behalf of the Australian Resuscitation Council

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: [email protected] or [email protected]

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.


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



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.


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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.



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.


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



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.


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

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Appendix S1. Management of a patient with sus-pected cyanide poisoning.

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