1. Departments of Surgery & Critical Care Medicine Characterization of the Murine Septic Response Using Wireless Telemetry Technology: Modeling the Murine 9-1-1 Anthony J. Lewis, MD Christopher W. Seymour, MD MS Du Yuan Xianghong Zhang, PhD Matthew R. Rosengart, MD MPH Departments of Surgery & Critical Care Medicine 18 April 2015

2. Departments of Surgery & Critical Care Medicine A problem that needs no introduction… Angus et al. (2001): over 750,000 hospital admissions for sepsis in US annually 1 20+ % mortality Death rate equivalent to deaths from acute MI Over 60+ therapeutic trials in 30 years 2 Benefit of early goal-directed therapy (2001) ProCESS, ARISE, ProMISe trials casting doubt on mainstays of sepsis therapy 18 Apr 2015 1. Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med. 2001;29(7):1303-1310. 2. Fink MP. Animal models of sepsis. Virulence. 2014;5(1):143-153.

3. Departments of Surgery & Critical Care Medicine Antibiotics Fluid Resuscitation They work. How quick is ‘quick enough’? 18 Apr 2015

4. Departments of Surgery & Critical Care Medicine Time to Antibiotics 18 Apr 2015 Figure courtesy Drs. Christopher Seymour and Matthew Rosengart, data taken from: Puskarich MA, Trzeciak S, Shapiro NI, et al. Association between timing of antibiotic administration and mortality from septic shock in patients treated with a quantitative resuscitation protocol. Critical Care Medicine. 2011;39(9):2066- 2071.

5. Departments of Surgery & Critical Care Medicine Median time to antibiotic therapy was 6 hours after recognition of shock Mortality increased 7.6% for every hour delay after onset of hypotension Starting antibiotics within the first hour: 79.9% survival to discharge Starting antibiotics after six hours: 42% survival to discharge 18 Apr 2015

6. Departments of Surgery & Critical Care Medicine Prehospital Care 18 Apr 2015

7. Departments of Surgery & Critical Care Medicine EMS Care Time sensitive conditions: trauma, ACS, stroke Care is initiated in the ambulance per protocol Advanced capabilities: endotracheal intubation, mechanical ventilation, vasopressors, neuromuscular blockade, anti-arrhythmics, ACLS 18 Apr 2015

8. Departments of Surgery & Critical Care Medicine EMS and Sepsis Sepsis encountered twice as often as myocardial infarction Fewer than 1/3 get an intravenous catheter prehospital Less than 25% get IV fluids Prehospital fluid administration was associated with a 55% reduction in odds of hospital mortality 18 Apr 2015 Seymour CW, Rea TD, Kahn JM, Walkey A, Yealy DM, Angus DC. Severe Sepsis in Prehospital Emergency Care: Analysis of Incidence, Care, and Outcome. American journal of respiratory and critical care medicine. 2012. Seymour CW, Band RA, Cooke CR, et al. Out-of-hospital characteristics and care of patients with severe sepsis: a cohort study. J Crit Care. 2010;25(4):553-562. Seymour CW, Cooke, C.R., Heckbert, S., Spertus, J.A., Callaway, C.A., Martin-Gill, C., Yealy, D.M., Rea, T.D., Angus, D.C.. Prehospital resuscitation is associated with reduced mortality in severe sepsis. Australia and New Zealand Intensive Care Society International Meeting [abstract]. 2013.

9. Departments of Surgery & Critical Care Medicine Interim Summary Protocols for sepsis treatment are effective and time- sensitive Sepsis is frequently encountered by EMS Opportunities exists to develop protocols –Fluids, antibiotics Up to 2 hour lead time possible on antibiotic initiation Significant room for improvement regarding IV fluids 18 Apr 2015

10. Departments of Surgery & Critical Care Medicine Prior to embarking on an RCT of prehospital sepsis care, it would be nice to have data supporting that such an incremental reduction in time of administration of fluids and antibiotics matters. 18 Apr 2015

11. Departments of Surgery & Critical Care Medicine Development of a Relevant Animal Model Current models use fixed time intervals after septic insult to test therapy Host response is widely variable both in temporality and magnitude 1 Human sepsis treatment is prompted by physiologic changes, not time  the “9-1-1” call 1. Poli-de-Figueiredo LF, Garrido AG, Nakagawa N, Sannomiya P. Experimental models of sepsis and their clinical relevance. Shock. 2008;30 Suppl 1:53-59. 18 Apr 2015

12. Departments of Surgery & Critical Care Medicine Aim #1: Determine the temporal changes in clinical and biologic parameters that correlate with acute deterioration in a murine model of sepsis. 18 Apr 2015

13. Departments of Surgery & Critical Care Medicine DSI HD-X11 Implantable telemetry Wireless monitoring Continuous measurement of ECG, blood pressure, core temperature, and animal activity 2 grams 1.4 cc in volume Image source: http://www.alnmag.com/product-releases/2012/02/telemetry-implant-mice 18 Apr 2015 Heart Rate Core Temperature

14. Departments of Surgery & Critical Care Medicine Aggregate Data – 24 hours, CLP, No treatment Core Temperature 18 Apr 2015 14 degree difference at 12 hours

15. Departments of Surgery & Critical Care Medicine Aggregate Data – 24 hours, CLP, No treatment Heart Rate 18 Apr 2015 Considerable heterogeneity in physiologic trajectory

16. Departments of Surgery & Critical Care Medicine Data Modeling: Heart Rate zeroed on death or last point of observation 18 Apr 2015

17. Departments of Surgery & Critical Care Medicine Data Modeling: Temperature zeroed on death or last point of observation 18 Apr 2015

18. Departments of Surgery & Critical Care Medicine Defining Deterioration Thresholds Wide heterogeneity in the onset and magnitude of sick response Need standardized approach to define point of deterioration or the “mouse 9-1-1 call” in order to test future interventions Currently testing thresholds based on bradycardic/hypothermic physiology observed in septic mice –HR decline by 10% off peak HR and core temperature decline by 10% x (peak temp. - 25°C) 18 Apr 2015

19. Departments of Surgery & Critical Care Medicine Thresholds Range of meeting physiologic threshold in original descriptive cohort: 356-1344 minutes post-CLP 12 hours 6 hours 18 Apr 2015

20. Departments of Surgery & Critical Care Medicine 9-1-1 18 Apr 2015

21. Departments of Surgery & Critical Care Medicine Thresholds: Inflammation 18 Apr 2015 p = 0.03 IL-6 (pg/mL)TNF-α (pg/mL)IL-10 (pg/mL)

22. Departments of Surgery & Critical Care Medicine Thresholds: Mixed Venous Blood Gas pH HCO 3 - Base Excess 18 Apr 2015 p < 0.05 for all parameters

23. Departments of Surgery & Critical Care Medicine 18 Apr 2015 Thresholds: Acute Kidney Injury p = 0.09

24. Departments of Surgery & Critical Care Medicine Future Directions 18 Apr 2015

25. Departments of Surgery & Critical Care Medicine Aim #2: Determine the effect of administering fluid resuscitation and/or antibiotic treatment at acute deterioration vs. after a 2-hr delay in a murine model of sepsis. 18 Apr 2015

26. Departments of Surgery & Critical Care Medicine Experimental Design Based upon data from Aim #1, we will recognize acute deterioration corresponding to the mouse “9-1-1” call Interventions will be antibiotics alone, IV fluid alone, combination antibiotics and IV fluid, or no treatment (control) Interventions will be “very early” (time of deterioration) or “early” (2 hour delay) 18 Apr 2015

27. Departments of Surgery & Critical Care Medicine Analysis of results Overall effect on mortality Measurement of biomarkers –IL-6, IL-10, TNF-α, lactate Measure effects on organ function –Cystatin C, alanine aminotransferase (ALT) Return to physiologic normal range Return of animal foraging activity 18 Apr 2015

28. Acknowledgments Matthew Rosengart, MD MPH Christopher Seymour, MD MSc Timothy Billiar, MD Du Yuan Xianghong Zhang, PhD Surgical Infection Society SIS Foundation