Valproic Acid Toxicity – The evidence behind different treatment options

The Case

50-year-old woman is brought in by EMS after intentional ingestion of her 500 mg extended release valproate in a suicide attempt approximately 40 minutes prior to arrival. She had recently filled her valproate prescription with 80 tablets and took nearly all of them. She admits to feeling depressed and has a history of previous suicide attempts. There are no co-ingestions. The patient is otherwise asymptomatic.

PMH: bipolar disorder

PSH: Knee surgery, lung surgery (swallowed pins, puncturing lung), tonsillectomy

Meds: folate, valproate, diphenhydramine

Allergies: NKDA

SH: denies tobacco, alcohol, or drug use

Physical Examination:

VS: HR 106 min^-1  RR 22 min^-1  BP 180/110 mmHg  T 98.7ºF (axillary)   SpO2 98%   FSG 85 mg/dL

Gen: No acute distress

HEENT: Moist mucous membranes, no salivation, no lacrimation

Pulm: clear to auscultation bilaterally, no wheezes, rales or rhonchi

CV: +S1/S2, no murmurs, rubs or gallops

GI: +bowel sounds, abdomen soft, non-tender, non-distended

Neuro: PERRL 2mm, no nystagmus, AAOx3, no ataxia, no fasciculations

Skin: warm, dry, no flushing, no ecchymoses

Extremities: cap refill < 2 seconds

Psych: +suicidal ideation, no visual or auditory hallucinations

Labs (drawn approximately 60-90 minutes post-ingestion):

Ammonia: 32 μmol/L
VBG: 7.29/54/35/25/-2
Lactate: 2.8 mmol/L
Valproic Acid Level: 451.8 μg/mL

ECG: normal sinus rhythm, normal PR and QTc intervals, normal QRS duration, no ST-T wave abnormalities

ED Course:

Upon arrival, the Poison Center was consulted, and the patient consented to orogastric tube placement for gastric lavage, activated charcoal, and then whole bowel irrigation. Unfortunately, an orogastric tube was unavailable so a nasogastric tube was used instead. L-Carnitine infusion was started. Critical care medicine was consulted early since the dose ingested (approximately 600 mg/kg) placed the patient at high risk of coma. On reassessment an hour after arrival, the patient developed progressive lethargy and became unresponsive with loss of airway reflexes and shallow breathing. The patient was intubated for airway protection/respiratory insufficiency, and the post-intubation chest x-ray showed the endotracheal tube in satisfactory position with no acute pathology. Renal was consulted for hemodialysis and the patient was admitted to the MICU.

Inpatient Course:

After two sessions of hemodialysis, the patient awoke and recovered uneventfully. She was transferred to psychiatry for further management.

Valproic Acid Toxicity

Valproate (VPA) is a branched-chain carboxylic acid commonly used for bipolar disorder, seizures, and migraines. It has a bioavailability of greater than 80% and reaches peak concentration in approximately 6 hours. However, for enteric-coated and extended release preparations, it may take up to 24 hours to reach peak concentrations (1). A study by Dutta and Reed in 2006 tested healthy adults and epileptic patients (who could metabolize valproate faster due to induction of hepatic enzymes) and found that the functional half-life of extended release valproate was nearly 2-3 times longer than the expected half-life in both populations (3). At therapeutic concentrations, VPA is 90% protein bound, but as VPA levels increase to supratherapeutic or toxic levels, binding sites become saturated and VPA becomes approximately 35% protein bound. VPA’s mechanism of action is not clearly understood, but it involves regional increases in γ-aminobutyric acid (GABA) concentrations while attenuating activation of N-methyl-D-aspartate (NMDA) receptors (1,2).

Metabolism of VPA (1)

VPA is primarily metabolized in the liver via similar mechanisms for mitochondrial lipid metabolism such as glucuronidation, β-oxidation, and ω-oxidation. After VPA is attached to coenzyme A (CoA) and transferred to carnitine, valproylcarnitine (VPA-carnitine) is created, which is renally excreted and inhibits an ATP-dependent carnitine transporter that brings carnintine into the cell. Other VPA metabolites trap mitochondrial CoA so that it cannot participate in ATP production, further inhibiting the ATP-dependent carnitine transporter. The breakdown of all of this intracellular machinery results in decreased formation of N-acetylglutamate, which is a necessary cofactor for carbamoylphosphate synthetase I (CPS I). If you recall your medical school biochemistry, CPS I is the enzyme that combines ammonia, bicarbonate, and phosphate to produce carbamoylphosphate, one of the first steps of the urea cycle. This will lead to buildup of ammonia as it can no longer be incorporated into urea and excreted. For many Emergency Physicians, learning these pathways is low yield, but the important thing to remember is that during the β-oxidation of VPA, carnitine stores are depleted (1,2) and that this ultimately leads to hyperammonemia. In a rat model of VPA toxicity, Raza et al also found a time-dependent decrease in glutathione concentrations in the kidney and liver compared to controls (4).

Complications

Potential complications of VPA toxicity include hyperammonemia, encephalopathy, cerebral edema, coma, hepatotoxicity, myelosuppression, renal failure, shock, hypernatremia, hypocalcemia, and an anion gap metabolic acidosis (1). A single-center, prospective study of 79 VPA overdoses – 15 isolated VPA poisonings – over a decade found minimal toxic effects from the overdose. In this small cohort, four patients had vomiting, five had tachycardia, and two had drowsiness. The two drowsy patients ingested between 300-400 mg/kg of VPA. The only patient in this study who had severe toxicity took over 500 mg/kg of VPA. Based on this and previous case reports, ingestions of at least 400 mg/kg of VPA are associated with significant toxicity (5). A multicenter, prospective case series by Spiller et al similarly found that most patients had minimal toxic effects, correlating to peak serum VPA concentrations <450 μg/mL. However, this case series had more significant and life-threatening overdoses that manifested with coma, respiratory depression, hypotension, acidosis, and myelosuppression. They found that a peak serum concentration >850 μg/mL was associated with the highest risk for these serious complications. All patients with a VPA level above 850 μg/mL developed coma, and 63% required mechanical ventilation. The few patients with leukopenia had VPA concentrations >1200 μg/mL. and when followed, myelosuppression reached its nadir in 3-5 days. Consistent with the pharmacokinetic profile of extended release and enteric coated preparations, these authors noted delays in serum peak concentrations of these ingestions, leading to their recommendation for a repeat VPA level 3-4 hours after the initial level (6).

Management

The cornerstone of VPA toxicity management is good supportive care, including discontinuation of VPA and maintenance of airway, breathing, and circulation. As discussed, the majority of cases involve minimal toxicity; however, with large ingestions, there is potential for serious morbidity. As with all toxicological ingestions, it is prudent to check for co-ingestions and obtain an electrocardiogram and serum acetaminophen concentration. A complete blood count, comprehensive metabolic panel, ammonia concentration, and VPA level should be obtained for significant ingestions, especially of enteric coated or extended release preparations. The VPA level should be repeated in 3-4 hours and possibly even again depending on the time of ingestion. Goldfrank’s recommends repeating VPA levels every 4-6 hours until it starts to trend downward (1). It should be noted that ammonia levels may not correlate well with clinical manifestations of toxicity or with VPA level. While only 10 patients in the Spiller et al study had ammonia concentrations measured, the mean ammonia concentration in patients with serious medical outcomes was actually lower than patients with no or minor symptoms, and two patients with mildly elevated ammonia had VPA concentrations >850 μg/mL (6).

There are a few therapeutic options one can consider in the treatment of VPA toxicity. Multi-dose activated charcoal may be useful to prevent absorption in acute ingestions, especially with enteric/extended release preparations (1). There have been mixed results in case reports of naloxone reversing respiratory depression and somnolence in VPA toxicity (7,8). Although literature supporting its use is comprised of retrospective studies and case reports, L-carnitine is safe, well-tolerated, and has theoretical benefits in VPA toxicity (7,9). The only commonly reported adverse effect is a noxious odor and mild gastrointestinal upset with oral administration, which may be obviated by intravenous administration. L-carnitine reduces ammonia levels in VPA toxicity through several possible mechanisms, including repletion of carnitine, increasing beta-oxidation of VPA, and by providing a VPA “sink” for its elimination. There have been no RCTs that demonstrate that L-carnitine is superior to supportive care in acute VPA overdoses in terms of clinically oriented outcomes. There have been multiple case reports demonstrating that supplementation with L-carnitine can reduce ammonia levels, but with unclear clinical benefit (9). Furthermore, there are no standard dosing regimens for this indication.

L-Carnitine for that sick pump, brah!

For VPA toxicity, Perrott et al propose administering 100 mg/kg IV of L-carnintine, then 50 mg/kg IV every eight hours, with a maximum of 3 g per dose, until ammonia concentrations decrease or there is evidence of clinical improvement (10). This initial dose is higher than the recommended dose for severe metabolic crisis due to carnitine deficiency and higher than the Pediatric Neurology Advisory Committee recommends for valproate-induced hepatotoxicity (7). Goldfrank’s recommends the same initial dose, but with a maximum dose of 6 g and 15 mg/kg every four hours with the same endpoints (1). Despite a lack of clear efficacy and standardized dosing, L-carnitine should be administered to patients with severe toxicity as the risk of serious complications far outweigh the adverse effects of L-carnitine (1,9,10).

Potential Therapy

As mentioned earlier, rat studies have demonstrated that VPA toxicity depletes stores of glutathione (4). One could reasonably assume that, similar to its use in acetaminophen overdose, n-acetylcysteine (NAC) may play a role in preventing or treating VPA-induced hepatotoxicity. A small study in rats found that NAC was effective in preventing VPA-induced hepatotoxicity, and a small pediatric study found that NAC may be helpful in treating it as well (11). The evidence for NAC is limited but warrants further investigation.

• TL;DR: VPA Toxicity
  • Check ammonia and VPA concentrations
    • • Recheck VPA concentrations every 3-4 hours until they downtrend
      • VPA concentration >850 μg/mL is associated with severe toxicity
  • Depending on time of ingestion, consider GI decontamination after discussion with your local Poison Control Center
  • Not much evidence that L-carnitine helps, but it is safe and does seem to decrease ammonia levels
    • • 100 mg/kg IV (max of 3g), then 50 mg/kg IV q8h
      • No definite dosing scheme for it so talk to your local toxicologists!
  • EXTRIP guidelines:
    • http://docs.wixstatic.com/ugd/363318_05a9ee49ff5240a69714389fbd8de5f9.pdf

References

1. Doyon S. Antiepileptics. In: Hoffman RS, Howland M, Lewin NA, Nelson LS, Goldfrank LR. eds. Goldfrank’s Toxicologic Emergencies, 10e New York, NY: McGraw-Hill; 2015.
2. Silva MF, Aires CC, Luis PB, et al. Valproic acid metabolism and its effects on mitochondrial fatty acid oxidation: a review. J Inherit Metab Dis. 2008;31(2):205-16.
3. Dutta S, Reed RC. Functional half-life is a meaningful descriptor of steady-state pharmacokinetics of an extended-release formulation of a rapidly cleared drug : asshown by once-daily divalproex-ER. Clin Drug Investig. 2006;26(12):681-90.
4. Raza M, Al-Bekairi AM, Ageel AM, Qureshi S. Biochemical basis of sodium valproate hepatotoxicity and renal tubular disorder: time dependence of peroxidative injury. Pharmacol Res. 1997;53(2):153-157.
5. Isbister GK, Balit CR, Whyte IM, Dawson A. Valproate overdose: a comparative cohort study of self poisonings. J Clin Pharmacol. 2003;55:398-404.
6. 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;38:755–760
7. Mock C, Schwetschenau K. Levocarnitine for valproic-acid-induced hyperammonemic encephalopathy. American Journal Of Health-System Pharmacy: AJHP: Official Journal Of The American Society Of Health-System Pharmacists [serial online]. January 1, 2012;69(1):35-39.
8. Jones AL, Proudfoot AT. Features and management of poisoning with modern drugs used to treat epilepsy. Q J Med. 1998;91:325–332.
9. Lheureux PE, Hantson P. Carnitine in the treatment of valproic acid-induced toxicity. Clin Toxicol (Phila). 2009;47(2):101-11.
10. Perrott J, Murphy NG, Zed PJ. L-carnitine for acute valproic acid overdose: a systematic review of published cases. Ann Pharmcother. 2010; 44:1287-93.
11. Said S, El-Agamy D. Prevention of sodium valproate-induced hepatotoxicity by curcumin, rosiglitazone and N-acetylcysteine in rats. Arzneimittel-Forschung [serial online]. 2010;60(11):647-653.

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edenkim

Eden Kim, DO, MPH PGY-3 Emergency Medicine Resident

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