Author: Grei Shele, DO, Emergency Medicine Resident, PGY1
Faculty: Alexis Cates, DO, Medical Toxicology/Emergency Medicine Attending
The Case…
A 51-year-old woman with a past medical history of bipolar affective disorder presents to the emergency department for evaluation after ingesting 120 tablets of valproic acid approximately 30 minutes prior to her arrival. Each tablet was 500 mg in strength; thus, a total of 60g was ingested. The patient was prescribed valproic acid as a mood stabilizer. The patient had a history of attempting suicide by ingestion. She had no complaints.
Vitals: BP 147/75 mmHg, HR 102 bpm, RR 20 breaths per minute, SP02 99% on room air, Temperature 37C
The physical exam was remarkable for a conscious patient who was alert and oriented to time, place, and person. The rest of the physical exam was otherwise unremarkable. A 12 lead electrocardiogram showed sinus tachycardia. Labs ordered included complete blood count, valproic acid level, renal and liver functions, ammonia levels, and venous blood gas.
You are concerned that she is not yet exhibiting physical symptoms given that it is so soon following her reported ingestion. You begin by reviewing potential manifestations of valproic acid toxicity and consider a toxicology consultation.
Learning Point 1: Valproic Acid Toxicity
Valproic acid (2-propylpentanoic acid) is a branched-chain carboxylic acid introduced in 1978 in the United States to prevent and treat absence seizures. It was later approved for the treatment of partial and generalized seizures, acute mania, and as prophylaxis for bipolar disorder and migraine headaches. Valproic acid (valproate) formulations include immediate release, enteric-coated, delayed-release (12 hours), and extended-release (24 hours) with therapeutic doses ranging from 15 to 60 mg/kg in children or 500 mg to 2 g in adults. Valproic acid is metabolized by the liver via glucuronide conjugation. Valproate is also metabolized by beta (within mitochondria) and omega oxidation (within cytoplasmic reticulum). Elimination occurs via first-order kinetics with a mean half-life of 11 hours but is prolonged up to 30 hours in acute overdose.
Acute valproic acid intoxication usually causes mild, self-limited nervous system depression but serious toxicity and death can occur. Valproic acid toxicity may occur with dose increases to achieve desired therapeutic effect or in acute intentional or unintentional overdose. Additionally, it can occur when there is normal total valproate concentration, but the free/unbound drug is elevated in elderly individuals, those with hypoalbuminemia (and thus low protein binding), pregnancy, renal dysfunction with low GFR, liver disease and those who use other medications that complete for albumin binding sites. According to the American Association of Poison Control Center 2020 Annual Reports, there were a total of 2788 cases involving valproic acid poisoning with 534 with no outcome, 578 with a minor outcome, 578 with a moderate outcome, 86 with a major outcome, and 3 deaths. Children with multiple comorbidities and those in chronic valproate therapy are at risk of valproate toxicity. Furthermore, there is a risk of fulminant and fatal hepatotoxicity with valproate exposure in children less than two years old.
During large ingestions of valproic acid, there is increased utilization of the omega oxidation pathway leading to hepatotoxicity, cerebral edema, and hyperammonemia. In valproate-induced steatohepatitis, valproate leads to the buildup of intracellular lipids and reactive oxygen species by inhibiting beta-oxidation and thus resulting in mitochondrial dysfunction. Metabolites such as 2-propyl-4-pentanoic acid (4-EN-VPA) may mediate hepatotoxicity, 2-propyl-2-pentanoic acid (2-EN-VPA) may be responsible for cerebral edema, and propionic acid are responsible for hyperammonemia. Clinical features of acute valproic acid toxicity are likely with acute ingestion of 200 mg/kg or serum concentrations greater than 180 mg/L. Serum concentrations could be less than 180 mg/dl in chronic valproic toxicity. Chronic valproic acid toxicity typically causes hepatotoxicity and moderate hyperammonemia. Findings may include:
| System | Symptoms |
| Cardiologic | Hypotension, tachycardia, heart block (rare) |
| Gastrointestinal | Nausea, vomiting, diarrhea, hepatotoxicity, pancreatitis |
| Hematologic | Leukopenia, thrombocytopenia, anemia |
| Metabolic | Hyperammonemia, AGAP metabolic acidosis, hyperosmolality, hypernatremia, hypocalcemia, fever, hallucinations |
| Neurologic | Tremors, agitation, miosis, myoclonus, stupor, seizure, cerebral edema, coma |
| Respiratory | Respiratory depression |
Learning Point #2: Evaluation of suspected valproic acid toxicity
Therapeutic serum concentrations of valproic acid range from 50 to 100 ug/mL. Those with serum concentrations greater than 180 mg/dl likely have central nervous system dysfunction. Routine laboratory testing for suspected valproic acid poisoning includes:
- Serum valproic acid concentration
- complete blood count with differential to evaluate for thrombocytopenia and decreased granulocyte count
- random blood glucose level to rule out hypoglycemia as the cause of altered mentation
- pregnancy test in women of childbearing age
- serum AST and ALT to assess for hepatotoxicity
- plasma ammonia level in those at risk for encephalopathy
- serum electrolytes and arterial blood gas to evaluate for hypernatremia, metabolic acidosis, and hypocalcemia
- screening for other anticonvulsants, aspirin, and acetaminophen ingestion as patients frequently take these drugs with valproate.
Furthermore, a 12 lead EKG should be obtained to evaluate for AV conduction block and atrial tachycardia, and a head CT is recommended when a patient shows signs of focal neurological deficits, profound CNS depression, and suspicion of cerebral edema.
The case continued…
You consulted Toxicology, and while your orders were pending, you discussed possible management and GI decontamination before she could potentially decompensate. You knew that significant toxicity was likely with the reported amount ingested, and wanted to get ahead.
In the emergency department, the patient was given 50 g of activated charcoal. She tolerated this well. Her valproic acid level resulted at 379 ug/ml and the patient was started on multiple doses of activated charcoal at a dose of 0.5 g/kg every 4 hours. Additionally, a loading dose of 100 mg/kg IV of L-carnitine was administered. This was followed by maintenance doses of L-carnitine at 15 mg/kg every 4 hours.
The remainder of her labs were not diagnostic. A computed tomography scan of the brain was unremarkable.
The patient was admitted into the medical intensive care unit for continued monitoring and frequent interventions. The valproic acid level was measured every 4 hours. The patient’s next level of valproic acid measurement was 764 ug/mL. Eight hours following the ingestion, the patient developed seizures and a depressed level of consciousness for which she was intubated. At 12 hours after presentation, the valproic level was 905 ug/mL, and continuous renal replacement therapy (CRRT) was planned and started almost 24 hours after presentation. The valproic acid level 8 hours after starting CRRT was 417. At this time, hemodialysis was started, and the repeat valproic acid level dropped to 94 ug/mL.
Learning Point #3: Management of valproic acid toxicity
Management for valproic acid toxicity is mainly supportive including maintenance of airway, breathing, and circulation, and discontinuing the medication. Patients are at times admitted to the medical intensive care unit for continuous monitoring and treatment. Those with severe respiratory depression may require endotracheal intubation and mechanical ventilation, and those with hypotension may require intravenous boluses of isotonic crystalloid solution or in severe cases vasopressors.
If the patient presents within 2 hours of valproate overdose, gastrointestinal decontamination may be considered with a single dose of 50 mg of activated charcoal for an adult. In certain preparations such as enteric-coated and extended-release, activated charcoal can be given after more than 2 hours of ingestion as there is slow absorption. Multi-dose activated charcoal can be considered in some cases to prevent continued absorption of valproic acid especially in the enteric-coated and extended-release preparations, but has not been shown to significantly affect the elimination of valproic acid.
In patients presenting with an acute overdose of valproic acid with altered mental status, the use of L-carnitine is recommended. L-carnitine supplementation may increase the beta-oxidation of valproic acid thus limiting cytosolic omega-oxidation and the production of toxic metabolites. Patients are given a loading dose of 100 mg/kg of L-carnitine via intravenous route followed by 50 mg/kg every 8 hours. While on L-carnitine therapy, ammonia levels should be measured, and when serum ammonia levels start decreasing with an improvement in encephalopathy, L carnitine therapy should be stopped. A prophylactic dose of oral L-carnitine 100 mg/kg/day four times a day is recommended in asymptomatic patients with an acute overdose or in those with chronic valproic acid toxicity.
The Extracorporeal Treatments in Poisoning Workgroup recommends intermittent hemodialysis with extracorporeal treatment if any of the following is present: valproate concentration is >1300 ug/mL, shock is present, or cerebral edema is present. If hemodialysis is not available, CRRT or intermittent hemoperfusion could be used. Extracorporeal treatment is discontinued once valproate concentration decreases to 50 to 100 ug/mL, and there is clinical improvement evident by normal hemodynamic status, improved mental status, and normalizing acid-base and electrolyte balance.
The case concluded…
The patient remained intubated in the ICU for several days during treatment. Ammonia levels peaked at 393 mmol/L by the second day but improved with management. The patient was successfully extubated on the 12th day of admission. On day 14, she was transferred to the psychiatric ward in stable condition for management of her bipolar affective disorder and suicidal behavior.
References:
1. Shaikha Al Jawder, Eiman AlJishi, Shaikhah Al-Otaibi, and Mohammed S Al-Shahrani (2018, January 25). All guns blazing: Management and survival of massive valproic acid overdose – Case report and literature review. Open access emergency medicine : OAEM. Retrieved June 26, 2022, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5790066/
2. Gummin DD;Mowry JB;Beuhler MC;Spyker DA;Bronstein AC;Rivers LJ;Pham NPT;Weber J; (2021, December 10). 2020 Annual Report of the American Association of Poison Control Centers’ National Poison Data System (NPDS): 38th Annual Report. Clinical toxicology (Philadelphia, Pa.). Retrieved June 26, 2022, from https://pubmed.ncbi.nlm.nih.gov/34890263/
3. Lheureux, P. E. R., & Hantson, P. (2009, February). Carnitine in the treatment of valproic acid-induced toxicity. Clinical toxicology (Philadelphia, Pa.). Retrieved June 26, 2022, from https://pubmed.ncbi.nlm.nih.gov/19280426/#:~:text=It%20is%20postulated%20that%20carnitine,liver%20toxicity%20and%20ammonia%20accumulation.
4. Patel AR, Nagalli S. Valproate Toxicity. [Updated 2022 Mar 29]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK560898/
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6. Valproic acid: Extrip-workgroup. extrip. (n.d.). Retrieved June 30, 2022, from https://www.extrip-workgroup.org/valproic-acid
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