Neurotoxicity of Intra-arterial Papaverine Preserved with Chlorobutanol Used for the Treatment of Cerebral Vasospasm After Aneurysmal Subarachnoid Hemorrhage

Abstract

Background and Purpose-Papaverine is used to vasodilate cerebral arteries undergoing vasospasm from subarachnoid hemorrhage. However, papaverine inhibits cellular respiration in vitro and could cause neurotoxicity in humans. Methods-We studied 5 consecutive patients with cerebral vasospasm who were treated with intra-arterial papaverine preserved with chlorobutanol and imaged with MRI fluid-attenuated inversion recovery and diffusion-weighted imaging after treatment. One patient had histological analysis of the brain at autopsy. Results-All 5 patients exhibited marked neurological decline immediately after treatment, and this was sustained through hospital discharge. In all cases, MRI images showed selective gray matter-only signal changes within the vascular territory treated with papaverine. Histological analysis of 1 case brought to autopsy showed selective injury to islands of neurons with relative sparing of white matter. Conclusions-Intra-arterial delivery of papaverine preserved with chlorobutanol into vasospastic anterior cerebral arteries may result in marked neurological deterioration with selective gray matter changes on MRI imaging. This effect is consistent with a permanent toxic effect to human brain. It is unclear whether this toxicity is caused by papaverine or chlorobutanol, and its use in the treatment of cerebral vasospasm should be reserved for cases without alternatives.

Intra-Arterial Nimodipine Infusion for Cerebral Vasospasm in Patients with Aneurysmal Subarachnoid Hemorrhage

“…one study demonstrated high signal intensity on diffusion-weighted and fluid-attenuated inversion recovery MrI at the gray matter within the vascular territories treated with papaverine, and concordant neuronal injury upon pathological examination 38 . In animal studies, opening of the blood brain barrier and endothelial cell injury after papaverine infusion were reported 39,40 .…”

Guidelines for the Management of Aneurysmal Subarachnoid Hemorrhage

“…231 Papaverine is used less frequently because it can produce neurotoxicity. 232 The primary limitation of vasodilator therapy is the short duration of benefit. As with hemodynamic augmentation, there have been no randomized trials of these interventions, but large case series have demonstrated angiographic and clinical improvement.…”

Milrinone for the Treatment of Cerebral Vasospasm After Aneurysmal Subarachnoid Hemorrhage

“…Intraarterial papaverine was the first drug to be tested and has been widely used in patients with symptomatic CVS, but no outcome improvement could be demonstrated in comparison to standard medical treatment. 9 Moreover, papaverine is associated with serious neurotoxic side effects including: severe brain stem depression, increased intracranial pressure, mydriasis, neurological deficits, seizures, and coma, 10 possibly related to precipitation of papaverin hydrochloride crystals. 8 Various calcium channel blockers have also been administered as intraarterial infusion.…”