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Phenytoin poisoning

Phenytoin poisoning
Literature review current through: Jan 2024.
This topic last updated: Nov 16, 2023.

INTRODUCTION — Phenytoin (eg, Dilantin) is an anticonvulsant medication used to treat many seizure disorders. It is also a Vaughan-Williams class IB antiarrhythmic agent, although it is now infrequently used for that indication.

Phenytoin toxicity is rarely fatal, but can cause neurologic symptoms ranging from nystagmus to ataxia to coma. Intravenous phenytoin administration may rarely be complicated by the Purple Glove Syndrome.

The basic pharmacology, presentation, and management of phenytoin toxicity will be reviewed here. The clinical use of phenytoin to treat epilepsy and general issues concerning management of the poisoned patient are discussed separately. A summary table to facilitate emergency management is provided (table 1). (See "Overview of the management of epilepsy in adults" and "General approach to drug poisoning in adults".)

EPIDEMIOLOGY — Phenytoin toxicity is associated with few serious adverse events or fatalities [1]. According to the 2015 Annual Report of the American Association of Poison Control Centers (AAPCC) National Poison Data System, 1606 single-substance phenytoin exposures resulted in only 33 major outcomes and two deaths [1]. There were four reported fatalities in cases of multiple-substance exposures in which phenytoin or fosphenytoin was deemed contributory, but in none of these cases was phenytoin determined to be the primary cause of death. This low prevalence of major outcomes and deaths is similar to that seen in previous years [2].

Fosphenytoin, a prodrug of phenytoin that is administered parenterally, is believed to have fewer adverse effects than phenytoin. However, there were 29 cases of cardiac events related to fosphenytoin infusion reported to the US Food and Drug Administration (FDA) between 1997 and 2002 [3]. Ten of these resulted in death. Arrhythmias included bradycardia, high degree AV block, and sinus arrest. It is unclear how many of these dysrhythmias can be directly attributed to fosphenytoin, since many of these patients had significant preexisting cardiac pathology or were presumed to be in a state of cardiac stress from status epilepticus. (See "Antiseizure medications: Mechanism of action, pharmacology, and adverse effects", section on 'Phenytoin and fosphenytoin'.)

PHARMACOLOGY AND CELLULAR TOXICOLOGY — Phenytoin binds to and inhibits voltage-dependent sodium channels, which are found on both neuronal and cardiac tissue. The increased membrane threshold for depolarization after sodium channel blockade lowers the susceptibility of neuronal tissue to epileptogenic stimuli. Excessive inhibition, however, may compromise normal cerebral function, leading to the incoordination and altered mental status characteristic of both acute and chronic phenytoin toxicity.

Inhibition of sodium channels in cardiac tissue reduces the risk of arrhythmia. Phenytoin shortens cardiac action potentials and prolongs the refractory period between them. Cardiac effects such as dysrhythmias and SA and AV nodal blockade have been reported, especially following intravenous administration of phenytoin [3-5]. Oral phenytoin has only rarely been reported to cause cardiac complications [6].

Phenytoin is available in oral (capsules, tablets, extended-release capsules, and oral suspension) and parenteral formulations. In parenteral formulations, phenytoin is diluted in propylene glycol, which may cause toxicity including hypotension and cardiac dysrhythmias [7]. Oral suspensions of phenytoin may contribute to toxicity due to solubility issues when increased concentrations of the drug are found in the liquid component of inadequately shaken preparations [8,9].

PHARMACOKINETICS — Phenytoin is 70 percent bioavailable after oral ingestion [10]. The volume of distribution is approximately 0.5 to 0.8 L/kg, with significant protein binding (to albumin) in vivo. Phenytoin may be displaced from plasma proteins by many drugs, which can result in toxicity [11,12]. At higher serum concentrations of phenytoin, protein binding saturates and free phenytoin concentrations (which determine toxicity) increase dramatically with only modest increases in overall phenytoin concentrations. This fact is important to bear in mind when interpreting toxic serum phenytoin concentrations. A list of drugs that alter serum phenytoin concentrations is provided (table 2). (See 'Laboratory evaluation' below.)

Phenytoin metabolism varies depending upon its serum concentration. Hydroxylation by the cytochrome p450 system is the critical step [13]. Metabolism follows first-order kinetics in the therapeutic range and mild overdoses, meaning that a fixed percentage of phenytoin is eliminated over a given period. At higher concentrations, the cytochrome p450 enzyme system becomes saturated, leading to zero-order kinetics in which a fixed amount of phenytoin is eliminated over a given period. This alteration in metabolism results in a prolonged half-life (24 to 230 hours in overdose) and contributes to persistently elevated serum concentrations [14,15].

The metabolism of phenytoin is affected by many substances that interact with the cytochrome p450 system. A large number of drug-drug interactions will either raise or lower serum phenytoin concentrations, depending upon whether they induce or inhibit the p450 system (table 2) [11]. Cytochrome p450 genetic polymorphism appears to predispose some individuals to phenytoin toxicity secondary to slow metabolism [16,17].

Fosphenytoin is a prodrug that is converted to phenytoin by serum and tissue alkaline phosphatases. Fosphenytoin is more expensive than phenytoin and is only available for intravenous and intramuscular administration. The fosphenytoin preparation does not contain propylene glycol and was initially thought to provide a safer means for rapid intravenous infusion, although cardiac toxicity and deaths from fosphenytoin have been reported [3,18]. Literature review demonstrates a similar adverse effect profile to phenytoin [19].

Fosphenytoin binds to serum proteins and, in the presence of renal or hepatic disease, its plasma concentration will be elevated and its rate of conversion to phenytoin may accelerate [20]. In addition, fosphenytoin will competitively displace phenytoin from plasma protein binding sites, thereby increasing the concentration of free phenytoin [19].

CLINICAL FEATURES

History and drug administration — Mild phenytoin toxicity (from overdoses or chronic toxicity) is frequently encountered in patients with epilepsy, particularly after a change in medication dosing. Such patients generally complain of worsening coordination. More serious intoxication is usually seen with intentional ingestions or therapeutic error. Drug interactions and alterations in drug metabolism or physiology may contribute [21]. Intravenous loading of phenytoin in a patient presumed to be noncompliant is a common scenario. To avoid the latter error, we recommend obtaining a serum phenytoin concentration prior to IV loading to treat assumed noncompliance. (See 'Management' below.)

Rapid administration of parenteral phenytoin and, to a possibly lesser extent, fosphenytoin, is associated with hypotension, bradyarrhythmias, and occasional asystole [3,22]. These manifestations are avoided by slow (less than 50 mg/min) intravenous administration.

In cases of overdose with oral phenytoin, the clinician should inquire about depression, intentional self-injury, coingestants, and use of illicit drugs. Additional history regarding trauma, past medical history, and current medications may help to identify comorbidities and coingestants. General issues related to the history and physical examination of the poisoned patient are discussed elsewhere. (See "General approach to drug poisoning in adults".)

Physical examination — Typically, acute phenytoin toxicity does not alter vital signs. However, mild to moderate hypothermia has been described in several case reports [23-26]. One report suggested that hypoadrenalism may have played a role [26], but this has not been reported in other cases. Phenytoin-induced hypothermia is likely uncommon and improves as blood phenytoin concentrations return to a normal range.

The earliest signs of phenytoin toxicity are typically horizontal nystagmus and unsteady gait. More severe toxicity results in slurred speech, along with a gradually worsening mental status typified by lethargy, confusion, or coma. Hyperreflexia is occasionally seen.

It is difficult to demonstrate a clear correlation between serum drug concentrations and clinical findings, and there is large individual variability. A table outlining approximate correlations is provided (table 3).

Although oral phenytoin has only rarely been reported to cause cardiac complications [6], intravenous infusions of phenytoin or fosphenytoin can cause hypotension and bradyarrhythmias [3,22].

Drug-induced hypersensitivity syndrome — Anticonvulsant hypersensitivity syndrome (AHS) is a rare but potentially life-threatening event associated with aromatic antiepileptics, including phenytoin. AHS represents an idiosyncratic drug reaction that occurs in 1 in 1000 to 1 in 10,000 patients treated with phenytoin and has a fatality rate of 10 percent. Symptoms vary but classically include fever, rash, lymphadenopathy, and possibly other organ involvement. Pharyngitis is common. When severe, the syndrome can include hepatitis, megaloblastic anemia, rhabdomyolysis, and arteritis. AHS is discussed in detail elsewhere. (See "Drug eruptions", section on 'Drug reaction with eosinophilia and systemic symptoms'.)

Signs of AHS are usually seen within two months of starting phenytoin therapy. The diagnosis is frequently missed, and must be considered in any patient taking phenytoin with suggestive symptoms. Patients who develop the hypersensitivity syndrome are at risk for recurrence and may exhibit similar reactions to other anticonvulsants.

Skin and soft tissue

Toxic epidermal necrolysis and Stevens-Johnson syndrome — Patients receiving phenytoin experience an estimated 1 in 1000 to 1 in 10,000 risk of developing toxic epidermal necrolysis or Stevens-Johnson syndrome. Development of these conditions following phenytoin exposure is idiosyncratic. Most cases occur within the first two months of phenytoin use [27]. (See "Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis".)

Purple glove syndrome — Another uncommon skin complication of phenytoin that is typically associated with intravenous administration is the so-called Purple Glove Syndrome (PGS) [22,28-31]. PGS generally develops within the first 24 hours after infusion and resolves within days to weeks [32-34]. It is not known what proportion of PGS cases resolve without intervention or without significant complications, as serious cases of PGS are rare and milder cases may be unreported. Typically, PGS presents with peripheral edema, blistering, pain, and discoloration of the extremity receiving intravenous phenytoin. Pulses and sensation may be diminished. Superficial venous thrombosis has been noted in histopathological samples, although arterial Doppler studies are usually normal [32,35]. Skin necrosis may develop, and treatment may require surgical intervention.

The pathophysiology of PGS is poorly understood, although many theoretical mechanisms have been proposed, including chemical irritation from added propylene glycol and sodium hydroxide, vasoconstriction, vasculitis, microthrombus formation, and phenytoin leakage into soft tissue with subsequent edema [35,36]. Extravasation is not uniformly present, and extravasation of phenytoin does not necessarily result in PGS. PGS has been reported after an overdose of oral phenytoin [37]. Use of large bore cannulas or central lines for phenytoin administration has been reported to decrease the incidence of PGS [36].

DIFFERENTIAL DIAGNOSIS — Toxic levels of other anticonvulsant agents, such as carbamazepine, may present with ataxia and altered mental status. Patients who are postictal may present with an abnormal neurological examination and depressed mental status, although isolated nystagmus and ataxia are unusual. Hypoglycemia should always be considered and ruled out in the setting of altered mental status or new-onset neurological abnormality. Ataxia may be encountered with a broad range of neurological disease and drug toxicities including: cerebellar disease (eg, stroke, hemorrhage, mass), Wernicke's Encephalopathy, ethanol or toxic alcohol overdose, and Parkinson disease. (See "Wernicke encephalopathy" and "Ethanol intoxication in adults" and "Clinical manifestations of Parkinson disease".)

The differential diagnosis of altered mental status and coma is vast and cannot be fully addressed here, but the emergency clinician should consider alternative infectious, metabolic, vascular, neurologic, toxicological, structural, and traumatic etiologies (table 4). (See "Stupor and coma in adults" and "Evaluation of abnormal behavior in the emergency department" and "Diagnosis of delirium and confusional states" and "Acute toxic-metabolic encephalopathy in adults".)

LABORATORY EVALUATION

Phenytoin concentration — Most emergency departments in developed nations can perform total serum phenytoin concentrations, which often correlate with patient examination findings. Discordant exam findings and serum concentrations should prompt consideration of alternative diagnoses. As an example, the presence of coma is generally not consistent with a serum phenytoin concentration below 30 mg/L (30 microg/mL or 120 micromol/L). However, in the setting of an acute overdose, serum concentrations may be rising rapidly enough to account for progression to coma. Serial measurements of the serum phenytoin concentration should be obtained when patients with an acute overdose deteriorate rapidly.

A serum albumin concentration may help explain discordance between the serum phenytoin concentration and clinical symptoms and signs. Hypoalbuminemia results in a higher free phenytoin concentration at any given total phenytoin level. Because it is the free phenytoin concentration that determines toxicity but the total phenytoin concentration that is measured and reported, hypoalbuminemic patients with a therapeutic or mildly elevated phenytoin concentration may exhibit significant toxicity that is greater than expected.

The Sheiner-Tozer formula may be used to correct for hypoalbuminemia in this setting:

Corrected total phenytoin concentration = Observed total phenytoin concentration/([0.2 x Albumin]+0.1); phenytoin in microgram/mL, albumin in g/dL

Free phenytoin concentrations are not routinely measured in hospital laboratories, and this equation may be useful if a patient has signs of phenytoin toxicity despite a "therapeutic" or "sub-therapeutic" phenytoin concentration [38]. However, a systematic review of studies of the Sheiner-Tozer equation found it to be imprecise in a number of clinical situations and prone to bias in some others [39].

Liver function and other specific testing — Further laboratory testing may include liver function tests and serum electrolytes. Hepatic dysfunction will increase the risk of phenytoin toxicity and prolong the effects of intoxication by reducing the rate of metabolism.

A complete blood count (CBC) rarely affects management. Remember that leukocytosis is commonly encountered after seizures, and a normal white blood cell count does not exclude meningitis or encephalitis. Computed tomography of the brain may be needed to screen for suspected intracranial pathology in patients with stupor or coma.

In patients with anticonvulsant hypersensitivity syndrome, liver function tests will often show elevated aminotransferases and the CBC with differential will frequently show eosinophilia or marked leukocytosis. Creatine phosphokinase may be elevated if myositis is present [40].

An electrocardiogram (ECG) reveals the arrhythmias, atrioventricular block, or sinus arrest with junctional or ventricular escape that may occur after intravenous (or very rarely oral) exposure [3,6].

Routine testing of poisoned patient — Routine laboratory evaluation of the poisoned patient should include the following:

Fingerstick glucose, to rule out hypoglycemia as the cause of any alteration in mental status

Acetaminophen and salicylate concentrations, to rule out these common coingestions

Electrocardiogram (ECG), to rule out conduction system poisoning by drugs that effect the QRS or QTc intervals

Pregnancy test in women of childbearing age

MANAGEMENT

General approach — Phenytoin toxicity is frequently encountered in general emergency practice, and most cases are readily managed with supportive care. Fatalities are rare. Protect the patient from falls secondary to ataxia. Treat nausea and vomiting with antiemetics, such as metoclopramide. A summary table to facilitate emergency management is provided (table 1).

Airway and breathing — For patients who require endotracheal intubation, standard rapid sequence intubation (RSI) protocols can be used. Most medications used in RSI are safe in patients with phenytoin intoxication, with the exception of lidocaine, which shares phenytoin's antidysrhythmic properties (Vaughan Williams Class IB) and should not be used. (See "Rapid sequence intubation in adults for emergency medicine and critical care".)

Cardiovascular — Symptomatic bradydysrhythmias following intravenous phenytoin administration are rare [3]. Most resolve soon after stopping the infusion, but some may require transcutaneous or transvenous pacing. Hypotension can be treated with IV boluses of isotonic saline. If dysrhythmias persist, alternative etiologies should be considered and cardiology consultation obtained. Atropine, epinephrine, and dopamine remain first line medical treatment for symptomatic bradydysrhythmias. (See "Advanced cardiac life support (ACLS) in adults".)

Gastrointestinal decontamination and removal — Activated charcoal (AC) may be useful in the setting of a recent ingestion (ie, within several hours). Multiple doses may remove some unbound phenytoin undergoing enterohepatic circulation, even if the phenytoin was administered intravenously [41], or in cases of chronic phenytoin toxicity [42].

When considering treatment with AC, clinicians must weigh the potential benefits of treatment with the risks of charcoal aspiration, particularly because nausea, vomiting, and central nervous system depression occur frequently with phenytoin intoxication.

We suggest that a single dose of activated charcoal be administered to patients with phenytoin overdose, unless they manifest a depressed mental status. We do not always use multidose activated charcoal (MDAC), but it appears to be effective. MDAC has been used successfully when phenytoin concentrations have remained persistently elevated secondary to impaired metabolism [43]. Charcoal should be withheld in patients who cannot protect their airway, unless endotracheal intubation is performed first. However, endotracheal intubation should not be performed solely for the purpose of giving charcoal. (See "Gastrointestinal decontamination of the poisoned patient".)

Gastric lavage and whole bowel irrigation are not recommended in patients with phenytoin toxicity.

Extracorporeal removal — Extracorporeal removal of phenytoin via hemodialysis or hemofiltration is usually unnecessary, but phenytoin appears to be moderately dialyzable despite its high protein binding. Following systematic review and analysis of clinical data obtained from 31 patients (30 case reports or case series), the Extracorporeal Treatments in Poisoning (EXTRIP) Workgroup proposes the use of either intermittent hemodialysis (preferred) or hemoperfusion (acceptable) in select cases of severe poisoning with prolonged coma or prolonged incapacitating ataxia [44]. We believe this is a reasonable approach, but recommend consultation with a medical toxicologist if possible when hemodialysis is considered. (See 'Additional resources' below.)

Seizures — Seizures from phenytoin toxicity have been reported, but may stem from a patient's preexisting seizure disorder. Seizures should be treated with benzodiazepines and barbiturates as needed.

Antidotal therapy — There is no specific treatment or antidote for phenytoin toxicity.

Hypersensitivity and skin reactions — Treatment of the anticonvulsant hypersensitivity syndrome is supportive and includes immediate discontinuation of phenytoin and any other potentially inciting medications (eg, carbamazepine, phenobarbital). Consultation with a rheumatologist or dermatologist is advised. Glucocorticoids are often used and may be helpful, but conclusive evidence of their efficacy is lacking. (See "Drug eruptions".)

Patients who develop toxic epidermal necrolysis or Stevens-Johnson syndrome, which are potentially life-threatening conditions, receive standard treatment. (See "Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis" and "Stevens-Johnson syndrome and toxic epidermal necrolysis: Management, prognosis, and long-term sequelae".)

The optimal management of Purple Glove Syndrome remains unclear. Case reports describe some improvement with the application of topical nitroglycerin and brachial plexus nerve block [32], as well as elevation, application of heat, and soft tissue massage of the affected extremity [33]. Vascular or hand surgical consultation should be obtained in cases of suspected digital or skin necrosis. Anticoagulation is occasionally performed although there is no clear evidence that it is effective [34]; we do not recommend routine anticoagulation unless suggested by the vascular or hand surgery consultant.

Standard care for cases not involving digital or skin necrosis includes close observation, elevation of the affected limb above the level of the heart, and analgesia. There is not yet sufficient data to formulate strong recommendations about how long an observation period is necessary. Since outcomes can be severe, we recommend a minimum of 24 hours of observation in asymptomatic individuals with PGS.

Monitoring and disposition — Patients with acute phenytoin overdose who are symptomatic should be admitted to the hospital. Serial phenytoin concentrations should be obtained roughly every two hours until the serum concentration begins to fall, as it can increase over the first several hours, especially if gastrointestinal decontamination is inadequate. Falling serum concentrations correlate with clinical improvement, generally noted by the resolution of ataxia, slurred speech, and nystagmus. Once medical symptoms resolve, psychiatric consultation is needed for all cases of intentional ingestion.

The disposition of the patient with chronic phenytoin toxicity depends on both the degree of toxicity and social circumstances. As a general rule, patients may be discharged home if they can ambulate safely and have someone (eg, family member, partner) who will stay with them and assist with the activities of daily living until toxicity has completely resolved. Patients who cannot ambulate safely or do not have someone to provide assistance should be admitted to the hospital.

PEDIATRIC CONSIDERATIONS — Clinicians should maintain a lower threshold to admit children with suspected phenytoin toxicity. Children may manifest clinical signs of phenytoin toxicity at serum concentrations lower than adults. Furthermore, the presentation of significant toxicity may be more subtle and examination findings limited.

As with adults, the basis for decision-making is clinical evaluation rather than laboratory testing. Phenytoin toxicity should be considered in the differential diagnosis for any pediatric patient with nystagmus and ataxia or altered mental status, and a family member known to take anticonvulsants. Infants and toddlers cannot demonstrate gait ataxia and intoxication may be difficult to detect. These patients may present with indistinct signs such as lethargy, poor feeding, or hypotonia [45].

Serum drug concentrations above 40 mg/L (40 microg/mL or 160 micromol/L), however, are sufficient reason for admission and observation. Older children with less significant symptoms (eg, nystagmus and mild ataxia), responsible caretakers, and prearranged neurology follow-up may be discharged home with clear instructions to return immediately for any worsening of symptoms.

Because many cases of lethal phenytoin toxicity in children are due to therapeutic error, children receiving parenteral administrations must be carefully monitored [3].

ADDITIONAL RESOURCES

Regional poison control centers — Regional poison control centers in the United States are available at all times for consultation on patients with known or suspected poisoning, and who may be critically ill, require admission, or have clinical pictures that are unclear (1-800-222-1222). In addition, some hospitals have medical toxicologists available for bedside consultation. Whenever available, these are invaluable resources to help in the diagnosis and management of ingestions or overdoses. Contact information for poison centers around the world is provided separately. (See "Society guideline links: Regional poison control centers".)

Society guideline links — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: General measures for acute poisoning treatment" and "Society guideline links: Treatment of acute poisoning caused by specific agents other than drugs of abuse".)

SUMMARY AND RECOMMENDATIONS

Clinical featuresPhenytoin toxicity is associated with few serious adverse events or fatalities. Signs of mild to moderate toxicity (serum concentrations below 40 mg/L [40 microg/mL or 160 micromol/L]) are typically confined to nystagmus, ataxia, slurred speech, nausea, and vomiting. At higher levels of toxicity, mental status can deteriorate to coma, and cardiac dysrhythmias and seizures may occur. A summary table to facilitate emergency management is provided (table 1). (See 'Epidemiology' above and 'Clinical features' above.)

Common iatrogenic causes – Two common iatrogenic causes of phenytoin intoxication include intravenous (IV) loading of phenytoin in a patient presumed to be noncompliant and overly rapid IV administration. To avoid these errors, a serum phenytoin concentration should be obtained prior to IV loading, and the rate of IV phenytoin administration should be kept below 50 mg/min. (See 'History and drug administration' above.)

Differential diagnosis – Toxic levels of other anticonvulsant agents, such as carbamazepine, may also present with ataxia and altered mental status. The differential diagnosis for symptoms consistent with phenytoin intoxication is broad, and includes hypoglycemia, postictal state, cerebellar disease (eg, stroke, hemorrhage, mass), Wernicke's encephalopathy, and ethanol or toxic alcohol overdose. (See 'Differential diagnosis' above.)

Laboratory testing – A serum phenytoin concentration should be obtained whenever poisoning with this drug is suspected. Serial levels can be helpful, particularly if the patient acutely decompensates. Serum concentrations generally correlate with clinical findings. Discordant serum concentrations and clinical signs should prompt consideration of alternative diagnoses. Hypoalbuminemia increases free phenytoin concentrations, which increase toxicity. (See 'Laboratory evaluation' above.)

Management – Management of phenytoin intoxication consists of supportive care. The airway, breathing, and circulation of the rare unstable patient are stabilized as necessary. In patients with phenytoin overdose but without a depressed mental status, we suggest administering a single dose of activated charcoal (Grade 2C). Multiple doses of activated charcoal may be helpful, even among patients with chronic or intravenous toxicity. (See 'Management' above.)

Hemodialysis and hemoperfusion may be beneficial in select patients with severe toxicity. (See 'Extracorporeal removal' above.)

Disposition – Patients who are symptomatic from an acute phenytoin overdose should be admitted to the hospital. Patients with chronic phenytoin toxicity may generally be discharged home if they can ambulate safely and have someone who will stay with them and assist with the activities of daily living until toxicity has completely resolved. (See 'Monitoring and disposition' above.)

Pediatric considerations – Children may manifest clinical signs of phenytoin toxicity at serum concentrations lower than adults, so a more liberal threshold for admission and monitoring is used. As with adults, the basis for decision-making is clinical evaluation rather than laboratory testing. Infants and toddlers may present with indistinct signs such as lethargy, poor feeding, or hypotonia. (See 'Pediatric considerations' above.)

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