1. Innovation in Pediatric Sepsis: Is there anything new on the horizon? Derek S. Wheeler, MD, FAAP, FCCP, FCCM Associate Professor of Clinical Pediatrics University of Cincinnati College of Medicine Clinical Director, Division of Critical Care Medicine Cincinnati Children’s Hospital Medical Center The James M. Anderson Center for Health Systems Excellence Co-Director, The Center for Acute Care Nephrology

2. Top Ten Causes of Death in the U.S. 1. Heart Disease 2. Cancer 3. Stroke (Cerebrovascular Disease) 4. Chronic lower respiratory disease 5. Accidents 6. Alzheimer’s Disease 7. Diabetes 8. Influenza and Pneumonia 9. Nephritis, Nephrotic Syndrome, and Nephrosis 10. Septicemia Source National Center for Health Statistics, 2007 #6 and #8 in neonatal and pediatric age group, respectively Sepsis is a Common Cause of Death

3. Many of these patients will die from sepsis!

4. Sepsis is #1 killer worldwide Lancet 2010; 375:1969 2008 worldwide data from WHO, UNICEF, and Bill and Melinda Gates Foundation 8.8 million deaths in children <5 years of age 68% (5.97 million) due to infectious diseases Sepsis is the final common pathway in deaths from malaria, dengue fever, pneumonia, HIV/AIDS, and diarrheal illness! Sepsis is a Common Cause of Death

5. Source NIH Funding Levels for Categories Research, Condition, and Disease Categorization (RCDC) …Yet Sepsis Receives Comparably Little Funding

7. Nature Rev Drug Discovery 2003, 2:391 1.Complexity (nonlinear) 2.Redundancy 3.Obligatory “No More Talk of Magic Bullets Please!”

8. Sepsis recognition is inconsistent at best Early Recognition = Early Treatment = Better Outcomes Sepsis is a syndrome, not a disease Minimize heterogeneity via better definition of target populations and severity Sepsis management is highly variable Minimize variation via explicit control of co-interventions Key Innovations in Sepsis

9. Sepsis recognition is inconsistent at best Early Recognition = Early Treatment = Better Outcomes Sepsis is a syndrome, not a disease Minimize heterogeneity via better definition of target populations and severity Sepsis management is highly variable Minimize variation via explicit control of co-interventions Minimize variation via explicit control of co-interventions Key Innovations in Sepsis

10. Innovations in Recognition Fever + Tachycardia + Risk Factor => Activation of EGDT Protocol “Door to antibiotics” decreased from 143 to 38 minutes TCH Sepsis Protocol Cruz et al. Pediatrics 2011; 127:e758 Computerized Best Practice Alerts (4,552 triggers/39,697 visits) 81% Sensitivity 89% Specificity PPV 4% NPV 99.9% Cruz et al. Pediatr Emerg Care 2012;28:889

11. Sepsis recognition is inconsistent at best Early Recognition = Early Treatment = Better Outcomes Sepsis is a syndrome, not a disease Minimize heterogeneity via better definition of target populations and severity Sepsis management is highly variable Minimize variation via explicit control of co-interventions Minimize variation via explicit control of co-interventions Key Innovations in Sepsis

12. Innovations in Definition LPS changed gene expression of 3,714 unique genes! Calvano et al. Nature 2005; 437:1032

13. Sepsis recognition is inconsistent at best Early Recognition = Early Treatment = Better Outcomes Sepsis is a syndrome, not a disease Minimize heterogeneity via better definition of target populations and severity Sepsis management is highly variable Minimize variation via explicit control of co-interventions Key Innovations in Sepsis

14. Infection 2009; 37:222 Prospective registry 276 ICU’s in 37 countries N=12,881 pts Minimize variation Too Much Variation in Treatment!

15. Open Crit Care Med 2010; 3:51 Retrospective analysis N=51 critically ill children with septic shock Significant variation in duration of treatment, use of weaning taper, duration of taper Practice variation at CCHMC (informal chart audit): 1.Choice, timing, and duration of antibiotic therapy 2.Choice and indication for vasoactive infusions 3.Choice and indication of mechanical ventilatory support 4.Route and threshold for nutritional support 5.Choice of sedative and level of sedation required 6.Threshold for Renal Replacement Therapy (RRT) Minimize variation Too Much Variation in Treatment!

16. Innovations in Study Design

17. Sepsis recognition is inconsistent at best Early Recognition = Early Treatment = Better Outcomes Sepsis is a syndrome, not a disease Minimize heterogeneity via better definition of target populations and severity Sepsis management is highly variable Minimize variation via explicit control of co-interventions Key Innovations in Sepsis

18. derek.wheeler@cchmc.org R18 HS020455 The James M. Anderson Center for Health Systems Excellence Stephen Muething, MD Patrick Brady, MD Uma Kotagal, MBBS, MSc Janet Jacob, RN, MBA Children’s Hospital of Akron Mary D. Patterson, MD, MEd Cincinnati Children’s Center for Simulation and Research Gary Geis, MD John Whitt, MD Tom LeMaster, RN, MSN, MEd, REMT-P, EMSI University of Cincinnati College of Medicine Amy Bunger, PhD University of Michigan Ross School of Business Kathleen M. Sutcliffe, MSN, PhD Applied Decision Science, LLC Laura Militello, MA MacroCognition, LLC Gary Klein, PhD Division of Critical Care Medicine Hector R. Wong, MD Carley Riley, MD Erika Stalets, MD Thank You!