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Three Part Question

In [children with prolonged seizures] does [buccal midazolam or rectal diazepam] lead to [quicker resolution of seizures]?

Clinical Scenario

A 4 year old boy presenting to Emergency department with high pyrexia of 39.5C and on going generalised clonic tonic seizure. No IV access is immediately obtainable. You have identified that the child requires urgent first line treatment for initial seizure control.

Search Strategy

Ovid MEDLINE(R) 1950 to December Week 4 2009 using the OVID interface. Medline: [Child OR children OR adolescence] AND [epilepsy OR seizure OR seizures OR fit OR fits OR status epilepticus OR febrile convulsion OR convulsions OR convulsion] AND [rectal diazepam OR PR diazepam] AND [mouth mucosa midazolam OR buccal midazolam]. Limited to Human AND English language
(((((((Child or children or adolescence) and epilepsy) or seizure or seizures or fit or fits or status epileptius or febrile convulsion or convulsions or convulsion) and rectal diazepam) or PR diazepam) and mouth mucosa midazolam) or buccal midazolam).af.

Search Outcome

Medline: 35 papers were identified, 4 were relevant to the three part question. 1 of the 4 relevant papers was only available as an abstract via NHS Scotland E-library.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Baysun S. Aydin OF. Atmaca E. Gurer YK. 2005 Nov-Dec Turkey	43 children aged 2 months to 12 years seen in emergency department Even days: Midazolam Odd days: diazepam	Comparative study	Termination of seizure in 10mins	Midazolam group 18/23 (78%); diazepam group 17/20 (85%) patients terminated Not Statistically different (p>0.05)	Abstract only available online Small sample size Not fully randomised sample
McIntyre J. Robertson S. Norris E. Appleton R. Whitehouse WP. Phillips B. Martland T. Berr 2005 July UK	219 seizure episodes in 177 young people; 7 months- 15 years. Median age 3. Seen in emergency department	Multi-centre RCT	Cessation of seizures within 10mins and for at least 1 hr without respiratory depression requiring intervention	(61/109) 56% for buccal midazolam and (30/110) 27% for rectal diazepam (% difference 29%, 95% CI 16-41). Median time for cessation of seizure; 8 min for buccal midazolam and 15min for rectal diazepam (p=0.01 95% CI 0.5-0.9) The rate of respiratory depression did not differ between groups	Emergency prehospital treated patients and patients with chronic epilepsy were excluded. No statistical calculations for respiratory depression rate.
Mpimbaza A. Ndeezi G. Staedke S. Rosenthal PJ. Byarugaba J. 2008 Jan Uganda	330 patients aged 3 months -12 years treated in acute care unit Randomised to receive either rectal diazepam and buccal placebo OR rectal placebo and buccal midazolam	Single blinded RCT	Cessation of seizures within 10mins, without recurrence in 1hr.	Treatment failure occurred in 71/165 (43%) in diazepam group compared with 50/165 (30.3%) in midazolam group (p=0.016). No statistical difference in malaria-related seizure. For children without malaria, buccal midazolam was superior (d=55.9% vs m=26.5%) (P=.002)	Study team is aware of treatment randomisation code, introducing bias of interpretation. Population not representative to UK population due to high incidence of malaria related seizures Small sample size in non-malaria related seizure group
Scott RC. Besag FM. Neville BG. 1999 Sep UK	79 seizures episodes in 24 young people aged 5-22 years with severe epilepsy living at a residential centre	RCT	Termination of seizure within 10mins	Response to midazolam in 30/40 (75%) ; rectal diazepam in 23/39 (59%) (P=0.016	Lack of power calculations Small sample size Two patient accounted for nearly half the episodes of seizures in study
			Mean time to termination of seizures	6 mins for midazolam & 8 mins for diazepam (P=0.31)

Comment(s)

Emergency treatment for prolonged tonic-clonic seizures has long involved early administration of benzodiazepine drugs, for example, diazepam via the rectal route or lorazepam via intravenous route where available. The efficacy of the intranasal or buccal midazolam have been debated more recently and shown to be effective in seizure cessation, although intranasal administration has only demonstrated variable success and was found to be ineffective in children with concurrent upper respiratory tract infections (McIntyre et al.). Buccal midazolam can be easily administered during on-going seizure activities, and the large surface area of the buccal mucosa allows the drug to be well absorbed into the systemic circulation, thus avoiding high first-pass metabolism. It also carries a lesser degree of social stigma compared to drugs given via the rectal route. The evidence presented from the UK multi-centre randomised control trial and the Ugandan single-blinded randomised control trial concurred that buccal midazolam is more effective than rectal diazepam in children presenting to hospital with acute seizures (McIntyre et al, Mpimbaza et al.). However, the subject sample in the Ugandan study is not representative to the UK population as its main cause of seizure was malaria, and the non-malaria related seizure group were too small to warrant any definitive conclusion.

Editor Comment

This is an update of BET 683

Clinical Bottom Line

Clinical Bottom Line Buccal midazolam is currently the recommended alongside rectal diazepam as the first-line treatment for prolonged seizure in children without immediate intravenous access and it has been shown to be more efficacious than rectal diazepam when used in the emergency department.

References

1. Baysun S. Aydin OF. Atmaca E. Gurer YK.; A comparison of buccal midazolam and rectal diazepam or the acute treatment of seizures; Clinical Pediatrics. Clinical Pediatrics 44(9):771-6, 2005 Nov-Dec
2. McIntyre J. Robertson S. Norris E. Appleton R. Whitehouse WP. Phillips B. Martland T. Berry K. Collier J. Smith S. Choonara I. Safety and efficacy of buccal midazolam versus rectal diazepam for emergency treatment of seizures in children: a randomised controlled trial Lancet 366(9481):205-10, 2005 Jul 16-22.
3. Mpimbaza A. Ndeezi G. Staedke S. Rosenthal PJ. Byarugaba J. Comparison of buccal midazolam with rectal diazepam in the treatment of prolonged seizures in Ugandan Children: A Randomised clinical trial Pediatrics 2008; 121;e58-e64
4. Scott RC. Besag FM. Neville BG. Buccal midazolam and rectal diazepam for treatment of prolonged seizures in childhood and adolescence: a randomised trial Lancet. 1999 Feb 20;353(9153):623-6.
5. Body R, Ijaz M. Buccal midazolam as an alternative to rectal diazepam for prolonged seizures in childhood and adolescence[Online] BestBETs 2005