title: Dantrolene for cerebral vasospasm after subarachnoid haemorrhage: a randomised double blind placebo-controlled safety trial.
abstract: BACKGROUND
  Dantrolene is neuroprotective in animal models and may attenuate cerebral vasospasm (cVSP) in human aneurysmal subarachnoid haemorrhage (aSAH). We evaluated safety, feasibility and tolerability of intravenous dantrolene (IV-D) in patients with aSAH.
  
  
  METHODS
  In this single-centre, randomised, double blind, placebo-controlled trial, 31 patients with aSAH were randomised to IV-D 1.25 mg every 6 h for 7 days (n=16) or equiosmolar free water/5% mannitol (placebo; n=15). Primary safety end points were incidence of hyponatraemia (sNa≤132 mmol/L) and liver toxicity (proportion of patients alanine transaminase, aspartate aminotransferase and AlkPhos >5× upper-limit-of-normal). Secondary end points included tolerability, systemic hypotension and intracranial hypertension. Efficacy was explored for clinical/radiological cVSP, delayed cerebral ischaemia (DCI), and 3-month functional outcomes. Quantitative analyses of angiograms and daily transcranial Doppler (TCD) were performed.
  
  
  RESULTS
  Between IV-D versus placebo, no differences were observed in the primary outcomes (hyponatremia 44% vs 67% (p=0.29); liver toxicity 6% vs 0% (p=1.0)). Three patients in the IV-D versus two in the placebo group had severe adverse events possibly attributable to infusion and reached stop criteria: one IV-D patient developed liver toxicity; two patients in each group developed brain oedema requiring osmotherapy. The majority of adverse events were not related to infusion (17 vs 5 (RR 2.2; 95% CI 0.7 to 6.7; p=0.16) in IV-D vs placebo). No differences in any categorical cVSP outcomes, DCI, 3-month outcomes or quantitative angiogram and TCD analyses were seen in this small safety trial not powered to detect efficacy.
  
  
  CONCLUSIONS
  In this small trial, IV-D after aSAH was feasible, tolerable and safe.
  
  
  BACKGROUND
  http://clinicaltrials.gov NCT01024972.
authors.affiliation: Departments of Neurology (Neurocritical Care), University of Massachusetts Medical School, Worcester, Massachusetts, USA Department of Anesthesia/Critical Care, University of Massachusetts Medical School, Worcester, Massachusetts, USA Department of Surgery, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Susanne
authors.identifier: http://orcid.org/0000-0002-5717-9246
authors.initials: S
authors.lastname: Muehlschlegel
authors.affiliation: Departments of Neurology (Neurocritical Care), University of Massachusetts Medical School, Worcester, Massachusetts, USA Department of Surgery, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Raphael
authors.initials: R
authors.lastname: Carandang
authors.affiliation: Departments of Neurology (Neurocritical Care), University of Massachusetts Medical School, Worcester, Massachusetts, USA Department of Surgery, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Wiley
authors.initials: W
authors.lastname: Hall
authors.affiliation: Department of Quantitative Health Sciences, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Nisha
authors.initials: N
authors.lastname: Kini
authors.affiliation: Departments of Neurology (Neurocritical Care), University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Saef
authors.initials: S
authors.lastname: Izzy
authors.affiliation: Departments of Neurology (Neurocritical Care), University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Bridget
authors.initials: B
authors.lastname: Garland
authors.affiliation: Departments of Neurology (Neurocritical Care), University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Ouillette
authors.affiliation: Department of Radiology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Imramsjah M J
authors.initials: IM
authors.lastname: van der Bom
authors.affiliation: Department of Radiology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Flood
authors.affiliation: Department of Radiology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Gounis
authors.affiliation: Department of Neurosurgery, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: John P
authors.initials: JP
authors.lastname: Weaver
authors.affiliation: Department of Quantitative Health Sciences, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Bruce
authors.initials: B
authors.lastname: Barton
authors.affiliation: Departments of Neurology (Neurocritical Care), University of Massachusetts Medical School, Worcester, Massachusetts, USA Department of Radiology, University of Massachusetts Medical School, Worcester, Massachusetts, USA Department of Neurosurgery, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Ajay K
authors.initials: AK
authors.lastname: Wakhloo
mesh_terms: D000328:Adult; D000368:Aged; D003620:Dantrolene / Q000009:adverse effects / Q000627:therapeutic use*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009125:Muscle Relaxants, Central / Q000009:adverse effects / Q000627:therapeutic use*; D013345:Subarachnoid Hemorrhage / Q000150:complications*; D016896:Treatment Outcome; D020301:Vasospasm, Intracranial / Q000188:drug therapy* / Q000209:etiology
chemical_list: D009125:Muscle Relaxants, Central; D003620:Dantrolene
keywords: INTENSIVE CARE; STROKE; SUBARACHNOID HAEMORRHAGE