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Do Intravenous Benzodiazepines or Benzodiazepines by an Alternative Route (Nonintravenous) Abort Seizures Faster?
NEUROLOGY/SYSTEMATIC REVIEW SNAPSHOT
TAKE-HOME MESSAGE Benzodiazepines by an alternative route abort seizures faster and possess superior efficacy compared with intravenous benzodiazepines in patients without intravenous access. Do Intravenous Benzodiazepines or Benzodiazepines by an Alternative Route (Nonintravenous) Abort Seizures Faster?
METHODS DATA SOURCES Investigators searched PubMed, the Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, and the Cochrane Central Register of Controlled Trials from inception to July 2016 comparing intravenous benzodiazepines and benzodiazepines by an alternative route as first-line treatment for pediatric and adult patients with status epilepticus. Investigators also searched unpublished studies in clinicaltrials.gov, Australian New Zealand Clinical Trials Registry, the EU Clinical Trials Register, and the WHO International Clinical Trials Registry Platform. Authors evaluated the reference lists of articles and conference proceedings for additional citations. Two investigators evaluated titles and abstracts of search results, evaluated the full text after retrieval, and resolved discrepancies by discussion. Authors included randomized or quasi-randomized controlled trials. Alternative routes to intravenous administration included intranasal, intramuscular, per rectal, and buccal. DATA EXTRACTION AND SYNTHESIS Two reviewers extracted data from included trials, using a standardized data collection protocol, including the type of study design, definition
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EBEM Commentators
Brit Long, MD Michael D. April, MD, DPhil Department of Emergency Medicine San Antonio Uniformed Services Health Education Consortium Fort Sam Houston, TX
Results Results of included trials. Outcome BDZ by alternative route vs IV BDZ in failure to stop seizures BDZ by alternative route vs IV BDZ in failure to stop seizures with inclusion of only the pediatric subset of the largest RCT contributing to the analysis BDZ by alternative route vs IV BDZ in time needed for seizure cessation, not considering time to IV access, min BDZ by alternative route vs IV BDZ in time needed for seizure cessation, with considering time to IV access, min
Number of Studies Patients
Odds Ratio or Mean Difference
Heterogeneity, I2, %
10
1,523
0.72 (0.56 to 0.92)
0
10
750
1.16 (0.74 to 1.81)
0
7
376
0.74 (0.52 to 0.95)
0
7
380
–3.41 (–5.13 to –1.69)
93
BDZ, Benzodiazepines; IV, intravenous; RCT, randomized controlled trial.
The authors included 11 studies, with 10 randomized controlled trials and 1 observational longitudinal study for analysis, with 1,633 patients. Ten of the 11 articles were predominantly pediatric, although a single study accounting for more than half the patients analyzed in the meta-analysis (893 patients) comprised both children and adults with mean age 43 years among patients receiving benzodiazepines by alternative routes and 44 years in the intravenous group.2 Comparison of failure,
defined by failure to stop seizure, favored benzodiazepines administered by alternative routes (odds ratio 0.72; 95% CI 0.56 to 0.92). Pediatric subgroup analysis demonstrated no difference in efficacy between benzodiazepines administered by alternative routes versus intravenous benzodiazepines (odds ratio 1.16; 95% CI 0.74 to 1.81) with removal of this study. Intravenous benzodiazepines have a shorter interval between drug administration and seizure abortion Annals of Emergency Medicine 1
Systematic Review Snapshot
of status epilepticus, age of patients, number of patients, specific benzodiazepines, medication route and dosage, definition and rate of seizure abortion, and complications. Additionally, 2 authors assessed the risk of bias for each study, using the Cochrane Handbook for Systematic Reviews of Interventions with 7-item checklist for bias, including risk of selection, performance, detection, attrition, reporting, and other bias.1 Authors determined pooled odds ratios and mean differences with 95% confidence intervals (CIs), using random-effects models.
(mean difference 0.74 minutes; 95% CI 0.52 to 0.95 minutes). However, this was not found when the time to seizure termination from decision to treat was assessed, which factors in delays to treatment because of venous access. When these delays were factored in, benzodiazepines administered by alternative routes achieved faster net effect (mean difference –3.41 minutes; 95% CI –5.13 to –1.69 minutes).3-5 The authors found no difference between the 2 groups in regard to incidence of respiratory depression.2-5
Commentary Status epilepticus results in significant morbidity and mortality, with fatality reaching up to 30% in high-risk patients.6-8 Treatment protocols generally seek to terminate continuous seizures within 5 minutes.9 As seizure activity lengthens, seizures become increasingly refractory to treatment and outcomes worsen.10,11 The goal for status epilepticus management is to attain rapid and prolonged cessation of seizures while avoiding complications, 2 Annals of Emergency Medicine
many of which are iatrogenic (eg, respiratory depression).2,9 Intravenous benzodiazepine administration is attractive as a highly reliable and rapid mode for medication administration.12 However, obtaining intravenous access in an actively seizing patient can be difficult. This meta-analysis demonstrates superiority of benzodiazepines administered by alternative routes for seizure cessation without intravenous access, although this finding did not hold in pediatric subgroups. Authors suggest this is a function of earlier administration of benzodiazepines by alternative routes, which results in improved response to therapy. Adverse effects were similar across all studies, although the largest study reported the highest proportions of patients experiencing adverse effects including respiratory 2 depression. Benzodiazepines administered by alternative routes achieve efficacy because of the rapidity of administration, which is important in overall speed of seizure cessation. Intravenous benzodiazepines may terminate seizure more quickly once they are given, but the delay in administration because of difficulties in obtaining intravenous access can be substantial and offset this advantage. No clear answer is present in regard to the optimal nonintravenous route of benzodiazepine administration (eg, inhaled, rectal, intramuscular). That said, a majority of included studies, to include the largest study by Silbergleit et al, evaluated intramuscular midazolam.2 By extension, we believe intramuscular midazolam is a reasonable therapeutic
option for physicians seeking an alternative to intravenous benzodiazepines. Limitations of this meta-analysis include a lack of high-quality studies, with underpowered or methodologically flawed studies. The specific benzodiazepines, routes of administration, and doses varied among the included studies. Future studies would benefit from evaluating specific medications, doses, and routes. Clinicians may consider administering intramuscular midazolam or another benzodiazepine by an alternative route for patients without existing intravenous access. Editor’s Note: This is a clinical synopsis, a regular feature of the Annals’ Systematic Review Snapshot (SRS) series. The source for this systematic review snapshot is: Alshehri A, Abulaban A, Bokhari R, et al. Intravenous versus nonintravenous benzodiazepines for the abortion of seizures: a systematic review and metaanalysis of randomized controlled trials. Acad Emerg Med. 2017; http://dx.doi.org/10.1111/acem. 13190. 1. Higgins JPT, Green S, eds. Cochrane Handbook for Systematic Reviews of Interventions. Version 5.1.0 (updated March 2011). Cochrane Collaboration; 2011. Available at: http://handbook. cochrane.org. Accessed May 20, 2017. 2. Silbergleit R, Durkalski V, Lowenstein D, et al. Intramuscular versus intravenous therapy for prehospital status epilepticus. N Engl J Med. 2012;366:591-600. 3. Mittal P, Manohar R, Rawat AK. Comparative study of intranasal midazolam and intravenous diazepam sedation for procedures and seizures. Indian J Pediatr. 2006;73:975-978. 4. Arya R, Gulati S, Kabra M, et al. Intranasal versus intravenous lorazepam for control of acute seizures in children: a randomized open-label study. Epilepsia. 2011;52:788-793. 5. Thakker A, Shanbag P. A randomized controlled trial of intranasal-midazolam versus intravenous-diazepam for acute childhood seizures. J Neurol. 2013;260:470-474.
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Systematic Review Snapshot 6. Sillanpaa M, Shinnar S. Status epilepticus in a population-based cohort with childhood-onset epilepsy in Finland. Ann Neurol. 2002;52:303-310. 7. Wu YW, Shek DW, Garcia PA, et al. Incidence and mortality of generalized convulsive status epilepticus in California. Neurology. 2002;58:1070-1076. 8. Gulati S, Kalra V, Sridhar MR. Status epilepticus in Indian children in a tertiary care center. Indian J Pediatr. 2005;72:105-108.
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9. 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;16:48-61. 10. Shorvon S. Clinical trials in acute repetitive seizures and status epilepticus. Epileptic Disord. 2012;14:138-147.
11. Morimoto K, Fahnestock M, Racine RJ. Kindling and status epilepticus models of epilepsy: rewiring the brain. Prog Neurobiol. 2004;73:1-60. 12. Meierkord H, Boon P, Engelsen B, et al. EFNS guideline on the management of status epilepticus. Eur J Neurol. 2006;13:445-450.
Michael Brown, MD, MSc, Jestin N. Carlson, MD, MS, and Alan Jones, MD, serve as editors of the SRS series.
Annals of Emergency Medicine 3
TAKE-HOME MESSAGE Benzodiazepines by an alternative route abort seizures faster and possess superior efficacy compared with intravenous benzodiazepines in patients without intravenous access. Do Intravenous Benzodiazepines or Benzodiazepines by an Alternative Route (Nonintravenous) Abort Seizures Faster?
METHODS DATA SOURCES Investigators searched PubMed, the Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, and the Cochrane Central Register of Controlled Trials from inception to July 2016 comparing intravenous benzodiazepines and benzodiazepines by an alternative route as first-line treatment for pediatric and adult patients with status epilepticus. Investigators also searched unpublished studies in clinicaltrials.gov, Australian New Zealand Clinical Trials Registry, the EU Clinical Trials Register, and the WHO International Clinical Trials Registry Platform. Authors evaluated the reference lists of articles and conference proceedings for additional citations. Two investigators evaluated titles and abstracts of search results, evaluated the full text after retrieval, and resolved discrepancies by discussion. Authors included randomized or quasi-randomized controlled trials. Alternative routes to intravenous administration included intranasal, intramuscular, per rectal, and buccal. DATA EXTRACTION AND SYNTHESIS Two reviewers extracted data from included trials, using a standardized data collection protocol, including the type of study design, definition
Volume
-,
no.
-
:
-
2017
EBEM Commentators
Brit Long, MD Michael D. April, MD, DPhil Department of Emergency Medicine San Antonio Uniformed Services Health Education Consortium Fort Sam Houston, TX
Results Results of included trials. Outcome BDZ by alternative route vs IV BDZ in failure to stop seizures BDZ by alternative route vs IV BDZ in failure to stop seizures with inclusion of only the pediatric subset of the largest RCT contributing to the analysis BDZ by alternative route vs IV BDZ in time needed for seizure cessation, not considering time to IV access, min BDZ by alternative route vs IV BDZ in time needed for seizure cessation, with considering time to IV access, min
Number of Studies Patients
Odds Ratio or Mean Difference
Heterogeneity, I2, %
10
1,523
0.72 (0.56 to 0.92)
0
10
750
1.16 (0.74 to 1.81)
0
7
376
0.74 (0.52 to 0.95)
0
7
380
–3.41 (–5.13 to –1.69)
93
BDZ, Benzodiazepines; IV, intravenous; RCT, randomized controlled trial.
The authors included 11 studies, with 10 randomized controlled trials and 1 observational longitudinal study for analysis, with 1,633 patients. Ten of the 11 articles were predominantly pediatric, although a single study accounting for more than half the patients analyzed in the meta-analysis (893 patients) comprised both children and adults with mean age 43 years among patients receiving benzodiazepines by alternative routes and 44 years in the intravenous group.2 Comparison of failure,
defined by failure to stop seizure, favored benzodiazepines administered by alternative routes (odds ratio 0.72; 95% CI 0.56 to 0.92). Pediatric subgroup analysis demonstrated no difference in efficacy between benzodiazepines administered by alternative routes versus intravenous benzodiazepines (odds ratio 1.16; 95% CI 0.74 to 1.81) with removal of this study. Intravenous benzodiazepines have a shorter interval between drug administration and seizure abortion Annals of Emergency Medicine 1
Systematic Review Snapshot
of status epilepticus, age of patients, number of patients, specific benzodiazepines, medication route and dosage, definition and rate of seizure abortion, and complications. Additionally, 2 authors assessed the risk of bias for each study, using the Cochrane Handbook for Systematic Reviews of Interventions with 7-item checklist for bias, including risk of selection, performance, detection, attrition, reporting, and other bias.1 Authors determined pooled odds ratios and mean differences with 95% confidence intervals (CIs), using random-effects models.
(mean difference 0.74 minutes; 95% CI 0.52 to 0.95 minutes). However, this was not found when the time to seizure termination from decision to treat was assessed, which factors in delays to treatment because of venous access. When these delays were factored in, benzodiazepines administered by alternative routes achieved faster net effect (mean difference –3.41 minutes; 95% CI –5.13 to –1.69 minutes).3-5 The authors found no difference between the 2 groups in regard to incidence of respiratory depression.2-5
Commentary Status epilepticus results in significant morbidity and mortality, with fatality reaching up to 30% in high-risk patients.6-8 Treatment protocols generally seek to terminate continuous seizures within 5 minutes.9 As seizure activity lengthens, seizures become increasingly refractory to treatment and outcomes worsen.10,11 The goal for status epilepticus management is to attain rapid and prolonged cessation of seizures while avoiding complications, 2 Annals of Emergency Medicine
many of which are iatrogenic (eg, respiratory depression).2,9 Intravenous benzodiazepine administration is attractive as a highly reliable and rapid mode for medication administration.12 However, obtaining intravenous access in an actively seizing patient can be difficult. This meta-analysis demonstrates superiority of benzodiazepines administered by alternative routes for seizure cessation without intravenous access, although this finding did not hold in pediatric subgroups. Authors suggest this is a function of earlier administration of benzodiazepines by alternative routes, which results in improved response to therapy. Adverse effects were similar across all studies, although the largest study reported the highest proportions of patients experiencing adverse effects including respiratory 2 depression. Benzodiazepines administered by alternative routes achieve efficacy because of the rapidity of administration, which is important in overall speed of seizure cessation. Intravenous benzodiazepines may terminate seizure more quickly once they are given, but the delay in administration because of difficulties in obtaining intravenous access can be substantial and offset this advantage. No clear answer is present in regard to the optimal nonintravenous route of benzodiazepine administration (eg, inhaled, rectal, intramuscular). That said, a majority of included studies, to include the largest study by Silbergleit et al, evaluated intramuscular midazolam.2 By extension, we believe intramuscular midazolam is a reasonable therapeutic
option for physicians seeking an alternative to intravenous benzodiazepines. Limitations of this meta-analysis include a lack of high-quality studies, with underpowered or methodologically flawed studies. The specific benzodiazepines, routes of administration, and doses varied among the included studies. Future studies would benefit from evaluating specific medications, doses, and routes. Clinicians may consider administering intramuscular midazolam or another benzodiazepine by an alternative route for patients without existing intravenous access. Editor’s Note: This is a clinical synopsis, a regular feature of the Annals’ Systematic Review Snapshot (SRS) series. The source for this systematic review snapshot is: Alshehri A, Abulaban A, Bokhari R, et al. Intravenous versus nonintravenous benzodiazepines for the abortion of seizures: a systematic review and metaanalysis of randomized controlled trials. Acad Emerg Med. 2017; http://dx.doi.org/10.1111/acem. 13190. 1. Higgins JPT, Green S, eds. Cochrane Handbook for Systematic Reviews of Interventions. Version 5.1.0 (updated March 2011). Cochrane Collaboration; 2011. Available at: http://handbook. cochrane.org. Accessed May 20, 2017. 2. Silbergleit R, Durkalski V, Lowenstein D, et al. Intramuscular versus intravenous therapy for prehospital status epilepticus. N Engl J Med. 2012;366:591-600. 3. Mittal P, Manohar R, Rawat AK. Comparative study of intranasal midazolam and intravenous diazepam sedation for procedures and seizures. Indian J Pediatr. 2006;73:975-978. 4. Arya R, Gulati S, Kabra M, et al. Intranasal versus intravenous lorazepam for control of acute seizures in children: a randomized open-label study. Epilepsia. 2011;52:788-793. 5. Thakker A, Shanbag P. A randomized controlled trial of intranasal-midazolam versus intravenous-diazepam for acute childhood seizures. J Neurol. 2013;260:470-474.
Volume
-,
no.
-
:
-
2017
Systematic Review Snapshot 6. Sillanpaa M, Shinnar S. Status epilepticus in a population-based cohort with childhood-onset epilepsy in Finland. Ann Neurol. 2002;52:303-310. 7. Wu YW, Shek DW, Garcia PA, et al. Incidence and mortality of generalized convulsive status epilepticus in California. Neurology. 2002;58:1070-1076. 8. Gulati S, Kalra V, Sridhar MR. Status epilepticus in Indian children in a tertiary care center. Indian J Pediatr. 2005;72:105-108.
Volume
-,
no.
-
:
-
2017
9. 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;16:48-61. 10. Shorvon S. Clinical trials in acute repetitive seizures and status epilepticus. Epileptic Disord. 2012;14:138-147.
11. Morimoto K, Fahnestock M, Racine RJ. Kindling and status epilepticus models of epilepsy: rewiring the brain. Prog Neurobiol. 2004;73:1-60. 12. Meierkord H, Boon P, Engelsen B, et al. EFNS guideline on the management of status epilepticus. Eur J Neurol. 2006;13:445-450.
Michael Brown, MD, MSc, Jestin N. Carlson, MD, MS, and Alan Jones, MD, serve as editors of the SRS series.
Annals of Emergency Medicine 3