Introduction

Prompt and effective treatment of convulsive status epilepticus in children is a medical emergency. The sooner a prolonged epileptic seizure is stopped the less likely the chance of it evolving into established or prolonged status epilepticus, and the less likely the child will be damaged or require paediatric intensive care, hence the need for out-of-hospital emergency treatment [1].

When intravenous (i.v.) access is not available, rectal diazepam is an effective treatment, with marketing authorisation i.e. has been widely “licensed”, e.g., by the FDA in the USA, since 1997, and the MHRA in the UK since 1982. It is still in use in many countries. In the USA, intramuscular (i.m.) and intranasal midazolam have been licensed just recently in 2022, but in Europe, in line with evolving clinical practice, buccal midazolam has been licensed in the UK by the MHRA since 2006, by the EMA since 2011, and intranasal but not i.m. midazolam since 2022. Furthermore, there is some evidence that buccal midazolam is superior to rectal diazepam in children with acute convulsive epileptic seizures lasting more than 5 minutes [2], and is more cost-effective [3]. A Cochrane review concluded in 2018, after consideration of the published evidence up to May 2017, that while i.v. lorazepam or i.v. diazepam was recommended, in the absence of immediate i.v. access, buccal midazolam or rectal diazepam was the best non-i.v. option in children [4]. All the 12 studies included in this review were undertaken in hospitals, mostly in Emergency Departments.

Much of the literature in this area focuses on the use of intranasal midazolam, which was preferred by carers, in a recent trial, although it was not more effective than buccal, or i.m. midazolam [5].

There is also evidence of the superiority of nasal midazolam compared to rectal diazepam in canine epilepsy [6].

However, we felt that in children febrile seizures are often associated with upper respiratory tract infections and nasal congestion or blockage, rendering intra-nasal administration less reliable than the buccal route [7]. The buccal fossa lies between the teeth and gums and the inside of the cheek, is outside the oral cavity, and therefore safe and accessible in an unconscious child even when the jaw is tightly shut, as can happen in some prolonged epileptic seizures.

We report a small study comparing out-of-hospital emergency seizure treatment given by parents or the usual carers (not paramedics, nurses, or doctors), comparing buccal midazolam and rectal diazepam, to see which is preferred by the parents, and to act as a pilot for a possible future larger efficacy trial.

Materials and methods

Results

Twelve children, three males, aged 2.5–8 (median 5) years at first dose, completed this trial. 10/12 had significant developmental delay or intellectual impairment, recorded in their routine hospital medical records. Each participant had between 2–4 types of epileptic seizures and was taking 2–3 different regular antiseizure medications. Each had been previously on 2–9 (median 3) regular other antiseizure medications in the past. All had had previous convulsive epileptic seizures lasting more than 5 minutes or clusters of seizures without recovering consciousness in between seizures. 5/12 had previously had at least one admission to paediatric intensive care with convulsive status epilepticus.

The first 2 treatments will be reported, one buccal midazolam and the other rectal diazepam, which were given to each child in randomised order.

Each participant received identical doses of buccal midazolam and rectal diazepam; which accounting for their body weight was 0.2–0.4 (median 0.3) mg/kg.

Of the 24 treatment episodes 16 (67%) were at home, 1 was in school, 1 was in public, 2 were in other locations, and 4 were in unspecified locations.

The main outcomes are in Table 1, 9/12 (75%) of parents/guardians preferred buccal midazolam.

Discussion

Although small, and underpowered for efficacy this trial was able to demonstrate a clear preference by parents/guardians for buccal over rectal administration which was statistically significant (P = 0.012). A larger study would be needed to demonstrate a difference in efficacy, however, this parental and caregiver preference is important and has not been demonstrated in a controlled trial before. The therapeutic success achieved with both treatments was in line with other studies, e.g., in paediatric emergency departments [2] and a recent retrospective report of pre-hospital use of buccal midazolam [8]. The lack of respiratory depression (0/24: 95% CI, 0 to 14%) was expected given the small participant numbers.

We regret being unable to secure sufficient funding for a larger trial, however, we have shown that parents and carers can manage this cross-over trial design, and provide satisfactory data for analysis. One advantage of the cross-over design is that each child and parent acted as their own controls so that within each pair the same indications and approach to documentation was used. The cross-over design requires fewer participants than the more common parallel group design.

One disadvantage of the trial design was that the parents/guardians were not blinded. This would have required a double-dummy design, increasing the cost and complexity of the trial which was not feasible.

Given that buccal midazolam is so well established now, in the UK, we doubt that a further larger trial powered for efficacy would find funding or be worth pursuing in the UK. This is to our knowledge the only trial comparing buccal midazolam with rectal diazepam in children, out-of-hospital, administered by trained parents/carers.