Metformin-associated lactic acidosis

Background

Acute and chronic use of metformin can lead to rare complication of Metformin-associate lactic acidosis (MALA)
Excreted (unmetabolized) in proximal tubules
Stimulates anaerobic glucose metabolism in splanchnic bed → increased lactate production
Inhibits mitochondrial respiratory chain → decreased gluconeogenesis from lactate → lactate accumulation
Associated with overdose, renal failure, liver disease, and septicemia^[1]
Acidosis onset several hours after acute ingestion
Mortality rate 45%^[2]
- Lactate only predictive of mortality in overdose patients, not in incidental metformin accumulation
- Elevated PT associated with increased mortality
- pH >6.9, lactate >25 portends a poor prognosis^[3]

Type A (tissue hypoperfusion)
- Hypovolemia
- Cardiac failure
- Sepsis
Type B (decreased utilization)
- Alcoholism
  - ↓ Lactate utilization secondary to hepatic dysfunction
  - ↓ NAD+/NADH ratio leads to ↑ conversion of pyruvate to lactate
- Metformin
- DKA
  - Mainly due to D-lactate production, though hypovolemia contributes
- Liver disease (decreased clearance)
- Adrenergic receptor agonism; viz., albuterol, epinephrine, etc
- Malignancy
- Carbon Monoxide poisoning
- Cyanide poisoning
Type D
- episodes of encephalopathy and metabolic acidosis typically following high carbohydrate meals in patients with short bowel syndrome
- metabolic acidosis and high serum anion gap, normal lactate level, short bowel syn or other forms of malabsorption, and characteristic neurologic findings
  - Type D lactate is not detected with standard lactate levels

If intubated, maintain minute ventilation so as to not remove respiratory compensation for acidosis
Activated charcoal if peri-ingestion/mental status appropriate
Metformin should not cause hypoglycemia and, if present, should lead to work up of cause
Sodium Bicarbonate
- No evidence to support its use in MALA patients^[5]
Hemodialysis
- Metformin can be cleared with hemodialysis and CVVH (continuous venovenous hemofiltration)^[6]
  - Former preferred
  - CVVH should be used in unstable patient
- Reduction in metformin levels following acute ingestion reported to require prolonged HD^[7]
- Consider if:
  - pH <7.1
  - Renal insufficiency
- Mortality benefits mainly from improving acidosis than from removing Metformin

↑ Goldfrank, Lewis R. Goldfrank's Toxicologic Emergencies. 9th Ed. New York: McGraw-Hill, 2011
↑ Seidowsky, A., Nseir, S., Houdret, N., & Fourrier, F. (2009). Metformin-associated lactic acidosis: a prognostic and therapeutic study. Critical care medicine, 7, 2191–2196.
↑ Dell'Aglio, D. M., Perino, L. J., Kazzi, Z., Abramson, J., Schwartz, M. D., & Morgan, B. W. (2009). Acute metformin overdose: examining serum pH, lactate level, and metformin concentrations in survivors versus nonsurvivors: a systematic review of the literature. Annals of emergency medicine, 6, 818–823.
↑ Dodda V and Spiro P. Albuterol, an Uncommonly Recognized Culprit in Lactic Acidosis. Chest. 2011;140.
↑ Kruse, J. A. (2001). Metformin-associated lactic acidosis. The Journal of emergency medicine, 3, 267–272.
↑ Barrueto, F., Meggs, W. J., & Barchman, M. J. (2002). Clearance of metformin by hemofiltration in overdose. Journal of toxicology. Clinical toxicology, 2, 177–180.
↑ Rifkin, S. I., McFarren, C., Juvvadi, R., & Weinstein, S. S. (2011). Prolonged hemodialysis for severe metformin intoxication. Renal failure, 4, 459–461.