What are the causes of lactic acidosis and how should it be evaluated?

Causes of Elevated Lactate Levels

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 to rely on anaerobic metabolism. 1, 2

Type A Lactic Acidosis (Tissue Hypoxia)

• Shock states of any etiology—hypovolemic, cardiogenic, distributive (septic), or obstructive—impair tissue perfusion and trigger anaerobic glycolysis, with lactate serving as an indirect marker of oxygen debt 3, 1
• Sepsis and septic shock cause lactic acidosis through both tissue hypoperfusion and inflammatory mediators that disrupt cellular metabolism, with lactate ≥4 mmol/L associated with 46.1% mortality 1, 4
• Hemorrhagic shock and major trauma produce lactate elevation that correlates directly with mortality; normalization within 24 hours is associated with 100% survival in trauma patients, dropping to 77.8% if normalized by 48 hours and 13.6% if elevated beyond 48 hours 3, 1
• Mesenteric ischemia presents with lactate >2 mmol/L in 88% of cases, with levels above this threshold carrying a 4.1-fold increased risk of irreversible intestinal ischemia 1, 4
• Cardiac arrest and severe cardiac failure reduce systemic oxygen delivery, forcing tissues into anaerobic metabolism 5, 2
• Severe anemia or carbon monoxide poisoning impair oxygen-carrying capacity, creating functional tissue hypoxia despite adequate perfusion 5
• Respiratory failure with severe hypoxemia limits oxygen availability at the alveolar level 4

Type B Lactic Acidosis (Without Tissue Hypoxia)

Medication-Induced Causes

• Metformin causes lactic acidosis primarily in patients with impaired clearance (eGFR <30 mL/min/1.73 m²), impaired lactate clearance (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; risk factors include obesity, female sex, prolonged use, and pregnancy 4
• Epinephrine and other beta-agonists elevate lactate through beta-2-adrenergic receptor stimulation in skeletal muscle, activating glycogenolysis and glycolysis independent of tissue perfusion 1
• Propofol infusion syndrome can cause severe lactic acidosis, particularly with prolonged high-dose infusions 5
• Linezolid causes mitochondrial toxicity with prolonged use (>28 days) 5

Metabolic and Organ Dysfunction

• Liver disease impairs lactate clearance because the liver is the major site of lactate removal through gluconeogenesis and oxidation; hepatic congestion from heart failure can cause both cholestatic patterns and elevated lactate 1, 4, 6
• Renal impairment reduces lactate clearance, with hyperlactatemia reported in 30-65% of adults with chronic kidney disease 4
• Thiamine (vitamin B1) deficiency impairs pyruvate dehydrogenase function, blocking conversion of pyruvate to acetyl-CoA and shunting metabolism toward lactate production 1, 5
• Diabetic ketoacidosis can cause concurrent lactate elevation through multiple mechanisms including dehydration and tissue hypoperfusion 7
• Malignancy—particularly hematologic malignancies and solid tumors with high metabolic rates—can produce lactate through aerobic glycolysis (Warburg effect) 5, 8
• D-lactic acidosis occurs in patients with short bowel syndrome and preserved colon, where colonic bacteria ferment carbohydrates to D-lactate 4

Physiologic and Benign Causes

• Recent exercise or physical exertion prior to blood draw commonly causes transient lactate elevation through increased muscle glycolysis 7, 5
• Labor and delivery transiently elevate lactate; lactate should not be used to diagnose sepsis during labor per CMS guidance 1, 4
• Seizure activity increases lactate through intense muscle activity and increased cerebral metabolism 5

Rare and Specialized Causes

• Rhabdomyolysis causes lactate elevation through damaged muscle tissue undergoing anaerobic metabolism, with risk of concurrent hyperkalemia and cardiac dysfunction 4
• Cyanide poisoning blocks cytochrome oxidase, preventing cellular oxygen utilization despite adequate delivery 6
• Inborn errors of metabolism—including methylmalonic acidemia, propionic acidemia, and maple syrup urine disease—can cause Type B lactic acidosis 4
• Severe hypophosphatemia (<0.32 mmol/L), particularly in refeeding syndrome or during prolonged kidney replacement therapy, triggers lactic acidosis through impaired ATP production 4

Evaluation Algorithm

Initial Assessment

• Measure serum lactate in all patients with suspected severe infection, shock, trauma, or unexplained metabolic acidosis; normal values are <2 mmol/L 1, 7
• Assess hemodynamic status: check blood pressure (target MAP ≥65 mmHg), heart rate, urine output (target ≥0.5 mL/kg/hr), mental status, capillary refill (target ≤2 seconds), and extremity temperature 1
• Obtain arterial blood gas to measure pH and calculate base deficit, which provides independent information about global tissue acidosis that doesn't strictly correlate with lactate 3, 1
• Calculate anion gap (Na − [Cl+CO₂]); values >16 suggest lactic acidosis 1, 4

Risk Stratification by Lactate Level

• Lactate <2 mmol/L: Normal; no immediate intervention required unless clinical deterioration occurs 1, 7
• Lactate 2-4 mmol/L: Moderate tissue hypoperfusion with ~30% mortality; warrants aggressive fluid resuscitation with at least 30 mL/kg IV crystalloid within first 3 hours and frequent reassessment 1
• Lactate ≥4 mmol/L: Medical emergency with 46.1% mortality; requires immediate protocolized resuscitation targeting CVP 8-12 mmHg, MAP ≥65 mmHg, urine output ≥0.5 mL/kg/hr, and ScvO₂ ≥70% within first 6 hours 1
• Lactate >5 mmol/L: Severe hyperlactatemia indicating serious, possibly life-threatening situation requiring ICU-level care 1

Targeted Diagnostic Workup

• If abdominal pain present: Immediately consider mesenteric ischemia; check D-dimer (>0.9 mg/L has 82% specificity for intestinal ischemia) and proceed urgently to CT angiography without delay, as diagnostic delay is the dominant factor in 30-70% mortality 1, 4
• If sepsis suspected: Obtain blood cultures before antibiotics, administer broad-spectrum antibiotics within 1 hour for septic shock, and initiate source control 1, 7
• If medication-induced suspected: Review medication list for metformin (check eGFR), NRTIs, propofol, linezolid, or recent epinephrine administration 1, 4
• If liver disease present: Check hepatic transaminases and synthetic function (INR, albumin), as liver dysfunction impairs lactate clearance 4, 6
• If renal impairment present: Check eGFR and creatinine; renal dysfunction reduces lactate clearance and contraindicates metformin when eGFR <30 mL/min/1.73 m² 1, 4
• If thiamine deficiency suspected: Consider thiamine supplementation, especially in alcoholism, malnutrition, or refeeding syndrome 1, 4

Serial Monitoring Strategy

• Repeat lactate every 2-6 hours during acute resuscitation to assess treatment response; target lactate clearance of ≥10% every 2 hours during first 8 hours 1
• Monitor complementary parameters: base deficit, ScvO₂, urine output, mental status, and capillary refill provide independent information about tissue perfusion 3, 1
• Target normalization within 24 hours, as this is associated with markedly improved survival across all shock states 3, 1

Critical Pitfalls to Avoid

• Do not ignore elevated lactate in hemodynamically stable patients—up to 23% of septic patients have lactate ≥2 mmol/L with ScvO₂ >70%, representing "cryptic shock" that doesn't fit traditional definitions; normal blood pressure does not rule out tissue hypoperfusion 1
• Do not delay imaging for mesenteric ischemia when lactate >2 mmol/L with abdominal pain, even in seemingly stable patients; the combination warrants immediate CT angiography 1, 4
• Do not use sodium bicarbonate for pH ≥7.15—it does not improve hemodynamics or survival and may cause harm by increasing lactate production, causing hypernatremia, and generating CO₂ 1, 4
• Do not rely on single hematocrit measurements to detect bleeding, as initial values are confounded by resuscitation fluids 3, 4
• Do not attribute all lactate elevation to tissue hypoxia—consider medication effects (especially epinephrine), recent exercise, liver disease, and malignancy as alternative causes 1, 5
• Do not continue metformin in patients with sepsis, acute kidney injury, dehydration, or any hypoxic state; discontinue immediately 1, 4
• Do not dismiss nonspecific gastrointestinal symptoms (nausea, vomiting, abdominal pain) in at-risk patients taking NRTIs, as these may represent a 1-6 week prodrome before severe acidosis develops 4
• Do not use lactate to diagnose sepsis during labor, as labor itself transiently elevates lactate 1, 4