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

摘要：背景资料：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，与住院时间延长、功能障碍、死亡率和阿尔茨海默病风险增加相关。在美国，在高达90%的手术中，麻醉是用吸入剂（GAS）维持的;然而，用静脉内麻醉剂（IV）维持是具有潜在优势的替代技术。关于IV与GAS是否可以降低老年手术患者术后不良结局的风险，目前还存在显著的知识差距。这是一个严重的公共卫生问题，因为超过一半的美国老年人在他们的一生中都会接受手术，而且手术人口的老龄化速度比美国人口快。考虑到GAS和IV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。职业发展计划：候选人致力于围手术期老龄化研究的学术生涯，并将专注于四个目标。(1)培训成为一名临床试验专家，并领导多学科团队在老年人中进行试验。发展将（2）老年医学原则和（3）生物标志物研究纳入老年人围手术期干预试验的专业知识。(4)加强领导力培训，成为老年麻醉学研究的有效领导者，并在临床实践中产生影响。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与支持学术部门和机构的专门导师团队来实现。完成将使候选人能够实现成为一名独立的医生科学家和老年麻醉研究的领导者的目标，重点是防止老年手术患者的神经认知和功能下降。研究建议：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结局（PRO）;（3）磷酸化tau 181（p-tau181）和老年人其他血液生物标志物的水平。假设：手术和全身麻醉后，IV与GAS相比，POD、POCD和功能下降的发生率降低。接下来，与GAS相比，IV将改善PRO并减少神经炎症和阿尔茨海默氏症的血液生物标志物。具体而言，GAS中血液p-tau181的术后增加大于IV，并且与POD和POCD相关。方法：这项单中心、1：1随机、双盲临床试验将在接受择期住院非心脏手术的≥ 75岁男性和女性中比较GAS与IV对POD、POCD、功能状态和PRO的影响。结果将提供证据，以帮助选择全身麻醉剂（IV与GAS），以优化老年手术患者的结局。这与NIA的战略目标一致，即制定有效的干预措施来维持健康、福祉和功能，并减轻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.