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Sepsis

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. • attributable mortality: 8%-2%=6% • YLL: Age 55 - Age 20 = 35 years

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Sepsis

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  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 • 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 Crude mortality (%) 8% 2% Physician Med/Students Midwives

  3. SIRS Fever or Hypothermia (>38º or 36º) Tachycardia (>90) Tachypnea (>20) Hi/Low WBC (>12, <4, >10% bands) Bone et al Chest 1992; 101: 1644-55

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

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

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

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

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

  9. 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 R R Hughes & Datta Nature 1981; 302:725

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

  11. Methicillin-Resistant S. aureus Region %methicillin resistance Northeast 35 Northwest 22 Southeast 49 Southwest 30 All 39 N= 3,567 SCOPE, 1995-2000.

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

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

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

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

  16. ICU BSI: Increased Mortality with Inadequate Antimicrobial Therapy Risk for death AOR Inadeq. Rx 6.9 Vasopres 3.0 No. organ fail 2.3 Risk for inad. Rx Candida 52 Prior AB 2.1  ALB 1.3  CVC days 1.03 62% Mortality (%) 29% Adequate Inadequate (n=345) (n=147) therapy Ibrahim et al Chest 2000; 118: 146-55

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

  18. Genetic Factors in Septic Shock Frequency-TNF a gene promoter Control Septic shock P (n=87) (n=89) Chromosome 6 Any poly- morphism 25 43 .008 TNFZ 16 35 .002 HLA class III genes TNF a gene promoter Outcome - Septic Shock (n=89) Lived Died P (n=41) (n=48) Any poly- morphism 14(34) 29(61) .01 TNFZ 10 25 .008 TNFZ: a single base pair change Mira et al JAMA 1999; 282:561-8

  19. 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

  20. Two Antimicrobial ImpregnatedCentral Venous Catheters Multicenter (n=12) study Minocycline - Silver Rifampin Sulfadiazine 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

  21. The Effect of an Alcohol-based Hand Disinfectant on Handwashing Compliance in the Medical ICU (no. of washes/no of opportunities) 48 % 41 25 23 22 19 16 10 188 112 122 96 106 79 93 173 Bischoff et al IDSA 1998 After Education Alcohol Dispenser Baseline 1:4 ratio 1:1 ratio

  22. 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 p<0.001 Mortality (percent) 39% 20% 44% 18% (n=119) (n=123) (n=139) (n=141) Takala et al NEJM 1999; 341: 785 Finnish study Multination study 32% vs 16% 26% vs 15% Proportion of deaths from septic shock/uncont.infection

  23. 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 50% ionized 40% protein bound 10% chelated Conc: Vit D PTH JAMA 1986; 256: 1924 Crit Care Med 2000; 28:266

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

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

  26. 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

  27. 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 72 • oxygen • best choice antibiotics ( I + D?) • rapid transfer to ICU with CCM trained experts

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