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

Table 1 Lactic acidosis due to inadequate tissue oxygenation versus mitochondrial dysfunction[35]

Clinically relevant considerations	Lactic acidosis due to inadequate tissue oxygen supply to meet demand (Type A lactic acidosis)	Lactic acidosis due to mitochondrial dysfunction (Type B lactic acidosis)
Selected causes	Hypovolemia/dehydration	Metformin toxicity
	Sepsis	Sepsis
	Heart failure	Cyanide poisoning
	Respiratory failure
Clinical and laboratory features	Capillary refill time > 3 s	Capillary refill time 0-3 s
	ScvO2 < 70%	ScvO2 ≥ 70% and CO2 gap < 6 mmHg
	ScvO2 ≥ 70% and CO2 gap > 6 mmHg
Treatment	Fluid challenge, followed by fluid loading if capillary refill time or blood pressure improves	Stop further administration and consider extracorporeal removal of toxic agent (e.g., metformin)
	Empirical broad-spectrum antimicrobials for suspected sepsis	Empirical broad-spectrum antimicrobials for suspected sepsis
	Vasopressors/inotropes to maintain a mean arterial pressure ≥ 65 mmHg
	Supplemental oxygen and mechanical ventilation to maintain an arterial oxygen saturation of 94%-98%
	Correct severe anemia and maintain hemoglobin 7-9 g/dL

CO₂ gap: Difference between the central venous partial pressure of carbon dioxide (measured from a blood sample taken from a central line with its tip around the junction of the superior vena cava and right atrium) and the arterial partial pressure of carbon dioxide (measured from an arterial blood sample); ScvO₂: Central venous oxygen saturation, which is measured from a blood sample taken from a central line with its tip around the junction of the superior vena cava and right atrium.

Table 2 Risk factors for metformin-associated lactic acidosis

Risk factors	Mechanism
Kidney failure (any cause)	Reduced renal elimination of metformin[45]
Cimetidine	Reduced renal elimination of metformin[51]
Ribociclib	Reduced renal elimination of metformin[52]
Excessive alcohol consumption	Ethanol oxidation consumes nicotinamide adenine dinucleotides that are also required for lactate metabolism[50]