The impact of blood pressure hemodynamics in acute ischemic stroke: a prospective cohort study

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ORIGINALRESEARCH OpenAccessTheimpactofbloodpressurehemodynamicsin acuteischemicstroke:aprospectivecohortstudyLathaGantiStead1,4*,SailajaEnduri1,MFernandaBellolio1,AnunayaRJain1,LekshmiVaidyanathan1, RachelMGilmore1,RahulKashyap1,AmyLWeaver3andRobertDBrownJr2AbstractObjective: Toassessrelationshipsbetweenbloodpressurehemodynamicmeasuresandoutcomesafteracute ischemicstroke,includingstrokeseverity,disabilityanddeath. Methods: Thestudycohortconsistedof189patientswhopresentedtoouremergencydepartmentwithischemic strokeoflessthan24hoursonsetwhohadhemodynamicparametersrecordedandavailableforreview.Blood pressure(BP)wasnon-invasivelymeasuredat5minuteintervalsforthelengthofthepatient semergency departmentstay.SystolicBP(sBP)anddiastolicBP(dBP)weremeasuredforeachpatientandadifferential(the maximumminustheminimumBP)calculated.Threeoutcomeswerestudied:strokeseverity,disabilityathospital discharge,anddeathat90days.StatisticaltestsusedincludedSpearmancorrelations(forstrokeseverity),Wilcoxon test(fordisability)andCoxmodels(fordeath). Results: LargerdifferentialsofeitherdBP(p=0.003)orsBP(p<0.001)weresignificantlyassociatedwithmore severestrokes.AgreaterdBP(p=0.019)orsBP(p=0.036)differentialwasassociatedwithasignificantlyworse functionaloutcomeathospitaldischarge.ThosepatientswithlargerdifferentialsofeitherdBP(p=0.008)orsBP (0.007)werealsosignificantlymorelikelytobedeadat90days,independentlyofthebasalBP. Conclusion: Alargedifferentialineithersystolicordiastolicbloodpressurewithin24hoursofsymptomonsetin acuteischemicstrokeappearstobeassociatedwithmoreseverestrokes,worsefunctionaloutcomeandearly deathIntroductionStrokeisassociatedwithahighmortalityandsignificant long-termfunctionaldisability.Ofthe15million patientsaffectedbystrokeworldwideyearly,theWorld HealthOrganizationreportsalmostathirdofthese patientsdie,andanotherthirdarepermanentlydisabled. Hypertensionaccountsfornearly12.7millionstrokes worldwide[1]. Closeto80%ofacuteischemicstroke(AIS)patients haveanelevatedbloodpressure[2].Theelevationof bloodpressure(BP)post-AIShasamultitudeofcauses, rangingfromchronichypertensionandsympathetic stressresponsetostroke-relatedpathologyitself[3]. Previousstudieshaveshownthatthelocationofthe stroke[4]andthetypeofstroke[5]havesomebearing onthebloodpressureresponsenotedacutelypost-AIS. Somecohortstudieshavealsosuggestedthatadmission bloodpressureprognosticatesoutcomeafteracute ischemicstroke[6],whereasothersconductedsimilarly haverefutedtheaboveresult[7,8]. Treatmentstrategiesforhypertensionpost-AISare centeredontheaimtosalvagetheischemicpenumbra [9],butthemanagementofhypertensioninpatients withacuteischemicstrokehasbeengreatlyunder debate,withnoclearconsensusonhowmuchorhow soontolowerthepressure[10]. Itiswellknownthatnormallycerebralauto-regulation maintainsperfusionoverawiderangeofsystemicblood pressures.Duringtheacutephaseofstroke,cerebral auto-regulationbecomesdysfunctional[11],andcerebral perfusionpressurebecomesdirectlydependentonsystemicpressure.Asaresultcerebralbloodflowbecomes passive,withalinearrelationshipbetweensystemicBP andcerebralbloodflowacrossawiderangeofpressure *Correspondence:lstead@ufl.edu1DepartmentofEmergencyMedicine,MayoMedicalSchool,Rochester,MN, USA FulllistofauthorinformationisavailableattheendofthearticleStead etal InternationalJournalofEmergencyMedicine 2012, 5 :3 http://www.intjem.com/content/5/1/3 2012Steadetal;licenseeSpringer.ThisisanOpenAccessarticledistributedunderthetermsoftheCreativeCommonsAttribution License(http://creativecommons.org/licenses/by/2.0),whichpermitsunrestricteduse,distribution,andreproductioninanymedium, providedtheoriginalworkisproperlycited.

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values.EvenarelativelysmalldegreeofsystemicBP reductioncouldcauseasignificantriskofhypoperfusion andischemia[12].Moreover,thereisalsoimpairment ofvasomotortoneafterAIS[13].Hence,ithasbeen deliberatedwhethersystemicpressurevariationhasany consequenceonstrokeseverity,functionaldisabilityor death. Previouslypublisheddat ademonstratethatacute bloodpressurevariabilitywithinearlyhoursofpresentationtotheemergencydepartment(ED)isassociated withanincreasedriskofdeathat90days[14].Both veryhighandverylowinitialbloodpressuresare knowntobepredictorsofworseoutcomesinAIS [15,16].WithpublishedguidelinesrecommendingpermissivehypertensionintheearlycourseofAIS[17], andpromisingresultsofcurrentresearchonhemodynamicaugmentationinAIS,acautiousapproachto treatmentofhypertensioninAISisthecallofthe hour[18]. Wesoughttodetermineiftherewasanyassociation betweenfluctuationsinsystolic(sBP)ordiastolic(dBP) bloodpressurewithin24hoftheonsetofAISand strokeseverity,functionaldisabilityandmortality.MethodsThestudycohortforthisIRB(institutionalreview board)approvedprospectivecohortfollow-upstudy consistedofprospectivelyenrolledconsecutiveadult patientspresentingtoouracademicEDwithAIS. PatientswithAISonset>24hpriortopresentation/ indeterminabletimeofonsetandpatientswithnonreviewableconsecutivevitalswereexcludedfromthe finalcohort. Bloodpressure(BP)wasnon-invasivelymeasuredat5minintervalsforthelengthofthepatient sEDstaywith thePhilipsM3046APatientMonitoringSystem(Philips MedicalSystems,Andover,MA).Thesystemdesign usestheoscillometricmethod,measuringthepulsed amplitudeofpressurechangesinthecuffasitdeflates, todemarcatethesystolican ddiastolicbloodpressures. The24-hdifferentialpressure,definedasthedifference betweenthemaximumandtheminimumpressures,was calculatedforboththesBPandthedBP. Besidestheroutinedemographics,dataonstroke severityonarrival,disabilityathospitaldischargeand deathat90dayswerecollectedforthestudycohort. StrokeseverityonarrivalwasmeasuredbytheNational InstitutesofHealthStrokeScale(NIHSS),anddisability atdischargewasmeasuredbythemodifiedRankin score(mRS).Poorfunctionaloutcomewasdefinedasa mRS 3atdischarge.Deathat3monthswasascertainedbyscriptedtelephonefollow-up,statedeathcertificatesandelectronicmedicalrecordswithpriorpatient authorization. JMP8.0wasusedfortheanalysisusingSpearmancorrelations(forstrokeseverity),Wilcoxontest(fordisability)andCoxmodels(fordeath).ResultsDemographicsandcharacteristicsofthecohortare summarizedinTable1.With58.7%males,thecohort hadameanageof74years(SD=15.0).Astudyofthe TOASTclassificationofthetypeofstrokesrevealedan unusuallyhighnumberofcardio-embolicstrokesinour cohort(50.3%). Themediannumberofbloodpressurereadingswas7, withaninter-quartilerange(IQR)of4to10.Themediansystolicbloodpressureonarrival(baselinesBP)was 161mmHg(IQR144to188mmHg),andthemedian diastolicbloodpressure(baselinedBP)was80mmHg (IQR70to90mmHg).ThemediandiastolicBPdifferentialwas27mmHg(IQR16to41mmHg),andthe mediansystolicBPdifferentialwas33mmHg(IQR19 to53mmHg). Astatisticallysignificantrelationwasfoundbetween baselinehypertensionanddeathat90days,whendefiningbaselinehypertensionasbaselinesBP=170mmHg and/orbaselinedBP=110mmHg.Atotalof41.07% patientshadbaselinehypertensionusingtheabovedefinition.Therelativeriskofmortalityat90daysfor patientswithbaselinehypertensionwas2.05witha95% confidenceintervalof1.02-4.10whencomparedto patientspresentingwithlowerBP( p =0.038). Wealsodividedthecohortintothosewithorwithout oneormoreepisodesoffrankhypotensionusingthe minimummeasureddBPcutoffof70mmHg.Sixty-five percentofthecohorthaddBP<70mmHgsometime duringthestayinED.Whenthisgroupwascompared Table1StudycohortdemographicsandcharacteristicsDemographicsandcharacteristics N =189 Malegender111(58.7%) Age(years) Mean(SD) 74.0(15.0) Range 26-98 TOAST 1.Largevessel 20(10.6%) 2.Cardioembolic 95(50.3%) 3.Smallvessel 29(15.3%) 4.Other,nocausesormultiplecauses45(23.8%) NIHSS Mean(SD) 9.9(8.5) Median(IQR) 6.0(3.8-15) Range 0-37 Rankinscoreatdismissal 0-2 58(31.0%) 3-6 129(69.0%) Stead etal InternationalJournalofEmergencyMedicine 2012, 5 :3 http://www.intjem.com/content/5/1/3 Page2of4

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tothosewithdBP>70mmHg,therewashoweverno statisticaldifferenceinstrokeseverity,outcomesof deathat90daysormRSatdischarge. ThemedianNIHSSscoreatarrivalwas6.0,withan interquartilerangeof3.75to15.0.Patientswithmore severestrokeshadlargerdifferentialdBP( p =0.003) anddifferentialsBP( p <0.001)(Spearmancorrelation r =0.22and r =0.26,respectively).TherewasnoassociationfoundbetweenbaselinehypertensionandNIHSS scoreonarrival( p =0.4734). Atotalof129patients(68.3%)hadaRankinscoreof 3ormoreathospitaldischarge(badoutcome).The mediandifferentialdBPforaRankinscore0-2was22.5 mmHg,whileforaRankinscoreof3ormorewas29 mmHg.ThemediandifferentialsBPforaRankinscore 0-2was26mmHg,whileforaRankinscoreof3or morewas36mmHg.AgreaterdBP( p =0.019)orsBP ( p =0.036)differentialwasassociatedwithasignificantlyworsefunctionaloutcomeathospitaldischarge (Table2).Again,aswithNIHSS,therewasnorelation betweenbaselinehypertensionandbadoutcome(p = 0.486). Atotalof40deaths(21.2%)occurredwithinthefirst 90days.ThosewithlargerdifferentialsofeitherdBP( p =0.008)orsBP(0.007)weresignificantlymorelikelyto bedeadat90days(Table3).Thisassociationretained statisticalsignificanceeven afteradjustingforstroke severity.DiscussionMosthemodynamicvariables,includingsystolicblood pressure,diastolicbloodpressure,meanarterialpressure pulsepressureandheartrate,havebeenassociatedwith poorfunctionaloutcomefollowingstroke[19].Likeearlierstudies,wetoofoundthatbaselinehypertensionwas associatedwithahigherriskofdeathat90dayspoststroke,althoughitwasnotassociatedwithstrokeseverityatpresentation.Forourcohortthishypertensioncutoffwasabloodpressureof170/110mmHg. Withtheongoingdiscussiononmanagementofblood pressureinacutestageofisc hemicstroke,researchers havetriedtoestablishrelat ionshipsbetweenoutcomes andbloodpressure.OnesuchstudybyToyodaetal.in 2009reportedthatsystolicbloodpressurevaluesbetween 12and36hpost-admissionwerepredictiveofneurologicaldeterioration,buttheauthorsdidnotfindthesame forbloodpressurevalueswithintheinitial6h[20]. Recentlyconcernhasbeenexpressedovertherelation betweenhigherpre-treatme ntsystolicbloodpressure andpoorre-canalizationinpatientstreatedwithIVtPA [21].Ourownresearchin2006revealedthatwidefluctuationsinbloodpressureinthefirst3hofemergency departmentstaypredictedmortalityover3months post-stroke[14]. Thisstudybuildsonourpriorworkonbloodpressure andacuteischemicstroke(14,15),afollow-uptoour earlierstudy.Wequestionedwhetheritwasindeedthe BPdifferentialthatresultedinpooroutcomesorrather anepisodeofhypotensionduringtheearlyEDcourse thatwastheculprit.Whenwecomparedthehypotensiveandnon-hypotensivegroups,wefoundthatthere wasnodifferenceintheoutcomesofdeathorfunctional Rankinscores,suggestingthatBPfluctuationwasan independentpredictorofpooroutcome.TheVISTA collaborationpresentedsimilarfindings,highlighting thatfluctuationsinsystolicbloodpressurewereassociatedwithworseoutcomepost-stroke[22]. Ourstudyalsofoundthatpatientswithmoresevere strokeshadgreaterfluctuationsinbloodpressure,but nottheinitialbaselinebloodpressure.Thisledtothe argumentthatitwastheinit ialseverityofthestroke thattranslatedtotheworseoutcome.However,when weadjustedfortheNIHSSseverityofstrokes,wefound thatthesBPdifferentialanddBPdifferentialco-related independentlywithdeathat90days. Hypotensionrelativetothebaseline,causingregional hypo-perfusion,isanincreasinglyunderstoodconcept immediatelyfollowinganischemicstroke.Theresultsof thepresentstudyandensuingdiscussionmaytempt onetosurmisethatbloodpressurevariabilityisbadand thatthereforesomehowtigh tlycontrollingitwithina specifiedrangeisthenextlogicalstep.Cautionmustbe exercisedhere.Onecannotassumethat correcting the associationwillresultinimprovedoutcome.Itisindeed Table2ComparisonbetweenRankinscoreandBPBP(mmHg) Rankinscore 0-2 ( n =41) Rankinscore 3-6 ( n =88) pvalue BaselinesBP(meanSD)170.835.3166.532.20.490 BaselinedBP(meanSD)80.921.080.222.00.855 ChangesBP(median, 25%-75%IQR) 26.0,15.5-48.536.0,22.0-53.5 0.036 ChangedBP(median,25%75%IQR) 22.5,12.0-37.029.0,18.5-45.0 0.019p-valueslessthan0.05consideredstatisticallysignificantareshowninbold. Table3ComparisonbetweenmortalityandBPBP(mmHg) Aliveat90 days ( n =149) Deadat90 days ( n =40) pvalue BaselinesBP(meanSD)168.832.4163.834.70.449 BaselinedBP(meanSD)80.720.380.425.20.956 ChangesBP(median, 25%-75%IQR) 30.0,17.0v51.542.5,29.0-61.0 0.033 ChangedBP(median,25%75%IQR) 25.0,14.0v38.035.0,23.3-51.8 0.006p-valueslessthan0.05consideredstatisticallysignificantareshowninbold.Stead etal InternationalJournalofEmergencyMedicine 2012, 5 :3 http://www.intjem.com/content/5/1/3 Page3of4

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thenextstepinclinicalinvestigation,butnotquite readyforimplementationintoclinicalpracticebefore thehypothesisisdefinitivelyinvestigatedinacontrolled trial.ConclusionFluctuationsinbloodpressureinthesettingofacute ischemicstrokeappeartoimpartanegativeimpacton strokeseverity,functionaloutcomeanddeathat90 days.Thisisahypothesis-generatingstudythatasks whetherpharmacologiccontr olofthesebloodpressure fluctuationswouldresultinimprovedclinicaloutcomes.PatientconsentThisprotocolwasapprovedbythedepartmentofEmergencyMedicineResearchCommittee(minuteexcerpt attached).ItwasalsoapprovedbytheMayoClinicInstitutionalReviewBoardasprotocol1054-04.CompetinginterestsstatementsTheauthorsdeclarethattheyhavenocompeting interests.Authordetails1DepartmentofEmergencyMedicine,MayoMedicalSchool,Rochester,MN, USA2DepartmentofNeurology,MayoMedicalSchool,Rochester,MN,USA3DivisionofBiostatistics,MayoMedicalSchool,Rochester,MN,USA4DepartmentofEmergencyMedicine,UniversityofFlorida,1329SW16thStreet,Gainesville,FL,32610,USA Authors contributions LGSconceivedthestudy,collectedthedataandwrotethepaper.SE,MFB, AJ,LV,RG,andRKcollecteddataandreviewedthepaper.ALWanalyzedthe data.RDBsupervisedtheproject.Allauthorsreadandapprovedthefinal manuscript. Received:11July2011Accepted:17January2012 Published:17January2012 References1.AmericanHeartAssociation: InternationalCardiovascularDisease Statistics StatisticalFactSheet Populations,2008Update.,Available athttp://www.who.int/whr/2002/en/whr02_en.pdf. 2.GilmoreRM,MillerSJ,SteadLG: Severehypertensionintheemergency departmentpatient[review]. EmergMedClinNAm 2005, 23 :1141-1158. 3.QureshiAI: Acutehypertensiveresponseinpatientswithstroke: pathophysiologyandmanagement[review]. Circulation 2008, 118 :176-187. 4.DickerD,MayaI,VasilevskyV,GofmanM,MarkowitzD,BeilinV,SaridM, YosefyC: Bloodpressurevariabilityinacuteischemicstrokedependson hemisphericstrokelocation. BloodPress 2006, 15(3) :151-156. 5.MarcheselliS,CavalliniA,TosiP,QuagliniS,MicieliG: Impairedblood pressureincreaseinacutecardioembolicstroke. JHypertens 2006, 24(9) :1849-1856. 6.AbboudH,LabreucheJ,PlouinF,AmarencoP: Highbloodpressurein earlyacutestroke:asignofapooroutcome? 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Acta NeurochirSuppl(Wien) 1993, 59 :3-10. 13.RobinsonT,PotterJ: Cardiopulmonaryandarterialbaroreflex-mediated controlofforearmvasomotortoneisimpairedafteracutestroke. Stroke 1997, 28(12) :2357-2362. 14.SteadLG,GilmoreRM,VedulaKC,WeaverAL,BrownRDJr,DeckerWW: ImpactofAcuteBloodPressureVariabilityonIschemicStrokeOutcome. Neurology 2006, 66(12) :1878-1881. 15.SteadLG,GilmoreRM,DeckerWW,WeaverAL,BrownRDJr: Initial emergencydepartmentasapredictorofsurvivalafteracuteischemic stroke. Neurology 2005, 65(8) :1179-1183. 16.VemmosKN,TsivgoulisG,SpengosK, etal : U-shapedrelationship betweenmortalityandadmissionbloodpressureinpatientswithacute stroke. JIntMed 2004, 255 :257-265. 17.AdamsHPJr,delZoppoG,AlbertsMJ,BhattDL,BrassL,FurlanA, GrubbRL,HigashidaRT,JauchEC,KidwellC,LydenPD,MorgensternLB, QureshiAI,RosenwasserRH,ScottPA,WijdicksEF: Guidelinesfortheearly managementofadultswithischemicstroke:aguidelinefromthe AmericanHeartAssociation/AmericanStrokeAssociationStrokeCouncil, ClinicalCardiologyCouncil,CardiovascularRadiologyandIntervention Council,andtheAtheroscleroticPeripheralVascularDiseaseandQuality ofCareOutcomesinResearchInterdisciplinaryWorkingGroups:the AmericanAcademyofNeurologyaffirmsthevalueofthisguidelineas aneducationaltoolforneurologists. Stroke 2007, 38(5) :1655-1711. 18.JainAR,BellolioMF,SteadLG: Treatmentofhypertensioninacute ischemicstroke. 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BloodPressMonit 2009, 14(1) :20-25.doi:10.1186/1865-1380-5-3 Citethisarticleas: Stead etal .: Theimpactofbloodpressure hemodynamicsinacuteischemicstroke:aprospectivecohortstudy. InternationalJournalofEmergencyMedicine 2012 5 :3.Stead etal InternationalJournalofEmergencyMedicine 2012, 5 :3 http://www.intjem.com/content/5/1/3 Page4of4


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