4/4/2015

Acuteliverfailureinchildren:Management

Officialreprintfrom UpToDate
www.uptodate.com 2015UpToDate

Acuteliverfailureinchildren:Management
Author
RobertHSquires,Jr,MD,FAAP

SectionEditor
ElizabethBRand,MD

DeputyEditor
AlisonGHoppin,MD

Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.
Literaturereviewcurrentthrough:Mar2015.|Thistopiclastupdated:Jul31,2014.
INTRODUCTIONPediatricacuteliverfailure(PALF)isacomplex,rapidlyprogressiveclinicalsyndromethatis
thefinalcommonpathwayformanydisparateconditions,someknownandothersyettobeidentified[13].The
estimatedfrequencyofacuteliverfailure(ALF)inallagegroupsintheUnitedStatesisabout17casesper100,000
populationperyear,butthefrequencyinchildrenisunknown.PALFaccountsfor10to15percentofpediatricliver
transplantsperformedintheUnitedStatesannually.
PALFisarapidlyevolvingclinicalcondition.Therearenoadequatelypoweredstudiestoinformdiagnostic
algorithms,toassessmarkersofdiseaseseverityandtrajectory,andtoguidedecisionsaboutlivertransplant.The
clinicianmustconstructanindividualizeddiagnosticapproachandmanagementstrategy.Managementrequiresa
multidisciplinaryteaminvolvingthehepatologist,criticalcarespecialist,andlivertransplantsurgeon.
ManagementofPALFanditscomplicationsinchildrenarediscussedhere.Anorganizedapproachtodiagnosing
thecauseofPALFispresentedseparately.(See"Acuteliverfailureinchildren:Etiologyandevaluation".)
ALFinadultsisaddressedinseparatereviews.(See"Acuteliverfailureinadults:Etiology,clinicalmanifestations,
anddiagnosis"and"Acuteliverfailureinadults:Managementandprognosis".)
GENERALMANAGEMENTPRINCIPLESAftertheinitialcharacterizationofthepatientpresentation,proper
patientmanagementneedstobeconductedalongmultipleparallelpaths[2,3]:
Evaluatethecauseofpediatricacuteliverfailure(PALF),guidedbythepatientsageandprioritizingthe
diagnosisoftreatabledisorders(see"Acuteliverfailureinchildren:Etiologyandevaluation")
Monitorthefunctionofeachorgansystem
Identifyandtreatcomplications
Providemedicalsupporttomaximizehealthandsurvival
ClinicalsettingManagementofPALFrequiresadmissiontoahighlyskillednursingenvironment(inmost
cases,apediatricintensivecareunit),whichallowsclosemonitoring,particularlyforchangesinmentalstatus.
Carefulandfrequentbedsideassessmentbyanexperiencednurseorclinicianisessential,andcannotbereplaced
byindirectmonitorssuchasacardiorespiratoryandoxygensaturationmonitor.Caregiversmustcarefullyexamine
thechildmultipletimesduringthedayandnighttoassessevidenceofchangingmentalstatusorhepatic
encephalopathy,increasedrespiratoryeffort,changingheartrateorchangesinbloodpressurethatmightbesigns
ofinfection,increasingcerebraledema,orelectrolyteimbalance.Fluidbalance(inputandoutput)shouldbestrictly
monitored.
LaboratorymonitoringLaboratorymonitoringshouldincludeacompletebloodcount,electrolytes,renal
functiontests,glucose,calcium,phosphorous,ammonia,coagulationprofile,totalanddirectbilirubin,andblood
cultures[3].Thefrequencyoflaboratorymonitoringshouldbeatleastdaily,butmultipletestsobtainedregularly
throughoutthedaymaybenecessarytomonitorthedynamicchangesthatcanoccurinPALF.
Formeasurementofammonia,arterialsamplesareidealbutnotalwaysclinicallypractical.Forchildrenwithstage
0toIIhepaticencephalopathy(HE),ammoniacangenerallybemonitoredwithvenoussamplesobtainedfroma
freeflowingcatheter,andpromptlyplacedoniceandtransportedtothelaboratory.ChildrenwithmoreadvancedHE
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oftenrequireelectiveintubationandventilatorysupportaccompaniedbyplacementofanarterialcatheter.If
available,ammoniasamplesshouldbeobtainedfromthearterialcatheter,butthearterialcathetershouldnotbe
placedsolelyforammoniatesting.
LaboratorystudiesfordiagnosingthecauseofthePALFarealsoimportant,andshouldbeplannedbasedonthe
patientsageandpresentation,prioritizingthosediagnosesthatmaybeamenabletospecifictreatment.(See
"Acuteliverfailureinchildren:Etiologyandevaluation",sectionon'Laboratorytesting'.)
FluidsIfthechildisinshock,fluidresuscitationandpressorsupportisneededtostabilizecardiovascular
status.However,asageneralrule,intravenousandoralfluidintakeshouldbemodestlyrestrictedformostpatients
withPALF.Totaldailyfluidintake(includingmedicationsandbloodproducts)shouldinitiallyberestrictedto
between85to95percentofthemaintenancefluidrequirement.PatientswithPALFaresensitivetofluidvolumeand
candeveloppulmonaryandperipheraledemaiftheyreceiveexcessivefluid.Atthesametime,theserumglucose
shouldbemaintainedbetween90and110mg/dL.Therefore,acentralvenouscathetermayberequiredif
concentrationsofintravenousglucoseover12.5percentareneededtomaintaintheserumglucosewhilerestricting
fluidvolume.Adjustmentinfluidratesisbasedupontheclinicalconditions.
CENTRALNERVOUSSYSTEM
EncephalopathyHepaticencephalopathy(HE)isaneuropsychiatricsyndromeassociatedwithhepatic
dysfunction.Inalargeregistryofpatientswithpediatricacuteliverfailure(PALF),somedegreeofencephalopathy
waspresentonadmissionin50percentofpatients,anddevelopedwithinthenextsevendaysinanadditional15
percent[1].
HEisdeterminedbyserialclinicalevaluationsofbehavior,cognition,neurologicalexamination,and,occasionally,
electroencephalogram(EEG)tocategorizethepatientintooneoffiveclinicalstagesofencephalopathy,ranging
fromstage0(minimalornoevidenceofneurologicaldysfunction)tostageIV(coma)[4].Stagesofencephalopathy
aredefinedslightlydifferentlyininfantsandchildrenupto48monthsofage(table1)ascomparedwitholder
childrenandadults(table2andfigure1).ClinicalstagingofHEwasoriginallydevelopedtoassesspatientswith
cirrhosisratherthanacuteliverfailure(ALF).Nonetheless,thescoringsystemhasbeenfoundtohaveimportant
clinicalandprognosticimplicationsinadultsandchildrenwithALF.ThepathogenesisanddiagnosisofHEin
adultsisdiscussedinseparatetopicreviews.(See"Hepaticencephalopathyinadults:Clinicalmanifestationsand
diagnosis"and"Hepaticencephalopathy:Pathogenesis".)
Theroleofothermodalitiestoassessneurologicalfunction,suchasvisualevokedpotentials,transcranialDoppler,
cerebralnearinfraredspectroscopy(NIRS),andbiomarkers,inthedetectionofHEisunclearatthepresenttime.
WhileneurologicmorbidityremainsamajordeterminantofoutcomefollowingpediatricALF,furtherstudiesare
neededtoimproveearlydetectionofneurologicinjury,standardizemanagementofseizuresandHE,andto
determinewhethersuchinterventionsimproveoutcomes.
Hepaticencephalopathyisnotalwaysclinicallyapparentininfantsandyoungchildren.Distinguishinghepatic
basedencephalopathyfromothercausesofanalteredmentalstatussuchassepsis,hypotension,electrolyte
disturbances,hypoglycemia,anxiety,orintensivecareunit(ICU)psychosisisdifficultforallagegroups.
HyperammonemiaplaysacentralroleinthedevelopmentofHEinmostcases.However,aspecificlevelof
ammoniadoesnotresultinapredictabledegreeofencephalopathy.
InitialtreatmentofHEincludesminimizingexcessstimulation,headelevationupto30degrees,initialrestrictionof
proteinintaketonomorethan1g/kg/day,treatingsuspectedsepsis,and,ifpossible,removingsedative
medicationsthatmightaffectmentalstatus.ForpatientswithprogressiveHE,wesuggestmedicaltherapywith
lactulose,whichisusedempiricallyalthoughthereisonlyweakevidencetosuggestthatitiseffective.Thestarting
doseoflactuloseis0.4to0.5g/kgeverytwohoursbymouthorvianasogastrictube,withthedoseadjustedas
neededtoproducetwotothreesoftstoolsdaily[5].Boweldecontaminationwithrifaximinorneomycincanbe
usedasasecondtiertreatment,butototoxicityandnephrotoxicityarepotentialriskswhenneomycinisused.
MedicalmanagementofHEhasnotbeenstudiedinchildren,andpracticesareextrapolatedfromtheclinical
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experienceinadults.(See"Hepaticencephalopathyinadults:Treatment".)
SomepatientswithHEdevelopaclinicallyimportantincreaseinintracranialpressure,whichcanhavedevastating
consequences.Directmonitoringofintracranialpressureisthemostsensitiveandspecificproceduretousewhen
comparedwithlessinvasiveneuroradiographicprocedures,suchascranialcomputedtomography(CT)or
transcranialultrasonography.(See'Cerebraledema'below.)
ChildrenwithALFmayexperiencegeneralizedorfocalseizures,ornonconvulsive(electrographic)seizures(NCS).
Inmostcases,treatmentbeginswithphenytoin,butpracticesarevariableandthereisnodefinitivestandardof
care.Forseizureswhicharerefractorytophenytoin,therapeuticoptionsmayincludemidazolaminfusion,
phenobarbital,levetiracetam,ortopiramate.Theselectionofdrugdependsonthepatientsmentalstatus,
physiologicstability,availabilityofEEGmonitoringtotitratedruginfusions,andinstitutionalexperience.
CerebraledemaCerebraledemaisalifethreateningcomplicationofALF.Itmayleadtoischemicandhypoxic
braininjury,orbrainstemherniationanddeath[6].Itoccursmostcommonlyinthosewithadvancedhepatic
encephalopathy(stageIIIorIV)andcanprogressrapidly.Detectionofcerebraledemaintheearlystagesis
difficult,becausenoninvasivemonitoringwithclinicalassessmentorradiographicstudieslackssensitivity.The
mostsensitivemeasureofintracranialpressure(ICP)requiressurgicalplacementofanICPmonitor.However,ICP
monitorplacementrequiresadequatecranialcalcificationandcannotbeusedininfantsthereforeitisnota
commonpracticeatmostpediatriccenters.Reportedrisksincludebleedingin10and20percent,althoughthe
amountofbleedingisoftenminimal[7].OncetheICPmonitorisinplaceandproperlyfunctioning,itcanbea
valuabletooltocontinuallyassessresponsetoICPanditstreatment[8].TheICPmonitorisalsofelttobevaluable
duringsurgicalprocedures,includinglivertransplantation,togaugefluidandmedicalmanagementofthe
unconsciouspatient.Monitoringofintracranialpressureinchildrenremainscontroversialduetoassociated
complicationsoftheprocedureandlackofevidencethatmonitoringimprovessurvival.Theindications,types,and
complicationsofICPpressuremonitoringinadultsarediscussedinaseparatetopicreview.(See"Acuteliver
failureinadults:Managementandprognosis",sectionon'Intracranialpressuremonitoring'.)
Thepathogenesisofcerebraledemaiscomplex,involvingtheinteractionamongammonia,cerebralbloodflow,and
inflammation[9].Elevatedlevelsofammoniaaregeneratedasaconsequenceofthefailingliver,whichleadsto
increasedintracerebralconcentrations.Ammoniaenterstheastrocyte,whichisrichinglutaminesynthetase.
Conversionofammoniaandglutamatetoglutamine,apotentintracellularosmolyte,resultsinanosmoticgradient
thatfavorsastrocyteswellingthatcontributestocerebraledemaandintracranialhypertension.Changesinthe
inflammatorymilieu,sepsis,fluidorbloodproductadministration,andotherfactorscanresultinasuddenandoften
unanticipatedincreaseinintracranialpressure.
Managementofcerebraledemainvolvesmeticuloussupportivecaretomaintainthefollowinggoals[9]:

Oxygensaturationabove95percent
Totaldailyfluidbetween85and90percentofmaintenance
Diastolicpressure>40mmHg
Adequatesedation
Headelevationof20to30
Considerationofempiricbroadspectrumantibioticstominimizethedevelopmentofbacterialinfection

Therapiestargetedspecificallytoimprovecerebraledemahavenotmetscientificrigor,buttheyincludehypertonic
salinetomaintainserumsodiumbetween145and150mEq/L,andmannitolkeepingserumosmolaritylessthan
320mOsm/Ltocreateamorefavorableosmoticgradienttoextractwaterfromthebrain.Hypothermiahasbeen
usedinadultswithacuteliverfailurewithsomesuccess,buthasnotbeenstudiedinchildren.(See"Acuteliver
failureinadults:Managementandprognosis",sectionon'Treatmentofintracranialpressureelevation'.)
HEMATOLOGIC
CoagulopathyTheprothrombintime(PT)andinternationalnormalizationratio(INR)areusedtoassessthe
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severityofliverinjuryinthesettingofacuteliverfailure(ALF),becausethesetestsreflecthepaticproductionof
clottingfactors,particularlyfactorsVandVII,whichhavetheshortesthalflives.However,thePTandINRarenot
goodmarkersfortheriskofbleedinginpatientswithALF.ThisisbecauseALFreducesbothprocoagulantproteins
(eg,factorV,VII,X,andfibrinogen)andanticoagulantproteins(eg,antithrombin,proteinC,andproteinS)[2,3].
(See"Coagulationabnormalitiesinpatientswithliverdisease".)
Thisbalancedreductionintheprocoagulantandanticoagulantproteinsmayaccountfortherelativeinfrequencyof
clinicallyimportantbleedinginthepediatricacuteliverfailure(PALF)patientintheabsenceofaprovocativeevent
suchasinfectionorincreasedportalhypertension.AsingledoseofvitaminKshouldbeadministeredonceto
initiallyassessresponseofthecoagulationprofile.However,dailyadministrationofvitaminKisunnecessary.
EffortstocorrectthePT/INRwithplasmaorotherprocoagulationproductssuchasrecombinantFactorVIIshould
beavoided.CorrectionofthePT/INRshouldbelimitedtopatientswithactivebleedingorinanticipationofan
invasivesurgicalprocedure.
AplasticanemiaBonemarrowfailure,characterizedbyaspectrumoffeaturesrangingfrommildpancytopenia
toaplasticanemia,occursinasignificantminorityofchildrenwithALF[10].Itisidentifiedmostcommonlyinthe
settingofindeterminatePALFandmaynotbeclinicallyevidentuntilafteremergentlivertransplantationorrecovery
withouttransplantation.Apossibleassociationwithhumanherpesvirus6(HHV6)hasbeensuggested,butnot
established.(See"Acuteliverfailureinchildren:Etiologyandevaluation",sectionon'Infectionwithvirusesother
thanhepatitisviruses'.)
Treatmentincludesimmunomodulatorymedicationsthatincludesteroids,cyclosporineA,andantilymphocyteor
antithymocyteglobulin,aswellashematopoieticstemcelltransplant.
GASTROINTESTINAL
AscitesAscitesdevelopsinsomebutnotallpatientswithacuteliverfailure(ALF).Precipitatingfactorsinclude
hypoalbuminemia,excessivefluidadministration,andinfection.Theprimarytreatmentismoderatefluidrestriction.
Diureticsshouldbereservedforpatientswithrespiratorycompromiseorgeneralizedfluidoverload.Overly
aggressivediuresismayprecipitatehepatorenalsyndrome.(See'Renal'below.)
BleedingGastrointestinalbleedingissurprisinglyinfrequent,giventhedegreeofcoagulopathy.Thisisprobably
becauseofabalancedreductionintheprocoagulantandanticoagulantproteins,describedabove.(See
'Coagulopathy'above.)
Prophylacticuseofacidreducingagentsisofteninitiatedwhenthepatientisadmitted,buttheirusefulnessis
difficulttoassess.Causesforbleedingincludegastricerosionsorulcersduetononsteroidalantiinflammatory
drugs(NSAIDs),oridiopathicgastroduodenalulceration.Infectioncanprecipitatebleedinginthisvulnerable
population,sobloodculturesandinitiationofantibioticsshouldalsobeconsideredwhenbleedingdevelops.
Administrationofplatelets,blood,andplasmaisnecessaryifbleedingishemodynamicallysignificant.
PancreatitisBiochemicalandclinicalpancreatitisisincreasinglyrecognizedasaconditionassociatedwith
multisystemfailureincriticallyillchildren.Inpatientswhodeveloppancreatitisinthesettingofacuteliverfailure,
glucoseandfluidmanagementmaybecomeevenmorechallenging.
RENALPatientswithevidenceofrenalinsufficiencyandacuteliverfailure(ALF)onadmissionshouldbe
assessedforevidenceofamedicationortoxinastheprecipitatingcause(includingacetaminophen,inhaled
solvents,mushrooms,recreationaldrugs,ormedicationinducedpediatricacuteliverfailure[PALF]).Duringthe
hospitalcourse,prerenalazotemiacandevelopiffluidrestrictionistooexcessiveforthepatientsneeds.Acute
deteriorationofrenalfunctionafterpresentationwithALFmayresultfromsystemichypotensionduetosepsisor
hemorrhage.
Hepatorenalsyndrome(HRS)isafearedrenalcomplicationassociatedwithALF,althoughitoccursmore
commonlyinthesettingofchronicliverdiseasewithestablishedcirrhosis.Thediagnosisissuspectedwhenthere
isevidenceofdeterioratingrenalfunctionintheabsenceofbleeding,hypotension,sepsis,ornephrotoxic
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medications.Unlikeprerenalazotemia,theurinesodiumtypicallyislow,andthereisnoimprovementwithvolume
expansion.Itcanprogressrapidlyoverthecourseoftwoweeks(type1HRS)ormoreslowly(typeIIHRS)[2].
Renalreplacementtherapywithcontinuousvenovenoushemofiltrationordialysismaybenecessaryinsome
cases,butonlylivertransplantationcanreverseHRS.
METABOLICMetabolicabnormalitiesoftenseeninpatientswithacuteliverfailure(ALF)include[3]:
HypoglycemiaHypoglycemiaiscausedbyimpairedhepaticgluconeogenesisanddepletedglycogen
stores.Hypoglycemiaistreatedwithcontinuousinfusionofglucose,whichisinfusedviaacentralvenous
cathetertoaccommodatethehypertonicsolution.Glucoseinfusionratesof10to15mg/kg/minutemaybe
requiredtoachievestableserumglucoselevels.
HypokalemiaHypokalemiamaybecausedbydilutionfromvolumeoverload,ascites,orrenalwasting.
HypophosphatemiaSerumphosphorusshouldbemonitoredfrequently,ashypophosphatemiacanbe
profound.Whilethemechanismisunknown,hypophosphatemiaispresumedtoresultfromincreasedneeds
duetoactivelivercellregeneration.Hyperphosphatemia,oftenassociatedwithrenalinsufficiency,is
consideredapoorprognosticsign[11].
AcidbasedisturbancesAcidbasedisturbancesarecausedbyavarietyofmechanisms,including
respiratoryalkalosisfromhyperventilation,respiratoryacidosisfromrespiratoryfailure,metabolicalkalosis
fromhypokalemia,andmetabolicacidosisfromhepaticnecrosis,shock,andincreasedanaerobicmetabolism
orastheresultofinbornerrorsofmetabolism.
INFECTIOUSPatientswithacuteliverfailure(ALF)aresusceptibletobacterialinfectionandsepsisbecauseof
immunesystemdysfunction[2].Evidenceofinfectionmaybesubtle,suchastachycardia,gastrointestinal
bleeding,reducedrenaloutput,orchangesinmentalstatus.Fevermayormaynotbepresent.
Thus,bloodculturesshouldbeobtainedwithanyevidenceofclinicaldeterioration,andantibioticsshouldbe
initiatedtocoverbothgrampositiveandgramnegativeorganisms[12].
CARDIOPULMONARYExcessivefluidadministrationcontributestopulmonaryedemaandshouldbeavoided.
Forpatientswhodeveloppulmonaryedema,carefulfluidrestrictionanddiscreteuseofdiureticsmaybeneededin
someinstances,butshouldbeusedwithcautionbecausetheseinterventionscanreduceorganperfusionand
precipitaterenalfailure.Centralvenouspressuremonitoringmayassistinassessingvolumeneedsforthechild.
Ionotropicsupportmaybeneededtomaintainperfusionofvitalorgans.
NUTRITIONNutritionsupportshouldbemaintainedtoavoidacatabolicstate.Ifitisnotsafeforthechildto
receiveoralorenteralfeeding,intravenousalimentation(parenteralnutrition[PN])shouldbeinitiated.(See
"Parenteralnutritionininfantsandchildren".)
WesuggestthefollowingparametersforPNinpatientswithpediatricacuteliverfailure(PALF):
TotalfluidinputincludingPN,bloodproducts,andmedicationsshouldgenerallybelimitedtobetween85to
95percentofthemaintenancefluidrequirementtoavoidexcessivehydration.
Proteininputshouldgenerallybenomorethan1g/kg/day,butthismayneedtobereducedto0.5mg/kg/day
forpatientswithelevatedserumammonialevels.
Tracemetals(traceelements)shouldgenerallybeeliminatedorreduced.Thisisbecausecopperand
manganesearemetabolizedintheliver.Moreover,chromium,molybdenum,andseleniumshouldbe
eliminatedorreducedifrenaldiseaseisalsopresent.
LIVERSUPPORTAnumberofapproachesarebeingdevelopedtoperformsomefunctionsoftheliverinan
attempttodelayoravoidtheneedforlivertransplantation.Theseincludeartificialhepaticassistdevices(eg,the
membraneadsorbentrecirculatingsystem[MARS]).Todate,nonehavebeenestablishedasavaluabletreatment
foracutehepaticfailure.(See"Acuteliverfailureinadults:Managementandprognosis",sectionon'Artificial
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hepaticassistdevicesandhepatocytetransplantation'.)
Plasmapheresisorplasmaexchangefacilitatestheremovalofsuspectedtoxinsinthebloodtofacilitateamilieuin
whichthelivermightrecoverorregenerate,buthasnotbeenhelpfulinthemanagementofchildrenoradultswith
acuteliverfailure(ALF).Whilecoagulationprofilesmayimprove,theprocedurehasnotbeenshowntoimprove
neurologicaloutcomeorabilityofthelivertorecoverspontaneously.AnexceptionisthatforpatientswithALFdue
toWilsondisease,plasmaexchangecanbevaluablebecauseitrapidlyremoveslargeamountsofcopper.(See
"Wilsondisease:Treatmentandprognosis",sectionon'Acuteliverfailure'.)
Anumberofspecificinterventionshavebeenstudied,butareunhelpfulforALFandshouldgenerallynotbeused.
Theseincludeglucocorticoids(exceptinthesettingofautoimmunehepatitis),hepaticregenerationtherapyusing
insulinandglucagon,charcoalhemoperfusion,andprostaglandinE.Furthermore,arandomized,doublymasked,
controlledtrialinpediatricacuteliverfailure(PALF)demonstratedthatintravenousNacetylcysteine(NAC)wasnot
beneficialinchildrenwithnonacetaminopheninducedALF[13].Oneyearsurvivalwithnativeliverwassignificantly
worseforthosereceivingNACthanplacebo,particularlyforthosechildrenyoungerthantwoyearsofage.(See
"Acuteliverfailureinadults:Managementandprognosis",sectionon'Unhelpfultreatments'.)
DISEASESEVERITYASSESSMENTTherearecurrentlynoreliabletoolstopredictsurvivalordeathinpatients
withpediatricacuteliverfailure(PALF).Biochemicaltests(lactate,totalbilirubin,phosphorous,international
normalizationratio[INR],prothrombintime,ammonia,Gcglobulin),clinicalfeatures(encephalopathy,cerebral
edema),diagnosis(eg,acetaminophen),orcombinationsofthethreehavebeentriedwithoutreliablesuccess.
Existingliverfailurescoringsystems,includingtheKingsCollegeHospitalCriteria(KCHC),theClichyscore,Model
forEndStageLiverDisease(MELD)score,andPediatricEndStageLiverDisease(PELD)score,arenotadequate
prognostictoolsbecausetheyareonlyweaklyassociatedwithoutcome[2].Amongthese,onlyPELDisspecific
tothepediatricagegroup,butitwasdevelopedforchronicratherthanacuteliverdisease,andincludesfactors
suchasgrowthfailurethatarelessrelevanttoprognosisinacuteliverfailure(ALF).KCHCiscommonlyusedto
predictprognosisandneedforlivertransplantationinadultswithALF,andisstratifiedbywhethertheALFis
causedbyacetaminophentoxicity.However,KCHCarenotusefulinPALF[14].(See"Acuteliverfailureinadults:
Managementandprognosis",sectionon'King'sCollegeCriteria'.)
TheLiverInjuryUnit(LIU)scorehasbeendevelopedspecificallyforPALFandissomewhatmoreuseful[15].It
includesfactorsforpeaktotalbilirubin,prothrombintime(PT)orinternationalnormalizationratio(INR),and
ammonia.AstudytestedthevalidityoftheLIUscoreusingdatafromthePediatricAcuteLiverFailureStudyGroup
(PALFSG),andafteroptimizationsensitivityandspecificitywere74and80percent,respectively[16].Whilethis
representsanimprovementcomparedwiththeotherscoringsystemsmentionedabove,LIUisnotsufficientto
makecriticaldecisionsaboutlivertransplantation.Webelievetheidealscoringsystemshouldreflectthedynamic
natureofPALFandincorporateperiodicclinicalchangesintoderivingthelikelihoodofdeathorsurvival[3].
LIVERTRANSPLANT
LivertransplantdecisionsIntheerabeforelivertransplantation(LT)wasavailable,thenaturalhistoryof
pediatricacuteliverfailure(PALF)wasforchildrentoeithersurviveordie.LTinterruptsthenaturalcourseofPALF,
andcansavethelifeofapatientwithacuteliverfailure(ALF)ifheorshehasaconditionthatisnotamenableto
treatmentorfailstorespondtotreatment(figure2).However,becausethecauseofPALFoftenisnotknown,and
thecourseofPALFisdifficulttopredict,itislikelythatsomepatientsmayreceiveLTinsituationsinwhich
spontaneousrecoverymayhaveoccurred.
LTdecisionsaredifficultbecauseofuncertaintyregardingthepatientsoutcomewithouttransplant,thepotential
morbidityandmortalityofthetransplantprocedure,andthelimitednumberoforgansavailable.Moreover,longterm
outcomesfollowingLTforPALFarelessfavorableascomparedwithLTforchronicliverdiseasessuchasbiliary
atresia.Thisislikelyduetomultiplefactors,includingtheseverityofillnessatthetimeofLT,andthepossibility
thatLTwasperformedincircumstancesinwhichdeathwasinevitableregardlessofLT.WhenlivingdonorLTis
considered,thedecisionalsoincludesconsiderationofpotentialriskstothedonor.
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Asdiscussedabove,noneofthecurrentscoringsystemsareadequatetodirectdecisionsaboutLTforpatients
withPALF.Amorereliablemodelingschemeisneededtoreadilyandeffectivelydistinguishthepatientwhowould
diefromtheonewhowouldsurvivewithoutLTandrecognizewhenitwouldbefutiletoproceedwithLT.Untilthen,
thebestsolutionisaglobalclinicalassessmentbyateamofclinicianswithexperienceinPALFandLT,
incorporatingtheprognosisassociatedwiththecauseoftheALF,andthepatientsdynamiccourse,basedon
repeatedassessmentsoftheprobabilityofsurvivalwithnativeliverfromonetimeintervaltothenext.
LTdecisionsareparticularlychallengingforpatientswithPALFcausedbyamitochondrialdisease.Multisystem
mitochondrialdysfunctionisacontraindicationtolivertransplantation[17].However,patientswhodonothave
extrahepaticmanifestationsofdiseasemayhaveisolatedhepaticmitochondrialdysfunctionandcouldbe
candidatesforlivertransplantation[18].Unfortunately,multisysteminvolvementmaynotbeapparentatthetimeof
LT,placingthechildatriskfordevelopingsymptomsinthefuture.Moreover,patientswhoseALFwastriggeredby
valproatehaveaverypoorprognosisafterLT,duetoahighlikelihoodofmitochondrialdisease(especiallyPOLG
mutations),andextrahepaticdiseaseprogression[17,19,20].(See"Acuteliverfailureinchildren:Etiologyand
evaluation",sectionon'Olderinfantsandyoungchildren'.)
OrganallocationinacuteliverfailureOrganallocationforchildrenwithALFremainsanevolvingprocess.
OrganallocationintheUnitedStatesismanagedbyUnitedNetworkforOrganSharing(UNOS),andisbased
largelyondiseaseseverityscoresforadults(ModelforEndStageLiverDisease[MELD])andchildren(Pediatric
EndStageLiverDisease[PELD])tosupportorganallocationforpatientswithchronicliverdisease.PELDis
calculatedbyUNOSorbyusingacalculator(calculator1).MELDisusedforpatients12yearsandolderandis
discussedindetailseparately.(See"ModelforEndstageLiverDisease(MELD)".)
PELDandMELDareusedtoallocateorgansforpatientswithchronicliverdiseasetheywerenotdesignedforuse
inALF.TheurgencyoflivertransplantationforPALFistypicallynotreflectedbytheirPELD/MELDscore.Patients
withALFandinneedoflivertransplantationaregivenpriorityoverthoselistedwithaPELD/MELDscoreandare
listedasStatus1A,thecategorywiththehighestprioritystatus.Status1Aisreservedforchildreninanintensive
careunit(ICU)inoneoffourdiagnosticcategories,includingfulminantliverfailure.Thethreeotherdiagnostic
categoriesqualifyingforStatus1Aareprimarygraftnonfunctionfollowinglivertransplantation,hepaticartery
thrombosis,andacutedecompensatedWilsondisease.
ToqualifyforStatus1Aforfulminantliverfailure,UNOSusesthefollowingcriteria:
Onsetofhepaticencephalopathywithineightweeksofthefirstsymptomsofliverdiseaseintheabsenceof
preexistingliverdisease,ANDoneofthefollowing:
Ventilatordependence
Needfordialysis,continuousvenovenoushemofiltration,orcontinuousvenovenoushemodialysis
INR>2.0
ChildrenwhoareclassifiedasStatus1Arequirereassessmentoftheirlistingstatusaftersevendays.Atanytime,
thechildcanberemovedfromthetransplantationlistifhe/shebecomestooilltoundergotransplantationor
recoverstoapointthattransplantationisnotnecessary.Ifthechildisstillonthelistaftersevendays,options
wouldbetocontinuetolistthepatientasStatus1Abyprovidingsupportiveclinicalinformation,removethechild
fromthelist,ordemotetheurgencybychangingthelistingstatusfromStatus1AtothecalculatedPELDscore.

TypesofgraftsLThasimprovedoverallsurvivalforchildrenwithALF.Becausethesupplyofappropriatelysized
organsfromdeceaseddonorsisinadequate,somechildrenwithPALFdiewhilewaitingforLT,andpretransplant
mortalityisworsethanforpatientswithchronicliverfailure.Asaresult,technicalvariantstowholegraftssuchas
splitandlivingdonorshavebeenintroduced.
InareportofLTforPALFfromcentersintheUnitedStatesandCanada,deceaseddonorwholeliverswereusedin
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46percentoftransplants,splitorcutdowngraftswereusedin38percent,andgraftsfromlivingdonorswereused
in14percent[21].Outcomesforpatientsreceivingdonororsplitlivergraftswerenotdifferentfromthosereceiving
wholelivergrafts.However,inaseparatestudythatfocusedonpatientswithALFandconcurrentmultiorganfailure,
livingdonortransplantwasassociatedwithimproved30dayand6monthsurvivalcomparedwithrecipientsofa
deceaseddonorliverallograft[22].ImprovedoutcomeforpatientsreceivingalivingdonorLTislikelyrelatedtoa
reducedcoldischemiatimeandwaittime,resultinginamoreexpeditioustimetotransplantfortheseseriouslyill
children.
Auxiliarylivertransplantationisanalternativeapproachthatconsistsofplacementofagraftadjacenttothe
patient'snativeliver(auxiliaryheterotopiclivertransplantation)orinthehepaticbedafteraportionofthenativeliver
(auxiliaryorthotopiclivertransplantation)hasbeenremoved.Thistechniquehasbeenusedasabridgetoprovide
needtimeforthenativelivertoregenerate,butchallengesremainastothetimingforwithdrawalof
immunosuppressionandinvolutionofthetransplantedgraft[23].(See"Acuteliverfailureinadults:Management
andprognosis",sectionon'Auxiliarylivertransplantation'.)
HepatocytetransplantTheroleofhepatocytetransplantationinPALFisyettobedeterminedandmaybean
opportunityforinvestigationinthefuture[17,24].Hepatocytetransplantationmayserveasabridgetotransplantor,
perhaps,acureforsomechildrenwithmetabolicdiseases.Ithasbeenusedinasmallnumberofchildrenwith
ALF.However,technicalchallengesaswellaslackofareadilyavailablesourceforhepatocyteshavelimitedthe
opportunityforthisprocedureatmostcenters.(See"Hepatocytetransplantation".)
OUTCOMESInthepretransplanteraandusinganadultdefinitionofacuteliverfailure(ALF),spontaneous
survivaloccurredin28percentofpatientsoverall,andonly4percentofthosewithstageIVcoma[25].More
recently,withimprovementsinmanagementofcriticallyillchildren,coupledwithamorelenientdefinitionof
pediatricacuteliverfailure(PALF),outcomeshaveimproved[13,26].However,itshouldbenotedthatallcurrent
studiesofoutcomesareaffectedbydecisionsaboutlivertransplantation(LT),becauseLTinterruptsthenatural
courseofPALF.SomechildrenwhoreceiveLTmayhaverecoveredspontaneously,andsomedieasa
consequenceofLTratherthanoftheunderlyingPALF.Patientoutcomedependsonanumberoffactorsincluding
theetiology,diseaseseverity,supportivemanagement,andtreatment.However,outcomesvaryamongchildren
withseeminglysimilaretiology,diseaseseverity,andtreatment.Additionalfactorsarelikelyinvolvedtoexplain
thesevariationsperhapsincludingtheinflammatorymilieu,endorgandamage,immuneactivation,andpotentialfor
liverregeneration.
DatafromthePediatricAcuteLiverFailureStudyGroup(PALFSG)inNorthAmericaandEuroperevealedthat21
dayoutcomevariedbydiagnosis,age,anddegreeofencephalopathy[1,26].Spontaneoussurvival(survivalwiththe
nativeliver)washighestamongstthosewithliverfailureduetoacetaminophen(94percent).Spontaneoussurvival
occurredlessfrequentlyforthosewithliverfailureduetometabolicdisease(44percent),forthosewithnon
acetaminophendruginduceddisease(41percent),andforthosewithanindeterminatediagnosis(45percent).As
mightbeexpected,thosewithhigherstagesofencephalopathyhadlowerspontaneoussurvival.
Unexpectedly,inthesamestudy,21percentofpatientswithminimalornoclinicalevidenceofencephalopathy(ie,
thosewithpeakhepaticencephalopathystage0)eitherdiedorreceivedaLT[1].Forchildrenwithanestablished
diagnosis,between20to33percentreceivedaLTandofthosewithacetaminopheninducedPALF,only2percent
receivedaLT.Incomparison,amongpatientswithadiagnosisofindeterminantPALF,46percentunderwentLT.
Therefore,childrenwhodonothaveaspecificdiagnosisaremorelikelytoreceiveaLT.Themajorcausesofdeath
forchildrenwithPALFwhodonotreceivealivertransplantaremultiorgansystemfailure,cerebraledemaand
herniation,andsepsis.
BothearlyandlategraftlossanddeathishigheramongchildrenwhoundergoLTforALFthanforthosewith
chronicliverdisease[27].Reasonsforthesefindingsareuncertain,butonepossibilityincludesimmune
dysregulationthatmaybeassociatedwithPALF,whichcouldleadtoincreasedsusceptibilitytoinfectionorgraft
rejection.AmongpatientsundergoingLTforPALF,overallsurvivalratesare74percentatoneyear,and69percent
atfouryears[21].
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SUMMARYANDRECOMMENDATIONSPediatricacuteliverfailure(PALF)isacomplex,rapidlyprogressive
clinicalsyndromethatprecipitatescomplicationsandfailureinmostotherorgansystems.TreatmentofPALF
requiresmanagementofeachofthesecomplications,supportivecare,andinformeddecisionsaboutliver
transplantation.
PatientswithPALFtypicallyshouldinitiallybemanagedinapediatricintensivecareunit,whichallowsclose
monitoring,particularlyfluidstatusandchangesinmentalstatus.(See'Clinicalsetting'above.)
Laboratorymonitoringshouldincludeacompletebloodcount,electrolytes,renalfunctiontests,glucose,
calcium,phosphorous,ammonia,coagulationprofile,totalanddirectbilirubin,andbloodcultures.(See
'Laboratorymonitoring'above.)
FluidintakeshouldbemodestlyrestrictedformostpatientswithPALF.Intheabsenceoftheneedforvolume
resuscitation,totalintravenousfluidsshouldinitiallyberestrictedtobetween85to95percentofthe
maintenancefluidrequirement.(See'Fluids'above.)
Hepaticencephalopathy(HE)developsinthemajorityofpatientswithPALFandisarelevantbutinconsistent
indicatorofprognosis.Serialclinicalevaluationsofbehavior,cognition,neurologicalexamination,and
electroencephalogram(EEG)areimportanttoassessthepresenceandprogressofHEandpossibleonsetof
cerebraledema.WesuggestthatpatientswithHEbetreatedinitiallywithlactulose,althoughtheevidenceto
supportthisapproachisweak(Grade2C).(See'Encephalopathy'above.)
Managementofcerebraledemarequiresmeticuloussupportivecare,sometimesguidedbysurgical
placementofanintracranialpressuremonitor.(See'Cerebraledema'above.)
Theprothrombintime(PT)andinternationalnormalizationratio(INR)areusedtoassesstheseverityofliver
injuryinthesettingofPALFbecausethesetestsreflecthepaticproductionofclottingfactors.However,the
PT/INRisnotagoodmarkerfortheriskofbleedinginpatientswithPALF,becausePALFreducesboth
procoagulantproteinsandanticoagulantproteins.Therefore,wesuggestNOTadministeringwithplasmaor
otherprocoagulationproductsexceptinpatientswithactivebleedingorinanticipationofaninvasivesurgical
procedure(Grade2C).(See'Coagulopathy'above.)
Hepatorenalsyndrome(HRS)isafearedrenalcomplicationassociatedwithPALF.Unlikeprerenalazotemia,
theurinesodiumtypicallyislow,andthereisnoimprovementwithvolumeexpansion.Renalreplacement
therapywithhemofiltrationordialysismaybenecessaryinsomecases,butonlylivertransplantation(LT)can
reverseHRS.(See'Renal'above.)
MetabolicdisturbancesoftenseeninpatientswithPALFincludehypoglycemia,hypokalemia
hypophosphatemia,andacidbasedisturbances.Managementrequiresclosemonitoringandreplacement.
Hypoglycemiamayrequireacontinuousinfusionofhypertonicglucosesolutionviaacentralvenouscatheter.
(See'Metabolic'above.)
PatientswithPALFaresusceptibletobacterialinfectionandsepsisbecauseofimmunesystemdysfunction.
Evidenceofinfectionmaybesubtle,andfevermaynotbepresent.Thus,bloodculturesshouldbeobtained
withanyevidenceofclinicaldeterioration,andantibioticsshouldbeinitiatedifthereisaclinicalconcernfor
sepsis.(See'Infectious'above.)
DecisionsaboutwhetherandwhentoperformaLTforapatientwithPALFaredifficultbecauseofuncertainty
regardingthepatientsoutcomewithoutLTandthepotentialmorbidityandmortalityoftheLTprocedure.None
ofthecurrentscoringsystemsareadequatetodirectdecisionsaboutLT.(See'Diseaseseverityassessment'
aboveand'Livertransplantdecisions'above.)
OutcomesforpatientswithPALFvarysubstantiallybydiagnosisacetaminophenrelatedPALFtypicallyhas
thehighestlikelihoodofsurvivalwithoutLT(94percent)ascomparedwithnonacetaminophendruginduced
PALF(41percent)orindeterminantPALF(45percent).Otherimportantprognosticfactorsincludeage,timing
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ofdiagnosisfortreatabledisorders,anddegreeofencephalopathy(althoughasignificantminorityofpatients
withoutencephalopathydieorrequireLT).
UseofUpToDateissubjecttotheSubscriptionandLicenseAgreement.
REFERENCES
1. SquiresRHJr,ShneiderBL,BucuvalasJ,etal.Acuteliverfailureinchildren:thefirst348patientsinthe
pediatricacuteliverfailurestudygroup.JPediatr2006148:652.
2. SquiresRHJr.Acuteliverfailureinchildren.SeminLiverDis200828:153.
3. SquiresRH,AlonsoEM.Acuteliverfailureinchildren.In:LiverDiseaseinChildren,4thed,SuchyFJ,Sokol
RJ,BalistreriWF(Eds),CambridgeUniversityPress,NewYork2012.
4. WhittingtonPF,AlonsoAE.Fulminanthepatitisandacuteliverfailure.In:Diseasesoftheliverandbiliary
systeminchildren,2nded,KellyDA(Ed),Blackwell,Oxford2003.p.107.
5. DebrayD,YousefN,DurandP.Newmanagementoptionsforendstagechronicliverdiseaseandacuteliver
failure:potentialforpediatricpatients.PaediatrDrugs20068:1.
6. WendonJ,LeeW.Encephalopathyandcerebraledemainthesettingofacuteliverfailure:pathogenesisand
management.NeurocritCare20089:97.
7. StravitzRT,KramerAH,DavernT,etal.Intensivecareofpatientswithacuteliverfailure:recommendationsof
theU.S.AcuteLiverFailureStudyGroup.CritCareMed200735:2498.
8. KamatP,KundeS,VosM,etal.Invasiveintracranialpressuremonitoringisausefuladjunctinthe
managementofseverehepaticencephalopathyassociatedwithpediatricacuteliverfailure.PediatrCritCare
Med201213:e33.
9. ShawcrossDL,WendonJA.Theneurologicalmanifestationsofacuteliverfailure.NeurochemInt2012
60:662.
10. HadziN,HeightS,BallS,etal.Evolutioninthemanagementofacuteliverfailureassociatedaplastic
anaemiainchildren:asinglecentreexperience.JHepatol200848:68.
11. SchmidtLE,DalhoffK.Serumphosphateisanearlypredictorofoutcomeinsevereacetaminopheninduced
hepatotoxicity.Hepatology200236:659.
12. RolandoN,HarveyF,BrahmJ,etal.Prospectivestudyofbacterialinfectioninacuteliverfailure:ananalysis
offiftypatients.Hepatology199011:49.
13. SquiresRH,DhawanA,AlonsoE,etal.IntravenousNacetylcysteineinpediatricpatientswith
nonacetaminophenacuteliverfailure:aplacebocontrolledclinicaltrial.Hepatology201357:1542.
14. SundaramV,ShneiderBL,DhawanA,etal.King'sCollegeHospitalCriteriafornonacetaminopheninduced
acuteliverfailureinaninternationalcohortofchildren.JPediatr2013162:319.
15. LiuE,MacKenzieT,DobynsEL,etal.Characterizationofacuteliverfailureanddevelopmentofacontinuous
riskofdeathstagingsysteminchildren.JHepatol200644:134.
16. LuB,ZhangS,NarkewiczM,etal.Validationofascoringsystemtopredictsurvivalin455patientswith
pediatricacuteliverfailure.Hepatology200950(4Suppl):424A.
17. SquiresRH,NgV,RomeroR,etal.Evaluationofthepediatricpatientforlivertransplantation:2014practice
guidelinebytheAmericanAssociationfortheStudyofLiverDiseases,AmericanSocietyofTransplantation
andtheNorthAmericanSocietyforPediatricGastroenterology,HepatologyandNutrition.Hepatology2014
60:362.
18. SokalEM,SokolR,CormierV,etal.Livertransplantationinmitochondrialrespiratorychaindisorders.EurJ
Pediatr1999158Suppl2:S81.
19. StewartJD,HorvathR,BaruffiniE,etal.PolymerasegenePOLGdeterminestheriskofsodiumvalproate
inducedlivertoxicity.Hepatology201052:1791.
20. LeeWS,SokolRJ.Mitochondrialhepatopathies:advancesingenetics,therapeuticapproaches,and
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outcomes.JPediatr2013163:942.
21. BaligaP,AlvarezS,LindbladA,etal.Posttransplantsurvivalinpediatricfulminanthepaticfailure:theSPLIT
experience.LiverTranspl200410:1364.
22. MackCL,FerrarioM,AbecassisM,etal.Livingdonorlivertransplantationforchildrenwithliverfailureand
concurrentmultipleorgansystemfailure.LiverTranspl20017:890.
23. GirlandaR,VilcaMelendezH,SrinivasanP,etal.Immunosuppressionwithdrawalafterauxiliaryliver
transplantationforacuteliverfailure.TransplantProc200537:1720.
24. SoltysKA,SotoGutirrezA,NagayaM,etal.Barrierstothesuccessfultreatmentofliverdiseaseby
hepatocytetransplantation.JHepatol201053:769.
25. PsacharopoulosHT,MowatAP,DaviesM,etal.Fulminanthepaticfailureinchildhood:ananalysisof31
cases.ArchDisChild198055:252.
26. SundaramSS,AlonsoEM,NarkewiczMR,etal.Characterizationandoutcomesofyounginfantswithacute
liverfailure.JPediatr2011159:813.
27. SoltysKA,MazariegosGV,SquiresRH,etal.Lategraftlossordeathinpediatriclivertransplantation:an
analysisoftheSPLITdatabase.AmJTransplant20077:2165.
Topic83172Version6.0

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GRAPHICS
Stagesofhepaticencephalopathyininfantsandchildrenfrombirthto
48monthsofage
Stage

Clinical

Reflexes

Neurological
signs

No
encephalopathy
(stage0)

Normal

Normal

None

Early
(stageIandII)

Inconsolablecrying,sleepreversal,
inattentiontotask,childisnotacting
likeselftoparents

Unreliable/
normalor
hyperreflexic

Untestable

Mid
(stageIII)

Somnolence,stupor,combativeness

Unreliable/
hyperreflexic

Likely
untestable

Late

Comatose,arouseswithpainfulstimuli

Absent

Decerebrateor

(stageIV)

(stageIVa)ornoresponse(stageIVb)

decorticate

Modifiedwithpermissionfrom:SquiresRH,AlonsoEM.Acuteliverfailureinchildren.In:LiverDiseasein
Children,4thed,SuchyFJ,SokolRJ,BalistreriWF(Eds),CambridgeUniversityPress,NewYork2012.
Copyright2012CambridgeUniversityPress.
Graphic83748Version2.0

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Gradingsystemforhepaticencephalopathy
Grade
I

Mentalstatus
Euphoria/depression

Asterixis

EEG

Yes/no

Usuallynormal

Yes

Abnormal

Yes

Abnormal

No

Abnormal

Mildconfusion
Slurredspeech
Disorderedsleep
II

Lethargy
Moderateconfusion

III

Markedconfusion
Incoherent
Sleepingbutarousable

IV

Coma

Graphic62922Version1.0

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Clinicalfeaturesofhepaticencephalopathy

Diagramdepic tingthegradeofhepatic enc ephalopathyandthec linic alfeatures

assoc iatedwithadvanc ingstages.
Datafrom:ConnHO,LieberthalMM.Thehepaticcomasyndromesandlactulose.Lippincott
Williams&Wilkins,Baltimore1979.
Graphic70740Version3.0

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Schematicmodelofthenaturalcourseandoutcomeofacute
liverfailureinchildren

SIRS:systemicinflammatoryresponsesyndrome.
Reproducedwithpermissionfrom:SquiresRH,AlonsoEM.Acuteliverfailureinchildren.In:
LiverDiseaseinChildren,4thed,SuchyFJ,SokolRJ,BalistreriWF(Eds),CambridgeUniversity
Press,NewYork2012.Copyright2012CambridgeUniversityPress.
Graphic83763Version1.0

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Disclosures

Disclosures:RobertHSquires,Jr,MD,FAAPNothingtodisclose.ElizabethBRand,MDNothingtodisclose.AlisonGHoppin,MD
Nothingtodisclose.
Contributordisclosuresarereview edforconflictsofinterestbytheeditorialgroup.Whenfound,theseareaddressedbyvettingthroughamultileve
contentisrequiredofallauthorsandmustconformtoUpToDatestandardsofevidence.
Conflictofinterestpolicy

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