WORKUP	Section 5 of 10
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Lab Studies:

• Valproate level and anticonvulsant screen

• Determination of the VPA level is an obvious test.

• Patients taking VPA are frequently taking other anticonvulsants that they may not disclose.

• Screening is preferably done early and helps in determining if potentially complicating co-ingestion has occurred.

• Consider screening for anticonvulsants, acetaminophen, and acetylsalicylic acid.

• CBC with differential

• Thrombocytopenia

• Agranulocytosis

• Chemistries: Include a lithium level because of its use in mood stabilization (eg, in bipolar disorder).

• Hypocalcemia

• Hypernatremia (sodium salt of divalproex), rare hyponatremia (postulated to be secondary to syndrome of inappropriate antidiuretic hormone secretion [SIADH], as shown in in vitro studies), and hyponatremia

• Hypophosphatemia and hyperphosphatemia

• Hyperglycemia or hypoglycemia (particularly in association with liver failure)

• Liver function studies
  • Fulminant hepatic failure is a potentially fatal but rare complication of both acute and chronic VPA toxicity.

  • Children younger than 3 years of age who are taking many anticonvulsants and who have medical comorbidities are at increased risk for this complication.

• Coagulation studies

• Measurement of the prothrombin time (PT) and international normalized ratio (INR)

• Pregnancy testing in women of childbearing age

• Arterial blood gas (ABG) analysis

• Test for nonlactate metabolic acidosis: In 1 series, no patient with levels <450 mg/L developed acidosis.

• Test for respiratory depression with hypercapnia: This may reveal metabolic acidosis.

• Lipase measurement

• Assessment of the anion gap
  • VPA can directly cause an anion gap.

  • In a large multicenter review of 134 patients (80 with toxic VPA levels), an elevated anion gap (>15) was seen in 26% of patients with VPA levels >450 mg/L.

• Assessment of the osmolar gap: Because of its small size, VPA may theoretically contribute to an elevated osmolar gap if the serum VPA level is >1000 mg/L.

Imaging Studies:

• Obtain a CT scan of the head to evaluate cerebral edema, which is well documented with acute overdose.

• Cerebral edema is usually associated with hyperammonemia and appears within 48-72 hours after acute ingestion.

• Patients with encephalopathy and hyperammonemia due to chronic VPA therapy are at risk for cerebral edema.

	TREATMENT	Section 6 of 10
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Prehospital Care: Stabilize all acute life-threatening conditions.

• Ensure a patent airway. Intubate if necessary, eg, 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 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 VPA poisoning is mainly supportive: management of airway, breathing, and circulation [ABCs]; oxygenation; administration of IV fluids; monitoring; and the like. 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 VPA 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 reports. Dialysis removes VPA metabolites and ammonia. The most dramatic report describes hemoperfusion and hemodialysis in series, which reduced the half-life of VPA from 13 hours before treatment to 1.7 hours during hemodialysis. 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 >850-1000 mg/L because these are associated with increased morbidity and mortality.

• Use of multidose activated charcoal (MDAC): Despite case reports in which MDAC decreased 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 above).

• Continuous venovenous hemodialysis (CVVHD): In cases of hemodynamic compromise, continuous renal-replacement therapy, eg, CVVHD may improve the elimination half-life and decrease the potential hemodynamic instability compared with standard dialysis.

• Naloxone
  • Isolated case reports have described reversal of sedation with naloxone.

  • However, the administration of naloxone (including aggressive administration of 30 mg total) with no response has been reported.

• L-carnitine
  • L-carnitine provides possible benefit, particularly in patients with concomitant hyperammonemia, encephalopathy, and/or hepatotoxicity. A relationship between VPA encephalopathy and hyperammonemia has been suggested. VPA combines with L-carnitine, which is an important component of long-chain fatty acid metabolism. In children with hyperammonemia who are taking VPA, L-carnitine reduces ammonia levels to the reference range.

  • One case report documented the administration of L-carnitine oral supplementation to a patient with acute VPA overdose. Levels of beta-oxidation metabolites (from mitochondrial metabolism, normal pathway) of VPA were low, levels of omega and omega-1 metabolites (nonmitochondrial-mediated metabolic byproduct) were elevated before treatment. After treatment, the former levels increased, and the latter decreased. Toxic metabolites (eg, 4-N-valproate, products of omega oxidation) initially detected in the urine were no longer present after carnitine supplementation.

  • The optimum route and dose of L-carnitine has not been determined. In a retrospective review of patients with hepatotoxicity secondary to VPA, improved outcomes were noted in patients who received IV L-carnitine compared with those receiving oral L-carnitine or control subjects who received only supportive care.

• 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. No patient developed hypotension or had an allergic reaction or other adverse effect.

• One group recommends IV 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)." However, no dose for IV 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.

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.

• If the patient's illness requires ventriculostomy, hemoperfusion to enhance elimination is appropriate.

	MEDICATION	Section 7 of 10
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No specific antidote has been identified for VPA toxicity. Despite the documented safety and theoretical efficacy of the early administration L-carnitine, no specific recommendations regarding the optimal dose, frequency, or route of administration can be made. L-carnitine should be administered in consultation with a medical toxicologist or a poison control center certified by the American Association of Poison Control Centers.

Drug Category: GI decontaminants -- These agents are used in the emergency treatment of poisoning caused by drugs and chemicals.

Drug Name	Activated charcoal (Liqui-Char) -- Has network of pores present that absorbs 100-1000 mg drug/g charcoal. Does not dissolve in water. For maximum effect, administer within 0.5-1 h of poison ingestion.
Adult Dose	1 g/kg PO initially; may administer MDAC 10-20 g (0.25 g/kg/h) NG q2-4h; ideal dosing for overdose is 10:1 charcoal to ingested toxin.
Pediatric Dose	1-2 g/kg PO; 15-30 g total
Contraindications	Documented hypersensitivity; poisoning or overdose of acid or alkali mixtures; poisoning with substances that charcoal does not bind (eg, metals, alcohols); unprotected airway with absent gag reflex, obstruction or ileus, concomitant GI bleed (consult gastroenterologist before administering and carefully weigh risk and benefit
Interactions	May inactivate syrup of ipecac if used concomitantly; effectiveness of other medications decrease with coadministration; do not mix charcoal with sherbet, milk, or ice cream (decreases absorptive properties of activated charcoal)
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Not effective in poisonings of ethanol, methanol, iron salts, lithium or other metals; protect airway during administration; check for bowel sounds before each dose to minimize risk of charcoal ileus; avoid charcoal-sorbitol mixtures in children (risk of vomiting, hypernatremia, and dehydration)

Drug Name	L-Carnitine -- Levocarnitine is endogenous carboxylic acid involved in fatty-acid metabolism. Carnitine deficiency can result from dietary deficiency, inborn errors of metabolism, therapy with many anticonvulsants, and VPA toxicity. VPA may interrupt fatty-acid metabolism, impairing mitochondrial function and ultimately urea metabolism, leading to hyperammonemia. Carnitine deficiency may allow for production of hepatotoxic VPA metabolites by increasing alternate routes of metabolism (gamma oxidation). Effectively treats hyperammonemia associated with chronic VPA toxicity. Carnitine also improves outcome in hepatotoxicity and coma associated with acute VPA ingestion. No consensus on dose, frequency, and route in VPA overdose. Supplementation appears to be well tolerated; few adverse reactions reported.
Adult Dose	100 mg/kg IV then 250 mg/kg IV q8h for 4d; exceeds maximum daily recommended dose, but no adverse reactions reported in treatment of VPA overdose; some limit total dose to 3 g/d in divided doses q8h
Pediatric Dose	Overdose or hyperammonemia: 150-500 mg/kg/d IV; not to exceed 3 g/d or until clinical improvement 1996 Pediatric Neurology Advisory Committee consensus guidelines: 100 mg/kg/d PO; not to exceed 2 g/d in divided doses
Contraindications	Previous reaction to carnitine or L-carnitine.
Interactions	Sodium benzoate
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Monitor vital signs in ICU setting during IV administration; monitor serum chemistries daily during therapy

	FOLLOW-UP	Section 8 of 10
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Further Inpatient Care:

• Depending on level of toxicity, patients with 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 CNS compartment.

• 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.

Further Outpatient Care:

• 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.

Transfer:

• After they are medically cleared, patients may be transferred to a psychiatric facility. However, this disposition highly depends on the patient's symptoms and the amount of ingestion.

• In 1 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).

Complications:

• VPA 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 the Lab Studies section).

Prognosis:

• The prognosis depends on the amount ingested, the decontamination and elimination strategies administered (if indicated), and the supportive care given.

• Severe ingestions may resolve without sequelae after aggressive decontamination, elimination, and adequate supportive care.

• L-carnitine is reportedly helpful in VPA overdose associated with hyperammonemia, hepatotoxicity, and coma. However, its role remains to be confirmed. Some authors recommend its empiric use in overdoses when levels are >450 mg/L.

• The optimum dose, frequency, and route of administration (oral or IV) remain to be determined.

Patient Education:

• For excellent patient education resources, visit eMedicine's Drug Overdose Center and Poisoning - First Aid and Emergency Center. Also, see eMedicine's patient education articles Poisoning, Drug Overdose, Activated Charcoal, and Poison Proofing Your Home.

	MISCELLANEOUS	Section 9 of 10
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Medical/Legal Pitfalls:

• Failure to diagnose a concomitant ingestion that results in serious morbidity

	BIBLIOGRAPHY	Section 10 of 10
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography

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Toxicity, Valproate excerpt