2014+AASLD／AST／NASPGHAN实践指南：儿童肝移植患者的评估

EvaluationofthePediatricPatientforLiverTransplantation:2014PracticeGuidelinebytheAmericanAssociationfortheStudyofLiverDiseases,AmericanSocietyofTransplantationandtheNorthAmericanSocietyforPediatricGastroenterology,

HepatologyandNutrition

RobertH.Squires,1VickyNg,2ReneRomero,3UdemeEkong,4WinitaHardikar,5SukruEmre,6and

GeorgeV.Mazariegos7

ThispracticeguidelinehasbeenapprovedbytheAmericanAssociationfortheStudyofLiverDiseases,theAmericanSocietyofTransplantationandtheNorthAmericanSocietyforPediatricGastroenterology,HepatologyandNutrition.

Abbreviations:ALF,acuteliverfailure;GRADE,GradingofRecommenda-tionAssessment,Development,andEvaluation;HB,hepatoblastoma;HCC,hepatocellularcarcinoma;HPE,hepatoportoenterostomy;LT,livertransplanta-tion;OTPN,OrganProcurementandTransplantationNetwork;PFIC,pro-gressivefamilialintrahepaticcholestasis;TIPS,transjugularintrahepaticportosystemicshunt.

Fromthe1DepartmentofPediatrics,UniversityofPittsburghSchoolofMed-icine;DivisionofPediatricGastroenterology,HepatologyandNutrition,Child-ren’sHospitalofPittsburghofUPMC,Pittsburgh,PA;2DepartmentofPediatrics,UniversityofToronto;DivisionofPediatricGastroenterology,Hepa-tologyandNutrition,SickKidsTransplantandRegenerativeMedicineCenter,HospitalforSickChildren,Toronto,Canada;3DepartmentofPediatrics,Divi-sionofPediatricGastroenterology,Hepatology,andNutrition,EmoryUniversitySchoolofMedicine;Children’sHealthcareofAtlanta,Atlanta,GA;4Depart-mentofPediatrics,DivisionofPediatricGastroenterologyandHepatology,YaleSchoolofMedicine,NewHaven,CT;5DepartmentofPaediatrics,UniversityofMelbourne;DepartmentofGastroenterology,RoyalChildren’sHospital,Mel-bourne,Australia;6DepartmentofSurgery,SectionofTransplantationandImmunology,YaleSchoolofMedicine,NewHaven,CT;7DepartmentofSur-gery,UniversityofPittsburghSchoolofMedicine;DivisionofPediatricTrans-plantation,HillmanCenterforPediatricTransplantation,Children’sHospitalofPittsburghofUPMC,Pittsburgh,PA.

FinancialsupporttodevelopthispracticeguidelinewasprovidedbytheAmericanAssociationfortheStudyofLiverDiseases.

AllAASLDPracticeGuidelinesareupdatedannually.IfyouareviewingaPracticeGuidelinethatismorethan12monthsold,http://wendang.chazidian.comforanupdateinthematerial.

ReceivedApril22,2014;acceptedApril22,2014.

Addressreprintrequeststo:RobertH.Squires,M.D.,ProfessorofPediatrics,UniversityofPittsburgh,Children’sHospitalofPittsburghofUPMC,4401PennAve.,Pittsburgh,PA15224.E-mail:squiresr@upmc.edu

C2014bytheAmericanAssociationfortheStudyofLiverDiseases.CopyrightV

http://wendang.chazidian.com.DOI10.1002/hep.27191

Potentialconflictofinterest:Dr.RomeroreceivedgrantsfromBristol-Myers

Squibb.

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Preamble

CurrentAmericanAssociationfortheStudyofLiverDiseases(AASLD)livertransplantevaluationguidelinesincludebothadultandpediatricpatients.1Whilepediatriclivertransplantsaccountfor??7.8%ofalllivertransplantsintheUnitedStates,suf?cientdif-ferencesbetweenpediatricandadultpatientsseekinglivertransplantation(LT)nowrequireindependent,yetcomplementarydocuments.Thisdocumentwillfocusonpediatricissuesateachleveloftheevaluationprocess.DiseasecategoriessuitableforreferraltoapediatricLTprogramaresimilartoadults:acuteliverfailure,autoimmune,cholestasis,metabolicorgenetic,oncologic,vascular,andinfectious.However,speci?cetiologiesandoutcomesdifferwidelyfromadultpatients,justifyingindependentpediatricguidelines.DatasupportingourrecommendationsarebasedonaMedlinesearchoftheEnglishlanguageliteraturefrom1997tothepresent.

Intendedforusebyphysicians,theserecommenda-tionssuggestpreferredapproachestothediagnostic,therapeutic,andpreventiveaspectsofcare.Theyareintendedtobe?exible,incontrasttostandardsofcare,whicharein?exiblepoliciestobefollowedineverycase.Speci?crecommendationsarebasedonrel-evantpublishedinformation.

Tomorefullycharacterizetheavailableevidencesupportingtherecommendations,theAASLDPracticeGuidelinesCommitteehasadoptedtheclassi?cationusedbytheGradingofRecommendationAssessment,Development,andEvaluation(GRADE)workgroupwithminormodi?cations(Table1).Theclassi?cationsandrecommendationsarebasedonthreecategories:thesourceofevidenceinlevelsIthroughIII;the

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HEPATOLOGY,Vol.60,No.1,2014SQUIRESETAL.363

Table1.GradingofRecommendations,Assessment,

DevelopmentandEvaluation(GRADE)

Criteria

Strengthof

RecommendationStrong[1]

Weak[2]

Factorsin?uencingthestrengthoftherecommen-dationincludedthequalityoftheevidence,presumedpatient-importantoutcomes,andcostVariabilityinpreferencesandvalues,ormoreuncertainty.Recommendationismadewithlesscertainty,highercostorresourceconsumption

QualityofEvidenceHigh[A]Moderate[B]Low[C]

Furtherresearchisunlikelytochangecon?denceintheestimateoftheclinicaleffect

Furtherresearchmaychangecon?denceintheesti-mateoftheclinicaleffect

Furtherresearchisverylikelytoimpactcon?denceontheestimateofclinicaleffect

topulmonarysyndrome,malignancy,etc.)wassearchedinthecontextoftheprimarysearchtermsaswellasindividuallywhenrelevantclinicalbackgroundinfor-mationwasneeded.

Theselectionofreferencesfortheguidelinewasbasedonavalidationoftheappropriatenessofthestudydesignforthestatedpurpose,arelevantnumberofpatientsunderstudy,andcon?denceinthepartici-patingcentersandauthors.Referencesonoriginaldatawerepreferredandthosethatwerefoundunsatisfac-toryinanyoftheserespectswereexcludedfromfur-therevaluation.Theremaybelimitationsinthisapproachwhenrecommendationsareneededonrareproblemsorproblemsonwhichscantoriginaldataareavailable.Insuchcasesitmaybenecessarytorelyonlessquali?edreferenceswithalowgrading.

PediatricLiverTransplantEvaluationTeam

qualityofevidencedesignatedbyhigh(A),moderate(B),orlowquality(C);andthestrengthofrecom-mendationsclassi?edasstrongorweak.

Childrenhavedistinctdiseases,clinicalsusceptibil-ities,physiologicalresponses,aswellasneurocognitiveandneurodevelopmentalfeaturesthatdistinguishthemfromadults.Infact,evenwithinthepediatricagegroupdifferencescanbefoundbetweennewborns,infants,children,andadolescents.Giventheintra-abdominalanatomicalvariationsassociatedwithbiliaryatresia,themostcommonindicationforpediatricLT,aswellastherestrictedabdominalcavityandsmallsizeofbloodvesselsininfantsandyoungchildren,surgicalteamswithexhaustivepediatricexperiencewillbene?tthepediatricrecipientofanLT.MembersofthepediatricLTteam(Table2)usetheirexpertisetotailortheLTevaluationplan(Table3)totheuniqueneedsofthechild.TheendproductoftheevaluationwillensuretheelementsforaninformeddecisiontoproceedtoLTaremet.2

Recommendation:

1.AmultidisciplinarypediatricLTevaluationteamshouldbeskilledinpediatricconditionsandproperlycommunicatewiththefamilyandthechild,whenappropriate,theprocesses,risks,andbene?tsassociatedwithLT.(2-B)

LiteratureReviewMethodsandAnalysis

EachAssociationappointedatleastoneauthortoserveonthewritinggroup.TheChairofthewritinggroupwasappointedbytheAASLD.Membersofthewritinggroupwerenotcompensatedfortheirworkandservedasvolunteersthroughouttheprocessfromconceptdesignthrough?nalpublication.Writinggroupmembershadno?nancialcon?ictofinterestor?nancialrelationshipwithcommercialentitiesrelevanttothearticle.Topicsrelevanttolivertransplantevalua-tioninthepediatricpatientswereidenti?edthroughaconferencecallwithallmembersofthewritinggrouponJuly11,2012andassignmentsweredistributedamongthemembersbasedontheirparticularexpertiseandinterest.

Theliteraturedatabasesandthesearchstrategiesareoutlinedbelow.Theresultingliteraturedatabasewasavailabletoallmembersofthewritinggroup.Theyselectedreferenceswithintheir?eldofexpertiseandexperienceandgradedthereferencesaccordingtotheGRADEsystem.Datasupportingourrecommenda-tionsarebasedonaMEDLINEsearchoftheEnglishlanguageliteraturefrom1973tothepresent.Primarysearchtermsincluded:livertransplantevaluation,livertransplant,child,pediatric,andlivertransplantout-come.Inaddition,eachassessment(e.g.,anesthesia,hepatology,renal,etc.);diagnosis(e.g.,biliaryatresia,organicacidemia,maplesyrupurinedisease,ductalplatemalformation,etc.)andcomplication(e.g.,hepa-

TimingofReferralforPediatricLiverTransplantEvaluation

BasedontheUnitedStatesOrganProcurementandTransplantationNetwork(OTPN)fromJanuary1,2011,throughMay31,2013,indicationsforLTincludebiliaryatresia(32%),metabolic/geneticcondi-tions(22%),acuteliverfailure(11%),cirrhosis(9%),livertumor(9%),immune-mediatedliverandbiliary

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364SQUIRESETAL.Table2.PotentialMembersofthePediatricLiver

TransplantTeam

General

Transplantsurgeon

Hepatologist/gastroenterologistwithexpertiseinpediatricliverdisease Infectiousdiseasespecialist Criticalcarespecialist Socialworker

Psychologist/neuropsychologist/childdevelopmentspecialist Dietician

Physical/occupationaltherapist Pharmacist Psychiatrist

Transplantcoordinator Anesthesiologist PatienteducatorSelectedpatients Cardiologist Nephrologist Neurologist

Genetic/metabolicspecialist Pulmonologist

Radiologist,diagnostic Radiologist,interventional Ethicsspecialist Childlifespecialist Pastoralcare

injury(4%),andothermiscellaneousconditions(13%)(Fig.1).Withinthesebroadcategoriesrestmanyrareconditionswithmyriadpresentations.

Astimingforreferralvariesdependingonthechild’sclinicalcircumstances,referralforLTmaybeemergent,urgent,oranticipatory.Acuteliverfailure(ALF)oranacutedecompensationofanestablishedliverdiseasemayhavearapidandunpredictablecourseprogressingtodeathorirreversibleneurologicaldamage.3Children

http://wendang.chazidian.componentsofthePediatricLiver

TransplantationEvaluation

Secureallpriorrecordstoidentifyrelevantdiagnostic,managementandclinicalinformation

Establishappropriateindicationsforreferral

Constructapatientanddiseasespeci?cappointmentitinerary

Con?rmoraf?rmthediagnosis,associatedsystemicmanifestations,andman-agementplan

AssessdiseaseseverityandurgencyforlivertransplantationIdentifyopportunitiestomaximizecurrentmedicaltherapyDetermineifnon-transplantsurgicaloptionsareavailableIdentifycontraindicationsforlivertransplantationConsiderappropriatenessofalivedonoroption

Con?rmimmunizationstatus;ifincomplete,establishastrategytocompleteimmunizations

Establishatrustingrelationshipamongthechild,familyandtransplantteamEnsure?nancesareavailable

Anticipatepotentialcomplicationsfollowingtransplant

Developamanagementandcommunicationplanwiththelocalmanagingphysician

Clarifylogisticswhenapotentialdonorliveris

available

HEPATOLOGY,July2014

Fig.1.Indicationsforpediatriclivertransplant.

withmetabolicliverdisease,suchasureacycledefectsormaplesyrupurinedisease,cansuffersigni?cantneurological4sequelaeasaconsequenceofmetaboliccrises.Primaryandsecondarylivertumorsarerareinchildren,withhepatoblastoma(HB)andhepatocellularcarcinoma(HCC)beingthemostcommon.SurvivalforchildrenwithHBisdependentonresponsetoini-tialchemotherapyandcompletesurgicalresection.5ScreeningforHCCisimperfect,butanelevatedorrising6alpha-fetoproteinidenti?esaheightenedriskforHCC.Only16%ofchildrenwithbiliaryatresiasur-viveto2yearswiththeirnativeliverifthetotalserumbilirubinmeasured3monthsfollowinghepatoportoen-terostomy(KasaiProcedure)isover6mg/dL,com-paredto84%forthosewithatotalbilirubinlessthan2mg/dL.7ForsomechildrenwithAlagillesyndromeandprogressivefamilialintrahepaticcholestasis(PFIC)types1,2,and3,pruritusand/ordeformingxantho-mascanseverelyimpactthechild’squalityoflifedespiterelativelypreservedliverfunction.8Sequelaeassociatedwithendstageliverdiseaseplacechildrenatriskforlife-threateningevents.

Recommendations:

2.ImmediatecontactwithapediatricLTcentershouldbeinitiatedforchildrenwithacuteliverfail-ureoracutedecompensationofanestablishedliverdisease;emergentreferralforLTevaluationmayberequired.(1-A)

3.Childrenwithliver-basedmetaboliccrisesrefractorytomedicaland/orsurgicaltherapy(1-B),unresectablehepatoblastoma(1-B),orevidenceofhepatocellularunresectablecarcinoma(1-B)shouldbereferredurgentlyforLTevaluation.

4.Biliaryatresia(BA)patientswhoarepost-hepatoportoenterostomy(HPE)shouldbepromptlyreferredforLTevaluationifthetotalbilirubinisgreaterthan6mg/dLbeyond3monthsfromHPE

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HEPATOLOGY,Vol.60,No.1,2014(1-B);livertransplantevaluationshouldbeconsid-eredinBApatientswhosetotalbilirubinremainsbetween2-6mg/dL.(1-B)

5.ReferralforLTevaluationshouldbeantici-patedforchildrenwithchronicliverdiseaseandevi-denceofdeterioratingliverfunctioncharacterizedbypoorweightgain,growthfailure,varicealhemor-rhage,intractableascites,recurrentcholangitis,orepisodesofspontaneousbacterialperitonitis,pruri-tus,advancingencephalopathy,and/oruncorrectablecoagulopathy.(1-B)

LiverTransplantEvaluation

AffirmDiagnosisandManagement

Thechild’sdiagnosticevaluationasitrelatestotheirprimarydisease,associatedcomorbidities,subspecialtyconsultations,andmanagementstrategiesshouldbedocumentedandprovidedbytheprimarypediatricspe-cialistresponsibleformanagementofthechild’sliverdisease.Thesedocumentsshouldincludeclinicalassess-ments,resultsoflaboratoryanddiagnosticstudies,med-icalandnutritionalmanagement,surgicalprocedures,pathologyreportsandslides,aswellasradiographicreportsandcopiesoftheradiographs.Personalcommu-nicationbetweenamemberoftheLTevaluationteamandthechild’sphysicianwillidentifyclinical,social,andpsychologicalfactorsthatmaynotbeapparentinthemedicalrecord.Neworworseningcomorbiditiesmaybeidenti?edduringtheLTevaluation.9

Recommendations:

6.AreviewofthelocalrecordsbytheLTteampriortotheLTevaluationwillinformtheevalua-tionscheduleandenableaf?rmationoftheprimarydiagnosis,assessmentofcomorbidities,andidentifytechnicalchallengesrelatedtoLT.(2-B)

7.Incollaborationwiththelocalprimarypediat-ricspecialist,managementoftheprimarydiseaseandcomorbiditiesshouldbereviewedandopti-mized.(2-B)

HepatologyAssessment

Complicationsassociatedwithendstageliverdiseaseincludeascites,pruritus,portalhypertension,malnutri-tion,vitaminde?ciencies,anddelayedgrowthanddevelopment.10Incirrhosispatients,accumulationofascitesisaresultofportalhypertension,vasodilatation,andhyperaldosteronism.11Hypoalbuminemiaisanadditionalriskfactorforascites.Ultrasonographyissensitiveenoughtodetectaslittleasanounceofintra-abdominal?uid,whilesigni?cantlymoreisrequired

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forittobedetectedonphysicalexamination.Decisionstoinitiatediuretictherapytomanageascitesareill-de?ned.Abdominaldistensionalonedoesnotreliablypredictascites,asorganomegalyandvascularconges-tionofthebowelmayalsocontributetodistension.Fluidthatiseasilypalpatedbetweentheabdominalwallandthesurfaceoftheliver(“ballotable?uid”)wouldsuggestsuf?cientascitestowarranttherapy;itspresencecanbeusedtojudgeresponsetotherapy.Ini-tialtreatmentincludesspironolactoneanda“no-added”saltdiet.Loop-diureticsshouldbeusedwithcautionasoveraggressivediuresiscanprecipitatehepa-torenalsyndrome.Forhospitalizedpatientswithsigni?-cantascites,intravenousalbumin,withorwithoutanaccompanyingdiuretic,12canimprovediuresisandresponsetodiuretics.Tenseascitescancompromiserespiratoryfunctionandrenalperfusion,heightentherisk13forinfection,http://wendang.chazidian.comrge-volumeparacentesis14andtransjugularintrahepaticportosystemicshunt(TIPS)15areeffectiveifascitesiscompromisingthechild’srespiratoryeffortandisnotresponsivetomedicaltherapy.Rapidaccumulationofascitesshouldraiseconcernforobstructionoftheportalorhepaticveinorbacterialperitonitis.

Evaluationandmanagementofesophagealvaricesinchildrenvarieswidelyamongpractitioners.16,17Intheabsenceofdatasupportingprimaryprophylacticther-apyforesophagealvaricesinchildren,screeningendos-copyforesophageal18varicieshasnotbeenrecommended.In?ammatoryboweldisease(IBD),particularlyulcerativecolitis,isanotablecomorbidityofchildrenwithprimarysclerosingcholangitis(PSC).FollowingLT,somepatientswithautoimmunehepati-tisandbilesaltexcretorypumpdiseaseareatriskforrecurrenceoftheirprimaryliverdisease19,20;thosewithPSCmayalsobeatincreasedriskforcoloncancer.21,22Recommendations:

8.Clinicallydetectableascitescanbemanagedinitiallywithanaldosteroneantagonist(2-B);moreaggressiveremovalofascitic?uidusingparacentesisortransjugularintrahepaticportosystemicshuntorsurgicalshuntshouldbereservedforascitesthatcompromisesrespiratoryeffortorseverelyaffectsqualityoflife.(2-B)

9.Patientswithconditionssuchasautoimmunehepatitis,PSC,andbilesaltexcretorypumpdiseaseshouldbeinformedthatliverdiseasecanrecurpost-LT.(2-B)

10.PatientsatriskforextrahepaticcomplicationssuchasIBDshouldbeinformedoftheneedfor

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366SQUIRESETAL.scheduledmonitoringforevidenceofIBD,includingcolonoscopy,forcoloncancersurveillance.(2-B)NutritionAssessment

Childrenwithchronicliverdiseaseareatriskformalnutritionastheyrequire20%-80%morecaloriesthannormalchildrentoachieveadequategrowth.23-25Increasedcaloricrequirementsresultfromahyperme-tabolicstatecoupledwithmalabsorption.AggressivenutritionalsupportpriortoLTimprovespatientandgraftsurvivalaswellasneurodevelopmentalout-come.26,27Serialtricepsskinfoldandmid-armcir-cumferencearethemostreliableanthropometricassessmentstojudgenutritionalstatus,asrelianceonweightalonemayoverestimatenutritionaladequacyinchildrenwithchronicliverdisease.24,25,28Fatsolublevitamin(FSV)de?ciencyiscommonanddosingandmonitoringrecommendations24,25,29,30topreventFSVde?-ciencyareavailable.Enteralformulasthatcontainmediumchaintriglycerides(MCT)arepre-ferredincholestaticpatients,butexcessiveadministra-tionof31MCTcanleadtoessentialfattyacidde?ciency.Proteinintakeshouldnotberestrictedintheabsenceofhyperammonemia.32Whenoralintakeisnotsuf?cient,initiationofnasogastric(NG)tubefeedingimprovesbody33compositioninchildrenwithchronicliverdisease.Parenteralnutritionmayhelpreversepoorweight34

gainandgrowthinmalnourishedchildrenwithBA.Lessthan15%ofchildrenreceivingalivertrans-plantareobese.35Patientswithbodymassindex(BMI)z-scores??3havesimilarshort-termsurvivalasnormal-weightcounterparts,buthadincreasedlate(>12years)mortalityandaremorelikelytoexperi-enceposttransplantobesity.36Metabolicsyndromeoccursfrequentlyinobeseadultlivertransplantrecipi-ents,buttherateinobesepediatricrecipientsisnotknown.37,38

Recommendations:

http://wendang.chazidian.completenutritionalassessmentshouldincludeserialtricepsskinfoldthicknessandmid-armcircumferencemeasurements(2-B);identi?ca-tionofnutritionalgoalstomaximizehealth;fatsolublevitaminsupplementationandmonitoring(2-B);andincholestaticinfants,useofmedium-chaintriglyceride-containingformulaswithnormalpro-teinadministration(2-4g/kg/day).(2-B)

12.AggressivenutritionalsupportforchildrenawaitingLTshouldbeinitiatedtooptimizeoutcomes(1-B);NGtubefeedingsandparenteralnutritionmaybeneededinsomecircumstances.(2-B)HEPATOLOGY,July2014

CardiopulmonaryAssessment

Structuralcardiacdiseasecan39beseeninchildrenwithBAandAlagillesyndrome.Cirrhoticcardiomy-opathy(CC),characterizedbyincreasedcardiacout-put,impaireddiastolicrelaxation,myocardialhypertrophy,andrepolarizationabnormalities,carriesahighriskofpost-LTmortalityinadults.Evidenceofcardiomyopathy,asdeterminedbytwo-dimensionalechocardiography(2-DE),canalsobefoundinchil-drenwithcirrhosisaswellasthosewithcardiomyopa-thyassociatedwithglycogenstoragediseaseorsystemicmitochondrialdisease.Inonestudy,70%ofchildrenwithBAhadevidenceofCC.40WhilethosewithCCexperiencedalongerICUandhospitalstay,therewerenodifferencesinthe2-DEbetweenthosewhodiedawaitingLTversusthosewhosurvivedtoLT.

Hepatopulmonarysyndrome(HPS)andporto-pulmonaryhypertension(PPHN),bothdescribedinmoredetailbelow,arepotentiallylife-threateningcon-ditionsthatdevelopasaconsequenceofportosystemicshunting41,42regardlessoftheseverityoftheliverdis-ease.Nonspeci?cclinical?ndingsincludedigitalclubbing,facialtelangiectasia,dyspnea,wheezing,andsyncope.ScreeningforHPSisperformedbypulseoxi-metrydetectionofoxygendesaturationwheninthesittingorstandingposition;pulseoximetrylessthan97%onroom43airshouldbeconsideredforfurtherevaluation.HPSiscon?rmedwith2-DEduringinfusionofagitatedsalinewiththeappearanceofsalinebubblesintheleftatriumwithin3-6cardiaccycles.A99mTechnetium-macroaggregatedalbumin(MAA)perfusionlungscancanbeusedtoquantifyandfollowthedegreeofintrapulmonaryshunting;anMAAshuntfractionof27.8%washighlyspeci?cforintrapulmonaryshuntingassociatedwithhypoxia.44,45UnlikeHPS,screeningproceduresforPPHNareimperfect.Whilethechestradiographandelectrocar-diogrammayrevealaprominentpulmonaryarteryandrightventricularhypertrophy,butbothmaybenormal.46Inaddition,2-DEwithDopplermayshowelevationsinrightventricularsystolicpressureswhichshouldbecon?rmedbycardiaccatheterizationtoexcludeothercausesofpulmonaryhypertensionsuchasincreasedcentralvolumeandhighcardiacoutputduetoahyperdynamiccardiacphysiology.47

Patientswithcystic?brosis(CF)referredforLTpresentauniquechallenge.InadditiontobeingatriskfordevelopmentofHPSandPPHN,theseverityofCF-relatedlungdiseasecanimpactoutcome.Theforcedexpiratoryvolumeinonesecond(FEV1)andforcedvitalcapacity(FVC)havebeenusedinamodel

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