另眼看镇静调节重症病人的交感兴奋性与炎症免疫反应课件

另眼看镇静:

调节重症病人的交感兴奋性与免疫反响南京大学医学院南京军区总医院重症中心全军普通外科研究所SICU李维勤ContentsSepsis1Propofol2Benzodiazepines3α2-Adrenoceptoragonists4Opioid5ICU-acquiredinfection6NatureImmunology2006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ContentsPropofol2Sepsis1Benzodiazepines3α2-Adrenoceptoragonists4Opioid5ICU-acquiredinfection6Propofol--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AntioxidanteffectPropofol--immunosuppressanteffectsLPS动物实验sepsis、ALI体外实验Propofol抑制释放Propofol抑制释放LPSiNOSNOPossiblemechanismMarch2011Volume6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PropofolFebruary2011|Volume6GABAAreceptorβ

2subunitexpressioninhumanmonocytespropofol/硫喷妥钠

actiononGABAAreceptorsinhibitsnormalmonocytebehaviour.(chemotaxisandphagocytosis)increasetheriskofinfectionincriticallyillpatientsapotentialsolution：monocyteGABAAreceptorsareinsensitivetodiazepamPropofol抑制中性粒、巨噬细胞吞噬Staphylococcusaureus和EscherichiacoliAtherapeuticapplicationforattenuationofsterileinflammationhowever,inthepresenceofinfectiontheimpairedclearanceofbacteriamayproveasignificantproblem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.ContentsBenzodiazepines3Sepsis1Propofol2α2-Adrenoceptoragonists4Opioid5ICU-acquiredinfection6Benzodiazepines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

MaybedetrimentalwithbenzodiazepinesincreasingmortalityfrominfectionsinanimalsImmunosuppressantBenzodiazepineuseasariskfactorforcomplicatedcommunity-acquiredlowerrespiratorytractinfectionContentsα2-Adrenoceptoragonists4Sepsis1Propofol2Benzodiazepines3Opioid5ICU-acquiredinfection6a2-Adrenoceptoragonists

Dexmedetomidine减少SleepdeprivationImmuneresponses

Autonomicnervoussystem

directindirectNEcentral-actingalpha-2agonistsinhibitnoradrenergicneurotransmissionhaveastrongsedativecomponentsecondarytosympatheticinhibitionGoBackTheelectroencephalogramandpatternofcerebralbloodflowshowgreatersimilaritytonaturalsleepwithdexmedetomidinethanwithbenzodiazepines.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-3SEPSISDEX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-inflammatoryphaseExaggeratedInflammatoryresponseDEXpromotemacrophagephagocytosisandbactericidalkillingDecreasedmortalityfrominfectionIL-6decreasedintheDexmedetomidinegroupOnlyDEXsuppressedtheexpressionofTNF-α,IL-1β,andIL-6;bothagentsimprovedoxygenation

2007DEX感染率降低DEX组拔管早28天死亡率、ICU住院时间无差异Aparticularclassofsedativebepreferredwhensedatingthesepticpatient？'no'oratleast'notyet'.AnimalmodelsofsedativesinsepsisAdrenergiccatecholamines，vasopressors

Otherimmunomodulatingtherapies?ClinicaldataislackingContentsOpioid5Propofol2Benzodiazepines3α2-Adrenoceptoragonists4Sepsis1ICU-acquiredinfection6Opioid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Possiblemechanism1.adirectinteractionontheimmunesystemLocationofopioidreceptorsonimmunocytesThesesuppressiveeffectsareblockedbynaloxoneSympathicnervoussystem2.CentralopioidreceptorsHypothalamic-pituitary-adrenalaxis激活SuppressimmunefunctionContentsICU-acquiredinfection6Propofol2Benzodiazepines3α2-Adrenoceptoragonists4Sepsis1Opioid5ICU-acquiredinfectionProspectivedatacollectionlasting6monthsin71ItalianadultICUs.9,493consecutivepatients,47%ICU-acquiredpneumonia37%ICU-acquiredbloodstreaminfection11.4%anICU-acquiredinfectionOthersACohort,multiple-center,observationalstudy.SETTING:198ICUin24Europeancountries.PATIENTS:AllnewadultadmissionstoaparticipatingICUbetweenMay1and15,2002.3,147patients,12%hadanICU-acquiredsepsis.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.ICU-acquiredinfectionasaside

effectofsedation--Pathophysiology1.Pronlongationofexposuretoriskfactorsforinfection5.Immunomodulatoryeffectofsedation:gastrointestinalmotilitydisturbances3.Microcirculatoryeffectsofsedation4.Intestinaleffectsofsedation2.Microaspiration:ImpairedtubularesophagealmotilityOutcomeContinuousIVsedationNoContinuousIVsedationPvalueDurationofMV,h185±19055.6±75.6<0.001Lengthofintensivecare,d13.5±33.74.8±4.1<0.001Lengthofhospitalstay,d21.0±25.112.8±14.1<0.001OutcomePersistantsedationNopersistentsedationDurationofMV,h4（IQR2-8）3（3-5）Lengthofintensivecare,d8（5-15）5（3-9）IncreasedexposuretoinvasiveproceduresProlongedstayintheICUThemajorriskfactorforVAP,bloodstreaminfection,andurinarytractinfectionDurationofMV：awell-knownriskfactorforVAP

Possiblesolution1.Dailyinterruptionofcontinuoussedation2.Nurse-implementedsedationprotocol3.ComparisonofsedativeagentsStudyDesign/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remifentanilan