Sepsis and Septic Shock, 2008

1. Sepsis and Septic Shock, 2008 Prof J Cohen

2. Sepsis and Septic Shock • Definitions • Epidemiology • Pathogenesis • Principles of management

3. Definitions • Infection: microbial phenomenon characterised by an inflammatory response to the presence of micro organisms or the invasion of normally sterile host tissue by these organisms • Bacteraemia: the presence of bacteria in the bloodstream • Septicaemia: no longer used ACCP/SCCM Consensus Conference: Bone et al, Chest 1992 101:1644

4. Definitions • Sepsis: systemic response to infection manifested by ≥ 2 of: • Temp > 38oC or < 36oC • HR > 90 bpm • RR > 20 bpm or PaCO2 < 32 mmHg • WBC > 12 x 109/L, < 4 x 109/L or >10% band form • Septic shock: sepsis with hypotension despite adequate fluid resuscitation, with perfusion abnormalities that could include, but are not limited to, lactic acidosis, oliguria, and/or acute mental status. ACCP/SCCM Consensus Conference: Bone et al, Chest 1992 101:1644

5. SIRS and Sepsis • SIRS: Systemic Inflammatory Response Syndrome • Fever, leucocytosis, organ failure • Recognises difficulty of always identifying infection, but… • As a result, high sensitivity but low specificity

6. Infection Parasite Severe Sepsis Virus SIRS Sepsis Fungus shock Trauma Severe SIRS Bacteria BSI Burns Adapted from SCCM ACCP Consensus Guidelines

7. Epidemiology

8. Where’s the infection ? Bernard & Wheeler NEJM 336:912, 1997

9. What’s the infection? Pure isolates, total n = 444 pts, 61% micro documented Cohen et al, J Infect Dis 1999 180:116

10. Martin et al: N Engl J Med 2003:348:1546

11. Severe sepsis incidence and mortality increase with age Mortality Incidence Angus Crit Care Med 29:1301, 2001

12. Organ dysfunction at time of severe sepsis recognition Bernard NEJM 344:699, 2001

13. Relationship between mortality on ICU and the number of failed organs From Brealey & Singer, 2000

14. Pathogenesis

16. PARASITE HOST PAMP Pathogen associated Molecular pattern PRR Pathogen recognition receptor

17. Sepsis and septic shock Bacterial infection Excessive host response Host factors lead to cellular damage Organ damage Death

18. Molecular architecture of the IR to sepsis Bacterial factors Cell wall components Extracellular products Host factors Acquired immunity Innate immunity Genetic susceptibility Effector mechanisms Lymphokine storm Chemokine activation Neutrophil migration Vascular inflammation

19. Cohen, Nature: 2002 420:885

20. Immune activation and immunosuppression in sepsis Hotchkiss et al, NEJM 2003 348:138

21. Management

22. Management of Sepsis • Recognition • Supportive care • Source control • Antibiotics • Specific (adjunctive) therapy

23. How likely is it that the diagnosis of sepsis is being missed? Is it... Total (n=497) Intensive Care Physicians (n=237) Extremely likely Very likely Somewhat likely Not very likely Not likely at all Not sure Ramsay, Crit Care 2004 8:R409.

24. Initial resuscitation of sepsis: therapeutic goals • Central venous pressure: 8 – 12 mmHg • Mean arterial pressure: ≥ 65 mmHg • Urine output: 0.5 mL/kg/h • Central venous (SVC) or mixed venous oxygen saturation: ≥ 70%

25. Dellinger, Crit Care Med, 2003 31:946 Dellinger, Crit Care Med, 2003 31:946

26. Issues in the rational choice of antibiotics EFFICACY • Spectrum of activity • Pharmacokinetics & pharmacodynamics • Patterns of resistance TOXICITY COST

27. Choosing antibiotics in sepsis • There is no, single, “best” regimen • Consider the site of the infection • Consider which organisms most often cause infection at that site • Choose antibiotic(s) with the appropriate spectrum • After obtaining cultures, give antibiotics quickly and empirically at appropriate dose

28. Inadequate treatment of bloodstream infections increases ICU mortality Ibrahim et al, Chest 2000 118:146

29. “Non-antibiotic” therapy for sepsis Low dose steroids Intensive insulin therapy – tight glycaemic control Activated protein C Goal directed therapy

30. Effect of steroids on 28 day mortality RR 0.88 (0.78 to 0.99) p = 0.03 Favours treatment Favours control Annane et al, BMJ 2004 329:480

31. Effect of steroids on shock reversal RR 1.6 (1.27 to 2.03) p < 0.0001 Favours control Favours treatment Annane et al, BMJ 2004 329:480

32. CORTICUS International, prospective double-blind RCT of hydrocortisone in patients with moderate – severe septic shock HC 50 mg q6h for 5 d then tapering to d 11. No fludrocortisone. Primary EP 28 d mortality in nonresponders Sprung et al, N Engl J Med 2008 358:111

33. CORTICUS - Results No effect on 28 day mortality in whole population or pre-identified subgroups Did not reverse shock in whole population or pre-identified subgroups Did reduce the time to shock reversal No significant problem with super-infection Sprung et al, N Engl J Med 2008 358:111

34. Intensive insulin therapy in critically ill patients Tight glycaemic control= 80-110 mg/dl (4.4-6.1 mmol/l) Van den Berghe et al, NEJM 2001 345:1359

35. Intensive insulin therapy in medical patients on ICU Van den Berghe et al, N Engl J Med 2006 354:449

36. Intensive insulin therapy in medical patients on ICU for > 3 days ARR (%) OR (95% CI) P value 38.1--- 31.3 Δ 6.8% 0.69 (0.50-0.95) 0.02 ICU mortality 0.63 (0.46-0.89) 0.003 In hospital mortality 52.5 --- 43.0 Δ 9.5% OR and p value corrected for type & severity of illness Van den Berghe et al, N Engl J Med 2006 354:449

37. Study terminated at first safety analysis because of significant hypoglycaemia in “intensive” group 12.1% vs 2.1% p < 0.001 The VISEP study of intensive insulin therapy and colloid resuscitation in sepsis Brunkhorst et al, N Engl J Med 2008 358:125

38. PROWESS – Drotrecogin alfa (activated)[activated protein C] in sepsis mortality (%) Absolute reduction in risk (%) P value Placebo aPC All treated pts 30.8 24.7 6.1 0.005 All treated pts stratified 32.1 25.7 6.4 0.009 All randomised pts 31.3 24.8 6.5 0.003 Bernard et al, N Engl J Med 2001 344:699

39. Drotrecogin alfa (activated) is not effective in adults with severe sepsis and a low risk of death*, and is associated with an increased rate of serious bleeding * APACHE II < 25 or Single organ failure Abraham et al, NEJM 2005 353: 1332. ADDRESS trial group

40. PROWESS – Continuing debate Is there confidence in the baseline comparability of the populations – especially the subpopulations? There are variable outcomes depending on the severity marker used (IL6, APII, SOFA) There is no confirmatory study ADDRESS severe subgroup did not show benefit

41. Early goal directed therapy • Purpose: to adjust cardiac preload, afterload and contractility to balance oxygen delivery with oxygen demand • Entry criteria: patients in the emergency dept with severe sepsis & shock • Plan: randomise to 6h of EGDT before transfer to ICU Rivers et al, N Engl J Med 2001 345:1368

42. Early Goal Directed Therapy A/E admissions with severe sepsis/shock treated for 6 h before ICU transfer Protocol designed to achieve: CVP ≥ 8 – 12 mmHg MAP ≥ 65 mmHg ScvO2 ≥ 70% Urine output ≥ 0.5 ml/kg.hr Rivers et al, N Engl J Med 2001 345:1368-77

43. Early goal-directed therapy in sepsis • But…. • Unexpectedly high placebo mortality • Unusual (ER) population • Single centre non-blinded study design Standard therapy n=133 Active therapy n=130 p In hospital mortality (%) All patients Severe sepsis Septic shock 46.5 30.5 0.009 30.0 14.9 0.06 56.8 42.3 0.04 Rivers et al, N Engl J Med 2001 345:1368

44. Current controversies Low dose steroids ? / Not confirmed Intensive insulin therapy ? / Not confirmed – safety concerns Activated protein C Licensed but ? requires confirmation Goal directed therapy ?/ Requires confirmation

45. “On microbes” Nor do I doubt if the most formidable armies ever heere upon earth is a sort of soldiers who for their smallness are not visible” Sir William Petty, 1640