The role of central CO2 chemosensitivity in postictal respiratory depression and SUDEP

中枢 CO2 化疗敏感性在发作后呼吸抑制和 SUDEP 中的作用

• 批准号: 10400927
• 负责人: Brian Gehlbach
• 金额: $ 59.41万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-15 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10400927
• 关键词: Admission activity; Affect; Ambulatory Care Facilities; Animal Model; Animals; Arousal; Biological Markers; Breathing; Carbon Dioxide; Cause of Death; Cessation of life; Chemoreceptors; Clinic; Data; Defect; Development; Electroencephalography; Epilepsy; Focal Seizure; Functional disorder; Goals; Heart Arrest; Human; Hypoventilation; Individual; Inpatients; Intractable Epilepsy; Knowledge; Laboratories; Lead; Measures; Mission; Monitor; Motor Seizures; Neurons; Outcome; Pathogenesis; Patients; Play; Population; Preventive treatment; Public Health; Research; Respiration; Risk; Role; Seizures; Serotonin; Temporal Lobe; Testing; Time; United States National Institutes of Health; Ventilatory Depression; Work; animal data; base; candidate marker; experience; high risk; human data; innovation; novel; novel marker; patient biomarkers; prevent; respiratory; response; sudden unexpected death in epilepsy; therapy design; therapy development; ventilation

Abstract Sudden Unexpected Death in Epilepsy (SUDEP) occurs in up to 50% of patients with refractory epilepsy and is the leading cause of death in this population. Because the mechanisms responsible for SUDEP have not been clearly defined, there are no specific treatments to prevent it. Recent observations from human and animal studies indicate that seizure-induced respiratory arrest typically precedes asystole, and that many patients experience varying degrees of respiratory depression following seizures. There is a fundamental gap in understanding how seizures depress respiration, and why some patients develop severe postictal respiratory depression and others do not. Low central CO2 chemosensitivity can contribute to respiratory depression, and it is possible that this predisposes to SUDEP, but has not been studied in this population. The long-term goal is to develop new treatments to prevent SUDEP by elucidating the mechanisms responsible for seizure-induced respiratory depression and by identifying biomarkers to identify patients at highest risk. The objective here is to characterize the relationship between CO2 chemosensitivity and postictal respiratory depression by measuring the slope of the hypercapnic ventilatory response (HCVR) in patients with epilepsy during the interictal and postictal states. The central hypothesis is that postictal hypoventilation will be more severe in patients with low interictal or postictal CO2 chemosensitivity. This hypothesis has been formulated based on human and animal data obtained from the applicants’ own laboratories, data that also suggest serotonin (5-HT) defects may contribute to SUDEP. Because 5-HT neurons are known to be important for normal CO2 chemosensitivity that stimulates breathing and cortical arousal, the rationale for the proposed research is that defective chemo- sensitivity might contribute to the pathophysiology of SUDEP. The central hypothesis will be tested by pursuing 3 specific aims. (1) Determine the relationship between baseline (interictal) central CO2 chemosensitivity and postictal respiratory depression. (2) Determine how seizures affect central CO2 chemosensitivity. (3) Determine the stability of the HCVR over time in patients with epilepsy, and the relationship of the HCVR to epilepsy control. In Aims 1 and 2 patients admitted to the Epilepsy Monitoring Unit will undergo HCVR testing during the interictal and postictal periods. The slope of the baseline HCVR will be correlated with ictal changes in CO2 levels and other cardiorespiratory variables (Aim 1), and the effect of different seizures on HCVR slope will be measured (Aim 2). The intraindividual variability of the HCVR and its stability in relation to epilepsy control (Aim 3) will be determined by measuring the HCVR 4 times over 2 years. This approach is innovative because it is the first to directly examine the relationship between postictal ventilation and central CO2 chemosensitivity in the ictal and postictal states. The proposed research is significant because identifying the mechanisms involved in postictal respiratory depression may lead to identification of a novel biomarker (HCVR) for SUDEP risk and to development of new treatments designed to defend ventilation in the postictal period.

抽象的 高达 50% 的难治性癫痫患者会发生癫痫性猝死 (SUDEP)，并且 因为导致 SUDEP 的机制尚未明确。 明确定义，但最近根据人类和动物的观察，没有具体的治疗方法可以预防它。 研究表明，癫痫发作引起的呼吸停止通常发生在心搏停止之前，并且许多患者 癫痫发作后经历不同程度的呼吸抑制存在根本性差距。 了解癫痫发作如何抑制呼吸，以及为什么一些患者会出现严重的发作后呼吸道症状 抑郁症和其他人则不会。中枢二氧化碳化学敏感性低会导致呼吸抑制，并且 这可能会导致 SUDEP，但尚未在该人群中进行研究。长期目标是。 通过阐明引起癫痫发作的机制来开发预防 SUDEP 的新疗法 呼吸抑制和生物标志物识别风险最高的患者。 通过测量来表征 CO2 化学敏感性与发作后呼吸抑制之间的关系 癫痫患者在发作间期和发作期期间高碳酸血症通气反应 (HCVR) 的斜率 中心假设是低通气患者的发作后通气不足会更严重。 发作间期或发作后 CO2 化学敏感性 该假设是根据人类和动物提出的。 从申请人自己的实验室获得的数据，也表明血清素（5-HT）缺陷的数据可能 因为已知 5-HT 神经元对于正常的 CO2 化学敏感性很重要， 刺激呼吸和皮质唤醒，拟议研究的基本原理是有缺陷的化学- 敏感性可能有助于 SUDEP 的病理生理学，将通过追求来检验中心假设。 3 个具体目标 (1) 确定基线（发作间期）中心 CO2 化学敏感性与 (2) 确定癫痫发作如何影响中枢 CO2 化学敏感性。 癫痫患者 HCVR 随时间的稳定性以及 HCVR 与癫痫的关系 在目标 1 和 2 中，入住癫痫监测室的患者将在治疗期间接受 HCVR 检测。 发作间期和发作后时期的基线 HCVR 斜率将与 CO2 的发作变化相关。 水平和其他心肺变量（目标 1），不同癫痫发作对 HCVR 斜率的影响将为 测量（目标 2）HCVR 的个体差异及其与癫痫控制相关的稳定性（目标 2）。 3) 将通过在 2 年内测量 HCVR 4 次来确定。这种方法是创新的，因为它是创新的。 第一个直接研究发作后通气与中枢 CO2 化疗敏感性之间的关系 所提出的研究具有重要意义，因为确定了其机制。 参与发作后呼吸抑制可能导致识别 SUDEP 的新型生物标志物 (HCVR) 风险以及开发旨在保护发作后期通气的新疗法。