What every intensivist should know about the biphasic kinetics of lactate in septic shock

Lactate is a central biomarker in septic shock, but its interpretation requires understanding its biphasic kinetics. In survivors, lactate clearance typically follows two phases: an initial 6-12 h, predominantly flow-dependent phase, where elevated levels reflect tissue hypoperfusion and improve with restoration of oxygen delivery via fluids, vasopressors, or correction of hypoxemia; and a later phase (>12 h), where persistent hyperlactatemia more often reflects metabolic reprogramming, immune activation, and mitochondrial dysfunction rather than ongoing hypoperfusion. Clinical and experimental data suggest that hyperlactatemia must be contextualized: severe systolic dysfunction may impair clearance despite restored flow, while excessive beta-stimulation (particularly epinephrine) can elevate lactate without metabolic shift. Observational studies demonstrate that persistent hyperlactatemia with a hypoperfusion context (e.g., abnormal CRT, low ScvO₂, or elevated P(cv-a)CO₂) carries worse outcomes, whereas persistent hyperlactatemia without hypoperfusion may be misleading and should not drive further resuscitation. The ANDROMEDA-SHOCK trial validated this concept, showing that CRT-guided resuscitation improved outcomes compared with lactate-guided therapy, highlighting the risk of overintervention. Emerging biomarkers such as lactylation, transcriptomic signatures, and metabolomic profiles may help identify transitions to the metabolic phase, expanding therapeutic opportunities. Lactate should therefore be interpreted as both a hemodynamic and metabolic biomarker, integrated with perfusion indices to guide escalation, timely deescalation, and potential adjunctive interventions in septic shock.