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SUPPLEMENT ARTICLE |
Division of Neurology, University of Pennsylvania School of Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
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ABSTRACT |
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 TOP ABSTRACT NEONATAL-SEIZURES TREATMENT...FUTURE DIRECTIONSREFERENCES |
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Key Words: EEG • seizures • congenital heart disease • neonatal seizures • phenobarbital
Abbreviations: HIE—hypoxic-ischemic encephalopathy • EEG—electroencephalogram • ENS—electroencephalographically detected neonatal seizure • ECMO—extracorporeal membrane oxygenation
The neurology group began its task by considering the areas of neonatal neurology that might be appropriate for consideration of large-scale, formal, randomized, controlled treatment trials. There are several important scenarios in neonatal neurology in which physicians must choose to offer or withhold treatment on the basis of scant or uncontrolled data. Topics considered included the efficacy and safety of anticoagulation for sinovenous thromboses or arterial ischemic strokes,1 activated tissue plasminogen for embolic strokes, and serial lumbar punctures or acetazolamide for posthemorrhagic hydrocephalus. However, none of these important topics seemed ready for large-scale clinical trials. As a consequence, the neurology group chose 2 conditions deemed sufficiently common, potent, and with adequate existing scientific bases to begin formal clinical studies: neonatal seizures and hypoxic-ischemic encephalopathy (HIE).
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NEONATAL-SEIZURES TREATMENT TRIAL |
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TOPABSTRACTNEONATAL-SEIZURES TREATMENT...FUTURE DIRECTIONSREFERENCES |
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Customary clinical practice includes visual monitoring of high-risk neonates for seizures, performance of a routine electroencephalogram (EEG) for suspicious clinical seizure activity, and empirical treatment with phenobarbital. There presently are no data that have demonstrated unequivocally the efficacy of barbiturates in the treatment of neonatal seizures. Goldberg et al15 reported a randomized, controlled study of thiopental administered soon after perinatal asphyxia. Seizures were diagnosed on clinical grounds and occurred in 76% of the treated infants and 73% of the placebo-treated controls. Hall et al16 reported the results of a neuroprotection trial that administered high-dose phenobarbital after perinatal asphyxia. The group that received phenobarbital had a lower recurrence of seizures than did the placebo group, but the difference was not statistically significant. Connell et al17 reported the response to antiepileptic drugs of electrographically detected neonatal seizures that were discovered during continuous EEG monitoring in 31 acutely ill neonates. Only 2 infants showed a complete cessation of both clinical and EEG-detected seizures, and 6 infants had an equivocal electroclinical response. Clinical cessation of seizures occurred in 13 infants, although their electrographically detected neonatal seizures persisted. The remaining 10 infants had the persistence of both clinical and EEG-detected seizures. Bye and Flanagan18 and Boylan et al19 also reported a mixed response of electroclinical seizures to phenobarbital treatment. Painter et al20 compared the relative response of electrographically detected neonatal seizures to either phenobarbital or phenytoin, which were administered in a randomized fashion. Cessation of electrographically detected neonatal seizures occurred in 43% of the phenobarbital-treated group and in 45% of the phenytoin-treated group. However, because there was not a placebo control arm of the study, absolute efficacy could not be determined. The most recent study of the treatment of neonatal seizures included a standard administration of phenobarbital at a dose of 40 mg/kg and video-EEG monitoring, but there was no control group. Of 22 infants, 11 (50%) had a cessation of seizures, and the choice of a second-line drug in the nonresponders was randomized to lignocaine or benzodiazepines.19 Finally, Evans and Levene21 state in their Cochrane review of the treatment of neonatal seizures that "at the present time, anticonvulsant therapy administered 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." In summary, there is a pressing need for randomized, placebo-controlled, ethically acceptable trials of phenobarbital efficacy and safety in the treatment of neonatal seizures.
Potential Clinical-Trial Frameworks
Before the Newborn Drug Development Initiative Workshop I, the neurology group explored 3 possible frameworks for clinical trials of phenobarbital in the treatment of neonatal seizures. The neurology group ultimately focused on an electroencephalographer-blinded study of phenobarbital versus placebo in a homogeneous group of newborns who are at high risk to develop early subclinical electroencephalographically detected neonatal seizures (ENSs). Anticipatory video-EEG monitoring or early phenobarbital treatment is not customary clinical care. Potential patient populations included those who had experienced HIE, extracorporeal membrane oxygenation (ECMO),22 or newborn heart surgery for serious congenital heart defects.23 This last group was selected to develop a working protocol because contemporary data were available in the congenital heart defects population in which 
11% develop postoperative ENSs that usually are subclinical.24 Because subclinical ENSs would not be diagnosed and treated if infants were not participating in the study, they could be studied ethically, at least for a few hours, by using either phenobarbital or placebo to assess seizure reduction. The occurrence of clinical seizures or electrographically detected status epilepticus would constitute escape criteria.
The neurology group initially proposed to use a commonly used definition of efficacy for seizure-reducing drugs (ie, a 50% reduction of seizures in at least half of the treated patients, adjusted for the controls). Sample-size estimates varied on the basis of the threshold values chosen for study entry, determined by preliminary data.24 For example, if at least 10 ENSs in a 3-hour pretreatment baseline were required to enter the phenobarbital treatment study, it was estimated that 46 patients (23 treated with phenobarbital and 23 treated with placebo) would be needed for enrollment. After additional discussion, however, the neurology group decided that in this specific clinical context, the definition of efficacy should be a total cessation of seizures, not merely a 50% reduction. This alteration reduces the number of subjects required for enrollment.
Clinical-Trial–Design Issues
The neurology group reported the following conclusions about the study-design issues.
Clinical End Points
Clinical end points for treatment of ENSs are notoriously elusive but are still important to clinicians.25 The customary clinical practice is to visually monitor high-risk neonates for the emergence of clinical seizures, perform routine EEG examinations when suspicious clinical activity appears, and empirically treat with phenobarbital. Video-EEG monitoring allows examination of the traditional end point of treatment (ie, cessation of clinical seizures) and ENSs. Although EEG-detected seizure end points are believed to be more objective,26 there are no data that demonstrate interobserver agreement; however, disputes can be adjudicated posthoc. In summary, the neurology group decided that ENSs should be the primary efficacy end point rather than clinical seizures.
Selection of the First Drug To Study
The neurology group agreed that phenobarbital should be the first drug studied on the basis of the following considerations.
25 mg/L, which has been shown to be safe in neonates.20 This level corresponds to a loading dose of 35 to 45 mg/kg per dose. The neurology group hopes that participating clinicians will accept this dose, which exceeds the often-cited clinical convention of 20 mg/kg loading dose.
Exclusion of Preterm Infants
The underlying causes of seizures in preterm infants are not as well understood as those for term infants. The preterm group is etiologically heterogeneous, and no consensus exists for an epileptic basis of paroxysmal clinical "seizures" (variable occurrence of electrographically detected seizures). Theoretically, 
-aminobutyric acid (GABAergic) drugs, paradoxically, may depolarize neurons and lower the seizure threshold in very low birth weight neonates,28 although this effect is not supported by typical clinical observations. As a consequence, the neurology group concluded that this inaugural phenobarbital study should focus on neonates of 
37 weeks' conceptional age.
Generalizability of Phenobarbital-Treatment–Trial Results
The neurology group acknowledged that great care must be exercised in applying the results of the proposed study to other neonatal-seizure populations. The neurology group considered the proposed clinical scenario of the phenobarbital-treatment trial as an example of early and mild seizures, albeit triggered by an acute stress in the form of serious congenital heart defects that require early heart surgery. It is possible that seizures might respond to phenobarbital differently in other circumstances such as for severe HIE, in the premature infant, or in those infants whose seizures arise from developmental abnormalities such as tuberous sclerosis.
Proposed Clinical-Trial Framework
The neurology group had sought a randomized, controlled trial study design that would be sensitive to and respectful of customary clinical practices. After examining 3 different study designs, the neurology group proposed a phenobarbital-efficacy trial for ENSs (see Fig 1) that would include the elements described in Table 1.
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The contemporary treatment of neonatal seizures is hampered by the absence of even a single randomized, controlled efficacy study of phenobarbital or any other antiepileptic drug.21 Although it is customary in the care of newborns with seizures to use phenobarbital or other traditional antiepileptic drugs, evidence of efficacy has never been established. The proposed study could provide the first concrete evidence of treatment efficacy because (1) it examines a homogeneous patient population (those with seizures provoked by acquired central nervous system stressors such as HIE, ECMO, or newborn heart surgery), (2) the recognition and quantification of seizures rests solely on the gold standard of seizure detection (the EEG), and (3) the dosing of phenobarbital is specifically matched to the phenobarbital-binding characteristics of the individual treated. In the contemporary treatment of neonatal seizures, physicians around the world most commonly choose phenobarbital as the first line of treatment. This study would be the first to affirm or refute this practice.
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FUTURE DIRECTIONS |
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TOPABSTRACTNEONATAL-SEIZURES TREATMENT...FUTURE DIRECTIONSREFERENCES |
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ACKNOWLEDGMENTS |
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My thanks go to Donna Ferriero, MD, for helpful comments.
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FOOTNOTES |
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Address correspondence to Robert R. Clancy, MD, Division of Neurology, University of Pennsylvania School of Medicine, Children's Hospital of Philadelphia, 324 S 34th St, Philadelphia, PA 19104. E-mail: clancy{at}email.chop.edu
The author has indicated he has no financial relationships relevant to this article to disclose.
The views presented in this article do not necessarily reflect those of the Food and Drug Administration (FDA). This article reflects discussions of designing clinical trials in newborns and should not be construed as an agreement or guidance from the FDA. Drug development and clinical-trial design must be discussed with the relevant review division within the FDA.
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REFERENCES |
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TOPABSTRACTNEONATAL-SEIZURES TREATMENT...FUTURE DIRECTIONSREFERENCES |
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This article has been cited by other articles:
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  J. M. Freeman The Use of Amplitude-Integrated Electroencephalography: Beware of Its Unintended Consequences Pediatrics, March 1, 2007; 119(3): 615 - 617. [Full Text] [PDF]
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