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Phenytoin is a commonly
prescribed antiepileptic drug. However, it has a narrow therapeutic
range, and a total serum level >20 mcg/mL is associated with
clinically relevant toxicity [1]. Deaths have been reported at
levels of 50-70 mg/L. However, treatment recommendations beyond
supportive care are unclear, and effectiveness of extracorporeal
elimination techniques is still under debate [2]. From the clinical
point of view, urgent lowering of phenytoin concentration may reduce
the risk of dysrhythmia, shorten length of stay in the intensive
care, possibly reduce the risk of nosocomial infection, presumably
reduce costs, and may therefore be favorable [3]. We present a case
of accidental ingestion of phenytoin that was treated successfully
with four sessions of charcoal hemoperfusion, resulting in both
clinical improvement and normalization of serum phenytoin
concentration.
Case Report
A 4 year old child was referred from a district
hospital for sudden onset of altered sensorium and involuntary head
nodding movements of 12 hours duration. There was no history of
fever, trauma and the parents denied any intoxication. There was no
significant family history except epilepsy in father, who was
receiving phenytoin. On examination, she had nystagmus and head
nodding movements and was in altered sensorium with a Glasgow coma
scale of 10/15. Pupils were normal size and reacting to light, deep
tendon reflexes were slightly depressed, Babinski sign was positive,
and fundal examination was normal. A differential diagnosis of
posterior fossa mass lesion or drug intoxication was entertained.
Airway, breathing and circulation were attended
to and stabilized. CT scan of the brain and cerebrospinal fluid
analysis were normal. The child was started on supportive measures
and phenytoin intoxication was suspected in view of nystagmus,
altered sensorium and father being on phenytoin. Serum phenytoin
levels were elevated and in the toxic range 88 mcg/mL (therapeutic
levels: 10-20 mcg/mL). She was started on supportive measures and
nasogastric feeds. Oral activated charcoal at that stage was not
thought of as it was already 42 hours after ingestion [4].
The sensorium continued to be the same, and the
levels, repeated a week later, were still elevated (94 mcg/mL).
Parents were counseled about the other options available including
hemodialysis and hemoperfusion. Parents consented for charcoal
hemoperfusion. Charcoal hemoperfusion was done with a
cellulose-coated activated charcoal hemoperfusion column. Charcoal
hemoperfusion cartridge (Hofpal, Sweden) adult size was used since
pediatric cartridge was not available. The only complication noted
was mild thrombocytopenia (platelet count of 90-100,000/mm) in the
first session that recovered back to the reference range on the 3rd
day. Four sessions of charcoal perfusion was performed and the child
recovered subsequently without any sequelae. The serum phenytoin
levels 24-hour after each hemoperfusion cycle were 56 µg/mL, 26 µg/mL,
23 µg/mL and 12 µg/mL, respectively.
Discussion
The narrow therapeutic index, the wide
inter-individual variability in the rate of phenytoin metabolism and
clearance, and the saturation (zero-order) pharmacokinetics of
phenytoin are responsible for the observed dose-related toxicity
[5]. The plasma half-life of phenytoin has been shown to be dose
dependent in humans. In other words, the time required for the
plasma level to halve itself increases as the concentration of the
drug increases. An explanation for the non exponential decline of
phenytoin is that the biotransformation mechanism approaches
saturation at higher plasma levels [6] and in the absence of
displacing agents, is bound tightly to plasma proteins (87% to 93%)
[7]. Therefore, disappearance of phenytoin is not a simple
exponential process and doesn’t follow apparent first order
kinetics, the elimination follows a zero order kinetics. This would
explain the persistence of symptoms for several days at high plasma
concentrations of the drug [6]. The increase in the concentration
levels from 89 to 94 mcg/mL can be attributed to the absorption from
the gut [6, 8]. The half life of phenytoin after the first
hemoperfusion was 64 hours and was 43 hours after the 2nd
hemoperfusion. The half life of phenytoin decreases as the levels
decrease, as seen in our child as the various metabolic pathways are
no longer saturated, and is in accordance with other reports [6, 9].
There have been a lot of controversy with regard
to management of phenytoin overdose [1,8,10]. Benefit from charcoal
hemoperfusion [10] and usage of molecular adsorbent recirculating
system [1] have been reported. The role of charcoal can be explained
by the fact that bound phenytoin has been found to dissociate from
albumin in the presence of activated charcoal and subsequently
becomes adsorbed to the activated charcoal [10].
There have been few reports of charcoal
hemoperfusion being not effective in oral intoxication as it was
attributed to absorption from the gut continuously and the levels
coming back to the pre-hemoperfusion state. There has been only one
report to the best of our knowledge of overdosage in a child who was
treated conservatively [9]. There have been no pediatric reports of
usage of any of these modalities in treatment of phenytoin overdose.
Charcoal hemoperfusion was planned in view of evidence indicating
severe neurological disabilities with phenytoin overdose [8]. The
absolute indications for hemoperfusion in children in phenytoin
toxicity are not described as reports of this condition in
literature are very few. We suggest that elimination techniques may
be considered in children with prolonged toxic concentrations of
phenytoin.
Funding: None;Competing interests:
None stated.
References
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Cooper CE, Patsalos PN, et al. Treatment of phenytoin
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