Janet S Soul1, Ann M Bergin1, Christian Stopp2, Breda Hayes1, Avantika Singh1, Carmen R Fortuno1, Deirdre O'Reilly3, Kalpathy Krishnamoorthy4, Frances E Jensen1, Valerie Rofeberg2, Min Dong5, Alexander A Vinks5, David Wypij2, Kevin J Staley4. 1. Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA. 2. Department of Cardiology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA. 3. Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA. 4. Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. 5. Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
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.
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.
Authors: Yijun Li; Ryan Cleary; Mark Kellogg; Janet S Soul; Gerard T Berry; Frances E Jensen Journal: J Chromatogr B Analyt Technol Biomed Life Sci Date: 2011-02-19 Impact factor: 3.205
Authors: Martha E O'Donnell; Lien Tran; Tina I Lam; Xiao Bo Liu; Steven E Anderson Journal: J Cereb Blood Flow Metab Date: 2004-09 Impact factor: 6.200
Authors: Ryan T Cleary; Hongyu Sun; Thanhthao Huynh; Simon M Manning; Yijun Li; Alexander Rotenberg; Delia M Talos; Kristopher T Kahle; Michele Jackson; Sanjay N Rakhade; Gerard T Berry; Gerard Berry; Frances E Jensen Journal: PLoS One Date: 2013-03-11 Impact factor: 3.240
Authors: Richard J Burman; Richard E Rosch; Jo M Wilmshurst; Arjune Sen; Georgia Ramantani; Colin J Akerman; Joseph V Raimondo Journal: Nat Rev Neurol Date: 2022-05-10 Impact factor: 44.711
Authors: Kelly Q Zhou; Alice McDouall; Paul P Drury; Christopher A Lear; Kenta H T Cho; Laura Bennet; Alistair J Gunn; Joanne O Davidson Journal: Int J Mol Sci Date: 2021-07-01 Impact factor: 5.923