Effects of a hydroxyl radical scavenger on delayed ischemic neurological deficits following aneurysmal subarachnoid hemorrhage: results of a multicenter, placebo-controlled double-blind trial

Abstract

✓ A water-soluble, novel synthetic compound, AVS ((±)-N,N′-propylenedinicotinamide; nicaraven) has no demonstrable vasoactive properties but scavenges hydroxyl radicals in aqueous environmental conditions at neutral pH. Based on the results of preceding experimental and clinical studies showing marked ameliorative effects of AVS on cerebral vasospasm and ischemic brain damage, a multicenter, placebo-controlled double-blind clinical trial was undertaken to verify its beneficial effects on delayed ischemic neurological deficits (DINDs) due to vasospasm and on the overall outcome of patients with subarachnoid hemorrhage (SAH). A total of 162 patients with SAH who had Glasgow Coma Scale scores between 7 and 15 on admission were enrolled in the trial. Drug administration (4 g AVS or 4 g glucose as placebo; infused intravenously for 6–8 hours once a day) was begun within 5 days post-SAH and continued for 10 to 14 days. Intent-to-treat analysis of these patients revealed that the overall incidence of DINDs, which was defined as an exacerbation of impaired consciousness and/or focal neurological deficits, was significantly reduced, by 34.5% (placebo 54.2%, AVS 35.5%; p < 0.05, Mann—Whitney U-test). The Glasgow Outcome Scale (GOS) score at 1 month was significantly improved by AVS (p < 0.05, U-test). At 3 months, the difference in the GOS scores between the groups became marginal on U-tests (p < 0.10), but the percentage of good outcome tended to increase, with a relative increase of 20.3% (AVS 76.3%, placebo 63.4%; p < 0.10, chi-square test), and the cumulative incidence of death was significantly reduced (p < 0.05, log-rank test). No significant adverse reaction attributable to treatment was observed. The usefulness of AVS in therapy for SAH is strongly indicated by the fact that the agent significantly ameliorated DINDs, leading to a marked improvement in the GOS scores at 1 month, as well as a reduction in the cumulative incidence of death by 3 months.