在麻醉和手術(shù)中預(yù)防中樞神經(jīng)系統(tǒng)并發(fā)癥(雙語(yǔ))課件

PreventingCNSComplicationsDuringAnesthesiaandSurgery

在麻醉和手術(shù)中預(yù)防中樞神經(jīng)系統(tǒng)并發(fā)癥原作：JamesE.Cottrell,M.D.Theassumptionthatanesthesiahasnoserious,long-term,adverseCNSconsequencesisprobablytrueformostpatients假設(shè)麻醉沒(méi)有嚴(yán)重的，長(zhǎng)期的，中樞神經(jīng)系統(tǒng)的不良后果，可能是適用于大多數(shù)患者。However,forpatientsyoungerthan6months,orolderthan60years,thatassumptionisunderchallengefromasubstantialbodyofevidence.然而，對(duì)于年齡小于6個(gè)月或年齡超過(guò)60歲的患者，這種假設(shè)受到大量證據(jù)的挑戰(zhàn)。

Fetusesandnewbornsappeartobeatriskbecausesystemsthatwouldenablethemtofullyrecoverfromtheeffectsofmorethan2hoursofanesthesiaarestillindevelopment.Indistinction,seniorsmaybeatriskbecausesystemsthatonceenabledfullrecoveryhaveever-diminishingcapacity.Evenforsomepatientsbetweentheageof6monthsand60years,fullrecoverymayrequirereplacingapoptosedneuronsandpruningdendriticspines…perhapsleavingthemnotquitethesamepersonthattheywerebeforetheywereanesthetized.胎兒和新生兒似乎處于危險(xiǎn)之中，因?yàn)槭顾麄兡軌驈亩嘤?個(gè)小時(shí)的麻醉中完全恢復(fù)的系統(tǒng)仍然在發(fā)育中。相對(duì)的，老年人可能存在風(fēng)險(xiǎn)是因?yàn)榭梢允顾麄兺耆謴?fù)的系統(tǒng)已經(jīng)日益衰竭。甚至對(duì)6個(gè)月以下和60歲以上的一些患者中，完全恢復(fù)可能需要更換凋亡神經(jīng)元和修剪樹突棘...或許會(huì)使他們變得和麻醉前不一樣的人。AggravatingFactors加重的因素（1）On-pumpvs.Off-pumpDoeson-pumpversusoff-pumpmakeaneurocognitivedifference?Morerecently,Puskasandcolleaguesfoundthat“Afterameanof7.5yearsoffollow-up,

patientsundergoingoff-pumpcoronaryarterybypassperformedbetterthanthoseundergoing[on-pump]cardiopulmonarybypass

inseveralneuropsychologicaldomains,”andinasortofpositive-controlstudy,Lietalfoundthatpreconditioningwith

hyperbaricoxygenreducedmarkersofcerebralinjuryinpatientsundergoingon-pumpbypassbutnotinpatientshavingoff

pump

bypass,reasoningthat“theprotectiveeffectsofHBOpreconditioningmayonlymanifestwhenthereisarelativelysevereinjury”.Lessdirectevidencecamefromastudyof

over16,000patientsinwhomagreaterincidenceofdeliriumoccurredafteron-pumpcardiopulmonarybypass,withdurationofsurgery(andsoanesthesia)asasignificantriskfactor.體外循環(huán)對(duì)比非體外循環(huán)是否產(chǎn)生認(rèn)識(shí)的神經(jīng)功能差異？最近，Puskas和他的同事發(fā)現(xiàn)，“平均7.5年的隨訪后，在幾個(gè)神經(jīng)心理學(xué)領(lǐng)域，接受非體外循環(huán)冠狀動(dòng)脈搭橋的患者表現(xiàn)比處于體外循環(huán)的患者更好”，并在排序陽(yáng)性對(duì)照研究中，Li等發(fā)現(xiàn)，接受體外循環(huán)搭橋術(shù)的患者中，預(yù)防性使用高壓氧可以減少腦損傷，但不能適用于非體外循環(huán)搭橋的患者，理由是“預(yù)防性使用高壓氧可能只在當(dāng)有相對(duì)嚴(yán)重的損傷時(shí)才表現(xiàn)出保護(hù)作用”。不那么直接的證據(jù)來(lái)自超過(guò)16,000例研究接受體外循環(huán)搭橋術(shù)后譫妄的發(fā)生率較高的患者，手術(shù)時(shí)間（麻醉時(shí)間）是一個(gè)顯著的危險(xiǎn)因素。AggravatingFactors加重的因素（2）

Inflammation炎癥

InflammationcausedbysurgicaltraumamayalsoaggravatePOCDandisassociatedwiththepathogenesisofAlzheimers’Disease(AD)inamousemodels.在小鼠模型中，手術(shù)創(chuàng)傷引起的炎癥可能加劇POCD和老年癡呆癥。EvidencethattheassociationiscausalcomesfromvomBergandcoauthors’findingthatintracerebroventriculardeliveryofanti-p40,andinhibitorofinflammatorysignaling,significantlyreducestheconcentrationofamyloidβ(Aβ)andreversescognitivedeficitsinagedAlzheimer’smice.這證據(jù)來(lái)自vomBerg和同事發(fā)現(xiàn)腦室內(nèi)傳遞anti

-P40、炎癥信號(hào)的抑制劑、β淀粉樣蛋白的濃度（Aβ）顯著降低和逆轉(zhuǎn)老年阿爾茨海默氏癥老鼠的認(rèn)知障礙。Weknowabouttheup-regulationofIL-1,andthisinturncanaffectanestheticreceptors.Theensuingcascadeofeventsultimatelyaffectstheanestheticgamma-aminobutyricacidandN-methyl-D-asparticacidreceptorsandincreasesproductionofAβ…andweknowthatsolubleoligomersofAβ,eveninnon-dementedpatients,associatewithcognitiveproblems.Geneticpredispositionsareanotheraggravatingfactor.我們知道上調(diào)白細(xì)胞介素-1，而這反過(guò)來(lái)又可以影響麻醉劑受體。隨后的連鎖反應(yīng)，最終影響了麻醉劑γ-氨基丁酸和N-甲基-D-天冬氨酸受體，提高Aβ的產(chǎn)生......我們知道，Aβ的可溶性低聚物，即使在非癡呆癥患者，也會(huì)與認(rèn)知問(wèn)題有關(guān)。遺傳傾向是另一種加重的因素。AggravatingFactors加重的因素（3）Anesthetics麻醉劑Areanestheticsaggravatingfactors?Ifso,aresomemoretoxicthanothers?LeFrecheandcoauthorswereabletolinkanincreaseinphosphorylatedtautodiminishedmemoryinsevoflurane-exposedadultmiceandLiuetalfoundthatsevofluraneacceleratestheprogressionofmildcognitiveimpairment(MCI)inMCIpatientsundergoingspinalsurgery.Dongandcolleaguesfoundthatjust2hoursofclinicalanesthesiawithisofluranegeneratescaspase-3andincreasesphosphorylatedtauinadultmice,whileXie’sgroupfoundthatisofluraneinducesmorecaspase-3activationandA-betaoligomerizationinADtransgenicneonatalmicethandoespropofol.Xie’sgroupalsofoundincreasedlevelsofAβandcaspase-3inadultmiceexposedto1.4%isofluranefor2hours,butgreatercognitivedeclineinpatients1weekaftersurgerywhoreceivedspinalanesthesiawithdesfluraneversusspinalanesthesiawithisofluraneorspinalanesthesiaalone.麻醉劑是否是加重因素？如果是這樣，是否一些比另一些更具有毒性？LeFreche和同事們能夠發(fā)現(xiàn)暴露在七氟醚中的成年小鼠tau蛋白磷酸化增加與記憶減退相關(guān)聯(lián)，Liu等人發(fā)現(xiàn)七氟醚可加重接受脊柱手術(shù)的輕度認(rèn)知障礙（MCI）的患者的認(rèn)知障礙。Dong和他的同事發(fā)現(xiàn)，短短2個(gè)小時(shí)臨床麻醉中應(yīng)用異氟醚可使得成年小鼠caspase-3產(chǎn)生和tau蛋白磷酸化增加，而謝的研究小組發(fā)現(xiàn)，在有AD基因的新生小鼠中，使用異氟醚比異丙酚誘導(dǎo)更多的caspase-3的活化和A-β齊聚。謝的研究小組還發(fā)現(xiàn)在暴露于1.4％異氟醚2小時(shí)成年小鼠的Aβ和caspase-3水平提高。但對(duì)比使用異氟醚的脊髓麻醉或單獨(dú)脊髓麻醉的患者，使用地氟醚的脊髓麻醉的患者在術(shù)后一周存在更大的認(rèn)知能力下降。AggravatingFactors加重的因素（3）Anesthetics麻醉劑Jevtovic-TodorovicandCarterreportedthatoldratbrainsareequally(nitrousoxide)ormoresensitive(ketamine)toanestheticneurotoxicitythaninfantratbrains,andCulleyandcoauthorsfoundthatspatialmemoryisimpairedfor2weeksafter2hoursof1.2%isofluranewith70%nitrousoxideinagedrats.Whataboutnitrousoxidealone?Culleyetalfoundthatagedratsexposedto70%nitrousoxidefor4hourstookmoretimetocompleteamazeandmadefewercorrectchoicesbeforemakingtheirfirsterrorcomparedtocontrolratsfortwoweeksafterexposure.Jevtovic-TodorovicandCarter報(bào)道，年老老鼠比幼年大鼠的大腦對(duì)麻醉劑神經(jīng)毒性也同樣（笑氣）或更敏感（氯胺酮）。卡利和同事發(fā)現(xiàn)，使用超過(guò)2小時(shí)1.2％異氟醚混合70％笑氣的老年大鼠在空間記憶受損2周。那么獨(dú)自笑氣呢？卡利等人發(fā)現(xiàn)，暴露在70％笑氣4小時(shí)的老齡大鼠花了更多的時(shí)間來(lái)完成一個(gè)迷宮，并作出比較，對(duì)照組大鼠在這2周時(shí)間做出更少錯(cuò)誤的選擇。AggravatingFactors加重的因素（4）Deepervs.Lighter&Regionalvs.GeneralAnesthesiaExaminingresultsfrom980patientswhounderwentintra-arterialtherapyforacuteischemicstrokeunderconscious(light)sedationversus(light)generalanesthesia,Abou-Cheblandcolleaguesfoundpoorerneurologicaloutcomeandhighermortalityinthegeneralanesthesiapatients.Neumanetalalsofoundhighermortalityandmorepulmonarycomplicationsingeneralanesthesiapatients,comparedtoregionalanesthesiapatients,undergoinghipfracturesurgery.IftheassociationbetweenPOCDanddeepsedationhadbeendiscoveredbeforetheassociationbetweenPOCDandgeneralanesthesia,perhapswewouldhavecomemorereadilytothehypothesisthatregionalanesthesiawithdeepsedationisequivalenttogeneralanesthesiawhenitcomestoincreasingtheriskofPOCD比較鎮(zhèn)靜和淺全麻的980例接受動(dòng)脈內(nèi)治療急性缺血性中風(fēng)的患者的結(jié)果，Abou-Chebl和他的同事發(fā)現(xiàn)全身麻醉的患者有著較差的神經(jīng)系統(tǒng)結(jié)果和較高死亡率。Neuman等人還發(fā)現(xiàn)，接受髖部骨折手術(shù)的全身麻醉的患者相比較于區(qū)域麻醉的病人，有著更高的死亡率和更多肺部并發(fā)癥。如果POCD和深度鎮(zhèn)靜之間的關(guān)系比POCD和全身麻醉之間的關(guān)系發(fā)現(xiàn)早，我們可以得到這樣的假設(shè)：對(duì)于增加POCD的危險(xiǎn)性，區(qū)域麻醉結(jié)合深度鎮(zhèn)靜相當(dāng)于全身麻醉。AggravatingFactors加重的因素AlthoughaconnectionbetweenanestheticsandADhasreceivedmoreattentionthanapossiblerelationshipbetweenanesthesiaandParkinson’sorHuntington’sdisease,twoinvestigationssuggestthatfurtherresearchiswarranted.PeretzandcoauthorshavefoundevidencethatsupportsanelevatedriskofParkinson’sdiseaseamonganesthesiologistsascomparedtointernistsandWangetalhavefoundinvitrolaboratoryevidencethatisofluranemayexacerbateHuntington’sdisease.雖然麻醉藥和AD之間的關(guān)系比麻醉和帕金森氏或亨廷頓氏舞蹈癥之間可能存在的關(guān)系已受到更多的關(guān)注，兩項(xiàng)調(diào)查表明，進(jìn)一步的研究是必要的。Peretz和同事們發(fā)現(xiàn)，與內(nèi)科醫(yī)師相比，麻醉科醫(yī)師患帕金森病的風(fēng)險(xiǎn)高，Wang等人發(fā)現(xiàn)在體外實(shí)驗(yàn)證據(jù)表明，異氟醚可能會(huì)加劇亨廷頓氏舞蹈癥的證據(jù)。PotentialAlleviatingFactors潛在的緩解因素（2）AGrabBagofAdjuvants各種輔助劑Whatabouterythropoietin,prophylacticanti-psychotics,melatonin,cholinesteraseinhibitors,memantine,insulin,statins,dantrolene,bexarotene，anN-terminalfragmentofaprionprotein,crenezumab,andexercise?LauretaniandcolleaguesfoundthatEPOlevelsarelowerin60-to-98-year-oldswithimpairedperipheralnervefunctionand/orclinicaldiagnosisofpolyneuropathy.HaljanetalfoundatrendtowardimprovedneurocognitiverecoverywitherythropoietinuseinCABG.Hakimandcoauthorsfoundthattheanti-psychoticrisperidonereducesdeliriumafteron-pumpcardiacsurgeryinelderlypatientsandTeslyarandcoauthors’meta-analysisfoundthatprophylacticanti-psychoticsreducepost-operativedeliriummoregenerally,whichmayaugerwellforreductionofsubsequentPOCD.促紅細(xì)胞生成素，預(yù)防性抗精神病藥，褪黑激素，膽堿酯酶抑制劑，美金剛，胰島素，他汀類，丹曲林，貝沙羅汀，朊病毒蛋白的N-末端片段，crenezumab單抗和運(yùn)動(dòng)，這些有什么作用？

Lauretani和他的同事發(fā)現(xiàn)，有受損周圍神經(jīng)功能和/或臨床診斷有多發(fā)性神經(jīng)病變的60到98歲老人的EPO（促紅細(xì)胞生成素）水平較低。Haljan等人發(fā)現(xiàn)在CABG（冠脈搭橋術(shù)）患者中使用促紅細(xì)胞生成素對(duì)改善神經(jīng)認(rèn)知功能有恢復(fù)趨勢(shì)。哈基姆和同事發(fā)現(xiàn)，抗精神病藥利培酮降低譫妄后體外循環(huán)心臟手術(shù)的老年患者，Teslyar和合作者在Meta分析發(fā)現(xiàn)，預(yù)防性抗精神病藥可減少術(shù)后譫妄，這可能是減少的隨后POCD的好兆頭。PotentialAlleviatingFactors潛在的緩解因素Chengandcolleagues’reviewofthebeneficialeffectsofmelatonininexperimentalmodelsofADisencouraging,asisNiandcoauthors’findingthatmelatoninpremedicationattenuatesisofluraneinducedAβinthehippocampusofagedrats.AclinicalstudybyFurioetalfoundthatmelatoninimprovedcognitivefunctioninelderlyoutpatientswhosufferedfrommildcognitiveimpairment.Morerecentstudiesindicatethatcholinesteraseinhibitors,memantine,andinsulintherapy,improvecognitivefunction,ordelayclinicalworsening,inADpatientsanddantrolenehasbeenshowntoreducememorydeficitsandamyloidplaqueinADmice.Bexarotene,anFDA-approvedanticancerdrugthatdramaticallyreducesAβinmiceandimprovesbehaviorisnowinaclinicaltrial.ThejuryhaslookedhardforevidencethatstatintherapypreventsoramelioratesAD,butadefinitiveverdictisstillpending.Cheng和同事們發(fā)現(xiàn)得褪黑素對(duì)于AD的實(shí)驗(yàn)?zāi)Ｐ痛嬖谟幸嬗绊懙慕Y(jié)論是令人鼓舞的，同樣Ni和合作者發(fā)現(xiàn)，對(duì)老年老鼠術(shù)前使用褪黑激素減輕Aβ降解。Furio等人一項(xiàng)臨床研究發(fā)現(xiàn)，褪黑激素對(duì)于已出現(xiàn)輕度認(rèn)知功能障礙的門診老年病人，有改善認(rèn)知功能的作用。最近的研究表明，在AD患者，膽堿酯酶抑制劑、美金剛和胰島素治療，可改善認(rèn)知功能或推遲臨床惡化。丹曲林已經(jīng)被證明對(duì)于AD的老鼠可以減少記憶損害。克雷內(nèi)治單抗，這是一種FDA批準(zhǔn)的抗癌藥物，可降低小鼠Aβ并改善行為，現(xiàn)在正處于臨床實(shí)驗(yàn)。評(píng)審委員會(huì)努力尋找他汀類藥物可預(yù)防或改善AD的證據(jù)，但最終裁決仍需等待。PotentialAlleviatingFactors潛在的緩解因素（3）Preconditioning預(yù)處理Clinicallyacceptablemeansofaccomplishingcerebralpreconditioningarebeingsought.Volatileanestheticsnotwithstanding,pharmacologicalcerebralpreconditioningmaybeeclipsedbymechanicalRemoteIschemicPreconditioning(RIPC).Clinicalstudieshaveestablishedthatthree5-minuteinflationsofabloodpressurecuffto200mmHgaroundapatient'supperarm,followedby5-minuteintervalsofreperfusion,improvesoutcomeaftersomecardiovascularproceduresandevidencefromlaboratoryinvestigationsindicatesthatthesametechniqueinitiatedpriortoneurosurgerymayimproveoutcome.ClinicalstudiesofRIPCinneurosurgicalpatientsareunderwayorhaverecentlybeencompleted,andapublishedstudybyHuandcolleagueshasreportedreducedbiochemicalmarkersofneuronalischemiaandimprovedrateofrecoveryaftercervicaldecompressioninpatientswhoreceivedRIPC.臨床上可接受的腦預(yù)處理的手段正在尋找中。揮發(fā)性麻醉藥也是如此，對(duì)比機(jī)械遠(yuǎn)端缺血預(yù)處理（RIPC），藥理腦預(yù)處理變得黯然失色。臨床研究證實(shí)，血壓袖帶圍繞患者的上臂進(jìn)行200毫米汞柱壓力間隔3個(gè)5分鐘的膨脹，再灌注5分鐘，經(jīng)過(guò)一番心血管的程序和證據(jù)化驗(yàn)結(jié)果表明可改善預(yù)后，同樣的技術(shù)應(yīng)用于神經(jīng)外科可能會(huì)改善預(yù)后。RIPC的神經(jīng)外科患者的臨床研究正在進(jìn)行或者最近已經(jīng)完成，胡和他的同事已發(fā)表的研究報(bào)告減少缺血神經(jīng)元的生化標(biāo)志物和頸椎減壓后使用RIPC患者可提高恢復(fù)率。PotentialAlleviatingFactors潛在的緩解因素（4）Neurogenesis神經(jīng)再