Phenobarbital Toxicity

Phenobarbital toxicity arises from overdose, accumulation at therapeutic doses, or interactions that raise serum levels. It causes drowsiness, ataxia, nystagmus, confusion, respiratory depression and, at high levels, coma.

It occurs in people with epilepsy taking long term phenobarbital, in neonates given loading doses, and in deliberate or accidental overdose. Concentrations above 40 mg/L are often toxic, above 60 mg/L cause marked sedation, and above 100 mg/L can cause coma.

Risk factors. Renal or hepatic impairment, older age, interacting drugs (valproate, which raises levels, and some antifungals), poor adherence with later double dosing, and dosing errors in children.

Course. The half life is 80 to 100 hours in adults (longer in neonates and older adults), so toxicity can last several days and resolves slowly.

Pathophysiology.

Enhancement of GABA-A chloride currents suppresses neuronal excitability, and at high concentrations depresses the respiratory centre and heart.

Enzyme induction alters the metabolism of many other drugs.

• Drowsiness, dysarthria, ataxia, nystagmus, diplopia and cognitive slowing.
• Confusion, irritability or paradoxical agitation, especially in children and older adults.
• Hypotension, hypothermia, respiratory depression and coma at high levels.
• Chronic toxicity: osteomalacia, megaloblastic anaemia and skin reactions.

Red flags.

• Glasgow Coma Scale under 9 or hypoventilation.
• Level over 100 mg/L.
• Rash with fever and mucosal involvement (severe cutaneous reaction).

• Serum phenobarbital concentration (therapeutic range about 15 to 40 mg/L; toxic above 40 mg/L), repeated every 12 to 24 hours in overdose.
• Glucose, electrolytes, renal and liver function, calcium, venous gas, full blood count and creatine kinase.
• Paracetamol and salicylate levels in overdose; review all current drugs for interactions.
• ECG and chest imaging if aspiration is possible.

Differential diagnosis. Other sedative or antiepileptic toxicity (phenytoin, carbamazepine), metabolic encephalopathy, hypoglycaemia, post-ictal state, stroke and alcohol intoxication.

• Mild to moderate toxicity from accumulation: withhold the next dose or doses, check the level, and restart at a reduced dose when the level falls to the therapeutic range; adjust the maintenance dose to levels and clinical response. Maximum maintenance dose in adults is usually 180 to 200 mg daily, titrated by level.
• Review interacting drugs (stop or reduce valproate, which raises levels) and treat intercurrent illness.
• Overdose: airway protection and ventilation as needed; there is no antidote, and flumazenil is not used.
• Activated charcoal 50 g orally once (1 g/kg, maximum 50 g, in children) within 1 hour of a significant ingestion if the airway is protected. Monitor the airway for aspiration. Avoid with reduced consciousness without a protected airway, ileus or gastrointestinal obstruction; no renal or hepatic adjustment; acceptable in pregnancy.
• Multiple dose activated charcoal 50 g orally or via nasogastric tube every 4 hours (children 1 g/kg, maximum 50 g) for up to 24 hours, with the airway protected. Monitor bowel sounds, abdominal distension and aspiration. Avoid with unprotected airway, ileus, obstruction or recent bowel surgery; no renal or hepatic adjustment.
• Urinary alkalinisation: sodium bicarbonate 8.4% 1 to 2 mmol/kg (1 to 2 mL/kg) intravenously, then an infusion of 150 mmol in 1 litre of 5% glucose at 250 mL/hour, titrated to urine pH 7.5 to 8.5. Maximum serum pH 7.55 and sodium 150 mmol/L. Monitor urine pH, potassium (replace to over 4.0 mmol/L), calcium, sodium and pH. Avoid in heart failure with fluid overload and renal failure.
• Haemodialysis or haemoperfusion for prolonged coma, shock, apnoea or a level over 100 mg/L.
• Hypotension: fluids, then noradrenaline 0.05 micrograms/kg/minute intravenously, titrated to a mean arterial pressure of 65 mmHg or higher (maximum 1 microgram/kg/minute; central line; monitor blood pressure and extravasation).
• Maintain antiseizure cover with a different drug when seizures are a risk, since abrupt phenobarbital loss in a person with epilepsy can cause seizures: levetiracetam 500 mg orally or intravenously twice daily, increased by 500 mg twice daily every 2 weeks to a maximum of 1500 mg twice daily (monitor mood and renal function; reduce dose when creatinine clearance is 50 to 80 mL/min, 500 to 1000 mg twice daily; 30 to 50 mL/min, 250 to 750 mg twice daily; under 30 mL/min, 250 to 500 mg twice daily).
• Chronic toxicity: folic acid and vitamin D supplementation; bone health review.

Monitoring. Phenobarbital level every 12 to 24 hours in overdose, and 1 to 2 weeks after any dose or interaction change; conscious level, respiratory rate and renal function.

Referral and escalation. Poisons information centre; epilepsy specialist for dose revision; intensive care for coma or apnoea.

Special groups. Neonates: longer half life, so dose by level. Older adults: lower doses and closer monitoring. Pregnancy: supplement folic acid 5 mg orally once daily before conception through the first trimester (maximum 5 mg daily; no renal adjustment).