pathologic mechanisms of septic shock - ohio university septic... · 2002-02-19 · and septic...
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Pathologic Mechanisms of Pathologic Mechanisms of Septic ShockSeptic Shock
Kenneth J. Goodrum, Ph.D. OUCOM
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Topics Topics ● 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
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SSystemic ystemic IInflammatory nflammatory RResponse esponse 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
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SepsisSepsis
● The presence of SIRS associated with a confirmed infectious process.
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Severe SepsisSevere Sepsis
● Sepsis with either hypotension or systemic manifestations of hypoperfusion– Lactic acidosis, oliguria, altered mental status
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Septic ShockSeptic Shock
● Sepsis with hypotension despite adequate fluid resuscitation, associated with hypoperfusion abnormalities
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Multiple Organ Dysfunction Multiple 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)
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Morbidity/Mortality of Sepsis Morbidity/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
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Pathogenesis of ShockPathogenesis of ShockInfectious or noninfectious triggers
Cytokine and inflammatory mediator cascade
Cardiac dysfunction and microvascular injury
Hypotension and shock
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Some Characteristics of Some 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
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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
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BacterialBacterial--Mediated SepsisMediated SepsisBacteriaBacteria MacrophageMacrophageLPSLPS + LBP+ LBP
LPSLPS = LipopolysaccharideLBPLBP = LPS-Binding Protein
TLRTLR= Toll-like receptor
++
deathdeath
MediatorsMediatorsofof
InflammationInflammation
CD14CD14
TLR4TLR4
Gram(-)
Gram(+)LTALTA
TLR2TLR2
LTALTA=Lipoteichoic acid
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Superantigen activation of T Lymphocytes
M HC class II
TcR
Vα Vβ
TSST-1
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Gram-negative organism
T-lymphocyte
Gram-positive organism
SuperantigenExotoxin
Macrophage
Interleukin-1Tumor necrosisfactor-α
LPS (endotoxin)
IL-2
IFN-γ
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Primary mediators (IL-1, TNFα)
Endothelial/Leukocyte molecular activation
Secondary mediators (NO,PAF, PG, LT, IL)
Vasodilation, capillary leak, endothelial damage
Shock M ODS Death
EFFECTS OF EXCESS CYTOKINE RELEASE
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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)
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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)
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ILIL--1 and TNF activities(1 and TNF activities(contcont.).)
● Cachexia ( lipoprotein lipase, disrupts glucose metabolism
● Activates coagulation ( intravascularthrombi, DIC, tissue factor, activated factor X, TFPI, activated protein C)
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Endotoxin
MembranePhospholipids
ArachidonicAcid
Lyso-phospholipid
PLA2
Prostaglandins Leukotrienes PlateletActivating
Factor
+
+
Cyclo-oxygenase
5-Lipoxy-genase
Thromboxanes
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Actions of LeukotrienesActions of Leukotrienes● Vasoconstriction● Bronchoconstriction● Chemotaxis● Leukocyte-Endothelial Cell Adhesion● Leukocyte Emigration● Vascular Leakage● Stimulate Leukotriene and Oxygen Free Radical
Release
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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
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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
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● 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
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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
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● 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..
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● 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
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PATHOPHYSIOLOGYPATHOPHYSIOLOGYContCont..
● Disseminated intravascular coagulation (DIC)● Blood dyscrasias
– leukopenia– thrombocytopenia– polycythemia
● Central and peripheral nervous dysfunction● Increased lactate occurs early
Other
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Therapies of Sepsis/Septic Therapies of Sepsis/Septic ShockShock
● Antibiotics (early administration)● Hemodynamic support
– (fluid resuscitation)● Restore tissue perfusion● Normalize cellular metabolism
– Vasopressor agents● Dopamine, norepinephrine, dobutamine
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Therapies of Sepsis/Septic Therapies 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
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Controversial Current Controversial Current Therapies for Septic ShockTherapies for Septic Shock
● Anti-inflammatory agents– Cortocosteroids– Ibuprofen– Prostaglandin E1– Pentoxifylline
● Oxygen Scavengers– N-acetylcysteine– selenium
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Controversial Current Controversial 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
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Controversial Current Controversial 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
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Experimental Therapies of Experimental 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)
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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.