Post on 23-Feb-2023
REVIEW ARTICLE
Review article: Management ofcyanide poisoningemm_1538 1..14
Michael C Reade,1,4,5 Suzanne R Davies,1 Peter T Morley,1,2 Jennifer Dennett1,3 and Ian C Jacobs,1,6 onbehalf of the Australian Resuscitation Council1Australian Resuscitation Council, Royal Australasian College of Surgeons, College of Surgeons’ Gardens,2Royal Melbourne Hospital and University of Melbourne, Melbourne, 3Central Gippsland Health Service,Sale, Victoria, 4Australian Defence Force, Canberra, Australian Capital Territory, 5University ofQueensland, Brisbane, 6University of Western Australia, Perth, Western Australia, Australia
Abstract
Cyanide poisoning is uncommon, but generates interest because of the presumed utility ofan antidote immediately available in those areas with a high risk of cyanide exposure. Aspart of its regular review of guidelines, the Australian Resuscitation Council conducted asystematic review of the human evidence for the use of various proposed cyanide antidotes,and a narrative review of the relevant pharmacological and animal studies. There havebeen no relevant comparative or placebo-controlled human trials. Nine case series wereidentified. Treatment with hydroxocobalamin was reported in a total of 361 cases. Noserious adverse effects of hydroxocobalamin were reported, and many patients with other-wise presumably fatal poisoning survived. Sodium thiosulphate use was reported in twocase series, similarly with no adverse effects. Treatment with a combination of sodiumnitrite, amyl nitrite and sodium thiosulphate was reported in 74 patients, with resultsindistinguishable from those of hydroxocobalamin and sodium thiosulphate. No case seriesusing dicobalt edetate or 4-dimethylaminophenol were identified, but successful use insingle cases has been reported. Hydroxocobalamin and sodium thiosulphate differ fromalternatives in having negligible adverse effects, and on the basis of current evidence arethe antidotes of choice. The indications for the use of an antidote, the requirements forsupportive care and a recommended approach for workplaces where there is a risk ofcyanide poisoning are presented.
Key words: antidote, cyanide, poisoning, resuscitation.
Introduction
Poisoning by plants containing cyanide has beenknown for millennia, but the first published descriptionof cyanide poisoning (due to bitter almonds) was byWepfer in 1679.1–3 Compounds containing cyanide ions(CN-) are rapidly acting poisons that interfere with
mitochondrial oxygen utilization. Cyanide can causepoisoning by:4
• Inhalation of cyanide-containing gas (such ashydrogen cyanide or cyanogen chloride) or dustcontaining solid or liquid cyanide. Typical sourcesare industrial (e.g. in gold and silver mining,acrylic manufacturing, electroplating, jewellery
Correspondence: Professor Michael C Reade, Level 9, Health Sciences Building, Royal Brisbane and Women’s Hospital, Herston, Qld4029, Australia. Email: m.reade@uq.edu.au or michael.reade@defence.gov.au
Michael C Reade, MBBS, MPH, DPhil, FANZCA, FCICM, Professor of Military Surgery and Medicine; Suzanne Davies, BAppSc, MPH, ResearchOfficer; Peter Morley, MBBS, FRACP, FANZCA, FCICM, Director of Medical Education; Jennifer Dennett, BAppSc(Education), MNursing,MRCNA, Nursing Unit Manager; Ian Jacobs, BAppSc, DipEd, PhD, RN, FRCNA, FACAP, Winthrop Professor of Resuscitation and Pre-HospitalCare.
doi: 10.1111/j.1742-6723.2012.01538.x Emergency Medicine Australasia (2012) ••, ••–••
© 2012 The AuthorsEMA © 2012 Australasian College for Emergency Medicine and Australasian Society for Emergency Medicine
manufacturing, steel fabrication and vermin eradica-tion), or (possibly5) combustion of plastics, acrylics,synthetic rubber, carpeting or upholstery in enclosedspaces
• Skin absorption of cyanide-containing liquids,such as hydrogen cyanide at room temperature, typi-cally in the industrial settings listed above
• Ingestion of cyanide compounds, either acutely (eitherwith suicidal intent or accidentally) or over time (e.g.in foods containing cyanogenic glycosides, such ascassava root, apricot seeds and bitter almonds)
• Metabolism of sodium nitroprusside when adminis-tered as an i.v. vasodilator at high doses over a pro-longed periodThe most common source of cyanide exposure is
smoke inhalation from residential or industrial fires,although whether the low levels of cyanide typicallyinhaled are sufficient to cause clinically important poi-soning is unclear.5
Three pharmaceuticals (sodium nitrite, sodiumthiosulphate and dicobalt edetate) are approved by theAustralian Therapeutic Goods Administration (TGA)as cyanide antidotes. Many Australian organizations,6
government departments7,8 and Poisons InformationServices9 have written guidelines that list these andother substances as part of an overall strategy, but thereis considerable variability in recommended approaches.Although industrial cyanide poisoning is rare in thedeveloped world10 (presumably because of good workpractices), maintaining a supply of a cyanide antidotethat might never be used is a significant expense.Moreover, some of the recommended antidotes arethemselves poisonous, which could make inappropriateuse a greater risk than cyanide poisoning itself.
No Australian or international authority has pub-lished a detailed evidence-based cyanide poisoningguideline resulting from a systematic review of the lit-erature. In 1996, the Australian Resuscitation Council(ARC) published a Basic Life Support guideline for themanagement of cyanide toxicity11 that gave generalfirst-aid advice but no recommendation on a particularcyanide antidote. As part of its regular update of guide-lines, the ARC conducted a systematic review of cyanidepoisoning management. We aimed to answer the ques-tion ‘in adult patients with confirmed severe cyanidepoisoning (including cardiac arrest due to cyanide poi-soning), does any intervention, as opposed to standardcare, improve survival?’. In addition, we sought litera-ture reporting evidence from animal studies, the clinicalfeatures of cyanide poisoning and the indications for theadministration of a cyanide antidote.
Methods
In November 2010, we performed a systematic literaturereview of English language publications indexed inMEDLINE, using the search terms (‘cyanides’ OR‘cyanogens’ OR ‘nitriles’ OR ‘azides’ OR ‘cyanogenicglycosides’ OR ‘nitriles’ OR ‘azides’) AND (‘antidote’ OR‘hydroxocobalamin’ OR ‘sodium nitrite’ OR ‘thiosulfate’OR ‘antidote’ OR ‘cyanokit’). In addition, we searchedthe Cochrane library by text word for ‘cyanide’,EMBASE for keywords ‘cyanide poisoning’ AND (‘anti-dote’ OR ‘hydroxocobalamin’), Scopus using both back-ward and forward strategies, and Google Scholar fortext words contained in unpublished documents. Weexcluded case reports of intoxications in which no con-clusion could be drawn regarding the efficacy of anintervention. We manually inspected reference lists ofall relevant articles.
We classified identified studies using the AustralianNational Health and Medical Research Council ‘Evi-dence Hierarchy’,12 and made treatment recommenda-tions according to ARC criteria.13
We also performed non-systematic literature reviewsfor relevant animal and cellular studies, for any consen-sus statements on the indications for the administrationof a cyanide antidote and for reports of the clinicalfeatures of cyanide poisoning. In February 2011, wesearched the Australian Register of TherapeuticGoods12 and online pharmaceutical catalogues in orderto determine the Australian availability of the variousdescribed antidotes to cyanide.
Results
Clinical features of cyanide poisoning
Early features of cyanide poisoning are irritation of oralmucous membranes (if ingested), sympathetic activa-tion leading to anxiety, tachycardia and/or arrhythmia,tachypnoea and hypertension, followed by headache,confusion, dyspnoea, hypotension and bradycardia.4,14
Later features (which can occur in rapid succession,depending on the dose) include neurological symptoms(reduced consciousness, seizure, opisthotonos ortrismus), pulmonary oedema and cardiac arrest.4 Theexpired gas from a patient with cyanide poisoning isclassically described as having a ‘bitter almond’ smell,as do many cyanide-containing compounds. However,the diagnostic sensitivity of this characteristic is low, as18% of men and 4% of women are unable to perceive
MC Reade et al.
2 © 2012 The AuthorsEMA © 2012 Australasian College for Emergency Medicine and Australasian Society for Emergency Medicine
this smell,15 a ratio that implies a sex-linked recessivetrait. The other widely quoted feature of cyanide poi-soning, bright-red (‘cherry’) discolouration of the skinand mucous membranes, is based on the theory thatdecreased tissue oxygen utilization will increase oxy-haemoglobin in venous blood. However, this degree ofcyanide toxicity is likely to cause circulatory failure,which would prevent such colouration.4 As oxidativephosphorylation is blocked, increased glycolysis leadsto lactic acidosis, the degree of which correlates with theseverity of the poisoning.16 Chronic cyanide poisoning(i.e. long-term exposure to sub-lethal concentrations ofcyanide) can be more insidious, with headaches, weak-ness, chest and abdominal pain, itch and rash.17
Supportive therapy for cyanide poisoning
The majority of deaths due to exposure to high concen-trations of cyanide are likely to occur before hospitalarrival. Although prehospital administration of specificcyanide antidotes might possibly assist victims ofcyanide poisoning, patients in cardiorespiratory arrestcan undoubtedly benefit from basic and advanced lifesupport according to ARC guidelines.18 There is,however, a risk of cyanide toxicity to rescuers perform-ing expired air resuscitation of cyanide-poisoned vic-tims,19,20 and with the exception of victims of smokeinhalation (who are unlikely to have high levels ofexpired cyanide gas, as discussed below), mouth-to-moth ventilation should not be attempted. Several pub-lished case reports demonstrate that survival is possibleafter substantial cyanide poisoning treated with sup-portive care alone. For example, nine patients simulta-neously poisoned in an industrial accident, with bloodlevels of cyanide considered lethal, had supportivetherapy alone. All survived.21 Numerous other casereports22–24 confirm this is possible. ‘Supportive care’ inthis context included the full spectrum of intensive careinterventions, including mechanical ventilation, circula-tory support and renal replacement therapy. Of note,only one patient in all of these reports suffered cardiacarrest, suggesting either supportive care instituted earlywas sufficient to prevent this, or that these patients hadin fact not ingested a lethal amount of cyanide.
One element of supportive care thought at times to beparticularly beneficial is oxygen administration. On thebasis of animal experiments, oxygen,25 and also hyper-baric oxygen,26 have been advocated as adjuncts tochemical cyanide antidotes. Any benefit appears not tobe mediated by reactivation of cytochrome oxidase oracceleration of rhodenase detoxification.27 A postulated
mechanism of action is redistribution of cyanide fromthe intracellular to intravascular compartments,28,29
although this effect could not be detected in a clinicaltrial of 25 patients.30 Oxygen significantly enhanced theantidotal effect of sodium nitrite and sodium thiosul-phate (in combination) in rats, but hyperbaric oxygenwas no more effective than normobaric 100% oxygen.31
On balance, although the mechanism remains unclear, itappears reasonable to treat victims of cyanide poisoningwith 100% oxygen.
Without studies comparing supportive care alone tothe use of an antidote, no conclusion can be drawn otherthan that the potential adverse effects of any antidotemust be weighed against the possibility that the patientmight recover with supportive care alone.
Postulated cyanide antidotes
Four types of cyanide antidotes are described in theliterature, grouped according to their modes of action.They are classified as: substances that increase themetabolism of cyanide (sodium thiosulphate, a rate-limiting substrate in the endogenous metabolic pathwayfor cyanide); substances that bind to cyanide (hydroxo-cobalamin [vitamin B12a] and dicobalt edetate); sub-stances that produce methaemoglobin, which reactswith cyanide to form non-toxic cyanomethaemoglobin(sodium nitrite, amyl nitrite and 4-dimethylaminophenol[4-DMAP]); and substances that might possibly reducethe absorption of ingested cyanide (ferrous sulphatedissolved in aqueous citric acid and aqueous sodiumcarbonate: ‘Solutions A and B’). Only sodium thiosul-phate, sodium nitrite and dicobalt edetate are listed onthe Australian Register of Therapeutic Goods for thetreatment of cyanide poisoning.32 Hydroxocobalamin islisted in the 1 mg/mL parenteral form used to treatpernicious anaemia and optic neuropathy, but not the2.5 g form studied as a cyanide antidote. Hydroxocobal-amin 2.5 g and amyl nitrite are available from Australiansuppliers through the TGA Special Access Scheme.
Review of available cyanide antidotes: caseseries and pharmacodynamic and animal studies
Amyl nitriteNitrite-based cyanide antidotes oxidize haemoglobinto methaemoglobin, which complexes with cyanideto form non-toxic cyanomethaemoglobin. However,20–30% methaemoglobin is required to optimally bindcyanide,5 a level capable of significantly impeding
Management of cyanide poisoning
3© 2012 The AuthorsEMA © 2012 Australasian College for Emergency Medicine and Australasian Society for Emergency Medicine
oxygen transport. Nitrites also typically cause vasodi-lation and hypotension.5 Amyl nitrite was the first pos-tulated cyanide antidote, in 1888.33 Its use is attractivefor first aid, as it is inhaled from a crushed capsule.However, it produces only about 7% methaemoglobin,which is probably insufficient to bind a lethal dose ofcyanide.4 Amyl nitrite apparently reversed the cardiacand respiratory effects of cyanide in 24 of 30 dogs stud-ied.34 These effects were observed before the generationof methaemoglobin, suggesting vasodilation andincreased cardiac output as an alternative mechanism ofaction. Amyl nitrite treatment of cyanide-exposed miceresulted in a significant increase in the number of sur-vivors.35 Amyl nitrite increased the median lethal sub-cutaneous dose of sodium cyanide in dogs from 5.36 to24.5 mg/kg.36 However, levels of methaemoglobinachieved in humans might be substantially less than inthese experimental conditions,4 and a systematic reviewin 201037 found little evidence of efficacy from compara-tive studies, and no comparative studies in humans, butfrequent reports of adverse reactions (such as hypoten-sion, syncope, excessive methaemoglobinaemia causinghypoxia and haemolysis in patients with glucose-6-phosphate deficiency). As a drug of abuse,38 it must beappropriately secured to prevent theft. This review37
concluded that the use of amyl nitrite could not bejustified.
Sodium nitriteThe first antidote strategy based on an understandingof biochemical mechanisms was described by Chen et al.in 1934,39 who suggested a combination of amyl nitrite,sodium nitrite and sodium thiosulphate based on resultsfrom animal studies. Sodium nitrite, at a minimum doseof 5 mg/kg, was shown to be an effective antidote forexperimental cyanide poisoning in dogs, whereas200 mg/kg was efficacious in rabbits.4 However, there isvery little other animal or clinical evidence in support ofthis approach.5 Animal and human experiments evalu-ating sodium nitrite find it produces higher methaemo-globin levels than amyl nitrite, but that this isaccompanied by problematic hypotension.4 A study of24 pigs poisoned with i.v. cyanide and subsequentlytreated with sodium thiosulphate and either hydroxoco-balamin or sodium nitrite found no difference inmortality or biochemical parameters but faster normal-ization of blood pressure with hydroxocobalamin.40
Intravenous sodium nitrite can cause severe hypoten-sion, cardiovascular instability and hypoxia in a dose-dependent manner,5,41 although the relationship of dose
to adverse effect has not been defined in humans.42 Thedose recommended in the TGA-approved product infor-mation43 is 300 mg (in a typical adult, approximately4 mg/kg, the same weight-adjusted dose as for children)at 75–150 mg/min, with half the initial dose repeated at30 min if required and with adjustment to maintainmethaemoglobin levels �40%. Caution is particularlyrequired in patients with smoke inhalation, as the meth-aemoglobin produced by such a dose of sodium nitrite,in combination with carboxyhaemoglobin, has beenobserved to precipitate ultimately fatal levels of non-oxygen-transporting haemoglobin.44 Similarly, theeffect of methaemoglobin on oxygen transport will bemagnified in anaemic patients.
4-Dimethylaminophenol4-Dimethylaminophenol produces a more rapid rise inmethaemoglobin than sodium nitrite,4,45 and is a com-monly used cyanide antidote in Germany.41,45 When4-DMAP was given intravenously to dogs 1 min afterpoisoning with a lethal dose of potassium cyanide, allthe animals survived.46 Eighteen case reports of the useof 4-DMAP have been summarized.4 In these 18 cases,there were seven deaths; 10 patients recovered, but onepatient had ongoing CNS impairment. 4-DMAP cancause tissue necrosis or phlebitis at the site of injection,nephrotoxicity,45 and in 6 of the 18 case reports, sub-stantial methaemoglobinaemia (up to 77%) wasobserved.4
Dicobalt edetateCobalt compounds were first advocated as cyanide anti-dotes in 1894.4 The cobalt atom in dicobalt edetate bindsto cyanide. Until withdrawing all advice on cyanideantidotes in 1996,47 dicobalt edetate (along with amylnitrite) was the antidote recommended by the UK gov-ernment.47 Dicobalt edetate has only been comparativelyevaluated in animal studies. In the 1950s and 1960s,Paulet published results of an extensive series of animalexperiments investigating various cobalt compounds,4
and subsequently reported that dicobalt edetate wasmore effective than a combination of sodium nitrite andthiosulphate.48 Comparisons in dogs found dicobaltedetate effective, but inferior to 4-DMAP.46,49 Dicobaltedetate has been used in numerous human cases inwhich patients survived.4 The utility of dicobalt edetateis limited by its serious adverse effects, which includevomiting, urticaria, anaphylactic shock, hypotensionand ventricular arrhythmias.50,51 These harmful effectsmight be more common and severe in the absence of
MC Reade et al.
4 © 2012 The AuthorsEMA © 2012 Australasian College for Emergency Medicine and Australasian Society for Emergency Medicine
cyanide.4 There is evidence from animal experimentsthat glucose protects against cobalt toxicity, and it isrecommended that this be simultaneously administered.Because of its toxicity, the TGA-approved productinformation mandates dicobalt edetate only be used incases of confirmed cyanide poisoning when a patienthas lost consciousness.52
Sodium thiosulphatePhysiological levels of cyanide are metabolized to thio-cyanate by the enzyme rhodanese, which requires thio-sulphate as a substrate. The body’s reserve ofthiosulphate is limited,4,53 suggesting supplementationmight be beneficial in cyanide poisoning. However,rhodanese is located within mitochondria, and thiosul-phate penetrates cell and mitochondrial membranespoorly.4 This might explain why sodium thiosulphateappears to act more slowly than other antidotes.5,54
Studies in rabbits55 and dogs56 found sodium thiosul-phate was an effective antidote to cyanide produced byhigh levels of sodium nitroprusside. By augmenting theendogenous capacity to metabolize cyanide, sodiumthiosulphate treats cyanide poisoning by a differentmechanism, implying its effect could be additive to thatof other antidotes. Most published animal studies4,57,58
have used sodium thiosulphate in combination withother antidotes. However, there is evidence that thiosul-phate alone is effective,59 particularly in the context ofsodium nitroprusside administration.56,60 In a pharmaco-dynamic study, the use of sodium nitroprusside at 5 mg/kg/min for 10 h, 10 mg/kg/min for 4 h or 20 mg/kg/minfor 1.5 h caused potentially toxic levels of cyanide,61 andthis was prevented by sodium thiosulphate. For thisreason, sodium thiosulphate has been recommended asprophylaxis against cyanide toxicity when nitroprus-side is required at high doses.4
Sodium thiosulphate can cause local skin and musclepain at the infusion site,62 nausea, vomiting, headacheand disorientation,45 but life-threatening adverse effectshave not been reported.4
‘Solutions A and B’‘Solutions A and B’ (ferrous sulphate in aqueous citricacid and aqueous sodium carbonate) had previouslybeen recommended as an oral antidote to cyanide inges-tion. When reviewed in 1988,63 only very limited, unpub-lished animal evidence was found. If effective at all, it islikely that solutions A and B have to be given withinseconds of cyanide ingestion. The review authors notedthat the main basis for recommendations was ‘custom
and practice’, which ‘made withdrawal of the antidotedifficult to achieve’. Solutions A and B are no longerrecommended as a practical antidote.64
Hydroxocobalamin (vitamin B12a)Hydroxocobalamin was first reported to be a promisingcyanide antidote in experimental cyanide poisoning inmice in 1952.65 Hydroxocobalamin prevented metabolicacidosis and reduced blood cyanide concentrations inbaboons infused with a high rate of sodium nitroprus-side.66 Similar results were found in humans.67 Hydroxo-cobalamin also safely reduced the low blood cyanideconcentrations found in heavy smokers.62 No significanttoxic effects of hydroxocobalamin have been reported inanimal studies or humans.4 Minor reported adverseeffects include transient hypertension and bradycar-dia,62 red-orange urine discolouration, transient head-ache and mild allergic reactions that were readilytreated.68 Serum pigmentation caused by hydroxocobal-amin interferes with photometric biochemical assays,such as measurements of carboxyhaemoglobin (particu-larly relevant in the differential diagnosis of the effectsof smoke inhalation) and methaemoglobin,69 lactate, andmany other commonly measured haematological andbiochemical indices.70 Ideally, and especially if the diag-nosis is unclear, blood should be taken for analysisbefore hydroxocobalamin is administered. A furtherproblem caused by hydroxocobalamin’s pigment isfalse triggering of the sensor that detects blood leakageacross the artificial kidney membrane during dialysis.This problem has been circumvented by recalibratingthis sensor using a continuous renal replacementmachine.71
Systematic review of studies reporting use ofcyanide antidotes in humans
The results of the systematic review are shown inFigure 1. There have been no comparative or placebo-controlled human trials evaluating treatment strategiesfor severe cyanide poisoning. Table 1 summarizes thenine relevant studies identified. All are small uncon-trolled case series (National Health and MedicalResearch Council level IV). None provides definitive evi-dence of the superiority of one approach over another, orover supportive care alone. Meaningful comparisons ofsurvival rates are impossible, as the severity of many ofthe poisonings is not described. Seven of the nine caseseries described, totalling reports of 361 patients(mostly smoke exposure victims), report treatment with
Management of cyanide poisoning
5© 2012 The AuthorsEMA © 2012 Australasian College for Emergency Medicine and Australasian Society for Emergency Medicine
hydroxocobalamin. In two papers,73,78 this was in com-bination with sodium thiosulphate. Three of the ninecase series,36,74,79 reporting 74 patients, describe treat-ment with amyl nitrite, sodium nitrite and sodium thio-sulphate in combination. One report74 describes fourpatients treated with each approach, in which all eightpatients survived.
The most important conclusion that can be drawnwith any certainty from this systematic review is that itis possible to survive cardiorespiratory arrest due tocyanide poisoning if given an antidote: of 136 reportedpatients in cardiac arrest, 16 (11.8%) survived to hospi-tal discharge. Interestingly, the rate of initial responsewas much higher: 50 out of 97 patients (51.5%) hadtransient return of spontaneous circulation.
Indications for the use of a cyanide antidote
Cardiorespiratory collapse, combined with either a highblood cyanide level or obvious evidence of cyanide poi-soning, is a clear indication for use of an antidote. Underthese circumstances, the use of antidotes with even
narrow therapeutic indices would appear reasonable.However, the indication for use of a cyanide antidote isless clear when smaller quantities are ingested, inpatients without cardiorespiratory collapse, or wherethe diagnosis is unclear. Under these circumstances, it islogical to avoid the more toxic antidotes, and this isreflected in the TGA-approved product information fordicobalt edetate.52 Unlike other strategies, hydroxoco-balamin and sodium thiosulphate have few adverseeffects, justifying their use in lesser degrees of cyanidepoisoning as well as in the prophylaxis of possiblecyanide toxicity due to high-rate sodium nitroprusside.
The most problematic possible indication for use of acyanide antidote is with smoke inhalation, the common-est cause of cyanide exposure. Such patients oftenpresent with metabolic acidosis, but this is more likelyto be caused by under-resuscitation, carbon monoxidepoisoning or missed traumatic injury than by cyanidepoisoning.5 Cyanide exposure during house fires wasmeasured in samples obtained from devices on firefight-ers’ coats.80 Only 27 of 253 samples contained hydrogencyanide, with a maximum concentration (3.6 p.p.m.) well
Figure 1. Results of the systematic search for relevant literature.
MC Reade et al.
6 © 2012 The AuthorsEMA © 2012 Australasian College for Emergency Medicine and Australasian Society for Emergency Medicine
Tab
le1
.Su
mm
ary
ofst
udie
sid
entifi
ed
Ref
eren
ceSt
udy
desi
gnPa
tient
sst
udie
dIn
terv
entio
nsR
esul
tsR
elev
ant
conc
lusi
onSt
udy
qual
ity
Bor
ron
etal
.72Pr
ospe
ctiv
eca
sese
ries
69pa
tient
sw
ithal
tere
dco
nsci
ousn
ess
due
tosu
spec
ted
cyan
ide
pois
onin
gaf
ter
smok
ein
hala
tion
who
surv
ived
toho
spita
lad
mis
sion
Hyd
roxo
coba
lam
in5
gre
peat
edup
to15
gat
the
disc
retio
nof
the
trea
ting
phys
icia
n
2/15
who
had
aca
rdio
resp
irat
ory
arre
stat
the
scen
esu
rviv
edto
hosp
itald
isch
arge
.H
ydro
xoco
bala
min
appe
ars
safe
tous
ein
the
preh
ospi
talc
onte
xt.
Fair
28/4
2pa
tient
sw
ithco
nfirm
edcy
anid
epo
ison
ing
(cya
nide
leve
ls�
39mm
ol/L
)tre
ated
with
hydr
oxoc
obal
amin
surv
ived
.
No
info
rmat
ion
onef
ficac
yca
nbe
infe
rred
.
19/6
9pa
tient
str
eate
dw
ithhy
drox
ocob
alam
inha
dbe
nign
adve
rse
effe
cts
(incl
udin
gch
rom
atur
ia,s
kin
disc
olou
ratio
n,er
ythe
ma
and
hype
rten
sion
).N
oal
lerg
icre
actio
nsw
ere
repo
rted
.
Itis
poss
ible
tosu
rviv
eca
rdio
resp
irat
ory
arre
stdu
eto
cyan
ide
pois
onin
gw
hen
hydr
oxoc
obal
amin
isus
ed.
Bor
ron
etal
.73R
etro
spec
tive
case
seri
es14
patie
nts
adm
itted
toIC
Uw
ithno
n-sm
oke-
rela
ted
cyan
ide
pois
onin
g(1
2/14
inge
sted
;1/1
4in
hale
dcy
anid
ega
s,1/
14un
know
n)fo
rw
hom
hydr
oxoc
obal
amin
was
used
asfir
st-li
netr
eatm
ent
Hyd
roxo
coba
lam
in5–
20g,
with
am
ixtu
reof
preh
ospi
tala
ndho
spita
lad
min
istr
atio
n.So
me
patie
nts
rece
ived
sodi
umth
iosu
lpha
te(5
/14)
ordi
coba
lted
etat
e(1
/14)
10/1
4pa
tient
ssu
rviv
edto
disc
harg
e.H
ydro
xoco
bala
min
appe
ars
safe
and
mig
htbe
effe
ctiv
e.Po
or7/
11w
itha
typi
cally
leth
al(>
100
mmol
/L)l
evel
ofcy
anid
esu
rviv
ed.
The
rate
ofsu
rviv
alw
ashi
gher
than
expe
cted
with
only
supp
ortiv
eca
re,
but
whe
ther
this
was
due
tohy
drox
ocob
alam
in,t
heot
her
antid
otes
used
,sel
ectio
nbi
asin
that
patie
nts
had
tosu
rviv
eun
tilIC
Uad
mis
sion
tobe
incl
uded
,or
chan
ce,
isun
clea
r.
The
mos
tco
mm
onhy
drox
ocob
alam
in-a
ttri
bute
dad
vers
eev
ents
wer
ech
rom
atur
iaan
dpi
nksk
indi
scol
orat
ion.
Chen
etal
.36R
etro
spec
tive
case
seri
es49
patie
nts
with
cyan
ide
pois
onin
gof
vari
ous
type
s.N
oqu
antifi
catio
nof
cyan
ide
leve
lsw
asm
ade
Am
ylni
trite
�so
dium
nitr
ite�
thio
sulp
hate
Case
seri
eson
ly,w
ithm
ost
patie
nts
surv
ivin
g.N
ote
this
isth
esi
ngle
clin
ical
pape
rbe
fore
1995
that
supp
orte
dth
ew
ides
prea
dus
eof
nitr
ites.
Poor
Esp
inoz
aet
al.74
Ret
rosp
ectiv
eca
sese
ries
8ch
ildre
nw
ithcy
anid
epo
ison
ing
due
tobi
tter
cass
ava
inge
stio
n,al
lwith
hypo
tens
ion,
brad
ycar
dia
and
resp
irat
ory
failu
re
Due
toa
shor
tage
ofan
tidot
e,4
rece
ived
hydr
oxoc
obal
amin
and
4so
dium
nitr
itean
dth
iosu
lpha
te
All
8ch
ildre
nsu
rviv
edto
hosp
itald
isch
arge
,ne
urol
ogic
ally
inta
ct.
Hyd
roxo
coba
lam
inm
ight
beeq
ually
asef
fect
ive
asso
dium
nitr
ite+
sodi
umth
iosu
lpha
te,a
lthou
ghth
eco
ntri
butio
nof
indi
catio
nbi
asto
outc
ome
isun
clea
r.
Fair
Fort
inet
al.75
Ret
rosp
ectiv
eca
sese
ries
101
patie
nts
adm
inis
tere
dhy
drox
ocob
alam
info
rsu
spec
ted
cyan
ide
pois
onin
gaf
ter
smok
ein
hala
tion
Hyd
roxo
coba
lam
in5
gfo
rad
ults
and
70m
g/kg
for
child
ren,
with
the
optio
nto
adm
inis
ter
ase
cond
dose
for
inco
mpl
ete
resp
onse
30pa
tient
ssu
rviv
ed,4
2di
ed(1
7at
the
fire
scen
e)an
dou
tcom
ew
asun
know
nin
29.
Hyd
roxo
coba
lam
inap
pear
ssa
feto
use
inth
epr
ehos
pita
lcon
text
.Po
or
Of
38pa
tient
sfo
und
inca
rdia
car
rest
,21
had
retu
rnof
spon
tane
ous
circ
ulat
ion
duri
ngpr
ehos
pita
lcar
e,bu
t19
/21
died
duri
ngho
spita
lizat
ion.
Giv
enth
e29
patie
nts
with
unkn
own
outc
omes
,sur
viva
laft
eran
unqu
antifi
edde
gree
ofcy
anid
ein
toxi
catio
nan
din
the
cont
ext
ofot
her
inju
ries
(e.g
.bur
nsin
atle
ast
53%
)whe
ntr
eate
dw
ithhy
drox
ocob
alam
inco
uld
beas
low
as30
%or
ashi
ghas
58%
.
Tw
oad
vers
eev
ents
–re
dor
pink
colo
ratio
nof
urin
eor
skin
(n=
5)an
dcu
tane
ous
rash
(n=
1)–
wer
eas
sess
edas
bein
gpo
ssib
lyre
late
dto
hydr
oxoc
obal
amin
.
Itis
poss
ible
tosu
rviv
eca
rdio
resp
irat
ory
arre
stdu
eto
cyan
ide
pois
onin
gw
hen
hydr
oxoc
obal
amin
isus
ed,b
utim
med
iate
retu
rnof
circ
ulat
ion
isof
ten
follo
wed
byde
laye
dde
ath.
Management of cyanide poisoning
7© 2012 The AuthorsEMA © 2012 Australasian College for Emergency Medicine and Australasian Society for Emergency Medicine
Tab
le1
.(C
ontin
ued)
Ref
eren
ceSt
udy
desi
gnPa
tient
sst
udie
dIn
terv
entio
nsR
esul
tsR
elev
ant
conc
lusi
onSt
udy
qual
ity
Fort
inet
al.76
Ret
rosp
ectiv
eca
sese
ries
161
fire
surv
ivor
sw
ithsu
spec
ted
orco
nfirm
edcy
anid
epo
ison
ing
Hyd
roxo
coba
lam
in2.
5–5
g(le
ssin
child
ren)
with
the
optio
nto
adm
inis
ter
ase
cond
dose
for
inco
mpl
ete
resp
onse
135/
161
patie
nts
had
aca
rdia
cco
mpl
icat
ion
(61/
161
card
iac
arre
st,5
7/16
1rh
ythm
diso
rder
,12/
161
repo
lari
zatio
ndi
sord
er,5
/161
cond
uctio
ndi
sord
er).
Hyd
roxo
coba
lam
inap
pear
ssa
fe.
Fair
The
abst
ract
stat
es‘h
ighe
rdo
ses
ofth
ean
tidot
ese
emto
beas
soci
ated
with
asu
peri
orou
tcom
ein
patie
nts
with
initi
alca
rdia
car
rest
’,bu
tth
isis
base
don
sim
ple
univ
aria
tean
alys
is;t
here
isno
quan
titat
ive
mul
tivar
iabl
ean
alys
isin
the
pape
rto
supp
ort
this
stat
emen
t.
Hig
her
dose
sm
ight
poss
ibly
beas
soci
ated
with
less
seve
reca
rdia
cco
mpl
icat
ions
ofcy
anid
epo
ison
ing,
but
only
indi
rect
and
ques
tiona
ble
info
rmat
ion
onef
ficac
yca
nbe
infe
rred
from
thes
eda
ta.
5/59
pts
foun
din
card
iac
arre
stsu
rviv
edto
hosp
ital
disc
harg
e(3
0di
edat
the
scen
ean
da
furt
her
24di
edin
hosp
ital).
Itis
poss
ible
tosu
rviv
eca
rdio
resp
irat
ory
arre
stdu
eto
cyan
ide
pois
onin
gw
hen
hydr
oxoc
obal
amin
isus
ed.
Hou
eto
etal
.77Pr
ospe
ctiv
eca
sese
ries
12pa
tient
str
eate
dw
ithhy
drox
ocob
alam
info
rsu
spec
ted
cyan
ide
pois
onin
gdu
eto
smok
ein
hala
tion
Hyd
roxo
coba
lam
in5
ggi
ven
with
in30
min
ofex
posu
re,w
ithbl
ood
sam
pled
for
cyan
ide
befo
rean
daf
ter
cyan
ocob
alam
intr
eatm
ent
Seru
mcy
anoc
obal
amin
leve
lsaf
ter
adm
inis
trat
ion
ofhy
drox
ocob
alam
inco
rrel
ated
clos
ely
with
pret
reat
men
tse
rum
cyan
ide
leve
lsup
to40
mmol
/Lse
rum
cyan
ide.
Inon
epa
tient
with
initi
albl
ood
cyan
ide
conc
entr
atio
nof
96mm
ol/L
,pla
sma
cyan
ocob
alam
inco
ncen
trat
ion
doub
led
afte
ra
seco
nd5
gdo
seof
hydr
oxoc
obal
amin
.Thi
ssu
gges
ts5
ghy
drox
ocob
alam
inca
nbi
ndal
lav
aila
ble
cyan
ide
ions
for
bloo
dcy
anid
eco
ncen
trat
ions
upto
abou
t40
mmol
/L.B
eyon
dth
is,
mor
ehy
drox
ocob
alam
inm
ust
begi
ven.
Hyd
roxo
coba
lam
inra
pidl
yan
def
fect
ivel
yre
mov
escy
anid
efr
omth
eci
rcul
atio
n.
Fair
No
com
men
tca
nbe
mad
ere
gard
ing
patie
ntou
tcom
ebe
nefit
,or
the
com
para
tive
effic
acy
ofot
her
agen
ts.
Pont
alet
al.78
Ret
rosp
ectiv
eca
sese
ries
24di
ssim
ilar
case
sof
non-
fata
lcy
anid
epo
ison
ing
Ava
riet
yof
antid
otes
,inc
ludi
nghy
drox
ocob
alam
in,d
icob
alt
edet
ate
and
sodi
umth
iosu
lpha
te;a
lso
supp
ortiv
etr
eatm
ent
with
mec
hani
cal
vent
ilatio
nal
one
7/24
patie
nts
with
initi
alca
rdio
resp
irat
ory
arre
stsu
rviv
ed.
Itis
poss
ible
tosu
rviv
eca
rdio
resp
irat
ory
arre
stdu
eto
cyan
ide
pois
onin
g.
Poor
Oth
ercl
inic
alfe
atur
esof
cyan
ide
pois
onin
gar
ede
scri
bed.
Yen
etal
.79R
etro
spec
tive
case
seri
es21
patie
nts
with
confi
rmed
orsu
spec
ted
cyan
ide
pois
onin
g(2
0w
ithor
alin
gest
ion,
1w
ithin
hala
tiona
lexp
osur
e)
16/2
1pa
tient
sre
ceiv
edLi
llyCy
anid
eA
ntid
ote
Kit,
cont
aini
ngam
ylni
trite
for
inha
latio
nan
d3%
sodi
umni
trite
and
25%
sodi
umth
iosu
lpha
teso
lutio
ns
The
clin
ical
feat
ures
ofcy
anid
epo
ison
ing
are
desc
ribe
d.N
oin
form
atio
non
the
effic
acy
orsa
fety
ofam
ylni
trite
,sod
ium
nitr
itean
dso
dium
thio
sulp
hate
can
bein
ferr
ed.
Poor
16pa
tient
spr
esen
ted
with
seve
resy
mpt
oms,
8su
rviv
ed.A
llof
the
8su
rviv
ors
pres
entin
gw
ithse
vere
sym
ptom
sre
ceiv
edth
eLi
llyCy
anid
eA
ntid
ote
Kit,
incl
udin
g4/
8w
ithse
vere
met
abol
icac
idos
is,c
oma,
and
resp
irat
ory
failu
re.8
/16
seve
rely
affe
cted
patie
nts
died
,of
who
m6
rece
ived
the
antid
ote
and
2di
dno
t.T
heef
fect
ofth
ean
tidot
eon
mor
talit
yw
asno
tsi
gnifi
cant
.
The
reis
insu
ffici
ent
deta
ilab
out
the
seve
rity
ofth
ecy
anid
epo
ison
ing
prev
ente
dan
yas
sess
men
tof
the
trea
tmen
tfo
rac
ute
cyan
ide
pois
onin
g.
All
stud
ies
iden
tified
are
Nat
iona
lHea
lthan
dM
edic
alR
esea
rch
Cou
ncil
class
IVev
iden
ce.12
The
qual
ityof
each
stud
yha
sal
sobe
enas
sess
edas
good
,fa
iror
poor
onth
eA
ustr
alia
nR
esus
cita
tion
Cou
ncil
scal
e13(g
ood
–th
em
etho
dolo
gica
lqua
lity
ofth
est
udy
ishi
ghw
ithth
elik
elih
ood
ofan
ysi
gnifi
cant
bias
bein
gm
inim
al;f
air
–th
em
etho
dolo
gica
lqua
lity
ofth
est
udy
isre
ason
able
with
the
pote
ntia
lfor
sign
ifica
ntbi
asbe
ing
likel
y;po
or–
the
met
hodo
logi
cal
qual
ityof
the
stud
yis
wea
kpo
sses
sing
cons
ider
able
and
sign
ifica
ntbi
ases
).
MC Reade et al.
8 © 2012 The AuthorsEMA © 2012 Australasian College for Emergency Medicine and Australasian Society for Emergency Medicine
below the recommended short-term exposure limit(15 p.p.m.). Conversely, 11 of 138 patients with fire-related deaths in Victoria, Australia had potentiallyfatal blood cyanide levels.81 Blood cyanide levels mightbe impossible to obtain before a treatment decision isrequired, necessitating clinical judgment. Althoughthere are no immediately available definitive laboratorytests for cyanide toxicity, a number of indices arehighly suggestive. Smoke inhalation patients with acarboxyhaemoglobin level >10% are particularly likelyto have inhaled a dangerous quantity of cyanide.81 Inthe context of smoke inhalation without severe burns,a plasma lactate >10 mmol/L had a sensitivity of87% and specificity of 94% for clinically significantcyanide poisoning.82 An increase in the central venouspartial pressure of oxygen and per cent oxygen satura-tion measured by blood gas analysers, such that theseapproach measured arterial values, has also beendescribed.83 In one study, 42 of 69 patients with smokeinhalation and neurological impairment had poisonousblood levels of cyanide. All 69 were treated withhydroxocobalamin, and 28 of the 42 with cyanide poi-soning survived.72 Although there is insufficient evi-dence to recommend routine use of a cyanide antidote inpatients with possible cyanide poisoning caused bysmoke inhalation, the presence of neurological impair-ment or elevated carboxyhaemoglobin or lactate levelsat least suggests one of the low-risk antidotes should beconsidered after other more likely causes – such ascarbon monoxide poisoning – have been appropriatelymanaged.
Cost and stability in storage
Representative retail costs of the various cyanide anti-dotes are listed in Table 2. Because of the infrequency ofcyanide poisoning, most cyanide antidote vials are
never used. If a workplace chooses to keep a cyanideantidote in its cyanide emergency kit, the cost will alsobe determined by the shelf life, which is also shown.Analysing acquisition costs alone and assuming recom-mended doses, dicobalt edetate is 2.8 times, hydroxoco-balamin is 11.2 times, and sodium thiosulphate 0.8 timesthe cost of amyl + sodium nitrite.
Prehospital availability and use ofcyanide antidotes
The majority of patients reported in papers identifiedin the systematic review were treated with cyanideantidotes before arrival in hospital. It would seem intu-itively obvious that earlier antidote administration willlead to better outcomes. This might not be true incases of equivocal diagnosis if using antidotes thatare themselves toxic, but as noted above, hydroxoco-balamin and sodium thiosulphate appear sufficientlysafe. However, the community incidence of cyanidepoisoning (ignoring the possibly much larger numberof exposures due to smoke inhalation) is low: forexample, only 257 of 2.8 million exposures to poisonsreported to US poison control centres in 2004 were dueto cyanide.86 Given their cost, this argues against uni-versally equipping prehospital emergency medical ser-vices with cyanide antidotes. However, workplaceswith a particular risk of cyanide exposure and perhapshospitals serving a high concentration of industries inwhich cyanide is used are logical places to stock thisresource. No firm conclusion can be drawn from theliterature as to whether emergency medical servicesshould stock cyanide antidotes for use in victims ofsmoke inhalation. If transport times to hospitals spe-cializing in burns care are short, only stocking cyanideantidotes in such centres would seem a reasonableapproach.
Table 2. Cost (in February 2011) and shelf life of various cyanide antidotes
Antidote Cost Shelf life
Hydroxocobalamin A$283884 for 2 ¥ 2.5 g 3 years4,41
NB. A 1 mg ampoule Pharmaceutical Benefits Scheme subsidizedfor the treatment of pernicious anaemia is A$15.8743
Dicobalt edetate A$696.9243 for 20 mL 1.5% 3 years4,41
Sodium nitrite A$787.5043 for 10 ¥ 300 mg in 10 mL or 5 years4,41
A$2 631.5843 for 5 ¥ 300 mg in 10 mLSodium thiosulphate A$203.5084 for 50 mL 25% 5 years41
Amyl nitrite A$174.2484 for 6 ¥ 0.6 mL 6 months85 to 2 years4
4-Dimethylaminophenol Not marketed in Australia 3 years4
Management of cyanide poisoning
9© 2012 The AuthorsEMA © 2012 Australasian College for Emergency Medicine and Australasian Society for Emergency Medicine
Recommendations
The ARC recommends that the contents of an industrialworkplace cyanide emergency kit should be determinedby a qualified occupational health assessor, taking intoaccount the nature of the cyanide threat, the training ofworkplace first aiders and the proximity of externalassistance (Appendix S1). Possible inclusions are:• Equipment for artificial respiration, including oropha-
ryngeal airways, laryngeal mask airways, equipmentfor endotracheal intubation, a self-inflating bag-valve-mask apparatus and a supply of medical oxygen suf-ficient to provide 100% inspired oxygen to the victim
• A tourniquet, i.v. cannulae, syringes and needles• A cyanide antidote
The sparse published human efficacy and safety evi-dence that exists supports the use of hydroxocobal-amin with or without sodium thiosulphate, or sodiumthiosulphate alone, for confirmed or suspected cyanidepoisoning. The onset of action of sodium thiosulphateappears slower than that of hydroxocobalamin. TheARC therefore recommends that adult patients withsuspected severe cyanide poisoning (including those incardiac arrest) should receive immediate parenteralhydroxocobalamin, 5 g over 15 min with repeat dosingup to 15 g. Paediatric doses should be adjusted accord-ing to weight: 70 mg/kg over 15 min, repeated twice ifnecessary.87 This is a considerably larger dose thancontained in parenteral vitamin B12a preparationsdesigned for other indications. The ARC therefore rec-ommends that a workplace cyanide emergency kit con-tains at least 2 ¥ 2.5 g ampoules of hydroxocobalamin(marketed as ‘Cyanokit’84), if an antidote is to bestocked. However, in February 2011, Cyanokit was notincluded on the Australian Register of TherapeuticGoods, with the supply of this product requiring anapplication through the TGA Special Access Scheme.Ambulance services and hospital EDs might not stockcyanide antidotes. Therefore, even if a workplace hasno personnel qualified to administer a cyanide antidote,a cyanide emergency kit containing an antidote is stillrecommended if the assessed risk of cyanide exposureis sufficiently high. The cyanide emergency kit shouldaccompany the patient for use when sufficiently quali-fied personnel become available. The ARC recom-mends that it is reasonable to treat inhalational burnpatients with neurological impairment or carboxyhae-moglobin >10% or plasma lactate >10 mmol/L withhydroxocobalamin, once other possible causes of meta-bolic acidosis have been addressed. Although there isno human evidence demonstrating harm, physiological
principles suggest that antidotes that produce methae-moglobin, such as the nitrites, are contraindicated incyanide poisoning due to smoke inhalation because ofthe likely presence of significant amounts of carboxy-haemoglobin.
The ARC also recommends that sodium thiosulphatebe considered as an adjunct to the treatment of severecyanide toxicity, but that this treatment should gener-ally be considered following failure to respondadequately to hydroxocobalamin. The exception to thisrecommendation is sodium nitroprusside toxicity, inwhich sodium thiosulphate has been successfully usedas a sole agent. The approved adult dose is 12.5 g(50 mL of a 25% solution) administered intravenouslyat 1.25 g/min (5 mL/min), with the higher recom-mended paediatric dose of 412.5 mg/kg at 0.625–1.25 g/min to a maximum of 12.5 g.43 If signs of cyanidetoxicity are still present 30 min to 2 h after administra-tion, half the original dose may be repeated. Sodiumthiosulphate is chemically incompatible with hydroxo-cobalamin, and so must be administered through aseparate i.v. line.
The ARC notes evidence of the efficacy of sodiumnitrite and sodium thiosulphate in combination. In theabsence of comparative studies, the known adverseeffects of sodium nitrite suggest this might be aninferior approach to use of hydroxocobalamin;however, financial cost-effectiveness may justify thisapproach. The approved adult dose of sodium nitrite(in combination with sodium thiosulphate) is 300 mgover 2–4 min, with half this dose repeated after 30 minif required. Recommended paediatric dosing is 4 mg/kg(although up to 10 mg/kg is listed as acceptable) at75–150 mg/min to a maximum of 300 mg, with half theinitial dose repeated at 30 min if required. In anaemicchildren less than 25 kg, the dose of sodium nitritemust be reduced according to the table provided in theproduct information. In all cases, methaemoglobinmust be monitored and kept below 40% by doseadjustment if required.88
The ARC recommends that prehospital emergencymedical services and hospitals assess their likelihoodof having to treat a victim of cyanide poisoning, andthe possible availability of the recommended cyanideantidotes from external sources, when deciding on theselection and quantity of cyanide antidote they shouldstock.
Our recommendations regarding choice of cyanideantidote accord with the conclusion of a similar recentsystematic review.89 The ARC categorizes13 the treat-ment recommendations made above as Class B: ‘accept-
MC Reade et al.
10 © 2012 The AuthorsEMA © 2012 Australasian College for Emergency Medicine and Australasian Society for Emergency Medicine
able’. Class B treatment recommendations are given tothose guidelines that might be beneficial and are accept-able to be used if considered appropriate in the relevantsetting. These recommendations are summarised inAppendix S1.
Conclusion
In the absence of comparative human trial data, treatingclinicians and those that make occupational health riskassessments must combine animal studies, case reportsand an understanding of pharmacology with clinicaljudgment. Although the published evidence favours theuse of hydroxocobalamin � sodium thiosulphate forcyanide poisoning, it is also true that no evidence dem-onstrates other strategies (including supportive carealone) might not be more effective in particular circum-stances. A randomized controlled clinical trial mightprovide better guidance, but the low number of cyanidepoisonings and the probable lack of equipoise makesuch a trial unlikely. One option is to make no recom-mendation for other than supportive care, as in the UK.47
The ARC, noting the reported frequency of enquiriesinto this topic9,47 and also the geographical remotenessfrom high-level intensive care of many Australianindustries and Australian Defence Force establish-ments, has chosen instead to make recommendationsbased on the evidence available. In so doing, we trustthese recommendations will be applied to the relevantcircumstances by competent practitioners.
Acknowledgements
Lieutenant Colonel Reade represents the AustralianDefence Force on the ARC. The support of the Austra-lian Defence Force and the contribution of GroupCaptain David Scott BMed FANZCA RAAF tothe preparation of this guideline are gratefullyacknowledged.
Author contributions
MCR designed the research question, interpreted theresults of the systematic review, and wrote and revisedthe manuscript. SRD performed the systematic reviewand summarized its conclusions. PTM, JD and ICJchaired the ARC discussion of the systematic reviewand critically revised the manuscript.
Competing interests
None declared.
Accepted 6 January 2012
References
1. Earles MP. Experiments with drugs and poisons in theseventeenth and eighteenth centuries. Ann. Sci. 1963; 19: 241–54.
2. Sykes AH. Early studies on the toxicology of cyanide. In:Vennesland B, Conn EE, Knowles CJ, Westley J, Wissing F, eds.Cyanide in Biology. London: Academic Press, 1981; 1–9.
3. Wepfer JJ. Cicutae Aquaticae. Basle: Konig, 1679.
4. Meredith TJ, Jacobsen D, Haines JA, Berger J-C, van Heijst ANP.Antidotes for Poisining by Cyanide. Geneva: World HealthOrganization, 1993. [Cited June 2011.] Available from URL:http://www.inchem.org/documents/antidote/antidote/ant02.htm#SectionNumber:1.2
5. Barillo DJ. Diagnosis and treatment of cyanide toxicity. J. BurnCare Res. 2009; 30: 148–52.
6. First Aid Management of Cyanide Poisoning. Brisbane:University of Queensland, 2009. Available from URL:http://www.uq.edu.au/ohs/pdfs/cyanidefirstaid.pdf (accessedFebruary 2012).
7. Cyanide Poisoning. 2. Canberra: Commonwealth of Australia,1993. Available from URL: http://safeworkaustralia.gov.au/AboutSafeWorkAustralia/WhatWeDo/Publications/Documents/26/CyanidePoisoning_1993_PDF.pdf (accessed February 2012).
8. National Occupational Health and Safety Commission. CyanidePoisoning – First Aid and Medical Treatment. Perth: Departmentof Consumer and Employment Protection, Government ofWestern Australia, 2009. Available from URL: http://dmp.wa.gov.au/documents/Bulletins/MS_GMP_OH_MB5_cyanidePoisoning.pdf (accessed February 2012).
9. Robinson J, Greene S. Cyanide Poisoning Antidote Kits.Melbourne: Victorian Poisons Information Centre, 2010.
10. Logsdon MJ, Hegelstein K, Mudder TI. The Management ofCyanide in Gold Extraction. Ottawa: International Council onMetals and the Environment, 1999.
11. Merlin T, Weston A, Tooher R, Middleton P et al. Cyanide Poi-soning. Melbourne: Australian Resuscitation Council, 1996. [Cited15 June 2011.] Available from URL: http://www.resus.org.au/policy/guidelines/section_9/cyanide_poisoning.htm
12. NHMRC Levels of Evidence and Grades for Recommendations forDevelopers of Guidelines. Canberra: National Health and MedicalResearch Council, 1 Dec 2009.
13. Principles and Format for Developing Guidelines. Melbourne:Australian Resuscitation Council, 2010.
14. DesLauriers CA, Burda AM, Wahl M. Hydroxocobalamin as acyanide antidote. Am. J. Ther. 2006; 13: 161–5.
15. Kirk RL, Stenhouse NS. Ability to smell solutions of potassiumcyanide. Nature 1953; 171: 698–9.
Management of cyanide poisoning
11© 2012 The AuthorsEMA © 2012 Australasian College for Emergency Medicine and Australasian Society for Emergency Medicine
16. Baud FJ, Borron SW, Megarbane B et al. Value of lactic acidosisin the assessment of the severity of acute cyanide poisoning. Crit.Care Med. 2002; 30: 2044–50.
17. Sandberg CG. A case of chronic poisoning with potassiumcyanide? Acta Med. Scand. 1967; 181: 233–6.
18. Australian Resuscitation Council Guidelines. Melbourne: Austra-lian Resuscitation Council, 2011. Available from URL: http://www.resus.org.au/ (accessed February 2012).
19. Berumen U Jr. Dog poisons man. JAMA 1983; 249: 353.
20. Padwell A. Cyanide Poisoning. Case studies of one homicide andtwo suicides. Am. J. Forensic Med. Pathol. 1997; 18: 185–8.
21. Peden NR, Taha A, McSorley PD, Bryden GT, Murdoch IB,Anderson JM. Industrial exposure to hydrogen cyanide: implica-tions for treatment. Br. Med. J. (Clin. Res. Ed) 1986; 293: 538.
22. Saincher A, Swirsky N, Tenenbein M. Cyanide overdose: survivalwith fatal blood concentration without antidotal therapy.J. Emerg. Med. 1994; 12: 555–7.
23. Prieto I, Pujol I, Santiuste C, Poyo-Guerrero R, Diego A. Acutecyanide poisoning by subcutaneous injection. Emerg. Med. J.2005; 22: 389–90.
24. Brivet F, Delfraissy JF, Duche M, Bertrand P, Dormont J. Acutecyanide poisoning: recovery with non-specific supportivetherapy. Intensive Care Med. 1983; 9: 33–5.
25. Way JL, Gibbon SL, Sheehy M. Cyanide intoxication: protectionwith oxygen. Science 1966; 152: 210–11.
26. Takano T, Miyazaki Y, Nashimoto I, Kobayashi K. Effect ofhyperbaric oxygen on cyanide intoxication: in situ changes inintracellular oxidation reduction. Undersea Biomed. Res. 1980; 7:191–7.
27. Isom GE, Way JL. Effects of oxygen on the antagonism ofcyanide intoxication: cytochrome oxidase, in vitro. Toxicol. Appl.Pharmacol. 1984; 74: 57–62.
28. Lawson-Smith P, Jansen EC, Johnsen AH, Hyldegaard O. Treat-ment of cyanide poisoning with HBO. Undersea Hyperb. Med.Soc. Annu. Meet. 2008; 35: 303–4.
29. Lawson-Smith P, Jansen EC, Hilsted L, Johnsen AH, HyldegaardO. Effect of acute and delayed hyperbaric oxygen therapy oncyanide whole blood levels during acute cyanide intoxication.Undersea Hyperb. Med. 2011; 38: 17–26.
30. Lawson-Smith P, Jansen EC, Hilsted L, Hyldegaard O. Effectof hyperbaric oxygen therapy on whole blood cyanideconcentrations in carbon monoxide intoxicated patients from fireaccidents. Scand. J. Trauma Resusc. Emerg. Med. 2010; 18: 32.
31. Way JL, End E, Sheehy MH et al. Effect of oxygen on cyanideintoxication. IV. Hyperbaric oxygen. Toxicol. Appl. Pharmacol.1972; 22: 415–21.
32. Australian Register of Therapeutic Goods. Canberra: TherapeuticGoods Administration, Department of Health and Ageing,28 Feb 2011. Available from URL: http://www.tga.gov.au/industry/artg.htm (accessed February 2012).
33. Pedigo LG. Antagonism between amyl nitrite and prussic acid.Trans. the Med. Soc. Virginia 1888; 19: 124–31.
34. Vick JA, Froehlich HL. Studies of cyanide poisoning. Arch. Int.Pharmacodyn. Ther. 1985; 273: 314–22.
35. Jandorf BJ, Bodansky O. Therapeutic and prophylactic effect ofmethemoglobinemia in inhalation poisoning by hydrogen cyanideand cyanogen chloride. J. Ind. Hyg. Toxicol. 1946; 28: 125–32.
36. Chen KK, Rose CL. Nitrite and thiosulfate therapy in cyanidepoisoning. J. Am. Med. Assoc. 1952; 149: 113–19.
37. Lavon O, Bentur Y. Does amyl nitrite have a role in the manage-ment of pre-hospital mass casualty cyanide poisoning? Clin.Toxicol. (Phila.) 2010; 48: 477–84.
38. Amyl nitrite. 2011. Available from URL: http://www.med.unsw.edu.au/ndarcweb.nsf/resources/ndarcfact_drugs6/$file/amyl.pdf (accessed December 2011).
39. Chen KK, Rose CL, Clowes GHA. Comparative values of severalantidotes in cyanide poisoning. Am. J. Med. Sci. 1934; 188: 767–81.
40. Bebarta VS, Tanen DA, Lairet J, Dixon PS, Valtier S, Bush A.Hydroxocobalamin and sodium thiosulfate versus sodium nitriteand sodium thiosulfate in the treatment of acute cyanide toxicityin a swine (Sus scrofa) model. Ann. Emerg. Med. 2010; 55: 345–51.
41. Baskin SI, Kelly JB, Maliner BI, Rockwood GA, Zoltani CK.Cyanide poisoning. In: Tuorinsky SD, ed. Medical Aspects ofChemical Warfare. Fort Sam Houston: US Army Medical Depart-ment, 2008; 371–410.
42. Baskin SI, Horowitz AM, Nealley EW. The antidotal action ofsodium nitrite and sodium thiosulfate against cyanide poisoning.J. Clin. Pharmacol. 1992; 32: 368–75.
43. MIMS Online. St Leonards: UBM Medica, 2011. Available fromURL: https://www.mimsonline.com.au (accessed February 2012).
44. Hall AH, Kulig KW, Rumack BH. Suspected cyanide poisoningin smoke inhalation: complications of sodium nitrite therapy.J. Toxicol. Clin. Exp. 1989; 9: 3–9.
45. Beasley DM, Glass WI. Cyanide poisoning: pathophysiology andtreatment recommendations. Occup. Med. (Lond.) 1998; 48: 427–31.
46. Klimmek R, Fladerer H, Weger N. Circulation, respiration, andblood homeostasis in cyanide-poisoned dogs after treatment with4-dimethylaminophenol or cobalt compounds. Arch. Toxicol.1979; 43: 121–33.
47. Elliot R. Cyanide Poisoning – New Recommendations on First AidTreatment. Merseyside: Health and Safety Executive, UK, 1996.Available from URL: http://www.hse.gov.uk/pubns/misc076.htm (accessed February 2012).
48. Paulet G. Nouvelles perspectives dans le traitement del’intoxication cyanhydrique. Arch. Mal. Prof. 1961; 22: 102–27.
49. Marrs TC, Swanston DW, Bright JE. 4-Dimethylaminophenoland dicobalt edetate (Kelocyanor) in the treatment of experimen-tal cyanide poisoning. Hum. Toxicol. 1985; 4: 591–600.
50. Hilmann B, Bardham KD, Bain JTB. The use of dicobalt edetate(Kelocyanor) in cyanide poisoning. Postgrad. Med. J. 1974; 50:171–4.
51. Naughton M. Acute cyanide poisoning. Anaesth. Intensive Care1974; 4: 351–6.
52. Dicobalt Edetate Product Information. Thornleigh, NSW: iNovaPharmaceuticals (Australia), 2007. Available from URL: http://www.inovapharma.com/_uploads/documents/Dicobalt%20edetate%20vs2.pdf (accessed February 2012).
53. Schulz V, Bonn R, Kammerer H, Kriegel R, Ecker N. Counterac-tion of cyanide poisoning by thiosulphate when administeringsodium nitroprusside as a hypotensive treatment. Klin.Wochenschr. 1979; 57: 905–7.
54. Cummings TF. The treatment of cyanide poisoning. Occup. Med.(Lond.) 2004; 54: 82–5.
MC Reade et al.
12 © 2012 The AuthorsEMA © 2012 Australasian College for Emergency Medicine and Australasian Society for Emergency Medicine
55. Pill J, Engeser P, Hobel M, Kreye VA. Sodium nitroprusside:comparison of the antidotal effect of hydroxocobalamin andsodium thiosulfate in rabbits. Dev. Toxicol. Environ. Sci. 1980; 8:423–6.
56. Krapez JR, Vesey CJ, Adams L, Cole PV. Effects of cyanideantidotes used with sodium nitroprusside infusions: sodium thio-sulphate and hydroxocobalamin given prophylactically to dogs.Br. J. Anaesth. 1981; 53: 793–804.
57. Chen KK, Rose CL, Clowes GHA. Methylene blue, nitrites, andsodium thiosulphate against cyanide poisoning. Proc. Soc. Exp.Biol. Med. 1933; 31: 250–1.
58. Chen KK, Rose CL, Clowes GHA. Potentiation of antidotal actionof sodium tetrathionate and sodium nitrite in cyanide poisoning.Proc. Soc. Exp. Biol. Med. 1933; 31: 252–3.
59. Ivankovich AD, Braverman B, Kanuru RP, Heyman HJ,Paulissian R. Cyanide antidotes and methods of their adminis-tration in dogs: a comparative study. Anesthesiology 1980; 52:210–16.
60. Vesey CJ, Krapez JR, Varley JG, Cole PV. The antidotal actionof thiosulfate following acute nitroprusside infusion in dogs.Anesthesiology 1985; 62: 415–21.
61. Schulz V, Gross R, Pasch T, Busse J, Loeschcke G. Cyanide toxicityof sodium nitroprusside in therapeutic use with and withoutsodium thiosulphate. Klin. Wochenschr. 1982; 60: 1393–400.
62. Forsyth JC, Mueller PD, Becker CE et al. Hydroxocobalamin as acyanide antidote: safety, efficacy and pharmacokinetics inheavily smoking normal volunteers. J. Toxicol. Clin. Toxicol.1993; 31: 277–94.
63. Callaghan JM, Halton DM. Solutions A and B: cyanide antidote orfolklore myth? J. Soc. Occup. Med. 1988; 38: 65–8.
64. Nicholson PJ, Ferguson-Smith J, Pemberton MA, Campbell A,Edwards JN, Ferner RE. Time to discontinue the use of solutionsA and B as a cyanide ‘antidote’. Occup. Med. (Lond.) 1994; 44:125–8.
65. Mushett CW, Kelley KL, Boxer GE, Richards JC. Antidotal effi-cacy of vitamin B12a (hydroxo-cobalamin) in experimentalcyanide poisoning. Proc. Soc. Exp. Biol. Med. 1952; 81: 234–7.
66. Posner MA, Rodkey FL, Tobey RE. Nitroprusside-inducedcyanide poisoning: antidotal effect of hydroxocobalamin. Anes-thesiology 1976; 44: 330–5.
67. Cottrell JE, Casthely P, Brodie JD, Patel K, Klein A, Turndorf H.Prevention of nitroprusside-induced cyanide toxicity withhydroxocobalamin. N. Engl. J. Med. 1978; 298: 809–11.
68. Uhl W, Nolting A, Golor G, Rost KL, Kovar A. Safety of hydroxo-cobalamin in healthy volunteers in a randomized, placebo-controlled study. Clin. Toxicol. (Phila.) 2006; 44 (Suppl 1): 17–28.
69. Lee J, Mukai D, Kreuter K, Mahon S, Tromberg B, Brenner M.Potential interference by hydroxocobalamin on cooximetryhemoglobin measurements during cyanide and smoke inhalationtreatments. Ann. Emerg. Med. 2007; 49: 802–5.
70. Carlsson CJ, Hansen HE, Hilsted L, Malm J, Odum L, Szecsi PB.An evaluation of the interference of hydroxycobalamin withchemistry and co-oximetry tests on nine commonly used instru-ments. Scand. J. Clin. Lab. Invest. 2011; 71: 378–86.
71. Abdelmalek J, Thornton S, Nizar J, Schneir A, Sanchez AP. Suc-cessful use of continuous renal replacement therapy afterhydroxocobalamin administration. Dial. Transplant. 2011; 40:415–17.
72. Borron SW, Baud FJ, Barriot P, Imbert M, Bismuth C. Prospec-tive study of hydroxocobalamin for acute cyanide poisoning insmoke inhalation. Ann. Emerg. Med. 2007; 49: 794–801.
73. Borron SW, Baud FJ, Megarbane B, Bismuth C. Hydroxocobal-amin for severe acute cyanide poisoning by ingestion or inhala-tion. Am. J. Emerg. Med. 2007; 25: 551–8.
74. Espinoza OB, Perez M, Ramirez MS. Bitter cassava poisoningin eight children: a case report. Vet. Hum. Toxicol. 1992; 34:65.
75. Fortin JL, Giocanti JP, Ruttimann M, Kowalski JJ. Prehospitaladministration of hydroxocobalamin for smoke inhalation-associated cyanide poisoning: 8 years of experience in theParis Fire Brigade. Clin. Toxicol. (Phila.) 2006; 44 (Suppl 1):37–44.
76. Fortin JL, Desmettre T, Manzon C et al. Cyanide poisoningand cardiac disorders: 161 cases. J. Emerg. Med. 2010; 38: 467–76.
77. Houeto P, Hoffman JR, Imbert M, Levillain P, Baud FJ. Relation ofblood cyanide to plasma cyanocobalamin concentration after afixed dose of hydroxocobalamin in cyanide poisoning. Lancet1995; 346: 605–8.
78. Pontal PG, Bismuth C, Garnier R. Therapeutic attitude in cyanidepoisoning: retrospective study of 24 non-lethal cases. Vet. Hum.Toxicol. 1982; 24: 286–7.
79. Yen D, Tsai J, Wang LM et al. The clinical experience of acutecyanide poisoning. Am. J. Emerg. Med. 1995; 13: 524–8.
80. Burgess WA, Treitman RD, Gold A. Air Contaminants in Struc-tural Firefighting. Boston: National Fire Prevention and ControlAdministration and The Society of Plastics Industry, 2011.
81. Yeoh MJ, Braitberg G. Carbon monoxide and cyanide poisoningin fire related deaths in Victoria, Australia. J. Toxicol. Clin.Toxicol. 2004; 42: 855–63.
82. Baud FJ, Barriot P, Toffis V et al. Elevated blood cyanide con-centrations in victims of smoke inhalation. N. Engl. J. Med. 1991;325: 1761–6.
83. Martin-Bermudez R, Maestre-Romero A, Goni-Belzunegui MV,Bautista-Lorite A, Arenas-Cabrera C. Venous blood arterioliza-tion and multiple organ failure after cyanide poisoning. IntensiveCare Med. 1997; 23: 1286.
84. Cyanide Antidote Kit Order Form. Joondalup: HPS Pharmacies,2010. [Cited 2 February 2012.] Available from URL: http://www.jhpharmacy.com.au/Cyanide%20Order%20Form.pdf(accessed 2 February 2012)
85. Beasley RW, Blow RJ, Lunau FW, Taylor BM. Amyl nitrite andall that. J. Soc. Occup. Med. 1978; 28: 142–3.
86. Watson WA, Litovitz TL, Rodgers GC et al. 2004 Annual reportof the American Association of Poison Control Centers ToxicExposure Surveillance System. Am. J. Emerg. Med. 2005; 23:589–666.
87. Cyanokit (Hydroxocobalamin for Injection). Silver Spring, MD:US Food and Drug Administration, 2011. Available from URL:http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022041s008s009lbl.pdf (accessed 2 February 2012).
88. Product Information: Sodium Nitrite Injection. Sydney: Phebra,2010. Available from URL: http://www.phebra.com.au/data/products/INJ004-pi.pdf (accessed 2 February 2012).
89. Hall AH, Saiers J, Baud F. Which cyanide antidote? Crit. Rev.Toxicol. 2009; 39: 541–52.
Management of cyanide poisoning
13© 2012 The AuthorsEMA © 2012 Australasian College for Emergency Medicine and Australasian Society for Emergency Medicine
Supporting Information
Additional Supporting Information may be found in theonline version of this article:
Appendix S1. Management of a patient with sus-pected cyanide poisoning.
Please note: Wiley-Blackwell are not responsible for thecontent or functionality of any supporting materialssupplied by the authors. Any queries (other thanmissing material) should be directed to the correspond-ing author for the article.
MC Reade et al.
14 © 2012 The AuthorsEMA © 2012 Australasian College for Emergency Medicine and Australasian Society for Emergency Medicine