Van Rooji 2010.

Study characteristics
Methods	Randomised controlled trial
Participants	Inclusion criteria: (quote:) "gestational age of ≥ 37 weeks, admission to 1 of the NICUs 24 hours after birth, and diagnosis of HIE and neonatal seizures. HIE was defined on the basis of meeting ≥ 3 of the following criteria: (1) signs of intrauterine asphyxia (i.e. late decelerations on foetal electrocardiograms or meconium‐stained liquor), (2) arterial cord blood pH of < 7.10, (3) delayed onset of spontaneous respiration, (4) Apgar score of ≤ 5 at 5 minutes, or (5) multiorgan failure (elevated liver enzyme levels, reduced diuresis, and cardiovascular problems)." Exclusion criteria: (quote:) "presence of congenital or chromosomal abnormalities, maternal use of narcotics or sedatives, treatment with phenytoin before referral, and administration of muscle‐relaxing drugs." "Subclinical status epilepticus at the beginning of the aEEG registration". Treatment of both clinical seizures and subclinical seizure patterns (group A) Gestational age, mean SD: wk 39.5 ± 1.8 Birth weight, mean SD: g 3254 ± 701 Gender, n (%): male 8 (42); female: 11 (58) Outborn, n (%): 17 (90) Apgar score at 5 min of 5, n (%): 12 (67) Cord pH, mean (range) (group A, N = 12): 6.87 (6.67 to 7.00) Lactate level, mean (range), mmol/L (group A, N = 15): 14.1 (2.2 to 26) HIE, n (%) Grade II: 11 (58) Grade III: 8 (42) Mode of delivery, n (%) Vaginal: 3 (16) Ventouse extraction: 2 (10) Caesarean section, emergency: 14 (74) Meconium‐stained liquor, n (%): 9 (47) Mechanical ventilation, n (%): 15 (79) Blinding of the aEEG registration and treatment of clinical seizures only (group B) Gestational age, mean SD: wk 39.9 ± 1.3 Birth weight, mean SD: g 3416 ± 487 Gender, n (%): male 7 (50); female 7 (50) Outborn, n (%): 12 (86) Apgar score at 5 min of 5 n (%): 11 (79) Cord pH, mean (range) (group B, N = 11): 6.88 (6.64 to 7.30) Lactate level, mean (range), mmol/L (group B, N = 13): 9.3 (3.1 to 29.0) HIE, n (%) Grade II: 7 (50) Grade III: 7 (50) Mode of delivery, n (%) Vaginal: 4 (29) Ventouse extraction: 3 (21) Caesarean section, emergency: 7 (50) Meconium‐stained liquor, n (%): 7 (50) Mechanical ventilation, n (%): 13 (93) The multicentre study was conducted at eleven perinatal centres in the Netherlands and Belgium between November 2003 and April 2008.
Interventions	Treatment of both clinical seizures and subclinical seizure patterns (group A) versus blinding of the aEEG registration and treatment of clinical seizures only (group B) In both groups, the treatment consisted of the following protocol: First‐line: PB: 20 mg/kg, eventually another 10 mg/kg Second‐line: midazolam: loading dose of 0.05 mg/kg, followed by continuous infusion of 0.15 mg/kg per h, to maximum of 0.2 mg/kg per hour (when seizures have been stopped for 24 hours, tapered to 0.1 mg/kg per h and stopped after 48 hours) Third‐line: lidocaine: loading dose of 2 mg/kg, followed by continuous infusion of 6 mg/kg per h for 6 hours, then 4 mg/kg per h for 12 hours, and then 2 mg/kg per hour for 12 hours (always stopped after 36 hours) Fourth‐line: clonazepam: loading dose of 0.1 mg/kg, followed by continuous infusion of 0.1 to 0.5 mg/kg per day Fifth‐line: pyridoxine: 50 mg/kg Sixth‐line: further treatment on the basis of clinician’s decisions
Outcomes	Primary outcome: reduction of the total duration of seizures detected on aEEG Other outcomes: degree of brain injury seen on MRI scans. These were obtained 4 to 10 days after birth and retrospectively reviewed and scored by 2 investigators blinded to aEEG results.
Notes	Funding: Dr van Rooji was supported by the Dutch Epilepsy Foundation (grant NEF 3‐15). Interests: not mentioned in the publication

aEEG: amplitude‐integrated electroencephalography; AGA: appropriate for gestational age; ASM: anti‐seizure medication; BSID: Bayley Scales of Infant Development; cEEG: continuous electroencephalography; CNS: central nervous system; EEG: electroencephalography; GE: genetic epilepsy; HIE: hypoxic‐ischaemic encephalopathy; HNNE: Hammersmitz Neurological Neonatal Neurological Examination; ICH: intracranial haemorrhage; IEM: inborn error of metabolism; IQR: inner‐quartile range; IUI: intrauterine infections; IV: intravenous; LEV: levetiracetam; LGA: large for gestational age; LSCS: lower segment caesarean section; MRI: magnetic resonance imaging; NICU: neonatal intensive care unit; NS: normal saline; NVD: normal vaginal delivery; PB: phenobarbitone; PIH: pregnancy‐induced hypertension; PHT: phenytoin; PROM: premature rupture of membranes; SD: standard deviation; SE: structural epilepsy; SGA: small for gestational age.