Valproic Acid Overdose (VPA Poisoning) – IBCC
Important history
Hx
* Timing of dose
* Quantity
* Type: immediate vs delayed/extended release
* Co-ingestions
* Intent
* With OD, absorption may be delayed → levels peaking 24 hrs (or later).
Toxicity Thresholds
- ~200 mg/kg → Mild
- ~400 mg/kg → Severe CNS
- 800 mg/kg → Risk of MOF (multi-organ failure)
=> ↑ risk of hyperammonemic encephalopathy in Patients with Genetic Urea Cycle Disorders.
Pharmacokinetics:
Protein binding
Metabolism
=>Protein Binding
* Highly protein bound, but in OD protein binding saturates → free drug levels ↑ substantially → ↑ tissue toxicity.
=> Metabolism in Liver
1. Glucuronidation (glucuronic acid conjugation) → excretable.
2. Conjugation to carnitine → leads to carnitine depletion.
3. β-oxidation (less toxic) → may deplete Acetyl-CoA.
4. ω-oxidation → produces toxic metabolites.
Omega oxidation produces foll. metabolites:
2EN VPA–> causes cerebral oedema
4EN VPA–> Causes hepatotoxicity
Propionic acid metabolites–> Hyperammonemia
Clinical features:
=>Systems affected
=>Major concerns
=> Systems affected:
* CNS
* GI
* Metabolic
=>Major concerns:
* Encephalopathy
* Seizures
* Cerebral oedema
* Hypotension, Shock
* Liver failure
Clinical presentation
=>Neurologic Manifestations
1. Hyperammonemic encephalopathy
* Due to urea cycle dysfunction caused by valproate & its metabolites.
=> Mechanism:
* Metabolites of VPA → deplete carnitine → hyperammonemia.
* ↑ NH₃ → cerebral edema.
2). Cerebral edema
-> Related to level of NH₃.
-> 2° effect of VPA metabolites.
-> May occur 2–3 days post ingestion, despite improvements in valproic acid levels.
Carnitine required to transport fatty acids into mitochondria for oxidation.
In carnitine deficiency-> accumulation of Fatty acids->inhibit urea cycle which detoxifies ammonia.
⬆️ NH3–> enters Astrocytes–>converted into glutamine intracellularly–> acts as osmole, ⬆️es intracellular osmolarity–>water drawn within cells–> cytotoxic oedema.
Role of Carnitine in hyperammonemia
Carnitine serves as a transporter of long chain fatty acids to mitochondria for energy production via Beta oxidation and TCA cycle
Carnitine deficiency–> accumulation of Fatty acids–>accumulated unoxidised fatty acids inhibit urea cycle–> Hyperammonemia
GI effects
- Nausea / vomiting
- Mild hepatitis
- Pancreatitis
CVS
- Heart block, bradycardia
- Hypotension, shock
- Drug-induced Brugada pattern
Metabolic effects
=>Metabolic Effects
➡️* HAGMA (high anion gap metabolic acidosis)
* Causes: ketoacids, prop
ionic acid, lactate, valproic acid
➡️* Hypernatremia (Na salt)
➡️* Hyponatremia (e.g. SIADH induced by valproic acid)
➡️* ↑ Transaminases
➡️* Cytopenias → 2–3 days post ingestion
Invx
=>VPA Levels
* 6000 μmol/L → serious
* Levels should be done every 2–4 hrs until peak is reached(delayed absorption possible)
➡️Imaging
* Ocular USG → to detect cerebral edema
* CT Brain → if concerns regarding ↓ GCS, head trauma, cerebral edema (± other causes)
➡️ PCM , alcohol levels to r/o other coingestions
Mx
Resuscitation
1)=> Airway/Breathing
* Intubation ± if seizures / ↓ GCS
2)=> Seizure Control
- Benzodiazepines = first line
3)=> Metabolic
- Manage hypernatremia/⬇️Na/⬇️Ca
* Correct metabolic acidosis
4)=> ICP
* ICP control measures
Aspirin Interaction
* Discontinue aspirin → ↑ VPA free levels (competition for protein binding).
Decontamination
=> Total Bowel irrigation- No high-level evidence for total bowel irrigation
- Can be useful in massive OD where absorption is delayed.
- Should be considered when HD unavailable immediately.
=>Activated charcoal - If given within 2–4 hrs of ingestion. - Either protecting own airway / need intubation for other reasons.
Specific Management
- Hemodialysis
- Can ↓ half-life.
- Directly removes NH₃ → improves hyperammonemic encephalopathy & cerebral edema.
- Should be considered in severe cases.
Dialysis
Indications
Mode
=>Cleared by hepatic metabolism (not kidney)
→ Renal function irrelevant to decision regarding dialysis.
=>Indications for Dialysis
1) Valproate level > 6000 μmol/L
2) CNS: cerebral edema, ↓ GCS requiring intubation, acute ↑ NH₃
3) CVS: shock
4) Acidosis: pH < 7.1
=>Mode
* Intermittent hemodialysis (not UF).
* CRRT = not very effective, even if patient is shocked.
* HD recommended (shock likely due to valproate).
* Discontinue → after clinical improvement.
Adjuncts
- L- Carnitine
- Carbapenam
- IV Dextrose
- Naloxone
- L- Arginine
Adjuncts
- Repeat Levels
- Suggested → rebound elevation may occur.
- Carnitine
- Carnitine depletion → due to metabolism via β-oxidation.
- Consequences of ↑ ω-oxidation → more toxic metabolites.
- Carnitine required for metabolism of fatty acids.
- Deficiency = energy substrate impairment & urea cycle dysfunction → exacerbates hyperammonemia.
->Indications:
* ↓ GCS
* Severe hepatotoxicity
* ↑ NH₃
* Level > 8000 μmol/L
Adjuncts cont..
3) . Naloxone
* Suggested by some case reports.
* Proposed mechanism: inhibition of GABA uptake.
* Role uncertain.
4) . Carbapenems
* ↓ Valproate levels- via enxyme inhibition
* Use in OD = controversial.
Carbapenem inhibit enzyme acyl peptide hydrolase, thereby reducing the enterohepatic circulation of valproate glucoronide and its conversion back into valproate(see IBCC)
Adjuncts cont..
5) Nutritional Support
* IV Dextrose = 2–3 g/kg/day–> ↓ protein catabolism–>↓ blood NH₃
->Beneficial in ↑ NH₃ & cerebral edema → 50% dextrose can be considered.
-> Withhold protein administration in acute phase.
6) IV L-Arginine
* Neutralises effects of toxic metabolites.
When to Restart Valproate
- Reduction in valproate levels below therapeutic range → may ↑ seizure risk.
- Consider alternative antiepileptic.
- Valproate can be restarted if levels below therapeutic range.
Summary
Summary cont..
