Low spontaneous variability in cerebral blood flow velocity in non-survivors after cardiac arrest

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Resuscitation

j o ur na l h o me p a g e:ww w . e l s e v i er . c o m / l o c a t e / r e s u s c i t a t i o n

Clinical

paper

Low

spontaneous

variability

in

cerebral

blood

flow

velocity

in

non-survivors

after

cardiac

arrest

夽

J.M.D.

van

den

Brule

,

E.J.

Vinke,

L.M.

van

Loon,

J.G.

van

der

Hoeven,

C.W.E.

Hoedemaekers

DepartmentofIntensiveCare,RadboudUniversityNijmegenMedicalCentre,Nijmegen,TheNetherlands

a

r

t

i

c

l

e

i

n

f

o

Articlehistory:

Received14October2016

Receivedinrevisedform5December2016 Accepted12December2016

Keywords: Meanflowvelocity Meanarterialpressure Variability

Cerebralbloodflow Coëfficiëntofvariation

a

b

s

t

r

a

c

t

Objective:Toinvestigatespontaneousvariabilityinthetimeandfrequencydomaininmeanflowvelocity

(MFV)andmeanarterialpressure(MAP)incomatosepatientsaftercardiacarrest,anddeterminepossible

differencesbetweensurvivorsandnon-survivors.

Methods:AprospectiveobservationalstudywasperformedattheICUofatertiarycareuniversity

hos-pitalintheNetherlands.Westudied11comatosepatientsand10controls.MFVinthemiddlecerebral

arterywasmeasuredwithsimultaneouslyrecordingofMAP.Coefficientofvariation(CV)wasusedasa

standardizedmeasureofdispersioninthetimedomain.Inthefrequencydomain,theaveragespectral

powerofMAPandMFVwerecalculatedintheverylow,lowandhighfrequencybands.

Results:InsurvivorsCVofMFVincreasedfrom4.66[3.92–6.28]to7.52[5.52–15.23]%atT=72h.In

non-survivorsCVofMFVdecreasedfrom9.02[1.70–9.36]to1.97[1.97–1.97]%.CVofMAPwaslow

immediatelyafteradmission(1.46[1.09–2.25]%)andremainedlowat72h(3.05[1.87–3.63]%)(p=0.13).

TherewerenodifferencesinCVofMAPbetweensurvivorsandnon-survivors(p=0.30).Wenoticed

significantdifferencesbetweensurvivorsandnon-survivorsintheVLFbandforaveragespectralpower

ofMAP(p=0.03)andMFV(p=0.003),wherebythepowerofbothMAPandMFVincreasedinsurvivors

duringadmission,whileremaininglowinnon-survivors.

Conclusions:Cerebralbloodflowisalteredaftercardiacarrest,withdecreasedspontaneousfluctuations

innon-survivors.Mostlikely,thesechangesaretheconsequenceofimpairedintrinsicmyogenicvascular

functionandautonomicdysregulation.

©2016TheAuthor(s).PublishedbyElsevierIrelandLtd.ThisisanopenaccessarticleundertheCCBY

license(http://creativecommons.org/licenses/by/4.0/).

Introduction

The incidence of post-anoxic encephalopathy after cardiac arrestishigh,resultinginhighmortalityandmorbidity.1_Crucialin

theICUtreatmentaftercardiacarrestistocreateanoptimal envi-ronment,forcerebralrecoveryincludingadequatecerebralblood flow(CBF).

Abbreviations:ABP,arterialbloodpressure;CBF,cerebralbloodflow;CV, coef-ficientofvariation;HF,highfrequency;LF,lowfrequency;MAP,meanarterial pressure;MCA,middlecerebralartery;MFV,meanflowvelocity;TCD,transcranial Doppler;VLF,verylowfrequency.

夽 ASpanishtranslatedversionoftheabstractofthisarticleappearsasAppendix inthefinalonlineversionathttp://dx.doi.org/10.1016/j.resuscitation.2016.12.005. ∗ Correspondingauthorat:RadboudUniversityNijmegenMedicalCentre, Depart-mentof Intensive Care,P.O. Box9101, 6500 HB Nijmegen,The Netherlands. Fax:+31243541612.

E-mailaddress:J.vandenBrule@radboudumc.nl(J.M.D.vandenBrule).

Undernormalcircumstances,CBFexhibitsrapidspontaneous fluctuations,inordertomaintaincerebrovascularhomeostasis.The adaptationofCBFtoperturbationsincerebralperfusionpressure isregulatedbycentralcontrolmechanisms2,3_{andbyanintrinsic}

variationviamyogenicvasoconstriction.4,5

Arterial pressure also varies spontaneously. Beat-to-beat changesinarterialpressureareregulatedbycardiovascularcontrol mechanisms,suchasthearterialbaroreflex,6_{therenin-angiotensin}

system,7 _{the vascular myogenic response}8 _{and the endothelial}

nitricoxiderelease.9_{Bloodpressurefluctuationselicitedby}

sympa-theticmodulationofvasculartoneoccurinthelowfrequencyband (LF,0.07–0.15Hz).Intrinsicvascularmyogenicchangesinarterial bloodpressureaffectsboththeLFandverylowfrequency(VLF, 0.02–0.07Hz)componentsofcardiovascularvariability. Endothe-lialNOaffectsbloodpressurevariabilityinthehighfrequencyrange inanimals(HF,0.15–0.40Hz).TheeffectofNOinhumansis con-troversialsincetheHFbandislargelydependentonrespiration. Theimpactoftherenin-angiotensinsystemonbloodpressure vari-abilityisunknown.Towhatlevelcerebralbloodflowvariabilityis http://dx.doi.org/10.1016/j.resuscitation.2016.12.005

dependentonpressurevariabilityisamatterofdebateinhealthy subjectsandyetunknowninpatientsaftercardiacarrest.10

Blood pressure variability is a well known risk factor for end organ damage in patientswithchronic conditions suchas hypertension.11,12 _{In acute ischemicstroke, beat to beat blood}

pressurevariabilitywasassociatedwithdeathanddependencyat 30days.13_{Incontrast,inacutebraininjurypatientsnodifferences}

inbloodpressurevariabilitybetweensurvivorsandnon-survivors weredetected.14_{Theimpactofbloodpressurevariabilityinthe}

timeandfrequencydomainsinacutebraindamagesuchasafter cardiacarrest,isunknown.

Themainobjectiveofourstudywastodeterminethe sponta-neousvariabilityinthetimeandfrequencydomaininmeanflow velocity((MFV)and meanarterialpressure((MAP)incomatose patientsduringthefirst72haftercardiacarrest.Inaddition, pos-sibledifferencesinspontaneousvariabilitybetweensurvivorsand non-survivorsweredetermined.

Materialsandmethods

Study

AprospectiveobservationalstudywasperformedattheICUof atertiarycareuniversityhospitaltheNetherlands.Thelocal Insti-tutionalReviewBoardapprovedthestudyandwaivedtheneedfor informedconsent.

Population

Westudied11comatosepatientssuccessfullyresuscitatedfrom acardiacarrestandtreatedwithmildtherapeutichypothermia. Inclusioncriteriawereage≥18yearsandaGlasgowComaScore≤6 afterreturnofspontaneouscirculation.Wealsostudied10normal controlsubjects.SevencontrolswerepatientsadmittedtotheICU forpre-operativehaemodynamicoptimizationonedaybefore elec-tiveesophagectomywithreconstructivesurgerybecauseofcancer. Threecontrolpatientswerehealthyvolunteersthatparticipatedin anexperimentalhumanendotoxemiastudy.Thesecontrolswere includedafterwritteninformedconsentandapprovalofthe pro-tocolbythelocalInstitutionalReviewBoard(documentnumber 2015-2079,NCT02675868).

Exclusioncriteriaforallgroupswereanirregularheartrhythm, absenttranstemporalbonewindow,pregnancy,thrombolytic ther-apy,refractorycardiogenicshockandlifeexpectancylessthan24h. Patientmanagement

Thepost-cardiacarrestpatientsweretreatedwith hypother-miaby rapid infusion of 30mL/kgbodyweight ofcold Ringer’s lactateat4◦Cfollowedbyexternalcoolingusingwater-circulating blankets(BlanketrollII,CincinnatiSubzero,TheSurgicalCompany, Amersfoort, The Netherlands). Temperature was maintained at 32–34◦Cfor24h,followedbypassiverewarmingto normother-mia(definedas37◦C).Allpatientsweresedatedwithmidazolam and/orpropofolandsufentanil.Sedationwasstoppedassoonas thebodytemperaturewas≥36◦_{C. Incaseof shivering,patients}

wereparalysedusingintravenousbolusinjectionsofrocuronium. Allpatientswereintubatedandmechanicallyventilatedtoobtaina PaO2>75mmHgandaPaCO2between34and41mmHg.Theradial

orfemoralarterywascannulatedformonitoringofarterialblood pressure(ABP)andsamplingofarterialblood.Accordingtoourlocal protocol,MAPwasmaintainedbetween80–100mmHg.If neces-sary,patientsweretreatedwithvolumeinfusionanddobutamine and/ormilrinoneand/ornoradrenaline(norepinephrine).

Allmeasurementsinthecontrolgroupwereperformedwhile subjectswereawake,withoutmechanicalventilationandbefore

fluidresuscitationorotherpre-operativeorresearchinterventions wereinitiated.

Datacollection

Demographic, pre-hospital and clinical data were collected uponandduringadmission.Anarterialcatheterwasusedfor mon-itoring of blood pressure and samplingof arterial blood in all patients.

TheMFVinthemiddlecerebralartery(MCA)wasmeasured bytranscranialDoppler(TCD)throughthetemporalwindowwith a 2-Mhz probe (Multi-Dop T Digital, Compumedics DWL, Sin-gen,Germany).Theprobewaspositionedoverthetemporalbone windowabovethezygomaticarchandfixedwithaframe.This procedure ensured that the angle and the individual depth of insonationremainedconstantduringtheinvestigation.The tempo-ralacousticwindowandDopplerdepthgivingthehighestvelocities weredeterminedandusedforallmeasurements.Twoinvestigators performedallmeasurements(J.B.andC.H.).Recordingsweremade withsubjectsinthesupinepositionwiththeheadelevatedto30◦. Aminimumof10–12minwindowsofMFV,heartrateandMAP weresimultaneouslyrecordedonalaptopcomputerandstored onaharddiskwithasamplerateof200HzbyanA/Dconverter (NIUSB-6211,NationalInstrument,Austin,TX,USA).Duringthe measurements,PaO2 andPaCO2 werewithinnormalrangesand

stable.

In thepatientsaftercardiac arrest measurementswere per-formedonadmissiontotheICUandat6,12,24,36,48,60and 72h.Onesinglemeasurementwasperformedinthecontrolgroup.

Dataanalysis

MAPandMFVdatawereanalysedusingcustom-written MAT-LABscripts(MatlabR2014b,TheMathWorksInc.Massachusetts, USA).MAPandMFVwereacquiredusingathirdorderzero phase-lagButterworthfilterwithacut-offfrequencyof0.5Hz.

FromtheseMAPandMFVsignals,5-minwindowswere auto-matically selected based on the least amount of artefacts. By averagingthese5-minwindowsoftheMAPandMFVsignals,mean valuesofMAPandMFVwereacquired.

Coefficientofvariation(CV)wasusedasastandardizedmeasure ofdispersionforbothMAPandMFVinthetimedomain.CVwas definedasthestandarddeviationofthesignaldividedbythemean ofthesignalandwascalculatedfromallfilteredsignals.Thisway, thevariationisexpressedinpercentageofthemean.

Inthefrequencydomain,theaveragespectralpowerofMAPand MFVwerecalculatedintheverylow(VLF,0.02–0.07Hz),low(LF, 0.07–0.15Hz),andhigh(HF,0.15–0.40Hz)frequencybands.This inordertoseewhetherthevariationcanbedesignatedtoacertain frequencybandandwhetherthisoriginofvariationchangesover timeinthepatients.20

Statisticalanalysis

StatisticalanalysiswasperformedusingGraphPadPrism ver-sion5.0(GraphPadSoftware,LaJolla,CA).Dataarepresentedas medianwith25thand75thpercentile.Figuresalsoshowminimum andmaximum(whiskers)values.Changesovertimewereanalyzed withtherepeated-measurestestfornonparametricdata.

Differences betweensurvivors and non-survivors were ana-lyzedwithtwo-wayanalysisofvariance.TheMann–Whitneytest wasusedforcomparisonbetweengroups.Ap-valueof<0.05was consideredtoindicatesignificance.

Table1

Demographicdataofcardiacarrestpatientsandnormalcontrols.

Characteristic Cardiacarrest Normalcontrols Pvalue

Numberofpatients,n 11 10

Male,n(%) 9(81%) 8(80%)

Age(years) 57[55–61] 65[31–67] 0.75

Numberofsurvivors,n(%) 7(64%) 10(100%) 0.36

Results

Demographicandclinicaldata

Weincluded9maleand2female(n=11)comatosepatients

aftercardiacarrest.Thedemographicdataofthepatientsareshown

inTable1.Eightpatientshadventricularfibrillationorventricular tachycardiaasinitialrhythm,3patientsinitiallyhadapulseless electricalactivityorasystole.FourpatientsdiedintheICU,allasa resultofseverepostanoxicbraindamage.Thedemographicdataof thecontrolgrouparealsosummarizedinTable1.

The clinical data on admissionare summarized in Table 2. Cardiacarrestpatientshadasignificantlyhigherhemoglobin con-centrationonadmission(p=0.03).ThepHwaslower(p=0.002)and thePaCO2wassignificantlyhigher(p=0.02)immediatelyafter

car-diacarrestcomparedtothenormalcontrolpatients,butnormalized rapidlyafteradmission.Ninepercentofthecardiacarrestpatients receivednoradrenalineonadmissiontomaintaintheMAPwithin thetargetrange.Thenormalcontrolswereawakeandbreathing spontaneouslyonroomair.

MAP was measured continuously in the patients after car-diacarrest andchangedsignificantly(p=0.04)duringthestudy periodaccording toa U-shapedpattern (electronic Supplement Fig. 1). MFV was low (28.00 [25.00–39.00]cm/s) upon admis-sion after cardiac arrest and increased significantly to 78.00 [65.00–123.00]cm/sat72h(p=0.008,electronicSupplementFig. 2). Therewere nodifferences in MAP at any measuring point betweensurvivorsandnon-survivors(p=0.09,datanotshown). MFVincreasedmoreinnon-survivors(from33.00[25.00–40.00] to71.50[61.25–96.75]cm/s)compared tosurvivors(from23.50 [20.25–28.25]to136.00[136.00–136.00]cm/s)inthecardiacarrest group(p<0.001).

Variabilityinthetimedomain MFV

TheCVofMFVaftercardiacarrestremainedstablewith5.37 [3.38–7.74]ont=0and7.49[4.09–14.97]%at72hafteradmission (p=0.44,datanotshown).InsurvivorstheCVofMFVincreased from4.66[3.92–6.28]to7.52[5.52–15.23]%.Incontrast,in

non-Table2

Clinicalandlaboratorydataofcardiacarrestpatientsandnormalcontrolson admission.

Characteristic Cardiacarresta _{Normalcontrols Pvalue}

Mechanicalventilation 11(100%) 0(0%) MAP(mmHg) 91.0[84.5–114.5] 91.1[86.3–105.1] 0.92 Heartrate(bpm) 85.0[80.0–92.0] 69.5[62.5–76.5] 0.09 Temperature(◦_{C) 35.5[34.3–35.9] 37.0[36.8–37.1] 0.006} Norepinephrine 1(9.1%) 0(0%) Dose(␮g/kg/min) 0.12 Milrinone 0(0%) 0(0%) Dobutamine 0(0%) 0(0%) Hemoglobin(g/dL) 14.7[12.9–14.7] 11.6[10.8–12.6] 0.03 pH 7.31[7.26–7.37] 7.45[7.43–7.46] 0.002 PaO2(mmHg) 102[81–168] 87[78–105] 0.28 PaCO2(mmHg) 42.0[39.0–43.5] 35.6[34.5–36.8] 0.01 a_{DatarepresentvaluesuponadmissiontotheICU.}

A

Time after admission to the ICU (hrs)

CV M F V (% )

B

Time after admission to the ICU (hrs)

CV M

A

P

(%

)

Fig.1.(A)CVofMFVinsurvivorsandnon-survivorssuccessfullyresuscitatedfrom acardiacarrestandtreatedwithmildtherapeutichypothermia,during72hof ICUadmissionandCVofMFVinnormalcontrols.(B)CVofMAPinsurvivorsand non-survivorssuccessfullyresuscitatedfromacardiacarrestandtreatedwithmild therapeutichypothermia,during72hofICUadmissionandCVofMAPinnormal controls.

CVMFV=coefficientofvariationofmeanflowvelocity. CVMAP=coefficientvariationmeanarterialpressure.

survivorstheCVofMFVdecreasedfrom9.02[1.70–9.36]to1.97 [1.97–1.97]%(Fig.1).TheCVofMFVwas7.40[4.95–12.98]in nor-malcontrols(Fig.1),anddidnotdiffersignificantlycomparedto thecardiacarrestgroup(p=0.14).

MAP

TheCVofMAPinthecardiacarrestgroupwaslowimmediately afteradmissiontotheICU(1.46[1.09–2.25])andremainedlowat 72h(3.05[1.87–3.63])(p=0.13,Fig.1).Therewerenodifferences inCVofMAPbetweensurvivorsandnon-survivorsinthecardiac arrestgroup(p=0.30,Fig.1).Normalcontrolshadasignificantly higherCVofMAP(4.10[3.23–6.43])comparedtothecardiacarrest grouponadmission(p=0.004,Fig.1).

Variabilityinthefrequencydomain MFV

Inthefrequencydomain,theaveragespectral powerofMFV increased from 0.28 [0.06–0.69] to 11.38 [1.58–30.86](cm/s)2

between admission and 72h after the arrest in the VLF band (p=0.008,Fig.2).ThisincreaseinspectralpowerofMFVintheVLF bandwasduetoanincreaseinthefavourableoutcomegroup dur-ingadmissionfrom0.38[0.10–0.59]to15.54[2.67–31.31](cm/s)2

(p=0.001), whereas VLF spectral power remained low in the patientswithanunfavourableoutcome(0.19[0.06–1.00]to1.58 [1.58–1.58](cm/s)2 _{(p=0.23)(Fig.3).Therewerenochanges in}

0 6 12 24 36 48 60 72 0 10 20 30 40

Time after admiss

ion to the ICU

(hrs)

Sp

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LF

(c

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Time after admission

to the ICU (hrs)

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Time after admission

to the ICU (hrs)

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)

Fig.2. TheaveragespectralpowerofMFVincreased,inthewholecardiacarrest group,betweenadmissionand72hafterthearrestintheVLFband.Therewasno increaseordecreaseintheLFandHFbands.

MFV=meanflowvelocity. VLF=verylowfrequency. LF=lowfrequency. HF=highfrequency.

averagespectralpowerofMFVintheLFandHFbandsafter admis-sion(respectivelyp=0.55and0.65,Fig.2).

TheaveragespectralpowerofMFVintheVLFbandwas signifi-cantlylowerinthecardiacarrestgrouponadmissioncomparedto thecontrolgroup(0.28[0.10–0.69]to9.01[4.53–19.71])(cm/s)2_,

p=0.002,Fig.3).TheaveragespectralpowerofMFVdidnot dif-fersignificantlybetweencardiacarrestpatientsonadmissionand controlsin theLF(0.17 [0.11–2.38] to1.99[0.47–2.45](cm/s)2_,

p=0.21) and HF (0.11 [0.07–0.37] to 0.05 [0.03–0.12](cm/s)2_,

p=0.13)bands.Inaddition,nodifferencesbetweensurvivorsand

0 6 12 24 36 48 60 72 0 5 10 15 20 25 survivors non-survivors controls

Time after admission to the ICU (hrs)

Sp ec tra l po we r V LF (c m /sec ) 2

Fig.3.SpectralpowerofMFVintheVLFbandinsurvivorsandnon-survivors successfullyresuscitatedfromacardiacarrestandtreatedwithmildtherapeutic hypothermia,during72hofICUadmissionandspectralpowerofMFVintheVLF bandinnormalcontrols.

MFV=meanflowvelocity. VLF=verylowfrequency.

non-survivorswerefoundintheLFandHFbands(electronic Sup-plementFig.3).

MAP

TheaveragespectralpowerofMAPdidnotchangeinthefirst 72haftercardiacarrestintheVLF(p=0.76),LF(p=0.91),andHF (p=0.14)frequencybands(datanotshown).

The average spectral power of MAP in the VLF frequency band increased in survivors from 0.70 [0.50–1.93] to 2.10 [1.03–5.54]mmHg2_{duringadmission,whileremaininglowin}

non-survivors 0.34[0.01–0.47] to0.68 [0.68–0.68] mmHg2 _(p=0.03, Fig.4).

Therewerenosignificantdifferencesforaveragespectralpower ofMAPandMFVbetweensurvivorsandnon-survivorsintheLFand HFbands(datanotshown).

TheaveragespectralpowerofMAPwassignificantlylowerin thecardiac arrestgrouponadmissioncompared tothecontrol groupintheVLF(0.57[0.27–1.02]to5.79[3.59–10.02]mmHg2_,

p=0.001),LF(0.37[0.13–0.67]to2.6[1.99–4.68]mmHg2_,p<0.001)

and HF (0.08 [0.01–0.40] to 0.91 [0.26–2.24]mmHg2_{, p=0.02)}

bands.

Discussion

ThespontaneousvariabilityofMFVMCA waslowaftercardiac

arrest. MFV variability returned to normal values in survivors whereasvariabilitydecreasedfurtherinnon-survivorsafter

car-0 6 12 24 36 48 60 72 0 5 10 15 survivors non-survivors controls

Time after admission to the ICU (hrs)

Sp ec tra l po we r V LF (m m H g ) 2

Fig.4. SpectralpowerofMAPintheVLFbandinsurvivorsandnon-survivors successfullyresuscitatedfromacardiacarrestandtreatedwithmildtherapeutic hypothermia,during72hofICUadmissionandspectralpowerofMAPintheVLF bandinnormalcontrols.

MAP=meanarterialpressure. VLF=verylowfrequency.

diacarrest.ThevariabilityoftheMAPremainedlowduringthe entirestudyperiodaftercardiacarrest.

TheaveragepowerintheVLFspectrumof theMFVMCA was

low aftercardiacarrest and restored towardsnormal values in survivors.ThepersistentlylowpowerintheVLFdomainin non-survivorssuggestperturbationsintheintrinsicmyogenicvascular function.8 _{In normal subjects,thecorrelation betweencerebral}

bloodflowvelocity andMAPfluctuationsislowfor frequencies below0.1Hz,suggestingthatinthisfrequencyrangeotherfactors mayleadtofluctuationsincerebralbloodflowvelocity.21_Indeed,in

normalvolunteers,changesinMFVMCAoscillationsinafrequencyof

0.03–0.15Hzcanprecedethoseinbloodpressureandheartrate.22

Thissuggeststhattheselowfrequencyoscillationshaveamore cen-tralcerebraloriginandaretransmitted“upstream”tothelarger cerebralarteries.Probably,theselowfrequencyoscillationsarise inthecerebralcirculationasaresultofautonomic(sympathetic) stimulation.

Cerebral blood flow is tightly regulated at the level of the neurovascularunitthroughamyriadofmetabolic,myogenicand autonomicpathways.23_{Cerebralbloodflowisdecreasedafter}

car-diacarrest and restores towards normal values in survivors.24

Non-survivorshaveasignificantlystrongerincreaseinMFVMCAin

thefirst72hafterthearrest.25_{Apparently,vasoactivetoneislost}

inpatientswithpooroutcome,resultinginadecreaseincerebral vascularresistanceandsubsequentincreaseincerebralbloodflow. Theseobservationsareinaccordancewithourcurrentstudythat intrinsicmyogenicvascularfunctionandsympatheticautonomic regulationmaybeimpairedinnon-survivorsaftercardiacarrest. Theimportanceof theautonomicnervous systemin regulation ofthecerebralbloodflowiswelldocumentedinhumans.Upper thoracic sympathectomy in patientswith palmarhyperhidrosis resultedin increasedblood volumeandbloodflow velocitiesin theMCA.26_{Trimetaphan(aso-calledganglionblocker,becauseit}

blocksthecholinergicsynaptictransmissioninsympatheticand parasympatheticpathways)changesstaticanddynamiccerebral autoregulationinhumans,indicatingthatremovalofautonomic neuralactivityplaysanimportantroleintheregulationofcerebral bloodflow.27

Beat to beat changes in cerebral blood flow are under the controlof myogenic and autonomicmechanisms under normal conditions.Cardiacarrestinducesastronginflammatoryresponse, accompanied by changes in NO production and production of reactiveoxygen species resulting in endothelium-dependent relaxation.28,29_{Animbalancebetweenlocalvasoconstrictorsand}

vasodilators, characterized by high endothelin levels and ini-tiallylow but gradually increasingcGMP levels issuggested to underlie the cerebral perfusion changes after cardiac arrest.30

Otherfactorsthatcontributetothisreducedbloodflow include areductioninneuronalactivity,vasospasm,edema,plateletand leukocyteadhesionand changes inviscosity.30–35 _We

hypothe-sizethatthesepathophysiologicalchangescancontributetothe changesinMFVMCA variabilityaftercardiacarrestandinfluence

thestateofdynamicautoregulationinthesepatients.

The spontaneous variability in MAP in post-cardiac arrest patientswassignificantlylowercomparedtoage-andsex-matched controlpatients.Similarly,heartratevariabilityisreducedinboth low and high frequency power spectra in survivors and non-survivorsaftercardiacarrest,suggestingadecreaseinautonomic cardiovascularfunction,thataffectsMAPvariabilityin asimilar manner.36,37 _{The relativelylow averagespectral powerof MAP}

intheVLFfrequencybandsupportsthishypothesisofautonomic failure.

This study has a number of limitations. We performed an observationalstudyin arelatively smallpopulation.We cannot excludethat in ourpatientsuseof medicationmayhave influ-enced these results. In the first hours after cardiac arrest, use

ofsedativesandvasopressiveagentswerecommon,whereas ␤-blockerswerefrequentlyusedafterrewarmingtonormothermia. Allpatientsweretreatedwithhypothermia.Hypothermiabyitself resultsin increasedheartratevariabilityinboth thelowerand higherfrequencyspectra,mostlikelyasaresultofthehypothermia inducedbradycardia.38_{Theuseofsedatives,vasoactiveagentsand}

hypothermiawassimilarinsurvivorsandnon-survivorsafter car-diacarrest.In addition,differencesinsystemic parameterssuch as MAP, pHor PaCO2 didnot account for these differences in

MFVMCAandMAPvariability(datanotshown).Wecannotexclude

otherunmeasuredeffectsoncerebralbloodflowandthe individ-ualpatient’sautoregulatorythresholdisunknown.Althoughthe observationalnatureofthis studydidnotallowmodificationof thesepossibleconfounders,theobservedpathophysiological dif-ferencesincerebralbloodflowvelocityandarterialbloodpressure stronglysuggestadiseasespecificpathophysiologicprocess.

ThechangesinspontaneousfluctuationsinMFVMCAandMAP

suggestchangesindynamicautoregulationaftercardiacarrest.We didnotquantifythestrengthofthedynamicautoregulationinthis population.Transferfunctionanalysisisconsideredthegold stan-dardfortheestimationofdynamiccerebralautoregulation.Since thistechniquereliesonspontaneous(orinduced)fluctuationsin MFVMCAandMAP,reducedvariabilityinoneofbothinputsignals

willstronglyreducethereliabilityoftheresultingoutputsignal.20

Conclusions

Cerebral blood flow is altered after cardiac arrest, with decreasedspontaneousfluctuationsinpatientswithapoor out-come. Most likely, these changes are the consequence of the associated severe brain damage, resulting in impaired intrinsic myogenicvascular functionand autonomicdysregulation.These perturbationsincerebrovascularregulationmayaccountforthe lossofvasoactivetoneandtheincreasedcerebralbloodflow veloc-ityinnon-survivorsaftercardiacarrest.

Conflictofintereststatement

Noconflictofinterest.

AppendixA. Supplementarydata

Supplementarydataassociatedwiththisarticlecanbefound, intheonlineversion,athttp://dx.doi.org/10.1016/j.resuscitation. 2016.12.005.

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