Elsevier

The Lancet

Volume 366, Issue 9481, 16–22 July 2005, Pages 205-210
The Lancet

Articles
Safety and efficacy of buccal midazolam versus rectal diazepam for emergency treatment of seizures in children: a randomised controlled trial

https://doi.org/10.1016/S0140-6736(05)66909-7Get rights and content

Summary

Background

Rectal diazepam and buccal midazolam are used for emergency treatment of acute febrile and afebrile (epileptic) seizures in children. We aimed to compare the safety and efficacy of these drugs.

Methods

A multicentre, randomised controlled trial was undertaken to compare buccal midazolam with rectal diazepam for emergency-room treatment of children aged 6 months and older presenting to hospital with active seizures and without intravenous access. The dose varied according to age from 2·5 to 10 mg. The primary endpoint was therapeutic success: cessation of seizures within 10 min and for at least 1 hour, without respiratory depression requiring intervention. Analysis was per protocol.

Findings

Consent was obtained for 219 separate episodes involving 177 patients, who had a median age of 3 years (IQR 1–5) at initial episode. Therapeutic success was 56% (61 of 109) for buccal midazolam and 27% (30 of 110) for rectal diazepam (percentage difference 29%, 95% CI 16–41). Analysing only initial episodes revealed a similar result. The rate of respiratory depression did not differ between groups. When centre, age, known diagnosis of epilepsy, use of antiepileptic drugs, prior treatment, and length of seizure before treatment were adjusted for with logistic regression, buccal midazolam was more effective than rectal diazepam.

Interpretation

Buccal midazolam was more effective than rectal diazepam for children presenting to hospital with acute seizures and was not associated with an increased incidence of respiratory depression.

Introduction

Tonic-clonic seizures requiring emergency drug treatment are a common problem in children, and convulsive status epilepticus causes significant mortality and morbidity.1 Immediate management of a continuing seizure follows the basic principles of emergency care with the role of drug treatment being to terminate the seizure promptly and safely. Ideally, a drug would be easy to give, effective, and safe, and would have a long-lasting antiseizure (anticonvulsant) action.2 Benzodiazepines are often used as first-line drugs,3 but a systematic review reported little supporting evidence for their use.4

Intravenous lorazepam, successfully used in status epilepticus both in the emergency room for children5 and out of hospital for adults,6 might be associated with less respiratory depression and a longer duration of action than diazepam.7 However, intravenous access can be a problem out of hospital or in small children. In these situations, rectal diazepam is the established first-line drug and is effective in 60–80% of patients,8, 9 but with a risk of seizure recurrence10 and respiratory depression.11 Intranasal midazolam has been used to treat acute seizures, but in a prospective study, it effectively controlled the seizure within 15 min in only ten of 20 children.12 For febrile seizures, intranasal midazolam controlled seizures in 23 of 26 children and seems as effective as intravenous diazepam, but treatment failures arose with upper respiratory tract infections.13 Intranasal midazolam has also been used for children with epilepsy14 and might be easier to administer and more effective than rectal diazepam.15, 16

Midazolam can also be given via the buccal or sublingual route. Buccal midazolam is well absorbed17 and might be easier for carers to administer. It stopped 30 of 40 seizures in 14 children with severe epilepsy and seems at least as effective as rectal diazepam for acute seizures.18 It has proved effective across a range of ages.19 The purpose of this study was to compare the efficacy and safety of buccal midazolam with rectal diazepam for treatment of children presenting to the hospital emergency room with an acute seizure.

Section snippets

Trial design and participants

Eligible children were those aged 6 months and older, who presented to the emergency room of one of the four participating hospitals (Alder Hey Children's Hospital, Liverpool; Derbyshire Children's Hospital; Queen's Medical Centre Nottingham; and Birmingham Children's Hospital) still having a seizure, who did not already have established intravenous access. Children who had chronic epilepsy or who had been given prehospital emergency or rescue treatment were not excluded from the trial. It was

Results

Study recruitment was from October, 2000, to February, 2004. Appointment of a research nurse coordinator in Derbyshire Children's Hospital and a research nurse at Alder Hey Children's Hospital enabled recruitment to start at an early stage in these centres. Consent was obtained for 219 separate episodes (123 [56%] male) involving 177 patients (98 [55%] male; table 1). Of the 42 patients recruited more than once, seven were recruited again within a week and four within a month, the remainder

Discussion

Our results show that buccal midazolam is more effective than rectal diazepam for treatment of children with seizures in a hospital emergency department, and does not appear to increase the risk of respiratory depression. Intravenous access is not always possible for administration of emergency anticonvulsant treatment for the children having a seizure, and an effective and safe alternative is frequently required. Traditionally, this has been the rectal route for diazepam and more recently the

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