Sodium Valproate Overdose (2023)

  • Chris Nickson

Revised and reviewed 3 September 2015


  • Sodium valproate is a commonly used anti-epileptic drug, that come sin standard and enteric coated forms
  • toxicity is characterised by metabolic failure, resulting in multi-organ dysfunction and cerebral edema


Mechanism is poorly understood

  • anticonvulsant effect is thought to be due to increased levels of GABA in the brain (reuptake inhibition and decreased degradation) and blockade of voltage dependent Na+ channels
  • in high doses acts as a mitochondrial toxin



  • Almost completely absorbed with peak serum concentrations of 1 – 4 hours (plain tablets/syrup), and 3-7 hours (enteric coated tablets)
  • Peak levels can be delayed up to 18 hours in overdose
  • In very large ingestion, particularly of enteric-coated formulations, formation of pharmacobezoars can significantly alter and delay the absorption kinetics of VPA


  • Rapid distribution, small Vd (0.1-0.4L/kg)
  • VPA displays nonlinear kinetics as a result of concentration dependent plasma protein binding and a short half-life
  • At therapeutic levels there is 90% plasma protein binding (60% to albumin) BUT in presence of high levels (>120mg/L) orlow serum albumin, binding sites become saturated, and result in higher concentration of free drug
  • It is estimated that at 150mg/L, 54-70% of VPA is protein bound; >300mg/L, 35% is protein bound; >500mg/L possibly <10% is protein bound (Licari et al, 2009)


  • Hepatic via glucuronidation (40-60%), beta-oxidation (30-40%), and omega-oxidation (fraction), producing active metabolites
  • A small amount is excreted unchanged in urine (1-3%)
  • Overdose or supra-therapeutic dosing result in increased toxic metabolite production and depletion of carnitine required for beta oxidation metabolism
  • Metabolites are implicated in hepatotoxicity (4-EN-VPA); omega oxidation), cerebral oedema (2-EN-VPA; beta oxidation), and precipitation of hyperammonia (propionic acid; omega oxidation) (Lhereux et al, 2005 and Lhereux et al, 2009)


  • Renal after extensive metabolism
  • Plasma half-life range is 4-16hrs, and can be prolonged to >30hours in overdose


(Video) Sodium valproate overdose and poisoning

Severity of toxicity is related to the dosage ingested:

  • <200mg/kg: nil to minor effects, i.e. mild drowsiness
  • 200 – 400mg/kg: moderate toxicity, i.e. CNS depression
  • 400 — 1000 mg/kg: severe toxicity, i.e. Coma
  • >1g/kg: potentially life threatening, i.e. profound coma, multi-organ toxicity including hypotension, metabolic (lactic) acidosis, cerebral oedema, biochemical abnormalities, bone marrow suppression



  • most overdoses are relatively benign
  • In large doses or overdose, multi-organ system effects are thought to be the result of the influence of increased GABA and interference with metabolic pathways.


  • CNS depression is the most common symptom (e.g. drowsiness, confusion)
  • coma almost universal in patients with drug levels >850mg/L and maypersist despite normalisation of VPA serum concentrations, possibly related to toxic metabolites implicated in CNS toxicity having prolonged half-lives
  • valproic acid induced hyperammonia encephalopathy (VHE)
  • Cerebral oedema, presenting up to 72 hours post ingestion, can occur (probably due tohyperammonemia and/or the neurotoxic metabolite 2-en-VPA)


  • Tachycardia (17% of all VPA overdose patients)
  • Hemodynamic instability, such as hypotension (~25% of those with levels >850mg/L)
  • Valproate toxicity does not manifest as cardiac sodium channel blockade


  • Nausea, vomiting and abdominal pain in overdose
  • Pancreatitis and hepatotoxicity can occur as adverse effects, but are rarelyassociated with toxicity


  • Hypernatraemia (secondary to “sodium” load delivered via in sodium valproate overdose)
  • high anion gap metabolic acidosis (HAGMA)
  • lactic acidosis
  • hypocalcaemia
  • hypoglycaemia
  • hyperammonemia (can occur in the absence of hepatotoxicity)


  • Renal failure
  • Bone marrow suppression (severe overdoses)



  • ECG (screening, tachycardia)
  • Blood gas (HAGMA, lactate)
  • Glucose (hypoglycaemia)


(Video) How to Remember Side Effects of Valproate/ Valproic Acid in 4 Minutes??

  • FBC (bone marrow suppression)
  • UEC (hypernatraemia, renal failure)
  • CK (rhabdomyolysis due to coma)
  • Ammonia
  • lipase
  • CMP(hypocalcaemia)
  • Plasma osmolality
  • LFTs
  • Coagulation profile
  • Valproate level
    • available in most hospital laboratories
    • normal therapeutic range is 50-100mg/L (350-700 uM)
    • <450 mg/L: limited toxicity
    • 450 – 850 mg/L: moderate to severe toxicity
    • >850 mg/L: greatest risk for serious or life-threatening effects including coma, respiratory depression, metabolic acidosis, hypotension
    • inaccurate valproate level measurementsin severe overdoses have been reported whensamples were not diluted before measurement — write on the laboratory order form suspected valproate overdose and the likely ingested dose so that laboratory staff are aware
    • levels are repeated q4-6h in symptomatic patients until levels are decreasing
  • Paracetamol level (screening)


  • CT head (cerebral oedema)



  • Attend to ABCs and address immediate life threats
  • Airway and breathing may be compromised by decreased level of consciousness (e.g. airway obstruction, aspiration and respiratory depression)
  • Hemodynamic instability
    • IV fluid boluses and vasopressors
  • Cerebral oedema
    • head up positioning, maintaincerebral perfusion pressure, consider osmotic therapy
    • unclear role for ICP monitoring

Supportive care and monitoring

  • Provide multi-organ and metabolic support as required
  • Seek and treat complications (e.g. compartment syndrome, rhabdomyolysis and presure injuries from coma)


  • Nil if <400mg/kg ingestion
  • 50g activated charcoal via CXR-confirmed NG tube following endotracheal tube if >400mg/kg; can be repeated after 4 hours if bowel sounds present and rising valproate levels (due to delayed absorption)
  • Whole bowel irrigation is sometimes advised but is of unproven benefit and is associated with risks even in intubated patients


  • Carnitine is sometimes considered (no convincing evidence of benefit)

Enhanced elimination

  • haemodialysis is given if life-threatening systemic toxicity is anticipated based on the risk assessment, and is ideally performed before multi-organ dysfunction develops
    • ingestion of >1g/kg with a serum valproate level >1,000 mg/L
    • any ingestion with a serum valproate level >1,500 mg/L
    • severe toxicity with haemodynamic instability and/or lactic acidosis
  • Valproate is readily dialysable in overdose because protein binding is saturable (resulting in increasing concentrations of free valproate the larger the ingested dose) and it has low Vd, low molecular weight, and high water solubility
  • CVVHDF will lead to slower removal than IHD and SLEED, but is more haemodynamically stable


  • If <200 mg/kg ingestion observe for 8 hours, if remain asymptomatic then ‘medically cleared’
  • Larger ingestions require observation in a high visibility area for progressive decreased level of consciousness
  • Intubated patients require ICU admission
  • Intentional overdoses usually require psychiatric referral

References and Links


  • Toxicology Conundrum 053 and 054

Journal articles and Textbooks

  • Lheureux PE, Penaloza A, Zahir S, Gris M. Science review: carnitine in the treatment of valproic acid-induced toxicity – what is the evidence? Critical care (London, England). 9(5):431-40. 2005. [pubmed] [free full text]
  • Lheureux PE, Hantson P. Carnitine in the treatment of valproic acid-induced toxicity. Clinical toxicology (Philadelphia, Pa.). 47(2):101-11. 2009. [pubmed]
  • Licari E, Calzavacca P, Warrillow SJ, Bellomo R. Life-threatening sodium valproate overdose: a comparison of two approaches to treatment. Critical care medicine. 37(12):3161-4. 2009. [pubmed]
  • Mock CM, Schwetschenau KH. Levocarnitine for valproic-acid-induced hyperammonemic encephalopathy. American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists. 69(1):35-9. 2012. [pubmed]
  • Murray, Lindsay, Daly, F, Little, M, Cadogan M. Toxicology handbook. 2nd ed. Sydney: Churchill Livingstone; 2010
  • Spiller HA, Krenzelok EP, Klein-Schwartz W. Multicenter case series of valproic acid ingestion: serum concentrations and toxicity. Journal of toxicology. Clinical toxicology. 38(7):755-60. 2000. [pubmed]
  • Sztajnkrycer MD. Valproic acid toxicity: overview and management. Journal of toxicology. Clinical toxicology. 40(6):789-801. 2002. [pubmed]
Sodium Valproate Overdose (1)

Critical Care


…more CCC

(Video) What is wrong with Sodium Valproate

Chris Nickson

Chris is an Intensivist and ECMO specialist at theAlfred ICU in Melbourne. He is also a Clinical Adjunct Associate Professor at Monash University.He is a co-founder of theAustralia and New Zealand Clinician Educator Network(ANZCEN) and is the Lead for theANZCEN Clinician Educator Incubatorprogramme. He is on the Board of Directors for theIntensive Care Foundationand is a First Part Examiner for theCollege of Intensive Care Medicine. He is an internationally recognised Clinician Educator with a passion for helping clinicians learn and for improving the clinical performance of individuals and collectives.

After finishing his medical degree at the University of Auckland, he continued post-graduate training in New Zealand as well as Australia’s Northern Territory, Perth and Melbourne. He has completed fellowship training in both intensive care medicine and emergency medicine, as well as post-graduate training in biochemistry, clinical toxicology, clinical epidemiology, and health professional education.

He is actively involved in in using translational simulation to improve patient care and the design of processes and systems at Alfred Health. He coordinates the Alfred ICU’s education and simulation programmes and runs the unit’s educationwebsite,INTENSIVE. He created the ‘Critically Ill Airway’ course and teaches on numerous courses around the world. He is one of the founders of theFOAMmovement (Free Open-Access Medical education) and is co-creator,theRAGE podcast, theResuscitologycourse, and theSMACCconference.

His one great achievement is being the father of three amazing children.

OnTwitter, he is@precordialthump.

| INTENSIVE | RAGE | Resuscitology | SMACC

(Video) Valproic Acid Mnemonic for USMLE

Leave a Reply

This site uses Akismet to reduce spam. Learn how your comment data is processed.

(Video) Valproic acid || Mechanism, side effects and indications


1. Prescribed Overdose of Sodium Valproate- FVSD Life
(FVSD Life)
2. Sodium Valproate Uses,Mode Of Action, Precautions,Dose In Hindi | sodium valproate in hindi
3. Pharmacology - Bipolar Drugs - Lithium, Valproic Acid, Carbamazepine nursing RN PN NCLEX
(Simple Nursing)
4. The Epilim/Sodium Valproate debacle - Dr. Jim Morrow
(Torie Robinson - Epilepsy Sparks Insights)
5. Epilepsy - English
(Focus Medica)
6. Valproic Acid (Depakene) - Uses, Dosing, Side Effects
(Drug Talk)
Top Articles
Latest Posts
Article information

Author: Geoffrey Lueilwitz

Last Updated: 11/04/2022

Views: 5905

Rating: 5 / 5 (60 voted)

Reviews: 83% of readers found this page helpful

Author information

Name: Geoffrey Lueilwitz

Birthday: 1997-03-23

Address: 74183 Thomas Course, Port Micheal, OK 55446-1529

Phone: +13408645881558

Job: Global Representative

Hobby: Sailing, Vehicle restoration, Rowing, Ghost hunting, Scrapbooking, Rugby, Board sports

Introduction: My name is Geoffrey Lueilwitz, I am a zealous, encouraging, sparkling, enchanting, graceful, faithful, nice person who loves writing and wants to share my knowledge and understanding with you.