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Research paper
Dantrolene for cerebral vasospasm after subarachnoid haemorrhage: a randomised double blind placebo-controlled safety trial
  1. Susanne Muehlschlegel1,2,3,
  2. Raphael Carandang1,3,
  3. Wiley Hall1,3,
  4. Nisha Kini4,
  5. Saef Izzy1,
  6. Bridget Garland1,
  7. Cynthia Ouillette1,
  8. Imramsjah M J van der Bom5,
  9. Thomas F Flood5,
  10. Matthew J Gounis5,
  11. John P Weaver6,
  12. Bruce Barton4,
  13. Ajay K Wakhloo1,5,6
  1. 1Departments of Neurology (Neurocritical Care), University of Massachusetts Medical School, Worcester, Massachusetts, USA
  2. 2Department of Anesthesia/Critical Care, University of Massachusetts Medical School, Worcester, Massachusetts, USA
  3. 3Department of Surgery, University of Massachusetts Medical School, Worcester, Massachusetts, USA
  4. 4Department of Quantitative Health Sciences, University of Massachusetts Medical School, Worcester, Massachusetts, USA
  5. 5Department of Radiology, University of Massachusetts Medical School, Worcester, Massachusetts, USA
  6. 6Department of Neurosurgery, University of Massachusetts Medical School, Worcester, Massachusetts, USA
  1. Correspondence to Dr Susanne Muehlschlegel, Departments of Neurology (Neurocritical Care), Anesthesia/Critical Care and Surgery, University of Massachusetts Medical School, 55 Lake Ave. North, S5, Worcester, MA 01655, USA; susanne.muehlschlegel{at}umassmemorial.org

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.

Trial registration number http://clinicaltrials.gov NCT01024972.

  • SUBARACHNOID HAEMORRHAGE
  • STROKE
  • INTENSIVE CARE

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