What are the causes of hyperlactemia in critically ill patients, particularly those with a history of diabetes?

Causes of Hyperlactatemia in Critically Ill Patients with Diabetes

Tissue hypoperfusion and hypoxia from shock states (septic, hypovolemic, cardiogenic) is the most common cause of hyperlactatemia in critically ill patients, regardless of diabetes status, though diabetic patients typically present with higher baseline lactate levels and may reach severe hyperlactatemia (>4 mmol/L) more frequently than non-diabetic patients. 1, 2

Primary Causes of Hyperlactatemia

Tissue Hypoperfusion and Shock States

• Sepsis and septic shock causes lactic acidosis through both inadequate tissue perfusion and inflammatory mediators disrupting cellular metabolism, representing a major cause in critically ill populations 3, 1
• Hypovolemic, cardiogenic, and distributive shock all impair tissue oxygen delivery, triggering anaerobic metabolism and lactate accumulation 1, 4
• Trauma with hemorrhagic shock produces elevated lactate that correlates directly with mortality risk 1

Metabolic and Systemic Causes

• Acute renal failure induces global metabolic derangements including hyperglycemia from peripheral insulin resistance and activated hepatic gluconeogenesis, with protein catabolism as the metabolic hallmark 3
• Accelerated aerobic glycolysis driven by excess beta-adrenergic stimulation increases lactate production independent of tissue hypoxia 1
• Diabetic ketoacidosis (DKA) commonly presents with hyperlactatemia (88% of cases show lactate >2 mmol/L, mean 3.2 mmol/L), which can persist beyond 12 hours in 28% of cases, particularly in females with aggressive glucose correction 5

Medication-Induced Hyperlactatemia (Critical in Diabetic Patients)

Metformin-Associated Lactic Acidosis

• Metformin causes lactic acidosis when combined with impaired clearance (eGFR <30 mL/min/1.73 m²), impaired lactate clearance (liver failure), or conditions causing anaerobic metabolism (sepsis, hypoxia, acute heart failure) 1, 6
• Metformin decreases hepatic lactate uptake, increasing blood lactate levels, with characteristic findings of lactate >5 mmol/L, anion gap acidosis, increased lactate:pyruvate ratio, and metformin plasma levels >5 mcg/mL 6
• Risk factors requiring metformin discontinuation: acute congestive heart failure with hypoperfusion, cardiovascular collapse, acute myocardial infarction, sepsis, conditions with hypoxemia, hepatic impairment, excessive alcohol intake, and radiologic contrast procedures 6

Other Medications

• Epinephrine elevates lactate through beta-2-adrenergic receptor stimulation in skeletal muscle, activating glycogenolysis and glycolysis independent of tissue perfusion status 1
• Various other medications can cause hyperlactatemia in therapeutic or supratherapeutic dosing, though this remains an uncommon cause that providers often fail to recognize 7

Renal Replacement Therapy-Related Causes

• Continuous renal replacement therapy (CRRT) using lactate-buffered substitution fluids or citrate anticoagulation can cause hyperlactatemia or metabolic alkalosis 3
• CRRT causes significant amino acid losses (10-15 g/day) and protein losses (5-10 g/day), contributing to metabolic derangements 3

Special Considerations in Diabetic Patients

Higher Baseline Lactate Levels

• Diabetic patients demonstrate higher lactate concentrations than non-diabetic patients in acute illness (mean 6.3 ± 3.4 mmol/L vs 5.1 ± 3.2 mmol/L), with 65.2% reaching severe hyperlactatemia (>4 mmol/L) compared to only 34.8% of non-diabetic patients 2
• The same lactate cut-off values may not hold equal prognostic significance in diabetic versus non-diabetic patients, as lactate >4 mmol/L was an independent predictor of mortality in non-diabetic patients but not in diabetic patients 2

Contributors to Severe Hyperlactatemia in Diabetic Patients

• Metformin consumption with concurrent factors potentiating accumulation (renal impairment, liver disease, sepsis) 2
• Sepsis/septic shock 2
• Ischemic conditions 2
• Malignancy 2

Embolic and Vascular Causes

• Arterial embolism to mesenteric vessels causes sudden lactate elevation >2 mmol/L (Hazard Ratio 4.1 for irreversible intestinal ischemia), typically presenting as sudden intense abdominal pain with minimal physical findings in patients with atrial fibrillation 1
• More than 88% of patients with mesenteric ischemia present with metabolic acidosis and elevated lactate 1

Critical Pitfalls to Avoid

• Don't ignore elevated lactate in hemodynamically stable diabetic patients: Blood pressure alone inadequately assesses tissue perfusion, and patients can maintain normal blood pressure through compensatory mechanisms while experiencing significant tissue hypoperfusion 1
• Don't assume metformin is safe in acute illness: Even therapeutic metformin dosing becomes dangerous when combined with sepsis, renal impairment (eGFR <45 mL/min/1.73 m²), liver disease, or hypoxic states 6
• Don't apply the same lactate thresholds uniformly: Diabetic patients may require higher lactate thresholds for prognostic assessment given their elevated baseline levels 2
• Don't delay imaging for suspected mesenteric ischemia: When lactate >2 mmol/L with abdominal pain, proceed urgently to CT angiography without waiting for lactate trends, as multi-visceral involvement is required before systemic lactate increases 1

Clinical Approach Algorithm

For lactate ≥4 mmol/L:

• Initiate immediate protocolized resuscitation targeting MAP ≥65 mmHg, CVP 8-12 mmHg, urine output ≥0.5 mL/kg/h, and ScvO2 ≥70% 1
• Discontinue metformin immediately if patient is taking it 6
• Administer 30 mL/kg IV crystalloid within first 3 hours 1

For lactate 2-4 mmol/L:

• Begin aggressive fluid resuscitation with at least 30 mL/kg IV crystalloid within first 3 hours 1
• Perform serial lactate measurements every 2-6 hours targeting normalization within 24 hours (associated with 100% survival in trauma patients) 1
• Assess for occult tissue hypoperfusion even if blood pressure is normal 1

In diabetic patients specifically:

• Check eGFR and discontinue metformin if <45 mL/min/1.73 m² or if any acute illness present 6
• Consider that lactate >4 mmol/L may not carry the same mortality prediction as in non-diabetic patients 2
• Monitor for prolonged hyperlactatemia in DKA, particularly in females with aggressive glucose correction (target glucose ≥11 mmol/L initially) 5