Vasospasm: my first 25 years-what worked? what didn't? what next?

Angiographic vasospasm as a complication of aneurysmal and other types of subarachnoid hemorrhage (SAH) was identified about 62 years ago. It is now hypothesized that angiographic vasospasm contributes to delayed cerebral ischemia (DCI) by multiple pathways, including reduced blood flow from angiographic vasospasm as well as microcirculatory constriction, microthrombosis, cortical spreading ischemia, and delayed effects of early brain injury. It is likely that other factors, such as systemic complications, effects of the subarachnoid blood, brain collateral and anastomotic blood flow, and the genetic and epigenetic makeup of the patient, contribute to the individual's response to SAH. Treatment of aneurysmal SAH and DCI includes neurocritical care management, early aneurysm repair, prophylactic administration of nimodipine, and rescue therapies (induced hypertension and balloon or pharmacologic angioplasty) if the patient develops DCI. Well-designed clinical trials of tirilazad, clasozentan, antiplatelet drugs, and magnesium have been conducted using more than a 1,000 patients each. Some of these drugs have almost purely vascular effects; other drugs are theoretically neuroprotective as well, but they share in common the ability to reduce angiographic vasospasm and, in many cases, DCI, but have no effect on clinical outcome. Experimental research in SAH continues to identify new targets for therapy. Challenges for the future will be to identify the most promising drugs to advance from preclinical studies and to understand why clinical trials have so frequently failed to show drug benefit on clinical outcome. Similar issues with treatment of ischemic stroke are being addressed by suggestions for improving the quality of experimental studies, collaborative preclinical trials, and multinational, multicenter clinical studies that can rapidly include many patients and be large enough to account for numerous factors that conspire to disrupt clinical trials.