What causes elevated lactate levels?

What Causes Elevated Lactate Levels

Elevated lactate results primarily from tissue hypoperfusion and hypoxia causing anaerobic metabolism, but can also occur from accelerated aerobic glycolysis driven by beta-adrenergic stimulation (particularly from epinephrine), liver failure impairing lactate clearance, and metformin in patients with renal or hepatic dysfunction. 1

Primary Mechanisms of Lactate Elevation

Tissue Hypoperfusion and Hypoxia (Most Common)

• Inadequate oxygen delivery to tissues forces cells into anaerobic metabolism, producing lactate as the end product of glycolysis without sufficient oxidative phosphorylation. 1, 2
• This represents an imbalance between systemic oxygen demand and oxygen availability, resulting in tissue hypoxia. 2
• Lactate >2 mmol/L indicates potential tissue hypoperfusion that warrants investigation. 1

Shock States

• Sepsis and septic shock cause lactic acidosis through both tissue hypoperfusion and inflammatory mediators affecting cellular metabolism. 1
• Hypovolemic, cardiogenic, and distributive shock all lead to impaired tissue perfusion. 1
• Hemorrhagic shock following major trauma produces elevated lactate levels that correlate directly with mortality. 1
• Cardiac failure and low flow states lead to tissue hypoxia and subsequent lactate elevation. 3

Beta-Adrenergic Stimulation (Independent of Hypoxia)

• Epinephrine causes elevated lactate through beta-2-adrenergic receptor stimulation in skeletal muscle, activating glycogenolysis and glycolysis. 1
• This produces increased lactate production independent of tissue perfusion status—meaning lactate can be elevated even with adequate oxygen delivery. 4, 5
• The mechanism involves aerobic glycolysis linked to ATP provision for the Na+-K+ pump, whose activity is stimulated by epinephrine. 5

Impaired Lactate Clearance

• Liver failure impairs lactate clearance, causing elevated lactate independent of tissue hypoperfusion. 6
• The liver is the primary site of lactate metabolism, so hepatic dysfunction prevents normal lactate utilization. 7

Medication-Induced Causes

• Metformin causes lactic acidosis in patients with impaired clearance (renal failure with eGFR <30 mL/min/1.73 m²), impaired lactate clearance (liver failure), or conditions causing anaerobic metabolism (sepsis, hypoxia). 1, 6
• Norepinephrine, when administered continuously to maintain blood pressure without adequate blood volume replacement, can cause tissue hypoxia and lactate acidosis through severe peripheral and visceral vasoconstriction, decreased renal perfusion, and poor systemic blood flow despite "normal" blood pressure. 8

Mesenteric Ischemia

• Non-occlusive mesenteric ischemia (NOMI) and acute mesenteric ischemia lead to lactic acidosis due to inadequate intestinal perfusion. 3
• Lactate >2 mmol/L with abdominal pain indicates irreversible intestinal ischemia (Hazard Ratio: 4.1). 1
• D-dimer >0.9 mg/L has 82% specificity for intestinal ischemia when abdominal pain is present. 1, 3

Clinical Significance and Prognostic Implications

Mortality Correlation

• Elevated lactate levels are associated with worse outcomes regardless of the source. 4
• Patients with sepsis and lactate ≥4 mmol/L have a mortality rate of 46.1%, comparable to patients with overt septic shock. 1
• Only lactate values >4 mmol/L, with or without hypotension, are significantly associated with in-hospital mortality on multivariable analysis. 9

Lactate Clearance as Prognostic Marker

• Normalization of lactate levels within 24 hours is associated with 100% survival in trauma patients, decreasing to 77.8% if normalization occurs within 48 hours, and to 13.6% if levels remain elevated beyond 48 hours. 1
• Serial lactate measurements provide an objective evaluation of response to therapy. 1
• Lactate-guided resuscitation shows moderate evidence for reduction in mortality compared to usual care. 4

Critical Pitfalls to Avoid

Don't Assume Lactate Always Means Hypoperfusion

• Lactate elevation from beta-adrenergic stimulation (especially epinephrine) reflects aerobic glycolysis in well-oxygenated tissues, not tissue hypoxia. 5
• This explains why hyperlactatemia often neither correlates with traditional indicators of perfusion nor diminishes with increased oxygen delivery. 5
• Continued attempts at resuscitation based solely on elevated lactate may lead to unnecessary fluid administration and volume overload. 10

Don't Ignore Elevated Lactate in Stable-Appearing Patients

• Blood pressure alone is inadequate to assess tissue perfusion—patients can maintain normal blood pressure through compensatory mechanisms while experiencing significant tissue hypoperfusion. 1
• Sepsis-induced tissue hypoperfusion is defined as either hypotension persisting after initial fluid challenge OR blood lactate ≥4 mmol/L. 1

Don't Confuse Serum Lactate with Lactate Dehydrogenase (LDH)

• Serum lactate reflects tissue hypoperfusion and metabolic stress (measured in mmol/L), whereas LDH is a tumor marker enzyme reflecting tumor burden (measured in U/L). 6

Assess Both Lactate and Base Deficit

• These parameters don't strictly correlate and provide complementary but independent information about tissue perfusion. 1, 6