Metformin toxicity causes a profound lactic acidosis and can be concerning in patients with existing kidney impairment.
Case Presentation
A 70-year-old man presented to the emergency department with significant chest and upper abdominal pain. He described the pain as intense pressure and reported he felt short of breath as well. He denied any diarrhea, no rash, and no changes in medication. He reported he had been feeling unwell for some time with some nausea and vomiting, but it worsened on the day of presentation with the new chest pressure and upper abdominal pain. His past medical history is significant for prostate cancer, coronary artery disease requiring stents, diabetes, and prior strokes.
On examination, the patient appeared ill and in acute distress. His skin was pale and capillary refill was delayed. He was tachypneic, but without wheezing or rhonchi. His abdominal exam revealed a soft but diffusely tender abdomen. He had no focal neurologic deficits, and his cardiac exam was benign.
CTA dissection was negative. Initial ED lab work-up revealed a significant metabolic acidosis with an anion gap of 29 and lactate of 7.7, severe acute kidney injury with Creatinine 5.38, beta-hydroxybutyrate >8.0, and elevated lipase of 136. While in the ED, the patient had worsening respiratory distress and intubation was completed due to respiratory failure. Prior to intubation, he was initiated on bicarb and D5W drips and given 2 cc of push dose epi for lower-than-normal blood pressure as well as 3 amps of bicarb. Following intubation, the patient was admitted to the ICU on a propofol drip for severe metabolic acidosis and to initiate dialysis. While admitted, the patient was found to have an initial presentation due to metformin toxicity.
Discussion
Metformin rarely causes hypoglycemia, but it can cause a profound lactic acidosis in overdose, especially in patients with preexisting renal failure. In healthy individuals, the kidneys can excrete excess lactate in the urine. However, in patients with kidney failure, there is an impaired ability for this function to occur, thus lactate builds up in the body and causes a significant metabolic acidosis.
Acutely worsening kidney function can be due to an underlying cause, such as sepsis, and must be evaluated further. Those with chronic kidney disease are at risk of shock and death in as little time as a few hours if the acidosis is not addressed appropriately.
Metabolic acidosis can either fall into the category of non-anion gap or high anion gap metabolic acidosis. This is calculated by subtracting the chloride and bicarb from the serum sodium. An elevated anion gap is defined as AG > 22 and is concerning because many causes of this are immediately life-threatening, whereas most causes of non-anion gap metabolic acidosis are non-life threatening.
Causes of an elevated anion gap metabolic acidosis (AGMA) can be easily remembered using the pneumonic MUDPILES CAT:
- Methanol
- Uremia
- DKA
- Paraldehyde
- Iron/Isoniazid
- Lactic acidosis
- Ethanol/Ethylene glycol
- Salicylate/ASA
- Carbon monoxide
- Aminoglycosides
- Theophylline
Metformin toxicity causes a profound lactic acidosis, placing it among the causes of MUDPILES. Once it has been established that an AGMA exists, further calculations regarding the bicarbonate, delta delta, and if there is appropriate respiratory compensation can be determined as well to aid in management of the condition.
The human body will initially attempt to compensate for the high levels of lactic acid by blowing off excess amounts of carbon dioxide via hyperventilating. As time goes on, the body will tire, causing normal to elevated levels of CO2 to accumulate and ultimately worsen the acidosis. Poor respiratory effort is pertinent physical exam finding to be aware of and can be reason itself for intubation. Mechanical ventilation can then be used as an additional tool for metabolic acidosis therapy. Optimal ventilator settings for treating AGMA include a high respiratory rate (RR) and low tidal volumes (TV). The high RR will aid in excretion of CO2 while the low TV will decrease the potential CO2 stores within the lungs themselves.
Supportive care and correcting the acidosis are key components to treating the shock and metabolic acidosis caused by metformin toxicity. If a patient presents within 2 hours of ingesting >10 grams of metformin, charcoal can be considered as therapy. The mainstay of treatment for this is vasopressors and, in severe cases, hemodialysis or continuous renal replacement therapy (CRRT) may be required to remove the lactate and metformin from circulation.
Although uncommon, shock in the setting of metformin toxicity can cause refractory shock, in which the severity of vasodilation is unresponsive to fluid resuscitation, high-dose vasopressors, oxygenation, and ventilation. In such cases, AV ECMO has been used as a modality of treatment for extracorporeal removal of toxins.
In contrast, in very mild cases of metformin toxicity, it would be appropriate for patients to be observed for at least 8 hours and recheck of labs including lactate, blood gas, and CMP. In most cases, however, admission to the ICU for enhanced elimination of lactate and metformin with optimal ventilatory settings and treatment of shock is required.
Case Conclusion
The patient was diagnosed with severe metabolic acidosis secondary to metformin toxicity in the setting of acute renal failure. He received renal replacement therapy (RRT) and dialysis while admitted with improvement in his condition and was extubated two days after admission. A tunneled dialysis catheter was placed on hospital day 13 and the patient was discharged with outpatient dialysis in place. His twice daily metformin was discontinued, and daily sitagliptin was substituted in its place.
Further Reading
- Barola S, Shabbir N. Refractory Shock. [Updated 2023 Aug 17]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024.
- Chu J, Stolbach A. Metformin Poisoning. In: Hendrickson, Ganetsky, eds. UpToDate. Accessed on September 21, 2024.
- Duong JK, Furlong TJ, Roberts DM, Graham GG, Greenfield JR, Williams KM, Day RO. The Role of Metformin in Metformin-Associated Lactic Acidosis (MALA): Case Series and Formulation of a Model of Pathogenesis. Drug Saf. 2013; 36(9):733-746.
- Frakes MA, McWade J, Ender V, Cohen JE, Wilcox SR. Ventilator Management in Metformin-Associated Lactic Acidosis: A Case Report. Air Med J. 2023;42(4):300-302.
- Lodeserto F. Simplifying Mechanical Ventilation – Part 3: Severe Metabolic Acidosis. REBEL EM. June 18, 2018.
- Pearlman BL, Fenves AZ, Emmett M. Metformin-associated lactic acidosis. Am J Med. 1996;101(1):109-10.
- Van Berlo-van de Laar IRF, Gedik A, van 't Riet E, et al. Identifying patients with metformin associated lactic acidosis in the emergency department. Int J Clin Pharm. 2020;42(5):1286-1292.
- Young P. CATMUDPILES. Life in the Fast Lane. November 3, 2020.