Seizures occur in 1 to 2 percent of newborns in neonatal intensive care units. Seizures are usually due to hypoxic encephalopathy, hemorrhage or cerebral infarction. The natural history of neonatal seizures has not been fully elucidated, although it has been observed that they are most severe during the first week of life and usually abate over time. Animal studies suggest that seizures are harmful to the developing brain. Consequently, the standard practice has been to treat newborns who have seizures with anticonvulsants. The two most commonly used are phenobarbital and phenytoin. However, efficacy data on these two therapies in neonates is lacking. Painter and colleagues performed a randomized trial to compare these two medications in the treatment of neonatal seizures.
Infants enrolled were at risk for seizures based on various historical factors, including an Apgar score of less than 5 at five minutes with a base deficit of more than 10 mmol per L, traumatic delivery, maternal exposure to nonprescription narcotics, amphetamines or barbiturates, central nervous system infection or malformation, or a history of abnormal movements. Standard 21-channel electroencephalography (EEG) was performed on those infants noted to be eligible. The studies were repeated over two days if initially negative. A seizure was defined as an episode lasting 10 seconds or more and consisting of a succession of abnormal repetitive electrical discharges.
Newborns with seizures were randomly assigned to receive intravenous phenobarbital or phenytoin. Dosing was adjusted as needed to maintain a plasma level of 25 mg per mL for phenobarbital and 3 mg per mL for phenytoin. Continuous EEG monitoring was maintained in all infants during the treatment phase of the study. If the neonate continued having seizures (i.e., an episode of electrical activity lasting for more than 2.5 minutes or a total of 2.5 minutes of seizure activity during any five-minute period of monitoring), the second drug was added. The medications were discontinued if no seizure activity was noted after seven days. The primary end point of the study was complete control of seizure activity with one or both drugs, based on interpretation of the EEG recording.
Of the 157 neonates who were initially screened, 59 met the EEG criteria for seizures. Approximately 65 percent of the infants had a gestational age of at least 37 weeks. Forty-nine of the infants had seizures secondary to birth asphyxia, hemorrhage or infarction. Twenty-nine were initially given phenytoin, and 30 received phenobarbital. Of those receiving phenobarbital, 13 (43 percent) had complete control of seizures. After adding phenytoin to those who failed single-drug treatment, four more children had control of seizures for an overall seizure-free rate of 57 percent. Among the group randomized to first receive phenytoin, 13 (45 percent) had complete control of seizures. Following the addition of phenobarbital, five more were seizure-free, for an overall rate of 62 percent. When the data were evaluated further, it was found that 24 of 30 neonates in the phenobarbital group and 21 of 29 in the phenytoin group had about an 80 percent reduction in seizures. The severity of the seizures was inversely related to control with one or both medications. No adverse events related to the drugs were reported.
The authors conclude that phenytoin and phenobarbital are equally effective in the treatment of neonatal seizures. However, they note the individual and combined effectiveness of the two medications to be “disappointing” based on the observed response rates in this study. They call for the development of new, more effective treatments for neonatal seizures as a research priority.