What are the causes of hyperlactatemia without impaired tissue perfusion?

From the Guidelines

High lactate levels can occur without impaired tissue perfusion through several mechanisms, including medications, seizures, liver dysfunction, malignancies, thiamine deficiency, mitochondrial disorders, diabetic ketoacidosis, and alcoholism. These conditions can lead to elevated lactate levels even with normal tissue oxygenation. Some key mechanisms include:

• Medications like metformin, which inhibits gluconeogenesis and promotes lactate production
• Seizures and excessive muscle activity generating lactate through increased glycolysis
• Liver dysfunction impairing lactate clearance since the liver normally metabolizes up to 70% of circulating lactate
• Certain malignancies, particularly lymphomas and leukemias, producing lactate through aerobic glycolysis (the Warburg effect)
• Thiamine deficiency disrupting pyruvate metabolism, leading to lactate accumulation
• Mitochondrial disorders impairing oxidative phosphorylation, forcing cells to rely on anaerobic metabolism despite adequate oxygen
• Diabetic ketoacidosis increasing lactate through altered metabolism
• Beta-agonist medications like albuterol and epinephrine stimulating glycolysis and lactate production
• Alcoholism causing lactate elevation through multiple pathways including direct metabolic effects and potential thiamine deficiency 1. Recognizing these non-hypoperfusion causes is crucial for proper clinical management, as treatment should target the underlying mechanism rather than focusing solely on improving tissue perfusion. The most recent and highest quality study, published in 2018, supports the idea that lactate guided resuscitation has been consistently shown to be effective 1. Additionally, the Surviving Sepsis Campaign guidelines recommend guiding resuscitation to normalize lactate in patients with elevated lactate levels as a marker of tissue hypoperfusion 1. Therefore, it is essential to consider these non-hypoperfusion causes of high lactate levels and to use lactate guided resuscitation as a marker of the adequacy of haemodynamic support.

From the FDA Drug Label

For each of the known and possible risk factors for metformin-associated lactic acidosis, recommendations to reduce the risk of and manage metformin-associated lactic acidosis are provided below: Renal impairment — The postmarketing metformin-associated lactic acidosis cases primarily occurred in patients with significant renal impairment 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. 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 high lactate without impaired tissue perfusion include:

• Renal impairment: Significant renal impairment can increase the risk of metformin-associated lactic acidosis.
• Drug interactions: Certain drugs can increase the risk of metformin-associated lactic acidosis by impairing renal function, resulting in significant hemodynamic change, interfering with acid-base balance, or increasing metformin accumulation.
• Age 65 or greater: Elderly patients have a greater likelihood of having hepatic, renal, or cardiac impairment, which can increase the risk of metformin-associated lactic acidosis.
• Excessive alcohol intake: Alcohol can potentiate the effect of metformin on lactate metabolism.
• Hepatic impairment: Patients with hepatic impairment can develop metformin-associated lactic acidosis due to impaired lactate clearance. 2

From the Research

Causes of High Lactate Without Impaired Tissue Perfusion

• High lactate levels can be caused by various factors beyond tissue hypoperfusion, including increased aerobic glycolysis during stress response 3
• Medications, such as certain antiseizure drugs, can also contribute to elevated lactate levels 4
• Other potential causes of hyperlactatemia include seizures, malignancy, liver disease, toxins, and medication overdose 5
• Lactate levels can be elevated in critically ill patients due to factors unrelated to tissue hypoxia/hypoperfusion, such as aerobic glycolysis 3
• The use of lactate as a diagnostic and prognostic tool is complex and should be considered in conjunction with other markers of tissue perfusion 6, 7

Pathophysiological Aspects

• Lactate metabolism and clearance are complex, especially in sepsis, making its use as a guiding tool for resuscitation more nuanced than previously thought 7
• Hyperlactatemia can result from both aerobic and anaerobic glycolysis, making it an unreliable marker of tissue hypoxia/hypoperfusion 3
• The relationship between lactate levels and tissue hypoperfusion is not always straightforward, and other factors can contribute to elevated lactate levels 5, 6

Clinical Implications

• Clinicians should be aware of the various potential causes of lactate level elevation and consider them when interpreting lactate levels in clinical practice 5
• The use of lactate as a marker of tissue perfusion should be considered in conjunction with other clinical parameters and markers of tissue hypoperfusion 6, 7
• Resuscitation strategies should take into account the potential for lactate levels to be elevated due to factors unrelated to tissue hypoxia/hypoperfusion 3