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.

del妄是住院老年患者可预防发病率和死亡率的六个主要原因之一。 患有高龄和阿尔茨海默氏病的人有最大的风险患del妄的风险。一个 在ir妄中幸存的患者中，很大一部分可能会遭受长期认知障碍 类似于温和的阿尔茨海默氏病，需要机构护理。这表明del妄和阿尔茨海默氏症 疾病具有在正常衰老的背景下出现的病理生理特征。与之相关的条件 del妄的特征是激活炎症级联反应而急性释放 介体进入血液。推定的机制是已关联的高白介素-6 在实验动物和人类中都有del妄。正常衰老与形态学转变有关 神经胶质到活化状态。遵循诸如危重疾病之类的系统性挑战，这些激活的神经胶质导致 与del妄有关的夸张的神经炎症状态。神经炎症进一步加剧了 睡眠障碍。那样，睡眠剥夺可能是del妄发展的可修改风险因素。 但是，没有当前药物（苯二氮卓类药物，抗精神病药）的药物治疗可诱导 自然的睡眠或可靠的人会减少ir妄的事件。我们发现这里定义的仿生睡眠 随着药物诱导快速眼动睡眠（REM）和非REM I-III睡眠状态的诱导 现在可以在人类中实现右美度胺。我们的具体目标寻求：（1）调查 先发制人的仿生睡眠，以降低随机发展del妄的风险； （2）调查 使用联合正电子发射断层扫描/磁性的del妄的细胞和分子机制 共振成像和血清代谢分析； （3）研究周期性的del妄的预测因子 脑电图记录。这些研究结束时，我们将扩大对 del妄的病理生理学评估了一种新的ir妄的先发制人治疗策略，建议 基于神经生理学的监测策略，可显着减少施用的麻醉量 对于古老的患者 - 可能是del妄），同时确定患者足够无意识地 手术（个性化麻醉护理），并能够继续投资于此 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