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Estimates of the Impact of Sepsis Syndromes Annually in U.S.

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. Sepsis Definitions. sepsis. severe sepsis. septic

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Estimates of the Impact of Sepsis Syndromes Annually in U.S.

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  1. 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

  2. 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

  3. 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

  4. Proinflammatory Molecules TNFa TNF R1 TRADD RelA TRAF2 RIP p50 IkB NIK IKK IL-1 R1 IL-1 RAcP TRAF-6 IL-1b IRAK RelA P p50 Ub NLS RelA p50 IkB RelA Christman et al Intensive Care Med 1998; 24:1131-1138 p50 mRNA

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

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

  7. Hydrocortisone (300 mg IV/d) vs Placebo for  5 days for Septic Shock with Vasopressors > 48 hrs Treatment Placebo Probability of Shock Reversal (%) Survival Probability (%) Days after Inclusion 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 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

  9. 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

  10. Independent Predictors of Mortality After Septic Shock (n=89) Variable OR (CI95) P Age (10 yr increase 1.46 (1.06-2.0) .02 SAPS-II score 1.22 (1.01-1.46) .04 TNFZ 3.75 (1.37-10.24) .01 Mira et al JAMA 1999; 282: 561-8

  11. 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

  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 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

  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

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