Metformin-Associated Lactic Acidosis

Metformin-associated lactic acidosis is severe lactic acidosis (lactate over 5 mmol/L with pH under 7.35) occurring in a patient taking metformin. It is rare, with an incidence of 3 to 10 cases per 100,000 patient-years, but mortality is 25 to 50% when severe. Metformin is renally excreted and is not metabolized. It inhibits mitochondrial complex I and gluconeogenesis, so lactate production rises and its hepatic clearance falls.

Precipitants

• Acute kidney injury or chronic kidney disease (the most important, with eGFR under 30 mL/min/1.73 m2)
• Sepsis, hypoperfusion, acute heart failure, hypoxia and cardiac arrest
• Iodinated contrast exposure, dehydration and gastroenteritis
• Liver disease and heavy alcohol use
• Acute overdose (over 5 g in adults, or over 100 mg/kg)

Two settings exist: metformin-associated (accumulation with a coexisting illness) and metformin-induced (acute massive overdose). Complications: multiorgan failure, refractory shock, cardiac arrest, hypoglycemia and death.

• Nausea, vomiting, abdominal pain, diarrhea, anorexia
• Rapid deep breathing (Kussmaul respiration), lethargy, confusion, myalgia
• Hypotension, tachycardia, hypothermia, oliguria
• Progression to stupor, coma and shock
• Red flags: pH under 7.1, lactate over 15 mmol/L, oliguria, hypotension and altered consciousness

1. Arterial blood gas and lactate: pH under 7.35 with lactate over 5 mmol/L. An anion gap over 16 mmol/L supports the diagnosis.
2. Renal function and electrolytes: creatinine, urea, bicarbonate, potassium, glucose, ketones, and beta-hydroxybutyrate to exclude ketoacidosis.
3. Metformin level (not needed for treatment, and not widely available).
4. Sepsis and shock evaluation: blood cultures, chest radiograph, ECG, troponin, liver tests, creatine kinase, osmolar gap to exclude toxic alcohols, and paracetamol and salicylate levels.
5. Medication history, including recent contrast and other nephrotoxic drugs.

Differentials: lactic acidosis from sepsis or shock, diabetic ketoacidosis, salicylate poisoning, toxic alcohols (methanol, ethylene glycol), uremia, liver failure.

1. Stop metformin and treat the precipitating illness (antibiotics for sepsis, fluid resuscitation, oxygen, support of perfusion, and treatment of acute kidney injury).
2. Resuscitation: IV balanced crystalloid 20 mL/kg initially with reassessment, norepinephrine 0.05 to 0.5 micrograms/kg/min for hypotension, and ventilation for respiratory failure.
3. Decontamination for acute overdose: activated charcoal 50 g orally (children 1 g/kg) within 1 to 2 hours.
4. Sodium bicarbonate: 1 to 2 mmol/kg IV (150 mmol in 1 L of 5% dextrose over 1 to 2 hours) for pH under 7.1, balanced against sodium and volume load and hypocalcemia. It is a bridge to dialysis.
5. Extracorporeal treatment (intermittent haemodialysis is preferred, and continuous therapy when unstable):
   • Indicated for lactate over 20 mmol/L, pH of 7.0 or less, shock, failure of standard therapy, or decreased consciousness.
   • Suggested for lactate of 15 to 20 mmol/L, or pH of 7.0 to 7.1, or when there is impaired kidney function (eGFR under 45 mL/min/1.73 m2), or other organ failure.
   • Continue until lactate is under 3 mmol/L and pH is over 7.35, which is usually 6 to 12 hours, and monitor for rebound.
6. Glucose: dextrose 10% IV infusion if hypoglycemic. Insulin if glucose is high.
7. Thiamine 200 to 500 mg IV daily for 3 days in patients with alcohol use or malnutrition.

Prevention: metformin should not be started when eGFR is under 45 mL/min/1.73 m2, and should be stopped when under 30. Temporarily stop it during acute illness with dehydration, and before iodinated contrast when eGFR is under 30 or in acute kidney injury, restarting after 48 hours when renal function is stable. Counsel on sick-day rules.