1. Sepsis Richard P. Wenzel, M.D., M.Sc. Professor and Chairman Department of Internal Medicine Medical College of Virginia Virginia Commonwealth University

2. Semmelweis’ Data - Impact of Poor Handwashing Practices Crude mortality (%) 8% 2% Physician Med/Students Midwives attributable mortality: 8%-2%=6% YLL: Age 55 - Age 20 = 35 years per death Attributable burden: 6 x 35 = 210 years lost per 100 deliveries

3. SIRS Fever or Hypothermia(>38º or 36º) Tachycardia(>90) Tachypnea(>20) Hi/Low WBC (>12, 10% bands) Bone et al Chest 1992; 101: 1644-55

4. 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

5. 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

7. Rank Order of Nosocomial Bloodstream Infections and Mortality SCOPE Surveillance System 40 30 20 10 CNS S.aureus Enterococcus Candida n=3908 n=1928 n=1354 n=934 proportion of BSI (%) 0 proportion crude mortality crude mortality (%) 32 21 16 25 11 32 8 40 Edmond et al CID 1999

8. 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

9. SCOPE: Years of Life Lost from Nosocomial Bloodstream Infections Attributable Mortality (%) YLL (x 1000) 10% total noso inf rate 5% total noso inf rate 2 1/2% total noso inf rate Mean age death - 60 yr Assume normal lifespan - 70 yr 350 525 700 875 1050 175 262.5 350 437.5 525 87.5 131.25 175 218.75 262.5

10. Conjugative Plasmids in the Pre-Antibiotic Era E.D.G. Murray - Enterobacteria gene 1917-54 Origin - N.Am., Europe, India, Mid East, Russia Strains - Salmonella (48%); Shigella (32%), E. coli (7%) 1917-41 Genetic transfer function (plasmids) - 24% AMP in 2%; tetra 9% No plasmids had resistance genes RR Hughes & Datta Nature 1981; 302:725

11. Coagulase-Negative Staph Nosocomial Bacteremia: Methicillin Resistance 17% 83% N=6,047

12. Methicillin-Resistant S. aureus N= 3,567 SCOPE, 1995-2000. Region%methicillin resistance Northeast35 Northwest22 Southeast49 Southwest30 All39

13. Nosocomial Enterococcal Bacteremia: Vancomycin Susceptibility by Species R R R E. faecalis (n=378) 3% vancomycin resistant 46% vancomycin resistant E. faecium (n=129)

14. Nosocomial Candidemia N=1,698 SCOPE, 1995-2000 R

15. SCOPE Project: Distribution of Candida Nosocomial BSIs 56 17 3 70 15 1 46 26 4 51 18 4 C. albicans C. glabrata C. krusei Edmond et al CID 1999

16. SCOPE: Nosocomial Bloodstream Infections proportion occurring in ICUs n=3908 n=1928 n=1354 n=934 59 44 53 57 Edmond et al CID 1999

17. ICU BSI: Increased Mortality with Inadequate Antimicrobial Therapy Risk for death AOR Inadeq. Rx6.9 Vasopres3.0 No. organ fail2.3 Risk for inad. Rx Candida52 Prior AB2.1  ALB1.3  CVC days1.03 Adequate Inadequate (n=345) (n=147) therapy 29% 62% Mortality (%) Ibrahim et al Chest 2000; 118: 146-55

23. 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

24. 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

25. 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

26. Two Antimicrobial Impregnated Central Venous Catheters Multicenter (n=12) study Minocycline - Silver RifampinSulfadiazine No. 356 382 BSI 1 (0.3%)13 (3.4%) 12 inf/~370 or 32 inf/1000 prevented Darouiche et al NEJM 1999; 340: 1-8

27. The Effect of an Alcohol-based Hand Disinfectant on Handwashing Compliance in the Medical ICU 173 18 8 11 2 10 22 16 25 19 41 23 48 12 2 9696 Baseline After Education Alcohol Dispenser 10 6 7979 9393 1:4 ratio 1:1 ratio (no. of washes/no of opportunities) % Bischoff et al IDSA 1998

31. 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

32. Hypocalcemia and Sepsis Malnourished patient:  Vit D intake and  Albumen (  total Ca ++ ) Allealosis:  prot binding,  ionized Ca ++ Sepsis:  FFA cause  prot binding cytokines cause  PTH liver, renal dysfunctions:  hydroxylation Vit D 10% chelated 50% ionized 40% protein bound bound JAMA 1986; 256: 1924 Crit Care Med 2000; 28:266 Conc: Vit D PTH

33. 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

34. Recombinant Human Activated Protein C and Sepsis APC antithrombotic profibrinolytic antiinflammatory Prot C to APC impaired in sepsis HAPC - PHASE IIdose-dep decrease d-dimer, IL-6 coag; inflam Arterioscler Throm 1992; 2:135 Intensive Care Med 1998; S77

35. Recombinant Human Activated Protein C and Severe Sepsis: Phase II Study Placebo (41) 2 low doses (51)12 and 18 mcg/kg/h 2 hi-doses (39)24 and 30 mcg/kg/h hi-dose: reduced d-dimer (p<0.01) trend  platelets Mortality: placebo (34%0 low dose (35%) hi dose (21%) Hartman et al Intens Care Med 1998; S77

38. 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