Elsevier

The Lancet

Volume 367, Issue 9522, 13–19 May 2006, Pages 1591-1597
The Lancet

Articles
Efficacy and safety of intranasal lorazepam versus intramuscular paraldehyde for protracted convulsions in children: an open randomised trial

https://doi.org/10.1016/S0140-6736(06)68696-0Get rights and content

Summary

Background

In sub-Saharan Africa, rectal diazepam or intramuscular paraldehyde are commonly used as first-line anticonvulsant agents in the emergency treatment of seizures in children. These treatments can be expensive and sometimes toxic. We aimed to assess a drug and delivery system that is potentially more effective, safer, and easier to administer than those presently in use.

Methods

We did an open randomised trial in a paediatric emergency department of a tertiary hospital in Malawi. 160 children aged over 2 months with seizures persisting for more than 5 min were randomly assigned to receive either intranasal lorazepam (100 μg/kg, n=80) or intramuscular paraldehyde (0·2 mL/kg, n=80). The primary outcome measure was whether the presenting seizure stopped with one dose of assigned anticonvulsant agent within 10 min of administration. The primary analysis was by intention-to-treat. This study is registered with ClinicalTrials.gov, number NCT00116064.

Findings

Intranasal lorazepam stopped convulsions within 10 min in 60 (75%) episodes treated (absolute risk 0·75, 95% CI 0·64–0·84), and intramuscular paraldehyde in 49 (61·3%; absolute risk 0·61, 95% CI 0·49–0·72). No clinically important cardiorespiratory events were seen in either group (95% binomial exact CI 0–4·5%), and all children finished the trial.

Interpretation

Intranasal lorazepam is effective, safe, and provides a less invasive alternative to intramuscular paraldehyde in children with protracted convulsions. The ease of use of this drug makes it an attractive and preferable prehospital treatment option.

Introduction

Acute protracted convulsions in children are one of the most common medical emergencies in sub-Saharan Africa. In areas with endemic malaria and a heavy burden of infectious diseases, including bacterial meningitis, and where resources are scarce, the incidence of seizures is many times greater than in well-resourced countries.1 Timely interventions are necessary to maintain cardiorespiratory function, stop the seizure, and diagnose and treat the underlying disorder. Failure to provide such interventions could lead to a protracted seizure episode that is more difficult to control, increasing the likelihood of death or long-term neurological sequelae.2, 3

In the prehospital setting in developed countries, rectal diazepam is the most commonly used first-line agent in childhood seizures. However, concerns over social acceptability and convenience of rectal administration have led to a search for alternatives. Two randomised trials have shown buccally-administered midazolam is better than, or at least as effective as, rectal diazepam in childhood seizures.4, 5

In developing countries, the context of care and the challenges faced in medical emergencies are different from those in developed countries. Patients often present late in an illness because of an absence of organised prehospital emergency services, the cost of transport, and the distances to travel. Many seizures at presentation are protracted and need several doses of anticonvulsant agents to be controlled. The risks of benzodiazepine-induced respiratory depression are substantial if the drug is given in excessive doses or in combination with other sedative agents, especially when provision of oxygen therapy might be scarce, or skills and resources for short-term ventilatory assistance are unavailable.6 Seizures are frequently due to acute central nervous or severe systemic infections, whereas in developed countries protracted febrile convulsions or poorly controlled idiopathic recurrent seizures are most common.5 The risk of recurrent seizures is great, and seizures might take place on wards that are inadequately staffed to monitor and manage them. Resource limitations reduce the availability of equipment such as appropriately sized cannulae, and so emergency therapy is often delivered by non-intravenous routes.

The ideal first-line anticonvulsant agent would be one that can be given safely and easily at a primary health-care facility. The anticonvulsant should be quick acting, have minimum cardiorespiratory side-effects, have a longlasting effect, and be inexpensive.

In view of its favourable pharmacokinetics and potential practical advantages, we wished to assess the efficacy and safety of intranasal delivery of lorazepam compared with intramuscular paraldehyde, which is our first-line anticonvulsant agent in the treatment of acute seizures in children.

Section snippets

Patients

Between July, 2004, and June, 2005, we did an open randomised trial comparing the efficacy and safety of intranasal lorazepam with intramuscular paraldehyde in consecutive patients with acute seizures presenting to the paediatric emergency department at the Queen Elizabeth Central Hospital, a teaching and referral hospital in Blantyre, southern Malawi. Participants were children aged between 2 months and 12 years who presented with generalised convulsions continuing for a minimum of 5 min.

Results

All 160 children randomised were followed up with no protocol violations by the end of the study. Of the 42 children excluded, most (29 episodes) stopped convulsing before randomisation and their convulsions were attributed to fever or hypoglycaemia (figure 2). Between treatment groups, children were similar for sex, age, median seizure duration pretreatment, median time to drug delivery, underlying cause, and HIV status. Seizures were exclusively due to acute brain infection secondary to

Discussion

Intranasal lorazepam stopped three-quarters of the presenting seizures in less than 10 min. Intramuscular paraldehyde was effective in two-thirds of children within 10 min. This difference was not significant, although significantly fewer patients receiving intranasal lorazepam needed two or more rescue anticonvulsant agents than did those who received paraldehyde. There were no clinically important cardiorespiratory events, suggesting both treatment options were safe. There were fewer

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