Acetazolamide in Aneurysmal Subarachnoid Hemorrhage

Approximately 30% of patients with subarachnoid hemorrhage (SAH) suffer from
delayed cerebral ischemia (DCI). This in-hospital complication increases the
risk of poor functional outcome. The only available drug that reduces the risk
of DCI is nimodipine. However, the effect of nimodipine is only modest.
Acetazolamide, a carbonic anhydrase inhibitor, could be a useful additional
drug for the prevention of DCI by acting on 3 different pathways: (1) it
increases cerebral blood flow via vasodilation, (2) it decreases brain edema
through carbonic anhydrase inhibition, and (3) it decreases cerebrospinal fluid
production. These combined actions of acetazolamide make it a promising drug
for the prevention of DCI in patients with SAH.

In a phase II study we will evaluate safety and proof-of-concept of
acetazolamide in patients with aneurysmal SAH. The primary aim of this study is
to evaluate whether acetazolamide improves cerebral perfusion as measured with
magnetic resonance imaging (MRI) performed 7±2 days after ictus. The secondary
objectives of this study are to investigate (1) the safety of acetazolamide
when given until day 14 after aneurysmal SAH (aSAH), (2) whether acetazolamide
improves cerebral perfusion also at day 12±2 after ictus, (3) whether the
proportion of patients with DCI is lower in the intervention group. The
tertiary objectives of this study are: (1) to investigate whether acetazolamide
improves the Quality of Life score and modified Rankin Scale (degree of
disability) at 10 weeks after SAH, and (2) to examine whether the proportion of
patients with hydrocephalus is lower in the intervention group.

This study will be an intervention study with a PROBE design (Prospective,
Randomized, Open-label study with Blinded End-point assessment) to evaluate the
safety and proof of concept of acetazolamide in patients with aneurysmal SAH.
The participant and treatment team will be open to group assignment, and the
researcher performing the data analysis will be blinded.

In the intervention group, subjects will receive acetazolamide intravenously as
well as treatment as usual. The dosage of acetazolamide will be similar to the
average dosage used for the treatment of intracranial hypertension: 1.5 grams
per day in three dosages of 0.5 grams in a 100 mL solution per dose. The
intervention will be initiated within 120 hours after ictus, after aneurysm
securing, and it will be continued until day 14 after ictus in addition to the
usual treatment. The control group will not receive any study medication and
will only receive treatment as usual.

The patients included in this study will undergo two MRI scans for the purpose
of the trial and they will receive either acetazolamide in addition to standard
clinical care or only standard clinical care. Treatment group will be randomly
assigned. There is no risk related to the MRI in this patient population and
no contrast agents (such as gadolinium) will be used. Patients in whom
acetazolamide is administered nearly always experience harmless side effects
such as tingling in the fingers, toes, and perioral region. A less common side
effect is malaise. Severe side effects are rare, and occur in 0.01-1% (see
Appendix 1). Rare side effects (frequency 1/100 - 1/10.000) include toxic skin
manifestations and hematological changes. All patients visit the UMC Utrecht
for neuropsychological testing at 10 weeks as part of standard clinical care.
At this visit, an additional 10 minute Quality of Life questionnaire will be
performed by the neuropsychologists. There is no risk related to the Quality of
Life questionnaire in this population. The modified Rankin Scale is
administered as part of standard clinical care during the neuropsychological
testing.