Anaphylaxis. Rapid Recognition and Treatment

25/1/2015
Anaphylaxis:Rapidrecognitionandtreatment
OfficialreprintfromUpToDate
www.uptodate.com2015UpToDate
Authors
FEstelleRSimons,MD,
FRCPC
CarlosACamargo,Jr,MD,
DrPH
SectionEditor
BruceSBochner,MD
DeputyEditor
AnnaMFeldweg,MD
Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.
Literaturereviewcurrentthrough:Dec2014.|Thistopiclastupdated:Dec18,2014.
INTRODUCTIONAnaphylaxisisapotentiallyfataldisorder.Inindustrializedcountries,thelifetimeprevalence
fromallcauseshasbeenestimatedtobebetween0.05and2percentinthegeneralpopulationandtherateof
occurrenceisincreasing[16].IntheUnitedStates,thelifetimeprevalenceofanaphylaxisisreportedtobe1.6
percent,basedonstrictclinicaldiagnosticcriteria[7].Anaphylaxisisnotalwaysrecognizedassuchbecauseit
canmimicotherconditionsandisvariableinitspresentation.
Thistopicwillreviewtherecognitionandtreatmentofanaphylaxisbyhealthcareprofessionalsworkinginsettings
suchasanemergencydepartment(ED),surgicalunit,hemodialysisfacility,hospitalward,clinic,orclinician's
office[812].Uniquefeaturesofanaphylaxisinpregnantwomenandinfantsarepresentedseparately,asisthe
pathophysiologyofanaphylaxis.(See"Anaphylaxisinpregnantandbreastfeedingwomen"and"Anaphylaxisin
infants"and"Pathophysiologyofanaphylaxis".)
DEFINITIONANDDIAGNOSISAnaphylaxisisdefinedasaseriousallergicorhypersensitivityreactionthatis
rapidinonsetandmaycausedeath[13,14].Thediagnosisofanaphylaxisisbasedprimarilyuponclinical
symptomsandsigns,aswellasadetaileddescriptionoftheacuteepisode,includingantecedentactivitiesand
eventsoccurringwithintheprecedingminutestohours.
Anaphylaxisisunderrecognizedandundertreated[13,5].Thismaypartlybeduetofailuretoappreciatethatitcan
presentwithoutobviousskinsymptomsandsignsandwithoutshock.Anaphylaxisisamuchbroadersyndrome
than"anaphylacticshock,"andthegoaloftherapyshouldbeearlyrecognitionandtreatmentwithepinephrineto
preventprogressiontolifethreateningrespiratoryand/orcardiovascularsymptomsandsigns,includingshock.
DiagnosticcriteriaDiagnosticcriteriaforanaphylaxiswerepublishedbyamultidisciplinarygroupofexpertsin
2005and2006[13,14].Thesecriteriawereintendedtohelpcliniciansrecognizethefullspectrumofsymptoms
andsignsthatcompriseanaphylaxis.Recognitionofthevariableandatypicalpresentationsofanaphylaxisis
criticaltoprovidingeffectivetherapyintheformofepinephrine,aswellasreducingoverrelianceonsecondline
medicationssuchasantihistaminesandglucocorticoidsthatarenotlifesavinginanaphylaxis[15].Ina
retrospectivecohortstudyof214emergencydepartment(ED)patients,thesecriteriawerefoundtohavea
sensitivityof97percentcomparedwithanallergist'sdiagnosisuponreviewofthecase,aswellasaspecificityof
82percent,apositivepredictivevalueof69percent,andanegativepredictivevalueof98percent[16].
Therearethreediagnosticcriteria,eachreflectingadifferentclinicalpresentationofanaphylaxis(table1)[13].
AnaphylaxisishighlylikelywhenanyONEofthefollowingthreecriteriaisfulfilled:
Criterion1Acuteonsetofanillness(minutestoseveralhours)involvingtheskin,mucosaltissue,orboth
(eg,generalizedhives,pruritusorflushing,swollenlipstongueuvula)andatleastoneofthefollowing:
Respiratorycompromise(eg,dyspnea,wheezebronchospasm,stridor,reducedpeakexpiratoryflow,
hypoxemia).
OR
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Reducedbloodpressure(BP)orassociatedsymptomsandsignsofendorgandysfunction(eg,hypotonia
[collapse]syncope,incontinence).(See'Criterion3'below.)
Note:Skinsymptomsandsignsarepresentinupto90percentofanaphylacticepisodes.Thiscriterionwill
thereforefrequentlybehelpfulinmakingthediagnosis.
Criterion2TwoormoreofthefollowingthatoccurrapidlyafterexposuretoaLIKELYallergenforthat
patient(minutestoseveralhours):
Involvementoftheskinmucosaltissue(eg,generalizedhives,itchflush,swollenlipstongueuvula).
Respiratorycompromise(eg,dyspnea,wheezebronchospasm,stridor,reducedpeakexpiratoryflow,
hypoxemia).
ReducedBPorassociatedsymptomsandsigns(eg,hypotonia[collapse],syncope,incontinence).
Persistentgastrointestinalsymptomsandsigns(eg,crampyabdominalpain,vomiting).
Note:Skinsymptomsorsignsareabsentorunrecognizedinupto20percentofanaphylacticepisodes.Criterion2
incorporatesgastrointestinalsymptomsinadditiontoskinsymptoms,respiratorysymptoms,andreducedBP.Itis
appliedtopatientswithexposuretoasubstancethatisalikelyallergenforthem.
Criterion3ReducedBPafterexposuretoaKNOWNallergenforthatpatient(minutestoseveralhours):
ReducedBPinadultsisdefinedasasystolicBPoflessthan90mmHgorgreaterthan30percentdecrease
fromthatperson'sbaseline
Ininfantsandchildren,reducedBPisdefinedaslowsystolicBP(agespecific)*orgreaterthan30percent
decreaseinsystolicBP
*LowsystolicBPforchildrenisdefinedas:
Lessthan70mmHgfrom1monthupto1year
Lessthan(70mmHg+[2xage])from1to10years
Lessthan90mmHgfrom11to17years
Note:Criterion3isintendedtodetectanaphylacticepisodesinwhichonlyoneorgansystemisinvolvedandis
appliedtopatientswhohavebeenexposedtoasubstancetowhichtheyareknowntobeallergic,forexample,
hypotensionorshockafteraninsectsting.
Therewilloccasionallybepatientswhodonotfulfillanyofthesecriteria,butforwhomtheadministrationof
epinephrineisappropriate.Asanexample,itwouldbeappropriatetoadministerepinephrinetoapatientwitha
historyofnearfatalanaphylaxistopeanutwhopresentswithurticariaandflushingthatdevelopedwithinminutes
ofaknownorsuspectedingestionofpeanut[14].
SymptomsandsignsAnaphylaxismaypresentwithvariouscombinationsofapproximately40potential
symptomsandsigns(table2)[814,1725].
Commonsymptomsandsignsofanaphylaxisincludethefollowing:
Skinsymptomsandsigns,whichoccurinupto90percentofepisodes,includinggeneralizedhives,itching
orflushing,swollenlipstongueuvula,periorbitaledema,conjunctivalswelling.
Respiratorysymptomsandsigns,whichoccurinupto70percentofepisodes,includingnasaldischarge,
nasalcongestion,changeinvoicequality,sensationofthroatclosureorchoking,stridor,shortnessofbreath,
wheeze,cough.
Gastrointestinalsymptomsandsigns,whichoccurinupto45percentofepisodes,includingnausea,
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vomiting,diarrhea,andcrampyabdominalpain.
Cardiovascularsymptomsandsigns,whichoccurinupto45percentofepisodes,includinghypotonia
(collapse),syncope,incontinence,dizziness,tachycardia,andhypotension.
Anaphylaxismaybemildandresolvespontaneouslyduetoendogenousproductionofcompensatorymediators
(eg,epinephrine,angiotensinII,endothelin,andothers)oritmaybesevereandprogresswithinminutesto
respiratoryorcardiovascularcompromiseanddeath[19].Thefactorsthatdeterminethecourseofanaphylaxisin
anindividualpatientarenotfullyunderstood.Attheonsetofananaphylacticepisode,itisnotpossibletopredict
howsevereitwillbecome,howrapidlyitwillprogress,andwhetheritwillresolvepromptlyandcompletelyor
becomebiphasicorprotracted.
Deathfromanaphylaxisusuallyresultsfromasphyxiationduetoupperorlowerairwayobstructionorto
cardiovascularcollapse[15,2633].(See"Fatalanaphylaxis".)
Uniqueaspectsoftheclinicalmanifestationsofanaphylaxisininfantsandinpregnantwomenduringlaborand
deliveryarereviewedseparately.(See"Anaphylaxisininfants"and"Anaphylaxisinpregnantandbreastfeeding
women".)
TimecourseAnaphylaxisisusuallycharacterizedbyadefinedexposuretoapotentialtrigger,followedby
rapidonset,evolution,andresolutionofsymptomsandsignswithinminutestohours.
BiphasicanaphylaxisBiphasicanaphylaxisisdefinedasarecurrenceofsymptomsthatdevelops
followingtheapparentresolutionoftheinitialanaphylacticepisodewithnoadditionalexposuretothetrigger.
Biphasicreactionshavebeenreportedtodevelopin4.5to23percentofanaphylacticepisodes.Biphasicreactions
werereportedinupto11percentofchildrenwithanaphylaxis[34,35].Theytypicallyoccurwithin8to10hours
afterresolutionoftheinitialsymptoms,althoughrecurrencesupto72hourslaterhavebeenreported.(See
"Biphasicandprotractedanaphylaxis".)
ProtractedanaphylaxisProtractedanaphylaxisisdefinedasananaphylacticreactionthatlastsforhours,
days,orevenweeksinextremecases[26].
PitfallsinmakingthediagnosisAnaphylaxisisnotalwayseasytorecognizeclinically.Thepatternsoftarget
organinvolvementarevariableandmaydifferamongindividuals,aswellasamongepisodesinthesame
individual.Anaphylaxisislikelyunderdiagnosedandunderreportedforavarietyofreasons[3,811,2024,36]:
Somehealthcareprofessionalsremainreluctanttodiagnoseanaphylaxisintheabsenceofhypotensionor
shock,eventhoughchangesinBParenotnecessarilyrequiredforthediagnosisaccordingtocriterion1or
criterion2[13].(See'Diagnosticcriteria'above.)
HypotensionmaygoundetectedwhentheinitialBPmeasurementisobtainedafterepinephrine
administration,orwhenaninappropriatelysmallBPcuffisused.Ininfantsandyoungchildren,BPislower
thanitisinteenagersandadults.
Manyofthedramaticphysicalsignsassociatedwithhypoxiaandhypotensioninanaphylaxisare
nonspecific,suchasdyspnea,stridor,wheeze,confusion,collapse,unconsciousness,andincontinence
(table2).
Skinsymptomsandsigns(suchashives,itching,flushing,andangioedema),whicharehelpfulinmakingthe
diagnosis,areabsentorunrecognizedinupto20percentofallepisodes.Skinsymptomsandsignsmaybe
absentifapatienthastakenanH1antihistamine.Theymayalsobemissedifanindividualcannotdescribe
itchingorisnotundressedandfullyexaminedduringtheepisode,orinpatientswhoaredrapedduring
surgery[19].(See"Perioperativeanaphylaxis:Clinicalmanifestations,etiology,anddiagnosis".)
Anaphylaxismaybedifficulttorecognizeincertainclinicalsituations.Forexample,hemodialysis,surgeryor
childbirth,whenforotherreasonspatientsmayexperiencedramaticphysiologicshiftswithconsequent
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changesinvitalsigns[812,19,36,37].Inaddition,inabilityofthepatienttocommunicatethepresenceof
earlysymptoms(eg,ifdysphonic,dyspneic,inshock,unconscious,oranesthetized)alsoimpedesprompt
recognitionofanaphylaxis.
Anaphylaxisinaknownasthmaticmaybemistakenforanasthmaexacerbationifaccompanyingskin
symptomsandsignssuchasitchingandhivesordizzinesssuggestiveofimpendingshockareoverlooked
[19].
Patientsexperiencingtheirfirstepisodemaynotrecognizethesymptomsasanaphylaxis.Asaresult,they
maynotreportsymptomsfullyormayfocusononeprominentsymptom(eg,unlessspecificallyasked,a
patientpresentingwithvomitingmaynotreportthattheepisodewasprecededbydiffuseitching).
Theabovefactorsarefurthercompoundedinpatientswithneurologic,psychiatric,orpsychologicproblems,
orthosewhotakemedicationsorsubstancessuchasasedatingH1antihistamine,ethanol,orrecreational
drugsthatpotentiallyimpaircognitionandjudgment,makinganaphylaxissymptomsdifficulttorecognize
(table3)[19,23].
TRIGGERSANDMECHANISMSMostanaphylaxisepisodesaretriggeredthroughanimmunologic
mechanisminvolvingimmunoglobulinE(IgE).Foodsarethemostcommontriggerinchildren,whilemedications
andinsectstingsaremorecommontriggersinadultsthaninchildren.Thetableprovidesamorecomprehensive
listofpotentialanaphylaxistriggers,categorizedbycausativemechanism(table4)[13,14,17,2024].
Inthisreview,thetermanaphylaxisappliestoallofthefollowing:
AcutesystemicreactionsinvolvingIgEdependentmechanisms.
Acutesystemicreactionsinvolvingotherimmunologicmechanisms(formerlycalledanaphylactoidreactions).
Acutesystemicreactionsthatoccurindependentlyofanyimmunologicmechanismduetodirectreleaseof
histamineandothermediatorsfrommastcellsandbasophils(eg,afterexerciseorexposuretocoldor
ultravioletlight,ingestionofopioids,etc).
Acutesystemicreactionswithoutanyobvioustriggerormechanism(idiopathicanaphylaxis).
Theacutemanagementofanaphylaxisisthesame,regardlessofthetriggerormechanisminvolved
[13,14,17].
CONTRIBUTORYFACTORSComorbiditiesandconcurrentmedicationsmayimpacttheseverityof
symptomsandsignsandresponsetotreatmentinpatientswithanaphylaxis(table5)[2024,38].
ComorbiditiesAsthmaandcardiovasculardiseasearethemostimportantriskfactorsforapooroutcomefrom
anaphylaxis.Otherdisordersmayalsoincreaserisk.
Persistentasthmaisariskfactorforanaphylaxis[39,40].Asthmaisalsoassociatedwithincreasedriskof
deathfromanaphylaxis,especiallyinadolescentsandyoungadultswithpoorlycontrolleddisease[15,2630].
Cardiovasculardiseaseisanimportantriskfactorfordeathfromanaphylaxisinmiddleagedandolder
individuals[31].
Otherrespiratorydiseases,eg,chronicobstructivepulmonarydisease(COPD),interstitiallungdisease,or
pneumoniaarealsoriskfactorsforsevereorfatalanaphylaxisinolderadults[31,41].
Acuteinfectionsuchasanupperrespiratorytractinfection,fever,emotionalstress,exercise,disruptionof
routine,andpremenstrualstatusmayalsoincreasetherisk.Withtheexceptionofexercise,theseamplifying
factorshavenotbeensystematicallystudiedinthecontextofanaphylaxis[21].
ConcurrentmedicationsConcurrentadministrationofcertainmedications,suchasbetaadrenergicblockers,
angiotensinconvertingenzyme(ACE)inhibitors,andalphaadrenergicblockersmayincreasethelikelihoodof
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severeorfatalanaphylaxis,andmayalsointerferewiththepatient'sabilitytorespondtotreatmentandwiththe
patient'scompensatoryphysiologicresponses(table5)[4245].
Betaadrenergicblockers,administeredorally,parenterally,ortopically(eg,eyedrops)aresometimes
associatedwithsevereanaphylaxisandmayalsopotentiallymakeanaphylaxismoredifficulttotreat.They
cancauseunopposedalphaadrenergiceffects,leadingtoparadoxicalhypertension,aswellasreducethe
bronchodilatorandcardiovascularresponsestobetaadrenergicstimulationbyendogenousorexogenous
epinephrine[46].(See'Glucagonforpatientstakingbetablockers'below.)
Alphaadrenergicblockersmaydecreasetheeffectsofendogenousorexogenousepinephrineatalpha
adrenergicreceptors,potentiallymakinganaphylaxislessresponsivetothealphaadrenergiceffectsof
epinephrine[44].
ACEinhibitorsareofparticularimportanceinregardstopatientswhohaveexperiencedanaphylaxisto
Hymenopteravenom[45,46].Theynotonlyblocktheeffectofangiotensin,acompensatoryresponse,but
alsoblockthedegradationofkininswhichareactiveintheproductionofsymptomsandsigns.
Inanemergencydepartment(ED)study,useofantihypertensivemedicationsinaggregate(betablockers,
ACEinhibitors,calciumchannelblockers,angiotensinreceptorblockers,ordiuretics)bypatientswith
anaphylaxiswasassociatedwithincreasedorgansysteminvolvementandincreasedoddsofhospital
admission,independentofage,gender,suspectedtrigger,orpreexistinglungdisease[47].
LABORATORYTESTSTheclinicaldiagnosisofanaphylaxiscansometimesbesupportedbydocumentation
ofelevatedconcentrationsofserumorplasmatotaltryptaseorplasmahistamine[38,4851].Itiscriticaltoobtain
bloodsamplesformeasurementofthesemastcellandbasophilmediatorssoonaftertheonsetofsymptoms
becauseelevationsaretransient.Instructionsforpropercollectionofsamplesareprovidedinthetable(table6).
SerumorplasmatotaltryptaseThestandardizedassayformeasurementoftotalserumorplasma
tryptaseiswidelyavailableinclinicallaboratories(normalrange1to11.4ng/mL,ThermoFisherScientific).
Ininfantsunderagesixmonths,normalbaselinetotaltryptaseconcentrationsarehigherthantheyarein
olderinfants,children,andadults[49,52].Optimally,thebloodsamplefortryptasemeasurementneedstobe
obtainedfrom15minutesto3hoursofsymptomonset.
Tryptaseelevationsaremorelikelytobedetectedinanaphylaxisfromstinginginsectvenomsormedications
andduringreactionsthatinvolvehypotension[48].
Atryptaselevelthatiswithinnormallimitscannotbeusedtorefutetheclinicaldiagnosisofanaphylaxis
[38].Thehistorytrumpsthetestresults.Asanexample,inindividualswithfoodinducedanaphylaxis,orin
patientswhoarenormotensive,tryptaselevelsareseldomelevated,eveninoptimallytimedbloodsamples
obtainedwithin15minutesto3hoursofsymptomonset[26].
Serialmeasurementsoftotaltryptaseinserumorplasmaoverseveralhoursmayincreasethesensitivity
andthespecificityofthetests.Inaprospectivestudy,sequentialserumtryptaseconcentrationswere
measuredin102adultswithanaphylaxis[53].Tryptaselevelsonetotwohoursafteronsetoftheepisode
weresignificantlyelevated(19.315.4mcg/L),comparedwithlevelsatfourtosixhoursandat12to24
hoursaftertheonset,andatbaseline(all<11.4mcg/L).However,tryptasewasnotelevatedin37percentof
cases.(See"Laboratoryteststosupporttheclinicaldiagnosisofanaphylaxis"and"Anaphylaxis:Confirming
thediagnosisanddeterminingthetrigger(s)".)
Ifatryptaselevelobtained24ormorehoursafterresolutionofclinicalsymptomsandsignsisstillelevated,
thepatientshouldbereferredtoanallergy/immunologyspecialistforevaluationofpossiblesystemic
mastocytosisormastcellactivationsyndrome.(See"Mastocytosis(cutaneousandsystemic):
Epidemiology,pathogenesis,andclinicalmanifestations".)
PlasmahistaminePlasmahistaminelevelstypicallypeakwithin5to15minutesoftheonsetof
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anaphylaxissymptoms,andthendeclinetobaselineby60minutesduetorapidmetabolismbyN
methyltransferaseanddiamineoxidase.Elevatedplasmahistaminelevelscorrelatewithanaphylaxis
symptomsandsignsandaremorelikelytobeincreasedthanaretotalserumtryptaselevels[51].(See
"Laboratoryteststosupporttheclinicaldiagnosisofanaphylaxis".)
Measurementofthismediatormaybeusefulincasesofanaphylaxisoccurringinahospitalsettinginwhich
bloodsamplescanbecollectedsoonaftertheonsetofsymptoms.Inmanycasesofanaphylaxisinthe
community,however,itisnotpracticaltomeasurehistaminebecausetypicallybythetimethepatient
reachestheemergencydepartment(ED),levelshavereturnedtobaseline[38,48].
Histamineshouldbemeasuredinplasma,notserum,becauseclottingmayresultinreleaseofhistamine
thatisartifactualandonlyoccursexvivoduetocompromisedbasophilcellmembranes.Bloodsamplesfor
histaminerequirespecialhandling:drawbloodthroughawideboreneedle,keepitcoldatalltimes,
centrifugeitimmediately,andfreezetheplasmapromptly[38].(See"Laboratoryteststosupporttheclinical
diagnosisofanaphylaxis".)
Histamineandhistaminemetabolitescansometimesbedetectedintheurinefollowinganaphylaxisand
elevationsarelessfleetingthanelevationsinplasmahistamine.However,a24hoururinecollectionstarted
assoonaspossibleafterthereactionbeginsisrequired.Thisisdiscussedseparately.(See"Laboratory
teststosupporttheclinicaldiagnosisofanaphylaxis",sectionon'Histaminemetabolites'.)
PotentialfuturetestsThedevelopmentofarapid,sensitive,specificlaboratorytestorpanelofteststhat
helpsclinicianstoconfirmthediagnosisofanaphylaxisinrealtimeremainsanimportantgoal[17,38].
Alaboratorytestformaturebetatryptase,abettermarkerofmastcellactivationthantotaltryptase(which
measuresconstitutivelysecretedalphatryptaseinadditiontobetatryptase)hasbeendeveloped,althoughit
isnotwidelyavailable[17].Testingformaturebetatryptaseisreviewedseparately.(See"Laboratorytests
tosupporttheclinicaldiagnosisofanaphylaxis"and"Anaphylaxis:Confirmingthediagnosisanddetermining
thetrigger(s)".)
Otherpotentialmarkersofmastcelland/orbasophildegranulation,suchasplateletactivatingfactor,mast
cellcarboxypeptidaseA3,chymase,andbasogranulinareunderinvestigation[38,51,5456].
DIFFERENTIALDIAGNOSISApproximately40otherdiseasesandconditionsmightneedtobeconsideredin
thedifferentialdiagnosisofanaphylaxis(table7)[50,5763].Themostcommondisordersinthedifferential
diagnosisincludeacutegeneralizedurticariaand/orangioedema,acuteasthmaexacerbations,syncope/faint,and
anxiety/panicattacks.Thesearereviewedindetailelsewhere.(See"Differentialdiagnosisofanaphylaxisin
childrenandadults"and"Anaphylaxisinpregnantandbreastfeedingwomen",sectionon'Differentialdiagnosis'
and"Anaphylaxisininfants",sectionon'Differentialdiagnosis'.)
IMMEDIATEMANAGEMENTThetablesproviderapidoverviewsoftheinitialassessmentandemergency
managementofanaphylaxisinadults(table8)andchildren(table9).
Promptassessmentandtreatmentarecriticalinanaphylaxis,asrespiratoryorcardiacarrestanddeathcanoccur
withinminutes[15,2633].Thecornerstonesofinitialmanagementarethefollowing[6469]:
Removaloftheincitingantigen,ifpossible(eg,stopinfusionofasuspectmedication).
Callforhelp(summonaresuscitationteaminahospitalsetting,orcall911oranequivalentemergency
medicalservicesnumberinacommunitysetting).
Intramuscularinjectionofepinephrine.
Placementofthepatientinthesupinepositionwiththelowerextremitieselevated,orifdyspneicorvomiting,
placementofthepatientsemirecumbentwithlowerextremitieselevated.
Supplementaloxygen.
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Volumeresuscitationwithintravenousfluids.
Inaseriesof164fatalitiesduetoanaphylaxis,themediantimeintervalbetweenonsetofsymptomsand
respiratoryorcardiacarrestwas5minutesiniatrogenicanaphylaxis,15minutesinstinginginsectvenominduced
anaphylaxis,and30minutesinfoodinducedanaphylaxis[15].Amoredetailedreviewoffatalanaphylaxisis
presentedelsewhere.(See"Fatalanaphylaxis".)
InitialassessmentAnumberofcriticalcomponentsintheinitialmanagementneedtobeinstituted
concomitantly[2024]:
Initially,attentionshouldfocusonairway,breathing,andcirculation,aswellasadequacyofmentation.The
skinshouldbeexamined.
Epinephrineshouldbeinjectedintramuscularlyintothemidouteraspectofthethigh(table8andtable9)[65
72].Ifsymptomsaresevere,anintravenousepinephrineinfusionshouldbeprepared.(See'Dosingand
administration'below.)
Thepatientshouldbeplacedintherecumbentpositionwiththelowerextremitieselevatedtomaximize
perfusionofvitalorgans.Thisalsohelpspreventthe"emptyventriclesyndrome,"inwhichsevere
hypotensionleadstoinadequatecardiacfillingandpulselesscardiacactivity.Inthissyndrome,deathcan
occurwithinseconds[69].Individualswithrespiratorydistressorvomitingmaynottoleratetherecumbent
positionandshouldbeplacedinapositionofcomfort,withlowerextremitieselevated.Emptyventricle
syndromeisdiscussedingreaterdetailseparately.(See"Fatalanaphylaxis".)
Supplementaloxygen,8to10litersbyfacemask,upto100percent,shouldbeadministered.
Twolargeboreintravenouscatheters(ideally14to16gaugesformostadults)shouldbeinsertedin
preparationforrapidadministrationoffluidsandmedications.
Innormotensiveadults,isotonic(0.9percent)salineshouldbeinfusedatarateof125mLperhourto
maintainvenousaccess.Innormotensivechildren,isotonicsalineshouldbeinfusedatanappropriate
maintenancerateforweightinordertomaintainvenousaccess.(See"Maintenancefluidtherapyin
children".)
Continuouselectronicmonitoringofcardiopulmonarystatus,includingbloodpressure(BP),heartrate,and
respiratoryrate,andmonitoringofoxygensaturationbypulseoximetryisrequiredforthedurationofthe
episode.
AirwaymanagementAsnotedabove,theinitialstepsinanaphylaxismanagementinvolvearapidassessment
ofthepatient'sairway[2024]:
Intubationshouldbeperformedimmediatelyifmarkedstridororrespiratoryarrestispresent.
Preparationsforpossibleintubationshouldbemadeifthereisanyairwayinvolvementorsignificantedema
ofthetongue,facial,ornecktissues.
Inaminorityofcases,anemergencycricothyroidotomymayberequiredtosecuretheairway.
Intubationmaybedifficultinindividualsinwhomedemadistortstheupperairwayanatomicallandmarks.Failed
attemptscanleadtocompleteairwayobstructionandfatality.Therefore,upperairwayclosureinthesettingof
anaphylaxisshouldbemanagedbythemostexperiencedclinicianavailable.Thismayrequireimmediate
collaborationbetweenanemergencymedicinespecialistandananesthesiologist,otolaryngologist,orintensivist
withtrainingandexperienceinthemanagementofthedifficultairway.Hospitalsandotherhealthcarefacilities
shouldhaveclearwrittenpoliciesabouthowsuchsituationswillbehandled.
IntravenousfluidsIntravenousaccessshouldbeobtainedincasefluidresuscitationisrequired.Massivefluid
shiftscanoccurrapidlyinanaphylaxisduetoincreasedvascularpermeability,withtransferofupto35percentof
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theintravascularvolumeintotheextravascularspacewithinminutes[65].Anypatientwhosehypotensiondoes
notrespondpromptlyandcompletelytoinjectedepinephrineshouldbeassumedtohaveintravascularvolume
depletioncausingpersistenthypotensiondespitemaximumvasoconstriction.Thesepatientsshouldreceivelarge
volumefluidresuscitation[2024].Thefollowingprinciplesshouldguidetherapy:
Fluidresuscitationshouldbeinitiatedimmediatelyinpatientswhopresentwithorthostasis,hypotension,or
incompleteresponsetointramuscularepinephrine.
Adultsshouldreceive1to2litersofnormalsalineatarateof5to10mL/perkilograminthefirstminutesof
treatment.Largevolumesoffluid(eg,upto7liters)mayberequired.
Childrenshouldreceivenormalsalineinbolusesof20mLperkilogram,eachover5to10minutes,and
repeatedasneeded.Largevolumesoffluid(upto100mLperkilogram)mayberequired.
Normalsalineispreferredoverothersolutionsinmostsituationsbecauseothersolutionshavepotential
disadvantages:
LactatedRinger'ssolutioncanpotentiallycontributetometabolicacidosis.
Dextroseisrapidlyextravasatedfromthecirculationintotheinterstitialtissues.
Colloidsolutions(eg,albuminorhydroxyethylstarch)confernosurvivaladvantageinpatientswith
distributiveshockandaremorecostly[73].
Patientsshouldbemonitoredcarefullyandcontinuouslyforclinicalresponseandforvolumeoverload.(See
"Treatmentofseverehypovolemiaorhypovolemicshockinadults"and"Hypovolemicshockinchildren:Initial
evaluationandmanagement".)
PregnantwomenAdditionalprecautionsandconsiderationsareimportantinthemanagementofanaphylaxisin
pregnantwomen.Forexample,duringlaboranddelivery,positioningofthepatientonherleftside,providinghigh
flowsupplementaloxygen,andmaintainingasystolicBPofatleast90mmHg,aswellascontinuousfetal
monitoring,arecriticallyimportant[21].(See"Anaphylaxisinpregnantandbreastfeedingwomen",sectionon
'Management'.)
PHARMACOLOGICTREATMENTSInhumansexperiencinganaphylaxis,randomized,placebocontrolled
trialsthatmeetcurrentstandardshavenotyetbeenperformedforanypharmacologicintervention.Epinephrineis
thebeststudiedmedicationinanaphylaxis.Theevidenceforitsusecomesfromobservationalstudiesduring
anaphylaxis,randomizedcontrolledclinicalpharmacologystudiesatbaseline,studiesofanaphylaxisinanimal
models,andepidemiologicstudies,includingfatalitystudies.TheevidenceforuseofH1antihistaminesin
anaphylaxisisextrapolatedfromtheiruseinurticaria.Theevidencefortheuseofbeta2adrenergicagonistsand
glucocorticoidsinanaphylaxisisextrapolatedfromtheiruseinacuteasthma.
Inthefuture,itispossiblethatrandomizedcontrolledtrialswillbeconductedinanaphylaxiswithglucocorticoids,
H1antihistamines,orH2antihistamineshowever,placebocontrolledtrialswithepinephrinewillneverbe
performed,duetoethicalconsiderations.Anaphylaxiscankillwithinminutes[15,2631]anddelayedepinephrine
injectionisassociatedwithfatalities[72,7478].
EpinephrineEpinephrineisthedrugofchoiceforanaphylaxis.Thepharmacologicactionsofthisagent
addressthepathophysiologicchangesthatoccurinanaphylaxisbetterthananyothermedication.Itdecreases
mediatorreleasefrommastcells[79].Moreover,itistheonlymedicationthatpreventsorreversesobstructionto
airflowintheupperandlowerrespiratorytractsandpreventsorreversescardiovascularcollapse(table8andtable
9).
TherapeuticactionsandadverseeffectsThetherapeuticactionsofepinephrineincludethefollowing(table
10)[66,72,7578,80]:
Alpha1adrenergicagonisteffectsIncreasedvasoconstriction,increasedperipheralvascularresistance,
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anddecreasedmucosaledema(eg,intheupperairway).
Beta1adrenergicagonisteffectsIncreasedinotropyandincreasedchronotropy.
Beta2adrenergicagonisteffectsIncreasedbronchodilationanddecreasedreleaseofmediatorsof
inflammationfrommastcellsandbasophils.
Inpatientsofallages,epinephrineadministeredintherapeuticdosesbyanyrouteoftencausesmildtransient
pharmacologiceffects,suchasanxiety,restlessness,headache,dizziness,palpitations,pallor,andtremor
[66,77,78,80].Thesesymptomsandsignsaresimilartothoseoccurringduringthephysiologic"fightorflight"
responseduetoendogenousepinephrinethatoccursnormallyinsuddenfrighteningorlifethreateningsituations.
Rarely,andespeciallyafteroverdose,epinephrinemayleadtoventriculararrhythmias,angina,myocardial
infarction,pulmonaryedema,suddensharpincreaseinbloodpressure(BP),andintracranialhemorrhage.Serious
adverseeffectsoccurmostcommonlyafteranintravenousbolusinjectionoranoverlyrapidintravenousinfusion
particularlyinpatientswhodonothavecontinuouselectronicmonitoringofBPandheartrateandfunction.They
alsooccuraftererroneousintravenousinjectionofa1mg/mLepinephrinesolutioninsteadofanappropriately
diluted0.1mg/mLor0.01mg/mLepinephrinesolution[72,77,81].(See'Situationsrequiringcaution'below.)
Anaphylaxisitselfcanleadtoangina,myocardialinfarction,andcardiacarrhythmiasintheabsenceofany
exogenousepinephrineorbeforeexogenousepinephrineisadministered[82].
DosingandadministrationConfusionpersistsamongcliniciansregardingtheoptimalepinephrinedose
androuteofadministrationfortheinitialtreatmentofanaphylaxis[81].
IntramuscularinjectionIntramuscularinjectionisrecommendedoversubcutaneousinjectionbecauseit
consistentlyprovidesamorerapidincreaseintheplasmaandtissueconcentrationsofepinephrine[67,68].
Epinephrineiscommerciallyavailableinseveraldilutionsandgreatcaremustbetakentousethecorrect
dilution[2024].Theepinephrinedilutionforintramuscularinjectioncontains1mgpermLandmayalsobe
labeledas1:1000.
Foradults,therecommendeddoseofepinephrine(1mgpermL)is0.3to0.5mgpersingledose,injected
intramuscularlyintothemidouterthigh(vastuslateralismuscle).Basedonclinicalexperienceand
consensusopinion,thisdosemayberepeatedat5to15minuteintervals[2123,80].
Forinfantsandchildren,therecommendeddoseofepinephrine(1mgpermL)is0.01mgperkilogram.The
doseshouldbedrawnupusinga1mLsyringe.Largechildrenweighing50kgormorecanreceiveuptoa
maximumof0.5mgperdose.Epinephrineshouldbeinjectedintramuscularlyintothemidouterthigh(vastus
lateralismuscle).Ifthereisnoresponseoriftheresponseisinadequate,theinjectioncanberepeatedin5to
15minutes[66,72,83].
Epinephrinecanalsobeadministeredintothemidouterthighusinganautoinjector.Theseareavailableonly
in0.15mgand0.3mgdoses.Childrenweighinglessthan25kilogramsshouldreceivethe0.15mgdose
[66]:
TheadultdoseisAuviQ0.3mg,EpiPen0.3mg,Jext0.3mg,orotherautoinjectorsasavailable,
includingEmerade0.5mgandAdrenaclick.AuviQiscalledAllerjectinCanada.
ThepediatricdoseisAuviQ0.15mg,EpiPenJr0.15mg,Jext0.15mg,orother,includingEmerade
0.15mgor0.3mgandAdrenaclick.
Theneedleusedinadultsandchildrenshouldbelongenoughtopenetratethesubcutaneousadiposetissue
overthevastuslateralismuscle.Realistically,however,intramuscularinjectionintothethighmaybe
impossibleinsomepatients,especiallythosewhoareoverweightorobese[84,85].Althoughthebest
approachinthissituationhasnotbeenstudied,wesuggestasdeepaninjectionaspossibleintothemuscle.
ResponsetointramuscularepinephrineMostpatientsrespondtoasingledoseofintramuscular
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epinephrine,particularlyifitisgivenpromptlyaftertheonsetofsymptoms.Whenadditionalintramuscular
dosesarerequired,typicallyoneorrarelytwoadditionaldosesareneeded(eg,inpatientswithsevere
anaphylaxisandthosewhocannotaccessemergencycarepromptly)[86,87].Inpatientswhoarenot
respondingtoinitialintramuscularepinephrine,intravascularfluidstatusshouldbeassessedcarefullybefore
progressingtointravenousepinephrineorotherinterventions.
IntravenousinfusionandindicationsPatientswhodonotrespondtoseveralintramuscularinjectionsof
epinephrineandaggressivefluidresuscitationmaynotbeadequatelyperfusingmuscletissues,asmost
commonlyoccursinindividualspresentingwithprofoundhypotensionorsymptomsandsignssuggestiveof
impendingshock(dizziness,incontinenceofurineand/orstool).
SuchpatientsshouldreceiveepinephrinebySLOWintravenousinfusion,withtheratetitratedaccordingto
responseandthepresenceofcontinuouselectronichemodynamicmonitoring.Slowcontinuousinfusionis
preferredoveranintravenousbolusdoseasthelatterisassociatedwithmoredosingerrorsandmore
adverseeffects[22,72,88].Anintravenousinfusionofepinephrineshouldpreferablybegivenbyclinicians
whoaretrained,skilled,andexperiencedinitsuseandcantitratetherateofinfusion(andthereforethe
epinephrinedose)usingcontinuousnoninvasivemonitoringofbloodpressure(BP),heartrate,andfunction.
Asnotedabove,epinephrineiscommerciallyavailableinseveraldilutions.Greatcaremustbetakentouse
thecorrectdilutioninordertoavoidoverdosingthepatient[81].Toprepareanepinephrineintravenous
maintenanceinfusionforuseinaperfusingpatient,thecommerciallyavailableepinephrinesolution(eg,
ampule,syringe)mustbefurtherdiluted.
Weuseadilutionof4microgramspermLinadultsandadolescents(1mgin250mL5percentdextrose
water)and10microgramspermLinchildrenandinfants(1mgin100mL5percentdextrosewater).Note:
Institutionalprotocolsfordilutionmayvary.
Initialinfusionrates:
Foradults,theinitialdoseforintravenousepinephrineinfusionis2to10microgramsperminutewith
useofaninfusionpump,titratedtoeffectonBPwithcontinuousnoninvasivemonitoring[20].
Forinfantsandchildren,thedoseforintravenousinfusionofepinephrineis0.1to1microgramper
kilogramperminutewithuseofaninfusionpump,titratedtoeffectonBPwithcontinuousnoninvasive
monitoring.
Epinephrineisavesicantandcentrallineadministrationispreferred.Whenapatientdoesnothavea
centralvenouscatheter,epinephrinecanbetemporarilyadministeredthroughanappropriately
positionedperipheralvenouscatheteruntilacentralvenouscatheterisinserted.Closelymonitor
cathetersitethroughoutinfusiontoavoidextravasationinjury.
Toreducetheriskofmakingamedicationerror,wesuggestthatcentershaveavailableaprotocolthat
includesstepsonhowtoprepareandadministerepinephrineinfusion.Examplesofadult(table11)and
pediatricinfusions(table12andtable13)areprovided.
EfficacySeveralcaseserieshaveimplicatedthefailuretoadministerepinephrineearlyinthecourseof
treatmentasaconsistentfindinginanaphylaxisdeaths[15,2631,89].
Inaseriesof13fatalandnearfatalfoodinducedanaphylacticreactionsinchildrenandadolescents,thesix
patientswhodiedhadsymptomonsetwithinonetofiveminutesafteringestionoftheculpritfood,butdidnot
receivetheirfirstdoseofepinephrineuntil25,60,80,90,125,and180minutesafterthefoodwasingested.
Theauthorsconcludedthatthefailuretorecognizeseverityofthereactionsandtoadministerepinephrine
promptlyincreasedtheriskofafataloutcome[26].
Inaseriesofanaphylacticdeathsoccurringfrom1992to1998,only20percentof24patientsweregiven
epinephrineatanypointintheirtreatment[27].
http://www.uptodate.com.pbidi.unam.mx:8080/contents/anaphylaxisrapidrecognitionandtreatment?topicKey=ALLRG%2F392&elapsedTimeMs=1&source
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Inthefatalityseriesdescribedpreviously,only14percentofthe164patientsdyingfromanaphylaxis
receivedepinephrinebeforerespiratoryorcardiacarrest,although62percentofthe164patientseventually
receiveditbeforedemise[15].
Inaddition,anaphylaxisoccurringduringevaluationofvenomimmunotherapyhasbeeninvestigatedprospectively.
Inonestudy,68patientswithahistoryofanaphylaxistoinsectstingswererandomlyassignedtovenom
immunotherapyorplaceboimmunotherapy[65].Followingthis,allwerestunginacontrolled,monitoredsetting
andtreatedifneededwithastandardizedprotocolofhighflowoxygen,epinephrineinfusion,andnormalsaline
rapidinfusion.Nineteenofthe21patientsintheplacebogroupdevelopedanaphylaxisandreceivedepinephrine.
Symptomsrespondedwithinfiveminutesinallbutonepatient.Inninepatients,aninitialattempttostopthe
epinephrineinfusionwasfollowedbyareturnofsymptoms,whichsubsidedagainoncetheepinephrineinfusion
wasrestarted.
Finally,thereisextensiveclinicalexperienceamongallergypractitionerswithgivingepinephrinetotreat
anaphylaxisoccurringinresponsetoimmunotherapy.Thisisauniquesituation,becauseallergyclinicstaff
observepatientscloselyforthesymptomsandsignsofanaphylaxisandreactionsaredetectedatveryearly
stages.Overthepastfewdecades,consensushasbeenreachedthatevenmildsystemicreactionsarebest
treatedimmediatelywithepinephrine,asthisappearstopreventprogressiontomoreseveresymptomsmore
effectivelythananyotheravailabletherapies.Asaresult,successiveguidelinesfortreatmentofimmunotherapy
reactionshavecalledforepinephrinetobegivenassoonasasystemicreactionofanyseverityisdetected[90].
Instudiesinwhichallormostpatientswhodevelopedanaphylaxisafterallergenimmunotherapyweretreated
promptlywithepinephrineinjections,symptomsweremildandnoadditionalinjectionsofepinephrineweregiven,
eveninthe10to23percentofreactionsthatwerebiphasic[91].
SituationsrequiringcautionThereareNOabsolutecontraindicationstoepinephrineuseinanaphylaxis
[2024,72,7578,80].
Subgroupsofpatientsmighttheoreticallybeathigherriskforadverseeffectsduringepinephrinetherapy.Formal
riskbenefitanalysesarenotpossible.
Patientswithcardiovasculardiseases:Reluctancetoadministerepinephrineduetofearofadversecardiac
effectsshouldbecounteredbytheawarenessthattheheartisatargetorganinanaphylaxis.Inthehealthy
humanheart,mastcellsarepresentthroughoutthemyocardiumandintheintimaofcoronaryarteries.In
patientswithcoronaryarterydisease,mastcellsarefoundinatheroscleroticlesionsandcontributeto
atherogenesis.Anaphylaxiscanunmasksubclinicalcoronaryarterydisease,andmyocardialinfarctionand/or
arrhythmiascanoccurduringanaphylaxis,evenifepinephrineisnotinjected[43,92].Moreover,anaphylaxis
itselfcancausevasospasm,arrhythmias,andmyocardialinfarctioninpatients,includingchildren,with
healthyheartsasconfirmedbynormalelectrocardiograms,echocardiograms,andcoronaryangiogramsafter
resolutionofanaphylaxis[93].
Patientsreceivingmonoamineoxidaseinhibitors(whichblockepinephrinemetabolism)ortricyclic
antidepressants(whichprolongepinephrinedurationofaction).
Patientswithcertainpreexistingconditions,suchasrecentintracranialsurgery,aorticaneurysm,
uncontrolledhyperthyroidismorhypertension,orotherconditionsthatmightplacethemathigherriskfor
adverseeffectsrelatedtoepinephrine.
Patientsreceivingstimulantmedications(eg,amphetaminesormethylphenidateusedinthetreatmentof
attentiondeficithyperactivitydisorder)orabusingcocainethatmightplacethemathigherriskforadverse
effectsfromepinephrine.
Toreiterate,therearenoabsolutecontraindicationstotheuseofepinephrineinthetreatmentofanaphylaxis.The
riskofdeathorseriousneurologicsequelaefromhypoxicischemicencephalopathyduetoinadequatelytreated
anaphylaxisusuallyoutweighsotherconcerns[2024,72,7578,80].Existingevidenceclearlyfavorsthebenefitof
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epinephrineadministrationinanaphylaxis.Soundclinicaljudgmentisessential.
GlucagonforpatientstakingbetablockersPatientsreceivingbetablockersmayberesistanttotreatment
withepinephrineandcandeveloprefractoryhypotensionandbradycardia.Inthissituation,glucagonshouldbe
administeredbecauseithasinotropicandchronotropiceffectsthatarenotmediatedthroughbetareceptors[94].A
doseof1to5mginadults(inchildren,20to30microgramsperkilogramtoamaximumof1mg)administered
intravenouslyoverfiveminutesisrecommended.Thisdosemayberepeatedorfollowedbyaninfusionof5to15
microgramsperminute.Rapidadministrationofglucagoncaninducevomiting.Therefore,protectionoftheairway,
forexample,byplacementinthelateralrecumbentposition,isimportantindrowsyorobtundedpatients.
AdjunctiveagentsAgentsthatmaybegivenasadjunctivetherapiestoepinephrineinthetreatmentof
anaphylaxisincludeH1antihistamines,H2antihistamines,bronchodilators,andglucocorticoids.Noneofthese
medicationsshouldbeusedasinitialtreatmentorassoletreatmentbecausetheydonotrelieveupperorlower
respiratorytractobstruction,hypotension,orshockandarenotlifesaving.
H1antihistaminesEpinephrineisfirstlinetreatmentforanaphylaxisandthereisnoknownequivalent
substitute.Asystematicreviewoftheliteraturehasfailedtoretrieveanyrandomizedcontrolledtrialsthatmeet
currentstandardsandsupporttheuseofH1antihistaminesinanaphylaxis[74].
Despitethis,H1antihistaminesarethemostcommonlyadministeredmedicationsinthetreatmentofanaphylaxis.
Thissuggestsoverrelianceontheseagents,whichshouldbeconsideredadjunctivetoepinephrineforthepurpose
ofrelievingitchingandhives[9598].
H1antihistaminesrelieveitchandhives.ThesemedicationsDONOTrelieveupperorlowerairway
obstruction,hypotensionorshock,andinstandarddoses,donotinhibitmediatorreleasefrommastcellsand
basophils.Itisprobablethattheimprovementinnoncutaneoussymptomsthatissometimesattributedto
antihistaminetreatmentoccursinsteadbecauseofendogenousproductionofepinephrineandother
compensatorymediators,includingothercatecholamines,angiotensinII,andendothelinI[19].Inaddition,
theonsetofactionofantihistaminessuchascetirizineordiphenhydraminetakes30to40minutesandistoo
slowtoprovideanyimmediatebenefit[99].H1antihistaminesadministeredintravenouslymayincrease
hypotension[100].
Forparenteraltreatment,onlyfirstgenerationagentsareavailable:
Foradults,considerdiphenhydramine25to50mgintravenously,whichmayberepeateduptoamaximum
dailydoseof400mgper24hours.
Forchildrenweighinglessthan40kg,considerdiphenhydramine1mgperkg(maximum40mg)
intravenously,whichmayberepeateduptoamaximumdailydoseof5mgperkgor200mgper24hours.
Fororaltreatment,secondgenerationH1antihistamines(eg,cetirizine)offercertainadvantagesoverfirst
generationagents(eg,diphenhydramine,chlorpheniramine,hydroxyzine,andpromethazine).Secondgeneration
H1antihistaminesarelesslikelytoimpaircognitionorpsychomotorperformance(eg,theabilitytodrivesafely),or
tocausesedation[74,78,101].Orallyadministeredcetirizineactswithin30to40minutes.However,second
generationH1antihistaminesarenotavailableinparenteralformulations.
H2antihistaminesAnH2antihistaminegivenwithanH1antihistaminemayprovidesomeadditionalrelief
ofitchandhives[102].
AlthoughH2antihistaminesaresometimesadministeredinanaphylaxistreatment,asystematicreviewdidnot
identifyanyrandomizedcontrolledtrialsthatsupporttheuseoftheseagentsinanaphylaxis[103].H2
antihistaminesDONOTrelieveupperorlowerairwayobstructionorshock.Moreover,asystematicreviewhasnot
identifiedrandomizedcontrolledtrialsthatsupporttheuseofH2antihistaminesinurticaria[104].
Ifused,ranitidine(50mginadults)(12.5to50mg[1mgperkilogram]inchildren),maybedilutedin5percent
dextrosetoatotalvolumeof20mLandinjectedintravenouslyoverfiveminutes.Rapidinfusionofcimetidinecan
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causehypotension.
BronchodilatorsForthetreatmentofbronchospasmnotresponsivetoepinephrine,inhaledbronchodilators,
suchasalbuterolshouldbeadministeredbyfacemaskandnebulizer/compressorasneeded.Theyareadjunctive
treatmenttoepinephrinebecausetheydonotpreventorrelievemucosaledemaintheupperairwayorshock,for
whichthealpha1adrenergiceffectsofepinephrinearerequired[2024].
GlucocorticoidsTheonsetofactionofglucocorticoidstakesseveralhours.Therefore,thesemedications
donotrelievetheinitialsymptomsandsignsofanaphylaxis.Therationaleforgivingthemistopreventthe
biphasicorprotractedreactionsthatoccurinsomecasesofanaphylaxis.However,asystematicreviewofthe
literaturefailedtoretrieveanyrandomizedcontrolledtrialsinanaphylaxisthatconfirmedtheeffectivenessof
glucocorticoids[105].
Ifgiven,adoseofmethylprednisoloneof1to2mgperkilogramperdayissufficient.Ifglucocorticoidtreatmentis
instituted,itcanbestoppedafteroneortwodayswithoutataper,sinceallbiphasicreactionsreportedtodate
haveoccurredwithin72hours.(See'Timecourse'above.)
RefractoryanaphylaxisAdmissiontoanintensivecareunitshouldoccurwithoutdelay.Therearenopublished
prospectivestudiesontheoptimalmanagementofrefractoryanaphylaxis.
Anaphylacticshockdisplaysfeaturesofbothdistributive(vasodilatory)andhypovolemicshock.Themanagement
ofsevereformsofthesetypesofshockisdiscussedseparately.(See"Systemicinflammatoryresponse
syndrome(SIRS)andsepsisinchildren:Definitions,epidemiology,clinicalmanifestations,anddiagnosis"and
"Hypovolemicshockinchildren:Initialevaluationandmanagement"and"Evaluationandmanagementofsevere
sepsisandsepticshockinadults",sectionon'Vasopressors'and"Treatmentofseverehypovolemiaor
hypovolemicshockinadults".)
Onetheoryaboutthepathogenesisofrefractoryanaphylaxisproposesthattheclinicalmanifestationsmay
becomerefractorytofurthercatecholamineadministration,perhapsduetosaturationordesensitizationof
adrenergicreceptors[106].Theuseofnonadrenergicvasopressors,suchasvasopressin,inthemanagementof
anaphylaxisrefractorytointravenousepinephrineinadultsisdiscussedelsewhere.(See"Useofvasopressors
andinotropes",sectionon'Vasopressinandanalogs'.)
Vasoplegia(profoundvasodilation)maybepresentinsomecasesofrefractoryanaphylaxis.Afewcasereports
andotherpublicationssupporttheuseofmethyleneblue,aninhibitorofnitricoxidesynthaseandguanylate
cyclase,insevereanaphylaxis[107,108].Theidealdoseofmethyleneblueisunknown,butasinglebolusof1to
2mg/kghasbeenused.Thisdrugshouldnotbegiventopatientswithpulmonaryhypertension,underlying
glucose6phosphatedehydrogenasedeficiency(G6PD),oracutelunginjury.Wealsoadvisecautionregarding
potentialdruginteractionswithserotonergicagents.(See"Postoperativecomplicationsamongpatientsundergoing
cardiacsurgery",sectionon'Vasodilatoryshock'.)
TREATMENTERRORSImportanterrorsinthetreatmentofanaphylaxisincludefailuretoadminister
epinephrinepromptlyanddelayinepinephrineinjectionduetooverrelianceonantihistamines,albuterol
(salbutamol),andglucocorticoids.(See'Adjunctiveagents'above.)
Epinephrineshouldbeadministeredassoonaspossibleonceanaphylaxisisrecognized.Delayed
administrationhasbeenimplicatedincontributingtofatalities[15,2631,89].Asnotedabove,astudyof13
fatalornearfatalfoodinducedanaphylacticreactionsinchildrenreportedthatsixofthesevenchildrenwho
survivedreceivedepinephrinewithin30minutesofingestingtheallergen,whereasonlytwoofthesix
childrenwhodiedreceivedepinephrinewithinthefirsthour[26].
H1antihistaminesareusefulforrelievingitchingandurticaria,asmentionedpreviously.TheydoNOTrelieve
stridor,shortnessofbreath,wheezing,gastrointestinalsymptomsandsigns,hypotensionorshock,and
shouldnotbesubstitutedforepinephrine[20,21,24,74,101].
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Bronchodilatortreatmentwithnebulizedalbuterolshouldbegiveninindividualswithseverebronchospasm,
asanadjunctivetreatmenttoepinephrine.However,albuteroldoesNOTpreventorrelieveupperairway
edema,hypotension,orshock,andshouldnotbesubstitutedforepinephrineinthetreatmentofanaphylaxis.
Glucocorticoidstheoreticallyreducethelatephaseresponse.However,theyhavenotbeenproventoprevent
orreducebiphasicorprotractedanaphylaxis.Theydonotrelievetheinitialsymptomsofanaphylaxis.
CAREUPONRESOLUTIONToreducetheriskofrecurrence,patientswhohavebeensuccessfullytreatedfor
anaphylaxissubsequentlyrequireconfirmationoftheanaphylaxistriggeraswellasanaphylaxiseducation.(See
"Anaphylaxis:Confirmingthediagnosisanddeterminingthetrigger(s)"and"Longtermmanagementofpatients
withanaphylaxis".)
ObservationThereisnoconsensusregardingtheoptimalobservationperiodforapatientwhohasbeen
successfullytreatedforanaphylaxisinahealthcarefacility.Wesuggestthefollowing:
Patientswithmoderateanaphylaxiswhodonotrespondpromptlytoepinephrineandallpatientswithsevere
anaphylaxisshouldbeadmittedtoanobservationunitortoahospital.
Forpatientswithanaphylaxisthatresolvedpromptlyandcompletelywithtreatment,wesuggestaminimum
observationperiodofafewhours,andpreferaperiodof8to10hours,ifpossible.Wealsosuggestthatif
patientsaresenthomeafteronlyafewhours,theyshouldbetrainedtouseanepinephrineautoinjectorand
shouldactuallybesuppliedwithone,ratherthansimplyhandedaprescriptionforone.Asnotedpreviously,
from4.5percentto23percentofpatientsmayexperienceabiphasicreaction[34].(See'Biphasic
anaphylaxis'above.)
DischargecareAllpatientswhohaveexperiencedanaphylaxisshouldbesenthomewithananaphylaxis
emergencyactionplan,oneormoreepinephrineautoinjectors,aplanforarrangingfurtherevaluation,andprinted
informationaboutanaphylaxisanditstreatment.
AnaphylaxisemergencyactionplanBeforedischarge,patientsshouldbegivenawrittenpersonalized
anaphylaxisemergencyactionplanthatliststhecommonsymptomsandsignsofanaphylaxisandcontains
informationaboutpromptrecognitionofanaphylaxisandselfinjectionofepinephrine(AnaphylaxisEmergency
ActionPlanEnglish)(AnaphylaxisEmergencyActionPlanSpanish)[19].
EpinephrineautoinjectorIdeally,patientsshouldbesuppliedwithanepinephrineautoinjectordirectly.
Instructionsintheproperuseofepinephrineautoinjectorsshouldbereviewedverballyandtheyshouldbegivena
DVDand/orwrittenmaterialanddirectedtoamanufacturer'swebsitevideoprovidingrelevantinformation(see
'Informationforpatients'below).Ifthisisnotpossible,theyshouldbeinstructedinhowtouseanepinephrine
autoinjectorcorrectly,providedwithaprescriptionforit,andadvisedtofilltheprescriptionimmediately.Ina
surveyof1885patientswhosurvivedanaphylaxis,28percentofthosewhodidnotinjectepinephrineduring
anaphylaxisreportedthattheyhadneverreceivedaprescriptionforanautoinjector[109].
CounselingThemnemonic"SAFE"wasdevelopedtoremindcliniciansofthefourbasicactionsteps
suggestedforpatientswithanaphylaxiswhohavebeentreatedandaresubsequentlyleavingtheemergency
department(ED)orhospital[110,111].Thesestepsare:Seeksupport,Allergenidentificationandavoidance,
Followupforspecialtycare,andEpinephrineforemergencies.TheSAFEcounselingisoutlinedbelowandhas
beenincorporatedintoprintablepatientinformationmaterials.(See'Informationforpatients'below.)
SeeksupportAdvisethepatientthat:
Theyhaveexperiencedanaphylaxisor"killerallergy,"whichisalifethreateningcondition.
Symptomsofthecurrentepisodemayrecur(withoutfurtherexposuretothetrigger)uptothreedays
aftertheinitialonsetofsymptoms.
Theyshouldselfinjectepinephrine,andcallemergencymedicalservicesorgettothenearest
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emergencyfacilityatthefirstsignofrecurrenceofsymptoms.
Theyareatriskforrepeatepisodesofanaphylaxisinthefuture.
Referthepatienttoresources.(See'Informationforpatients'below.)
AllergenidentificationandavoidanceBeforethepatientisdischarged,aneffortshouldbemadeto
confirmtheanaphylaxistriggersuspectedfromthepatient'shistory(bymeasuringspecificimmunoglobulinE
[IgE]totheallergenidentifiedbythehistory).Ifthepatienthasreceivedvolumeresuscitation,IgElevels
mightbefalselyabsentorundetectableduetothepotentialdilutionaleffectsoncirculatingIgE,anditmight
benecessarytorecheckthelevelsdaysorweeksaftertheanaphylacticepisode.
Emphasizetheimportanceofsubsequentallergyskintestingtoconfirmthetrigger,sothatitcanbe
successfullyavoidedinthefuture.
Followupforspecialtycare
Advisethepatienttofollowupwithhisorherprimarycareclinicianandobtainareferraltoanallergist
ortoseekconsultationdirectlywithanallergistfortestingandongoingmanagement.
Comorbiditiessuchasasthma,otherchronicpulmonarydisease,andcardiovasculardiseaseshouldbe
optimallycontrolled.
Epinephrineforemergencies
Providethepatientwithanepinephrineautoinjectororwithaprescriptionforoneanddemonstrateproper
use.Inaddition,givethepatientwritteninformationabouthowtorecognizeanaphylaxisandhowtousean
epinephrineautoinjector,andprovidedirectionstoappropriatewebsitesforvideodemonstrationsof
autoinjectoruse.(See'Informationforpatients'below.)
Explaintheimportanceofcarryingtheepinephrineautoinjectoratalltimes.
Advisethepatienttomakesurethatfamilyandfriendsareawareoftherisksofanaphylaxis,the
triggers,andhowtoadministerepinephrine.Thecorrectinjectiontechniqueisimportanttoavoid
unintentionalinjectionintofingers,thumbs,orotherbodyparts[112].
LONGTERMPROGNOSISPatientswhohaveexperiencedanaphylaxisareatriskforrecurrentepisodes
unlesslongtermriskreductionmeasuresareimplemented[20,21].Specifically,thetriggerfortheanaphylactic
episodeshouldbeverified.Inaddition,anaphylaxiseducationisrequiredinordertohelppatientssuccessfully
avoidtheirconfirmedtrigger(s),andselfinjectepinephrinepromptlyandconfidentlyintheeventofarecurrent
anaphylacticepisode.Forthesereasons,patientswithanaphylaxisbenefitfromreferraltoanallergyspecialist.
INFORMATIONFORPATIENTSUpToDateofferstwotypesofpatienteducationmaterials,"TheBasics"and
"BeyondtheBasics."TheBasicspatienteducationpiecesarewritteninplainlanguage,atthe5thto6thgrade
readinglevel,andtheyanswerthefourorfivekeyquestionsapatientmighthaveaboutagivencondition.These
articlesarebestforpatientswhowantageneraloverviewandwhoprefershort,easytoreadmaterials.Beyond
theBasicspatienteducationpiecesarelonger,moresophisticated,andmoredetailed.Thesearticlesarewritten
atthe10thto12thgradereadinglevelandarebestforpatientswhowantindepthinformationandarecomfortable
withsomemedicaljargon.
Herearethepatienteducationarticlesthatarerelevanttothistopic.Weencourageyoutoprintoremailthese
topicstoyourpatients.(Youcanalsolocatepatienteducationarticlesonavarietyofsubjectsbysearchingon
"patientinfo"andthekeyword(s)ofinterest.)
Basicstopics(see"Patientinformation:Anaphylaxis(TheBasics)"and"Patientinformation:Epinephrine
autoinjectors(TheBasics)")
BeyondtheBasicstopics(see"Patientinformation:Anaphylaxissymptomsanddiagnosis(Beyondthe
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Basics)"and"Patientinformation:Anaphylaxistreatmentandpreventionofrecurrences(BeyondtheBasics)"
and"Patientinformation:Useofanepinephrineautoinjector(BeyondtheBasics)")
OthersourcesofaccuratepatientinformationaccessiblethroughtheinternetincludetheAmericanAcademyof
Allergy,AsthmaandImmunology(www.aaaai.org)andtheAmericanCollegeofAllergy,AsthmaandImmunology
(www.acaai.org)[113,114].
SUMMARYANDRECOMMENDATIONS
Anaphylaxisisaseriousallergicreactionthatisrapidinonsetandmaycausedeath.(See'Definitionand
diagnosis'above.)
Therearethreeclinicalcriteriaforthediagnosisofanaphylaxis,whichreflectthedifferentwaysinwhich
anaphylaxismaypresent(table1).AnaphylaxisishighlylikelywhenanyONEofthethreecriteriaisfulfilled.
(See'Diagnosticcriteria'above.)
Recognitionisnotalwayseasy,becauseanaphylaxiscanmimicmanyotherdisordersandcanbe
variableinitspresentation.Anaphylaxismaypresentwithvariouscombinationsofasmanyas40
potentialsymptomsandsigns(table2).(See'Symptomsandsigns'above.)
Patientsandhealthcareprofessionalscommonlyfailtorecognizeanddiagnoseanaphylaxisinitsearly
stages,whenitismostresponsivetotreatment.Inparticular,thereisareluctancetodiagnose
anaphylaxisintheabsenceofhypotension,eventhoughthissignisnotrequiredforthediagnosisand
isuncommoninchildrenwithanaphylaxisorinfoodinducedanaphylaxis.(See'Pitfallsinmakingthe
diagnosis'above.)
AnaphylaxismostoftenresultsfromanimmunoglobulinE(IgE)mediatedallergicreaction.Commontriggers
includefoods,insectstings,andmedications.Thereisarapidlyexpandinglistofnoveland/orunusual
triggers(table4).(See'Triggersandmechanisms'above.)
Thediagnosisofanaphylaxisisbasedonclinicalcriteria,andtheresultsofmeasurementsoftryptaseand
othermediatorsarenotavailableimmediately(ie,STAT)atthepointofcare.However,detectionofelevated
totaltryptase(inserumorplasma)orhistamine(inplasma)canbehelpfulinexcludingotherdisordersthatdo
notinvolveactivationofmastcellsandbasophils.Ofnote,elevationsinthesemediatorsaretransient.The
bloodsamplefortryptaseshouldbeobtainedfrom15minutesto3hoursofsymptomonset(table6).(See
'Laboratorytests'above.)
Promptrecognitionandtreatmentarecriticalinanaphylaxis.Infatalanaphylaxis,mediantimesto
cardiorespiratoryarrestare5minutesiniatrogenicanaphylaxis,15minutesinstinginginsectvenominduced
anaphylaxis,and30minutesinfoodinducedanaphylaxis.(See'Timecourse'above.)
Initialmanagementissummarizedinarapidoverviewtableforadults(table8)andchildren(table9).(See
'Immediatemanagement'above.)
Epinephrineislifesavinginanaphylaxis.Itshouldbeinjectedasearlyaspossibleintheepisodeinorderto
preventprogressionofsymptomsandsigns.Therearenoabsolutecontraindicationstoepinephrineuse
anditisthetreatmentofchoiceforanaphylaxisofanyseverity.Werecommendepinephrineforpatients
withapparentlymildsymptomsandsigns(eg,afewhivesandmildwheezing)(Grade1B)andforpatients
withmoderatetoseveresymptomsandsigns(Grade1A).
Therouteofepinephrineadministrationdependsuponthepresentingsymptoms.Forpatientswhoarenot
profoundlyhypotensiveorinshockorcardiorespiratoryarrest,intramuscularinjectionintothemidouterthigh
astheinitialrouteofadministrationisadvised,inpreferencetosubcutaneousadministrationorintravenous
administration:
Foradults,thedoseofepinephrineis0.3mgto0.5mg,injectedintramuscularlyintothemidouter
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thigh.Thistreatmentmayberepeatedat5to15minuteintervals.
Forinfantsandchildren,thedoseofepinephrineis0.01mgperkilogram.Largechildrenweighing50kg
orcanreceiveuptoamaximumof0.5mgperdose,injectedintramuscularlyintothemidouterthigh.If
noresponseorinadequateresponse,thistreatmentcanberepeatedin5to15minutes.
Intravenousepinephrineisindicatedforpatientswithprofoundhypotensionorsymptomsandsigns
suggestiveofimpendingshock(dizziness,incontinenceofurineorstool)orthosewhodonotrespondtoan
initialintramuscularinjectionofepinephrineandfluidresuscitation.Forthesepatientswesuggestthat
epinephrinebeadministeredbycontinuousslowintravenousinfusionratherthanbyintermittentintravenous
bolus(Grade2C).Patientsreceivingintravenousepinephrineshouldhavecontinuouselectronicmonitoringof
bloodpressure(BP),heartrate,andfunction.(See'Epinephrine'aboveand'Dosingandadministration'
above.)
Massivefluidshiftscanoccurinanaphylaxis,andallpatientswithorthostasis,hypotension,orincomplete
responsetoepinephrineshouldreceivelargevolumefluidresuscitationwithnormalsaline.Normotensive
patientsshouldreceivenormalsalinetomaintainvenousaccessincasetheirstatusdeteriorates.(See
'Intravenousfluids'above.)
Supplementaloxygenshouldbeadministered.(See'Initialassessment'above.)
Patientssuccessfullytreatedforanaphylaxisshouldbedischargedwithapersonalizedwrittenanaphylaxis
emergencyactionplan(AnaphylaxisEmergencyActionPlanEnglish)(AnaphylaxisEmergencyActionPlan
Spanish),anepinephrineautoinjector,writteninformationaboutanaphylaxisanditstreatment,andaplan
forfurtherevaluation.(See'Careuponresolution'aboveand'Informationforpatients'above.)
Itiscriticalthatpatientsbeevaluatedfurthertoconfirmthetrigger,asspecificavoidancemeasuresare
usefulinreducingtheriskofrecurrence.Additionally,forsomeallergens,immunomodulationisalsoavailable
toreducetherisk.(See'Careuponresolution'aboveand'Longtermprognosis'above.)
UseofUpToDateissubjecttotheSubscriptionandLicenseAgreement.
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GRAPHICS
Diagnosticcriteriaforanaphylaxis
AnaphylaxisishighlylikelywhenanyONEofthefollowingthreecriteria
isfulfilled:
1.Acuteonsetofanillness(minutestoseveralhours)withinvolvementoftheskin,
mucosaltissue,orboth(eg,generalizedhives,pruritusorflushing,swollenlips
tongueuvula)
ANDATLEASTONEOFTHEFOLLOWING:
A.Respiratorycompromise(eg,dyspnea,wheezebronchospasm,stridor,hypoxemia)
B.ReducedBP*orassociatedsymptomsofendorgandysfunction(eg,hypotonia,collapse,
syncope,incontinence)
2.TWOORMOREOFTHEFOLLOWINGthatoccurrapidlyafterexposuretoaLIKELY
allergenforthatpatient(minutestoseveralhours):
A.Involvementoftheskinmucosaltissue(eg,generalizedhives,itchflush,swollenlips
tongueuvula)
B.Respiratorycompromise(eg,dyspnea,wheezebronchospasm,stridor,hypoxemia)
C.ReducedBP*orassociatedsymptoms(eg,hypotonia,collapse,syncope,incontinence)
D.Persistentgastrointestinalsymptoms(eg,crampyabdominalpain,vomiting)
3.ReducedBP*afterexposuretoaKNOWNallergenforthatpatient(minutesto
severalhours):
A.InfantsandchildrenLowsystolicBP(agespecific)*orgreaterthan30percentdecrease
insystolicBP
B.AdultsSystolicBPoflessthan90mmHgorgreaterthan30percentdecreasefromthat
person'sbaseline
BP:bloodpressure.
*Lowsystolicbloodpressureforchildrenisdefinedas:
Lessthan70mmHgfromonemonthtooneyear,
Lessthan(70mmHg+[2xage])from1to10years,and
Lessthan90mmHgfrom11to17years
Adaptedwithpermissionfrom:SampsonHA,MunozFurlongA,CampbellRL,etal.Secondsymposiumon
thedefinitionandmanagementofanaphylaxis:summaryreportSecondNationalInstituteofAllergyand
InfectiousDisease/FoodAllergyandAnaphylaxisNetworksymposium.JAllergyClinImmunol2006
117:391.Copyright2006TheAmericanAcademyofAllergy,Asthma,andImmunology.
Graphic72225Version11.0
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Symptomsandsignsofanaphylaxis
Skin
Feelingofwarmth,flushing(erythema),itching(mayoccurinareas,suchasexternalauditory
canals,palms,soles,orgroin),urticaria,angioedema,morbilliformrash,and"hairstandingon
end"(pilorerection)
Oral
Itchingortinglingoflips,tongue,orpalate
Edemaoflips,tongue,uvula,metallictaste
Respiratory
NoseItching,congestion,rhinorrhea,andsneezing
LaryngealItchingand"tightness"inthethroat,dysphonia,hoarseness,stridor
LowerairwaysShortnessofbreath(dyspnea),chesttightness,deeporrepetitivecough,
wheezing,andcyanosis
Gastrointestinal
Nausea,abdominalpain(colic,cramps),vomiting(largeamountsof"stringy"mucus),diarrhea,
anddysphagia(difficultyswallowing*)
Cardiovascular
Feelingoffaintnessordizzinesssyncope,alteredmentalstatus,chestpain,palpitations,
tachycardia,bradycardiaorotherdysrhythmia,hypotension,tunnelvision,difficultyhearing,
urinaryorfecalincontinence,andcardiacarrest
Neurologic
Anxiety,apprehension,senseofimpendingdoom,seizures,headache ,andconfusionchildren
maybecomeirritable,ceasetoplay,orhaveothersuddenbehavioralchanges
Ocular
Periorbitalitching,erythemaandedema,tearing,andconjunctivalerythema
Other
Uterinecrampsandbleedinginwomenandgirls
*Oftenoccursinassociationwiththroattightnessandotherupperairwaysymptoms.
Notcommoninanaphylaxisoverallhowever,reportedinupto30percentofpatientswithexercise
inducedanaphylaxis.
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Anaphylaxis:Comorbiditiesandconcurrentmedicationsthatmight
interferewithrecognitionoftriggerorsymptoms
Comorbidities
Impairmentofvisionorhearing
Neurologicdisease
Psychiatricillness(eg,depression,ADHD,autismspectrumdisorder,cognitivedisorder,
substanceabuse)
Concurrentlyadministeredmedications
Sedatives(eg,impairingsedatingH 1 antihistamines)
Hypnotics
Ethanol
Recreationaldrugs
ADHD:attentiondeficithyperactivitydisorder.
Modifiedwithpermissionfrom:SimonsFER.Anaphylaxis,killerallergy:Longtermmanagementinthe
community.JAllergyClinImmunol2006117:367.Copyright2006Elsevier.
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Triggersofanaphylaxis
Allergentriggers(IgEdependentimmunologicmechanism)
Foods,especiallypeanut,treenut,crustaceanshellfish,finnedfish,milk,egg
Insectstings(eg,hymenopteravenom)andinsectbites(eg,kissingbugs,mosquitoes)
Medications(eg,betalactamantibiotics,someNSAIDs)
Biologicalmaterials,includingallergens,allergenimmunotherapy,monoclonalantibodies,
vaccinestopreventinfectiousdisease*,andhormones(eg,progesterone)
Naturalrubberlatex
Foodadditives,includingspices,insectderivedcolorants(eg,carmine),andvegetablegums
Inhalants(rare)(eg,horsedander,catdander,grasspollen)
Humanseminalfluid(raretriggerofanaphylaxisinwomen)
Occupationalallergens(eg,stinginginsects,naturalrubberlatex)
Immunologictriggers(IgEindependentmechanism)
IgGdependent(rare)(eg,tohighmolecularweightdextran,infliximab)
Coagulationsystemactivation(eg,heparincontaminatedwithoversulfatedchondroitinsulfate)
Idiopathicanaphylaxis
Considerthepossibilityofahiddenorpreviouslyunrecognizedtrigger
Considerthepossibilityofamastcellactivationsyndrome,includingsystemicmastocytosis
Nonimmunologictriggers(directactivationofmastcellsandbasophils)
Physicalfactors(eg,exercise ,cold,heat,sunlight/ultravioletradiation)
Medications(eg,opioids,someNSAIDs)
Alcohol(ethanol)(mayaugment,rarelyinduces)
Anyfood,insectstingorbite,ormedicationorbiological,canpotentiallytriggeranaphylaxis.
Novelorunusualallergentriggersincludefoods,suchasvegetables,lupinflour,bird'snest
soup,seal,whale,andkangaroomeats,andstoragemitecontaminatedflour.Theyalso
includesalivafromkissingbugs,mosquitoes,pigeonticks,greenants,andpharaohants,and
venomsfromjellyfish,scorpions,andsnakes.Medicationsincludetaxanes,platins,andother
chemotherapydrugsbiologicagents,includingmonoclonalantibodies,suchasrituximab,
cetuximab,infliximab,anduncommonly,omalizumab.Otherinjectantsandingestants,
includingBotox,beeproducts,andherbalformulationsarealsoimplicated.
Sometriggers,suchasradiocontrastmedia,insectvenoms,andmedications(suchas
NSAIDs),canactthroughmorethanonemechanism.
IgE:immunoglobulinENSAIDs:nonsteroidalantiinflammatorydrugsIgG:immunoglobulinG.
*Reactionstovaccinesarerareandtypicallyinvolveanexcipientsuchasdextranorgelatinratherthan
microbialcontent.
Usuallyinvolvesacotrigger,suchasafood,medication(eg,anNSAID),orexposuretocoldairorwater.
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Comorbiditiesandconcurrentmedicationsthatmightimpactthe
severityandtreatmentofanaphylaxis
Comorbidities
Asthma
Otherpulmonarydiseases(eg,COPD,interstitiallungdisease)
Cardiovasculardiseases(eg,ischemicheartdisease,hypertensivevasculardisease,
cardiomyopathy)
Mastocytosisandclonalmastcelldisorders
Concurrentlyadministeredmedications
Betaadrenergicblockers*
Alphaadrenergicblockers
Angiotensinconvertingenzymeinhibitors
AngiotensinIIreceptorblockers
Tricyclicantidepressants
Monoamineoxidaseinhibitors
ADHDmedications (eg,stimulantssuchasmethylphenidateandamphetamines)
Recreationaluseofcocaine
COPD:chronicobstructivepulmonarydiseaseADHD:attentiondeficithyperactivitydisorder.
*Betaadrenergicblockers,administeredorallyortopically(eg,eyedrops)maybeassociatedwith
severeanaphylaxisandmayalsomakeanaphylaxismoredifficulttotreatbycausingunopposedalpha
adrenergiceffects,hypertension,andreducedbronchodilatorresponsetothebetaadrenergiceffectsof
endogenousorexogenousepinephrine.
Alphaadrenergicblockersmaydecreasetheeffectsofendogenousorexogenousepinephrineatalpha
adrenergicreceptors,potentiallymakingpatientslessresponsetothealphaadrenergiceffectsof
epinephrine.
Potentialinterferencewithendogenouscompensatoryresponses.
Potentialincreaseinadverseeffectsofepinephrinebecauseofpreventionofepinephrineuptakeat
adrenergicreceptors.
Potentiateepinephrine'seffectsbyinhibitingitsmetabolismbymonoamineoxidase.
Sideeffectsaresimilartothoseofepinephrine.
Potentiatesepinephrine'seffects,especiallycardiovasculareffects,bypreventingitsreuptakeinto
adrenergicneurons.
Modifiedwithpermissionfrom:SimonsFER.Anaphylaxis,killerallergy:Longtermmanagementinthe
community.JAllergyClinImmunol2006117:367.Copyright2006Elsevier.
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Instructionsforoptimalcollectionandhandlingofbloodsamplesfor
measurementoftryptaseandhistaminefollowingsuspected
anaphylaxis
Tryptase*(serumorplasma)
Whentocollectthesample:
Bloodshouldbecollectedbetween15minutesand3hoursaftersymptomonsetwhenever
possible.Samplescollected<15minutesor>3hoursaftersymptomonsetarelesslikelytobe
informative.
Howtocollectthesample:
Bloodcanbedrawnusingstandardtechnique.Collectbloodforserum(redtoptube)orplasma
(tubewithheparin,citrate,orEDTA).Aminimumof1mLisrecommended.
Forpostmortemsamples,collectbloodfromthefemoralarteryorvein,nottheheart.
Howtoprocessthesample:
Serumorplasmashouldbeplacedoniceandfrozenassoonaspossible.Samplesshouldbe
shippedfrozenbyovernightcourieriftheassaycannotbeperformedonsite.
Histamine(plasma)
Whentocollectthesample:
Plasmaforhistaminelevelsshouldbecollectedbetween5and15minutesaftersymptom
onset.Samplescollected<5minutesor>15minutesaftersymptomonsetarelesslikelytobe
informative.
Howtocollectthesample:
Pullbloodmanually(DONOTusevacuumtubes)undergentlepressurethrougha20gaugeor
largerneedleintoasyringecontainingeithercitrateorEDTA.
Howtoprocessthesample:
Anticoagulatedbloodshouldbeplacedoniceandcentrifugedtoseparateplasmafromcellsas
soonaspossible,andthentheplasmashouldbefrozenuntilreadytobeanalyzed.
Theassayfortotaltryptaseisstandardized.Theassayforhistamineisnot.
EDTA:ethylenediaminetetraaceticacid.
*Normalreferencerangeissimilarinadultsandininfants,children,andteensages6monthsto18
years.KomarowHD,HuZ,BrittainE,etal.Serumtryptaselevelsinatopicandnonatopicchildren.J
AllergyClinImmunol2009124:845.Thenormalreferencerangeishigherininfantslessthanthree
months.BelhocineW,IbrahimZ,GrandneV,etal.Totalserumtryptaselevelsarehigherininfants
youngerthan3monthsofage,particularlyinatopicinfants.PediatrAllergyImmunol201122:600.
Plasmaisusedtoavoidtheartifactualreleaseofhistaminefrombasophilsthatcanoccurduringblood
clotting.
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Differentialdiagnosisofanaphylaxis
Commondisorders
Acuteasthma*
Acutegeneralizedurticaria*
Acuteangioedema
Syncope(faint)
Panicattack/acuteanxietyattack
Aspirationofaforeignbody
Cardiovascularevents(myocardialinfarction*,pulmonaryembolus)
Neurologicevents(seizure,cerebrovascularevent)
Postprandialsyndromes
Scombroidosis
Pollenfoodallergysyndrome
Monosodiumglutamate
Sulfites
Foodpoisoning
Excessproductionofendogenoushistamine
Mastocytosisandotherclonalmastcelldisorders
Basophilicleukemia
Flushsyndromes
Perimenopause
Carcinoidsyndrome
Autonomicepilepsy
Medullarycarcinomaofthethyroid
Othernonorganicdisease
Vocalcorddysfunction
Hyperventilation
Psychosomaticepisode
Shock
Hypovolemic
Cardiogenic
Distributive
Septic
Other
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Nonallergicangioedema(hereditaryangioedematypesI,II,andIII,ACEinhibitorassociated
angioedema)
Systemiccapillaryleaksyndrome
Redmansyndrome(vancomycin)
Pheochromocytoma(paradoxicalresponse)
Thedifferentialdiagnosisinchildrenandadultsisshown.Ininfants,thedifferentialdiagnosis
ofanaphylaxisisunique.
ACEinhibitors:angiotensinconvertingenzymeinhibitors.
*Acuteasthmasymptoms,acutegeneralizedurticaria,ormyocardialinfarctionsymptomscanalso
occurduringananaphylacticepisode.
Inanaphylaxis,shockisdistributiveandhypovolemic.Distributiveshockmaybeduetoanaphylaxisor
tospinalcordinjury.
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Rapidoverview:Emergentmanagementofanaphylaxisinadults
Diagnosisismadeclinically:
Themostcommonsignsandsymptomsarecutaneous(eg,suddenonsetofgeneralizedurticaria,
angioedema,flushing,pruritus).However,10to20percentofpatientshavenoskinfindings.
Dangersigns:Rapidprogressionofsymptoms,respiratorydistress(eg,stridor,
wheezing,dyspnea,increasedworkofbreathing,persistentcough,cyanosis),
abdominalpain,hypotension,dysrhythmia,chestpain,collapse.
Acutemanagement:
Thefirstandmostimportanttreatmentinanaphylaxisisepinephrine.ThereareNOabsolute
contraindicationstoepinephrineinthesettingofanaphylaxis.
Airway:Immediateintubationifevidenceofimpendingairwayobstructionfromangioedema.
Delaymayleadtocompleteobstruction.Intubationcanbedifficultandshouldbeperformedbythe
mostexperiencedclinicianavailable.Cricothyrotomymaybenecessary.
Promptlyandsimultaneously,give:
IMepinephrine(1mg/mLpreparation):Giveepinephrine0.3to0.5mgintramuscularly,
preferablyinthemidouterthigh.Canrepeatevery5to15minutesasneeded.Ifepinephrineis
injectedpromptlyIM,mostpatientsrespondtoone,two,oratmost,threedoses.Ifsymptoms
arenotrespondingtoepinephrineinjections,prepareIVepinephrineforinfusion(seebelow).
Placepatientinrecumbentposition,iftolerated,andelevatelowerextremities.
Oxygen:Give8to10litersperminuteviafacemask,orupto100percentoxygenasneeded.
Normalsalinerapidbolus:Treathypotensionwithrapidinfusionof1to2litersIV.Repeatas
needed.Massivefluidshiftswithseverelossofintravascularvolumecanoccur.
Consideradministrationof:
Albuterol(salbutamol):ForbronchospasmresistanttoIMepinephrine,give2.5to5mgin3
mLsalinevianebulizer.Repeatasneeded.
H1antihistamine*:Considergivingdiphenhydramine25to50mgIV(forreliefofurticaria
anditchingonly).
H2antihistamine*:Considergivingranitidine50mgIV.
Glucocorticoid*:Considergivingmethylprednisolone125mgIV.
Monitoring:Continuousnoninvasivehemodynamicmonitoringandpulseoximetrymonitoring
shouldbeperformed.UrineoutputshouldbemonitoredinpatientsreceivingIVfluidresuscitation
forseverehypotensionorshock.
Treatmentofrefractorysymptoms:
Epinephrineinfusion :ForpatientswithinadequateresponsetoIMepinephrineandIVsaline,
giveepinephrinecontinuousinfusion,2to10microgramsperminutebyinfusionpump.Titratethe
dosecontinuouslyaccordingtobloodpressure,cardiacrateandfunction,andoxygenation.
Vasopressors :Somepatientsmayrequireasecondvasopressor(inadditiontoepinephrine).All
vasopressorsshouldbegivenbyinfusionpump,withthedosestitratedcontinuouslyaccordingto
bloodpressureandcardiacrateandfunctionmonitoredcontinuously,andoxygenationmonitored
bypulseoximetry.
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Glucagon:Patientsonbetablockersmaynotrespondtoepinephrineandcanbegivenglucagon1
to5mgIVoverfiveminutes,followedbyinfusionof5to15microgramsperminute.Rapid
administrationofglucagoncancausevomiting.
IM:intramuscularIV:intravenous.
*Thesemedicationsshouldnotbeusedasinitialorsoletreatment.
Allpatientsreceivinganinfusionofepinephrineandanothervasopressorrequirecontinuous
noninvasivemonitoringofbloodpressure,heartrateandfunction,andoxygensaturation.
Adaptedfrom:SimonsFER.Anaphylaxis.JAllergyClinImmunol2010125:S161.
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Rapidoverview:Emergentmanagementofanaphylaxisininfants
andchildren*
Diagnosisismadeclinically:
Themostcommonsignsandsymptomsarecutaneous(eg,suddenonsetofgeneralized
urticaria,angioedema,flushing,pruritus).However,10to20percentofpatientshavenoskin
findings.
Dangersigns:Rapidprogressionofsymptoms,evidenceofrespiratorydistress(eg,
stridor,wheezing,dyspnea,increasedworkofbreathing,retractions,persistent
cough,cyanosis),signsofpoorperfusion,abdominalpain,dysrhythmia,hypotension,
collapse.
Acutemanagement:
Thefirstandmostimportanttherapyinanaphylaxisisepinephrine.ThereareNOabsolute
contraindicationstoepinephrineinthesettingofanaphylaxis.
Airway:Immediateintubationifevidenceofimpendingairwayobstructionfromangioedema
delaymayleadtocompleteobstructionintubationcanbedifficultandshouldbeperformedby
themostexperiencedclinicianavailablecricothyrotomymaybenecessary.
IMepinephrine(1mg/mLpreparation):Epinephrine0.01mgperkilogramshouldbe
injectedintramuscularlyinthemidouterthigh.Forlargechildren(>50kilograms),the
maximumis0.5mgperdose.Ifthereisnoresponseortheresponseisinadequate,the
injectioncanberepeatedin5to15minutes.IfepinephrineisinjectedpromptlyIM,patients
respondtoone,two,oratmost,threeinjections.Ifsignsofpoorperfusionarepresentor
symptomsarenotrespondingtoepinephrineinjections,prepareIVepinephrineforinfusion(see
below).
Placepatientinrecumbentposition,iftolerated,andelevatelowerextremities.
Oxygen:Give8to10litersperminuteviafacemask,orupto100percentoxygenasneeded.
Normalsalinerapidbolus:Treatpoorperfusionwithrapidinfusionof20mLperkilogram
reevaluateandrepeatfluidboluses(20mLperkilogram)asneededmassivefluidshiftswith
severelossofintravascularvolumecanoccurmonitorurineoutput.
Albuterol:ForbronchospasmresistanttoIMepinephrine,givealbuterol0.15mgperkilogram
(minimumdose:2.5mg)in3mLsalineinhaledvianebulizerrepeatasneeded.
H1antihistamine:Considergivingdiphenhydramine1mgperkilogram(max40mg)IV.
H2antihistamine:Considergivingranitidine1mgperkilogram(max50mg)IV.
Glucocorticoid:Considergivingmethylprednisolone1mgperkilogram(max125mg)IV.
Monitoring:Continuousnoninvasivehemodynamicmonitoringandpulseoximetrymonitoring
shouldbeperformedurineoutputshouldbemonitoredinpatientsreceivingIVfluid
resuscitationforseverehypotensionorshock.
Treatmentofrefractorysymptoms:
Epinephrineinfusion :PatientswithinadequateresponsetoIMepinephrineandIVsaline,
giveepinephrinecontinuousinfusionat0.1to1microgramperkilogramperminute,titratedto
effect.
Vasopressors :PatientsmayrequirelargeamountsofIVcrystalloidtomaintainblood
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pressureifresponsetoepinephrineandsalineisinadequate,dopamine(5to20micrograms
perkilogramperminute)canbegivenwiththedosetitratedtoeffectoncontinuously
monitoredbloodpressure,cardiacrate,andfunction.
IM:intramuscularIV:intravenous.
*Achildisdefinedasaprepubertalpatientweighinglessthan40kg.
Allpatientsreceivinganinfusionofepinephrineand/oranothervasopressorrequirecontinuous
noninvasivemonitoringofbloodpressure,heartrateandfunction,andoxygensaturation.Wesuggest
thatpediatriccentersprovideinstructionsforpreparationofstandardconcentrationsandalsoprovide
chartsforestablishedinfusionrateforepinephrineandothervasopressorsininfantsandchildren.
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Beneficialeffectsandadverseeffectsofepinephrineinthe
treatmentofanaphylaxis
Beneficialeffects
Atalpha1receptor:
Increasedvasoconstriction(atlowdoses)
Increasedperipheralvascularresistance
Increasedbloodpressure
Decreasedmucosaledema(eg,inlarynx)
Atbeta1receptor:
Increasedheartrate(chronotropy)
Increasedforceofcardiaccontraction(inotropy)
Atbeta2receptor:
Decreasedmediatorreleasefrommastcellsandbasophils
Increasedbronchodilation
Increasedvasodilation
Adverseeffects*
Commonand
transient
Anxiety,palpitations,pallor,tremor,fear,restlessness,dizziness,
headache
Uncommon
(typicallyoccurafter
overdose)
Ventriculararrhythmias,angina,myocardialinfarction,pulmonary
edema,suddensharpincreaseinbloodpressure,intracranialhemorrhage
*Riskofadverseeffectsmaybeincreasedinthefollowingconditions:
Useoftricyclicantidepressants,monoamineoxidaseinhibitors,orcocaine.
Somepreexistingcardiovascular,centralnervoussystem,orthyroiddiseases.Examplesinclude
intracranialsurgery,acuteaneurysm,oruntreatedhyperthyroidism.
Seriousadverseeffectssuchasthoselistedinthetablepotentiallyoccurwhenepinephrineisgivenin
overdosebyanyroute,mostcommonlyafteranintravenousbolusinjection,anoverlyrapidintravenous
infusion,oranerroneousintravenousinjectionofa1mg/mL(1:1000)epinephrinesolutioninsteadof
anappropriatelydiluted0.1mg/mL(1:10,000)ora0.01mg/mLepinephrinesolution.
Anaphylaxiscanpresentasanacutecoronarysyndrome(ACS),arrhythmias,myocardialinfarction,or
angina,beforeorintheabsenceofepinephrineinjection.Thispotentiallyoccursinpatientswithknown
coronaryarterydisease,patientsinwhomsubclinicalcoronaryarterydiseaseisunmasked,andpatients
(includingchildren)withtransientcoronaryarteryvasospasminwhomnocardiovascularabnormalities
canbedetectedbyelectrocardiogramorechocardiographyafterrecoveryfromanaphylaxis.
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ExampleofepinephrineinfusionAdult
Exampleofpreparationofepinephrineinfusionforrefractorysymptoms
ofanaphylaxis(adultpatient)foremergency/criticalcareunits
Epinephrine4micrograms/mL(0.004mg/mL)
Add1mg(1000micrograms)ofepinephrineto250mLof5percentdextrosewater
(D5W).
Resultingconcentrationis4microgramspermilliliter(mL).
Preparation
1.CHECKvialstrength.
2.Toprepareepinephrineinfusionforafinalconcentrationof4microgramspermL,dilute10
mLof0.1mg/mLepinephrine(alsolabeled1:10,000)OR1mLof1mg/mLepinephrine(also
labeled1:1000)in250mLofD5W.*
Administration
Infuseaninitialdoseof2to10microgramsperminuteusingaprogrammableinfusionpump
andtitrateasneededwhilecontinuouslymonitoringthepatient'scardiacrhythmandblood
pressure.
Administrationrate
Adultdose
1milligramepinephrinedilutedin250mLD5W
4microgramspermilliliter
Microgramsperminute
mLperminute
mLperhour
0.25
15
0.5
30
0.75
45
60
1.25
75
1.5
90
1.75
105
120
2.25
135
10
2.5
150
11
2.75
165
12
180
13
3.25
195
14
3.5
210
15
3.75
225
16
240
Toreducetheriskofmakingamedicationerror,wesuggestthatcentershaveavailablean
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institutionallyapprovedprotocolforepinephrineinfusionthatincludesstepsonhowtoprepare
andadministertheinfusionandstandardconcentration(s).
Theabovetableisprovidedasanexample.Thereareotheracceptableconcentrations.
Intravenousepinephrine,likeallvasopressors,cancauselifethreatening
hypertension,cardiacischemia,andventriculararrhythmias.Itshouldbe
administeredONLYbyclinicianstrainedandexperiencedindosetitrationof
intravenousepinephrineusingcontinuousnoninvasiveelectronicmonitoringof
heartrateandbloodpressure.
Epinephrineisanischemiacausingagentandvesicant.Monitorinfusionsiteforextravasation.
SeeLexicompdrugreferenceforinformationonmanagingextravasationincludinginfiltrationof
phentolamine.Centrallineadministrationispreferredwhenavailable.
*Unuseddilutedsolutionsshouldbediscardedwithin24hoursorlessofpreparationdependingonlocal
standards.
Tocalculatetheadultdosebasedonbodyweight,initialdoserangeis0.03micrograms/kgofbody
weightperminutetoupto0.14micrograms/kgofbodyweightperminute.
References:
1. GahartBL,NazarenoAR.IntravenousMedications31sted.ElsevierMosby2014St.Louis,MO.
2. LiebermanP,etal.JAllergyClinImmunol2010126(3):477.
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ExampleofepinephrineinfusionPediatric10kg
ofanaphylaxisforpediatricpatientof10kgbodyweightfor
emergency/criticalcareunits
(D5W).
Preparation
mLof0.1mg/mLepinephrine(alsolabeled1:10,000)in100mLofD5WOR1mLof1
mg/mLepinephrine(alsolabeled1:1000)in100mLofD5W.*
Administration
Infuseaninitialdoseof0.1microgramsperkgperminuteusingaprogrammableinfusionpump
pressure.
Administrationrate
Pediatricdosefor10kgchild
1milligramepinephrinedilutedin100mL
D5W
Micrograms
perkgper
minute
Micrograms
perminute
mLper
minutefor10
kgchild
mLperhour
for10kg
child
0.05
0.5
0.05
0.1
0.1
0.2
0.2
12
0.3
0.3
0.4
Multiplyby
patient
weight
(10kg)
18
Multiplyby60
minutes
0.4
0.5
30
0.6
0.6
36
0.7
0.7
42
0.8
0.8
48
0.9
0.9
54
10
60
0.5
24
Theabovetableisprovidedasanexamplethereareotheracceptableconcentrations.
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standards.
References:
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ExampleofepinephrineinfusionPediatric20kg
ofanaphylaxisforpediatricpatientof20kgbodyweightfor
emergency/criticalcareunits
(D5W).
Preparation
mLof0.1mg/mLepinephrine(alsolabeled1:10,000)in100mLofD5WOR1mLof1
mg/mLepinephrine(alsolabeled1:1000)in100mLofD5W.*
Administration
Infuseaninitialdoseof0.1microgramsperkgperminuteusingaprogrammableinfusionpump
pressure.
Administrationrate
Pediatricdosefor20kgchild
1milligramepinephrinedilutedin100mL
D5W
Micrograms
perkgper
minute
Micrograms
perminute
mLper
minutefor20
kgchild
mLperhour
for20kg
child
0.05
0.1
0.1
0.2
12
0.4
0.2
0.3
Multiplyby
patient
weight
(20kg)
24
Multiplyby60
minutes
0.6
0.8
48
0.5
10
60
0.6
12
1.2
72
0.7
14
1.4
84
0.8
16
1.6
96
0.4
36
Theabovetableisprovidedasanexamplethereareotheracceptableconcentrations.
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standards.
References:
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Disclosures
Disclosures:FEstelleRSimons,MD,FRCPCConsultant/AdvisoryBoards:SanofiCanada
[Anaphylaxis].CarlosACamargo,Jr,MD,DrPHGrant/Research/ClinicalTrialSupport:GSKNovartis
[asthma].Consultant/AdvisoryBoards:GSKMerckNovartisTeva[asthma].BruceSBochner,MD
Grant/Research/ClinicalTrialSupport:NIAIDNHLBIGSK[Siglec8,Siglec9,asthma,COPD,
anaphylaxis,imagingeosinophilicgranulomatosiswithpolyangiitis(Mepolizumab)].Consultant/Advisory
Boards:TEVASanofiMerckGlycomimeticsAllakosBiogenIdecSvelteMedicalSystems.Patent
Holder:Siglec8anditsligandantiSiglec8antibodies[heldbyJohnsHopkinsUniversity].Employment:
NorthwesternUniversityFeinbergSchoolofMedicine.EquityOwnership/StockOptions:Glycomimetics
Allakos.OtherFinancialInterest:Elsevier[publicationroyalties].AnnaMFeldweg,MDEmployeeof
UpToDate,Inc.
Contributordisclosuresarereviewedforconflictsofinterestbytheeditorialgroup.Whenfound,theseare
addressedbyvettingthroughamultilevelreviewprocess,andthroughrequirementsforreferencestobe
providedtosupportthecontent.Appropriatelyreferencedcontentisrequiredofallauthorsandmust
conformtoUpToDatestandardsofevidence.
Conflictofinterestpolicy
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