Cortical Blood Flow and Cerebral Perfusion Pressure in.docx

Cortical Blood Flow and Cerebral Perfusion Pressure in.docx

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CorticalBloodFlowandCerebralPerfusionPressurein

CorticalBloodFlowandCerebralPerfusionPressureinaNewNoncraniotomyModelofSubarachnoidHemorrhageintheRat

JoshuaB.Bederson,MD;IsabelleM.Germano,MD;LorraineGuarino,BS

FromtheDepartmentofNeurosurgery,TheMountSinaiSchoolofMedicine,NewYork,NY.

CorrespondencetoJoshuaB.Bederson,MD,DepartmentofNeurosurgery,Box1136,TheMountSinaiSchoolofMedicine,1GustaveL.LevyPl,NewYork,NY10029.

Abstract

BackgroundandPurposeAcutecerebralischemiaaftersubarachnoidhemorrhage（SAH）isamajorcauseofmorbiditywhosepreciseetiologyisunclear.Thepurposeofthisstudywastoexaminetherelationshipsbetweencerebralperfusionpressure（CPP）andcorticalbloodflowduringSAHusinganewexperimentalmodelintherat.

MethodsCPP（meanarterialpressureminusintracranialpressure）,corticallaser-Dopplerflowmetry（LDF）,andelectroencephalogramwerecontinuouslyrecordedduringandafterSAHin16ventilatedrats.SAHwasproducedbyadvancinganintraluminalsuturefromtheexternalcarotidarterythroughtheinternalcarotidarterytoperforatethevesselnearitsintracranialbifurcation.

ResultsEightrats（50%）diedwithin24hoursofSAH.Inallrats,bloodwaswidelydistributedthroughoutthebasal,convexity,andinterhemisphericsubarachnoidspacesandthroughouttheventricularsystem.CPPdecreasedafterSAHataninitialrateof1.1±0.2mmHg/s,reachingitsnadir59±9secondsaftertheonsetofSAH.Duringthesameperiod,LDFfellatarateof1.4±0.3%/s（P=NSvsCPP）.Afterreachingitsnadir,CPProseatarateof0.4±0.01mmHg/s,butLDFcontinuedtofallat0.2±0.03%/s（P<.05vsCPP）reachinganadirof21.7±2.5%significantlylaterthanCPP（189.5±39safterSAH,P<.05）.NocorrelationwasfoundbetweenpeakchangesinCPPandLDF.ElectroencephalogramactivityfollowedthechangesinLDF,reachingnadirvalues289±55secondsafterSAH.

ConclusionsThesefindingsdemonstratethatalthoughreducedCPPcausestheinitialdecreaseincorticalbloodflowafterSAH,secondaryreductionsoccurringafterCPPhasreacheditsnadirarecausedbyotherfactorssuchasacutevasoconstriction.ThisnoncraniotomymodelofSAHintherathasseveraladvantagesoverexistingmodels.

KeyWords:

animalmodels•cerebralbloodflow•hemodynamics•subarachnoidhemorrhage•rats

Introduction

Subarachnoidhemorrhage（SAH）causesbraininjurybothacutelyandastheresultofdelayedvasospasm.Despiteprogressinunderstandingandtreatingdelayedischemia,acutebraindamageistheprimarycauseofmortalityafterSAH,1yetitsetiologyremainsunclear.Acutecerebralischemiaisanimportantcontributortobraindamageinthissetting,asdemonstratedinpatientswhodieshortlyafterSAH,inwhosebrainsextensiveischemicdamageisseen.2AcuteischemiafromSAHhasbeenattributedtodecreasedcerebralperfusionpressure（CPP）,3andthisissupportedbydatafromrepeathemorrhagesinhumanswithintracranialpressure（ICP）monitors.45However,braincomplianceisreducedbytheinitialbleedandmayleadtogreaterrisesinICPduringthesecondbleed.Experimentalstudiesoffirst-timehemorrhagesdemonstratethatCPPdoesnotdroptothepointofperfusionarrest.678PhysiologicaldatasuggestthatdecreasedCPPcannotfullyaccountforacuteischemicbraindamageafterSAH.567910However,previousstudieshaveusedtime-averagedorintermittentmeasurementsofcerebralbloodflow（CBF）thatmaynotdemonstrateacutechangesafterSAH.SuchchangescouldbeevaluatedbyuseofanexperimentalmodelwithcontinuousrecordingsofCBF.

CurrentlyavailableanimalmodelsofSAH6891011121314151617arelimitedbytheneedforcraniotomyandarachnoidaldissectionorsurgicalplacementofaninfusioncatheter,bytheuseofdorsalcisternsratherthanthebasalsubarachnoidspace,andbycatheter-induceddampeningofarterialpulsations,smallelevationsofICP,orlimiteddistributionofblood.

InthisstudyweinvestigatedanewratmodelofSAHthatavoidsmanyproblemsofcurrentlyavailablemodelsandallowscontinuousundisturbedmeasurementsofcorticalbloodflowandCPPduringthehemorrhage.Basedonpreliminaryresults,18ourprimaryhypothesiswasthatacuteSAH-inducedreductionsinCBFare,atleastinpart,independentofreductionsinCPP.

MaterialsandMethods

SurgicalPreparation

Allprocedureswereapprovedbyouraccreditedanimalcarecommittee.MaleSprague-Dawleyrats（n=22）weighing250to300gwerehousedunderdiurnallightingconditionsandgivenfreeaccesstofoodandwaterbeforeandaftertheexperiment.Theratswereanesthetizedwithchloralhydrate（350mg/kgIP）andintubatedtransorallywithapolyethylenecatheter（OD2.5mm）;anesthesiawasmaintainedwithinspiredhalothane（1%to2%inO2-supplementedroomair）.Therightfemoralarterywascannulatedformonitoringbloodgases,andventilationwasadjustedtomaintainarterialbloodgasesinthenormalrange（PCO2,37±1mmHg;PO2,140±3mmHg;pH7.37±0.01[mean±SEM]）.Bodytemperaturewasmonitoredwitharectalprobeandmaintainedat37°Cwithahomeothermicblanket（HarvardApparatus）.

Ratswereplacedinastereotaxicframe（Stoelting）modifiedtoallowlongitudinalrotationandpermitmanipulationswiththeratproneorsupine.Four1-mm-diameterburrholeswereplaced4mmlateral,2mmrostral,and2mmcaudaltobregma.Epiduralelectroencephalogram（EEG）electrodeswerehookedundertheedgeofeachburrholeandsecuredtothestereotaxicframe.Nasionreferenceandfemoralgroundelectrodeswereconnectedtoacustom-builtamplifier-computer（seebelow）toachieveabilateralhemisphericbipolarEEGmontage.

Formeasurementofcorticalbloodflow,a3-mmburrholewasmade5mmtotheleftofmidlineatthecoronalsuture,andalaser-Dopplerflowmetry（LDF）probe（0.8mmdiameter,modelP-433,VasamedicsInc）wasadvancedunderstereotaxiccontroltothecorticalepiduralsurfaceawayfromlargepialvessels.ThesidecontralateraltothesiteofSAHwaschosentoensurethatobservedchangeswereattributabletoSAHratherthantotransientocclusion.AmodificationofthetechniqueofBarthetal19wasusedtomonitorICP.Aburrholewasmadeinthemidlineoccipitalbonetoacceptastainlesssteelscrew.A25-gaugebutterflycannulaprimedwithsalineandattachedtoapressuretransducercenteredattheearbarswasadvancedthroughtheatlanto-occipitalmembraneintothecisternamagnauntilagoodICPwaveformwasobtained.Thecannulawassecuredtothescrewwithmethylmethacrylatecement.Theratwasthenrotatedintothesupinepositionwithallrecordingdevicesinplaceandkepttherefortheremainderoftheexperiment.

InductionofSAH

ThecerebralischemiamodelofZea-Longaetal20wasmodifiedtoproduceSAH.Inbrief,therightcarotidarterywasidentifiedalongwithallitsextracranialbranches,andtheexternalcarotidarterywasdissected,transecteddistally,andreflectedinferiorly.A3-0monofilamentsuturewithoneendsharpenedwasadvancedcentripetallyintotheexternalcarotidarterypastthecommoncarotidbifurcationandintotheinternalcarotidartery（ICA）.ThesuturewasadvanceddistallyintotheintracranialICAuntilresistancewasfelt（at18to20mm）andthenwaspushed3mmfurther,penetratingtheICAnearitsintracranialbifurcation（n=18）.Preliminarystudiesin4ratsshowedthatthesuturepenetratedtheICA,middlecerebralartery,oranteriorcerebralarterywithin1mmoftheintracranialbifurcation.Thesuturewasthenwithdrawnintotheexternalcarotidartery,reperfusingtheICAandproducingSAH（Fig1

）.18Thedurationofendovascularocclusionwas30secondsto4minutes.Foursham-operatedcontrolratsunderwentanidenticalprocedureexceptthatthesuturewasnotadvancedbeyondthepointofresistance;reperfusionoccurredafter4minutesofocclusion.Aftereachexperiment,theICPcatheterwascrimpedandcutatitsattachmenttotheoccipitalscrew,whichwasleftinsitu.Ratswerereturnedtosingle,warmedcageswhilestillintubatedforairwayprotection.Self-extubationoccurredastheratsrecoveredfromanesthesia,usuallywithin30minutes.Ratsunderwentneurologicalexaminationafterrecoveryfromanesthesiaand24hoursafterSAH,aspreviouslydescribed,21andwerekilledafterthesecondexamination.

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Figure1.Diagramshowsendovascularsuturetechniqueforinducingsubarachnoidhemorrhage.A3-0monofilamentsuturesharpenedatoneendisintroducedthroughtheexternalcarotidartery（eca）andadvancedthroughtheintracranialinternalcarotidartery（ica）,penetratingnearthebifurcation.Withdrawalofthesutureresultsinsubarachnoidhemorrhage.acaindicatesanteriorcerebralartery;mca,middlecerebralartery;pta,pterygopalatineartery;andcca,commoncarotidartery.

DataAcquisitionandStorage

Bloodpressure,LDF,ICP,andEEGwaveformswereprocessedandstoredonaMacintoshQuadra950（AppleComputerInc）byuseofcustomizedanalog-to-digitalsignalconversionandprocessinghardwareandsoftwarefromNationalInstruments（SCSI,NB-MIO16XL,LABVIEW3.0）.Thesystemwasconfiguredtoacquire16bipolarsignalsatsamplingratesof1024Hz.TheEEGsignalwasprocessedon-linewithafastFouriertransformat4-secondintervals,andtheresultingspectrumwasdividedintopowerbands.LDF,ICP,meanarterialpressure（MAP）,andtheamplitude（µV2）ofthedeltapowerband（1to4Hz）wereloggedat0.25Hz.CPP,definedasMAPminusICP,wascomputedforeachpairofsimultaneouslyloggeddatapoints.LDFdatawerenormalizedbycomparingeach4-secondepochtotheaverageofa