From the Guidelines
Elevated lactate levels are primarily caused by tissue hypoxia, which can result from various conditions, including shock states, severe sepsis, cardiac failure, respiratory failure, and other causes that impair oxygen delivery to tissues. The most common causes of elevated lactate include:
- Shock states (septic, cardiogenic, hypovolemic, or obstructive)
- Severe sepsis, with bacterial endotoxins impairing cellular oxygen utilization
- Cardiac failure
- Respiratory failure
- Severe anemia
- Carbon monoxide poisoning
- Seizures Certain medications and toxins can also elevate lactate, including:
- Metformin (especially in overdose or renal failure)
- Alcohols (ethanol, methanol)
- Salicylates
- Cyanide
- Nucleoside reverse transcriptase inhibitors Some conditions can cause elevated lactate without tissue hypoxia, such as:
- Liver dysfunction (reducing lactate clearance)
- Malignancies (particularly lymphomas and leukemias)
- Diabetic ketoacidosis
- Thiamine deficiency
- Rare genetic mitochondrial disorders Vigorous exercise can temporarily increase lactate levels due to increased muscle metabolism 1. When evaluating elevated lactate, it's essential to consider the clinical context and search for underlying causes, as lactate serves as an important marker of tissue perfusion and cellular metabolism 1. In the context of sepsis, lactate-guided resuscitation has been shown to be effective in reducing mortality 1. However, it's crucial to note that lactate is not a direct measure of tissue perfusion, and increases in lactate levels may represent various causes, including tissue hypoxia, accelerated aerobic glycolysis, or other conditions 1. Therefore, lactate levels should be interpreted in conjunction with clinical assessment and other diagnostic tools to guide management and resuscitation efforts.
From the FDA Drug Label
Metformin decreases liver uptake of lactate increasing lactate blood levels which may increase the risk of lactic acidosis, especially in patients at risk. The risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment because metformin is substantially excreted by the kidney. Drug interactions —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 Age 65 or greater —The risk of metformin-associated lactic acidosis increases with the patient's age because elderly patients have a greater likelihood of having hepatic, renal, or cardiac impairment than younger patients. Radiologic studies with contrast —Administration of intravascular iodinated contrast agents in metformin-treated patients has led to an acute decrease in renal function and the occurrence of lactic acidosis. Hypoxic states —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) 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 elevated lactate levels associated with metformin use include:
- Renal impairment: Increased risk of metformin accumulation and lactic acidosis due to decreased renal excretion 2
- Drug interactions: Concomitant use of certain drugs that impair renal function, result in significant hemodynamic change, interfere with acid-base balance, or increase metformin accumulation 2
- Age 65 or greater: Increased risk of lactic acidosis due to greater likelihood of hepatic, renal, or cardiac impairment 2
- Radiologic studies with contrast: Acute decrease in renal function and occurrence of lactic acidosis due to administration of intravascular iodinated contrast agents 2
- Hypoxic states: Lactic acidosis associated with acute congestive heart failure, hypoperfusion, and hypoxemia 2
- Excessive alcohol intake: Potentiation of metformin's effect on lactate metabolism 2
- Hepatic impairment: Impaired lactate clearance resulting in higher lactate blood levels 2
From the Research
Causes of Elevated Lactate
- Tissue hypoperfusion is considered the most common cause of elevated lactate levels, but other etiologies and contributing factors exist 3
- Medication-induced hyperlactatemia and lactic acidosis are diagnoses of exclusion and can be overlooked, with 59 unique medications identified as potential causes 4
- Metformin use can alter lactate metabolism and may affect its prognostic value in septic shock patients 5, 6
- Lactic acidosis can occur due to various reasons, including sepsis, cardiac arrest, trauma, seizure, ischemia, diabetic ketoacidosis, thiamine deficiency, malignancy, liver disease, toxins, overdose, and medication 3, 7
Medication-Related Causes
- Epinephrine and albuterol are commonly identified agents that can cause medication-induced lactate level elevations 4
- Metformin is known to affect lactate metabolism, but its impact on lactate kinetics in patients with severe sepsis and septic shock is still being studied 5, 6
- Medication management strategies for lactate level elevations are heterogeneous and may include supportive care, exogenous bicarbonate therapy, medication-specific antidotes, and decontamination strategies 4
Clinical Significance
- Elevated lactate levels have important implications for morbidity and mortality in critically ill patients 7
- Lactate measurement can be useful in diagnosing and managing patients with lactic acidosis, but methodological issues related to interferences in assays must be considered 7
- The prognosis of extremely elevated plasma lactate levels in patients with septic shock may be affected by metformin use, with some studies suggesting lower mortality rates in metformin users 5