另眼看镇静-调节重症病人交感兴奋性与炎症免疫反应2015年

ContentsSepsis1Propofol2Benzodiazepines3α2-Adrenoceptoragonists4Opioid5ICU-acquiredinfection6第一页，共41页。NatureImmunology2006脓毒症是什么？感染急性器官衰竭高炎反应状态Early免疫抑制状态Late脓毒症炎症因子过度释放免疫细胞凋亡治疗抗炎治疗抑制凋亡增强免疫功能第二页，共41页。ContentsPropofol2Sepsis1Benzodiazepines3α2-Adrenoceptoragonists4Opioid5ICU-acquiredinfection6第三页，共41页。Propofol--Antioxidanteffect抑制脂质过氧化减少缺血再灌注损伤减少ROS相关的组织炎症、损伤Antioxidanteffect第四页，共41页。Propofol--immunosuppressanteffectsLPS动物实验sepsis、ALI体外实验Propofol抑制释放Propofol抑制释放LPSiNOSNO第五页，共41页。PossiblemechanismMarch2011Volume6第六页，共41页。细胞膜核膜TNF-α、IL-1、IL-8、IL-12、IL-6iNOSTLR4细菌产物LPSPropofol抑制IKK磷酸化Propofol抑制NF-κB磷酸化、转录Propofol第七页，共41页。February2011|Volume6GABAAreceptorβ

2subunitexpressioninhumanmonocytes第八页，共41页。propofol/硫喷妥钠

actiononGABAAreceptorsinhibitsnormalmonocytebehaviour.(chemotaxisandphagocytosis)increasetheriskofinfectionincriticallyillpatientsapotentialsolution：monocyteGABAAreceptorsareinsensitivetodiazepam第九页，共41页。Propofol抑制中性粒、巨噬细胞吞噬Staphylococcusaureus和EscherichiacoliAtherapeuticapplicationforattenuationofsterileinflammationhowever,inthepresenceofinfectiontheimpairedclearanceofbacteriamayproveasignificantproblem第十页，共41页。丙泊酚乳剂：脂肪乳可能参与免疫抑制长时间使用高甘油三脂血症代酸Awater-solublepreparation(Aquavan,fospropofoldisodium,MGIPharma)willsoonbeavailable.第十一页，共41页。ContentsBenzodiazepines3Sepsis1Propofol2α2-Adrenoceptoragonists4Opioid5ICU-acquiredinfection6第十二页，共41页。Benzodiazepines动物、体外实验抑制LPS诱导的COX2、iNOS、IkB-a降解、NF-kB转录活性、p38MAPK磷酸化、过氧化物、TNFa、IL-6抑制中性粒、巨噬细胞氧爆发、吞噬金葡菌能力抑制分叶白细胞的吞噬作用、粘附、趋化抑制肥大细胞趋向作用、释放颗粒物质Theperipheralbenzodiazepinereceptorinimmunecells

MaybedetrimentalwithbenzodiazepinesincreasingmortalityfrominfectionsinanimalsImmunosuppressant第十三页，共41页。Benzodiazepineuseasariskfactorforcomplicatedcommunity-acquiredlowerrespiratorytractinfection第十四页，共41页。Contentsα2-Adrenoceptoragonists4Sepsis1Propofol2Benzodiazepines3Opioid5ICU-acquiredinfection6第十五页，共41页。a2-Adrenoceptoragonists

Dexmedetomidine减少SleepdeprivationImmuneresponses

Autonomicnervoussystem

directindirect第十六页，共41页。NEcentral-actingalpha-2agonistsinhibitnoradrenergicneurotransmissionhaveastrongsedativecomponentsecondarytosympatheticinhibitionGoBack第十七页，共41页。Theelectroencephalogramandpatternofcerebralbloodflowshowgreatersimilaritytonaturalsleepwithdexmedetomidinethanwithbenzodiazepines.第十八页，共41页。InvitroandinvivostudyofDEXStudyDesignSubjectα2adrenoceptoragonistsResultTaniquchiTetal2004CCMRandomizedlaboratorystudy57maleratsEcoliendotoxin-inducedshockDEX5micog/kg.hReducedmortalityInhibitinflammatoryresponseLai-YCetal2009JofsurgicalresearchRandomizedinvivostudyMurinemacrophageDEXclinicallrelevantdosex1,x10,x100,x1000DEXhigherthanclinicaldoseinhibitenhancinginflammtorymoleculesTakumiTetal.2008JAnesthRandomizedlaboratorystudy96maleratsEndoxininducedshockDEX:dose2.5ug/kg.h5ug/kg.h10ug/kg.hTime:1hafterendotoxininjection2hafterinjectionMortalityrateandplasmacytokineconcentrationaredoseandtimedependentStefanHetal2009criticalcareRandomizedlaboratorystudyMurineCLPinducedsepsisClonidine5ug/kgDEX40ug/kgPre-emptiveadministrationimprovesurvival，downregulatingpro-inflammatoryHongQetal2009criticalcareRandomizedlaboratorystudy60SpragueDawleyratsCLIPinducedsepsisMidazolam0.6mg/kg.hDEX5ug/kg.hBothreducemortalityrateandTNF.DEXreducedIL-6andcaspase-3第十九页，共41页。SEPSISDEX降低COX-2,iNOS,TNF-2,IL-1,IL-6,IFNγ水平抑制Caspase-3活性抑制神经细胞凋亡CytokinestormApoptosisofBandTlymphocytesAhypo-inflammatoryphaseExaggeratedInflammatoryresponseDEXpromotemacrophagephagocytosisandbactericidalkillingDecreasedmortalityfrominfection第二十页，共41页。IL-6decreasedintheDexmedetomidinegroup第二十一页，共41页。OnlyDEXsuppressedtheexpressionofTNF-α,IL-1β,andIL-6;bothagentsimprovedoxygenation

2007第二十二页，共41页。第二十三页，共41页。第二十四页，共41页。DEX感染率降低DEX组拔管早28天死亡率、ICU住院时间无差别

第二十五页，共41页。第二十六页，共41页。Aparticularclassofsedativebepreferredwhensedatingthesepticpatient？'no'oratleast'notyet'.AnimalmodelsofsedativesinsepsisAdrenergiccatecholamines，vasopressors

Otherimmunomodulatingtherapies?Clinicaldataislacking第二十七页，共41页。ContentsOpioid5Propofol2Benzodiazepines3α2-Adrenoceptoragonists4Sepsis1ICU-acquiredinfection6第二十八页，共41页。Opioid体外实验、动物模型抑制分裂素诱导的淋巴细胞增殖抑制NK细胞毒性抑制巨噬细胞吞噬、迁移功能抑制IL-2、γIFN、TNFα、NO浓度

ImmunosuppressantBebeneficialinsepticpatients？

nopublisheddatasupportthishypothesisAcuteexposuretoopioids抑制组织巨噬细胞吞噬细菌Chronicexposuretoopioids与免疫系统的相关性不如acuteexposeOpioidswithdraw动物实验：免疫抑制增强、时间延长第二十九页，共41页。Possiblemechanism1.adirectinteractionontheimmunesystemLocationofopioidreceptorsonimmunocytesThesesuppressiveeffectsareblockedbynaloxoneSympathicnervoussystem2.CentralopioidreceptorsHypothalamic-pituitary-adrenalaxis激活Suppressimmunefunction第三十页，共41页。ContentsICU-acquiredinfection6Propofol2Benzodiazepines3α2-Adrenoceptoragonists4Sepsis1Opioid5第三十一页，共41页。ICU-acquiredinfectionProspectivedatacollectionlasting6monthsin71ItalianadultICUs.9,493consecutivepatients,47%ICU-acquiredpneumonia37%ICU-acquiredbloodstreaminfection11.4%anICU-acquiredinfectionOthers第三十二页，共41页。ACohort,multiple-center,observationalstudy.SETTING:198ICUin24Europeancountries.PATIENTS:AllnewadultadmissionstoaparticipatingICUbetweenMay1and15,2002.3,147patients,12%hadanICU-acquiredsepsis.第三十三页，共41页。SedationandICU-acquiredinfectionDesign—Prospectivedescriptivestudyconductedovera2-yrperiodSetting—FiveICUinauniversity-affiliatedmedicalcenterwithlevelItraumastatus.Patients—Eachofthe360adultpatientsparticipatedfor4days.theinclusioncriteriawere：mechanicalventilationandtubefeedings.VariableWaldStatisticPValueRisk95%confidenceIntervalHigh-aspirationgroup37.22.0004.22.7-6.7Paralyticagentsused13.98.0002.71.6-4.5HighSedation7.68.0062.31.3-4.1Preliminaryidentificationofriskfactorsassociatedwithpneumoniaintube-fedpatients,determinedbymultivariatestepwiselogisticregression.第三十四页，共41页。ICU-acquiredinfectionasaside

effectofsedation--Pathophysiology1.Pronlongationofexposuretoriskfactorsforinfection5.Immunomodulatoryeffectofsedation:gastrointestinalmotilitydisturbances3.Microcirculatoryeffectsofsedation4.Intestinaleffectsofsedation2.Microaspiration:Impairedtubularesophagealmotility第三十五页，共41页。OutcomeContinuousIVsedationNoContinuousIVsedationPvalueDurationofMV,h185±19055.6±75.6<0.001Lengthofintensivecare,d13.5±33.74.8±4.1<0.001Lengthofhospitalstay,d21.0±25.112.8±14.1<0.001第三十六页，共41页。OutcomePersistantsedationNopersistentsedationDurationofMV,h4（IQR2-8）3（3-5）Lengthofintensivecare,d8（5-15）5（3-9）IncreasedexposuretoinvasiveproceduresProlongedstayintheICUThemajorriskfactorforVAP,bloodstreaminfection,andurinarytractinfectionDurationofMV：awell-knownriskfactorforVAP

第三十七页，共41页。Possiblesolution1.Dailyinterruptionofcontinuoussedation2.Nurse-implementedsedationprotocol3.Comparisonofsedativeagents第三十八页，共41页。第三十九页，共41页。StudyDesign/PatientsMainresultAryaetalIndianPediatr2001RCT研究，将midazolam和morphine+midazolam对比/33新生儿两组的感染发生率无差别MuellejansetalCritCare2006RCT研究，将