Effect of the 1-hour Sepsis Bundle on In-hospital Mortality in Patients With Sepsis in the Emergency Department: a Randomized Controlled Trial

In Europe, one third of patients with sepsis and septic shock are admitted through the emergency department (ED), with an overall in-hospital mortality of 20%, and 90 days mortality of 25%. Reducing the mortality and morbidity of sepsis is thus a worldwide priority.

In 2016, the "Surviving Sepsis Campaign" (SSC), an international group of experts, recommended that physicians should complete the sepsis bundle in the first 3-h, which included blood culture, lactate measurement, broad spectrum antibiotics, and 30ml/kg fluid resuscitation in case of hypotension. Subsequently to the publication of a large retrospective study in NYC that reported a higher risk of mortality for each additional hour to complete the sepsis bundle, the 2018 update of the SSC guidelines moved further and recommended an even shorter timeframe of 1-h from ED triage to initiate the sepsis bundle. This new recommendation is vividly debated and several scientific societies, such as the SCCM, ACEP, and EUSEM have recommended that hospitals should not implement the one-hour sepsis bundle before having more evidence. Indeed, the quality of evidence supporting this new guidance was acknowledged overall as low to moderate and as requiring confirmatory studies. Moreover, no trial has ever studied a sepsis intervention when applied as early as ED triage (newly recommended 1-h sepsis bundle consider time zero as time of ED triage).

The primary objective of this trial is thus to demonstrate that the early implementation at ED triage of the 1-hour bundle by ED physicians improves in-hospital mortality in patients with sepsis, and therefore provides the required robust evidence for the SSC guidance to enhance physicians and stakeholder adherence. In-hospital mortality has been chosen as a primary endpoint in several major trials, such as ProCESS and ANDROMEDA SCHOCK. This in-hospital mortality will be truncated at 28 days because longer term to death may not reflect an effect of an early intervention. Furthermore, it has been described that mortality that occurs after hospital discharge may not be linked with the index acute disease, but rather mostly due to comorbidities (Frog ICU) and thus less relevant for assessing the efficacy of two early interventions.

Secondary objectives include the in-hospital morbidity, antibiotic exposure and fluid resuscitation, an all cause 28-day mortality with the implementation of the 1-hour sepsis bundle at ED triage vs practice in patients with sepsis in the ED.

The recommended 1-hour sepsis bundle (intervention group) carries the risk of over-exposition to antibiotics and excessive fluids resuscitation that may contribute to acute heart failure. However, the routine practice with longer time frame to complete the bundle carries the risk of sub-optimal treatment of sepsis with potential higher risk of mortality. Equipoise remains on which strategy carries the higher risk. Data from one large observational study suggest that each additional hour to the 1-hour sepsis bundle could increase mortality by an adjusted Odds Ratio of 1.04 (1.03 - 1.06).