Clevidipine for Vasospasm After Subarachnoid Hemorrhage (SAH)

Cerebral vasospasm after aneurysmal subarachnoid hemorrhage (SAH) is a major cause of
morbidity and mortality days after securing the aneurysm due to development of cerebral
ischemia and strokes. Vasospasm is detected by measuring the blood flow velocities in the
cerebral circulation via daily Transcranial Dopplers (TCD). There is no effective treatment
except for a per os calcium channel blocker (nimodipine) and for keeping the patient
hypertensive and with euvolemia or hypervolemia. A recently proposed option is to dilate the
cerebral vessels by infusing continuously another vasodilatory calcium channel blocker,
nicardipine, and supporting the systemic blood pressure (BP) with vasopressors which do not
constrict the cerebral vasculature at the same time. Nicardipine has also been used
extensively intra-arterially as a bolus or infusion to dilate the vasospastic cerebral
vessels as a rescue therapy for severe vasospasm.

Clevidipine is a novel, short-acting calcium channel blocker, which in a small series of
patients with SAH at Henry Ford Hospital, was able to control the elevated BP very
efficiently and within a narrow window, without adverse events. It has never been used
before for ameliorating vasospasm, but theoretically offers advantages compared to
nicardipine due to its shorter half-life and easier titratability. Except for use of
clevidipine for BP control in the investigators previous study, there are no data on
clevidipine use after SAH and no data about effect of the drug on vasospasm.

In this single-center, open-label, uncontrolled, pilot clinical study, the investigators
hypothesize that clevidipine low-rate infusion will decrease sonographically-detected
moderate cerebral vasospasm after aneurysmal SAH. The dose of the drug in this exploratory
study is 2.5 to 5 times lower than the dose used previously to control BP. The effect of the
drug will be evaluated in 20 patients by TCD monitoring during 3 periods: 1-hour
pre-infusion, 4-hour infusion and 4-hour post infusion. The cerebral blood flow velocities,
which are a surrogate marker of vasospasm, will be compared between the 3 periods. The
primary efficacy end-point will be the percentage of measurements with at least a 10% or
more decrease of the velocities during the infusion period. Potential long-term effects
after discontinuation of the drug will be also evaluated in the post-infusion 4-hour period
and beyond, until the last follow up. The major safety issue is hypotension induced by the
drug during a period when vasospasm is present. For that reason, two measures will be taken.
First, only patients with moderate vasospasm will be evaluated. Second, vasopressors will be
used as needed during the infusion period to counteract the systemic circulatory effect of
the drug and maintain a stable systemic Mean Arterial Pressure (MAP) within 10% range
compared to pre-infusion. Potential effect of cerebral vasodilation on intracranial pressure
(ICP) will be also evaluated during the infusion and post-infusion periods and any elevation
> 10 mm Hg will be reported.

Inclusion Criteria:

- Age 18-80 years

- Diagnosis of SAH (as diagnosed per history, neuroimaging or lumbar puncture)

- Presence of a secured aneurysm via clipping or coiling

- Hunt and Hess grade < 5 (non-sedated or paralyzed patients)

- Glasgow Coma scale > 4 (non-sedated or paralyzed patients)

- MAP goal set by the treating physicians

- Temporal insonation window presence on TCD

- Moderate supratentorial vasospasm as per daily TCD (CBFV between 130-180 cm/sec or
Lindergaard index 3-5 for the Middle Cerebral artery or Internal Cerebral artery or
Anterior Cerebral artery)

Exclusion Criteria:

- Very young or very old patients (<18 or >80 years old)

- Traumatic SAH (no aneurysm identified after initial work-up) or Perimesencephalic SAH
is also excluded

- Hunt and Hess grade 5 (deeply comatose or brain dead patients)

- Glasgow Coma scale 3 or 4 (brain dead or deeply comatose patients)

- Patients with mild or severe supratentorial vasospasm (CBFV < 120 cm/sec or
Lindergaard index < 3 or > 200 cm/sec or Lindergaard index > 6, respectively, for the
Middle Cerebral artery or Internal Cerebral artery or Anterior Cerebral artery)

- Patients with vasospasm only in the posterior circulation (CBFV > 80 cm/sec for
Vertebral or Basilar artery)

- Patients with severe tachycardia (heart rate > 110)

- Patients with preexisting left bundle branch block or permanent ventricular pacemaker

- Patients with known allergy to dihydropyridines including clevidipine or allergic to
soybeans, soy products, eggs, or egg products

- Patients with defective lipid metabolism such as pathologic hyperlipemia or lipoid
nephrosis

- Patients with acute pancreatitis, if it is accompanied by hyperlipidemia

- Patients with severe aortic stenosis

- Pregnant patients