emDOCs Podcast – Episode 131: Metformin Toxicity

Terminology

• Metformin is one of the most prescribed medications for diabetes mellitus and is generally considered safe.
• There are several major adverse events; most serious complication is metformin-associated lactic acidosis (MALA). Mortality rates for MALA can reach up to 25-50%
• 2017 study proposed a spectrum of metformin toxicity with 3 clinical conditions: MALA, metformin-induced lactic acidosis (MILA),and metformin-unrelated lactic acidosis (MULA).

Pathophysiology

• Metformin inhibits hepatic gluconeogenesis, it decreases intestinal glucose absorption, and it increases insulin sensitivity.
• Metformin oral bioavailability 40-60% and is absorbed within 6 hours of ingestion. Half-life of 2-9 hours. Once absorbed, 90% renally excreted unchanged.
  • Therapeutic concentration of metformin is 0.5-3 mg/L.
  • Lethal plasma concentration is > 50 mg/L; toxic dose is > 5 g in adults and > 100 mg/kg in pediatric patients.
• Patients with significant renal disease have a prolonged half-life of metformin and are at greater risk of metformin toxicity.
• Most common adverse events associated include nausea, vomiting, and diarrhea,
• For every 100,000 patient-years of exposure to metformin, there are approximately 10 events of severe MALA with mortality rates reaching 50%.
• Metformin raises lactate: electron transport chain inhibitor, which limits ATP production. NADH increases; pyruvate converted to lactate.

What’s the difference between metformin-induced lactic acidosis, metformin-associated lactic acidosis, and metformin-unrelated lactic acidosis?

• All have lactic acidosis.
• MILA: exclusively related to metformin and occurs when high serum levels of metformin are the issue. Metformin is the primary driver of the lactic acidosis here. Usually occurs in patients with renal failure who are taking metformin chronically or in patients without renal failure who are naïve to methform with massive acute overdose. Serum concentrations of metformin > 5 mg/L.
• MALA: highest mortality rate. A critical condition (e.g., sepsis, cardiogenic shock, stroke) develops in a patient on metformin. Not an acute overdose of metformin. Metformin increases the degree of lactic acidosis, but only as a contributor. Metformin concentrations can be higher than 5 mg/L.
• MULA: elevated lactic acid with low or therapeutic metformin concentrations (< 5 mg/L). Lactic acidosis is the product of another disease.
• Differentiating these entities is Metformin concentrations are usually send outs and can take several days to result.
• Key: Consider MILA, MALA, and MULA based on risk factors in the patient’s history.
  • Think MILA or MALA if the high lactate level does not make sense otherwise or if the number is significantly elevated .

What findings can suggest metformin toxicity?

• History is major driving factor. Does the patient take metformin? Was this an intentional overdose? Is there some other sort of condition or disease like sepsis or some other shock state? If no intentional ingestion, likely MALA.
• Presentation: GI symptoms typically predominate (n/v, diarrhea, pain), hypothermia, hypotension (may be refractory to vasopressors), may be altered.
• Risk factors for MALA: alcohol use, chronic hypoxia, sepsis, advanced age, dehydration, renal dysfunction, and shock.
• Labs: serum glucose, blood gas, chemistries, liver function, coag panel, lactate, beta hydroxybutyrate.
• Double digit lactate and single digit serum bicarbonate may be present.
• PT value < 50% normal, lower pH (<7), higher lactate (>15) associated with worse outcomes in acute intoxication.

What other conditions must be considered, and what conditions may result in single digit bicarbonate and double-digit lactate concentrations?

1. Medications associated with severe lactic acidosis:

2. Medical conditions associated with severe lactic acidosis:

3. Laboratory error and interference (ethylene glycol intoxication). Most common with using point of care lactate versus serum lactate testing, as POC testing may not be able to differentiate the metabolites of ethylene glycol, glycolate, and glyoxalate (structurally similar to lactate). Serum testing of lactate does not have this issue.

What are the detailed components of management?

• The key components of management: consult toxicology and nephrology, treat any concomitant conditions like sepsis, IV dextrose if needed, resuscitation with fluids, bicarbonate infusion in select patients, and HD.
• Activated charcoal can play a role in acute overdose.
• Check fingersticks regularly and provide IV dextrose if low.
• IV fluids are the mainstay of treatment for undifferentiated shock. Target euvolemia.
  • No one fluid that is superior. NS is associated with hyperchloremic metabolic acidosis. LR can be an issue because these critically ill patients cannot metabolize lactate efficiently. Plasmalyte or normosol contain acetate (normally metabolized into bicarbonate via the Krebs cycle)
  • Compromise may be using D5W with ½ NS plus one amp of bicarb per liter. Another option is NS and isotonic bicarb together, with the NS infused about 6 times faster than the bicarb. This produces an isotonic solution with a bicarb concentration of 25.
  • Summary: even with the issues, balanced fluids are likely best.
• Bicarbonate is more strongly recommended for those with pH < 7 and if the serum bicarbonate is extremely low while waiting for HD.
• HD is potentially a key therapy.
  • Metformin is a small molecule but has a high volume of distribution with little protein binding. This should make it a poor candidate for HD, but there are several case reports suggesting HD can be effective.
  • The 2015 Extracorporeal Treatments in Poisoning (EXTRIP) group guideline supports HD in critically ill patients based on a review of evidence. The group concluded that metformin is “moderately dialyzable” with variability relating to the type of dialysis and the patient’s renal function.
  • Main indications for HD: lactate > 20 mmol/L, serum pH <0, and failure to improve despite standard care (e.g., IV fluid resuscitation, vasopressors).
  • Comorbid conditions that lower the threshold for HD: shock, impaired renal function, liver failure, decreased level of consciousness.
  • Guidelines recommend intermittent HD with bicarbonate buffer, but CRRT may be used if HD is not available.
• Controversial treatments: GIK therapy and methylene blue.
  • Insulin may reduce lactate and ketoacid generation, but glucose and potassium supplementation are necessary if insulin is administered.
  • Euglycemic DKA can be difficult to differentiate because it can result in ketoacid production. If patients don’t improve with glucose and IV fluid, consider using IV insulin.
  • Methylene blue is an option in decompensating patients who are refractory to other therapies. May be a “metabolic rescue” in the mitochondria because it accepts electrons from NADH while transferring them to cytochrome c; also functions as a vasoconstrictor. Dosing 2 mg/kg IV over 30 minutes, followed by 0.25 mg/kg/hour IV.
  • Both GIK and methylene blue should be used only if other therapies aren’t effective.
• Respiratory: Intubation usually not necessary. If it is, use a high minute ventilation. Can start with HFNC to improve ventilation efficiency and reduce work of breathing.

What mistakes are made during the initial evaluation and resuscitation?

1. Anchoring on diagnosis of MALA and not thinking about another condition that causes elevated lactate.
2. Waiting to involve toxicology, critical care and nephrology.
3. Not repeating labs at regular intervals to ensure they improve with therapies.

Summary:

• Metformin toxicity exists along a spectrum and includes MULA, MALA, and MILA.
• Patients with metformin toxicity typically present with GI symptoms and mental status changes.
• Review the home/outpatient medications of all patients with undifferentiated “shock” to evaluate for potential causes and concomitant conditions.
• Think about metformin toxicity in patients who are critically ill on metformin. Also think about this in patients with high lactate levels who aren’t improving with your therapies.
• Make sure you run through that differential for elevated lactate: severe infection/sepsis, other toxicologic ingestion, ketoacidosis state, primary medical causes, ischemia, organ failure, and/or laboratory errors.
• Management of metformin toxicity includes involving toxicology and nephrology, treating concomitant conditions, resuscitating with IV fluids, and bicarbonate infusion and HD for select patients.

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