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 > 38 o C or < 36 o C – HR > 90 bpm – RR > 20 bpm or PaCO 2 < 32 mmHg – WBC > 12 x 10 9 /L, 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 Virus Fungus Bacteria Trauma Burns Sepsis SIRS SevereSepsis SevereSIRS Adapted from SCCM ACCP Consensus Guidelines shock BSI

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

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

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

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

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

15. Pathogenesis

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

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

19. 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

20. Cohen, Nature: 2002 420:885

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

22. Management

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

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

25. 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%

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

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

28. 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

29. Adequate initial antibiotic therapy reduces mortality Kollef et al, Chest 1999 115:462

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

31. Impact of antibiotic choice on survival of community-acquired BSI Vallés et al, Chest 2003 123:1615

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

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

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

35. 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

36. 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

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

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

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

40. Growing concerns about tight glycaemic control Uncertainty about feeding regimen and highly selected pt population in first NEJM study. Single centre study. Failure of second NEJM study to confirm clear survival benefit German VISEP study terminated because of XS hypoglycaemia & no survival benefit

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

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

43. Drotrecogin alfa – UK NICE guidelines Drotrecogin alfa (activated) is recommended for use in adult patients who have severe sepsis that has resulted in multiple organ failure (that is, two or more major organs have failed) and who are being provided with optimum intensive care support. The use of Drotrecogin alfa (activated) should only be initiated and supervised by a specialist consultant with intensive care skills and experience in the care of patients with sepsis NICE Technology appraisal 84; September 2004

44. 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 Abraham et al, NEJM 2005 353: 1332. ADDRESS trial group * APACHE II < 25 or Single organ failure

45. Meta-analysis of 28d mortality outcomes in the two RCTs of drotrecogin alfa Costa et al, BMC Anesthesiol 2007; 7:5

46. 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

47. 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

48. rivers Rivers et al, N Engl J Med 2001 345:1368

49. 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 – ScvO 2 ≥ 70% – Urine output ≥ 0.5 ml/kg.hr Rivers et al, N Engl J Med 2001 345:1368-77

50. Early goal-directed therapy in sepsis Standard therapy n=133 Active therapy n=130 p In hospital mortality (%) All patients Severe sepsis Septic shock 46.530.50.009 30.014.90.06 56.842.30.04 Rivers et al, N Engl J Med 2001 345:1368 But…. Unexpectedly high placebo mortality Unusual (ER) population Single centre non-blinded study design

51. 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

52. “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