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

项目摘要/摘要 蛛网膜下腔出血是一种破坏性的中风类型，其中血管破裂 导致脑部蛛网膜下腔出血。脑血管痉挛，即， 约30%的患者术后出现异常的脑血管收缩 蛛网膜下腔出血，并可导致迟发性脑缺血 萨哈。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 延迟性缺血缺乏。2010年埃默里大学医院实施鞘内注射 尼卡地平，一种钙通道阻滞剂，作用于扩张脑血管，作为一种 蛛网膜下腔出血疑似血管痉挛患者的治疗。我们的 400例患者的初步回顾结果显示鞘内注射尼卡地平 并发症发生率低，在诱导大血管扩张方面有效， 降低迟发性脑缺血的风险。然而，为这一点选择患者 治疗以及估计个体受试者的益处仍然是缺乏的。我们的 总体目标是开发SAH后预后的生物标记物，有助于优化 治疗策略和改善结果。非侵入式漫反射光学光谱仪 (DOS)展示了提供此类生物标记物的前景。在20SAH中使用DOS的初步数据中 患者，我们发现第一剂尼卡地平对脑血流的反应 在发生DCI的患者和没有发生DCI的患者中有显著差异。 具体地说，未发展为DCI的患者的脑血流量增加。 (如预期)，而那些发展为DCI的人表现出缺乏反应或减少 治疗后血流速度下降(矛盾反应)。这些有希望的数据表明 DOS可能为SAH患者的微血管环境提供有价值的见解 这可以用来指导治疗和改善结果。此外，初步的 数据表明，IT尼卡地平的药代动力学可能提供了一种替代方案 脑脊液中靶向治疗性尼卡地平浓度的生物标志物。 在这个有希望的数据的基础上，在这个提案中，我们将确定早期、非侵入性 与脑血管血流动力学相关的光学生物标记物的研究 延迟脑缺血(目标1)，我们将前瞻性地确定两者之间的关系 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)。

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).