Fever in Infants and Children - Pathophysiology and Management2

10/2/2016
Feverininfantsandchildren:Pathophysiologyandmanagement
OfficialreprintfromUpToDate
www.uptodate.com2016UpToDate
Author
MarkAWard,MD
SectionEditor
MorvenSEdwards,MD
DeputyEditor
MaryMTorchia,MD
Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.
Literaturereviewcurrentthrough:Jan2016.|Thistopiclastupdated:Nov18,2015.
INTRODUCTIONFeverisanabnormalelevationofbodytemperaturethatoccursaspartofaspecific
biologicresponsethatismediatedandcontrolledbythecentralnervoussystem.
Thepathophysiologyandtreatmentoffeverininfantsandchildrenwillbereviewedhere.Othercausesof
elevatedbodytemperatureinchildrenandtheevaluationandmanagementoffeverinspecificpopulationsof
infantsandchildrenarediscussedseparately:
(See"Heatstrokeinchildren"and"Heatillness(otherthanheatstroke)inchildren".)
(See"Evaluationandmanagementofthefebrileyounginfant(7to90daysofage)"and"Feverwithouta
sourceinchildren3to36monthsofage".)
(See"Managementoffeverinchildrenwithsicklecelldisease".)
(See"Feverofunknownorigininchildren:Etiology"and"Feverofunknownorigininchildren:
Evaluation".)
(See"Riskofinfectioninchildrenwithfeverandnonchemotherapyinducedneutropenia"and"Evaluation
andmanagementoffeverinchildrenwithnonchemotherapyinducedneutropenia".)
(See"Feverinchildrenwithchemotherapyinducedneutropenia".)
(See"Feverinhumanimmunodeficiencyvirusinfectedchildren".)
TEMPERATUREMEASUREMENT
SiteandmethodofmeasurementThemostcommonsitesoftemperaturemeasurementinclinical
practicearetherectum,mouth,andaxillainaddition,parentsandcaregiversmaymeasuretemperatureatthe
tympanicmembraneorforehead(temporalartery).Eachofthesesiteshasitsownrangeofnormalvalues[1].
Opinionsdifferaboutthebestsiteoftemperaturemeasurementforyoungchildrenwhocannotcooperatewith
oralthermometry.TheBrightFuturesGuidelinesforHealthSupervisionsuggestrectalthermometryforchildren
youngerthanfouryearsofage[2].Incontrast,theNationalInstituteforHealthandCareExcellence
recommendselectronicaxillarythermometryforchildrenyoungerthanfourweeks,andaxillary(electronicor
chemicaldot)orinfraredtympanicmembranethermometryforchildrenfourweekstofiveyearsofage
becausethesemethodsarequicker,easiertouse,andbetteracceptedbychildrenandtheircaregivers[3].
Rectalthermometryisgenerallyconsideredthereferencestandardformeasurementofcorebodytemperature
[4],butthereisalagbetweenchangesincorebodytemperatureandtemperatureintherectalvault[5].Rectal
thermometryisusuallyperformedininfantsandyoungchildreniftheresulthasclinicalimplications.The
majorityofstudiesestablishingtheriskofseriousinfectionsinfebrileinfantsandyoungchildrenhavereliedon
rectaltemperatures.Rectalthermometryiscontraindicatedinpatientswithneutropenia.
Oralthermometrygenerallyispreferredinchildrenwhoareoldenoughtocooperate.Oraltemperatureis
typically0.6C(1.0F)lowerthanrectaltemperaturebecauseofmouthbreathing,whichisparticularly
importantinpatientswithtachypnea.Oraltemperaturesalsomaybeaffectedbyrecentingestionofhotorcold
liquids[1,6].
Axillarytemperatureisconsistentlylowerthanrectaltemperature,buttheabsolutedifferencevariestoowidely
forastandardconversion[7].Axillarytemperaturesmaybemeasuredinneutropenicpatientswhoareunable
touseanoralthermometer.
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Infraredtympanicmembrane(TM)thermometersmeasuretheamountofheatproducedbythetympanic
membrane.Temperaturereadingsareclosetocoretemperature,althoughtheinfraredTMreflectivedevices
commonlyusedinhomes,hospitals,andofficesareconsiderablylessaccuratethanTMthermistorsusedin
researchandbyanesthesiologists[5,816].IndividualstudiescomparingTMandrectaltemperaturesinchildren
havehadcontradictoryresults.SystematicreviewshaveconcludedthatTMthermometryshowsinsufficient
agreementwithestablishedmethodsofcoretemperaturemeasurementtobeusedinsituationswhere
detectionoffeverhasclinicalimplications(eg,laboratoryevaluationofthefebrileneonateoryounginfant)
[4,17,18].
Infraredcontactandnoncontactforeheadthermometersmeasuretheamountofheatproducedbythetemporal
arteries.Theaccuracyofsuchmeasurementsmaybeaffectedbysweatingorvascularchanges[1].Aswith
tympanictemperaturemeasurement,studiescomparingtemporalarteryandrectaltemperatureshave
contradictoryresults,andtemporalarterytemperaturesshouldnotbeusedtomakeclinicaldecisions[4,5,19
31].Readingsmaybegreaterorlowerthanrectaltemperature.
ConvertingbetweenFahrenheitandCelsiusFahrenheitandCelsiustemperatureequivalentsareprovided
inthetable(table1)orcanbecalculated(calculator1).
ToconvertatemperaturemeasuredinFahrenheittoCelsius:
(TemperatureinF32)x(5/9)=TemperatureinC
ToconvertatemperaturemeasuredinCelsiustoFahrenheit:
[(9/5)xTemperatureinC]+32=TemperatureinF
TEMPERATUREHOMEOSTASISBodytemperatureiscontrolledbythethermoregulatorycenterofthe
hypothalamus.Thethermoregulatorycenterbalancesheatproduction,derivedprimarilyfrommetabolicactivity
inmuscleandtheliver,withheatdissipationfromtheskinandlungs.Thethermoregulatorycenterisableto
maintainafairlysteadybodytemperatureinnormaltemperatureenvironments.However,atenvironmental
temperatureshigherthanapproximately35C(95F),thebody'sabilitytodissipateheatisoverwhelmed,and
coretemperaturerises.(See"Heatstrokeinchildren",sectionon'Pathophysiology'.)
NORMALBODYTEMPERATUREThemeannormaltemperatureisgenerallyconsideredtobe37C
(98.6F)[32].Thisvalueusuallyisattributedtostudiesdatingtothe19thcentury.Inamorerecentstudyof
youngadults,theupperlimitofnormalbodytemperature(measuredorally)was37.2C(98.9F)inthemorning
and37.7C(99.9F)overall[33].Normalbodytemperaturevarieswithage,timeoftheday,levelofactivity,
andphaseofthemenstrualcycle,amongotherfactors[1,6].
Infantsandyoungchildrengenerallyhavehighertemperaturesthanolderchildrenandadults.Thisrelatesto
thegreatersurfaceareatobodyweightratioandthehighermetabolicrateofinfantsandsmallchildren.Inthe
newbornperiod(age0to28days),themeannormaltemperature(measuredrectally)is37.5C,withanupper
limitofnormal(ie,twostandarddeviationsabovethemean)of38C(100.4F)[34].
Normaltemperaturevariesdaily,withamorningnadirandlateafternoon/earlyeveningpeak.Themean
amplitudeofvariationis0.5C(0.9F)[33].Duringafebrileillness,dailylowandhightemperaturereadingsare
maintained,butathigherthannormallevels.Dailyvariationcanbeashighas1Cinsomeindividuals
recoveringfromafebrileillness.
ELEVATEDBODYTEMPERATUREElevatedbodytemperaturemayresultfromfever(increasedbody
temperaturewithelevatedhypothalamicsetpoint)orhyperthermia(increasedbodytemperaturewithnormal
hypothalamicsetpoint)(figure1).Itisimportanttodifferentiatebetweentheseconditionsbecausetheyhave
differentclinicalimplicationsandmanagementstrategies.(See'Managementoffever'belowand"Heatstroke
inchildren",sectionon'Hospitalmanagement'.)
FeverFeverisanabnormalelevationofbodytemperaturethatoccursaspartofaspecificbiologicresponse
thatismediatedandcontrolledbythecentralnervoussystem.(See'Pathogenesis'below.)
Thetemperatureelevationthatisconsidered"abnormal"dependsupontheageofthechildandthesiteof
measurement.Thetemperatureelevationthatmaypromptclinicalinvestigationforinfectiondependsuponthe
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ageofthechildandtheclinicalcircumstances(eg,immunedeficiency,sicklecelldisease,illappearance,etc)
[3538].
Intheotherwisehealthyneonate(0to28to30daysofage)andyounginfant(onetothreemonthsof
age),feverofconcerngenerallyisdefinedbyrectaltemperature38.0C(100.4F).(See"Febrileinfants
(7to90daysofage):Definitionandetiologyoffever",sectionon'Definitionoffever'.)
Inchildren3to36months,fevergenerallyisdefinedbyrectaltemperaturesrangingfrom38.0to39.0C
(100.4to102.2F)andfeverofconcernbyrectaltemperatures39.0C(102.2F).(See"Feverwithouta
sourceinchildren3to36monthsofage",sectionon'Feverofconcern'.)
Inolderchildrenandadults,fevermaybedefinedbyoraltemperaturesrangingfrom37.8to39.4C
(100.0to103.0F)andfeverofconcernbyoraltemperatures39.5C(103.1F).
Thetemperaturethresholdsofconcernforchildrenwithunderlyingconditions(eg,sicklecelldisease,
neutropenia,HIV)arediscussedseparately.(Seeappropriatetopicreviews.)
PathogenesisFeveristheresultofahighlycoordinatedseriesofeventsthatbeginsperipherallywith
thesynthesisandreleaseofinterleukin(IL)1,IL6,tumornecrosisfactor(TNF),interferon(IFN)alpha,and
otherendogenouspyrogeniccytokinesbyphagocyticcellsinthebloodortissues(algorithm1)[39].These
cytokinesenterthebloodandarecarriedtotheanteriorhypothalamus,wheretheyinduceanabruptincreasein
thesynthesisofprostaglandins,especiallyprostaglandinE2(PGE2).TheinductionofPGE2inthebrainraises
thehypothalamicsetpointforbodytemperature(figure1).
Afterthesetpointisraised,thethermoregulatorycenterrecognizescurrentbodytemperaturetobetoolowand
initiatesaseriesofeventstoraisebodytemperaturetothenewsetpoint.Thisinvolvesaugmentationofheat
productionbyincreasedmetabolicrateandincreasedmuscletoneandactivity,anddecreasedheatloss
throughdiminishedperfusionoftheskin.Bodytemperaturerisesuntilanewequilibriumisachievedatthe
elevatedsetpoint.Theupperlimitoftemperatureduetofeverappearstobe42C(107.6F),butitisunusual
fortemperaturetoexceed41C(106F)withoutsomeelementofconcomitanthyperthermia[1,40,41].
Inadditiontocausingfever,pyrogeniccytokinesincreasethesynthesisofacutephaseproteinsbytheliver,
decreaseserumironandzinclevels,provokeleukocytosis,andaccelerateskeletalmuscleproteolysis.IL1
alsoinducesslowwavesleep,perhapsexplainingthesomnolencefrequentlyassociatedwithfebrileillnesses.
TheincreaseinperipheralPGE2mayaccountforthemyalgiasandarthralgiasthatoftenaccompanyfever.
Increasedheartrateisanormalphysiologicresponsetofever.
BenefitsandharmsWhetherfeverisbeneficialorharmfulisdisputed[41].Feverisanintegralpartof
theinflammatoryresponseand,assuch,mayhavearoleinfightinginfection.However,defensemechanisms
cangoawry.Eveniffeverdoeshavearoleindefendingthehostagainstinfection,itmaystillbethat,insome
circumstances,feverdoesmoreharmthangood[42,43].
PotentialbenefitsPotentialbenefitsoffeverincluderetardationofthegrowthandreproductionofsome
bacteriaandviruses(perhapsrelatedtodecreasedserumiron)andenhancedimmunologicfunctionat
moderatelyelevatedtemperatures(althoughsomeofthebenefitsarereversedattemperatures
approaching40C[104F])[41,4449].Someanimalstudieshavedemonstratedenhancedsurvivalwith
fever[50,51].However,aswithimmunefunction,thebenefitsmaybediminishedorevenreversedas
temperatureincreases[51,52].Whetherthesefindingsapplytohumansisnotknown.
PotentialharmsFevercanmakepatientsuncomfortable.Itisassociatedwithincreasedmetabolic
rate,oxygenconsumption,carbondioxideproduction,anddemandsonthecardiovascularandpulmonary
systems.Forthenormalchild,thesestressesareoflittleornoconsequence.However,forthechildin
shockorforthechildwithapulmonaryorcardiacabnormality,theincreaseddemandscanbedetrimental
andmayoffsetanyimmunologicbenefitfromthefever.
Inexperimentalstudies,feverhasbeenassociatedwithimpairedimmunologicresponses(eg,
phagocytosisofstaphylococciandlymphocytetransformationinresponsetomitogens)andcerebral
injury(includingedemaandhemorrhage)[5355].Whetherthesefindingsapplytohumansisnotknown.
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Thereisnoevidencetosuggestthatfever40C(104F)isassociatedwithincreasedriskofadverse
outcome(eg,braindamage)althoughthisbeliefisheldbymanycaregiversandclinicians[44,56,57].
HyperthermiaHyperthermiaisanabnormalelevationofbodytemperaturethatoccurswithoutachangein
thethermoregulatorysetpointinthehypothalamus(figure1).Thisfailureofnormalhomeostasisresultsinheat
productionthatexceedsthebody'scapacityfordissipation[44].
Characteristicclinicalfeaturesofhyperthermiaincludeahistoryofenvironmentalheatexposureoruseofdrugs
thatinterferewithnormalthermoregulation(eg,anticholinergics)hot,dryskinandcentralnervoussystem
dysfunction(eg,delirium,convulsions,coma).Hyperthermiacanberapidlyfataladversephysiologiceffects
begintooccurattemperatures>41C(105.8F).(See"Heatstrokeinchildren",sectionon'Clinicalfeatures'
and"Heatillness(otherthanheatstroke)inchildren",sectionon'Evaluationandmanagement'.)
EVALUATIONOFFEVERFeverisasignofunderlyingdisease,thecauseofwhichshouldbeevaluated,
particularlyifthechildisillappearingorthefeverpersists.Inmostcases,thechildhasadditionalsymptoms
andsignsofanacuteinfection,whichcanbemanagedasindicated.However,insomechildren,particularly
childrenwithunderlyingdisease,fevermaybeasignofamoreseriousorevenlifethreateningprocess.The
evaluationoffeverinspecificpopulationsofchildrenisdiscussedseparately:
(See"Evaluationandmanagementofthefebrileyounginfant(7to90daysofage)"and"Feverwithouta
sourceinchildren3to36monthsofage".)
(See"Feverofunknownorigininchildren:Etiology"and"Feverofunknownorigininchildren:
Evaluation".)
(See"Managementoffeverinchildrenwithsicklecelldisease".)
(See"Riskofinfectioninchildrenwithfeverandnonchemotherapyinducedneutropenia"and"Evaluation
andmanagementoffeverinchildrenwithnonchemotherapyinducedneutropenia",sectionon'Initial
evaluation'.)
(See"Feverinchildrenwithchemotherapyinducedneutropenia".)
(See"Feverinhumanimmunodeficiencyvirusinfectedchildren",sectionon'Diagnosticevaluation'.)
MANAGEMENTOFFEVERFeverisanimportantclinicalsign.Thefirststepinthemanagementoffever
istodetermineitscause(see'Evaluationoffever'above).Oncethecauseisknown,themainreasontotreat
feveristoimprovethechild'scomfort[44].
AnticipatoryguidancePatients,parents,andothercaregiversfrequentlymakethedecisiontotreatfever
withoutconsultingahealthcareprovider.Manypatientsandcaregiversbelievethatfeverisharmfulandthat
temperatureelevationrequirestreatmentregardlessofitscauseoreffects[56,5860].Educationofpatients,
parents,andcaregiversisrequiredtocounterthesebeliefs[6,41,44].Sucheducationshouldbeprovidedat
healthsupervisionvisitsandreinforcedduringacutevisitsforacutefebrileillnesses.
Importantcomponentsoftheanticipatoryguidanceforfeverinclude[1,3,6,41,44]:
Feverisnotanillness,butaphysiologicresponse.
Inotherwisehealthychildren,mostfeversareselflimitedandbenign,providedthatthecauseisknown
andfluidlossisreplacedfeverdoesnotcausebraindamage.Iftherearesignsofseriousillnessa
healthcareprovidershouldbeconsulted.
Thereisnoevidencethatfevermakestheillnessworse.
Initialmeasurestoreducethechild'stemperatureincludeprovisionofextrafluidsandreducedactivity.
Fevermaymerittreatmentwithanantipyreticagentifthechildisuncomfortable(asindicatedby
decreasedactivitylevel,decreasedfluidintake,etc).
Childrenwhoarereceivingtreatmentforfeverdonotneedtobeawakenedtoreceivetheantipyretic
agent.
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Childrenwhoarereceivingantipyreticmedicationsshouldnotbegivencombinationcoughandcold
preparations,whichoftencontainantipyreticmedicationsgivingbothmedicationsmayleadto
inadvertentoverdose.
Antipyreticmedicationsshouldbedosedaccordingtoweight,ratherthanage.Whensuggestingtheuse
ofantipyreticmedications,theriskofunderoroverdosingantipyreticscanbeminimizediftheclinician
provideswrittendosinginstructionsandameasuringdevice,suchasaproperlymarkedsyringe(forliquid
formulations)thedosingdirectionsandmeasuringdevicesthatareincludedwithoverthecounter
medicationsarevariableandinconsistent[61].Theinstructionsshouldincludewhichformulation(or
whichconcentrationofaliquidformulation)howtomeasuretheappropriatevolume(forliquid
formulation)howoftentoadministerhowtomonitortheresponsewhentodiscontinueandwhento
contactthehealthcareprovider.
Instructionsforsafestorageofantipyreticmedications.
AntipyreticagentsAntipyreticagentstreatfeverbyrestoringthethermoregulatorysetpointtonormal.The
mostcommonlyusedantipyreticagentsinchildrenandadolescentsareacetaminophenandibuprofen.Aspirin
shouldnotbeusedbecauseofitsassociationwithReyesyndrome[44].
IndicationsRoutinetreatmentoffeverinotherwisenormalchildrenisnotwarranted[1,3].Decisions
regardingthetreatmentoffeverinchildrenshouldbemadeonacasebycasebasisdependinguponthe
clinicalcircumstances(eg,underlyingdisease,levelofdiscomfort,desiretomonitorfevercurve,etc)[1].
Thereisnoevidencethatreducingfeverreducesthemorbidityormortalityfromafebrileillness(withthe
possibleexceptionofchildrenwithunderlyingconditionsthatlimittheabilitytotolerateincreasedmetabolic
demands)orthatantipyretictherapydecreasestherecurrenceoffebrileseizures[44].(See"Treatmentand
prognosisoffebrileseizures".)
Potentialbenefitsoftreatingfeverwithantipyreticsincludeimprovementofdiscomfortanddecreasein
insensiblewaterloss,whichmaydecreasetheriskofdehydration[44].Antipyreticagentsalsohaveanalgesic
effects,whichmayenhancetheiroveralleffect.Potentialdownsidesoftreatingfeverincludedelayed
identificationofanunderlyingillnessanddrugtoxicityitisuncertainwhethertreatingfeverincreasestherisk
fororcomplicationsofcertaintypesofinfections.(See'Benefitsandharms'above.)
Indicationsfortheshorttermtreatmentoffevermayinclude[1,41]:
Shock
Underlyingneurologicorcardiopulmonarydisease,orotherconditionwithincreasedmetabolicrate(eg,
burn,postoperativestate)
Alterationinfluidandelectrolytebalance
Highfever(ie,40C[104F])
Discomfort
Childrenwithtemperatureelevationandthepossibilityofhyperthermiaalsorequiretreatment,butthetreatment
ofhyperthermiadiffersfromthatoffever.Antipyreticmedicationsareineffectiveinchildrenwithheatstroke
andmayexacerbateconcomitantliverinjuryorcoagulopathy.(See"Heatstrokeinchildren",sectionon
'Hospitalmanagement'and"Heatillness(otherthanheatstroke)inchildren",sectionon'Evaluationand
management'.)
SuggestedapproachThechoiceofantipyreticagentforchildrenwithunderlyingmedicalconditions
maybeinfluencedbytheunderlyingmedicalconditions(eg,avoidanceofacetaminopheninchildrenwithliver
failure)ordesiretoavoiddruginteractionswithchronicmedications(eg,selectiveserotoninreuptakeinhibitors
mayenhancetheantiplateleteffectofibuprofen).
Whenantipyretictherapyisindicatedforchildrenwithoutunderlyingmedicalconditions,orwithunderlying
medicalconditionsthatdonotinfluencethechoiceofantipyretic,wesuggestbeginningtreatmentwithoral
acetaminophen.Oralibuprofenisanalternativetoacetaminophen,particularlyifantiinflammatoryeffectis
desiredinadditiontoantipyresis.Patient/parentpreferenceisamajorfactorinthechoiceofantipyretic
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becausepatients/parentsfrequentlymakethedecisiontotreatfeverwithoutconsultingahealthcareprovider.
Inrandomizedtrials,acetaminophenandibuprofenaremoreeffectivethanplaceboinreducingtemperature
ibuprofenisslightlymoreeffectiveandlongerlastingthanacetaminophen[6267].However,weprefer
acetaminophenbecauseofitslongtrackrecordofsafetywiththerapeuticdosing[1].(See'Acetaminophen'
belowand'Ibuprofen'below.)
Wedonotsuggestcombiningoralternatingacetaminophenwithibuprofenbecauseofthepotentialfordosing
confusion,increasedtoxicity,andcontributiontofeverphobia[44,68,69].Althoughcombiningoralternating
acetaminophenandibuprofenmaybemoreeffectivethaneitheragentaloneinreducingfever,itisnotclear
thatthistemperaturereductionisclinicallysignificant[70,71].Inaddition,thereislittleinformationaboutthe
effectsonthechild'sdiscomfortorthesafetyofcombiningoralternatingantipyretictherapyandthereare
theoreticconcernsofliverorkidneyinjury,particularlyforchildrenwithvolumedepletion[70,7274].(See
'Combiningoralternatingtherapy'below.)
Ifthetemperatureremainselevatedandthechild'sdiscomfortisnotimprovedthreetofourhoursafter
administrationofacetaminophenoribuprofen,itisreasonabletoswitchfromacetaminophentoibuprofenor
ibuprofentoacetaminophen[1,3].(See'Treatmentresponse'below.)
Antipyreticregimens
AcetaminophenFormostchildrenwithfeverwhoaretreatedwithanantipyreticagent,wesuggest
oralacetaminophenbecauseofitslongtrackrecordofsafetyattherapeuticdoses[1].
Acetaminophengenerallyisnotrecommendedforinfantsyoungerthanthreemonthsofagewithoutprior
consultationwithahealthcareproviderbecausefevermaybetheonlysignofseriousinfectioninsuchinfants.
(See"Febrileinfants(7to90daysofage):Definitionandetiologyoffever",sectionon'Invasivebacterial
infection'and"Evaluationandmanagementofthefebrileyounginfant(7to90daysofage)".)
Thedoseofacetaminophenis10to15mg/kgperdose(maximumdose800mgto1g)orallyeveryfourtosix
hours(withnomorethanfivedosesina24hourperiod)withamaximumdailydoseof75mg/kgperdayupto
4g/day(someformulationssuggestalowermaximumdailydose).Wedonotrecommenda"loadingdose"(eg,
aninitialdoseof30mg/kg)ofacetaminophenforroutineclinicalcarebecauseitmayincreasetheriskof
dosingconfusion[44].
Approximately80percentoffebrilechildrenwhoaretreatedwithacetaminophenhaveareductionin
temperatureof1to2C(1.8to3.6F)[44,75].Acetaminophenbeginstoworkin30to60minutesandhasits
peakeffectinthreetofourhours.Thedurationofactionisfourtosixhours.
Whenadministeredatappropriatedoses,acetaminophenisremarkablyfreeofsideeffects[67,76].InAugust
2013,theUSFoodandDrugAdministration(FDA)issuedasafetycommunicationaboutseriousand
potentiallyfatalacetaminophenassociatedskinreactionsincludingStevensJohnsonsyndrome,toxic
epidermalnecrolysis,andacutegeneralizedexanthematouspustulosisthatcanoccurwiththefirstexposureto
acetaminophenoratanytimeduringuse[77].Thesereactionsarerare(theFDAreviewfoundatotalofonly
107casesbetween1969and2012)andcanoccurwithotherantipyreticagents.Childrenwhodevelopskin
lesionswhileusingacetaminophenshoulddiscontinueacetaminophenandseekpromptmedicalattention.(See
"StevensJohnsonsyndromeandtoxicepidermalnecrolysis:Pathogenesis,clinicalmanifestations,and
diagnosis"and"Acutegeneralizedexanthematouspustulosis(AGEP)".)
Anassociationbetweenacetaminophenandasthmahasbeendescribed,butcausalityhasnotbeen
demonstrated.(See"Riskfactorsforasthma",sectionon'Acetaminophen'.)
Overdoseofacetaminophenmaybelethal.Overdosemayoccurifacetaminophenisadministered
simultaneouslywithcombinationcoughandcoldremediesthatcontainacetaminophen,withunsupervised
ingestion,andwithunclearinstructionsforadministration[44,78].(See"Clinicalmanifestationsanddiagnosis
ofacetaminophen(paracetamol)poisoninginchildrenandadolescents",sectionon'Epidemiology'.)
IbuprofenWesuggestibuprofenastheinitialantipyreticagentwhenantipyreticandantiinflammatory
activityaredesired(eg,inchildrenwithjuvenilearthritis)[1].
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Thedoseofibuprofenis10mg/kgperdose(maximumdose600mg)orallyeverysixhourswithamaximum
dailydoseof40mg/kgupto2.4g/day[44].Ibuprofenbeginstoworkin<60minutesandhasitspeakeffect
(declineintemperatureof1to2C(1.8to3.6F))inthreetofourhours.Thedurationofactionissixtoeight
hours[44,75].
Ibuprofengenerallyisnotrecommendedforinfantsyoungerthansixmonths[44].Suchinfantshavelimited
renalfunctionrelativetoolderinfantsandchildrenandpotentiallyareatincreasedriskforrenaltoxicity[44].
Adverseeffectsofibuprofenmayincludegastritisandgastrointestinalbleeding[79].Whenadministeredat
appropriatedosesandtakenwithfood,ibuprofenusuallyissafe[67,80].However,acutekidneyinjuryhas
beenreportedfollowingappropriatedosesofibuprofen[81].Anecdotalreportshavelinkednonsteroidal
antiinflammatorydrugswiththedevelopmentormorerapidprogressionofnecrotizingfasciitisduetogroupA
streptococciinchildrenwithvaricella[82,83].However,areviewoftheliterature,includingfiveprospective
studies,didnotdemonstrateacorrelation[84].
Overdosemayoccurifibuprofenisadministeredsimultaneouslywithcombinationcoughandcoldremedies
thatcontainibuprofen,withunsupervisedingestion,andunclearinstructionforadministration[44].Overdoseof
ibuprofenappearsmoreeasilymanagedthanoverdoseofacetaminophen[85].(See"Overviewofibuprofen
poisoninginchildrenandadolescents",sectionon'Epidemiology'and"Overviewofibuprofenpoisoningin
childrenandadolescents",sectionon'Clinicalfeaturesofacuteoverdose'.)
CombiningoralternatingtherapyWedonotsuggestcombiningoralternatingtherapywith
acetaminophenandibuprofentotreatfeverinchildren.Althoughcombiningoralternatingacetaminophenand
ibuprofenmaybemoreeffectivethaneitheragentaloneinreducingfever,itisnotclearthatthisreductionis
clinicallysignificant[70,71].Inaddition,thereislittleinformationabouttheeffectsonthechild'sdiscomfortor
thesafetyofcombiningoralternatingantipyretictherapyandtherearetheoreticconcernsofliverorkidney
injury,particularlyforchildrenwithvolumedepletion[70,7274].
A2013systematicreviewincludedsixrandomizedtrials(915patients)evaluatingcombinationoralternating
versussingleagentantipyretictherapyinchildren[70].Theindividualtrialsuseddifferentthresholdsforfever,
sitesoftemperaturemeasurement(eg,rectal,axillary),dosingregimens,andperiodsofobservationfor
outcomeassessment[71,8690].
Inpooledanalysis,combinationtherapyresultedindecreasedmeantemperatureonehouraftertreatment
(meandifference0.27C[0.48F],95%CI0.45to0.08[0.81Fto0.14F]twotrials163patients)and
fourhoursaftertreatment(meandifference0.70C[1.26F],95%CI1.05to0.35[1.89Fto0.63F]
twotrials173patients)althoughthemeantemperatureinthesingleagentgrouponeandfourhoursafter
treatmentwas<38C(100.4F)[70].Fewerchildrenreceivingcombinationtherapyremainedorbecame
febrilefourhoursaftertreatment(2versus23percentRR0.08,95%CI,0.020.42twotrials196
patients).
Inpooledanalysis,alternatingtherapywasassociatedwithdecreasedmeantemperatureonehourafter
thesecondagent(meandifference0.60C[1.08F],95%CI0.94to0.26[1.69Fto0.47F]twotrials
78patients)althoughthemeantemperatureinthesingleagentgroupwas38C(100.4F)[70].Fewer
childrenreceivingalternatingtherapyremainedorbecamefebrilethreehoursafterthesecondagent(11
versus45percentRR0.25,95%CI0.110.55twotrials109patients).
Onetrialcomparedcombinationwithalternatingtherapy,andfoundnodifferenceinmeantemperature
reductionorproportionofchildrenwhoremainedorbecamefebrile[90].
Amongthetrialsthatassessedmeasuresotherthantemperature,onefoundnodifferenceinchild
discomfortbetweencombinationandsingleagenttherapy[89]onefoundthatparentsperceivedno
differenceinefficacydespitetemperaturereductionwithalternatingtherapy[71]andonefoundthat
childrenwhoreceivedalternatingantipyretictherapyhadlowerscoresonapainchecklistthanthosewho
receivedsingleagenttherapy,althoughitwasnotclearthattheassignedantipyreticregimenswere
followedappropriately(childrenassignedtothealternatinggroupreceivedalowermeannumberofdoses
ofantipyreticthanthoseassignedtosingleagenttherapy),makingtheresultsdifficulttointerpret[87].
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Noseriousadverseeventswereobservedinthetrialsthatreportedseriousadverseeventsofcombining
oralternatingtherapy[71,8789].Inonetrial,mild,transientelevationofliverenzymesandmildly
abnormalrenalfunctionoccurredin1.7and3percentofparticipants,respectively,butdidnotdiffer
betweengroups[87].
TheAmericanAcademyofPediatricsclinicalreportonfeverandantipyreticuseinchildrensuggeststhat
combinedtreatmentwithacetaminophenandibuprofenmayincreasethepossibilityofinaccuratedosingand
maycontributeto"feverphobia"[44].TheNationalInstituteforHealthandCareExcellenceadvisesagainst
thesimultaneoususeofacetaminophenandibuprofenandsuggeststhatalternatingtheseagentsbe
consideredonlyifthechild'sdistressordiscomfortpersistsorrecursbeforethenextdoseisdue[3].Ifthe
decisionismadetousecombinedoralternatingtherapy,dosinginstructionsandintervalsmustbethoroughly
explained.(See'Anticipatoryguidance'above.)
DurationThedurationofadministrationofantipyretictherapydependsuponthechild'sresponsethe
endpointisthechild'scomfort[44].Prolongeduseofantipyreticagentsgenerallyisnotnecessarybecause
mostfebrileillnessesinchildrenareselflimitedviralinfections.
TreatmentresponseTreatmentwithantipyreticagentsshouldmakethefebrilechildmorecomfortable.
Itismoreimportantforcaregiverstomonitorthechild'sgeneralappearance(forsignsofseriousillnesssuch
aslethargy,stiffneck,alteredmentalstatus,petechialorpurpuricrash,etc),activitylevel,andfluidintakethan
tomonitorthetemperaturecurve.Witheitheracetaminophenoribuprofen,aresponseshouldbeseenwithin60
minutestheresponsepeaksinthreetofourhours[44].Ifthetemperatureremainselevatedandthechild's
discomfortisnotimprovedthreetofourhoursafteradministrationofacetaminophenoribuprofen,someexperts
wouldsuggestswitchingfromacetaminophentoibuprofenoribuprofentoacetaminophen[1].Thereareno
publishedstudiestoevaluatethesafetyorefficacyofthispracticehowever,intheory,somefeversmay
respondbettertooneantipyreticagentthananother.
Persistenceofafebrileillnessbeyondfourorfivedays,amarkedincreaseintheheightofthemaximumfever
duringthecourseoftheillness,orthedevelopmentofnewlocalizingsymptomsshouldraiseconcernsabout
alternativediagnosesorbacterialsuperinfection,whichshouldbeevaluatedbyahealthcareprovider(orre
evaluatedbyahealthcareproviderifthechildwasseenattheonsetofillness)[44].
UseinyounginfantsTheAmericanAcademyofPediatricsclinicalreportonfeverandantipyreticuse
inchildrensuggeststhatacetaminophennotbeadministeredtoinfantsyoungerthanthreemonthsandthat
ibuprofennotbeadministeredtochildrenyoungerthansixmonthswithoutevaluationbyaclinician[44].Fever
maybetheonlysignofseriousinfectioninayounginfant,andsuchinfectionsshouldbeexcludedbefore
symptomatictreatmentoffeverisinitiated.(See"Febrileinfants(7to90daysofage):Definitionandetiology
offever",sectionon'Invasivebacterialinfection'and"Evaluationandmanagementofthefebrileyounginfant
(7to90daysofage)".)
Decisionsregardingtheuseofacetaminophenininfantsyoungerthanthreemonthsafterseriousinfectionhas
beenexcludedshouldbemadeonacasebycasebasis.Thesafetyofacetaminopheninyounginfantscanbe
extrapolatedfromitsuseasananalgesicinthispopulation.(See"Preventionandtreatmentofneonatalpain",
sectionon'Acetaminophen'.)However,thereislittleinformationaboutitsefficacyasanantipyretic.
ExternalcoolingExternalcoolingisthetreatmentofchoiceforheatstrokeandotherformsofheatillness
inwhichrapidcoolingisnecessarytopreventendorgandamage.(See"Heatstrokeinchildren",sectionon
'Rapidcooling'and"Heatillness(otherthanheatstroke)inchildren",sectionon'Evaluationandmanagement'.)
Wedonotroutinelysuggestexternalcoolingfortemperaturereductioninpreviouslywellinfantsandchildren
withafebrileillness.Inrandomizedtrialscomparingthecombinationoftepidspongingandantipyretictherapy
toantipyretictherapyalone,theaddedbenefitoftepidspongingintemperaturereductionwasshortlived,and
spongingwasassociatedwithincreaseddiscomfort[9193].
Externalcoolingmaybeusedasanadjuncttoantipyretictherapyforchildreninwhommorerapidandgreater
reductionofbodytemperatureisnecessarythancanbeachievedwithantipyreticagentsalone.Insuchcases,
antipyreticagentsshouldbeadministeredatleast30minutesbeforeexternalcooling[6].Antipyreticagentsare
necessarytoresetthethermoregulatorysetpoint,withoutwhichexternalcoolingwillresultinanincreasein
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heatproduction[1].
Possibleindicationsforconcomitantantipyreticadministrationandmechanicalcoolinginchildreninclude:
Uncertaintyaboutthecauseofelevatedtemperature(heatillnessversusfever)(see'Hyperthermia'
above)
Fevercombinedwithacomponentofheatillness(eg,fromoverwrapping,hypovolemia,ordrugssuchas
atropine)
Underlyingneurologicdisorder,inwhichthechildmayhaveabnormaltemperaturecontrolandpoor
responsetoantipyreticagents
Whenmechanicalcoolingisnecessarytotreatfever,wesuggestspongingwithcomfortablywarmortepid
water(generallyaround30C[85F]).Spongingismoreeffectivethanimmersionbecauseevaporationfromthe
skinaugmentsheatloss.Althoughtemperaturereductionmaybefasterwithcoldwater,spongingwithcold
waterisalsomoreuncomfortable.Alcoholshouldnotbeused,becauseitsfumesareabsorbedacrossthe
alveolarmembraneandpossiblyacrosstheskin,resultingincentralnervoussystemtoxicity[94].
Coolingblanketscanbeusefulinhospitalizedchildrenwhoarecriticallyillorwhohaveproblemswith
temperaturecontrol(eg,childrenwithacuteheadinjury).
AlternativetherapiesPractitionersofcomplementaryandalternativetherapymaysuggestanumberof
remediesforfeverininfantsandchildren(eg,calciumlactate).Theseremedieshavenotbeenstudiedin
clinicaltrials,andthereislittletonoinformationabouttheirefficacyorsafety.Wedonotrecommendtheiruse.
INFORMATIONFORPATIENTSUpToDateofferstwotypesofpatienteducationmaterials,"TheBasics"
and"BeyondtheBasics."TheBasicspatienteducationpiecesarewritteninplainlanguage,atthe5thto6th
gradereadinglevel,andtheyanswerthefourorfivekeyquestionsapatientmighthaveaboutagiven
condition.Thesearticlesarebestforpatientswhowantageneraloverviewandwhoprefershort,easytoread
materials.BeyondtheBasicspatienteducationpiecesarelonger,moresophisticated,andmoredetailed.
Thesearticlesarewrittenatthe10thto12thgradereadinglevelandarebestforpatientswhowantindepth
informationandarecomfortablewithsomemedicaljargon.
Herearethepatienteducationarticlesthatarerelevanttothistopic.Weencourageyoutoprintoremailthese
topicstoyourpatients.(Youcanalsolocatepatienteducationarticlesonavarietyofsubjectsbysearchingon
"patientinfo"andthekeyword(s)ofinterest.)
Basicstopic(see"Patientinformation:Givingyourchildoverthecountermedicines(TheBasics)")
BeyondtheBasicstopic(see"Patientinformation:Feverinchildren(BeyondtheBasics)")
SUMMARYANDRECOMMENDATIONS
Feverisanabnormalincreaseinbodytemperaturethatresultsfromelevationofthehypothalamicset
point(algorithm1).Themagnitudeoftemperatureincreasethatpromptsevaluationdependsupontheage
ofthechildandtheclinicalcircumstances.(See'Fever'above.)
Thecauseoffevershouldbeevaluated,particularlyininfantsyoungerthanthreemonthsofageand
infantsandchildrenwithunderlyingmedicalconditionsthatincreasetheriskofseriousinfection(eg,
sicklecelldisease,neutropenia,humanimmunodeficiencyvirusinfection).(See'Evaluationoffever'
above.)
Decisionsregardingthetreatmentoffeverinchildrenshouldbemadeonacasebycasebasis.
Indicationsforthetreatmentoffevermayincludeshockunderlyingmedicalconditionsthatwouldbe
exacerbatedbyincreasedmetabolicdemandfluidorelectrolyteimbalancetemperature40C(104F)
anddiscomfort.(See'Indications'above.)
Thechoiceofantipyreticagentforchildrenwithunderlyingmedicalconditionsmaybeinfluencedbythe
underlyingmedicalconditionandchronicmedications.(See'Suggestedapproach'above.)
Whenthedecisionismadetouseanantipyreticagentinachildwithoutanunderlyingmedicalcondition,
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orwithanunderlyingmedicalconditionthatdoesnotinfluencethechoiceofantipyretic,wesuggest
beginningtreatmentwithacetaminophen(Grade2B).Thedoseis10to15mg/kgperdose(maximum
dose800mgto1g)orallyeveryfourtosixhours(withnomorethanfivedosesina24hourperiod
maximumdailydose:75mg/kgperdayupto4g/day).(See'Acetaminophen'above.)
Ibuprofenisanalternativetoacetaminophen,particularlyifantiinflammatoryeffectisdesired.Thedoseof
ibuprofenis10mg/kgperdose(maximumdose600mg)orallyeverysixhours(maximumdailydose:40
mg/kgupto2.4g/day).(See'Ibuprofen'above.)
Wedonotsuggestcombiningoralternatingacetaminophenwithibuprofen(Grade2B).(See'Combining
oralternatingtherapy'above.)
Ifthetemperatureremainselevatedandthechild'sdiscomfortisnotimprovedthreetofourhoursafter
administrationofacetaminophenoribuprofen,someexpertswouldsuggestswitchingfrom
acetaminophentoibuprofenoribuprofentoacetaminophen.(See'Treatmentresponse'above.)
Prolongeduseofantipyreticagentsgenerallyisnotnecessary.Persistenceoffeverbeyondfourorfive
days,amarkedincreaseintheheightofthefeverduringthecourseofillness,orthedevelopmentofnew
localizingsymptomsshouldraiseconcernsaboutalternativediagnosesorbacterialsuperinfection,which
shouldbeevaluated.(See'Duration'above.)
Wedonotroutinelysuggestexternalcoolingfortemperaturereductioninpreviouslywellinfantsand
childrenwithafebrileillness(Grade2A).(See'Externalcooling'above.)
UseofUpToDateissubjecttotheSubscriptionandLicenseAgreement.
Topic5989Version30.0
http://aplicacionesbiblioteca.udea.edu.co:4560/contents/feverininfantsandchildrenpathophysiologyandmanagement?topicKey=PEDS%2F5989&elap
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GRAPHICS
FahrenheitandCelsiustemperatureequivalents
Fahrenheit
Celsius
96.0
Fahrenheit
Celsius
35.6
102.0
38.9
96.2
35.7
102.2
39.0
96.4
35.8
102.4
39.1
96.6
35.9
102.6
39.2
96.8
36.0
102.8
39.3
97.0
36.1
103.0
39.4
97.2
36.2
103.2
39.6
97.4
36.3
103.4
39.7
97.6
36.4
103.6
39.8
97.8
36.6
103.8
39.9
98.0
36.7
104.0
40.0
98.2
36.8
104.2
40.1
98.4
36.9
104.4
40.2
98.6
37.0
104.6
40.3
98.8
37.1
104.8
40.4
99.0
37.2
105.0
40.6
99.2
37.3
105.2
40.7
99.4
37.4
105.4
40.8
99.6
37.6
105.6
40.9
99.8
37.7
105.8
41.0
100.0
37.8
106.0
41.1
100.2
37.9
106.2
41.2
100.4
38.0
106.4
41.3
100.6
38.1
106.6
41.4
100.8
38.2
106.8
41.6
101.0
38.3
107.0
41.7
101.2
38.4
101.4
38.6
101.6
38.7
101.8
38.8
ToconvertfromFahrenheittoCelsius:
(Temperature32)x(5/9)
ToconvertfromCelsiustoFahrenheit:
((9/5)xTemperature)+32
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Graphic73846Version2.0
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Relationshipofhypothalamicsetpointtobody
temperature
Euthermia:hypothalamicsetpointisnormal,andbodytemperature
approximatessetpointandisalsonormal.
Fever:hypothalamicsetpointiselevated,andbodytemperature
followssetpointandisalsoelevated.
Heatillness:hypothalamicsetpointisnormal,andbodytemperature
iselevateddespitenormalsetpoint.
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Pathwaysoffeverproduction
Startingfromthetopleft,infectiousagentsand/ormicrobialproducts,aswellas
cytokinesandotherinflammatoryprocesses,inducemacrophages,endothelial
cells,andthereticuloendothelialsystemtoproduceandsecretepyrogenic
cytokinesintothecirculation.Thesepyrogeniccytokinesinducethesynthesisof
prostaglandinE2(PGE2)inthehypothalamus.Inaddition,microbialtoxins,
actingasligandstothetolllikereceptorsinthehypothalamus,stimulatethe
synthesisofPGE2bythehypothalamus.PGE2raisesthethermostaticsetpoint
inthehypothalamustofebrilelevels.Thevasomotorcentersendssignalsfor
heatconservation(vasoconstriction)andheatproduction(shivering).
Corticosteroidsreducetheperipheralsynthesisofpyrogeniccytokines,whereas
antipyreticsreducePGE2levelsinthebrain.
TLR:tolllikereceptorIL1:interleukin1IL6:interleukin6TNF:tumornecrosisfactor
IFN:interferonPGE2:prostaglandinE2.
CourtesyofReuvenPorat,MDandCharlesADinarello,MD.
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