Dose-related efficacy of a continuous intracisternal nimodipine treatment on cerebral vasospasm in the rat double subarachnoid hemorrhage model.

OBJECTIVE: Intracisternal continuous therapy is a concept in the treatment of cerebral vasospasm after subarachnoid hemorrhage. The purpose of the current study was to investigate the effect of intracisternal nimodipine after induced vasospasm. METHODS: Sixty-five male Wistar rats were randomized into 4 groups: the control sham-operated group, the control subarachnoid hemorrhage-only group, and the treatment groups receiving 5 or 10 microL/hour of intracisternal nimodipine continuously for 5 days via subcutaneously implanted Alzet osmotic pumps (Durect Corp., Cupertino, CA). Vasospasm was analyzed 5 days later by means of digital subtraction angiography. Morphological examination of the brain parenchyma was performed using Nissl-staining, c-Fos immunohistochemistry, and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling. RESULTS: Detailed analysis of the digital subtraction angiography was possible for 31 animals. Significant angiographic vasospasm was induced in the double hemorrhage-only group compared with the sham-operated group (P = 0.002). Among the 4 groups, there were statistically significant differences of the arterial vessel caliber as measured by digital subtraction angiography (P = 0.001, Kruskal-Wallis test). The treatment group receiving 5 microL/hour of nimodipine and the control sham-operated group demonstrated the largest intracranial artery diameters with a significant difference between control subarachnoid hemorrhage-only group and the treatment group receiving 10 microL/hour of nimodipine (P = 0.0328, Wilcoxon rank-sum test). Variation in vessel calibers, however, did not result in different brain tissue alterations, even when using sensitive markers for the induction of the stress response or apoptosis. CONCLUSION: Intracisternal nimodipine lavage with 5 microL/hour, but not with 10 microL/hour leads to significant arterial relaxation. Further research is needed to elucidate the underlying cause of the decreasing nimodipine effect at higher dosage.

Feasibility and safety of intrathecal nimodipine on posthaemorrhagic cerebral vasospasm refractory to medical and endovascular therapy.

OBJECTIVE: The effectiveness of balloon angioplasty and intra-arterial infusion of vasodilating agents for patients suffering from severe vasospasm following aneurysmal subarachnoid haemorrhage (SAH) is often unsatisfying and there is still demand for further last resort treatment strategies. In the current prospective study, we attempted the intrathecal lavage administration of nimodipine in cases of severe cerebral vasospasm that were refractory to medical and endovascular therapy. METHODS: Eight of 146 patients with aneurysmal SAH were included in the prospective study, which had been approved by the local ethics committee. Treatment was instituted by intraventricular nimodipine bolus (0.4 mg), followed by a continuous lumbar intrathecal infusion (0.4 mg/h). Effectiveness was monitored angiographically, with transcranial Doppler (TCD), perfusion CT (pCT), and by neurological examination during treatment course and follow-up. RESULTS: The neurological condition improved directly in three patients and remained unchanged in four patients. Seventeen (70.8%) CT perfusion analyses revealed improved perfusion. A reduction of vasospasm was seen angiographically by digital subtraction angiography (DSA) in seven (66.6%) investigations. Additional ischaemic infarction after onset of the intrathecal therapy was documented in two (25%) patients. There were no serious adverse effects observed. CONCLUSION: The present study has for the first time demonstrated the feasibility and safety of intrathecal nimodipine lavage in patients with severe vasospasm resistant to the established medical and endovascular treatment strategies. The results of the study are therefore encouraging, and further experimental and clinical trials should be carried out so as to investigate the efficacy of intrathecal nimodipine lavage in vasospasm therapy.