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 项目摘要 谵妄是一种令人痛苦的临床综合征，其特征是基本认知功能的失败， 约20 - 50%的老年外科患者。手术恢复期间的谵妄与增加 死亡率、医疗保健支出增加以及未来认知和功能下降。此外， 谵妄和阿尔茨海默病相关痴呆之间的病理生理学重叠; 谵妄表现出未来痴呆的风险增加。不幸的是，精神错乱的神经生物学基础 仍然不完全了解，也没有生物学上的信息，有效的治疗方法来预防 术后谵妄及相关并发症。我们的初步数据表明咖啡因能减少谵妄 在麻醉后监护室（PACU）中，通过将皮质动力学向神经动力学转移， 临界性关键性是指系统状态准备动态波动以满足需求。为 神经临界性是一种潜在的机制，通过这种机制，大脑的功能分离区域可以被 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， 手术结束时的咖啡因显示出脑电（EEG）危急标记物增加， PACU同时伴有谵妄减少。尽管如此，咖啡因，神经临界状态， 和术后神经认知恢复需要额外的严格测试。我们的长期目标是改善 对谵妄和相关神经认知障碍的神经生物学理解， 可以开发。本提案的目标是：（1）测试干预措施，以减少早期 术后谵妄，同时（2）识别反映认知脆弱性的动态脑变化。的 中心假设是咖啡因将改善老年人术后神经认知恢复。我们将 通过随机、安慰剂对照、四盲临床试验来检验这一假设。目标1将决定 咖啡因是否能降低术后早期谵妄的发生率。将对受试者（n = 250）进行随机分组 安慰剂，低剂量咖啡因，或高剂量咖啡因在一个三臂平行设计。顺序随机化 设计也将用于测试一天与两天的咖啡因治疗。目标2将识别皮质动力学 潜在的术后早期谵妄一个无线的，高密度的全头皮脑电图系统将使 分析神经临界状态以及咖啡因和谵妄的关系。最后，Aim 3将使用相同的 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状态， 因为在患有这种疾病以及阿尔茨海默病的患者中已经报道了偏离临界状态。 总体而言，拟议的研究意义重大，因为结果可能提供有效的神经生物学方法 减少术后早期谵妄和相关后果的知情干预。此外，结果 将提供神经生物学洞察脆弱的皮质动力学，预示着谵妄，可能， 神经认知障碍。