Sildenafil for DCI

Study Overview
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Brief Summary
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Each year, approximately 30,000 people in the United States suffer an intra-cranial hemorrhage due to aneurysmal rupture. Of those surviving the initial event, up to 40% will go on to have further neurological injury secondary to stroke (delayed cerebral ischemia) caused by constriction of blood vessels (i.e. vasospasm). Previous studies have shown that the medication sildenafil, given intravenously, improves vasospasm, but has an associated degree of hypotension. The degree of hypotension was well within safety thresholds for these patients. Sildenafil is a medication that strongly inhibits the protein phosphodiesterase-V (PDE-V). The hypothesis for this study is that oral sildenafil will also improve vasospasm, but does not result in as much hypotension. Specifically, the investigators look to show that comparable doses of oral sildenafil produces the same degree of PDE-V inhibition as an intravenous dose while the degree of hypotension is reduced. Additionally, using measurements of cerebral blood flow regulation acquired using transcranial Doppler ultrasound, the investigators look to show that oral sildenafil produces the same degree of improvement in vasospasm and blood flow regulation.

Official Title
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Sildenafil for the Treatment of Delayed Cerebral Ischemia Following Subarachnoid Hemorrhage

Conditions
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Subarachnoid Hemorrhage, Cerebral Vasospasm

Intervention / Treatment
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* Drug: Low dose sildenafil citrate
* Drug: High dose sildenafil citrate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age >= 21 Onset of symptoms within 72 hours from presentation Subarachnoid hemorrhage from ruptured cerebral aneurysm Cerebral vasospasm diagnosed on transcranial doppler, CT angiography, or digital subtraction angiography Exclusion Criteria: Pregnancy Subarachnoid hemorrhage secondary to traumatic or mycotic aneurysm Pre-ictal sildenafil therapy (last dose within 1 week of presentation) Contraindications to sildenafil therapy (i.e. use of nitrates, left ventricular outflow obstruction, impaired autonomic blood pressure control)

Ages Eligible for Study
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Minimum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Patients will be randomly assigned to either low dose sildenafil (20mg oral and 10mg intravenous) or high dose sildenafil (60mg oral and 30 mg intravenous)
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Low dose sildenafil<br>Twelve patients with cerebral vasospasm following aneurysmal subarachnoid hemorrhage will be assigned to low dose sildenafil citrate and will receive a 20mg oral dose and a subsequent 10mg intravenous dose of sildenafil citrate. | Drug: Low dose sildenafil citrate<br> <br> |
| Experimental: High dose sildenafil<br>Twelve patients with cerebral vasospasm following aneurysmal subarachnoid hemorrhage will be assigned to high dose sildenafil citrate and will receive a 60mg oral dose and a subsequent 30mg intravenous dose of sildenafil citrate. | Drug: High dose sildenafil citrate<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in mean arterial blood pressure |  | baseline and 2 hours post-dose | 
| Area under the plasma concentration versus time curve (AUC) of sildenafil |  | 0, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 16, 20, and 24 hours post-dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the cerebral spinal fluid concentration versus time curve (AUC) of sildenafil |  | 0, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 16, 20, and 24 hours post-dose | 
| Change from baseline in cerebral autoregulation |  | baseline and 2 hours post-dose |