6/11/23, 22:05 Valproic acid poisoning - UpToDate

Official reprint from UpToDate®

[Link] © 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Valproic acid poisoning

AUTHOR: Matthew D Sztajnkrycer, MD, PhD
SECTION EDITOR: Andrew Stolbach, MD, MPH, FAACT, FACMT, FACEP
DEPUTY EDITOR: Michael Ganetsky, MD

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Oct 2023.

This topic last updated: Jul 10, 2023.

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".)

● The general evaluation and management of the poisoned patient is discussed

separately. (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

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'.)

[Link] 1/25
6/11/23, 22:05 Valproic acid poisoning - UpToDate

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 125 mcg/mL (350 to 875
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 (875 micromol/L) as the upper therapeutic limit [1,5,6]. 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) [1,5,7].

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 [1,5,7]. 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 [1,7,8].

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].

CLINICAL FEATURES

[Link] 2/25
6/11/23, 22:05 Valproic acid poisoning - UpToDate

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 [17,18]. 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]. 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 mcg/mL (1260 micromol/L) usually develop
some degree of CNS depression [1,16]. 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 [9,11,12]:

● 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
[Link] 3/25
6/11/23, 22:05 Valproic acid poisoning - UpToDate

edema, seizures, optic nerve atrophy, and acute respiratory distress syndrome [9,12]. In rare
cases, reversible Parkinsonian signs have been noted, particularly in elder adults with
concomitant neurodegenerative conditions taking antipsychotic medications [19,20]. 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 [21]. 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 [8,9,14] (see "Antiseizure medications:
Mechanism of action, pharmacology, and adverse effects", section on 'Valproate').
Myelodysplastic changes may also be seen. (See "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 is
not clearly correlated with the dose of VPA ingested [11]. When associated with acute
intoxication, cerebral edema becomes clinically apparent 12 hours to four days after
overdose [9,11,12,22]. Cerebral edema from VPA toxicity may result in early herniation and
ischemia with focal neurologic deficits [23]. 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 [8,9].

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 [7-10,15,16,24]. In addition, valproic–acid associated
hyperammonemia does not necessarily result in clinical encephalopathy, and in half the
cases is asymptomatic [25,26].

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 [27]. In a review of 14 cases in a psychiatric setting, the mean increase in ammonia
concentration was 3.6 times the maximal normal value [28].

[Link] 4/25
6/11/23, 22:05 Valproic acid poisoning - UpToDate

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 [10]. If the action of this enzyme is sufficiently impaired,
ammonia levels will accumulate, frequently producing encephalopathy [15]. 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 [13,24,29].

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 [10,28,30-36]:

● 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) [37,38], while the peak ammonia concentration in a fatal
acute ingestion was 1191 mcg/dL (699 μmol/L) [39].

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 [33,40,41]. 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 [8,9,12]. Chronic
dosing of VPA is also associated with mild aminotransferase elevations in up to 44 percent of
patients [14,42,43]. 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
[14,44,45]. The rates of both non-fatal and fatal hepatic failure appear to be higher when
[Link] 5/25
6/11/23, 22:05 Valproic acid poisoning - UpToDate

valproic acid is administered with another medication (most often antiepileptics or

benzodiazepines) as opposed to monotherapy [46]. (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 [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 anticonvulsants [14]. 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 [14]. 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 [47].

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 [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 [13,24,29,48].
Hypocarnitinemia results both in impaired mitochondrial fatty acid oxidation for energy
production and impaired VPA metabolism. Microvesicular steatosis and subsequent hepatic
failure can occur [14]. VPA-induced lipid peroxidation and glutathione depletion may also
contribute to hepatotoxicity through less well understood mechanisms [49].

Electrolyte abnormalities — Common metabolic abnormalities after VPA overdose include

hypernatremia, hyperosmolality, hypocalcemia, and anion gap metabolic acidosis [8,9,12,16].
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

[Link] 6/25
6/11/23, 22:05 Valproic acid poisoning - UpToDate

Valproic acid concentration — Therapeutic serum concentrations of valproic acid (VPA)

typically range from 50 to 125 mg/L (350 to 875 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 (875 micromol/L) as the upper
therapeutic limit [1,5,6]. 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 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 mcg/mL (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 [1,16].

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

[Link] 7/25
6/11/23, 22:05 Valproic acid poisoning - UpToDate

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

[Link] 8/25
6/11/23, 22:05 Valproic acid poisoning - UpToDate

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 [4,12]. 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
"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 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 [50-53], although this effect is not
universal [54,55]. 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.

[Link] 9/25
6/11/23, 22:05 Valproic acid poisoning - UpToDate

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 [25,56]. 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 [56].

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 [56-59].

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 [60].

Oral carnitine administration reverses carnitine deficiency, leads to resolution of elevated

ammonia levels, and improves lethargy in patients treated chronically with VPA [24,29,61,62].
In addition, carnitine may hasten the resolution of coma, prevent hepatic dysfunction, and
reverse mitochondrial metabolic abnormalities in patients with acute VPA intoxication
[Link] 10/25
6/11/23, 22:05 Valproic acid poisoning - UpToDate

[13,63]. 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 [64]. 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 [58]. 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 [65]. 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 [4,55], 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 [66]. The authors of a systematic review of the literature
concur and do not recommend the use of MDAC for valproic acid toxicity [67].

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.)

[Link] 11/25
6/11/23, 22:05 Valproic acid poisoning - UpToDate

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
[68,69]. 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 [70-72].

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 [67].

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 [67]. 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 mcg/mL (>9000 micromol/L)

• Cerebral edema
• Shock

● Extracorporeal treatment may be effective and is reasonable to perform in the

following circumstances:

• VPA concentration >900 mcg/mL (>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 mcg/mL (350 to 700 micromol/L) is achieved. Signs of improvement might include
extubation, improved mental status, normalizing hemodynamic status, resolving electrolyte

[Link] 12/25
6/11/23, 22:05 Valproic acid poisoning - UpToDate

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 [73]. 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 [74,75].
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 [4,16,48,67,76-85]. 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 [73]. 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 [86]. There are several case reports of continuous renal replacement
therapy to treat VPA toxicity, particularly in hemodynamically unstable patients [81,82,84],
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 [14]. The most common clinical findings in these
patients include lethargy, jaundice, anorexia, and worsening seizures [25]. 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.)

[Link] 13/25
6/11/23, 22:05 Valproic acid poisoning - UpToDate

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 mcg/mL (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 [87].

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".)

[Link] 14/25
6/11/23, 22:05 Valproic acid poisoning - UpToDate

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 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
[Link] 15/25
6/11/23, 22:05 Valproic acid poisoning - UpToDate

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 mcg/mL (>9000 micromol/L)

• Cerebral edema
• Shock

Hemodialysis is reasonable to perform in the following circumstances: coma, VPA

concentration >900 mcg/mL (>6250 micromol/L); coma or respiratory depression
requiring mechanical ventilation; pH <7.10; and, acute hyperammonemic
encephalopathy. (See 'Hemodialysis and hemoperfusion' above.)

[Link] 16/25
6/11/23, 22:05 Valproic acid poisoning - UpToDate

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.

Use of UpToDate is subject to the Terms of Use.

REFERENCES

1. McNamara JO. Drugs effective in the therapy of the epilepsies. In: Goodman & Gilman's T
he Pharmacological basis of therapeutics, Hardman JG, Limbird LE, Molinoff PB et al (Ed
s), McGraw-Hill, New York 1996. p.476.
2. Ingels M, Beauchamp J, Clark RF, Williams SR. Delayed valproic acid toxicity: a
retrospective case series. Ann Emerg Med 2002; 39:616.
3. Spiller HA, Krenzelok EP, Klein-Schwartz W, et al. Multicenter case series of valproic acid
ingestion: serum concentrations and toxicity. J Toxicol Clin Toxicol 2000; 38:755.
4. Graudins A, Aaron CK. Delayed peak serum valproic acid in massive divalproex overdose-
-treatment with charcoal hemoperfusion. J Toxicol Clin Toxicol 1996; 34:335.
5. Chadwick DW. Concentration-effect relationships of valproic acid. Clin Pharmacokinet
1985; 10:155.
6. American Psychiatric Association, Work Group on Bipolar Disorder. Practice Guideline for
the Treatment of Patients With Bipolar Disorder, Second Edition. April 2002. [Link]
[Link]/pb/assets/raw/sitewide/practice_guidelines/guidelines/bipolar-1410197
[Link] (Accessed on June 19, 2023).
7. Gugler R, von Unruh GE. Clinical pharmacokinetics of valproic acid. Clin Pharmacokinet
1980; 5:67.
8. Gram L, Bentsen KD. Valproate: an updated review. Acta Neurol Scand 1985; 72:129.
9. Dupuis RE, Lichtman SN, Pollack GM. Acute valproic acid overdose. Clinical course and
pharmacokinetic disposition of valproic acid and metabolites. Drug Saf 1990; 5:65.
10. Coulter DL, Allen RJ. Secondary hyperammonaemia: a possible mechanism for valproate
encephalopathy. Lancet 1980; 1:1310.
11. Khoo SH, Leyland MJ. Cerebral edema following acute sodium valproate overdose. J
Toxicol Clin Toxicol 1992; 30:209.
12. Anderson, GO, Ritland, S. Life threatening intoxication with sodium valproate. Clin
Toxicol 1995; 33:279.
13. Ishikura H, Matsuo N, Matsubara M, et al. Valproic acid overdose and L-carnitine
therapy. J Anal Toxicol 1996; 20:55.
[Link] 17/25
6/11/23, 22:05 Valproic acid poisoning - UpToDate

14. Bryant AE 3rd, Dreifuss FE. Valproic acid hepatic fatalities. III. U.S. experience since 1986.
Neurology 1996; 46:465.
15. Coulter DL, Allen RJ. Hyperammonemia with valproic acid therapy. J Pediatr 1981; 99:317.
16. Mortensen PB, Hansen HE, Pedersen B, et al. Acute valproate intoxication: biochemical
investigations and hemodialysis treatment. Int J Clin Pharmacol Ther Toxicol 1983; 21:64.
17. Jones AL, Proudfoot AT. Features and management of poisoning with modern drugs
used to treat epilepsy. QJM 1998; 91:325.

18. Tønnesen E. Delirium tremens and hypokalemia. Lancet 1982; 2:97.

19. Silver M, Factor SA. Valproic acid-induced parkinsonism: levodopa responsiveness with
dyskinesia. Parkinsonism Relat Disord 2013; 19:758.
20. Mahmoud F, Tampi RR. Valproic acid-induced parkinsonism in the elderly: a
comprehensive review of the literature. Am J Geriatr Pharmacother 2011; 9:405.
21. Muñiz AE. Valproic Acid Overdose Review of a Case With Electrocardiographic Changes. J
Emerg Med 2017; 53:333.
22. Berthelot-Moritz F, Chadda K, Chanavaz I, et al. Fatal sodium valproate poisoning.
Intensive Care Med 1997; 23:599.
23. Rupasinghe J, Jasinarachchi M. Progressive encephalopathy with cerebral oedema and
infarctions associated with valproate and diazepam overdose. J Clin Neurosci 2011;
18:710.
24. Ohtani Y, Endo F, Matsuda I. Carnitine deficiency and hyperammonemia associated with
valproic acid therapy. J Pediatr 1982; 101:782.
25. Lheureux PE, Hantson P. Carnitine in the treatment of valproic acid-induced toxicity. Clin
Toxicol (Phila) 2009; 47:101.
26. Murphy JV, Marquardt K. Asymptomatic hyperammonemia in patients receiving valproic
acid. Arch Neurol 1982; 39:591.
27. Chicharro AV, de Marinis AJ, Kanner AM. The measurement of ammonia blood levels in
patients taking valproic acid: looking for problems where they do not exist? Epilepsy
Behav 2007; 11:361.
28. Dealberto MJ. Valproate-induced hyperammonaemic encephalopathy: review of 14 cases
in the psychiatric setting. Int Clin Psychopharmacol 2007; 22:330.
29. Gidal BE, Inglese CM, Meyer JF, et al. Diet- and valproate-induced transient
hyperammonemia: effect of L-carnitine. Pediatr Neurol 1997; 16:301.

30. Marescaux C, Warter JM, Micheletti G, et al. Stuporous episodes during treatment with
sodium valproate: report of seven cases. Epilepsia 1982; 23:297.
31. Zaret BS, Beckner RR, Marini AM, et al. Sodium valproate-induced hyperammonemia
without clinical hepatic dysfunction. Neurology 1982; 32:206.
[Link] 18/25
6/11/23, 22:05 Valproic acid poisoning - UpToDate

32. Batshaw ML, Brusilow SW. Valproate-induced hyperammonemia. Ann Neurol 1982;
11:319.
33. Duarte J, Macias S, Coria F, et al. Valproate-induced coma: case report and literature
review. Ann Pharmacother 1993; 27:582.
34. Verrotti A, Trotta D, Morgese G, Chiarelli F. Valproate-induced hyperammonemic
encephalopathy. Metab Brain Dis 2002; 17:367.
35. Auinger K, Müller V, Rudiger A, Maggiorini M. Valproic acid intoxication imitating brain
death. Am J Emerg Med 2009; 27:1177.e5.
36. Cheng M, Tang X, Wen S, et al. Valproate (VPA)-associated hyperammonemic
encephalopathy independent of elevated serum VPA levels: 21 cases in China from May
2000 to May 2012. Compr Psychiatry 2013; 54:562.
37. Eubanks AL, Aguirre B, Bourgeois JA. Severe acute hyperammonemia after brief
exposure to valproate. Psychosomatics 2008; 49:82.
38. Yehya N, Saldarini CT, Koski ME, Davanzo P. Valproate-induced hyperammonemic
encephalopathy. J Am Acad Child Adolesc Psychiatry 2004; 43:926.
39. Camilleri C, Albertson T, Offerman S. Fatal cerebral edema after moderate valproic acid
overdose. Ann Emerg Med 2005; 45:337.
40. Sackellares JC, Lee SI, Dreifuss FE. Stupor following administration of valproic acid to
patients receiving other antiepileptic drugs. Epilepsia 1979; 20:697.
41. Yamamoto Y, Takahashi Y, Imai K, et al. Risk factors for hyperammonemia in pediatric
patients with epilepsy. Epilepsia 2013; 54:983.
42. Powell-Jackson PR, Tredger JM, Williams R. Hepatotoxicity to sodium valproate: a review.
Gut 1984; 25:673.
43. Pinkston R, Walker LA. Multiorgan system failure caused by valproic acid toxicity. Am J
Emerg Med 1997; 15:504.
44. Koenig SA, Buesing D, Longin E, et al. Valproic acid-induced hepatopathy: nine new
fatalities in Germany from 1994 to 2003. Epilepsia 2006; 47:2027.
45. Star K, Edwards IR, Choonara I. Valproic acid and fatalities in children: a review of
individual case safety reports in VigiBase. PLoS One 2014; 9:e108970.
46. Schmid MM, Freudenmann RW, Keller F, et al. Non-fatal and fatal liver failure associated
with valproic acid. Pharmacopsychiatry 2013; 46:63.
47. Mindikoglu AL, King D, Magder LS, et al. Valproic acid-associated acute liver failure in
children: case report and analysis of liver transplantation outcomes in the United States.
J Pediatr 2011; 158:802.
48. Matsumoto J, Ogawa H, Maeyama R, et al. Successful treatment by direct hemoperfusion
of coma possibly resulting from mitochondrial dysfunction in acute valproate

[Link] 19/25
6/11/23, 22:05 Valproic acid poisoning - UpToDate

intoxication. Epilepsia 1997; 38:950.

49. Raza M, Al-Bekairi AM, Ageel AM, Qureshi S. Biochemical basis of sodium valproate
hepatotoxicity and renal tubular disorder: time dependence of peroxidative injury.
Pharmacol Res 1997; 35:153.

50. Alberto G, Erickson T, Popiel R, et al. Central nervous system manifestations of a valproic
acid overdose responsive to naloxone. Ann Emerg Med 1989; 18:889.
51. Steiman GS, Woerpel RW, Sherard ES Jr. Treatment of accidental sodium valproate
overdose with an opiate antagonist. Ann Neurol 1979; 6:274.
52. Montero FJ. Naloxone in the reversal of coma induced by sodium valproate. Ann Emerg
Med 1999; 33:357.
53. Dingledine R, Iversen LL, Breuker E. Naloxone as a GABA antagonist: evidence from
iontophoretic, receptor binding and convulsant studies. Eur J Pharmacol 1978; 47:19.
54. Connacher AA, Macnab MS, Moody JP, Jung RT. Fatality due to massive overdose of
sodium valproate. Scott Med J 1987; 32:85.
55. Farrar HC, Herold DA, Reed MD. Acute valproic acid intoxication: enhanced drug
clearance with oral-activated charcoal. Crit Care Med 1993; 21:299.
56. Perrott J, Murphy NG, Zed PJ. L-carnitine for acute valproic acid overdose: a systematic
review of published cases. Ann Pharmacother 2010; 44:1287.
57. Howland MA. L-Carnitine. In: Goldfrank's Toxicological Emergencies, 9th, McGraw Hill Me
dical, New York 2011. p.711.

58. Mock CM, Schwetschenau KH. Levocarnitine for valproic-acid-induced hyperammonemic

encephalopathy. Am J Health Syst Pharm 2012; 69:35.
59. Glatstein M, Bonifacio Rino P, de Pinho S, et al. Levocarnitine for the Treatment of
Valproic Acid-Induced Hyperammonemic Encephalopathy in Children: The Experience of
a Large, Tertiary Care Pediatric Hospital and a Poison Center. Am J Ther 2019; 26:e344.
60. Russell S. Carnitine as an antidote for acute valproate toxicity in children. Curr Opin
Pediatr 2007; 19:206.
61. Raby WN. Carnitine for valproic acid-induced hyperammonemia. Am J Psychiatry 1997;
154:1168.
62. Nakamura M, Nagamine T. The Effect of Carnitine Supplementation on
Hyperammonemia and Carnitine Deficiency Treated with Valproic Acid in a Psychiatric
Setting. Innov Clin Neurosci 2015; 12:18.

63. Murakami K, Sugimoto T, Woo M, et al. Effect of L-carnitine supplementation on acute

valproate intoxication. Epilepsia 1996; 37:687.

64. Bohan TP, Helton E, McDonald I, et al. Effect of L-carnitine treatment for valproate-
induced hepatotoxicity. Neurology 2001; 56:1405.

[Link] 20/25
6/11/23, 22:05 Valproic acid poisoning - UpToDate

65. Zeiler FA, Sader N, Gillman LM, West M. Levocarnitine induced seizures in patients on
valproic acid: A negative systematic review. Seizure 2016; 36:36.
66. al-Shareef A, Buss DC, Shetty HG, et al. The effect of repeated-dose activated charcoal on
the pharmacokinetics of sodium valproate in healthy volunteers. Br J Clin Pharmacol
1997; 43:109.

67. Ghannoum M, Laliberté M, Nolin TD, et al. Extracorporeal treatment for valproic acid
poisoning: systematic review and recommendations from the EXTRIP workgroup. Clin
Toxicol (Phila) 2015; 53:454.
68. Tobin JK, Golightly LK, Kick SD, Jones MA. Valproic acid-carbapenem interaction: report of
six cases and a review of the literature. Drug Metabol Drug Interact 2009; 24:153.
69. Mancl EE, Gidal BE. The effect of carbapenem antibiotics on plasma concentrations of
valproic acid. Ann Pharmacother 2009; 43:2082.
70. Khobrani MA, Dudley SW, Huckleberry YC, et al. Intentional use of carbapenem
antibiotics for valproic acid toxicity: A case report. J Clin Pharm Ther 2018; 43:723.
71. Dreucean D, Beres K, McNierney-Moore A, Gravino D. Use of meropenem to treat
valproic acid overdose. Am J Emerg Med 2019; 37:2120.e5.
72. Thomas C, Priano J, Smith TL. Meropenem as an antidote for intentional valproic acid
overdose. Am J Emerg Med 2020; 38:690.e1.
73. Marbury TC, Lee CS, Bruni J. Hemodialysis of valproic acid in uremic patients. Dial
Transplant 1980; 9:961.

74. Klotz U, Antonin KH. Pharmacokinetics and bioavailability of sodium valproate. Clin
Pharmacol Ther 1977; 21:736.
75. Bowdle AT, Patel IH, Levy RH, Wilensky AJ. Valproic acid dosage and plasma protein
binding and clearance. Clin Pharmacol Ther 1980; 28:486.
76. van der Merwe AC, Albrecht CF, Brink MS, Coetzee AR. Sodium valproate poisoning. A
case report. S Afr Med J 1985; 67:735.
77. Roodhooft AM, Van Dam K, Haentjens D, et al. Acute sodium valproate intoxication:
occurrence of renal failure and treatment with haemoperfusion-haemodialysis. Eur J
Pediatr 1990; 149:363.
78. Tank JE, Palmer BF. Simultaneous "in series" hemodialysis and hemoperfusion in the
management of valproic acid overdose. Am J Kidney Dis 1993; 22:341.
79. Williams, SR, Clark, RF. Hemodialysis of a valproic acid poisoning (abstract). J Toxicol Clin
Toxicol 1995; 33:491.
80. Fernandez MC, Walter FG, Kloster JC, et al. Hemodialysis and hemoperfusion for
treatment of valproic acid and gabapentin poisoning. Vet Hum Toxicol 1996; 38:438.

[Link] 21/25
6/11/23, 22:05 Valproic acid poisoning - UpToDate

81. Kay TD, Playford HR, Johnson DW. Hemodialysis versus continuous veno-venous
hemodiafiltration in the management of severe valproate overdose. Clin Nephrol 2003;
59:56.
82. Al Aly Z, Yalamanchili P, Gonzalez E. Extracorporeal management of valproic acid toxicity:
a case report and review of the literature. Semin Dial 2005; 18:62.
83. Licari E, Calzavacca P, Warrillow SJ, Bellomo R. Life-threatening sodium valproate
overdose: a comparison of two approaches to treatment. Crit Care Med 2009; 37:3161.

84. van den Broek MP, Sikma MA, Ververs TF, Meulenbelt J. Severe valproic acid intoxication:
case study on the unbound fraction and the applicability of extracorporeal elimination.
Eur J Emerg Med 2009; 16:330.
85. Sidlak AM, York SR, Janicki AJ, Pizon AF. Highest reported clearance of valproate by
hemodialysis in massive overdose. Am J Emerg Med 2021; 39:255.e5.
86. Kandrotas RJ, Love JM, Gal P, Oles KS. The effect of hemodialysis and hemoperfusion on
serum valproic acid concentration. Neurology 1990; 40:1456.
87. Manoguerra AS, Erdman AR, Woolf AD, et al. Valproic acid poisoning: an evidence-based
consensus guideline for out-of-hospital management. Clin Toxicol (Phila) 2008; 46:661.
Topic 338 Version 35.0

[Link] 22/25
6/11/23, 22:05 Valproic acid poisoning - UpToDate

GRAPHICS

Valproate toxicity: Rapid overview of emergency management

To obtain emergency consultation with a medical toxicologist, in the United States, call 1-800-222-
1222 for the nearest regional poison control center. Contact information for poison control centers
around the world is available at the WHO website and in the UpToDate topic on regional poison
control centers (society guideline links).

Clinical presentation
CNS depression, encephalopathy (acute overdose or therapeutic use)

Vital sign abnormalities (severe acute overdose): Hypotension; also, respiratory depression,
tachycardia, hyperthermia

Metabolic acidosis (severe acute overdose)

Electrolyte abnormalities (acute overdose)

Elevated transaminase levels (acute overdose or therapeutic use)

Hyperammonemia (acute overdose or therapeutic use)

Idiosyncratic hepatotoxicity (therapeutic use)

History

[Link] 23/25
6/11/23, 22:05 Valproic acid poisoning - UpToDate

Ask about amount ingested (ingestion >200 mg/kg usually causes CNS depression)

Ask whether immediate or sustained release preparation was ingested

Ask about concurrent carnitine supplementation

Examination
Assess CNS depression

Look for stigmata of hepatotoxicity (eg, jaundice, hepatomegaly, right upper quadrant
abdominal tenderness)

Laboratory

Measure valproic acid concentration every 2 to 4 hours until declining; check acid-base status,
basic electrolytes, liver function tests, ammonia concentration

Treatment
Gastrointestinal decontamination

Give single dose of activated charcoal (1 g/kg; maximum dose 50 g)

Hypotension in acute overdose

Fluid resuscitation with IV boluses of isotonic crystalloid; vasopressors if necessary

Consider hemodialysis or hemoperfusion for refractory hypotension or other signs of severe

toxicity; consult nephrology early

Carnitine for VPA toxicity associated with hyperammonemia, lethargy, coma, or hepatic
dysfunction

Give carnitine, 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

CNS and respiratory depression in acute overdose

Supportive care: Patients with altered mental status often require tracheal intubation and
mechanical ventilation

Naloxone (if no risk of acute opioid withdrawal) 0.04 mg IV initial dose, gradually escalate
repeated doses every several minutes to 2 mg maximum dose per administration;
discontinue if no response after total of 10 mg IV

Benzodiazepine for seizures (eg, lorazepam 2 mg IV; repeat after 5 to 10 minutes as needed
for refractory seizures)

CNS: central nervous system; IV: intravenous; VPA: valproic acid.

Graphic 74180 Version 12.0

[Link] 24/25
6/11/23, 22:05 Valproic acid poisoning - UpToDate

Contributor Disclosures
Matthew D Sztajnkrycer, MD, PhD No relevant financial relationship(s) with ineligible companies to
disclose. Andrew Stolbach, MD, MPH, FAACT, FACMT, FACEP Grant/Research/Clinical Trial Support:
National Institute on Drug Abuse [Opioid-related illnesses]. All of the relevant financial relationships
listed have been mitigated. Michael Ganetsky, MD No relevant financial relationship(s) with ineligible
companies to disclose.

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these
are addressed by vetting through a multi-level review process, and through requirements for
references to be provided to support the content. Appropriately referenced content is required of all
authors and must conform to UpToDate standards of evidence.

Conflict of interest policy

[Link] 25/25