A Pilot Randomized, Controlled, Double-Blind Trial of Bumetanide to Treat Neonatal Seizures

Abstract

Objective: In the absence of controlled trials, treatment of neonatal seizures has changed minimally despite poor drug efficacy. We tested bumetanide added to phenobarbital to treat neonatal seizures in the first trial to include a standard-therapy control group.

Methods: A randomized, double-blind, dose-escalation design was employed. Neonates with postmenstrual age 33 to 44 weeks at risk of or with seizures were eligible. Subjects with electroencephalography (EEG)-confirmed seizures after ≥20 and <40mg/kg phenobarbital were randomized to receive additional phenobarbital with either placebo (control) or 0.1, 0.2, or 0.3mg/kg bumetanide (treatment). Continuous EEG monitoring data from ≥2 hours before to ≥48 hours after study drug administration (SDA) were analyzed for seizures.

Results: Subjects were randomized to treatment (n = 27) and control (n = 16) groups. Pharmacokinetics were highly variable among subjects and altered by hypothermia. The only statistically significant adverse event was diuresis in treated subjects (48% vs 13%, p = 0.02). One treated (4%) and 3 control subjects died (19%, p = 0.14). Among survivors, 2 of 26 treated subjects (8%) and 0 of 13 control subjects had hearing impairment, as did 1 nonrandomized subject. Total seizure burden varied widely, with much higher seizure burden in treatment versus control groups (median = 3.1 vs 1.2 min/h, p = 0.006). There was significantly greater reduction in seizure burden 0 to 4 hours and 2 to 4 hours post-SDA (both p < 0.01) compared with 2-hour baseline in treatment versus control groups with adjustment for seizure burden.

Interpretation: Although definitive proof of efficacy awaits an appropriately powered phase 3 trial, this randomized, controlled, multicenter trial demonstrated an additional reduction in seizure burden attributable to bumetanide over phenobarbital without increased serious adverse effects. Future trials of bumetanide and other drugs should include a control group and balance seizure severity. ANN NEUROL 2021;89:327-340.

FIGURE 1:

Study algorithm. EEG = electroencephalography; HIE = hypoxic–ischemic encephalopathy.

FIGURE 2:

Data collection and laboratory drawing schedule. ALT = alanine aminotransferase; AST = aspartate aminotransferase; BTN = bumetanide; BUN = blood urea nitrogen; EEG = electroencephalography.

FIGURE 3:

Screening, enrollment, and randomization of the study subjects. EEG = electroencephalographic.

FIGURE 4:

Total seizure burden (min/h) by subject (ranked).

FIGURE 5:

Effect of bumetanide on seizure reduction. (A) Seizure burden (min/h) for 0 to 2 hours before study drug administration (SDA), then the difference in seizure burden for 0 to 4 hours post-SDA and 2 to 4 hours post-SDA compared with 0 to 2 hours pre-SDA, across control and bumetanide dose groups. (B) Relationship between difference in seizure burden for 0 to 4 hours post-SDA and total seizure burden, across control and combined bumetanide groups. For all subjects receiving bumetanide (red), there was a greater reduction in seizure burden as a function of total seizure burden (slope = −1.12min/h per unit increase in total seizure burden; 95% confidence interval [CI] = −1.71 to −0.53; p < 0.001). For controls (blue), there was no significant change in seizure burden as a function of total seizure burden (slope = 0.27; 95% CI = −0.27 to 0.81; p = 0.34). (C) Relationship between difference in seizure burden for 2 to 4 hours post-SDA and total seizure burden. For all subjects receiving bumetanide (red), there was a greater reduction in seizure burden as a function of total seizure burden (slope = −1.10; 95% CI = −1.61 to −0.58; p < 0.001). For controls (blue), seizure burden increased as a function of total seizure burden (slope = 0.63; 95% CI = 0.06–1.21; p = 0.048).

FIGURE 6:

Effect of bumetanide exposure (area under the curve [AUC]) on seizure reduction. The scatterplot shows the relationship between difference in seizure burden for 0 to 4 hours after study drug administration (SDA) compared with 0 to 2 hours pre-SDA and total seizure burden, across control and combined bumetanide groups. The interaction model was based on the effect of bumetanide exposure (AUC) and total seizure burden to predict difference in seizure burden (interaction p = 0.008). The model is graphed for the control group (solid blue; slope = 0.24; 95% confidence interval [CI] = −0.58 to 1.05; p = 0.56) and at the median exposure of the 0.1mg/kg (dashed yellow; slope = −0.20 at median AUC_0–4h = 1,598μg·h/l; 95% CI = −0.79 to 0.40; p = 0.51), 0.2mg/kg (dashed orange; slope = −0.60 at median AUC_0–4h = 3,050μg·h/l; 95% CI = −1.08 to −0.10; p = 0.02), and 0.3mg/kg (dotted red; slope = −1.06 at median AUC_0–4h = 4,790μg·h/l; 95% CI = −1.63 to −0.50; p < 0.001) groups.