急性缺血性卒中溶栓治疗相关因素分析

1急性缺血性卒中溶栓

治疗相关因素分析定义脑梗死：指因脑部血流循环障碍、缺血、缺氧所致的局限性脑组织的缺血性坏死或软化。溶栓治疗：静脉溶栓、动脉溶栓及机械取栓等治疗。2

ThecentralpathophysiologicalhypothesisunderlyingAIStherapyisthatafteracerebralarterybecomesoccluded,thereissomeamountofhypoperfusedbraintissueatriskfor

permanentinfarctionthatcouldbesalvagedbyexpeditiousrestorationofbloodflow.治疗目的Preventingtheischemicpenumbrafromprogressingtoirreversibleinfarctionisthegoalofacutereperfusiontherapy3Schematicrepresentationofregionsofhypoperfusedbraintissuefollowingacuteocclusionofthemiddlecerebralartery.Theischemiccoreisanareaofirreversibleischemiaandcelldeath;

ischemicpenumbra,potentiallysalvageabletissuewithpromptreperfusion;benignoligemia,decreasedperfusionbutnoinfarctionriskregardlessoftreatment.Theinfarctcorecanenlargeintothepenumbraifreperfusionisnotsuccessful.缺血半暗带4Diffusion-weightedimagediffusion-weightedMRIshowingahyperintensityconsistentwithirreversibleischemia(ischemiccore)inthedeepperforatingterritoryoftherightmiddlecerebralarteryaffectingthecaudate,internalcapsule,andlentiformnucleus.5PWIatthesamelevelastheDWIshowedamuchlargerareaofhypoperfusion.PWIusescontrastmaterialtoestimatecerebralbloodflow.Thecolorscalerepresentsmeantransittimeofacontrastbolus;blueindicatesnormaltransittimeandshadesofgreen,yellow,orange,andredindicatedelayintransittime(ischemia).TheregionoftheischemiccoreasdefinedintheDWIshowsareasofnocontrast(black)inthePWI,indicativeofirreversibleinjury.Perfusion-weightedimage6缺血半暗带Overthefirstfewminutestohoursafteranacutearterialocclusion,ischemicpenumbraltissueprogressestoaninfarctcore.Itisestimatedthatforeveryminuteanarteryisoccludedduringanischemicstroke,2millionneuronsdie,whichover10hoursisequivalenttotheexpectedneuronallossoccurringwith26yearsofnormalaging.thepotentialbenefitofrestoringbloodflowreducesovertime.

7再灌注治疗Strategiestorapidlyreperfusebraintissueatriskofinfarctionincludeintravenousandintra-arterialadministrationofthrombolyticdrugsandtheuseofvariousthrombectomydevicesunderangiographicandfluoroscopicguidancethrombolyticdrugs8静脉溶栓机制Thrombolyticagentsaimatdisruptingthefibrin-richclotthatiscreatedinresponsetoinjuryoftheendothelium.Byactivatingplasminogen,theadministrationofthrombolyticsleadstoanincreasedproductionofplasmin,whichdissolvesthefibrinbondsintheclot.9In1995,theNINDS(NationalInstituteofNeurologicalDisordersandStroke)tPA(tissueplasminogenactivator)StrokeStudyGrouppublishedtheresultsofalargemulticenterclinicaltrialdemonstratingefficacyofintravenoustPAbyrevealinga30%relativeriskreduction(absoluteriskreduction11%–15%)comparedwithplaceboat90daysinthelikelihoodofhavingminimalornodisability.Sinceapprovalin1996,tPAremainstheonlydrugtreatmentforacuteischemicstrokeapprovedbytheUSFoodandDrugAdministration.静脉溶栓10静脉溶栓strokeremainsaleadingcauseofseriouslong-termdisabilityanddeathworldwide；almost20yearssinceitsapproval,anabundanceofresearchandclinicaldatahassupportedthesafeandefficacioususeofintravenoustPAinalleligiblepatients.itremainssubstantiallyunderutilizedIVtPA,yethighlyefficaciousfirst-linetreatment.11ChallengestotheutilizationoftPAinclude：①narroweligibilityandtreatmentwindows;②riskofsymptomaticintracerebralhemorrhage;③perceivedlackofefficacyincertainhigh-risksubgroups;④alimitedpoolofneurologicalandstrokeexpertiseinthecommunity.ChallengestotheutilizationoftPA12相对禁忌症3小时内溶栓1、轻型或快速改善的卒中2、妊娠3、癫痫发作后出现的神经功能损害症状4、近2周内有大型外科手术或严重外伤5、近3周内有胃肠道或泌尿系出血6、近3个月内有心肌梗死史13相对禁忌症3-4.5小时内溶栓1、年龄大于80岁2、严重卒中（NIHSS评分大于25分）3、口服抗凝药物（不考虑INR水平）4、有糖尿病和缺血性卒中病史14Theimportanceoftime-totreatmentwitheverypassingminuteuntilreperfusionisachieved,about2millionneuronsand14billionsynapsesarelost.

Mostrecently,astudyof58,353tPA-treatedpatientshighlightedthatforevery15-minuteimprovementintime-to-treatment,patientswerelesslikelytodie，experiencesICHandweremorelikelytobeambulatoryatdischarge;15Theimportanceoftime-totreatmentBasedonthemostcurrent2013AHA/ASAguidelineupdateregardingfibrinolysisinacutestroke,tPAisrecommendedforeligiblepatientswhopresentwithin3hoursofstrokeonsetandupto4.5hoursineligiblepatients;thefollowingadditionalexclusions:patients>80yearsofage,thosetakingoralanticoagulantsregardlessofinternationalnormalizedratio(INR),baselineNIHSS>25,thosewithimagingevidenceofischemicinjuryinvolvingmorethanonethirdofthemiddlecerebralarteryterritory,andthosewithahistoryofbothstrokeanddiabetesmellitus16ThebenefitsandrisksofIVthrombolysisincertainsubgroups17Mildandrapidlyimprovingstrokes

mildand/orrapidlyimprovingstrokeswillfollowanaturalcourseoffavorablefunctionaloutcomeinspiteofacceptingtheadditionalriskoftPA.alarge-vesselocclusiononmagneticresonanceangiographycorrespondingtotheacutestrokein33%ofpatientsexcludedfromtPAduetoRIMS.28.3%ofuntreatedpatientswithRIMSnotdischargedhomeand28.5%unabletoambulatewithoutassistanceatdischarge.18MildandrapidlyimprovingstrokesWhereasalloftheabovestudiesevaluatedoutcomesattimeofdischarge,Nedeltchevetalevaluated3-monthoutcomesforuntreatedpatientswithRIMSandfoundthat75%hadafavorableoutcome;threesmallstudieshaveshownasignificantimprovementinclinicaloutcomewithnoincreasedriskofhemorrhageintPA-treatedRIMSpatients;19Athirdofthepatientspresentingwithischemicstrokeareovertheageof80;

elderlypatientsmaybeatanincreasedriskofICHduetocerebralamyloidangiopathy,impairedrenalclearance,andfrailvasculature;Manyclinicianswithholdtreatmentduetofearthatageisassociatedwithpoorprognosisandincreasedriskofhemorrhage;Olderage20OlderageOfthe49patientsovertheageof75includedintheNINDStPAtrial,outcomewasrelatedtoage-by-neurologicdeficitbutdidnotaltertreatmenteffect.Inaddition,agedidnotindependentlyincreasetheriskofhemorrhage.TheThirdInternationalStrokeTrial(IST-3)wasthefirstprospectiverandomizedtrialtoincludeasizablenumberofpatients﹥80years(53%).AsubgroupanalysisfromIST-3suggestedagreaterbenefitfromtPAinpatientsolderthan80comparedwiththeiryoungercounterparts(P=0.027).Basedontheseresults,tPAshouldnotbewithheldbasedpurelyonage,andinfact,patientsolderthan80maydoaswellifnotbetterwithtreatmentcomparedwithcontrol.21Strokemimics22StrokemimicsTheneedforrapidrecognitionandtreatmentofAISpotentiatesthelikelihoodofadministeringtPAtoastrokemimic;ThefractionofstrokemimicsamongtPA-treatedpatientsinvariouscohortshasbeenreportedbetween1%and31%,withcommunityhospitalsreportingratesashighas25%–29%;thesepercentagesreflectthelackofstandardmimicdefinitionsand/orinaccuraciesindiagnosisreporting;Commoncharacteristicsofstrokemimicsareyoungage,femalesex,noorfewbaselineriskfactors,lefthemisphericsyndromes,andmilderpresentingstrokeseverity.23aphasia,particularlywhenglobalandnotpresentingwithanyotherdeficits,isoneofthemostcommonlycitedpresentationsofstrokemimics;ThesafetyoftPAinstrokemimicswasevaluatedinamulticenterobservationalstudythatrevealedansICHrateof1.0%(CI0.0–5.0)inmimicscomparedwith7.9%(CI7.2–8.7)inimaging-confirmedischemicstroke;treatedstrokemimicsweremorelikelytoexperienceanexcellentoutcomeat3monthscomparedwithAIS(75%versus39.5%;P,0.0001)Strokemimics2435%ofAISpatientseligibleforreperfusiontherapiesareunderanantiplateletregimen.TheproportionofsICHinpatientstreatedwithantiplatelettherapywithintheprevious48hourswas9%forthoseallocatedr-tPAversus1%incontrol,comparedwith5%forr-tPAand1%controlforthosewithnorecentantiplatelettherapy.Priorantiplateletuseandclinicaloutcome25

whenmultivariateanalyseswereconducted,priorantiplateletusewasnotassociatedwithICHincreasedrisk,aswellas,withotherclinicaloutcomes;Priorantiplateletusehastobeconsideredasanindicatorofpastvasculardisease,whichisbyitselfassociatedwithunfavorableoutcome;nosignificantdifferencewasfoundinhemorrhagiccomplicationand90-daymortalityratesaccordingtopriorantiplateletuseInsummary,onthebasisofavailableliterature,priorantiplateletuseshouldnotconsideredasacriterionofineligibilityforanyAISrevascularization.

Priorantiplateletuse26TheaimsoftheThirdInternationalStrokeTrial(IST-3)weretoestablishwhetherawidergroupofpatientswouldbenefitfromstrokethrombolysisandwhichcategoriesofpatientsweremostlikelytobenefitorbeharmedbytreatment.

AlteplaseforAcuteIschemicStrokeOutcomesbyClinicallyImportantSubgroupsintheThirdInternationalStrokeTrial27IST-3recruited3035patientswhowererandomizedtor-tPAorcontrolwithin6hoursofstrokeonset;themainresultsandprincipalprespecifiedsubgroupanalyseshavebeenpreviouslypublished.StrokeonJuly3,2016patientshadtomeetthefollowingcriteria:1.symptomsandsignsofclinicallydefiniteacutestroke;2.thetimeofstrokeonsetwasknown;3.treatmentcouldbestartedwithin6hoursofonset;4.CTorMRIhadreliablyexcludedbothintracranialhemorrhageandstructuralbrainlesions,whichcouldmimicstroke(eg,cerebraltumor);

28BeforeIST-3,dataaboutthefrequencyofhemorrhagictransformationofcerebralinfarctioninthenaturalhistoryofuntreatedstroke:largevolumesofinfarction,masseffect,earlytissuehypoattenuation,andolderage(age>70years);

recentsystematicreviewofsICHinpatientstreatedwiththrombolysis:highplasmaglucose;prioruseofaspirin;statins;leukoariosisis;atrialfibrillation;diabetesmellitus;previousischemicheartdisease;previouscerebralvasculardisease;andcongestivecardiacfailure.StrokeonJuly3,2016themajorrisksofhemorrhagictransformation29weonlyobservedamarginallysignificantinteractiononsICHwithpriorantiplateletuse,mainlyattributabletoprioraspirinuse;butthiswasnotassociatedwithaneffecton6-monthfunctionaloutcome.Oneexplanationforthismightbeasaresultofacounterbalancinglaterbenefitofantiplatelettreatment,perhapsbymaintainingvesselpatencyaftersuccessfulrecanalizationthemarginallysignificantrisks30WewereunabletoidentifyanyparticularsubgroupwithanegligibleriskofsICH,eventhosewithstrokeseverityofNIHSS<6wereobservedtohaveanearlysICHrateof3%andthose