesia procedures; Anesthesiology; Anesthetics; Animals; Arousal; Attention; Characteristics; Clinical; Cognition; Conscious; Control Animal; Data; Delirium; Dependence; Dependovirus; Development; Dose; Drug resistance; Drug usage; Elderly; Enterobacteria phage P1 Cre recombinase; Exhibits; Exposure to; Genetic; Human Volunteers; Impaired cognition; Impairment; Inbred Mouse; Individual; Individual Differences; Investigation; Isoflurane; Link; Longevity; Longitudinal Studies; Measures; Mediating; Methodology; Mus; Neurobiology; Neurons; Operative Surgical Procedures; Pathway interactions; Patients; Performance; Pharmaceutical Preparations; Pharmacology; Pharmacology Study; Population; Population Study; Postoperative Complications; Publishing; Recording of previous events; Recovery; Reflex action; Reproducibility; Resistance; Role; Sleep; Speed; Testing; Time; Transfection; Transgenic Mice; Wakefulness; aged; behavior test; cognitive function; cognitive performance; cognitive recovery; cognitive testing; cohort; cost; designer receptors exclusively activated by designer drugs; drug sensitivity; drug standard; human old age (65+); hypocretin; improved; inattention; innovation; inter-individual variation; novel; older patient; patient population; personalized medicine; population based; postoperative delirium; precision drugs; promoter; response; restoration; selective expression; sustained attention; virtual

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.

抽象的。 关于麻醉剂量的决定通常依赖于基于人群的药物效力的度量。 但是，类似的麻醉剂量对不同个体的影响明显不同。而有些患者 从麻醉中恢复不利，在其他麻醉中，术后del妄和 认知功能障碍。这种并发症在古老的情况下非常普遍。提出不清楚 为什么一些古老的患者表现出这些令人衰弱和昂贵的并发症。要回答这个问题， 必须制定基于个体的基于人群的药物效应措施。我们创建这样的 小鼠麻醉剂的措施。初步数据，表明基于人口的标准措施 麻醉效力，例如半最大有效浓度（EC50），不足以解释麻醉剂 每个人的回应。这是因为以固定的麻醉浓度，意识水平 每个人都在波动。虽然自发地发生在唤醒状态下发生波动，但有一个惯性 每种动物趋于抵抗状态转变。因此，每个人的响应不仅取决于 在麻醉浓度的情况下，以及个人以前的唤醒状态。标准药物 效力措施无法解释这一历史依赖性。这是为了充分量化基于个人的 对麻醉剂的反应，我们制定了两种独立的措施：个性化药物敏感性和抗性 国家过渡。我们假设对状态过渡的抵抗有助于延迟恢复 麻醉后的认知功能。我们研究了对国家转变的年龄依赖性 一项纵向研究（AIM 1）。为了研究对国家过渡的抵抗的神经生物学基础，我们 有选择地降低对状态过渡的抗性，使用甲状腺素能神经元的化学发生激活 与睡眠和清醒的稳定相关（AIM 2）。确定是否抵抗 国家过渡有时与认知的恢复有关，我们使用持续关注的行为测试 （SA）麻醉后立即进行康复后。我们发布的结果表明SA是 从人类志愿者的麻醉中康复后动态中断。我们确定是否增加 对国家过渡的抵抗与出现后SA性能的更大损害有关 老鼠。我们尝试通过使用使用抵抗来恢复正常的SA性能。 甲虫能神经元的化学发生激活（AIM 3）。总而言之，我们开发了一个定性新颖的测量 个性化的，而不是基于人群的麻醉反应：对国家过渡的抵抗。我们 确定对状态过渡的抵抗力的神经生物学基础，并研究其与 随后的认知恢复。这是我们为发展真正个性化的关键第一步 麻醉和描述意识延迟恢复的根本因素。