Caffeine and Postoperative Neurocognitive Recovery

咖啡因与术后神经认知恢复

• 批准号: 10517443
• 负责人: Phillip Eleas Vlisides
• 金额: $ 57.37万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-02 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10517443
• 关键词: Acetylcholine; Acute; Affect; Alzheimer' s Disease; Alzheimer' s disease related dementia; Anesthetics; Area; Arousal; Awareness; Blinded; Brain; Caffeine; Caring; Characteristics; Clinical; Clinical Trials; Cognition; Cognitive; Consumption; Data; Delirium; Dementia; Diagnostic; Distress; Dose; Elderly; Failure; Family; Foundations; Future; Goals; Health Expenditures; Hospitalization; Hour; Impaired cognition; Incidence; Intervention; Intravenous; Length of Stay; Measures; Memory; Neurobiology; Neurocognitive; Operative Surgical Procedures; Outcome; Participant; Patients; Pharmacology; Placebo Control; Placebos; Postoperative Period; Process; Public Health; Purinergic P1 Receptors; Randomized; Randomized Clinical Trials; Recovery; Reporting; Research; Risk; Scalp structure; Severities; Subgroup; Surgical complication; Syndrome; System; Techniques; Testing; Therapeutic; Time; Wakefulness; arm; base; cognitive function; cognitive testing; density; design; effective intervention; effective therapy; experience; falls; flexibility; functional decline; improved; insight; meetings; mild cognitive impairment; mortality; neurocognitive disorder; novel; postoperative delirium; prevent; primary outcome; public health relevance; randomized placebo controlled trial; recruit; relating to nervous system; secondary analysis; secondary outcome; wireless

TITLE: CAFFEINE AND POSTOPERATIVE NEUROCOGNITIVE RECOVERY PROJECT SUMMARY Delirium is a distressing clinical syndrome characterized by failure of basic cognitive functions that affects approximately 20-50% of older surgical patients. Delirium during surgical recovery is associated with increased mortality, increased healthcare expenditures, and future cognitive and functional decline. Moreover, there is pathophysiologic overlap between delirium and Alzheimer’s Disease-Related Dementias; patients experiencing delirium demonstrate increased risk of future dementia. Unfortunately, the underlying neurobiology of delirium remains incompletely understood, and there are no biologically informed, effective therapies for preventing postoperative delirium and related complications. Our preliminary data suggest that caffeine reduces delirium in the postanesthesia care unit (PACU) after major surgery by shifting cortical dynamics towards neural criticality. Criticality refers to a system state that is poised to dynamically fluctuate to meet demands. For cognition, neural criticality is a potential mechanism by which functionally segregated areas of the brain can be dynamically integrated over space and time to optimize cognition. In our preliminary trial, participants receiving caffeine at the end of surgery demonstrated increased electroencephalographic (EEG) markers of criticality in the PACU concurrent with delirium reduction. Nonetheless, the relationships among caffeine, neural criticality, and postoperative neurocognitive recovery require additional, rigorous testing. Our long-term goal is to improve neurobiological understanding of delirium and related neurocognitive disorders, such that effective therapies can be developed. The objectives of this proposal are to (1) test an intervention for reducing early postoperative delirium while (2) identifying dynamic brain changes that reflect cognitive vulnerability. The central hypothesis is that caffeine will improve postoperative neurocognitive recovery in older adults. We will test this hypothesis via a randomized, placebo-controlled, quadruple-blinded clinical trial. Aim 1 will determine whether caffeine reduces the incidence of early postoperative delirium. Participants (n=250) will be randomized to placebo, low-dose caffeine, or high-dose caffeine in a three-arm parallel design. A sequential randomization design will also be used to test one vs. two days of caffeine therapy. Aim 2 will identify cortical dynamics underlying early postoperative delirium. A wireless, high-density whole-scalp EEG system will enable the analysis of neural criticality and the associations with caffeine and delirium. Lastly, Aim 3 will use the same EEG system to test baseline neural criticality in trial participants meeting criteria for Mild Cognitive Impairment, as deviations from criticality have been reported in patients with this condition as well as Alzheimer’s Disease. Overall, the proposed research is significant because results may provide an effective, neurobiologically informed intervention for reducing early postoperative delirium and related consequences. Additionally, results will provide neurobiological insight into vulnerable cortical dynamics that portend delirium and, possibly, subsequent neurocognitive disorders.

标题：咖啡因与术后神经认知恢复 项目总结 精神错乱是一种令人痛苦的临床综合征，其特征是基本认知功能的丧失，从而影响 大约20%-50%的老年外科患者。外科恢复期的精神错乱与 死亡率，增加的医疗费用，以及未来的认知和功能下降。此外，还有 精神错乱和阿尔茨海默病相关痴呆之间的病理生理学重叠：患者经历 精神错乱表明未来患痴呆症的风险增加。不幸的是，精神错乱的潜在神经生物学 仍然没有完全了解，也没有生物学上知情的有效治疗方法来预防 术后精神错乱及相关并发症。我们的初步数据显示咖啡因可以减少精神错乱。 在大手术后的感觉后护理病房(PACU)，通过将皮质动力学转向神经 临界性。临界性是指系统状态随时准备动态波动以满足需求。为 认知，神经临界性是一种潜在的机制，通过它大脑的功能隔离区域可以 在空间和时间上动态整合以优化认知。在我们的初步试验中，参与者收到了 手术结束时咖啡因显示脑电(EEG)标志增加的危重 PACU伴随着神志不清的减少。尽管如此，咖啡因、神经临界性、 术后的神经认知恢复需要额外的、严格的测试。我们的长期目标是改进 对精神错乱和相关神经认知障碍的神经生物学了解，以便有效的治疗 可以被开发出来。这项建议的目标是(1)测试干预措施，以期及早减少 术后神志不清，同时(2)辨认反映认知脆弱性的动态脑变化。这个 中心假设是咖啡因将改善老年人术后的神经认知恢复。我们会 通过一项随机、安慰剂对照、四盲的临床试验来检验这一假设。目标一号将决定 咖啡因是否能降低术后早期精神错乱的发生率。参与者(n=250)将被随机分配 到安慰剂、低剂量咖啡因或高剂量咖啡因的三臂平行设计。顺序随机化 设计还将用于测试一天和两天的咖啡因治疗。目标2将确定大脑皮层动力学 术后早期精神错乱的潜在原因。无线、高密度全头皮脑电系统将使 神经临界性分析及其与咖啡因和精神错乱的关系。最后，《目标3》也将使用同样的方法 EEG系统用于测试符合轻度认知障碍标准的试验参与者的基线神经临界性， 据报道，在患有这种疾病和阿尔茨海默病的患者中，已经出现了偏离临界值的情况。 总体而言，拟议的研究具有重要意义，因为结果可能提供有效的、神经生物学的 减少术后早期精神错乱及相关后果的知情干预。此外，结果 将提供对脆弱的皮质动力学的神经生物学洞察，这些动力学预示着精神错乱，甚至可能， 随后的神经认知障碍。