A Multi-Modal Combination Intervention to Promote Cognitive Function in Older Intensive Care Unit Survivors

这个指导以病人为导向的研究职业发展奖的目的是准备候选人，玛雅埃利亚斯博士，老年重症监护研究的独立计划。超过60%的重症监护病房（ICU）患者是60岁及以上的成年人。出院后，约25%的ICU幸存者经历认知障碍，其严重程度与轻度阿尔茨海默病和相关痴呆相当。此外，ICU幸存者经常经历睡眠障碍和不活动，几乎80%的ICU患者经历昼夜节律紊乱，这可能影响认知功能。拟议研究的科学前提是：1）联合睡眠促进和认知训练干预将具有协同效应，以减轻老年ICU幸存者中认知障碍和阿尔茨海默病及相关痴呆症发展的风险;以及2）干预的时间安排（即，根据昼夜节律曲线调整干预的时机）可以提高干预的功效。拟议的研究和培训建立在由Elias博士（F32 NR 018585）进行的NIH资助的博士后研究基础上。培训目标1将通过临床试验方法和统计分析培训，培养设计和完善行为睡眠和认知干预措施的专业知识。培训目标2将扩展昼夜节律科学和时间疗法的知识，以检查昼夜节律作为老年ICU幸存者中与阿尔茨海默病和相关痴呆相关的谵妄和认知下降的机制因素。该职业发展奖还将支持埃利亚斯博士领导一项临床试验，该试验将评估现有行为睡眠和认知干预措施的可行性，以指导更大规模的随机对照试验的设计。使用2 x 2析因设计，100名讲英语或西班牙语的老年ICU幸存者将在ICU出院后入组，并随机接受两种干预措施的4种组合之一：SLEEP [夜间使用耳塞和眼罩]和COG [每日计算机认知训练课程]。具体目标1将测试睡眠和COG与AC [积极控制]相比在改善老年ICU幸存者认知功能方面的单独和联合作用。具体目标2将检查连续体温的昼夜节律参数，以确定COG干预时间的最佳窗口。具体目标3将检查每种干预[睡眠+ COG、睡眠、COG]对认知功能的影响是否由睡眠和活动介导，并将检查选定的生物学和临床因素是否减轻了干预效果。探索性目标4将探索每种干预措施对出院后1个月认知功能以及6个月和12个月阿尔茨海默病和相关痴呆事件的影响。结果将为未来的临床试验提供关键的初步数据，并将指导埃利亚斯博士建立一个研究测试干预措施的计划，以改善老年ICU幸存者从危重病中恢复的结果。

The purpose of this Mentored Patient-Oriented Research Career Development Award is to prepare the candidate, Dr. Maya Elias, for an independent program of geriatric critical care research. More than 60% of intensive care unit (ICU) patients are adults ages 60 and older. Following hospital discharge, about 25% of ICU survivors experience cognitive impairment comparable in severity to mild Alzheimer’s disease and related dementias. Moreover, ICU survivors often experience sleep disturbances and inactivity, and almost 80% of ICU patients experience disturbances in circadian rhythm, which may affect cognitive function. The scientific premises of the proposed study are: 1) a combined sleep promotion and cognitive training intervention will have synergistic effects to mitigate the risk of cognitive impairment and development of Alzheimer’s disease and related dementias in older ICU survivors; and 2) chronotherapeutic timing of interventions (i.e., adjusting timing of interventions according to circadian rhythm profiles) may improve intervention efficacy. The proposed research and training build upon prior NIH-funded postdoctoral research conducted by Dr. Elias (F32NR018585). Training Aim 1 will develop expertise in designing and refining behavioral sleep and cognitive interventions through training in clinical trial methodologies and statistical analyses. Training Aim 2 will expand knowledge of circadian science and chronotherapy to examine circadian rhythm as a mechanistic factor underlying delirium and cognitive decline related to Alzheimer’s disease and related dementias in older ICU survivors. This Career Development Award will also support Dr. Elias to lead a clinical trial, which will evaluate feasibility of existing behavioral sleep and cognitive interventions to inform the design of a larger randomized controlled trial. Using a 2 x 2 factorial design, 100 English- or Spanish-speaking older ICU survivors will be enrolled after discharge out of the ICU and randomized to one of 4 combinations of two interventions: SLEEP [nighttime use of earplugs and eye masks] and COG [daily computerized cognitive training sessions]. Specific Aim 1 will test the separate and combined effects of SLEEP and COG, versus AC [active control], in improving cognitive function for older ICU survivors. Specific Aim 2 will examine circadian rhythm parameters of continuous body temperature to determine the optimal window for timing of the COG intervention. Specific Aim 3 will examine if the effects of each intervention [SLEEP + COG, SLEEP, COG] on cognitive function are mediated by sleep and activity, and will examine if selected biological and clinical factors moderate the intervention effects. Exploratory Aim 4 will explore the effect of each intervention on cognitive function at 1 month and incident Alzheimer’s disease and related dementias at 6 months and 12 months after hospital discharge. Results will yield crucial preliminary data for future clinical trials and will guide Dr. Elias to establish a program of research testing interventions that will improve outcomes for older ICU survivors throughout recovery from critical illness.