Emergency Medicine Australasia (2004) 16, 361–365

Blackwell Publishing, Ltd. ToxicologyPhenytoin overdose: multiple sequelae

Phenytoin overdose complicated by prolonged intoxication and residual neurological deficitsSimon CraigMonash Medical Centre, Melbourne, Victoria, Australia

Abstract

This report describes a case of massive phenytoin deliberate self-poisoning, notable fordelayed peak serum concentrations, multiple general complications, and permanentcerebellar injury. A 38-year-old 70 kg male patient presented to the ED after ingestion ofat least 10 g of phenytoin 12–16 h earlier. Marked cerebellar dysfunction and persistentvomiting were observed, with an initial serum phenytoin concentration of 181 µmol/L.Initial conservative treatment (activated charcoal, whole bowel irrigation), and laterattempts at charcoal haemoperfusion were unsuccessful. The serum phenytoinconcentration peaked on day 15 (354 µmol/L). The patient developed seizures followedby a prolonged depression in conscious state requiring intubation. Multiple medicalsequelae occurred and the patient was discharged to a rehabilitation facility 100 daysafter admission exhibiting signs consistent with permanent cerebellar dysfunction.

Key words: activated charcoal, phenytoin, poisoning, overdose, toxicity.

Introduction

Deliberate self-poisoning with phenytoin usuallycauses cerebellar toxicity which may last for hours todays. Rarely, massive ingestions can result in delayedand erratic absorption, with time to peak serumconcentrations greater than 2 weeks.

Case report

A 75 kg 38-year-old male patient attended the EDfollowing ingestion of an unknown quantity of alcoholand at least one hundred 100 mg phenytoin capsules(total ingestion 10 g; 133 mg/kg). The time of ingestion

was reported to be the previous evening, between 12and 16 h prior to presentation.

On arrival, he complained of nausea and dizziness.He was alert, orientated, haemodynamically stable,but mildly agitated. Examination revealed dysarthria,bidirectional nystagmus, and ataxia. He was unableto walk unaided. A provisional diagnosis of acutephenytoin toxicity was made. Activated charcoal wasnot administered due to delayed presentation pluspersistent nausea and vomiting. Intravenous metoclo-pramide 20 mg and normal saline were administered,and he was referred to the medical unit for admission.

His past medical history included a right basalganglia haemorrhage 2 years previously, which had atthat time presented with generalized seizures. He had

Correspondence: Dr Simon Craig, Emergency Medicine Registrar, Emergency Department, Monash Medical Centre, Locked Bag 29, Clayton South, Vic. 3169, Australia. Email: simoncraig@email.com

Simon Craig, MBBS (Hons), Registrar.Conflicts of interests: None

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been placed on phenytoin 300 mg daily, and had beenseizure-free since. The underlying cause of thehaemorrhage was thought to be Moya Moya disease,a rare occlusive disease of intracranial arteries; thishad never been confirmed. Other past history includedhyperlipidaemia, hypertension, insulin requiring dia-betes mellitus (on Humulin 20 units twice daily), andintermittent binge drinking of alcohol.

Initial investigations showed a mild neutrophilia,normal biochemistry and liver function (serum albumin38 g/L). Paracetamol, salicylate and blood ethanol con-centrations were not detected. The serum phenytoinconcentration was 181 µmol/L (normal therapeutic range40–80 µmol/L). Free phenytoin concentrations werenot measured. A 12-lead ECG showed normal sinusrhythm, rate of 90 bpm, but prolongation of the cor-rected QT interval (460 milliseconds). No arrhythmiaswere documented during his ED stay of over 12 h.

The patient was admitted to the ward for intraven-ous hydration and supportive care. He was prescribedthiamine (100 mg daily), and received intravenous

diazepam (5 mg) for a single short-lived seizure on thefirst night of admission.

On day 6, the patient continued to suffer nausea,ataxia and agitation, associated with persistent increasein phenytoin concentration (Fig. 1). Phenytoin concretionswere considered, so whole-bowel irrigation using poly-ethylene glycol-electrolyte solution (Golytely, GolytelyProducts, Australia) was commenced. Unfortunately,this was poorly tolerated and ceased due to ileus.

The patient’s serum phenytoin concentration con-tinued to rise (347 µmol/L day 9). This was associatedwith persistent vomiting, intermittent drowsiness andworsening cerebellar toxicity. Charcoal haemoperfusionwas instituted following admission to the ICU. Heunderwent two treatments of haemoperfusion (day 9and day 13), each associated with transient decrease inserum phenytoin concentration and mild symptomaticimprovement (Fig. 1). Cessation of haemoperfusion wasassociated with rapid return of serum phenytoin toprehaemoperfusion concentrations. Further haemo-perfusion was abandoned due to the transient response

Figure 1. Serum phenytoin level by day of admission.

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and exhausted supplies of charcoal cartridges. Despiterising phenytoin concentrations, the patient wasdischarged from the ICU on day 14. His clinicalcondition was little changed from admission, withpersistent cerebellar signs and intermittent drowsiness.

On day 15, the phenytoin concentration was356 µmol/L. The patient developed high fevers relatedto haemoperfusion catheter-related sepsis. The femoralline was removed, and ceftriaxone and flucloxacillinwere commenced. On day 16, the patient had a tonic-clonic seizure lasting 5–10 min, which resolvedspontaneously. This was followed by prolongeddepression in conscious state, eventually requiringintubation and readmission to the ICU. Neurologicexamination revealed no new focal changes. Computedtomography of his brain was consistent with previoushaemorrhage. Electroencephalogram showed generalizedslow wave changes consistent with a non-specificencephalopathy, presumed drug-induced. Persistentlyhigh (above 280 µmol/L) phenytoin concentrationsprompted administration of multidose activatedcharcoal (25 g every 3 h) once his ileus had resolved.This was commenced on day 18, and the phenytoin fellconcentration rapidly over 5 days.

During this second admission to ICU (days 16–28),the patient developed aspiration pneumonia and catheter-related sepsis. Slow ventilator weaning necessitatedtracheostomy. On discharge from ICU, he was profoundlydebilitated, with minimal movement of voluntarymuscles, and required a lifting machine for all transfers.

On the medical ward the patient developedextensive lower limb deep venous thrombosis andbibasal pneumonia. He required gastrostomy feedingbefore eventual removal of the tracheostomy. Thepatient had relative sparing of cognitive function butshowed signs of critical care myopathy and persistentcerebellar toxicity. He was discharged to slow-streamrehabilitation, after 100 days in hospital.

Discussion

This case illustrates the potential for prolonged acutetoxicity following large ingestions of phenytoin as wellas the potential for significant prolonged morbidity.

Pharmacokinetics of phenytoin in acute overdose

Phenytoin precipitates in the acid gastric environment.The size of the precipitate determines the rate andextent of gastrointestinal absorption, which may be

slow, variable and incomplete. In addition, phenytoinreduces gastrointestinal motility,1 which may explainthe delay to peak serum concentrations in this case (15days) and a previously reported case (2 weeks). Onceabsorbed, phenytoin is highly protein-bound. It dis-tributes to all tissues (notably those of the centralnervous system) and becomes firmly tissue-bound (volumeof distribution 0.6–0.7 L/kg).2 Serum concentrationsmay underestimate the concentration of CNS-bounddrug. Phenytoin is metabolized by hepatic microsomalenzymes to an inactive metabolite, which is thenconjugated with glucuronide and excreted in the bileand urine. The rate of metabolism is influenced by geneticvariability in cytochrome P450 2C9 enzymes (threealleles CYP 2C9*1, *2, *3) resulting in slower metabolismin some patients.3 The oxidative metabolic pathway issaturable in the upper therapeutic range, thus phenytoinelimination changes from first-order to zero-orderkinetics. This results in a constant rate of metabolismand excretion despite high drug concentrations.2

Phenytoin toxicity

Phenytoin is concentrated in the central nervous sys-tem, especially in the cerebellum. Common signs ofphenytoin toxicity following acute ingestion arereversible and correlate well with serum concen-trations (Table 1).4 Seizures are uncommon followingphenytoin overdose. This patient’s seizures may have

Table 1. Correlation of plasma phenytoin concentration andclinical effects (adapted from Osborn, in Tintinalli et al.)4

Serum phenytoin concentration (µmol /L)

Clinical effects

< 40 Usually no effects40–80 Normal therapeutic range

Occasional mild horizontal nystagmus on lateral gaze

80–120 Nystagmus (spontaneous)120–160 Vertical nystagmus, diplopia

Ataxia, slurred speech, hyperreflexia

Nausea and vomiting160–200 Lethargy, confusion,

disorientation, hyperactivityOther movement disorders

(spasticity, clonus, choreoathetosis)

> 200 Coma, seizures

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been due to his pre-existing cerebrovascular disease orsepticaemia. The prolonged depression in consciousstate due to high serum concentrations predisposedthis patient to complications related to prolongedimmobility and hospitalization.

Irreversible cerebellar atrophy has been reported5

following acute overdose. This is also an uncommoncomplication of prolonged use. This patient’s prognosiswith regard to his cerebellar atrophy is unclear.

Management of acute phenytoin overdose

Most patients presenting with unintentional phenytoinpoisoning or mild-moderate deliberate self-poisoningonly require clinical observation and supportive care.Serial monitoring of phenytoin concentrations may berequired if there are signs of severe intoxication or amassive ingestion is suspected. Acute cerebellar toxicitymay place the patient at risk of injuries due to falls.

If the history suggests a large overdose, early wholebowel irrigation may be considered in an attempt toprevent prolonged toxicity. Similarly, in largeringestions, activated charcoal may be helpful, both forgastrointestinal decontamination and enhancedelimination. There are reports of the effectiveness ofmultiple-dose activated charcoal in reducing the timeto peak phenytoin concentration, the duration oftoxicity6,7 and length of hospital stay8 in patients withacute phenytoin toxicity. Enhanced elimination isrelated to the absorption of phenytoin from the portalcirculation into the gastrointestinal tract, thus creatinga concentration gradient between the blood and theintestinal lumen — so-called ‘gastrointestinal dialysis.’9

There is some experimental evidence that multiple-dose activated charcoal reduces half-life and enhanceselimination following intravenous phenytoin admin-istration.10,11 However, there is no evidence that treat-ment with multiple doses of activated charcoal reducesmorbidity or mortality12 and current consensusguidelines do not recommend multiple-dose charcoalin phenytoin overdose, citing insufficient clinical data.

There are few reports of successful13,14 and unsuc-cessful15 use of charcoal haemoperfusion in phenytointoxicity. This therapy has been considered in severecases of phenytoin toxicity, but is not routinelyrecommended. In this patient, the rapid return toprehaemoperfusion concentrations may have been dueto redistribution from other sites into the plasma, orfrom continued absorption from the gastrointestinaltract. There are case reports of disappointing resultswith plasmapharesis.16,17

Due to phenytoin’s high protein binding, low-fluxhaemodialysis has only had a minor role18 in elim-ination of phenytoin. Uraemic products may increasefree phenytoin concentrations by displacing the drugfrom albumin.19 Removal of these products usingdialysis with a high-flux cellulose membrane reducesfree phenytoin concentrations20 that may have thera-peutic benefit. A recent report describes the use ofhaemofiltration concomitantly with an extracorporealliver support device (Molecular Adsorbents RecirculatingSystem; MARS) in a patient with phenytoin into-xication, leading to rapid clinical improvement.21 Thissystem removes albumin-bound toxins using theprinciple of albumin dialysis.

Conclusion

Most ingestions of phenytoin are relatively benign,requiring no more than temporary cessation of thedrug and supportive care. However, large ingestionsmay be associated with unpredictable pharmaco-kinetics and multiple complications associated withprolonged hospitalization. This patient may havebenefited from early whole bowel irrigation and/ormultiple-dose activated charcoal.

These interventions are not the standard of care foracute phenytoin toxicity, but may be considered inindividual patients based on risk assessment. Factorssuch as history of large ingested dose or persistentlyrising serum concentrations may prompt their con-sideration. There is insufficient evidence to recommendany particular method of enhanced elimination foracute phenytoin toxicity. Invasive methods of gastroin-testinal decontamination and enhanced elimination arebest performed under guidance of a clinical toxicologist.

Acknowledgements

Thanks to Dr Paul King, Dr George Braitberg, Dr IanSummers and Dr Graeme Thomson for reviewing themanuscript and providing helpful advice.

Accepted 20 April 2004

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