[Prevention of hypoxic-ischemic encephalopathy with high-dose, early phenobarbital therapy]. Treatment of cerebral irritation in the newborn: double-blind trial with chloral hydrate and diazepam. Use of barbiturate therapy in severe perinatal asphyxia: a randomized controlled trial. [Preventive treatment of convulsions in perinatal asphyxia]. Effect of phenobarbital on free radicals in neonates with hypoxic ischemic encephalopathy--a randomized controlled trial. High-dose phenobarbital therapy in term newborn infants with severe perinatal asphyxia: a randomized, prospective study with three-year follow-up.
To assess usefulness of high-dose early phenobarbital therapy for prevention of hypoxic-ischemic encephalopathy (HIE) secondary to perinatal asphyxia (PNA).
                By means of a randomized clinical trial, asphyxiated full-term or post-term newborn infants were divided in two groups: Group A was the experimental group, while group B was the control group. Infants in group A received phenobarbital, 40 mg/kg, during the first 60 min after birth. Infants on group B received phenobarbital at conventional doses, only if there was clinical evidence of seizures; otherwise, treatment was similar in both groups. We estimated frequency of HIE according to Sarnat classification and also rate of post-asphyxial complications in other organs. Phenobarbital levels were measured in Group A. Statistical tests used were Student t, Mann-Whitney U, X2 or Fisher. Informed consent was obtained from parents of each infant.
                37 infants belonged to Group A, while Group B was composed of 36 infants. Both groups were similar in sex, gestational age and cord gases. Birth weight was higher in Group A (p<0.05). Diagnostic criteria for PNA a cord pH < or = 7.00 plus one or two criteria of commonly used parameters for asphyxia. There was a difference in total dose of phenobarbital and time of initial dose in both groups. HIE was present in 13.5% (5/37) of group A, and 22.2% (8/36) of group B. Seizures (Stage II of HIE) occurred in 10.8% (4/37) and 11.1% (4/36), respectively, without significant statistical difference. There was also no difference in rate of post-asphyxial, non-brain complications in both groups. There were no side effects or changes in vital signs associated with use of phenobarbital. Only one infant had toxic phenobarbital serum levels.
                There was no significant difference in the overall frequency of HIE, nor in the incidence of seizures or stage II of HIE in both groups. According to these results and even though there were no side effects, we think phenobarbital is not useful for these purposes. Long-term follow-up of the treated infants is justified, since phenobarbital might have a beneficial effect on neuro-behavioral development. nan The possible cerebral sparing effect of thiopental was evaluated in 32 severely asphyxiated neonates randomly assigned to either a thiopental treatment or control group. All infants had neurologic manifestations of asphyxia and required assisted ventilation. Thiopental was begun at a mean age of 2.3 hours and was given as a constant infusion that delivered 30 mg/kg over 2 hours. Treatment was continued at a lower dose for 24 hours. Seizure activity occurred in 76% of infants given thiopental and 73% of control infants at a mean age of 1.5 and 2.5 hours, respectively. Although initial arterial blood pressure was similar in both groups, hypotension occurred in 88% of treated and 60% of control infants. The amount of blood pressure support required was significantly greater (P less than 0.005) in the thiopental treatment group. Three infants died in the control group, and five in the treatment group. Developmental assessment was performed at a minimum of 12 months of age in 22 infants. There were no significant differences in neurologic, cognitive, or motor outcome between groups. Deteriorating performance over time was a consistent trend in both groups. These findings indicate that treatment of severe perinatal asphyxia with thiopental does not appear to have a cerebral sparing effect and may be associated with significant arterial hypotension. A double blind randomized study has been performed in 17 newborn infants bearing a diagnosis of perinatal asphyxia and treated with phenobarbital (FB) or phenytoin (DPH) to prevent the onset of seizures. The initial dose for both drugs was 12 m/kg IM the first day, followed by 6 mg/kg/day through the seventh day. Patients were clinically assessed daily and drug blood levels were also determined daily by enzyme immunoassay (EMIT). Mean FB levels along the seven days were 17.6, 23.7, 25.6, 31.6, 31.4, 36.7, and 44.6 micrograms/ml. One child treated with FB exhibited seizures on the second day and six children showed drowsiness and bradycardia on the last two days, that were attributable to high levels of FB. Mean (DPH) levels along the study were: 4.6, 7.0, 9.7, 6.5, 4.5, and 5.2 micrograms/ml. Seizures occurred in one of the DPH-treated patients and signs of therapeutic inefficacy such as hypertonus and abnormal movements appeared in four children. Phenobarbital is one of the oldest, cheapest and easily available cerebroprotective drugs for the hypoxic brain. However, its potential and various actions have not been fully explored.
                To evaluate the effects of Phenobarbital on levels of oxidants and anti-oxidants in term and near term neonates with hypoxic ischemic encephalopathy.
                Design--randomized controlled trial. Setting--tertiary care referral perinatal centre. Procedure--asphyxiated neonates (gestation > or = 34 weeks) with HIE were randomized to receive Phenobarbital 20 mg/kg i.v. within first six hours of life or to control group. CSF levels of malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GPx) and blood levels of vitamins A and E were estimated at 10-12 hours of age.
                CSF levels of MDA, SOD, GPx and blood levels of vitamins A and E were significantly lower in the Phenobarbital group (p<0.001). There was a trend towards lower levels of CSF MDA, SOD, GPx and blood vitamins A and E in babies with normal outcome as compared to babies with adverse outcome (death or neurologically abnormal at discharge).
                Phenobarbital in the dose of 20 mg/kg i.v. given within 6 hours of life in term and near-term neonates with HIE, was associated with a decrease in lipid peroxides, anti-oxidant enzymes and anti-oxidant vitamins. To determine whether 40 mg/kg phenobarbital given to term infants with severe asphyxia would result in a lower incidence of seizures in the newborn period and an improved neurologic outcome.
                We conducted a randomized, controlled, prospective study. Entry criteria included (1) an initial arterial pH less than or equal to 7.0 with a base deficit 15 mEq/L or more, (2) Apgar score less than or equal to 3 at 5 minutes of age, or (3) failure to initiate spontaneous respiration by 10 minutes of age. Sample size was calculated to detect a 50% reduction in the incidence of neonatal seizures.
                No differences were present between treatment and control groups with respect to severity of asphyxia assessed by initial arterial pH, base excess, cerebrospinal fluid lactate dehydrogenase concentration or detection of CSF creatine kinase of its BB isoenzyme. Seizures occurred in 9 of 15 infants in the treatment group and 14 of 16 infants in the control group (p = 0.11). No adverse effects were observed from phenobarbital on heart rate, respiratory rate, blood pressure, or arterial blood gas values. Three-year follow-up revealed normal outcome in 11 of 15 infants in the treatment group and 3 of 16 in the control group (p = 0.003).
                Phenobarbital, when administered in a dose of 40 mg/kg intravenously over 1 hour in term, severely asphyxiated newborn infants appeared to be safe and was associated with a 27% reduction in the incidence of seizures and a significant improvement in neurologic outcome at 3 years of age.
At the present time, anticonvulsant therapy to term infants in the immediate period following perinatal asphyxia cannot be recommended for routine clinical practice, other than in the treatment of prolonged or frequent clinical seizures. Any future studies should be of sufficient size to have the power to detect clinically important reductions in mortality and severe neurodevelopmental disability.