INTRODUCTION
Mr P. was an 81-year-old white male patient who was admitted to the emergency department (ED) for dyspnea. He had experienced vomiting, increased output from his ileostomy, and weakness over the previous 24 hours. Eighteen days before ED admission, he underwent a minimally invasive low anterior resection with a diverting ileostomy for a locally advanced rectal cancer and was discharged home in good condition on postoperative day 13. His past medical history was significant for type 2 diabetes and hypertension. His medications included metformin, linagliptin, acarbose, and bisoprolol.
On arrival at the ED, Mr P. was unresponsive, hemodynamically unstable (wide-complex tachycardia, heart rate 120 beats per minute, blood pressure 80/50 mm Hg) and hypoxic (SpO2 79%). The arterial blood gas analyses revealed metabolic acidosis (pH 6.95, pCO2 16.3 mm Hg, HCO3- 3.5 mEq/L, and standardized calculated base excess -28.6 mmol/L), severe hyperlactatemia (Lac 15.8 mmol/L), hyperkalemia (K 7.18 mmol/L), and acute renal failure (creatinine 9.98 mg/dL, 882 [mu]mol/L).
Mr P. was promptly intubated and mechanically ventilated, fluid resuscitation was begun, along with vasoactive agent administration (norepinephrine continuous infusion at increasing doses up to 1 [mu]g/kg/min). Subsequently, a 12-French central venous line was placed in the femoral vein and continuous venovenous hemodialysis was initiated for persistent severe metabolic acidosis, hyperkalemia, and anuria despite adequate fluid and vasoactive resuscitation.
Mr P. experienced an episode of cardiac arrest (pulseless electrical activity) despite these aggressive treatment efforts. He regained a spontaneous pulse after 2 minutes of advanced life support. As treatment efforts continued, the patient experienced another episode of cardiac arrest. Death occurred 3 hours after admission to the ED. When Mr P.'s case was critically reviewed by the medical staff, his clinical condition was interpreted as late-occurring postoperative severe metabolic acidosis due to the combination of metformin use and dehydration due to high-volume output from his ileostomy.
DISCUSSION
Metformin is a biguanide, a class of oral antihyperglycemic agents with lower tendency toward hypoglycemia compared to other antidiabetic drugs.1,2 It is recommended as a first-line pharmacologic agent for type 2 diabetes mellitus in the absence of contraindications.1 Metformin is rapidly absorbed from the small intestine, and peak plasma concentrations are achieved 2 hours following ingestion.2 It is filtered from the glomerulus and secreted from the proximal tubule in a nonmetabolized and non-protein-bound form.3
As an antihyperglycemic agent, metformin reduces glucose through multiple mechanisms: inhibition of hepatic gluconeogenesis, augmentation of insulin sensitivity, increased insulin-mediated uptake of glucose in peripheral tissues such as muscles and liver, and reduction of free fatty acids as a substrate for gluconeogenesis.4,5 Metformin reduces insulin resistance, helps maintain euglycemia, favorably impacts dyslipidemia, and promotes modest weight reduction and/or stabilization in obese patients.6 It also reduces cardiovascular morbidity and mortality. Despite its generally safe and favorable effects, metformin is associated with adverse side effects, the most common being nausea and diarrhea leading to dehydration in many patients.7
Colorectal cancer (CRC) is the second most prevalent malignancy worldwide and the second cause of mortality in most developed countries.8 As a result of the aging population and associated diagnostic and therapeutic advances, the number of cancer patients has increased significantly, with a significant impact on the cancer care system. Accordingly, the incidence of CRC in older patients is increasing, resulting in a greater number of patients who present with concomitant medical illnesses. A temporary ileostomy is often created after surgery for CRC to allow diversion, while the surgical area heals without the danger of irritation or infection from fecal bacteria. This is usually a well-tolerated procedure. Findings from multiple studies indicate that the persons with diabetes mellitus are at a significantly higher risk of developing many forms of cancer, especially solid tumors. In addition to pancreatic and breast cancers, a relationship between type 2 diabetes mellitus and an increased risk of CRC has been found.9,10
Metformin-associated lactic acidosis (MALA) is a rare complication of metformin; it is characterized by a high anion gap metabolic acidosis with elevated serum lactate levels without hypoperfusion. It can lead to type B nonhypoxemic lactic acidosis and may result from metformin accumulation in the setting of acute kidney injury, chronic kidney disease, and/or metformin overdose.11 Metformin-associated lactic acidosis impairs mitochondrial function, leading to reduced gluconeogenesis, increasing glycolysis, and activation of anaerobic metabolism in the intestine.11,12 Severe MALA can induce serious effects on cardiovascular, respiratory, and central nervous system functions, resulting in a reported mortality rate up to 45%.11,13 When a patient who is taking metformin shows abnormal vital signs, malaise, and abdominal cramping, MALA should be considered, especially when there is unexplained metabolic acidosis.
A state of high output from the ileostomy can lead to dehydration with a loss of fluids and electrolytes; dehydration is considered the most frequent cause of hospital readmission after diverting ileostomy creation.14 Administration of metformin may aggravate this condition; it is known to cause gastrointestinal upset by its osmotic effect in the intestinal lumen, resulting in loose stools. We hypothesize that Mr P.'s demise was attributable to by a combination of 2 factors that singularly would not have led to an extreme situation, high-volume output from his ileostomy and metformin resulting in acute kidney injury and lactic acidosis.
CONCLUSION
Considering the prevalence and incidence of diabetes mellitus, the use of metformin is increasingly common in the general population. The incidence of CRC is also significant, and approximately 100,000 ostomies are created each year in the United States for management of colorectal pathology.15 The coexistence of these conditions is frequently encountered in the clinical practice and raises the awareness for the necessity of an aggressive prevention plan to avoid fluid and electrolyte imbalance. Thus, potentially preventing a fatal adverse event is important since a careful perioperative management of medications and a tailored surgical strategy could avoid extreme complications.
KEY POINTS
* Metformin-associated lactic acidosis is associated with serious adverse effects of the cardiovascular, respiratory and central nervous systems.
* These effects may be exacerbated by high volume output from an ileostomy.
REFERENCES