Time to antimicrobial therapy in septic shock patients treated with an early goal-directed resuscitation protocol: a post-hoc analysis of the ARISE trial

Objective: Intravenous antimicrobial therapy within 1 h of the diagnosis of septic shock is recommended in international sepsis guidelines. We aimed to evaluate the association between antimicrobial timing and mortality in patients presenting to the ED with septic shock. Methods: Post-hoc analysis of 1587 adult participants enrolled in the Australasian Resuscitation in Sepsis Evaluation (ARISE) multicentre trial of early goal-directed therapy for whom the time of initial antimicrobial therapy was recorded. We compared participants who had initiation of antimicrobials within the first hour (early) or later (delayed) of ED presentation. A propensity score model using inverse probability of treatment weighting was constructed to account for confounding baseline covariates. The primary outcome was 90-day mortality. Results: The median (interquartile range) time to initiating antimicrobials was 69 (39–112) min with 712 (44.9%) participants receiving the first dose within the first hour of ED presentation. Compared with delayed therapy, early administration was associated with increased baseline illness severity score and greater intensity of resuscitation pre-randomisation (fluid volumes, vasopressors, invasive ventilation). All-cause 90-day mortality was also higher; 22.6% versus 15.5%; unadjusted odds ratio (OR) 1.58 (95% confidence interval [CI] 1.16–2.15), P = 0.004. After inverse probability of treatment weighting, the mortality difference was non-significant; OR 1.30 (95% CI 0.95–1.76), P = 0.1. Live discharge rates from ICU (OR 0.81, 95% CI 0.72–0.91; P = 0.80) and hospital (OR 0.93, 95% CI 0.82–1.06; P = 0.29) were also not different between groups. Conclusion: In this post-hoc analysis of the ARISE trial, early antimicrobial therapy was associated with increased illness severity, but 90-day adjusted mortality was not reduced.