What causes worsening lactic acidosis?

From the Guidelines

Worsening lactic acidosis is primarily caused by tissue hypoxia, where inadequate oxygen delivery to tissues forces cells to switch to anaerobic metabolism, producing excess lactic acid, and certain medications such as metformin, especially in patients with kidney dysfunction, as evidenced by a recent study from China, including more than 1200 patients with type 2 diabetes and COVID-19, where inpatient use of metformin was associated with increased incidence of lactic acidosis 1.

Causes of Lactic Acidosis

• Tissue hypoxia due to circulatory shock (septic, cardiogenic, or hypovolemic), severe hypoxemia, or carbon monoxide poisoning
• Medications such as metformin, nucleoside reverse transcriptase inhibitors, and propofol (with prolonged high-dose infusions)
• Underlying conditions like liver disease impairing lactate clearance
• Seizures, excessive exercise, and malignancies increasing production
• Thiamine deficiency disrupting aerobic metabolism

Management of Lactic Acidosis

• Treatment should address the underlying cause while supporting circulation and oxygenation
• In metformin-associated cases, drug discontinuation and sometimes hemodialysis may be necessary 1
• Severe cases may require sodium bicarbonate administration, though this remains controversial as it can paradoxically worsen intracellular acidosis, and its use is not recommended for the purpose of improving hemodynamics or reducing vasopressor requirements in patients with hypoperfusion-induced lactic acidemia with pH ≥ 7.15 1

Key Considerations

• Lactic acidosis can be a life-threatening condition, and prompt recognition and treatment are essential to improve outcomes
• The use of metformin in patients with kidney dysfunction should be carefully monitored, and dose reduction or discontinuation may be necessary to prevent lactic acidosis 1
• Sodium bicarbonate administration should be used with caution and only in severe cases, as its effectiveness and safety are still debated 1

From the FDA Drug Label

Metformin associated lactic acidosis was characterized by elevated blood lactate concentrations (>5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), and an increased lactate: pyruvate ratio; metformin plasma levels were generally >5 mcg/mL Metformin decreases liver uptake of lactate increasing lactate blood levels which may increase the risk of lactic acidosis, especially in patients at risk. The concomitant use of metformin hydrochloride tablets with specific drugs may increase the risk of metformin-associated lactic acidosis: those that impair renal function, result in significant hemodynamic change, interfere with acid-base balance, or increase metformin accumulation Several of the postmarketing cases of metformin-associated lactic acidosis occurred in the setting of acute congestive heart failure (particularly when accompanied by hypoperfusion and hypoxemia) Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with hypoxemia have been associated with lactic acidosis and may cause prerenal azotemia. Excessive alcohol intake —Alcohol potentiates the effect of metformin on lactate metabolism Hepatic impairment —Patients with hepatic impairment have developed cases of metformin- associated lactic acidosis.

The causes of worsening lactic acidosis include:

• Renal impairment: The risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment.
• Drug interactions: The concomitant use of metformin with specific drugs that impair renal function, result in significant hemodynamic change, interfere with acid-base balance, or increase metformin accumulation.
• Hypoxic states: Conditions such as acute congestive heart failure, cardiovascular collapse, acute myocardial infarction, sepsis, and other conditions associated with hypoxemia.
• Excessive alcohol intake: Alcohol potentiates the effect of metformin on lactate metabolism.
• Hepatic impairment: Patients with hepatic impairment have developed cases of metformin-associated lactic acidosis. 2 2 2

From the Research

Causes of Worsening Lactic Acidosis

• Metformin-associated lactic acidosis (MALA) is a potentially lethal condition that can result from the use of metformin in the setting of risk factors such as renal insufficiency or hypoperfusion 3, 4, 5, 6
• Risk factors for MALA include those that reduce renal elimination of metformin, such as renal impairment, and excessive alcohol consumption 6
• Sepsis and shock can also contribute to worsening lactic acidosis 3, 4, 7
• Failure to respond to intravenous fluids and vasopressors can lead to worsening hemodynamic instability and acidosis 3, 4

Factors Contributing to Worsening Lactic Acidosis

• Delayed diagnosis and treatment of MALA can contribute to worsening outcomes 3, 4, 5
• Inadequate management of underlying conditions, such as sepsis and renal impairment, can also contribute to worsening lactic acidosis 3, 4, 7
• The use of bicarbonate therapy for lactic acidosis due to shock is controversial and may not be effective in all cases 7