Source: Klowak JA, Hewitt M, Catenacci V, et al. Levetiracetam versus phenytoin or fosphenytoin for second-line treatment of pediatric status epilepticus: a meta-analysis. Pediatr Crit Care Med. Published online March 10, 2021.
Study Population: 1,575 children (<18 years of age) with status epilepticus who failed benzodiazepine therapy for seizure cessation
Efficacy Endpoints: Time from intervention to seizure cessation, early seizure cessation (within 20-40 minutes of intervention), and late seizure cessation (within 1-3 hours)
Harm Endpoints: Failure of response (seizure recurrence or need for third-line antiepileptic medication), pediatric intensive care unit admission, intubation, and development/neurocognitive assessment after hospital discharge, hypotension, respiratory depression, arrhythmia, acute behavioral change, extravasation, drug-related severe adverse event, and death
Narrative: Status epilepticus, defined by continuous seizure activity for at least 5 minutes or recurrent seizures without a return to baseline, is a neurologic emergency.1, 2, 3 The annual incidence in children approximates 20 per 100,000 population.4 Unfortunately, a significant portion of children presenting with status epilepticus can experience long-term neurologic, cognitive, or behavior abnormalities;5 therefore, rapid treatment is essential.3 While benzodiazepines are considered first-line treatment, they fail to stop seizure activity in approximately one-third of patients.6, 7 Common second-line agents include phenytoin, its prodrug fosphenytoin, and levetiracetam.6, 7, 8, 9
The meta-analysis summarized here examined data from randomized controlled trials (RCTs) comparing levetiracetam with phenytoin or fosphenytoin for status epilepticus refractory to at least one dose of benzodiazepine.10 Authors included data from trials enrolling primarily patients under age 18 years, or else reported the results of a pediatric subgroup from trials enrolling patients of all ages. The three main endpoints included overall time from intervention to seizure cessation, early seizure cessation (within 20-40 minutes), and late seizure cessation (within 1-3 hours). Additional outcomes included medication failure (seizure recurrence or need for thirdline medication), requirement for pediatric intensive care unit admission, and neurocognitive function after hospital discharge. Major safety outcomes included hypotension, intubation, arrhythmia, and death.
Seven relevant RCTs (n=1,575) were identified and their data pooled. Mean patient age ranged from 2.3 to 6.1 years. Four studies used phenytoin and 3 studies used fosphenytoin. There was no difference between levetiracetam and the comparator for any measure of seizure cessation. There was also no difference in failure of response, pediatric intensive care unit admission, intubation, and drug-related severe adverse events.
Caveats: There are several limitations associated with this meta-analysis.10 First, seizure etiology varied, including central nervous system infection, cryptogenic seizure, epilepsy, and febrile seizure. Over 75% of patients experienced generalized seizures, the remainder experienced focal seizures. While the meta-analysis protocol was pre-registered, three included RCTs were not. Trials varied in reporting and definition of primary outcomes. Moreover, evaluating timing of seizure cessation is complicated by the different infusion durations of the agents. Dosing of levetiracetam also differed between studies, ranging from 20 mg/kg to 60 mg/kg, with infusion durations of 5-20 minutes. Authors of this meta-analysis defined a minimal important difference as 5 minutes for seizure cessation, and thus deemed a 3.1-minute difference between groups as clinically nonsignificant, a threshold that could be debated.
In addition, analysis of safety outcomes such as respiratory depression suffered from heterogeneity, imprecision, and low certainty evidence. This resulted in the outcome ‘intubation’ being no different between groups in 5 trials, while ‘respiratory depression’, theoretically defined by the need for intubation, was slightly (about 4%) more common with phenytoin—a difference driven by results from a single trial.11 Therefore, we did not present the number-needed-to-harm for respiratory depression/intubation reported by the meta-analysis.
The Established Status Epilepticus Treatment Trial (ESETT), included in the meta-analysis, may be the most reliable evidence on second-line anticonvulsants for generalized convulsive status epilepticus.11 Its inclusion in pooled data is a bit fraught, however, as the trial compared three agents, not two, and was then extended, by over a year, for additional pediatric enrollments. Of the three large multicenter efforts that together contributed nearly 80% of the data in the metaanalyses, ESETT and one other trial utilized a double-blinded design.11, 12 This other trial also evaluated three arms, including phenytoin, valproate, and levetiracetam in 110 patients age 3 months to 12 years.12 All other included trials were open label with two arms. ESETT compared levetiracetam, fosphenytoin, and valproate for patients > 2 years of age with status epilepticus who continued to seize despite receiving benzodiazepines.11 Approximately half of the 462 subjects in each arm achieved the primary endpoint (seizure cessation <60 minutes), with no difference between groups. The safety outcomes of life-threatening hypotension and cardiac arrhythmia were rare and did not differ by treatment group. However, in children (n=225), endotracheal intubation appeared to occur more in the fosphenytoin group (33%) than the levetiracetam (8%) or valproate group (11%).11, 13 As the authors note, this was a secondary outcome measured in a subgroup, and suggests a safety concern of unclear significance, not found in any other setting or by any other research group.
Based on the available evidence, the review summarized here found levetiracetam compared to phenytoin or fosphenytoin was associated with similar time to seizure cessation and a similar safety profile. Because of similarity in efficacy and safety profiles, we have assigned a color recommendation of Yellow (similar efficacy and safety profiles). One reasonable conclusion from the data is that levetiracetam is not superior to phenytoin/fosphenytoin in the acute setting. Whether they are truly equivalent would require equivalence (non-inferiority) trials, which have yet to be done. However no clinically important safety or efficacy differences were found in the trials data reviewed. For patients with benzodiazepine-refractory status epilepticus, existing data suggest that levetiracetam and phenytoin are both reasonable agents.
The original manuscript was published in Academic Emergency Medicine as part of the partnership between TheNNT.com and AEM.
Author: Brit Long, MD; Michael Gottlieb, MD
Supervising Editors: Shahriar Zehtabchi, MD
Published/Updated: June 16, 2021
The title bar is color-coded with our overall recommendation.