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Valproate Toxicity

  • Author: Asim A Abbasi, MD, FAAP; Chief Editor: Asim Tarabar, MD  more...
 
Updated: Dec 04, 2015
 

Practice Essentials

Although most cases of valproate (valproic acid [VPA]) overdose are benign, serious toxicity, including death, may occur after acute ingestion.

Signs and symptoms

Few historical features are specifically suggestive of valproate toxicity. The following information should be elicited if possible:

  • Exact time of overdose
  • VPA formulation used
  • Amount of VPA taken
  • Any previous medical and psychiatric problems
  • Any other prescription and nonprescription medications being taken
  • Any suicidal ideation
  • Any indications of domestic violence

Physical examination may provide clues to the nature of the poisoning. Altered vital signs that may be seen in VPA overdose include the following:

  • Hyperthermia/hypothermia
  • Tachycardia
  • Hypotension (with severe overdose)
  • Cardiac arrest (with severe overdose)
  • Respiratory depression necessitating intubation

CNS findings in cases of VPA overdose may include the following:

  • Coma
  • Confusion
  • Somnolence
  • Worsened seizure control
  • Dizziness
  • Hallucinations
  • Irritability
  • Headache
  • Ataxia
  • Cerebral edema

Additional physical findings that may be noted include the following:

  • Alopecia (with severe and chronic overdose)
  • Anorexia, nausea, and vomiting (the most common symptoms in acute toxicity)
  • Renal failure (rare), anuria, and enuresis
  • Tremors and chorea
  • Miosis and nystagmus

See Presentation for more detail.

Diagnosis

Laboratory studies that may be helpful include the following:

  • Serum VPA
  • Screening for anticonvulsants, acetaminophen, and acetylsalicylic acid
  • Complete blood count (CBC) with differential
  • Serum chemistries (electrolytes, glucose, lithium)
  • Liver function studies
  • Determination of anion gap and osmolar gap
  • Coagulation studies
  • Prothrombin time (PT) and international normalized ratio (INR)
  • Pregnancy testing (in women of childbearing age)
  • Serum lipase

Other studies that may be warranted are as follows:

  • Computed tomography (CT) of the head (for cerebral edema)
  • Electrocardiography (ECG)

See Workup for more detail.

Management

Treatment of patients with valproate toxicity is mainly supportive but may also include decontamination, procedures to enhance elimination, and pharmacotherapy.

Initial stabilization and resuscitation includes the following:

  • Stabilize all acute life-threatening conditions
  • Ensure a patent airway; intubate if necessary
  • Establish IV access
  • Obtain information about the overdose, including (1) amount of drug ingested, (2) prescribed dosage; and (3) last date the prescription was filled
  • Check blood sugar levels
  • Consider possible need for naloxone

Decontamination methods include the following:

  • Administration of activated charcoal (ideally within 1 hour after ingestion); the optimum activated charcoal–to-toxin ratio is 10:1
  • Whole-bowel irrigation (WBI)

Elimination-enhancing procedures that may be considered include the following:

  • Hemodialysis (including high-flux) with or without hemoperfusion
  • Continuous venovenous hemodialysis (CVVHD)
  • Multidose activated charcoal (MDAC; probably best used in conjunction with WBI in cases of massive ingestion or ingestion of extended-release products)

Pharmacologic agents that may be tried are as follows:

  • Naloxone
  • L-carnitine (levocarnitine)

See Treatment and Medication for more detail.

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Background

Ingestions of valproic acid (VPA), or valproate, have become increasingly common since 1995, when the US Food and Drug Administration (FDA) approved this agent for the treatment of acute mania in patients with mood disorders. Although most cases of VPA overdose are benign, serious toxicity, including death, may occur after acute valproic acid ingestion.

VPA is an 8-carbon 2-chain fatty acid used mainly for the primary and adjuvant control of simple and complex partial seizures, absence seizures, generalized tonic-clonic seizures, and myoclonic epilepsy. It was approved for use as an anticonvulsant in the United States in 1978. It is also used for acute and maintenance therapy of bipolar disease, for migraine prophylaxis, as an adjunct to benzodiazepines for treatment of alcohol and other sedative-hypnotic withdrawal syndromes, and occasionally for chronic pain syndromes.

For patient education resources, see the First Aid and Injuries Center, as well as Poisoning, Drug Overdose, Activated Charcoal, and Poison Proofing Your Home.

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Pathophysiology and Etiology

VPA toxicity occurs by the following means:

  • Intentional ingestions in attempted suicide
  • Accidental ingestions
  • Intentional poisoning of another person
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Pharmacokinetics

Absorption

VPA is usually absorbed rapidly from the gastrointestinal (GI) tract. Peak serum concentration (Cmax) is recorded at 1-4 hours. In the United States, 5 preparations of VPA are available for oral administration. These products have been compared in fasting individuals receiving a 250-mg dose. Measurements that included time to Cmax (Tmax), which represents the rate of absorption, were obtained. Large differences were found among the various preparations, as follows:

  • VPA syrup - 34.2 mg/L; 0.9 hours
  • VPA capsule - 31.4 mg/L; 2.2 hours
  • Divalproex sodium enteric-coated delayed-release tablet - 26.0 mg/L; 3.4 hours
  • Divalproex sodium extended-release (divalproex-ER) tablet - 11.8 mg/L; 19.7 hours

These differences may even increase, or change dramatically, in an overdose setting. Clinically, the divalproex-ER tablet has been found to cause the longest delays to peak levels in overdose settings.

Serial measurements documenting declining VPA concentrations or prolonged observation are recommended to determine whether discharge or psychiatric placement can be safely accomplished. In massive overdose of enteric-coated or extended-release VPA preparations, Tmax may be decreased to nearly 20 hours. In one case,[1] a woman presented 3 hours after ingestion with an undetectable level (< 2.8 mg/L) but subsequently exhibited a decreasing level of consciousness. At 11 hours, her level was 1160 mg/L.

Distribution

The volume of distribution (Vd) for VPA is 0.1-0.5 L/kg, with most of the agent confined to the extracellular space. After an overdose, protein-binding sites are saturated, increasing the free fraction of VPA and Vd.

Protein binding

At normal serum levels, protein binding for VPA is greater than 80-95%. However, during acute overdose, when protein-binding sites are saturated, this percentage decreases. At a VPA concentration of 40 mg/L, protein binding is about 90%, and at a concentration of 130 mg/L, binding is about 81%. Concentrations exceeding 150 mg/L saturate protein binding, which falls below 70%. In one case report, protein binding was only 29% at a VPA concentration of 451 mg/L.[2] Protein binding may also be lowered in patients with uremia.

Metabolism

VPA is primarily metabolized in the liver through conjugation to form a glucuronide ester and through oxidation by mitochondria. Less than 5% is excreted unchanged in the urine. Many of the metabolites are biologically active and contribute to anticonvulsant action. They may also be responsible for ongoing toxicity (eg, persistent coma) even as serum VPA levels return to normal. VPA metabolites are not represented on serum VPA screening.

Half-life

The elimination half-life for VPA ranges from 5 to 20 hours. It may be increased in neonates, in patients with liver disease, and in those ingesting an acute overdose, particularly with extended-release divalproex. The half-life is 4-14 hours in children, 8-17 hours in adults, and up to 30 hours in those with an acute overdose. Considerable interindividual variation and variability exist, depending upon whether coingestants that may slow GI motility (eg, anticholinergic or opiate drugs) were involved. VPA will cause decreased GI motility.

Dosing and drug interactions

The initial dosage can be as low as 10 mg/kg/day in 2 or 3 divided doses. The maintenance dosage may be as high as 60 mg/kg/day in 2 or 3 divided doses. The therapeutic range is 350-690 µmol/L (50-100 mg/L). Control of symptoms may be improved with levels higher than 690 µmol/L (100 mg/L).

Mild symptoms may occur when levels are in the therapeutic range. Serious intoxication is likely when levels exceed 450 mg/L. Patients with levels above 850 mg/L uniformly present with coma, and 63% of them require intubation. Hemodynamic instability and metabolic acidosis may occur at levels higher than 850-1000 mg/L. Because of the prolonged half-life in overdose, it may take longer than 3 days for levels exceeding 1000 mg/L to drop into the therapeutic range.

VPA increases serum levels of carbamazepine, phenobarbital, and primidone, mainly by inhibiting various cytochrome P450 (CYP450) isoenzymes involved in their metabolism.[3] Cimetidine and ranitidine increase VPA levels by inhibiting hepatic mixed-function oxidase (thereby decreasing VPA metabolism). Drugs that slow the GI tract (eg, opiates and antihistamines) may delay absorption of VPA during coingestion.

Mechanism of toxicity

VPA has been found to affect the action of gamma-aminobutyric acid (GABA). Unlike sedative-hypnotics that enhance the postsynaptic action of GABA (eg, phenobarbital and benzodiazepines), VPA appears to indirectly increase the amount of GABA available to the central nervous system (CNS). In vitro studies have shown that VPA increases GABA levels by increasing the activity of glutamic acid decarboxylase and by inhibiting GABA transaminase.

VPA interacts with voltage-sensitive sodium channels. Its presence inhibits repetitive firing of neurons and is frequency-dependent. In this way, its action is similar to those of phenytoin and carbamazepine. Despite this effect, sodium-channel blockade is not thought to underlie the anticonvulsant activity, and it does not substantially contribute to valproate toxicity.

VPA alters fatty-acid metabolism, impairs beta-oxidation (a mitochondrial process), and disrupts the urea cycle. This leads to hyperammonemia,[4] among other metabolic derangements. Ultimately, end-organ effects (eg, hepatitis, pancreatitis, and hemodynamic compromise) may be the result of severe toxicity due to these impaired metabolic processes.

Through several mechanisms, VPA depletes carnitine levels, resulting in decreased transport of fatty acids and their accumulation in the cytoplasm. This process may result in development of fatty liver.

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Epidemiology

United States and international statistics

Reported acute ingestions of VPA steadily increased around the turn of the 21st century, from 2717 exposures in 1994 to 8705 in 2005, according to the American Association of Poison Control Centers.[5] A likely reason for the increase of exposures was the wider use of valproate for mood stabilization, as opposed to its initial use predominantly as an anticonvulsant. In recent years, however, VPA exposures have stabilized at a lower rate, with 3211 single exposures reported in 2010 and 2998 reported in 2014.[6, 7]

The international frequency of valproic acid toxicity is unknown.

Age-, sex-, and race-related demographics

Although most acute VPA ingestions occur in persons older than 20 years, age does not influence outcomes after an acute ingestion. Children younger than 3 years who are on long-term anticonvulsant medications (long-term valproate theray) and have a coexistent medical illness (eg, influenza, varicella) may be at increased risk for a Reyes-like syndrome, which can result in fever, lethargy, and vomiting. Of note, children younger than 2 years are at significant risk (1:800) for an idiosyncratic, potentially fatal hepatotoxic syndrome, even without the previously mentioned risk factors.[8]

Outcomes after an acute valproic acid overdose do not vary with either sex or race.

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Prognosis

The prognosis for a patient with valproate toxicity depends on the amount ingested, the decontamination and elimination strategies administered (if indicated), and the supportive care given. Severe ingestions may resolve without sequelae after aggressive decontamination, elimination, and adequate supportive care.

In addition to its use as an antiseizure medication, VPA is employed to treat mood disorders. Accordingly, emergency personnel must consider the possibility of multidrug overdoses and the availability of other antiseizure medications, including sedative-hypnotics, lithium, and other medications used to treat mood disorders. Patients must be monitored for signs and symptoms of other toxic syndromes. Acetaminophen levels should be obtained to rule out ingestion of this substance.

L-carnitine is reportedly helpful in cases of VPA overdose associated with hyperammonemia, hepatotoxicity, and coma; however, its role remains to be confirmed, and its optimal usage is yet to be determined. Some authors recommend empiric use of L-carnitine in overdoses when VPA levels exceed 450 mg/L.

However, a review of 316 patients with VPA toxicity who received supportive care, without L-carnitine, found that overall, these patients had a good outcome. On multivariate analysis, the principal risk factor for poor prognosis was coma on presentation.[9]

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Contributor Information and Disclosures
Author

Asim A Abbasi, MD, FAAP Instructor, Department of Emergency Medicine, Strong Memorial Hospital, University of Rochester School of Medicine and Dentistry

Asim A Abbasi, MD, FAAP is a member of the following medical societies: American Academy of Pediatrics

Disclosure: Nothing to disclose.

Coauthor(s)

Kent R Olson, MD, FACEP Clinical Professor of Medicine and Pharmacy, University of California, San Francisco, School of Medicine; Medical Director, San Francisco Division, California Poison Control System

Kent R Olson, MD, FACEP is a member of the following medical societies: American Academy of Clinical Toxicology, American College of Medical Toxicology

Disclosure: Nothing to disclose.

Timothy J Wiegand, MD Director, Ruth A Lawrence Poison and Drug Information Center, Associate Clinical Professor of Medicine and Emergency Medicine, University of Rochester Medical Center and Strong Memorial Hospital

Timothy J Wiegand, MD is a member of the following medical societies: American Academy of Clinical Toxicology, American College of Medical Toxicology, American College of Physicians

Disclosure: Nothing to disclose.

Chief Editor

Asim Tarabar, MD Assistant Professor, Director, Medical Toxicology, Department of Emergency Medicine, Yale University School of Medicine; Consulting Staff, Department of Emergency Medicine, Yale-New Haven Hospital

Disclosure: Nothing to disclose.

Acknowledgements

Fred Harchelroad, MD, FACMT, FAAEM, FACEP Attending Physician in Emergency Medicine, Excela Health System

Disclosure: Nothing to disclose.

Herbert E Hern Jr, MD Assistant Clinical Professor, Department of Emergency Medicine, University of California, San Francisco; Residency Director, Department of Emergency Medicine, Highland General Hospital

Herbert E Hern Jr, MD, is a member of the following medical societies: American College of Emergency Physicians and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Lance W Kreplick, MD, FAAEM, MMM Medical Director of Hyperbaric Medicine, Fawcett Wound Management and Hyperbaric Medicine; Consulting Staff in Occupational Health and Rehabilitation, Company Care Occupational Health Services; President and Chief Executive Officer, QED Medical Solutions, LLC

Lance W Kreplick, MD, FAAEM, MMM, is a member of the following medical societies: American Academy of Emergency Medicine and American College of Physician Executives

Disclosure: Nothing to disclose.

John T VanDeVoort, PharmD Regional Director of Pharmacy, Sacred Heart and St Joseph's Hospitals

John T VanDeVoort, PharmD is a member of the following medical societies: American Society of Health-System Pharmacists

Disclosure: Nothing to disclose.

Acknowledgments

The staff, faculty, and fellows of the San Francisco Bay Area Regional Poison Control Center contributed insight, review, and encouragement for this article.

References
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