This post details some of the pediatric considerations for the management of ongoing status epilepticus. Prior to the completion of the ESETT (Established Status Epilepticus Treatment Trial) study levetiracetam (keppra), fosphenytoin, and valproate (depakote) had equipoise for use as second line therapy after two doses of benzodiazepines in status epilepticus.
Efficacy of levetiracetam, fosphenytoin, and valproate for established status epilepticus by age group (ESETT): a double-blind, responsive-adaptive, randomised controlled trial
Chamberlain et al.
LANCET, March, 2020
The original ESETT trial (published November 2019 in NEJM) included 225 children (<18 years old) among the total of 478 patients in the cohort. The individual groups, children, adults and older adults were all randomized, in a blinded fashion, separately to get levetiracetam, fosphenytoin or valproate. The primary outcome was cessation of clinically apparent seizures with improving mental status at 60 minutes after the start of study drug infusion, without administering other anticonvulsant medications (including medications for intubation). Overall, each agent had an approximately 50% efficacy of refractory status cessation; 52% levetiracetam (95% CI 41%-62%), 49% fosphenytoin (95%CI 38%-61%), and 52% valproate (95%CI 41%-63%). See Tables 2 and 3 below for more details broken down by age.
Since this is a pediatric blog I wanted to share some additional observations and thoughts on the pediatric group.
Primary safety outcomes
There was no difference in life-threatening hypotension within 60 minutes of the start of study drug infusion – 0% levetiracetam, 3% fosphenytoin, and 4% valproate.
No episodes of life-threatening cardiac arrhythmia within 60 min of the start of study drug infusion happened in with any of the drugs in children.
Selected secondary outcomes
There was a higher rate of endotracheal intubation within 60 minutes of the start of study drug infusion in the fosphenytoin group (33%) versus 8% for levetiracetam and 11% in valproate. There was a signifiant difference here – Fisher’s exact test p-value 0.0001. This is interesting given that this was not seen in the EcLIPSE and ConSEPT trials, which compared levetiracetam and fospheytoin.
There was no statistical difference in acute seizure recurrence between 60 minutes and 12 hours after the start of study drug infusion; 9% levetiracetam, 15% fosphenytoin, and 9% valproate
There was no statistical difference in acute respiratory depression at any time in the pediatric age group; 6% levetiracetam, 18% fosphenytoin, 10% valproate.
And finally, there was no difference in mortality in children; 1% levetiracetam, 0% fosphenytoin, 1% valproate.
Two other recent studies (EcLiPSE and ConSEPT trials) in kids only included levetiracetam and fosphenytoin. Additionally, they did not consider administration of another anti epileptic drug in the first hour as treatment failure. Therefore, in a way, ESETT is a more pure comparison of second line therapies. It is clear that in terms of their ability to stop seizures, there is still equipoise, with nary a difference in most clinically significant outcomes. So, you could conceivably choose any of them at your institution, unless there is a contraindication (Dravet syndrome and fosphenytoin, drug allergy, previous treatment failure with one of the drugs).
Interestingly there was a signifiant difference in the need for endotracheal intubation in the fosphenytoin group. As I noted earlier, this wasn’t seen in other studies, and there was also no difference in other outcomes and adverse closely aligned with intubation like respiratory depression, decreased level of consciousness, or length of intensive care unit or hospital stay. The authors concluded that this result was an isolated and unanticipated finding, and therefore it shouldn’t necessarily be a part of your future clinical decision making.
The authors did a good job accounting for their limitations. The most notable is the presence/absence of seizures when patients were enrolled not being confirmed by EEG in the ED because it is impractical and not widely available. They did specify that improved mental status was part of the main outcome, which is important because if you stop seizing, even sub-clinical status, your mental status should get better. So, the lack of availability of a “gold standard” test for “are they seizing?” was buffered appropriately.
All three are reasonable choices for second line therapy in refractory status epilepticus in children
Chamberlain et al. Efficacy of levetiracetam, fosphenytoin, and valproate for established status epilepticus by age group (ESETT): a double-blind, responsive-adaptive, randomised controlled trial. LANCET, March, 2020