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

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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).