A 35-Year-Old Woman With Shock, Pulseless Electrical Activity Arrest, and Hemodynamic Collapse

Case Presentation

A 35-year-old woman presented with 2 days of nausea, abdominal pain, and fatigue. On the day of presentation, her abdominal pain worsened, she developed progressive somnolence, and had several bouts of nonbloody, nonbilious emesis. She denied prior headache, rashes, and toxic or illicit ingestions. The patient had a medical history of diabetes mellitus type 2, hyperlipidemia, and mild cognitive delay (highly functional, maintaining a job, home, and medication responsibilities). She reported taking only simvastatin and short-acting insulin. She had an unknown adverse reaction to metformin. She was a nonsmoker and denied history of drug and alcohol use.

Physical Examination

Vitals upon arrival to the ED: 31.7°C; heart rate, 90 beats/min; 99/61 mm Hg, respiratory rate, 20; and oxygen saturation, 98% on room air. She appeared fatigued, but was easily oriented and cooperative. Over the next hour, she developed tachycardia to 115 beats/min and tachypnea to respiratory rate of 29, became more confused, and eventually minimally responsive. The remainder of her physical examination was unremarkable.

Diagnostic Studies

The patient’s laboratory levels were: hemoglobin, 10.4 g/dL; WBC, 14 ×10³/μL, 72.5% neutrophils; sodium, 138 mmol/L; potassium, 5.1 mmol/L; chloride, 85 mmol/L; bicarbonate, 5 mmol/L; creatinine, 6.68 mg/dL; BUN, 59 mg/dL; anion gap, 53; osmolar gap, 10; blood glucose, 16 mg/dL; magnesium, 1.4 mg/dL; phosphorous, 9.1 mg/dL; and ionized calcium 0.91, mmol/L. Hepatic function and coagulation panels were both normal. Beta human chorionic gonadotropin was negative, serum osmolality was 308 mOsm/kg, and lactic acid level was 21.5 mmol/L. Her arterial blood gas was pH 6.81, Pco₂, 12 mm Hg; and Po₂, 184 mm Hg. Her base deficit was 31 mmol/L. Urinalysis showed 8 WBC/high-power field, 3 RBC/high-power field, and 34 epithelial cells. ECG showed tachycardia, sinus rhythm.

What is the diagnosis?

Diagnosis: Acute metformin-associated lactic acidosis

Discussion

Metformin is a first-line therapy for diabetes mellitus, one of the most common ailments among adult patients with a prevalence between 12% and 14%, which has been rising in recent years. One of the classically taught, though rarely seen, complications of this therapy is acute metformin-associated lactic acidosis (MALA). It presents a diagnostic dilemma because high lactate levels and renal dysfunction may misguide providers into a diagnosis of septic shock.

The incidence of MALA is unknown, but is thought to be exceedingly rare, estimated at 3 to 8 per 100,000 patients using metformin per year. It is mostly associated with other preexisting comorbidities such as renal failure, hepatic failure, congestive heart failure, and dehydration; mortality is linked to underlying comorbidities rather than specifically to pH or serum metformin levels.

Metformin inhibits mitochondrial respiratory chain complex 1, increasing lactic acid production by increasing the redox state, impairing the conversion of lactate to pyruvate. In the setting of this cellular energy failure, acid-base homeostasis becomes compromised because it is maintained through energy dependent processes such as hepatic gluconeogenesis, which is itself impaired by metformin. Because of these pathophysiologic processes, patients often present with severe metabolic acidosis, lactic acid levels well above the levels typically seen in patients with other forms of shock, and hypoglycemia, often in the setting of normal or nearly normal hemodynamics. Significant hypothermia is seen in the majority of patients and is likely related to the failure of ATP-dependent metabolic processes of autothermoregulation including that of “uncoupled” mitochondrial oxidative phosphorylation as well as other thermogenic cellular activities. These hallmarks of metformin poisoning distinguish it from other forms of shock, but nonspecific symptoms of nausea, vomiting, abdominal pain, diarrhea, altered mentation, and dyspnea are common.

High suspicion for metformin toxicity should be maintained when patients show evidence of severe acidosis and markedly elevated lactate levels, particularly when out of proportion to hemodynamic parameters. Metformin levels should be sent, but these take considerable time (days to weeks) to return in many institutions, so will not be helpful during the acute phase of treatment. This serves to highlight the importance of the clinical presentation.

Initial management of MALA includes anticipating the need for an advanced airway and hemodynamic support. Severe and persistent hypotension indicates substantial ingestion and usually requires emergent hemodialysis or continuous renal replacement therapy. Prompt recognition of the correct diagnosis is imperative in patients with MALA because initiation of renal replacement therapy dramatically improves survival and is a time-sensitive intervention. Although a direct relationship between time of initiation of dialysis and mortality has not been clarified because of the difficulty in establishing the onset of MALA, quick action is vital in severe intoxications in which patients can rapidly deteriorate. Hemodialysis treats elevated metformin levels and lactic acidosis concurrently. Activated charcoal may be considered in patients who had a very recent large ingestion in the absence of contraindications, but should not delay dialysis. Dextrose and sodium bicarbonate infusion may be considered in patients with hypoglycemia or profound acidosis. Active rewarming techniques should be used in those patients with hypothermia.

Although MALA is a rare complication, it has an exceptionally high mortality rate, ranging from 17% to 50%. Serum lactate levels are higher in nonsurvivors and, at levels > 20 mmol/L, the lactate level linearly predicts mortality. Prognosis is interestingly not affected by pH, metformin level, or bicarbonate level.

Clinical Course

The patient developed progressive altered mental status, tachycardia, and hypotension and received 2 ampules of D50, 3 ampules of sodium bicarbonate, and 1 L of lactated Ringers. She rapidly deteriorated into pulseless electrical activity arrest and was intubated and resuscitated with large volumes of fluids, bicarbonate, and vasopressors. Forced-air patient warming was initiated for persistent hypothermia and broad-spectrum antibiotics were initiated. Central venous access was obtained and emergent hemodialysis started. The lactic acidosis and renal function improved rapidly with dialysis. She was extubated and weaned off vasopressors within 12 h. Though she initially denied it, she ultimately admitted to surreptitious intake of metformin stating, “It helped my blood glucose when I took it previously.” Her documented allergy to metformin was secondary to two prior MALA (though much less severe) episodes. Our institution had launched a new electronic medical record 2 days before her presentation, and this information was not available upon admission. She transferred to the medical floor after 2 days and was discharged home 2 days later.

Clinical Pearls

• 1.Severe lactic acidosis that is disproportionate to hemodynamic instability should prompt consideration of MALA or other impaired redox states.
• 2.Although profound hypoglycemia and hypothermia may be seen in sepsis, they occur nearly universally in MALA and may help distinguish the two.
• 3.The mortality of MALA is high, so an elevated index of suspicion is essential in patients with severe acidosis, hypothermia, and renal failure.
• 4.A lactate level > 20 mmol/L is predictive of mortality in MALA, but renal replacement therapy improves mortality.