Metformin-associated lactic acidosis

Background

Metformin is a commonly prescribed medication. Patients and clinicians must be educated about the potentially lethal complications of continuing its use when unwell.

Case presentation

A 58-year-old female was brought to the emergency department by ambulance. She had a background of established tablet-controlled type 2 diabetes mellitus, hypertension, appendicectomy and gastric banding. She was a non-smoker, had minimal alcohol intake, was functionally independent and working as a carer.

She had a history of diarrhoea and vomiting for the preceding 8 days, poor oral intake and, more recently, minimal urine output. She had been complaining of abdominal pain for which she had been taking diclofenac.

When the pain became severe, her daughter called for an ambulance. She was found by paramedics to have a blood glucose of 2.5 mmol/L, which they treated with intravenous dextrose. She was hypotensive with a blood pressure (BP) of 86/50 mmHg, centrally cyanosed and clammy. She was brought into the emergency department (ED) as a ‘standby sepsis’.

Initial assessment revealed the following:

Airway: Own.

Breathing: Respiratory rate 36 breaths/min, hypoxic with oxygen saturation (SpO₂) 72% on 15 L/min via non-rebreather mask.

Cardiovascular: BP 70/50 mmHg, heart rate (HR) 70 beats/min, thready radial pulse, cool and mottled peripheries.

Disability: Agitated, blood glucose 7.8 mmol/L, pupils equal and reactive.

Exposure: Temperature 32°C, abdomen soft but globally tender, bowel sounds present.

Her initial arterial blood gas (ABG) showed a profound metabolic acidosis: pH 6.6, pCO₂ 2.6 kPa, pO₂ 12.3 kPa, Base Excess −33.6 mmol/L, HCO₃ ^– 3.4 mmol/L and lactate 14 mmol/L. Management by the ED team included oxygen, intravenous access, intravenous crystalloid and empirical antibiotics. She appeared to be peri-arrest. The ED registrar performed a Focused Assessment with Sonography for Trauma (FAST) scan, which was negative. At this point, their differentials were as follows:

(1) intra-abdominal sepsis and (2) surgical cause (possible perforation). The critical care, anaesthetic and surgical teams were called.

During positioning for a chest X-ray (CXR), she became bradycardic, then asystolic. Return of spontaneous circulation (ROSC) was achieved after one cycle of cardiopulmonary resuscitation. Immediately post-ROSC, her observations improved (BP 131/54 mm Hg, HR 71 beats/min and sinus rhythm). However, as she became increasingly agitated and combative, the decision was made to proceed with intubation and ventilation to enable effective treatment. A delayed sequence induction was performed, using ketamine and a phenylephrine infusion. She was cardiovascularly unstable for the next hour. She was managed with intravenous fluid resuscitation, intravenous bicarbonate, hydrocortisone and calcium gluconate. Arterial and central lines were inserted and a norepinephrine infusion commenced.

Once cardiovascular stability was achieved, the following issues were considered:

1. Profound metabolic acidosis, not improving with fluids/bicarbonate. Her lactate climbed to 20 mmol/L.

2. A prolonged period of hypotension before cardiac arrest and post-induction of anaesthesia.

3. Multiorgan dysfunction (renal/metabolic/cardiovascular/neurological). No urine output until 4 L of intravenous fluids were given.

4. Hypovolaemic shock.

The postulated diagnosis at this point was metformin-associated lactic acidosis (MALA) versus intra-abdominal pathology. The report of her abdominal CT scan described possible pancolitis, but no perforation. Senior surgical review excluded the need for surgical intervention.

She was transferred to critical care. Management included further intravenous fluid resuscitation, norepinephrine and vasopressin and continuous veno-venous haemodiafiltration (CVVHDF). Her ketones were noted to be 6.2 mmol/L (possibly related to poor oral intake), for which a fixed-rate intravenous insulin infusion was started. Empirical antibiotics were continued. Her metabolic acidosis vastly improved within 24 hours.

Discussions with family confirmed that she had been unwell for the preceding week, with poor oral intake, but she had continued to take her medication (including metformin 1 g twice daily, gliclazide, ramipril and diclofenac).

Investigations

Blood results (reference values shown in brackets)

Initial ABG: pH 6.6 (7.35–7.45), pCO₂ 2.6 kPa (4.5–6.0), pO₂ 12.3 kPa (>10),

BE −33.6 mmol/L (−2 to +2), HCO₃ ^– 3.4 mmol/L (22–26) and lactate 14 mmol/L (<1.3).

Inflammatory markers: White cell count 12.5×10⁹/L (4–11), C-reactive protein 14 mg/L (<4).

Urea and electrolytes: Na 132 mmol/L (135–145), K 6.0 mmol/L (3.5–5.3), urea 54 mmol/L (2.5–7.8), Cr 1057 μmol/L (45–90), glucose 7.7 mmol/L (4–6 fasting) and ketones 6.2 mmol/L (<0.6).

Liver function tests: mildly elevated.

Imaging

CXR: nil focal.

CT abdomen: possible pancolitis.

Differential diagnosis

MALA—most likely diagnosis in view of history and investigations.

Intra-abdominal sepsis or perforation—important to consider in view of abdominal pain, cardiovascular instability, raised lactate and hypothermia. No evidence of perforation or collection on CT.

Euglycaemic diabetic ketoacidosis in the presence of sepsis—more commonly associated with sodium-glucose cotransporter-2 inhibitors, which were not present in this case.

Treatment

Withhold metformin and other nephrotoxins.

Intravenous fluids.

Vasopressors.

Intravenous bicarbonate.

Renal replacement therapy.

Insulin.

Ventilatory support as required.

Outcome and follow-up

The patient required CVVHDF for 3 days. She was successfully extubated on day 6. Despite developing a ventilator-associated pneumonia, she was well enough to be discharged to a medical ward on day 14, then home on day 16.

She was provided with information on MALA and given advice about pausing treatment in the future when unwell. She has not had any further similar episodes.