OfficialreprintfromUpToDate

www.uptodate.com2016UpToDate

Cyanidepoisoning

Authors: ShomaDesai,MD,MarkSu,MD,MPH
SectionEditor: StephenJTraub,MD
DeputyEditor: JonathanGrayzel,MD,FAAEM

Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.
Literaturereviewcurrentthrough:Oct2016.|Thistopiclastupdated:Sep28,2016.

INTRODUCTIONCyanideisamitochondrialtoxinthatisamongthemostrapidlylethalpoisonsknowntoman.Used
inbothancientandmoderntimesasamethodofexecution,cyanidecausesdeathwithinminutestohoursofexposure.
Thoughsignificantcyanidepoisoningisuncommon,itmustberecognizedrapidlytoensurepromptadministrationoflife
savingtreatment.Asummarytabletofacilitateemergentmanagementisprovided(table1).

Thistopicreviewwilldiscussthetoxicityandmanagementofcyanidepoisoning.Ageneralapproachtothepoisoned
patientisfoundelsewhere.(See"Generalapproachtodrugpoisoninginadults".)

EPIDEMIOLOGYAccordingtotheToxicExposureSurveillanceSystem,therewere3165humanexposuresto
cyanidefrom1993to2002.Ofthese,2.5percentwerefatal[1].Cyanidepoisoningmayresultfromabroadrangeof
exposures(table2).

FireInindustrializedcountries,themostcommoncauseofcyanidepoisoningisdomesticfires[2].Cyanidecanbe
liberatedduringthecombustionofproductscontainingbothcarbonandnitrogen.Theseproductsincludewool,silk,
polyurethane(insulation/upholstery),polyacrylonitriles(plastics),melamineresins(householdgoods),andsynthetic
rubber[35].Vehicularfirescanalsoexposevictimstocyanide.Toxicologicevaluationofpassengersfollowingthe
explosionin1985ofaBoeing737duringtakeoffinManchester,England,revealedthat20percentofthe137
victimswhoescapedhaddangerouslyelevatedlevelsofcarbonmonoxide,while90percenthaddangerously
elevatedlevelsofcyanide[6].Overall,itisreportedthatsignificantlevelsofcyanidearepresentinupto35percent
ofallfirevictims[7].

IndustrialWorldwideindustrialconsumptionofcyanideisestimatedtobe1.5milliontonsperyear,and
occupationalexposuresaccountforasignificantnumberofcyanidepoisonings[8].Metalextractioninmining,
electroplatinginjewelryproduction,photography,plasticsandrubbermanufacturing,hairremovalfromhides,and
rodentpesticideandfumigantshaveallbeenimplicatedincyanidepoisonings.Skincontactwithcyanidesaltscan
resultinburns,whichallowforenhancedabsorptionofcyanidethroughtheskin.Thecombinationofcyanidesalts
andacid,asutilizedinelectroplating,resultsinthereleaseofcyanidegas,whichcanleadtolethalinhalational
exposures.Splashesofcyanidesolutionscanresultindermalaswellasmucosalabsorption[2,9].

MedicalCyanideexposurescanresultfromalternativeandstandardmedicaltreatments.Amygdalin(tradename
Laetrile),asubstancederivedfromapricotandpeachkernels,andintroducedasanantineoplasticagentinthe
1950s,cancauseseverecyanidetoxicity[1012].Thedrugisallegedtokillcancercellsselectivelyviaitsmetabolite,
hydrocyanicacid.Laetrileisavailableasa500mgoraltabletthatcontains30to150mgofamygdalin[13].Intestinal
betadglucosidasedigeststheamygdalin,releasinghydrogencyanide(HCN).Thisenzymaticreactionexplainswhy
onlygastrointestinalexposure,incontrasttointravenousadministration,resultsintoxicity[10].

Sodiumnitroprusside,amedicationusedinthetreatmentofhypertensiveemergencies,containsfivecyanidegroups
permolecule.Toxiclevelsofcyanidemaybereachedinpatientswhoreceiveprolongedinfusionsofsodium
nitroprusside,inpatientswithchronicrenalfailure,orinpediatricpatients[14,15].Treatmentfor3to10hourswith5
to10mcg/kg/minhasresultedinfatalities[16].Methodsforpreventingnitroprussideinducedcyanidepoisoning
includeusingsilverfoilonIVtubing(preventinglightfromdecomposingthenitroprussidemolecule),usingmaximal
infusionratesof2mcg/kg/min,andaddingsodiumthiosulfatetothenitroprussidesolution[17].
 DietThefamilyRosaceae,whichincludesthebitteralmond,cherrylaurel,apricot,plum,peach,pear,andapple,is
responsibleformanyreportedcyanidepoisonings.Thesefoodsallcontaincyanogenicglycosides,suchas
amygdalin,intheirpitsandseeds.Thecommon(ie,sweet)almonddoesnotcausecyanideintoxication.Otherfoods
containingpossiblecyanogensincludecassavaroot,bambooshoots,andsoy[18].

OtherMiscellaneousexposuretocyanidemayoccurduringillicitsynthesisofphencyclidine,terroristattacks,
ingestionofacetonitrile(artificialnailpolishremover),producttampering,andcigarettesmoking.Becauseofthe
naturalcyanidefoundintobacco,cigarettesmokershavemorethan2.5timesthemeanwholebloodcyanidelevelof
nonsmokers(table1)[19].

PATHOPHYSIOLOGYInnormalcellularmetabolism,mostadenosinetriphosphate(ATP)isgeneratedfromoxidative
phosphorylation.Animportantpartofthisprocessistheshuttlingofelectronsthroughthemitochondrialcytochrome
complex(alsoknownastheelectrontransportchain)(figure1).

Cyanideavidlybindstotheferricion(Fe3+)ofcytochromeoxidasea3,inhibitingthisfinalenzymeinthemitochondrial
cytochromecomplex.Whenthisenzyme'sactivityisblocked,oxidativephosphorylationceases.Thecellmustthen
switchtoanaerobicmetabolismofglucosetogenerateATP.

Anaerobicmetabolismleadstotheformationoflacticacidandthedevelopmentofmetabolicacidosis.Hydrogenions
producedbyATPhydrolysisarenolongerconsumedinaerobicATPproduction,exacerbatingthisacidosis[20].Serum
bicarbonatedecreasesasitbuffersexcessacid,leadingtoanincreasedaniongap.

Despiteanampleoxygensupply,cellscannotutilizeoxygenbecauseoftheirpoisonedelectrontransportchain.This
functional(or"histotoxic)hypoxiaisparticularlydeleterioustothecardiovascularandcentralnervoussystems
(especiallythebasalganglia).

Anumberofothermechanismsmayexacerbatebraininjury.Cyanide'snonspecificinhibitionofantioxidants(suchas
catalase,glutathionereductase,andsuperoxidedismutase)resultsintheaccumulationoftoxicoxygenfreeradicals.
CyanidestimulatesNmethylDaspartate(NMDA)receptors,inducingapoptoticcelldeath.Italsoinhibitsglutamicacid
decarboxylase(GAD),theenzymeresponsiblefortheformationoftheinhibitoryneurotransmittergammaaminobutyric
acid(GABA)fromglutamicacid.Consequently,cyanideincreasestheriskofseizuresasGABAlevelsfall[2123].

Althoughcyanidehasaprimaryaffinityforferric(Fe3+)iron,asmallamountmaybindtotheferrous(Fe2+)ironof
hemoglobin,formingcyanohemoglobin,whichisunabletotransportoxygen,therebyfurtherexacerbatingtissuehypoxia
[16].

KINETICSANDMETABOLISMCyanideisrapidlyabsorbedthroughtherespiratorytractandmucousmembranes,
anditcanalsobeabsorbedthroughthegastrointestinaltractandskin[24].Symptomsandsignsofpoisoningbeginat
bloodcyanideconcentrationsofapproximately40mol/L[25].Onceabsorbed,cyanideisquicklydistributedinthebody
withanestimatedvolumeofdistributionof1.5L/kg.Approximately60percentisproteinbound[7].

Invivo,cyanidemetabolismandneutralizationinvolveanumberofmechanisms.Themostimportantisthedetoxification
ofcyanideviarhodanese.Rhodaneseisanenzymefoundabundantlyinmanytissues,particularlytheliverandmuscle
[24].Thiosulfateservesasasulfurdonorinthereactioncatalyzedbyrhodanesethatconvertscyanidetothiocyanate,a
watersolublemoleculeexcretedintheurine[2].

Aminorpathwayforcyanidedetoxificationinvolveshydroxocobalamin,theprecursortovitaminB12.Circulating
hydroxocobalamincombineswithcyanidetoformcyanocobalamin,whichissafelyexcretedintheurine.Finally,asmall
amountofunmetabolizedcyanideiseliminatedthroughurine,sweat,andexpiration[2].

CLINICALPRESENTATIONClinicalfeaturesofcyanidepoisoningaredependentupontheroute,duration,and
amountofexposure.Centralnervoussystemandcardiovascularsystemdysfunctionaremostprominent.Symptomsand
signscanincludethefollowing:

CentralnervoussystemHeadache,anxiety,confusion,vertigo,coma,seizures

CardiovascularInitialtachycardiaandhypertension,thenbradycardiaandhypotension,atrioventricularblock,
ventriculardysrhythmias[26]
 RespiratoryInitialtachypneathenbradypnea,pulmonaryedema

GastrointestinalVomiting,abdominalpain

SkinFlushing(cherryredcolor),cyanosis(latefinding),irritantdermatitis(itching,erythema,edema,vesicles
resultingfromskinexposure)[27]

RenalRenalfailure

HepaticHepaticnecrosis

MiscellaneousRhabdomyolysis,brightredvenulesseenonfunduscopy[26,28]

Ofnote,becauseofthedecreasedutilizationofoxygenbytissues,thevenousoxyhemoglobinconcentrationwillbehigh,
makingvenousbloodappearbrightred.Therefore,despitehypotension,apnea,and/orbradycardia,thepatientdoesnot
usuallyappearcyanoticinthesettingofcyanidepoisoning[16].

Symptomsdependontheseverityandrouteofcyanidepoisoning(table3).Afterinhalinghydrogencyanide(HCN),the
victimmaydetectabitter,almondodor(discernibletoapproximately60percentofthepopulation)[28].Initially,inhalation
ofsmallamountsofHCNcausesheadache,anxiety,nausea,andametallictaste[9].Incontrast,cyanogenchloride
(CNCl)exposurepredominantlyresultsineyeandmucousmembraneirritationandthenpulmonarysymptoms,namely
bronchorrhea,cough,anddyspnea[22].Inhalationof100ppmfor30minutesor300ppmforfiveminutesisusuallyfatal
[9].

Whiletoxicityfromparenteralexposurebeginswithinseconds,toxicityfromingestionordermalexposureisdelayedfrom
minutestohours,dependingontheextentofexposure.Ingestionofcyanidesaltsresultsingastricirritation,frequently
causingvomitingandabdominalpain[16].Thelethaloraldoseis50mgofhydrogencyanide(HCN)or200mgof
potassiumcyanide(KCN)inanadult[9,22].Thelethaldermalexposureisestimatedtobe100mg/kg(table3)[7].

DelayedsequelaeSurvivorsofseverecyanidepoisoningmaydevelopdelayedonsetParkinsonismorother
neurologicsequelae.Thebasalgangliaareparticularlysensitivetocyanidetoxicity[28].Basalgangliainjurymaybedue
toeitherdirectcellularinjuryorsecondarytohypoxiceffects.Computedtomography(CT)andmagneticresonance
imaging(MRI)ofthebrainmaydemonstrateradiologicchangesseveralweeksaftertheexposure.Resolutionof
symptomsisvariable,andtreatmentissupportive.

ChroniccyanideexposureChroniccyanideexposureresultsinvaguesymptoms,suchasheadache,dysgeusia
(abnormaltaste),vomiting,chestpain,abdominalpain,andanxiety[9].Thereareatleastthreeinsidioussyndromes
associatedwithchronic,lowlevelcyanideexposure:tobaccoamblyopia,tropicalataxicneuropathy,andLeberhereditary
neuropathy.

Tobaccoamblyopiaoccurspredominantlyinmalecigarettesmokersandmanifestsasprogressivevisualloss.Itmay
resultfromaninherentinabilitytodetoxifycyanide,andsymptomsmayreversefollowingsmokingcessationor
hydroxocobalamin(Cyanokit)administration.

Tropicalataxicneuropathy(TAN)isademyelinatingconditionassociatedwithexcessivecassavaconsumption,usuallyin
thepoorandmalnourished.Thecassavaplantcontainsacyanogen,linamarin,whichmaynotberemovedwith
inadequateprocessing.SignsandsymptomsofTANincludeparesthesias,ataxia,hearingloss,andopticatrophy.
VitaminB12deficiencymaycontributetothecondition.CessationofdietarycassavaandadministrationofvitaminB12
amelioratesymptoms.

Leber'shereditaryopticneuropathyisarare,graduallossofcentralvisionthatappearstobeduetoadefectincyanide
metabolism.Adeficiencyofrhodaneseisoneproposedmechanism.

LABORATORYEVALUATION

GeneraltestingRoutinelaboratoryevaluationinthepotentiallypoisonedpatientshouldincludethefollowing:

Pointofcare(egfingerstick)glucoseconcentration,toruleouthypoglycemiaasthecauseofanyalterationinmental
status
 Acetaminophenandsalicylatelevels,toruleoutthesecommoncoingestions

Electrocardiogram,toruleoutconductionsystempoisoningbydrugsthateffecttheQRSorQTcintervals

Pregnancytestinwomenofchildbearingage

SpecifictestingSpecifictestingincasesofpotentialcyanidepoisoningshouldalsoincludethefollowing:

Basicchemistries(eg,Na+,Cl,K+,HCO3)andarterialbloodgastoassessforaniongapmetabolicacidosis

Serumlactateconcentrationtoconfirmlacticacidosis

Centralvenousbloodgas,ifpossible,toassessvenousarterialPO2gradient

Carboxyhemoglobinandmethemoglobinlevels(measuredbycooximetry),particularlyifthereisanyconcernfor
concomitantcarbonmonoxideexposure(eg,houseorvehiclefire)orexposuretodrugsthatproduce
methemoglobinemia(table1)(see"Carbonmonoxidepoisoning"and"Inhalationinjuryfromheat,smoke,or
chemicalirritants")

AniongapacidosisAseveremetabolicacidosiswithanincreasedaniongapisexpectedincyanidepoisoning.In
additiontoitsinhibitoryeffectsoncellularrespiration,cyanidecaninducecardiovascularcollapseandseizures,which
exacerbateaniongapmetabolicacidosis.(See'Pathophysiology'above.)

LactateCyanidepoisonedpatientshaveanelevatedbloodlactateconcentration.Aretrospectivestudyof11ICU
patientswithcyanidepoisoningfoundthatplasmalactateconcentrationscorrelatedcloselywiththeseverityofcyanide
toxicity[29].Thereweresignificantinversecorrelationsbetweenlactateandsystolicbloodpressure,respiratoryrate,and
arterialpH.Infact,lactateconcentrationsof10mmol/Lorgreaterhavebeenshowntobebothsensitiveandspecificfor
cyanidepoisoninginsmokeinhalationvictims[30].Consequently,anormalserumlactateshouldleadtheclinicianto
entertainotherdiagnoses,whileseriallactatemeasurementscanbeusedtomonitortheprogressofpatientsbeing
treatedforcyanidepoisoning.

VenousPO2AnarrowingofthevenousarterialPO2gradient(ie,venoushyperoxia)maybeseeninthecyanide
poisonedpatient[31].Cyanideinhibitscellularoxidativephosphorylationresultinginamarkeddecreaseinperipheral
tissueoxygenextractionfromtheblood.Thisresultsinelevatedcentralvenousoxygenation.Onexamination,theskin
mayappearflushedandthevenulesintheretinabrightred.Laboratoryevaluationmayrevealadecreasedarterial
venousoxygengradient.Cliniciansshouldkeepinmindthatadecreasedoxygengradientisnonspecificandcanresult
fromotherinhibitorsofoxidativephosphorylation,suchascarbonmonoxide,hydrogensulfide,andazides.

Cyanideconcentration(level)Bloodcyanideconcentrationsmaybeobtainedfordiagnosticconfirmationbut
resultsarenotavailableintimetobeclinicallyuseful.Evenwhenavailable,theresultsofdirecttestingmaybeunreliable
asbothproperstorageconditionsandpromptblooddrawsarerequired.Furthermore,bloodcyanideconcentrationsdo
notcorrelatedirectlywithsurvival.Nonetheless,bloodcyanideconcentrationsof0.5to1mg/L(12to23mol/L)
generallycorrelatewithtachycardiaandflushing,1to2.5mg/L(23to58mol/L)withobtundation,2.5to3mg/L(58to
69mol/L)withcoma,andgreaterthan3mg/L(>69mol/L)withdeath[22].

Cyantesmoteststripsarecolorimetricstripsusedinthetestingofwastewaterandduringautopsies.Oneinvitrostudy
assessedtheabilityofthesestripstodetectcyanideinsimulatedsamples[32]andfoundtheywereaccurateonlyat
markedlyelevatedcyanidelevels.Additionalworkisneededbeforethistestcanbeconsideredforroutineclinicaluse.

Giventhelimitationsofcyanideconcentrationtesting,antidotaltreatmentshouldbeadministeredempiricallybasedon
theclinicalpresentation,andbloodcyanidelevelsshouldservemainlyasconfirmation.

DIAGNOSISCyanidepoisoningisanuncommonentity.Therefore,makingthediagnosisrequiresthattheclinician
maintainahighindexofsuspicionbasedonhistoryandclinicalpresentation.Patientswhoarevictimsoffiresorreported
ingestions,areexposedatwork,orhaverecentlybeentreatedwithsodiumnitroprussideshouldallbeconsidered
potentiallycyanidepoisoned.Whenaclearhistoryisunavailable,cliniciansshouldconsideranypatientwithaltered
mentalstatusandametabolicacidosisofunknownetiologyapossiblevictimofcyanidepoisoning.Bloodcyanide
concentrationsarenotavailableintimetoguidetheclinicalmanagementofacutepoisoning.
DIFFERENTIALDIAGNOSISCarbonmonoxidepoisoningissimilartocyanideinpresentation.(See"Carbon
monoxidepoisoning".)

Duetocyanide'swiderangeofpossiblesymptomsandsigns,theclinicianmustconsideranumberofpotential
diagnoses,includingthoselistedbelow.Generally,thediagnosisismadebasedonahistoryofexposureanda
consistentclinicalpresentation,sinceveryfewoftheseintoxicantshavearapidlyavailablediagnostictest.Ifthe
diagnosisisindoubt,cliniciansshouldseekassistancefromamedicaltoxicologistorregionalpoisoncenter.(See
'Additionalresources'below.)

Apatientwithalteredmentalstatus,seizures,hypotension,andlacticacidosismaybepoisonedwith:

Tricyclicantidepressants(see"Tricyclicantidepressantpoisoning")

Isoniazid(see"Isoniazid:Anoverview")

Organophosphates(see"Organophosphateandcarbamatepoisoning")

Salicylates(see"Salicylate(aspirin)poisoninginadults")

Methemoglobinproducingagents(see"Clinicalfeatures,diagnosis,andtreatmentofmethemoglobinemia")

Strychnine(see"Strychninepoisoning")

Apatientwhosuddenlycollapsedafterexposuretoagasmaybepoisonedwith:

Carbonmonoxide(see"Carbonmonoxidepoisoning")

Hydrogensulfidegas

Phosphine

Arsine(see"Chemicalterrorism:Rapidrecognitionandinitialmedicalmanagement")

Asphyxiants(eg,methane)

Also,exposuretocyanogenchloridecanmimicexposuretoanychemicalirritant(eg,chlorine)[28].

MANAGEMENTUntreated,cyanidepoisoningisrapidlylethal.Ifclinicalhistoryandexaminationaresuggestiveof
cyanidepoisoning,antidotaltherapymustbegivenimmediately,barringanycontraindications.Managementshouldalso
includeresuscitationanddecontamination.Asummarytabletofacilitateemergentmanagementisprovided(table2).
(See'Antidotaltreatmentguidelines'below.)

Caremustbetakenwhenevaluatingvictimsofsmokeinhalation.Carbonmonoxidepoisonedpatientspresentsimilarlyto
thosealsopoisonedbycyanide,andcliniciansmayfocusoneasilyobtainedcarboxyhemoglobinlevels,inadvertently
neglectingtomanagecoexistentcyanidetoxicity[18].Cyanidetoxicityshouldbeconsideredinallsmokeinhalation
patientswithtwoormoreofthefollowing:carbonaceousmaterialintheoropharynx,neurologicdysfunction,metabolic
acidosisonarterialbloodgas,andserumlactate>8mmol/L[33].(See"Inhalationinjuryfromheat,smoke,orchemical
irritants".)

Therecognitionandmanagementofcyanidepoisoningcanbedifficult,andcliniciansshouldseekassistancefroma
medicaltoxicologistoraregionalpoisoncenteriftheyhaveanyquestionsorconcerns.(See'Additionalresources'
below.)

ResuscitationFirst,cliniciansmuststabilizethepatient'sairway,breathing,andcirculation.Thepatient'sairway
shouldbesecuredasnecessaryandhighflowoxygenshouldbegiven,regardlessofpulseoximetryreadings.Mouthto
mouthresuscitationiscontraindicatedincyanidepoisoningduetotheriskofexposuretotheproviderofcardiopulmonary
resuscitation(CPR)[16].Otherwise,CPRshouldbeprovidedasperadvancedcardiaclifesupportprotocols.(See
"Advancedcardiaclifesupport(ACLS)inadults"and"Basiclifesupport(BLS)inadults"and"Pediatricbasiclifesupport
forhealthcareproviders".)
Inunresponsivepatients,pointofcaretestingofserumglucoseshouldbeperformedandsupplementaldextrose
administeredifthepatientishypoglycemic.Naloxoneshouldbeadministeredifopioidtoxicityissuspectedinadditionto
cyanidepoisoning.Thiamineisabenignantidoteanditsadministrationshouldbeconsidered,particularlyinpatientswith
ahistoryofalcoholabuse.(See"Stuporandcomainadults".)

Seizuresassociatedwithcyanidepoisoningaretreatedwithbenzodiazepines.Hypotensionistreatedwithfluidsand
vasopressorsasneeded.Comorbidconditionsandconcurrentexposuresaretreatedasnecessary.Detaileddiscussions
ofthegeneralmanagementofthepoisonedpatientareprovidedseparately.(See"Initialmanagementofthecriticallyill
adultwithanunknownoverdose"and"Generalapproachtodrugpoisoninginadults".)

DecontaminationPatientspoisonedbycyanidethroughinhalationortopicalexposuremustberapidlyremovedfrom
thesource,andtheirclothingtakenoffandappropriatelydiscarded.Indermalexposures,woundsmustbecleansedwith
soapandwatertopreventfurtherabsorption.Rescuersshouldwearprotectivesuitsandrespiratorsuntilproper
decontaminationiscompleted[34].(See"Topicalchemicalburns".)

Gastrointestinaldecontaminationshouldbeperformedrapidlyincasesoforalingestion,ascyanideisquicklyabsorbed.
Althoughlaboratorystudieshavedemonstratedthatcyanidebindspoorlytoactivatedcharcoal(AC),animalstudies
reportdecreasedmortalityamongratsgivenACafterlethalpotassiumcyanideingestions[35].Therefore,wesuggest
thatasingledoseofACbeadministered(50ginadults1g/kg,upto50gmaximum,inchildren).Thereisnorolefor
multipledosesofACorcathartics,suchasmagnesiumcitrateorsorbitol.Charcoalshouldbewithheldinnonintubated
patientswithadepressedmentalstatus.(See"Gastrointestinaldecontaminationofthepoisonedpatient".)

Orogastriclavageisnotrecommended.Itmaybeattemptedonlyifingestionoccurredwithin60minutesofpresentation
andalargeamountofcyanideisthoughttobepresentintheuppergastrointestinaltract[36].

AntidotesIfclinicalhistoryandexaminationaresuggestiveofcyanidepoisoning,antidotaltherapymustbegiven
immediately,barringanycontraindications.(See'Antidotaltreatmentguidelines'below.)

Antidotaltreatmentofcyanidepoisoninginvolvesthreestrategies:bindingofcyanide,inductionofmethemoglobinemia,
anduseofsulfurdonors.InEurope,thecombinationofsodiumthiosulfateandhydroxocobalaminhasprovided
successfultreatmentofseverepoisoning.IntheUnitedStates,theCyanideAntidoteKitmaystillbeusedinsome
locationstoprovidethecyanideantidotesifhydroxocobalaminisnotavailable.Thetraditionalkit(whichisnolonger
manufactured)includesamylnitrite(120.3mLampules)andsodiumnitrite(two300mg/10mLampules)toinduce
methemoglobinemia,andsodiumthiosulfate(two12.5g/50mLvials)toactasasulfurdonor.Thiskitisdesignedtotreat
twoadultpatientsoroneadultpatienttwice.Analternativekitcontainingsodiumnitriteandsodiumthiosulfateonlyis
available(Nithiodote),butagainhydroxocobalaministhepreferredtreatment.

Treatmentwithamylnitriteorsodiumnitriteiscontraindicatedincasesofconcurrentcarbonmonoxidetoxicity(see
'Inductionofmethemoglobinemia'below).

DirectcyanidebindingOnestrategyincyanideneutralizationinvolvesdirectbindingofcyanide,preferablyusing
hydroxocobalamin(Cyanokit).Dicobaltedetatealsobindscyanidebutcancauseseveresideeffects.

HydroxocobalaminHydroxocobalamin,aprecursorofvitaminB12,containsacobaltmoietythatavidlybindsto
intracellularcyanide(withgreateraffinitythancytochromeoxidase)formingcyanocobalamin[37].Thismoleculeisstable
andreadilyexcretedintheurine.Becausehydroxocobalaminactsrapidly,doesnotadverselyaffecttissueoxygenation,
andisrelativelysafe,manyinvestigatorsrecommenditbeusedasthefirstlineagentincyanidepoisoningandwe
concurwiththisapproach[38,39].

Thedoseofhydroxocobalaminis70mg/kg(typicaladultdoseis5g)givenintravenously(IV).Thisdoseiseffectivefor
themajorityofadultpatients.Asecondhalfdosemaybegivendependingupontheseverityofpoisoningortheclinical
responsetotreatment.Althoughoptimumpediatricdosingisnotwellestablished,somerecommend70mg/kgIV
(maximumdose5g)[22].Thehalflifeis24to48hours.

InFrance,hydroxocobalaminiscommonlyusedinconjunctionwithsodiumthiosulfate,acombinationshowntobe
effectiveandsafeinseverecyanidepoisoning[7,4042].Onestudyofheavysmokersfoundthathydroxocobalamin
decreasedcyanidelevelsby59percent[43].
Hydroxocobalamin,whengivenattherecommendeddose,maycauseatemporaryreddishdiscolorationoftheskin,
plasma,urine,andmucousmembranes[44,45].Thesechangeslastforapproximatelytwotothreedays,alteringthe
laboratoryvaluesoftestsperformedusingcooximetryorspectrophotometry.Bloodteststhatmaybeaffectedinclude
creatinine,lactate,aspartateaminotransferase(AST)andalanineaminotransferase(ALT),bilirubin,andmagnesium
[18,4648].Commonurinalysistestsmayalsobeaffected(eg,glucose,protein,ketones,andleukocyteanderythrocyte
counts).

Ofnote,IVinfusionofhydroxocobalaminappearstointerferewithcooximetrymeasurementsoftotalhemoglobin,
carboxyhemoglobin,methemoglobin,andoxyhemoglobin[49,50].Thismaycomplicatetheassessmentofsmoke
inhalationvictims(whomaysufferfrombothcyanideandcarbonmonoxidepoisoning)ifhydroxocobalaminis
administeredbeforebloodisobtainedfortesting.

Inonestudyofhydroxocobalaminadministrationinadults,adverseeffectsfromhighdosesincludedrash,headache,
nausea,chestdiscomfort,decreasedlymphocytepercentage,anddysphagia[51].Attherecommendeddose,both
transienthypertensionandslowingoftheheartratehavebeenreported[7,43,47].Overall,hydroxocobalaminis
consideredsafeandeffective[37,52].

DicobaltedetateDicobaltedetateisanintravenouschelatorofcyanide,witharapidonsetofaction,usedinthe
UnitedKingdom.Thedoseis20mLofa1.5percentsolutiongivenoveroneminute.Althoughitsusehasbeen
associatedwithmultipleseveresideeffectsincludingseizures,anaphylaxis,hypotension,andcardiacdysrhythmias[2],a
systematicreviewreportsthatthisantidoteisefficaciousandthatadverseeffectsmaybelessseverethanpreviously
thought[53].Adverseeffectsappeartobemoreprominentwhenevidenceofcyanidetoxicityismildorabsent.Published
casesofdicobaltedetateasanantidoteforcyanidepoisoningarelimitedto39[53],andadditionalexperiencewiththis
antidoteisnecessarytodetermineitssafetyandefficacy.

InductionofmethemoglobinemiaAnotherantidotalstrategyinvolvestheinductionofmethemoglobin.The
formationofmethemoglobinentailstheoxidationoftheferrous(Fe2+)moietyinhemoglobintotheferric(Fe3+)form.
Thisprovidesanattractivealternativebindingsiteforcyanide,indirectcompetitionwiththesiteonthecytochrome
complex.Whencyanidebindsmethemoglobin,arelativelylesstoxiccyanomethemoglobinisformed[16].

Theinductionofmethemoglobinemiaisaccomplishedbytheadministrationofamylnitrite,sodiumnitrite,or
dimethylaminophenol.Amylnitriteampulesarecrushedandtheninhaledbythepatient(eitherfromunderthepatient's
noseorviatheendotrachealtube)for30secondsofeachminute.Thirtysecondpausesallowforadequateoxygenation
duringtreatment.Amylnitriteinducesonlya5percentmethemoglobinemia,andisthusonlyatemporizingmeasure.It
maybeusedwhenintravenousaccessisunavailable,suchasintheprehospitalsetting[16].

Sodiumnitrite300mg(or10mg/kg)isadministeredintravenously,inducinga15to20percentmethemoglobinemia[51].
Thislevelofmethemoglobinemiaiseasilytoleratedbymostpatients.However,methemoglobinshiftstheoxygen
hemoglobindissociationcurvetotheleftfurtherhinderingoxygendeliverytotissues(figure2).Adecreaseddoseis
requiredforchildrenweighinglessthan25kgandpatientswithanemia.A20to30percentlevelofmethemoglobinemia,
thegoalofcyanidetreatmentintheaverageadultpatient,maybelethalinchildrenoranemicpatients,whohavelittle
reserve.Nitritesshouldbeavoidedinpregnantwomen.

Theappropriatedoseofsodiumnitritegiventoadultpatientsincapableoftoleratingsignificantmethemoglobinemiais
adjustedaccordingtothepatient'shemoglobin.Amedicaltoxicologistorregionalpoisoncentershouldbeconsultedfor
appropriatedosing.Approximateinitialdosingisasfollows:

Hemoglobin7g/dL,doseis0.19mL/kgof3percentsodiumnitrite
Hemoglobin8g/dL,doseis0.22mL/kgof3percentsodiumnitrite
Hemoglobin9g/dL,doseis0.25mL/kgof3percentsodiumnitrite
Hemoglobin10g/dL,doseis0.27mL/kgof3percentsodiumnitrite
Hemoglobin11g/dL,doseis0.30mL/kgof3percentsodiumnitrite

Patientsreceivingnitritesmaydevelophypotensionandtachycardia[16].Thesesideeffectsaresomewhatrate
dependent.Arthralgias,myalgias,vomiting,andpsychosismayalsooccur.
Inadditiontoinducingamethemoglobinemia,nitritesmayprovidebenefitbycausingvasodilation.Nitritesreleasenitrous
oxide,avasodilator,leadingtoincreasedbloodflowtotheliverandotherorgans,therebyenhancingthemetabolismof
cyanide.Thisproposedeffectissupportedbythesuccessofothervasodilatorsinprotectingthebodyfromcyanide
toxicity[22,54].

Dimethylaminophenol(4DMAP),anagentintroducedinGermany,isanotherinducerofmethemoglobin.4DMAPis
giveninadoseof5mLofa5percentsolutionIVoveroneminute.Itispotentandrapidlyacting,achievingpeaklevelsof
methemoglobinwithinfiveminutesofadministration.Thepotencyof4DMAP,whichcanrequiremethyleneblueto
reversetheextentofmethemoglobinemia,isproblematic.Methyleneblue,therecommendedreversalagentfor
methemoglobinemia,shouldbeavoidedinthesettingofcyanidepoisoningbecauseitsusecanreleasefreecyanide[55].
Otherpotentialadverseeffectsof4DMAPincludereticulocytosis,nephrotoxicity,andhemolysis[2].(See"Clinical
features,diagnosis,andtreatmentofmethemoglobinemia".)

Ofspecialnote,patientswhoarevictimsoffiresmaybesufferingfrombothcarbonmonoxideandcyanidetoxicity.
Carboxyhemoglobincausestheoxygenhemoglobindissociationcurvetobeshiftedtotheleftcreatingtissuehypoxia.In
thesepatients,theinductionofmethemoglobinemiacouldbelethal[56].(See"Carbonmonoxidepoisoning"and
"Inhalationinjuryfromheat,smoke,orchemicalirritants".)

SulfurdonorsAthirdantidotalstrategyinvolvesmaximizingtheavailabilityofsulfurdonorsforrhodanese,a
ubiquitousenzymethatdetoxifiescyanidebytransformingittothiocyanate.Thiocyanateisthenrenallyexcreted.Sodium
thiosulfateisthetherapeuticsulfurdonorofchoice.

Intheory,a3:1ratioofsodiumthiosulfatetocyanideisrequiredforcompletedetoxification.Thestandardadultdoseof
sodiumthiosulfateis50mLofa25percentsolution,or12.5g[16,22].Theonsetofactionmaybeslow(upto30
minutes).Becausethiocyanatelevelsof10mg/dLorhighermaycausepsychosis,arthralgias,vomiting,andmyalgias,
patientswithrenalfailuremayrequirehemodialysistoremoveitfromthebloodstream[7].However,inmostpatients
sodiumthiosulfateissafeandwelltolerated.

Inananimalexperiment,nitritetreatmentalonetripledthedoseofcyanideneededtocausedeath,whilethiosulfate
treatmentalonequadrupledthedose.Incombination,however,nitritesandthiosulfateincreasedthedoseofcyanide
requiredtocausedeath13fold[22],suggestingsynergybetweenthetwotreatments.

HyperbaricoxygenTheresultsoftwoanimalstudiessuggestthathyperbaricoxygen(HBO),usedincombination
withantidotaltherapy,isaneffectivetreatmentforcyanidetoxicity[57,58].OnestudyfoundthatHBOmayfacilitate
transportofcyanidefromtissuetoblood,theoreticallyenhancingdetoxification[57].Theotherreportedimproved
respiratorystatusandadecreasedsurgeinbrainlactatewithHBOtherapy[58].However,duetoinconsistentfindingsin
theliteratureoverall,theuseofHBOtherapyincyanidepoisoningremainscontroversial.Furtherresearchandcontrolled
studiesinhumansareneeded.

AntidotaltreatmentguidelinesCyanidepoisoningisrare,butwhenpresentrequiresdecisiveaction.We
recommendtreatmentwithsodiumthiosulfateandhydroxocobalaminwhenavailable.Inhospitalswithout
hydroxocobalamin,treatmentwithnitritesmaybelifesaving,butinductionof20to30percentmethemoglobinemiaina
patientwhoiscriticallyillfromanothercausemayprovecatastrophic.Whenthehistorystronglysuggestscyanide
toxicity,werecommendprompttreatmentwithbothnitritesandsodiumthiosulfate.Insuchcases,thebenefitsoftherapy
outweightherisksofmethemoglobinemia.Notethatmethemoglobinemiamaybelethalinchildrenoranemicpatients,
whohavelittlereserve,andnitritesshouldbeavoidedinpregnantwomen.(See'Inductionofmethemoglobinemia'
above.)

ProbablecyanideintoxicationAvailabilityoftreatmentvariesbyregionandhospital.Immediatelybelowisa
seriesofantidotalmanagementrecommendations,basedupontreatmentavailability,forpatientswithprobablecyanide
intoxication:

Forpatientsinlocationswherehydroxocobalaminisavailable,itisthepreferredtreatmentandwerecommend:

Sodiumthiosulfate25percent,1.65mL/kgIV(maximumdose12.5g)AND

Hydroxocobalamin70mg/kgIV(5gisthestandardadultdose)
 Forpatientswithoutcontraindicationtonitrites,inlocationswherehydroxocobalaminisnotavailable,werecommend
theCyanideAntidoteKit,ifavailable,whichconsistsofthefollowingthreemedications:

Amylnitriteinhaledbythepatient(heldunderthepatient'snoseorviatheendotrachealtube)for30secondsof
eachminute,forthreeminutes

Sodiumnitrite10mg/kgIVAND

Sodiumthiosulfate(25percent)1.65mL/kgIV(maximumdose12.5g)

Somekitsdonotcontainamylnitrite.Insuchcases,givesodiumnitriteandsodiumthiosulfateinthesamedoses.

Forpatientswithcontraindicationstonitritesorwithsmokeinhalation(pendingtestresultsforcarboxyhemoglobin),
inlocationswherehydroxocobalaminisnotavailable,werecommend:

Sodiumthiosulfate(25percent)1.65mL/kgIV(maximumdose12.5g)only

Inlocationswhere4dimethylaminophenol(4DMAP)ordicobaltedetateisavailable,andthereareno
contraindicationstoeitherdrug,andneitherhydroxocobalaminnortheCyanideAntidoteKitisavailable,we
recommend:

4DMAP(5percent)5mLIVoveroneminuteOR

If4DMAPisunavailableandthediagnosisisclear,dicobaltedetate(1.5percent)20mLIVoveroneminute,
ONLYifcyanidepoisoningishighlysuspectedorconfirmed

QuestionablecyanideintoxicationImmediatelybelowisaseriesofantidotalmanagementrecommendations,
basedontreatmentavailability,forpatientswithquestionablecyanideintoxication:

Forpatientsinlocationswherehydroxocobalaminisavailable,werecommend:

Sodiumthiosulfate(25percent)1.65mL/kgIV(maximumdose12.5g)AND

Hydroxocobalamin70mg/kgIV(5gisthestandardadultdose)

Forpatientsinlocationswherehydroxocobalaminisnotavailable,buttheCyanideAntidoteKitisavailable,we
recommend:

Sodiumthiosulfate(25percent)1.65mL/kgIV(maximumdose12.5g)withouttheuseofnitrites

Aftersodiumthiosulfateisadministered,furthertesting(eg,mixedcentralvenousoxygensaturation,bloodgas
analysis,andcooximetryforcarboxyhemoglobinemiaandmethemoglobinemia)shouldbeobtainedpromptly.If
ancillarydatastronglysupportcyanidetoxicityoverotherpotentialcausesofthepatient'ssymptoms,werecommend
theadministrationofnitritesasdescribedabove.(See'Probablecyanideintoxication'above.)

EmpirictreatmentforsmokeinhalationCliniciansshouldconsiderthepossibilityofcyanidetoxicityandmaintain
alowthresholdforinitiatingtreatmentinvictimsofsmokeinhalation.Frequently,victimsofhousefireshaveadepressed
levelofconsciousness,whichmaybecausedbycyanide,carbonmonoxide,otherinhaledoringestedtoxins,traumatic
shock,orheadinjury.Thepathophysiologyandgeneralmanagementofsmokeinhalationisdiscussedelsewhere.(See
"Inhalationinjuryfromheat,smoke,orchemicalirritants".)

Wesuggestempirictreatmentforcyanidetoxicitybeinitiatedinvictimsofsmokeinhalationwithanunexplainedlactic
acidosisoralowordecliningendtidalCO2(EtCO2)level.Ifthesemeasurementsareunavailable,wesuggesttreatment
beinitiatedinanypatientdemonstratingadepressedlevelofconsciousness,cardiacarrest,orhemodynamic
decompensation[59].

Wesuggestthefollowingantidotaltreatment:

Sodiumthiosulfate(25percent)1.65mL/kgIV(maximumdose12.5g)AND

Hydroxocobalamin70mg/kgIV(5gisthestandardadultdose)
Treatmentwithamylnitriteorsodiumnitriteiscontraindicatedincasesofpotentialcarbonmonoxidetoxicity(eg,froma
fire),untilcarbonmonoxidetoxicityhasbeenexcluded.

SerumlactateandEtCO2monitoringmayprovideusefulinformationwhendeterminingmanagementofsmokeinhalation
victims.Cyanidetoxicitypoisonsmitochondria,forcingcellstouseanaerobicmetabolism.Thisresultsinalacticacidosis
andacompensatorydropinEtCO2.(See'Pathophysiology'above.)

PEDIATRICCONSIDERATIONSThepathophysiologyandclinicalmanifestationsofacutecyanidepoisoningare
similarforchildrenandadults[60].However,pediatricpatientsappeartobemorevulnerabletocyanidepoisoningfrom
smokeinhalation.Thisisthoughttobeduetotheirimmaturemetabolism,lowerbodymass,andhigherrespiratoryrate.
(See'Clinicalpresentation'above.)

Asyoungchildrenhavehigherconcentrationsoffetalhemoglobinandlessmethemoglobinreductasethanadults,
inducedmethemoglobinemiacanreduceoxygencarryingcapacitytodangerouslylowlevels.Therefore,
hydroxocobalaministhepreferredtreatmentforcyanideintoxication,anditisconsideredsafeinchildren[61].Although
optimumpediatricdosingisnotwellestablished,somerecommend70mg/kgIV(maximum5g)[22,61].

ThemajorconcerninpediatricpatientswithcyanidepoisoninginvolvesmanagementusingtheCyanideAntidoteKit,
whenhydroxocobalaminisunavailable.

Inordertoavoiddangerouslyhighmethemoglobinlevels,sodiumnitriteshouldbedosedaccordingtothepatient's
hemoglobin.Amedicaltoxicologistorregionalpoisoncentershouldbeconsultedfordosingdetailsandassistancewith
management.Theapproximateinitialdoseofsodiumnitrite,tobegivennofasterthan5mL/min,isasfollows[9]:

Hemoglobin7g/dL,doseis0.19mL/kgof3percentsodiumnitrite
Hemoglobin8g/dL,doseis0.22mL/kgof3percentsodiumnitrite
Hemoglobin9g/dL,doseis0.25mL/kgof3percentsodiumnitrite
Hemoglobin10g/dL,doseis0.27mL/kgof3percentsodiumnitrite
Hemoglobin11g/dL,doseis0.30mL/kgof3percentsodiumnitrite
Hemoglobin12g/dL,doseis0.33mL/kgof3percentsodiumnitrite
Hemoglobin13g/dL,doseis0.36mL/kgof3percentsodiumnitrite
Hemoglobin14g/dL,doseis0.39mL/kgof3percentsodiumnitrite

Pointofcarehemoglobintestingmakesthisapproacheasiertoperform.Inemergencydepartmentswherearapid
hemoglobinlevelisdifficulttoobtain,pediatricpatientscanbedosedonthebasisofweight.Sodiumnitriteisgiven10
mg/kgIV,or0.33mL/kgofa3percentsolutionIV.Thedoseshouldnotexceed10mLandshouldnotbegivenatarate
greaterthan5mL/mininordertoavoidsignificanthypotension.

SodiumthiosulfateisgivenIV1.65mL/kgofa25percentsolution,uptoamaximumof12.5g(50mL).Sodium
thiosulfateappearstocausefeweradverseeffectsthansodiumnitriteandisconsideredsafeforuseinchildren[9,16].
Gastrointestinalsymptomsandlocalizedburningattheinjectionsitewerenotedinonevolunteerstudy[43].

ADDITIONALRESOURCESRegionalpoisoncontrolcentersintheUnitedStatesareavailableatalltimesfor
consultationonpatientswhoarecriticallyill,requireadmission,orhaveclinicalpicturesthatareunclear(1800222
1222).Inaddition,somehospitalshaveclinicaland/ormedicaltoxicologistsavailableforbedsideconsultationand/or
inpatientcare.Wheneveravailable,theseareinvaluableresourcestohelpinthediagnosisandmanagementof
ingestionsoroverdoses.TheWorldHealthOrganizationprovidesalistingofinternationalpoisoncentersatitswebsite:
www.who.int/gho/phe/chemical_safety/poisons_centres/en/index.html

SUMMARYANDRECOMMENDATIONSCyanideisamongthemostrapidlylethalpoisonsknowntoman.Asummary
tabletofacilitateemergentmanagementisprovided(table1).Cliniciansshouldseekassistancefromamedical
toxicologistoraregionalpoisoncenter.(See'Additionalresources'above.)

Acutecyanidepoisoningmayresultfromabroadrangeofexposures(table2).Inindustrializedcountries,themost
commoncauseisdomesticfires.Poisoningcanalsooccurfromindustrialexposure(eg,mining,electroplating,plastic
manufacturing),standardandalternativemedicaltreatments(eg,nitroprusside,laetrile),andcertainfoods(eg,Rosaceae
family).(See'Epidemiology'above.)
Cyanidetoxicityoccursfromcellularhypoxia,whichresultsinananiongapmetabolicacidosis.(See'Pathophysiology'
above.)

Clinicalfindings

Clinicalfeaturesofcyanidepoisoningaredependentupontheroute,duration,andamountofexposure.Central
nervoussystemandcardiovascularsystemdysfunctionaremostprominent.Symptomsandsignsaredescribedin
detailabove.(See'Clinicalpresentation'above.)

Becauseofthedecreasedutilizationofoxygenbytissues,venousoxyhemoglobinconcentrationwillbehigh,making
venousbloodappearbrightred.Therefore,despitehypotension,apnea,and/orbradycardia,thepatientdoesnot
appearcyanoticinthesettingofcyanidepoisoning.(See'Clinicalpresentation'above.)

Toxicityfromparenteralexposurebeginswithinseconds,toxicityfromaningestionordermalexposureisdelayed
fromminutestohours(table3).Delayedandchronicsequelaearediscussedabove.(See'Clinicalpresentation'
above.)

Patientswhoarevictimsoffiresorreportedingestions,areexposedtocyanideatwork,orhaverecentlybeen
treatedwithsodiumnitroprussideareallpotentiallycyanidepoisoned.Intheeventthathistoryisunavailable,
cliniciansshouldconsideranypatientwithalteredmentalstatusandasevereaniongapmetabolicacidosisof
unknownetiologyapossiblecyanidepoisoning.(See'Diagnosis'above.)

Testing

Routinelaboratoryevaluationinpotentialcyanideintoxicationshouldincludethefollowing:pointofcare(eg,
fingerstick)glucose,acetaminophenandsalicylatelevels,electrocardiogram,andapregnancytestinwomenof
childbearingage.(See'Laboratoryevaluation'above.)

Specifictestinginpotentialcyanideintoxicationshouldincludethefollowing:

Basicchemistries(Na+,Cl,K+,HCO3)andarterialbloodgastoassessforaniongapmetabolicacidosis

Serumlactatetoconfirmlacticacidosisandassessseverityofexposure

Centralvenousbloodgas,ifpossible,toassessforadiminishedvenousarterialPO2gradient

Carboxyhemoglobinandmethemoglobinlevels(measuredbycooximetry),particularlyifthereisanyconcernfor
concomitantcarbonmonoxideexposure(eg,houseorvehiclefire)orexposuretodrugsthatproduce
methemoglobinemia(table4).IVinfusionofhydroxocobalaminmayinterferewithcooximetrymeasurementsoftotal
hemoglobin,carboxyhemoglobin,methemoglobin,andoxyhemoglobin.(See'Laboratoryevaluation'aboveand
"Inhalationinjuryfromheat,smoke,orchemicalirritants".)

TreatmentCliniciansshouldseekassistancefromamedicaltoxicologistoraregionalpoisoncenter.(See'Additional
resources'above.)

Theclinician'sfirstresponsibilityistostabilizethepatient'sairway,breathing,andcirculation.Mouthtomouth
resuscitationiscontraindicatedduetothepotentialforproviderexposure.Otherwise,cardiopulmonary
resuscitationshouldbeprovidedasperadvancedcardiaclifesupportprotocols.(See"Advancedcardiaclifesupport
(ACLS)inadults".)(See'Resuscitation'above.)

Patientspoisonedbycyanidethroughinhalationortopicalexposuremustberapidlyremovedfromthesource,and
theirclothingtakenoffandappropriatelydiscarded.Indermalexposures,woundsmustbecleansedwithsoapand
watertopreventfurtherabsorption.Rescuersshouldwearprotectivesuitsandrespiratorsuntilproper
decontaminationiscompleted.

Gastrointestinaldecontaminationshouldbeperformedincasesoforalingestion.Duetotherapidabsorptionof
cyanide,oraldecontaminationshouldbeperformedrapidly.Werecommendthatasingledoseofactivatedcharcoal
(AC)beadministered(Grade1B)thetypicaldoseis50ginadultsand1g/kginchildren.Thereisnorolefor
multipledosecharcoalorcharcoalcathartics,suchasmagnesiumcitrateorsorbitol.Charcoalshouldbewithheldin
 patientswhoaresedatedormaynotbeabletoprotecttheirairway,unlesstrachealintubationisperformedfirst.
(See"Gastrointestinaldecontaminationofthepoisonedpatient".)

Antidotaltreatmentofcyanidepoisoninginvolvesthreestrategies:bindingofcyanide,inductionof
methemoglobinemia,anduseofsulfurdonors.Eachisdescribedinthetext.(See'Antidotes'above.)

Basedupontreatmentavailability,werecommendthefollowingapproachestoantidotaltherapyforpatientswith
probablecyanideintoxication.Treatmentforpatientsinwhomcyanidepoisoningispossiblebutunlikelyisdescribed
indetailabove.(See'Antidotaltreatmentguidelines'above.):

Forpatientsinlocationswherehydroxocobalaminisavailableitisthepreferredtherapy,andwerecommendthe
followingtreatment(Grade1B):

Sodiumthiosulfate(25percent)1.65mL/kgIV(maximumdose12.5g),and

Hydroxocobalamin70mg/kgIV(5gisthestandardadultdose)

Forpatientswithoutcontraindicationtonitrites,inlocationswherehydroxocobalaminisnotavailable,andthe
CyanideAntidoteKitisavailable,werecommendthefollowingtreatment(Grade1B):

Amylnitriteinhaledbythepatient(heldunderthepatient'snoseorviatheendotrachealtube)for30secondsof
eachminute,forthreeminutes

Sodiumnitrite10mg/kgIV,and

Sodiumthiosulfate(25percent)1.65mL/kgIV(maximumdose12.5g)

Somekitsdonotcontainamylnitrite.Insuchcases,givesodiumnitriteandsodiumthiosulfateinthesamedoses.

Forpatientswithcontraindicationstonitritesorwithsmokeinhalation(pendingtestresultsforcarboxyhemoglobin),
inlocationswherehydroxocobalaminisnotavailable,werecommendthefollowingtreatment(Grade1B):

Sodiumthiosulfate(25percent)1.65mL/kgIV(maximumdose12.5g)only

Inlocationswhere4dimethylaminophenol(4DMAP)ordicobaltedetateisavailable,andthereareno
contraindicationstoeitherdrug,andneitherhydroxocobalaminnortheCyanideAntidoteKitisavailable,we
recommendthefollowingtreatment(Grade1B):

4DMAP(5percent)5mLIVoveroneminute

OR,if4DMAPisunavailable,

Dicobaltedetate(1.5percent)20mLIVoveroneminute,ONLYifcyanidepoisoningishighlysuspectedor
confirmed

UseofUpToDateissubjecttotheSubscriptionandLicenseAgreement.

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braininterstitiallactateandglucoseandhyperbaricoxygenimprovesrespiratorystatusincyanideintoxicatedrats.
UnderseaHyperbMed201138:223.
59.ErdmanAR.Ishydroxocobalaminsafeandeffectiveforsmokeinhalation?Searchingforguidanceinthehaze.Ann
EmergMed200749:814.
60.GellerRJ,BartholdC,SaiersJA,HallAH.Pediatriccyanidepoisoning:causes,manifestations,management,and
unmetneeds.Pediatrics2006118:2146.
61.MintegiS,ClerigueN,TipoV,etal.Pediatriccyanidepoisoningbyfiresmokeinhalation:aEuropeanexpert
consensus.ToxicologySurveillanceSystemoftheIntoxicationsWorkingGroupoftheSpanishSocietyofPaediatric
Emergencies.PediatrEmergCare201329:1234.

Topic299Version17.0
GRAPHICS

Cyanidepoisoning:Rapidoverview

Toobtainemergentconsultationwithamedicaltoxicologist,calltheUnitedStatesPoisonControlNetworkat18002221222,or
accesstheWorldHealthOrganization'slistofinternationalpoisoncenters
(www.who.int/gho/phe/chemical_safety/poisons_centres/en/index.html).

Generalinformation
Cyanidepoisoningisrapidlylethalunlesstreatedwithantidote

Clinicalfeatures
History

Ascertainifpatienthasaccesstocyanide,orifpatientwaspartofahighriskevent(eg,fire,industrialexposure)

Initialsymptomsarenonspecific:headache,anxiety,confusion,abdominalpain

Physicalexamination

Vitalsigns:initialhypertension/tachycardia/tachypneaprogressestorespiratoryandcirculatorycollapse

Skin:maybeflushedwith"cherryred"color

Neurologic:seizuresandcomaaspoisoningprogresses

Laboratoryevaluation
Obtainthefollowing:

Fingerstickglucose,acetaminophenandsalicylatelevels,electrocardiogram,andpregnancytest(whenappropriate)

Basicchemistriesandserumlactate
Elevatedaniongapacidosis,withelevatedlactate,expectedincyanidepoisoning
Venousbloodappearsbrightred

Centralvenousbloodgaswithconcomitantarterialbloodgas
NarrowedvenousarterialPO2gradientsupportscyanidetoxicity

Carboxyhemoglobinandmethemoglobinlevels
Ruleoutdyshemoglobinemias
Usenitrites(seebelow)cautiouslyornotatallinpresenceofdyshemoglobinemias

Cyanidepoisoningcancause:renalfailure,hepaticfailure,rhabdomyolysis,pulmonaryedemaobtainrelevantstudiesas
indicated

Generaltreatment
Secureairway,breathing,andcirculation.Intubationisusuallyrequired.Administerhighflowoxygenbynonrebreather
facemaskregardlessofpulseoximetryreading.

DoNOTperformmouthtomouthresuscitationincasesofsuspectedcyanidetoxicity.Patientswithdermalexposuremust
bedecontaminatedusingproperprecautions.

Giveasingledoseofactivatedcharcoaliftheairwayisadequatelyprotected(50ginadults1g/kginchildrenwithmaximum
doseof50g)

TreathypotensionwithrapidIVbolusesofisotonicfluidandvasopressorsasneeded.Treatseizureswithabenzodiazepine(eg,
diazepam5mgIV).

Obtainassistancefrommedicaltoxicologistorpoisoncontrolcenter

Antidotaltreatment
Administercyanideantidotewhencyanidepoisoningisclinicallysuspected.Hydroxocobalaministhepreferredantidote.

Ifhydroxocobalaminisavailable,givethefollowing:
Hydroxocobalamin70mg/kgupto5gIV(5gisstandardadultdose)
Sodiumthiosulfate(25percent):1.65mL/kgupto50mLIVmayrepeatonce(maximumdose12.5g)

Ifhydroxocobalaminisnotavailable,cyanidetoxicityisknownorstronglysuspected,andtherearenocontraindicationsto
nitrites,givethefollowing:
Sodiumnitrite10mg/kgupto300mgbyslowIVinfusionmayrepeatonce
Sodiumthiosulfate(25percent)1.65mL/kgupto50mLIVmayrepeatonce

Ifhydroxocobalaminisnotavailableandcyanidetoxicityispossiblebutnotcertain,orthepatienthascontraindicationsto
 nitrites,givethefollowing:
Sodiumthiosulfate(25percent)1.65mL/kgupto50mLIVmayrepeatonce

Refertotopicfordetailsaboutnitritetreatmentforchildrenandpatientswithanemia,andfortreatmentincasesofunlikely
cyanidepoisoning

Graphic65052Version12.0
Sourcesofcyanide

Industrialexposures
Plasticsproduction

Photography

Fumigation

Pesticides/Rodenticides

Syntheticrubberproduction

Fertilizerproduction

Metalpolish

Hairremovalfromhides

Electroplating

Metallurgy

Plantsandfruits
Bamboosprout

Macadamianuts

Hydrangea

Rosaceaefamily(plum,peach,pear,apple,bitteralmond,cherry)

Miscellaneous
Cigarettesmoking

Phencyclidinesynthesis

Artificialnailglueremover

Producttampering

Suicide/Terroristattack

Drugs
SodiumNitroprusside

Laetrile

Combustion
Wool

Silk

Polyurethanes

Polyacrylonitriles

Nylon

Melamineresins

Plastics

Graphic76365Version1.0
Mitochondrialmetabolism

Schematicrepresentationshowingthestepswithinthemitochondriainwhichenergystoredinfattyacids,
pyruvate,andaminoacidsistransformedintoATP.Energysubstratesarefirsttransportedintothe
mitochondriawhere,afterconversionintoacetylCoA,theyenterthetricarboxylicacidcycle(TCA).The
reducedformsofnicotinamideadeninedinucleotide(NADH)andflavinadeninedinucleotide(FAD)are
formedfromthecitricacidcycleandthebetaoxidationoffattyacidsinthemitochondrialmatrix.
Subsequently,oxidativephosphorylationortherespiratorychain,whichiscomposedoffourmultisubunit
complexes(I,II,III,andIV)linkedbythemobileelectroncarrierscoenzymeQandcytochromec.The
respiratorychaintransferselectronsfromNADH(viacomplexI)andfromreducedflavoproteins(via
complexIIandelectrontransferflavoproteincoenzymeQoxidoreductase[ETFQo])tocoenzymeQ10,
thencomplexIII,cytochromecandfinallycomplexIV,wheretheycombinewithmolecularoxygento
formwater.

CoQ:CoenzymeQNADH:NicotinamideadeninedinucleotidereducedFMN:FlavinmononucleotideFES:Non
hemeironsulfurproteinPi:InorganicphosphateTCA:Tricarboxylicacidcycle.

Redrawnwithpermissionfrom:DiMauro,S,DeVivo,D.Diseasesofcarbohydrate,fattyacid,andmitochondrial
metabolism.In:BasicNeurochemistry,Seigel,G,etal(Eds),Raven,NewYork,1989,p.647.

Graphic78699Version1.0
Toxiccyanidedoses

RouteofExposure ToxicDose

Inhalation 100ppmx30min

300ppmx5min

Oral 50mg(HCN)

200mg(KCN)

Dermal 100mg/kg

Intravenous 510g/kg/minx310hrs

Graphic52242Version2.0
Oxyhemoglobindissociationcurve

Depictedhereistheoxyhemoglobindissociationcurvefornormaladulthemoglobin
(hemoglobinA,solidline).Notethatatapartialpressureofoxygenof27mmHgon
theXaxis,hemoglobinis50%saturatedwithoxygen(theP50is27mmHg),andatan
arterialpartialpressureofoxygenof100mmHg,hemoglobinis100%saturated.At
thetypicalmixedvenousoxygentensionofapproximately40mmHg,theoxygen
saturationofhemoglobinisapproximately75%.Shiftingthecurvetotheright(red
line)canreduceoxygensaturationto50to60%forthepartialoxygenpressureof40
mmHg,meaningthatlessoxygenisboundtohemoglobinandmoreoxygenis
deliveredtothetissues.Theoppositeoccurswithleftshifts(blueline).Ahigh
proportionoffetalhemoglobin,whichhashighoxygenaffinity,shiftsthiscurvetothe
leftinnewborns.Theeffectofrightorleftshiftingofthecurveismostpronouncedat
lowpartialpressuresofoxygen.

Graphic81216Version7.0
Agentsknowntocausemethemoglobinemia

Acetanilide Naphthoquinone

pAminosalicylicacid Naphthalene

Aniline,anilinedyes Nitrites

Benzenederivatives Amylnitrite
Farrylnitrite
Clofazimine
Sodiumnitrite
Chlorates
Nitroglycerin
Chloroquine Nitricoxide
Dapsone Nitrobenzene
Localanestheticagents Paraquat
Benzocaine
Phenacetin
Lidocaine
Phenazopyridine
Prilocaine
Primaquine
Menadione
Rasburicase
Metoclopramide
Resorcinol
Methyleneblue*
Sulfonamides

*Whilemethyleneblueisarecognizedtreatmentformethemoglobinemia,itisanagentwithoxidantpotential,andmayworsenthe
clinicalsituation,sinceinindividualswithglucose6phosphatedehydrogenasedeficiencyitinducesacutehemolysisthatcanfurther
decreaseoxygendeliverytothetissues.Paradoxically,inhighdosesmethylenebluecanalsoincreasemethemoglobinemia.

Graphic51406Version4.0
Contributor Disclosures
Shoma Desai, MD Nothing to disclose Mark Su, MD, MPH Nothing to disclose Stephen J Traub, MD Nothing to
disclose Jonathan Grayzel, MD, FAAEM Nothing to disclose

Contributor disclosures are reviewed for conicts of interest by the editorial group. When found, these are addressed by
vetting through a multi-level review process, and through requirements for references to be provided to support the
content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of
evidence.

Conict of interest policy