Design and implementation of the AIRWAYS 2 trial: A multi centre cluster randomised controlled trial of the clinical and cost effectiveness of the i gel supraglottic airway device versus tracheal intubation in the initial airway management of out of hospi

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

Design

and

implementation

of

the

AIRWAYS-2

trial:

A

multi-centre

cluster

randomised

controlled

trial

of

the

clinical

and

cost

effectiveness

of

the

i-gel

supraglottic

airway

device

versus

tracheal

intubation

in

the

initial

airway

management

of

out

of

hospital

cardiac

arrest

夽

Jodi

Taylor

,

Sarah

Black

,

Stephen

J.

Brett

,

Kim

Kirby

,

Jerry

P.

Nolan

,

Barnaby

C.

Reeves

,

Maria

Robinson

,

Chris

A.

Rogers

,

Lauren

J.

Scott

,

Adrian

South

,

Elizabeth

A.

Stokes

,

Matthew

Thomas

,

Sarah

Voss

,

Sarah

Wordsworth

,

Jonathan

R.

Benger

a_{ClinicalTrialsandEvaluationUnit,SchoolofClinicalSciences,UniversityofBristol,Bristol,UK} b_{SouthWesternAmbulanceServiceNHSFoundationTrust,Exeter,UK}

c_{CentreforPerioperativeMedicineandCriticalCareResearch,ImperialCollegeHealthcareNHSTrust,London,UK} d_{SchoolofClinicalSciences,UniversityofBristol,Bristol,UK}

e_{DepartmentofAnaesthesia,RoyalUnitedHospitalBathNHSTrust,Bath,UK}

f_{HealthEconomicsResearchCentre,NuffieldDepartmentofPopulationHealth,UniversityofOxford,Oxford,UK} g_{IntensiveCareUnit,UniversityHospitalsBristolNHSFoundationTrust,Bristol,UK}

h_{FacultyofHealthandAppliedSciences,UniversityoftheWestofEngland,Bristol,UK}

i_{AcademicDepartmentofEmergencyCare,TheUniversityHospitalsNHSFoundationTrust,Bristol,UK}

a

r

t

i

c

l

e

i

n

f

o

Articlehistory:

Received23May2016

Receivedinrevisedform23August2016 Accepted5September2016

Keywords:

Cardiacarrest

Emergencymedicalservices Trachealintubation Supraglotticairwaydevice Randomisedclinicaltrial

a

b

s

t

r

a

c

t

Healthoutcomesafteroutofhospitalcardiacarrest(OHCA)areextremelypoor,withonly7–9%ofpatients intheUnitedKingdom(UK)survivingtohospitaldischarge.Currentlyemergencymedicalservices(EMS) useeithertrachealintubationornewersupraglotticairwaydevices(SGAs)toprovideadvancedairway managementduringOHCA.Equipoisebetweenthetwotechniqueshasledtocallsforawell-designed randomisedcontrolledtrial.

TheprimaryobjectiveoftheAIRWAYS-2trialistoassesswhethertheclinicaleffectivenessofthei-gel, asecond-generationSGA,issuperiortotrachealintubationintheinitialairwaymanagementofOHCA patientsintheUK.ParamedicsrecruitedtotheAIRWAYS-2trialarerandomisedtouseeithertracheal intubationori-gelastheirfirstadvancedairwayintervention.Adultswhohavehadanon-traumaticOHCA andareattendedbyanAIRWAYS-2paramedicareretrospectivelyassessedagainsteligibilitycriteriafor inclusion.

TheprimaryoutcomeisthemodifiedRankinScalescoreathospitaldischarge.Secondaryobjectives areto:(i)estimatedifferencesbetweengroupsinoutcomemeasuresrelatingtoairwaymanagement, hospitalstayandrecoveryat3and6months;(ii)estimatethecosteffectivenessofthei-gelcomparedto trachealintubation.BecauseOHCApatientneedsimmediatetreatmentthereareseveralunusualfeatures andchallengestothedesignandimplementationofthistrial;theseincludelevelofrandomisation,the automaticenrolmentmodel,enrolmentofpatientsthatlackcapacityandminimisationofbias.

Abbreviations:CAD,computeraideddispatch;CAG,ConfidentialityAdvisoryGroup;CPR,cardiopulmonaryresuscitation;CRF,casereportform;CTEU,ClinicalTrialsand EvaluationUnit;EEAST,EastofEnglandAmbulanceServiceNHSTrust;EMAS,EastMidlandsAmbulanceServiceNHSTrust;EMS,EmergencyMedicalServices;HES,Hospital EpisodeStatistics;ICC,intraclasscorrelation;ILCOR,InternationalLiaisonCommitteeonResuscitation;JRCALC,JointRoyalCollegesAmbulanceLiaisonCommittee;mRS, modifiedRankinScale;NICE,NationalInstituteforHealthandCareExcellence;NHS,UKNationalHealthService;OHCA,outofhospitalcardiacarrest;QALY,qualityadjusted lifeyear;RCT,randomisedcontrolledtrial;ROSC,returnofspontaneouscirculation;SADE,seriousadversedeviceevent;SAE,seriousadverseevent;SGA,supraglotticairway; SWAST,SouthWesternAmbulanceServiceNHSFoundationTrust;UK,UnitedKingdom;YAS,YorkshireAmbulanceServiceNHSTrust.

夽ASpanishtranslatedversionoftheabstractofthisarticleappearsasAppendixinthefinalonlineversionathttp://dx.doi.org/10.1016/j.resuscitation.2016.09.016.

∗Correspondingauthorat:FacultyofHealthandAppliedSciences,UniversityoftheWestofEngland,Bristol,UK.

E-mailaddress:[email protected](J.R.Benger).

http://dx.doi.org/10.1016/j.resuscitation.2016.09.016

PatientenrolmentbeganinJune2015.Thetrialwillenrol9070patientsovertwoyears.Theresultsare expectedtoinfluencefutureresuscitationguidelines.

TrialRegistrationISRCTN:08256118.

CrownCopyright©2016PublishedbyElsevierIrelandLtd.ThisisanopenaccessarticleundertheCC BY-NC-NDlicense(http://creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction

TheUnitedKingdom(UK)hasthehighestreportedincidence ofoutofhospitalcardiacarrest(OHCA)inEurope;123casesper 100,000populationper annum.1 _{Despite recent improvements,} survivalratesfromcardiacarrestremainpoorwithapproximately 7–9%ofpatientsintheUKsurvivingtohospitaldischarge, com-paredwithestimatesofbetween5%and25%internationally.2–5 Duringacardiacarrest,thebrainisexposedtoaperiodof hypox-aemia and ischaemia, which may result in death or cognitive deficits.6_{Optimalcardiopulmonaryresuscitation(CPR)andreturn} ofspontaneouscirculation(ROSC)arekeyfactorsassociatedwith avoidingorminimisingneurologicalimpairmentinthesurvivorsof OHCA,9,10_{andearlyeffectiveairwaymanagementisfundamental} tothis.

Traditionalteaching suggests that tracheal intubation is the bestway to manage theairway during OHCA.11 _{However, this} assumptionhasnotbeenwelltested,12_{andpre-hospitalintubation} attemptsbyparamedicscanbeassociatedwithcomplicationssuch asinterruptionsinchestcompressions,unrecognisedoesophageal intubation(particularlyifwaveformcapnographyisnotavailable), anddelaysinaccessingdefinitivecare.13,14

Supraglotticairwaydevices(SGAs)areanalternativeto intu-bation.Theyarequickerand easiertoplace andmayavoidthe complications of tracheal intubation.15 _{SGAs are usedsafely to} managetheairwayduringhospitalprocedures.16–18_Theyarealso inwidespreaduseinUKNationalHealthService(NHS)emergency medicalservices(EMS);in2014/15theLondonAmbulanceService reported 1469/1775 (83%) successful OHCA intubations, com-paredto3149/3494(90%)successfulSGAplacements.5_Equipoise betweenthetwotechniqueshasledtorecentcallsforalarge ran-domisedcontrolledtrial(RCT)ofthetwoapproaches.19,20

BetweenMarch2012andFebruary2013wecarriedoutastudy (REVIVE-Airways)inasingleNHSEMSprovidertoassessthe fea-sibilityofrecruitingparamedicsandpatientstoastudycomparing twoSGAs(i-gel andtheLaryngealMaskAirway Supreme)with currentpractice(includingtrachealintubation).21_{REVIVE-airways} demonstratedthatthestudywasfeasibleandinformedthedesign ofAIRWAYS-2.

TheResuscitationCouncil(UK)2015guidelinesstatethatthe optimalairwaytechniqueforcardiacarrestisstillunknown,andis likelytodependontheskillsoftheoperator,theanticipated pre-hospital time and patient-dependent factors.22 _{Evidence-based} interventionstoimproveOHCAsurvivalarestillurgentlyrequired. The AIRWAYS-2 trial has the potential to answer important questionsabout initialadvanced airwaymanagement in OHCA, examiningbothsurvivalratesandthequalityofthatsurvival.

Methodsandanalysis

Aimsandobjectives

TheaimofAIRWAYS-2istodeterminewhetherthei-gel (Inter-surgical;Wokingham,UK),asecond-generationSGA,issuperiorto trachealintubationwhenusedbyanAIRWAYS-2studyparamedic innon-traumaticOHCAinadults,intermsofbothclinicalandcost effectiveness.

Specificobjectivesaretoestimate:

1.ThedifferenceintheprimaryoutcomeofthemodifiedRankin Scale(mRS)athospitaldischarge(or30dayspostOHCAifthe patient is still in hospital)betweengroups of patients man-agedwitheitherthei-gelortrachealintubationastheirinitial advancedairwaymanagementstrategyfollowingOHCA. 2.Differencesinsecondaryoutcomemeasuresrelatingtoairway

management, hospital stay and recoveryat 3 and 6 months betweengroupsofpatientsmanagedwitheitherthei-gelor trachealintubation.

3.Thecosteffectivenessofthei-gelcompared totracheal intu-bation,includingestimationofmajorin-hospitalresourceuse (e.g.lengthofstayinintensiveandhighdependencycare),and associatedcostsineachgroup.

Design

AIRWAYS-2is anopenparalleltwo-group multi-centre clus-terRCT. Thetrialschemaisshown inFig.1.Paramedicsrather thanpatientsarerandomisedtooneofthetreatmentgroupsand allenrolledpatientsshouldbetreatedaccordingtotheenrolling paramedic’sallocation.

Setting

The trial involves collaboration between four UK NHS EMS providers (South Western Ambulance Service NHS Foundation Trust (SWAST), East of England Ambulance Service NHS Trust (EEAST),EastMidlandsAmbulanceServiceNHSTrust(EMAS), York-shireAmbulanceServiceNHSTrust(YAS))andthe95NHShospitals servedbytheparticipatingEMSproviders.

Paramedicpopulation

Paramedicsareeligibleiftheyareemployedbyoneofthefour participatingEMSproviders,undertakegeneraloperationalduties, andcanthereforebedespatchedtoattendanOHCAasthefirstor secondparamedictoarriveatthepatient’sside.Theymustbe regis-teredwiththeHealthandCareProfessionsCouncilandbequalified topracticetrachealintubationintheircurrentclinicalrole.

Randomisation

In AIRWAYS-2, paramedics working within SWAST, EMAS, EEASTorYASwhoconsenttoparticipateinthetrialarerandomly allocatedina1:1ratiotooneofthetwogroups:i-gelorintubation (i.e.eachparamedicisarandomisedcluster).

RandomisationisstratifiedbyEMSprovider,yearsofparamedic experience(greaterthanorequalto5yearsfull-timeoperational experienceversus lessthan 5 yearsfull-time operational expe-rience) and urban/rurallocation of the baseambulance station (definedasgreater than orequal to5 milesversus lessthan 5 milesfromthenearest hospitalwithanemergencydepartment thatreceivescardiacarrestpatients).

Paramedic expressions of interest (n=)

Randomised paramedics (n=)

I-gel (n=)

Attended an OHCA: n paramedics, n patients

Patients per paramedic: median=n, IQR=n to n, range=n to n

Enrolled patients: n paramedics, n patients

Patients per paramedic: median=, IQR=n to n, range=n to n

Not yet attended an OHCA: n paramedics

Attended an OHCA: n paramedics, n patients

Patients per paramedic: median=n, IQR=n to n, range=n to n

Enrolled patients: n paramedics, n patients

Patients per paramedic: median=n, IQR=n to n, range=n to n

Not yet attended an OHCA: n paramedics

Excluded (n=)

Withdrew: n= Has not attended training: n= Attended training but did not consent: n=

Analysis population for primary outcome: n=

Consented to active follow-up: n=

Follow-up successful at 3 months: n=

Follow-up successful at 6 months: n=

Analysis population for primary outcome: n=

Consented to active follow-up: n=

Follow-up successful at 3 months: n=

Follow-up successful at 6 months: n= Intubation (n=)

Fig.1. Consortdiagram.

Theallocationisnotrevealeduntilsufficientinformationtoidentify theparamedichasbeenenteredintothesystem.Inordertoavoid biascausedbyparamedicswithdrawingfromthestudyonthebasis oftheirallocation,paramedicsarenotrandomiseduntilhalfway throughatrialspecifictrainingsession;priortorandomisationthe trialdesignandtheneedforindividualequipoiseisexplained.Ifthe paramediciswillingtotreatallOHCApatienttheyattendduring thestudyperiodbyeitherinterventiontheygiveconsenttotake partinthestudy.Theparamedicisthenrandomisedandcompletes thetrainingsessionwithtrainingthatisspecifictotheirallocation.

Patientenrolment

Patient inclusion and exclusion criteria are described in

Table1.

Inordertopreventparamedicsfrombeingabletochoosewhich patientstoenrol,thistrialusesanautomaticenrolmentmodel;all eligiblepatientsattendedbyanAIRWAYS-2paramedicforwhom resuscitation is attempted are includedin thetrial. A research paramedicateachambulancetrustthencarriesoutretrospective checksagainstthestudyeligibilitycriteria.

Table1

Patientinclusion/exclusioncriteria.

Inclusioncriteria Exclusioncriteria

Patienthashadanon-traumaticcardiacarrestoutsidehospital Patientpreviouslybeenrecruitedtothetrial(determinedretrospectively)

18yearsofageorolder Resuscitationisconsideredinappropriate(basedonguidelinesproducedbytheJoint

RoyalCollegesAmbulanceLiaisonCommittee;JRCALC) Attendedbyaparamedicwhoisparticipatinginthetrialandiseither

the1stor2ndparamedictoarriveatthepatient’sside

Advancedairwaymanagement,insertedbyanotherregisteredparamedic(not participatinginAIRWAYS-2)doctorornurse,isalreadyinplacewhentheAIRWAYS-2 paramedicarrivesatpatient’sside

ResuscitationiscommencedorcontinuedbyEMSstafforrespondera _{Theyareknowntobealreadyenrolledinanotherpre-hospitalRCT}

Mouthopening<2cm

PatientdetainedbyHerMajesty’sPrisonService

a_{Aresponderissomeoneactingfortheambulanceserviceanddispatchedbytheambulanceservicetorespondtoemergencycallsintheirlocalarea.Theyareoftena}

The automatic enrolment model can give rise to situations whichcouldleadtoprotocoldeviations:(i)ineligiblepatientsmay beconsciouslyenrolled(thesepatientswillbeexcludedfromfinal analysis),(ii)someeligiblepatientsincludedinthefinalpopulation maynothavebeenconsciouslyenrolledbytheattending AIRWAYS-2paramedicand(iii)thewrongAIRWAYS-2paramedicmaytreat thepatientwhentwoormoreAIRWAYS-2paramedicsarepresent onscene.

Toensurenear-completepatientidentificationweareusinga triangulationmethoddevelopedduringourfeasibilitystudy.Data arecollectedonallOHCAsoccurringwithineachEMSproviderfrom threeseparatesources:

A.Directparamedicreport:participatingparamedicsareaskedto completeacasereportform(CRF)immediatelyaftereach eligi-bleOHCAthattheyattend,andnotifythecoordinatingresearch paramedicbytelephone,textore-mail.

B.DailyreviewoftheEMScomputeraideddispatch(CAD)system, byaresearchparamedic,toidentifyall999callsidentifiedas suspectedorconfirmedcardiacarrest,andfollow-upwiththe relevantstafftodeterminewhetherOHCAhadoccurred. C.RegularreviewoftheOHCAdataroutinelycollectedbya

par-ticipatingEMSprovider,andreportedaspartoftheAmbulance ServiceNationalQualityIndicatorsetinEngland.

Patientconsent

Allenrolled patientswho survive tohospital admission are followed-upbyamemberoftheresearchteam.Ifapatientislikely tosurvivetohospitaldischarge,theresearchstaffconsultwith clin-icalstaffcaringforthepatientto(a)decidewhetherthesurvivor hasthementalcapacitytoprovideconsent,and(b)todetermine theoptimaltimetoapproachthepatientand/ortheirfamilytoseek consent/assentforfurtherfollow-upanddatacollection.

Thepatientorconsulteecanchoseoneofthefollowingconsent options:

A.Activefollow-up:Thepatientwillbeactivelyfollowedupat dis-charge,3and6monthsaftertheindexOHCA.Qualityoflifeand mRSscorewillbecollectedatthesetimepoints.

B.Passivefollow-up;routinedatawillbecollectedandthepatient willnotbecontactedagainaboutthestudy.

Thepatientorconsulteecanalsodecline totakepartinthe study.Ifthisoptionischosennofurtherdatacollectionwilltake place.

Incaseswhereconsulteeconsentisobtained,patientcapacity willbeassessedatthe3and 6month follow-up.Ifthepatient regainscapacity,consenttocontinuetheirinvolvementinthestudy willbesoughtfromthepatient.

Trialinterventions

Trachealintubation(controlgroup)

Thecurrentstandardcarepathwayistrachealintubation:the placementofacuffedtubeinthepatient’stracheatoprovide oxy-gentothelungsandremovecarbondioxide.Trachealintubationis consideredthe“goldstandard”ofairwaymanagement,andisused universallyincomatosesurvivorsofcardiacarrestfollowingtheir admissiontohospital.

i-gel(experimentalgroup)

Theinterventionbeingstudiedisinsertionofani-gel,a second-generationSGA,asanalternativetotrachealintubation.

Aspectsofairwaymanagementcommontobothgroups

Astandardisedairwaymanagementalgorithmwasdeveloped bythe4participatingEMSproviders.Fig.2a–dfocusesontheinitial airwaymanagementattempts.Fulldetailsoftheairway manage-mentpathwayareshowninSupplementarymaterialsFigs.1and2. CareproceedsasnormalforOHCApatientsenrolledinthetrial, asidefromtheinitialadvancedairwaymanagement.Allother inter-ventionsproceedaccordingtostandardresuscitationguidelines22 thataredisseminatedwidelyintheUKandinternationally. Fol-lowingROSCsedationorneuromuscularblockadeisnotnormally providedpriortohospitalarrival,andifanairwaydeviceisnot tolerateditwillberemoved.Patientswhodieatthesceneare man-agedinaccordancewithnationallydisseminatedEMSprotocols. Patientswhodonotdieatscenearetransportedtohospitaland treatedusingstandardpost-OHCAcarepathways.

Duetotheemergencynatureofthetrialwedoexpect devia-tionsfromtheAIRWAYS-2treatmentalgorithm.Truecrossover isdefinedasthepatientreceivingtheincorrectinventiononthe firstadvancedairwaymanagementattempt;otherdeviationscan occurduringsubsequentairwaymanagementattempts(see pro-tocoldeviations).

Outcomemeasures

Primaryoutcome

TheprimaryoutcomeisthemodifiedRankinScale(mRS) mea-suredathospitaldischarge(or30daysafterOHCAifthepatientis stillinhospital).ThemRS,whichincorporatesbothqualityoflife andsurvival,iswidelyusedinOHCAresearch25,26_andcomprises asevenpointscale(0to6)withlowerscoresrepresenting bet-terrecovery.Patientswhodiearegivenascoreofsix.ThemRSis determinedbyaresearchnursewhowillassessthepatientusinga simpleflowchartthathasbeenusedpreviouslytoassesspatients who have had a cardiac arrest.27 _{With prior permission ofthe} HealthResearchAuthorityConfidentialityAdvisoryGroup(CAG), wearecollectingsurvivaldataandmRSathospital discharge/30-daysforallenrolledpatients,regardlessoftheirconsentstatus, thereby ensuring close to 100% ascertainment of the primary outcome.

Secondaryoutcomes

Thereare12secondaryoutcomes.ThesearelistedinTable2.

Samplesizeconsiderations

Patientsamplesize

IntheREVIVE-Airwaysfeasibilitystudy,9%ofrecruitedpatients survivedtohospitaldischarge.28,29_{Thisisin-linewiththecurrent} rateofoverallsurvivaltodischargereportedbyEnglishEMS.3_Using survivalasaproxyformRSscore,a2%improvementinthe propor-tionofpatientsachievinga goodneurologicaloutcome(defined asanmRSscoreof0–3),wouldbeclinicallysignificant,and simi-lartothe2.4%differenceinsurvivaltodischargebetweentracheal intubationandSGAsreportedinaretrospectiveanalysis.13

Toidentifyadifferenceof2%(8%vs.10%,i.e.centredon9%) requires4400patientspergroup(atthe5%levelforstatistical sig-nificanceand90%power).However,eachOHCAisnotan indepen-dentobservation,asthepatientsarenestedwithinalimited num-berofparamedicsparticipatinginthetrial.Usingdatafromour fea-sibilitystudyof171paramedicsattending597OHCAs(3.6patients perparamedicperyear),weestimatedtheintraclasscorrelation (ICC)tobe<0.001.However,whenestimatingthesamplesizewe haveassumedaconservativeestimatefortheICCof0.005. There-forewerequireasamplesizeof9070patients(4535pergroup).

Fig.2.Airwaymanagementalgorithm.(a)i-gelAirways-2paramedicandatleastoneotherpersontrainedinCPR.(b)i-gelSoloAirways-2ParamedicResponse.(c)Intubation Airways-2paramedicandatleastoneotherpersontrainedinCPR.(d)IntubationSoloAirways-2ParamedicResponse.

Table2

Outcomemeasuresanddatacollectionpoints.

Dataitem Outofhospitaltreatment

phase(datacollectionby paramedics)

Inhospital/hospital discharge(datacollection byhospitalstaff)

3monthpostOHCA (datacollectedby researchteam)

6monthpostOHCA (datacollectedby researchteam)

Primaryandsecondaryoutcomes

Initialventilationsuccess(visiblechestrise) √a

Regurgitation/aspiration √a

Lossofapreviouslyestablishedairway √a

Actualsequenceofairwayinterventionsdelivered √a

Returnofspontaneouscirculation √a

AirwaymanagementinplacewhenROSCachieved orresuscitationdiscontinued

√a

Survival √a √a √c √c

ModifiedRankinScale √a √b √b

EQ-5D √b √b √b

Resourceusedata √a √c √c √c

Seriousadverseevents √a √c √c √c

Lengthofhospitalstay(capturedseparatelyfor differentlevelsofcare)

√c

Otherdataitems

Eligibility √a

Demography √a √a

Approachedforconsent √a

a_{Collectedforallpatientsenrolledintrial(wherepatientsurvivestothatpointinthepatientpathway).} b_{Onlycollectedforpatientsthatconsenttoactivefollow-up.}

cannotbegreaterthanthepercentageofpatientswhosurvive.If wehadpoweredthetrialfora2%differenceinmRS,wewouldnot havehad90%powertodetectthe2%differenceinmortality,which weacknowledgeisakeysecondaryoutcome.

Paramedicsamplesize

Inourfeasibilitystudythemeannumberofpatientsenrolled perparticipatingparamedicwas3.6peryear.Thereforeinorderto enrolthe9070patientswithinthetwoyearrecruitmentperiodwe estimatethatweneedtorecruitatleast1300paramedics.Across thefourEMSprovidersparticipatinginAIRWAYS-2,therearemore than4300eligibleparamedics;wethereforeneedtoenrolover30% oftheparamedicsemployedbythefourEMSproviders.

Paramedictraining

Standardisedtrainingmaterialshavebeendevelopedtosupport traininginresearchproceduresandtheallocatedairway manage-menttechniquefor boththeintubationand i-gelgroups. These areadministeredtoallparticipatingparamedicsbeforeenrolment commences,witharesearchrefresherhalfwaythroughthe recruit-mentperiod(at12months).Concernshavebeenraisedthatafter twoyearsusingjustonemethodofadvancedairwaymanagement, participatingparamedicsrisk becomingde-skilledinalternative approaches.Therefore,tosupporteffectiveparamedicrecruitment andretention,wewillofferadditionalexittrainingtoall partici-patingparamedicstoupdatetheirairwaymanagementskillsonce patientenrolmenthasbeencompleted.

TheAIRWAYS-2trialhasbeenformallyendorsedbytheCollege ofParamedics.

Datacollection

For each eligible OHCA patient enrolled in the trial, the paramedicwhoenrolsthepatientcompletesanairway manage-mentCRF tocapturebaselineand secondaryoutcome data.If a patientis admitted to hospitalthe consentand follow-up pro-cessiscoordinatedbyaregionally-basedresearchnurse.Hospitals provideinformationonpatientsurvivalandrecoverydependingon theconsentoptionchosenbythepatient/consultee.

ThedatacollectionscheduleissummarisedinTable2.

Patientfollow-up

Follow-upoccursat3and 6months(±4weeks)afterOHCA. Patientsareaskedtocompletetheleveloffunctionsurvey (mRS-9Q), the EQ5D-5L questionnaire, and a bespoke resource use questionnairethatcapturesinformationabout(i)anyequipment oraids thepatientrequires,(ii)any staysaway fromhomefor medicalreasonsand(iii)informationonanycontactwithhealth careprofessionals.Follow-upiscarriedoutbytelephoneorpost, co-ordinatedbythecentralCTEUteam.

Seriousadverseeventmanagement

Seriousadverseevents(SAEs)andseriousadversedeviceevents (SADEs)arereportedinaccordancewiththesponsor’s research-relatedadverseeventreportingpolicy.

Alltrialpatientsareinanimmediatelylife-threatening situa-tion,mostdonotsurvive,andallsurvivorsarehospitalised.SAEs andSADEsareonlyreportediftheyarepotentiallyrelatedtotrial participationand they are unexpected(i.e. theevent is not an expectedoccurrenceforpatientswhohavehadacardiacarrest).

Endofthetrial

Forpatientswhoconsenttofollow-up,theirparticipationends afterthefinalfollow-up,sixmonthsaftertheindexcardiacarrest. Forpatientswhodonotconsenttofollow-up,theirparticipation endsimmediatelyafterapproachforconsent.Thetrialwillendonce allparticipantshavecompletedthefollow-upphase.

Dataanalysis

Theprimaryanalysiswilltakeplacewhenfollow-upiscomplete forallrecruitedparticipants.Aformalinterimanalysisisplanned atthemid-pointofrecruitment.Thetrialwillcontinueasplanned unlesstheData MonitoringandSafety Committeerecommends termination.

TheprimaryoutcomeofmRSatdischargeor30dayspostOHCA willbedichotomisedintogoodrecovery(0–3)versuspoor recov-ery/death(4–6),inlinewithpreviousreports.ThemRSandother binaryoutcomeswillbeanalysedusingmultilevelmixedeffects logisticregression models,accounting fortheclusteringofdata withinparamedics.Survivalto6monthsandothertime-to-event outcomeswillbeanalysedusingsurvivalanalysismethods,again allowingforclusteringofpatientsbyparamedic.Overallqualityof lifeutilityscoresandpatientsurvivalwillbeconsideredjointlyto assesswhethertheuseofthei-gelsimultaneouslyimprovesthe patient’squalityoflifeandreducestheriskofdeath.

Analyses will be performed according to the principle of intention-to-treat, and reported according to CONSORT guidelines.30,31_{Twosub-groupanalysesareplanned:theUtstein} comparatorgroup(definedasanarrestofapresumedcardiaccause thatwasbystanderwitnessedwithaninitialrhythmofventricular fibrillationorpulselessventriculartachycardia;estimatedtomake upabout20%ofthetotal)versusnon-comparatorgroup,andarrest witnessedbyEMSstaff(estimatedtomakeup6%ofthetotal)versus notwitnessedbyEMSstaff.

Protocoldeviations

Most AIRWAYS-2 paramedics attend one to three eligible patients per year and therefore some protocol deviations are expected(seeSupplementarymaterial).Totrytoreducedeviations asmuchaspossible,monthlymonitoringiscarriedout;research paramedicsarerequiredtofollow-upprotocoldeviationswiththe relevantAIRWAYS-2 paramedicand reiteratethecorrect proce-dures.Webelievethat≥80%adherencetotheAIRWAYS-2protocol isnecessarytomaintaintheintegrityofthestudy,with<10%“true crossover”(incorrectinterventionattemptedfirst).

Economicevaluation

An economic evaluation is being undertaken as part of AIRWAYS-2toestimatethecosteffectivenessofthei-gelcompared tointubation,inaccordancewithrecognisedNationalInstitutefor HealthandCareExcellence(NICE)guidelines.32_{Thiswillhelpto} determinewhichtypeofairwaymanagementrepresentsthebest useofNHSresourcesinthiscontext.

Planneddissemination

Researchapprovals

Researchethicsapprovalwasgranted bytheOxfordC-South Central Research Ethics Committee (reference 14/SC/1219) in September 2014 and the Confidentiality Advisory Group gave approvalforthetrialunderRegulation5oftheHealthService (Con-trolof PatientInformation)Regulations 2002toprocesspatient identifiableinformationwithoutconsent.

Trialmanagement

TheSponsororganisationistheSouthWesternAmbulance Ser-vicesNHSFoundationTrust.

Thecontributionofthemanufacturersofthei-gelislimitedto confirmingthatthetrainingofparamedicsintheuseofthedevices conformstotheirrecommendedguidelines.Themanufacturerhas norolein supplyingdevices orthedesign, conduct,analysisor reportingofthetrial.

ThetrialisoverseenbyaTrialSteeringCommitteeandData MonitoringandSafetyCommittee.

Apatientandpublicresearchadvisorygroupconsistingof10 membersmeetsevery4–6months.Theadvisorygroupareinvolved indebatingvariouschallengesregardingpatientinvolvement;their feedbackhashelpedinformedthedesignofthestudy.

Discussion

Due to OHCAbeing an extreme medical emergency requir-ingimmediateattendanceandactionbyskilledclinicalstaffina widerange of unpredictableenvironments, theimplementation anddesignoftheAIRWAYS-2trialhaspresentedseveralchallenges relatingtobothethicalconsiderationsaroundpatientconsentand thepotentialforbias.

AsAIRWAYS-2involvestherecruitmentofincapacitatedadults andthereisnoopportunitytoobtaininformedconsentpriorto treatment, we use a deferred consent model for survivors and waiverofconsentforthosewhodonotsurvivetodischargefrom intensive/coronarycare.Followingconsultationwithourpatient andpublicadvisorygroupwe madethedecision nottoinform therelativesofenrolledpatientswho donot survivetheinitial cardiacarrestthattheywereinvolvedinresearch;thisappliesto themajorityofpatientsenrolled,andisamodelthatwasadopted successfullyinourfeasibilitystudy.Informingrelativesthattheir recentlydeceasedlovedonewasinvolvedinresearchhasahigh risk of increasingdistress and uncertainty without benefit. We believethatthisapproachrepresentsthebestwayofanswering thisimportantclinicalquestion,andthatthetrialisjustifiedby bothitsrelevancetofuturehealthcareandthedegreeofclinical equipoisethatcurrentlyexists,sincebothtrachealintubationand thei-gelarealreadyusedroutinelyinEnglishEMSproviders,and informationontheadvancedairwaymanagementstrategiesused duringresuscitationisnotroutinelyprovidedtotherelativesof patientswhodonotsurviveOHCA.

Tominimisebiasweareusingacombinationofmethodsto iden-tifyalleligiblepatients,andanobjectiveprimaryoutcomemeasure (mRS)thatwiththepermissionoftheCAG,canbeobtainedforall survivingpatientsregardlessoftheirconsentstatus.

Ideallyatrialwouldrandomiseatthelevelofthepatient. How-ever, due to theemergency situation this is not practicable in AIRWAYS-2. Theprocedures that would berequiredto achieve randomisationofaneligiblepatient(contactinga remoteserver ortelephoneline,orevenopeningasealedopaqueenvelope)are impracticableatthepointwhenaneligiblepatientisidentified. Onecouldarguethatitwouldbepossibletorandomiseatpatient levelonthewaytoanarrestbutpatientlevelrandomisationbefore patienteligibilityisassessedwouldleadtomanyineligiblepatients

beingrandomised.Almostallsimilarresearchstudieshavebeen cluster-randomised,oftenatthelevelofambulancestations,33–35 whichhasalsoledtochallengesrelatingtoadherencewiththe allo-catedinterventionsandbias.OnthebasisoftheREVIVE-Airways feasibilitystudy,28,29 _{wechosetorandomiseparamedics,which} is advantageous because it more closely approaches individual patientrandomisation(i.e.moreclustersandfewerparticipants percluster).

OneofthekeychallengesfacedwhilstdesigningtheAIRWAYS-2 studywasensuringthattherewasarobustmodelofpatient enrol-ment.Theautomaticpatientenrolmentmodelusedinthisstudy hastheadvantageofensuringthatalleligiblepatientsareidentified andincludedinthestudypopulation.Thissignificantlyreducesthe abilityofAIRWAYS-2paramedicstointroduceselectionbias.

The use of an automatic enrolment model could however increase the likelihood of protocol deviations, including non-adherencetotheairwaymanagementalgorithm. Theautomatic enrolmentmodelwillalsohavesomelimitationsthatmayaffect thequalityofthedata;ifapatientisincludedinthestudythat theAIRWAYS-2paramedicdidnotconsciouslyenrolthismaylead tomissing airway management data orpoor qualitydata ifan AIRWAYS-2paramedicisaskedtoretrospectivelyrecallthedetails ofanevent.

TheresultsfromtheAIRWAYS-2trial,togetherwithresultsfrom thePARTtrial(asimilarNorthAmericanstudy),36_havethe poten-tialtoanswerimportantquestionsaboutinitialadvancedairway managementinOHCA.Itishopedthatfindingsfromthesetrials willhelptoreduceprematuremortality,enhancequalityoflife andreducetheuseofhealthandsocialcareresourcesbyleading toimportantchangesinthetreatmentprotocolsrecommendedby theInternationalLiaisonCommitteeonResuscitation(ILCOR).

Trialstatus

ThefirstparamedicwasrandomisedinMarch2015.Thetrial openedtopatientenrolmentinthreeEMSprovidersinJune2015 andtheotherEMSproviderinJuly2015.Paramedicandpatient recruitmentison-going.

The full protocol is available from www.nets.nihr.ac.uk/ projects/hta/12167102.

IndependentTrialSteeringCommitteemembers

•Simon Gates(Chair), Professor of ClinicalTrials, University of Warwick.

•Charles Deakin, Honorary Professor of Resuscitationand Pre-Hospital Emergency Medicine, University of Southampton UniversityofSouthampton.

•GavinPerkins,ClinicalProfessorinCriticalCareMedicine, Uni-versityofWarwick.

•JasSoarConsultantinAnaesthesiaandIntensiveCaremedicine, SouthmeadHospital.

•KeithDouglas,LayMember. •MargaretDouglas,LayMember.

Independentdatamonitoringandsafetycommittee

members

•GordonTaylor(Chair),Reader/SeniorMedicalStatistician, Uni-versityofBath.

•HelenSnooks,Professor ofHealthServicesResearch, Swansea University.

Conflictofintereststatement

Theauthorsdeclarenofinancialorotherconflictinginterests.

Fundingstatement

ThetrialisfundedbytheNationalInstituteforHealthResearch (NIHR) Health Technology Assessment (HTA) (project number 12/167/102).Theviewsandopinionsexpressedthereinarethose oftheauthorsanddonotnecessarilyreflectthoseoftheHTA,NIHR, NHSortheDepartmentofHealth.

Authors’contributions

Allauthorscontributedtothetrialprotocol.JRB,CAR,BCRled theapplicationforfunding.ESandSWdesignedthehealth eco-nomicevaluation.JTandJRBdraftedthemanuscript,allauthors contributedtoitscriticalreviewandreadandapprovedthefinal version.

AppendixA. Supplementarydata

Supplementarydataassociatedwiththisarticlecanbefound, intheonlineversion,athttp://dx.doi.org/10.1016/j.resuscitation. 2016.09.016.

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