2. Sepsis: A New Look at an Old Problem Nathan Shapiro, MD, MPH Beth Israel Deaconess Medical Center Harvard Medical School

3. Sepsis 750,000 cases per year in US Mortality ranges 10-60% 215,000 deaths/year More than 640 deaths/day in US $22,000 per case $16.7 billion per year in US Angus et al. Crit Care Med. 2001;29:7:1303-1309

4. Severe Sepsis: Comparison With Other Major Diseases † National Center for Health Statistics, 2001. § American Cancer Society, 2001. *American Heart Association. 2000. ‡ Angus DC et al. Crit Care Med. 2001 (In Press). AIDS*Colon Breast Cancer § CHF † Severe Sepsis ‡ Cases/100,000 Incidence of Severe SepsisMortality of Severe Sepsis AIDS* Severe Sepsis ‡ AMI † Breast Cancer §

5. What is sepsis? Host Infection Systemic Inflammatory Response Pro-inflammatory/Anti Inflammatory Activity Accelerated Inflammatory Cascade Sepsis Syndromes

6. Sepsis Definitions Systemic Inflammatory Response Syndrome: (SIRS): two or more of the following 1.T>38 or <36 2.HR > 90 beats/min 3.RR>20 beats/min or pCo2<32 torr 4.WBC>12,000 or 10% bands SEPSIS – SIRS due to an infection ACCM/SCCM Consensus Conference:Chest :1992:20:6

7. Sepsis Definitions SEVERE SEPSIS - Sepsis + Organ Dysfunction, signs of organ dysfunction in the following systems: –Cardiovascular –Renal –Respiratory –Hepatic –Hemostasis –CNS –Unexplained metabolic acidosis SEPTIC SHOCK – Severe Sepsis + hypotension (despite adequate fluid resuscitation)

9. The Natural History of the Systemic Inflammatory Response Syndrome 3708 patients, multi-center prospective study in ICU/inpatient population SyndromeMortality SIRS2.2% (2.3-4.1) Sepsis2%(1.0-3.5) Severe Sepsis9%(7.2-10.7) Septic Shock15%(9.5-20.3) Rangel-Frausto et. al. JAMA:1995:273:117-123.

10. Sepsis Syndromes in the Emergency Department 3179 patients, prospective, ED based study SyndromeMortality No SIRS3.2%(2.3-4.1%) SIRS/Sepsis8%(1.1-3.5%) Severe Sepsis10%(7.4-10.8%) Septic Shock27%(16.5-41.2%) Shapiro et al. 2001 SCCM Meeting

11. “Patients die of complications of their disease, rather than the disease itself ” Sir William Osler

12. Mediators of Sepsis LPS TNF IL-1 IL-6/IL-8 NO,PAF, others Local Inflammation SepsisSevere Sepsis (low levels)(medium levels)(high levels) Anti-Inflammatory IL-4 IL-6 (both) IL-10 IL-11 IL-13

13. Approach to Sepsis Recognition of SIRS/Sepsis Identify etiology Early and Aggressive Treatment

14. “Sick, or not sick? That is the question!” (Adapted from) Shakespeare

15. “Hectic Fevers at its inception is difficult to recognize, but easy to treat; Left untended, it becomes easy to recognize, but difficult to treat.” Niccollo Machievielli, in “The Prince”(1513)

16. What are the RED FLAGS in Emergency Department patients with sepsis?

17. Mortality in Emergency Department Sepsis (MEDS) Score Objective: To identify predictors of death from sepsis present in Emergency Department (ED) patients Prospective Study of 3179 ED patients admitted to hospital with suspected infection Logistic regression to identify “predictors of death” Shapiro et al/ Critical Care Medicine. March 2003

18. 3,301 Patient Encounters 3,179 (96%) Enrolled 122 (4%) missed Visits randomly assigned 2/3 1/3 2,070 Derivation Set 1,109 Validation Set Regression and Prediction Rule Patient Enrollment

19. Independent Predictors Identified by Multivariate Analysis __________________________________________________ Variable Odds Ratio95% CI Points __________________________________________________ Terminal illness (<30d) 6.3 (3.7 to 10.4)6 Tachypnea or hypoxia 2.6 (1.6 to 4.2)3 Platelets < 150,000 /mm 3 2.6 (1.6 to 4.4)3 Bands > 5% 2.3 (1.4 to 3.5)3 Age > 652.3(1.4 to 3.7)3 Suspected pneumonia2.0 (1.3 to 3.2)2 Nursing home resident 1.9 (1.2 to 3.1)2 Septic Shock 2.6 (1.0 to 3.3)3 Altered mental status 1.7 (1.1 to 2.7)2 Shapiro et al/ Critical Care Medicine. March 2003

20. Mortality by MEDS score.6% 2.3% 8% 18% 51%.7% 4.7% 9.1% 16% 39% 0% 10% 20% 30% 40% 50% 60% 0-45-78-1212-15>15 MEDS score Derivation Validation Mortality % **ROC Area =.81

21. ED Predictors of death from Sepsis Host Status Terminal illness (<30d) Age > 65 Nursing home resident Infection Type Suspected pneumonia Findings: **Tachypnea or hypoxia **Septic Shock Altered mental status Lab Abnormalities Platelets < 150,000 /mm 3 Bands > 5%

22. Therapy “Over 13,000 patients have been enrolled in 23 multi-center, placebo-controlled, clinical trials……results have been generally disappointing with some spectacular failures” From “Clinical Trials for Severe Sepsis. Past Failures and Future Hopes, 1999 Opal et al. Infectious Disease Clinics of North America. 1999:13:2.

23. Sepsis Systemic Inflammation Infection Coagulation Protein C

24. Sepsis: A Network of Cascading Events FIBRINOLYSIS PROINFLAMMATORY MEDIATORS INFECTION TF ANTI-INFLAMMATORY MEDIATORS INFLAMMATION Activated Protein C Activated Protein C T TM COAGULATION PAI-1 T-PATAF-1 ENDOTHELIAL INJURY

25. Homeostasis Anti-Inflammatory Pro-Inflammatory Endogenous Activated Protein C Modulates Coagulation, Fibrinolysis, and Inflammation in Severe Sepsis Carvalho AC et al. J Crit Illness. 1994;9:51-75; Kidokoro A et al. Shock. 1996;5:223-8; Vervloet MG et al. Semin Thromb Hemost. 1998;24:33-44. Pro-Coagulant Fibrinolytic

26. Recombinant Human Activated Protein C 1690 patients, double blind, placebo controlled Inclusion: –known/suspected sepsis –> 3 SIRS criteria –dysfunction > 1 organ systems Bernard et.al. NEJM. March 8, 2001:344:10:699-709.

27. Results Mortality ControlProtein C Group 30.8% VS24.7% 6.1% absolute reduction in DEATH (Number needed to treat = 17) Bernard et.al. NEJM. March 8, 2001:344:10:699-709.

28. APC “PROS” Well designed RANDOMIZED, DOUBLE BLIND, MULTICENTER, PLACEBO CONTROLLED study showing benefit in meeting primary objective Makes good biological sense

29. APC CONS Single Study Numerous exclusion criteria Altered exclusion criteria mid-study Very expensive Unclear benefit in patients with lower APACHE Scores FDA mandated follow-up study (lower acuity) starting soon

30. 1 Cost-Benefit All patients: $27,936 per life-year APACHE II > 25 $24,484 per life-year APACHE II < 24 $575,054 per life-year 1 Manns et al. NEJM:347:13:993-1000