教科书-hanyuan麻醉学笔记

SectionI–1–HistoryofAnestheticPracticeMerlinD.LarsonKeyMethodstosafelyalleviateseverepainarerelativelyrecentdiscoveries,asviewedwithinthetimespanofhumanhistory.ThepublicdemonstrationofetheranesthesiaonOctober16,1846,ranksasoneofthemostsignificanteventsinthehistoryofmedicine.NosingleindividualcanbesaidtohavediscoveredThespecialtyofanesthesiarestsondiscoveriesmadefromseveralscientificMajordiscoverieswereoftenmadebysmallgroupsofcuriousindividualswithdiverseTechniquesincommonuseatanyonetimeoftenseemdangeroustosubsequentgenerationsofanesthesiologists.MajorinnovationsweresometimesignoreduntiltheirrediscoveryseveraldecadesDevelopmentsinanesthesiaoftenarosetomeettheneedsofpatientswithseverecomorbidconditionsthatrequiredcomplexsurgicalprocedures.Consequently,advanceswithinthespecialtiesofsurgeryandanesthesiaarecloselyintegrated.SectionII–Anesthetic11–Sleep,Memory,andConsciousnessMaxB.Kelz,GeorgeA.Mashour,TedG.Abel,MervynMazeKeySleepisanactiveprocessgeneratedintheStructuresinthebrainstem,diencephalon,andbasalforebraincontrolthesleep-wakecycleandaredirectlymodulatedbygeneralanesthetics.Sleepandanesthesiaaresimilarstateswithdistincttraits,witheachsatisfyingneurobiologicfeaturesoftheother.DistinctmemoryfunctionsaresubservedbydistinctneuralLimbicsystemstructuressuchasthehippocampusandamygdalaarecriticalformemoryandplayaroleinanesthetic-inducedamnesia.Althoughbrainstem,diencephalon,andbasalforebrainstructuresgeneratewakefulness,thecontentsofconsciousnessarethoughttobegeneratedbythecortex.MultipleneuralcorrelatesofconsciousnessarethoughttobethetargetsofgeneralConsciousnessandsubsequentexplicitrecallofintraoperativeevents—knownas“awarenessduringgeneralanesthesia”—occurin1to2casesper1000.Monitoringanestheticdepthhasevolvedtoelectroencephalographicmethods,althoughlimitationsstillexist.【140731ethernitrousoxide Anesthetizedstate,includingamnesia,hypnosis,gesia,immobility,andbluntingofautonomicreflexes.Thebeneficialeffectsofsleepincluderestorationoftheneuronalhomeostasisessentialforsynapticfunction,consolidationofmemoriesandinitiationandexpressionofneuronalplasticity.Theneuronalunderpinningsforcontrolofarousallieinsubcorticalstructuresdeepwithinthebrainstemthalamus,andhypothalamusinregionswheretheyareconservedacrosstheanimalkingdom.的控制基于皮质下结构，以及脑干、丘脑和下丘脑。睡眠的学Bremer实验（cerveauisolecat），横切延髓尾端，需要机械通气，但睡眠-周期正常；Underthispassiveview,sleepwasnothingmorethanadefaultstateproducedbycessationoftheactivestate—waking. BremerMoruzziascendingreticularactivatingsystem（网状结构上行激活系Sleepisgeneratedwhenspecificneuronalsystemsincreasetheirfiringratesandthusinhibittheoutputofotherneuronalstructuresrequiredforwakefulness. 【140807睡眠和的生理模式由EEG和EMG（肌电图）记Wakefulnessisdefinedbyadesynchronized,low-amplitudefast-frequencyelectroencephalogram(EEG)withprominentmuscleactivity.REMsleepshowssimilarsignsofcorticalactivationwithadesynchronized,low-amplitude,fast-frequencyEEGinwhichθrhythmsof4to8HzdominatethepowerspectrumHowever,unlikewakefulness,motoractivityisminimalinthisstate.NREMsleephasanEEGappearancethatismarkedlydifferentfromtheothertwostates.DuringNREMsleep,theEEGdisplaysslow-frequencylarge-amplitudeoscillations.MotortoneduringNREMisdramaticallyreduced. 是去同步化的、低幅、高频的EEG，以及显著的肌肉运动。EEG，0.5-4Hz的δnoradrenergicneuronsofthelocusceruleus(LC),histaminergicneuronsofthetuberomammillarynucleus(TMN),serotonergicneuronsofthedorsalandmedianraphenuclei(RN),andthenewlyrecognizedpopulationofdopaminergicneuronsintheventralperiaqueductalgray(vPAG)matterareallmonoaminergiccentersthatdisplayarousalstate–dependentfiringpatterns. 斑LC、组胺能神经元结节核TMN、胺能神经元中缝核RN的背侧核和正中vPAG。Neuronscontainingthewake-promotingandwake-sustainingneuropeptideorexinalsoknownashypocretin)sharesimilaritieswithothermonoaminergicsystems.Theseneuronsexhibitalactivityduringwakefulness,reducetheirfiringduringNREMsleep,and equiescentduring 促和唤醒维持的神经肽食欲素orexin与其它单胺能系统相似，在时表现出最大活性，NREM时放电频率减少，REM期间为静态。Orexin正性刺激单胺能系统，维持。破坏orexin信号传递导致发作性嗜睡病。对于而言，没有任何一种单胺类神LDTPPT投射至前脑。单胺类神经元弥散投射至前脑，并直接调节下丘脑核团，为活性区域。睡眠促进神经元腹外侧视前区核VLPO，含有抑制性神经γ-氨基丁酸和甘丙肽，VLPO抑制性拮抗上行网状激活结构。Orexin能神经元与Althoughbrainstemandhypothalamicactivitymodulateswakefulness,thecerebralcortexitselfcontributestoself-awakeningthroughitsefferentprojectionstothethalamusandreticular 【140808Neuronsthatareactiveduringwakefulness(W)includethosewithascendingprojectionstothecortexthatstimulateafast-frequencydesynchronizedEEG(gamma+),alongwithdescendingprojectionstothespinalcordthatstimulatetheposturalmuscletonerequiredforwakingbehavior.Wake-activeneuronsdisplayalactivityduringwakefulness,dramaticallyslowtheirfiringduringnon–rapideyemovement(NREM)sleep,and evirtuallyquiescentduringrapideyemovement(REM)sleep. 活性神经元，上行投射至皮质刺激形成高频EEG（γ波），下行至脊髓刺激形成肌张力，这些神经元在时显示出最大活性，而在NREM时放电频率大幅下降，REMNAH、食欲素能Orx、谷氨GluACh、谷氨酰胺能Gluγ-氨基丁酸能GABA等神经元REM时也激活。Sleep-activeneuronsincludecellswhosecorticalascendingprojectionsdampenfastcorticalactivityandthosewithdescendingprojectionstothespinalcordandbrainstem,whichdiminishbehavioralarousalandmuscletoneThesleep-activeneuronsdischargeinassociationwithslowEEGactivity(gamma-/delta+)duringNREMsleep. 和下行消除行为和肌张力的细胞，在NREM时呈慢波（Δ波）。NREMWithanotableexceptionoftheventrolateralpreoptic(VLPO)nucleus,overallelectricalactivityinmostregionsofbrainisdecreasedduringNREMsleep.DuringNREMsleep,monoaminergic,orexinergic,andcholinergicgroupsareinhibitedbyefferentsignalsemanatingfromthepreopticanteriorhypothalamus,specifically,aclusterofneuronslocalizedtotheVLPOnucleusthatusetheinhibitoryneurotransmittersGABAandgalanin.VLPOneuronsaresleepactiveanddisplayincreasedfiringratesandc-Fosimmediateearlygeneexpressionduringsleep.Sleep-activeVLPOneuronshaveanantagonisticrelationshipwithwake-activecenterssuchthatVLPOactivationinhibitsfiringinwake-activecenters.Conversely,rapidfiringofwake-activeregionsinhibitstheVLPOnucleus.Thisnetworkdesignleadstoabistablebehavioralstateofarousalfavoringeithersleeporwakefulnessbutnotrapidtransitionsbetweenthetwo.NotsurprisinglydestructionoftheVLPOnucleuswithanexcitatoryaminoacidlesionthatdestroyscellbodieswhileleavingfibersofpassageintactcausesinsomnia. VLPO之外，NREM时脑电活性全面减弱。VLPO释放抑制性神经递质GABA和甘丙肽抑制单胺能、食欲素能、胆碱能等神经元。VLPO在睡眠时激活，放电频率增加，c-Fos即刻早期表达。睡眠活性神经元VLPO与活VLPO后引起失眠。Burstfiringofthalamocorticalneuronstransientlycausesdeafferentationofthecortexbyreversiblydisconnectingitfromsensorystimulinormallyconveyedtothecortexfromthe NREM时改变脑电活动，形成睡眠REMAlthoughseveralneuroanatomiccentersparticipateinregulationandcoordinationofREMonsetandoffset,themaineffectorresponsibleforthegenerationofREMsleepresidesinthepontinereticularformation.TheponstothenucleuspontisoralisPnOwhichappearstobenecessaryforREMexpression.DirectinjectionofcholinergicagonistsintothePnOproducesastatethatmimicsnaturalREMsleep.TheendogenouscholinergictoneinthebrainstemarisesfromtheLDTandPPT,twonucleilocatedatthejunctionbetweentheponsandmidbrain.ExcitotoxiclesionsthatablatetheLDTandPPTdramaticallyimpairREMsleep.LDTandPPTcholinergicneuronalactivitymayinitiateREMsleep.NeuronsoftheextendedVLPO(eVLPO)nucleusalsoexhibitpreferentialactivationduringREMsleep. REM的产生中具有重要作用，REMREM睡眠的启动者。延伸的eVLPO核在REM中也具有特异性的重要作用。ThecardinalsignsofREMsleepincluderapideyemovement,atoniaofallmotorgroupsexceptforthediaphragm,andactivationofalow-voltage,fast-frequencyEEGrhythm.Subcorticalrecordingsdemonstrateponto-geniculo-occipital(PGO)waves.ThischaracteristicyEEGpatternofREMsleeporiginatesinthepons,istransmittedtothethalamiclateralgeniculate,andterminatesintheoccipitalcortex.TheREMandwake-activepopulationofLDTandPPTneuronswithrostralprojectionsisimportantforproductionofthedesynchronizedfast-frequency,low-amplitudeEEGfoundinbothwakefulnessandREMsleep.REMatoniaisinitiatedbyagroupofpontinereticularneuronsthatsynapseinthebulbarreticularformationbeforeterminatingtheirsignalonspinalcordmotorneurons. REM的主要特征斑块快速眼球运动、膈肌外的其他肌EEGPGO波，这种高尖的波产生于脑桥，发送到丘脑外侧膝状体，并终止于枕叶皮质。LDT和PPT是产生和REM中快频低幅EEG的关键。REM肌肉麻痹由一组延髓网状神经元形成，终止于脊髓运动神经元。ExitfromREMsleeptransitionsintoeitherNREMsleeporwakefulnessandistriggeredby“REM-off”groups.TheobservationthatnoradrenergicLCneuronsdecreasetheirfiringrateduringNREMsleepand evirtuallyquiescentduringREMsleep,togetherwithpharmacologicandlesionstudies,hadsuggestedthatinhibitionoftheLCwasarequirementforentryintoREMsleepandthatLCneuronsmightserveasREM-offcells.However,geneticstudiesinnoradrenergic-deficientmicehaveconclusivelydemonstratedthecontinuedexistenceofnormal,ornearlynormal,REMsleepdespitetheabsenceofnorepinephrine.Thus,theadrenergicneuronsoftheLCcannotbeanexclusiveREM-offpopulation.Neuronsoftheventrolateralperiaqueductalgray(vlPAG)matteralsoservetoterminateREMepisodes,asprovedbypharmacologicstudiesduringwhichmuscimolinhibitionofthisregionincreasesREMsleepandalsobyelegantimmunohistochemicalmapcombinedwithvlPAGlesions.vlPAGneuronsformamutuallyantagonisticinhibitoryloopwiththoseoftheSLDnucleustoefficientlygenerateorinhibitREMsleep. 从REM进入到NREM或状态是由REM-off群组触发的。LC神NREMREMLCREM的关键，故其可REM-off细胞。然而，胆碱能缺陷小鼠尽管缺少去甲肾上腺素，仍表现正常或接近正常。vlPAGREMSLDREM睡眠。【120809Intrathecalinfusionofcerebrospinalfluid(CSF)harvestedfromsleep-depriveddogsintorestednormaldogscausedtherecipientdogstopromptlyfallasleep.Thisresultsuggestedtheexistenceofanendogenoussomnogen,ahormonecirculatingintheCSFwhoseaccumulationcouldcausetheonsetofsleep. 正常狗鞘内注射来自失眠狗的CSF后立即入睡。睡眠或状态的进入或脱离机制尚不明确，体液理论认为存在一种内源Somnogen，在CSF中积聚引起InfusionoffemtomolarconcentrationsofPGD2intothethirdventricleinducesbothNREMandREMsleepinratsthatisindistinguishablefromnaturalsleep.PGD2levelsfluctuateintheCSF,withcircadianfrequencyparallelingsleep-wakecycles.SleepdeprivationproportionallyelevatesCSFPGD2levels,thusalsosupportingaroleforPGD2asanendogenoussomnogen.PGD2issynthesizedbytheenzymeprostaglandinDsynthetase,whichislocalizedinthearachnoidmembraneandchoroidsplexus,andissecreteddirectlyintoCSF,whereitisthesecondmostabundantprotein.However,thissomnogenicactivityispresentonlywhenPGD2isinfusedinthevicinityofthepreopticareaofthehypothalamus.ThemostpronouncedactivityofPGD2isobservedwhenitisinfusedbeneaththeVLPOnucleus.InfusionofaPGD2antagonistintothethirdventriclereversiblyanddose-dependentlyinhibitsbothREMandNREM 与睡眠-周期相似，失眠者CSF中PGD2水平增高。PGD2由位于蛛网膜和脉络膜的前DCSFCSF中第二丰富的蛋白。Somnogen效应仅在PGD2VLPO核附近效应最强，而注射其拮抗剂可REM和NREM。OnbindingtotheD-typeprostanoidreceptor(DPR),whichislocalizedtothearachnoidmembraneliningtheventralsurfaceofthebrain,thesomnogenicsignalofPGD2appearstobetransducedindirectlybyactivationoftheVLPOnucleus.ThemechanismforVLPOactivationaftersubarachnoidinfusionofPGD2appearstorequireadenosinebecausecoadministrationofanadenosinereceptorA2aantagonistblocksthesomnogenicactivityofPGD2.Conversely,administrationofanadenosineA2aagonistmimicsthesomnogenicactivityofPGD2.Asadenosinelevelsaccumulate,theyactivateA2areceptor–expressingneuronstodirectlyorindirectlyactivatetheVLPOnucleus.Hence,itappearsthatadenosinemayfunctionastheneurotransmitterthatcouplesthehumoraltotheneuralmechanismsdrivingsleep-wakeregulation. 侧蛛网膜的D型素受体DPR，PGD2的somnogenic信号可能是由活化的VLPO核间PGD2VLPO还需要腺苷，因为合用腺苷受体A2a拮抗剂阻断PGD2somnogenic活动。而A2a受体激动剂能够模拟的PGD2somnogenic活性。腺苷积聚激活A2a受体直接或间接激活VLPO核。因此，腺苷作为神经递质，可能Duringsleepandgeneralanesthesia,thereisreducedresponsivenesstoexternalstimuli.Functionalbrainimagingduringanesthetic-inducedunconsciousnesshasbeenshowntoinhibitthalamicandmidbrainreticularformationnuclei.Anestheticblockadeofthalamicinformationtransfer,whichdisruptssomatosensoryinputfromreachinghighercorticalcenters,hasalsobeenconfirmedwithmoredirectmicroelectroderecordings.Inbothinstances,theseanestheticeffectsonthethalamusresemblethenaturallyoccurringthalamocorticalinhibitioncharacteristicofNREM NREMInfusionofadenosineinlowdosespotentiatesthehypnoticactionsofintravenousandvolatileanesthetics,therebyreducingtheamountofanestheticrequiredtoachieveagivendepthofanesthesia.Mechanistically,thesedatafitwellwithaneffectofadenosineonactivationofthehypothalamicsleepcenter,theVLPOnucleus.Meanwhile,exposuretoanestheticssuchasisofluraneaffectsthelevelsofendogenoussomnogens,withisofluranealteringthebalancebetweenprostaglandinE2,awake-promotingprostaglandin,andPGD2,asleep-inducingprostaglandin,inthehypothalamus. 度的药物剂量。于异氟烷影响内源性somnogens，改变prostaglandinE2（促）和【140812AnestheticsappeartoactonNREMsleepcircuits,therebyleadingtosharedmechanismsofaction.Withinthethalamus,thereisasimplearchitectureofcelltypesconsistingofreticularneuronsandthalamocorticalneuronsthatcommunicatewiththecortexwhilealsointegratingperipheralinput.ActivationofthereticularneuronsduringNREMsleepandanesthesiacauseshyperpolarizationofthalamocorticalrelayneurons,whichinturnblockspropagationoftheactionpotentialthroughthalamocorticalrelayneurons.Asaresult,thalamocorticalneuronsarepreventedfromrelayingperipheralinputtohighercorticalcenters.Midlinethalamicnucleiarethoughttoplayacriticalroleingeneratingconsciousawarenessandappropriayreceivingafferentinputfrommostreticularactivatingarousal-promotingcenters.Imagingstudiesconfirmaregionallyselectivereductioninmidlinethalamicbloodflow,metabolism,andbyextension,activity.Supportforathalamocorticalconsciousnessswitchhasrecentlybeenstrengthenedbythefindingthatmicroinjectionofnicotineintothecentromediannucleusofthethalamusreversessevoflurane-inducedhypnosis.Theseconclusionsaremitigatedbythefactthatadministrationofnicotineintothecentromediannucleusresultsinseizures.However,supportforthecentralthalamusasanarousalcenterthatiscapableofreversingunconsciousnessalsocomesfromliteratureonthepersistentvegetativestate.High-frequencystimulationofthecentralthalamusintherathasbeenassociatedwithwidespreadcorticalactivationandenhancedcognitivefunction.Furthermore,deepbrainstimulationofthecentralthalamushasbeenshowntoreversesomeofbehavioraldeficitsinapatientsufferingtraumaticbraininjury. NREM睡眠相似，其机NREM和麻醉时网状神经元激活引起丘脑皮质传递神经元超极化，阻断丘脑皮质神经元动Becausenicotinicacetylcholinereceptorsareheavilyexpressedinthethalamusandbecausemanyanestheticsinhibitsignalingvianicotinicacetylcholinereceptors,suppressionofthecholinergicarousalsystemmaybeonemechanismthroughwhichmanyanestheticsproduceunconsciousness.ProcessedEEGmeasuresofanestheticdepthalsorevealanimportantroleforthecholinergicarousalsysteminasmuchasintracerebroventricularinfusionsofneostigmineorthemuscarinicagonistoxotremorinearouseisoflurane-anesthetizedrats. 【140813Thalamicnucleireceiveinputfromtheascendingbrainstemreticularactivatingsystemviaadorsalpathwayandalsoreceivehypothalamicinputfromwake-activecenterssuchashistaminergicandorexinergicneurons.Asdiscussedearlier,thethalamicgatescloseduringNREMsleepandexposuretoseveralanestheticsandthisclosureisfacilitatedbydecreasedinputofmonoaminergiccholinergicandorexinergicsignalsduringanesthesia.GABAergicanestheticssuchaspropofolandbarbituratesexerttheirhypnoticeffectsbyinactivatinghistaminergicneuronsoftheTMN.ThisactionmaybeexplainedatthemolecularlevelbypotentiationofinhibitoryGABAergicprojectionfromthesleepcenter,theVLPOnucleus.DisinhibitionoftheVLPOnucleus,inturn,shutsdownotherwake-activegroupsandfurtherreinforcesVLPOactivity.Thisfeed-forwardmechanismstabilizesthehypnoticstate.Blockadeofthewake-promotinghistaminergicsignalisalsothemechanismbywhichtheantihistaminergicdrugdiphenhydramineprecipitatessleep.Recoveryoremergencefromanesthetichypnosisisfacilitatedbywake-promotingorexinergicneurons,whichareinhibitedbyvolatileanestheticssuchasisofluraneandsevoflurane. 息，并接收来自下丘脑唤醒活性中心如组胺能和orexinergic神经元的传入信息。NREM眠和麻醉时，丘脑关闭，而这种封闭通过减少单胺能、胆碱能、orexinergic的输入。GABA能丙泊酚和巴比妥类药物通过灭活TMN的组胺能神经元发挥作用。VLPO核的去抑制，阻断其他唤醒活性基团，并进一步增强了VLPO活性。这种前馈机制稳定了状态。抗组胺能药物苯海拉明阻断促组胺能信号。促orexinergic神经Onefindingthathasemergedfromstudyingthehypnoticpropertiesofdifferentanestheticagentsisthatthereisneitheraunitarymoleculartargetnoraninvariantneuronalsiteofactioncommontoallanesthetics.Thispointisillustratedbydexmedetomidine,anα2-adrenergicagonist.Thebehavioralhypnosisofdexmedetomidineresultsfromthedrug'sabilitytoinactivatenoradrenergicneuronsoftheLC.ThiseventdisinhibitstheVLPOnucleus,whichsubsequentlyinactivatesotherarousalcentersviatheVLPO'sGABAergicandgalaninergicinhibitorysignaling.AswithpropofolandbarbituratesactingontheTMN,thecommonconsequenceofVLPOdisinhibitionisstabilizationofthehypnoticstate.Pharmacologicandlesionexperimentsthatalterbothmonoaminergicreticularactivatingfunctionandanestheticsensitivitycannowbereinterpretedintheframeworkofintegratedarousalnetworkactivity.DepletionofCNScatecholamines,includingnorepinephrine,serotonin,dopamine,andhistamine,produceshypersensitivitytoanesthetics.Conversely,pretreatmentwithamonamineoxidaseinhibitororacuteexposuretoamphetamine,bothofwhichincreasecatecholaminelevelsinthebrain,producespartialtoanesthetics.FocusingonceagainonnoradrenergicneuronsoftheLC,chemicaldepletionofnorepinephrinewith6-hydroxydopamineandelectrolyticdestructionofLCneuronsbothproducehypersensitivitytoanesthetics,probablybyremovinganinhibitorysignaltotheVLPOnucleus.DestructionofserotonergicRNneuronswiththetoxin5,6-dihydroxytryptamineordirectelectrolyticlesionsofserotonergicRNneuronsalsocausehypersensitivitytoanesthetics.不同物的特性并腺素能受体激动剂）LC的去甲肾上腺素能神经元灭活，VLPO核去抑制，继而灭活其它经由VLPO的GABA能的中心和甘丙肽能抑制性信号。如丙泊酚和巴比妥类作用在TMN，VLPO去抑制稳定的状态。药理和病损实验改变单胺能网状激活功能和麻醉敏性于安非他明，都增加大脑中儿茶酚胺水平，对麻醉产生部分抵抗。6羟基多巴胺化学性消耗或电解破坏去甲肾上腺素，都对产生过敏，可能由于去除VLPO核的抑制性信号。用毒素5,6双羟色胺或直接电解破坏素神经元RN也会引起对的过Thediscoverythatpentobarbitalandmuscimol,aGABAAagonist,causebehavioralandEEGsignsofhypnosiswhenmicroinjectedintoad