What are the causes of elevated blood lactate?

Causes of Elevated Lactic Acid

Primary Mechanisms of Lactate Elevation

Tissue hypoperfusion and hypoxia is the most common cause of elevated lactate, resulting from inadequate oxygen delivery to tissues that forces cells into anaerobic metabolism. 1, 2 This occurs across all shock states—hypovolemic, cardiogenic, distributive (septic), and obstructive—where the imbalance between systemic oxygen demand and availability creates tissue hypoxia. 1, 2

Type A Lactic Acidosis (Tissue Hypoxia)

• Sepsis and septic shock causes lactic acidosis through both tissue hypoperfusion and inflammatory mediators that disrupt cellular metabolism, with lactate ≥4 mmol/L associated with 46.1% mortality comparable to overt septic shock. 1
• Hemorrhagic shock and trauma leads to elevated lactate that directly correlates with mortality, with normalization within 24 hours associated with 100% survival versus only 13.6% survival if lactate remains elevated beyond 48 hours. 1
• Cardiogenic shock from myocardial infarction or heart failure reduces cardiac output and systemic perfusion. 1, 3
• Mesenteric ischemia presents with lactate >2 mmol/L and abdominal pain, carrying a 4.1-fold increased risk of irreversible intestinal ischemia, with >88% of patients showing metabolic acidosis and elevated lactate. 1, 4

Type B Lactic Acidosis (Without Tissue Hypoxia)

Accelerated aerobic glycolysis driven by beta-adrenergic stimulation can increase lactate production independent of tissue perfusion, challenging the traditional assumption that elevated lactate always indicates hypoxia. 1, 5, 6

Medication-Induced Causes

• Epinephrine causes lactate elevation through beta-2-adrenergic receptor stimulation in skeletal muscle, activating glycogenolysis and glycolysis without tissue hypoperfusion. 1
• Metformin causes lactic acidosis in patients with impaired clearance (eGFR <30 mL/min/1.73 m²), impaired lactate metabolism (liver failure), or conditions causing anaerobic metabolism (sepsis, hypoxia), with an incidence of 2-9 per 100,000 patients/year. 1, 4
• Nucleoside reverse transcriptase inhibitors (NRTIs), particularly stavudine and didanosine, cause mitochondrial toxicity leading to lactic acidosis with an incidence of 1.3 cases per 1,000 person-years of NRTI exposure. 4

Metabolic and Organ Dysfunction

• Liver disease impairs lactate clearance since the liver is the major site of lactate removal through gluconeogenesis and oxidation. 4, 7
• Renal impairment reduces lactate clearance, with hyperlactatemia reported in 30-65% of adults with chronic kidney disease. 4
• Thiamine deficiency causes pyruvate dehydrogenase dysfunction, impairing lactate metabolism. 1, 8
• Malignancy can cause lactate overproduction through increased glycolytic activity in tumor cells. 8, 7

Clinical Interpretation Framework

Diagnostic Thresholds

• Lactate <2 mmol/L is considered normal. 1, 4
• Lactate 2-4 mmol/L indicates potential tissue hypoperfusion with ~30% mortality, warranting investigation and aggressive fluid resuscitation. 1
• Lactate ≥4 mmol/L represents a medical emergency with 46.1% mortality, requiring immediate protocolized resuscitation. 1
• Lactate >5 mmol/L indicates serious, possibly life-threatening situations. 1
• Lactate >10 mmol/L is life-threatening regardless of cause. 3

Critical Pitfall: "Cryptic Shock"

Up to 23% of septic patients have lactate ≥2 mmol/L with central venous oxygen saturation (ScvO2) >70%, representing "cryptic shock" where normal hemodynamics mask tissue hypoperfusion. 1 This occurs because sepsis impairs cellular oxygen extraction despite adequate oxygen delivery, making traditional perfusion markers unreliable. 1

Alternative Mechanism: Aerobic Glycolysis

Lactate elevation does not always indicate tissue hypoxia—aerobic glycolysis stimulated by epinephrine can produce lactate in well-oxygenated tissues, particularly skeletal muscle. 1, 5, 6 This mechanism explains why hyperlactatemia often fails to correlate with traditional perfusion indicators and may not respond to increased oxygen delivery. 5

Systematic Diagnostic Approach

When encountering elevated lactate, assess for:

• Signs of shock: hypotension (MAP <65 mmHg), cold/sweaty extremities, oliguria (<0.5 mL/kg/hr), altered mental status, narrow pulse pressure. 1
• Infection source: fever, tachycardia, leukocytosis suggesting sepsis. 1
• Abdominal pain: with lactate >2 mmol/L, immediately consider mesenteric ischemia and obtain CT angiography urgently. 1, 4
• Medication review: metformin (especially with renal impairment), NRTIs, epinephrine infusions. 1, 4
• Organ dysfunction: check renal function (eGFR), liver function tests, and calculate anion gap (Na - [Cl+CO2] >16 suggests lactic acidosis). 1, 4

Essential Laboratory Evaluation

• Serial lactate measurements every 2-6 hours during acute resuscitation to assess treatment response. 1
• Arterial blood gas with pH and base deficit provides independent information about global tissue acidosis that doesn't strictly correlate with lactate. 1
• Complete metabolic panel including electrolytes, creatinine, and liver function tests. 1
• D-dimer >0.9 mg/L has 82% specificity for intestinal ischemia when abdominal pain is present. 1

Management Principles

The primary treatment of elevated lactate is identifying and aggressively treating the underlying cause—tissue hypoperfusion requires immediate fluid resuscitation and hemodynamic support. 1, 4

• Initial fluid resuscitation: 30 mL/kg IV crystalloid within first 3 hours for sepsis-associated hyperlactatemia. 1
• Vasopressor support: norepinephrine as first-line when MAP <65 mmHg persists despite adequate fluid resuscitation. 1
• Target lactate clearance: ≥10% every 2 hours during the first 8 hours of resuscitation. 1
• Discontinue offending medications: immediately stop metformin in sepsis/AKI, consider switching NRTIs in HIV patients. 1, 4

Bicarbonate Controversy

Sodium bicarbonate should NOT be used for pH ≥7.15 in hypoperfusion-induced lactic acidemia, as it does not improve outcomes and may cause harm. 1, 4 Bicarbonate increases lactate production, causes hypernatremia and volume overload, generates CO₂, and has never been shown to improve survival. 4

Prognostic Significance

Lactate clearance time is the most significant predictor of survival—normalization within 24 hours associates with 100% survival in trauma patients, declining to 77.8% if normalized within 48 hours, and only 13.6% if elevated beyond 48 hours. 1 The duration of lactic acidosis (time with lactate >2 mmol/L) is the best predictor of multi-organ failure development. 1