Patrick M. Lank and Sean M. Bryant
Originally synthesized from a chemical found in valerian root, valproic acid has been in clinical use as an antiepileptic drug for over 45 years. Initially prescribed for a broad range of seizures, including absence, partial, and generalized tonic–clonic, valproic acid has also been used for the treatment of mania in bipolar disorder, migraine headaches, and neuropathic pain (1). Given valproic acid’s multiple indications, particularly for psychiatric disorders, it is commonly encountered in both intentional and unintentional overdoses (2). In 2011, 8,052 toxic exposures to valproic acid were reported to US poison centers (more than carbamazepine and phenytoin combined) and were associated with more than 20 poison-related deaths in the same year (2).
Valproic acid is a simple branched chain carboxylic acid that is structurally dissimilar to other anticonvulsants. Antiepileptic effects of valproic acid come from various mechanisms including 1) increasing γ-aminobutyric acid (GABA) activity, 2) decreasing NMDA receptor–mediated glutamate activity, and 3) inhibiting voltage-gated sodium channels (3). Mechanisms related to valproic acid’s newer uses as a mood stabilizer and adjunctive agent in pain syndromes are complex and yet to be defined (4).
Valproic acid (Depakene) is available as a syrup, capsule, and intravenous formulation (Depacon). Divalproex sodium (Depakote) is a 1:1 ratio of valproic acid and sodium valproate. It is packaged as a sprinkle, delayed- or extended-release capsule. Oral bioavailability is near 100%, and peak concentrations are reached within 6 hours for therapeutic dosing. In overdose, especially with delayed- or extended-release formulations, initial levels may be undetectable, and peak levels are extended out as far as 18 hours or longer (4). The volume of distribution is small, and the drug is rapidly distributed throughout the body. Protein binding is significant, though this decreases in overdose. The half-life at therapeutic levels is 8 to 17 hours, but after overdose, it may be as long as 19 to 20 hours (5).
The bulk of valproic acid is metabolized by hepatic glucuronidation, and then its metabolites are largely excreted in the urine. Through multiple direct and indirect mechanisms, valproic acid interferes with the normal mitochondrial function in the urea cycle, leading to accumulation of ammonia. Carnitine is a required co-factor for the metabolism of ammonia as part of the urea cycle, but the use of valproic acid has been associated with carnitine depletion (6). This mechanism of carnitine depletion-related hyperammonemia is the physiologic basis for the potential use of supplemental carnitine in valproate-associated hyperammonemia.
CLINICAL PRESENTATION
Slow absorption delays the onset of symptoms. Central nervous system depression including coma is the predominant finding in severe valproic acid toxicity (7). Valproic acid toxicity may also cause nausea, vomiting, pancreatitis, hepatitis (although rare after acute ingestion), hemodynamic instability, and cerebral edema. Metabolic effects are seen with more severe toxicity and may include hypernatremia and lactic acidosis with an anion gap.
ED EVALUATION
Because valproic acid overdose primarily manifests as central nervous system depression, the airway must be carefully assessed. After completion of the primary survey and appropriate interventions, a detailed history should include whether the ingestion was accidental or intentional, the potential for co-ingestants, other medications the patient has had access to, time of ingestion, and apparent acute versus chronic ingestion. Physical examination should focus on mental status. History provided by paramedics, friends, family, and old medical records is often helpful in the patient with altered mental status.
Serum valproic acid concentrations between 50 and 100 μg/mL are considered therapeutic, but the exact range depends on the laboratory-specific range. Although higher levels do not correlate exactly with clinical findings, some generalizations can be made. Levels <450 μg/mL are associated with less serious toxicity, and those >850 μg/mL are associated with critical illness including coma (7). This leaves a wide range of concentrations correlating with variable clinical effects, though it is clear that patients with levels between 450 and 850 μg/mL may also be critically ill. Slow absorption and late peak serum concentration of valproic acid mandates serial testing regardless of the presence or absence of symptoms.
DIFFERENTIAL DIAGNOSIS
The list of agents that can cause altered mental status is extensive (see Chapter 11, “Altered Mental Status and Coma”). Valproic acid intoxication can mimic most other central nervous system depressant drugs. Postictal states, metabolic derangements, central nervous system lesions, trauma, infection, hypoglycemia, and hypoxia may present similarly. Ammonia may be elevated in liver disease. The key to arriving at the correct diagnosis is a good history, exclusion of alternate etiologies, and serial serum valproic acid concentrations.
KEY TESTING
• CBC, chemistry (with anion-gap calculation), lactic acid
• Valproic acid concentration
• Ammonia level
• Liver function tests and lipase
ED MANAGEMENT
Aggressive supportive care and strict attention to airway and breathing is critical, with intubation and ventilation for airway compromise or respiratory depression. Prior to definitive airway management, naloxone and bedside glucose testing are appropriate in the undifferentiated comatose patient but not helpful for valproic acid.
Early decontamination may prevent absorption and subsequent toxicity, however an intact airway and mental status are required for this. For larger overdoses, activated charcoal is the preferred mode of decontamination, as it readily adsorbs valproic acid. Appropriate initial dosing of activated charcoal is in a 10:1 ratio to amount of drug ingested (e.g., 50 g of activated charcoal should be given for a 5 g ingestion), as tolerated, up to 100 g initially. Repeat dosing may be indicated if continued absorption is occurring.
Enhanced elimination with hemodialysis may result in lowering of drug levels, especially in cases where the valproic acid concentration is excessive (>850 mg/L). Hemodialysis should particularly be considered when there is renal insufficiency, significant electrolyte disturbance, or acid–base derangement (7).
L-carnitine has been used to hasten resolution of coma in patients with valproic acid–associated hyperammonemia (8). Although use of L-carnitine for valproic acid–associated hyperammonemia in the overdose setting has limited evidence, it is safe, has minimal side effects, and is a reasonable adjunct to therapy. Dosing recommendations vary, but 100 mg/kg intravenously (up to 6 g) over 30 minutes, followed by 15 mg/kg every 4 hours, is appropriate. The end point is clinical improvement or 3 days of therapy.
CRITICAL INTERVENTIONS
• Airway management for severely poisoned patients with depressed mental status
• For patients with overdose: electrolyte panel, liver function panel, ammonia level
• Monitor anion gap and lactate in critically ill patients
• Serial valproic acid concentrations in all patients with acute overdose
• Hemodialysis for renal failure
• l-carnitine for elevated ammonia
DISPOSITION
All patients with evidence of mental status decline or respiratory insufficiency warrant an intensive care unit admission with continuous cardiac monitoring and airway assessment. In suicidal patients, clearance for psychiatric admission should wait until a downward trend in valproic acid concentration is confirmed. Both therapeutic and subtherapeutic concentrations have been reported to steadily rise, with concurrent signs of significant poisoning after acute overdose (9). Patients should not be discharged until serum levels are falling based on serial levels, are in the therapeutic range, and the patient is asymptomatic.
Common Pitfalls
• Failure to detect a delayed rise of valproic acid levels. Serial levels are required.
• Failure to consider delayed onset of toxicity.
• Premature medical clearance.
• Failure to work up patients completely for alternate etiologies of abnormal mental status.
REFERENCES
1. Terbach N, Williams RS. Structure-function studies for the panacea, valproic acid. Biochem Soc Trans. 2009;37(5):1126–1132.
2. Bronstein AC, Spyker DA, Cantilena LR Jr, et al. 2011 Annual report of the American Association of Poison Control Centers System (NPDS): 29th annual report. Clin Toxicol (Phila). 2012;50(10):911–1164.
3. Monti B, Polazzi E, Contestabile A. Biochemical, molecular and epigenetic mechanisms of valproic acid neuroprotection. Curr Mol Pharmacol. 2009;2(1):
95–109.
4. Bialer M. Why are antiepileptic drugs used for nonepileptic conditions? Epilepsia. 2012;53(7):26–33.
5. Leikin JB, Palouchek FP, eds. Poisoning and Toxicology Handbook. Boca Raton, FL: Lexi-Comp, Inc., CRC Press, Taylor & Francis Group; 2002.
6. Aires CC, van Cruchten A, Ijlst L, et al. New insights on the mechanisms of valproate-induced hyperammonemia: Inhibition of hepatic N-acetylglutamate synthase activity by valproyl-CoA. J Hepatol.2011;55(2):426–434.
7. Thanacoody RH. Extracorporeal elimination in acute valproic acid poisoning. Clin Toxicol (Phila). 2009;47(7):609–616.
8. Perrott J, Murphy NG, Zed PJ. L-carnitine for acute valproic acid overdose: A systematic review of published cases. Ann Pharmacother. 2010;55(7–8):1287–1293.
9. Ingels M, Beauchamp J, Clark RF, et al. Delayed valproic acid toxicity: A retrospective case series. Ann Emerg Med. 2002;39(6):616–621.