Survival Benefit and Cost Savings From Compliance With a Simplified 3-Hour Sepsis Bundle in a Series of Prospective, Multisite, Observational Cohorts

Daniel E. Leisman, BS; Martin E. Doerfler, MD; Mary Frances Ward, RN, MS, ANP; Kevin D. Masick, PhD; Benjamin J. Wie, BA; Jeanie L. Gribben, BS; Eric Hamilton, BA; Zachary Klein, MS; Andrea R. Bianculli, BS; Meredith B. Akerman, MS; John K. D'Angelo, MD; Jason A. D'Amore, MD


Crit Care Med. 2017;45(3):395-406. 

In This Article

Abstract and Introduction


Objectives: To determine mortality and costs associated with adherence to an aggressive, 3-hour sepsis bundle versus noncompliance with greater than or equal to one bundle element for severe sepsis and septic shock patients.

Design: Prospective, multisite, observational study following three sequential, independent cohorts, from a single U.S. health system, through their hospitalization.

Setting: Cohort 1: five tertiary and six community hospitals. Cohort 2: single tertiary, academic medical center. Cohort 3: five tertiary and four community hospitals.

Patients: Consecutive sample of all severe sepsis and septic shock patients (defined: infection, ≥ 2 systemic inflammatory response syndrome, and hypoperfusive organ dysfunction) identified by a quality initiative. The exposure was full 3-hour bundle compliance. Bundle elements are as follows: 1) blood cultures before antibiotics; 2) parenteral antibiotics administered less than or equal to 180 minutes from greater than or equal to two systemic inflammatory response syndrome "and" lactate ordered, or less than or equal to 60 minutes from "time-zero," whichever occurs earlier; 3) lactate result available less than or equal to 90 minutes postorder; and 4) 30 mL/kg IV crystalloid bolus initiated less than or equal to 30 minutes from "time-zero." Main outcomes were in-hospital mortality (all cohorts) and total direct costs (cohorts 2 and 3).

Measurements and Main Results: Cohort 1: 5,819 total patients; 1,050 (18.0%) bundle compliant. Mortality: 604 (22.6%) versus 834 (26.5%); CI, 0.9–7.1%; adjusted odds ratio, 0.72; CI, 0.61–0.86; p value is less than 0.001. Cohort 2: 1,697 total patients; 739 (43.5%) bundle compliant. Mortality: 99 (13.4%) versus 171 (17.8%), CI, 1.0–7.9%; adjusted odds ratio, 0.60; CI, 0.44–0.80; p value is equal to 0.001. Mean costs: $14,845 versus $20,056; CI, –$4,798 to –5,624; adjusted β, –$2,851; CI, –$4,880 to –822; p value is equal to 0.006. Cohort 3: 7,239 total patients; 2,115 (29.2%) bundle compliant. Mortality: 383 (18.1%) versus 1,078 (21.0%); CI, 0.9–4.9%; adjusted odds ratio, 0.84; CI, 0.73–0.96; p value is equal to 0.013. Mean costs: $17,885 versus $22,108; CI, –$2,783 to –5,663; adjusted β, –$1,423; CI, –$2,574 to –272; p value is equal to 0.015.

Conclusions: In three independent cohorts, 3-hour bundle compliance was associated with improved survival and cost savings.


Sepsis is a leading cause of death and healthcare spending globally.[1,2] U.S. prevalence alone conservatively exceeds 1,000,000 cases per year in patients greater than or equal to 65, accounting for approximately 350,000 deaths.[3] In 2011, sepsis accounted for $20 billion in payer costs.[4]

Despite substantial effort, advances in understanding and managing sepsis have been modest. For years, best-practice discourse focused on "early goal-directed therapy", based on a 6-hour septic shock bundle that espoused optimizing central venous pressure (CVP) and oxygenation with inotropes and blood transfusion, adjusted based on rigorous hemodynamic monitoring.[5] Three recent multisite randomized trials all failed to demonstrate mortality benefits from EGDT versus "usual care".[6–8] However, although standard-of-care has changed over ensuing years prohibiting direct comparisons, both study and control arm patients in all three recent trials, and in the trial by Rivers et al,[5] received early antibiotics and empiric IV fluid resuscitation with average times less than 3 hours. Several studies investigating bundle "compliance," of which early IV fluid and antibiotic administration is a component, report association between full compliance and better outcomes.[9–13] This raises the question as to whether the original benefit of EGDT lied not in invasive, resource-intensive, hemodynamic monitoring, but earlier sepsis identification and intervention. The impact of full compliance with a 3-hour bundle alone in a population where there was no requirement to apply a 6-hour bundle has not been investigated.

Recently, a joint Society for Critical Care Medicine (SCCM) and European Society of Intensive Care Medicine (ESICM) Task Force recommended changes to definitions of septic disease and identification measures, focusing on sepsis-induced organ dysfunction and diagnostic criteria.[14–16] The literature and recommendations reflect ambiguity in both defining sepsis and executing evidence-based management. Despite this, consensus remains on the importance of early intervention with IV fluids and antibiotics.

Reliable timely parenteral antibiotics and fluid administration for severe sepsis and septic shock (SS/SS) is the accepted standard in randomized trials, but often not achieved in community settings. We began a quality improvement (QI) project based upon the hypothesis that reliably implementing an aggressive 3-hour sepsis treatment bundle for every patient, every time, in a large multihospital health system would improve outcomes. The adopted bundle emphasizes early recognition with a focus on "time-zero" entry points followed by aggressive, time-sensitive collection of blood cultures, ordering and return of lactate levels, and administration of fluids and antibiotics within 180 minutes. Importantly, this approach obligates only rapid delivery of simple interventions with a focus on preventing further organ injury, and has no reliance on physiologic endpoints. It leaves all management beyond 3 hours to physician discretion.

We hypothesize that time-dependent adherence to all elements of a 3-hour sepsis bundle, without reliance on specific physiologic goals, may be sufficient to improve in-hospital mortality while reducing spending for providers and payers alike in this high-incidence, high-acuity population. We conducted a series of sequential, prospective, observational cohort studies with the objective of determining mortality and costs associated with 3-hour bundle compliance.