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Section of Critical Care Medicine Section of Infectious Diseases

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

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Section of Critical Care Medicine Section of Infectious Diseases

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

  2. Incidence of Severe Sepsis/Septic Shock Approximate Cases/Year 800,000 Severe sepsis 800,000 600,000 400,000 Septic shock 400,000 200,000 Deaths from septic shock 200,000 0 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 4.1 4.0 3.0 2.0 Rate per 100,000 Population 1.0 0.0 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 1960 1980 1975 1990 1970 1965 1985 Chart adapted from CDC/National Center for Health Statistics, 1992.

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

  5. 45% • Without Co-morbidity • 40% • With Co-morbidity • Overall • 35% • 30% • 25% Mortality • 20% • 15% • 10% • 5% • 0% • 0 • 1 • 5 • 10 • 15 • 20 • 25 • 30 • 35 • 40 • 45 • 50 • 55 • 60 • 65 • 70 • 75 • 80 • 85 Age Mortality of Severe Sepsis by Age in the United States Angus DC, et al. Crit Care Med. 2001.

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

  7. Systemic Inflammatory Response Syndrome (SIRS) Systemic inflammatory response to a variety of severe clinical insults. Manifested by two or more of the following: • Temperature > 38oC or < 36oC • Heart rate > 90 beats/min • Respiratory rate > 20 breaths/min or PaCO2 < 32 mm Hg • WBC > 12,000/mm3, < 4000/mm3, or > 10% immature (band) forms ACCP/SCCM Consensus Statement Chest. 1992;1644-1655.

  8. Infection Inflammatory response to microorganisms or invasion of normally sterile tissues Sepsis The systemic response to infection – i.e., confirmed or suspected infection plus 2 SIRS criteria Severe Sepsis Sepsis associated with organ dysfunction, hypoperfusion, or hypotension Hypoperfusion abnormalities may include but are not limited to lactic acidosis, oliguria, acute alteration in mental status Sepsis: ACCP/SCCM Definitions ACCP/SCCM Consensus Statement. Chest. 1992;101:1644-55.

  9. Altered mental status Edema or increased fluid balance Hyperglycemia (absent diabetes) Increased CRP or procalcitonin Hypotension Increased SvO2 CI > 3.5 L/min/m2 Arterial hypoxemia (PaO2/FiO2 < 300) Acute oliguria (> 2 hours) Increased serum Cr (> 0.5 mg/dL) Coagulopathy (INR > 1.5) Ileus (absent bowel sounds) Thrombocytopenia (< 100,000/uL) Hyperbilirubinemia (> 40 mg/dL or 70 mmol/L) Hyperlactatemia (> 1 mmol/L) Decreased capillary refill or mottling Sepsis - ACCP/SCCM Definitions: The Update Levy MM, et al. Crit Care Med. 2003.

  10. Sepsis-induced hypotension despite adequate fluid resuscitation along with the presence of perfusion abnormalities that may include, but are not limited to, lactic acidosis, oliguria, or an acute alteration of mental status; patients receiving inotropic or vasopressor agents may not be hypotensive at the time that perfusion abnormalities are measured. Septic Shock : ACCP/SCCM Definition ACCP/SCCM Consensus Statement. Chest. 1992;101:1644-55.

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

  12. Nosocomial Infection vs. Severe Sepsis in MICU Nosocomial Infection (NNIS 92-97) Severe Sepsis Lower Respiratory Skin/soft tissue 10% Tract Infections (5 - 15%) 4% Other Pneumonia 45% 6% Eye, Ear, Nose and (37 - 54%) Throat Pneumonia 4% 27% Cardiovascular System 4% Gastrointestinal Infections 5% GI 25% (15 - 30%) Primary Bloodstream Infections 19% Primary bloodstream UTI 15% Infections 5% Urinary Tract (8 - 20%) (2.5 - 7.5%) Infection 31% Richards MJ, et al. Crit Care Med. 1999;27:887-92. 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.

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

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

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

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

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

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

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

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

  21. Hemodynamic Effects of Putative Septic Shock Mediators Kumar, et al. J Cardiovasc Thor Anes. 2001.

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

  23. Modern View of the Coagulation Cascade Steps in coagulation Coagulationcascade Initiation 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. TF/VIIa X IX IXa Propagation VIIIa Xa Va II Thrombin activity IIa Fibrinogen Fibrin Weitz JI, et al. Chest. 2001.

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

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

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

  27. Nitric Oxide in the Vasculature L-Arg O2 Platelets cGMP cNOS L-citrulline cGMP GTP . GC GC NO GTP Blood Endothelium Smooth Muscle

  28. Nitric Oxide in Sepsis Endotoxin Cytokines L-Arg iNOS O2 Platelets cGMP iNOS NO cNOS L-citrulline cGMP GTP GC GC NO GTP Blood Endothelium Smooth Muscle

  29. Warm (hyperdynamic) shock hypotensive tachycardia tachypnea bounding pulse warm, well perfused extremities skin flushed, moist Cold (hypodynamic) shock hypotensive tachycardia tachypnea narrow, thready pulse cold, poorly perfused extremities skin pale, dry Septic Shock Hemodynamics

  30. Septic Shock Hemodynamics • CVP does not accurately estimate ventricular filling pressures in the critically ill. • When PWP is appropriately elevated to 12 - 15 mm Hg with fluid resuscitation, 90% of patients with septic shock exhibit a hyperdynamic circulatory state. • Hyperdynamic state persists to death

  31. Cardiac Index in Septic Shock (post - 1980) 7 6 5 4 Cardiac Index (L/min/m2) 3 2 SurvivorsNonsurvivors All Patients 1 0 1 2 4 7 10 1 2 4 7 10 Time (days) Parker et al. Ann Intern Med. 1984.

  32. Hypovolemia in Septic Shock: Causes • Venous pooling • Interstitial “third-spacing” •  insensible losses (fever, RR) •  oral intake

  33. Septic Shock Hemodynamics Hypodynamic septic shock in humans = inadequately fluid resuscitated septic shock (until PWP shows filling pressures between 12 - 15 mm Hg).

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

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

  36. Pathogenesis of Septic Shock VascularAbnormality Capillary Arteriole Venule Neutrophil Aggregation Vasoconstriction Vasodilation Cell Endothelial Cell Destruction

  37. Metabolic Derangements in Sepsis: Lactate, MVO2 • Micro-anatomic shunts (non-nutrient capillaries) • Functional shunts (impaired micro-circulatory vasomotor control) • Citric acid (Kreb’s) cycle defect with anaerobic glycolysis • Aerobic glycolysis with lactate production

  38. References • Annane D, Bellissant E, Cavaillon JM. Septic shock. Lancet. 2005;365:63-78. • Aird WC. Vascular bed-specific hemostasis: role of endothelium in sepsis pathogenesis. Crit Care Med. 2001;29:S28-S34. • Kumar A, Haery C, Parrillo JE. Myocardial dysfunction in septic shock. Crit Care Clin. 2000;16;251-287.

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