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Valproic acid poisoning

Valproic acid poisoning
Author:
Matthew D Sztajnkrycer, MD, PhD
Section Editor:
Stephen J Traub, MD
Deputy Editor:
Michael Ganetsky, MD
Literature review current through: Sep 2022. | This topic last updated: Jun 27, 2022.

INTRODUCTION — Valproic acid (2-propylpentanoic acid; VPA) is a branched-chain carboxylic acid introduced as an anti-epileptic drug in 1978 in the United States. It is used to treat partial and generalized seizures and acute mania, and as prophylaxis for bipolar disorder and migraine headaches. Although acute VPA intoxication frequently results in mild, self-limited central nervous system depression, serious toxicity and death may occur.

The clinical features and treatment of VPA intoxication are reviewed here. A summary table to facilitate the emergency management of VPA overdose is provided (table 1). The use of VPA as an antiepileptic agent is detailed separately. (See "Overview of the management of epilepsy in adults".)

PHARMACOLOGY — Although not fully elucidated, the anti-epileptic effects of VPA appear to be mediated by several mechanisms. The pharmacology of VPA is discussed separately. (See "Antiseizure medications: Mechanism of action, pharmacology, and adverse effects", section on 'Valproate'.)

FORMULATIONS, PHARMACOKINETICS, AND METABOLISM — Valproic acid (VPA) is available in immediate-release and enteric-coated, delayed-release (12 hour) and extended release (24 hour) oral preparations, as well as an intravenous formulation. Delayed and extended release products are typically formulated as divalproex sodium. Therapeutic daily doses range from 500 mg to 2 g in adults or 15 to 60 mg/kg in children [1].

Nonenteric-coated preparations of VPA are rapidly and nearly completely absorbed from the gastrointestinal tract; peak plasma concentrations are observed from one to four hours after ingestion [1]. Peak plasma concentrations occur four to five hours after therapeutic doses of enteric-coated tablets but may be markedly delayed following overdose [1,2]. A multicenter study of VPA ingestions revealed a mean time to peak plasma concentration of 7.4±3.9 hours; 14 percent of patients had peak concentrations delayed greater than 10 hours [3]. In one case report, peak plasma VPA concentrations occurred 17 hours following overdose of divalproex sodium [4].

Therapeutic serum concentrations typically range from 50 to 100 mg/L (350 to 700 micromol/L) [1,5]. At therapeutic concentrations, VPA is 80 to 90 percent bound to plasma proteins and has a small volume of distribution (0.13 to 0.23 L/kg) [1,5,6].

VPA is metabolized extensively by the liver via glucuronic acid conjugation and beta and omega oxidation to produce multiple metabolites, some of which are biologically active. Less than 3 percent of VPA is excreted unchanged in the urine [1,5,6]. VPA is eliminated by first-order kinetics with a half-life ranging from 5 to 20 hours (mean 11 hours); the half-life may be prolonged to as great as 30 hours after overdose [1,6,7].

CYP (p450) mediated omega oxidation, which is normally responsible for a small component of VPA metabolism, may generate toxic metabolites that have been implicated in the dose-related and idiosyncratic hepatic, metabolic, and neurologic adverse effects of VPA [7-14]. During long-term or high-dose VPA therapy, a greater degree of omega oxidation may occur, increasing the risk of toxicity. 2-propyl-2-pentenoic acid (2-EN-VPA) may mediate cerebral edema [7,8,10,11], 2-propyl-4-pentenoic acid (4-EN-VPA) may mediate hepatotoxicity [12,13], and propionic acid metabolites may precipitate hyperammonemia [9,14]. Other metabolites may produce a false-positive urine ketone determination [15].

CLINICAL FEATURES — Evaluation of the poisoned patient includes recognition that poisoning has occurred based upon the history, physical examination, and laboratory assessment; identification of the agents involved; and an assessment of the severity of the poisoning. The clinical features associated with valproic acid poisoning are described below. (See "General approach to drug poisoning in adults" and "Initial management of the critically ill adult with an unknown overdose".)

History — Important historical information in the patient with suspected valproic acid (VPA) poisoning includes:

Identity of any ingested pills, including dose and formulation (eg, immediate-release or controlled-release)

Approximate number of pills ingested

Time of ingestion

Whether the patient takes valproic acid or any other medication chronically

Possible coingestants, including over-the-counter medications, herbal medicines, illicit drugs, and alcohol.

The role of the history in poisoned patients is reviewed in detail separately. (See "General approach to drug poisoning in adults", section on 'History'.)

General findings — The majority of patients with acute VPA intoxication experience mild to moderate lethargy and recover uneventfully [16,17]. Central nervous system (CNS) dysfunction is the most common manifestation of toxicity, ranging in severity from mild drowsiness to coma or fatal cerebral edema [8,10,11]. The onset and progression of CNS depression is usually rapid, but may be delayed with ingestion of delayed release preparations [4,11]. Although free and total VPA concentrations do not correlate precisely with severity of clinical effects, patients who ingest greater than 200 mg/kg of VPA and/or have serum concentrations greater than 180 mg/L (1260 micromol/L) usually develop some degree of CNS depression [1,15]. Despite considerable clinical variability, signs of severe poisoning, such as coma and metabolic acidosis, are most likely to occur in cases where peak serum concentration exceeds 850 mg/L [3].

Other clinical findings following overdose may include [8,10,11]:

Vital signs – Respiratory depression, hypotension, tachycardia, hyperthermia

Metabolic – Hyperammonemia, anion gap metabolic acidosis, hyperosmolality, hypernatremia, hypocalcemia

Gastrointestinal – Nausea, vomiting, diarrhea, mild toxic hepatitis

Additional neurologic – Miosis, agitation, tremors, myoclonus

Recognized but rare complications of overdose include fever, hallucinations, heart block, pancreatitis, acute renal failure, alopecia, leukopenia, thrombocytopenia, anemia, cerebral edema, seizures, optic nerve atrophy, and acute respiratory distress syndrome [8,11]. In rare cases, reversible Parkinsonian signs have been noted, particularly in elder adults with concomitant neurodegenerative conditions taking antipsychotic medications [18,19]. In contrast to poisoning with phenytoin or carbamazepine, nystagmus, dysarthria, and ataxia are rarely noted following VPA overdose. (See "Phenytoin poisoning" and "Carbamazepine poisoning".)

A pediatric case report involved ischemic-appearing electrocardiogram (ECG) changes that resolved without specific therapy [20]. Cardiac biomarkers remained within normal limits.

Chronic VPA therapy may be associated with non-dose-related (idiosyncratic) toxicity, including hepatic failure, hyperammonemia without hepatic failure, pancreatitis, alopecia, leukopenia, thrombocytopenia, and anemia [7,8,13] (see "Antiseizure medications: Mechanism of action, pharmacology, and adverse effects", section on 'Valproate'). Myelodysplastic changes may also be seen. (See "Clinical manifestations and diagnosis of myelodysplastic syndromes (MDS)", section on 'Clinical presentation'.)

Cerebral edema — Cerebral edema is associated with acute and chronic VPA toxicity and is not clearly correlated with the dose of VPA ingested [10]. When associated with acute intoxication, cerebral edema becomes clinically apparent 12 hours to four days after overdose [8,10,11,21]. Cerebral edema from VPA toxicity may result in early herniation and ischemia with focal neurologic deficits [22]. Cerebral edema likely reflects abnormal VPA metabolism that allows accumulation of the 2-EN-VPA metabolite in the brain and plasma. 2-EN-VPA has a prolonged elimination half-life (mean half-life 43 hours) and may be responsible for the prolonged coma exhibited by some patients despite normalization of plasma VPA concentrations [7,8].

Hyperammonemia — Valproic-acid associated hyperammonemia is typically defined as a plasma ammonia concentration greater than 80 mcg/dL (47 μmol/L). Hyperammonemia may occur after acute overdose or chronic use of VPA, and is not always accompanied by abnormal liver function tests [6-9,14,15,23]. In addition, valproic–acid associated hyperammonemia does not necessarily result in clinical encephalopathy, and in half the cases is asymptomatic [24,25].

The incidence of valproate-induced hyperammonemia in the general population of patients taking VPA is not well established, but it is likely higher in those who come to the attention of health care facilities. Cross-sectional studies have suggested a prevalence for this condition of 16 to 100 percent, while prospective studies have reported a prevalence of 70 to 100 percent [26]. In a review of 14 cases in a psychiatric setting, the mean increase in ammonia concentration was 3.6 times the maximal normal value [27].

Hyperammonemia is believed due to propionic acid, a metabolite of VPA, which inhibits mitochondrial carbamoyl phosphate synthetase, an enzyme necessary for ammonia elimination via the urea cycle [9]. If the action of this enzyme is sufficiently impaired, ammonia levels will accumulate, frequently producing encephalopathy [14]. In addition, VPA may raise plasma ammonia levels through interaction with carnitine, a cofactor necessary for mitochondrial long-chain fatty acid metabolism. In states of relative carnitine deficiency, metabolism of VPA via omega oxidation increases; omega oxidation products also inhibit carbamoyl phosphate synthetase. Plasma ammonia concentrations directly correlate with the dose and serum concentrations of VPA, and inversely with serum concentrations of carnitine [12,23,28].

Valproate-related hyperammonemic encephalopathy — Symptomatic hyperammonemia with valproate therapy is often referred to as "VHE," and can sometimes occur without abnormalities of liver function tests. VHE has the following characteristics [9,27,29-35]:

Clinical features can include confusion, lethargy, vomiting, and increased seizure frequency.

Progression to stupor, coma, and death may rarely occur.

Onset may be immediate with loading of VPA, or insidious with chronic VPA therapy.

The degree of encephalopathy is not clearly related to VPA serum levels, which may be in the normal range.

Plasma ammonia concentrations should be monitored if VHE is suspected clinically. Ammonia levels in VHE associated with chronic VPA therapy ranged from 127 mcg/dL (75 μmol/L) to 482 mcg/dL (283 μmol/L) [36,37], while the peak ammonia concentration in a fatal acute ingestion was 1191 mcg/dL (699 μmol/L) [38].

A mild asymptomatic hyperammonemia is common with therapeutic valproate use, and no acute intervention is typically required when such cases are discovered incidentally. VPA should be discontinued in the setting of symptomatic hyperammonemia or VHE. VHE is more likely when VPA is used in combination with phenobarbital, phenytoin, carbonic anhydrase inhibitors (eg, acetazolamide), or carbamazepine [32,39,40]. Urea cycle defects and carnitine deficiency may increase the risk of developing hepatic failure with VHE. (See 'Hepatotoxicity' below and "Urea cycle disorders: Clinical features and diagnosis".)

Hepatotoxicity — Acute VPA ingestion may result in dose-related and reversible hepatotoxicity, which manifests as minor elevations in aminotransferases [7,8,11]. Chronic dosing of VPA is also associated with mild aminotransferase elevations in up to 44 percent of patients [13,41,42]. Discontinuation of the drug usually results in complete resolution of these liver function abnormalities, although idiosyncratic fulminant hepatic failure and death (with histopathologic changes similar to those of Reye syndrome) have also occurred [13,43,44]. The rates of both non-fatal and fatal hepatic failure appear to be higher when valproic acid is administered with another medication (most often antiepileptics or benzodiazepines) as opposed to monotherapy [45]. (See "Approach to the patient with abnormal liver biochemical and function tests", section on 'Common liver biochemical and function tests'.)

Severe idiosyncratic reactions usually occur during the first six months of VPA therapy and are not preceded by minor aminotransferase elevation [13]. Patients at greatest risk for fatal hepatotoxicity due to chronic VPA are children less than two years old, particularly those with organic brain disease, developmental delay, congenital metabolic disorders, and severe epilepsy treated with multiple anticonvulsants [13]. The incidence of fatal hepatic reactions in this at-risk group may be as high as 1 in 500, whereas the overall incidence is one in 50,000 patients [13]. Liver transplant in children with valproic acid-associated acute hepatic failure results in significantly decreased survival rates compared to liver transplant in children with drug-induced acute liver failure unrelated to valproic acid. This may be due to the "unmasking" of mitochondrial disease by VPA [46].

Patients with unsuspected mitochondrial disease (eg, Alpers-Huttenlocher disease) are particularly at risk for hepatotoxicity from VPA. The presence of an underlying mitochondrial disorder alters clinical management and should be considered in children (and adults) presenting with VPA hepatotoxicity. (See "Acute liver failure in children: Etiology and evaluation", section on 'Inherited metabolic disease' and "Acute liver failure in children: Management, complications, and outcomes".)

Both acute hepatotoxicity and idiosyncratic hepatic failure following chronic VPA use are probably mediated by 4-EN-VPA, an omega oxidation metabolite of VPA, and carnitine deficiency [12,13]. VPA (itself a short-chain fatty acid) combines with carnitine and results in carnitine depletion during long-term or high-dose VPA therapy [12,23,28,47]. Hypocarnitinemia results both in impaired mitochondrial fatty acid oxidation for energy production and impaired VPA metabolism. Microvesicular steatosis and subsequent hepatic failure can occur [13]. VPA-induced lipid peroxidation and glutathione depletion may also contribute to hepatotoxicity through less well understood mechanisms [48].

Electrolyte abnormalities — Common metabolic abnormalities after VPA overdose include hypernatremia, hyperosmolality, hypocalcemia, and anion gap metabolic acidosis [7,8,11,15]. VPA is administered as a sodium salt (13.8 mg sodium per 100 mg VPA) and therefore can produce hypernatremia in large doses. VPA and its metabolites are low molecular weight, osmotically-active acids and anions that may produce elevated osmolal and anion gaps and metabolic acidosis. Hypocalcemia develops when calcium binds anionic VPA metabolites.

LABORATORY EVALUATION

Valproic acid concentration — Therapeutic serum concentrations of valproic acid (VPA) range from 50 to 100 mg/L (350 to 700 micromol/L) [1,5]. Serum concentrations should be measured in any case of known or suspected overdose or toxicity. Because valproic acid levels often peak several hours after ingestion, we recommend that serial valproic acid concentrations be assessed every two to four hours until a steady decline in the level is noted, which suggests that a peak serum level has been reached. Patients with serum concentrations greater than 180 mg/L (1260 micromol/L) usually develop some degree of central nervous system (CNS) depression, although free and total VPA concentrations correlate imprecisely with the severity of toxicity [1,15].

General testing — Routine laboratory evaluation of the poisoned patient should include the following:

Fingerstick glucose, to rule out hypoglycemia as the cause of any alteration in mental status

Acetaminophen and salicylate levels, to rule out these common coingestions

Electrocardiogram (ECG), to rule out conduction system impairment by drugs that prolong the QRS or QTc intervals

Pregnancy test in women of childbearing age

In addition, the following tests should be obtained for any patient at risk for significant VPA toxicity:

Basic serum electrolyte concentrations, paying particular attention to sodium (concern for hypernatremia), bicarbonate (concern for acidemia), and calcium (concern for hypocalcemia)

Serum transaminase concentrations (AST, ALT)

Plasma ammonia concentration

Platelet concentration

IMAGING STUDIES — Valproic acid (VPA) overdose often causes a depressed mental status, but may also lead to cerebral edema in some cases, generally 12 hours to four days after acute intoxication. Thus, clinicians may need to obtain a head CT in some patients with VPA poisoning to assess for cerebral edema. No guidelines can address all clinical scenarios, and physicians should obtain a head CT if they suspect the development of cerebral edema based upon clinical findings.

We suggest obtaining a head CT in the following circumstances:

Patients with VPA toxicity and focal neurologic deficits (ie, not simply a mildly depressed mental status)

Patients with VPA toxicity, depressed mental status, and an elevated plasma ammonia concentration

Patients with a depressed mental status 12 hours or longer after an acute VPA overdose

A head CT is generally not necessary during the first few hours after an acute VPA ingestion in patients with a mildly depressed mental status and a normal plasma ammonia concentration.

DIAGNOSIS — The diagnosis of acute valproic acid (VPA) poisoning is suspected on the basis of a history of overdose associated with typical physical findings, primarily central nervous system depression, which can range from mild cognitive impairment to coma. Other findings can include vital sign abnormalities (respiratory depression, hypotension, tachycardia, hyperthermia), gastrointestinal complaints (eg, vomiting), and other neurologic findings (miosis, agitation, tremors, myoclonus). Chronic toxicity may be associated with non-dose-related (idiosyncratic) toxicity, including hepatic failure, hyperammonemia without hepatic failure, pancreatitis, or myelodysplastic changes. Elevations in blood ammonia and aminotransferase concentrations are suggestive of either acute or chronic toxicity. The diagnosis is confirmed by an elevated serum concentration of VPA.

DIFFERENTIAL DIAGNOSIS — The most salient feature of valproic acid (VPA) toxicity is a depressed mental status. Therefore, the potential differential diagnosis for VPA poisoning is extremely broad and includes intracerebral hemorrhage, infections of the central nervous system (meningitis, encephalitis), metabolic derangements (eg, hypoglycemia, hyponatremia), as well as other poisonings (eg, sedative-hypnotics, anti-epileptics). The diagnosis of VPA poisoning is suspected on the basis of the history and suggestive clinical findings (eg, elevated serum transaminase and/or plasma ammonia concentrations), and confirmed by the presence of an elevated serum VPA concentration, which distinguishes the diagnosis from alternatives. Common causes of altered mental status, such as hypoglycemia and hyponatremia, should be ruled out during the initial evaluation using bedside and basic laboratory tests. The differential diagnosis of depressed mental status is reviewed in greater detail separately. (See "Diagnosis of delirium and confusional states" and "Evaluation of abnormal behavior in the emergency department".)

TREATMENT — A summary table to facilitate the emergency management of patients with valproic acid (VPA) overdose is provided (table 1). Management is described in greater detail below. Patients with clinical signs or laboratory values suggesting severe poisoning require intensive monitoring and care; early transfer to hospitals capable of providing such care is generally necessary.

Supportive care — Supportive care is the principal treatment for VPA intoxication and results in good outcomes in the vast majority of patients [4,11]. Treatment with naloxone and carnitine may be beneficial. (See 'Naloxone' below and 'Carnitine supplementation' below.)

Patients with altered mentation may require tracheal intubation for airway protection. (See "Approach to advanced emergency airway management in adults" and "Rapid sequence intubation for adults outside the operating room".)

Benzodiazepines should be administered if seizures occur (eg, lorazepam 2 mg IV; dose can be repeated every 5 to 10 minutes as necessary for refractory seizures). The use of benzodiazepines to control severe seizures is reviewed separately. (See "Initial management of the critically ill adult with an unknown overdose", section on '"D": Disability and neurological stabilization' and "Convulsive status epilepticus in adults: Management", section on 'First therapy: Benzodiazepines'.)

Electrolyte abnormalities are generally managed in standard fashion, however, hemodialysis may be preferable for treating severe hypernatremia in patients with cerebral edema. (See "Treatment of hypernatremia in adults" and "Treatment of hypocalcemia" and 'Hemodialysis and hemoperfusion' below.)

Naloxone — Naloxone (0.8 to 2 mg) has been reported to reverse central nervous system (CNS) depression in several cases of VPA poisoning [49-52], although this effect is not universal [53,54]. While the efficacy of naloxone is questionable, the risks associated with treatment are low and thus we suggest that naloxone be given to patients with acute VPA poisoning and signs of central nervous system depression (depressed mental status), unless the patient is known or suspected to be habituated to opioids but acute opioid intoxication is not suspected. In such patients we recommend withholding naloxone so as to not precipitate acute opioid withdrawal.

We suggest starting with a dose of 0.04 mg IV. This dose is titrated upwards every few minutes until the patient responds (improved mental status) or a maximum single dose of 2 mg IV is reached. Once a 2 mg dose has been reached, additional naloxone, given in 2 mg increments, may be given up to a total cumulative dose of 10 mg. If there is no patient response after a total of 10 mg IV, no further naloxone should be given. In patients who are known or are suspected to be habituated to opioids but in whom opioid intoxication is not suspected, we recommend withholding this treatment so as to not precipitate acute opioid withdrawal.

Carnitine supplementation — VPA-induced hyperammonemia and hepatotoxicity may be mediated in part by carnitine deficiency; carnitine supplementation may prevent and attenuate these adverse effects [24,55]. In the absence of robust data, it is reasonable to give carnitine supplementation to patients with VPA toxicity and any of the following:

Coma

Severe hepatoxicity

Valproic acid serum concentration >450 mcg/mL (>3120 micromol/L) (see 'Valproic acid concentration' above)

Valproic-related hyperammonemic encephalopathy (see 'Valproate-related hyperammonemic encephalopathy' above)

Carnitine supplementation may also be given to patients with asymptomatic hyperammonemia, particularly in the setting of significant VPA toxicity.

There are no controlled studies evaluating the optimal dose of carnitine supplementation in the setting of valproic acid toxicity. Based upon the available literature, a reasonable approach to L-carnitine dosing is 100 mg/kg IV over 30 minutes (maximum dose 6 g), followed by 50 mg/kg IV (maximum dose 3 g) given every eight hours [55].  

A number of case reports describe various doses for carnitine supplementation, ranging from 50 to 100 mg/kg IV for the loading dose, to 50 to 100 mg/kg IV for the daily dose thereafter, but no approach has been shown to be more efficacious than that described above [55-58].

Treatment with carnitine is continued until the clinical signs of severe poisoning resolve. For patients with an acute overdose of VPA but no clinical or laboratory signs of toxicity, oral carnitine supplements can be administered prophylactically at a dose of 100 mg/kg per day (up to 3 g total) divided every six hours [59].

Oral carnitine administration reverses carnitine deficiency, leads to resolution of elevated ammonia levels, and improves lethargy in patients treated chronically with VPA [23,28,60,61]. In addition, carnitine may hasten the resolution of coma, prevent hepatic dysfunction, and reverse mitochondrial metabolic abnormalities in patients with acute VPA intoxication [12,62]. As an example, a retrospective study of patients with severe valproate-induced hepatotoxicity noted that intravenous carnitine therapy was associated with a marked increase in survival [63]. Furthermore, a retrospective review of all published English language articles from 1948 to 2011 related to carnitine therapy for VHE revealed no significant adverse effects [57]. Although theoretical concern exists for the potential development of seizures with carnitine supplementation, another systematic review found no evidence of increased risk with carnitine supplementation [64]. Nevertheless, published evidence supporting the use of carnitine consists solely of observational studies.

Gastrointestinal decontamination and other enhanced elimination techniques

Activated charcoal — Single dose activated charcoal (AC) alone is sufficient for the vast majority of patients with a VPA overdose; we suggest this treatment for all patients with suspected VPA poisoning who present within two hours of an acute ingestion. The standard dose is 1 g/kg (maximum dose 50 g). AC should be withheld in patients who are sedated and may not be able to protect their airway, unless tracheal intubation is performed first. However, tracheal intubation should not be performed solely for the purpose of giving charcoal. AC should also be withheld in patients who refuse to ingest it willingly; a nasogastric tube should not be placed to administer AC in such patients. (See "Gastrointestinal decontamination of the poisoned patient".)

We do not recommend the routine use of multiple-dose activated charcoal (MDAC) in patients with VPA poisoning. In the past, MDAC was given to patients who had ingested enteric-coated, delayed-release preparations in order to prevent on-going absorption, which may occur with such ingestions [4,54], and to patients who had ingested a large amount of VPA. However, we do not believe the medical literature has established that the potential benefits of this therapy, even in the two aforementioned clinical scenarios, outweigh the risks of pulmonary aspiration and bowel obstruction. In volunteer studies, MDAC was not shown to alter the pharmacokinetics of VPA [65]. The authors of a systematic review of the literature concur and do not recommend the use of MDAC for valproic acid toxicity [66].

Other approaches — Orogastric lavage is not routinely recommended for the enhanced elimination of VPA because the morbidity from this procedure outweighs its theoretic advantages over activated charcoal alone.

We do not recommend the routine use of whole bowel irrigation (WBI) in patients with VPA poisoning. WBI has not demonstrated clinical benefit in such cases. In patients who have rising VPA plasma concentrations and clinical deterioration despite appropriate treatment, clinicians should make use of more definitive therapies, such as hemodialysis or hemoperfusion. (See 'Hemodialysis and hemoperfusion' below.)

Because little excretion of VPA occurs at the kidney, forced diuresis (with or without manipulation of urinary pH) is ineffective for increasing drug elimination.

Administration of carbapenem antibiotics to patients concurrently taking VPA has been found to decrease serum VPA concentrations, leading to warnings in the package insert [67,68]. While this knowledge has prompted a few clinicians to treat patients with acute VPA ingestion with meropenem to decrease serum VPA concentrations, we do not recommend the routine use of carbapenem drugs for this purpose [69-71].

Hemodialysis and hemoperfusion — Although there are no controlled studies that confirm the benefits of extracorporeal removal of VPA in overdose patients, the relatively low molecular weight (144 daltons) and low volume of distribution of VPA suggest a potential benefit from such therapy, and numerous case reports suggest that extracorporeal removal is effective in particular clinical circumstances [66].

We concur with the approach published by the Extracorporeal Treatments in Poisoning (EXTRIP) workgroup about the clinical circumstances when extracorporeal removal is most likely to be effective in patients with VPA poisoning [66]. These guidelines are based upon a systematic review of 79 articles – largely case studies and case series – involving extracorporeal removal in this setting. We use the following indications for extracorporeal removal, which are slightly modified from the EXTRIP guidelines:

Extracorporeal treatment is suggested for severe VPA poisoning, including the presence of any of the following:

VPA concentration >1300 mg/L (>9000 micromol/L)

Cerebral edema

Shock

Extracorporeal treatment may be effective and is reasonable to perform in the following circumstances:

VPA concentration >900 mg/L (>6250 micromol/L)

Coma or respiratory depression requiring mechanical ventilation

pH <7.10

Acute hyperammonemic encephalopathy

Intermittent hemodialysis is the preferred extracorporeal elimination technique, although intermittent hemoperfusion or continuous renal replacement therapy are acceptable alternatives if hemodialysis is unavailable. Extracorporeal treatment can be discontinued with evidence of clinical improvement or when a serum VPA concentrations between 50 to 100 mg/L (350 to 700 micromol/L) is achieved. Signs of improvement might include extubation, improved mental status, normalizing hemodynamic status, resolving electrolyte and acid-base abnormalities. (See "Intermittent dialysis and continuous modalities for patients with hyperammonemia".)

Hemodialysis has little impact on the overall elimination of VPA at therapeutic serum concentrations because the high degree of protein binding limits the amount of free drug available for diffusion across the dialysis membrane [72]. However, the efficacy of hemodialysis for eliminating VPA increases in overdose. At serum concentrations above 90 to 100 mg/L, protein-binding sites become saturated and there is a progressive elevation in the concentration of free drug, which can be readily cleared across a dialysis membrane [73,74]. Hemodialysis has the added benefit of reversing VPA-associated severe metabolic abnormalities, including elevated ammonia concentrations. As VPA is metabolized primarily by the liver and is highly protein-bound, baseline renal function is not an important consideration when determining the need for hemodialysis during overdose.

There are a number of reports describing the use of hemodialysis and/or hemoperfusion in the treatment of VPA overdose [4,15,47,66,75-84]. Alone or in combination, these modalities appear to enhance the plasma clearance and decrease the elimination half-life of VPA substantially. Plasma VPA clearances range from approximately 50 to 90 mL/min with extracorporeal methods, as compared with an intrinsic clearance that ranges from approximately 5 to 10 mL/min [72]. Elimination half-lives ranged from 1.7 to 3 hours during extracorporeal methods as compared with 4.8 to 21 hours in these patients before and after extracorporeal removal. In one series, accelerated clinical recovery (resolution of coma, hypotension, or the need for pressor support) was described in five of eight patients during extracorporeal treatment. Although a slight increase in clearance was noted with charcoal hemoperfusion cartridge when compared with hemodialysis, this involved older less efficient hemodialysis modalities [85]. There are several case reports of continuous renal replacement therapy to treat VPA toxicity, particularly in hemodynamically unstable patients [80,81,83], but these modalities do not appear as effective as traditional hemodialysis in increasing VPA clearance.

PEDIATRIC CONSIDERATIONS — The patients at greatest risk for fatal hepatotoxicity/Reye-like syndrome due to chronic valproic acid (VPA) toxicity are children less than two years old, particularly those with organic brain disease, developmental delay, congenital metabolic disorders, and severe epilepsy treated with multiple anticonvulsants [13]. The most common clinical findings in these patients include lethargy, jaundice, anorexia, and worsening seizures [24]. Management is essentially unchanged in children. (See "Seizures and epilepsy in children: Initial treatment and monitoring", section on 'Monitoring for specific drugs' and 'Hepatotoxicity' above.)

DISPOSITION — Patients with signs or symptoms (eg, somnolence) of severe valproic acid (VPA) poisoning are admitted to an intensive care setting. In addition, adult patients who ingest greater than 200 mg/kg of VPA and/or have serum concentrations greater than 180 mg/L (1260 micromol/L) usually develop some degree of central nervous system (CNS) depression and warrant admission to a closely monitored setting.

Asymptomatic patients who ingest immediate-release preparations should be observed closely for six hours. If the VPA concentration is low and the patient remains asymptomatic, further clinical deterioration is highly unlikely. Unless the ingestion is intentional, such patients can be discharged home in the care of a responsible adult following this period of observation and appropriate reassessment.

Patients who ingest delayed-release or extended-release preparations of VPA should be observed for at least 12 hours. Serial serum VPA concentrations should be obtained, as rising serum VPA concentrations would prompt hospital admission even if asymptomatic. In one study, 15 percent of patients who eventually developed toxic levels had non-toxic or unmeasurable levels upon presentation [2]. Asymptomatic patients with non-toxic levels that are stable or decreasing after the observation period may be discharged in the care of a responsible adult.

These recommendations for the management of unintentional ingestions of VPA are consistent with those developed by the American Association of Poison Control Centers [86].

ADDITIONAL RESOURCES

Regional poison control centers — Regional poison control centers in the United States are available at all times for consultation on patients with known or suspected poisoning, and who may be critically ill, require admission, or have clinical pictures that are unclear (1-800-222-1222). In addition, some hospitals have medical toxicologists available for bedside consultation. Whenever available, these are invaluable resources to help in the diagnosis and management of ingestions or overdoses. Contact information for poison centers around the world is provided separately. (See "Society guideline links: Regional poison control centers".)

Society guideline links — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: General measures for acute poisoning treatment" and "Society guideline links: Treatment of acute poisoning caused by specific agents other than drugs of abuse".)

SUMMARY AND RECOMMENDATIONS

Clinical features – Valproic acid (VPA) is widely used to treat seizures and other disorders. The majority of patients with acute VPA poisoning experience mild to moderate lethargy and recover uneventfully.

Central nervous system (CNS) dysfunction is the most common manifestation of VPA toxicity, ranging in severity from mild drowsiness to coma or fatal cerebral edema. The onset and progression of CNS depression is usually rapid, but may be delayed with ingestion of delayed release preparations. A summary table to facilitate the emergency management of VPA overdose is provided (table 1). (See 'Clinical features' above.)

Other clinical findings following overdose can include:

Vital signs – Respiratory depression, hypotension, tachycardia, hyperthermia

Metabolic – Hyperammonemia, metabolic acidosis, hyperosmolality, hypernatremia, hypocalcemia (see 'Electrolyte abnormalities' above)

Gastrointestinal – Vomiting, diarrhea, hepatitis (see 'Hepatotoxicity' above)

Additional neurologic – Miosis, agitation, tremors, myoclonus

Hyperammonemia, hepatotoxicity, and other toxicities – Hyperammonemia may occur after acute overdose or chronic use of VPA. It may be symptomatic (ie, associated with some degree of encephalopathy) or not, and is not always accompanied by abnormal liver function tests. Hepatotoxicity too may develop with acute ingestion or chronic use. In addition, chronic VPA therapy may be associated with non-dose-related toxicity, including hepatic failure, pancreatitis, alopecia, leukopenia, thrombocytopenia, anemia, or myelodysplasia. (See 'Hyperammonemia' above and 'Valproate-related hyperammonemic encephalopathy' above and 'Hepatotoxicity' above and 'General findings' above.)

Cerebral edema – Patients with VPA poisoning may develop cerebral edema; a head CT is often needed if cerebral edema is suspected based upon clinical findings. Guidance about obtaining a CT is provided in the text. (See 'Cerebral edema' above and 'Imaging studies' above.)

Laboratory evaluation – Therapeutic serum concentrations of VPA range from 50 to 100 mg/L (350 to 700 micromol/L). Serum concentrations should be measured in any case of known or suspected overdose or toxicity. Because concentrations often peak several hours after ingestion, we recommend that serial VPA concentrations be assessed every two to four hours until a steady, significant decline is noted. Ammonia concentrations should also be monitored if hyperammonemic encephalopathy is suspected. Common metabolic abnormalities after VPA overdose include hypernatremia, hypocalcemia, and anion gap metabolic acidosis. (See 'Laboratory evaluation' above.)

General management – Supportive care is the principal treatment for VPA intoxication and results in good outcomes in the vast majority of patients. A summary table to facilitate the emergency management of VPA overdose is provided (table 1). Patients with significant alterations in mental status are likely to require tracheal intubation. Seizures are treated initially with benzodiazepines (eg, lorazepam 2 mg IV; dose can be repeated every 5 to 10 minutes as necessary for refractory seizures). (See 'Treatment' above.)

Gastrointestinal decontamination – We suggest treatment with a single dose of activated charcoal for patients who present within two hours of a VPA overdose (Grade 2C). The standard dose is 1 g/kg (50 g maximum). Activated charcoal (AC) should be withheld in patients who are sedated and may not be able to protect their airway. We do not suggest treatment with multiple dose activated charcoal or whole bowel irrigation (Grade 2C). (See 'Gastrointestinal decontamination and other enhanced elimination techniques' above.)

Naloxone and L-carnitine therapy – Treatment with naloxone and L-carnitine supplementation may be beneficial in some cases. We suggest the administration of naloxone to patients with VPA toxicity and a depressed mental status, provided they are not at risk for acute opioid withdrawal (Grade 2C). Dosing directions are provided in the text. We suggest an initial dose of L-carnitine (100 mg/kg IV loading dose; maximum dose 6 g) for patients with VPA toxicity associated with hyperammonemia, lethargy, coma, or hepatic dysfunction (Grade 2C). (See 'Naloxone' above and 'Carnitine supplementation' above.)

Indications for hemodialysis – We recommend consultation with a nephrologist for extracorporeal treatment for all patients with clinically severe VPA poisoning. Indications for hemodialysis include:

VPA concentration >1300 mg/L (>9000 micromol/L)

Cerebral edema

Shock

Hemodialysis is reasonable to perform in the following circumstances: coma, VPA concentration >900 mg/L (>6250 micromol/L); coma or respiratory depression requiring mechanical ventilation; pH <7.10; and, acute hyperammonemic encephalopathy. (See 'Hemodialysis and hemoperfusion' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Colleen Rivers, MD and Michael J Burns, MD who both contributed to an earlier version of this topic review.

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