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

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, d...

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Published inAnnals of neurology Vol. 89; no. 2; pp. 327 - 340
Main Authors Soul, Janet S., Bergin, Ann M., Stopp, Christian, Hayes, Breda, Singh, Avantika, Fortuno, Carmen R., O'Reilly, Deirdre, Krishnamoorthy, Kalpathy, Jensen, Frances E., Rofeberg, Valerie, Dong, Min, Vinks, Alexander A., Wypij, David, Staley, Kevin J.
Format Journal Article
LanguageEnglish
Published Hoboken, USA John Wiley & Sons, Inc 01.02.2021
Wiley Subscription Services, Inc
Subjects
Anticonvulsants - therapeutic use
Bumetanide
Bumetanide - therapeutic use
Diuresis
Double-Blind Method
Double-blind studies
Drug efficacy
Drug Therapy, Combination
EEG
Electroencephalography
Female
GABA Modulators - therapeutic use
Genetic Diseases, Inborn - complications
Hearing loss
Humans
Hypothermia
Hypoxia-Ischemia, Brain - complications
Infant, Newborn
Intracranial Hemorrhages - complications
Male
Meningoencephalitis - complications
Neonates
Nervous System Malformations - complications
Pharmacokinetics
Phenobarbital
Phenobarbital - therapeutic use
Pilot Projects
Placebos
Reduction
Seizures
Seizures - drug therapy
Seizures - etiology
Sodium Potassium Chloride Symporter Inhibitors - therapeutic use
Statistical analysis
Stroke - complications
Online AccessGet full text

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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
AbstractList 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.OBJECTIVEIn 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.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.METHODSA 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.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.RESULTSSubjects 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.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.INTERPRETATIONAlthough 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.
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. 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. 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. 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
ObjectiveIn 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.MethodsA 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.ResultsSubjects 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.InterpretationAlthough 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
Author Soul, Janet S.
Rofeberg, Valerie
Fortuno, Carmen R.
Dong, Min
O'Reilly, Deirdre
Hayes, Breda
Krishnamoorthy, Kalpathy
Wypij, David
Staley, Kevin J.
Jensen, Frances E.
Singh, Avantika
Bergin, Ann M.
Stopp, Christian
Vinks, Alexander A.
AuthorAffiliation 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
3 Department of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA
2 Department of Cardiology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA
1 Department of Neurology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA
AuthorAffiliation_xml – name: 3 Department of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA
– name: 5 Division of Clinical Pharmacology, Cincinnati Children’s Hospital Medical Center and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA
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– name: 1 Department of Neurology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA
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BackLink https://www.ncbi.nlm.nih.gov/pubmed/33201535$$D View this record in MEDLINE/PubMed
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Author Contributions
J.S.S., A.M.B., D.O., K.K., F.E.J., A.A.V., D.W., and K.J.S. contributed to the conception and design of the study; all authors contributed to the acquisition and analysis of data; J.S.S., C.S., V.R., A.A.V., D.W., and K.J.S. contributed to drafting a significant portion of the manuscript or figures.
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Snippet Objective In the absence of controlled trials, treatment of neonatal seizures has changed minimally despite poor drug efficacy. We tested bumetanide added to...
In the absence of controlled trials, treatment of neonatal seizures has changed minimally despite poor drug efficacy. We tested bumetanide added to...
ObjectiveIn the absence of controlled trials, treatment of neonatal seizures has changed minimally despite poor drug efficacy. We tested bumetanide added to...
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StartPage 327
SubjectTerms Anticonvulsants - therapeutic use
Bumetanide
Bumetanide - therapeutic use
Diuresis
Double-Blind Method
Double-blind studies
Drug efficacy
Drug Therapy, Combination
EEG
Electroencephalography
Female
GABA Modulators - therapeutic use
Genetic Diseases, Inborn - complications
Hearing loss
Humans
Hypothermia
Hypoxia-Ischemia, Brain - complications
Infant, Newborn
Intracranial Hemorrhages - complications
Male
Meningoencephalitis - complications
Neonates
Nervous System Malformations - complications
Pharmacokinetics
Phenobarbital
Phenobarbital - therapeutic use
Pilot Projects
Placebos
Reduction
Seizures
Seizures - drug therapy
Seizures - etiology
Sodium Potassium Chloride Symporter Inhibitors - therapeutic use
Statistical analysis
Stroke - complications
Title A Pilot Randomized, Controlled, Double‐Blind Trial of Bumetanide to Treat Neonatal Seizures
URI https://onlinelibrary.wiley.com/doi/abs/10.1002%2Fana.25959
https://www.ncbi.nlm.nih.gov/pubmed/33201535
https://www.proquest.com/docview/2478253775
https://www.proquest.com/docview/2461394139
https://pubmed.ncbi.nlm.nih.gov/PMC8122513
Volume 89
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