Occup. Med. Vol. 48, No. 7, pp.

427-431, 1998
Copyright © 1998 Lippincott Williams & Wilkins for SOM
Printed in Great Britain. All rights reserved
0962-7480/98

Cyanide poisoning:
pathophysiology and treatment
recommendations
D. M. G. Beasley* and W. I. Glass**
Formerly** University of Otago School of Medicine, Dunedin,
New Zealand*

This paper aims to assess and compare currently available antidotes for cyanide poisoning.
Such evaluation, however, is difficult. Thus, extrapolation from the results of animal studies has
potential pitfalls, as significant inter-species differences in response may exist, and these
experiments often involve administration of toxin and antidote almost simultaneously, rather

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than incorporating a more realistic time delay before initiation of treatment. Direct inference from
human case reports is also problematic; either because of uncertainties over the exposure
levels involved (and hence the likely outcome without treatment), or because of difficulties in
identifying the specific contribution of a particular antidote within the overall treatment regimen.
Certainly an effort to compare the relative efficacy of cyanide antidotes produces equivocal
findings, with no single regimen clearly standing out. Indeed, factors such as the risks of
antidote toxicity to various individuals and other practical issues, may be more important
considerations. There is therefore no single treatment regimen which is best for all situations.
Besides individual risk factors for antidote toxicity, the nature of the exposure and hence its
likely severity, the evolving clinical features and the number of persons involved and their
proximity to hospital facilities, all need to be considered. Clinically mild poisoning may be treated
by rest, oxygen and amyl nitrite. Intravenous antidotes are indicated for moderate poisoning.
Where the diagnosis is uncertain, sodium thiosulphate may be the first choice. With severe
poisoning, an additional agent is required. Given the various risks with methaemoglobin formers
or with unselective use of kelocyanor, hydroxocobalamin may be preferred from a purely
risk-benefit perspective. However the former alternatives will likely remain important.

Key words: Cyanide poisoning; oxygen and amyl nitrite; pathophysiology; treatment
recommendations.

Occup. Med. Vol. 48, 427-431, 1998

Received June 1994; accepted in final form February 1995

INTRODUCTION one country to the next, which has influenced the pattern
of clinical use and experience in different nations,
Hydrogen cyanide was first isolated from Prussian blue and their current licensing arrangements, which tend to
dye in 1786, and cyanide was extracted from bitter favour some antidotes over others. For this reason alone it
almonds around 1800, although the poisonous properties is not practical to recommend universal use of a single
of these had been recognized since antiquity. Today there antidote regimen unless it is clearly superior.
are a range of cyanide compounds encountered in such
industries as electroplating, metal cleaning, gold extrac-
tion, and as rodenticides, fumigants or as raw materials MECHANISM OF POISONING
including in the plastics industry. Many are rapidly ab-
sorbed through the skin as well as the respiratory and The primary effect of cyanide poisoning is impair-
gastrointestinal tracts. Inhalation of airborne concentra- ment of oxidative phosphorylation, a process whereby
tions in excess of 100 ppm can be fatal within an hour, oxygen is utilized for the production of essential cellular
and concentrations above 300 ppm are generally fatal energy sources in the form of ATP (adenosine triphos-
within several minutes. phate). A necessary part of this process is transfer of
Investigation into antidotes, including studies of both electrons from NADH (nicotinamide adenine dinucleo-
cobalt compounds and nitrites, had begun by the late tide, supplied via the Kreb's Cycle) to oxygen, via a series
nineteenth century. Research emphases have varied from of electron carriers. This is catalyzed by the cytochrome
oxidase enzyme system in the mitochondria, and the
Correspondence and reprint requests to: D. M. G. Beasley, University of
impairment arises from the inhibition by cyanide of cyto-
Otago School of Medicine, Dunedin, New Zealand. chrome oxidase a3.'"6 This in turn arises from the high
428 Occup. Med. Vol. 48, 1998

binding affinity of cyanide to the ferric ion found in has been the administration of exogenous rhodanese as
the haem moiety of the oxidized form of this enzyme. well as a sulphur-donating compound,8 so that the whole
The resulting chemical combination results in loss of reaction can take place readily within the blood, reducing
the structural integrity and, hence, effectiveness of the need for thiosulphate access into the mitochondria.
the enzyme. As a result tissue utilization of oxygen is However this has not progressed beyond the experi-
inhibited with rapid impairment of vital functions. Other mental stage. Similarly the use of B-mercaptopyruvates
metabolic processes continue and the rate of glycolysis is or similar sulphur donors, interacting with sulphur trans-
increased markedly; however the pyruvate so produced ferase enzyme systems which are not intra-mitochondrial,
can no longer be utilized via the impaired Kreb's Cycle, has not progressed to the clinical stage.
and is reduced to lactate, resulting in a metabolic acidosis.
Thus it has been shown that cyanide significantly de-
creases brain ATP and increases brain lactate levels.3
Methaemoglobin formation
The cytochrome oxidase aa3 complex is not the only
enzyme affected,1 and other mechanisms are con- Various methaemoglobin formers have been tested as
sidered significant, particularly in severe poisoning. Thus antidotes since it was observed that cyanide interacts with
it is postulated that pulmonary arteriolar and/or coronary met-Hb. In the conversion of oxy-Hb to met-Hb, the iron
artery vasoconstriction can occur, decreasing cardiac out- atoms in the haem groups are oxidized from the ferrous
put, and in extreme cases resulting in cardiac shock.7 It is (2 + ) to the ferric (3 + ) state and it is the high affinity
possible that the release of biogenic amines may also between cyanide and iron in the trivalent ferric state
contribute. Pulmonary oedema has also been observed. It that is exploited. Methaemoglobin formation provides

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is thought that this is more related to left ventricular a large circulating source of ferric ion to counteract the
failure than capillary endothelial damage or neurogenic critical cyanide binding to the ferric ion of cytochrome
causes.3 However the precise mechanisms behind the oxidase a3. While the binding affinity of cyanide to
circulatory changes remain speculative. metHb is less than that to cytochrome oxidase, the pro-
duction of large amounts of the alternative substrate can
counteract this situation to some extent, with a significant
fraction of cyanide combining to form cyanmethaemo-
SIGNS AND SYMPTOMS globin. This in turn slowly releases cyanide which dif-
fuses out of the red cells in a gradual fashion producing
The symptoms of mild poisoning include headache, plasma levels that can be more readily coped with by
nausea, metallic taste, drowsiness, dizziness, anxiety, hepatic rhodanese and other sulphur detoxification
mucous membrane irritation and hyperpnoea. Later enzyme systems. It has been customary to provide
frank dyspnoea, bradycardia, hypotension, arrythmias exogenous sources of sulphur to facilitate the process and
and periods of cyanosis and unconsciousness develop. In this forms the basis of the classical regimen supported
severe cases, progressive coma, convulsions and cardio- by Chen and Rose9'10 and others, of intravenous sodium
vascular collapse with shock and pulmonary oedema can nitrite and sodium thiosulphate.
occur, with a fatal outcome.
Methaemoglobin-generating chemicals have been
divided into three groups: directly and indirectly acting
compounds (the latter requiring metabolic activation),
MECHANISMS OF TREATMENT and those requiring the presence of oxygen." While the
nitrites are direct-acting, sodium nitrite is a relatively
Cyanide antidotes have been classified into three main slow metHb former relative to 4-dimethylaminophenol
groups according to their primary mechanism of action: (DMAP).12 It is largely for this reason that it has been
sulphur detoxification, methaemoglobin formation and superseded in Germany and other countries by DMAP
direct combination. (which falls into the third group). However there is evid-
ence that the effect of nitrites is only partially related
to met-Hb. Thus there is good evidence for some thera-
Sulphur detoxification peutic effect before any significant metHb formation
The most important naturally occurring cyanide de- could have occurred, and indeed in one experimental
toxifying mechanism involves the addition of a sulphur study, when such formation was prevented by methylene
atom to form the much less toxic thiocyanate ion. The blue, sodium nitrite still conferred protection.13'14
two most significant enzymes in this process are Further, the effects of nitrites on circulatory haemo-
mitochondrial rhodanese (thiosulphate-cyanide sulphur dynamics may offer an explanation.15 With cyanide,
transferase) and B-mercaptopyruvate sulphur transfer- effects on the cardiovascular system can include sys-
ase.8 Various synthetic compounds have been used as temic hypotension in association with a sharp increase
sources of additional sulphur to facilitate this natural in central venous pressure, while, following amyl nitrite
process. The most frequently used has been sodium treatment in experimental studies, the raised CVP rever-
thiosulphate, although this does not readily penetrate the sed rapidly along with improvement in arterial pressure.16
mitochondrial membrane within which the rhodanese This has been attributed to the greater vasodilating
system operates,1'8 and is hence not ideal from a theoret- effect of nitrites on the venous side than on the
ical basis. A novel antidotal approach in animal studies arteriolar resistance vessels.
 D. M. G. Beasley and W. I. Glass: Cyanide poisoning 429

Direct combination Nevertheless attempts have been made at comparison

within the limits of the data available. Paulet found that
Cobalt compounds have received by far the greatest at-
Kelocyanor was more effective than sodium nitrite
tention as direct combiners with cyanide, with effects
alone or in combination with thiosulphate.18 This is not
noted before the turn of the century and since confirmed
surprising given its relatively quick reaction with cyanide
by several workers. Significant toxicity was observed with
compared with the slower, indirect effect of metHb
various cobalt salts, however, so that compounds such
formation by nitrites, although the latter may act in other
as dicobalt edetate (cobalt EDTA) containing cobalt in
ways as well.16 However some studies have suggested
a chelated form, were also investigated in the hope of their
that the more rapid metHb former, DMAP, could be
being less toxic. Evans17 compared a cobalt salt (the
more effective than Kelocyanor.8 A firm conclusion
acetate), di cobalt edetate, hydroxocobalamin and
regarding comparative efficacy appears difficult
cobinamide, largely in mice and rabbits. He concluded
to make, certainly from the human data alone. While
that 1 mole of cobalt as a salt could combine with 6 moles
Kelocyanor may be slightly more effective than the
of cyanide to form a relatively non-toxic anion, while di
nitrites, it may be less so than DMAP, and the effec-
cobalt edetate combines at a molar ratio of 2 only. One
tiveness of all the antidotes is enhanced by thiosulphate.
therefore might expect that equimolar doses of the
Partly due to these uncertainties, toxicity considerations
edetate should be less toxic (and efficacious) than
are important in any evaluation.
cobalt salts. However this question does not appear to be
resolved completely.8 Certainly toxicity with Kelocyanor The major concern with nitrites and DMAP is excess-
(the commercial form of di cobalt edetate) can occur; this ive metHb production. This is a particular risk in young
may be related in part to the fact that this preparation children,22 with serious complications and death being

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contains some additional free cobalt. As regards effi- described especially in those more susceptible due to
cacy, Paulet claimed that di cobalt edetate was more metHb reductase deficiency.7 MetHb levels over about
effective in dogs than various cobalt salts, and in- 40% pose significant risk. It is established that cyanide
deed, more effective than sodium nitrite either alone toxicity, as well as carbon monoxide (and smoke partic-
or in combination with thiosulphate.18 ulates) can be a risk for fire victims23 and the possibility of
combined toxicity or even synergy should not be over-
Hydroxocobalamin (Vitamin B12a) was later inves- looked.24 It is preferable, however, that any cyanide com-
tigated as a potentially less toxic source of cobalt. ponent should not be treated with metHb formers, as
It binds cyanide strongly to form cyanocobalamin or significant carboxyHb may already be present, reducing
Vitamin B12. In animal studies it was found to be a oxyHb levels and conferring increased sensitivity to such
rapidly acting antidote19 and clinical studies have agents.25 Further, a degree of 'baseline' methaemo-
suggested few toxic effects. The antidotal effect globinaemia has been described in smoke inhalation
is enhanced by thiosulphate. victims,26 reinforcing the argument for other types of
antidotes for any cyanide component in this situation.
A further difficulty is that while the level of met-
ADVANTAGES AND DISADVANTAGES OF haemoglobin can be measured, the test does not in fact
TREATMENTS detect cyanmethaemoglobin and hence does not provide
an accurate guide to the amount of oxyhaemoglobin. Hy-
Evaluation and comparison of antidotes, with regard to potension has also been cited as a hazard with nitrites,
relative efficacy and toxicity, is not straightforward. although the cardiovascular effects of nitrites can be
Results from animal studies must be interpreted caut- beneficial13"14 and the hazard relates more to excessive
iously, giving consideration to possible inter-species dif- speed of administration.27 DMAP does not have the disad-
ferences plus the particular route and timing of antidote vantage of nitrites in posing a risk of hypotension. How-
administration relative to that of the toxin. Prophylactic ever it also does not share their beneficial vasoactive
or contemporaneous use gives no idea of the time after properties, and given its more rapid production of metHb,
exposure within which treatment can still be effec- may pose a greater risk for those especially susceptible to
tively initiated. On the other hand interpretation of this effect28 which can be unpredictable in its degree.
human case reports can also be difficult because of Haemolysis is a rare complication from nitrites and is also
uncertainties over the dose ingested or the exposure levels a risk with DMAP, patients with glucose-6-phosphate-
involved, and hence the likely clinical course in the ab- dehydrogenase deficiency being most susceptible.7
sence of antidotal treatment. Thus it has been pointed Toxicity is a major concern with Kelocyanor.
out3 that in the review by Chen and Rose of 48 cases Adverse effects include possible anaphylactic reac-
suggesting a high effectiveness of the 'classical' ther- tions which may manifest as urticaria, angioedema af-
apy combination, in very few were blood cyanide levels or fecting the face and neck and also occasionally the larynx,
other indices of severity documented. Even where such dyspnoea and hypotension. Cardiac arrythmias and con-
indices are available, it is difficult to distinguish be- vulsions have also been described. The cobalt and cyan-
tween the roles played by different elements of the ide interaction involves mutual inactivation so that the
treatment regimen, and to define the contribution of combination is less toxic than either on their own. Thus
a specific antidote. (Indeed, there is good evidence that cobalt toxicity per se should be much less of a risk in cases
antidotes are not always essential for a satisfactory out- where cyanide poisoning genuinely exists. This has led to
come even in the presence of severe poisoning).20'21 recommendations that Kelocyanor should only be used in
430 Occup. Med. Vol. 48, 1998

well-established cases and not in equivocal cases where This implies that there is no single best antidote for all
exposure seems just a possibility.29 This requires clinical situations. Thus nitrites or other metHb formers cannot
experience and strict criteria for the diagnosis, as anxious be recommended for fire victims, young children or those
patients involved in 'scares' over possible exposures may with certain enzyme (e.g., G6PD) deficiencies which in-
exhibit signs and symptoms resembling mild or early crease susceptibility. On the other hand Kelocyanor is not
poisoning. Administration of Kelocyanor in such cases recommended for equivocal or mild cases.
would not be warranted and is more likely to result in
toxicity. While good judgement has generally resulted in Mild poisoning
few adverse effects in industrial settings, inappropri-
ate use with adverse consequences remains a possibility.29 Where symptoms suggest mild poisoning, rest and
Furthermore, toxic reactions have been described even in oxygen treatment may be all that is required. Any deterio-
cases of unequivocal cyanide poisoning.30 The toxicity is ration is an indication for amyl nitrite treatment
considerably reduced by co-administration of glucose (0.2-0.4 ml via Ambu bag) and arrangement for transfer
(mechanism uncertain), which is thus incorporated into to hospital. Symptoms may be somewhat delayed with
the formulation. However the recommendation not to use some compounds (e.g., acetonitrile) which only release
in doubtful or mild cases still stands. cyanide on metabolism and judgement is required on if
The relatively low toxicity of hydroxocobalamin com- and when to transfer. While amyl nitrite has been found
bined with its rapid action are major advantages of its use. (at least in inhalation and self-administration) to produce
However a practical inconvenience is that large volumes only very modest metHb levels (up to 7%) which are
of the commercial preparation are required to deliver insufficient to bind a potentially lethal dose of cyan-

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a sufficient dosage, due to its high molecular weight ide, there is increasing evidence that the cardiovascular
plus the fact that it can only combine with cyanide on effects of nitrites are their most important mecha-
a one-to-one molar basis. Thus detoxification of 1 mmol nism of action.
cyanide (or 65 mg KCN) requires 1406 mg hydroxo-
cobalamin, while in most countries it is only available in Moderate poisoning
formulations of 1-2 mg. In other countries it is available
For more moderate poisoning where symptoms may
as a reconstitutable powder but still requires large vol-
include brief periods of unconsciousness, convulsions or
umes of solution best given as an IV infusion, making its
cyanosis, intravenous antidotes are also indicated. Clearly
use outside a hospital environment rather impractical. It
has been used principally in France, often in combination these are most easily administered within a hospital setting,
with thiosulphate, for several years.31 While clinical ex- ideally an intensive care unit, where overall management
perience elsewhere has been limited, this combination is will be most effective. Sodium thiosulphate may be
gaining increasing support, principally because of its ap- the first choice, particularly if the diagnosis is uncertain.
parent lower toxicity and fewer at-risk situations than
with the other major alternatives. The most common Severe poisoning
adverse effect is a harmless orange-red discoloration In severe poisoning with deep coma, dilated non-reacting
of the skin, mucous membranes and urine. However pupils and worsening cardiorespiratory function, an
some issues remain to be addressed, such as its relative additional intravenous antidote should be administered.
cost and apparent toxicity in animal studies.32 Methaemoglobin formers can be hazardous in some cir-
The findings from cyanide antidote comparison exer- cumstances, and kelocyanor can be a risk particularly
cises are arguably equivocal rather than clear-cut, and this when cyanide poisoning is an incorrect diagnosis. From
appears to be reflected in the recommendations of the a strictly risk-benefit point of view, hydroxocobalamin is
IPCS/CEC Committee set up for their evaluation. Thus arguably the best alternative. However due to its relative
the two metHb generating compounds discussed above cost and some practical difficulties with administra-
are presented as alternatives, as are the two cobalt tion, it is probable that nitrites and kelocyanor will retain
compounds. This may be partly due to practical consid- a role, particularly for physicians familiar with them.
erations such as the varied clinical experiences and li- Recommended dosage regimens for available antidotes
censing arrangements in different countries. The are listed in Table 1. Repeat dosing may be indicated in
layout of the overview in this publication however may the case of a poor response. Recommendations are the
present some risk of misinterpretation. same dose for thiosulphate or Kelocyanor, or half the
initial dose of sodium nitrite after a 30 min interval.
However it is strongly advised to review the diagnosis and
FACTORS IN THE CHOICE OF ANTIDOTE monitor for toxicity before repeat-dosing with Kelo-
cyanor or sodium nitrite.
The IPCS/CEC Committee7 identified several factors
which should influence the choice of antidote (if any) to
use in cyanide poisoning. These include: (1) the nature of SUPPORTIVE TREATMENT
the cyanide compound and the exposure circumstances;
(2) the severity of poisoning; (3) the presence of certain What has emerged is the importance of oxygen treatment
risk factors for antidote toxicity; (4) the number of pa- and the need for ongoing clinical and biochemical
tients involved and (5) proximity to hospital facilities. monitoring. There is now experimental evidence that
 D. M. G. Beasley and W. I. Glass: Cyanide poisoning 431

Table 1 . Recommended cyanide antidote dosage regimens* 4. Berlin C. Cyanide poisoning — a challenge [Editorial]. Arch Inl
Med 1977; 137: 993-994.
Sodium thiosulphate 50 ml of 25% solution (12.5 g) IV 5. Which antidote for cyanide? [Editorial]. Lancet 1977; ii: 1167.
over 10 min 6. Holland MA, Kozlowski LM. Clinical features and manage-
Sodium nitrite 10 ml of 3% solution (300 mg) IV ment of cyanide poisoning. Clin Pharm 1986; 5: 737-741.
over 5-20 min 7. Meredith TJ, Jacobsen D, Haines JA, Berger JC, Van Heijst
4-DMAP 5 ml of 5% solution (250 mg) ANP, eds. IPCS/CEC Evaluation of Antidotes Series. Vol. 2.
IV over 1 min Antidotes for Poisoning by Cyanide. Cambridge, UK: Cambridge
Dicobalt edetate 20 ml of 1.5% solution (300 mg) University Press, 1993.
IV over 1 min 8. Marrs TC. Antidotal treatment of acute cyanide poisoning.
Hydroxocobalamin 10 ml of 40% solution (4 g) Adv Drug React Acute Pois Rev 1988; 4: 179-206.
IV over 20 min 9. Chen KK, Rose CL. Nitrite and thiosulfate therapy in cyanide
poisoning. JAMA 1952; 149: 113-119.
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dren,7 e.g., sodium thiosulphate: 300-500 mg/kg; sodium nitrite:
10. Chen KK, Rose CL. Treatment of acute cyanide poisoning.
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11. Kiese M. Methemoglobinemia, A Comprehensive Treatise. Cleve-
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other modes of action. Artificial ventilation with 100% Eur J Pharmacol 1969; 7: 97-105.
oxygen is recommended, though for no longer than 13. Way JL. Cyanide antagonism. Fundam Appl Toxicol 1983; 3:
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