Trial Description

Subarachnoid hemorrhage (SAH) is a devastating acute brain injury due to bleeding onto the brain surface from a ruptured aneurysm. Cerebral vasospasm (cVSP; critical narrowing of brain arteries) is a known complication after SAH and significantly increases disability and death after SAH. Vasospasm is difficult to treat and can lead to stroke. Animal studies have shown that the muscles in the artery wall play a role in cVSP.
Dantrolene has been FDA approved and extensively used in clinical practice as a muscle relaxant for more than 30 years. It has been shown to provide some benefit in animal studies of cVSP, as well as in a small number of humans. However, the first human studies have only been observational and over a short period of time.
This study will evaluate the safety and tolerability of intravenous dantrolene given every 6 hours over seven days to patients with or at risk for cVSP after SAH. The goal is to determine if future efficacy studies should be done to determine if treatment with Dantrolene may improve the outcome of patients with cVSP after SAH.

Detailed Description

Once eligibility criteria are met, patients will be randomized to either dantrolene-IV or placebo (equiosmolar, volume-equivalent sterile water with 5% mannitol as dantrolene-IV also contains 5% mannitol). Study subjects will be visited daily by a study nurse to determine side effects, tolerability, record hemodynamic measures and laboratory values. Patients will have daily serum Na, osmolality, AST, ALT and ALK measured. In addition, daily bedside transcranial doppler will be performed by a blinded examiner. Patients will undergo cerebral angiograms per clinical routine. Angiographic measurements of arterial narrowing will be performed by a blinded radiologist. Specific stop criteria are pre-defined.

Conditions

• Subarachnoid Hemorrhage
• Cerebral Vasospasm

Interventions

• Placebo Drug

  Intervention Desc:	A placebo is a substance or procedure which a patient accepts as a medicine or therapy but which has no specific therapeutic activity for the condition.

• Dantrolene (Dantrium (in North America) and Dantrolen (Europe))Drug

  Intervention Desc:

  Dantrolene sodium is a muscle relaxant that acts by abolishing excitation-contraction coupling in muscle cells, probably by action on the ryanodine receptor. It is also used in the management of neuroleptic malignant syndrome, muscle spasticity (e.g. after strokes, in paraplegia, cerebral palsy, or patients with multiple sclerosis), ecstasy intoxication, serotonin syndrome, and 2,4-dinitrophenol poisoning.

• Dantrolene vs. Placebo Drug

  Other Names:	Dantrium
  Intervention Desc:	Dantrolene 1.25mg/kg IV (includes 5% mannitol) or equiosmolar placebo (5% mannitol) every 6 hours x 7 days
  ARM 1:	Kind: Experimental
  	Label: Dantrolene
  	Description: Dantrolene 1.25mg/kg IV every 6 hours x 7 days
  ARM 2:	Kind: Experimental
  	Label: Placebo
  	Description: Equiosmolar volume (5% Mannitol)

Trial Design

• Allocation: Randomized
• Masking: Double Blind (Subject, Investigator, Outcomes Assessor)
• Purpose: Treatment
• Endpoint: Safety Study
• Intervention: Parallel Assignment

Patient Involvement

Once eligibility criteria are met, patients will be randomized to either dantrolene-IV or placebo (equiosmolar, volume-equivalent sterile water with 5% mannitol as dantrolene-IV also contains 5% mannitol). Study subjects will be visited daily by a study nurse to determine side effects, tolerability, record hemodynamic measures and laboratory values. Patients will have daily serum Na, osmolality, and LFTs measured. In addition, daily bedside transcranial doppler will be performed by a blinded examiner. Patients will undergo cerebral angiograms per clinical routine. Angiographic measurements of arterial narrowing will be performed by a blinded radiologist. Specific stop criteria are pre-defined.

Sponsors

• University of Massachusetts, Worcester Lead
• American Heart Association