Persistent tissue hypoperfusion improves risk stratification beyond vasopressor dose in refractory septic shock: a secondary analysis of the ANDROMEDA-SHOCK-2 trial

Purpose: A recent Delphi consensus highlighted elements for defining refractory septic shock. We assessed whether integrating persistent tissue hypoperfusion with vasopressor dose after protocolized resuscitation improves mortality risk stratification compared with vasopressor dose alone. Methods: We performed an exploratory secondary analysis of the ANDROMEDA-SHOCK-2 trial. After 6 h of hemodynamic resuscitation, refractoriness was operationalized as a norepinephrine equivalent dose (NEE) > 0.5 µg/kg/min plus an abnormal capillary refill time (> 3 s) and non-decreasing lactate (two-hypoperfusion criteria). A complementary analysis included NEE > 0.5 µg/kg/min combined with either of the tissue perfusion criteria. The primary outcome was 28-day mortality. Results: Among 1363 patients with complete data, 188 (13.8%) had NEE > 0.5 µg/kg/min at 6-h, with 47.9% mortality. Fifty-three patients (3.9%) were classified as refractory septic shock under the two-hypoperfusion criteria and 124 (9.1%) under the ≥ 1-hypoperfusion criterion. Mortality was 73.6% (39/53) among patients meeting two-hypoperfusion criteria, compared with 23.7% (310/1310) among those classified as non-refractory according to these criteria. (aHR, 4.68; 95% CI 3.31-6.64;p < 0.001). Under ≥ 1-hypoperfusion criterion, mortality was 55.0% (68/124), compared with 22.7% (281/1239) among those classified as non-refractory under this approach (aHR, 2.62; 95% CI 1.90-3.46;p < 0.001). Refractory patients under either approach required had fewer life-support free days. Compared with NEE > 0.5 µg/kg/min alone, the two-hypoperfusion construct yielded superior prognostic enrichment for 28-day mortality (LR + , 8.12; 95% CI 4.70-14.03 vs. 2.71; 95% CI 2.10-3.50;p < 0.001). Conclusion: In early septic shock, combining persistent tissue hypoperfusion with vasopressor dose improves risk stratification beyond vasopressor dose alone and identifies a subgroup with markedly increased mortality. These hypothesis-generating findings require validation in future studies.