Metformin Overdose

Metformin overdose can cause metformin associated lactic acidosis, with severe metabolic acidosis, hyperlactataemia, vomiting, hypotension and multiorgan failure. Acute overdose is usually benign, but severe cases carry a high mortality, especially in renal impairment.

Metformin is among the most prescribed drugs. Lactic acidosis is more likely above 5 g (or 50 mg/kg) in acute overdose, and can occur at therapeutic doses in patients with renal impairment, liver disease, sepsis or hypoxia. Mortality in severe metformin associated lactic acidosis is 25 to 50%.

Risk factors for harm. Renal impairment (eGFR under 30), hepatic failure, sepsis, hypoxia, alcohol excess, dehydration and iodinated contrast.

Course. Onset of acidosis may be delayed 6 to 12 hours or longer, and may persist for 24 to 72 hours.

Pathophysiology.

Metformin inhibits mitochondrial complex I and gluconeogenesis, so lactate accumulates from impaired hepatic uptake and increased anaerobic glycolysis.

Renal failure reduces clearance, raising metformin levels further.

• Nausea, vomiting, abdominal pain, diarrhoea and malaise.
• Tachypnoea with deep (Kussmaul) breathing, hypotension, hypothermia and confusion.
• Severe lactic acidosis (lactate over 10 mmol/L, pH under 7.2), shock and acute kidney injury.
• Hypoglycaemia when co-ingested with insulin or sulphonylureas.

Red flags.

• pH under 7.1 or lactate over 15 mmol/L.
• Shock, coma or renal failure.
• Co-ingested alcohol or sulphonylurea.

• History of dose, formulation (modified release) and co-ingestants; paracetamol and salicylate levels.
• Venous or arterial blood gas with lactate on arrival and every 2 to 4 hours; electrolytes with anion gap, glucose, renal and liver function, creatine kinase and ketones.
• Metformin level where available (not required for treatment).
• Exclude sepsis, ischaemia, toxic alcohols and salicylates.

Differential diagnosis. Sepsis, salicylate poisoning, toxic alcohol poisoning, diabetic ketoacidosis, tissue ischaemia, liver failure and other drug induced lactic acidosis (linezolid, nucleoside analogues).

• 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, ileus or gastrointestinal obstruction; no renal or hepatic adjustment; acceptable in pregnancy.
• Intravenous fluids (0.9% sodium chloride or balanced crystalloid) to restore perfusion; treat sepsis and hypoxia.
• Sodium bicarbonate 8.4% 1 to 2 mmol/kg (1 to 2 mL/kg) intravenously over 20 to 30 minutes for pH under 7.1, repeated as needed. Maximum serum pH 7.55 and sodium 150 mmol/L. Monitor pH, potassium, sodium and calcium; avoid in heart failure with fluid overload; it is a bridge to dialysis rather than a cure.
• Noradrenaline 0.05 micrograms/kg/minute intravenously for hypotension, titrated to a mean arterial pressure of 65 mmHg or higher. Maximum 1 microgram/kg/minute. Give by central line; monitor blood pressure, extravasation and arrhythmia.
• Extracorporeal removal: intermittent haemodialysis for lactate over 20 mmol/L, pH of 7.0 or lower, failure of supportive care, shock, decreased consciousness or a metformin concentration over 50 mg/L; it is suggested for lactate 15 to 20 mmol/L or pH 7.0 to 7.1, and for patients with impaired kidney function. Continue until lactate is under 3 mmol/L and pH over 7.35. Monitor glucose, potassium, phosphate and haemodynamics; use anticoagulation as the dialysis unit directs; continuous techniques are an alternative if haemodynamically unstable.
• Hypoglycaemia: glucose 10% 2 mL/kg intravenously, repeated as needed; monitor glucose hourly.
• Observe for at least 12 hours (24 hours for modified release or renal impairment), with normal lactate, pH and renal function before discharge.
• Stop metformin until renal function and lactate return to normal; review diabetes treatment.

Monitoring. Lactate and pH every 2 to 4 hours until normal; glucose, potassium and creatinine; urine output.

Referral and escalation. Poisons information centre; intensive care and nephrology for acidosis, shock or renal failure.

Special groups. Renal impairment and older adults: higher risk and lower thresholds for dialysis. Pregnancy: the same treatment applies, with obstetric input.