ali/ards in sepsis
DESCRIPTION
ALI/ARDS IN SEPSIS. Dr Gül Gürsel Gazi University School of Medicine Department of Pulmonary Diseases. 60% of etiologies in ALI are sepsis Pulmonary source 46%, other source 33% 1. 1 NEJM 2005; 353:1685-93(King County Lung Injury Project-KCLIP) 2 Am J Respir Crit Care Med 1999; 159:1849-61 - PowerPoint PPT PresentationTRANSCRIPT
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ALI/ARDS IN SEPSISALI/ARDS IN SEPSIS
Dr Gül GürselDr Gül GürselGazi University School of Gazi University School of Medicine Department of Medicine Department of
Pulmonary DiseasesPulmonary Diseases
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60% of etiologies in ALI are sepsis60% of etiologies in ALI are sepsisPulmonary source 46%, other source 33%Pulmonary source 46%, other source 33%11
KCLIPKCLIP11
ScandinaviScandinaviaa22
AustraliAustraliaa33
ALI incidenceALI incidence
Cases per Cases per 100000 100000 person-yearperson-year
78.978.9 17.917.9 3434
Mortality Mortality from ALIfrom ALI
38.538.5 41.441.4 3232
1 NEJM 2005; 353:1685-93(King County Lung Injury Project-KCLIP)2 Am J Respir Crit Care Med 1999; 159:1849-613 Am J Respir Crit Care Med 2000; 165:443-8
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The American-European consensus The American-European consensus conference criteria for ALI and ARDSconference criteria for ALI and ARDS
ALIALI Acute onset PaO2/FiO2300
mmHg(regardless of PEEP level)
Bilateral infiltrates PAOP 18 mmHg or no
clinical evidence of left atrial hypertension
ARDSARDS• Acute onset• PaO2/FiO2200
mmHg(regardless of PEEP level)
• Bilateral infiltrates• PAOP 18 mmHg or no
clinical evidence of left atrial hypertension
Am J Resp Crit Care Med 1994;149:818-824
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Edema fluid to plasma protein concentrations <0.65 transudate in hydrostatic pulmonary edema>0.65 exudate in increased permeability pulmonary edema(ALI/ARDS)
Matthay MA et al Physiol Rev 2002; 82:569-600
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Clinical disorders associated with the development of ALI and ARDS
DİRECT LUNG INJURY(PULMONARY) Aspiration of gastric
contents Pneumonia Near drowning Inhalational injuries Pulmonary contusion Pulmonary embolic
disorders Reperfusion injury Thoracic radiotherapy
INDIRECT LUNG INJURY(EXTRAPULMONARY) Sepsis, SIRS Severe trauma with shock Acute pancreatitis Transfusion of blood
products Drug overdose and toxins Anaphylaxis ECMO, CAGS Decompression sickness
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Type I(90%), Type I(90%), Type II(10%) alveolar Type II(10%) alveolar
epitelial cellsepitelial cells Capillary endothelial cellsCapillary endothelial cells İnterstitiumİnterstitium
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Problems in ALIProblems in ALI
ALI=edema+inflammationALI=edema+inflammation Leukocyte recruitment and/or activationLeukocyte recruitment and/or activation Alveolar epitheal cell damage/alterationAlveolar epitheal cell damage/alteration Lung surfactant dysfunction/inactivationLung surfactant dysfunction/inactivation Pulmonary interstitial injuryPulmonary interstitial injury Inflammatory mediators/factors producedInflammatory mediators/factors produced Microvascular dysfunctionMicrovascular dysfunction Airway injuryAirway injury Coagulation abnormalitiesCoagulation abnormalities
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NEJM 2000 ;342 :1334-48
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Resident and Recruited Cells of The Lung Inflammatory Response
Cell typeCell type Chemotactic and activating Chemotactic and activating mediatorsmediators
Role in Role in inflammationinflammation
NeutrophilsNeutrophils Bacterial products, Bacterial products, TNFTNF,IL8,GM-CSF,,IL8,GM-CSF,IFN,C5a, IFN,C5a, LTB4,endothelial adhesion LTB4,endothelial adhesion moleculesmolecules
Phygocytosis; Phygocytosis; production of production of oxidants, oxidants, proteinases, proteinases, defensinsdefensins
Monocytes/Monocytes/
MacrophagMacrophageses
MCP-1, MIP-1 MCP-1, MIP-1 ,IFN- ,IFN- , TNF , TNF, , IL- 1 IL- 1
production of production of oxidants, NO, oxidants, NO, proteinases,proteinases,
““Walling off “ insult Walling off “ insult (granuloma)(granuloma)
LymphocytLymphocyteses
IL-2, IL12, IFN- IL-2, IL12, IFN- , IL-4, IL-10, IL-4, IL-10 Release of cytoxins Release of cytoxins that injure cells, that injure cells, release of proformed release of proformed antibodies to forign antibodies to forign substancesubstance
PlateletsPlatelets IL-1 IL-1 , HMBG, chemokines, HMBG, chemokines
Sphingosine-1 phosphateSphingosine-1 phosphateOrganise fibrin clotsOrganise fibrin clots
Promotes endothelial Promotes endothelial barier barier function(repair)?function(repair)?
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Resident and Recruited Cells of The Lung Inflammatory Response
Cell typeCell type Chemotactic and Chemotactic and activating mediatorsactivating mediators
Role in inflammationRole in inflammation
EosinophilEosinophil Rantes, MIP-1 Rantes, MIP-1 ,eotaxin, histamine,eotaxin, histamine
Release of oxidants and Release of oxidants and cationic proteins; airway cationic proteins; airway reactivityreactivity
BasophilsBasophils MCP-1MCP-1 Major source of vasoactive Major source of vasoactive aminesamines
Endothelial Endothelial cellscells
TNFTNF, IL- 1 , IL- 1 , oxidants, oxidants Generation of Generation of oxidants;increase of leakiness oxidants;increase of leakiness for leokocyte infiltration and for leokocyte infiltration and other blood borne mediatorsother blood borne mediators
Epithelial Epithelial cellscells
TNFTNF, IL- 1 , IL- 1 , oxidants, oxidants Generation of oxidants, Generation of oxidants, surfactant;barier function to surfactant;barier function to protect systemprotect system
FibroblastsFibroblasts TNFTNF, IL- 1 , IL- 1 , oxidants, , oxidants, FGF, TGF FGF, TGF
Generation of Generation of oxidants;”walling off” oxidants;”walling off” insult;initial repeir to insult;initial repeir to structural damage structural damage
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Soluble mediators of Soluble mediators of inflammationinflammationMediatorsMediators Major sourceMajor source İnflammatory roleİnflammatory role
Vazoactive Vazoactive peptidespeptides
Mast cells, Mast cells, basophils, pltbasophils, plt
Vasodilatation, increased vascular Vasodilatation, increased vascular permeabilitypermeability
ComplemeComplementnt
Liver(9),mono,MALiver(9),mono,MA, fibroblast, fibroblast
Augmented phagocytosis, increased Augmented phagocytosis, increased vascular permeability, chemotaxisvascular permeability, chemotaxis
KininsKinins Soluble forms in Soluble forms in bloodblood
Vasoconstriction, increased vascular Vasoconstriction, increased vascular permeability, chemotaxispermeability, chemotaxis
Fibrinolytic Fibrinolytic peptidespeptides
Proteolytic Proteolytic clevage of fibrinclevage of fibrin
Activaion of C and FXIIActivaion of C and FXII
PGsPGs Mo,MA, neutro, Mo,MA, neutro, endotelial cell, endotelial cell, pltplt
İncreased body temp, stim f İncreased body temp, stim f nociceptorsincreased vascular nociceptorsincreased vascular permeabilitypermeability
LTsLTs Lc with Lc with methabolic methabolic conversionconversion
Vasoconstriction, increased vascular Vasoconstriction, increased vascular permeability,neutrophil rec and permeability,neutrophil rec and activationactivation
PAFPAF Plt, Lc, Plt, Lc, endotheial cellendotheial cell
Plt aggregation, leucocyte rec and Plt aggregation, leucocyte rec and activationactivation
CytokinesCytokines Lc and structural Lc and structural cellscells
Recruit and activate leucocytes, Recruit and activate leucocytes, augment, modulate and resolve the augment, modulate and resolve the inflam responseinflam response
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Soluble Chemical Effectors of Soluble Chemical Effectors of InflammationInflammation
EffectorsEffectors SourceSource Inflammatory Inflammatory functionfunction
Negative effectsNegative effects
OxidantsOxidants Lc, Enc, Lc, Enc, EpcEpc
Kill microbes and Kill microbes and cells harbouring cells harbouring microbesmicrobes
Dmamage proteins, Dmamage proteins, lipids, and nuc acids, lipids, and nuc acids, cell death,inactivate cell death,inactivate antiproteinasesantiproteinases
ProteinasesProteinases All cells All cells followed followed injuryinjury
Activate the Activate the inflammatory inflammatory responseresponse
Damage connective Damage connective tissue,cell tissue,cell membranes, membranes, inactivate inactivate antiaxidantsantiaxidants
NONO Enc,Mo/Enc,Mo/MacMac
VasorelaxationVasorelaxation May generate highly May generate highly toxic reactive toxic reactive nitrogennitrogen
AntioxidantsAntioxidants All cellsAll cells Terminate oxidant Terminate oxidant activityactivity
AntiproteasisAntiproteasis All cellsAll cells Terminate proteinase Terminate proteinase activityactivity
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The role of Toll-like The role of Toll-like receptors(TLRs) in pulmonary host receptors(TLRs) in pulmonary host
responseresponse
TLR are the first to detect host TLR are the first to detect host invasion by pathogens, initiate invasion by pathogens, initiate immune responses and form the immune responses and form the crucial link between the innate and crucial link between the innate and adaptive immune systemsadaptive immune systems
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The role of Toll-like receptors(TLRs) in The role of Toll-like receptors(TLRs) in pulmonary host responsepulmonary host response
TLR4 recognizes LPS of gram-negative TLR4 recognizes LPS of gram-negative bacteria and subsequently induces an bacteria and subsequently induces an inflammatory responseinflammatory response
Gram-positive PAPMs are all ligans of TLR2Gram-positive PAPMs are all ligans of TLR2 Lipoteichoic acidLipoteichoic acid LipoproteinsLipoproteins peptidoglycanpeptidoglycan
SHOCK 2005; 24:12-18
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1616
1717NEJM 2004; 351:853-855
Role of Surfactant in ALIRole of Surfactant in ALI
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Endogenous compouns that Endogenous compouns that inhibit lung surfactant activityinhibit lung surfactant activity
Biophysical inhibitorsBiophysical inhibitors Plasma en blood proteins(alb, Hb, fibrinogen)Plasma en blood proteins(alb, Hb, fibrinogen) Cell membrane lipidsCell membrane lipids LysophospholipidsLysophospholipids Fluid free fatty acidsFluid free fatty acids Glycolipids and sphingolipidsGlycolipids and sphingolipids
Chemically acting inhibitorsChemically acting inhibitors Lytic enzymes(proteases, phospholipases)Lytic enzymes(proteases, phospholipases) Reactive oxygen and nitrogen speciesReactive oxygen and nitrogen species Antibodies to surfactant proteinsAntibodies to surfactant proteins
2020Am J Respir Cell Moll Biol 2005; 33:319-327
2121Am J Respir Cell Moll Biol 2005; 33:319-327
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ApoptosisApoptosis
Neutrophil apoptosis is inhibited early in Neutrophil apoptosis is inhibited early in ARDS and that the lifespan of neutrophils ARDS and that the lifespan of neutrophils returns to normal as inflammation returns to normal as inflammation resolvesresolves
Apoptosis of alveolar epithelial cells by Apoptosis of alveolar epithelial cells by the Fas/Fas ligand system may also be of the Fas/Fas ligand system may also be of particular importance in the development particular importance in the development of the permeability changesof the permeability changes
Critical Care 2003; 7: 355-8
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Am J Respir Cell Moll Biol 2005; 33:319-327Mutlu G, Am J Respir Crit Care Med 2004;170:1270-1275
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The influence of preexisting The influence of preexisting inflammationinflammation
During severe inflammation such as sepsis During severe inflammation such as sepsis immune response follows a biphasic patternimmune response follows a biphasic pattern
Overwhelming proinflammatory response leads Overwhelming proinflammatory response leads to tissue injuryto tissue injury
Excessive activation of antiinflammatory Excessive activation of antiinflammatory pathways results in impaired pulmonary host pathways results in impaired pulmonary host defencedefence Dysfunctional mononuclear cellsDysfunctional mononuclear cells Apoptosis of immune cellsApoptosis of immune cells Production of anti-inflammatory cytokines such as IL-Production of anti-inflammatory cytokines such as IL-
1010
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Local pulmonary host defense during Local pulmonary host defense during respiratory tract infections is respiratory tract infections is influenced by sepsis or sepsis like influenced by sepsis or sepsis like sydromessydromes
J Immunol 1999; 162:392-399J Immunol 1999; 162:392-399 J Immunol 2000; 165:6496-6503J Immunol 2000; 165:6496-6503 Shock 2004; 21:415-425Shock 2004; 21:415-425
Incidence of VAP in ARDS =60%Incidence of VAP in ARDS =60% Am J Respir Crit Care Med 1997;156:1092-8Am J Respir Crit Care Med 1997;156:1092-8
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JAMA 1999;282:54-61
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J Pathol 2004; 203:631-7
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Angiotensin-converting enzyme and Angiotensin-converting enzyme and ALIALI
Angiotensin-converting enzyme(ACE) has Angiotensin-converting enzyme(ACE) has been identified as the functional receptor for been identified as the functional receptor for SARS-CoVSARS-CoV
Wenhui Li NATURE 2003; 426:450-454Wenhui Li NATURE 2003; 426:450-454
Mice deficient for ACE showed markedly Mice deficient for ACE showed markedly improved disease and recombinant ACE2 improved disease and recombinant ACE2 can protect mice from severe acute lung can protect mice from severe acute lung injuryinjury
NATURE 2005;436:112-6NATURE 2005;436:112-6 ACE polymorfism is a significant prognostic ACE polymorfism is a significant prognostic
factor for the outcome of ARDSfactor for the outcome of ARDS Crit Care Med 2006;34:1001-6Crit Care Med 2006;34:1001-6
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Crit Care Med 2006;34:1001-6Crit Care Med 2006;34:1001-6