Do Intravenous First-Line Benzodiazepines Terminate Seizures Faster Than Non-Intravenous Routes?

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  • Article: Alshehri A, Abulaban A, Bokhari R, et al. Intravenous versus Non-Intravenous Benzodiazepines for the Abortion of Seizures: A Systematic Review and Meta-analysis of Randomized Controlled Trials. Acad Emerg Med. 2017 Mar 25.
  • Design: Systematic review and meta-analysis of randomized and quasi-randomized controlled trials.
  • Population: Included: Adults and children treated with BZD for status epilepticus (seizures ≥ 5 minutes in duration). Excluded: None specified.
  • Intervention: IV BZD as first-line therapy for status epilepticus.
  • Comparison: Rectal, buccal, IN or IM (non-IV) BZD for status epilepticus.
  • Outcomes: Primary: Failure to terminate seizure.


Why is this study important?
The failure of anticonvulsive treatment and the risk of morbidity and mortality from seizures increase with seizure duration. While the intravenous (IV) delivery of benzodiazepines (BZD) is the most direct and reliable route, non-IV administration of BZDs may be more effective due to more rapid administration.

Which, if any, threats to validity are most likely to have an impact on the results and how? 
The summary estimates were pooled across studies with inconsistent definitions of status epilepticus and multiple comparators; thereby, making it difficult to determine which administration route of BZD is superior. Furthermore, the pediatric subgroup was not defined a priori, so this analysis is post hoc and potentially biased. Also, 58.6% of the patients within this meta-analysis are from 1 study.

How do the key results compare with the current evidence? 
Recently published guidelines from the American Epilepsy Society assert that intramuscular (IM) midazolam has superior effectiveness to IV lorazepam in convulsive status epilepticus patients without IV access, and in children, non-IV midazolam (IM/intranasal [IN]/Buccal) is probably more effective than diazepam (IV/rectal) [1]. Therapeutic guidelines recommend midazolam IN, IM, or buccally as equally effective as IV clonazepam, diazepam or midazolam [2].

How should this study impact the care of emergency department (ED) patients? 
In convulsive status, IV administration of BZD should be used if IV access is established (or readily established). If there is no IV access, then non-IV administration, especially IM or IN midazolam is the treatment of choice.

Funding: Not Stated

Conflicts of Interest: Not stated.

Potential Threats to Validity:

Chance: The analysis of the incidence of adverse events is underpowered with < 10% of patients experiencing complications.

Selection Bias: The authors defined status epilepticus as a seizure ≥ 5 minutes in duration but include studies with different definitions.

Measurement Bias: Details on study selection are missing, although it is assumed that independent screening was done in duplicate given that the authors have reported a kappa statistic. Results of quality assessments also are missing.

Analysis Bias: The subgroup analyses were not stated a priori. It was initially noted that only 1 study could not be included in the meta-analysis; however, 2 additional studies were excluded post hoc.

Confounding: IV diazepam was compared to non-IV midazolam in 9 out of 10 studies.

Appraisers: Bedard C; Worster A; Doherty S & Cave G.


  1. 1. Glauser T, Shinnar S, Gloss D, et al. Evidence-Based Guideline: Treatment of Convulsive Status Epilepticus in Children and Adults: Report of the Guideline Committee of the American Epilepsy Society. Epilepsy Curr. 2016 Jan-Feb; 16(1): 48–61.
  2. 2. Therapeutic Guidelines Ltd 2017. Available at: (accessed 2017 May 02).

This column was produced in collaboration with Best Evidence in Emergency Medicine (BEEM)

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