Timing of Core Sepsis Bundle Elements Initiation in Critically Ill Patients: A Multicenter Target Trial Emulation Study

Purpose: One-hour sepsis bundle was developed in 2018. However, the optimal timing for antibiotic, fluid resuscitation, and vasopressor initiation in intensive care units (ICUs) remains debated. High-quality randomized evidence is limited, particularly for ICU patients. Therefore, we emulated three target trials using observational data. Patients and Methods: We conducted a retrospective, multicenter cohort study using data from the Medical Information Mart for Intensive Care-IV database (primary dataset), and two ICU cohorts from China (Zhujiang and Xiangya hospitals). Within a target trial emulation framework with inverse probability of treatment weighting, we constructed three two-arm trials comparing initiation of (1) antibiotics, (2) fluid resuscitation, and (3) vasopressors within 0-1 hour versus 1-3 hours after a prespecified time zero. Results: In the target trial emulations, antibiotic initiation within 1 hour was associated with lower 28-day mortality (HR 0.65; 95% CI 0.54-0.79) and earlier ICU discharge (competing-risk analysis; SHR 1.20; 95% CI 1.12-1.27) compared with initiation at 1-3 hours. For fluid resuscitation, initiating within 1 hour and delivering ≥30 mL/kg crystalloid within 3 hours resulted in lower mortality (HR 0.72; 95% CI 0.53-0.97) and earlier discharge (SHR 1.17; 95% CI 1.02-1.33). However, vasopressor initiation within 1 hour showed no survival benefit (HR 1.07; 95% CI 0.89-1.29) or reduction in time to ICU discharge (SHR 1.02; 95% CI 0.95-1.08). These findings remained consistent across sensitivity and subgroup analyses, including comparisons using a 1-6 hour window. Conclusion: In ICUs, early administration of antibiotics and initiation of fluid resuscitation within 1 hour were associated with improved survival and earlier ICU discharge, whereas early vasopressor use was not. These findings might support a bedside emphasis on timely antibiotics and fluids during early resuscitation and provide evidence for refining time targets in future sepsis guidelines.