Expired carbon dioxide during newborn resuscitation as predictor of outcome

Clinical paper

Expired carbon dioxide during newborn resuscitation as predictor of outcome

Kari Holte

*, Hege Ersdal

, Claus Klingenberg

, Joar Eilevstjønn

, Hein Stigum

, Samwel Jatosh

, Hussein Kidanto

, Ketil Størdal

aDepartmentofPaediatricsandAdolescenceMedicine,ØstfoldHospitalTrust,Norway

bFacultyofHealthSciences,UniversityofStavanger,Norway

cCriticalCareandAnaesthesiologyResearchGroup,StavangerUniversityHospital,Norway

dDepartmentofPaediatricsandAdolescenceMedicine,UniversityHospitalofNorthNorway,Tromsø,Norway

ePaediatricResearchGroup,FacultyofHealthSciences,UniversityofTromsø-ArcticUniversityofNorway,Tromsø,Norway

fStrategicResearchDepartment,LaerdalMedical,Stavanger,Norway

gNorwegianInstituteofPublicHealth,Oslo,Norway

hHaydomLutheranHospital,Mbulu,Manyara,Tanzania

iMedicalCollege,AgakhanUniversity,DaresSalaam,Tanzania

jDepartmentofPaediatricResearch,FacultyofMedicine,UniversityofOslo,Norway

Abstract

Aim:ToexploreandcompareexpiredCO2(ECO2)andheartrate(HR),duringnewbornresuscitationwithbag-maskventilation,aspredictorsof24-h outcome.

Methods:ObservationalstudyfromMarch2013toJune2017inaruralTanzanianhospital.Side-streammeasuresofECO2,ventilationparameters, HR,clinicalinformation,and24-houtcomewererecordedinlivebornbag-maskventilatednewbornswithinitialHR<120bpm.Weanalysedthedata usinglogisticregressionmodelsandcomparedareasunderthereceiveroperatingcurves(AUC)forECO2andHRwithinthreeselectedtimeintervals afteronsetofventilation(0 30s,30.1 60sand60.1 300s).

Results:Among434includednewborns(medianbirthweight3100g),378werealiveat24h,56haddied.BothECO2andHRwereindependently significantpredictorsof24-houtcome,withnodifferencesinAUCs.Inthefirst60sofventilation,ECO2addedextrapredictiveinformationcomparedto HRalone.After60s,ECO2lostsignificancewhenadjustedforHR.In70%ofnewbornswithinitialECO2<2%andHR<100bpm,ECO2reached2%

beforeHR100bpm.Survivalat24hwasreducedby17%perminutebeforeECO2reached2%and44%perminutebeforeHRreached100bpm.

Conclusions:HigherlevelsandafasterriseinECO2andHRduringnewbornresuscitationwereindependentlyassociatedwithimprovedsurvival comparedtopersistinglowvalues.ECO2increasedbeforeHRandmayserveasanearlierpredictorofsurvival.

Keywords:Newbornresuscitation,Bag-maskventilation,Expiredcarbondioxide,Heartrate,24Houroutcome

Abbreviations:AUC,areaunderthereceiveroperatingcurves;BMV,bag-maskventilation;BW,birthweight;bpm,beatsperminute;ECO2,expired carbondioxide;GA,gestationalage;HR,heartrate;Mbar,millibar;ROC,receiveroperatingcharacteristics;VTE,expiredtidalvolume.

* Correspondingauthorat:DepartmentofPaediatricsandAdolescenceMedicine,P.O.Box300,ØstfoldHospital,N-1714Grålum,Norway.

E-mailaddress:[email protected](K.Holte).

https://doi.org/10.1016/j.resuscitation.2021.05.018

0300-9572/©2021TheAuthor(s).PublishedbyElsevierB.V.ThisisanopenaccessarticleundertheCCBYlicense(http://creativecommons.org/licenses/

by/4.0/).

Availableonlineatwww.sciencedirect.com

Resuscitation

j our na lho me pa g e :ww w. e l s e v i e r. c om/ l o ca t e / re s usc i ta t i on

Introduction

Adequate ventilation is the key to successful resuscitation in newborns who fail to initiatespontaneous breathing at birth. An increaseinheartrate(HR)iscurrentlyconsideredthemostimportant indicator for apositiveresponse to ventilations. HR response is, however,anindirectmeasuredependentonsufficientoxygendelivery totheheart,andgivesnodirectfeedbackonlungaerationandairway patency.The2015internationalconsensusfornewbornresuscitation mentioned expired carbon dioxide (ECO2) as a potentially more sensitivemarkerofeffectiveventilation,andstatedthatmoreresearch isneededtodeterminewhetherECO2monitoringisusefultoassess responsetoresuscitation.¹

Atbirthasuccessfultransitionfromplacentaltopulmonarygas exchangeiscriticalforsurvival.²ECO2mayserveasamarkerforlung aeration and pulmonary circulation.^3,4 ECO2 also depends on ventilation technique, and is used by resuscitation teams to aid recognizingairwayobstruction,maskleakandcorrectendotracheal tube placement.^{5 9} In cardiopulmonary resuscitation after the newbornperiod,persistinglowECO2isassociatedwithdecreased survival.^{10 12}Resultsfromclinicalstudiesinmainlypretermnew- borns suggest that ECO2 increases before HR during positive pressureventilationinthedeliveryroom.^3,13,14Lindeetal.foundthat medianECO2inthefirstminuteofbag-maskventilation(BMV)atbirth waslowerinnewbornswhodiedbefore24hofagecomparedto survivors.¹⁵

TheaimsofthisstudyweretoexploreECO2asapredictorof24-h outcome(survivalvsdeath)duringnewbornresuscitationwithBMV, andtocomparethepredictiveinformationofECO2andHR.

Methods

Studydesignandsetting

ThisdescriptiveobservationalstudyispartofSaferBirths,aresearch project on labour surveillance and newborn resuscitation in low- incomesettings.¹⁶WeuseddatacollectedbetweenMarch1st2013 andJune1st2017atHaydomLutheranHospital,aruralTanzanian referralhospitalwith3600 4600deliveriesannually.¹⁷

ThelocalprocedurefornewbornresuscitationfollowedHelping BabiesBreathe(HBB)emphasizingstimulationandearlyinitiationof BMV,excluding chestcompressions,intubationandmedication.¹⁸ Newbornresuscitation was mainlythe responsibilityof midwives.

Cord clamping was done prior to BMV. After resuscitation the midwivesdecided,basedontheclinicalcondition,whethertokeepthe newbornwiththemotherortransfertoaneonatalwardofferingbasic careincludingantibiotics,phototherapy,andintravenousfluids,butno respiratorysupportexceptsupplementaloxygenbynasalcannula.¹⁹

Datacollection

Anewbornresuscitationmonitor(LaerdalGlobalHealth,Stavanger, Norway)wasmountedonthewallaboveallresuscitationtables.²⁰ Eachmonitorwasequippedwithaself-inflatingbag(230mlstandard or320mlUprightbag-mask,LaerdalMedical,Stavanger,Norway) and adry-electrode ECGsensor to be easilyplaced around the newborns’trunk.Sensorsforside-streammeasuresofECO2(ISA^TM, Masimo,Irvine,California,USA),pressure(Freescalesemiconductor,

Austin,Texas,USA)andflow(AcutronicMedicalSystems,Hirzel, Switzerland)wereplacedbetweenthemaskandbag.Themonitors starteddatarecordingautomaticallywhenused,andprovidedHR feedbackduringresuscitation.ECO2andventilationparameterswere notdisplayed.Pulseoximetrywasnotavailable.Trainednon-medical researchassistants observed alldeliveries documenting perinatal information,timeintervals,and24-houtcomes.

Weincludedalllive-bornnewbornswithinitialHR<120beatsper minute(bpm)andavailabledataforbothECO2andHR(n=434) (Fig.1).Stillborns,definedlocallyasApgarscore0atboth1and5min orgestationalage(GA)<28weeks,wereexcluded.Wealsoexcluded newbornsventilatedwithpositiveend-expiratorypressureaspartofa concurrentrandomizedtrialasthiscouldpotentiallyaffectECO2and HR.²¹Datafromthesamecohortofnewbornswereusedinarecently published article on predictors of ECO2 during newborn resuscitation.²²

Regressionmodels

Tostudytheassociationsbetween24-houtcome(survivalvs.death) andthecovariates ECO2,HR,andexpiredtidalvolume(VTE),we performedlogisticregressionanalyses.Inthemainmodels,ECO2and HRwerestudiedindependently(unadjusted).Insecondarymodels, ECO2andHRweremutuallyadjusted,andthenadjustedforVTE. ECO2wasrecordedasmaximumpercentofexpiredairperventilation.

AllobservationsofECO2,regardlessofleakandVTE,wereincluded.

HRwassmoothedperapproximately12beatsperalgorithminthe monitor.

ExploringgraphsmadetodisplayECO2andHRbytimeinthefirst 300sofventilation(SupplementalFig.1),weselectedthreetime intervals(0 30s,30.1 60s,and60.1 300s)forfurtheranalyses.

DuetolargevariationsinespeciallyECO2(betweenventilations),we decidedtostudyboththesinglemaximumvalueandthemedianofall recordedECO2-andHR-valuespernewbornwithineachtimeinterval.

We also studied time from first delivered ventilation until ECO2

reached2%andHR100bpminsecondarymodels.Todetermine time to ECO2 2%, we used ECO2 smoothed as means per 5

Fig.1–Flowchart.

ventilations.ForVTE,themedianvaluepernewbornwithineachtime intervalwasused.

Non-linearassociationsbetweenECO2,HRand24-houtcome wereassessed bycategorical logisticregressionmodels. Dueto potentialdifferencesinpathophysiologybetweenpretermorsmallfor GAnewbornscomparedtotermnewborns,stratifiedanalysesforbirth weight(BW)2500gvs.<2500gwereperformed.

Furtheranalyses

Receiveroperatingcharacteristics(ROC)curvesgraphicallydisplay sensitivityasafunctionof1-specificityforallpossiblecutoffvaluesof thetestparametersindiagnostictestswithbinaryoutcomes.²³The areaundertheROCcurves(AUC) givesameasureforthetotal predictive information of the test parameters. To estimate the classificationaccuracyofECO2andHRaspredictorsof24-hsurvival, wemadeROCcurvesandcalculatedAUCforpredictedsensitivity andspecificityofthecovariates,basedontheresultsofthemain (unadjusted) logistic regression models. We used Pearson Chi SquareteststocomparetheAUCsformaximumECO2andHRwithin eachtimeinterval.Wefurtherplottedsensitivityandspecificityfor selectedcut-offvaluesformaximumECO2(1,2and4%)andHR (60,100and120bpm)intheROCs.WealsocalculatedAUCsforthe secondary (adjusted) models to estimate the total predictive informationofallincludedcovariates.

TheECO2andHRthresholdsof2%and100bpm,respectively, werestudiedinmoredetail.AmongnewbornswithinitialECO2<2%

andHR<100bpm,wecomparedtimeintervalsfromfirstventilation untilECO22%andHR100bpm.Weperformedposthocanalyses usingWilcoxonranksumteststoassessfordifferencesininitialHR, Apgar scores, BW and ventilation factors (VTE and mask leak) dependingonwhichthresholdwasreachedfirst.

Data processing and analyses were performed using Matlab (MathWorks,Natick,MA,USA)andStataSEversion16(StataCorp., Texas,USA).Significancelevelwassettop<0.05.

Ethicalconsiderations

EthicalapprovalwasgrantedbytheNationalInstituteforMedical Research in Tanzania (Ref. NIMR/HQ/R.8a/Vol.IX/1434) and the

Regional Committee for Medical andHealth Research Ethicsfor WesternNorway(Ref.2013/110).Allwomenwereinformed.Consent wasnotconsiderednecessarybytheethicalcommittees.

Results

Among 434 live born newborns who received BMV, with first registeredHR<120bpmandcompletedata,378survivedto24h, 56(12.9%)died(Fig.1).SurvivorshadsignificantlyhigherBWand Apgar scoresthan deaths andwereventilated for ashortertime (Table1).

ECO2andHRaspredictorsforsurvival

Both ECO2and HR increased during BMV, withhigher levels in survivorscomparedtodeaths(Fig.2andSupplementalFig.1).Odds ratiosfor24-hsurvivalincreasedsignificantlywithhigherlevelsof ECO2andHR(Table2).InthefirstminuteofBMV,maximumECO2

and HR were both significant predictors for survival in adjusted models,indicatingindependenteffects.Afterthefirstminute,ECO2

lost significance when adjusted for HR. Adjusting for VTE non- significantlyincreasedtheoddsratiosforsurvivalbyECO2.

Whenstudiedindependently,wefoundnosignificantdifferences inAUCsformaximumECO2comparedtoHR(Fig.3).Thoughnot significant,maximumECO2gaveslightlylargerAUCswithinthefirst minuteofBMV.Afterthefirstminute,AUCforHRwaslargest.AUCs weresimilarusingmedianscomparedtomaximumspertimeinterval forbothECO2andHR(Table2).

Sensitivityandspecificityforselectedcut-offsofmaximumECO2

andHR withintimeintervalsareplottedin ROCcurvesin Fig.3.

ReachingECO22%withinthefirst30sofventilationhadahigher sensitivitytopredict24-hsurvivalthanHR100bpm(80%versus 68%).Afteroneminuteofventilation,ECO22%hadslightlylower sensitivitythanHR100bpm(94%versus99%).

In categoricalmodels,we foundno non-linear associationsto support decreased survival with high levels of ECO2 or HR (Supplemental Table 1). Thepredictive information ofECO2 and HRonsurvivalwereweakerinnewbornswithBW<comparedto 2500g(SupplementalTable2).

Table1–Comparisonofdemographicanddeliveryroomdatabetweensurvivorsanddeathsat24h.

Survivors Deaths

n n p-value

Birthweight(grams) 378 3100(2780,3450) 56 3000(2500,3200) 0.01

Birthweight<2500g,n=60(14%) 46 12% 14 25% 0.01

Gestationalage(weeks) 356 38(37,40) 47 38(36,39) 0.46

Gestationalage<37weeks,n=97(22%) 85 21% 12 22% 0.86

Female,n=169(39%) 146 41% 23 39% 0.73

CaesareanSection,n=215(50%) 182 59% 33 48% 0.13

Timefrombirthtocordclamping(seconds) 376 22(12,57) 55 18(13,49) 0.37

Apgarat1min 378 7(5,7) 56 4(3,5) <0.001

Apgarat5min 378 10(8,10) 56 7(4,10) <0.001

TimefrombirthtofirstBMV(seconds) 375 125(84,160) 54 111(77,158) 0.49

TimefromfirsttolastBMV(seconds) 378 162(71,317) 56 624(227,1358) <0.001

Dataaredisplayedasmedians(IQR)ornumbers(%).P-valueswerecalculatedbyWilcoxonsranksumtestorPearsonsChi²testasappropriate.

HR=heartrate,BMV=bag-maskventilation.

Timetothresholds

Thetime toreach ECO2 2% andHR 100 bpm,in analyses includingonlynewbornswithinitialmeasuresbelowthethresholds, wassignificantlylowerinsurvivorscomparedtodeaths(Table3).

Oddsratio(95%CI)forsurvivalperminuteincreaseintimetoreach ECO22%was0.83(0.71,0.97)comparedto0.56(0.40,0.78)per minute before HR reached 100 bpm. Thus, 24-h survival was reducedbyapproximately17%perminutebeforeECO2reached2%

and44%perminutebeforeHRreached100bpm.

A majority of newborns (159/226, 70%) who reached both thresholds,crossedECO22% beforeHR100bpm.Thiswas evenly distributed between thegroups (131/188 (70%) survivors comparedto28/38(74%)deaths,p=0.62).Newbornswhoreached HR100bpmfirsthadlowermedianVTE(3.9(1.0 8.2)vs.5.6(2.9 10.1)ml/kg,p=0.007)andahigherleak(64(35 83)vs.45(22 71)%, p= 0.005)in ventilations priorto reachingthethreshold comparedtonewbornswhoreachedECO22%first.Timetoreach HR100bpmwasindependentofwhichthresholdwasreachedfirst (31(21 61)s),buttimetoreachECO22%wassignificantlylongerin newbornswhocrossedHR100bpmfirst(12(5 29)vs.67(39 120)s,p<0.001).WefoundnodifferencesininitialHR,Apgarscore orBWdependingonwhichthresholdwasreachedfirst.

Discussion

AssociationbetweenHRandoutcomeinnewbornresuscitationiswell established,andacornerstoneforrecommendationstoventilateifHR is<100bpm.15,19,24 27

NewinthisstudyisthatECO2measured duringBMVatbirthcanalsoserveasapredictorofsurvival.Wefound ECO2tobeanearliermarkerof24-hsurvivalthanHR.Afterthefirst

minuteof ventilation,ECO2addedno extrapredictiveinformation comparedtoHR.

ThemainfindingofhigherlevelsofECO2asapredictorofsurvival is similar to results from cardiopulmonary resuscitation after the newbornperiod.^11,12However,newbornsinneedofpositivepressure ventilationatbirtharerarelyincardiacarrest.Inarecentstudyof apnoeicnewborns,thefirstrecordedHRwasdistributedintwopeaks around60and165bpm.²⁵Thus,anincreaseinECO2duringnewborn resuscitation,isusuallynotasignofreturnofspontaneouscirculation, but may be seen as a marker for established pulmonary gas exchange.

MeasuredvaluesofECO2duringmaskventilationwillgenerallybe lowerthaninintubatednewbornsduetodilutioninalargerdeadspace andoccurrenceofleakandobstructedairway.Noexclusionscanbe donewheninterpretingmeasuredvaluesduringongoingresuscita- tion,andtheventilationtechniqueispotentiallyrelevantforsurvival.

Wethereforedecidedtoretainallobservations.Thismayexplainthe largevariationinECO2betweenventilations,andalowermedian ECO2inourresultsthaninstudieswhereexclusionsofventilations withlowVTEorhighleakweredone.^3,4,28,29

As ECO2 during BMV is highly dependent on ventilation parameters, especially VTE,^6,22 inadequate ventilation cannot be ruledoutasacontributingexplanationforlowECO2innon-surviving newborns.However,weproposethatthereasonforlowerECO2in deaths compared to survivors was mainly a more severely compromisedclinicalconditionatbirth.Priorstudiesfromthesame studysitehaveestimatedthataround60%of24-hnewborndeaths wereduetointrapartumrelatedevents(birthasphyxiaandmeconium aspirationsyndrome).^30,31 Despiteapresumptivelargerimpactof ventilationtechniqueonmedianscomparedtomaximums,wefound maximumECO2withintheselectedtimeintervaltopredictsurvivalas good as medians. If newborn death was often associated with inadequateVTE,wewouldexpectadjustmentforVTEtoreduceOR andAUCinmodelswithECO2.However,adjustingforVTEinour analyses non-significantly increased the predictive information, especially of median ECO2. This suggests against inadequate ventilation as a major cause of death, but rather points to low ECO2withsimultaneouslyhighVTEasasignofamorecompromised clinicalcondition.

Threepriorsmallerstudiesofmainlypretermnewbornsinhigh resourced settings have shown a significant increase in ECO2

preceding HR response during mask ventilation in newborn resuscitation.^3,13,14 Different from these studies, our study was performed in a larger sample of mainly term newborns in rural Tanzania.Inconcordancewiththepreviousstudies,wefoundthat among newborns who reached both predefined thresholds, 70%

crossedECO22%beforeHR100bpm.ThisunderpinsECO2as anearliermarkerfortreatmentresponsethanHR.Wealsofounda groupwhoreachedHR100bpmbeforeECO22%.AlowerVTE

and higher leakin thisgroup,suggest suboptimalventilations as explanation for theslowerrise in ECO2. Becausethere were no differencesintimetoHR100bpmforthosewhoreachedHR100 bpm first compared to those who reached ECO2 2% first, we speculatethatthesenewbornswerelikelylessseverelyasphyxiated, despitethelowinitialHR,andmayhavehadsome spontaneous breathingandintactreflexes.ThedelayfrombirthuntilBMVwas startedmayhavecontributedtoincreaseddifferencesinECO2and HRbetweenmildandseverelycompromisednewborns.

SlightdifferencesinpredictivevalueofECO2andHRinnewborns withBW<2500gcomparedto2500g,maybeduetoahigherriskof Fig.2–ECO2andHRbytimeinsurvivorscomparedto

deathsinthefirst60sofbag-maskventilation.

ECO2increased before HR in amajority ofnewborns, survivorshadhigherlevelsofECO2andHRthandeaths.

Thegraphsaresmoothed localpolynomial plotsofall measured values for ECO2 and HR in all included newborns.

ECO2=expiredCO2,HR=heartrate.

deathbyothercausesthanbirthasphyxiainnewbornswhowere pretermorsmallforGA.³⁰

Toourknowledge,thisisthefirststudytocompareECO2andHR measured in the delivery room as predictors of 24-h survival in newbornswhoreceiveBMVatbirth.Theuniqueresearchinfrastruc- turecomprisingbothcontinuousprospectiveobserver-monitoredand automaticallyrecordedbiomedicalsignal-dataofalargecohortof newbornsisamajorstrength.Data werecollectedinarurallow- incomesettingwithhighmorbidity,longtransportandpotentialdelay forcomplicateddeliveriestobeassisted,representativeforwhere most newborn deathsoccur.³² The local resuscitation procedure followedHBB.¹⁸ Advancedneonatal careand respiratory support after initial resuscitation, including continuous positive airway pressure therapy, were not available. This likely affected 24-h survival,andthustheresultsmaynotbegeneralizabletoallsettings.

Variation in clinical condition between included newborns and experience between providers will naturally occur in all studies performed in real life situations. This make the results more representativefornewbornsinneedforrespiratorysupportatbirth,

but is also alimitation assome newborns may have had some spontaneous breathingand some mayhavereceived suboptimal care.

Largebreath-to-breathvariationmakesECO2measuredduring BMV potentially difficult to interpret in clinical situations. Finding maximumECO2togiveasgoodpredictiveinformationasmedian values,wesuggestusingthehighestobservedvalueswithintime intervalsifECO2shouldbeutilisedasprognosticinformationduring newbornresuscitation.

Plottingselectedcut-offvaluesformaximumECO2andHRinROC curves,we foundthatchoosinglowercut-offswould giveamore sensitive,butlessspecificpredictivetestforsurvivalthanhighercut- off values. ECO2 2% is approximately equivalent to a partial pressureof15mmHgor2kPa,whichisthelimitforcolourchangein colorimetricECO2-sensors.¹⁴Thismaybeareasonablechoiceto indicate successfullungaerationandfavourableprognosisduring BMVofasphyxiatednewborns.

ThedualnatureofECO2asbothamarkerforseverityoftheclinical condition and of ventilation quality,²² makes ECO2-monitoring Table2–Logisticregressionmodelsandareaunderreceiveroperatingcharacteristicscurves(AUC)for24-h survivalbymaximum(upperpanel)andmedian(lowerpanel)expiredCO2andheartratepernewbornforthethree selectedtimeintervals.

Mainmodels Secondarymodels

Unadjusted Mutualadjustment

ECO2/HR

Adjustedfor ECO2/HRandVTE

a

MaximumECO2andHR n OR(95%CI) AUC^b OR(95%CI) AUC^c OR(95%CI) AUC^c

0 30sofBMV 422

ECO2 Per1ppincrease 1.31(1.17,1.46)^d 0.72 1.24(1.10,1.39)^d 0.73 1.27(1.12,1.44)^d 0.74 HR Per10bpmincrease 1.18(1.09,1.28)^d 0.67 1.10(1.00,1.20)^f 1.10(1.00,1.20)^f

30.1 60sofBMV 363

ECO2 Per1ppincrease 1.26(1.13,1.40)^d 0.69 1.17(1.04,1.32)^e 0.69 1.18(1.02,1.22)^f 0.69 HR Per10bpmincrease 1.18(1.09,1.28)^d 0.66 1.11(1.02,1.22)^f 1.12(1.02,1.22)^e

60.1 300sofBMV 354

ECO₂ Per1ppincrease 1.18(1.07,1.32)^e 0.62 1.06(0.95,1.19) 0.64 1.07(0.95,1.20) 0.68 HR Per10bpmincrease 1.28(1.17,1.40)^d 0.64 1.25(1.13,1.38)^d 1.27(1.14,1.41)^d MedianECO₂andHR

0 30sofBMV 422

ECO2 Per1ppincrease 1.43(1.17,1.74)^d 0.65 1.31(1.08,1.60)^e 0.71 1.46(1.16,1.83)^d 0.74 HR Per10bpmincrease 1.28(1.13,1.45)^d 0.68 1.23(1.09,1.40)^d 1.22(1.07,1.38)^e

30.1 60sofBMV 363

ECO2 Per1ppincrease 1.27(1.08,1.49)^e 0.65 1.15(0.97,1.37) 0.67 1.21(0.99,1.47) 0.67 HR Per10bpmincrease 1.16(1.07,1.25)^d 0.65 1.11(1.02,1.22)^f 1.12(1.02,1.22)^f

60.1 300sofBMV 354

ECO2 Per1ppincrease 1.20(1.02,1.40)^f 0.61 1.00(0.84,1.21) 0.63 1.07(0.88,1.29) 0.67 HR Per10bpmincrease 1.20(1.11,1.29)^d 0.63 1.19(1.09,1.31)^d 1.20(1.09,1.32)^d

ECO2=expiredCO2,HR=heartrate,OR=OddsRatio,pp=percentpoint,bpm=beatsperminute,VTE=expiredvolume,BMV=bag-maskventilation,AUC=area underthereceiveroperatorcurve.

ThemainmodelspresentunadjustedORof24-hsurvivalforbothECO2andHRindependently.ThesecondarymodelspresentORof24-hsurvivalfor1)ECO2and HRwhenmutuallyadjustedand2)ECO2andHRwhenadjustedforeachotherandforthemedianVTEwithineachtimeinterval.TheAUCvaluesdisplayed,were calculatedbasedontheresultsofthecorrespondinglogisticregressionmodels.Newborns(n)withavailabledataforbothECO2andHRwithineachtimeinterval wereincluded.

aMedianVTEturnedsignificantwithnegativeimpactonsurvival30sandbetween60.1 300sofventilationinmodelswithmedianECO2andbetween60.1 300 sinmodelswithHR.MedianVTEwasnotassociatedwithsurvivalinunadjustedmodels.

bReceiveroperatingcharacteristicscurvesandAUCwith95%confidenceintervalsformaximumECO2andHRintheunadjustedmodels,andstatisticalteststo assessfordifferences,aredisplayedinFig.3.

cAUCreportedforadjustedmodelsdescribesthecombinedpredictiveinformationofalltheincludedparametersinthemodel.

dp<0.001.

ep<0.01.

fp<0.05.

potentiallyusefulduringresuscitationforprognosticinformationandto helpimproveventilations.However,thedualityalsoimpliespitfallsfor theinterpretation.ProvidersmustbeawarethatlowECO2mayhave severalcauses,includinghighleak,airwayobstruction,unaerated lungsorcompromisedpulmonarycirculation.^3,4,6,22Theresultsofthis studyindicatethatpersistinglowECO2may,likepersistinglowHR,be usedtosupportdecisionstodiscontinueresuscitation.ECO22%or HR100shouldencouragefurtherefforts,eveninseeminglynon- viablenewborns.However,wefoundlowspecificitiesofECO2orHR used as tests to predict survival, and strongly advice against

dependingon thisalone.Theinformationmustbe combinedwith thorough considerations taking the quality of given ventilations, clinical responses, duration of resuscitation and availability of advancedneonatalcareintoaccount.

Importantly,HRwastheonlydisplayedparameterinthisstudy, andthusthemidwivescouldnotadjustventilationtechniqueasa response to changes in ECO2. A feedback on ECO2 may help providersimproveventilationtechnique,whichmayfurtherimprove prognosisandthepredictiveinformationbyECO2.Wedonotthinkthat ECO2shouldreplaceHRforprognosticinformationduringnewborn Fig.3–ReceiveroperatingcharacteristicscurvesformaximumECO2andHRwithintimeintervalsaspredictorsfor24- hsurvival.

ThegraphsdisplayROCcurvesformaximumECO2andHRwithinthethreeselectedtimeintervalsafterstartof ventilation(A:0 30s,B:30.1 60s,andC:60.1 300s)aspredictorsfor24-hsurvival.Sensitivityandspecificityfor selectedcut-offvaluesofmaximumECO2(leftpanel;ECO21,2,and4%)andHR(rightpanel;HR60,100,and120 bpm)areplotted.

ComparisonofAUCforECO2andHR(PearsonsChi²-test).

A:AUCformaximumECO2=0.72(0.65,0.79),AUCformaximumHR=0.67(0.58,0.76),p=0.21.

B:AUCformaximumECO2=0.69(0.60,0.78,AUCformaximumHR=0.66(0.56,0.76),p=0.56.

C:AUCformaximumECO2=0.62(0.53,0.71),AUCformaximumHR=0.64(0.54,0.64),p=0.74.

ECO2 =expired CO2in percent ofexpired air, HR = heartrate inbeats per minute, ROC= Receiver Operating Characteristics,AUC=areaundertheROCcurves.

resuscitation.However,beinganearlierandmoredirectmarkerof effective ventilation, ECO2 may add useful information. In low resourced settings, colorimetric end-tidal CO2-detectors may be moreeasilyavailablethanHRmonitoring.¹⁴Furtherclinicaltrialswith ECO2-feedbacktotheproviderareneededtoaddressthepractical valuebeforeECO2-monitoringduringBMVinnewbornresuscitation couldberecommendedforroutineclinicaluse.

Conclusions

ECO2duringBMVinthedeliveryroomcanpredict24-hsurvival.ECO2

increasedbeforeHRinmostcases.ECO2mayserveasanearly markerforseverityofclinicalcondition,ventilationquality,treatment responseandprognosisduringnewbornresuscitation.

Funding sources

ThestudywassupportedbytheLaerdalfoundationandtheResearch Council of Norway through the Global Health and Vaccination Program (GLOBVAC), project number 228203. Dr. Holte was supportedbytheSouth-EasternNorwayRegionalHealthAuthority.

Financial disclosure

Theauthorshavenofinancialrelationshipsrelevanttothisarticleto disclose.Theexternalfundingsourceshadnoroleinstudydesign, datacollection,dataanalysis,datainterpretation,writingofthereport, orinthedecisiontosubmitthepaperforpublication.

Conflicts of interest

JoarEilevstjønnisanemployeeatLaerdalMedical.Theotherauthors havenopotentialconflictsofinteresttodisclose.

CRediT authorship contribution statement

Holtedesignedthestudy,carriedouttheanalyses,anddraftedthe initialmanuscript.ErsdalandKlingenbergcontributedtostudydesign, analysis and writing. Ersdal also planned and supervised data collection,andistheprincipalinvestigatoroftheSaferBirthsstudy group.Eilevstjønndesignedtheequipmentusedfordatacollection, gavetechnicalsupport,extractedandprocesseddataandcontributed to analysingthedata.Stigumwas thestudystatistician providing supervisionandqualitycontrolofthestatisticalanalyses.Kidantoand Jatoshcoordinatedandsuperviseddatacollection.Størdalconcep- tualizedanddesignedthestudytogetherwiththefirstauthor,and contributedconsiderablytodataanalysesandinthewritingprocess.

Allauthorsreviewedandrevisedthemanuscriptcritically,approved thefinalmanuscriptassubmittedandagreetobeaccountableforall aspectsofthework.

Acknowledgements

We want to thank all contributors to the study, especially the participants - mothers and childen andall midwives, research assistantsandresearchnursesatHaydomLutheranHospital.

Appendix A. Supplementary data

Supplementary materialrelatedtothisarticlecanbefound,inthe onlineversion,atdoi:https://doi.org/10.1016/j.resuscitation.2021.05.

018.

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