Updates in sepsis: ‘usual care’ and SOFA

1. Updates in sepsis:‘usual care’ and SOFA Said “Moo” Sultan, PharmD, BCPS, BCCCP Clinical Specialist, Burn Intensive Care Unit Program Director, Pharmacy Practice Residency University of North Carolina Medical Center Adjunct Faculty Eshelman School of Pharmacy

2. Objectives • Review the epidemiology and pathophysiology of sepsis • Describe guideline recommendations for protocolized resuscitation of septic patients • Assess recent literature updates regarding the management of sepsis • Evaluate the new definition of sepsis and its impact on management

3. Disclosures • Nothing to disclose

4. Background Pathophysiology and Epidemiology

5. Defining Sepsis Infection Sepsis Infection + SIRS • T > 38.3 or T < 36 • HR > 90 • RR > 20 or PCO2 < 32 • WBC > 12 or WBC < 4 Severe Sepsis Septic Shock Sepsis + EOD • AMS • oliguria, increased SCr • increased LFT’s • acute lung injury • lactic acidosis Severe Sepsis + Hypotension Surviving Sepsis 2012. Crit Care Med 2013;41:580-637.

6. Pathophysiology of Sepsis Angus DC, van der Poll T. N Engl J Med 2013;369(9):840-51.

7. Epidemiology of Sepsis Gaieski DF, Edwards JM, Kallan MJ, Carr, BG. Crit Care Med 2013;41:1167-74.

8. Epidemiology of Sepsis Stevenson EK, Rubenstein AR, Radin GT, Wiener RS, et al. CritCare Med 2014;42(3):625-31.

9. Epidemiology of Sepsis Iwashyna TJ, Ely EW, Smith DM, Langa KM. JAMA 2010;304(16):1787-94.

10. Audience Participation! The last decade has seen a decrease in the case fatality rate from sepsis. However, over that same timeframe, the incidence of sepsis (and total annual mortality) continues to increase because of which of the following: • Better education about and recognition of sepsis • An aging population with more comorbid conditions and risk factors • Better reporting of cases of sepsis • All of the above

11. Sepsis Resuscitation Early Goal-Directed Therapy (EGDT) and The Rivers Protocol

12. Quick Tangent - Infection Control Mortality Ferrer R, Martin-Loeches I, Phillips G, Osborn TM, et al. CritCare Med 2014;42(8):1749-55.

13. Why EGDT? • Case mortality rates for severe sepsis and septic shock unacceptably high • “Late” interventions (after admission to intensive care unit) routinely show no benefit • Routine physical assessment has inadequate sensitivity to detect ongoing tissue hypoxia • Variability in the assessment and resuscitation of septic patients Rivers E, Nguyen B, Havstad S, Ressler J, et al. N Engl J Med 2001;345:1368-77.

14. Early Goal-Directed Therapy Rivers E, Nguyen B, Havstad S, Ressler J, et al. N Engl J Med 2001;345:1368-77.

15. Early Goal-Directed Therapy Rivers E, Nguyen B, Havstad S, Ressler J, et al. N Engl J Med 2001;345:1368-77.

16. Early Goal-Directed Therapy Oxygen ± Intubation Central and arterial catheters ± Sedation and/or paralysis No 8-12 mmHg ≥ 65 mmHg ≥ 70% GoalsAchieved MAP CVP ScVO2 < 65 mmHg < 70% < 8 mmHg Transfuse RBC until HCT > 30% Vasoactive Agents Yes Crystalloid Colloid < 70% Hospital Admission Inotropic Agents Rivers E, Nguyen B, Havstad S, Ressler J, et al. N Engl J Med 2001;345:1368-77.

17. Early Goal-Directed Therapy Rivers E, Nguyen B, Havstad S, Ressler J, et al. N Engl J Med 2001;345:1368-77.

18. EGDT Implementation Nguyen HB, Corbett SW, Steele R, Banta J, et al. Crit Care Med 2007;35(4):1105-12: Patel GW, Roderman N, Gehring H, Saad J, Bartek W. Ann Pharmacother 2010;44(11):1733-8. Rhodes A, Phillips G, Beale R, Cecconi M, et al. Intensive Care Med 2015;41(9):1620-8.

19. Concerns with Rivers, et al. McKenna M. Ann Emerg Med 2008;52(6):651-4. Rhodes A, Phillips G, Beale R, Cecconi M, et al. Intensive Care Med 2015;41(9):1620-8.

20. EGDT Under Fire Marik PE, Baram M, Vahid B. Chest 2008;134(1):172-8. Holst LB, Haase N, Wetterslev J, Wernerman J, et al. N Engl J Med 2014;371(15):1381-91. Jones AE, Shapiro NI, Trzeciak S, Arnold RC, et al. JAMA 2010;303(8):739-46.

21. Audience Participation! Which statement about the goals of the original Rivers Protocol for sepsis resuscitation is NOT accurate? • The MAP goal targeted by Rivers should have been higher • CVP might not be a valid assessment of fluid responsiveness when used in isolation • Septic patients do not require a transfusion threshold of HCT > 30% for oxygen delivery • ScVO2 can be replaced by lactate to monitor sepsis resuscitation

22. Advances in EGDT ProCESS, ProMISE, and ARISE

23. Mouncey P, Osborn T, Power S, Harrison D, et al. N Engl J Med 2015;372:1301-11. PROCESS Investigators. N Engl J Med 2014;370:1683-93. ARISE Investigators. N Eng J Med 2014;371:1496-506.

24. Early Goal-Directed Therapy Oxygen ± Intubation Central and arterial catheters ± Sedation and/or paralysis No 8-12 mmHg ≥ 65 mmHg ≥ 70% GoalsAchieved MAP CVP ScVO2 < 65 mmHg < 70% < 8 mmHg Transfuse RBC until HCT > 30% Vasoactive Agents Yes Crystalloid Colloid < 70% Hospital Admission Inotropic Agents Rivers E, Nguyen B, Havstad S, Ressler J, et al. N Engl J Med 2001;345:1368-77.

25. Usual Care Oxygen ± Intubation Central and arterial catheters ± Sedation and/or paralysis No 8-12 mmHg ≥ 65 mmHg ≥ 70% GoalsAchieved MAP CVP ScVO2 < 65 mmHg < 70% < 8 mmHg Transfuse RBC until HCT > 30% Vasoactive Agents Yes Crystalloid Colloid < 70% Hospital Admission Inotropic Agents Rivers E, Nguyen B, Havstad S, Ressler J, et al. N Engl J Med 2001;345:1368-77.

26. Baseline Characteristics Mouncey P, Osborn T, Power S, Harrison D, et al. N Engl J Med 2015;372:1301-11. PROCESS Investigators. N Engl J Med 2014;370:1683-93. ARISE Investigators. N Eng J Med 2014;371:1496-506.

27. Primary Outcomes Mouncey P, Osborn T, Power S, Harrison D, et al. N Engl J Med 2015;372:1301-11. PROCESS Investigators. N Engl J Med 2014;370:1683-93. ARISE Investigators. N Eng J Med 2014;371:1496-506.

28. Primary Outcomes • No statistically significant difference in primary or secondary outcomes in any of the three studies • None of the trials met pre-defined power Mouncey P, Osborn T, Power S, Harrison D, et al. N Engl J Med 2015;372:1301-11. PROCESS Investigators. N Engl J Med 2014;370:1683-93. ARISE Investigators. N Eng J Med 2014;371:1496-506.

29. Resuscitation Elements Mouncey P, Osborn T, Power S, Harrison D, et al. N Engl J Med 2015;372:1301-11.

30. Take-Home Points • There is NO DIFFERENCE between “Usual Care” and Early Goal-Directed Therapy… BUT • The only real differences in Usual Care and EGDT were driven by changes in monitoring (CVP, ScVO2) • The key interventions driven by Usual Care (fluid volume, pressors) were similar to those in EGDT • We might not need to be quite so aggressive in patients that don’t respond to 1 liter of IV fluids, but… • Early intervention and resuscitation is STILL IMPORTANT

31. Surviving Sepsis Campaign • Changes to 6-hour bundle reflect recent literature • Removed requirement for CVC insertion for CVP and ScVO2 monitoring • Continuous reassessment of volume status and tissue perfusion with: • Repeated focused exam, OR • Two of the following: • CVP • ScVO2 • Bedside cardiovascular ultrasound • Dynamic assessment of fluid responsiveness http://www.survivingsepsis.org/SiteCollectionDocuments/SSC_Bundle.html

32. Audience Participation! Which of the following statements accurately summarizes the findings of new trials in the resuscitation of septic patients? • Resuscitation protocols do not work for the resuscitation of septic patients • The Rivers Protocol is probably more aggressive than necessary for all patients • There is no role for ScVO2 monitoring in septic patients • All of the above

33. SEPSIS-3 A Meaningful Redefinition of Sepsis

34. “Old” Sepsis Infection Sepsis Infection + SIRS • T > 38.3 or T < 36 • HR > 90 • RR > 20 or PCO2 < 32 • WBC > 12 or WBC < 4 Severe Sepsis Septic Shock Sepsis + EOD • AMS • oliguria, increased SCr • increased LFT’s • acute lung injury • lactic acidosis Severe Sepsis + Hypotension Vincent JL, Opal SM, Marshall JC, Tracey KJ. Lancet 2013;381(9868):774-5.

35. “Old” Sepsis • Sensitivity? • Missing 1 in 8patients with infection and organ failure • Predictive Value? Kaukonen K, Bailey M, Pilcher D, Cooper D, et al. N Engl J Med 2015;372:1629-38.

36. “New” Sepsis – SEPSIS-3 Singer M, Deutschman C, Seymour C, Shankar-Hari M, et al. JAMA 2016;315(8):801-10.

37. SOFA and Organ Dysfunction Singer M, Deutschman C, Seymour C, Shankar-Hari M, et al. JAMA 2016;315(8):801-10.

38. Bedside Application

39. Limitations of SEPSIS-3 • Still subjective • SOFA and qSOFA are mortality predictors, not objective tests for sepsis • “Suspected Infection” remains elusive • Still non-specific • Can meet SOFA criteria without having sepsis • Might not be more sensitive • Not prospectively validated

40. Practical Implications

41. Audience Participation Which of the following is true of the new definition of sepsis (SEPSIS-3)? • SEPSIS-3 is more specific for identification of septic patients • SEPSIS-3 is more sensitive for the identification of septic patients • SEPSIS-3 has better defined prognostic implications for septic patients • All I can remember is Justin Bieber

42. Conclusions • Sepsis is characterized by a dysregulated response of the immune system with resultant tissue damage • Care of the septic patient is governed by two principles: infection control and resuscitation • Recent data suggests that resuscitation efforts might not have to be as aggressive as we once thought • The new definition of sepsis reflects the importance of a focus on organ dysfunction

43. Updates in sepsis:‘usual care’ and SOFA Said “Moo” Sultan, PharmD, BCPS, BCCCP Clinical Specialist, Burn Intensive Care Unit Program Director, Pharmacy Practice Residency University of North Carolina Medical Center Adjunct Faculty Eshelman School of Pharmacy