Valproate Toxicity Treatment & Management
- Author: Timothy J Wiegand, MD; Chief Editor: Asim Tarabar, MD more...
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]
Naloxone
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.
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