What causes elevated lactate (lactic acid) levels in sepsis?

Causes of Elevated Lactate in Sepsis

Elevated lactate in sepsis is primarily caused by a combination of tissue hypoxia due to inadequate perfusion AND increased aerobic glycolysis driven by inflammatory mediators and catecholamines, rather than solely by tissue hypoxia as traditionally believed. 1, 2, 3

Multiple Mechanisms of Lactate Elevation in Sepsis

1. Tissue Hypoxia and Anaerobic Metabolism

• Inadequate tissue perfusion leads to oxygen debt and anaerobic metabolism
• Reduced oxygen delivery forces cells to produce ATP through anaerobic glycolysis, generating lactate 1
• This represents the traditional understanding of hyperlactatemia in sepsis

2. Aerobic Glycolysis (Non-Hypoxic Mechanisms)

• Increased aerobic glycolysis occurs even in well-oxygenated tissues during sepsis 4, 5
• Key drivers of this process include:
  • Epinephrine-stimulated Na+/K+-ATPase activity in skeletal muscle 4, 5
  • Inflammatory mediators that accelerate glycolysis
  • Catecholamine surge (both endogenous and exogenous) 1
  • β-adrenergic stimulation increasing glycolytic flux

3. Impaired Lactate Clearance

• Liver dysfunction in sepsis reduces lactate clearance 1
• Renal impairment may contribute to lactate accumulation
• Microcirculatory dysfunction further impairs lactate metabolism and clearance

Clinical Implications

Lactate levels serve as:

• Direct marker of anaerobic metabolism
• Indirect marker of oxygen debt
• Prognostic indicator of mortality 6

Lactate elevation severity correlates with outcomes:

• Normal: ≤2 mmol/L
• Moderate elevation: 2-4 mmol/L
• Severe elevation: >4 mmol/L 1

Both intermediate (2-3.9 mmol/L) and high (≥4 mmol/L) lactate levels are independently associated with increased mortality, regardless of the presence or absence of shock 6

Common Pitfalls in Lactate Interpretation

• Misattribution to tissue hypoxia alone: Assuming elevated lactate solely indicates tissue hypoxia may lead to excessive fluid administration or blood transfusions 3, 4
• Medication effects: Certain medications (e.g., metformin, epinephrine) can elevate lactate independently of tissue perfusion 1
• Failure to recognize non-septic causes: Conditions like diabetic ketoacidosis, seizures, severe asthma, and liver disease can all cause hyperlactatemia 1

Clinical Approach

1. Recognize that lactate elevation reflects both hypoxic and non-hypoxic mechanisms
2. Target the underlying cause while ensuring adequate tissue perfusion
3. Monitor lactate clearance (aim for ≥10% reduction within 2-4 hours) 1
4. Maintain mean arterial pressure ≥65 mmHg to support tissue perfusion 1
5. Consider both perfusion status and metabolic factors when interpreting lactate levels

Understanding the complex pathophysiology of lactate elevation in sepsis helps avoid inappropriate interventions based solely on lactate levels and guides more targeted resuscitation strategies.