Safety Study of Sildenafil in Treatment of Cerebral Aneurysm Vasospasm

When a cerebral aneurysm ruptures, the surface of the brain and its blood vessels are covered with clotted blood. This condition is called subarachnoid hemorrhage (SAH). Subarachnoid hemorrhage secondary to rupture of a cerebral aneurysm is a medical condition associated with a high morbidity and mortality; approximately 10-15% of patients die before reaching medical care, and overall mortality is approximately 45%. Of those that survive, 30% suffer permanent disability graded as moderate to severe, and two-thirds of survivors never return to the same quality of life as they had prior to their hemorrhage. A large number of patients (30-70%) who are able to make it to the hospital and have successful treatment of their aneurysm will develop delayed cerebral vasospasm that is related to the blood clot from their initial aneurysm rupture. Of patients that survive their initial aneurysm rupture, vasospasm results in an additional 7% mortality and another 7% of severe disabilities secondary to ischemic strokes from severe spasm of cerebral arteries.

The pathogenesis of cerebral vasospasm has been a topic of significant research. The occurrence and severity are directly related to the volume of hemorrhage and the thickness of the blood clot encasing the arteries. Arterial vasospasm and impaired vasodilation are delayed processes that have a gradual onset, typically starting no earlier than 3 days post-hemorrhage and clinically resolving within 12 days of the initial aneurysm rupture. Breakdown of the clotted subarachnoid blood impairs the normal vasodilator and constrictor mechanisms of the cerebral arteries by altering the levels of several molecules including nitric oxide (NO), a vasodilator. Nitric oxide is normally produced by vascular endothelial cells and leads to vasodilation by stimulating the enzyme soluble guanylate cyclase. This enzyme catalyzes the production of cyclic guanosine monophosphate (cGMP), which is responsible for vasodilation through both direct and indirect actions. Selective deactivation of cGMP is accomplished by the enzyme phosphodiesterase subtype V (PDE-V). Studies have revealed elevated levels of PDE-V and diminished levels of cGMP in animals with experimentally induced SAH, while levels of nitric oxide synthase remain stable after hemorrhage. This prior research points toward SAH causing an enhancement in PDE-V activity, subsequently decreasing cGMP levels and impairing normal vasodilation.

Papaverine, a nonselective phosphodiesterase inhibitor, is beneficial and selectively used for treatment of active vasospasm. Its use is limited by its short duration of action, and its nonspecific nature results in systemic vasodilation and subsequent hypotension. Sildenafil citrate, a selective PDE-V inhibitor, has been shown to enhance the reactivity of the cerebral vasculature in normal healthy adults and has been shown to decrease the severity of vasospasm in animals with experimentally induced SAH. These effects have been noted with minimal effects on systemic hemodynamics. Given that sildenafil citrate has safely demonstrated the expected clinical effect of cerebral arterial dilation in normal healthy humans as well as animals with and without induced SAH, the aim of this study is to determine if this medicine shows efficacy in humans with SAH secondary to ruptured aneurysm.