Effect modification by baseline lactate in the association between time to assigned mean arterial pressure target and outcomes in older patients with septic shock: a post hoc analysis of the OPTPRESS trial

Time to target mean arterial pressure (TTT-MAP) may capture the temporal dimension of circulatory recovery in septic shock; however, its prognostic relevance needs clarification. This study aimed to investigate the impact of baseline lactate on the TTT-MAP-clinical outcome association. We performed a post hoc secondary analysis of the OPTPRESS trial, a multicenter randomized controlled trial of older patients with septic shock. TTT-MAP (the time from randomization to first attainment of the assigned MAP threshold) was treated as a post-randomization process variable (not an independent baseline exposure). Regression models assessed effect modification by baseline lactate. For clinical interpretation, we examined lactate-informed TTT-MAP phenotypes (initial lactate dichotomized at the cohort median) and TTT-MAP (dichotomized according to the within-group median time to target attainment). The primary outcome was 90-day all-cause mortality. Secondary outcomes were 28-day all-cause mortality, ventilator-free days at day 28, and renal replacement therapy-free days at day 28. The complete-case cohort included 472 of 516 patients in the OPTPRESS dataset. The primary continuous interaction between initial lactate and TTT-MAP was significantly associated with 90-day mortality, indicating that the prognostic association of TTT-MAP differed by baseline lactate. Compared with the low lactate/short TTT-MAP phenotype, the high lactate/long TTT-MAP phenotype was associated with higher 90-day and 28-day mortalities after covariate adjustment and fewer ventilator-free and renal replacement therapy-free days. Prolonged TTT-MAP in the low-lactate context was not associated with adverse outcomes. These findings remained consistent after adjustment for pre-randomization norepinephrine dose and in sensitivity analyses classifying unreached patients into the long TTT-MAP group. The prognostic association between TTT-MAP and 90-day mortality differed by baseline lactate in older patients with septic shock. TTT-MAP should be interpreted as a post-randomization process marker reflecting evolving shock severity and treatment responsiveness, rather than an independent or directly modifiable exposure. These hypothesis-generating findings suggest that delayed target MAP attainment may convey greater adverse prognostic information when baseline lactate is elevated and require external validation. The OPTPRESS trial was registered in the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR; UMIN000041775) on 13 September 2020.