Patterns of benzodiazepine underdosing in the Established Status Epilepticus Treatment Trial

Abhishek G. Sathe; Ellen Underwood; Lisa D. Coles; Jordan J. Elm; Robert Silbergleit; James M. Chamberlain; Jaideep Kapur; Hannah R. Cock; Nathan B. Fountain; Shlomo Shinnar; Daniel H. Lowenstein; Eric S. Rosenthal; Robin A. Conwit; Thomas P. Bleck; James C. Cloyd

doi:10.1111/epi.16825

Patterns of benzodiazepine underdosing in the Established Status Epilepticus Treatment Trial

Abhishek G. Sathe, Ellen Underwood, Lisa D. Coles, Jordan J. Elm, Robert Silbergleit, James M. Chamberlain, Jaideep Kapur, Hannah R. Cock, Nathan B. Fountain, Shlomo Shinnar, Daniel H. Lowenstein, Eric S. Rosenthal, Robin A. Conwit, Thomas P. Bleck, James C. Cloyd

Neurology

Research output: Contribution to journal › Article › peer-review

40 Scopus citations

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.).

Original language	English (US)
Pages (from-to)	795-806
Number of pages	12
Journal	Epilepsia
Volume	62
Issue number	3
DOIs	https://doi.org/10.1111/epi.16825
State	Published - Mar 2021

Keywords

ESETT
benzodiazepine dose
diazepam
lorazepam
midazolam

ASJC Scopus subject areas

Neurology
Clinical Neurology

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10.1111/epi.16825

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Sathe, A. G., Underwood, E., Coles, L. D., Elm, J. J., Silbergleit, R., Chamberlain, J. M., Kapur, J., Cock, H. R., Fountain, N. B., Shinnar, S., Lowenstein, D. H., Rosenthal, E. S., Conwit, R. A., Bleck, T. P., & Cloyd, J. C. (2021). Patterns of benzodiazepine underdosing in the Established Status Epilepticus Treatment Trial. Epilepsia, 62(3), 795-806. https://doi.org/10.1111/epi.16825

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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.).",

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year = "2021",

month = mar,

doi = "10.1111/epi.16825",

language = "English (US)",

volume = "62",

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AU - Sathe, Abhishek G.

AU - Underwood, Ellen

AU - Coles, Lisa D.

AU - Elm, Jordan J.

AU - Silbergleit, Robert

AU - Chamberlain, James M.

AU - Kapur, Jaideep

AU - Cock, Hannah R.

AU - Fountain, Nathan B.

AU - Shinnar, Shlomo

AU - Lowenstein, Daniel H.

AU - Rosenthal, Eric S.

AU - Conwit, Robin A.

AU - Bleck, Thomas P.

AU - Cloyd, James C.

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N2 - 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.).

AB - 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.).

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Patterns of benzodiazepine underdosing in the Established Status Epilepticus Treatment Trial

Abstract

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