1. Corticoïdes, Sucre et Sepsis Djillali Annane Hôpital Raymond Poincaré (AP-HP), Université de Versailles SQ, Garches

2. Cortisol & Cardiovascular Tolerance to LPS CONTRACTION TO NE LPS Szabo C, PNAS USA, 1993

3. Impaired Pressor Sensitivity to Noradrenaline in Septic Shock Patients with and without Impaired Adrenal Function Reserve Annane, British Journal of Clinical Pharmacology, 1998 Adrenal Insufficiency Normal Adrenal Function

4. Brain Adrenals HT- PG cortisone cortisol CBG elastase Tissue inflammation Il-1 TNF - T0 Th1 Th2 + vagus Circulating cytokines reductase 11bHSD IL-4, Il-13

5. AI AND SYSTEMIC INFLAMMATION * * *

6. INSUFFISANCE SURRENALE ET SEPSIS

7. iNOS

8. MechanismsDrugs Primary adrenal insufficiency Haemorrhage Anticoagulant therapy (heparin, warfarin) Cortisol synthesis enzyme inhibition Aminogluthethimide Ketoconazole, Fluconazole Etomidate, Dexmedetomidine Cortisol metabolism activation Phenobarbital, Phenytoin Rifampin Secondary adrenal insufficiency Suppression of CRH and ACTH synthesis Glucocorticoid therapy (systemic or topical) Megestrol acetate, Medroxyprogesterone Ketorolac tromethamine Antidepressant drugs (e.g. imipramine) Opiate drugs Peripheral resistance to GC Interaction with GC receptor Mifepristone inhibition of the GC-induced gene transcription Antipsychotic drugs (e.g. chlorpromazine) Antidepressant drugs (e.g. imipramine)

10. CORTISOL RESPONSE TO ACTH Rothwell, Lancet 1991 250

11. INSUFFISANCE SURRENALE ET SEPSIS Cortisol Insuffisance Surrénale < 10 µg/dL T60-T0 < 9 µg/dL Test à ACTH  10 - <44 µg/dL Fonction Normale T60-T0 > 9 µg/dL & T60 < 44 µg/dl T60  44 µg/dL  44 µg/dL or Insuffisance Surénale ???? Metopyrone Ou insuline test

12. GR GC Chaperones proteins mRNA Proteins NF-  B Direct transcriptional effects - Or + Post-transcriptional Nucleus membrane Cell’s membrane Membrane binding sites PI3 kinase AKT MAPK ?- Other putative nongenomic effects GR

13. Impaired Pressor Sensitivity to Noradrenaline in Septic Shock Patients with and without Impaired Adrenal Function Reserve Annane, British Journal of Clinical Pharmacology, 1998 Normal adrenal function Impaired adrenal function

14. NON RESPONDERS Annane et al, JAMA. 2002 RESPONDERS HR=0.853 P=0.637 HR=1.889 P=0.002 Effect of Treatment With Low Doses of Hydrocortisone and Fludrocortisone on Mortality in Patients With Septic Shock

15. Adrenal Function Influences Systemic Inflammation * * * Annane, CCM 2006

16. Immunologic and Hemodynamic Effects of "Low-Dose" Hydrocortisone in Septic Shock: A Double-Blind, Randomized, Placebo-controlled, Crossover Study. Didier Keh, et al AJRCCM 2003;167: 512-520

17. Immunologic and Hemodynamic Effects of "Low-Dose" Hydrocortisone in Septic Shock: A Double-Blind, Randomized, Placebo-controlled, Crossover Study. Didier Keh, et al AJRCCM 2003;167: 512-520

18. NON RESPONDERS HR = 0.670 p=0.023 Annane et al, JAMA. 2002 RESPONDERS Effect of Treatment With Low Doses of Hydrocortisone and Fludrocortisone on Mortality in Patients With Septic Shock

19. Resultats 26 RCTs 7 RCTs exclues population mixe, n=3 information Incomplete, n=3 Effets à court terme, n=1 19 RCTs inclues 1 Crossover, n=40 18 groupes Parallels, n=2,137 CS-Replacement 9 RCTs N=570

20. Resultats Mortalité à J28 (toutes études) Favors CSFavors Control P=0.03 RR=0.88 (0.78 to 0.99)

21. Resultats Mortalité à J28 (opothérapie)

22. Resultats EIG (opothérapie) Favors CSFavors Control

23. Limitations 1/ 7 RCT avait > 2 centres ( (62% patients dans la meta-analysis) Hétérogénéité : - Phase tardive vs précoce - HC versus autres traitements (HC+FC, prednisone…) - Perfusion continue versus bolus - Test à ACTH ou non Adrenal Insufficiency Normal Adrenal Function

24. MODALITES D’ADMINISTRATION DU TRAITEMENT Dose 200 à 300 mg/jour Voie: bolus ou perfusion continue 50 mg iv / 6 heures, ou 100 mg iv / 8 heures ou l’équivalent de 200 à 300 mg par jour en perfusion continue Durée: minimum 5 jours à pleine dose maximum 7 jours à pleine dose Arrêt: si 7 jours arrêt sans décroissance, si 5 5 jours arrêt progressif sur 2 à 6 jours

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

26. LPS Regulates Proinflammatory Cytokine Expression in Skeletal Muscle Frost, A J P Regul Integr Comp Physiol, 2002

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

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

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

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

31. Hyperglycemia and Outcome in the Acutely van den Berghe, CCM 2003 <110 110-150 >150

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

33. Effects of Intensive Insulin Therapy on Morbidity in Surgical ICU patients. Van den Berghe, NEJM 2002 * * *

34. Glucose Control and Mortality in Critically Ill Patients Finney et al JAMA 2003 IIT VDB study Control

35. 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

36. "Van den Berghe et al followed their original trial with a similar study of 1200 subjects recruited from the medical ICU at the same institution, reporting a significant improvement in mortality among long-stay patients in an oral session at this year’s ESICM scientific meeting."

37. CONTRÔLE STRICT DE LA GLYCEMIE: Pas pour l’instant!