Efficacy and safety of intranasal lorazepam versus intramuscular paraldehyde for protracted convulsions in children: an open randomised trial
Ahmad S, Ellis JC, Kamwendo H, Molyneux E;
Commented by , 24 Aug 2006
Background
Acute prolonged seizures require prompt treatment to reduce associated mortality and morbidity. In many resource-restricted countries, intramuscular (i.m.) paraldehyde is used as first line therapy when an intravenous (i.v.) access is unavailable (ref. 1, ref. 2, ref. 3). Transmucosal delivery of a benzodiazepine may provide a better alternative.
Aim
To compare intranasal lorazepam with i.m. paraldehyde as first line treatment of acute prolonged seizures in children.
Methods
- in an open-label trial, 160 children presenting with generalized convulsions of >5 min duration at an emergency department in Malawi were randomized to receive i.m. paraldehyde (0.2 ml/kg) or intranasal lorazepam (100 micrograms/kg, squirted into a nostril through a mucosal atomization device)
- primary endpoint was cessation of convulsions within 10 min
- if seizures persisted at 10 min, rescue paraldehyde (0.2 ml/kg) was given. Phenobarbitone was used as second rescue if seizures persisted at 20 min.
Results
- median age of the children was 19 months; most had acute brain infection, especially cerebral malaria or bacterial meningitis. Median seizure duration at time of treatment was 2 hours
- cessation of seizures within 10 min occurred in 75% of children with intranasal lorazepam and 61% with i.m. paraldehyde (p=0.06)
- 10% in the lorazepam group needed at least 2 rescue anticonvulsants, compared with 26% in the paraldehyde group (p=0.007)
- no major adverse cardiorespiratory events were recorded.
Professor Perucca's comments
I.m. paradehyde is effective to treat acute seizures (ref. 1, ref. 2, ref. 3), but it can result in sciatic nerve injury, skin sloughing and sterile abscesses (ref. 4). In the developed world, benzodiazepines are the preferred treatment: when the i.v. route is unavailable, diazepam can be given rectally, while midazolam can be given intramuscularly, buccally and intranasally (ref. 5, ref. 6, ref. 7, ref. 8).
Lorazepam is the benzodiazepine of choice for the i.v. treatment of status epilepticus ref. 9,, ref. 10), partly because its action is longer than that of diazepam or midazolam (ref. 5). Lorazepam is absorbed rapidly after nasal administration (ref. 11), but it had not been previously tested by this route in the acute seizure setting.
The results of this study suggest that intranasal lorazepam is effective and safe to treat children with prolonged seizures due mostly to acute brain infection. Intranasal lorazepam may have advantages over i.m. paraldehyde:
- it is non-invasive
- it is cheaper and
- it seems to be more effective, even though in this study assessment of response was suboptimal because the EEG was not monitored to exclude residual subclinical ictal activity.
Children given lorazepam needed less frequently two or more rescue anticonvulsants compared with those given initially paraldehyde. This might reflect a greater effectiveness of lorazepam, but could also be due to the protocol requiring use of i.m. paraldehyde as first rescue medication (which might not have been the best choice in the subgroup that already failed a first dose of paraldehyde).
The authors suggest that intranasal lorazepam may be preferable for pre-hospital treatment, even though it was not tested in this setting. The need for an atomization device, and the fact that lorazepam injectable solution needs to be stored at 2-8°C might be problematic outside the hospital setting in resource-restricted countries (ref. 12).
Irrespective of the anticonvulsant agent to be preferred, management strategy in these countries should be directly primarily in shortening the delay before treatment onset. In this study, children convulsed for a median of 2 hours before receiving medical attention, possibly due to inadequate access to health services and lack of information about the need for rapid intervention. Strategies to prevent underlying causes of seizures, e.g., malnutrition, malaria, are also essential.
Intranasal lorazepam could also be of value for the pre-hospital treatment of acute seizures in the developed world. Randomized studies may be conducted to compare its effectiveness with other treatments such as rectal diazepam and intramuscular, buccal and intranasal midazolam. These studies should address not only its efficacy in stopping seizure activity, but also seizure recurrence rates after initial control.
The possibility of potentially impaired absorption in children with nasal infection, inflammation and ictal mucus production also needs to be explored.
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