Electroencephalographic signatures of dysfunctional cerebrovascular autoregulation as biomarkers of brain injury in aneurysmal subarachnoid hemorrhage (SAH)

脑血管自动调节功能障碍的脑电图特征作为动脉瘤性蛛网膜下腔出血（SAH）脑损伤的生物标志物

• 批准号: 10667162
• 负责人: Jennifer A Kim
• 金额: $ 25.13万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-15 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10667162
• 关键词: Acute; Adult; Affect; Aneurysmal Subarachnoid Hemorrhages; Benchmarking; Biological Markers; Blood Pressure; Blood Vessels; Brain; Brain Injuries; Brain hemorrhage; Caring; Cerebral Ischemia; Cerebral hemisphere hemorrhage; Cerebral perfusion pressure; Cerebrovascular Circulation; Cerebrovascular Disorders; Cerebrovascular Spasm; Cerebrum; Clinical; Clinical Trials; Cohort Studies; Compensation; Complication; Coupled; Critical Illness; Data; Detection; Deterioration; Development; Disabled Persons; Disease; Distress; Early Diagnosis; Early Intervention; Electroencephalography; Exogenous Factors; Failure; Fright; Functional disorder; Future; Goals; Hemorrhage; Homeostasis; Individual; Informatics; Infrastructure; Intervention; Intracranial Pressure; Ischemia; Ischemic Stroke; Knowledge; Link; Metabolic; Metabolism; Mission; Modeling; Monitor; Morbidity - disease rate; Nature; Near-Infrared Spectroscopy; Nervous System Trauma; Neurologic; Neurologic Deficit; Neurology; Neurons; Operative Surgical Procedures; Outcome; Patients; Pattern; Perfusion; Phase; Phenotype; Physiological; Physiology; Play; Principal Investigator; Protocols documentation; Quality of life; Recovery; Research; Research Proposals; Resources; Rest; Risk; Risk Assessment; Ruptured Aneurysm; Sedation procedure; Signal Transduction; Stroke; Subarachnoid Hemorrhage; Subarachnoid Space; Survivors; Technology; Testing; Therapeutic; Time; Transcranial Doppler Ultrasonography; United States; United States National Institutes of Health; Vasospasm; biomarker driven; blood pressure control; cerebral hemodynamics; cerebral hypoperfusion; cerebrovascular; clinical center; clinical investigation; clinical practice; cohort; data repository; diagnostic strategy; disability; epileptiform; exhaust; functional improvement; functional outcomes; high risk; hypoperfusion; improved; individual patient; innovation; insight; nervous system disorder; neurophysiology; neuroprotection; neurovascular; novel; personalized approach; personalized medicine; pharmacologic; population based; precision medicine; pressure; prevent; prospective; risk mitigation; signal processing; tissue oxygenation; tool; treatment strategy

Abstract Aneurysmal subarachnoid hemorrhage (aSAH) remains a devastating disease affecting approximately 30,000 adults in the United States per year. Forty percent of aSAH patients die within 30 days, and over one-third of survivors sustain major neurologic deficits, in part due to feared secondary complications like vasospasm and delayed cerebral ischemia (DCI). Despite advances in care, few interventions can mitigate the risk of neurologic worsening after the initial bleed, and current monitoring strategies to identify impending DCI have limited accuracy. Abnormalities in cerebrovascular autoregulation and flow-metabolism uncoupling in the acute phase after aSAH have been shown to increase the risk of secondary brain injury and likely represent key players in the development of DCI. In this proposal, we plan to develop and refine an innovative, personalized approach to blood pressure management to identify patients most likely to benefit from therapeutic BP manipulation. To carry out this overarching aim, we will track continuous recordings of intracranial pressure, near-infrared spectroscopy, and EEG to determine patient-specific blood pressure targets that yield optimal brain blood flow and metabolism. This research proposal will evaluate if cerebral hemodynamic dysregulation drives EEG deterioration (Aim 1) and if a deviation from optimized blood pressure targets is associated with DCI and poor outcomes (Aim 2). We will then prospectively validate our results in a pilot cohort study. This proposal’s feasibility rests on (1) several years of research conducted by the principal investigators on signal processing, autoregulatory physiology, and continuous EEG in disease states like SAH and ischemic stroke, and (2) promising preliminary analyses evaluating the hypotheses being explored in this proposal. In total, this autoregulation-oriented neuroprotective therapy aims to optimize cerebral perfusion and ultimately improve clinical and functional outcomes. This research proposal is thus directly aligned with the NIH mission to reduce the burden of neurological disorders and enhance the quality of life of people with disabilities. The study will leverage Yale’s cutting-edge neuro- monitoring technologies along with extensive informatics and research resources of the Yale Center for Clinical Investigation to generate new insights into cerebral hemodynamics after aSAH and identify treatment opportunities. This line of research is readily translatable to the bedside and also applies to other cerebrovascular diseases like intracerebral hemorrhage and ischemic stroke, both of which likely encompass dysautoregulation as a critical physiologic variable. Knowledge gained in this study is anticipated to lead to a significant shift in the treatment approach for aSAH patients. It may ultimately lead to a clinical trial testing autoregulation-based treatment strategies, including tailored pharmacologic BP modulation based on patients’ real-time autoregulatory status. Our long-term goal is to use neuro-monitoring to develop physiology-based, personalized, early interventions to reduce the disability and morbidity associated with neurologic injury.

摘要 动脉瘤性蛛网膜下腔出血（aSAH）仍然是一种破坏性疾病，影响约30，000人， 美国成年人每年。40%的aSAH患者在30天内死亡， 幸存者仍有严重的神经功能缺陷，部分原因是担心血管痉挛等继发性并发症， 迟发性脑缺血（DCI）。尽管在护理方面取得了进展，但很少有干预措施可以减轻神经系统疾病的风险。 首次出血后恶化，目前的监测策略，以确定即将发生的DCI有限 精度急性期脑血管自动调节功能异常和血流代谢解偶联 aSAH后已被证明会增加继发性脑损伤的风险，并可能代表 DCI的发展。在本提案中，我们计划开发和完善一种创新的个性化方法， 血压管理，以确定最有可能从治疗性血压控制中获益的患者。携带 出于这个首要目标，我们将跟踪颅内压，近红外光谱， 和EEG来确定产生最佳脑血流和代谢的患者特定血压目标。 本研究提案将评估脑血流动力学失调是否会导致EEG恶化（目标1） 以及与优化血压目标的偏差是否与DCI和不良结局相关（目标2）。我们 然后将在一项试点队列研究中前瞻性地验证我们的结果。该提案的可行性取决于（1）几个 主要研究人员在信号处理、自动调节生理学和 SAH和缺血性卒中等疾病状态下的连续EEG，以及（2）有希望的初步分析 评估本提案中探索的假设。总的来说，这种自我调节导向的神经保护作用 治疗旨在优化脑灌注并最终改善临床和功能结果。这 因此，这项研究提案与NIH的使命直接一致，即减轻神经系统疾病的负担 提高残疾人的生活质量。这项研究将利用耶鲁大学的尖端神经- 监测技术沿着耶鲁临床研究中心的广泛信息和研究资源， 研究旨在对aSAH后的脑血流动力学产生新的见解并确定治疗方法 机会这条研究路线很容易转化为床边，也适用于其他脑血管疾病。 脑出血和缺血性中风等疾病，这两种疾病都可能包括自动调节障碍 作为一个重要的生理变量本研究中获得的知识预计将导致 aSAH患者的治疗方法。它可能最终导致一项基于自我调节的临床试验。 治疗策略，包括根据患者的实时自动调节功能定制的药物BP调节 status.我们的长期目标是使用神经监测来开发基于生理学的，个性化的，早期的 干预措施，以减少与神经损伤相关的残疾和发病率。