1. Estimates of the Impact of Sepsis Syndromes Annually in U.S. Sepsis 200,000 Severe sepsis 200,000 Septic shock 200,000 Mortality Deaths -46%92,000 -20%40,000 -16%32,000 600,000 cases/yr 164,000 deaths/yr

2. Sepsis Definitions sepsisseveresepsissepticshock SIRS (  2) fever or SIRS Sepsis Severe sepsis hypothermia + + + tachycardia (>90)infectionhypotension hypoperfusion tachypnea (>20)or + H./low WBC orhypoperfusion hypotension  10% bands despite 500 ml bolus fluid

3. Attributable Mortality: The Promise of Better Antimicrobial Therapy 80 70 60 50 40 30 20 10 all-cause (crude) mortality - percent- Attributable mortality of resistance gene Attributable mortality of infection Mortality from underlying disease infection and no Rx infection and Rx infection and no Rx resistance gene resistance gene infection and Rx effect of existing Rx 1 2 3 4 5 scenarios effect of existing Rx

4. Proinflammatory Molecules TNF R1 TRADD RelA TRAF2RIP p50 IkB IKK NIK TRAF-6 IRAK IL-1 R1 IL-1 RAcP RelA p50 P Ub RelA p50 IkB TNF  IL-1  mRNA NLS p50 Christman et al Intensive Care Med 1998; 24:1131-1138

5. Therapy of Sepsis volume replacement !! if BP remains low - pressors eg dopamine if BP still low, r/o adrenal insufficiency, severe acidosis hypocalcemia, hypocalcemia correct pH to 7 2 oxygen best choice antibiotics ( I + D?) rapid transfer to ICU with CCM trained experts

6. TNF-MAb TNFr TNF-MAb IL-1ra PAFra TNF-MAb Anti-Bradykinin P-55/sTNFr TNF-MAb PAFra Anti-Bradykinin TNF-Mab Ibuprofen-Prosta Number of Patients Enrolled Clinical Trial Therapy Type Control Treated of Agent 0.125 0.25 0.5 0.67 1 1.5 2.0 4.0 8.0 No effect Odds Ratio Natanson et al, Crit Care Med 1998; 26: 1928

7. Hydrocortisone (300 mg IV/d) vs Placebo for  5 days for Septic Shock with Vasopressors > 48 hrs Probability of Shock Reversal (%) Days after Inclusion Treatment Placebo Survival Probability (%) Days after Inclusion Steroid (n=22) Controls (n=19) Bollaert et al Crit Care Med 1998; 26:645-50

8. Adrenal Insufficiency in Refractory (4 hours) Hypotension Among ICU Patients percent subjects 46% 0% 40% 0% Peak  20  g/ml Baseline after 1  g ACTH  15  g/ml R.H. (n=15) Controls (n=9) Beale et al Chest 1999; 4:(S-2)366S

9. Genetic Factors in Septic Shock TNFZ: a single base pair change TNF  gene promoter HLA class III genes Chromosome 6 Frequency- TNF  gene promoter Control Septic shock P (n=87) (n=89) Any poly- morphism 25 43.008 TNFZ 16 35.002 Outcome - Septic Shock (n=89) Lived DiedP (n=41) (n=48) Any poly- morphism 14(34)29(61).01 TNFZ 10 25.008 Mira et al JAMA 1999; 282:561-8

10. Independent Predictors of Mortality After Septic Shock (n=89) VariableOR (CI 95 )P Age (10 yr increase 1.46 (1.06-2.0).02 SAPS-II score1.22 (1.01-1.46).04 TNFZ3.75 (1.37-10.24).01 Mira et al JAMA 1999; 282: 561-8

11. Time course of NFkB binding activity Days 1 2 3 4 5 6 8 10 14 % NFkB binding activity (day 1=100%) NFkB-binding activity (EMSA) Böher et al 1997 J Clin Invest 100:972-985

12. Predictive Power of NFkB Binding Activity and APACHE-II Score % of correctly classified cases Discriminant Survivors Nonsurvivors Survivors score (group1) (group 2) and non- survivors APACHE-II score >14 83% 79% 82% NFkB binding activity >137 89% 74% 85% Discriminant analysis of APACHE-II score and NFkB binding activity in PBMC of survivors and nonsurvivors for each analysis point, starting at the day of diagnosis. Böhrer et al J Clin Invest 1997; 100:972-985

13. Sepsis and Death After Hi-Dose Growth Hormone in ICU Patients RP=1.9 (1.3-2.9) RP=2.4 (1.6-3.5) p<0.001 Mortality (percent) 39% 20% 44% 18% (n=119) (n=123) (n=139) (n=141) Finnish study Multination study 32% vs 16% 26% vs 15% Proportion of deaths from septic shock/uncont.infection Takala et al NEJM 1999; 341: 785

14. Sepsis: Variables Predicting Mortality Host:genetics co-morbidities temperature Organism:Ps. Aeruginosa; Candida 2 inf vs 1 Polymicrobial vs Unimicrobial Therapy:Appropriate Antibiotics Trained ICU team