1. Copyright Wigfull 2013 The Sepsis Timebomb James Wigfull Critical Care and Anaesthesia Sheffield Teaching Hospitals

2. Copyright Wigfull 2013 Some slides may have been altered due to the size of the presentation If this is a problem to you, please contact vbevan@bsmt.org.uk

3. Copyright Wigfull 2013 Time is life Empiric broad spectrum Antibiotics Source Control Surviving Sepsis Guidelines

4. Copyright Wigfull 2013 Relationship of SIRS, Sepsis and Infection The ACCP/SCCM consensus Conference Committee, Chest 1992;101:1644-55. INFECTION SEPSIS SIRS BURNS OTHER TRAUMA BACTEREMIA FUNGEMIA PARASITEMIA VIREMIA OTHER PANCREATITIS POST-PUMP SYNDROME

5. Copyright Wigfull 2013 Sepsis and mortality Vallés et al. Chest 2003;123:1615–1624

6. Copyright Wigfull 2013 Time Antiinflammatory(endogenous)Antiinflammatory(endogenous) CARSCARS SIRSSIRS RECOVERY OrganInjuryOrganInjury van der Poll T, van Deventer SJH. Infect Dis Clin N Am Infection Antimicrobials Sepsis and Septic Shock: An Intensivist’s Immunologic View

7. Copyright Wigfull 2013 Microbial load Inflammatory response Toxic burden Cellular dysfunction/tissue injury TIME Sepsis and Septic Shock: An ID View Shock Threshold

8. Copyright Wigfull 2013 “An Injury Paradigm of Sepsis and Septic Shock” Prof A Kumar, University of Manitoba Microbial load Inflammatory response Toxic burden Cellular dysfunction/tissue injury TIME Antimicrobial therapy Shock Threshold

9. Copyright Wigfull 2013 Prof A Kumar, University of Manitoba “An Injury Paradigm of Sepsis and Septic Shock” Prof A Kumar, University of Manitoba Microbial load Inflammatory response Toxic burden Cellular dysfunction/tissue injury TIME earlier antimicrobial therapy Shock Threshold

10. Copyright Wigfull 2013 Prof A Kumar, University of Manitoba “An Injury Paradigm of Sepsis and Septic Shock” Prof A Kumar, University of Manitoba TIME more intense antimicrobial therapy Microbial load Toxic burden Inflammatory response Cellular dysfunction/tissue injury Shock Threshold

11. Copyright Wigfull 2013 Prof A Kumar, University of Manitoba “An Injury Paradigm of Sepsis and Septic Shock” Prof A Kumar, University of Manitoba Microbial load Inflammatory response Toxic burden Cellular dysfunction/tissue injury TIME Antimicrobial therapy + Source control Shock Threshold

12. Copyright Wigfull 2013 Bundle element 4a: in the event of hypotension and/or serum lactate >4mmol/l deliver fluid bolus 20ml/kg crystalloid or equivalent colloid Severe Sepsis Resuscitation Bundle Bundle element 1: measure serum lactate Bundle element 2: obtain blood cultures prior to antibiotic administration Bundle element 3: administer broad spectrum intravenous antibiotics within one hour

13. Copyright Wigfull 2013 Severe Sepsis Resuscitation Bundle Bundle element 4b: Apply vasopressors if initial fluid bolus does not maintain MAP >65mmHg Bundle element 5: In the event of persistent hypotension despite fluid resuscitation a: achieve CVP > 8cmH2O b: achieve ScvO2 > 70% Bundle element 5: In the event of persistent hypotension despite fluid resuscitation a: achieve CVP > 8cmH2O b: achieve ScvO2 > 70%

14. Copyright Wigfull 2013

16. Kumar et al. CCM. 2006:34:1589-96. Cumulative Initiation of Effective Antimicrobial Therapy and Survival in Septic Shock time from hypotension onset (hrs) 0-0.50.5-1 1-22-33-44-55-66-9 9-12 12-2424-36 36+ fraction of total patients 0.0 0.2 0.4 0.6 0.8 1.0 survival fraction cumulative antibiotic initiation

17. Copyright Wigfull 201317

18. Copyright Wigfull 2013 Kumar et al, CCM. 2006:34:1589-96. Mortality Risk with Increasing Delays in Initiation of Effective Antimicrobial Therapy Time (hrs) 1-1.992-2.993-3.994-4.995-5.996-8.99 9-11.99 12-23.9924-35.99 > 36 Odds Ratio of Death (95% Confidence Interval) 1 10 100

19. Copyright Wigfull 2013

22. Comparison with other time dependent interventions Not recognized early Easy diagnosis Insidious onset Clear onset Often develops on wards Presents to A&E NNT Severe sepsis 6-8 Septic shock NNT MI 30 MI 30 CVA 30-40 CVA 30-40 Trauma 30 Trauma 30

23. Copyright Wigfull 2013 Door to balloon time and mortality in AMI Adapted from Cannon et al. JAMA 2000; 283: 2941-7.

24. Copyright Wigfull 2013 Door to balloon time and mortality in AMI By getting door-to-balloon times of <2h for ALL STEMI patients, we would save 4775 lives per year. Adapted from Cannon et al. JAMA 2000; 283: 2941-7.

25. Copyright Wigfull 2013 Shock to effective antibiotic time and mortality in septic shock Adapted from Kumar et al. Crit Care Med 2006; 34: 1589-96.

26. Copyright Wigfull 2013 Shock to effective antibiotic time and mortality in septic shock Adapted from Kumar et al. Crit Care Med 2006; 34: 1589-96. By getting shock-to-antibiotic times of <2h for ALL septic shock patients, we would save 32,360 lives per year.

27. Copyright Wigfull 2013 Effect of Failure to Implement Source Control if Required 0 20 40 60 80 100 Source Control Implemented Source Control Not Implemented % total patients % survival

28. Copyright Wigfull 2013 Cumulative Source Control Implementation and Survival in Septic Shock time from hypotension onset (hrs) 0-3 3-6 6-12 12-24 >24 not implemented fraction of total patients 0.0 0.2 0.4 0.6 0.8 1.0 survival fraction cumulative source control implementation

29. Copyright Wigfull 2013 Mortality Risk with Increasing Delays in Implementation of Source Control in Septic Shock Time (hrs) 3-5.99 6-11.99 12-23.99 >24 Odds Ratio of Death (95% Confidence Interval) 0 2 4 6 8 10 12 14

30. Copyright Wigfull 2013 Survival and Rapidity of Source Control Source Control Delay (hrs) Survival (%)

31. Copyright Wigfull 2013 Source Control/Antimicrobial Interaction and Survival in Septic Shock Antimicrobial Initiation Post-Shock < 3 h3-6 h Source Control Initiation Post-Shock < 6 h > 24 h 92% (n=75) 70.3% (n=37) 80.0% (n=60) 46.0% (n=50) 44.4% (n=63) 13.0% (n=100) 19.0% (n=94) 36.0% (n=25) 69.0% (n=29) > 6 h 6-24 h

32. Copyright Wigfull 2013 A: SHEWS 2 to SpR review B: SpR review to Antibiotics C: CT booking to scan D: CTscan to report E: Scan to theatre booking F: Booking to arrival Audit of Event timing from SHEWS 2 to theatre for the deteriorating colorectal patient at NGH from October 2009 to March 2010 hours

33. Copyright Wigfull 2013 Audit of Event timing from SHEWS 2 to theatre for the deteriorating colorectal patient at NGH from October 2009 to March 2010

34. Copyright Wigfull 2013 Conclusions With the onset of shock – the mortality clock starts ticking! Your team need to understand that delivery of intravenous antibiotics is their responsibility Source control – the mortality clock does not wait for a convenient theatre slot