eMedicine Specialties > Emergency Medicine > Toxicology

Toxicity, Valproate

Timothy Wiegand, MD, Clinical Assistant Professor of Medicine, University of Vermont College of Medicine and Maine Medical Center; Associate Medical Director, Northern New England Poison Center
Kent R Olson, MD, FACEP, Clinical Professor of Medicine and Pharmacy, University of California San Francisco; Medical Director, San Francisco Division, California Poison Control System; 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

Updated: Jan 26, 2009

Introduction

Background

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

Valproic acid 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. Valproic acid is also used for acute and maintenance therapy of bipolar disease, for migraine prophylaxis, more recently as adjunctive therapy to benzodiazepines for treatment of alcohol and other sedative-hypnotic withdrawal syndromes and occasionally for chronic pain syndromes.

Pathophysiology

Mechanism of action

Valproic acid increases levels of gamma-aminobutyric acid and prolongs the recovery of inactivated sodium channels. These properties may be responsible for its action as a CNS depressant. Valproic acid may also cause impairments in fatty-acid metabolism and disrupt the urea cycle, leading to hyperammonemia.

Valproic acid 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 the toxicity of valproic acid.

Valproic acid affects the action of gamma-aminobutyric acid (GABA). Unlike sedative-hypnotics that enhance the postsynaptic action of GABA (eg, phenobarbital, benzodiazepines), valproic acid appears to indirectly increase the amount of GABA available to the CNS. In vitro studies have shown that valproic acid increases GABA levels by increasing the activity of glutamic acid decarboxylase and by inhibiting GABA transaminase.

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

Through several mechanisms, valproic acid 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.

Pharmacokinetics

Absorption

Valproic acid is usually absorbed rapidly from the GI tract. Peak serum concentrations are recorded at 1-4 hours. In the United States, 5 preparations of valproic acid are available for oral administration. These products have been compared in fasting individuals at a 250-mg dose administration. Measurements including time to maximum concentration (T_max and C_max), which represent the rate of absorption, were obtained. Large differences were found (which may even increase, or change dramatically, in an overdose setting) from valproic acid syrup (34.2 mg/L, 0.9 h) and valproic acid capsule (31.4 mg/L, 2.2 h) to divalproex sodium enteric-coated delayed-release tablet (26.0 mg/L, 3.4 h) and finally, divalproex sodium extended-release (divalproex-ER) tablet (11.8 mg/L, 19.7 h). Clinically, the divalproex-ER tab has been found to cause the longest delays to peak levels in overdose setting.  

Serial measurements documenting declining valproic acid concentrations or prolonged observation are recommended to determine whether a patient is medically safe for discharge or psychiatric placement. In massive overdose of enteric-coated or extended-release valproic acid preparations, delays to peak concentrations have been reported out to nearly 20 hours. In one case with enteric-coated valproic acid, the patient presented 3 hours after ingestion, alert and asymptomatic with a nondetectable level.¹  She later became comatose. At 13 hours, her level was 1075 mg/L.

Protein binding

At normal serum levels, valproic acid is greater than 80-95% protein bound. However, this percentage decreases during acute overdose, when protein-binding sites are saturated: About 90%, binding occurs at valproic acid concentrations of 40 mg/L, and at 81%, binding occurs at 130 mg/L. Concentrations greater than 150 mg/L saturate protein binding, which decreases to less than 70%. In one case report, protein binding was only 29% at valproic acid levels of 451 mg/L.² Protein binding may also be lowered in patients with uremia.

Metabolism

Valproic acid is metabolized primarily in the liver by means of conjugation to form a glucuronide ester and by means of 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 levels of valproic acid return to normal. Valproic acid metabolites are not represented on serum valproic acid screening.

Half-life

The elimination half-life varies from 5-20 hours. The half-life may be increased in neonates, in patients with liver disease, and in those ingesting an acute overdose, particularly with Divalproex ER. 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. A large amount of inter-individual variation and variability exists, depending upon whether co-ingestants that may slow GI motility (eg, anticholinergic or opiate drugs) were involved. Valproic acid will cause decreased GI motility.

Dosing
 
Initial dosing can be as low as 10 mg/kg/d given in 2-3 divided doses. Maintenance therapy may be dosed as high as 60 mg/kg/d in 2-3 divided doses.

Therapeutic range

The therapeutic range is 350-690 µmol/L (50-100 mg/L). Control of symptoms may be improved with levels greater than 690 µmol/L (100 mg/L).

Toxic range 

Mild symptoms may occur when levels are in the therapeutic range (see above). Serious intoxication is likely at levels greater than 450 mg/L. Patients with levels greater than 850 mg/L uniformly present with coma, and 63% of them require intubation. Hemodynamic instability and metabolic acidosis may occur at levels greater than 850-1000 mg/L. Because of prolongation of half-life in overdose, a level greater than 1000 mg/L may not drop into the therapeutic range for over 3 days.

Conversion

To convert from traditional units or milligrams per liter into International System of Units (SI) units of micromoles per liter, multiply the traditional units by 6.934. To convert SI units to traditional units, divide by 6.934.

Drug interactions

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

Frequency

United States

Reported acute ingestions of valproic acid have steadily increased over the last decade. According to the 2005 Annual Report of the American Association of Poison Control Center's Toxic Exposure Surveillance System (TESS), 8705 acute exposures to valproic acid occurred. Of these exposures, 866 were in children younger than 6 years, and 5965 were in individuals older than 19 years. Major adverse outcomes were noted in 404 patients of this cohort, and 26 fatalities were reported.³ By comparison, in 1995, 4149 exposures (88 major adverse outcomes, 3 fatal) occurred, and in 1994, 2717 exposures (69 major adverse outcomes, 4 fatal) occurred. A likely reason for the increase of exposures is the increased use of valproate for mood stabilization, as opposed to its initial use predominantly as an anticonvulsant.

International

The international frequency of valproic acid toxicity is unknown.

Race

Outcomes after an acute valproic acid overdose do not depend on race.

Sex

Outcomes after an acute valproic acid overdose do not depend on sex.

Age

• Although most acute valproic acid ingestions occur in persons older than 19 years, age does not influence outcomes after an acute ingestion.
• Children younger than 3 years who are taking several anticonvulsant medications and who have coexistent medical illness may be at increased risk for fatal hepatotoxicity related to long-term valproic acid therapy; the incidence is 1 case in 500 patients. Additional sources suggest that children younger than 2 years are at significant risk (1:800) for developing an idiosyncratic, potentially fatal hepatotoxic syndrome, even in the absence of the previously mentioned risk factors.

Clinical

History

Few historical features are suggestive of valproic acid poisoning. As in most poisonings, a clinical history of the ingestion, including the amount and exact time of ingestion, are helpful. Adequate documentation of previous medical and psychiatric problems is essential.

• Medical and psychiatric diagnoses and medications
  • Prescription and nonprescription medications (including over-the-counter drugs and drugs of abuse) may contribute or mask symptoms of overdose. Adequate documentation of all medications is necessary.
  • Consider herbal and natural remedies as co-ingestants.
• Exact description of the type and amount of overdose
  • The formulation of valproic acid (eg, capsules, sprinkles, syrup, extended-release tablets) taken should be noted, as should the exact amount taken. In particular, Divalproex and the extended-release form may cause significant delays in peak concentration during overdose.
  • Count the remaining or unused portion in the prescription bottle. Subtract this count from the original amount dispensed from the pharmacy. A discrepancy between the number missing and the number that should be missing if the prescribed regimen was followed provides a rough estimate of the amount the patient may have taken.
  • Record the exact time of the overdose.
• Previous suicide attempts
  • Previous suicidal attempts are important because they can lead the clinician to consider referring the patient to a psychiatrist.
  • If a patient continues to have suicidal ideation, holding the patient for psychiatric evaluation on legal grounds may be warranted.
• Domestic violence
  • Remember to screen for domestic violence in all patients with valproic acid overdose.
  • Because domestic violence is widely underreported, be aware of other indications of such abuse, including assault, depression, or suicide attempts.

Physical

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

• Vital signs: Vital signs are highly variable in patients with valproic acid poisoning.
• Fever and hypothermia have been reported.
• Hypotension has been reported with severe overdoses. Many case reports of severe valproic acid overdose discuss hypotension refractory to aggressive use of intravenous 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 valproic acid ingestion, and 25% of patients with levels greater than 850 mg/L had hypotension.⁴  Levels greater than 1000 mg/L may be associated with refractory hypotension. (Despite that hypotension hemodialysis is often recommended for these patients to rapidly increase elimination as these levels are associated with severe morbidity and mortality. Hemodialysis is often effective and may produce dramatic improvements for these patients. (See elimination discussed in Emergency Department Care).
• Cardiac arrest has been reported in severe valproic acid overdoses. The clinical condition of patients with valproic acid overdose can worsen dramatically as the drug is being absorbed. Patients with massive overdose can develop apnea and cardiac arrest.
• Respiratory depression requiring intubation occurs with increasing frequency as valproic acid levels rise.
• CNS: 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.⁴ All patients with serum levels greater than 850 mg/L were comatose, and 63% of these patients needed intubation. CNS findings 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. It has been suggested that elevated serum ammonia (NH₃) 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.
• Dermatologic findings: Alopecia has been reported in severe and chronic overdose.
• GI findings: Anorexia, nausea, and vomiting are the most common symptoms in acute toxicity.
• Genitourinary (GU) findings: Renal failure is rare. Case reports describe renal failure in patients with serum levels of greater than 1000 mg/L. Anuria and enuresis may be noted.
• Musculoskeletal findings: Patients may present with tremors and chorea.
• Ocular findings: Miosis and nystagmus may be observed.

Causes

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

Differential Diagnoses

Workup

Laboratory Studies

• Valproate level and anticonvulsant screen
  • Determination of the valproic acid level is an obvious test. Because of reviews that have shown nearly 20% of valproic acid overdoses may present with initial valproic acid concentration in a therapeutic, or even nondetectable range, serial levels should be obtained until a peak level occurs and the levels are clearly trending down. Delayed absorption, in particular with Divalproex and the extended-release forms, has been frequently reported.
  • Patients taking valproic acid are frequently taking other anticonvulsants that they may not disclose.
  • Screening is preferably completed early and helps in determining if potentially complicating co-ingestion has occurred.
  • Consider screening for anticonvulsants, acetaminophen, and acetylsalicylic acid.
• CBC count with differential
  • Thrombocytopenia
  • Agranulocytosis
• Chemistries: Include a lithium level because of its use in mood stabilization (eg, in bipolar disorder).
  • Hypocalcemia
  • Hypernatremia (sodium salt of divalproex), rare hyponatremia (postulated to be secondary to syndrome of inappropriate antidiuretic hormone secretion [SIADH], as shown in in vitro studies), and hyponatremia
  • Hypophosphatemia and hyperphosphatemia
  • Hyperglycemia or hypoglycemia (particularly in association with liver failure)
• Liver function studies
  • Fulminant hepatic failure is a potentially fatal but rare complication of both acute and chronic valproic acid toxicity.
  • Children younger than 3 years who are taking many anticonvulsants and who have medical comorbidities are at increased risk for this complication.
• 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
• Test for nonlactate metabolic acidosis: In one series, no patient with levels less than 450 mg/L developed acidosis.⁴
• Test for respiratory depression with hypercapnia: This may reveal metabolic acidosis.
• Lipase measurement
• Assessment of the anion gap
  • Valproic acid can directly cause an anion gap. Conversion of valproic acid level to mmol/L has been shown to correspond with the anion gap in individuals with significantly elevated valproic acid 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 valproic acid levels >450 mg/L.⁴
• Assessment of the osmolar gap: Because of its small size, valproic acid may theoretically contribute to an elevated osmolar gap if the serum valproic acid level is very high (eg, >1000 mg/L).

Imaging Studies

• Obtain a CT scan of the head to evaluate cerebral edema, which is well documented with acute overdose. 
• Cerebral edema is usually associated with hyperammonemia and appears within 48-72 hours after acute ingestion.
• Patients with encephalopathy and hyperammonemia due to chronic valproic acid therapy are at risk for cerebral edema.

Other Tests

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

Treatment

Prehospital Care

Stabilize all acute life-threatening conditions.

• Ensure a patent airway. Intubate if necessary, such as to manage profound respiratory depression.
• Establish intravenous (IV) lines.
• Obtain information about the overdose, including the following:
  • Amount 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.
• Rare reports describe a positive response to naloxone in patients without findings of opiates on toxicology screen; the mechanism is unexplained.

Emergency Department Care

Treatment of patients with valproic acid poisoning is mainly supportive such as management of airway, breathing, and circulation (ABCs); oxygenation; administration of intravenous fluids; and monitoring. However, respiratory depression and cardiopulmonary arrest have been documented. Proceed with resuscitative maneuvers (eg, intubation, defibrillation) if appropriate. Ventilate the patient and provide circulatory assistance as needed.

• Decontamination
  • Activated charcoal should be administered to patients presenting within 1 hour 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 (eg, Depakote, Depakote ER).
  • Whole-bowel irrigation (WBI) may be useful when large amounts of sustained-release products (eg, Depakote, Depakote ER) are ingested.
• Enhancement of elimination: As levels rise, the percentage of valproic acid bound to protein decreases; procedures to enhance elimination may be considered.
  • Hemodialysis and hemoperfusion: These therapies can decrease the elimination half-life, as described in many case series, reviews, and reports. Dialysis removes valproic acid metabolites and ammonia. One of the most dramatic reports describes hemoperfusion and hemodialysis in series, which reduced the half-life of valproic acid from 13 hours before treatment to 1.7 hours during hemodialysis.⁵ Four hours after treatment and within 20 hours of ingestion, the patient was alert, responsive, and following commands. However, indications for dialysis are not well established; some advocate hemodialysis in cases of refractory hemodynamic instability and metabolic acidosis not responsive to fluid resuscitation. Hemodialysis is ideally started before the onset of hemodynamic compromise. Consider dialyses when levels are greater than 850-1000 mg/L because these levels are associated with increased morbidity and mortality.
  • High-flux hemodialysis without hemoperfusion has been shown to significantly decrease the elimination half-life, as described in case reports of valproic acid overdoses. 
    • In one case, high-flux hemodialysis was used in a 25-year-old patient who developed hypotension and lactic acidosis as valproic acid level concentrations increased to greater than 1200 mcg/mL. High-flux hemodialysis was performed for 4 hours.⁶  The half-life during dialysis was 2.74 hours compared to 23.41 hours posthemodialysis. The patient recovered as her serum levels of valproic acid declined. 
    • Multiple other reports describe successful use of hemodialysis without hemoperfusion for severe valproic acid overdose. In fact, in review of the literature regarding high-flux dialysis and/or hemoperfusion for valproic acid overdose, toxic concentrations of valproic acid 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.
  • Use of multidose activated charcoal (MDAC): Despite case reports in which MDAC decreased the serum half-life of valproic acid, 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 above).
  • Continuous venovenous hemodialysis (CVVHD): In cases of hemodynamic compromise, continuous renal-replacement therapy such as CVVHD may improve the elimination half-life compared with the patient's baseline function. Whether it may decrease the potential hemodynamic instability compared with standard dialysis, in particular, low-flux dialysis, is up for debate. One case report discusses a potentially fatal valproic acid overdose that did not respond to CVVHD but was successfully treated with low-flux hemodialysis.⁷
• Isolated case reports have described reversal of sedation with naloxone.
  • Naloxone has been postulated to act as a GABA antagonist or inhibit postsynaptic GABA transport due to valproic acid in addition to its opioid receptor antagonism.
  • However, the administration of naloxone (including aggressive administration of 30 mg total) with no response has been reported. The literature is varied in regard to the efficacy of naloxone in reversing VPA-induced coma. In one case report, naloxone administration in 2 separate doses reversed coma with VPA level of 487.8 mg/L.⁸ 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 coma in cases of VPA-associated coma may actually be due to reversal of opiate/opioid effects where an opioid/opiate was unsuspected or not confirmed via urine toxicology screen (eg, a negative opiate screen on a drugs of abuse assay). Many opioids will not be positive on such assays including fentanyl, oxycodone, and meperidine.
• L-carnitine
  • L-carnitine 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 valproic acid is associated with depletion of serum carnitine levels. This is due to 2 distinct mechanisms. First, valproic acid combines with carnitine to form valproylcarnitine, which is freely excreted in the urine. Additionally, during treatment with valproic acid, renal reabsorption of both free carnitine and acylcarnitine is decreased.
  • Ultimately, carnitine deficiency effects mitochondrial metabolism of valproic acid 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 is associated with chronic 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 thought to provide benefit, particularly in patients with concomitant hyperammonemia, encephalopathy, and/or hepatotoxicity.
  • One case report documented the administration of L-carnitine oral supplementation to a patient with acute valproic acid overdose.⁹ Levels of beta-oxidation metabolites (from mitochondrial metabolism, normal pathway) of valproic acid were low, levels of omega and omega-1 metabolites (non-mitochondrial–mediated metabolic byproduct) were elevated before treatment. After treatment, the former levels increased, and the latter decreased. Toxic metabolites (eg, 4-en-valproate, products of omega oxidation) 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.
  • The optimum route and dose of L-carnitine has not been determined. In a retrospective review of patients with hepatotoxicity secondary to valproic acid, improved outcomes were noted in patients who received intravenous L-carnitine compared with those receiving oral L-carnitine or control subjects who received only supportive care. Some dosing guidelines included patients with acute overdose of valproic acid and without hepatic enzyme abnormalities or hyperammonemia can receive prophylactic carnitine of 100 mg/kg/day, divided every 6 hours, to a maximum dose of 3 g/d. For patients with symptomatic hyperammonemia or hepatotoxicity, dosing is more aggressive. A loading dose of 100 mg/kg intravenously is administered (up to a maximum of 6 g) over 30 minutes followed by 15 mg/kg every 4 hours over 10–30 minutes until clinical improvement occurs.
  • The toxicity profile of L-carnitine has been found to be relatively benign. In a systematic review of 674 acute valproic acid overdoses, 55 doses of L-carnitine were given to 19 patients with isolated valproic acid ingestion and 196 doses were given to patients with mixed overdoses that included valproic acid.¹⁰ No patient developed hypotension or had an allergic reaction or other adverse effect.
  • One group recommends intravenous administration of L-carnitine, stating, "in any patient with coma, despite falling VPA concentrations, and climbing ammonia levels and (pending further study), in all patients with VPA concentrations greater than 450 mcg/mL (mg/L)."¹¹ However, no dose for intravenous therapy was given.
  • 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 physiologic sense and case reports documenting favorable outcomes, further study, in particular randomized controlled studies, is 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 the head CT scan reveals severe cerebral edema.
  • One case report discusses management of cerebral edema and increased intracranial pressure (ICP) with ventriculostomy, hyperventilation to maintain a perfusion pressure at 60-70 mm Hg, and 1 dose of mannitol 25 g and dopamine 1-8 mcg/kg/min.¹²
  • If the patient's illness requires ventriculostomy, high-flux hemodialysis or hemoperfusion to enhance elimination is appropriate.

Medication

Despite favorable reviews and outcomes in case reports, it remains to be seen, prospectively, whether the use of L-carnitine in valproic acid (VPA) overdose impacts clinical outcome. Despite this lack of evidence, however, some groups advocate use when the VPA levels exceed 450 mg/L, VPA-associated hepatotoxicity and/or encephalopathy occurs and in any case of primary carnitine deficiency (particularly relevant in the pediatric population). Specific recommendations regarding the optimal dose, frequency, or route of administration are limited (some recommendations are given above). L-carnitine should be administered in consultation with a medical toxicologist or a poison control center certified by the American Association of Poison Control Centers.

Antidotes

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

Naloxone (Narcan)

Pure competitive opioid antagonist used for reversal of respiratory depression after opioid exposure.
Reversal in VPA exposure may be due to nonspecific action of naloxone or due to reversal of the effect of undetected opioid (coingestant).

Dosing

Adult

0.4-2 mg IV can reverse respiratory depression in majority of opioid exposure
Some clinicians recommend lower doses at 0.05-0.1 mg IV as initial dose in order to avoid complications of precipitous opioid withdrawal (eg, vomiting, aspiration)
(In VPA exposure, administration of large cumulative dose of naloxone, up to 10 mg, may be required in order to reverse respiratory depression and/or change of mental status)

Pediatric

Patients weighing <20 kg or <5 years: 0.1 mg/kg
Patients weighing >20 kg or >5 years: 0.1-0.2 mg/kg
If cumulative dose of 10 mg of naloxone does not produce improvement of symptoms, it is very unlikely that naloxone will have any effect

Interactions

Decreases analgesic effects of narcotics

Contraindications

None for this indication

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Patients who have opioids in their system may experience precipitous withdrawal and consequent vomiting and aspiration
Pregnant patients who are opioid dependent can experience precipitous withdrawal and consequent labor complications after naloxone administration
Infants of pregnant mothers who are opioid dependent can experience severe/life-threatening withdrawal after administration of naloxone

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

Has network of pores present that absorbs 100-1000 mg drug per gram charcoal. Does not dissolve in water. For maximum effect, administer within 0.5-1 h of poison ingestion.

Dosing

Adult

1 g/kg PO initially; may administer MDAC 10-20 g (0.25 g/kg/h) NG q2-4h; ideal dosing for overdose is 10:1 charcoal to ingested toxin

Pediatric

1-2 g/kg PO; 15-30 g total

Interactions

May inactivate syrup of ipecac if used concomitantly; effectiveness of other medications decrease with coadministration; do not mix charcoal with sherbet, milk, or ice cream (decreases absorptive properties of activated charcoal)

Contraindications

Documented hypersensitivity; poisoning or overdose of acid or alkali mixtures; poisoning with substances that charcoal does not bind (eg, metals, alcohols); unprotected airway with absent gag reflex, obstruction or ileus, concomitant GI bleed (consult gastroenterologist before administering and carefully weigh risk and benefit)

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Not effective in poisonings of ethanol, methanol, iron salts, lithium, or other metals; protect airway during administration; check for bowel sounds before each dose to minimize risk of charcoal ileus; avoid charcoal-sorbitol mixtures in children (risk of vomiting, hypernatremia, and dehydration)

L-Carnitine

Levocarnitine is endogenous carboxylic acid involved in fatty-acid metabolism. Carnitine deficiency can result from dietary deficiency, inborn errors of metabolism, therapy with many anticonvulsants, and VPA toxicity. VPA may interrupt fatty-acid metabolism, impairing mitochondrial function and ultimately urea metabolism, leading to hyperammonemia. Carnitine deficiency may allow for production of hepatotoxic VPA metabolites by increasing alternate routes of metabolism (gamma oxidation). Effectively treats hyperammonemia associated with chronic VPA toxicity. Carnitine also improves outcome in hepatotoxicity and coma associated with acute VPA ingestion.

No consensus on dose, frequency, and route in VPA overdose. Supplementation appears to be well tolerated; few adverse reactions reported.

Dosing

Adult

Initial dose of 100 mg/kg IV (not to exceed 6 g) with additional doses of 15 mg/kg IV q4h over 30 min
Note that recommendations vary; some groups advocate limiting total dose to 3 g/d, although the basis for this recommendation is unclear

Pediatric

Overdose or hyperammonemia: 150-500 mg/kg/d IV; not to exceed 3 g/d or until clinical improvement observed
1996 Pediatric Neurology Advisory Committee consensus guidelines: 100 mg/kg/d PO; not to exceed 2 g/d in divided doses

Interactions

None reported

Contraindications

Documented hypersensitivity to carnitine or L-carnitine

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Monitor vital signs in ICU setting during IV administration; monitor serum chemistries daily during therapy

Follow-up

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.

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.

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).⁴

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).

Prognosis

• The prognosis 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.
• L-carnitine is reportedly helpful in valproic acid overdose associated with hyperammonemia, hepatotoxicity, and coma. However, its role remains to be confirmed. Some authors recommend its empiric use in overdoses when levels are greater than 450 mg/L.
• The optimum dose, frequency, and route of administration (oral or intravenous) remain to be determined.

Patient Education

• For excellent patient education resources, visit eMedicine's Drug Overdose Center and Poisoning - First Aid and Emergency Center. Also, see eMedicine's patient education articles Poisoning, Drug Overdose, Activated Charcoal, and Poison Proofing Your Home.

Miscellaneous

Medicolegal Pitfalls

• Failure to diagnose a concomitant ingestion or underlying medical condition that results in serious morbidity
• Failure to obtain serial serum valproic acid levels, especially after ingestion of extended-release formulations
• Failure to aggressively decontaminate GI tract with whole-bowel irrigation after exposure to the extended-release formulation

References

1. Graudins A, Aaron CK. Delayed peak serum valproic acid in massive divalproex overdose--treatment with charcoal hemoperfusion. J Toxicol Clin Toxicol. 1996;34(3):335-41. [Medline].

2. Flomenbaum N, Goldfrank L, Hoffman R, Howland MA, Lewin N, Nelson L, et al. Goldfrank's Toxicologic Emergencies. 8^th ed. New York: McGraw-Hill Companies; 2006.

3. Lai MW, Klein-Schwartz W, Rodgers GC, Abrams JY, Haber DA, Bronstein AC, et al. 2005 Annual Report of the American Association of Poison Control Centers' national poisoning and exposure database. Clin Toxicol (Phila). 2006;44(6-7):803-932. [Medline]. [Full Text].

4. Spiller HA, Krenzelok EP, Klein-Schwartz W, et al. Multicenter case series of valproic acid ingestion: serum concentrations and toxicity. J Toxicol Clin Toxicol. 2000;38(7):755-60. [Medline].

5. Tank JE, Palmer BF. Simultaneous "in series" hemodialysis and hemoperfusion in the management of valproic acid overdose. Am J Kidney Dis. Aug 1993;22(2):341-4. [Medline].

6. Kane SL, Constantiner M, Staubus AE, Meinecke CD, Sedor JR. High-flux hemodialysis without hemoperfusion is effective in acute valproic acid overdose. Ann Pharmacother. Oct 2000;34(10):1146-51. [Medline].

7. Kay TD, Playford HR, Johnson DW. Hemodialysis versus continuous veno-venous hemodiafiltration in the management of severe valproate overdose. Clin Nephrol. Jan 2003;59(1):56-8. [Medline].

8. Thanacoody HK. Chronic valproic acid intoxication: reversal by naloxone. Emerg Med J. Sep 2007;24(9):677-8. [Medline].

9. Ishikura H, Matsuo N, Matsubara M, Ishihara T, Takeyama N, Tanaka T. Valproic acid overdose and L-carnitine therapy. J Anal Toxicol. Jan-Feb 1996;20(1):55-8. [Medline].

10. LoVecchio F, Shriki J, Samaddar R. L-carnitine was safely administered in the setting of valproate toxicity. Am J Emerg Med. May 2005;23(3):321-2. [Medline].

11. Russell S. Carnitine as an antidote for acute valproate toxicity in children. Curr Opin Pediatr. Apr 2007;19(2):206-10. [Medline].

12. Khoo SH, Leyland MJ. Cerebral edema following acute sodium valproate overdose. J Toxicol Clin Toxicol. 1992;30(2):209-14. [Medline].

13. Alberto G, Erickson T, Popiel R, Narayanan M, Hryhorczuk D. Central nervous system manifestations of a valproic acid overdose responsive to naloxone. Ann Emerg Med. Aug 1989;18(8):889-91. [Medline].

14. Andersen GO, Ritland S. Life threatening intoxication with sodium valproate. J Toxicol Clin Toxicol. 1995;33(3):279-84. [Medline].

15. Bigler D. Neurological sequelae after intoxication with sodium valproate. Acta Neurol Scand. Sep 1985;72(3):351-2. [Medline].

16. Caraccio TR, Mofenson HC. Carnitine. J Toxicol Clin Toxicol. 2003;41(6):897; author reply 901-2. [Medline].

17. Chicharro AV, de Marinis AJ, Kanner AM. The measurement of ammonia blood levels in patients taking valproic acid: looking for problems where they do not exist?. Epilepsy Behav. Nov 2007;11(3):361-6. [Medline].

18. Connacher AA, Macnab MS, Moody JP, Jung RT. Fatality due to massive overdose of sodium valproate. Scott Med J. Jun 1987;32(3):85-6. [Medline].

19. Dart RC, ed. Medical Toxicology. 3^rd ed. Lippincott Wiliams and Wilkins; 2004.

20. Doyon S. Anticonvulsants. In: Goldfrank L, ed. Goldfrank's Toxicologic Emergencies. 7^th ed. New York, NY: McGraw Hill; 2002:614-30.

21. Dupuis RE, Lichtman SN, Pollack GM. Acute valproic acid overdose. Clinical course and pharmacokinetic disposition of valproic acid and metabolites. Drug Saf. Jan-Feb 1990;5(1):65-71. [Medline].

22. Eeg-Olofsson O, Lindskog U. Acute intoxication with valproate. Lancet. Jun 5 1982;1(8284):1306. [Medline].

23. Eyer F, Felgenhauer N, Gempel K, Steimer W, Gerbitz KD, Zilker T. Acute valproate poisoning: pharmacokinetics, alteration in fatty acid metabolism, and changes during therapy. J Clin Psychopharmacol. Aug 2005;25(4):376-80. [Medline].

24. Farrar HC, Herold DA, Reed MD. Acute valproic acid intoxication: enhanced drug clearance with oral-activated charcoal. Crit Care Med. Feb 1993;21(2):299-301. [Medline].

25. Fernandez MC, Walter FG, Kloster JC, et al. Hemodialysis and hemoperfusion for treatment of valproic acid and gabapentin poisoning. Vet Hum Toxicol. Dec 1996;38(6):438-43. [Medline].

26. Franssen EJ, van Essen GG, Portman AT, et al. Valproic acid toxicokinetics: serial hemodialysis and hemoperfusion. Ther Drug Monit. Jun 1999;21(3):289-92. [Medline].

27. Gourru J. Intoxication aigue massive par le valproate de sodium: a propos d'une observation d1intoxication voluntaire mortelle [medical thesis]. Lyons, France: University of Lyons; 1981.

28. Haller C. L-Carnitine. In: Olson K, ed. Poisoning and Drug Overdose. 7. 4^th ed. New York, NY: McGraw-Hill; 2004:426.

29. Ingels M, Beauchamp J, Clark RF, Williams SR. Delayed valproic acid toxicity: a retrospective case series. Ann Emerg Med. Jun 2002;39(6):616-21. [Medline].

30. Janssen F, Rambeck B, Schnabel R. Acute valproate intoxication with fatal outcome in an infant. Neuropediatrics. Nov 1985;16(4):235-8. [Medline].

31. Karlsen RL, Kett K, Henriksen O. Intoxication with sodium valproate. A case report. Acta Med Scand. 1983;213(5):405-6. [Medline].

32. Kearney TE. Valproic acid. In: Olson K, ed. Poisoning and Drug Overdose. 5^th ed. New York, NY: McGraw-Hill Medical; 2005.

33. Lakhani M, McMurdo ME. Survival after severe self poisoning with sodium valproate. Postgrad Med J. May 1986;62(727):409-10. [Medline].

34. Leggio L, Kenna GA, Swift RM. New developments for the pharmacological treatment of alcohol withdrawal syndrome. A focus on non-benzodiazepine GABAergic medications. Prog Neuropsychopharmacol Biol Psychiatry. Jul 1 2008;32(5):1106-17. [Medline].

35. Lheureux PE, Penaloza A, Zahir S, Gris M. Science review: carnitine in the treatment of valproic acid-induced toxicity - what is the evidence?. Crit Care. Oct 5 2005;9(5):431-40. [Medline].

36. LoVecchio F, Thole D, Bagnasco T. Delayed absorption of valproic acid, resulting in coma. Acad Emerg Med. Dec 2002;9(12):1464. [Medline].

37. Marklund N, Enblad P, Ronne-Engstrom E. Neurointensive care management of raised intracranial pressure caused by severe valproic acid intoxication. Neurocrit Care. 2007;7(2):160-4. [Medline].

38. Meek MF, Broekroelofs J, Yska JP, et al. Valproic acid intoxication: sense and non-sense of haemodialysis. Neth J Med. Oct 2004;62(9):333-6. [Medline].

39. Mortensen PB, Hansen HE, Pedersen B, Hartmann-Andersen F, Husted SE. Acute valproate intoxication: biochemical investigations and hemodialysis treatment. Int J Clin Pharmacol Ther Toxicol. Feb 1983;21(2):64-8. [Medline].

40. Olson K, ed. Poisoning and Drug Overdose. 4^th ed. New York: McGraw-Hill Companies; 2004:362-64, 426-27.

41. Palatnik W, Hoorcharik N, Roberts D, et al. Coma anion gap and metabolic derangements associated with massive valproic acid ingestion. Vet Hum Toxicol. 1989;31:368.

42. Perez A, McKay CA. Role of carnitine in valproic acid toxicity. J Toxicol Clin Toxicol. 2003;41(6):899; author reply 901-2. [Medline].

43. Roodhooft AM, Van Dam K, Haentjens D, Verpooten GA, Van Acker KJ. Acute sodium valproate intoxication: occurrence of renal failure and treatment with haemoperfusion-haemodialysis. Eur J Pediatr. Feb 1990;149(5):363-4. [Medline].

44. Seger DL. Anticonvulsant medications. In: Dart R, ed. Medical Toxicology. 3^rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2004:798-801.

45. Singh SM, McCormick BB, Mustata S, Thompson M, Prasad GV. Extracorporeal management of valproic acid overdose: a large regional experience. J Nephrol. Jan-Feb 2004;17(1):43-9. [Medline].

46. Snodgrass WR. Valproic acid. In: Brent J, Wallace K, Burkhart K, et al, eds. Critical Care Toxicology. St Louis, MO: Mosby; 2005:565-9.

47. Sztajnkrycer MD. Valproic acid toxicity: overview and management. J Toxicol Clin Toxicol. 2002;40(6):789-801. [Medline].

48. Unal E, Kaya U, Aydin K. Fatal valproate overdose in a newborn baby. Hum Exp Toxicol. May 2007;26(5):453-6. [Medline].

49. Wadzinski J, Franks R, Roane D, Bayard M. Valproate-associated hyperammonemic encephalopathy. J Am Board Fam Med. Sep-Oct 2007;20(5):499-502. [Medline].

Keywords

valproic acid, toxicity valproate, valproate overdose, valproate poisoning, VPA, valproic acid overdose, anticonvulsant, antiseizure, seizure treatment, valproate, divalproate, sodium valproate toxicity, dipropylacetic acid toxicity, divalproex sodium toxicity, valproate semisodium toxicity, 2-propylpentanoic acid toxicity, 2-propylvaleric acid toxicity, Depacon, Depakene, Depakote, Depakote ER, Epilim, Ergenyl, Leptilan, Valkote, Sprinkles

Contributor Information and Disclosures

Author

Timothy Wiegand, MD, Clinical Assistant Professor of Medicine, University of Vermont College of Medicine and Maine Medical Center; Associate Medical Director, Northern New England Poison Center
Timothy Wiegand, MD is a member of the following medical societies: American Academy of Clinical Toxicology, American College of Medical Toxicology, American College of Physicians, and Maine Medical Association
Disclosure: Nothing to disclose.

Coauthor(s)

Kent R Olson, MD, FACEP, Clinical Professor of Medicine and Pharmacy, University of California San Francisco; 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 and American College of Medical Toxicology
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.

Medical Editor

Lance W Kreplick, MD, MMM, FAAEM, FACEP, 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, MMM, FAAEM, FACEP is a member of the following medical societies: American Academy of Emergency Medicine and American College of Physician Executives
Disclosure: Nothing to disclose.

Pharmacy Editor

John T VanDeVoort, PharmD, Regional Director of Pharmacy, Sacred Heart & 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.

Managing Editor

Fred Harchelroad, MD, FACMT, FAAEM, FACEP, Chair, Department of Emergency Medicine, Director of Medical Toxicology - Allegheny General Hospital, Associate Professor, Department of Emergency Medicine, Drexel University College of Medicine
Disclosure: Nothing to disclose.

CME Editor

John D Halamka, MD, MS, Associate Professor of Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center; Chief Information Officer, CareGroup Healthcare System and Harvard Medical School; Attending Physician, Division of Emergency Medicine, Beth Israel Deaconess Medical Center
John D Halamka, MD, MS is a member of the following medical societies: American College of Emergency Physicians, American Medical Informatics Association, Phi Beta Kappa, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.

Chief Editor

Asim Tarabar, MD, Assistant Professor, Department of Surgery, Section of Emergency Medicine, Yale University School of Medicine; Consulting Staff, Department of Emergency Medicine, Yale-New Haven Hospital
Disclosure: Nothing to disclose.

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

© 1994- by Medscape.
All Rights Reserved
(http://www.medscape.com/public/copyright)