ArticlesBuccal midazolam and rectal diazepam for treatment of prolonged seizures in childhood and adolescence: a randomised trial
Introduction
The search for new treatments for status epilepticus is justified by substantial associated morbidity and mortality.1 Convulsive status epilepticus is common2 and potentially harmful.1, 3, 4, 5 There are at least 25 000 episodes of convulsive status epilepticus every year in the UK, with the highest incidence among children.2 The primary determinants of outcome from convulsive status epilepticus are underlying aetiology and seizure duration.1, 3, 4, 5 Early treatment of seizures may decrease mortality and morbidity.6 Transfer of a child from home to hospital by ambulance can delay treatment substantially. If treatment is delayed, the chances of successful response to a single medication is lessened.7 This finding implies that early treatment of seizures in the community with drugs that can be administered by non-medical staff should be beneficial. Prompt treatment leads to fewer drugs being required in hospital and the overall seizure length is generally shorter.7, 8 Rectal diazepam is the most commonly used medication before admission to hospital. The rectal route of administration is not, however, always acceptable or convenient. Many teachers, parents, and carers are reluctant to administer rectal medication for fear of allegations of sexual abuse. An effective treatment that can easily be administered by a more convenient route is therefore needed.
Buccal midazolam may offer a suitable alternative to rectal diazepam. The mouth and the rectum have similar surface areas and pH, have rich blood supplies, and absorption is directly into the systemic circulation, which avoids high first-pass metabolism.9 A pharmacokinetic study in healthy adult volunteers showed that midazolam is quickly absorbed into venous blood and has a rapid effect on the central nervous system, shown on electroencephalography.10 Midazolam is effective in the treatment of acute repetitive seizures, with 80% of the episodes ending within 10 min of buccal administration.11
Status epilepticus is a seizure or a series of seizures that lasts for 30 min or more, without complete recovery of consciousness. If a seizure is continuing after 5 min it will commonly continue for at least 30 min unless treatment is given. Children who have seizures for 5 min or longer are likely to be in the early stages of convulsive status epilepticus and should be treated quickly. We aimed to find out whether efficacy and adverse events differ between buccal administration of liquid midazolam and rectal administration of liquid diazepam in the acute treatment of seizures.
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Patients
We enrolled students from St Piers Lingfield, Lingfield, Surrey, a residential centre for children and young people with severe epilepsy and other needs, including learning difficulties. The centre has full-time medical and nursing staff on site. 224 students attend, aged 5–22 years. One of the major difficulties in researching management of status epilepticus has been obtaining consent. We enrolled students who had previously received rectal diazepam as an emergency treatment for acute
Methods
The unit of randomisation was the seizure. Sealed, unmarked, identical envelopes that contained the name of the drug to be administered were randomised by shuffling. A box containing diazepam and midazolam and the randomisation envelopes was kept in the on-site medical centre. Care and teaching staff were informed which students had been enrolled into the study. When one of these students had a seizure that lasted at least 3 min, the medical centre was contacted. The on-duty nurse took the
Results
Students did not differ significantly for sex, age, seizure type, or seizure frequency at baseline with respect to medication prescribed (table 1). 40 episodes in 14 patients were treated with buccal midazolam, and 39 episodes in 14 patients with rectal diazepam. A breakdown of the treated seizures by type is shown in table 2. Response to midazolam occurred in 30 (75%) of 40 episodes. Response to rectal diazepam occurred in 23 (59%) of 39 episodes (p=0·16). In analysis of the episodes as
Discussion
This study was done in a special residential centre for children with epilepsy and all of the students enrolled had severe epilepsy that was difficult to treat. The setting and facilities, with on-site medical and nursing staff, made this study possible. Because of difficulties with obtaining consent, randomised controlled trials of treatments administered outside hospitals for status epilepticus are seldom undertaken. Overall, we found no significant differences between the drugs for efficacy,
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Cited by (325)
A Phase 3 open-label study of the efficacy, safety and pharmacokinetics of buccally administered midazolam hydrochloride for the treatment of status epilepticus in pediatric Japanese subjects
2021, Epilepsy ResearchCitation Excerpt :Furthermore, rectal administration of drugs to a child in convulsive SE can be challenging and may not be convenient or socially acceptable. To address the need for an easy to use, fast-acting anti-epileptic agent without the limitations of IV and rectally-administered drugs, midazolam hydrochloride oromucosal solution (MHOS) was developed, which allows rapid absorption of midazolam directly from the buccal cavity (Scott et al., 1999). Three pivotal studies have compared buccal MHOS with rectal diazepam; they concluded that buccal MHOS had a similar safety profile to rectal diazepam, and was more convenient and at least as effective (McIntyre et al., 2005; Mpimbaza et al., 2008; Scott et al., 1999).
Brian George Richard Neville
2021, Child Neurology: Its Origins, Founders, Growth and EvolutionThe neurology-psychiatry interface in epilepsy
2021, Irish Journal of Psychological Medicine