Heeding clues to metformin-associated lactic acidosis: prompt response can save life

Abstract

The case history is presented of a patient who developed metformin-associated lactic acidosis. The patient made a complete recovery with supportive care. Recognition of metformin-associated lactic acidosis requires a high index of suspicion, as presentation can be very subtle.

BACKGROUND

Metformin is one of the most commonly used oral hypoglycaemic drugs all over the world. Side effects of metformin are seen in up to 20% of patients, but they are minor and do not cause significant morbidity or mortality.¹ Lactic acidosis is a very rare and potentially life-threatening side effect of metformin therapy with an estimated incidence of 5 cases/100 000 patient-years. The clinical manifestations of lactic acidosis may be very subtle and may mimic various acute conditions. A case of metformin-associated lactic acidosis is presented; the patient made a complete recovery with supportive care.

CASE PRESENTATION

A 65-year-old woman with diabetes was brought to the emergency room with recent onset of epigastric pain, vomiting and syncope. She had been taking metformin in combination with sulfonylurea for the last 3 years. There was no history of fever or chest pain and no other history of systemic illness in the past.

Her physical examination revealed a pulse rate of 40 beats/min, blood pressure was not recordable, the respiratory rate was 26 breaths/min and there was mild epigastric tenderness on abdominal examination. The rest of the physical examination was unremarkable.

Laboratory examination revealed a blood glucose level of 383 mg/dl (21.26 mmol/l), absent urinary ketones, Na⁺ 139.4 mEq/l (139.4 mmol/l), K⁺ 6.2 mEq/l (6.2 mmol/l), ionised Ca²⁺ 1.210 mmol/l, blood urea 78 mg/dl (27.85 mmol/l) and total leucocyte count 15×10³/mm³ (15×10⁹/l). Arterial blood gas analysis showed pH 7.12, Po₂ 97.5 mm Hg, Pco₂ 52.2 mm Hg, HCO₃ 12.0 mEq/l (12.0 mmol/l) on inhaled oxygen through a mask and an anion gap of 21.0. The ECG revealed sinus arrest with junctional escape rhythm with an escape rate of 50–60 beats/min without ST-T changes. Troponin T was negative on two occasions 12 h apart. A chest radiograph revealed bilateral infiltrates suggestive of pneumonitis.

During her stay in the emergency room the patient required tracheal intubation and mechanical ventilation. She was treated with intravenous fluids, inotropes, antihyperkalaemic measures, parenteral antibiotics and other supportive measures. Oral hypoglycaemic drugs were stopped and blood sugar was controlled using plain insulin according to a sliding scale.

The patient showed substantial improvement during the next 72 h with restoration of normal blood pressure, haematological and biochemical parameters. The ECG reverted to normal sinus rhythm and she was extubated successfully. Echocardiography and Holter studies were normal. The serum lactate level, which was estimated after the resolution of hypotension, was 66.80 mg/dl (7.41 mmol/l) (normal range 3.00–12.00 mg/dl, 0.33–1.33 mmol/l).

Serial arterial blood gas tensions and serum lactate measurements revealed a gradual decline in high anion gap metabolic acidosis and the serum lactate level with complete normalisation on day 14, and the patient was discharged.

DISCUSSION

Commonly reported side effects of metformin are gastrointestinal disturbances such as nausea, anorexia, metallic taste, abdominal discomfort and diarrhoea, while vitamin malabsorption and lactic acidosis occur less frequently.² Lactic acidosis is a serious adverse effect of metformin treatment and is associated with mortality as high as 50%.³

Factors predisposing to the development of metformin-associated lactic acidosis are renal impairment (major risk factor), a concomitant illness like septicaemia, acute hepatic decompensation, alcohol abuse, acute myocardial infarction and cardiovascular collapse (shock), old age, use of radiological contrast media, surgery and pregnancy. However, metformin-associated lactic acidosis can also occur in the absence of any precipitating factors.⁴

The exact mechanism by which biguanides cause lactic acidosis is unknown. It has been shown that biguanides cause suppression of hepatic gluconeogenesis from lactate, decreased lactate uptake by the liver, a paradoxical increase in lactate production by hepatocytes in the acidotic state and impaired renal excretion of an acid load.⁵ In the presence of declining renal function, accumulation of metformin may occur and may lead to lactic acidosis.

Recognition of metformin-associated lactic acidosis begins with awareness of the disorder. Associated symptoms are non-specific but include malaise, somnolence, abdominal discomfort and respiratory distress. Respiratory failure requiring mechanical ventilation, hypotension and cardiac dysrhythmias—all of which occurred in our patient—have been reported previously. Some of these effects may be secondary to acidaemia. Hypoglycaemia, while not normally seen with metformin therapy, can occur in the setting of metformin-associated lactic acidosis.

Metformin levels are generally increased in metformin-associated lactic acidosis, although lactic acidosis can be seen with normal therapeutic concentrations of metformin. Haemodialysis is therefore recommended as standard treatment to enhance metformin elimination as well as to treat metabolic acidosis. Sodium bicarbonate administration has not been shown to be beneficial. Supportive care includes mechanical ventilatory support for patients with respiratory distress, a depressed sensorium or haemodynamic instability; assurance of adequate systemic perfusion; correction of fluid deficits and electrolyte abnormalities; monitoring and treatment for hypoglycaemia.

In conclusion, recognition of metformin-associated lactic acidosis requires a high index of suspicion as presentation can be very subtle. Adherence to the exclusion criteria for the use of metformin and prompt withdrawal of metformin during a concurrent illness or during the use of radiological contrast media can prevent this life-threatening complication.

LEARNING POINTS

• Metformin is the most commonly used antidiabetic drug.

• 20 % of patients experience a side effect, normally mild diarrhoea.

• Lactic acidosis is a deadly but rare side effect of metformin; it can be triggered by renal, hepatic or cardiac failure.