Pathologic Mechanisms ofPathologic Mechanisms of
Septic ShockSeptic Shock
Kenneth J. Goodrum, Ph.D.
OUCOM
TopicsTopics
● Definitions: SIRS,sepsis,shock,MODS
● Morbidity/mortality of Sepsis/Shock
● Pathogenesis of shock
● Microbi...
SSystemicystemic IInflammatorynflammatory
RResponseesponse SSyndrome (SIRS)yndrome (SIRS)
● Systemic inflammatory response...
SepsisSepsis
● The presence of SIRS associated with a
confirmed infectious process.
Severe SepsisSevere Sepsis
● Sepsis with either hypotension or systemic
manifestations of hypoperfusion
– Lactic acidosis,...
Septic ShockSeptic Shock
● Sepsis with hypotension despite adequate
fluid resuscitation, associated with
hypoperfusion abn...
Multiple Organ DysfunctionMultiple Organ Dysfunction
Syndrome (MODS)Syndrome (MODS)
● Progressive distant organ failure (i...
Morbidity/Mortality of SepsisMorbidity/Mortality of Sepsis
and Septic Shockand Septic Shock
● Leading cause of death in no...
Pathogenesis of ShockPathogenesis of Shock
Infectious ornoninfectioustriggers
Cytokineandinflammatorymediatorcascade
Cardi...
Some Characteristics ofSome Characteristics of
Septic ShockSeptic Shock
● Systemic vasodilation and hypotension
● Tachycar...
Microbial TriggersMicrobial Triggers
● Gram-negative
bacteria:lipopolysaccharide
● Gram-positive bacteria:
– Lipoteichoic ...
BacterialBacterial--Mediated SepsisMediated Sepsis
BacteriaBacteria MacrophageMacrophageLPSLPS + LBP+ LBP
LPSLPS = Lipopol...
Superantigen activation of T Lymphocytes
M HC classII
TcR
Vα Vβ
TSST-1
Gram-negativeorganism
T-lymphocyte
Gram-positive organism
Superantigen
Exotoxin
Macrophage
Interleukin-1
Tumornecrosis
fac...
Primary mediators(IL-1, TNFα)
Endothelial/Leukocytemolecularactivation
Secondarymediators(NO,PAF, PG, LT,IL)
Vasodilation,...
ILIL--1 and TNF activities1 and TNF activities
● Synergistically induce genes in endothelial
cells and monocytes/macrophag...
ILIL--1 and TNF activities(1 and TNF activities(contcont.).)
● Synergistically induce genes in endothelial
cells and monoc...
ILIL--1 and TNF activities(1 and TNF activities(contcont.).)
● Cachexia ( lipoprotein lipase, disrupts
glucose metabolism
...
Endotoxin
Membrane
Phospholipids
Arachidonic
Acid
Lyso-
phospholipid
PLA2
Prostaglandins Leukotrienes Platelet
Activating
...
Actions of LeukotrienesActions of Leukotrienes
● Vasoconstriction
● Bronchoconstriction
● Chemotaxis
● Leukocyte-Endotheli...
Actions of PAFActions of PAF
● Vasoconstriction/Vasodilation
● Hypotension & Cardiac Depression
● Bronchoconstriction
● Ch...
Actions of Nitric OxideActions of Nitric Oxide
● Vasodilation
● Inhibits leukocyte-endothelial cell adhesion
● Inhibits pl...
● Flu-like symptoms
– fever, chills
– general malaise, irritability, lethargy
● Tachycardia and hypotension
● Hyperventila...
PATHOPHYSIOLOGYPATHOPHYSIOLOGY
● Systemic vasodilation and hypotension (Psys < 90
mmHg)
● Tachycardia (>100 beats/min)
● I...
● Hypovolemia due to vascular leakage; central
venous pressure may be decreased or
increased depending upon fluid resuscit...
● Hyperventilation with respiratory alkalosis
● Pulmonary hypertension and edema
● Hypoxemia (arterial pO2 < 50 mmHg)
● Re...
PATHOPHYSIOLOGYPATHOPHYSIOLOGYContCont..
● Disseminated intravascular coagulation (DIC)
● Blood dyscrasias
– leukopenia
– ...
Therapies of Sepsis/SepticTherapies of Sepsis/Septic
ShockShock
● Antibiotics (early administration)
● Hemodynamic support...
Therapies of Sepsis/SepticTherapies of Sepsis/Septic
Shock (Shock (contcont.).)
● Source control
– Surgical debridement of...
Controversial CurrentControversial Current
Therapies for Septic ShockTherapies for Septic Shock
● Anti-inflammatory agents...
Controversial CurrentControversial Current
Therapies for Septic ShockTherapies for Septic Shock((contcont.).)
● Drugs modi...
Controversial CurrentControversial Current
Therapies for Septic ShockTherapies for Septic Shock((contcont.).)
● Other drug...
Experimental Therapies ofExperimental Therapies of
Sepsis/Septic ShockSepsis/Septic Shock
● Anti-endotoxin therapies
– IVI...
ReferencesReferences
● Immunological therapy of
sepsis:experimental therapies. P. Arndt and
E. Abraham. Intensive Care med...
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Pathologic Mechanisms of Pathologic Mechanisms of Septic ...

  1. 1. Pathologic Mechanisms ofPathologic Mechanisms of Septic ShockSeptic Shock Kenneth J. Goodrum, Ph.D. OUCOM
  2. 2. TopicsTopics ● Definitions: SIRS,sepsis,shock,MODS ● Morbidity/mortality of Sepsis/Shock ● Pathogenesis of shock ● Microbial triggers(endotoxin, TSSTs) ● Cytokine and non-cytokine mediators of SIRS and shock ● Pathophysiology of shock ● Therapy
  3. 3. SSystemicystemic IInflammatorynflammatory RResponseesponse SSyndrome (SIRS)yndrome (SIRS) ● Systemic inflammatory response to a variety of severe clinical insults manifested by ≥ 2 of the following conditions ● Temperature >38ºC or <36ºC ● Heart rate >90 beats/min ● Respiratory rate >20 breaths/min or PaCO2 ,<32 torr (<4.3 kPa) ● White blood cell count >12,000 cells/mm3, <4000 cells/mm3, or >10% immature (band) cells
  4. 4. SepsisSepsis ● The presence of SIRS associated with a confirmed infectious process.
  5. 5. Severe SepsisSevere Sepsis ● Sepsis with either hypotension or systemic manifestations of hypoperfusion – Lactic acidosis, oliguria, altered mental status
  6. 6. Septic ShockSeptic Shock ● Sepsis with hypotension despite adequate fluid resuscitation, associated with hypoperfusion abnormalities
  7. 7. Multiple Organ DysfunctionMultiple Organ Dysfunction Syndrome (MODS)Syndrome (MODS) ● Progressive distant organ failure (initially uninvolved) following severe infectious or noninfectious insults (severe burn, multiple trauma, shock, acute pancreatitis)
  8. 8. Morbidity/Mortality of SepsisMorbidity/Mortality of Sepsis and Septic Shockand Septic Shock ● Leading cause of death in noncoronary ICU patients ● 500,000 episodes sepsis/year in U.S. (35% crude mortality) ● 200,000 cases septic shock (40% of sepsis cases) (40-70% mortality) ● 40% hospital deaths after injury due to MODS
  9. 9. Pathogenesis of ShockPathogenesis of Shock Infectious ornoninfectioustriggers Cytokineandinflammatorymediatorcascade Cardiac dysfunction and microvascularinjury Hypotension andshock
  10. 10. Some Characteristics ofSome Characteristics of Septic ShockSeptic 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 and multiple organ failure
  11. 11. Microbial TriggersMicrobial Triggers ● Gram-negative bacteria:lipopolysaccharide ● Gram-positive bacteria: – Lipoteichoic acid/cell wall muramyl peptides – Superantigens ● Staphylocococal Toxic Shock Syndrome Toxin, TSST ● Streptococcal pyrogenic exotoxin, SPE
  12. 12. BacterialBacterial--Mediated SepsisMediated Sepsis BacteriaBacteria MacrophageMacrophageLPSLPS + LBP+ LBP LPSLPS = Lipopolysaccharide LBPLBP = LPS-Binding Protein TLRTLR= Toll-like receptor ++ deathdeath MediatorsMediators ofof InflammationInflammation CD14CD14 TLR4TLR4 Gram(-) Gram(+) LTALTA TLR2TLR2 LTALTA=Lipoteichoic acid
  13. 13. Superantigen activation of T Lymphocytes M HC classII TcR Vα Vβ TSST-1
  14. 14. Gram-negativeorganism T-lymphocyte Gram-positive organism Superantigen Exotoxin Macrophage Interleukin-1 Tumornecrosis factor-α LPS (endotoxin) IL-2 IFN-γ
  15. 15. Primary mediators(IL-1, TNFα) Endothelial/Leukocytemolecularactivation Secondarymediators(NO,PAF, PG, LT,IL) Vasodilation,capillaryleak,endothelialdamage Shock M O D S Death EFFECTS OF EXCESS CYTOKINE RELEASE
  16. 16. ILIL--1 and TNF activities1 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)
  17. 17. ILIL--1 and TNF activities(1 and TNF activities(contcont.).) ● Synergistically induce genes in endothelial cells and monocytes/macrophages – Adhesion molecules ( leukocyte adhesion/activation – Other Cytokines ( Acute phase proteins, recruits new phagocytes)
  18. 18. ILIL--1 and TNF activities(1 and TNF activities(contcont.).) ● Cachexia ( lipoprotein lipase, disrupts glucose metabolism ● Activates coagulation ( intravascular thrombi, DIC, tissue factor, activated factor X, TFPI, activated protein C)
  19. 19. Endotoxin Membrane Phospholipids Arachidonic Acid Lyso- phospholipid PLA2 Prostaglandins Leukotrienes Platelet Activating Factor + + Cyclo- oxygenase 5-Lipoxy- genase Thromboxanes
  20. 20. Actions of LeukotrienesActions of Leukotrienes ● Vasoconstriction ● Bronchoconstriction ● Chemotaxis ● Leukocyte-Endothelial Cell Adhesion ● Leukocyte Emigration ● Vascular Leakage ● Stimulate Leukotriene and Oxygen Free Radical Release
  21. 21. Actions of PAFActions of PAF ● Vasoconstriction/Vasodilation ● Hypotension & Cardiac Depression ● Bronchoconstriction ● Chemotaxis ● Leukocyte-Endothelial Cell Adhesion ● Leukocyte Emigration ● Vascular Leakage ● Platelet Aggregation ● Stimulates Leukotriene, PAF, Cytokine and Oxygen Free Radical Release
  22. 22. Actions of Nitric OxideActions of Nitric Oxide ● Vasodilation ● Inhibits leukocyte-endothelial cell adhesion ● Inhibits platelet adhesion/aggregation ● Decreases vascular permeability ● Scavenges superoxide radicals ● High concentrations are cytotoxic
  23. 23. ● Flu-like symptoms – fever, chills – general malaise, irritability, lethargy ● Tachycardia and hypotension ● Hyperventilation ● Site of infection may or may not be evident PATHOPHYSIOLOGYPATHOPHYSIOLOGY General Clinical Signs
  24. 24. PATHOPHYSIOLOGYPATHOPHYSIOLOGY ● Systemic vasodilation and hypotension (Psys < 90 mmHg) ● Tachycardia (>100 beats/min) ● Increased cardiac output (hyperdynamic), although contractility is depressed; hypodynamic in late shock ● Ventricular dilation; decreased ejection fraction ● Loss of sympathetic responsiveness Cardiovascular
  25. 25. ● Hypovolemia due to vascular leakage; central venous pressure may be decreased or increased depending upon fluid resuscitation ● Compromised nutrient blood flow to organs; decreased organ oxygen extraction CardiovascularCont. PATHOPHYSIOLOGYPATHOPHYSIOLOGYContCont..
  26. 26. ● Hyperventilation with respiratory alkalosis ● Pulmonary hypertension and edema ● Hypoxemia (arterial pO2 < 50 mmHg) ● Reduced pulmonary compliance; increased work ● Respiratory muscle failure ● Renal hypoperfusion; oliguria ● Acute tubular necrosis and renal failure PATHOPHYSIOLOGYPATHOPHYSIOLOGYContCont.. Pulmonary & Renal
  27. 27. PATHOPHYSIOLOGYPATHOPHYSIOLOGYContCont.. ● Disseminated intravascular coagulation (DIC) ● Blood dyscrasias – leukopenia – thrombocytopenia – polycythemia ● Central and peripheral nervous dysfunction ● Increased lactate occurs early Other
  28. 28. Therapies of Sepsis/SepticTherapies of Sepsis/Septic ShockShock ● Antibiotics (early administration) ● Hemodynamic support – (fluid resuscitation) ● Restore tissue perfusion ● Normalize cellular metabolism – Vasopressor agents ● Dopamine, norepinephrine, dobutamine
  29. 29. Therapies of Sepsis/SepticTherapies of Sepsis/Septic Shock (Shock (contcont.).) ● Source control – Surgical debridement of infected, devitalized tissue – Catheter replacement ● Supplemental oxygen (treatment of acute respiratory distress syndrome,ARDS) ● Nutritional support
  30. 30. Controversial CurrentControversial Current Therapies for Septic ShockTherapies for Septic Shock ● Anti-inflammatory agents – Cortocosteroids – Ibuprofen – Prostaglandin E1 – Pentoxifylline ● Oxygen Scavengers – N-acetylcysteine – selenium
  31. 31. Controversial CurrentControversial Current Therapies for Septic ShockTherapies for Septic Shock((contcont.).) ● Drugs modifying coagulation – Anti-thrombin III ● Drugs enhancing host defenses – Intravenous immunoglobulin (IVIG) – Interferon-gamma – GM-CSF – immunonutrition
  32. 32. Controversial CurrentControversial Current Therapies for Septic ShockTherapies for Septic Shock((contcont.).) ● Other drugs – Growth hormone, antibiotics, fresh frozen plasma, anesthetic sedative and analgesic agents, catecholamines ● Hemofiltration, plasma filtration, plasma exchange
  33. 33. Experimental Therapies ofExperimental Therapies of Sepsis/Septic ShockSepsis/Septic Shock ● Anti-endotoxin therapies – IVIG, BPI protein ● IL-1Ra ● Anti-TNF-alpha, soluble TNFR ● PLA2 inhibitors, PAF inhibitors ● iNOS inhibitors ● Anti-coagulants (APC)
  34. 34. ReferencesReferences ● Immunological therapy of sepsis:experimental therapies. P. Arndt and E. Abraham. Intensive Care med (201)27:S104-115. ● Immunological therapy in sepsis:currently available. J.Carlet. Intensive Care Med (2001)27:S93-S103.

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