Valproate Toxicity 

Updated: May 30, 2020
Author: Asim A Abbasi, MD, FAAP; Chief Editor: Michael A Miller, MD 

Overview

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)

  • Arterial blood gas (ABG) analysis

  • 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.

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. Most cases of VPA overdose are benign, but serious toxicity, including death, may occur after acute VPA 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.

Pathophysiology and Etiology

VPA toxicity occurs by the following means:

  • Intentional ingestions in attempted suicide

  • Accidental ingestions

  • Intentional poisoning of another person

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.

In males, long-term use of VPA may lead to an impairment of reproductive function. The supposition that this impairment is largely due to oxidative stress is supported by animal studies demonstrating a protective effect of antioxidants.[5, 6]

Alpers-Huttenlocher syndrome (AHS), a neurometabolic disorder caused by mutations in mitochondrial DNA polymerase gamma (POLG), is associated with an increased risk of developing fatal VPA hepatotoxicity.[7]

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.

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.[8] 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 2996 reported in 2018.[9, 10]

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.[11]

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

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.[12]

 

Presentation

History

Few historical features are specifically suggestive of valproate (valproic acid [VPA]) toxicity. As in most poisonings, a clinical history of the ingestion, including the amount and exact time of ingestion, is helpful. Adequate documentation of previous medical and psychiatric problems is essential.

Prescription and nonprescription medications (including over-the-counter drugs and drugs of abuse) may contribute or mask symptoms of overdose. Accordingly, all medications taken must be documented. The possibility of other coingestions not reported by the patient, family, or prehospital providers (including herbal and natural remedies) must also be considered.

The exact time of the overdose should be recorded if possible. The VPA formulation (eg, capsules, sprinkles, syrup, or extended-release tablets) should be noted, as should the exact amount taken. In particular, divalproex and extended-release formulations may cause significant delays in peak concentration during overdose.

The remaining or unused amount in the prescription bottle should be counted or measured and subtracted from the original amount dispensed from the pharmacy. A discrepancy between the amount actually missing and the amount that should be missing if the prescribed regimen was correctly followed provides a rough estimate of the amount the patient may have taken.

Previous suicidal attempts should be inquired into; these are important in that they can lead the clinician to consider referring the patient to a psychiatrist. If a patient continues to have suicidal ideation, holding him or her for psychiatric evaluation on legal grounds may be warranted.

All patients with VPA overdose should also be screened for domestic violence. Because domestic violence is widely underreported, it is important to be aware of and alert to other potential indications of such abuse, including assault, depression, and suicide attempts.

Physical Examination

Physical examination may provide clues to the nature of the poisoning. Physical findings may help in determining the severity of the overdose, but they are not specific for VPA overdose. Gastrointestinal (GI) upset with nausea and vomiting is the most common presentation of patients with VPA overdose, closely followed by central nervous system (CNS) symptoms of decreased consciousness level and confusion.

Altered vital signs

Vital signs are highly variable in patients with VPA poisoning. Both fever and hypothermia have been reported.

Hypotension has been reported with severe overdoses. Many case reports of severe VPA overdose discuss hypotension refractory to aggressive use of intravenous (IV) fluids and pressor agents. In a large multicenter review of 134 patients (80 of whom had VPA levels in the toxic range), 3% of patients had hypotension in association with acute VPA ingestion, and 25% of patients with levels above 850 mg/L had hypotension.[13] VPA levels above 1000 mg/L may be associated with refractory hypotension.

The risk of hypotension notwithstanding, hemodialysis is often recommended for these patients to achieve a rapid increase in elimination, on the grounds that these high VPA levels are associated with severe morbidity and mortality. Hemodialysis is often effective and may produce dramatic improvements for these patients.

Cardiac arrest has been reported in severe VPA overdoses. The clinical condition of patients with VPA overdose can worsen dramatically as the drug is being absorbed. In cases involving a massive overdose, apnea and cardiac arrest can develop.

Respiratory depression necessitating intubation occurs with increasing frequency as VPA levels rise.

CNS manifestations

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

  • Coma

  • Confusion

  • Somnolence

  • Worsened seizure control

  • Dizziness

  • Hallucinations

  • Irritability

  • Headache

  • Ataxia

  • Cerebral edema - This well-documented manifestation usually occurs 48-72 hours after ingestion, even as serum levels are decreasing

In a large multicenter review of 134 patients (80 with VPA levels in the toxic range), 71% of patients presented with lethargy, and 15% were comatose.[13] All patients with serum levels greater than 850 mg/L were comatose, and 63% of these patients needed intubation.

It has been suggested that elevated serum ammonia levels can produce encephalopathy via the inhibition of glutamate uptake by astrocytes, which may lead to potential neuronal injury and perhaps cerebral edema. It has also been suggested that hyperammonemia may lead to a disruption of the osmotic gradient, which is thought to precipitate the edema.[14]

This valproate-induced hyperammonemic encephalopathy[15] may be an adverse effect of the drug and is characterized by lethargy, vomiting, altered cognitive function, focal neurologic deficits, and decreased level of consciousness. Its onset or severity may not be related to the drug dosage administered or to the duration of previous treatment.

In contrast, Caruana Galizia and colleagues report a case of akinetic-rigid syndrome, with ataxia and marked cognitive impairment, that developed in a patient on long-term valproate therapy. The patient's serum ammonia and valproate levels were normal, but after withdrawal of valproate, her motor symptoms resolved within 2 weeks and her cognitive impairment markedly improved.[16]

Other findings

Additional physical findings that may be noted in patients with valproate toxicity include the following:

  • Dermatologic - Alopecia has been reported in severe and chronic overdose

  • GI - Anorexia, nausea, and vomiting are the most common symptoms in acute toxicity

  • Genitourinary (GU) - Renal failure is rare; case reports describe renal failure in patients with serum VPA levels higher than 1000 mg/L; anuria and enuresis may be noted

  • Musculoskeletal - Patients may present with tremors and chorea

  • Ocular - Miosis and nystagmus may be observed

 

DDx

 

Workup

Approach Considerations

Determination of the valproate (valproic acid [VPA]) level is obviously warranted. Reviews have shown that nearly 20% of VPA overdose patients may present with initial VPA concentrations that are in the therapeutic range, or even undetectable; accordingly, serial levels should be obtained until a peak level has been reached and the levels are clearly trending downward. Delayed absorption has been frequently reported, particularly with divalproex and extended-release formulations.

Screening for anticonvulsants, acetaminophen, and acetylsalicylic acid should be considered. Patients taking VPA are frequently taking other anticonvulsants that they may not disclose. Screening is preferably completed early and helps in determining if potentially complicating coingestion has occurred.

A complete blood count (CBC) with differential should be performed. Thrombocytopenia and agranulocytosis may be noted.

Serum chemistries should be ordered. The lithium level should be included because of the use of this agent in mood stabilization (eg, in bipolar disorder). The following abnormalities may be noted:

  • Hypocalcemia

  • Hypernatremia (sodium salt of divalproex), rare hyponatremia (postulated to be secondary to syndrome of inappropriate antidiuretic hormone secretion [SIADH])

  • Hypophosphatemia or hyperphosphatemia

  • Hyperglycemia or hypoglycemia (particularly in association with liver failure)

Liver function studies are indicated. Fulminant hepatic failure is a potentially fatal but rare complication of both acute and chronic valproate toxicity. Children younger than 3 years who are taking many anticonvulsants and who have medical comorbidities are at increased risk for this complication.

Nonlactate metabolic acidosis should be tested for. In one series, no patients with VPA levels lower than 450 mg/L developed acidosis.[8] Respiratory depression with hypercapnia should also be assessed; this may reveal metabolic acidosis.

VPA can directly cause an anion gap (see the Anion Gap calculator). Conversion of the VPA level to mmol/L has been shown to correspond with the anion gap in individuals with significantly elevated VPA levels. In a large multicenter review of 134 patients (80 with toxic VPA levels), an elevated anion gap (>15) was seen in 26% of patients with VPA levels exceeding 450 mg/L.[13]

Because of its small size, valproic acid may theoretically contribute to an elevated osmolar gap if the serum VPA level is very high (eg, >1000 mg/L).

Other studies that may be helpful include the following:

  • Coagulation studies

  • Measurement of the prothrombin time (PT) and international normalized ratio (INR)

  • Pregnancy testing in women of childbearing age

  • Arterial blood gas (ABG) analysis

  • Lipase measurement

Head CT

Computed tomography (CT) of the head should be performed to evaluate cerebral edema, which is well documented with acute VPA overdose.[17] Cerebral edema is usually associated with hyperammonemia and appears within 48-72 hours after acute ingestion. Patients with encephalopathy and hyperammonemia due to long-term VPA therapy are also at risk for cerebral edema.

Electrocardiography

An electrocardiogram (ECG) should be obtained in all patients with a VPA overdose. Particular findings reported with VPA ingestion include atrial tachyarrhythmias (in particular, sinus tachycardia). Nonspecific ST- and T-wave changes have been reported, as well as drug-induced Brugada syndrome. VPA has been studied as an antiarrhythmic; in normal doses, it may actually decrease the frequency of premature ventricular contractions.

 

Treatment

Approach Considerations

Treatment of patients with valproate (valproic acid [VPA]) toxicity is mainly supportive, commonly including the following:

  • Management of airway, breathing, and circulation (ABCs)
  • Oxygenation
  • Administration of intravenous (IV) fluids
  • Monitoring

However, respiratory depression and cardiopulmonary arrest have been documented. Proceed with resuscitative maneuvers (eg, intubation or defibrillation) if appropriate. Ventilate the patient, and provide circulatory assistance as needed. Treatment may also include decontamination, procedures to enhance elimination, and pharmacotherapy.

Depending on the level of toxicity, patients with a VPA overdose usually require admission to the intensive care unit (ICU) for continuous monitoring. Their condition may progressively deteriorate as VPA is absorbed and moves from the intravascular compartment to the central nervous system (CNS). Intestinal absorption after overdose may be delayed several hours.

Patients with overdose must be evaluated from a psychiatric point of view for plan of suicide or grave disability. After patients are medically cleared, they may be transferred to a psychiatric facility. However, this disposition depends on the patient’s symptoms and the amount of ingestion.

In one multicenter case series of 134 patients with VPA ingestions (80 with toxic VPA levels at admission), the mean hospital stay for all patients was 44.7 hours (standard deviation, 28 h).[13]

After the patient’s condition is stabilized and he or she is discharged, an ongoing relationship between the patient and a mental health professional is recommended if the overdose was intentional.

Initial Stabilization and Resuscitation

Stabilize all acute life-threatening conditions. Ensure a patent airway. Intubate if necessary (eg, for the management of profound respiratory depression). Establish IV access.

Obtain information about the overdose, including the following:

  • Number of pills
  • Dosage
  • Last date the prescription was filled (the bottles should be brought to the hospital if possible)

Check blood sugar levels with a bedside test, or administer a bolus of dextrose if bedside testing is not available.

Naloxone may be indicated if the patient has stupor or coma, depressed respiration, and small pupils (see Pharmacologic Therapy). Rare reports describe a positive response to naloxone in patients without findings of opiates on toxicology screening; the mechanism is unexplained.[18]

Decontamination

Activated charcoal should be administered to patients presenting within 1 hour after ingestion of VPA unless contraindications are present. The optimum activated charcoal–to-toxin ratio is 10:1. If the patient presents more than 1 hour after the ingestion, activated charcoal may still be indicated because of the potentially delayed absorption with enteric-coated or extended-release preparations.

Whole-bowel irrigation (WBI) may be useful when large amounts of sustained-release products are ingested.

Procedures to Enhance Elimination

As levels rise, the percentage of valproic acid bound to protein decreases; procedures to enhance elimination may be considered.

Hemodialysis and hemoperfusion

Hemodialysis and hemoperfusion can decrease the elimination half-life of VPA, as described in many case series, reviews, and reports. One of the most dramatic reports describes hemoperfusion and hemodialysis in series, which reduced the half-life of VPA from 13 hours before treatment to 1.7 hours during hemodialysis.[18] When assessed 4 hours after treatment and within 20 hours of ingestion, the patient was alert, responsive, and capable of following commands.

However, indications for dialysis in this setting are not well established; some advocate hemodialysis in cases of refractory hemodynamic instability and metabolic acidosis that do not respond to fluid resuscitation. Ideally, hemodialysis should be started before the onset of hemodynamic compromise. It should be considered when VPA levels exceed 850-1000 mg/L; such high levels are associated with increased morbidity and mortality.

High-flux hemodialysis without hemoperfusion can substantially decrease the elimination half-life, as described in case reports of VPA overdose. In one case, high-flux hemodialysis was used in a 25-year-old patient who developed hypotension and lactic acidosis as VPA levels rose above 1200 mg/L. High-flux hemodialysis was performed for 4 hours.[19] The half-life was 2.74 hours during dialysis and 23.41 hours after hemodialysis. The patient recovered as her serum VPA levels declined.

Multiple other reports describe successful use of hemodialysis without hemoperfusion for severe VPA overdose. In fact, a review of the literature regarding high-flux dialysis and hemoperfusion for VPA overdose suggests that toxic concentrations of VPA can be effectively removed via high-flux dialysis without concomitant hemoperfusion. Use of this single method of elimination eliminates the associated risks that hemoperfusion may bring.

Continuous venovenous hemodialysis

In cases of hemodynamic compromise, continuous renal-replacement therapy, such as continuous venovenous hemodialysis (CVVHD), may improve the elimination half-life vis-à-vis the patient’s baseline function. Whether it may decrease the potential hemodynamic instability in comparison with standard dialysis (in particular, low-flux dialysis) is up for debate. One case report discusses a potentially fatal VPA overdose that did not respond to CVVHD but was successfully treated with low-flux hemodialysis.[20]

Multidose activated charcoal

Despite case reports in which multidose activated charcoal (MDAC) was found to decrease the serum half-life of VPA, this treatment did not affect the elimination half-life in volunteer studies. MDAC may be considered in conjunction with WBI in cases of massive ingestion or ingestion of extended-release products (see Decontamination).

Pharmacologic Therapy

Naloxone

Naloxone has been postulated to act as a gamma-aminobutyric acid (GABA) antagonist or to inhibit postsynaptic GABA transport due to VPA in addition to its opioid receptor antagonism. Isolated case reports have described reversal of sedation with naloxone. However, the administration of naloxone (including aggressive administration of a total of 30 mg) with no response has been reported.

The literature is conflicting with regard to the efficacy of naloxone in reversing VPA-induced coma. In one case report, administration of naloxone in 2 separate doses reversed coma with a VPA level of 487.8 mg/L.[21] On the other hand, in cases of severe valproate intoxication with plasma concentrations exceeding 850 mg/L, administration of naloxone has been unsuccessful.

Many medical toxicologists and pharmacologists believe that reversal of VPA-associated coma may actually be due to reversal of opiate/opioid effects in which an opioid/opiate was unsuspected or was not confirmed via urine toxicology screen (eg, a negative opiate screen on a drugs-of-abuse assay). Many opioids will not be confirmed by such assays, including fentanyl, oxycodone, and meperidine.

L-carnitine

L-carnitine (levocarnitine) is the active form of carnitine and is an essential cofactor in the beta-oxidation of fatty acids in the liver. Long-term use of VPA is associated with depletion of serum carnitine levels. This depletion is due to 2 distinct mechanisms, as follows:

  • VPA combines with carnitine to form valproylcarnitine, which is freely excreted in urine

  • During treatment with VPA, renal reabsorption of both free carnitine and acylcarnitine is decreased

Ultimately, carnitine deficiency affects mitochondrial metabolism of VPA, as well as energy synthesis. Hyperammonemia may also develop with carnitine deficiency as the production of urea is disrupted within the mitochondria. Thus, carnitine deficiency plays a large role in the development of hyperammonemia and VPA-induced hyperammonemic encephalopathy. This development is associated with long-term or high-dose VPA use, as well as overdose. Carnitine also plays a direct role in the metabolism and elimination of VPA.

L-carnitine supplementation, then, is believed to provide benefit in the setting of valproate toxicity, particularly in patients who have concomitant hyperammonemia, encephalopathy, or hepatotoxicity.

One case report documented the use of L-carnitine oral supplementation in a patient with acute VPA overdose.[19] Before treatment, levels of beta-oxidation metabolites of VPA were low, and levels of omega and omega-1 metabolites were elevated. After treatment, the former increased, and the latter decreased. Toxic metabolites initially detected in the urine were no longer present after carnitine supplementation. Carnitine supplementation makes sense, physiologically, in cases where hepatotoxicity occurs or is potential.

A 2010 review concluded that more rigorous studies were needed to validate carnitine as an antidote for acute VPA overdose[22] ; however, current evidence suggests that it can be used for ingestions exceeding 100 mg/kg or ingestions expected to result in blood peak concentrations greater than 450 mg/L in conjunction with a decreasing level of consciousness. The same review recommended 100 mg/kg initially (by bolus over 2-3 minutes or infusion over 15-30 minutes), then 50 mg/kg (up to 3 g) IV every 8 hours until clinical improvement is seen.

In 2017, Glatstein et al reported that treatment with L-carnitine proved safe and effective in 13 children with valproate-induced hyperammonemic encephalopathy (associated with therapeutic dosing in 12 cases and with an overdose in one). These authors administered L-carnitine intravenously  over 30 minutes at a dose of 100 mg/kg/day in 3 divided doses until clinical improvement occurred.[23]

The toxicity profile of L-carnitine has been found to be relatively benign. In a systematic review of 674 acute VPA overdoses, 55 doses of L-carnitine were given to 19 patients with isolated VPA ingestion, and 196 doses were given to patients with mixed overdoses that included VPA.[20] None of the patients became hypotensive or had an allergic reaction or other adverse effect.

L-carnitine is best administered in consultation with a regional poison control center certified by the American Association of Poison Control Centers or a medical toxicologist certified by the American Board of Emergency Medicine or the American College of Medical Toxicology.

Despite the plausible physiologic rationale and the case reports documenting favorable outcomes, further studies (in particular, randomized controlled studies) are needed before the use of carnitine for valproate toxicity becomes a true standard of care.

Consultations

Consult a regional poison control center certified by the American Association of Poison Control Centers or a medical toxicologist certified by the American Board of Emergency Medicine or the American College of Medical Toxicology.

Consultation with a nephrologist may be necessary for emergency hemodialysis and hemoperfusion.

Consider consultation with a neurosurgeon if computed tomography (CT) of the head reveals severe cerebral edema. One case report discussed management of cerebral edema and increased intracranial pressure with ventriculostomy, hyperventilation to maintain a perfusion pressure at 60-70 mm Hg, and 1 dose of mannitol 25 g and dopamine 1-8 µg/kg/min.[24] If the patient’s illness necessitates ventriculostomy, high-flux hemodialysis or hemoperfusion to enhance elimination is appropriate.

 

Medication

Medication Summary

Despite favorable reviews and good outcomes in case reports, it remains to be seen, prospectively, whether the use of L-carnitine in valproate (valproic acid [VPA]) toxicity has a positive impact on clinical outcome. Nevertheless, some groups advocate use when VPA levels exceed 450 mg/L, VPA-associated hepatotoxicity or encephalopathy occurs, or primary carnitine deficiency is present (particularly in the pediatric population). Recommendations regarding the optimal dosage, frequency, or route of administration are limited.

Antidotes

Class Summary

Antidotes are used in the emergency treatment of poisoning caused by drugs and chemicals.

Naloxone

Naloxone is a pure competitive opioid antagonist used for reversal of respiratory depression after opioid exposure. Its capacity for reversal in VPA exposure may be due to a nonspecific action or to reversal of the effect of an undetected opioid (coingestant).

Activated charcoal (Liqui-Char, Actidose-Aqua, Insta-Char)

Activated charcoal has a network of pores that absorbs 100-1000 mg of drug per 1 g of charcoal. It does not dissolve in water. For maximum effect, it should be administered within 0.5-1 hours of poison ingestion.

Levocarnitine (Carnitor, Carnitor SF)

Levocarnitine (L-carnitine) is an endogenous carboxylic acid involved in fatty-acid metabolism. VPA may interrupt fatty-acid metabolism, impairing mitochondrial function and ultimately urea metabolism, leading to hyperammonemia. Carnitine deficiency can result from dietary deficiency, inborn errors of metabolism, therapy with many anticonvulsants, and VPA toxicity. Carnitine deficiency may allow production of hepatotoxic VPA metabolites by increasing alternate routes of metabolism (gamma oxidation).

Levocarnitine effectively treats hyperammonemia associated with chronic VPA toxicity. It also improves outcome in patients with hepatotoxicity and coma associated with acute VPA ingestion. There is no consensus on the optimal dose, frequency, and route in VPA overdose. Supplementation appears to be well tolerated; few adverse reactions have been reported.

 

Follow-up

Further Outpatient Care

After the patient's condition is stabilized and he or she is discharged, an ongoing relationship between the patient and a mental health professional is recommended if the overdose was intentional.

Further Inpatient Care

Depending on level of toxicity, patients with valproic acid overdose usually require admission to the intensive care unit (ICU) for continuous monitoring. Their condition may progressively deteriorate as valproic acid is absorbed and moves from the intravascular compartment to the CNS compartment. Intestinal absorption after overdose may be delayed several hours.

Patients with overdose must be evaluated from a psychiatric point of view for plan of suicide or grave disability.

Transfer

After patients are medically cleared, they may be transferred to a psychiatric facility. However, this disposition highly depends on the patient's symptoms and the amount of ingestion.

In one multicenter case series of 134 patients with valproic acid ingestions (80 with toxic VPA levels at admission), the mean hospital stay for all patients was 44.7 hours (standard deviation, 28 h).[13]

Complications

Valproic acid is used in the treatment of mood disorders in addition to its use as an antiseizure medication. Emergency personnel must consider the possibility of multidrug overdoses and 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.

Obtain acetaminophen levels to rule out ingestion of this substance (see Laboratory Studies).

 

Questions & Answers

Overview

What is valproate toxicity?

What are the signs and symptoms of valproate toxicity?

Which altered vital signs are characteristic of valproate toxicity?

Which CNS findings suggest valproate overdose?

Which physical findings suggest valproate toxicity?

Which lab studies are performed in the diagnosis of valproate toxicity?

Which imaging studies may be performed in the diagnosis of valproate toxicity?

What is included in the initial stabilization and resuscitation of patients with valproate toxicity?

Which decontamination methods are used in the treatment of valproate toxicity?

How are elimination-enhancing procedures used in the treatment of valproate toxicity?

Which medications are used in the treatment of valproate toxicity?

What is valproate toxicity?

How does valproate toxicity occur?

What is the role of absorption in the pharmacokinetics of valproate toxicity?

What is the role of volume of distribution in the pharmacokinetics of valproate toxicity?

What is the role of protein binding in the pharmacokinetics of valproate toxicity?

What is the role of metabolism in the pharmacokinetics of valproate toxicity?

What is the elimination half-life for valproate?

Which dosing and drug interactions lead to valproate toxicity?

What are the pharmacokinetic mechanisms of valproate toxicity?

What is the annual incidence of valproate toxicity?

Which age groups are at highest risk for valproate toxicity?

What is the prognosis of valproate toxicity?

Presentation

Which clinical history findings are characteristic of valproate toxicity?

Which physical findings are characteristic of valproate toxicity?

Which altered vital signs suggest valproate toxicity?

What are the CNS manifestations of valproate overdose?

Which physical findings are characteristic of valproate toxicity?

DDX

What are the differential diagnoses for Valproate Toxicity?

Workup

Which lab tests should be performed in the workup of valproate toxicity?

What is the role of serum chemistries in the diagnosis of valproate toxicity?

What is the role of liver function studies in the workup of valproate toxicity?

Why is respiratory depression with hypercapnia assessed in the workup of valproate toxicity?

How frequently is an anion gap present during the workup for valproate toxicity?

Which lab tests may be helpful in the workup of valproate toxicity?

What is the role of CT scanning in the workup of valproate toxicity?

What is the role of electrocardiography in the workup of valproate toxicity?

Treatment

What is included in the treatment of valproate toxicity?

What is included in the initial stabilization and resuscitation of patients with valproate toxicity?

Which decontamination methods are used in the treatment of valproate toxicity?

When are procedures to enhance elimination indicated in the treatment of valproate toxicity?

What is the role of hemodialysis and hemoperfusion in the treatment of valproate toxicity?

What is the role of continuous venovenous hemodialysis (CVVHD) in the treatment of valproate toxicity?

What is the role of multidose activated charcoal in the treatment of valproate toxicity?

What is the role of naloxone in the treatment of valproate toxicity?

What is the role of L-carnitine (levocarnitine) in the treatment of valproate toxicity?

What is the efficacy of L-carnitine oral supplementation for treatment of valproate toxicity?

Which specialist consultations are beneficial for patients with valproate toxicity?

Medications

Which medications are used in the treatment of valproate toxicity?

Which medications in the drug class Antidotes are used in the treatment of Valproate Toxicity?

Follow-up

What long-term care is needed following treatment for valproate toxicity?

What is included in inpatient care for valproate toxicity?

When is patient transfer indicated in the treatment of valproate toxicity?

What are complications of valproate toxicity?