5. Phenobarbital.

RCT ID	Population	Intervention	Comparison	Outcomes	Notes
Anwar 1986	58 preterm infants (BW less than 1500 g) who had no congenital malformations and whose mother had not received PHE before their delivery. Mean/median GA: not reported. Number of ventilated infants: not reported.	PHE (a loading dose of 20 mg/kg divided into 2 equal doses administered intravenously 12 h apart, following a maintenance dose of 2 to 5 mg/kg every 12 h); for the first week of life, starting at less than 6 h of age. N = 30	Supportive care N = 28	Germinal matrix hemorrhage‐intraventricular hemorrhage (GMH‐IVH) incidence and degree (ultrasound brain scans were performed on days 1, 3, and 7 of life and subsequently at weekly intervals in infants with GMH‐IVH), posthemorrhagic hydrocephalus, deaths. Blood concentration of PHE before the first maintenance dose and then at 3 to 5 days of age was also measured.	Additional treatment: not reported (with exception of indomethacin, bicarbonate). Cerebral ultrasound was not carried out prior to trial entry so it was not possible to exclude babies who already had GMH‐IVH before the first dose of PHE.
Bedard 1984	42 premature infants (< 37 wks of GA), less than 24 h of age with normal admission encephalograms; infants < 1500 g or less than 33 wks of GA were eligible regardless of the need for MV; larger or older infants were eligible only if required MV for hyaline membrane disease. Mean GA ± SD: 32.2 ± 1.7 in PHE group; 31.1 ± 2.7 in CON group. Mean BW: 1491 ± 421 in PHE group; 1271 ± 422 in CON group. n of MV: 19/21 in PHE group; 17/21 in CON group.	PHE (2 intravenous loading doses of 10 mg/kg 12 h apart, followed by a maintenance dose of 2.5 mg/kg every 12 h for 6 days, latter one, given intravenously or orally). N = 21	Unspecified control group N = 12	Incidence of central nervous system (periventricular) hemorrhage and its severity (mild, moderate and severe based on Shankaran 1982), and age at diagnosis (diagnosed by ultrasound imaging). Deaths. Need for mechanical ventilation, the incidence of pneumothorax. Frequency of hypotension acidosis, hypercarbia, hypocarbia, all during the first 3 days. Sodium bicarbonate administration and volume expansion. Serum phenobarbital levels (measured, but not an outcome).	Additional treatment not reported (with exception of bicarbonates and blood‐volumes expanders).
Donn 1981	60 infants with BW less than 1500 g and who were less than 6 h old, without obvious congenital malformations, and whose mothers had not taken barbiturates during pregnancy. Mean GA ± SD: 28.9 ± 1.9 in PHE group; 28.6 ± 1.8 in CON group. MV: 25/30 in PHE group; 21/30 in CON group	PHE (intravenously, 2 loading dose of 10 mg/kg each administered intravenously 12 h apart; following the maintenance doses of 2 to 5 mg/kg every 12 h begun 12 h after the second loading dose and continued intravenously/ intramuscularly or orally for 6 days; at third postnatal day dosages were adjusted to maintain levels in 20 to 30 mcg/ml range). N = 30 At the end of the seventh day therapy was stopped.	Unspecified control group N = 30	GMH‐IVH (diagnosed with cranial ultrasonography at third, fourth or fifth postnatal day, CT or postmortem examination), and graded using Papile 1978 classification. Deaths. Need for MV, oxygen therapy only, continuous distending pressure, thoracostomy drainage. Hyperoxia, hypoxia, hypercapnia, hypocapnia, acidosis, hypotension were also reported. Sodium bicarbonate and blood‐volumes expanders administration.	Additional treatment not reported (with exception of bicarbonates and blood‐volumes expanders).
Kuban 1986	280 intubated newborns with BW less than 1751 g; with endotracheal intubation before 12 h of age; without major congenital anomaly; and with no evidence of intracranial hemorrhage on US before drug administration; neonatal PHE level less than 5 mcg/ml (measured only if mother received PHE before delivery). Mean GA: 29.5 in PHE group; 30.1 in CON group.	PHE (10 mg/ml; or 25 mg/ml; all were single lot; first dose of 10 mg/kg administered intravenously at or before 12 h of age, second dose administered 0.5 h later (20 mg of a loading dose in sum); 12 h later, the first of 9 maintenance doses of 2.5 mg/kg was given intravenously or orally, then at 12 h intervals). N = 145	Non‐specified placebo (at the same rate as PHE). N = 135	Incidence of any hemorrhage (subependymal hemorrhage/GMH‐IVH; diagnosed with ultrasound) and grading using the Papile 1978 classification. Pneumothorax or pulmonary interstitial emphysema on day 1, mean arterial pressure < 30 mmHg on day 1, use of morphine on day 1, cranial bruising, and days of ventilation were also reported. Serum PHE level between the third and fifth day was measured, and then, again between 7 h and 10th day in half of infants.	Additional treatment: not reported (with exception of morphine). Mortality data were by personal communication between Dr Kuban and Dr Horbar, although age at death was not clear.
Mas‐Munoz 1993	60 preterm neonates (27 to 34 wks of GA), who required mechanical ventilation from birth, without GMH‐IVH in the first 6 h of life (by cranial ultrasound). Mean GA ± SD: 31.5 ± 2 in PHE group; 31 ± 2 in CON group	PHE (intravenously, a loading dose of 20 mg/kg, followed by the 2.5 mg/kg at 12 h apart as the maintenance dose for 5 d). N =30	Control group: no placebo was used N = 30	GMH‐IVH incidence, graded following the Papile 1978 classification (diagnosed by cranial ultrasound). Glycemia, blood pressure, PaCo2, PaO2, pH, and pressure in mean pressure in ventilatory vessels; were also reported. Postnatal complications, i.e. membrane hyaline disease, sepsis, pneumothorax, hypotension, pulmonary hypertension, pneumonia, mortality. Additional treatment not reported.	Additional treatment not reported.
Morgan 1982	60 VLBW infants (all < 1250 g of BW and all infants 1250 to 1500 BW who required artificial ventilation in the first 24 h of life), without hemorrhage on ultrasound imaging at entry. Mean GA ± SD: 30.1 ± 2.7 in PHE group; 28.8 ± 2.8 in CON group	PHE (20 mg/kg administered intramuscularly at a median time of 2 h after birth (range 1 to 22 h) N = 30	No placebo injection was given to untreated infants – no treatment N = 30	Periventricular hemorrhage (by real‐time ultrasound scanning performed daily or more frequently for the first 5 d and at least once thereafter; if needed, confirmed postmortem); graded 1 to 4 following the Papile 1978 classification. Need for ventilation. Serum PHE level, frequency of pneumothorax, hypercapnia, acidosis, and survival were also measured.	Additional treatment not reported.
Porter 1985	19 newborns, < 1500 BW, admitted to NICU within the first 6 h of life; without GMH‐IVH on initial ultrasound screening, congenital malformations; with a diagnosis of respiratory disease requiring respiratory support. Mean GA ± SD: 29.4 ± 2.8 in PHE group; 28.8 ± 2.2 in CON group.	PHE (intravenously, within 6 h of delivery in a loading dose of 30 mg/kg, a level within the therapeutic range, followed by the maintenance dose of 5 mg/kg/24 h for 72 h. N = 7	Placebo injections were not administered, nor PHE levels controlled; equal management as in PHE group but without PHE. N = 12	GMH‐IVH incidence (diagnosed by ultrasound scanning), and severity (graded following the Papile system); ventilation (intermittent positive pressure ventilation, continuous positive airway pressure), pneumothorax, hypercapnia, acidosis, survivals; frequency of movements (limbs, extremities, trunk). Serum PHE levels were measured (only in PHE group.	Serum phenobarbital levels were measured at 36 h of age
Ruth 1985	52 premature infants with BW < 1500 g, admitted at NICU at the age of < 2 h; without malformations, and epileptic mothers. Mean GA ± SD: 28.7 ± 2.1 in PHE group; 29.3 ± 1.8 in CON group MV: 21/25 in PHE group; 22/27 in CON group	PHE (administered intravenously; a loading dose of 15 mg/kg 4 h apart starting before the age of 2 h to achieve 200 to 300 µmol/l of serum level, followed by the maintenance dose of 5 mg/kg starting 24 h after the first dose, and given once a day for 5 days). N = 25	Unspecified control N = 27	Incidence of GMH‐IVH, graded following the Papile 1978 classification (by cranial US; EEG during first week; neurological follow‐up with cranial US performed at 4 and 9 mo of age); ventricular dilatation (central atrophy), hydrocephalus and neurological abnormalities, pneumothorax, need for mechanical ventilation, death.
Ruth 1988	111 preterm (≥ 25 wks of GA or more) infants, admitted to NICU, ≤ 1500 g of BW at birth, without major congenital malformation, with no history of maternal barbiturate treatment, and early admission to allow randomization before the age of 4 h.	PHE (a first dose of 15 mg/kg was infused intravenously for 15 minutes as soon as possible after birth, followed by the maintenance dose of 5 mg/kg at 24‐h intervals after the loading dose for 5 days) N = 54	Control group (routine intravenous glucose infusion) N = 57	GMH‐IVH (measured by real‐time ultrasound scanning on the brain performed on the first, third, fifth and seventh day, if possible, and then once a week; it was repeated at 4 and 9 months old; classified according to Papile 1978 classification). Neurodevelopmental assessment was done at 4, 9, 15, and 27 months of postnatal age.	10 infants excluded after randomization (finally, 47 in PHE group and 54 in CON group); Mean BW and GA only for 101 infant included in final analysis.

BW = birth weight, in grams; CON = control group; CT = computer tomography; d = days; EEG = electroencephalogram; GA = gestational age, in weeks; GMH‐IVH = germinal matrix hemorrhage‐intraventricular hemorrhage; h = hour; mo = month; MV = mechanical ventilation; n = number; NICU = neonatal intensive care unit; PaCO₂ = partial pressure of carbon dioxide in arterial blood; PaO_{2 =} partial pressure of oxygen in arterial blood; PHE = phenobarbital; RCT = randomized controlled trial; RDS = respiratory distress syndrome; SD = standard deviation; US = ultrasound; VLBW: very low birth weight; wks = weeks.