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

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

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

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

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, %40, %32, ,000 cases/yr 164,000 deaths/yr

Rank Order of Nosocomial Bloodstream Infections and Mortality SCOPE Surveillance System CNS S.aureus Enterococcus Candida n=3908 n=1928 n=1354 n=934 proportion of BSI (%) 0 proportion crude mortality crude mortality (%) Edmond et al CID 1999

Attributable Mortality: The Promise of Better Antimicrobial Therapy 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 scenarios effect of existing Rx

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

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

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

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

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

Nosocomial Candidemia N=1,698 SCOPE, R

SCOPE Project: Distribution of Candida Nosocomial BSIs C. albicans C. glabrata C. krusei Edmond et al CID 1999

SCOPE: Nosocomial Bloodstream Infections proportion occurring in ICUs n=3908 n=1928 n=1354 n= Edmond et al CID 1999

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:

Time course of NFkB binding activity Days % NFkB binding activity (day 1=100%) NFkB-binding activity (EMSA) Böher et al 1997 J Clin Invest 100:

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 TNFZ Outcome - Septic Shock (n=89) Lived DiedP (n=41) (n=48) Any poly- morphism 14(34)29(61).01 TNFZ Mira et al JAMA 1999; 282:561-8

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

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

The Effect of an Alcohol-based Hand Disinfectant on Handwashing Compliance in the Medical ICU Baseline After Education Alcohol Dispenser :4 ratio 1:1 ratio (no. of washes/no of opportunities) % Bischoff et al IDSA 1998

Sepsis and Death After Hi-Dose Growth Hormone in ICU Patients RP=1.9 ( ) RP=2.4 ( ) 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

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

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

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

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

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