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: 10624776
• 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/10624776
• 关键词: Admission activity; Affect; Ambulatory Care Facilities; Animal Model; Animals; Arousal; Breathing; Carbon Dioxide; Cause of Death; Cessation of life; Chemoreceptors; Clinic; Data; Defect; Development; Electroencephalography; Epilepsy; Esthesia; Focal Seizure; Functional disorder; Goals; Heart Arrest; Human; Hypoventilation; Individual; Inpatients; Intractable Epilepsy; Knowledge; Laboratories; Measures; Mission; Monitor; Motor Seizures; Neurons; Outcome; Pathogenesis; Patient Admission; 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; biomarker identification; candidate marker; experience; high risk; high risk population; human data; individual variation; innovation; novel; novel marker; novel therapeutic intervention; 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 多达50％的难治性癫痫患者发生癫痫突然出现癫痫病（SUDEP），IS 该人群的主要死亡原因。因为负责SUDEP的机制尚未 明确定义的是，没有特定的治疗方法可以防止它。人类和动物的最新观察 研究表明，癫痫发作诱导的呼吸停滞通常是在障碍之前的，许多患者 癫痫发作后，经历不同程度的呼吸抑郁症。有根本的差距 了解癫痫发作是如何降低呼吸的，为什么某些患者会出现严重的邮政呼吸道 抑郁症和其他人没有。低中央二氧化碳化学敏感性会导致呼吸抑郁症，并且 这可能会倾向于Sudep，但在这个人群中尚未研究。长期目标是 通过阐明负责癫痫发作的机制来开发新的治疗以防止SUDEP 通过识别生物标志物来识别有最高风险的患者，呼吸道抑郁症。这里的目的是 通过测量来表征二氧化碳化学效率与邮政呼吸道抑郁症之间的关系 临时癫痫患者的高碳酸通气反应（HCVR）的斜率 邮政状态。中心假设是邮政不足的患者将更严重 间歇性或邮政二氧化碳化学敏感性。该假设是根据人和动物提出的 从申请人自己的实验室获得的数据，也表明5-羟色胺（5-HT）缺陷的数据可能 为Sudep做出贡献。因为已知5-HT神经元对于正常CO2化学敏感很重要 刺激呼吸和皮质唤醒，提出的研究的理由是 敏感性可能有助于SUDEP的病理生理学。中心假设将通过追求来检验 3个具体目标。 （1）确定基线（间隔）中央二氧化碳化学敏感性与 媒体呼吸抑郁症。 （2）确定癫痫发作如何影响中央二氧化碳化学敏感性。 （3）确定 HCVR随着时间的推移在癫痫患者中的稳定性以及HCVR与癫痫的关系 控制。在AIMS 1和2位接受癫痫监测单元的患者将在此期间进行HCVR测试 临时和邮政期。基线HCVR的斜率将与CO2的发射变化相关 水平和其他心肺变量（AIM 1），以及不同癫痫发作对HCVR斜率的影响 测量（目标2）。 HCVR的个体差异及其相对于癫痫控制的稳定性（AIM 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 第一个直接检查邮政通风与中央二氧化碳化学敏感性之间的关系 ICTAL和邮政国家。拟议的研究很重要，因为识别机制 参与邮政呼吸抑郁症可能会导致鉴定出新的生物标志物（HCVR） 风险和开发旨在捍卫通风的新疗法。

项目成果

Seizure Clusters, Seizure Severity Markers, and SUDEP Risk.

• DOI: 10.3389/fneur.2021.643916
• 发表时间: 2021
• 期刊: Frontiers in neurology
• 影响因子: 3.4
• 作者: Ochoa-Urrea M;Lacuey N;Vilella L;Zhu L;Jamal-Omidi S;Rani MRS;Hampson JP;Dayyani M;Hampson J;Hupp NJ;Tao S;Sainju RK;Friedman D;Nei M;Scott C;Allen L;Gehlbach BK;Reick-Mitrisin V;Schuele S;Ogren J;Harper RM;Diehl B;Bateman LM;Devinsky O;Richerson GB;Zhang GQ;Lhatoo SD
• 通讯作者: Lhatoo SD