Randomized Controlled Trial Evaluating Levetiracetam as First-line Therapy for Seizures in Neonates
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Randomized Controlled Trial Evaluating Levetiracetam as First-line Therapy for Seizures in Neonates Source Citation: Sharpe C, Reiner GE, Davis SL, Nespeca M, Gold JJ, Rasmussen M, et al. Levetiracetam versus phenobarbital for neonatal seizures: A randomized controlled trial. Pediatrics. 2020;145(6): e20193182.
SUMMARY
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This multicenter, randomized, blinded, controlled, trial investigated the efficacy and safety of levetiracetam compared with phenobarbital as a preferred treatment for neonatal seizures of any cause. The primary outcome variable was complete seizure freedom for 24 hours, assessed by independent review of the EEGs by 2 experts. Eighty percent of patients randomly assigned to phenobarbital remained seizure free for 24 hours, compared with 28% of patients randomly assigned to levetiracetam (P, .001; relative risk 0.35 [95% confidence interval: 0.22-0.56]; modified intention-to-treat population). A 7.5% improvement in efficacy was achieved with a dose escalation of levetiracetam from 40 to 60 mg/kg. More adverse effects were seen in subjects randomly assigned to phenobarbital (not statistically significant). The authors concluded that phenobarbital was more effective than levetiracetam for the treatment of neonatal seizures and higher rates of adverse effects were seen with phenobarbital treatment.
Allocation concealment: The random sequence was communicated to pharmacies of the participating institutions, who prepared identical appearing levetiracetam and phenobarbital injections (such that the same volume would be injected, whichever drug was used). However, it is not clear whether sequentially numbered injections were provided to treating physicians, or they had to use other means such as opening sealed envelopes to identify the allocation. Blinding: The pharmacies prepared both medications so that identical volume would be injected in both treatment arms. However, the method of ensuring similar appearance of the medication was not specified. The investigators mentioned that all investigators, clinical personnel, neurophysiologists interpreting the EEG, and parents of enrolled neonates, were blinded. Strengths and Limitations: A major strength of this study is that the occurrence of seizures was defined by cEEG, rather than identifying convulsions clinically or indirectly through changes in vital sign parameters detected electronically. An elaborate protocol was developed for real-time reading and interpreting of cEEG recordings by trained technicians. Additional inputs by automated software were also used. This ensured high sensitivity for seizure detection (so that no seizure episode was missed). This is perhaps one of very few clinical trials wherein elaborate measures were taken to define and document seizures. However, it is unclear whether heightened sensitivity could compromise specificity or trigger administration of medications for episodes that would have been otherwise missed or ignored. The investigators also have acknowledged the latter point.
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