【体外膜肺ECMO课件】-Classification-of-microcirculatory-

ClassificationofmicrocirculatoryabnormalitiesindistributiveshockCanInceClinicalPhysiologyAcademicMedicalCenterUniversityofAmsterdamDeclaredinterest:IamCSOofMicroVisionMedicalanAMCbasedcompany

Classificationofmicrocircula1WeilMH,ShubinH(1971)AdvExpMedBiol23:13-23.

Proposedreclassificationofshockstateswithspecialreferencetodistributivedefects.WeilMH,ShubinH(1971)Adv2Hypovolemic,cardiogenic,andobstructiveshockoccursasaresultofdecreaseincardiacoutputleadingtoanaerobictissuemetabolism.Septicshockresultsfromdistributivealterationsintissueperfusioncausedbyabnormalcontrolofmicrovasculaturewithabnormaldistributionofanormalorincreasedcardiacoutput.Henceend-pointshavebeendifficulttodefine.VincentJLHemodynamicsupportinsepticshockIntensiveCareMedicine(2001)27:S80-S92Hypovolemic,cardiogenic,an3

“…Ourunderstandingofhemodynamicmechanisms(indistributiveshock)dependsnotsomuchonthetotalvolumeofbloodthatflowspasttheaorticvalveorthe

cardiacoutputasontheamountofblooddeliveredtotheexchangesites.Eventhoughcardiacoutputmaybesubstantial,ifthatbloodflowdoesnotarriveattheexchangesites,theultimatemetabolicdetrimentisnodifferentfromlowcardiacoutputwithoutshuntflow.”

WeilMH,ShubinH(1971)AdvExpMedBiol23:13-23.

“…Ourunderstandingofhemody4ShuntingmodelofsepsisO2lactateCO2vaImplication:thatactiverecruitmentofthemicrocirculationisanimportantcomponentofresuscitation.InceC&SinaasappelM(1999)CritCareMed

27:1369-1377ShuntingmodelofsepsisO2lact5Whythemicrocirculationisimportantinshock.Itiswhereoxygenexchangetakesplace.Everyparameterinthemicrocirculationisdifferentthaninthesystemiccirculation.Itplaysacentralroleintheimmunesystem.Duringsepsisandshockitthefirsttogoandlasttorecover.Rescueofthemicrocirculation=resuscitationend-point.Whythemicrocirculationisim6SpronkP,ZandstraD,InceC(2004)CriticalCare8:462-468SepsisisadiseaseofthemicrocirculationSpronkP,ZandstraD,InceC(7InflammatoryactivationCoagulatory/RBCdysfunctionEndothelialbarrierdysfunctionCapillaryfalloutWeakmicrocirculatoryunitsareshuntedHypoxia,apoptosis,organdysfunctionNotdetectedbysystemicvariablesNotresponsivetotherapyperse

Sepsisisadiseaseofthemicrocirculation

(vessels<250m)SpronkP,ZandstraD,InceC(2004)CriticalCare8:462-468InflammatoryactivationSepsis8MicrocirculatoryandMitochondrialDistressSyndrome (MMDS)MMDS=sepsis+genes+therapy+timeInceC(2005)CriticalCare9:S13-S19MicrocirculatoryandMitochond9Co-morbidityGenesInitialHitCirculatoryShock+InflammationResuscitationbasedoncorrectionofsystemichemodynamics+inflammationMicrocirculatoryDysfunctionTimeTherapyRBCDeformability,AggregationO2transportCoagulationNaturalAnticoagulantsMicrovascularThrombosisLeukocytesAdhesion,Cytokines,ROSEndothelialDysfunctionBarrier,CommunicationCoagulation,RegulationDysfunctionAutoregulationMicrocirculatoryshunting

supply-demandmismatchHypoxiaCellularDistressMitochondriaHibernationApoptosisOrganFailureTimeTherapyMicrocirculatoryMitochondrialDistressSyndrome.CriticalCare(2005)9:S13-S19Co-morbidityInitialHitCircula10MicrocirculationisshuntedwhenµpO2

becomeslessthanvenouspO2

valuesremainunchanged.Microcirculationisshuntedwh11FunctionalshuntingismoresevereinsepticshockthaninbloodpressurematchedhemorrhagicshockinpigintestinesInceC&SinaasappelM(1999)CritCareMedicine

27:1369-1377Functionalshuntingismorese12Gutmicrocirculatoryshunt(pO2gap)andtissueCO2µPo2/MesVen.Hem.1.00.10.730.1µPo2/MesVen.Sep.1.10.10.570.1p=0.02Pco2gut(mmHg)Hem

4941.220.1

Pco2gut.(mmHg)Sep.4831.440.1p=0.002GutRegionalflowandoxygendeliverySMAbloodflow.(ml/min)

Hem

510690.440.1NSSMAbloodflow(ml/min)Sep507380.460.1Do2gut(mM/min)Hem3.50.40.380.1Do2gut(mM/min)Sep3.20.20.480.1P=0.04pO2gaptissueCO2Gutmicrocirculatoryshunt(pO13Hbbasedoxygencarriers(DCLHb)resuscitatesgutserosaandmucosaequallyfollowinghemhorrhage.mucosaserosaheartVanItersonM,SiegemundM,BurhopK,InceC(2003)J.ofTrauma55:1111-1124Hbbasedoxygencarriers(DCLH14DopexaminresuscitatesthemicrocirculationofthemucosabutnotoftheserosaandguttissueCO2.Dopexaminresuscitatesthemic15TheNOdonorSIN-1resuscitatesgutserosalandmucosalmicrocirculationaswellasgastricCO2Serosa(μpO2)Mucosa(μpO2)GastricCO2SiegemundM,vanBommelJ,VollebrechtK,DriesJ,InceC(2000)IntensiveCareMed26:S362TheNOdonorSIN-1resuscitate16MicrocirculationRecruitmentManoeuvres

Correctpathologicalflowheterogeneity,microcirculatoryshuntingandrestoreautoregulatorydysfunctionbycontrolofinflammation,vascularfunctionandcoagulation.

Openthemicrocirculationandkeepitopenbysupportofthepump,fluids,vasodilatorsandrestricteduseofvasopressoragents.InceC(2005)CriticalCare9:S13-S19

MicrocirculationRecruitmentM173cmMathuraetal.(2001)J.AppliedPhysiology91:74-78.OPSimagingvalidatedagainstcapillarymicroscopyAnalyzerPolarizer3cmMathuraetal.(2001)J.A18FirstdirectvisualizationsofthemicrocirculationinhumaninternalorgansusingOPSimaging.Groneretal.(1999)NatureMed5:1209

Mathuraetal.(2001)TheLancet58:1698Mathuraetal.(2001)J.ApplPhysiol91:74Spronketal.(2001)TheLancet360:1395Penningsetal.(2004)Stroke35:1284. SAH

BraintumoursduringhyperventilationBeforeHVAfterHVFirstdirectvisualizationsof19SDFimagingSidestreamDarkFieldimagingforimprovedtechniqueforobservationofthemicrocirculationInceC(2005)CriticalCare9:S13-S19Calculatevelocity(30.49pixels/s)SDFimagingSidestreamDarkFie20Flowscore:0=noflow1=intermittent2=sluggish3=continuousSmall:10-25μmMedium:26-50μmLarge:51-100μmBoermaetal(2005)CritCare9:R601-R606Flowscore:Small:10-25μmBoer21DeBacker,Creteur,Preiser,Dubois,VincentAmJRespirCritCareMed(2002)166:98-104.DeBacker,Creteur,Preiser,D22Sakretal.CritCareMed(2004)32:1825-1831Therewasnodifferenceinsytemichemodynamicandoxygenationvariablesortheamountortypeofdrugsusedbetweensurvivorsandnon-survivors.Microcirculatorydysfunctionwasthesinglemostsensitiveandspecificpredictorofoutcome.Sakretal.CritCareMed(20023Creteur,J.,DeBacker,D.Sakr,Y.Koch,M.,Vincent,J.L.(2004)

CritCareMedSupplVol.31(12):419Resuscitatationisaffectiveinrecruitmentofcapillariesandcorrectionofsub-lingualCO2Creteur,J.,DeBacker,D.Sak24SublingualOPSimaginginapatientwithsepticshockafterpressureguidedvolumeresuscitation.thesamepatientaftersubsequentnitroglycerin0.5mgivbolus

NitroglycerinpromotesmicrovascularrecruitmentinsepticandcardiogenicshockpatientsSpronk,Ince,Gardien,Mathura,Oudemans-vanStraaten,ZandstraDF.(2002)TheLancet360:1395-1396.SublingualOPSimaginginapa25.

Capillaryflowbuttoamuchlesserdegreevenularflow,isimpaired duringpressureguidedresuscitationfromsepticshock.NOdonorcanrecruitthemicrocirculationbypromotingflow.Nitroglycerinpromotesmicrovascularrecruitmentinpressureresuscitatedsepticshockpatientssub-lingualOPSimagingSpronk,Ince,Gardien,Mathura,Oudemans-vanStraaten,ZandstraDF. TheLancet2002;360(9343):1395-1396..Capillaryflowbuttoamuc26Theeffectsofdobutamineonmicrocirculatoryalterationsinpatientswithsepticshockareindependentofitssystemiceffects.DeBackerDetal.(2006)CritCareMed2006;34:403–408)Theeffectsofdobutamineonm27Thrombolysisinfulminantpurpura:observationsonchangesinmicrocirculatoryperfusionduringsuccessfultreatment.SpronkPERommesJH,SchaarC,InceC

(2006)

ThrombHaemost.95(3):576-8Thrombolysisinfulminantpurp28Microvascularflowindex(MFI)ofsmallvesselsinthesublingualregionversustheMFIinthestomaregionChristianBoermaMicrovascularflowindex(MFI)29SWan,JLLeClerc,JLVincent.Chest1997;112InflammatoryResponsetoCardiopulmonaryBypassMechanismsInvolvedandPossibleTherapeuticStrategiesSWan,JLLeClerc,JLVincent.30ECMOreducesFCDinprematureinfantsJ.E.vanVelzen,CInce,DTibbeauProc.Symp.Micro.Mit.DysfuntioninICM(2003)ECMOreducesFCDinpremature31HealthysublingualmicrocirculationobservedbySDFimaging

Healthysublingualmicrocircu32CardiogenicShockCardiogenicShock33【体外膜肺ECMO课件】-Classification-of-microcirculatory-34

ClassifyingmicrocirculatoryflowabnormalitiesindistributiveshockClassCapillaryhemodynamicsObservedindiseasedstatesIStagnantPressureguidedresuscitationfromsepsisIIContinuous/capillaryfall-outOn-pumpCABGsurgery,ECMOIIIContinuous/stagnantResuscitatedSepsis,reperfusioninjury,sicklecellcrises,malariaIVHyperdynamic/stagnantResuscitatedsepsisVHyperdynamicResuscitatedsepsis,exercise

Functionallyallclassescauseadistributivedefectandfunctionalshuntingofthemicrocirculation.Capillaryhemodynamicsunderlyingdistributivedefect

ClassCapillaryhemodynamicsO35【体外膜肺ECMO课件】-Classification-of-microcirculatory-36Conclusions

Distributiveshockhasabadprognosiswithdifficulttodefinehemodynamicsend-points.2)Itcausesadistributivedefectatthecapillarylevelofthemicrocirculationcausingfunctionalshuntingofweakmicrocirculatoryunits.

3)Itisthereasonwhydistributiveshockcannotbeadeqautelymonitoredbysystemichemodynamicparameters.4)OPS/SDFentissuecapnographyprovideanintegrativeevaluationofthefunctionalstateofthemicrocirculation.5)MicrocirculatoryRecruitmentManeuvresareaffectiveincorrectingdistributiveshockConclusions

37【体外膜肺ECMO课件】-Classification-of-microcirculatory-38Time(sec)Vessellength(μm)5020015010014012345230ABAtypicalspace-timediagramofmicrovascularbloodflowbeforepump(A)andduringpump(B).showingapulsatileflowandrespectivelyacontinuousflow.Ligthbandsrepresenteitherplasmagapsorwhitebloodcellsanddarkbandsrepresentredbloodcells.Theslope(v)ofabandinaspace-timediagramisthevelocity.Thehorizontallightanddarkbandsareindicativeofvariationsinthebackgroundlightintensity.PanelAshowswaivybandsindicatingpulsatileflowpatternwitharapid(v1)andaslow(v2)phase.PanelBshowsstraightlinearbandsindicatingnon-pulsatilecontinuousflowpattern.Thevelocitiesarev1=428μm/s

v2=86μm/s

v3=327

μm/s.ν1ν3ν2Time(sec)Vessellength(μm)5039MicrocirculationRecruitmentManoeuvres

InceC(2005)CriticalCare9:S13-S19Correctpathologicalflowheterogeneity,microcirculatoryshuntingandrestoreautoregulatorydysfunctionbycontrolofinflammation,vascularfunctionandcoagulation.

Avontuur(1997)CardiovasRes35:368-376.

SiegmundM(2005)IntenCareMed31:985-992.

Openthemicrocirculationandkeepitopenbysupportofthepump,fluids,vasodilatorsandrestricteduseofvasopressoragents.:

Boerma(2005)ActaAnaesthesiolScand.49(9):1387-90. Spronk(2001)TheLancet360:1395-1396 Siegemund(2006)IntensiveCareMedMicrocirculationRecruitmentM40GutserosaandmucosaBraincortexHeartandgutserosaGutserosaandmucosaBraincor41Signsofregionaldysoxiainthepresenceofapparentadequateoxygendelivery.Cytopathichypoxia:mitochondrialdysfunctioninthepresenceofadequatetissueoxygenation.

FinkMP(1997)ActaAnaesth.Scan.110:87-95.Shuntingtheoryofsepsis:microcirculatoryshutdownofweakmicrocirculatoryunitscreatinghypoxicpockets.InceC&SinaasappelM(1999)CritCareMed.27:1369-1377.Signsofregionaldysoxiaint42ClassificationofmicrocirculatoryabnormalitiesindistributiveshockCanInceClinicalPhysiologyAcademicMedicalCenterUniversityofAmsterdamDeclaredinterest:IamCSOofMicroVisionMedicalanAMCbasedcompany

Classificationofmicrocircula43WeilMH,ShubinH(1971)AdvExpMedBiol23:13-23.

Proposedreclassificationofshockstateswithspecialreferencetodistributivedefects.WeilMH,ShubinH(1971)Adv44Hypovolemic,cardiogenic,andobstructiveshockoccursasaresultofdecreaseincardiacoutputleadingtoanaerobictissuemetabolism.Septicshockresultsfromdistributivealterationsintissueperfusioncausedbyabnormalcontrolofmicrovasculaturewithabnormaldistributionofanormalorincreasedcardiacoutput.Henceend-pointshavebeendifficulttodefine.VincentJLHemodynamicsupportinsepticshockIntensiveCareMedicine(2001)27:S80-S92Hypovolemic,cardiogenic,an45

“…Ourunderstandingofhemodynamicmechanisms(indistributiveshock)dependsnotsomuchonthetotalvolumeofbloodthatflowspasttheaorticvalveorthe

cardiacoutputasontheamountofblooddeliveredtotheexchangesites.Eventhoughcardiacoutputmaybesubstantial,ifthatbloodflowdoesnotarriveattheexchangesites,theultimatemetabolicdetrimentisnodifferentfromlowcardiacoutputwithoutshuntflow.”

WeilMH,ShubinH(1971)AdvExpMedBiol23:13-23.

“…Ourunderstandingofhemody46ShuntingmodelofsepsisO2lactateCO2vaImplication:thatactiverecruitmentofthemicrocirculationisanimportantcomponentofresuscitation.InceC&SinaasappelM(1999)CritCareMed

27:1369-1377ShuntingmodelofsepsisO2lact47Whythemicrocirculationisimportantinshock.Itiswhereoxygenexchangetakesplace.Everyparameterinthemicrocirculationisdifferentthaninthesystemiccirculation.Itplaysacentralroleintheimmunesystem.Duringsepsisandshockitthefirsttogoandlasttorecover.Rescueofthemicrocirculation=resuscitationend-point.Whythemicrocirculationisim48SpronkP,ZandstraD,InceC(2004)CriticalCare8:462-468SepsisisadiseaseofthemicrocirculationSpronkP,ZandstraD,InceC(49InflammatoryactivationCoagulatory/RBCdysfunctionEndothelialbarrierdysfunctionCapillaryfalloutWeakmicrocirculatoryunitsareshuntedHypoxia,apoptosis,organdysfunctionNotdetectedbysystemicvariablesNotresponsivetotherapyperse

Sepsisisadiseaseofthemicrocirculation

(vessels<250m)SpronkP,ZandstraD,InceC(2004)CriticalCare8:462-468InflammatoryactivationSepsis50MicrocirculatoryandMitochondrialDistressSyndrome (MMDS)MMDS=sepsis+genes+therapy+timeInceC(2005)CriticalCare9:S13-S19MicrocirculatoryandMitochond51Co-morbidityGenesInitialHitCirculatoryShock+InflammationResuscitationbasedoncorrectionofsystemichemodynamics+inflammationMicrocirculatoryDysfunctionTimeTherapyRBCDeformability,AggregationO2transportCoagulationNaturalAnticoagulantsMicrovascularThrombosisLeukocytesAdhesion,Cytokines,ROSEndothelialDysfunctionBarrier,CommunicationCoagulation,RegulationDysfunctionAutoregulationMicrocirculatoryshunting

supply-demandmismatchHypoxiaCellularDistressMitochondriaHibernationApoptosisOrganFailureTimeTherapyMicrocirculatoryMitochondrialDistressSyndrome.CriticalCare(2005)9:S13-S19Co-morbidityInitialHitCircula52MicrocirculationisshuntedwhenµpO2

becomeslessthanvenouspO2

valuesremainunchanged.Microcirculationisshuntedwh53FunctionalshuntingismoresevereinsepticshockthaninbloodpressurematchedhemorrhagicshockinpigintestinesInceC&SinaasappelM(1999)CritCareMedicine

27:1369-1377Functionalshuntingismorese54Gutmicrocirculatoryshunt(pO2gap)andtissueCO2µPo2/MesVen.Hem.1.00.10.730.1µPo2/MesVen.Sep.1.10.10.570.1p=0.02Pco2gut(mmHg)Hem

4941.220.1

Pco2gut.(mmHg)Sep.4831.440.1p=0.002GutRegionalflowandoxygendeliverySMAbloodflow.(ml/min)

Hem

510690.440.1NSSMAbloodflow(ml/min)Sep507380.460.1Do2gut(mM/min)Hem3.50.40.380.1Do2gut(mM/min)Sep3.20.20.480.1P=0.04pO2gaptissueCO2Gutmicrocirculatoryshunt(pO55Hbbasedoxygencarriers(DCLHb)resuscitatesgutserosaandmucosaequallyfollowinghemhorrhage.mucosaserosaheartVanItersonM,SiegemundM,BurhopK,InceC(2003)J.ofTrauma55:1111-1124Hbbasedoxygencarriers(DCLH56DopexaminresuscitatesthemicrocirculationofthemucosabutnotoftheserosaandguttissueCO2.Dopexaminresuscitatesthemic57TheNOdonorSIN-1resuscitatesgutserosalandmucosalmicrocirculationaswellasgastricCO2Serosa(μpO2)Mucosa(μpO2)GastricCO2SiegemundM,vanBommelJ,VollebrechtK,DriesJ,InceC(2000)IntensiveCareMed26:S362TheNOdonorSIN-1resuscitate58MicrocirculationRecruitmentManoeuvres

Correctpathologicalflowheterogeneity,microcirculatoryshuntingandrestoreautoregulatorydysfunctionbycontrolofinflammation,vascularfunctionandcoagulation.

Openthemicrocirculationandkeepitopenbysupportofthepump,fluids,vasodilatorsandrestricteduseofvasopressoragents.InceC(2005)CriticalCare9:S13-S19

MicrocirculationRecruitmentM593cmMathuraetal.(2001)J.AppliedPhysiology91:74-78.OPSimagingvalidatedagainstcapillarymicroscopyAnalyzerPolarizer3cmMathuraetal.(2001)J.A60FirstdirectvisualizationsofthemicrocirculationinhumaninternalorgansusingOPSimaging.Groneretal.(1999)NatureMed5:1209

Mathuraetal.(2001)TheLancet58:1698Mathuraetal.(2001)J.ApplPhysiol91:74Spronketal.(2001)TheLancet360:1395Penningsetal.(2004)Stroke35:1284. SAH

BraintumoursduringhyperventilationBeforeHVAfterHVFirstdirectvisualizationsof61SDFimagingSidestreamDarkFieldimagingforimprovedtechniqueforobservationofthemicrocirculationInceC(2005)CriticalCare9:S13-S19Calculatevelocity(30.49pixels/s)SDFimagingSidestreamDarkFie62Flowscore:0=noflow1=intermittent2=sluggish3=continuousSmall:10-25μmMedium:26-50μmLarge:51-100μmBoermaetal(2005)CritCare9:R601-R606Flowscore:Small:10-25μmBoer63DeBacker,Creteur,Preiser,Dubois,VincentAmJRespirCritCareMed(2002)166:98-104.DeBacker,Creteur,Preiser,D64Sakretal.CritCareMed(2004)32:1825-1831Therewasnodifferenceinsytemichemodynamicandoxygenationvariablesortheamountortypeofdrugsusedbetweensurvivorsandnon-survivors.Microcirculatorydysfunctionwasthesinglemostsensitiveandspecificpredictorofoutcome.Sakretal.CritCareMed(20065Creteur,J.,DeBacker,D.Sakr,Y.Koch,M.,Vincent,J.L.(2004)

CritCareMedSupplVol.31(12):419Resuscitatationisaffectiveinrecruitmentofcapillariesandcorrectionofsub-lingualCO2Creteur,J.,DeBacker,D.Sak66SublingualOPSimaginginapatientwithsepticshockafterpressureguidedvolumeresuscitation.thesamepatientaftersubsequentnitroglycerin0.5mgivbolus

NitroglycerinpromotesmicrovascularrecruitmentinsepticandcardiogenicshockpatientsSpronk,Ince,Gardien,Mathura,Oudemans-vanStraaten,ZandstraDF.(2002)TheLancet360:1395-1396.SublingualOPSimaginginapa67.

Capillaryflowbuttoamuchlesserdegreevenularflow,isimpaired duringpressureguidedresuscitationfromsepticshock.NOdonorcanrecruitthemicrocirculationbypromotingflow.Nitroglycerinpromotesmicrovascularrecruitmentinpressureresuscitatedsepticshockpatientssub-lingualOPSimagingSpronk,Ince,Gardien,Mathura,Oudemans-vanStraaten,ZandstraDF. TheLancet2002;360(9343):1395-1396..Capillaryflowbuttoamuc68Theeffectsofdobutamineonmicrocirculatoryalterationsinpatientswithsepticshockareindependentofitssystemiceffects.DeBackerDetal.(2006)CritCareMed2006;34:403–408)Theeffectsofdobutamineonm69Thrombolysisinfulminantpurpura:observationsonchangesinmicrocirculatoryperfusionduringsuccessfultreatment.SpronkPERommesJH,SchaarC,InceC

(2006)

ThrombHaemost.95(3):576-8Thrombolysisinfulminantpurp70Microvascularflowindex(MFI)ofsmallvesselsinthesublingualregionversustheMFIinthestomaregionChristianBoermaMicrovascularflowindex(MFI)71SWan,JLLeClerc,JLVincent.Chest1997;112InflammatoryResponsetoCardiopulmonaryBypassMechanismsInvolvedandPossibleTherapeuticStrategiesSWan,JLLeClerc,JLVincent.72ECMOreducesFCDinprematureinfantsJ.E.vanVelzen,CInce,DTibbeauProc.Symp.Micro.Mit.DysfuntioninICM(2003)ECMOreducesFCDinpremature73HealthysublingualmicrocirculationobservedbySDFimaging

Healthysublingualmicrocircu74CardiogenicShockCardiogenicShock75【体外膜肺ECMO课件】-Classification-of-microcirculatory-76

ClassifyingmicrocirculatoryflowabnormalitiesindistributiveshockClassCapillaryhemodynamicsObservedindiseasedstatesIStagnantPressureguidedresuscitationfromsepsisIIContinuous/capillaryfall-outOn-pumpCABGsurgery,ECMOIIIContinuous/stagnantResuscitatedSepsis,reperfusioninjury,sicklecellcrises,malariaIVHyperdynamic/stagnantResuscitatedsepsisVHyperdynamicResuscitatedsepsis,exercise

Functionallyallclassescauseadistributivedefectandfunctionalshuntingofthemicrocirculation.Capillaryhemodynamicsunderlyingdistributivedefect

ClassCapillaryhemodynamicsO77【体外膜肺ECMO课件】-Classification-of-microcirculatory-78Conclusions

Distributiveshockhasabadprognosiswithdifficulttodefinehemodynamicsend-points.2)Itcausesadistributivedefectatthecapillarylevelofthemicrocirculationcausingfunctiona