Abstracts

Rationale: Benzodiazepines (BDZ) are considered effective rescue therapies for seizure emergencies. Currently, FDA-approved routes of administration are intravenous (IV) and rectal (diazepam [DZ]). Since currently approved methods can be associated with administration challenges, several alternatives have been reported or are in development. This review describes published evidence for administration of BDZ by various routes in treatment of seizure emergencies.Methods: We conducted a systematic review of PubMed using, English language, human subject, and clinical trial filters, and the search terms Seizure Emergency; Status Epilepticus; Acute Repetitive Seizure; Prolonged Seizure; Seizure Clusters; Seizure + Out of Hospital + individual BDZ (alprazolam, clonazepam [CLZ], DZ, lorazepam [LZ], midazolam [MDZ], clobazam [CLB]). Search results were categorized by BDZ, age, and route of administration. Studies in healthy subjects, and in those using BDZ for seizure prevention, as second-line treatment, or in combination with other antiepileptic drugs, were excluded.Results: In total, 50 unique citations were retrieved. Of these, 35 were in children (1 month to 17 years), 10 in adults and 5 in both children and adults. BDZ used were CLZ (2), DZ (30), LZ (13), CLB (1), and MDZ (23), with several comparing BDZ. Routes of administration included IV (N=37; CLZ=2, DZ=12, LZ=12, MDZ=11), intramuscular (IM; N=2; MDZ=2), rectal (N=23; DZ=21; LZ=1; MDZ=1), buccal/oral (N=9; CLB=1, MDZ=8), and intranasal (IN; N=6; LZ=2, MDZ=4). Time from BDZ administration to seizure cessation was generally rapid (IV: 1.3-65 minutes [min]; IM: 3.3-7.8 min; rectal: 1.24-15 min; buccal/oral: 2.8-10 min; IN: 3.0-10 min), and recurrence was reduced. Rectal, buccal, IM, and IN delivery were as effective as IV administration (overall range 50%-89% effective at terminating seizure activity without requirement for additional medication). When compared, non-parenteral formulations were more rapidly administered versus IV and could also be given in the pre- or out-of-hospital setting. Furthermore, caregivers found buccal and IN methods significantly more acceptable than rectal administration. Regardless of route of administration, adverse events (AEs) associated with BDZ use included dizziness, somnolence, sedation, and occasionally psychomotor agitation. Incidence of respiratory AEs (persistent O₂ saturation <92% or <12 breaths/min) was low and more frequently found with continuous infusion (IV: 0%-20.5%; rectal: 0%-6%; oral/buccal: 0%-5%; IN: 2% [reported in only one study]; no IM studies measured respiratory AEs).Conclusions: There is a perceived need for alternative administration methods that offer fast onset of effect and rapid and convenient administration for different populations with varying needs/preferences. Mounting evidence supports multiple safe and effective alternative routes of BDZ administration for rapid treatment of seizures in children and adults.