DALLAS – Contrary to expectation, lorazepam and diazepam displayed similar efficacy and safety for treatment of pediatric status epilepticus in a definitive head-to-head randomized controlled trial.
"Both medications are efficacious 70% of the time and both have rates of respiratory depression below 20%. These results contrast with retrospective studies which suggested lorazepam was more effective. The results of our trial suggest that logistic considerations such as need for refrigeration and medication availability rather than concerns about efficacy should influence the choice of benzodiazepine for pediatric status epilepticus," Dr. Jill M. Baren declared at the annual meeting of the Society for Academic Emergency Medicine.
Surveys show that 80% of neurologists have a preference for lorazepam over diazepam on the basis of single-center retrospective studies that reported lorazepam to be more effective in terminating convulsions, with less respiratory depression and a longer duration of action. On the downside, lorazepam, unlike diazepam, is not stable at room temperature. And it is not approved by the Food and Drug Administration for pediatric status epilepticus, so its use there is off label.
Because lorazepam hadn’t been well studied in children, Congress identified it as a high-priority drug in the Best Pharmaceuticals for Children Act. That was the impetus for Dr. Baren and her colleagues in the Pediatric Emergency Care Applied Research Network to conduct their randomized, double-blind, controlled clinical trial involving 273 children and adolescents who presented with convulsive status epilepticus at 14 U.S. and Canadian medical centers. They received either 0.1 mg/kg of IV lorazepam or 0.2 mg/kg of diazepam delivered over a 1-minute push. Half of the initial dose could be repeated at 5 minutes if necessary.
The primary efficacy outcome was cessation of status epilepticus by 10 minutes with no recurrence by 30 minutes. This was achieved in 72.1% of the diazepam group and 72.9% on lorazepam. The primary safety outcome – need for assisted ventilation within 4 hours of giving the study drug – occurred in 16% of the diazepam group and 17.6% of patients on lorazepam, reported Dr. Baren of the University of Pennsylvania, Philadelphia.
Rates of nearly all the prespecified secondary outcomes also were closely similar in the two groups. For example, 62% of patients were successfully treated with a single dose of diazepam, as were 60% on lorazepam. Generalized convulsions recurred within 60 minutes in 11% of the diazepam group and 10% on lorazepam. Response latency averaged 2.5 minutes with diazepam and 2.0 minutes with lorazepam.
Statistically significant differences were seen in only two secondary endpoints. Fifty percent of the diazepam group needed to be placed in deep sedation, compared with 67% of the lorazepam group. And sedation recovery time averaged 104 minutes in the diazepam group versus 120 minutes with lorazepam.
Dr. Baren said that the results of this study, considered together with the findings of the landmark Rapid Anticonvulsant Medication Prior to Arrival Trial (RAMPART), which demonstrated that intramuscular midazolam was comparable in effectiveness to IV lorazepam for pediatric status epilepticus (N. Engl. J. Med. 2012;366:591-600), provide persuasive evidence that any of the three benzodiazepines can be considered acceptable first-line therapy.
"Future research should focus on the development of agents for seizure control in patients with benzodiazepine-refractory seizures and high risk of respiratory failure," she concluded.
Roughly 10,000 children per year in the United States experience status epilepticus. Rapid control is key in order to avoid acute life-threatening complications along with permanent neuronal injury.
This randomized trial was funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and carried out by the Pediatric Emergency Care Applied Research Network, which is supported by the Department of Health and Human Services. Dr. Baren reported having no financial conflicts.