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

Area of Science:

• Critical Care Medicine
• Sepsis Management
• Clinical Epidemiology

Background:

• The optimal timing for sepsis interventions in intensive care units (ICUs) remains debated.
• Limited high-quality randomized evidence exists for early sepsis management in ICU patients.
• The one-hour sepsis bundle, established in 2018, guides initial care, but specific timing for key interventions requires further clarification.

Purpose of the Study:

• To emulate target trials using observational data to investigate the optimal timing of antibiotic, fluid resuscitation, and vasopressor initiation in ICU patients with sepsis.
• To compare the outcomes of initiating these interventions within 0-1 hour versus 1-3 hours after a prespecified time zero.
• To provide evidence-based recommendations for refining sepsis treatment guidelines.

Main Methods:

• Retrospective, multicenter cohort study using the Medical Information Mart for Intensive Care-IV database and two Chinese ICU cohorts.
• Emulation of three target trials using a target trial emulation framework.
• Inverse probability of treatment weighting (IPTW) was applied to adjust for confounding factors.
• Comparison of interventions initiated within 0-1 hour versus 1-3 hours, with sensitivity analyses using a 1-6 hour window.

Main Results:

• Initiation of antibiotics within 1 hour was associated with significantly lower 28-day mortality (HR 0.65) and earlier ICU discharge (SHR 1.20).
• Fluid resuscitation initiated within 1 hour, with ≥30 mL/kg crystalloid delivered within 3 hours, resulted in lower mortality (HR 0.72) and earlier ICU discharge (SHR 1.17).
• Vasopressor initiation within 1 hour showed no significant survival benefit (HR 1.07) or reduction in time to ICU discharge (SHR 1.02).

Conclusions:

• Early administration of antibiotics and initiation of fluid resuscitation within the first hour are associated with improved survival and earlier ICU discharge in sepsis patients.
• Early vasopressor use within the first hour did not demonstrate a survival benefit or reduced time to ICU discharge.
• These findings support prioritizing timely antibiotic and fluid administration in early sepsis resuscitation and may inform future guideline revisions.