Metformin-Associated Lactic Acidosis (MALA): Case Files of the Einstein Medical Center Medical Toxicology Fellowship

Abstract

A 39-year-old man presented to the emergency department after intentionally ingesting 50 tablets of metformin 1,000 mg. The reported time of ingestion was 6 h prior to arrival. Vital signs were: temperature, 37.4°C; pulse, 94 beats per minute; blood pressure, 117/74 mmHg; respirations, 16/min; and oxygen saturation, 96 % on room air. Gastric lavage was performed, and a single dose of activated charcoal was given. His initial serum lactate was 4.3 mmol/L (normal00.67-1.8 mmol/L). The patient had a negative urine drug screen, and acetaminophen and salicylate levels were below detection limits. The patient was admitted for monitoring of lactic acidosis.Twenty hours after arrival, the patient became hypotensive with a blood pressure of 85/45 mmHg. Arterial blood gas analysis revealed a pH of 7.20, pCO 2 19 mmHg, and bicarbonate HCO 3 of 6 mmol/L. A repeat serum lactate at this time was 20 mmol/L, and a basic metabolic panel showed sodium of 134 mmol/L, potassium 3.8 mmol/L, chloride 98 mmol/L, bicarbonate 16 mmol/L, BUN 32 mg/ dL, and creatinine 1.3 mg/dL; the calculated anion gap was 20 mmol/L. A 1-L normal saline bolus was administered, and serum alkalinization was initiated with a sodium bicarbonate drip.

Metformin-Induced Lactic Acidosis with Emphasis on the Anion Gap

“…Biguanides also decrease hepatic metabolism of lactate and have a negative ionotropic eff ect on the heart, both of which elevate lactate levels (11). Metformin dose, along with the duration of exposure from accumulation in patients with decreased renal clearance, can cause lactic acidosis (3). Gradual toxicity, as demonstrated in our patient, is usually multifactorial and related to the drug's decreased renal excretion.…”

The Role of Renal Replacement Therapy in the Management of Pharmacologic Poisonings

“…Besides treatment of type 2 diabetes mellitus and prediabetes, it is often used in the management of polycystic ovarian syndrome [59]. Metformin's mechanism of action includes decreased hepatic and intestinal gluconeogenesis, enhanced glucose utilization, and modulation of mitochondrial oxidation of fatty acids [20, 59]. The majority of overdose cases occur in patients with renal disease (either acute or chronic), advanced liver disease, and acute concurrent illness [20].…”

“…Metformin's mechanism of action includes decreased hepatic and intestinal gluconeogenesis, enhanced glucose utilization, and modulation of mitochondrial oxidation of fatty acids [20, 59]. The majority of overdose cases occur in patients with renal disease (either acute or chronic), advanced liver disease, and acute concurrent illness [20]. Metformin was responsible for 8,829 toxicities including 12 fatalities in the year 2013 [1].…”

“…The pharmacokinetics of metformin are generally favorable for hemodialysis and extracorporeal elimination such as a low molecular weight and minimal protein binding except with high volume of distribution [20, 21]. Clinical manifestations of metformin poisoning are nonspecific and may include gastrointestinal symptoms such as nausea, vomiting, diarrhea, abdominal pain, altered mental status, and hemodynamic instability.…”

“…Laboratory features of metformin poisoning include a high anion gap metabolic acidosis due to accumulation of lactic acid. The initial mechanism of lactic acidosis involves modulation of gluconeogenesis [20]. However, later, hemodynamic deterioration may underlie the perpetuation of lactic acidosis.…”