Isoniazid Poisoning

Isoniazid poisoning causes refractory seizures, severe anion gap metabolic acidosis and coma. Isoniazid inhibits pyridoxal phosphokinase and forms inactive complexes with pyridoxine (vitamin B6), depleting pyridoxal phosphate, the cofactor for glutamic acid decarboxylase. Brain gamma-aminobutyric acid falls, so seizures follow, and are resistant to benzodiazepines because the receptor is intact but the transmitter is lacking. Lactic acidosis results from seizures, and from inhibition of lactate dehydrogenase.

Ingestion of over 20 mg/kg can cause toxicity, over 35 to 40 mg/kg commonly causes seizures, and over 80 to 150 mg/kg is life-threatening. Onset is within 30 minutes to 3 hours of ingestion. Risk factors for chronic toxicity: slow acetylators, malnutrition, alcohol use, HIV, pregnancy, diabetes and renal failure. Complications: status epilepticus, hepatotoxicity, rhabdomyolysis, aspiration, brain injury, peripheral neuropathy (chronic therapy) and death.

• Nausea, vomiting, slurred speech, dizziness, tachycardia, hyperreflexia
• Generalized seizures (often recurrent, refractory), coma
• Severe anion gap metabolic acidosis (pH under 7.0 can occur) and hyperglycemia
• Hypotension, respiratory depression, rhabdomyolysis, oliguria
• Red flags: seizure, coma, pH under 7.1 and any intentional ingestion by a patient on antituberculous treatment

1. Clinical triad: refractory seizures, metabolic acidosis with elevated lactate, and coma, after a known or suspected ingestion.
2. Arterial blood gas, lactate, electrolytes, anion gap, glucose, creatinine, creatine kinase.
3. Liver tests (initially normal, they may rise at 24 to 72 hours), and prothrombin time.
4. Paracetamol and salicylate levels, and a toxicology screen. Isoniazid levels are not rapidly available.
5. ECG, and CT head if seizures are focal or consciousness remains low.

Differentials: other seizure-inducing poisons (theophylline, tricyclics, bupropion, organophosphates), salicylate poisoning, status epilepticus of other cause, sepsis, central nervous system infection.

1. Airway and ventilation: intubate for coma or recurrent seizures, with rapid sequence induction.
2. Pyridoxine (the specific antidote):
   • Give 1 g for each 1 g of isoniazid ingested, up to a maximum of 5 g IV initially. If the amount is unknown, give 5 g IV (children 70 mg/kg, maximum 5 g).
   • Infuse over 5 to 30 minutes (in 50 to 100 mL of 5% dextrose) and repeat in 20 to 30 minutes if seizures or coma persist, up to 10 g in total, then 5 to 10 g for each 24 hours in selected cases.
   • If IV pyridoxine is unavailable, use oral pyridoxine in the same dose crushed through a nasogastric tube.
3. Benzodiazepines (given with pyridoxine for synergy): lorazepam 4 mg IV (children 0.1 mg/kg, maximum 4 mg), repeated, or diazepam 10 mg IV (children 0.2 mg/kg).
4. Refractory seizures: phenobarbital 15 to 20 mg/kg IV over 20 minutes, then propofol infusion. Avoid phenytoin, which has no effect.
5. Metabolic acidosis: sodium bicarbonate 1 to 2 mmol/kg IV for pH under 7.1, as acidosis usually resolves quickly after seizures stop and pyridoxine is given.
6. Decontamination: activated charcoal 50 g orally (children 1 g/kg, maximum 50 g) once the seizures are controlled and the airway protected, within 1 to 2 hours.
7. Haemodialysis: for very large ingestions, refractory acidosis or seizures despite pyridoxine and renal failure.
8. Rhabdomyolysis: IV crystalloid to maintain urine output over 1 mL/kg/h.
9. Hepatic injury: monitor for 72 hours, and treat acute liver failure with standard support.

Prevention for patients taking isoniazid: pyridoxine 10 to 25 mg orally daily (also for pregnancy, HIV, malnutrition, diabetes, alcohol use and neuropathy), with monthly liver tests for those at risk. Counsel on safe storage of antituberculous tablets, and complete psychiatric assessment before discharge in intentional overdose.