Metformin is a biguanide antihyperglycemic agent that is recommended as the initial drug treatment in patients with type II diabetes. Metformin toxicity can occur after acute overdose or in the setting of chronic use, particularly in patients with renal impairment, with a mortality rate as high as 30%.

1. Metformin acts by inhibiting gluconeogenesis and glycogen breakdown, decreasing glucose absorption and improving peripheral insulin sensitivity.
2. Other pharmacologic actions include inhibition of fatty acid oxidation and oxidative phosphorylation and increased intestinal lactate production.
3. Pharmacokinetics. Oral bioavailability is 55% and peak absorption occurs approximately 3 hours after ingestion but is delayed with sustained-release formulations. The volume of distribution has been reported as high as several hundred liters but is probably closer to 80 L in an adult. Elimination is entirely renal, with a half-life of approximately 2-6 hours.

1. Adults. Lactic acidosis occurred 9 hours after ingestion of 25 g of metformin by an 83-year-old, and fatal lactic acidosis and cardiovascular collapse occurred 4 hours after ingestion of 35 g by a 33-year-old.
2. Children. Based on a multicenter pediatric case series, unintentional ingestion of less than 1,700 mg is unlikely to cause significant toxicity.

1. The most common effects after acute metformin overdose are nausea, vomiting, lethargy, and abdominal pain. More serious poisoning is associated with coma, seizures, and cardiovascular collapse.
2. The most serious manifestation of both therapeutic use and in overdose is metformin-associated lactic acidosis (MALA). The risk increases in the presence of renal dysfunction. Following an acute overdose, MALA is likely to manifest within 6 hours but may be delayed.
3. Pancreatitis has been reported in both therapeutic use and overdose of metformin.
4. Hypoglycemia is not common (metformin does not increase insulin release) but has been reported, even in the absence of other hypoglycemic drugs such as sulfonylureas or insulin.

Metformin toxicity should be suspected in any patient with severe lactic acidosis.

1. Specific levels. Serum metformin levels can be measured in specialty laboratories but are not readily available in most hospitals. The therapeutic plasma concentration is 0.5-2.5 mg/L. Levels greater than 50 mg/L were associated with serious toxicity and high mortality.
2. Other useful laboratory studies. Blood gas, electrolytes, glucose, lactate, lipase, prothrombin time, creatine kinase, and renal function tests.

1. Emergency and supportive measures
   1. Maintain an open airway and assist ventilation if necessary.
   2. Treat hypotension, coma, seizures, or hypoglycemia if they occur.
   3. Closely monitor electrolytes, glucose, lactate, renal function, and serum pH.
   4. Search for and treat any underlying medical condition(s) that may have precipitated MALA (eg, sepsis, acute kidney injury).
2. Specific drugs and antidotes. No specific antidotes are available. Lactic acidosis can be treated with sodium bicarbonate; however, bicarbonate infusions alone are often ineffective and patients with severe acidosis may require hemodialysis.
3. Decontamination. Administer activated charcoal orally if conditions are appropriate (see Table I-37,).
4. Enhanced elimination
   1. Hemodialysis is recommended for correction of severe acidosis, and it also enhances the clearance of metformin. Indications include any of the following: lactate concentrations greater than 20 mmol/L, pH less than or equal to 7.0, shock, failure of supportive measures or decreased level of consciousness.
   2. Continuous renal replacement therapies can be considered if hemodialysis is unavailable or in hemodynamically unstable patients.
   3. Extracorporeal treatment should be continued until lactate is less than 3 mmol/L and the pH is greater than 7.35.
   4. Rebound lactic acidosis may occur and may require prolonged dialysis or renal replacement therapy, especially in patients with renal dysfunction.