he neonatal period is the highest risk period for
seizures during the lifespan of humans, with seizures occurring in 1-5%
of the neonates [1]. Despite the magnitude of the problem, the current
treatment paradigms are based on limited clinical evidence; the debate
concerning the best drug or drugs, their dose and duration still
continues. Phenobarbital is the most commonly prescribed anticonvulsant
worldwide for treatment of neonatal seizures. There are limited studies
exploring the effectiveness of phenobarbital. The reported seizure
cessation rates vary between 33% to 40% after a single loading dose of
15-20 mg/kg [2]. In a study by Gilman, et al. [3], rapid
sequential loading with phenobarbital (up to 40 mg/kg) could improve the
clinical response rate in neonates with seizures (n=120) till a
cumulative response rate of 77%. However, the therapeutic effect
plateaued after serum levels of 40 µg/mL [3]. Furthermore, there is
limited data on efficacy and safety of phenobarbital in relation to its
dosage and blood levels [4]. The study by Wasim, et al. [5] in
this issue of Indian Pediatrics addresses this critical issue of
drug efficacy and serum drug levels. The authors performed a prospective
observational-study in 99 neonates. They reported clinical seizure
cessation in 44 neonates (44%) after a single loading dose of 20 mg/kg
of phenobarbital. Interestingly, more than a third of neonates with
sub-therapeutic serum phenobarbital levels had clinical seizure
cessation. This finding could indicate that either the seizure control
is independent of serum levels or the current cut-off values of
therapeutic drug levels need to be revisited.
Rapid achievement of therapeutic levels (through
intravenous or intramuscular routes) has been reported to result in
earlier control of serial seizures in neonates [6]. However, neonates
with adequate serum phenobarbital levels may still not achieve seizure
control [6-8]. There may be several reasons for this observation; the
underlying etiology, altered drug pharmacokinetics, and altered
blood-brain barrier properties. Additionally, greater serum
phenobarbital levels may be required for seizure control in preterms as
they have a lower brain to plasma ratio of phenobarbital [9]. There is
also a wide variability in the pharmacokinetic parameters in neonates;
like the volume of distribution, fraction unbound in plasma, and the
elimination half-life [10]. Additional factors influencing drug
pharmacokinetics include frequent use of hypothermia and other drugs
used to treat the sick neonate. Given the multitude of factors,
therapeutic drug monitoring for phenobarbital should be encouraged for
optimal care of neonates with seizures.
The work by Wasim, et al. [5] has certain
limitations which can be avoided in future studies. The foremost
limitation was the lack of use of video EEG as a diagnostic tool and for
defining endpoints. Neonatal seizures are difficult to recognize
clinically, and both over- and under-diagnosis are common. Electrical
seizures (as confirmed by EEG) have been shown to persist in 53%
neonates treated with phenobarbital/phenytoin [11]. Phenobarbital has
also been reported to increase electro-clinical dissociation in neonatal
seizures [12]. Therefore, the clinical assessment alone should not be
used for evaluating the efficacy of phenobarbital in controlling the
seizure activity. Any research in the field of neonatal seizures should
preferably use multichannel video-EEG to define and monitor seizure
activity. While using the EEG, the degree to which electrical seizures
need to be suppressed, is again an unresolved issue. The pharmacodynamic
curves for clinical and EEG seizure control with phenobarbital have been
suggested [3,12,13]. The ideal goal may be a total suppression of
electrographic seizures. However, such suppression will require
intensive monitoring, use of drugs in high doses, and a possibility of
drug-related toxicities. An integral part of intensive monitoring should
be therapeutic drug monitoring.
Phenobarbital may have a role in the prevention of
seizures as well. Phenobarbital (20 mg/kg IV) given within 6 hours of
life to term and near-term neonates with hypoxic ischemic
encephalopathy, significantly decreased the incidence of neonatal
seizures as compared to placebo (8% vs. 40%; P=0.01) in
one randomized trial with small sample size [14]. When used as a
preventive drug, the target should be to achieve seizure prevention with
no drug-related toxicity. In this context, therapeutic drug monitoring
can help to titrate the serum levels in the therapeutic range.
There has been a concern of long-term
neurodevelopmental adverse effects of drugs used during the neonatal
period. Phenobarbital enhances chloride flux through the GABA-A receptor
and may cause neuronal apoptosis; an observation demonstrated in the
immature rat brain at plasma concentrations relevant for seizure control
in humans [15]. In the study by Wasim, et al. [5], repeated
loading doses of phenobarbitone resulted in significant increase in the
number of neonates attaining toxic levels (4/6 neonates loaded with 40
mg/kg phenobarbital had toxic levels after 12 hours). The study raises a
question over the practice of repeated loading with phenobarbital in
neonates who do not respond to the initial dose or who have recurrences
while on maintenance doses.
The study by Wasim, et al. [5] has not
addressed many factors (like hepatic, renal functions, serum proteins,
co-medications), which may have potentially influenced the serum
phenobarbital levels. Any future studies on therapeutic drug monitoring
should also consider these and other factors that can potentially
influence drug levels. Despite this, findings of the study by Wasim,
et al. [5] are significant, and should stimulate further scientific
exploration of therapeutic monitoring of phenobarbital and other drugs
in neonates. Neonates are a special and vulnerable research group among
an already vulnerable group of children; and therefore, drugs in wide
use like phenobarbital need to be evaluated with rigor. The reports of
long-term adverse effects of antiepileptics and other drugs used in
neonates should serve as the basis for more rigorous study of
pharmacokinetics and pharmacodynamics of these drugs in neonates.
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