1. Current issues in the management of adult sepsis Jon Cohen MRF London Nov 2007

2. Current controversies Low dose steroids Intensive insulin therapy – tight glycaemic control Activated protein C Goal directed therapy

3. 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

4. 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

5. 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 Approx 500 patients enrolled, study closed Nov 2005

6. 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., 2007

7. 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)

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

9. 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

10. 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

11. 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

12. 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

13. 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

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

15. 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

16. Haemodynamic monitoring in sepsis – Background Long standing “discussions” about how to measure/quantify shock Clinical and laboratory biomarkers poorly defined Role of invasive monitoring uncertain Shoemaker develops “goal directed therapy” based on CI, DO 2 & VO 2, but clinical studies fail to support this approach

17. Recent recommendations on haemodynamic monitoring in shock Shock now defined on the basis of tissue dysoxia Hypotension not a requirement Lactate only useful biomarker Routine measurement of CO not required PAC not helpful Support for Early Goal Directed Therapy Antonelli et al, International Consensus Conference, Intensive Care Med 2007 33:575 - 590

18. Early Goal Directed Therapy ER 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

19. 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 study

20. Current controversies Low dose steroids ? / Not confirmed Intensive insulin therapy ? / Not confirmed Activated protein C ?/ Requires confirmation Goal directed therapy ?/ Requires confirmation

21. Updated version, 2008, in press

22. Experimental & Investigational Agents, 2007 Statins Cytokines –Polyclonal anti-TNF –MIF –HMG-B1 Cholinergic pathway –JCI 2007 111:289 Coagulation pathway –TFPI –AT Anti-TLR strategies –TAK 242 –Eritoran

23. TAK-242 Novel small molecule signal transduction inhibitor Effective when given up to 4 h after LPS challenge in mice Phase I human studies confirm broad inhibition of cytokines Excellent safety profile

24. TAK-242 exhibits a TLR4-specific mode of action

25. E5564 inhibits LPS-induced TLR4-mediated NF-kB reporter activity Mullarkey et al, J Pharmacol Exp Ther 2003 304:1093 HEK293 cells stably transfected with TLR4, MD-2, and a luciferase reporter gene driven by an NF-kB-dependent promotor

26. Mean change in heart rate from baseline among healthy volunteers with experimental endotoxemia who received E5564 or placebo Lynn et al, J Infect Dis 2003 187:631

27. Phase II study of Eritoran (E5564) in sepsis Placebo Low dose High dose 28 d mortality (%)RRR (%)p 33.3 32.0 26.96.40.34 N = 293 Eisai, press release, Aug 2005

28. Phase II study of Eritoran (E5564) in sepsis High risk subgroup Placebo Low dose High dose 28 d mortality (%)RRR (%)p Eisai, press release, Aug 2005 50.9 37.9 33.3 13 17.6 0.17 0.07 N = 162

29. Cuban Hospital, 1898 Greetings from ICU at Brighton General Hospital !

30. A role for statins in sepsis? Pleiotropic anti-inflammatory effects Prevents lethal sepsis in mice used either as prophylaxis or therapy (Merx, Circulation 2005 112:117) Beneficial in human LPS-challenge model (Steiner, Circulation 2005 111:1841) Clinical observational studies suggest statins reduce risk of complications/death in pts admitted with sepsis (Almog, Circulation 2004 110:880) (Kruger, Intensive Care Med 2006 32:75)

31. Statin use and mortality after bacteraemia Statin use YES NOMRRp Death (%) Risk period 0 – 30 d n = 5353 2021.60.930.66 Thomsen et al, Crit Care Med 2006 34:1080

32. Statin use and mortality after bacteraemia Statin use YES NOMRRp Risk period 31 – 180 d Death (%)8.417.50.44< 0.05 Thomsen et al, Crit Care Med 2006 34:1080

33. Statins reduce infection-related mortality in patients with atherosclerosis, independently of other comorbidities Almog et al, Crit Care Med 2007 35:372

34. Modlin & Cheng, Nature Med 2004 10:1173

35. TAK-242 has a broad suppressive effect on LPS induced inflammatory mediators Yamada et al, J Med Chem 2005 48:7457

36. Early initiation of antimicrobial therapy is critical Kumar et al, Crit Care Med 2006 34:1589

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