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Background Carilion Roanoke Memorial Hospital (CRMH), an academic medical center in southwestern Virginia, manages over 70,000 annual Emergency Department (ED) visits. Sepsis is the leading cause of hospital admission and mortality nationwide and in November 2022, CRMH’s Vizient sepsis mortality index was 1.52—well above national benchmarks.A multidisciplinary team, supported by a Six Sigma Black Belt (SSBB), launched a structured improvement project to reduce mortality and streamline ED sepsis care.Objectives Discuss Lean Six Sigma tools to improve sepsis recognition and treatment.Demonstrate how data driven analysis supports effective root cause analysis.Describe how Failure Mode and Effect Analysis (FMEA) can build engagement among front-line practitioners.Methods Using the Define, Measure, Analyze, Improve, Control (DMAIC) framework, the SSBB conducted front-line observations and interviews to validate ‘work as performed’ and collaborated with the team to map the process using the Suppliers, Inputs, Process steps, Outputs, and Customers (SIPOC), swim lane diagrams, and Value Stream Mapping ( figure 1) that helped define workflows and gaps.Statistical analysis progressed from two-variable testing to multivariate analysis (figure 2). Causes of antibiotic delays were visualized with a Fishbone diagram (figure 3).To identify and quantify impact from potential disruptions, a Failure Modes and Effect Analysis - FMEA (figure 4) was facilitated with participation from dozens of ED staff, nurses, providers, and pharmacists. Identified disruptions—from patient arrival to inpatient transfer— were grouped by hazard scores and used to prioritize next steps and plan countermeasures.Key Interventions (September 2023 Launch)New ED sepsis workflow & screening processVisual trackboard icons and optimized sepsis order setsSystem-wide Sepsis Awareness CampaignElectronic health record (EHR) logic to prevent redundant inpatient alertsSepsis dashboard to monitor key process indicators (KPIs)Results Increased Sepsis recognition & screening ( figures 5 and 6)Increased On-time antibiotics (figure 7)Increased Orderset utilization (figure 8)Decreased Sepsis Mortality Index by 30% ≈ 51 lives saved (January-November 2024) (figure 9)Conclusions Structured PI + Six Sigma expertise, enabled the structure needed to assess sepsis care in the ED, identify root causes, and design impactful, sustainable solutions.A multidisciplinary team is essential for accurate assessment, solution design, and successful implementation.Combining quantitative data analysis with qualitative input from FMEA is an effective strategy to guide meaningful and lasting quality improvement initiatives in healthcare.Abstract 46 Figure 1Value stream mapping for sepsis present on admission patients (current state)Abstract 46 Figure 2Multi variable chart example for NEDOCS score + antibiotic administration + patient outcomeAbstract 46 Figure 3Ishikawa diagram for delays in antibiotic administration for sepsis patientsAbstract 46 Figure 4Partial section of the failure mode and effect analysis for sepsis- sepsis screening stepAbstract 46 Figure 5Carilion Roanoke memorial hospital - sepsis recognition* in the emergency departmentAbstract 46 Figure 6Carilion Roanoke memorial hospital sepsis screening completion* in the emergency departmentAbstract 46 Figure 7Carilion Roanoke memorial hospital - antibiotics administration* for sepsis present on admissionAbstract 46 Figure 8Carilion Roanoke memorial hospital sepsis orderset utilization* for sepsis present on admissionAbstract 46 Figure 9