A 76-year-old woman presented to the ED with altered mental status. Her family said she had increasing fatigue for two days. That morning, the patient had nausea, vomiting, and shoulder pain. EMS found she had a blood glucose of 34. She was given an ampule of D50 and brought to the ED.
The patient reported dizziness and fatigue in the ED, and stated that she had not eaten for a few days. Her initial vital signs included temperature 94.1℉, pulse 76 bpm, blood pressure 120/67 mm Hg, respiratory rate 18 bpm, and pulse oximetry 99% on room air. Her physical examination is unremarkable.
Initial laboratory values are remarkable for a pH 6.97, HCO3 4, PCO2 18, and lactate 13.5. Initial BMP was remarkable for a HCO3 5, BUN 75, creatinine 5.78, and an anion gap of 30. CBC demonstrated a WBC of 27.1, Hb 12.3, Hct 38.6, and Plt-395. The family said the patient had diabetes and Parkinson's disease. Her medications include sitagliptin, rosuvastatin, telmisartan, and metformin.
Differential for Elevated Lactic Acidosis
- Cyanide poisoning
- Metformin Associated Lactic Acidosis (MALA)
- Propylene glycol toxicity
- Antiretroviral drugs
- Erroneously elevated lactate levels due to interference of the assay with ethylene glycol
Metformin is a commonly prescribed medication for diabetes mellitus. It is in the biguanide class of medications, which maintain euglycemia by inhibiting gluconeogenesis, enhancing peripheral glucose uptake and increasing intestinal use of glucose. Metformin does not undergo hepatic metabolism and is mainly eliminated renally. It is not protein bound and has a volume of distribution of 3 L/Kg.
Acute overdose may present as abdominal pain, vomiting, and diarrhea. The remaining clinical manifestations are secondary to the profound lactic acidosis and include altered mental status, tachypnea, hypotension, hypothermia, shock, and death. MALA refers to a blood lactate concentration > 5 mmol/L and a pH < 7.35.
Metformin toxicity can lead to hyperlactatemia by inhibiting lactate conversion to glucose in the hepatocytes, which leads to elevation of lactate causing a decrease in hepatocellular pH. This decrease in pH then inhibits the lactate uptake by the hepatocytes.
MALA may occur from an acute intentional overdose or therapeutic chronic dosing. In acute overdose, the lactic acidosis is often delayed in presentation and can occur as far out as 24 hours after ingestion. During chronic therapy, there is a small but significant risk for MALA often precipitated by renal insufficiency or illness leading to renal failure (i.e., sepsis, alcohol abuse, liver disease, ischemia or shock, use of radiologic contrast media). Mortality from MALA ranges between 30 and 50 percent.
The management for an acute overdose is slightly different from chronic toxicity in that these patients may have some nausea and vomiting but appear well. The lactic acidosis may not appear until eight hours and in some cases as long as 20-24 hours out from ingestion. In cases where patients report a large ingestion, patients should be administered activated charcoal, serial lactate levels should be obtained every four hours, and the patient should be admitted for observation.
When the patient already has a metabolic acidosis with elevated lactate levels, treatment is resuscitation with good supportive care. A bicarbonate infusion can be administered to help reverse acidemia, and if the acidosis and lactatemia are severe enough, dialysis is recommended.
The indications for extracorporeal treatments (ECTR) in patients with MALA (from the Extracorporeal Treatments in Poisoning Workgroup) are:
- ECTR is indicated if:
- Lactate >20 mmol/L
- Blood pH <7.0
- Standard therapy fails
ECTR is suggested when:
- Lactate >15.0-20.0 mmol/
- Blood pH <7.0-7.1
- Comorbid conditions that lower the threshold for dialysis: Impaired kidney function, shock, decreased level of consciousness, and liver failure
Cessation of ECTR:
- Lactate <3.0 mmol/L
- pH >7.35
The patient was started on a bicarbonate infusion, and nephrology was consulted for hemodialysis. She was actively warmed with a bear hugger and warm IV fluids and was administered antibiotics for suspected sepsis. The patient received four days of intermittent hemodialysis, and creatinine improved to 2.25. She was discharged home with close follow-up with nephrology and metformin was removed from her medication list.
1. Calello DP, et al. Extracorporeal Treatment for Metformin Poisoning: Systematic Review and Recommendations from the Extracorporeal Treatments in Poisoning Workgroup." Crit Care Med 2015;43(8):1716.
2. Spiller HA, Sawyer TS. Toxicology of Oral Antidiabetic Medications. Am J Health Syst Pharm 2006;63(10):929
3. Nelson L, ed. Goldfrank's Toxicologic Emergencies. New York: McGraw-Hill Medical, 2011.