REVIEW ARTICLE

Review article: Management of

cyanide poisoningemm_1538 225..238
Michael C Reade,
1,4,5
Suzanne R Davies,
1
Peter T Morley,
1,2
Jennifer Dennett
1,3
and Ian C Jacobs,
1,6
on
behalf of the Australian Resuscitation Council
1
Australian Resuscitation Council, Royal Australasian College of Surgeons, College of Surgeons Gardens,
2
Royal Melbourne Hospital and University of Melbourne, Melbourne,
3
Central Gippsland Health Service,
Sale, Victoria,
4
Australian Defence Force, Canberra, Australian Capital Territory,
5
University of
Queensland, Brisbane,
6
University of Western Australia, Perth, Western Australia, Australia
Abstract
Cyanide poisoning is uncommon, but generates interest because of the presumed utility of
an antidote immediately available in those areas with a high risk of cyanide exposure. As
part of its regular review of guidelines, the Australian Resuscitation Council conducted a
systematic 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 have
been no relevant comparative or placebo-controlled human trials. Nine case series were
identied. Treatment with hydroxocobalamin was reported in a total of 361 cases. No
serious adverse effects of hydroxocobalamin were reported, and many patients with other-
wise presumably fatal poisoning survived. Sodium thiosulphate use was reported in two
case series, similarly with no adverse effects. Treatment with a combination of sodium
nitrite, amyl nitrite and sodium thiosulphate was reported in 74 patients, with results
indistinguishable from those of hydroxocobalamin and sodium thiosulphate. No case series
using dicobalt edetate or 4-dimethylaminophenol were identied, but successful use in
single cases has been reported. Hydroxocobalamin and sodium thiosulphate differ from
alternatives in having negligible adverse effects, and on the basis of current evidence are
the antidotes of choice. The indications for the use of an antidote, the requirements for
supportive care and a recommended approach for workplaces where there is a risk of
cyanide poisoning are presented.
Key words: antidote, cyanide, poisoning, resuscitation.
Introduction
Poisoning by plants containing cyanide has been
known for millennia, but the rst published description
of cyanide poisoning (due to bitter almonds) was by
Wepfer in 1679.
13
Compounds containing cyanide ions
(CN
-
) are rapidly acting poisons that interfere with
mitochondrial oxygen utilization. Cyanide can cause
poisoning by:
4
Inhalation of cyanide-containing gas (such as
hydrogen cyanide or cyanogen chloride) or dust
containing solid or liquid cyanide. Typical sources
are 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 Womens Hospital, Herston, Qld
4029, 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, Research
Ofcer; 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-Hospital
Care.
doi: 10.1111/j.1742-6723.2012.01538.x Emergency Medicine Australasia (2012) 24, 225238
bs_bs_banner
2012 The Authors
EMA 2012 Australasian College for Emergency Medicine and Australasian Society for Emergency Medicine
manufacturing, steel fabrication and vermin eradica-
tion), or (possibly
5
) combustion of plastics, acrylics,
synthetic rubber, carpeting or upholstery in enclosed
spaces
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 (either
with suicidal intent or accidentally) or over time (e.g.
in foods containing cyanogenic glycosides, such as
cassava 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 period
The most common source of cyanide exposure is
smoke inhalation from residential or industrial res,
although whether the low levels of cyanide typically
inhaled are sufcient to cause clinically important poi-
soning is unclear.
5
Three pharmaceuticals (sodium nitrite, sodium
thiosulphate and dicobalt edetate) are approved by the
Australian Therapeutic Goods Administration (TGA)
as cyanide antidotes. Many Australian organizations,
6
government departments
7,8
and Poisons Information
Services
9
have written guidelines that list these and
other substances as part of an overall strategy, but there
is considerable variability in recommended approaches.
Although industrial cyanide poisoning is rare in the
developed world
10
(presumably because of good work
practices), maintaining a supply of a cyanide antidote
that might never be used is a signicant expense.
Moreover, some of the recommended antidotes are
themselves poisonous, which could make inappropriate
use a greater risk than cyanide poisoning itself.
No Australian or international authority has pub-
lished a detailed evidence-based cyanide poisoning
guideline resulting from a systematic review of the lit-
erature. In 1996, the Australian Resuscitation Council
(ARC) published a Basic Life Support guideline for the
management of cyanide toxicity
11
that gave general
rst-aid advice but no recommendation on a particular
cyanide antidote. As part of its regular update of guide-
lines, the ARC conducted a systematic reviewof cyanide
poisoning management. We aimed to answer the ques-
tion in adult patients with conrmed severe cyanide
poisoning (including cardiac arrest due to cyanide poi-
soning), does any intervention, as opposed to standard
care, improve survival?. In addition, we sought litera-
ture reporting evidence from animal studies, the clinical
features of cyanide poisoning and the indications for the
administration of a cyanide antidote.
Methods
In November 2010, we performed a systematic literature
review of English language publications indexed in
MEDLINE, using the search terms (cyanides OR
cyanogens OR nitriles OR azides OR cyanogenic
glycosides OR nitriles OR azides) AND (antidote OR
hydroxocobalamin OR sodium nitrite OR thiosulfate
OR antidote OR cyanokit). In addition, we searched
the 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 for
text words contained in unpublished documents. We
excluded case reports of intoxications in which no con-
clusion could be drawn regarding the efcacy of an
intervention. We manually inspected reference lists of
all relevant articles.
We classied identied studies using the Australian
National 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 reviews
for relevant animal and cellular studies, for any consen-
sus statements on the indications for the administration
of a cyanide antidote and for reports of the clinical
features of cyanide poisoning. In February 2011, we
searched the Australian Register of Therapeutic
Goods
12
and online pharmaceutical catalogues in order
to determine the Australian availability of the various
described antidotes to cyanide.
Results
Clinical features of cyanide poisoning
Early features of cyanide poisoning are irritation of oral
mucous 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 or
trismus), pulmonary oedema and cardiac arrest.
4
The
expired gas from a patient with cyanide poisoning is
classically described as having a bitter almond smell,
as do many cyanide-containing compounds. However,
the diagnostic sensitivity of this characteristic is low, as
18% of men and 4% of women are unable to perceive
MC Reade et al.
226 2012 The Authors
EMA 2012 Australasian College for Emergency Medicine and Australasian Society for Emergency Medicine
this smell,
15
a ratio that implies a sex-linked recessive
trait. The other widely quoted feature of cyanide poi-
soning, bright-red (cherry) discolouration of the skin
and mucous membranes, is based on the theory that
decreased tissue oxygen utilization will increase oxy-
haemoglobin in venous blood. However, this degree of
cyanide toxicity is likely to cause circulatory failure,
which would prevent such colouration.
4
As oxidative
phosphorylation is blocked, increased glycolysis leads
to lactic acidosis, the degree of which correlates with the
severity of the poisoning.
16
Chronic cyanide poisoning
(i.e. long-term exposure to sub-lethal concentrations of
cyanide) 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 hospital
arrival. Although prehospital administration of specic
cyanide antidotes might possibly assist victims of
cyanide poisoning, patients in cardiorespiratory arrest
can undoubtedly benet from basic and advanced life
support 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 smoke
inhalation (who are unlikely to have high levels of
expired cyanide gas, as discussed below), mouth-to-
moth ventilation should not be attempted. Several pub-
lished case reports demonstrate that survival is possible
after substantial cyanide poisoning treated with sup-
portive care alone. For example, nine patients simulta-
neously poisoned in an industrial accident, with blood
levels of cyanide considered lethal, had supportive
therapy alone. All survived.
21
Numerous other case
reports
2224
conrm this is possible. Supportive care in
this context included the full spectrum of intensive care
interventions, including mechanical ventilation, circula-
tory support and renal replacement therapy. Of note,
only one patient in all of these reports suffered cardiac
arrest, suggesting either supportive care instituted early
was sufcient to prevent this, or that these patients had
in fact not ingested a lethal amount of cyanide.
One element of supportive care thought at times to be
particularly benecial is oxygen administration. On the
basis of animal experiments, oxygen,
25
and also hyper-
baric oxygen,
26
have been advocated as adjuncts to
chemical cyanide antidotes. Any benet appears not to
be mediated by reactivation of cytochrome oxidase or
acceleration of rhodenase detoxication.
27
A postulated
mechanism of action is redistribution of cyanide from
the intracellular to intravascular compartments,
28,29
although this effect could not be detected in a clinical
trial of 25 patients.
30
Oxygen signicantly enhanced the
antidotal effect of sodium nitrite and sodium thiosul-
phate (in combination) in rats, but hyperbaric oxygen
was no more effective than normobaric 100% oxygen.
31
On balance, although the mechanism remains unclear, it
appears reasonable to treat victims of cyanide poisoning
with 100% oxygen.
Without studies comparing supportive care alone to
the use of an antidote, no conclusion can be drawn other
than that the potential adverse effects of any antidote
must be weighed against the possibility that the patient
might recover with supportive care alone.
Postulated cyanide antidotes
Four types of cyanide antidotes are described in the
literature, grouped according to their modes of action.
They are classied as: substances that increase the
metabolism of cyanide (sodium thiosulphate, a rate-
limiting substrate in the endogenous metabolic pathway
for cyanide); substances that bind to cyanide (hydroxo-
cobalamin [vitamin B
12a
] and dicobalt edetate); sub-
stances that produce methaemoglobin, which reacts
with cyanide to form non-toxic cyanomethaemoglobin
(sodiumnitrite, amyl nitrite and 4-dimethylaminophenol
[4-DMAP]); and substances that might possibly reduce
the absorption of ingested cyanide (ferrous sulphate
dissolved in aqueous citric acid and aqueous sodium
carbonate: Solutions A and B). Only sodium thiosul-
phate, sodium nitrite and dicobalt edetate are listed on
the Australian Register of Therapeutic Goods for the
treatment of cyanide poisoning.
32
Hydroxocobalamin is
listed in the 1 mg/mL parenteral form used to treat
pernicious anaemia and optic neuropathy, but not the
2.5 g form studied as a cyanide antidote. Hydroxocobal-
amin 2.5 g and amyl nitrite are available fromAustralian
suppliers through the TGA Special Access Scheme.
Review of available cyanide antidotes: case
series and pharmacodynamic and animal studies
Amyl nitrite
Nitrite-based cyanide antidotes oxidize haemoglobin
to methaemoglobin, which complexes with cyanide
to form non-toxic cyanomethaemoglobin. However,
2030% methaemoglobin is required to optimally bind
cyanide,
5
a level capable of signicantly impeding
Management of cyanide poisoning
227 2012 The Authors
EMA 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 rst pos-
tulated cyanide antidote, in 1888.
33
Its use is attractive
for rst aid, as it is inhaled from a crushed capsule.
However, it produces only about 7% methaemoglobin,
which is probably insufcient to bind a lethal dose of
cyanide.
4
Amyl nitrite apparently reversed the cardiac
and respiratory effects of cyanide in 24 of 30 dogs stud-
ied.
34
These effects were observed before the generation
of methaemoglobin, suggesting vasodilation and
increased cardiac output as an alternative mechanismof
action. Amyl nitrite treatment of cyanide-exposed mice
resulted in a signicant 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 to
24.5 mg/kg.
36
However, levels of methaemoglobin
achieved in humans might be substantially less than in
these experimental conditions,
4
and a systematic review
in 2010
37
found little evidence of efcacy from compara-
tive studies, and no comparative studies in humans, but
frequent reports of adverse reactions (such as hypoten-
sion, syncope, excessive methaemoglobinaemia causing
hypoxia and haemolysis in patients with glucose-6-
phosphate deciency). As a drug of abuse,
38
it must be
appropriately secured to prevent theft. This review
37
concluded that the use of amyl nitrite could not be
justied.
Sodium nitrite
The rst antidote strategy based on an understanding
of biochemical mechanisms was described by Chen et al.
in 1934,
39
who suggested a combination of amyl nitrite,
sodiumnitrite and sodiumthiosulphate based on results
from animal studies. Sodium nitrite, at a minimum dose
of 5 mg/kg, was shown to be an effective antidote for
experimental cyanide poisoning in dogs, whereas
200 mg/kg was efcacious in rabbits.
4
However, there is
very little other animal or clinical evidence in support of
this approach.
5
Animal and human experiments evalu-
ating sodium nitrite nd it produces higher methaemo-
globin levels than amyl nitrite, but that this is
accompanied by problematic hypotension.
4
A study of
24 pigs poisoned with i.v. cyanide and subsequently
treated with sodium thiosulphate and either hydroxoco-
balamin or sodium nitrite found no difference in
mortality 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 dened in humans.
42
The
dose recommended in the TGA-approved product infor-
mation
43
is 300 mg (in a typical adult, approximately
4 mg/kg, the same weight-adjusted dose as for children)
at 75150 mg/min, with half the initial dose repeated at
30 min if required and with adjustment to maintain
methaemoglobin levels 40%. Caution is particularly
required in patients with smoke inhalation, as the meth-
aemoglobin produced by such a dose of sodium nitrite,
in combination with carboxyhaemoglobin, has been
observed to precipitate ultimately fatal levels of non-
oxygen-transporting haemoglobin.
44
Similarly, the
effect of methaemoglobin on oxygen transport will be
magnied in anaemic patients.
4-Dimethylaminophenol
4-Dimethylaminophenol produces a more rapid rise in
methaemoglobin than sodium nitrite,
4,45
and is a com-
monly used cyanide antidote in Germany.
41,45
When
4-DMAP was given intravenously to dogs 1 min after
poisoning with a lethal dose of potassium cyanide, all
the animals survived.
46
Eighteen case reports of the use
of 4-DMAP have been summarized.
4
In these 18 cases,
there were seven deaths; 10 patients recovered, but one
patient had ongoing CNS impairment. 4-DMAP can
cause 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%) was
observed.
4
Dicobalt edetate
Cobalt compounds were rst advocated as cyanide anti-
dotes in 1894.
4
The cobalt atom in dicobalt edetate binds
to cyanide. Until withdrawing all advice on cyanide
antidotes in 1996,
47
dicobalt edetate (along with amyl
nitrite) was the antidote recommended by the UK gov-
ernment.
47
Dicobalt edetate has only been comparatively
evaluated in animal studies. In the 1950s and 1960s,
Paulet published results of an extensive series of animal
experiments investigating various cobalt compounds,
4
and subsequently reported that dicobalt edetate was
more effective than a combination of sodium nitrite and
thiosulphate.
48
Comparisons in dogs found dicobalt
edetate effective, but inferior to 4-DMAP.
46,49
Dicobalt
edetate has been used in numerous human cases in
which patients survived.
4
The utility of dicobalt edetate
is limited by its serious adverse effects, which include
vomiting, urticaria, anaphylactic shock, hypotension
and ventricular arrhythmias.
50,51
These harmful effects
might be more common and severe in the absence of
MC Reade et al.
228 2012 The Authors
EMA 2012 Australasian College for Emergency Medicine and Australasian Society for Emergency Medicine
cyanide.
4
There is evidence from animal experiments
that glucose protects against cobalt toxicity, and it is
recommended that this be simultaneously administered.
Because of its toxicity, the TGA-approved product
information mandates dicobalt edetate only be used in
cases of conrmed cyanide poisoning when a patient
has lost consciousness.
52
Sodium thiosulphate
Physiological levels of cyanide are metabolized to thio-
cyanate by the enzyme rhodanese, which requires thio-
sulphate as a substrate. The bodys reserve of
thiosulphate is limited,
4,53
suggesting supplementation
might be benecial in cyanide poisoning. However,
rhodanese is located within mitochondria, and thiosul-
phate penetrates cell and mitochondrial membranes
poorly.
4
This might explain why sodium thiosulphate
appears to act more slowly than other antidotes.
5,54
Studies in rabbits
55
and dogs
56
found sodium thiosul-
phate was an effective antidote to cyanide produced by
high levels of sodium nitroprusside. By augmenting the
endogenous capacity to metabolize cyanide, sodium
thiosulphate treats cyanide poisoning by a different
mechanism, implying its effect could be additive to that
of other antidotes. Most published animal studies
4,57,58
have used sodium thiosulphate in combination with
other antidotes. However, there is evidence that thiosul-
phate alone is effective,
59
particularly in the context of
sodium 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/min
for 1.5 h caused potentially toxic levels of cyanide,
61
and
this was prevented by sodium thiosulphate. For this
reason, sodium thiosulphate has been recommended as
prophylaxis against cyanide toxicity when nitroprus-
side is required at high doses.
4
Sodium thiosulphate can cause local skin and muscle
pain at the infusion site,
62
nausea, vomiting, headache
and disorientation,
45
but life-threatening adverse effects
have not been reported.
4
Solutions A and B
Solutions A and B (ferrous sulphate in aqueous citric
acid and aqueous sodium carbonate) had previously
been 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 is
likely that solutions A and B have to be given within
seconds of cyanide ingestion. The review authors noted
that the main basis for recommendations was custom
and practice, which made withdrawal of the antidote
difcult to achieve. Solutions A and B are no longer
recommended as a practical antidote.
64
Hydroxocobalamin (vitamin B
12a
)
Hydroxocobalamin was rst reported to be a promising
cyanide antidote in experimental cyanide poisoning in
mice in 1952.
65
Hydroxocobalamin prevented metabolic
acidosis and reduced blood cyanide concentrations in
baboons 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 cyanide
concentrations found in heavy smokers.
62
No signicant
toxic effects of hydroxocobalamin have been reported in
animal studies or humans.
4
Minor reported adverse
effects include transient hypertension and bradycar-
dia,
62
red-orange urine discolouration, transient head-
ache and mild allergic reactions that were readily
treated.
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 effects
of smoke inhalation) and methaemoglobin,
69
lactate, and
many other commonly measured haematological and
biochemical indices.
70
Ideally, and especially if the diag-
nosis is unclear, blood should be taken for analysis
before hydroxocobalamin is administered. A further
problem caused by hydroxocobalamins pigment is
false triggering of the sensor that detects blood leakage
across the articial kidney membrane during dialysis.
This problem has been circumvented by recalibrating
this sensor using a continuous renal replacement
machine.
71
Systematic review of studies reporting use of
cyanide antidotes in humans
The results of the systematic review are shown in
Figure 1. There have been no comparative or placebo-
controlled human trials evaluating treatment strategies
for severe cyanide poisoning. Table 1 summarizes the
nine relevant studies identied. All are small uncon-
trolled case series (National Health and Medical
Research Council level IV). None provides denitive evi-
dence of the superiority of one approach over another, or
over supportive care alone. Meaningful comparisons of
survival rates are impossible, as the severity of many of
the poisonings is not described. Seven of the nine case
series described, totalling reports of 361 patients
(mostly smoke exposure victims), report treatment with
Management of cyanide poisoning
229 2012 The Authors
EMA 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 nine
case series,
36,74,79
reporting 74 patients, describe treat-
ment with amyl nitrite, sodium nitrite and sodium thio-
sulphate in combination. One report
74
describes four
patients treated with each approach, in which all eight
patients survived.
The most important conclusion that can be drawn
with any certainty from this systematic review is that it
is possible to survive cardiorespiratory arrest due to
cyanide poisoning if given an antidote: of 136 reported
patients in cardiac arrest, 16 (11.8%) survived to hospi-
tal discharge. Interestingly, the rate of initial response
was much higher: 50 out of 97 patients (51.5%) had
transient return of spontaneous circulation.
Indications for the use of a cyanide antidote
Cardiorespiratory collapse, combined with either a high
blood cyanide level or obvious evidence of cyanide poi-
soning, is a clear indication for use of an antidote. Under
these circumstances, the use of antidotes with even
narrow therapeutic indices would appear reasonable.
However, the indication for use of a cyanide antidote is
less clear when smaller quantities are ingested, in
patients without cardiorespiratory collapse, or where
the diagnosis is unclear. Under these circumstances, it is
logical to avoid the more toxic antidotes, and this is
reected in the TGA-approved product information for
dicobalt edetate.
52
Unlike other strategies, hydroxoco-
balamin and sodium thiosulphate have few adverse
effects, justifying their use in lesser degrees of cyanide
poisoning as well as in the prophylaxis of possible
cyanide toxicity due to high-rate sodium nitroprusside.
The most problematic possible indication for use of a
cyanide antidote is with smoke inhalation, the common-
est cause of cyanide exposure. Such patients often
present with metabolic acidosis, but this is more likely
to be caused by under-resuscitation, carbon monoxide
poisoning or missed traumatic injury than by cyanide
poisoning.
5
Cyanide exposure during house res was
measured in samples obtained from devices on reght-
ers coats.
80
Only 27 of 253 samples contained hydrogen
cyanide, with a maximumconcentration (3.6 p.p.m.) well
Figure 1. Results of the systematic search for relevant literature.
MC Reade et al.
230 2012 The Authors
EMA 2012 Australasian College for Emergency Medicine and Australasian Society for Emergency Medicine
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MC Reade et al.
232 2012 The Authors
EMA 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 re-
related deaths in Victoria, Australia had potentially
fatal blood cyanide levels.
81
Blood cyanide levels might
be impossible to obtain before a treatment decision is
required, necessitating clinical judgment. Although
there are no immediately available denitive laboratory
tests for cyanide toxicity, a number of indices are
highly suggestive. Smoke inhalation patients with a
carboxyhaemoglobin level >10% are particularly likely
to have inhaled a dangerous quantity of cyanide.
81
In
the context of smoke inhalation without severe burns,
a plasma lactate >10 mmol/L had a sensitivity of
87% and specicity of 94% for clinically signicant
cyanide poisoning.
82
An increase in the central venous
partial pressure of oxygen and per cent oxygen satura-
tion measured by blood gas analysers, such that these
approach measured arterial values, has also been
described.
83
In one study, 42 of 69 patients with smoke
inhalation and neurological impairment had poisonous
blood levels of cyanide. All 69 were treated with
hydroxocobalamin, and 28 of the 42 with cyanide poi-
soning survived.
72
Although there is insufcient evi-
dence to recommend routine use of a cyanide antidote in
patients with possible cyanide poisoning caused by
smoke inhalation, the presence of neurological impair-
ment or elevated carboxyhaemoglobin or lactate levels
at least suggests one of the low-risk antidotes should be
considered after other more likely causes such as
carbon monoxide poisoning have been appropriately
managed.
Cost and stability in storage
Representative retail costs of the various cyanide anti-
dotes are listed in Table 2. Because of the infrequency of
cyanide poisoning, most cyanide antidote vials are
never used. If a workplace chooses to keep a cyanide
antidote in its cyanide emergency kit, the cost will also
be 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 sodiumthiosulphate 0.8 times
the cost of amyl + sodium nitrite.
Prehospital availability and use of
cyanide antidotes
The majority of patients reported in papers identied
in the systematic review were treated with cyanide
antidotes before arrival in hospital. It would seem intu-
itively obvious that earlier antidote administration will
lead to better outcomes. This might not be true in
cases of equivocal diagnosis if using antidotes that
are themselves toxic, but as noted above, hydroxoco-
balamin and sodium thiosulphate appear sufciently
safe. However, the community incidence of cyanide
poisoning (ignoring the possibly much larger number
of exposures due to smoke inhalation) is low: for
example, only 257 of 2.8 million exposures to poisons
reported to US poison control centres in 2004 were due
to cyanide.
86
Given their cost, this argues against uni-
versally equipping prehospital emergency medical ser-
vices with cyanide antidotes. However, workplaces
with a particular risk of cyanide exposure and perhaps
hospitals serving a high concentration of industries in
which cyanide is used are logical places to stock this
resource. No rm conclusion can be drawn from the
literature as to whether emergency medical services
should stock cyanide antidotes for use in victims of
smoke inhalation. If transport times to hospitals spe-
cializing in burns care are short, only stocking cyanide
antidotes in such centres would seem a reasonable
approach.
Table 2. Cost (in February 2011) and shelf life of various cyanide antidotes
Antidote Cost Shelf life
Hydroxocobalamin A$2838
84
for 2 2.5 g 3 years
4,41
NB. A 1 mg ampoule Pharmaceutical Benets Scheme subsidized
for the treatment of pernicious anaemia is A$15.87
43
Dicobalt edetate A$696.92
43
for 20 mL 1.5% 3 years
4,41
Sodium nitrite A$787.50
43
for 10 300 mg in 10 mL or 5 years
4,41
A$2 631.58
43
for 5 300 mg in 10 mL
Sodium thiosulphate A$203.50
84
for 50 mL 25% 5 years
41
Amyl nitrite A$174.24
84
for 6 0.6 mL 6 months
85
to 2 years
4
4-Dimethylaminophenol Not marketed in Australia 3 years
4
Management of cyanide poisoning
233 2012 The Authors
EMA 2012 Australasian College for Emergency Medicine and Australasian Society for Emergency Medicine
Recommendations
The ARC recommends that the contents of an industrial
workplace cyanide emergency kit should be determined
by a qualied occupational health assessor, taking into
account the nature of the cyanide threat, the training of
workplace rst aiders and the proximity of external
assistance (Appendix S1). Possible inclusions are:
Equipment for articial respiration, including oropha-
ryngeal airways, laryngeal mask airways, equipment
for endotracheal intubation, a self-inating bag-valve-
mask apparatus and a supply of medical oxygen suf-
cient to provide 100% inspired oxygen to the victim
A tourniquet, i.v. cannulae, syringes and needles
A cyanide antidote
The sparse published human efcacy and safety evi-
dence that exists supports the use of hydroxocobal-
amin with or without sodium thiosulphate, or sodium
thiosulphate alone, for conrmed or suspected cyanide
poisoning. The onset of action of sodium thiosulphate
appears slower than that of hydroxocobalamin. The
ARC therefore recommends that adult patients with
suspected severe cyanide poisoning (including those in
cardiac arrest) should receive immediate parenteral
hydroxocobalamin, 5 g over 15 min with repeat dosing
up to 15 g. Paediatric doses should be adjusted accord-
ing to weight: 70 mg/kg over 15 min, repeated twice if
necessary.
87
This is a considerably larger dose than
contained in parenteral vitamin B
12a
preparations
designed 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 be
stocked. However, in February 2011, Cyanokit was not
included on the Australian Register of Therapeutic
Goods, with the supply of this product requiring an
application through the TGA Special Access Scheme.
Ambulance services and hospital EDs might not stock
cyanide antidotes. Therefore, even if a workplace has
no personnel qualied to administer a cyanide antidote,
a cyanide emergency kit containing an antidote is still
recommended if the assessed risk of cyanide exposure
is sufciently high. The cyanide emergency kit should
accompany the patient for use when sufciently quali-
ed personnel become available. The ARC recom-
mends that it is reasonable to treat inhalational burn
patients with neurological impairment or carboxyhae-
moglobin >10% or plasma lactate >10 mmol/L with
hydroxocobalamin, once other possible causes of meta-
bolic acidosis have been addressed. Although there is
no human evidence demonstrating harm, physiological
principles suggest that antidotes that produce methae-
moglobin, such as the nitrites, are contraindicated in
cyanide poisoning due to smoke inhalation because of
the likely presence of signicant amounts of carboxy-
haemoglobin.
The ARC also recommends that sodium thiosulphate
be considered as an adjunct to the treatment of severe
cyanide toxicity, but that this treatment should gener-
ally be considered following failure to respond
adequately to hydroxocobalamin. The exception to this
recommendation is sodium nitroprusside toxicity, in
which sodium thiosulphate has been successfully used
as a sole agent. The approved adult dose is 12.5 g
(50 mL of a 25% solution) administered intravenously
at 1.25 g/min (5 mL/min), with the higher recom-
mended paediatric dose of 412.5 mg/kg at 0.6251.25 g/
min to a maximum of 12.5 g.
43
If signs of cyanide
toxicity are still present 30 min to 2 h after administra-
tion, half the original dose may be repeated. Sodium
thiosulphate is chemically incompatible with hydroxo-
cobalamin, and so must be administered through a
separate i.v. line.
The ARC notes evidence of the efcacy of sodium
nitrite and sodium thiosulphate in combination. In the
absence of comparative studies, the known adverse
effects of sodium nitrite suggest this might be an
inferior approach to use of hydroxocobalamin;
however, nancial cost-effectiveness may justify this
approach. The approved adult dose of sodium nitrite
(in combination with sodium thiosulphate) is 300 mg
over 24 min, with half this dose repeated after 30 min
if required. Recommended paediatric dosing is 4 mg/kg
(although up to 10 mg/kg is listed as acceptable) at
75150 mg/min to a maximum of 300 mg, with half the
initial dose repeated at 30 min if required. In anaemic
children less than 25 kg, the dose of sodium nitrite
must be reduced according to the table provided in the
product information. In all cases, methaemoglobin
must be monitored and kept below 40% by dose
adjustment if required.
88
The ARC recommends that prehospital emergency
medical services and hospitals assess their likelihood
of having to treat a victim of cyanide poisoning, and
the possible availability of the recommended cyanide
antidotes from external sources, when deciding on the
selection and quantity of cyanide antidote they should
stock.
Our recommendations regarding choice of cyanide
antidote accord with the conclusion of a similar recent
systematic review.
89
The ARC categorizes
13
the treat-
ment recommendations made above as Class B: accept-
MC Reade et al.
234 2012 The Authors
EMA 2012 Australasian College for Emergency Medicine and Australasian Society for Emergency Medicine
able. Class B treatment recommendations are given to
those guidelines that might be benecial and are accept-
able to be used if considered appropriate in the relevant
setting. These recommendations are summarised in
Appendix S1.
Conclusion
In the absence of comparative human trial data, treating
clinicians and those that make occupational health risk
assessments must combine animal studies, case reports
and an understanding of pharmacology with clinical
judgment. Although the published evidence favours the
use of hydroxocobalamin sodium thiosulphate for
cyanide poisoning, it is also true that no evidence dem-
onstrates other strategies (including supportive care
alone) might not be more effective in particular circum-
stances. A randomized controlled clinical trial might
provide better guidance, but the low number of cyanide
poisonings and the probable lack of equipoise make
such 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 enquiries
into this topic
9,47
and also the geographical remoteness
from high-level intensive care of many Australian
industries and Australian Defence Force establish-
ments, has chosen instead to make recommendations
based on the evidence available. In so doing, we trust
these recommendations will be applied to the relevant
circumstances by competent practitioners.
Acknowledgements
Lieutenant Colonel Reade represents the Australian
Defence Force on the ARC. The support of the Austra-
lian Defence Force and the contribution of Group
Captain David Scott BMed FANZCA RAAF to
the preparation of this guideline are gratefully
acknowledged.
Author contributions
MCR designed the research question, interpreted the
results of the systematic review, and wrote and revised
the manuscript. SRD performed the systematic review
and summarized its conclusions. PTM, JD and ICJ
chaired the ARC discussion of the systematic review
and critically revised the manuscript.
Competing interests
None declared.
Accepted 6 January 2012
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Management of cyanide poisoning
237 2012 The Authors
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Supporting Information
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online version of this article:
Appendix S1. Management of a patient with sus-
pected cyanide poisoning.
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