Anticonvulsants for neonates with seizures

Abstract

Background: Neonatal seizures are a common problem and most neonates with seizures are treated with anticonvulsants. There is wide variation in clinical practice in both diagnosis and treatment of such seizures and this reflects the lack of clear evidence of the relative benefit and harm of the anticonvulsants used. The routine use of anticonvulsants to treat seizures in neonates needs to be evaluated.

Objectives: To assess and compare (with respect to benefits and harm) different anticonvulsants administered to neonates for the treatment of established seizures.

Search strategy: Relevant randomised controlled trials were identified using a combination of electronic database searches (MEDLINE 1966 - March 2004, EMBASE 1980 - March 2004), the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 1, 2004) and hand searches. Identification of ongoing or unpublished trials was attempted by contacting prominent authors in the field and searching electronic registers of ongoing trials.

Selection criteria: All randomised or quasi-randomised controlled clinical trials with reported data comparing the following outcomes: mortality, neurodevelopmental disability, need for additional anticonvulsants, need for maintenance anticonvulsants at discharge and adverse events (hypotension requiring volume or inotropic support, arrhythmia, respiratory depression, hepatotoxicity) in neonates treated for seizures with systemic anticonvulsants compared to placebo, no drug or alternative anticonvulsants.

Data collection and analysis: Methodological quality and validity were assessed without consideration of the results. The first reviewer screened the title and abstracts of studies identified by the above search strategy. Full text versions of studies of potential relevance were re-screened by both reviewers. Studies meeting the pre-specified inclusion criteria were included. Relevant data were extracted and analysed separately and any disagreements were resolved by discussion.

Main results: Only two randomised controlled trials published in full could be identified. Painter 1999 showed that both of the two most commonly used anticonvulsants (phenobarbital and phenytoin) were similarly effective (RR 1.03 95% CI 0.96 to 1.62), controlling seizures in less than fifty percent of infants. Painter 1999 did not report mortality or neurodevelopmental outcome. Boylan 2004 randomised infants who failed to respond to phenobarbital to receive either lidocaine or midazolam as second-line agents. There was a trend for lidocaine to be more effective in reducing seizure burden (RR 0.40 95% CI 0.14 to 1.17) but both groups had similarly poor long term outcomes assessed at one year.

Reviewers' conclusions: At present there is little evidence from randomised controlled trials to support the use of any of the anticonvulsants currently used in the neonatal period. In the literature, there remains a body of opinion that seizures should be treated because of the concern that seizures in themselves may be harmful, although this is only supported by relatively low grade evidence (Levene 2002; Massingale 1993). Development of safe and effective treatment strategies relies on future studies of high quality (randomised controlled trials with methodology that assures validity) and of sufficient size to have the power to detect clinically important reductions in mortality and severe neurodevelopmental disability in addition to any short term reduction in seizure burden.

1.4. Analysis

Comparison 1 Phenobarbital versus phenytoin, Outcome 4 Proportion of infants who require additional anticonvulsants during neonatal period.

1.7. Analysis

Comparison 1 Phenobarbital versus phenytoin, Outcome 7 Failure of seizure control.

2.1. Analysis

Comparison 2 Addition of midazolam vs lidocaine after treatment failure with phenobarbitone, Outcome 1 Death within first 28 days of life or death within 1st year of life.

2.2. Analysis

Comparison 2 Addition of midazolam vs lidocaine after treatment failure with phenobarbitone, Outcome 2 Neurodevelopmental impairment assessed at 1‐2 years of age.

2.3. Analysis

Comparison 2 Addition of midazolam vs lidocaine after treatment failure with phenobarbitone, Outcome 3 Death or significant neurodevelopmental impairment at 1‐2 years of age.

2.4. Analysis

Comparison 2 Addition of midazolam vs lidocaine after treatment failure with phenobarbitone, Outcome 4 Proportion of infants who require additional anticonvulsants during the neonatal period.

2.7. Analysis

Comparison 2 Addition of midazolam vs lidocaine after treatment failure with phenobarbitone, Outcome 7 Failure of seizure control.