Middle cerebral artery flow, the critical closing pressure, and the optimal mean arterial pressure in comatose cardiac arrest survivors: An observational study

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ContentslistsavailableatScienceDirect

Resuscitation

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

Clinical

paper

Middle

cerebral

artery

ﬂow,

the

critical

closing

pressure,

and

the

optimal

mean

arterial

pressure

in

comatose

cardiac

arrest

survivors—An

observational

study

夽

Judith

M.D.

van

den

Brule

∗

,

Eline

Vinke,

Lex

M. van

Loon,

Johannes

G. van

der

Hoeven,

Cornelia

W.E.

Hoedemaekers

DepartmentofIntensiveCareMedicine,RadboudUniversityMedicalCenter,Nijmegen,TheNetherlands

a

r

t

i

c

l

e

i

n

f

o

Articlehistory: Received30August2016

Receivedinrevisedform17October2016 Accepted21October2016

Keywords:

Criticalclosingpressure Cerebralbloodﬂow Cerebrovascularresistance

a

b

s

t

r

a

c

t

Aim:Thisstudyestimatedthecriticalclosingpressure(CrCP)ofthecerebrovascularcirculationduring thepost-cardiacarrestsyndromeanddeterminedifCrCPdiffersbetweensurvivorsandnon-survivors. Wealsocomparedpatientsaftercardiacarresttonormalcontrols.

Methods:AprospectiveobservationalstudywasperformedattheICUofatertiaryuniversityhospital inNijmegen,theNetherlands.Westudied11comatosepatientssuccessfullyresuscitatedfromacardiac arrestandtreatedwithmildtherapeutichypothermiaand10normalcontrolsubjects.Meanﬂowvelocity (MFV)inthemiddlecerebralarterywasmeasuredbytranscranialDoppleratseveraltimepointsafter admissiontotheICU.CrCPwasdeterminedbyacerebrovascularimpedancemodel.

Results:MFVwassimilarinsurvivorsandnon-survivorsuponadmissiontotheICU,butincreasedstronger innon-survivorscomparedtosurvivorsthroughouttheobservationperiod(P<0.001).MFVwas signifi-cantlylowerinsurvivorsimmediatelyaftercardiacarrestcomparedtonormalcontrols(P<0.001),with agradualrestorationtowardnormalvalues.CrCPdecreasedsignificantlyfrom61.4[51.0–77.1]mmHgto 41.7[39.9–51.0]mmHginthefirst48h,afterwhichitremainedstable(P<0.001).CrCPwassignificantly higherinsurvivorscomparedtonon-survivors(P=0.002).CrCPimmediatelyaftercardiacarrestwas significantlyhighercomparedtothecontrolgroup(P=0.02).

Conclusions:CrCPishighaftercardiacarrestwithhighcerebrovascularresistanceandlowMFV.This sug-geststhatcerebralperfusionpressureshouldbemaintainedatasufﬁcienthighleveltoavoidsecondary braininjury.Failuretonormalizethecerebrovascularproﬁlemaybeaparameterofpooroutcome.

Introduction

Prognosis after cardiac arrest is mainly determined by the neurologicalinjury inducedby thecirculatory arrest.Return of spontaneous circulation (ROSC) does not automatically restore

Abbreviations: ABP,arterialbloodpressure;Ca,compliance;CABV,cerebral

arterialbloodvolume;CBF,cerebralbloodﬂow;CPP,cerebralperfusionpressure; CrCP,criticalclosingpressure;CVR,cerebrovascularresistance;HR,heartrate;ICP, intracranialpressure;MAP,meanarterialpressure;MCA,middlecerebralartery; MFV,meanﬂowvelocity;ROSC,returnofspontaneouscirculation;TCD,transcranial Doppler.

夽 ASpanishtranslatedversionoftheabstractofthisarticleappearsasAppendix intheﬁnalonlineversionathttp://dx.doi.org/10.1016/j.resuscitation.2016.10.022. ∗ Correspondingauthorat:RadboudUniversityNijmegenMedicalCentre, Depart-ment of Intensive Care, P.O. Box 9101, 6500HB Nijmegen, The Netherlands. Fax:+31243541612.

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

cerebralperfusion.Cerebralperfusionfailureafterrestorationof circulationisawellknownphenomenoninanimalmodelswith no-reﬂow,cerebralhyperperfusionand hypoperfusionthat ulti-matelyrestorestowardnormalcerebralbloodﬂow(CBF).1_Humans

havea similarﬂow patternaftercardiacarrestwithlowCBFin theinitialphaseaftercardiacarrestthatgraduallyrestorestoward normalvaluesduringthepost-resuscitationsyndrome.2–4_This_so

called“delayedhypoperfusionphase”rendersthebrainatriskfor ischemiaandsecondarybraininjury.

Thecerebralvascular toneplaysanessential roleinchanges in CBFaftercardiac arrest.Increased cerebrovascularresistance hasbeensuggested tocontributetothedelayedhypoperfusion phase, based on high transcranial Doppler pulsatility indexes of themiddlecerebralartery(MCA) measuredduringtheearly post-cardiacarrestperiod.2–4_A_subsequent_strong_decrease_in

tran-scranialDoppler(TCD)pulsatilityindexwithincreasedmeanﬂow velocities (MFV)duringthe ﬁrst24hafterthearrest was mea-http://dx.doi.org/10.1016/j.resuscitation.2016.10.022

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sured in non-survivors, whereas in survivors these parameters normalized.5_In_addition,_{autoregulation}_is_disturbed_in

approxi-mately1/3ofpatientsaftercardiacarrest,mainlyinthosewith apooroutcome.6,7 _Taken _together,_these_data_indicate _that_the

cerebrovascularresistanceisalteredaftercardiacarrest,mainlyin patientswithapoorneurologicaloutcome.

Thecriticalclosingpressure(CrCP)isamethodtodescribeand quantifycharacteristicsofthecerebrovascularbedinmoredetail andisdeﬁnedasthelowerlimitofarterialbloodpressurebelow whichvesselscollapseandﬂowceases.8,9_Because_CrCP_cannot_be

measureddirectly,severalmodelshavebeendevelopedtoestimate CrCPindirectlyfromothermeasurablephysiological parameters ortheirderivatives.CrCP inthemodel of Burtonis thesumof intracranialpressure(ICP)andvascularwalltension.8_Varsos_et_al.

proposedamodiﬁcation oftheCrCP calculation,usinga model ofcerebrovascularimpedance.Withthismodel,thegenerationof negativevalues forCrCP isprevented and themodel can accu-ratelydetectchangesinvascularpropertiesinducedbychanges inICP,PaCO2andbloodpressure.10CrCPisavaluableandclinically relevanttoolincerebrovascularresearch,asitallowstoestimate changesincerebrovasculartoneandminimalcerebralperfusion pressuretopreventcollapseofvesselsandischemia.11–13

TheaimofthecurrentstudywastoestimateCrCPof cerebrovas-cularmotortoneduringthepost-cardiacarrestsyndromeandto determineifCrCPdiffersbetweensurvivorsandnon-survivors.To placethesevaluesinabroadercontext,wealsocomparedCrCPin post-cardiacarrestpatientstonormalcontrols.

Methods Study

AprospectiveobservationalstudywasperformedattheICUof atertiaryuniversityhospitalintheNetherlands.Allexperiments wereinaccordancewiththeDeclarationofHelsinkiandGood Clin-icalPracticeguidelines.

Population

Westudied11comatosepatientssuccessfullyresuscitatedfrom acardiacarrest andtreatedwithmildtherapeutichypothermia. Inclusioncriteriawereage≥18yearsand coma(Glasgowcoma scale≤6)afterreturnofspontaneouscirculation.“Survivors”and “non-survivors”denotesurvivaltohospitaldischarge.Asacontrol group,weincluded10subjectswithoutbraininjury.Sevencontrols werepatientsadmittedtotheICUforpre-operativehemodynamic optimizationonedaybeforeesophagectomy.Threecontrolswere healthy volunteers who participated in an experimentalstudy. Thesehealthy volunteerswere includedafter writteninformed consentand approval of theprotocol by the localInstitutional ReviewBoard.For thepatientsaftercardiacarrest andpatients admitted for hemodynamic optimization thelocal Institutional ReviewBoardwaivedtheneedforinformedconsent.Exclusion cri-teriaforallpatientswereanirregularheartrhythm,insufﬁcient transtemporal bone window, pregnancy, thrombolytic therapy, refractorycardiogenicshockoralifeexpectancy<24h.

Patientmanagement

Thepost-cardiacarrestpatientsweretreatedwithhypothermia byrapidinfusionof30mL/kgbodyweightofcoldRinger’slactate at4◦Cfollowedbyexternalcoolingusingtwowater-circulating blankets(BlanketrollII,CincinnatiSubzero,TheSurgicalCompany, Amersfoort, The Netherlands). Temperature was maintained at 32–34◦Cfor24h,followedbypassiverewarmingto normother-mia(deﬁnedas37◦C).Cardiacarrestpatientsweresedatedwith

midazolamand/orpropofolandsufentanil.Sedationwasstopped assoonastemperaturewas≥36◦_C._In_case_of_shivering,_patients wereparalyzedusingintravenousbolusinjectionsofrocuronium. Allpatientswereintubatedandmechanicallyventilatedtoobtain PaO2 >75mmHg and PaCO2 34–41mmHg. Mean arterial pres-sure(MAP)wasmaintainedbetween80–100mmHg.Ifnecessary, patientsweretreatedwithvolumeinfusionanddobutamineand/or milrinoneand/ornoradrenaline(norepinephrine).

ControlswereadmittedtotheICUthedaybeforesurgeryfor hemodynamicoptimizationortotheresearchunitoftheICU.All measurementsinthisgroupwereperformedwhilesubjectswere awake,withoutmechanicalventilationandbeforeﬂuid resuscita-tion,pre-operativeorstudyrelatedinterventionswereinitiated. Datacollection

Demographic, pre-hospital and clinical data were collected uponandduringadmission.Anarterialcatheterwasusedfor mon-itoringofbloodpressureinallsubjects.

MFVinthemiddlecerebralartery(MFVMCA)wasmeasuredby TCDthroughthetemporalwindowwitha2-Mhzprobe (Multi-DopTDigital,CompumedicsDWL,Singen,Germany)accordingto themethoddevelopedbyAaslidetal.14_The_probe_was_positioned

over thetemporal bone windowabovethezygomatic archand ﬁxed.Thisprocedureensuredthattheangleandindividualdepthof insonationremainedconstantduringinvestigation.Thetemporal acousticwindowandDopplerdepthgivingthehighestvelocities wereusedforallmeasurements.Twoinvestigatorsperformedall measurements(J.B.andC.H.).Recordingsweremadewithsubjects insupineposition,theheadelevatedto30◦.

A minimum of 10–12minwindows of MFV, heart rate and arterialbloodpressure(ABP)weresimultaneouslyrecordedona computerandstoredonaharddiskwithasamplerateof200Hz byanA/Dconverter(NIUSB-6211,NationalInstrument,Austin, TX,USA).Duringthemeasurements,PaO2,PaCO2andtemperature werewithinnormalrangesandpatientswerenormotensive.

Inpatientsaftercardiacarrest,measurementswereperformed onadmissiontotheICUandat6,12,24,36,48,60and72h.Subjects inthecontrolgroupweremeasuredonce.

Dataanalysis

ABPandMFVdatawereanalyzedusingcustom-written MAT-LABscripts(MatlabR2014b,TheMathWorksInc.,Massachusetts, USA).First,thetimeserieswerefilteredwithan5th-orderlow-pass Butterworthfilter(25Hz),toascertainsignalstationarity.Second, periodsof5minofartefact-andcalibration-freedatawereselected byvisualinspectionforsubsequentanalysis.Last,meanblood pres-sureandcerebralbloodflowvelocitywereobtainedsynchronically usinga4thorderlow-passButterworthfilter.

CrCP

CrCPwasdeterminedaccordingtothemethodsuggestedby Varsosetal.10,15

CrCP=ABP−

CPP

(CVR·Ca·HR·2)2 +1

WithCVRcerebrovascularresistance,Cacomplianceofthe vas-cularbedandHRheartrate.ThemultiplicationofCVRandCais calledthetimeconstantTau().CPPisdeﬁnedasABP−ICP, how-everinthisstudyICPwasnotmeasured.ThereforeABPmeanwas usedasanapproachofCPP,asdescribedbyVarsosetal.10_CVR_was

calculatedbydividingABPmeanbyMFVmean.TodetermineCa, cerebralarterialbloodvolume(CABV)wascalculatedby

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integrat-Table1

Demographicdatacardiacarrestpatientsandcontrols.

Characteristic Cardiacarrest Control Pvalue Numberofpatients,n 11 10 Male,n(%) 9(81%) 8(80%) Age(years) 57[55–61] 65[31–67] 0.75 SAPSII 60[41–69] 13[7.3–18] <0.001 APACHEII 26[24–30] 4.5[0.8–9.0] <0.001 Numberofsurvivors,n(%) 7(64%) 10(100%) 0.36 SAPSII:SimpliﬁedAcutePhysiologyScoreII.

APACHEII:AcutePhysiologyandChronicHealthEvaluationII.

ingtheMFVsignalovertime.ThenCawascalculatedbydividing

theamplitudeoftheﬁrstharmonicoftheCABVbytheamplitudeof

thefirstharmonicoftheABP.HRwasdefinedasthefirstharmonic

frequencyofABP.

Statisticalanalysis

StatisticalanalysiswasperformedusingGraphPadPrism

ver-sion5.0(GraphPadSoftware,LaJolla,CA).Dataarepresentedas

medianwith25thand75thpercentile.Figuresalsoshowminimum

andmaximum(whiskers)values.Changesovertimewereanalyzed

withtherepeated-measurestestfornonparametricdata.

Differ-encesbetweensurvivorsand non-survivorswereanalyzedwith

two-wayanalysisofvariance.TheMannWhitneytestwasusedfor

comparisonbetweengroups.AP-valueof<0.05wasconsideredto

indicatesigniﬁcance.

Results

Demographicandclinicaldata

Weincluded9maleand2female(n=11)comatosepatients

aftercardiacarrest.Thedemographicdataofthepatientsand

con-trolsareshowninTable1.Eightpatientshadventricularﬁbrillation

orventriculartachycardiaasinitialrhythm,3patientsinitiallyhad apulselesselectricalactivityorasystoleFourpatientsdiedinthe ICU,allasresultofseverepostanoxicbraindamage.Theclinical dataaresummarizedinTable2.Cardiacarrestpatientshada sig-niﬁcantlyhigherhemoglobinonadmission(P=0.03).ThepHwas lower(P=0.002)andthearterialcarbondioxidetensionwas signif-icantlyhigher(P=0.01)immediatelyaftercardiacarrestcompared tonormalcontrolpatients.

Cerebralbloodﬂowvelocity

Asexpected,MFV increasedsigniﬁcantly aftercardiac arrest from28.0[25.0–39.0]uponICUadmissionto78.0[65.0–123.0]cm/s after 72h, P<0.001 (Fig. 1). The MFVMCA was similar in

sur-Table2

Clinicalandlaboratorydata.

Characteristic Cardiacarresta _Normal _P_value

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 Noradrenaline 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_Data_represent_values_upon_admission_to_the_ICU.

0 6 12 24 36 48 60 72 0 50 100 150 Survivors Non-survivors Controls

Time after admission to the ICU (hrs)

MFV-MCA (cm/s)

Fig.1. MFVofsurvivorsandnon-survivorsincomatosepatientssuccesfully resus-citatedfromacardiacarrestandtreatedwithmildhypothermia,during72hofICU admission.

MFV=meanﬂowvelocity.

vivors and non-survivors upon admission to the ICU, but the MFVMCA increased stronger in non-survivors compared to sur-vivorsthroughouttheobservationperiod(P=0.001).MFVMCAwas signiﬁcantlylower insurvivorsimmediatelyaftercardiacarrest comparedtonormalcontrols(P<0.001),withagradualrestoration towardnormalvalues.

MAP decreased after cardiac arrest from 91.0[83.0–123] on admissionto82.5[77.8–87.8]at48hand88.0[83.0–98.0]mmHgat 72h(P=0.009)withnosigniﬁcantdifferencesbetweensurvivors andnon-survivors(P=0.09)(datanotshown).MAPinthecontrol patientswas92.6[86.3–105.1]andcomparabletothecardiacarrest group(datanotshown).

Criticalclosingpressure

After cardiac arrest, the CrCP decreased significantly from 61.4[51.0–77.1]onadmissionto41.7[39.9–51.0]mmHgat 48h, after which it remained stable (P<0.001), (Fig. 2). The CrCP wassignificantlyhigherin survivorscompared tonon-survivors (P=0.002).TheCrCPimmediatelyaftercardiacarrestwas signifi-cantlyhighercomparedtothecontrolgroup(P=0.02).

The Ca represents the change of arterial blood volume in responsetochangeinarterialpressureandisestimatedasaratio ofpulseamplitudeofCABVderivedfromthecerebralbloodflow velocityandpulseamplitudeoftheABP.Aftercardiacarrest,Ca increased significantly from0.05[0.05–0.08] upon admission to 0.10[0.08–0.16]mmHg/cm3_at₇₂_h_(P₌_0.02),_with_no_differences betweensurvivorsandnon-survivors(P=0.81)(datanotshown). Ca values immediately after cardiac arrest were significantly

0 6 12 24 36 48 60 72 0 20 40 60 80 Survivors Non-Survivors Controls

CrCP (mmHg)

Fig.2. CrCPofsurvivorsandnon-survivorsincomatosepatientssuccesfully resus-citatedfromacardiacarrestandtreatedwithmildhypothermia,during72hofICU admission.

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0 6 12 24 36 48 60 72 0 2 4 6

Survivors

Non-survivors

Controls

Time after admission to the ICU (hrs)

**CVR (mmHg*sec/cm)**

Fig.3. CVRofsurvivorsandnon-survivorsincomatosepatientssuccesfully resus-citatedfromacardiacarrestandtreatedwithmildhypothermia,during72hofICU admission. CVR=cerebrovascularresistance. 0 6 12 24 36 48 60 72 0.0 0.1 0.2 0.3 0.4 Survivors Non-survivors Controls

Tau (sec)

Fig.4.Tau(timeconstant)ofsurvivorsandnon-survivorsincomatosepatients succesfullyresuscitatedfromacardiacarrestandtreatedwithmildhypothermia, during72hofICUadmission.

lower compared to normal values (0.11[0.08–0.25]mmHg/cm3_, P=0.007).

TheCVR istheresistanceofsmallcerebralarteriesand arte-riolesand wasestimatedfromtheABPand cerebralblood flow velocity. The initial CVR in patients after cardiac arrest was high(3.91[2.94–5.37]) and significantly decreased after72hto 1.35[0.88–1.81]mmHgs/cm(P<0.001),withastrongerdeclinein non-survivors(P=0.02),(Fig.3).TheCVRonadmissionwas sig-nificantlyhigherinthecardiacarrestgroupcomparedtonormal controls(1.67[1.25–2.62]mmHgs/cm,P<0.001).

Tau()isthetimeconstantofcerebralarterialbedandisthe productofbrainarterialcomplianceCaandCVR.Itestimateshow fastcerebralbloodarrivesinthecerebralarterialbedduringeach cardiac cycle. Tau decreased signiﬁcantly from 0.22[0.19–0.26] to0.13[0.11–0.20]s(P=0.005),withastrongerdecreasein non-survivorscomparedtosurvivors(P=0.01)(Fig.4).Tauinthecontrol groupwas0.18[0.15–0.25]s,anddidnotdiffersigniﬁcantlyfrom valuesonadmissionaftercardiacarrest.

Discussion

Cerebralhemodynamicparameters changesignificantlyafter cardiacarrest.MFVMCAislowinthefirsthoursaftercardiacarrest, withahighCrCPandCVR.Duringthefirst72h,theMFVgradually increasestowardnormalvalues,withaconcomitantdecreasein CrCPandCVR.Thischangeincerebrovascularprofileaftercardiac arrestismostlikelytheresultofachangeincerebrovascularmotor tone,switchingfromvasoconstrictionatadmissiontovasodilation after72h.

CrCPisthesumofcerebralarterysmoothmuscletoneandICP.8

Intheory,changesinCrCPcanoriginatefromchangesinboth com-ponents.Mostlikely,theincreasedCrCPaftercardiacarrestisthe resultofcerebralvasoconstrictionin theﬁrsthoursafterROSC. Inourpatients,theresistanceofsmallcerebralarteriesand arte-rioles,estimatedbytheCVR,washighand graduallydecreased towardnormalvalues.Inhumans,thetranscranialDoppler pul-satility index of theMCA is high duringthe earlypost-cardiac arrestperiodanddecreasestowardnormalvaluesafter24–48h,2–4

alsoimplicatingincreasedcerebralarterialresistance. The com-binationof lowcerebralblood ﬂow velocitieswithhighCVR is a characteristic of the “delayed cerebral hypoperfusion phase” described in post-resuscitation animal models.1 _An _imbalance

betweenlocalvasoconstrictorsandvasodilators,characterizedby highendothelinlevels,graduallydecreasingnitrateconcentrations, andgraduallyincreasingcGMPlevelsissuggestedtounderliethe cerebralperfusionchangesaftercardiacarrest.3_Other_factors_that

contributetothisreducedbloodﬂowincludeareductionin neu-ronalactivity,vasospasm,edema,plateletandleukocyteadhesion andchangesinviscosity.1,3,16–19

Theincidenceofintracranialhypertensionaftercardiacarrest isunknown,andhasbeenstudiedinonlyasmallnumberofhighly selectedpatients.20–24_In_those_patients,_ICP_upon_admission_to_the

ICUwaslow,eveninpatientswhodevelopedintracranial hyper-tensionlaterduringthecourseofadmission.21_As_CrCP_was_high_on

admissionanddecreasedintheﬁrsthoursafterROSC,increasedICP isprobablynotamajorfactordeterminingCrCPinourpopulation. ThisissupportedbythefactthatCrCPwaslowerinnon-survivors comparedtosurvivors,whereaspost-cardiacarrestpatientswith intracranialhypertension(resultinginhighCrCP)hadapoor out-comeinallstudies.20–24

Ourresultsstresstheimportanceofmaintainingasufﬁciently highcerebralperfusionpressure,especiallyintheﬁrsthoursafter cardiacarrest toavoid secondarybrain ischemia.Ourdata sug-gestthatthewidelyusedMAPrangeof65–70mmHgisprobably suboptimal.25_This_is_in_agreement_with_a_previous_study_on_the

optimalcerebralperfusionpressureaftercardiacarrest,suggesting anoptimalMAPbetween85–105mmHg.6

Survivors and non-survivors revealed significantly different cerebralperfusioncharacteristicsduringthe post-cardiacarrest period. Non-survivors showed a more pronounced increase in MFVMCA inthefirst72hafterthearrest.Thiswasaccompanied byastrongerdecreaseinCrCPandCVRinnon-survivors. Differ-encesinsystemicparameterssuchasMAP,pHorPaCO2 tension ordifferencesinuseofvaso-activedrugsdidnotaccountforthese differencesincerebralperfusion.Thesedataareinaccordancewith previousobservationsofasignificantdecreaseinpulsatilityindex andanincreaseinMFVMCAinnon-survivorsaftercardiacarrest.5 Apparently,vasoactivetoneislostinpatientswithpooroutcome, resultingin a decreasein CVRand subsequently anincrease in cerebralbloodflow.Undernormalcircumstances,cerebralblood flow is maintainedat a constant level throughthe mechanism ofcerebrovascularautoregulation.Autoregulationisdisturbedin approximately1/3ofpatientsaftercardiacarrest,mainlyinthose withpooroutcome.6,7_A_loss_of_{autoregulation}_may_have_resulted

in increasedblood ﬂow withlow CVR in the non-survivors. In addition,theischemia-reperfusionresponseactivatesalarge num-ber of pathophysiological pathways including oxidative stress, inﬂammationandcoagulationresultinginreactivehyperemia.26,27

Thisreactivehyperemiaislikelytobemorepronouncedinmore severelyaffectedpatients,explainingtheincreasedﬂowwithlow resistanceinnon-survivors.

We compared thecardiacarrest patientsupon admissionto normalcontrolsubjects.MFVMCA wassigniﬁcantlylower imme-diatelyaftercardiacarrestcomparedtonormalcontrolpatients.

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CrCPandCVRwerehighercomparedtocontrols.Useofsedatives andvasopressorsiscommonduringthepost-cardiacarrestperiod andmayinﬂuencethecerebrovascularperfusioncharacteristics. Normalcontrolpatientsweremeasuredwithoutanysedativesor vasopressiveagents.Thepost-resuscitationperfusionpatternwas differentinsurvivorsversusnon-survivors,despitesimilarlevels ofbloodpressure,useofsedativesandvasopressorsand labora-toryvalues,stronglysuggestingadistinctpathophysiologicalentity ratherthananICUordrug-inducedeffectoncerebralbloodﬂow.

Auniquefeatureofthetreatmentaftercardiacarrestwasthe useofmildhypothermiainourpatients.Hypothermiamaydelay restorationofcerebralbloodﬂowtowardnormalvalues,butdoes notalterthepatternofhypoperfusionfollowedbynormalor hyper-perfusionandisprobablynotamajordeterminantofthecerebral bloodﬂowaftercardiacarrest.2,28_The_contribution_of_hypothermia

tothehighCrCPandCVRuponadmissioncannotbeestablished fromthisstudy,butseemsrelativelyminorsincebothCrCPand resistancedecreasewhiletemperaturesdeclineintheﬁrsthours afteradmission.

Thisstudyhasa numberoflimitations.First,CrCPcannotbe measuredinvivo butisestimatedusingamathematicalmodel, withitsinherentrisksofbias.Mostimportantly,ICPisrequiredfor amostaccuratecalculationofthemodel.SinceICPislowunder normalconditions,itdoesnotsignificantlyaltertheestimationof CrCP.ICPisunlikelytohaveamajorinfluenceonourresults,asCrCP decreasesin non-survivors (whereas raised ICP would increase CrCP).WemeasuredABPthroughacatheterintheradialartery. MeasurementoftheABPintheMCAwouldhaveresultedinamore accurateestimationofcerebralperfusionpressurebutisnot feasi-bleinpatients.Second,thecerebralperfusionchangesaftercardiac arrestareprobablyheterogeneouslydistributedthroughthebrain, withsomeareas moreaffected thanothers. AsCrCP is derived fromtheMFVMCA,theseheterogeneitiescannotbemeasuredby thistechnique. Thisstudyalsohaslimitationsinherentin com-paringsubjectswithregimentedhemodynamicsandventilation toawakecontrolsubjects.ABPandHRarebothcomponentsinthe methodofVarsos,buttherewerenosignificantdifferencesinthese componentsbetweencardiacarrestpatientsandnormalcontrols. AnothercomponentinthemethodofVarsosisMFV,whichis influ-encedbythediameteroftheMCAandthusbypH/carbondioxide tension.pH/carbondioxidetensionwasdifferentbetweencardiac arrestpatientsandnormalcontrolsonadmissionand mayhave affectedthe results, butthis component normalized earlyafter admission.

Althoughwestudiedonly11patients,theresultsappeartobe physiologicallysound.

Conclusions

Inconclusion,CrCPishighaftercardiacarrestwithhigh cere-brovascularresistanceandlowcerebralbloodflowvelocities.This suggeststhatcerebralperfusionpressureshouldbemaintainedat asufficienthighleveltoavoidsecondarybraininjury.Failureto normalizethecerebrovascularprofilemaybeaparameterofpoor outcome.

Conﬂictofintereststatement Noconﬂictsofinterest.

References

1.SafarP.Cerebralresuscitationaftercardiacarrest:researchinitiativesandfuture directions.AnnEmergMed1993;22:324–49.

2.BisschopsLL,HoedemaekersCW,SimonsKS,vanderHoevenJG.Preserved metaboliccouplingandcerebrovascularreactivityduringmildhypothermia aftercardiacarrest.CritCareMed2010;38:1542–7.

3.BuunkG,vanderHoevenJG,FrolichM,MeindersAE.Cerebral vasoconstric-tionincomatosepatientsresuscitatedfromacardiacarrest.IntensiveCareMed 1996;22:1191–6.

4.LemialeV,HuetO,VigueB,etal.Changesincerebralbloodﬂowandoxygen extractionduringpost-resuscitationsyndrome.Resuscitation2008;76:17–24.

5.BuunkG,vanderHoevenJG,MeindersAE.Prognosticsigniﬁcanceofthe differ-encebetweenmixedvenousandjugularbulboxygensaturationincomatose patientsresuscitatedfromacardiacarrest.Resuscitation1999;41:257–62.

6.AmelootK,GenbruggeC,MeexI,etal.Anobservationalnear-infrared spec-troscopystudyoncerebralautoregulationinpost-cardiacarrestpatients:time todrop‘one-size-ﬁts-all’hemodynamictargets.Resuscitation2015;90:121–6.

7.SundgreenC,LarsenFS,HerzogTM,KnudsenGM,BoesgaardS,Aldershvile J.Autoregulationofcerebralbloodﬂowinpatientsresuscitatedfromcardiac arrest.Stroke2001;32:128–32.

8.BurtonAC.Onthephysicalequilibriumofsmallbloodvessels.AmJPhysiol 1951;164:319–29.

9.DeweyRC,PieperHP,HuntWE.Experimentalcerebralhemodynamics. Vaso-motortone,criticalclosingpressure,andvascularbedresistance.JNeurosurg 1974;41:597–606.

10.VarsosGV,RichardsH,KasprowiczM,etal.Criticalclosingpressure deter-minedwithamodelofcerebrovascularimpedance.JCerebBloodFlowMetab 2013;33:235–43.

11.VarsosGV,BudohoskiKP,CzosnykaM,etal.Cerebralvasospasmaffectsarterial criticalclosingpressure.JCerebBloodFlowMetab2015;35:285–91.

12.VarsosGV,CzosnykaM,SmielewskiP,etal.Cerebralcriticalclosingpressurein hydrocephaluspatientsundertakinginfusiontests.NeurolRes2015;37:674–82.

13.VarsosGV,deRivaN,SmielewskiP,etal.Criticalclosingpressureduring intracranialpressureplateauwaves.NeurocritCare2013;18:341–8.

14.AaslidR,MarkwalderTM,NornesH.NoninvasivetranscranialDoppler ultra-sound recording of ﬂow velocity in basal cerebral arteries. J Neurosurg 1982;57:769–74.

15.VarsosGV,KasprowiczM,SmielewskiP,CzosnykaM.Model-basedindices describingcerebrovasculardynamics.NeurocritCare2014;20:142–57.

16.Beckstead JE, Tweed WA, Lee J, MacKeen WL. Cerebral blood ﬂow and metabolisminmanfollowingcardiacarrest.Stroke1978;9:569–73.

17.BisschopsLL,PopGA,TeerenstraS,StruijkPC,vanderHoevenJG,Hoedemaekers CW.Effectsofviscosityoncerebralbloodﬂowaftercardiacarrest.CritCareMed 2014;42:632–7.

18.ForsmanM,AarsethHP,NordbyHK,SkulbergA,SteenPA.Effectsofnimodipine oncerebralbloodﬂowandcerebrospinalﬂuidpressureaftercardiacarrest: correlationwithneurologicoutcome.AnesthAnalg1989;68:436–43.

19.SafarP,StezoskiW,NemotoEM.Ameliorationofbraindamageafter12minutes’ cardiacarrestindogs.ArchNeurol1976;33:91–5.

20.IidaK,SatohH,AritaK,NakaharaT,KurisuK,OhtaniM.Delayedhyperemia causingintracranialhypertensionaftercardiopulmonaryresuscitation.CritCare Med1997;25:971–6.

21.NaitoH,IsotaniE,CallawayCW,HagiokaS,MorimotoN.Intracranialpressure increasesduringrewarmingperiodaftermildtherapeutichypothermiain post-cardiacarrestpatients.TherHypothermiaTempManage2016,http://dx.doi. org/10.1089/ther.2016.0009,aheadofprint.

22.NordmarkJ,RubertssonS,MortbergE,NilssonP,EnbladP.Intracerebral moni-toringincomatosepatientstreatedwithhypothermiaafteracardiacarrest.Acta AnaesthesiolScand2009;53:289–98.

23.SakabeT,TateishiA,MiyauchiY,etal.Intracranialpressurefollowing cardiopul-monaryresuscitation.IntensiveCareMed1987;13:256–9.

24.SenterHJ,WolfA,WagnerJrFC.Intracranialpressureinnontraumaticischemic andhypoxiccerebralinsults.JNeurosurg1981;54:489–93.

25.PeberdyMA,CallawayCW,NeumarRW,etal.Part9:post-cardiacarrestcare: 2010AmericanHeartAssociationGuidelinesforCardiopulmonaryResuscitation andEmergencyCardiovascularCare.Circulation2010;122:S768–86.

26.OnettiY,DantasAP,PerezB,etal.Middlecerebralarteryremodelingfollowing transientbrainischemiaislinkedtoearlypostischemichyperemia:atargetof uricacidtreatment.AmJPhysiolHeartCircPhysiol2015;308:H862–74.

27.PinardE,EngrandN,SeylazJ.Dynamiccerebralmicrocirculatorychangesin transientforebrainischemiainrats:involvementoftypeInitricoxidesynthase. JCerebBloodFlowMetab2000;20:1648–58.

28.BisschopsLL,vanderHoevenJG,Hoedemaekers CW.Effects ofprolonged mildhypothermiaoncerebralbloodﬂowaftercardiacarrest.CritCareMed 2012;40:2362–7.