Metformin-associated lactic acidosis: A mini review of pathophysiology, diagnosis and management in critically ill patients

Abstract

Metformin is a common diabetes drug that may reduce lactate clearance by inhibiting mitochondrial oxidative phosphorylation, leading to metformin-associated lactic acidosis (MALA). As diabetes mellitus is a common chronic metabolic condition found in critically ill patients, pre-existing metformin use can often be found in critically ill patients admitted to the intensive care unit or the high dependency unit. The aim of this narrative mini review is therefore to update clinicians about MALA, and to provide a practical approach to its diagnosis and treatment. MALA in critically ill patients may be suspected in a patient who has received metformin and who has a high anion gap metabolic acidosis, and confirmed when lactate exceeds 5 mmol/L. Risk factors include those that reduce renal elimination of metformin (renal impairment from any cause, histamine-2 receptor antagonists, ribociclib) and excessive alcohol consumption (as ethanol oxidation consumes nicotinamide adenine dinucleotides that are also required for lactate metabolism). Treatment of MALA involves immediate cessation of metformin, supportive management, treating other concurrent causes of lactic acidosis like sepsis, and treating any coexisting diabetic ketoacidosis. Severe MALA requires extracorporeal removal of metformin with either intermittent hemodialysis or continuous kidney replacement therapy. The optimal time to restart metformin has not been well-studied. It is nonetheless reasonable to first ensure that lactic acidosis has resolved, and then recheck the kidney function post-recovery from critical illness, ensuring that the estimated glomerular filtration rate is 30 mL/min/1.73 m² or better before restarting metformin.

Keywords: Acid-base equilibrium; Biguanides; Oxidative phosphorylation; Pyruvic acid; Renal replacement therapy.

Figure 1

Pathophysiology of metformin-associated lactic acidosis. ¹Metformin is eliminated unchanged by the kidney.

Figure 2

Diagnosis and management of metformin-associated lactic acidosis. HCO₃: Serum bicarbonate concentration; PaCO₂: Arterial partial pressure of carbon dioxide; VA-ECMO: Venoarterial extracorporeal membrane oxygenation.