Content uploaded by Corstiaan den Uil
Author content
All content in this area was uploaded by Corstiaan den Uil on Mar 15, 2021
Content may be subject to copyright.
Membranes2021,11,208.https://doi.org/10.3390/membranes11030208www.mdpi.com/journal/membranes
Article
InitialArterialpCO
2
anditsCourseintheFirstHours
ofExtracorporealCardiopulmonaryResuscitationShowNo
AssociationwithRecoveryofConsciousnessinHumans:
ASingle‐CentreRetrospectiveStudy
LoesMandigers
1,
*,CorstiaanA.denUil
1,2
,JeroenJ.H.Bunge
1,2
,DiederikGommers
1
andDinisdosReisMiranda
1,
*
1
DepartmentofIntensiveCare,ErasmusMCUniversityMedicalCenter,
3015GDRotterdam,TheNetherlands;c.denuil@erasmusmc.nl(C.A.d.U.);j.bunge@erasmusmc.nl(J.J.H.B.);
d.gommers@erasmusmc.nl(D.G.)
2
DepartmentofCardiology,ErasmusMCUniversityMedicalCenter,3015GDRotterdam,TheNetherlands
*Correspondence:l.mandigers@erasmumc.nl(L.M.);d.dosreismiranda@erasmusmc.nl(D.d.R.M.);
Tel.:+31‐010‐703‐5142(D.d.R.M.)
Abstract:Background:Cardiacarrestisasevereconditionwithhighmortalityrates,especiallyin
thecaseofprolongedlow‐flowdurationsresultinginsevereischaemiaandreperfusioninjury.
Changesinpartialcarbondioxideconcentration(pCO
2
)mayaggravatethisinjury.Extracorporeal
cardiopulmonaryresuscitation(ECPR)shortensthelow‐flowdurationandenablescloseregulation
ofpCO
2
.WeexaminedwhetherpCO
2
isassociatedwithrecoveryofconsciousness.Methods:We
retrospectivelyanalysedECPRpatients≥16yearsoldtreatedbetween2010and2019.Weevaluated
initialarterialpCO
2
andthecourseofpCO
2
≤6hafterinitiationofECPR.Theprimaryoutcomewas
therateofrecoveryofconsciousness,definedasGlasgowcomascalemotorscoreofsix.Results:
Outof99ECPRpatients,84patientswereeligibleforthisstudy.Themeanagewas47years,63%
weremale,93%hadawitnessedarrest,45%hadanout‐of‐hospitalcardiacarrest,and38%hada
recoveryofconsciousness.NeitherinitialpCO
2
(OddsRatio(OR)0.93,95%confidenceinterval95%
(CI)0.78–1.08)normaximumdecreaseofpCO
2
(OR1.03,95%CI0.95–1.13)wasassociatedwiththe
recoveryofconsciousness.Conclusion:InitialarterialpCO
2
andthecourseofpCO
2
inthefirstsix
hoursafterinitiationofECPRwerenotassociatedwiththerecoveryofconsciousness.
Keywords:cardiacarrest;heartarrest;extracorporealcardiopulmonaryresuscitation;
extracorporealmembraneoxygenation;carbondioxide;outcome
1.Introduction
Survivalandfavourableneurologicalsurvivalaftercardiacarrestarehighly
influencedbylow‐flowdurationandtheassociatedseverityofischaemiaandreperfusion
injury[1].Thisischaemiaandreperfusioninjuryisinfluencedbythelevelandcourseof
partialoxygenpressure(pO
2
)andpartialcarbondioxidepressure(pCO
2
)duringandafter
cardiopulmonaryresuscitation(CPR)[2].DuringCPR,hypoxemiacausesneuron
ischaemiaandcelldeathwhereashypercapniacausescerebrovascularvasodilatation,
whichmayraiseintracranialpressure[2].Afterregainingcirculation,pO
2
andpCO
2
will
changeimmediately,whichcancontributetoreperfusioninjury.Especiallyinthecaseof
hyperoxemia,oxygen‐freeradicalswillbeproducedcausingintracellularoxidation.If
hypocapniaoccurs,thiswillresultincerebrovascularvasoconstriction,causinga
decreasedCBF[2].Clinically,theimportanceofregulatingpO
2
duringandafter
Citation:Mandigers,L.;denUil,
C.A.;Bunge,J.J.H.;Gommers,D.;
dosReisMiranda,D..InitialArterial
pCO
2
andItsCourseintheFirst
HoursofExtracorporeal
CardiopulmonaryResuscitation
ShowNoAssociationwithRecovery
ofConsciousnessinHumans:
ASingle‐CentreRetrospective
Study.Membranes2021,11,208.
https://doi.org/10.3390/
membranes11030208
AcademicEditor:GennaroMartucci
Received:20February2021
Accepted:9March2021
Published:15March2021
Publisher’sNote:MDPIstays
neutralwithregardtojurisdictional
claimsinpublishedmapsand
institutionalaffiliations.
Copyright:©2021bytheauthors.
LicenseeMDPI,Basel,Switzerland.
Thisarticleisanopenaccessarticle
distributedunderthetermsand
conditionsoftheCreativeCommons
Attribution(CCBY)license
(http://creativecommons.org/licenses
/by/4.0/).
Membranes2021,11,2082of10
conventionalCPRhasalreadybeenproven[3–5].However,researchinpCO2valuesis
morelimitedandtheresultsvaryalot[3,5–7].
Inanattempttolimitischaemiaandreperfusioninjury,extracorporeal
cardiopulmonaryresuscitation(ECPR)canbeusedtorestorecirculationtovitalorgans
assoonaspossible.TheuseofthisECPRenablesveryfastoxygenationand
decarboxylation.However,itisnotclearwhetherthesechangesinpO2andpCO2should
occurrapidly.InpatientstreatedwithECPR,hypoxemiaaswellashyperoxemiaare
associatedwithlowersurvivalrates[8,9].Thebestneurologicalsurvivaloutcomesare
seeninpatientswithnormoxia.[8].DespitethepossibleeffectsofpCO2inischaemiaand
reperfusion,limitedstudieshavebeenperformedonthecourseofpCO2duringandafter
ECPR.ArecentstudyshowedthatalargedecreaseofpCO2afterinitiationof
extracorporealmembraneoxygenation(ECMO)forrespiratoryfailureisassociatedwith
neurologicalcomplications[10].
WehypothesisethatinECPR,arapiddecreaseinpCO2couldsimulatetheoccurrence
ofhypocapnia,leadingtocerebralvasoconstriction,whichcouldhaveanegativeimpact
onneurologicaloutcomes.Therefore,theaimofthisstudywastoinvestigatethe
associationbetweenpCO2inthefirsthoursafterinitiationofECPRandtherecoveryof
consciousness.
2.MaterialsandMethods
WeperformedaretrospectivestudyattheErasmusUniversityMedicalCentrein
Rotterdam,theNetherlands.Thishospitalhasalocaldatabaseinwhichalladultpatients
treatedattheemergencydepartmentand/orpatientsof≥16yearsoldadmittedtothe
intensivecareunit(ICU)foradults,treatedwithECMOareregistered.Thestudywas
conductedinaccordancewiththeDeclarationofHelsinki,andtheMedicalEthics
CommitteeoftheErasmusUniversityMedicalCentrereviewedandapprovedthestudy
protocol(numberMEC‐2019‐0681).Theneedforinformedconsentwaswaived.
2.1.Patients
AllpatientstreatedwithECMOwhoreceivedECPRintheperiod1January2010
until1January2020wereselected.AfterinitiationofECPR,atleastthreearterialblood
gasanalyseswithinthefirst6hhadtobeknown.Weexcludedallpatientswithreturnof
spontaneouscirculation(ROSC)beforeECPRinitiation.Inourhospital,weconsider
ECPRinbothoutofhospitalcardiacarrest(OHCA)andin‐hospitalcardiacarrest(IHCA)
patientswhenthefollowingcriteriaaremet:age≤70years,witnessedcardiacarrest(last
seen<5min),goodqualityofbasiclifesupport(BLS)oradvancedlifesupport(ALS)
leadingtoanend‐tidalcarbondioxide>1.33kPa,maximumno‐flowtimeof5min,alow
flowdurationof<60minatthestartofECPRplacement,noknownterminalillnesses,and
noimpairmentofdailylivingactivities.
2.2.ECPRProcedure
ECPRplacementwasperformedbyaninterventionalcardiologist,cardiothoracic
surgeonorintensivist,dependingonthelocationwherethepatientresided.This
procedureismostlyperformedpercutaneouslyandultrasound‐guided.Inthecasethisis
notsuccessful,orifitisperformedintheoperationroom,itisperformedsurgically.The
cannulasareplacedinthefemoralarteryandfemoralvein.Everypatientreceivesan
antegradecannulainordertoperfusethelegdistallyfromthecannulaplacement.
CannulationwasstartedataminimumCPRdurationof20min.Thedecisiontocontact
theECPRteamwasmadebytheattendingintensivist.ForOHCApatients,wefirststarted
withECPRproceduresinpatientswithmassivepulmonaryembolismasthecauseof
arrest.Startingfrom1February2019,everyOHCApatientcouldbeeligibleforECPR.
Membranes2021,11,2083of10
2.3.MeasuredVariables
Weextractedthefollowingvariables:patientcharacteristics(sex,age,andbodymass
index(BMI));clinicalcharacteristics(AcutePhysiologyandChronicHealthEvaluation
(APACHE)IV‐score,witnessedthearrest,OHCA/IHCA,BLS,directlifesupport(i.e.,BLS
orALS);no‐flowduration,low‐flowduration,mechanicalcompressiondevice,primary
cardiacrhythm,locationofarrest,causeofarrest,laboratoryresults,andcomplications);
andoutcomes(primaryoutcome:recoveryofconsciousnessandsecondaryoutcomes:
ECMOsurvival,ICU‐survival,hospitalsurvival,andcauseofdeath).Allknownpre‐
ECMOdatawerereportedaccordingtotheUtsteincriteria[11].
2.4.StatisticalAnalysis
ThedistributionofthevariableswastestedusingtheShapiro–Wilktest.Normally
distributedcontinuousvariableswerereportedasmeanandstandarddeviation(SD),and
categoricalvariablesasnumbersandpercentages(%).Non‐normallydistributed
continuousvariableswerereportedasmedianandinterquartileranges(IQR).Tostudy
statisticaldifferencesofcontinuousvariables,weusedtheunpairedT‐testfornormally
distributedvariablesandtheMann–WhitneyUtestfornon‐normallydistributed
variables.Forthecategoricalvariables,weusedtheChi2testortheFisher’sexacttest
dependingonthenumbersineachcell.
ToexaminethepossibleeffectofpCO2onourprimaryoutcome,weperformeda
binarylogisticregressionanalysis.WeincludedthefollowingpCO2values:initialpCO2
valueafterinitiationofEPCR(definedasthefirstarterialpCO2afterstartingECMOflow
orthelastpCO2withinfiveminutesbeforestartingECMOflow),courseofpCO2(defined
astheslopebetweenthefirstandlastpCO2measurementwithin6h),andtheinteraction
betweentheinitialpCO2andthecourseofpCO2.Next,weperformedabinarylogistic
regressionanalysisincludingtheinitialpCO2valueafterinitiationofEPCR,themaximum
decreaseofpCO2(definedasthemaximumpercentageofdecreaseperhourbetweentwo
measurementswithin6hafterinitiationofECPR),andtheinteractionbetweentheinitial
pCO2andthemaximumdecreaseofpCO2.Assensitivityanalyses,weperformedbinary
logisticregressionanalysisforsustainedregainofconsciousnessathospitaldischargeand
expectedaneurologicallyfavourableoutcomeatanytimeafterhospitaldischarge.This
expectedfavourableneurologicaloutcomewasdeterminedbyreviewingpatientcharts.
Ap‐value<0.05wasdefinedasstatisticallysignificantandtheanalyseswereperformed
inRstudio,version3.6.0.
3.Results
InourECMOdatabase,99patientsunderwentECPR.Weexcludedpatientswithtwo
orlessarterialbloodgasmeasurementsafterinitiationofECPR(n=11),andweexcluded
patientswithROSCbeforeECPRinitiation(n=4).Atotalof84patientswereincludedin
thisstudy,ofwhich32(38%)hadarecoveryofconsciousnessattheICU.Patient
characteristics,clinicalcharacteristics,andoutcomesareshowninTable1.
Table1.Characteristicsofextracorporealcardiopulmonaryresuscitation(ECPR)patientsfor
patientswhodidanddidnotexperiencearecoveryofconsciousness.
Total
Recoveryof
Consciousness
(N=32)
NoRecoveryof
Consciousness
(N=56)
p‐Value
Patientnumber
(%)8432(38.1)52(61.9)
Patient
characteristics
Membranes2021,11,2084of10
Ageinyears(SD)46.9(15.6)47.1(15.5)46.7(15.7)0.91
Sex;Male(%)53(63.1)19(59.4)34(65.4)0.75
BMI(IQR)26.3(24.6–29.8)26.5(25.2–30.1)25.8(24.5–29.4)0.40
Clinical
characteristics
APACHEIV‐
score(SD)
(MissingN=36)
112(31)110(36)113(27)0.74
Witnessedarrest
(%)78(92.9)31(96.9)47(90.4)0.40
OHCA(%)38(45.2)13(40.6)25(48.1)0.66
BLS(%)37(44.0)15(46.9)22(42.3)0.85
Directlife
support(%)79(94.0)30(93.8)49(94.2)1.00
No‐flowin
minutes(IQR)0(0–0)0(0–0)0(0–0)0.25
Totallow‐flow
durationin
minutes(IQR)
(MissingN=3)
51.0(37.0–80.0)45.0(30.0–76.5)58.0(40.0–84.0)0.24
Mechanical
compression
device,e.g.,
LUCAS(%)
27(32.1)6(18.8)21(41.2)0.06
Primarycardiac
rhythm
Shockable(%)26(31.0)11(34.4)15(29.4)0.82
Ventricular
fibrillation(%)23(27.4)9(28.0)14(28.1)1.00
Ventricular
tachycardia(%)3(3.6)2(6.3)1(2.0)0.56
Non‐shockable
(%)57(68.7)21(65.6)36(70.6)0.82
Pulseless
electricalactivity
(%)
47(56.0)20(62.5)27(54.0)0.60
Asystole(%)9(10.7)1(3.1)8(16.0)0.08
Locationofarrest
Home(%)23(27.4)8(25.0)15(28.8)0.90
Public(%)13(15.5)5(15.6)8(15.4)1.00
ICU(%)24(28.6)9(28.1)16(30.8)0.99
Ward(%)10(11.9)3(9.4)7(13.5)0.73
Emergency
department(%)4(4.8)1(3.1)3(5.8)1.00
Operationroom
(%)4(4.8)3(9.4)1(1.9)0.15
Catherisation
laboratory(%)3(3.6)3(9.4)0(0.0)0.14
Other(%)1(1.2)0(0.0)1(1.9)1.00
Membranes2021,11,2085of10
Causeofarrest
Acutecoronary
syndrome(%)25(29.8)12(37.5)13(25.0)0.33
Pulmonary
embolism(%)30(35.7)11(34.4)19(36.5)1.00
Tamponade(%)3(3.6)2(6.3)1(1.9)0.55
Hypothermia/dr
owning(%)5(6.0)1(3.1)4(7.8)0.64
Postcardiac
surgery(%)2(2.4)0(0.0)2(3.8)0.52
Myocarditis(%)3(3.6)2(6.3)1(1.9)0.55
Heartfailure(%)3(3.6)2(6.3)1(1.9)0.55
Hypoxemia(%)2(2.4)0(0.0)2(3.8)0.52
Sepsis(%)2(2.4)1(3.1)1(1.9)1.00
Other(%)7(8.3)0(0.0)7(12.5)0.04
Unknown(%)2(2.4)1(3.1)1(1.9)1.00
Complications
Bleeding(%)56(66.7)24(75)32(61.5)0.30
Limbischaemia
(%)5(6.0)2(6.3)3(5.8)1.00
Cerebrovascular
accident(%)6(7.1)4(12.5)2(3.8)
Cerebral
bleeding(%)5(6.0)3(9.4)2(3.8)0.36
Cerebral
infarction(%)1(1.2)1(3.1)0(0.0)0.38
Infection(%)28(33.3)16(50.0)12(25.0)0.04
Acutekidney
injury(%)43(51.2)21(65.6)23(44.2)0.09
CRRT(%)15(17.9)6(18.8)9(17.3)1.00
Tamponade(%)6(7.1)2(6.3)4(7.7)1.00
Abdominal
compartment
syndrome(%)
4(4.8)1(3.1)3(5.8)1.00
Laboratory
results
InitialpCO2in
kPa(IQR)7.3(5.7–9.9)7.1(5.3–8.9)7.7(6.0–9.9)0.30
CourseofpCO2
in%/h(IQR)
−5.22(−8.69to
−1.99)
−4.09(−8.38to
−1.30)
−6.28(−8.69to
−2.08)0.37
Maximum
decreasepCO2
in%/hour(IQR)
0.67(0.38–1.06)0.58(0.24–1.06)0.72(0.41–0.82)0.43
Maximum
differencepCO2
in%/hour(IQR)
−0.52(−0.87to
0.39)
−0.30(−0.88to
0.08)
−0.59(−0.86to
0.71)0.76
InitialpO2inkPa
(IQR)25.3(10.8–43.5)17.4(9.4–42.5)32.8(11.5–47.1)0.10
Membranes2021,11,2086of10
CourseofpO2
in%/hour(IQR)
−6.29(−11.65to
9.31)
−4.26(−12.85to
12.53)
−7.15(−11.30to
5.97)0.90
InitialpH(IQR)6.96(6.80–7.08)7.07(6.84–7.21)6.90(6.79–7.00)<0.01
CourseofpH
in%/hour(SD)0.68(0.53)0.68(0.48)0.69(0.57)0.98
Initiallactatein
mmol/L(SD)13.7(5.8)12.5(6.0)14.5(5.7)0.14
Courseoflactate
in%/h(IQR)
−7.44(−11.89to
−1.33)
−10.38(−12.98to
−5.06)
−6.11(−11.12to
−5.48)<0.05
Outcomes
ECMOsurvival
(%)32(38.1)28(87.5)4(7.7)<0.01
ICU‐survival(%)25(29.8)24(75.0)1(1.9)<0.01
Hospitalsurvival
(%)24(28.6)23(71.9)1(1.9)
CauseofdeathN=59N=9N=50
Braindeath(%)5(8.5)0(0.0)5(10.0)1.00
Neurology(%)23(39.0)4(44.4)19(38.0)0.73
Cardiac(%)4(6.8)1(11.1)3(6.0)0.49
Haemorrhagic
shock(%)2(3.4)0(0.0)2(4.0)1.00
Multi‐organ
disease(%)14(23.7)2(22.2)13(26.0)1.00
Persistingcardiac
arrest(%)2(3.4)0(0.0)2(4.0)1.00
Other(%)7(11.9)2(22.2)5(10.0)0.29
Variableswerereportedasmeanandstandarddeviation(SD),medianandinterquartileranges
(IQR),andnumbersandpercentages(%)whenappropriate.ECPR:extracorporeal
cardiopulmonaryresuscitation,BMI:bodymassindex,APACHE:AcutePhysiologyandChronic
HealthEvaluation,OHCA:outofhospitalcardiacarrest,BLS:basiclifesupport,ICU:intensive
careunit,CRRT:continuousrenalreplacementtherapy,ECMO:extracorporealmembrane
oxygenation,T0:initialtimepoint,Tmax:maximumtimevalueknownwithin6hafterinitiation,
pCO2:partialcarbondioxideconcentration,pO2:partialoxygenconcentration.Bleedingwas
definedaseverycaseofbleedingthatneededanintervention(e.g.,bloodtransfusionorsurgical
repair)andtamponadewasdefinedasbloodinthepericardiumthatneededintervention.
3.1.ClinicalCharacteristics
Themeanageofthepatientswas47years(SD16),andthemajorityofthepatients
weremale(n=53,63%).AlmosthalfofthepatientshadanOHCA(n=38,45%),andin78
patients(93%)thearrestwaswitnessed.Themedianlow‐flowdurationwas51min(IQR
37–80).Thisdurationdidnotsignificantlydifferbetweenpatientswhorecovered
consciousnessversuspatientswhodidnotrecoverconsciousness.Mostpatientshada
non‐shockableprimarycardiacrhythm(n=57,69%).Wefoundnosignificantdifference
intheprimarycardiacrhythmforpatientswithandwithoutrecoveryofconsciousness.
Thecauseofarrestwasprimarilypulmonaryembolism(36%)followedbyacutecoronary
syndrome(30%).
3.2.LaboratoryResults
PatientswiththerecoveryofconsciousnesshadhighermedianpHvalues(7.07,IQR
6.84–7.21)thanpatientswithouttherecoveryofconsciousness(6.90,IQR6.79–7.00,p<
Membranes2021,11,2087of10
0.01).NodifferenceswereseenininitialpO2values(p=0.10)andinitiallactatevalues(p
=0.14)forpatientswiththerecoveryofconsciousnessandpatientswithouttherecovery
ofconsciousness.ThedecreaseinlactatevaluesfrominitiationofECPRuntilsixhours
afterinitiationofECPRwassignificantlyhigherinpatientswiththerecoveryof
consciousness(10.38%/h,IQR12.98–5.06)thaninpatientswithouttherecoveryof
consciousness(6.11%/hIQR11.12–5.48,p<0.05).Nosignificantdifferenceswerefoundin
changesofpHandpO2valuesfrominitiationofECPRuntilsixhoursafterinitiationof
ECPR.
3.3.Outcomes
Intotal,32patients(38%)couldbeweanedfromtheECMO:28(33%)ofthesepatients
recoveredconsciousness.Twenty‐fivepatients(30%)survivedICUadmission,and24
patients(29%)surviveduntilhospitaldischarge.Ofthose,onlyonepatient(2%)didnot
recoverconsciousness.ThispatientwastransferredtoanotherhospitalwithaGlasgow
comascalemotorscoreoffive.Inmostcases,thecauseofdeathwasneurologic(47%,of
which9%braindeathand39%otherneurologiccauses).
AsshowninTable2,theinitialpCO2orpCO2courseswerenotassociatedwiththe
recoveryofconsciousness.InSupplementaryMaterialFigureS1,weincludedthecourses
ofpCO2inthefirstsixhoursafterinitiationofECPRforeveryindividualpatient.Asa
sensitivityanalysis,weperformedthebinarylogisticregressionforpatientswhohada
sustainedrecoveryofconsciousnessathospitaldischarge.Theseresultsareshownin
SupplementaryMaterialTableS1.Additionally,wedeterminedanexpectedneurological
favourableoutcomebasedonpatientcharts(classifiedascerebralperformancecategory
(CPC)score1–2)atanytimefromhospitaldischarge,showninSupplementaryMaterial
TableS2.Wealsoperformedthebinarylogisticregressionbasedonthisoutcome.As
showninSupplementaryMaterialTableS3,thesesensitivityanalyses,nosignificant
differenceswerefound.
Table2.BinarylogisticregressionanalysisofECPRpatientsregardingpCO2measurementsand
therecoveryofconsciousness.
(a)(b)(c) (d)(e)
InitialpCO20.93(0.78–
1.09)
0.97(0.79–
1.20)
0.92(0.65–
1.30)
0.94(0.78–
1.12)
0.75(0.52–
1.05)
Courseof
pCO2infirst6
h
1.03(0.9–1.13)1.05(0.92–
1.26)
Interaction
initialand
coursepCO2
0.99(0.97–
1.02)
Maximum
decreaseof
pCO2infirst6
h
1.07(0.48–
2.30)
0.14(0.01–
2.07)
Interaction
initialand
maximum
decreasepCO2
1.29(0.93–
1.88)
N8383838080
Nagelkerke
R20.030.040.040.100.13
AIC113.82115.22117.06111.36111.02
Membranes2021,11,2088of10
Thevaluesaredisplayedasoddsratioswith95%confidenceintervals(CI).T0:initial
values,pCO2:partialcarbondioxideconcentration.
4.Discussion
Inthisstudy,wefoundthatinitialpCO2valuesandthecourseofpCO2afterinitiation
ofECPRarenotassociatedwiththerecoveryofconsciousness.Wealsofoundno
significantdifferenceforinitialpO2values,courseofpO2andpH,andinitiallactate
values.Inpatientswithrecoveryofconsciousness,wefoundasignificantlyhigherinitial
pHandasignificantlymorerapiddecreaseoflactatethaninpatientswithoutrecoveryof
consciousness.
Contrarytoourhypothesis,recoveryofconsciousnesswasnotassociatedwithaless
rapiddecreaseofpCO2inthefirsthoursafterinitiationofECPR.Basedonthesefindings,
arapiddecreaseofpCO2untilnormocapniamightnotnegativelyinfluencecerebral
perfusion.SomestudiesperformedinpatientstreatedwithconventionalCPRexamined
theeffectsofpCO2onsurvival.Wangetal.[5]evaluatedthepresenceofhypercapniaand
hypocapniainthefirst24hafterhospitalarrival.Theyfoundincreasedhospitalmortality
inthecaseofanyhypercapniaorforfinalhypocapnia[5].Helmerhorstetal.[3]found
onlyincreasedhospitalmortalityinthecaseofasinglemeasurementofhypocapniainthe
first24hinpatientsadmittedtotheICUintheNetherlands.Incontrasttothesetwo
studies,Vaahersaloetal.[7]foundapositiveassociationforthedurationofhypercapnia
withinthefirst24hongoodneurologicaloutcome.However,thesestudiesdidnot
evaluatetheeffectsofthecourseofpCO2ontheoutcome.Ebneretal.[6]didstudythis
courseofpCO2incardiacarrestpatientsnottreatedwithECPR.Similartoourresults,
theyhaveshownnosignificantassociationofmaximumamplitudeinpCO2withpoor
neurologicaloutcome.Additionally,theyalsofoundnosignificantdifferenceforanarea
underthecurveanalysisforthefirstfourpCO2measurementsaswellasallpCO2
measurementsandneurologicaloutcomes[6].InastudybyBemtgenetal.[12],pCO2
valuesweremeasuredseveraltimesinthefirst24hafterECPRinitiation.Theyfoundno
significantdifferenceinsurvivalforpatientswithhypercapnia,hypocapnia,and
normocapnia[12].
Inadditiontoourprimaryoutcome,wefoundthreeotherresultsintheunivariate
analyses.First,wefoundatrendforlowerinitialpO2valuesinpatientswithrecoveryof
consciousnessthaninpatientswithoutrecoveryofconsciousness.Thisisinlinewiththe
recentstudybyHalteretal.[9]TheyhaveshownthatECPRpatientswithhyperoxemia
hadahigheroddsratio(OR)formortalityatday28(OR1.89,95%confidenceinterval(CI)
1.74–2.07)[9].Thesefindingssuggestthattheoutcomemaybeimprovedbyusingan
oxygenblenderwithcarefultitrationofthepercentageofoxygenformembranegasflow.
Second,inthisstudy,patientswithrecoveryofconsciousnesshadaslightlyhigher
initialpHthanpatientswithoutrecoveryofconsciousness.Acomparableresultwas
foundbyBemtgenetal.[12],whohaveshownhighersurvivalratesinpatientswith
higherpHvaluesduringthefirst24hafterinitiationofECPR.However,whencompared
withthestudyofBartosetal.[13],itseemsthatpHvaluesbeforeECPRinitiationarenot
associatedwithsurvivalwithfavourableneurologicaloutcomes.Despitethepossible
positiveassociationofhigherpHandfavourableoutcomes,thedifferencesaresmall(the
differenceofmedianpHbetweenpatientswithandwithoutrecoveryofconsciousness
was0.17).Therefore,itisstillnotpossibletodetermineatwhichpHapatientwillorwill
notbeeligibleforECPR.
Last,wefoundahigherlactatedecreaseinthefirstsixhoursafterinitiationofECPR
inpatientswhohadrecoveryofconsciousnessthaninpatientswithoutrecoveryof
consciousness.Thissignificantdifferenceinlactateclearanceisinlinewiththeresults
foundbyMizutanietal.[14].Theyfoundaneurologicallyfavourablesurvivalrate
(cerebralperformancecategory1–2)of63.1%inpatientswithhighlactateclearanceanda
neurologicallyfavourablesurvivalrateof22.2%inpatientswithlowlactateclearance
afterECPR.
Membranes2021,11,2089of10
Thisstudyalsohadsomelimitations.First,thearterialbloodgassamplingwasnot
scheduled,sothemeasurementswereperformedbyindicationdecidedbythetreating
physicians.Therefore,thenumberofsamplesaswellasthetimebetweenthesampleswas
varyingalotandcouldhaveinfluencedtheoutcomeofthestudy.Inordertominimize
thisinfluence,wedividedthesamplesintotimeframes.Second,thenumberofincluded
patientswasquitesmall.Duetothissmallsample,wewerenotabletoperforma
multivariablelogisticregressionanalysis.Therewerenosignificantdifferencesbetween
thepatientcharacteristicsandcardiacarrestcharacteristicsofthepatientswithand
withoutrecoveryofconsciousness.However,someofthecardiacarrestcharacteristics
couldhaveinfluencedtheoutcome.Third,weincludedahighrateofpatientswithnon‐
cardiaccausesofarrest.InordertodetermineiftheinitialpCO2orlow‐flowdurationin
patientswithcardiacversusnon‐cardiaccausesofarrestinfluencedtheoutcome,we
studiedthesevariablesanddidnotfindastatisticallysignificantdifference.Fourth,inthis
studywefoundhighratesofBLSinOHCApatients,shortno‐flowdurations,andlimited
low‐flowdurations.IntheNetherlands,bystanderCPRrates,populationeducatedto
performbystanderCPR,anduseofanautomaticexternaldefibrillator(AED)ishighand
risingeveryyear.[15,16]InourECPRprogram,weselectpatientswithanassumedhigh
chanceoffavourableoutcomes(i.e.,patientswithwitnessedarrest,shortno‐flowtimes,
highqualityofCPR,andlow‐flowdurationsof<60min).TheselectionofECPRpatients,
highCPReducation,andAEDuseprobablyexplainsthehighratesofdirectstartofBLS
andassociatedshortno‐flowdurationsinthisstudy.Last,duetothehypothesis,itcould
bethatthephysicianshaveadjustedtheECPRsettingsinordertopreventarapiddecrease
inpCO2.Thiscouldresultinlowermaximumdecreases.Therefore,itwouldbeadvisable
torepeatthisstudyinanotherpatientsample.
WedidnotfindanassociationbetweenthecourseofpCO2inthefirsthoursafter
initiationofECPRandtherecoveryofconsciousness.Futurestudiesshouldfocuson
performinganalysesofarterialbloodgasvaluesafterinitiationofECPRinorderto
determinethemostoptimalECMOsettingsforneurologicalfavourableoutcomes.These
studiesshouldbeperformedinlargersamplesandwithbloodgasanalysesatsettime
points.
5.Conclusions
InitialarterialpCO2andthecourseofpCO2inthefirstsixhoursafterinitiationof
ECPRwerenotassociatedwiththerecoveryofconsciousness.
SupplementaryMaterials:Thefollowingareavailableonlineatwww.mdpi.com/2077‐
0375/11/3/208/s1,FigureS1:CourseofarterialpCO2inpatientswithandwithoutrecoveryof
consciousness,TableS1:BinarylogisticregressionanalysisofECPRpatientsregardingpCO2
measurementsandpersistingrecoveryofconsciousness(GCS6athospitaldischarge),TableS2:
CPCscoresandexpectedCPCscoresatanytimeafterhospitaldischarge,TableS3:Binarylogistic
regressionanalysisofECPRpatientsregardingpCO2measurementsandexpectedfavourable
neurologicaloutcome.
AuthorContributions:L.M.participatedinthestudydesign,analysedandinterpretedthepatient
data,anddraftedthemanuscript.C.A.d.U.participatedinthestudydesign,helpedinterpretthe
results,andwasamajorcontributorinwritingthemanuscript.J.J.H.B.wasacontributorin
writingthemanuscript.D.G.participatedinthestudydesignandwasacontributorinwritingthe
manuscript.D.d.R.M.majorlycontributedtotheconceptionofthestudy,participatedinthestudy
design,helpedinterprettheresults,andwasamajorcontributorinwritingthemanuscript.All
authorshavereadandagreedtothepublishedversionofthemanuscript.
Funding:Thisresearchreceivednoexternalfunding.
InstitutionalReviewBoardStatement:Thestudywasconductedinaccordancewiththe
DeclarationofHelsinki,andtheMedicalEthicsCommitteeoftheErasmusUniversityMedical
Centrereviewedandapprovedthestudyprotocol(numberMEC‐2019‐0681),date23February2020.
Membranes2021,11,20810of10
InformedConsentStatement:PatientconsentwaswaivedbytheMedicalEthicsCommitteedueto
onlyincludingretrospectivechartinformation.
EthicsStatements:TheMedicalEthicsCommitteeofthisinstitutionreviewedandapprovedthe
studyprotocol(numberMEC‐2019‐0681).Theneedforconsentwaswaived.
AvailabilityofDataandMaterials:Thedatasetsusedandanalysedduringthecurrentstudyare
availablefromthecorrespondingauthoronreasonablerequest.
ConflictsofInterest:Theauthorsdeclarenoconflictofinterest.
References
1. Rea,T.D.;Cook,A.J.;Hallstrom,A.CPRduringischemiaandreperfusion:Amodelforsurvivalbenefits.Resuscitation2008,77,
6–9.
2. Sekhon,M.S.;Ainslie,P.N.;Griesdale,D.E.Clinicalpathophysiologyofhypoxicischemicbraininjuryaftercardiacarrest:A
“two‐hit”model.Crit.Care2017,21,1–10.
3. Helmerhorst,H.J.;Roos‐Blom,M.J.;vanWesterloo,D.J.;Abu‐Hanna,A.;deKeizer,N.F.;deJonge,E.Associationsofarterial
carbondioxideandarterialoxygenconcentrationswithhospitalmortalityafterresuscitationfromcardiacarrest.Crit.Care2015,
19,348.
4. Roberts,B.W.;Kilgannon,J.H.;Hunter,B.R.;Puskarich,M.A.;Pierce,L.;Donnino,M.;Leary,M.;Kline,J.A.;Jones,A.E.;Shapiro,
N.I.;etal.AssociationBetweenEarlyHyperoxiaExposureAfterResuscitationFromCardiacArrestandNeurologicalDisability:
ProspectiveMulticenterProtocol‐DirectedCohortStudy.Circulation2018,137,2114–2124.
5. Wang,H.E.;Prince,D.K.;Drennan,I.R.;Grunau,B.;Carlbom,D.J.;Johnson,N.;Hansen,M.;Elmer,J.;Christenson,J.;
Kudenchuk,P.;etal.Post‐resuscitationarterialoxygenandcarbondioxideandoutcomesafterout‐of‐hospitalcardiacarrest.
Resuscitation2017,120,113–118.
6. Ebner,F.;Harmon,M.B.;Aneman,A.;Cronberg,T.;Friberg,H.;Hassager,C.;Juffermans,N.;Kjærgaard,J.;Kuiper,M.;
Mattsson,N.;etal.Carbondioxidedynamicsinrelationtoneurologicaloutcomeinresuscitatedout‐of‐hospitalcardiacarrest
patients:AnexploratoryTargetTemperatureManagementTrialsubstudy.Crit.Care2018,22,196.
7. Vaahersalo,J.;Bendel,S.;Reinikainen,M.;Kurola,J.;Tiainen,M.;Raj,R.;Pettilä,V.;Varpula,T.;Skrifvars,M.B.;FINNRESUSCI
StudyGroup.Arterialbloodgastensionsafterresuscitationfromout‐of‐hospitalcardiacarrest:Associationswithlong‐term
neurologicoutcome.Crit.CareMed.2014,42,1463–1470.
8. Chang,W.T.;Wang,C.H.;Lai,C.H.;Yu,H.Y.;Chou,N.K.;Wang,C.H.;Huang,S.‐C.;Tsai,P.R.;Chou,F.‐J.;Tsai,M.‐S.;etal.
OptimalArterialBloodOxygenTensionintheEarlyPostresuscitationPhaseofExtracorporealCardiopulmonaryResuscitation:
A15‐YearRetrospectiveObservationalStudy.Crit.CareMed.2019,47,1549–1556.
9. Halter,M.;Jouffroy,R.;Saade,A.;Philippe,P.;Carli,P.;Vivien,B.Associationbetweenhyperoxemiaandmortalityinpatients
treatedbyeCPRafterout‐of‐hospitalcardiacarrest.Am.J.Emerg.Med.2020,38,900–905.
10. Cavayas,Y.A.;Munshi,L.;DelSorbo,L.;Fan,E.TheEarlyChangeinPaCO2afterExtracorporealMembraneOxygenation
InitiationIsAssociatedwithNeurologicalComplications.Am.J.Respir.Crit.CareMed.2020,201,1525–1535.
11. Nolan,J.P.;Berg,R.A.;Andersen,L.W.;Bhanji,F.;Chan,P.S.;Donnino,M.W.;Lim,S.H.;Ma,M.H.‐M.;Nadkarni,V.M.;Starks,
M.A.;etal.CardiacArrestandCardiopulmonaryResuscitationOutcomeReports:UpdateoftheUtsteinResuscitationRegistry
TemplateforIn‐HospitalCardiacArrest:AConsensusReportFromaTaskForceoftheInternationalLiaisonCommitteeon
Resuscitation(AmericanHeartAssociation,EuropeanResuscitationCouncil,AustralianandNewZealandCouncilon
Resuscitation,HeartandStrokeFoundationofCanada,InterAmericanHeartFoundation,ResuscitationCouncilofSouthern
Africa,ResuscitationCouncilofAsia).Circulation2019,140,e746–e757.
12. Bemtgen,X.;Schroth,F.;Wengenmayer,T.;Biever,P.M.;Duerschmied,D.;Benk,C.;Bode,C.;Staudacher,D.L.Howtotreat
combinedrespiratoryandmetabolicacidosisafterextracorporealcardiopulmonaryresuscitation?Crit.Care2019,23,183.
13. Bartos,J.A.;Grunau,B.;Carlson,C.;Duval,S.;Ripeckyj,A.;Kalra,R.;Raveendran,G.;John,R.;Conterato,M.;Frascone,R.J.;et
al.ImprovedSurvivalWithExtracorporealCardiopulmonaryResuscitationDespiteProgressiveMetabolicDerangement
AssociatedWithProlongedResuscitation.Circulation2020,141,877–886.
14. Mizutani,T.;Umemoto,N.;Taniguchi,T.;Ishii,H.;Hiramatsu,Y.;Arata,K.;Takuya,H.;Inoue,S.;Sugiura,T.;Asai,T.;etal.
Thelactateclearancecalculatedusingserumlactatelevel6hafterisanimportantprognosticpredictorafterextracorporeal
cardiopulmonaryresuscitation:Asingle‐centerretrospectiveobservationalstudy.J.IntensiveCare2018,6,33.
15. Blom,M.T.;Beesems,S.G.;Homma,P.C.M.;Zijlstra,J.A.;Hulleman,M.;VanHoeijen,D.A.;Bardai,A.;Tijssen,J.G.P.;Tan,H.L.;
Koster,R.W.ImprovedSurvivalAfterOut‐of‐HospitalCardiacArrestandUseofAutomatedExternalDefibrillators.Circulation
2014,130,1868–1875.
16. Hartstichting.Jaarverslag2019.WerkenaaneenHartgezondeSamenleving.Availableonline:
https://magazines.hartstichting.nl/jaarverslag2019/cover/?_ga=2.261012493.1236433838.1615061661‐1639466317.1605858018
(accessedon5March2021).
