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).

项目概要/摘要 蛛网膜下腔出血是一种破坏性的中风，其中血管破裂 导致大脑周围蛛网膜下腔的血液。脑血管痉挛，即 约 30% 的患者术后会出现脑血管异常收缩 蛛网膜下腔出血，可导致继发性迟发性脑缺血 SAH。迟发性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，治疗血管痉挛和预防的治疗策略 缺乏迟发性缺血。 2010年埃默里大学医院实施鞘内注射 尼卡地平是一种钙通道阻滞剂，可扩张脑血管， 治疗疑似血管痉挛的蛛网膜下腔出血患者。我们的 来自超过 400 名患者的初步回顾性结果表明，鞘内注射尼卡地平 并发症发生率低，可有效诱导大血管舒张，并且 降低迟发性脑缺血的风险。然而，为此选择患者 治疗以及对个体受试者的益处的估计仍然缺乏。我们的 总体目标是开发 SAH 后结果的生物标志物，有助于优化 治疗策略并改善结果。非侵入式漫射光学光谱 （DOS）承诺提供此类生物标志物。 20 SAH 中 DOS 的初步数据 我们发现患者对第一剂 IT 尼卡地平的脑血流反应 发生 DCI 的患者与未发生 DCI 的患者存在显着差异。 具体而言，未发展为 DCI 的患者脑血流量增加 （如预期），而那些发生 DCI 的人则表现出缺乏反应或减少 治疗后的血流量（矛盾反应）。这些有希望的数据表明 DOS 可以为 SAH 患者的微血管环境提供有价值的见解 可用于指导治疗和改善结果。此外，初步 数据表明 IT 尼卡地平的药代动力学可能提供替代方案 脑脊液中尼卡地平目标治疗浓度的生物标志物。 基于这些有希望的数据，在本提案中，我们将确定早期的、非侵入性的 与发展相关的脑血管血流动力学光学生物标志物 延缓脑缺血（目标1），我们将前瞻性地确定两者之间的关系 IT 尼卡地平在脑脊液中的药代动力学与结果之间的关系（目标 2）。