Meral SÖNMEZOĞLU, Prof Yeditepe University Hospital Infectious Diseases Department

1. Sepsis, Severe Sepsis & Septic Shock Meral SÖNMEZOĞLU, Prof Yeditepe University Hospital Infectious Diseases Department 1

2. Overview • Differentiation between Septic Shock in relation to other conditions in current code, Sepsis, and Severe Sepsis • Disease Epidemiology, Incidence and Mortality • Inadequacy of Current Diagnostic Codes • Proposed Modifications and Clarification • Discussion 2

3. KEY POINTS • Severe sepsis and septic shock have high prevalence and mortality. • Treatment is time-sensitive and depends on early identification and risk-stratification. • Treatment must include antibiotics and targeted therapies designed to optimize oxygen delivery. • Adherence to a treatment algorithm decreases mortality 3

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5. Systemic Inflammatory Response • At least 2 of 4 ( abnormal temp or leukocytes count is amust) • Coretemp>38.5 or <36 • Tachycardia: HR >2 sd above Normal for age orbradycardia <10% forage • Tachypnea: RR >2 sd for age or mechanical ventilationforacuteprocess • Leukocyte elevated or depressed for age or >10%immatureneutrophils 5

6. Definitions • Infection: Suspected or proven caused byany pathogen Or clinical syndromeassociated with high probability of infection • Sepsis: SIRS in the presence of or as a resultof suspected of proven infection 6

7. Definitions • Sepsis is defined as the presence (probable or documented) ofinfection together with systemic manifestations of infection. • Severe sepsis is defined as sepsis plus sepsis-induced organdysfunctionortissuehypoperfusion 7

8. Definitions • Severe Sepsis: sepsis + one • Cardiovasculardysfunction • ARDS • OR 2 or more other organ dysfunctions • Septicshock • Sepsis and cardiovascular organ dysfunction 8

9. Definitions • Septicshock • Sepsis and cardiovascular organ dysfunction • Septic shock is defined assepsis-induced hypotension persisting despite adequate fluid • resuscitation. • Sepsis-induced tissue hypoperfusion is defined • as infection-induced hypotension, elevated lactate, or oliguria 9

10. Sepsis: Defining a Disease Continuum Infection/Trauma Sepsis Severe Sepsis SIRS SIRS with a presumed or confirmed infectious process A clinical response arising from a nonspecific insult, including  2 of the following: • Temperature 38oC or 36oC • HR 90 beats/min • Respirations 20/min • WBC count 12,000/mm3or 4,000/mm3 or >10% immature neutrophils SIRS = Systemic Inflammatory Response Syndrome Adapted from: Bone RC, et al. Chest 1992;101:1644 Opal SM, et al. Crit Care Med 2000;28:S81 10

11. Shock Sepsis: Defining a Disease Continuum Infection/Trauma Sepsis Severe Sepsis SIRS • Sepsis with 1 sign of organ failure • Cardiovascular (refractory hypotension) • Renal • Respiratory • Hepatic • Hematologic • CNS • Metabolic acidosis 11 Bone et al. Chest 1992;101:1644; Wheeler and Bernard. N Engl J Med 1999;340:207

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13. SEPSIS PANCREATITIS SEVERE SEPSIS SIRS BURNS INFECTION SEPTICSHOCK TRAUMA OTHER Relationship Of Infection, SIRS, Sepsis Severe Sepsis and Septic Shock 13 Bone et al. Chest 1992;101:1644

14. Monocytic Cells Inflamatory Cascade Chemotaxis Superoxide Radicals Lysosomal Enzymes Complement Gram-negative Bacteria/Endotoxin System Neutrophil Accumulation Capillary Leak Neutrophils Adhesion Molecules Hypotension, ARDS, DIC, Multiple Organ Failure, Death Fever Metabolic Changes Cytokines Hormonal Changes* TNF-a, IL-1, IL-6, IL-8, etc. Vasodilation Lipid Mediators Nitric Oxide Clotting Abnormalities Endothelial Cells Bradykinin Tissue Factor = inhibited by rBPI in vivo or in vitro = not investigated Coagulation System * 14

15. SEPSIS MEDIATORS 15 Russell J. N Engl J Med 2006;355:1699-1713

16. Sepsis Easily edited and animated! Septic ShockThis is a placeholder text. Color all elements individually. Severe Sepsis This is a placeholder text. Before SepsisThis is a placeholder text. This product is available in the category Pyramids/ Funnels View category

17. Sepsis 400,000 7-17% Severe Sepsis 300,000 20-53% Septic Shock 53-63% Mortality Increases in Septic Shock Patients Incidence Mortality Approximately 200,000 patients including 70,000 Medicare patients have septic shock annually 17 Balk, R.A. Crit Care Clin 2000;337:52

18. Septic Shock is Unique within 785.59 785.5 Unspecified Shock 7% 785.59 Other Shock 62% 785.59 Details 10,100 45,200 88,600 785.51 Cardiogenic Shock 31% * Represents Septic Shock Patients ICD-9-CM code 785.5X Population Septic Shock patients have a longer length of stay and a higher cost than other patients within 785.59 18

19. Severe Sepsis: A Significant Healthcare Challenge • Major cause of morbidity and mortality worldwide • Leading cause of death in noncoronary ICU (US)* • 11th leading cause of death overall (US) †§ 1 About 1,000,000 cases of severe sepsis in US annually‡ 2 In the US, about 600-1000 patients die of severe sepsis daily 3 *Sands KE et al. JAMA. 1997;278:234-40; †Based on data for septicemia. §Murphy SL. National Vital Statistics Reports. ‡Angus DC et al. Crit Care Med. 2001 (In Press); reflects hospital-wide cases of severe sepsis as defined by infection in the presence of organ failure. www.themegallery.com

20. Sepsis Epidemiology: Effect of the Aging Population www.themegallery.com

21. Severe Sepsis: Comparison With Other Major Diseases Incidence of Severe Sepsis Mortality of Severe Sepsis Cases/100,000 Deaths/Year AIDS* Breast CHF† Severe Sepsis‡ Colon Severe Sepsis‡ AIDS* Breast Cancer§ AMI† Cancer§ †National Center for Health Statistics, 2001.§American Cancer Society, 2001. *American Heart Association. 2000. ‡Angus DC et al. Crit Care Med. 2001 www.themegallery.com

22. Mortality of Sepsis over Time Proportion of Patients with Sepsis Who Died 1979 1981 1983 1985 1987 1989 1991 1993 1995 1997 1999 2001 www.themegallery.com

23. Epidemiology [1993-2001]...a 75% increase in... severe sepsis... Incidence of Sepsis [1993 - 2001]...a 17% reduction in mortality. Mortality of Sepsis Brun-Buisson, C., Meshaka, P., Pinton, P., Vallet, B., EPISEPSIS Study Group. (2004). EPISEPSIS: a reappraisal of the epidemiology and outcome of severe sepsis in French intensive care units. Intensive Care Medicine, 30(4), 580–588. Harrison, D. A., Welch, C. A., & Eddleston, J. M. (2006). The epidemiology of severe sepsis in England, Wales and Northern Ireland, 1996 to 2004: secondary analysis of a high quality clinical database, the ICNARC Case Mix Programme Database. Critical Care, 10(2), R42. Martin, G. S., Mannino, D. M., Eaton, S., & Moss, M. (2003). The epidemiology of sepsis in the United States from 1979 through 2000. New England Journal of Medicine, 348(16), 1546–1554.

24. Mortality Evolution of Sepsis care Established Core Rx: Source Control More Antibiotics Faster Resuscitation Better Supportive Care Established Core Rx: Source Control Antibiotics Resuscitation Supportive Care In general the process of care has improved Steroids No Steroids Endotoxin Antagonists LPS/LPS receptor antagonist anti-TNF NSAIDs Nitric Oxide Synthase Inhibitors Tissue Factor Pathway Inhibitors anti-TLR4 Xigris Tight Glycemic Control Immunonutrition Steroids Loose Glycemic Control Immunonutrition? ?Not Steroids ? No Xigris Steroids

25. Economics of Sepsis • Severe Sepsis • $22,000 per case • US annual cost $16.7Billion • Nosocomial Sepsis • increased LOS - ICU 8 days, Hosp 24 days • $40,890 per case Angus CCM, 2001 Pittet JAMA, 1994 www.themegallery.com

26. Time Sensitive Interventions “Door to PCI”Focus on the timely return of blood flow to the affected areas of the heart.(percutanous coronary intervention) AMI “Time is Brain” The sooner that treatment begins, the better are one’s chances of survival without disability. Stroke “The Golden Hour” Requires immediate response and medical care “on the scene.” Patients typically transferred to a qualified trauma center for care. Trauma www.themegallery.com

27. Trauma vs. Sepsis Patient CareWhere we spend our efforts www.themegallery.com

28. Severe Sepsis vs. Current Care Priorities Source: (1) Ryan TJ, et al. ACC/AHA Guidelines for management of patients with AMI. JACC. 1996; 28: 1328-1428. (2) American Heart Association. Heart Disease and Stroke Statistics – 2005 Update. Available at: www.americanheart.org. (3) National Highway Traffic Safety Administration. Traffic Safety Facts 2003: A Compilation of Motor Vehicle Crash Data from the Fatality Analysis Reporting System and the General Estimates System. Available at http://www.nhtsa.dot.gov/. (4) Angus DC et al. Crit Care Med 2001;29(7): 1303-1310. www.themegallery.com

29. The Surviving Sepsis Campaign 25% Reduction In Sepsis Mortality within next 5 yrs • = ~ 50,000 people in the United States each year. • = ~ 1,100,000 individuals worldwide each year. Angus DC, et al. Epidemiology of severe sepsis in the United States: Analysis of incidence, outcome, and associated costs of care. Critical Care Medicine. Jul 2001;29(7):1303-1310. www.themegallery.com

30. Cardiovascular Dysfunction • Despite administration of isotonic intravenous fluid • bolus ≥40 mL/kg in 1 hr • Hypotension: BP <5th % or <2 sd OR • Need for vasoactive drug to maintain BP (dopamine >5mcg/kg/min or dob, epi, or norepi at any dose) OR • Two of the following • Unexplained metabolic acidosis: Base deficit >5.0 mEq/L • Arterial lactate: >2 times upper limit of normal • Oliguria: Urine output <0.5 mL/kg/hr • Capillary refill: >5 secs • Core to peripheral temperature gap >3°C 30

31. Respiratory Dysfunction • PaO2 /Fio2 <300 in absence of cyanotic heart • disease or preexisting lung disease OR • PaCo2 >65 or 20 mm Hg over baseline Paco2 OR • Need or >50% Fio2 to maintain saturation ≥92% OR • Need for non-elective invasive or non-invasive • mechanical ventilation 31

32. Neurologic Dysfunction • Glasgow Coma Score ≤11 OR • Acute change in mental status with adecrease in Glasgow Coma Score ≥3 points from abnormal baseline 32

33. Hematologic Dysfunction • Platelet count <80,000/mm or a decline of50% in platelet count from highest valuerecorded over the past 3 days • INR >2 33

34. Renal Dysfunction • Serum creatinine ≥2 times upper limit of • normal for age or • 2-fold increase in baseline creatinine 34

35. Hepatic Dysfunction • Total bilirubin ≥4 mg/dL (not applicable for • newborn) OR • ALT 2 times upper limit of normal for age 35

36. Mortality and SIRS 36

37. Mortality

38. Mortality

39. Conclusion • Septic shock has distinct characteristics that support the creation of a unique code (785.52) • Septic shock should be linked to severe sepsis • Modification of current SIRS coding will better represent the clinical presentation of the sepsis syndrome • 995.51, sepsis • Modification to “code also” list in 995.92 39

40. Deficiencies of 1991 Consensus Conference • Limitations inherent in these definitions: • Incomplete agreement as to what defines “Systemic Response" • Inflammation only? • Organ/System failures not defined • Except hypotension (SBP <90 mmHg or >40 mmHg decline from baseline; need for vasopressor support) "Dear SIRS, I do not like you" Jean Louis Vincent

41. 2001 Sepsis Definitions Conference • Current definitions will remain unchanged • However, will accept the uncertainty of definitions • SIRS expanded to signs and symptoms • Chills • Alteration in temperature • Tachypnea • Change in mental status • Tachycardia • Altered WBC, Bandemia • Thrombocytopenia • Decreased perfusion: mottling, poor capillary refill • Increased blood sugar • Petichiae/Purpura 41

42. 2001 Sepsis Definitions Conference • PIRO staging system proposed • Predisposition: Genetics, Chronic illness • Insult: Infection, Injury, Ischemia • Response: Physiologic, Mediators, Markers • Organ Dysfunction: Outcome, Organ dysfunction 42 To be published 2002 (Verbal communication Mitchell Levy, SCCM 2002)

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44. Pathophysiology of Sepsis

45. Pathophysiology of Sepsis Disorder Due to Uncontrolled Inflammation? • Increased inflamatory mediators like IL-1, TNF, IL-6. • Based on animal studies. • In a study in children with meningococcemia, TNF levels directly correlated with mortality. • Clinical trials involving TNF anagonist, antiendotoxin antibodies, IL-1 receptor antagonists, cortocosteroids failed to show any benefits. • Patients with RA treated with TNF antagonist develop infectious complications.

46. Pathogenesis of Sepsis

47. Pathophysiology of Sepsis Failure of Immune System to Eliminate Microorganism? • Shift from inflammatory (ThI) to antiinflammatory response (Th2). • Anergy. • Apotosis of B cells, T cells, Dendritic cells. • Loss of macrophage expression of MHC Class I and co-stimulatory molecules. • Immunosuppressive effect of apoptotic cells.

48. Pathogenesis of Sepsis

49. Pathogenesis of Sepsis

50. Inflammatory Responses to Sepsis Russell J. N Engl J Med 2006;355:1699-1713 50