Pathophysiology of postoperative delirium and the use of biomimetic sleep as a treatment strategy in the CSICU

术后谵妄的病理生理学以及仿生睡眠在 CSICU 中作为治疗策略的应用

• 批准号: 10179061
• 负责人: Oluwaseun Johnson-Akeju
• 金额: $ 62.68万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10179061
• 关键词: Acute; Age; Aging; Alzheimer' s Disease; Anesthesia procedures; Anesthetics; Antipsychotic Agents; Astrocytes; Attention; Awareness; Benzodiazepines; Binding; Biological Markers; Biomimetics; Blood Circulation; Blood specimen; Brain; Cardiac; Caring; Cells; Chronic; Clinical; Cognition; Cognitive deficits; Control Groups; Critical Illness; Data; Delirium; Dementia; Development; Dexmedetomidine; Diagnosis; Disease; Elderly; Electroencephalogram; Failure; Functional disorder; Health Care Costs; Hospitalization; Human; Impaired cognition; Incidence; Individual; Inflammation Mediators; Inflammatory; Institutionalization; Intensive Care Units; Interleukin-6; Intervention; Investigation; Knowledge; Laboratory Animals; Magnetic Resonance Imaging; Maintenance; Medical; Methods; Microglia; Molecular; Monitor; Morbidity - disease rate; Morphology; Nerve Degeneration; Neuroglia; Operative Surgical Procedures; Outcome; Overdose; Patients; Perioperative; Pharmaceutical Preparations; Pharmacological Treatment; Pharmacology; Positron-Emission Tomography; Procedures; Process; Proteins; REM Sleep; Randomized; Randomized Controlled Trials; Risk; Risk Factors; Sepsis; Serum; Severities; Sleep; Sleep Deprivation; Sleep disturbances; Surgical Intensive Care; Therapeutic; Unconscious State; United States; Work; aging brain; base; brain dysfunction; comorbidity; experience; metabolic profile; modifiable risk; mortality; neurocognitive disorder; neuroinflammation; neurophysiology; non rapid eye movement; normal aging; older patient; postoperative delirium; prevent; radioligand; standard care; systemic inflammatory response; treatment strategy

Delirium is one of the six leading causes of preventable morbidity and mortality in hospitalized elderly patients. Individuals with advanced age and Alzheimer's disease are at greatest risk of developing delirium. A substantial proportion of patients who survive delirium are likely to experience long-term cognitive impairment similar to mild Alzheimer's disease, and require institutional care. This suggests that delirium and Alzheimer's disease share pathophysiological features that arise in the context of normal aging. Conditions associated with delirium are characterized by activation of the inflammatory cascade with acute release of inflammatory mediators into the bloodstream. A putative mechanism is the high interleukin-6 level that has been associated with delirium in both laboratory animals and humans. Normal aging is associated with a morphological shift of glia to an activated state. Following a systemic challenge such as critical illness, these activated glia result in an exaggerated neuroinflammatory state associated with delirium. Neuroinflammation is further exacerbated by sleep disturbances. Thus, sleep deprivation may be a modifiable risk factor for the development of delirium. However, pharmacological treatment with no current medication (benzodiazepines, antipsychotics) induces natural sleep or reliably reduces the incidence of delirium. We have found that biomimetic sleep, defined here as pharmacological induction of rapid eye movement sleep (REM) and non-REM I-III sleep states using dexmedetomidine, can now be achieved in humans. Our Specific Aims seek to: (1) investigate the benefits of preemptive biomimetic sleep for reducing the risk of developing delirium in a randomize; (2) investigate the cellular and molecular mechanisms of delirium using combined Positron Emission Tomography/Magnetic Resonance imaging and serum metabolic profiling; and (3) investigate predictors of delirium from perioperative electroencephalogram recordings. At the conclusion of these studies, we will have expanded our knowledge of the pathophysiology of delirium, evaluated a new preemptive therapeutic strategy for delirium, suggest neurophysiologically based monitoring strategies to reduce significantly the amount of anesthetic administered to elderly patients – and possibly delirium – while being certain the patient is sufficiently unconscious for surgery (individualized anesthesia care), and enable continued investigation into the pathophysiology of this clinically important disorder.

谵妄是住院老年患者可预防的发病率和死亡率的六大主要原因之一。 患有阿尔茨海默病的高龄人士患谵妄 A 的风险最大。 大部分在谵妄中幸存的患者可能会出现长期认知障碍 与轻度阿尔茨海默病相似，需要机构护理这表明谵妄和阿尔茨海默病。 疾病具有与正常衰老相关的病理生理学特征。 谵妄的特征是炎症级联的激活和炎症的急性释放 一种推测的机制是相关的高白细胞介素 6 水平。 实验动物和人类的谵妄都与正常衰老有关。 神经胶质细胞进入激活状态后，如危重疾病，这些激活的神经胶质细胞会导致 与谵妄相关的过度神经炎症状态会因谵妄而进一步加剧。 因此，睡眠不足可能是发生谵妄的一个可改变的危险因素。 然而，目前没有药物（苯二氮卓类药物、抗精神病药物）的药物治疗会诱发 自然睡眠或可靠地降低谵妄的发生率我们发现仿生睡眠（此处定义）。 作为快速眼动睡眠 (REM) 和非 REM I-III 睡眠状态的药物诱导，使用 右美托咪定现在可以在人类身上实现，我们的具体目标是：（1）研究其益处。 (2) 随机研究先发性仿生睡眠以降低发生谵妄的风险； 使用正电子发射断层扫描/磁力结合谵妄的细胞和分子机制 共振成像和血清代谢分析；(3) 研究围手术期谵妄的预测因素 在这些研究结束时，我们将扩展我们的知识。 谵妄的病理生理学，评估了一种新的谵妄先发性治疗策略，建议 基于神经生理学的监测策略可显着减少麻醉剂的用量 老年患者可能会出现谵妄，同时确定患者已经完全失去知觉 手术（个体化麻醉护理），并能够继续研究其病理生理学 临床上重要的疾病。

项目成果

Sex Differences in the Incidence of Postoperative Delirium after Cardiac Surgery: A Pooled Analyses of Clinical Trials.

心脏手术后谵妄发生率的性别差异：临床试验的汇总分析。

• DOI: 10.1097/aln.0000000000004656
• 发表时间: 2023
• 期刊: Anesthesiology
• 影响因子: 8.8
• 作者: Wiredu,Kwame;Mueller,Ariel;McKay,TinaB;Behera,Alkananda;Shaefi,Shahzad;Akeju,Oluwaseun
• 通讯作者: Akeju,Oluwaseun

Minimizing ICU Neurological Dysfunction with Dexmedetomidine-induced Sleep (MINDDS): protocol for a randomised, double-blind, parallel-arm, placebo-controlled trial.

• DOI: 10.1136/bmjopen-2017-020316
• 发表时间: 2018-04-20
• 期刊: BMJ open
• 影响因子: 2.9
• 作者: Shelton KT;Qu J;Bilotta F;Brown EN;Cudemus G;D'Alessandro DA;Deng H;DiBiasio A;Gitlin JA;Hahm EY;Hobbs LE;Houle TT;Ibala R;Loggia ML;Pavone KJ;Shaefi S;Tolis G;Westover MB;Akeju O
• 通讯作者: Akeju O

Association of Poor Sleep Burden in Middle Age and Older Adults With Risk for Delirium During Hospitalization.

• DOI: 10.1093/gerona/glab272
• 发表时间: 2022-03-03
• 期刊: The journals of gerontology. Series A, Biological sciences and medical sciences
• 作者: Ulsa MC;Xi Z;Li P;Gaba A;Wong PM;Saxena R;Scheer FAJL;Rutter M;Akeju O;Hu K;Gao L
• 通讯作者: Gao L

A Systematic Review and Meta-Analysis Examining the Impact of Sleep Disturbance on Postoperative Delirium.

• DOI: 10.1097/ccm.0000000000003400
• 发表时间: 2018-12
• 期刊: Critical care medicine
• 影响因子: 8.8
• 作者: Fadayomi AB;Ibala R;Bilotta F;Westover MB;Akeju O
• 通讯作者: Akeju O

A polysomnography study examining the association between sleep and postoperative delirium in older hospitalized cardiac surgical patients.

• DOI: 10.1111/jsr.13322
• 发表时间: 2021-10
• 期刊: Journal of sleep research
• 影响因子: 4.4
• 作者: Ibala R;Mekonnen J;Gitlin J;Hahm EY;Ethridge BR;Colon KM;Marota S;Ortega C;Pedemonte JC;Cobanaj M;Chamadia S;Qu J;Gao L;Barbieri R;Akeju O
• 通讯作者: Akeju O