Patterns of benzodiazepine underdosing in the Established Status Epilepticus Treatment Trial.


Sathe AG(1), Underwood E(2), Coles LD(1), Elm JJ(2), Silbergleit R(3), Chamberlain JM(4), Kapur J(5), Cock HR(6), Fountain NB(7), Shinnar S(8), Lowenstein DH(9), Rosenthal ES(10), Conwit RA(11), Bleck TP(12), Cloyd JC(1).
Author information:
(1)Department of Experimental and Clinical Pharmacology, College of Pharmacy and Center for Orphan Drug Research, University of Minnesota, Minneapolis, Minnesota, USA.
(2)Department of Public Health Science, Medical University of South Carolina, Charleston, South Carolina, USA.
(3)Department of Emergency Medicine, University of Michigan, Ann Arbor, Michigan, USA.
(4)Division of Emergency Medicine, Children's National Hospital and Department of Pediatrics and Emergency Medicine, School of Medicine and Health Sciences, George Washington University, Washington, District of Columbia, USA.
(5)Department of Neurology and Department of Neuroscience, Brain Institute, University of Virginia, Charlottesville, Virginia, USA.
(6)Clinical Neurosciences Academic Group, Institute of Molecular and Clinical Sciences, St. George's University of London, London, UK.
(7)Department of Neurology, Comprehensive Epilepsy Program, University of Virginia, Charlottesville, Virginia, USA.
(8)Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York, USA.
(9)Department of Neurology, University of California, San Francisco, San Francisco, California, USA.
(10)Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts, USA.
(11)National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.
(12)Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.


OBJECTIVE: This study was undertaken to describe patterns of benzodiazepine use as first-line treatment of status epilepticus (SE) and test the association of benzodiazepine doses with response to second-line agents in patients enrolled in the Established Status Epilepticus Treatment Trial (ESETT). METHODS: Patients refractory to an adequate dose of benzodiazepines for the treatment of SE were enrolled in ESETT. Choice of benzodiazepine, doses given prior to administration of second-line agent, route of administration, setting, and patient weight were characterized. These were compared with guideline-recommended dosing. Logistic regression was used to determine the association of the first dose of benzodiazepine and the cumulative benzodiazepine dose with the response to second-line agent. RESULTS: Four hundred sixty patients were administered 1170 doses of benzodiazepines (669 lorazepam, 398 midazolam, 103 diazepam). Lorazepam was most frequently administered intravenously in the emergency department, midazolam intramuscularly or intravenously by the emergency medical services personnel, and diazepam rectally prior to ambulance arrival. The first dose of the first benzodiazepine (N = 460) was lower than guideline recommendations in 76% of midazolam administrations and 81% of lorazepam administrations. Among all administrations, >85% of midazolam and >76% of lorazepam administrations were lower than recommended. Higher first or cumulative benzodiazepine doses were not associated with better outcomes or clinical seizure cessation in response to second-line medications in these benzodiazepine-refractory seizures. SIGNIFICANCE: Benzodiazepines as first-line treatment of SE, particularly midazolam and lorazepam, are frequently underdosed throughout the United States. This broad and generalizable cohort confirms prior single site reports that underdosing is both pervasive and difficult to remediate. (ESETT identifier: NCT01960075.).