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Indian Pediatr 2013;50:
735-736 |
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Anticonvulsants for Neonates: High Time We
Were Seized of the Matter
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Sourabh Dutta
Division of Neonatology, Department of Pediatrics,
PGIMER, Sector 12, Chandigarh 160 023, India.
Email:
[email protected]
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Seizures are a common problem in the neonatal
intensive care unit (NICU). Surprisingly, there is scant evidence
regarding the optimal anticonvulsant for treating neonatal seizures [1].
In the USA, of the neonatal seizures that are treated with a
non-benzodiazepine drug, phenobarbitone accounts for 76% and phenytoin
for 16% [2]. Until now, the only good quality randomised controlled
trial (RCT) comparing phenobarbitone and phenytoin was by Painter, et
al. [3] in 1999. Pathak, et al. [4] have conducted a
much-needed randomized controlled trial comparing phenobarbitone and
phenytoin. This RCT is commendable because it was conducted within the
resource constraints of a level II neonatal unit in India. They were
unable to measure serum phenobarbitone and phenytoin levels, presumably
owing to financial constraints. The authors also acknowledge that their
unit–like most units in developing countries has no access to EEG
monitoring.
However, the fact remains that the non-availability
of EEG raises several methodological issues. The correct clinical
identification rate of clonic seizures is only 66%; of subtle seizures
is 32% and of non-seizure movements is 47% [5]. The inter-observer
agreement (kappa) among pediatricians for the identification of neonatal
seizures is just 0.21. Thus, in clinical practice, there is widespread
overdiagnosis and underdiagnosis of neonatal seizures and disagreement
between observers [6]. This poses a problem in a research study, such as
the one conducted by Pathak, et al. [4], where the
inclusion of patients is solely on clinical grounds. The relationship
between EEG and clinical seizures is particularly weak in the case of
subtle seizures and tonic seizures; and in the current study, 87% of all
seizures were either subtle or tonic [4,7]. In this open-label trial
with fixed, small block sizes (27 blocks of 4 each), non-concealment of
allocation towards the end of each block was inevitable. Thus, at least
27 (25%) patients would have their allocated intervention known
beforehand. A selection bias in allocating 25% or more patients could
easily swing the results of the study. Being open-label, there was an
unavoidable risk of performance and ascertainment bias – further
compounded by the fact that cessation of neonatal seizures (like the
diagnosis of seizures) has a high rate of misclassification and
inter-observer disagreement. Pathak, et al. [4] did not mention
the time frame for measurement of the primary outcome nor the waiting
time before giving the second anticonvulsant for persistent seizures-
both of which could affect the measurement of the primary outcome.
Painter, et al. [3] had enrolled neonates on
the basis of a risk for seizures and presence of electrographic evidence
of seizures. They reported no evidence of the superiority of
phenobarbitone or phenytoin in terms of electrographic seizure
cessation. The small sample size precluded any change of practice based
on Painter’s study alone. Pathak, et al. [4] claim a much higher
success rate for phenobarbitone for clinical seizures and recommend its
use. Previous EEG-based studies–both randomized and non-randomized – on
the efficacy of phenobarbitone have reported efficacy rates ranging from
43% to 50% only [3,8,9]; hence the efficacy rate of 72% in the study by
Pathak, et al. [4] is exceptional. They state that their study
resembles real-life situations in developing countries and therefore has
a high external validity. However, one must be cautious before accepting
this conclusion because without robust internal validity, external
validity is of limited relevance.
There is an urgent need for large, well-designed RCTs
with a low-risk of bias and adequate follow-up, comparing phenobarbitone
with phenytoin and newer anti-convulsants. The RCT by Pathak, et al.
[4] has certainly brought back our focus on to this important area. It
is high time that researchers in this field were seized of the matter.
Funding: None; Competing interests: None
declared.
References
1. Booth D, Evans DJ. Anticonvulsants for neonates
with seizures. Cochrane Database Syst Rev. 2004;CD004218.
2. Blume HK, Garrison MM, Christakis DA. Neonatal
seizures: treatment and treatment variability in 31 United States
pediatric hospitals. J Child Neurol. 2009;24:148-54.
3. Painter MJ, Scher MS, Stein AD, Armatti S, Wang Z,
Gardiner JC, et al. Phenobarbital compared with phenytoin for the
treatment of neonatal seizures. N Engl J Med. 1999;341:485-9.
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Phenobarbitone and phenytoin for treatment of neonatal seizures:
Open-label randomized controlled trial. Indian Pediatr.
2013;50:753-7.
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clinical correlates, associated brain lesions, and risk for neurologic
sequelae. Pediatrics. 1993;91:128-34.
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8. Boylan GB, Rennie JM, Chorley G, Pressler RM, Fox
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