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.

Pharmaco‐resistant Neonatal Seizures: Critical Mechanistic Insights from a Chemoconvulsant Model

“…Less than 1% of BTN has been shown to reach the brain 1h post‐IP injection (Puskarjov et al, ), yet its efficacy in few preclinical models has been attributed to its neuronal actions on NKCC1 (Dzhala et al, ; Cleary et al, ; Vlaskamp et al, ). The post‐BTN aggravation of PB‐suppressed seizures in the PTZ model could be due to (1) PB‐rebound seizures not responsive to BTN alone (Low et al, ); (2) Diuretic effects of BTN [NCT01434225, 2015; NCT00830531, ]; (3) BTN’s action on NKCC1 expressing ependymal cells lining cerebral blood vessels (Dzhala et al, ; Kahle et al, ); (4) Changes to extracellular matrix volumes in the seizing brain (Glykys et al, ). Cerebral edema has been proposed to aggravate seizures in HIE where the role of hyperosmolar agents has been investigated with differential results (Vannucci, ; Haglund and Hochman, ).…”

“…Neonatal seizures are an early sign of brain injury in newborns (Thibeault‐Eybalin et al, ) that can disrupt normal brain development. Phenobarbital (PB) is the first‐line anti‐seizure drug (ASD) administered clinically but is only efficacious in about 50% of neonatal seizures (Low et al, ).…”

“…Neonatal seizures are an early sign of brain injury in newborns (Thibeault-Eybalin et al, 2009) that can disrupt normal brain development. Phenobarbital (PB) is the first-line anti-seizure drug (ASD) administered clinically but is only efficacious in about 50% of neonatal seizures (Low et al, 2016). K-Cl cotransporter 2 (KCC2) and Na-K-Cl cotransporter 1 (NKCC1) expression and function affect the anti-seizure efficacy of GABA A -agonists (Khirug et Developmental Neurobiology al., 2010).…”

Treatment Trials for Neonatal Seizures: The Effect of Design on Sample Size

“…Our findings suggest that this trial was powered to detect differences in seizure efficacy considerably larger than 25% between AEDs (see positive control, first line, rSB 1 in Table 2 – 75% efficacy for positive control vs 100% efficacy for trial drug); in other words, the efficacy of phenobarbitone was not greater than 25% different from phenytoin. A recent uncontrolled study observed AED efficacy with a measure similar to the seizure burden response in a cohort of 19 neonates [17]. In an RCT with a similar design and effect size (placebo control, first line, rSB 1 , T d = 1h in Table 1); our model would have predicted a sample size of 14 neonates per group.…”

“…The efficacy of phenobarbitone was assumed to be a 75% reduction in seizures for 3h [17]. The T d variable represents delays in the clinical recognition of seizures and the speed of execution of the trial protocol and was varied from 1h to 8h [18].…”