Short-Term Effects of Phenobarbitone on Electrographic Seizures in Neonates

Abstract

Background: Phenobarbitone is the most common first-line anti-seizure drug and is effective in approximately 50% of all neonatal seizures.

Objective: To describe the response of electrographic seizures to the administration of intravenous phenobarbitone in neonates using seizure burden analysis techniques.

Methods: Multi-channel conventional EEG, reviewed by experts, was used to determine the electrographic seizure burden in hourly epochs. The maximum seizure burden evaluated 1 h before each phenobarbitone dose (T-1) was compared to seizure burden in periods of increasing duration after each phenobarbitone dose had been administered (T+1, T+2 to seizure offset). Differences were analysed using linear mixed models and summarized as means and 95% CI.

Results: Nineteen neonates had electrographic seizures and met the inclusion criteria for the study. Thirty-one doses were studied. The maximum seizure burden was significantly reduced 1 h after the administration of phenobarbitone (T+1) [-14.0 min/h (95% CI: -19.6, -8.5); p < 0.001]. The percentage reduction was 74% (IQR: 36-100). This reduction was temporary and not significant within 4 h of administrating phenobarbitone. Subgroup analysis showed that only phenobarbitone doses at 20 mg/kg resulted in a significant reduction in the maximum seizure burden from T-1 to T+1 (p = 0.002).

Conclusions: Phenobarbitone significantly reduced seizures within 1 h of administration as assessed with continuous multi-channel EEG monitoring in neonates. The reduction was not permanent and seizures were likely to return within 4 h of treatment.

Fig. 1

An example plot of the hourly seizure burden (HSB) over time (blue line; color in online version only) for one neonate with seizures overlaid with the time periods used to assess the effectiveness of phenobarbitone. The change in HSB was compared 1 h before (T_-1), 1 h after (T₊₁) and in the remaining hours of electrographic recorded seizures after the administration of phenobarbitone (T_+LR). The upper plot is the complete seizure time course for the neonate with T_+LR (black horizontal lines) shown for each 20 mg/kg dose of phenobarbitone (red vertical lines). After the second dose of phenobarbitone was given, electroclinical dissociation of seizures occurred and subsequent seizures were not highlighted to the clinical team, so there was no additional anti-seizure drug (ASD) given for seizures between 30 and 40 h. The lower plot is the magnified version of the upper plot with T_-1 (red boxes) and T₊₁ (black boxes) shown for each dose of phenobarbitone (red vertical lines). There is a clear reduction in maximum HSB between T_-1 and T₊₁ following the administration of each dose of phenobarbitone and these seizures return within T_+LR. Note that some smoothing is apparent in the HSB as both future and past values are used to estimate the HSB and a 30-min delay is taken into account for phenobarbitone infusion.

Fig. 2

The short-term reduction in seizure burden of phenobarbitone associated with accumulated dosage. ΔMSB denotes the change in MSB between time periods T₊₁ and T_-1. A negative ΔMSB implies a reduction in seizure burden between T_-1 and T₊₁. The ΔMSB at accumulated doses of 20 and 40 mg/kg are significantly lower than accumulated doses of 30 mg/kg. Only 1 neonate had a dose of 10 mg/kg as a first dose (accumulated dosage of 10 mg/kg).