Valproic acid poisoning

INTRODUCTION — 

Valproic acid (2-propylpentanoic acid; VPA) is a branched-chain carboxylic acid introduced as an antiseizure medication 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 following related content is discussed separately:

●The use of VPA as an antiseizure medication (see "Overview of the management of epilepsy in adults")

●The general evaluation and management of the poisoned patient (see "General approach to drug poisoning in adults" and "Initial management of the critically ill adult with an unknown overdose" and "Approach to the child with occult toxic exposure")

PHARMACOLOGY AND PHARMACOKINETICS

●Mechanism of action – Although not fully elucidated, the antiseizure effects of valproic acid (VPA) appear to be mediated by several mechanisms (eg, blocking voltage-dependent sodium channels, increasing brain gamma-aminobutyric acid [GABA] concentrations). The pharmacology of VPA is discussed separately. (See "Antiseizure medications: Mechanism of action, pharmacology, and adverse effects", section on 'Valproate'.)

●Formulations – 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].

●Absorption – 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].

●Distribution – 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]. Following overdose, protein-binding sites become saturated, and there is a progressive elevation in the concentration of free drug (as an example, in a case report with VPA concentrations near 450 mg/L, 71 percent was free drug) [7].

●Metabolism – VPA is metabolized extensively by hepatic glucuronic acid conjugation and beta and omega oxidation to produce multiple metabolites, some of which are biologically active. Cytochrome (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 [8-15]. 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 [8,9,11,12], 2-propyl-4-pentenoic acid (4-EN-VPA) may mediate hepatotoxicity [13,14], and propionic acid metabolites may precipitate hyperammonemia [10,15]. Other metabolites may produce a false-positive urine ketone determination [16].

●Elimination – 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 long as 30 hours after overdose [1,6,8]. VPA also undergoes enterohepatic reabsorption, which can delay clearance [17,18].

CLINICAL MANIFESTATIONS OF POISONING

Overview — Most patients with acute valproic acid (VPA) intoxication experience mild to moderate lethargy and recover uneventfully [19,20]. Central nervous system (CNS) dysfunction is the most common manifestation of toxicity, ranging in severity from mild drowsiness to coma or fatal cerebral edema [9,11,12]. The onset and progression of CNS depression is usually rapid but may be delayed with ingestion of delayed release preparations [4,12]. Free and total VPA concentrations do not correlate precisely with severity of clinical effects [1,16,21]. Despite considerable clinical variability, signs of severe poisoning, such as coma, metabolic acidosis, and hemodynamic instability (ie, shock), are most likely to occur in cases where peak serum concentration exceeds 850 mg/L (5890 micromol/L) [3].

Other clinical findings following overdose may include [9,11,12]:

●Vital sign abnormalities – Respiratory depression, hypotension, tachycardia, hyperthermia, shock/cardiovascular collapse (typically following massive overdose)

●Electrolyte and metabolic abnormalities – Hyperammonemia, elevated anion gap metabolic acidosis, hyperosmolality, hypernatremia, hypocalcemia

●Gastrointestinal – Nausea, vomiting, diarrhea, mild hepatocellular injury

●Additional neurologic – Miosis, agitation, tremors, myoclonus

Recognized but rare complications of overdose include hyperthermia, hallucinations, heart block, pancreatitis, acute kidney failure, alopecia, leukopenia, thrombocytopenia, anemia, cerebral edema, seizures, optic nerve atrophy, and acute respiratory distress syndrome [9,12]. In rare cases, reversible Parkinsonian signs have been noted, particularly in older adults with concomitant neurodegenerative conditions taking antipsychotic medications [22,23]. 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 [24]. Cardiac biomarkers remained within normal limits.

Chronic VPA therapy may be associated with non-dose-related (idiosyncratic) toxicity, including hepatocellular injury, hyperammonemia without hepatocellular injury, pancreatitis, alopecia, leukopenia, thrombocytopenia, anemia, and myelodysplastic changes [8,9,14]. (See "Antiseizure medications: Mechanism of action, pharmacology, and adverse effects", section on 'Valproate' and "Clinical manifestations, diagnosis, and classification of myelodysplastic syndromes (MDS)", section on 'Clinical presentation'.)

Cerebral edema — Cerebral edema is associated with acute and chronic VPA toxicity and does not clearly correlate with the dose of VPA ingested [11]. When associated with acute intoxication, cerebral edema becomes clinically apparent 12 hours to 4 days after overdose [9,11,12,25]. Cerebral edema from VPA toxicity may cause early herniation and ischemia with focal neurologic deficits [26]. Cerebral edema likely occurs from accumulation of the 2-propyl-2-pentenoic acid (2-EN-VPA) metabolite in the brain and serum. 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 serum VPA concentrations [8,9]. (See 'Pharmacology and pharmacokinetics' above.)

Hyperammonemia — VPA-associated hyperammonemia is typically defined as a plasma ammonia concentration greater than 80 mcg/dL (47 micromol/L). Hyperammonemia may occur after acute overdose or chronic use of VPA and is not always accompanied by abnormal liver biochemical tests [6,8-10,15,16,27]. VPA-associated hyperammonemia does not necessarily result in clinical encephalopathy and is asymptomatic in one-half of the cases [28,29]. No acute intervention is typically required when mild asymptomatic hyperammonemia is discovered incidentally.

The incidence of VPA-induced hyperammonemia in patients taking VPA is not well established, but it is likely higher in those who seek medical care. Cross-sectional studies have found a prevalence of hyperammonemia of 16 to 100 percent, while prospective studies have reported a prevalence of 70 to 100 percent [30]. In a review of 14 cases in a psychiatric setting, the mean increase in ammonia concentration was 3.6 times the maximal normal value [31].

Hyperammonemia likely occurs from accumulation of propionic acid, a metabolite of VPA, which inhibits mitochondrial carbamoyl phosphate synthetase (CPS), an enzyme necessary for ammonia elimination via the urea cycle (figure 1) [10]. Sufficient inhibition of CPS activity causes ammonia accumulation and frequently produces encephalopathy [15]. In addition, VPA may cause hyperammonemia by interacting with carnitine, a cofactor necessary for mitochondrial long-chain fatty acid metabolism (figure 2). CPS is also inhibited by VPA omega oxidation metabolites, which accumulate in states of relative carnitine deficiency. Plasma ammonia concentrations directly correlate with the dose and serum concentrations of VPA and inversely with serum concentrations of carnitine [13,27,32].

Valproate-related hyperammonemic encephalopathy — Symptomatic hyperammonemia with VPA therapy is often referred to as "VHE," and can sometimes occur without abnormalities of liver biochemical tests. VHE has the following characteristics [10,31,33-39]:

●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 concentrations, which may be in the therapeutic range.

Ammonia concentrations in VHE associated with chronic VPA therapy ranged from 127 mcg/dL (75 micromol/L) to 482 mcg/dL (283 micromol/L) [40,41], while the peak ammonia concentration in a fatal acute ingestion was 1191 mcg/dL (699 micromol/L) [42].

VHE is more likely when VPA is combined with phenobarbital, phenytoin, carbonic anhydrase inhibitors (eg, acetazolamide), or carbamazepine [36,43,44]. Urea cycle defects and carnitine deficiency may increase the risk of developing hepatocellular injury with VHE. (See "Urea cycle disorders: Clinical features and diagnosis" and "Specific fatty acid oxidation disorders".)

Hepatotoxicity — Acute VPA ingestion can cause dose-related, reversible hepatocellular injury with mild serum aminotransferase elevation [8,9,12]. Chronic VPA use is also associated with mild aminotransferase elevation in up to 44 percent of patients [14,45,46]. Liver biochemical abnormalities usually completely resolve following VPA discontinuation, but idiosyncratic fulminant hepatic failure and death (with histopathologic changes similar to those of Reye syndrome) have also occurred [14,47,48]. The rates of both non-fatal and fatal hepatocellular injury appear to be higher when VPA is taken with another medication (most often antiseizure or benzodiazepines) compared with monotherapy [49].

Severe idiosyncratic reactions usually occur during the first six months of VPA therapy and are not preceded by minor aminotransferase elevation [14]. 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 antiseizure medications [14]. The most common clinical findings in children with VPA-associated liver failure include lethargy, jaundice, anorexia, and worsening seizures [28]. The incidence of fatal hepatic reactions in this at-risk group may be as high as 1 in 500, whereas the overall incidence is 1 in 50,000 patients [14]. Survival rates are significantly decreased in children with liver transplantation from VPA-associated acute liver failure compared with liver transplantation in children with drug-induced acute liver failure unrelated to VPA, possibly from the "unmasking" of mitochondrial disease by VPA [50]. (See "Seizures and epilepsy in children: Initial treatment and monitoring", section on 'Monitoring for specific drugs' and "Acute liver failure in children: Management, complications, and outcomes".)

Patients with undiagnosed 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 "Mitochondrial myopathies: Clinical features and diagnosis" and "Drug-induced liver injury".)

Both acute hepatocellular injury and idiosyncratic reactions with chronic VPA use are probably mediated by carnitine deficiency and accumulation of 2-propyl-4-pentenoic acid (4-EN-VPA), a VPA omega oxidation metabolite [13,14]. VPA (itself a short-chain fatty acid) combines with carnitine and results in carnitine depletion during long-term or high-dose VPA therapy [13,27,32,51]. Hypocarnitinemia impairs both mitochondrial fatty acid oxidation for energy production and VPA metabolism. Microvesicular steatosis and subsequent liver failure can occur [14]. VPA-induced lipid peroxidation and glutathione depletion may also contribute to hepatocellular injury through less well-understood mechanisms [52].

Electrolyte and metabolic abnormalities — Common electrolyte and metabolic abnormalities after VPA overdose include hypernatremia, hyperosmolality, hypocalcemia, and elevated anion gap metabolic acidosis [8,9,12,16]. VPA is administered as a sodium salt (13.8 mg sodium per 100 mg VPA) and can therefore 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.

DIAGNOSTIC EVALUATION — 

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.

History and examination — 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 physical examination should focus on hemodynamic and respiratory status and neurologic findings, including mental status. There are no examination findings pathognomic for VPA poisoning. Patients usually develop some central nervous system (CNS) depression; other findings are discussed above. (See 'Overview' above.)

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

Valproic acid concentration — Any patient with known or suspected VPA overdose or toxicity should have a serum VPA concentration measured. Therapeutic serum concentrations typically range from 50 to 125 mg/L (350 to 870 micromol/L) for treatment of bipolar disorder and from 50 to 100 mg/L (350 to 700 micromol/L) for treatment of seizure disorder; for the latter indication, some experts also consider 125 mg/L (870 micromol/L) as the upper therapeutic limit [1,5,53]. Toxicity can still occur with concentrations in the upper portion of this range. Free and total VPA concentrations correlate imprecisely with the severity of toxicity [1,16,21]. Although concentration alone does not predict severity of toxicity, in general, moderate toxicity develops with VPA concentrations >450 mg/L (3120 micromol/L) and severe toxicity (eg, coma, respiratory depression, metabolic acidosis, shock) with concentrations >850 mg/L (5890 micromol/L) [3]. VPA concentrations >1200 mg/L (8320 micromol/L) in patients who do not receive prompt definitive treatment are often reported in fatalities, although deaths have been reported with lower concentrations [3,54].

Patients with suspected acute VPA poisoning should have more than one VPA concentration measured to ensure there is no ongoing absorption. (See 'Post-diagnostic testing' below.)

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

●Serum ethanol, acetaminophen, and salicylate concentrations, 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 females 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).

●Liver biochemical tests (serum aminotransferases).

●Plasma ammonia concentration.

●Complete blood count including platelet concentration.

●Arterial or venous blood gas and serum lactate if low serum bicarbonate to assess extent of acidosis.

●Head computed tomography (CT) in a patient with severely depressed mental status, focal neurologic deficits, or elevated plasma ammonia concentration to assess for cerebral edema, which may generally develop 12 hours to 4 days after acute ingestion. A head CT is generally not necessary during the first few hours after an acute VPA ingestion in a patient with a mildly depressed mental status and a normal plasma ammonia concentration unless the diagnosis is in question. No guidelines can address all clinical scenarios, and a head CT should be obtained if cerebral edema is suspected based on clinical findings, including during the first several days of management. (See 'Post-diagnostic testing' below.)

Diagnosis — The diagnosis of acute valproic acid (VPA) poisoning is suspected on the basis of a history of overdose associated with typical signs, primarily CNS depression, which can range from mild cognitive impairment to coma. Other suggestive findings include tremors, myoclonus, hyperammonemia, elevated anion gap metabolic acidosis, hypernatremia, hypocalcemia, and elevated serum aminotransferases.

The diagnosis of acute VPA poisoning is confirmed by an elevated serum concentration of VPA.

Chronic toxicity may be associated with non-dose-related (idiosyncratic) toxicity, including acute hepatocellular injury, hyperammonemia without hepatocellular injury, valproate-related hyperammonemic encephalopathy, pancreatitis, or myelodysplastic changes. Elevations in blood ammonia and serum aminotransferases are suggestive of either acute or chronic toxicity. (See "Antiseizure medications: Mechanism of action, pharmacology, and adverse effects", section on 'Valproate'.)

Post-diagnostic testing — A patient with acute VPA poisoning should have the VPA concentration, ammonia concentration, and serum electrolytes (including sodium and calcium) repeated every two to four hours during initial management. Serial VPA concentrations should be obtained in patients who are symptomatic and those with a history of overdose, even if the initial concentration is in the therapeutic range or only mildly supratherapeutic, as delayed peak serum concentrations have been noted to occur [3]. Serial VPA concentrations should be measured until a steady decline is noted, suggesting no further ongoing absorption and that the peak has occurred.

Plasma ammonia concentrations should be monitored if VPA-related hyperammonemic encephalopathy (VHE) is suspected clinically. (See 'Valproate-related hyperammonemic encephalopathy' above.)

A patient with acute VPA poisoning whose mental status does not start to improve 12 or more hours after the ingestion or who develops new focal neurologic deficits or worsening mental status should have a head CT to assess for cerebral edema, which may have a delayed onset. (See 'Cerebral edema' above.)

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 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, opioid, antiseizure medications). 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".)

MANAGEMENT — 

A summary table to facilitate the emergency management of patients with valproic acid (VPA) overdose is provided (table 1).

All patients: supportive care — Supportive care is the principal treatment for VPA intoxication and results in good outcomes in the vast majority of patients [4,12].

Patients with altered mentation may require tracheal intubation for airway protection. (See "Overview of advanced airway management in adults for emergency medicine and critical care" and "Rapid sequence intubation in adults for emergency medicine and critical care".)

Benzodiazepines should be administered if seizures occur (eg, lorazepam 2 mg intravenously [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 'Extracorporeal removal (hemodialysis)' below.)

Patients with hypotension and/or shock may require treatment with one or more vasopressors. (See "Use of vasopressors and inotropes".)

Role of gastrointestinal decontamination

●Activated charcoal – We suggest single-dose activated charcoal (AC) for patients with suspected VPA poisoning who present within one hour 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. A single dose of AC is sufficient for the majority of patients with a VPA overdose. (See "Gastrointestinal decontamination of the poisoned patient", section on 'Activated charcoal'.)

●Ineffective therapies – 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 to prevent ongoing absorption and to patients with large ingestions to block enterohepatic reabsorption [4,7]. However, we do not believe the evidence supports that the potential benefit of increased elimination outweighs the risks of aspiration and bowel obstruction [55]. In volunteer studies, MDAC was not shown to alter the pharmacokinetics of VPA in therapeutic dosing [56]. For a patient with an elevated or rising VPA concentration, without central nervous system (CNS) depression or airway compromise, a second dose of AC is a reasonable option to reduce ongoing absorption and block enterohepatic reabsorption. (See "Gastrointestinal decontamination of the poisoned patient", section on 'Multidose activated charcoal'.)

We do not recommend orogastric lavage because the morbidity from this procedure outweighs its theoretical advantages over activated charcoal alone. We do not recommend whole bowel irrigation as it has not demonstrated clinical benefit in VPA poisoning. Forced diuresis (with or without manipulation of urinary pH) does not increase VPA elimination since only a small percentage is excreted by the kidneys. For 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 'Extracorporeal removal (hemodialysis)' below.)

Role of carnitine supplementation — Carnitine supplementation may prevent and attenuate VPA-induced hyperammonemia and hepatotoxicity since these may be mediated in part by carnitine deficiency [28,57]. We suggest carnitine supplementation for patients with VPA toxicity and any of the following:

●Coma

●Severe hepatocellular injury (approximately 15 times the upper limit of normal or higher of aminotransferase)

●Valproic acid serum concentration >450 mcg/mL (>3120 micromol/L)

●Valproate-related hyperammonemic encephalopathy, including cerebral edema (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 for VPA toxicity. Based upon the available data and poison center guidelines, 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 [57].

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 [57-60]. A dosing regimen based on pharmacokinetic data has been proposed; an initial 5 mg/kg IV bolus followed by 1 to 2 mg/kg/hour continuous infusion would be expected to maintain serum carnitine concentrations of 100 to 150 micromol/L [61].

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 [62].

Evidence supporting the benefit of carnitine consists solely of observational studies. Oral carnitine administration reverses carnitine deficiency, leads to resolution of elevated ammonia levels, and improves lethargy in patients treated chronically with VPA [27,32,57,60,63,64]. In addition, carnitine may hasten the resolution of coma, prevent hepatic dysfunction, and reverse mitochondrial metabolic abnormalities in patients with acute VPA intoxication [13,65]. As an example, a retrospective study of patients with severe VPA-induced hepatotoxicity found that intravenous carnitine therapy was associated with a marked increase in survival [66]. Furthermore, a retrospective review of all published English language articles from 1948 to 2011 related to carnitine therapy for VPA-related hyperammonemic encephalopathy (VHE) revealed no significant adverse effects [59]. 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 [67].

Patients with severe toxicity (eg, coma, shock) — We consider severe VPA toxicity to include coma, cerebral edema, respiratory depression requiring mechanical ventilation, shock, and/or significant metabolic acidosis. 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. In addition to carnitine supplementation (see 'Role of carnitine supplementation' above), we also do the following:

Carbapenems — Administration of carbapenem antibiotics to patients concurrently taking VPA has been found to decrease serum VPA concentrations, leading to warnings in the package insert [68,69]. Carbapenem antibiotics are safe, more available than other therapies (eg, hemodialysis), and have a well-characterized pharmacokinetic interaction with VPA. Administering a carbapenem antibiotic has been proposed for a patient with severe VPA poisoning (eg, meeting hemodialysis criteria) and potentially for a patient anticipated to develop severe poisoning based on the ingested dose [70]. In a patient with normal kidney function, a reasonable dosing regimen is meropenem 1 g IV, repeated every 8 hours, or ertapenem 1 g IV repeated every 24 hours, as needed for elevated VPA concentrations. Evidence is based on case reports [71-79].

Extracorporeal removal (hemodialysis) — Hemodialysis is the treatment of choice for severe VPA poisoning because VPA is readily dialyzable due to its low molecular weight (144 daltons), small volume of distribution, and saturation of protein binding at toxic concentrations (thus increasing amount of free VPA). Our approach is consistent with the Extracorporeal Treatments in Poisoning Workgroup (EXTRIP) guidelines [80].

We recommend extracorporeal removal (ie, hemodialysis) for a patient with VPA poisoning and any of the following:

●VPA concentration >1300 mcg/mL (>9000 micromol/L)

●Cerebral edema

●Shock

We suggest extracorporeal removal for a patient with VPA poisoning and any of the following:

●VPA concentration 900 to 1300 mcg/mL (6250 to 9000 micromol/L)

●Coma or respiratory depression requiring mechanical ventilation

●Blood pH <7.10

●Significant acute hyperammonemic encephalopathy (eg, coma, seizures)

Given the high mortality associated with cerebral edema and shock in VPA poisoning, the benefit of extracorporeal removal appears to outweigh the risks. These VPA concentration thresholds are based on studies and case reports describing likelihood of mortality and severe toxicity [80]. (See 'Valproic acid concentration' above.)

Intermittent hemodialysis is the preferred extracorporeal elimination technique, although intermittent hemoperfusion or continuous kidney 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 mcg/mL (350 to 700 micromol/L) is achieved. Signs of improvement might include tracheal extubation, improved mental status, normalizing hemodynamic status, and 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 [81]. 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 [82,83]. 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 kidney function is not an important consideration when determining the need for hemodialysis during overdose.

Evidence for hemodialysis and/or hemoperfusion in the treatment of VPA overdose is based on numerous case reports and the dialyzability of the unbound VPA portion [4,16,51,80,84-93]. There are no controlled trials that confirm the benefits of extracorporeal removal of VPA in overdose patients. Alone or in combination, these modalities appear to enhance the serum clearance and decrease the elimination half-life of VPA substantially. Serum 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 [81]. In patients before and during extracorporeal removal, elimination half-lives ranged from 4.8 to 21 hours compared with 1.7 to 3 hours, respectively [4,51,86]. Although a slight increase in clearance was noted with charcoal hemoperfusion as compared with hemodialysis, this case involved older, less efficient hemodialysis modalities [94]. There are several case reports of continuous kidney replacement therapy to treat VPA toxicity, particularly in hemodynamically unstable patients [89,90,92], but these modalities do not appear as effective as traditional hemodialysis in increasing VPA clearance.

DISPOSITION — 

Patients with signs or symptoms 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 mcg/mL (1260 micromol/L) usually develop some degree of central nervous system (CNS) depression and warrant observation in a closely monitored setting, either in-patient or in an emergency department-based observation unit.

Asymptomatic patients who ingest immediate-release preparations should be observed closely for six hours, including repeating VPA concentrations every two to four hours. In general, we do not discharge a patient with a VPA ingestion with only a single measured VPA concentration. If the VPA concentrations are decreasing, fall at or below therapeutic concentrations, 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 longer observation even if asymptomatic. In one study, 15 percent of patients who eventually developed toxic concentrations had non-toxic or unmeasurable concentrations upon presentation [2]. Asymptomatic patients with non-toxic concentration that are stable or decreasing after the observation period may be discharged in the care of a responsible adult or referred for mental health evaluation.

These recommendations for the management of unintentional ingestions of VPA are consistent with those developed by America’s Poison Centers [95].

ADDITIONAL RESOURCES

Regional poison centers — Regional poison 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 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 manifestations of poisoning – Most patients with acute valproic acid (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. (See 'Clinical manifestations of poisoning' above.)

Other clinical findings following overdose can include:

•Vital signs abnormalities – Respiratory depression, hypotension, tachycardia, hyperthermia, shock/cardiovascular collapse

•Electrolyte and metabolic abnormalities – Hyperammonemia, metabolic acidosis, hyperosmolality, hypernatremia, hypocalcemia

•Gastrointestinal – Vomiting, diarrhea, hepatocellular injury

•Additional neurologic – Miosis, agitation, tremors, myoclonus, cerebral edema

●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 biochemical tests. Hepatotoxicity may develop with acute ingestion or chronic use. In addition, chronic VPA therapy may be associated with non-dose-related toxicity, including hepatocellular injury, pancreatitis, alopecia, leukopenia, thrombocytopenia, anemia, or myelodysplasia. (See 'Hyperammonemia' above and 'Valproate-related hyperammonemic encephalopathy' above and 'Hepatotoxicity' above and 'Overview' above.)

●Diagnostic evaluation – Therapeutic serum concentrations of VPA typically range from 50 to 125 mcg/mL (350 to 875 micromol/L), but toxicity can still occur with concentrations in the upper portion of this range. 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. Obtain head computed tomography (CT) in a patient with severely depressed mental status, focal neurologic deficits, or elevated plasma ammonia concentration to assess for cerebral edema, which may generally develop 12 hours to four days after acute ingestion. (See 'Diagnostic evaluation' above.)

●Management – Supportive care is the principal treatment for VPA intoxication and results in good outcomes in most 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 intravenously [IV]; dose can be repeated every 5 to 10 minutes as necessary for refractory seizures). Patients with hypotension and/or shock may require treatment with one or more vasopressors. (See 'Management' above.)

•Gastrointestinal decontamination – For patients who present within one hour of a VPA overdose, we suggest administering activated charcoal (AC) (Grade 2C). We administer a single dose of 1 g/kg (50 g maximum). AC should be withheld in patients who are sedated and may not be able to protect their airway. (See 'Role of gastrointestinal decontamination' above and "Gastrointestinal decontamination of the poisoned patient", section on 'Evidence of efficacy and adverse effects'.)

•Patient with severe toxicity – We consider severe VPA toxicity to include coma, cerebral edema, respiratory depression requiring mechanical ventilation, shock, and/or significant metabolic acidosis. For a patient with severe VPA toxicity, we suggest carnitine and a carbapenem antibiotic (Grade 2C). 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. Carnitine may hasten the resolution of coma, prevent hepatic dysfunction, and reverse mitochondrial metabolic abnormalities in patients with acute VPA intoxication. Meropenem 1 g IV every 8 hours or ertapenem 1 g IV every 24 hours are reasonable options. Carbapenems decrease serum VPA concentrations via a pharmacokinetic interaction. (See 'Role of carnitine supplementation' above and 'Carbapenems' above.)

In a patient with any of the following indications, we also recommend hemodialysis (Grade 1C):

-VPA concentration >1300 mcg/mL (>9000 micromol/L)

-Cerebral edema

-Shock

In a patient with any of the following indications, we also suggest hemodialysis (Grade 2C):

-VPA concentration 900 to 1300 mcg/mL (6250 to 9000 micromol/L)

-Coma or respiratory depression requiring mechanical ventilation

-Blood pH <7.10

-Significant acute hyperammonemic encephalopathy (eg, coma, seizures)

VPA is readily dialyzable due to its low molecular weight, small volume of distribution, and saturation of protein binding at toxic concentrations. (See 'Extracorporeal removal (hemodialysis)' above.)

•Patient with moderate toxicity – For a patient with VPA toxicity and hyperammonemia, severe hepatocellular injury, or VPA concentration >450 mcg/mL (>3120 micromol/L), we suggest carnitine (Grade 2C). (See 'Role of carnitine supplementation' above.)

ACKNOWLEDGMENT — 

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