1. Section of Critical Care Medicine Section of Infectious Diseases University of Manitoba, Winnipeg, Canada UMDNJ-Robert Wood Johnson Medical School Cooper Hospital, NJ Anand Kumar, MD Sepsis and Septic Shock Old Concepts, New Precepts

2. Incidence of Severe Sepsis/Septic Shock Approximate Cases/Year 800,000 600,000 400,000 200,000 0 Severe sepsis 800,000 Septic shock 400,000 Deaths from septic shock 200,000 Sepsis and sequelae are a leading cause of death in ICU Mortality in septic shock remains at 35 - 50% -unchanged since advent of antibiotics (from 55 - 75%)

3. Bacterial Sepsis Death Rate in the United States 5.0 Chart adapted from CDC/National Center for Health Statistics, 1992. 4.0 3.0 2.0 1.0 0.0 0.8 0.7 0.5 0.4 0.6 0.2 0.1 0.3 1960 1965 1970 1975 1980 1985 1990 Rate per 100,000 Population 4.1

4. Severe Sepsis: Comparative Incidence and Mortality Angus DC, et al. Crit Care Med. 2001; ACS. Incidence Cases/100,000 Mortality Deaths/Year

6. Projected Incidence of Severe Sepsis in the US: 2001 - 2050 200,000 400,000 600,000 800,000 1,000,000 1,200,000 1,400,000 1,600,000 1,800,000 2001 2025 2050 Year 100,000 200,000 300,000 400,000 500,000 600,000 Severe Sepsis Cases US Population Sepsis Cases Total U.S. Population/1,000 Angus DC, et al. Crit Care Med. 2001.

13. Relationship of Sepsis, Severe Sepsis, and Septic Shock Sepsis Severe Sepsis Septic shock MODS Death Sepsis and organ dysfunction, hypoperfusion, or hypotension Sepsis-induced hypotension

14. Nosocomial Infection vs. Severe Sepsis in MICU Reinhart, et al. Crit Care Med. 2001; Bernard et al (aPC). N Engl J Med. 2001; Fisher et al (IL-1ra). JAMA. 1994; Abraham et al (TNF  Mab). JAMA 1995; Bernard et al (Ibuprofen). N Engl J Med. 1997. UTI 15% (8 - 20%) GI 25% (15 - 30%) Skin/soft tissue 10% (5 - 15%) Primary bloodstream Infections 5% (2.5 - 7.5%) Pneumonia 45% (37 - 54%) Richards MJ, et al. Crit Care Med. 1999;27:887-92. Urinary Tract Infection 31% Primary Bloodstream Infections 19% Gastrointestinal Infections 5% Cardiovascular System 4% Eye, Ear, Nose and Throat 4% Lower Respiratory Tract Infections 4% Other 6% Pneumonia 27% Nosocomial Infection (NNIS 92-97) Severe Sepsis

15. Nidus of Infection Abscess Pneumonia Peritonitis Pyelonephritis Cellulitis Organism Exotoxin TSST-1 Toxin-A Structural Component Teichoic Acid Antigen Peptidoglycan, Endotoxin (LPS) Bacterial nucleic acids Gut release of endotoxin Plasma - Extrinsic / intrinsic pathways - Protein C; S - TFPI Complement Kinins Coagulation Monocyte-Macrophage - TNF - Interleukins - Interferons - MIF - HMGB1 Cytokines Endothelial Cells Selectins, Icams Renin-angiotensin system Prostaglandins Leukotrienes Prostacyclin Thromboxane Endothelin Neutrophils Lysosomes Oxygen free radicals (superoxides) Granulocyte Colony Stimulating Factor (G-CSF) Cellular Dysfunction Continued... Pathogenesis of Septic Shock Platelet Activating Factor Nitric Oxide Tissue Factor

16. Vasculature - Vasodilation - Vasoconstriction - Leukocyte aggregation - Endothelial cell dysfunction Cellular Dysfunction Organs - Dysfunction - Metabolic abnormalities Myocardium - Depression - Dilatation Shock Refractory Hypotension Multiple Organ Dysfunction Recovery Death Nucleus Lysosome Mitochondria Actin/Myosin Membrane channel Membrane receptor Pathogenesis of Septic Shock

17. Pili Adapted from Young, et al. Ann Intern Med. 1977;86:456-71. Capsule (K antigen) Outer membrane Solid membrane (peptidoglycan) Flagellum (H antigen) LPS (endotoxin: O antigen) Oligosaccharide side chains Core polysaccharide Lipid A Inner cytoplasmic membrane Endotoxin (LPS): A Component of the Gram-negative Bacterial Cell Wall

18. LPS LBP LBP LPS LBP Extra- cellular space Macrophage Extra- cellular space LPS CD14 TNF  PAF IL-6 IL-1  LPS Signaling Pathways, 1990

19. Signaling Pathways Related to CD14 and TLR LPS LBP LBP LPS LBP Toll4 Toll2 MYD88 IRAK MYD88 IRAK TRAF 6 NIK IKK  I  B NF  B I  B NF  B Extra- cellular space Cytoplasm Nucleus LPS CD14 NF  B HDL Elimination LPS HDL HDL STATs? IRFs? HMGs? MAP kinases? ? CD14 MD-2

20. Toll-like Receptor (TLR) Receptors and Ligands Bochud P, Calandra T. BMJ. 2003.

21. 50 Patients (%) 0 10 20 30 40 Modified from Danner RL, et al. Chest. 1991;99:172. Hours 0 4 8 12 16 20 >24 Cumulative Percentage of Clinically Septic Patients with Detectable Endotoxemia (N = 100)

22. 150,000 TNF units/mL serum 10 400 600 1,000 1,200 Waage A, Halstensen A, Espevick T. Lancet. 1987. Serum from patients who died Serum Concentrations in Survivors and Nonsurvivors of Septic Shock Serum from patients who survived Detection limit for TNF 100,000 1,400 1,000 200 Tumor Necrosis Factor (TNF)

23. Kumar, et al. J Cardiovasc Thor Anes. 2001. Hemodynamic Effects of Putative Septic Shock Mediators Hepatic acute phase response ? No change (canine) No change (canine) No change (canine) IL - 6 Pyrexia,  platelets Decreased (canine) Decreased (human, canine) Increased (human, canine) Decreased (human, canine) IL - 1  Lactic acidosis, pulmonary edema,  WBC, pyrexia DIC,  platelets Decreased (canine) Decreased (human, canine) Increased (human, canine) Decreased (human, canine) TNF   WBC, pyrexia  TNF, IL - 1, IL - 6 Decreased (human, canine) Decreased (human, canine) Increased (human, canine) Decreased (human, canine) Endotoxin Miscellaneous Effects Ejection Fraction Systemic Vascular Resistance Cardiac Output Arterial Pressure Putative Mediator

26. Pathogen Inflammation Coagulation Monocyte Pathophysiology of Sepsis - A New Paradigm Tissue Factor Cytokines

27. Modern View of the Coagulation Cascade Steps in coagulation Coagulation cascade Initiation TF/VIIa Propagation VIIIa Thrombin activity Fibrinogen Fibrin IXa IX X Xa II Va IIa II indicates prothrombin; IIa, thrombin; IX, factor IX; IXa, activated factor IX; TF, tissue factor; Va, activated factor V; VIIa, activated factor VII; VIIIa, activated factor VIII; X, factor X; Xa, activated factor X. Weitz JI, et al. Chest. 2001.

28. Coagulation in Sepsis Bernard GR, et al. New Engl J Med, 2001;344:699-709. Inflammatory Response to Infection Thrombotic Response to Infection Fibrinolytic Response to Infection Endothelium TAFI PAI-1 Suppressed fibrinolysis Neutrophil Monocyte IL-6 IL-1 TNF  Bacterial, viral, fungal or parasitic infection/endotoxin Bacterial, viral, fungal or parasitic infection/endotoxin IL-6 Tissue Factor Tissue Factor COAGULATION CASCADE Factor Va Factor VIIIa THROMBIN Fibrin Fibrin clot

31. Activation of Coagulation in Severe Sepsis Data from: Bernard et al. The Ibuprofen in Sepsis Trial (In Press). 0 20 40 60 80 100  Platelets  PTT  PT Any One Any Two All Three  Protein C  D-Dimers Percentage of Patients Markers of DIC

32. Protein C Levels Decrease Before the Clinical Diagnosis of Severe Sepsis Mesters et al. Crit Care Med. 2000;28:2209-16. 20 40 60 80 100 120 PC HEM  WBC Fever 6 hr 12 hr 18 hr 24 hr 36 hr 48 hr 60 hr 72 hr PC Antigen (%) Severe Sepsis Patients Septic Shock Patients Average Time to Diagnose Severe Sepsis

33. GTP cGMP Blood Endothelium Smooth Muscle GTP cGMP GC L-Arg O 2 L-citrulline GC NO . cNOS Platelets Nitric Oxide in the Vasculature

34. GTP cGMP Blood Endothelium Smooth Muscle GTP cGMP GC L-Arg O 2 L-citrulline GC NO iNOS Platelets iNOS cNOS Endotoxin Cytokines NO Nitric Oxide in Sepsis

37. 1 0 2 5 6 Cardiac Index (L/min/m 2) 3 4 1 2 4 7 10 1 2 4 7 10 Time (days) 7 Survivors Nonsurvivors All Patients Parker et al. Ann Intern Med. 1984. Cardiac Index in Septic Shock (post - 1980)

40. Mizock BA. Crit Care Med. 1992;20:80-93. Oxygen Consumption Oxygen Delivery Critical Delivery Threshold Lactic Acidosis Physiologic Oxygen Supply Dependency Indicating a Critical Delivery Threshold Below Which Lactic Acidosis Ensues

41. Mizock BA. Crit Care Med. 1992;20:80-93. Oxygen Consumption Oxygen Delivery Pathologic Physiologic Relationship Between Oxygen Delivery and Consumption Under Physiologic and Pathologic Conditions

42. Capillary Vascular Abnormality Arteriole Neutrophil Aggregation Vasoconstriction Vasodilation Endothelial Cell Destruction Venule Cell Pathogenesis of Septic Shock