Diazepam as Effective as Lorazepam for Pediatric Status Epilepticus

There’s no apparent difference in efficacy or safety between anti-epileptic drugs diazepam and lorazepam in treating pediatric status epilepticus (SE)-a finding that challenges the results of some studies.

In fact, the only statistically significant difference found in a recent study of patient outcomes was a modest increase in sedation rates for patients given lorazepam, according to new research published in the Journal of the American Medical Association.¹

In the double-blind study led by James M. Chamberlain, MD, emergency division chief at Children’s National Hospital in Washington, DC, researchers analyzed outcomes in 273 children, aged 3 months to 18 years, who presented with SE at emergency rooms in 11 participating hospitals. 

[[{"type":"media","view_mode":"media_crop","fid":"25694","attributes":{"alt":"James M. Chamberlain, MD (Children's National Health System photo)","class":"media-image media-image-right","id":"media_crop_4873788030637","media_crop_h":"0","media_crop_image_style":"-1","media_crop_instance":"2391","media_crop_rotate":"0","media_crop_scale_h":"0","media_crop_scale_w":"0","media_crop_w":"0","media_crop_x":"0","media_crop_y":"0","style":"height: 151px; width: 110px; float: right; margin: 5px;","title":"James M. Chamberlain, MD (Children's National Health System photo)","typeof":"foaf:Image"}}]]The results showed efficacy at eliminating seizure activity within 10 minutes of IV dosage with no recurrence for at least 30 minutes in 101 (72.1%) of 140 patients in the diazepam cohort and in 97 (72.9%) of 133 patients in the lorazepam cohort. In each cohort, a second IV dosage equal to half the original dose was given 5 minutes after the first if seizure activity persisted at that time. Patients who did not respond to 2 doses of the study medication were given IV fosphenytoin or phenytoin. 

The dependent primary safety outcome variable was defined as the need for assisted ventilation at any point within 4 hours of dosage. Twenty-six patients in each group required assisted ventilation (16% of diazepam recipients and 17.6% of lorazepam recipients, respectively). This difference was not statistically significant.

Previous research has given some indication that lorazepam may be a superior choice in resolving SE in studies involving adults, although Chamberlain cautioned in an interview that “it is not clear that lorazepam is superior to diazepam in adults. Some studies suggest this but it is not definitive.”

Still, enough evidence had accumulated to justify his hypothesis that lorazepam could outperform diazepam in pediatric cases, which he and his colleagues sought to confirm in this study.

“Benzodiazepine medications are more effective overall in children than in adults, probably because the causes of seizures are different,” Chamberlain said. “Therefore, demonstrating a difference is going to be more difficult because both medications [lorazepam and diazepam] will be more effective.”

In spite of the difficulty, his hypothesis concurred with the earlier studies in adults. “We expected lorazepam to be more effective and safer,” he said.

The absence of any statistically significant difference between the efficacy and safety of the two drugs was not inherently a disappointing outcome for the researchers. 

“I think what’s important now is what’s available and what can you get into the child as fast as possible,” Chamberlain said. “In the case where you can’t get an IV started, you’d probably want to use rectal diazepam or intramuscular midazolam.”

There was a modest difference in sedation rates between the two study cohorts: 16.9% more patients in the lorazepam cohort experienced experienced sedative effects. 

In 2012, Chamberlain and colleagues² published a study that examined safe dosages for lorazepam in pediatric SE; in that study, no excessive sedation rates were associated with the drug. Referring to the current results, Chamberlain noted that “although the differences [in sedation] were statistically different, they are probably not clinically significant.”

“Lorazepam patients took, on average, about 15 minutes longer to return to baseline mental status. This is not clinically important,” he said. 

The results still leave some potential for second-guessing. Study authors noted in their discussion that “the confidence intervals suggest that one medication could be superior in efficacy by as much as approximately 10% to 11% and in safety by approximately 7% to 10%.” However, Chamberlain currently has his eye on other questions raised by his research.

“Almost 30% of children failed treatment,” he said. “That number is higher in adults. Our next study will look at the best medication for patients who do not stop seizures with the benzodiazepines. We are working with our adult colleagues to perform a study called the Established Status Epilepticus Treatment Trial (ESETT), which will answer this question.”

References

1. Chamberlain JM, Okada P, Holsti M, et al. Lorazepam vs diazepam for pediatric status epilepticus: a randomized clinical trial. JAMA. 2014;311:1652-1660.
http://jama.jamanetwork.com/article.aspx?articleid=1861799.

2. Chamberlain JM, Capparelli EV, Brown KM. Pharmacokinetics of intravenous lorazepam in pediatric patients with and without status epilepticus. J Pediatr. 2012;160:667-672.
http://www.jpeds.com/article/S0022-3476(11)00962-0/abstract.