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Neurocritical Care
Copyright © 2005 Humana Press Inc.
All rights of any nature whatsoever are reserved.
ISSN 1541-6933/05/3:161–170
DOI: 10.1385/Neurocrit. Care 2005;3:161–170

Perspectives in Intoxications

Phenytoin Poisoning
Simon Craig*
Emergency Registrar, Monash Medical Centre, Clayton,Victoria,Australia

Abstract
Phenytoin toxicity may result from intentional overdose, dosage adjustments, drug interac-
tions, or alterations in physiology. Intoxication manifests predominantly as nausea, central
nervous system dysfunction (particularly confusion, nystagmus, and ataxia), with depressed
conscious state, coma, and seizures occurring in more severe cases. Cardiac complications
such as arrhythmias and hypotension are rare in cases of phenytoin ingestion, but they
may be seen in parenteral administration of phenytoin or fosphenytoin. Deaths are
unlikely after phenytoin intoxication alone. A greatly increased half-life in overdose due
to zero-order pharmacokinetics can result in a prolonged duration of symptoms and thus
prolonged hospitalization with its attendant complications. The mainstay of therapy for
a patient with phenytoin intoxication is supportive care. Treatment includes attention to
vital functions, management of nausea and vomiting, and prevention of injuries due to
confusion and ataxia. There is no antidote, and there is no evidence that any method of
gastrointestinal decontamination or enhanced elimination improves outcome.
Activated charcoal should be considered if the patient presents early; however, the role of
multiple-dose activated charcoal is controversial. Experimental studies have proven
increased clearance rates, but this effect has not been translated into clinical benefit. There
is no evidence that any invasive method of enhanced elimination (such as plasmaphere-
sis, hemodialysis, or hemoperfusion) provides any benefit. This article provides an overview
of phenytoin pharmacokinetics and the clinical manifestations of toxicity, followed by a
detailed review of the various treatment modalities.
Key Words: Phenytoin; fosphenytoin; phenytoin poisoning; activated charcoal; phenytoin
intoxication.
(Neurocrit. Care 2005;3:161–170)
*
Address for correspondence:
Simon Craig Introduction toxicity was less than common than toxicity
Emergency Registrar, due to carbamazepine or valproic acid (1). A
Monash Medical Centre, Phenytoin is a commonly prescribed anti- similar trend is noted in data from an
Locked Bag 29, convulsant medication, useful for the acute
Clayton, Victoria Australian poison center (2), with less calls
and chronic management of most seizure dis- for phenytoin toxicity compared with those
Australia 3169.
orders. Toxicity can result from intentional for carbamazepine or valproic acid.
E-mail:
simoncraig@email.com overdose, dosage adjustments, drug inter- This article aims to provide a brief overview
actions, or physiological alterations in the of the pharmacology of phenytoin and fos-
setting of chronic therapy. Fosphenytoin is phenytoin, to describe the clinical picture of
a water-soluble prodrug of phenytoin for acute toxicity, and to present a detailed review
parenteral administration. of current treatment modalities.
Humana Press The narrow therapeutic index of pheny-
toin is reflected in that 2103 of the 4017 cases Pharmacology
reported in the United States in 2002 were due Phenytoin has been used as an anti-
to unintentional toxicity. However, phenytoin convulsant since the late 1930s (3). It blocks

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162 ______________________________________________________________________________________________________Craig
voltage-dependent sodium channels, limiting the propagation
of seizure discharges (4). This response is mediated by a use-
dependent and voltage-dependent slowing in the rate of recov-
ery of voltage-activated sodium channels from inactivation (3).
Other reported uses for phenytoin include trigeminal
neuralgia (4), some behavioral disorders (5), and as a mood
stabilizer in bipolar affective disorder (6). Although previ-
ously used as an antiarrhythmic for digoxin intoxication (7)
or poisoning with tricyclic antidepressants (8), phenytoin is
essentially obsolete in these settings.
Phenytoin is available in oral (capsules, tablets, extended
release capsules, and oral suspension) and parenteral formu-
lations. Intramuscular administration is not recommended due
to erratic absorption and local irritation (9). Fosphenytoin is
only available for injection and may be given intravenously or
intramuscularly.
Due to its poor water solubility, parenteral phenytoin is avail-
able in a solution that contains propylene glycol and alcohol.
These vehicles are thought to be responsible for some of the
adverse effects related to intravenous administration of pheny-
toin. Fosphenytoin was developed as a water-soluble prodrug
of phenytoin, and it does not contain these compounds (3,4,9).
Pharmacokinetics
Phenytoin is a weak acid that precipitates in the acid gas-
tric environment. The size of the precipitate determines the
rate and extent of intestinal absorption, which is slow, vari-
able, and occasionally incomplete (10). In therapeutic doses,
phenytoin is usually completely absorbed after oral ingestion,
with peak serum concentrations in 1.5 to 3 hours. Extended
release preparations reduce the rate of absorption to produce
peak levels at 4 to 12 hours (11). In the setting of acute inges-
tions, ongoing absorption has been reported to last longer than
2 weeks (12–15); this extended absorption may be due to pheny-
toin’s poor water solubility as well as its effect on reducing
gastrointestinal motility (11).
Fosphenytoin is converted into phenytoin by phosphatases
in the liver and erythrocytes, with a half-life of 8–15 minutes
(3). Therapeutic phenytoin concentrations can be achieved
within 10–30 minutes, depending on the rate of infusion (16).
Phenytoin binds extensively (approximately 90%) to serum
proteins, especially albumin (3). Only the free drug is pharma-
cologically active. The extent of protein binding can be reduced
by drug interactions and conditions such as hypoalbuminemia
or uraemia (4). It freely diffuses into all tissues (notably those
of the central nervous system) and becomes firmly tissue-bound,
with a large volume of distribution (0.6–0.7 L/kg) (17). Phenytoin
levels are higher in the tissues of the nervous system than in
serum. Owing to this property, serum levels may underestimate
the level of central nervous system-bound drug (8).
Phenytoin is metabolized by hepatic microsomal enzymes
to inactive metabolites. It then undergoes enterohepatic recy-
cling and is excreted in the urine, in either the free or conjugated
forms. The mean plasma half-life is approximately 22 hours in
the steady state, but it is variable and dose-dependent (18).
Differences in the rate of metabolism between individuals can
be partially explained by genetic variability in phenytoin
uptake (19) as well as cytochrome P450 enzymes, particularly
CYP2C9. Alleles that differ from the wild type (CYP2C9*1),
such as CYP2C9*2, CYP2C9*3, and CYP2C9*6, are associated
Neurocritical Care
with impaired rates of metabolism, prolonged half-lives (up
to 13 days with CYP2C9*6), and increased risk of toxicity with
“routine” doses (20–24).
The oxidative metabolic pathway is saturable in the upper
therapeutic range; thus, phenytoin elimination changes from
first-order to zero-order kinetics. This change results in a con-
stant rate of metabolism and excretion, despite high drug
concentrations (25,26). Different patients have different rates
of metabolism in overdose (27), due to both differences in
genetic variability as well as exposure to enzyme-inducing
or -inhibiting medication.
Risk Factors for Phenytoin Toxicity
Phenytoin toxicity may be precipitated by the following.
1. Acute overdose. Overdose can occur either by ingestion of
a large amount of drug (e.g., in a suicide attempt or acci-
dental overdose in a young child) or by excessive admin-
istration of phenytoin or fosphenytoin in the hospital
setting. Fosphenytoin, the dose of which is expressed in
phenytoin equivalents (150 mg fosphenytoin = 100 mg
phenytoin) has been administered in excessive doses due
to confusion over product labeling (28). Ingestions of more
than 20 mg/kg usually result in clinical toxicity (29).
2. Inadvertent toxicity from chronic use. As mentioned in the
Introduction, more than one-half the cases of phenytoin
toxicity reported in the United States in 2002 were due to
inadvertent toxicity. This situation may be due to errors
in prescribing, dispensing, or administration; increases
in doses; or changes in brands or formulations of the drug
(30–34).
3. Altered physiology, such as pregnancy, or various disease states.
Phenytoin is highly bound to albumin, with only the free
portion being pharmacologically active. Hypoalbuminemia
of any cause, such as pregnancy, nephrotic syndrome, malig-
nancy, and malnutrition (4,35) may precipitate toxicity, as
may abnormal protein binding as seen in uraemia. Liver
disease may cause both a decrease in function of oxidative
enzymes as well as hypoalbuminemia and also may place
a patient at risk of toxicity (11).
4. Drug interactions (Tables 1–3). Owing to the prominence
of cytochrome P450 enzymes in phenytoin metabolism
(especially 2C9 but to a lesser extent 2C19), drugs that
alter the function of these enzymes can place the patient
at risk for toxicity. Medications that inhibit these enzymes
increase plasma phenytoin concentrations and include
amiodarone, cimetidine, cotrimoxazole, disulfiram, flu-
conazole, isradipine (38), metronidazole, miconazole,
various antidepressants (39–41), 5-fluorouracil (42), and
sulphonamides.
Medications that induce cytochrome P450 enzymes
decrease plasma phenytoin concentrations. These drugs
include alcohol, barbiturates, carbamazepine, theo-
phylline, and rifampicin. Cessation of these drugs, with-
out dosage adjustment, may lead to toxic phenytoin
concentrations (43).
Some drugs (such as sulfonylureas and valproic acid) can
displace phenytoin from plasma protein binding sites,
increasing free (active) phenytoin concentrations and
occasionally precipitating toxicity.
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Phenytoin Poisoning _________________________________________________________________________________________163

Table 1
Important Drug Interactions With Phenytoin Metabolism (11,36,37,43,44,48)

Drugs that may increase serum phenytoin levels

Known substrate for CYP2C9 Known substrate for CYP2C19 Other

Amiodarone Cimetidine Allopurinol Methsuximide

Azapropazone Diazepam Amphotericin Methylphenidate
Co-trimoxazole Felbamate Carbamazepine Namifidone
Dextropropxyphene Fluvoxamine Chloramphenicol Nifedipine
Fluconazole Fluoxetine Chlordiazepoxide Oestrogens
Fluvoxamine Imipramine Chlorpromazine Phenylacetylurea
Isoniazid Ketoconazole Clobazam Pheneturide
Losartan Methoin Clofibrate Phenyramidol
Metronidazole Methylphenobarbital Clopridogrel Pindolol
Miconazole Nor-diazepam Dexamethasone Prochlorperazine
Paroxetine Omeprazole Dicoumarol Progabide
Phenylbutazone Oxcarbazine Diltiazem Ranitidine
Sertraline Proguanyl Disulfiram Remacemide
Stiripentol Propanolol Erythromycin Salicylates
Sulfaphenazole Ticlopidine Ethanol (acute) Sulthiame
Ticlopidine Topiramate Ethosuximide Thioridazine
Tolbutamide Famotidine Tolbutamide
Torsemide Flucytosine Trazodone
Trimethoprim Halothane Troxidone
Warfarin Itraconazole Valproate
Verapamil
Viloxazine

Drugs that may decrease serum phenytoin levels

Other
Rifampicin Acyclovir Diazoxide Sucralfate
(induces CYP2C9 Aspirin Folic acid Theophylline
and CYP2C19) Cisplatin Methotrexate Tolbutamide
Dexamethasone Nitrofurantoin Vigabatrin
Carbamazepine Diazepam Oxacillin Vinblastine
(induces CYP2C19) Diazoxide Phenobarbital
Dichloralphenazone Pyridoxine Hypericum
Doxycycline Reserpine perforatum
Ethanol (chronic) Salicylates (St. John’s wort)

Drugs that have variable effects on serum phenytoin levels

Antineoplastic Diazepam Sodium valproate

agents Phenobarbitone Teniposide
Carbamazepine Primidone/mysoline Valproic acid
Chlordiazepoxide

Other drugs bind to phenytoin, thereby decreasing
absorption and/or enterohepatic recirculation. Antacids,
sucralfate, and enteral feeding may all reduce phenytoin
bioavailability. Activated charcoal is used therapeutically
in the setting of phenytoin overdose to enhance the elim-
ination of the drug (4).
5. Unintentional ingestion of phenytoin. There have been case
reports of phenytoin toxicity due to smoking crack cocaine
adulterated with phenytoin (45) as well as due to Chinese
medicine containing various anticonvulsants (46).
Suggestive clinical features, such as nystagmus, ataxia,
and vomiting, may lead the clinician to consider pheny-
toin toxicity as part of the differential diagnosis in these
settings.
Clinical Features of Phenytoin Toxicity
Cardiovascular toxicity is rarely observed with oral over-
dose, but it is the major toxicity seen with too rapid admin-
istration of intravenous phenytoin. Most signs of toxicity
after oral ingestion can be related to central nervous system
dysfunction.
Phenytoin is concentrated in the tissues of the central nerv-
ous system, especially the cerebellum and brainstem (47).
Common signs of phenytoin toxicity after acute ingestion are
reversible and correlate well with serum levels (48). These signs
are presented in Table 4. It should be noted that injuries from
falls can result from ataxia due to cerebellar toxicity. In one
case series, 59 of 94 patients suffered ataxia. Eighteen had fallen,

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Table 2 Table 3
Other Important Drug Interactions With Phenytoin Phenytoin Effects on Effectiveness of Other Medications
(11,36,37,43,44,48) (11,36,37,43,44,48)

Drugs that may decrease oral bioavailability of phenytoin Phenytoin causes increased toxicity of

Calcium-containing antacids Paracetamol (acetaminophen)

Calcium sulfate (within phenytoin capsules) Acetazolamide
Activated charcoal
Protein hydrolysates for enteric feeding Phenytoin impairs the effect of
Sucralfate
Theophylline Alcuronium Oral contraceptives
Azoles Oxcarbazine
Physical interactions with phenytoin Chlorpromaide Pancuronium
Clozapine Paroxetine
Glucose-containing solutions can cause Corticosteroids Praziquantel
crystallization of phenytoin Coumarin anticoagulants Quinidine
Cyclosporine Rifampicin
Drugs that may displace phenytoin from plasma proteins Diazoxide Sertraline
Doxycycline Teniposide
Acetazolamide Phenylbutazone Frusemide Tetracycline
Ceftriaxone Primidone Glibenclamide Theophylline
Diazoxide Salicylates (high-dose) Lamotrigine Tolbutamide
Heparin Sulphamethoxazole Methadone Topiramate
Ibuprofen Tolbutamide Nicardipine Verapamil
Nafacillin Valproate Nimodipine Vecuronium
Oxacillin Oestrogens Vitamin D

Phenytoin interferes with metabolism, Drugs that are variably effected (either ↑ or ↓) by phenytoin
causing raised concentrations
Carbamazepine
Chloramphenicol Tirilazad Phenobarbitone
Phenobarbital Warfarin Sodium valproate
Primidone Zidovudine Valproic acid

Phenytoin interferes with metabolism, causing reduced

concentrations
Hypotension, prolonged QT interval, and cardiac arrhyth-
Antipyrine Haloperidol Phenobarbital mias can complicate intravenous administration (51), but they
Atorvastatin Itraconazole Prednisolone are rare with ingested phenytoin. Reported complications
Bromphenac Lamotrigine Primidone include hypotension with decreased peripheral vascular resist-
Carbamazepine Lignocaine Praziquantel ance, bradycardia, various conduction delays, ventricular tachy-
Chloramphenicol Methadone Quinidine cardia, ventricular fibrillation, and asystole. Electrocardiogram
Clobazam Metyrapone trans-Retinoic acid (ECG) changes include increased PR interval, widened QRS
Clonazepam Mexilitine β-cis-Retinoic acid interval, and altered ST segments and T waves (48). The cardiac
Clozapine Midazolam Simvastatin effects have previously been thought to be the result of the pro-
Cyclosporine Misonidazole Theophylline
pylene glycol diluent used in the intravenous preparation (8),
Dexamethasone Nisoldapine Topiramate
Dicoumarol Nortryptiline Tricyclic and the risk of these is reduced by adhering to the maximum
antidepressants recommended infusion rate of 50 mg/minute (or 25 mg/minute
Digoxin Oral contraceptives Valproate if the patient is >50 years old) (17). However, serious arrhyth-
Disopyramide Oxazepam Warfarin mias have also been reported with excessively rapid adminis-
Doxycycline Paracetamol Zonisamide tration of fosphenytoin (17), which does not contain propylene
Felbamate Pethidine glycol, and there is a case report of phenytoin mistakenly being
Flunarazine Phenazone infused at a rapid rate (appropriate for fosphenytoin), causing
cardiac arrest (52). It is now recognized that parenteral admin-
istration of propylene glycol, phenytoin, or fosphenytoin can
cause significant cardiovascular toxicity.
and nine of these had suffered injuries from their falls severe A retrospective review of 44 patients with oral phenytoin
enough to require medical care (49). overdose did not demonstrate any significant cardiovascu-
Seizures are uncommonly seen in phenytoin intoxication lar arrhythmias or complications, suggesting that routine
(50), but they may be seen with phenytoin concentrations admission to a telemetry bed is not required (53). The above-
greater than 200 µmol/L (50 mg/L) (43). Their presence should mentioned review of 94 patients admitted over a 10-year period
lead to consideration of a search for an alternative cause (48). found no ECG abnormalities in the 71 patients who had ECGs

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Table 4 “therapeutic error” involving activated charcoal and aspira-

Correlation of Serum Phenytoin Level and Clinical Effects tion/ingestion in the setting of chronic phenytoin therapy (1).

Serum phenytoin level Investigations

(µM/L) (mg/L) Clinical effects
<40 <10 Usually no effects
40–80 10–20 Occasional mild horizontal nystagmus
“Therapeutic” on lateral gaze
80–120 20–30 Nystagmus (spontaneous)
120–160 30–40 Vertical nystagmus, diplopia
Ataxia, slurred speech, tremor,
hyperreflexia
Nausea and vomiting
160–200 40–50 Lethargy, confusion, disorientation,
hyperactivity
Other movement disorders
(clonus, asterixis, choreoathetosis)
>200 >50 Coma, seizures
Adapted from Osborn in Tintinalli et al. (48).
taken (49). There is a single case report of an atrioventricular
junctional arrhythmia in the setting of chronic phenytoin intox-
ication (54).
“Purple glove syndrome” (progressive distal limb edema,
discoloration, and pain) can occur after intravenous adminis-
tration. It is more common in the elderly and those receiving
large or multiple doses. It may resolve spontaneously, but
severe cases can result in extensive skin necrosis and limb
ischemia (4,55).
Inadvertent intra-arterial injection of phenytoin (through
cannulation of the brachial artery in the antecubital fossa) has
reportedly resulted in digital gangrene, necessitating ampu-
tation of the fingers (56) as well as a fatality due to extensive
upper limb and chest wall gangrene in an elderly lady (57).
Prolonged use of phenytoin may induce reversible cos-
metic changes, hypersensitivity, peripheral neuropathy, or a
lupus-like syndrome (4). Phenytoin hypersensitivity is a rare
but serious syndrome, usually occurring after 1–4 weeks of
therapy. It is characterized by fever, rash, and systemic organ
involvement (hepatitis, myocarditis, pneumonitis, and lym-
phadenopathy).
Irreversible cerebellar atrophy has been reported after an
acute overdose (58–62), although it is controversial whether
this effect is due to phenytoin itself, the underlying seizure
disorder, or other causes (62).
Death is a rare complication of phenytoin intoxication. Fatal
cases typically involve phenytoin concentrations of more
than 400–500 µM/L (120–125 mg/L) (43). Early case reports
describe attempted interventions (such as large doses of amphet-
amine or caffeine) as well as limited capabilities for intensive
care, which may have contributed to the outcome (63–65). Of
the four fatalities reported in the United States in 2002 (4017
reported cases), three had coingestants (amlodipine and
isosorbide mononitrite in the first case, desipramine and dex-
tromethorphan in the second, and alcohol in the third). The
fourth patient, an 84-year-old, is listed as having died from a
Serum phenytoin concentrations can be measured, usually
by chromatography or immunoassay, and correlate well with
the severity of the central nervous system effects (66). The
concentration is expressed in either micromoles per liter
(µM/L) or milligrams per liter (mg/L). Conversion between
units can be performed as mg/L × 3.96 = µM/L or
µM/L × 0.252 = mg/L.
Free phenytoin blood levels (therapeutic range = 1–2 mg/L,
toxicity usual when >5 mg/L) most accurately reflect clinical
effects (17), but they are not widely available. They may be
more useful in hospitalized patients, especially in those with
low phenytoin binding capacity (hypoalbuminemia, renal fail-
ure, and drugs that displace phenytoin from plasma proteins)
in whom clinical toxicity may be seen with normal serum
phenytoin levels (43,48). However, in the absence of a specific
reason to obtain free phenytoin levels, total levels are suffi-
cient to guide treatment for the majority of patients.
A comparison of total and free serum phenytoin concen-
trations, adjusted for serum albumin, was performed on 48
hospitalized patients. Significant interpatient and intrapa-
tient variability was demonstrated, leading the authors to
conclude that “monitoring of total serum concentrations is
unreliable and free phenytoin serum concentrations should
be considered for monitoring in hospitalised patients” (67).
In another study, 30% of 139 patients demonstrated a dis-
crepancy between therapeutic, subtherapeutic, or suprather-
apeutic concentrations between free and total phenytoin
concentrations (68).
Despite the inaccuracies noted, in the hypoproteinemia
patient, total corrected serum phenytoin levels can be esti-
mated, if the serum albumin is known using various formulae,
an example of which is presented below:
Phenytoinmeasured × 4.4
Phenytoinnormal =
albumin concentration
where the phenytoin concentration (Phenytoinnormal is the effec-
tive total serum phenytoin concentration if the patient had a
normal albumin level) is in micrograms per milliliter and the
albumin concentration is in grams per deciliter (48).
Despite the greater precision of free phenytoin, total serum
phenytoin is sufficiently accurate to gage toxicity and guide
treatment in most patients.
Most authorities recommend a minimum of two serial
phenytoin levels in acute oral overdose, due to phenytoin’s
prolonged absorption and delay to peak levels (9,48,69).
However, there is no firm recommendation on how many lev-
els, or the duration of monitoring required, to exclude serious
toxicity. There is little correlation between the phenytoin con-
centration at presentation and the severity of intoxication or
hospital length of stay (49).
An ECG should be performed in all patients with toxic con-
centrations and should be repeated if there is a significant rise
in serum phenytoin. Abnormal ECGs should prompt contin-
uous ECG monitoring in an appropriate setting.

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Differential Diagnosis
The typical presentation of phenytoin overdose (sedation,
dysarthria, ataxia, and nystagmus) may be due to intoxica-
tions with many centrally acting drugs, including alcohol,
lithium, benzodiazepines, and most other anticonvulsants.
Nondrug causes may include Wernicke’s encephalopathy,
hypoglycaemia, and posterior cranial fossa disease, such as
tumor or hemorrhage (43).
Seizures in the setting of phenytoin toxicity may be not only
the result of the drug itself but also the coingested medica-
tions, trauma, drug or alcohol withdrawal, and infection (48).
Treatment
Most patients presenting with unintentional phenytoin poi-
soning or mild-to-moderate deliberate self-poisoning only
require clinical observation and supportive care. Severe intox-
ication should result in measures being taken to secure the
airway and support breathing and circulation as appropriate.
The decision to admit, and the admission destination, should
be determined on clinical grounds (amount ingested, pre-
senting symptoms and signs, access to appropriate follow-up
and monitoring, and intent for self-harm), with additional
information gained from serum phenytoin levels and the ECG.
Patients with a normal ECG can be admitted to a nonmoni-
tored bed, provided there are no other indications for intensive
care unit observation (such as decreased conscious state or
seizures).
Stopping the infusion and standard advanced cardiac life
support is indicated for severe complications of intravenous
administration, such as apnoea, hypotension, and cardiac
arrhythmias. These patients should initially be admitted to
intensive care.
There is no specific antidote to phenytoin, and therefore
supportive care is the mainstay of treatment. Attention should
be paid to adequate observation of conscious state, ensuring
safety from injuries due to falls, maintenance of vital functions,
treatment of nausea, and vomiting, and treating seizures if
they occur. Various methods may be used to reduce phenytoin’s
absorption or enhance elimination, but there is no evidence that
any of these measures will change clinical outcome.
The nausea and vomiting associated with phenytoin intoxi-
cation can lead to dehydration, and treatment with antiemetics
and intravenous fluid replacement should be considered.
Gastrointestinal Decontamination
The role of gastrointestinal decontamination is to bind or
remove the ingested drug before it is absorbed into the circu-
lation and able to exert its toxic effects. Three basic approaches
(gastric emptying, administration of activated charcoal, and
catharsis) are used in various poisonings, and their role in
phenytoin toxicity is discussed here. Apart from stopping the
infusion, there is little to be done to reduce absorption of par-
enterally administered overdoses.
Gastric emptying is performed by either induced emesis
with ipecac, or gastric lavage. Induced emesis with syrup of
ipecac is not recommended, especially once the patient has
reached the hospital (70). It is most effective if administered
within 30 minutes of ingestion, and it may reduce serum drug
levels if used appropriately. However, phenytoin toxicity may
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induce a depressed conscious state, placing the vomiting
patient at risk of aspiration. Common complications of ipecac
administration include diarrhea, lethargy, drowsiness, and
prolonged vomiting (29).
Gastric lavage may be considered for potentially life-threat-
ening ingestions if it can be performed soon after ingestion
(within 60 minutes). However, it is an invasive treatment, with
many potential complications, including aspiration pneumo-
nia; respiratory failure; fluid and electrolyte imbalance; and
injuries to the throat, esophagus, and stomach (71).
Neither induced emesis nor gastric lavage has been reliably
demonstrated to remove consistent amounts of ingestants from
the stomach, and both have negligible effects if attempted more
than 1 hour after ingestion (70,71). Gastric emptying should
not be considered routine treatment in phenytoin toxicity, but
it may occasionally have a role in an unconscious patient pre-
senting within 1 hour of ingestion (72), in which case gastric
lavage may be considered only after the airway is secured.
Activated charcoal effectively binds most drugs, including
phenytoin, and is often recommended in the initial treatment
of the intoxicated patient (43). However, its effect diminishes
rapidly with time, and the greatest benefit is seen when admin-
istered within 1 hour of ingestion. Pulmonary aspiration of
activated charcoal may be fatal, and administration to the
vomiting or unconscious patient with airway compromise is
potentially dangerous. Despite the appeal of a therapeutic inter-
vention that reduces absorption as effectively as charcoal, there
is no evidence that its use improves clinical outcome (73).
Cathartics such as sorbitol are sometimes added to activated
charcoal preparations, but there is no evidence of any addi-
tional clinical benefit (74,75).
Whole-bowel irrigation — the administration of large doses
of polyethylene glycol solution by nasogastric tube until a clear
rectal effluent is obtained — may be useful in the patient with
an overdose of sustained-release phenytoin, but it is not gen-
erally recommended. Although it is proven to reduce absorp-
tion of slow-release medications in volunteer studies, thus
potentially being of use, there is no conclusive clinical benefit
demonstrated to date (75–77). If it is considered, ensuring
absence of contraindications (such as ileus or bowel obstruc-
tion), adequate intravenous fluids, and appropriate airway
protection is vital.
Current recommendations suggest that a single dose of acti-
vated charcoal may be useful, even in presentations delayed
up to 2 hours from ingestion (29,43). There is little, if any, role
for gastric emptying. Whole-bowel irrigation may be consid-
ered in patients whose serum phenytoin levels continue to rise
after 24 hours in the setting of a large overdose — this approach
could reduce the ongoing absorption of phenytoin, which may
last for many days in some cases.
Treatment of Specific Complications
Seizures in the setting of phenytoin overdose should be
treated with appropriate doses of benzodiazepines, with the
use of phenobarbital for persistent or recurrent seizures (29).
The patient should be monitored for complications related
to either the seizure or its treatment, such as aspiration,
respiratory depression, hypotension, and arrhythmias.
Endotracheal intubation should be performed for airway com-
promise or persistently decreased conscious state. Hypoxia,
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Phenytoin Poisoning _________________________________________________________________________________________167
electrolyte disturbances, and hypoglycemia should be treated
if present.
As mentioned, seizures should prompt a search for other
causes such as coingestants that may lower the seizure thresh-
old, sepsis, underlying epilepsy, and metabolic abnormalities.
Hypotension is rarely seen with oral overdose, but it may be
seen after parenteral administration of phenytoin or fospheny-
toin. Treatment should commence with slowing or cessation of
the infusion, and a bolus of crystalloid, such as isotonic saline.
Persistent hypotension despite 10–20 mL/kg intravenous fluid
may require dopamine or noradrenaline to maintain blood pres-
sure. If this is the case, consideration of central venous access
and monitoring of central venous pressure to guide further fluid
therapy is appropriate (29).
Bradycardia and other arrhythmias due to parenteral pheny-
toin or fosphenytoin toxicity should be treated along standard
advanced cardiac life support guidelines, by using atropine or
adrenaline where appropriate (29).
Elimination Enhancement
Multiple-Dose Activated Charcoal
There is some experimental evidence that multiple-dose
activated charcoal (MDAC) reduces half-life and enhances
elimination of phenytoin in animal studies (78), as well as
with normal volunteers administered intravenous phenytoin.
In seven normal volunteers, MDAC resulted in a decrease of
apparent half-life from 55.5 to 22.3 hours (79). In another
study, MDAC also resulted in a significant decrease in area
under the curve and in total body clearance in eight normal
volunteers after intravenous phenytoin administration (80).
In addition to the role of activated charcoal in reducing
phenytoin absorption from the gut, the mechanism of action
of MDAC to enhance elimination is thought to be
twofold: interruption of enterohepatic circulation, and “gas-
trointestinal dialysis” (72). Gastrointestinal dialysis describes
a process by which activated charcoal absorbs the ingested
drug in the gut lumen. Drug diffusion into the gastrointesti-
nal tract is enhanced by the concentration gradient maintained
by phenytoin binding to charcoal, resulting in movement of
drug across the gastrointestinal mucosa from the circulation
into the gut lumen (81).
Various case reports suggest a beneficial effect of MDAC in
phenytoin intoxication, reducing the duration of clinical tox-
icity and time to peak serum levels compared with historical
controls (82–84) or previously reported pharmacokinetic param-
eters (85). Other claims include a reduction in the duration
of clinical toxicity, and reduction in length of stay.
However, MDAC is not without risks. Problems include
vomiting, aspiration pneumonia, constipation, electrolyte dis-
turbances, and decreased absorption of concurrently adminis-
tered medications (86). Rare complications include appendicitis
(87), intestinal perforation (88), and small bowel obstruction
(89). These gastrointestinal complications may be more likely
in patients who have ingested drugs that impair intestinal motil-
ity, and repeated abdominal examination and assessment of
bowel sounds is mandatory if MDAC is to be administered.
There is no evidence from controlled trials that MDAC affects
patient outcome, need for, or duration of hospitalization after
phenytoin overdose (29). Routine use is not recommended for
Neurocritical Care
phenytoin intoxication (90), but it should be considered in the
patient with a life-threatening ingestion. It is reasonable to
administer a second dose of activated charcoal in patients with
rising serum levels or worsening clinical condition, despite
gastrointestinal decontamination (29).
Administration of activated charcoal, if decided on, may be
difficult because of phenytoin-induced nausea and vomiting.
Aggressive treatment with antiemetics and intravenous fluids
may be required to facilitate its administration.
Extracorporeal Methods
There are no extracorporeal methods of elimination that
have proven effectiveness on clinical outcomes in phenytoin
toxicity. Due to the high likelihood of a positive outcome with
supportive care alone, it is difficult to justify the use of these
invasive techniques unless toxicity is thought to be truly life-
threatening. These measures may be considered in patients
with severe hepatic or renal disease and ongoing intoxication
where more conservative measures have failed.
HEMOPERFUSION
Case reports of charcoal hemoperfusion in phenytoin intox-
ication describe varying results, with one case reporting no
apparent clinical improvement (91), but another reporting a
decrease in total serum levels from 40.0 to 16.2 mg/L after 3
hours of hemoperfusion, with a total phenytoin elimination
half-life of 3.9 hours (92). Another patient underwent five ses-
sions of direct hemoperfusion, resulting in an improvement
in consciousness, and a reduction in total serum phenytoin
from 54 to 16.5 mg/L after four treatments. A similar rate of
decline in concentration of phenytoin (23.7% reduction rate
after a direct hemoperfusion session) was noted in periodic
cerebrospinal fluid samples from the same patient (93).
An evaluation of a newly developed biocompatible
absorbent system showed effective removal of phenytoin
(among many other drugs) from uremic blood in an in vitro
hemoperfusion circuit (94). At this stage, however, there is no
clinical evidence upon which to base any recommendations
for its use in the intoxicated patient.
PERITONEAL DIALYSIS
Reports of the effectiveness of peritoneal dialysis vary.
Peritoneal dialysis in combination with exchange transfusion
was found to be ineffective in a patient with acute intoxication,
with removal of less than 1.5 and 11% of total body burden (95).
Peritoneal dialysis alone was considered ineffective in the
treatment of a 3-year-old boy with chronic phenytoin intoxi-
cation (96). It also was used in a neonate with toxicity after
intravenous phenytoin, removing 1.8 mg phenytoin/hour
(compared with hepatic elimination of 1.4 mg phenytoin/hour)
and decreased signs of cardiac toxicity (97). The authors hypoth-
esized that low phenytoin binding to albumin, and a higher
diffusion speed through the peritoneum compared with older
patients, may have contributed to the success in this case.
HEMODIALYSIS
Because phenytoin is 90% albumin-bound, it is not removed
by low-flux hemodialysis (98,99). In renal failure, the drug may
be displaced from albumin by uraemic toxins, precipitating
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168 ______________________________________________________________________________________________________Craig
intoxication from raised free drug levels (100). Removal of these
uremic toxins, by using dialysis with a high-flux cellulose mem-
brane, can significantly reduce free phenytoin levels, and this
reduction has precipitated seizures in end-stage renal failure
patients treated with phenytoin (101). To date, there are no
reports of therapeutic use of high-flux dialysis for acute pheny-
toin intoxication, and this intervention cannot be recommended.
HEMOFILTRATION
There is a single case report of continuous veno-venous
hemofiltration with charcoal filter being used in an 8-month-
old child who sustained severe cardiac complications after
intravenous fosphenytoin (102). This resulted in a reduction
of total phenytoin levels from 82 mg/L approximately 8 hours
pre-continuous veno–venous hemofiltration (CVVHF) to 33.9
mg/L 1 hour after completion of CVVHF. Without further
study, CVVHF cannot be recommended as a therapeutic modal-
ity at this time.
PLASMAPHARESIS
Plasmapharesis cannot be recommended for treatment of
phenytoin toxicity. The few reports available in the literature
describe limited effectiveness (103–105), and plasma pheny-
toin levels may actually increase after treatment (106).
NEWER TECHNOLOGIES
A recently published case report describes the use of
hemofiltration along with an extracorporeal liver support
device — the Molecular Adsorbents Recirculating System
(MARS) — in a patient with significant phenytoin intoxication
due to intravenous administration in the setting of acute renal
failure and hemodynamic instability. After an 11.5-hour treat-
ment, the patient demonstrated a reduction in total (32 to 11
µM) and free (9.8 to 2.0 µM) serum phenytoin levels, associ-
ated with clinical improvement over the next 2 days (107).
MARS removes albumin-bound toxins based on the princi-
ple of albumin dialysis. Activated charcoal and anion-exchange
resin are used to cleanse the albumin, allowing it to recirculate.
The main site of phenytoin removal in this patient was found
to be the activated charcoal column. The authors postulate that
some of the beneficial effect of MARS may have been related
to its removal of free radicals, thereby reducing oxidative stress
(107). Despite the positive response in this single case, how-
ever, MARS cannot be recommended at this time.
Follow-Up
Recovery may take many days due to the long half-life of
phenytoin in overdose. However, major morbidity and mor-
tality can usually be avoided with appropriate and attentive
supportive care.
The small risk of persistent cerebellar signs and symptoms
after intoxication should prompt referral of all patients back
to their general practitioner for appropriate follow-up. If these
symptoms are present, consideration of specialist evaluation
is warranted.
In the setting of intentional overdose, formal psychiatric eval-
uation before discharge is necessary to ensure the patient’s safety.
Inadvertent overdose should prompt education about possible
precipitants and ensure that children do not have access to the
Neurocritical Care
medications of others. Attention also should be paid to the patient
with an underlying seizure disorder — their medication may
need to be recommenced or changed before discharge.
Summary
Supportive treatment is the mainstay of therapy for acute or
chronic phenytoin toxicity. Cessation of parenteral administra-
tion and institution of standard advanced cardiac life support
is indicated in the patient who becomes hemodynamically unsta-
ble while receiving intravenous fosphenytoin or phenytoin.
There is no antidote for phenytoin toxicity, and there is no
evidence that any means of gastrointestinal decontamination
or enhanced elimination actually change outcome.
Multiple doses of activated charcoal seem to be a promis-
ing therapeutic intervention to enhance elimination and reduce
the duration of phenytoin toxicity; however, at this stage, there
is insufficient outcome data upon which to base any firm
recommendation.
There is insufficient evidence to recommend any particular
method of enhanced elimination for acute phenytoin toxicity.
The decision to use any invasive method should be made in
conjunction with a clinical toxicologist.
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♦ Volume 3, 2005