1. SEPSIS Where are the goal posts now?

2. What is the new evidence? RCTs: Trilogy of EGDT trials (2014-2015) RCT: SEPSIS-PAM (2014) RCT: ALBIOS (2014) Observational data: fluids and vasopressors (2014) Observational data: peripheral norad (2015)

3. A new PROCESS ARISE strikes Back PROMISE of the Jedi

4. A new PROCESS ARISE strikes Back PROMISE of the Jedi

5. PROCESS ARISE PROMISE RIVERS EGDT Detroit 1997-2000 Control (133 patients) Mortality 46.5% EGDT SUPERIOR (30.5%) 31 Academic centres in USA – 2008-2013 Control (456 patients) Mortality 19% 51 centres (95% pts from ANZ) – 2008-2014 Control (798 patients) Mortality 16% 56 centres in the UK – 2011-2014 Control (630 patients) Mortality 25%

6. PROCESS ARISE PROMISE RIVERS EGDT Detroit 1997-2000 Control (133 patients) Mortality 46.5% EGDT SUPERIOR (30.5%) 31 Academic centres in USA – 2008-2013 Control (456 patients) Mortality 19% 51 centres (95% pts from ANZ) – 2008-2014 Control (798 patients) Mortality 16% 56 centres in the UK – 2011-2014 Control (630 patients) Mortality 25% EGDT NO BENEFIT

7. PROCESS ARISE PROMISE RIVERS EGDT Detroit 1997-2000 Control (133 patients) Mortality 46.5% EGDT SUPERIOR (30.5%) 31 Academic centres in USA – 2008-2013 Control (456 patients) Mortality 19% 51 centres (95% pts from ANZ) – 2008-2014 Control (798 patients) Mortality 16% 56 centres in the UK – 2011-2014 Control (630 patients) Mortality 25% EGDT NO BENEFIT

8. PROCESS ARISE PROMISE RIVERS EGDT Detroit 1997-2000 Control (133 patients) Mortality 46.5% EGDT SUPERIOR (30.5%) 31 Academic centres in USA – 2008-2013 Control (456 patients) Mortality 19% 51 centres (95% pts from ANZ) – 2008-2014 Control (798 patients) Mortality 16% 56 centres in the UK – 2011-2014 Control (630 patients) Mortality 25% EGDT NO BENEFIT

9. EGDT studies – early activities RIVERSProMISEProCESSARISE Time to randomisation <1 hour2 hrs 30 mins3 hours2 hrs 45 mins Fluid before randomisation UNK (0-1)2.0 litres2.1 litres2.5 litres Initial ScvO2 (EGDT arm) 49%70%71%72% Lactate at randomisation (EGDT arm) 7.7 mmol/l5.1 mmol/l4.9 mmol/l4.4 mmol/l Antibiotics (EGDT arm) 86% by 6hrs100% before randomisation 76% before randomisation, 98% by 6 hrs 100% before randomisation Control mortality 46.5%24.5%18.9%15.7%

10. Take home from EGDT studies: 1.Don’t put in a CVL to measure ScvO2 2.Aggressive early fluid is probably a good thing 3.Mortality of ED septic shock in ANZ: <20% PROCESS ARISE PROMISE

11. Early Therapy for Septic Shock Early fluids Early antibiotics MAP>65 Lactate clearance Fluids, vasopressors Urine output Source control, organ support.

12. The many questions How much fluid? What filling target? What type of fluid? What BP target? When to start norad? How much norad? What’s after norad? Is there a role for inotropes? What transfusion target?

13. The many questions How much fluid? What filling target? What type of fluid? What BP target? When to start norad? How much norad? What’s after norad? Is there a role for inotropes? What transfusion target?

14. What type of fluid? Saline Balanced crystalloid – Hartmann’s Colloids – starch, gels, albumin

15. Retrospective analysis (USA ) Database : 53,500 ICU patients with vasopressor dependent septic shock 3,365 patients - balanced crystalloid in 1 st 2 days Propensity-matched analysis

16. Hospital mortality Balanced = 19.6% Isotonic = 22.8% RR 0.86 (0.78-0.94) p = 0.001

17. Should we use Hartmann’s as crystalloid for septic shock resuscitation?

18. Sometimes maybe

19. The ALBIOS trial

20. The ALBIOS trial 1818 Italian ICU patients with severe sepsis in last 24 hours SALINE ALBUMIN 300ml 20% Albumin initially Further albumin for 30g/l

21. The ALBIOS trial 1818 Italian ICU patients with severe sepsis in last 24 hours SALINE ALBUMIN 300ml 20% Albumin initially Further albumin for 30g/l

22. The ALBIOS trial 1818 Italian ICU patients with severe sepsis in last 24 hours SALINE ALBUMIN 300ml 20% Albumin initially Further albumin for 30g/l

23. The ALBIOS trial 1818 Italian ICU patients with severe sepsis in last 24 hours NO significant difference 28d mortality: Albumin 31.8% Saline 32% 90d mortality: Albumin 41.1% Saline 43.6%

28. Albumin you have chosen? A wise decision you have made…

29. The Force

30. What MAP target?

31. SEPSISPAM

32. SEPSISPAM 776 septic shock patients in French ICUs MAP 65-70 MAP 80-85

33. SEPSISPAM 776 septic shock patients in French ICUs MAP 65-70 MAP 80-85

34. SEPSISPAM 776 septic shock patients in French ICUs

35. MAP 65-70 MAP 80-85

36. MAP 65 is a good start… What’s the target??

37. When should we start norad?

38. Retrospective study 213 surgical ICU patients with septic shock Examined outcomes related to time of norad commencement

40. Less hypotension Less norad Less fluid in 24h

41. Crit Care Med 2014;42:2158-2168

42. 2849 ICU patients with septic shock (Canada, USA, Saudi Arabia) Documented fluid given TEV 0-1 TEV 1-6 TEV 6-24 And classified time of norad commencement

43. Crit Care Med 2014;42:2158-2168 (2) (3.7)

44. Crit Care Med 2014;42:2158-2168

45. Noncompliant odds ratio for mortality (referent compliant) ED process of care (POC)Compliant (n, %) unadjustedadjusted SAPS II Lactate measured a 197 (91.2)1.56 (0.56-4.34)1.97 (0.63-6.23) Time to appropriate AB < 2hrs b 151 (39.1)0.74 (0.44-1.24)1.54 (0.83-2.89) Fluid >2 litres in 1 st 6 hours237 (59.4)1.09 (0.66-1.80)2.01 (1.11-3.67) Fluid >3 litres in 1 st 6 hours139 (34.8)1.16 (0.69-1.98)2.47 (1.29-4.72) Fluid >4 litres in 1 st 6 hours88 (22.1)1.37 (0.73-2.58)3.52 (1.59-7.78) NA in ED for hypotension admitted to ICU c 81 (72.3)2.33 (0.78-6.94)3.58 (1.07-12.00) Albumin given in ED132 (33.1)0.80 (0.48-1.33)1.49 (0.81-2.74) Septic shock in the RBWH ED 399 cases of septic shock admitted over 162 weeks Denominators: a 216 (hypotension), b 386, c 112, otherwise = 399.

46. Noncompliant odds ratio for mortality (referent compliant) ED process of care (POC)Compliant (n, %) unadjustedadjusted SAPS II Lactate measured a 197 (91.2)1.56 (0.56-4.34)1.97 (0.63-6.23) Time to appropriate AB < 2hrs b 151 (39.1)0.74 (0.44-1.24)1.54 (0.83-2.89) Fluid >2 litres in 1 st 6 hours237 (59.4)1.09 (0.66-1.80)2.01 (1.11-3.67) Fluid >3 litres in 1 st 6 hours139 (34.8)1.16 (0.69-1.98)2.47 (1.29-4.72) Fluid >4 litres in 1 st 6 hours88 (22.1)1.37 (0.73-2.58)3.52 (1.59-7.78) NA in ED for hypotension admitted to ICU c 81 (72.3)2.33 (0.78-6.94)3.58 (1.07-12.00) Albumin given in ED132 (33.1)0.80 (0.48-1.33)1.49 (0.81-2.74) Septic shock in the RBWH ED 399 cases of septic shock admitted over 162 weeks Denominators: a 216 (hypotension), b 386, c 112, otherwise = 399.

47. Noncompliant odds ratio for mortality (referent compliant) ED process of care (POC)Compliant (n, %) unadjustedadjusted SAPS II Lactate measured a 197 (91.2)1.56 (0.56-4.34)1.97 (0.63-6.23) Time to appropriate AB < 2hrs b 151 (39.1)0.74 (0.44-1.24)1.54 (0.83-2.89) Fluid >2 litres in 1 st 6 hours237 (59.4)1.09 (0.66-1.80)2.01 (1.11-3.67) Fluid >3 litres in 1 st 6 hours139 (34.8)1.16 (0.69-1.98)2.47 (1.29-4.72) Fluid >4 litres in 1 st 6 hours88 (22.1)1.37 (0.73-2.58)3.52 (1.59-7.78) NA in ED for hypotension admitted to ICU c 81 (72.3)2.33 (0.78-6.94)3.58 (1.07-12.00) Albumin given in ED132 (33.1)0.80 (0.48-1.33)1.49 (0.81-2.74) Septic shock in the RBWH ED 399 cases of septic shock admitted over 162 weeks Denominators: a 216 (hypotension), b 386, c 112, otherwise = 399.

48. START THE NORAD EARLY! (Rebel Scum) START THE NORAD EARLY! (Rebel Scum)

49. PERIPHERAL NORADRENALINE

51. http://emcrit.org/podcasts/peripheral-vasopressors-extravasation/ Podcast 107 – Peripheral Vasopressor Infusions and Extravasation PERIPHERAL NORADRENALINE Sept 16, 2013

52. The force is strong with you That’s my timely peripheral norad

53. Summary Early fluid – cystalloid or albumin ALBIOS MAP 65-70 SEPSISPAM Early norad – peripherally is OK to start convert to CVL if required Don’t use CVL to measure ScvO2 ProCESS / ARISE / ProMISE

54. TWO! FREAKIN! BLOOD! CULTURES !!!!!!