Intended for healthcare professionals

Endgames Case Report

Life threatening lactic acidosis

BMJ 2010; 340 doi: https://doi.org/10.1136/bmj.c857 (Published 25 March 2010) Cite this as: BMJ 2010;340:c857
  1. M Lemyze, specialist registrar in critical care medicine1,
  2. J F Baudry, specialist registrar in critical care medicine2,
  3. F Collet, specialist registrar in critical care medicine2,
  4. N Guinard, specialist registrar in critical care medicine2
  1. 1Department of Critical Care Medicine, Schaffner Hospital, 62300 Lens, France
  2. 2Department of Critical Care Medicine, Broussais Hospital, 35400 Saint Malo, France
  1. Correspondence to: M Lemyze malcolmlemyze{at}yahoo.fr

    An 83 year old woman with diabetes presented to the emergency department with progressive shortness of breath and a two week history of diarrhoea. Her drugs included aspirin, 75 mg four times a day; a combination of irbesartan with hydrochlorothiazide, 300/25 mg four times a day; and metformin, 1000 mg three times a day. She had no previously known renal insufficiency, but on arrival she was oliguric, disoriented, and confused.

    Her respiratory rate was 32 breaths/min, blood pressure was 76/46 mm Hg, heart rate was 125 beats/min, and rectal temperature reached 36.8°C. She had cool and clammy extremities and a persistent skinfold—additional evidence of severe dehydration. Arterial blood gases showed a profound lactic acidosis, with pH 6.72, partial pressure of carbon dioxide (PCO2) 14 mm Hg, partial pressure of oxygen (PO2) 106 mm Hg, bicarbonate 12 mmol/l, and a high lactate concentration of 17.4 mmol/l. Laboratory results showed a normal blood glucose concentration of 9 mmol/l, a serum urea of 22 mmol/l, a serum creatinine of 779 μmol/l, an increased serum potassium concentration of 6.8 mmol/l, and a decreased prothrombin activity of 43% (prothrombin time of 21 seconds). Chest and abdominal examination, chest radiography, urine dipstick, plasma C reactive protein (<5 mg/l), and procalcitonin (<0.5 μg/l) concentrations showed no evidence of an infection.

    Questions

    • 1 What are the differential diagnoses in severe lactic acidosis?

    • 2 What is the most likely diagnosis?

    • 3 What is the prognosis of this acute critical illness?

    • 4 How should this patient be managed?

    Answers

    1 What are the differential diagnoses in severe lactic acidosis?

    Short answer

    In the differential diagnosis of severe lactic acidosis, poor tissue perfusion and oxygenation are the main considerations, and these occur in septic shock, acute heart failure, unrecognised bowel ischaemia, and acute liver failure. Some drugs can also cause life threatening lactic acidosis, especially metformin and nucleoside reverse transcriptase inhibitors.

    Long answer

    As originally described by the Cohen-Woods classification, lactic acidosis is subdivided into type A, in which the underlying mechanism is inadequate oxygenation of tissues, and type B, which includes all causes not associated with tissue hypoxia (box 1).1 When diagnosing the cause of severe metabolic lactic acidosis in a critically ill patient, hypoxaemia and poor tissue perfusion should be the main consideration; these occur in septic shock, acute heart failure, unrecognised bowel ischaemia, and acute liver failure. Of the many drugs implicated in lactic acidosis, metformin is the most common (box 1).

    Classification of causes of lactic acidosis1

    Type A
    • Poor tissue perfusion

    • Shock (hypovolaemic, cardiogenic, haemorrhagic, or septic)

    • Acute hypoxaemia

    • Carbon monoxide poisoning

    Type B1
    • Renal failure

    • Diabetes

    • Liver disease

    • Infection (especially AIDS)

    • Leukaemia, lymphoma, large tumours

    • Thiamine deficiency in alcohol misuse (inhibition of pyruvate dehydrogenase)

    Type B2
    • Ingestion or administration of drugs or other toxic substances:

      • •Metformin

      • •Antiretroviral treatment for HIV infection with nucleoside analogue reverse transcriptase inhibitors

      • •Cancer chemotherapy

      • •Ethanol

      • •Toluene

      • •Sorbitol

      • •Salicylates

      • •Isoniazid

      • •Nitroprusside

      • •Cyanide

    Type B3
    • Hereditary forms:

      • •Glucose-6-phosphate deficiency (type I glycogenosis)

      • •Fructose-1,6-diphosphatase deficiency

      • •Pyruvate carboxylase deficiency

      • •Pyruvate dehydrogenase deficiency

      • •Deficiencies of oxidative phosphorylation

      • •Methylmalonicaciduria

    2 What is the most likely diagnosis?

    Short answer

    The most likely diagnosis is incidental metformin associated lactic acidosis. This was caused by diarrhoea induced dehydration associated with drug induced acute kidney injury, which resulted in acute renal failure and accumulation of the metformin.

    Long answer

    Metformin is used worldwide to treat type 2 diabetes. It improves insulin sensitivity and decreases insulin resistance in patients with non-insulin dependent diabetes, thereby improving morbidity and mortality.2 Metformin is now the most popular antidiabetic drug in the United States—with more than 40 million prescriptions filled in 2008 for generic metformin alone—and it is also one of the most commonly prescribed oral glucose lowering drugs in Europe.3 4 However, its main contraindications and precautions for use should be strictly respected (box 2). Use of metformin in patients with these major contraindications or those who develop acute renal failure because of sepsis, drug induced acute kidney injury, or severe dehydration may lead to metformin associated lactic acidosis. This condition is a rare (estimated incidence <0.01-0.09 cases/1000 patient years) but life threatening toxicological emergency.4 Unfortunately, metformin continues to be prescribed to half of patients at high risk of lactic acidosis.5

    Metformin associated lactic acidosis is a clinical diagnosis that is based on the recognition of the rapid onset of severe lactic acidosis (>5 mmol/l). It can result from attempted suicide using an overdose of metformin or from an accumulation of the drug because of acute renal failure. The first situation is rare—most cases of metformin associated lactic acidosis are caused by incidental overdoses.6 7 The diagnosis of metformin associated lactic acidosis is an emergency, and treatment should not be delayed until confirmation with a metformin bioassay. Half of patients are in circulatory shock and need vasoactive support at admission, 45% need mechanical ventilation, 74% develop acute renal failure, and 15% have severe neurological dysfunction.6 Consequently, the diagnosis can be made only after exclusion of other sources of shock. In our case, septic shock, cardiogenic shock, obstructive shock, and hypovolaemic shock were ruled out. However, hypotension and myocardial depression, which are usually present in the most severe cases, may be misleading. In addition, sepsis is a commonly associated confounding factor that precipitates acute renal failure and metformin overdose.

    Box 2 Absolute contraindications and precautions for prescribing metformin4

    Contraindications
    • Renal dysfunction

    • Congestive heart failure requiring drug treatment

    • Acute or chronic metabolic acidosis

    • Liver disease as shown by abnormal liver function tests

    • Use of intravenous radiographic contrast agents

    Precautionary conditions
    • Age over 80 years

    • Excessive alcohol intake

    • Presence of any conditions associated with hypoxaemia, dehydration, or sepsis

    • Concomitant use of nephrotoxic drugs

    The pathogenesis of metformin associated lactic acidosis is unclear. The condition is thought to result from an intracellular shift to anaerobic metabolism coupled with impaired utilisation of glucose due to suppression of gluconeogenesis. Metformin can affect the respiratory chain and alter oxidative phosphorylation to yield large quantities of lactate.8 Moreover, metformin can directly harm hepatocytes and thereby impair the process by which lactate is normally removed from the body.9

    3 What is the prognosis of this acute critical illness?

    Short answer

    Incidental metformin associated lactic acidosis is a life threatening toxicological emergency. It carries a poor prognosis, with mortality approaching 50%.

    Long answer

    Incidental metformin overdose has a worse prognosis (mortality approaching 50%) than intentional metformin overdose, after which patients usually recover well.6 10 Box 3 lists the factors known to be associated with mortality in this condition.6 11

    Box 3 Initial factors associated with mortality in severe metformin associated lactic acidosis6

    • Age over 60 years

    • Incidental (rather than intentional) metformin overdose

    • Presence of shock and the need for vasopressors at admission

    • Receipt of mechanical ventilation

    • Multiple organ failure (assessed by a high total logistic organ dysfunction system (LODS) score)11

    • Renal LODS score ≥4 points

    • Arterial lactate ≥15 mmol/l

    • pH ≤7.2

    • Prothrombin activity ≤50%

    4 How should this patient be managed?

    Short answer

    Successful treatment of metformin associated lactic acidosis depends on early admission to the intensive care department to ensure supportive care (haemodynamic and ventilatory support) coupled with prompt renal replacement therapy.

    Long answer

    Treatment of severe metformin associated lactic acidosis is a challenge. It is based on early recognition of the diagnosis, which should lead to prompt renal replacement therapy combined with vigorous resuscitation.

    The patient should be admitted promptly in an intensive care unit. There, the mainstay of management includes supportive care with oxygen supplementation, fluid resuscitation, and vasoactive drugs to restore cardiac output and maintain tissue perfusion and oxygenation. In case of circulatory shock or acute respiratory failure, endotracheal intubation should be performed and mechanical ventilation must be instituted. Because septic shock is common in this situation, empirical broad spectrum antibiotics must be given immediately. Detoxification by activated charcoal is probably useless in the clinical course of prolonged metformin usage. The use of buffer therapy (bicarbonate infusions) is controversial because it is associated with excess sodium load, rebound metabolic alkalosis, disturbances in serum potassium and calcium, impaired cardiac contractility, and worsening of intracellular acidosis.12 To ensure that metformin and lactate are removed rapidly, haemodialysis with a bicarbonate buffered replacement fluid is still the most reliable method of renal replacement therapy and should be part of the first line treatment.6 10 12 Haemodialysis may reduce morbidity and mortality in the most serious cases of metformin associated lactic acidosis.10 13 Most authors recommend a prolonged duration of haemodialysis, and the one therapeutic study in this area reported a mean duration of 13 (standard deviation 9) hours.6 In our patient, haemodialysis was more efficient than continuous veno-venous haemofiltration (CVVHF) at rapidly removing metformin and lactate from the central plasmatic compartment. In addition CVVHF was followed by a rebound in metformin plasma concentrations and a new increase in lactate concentration (figure). Using continuous renal replacement therapy like CVVHF instead of conventional haemodialysis for the sole purpose of improving haemodynamic tolerance in critically ill patients is controversial, especially when the cause of the haemodynamic instability can be more rapidly removed from the body by haemodialysis. However, in our case, CVVHF may have failed to reverse lactic acidosis because the ultrafiltration rate was too low (35 ml/kg/h). One reported intentional metformin overdose was successfully treated with haemodialysis followed by high volume CVVHF.14 The authors of the report described the same haemodynamic instability and concomitant further rise in lactate concentration under CVVHF, leading them to use two CVVHF machines and two femoral catheter accesses to increase the ultrafiltration rate to 5 l/h. Ultrafiltration and diffusion (dialysis) can be combined by using continuous veno-venous haemodiafiltration (CVVHDF), which can double or triple solute clearance compared with CVVHF and be a simpler way to relay initial haemodialysis, as shown here (figure).

    Figure1

    Serum concentrations of lactate and metformin and pH monitoring during the different renal replacement treatments. Note that conventional haemodialysis is the most efficient technique to remove lactate and metformin and to correct acidosis. HD=haemodialysis; CVVHF=continuous veno-venous haemofiltration; CVVHDF=continuous veno-venous haemodiafiltration

    A therapeutic strategy combining prompt haemodialysis with intensive resuscitation that involves haemodynamic support and ventilatory support is still the key to recovery.6 10

    Patient outcome

    Our patient developed extensive ventilator acquired pneumonia, which led to acute respiratory distress syndrome with profound and refractory hypoxaemia. She survived and was discharge at day 14 with no serious sequelae even though at admission she had all the factors associated with mortality in severe metformin associated lactic acidosis. After this event metformin was contraindicated for the rest of her life.

    Notes

    Cite this as: BMJ 2010;340:c857

    Footnotes

    • Competing interests: None declared.

    • Patient consent obtained.

    • Provenance and peer review: Not commissioned; externally peer reviewed.

    References