Susanne Muehlschlegel1, Raphael Carandang2, Wiley Hall2, Nisha Kini3, Saef Izzy4, Bridget Garland4, Cynthia Ouillette4, Imramsjah M J van der Bom5, Thomas F Flood5, Matthew J Gounis5, John P Weaver6, Bruce Barton3, Ajay K Wakhloo7. 1. 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. 2. Departments of Neurology (Neurocritical Care), University of Massachusetts Medical School, Worcester, Massachusetts, USA Department of Surgery, University of Massachusetts Medical School, Worcester, Massachusetts, USA. 3. Department of Quantitative Health Sciences, University of Massachusetts Medical School, Worcester, Massachusetts, USA. 4. Departments of Neurology (Neurocritical Care), University of Massachusetts Medical School, Worcester, Massachusetts, USA. 5. Department of Radiology, University of Massachusetts Medical School, Worcester, Massachusetts, USA. 6. Department of Neurosurgery, University of Massachusetts Medical School, Worcester, Massachusetts, USA. 7. 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.
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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
RCT Entities:
BACKGROUND:Dantrolene is neuroprotective in animal models and may attenuate cerebral vasospasm (cVSP) in humananeurysmal 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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
Authors: Christian Burrell; Nicole E Avalon; Jason Siegel; Michael Pizzi; Tumpa Dutta; M Cristine Charlesworth; William D Freeman Journal: Expert Rev Neurother Date: 2016-07-11 Impact factor: 4.618
Authors: Maria J Crespo; Marie Roman; Jonathan Matias; Myrna Morales; Hector Torres; Jose Quidgley Journal: Int J Endocrinol Date: 2018-04-19 Impact factor: 3.257