Sodium Valproate Overdose

Revised and reviewed 3 September 2015

OVERVIEW

• 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 OF TOXICITY

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

TOXICOKINETICS

Absorption

• 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

Distribution

• 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) or low 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)

Metabolism

• 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)

Elimination

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

RISK ASSESSMENT

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

CLINICAL FEATURES

General

• 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 effects

• CNS depression is the most common symptom (e.g. drowsiness, confusion)
• coma almost universal in patients with drug levels >850mg/L and may persist 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 to hyperammonemia and/or the neurotoxic metabolite 2-en-VPA)

Cardiovascular

• 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

Gastrointestinal

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

Metabolic

• 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)

Other

• Renal failure
• Bone marrow suppression (severe overdoses)

INVESTIGATIONS

Bedside

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

Laboratory

• 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 measurements in severe overdoses have been reported when samples 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)

Imaging

• CT head (cerebral oedema)

MANAGEMENT

Resuscitation:

• 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, maintain cerebral perfusion pressure, consider osmotic therapy
  • unclear role for ICP monitoring

Supportive care and monitoring

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

Decontamination

• 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

Antidotes

• 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

Disposition

• 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

LITFL

• 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]