Patterns of benzodiazepine underdosing in the established status epilepticus treatment trial
Sathe AG, Underwood E, Coles LD, et al. Epilepsia. 2021;62(3):795-806.
SUMMARY:
Benzodiazepines (BZDs) are first-line agents for seizure termination. The recommended minimum dose is 0.1 mg/kg for lorazepam (4 mg for adults), and 0.15-0.3 mg/kg for diazepam or midazolam (10 mg for adults), depending on whether the administration route is IM, IV, buccal, or rectal.
Previous studies have suggested that underdosing is common and is associated with poorer outcomes. We have in fact covered several articles showing this trend in the past, but those articles involved only small numbers of patients or sites, or lacked rigorous research methods.
In this study, the authors examined patients enrolled in the Established Status Epilepticus Treatment Trial (ESETT) to determine whether these preliminary findings held. The ESETT results, published in the New England Journal of Medicine, established that levetiracetam, valproate, and fosphenytoin were similarly efficacious to first-line treatment for status epilepticus in adults and children.
To be enrolled in this trial, patients were required to have BZD refractory seizures. The research questions in this current study were (1) how often did enrolled patients receive “adequate” BZD, and (2) did outcomes differ between those who did and did not receive adequate dosing?
This was a large trial on 460 patients from >20 centers in the U.S., including 224 children and 236 adults.
The main finding was that BZDs were substantially underdosed. Only 24% of lorazepam doses met the 0.1 mg/kg (maximum 4 mg) guideline, and only 14% of midazolam doses met the guideline. These findings describe not just the first dose of BZD but the cumulative dose. The results were better for diazepam: 78% met the guideline, and rectal diazepam was given by EMS staff, who tend to follow guidelines better than ED providers. The results were markedly worse for adults than children.
No apparent difference was observed in the rate of seizure control for those who received adequate vs inadequate dosing, in contrast to previous observations in some smaller evaluations. However, this finding may be misleading because patients were required to have BZD refractory seizure for enrollment. Therefore, patients who received adequate dosing and whose seizures stopped would not have been enrolled and might not even have needed to be exposed to another agent.
The authors performed a variety of analyses, including decreasing the “adequate dose” to reflect some uncertainty in patient weights, but the findings did not change. BZDs appeared to be severely underdosed.
EDITOR’S COMMENTARY: This is yet another study documenting that EMS and ED providers consistently underdose BZDs in patients with seizure or status epilepticus. This article does not speak to the reasons why this might happen, but it does call on providers to be familiar with the dosing strategies for adults and children to ensure adequate dosing. However, adverse clinical consequences of underdosing were not confirmed in this analysis.
