Twenty-five years of septic shock hemodynamic resuscitation trials: a conceptual perspective

Twenty-five years of septic shock resuscitation trials have progressively transformed the physiological understanding of shock and the way bedside interventions are conceptualized. Early strategies focused on correcting isolated global hemodynamic or metabolic targets through protocolized interventions, whereas more recent approaches increasingly recognize septic shock as a heterogeneous, dynamic, and context-dependent condition requiring individualized physiological assessment.

This perspective discusses how hemodynamic resuscitation trials during this quarter of a century have reshaped both the physiological understanding and methodological foundations of early shock management. Initial strategies, exemplified by early goal-directed therapy, aimed to correct global oxygen-derived variables through protocolized interventions designed to optimize oxygen delivery. However, the lack of reproducibility of this approach in subsequent multicenter trials, together with the recognition of the limitations of several other variables as potential resuscitation targets, revealed that septic shock cannot be adequately addressed through rigid algorithms based on isolated endpoints. Subsequent progress incorporated peripheral perfusion assessment, systematic evaluation of fluid responsiveness, critical care echocardiography, and hemodynamic phenotyping. Within this trajectory, ANDROMEDA-SHOCK shifted attention toward capillary refill time as a rapidly responsive clinical perfusion signal, contributing to improve some outcomes, and potentially limiting over-resuscitation. ANDROMEDA-SHOCK-2 further operationalized a personalized strategy based on capillary refill time, sequential phenotyping, reversible hemodynamic tests, and serial reassessment.

A quarter of a century of septic shock resuscitation trials reveal a consistent pattern: strategies centered on fixed and isolated physiological targets have repeatedly failed to achieve reproducible improvements in patient-centered outcomes. Recent data support a shift from isolated hemodynamic or metabolic targets, toward a physiology-guided, phenotype-driven resuscitation strategy, in which interventions are applied as reversible tests within short decision cycles and guided by rapidly responsive perfusion signals. Trials such as ANDROMEDA-SHOCK-2 represent important steps in this ongoing transition, but further refinement, validation, and implementation across diverse settings remain necessary.