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: 10710394
• 负责人: Ofer Sadan
• 金额: $ 38.68万
• 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/10710394
• 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; Hemorrhage; Individual; Injury; Ischemia; Measures; Monitor; Nature; Near-Infrared Spectroscopy; Nicardipine; Nimodipine; Observational Study; Optics; Oral Administration; Outcome; Patient Selection; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Pharmacology Study; Prevention; Protocols documentation; Recommendation; Risk Reduction; Role; Rupture; Ruptured Aneurysm; Sampling; Smooth Muscle Myocytes; Spectrum Analysis; Stroke; Subarachnoid Hemorrhage; Subarachnoid Space; Testing; Therapeutic; Time; Titrations; Treatment outcome; University Hospitals; Vasodilation; Vasospasm; Ventricular; Work; biomarker development; blood pressure reduction; cerebrovascular; cohort; constriction; deoxyhemoglobin; frontal lobe; functional improvement; 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).

项目总结/摘要 蛛网膜下腔出血是一种破坏性的中风， 导致大脑周围的蛛网膜下腔出血脑血管痉挛，即， 脑血管异常收缩，发生在约30%的患者， 蛛网膜下腔出血，并可导致迟发性脑缺血后， SAH。迟发性脑缺血是患者存活和长期存活的主要因素。 功能性成果。不幸的是，治疗血管痉挛和预防 缺乏延迟性缺血。2010年，埃默里大学医院实施了鞘内 尼卡地平是一种钙通道阻滞剂，作用是扩张血管系统， 蛛网膜下腔出血疑似血管痉挛患者的治疗。我们 来自>400例患者的初步回顾性结果显示，鞘内尼卡地平 并发症发生率低，可有效诱导大血管舒张， 降低了迟发性脑缺血的风险。然而，选择患者 治疗，以及估计个体受试者的益处仍然缺乏。我们 总体目标是开发SAH后结局的生物标志物， 治疗策略和改善结果。非侵入性漫射光谱 (DOS)显示出提供这种生物标志物的前景。在20例SAH中使用DOS的初步数据中 我们发现，首次注射尼卡地平后， 在发生DCI的患者与未发生DCI的患者之间存在显著差异。 具体来说，脑血流量增加的患者谁没有继续发展DCI (as预期），而那些发展DCI的人表现出缺乏反应或减少 治疗后的血液流动（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 可以用来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一种替代方法， 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，非侵入性 脑血管血流动力学的光学生物标志物与脑血管病的发展相关 延迟性脑缺血（目标1），我们将前瞻性地确定 IT尼卡地平在脑脊液中的药代动力学和结果之间的关系（目的2）。

项目成果

Normative cerebral microvascular blood flow waveform morphology assessed with diffuse correlation spectroscopy.

用弥散相关光谱法评估正常脑微血管血流波形形态。

• DOI: 10.1364/boe.489760
• 发表时间: 2023
• 期刊: Biomedical optics express
• 影响因子: 3.4
• 作者: Urner,TaraM;Cowdrick,KyleR;Brothers,RowanO;Boodooram,Tisha;Zhao,Hongting;Goyal,Vidisha;Sathialingam,Eashani;Quadri,Ayesha;Turrentine,Katherine;Akbar,MariamM;Triplett,SydneyE;Bai,Shasha;Buckley,ErinM
• 通讯作者: Buckley,ErinM

Microvascular cerebral blood flow response to intrathecal nicardipine is associated with delayed cerebral ischemia.

• DOI: 10.3389/fneur.2023.1052232
• 发表时间: 2023
• 期刊: Frontiers in neurology
• 影响因子: 3.4