Академический Документы
Профессиональный Документы
Культура Документы
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.
REFERENCES
1.AmericanAssociationofPoisonControlCenters.ToxicExposureSurveillanceSystem.AnnualReports19932002.
www.aapcc.org
2.MgarbaneB,DelahayeA,GoldgranToldanoD,BaudFJ.Antidotaltreatmentofcyanidepoisoning.JChinMed
Assoc200366:193.
3.VogelSN,SultanTR,TenEyckRP.Cyanidepoisoning.ClinToxicol198118:367.
4.BismuthC,BaudFJ,DjeghoutH,etal.Cyanidepoisoningfrompropionitrileexposure.JEmergMed19875:191.
5.WegerNP.Treatmentofcyanidepoisoningwith4dimethylaminophenol(DMAP)experimentalandclinical
overview.FundamApplToxicol19833:387.
6.WalshDW,EcksteinM.Hydrogencyanideinfiresmoke:anunderappreciatedthreat.EmergMedServ2004
33:160.
7.SauerSW,KeimME.Hydroxocobalamin:improvedpublichealthreadinessforcyanidedisasters.AnnEmergMed
200137:635.
8.CummingsTF.Thetreatmentofcyanidepoisoning.OccupMed(Lond)200454:82.
9.Sullivan,JB,Krieger,CR.ClinicalEnvironmentalHealthandToxicExposures,2nd,LippincottWilliamsandWilkins,
Philadelphia2001.p.705.
10.HallAH,LindenCH,KuligKW,RumackBH.Cyanidepoisoningfromlaetrileingestion:roleofnitritetherapy.
Pediatrics198678:269.
11.O'BrienB,QuiggC,LeongT.Severecyanidetoxicityfrom'vitaminsupplements'.EurJEmergMed200512:257.
12.BromleyJ,HughesBG,LeongDC,BuckleyNA.Lifethreateninginteractionbetweencomplementarymedicines:
cyanidetoxicityfollowingingestionofamygdalinandvitaminC.AnnPharmacother200539:1566.
13.LitovitzTL,LarkinRF,MyersRA.Cyanidepoisoningtreatedwithhyperbaricoxygen.AmJEmergMed19831:94.
14.GonzalesJ,SabatiniS.Cyanidepoisoning:pathophysiologyandcurrentapproachestotherapy.IntJArtifOrgans
198912:347.
15.VeseyCJ,ColePV,SimpsonPJ.Cyanideandthiocyanateconcentrationsfollowingsodiumnitroprussideinfusionin
man.BrJAnaesth197648:651.
16.Bryson,PD.ComprehensiveReviewinToxicologyforEmergencyClinicians,3rd,TaylorandFrancis,Denver1996.
p.352.
17.TheNewYorkPoisionControl,Center.AnIntensiveReviewCourseinClinicalToxicology,2005.p.141.
18.HuzarTF,GeorgeT,CrossJM.Carbonmonoxideandcyanidetoxicity:etiology,pathophysiologyandtreatmentin
inhalationinjury.ExpertRevRespirMed20137:159.
19.HallAH,RumackBH.Clinicaltoxicologyofcyanide.AnnEmergMed198615:1067.
20.MizockBA.Lacticacidosis.DisMon198935:233.
21.TURSKYT,SAJTERV.Theinfluenceofpotassiumcyanidepoisoningonthegammaaminobutyricacidlevelinrat
brain.JNeurochem19629:519.
22.MoroccoAP.Cyanides.CritCareClin200521:691.
23.MohanA,LeeT,SachdevP.Survivingacutecyanidepoisoning:alongitudinalneuropsychologicalinvestigationwith
intervalMRI.BMJCaseRep20142014.
24.Amdur,MO,Doull,J,Klacessan,CD,et,al.CasarettandDoull'sToxicology:TheBasicScienceofPoisons,4th,
McGrawHill,NewYork1991.p.227.
25.GeldnerG,KochEM,GottwaldHostalekU,etal.Reportonastudyoffireswithsmokegasdevelopment:
determinationofbloodcyanidelevels,clinicalsignsandlaboratoryvaluesinvictims.Anaesthesist201362:609.
26.FortinJL,DesmettreT,ManzonC,etal.Cyanidepoisoningandcardiacdisorders:161cases.JEmergMed2010
38:467.
27.RajashekarTs,OkadeR.Irritantcontactdermatitistoaccidentalexposureofcyanide.IndianJDermatol2013
58:162.
28.Greenberg,MI,Hamilton,RJ,Phillips,SD.Occupational,Industrial,andEnvironmentalToxicology,Mosby,St.Louis
1997.p.165.
29.BaudFJ,BorronSW,MgarbaneB,etal.Valueoflacticacidosisintheassessmentoftheseverityofacutecyanide
poisoning.CritCareMed200230:2044.
30.BaudFJ,BarriotP,ToffisV,etal.Elevatedbloodcyanideconcentrationsinvictimsofsmokeinhalation.NEnglJ
Med1991325:1761.
31.JohnsonRP,MellorsJW.Arteriolizationofvenousbloodgases:acluetothediagnosisofcyanidepoisoning.J
EmergMed19886:401.
32.RellaJ,MarcusS,WagnerBJ.RapidcyanidedetectionusingtheCyantesmokit.JToxicolClinToxicol2004
42:897.
33.LawsonSmithP,JansenEC,HyldegaardO.Cyanideintoxicationaspartofsmokeinhalationareviewon
diagnosisandtreatmentfromtheemergencyperspective.ScandJTraumaResuscEmergMed201119:14.
34.HoustonM,HendricksonRG.Decontamination.CritCareClin200521:653.
35.LambertRJ,KindlerBL,SchaefferDJ.Theefficacyofsuperactivatedcharcoalintreatingratsexposedtoalethal
oraldoseofpotassiumcyanide.AnnEmergMed198817:595.
36.MokhlesiB,CorbridgeT.Toxicologyinthecriticallyillpatient.ClinChestMed200324:689.
37.ThompsonJP,MarrsTC.Hydroxocobalaminincyanidepoisoning.ClinToxicol(Phila)201250:875.
38.DriesDJ,EndorfFW.Inhalationinjury:epidemiology,pathology,treatmentstrategies.ScandJTraumaResusc
EmergMed201321:31.
39.DumestreD,NickersonD.UseofcyanideantidotesinburnpatientswithsuspectedinhalationinjuriesinNorth
America:acrosssectionalsurvey.JBurnCareRes201435:e112.
40.BorronSW,BaudFJ,BarriotP,etal.Prospectivestudyofhydroxocobalaminforacutecyanidepoisoninginsmoke
inhalation.AnnEmergMed200749:794.
41.FortinJL,GiocantiJP,RuttimannM,KowalskiJJ.Prehospitaladministrationofhydroxocobalaminforsmoke
inhalationassociatedcyanidepoisoning:8yearsofexperienceintheParisFireBrigade.ClinToxicol(Phila)2006
44Suppl1:37.
42.HallAH,RumackBH.Hydroxycobalamin/sodiumthiosulfateasacyanideantidote.JEmergMed19875:115.
43.ForsythJC,MuellerPD,BeckerCE,etal.Hydroxocobalaminasacyanideantidote:safety,efficacyand
pharmacokineticsinheavilysmokingnormalvolunteers.JToxicolClinToxicol199331:277.
44.BorronSW,BaudFJ,MgarbaneB,BismuthC.Hydroxocobalaminforsevereacutecyanidepoisoningbyingestion
orinhalation.AmJEmergMed200725:551.
45.HeitzmanJ,ShenQ,CazaresJ,IllohO.Transfusionmedicineillustrated:hydroxocobalamincoloredplasma.
Transfusion200949:2555.
46.CurrySC,ConnorDA,RaschkeRA.Effectofthecyanideantidotehydroxocobalaminoncommonlyorderedserum
chemistrystudies.AnnEmergMed199424:65.
47.DesLauriersCA,BurdaAM,WahlM.Hydroxocobalaminasacyanideantidote.AmJTher200613:161.
48.BeckermanN,LeikinSM,AitchinsonR,etal.Laboratoryinterferenceswiththenewercyanideantidote:
hydroxocobalamin.SeminDiagnPathol200926:49.
49.LeeJ,MukaiD,KreuterK,etal.Potentialinterferencebyhydroxocobalaminoncooximetryhemoglobin
measurementsduringcyanideandsmokeinhalationtreatments.AnnEmergMed200749:802.
50.LivshitsZ,LugassyDM,ShawnLK,HoffmanRS.Falselylowcarboxyhemoglobinlevelafterhydroxocobalamin
therapy.NEnglJMed2012367:1270.
51.UhlW,NoltingA,GolorG,etal.Safetyofhydroxocobalamininhealthyvolunteersinarandomized,placebo
controlledstudy.ClinToxicol(Phila)200644Suppl1:17.
52.ShepherdG,VelezLI.Roleofhydroxocobalamininacutecyanidepoisoning.AnnPharmacother200842:661.
53.MarrsTC,ThompsonJP.Theefficacyandadverseeffectsofdicobaltedetateincyanidepoisoning.ClinToxicol
(Phila)201654:609.
54.Goldfrank,LR,Flomenbaum,NE,Lewin,NA,et,al.Goldfrank'sToxicologicEmergencies,7th,McGrawHill,New
York2002.p.1511.
55.MokhlesiB,LeikinJB,MurrayP,CorbridgeTC.Adulttoxicologyincriticalcare:PartII:specificpoisonings.Chest
2003123:897.
56.Rosen,P,Barkin,RM.EmergencyMedicine:ConceptsandClinicalPractice,3rd,Mosby,St.Louis1992.p.2682.
57.LawsonSmithP,JansenEC,HilstedL,etal.Effectofacuteanddelayedhyperbaricoxygentherapyoncyanide
wholebloodlevelsduringacutecyanideintoxication.UnderseaHyperbMed201138:17.
58.LawsonSmithP,OlsenNV,HyldegaardO.Hyperbaricoxygentherapyorhydroxycobalaminattenuatessurgesin
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.