Optimizing anesthesia to prevent postoperative cognitive and functional decline in older adults

摘要：背景：术后谵妄（POD）和术后认知功能障碍（POCD）是老年人最常见的手术并发症，并与住院时间延长、功能残疾、死亡率和阿尔茨海默病风险相关。在美国，高达90%的手术中使用吸入剂（GAS）维持麻醉；然而，静脉注射药物维持是一种具有潜在优势的替代技术。关于静脉注射与气体注射是否能降低老年外科患者术后不良后果的风险，目前还存在很大的知识差距。这是一个重要的公共卫生问题，因为超过一半的美国老年人将在他们的一生中接受手术，手术人口的老龄化速度比美国人口快。考虑到气体和静脉注射都是现成的、有效的、安全的和具有成本效益的，从一种转换到另一种将是一个简单的临床实践改变。职业发展规划：候选人将致力于围手术期衰老研究的学术生涯，并将专注于四个目标。(1)培训成为临床试验学家，带领多学科团队在老年人中进行试验。发展将(2)老年医学原理和(3)生物标志物调查纳入老年人围手术期干预试验的专业知识。(4)加强领导能力培训，成为老年麻醉学研究和临床效果改变的有效领导者。目标将通过正式的课程、会议、研讨会、指导、技能培训和体验式学习来实现，并由一个专业的指导团队在一个支持性的学术部门和机构中进行。完成该课程将使候选人能够实现成为一名独立的内科科学家和老年麻醉研究的领导者的目标，重点是预防老年外科患者的神经认知和功能衰退。研究计划：具体目的是确定IV与GAS对(1)老年人POD和POCD发生率的影响；(2)老年人术后功能下降的发生率和患者报告的预后（PROs）；(3)老年人磷酸化tau181 （p-tau181）和其他血液生物标志物的水平。假设：与GAS相比，手术和全身麻醉后POD、POCD和功能下降的发生率降低。接下来，与GAS相比，静脉注射将改善PROs，降低神经炎症和阿尔茨海默氏症血液生物标志物。具体而言，术后GAS组血p-tau181升高高于IV组，且与POD和POCD相关。方法：这项单中心、1:1随机、双盲临床试验将比较≥75岁接受选择性、住院、非心脏手术的男性和女性中，GAS与IV对POD、POCD、功能状态和PROs的影响。结果将提供证据，以帮助选择全麻（静脉麻醉与气体麻醉），以优化老年外科患者的结果。这与NIA的战略目标一致，即制定有效的干预措施，以保持健康、福祉和功能，并减少与年龄相关的疾病和残疾的负担。

ABSTRACT: Background: Postoperative delirium (POD) and postoperative cognitive dysfunction (POCD) are the most common surgical complications in older adults and are associated with increased hospital length of stay, functional disability, mortality, and risk of Alzheimer’s. In the U.S., anesthesia is maintained with inhalational agents (GAS) in up to 90% of operations; however, maintenance with intravenous agents (IV) is an alternative technique with potential advantages. There is a significant gap in knowledge regarding whether IV vs. GAS can decrease the risk of deleterious postoperative outcomes in older surgical patients. This is a critical public health problem considering over half of older Americans will undergo surgery during their lives, and the surgical population is aging faster than the U.S. population. Considering both GAS and IV are readily available, effective, safe, and cost-effective, switching from one to the other would be a simple clinical practice change. Career Development Plan: The candidate is dedicated to an academic career in perioperative aging research and will focus on four objectives. (1) Training to become a clinical trialist and lead multidisciplinary teams conducting trials in older adults. Develop expertise in incorporating (2) geriatric medicine principles and (3) biomarker investigations into perioperative intervention trials in older adults. (4) Enhance leadership training to be an effective leader in geriatric anesthesiology research and effect change in clinical practice. Objectives will be met by formal coursework, meetings, seminars, mentoring, skills training, and experiential learning with a dedicated mentorship team in a supportive academic department and institution. Completion will enable the candidate to achieve the goal of becoming an independent physician-scientist and a leader in geriatric anesthesia research focused on preventing neurocognitive and functional decline in older surgical patients. Research Proposal: The specific aims are to determine the effects of IV vs. GAS on (1) incidence of POD and POCD in older adults; (2) incidence of postoperative functional decline and patient-reported outcomes (PROs) in older adults; and (3) levels of phosphorylated tau 181 (p-tau181) and other blood biomarkers in older adults. Hypotheses: There is a decreased incidence of POD, POCD, and functional decline following surgery and general anesthesia with IV vs. GAS. Next, compared to GAS, IV will improve PROs and decrease neuroinflammatory and Alzheimer’s blood-based biomarkers. Specifically, the postoperative increase in blood p-tau181 is greater in GAS than IV and is associated with POD and POCD. Approach: This single-center, 1:1 randomized, double-blind clinical trial will compare GAS vs. IV on POD, POCD, functional status, and PROs in men and women ≥ 75 years of age undergoing elective, inpatient, non-cardiac surgery. Results will provide evidence to aid the choice of general anesthetic (IV vs. GAS) to optimize outcomes in geriatric surgical patients. This aligns with the NIA’s strategic goal to develop effective interventions to maintain health, well-being, and function, and reduce the burden of age-related disorders and disabilities.