Development of biomarkers to optimize intrathecal nicardipine treatment for cerebral vasospasm and delayed cerebral ischemia after subarachnoid hemorrhage

开发生物标志物以优化鞘内尼卡地平治疗蛛网膜下腔出血后脑血管痉挛和迟发性脑缺血的疗效

• 批准号: 10567953
• 负责人: Ofer Sadan
• 金额: $ 49.74万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-27 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10567953
• 关键词: Adopted; Affinity; Aftercare; Bilateral; Biological Markers; Blood; Blood Vessels; Blood flow; Brain; Brain Injuries; Calcium Channel Blockers; Cerebral Ischemia; Cerebrospinal Fluid; Cerebrovascular Circulation; Cerebrovascular Spasm; Cerebrovascular system; Cerebrum; Data; Detection; Development; Diffuse; Dose; Drug Kinetics; Environment; Frequencies; Future; Half-Life; Hemoglobin; Individual; Injury; Ischemia; Lead; Measures; Monitor; Nature; Near-Infrared Spectroscopy; Nicardipine; Nimodipine; Observational Study; Optics; Oral Administration; Outcome; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Pharmacology Study; Prevention; Protocols documentation; Risk; Role; Rupture; Ruptured Aneurysm; Sampling; Smooth Muscle Myocytes; Spectrum Analysis; Stroke; Subarachnoid Hemorrhage; Subarachnoid Space; Testing; Therapeutic; Time; Treatment outcome; University Hospitals; Vasodilation; Vasospasm; Ventricular; Work; biomarker development; blood pressure reduction; cerebrovascular; cohort; constriction; deoxyhemoglobin; frontal lobe; functional outcomes; hemodynamics; high risk; hospital utilization; improved; improved outcome; individualized medicine; insight; intravenous administration; liquid chromatography mass spectrometry; prevent; prophylactic; prospective; response; standard of care; targeted biomarker; targeted treatment; treatment as usual; treatment effect; treatment optimization; treatment strategy

Project Summary/Abstract Subarachnoid hemorrhage is a devastating type of stroke wherein a ruptured blood vessel leads to blood in the subarachnoid space around the brain. Cerebral vasospasm, i.e., aberrant constriction of brain blood vessels, occurs in ~30% of patients after subarachnoid hemorrhage and can lead to delayed cerebral ischemia following the initial SAH. Delayed cerebral ischemia is a main contributor to patient survival and long-term functional outcome. Unfortunately, therapeutic strategies to treat vasospasm and prevent delayed ischemia are lacking. In 2010 Emory University Hospital implemented intrathecal nicardipine, a calcium channel blocker that acts to dilate the cerebrovasculature, as a treatment for subarachnoid hemorrhage patients with suspected vasospasm. Our preliminary retrospective results from >400 patients showed that intrathecal nicardipine has a low rate of complications, is effective at inducing macrovascular vasodilation, and reduces the risk of delayed cerebral ischemia. However, selecting patients for this treatment, as well as estimating the benefit for the individual subject is still lacking. Our overall objective is to develop biomarkers of outcome after SAH that can help optimize treatment strategies and improve outcomes. Non-invasive diffuse optical spectroscopies (DOS) show promise to provide such biomarkers. In preliminary data with DOS in 20 SAH patients, we found that the cerebral blood flow response to the first dose of IT nicardipine was significantly different in patients who developed DCI versus those who did not. Specifically, cerebral blood flow increased in patients who did not go on to develop DCI (as expected), whereas those who developed DCI showed a lack of response or decrease in blood flow after treatment (paradoxical response). These promising data suggest that DOS may provide valuable insights into the microvascular environment in SAH patients that could be used to guide treatment and improve outcomes. Furthermore, preliminary data suggest that the pharmacokinetics of IT nicardipine may provide an alternative biomarker of target therapeutic nicardipine concentrations in the cerebrospinal fluid. Building on this promising data, in this proposal we will determine early, non-invasive optical biomarkers of cerebrovascular hemodynamics associated with development of delay cerebral ischemia (Aim 1), and we will prospectively determine the relationship between IT nicardipine pharmacokinetics in the cerebrospinal fluid and outcome (Aim 2).

项目摘要/摘要 蛛网膜下腔出血是一种毁灭性的中风类型 在大脑周围的亚蛛网膜下腔中导致血液。脑血管痉挛，即 脑血管的异常收缩，发生在约30％的患者中 蛛网膜下腔出血，并可能导致最初的脑缺血延迟 SAH。延迟的脑缺血是患者生存和长期生存的主要因素 功能结果。不幸的是，治疗血管痉挛的治疗策略 缺乏延迟的缺血。 2010年，埃默里大学医院实施了鞘内 Nicardipine是一种钙通道阻滞剂，可用于扩张脑桥梁，作为一个 可疑血管痉挛的亚蛛网膜下腔出血患者的治疗。我们的 > 400名患者的初步回顾性结果表明胸膜炎 并发症率较低，有效诱导大血管血管舒张，并且 降低了大脑缺血延迟的风险。但是，为此选择患者 仍缺乏治疗以及估计个人受试者的收益。我们的 总体目标是在SAH之后发展结果的生物标志物，可以帮助优化 治疗策略并改善结果。非侵入性弥散光谱 （DOS）显示出提供此类生物标志物的希望。在20 SAH中的DOS的初步数据中 患者，我们发现大脑血流对尼卡迪平的第一剂量的反应 与未开发DCI相比的患者的患者有显着差异。 具体而言，未继续发展DCI的患者的脑血流增加 （如预期），而开发DCI的人表现出缺乏反应或减少 治疗后的血液流动（反应反应）。这些有希望的数据表明 DO可以为SAH患者的微血管环境提供宝贵的见解 可以用来指导治疗和改善预后。此外，初步 数据表明，尼卡迪平的药代动力学可能会提供替代方案 脑脊液中靶标的尼卡迪平浓度的生物标志物。 在这些有希望的数据的基础上，在此提案中，我们将确定早期无创的 与发展有关的脑血管血流动力学的光学生物标志物 延迟脑缺血（AIM 1），我们将前瞻性地确定这种关系 在脑脊液和结局中的尼古丁药代动力学之间（AIM 2）。