83590013 ppt patofisiologi septic shock
TRANSCRIPT
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Pathologic Mechanisms of Septic Shock
Kenneth J. Goodrum, Ph.D.Dept. Biomedical Sciences
Ohio University College of Osteopathic Medicine
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Outline of Topics
• Definitions: SIRS, sepsis, shock, MODS• Morbidity/mortality of Sepsis/Shock• Microbial triggers (endotoxin, TSSTs) • Pathogenesis/Pathophysiology of shock• Therapy
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Systemic Inflammatory Response Syndrome (SIRS)
• Systemic inflammatory response to a variety of severe clinical insults manifested by 2 or more of the following conditions
• Temperature >38.5ºC or <35ºC• Heart rate >90 beats/min• Respiratory rate >20 breaths/min or PaCO2,
<32 torr (<4.3 kPa)• White blood count >12,000 cells/mm3,
<4000 cells/mm3, or >10% immature (band) cells
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Sepsis
• The presence of SIRS associated with a confirmed infectious process.
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Severe Sepsis
• Sepsis and at least one sign of organ hypoperfusion or organ dysfunction– Lactic acidosis, oliguria, altered mental
status, mottled skin, capillary refilling time >3s, platelet counts < 100,000/ml or DIC, acute lung injury, cardiac dysfunction
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Septic Shock
• Sepsis with hypotension despite adequate fluid resuscitation, associated with hypoperfusion abnormalities• Systemic mean blood pressure <60 mm Hg
(<80 mm Hg if previous hypertension)• Need for vasopressors to maintain blood
pressure above 60 mm Hg
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Multiple Organ Dysfunction Syndrome (MODS)
• Progressive distant organ failure (initially uninvolved) following severe infectious or noninfectious insults (severe burn, multiple trauma, shock, acute pancreatitis)
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Morbidity/Mortality of Sepsis and Septic Shock
• Leading cause of death in noncoronaryICU patients
• 500,000 cases sepsis/yr in U.S. (35% crude mortality)
• 200,000 cases septic shock (40-70% mortality)
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Some Characteristicsof Septic Shock
• Systemic vasodilation and hypotension• Tachycardia; depressed contractility• Vascular leakage and edema; hypovolemia• Compromised nutrient blood flow to organs• Disseminated intravascular coagulation• Abnormal blood gases and acidosis• Respiratory distress, renal hypoperfusion &
oliguria, multiple organ failure
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Main Pathogens in Septic Shock
• Gram-positive bacteria- 30-50%– coagulase-negative staphylococci, Staphylococcus
aureus, Streptococcus pneumoniae, Enterococcus, other
• Gram-negative bacteria- 25-30%– E. coli, Ps. aeruginosa, K. pneumoniae, other
• Fungi- 1-3%– Candida albicans, other
• Parasites (1-3%) and Viruses (2-4%)
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Common origins of sepsis
• Lung– bacteremia associated with nosocomial
pneumonia• Abdomen (Intraabdominal infections)• Genitourinary tract• Postoperative wound infections• Primary bloodstream infection via
intravascular lines
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Pathogenesis of Septic ShockInfectious Triggers
Cytokine and inflammatory mediator Cytokine and inflammatory mediator cascadecascade
Cardiac dysfunction and Cardiac dysfunction and microvascularmicrovascularinjuryinjury
Hypotension and shockHypotension and shock
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Systemic Interleukin-1, Tumor Necrosis Factor-α
Endothelial/Leukocyte molecular activation
Secondary mediators (NO,PAF, PG, LT, IL)
Vasodilation, capillary leak, endothelial damage
Shock MODS Death
Primary Cytokine Mediators of Septic ShockSystemic Macrophage activation by microbes
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Microbial Triggers = Pathogen Associated Molecular Patterns• Gram-negative bacteria:
lipopolysaccharide, lipoproteins• Gram-positive bacteria:
– Lipoteichoic acid, peptidoglycan– Superantigens (TSST, SPE)
• Bacterial flagellin• Viral and bacterial nucleic acid
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Innate Cellular Receptors for Microbes
• Toll-Like Receptors (TLR) are pattern recognition receptors (PRR) that respond to pathogen-associated molecular patterns (PAMP) common to diverse microbes
• TLR ligation triggers innate immune system release of proinflammatorymediators
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IL-1 and TNF activities• Synergistically induce genes in endothelial
cells and monocytes/macrophages– iNOS NO (vasodilation, pulmonary
artery pressure, cardiac output)– PLA2 PAF(hypotension)– COX-2 PGE2 (fever,pain)– Lipoxygenase leukotrienes (neutrophil
recruitment)
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IL-1 and TNF activities (cont.)• Synergistically induce genes in endothelial
cells and monocytes/macrophages
– Adhesion molecules ( leukocyte
adhesion/activation– Other Cytokines ( Acute phase
proteins, recruits new phagocytes)
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IL-1 and TNF activities (cont.)
• Cachexia ( lipoprotein lipase, disrupts glucose metabolism
• Activates coagulation ( intravascularthrombi, DIC, tissue factor, activated factor X, TFPI, activated protein C)
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Pathogenic Mechanisms in Septic Shock
• Neutrophil and Vascular Endothelium activation– Cytokine induced neutrophil adhesion
and vascular occlusion• Neutrophil damage of endothelium
– Neutrophil release of elastase, superoxide, PLA2, PAF, LTB4
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Pathogenic Mechanisms in Septic Shock (continued)
• Endothelial procoagulant state– Prothrombotic, pro-inflammatory, anti-
fibrinolytic state• Increased tissue factor expression• Decreased tissue factor pathway
inhibitor• Decreased activated protein C
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Pathogenic Mechanisms in Septic Shock (continued)
• Secondary Inflammatory Mediators– Complement activation
• C5a mediated histamine release and neutrophil recruitment
– Pro-inflammatory cytokines• TNF, IL-1, IFN-γ, HMGB1
– Prostaglandins, leukotrienes, PAF, superoxide, NO (mediates apoptosis)
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Pathogenic Mechanisms in Septic Shock (continued)
• Neuroendocrine Reflex– Cytokine activated hypothalamus-
pituitary axis (HPA)• Fever, leukocytosis, acute phase
protein response• Metabolic alterations
–increased catabolism of proteins, carbohydrates, and lipids
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Pathophysiological Effects in the Cardiovascular System
• Vasodilatation (relative hypovolemia)– NO mediated– Resistance to vasopressors
• Maldistribution of blood flow– some arteriolar constriction, leukocyte and thrombotic
microvascular plugs
• Myocardial depression– IL-1, TNF, and NO mediated
• Result = Decreased oxygen delivery, tissue hypoxia, organ failure
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Treatments for Septic Shock
• Controlling the source of infection–Antibiotics (early administration)–Removal of infected and necrotic
tissue
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Treatments for Septic Shock-continued
• Management of Shock–Restoration of central venous
pressure• Fluid resuscitation• Vasopressors
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Treatments for Septic Shock-continued
• Management of Organ Dysfunction–Dialysis for renal failure–Mechanical ventilation
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Treatments for Septic Shock-continued
• Replacing/enhancing host endocrineand hemostatic Responses–Corticosteroids (low dose) and
Drotrecognin alfa (activated protein C)• Reduces shock duration and mortality
–Low dose vasopressin• Reduces shock duration
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Controversial Current Therapies for Septic Shock
• Anti-inflammatory agents– Corticosteroids– Ibuprofen– Prostaglandin E1– Pentoxifylline
• Oxygen Scavengers– N-acetylcysteine– selenium
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Controversial Current Therapies for Septic Shock (cont.)
• Drugs modifying coagulation– Anti-thrombin III
• Drugs enhancing host defenses– Intravenous immunoglobulin (IVIG)– Interferon-gamma– GM-CSF– immunonutrition
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Controversial Current Therapies for Septic Shock (cont.)
• Other drugs– Growth hormone, antibiotics, fresh frozen
plasma, anesthetic sedative and analgesic agents, catecholamines
• Hemofiltration, plasma filtration, plasma exchange
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Experimental Therapies of Sepsis/Septic Shock
• Anti-endotoxin therapies– IVIG, BPI protein
• IL-1Ra• Anti-TNF-alpha, soluble TNFR• PLA2 inhibitors, PAF inhibitors• iNOS inhibitors
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Summary Points
• Septic shock is sepsis with hypotension that persists after fluid resuscitation.
• Excessive or poorly regulated immune generation of cytokines and inflammatory compounds lead to shock.
• Pathogenic mechanisms include neutrophil and endothelial activation, complement and coagulation activation, and neuroendocrine reflexes
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Summary Points- continued
• Early recognition of sepsis, antibiotic treatment and aggressive resuscitation is necessary to prevent progression to shock
• Recent randomized controlled trials support treatment approaches that replace hormones (corticosteroids) or coagulation inhibitors (activated protein C).
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Summary Points- continued
• Future therapies will target both early and late mediators of septic shock (TLR,cytokines, iNOS, HMGB1).
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References• Septic Shock. Annane, D., Bellissant, E., and Cavaillon, J.-M. 2005.
The Lancet 365:63-78.• Septic Shock; current pathogenetic concepts from a clinical
perspective. Tsiotou, A.G., Sakorafas, G.H., Anagnostopoulos, G., and Bramis, J. 2005. Med. Sci. Monitor 11:RA76-85.
• Cardiovascular aspects of septic shock: Pathophysiology, monitoring, and treatment. Bridges, E.J., and Dukes, S. 2005. Critical Care Nurse 25:14-16,18-20,22-24.
• Immunological therapy of sepsis:experimental therapies. P. Arndt and E. Abraham. Intensive Care Med (2001)27:S104-115.
• Immunological therapy in sepsis:currently available. J.Carlet. Intensive Care Med (2001)27:S93-S103.