Metformin toxicity in the intensive care unit: A case series and review of the literature

ABSTRACT

Metformin toxicity is a life-threatening condition with high morbidity and mortality. Toxicity predominantly occurs in the setting of acute renal dysfunction, as the drug is solely eliminated by the kidneys. While this risk is widely known to clinicians, diagnosing metformin toxicity is challenging because commercially available serum metformin levels require days to weeks to result. Therefore, the intensivist must rely on medical history, clinical presentation, and routine laboratory findings to make the preliminary diagnosis. Treatment of metformin toxicity includes supportive fluid hydration, vasopressors, and emergent hemodialysis (HD). We report three critically ill patients who had near-fatal severe metformin-induced lactic acidosis. Their metformin levels were markedly higher than the toxicity threshold reported by the Federal Drug Agency. These patients made a prompt and complete recovery after the initiation of HD. We also review the pathophysiology, clinical presentation, diagnosis, and treatment of metformin toxicity.

INTRODUCTION

Metformin is the most commonly prescribed antidiabetic oral medication in the United States.[1,2] The glucose-lowering drug is well known for its efficacy, easy administration, and relatively minimal side effect profile.[3,4,5] Its mechanism of action is primarily through the suppression of hepatic gluconeogenesis.[3,6] Metformin does not undergo hepatic catabolism and is exclusively eliminated by the kidneys.[7] Therefore, any cause of decreased glomerular filtration of metformin will result in its serum elevation.[7,8] Once a toxic threshold has been exceeded, several organ systems may be affected [Figure 1].[2,9,10,11,12,13,14] The Federal Drug Agency has defined metformin toxicity as serum levels ≥ 5 μg/ml.[15] However, metformin levels are seldomly evaluated in clinical settings due to the nonavailability of rapid laboratory tests. Thus, clinicians must rely upon clinical and laboratory parameters to establish a preliminary diagnosis of metformin toxicity.

Figure 1.

Spider diagram summarizing the multisystemic effects of metformin toxicity

The most prominent presenting vital signs of metformin toxicity include hypothermia, tachy/bradycardia, and hypotension.[16,17] Abnormal laboratory findings include elevated hepatic transaminases, creatinine, urea, and hypoglycemia.[13,14,17,18] Most striking is a profound metabolic acidosis refractory to intravenous (IV) fluids and vasopressors. Contrary to its portended poor prognosis and high mortality, the successful treatment of metformin toxicity can be achieved by early recognition and emergent hemodialysis (HD).[19,20,21,22]

We present three cases of metformin toxicity with near-fatal severe acidosis. The importance of recognizing the symptoms of toxicity and laboratory parameters immediately upon presentation is emphasized, followed by the emergent need for HD. We report the metformin levels associated with each case and summarize their clinical timelines with the aim of alerting the intensivist to this largely under-recognized and challenging scenario.

CASE REPORTS

For each patient, the pH and lactic acid-level response to HD is illustrated in Figure 2.

Figure 2.

Temporal representation of venous pH (red) and lactic acid levels (blue), before and after the initiation of hemodialysis (green)

Patient 1

A 49-year-old woman with a medical history of stage III chronic kidney disease (CKD) and type II diabetes mellitus was found nearly unresponsive at home by her family members. For the previous 5 days, she had experienced abdominal pain, nausea, vomiting, and diarrhea. On the way to the hospital by emergency medical services (EMS), the patient’s blood glucose level was 28 mg/dL, at which time she was administered IV dextrose.

On admission, the patient’s blood pressure was 86/40 mmHg, heart rate 53 bpm, respiratory rate 14 bpm, and temperature 85°F. Physical examination revealed an altered mental status and dry mucous membranes. The patient was immediately covered with blankets and started on warmed IV fluids. Despite these efforts, the patient became increasingly unresponsive and tachypneic with paradoxical respirations. She became bradycardic and pulseless. Advanced cardiovascular life support-guided resuscitation was commenced with return of spontaneous circulation within 2–3 min. She remained hypotensive despite adequate volume resuscitation requiring norepinephrine infusion. Creatinine and blood urea nitrogen (BUN) were 13.23 mg/dL and 110 mg/dL, respectively, indicating acute-on-chronic renal failure (baseline creatinine: 1.2 mg/dL). Potassium was 6.7 mmol/L and phosphorus 16.6 mg/dL. Her white count was 17.9 thousand/uL, lactate 18.2 mmol/L, and lipase 1862 u/L. Arterial blood gas demonstrated severe metabolic acidosis with a pH of 6.42. Chest X-ray and computed tomography (CT) imaging revealed bilateral infiltrates of the lungs, concerning for multifocal aspiration pneumonia. CT abdomen and pelvis revealed diffuse small and large bowel edema and pancreatic inflammation. The patient was initiated on sodium bicarbonate infusion and broad-spectrum antibiotics for presumed septic shock. Urinalysis and urine culture revealed ketonuria, sterile pyuria, and hyaline casts. Blood cultures later returned negative.

The patient needed endotracheal intubation and mechanical ventilation. There was suspicion that her severe acidosis was potentially due to toxic levels of metformin, which had been discontinued on admission. Metformin levels were later found to be 34 μg/mL (therapeutic range: 1–2 μg/mL). A retrospective chart review revealed that the patient’s metformin dose had been increased from 500 to 1000 mg two times daily a month prior. Despite receiving bicarbonate and IV fluids, the patient’s elevated lactic acid levels and severe metabolic acidosis persisted. Continuous venovenous HD (CVVHD) was started immediately within 24 h of initial presentation.

The patient’s metabolic acidosis resolved after 18 h of renal replacement therapy. Continuous renal replacement therapy (CRRT) was transitioned to intermittent HD with improved hemodynamics and resolution of acidosis. Her renal function improved, and HD was discontinued before discharge from the hospital. After an 18-day hospital course, the patient was deemed stable for outpatient care. On discharge, her home regimen of metformin was replaced with insulin therapy for the management of her type II diabetes.

Patient 2

A 68-year-old male with a medical history of type II diabetes mellitus treated with metformin, Parkinson’s disease, and hypertension presented from a nursing home to the emergency department (ED) with a 1-day history of shortness of breath and altered mental status. The patient was noted to have hypotension, prompting an ED evaluation.

On admission, the patient’s blood pressure was 71/41 mmHg, heart rate 90 bpm, respiratory rate 21 bpm, and temperature 94.6°F. Upon physical examination, the patient was toxic appearing with pale skin and dry mucous membranes. He had deep, infrequent respirations and nonpalpable peripheral pulses. Given the patient’s hypothermic core temperature, he was administered warmed IV fluids and placed on a Bair hugger. Initial laboratories demonstrated a pH of 6.739, lactic acid 20.4 mmol/L, creatinine 7.32 mg/dL, and potassium 6.6 mmol/L. The patient was volume resuscitated and started on vasopressors for persistent hypotension but progressively worsened. An elevated white count of 22.77 thousand/uL was concerning for infection. Empiric cefepime and vancomycin were administered. Urinalysis, viral panel, and sepsis panel returned negative. CT of the chest revealed possible bilateral aspiration pneumonia. CT abdomen and pelvis revealed mild left hydronephrosis and hydroureter with calculi in the bladder that may have recently passed.

The patient was initiated on IV ampicillin, as one of two blood cultures grew Enterococcus. Although bacteremia as the etiology of shock was strongly considered, the severe metabolic acidosis was also concerning for metformin toxicity. The patient’s home regimen of metformin 850 mg two times daily had been discontinued on admission. Metformin levels were later found to be 59 μg/mL. Despite receiving bicarbonate and IV fluids, the patient continued to rapidly decompensate. CRRT was initiated within 24 h of initial presentation.

The patient’s metabolic acidosis improved after 2 days of CVVHD. Laboratories improved with a lactic acid of 3.0 mmol/L, creatinine 1.80 mg/dL, and pH 7.470. With improved hemodynamics, acidosis, and renal function, he was transitioned off renal replacement therapy to be maintained on IV fluids. He continued to improve clinically and completed a 14-day antibiotic course of ampicillin for Enterococcus bacteremia. The patient was discharged to postacute rehabilitation services, no longer on metformin, after a 22-day hospital course.

Patient 3

A 62-year-old man with a medical history of coronary artery disease, type II diabetes mellitus, hypertension, hyperlipidemia, and depression with suicidal ideation was found to be poorly responsive by family members. EMS reported a glucose of 49 mg/dL. Blood sugar and cognition improved after administration of IV dextrose. For the prior 24 h, the patient had experienced loose stools, nausea, abdominal discomfort, and memory loss. The family reported that a number of pills from his home medications were missing. His home medications included metformin, empagliflozin-metformin hydrocholride, and glipizide.

On admission, the patient’s blood pressure was 103/52 mmHg, heart rate 72 bpm, respiratory rate 18 bpm, and temperature 95.8°F. Physical examination revealed fatigue, weakness, and confusion. Empiric ceftriaxone was initiated due to a white count of 13.6 thousand/uL, however, soon discontinued as blood cultures, a COVID-19 test, and urinalysis later returned negative. Creatinine and BUN were elevated at 7.22 mg/dL and 46 mg/dL, respectively, representing acute renal injury. A lactate of 7.1 mmol/L and pH of 7.258 revealed metabolic acidosis with an anion gap of 23 mmol/L. In addition, an elevated acetaminophen level of 11.4 μg/mL was detected. It was highly suspected that this presentation could be explained by polypharmacy ingestion with acetaminophen, metformin, and sulfonylurea toxicity. Therefore, N-acetylcysteine, bicarbonate, and octreotide were administered. Metformin level was later found to be elevated at 23 μg/mL. CT abdomen and pelvis revealed a nonobstructing calculus at the lower pole of the left kidney and mild perinephric stranding.

The patient’s condition showed no improvement with volume administration. His condition progressively worsened with new onset right-sided flank pain, abdominal distension, and left lower quadrant tenderness. A decline in urine output, vomiting, and diarrhea was also noted. HD was initiated on day 2 of admission due to persistent lactic acidosis and worsening renal function.

The patient’s renal function and severe acidosis rapidly improved with commencement of renal replacement therapy. He was transitioned off HD and continued to show clinical improvement. On discharge, the patient was placed on an insulin regimen in place of metformin for maintenance of his type II diabetes. After a 16-day hospital course, he was voluntarily admitted into a behavioral health facility.

DISCUSSION

Metformin toxicity in the intensive care unit

These cases emphasize the importance of recognizing the clinical and laboratory findings [Table 1] of metformin toxicity and initiating early renal replacement therapy. Common to all cases was impaired consciousness, hypothermia, hypotension, bradycardia, hypoglycemia, and lactic acidosis with renal failure on presentation. In addition, two patients also reported nausea and vomiting, well-known side effects of metformin toxicity. The abnormal vital signs (hypotension, bradycardia, and hypothermia), as well as laboratory findings (lactic acidosis), are nonspecific and common to other emergencies, such as myxedema coma and adrenal insufficiency. In the case of metformin toxicity, lactic acidosis occurs as a result of impaired gluconeogenesis (as opposed to hypoperfusion) and therefore does not improve with the administration of IV fluids or vasopressor therapy. The metabolic abnormalities and symptoms of our patients were rapidly improved with renal replacement therapy. A clinical presentation as highlighted herein in a patient with documented type 2 diabetes or metformin use should alert the critical care physician to the possibility of metformin toxicity.

Table 1.

Vitals and laboratory values of the three patients described herein

	Patient 1	Patient 2	Patient 3
Vitals*
Temperature (°F)	85	93.9	95.8
Heart Rate (bpm)	53	80	72
Blood Pressure (mmHg)	86/40	69/46	103/52
Respiratory rate (bpm)	14	21	18
Laboratory values*
pH**	6.42	6.73	7.24
Lactate (mmol/L)	18.2	20.4	7.1
Blood Glucose (mg/dL)	28	75	49
Creatinine (mg/dL)	13.23	7.32	7.22
Metformin level (mcg/mL)	34	59	23
Glomerular Filtration Rate (mL/min/1.73 m2)	3	6	7

*Vitals and laboratory values represent initial values obtained on presentation to the emergency department, **pH values are based on venous blood gas

Over a 5-year period during which 3556 patients were admitted to the intensive care unit (ICU), Peters et al. found that 30 patients (0.84%) presented with metformin-associated lactic acidosis (MALA). Of these patients, 9 died (5 dialyzed) and 21 survived (11 dialyzed), corresponding to a mortality rate of 30%.[20] A similar 5-year study found that MALA was diagnosed in 6 per 1000 ICU admissions, with a mortality rate of 29%.[23] Respectively, lower and higher mortality rates of 20% and 50% have also been reported.[14,24] Factors associated with mortality include a high Acute Physiology and Chronic Health Evaluation (APACHE) III score, shock as the reason for ICU admission, and possibly a high peak lactate level [Table 2].[20,23] Patients referred for shock had an increased risk for death compared to those referred for acute renal failure or suicide attempt.[20] The serum level of metformin does not appear to be prognostically predictive. Survival is reported in patients with levels as high as 678 μg/mL.[25] Not surprisingly, an observational study of 105 patients with MALA reported that a lower APACHE II score and time to dialysis (<6 h) are associated with lower 30-day mortality.[26]

Table 2.

Poor prognostic indicators of metformin toxicity

Referral to the ICU for shock20

Higher illness severity scores on admission (SAPSII, mean in non- survivors = 75 +/- 23; APACHEIII, mean in non-survivors = 142.3 +/- 26.0)20,23

Prothrombin activity < 50% and increased prothrombin time (mean in non-survivors = 21 sec +/- 3)20

Low arterial pH on admission (mean in non-survivors = 6.68 +/- 0.13)23

Male sex23

Prognosis does not appear to be influenced by metformin levels; however, metformin levels are useful in confirming the diagnosis

Pathophysiology of metformin

The glucose-lowering effect of metformin is primarily achieved through the suppression of hepatic gluconeogenesis [Figure 3].[3,6] Gluconeogenesis is a process of converting substrates such as lactate, glycerol, and glucogenic amino acids into glucose. Metformin disrupts this pathway by inhibiting complex I on the inner mitochondrial membrane. Complex I inhibition decreases adenosine triphosphate production, which increases the intracellular concentrations of adenosine monophosphate (AMP) and adenosine diphosphate (ADP).[3,6] The increase in AMP and ADP activates AMP-activated protein kinase, which in turn decreases gluconeogenic gene expression.[3,6] Moreover, metformin inhibits mitochondrial glycerol-3-phosphate dehydrogenase (mGPD).[3,6] Inhibition of mGPD disrupts the glycerol phosphate redox shuttle, which increases cytosolic nicotinamide adenine dinucleotide (NADH).[3,6] Elevated levels of NADH further inhibit gluconeogenesis. Additional mechanisms include increased insulin sensitivity in peripheral tissues and decreased intestinal absorption of glucose.[3,6] The hindrance of gluconeogenesis results in the accumulation of other substrates, in particular lactate. This leads to lactic acidosis, categorized as type B (see below). Furthermore, metformin may also cause refractory vasodilation by increasing nitric oxide production, which further potentiates the hypotensive effect of metformin toxicity.[27]

Figure 3.

Schematic depicting the mechanistic basis by which metformin inhibits gluconeogenesis. OCT1: Organic cation transporter 1; mGPD: Mitochondrial glycerol phosphate dehydrogenase; ATP: Adenosine triphosphate, ADP: Adenosine diphosphate, AMP: Adenosine monophosphate; AMPK: AMP-activated protein kinase; NADH: Nicotinamide adenine dinucleotide

Types of lactic acidosis

Lactic acidosis is categorized as type A or B based on the underlying pathophysiological mechanism. Type A lactic acidosis is due to tissue hypoperfusion and hypoxia.[28] This occurs in instances of ischemia as a result of reduced arterial oxygen delivery to the peripheral tissues, leading to anaerobic respiration.[29] Examples of causes of type A lactic acidosis include regional ischemia, seizures, and septic, cardiogenic, hypovolemic, or hemorrhagic shock.[28]

In contrast, type B lactic acidosis occurs with increased production or decreased clearance of lactic acid.[28] In the instance of increased lactate production, whatever the underlying cause, glucose metabolism exceeds the mitochondria’s ability to perform oxidative phosphorylation.[28] The result is a rise in pyruvate, which is converted to lactate.[30] Causes of type B lactic acidosis include malignancy, mitochondrial dysfunction, liver disease, pharmaceutical agents (e.g., metformin, propofol, epinephrine, and linezolid), alcohol intoxication, diabetes mellitus, thiamine deficiency, and human immunodeficiency virus infection.[28] The common causes of type B lactic acidosis in the ICU are summarized in Table 3.[28,31,32,33]

Table 3.

Common causes of type B lactic acidosis in the intensive care unit

Cause	Presentation	Mechanism
Ethanol	Nausea, vomiting, abdominal pain, tachypnea, hyponatremia, hypokalemia, hypophosphatemia, hypotension, altered mental status, symptoms of ethanol withdrawal (tremors, seizures, tachycardia)	Ethanol increases the concentration of NADH in hepatocytes.  The change in the redox state causes pyruvate to be metabolized to lactate and NAD[33]
Propylene glycol	Agitation, coma, seizures, hypotension	Propylene glycol is metabolized to lactic acid via the enzymes alcohol dehydrogenase and aldehyde dehydrogenase[33]
Thiamine deficiency	High-output heart failure (wet beriberi), Wernicke’s encephalopathy, Leigh syndrome	Thiamine is a cofactor of pyruvate dehydrogenase. Pyruvate dehydrogenase activity is suppressed without thiamine, causing an accumulation of pyruvate and NADH.[33] Pyruvate and NADH are then metabolized to lactate and NAD+
Malignancy	Weight loss, fatigue, lethargy, malaise, bruising, weakness, nausea, shortness of breath, night sweats, pruritus, lymphadenopathy, persistent or recurrent infections, fever, abdominal pain, pallor	Multiple mechanisms have been proposed such as the Warburg effect (the ability of tumor cells to rely on anaerobic respiration for ATP production despite sufficient oxygenation), hypoxia of malignant tissue, malabsorption of thiamine and riboflavin, and decreased liver function from metastases[33]
Liver dysfunction	Nausea, vomiting, fatigue, lethargy, malaise, jaundice, pruritus, anorexia, abdominal pain located in the right upper quadrant, ascites, cerebral edema, hepatic encephalopathy	The liver is the primary site of lactate clearance and thus with decreased liver function an accumulation of lactic acid will result[31,33]
Diabetic ketoacidosis	Hyperglycemia, tachycardia, weight loss, hypotension, polyuria, polydipsia, nausea, vomiting, dry oral mucosa, decreased skin turgor, altered mental status, blurred vision, weakness, lethargy, fruity odor to the breath, hyperventilation, abdominal pain	Multiple mechanisms have been proposed such as tissue hypoperfusion and altered glucose metabolism.[32] It has been hypothesized that in these patients, the altered glucose metabolism exceeds the oxidation capacity of the mitochondria.[28,32] Thus, the accumulation of pyruvate from anaerobic respiration drives lactate dehydrogenase to form lactate and NAD+ from pyruvate and NADH[28,32]
Propofol infusion syndrome	Severe metabolic acidosis, rhabdomyolysis, renal failure, cardiac failure	Propofol inhibits complex IV of the mitochondrial respiratory chain and thus acts as an uncoupling agent of oxidative phosphorylation[33]

NADH: Nicotinamide adenine dinucleotide, ATP: adenosine triphosphate, NAD: Nicotinamide adenine dinucleotide

In situations of severe metabolic acidosis and cardiovascular collapse, both type A and B lactic acidosis may occur simultaneously.[34] Both types of lactic acidosis likely contributed to the profound acidosis experienced by patients 1 and 2. Such a combined clinical picture may further complicate and prolong time to the correct diagnosis.

Lactic acidosis in patients taking metformin

Lactic acidosis in patients taking metformin can be characterized into three possible clinical scenarios: metformin induced, metformin associated, and metformin unrelated. Metformin-induced lactic acidosis (MILA) occurs in the absence of comorbidities, as may be seen in intentional drug overdose.[30] Of note, the time to MILA after initial ingestion is about 6–12 h.[35] MALA occurs when metformin toxicity is secondary to the presence of other disease conditions, such as CKD.[30] Metformin-unrelated lactic acidosis describes the scenario wherein metformin is not the cause.[30] Of the three, MALA is the most common type and the most likely to be encountered in the ICU, especially in patients with acute renal dysfunction.[30]

Treatment and management

The treatment of metformin toxicity is aimed at achieving hemodynamic stabilization, correcting the acidosis, and removing metformin.[19,20] While supportive measures play an important role in the initial management, renal replacement therapy has become the gold standard therapy.[19,20,21,22,36] HD rapidly removes metformin and assists in restoring blood volume while correcting the acidosis.[22] CRRT, such as CVVHD, is the favored modality for hemodynamically unstable patients.[22,36,37,38] Sustained low-efficiency dialysis (SLED), a viable alternative approach to CRRT, has also shown to adequately remove metformin, correct metabolic derangements, and improve renal function.[17] Prolonged dialysis is likely necessary as metformin levels may rebound postdialysis due to a large volume of distribution.[39] The administration of methylene blue, an inhibitor of nitric oxide synthase, has been shown to provide transient improvements in hypotension.[25,27] In cases of refractory shock, venoarterial extracorporeal membrane oxygenation (ECMO) may be considered.[25] Indications for ECMO from the Extracorporeal Treatments in Poisoning Workgroup include lactate levels >20 mmol/L, pH ≤7.0, shock, failure of supportive care, and decreased level of consciousness.[39]

In all three of the cases reported here, renal replacement therapy was initiated due to severe metabolic acidosis refractory to volume resuscitation and bicarbonate therapy. Patients 1 and 2 improved on CVVHD, while patient 3 improved with intermittent HD. The severe lactic acidosis in these patients resolved within 48 h of therapy [Figure 2].

CONCLUSION

The incidence of metformin toxicity is about 2–9 per 100,000 cases per year, with a mortality rate as high as 50%.[24,40] Prognostic indicators include the APACHE III score, shock as the reason for ICU admission, and possibly the peak lactate level.[20,23] Diagnostically, the combined presence of acute renal failure, pH ≤7.35, lactate ≥8.4 mmol/L, and known use of metformin is sensitive and specific for MALA.[41] Once identified, the treatment is supportive with the use of IV fluids, vasopressors, and dextrose drips.[35,39] Most important is the immediate implementation of dialysis. Several studies have compared CRRT, conventional HD, and SLED, all of which have shown benefit in the treatment of MALA.[36,37,38,39,41] ECMO may provide the necessary hemodynamic support if dialysis and supportive care are insufficient.[25]

Research quality and ethics statement

This case report did not require approval by the Institutional Review Board/Ethics Committee. The authors followed applicable EQUATOR Network (http://www.equator-network.org/) guidelines, specifically the CARE guideline, during the conduct of this research project.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patients have given their consent for their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.