Patterns of benzodiazepine underdosing in the Established Status Epilepticus Treatment Trial

Abstract

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 ClinicalTrials.gov identifier: NCT01960075.).

Keywords: ESETT; benzodiazepine dose; diazepam; lorazepam; midazolam.

Conflict of interest statement

CONFLICTS OF INTEREST

All authors were supported by the ESETT study grant from NIH/NINDS (U01NS088034). L.D. Coles reports grants from NIH/NINDS, during the conduct of the study; personal fees from Neurelis Pharmaceuticals, grants from Sollievo, outside the submitted work; H.R. Cock reports grants from NINDS, during the conduct of the study; personal fees from Sage Pharmaceuticals Ltd, Eisai Europe Ltd, UCB Pharma Ltd, UK Epilepsy Nurse Specialist Association, non-financial support from Special Products Ltd, International League Against Epilepsy, Epilepsy Certification (education) Task Force, European Academy of Neurology, personal fees from Bial and Eisai, outside the submitted work; N.B. Fountain reports grants from NINDS during the conduct of the study; grants from SK Lifesciences, Neurelis, Takeda, GW Pharma, Biogen, and UCB outside the submitted work. S. Shinnar reports grants from NINDS during the conduct of the study; personal fees from UCB Pharma, Eisai and Insys, outside the submitted work; E.S. Rosenthal reports grants from NIH/NINDS and the Department of Defense during the conduct of the study; personal fees from UCB Pharma and Ceribell, Inc., during the conduct of the study. J.C. Cloyd reports a grant from National Institute of Neurological Disorders and Stroke during the conduct of the study and personal fees from Neurelis Pharmaceuticals, grants from Sollievo, outside the submitted work; J.C. Cloyd has a patent entitled "Intranasal Drug Delivery". The remaining authors have no conflicts of interest. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

© 2021 International League Against Epilepsy.

Figures

Figure 1:

Distribution of first dose of the first administered benzodiazepine (DZP, MDZ or LZP) (n=460). Top panel: fixed dosing, bottom panel: weight-based dosing. A: DZP doses for those ≥ 66.7kg (IV) or ≥ 50 kg (rectal); B: MDZ doses for those > 40 kg; C: LZP doses for those ≥ 40 kg; D: DZP doses for those

Figure 2:

Administrations that met (blue) and did not meet (red) guideline recommendations among all administrations for DZP, MDZ and LZP (N=1170).

Figure 3:

Distribution of the cumulative benzodiazepine dose in lorazepam equivalents for subjects weighing ≥ 32 kg (top panel) and

Figure 4:

Time trend of the proportion of first doses that met guidelines over the course of ESETT for children (orange) and adults (blue) for all first doses (top panel) and first doses administered in the emergency department (ED) (bottom panel). The red arrows indicate the total number of adult and children included (115 adults, 85 children) in the first cohort (top panel) and number of first doses administered in the ED (61 in adults, 38 in children) in the first cohort (bottom panel).