Soul 2021.

Study characteristics
Methods	Randomised controlled trial
Participants	Inclusion criteria: (quote:) "neonates at postmenstrual age 34 to 44 weeks if they had clinically suspected or EEG‐proven (i.e. confirmed) seizures, or were at high risk for developing seizures caused by hypoxic–ischaemic encephalopathy (HIE), focal stroke, ICH, acute meningoencephalitis, brain malformation, or a suspected/known genetic disorder." Exclusion criteria: (quote:) "neonates with seizures caused by transient metabolic abnormalities or inborn errors of metabolism; neonates who had received bumetanide, furosemide, phenytoin, or ≥ 40 mg/kg PB; neonates with total bilirubin > 15 mg/dL; and neonates treated with extracorporeal membrane oxygenation or at risk of imminent death" 0.1 mg/kg bumetanide, 7 patients Male sex, n (%): 3 (34) Gestational age at birth, wk, median (IQR): 39 (38, 40) Birth weight, kg, median (IQR): 3.4 (3.1‐3.8) Race Caucasian, n (%): 6 (86) Asian, n (%): 0 Unreported, n (%): 1 (14) Hispanic or Latino ethnicity, n (%): 1 (14) Seizure aetiology Hypoxic ischaemic encephalopathy, n (%): 3 (43) Stroke, n (%): 4 (57) Intracranial haemorrhage, n (%): 0 Other, n (%): 0 Therapeutic hypothermia, n (%): 3 (43) 0.2 mg/kg bumetanide, 15 patients Male sex, n (%): 10 (67) Gestational age at birth, wk, median (IQR): 40 (38‐41) Birth weight, kg, median (IQR): 3.4 (3.1‐ 3.8) Race Caucasian, n (%): 13 (87) Asian, n (%): 1 (7) Unreported, n (%): 1 (7) Hispanic or Latino ethnicity, n (%): 1 (7) Seizure aetiology Hypoxic ischaemic encephalopathy, n (%): 7 (47) Stroke, n (%): 3 (20) Intracranial haemorrhage, n (%): 2 (13) Other, n (%): 03 (20) Therapeutic hypothermia, n (%): 4 (27) 0.3 mg/kg bumetanide, 5 patients Male sex, n (%): 1 (20) Gestational age at birth, wk, median (IQR): 39 (39, 39) Birth weight, kg, median (IQR): 3.0 (2.9‐3.3) Race Caucasian, n (%): 4 (80) Asian, n (%): 0 Unreported, n (%): 1 (20) Hispanic or Latino ethnicity, n (%): 0 Seizure aetiology Hypoxic ischaemic encephalopathy, n (%): 4 (80) Stroke, n (%): 0 Intracranial haemorrhage, n (%): 1 (20) Other, n (%): 0 Therapeutic hypothermia, n (%): 3 (60) Control, 16 patients Male sex, n (%): 7(44) Gestational age at birth, wk, median (IQR): 39.5 (39, 41) Birth weight, kg, median (IQR): 3.3 (3.0‐3.5) Race Caucasian, n (%): 12 (75) Asian, n (%): 1 (6) Unreported, n (%): 3 (19) Hispanic or Latino ethnicity, n (%): 4 (25) Seizure aetiology Hypoxic ischaemic encephalopathy, n (%): 8 (50) Stroke, n (%): 0 Intracranial haemorrhage, n (%): 4 (25) Other, n (%): 4 (25) Therapeutic hypothermia, n (%): 5 (31) The study was conducted at 4 neonatal intensive care units in Boston, USA. Patients were enrolled from 2010 to 2017.
Interventions	Subjects were randomised if an EEG‐proven seizure (confirmed by a study paediatric neurophysiologist) occurred at least 30 minutes after a loading dose of ≥ 20 to < 40 mg/kg phenobarbital. (Quote:) "bumetanide doses of 0.1, 0.2, and 0.3 mg/kg in comparison to a control group (normal saline), given in conjunction with 5 to 10 mg/kg phenobarbital (bumetanide + phenobarbital vs saline + phenobarbital). The choice of 5 or 10 mg/kg phenobarbital was at the discretion of the treating physician; doses and levels were the same in the control and bumetanide groups".
Outcomes	Determination of the pharmacokinetics and safety of bumetanide as add‐on therapy to treat neonatal seizures An exploratory endpoint was the effect of bumetanide dose and exposure on seizure burden.
Notes	Funding: Quote: "The trial was funded by NIH National Institute of Neurological Disorders and Stroke grant 5R01 NS066929, and grants from the CURE foundation, Harvard Catalyst–Harvard Clinical and Translational Science Center, Charles H. Hood Foundation, Translational Research Program at Boston Children’s Hospital, and Mooney Family Initiative for Translation and Clinical Studies in Rare Diseases. Tufts Clinical and Translational Science Institute (CTSI), UL1 TR001064." The authors reported not having potential conflicts of interest to disclose.