Inhibition of cerebral vasospasm by intracranial delivery of ibuprofen from a controlled-release polymer in a rabbit model of subarachnoid hemorrhage

Abstract

Object. Leukocyte—endothelial cell interactions may play a role in the development of cerebral vasospasm after aneurysmal subarachnoid hemorrhage (SAH) because the extravasation of circulating leukocytes into the periadventitial space within 24 hours after the hemorrhage appears to be a critical event in this process. Ibuprofen is an antiinflammatory agent that inhibits the expression of specific cell adhesion molecules and, consequently, disrupts leukocyte—endothelial cell interactions. The authors investigated the efficacy of ibuprofen delivered locally from controlled-release polymers in the rabbit basilar artery (BA) model of cerebral vasospasm. Methods. Ibuprofen was incorporated into controlled-release ethylene—vinyl acetate copolymer (EVAc) constituting 45% of the resulting polymer by weight. Fifty-four New Zealand White rabbits were randomized to 10 groups: sham operation (seven animals); SAH only (seven animals); and SAH plus either empty EVAc or ibuprofen—EVAc polymer at 30 minutes or 6, 12, or 24 hours (five animals per group; 40 total). The rabbits were killed 72 hours after induction of SAH, at the time of maximal vasospasm. The efficacy of ibuprofen in preventing vasospasm was assessed by measuring lumen patency of the rabbit's BAs. The intracranial controlled release of ibuprofen resulted in a significant inhibition of vasospasm when treatment was initiated at 30 minutes (patency 92.3 ± 5.1% compared with 52.1 ± 5.1% in animals given empty EVAc; p < 0.001) and 6 hours (patency 69.5 ± 3.5% compared with 47.2 ± 1.5% in animals given empty EVAc; p < 0.03) after blood deposition compared with treatment with empty EVAc. No effect was observed when treatment was begun at either 12 or 24 hours. Conclusions. Local intracranial delivery of ibuprofen accomplished using controlled-release polymers prevents vasospasm in the rabbit BA model of vasospasm when administered within 6 hours after blood exposure.