1. Traitements non Antibiotiques du Choc Septique Djillali ANNANE, Hôpital Raymond Poincaré 92380 Garches, Djillali.annane@rpc.ap-hop-paris.fr

2. TIME IS IMPORTANT

3. Patients with global tissue hypoxia and early stage of disease

4. Fluid Therapy - Liters * = P<0.01 * *

5. TYPE OF FLUID DOES NOT REALLY MATTER

6. SAFE Flow Chart Finfer et al, NEJM 2004

7. SAFE - Outcome Data Finfer et al, NEJM 2004

8. CRISTAL MULTI-NATIONAL RCT publicly funded (French Ministry for Health) OBJECTIVE TO COMPARE THE EFFICACY AND SAFETY OF CRYSTALLOIDS AND SYNTHETIC COLLOIDS WHEN GIVEN FOR FLUID RESUSCITATION IN CRITICALLY ILL PATIENTS

9. TYPE OF CATECHOLAMINES DOES NOT REALLY MATTER

10. Vasopressors for shock. Müllner M et al, Cochrane Database Syst Rev. 2004;(3):CD003709.

11. Vasopressors for shock. Müllner M et al, Cochrane Database Syst Rev. 2004;(3):CD003709.

12. ADJUVANT THERAPIES

13. Insulin Signaling Pathways That Regulate Glucose Metabolism in Muscle Cells and Adipocytes

14. Role of Muscles Expression of Cytokines in Insulin Resistance Syndrome (triangles) Insulin sensitive (circles) Insulin resistant (squares) Diabetic Saghizadeh, JCI 1996

15. Tumor Necrosis Factor-–Induced Insulin Resistance in Adipocytes Qi, Exp Biol Med 2000

16. Marked Reduction of GLUT4 in Muscle or Adipose Tissue Causes Insulin Resistance Minokoshi, JBC, 2003

17. Hyperglycemia and Outcome in the Acutely Ill Umpierrez, JCEM 2002

18. Effects of Intensive Insulin Therapy on Survival in Surgical ICU patients. Van den Berghe, NEJM 2002

19. Intensive insulin therapy in the medical ICU

21. Efficacy of Volume Substitution and Insulin Therapy in Severe Sepsis (VISEP Trial) This study has been suspended. Verified by German Competence Network Sepsis August 2005

22. GLUCOCORTICOIDS

24. Keh et al, AJRCCM 2003

26. COCHRANE INFECTIOUS GROUP SYSTEMATIC REVIEW

27. CORTISOL RESPONSE TO ACTH Rothwell, Lancet 1991 250

28. NON RESPONDERS RR=1.889 P=0.002 Effect of Treatment With Low Doses of Hydrocortisone and Fludrocortisone on Mortality in Patients With Septic Shock Annane et al, JAMA. 2002

29. RESPONDERS RR=0.853 P=0.637 Effect of Treatment With Low Doses of Hydrocortisone and Fludrocortisone on Mortality in Patients With Septic Shock Annane et al, JAMA. 2002

30. AI AND SYSTEMIC INFLAMMATION * * *

31. 0.00 0.25 0.50 0.75 1.00 07142128 Time (days)  max > 9 µg/dl Probability of survival  max  9 µg/dl AI AND SURVIVAL Annane, JAMA 2000

32. 28-DAY SURVIVAL IN NON RESPONDERS HR = 0.670 p=0.023 Annane, JAMA 2002

33. 28-DAY SURVIVAL IN RESPONDERS Annane, JAMA 2002

34. 0 4 8 12 16 0.0 1.0 2.0 3.0 4.0 5.0 6.0 Coagulation Is Activated in Sepsis Levi et al. JAMA. 1993;270:975. Lorente et al. Chest. 1993;103:1536. Levi et al. JAMA. 1993;270:975. Lorente et al. Chest. 1993;103:1536. Time After Administration (min) TAT complex (ng/L) 30024018012060 74 1 *P <.05 vs controls Healthy volunteers + TNF  (n=6) Healthy volunteers + LPS (n=6) Survivors (n=23) Nonsurvivors (n=25) * * * * Controls D- dimer (mg/L) Time After Hosp. Admission (day)

35. Fibrinolysis Is Suppressed in Sepsis Levi et al. JAMA. 1993;270:975. Time after Administration (min) tPA Activity (%) 0 100 200 300 400 500 PAI-1 (ng/mL) PAI-1 (ng/mL) 0 10 20 30 40 50 30024018012060 30024018012060 Time after Administration (min) Healthy volunteers + TNF  (n=6) Healthy volunteers + LPS (n=6)

36. AT in Severe Sepsis : Kybersept Primary end-point : 28-day all cause mortality N = 2314 total AT levels achieved : 180% nl (120-230) Concomitant heparin : 1616 pts. 38.7 38.9 Warren et al. JAMA 2001;286:1869-78

37. TFP007 Primary Cohort - 28-Day Mortality P value from logistic regression adjusted for baseline APACHE II score and baseline log 10 IL-6, per protocol.

38. Summary of 28-Day All Cause Mortality30.8% 24.7% Primary Analysis Results 2-sided p-value 0.005 Relative Risk Reduction19.4% Increase in Odds of Survival38.1% Placebo (N=840) DrotrecoginAlfa(activated)(N=850) G. Bernard, et al. N Engl J Med 2001;344:699-709

39. Subgroups – Disease Severity Measures

40. BLEEDING RISKS

41. Drotrecogin Alfa (Activated) for Adults with Severe Sepsis and a Low Risk of Death Edward Abraham, NEJM 2005