• Lisiane Pruinelli, Bonnie L Westra, Pranjul Yadav, Alexander Hoff, Michael Steinbach, Vipin Kumar, Connie W Delaney, and Gyorgy Simon.
• Population Health and Systems, University of Minnesota, School of Nursing, Minneapolis, MN.
• Crit. Care Med. 2018 Apr 1; 46 (4): 500-505.

ObjectivesTo specify when delays of specific 3-hour bundle Surviving Sepsis Campaign guideline recommendations applied to severe sepsis or septic shock become harmful and impact mortality.DesignRetrospective cohort study.SettingOne health system composed of six hospitals and 45 clinics in a Midwest state from January 01, 2011, to July 31, 2015.PatientsAll adult patients hospitalized with billing diagnosis of severe sepsis or septic shock.InterventionsFour 3-hour Surviving Sepsis Campaign guideline recommendations: 1) obtain blood culture before antibiotics, 2) obtain lactate level, 3) administer broad-spectrum antibiotics, and 4) administer 30 mL/kg of crystalloid fluid for hypotension (defined as "mean arterial pressure" < 65) or lactate (> 4).Measurements And Main ResultsTo determine the effect of t minutes of delay in carrying out each intervention, propensity score matching of "baseline" characteristics compensated for differences in health status. The average treatment effect in the treated computed as the average difference in outcomes between those treated after shorter versus longer delay. To estimate the uncertainty associated with the average treatment effect in the treated metric and to construct 95% CIs, bootstrap estimation with 1,000 replications was performed. From 5,072 patients with severe sepsis or septic shock, 1,412 (27.8%) had in-hospital mortality. The majority of patients had the four 3-hour bundle recommendations initiated within 3 hours. The statistically significant time in minutes after which a delay increased the risk of death for each recommendation was as follows: lactate, 20.0 minutes; blood culture, 50.0 minutes; crystalloids, 100.0 minutes; and antibiotic therapy, 125.0 minutes.ConclusionsThe guideline recommendations showed that shorter delays indicates better outcomes. There was no evidence that 3 hours is safe; even very short delays adversely impact outcomes. Findings demonstrated a new approach to incorporate time t when analyzing the impact on outcomes and provide new evidence for clinical practice and research.

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