Studies Evaluating use of Dantrolene in the Management of Cerebral Vasospasm

Dantrolene form and dose

No changes in BMP, osmolality, ABG of LFT

One instance of hypotension

Significant decrease in PSV in low dose group and not high dose group

No difference in incidence of hyponatremia

One incidence of liver toxicity

No significant difference in rate of adverse events compared to control group

No significant changes in vessel diameter

Significant decrease in MFV, non-significant decrease in PSV

No hemodynamic adverse effects, improvement in angiographic vasospasm

IV, intravenous; ABG, arterial blood gas; BMP, basic metabolic panel; LFT, liver function test; PSV, peak systolic velocity; MFV, mean flow velocity; IA, intra-arterial; q6h, every 6 hours

Intra-Arterial Dantrolene for Refractory Cerebral Vasospasm in Patients with Aneurysmal Subarachnoid Hemorrhage

Design

Case 1

A 63-year-old woman presented two days after being found unresponsive at home. Computed tomography and computed tomography angiography showed extensive subarachnoid hemorrhage (SAH) layering in the interhemispheric and Sylvian fissures, along with an aneurysm arising at the junction of the anterior communicating artery and the A1 segment of the left anterior cerebral artery (ACA). Following the endovascular oil embolization she developed the first episode of recurrent severe vasospasm. She was treated with IA vasodilators (nicardipine and verapamil) with initial angiographic and clinical improvement followed by re-deterioration within 24 hours of each treatment. IA nicardipine 25 mg was manually injected into the left ICA over 10 minutes, with no improvement in lumen diameter. IA dantrolene was prepared by reconstituting 2 vials of lyophilized powder mixture of dantrolene sodium 20 mg, mannitol 300 mg, and sodium hydroxide. After reconstitution with sterile water for injection 60 mL, each vial contained dantrolene sodium 20 mg. The solution was then drawn up into 5 or 10 mL syringes and visually inspected to ensure no particulate matter. Then IA dantrolene treatment was injected in doses of 15 mg over 20 minutes in the affected distributions. Mean arterial pressure, intracranial pressure, and heart rate were monitored. Following the injection of dantrolene, immediate improvement in the lumen diameter of the affected vessels was observed. There were no significant differences in mean arterial pressure or intracranial pressure before and after IA dantrolene administration. Follow-up angiography 48 hours post-dantrolene showed a sustained improvement in lumen diameter. The patient was discharged 34 days after admission to an inpatient rehabilitation facility.  

Case 2 

A 36-year-old woman was found down and seizing several hours after complaining of a headache in a drug rehabilitation facility. Computed tomography and computed tomography angiography showed SAH in the interhemispheric fissure and bilateral A2 segment ACA aneurysms. Following a microsurgical clipping of both aneurysms she developed severe vasospasm of the entire right supraclinoid ICA, right M1 segment of the MCA, and entire right ACA, moderate vasospasm of the entire left supraclinoid ICA, left M1 segment of the MCA, and entire left ACA, and moderate vasospasm of the V4 segment of the left VA. Initially, she was treated with verapamil but no improvement was observed. IA nicardipine 15 mg was manually injected into the right ACA over 10 minutes, with no improvement in lumen diameter. This was followed by IA dantrolene 15 mg injected over 10 minutes. The catheter was then retracted proximally and the supraclinoid segment of the right ICA was also treated with IA dantrolene 15 mg over 10 minutes. Following the administration of dantrolene, angiography showed prominent improvement in lumen diameter. Finally, IA dantrolene 30 mg was injected into the left VA over 15 minutes where the angiography showed mild improvement in lumen diameter. There were no significant differences in mean arterial pressure or intracranial pressure before and after IA dantrolene administration. Follow-up angiography 48 hours post-dantrolene showed a sustained improvement in lumen diameter. The patient was discharged 25 days after admission to a skilled nursing facility.

Study Author Conclusions

IA dantrolene can result in persistent resolution of angiographic vasospasm in patients with multiple recurrences despite IA vasodilators. Further studies are required to identify the appropriate dose, route, and timing of administration to prevent and treat cerebral vasospasm associated with aneurysmal SAH. Dantrolene is an attractive agent for the treatment of cerebral vasospasm once patients have run out of endovascular options. These case studies add additional positive experiences with this treatment option to our existing literature, in which there is only a paucity of data regarding dantrolene’s role in this setting.

Intra-arterial Dantrolene for Refractory Cerebral Vasospasm After Aneurysmal Subarachnoid Hemorrhage

Design

Case presentation

A 56-year-old woman was evaluated for an episode of unresponsiveness in the emergency department after a recent episode of falling and confusion a week prior, leading to progressively more irritability, somnolence, and unsteady gait afterward. Initial physical examination revealed a Glasgow Coma Scale (GCS) score of 15 and mild hemiparesis of the right upper extremity (4/5 strength). Initial head CT scan and CT angiography demonstrated left frontal intraparenchymal and subarachnoid hemorrhages with anterior communicating artery aneurysm. Thus, the patient was taken to the neurointerventional suite, and the aneurysm was treated by endovascular coil embolization. As the initial cerebral angiogram also observed moderate bilateral anterior cerebral artery vasospasm, treatment with super-selective intraarterial infusion of nicardipine (5 mg in each vessel) was commenced without any significant angiographic improvement. 

As the follow-up angiogram on the next day revealed worsening in the severity of the anterior cerebral artery vasospasm bilaterally, the decision was made to administer intra-arterial dantrolene infusion. Through the guide catheter placed in the proximal right internal carotid artery, a SL-10 microcatheter was advanced into the right anterior cerebral artery over a Transcend EX microwire. Following the placement of the microcatheter, 20 mg of dantrolene was diluted in 20 mL of sterile water, with a total of 18 mL (1 mg/mL) dantrolene slowly infused through the microcatheter into various segments of the A1 segment of the right anterior cerebral artery. With close monitoring of vital signs, the rate of infusion was approximately 1 mL/min. Upon completion of the infusion, the microcatheter was withdrawn into the internal carotid artery, and follow-up angiographic images indicated improvement in the diameter of the right A1 and A2 segments.

Subsequently, the guide catheter was placed in the left proximal internal carotid artery, and SL-10 microcatheter was advanced into the A1 segment and further into the distal A2 segment of the left anterior cerebral artery. Another 12 mg of dantrolene was infused through the microcatheter with the same technique; first into the left A2 segment and then into the left A1 segment by retraction of the microcatheter. Following this, three sequential angioplasties were performed using a 1.5 x 9 mm over-the-wire Gateway balloon in the proximal left A1 segment. Again, follow-up images showed marked improvement in the appearance of the right A1 segment without evidence of recurrent vasospasm involving the previously treated right and left anterior cerebral arteries.  

Study Author Conclusions

In this case report, feasibility and safety of intra-arterial dantrolene as a therapeutic agent in cerebral vasospasm have been tested. Authors demonstrated that intra-arterial infusion of 30 mL (1 mg/mL) of dantrolene may lead to sustained amelioration of cerebral vasospasm. Patient hemodynamic parameters remained stable after drug infusion.

To our knowledge, this is the first report of using intra-arterial dantrolene infusion for the treatment of refractory cerebral vasospasm secondary to subarachnoid hemorrhage. Intra-arterial administration of dantrolene in combination with balloon angioplasty was well tolerated in a patient with severe vasospasm. There were no significant changes in the patient’s hemodynamic parameters. There is a need for a larger and controlled setting to evaluate the efficacy of intra-arterial dantrolene in treating cerebral vasospasm.