Valproate Toxicity Treatment & Management

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.

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]

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).

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.

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).

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.

Success use of meropenem as monotherapy and concurrent with L-carnitine to enhance the clearance of VPA in cases of severe overdose have been reported. ^{[24, 25, 26]}

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. ^[27] If the patient’s illness necessitates ventriculostomy, high-flux hemodialysis or hemoperfusion to enhance elimination is appropriate.