Poison Center, MacKay Memorial Hospital

2026年8月17日星期一

Depakine (Valproic Acid) Poisoning

Depakine (Valproic Acid) Poisoning

Substance

Generic name: Valproic acid (VPA)
Other formulations: Sodium valproate, divalproex sodium

COMMON trade NAMES: Depakine®, Depakote®, Convulex®, Common name: Depakine

Involving system

Neurologic

The central nervous system (CNS) is most commonly affected.

Drowsiness [1]
Confusion [2]
Ataxia [3]
Altered mental status
Coma [4]
Respiratory depression [5].
Seizures, which are uncommon but may occur in severe poisoning [1].
Cerebral edema in severe cases [6]

Gastrointestinal

Nausea [1]
Vomiting [1]
Abdominal pain

Cardiovascular

Hypotension. [4]
Tachycardia
Shock in severe poisoning

Respiratory

Respiratory depression [5]
Aspiration
Aspiration pneumonia

Metabolic

Hyperammonemia [5].
Metabolic acidosis [7].
Hyperlactatemia
Hypoglycemia, which is uncommon. [7]

Mechanism of Action and Toxicity

Valproic acid is used as: An antiepileptic drug, A mood stabilizer, A medication for migraine prophylaxis [8]

Its therapeutic effects are primarily related to:

Increased GABA availability
Inhibition of voltage-gated sodium channels
Inhibition of T-type calcium channels

PRESENTATION

CNS depression
Hyperammonemia
Mitochondrial dysfunction [6]
Inhibition of fatty-acid β-oxidation
Carnitine depletion

Toxic Dose, [9].

VPA dose	Expected toxicity
<200 mg/kg	Usually mild symptoms
200–400 mg/kg	Moderate toxicity
≥400 mg/kg	Potentially severe toxicity
~1,000 mg/kg	Highly dangerous; severe poisoning is likely

Clinical severity should always be interpreted together with the patient's clinical condition and serum VPA concentration.

Serum Valproic Acid Concentration, [10].

VPA concentration (µg/mL)	Clinical significance
50–100	Usual therapeutic range
100–180	Possible toxicity
>180	Significant toxicity becomes more likely
>450	Consider L-carnitine therapy, particularly with clinical toxicity
850–900	Often associated with severe poisoning
≥1,300	Strong indication to consider extracorporeal treatment

Important: Serum VPA concentration should not be interpreted in isolation. Clinical status, hyperammonemia, acid-base abnormalities, and end-organ dysfunction are important determinants of severity.

Major Complications: Hyperammonemic Encephalopathy, [11]

Hyperammonemic encephalopathy may occur even when the serum VPA concentration is declining.

It may be particularly important in:

Patients with persistent or worsening neurologic deterioration despite decreasing VPA concentrations
Long-term VPA users
Patients with carnitine deficiency

Clinical manifestations include:

Progressive alteration of consciousness
Coma
Cerebral edema

Key point: A falling VPA concentration does not necessarily indicate clinical recovery.

Acute Liver Failure, [12].

Less common but potentially life-threatening
Monitor AST/ALT, bilirubin, coagulation parameters, and clinical evidence of hepatic dysfunction

Pancreatitis: May occur following VPA exposure, Check serum lipase when clinically suspected

Extended-Release Formulations, Extended-release (ER) VPA formulations may have delayed absorption. [13]

Peak serum concentrations may be delayed for 12–24 hours
An initially normal VPA concentration does not exclude significant poisoning
Serial VPA measurements are recommended when a significant overdose is suspected, particularly after ingestion of an ER formulation

Antidote and Initial Management

Essential investigations

Serum valproic acid concentration
Serum ammonia
Arterial or venous blood gas (ABG/VBG)
Electrolytes
Blood glucose
Creatinine
AST/ALT
Complete blood count (CBC)

Additional investigations

Lactate
Coagulation profile
Lipase and/or amylase
ECG

ABC Stabilization

Airway

Endotracheal intubation should be considered or performed when there is:

Severe CNS depression
Inability to protect the airway
Significant respiratory depression
High aspiration risk

A GCS <8 is a commonly used trigger for airway intervention, but clinical judgment should guide the decision.

Breathing

Supplemental oxygen; Mechanical ventilation when indicated
Monitor for aspiration and respiratory failure

Circulation

IV fluid resuscitation, Vasopressors for persistent hypotension or shock

Gastrointestinal Decontamination

Activated charcoal may be considered when:

The ingestion occurred within approximately 1–2 hours
The patient has an intact or protected airway
The potential benefit outweighs the aspiration risk

Dose: 1 g/kg orally or via NG tube; Typical adult dose: 50 g

Do not administer activated charcoal to a patient with significant CNS depression unless the airway is adequately protected.

Whole-Bowel Irrigation: Whole-bowel irrigation may be considered in selected cases involving: Large ingestions of extended-release formulations, Significant residual drug within the gastrointestinal tract

Its role is individualized and should be considered in consultation with a toxicologist or poison center.

L-Carnitine Therapy: Rationale

L-carnitine supplementation may help restore:

Mitochondrial function, Ammonia metabolism, and Fatty-acid β-oxidation

When to Consider L-Carnitine: L-carnitine should be considered particularly in patients with significant VPA toxicity, including:

VPA concentration >450 µg/mL ; Hyperammonemia; Altered mental status; Hepatotoxicity; Significant metabolic acidosis; Cerebral edema [14].

Suggested Dose

Loading dose

100 mg/kg IV, Maximum: 6 g (1g/5mL/amp) [15]

Maintenance dose

50 mg/kg IV every 8 hours [14].
Maximum: 3 g per dose

Treatment may be continued until:

Clinical improvement occurs
VPA concentration decreases to a safe range
Hyperammonemia improves

Naloxone [2]

Naloxone has been reported to improve CNS depression in a small number of VPA-poisoned patients.

A therapeutic trial may be considered:

Naloxone 0.4–2 mg IV

However:

Clinical responses are inconsistent
Evidence supporting routine use is limited
Naloxone must not replace supportive care or definitive management

Hemodialysis / Extracorporeal Treatment

At high VPA concentrations, protein binding becomes saturated, increasing the free fraction of VPA and making the drug more amenable to extracorporeal removal.

EXTRIP Recommendations

Hemodialysis is strongly recommended

Consider extracorporeal treatment, preferably intermittent hemodialysis, in patients with:

VPA concentration >1,300 µg/mL, Cerebral edema, and Shock [10].

Hemodialysis is suggested

Consider extracorporeal treatment in patients with:

VPA concentration >900 µg/mL
Coma requiring mechanical ventilation
Severe hyperammonemia
Severe metabolic acidosis, particularly pH <7.10
Refractory hypotension

Benefits of Hemodialysis

Hemodialysis can rapidly reduce: Serum VPA concentration and Ammonia concentration

and may improve:

Level of consciousness
Metabolic acidosis
Hemodynamic instability

Disposition

Discharge: Discharge may be considered when the patient:

Remains asymptomatic
Has a clearly declining VPA concentration
Has normal or improving ammonia levels
Has no significant metabolic or organ dysfunction
Has completed an appropriate psychiatric assessment when the ingestion was intentional

Hospital Admission

Admission should be considered for patients with:

Clinical symptoms
Hyperammonemia
Persistently elevated or rising VPA concentrations
Metabolic abnormalities
Significant or uncertain ingestion of an extended-release formulation

ICU Admission

ICU-level care is appropriate for patients with:

Endotracheal intubation or mechanical ventilation
Coma
Shock
Cerebral edema
Severe metabolic acidosis
Severe hyperammonemia
Need for hemodialysis/extracorporeal treatment

Prognosis

Most patients with VPA poisoning recover within approximately 24–72 hours with appropriate supportive care and treatment.

Poor Prognostic Factors

Cerebral edema
Persistent severe hyperammonemia
Acute liver failure
Multiorgan failure
Severe metabolic acidosis
Refractory shock
Delayed initiation of extracorporeal treatment when indicated

Summary

Valproic acid overdose primarily causes CNS depression and hyperammonemia.
Extended-release formulations may cause delayed absorption and delayed peak concentrations; serial VPA measurements are therefore important.
A decreasing VPA concentration does not exclude ongoing or worsening hyperammonemic encephalopathy.
L-carnitine is an important adjunctive therapy in significant VPA poisoning, particularly in the presence of hyperammonemia, altered mental status, hepatotoxicity, or severe metabolic abnormalities.
Hemodialysis should be strongly considered for VPA concentrations ≥1,300 µg/mL, cerebral edema, or shock.
Hemodialysis may also be considered at lower concentrations when severe clinical manifestations are present, such as coma requiring ventilation, severe hyperammonemia, severe acidosis, or refractory hypotension.
Clinical status should always take precedence over serum VPA concentration alone when determining severity and disposition.