PAGE 1

Cyanide as a Chemical Weapon:

A Review
Charles Stewart MD FACEP FAAEM

Document Title: Cyanide toxicity - review article.doc
Document Size: 249344 bytes
WORD COUNT: 6790 IN 31 PAGES.
CYANI DE TOXI CI TY REVI EW
PAGE - 2-
INTRODUCTION
The blood agents or tissue toxins act by destroying the ability of the blood and tissues
to carry or process oxygen. Cyanide, an ancient compound, is the prototype agent in this
group. These agents have long been considered a threat for use in terrorism.
Physical and Chemical Properties
Hydrogen cyanide

Hydrogen cyanide is a colorless liquid which boils at 26 C. The vapor is lighter than air
and dissipates rapidly. Hydrogen cyanide is found in widespread industrial use.
The sodium and potassium salts of cyanides are used in metallurgy for the extraction of
gold and silver from ores and the in the deposition of these metals on other products.
When these cyanide salts are mixed with any acid, hydrogen cyanide gas is formed.
Hydrogen cyanides CAS Number is 74-90-8.

Cyanogen chloride

Cyanogen chloride is a colorless, highly volatile liquid with a pungent, biting odor. The
odor will often be unnoticed because of the agents irritating properties to the mucous
membrane. Cyanogen chlorides CAS number is 506-77-4.
History
Cyanide was identified and isolated from cherry laurel by the Swedish chemist Scheele
in 1782.
1
Hydrogen cyanide was first isolated from Prussian blue dye in 1786, although
the poisonous properties of cherry laurel leaves, cassava, bitter almonds and Prussian
blue dye had been recognized since antiquity. The first description of cyanide poisoning
was by Wepfer in 1679 and dealt with the effects of extract of bitter almonds.
2

Although part of a murder plot, and not random terrorism, cyanide compounds were
used as adulterants in packages of Tylenol in 1982 in the Chicago area.
3
Cyanide
laced drinks were used for the mass suicide of the Reverend Jim Jones Peoples
Temple in Guyana in 1978.
4
Cyanide gas precursor compounds were found in several
subway restrooms in Tokyo following the release of Sarin in Tokyo in 1995.
5
Allegedly,
cyanide was added to the explosives used in the first attack on the World Trade Center
in New York City.
6

Cyanide gas is famous as the lethal agent used for judicial executions in many states.
Cyanide-containing compounds have been stocked by some nations for use as a
chemical warfare agent. The NATO military designators for the cyanide compounds
used in warfare are:
AC (hydrogen cyanide HCN)
CYANI DE TOXI CI TY REVI EW
PAGE - 3-
CK (cyanogen chloride CNCL)
The military incorrectly calls cyanide a "blood agent," implying that the action is in the
blood when it is, in fact, a tissue toxin. The widespread distribution of absorbed nerve
agents and vesicants through the blood makes this an antiquated term.
As chemical warfare or terrorism agents, these agents may be delivered by munitions
from artillery, mortar, bombs, or simply released from canisters. The preferred way to
deliver cyanide is by large munitions because smaller weapons will not provide the
concentration needed for lethal effect. Like all of the chemical warfare agents, the area
of action is weather- and wind-dependent. As noted earlier, cyanide is not persistent at
all and dissipates rapidly. The tissue toxins were abandoned as war agents during WWI
because they are too volatile in open air, require high concentrations for effect, the
munitions delivering them were crude, and protection against their effects is too simple.
Cyanide was used in World War I, but did not prove to be as successful as chlorine,
because of the gases high volatility. It has been reported that hydrogen cyanide was
used by Iraq in the war against Iran and against the Kurds in northern Iraq during the
1980s. During the Second World War, a form of hydrogen cyanide (Zyklon B) was used
in the Nazi gas chambers.
7

Its high volatility, and the fact that it is lighter than air, probably makes hydrogen cyanide
difficult to use as a terrorist agent, since there are problems in achieving sufficiently high
concentrations outdoors. On the other hand, the concentration of hydrogen cyanide may
rapidly reach lethal levels if it is released in confined spaces. Potassium cyanide
poisoning of food and water supplies is an ancient terrorist tactic.
Cyanogen chloride has similar action to that of hydrogen cyanide. It interferes with the
use of oxygen by the body tissues. Like cyanide, cyanogen chloride is not lethal at lower
concentrations. The late effects are similar to those seen with cyanide.
Cyanogen chloride will cause irritation to the eyes, nose and airway like the riot-control
agents. This action is considered to be of little military importance compared to its tissue
effects. CK irritates the respiratory tract in a manner similar to phosgene. The patient will
develop marked lacrimation, rhinorrhea, and bronchial secretions. Cyanogen chloride
causes pulmonary edema much faster than in phosgene poisoning.
Cyanogen chloride is considered a non-persistent agent and is used as a quick-acting
casualty agent. Although cyanogen chloride evaporates quickly, the vapors may persist
in heavily wooded areas under the right conditions.
Sources
Cyanide is surprisingly available. Industry in the United States manufactures over
300,000 tons of hydrogen cyanide each year. These cyanides are used in chemical
processes, electroplating, mineral extraction, dye manufacturing, printing, photography,
and agriculture. It is a major chemical in the synthesis of synthetic fibers, plastics, and
nitrites. Hydrogen cyanide is also widely used as a fumigant on ships and in
warehouses.
CYANI DE TOXI CI TY REVI EW
PAGE - 4-
The would-be terrorist may readily find this agent in tank-car lots. Although it was not
found to be particularly effective as a chemical warfare agent in WWI, the terrorist may
find it more useful in a confined area or enclosed space.
Cyanide gas may be generated in blast furnaces, gas works, and coke ovens. Cyanide
is also found in the burning fumes of X-ray film, wool, silk, nylon, paper, nitriles, rubber,
urethanes, polyurethane and other plastics.
8

9

10

11

12
As a product of combustion, CN is
commonly mixed with isocyanates, which are intense respiratory irritants. The reaction
is often temperature limited. Fires that occur in poorly ventilated areas can produce
potentially fatal amounts of cyanide.
The effects of cyanide and carbon monoxide (both found in fires) are additive. Both
agents contribute to tissue hypoxia by different mechanisms. Many fire-related fatalities
are caused by one or both of these chemicals. Cigarette smoke contains cyanide and
smokers cyanide levels are two to three times higher than non-smokers blood levels.
Cyanogenetic glycosides are naturally occurring compounds found in such foods as
almonds, fruit pits, and cassava beans. Under certain conditions, these compounds can
release cyanide.
The most important of these organic compounds is probably amygdalin (Laetrile) which
is found in apple seeds, peach pits, plum pits, cherry pits, and almond kernels.
Amygdalin has produced fatalities in both children and adults when taken in excessive
quantities.
13
The seeds contain an enzyme that converts amygdalin into glucose,
benzaldehyde, and hydrogen cyanide. This enzyme is released when the seeds are
crushed and moistened. The reaction is slow in acid, but rapid in alkaline solution.
Therefore symptoms of cyanide poisoning due to amygdalin do not occur immediately
after ingestion but are delayed until sufficient quantities of cyanide have been formed in
the alkaline duodenum.
Cyanide is also formed when nitroprusside is used as a vasodilation agent, particularly
when therapy is prolonged or exceeds the maximum recommended dose of 10 g/kg per
minute.
14

15

16

Normal Metabolism
Cyanide is metabolized in the body to thiocyanate in a reaction catalyzed by rhodanese
using thiosulfate as a precursor. This reaction requires a source of sulfane sulfur, but
endogenous supplies of this substance is limited. The thiocyanate is nontoxic and is
eliminated by the renal system. The detoxification of cyanide is slow, at a rate of about
0.017 mg/kg per minute.
17
The detoxification product, thiocyanate, is excreted in the
urine.
The human body can tolerate low levels of cyanide without harm. Indeed, some cyanide
is normally present in the human body. This means that the amount of cyanide that
could kill if administered over a few minutes may be fully metabolized by the body if
given over several hours.
The classical theory that mitochondrial thiosulfate sulfurtransferase is the most important
enzyme in this reaction is now open to question because thiosulfate penetrates lipid
CYANI DE TOXI CI TY REVI EW
PAGE - 5-
membranes slowly. The serum albumin-sulfane complex may be the primary cyanide
detoxification in normal metabolism of cyanide.
18

CN- + Vitamin B12a Cyanocobalamin (B12)

CN- + Sulfanes (S-S-) Thiocyanates (SCN-)
+ Sulfates (SO32-)

Toxic Levels of Cyanide
Inhalation of cyanide gas is the fastest route of poisoning. Both gaseous and liquid
hydrogen cyanide, as well as cyanide salts in solution, can also be absorbed through the
skin or ingested.
Hydrogen cyanide toxicity by inhalation
19

Concentration (mg/m
3
) Effect

300 lethal within seconds
200 Lethal after 10 minutes
150 Lethal after 30 minutes
120-l50 Highly dangerous (fatal)
after 30-60 mm.
50-60 Endurable for 20 mm to 1 h
without effect
20-40 Minimal symptoms after
several hours.

Inhaled hydrogen cyanide can be quite lethal. For inhalation of large doses of cyanide,
the toxic effect of cyanide depends on both the concentration of cyanide in the air
inhaled [C] and duration of exposure (t) [Ct]. In high concentration, the Ct product
determines a specific relationship between the inhaled dose and the effect. Exposure to
140 ppm for 60 minutes or 1500 ppm for 3 minutes is has an estimated 50% mortality
(LCt
50
2500-500 mg/min/m
3
). The median lethal dose is about twice this level for the
most resistant individuals. The LCt
50
for cyanogen chloride is about 1.1 g/min/m3.
At low concentrations, the Ct product does not apply, since the body is capable of
limited detoxification of cyanide. The injected or ingested dose at which 50% of the
exposed people will die (LD
50
) is 1 mg/kg for hydrogen cyanide. The estimated LD
50
for
skin contamination exposure of hydrogen cyanide is about 100 mg/kg.
Mechanism of action
Cyanide is readily absorbed through the skin and mucous membranes and by inhalation.
Inhalation of the gas causes the most rapid onset of toxicity. Alkali salts of cyanide are
toxic only when ingested. The effects of ingestion are often delayed because of
gastrointestinal absorption.
CYANI DE TOXI CI TY REVI EW
PAGE - 6-
After cyanide is absorbed, it is rapidly distributed through the body. The majority of
cyanide in the body is protein bound (60%). Cyanide reacts reversibly but with high
affinity with metals such as the ferric ion (Fe
3+
)

and cobalt. Cyanide also reacts with
sulfur containing compounds.
The primary effect of cyanide poisoning results from inhibition of the metal-containing
enzymes. The critical interaction appears to be inhibition of the enzyme cytochrome
oxidase a
3
(containing iron) within the mitochondria. This enzyme is a necessary part of
the production of adenosine triphosphate (ATP). As a result, aerobic oxidative
metabolism and phosphorylation are compromised causing cellular hypoxia. Other
metabolic processes continue and the rate of glycolysis is increased markedly. The
pyruvate that is produced can no longer be used and is now reduced to lactate.

Cyanide inhibits cytochrome oxidase, the terminal oxidase of the mitochondrial
respiratory chain.

This leads to a profound lactic acidosis as the body attempts to use the less efficient
anaerobic metabolism. Subsequent central nervous system (CNS), respiratory, and
myocardial depression complicate the picture.
cyt c cyt a cyt a
3

Cu
O
2
and H
+
H
2
O
Cytochrome c oxidase
(cytochrome aa
3
)
ADP ATP
cyt c cyt a cyt a
3
Cu
O
2
and H
+
H
2
O
Cytochrome c oxidase
(cytochrome aa
3
)

ADP ATP
CN
-
CYANI DE TOXI CI TY REVI EW
PAGE - 7-
More recent evidence suggests that massive cyanide poisoning ( >5 times LD50) results
from complex mechanisms that involve more than one biochemical lesion.
20
Other
mechanisms include pulmonary arteriolar and/or coronary vasoconstriction can occur.
21

This decreases cardiac output and can, in extreme cases, cause cardiogenic shock.
Pulmonary edema may be related to this left ventricular failure.
Cyanide directly stimulates chemoreceptors in the aorta and carotid artery, causing
hyperpnea. Respiratory arrest may occur in these victims because of paralysis of the
medullary center and not asphyxia.
Contributions to toxicity by vasoactive amines are suggested by the rapid onset of
cardiovascular collapse, elevation of the plasma histamine levels and
hemoconcentration after poisonings.
22

23
Vascular mechanisms are suggested by the
finding that alpha-adrenergic blockers and vasodilators such as the nitrites can prevent
or reverse cyanides lethal effects.
24
The observation that phenoxybenzamine, an alpha-
adrenergic blocking drug, partially prevented these changes supports the concept of an
early shock-like stated that is not related to the cytochrome oxidase system.
25

Subacute exposure to lower doses may cause symptoms of headache, dizziness,
nausea and vomiting. These symptoms are similar to those with short-term, high dose
exposure and may be due to the inhibitory effect on the cellular enzyme systems.
Contact with cyanide may cause mucous membrane and skin irritation. This is most
evident with cyanogen chloride. At high hydrogen cyanide concentrations, absorption
occurs through the skin and the irritation facilitates this absorption.
Clinical features
In action novels, death by cyanide intoxication is so quick that there are few treatments
available. Cyanide is not the surely lethal agent of the thrillers, however. Cyanide is the
least toxic of the lethal chemical agents.
The symptoms are relatively nonspecific. (Table 1)
The degree of symptoms and rapidity of the onset of the symptoms is related to the
route of exposure and the amount of exposure. The most significant clinical
manifestations of cyanide poisoning are cerebral, respiratory, and cardiac.
Early symptoms may include dryness and burning of the throat and air hunger. In small
doses, headache, confusion, anxiety, dizziness, nausea, palpitations, tachycardia,
vertigo, personality changes, agitation, tachypnea, and combativeness may all be found.
Other symptoms may include flushing, diaphoresis, and weakness. This will be followed
by dyspnea, cyanosis, hypotension, bradycardia, and sinus or AV nodal arrhythmias.
The skin will become cold, clammy, and moist.
High concentrations of cyanide also indirectly stimulate the release of epinephrine with
subsequent tachycardia and hypertension. Later symptoms include hypotension,
impaired consciousness and coma. This is followed in 15 to 30 seconds by the onset of
convulsions. Late signs of cyanide toxicity include profound hypotension, complex
arrhythmias, cardiovascular collapse, pulmonary edema, and death. Respiratory activity
stops in 2-3 minutes and cardiac activity stops several minutes later.
CYANI DE TOXI CI TY REVI EW
PAGE - 8-
It should be emphasized that the bright-red coloration of skin and the absence of
cyanosis that is often mentioned in textbooks is seldom described in case reports. This
sign is theoretically explained by the high concentration of oxyhemoglobin in the venous
circulation. Particularly in massive poisoning, rapid cardiovascular collapse will prevent
the reddened skin coloration. In some cases, cyanosis can be initially observed only to
have the patient become bright pink later.
26

Inhalation of large concentrations of cyanide is often fatal within minutes. In large doses,
bradycardia, bradypnea, coma, gasping respirations, apnea, and rapid death may all be
common manifestations. The carotid body chemoreceptors, responsible for oxygen
mediated respiratory reflexes, are rapidly stimulated by the presence of high
concentrations of cyanide and cause a gasping reflex. (An audible gasp is thought to be
characteristic of extreme exposure to HCN.)
The long-term effects of exposure to cyanide are nebulous and include intellectual
deterioration, confusion, and Parkinson-like syndromes.
27
Chronic low-dose neurotoxicity
has been suggested by epidemiologic studies of populations ingesting naturally
occurring plant glycosides.
28
Perhaps the most wide-spread pathologic condition
attributed to chronic cyanide poisoning is tropic ataxic neuropathy associated with
cassava consumption.
29

Diagnosis
The initial diagnosis of severe cyanide poisoning is difficult. Cyanide poisoning is an
uncommon cause of clinical presentation of coma, shock, seizures, and metabolic
acidosis with elevated anion gap. The medical provider should be suspicious of acute
cyanide intoxication if the patient has had an abrupt collapse without apparent cause
and subsequently does not respond well to oxygen administration.
The diagnosis of hydrogen cyanide poisoning is difficult without a history of exposure.
Particularly in the field, without laboratory support, these agents are difficult to identify.
There are no specific physical findings that would implicate cyanide. The examiner may
smell the odor of almonds on the patients breath, but about 18% of males and 5% of
females are unable to smell the odor of cyanide.
30

31

32

Cyanide toxicity should be considered in all smoke inhalation victims with CNS or
cardiovascular findings.
33

34
This poisoning with cyanide associated with smoke
inhalation should be considered in terrorist events promulgated by conventional
explosives or incendiary agents.
Laboratory testing
There is no readily available assay that can be done in "real time" to confirm cyanide
poisoning while trying to treat an acutely poisoned patient. Spectrophotometry and gas
chromatography are tools for the pathologist, not the clinician.
Before intravenous treatment with available antidotes is started, the physician should
collect a heparinized specimen of blood for determination of the cyanide concentration.
Samples that are obtained after treatment are totally unreliable.
CYANI DE TOXI CI TY REVI EW
PAGE - 9-
A new semiquantitative assay that uses calorimetric test strips may improve the
laboratory evaluation of hydrogen cyanide poisoning.
35
Before any cyanide level is
correlated with clinical appearance, the elapsed time since the exposure and since the
specimen was obtained must be considered.
Arterial blood gases
Arterial blood gases will often show a metabolic acidosis with normal oxygenation and
calculated hemoglobin saturation. Venous gases have the same pattern, because the
oxygen is not used up at the tissues! Venous blood often looks arterial in color and this
may be clinically obvious when fundal veins and arteries appear to be equally red. The
measured arterial oxygen saturation will be decreased, while the calculated saturation is
normal.
36

This picture of an abnormal hemoglobin and less than adequate saturation is found
commonly in only four poisons. The toxidrome includes cyanide, carbon monoxide,
hydrogen sulfide, and methemoglobin. Methemoglobin and carboxyhemoglobin are
easily measured. Hydrogen sulfide and cyanide are treated in a similar manner.
Cyanide levels should be obtained in all cases. An elevated anion gap metabolic
acidosis may exist but is not diagnostic.
Lactic acidosis
Since oxidative phosphorylation is blocked by cyanide, the rate of glycolysis is markedly
increased. This leads to a profound lactic acidosis. Unexplained lactic acidosis may also
be caused by several different toxins and all are difficult to rapidly measure except
carbon monoxide and methemoglobin. A blood lactate level above 8 mmol/L (72 mg/dL)
should increase the suspicion of cyanide intoxication.
37
In this small study, this cutoff
level of lactate was associated with a negative predictive value of 98%.
Hyperglycemia
A reversible toxic effect of cyanide on the pancreatic beta cells may markedly increase
glucose. This may cause an erroneous diagnosis of hyperglycemic diabetic coma.
Lee-Jones cyanide diagnostic testing
The "Lee-Jones" rapid cyanide diagnostic test may be performed on gastric aspirate but
is not useful in inhalation injuries.
Lee Jones Test
Add crystal FeSO4 to 5 to 10 cc of gastric contents
Add 4-5 drops of 20% NaOH
Boil and allow to cool.
Add 8-10 drops of 10% HCL
Positive for cyanide is a greenish blue color
CYANI DE TOXI CI TY REVI EW
PAGE - 10-
Salicylates will turn greenish blue and then purple.
Differential Diagnosis
The differential diagnosis of cyanide intoxication includes all other causes of respiratory
failure including intoxication with other agents or drugs.
Treatment
Removal from the area
The patient should be immediately removed from the contaminated atmosphere. Early
use of a protective mask for the patient will also prevent further inhalation. Removal of
any liquid on skin or clothing should be performed as soon as possible. The patients
clothing should be removed once they are in a safe environment to prevent liquid
cyanide from releasing vapors or being absorbed by the patient.
Supportive therapy
Initial treatment is supportive and should include airway support, high flow oxygen
supplementation, cardiac monitoring, intravenous fluids and possibly intravenous sodium
bicarbonate to offset the profound lactic acidosis. There is evidence that cyanide
intoxication responds to the administration of 100% oxygen. It should be a part of
supportive care for all patients suspected to have cyanide intoxication.
In moderate and severe cyanide intoxication, the clinical outcome is dependent both on
the severity of the exposure, and the delay until treatment is started. The success of
therapy of acute cyanide intoxication depends primarily on the speed with which the
cellular oxygen utilization is restored. Since hypoxia is a major component of this
agents toxicity, cerebral hypoxia and subsequent encephalopathy is common in
severely poisoned casualties.
The mainstays of hospital treatment are oxygen and ventilation. Activated charcoal is
routinely recommended for use in ingestions, but there is no evidence of its efficacy.
Urgent specific antidotal therapy in cyanide intoxication is not indicated unless the
patient has coma, dilated pupils and a deteriorating cardio-respiratory function. A patient
who is exposed to hydrogen cyanide who is fully conscious requires only observation
and reassurance.
There is also good evidence that some patients who have ceased breathing will survive
when appropriate respiratory support is given.
38

39
If the patient still has intact circulation,
then airway support and antidote therapy may be lifesaving. Therapy beyond the basics
is controversial and includes hyperbaric oxygenation and use of a cyanide antidote. Lack
of an antidote should not preclude treatment with airway support and ventilation in these
patients. There is good evidence that antidotes are not always essential for a
satisfactory outcome, even in the face of severe poisoning.
40

41

CYANI DE TOXI CI TY REVI EW
PAGE - 11-
Hyperbaric Oxygenation
Hyperbaric oxygenation may be the ideal adjunct to both hydroxycobalamin and nitrite
therapies. Hyperbaric oxygenation will mitigate concern about the methemoglobinemia
formed by nitrite administration since the dissolved oxygen in the tissues and blood
stream can support the metabolic requirements. The oxygen may act competitively to
displace cyanide from the cytochrome oxidase.
42
In the case of a mixed gas inhalation,
carbon monoxide will be effectively displaced from hemoglobin and will allow higher
levels of nitrite to be used. Hyperbaric oxygen therapy should not be used to replace the
chemical treatments, however, due to the deleterious effects of delay in institution of the
treatment in most cases. Hyperbaric oxygen therapy is unlikely to be available in the
event of a terrorist attack with cyanide, since most available chambers have the capacity
for at most a few patients.
Cyanide antidotes
Cyanide antidotes have been classified into three main groups according to their primary
mechanism of action: detoxification with sulfur to produce the much less toxic
thiocyanate ion, formation of methemoglobin, and direct combination. The definitive
treatment of cyanide intoxication differs in various countries, but only one method is
approved for use in the United States. The safety and efficacy of each of these antidotes
is a source of significant debate. There is no worldwide consensus for treatment of
cyanide intoxication.
Production of methemoglobin
Proposed in the 1930s by Chen and colleagues, intentional production of
methemoglobin is used to compete with cyanide for sites on the cytochrome oxidase
system.
43
While cyanide is preferentially bound to the ferric ion in the cytochrome
oxidase system, an appreciable quantity of cyanide will be attracted to the ferric ion in
other compounds, such as methemoglobin. If sufficient quantities of methemoglobin are
produced, the symptoms of cyanide intoxication will be alleviated. Methemoglobinemia
can be produced by inhalation of amyl nitrite and then intravenous administration of
sodium nitrite. About 30% methemoglobinemia is considered optimum, and the levels
should be kept below 40% methemoglobin. Other substances such as 4-DMAP exist
that may produce methemoglobin more rapidly.
Since methemoglobin is unable to carry sufficient quantities of oxygen, these
hemoglobin molecules are now non-functional. Production of greater than 50%
methemoglobinemia is potentially fatal. Reversal of methemoglobinemia with methylene
blue, the usual treatment of methemoglobinemia, can result in re-release of the cyanide
ion and resumption of cyanide toxicity. Exchange transfusion may be the treatment of
choice of excessive methemoglobinemia produced by the treatment of cyanide toxicity.
Cyanide combines with methemoglobin to form cyanmethemoglobin.
Cyanmethemoglobin is bright red in color as opposed to the chocolate brown color of
methemoglobin.
44

CYANI DE TOXI CI TY REVI EW
PAGE - 12-

Displacement of cyanide from cytochrome a3 oxidase by methemoglobin.
The cyanide antidote kit
The United States currently advocates the combined use of nitrites and thiosulfate for
treatment of cyanide intoxication (the classic Lilly cyanide kit)
1
. This is the only United
States approved antidote to cyanide intoxication at this time. Sodium nitrite (10 milliliters
of 3% solution) is used intravenously followed by sodium thiosulfate (50 milliliters of 25%
solution). Sodium nitrite should be given at 2.5 to 5 mL per minute over 2-3 minutes.
Sodium thiosulfate should be administered immediately following the sodium nitrite. The
sodium thiosulfate should be administered intravenously as 12.5 mg of 25% solution
over 10 minutes.
The cyanide antidote kit is not generally available in bulk stock in hospitals.
45

46
It is not a
prehospital drug. If it is available in pre-positioned medical supplies, there is a
significant chance that the bulk of the patients will either be beyond salvage or will need
no further therapy before pre-positioned stocks can be released and distributed.
Instructions are on the cyanide kits and should be followed explicitly.
Amyl nitrite
Amyl nitrite produces only about 5% methemoglobin and is not thought to be adequate
therapy given alone. Doses of the amyl nitrite that can produce higher levels of
methemoglobin are often associated with profound hypotension. Indeed, amyl nitrite has
been removed from the military field kits of the United States Army formulary because of
unpredictability of the methemoglobin formation and the associated vasodilatation and
the subsequent hypotension.

1
Lilly has ceased making the Lilly cyanide kit. Today, the cyanide antidote kit is available from one source,
Taylor Pharmaceuticals (formerly Pasadena Research Laboratories). For a while, the replacement was
called the Pasadena kit after the company that manufactured it. It is probably better to just call it the
cyanide antidote kit. Sauer SW -Hydroxocobalamin: improved public health readiness for cyanide
disasters. Ann Emerg Med - 01-Jun-2001; 37(6): 635-41
O
2
Lungs
Tissues
Hb
(Fe
2+
)
HbO
2
(Fe
2+
)
CN
-
cyt a
3
(Fe
2+
and Fe
3+
)
cyt a
3
- CN
NO
2
-
metHb
(Fe
3+
)
CNmetHb
O
2
CYANI DE TOXI CI TY REVI EW
PAGE - 13-
Amyl nitrate may also induce significant vasodilation that can reverse the early cyanide
induced vasoconstriction.
47

48
Use of amyl nitrate broken into bag-valve-mask units has
been reported as a life-saving measure in dogs poisoned with cyanide prior to induction
of any significant methemoglobinemia.
49

Sodium nitrite
Sodium nitrite is the most prevalent drug for cyanide poisoning. The standard initial
dose of 3% sodium nitrite solution is 10 ml, equivalent to one of the two sodium nitrite
vials in the cyanide antidote kit. This takes about 12 minutes to generate about 40%
methemoglobin. The initial dose of sodium thiosulfate is 50 ml, equivalent to one of the
sodium thiosulfate vials in the cyanide antidote kit. A second dose of each antidote may
be given at up to half of the original dose, if the clinician feels that this is appropriate.
The use of sodium nitrite is not without risk, because an excess can cause marked
methemoglobinemia and subsequent hypoxia or hypotension and vascular collapse.
This is accentuated in the presence of coexisting carbon monoxide toxicity. Levels of
methemoglobin should be monitored.
There is evidence that the antidotal efficacy of nitrites is not solely due to formation of
methemoglobin.
50
The mechanism of this additional antidotal effect of nitrites is thought
to be vasodilation. Pretreatment of experimental animals with methylene blue prevents
nitrite-induced methemoglobin formation. This pretreatment appears to have little effect
on the capacity of amyl or sodium nitrite to antagonize cyanide.
51

52

In those with mixed gas exposure, induction of methemoglobinemia may induce tissue
hypoxia. It is therefore not recommended for fire victims where carbon monoxide
intoxication may accompany cyanide intoxication. Since carbon monoxide also impairs
the oxygen carrying capacity of the blood, administration of sodium nitrite could
aggravate the underlying hypoxia.
Too rapid administration of sodium nitrite may cause vasodilation and subsequent
hypotension. If methylene blue is given, all of the cyanide bound to the methemoglobin
will be released with a relapse of symptoms.
Sodium nitrate is not advised for patients with glucose-6-phosphate dehydrogenase
(G6PD) deficient red cells. In these patients, serious hemolytic reactions may be
possible.
Use of nitrates in pediatric patients
As noted above, therapy with nitrites is not innocuous. The doses given to an adult can
potentially cause a fatal methemoglobinemia in children or may cause profound
hypotension.
53

54
Treatment of children affected with cyanide intoxication must be
individualized and is based upon their body weight and hemoglobin concentration.
The dose of sodium nitrite in children is 10 mg/kg immediately and 5 mg/kg repeated
within 30 mm. if necessary. Use of adult doses of sodium nitrite in children may result in
fatal methemoglobinemia.
CYANI DE TOXI CI TY REVI EW
PAGE - 14-
If the hemoglobin of the child is less than 12 gm/100 ml, a smaller amount of sodium
nitrite should be used.
When less than full adult dose of sodium nitrite is given, 5 ml of 25% sodium thiosulfate
should be given for every 1 ml of 3% sodium nitrite.
(Table 2)
4-DMAP

4-DMAP (4-dimethylaminophenol) CAS # 619-60-3
2

4-Dimethylaminophenol (4-DMAP) is a methemoglobin forming compound with rapid
effects against cyanide.
55
4-DMAP was proposed by the Germans as a more rapid
antidote than nitrates and with lower toxicity. It is used currently by the German military
and by the civilian population. In humans, intravenous injection of 3 mg/kg of 4-DMAP
will produce 15% methemoglobin levels within 1 minute.
56

57

4-DMAP must be used with thiosulfate in order to transform methemoglobin-bound
cyanide to thiocyanate as with the cyanide antidote kit.
4-DMAP can cause necrosis in the area of injection after IM injection and may cause
pain, fever, and elevated muscle enzymes in patients who have received IM injections of
this agent. In some patients, extremely high levels of methemoglobin may be seen.
Hemolysis as a result of 4-DMAP therapy has been observed even with therapeutic
doses, but is more common with overdose of the medication. Treatment with 4-DMAP is
contraindicated in patients with G6PD deficiency.
Other agents that are similar methemoglobin-forming compounds with protective effects
against cyanide include p-aminioheptanoylphenone (PAHP), p-aminopropiophenone
(PAPP) and p-aminiooctanoylphenone (PAOP).
58
PAHP may be the safest phenone of
the group. These agents reduce cyanide levels within red blood cells. PAPP in particular,
has an enhanced effect in the presence of thiosulfate.
Stroma-free methemoglobin
Stroma-free methemoglobin has been tried in experimental animals.
59
It binds cyanide
without reducing the oxygen carrying capacity of blood. Stroma-free hemoglobin must be
converted to methemoglobin. Stroma-free hemoglobin has not been studied for this
indication in humans and the product is not yet available for administration in the US.

2
Manufacturer: Dr Franz Koehler Chemie GmbH, Alsbach, Germany
CYANI DE TOXI CI TY REVI EW
PAGE - 15-
Sulfur detoxification
After the methemoglobin has relieved the symptoms, the cyanide can be converted to
thiocyanate by the use of sodium thiosulfate. The second step provides a sulfur donor to
allow rhodanese to convert the cyanmethemoglobin into thiocyanate. As noted earlier
endogenous sulfur donors are often limited. The thiocyanate ion then is excreted by the
kidney. High tissue oxygen markedly potentiates the effects of this reaction. In cases
where nitrates and the subsequent formation of methemoglobinemia may be dangerous,
thiosulfate together with oxygen may be appropriate.

Conversion of cyanmethemoglobin to thiocyanate by rhodanese and thiosulfate.
Direct combination
There are two different mechanisms of direct combination of cyanide that are currently
used: combination with a cobalt compound and combination with hydroxycobalamin.
Hydroxycobalamin (Vitamin B
12a
)
Hydroxycobalamin is a precursor molecule of cyanocobalamin (Vitamin B
12
). Vitamin
B12a is the drug of choice for pernicious anemia, is approved by the FDA, and hundreds
of thousands of doses are used yearly in the United States. For uncertain reasons,
hydroxycobalamin has not yet been adopted in the United States for treatment of
cyanide intoxication.
60

Hydroxycobalamin has been used to prevent cyanide toxicity from prolonged
administration of sodium nitroprusside as well as in the acute treatment of cyanide
poisoning for over 40 years.
61

62

63

64

65

66
This agent reacts directly with the cyanide and
does not act on the hemoglobin to form methemoglobin.
Hydroxycobalamin works both within the intravascular space and within the cells to
combat cyanide intoxication. This contrasts with methemoglobin which only acts within
the vascular space as an antidote. Administration of sodium thiosulfate improves the
ability of the hydroxycobalamin to detoxify cyanide poisoning.
67
If the current cyanide
antidote kit has been used, hydroxycobalamin will not cause additional side effects.
O
2
Lungs
Tissues
Hb HbO
2
(Fe
2+
)
CN
-
cyt a
3
(Fe
2+
and Fe
3+
)
cyt a
3
- CN
NO
2
-
metHb
(Fe
3+
)
CNmetHb
+ Na
2
S
2
O
3
SCN
-
+ SO
3
2-
(urine)
rhodanese
O
2
CYANI DE TOXI CI TY REVI EW
PAGE - 16-

(dimethyl-5,6-benzimadazolyl) hydroxocobamide CAS number: 13 422-51-0

Cyanocobalamin is the combination of hydroxycobalamin and cyanide.
A dose of at least 2.5 grams in the adult is needed to neutralize a lethal amount of
cyanide.
68

69
It is not currently available in the United States in the appropriate strength
(current available formulation in the US would require a minimum of 4000 1 cc (1 mg)
ampoules to be given for an appropriate dose.)
EMD Pharmaceutical Company has produced a lyophilized (freeze-dried) packaging of
2.5 grams of hydroxycobalamin that can be rapidly reconstituted with 100 mL of sodium
chloride solution. The dose can be repeated once as necessary. This product is pending
FDA approval. It has been in use in Europe since 1996 as the Cyanokit. The
manufacturers estimated shelf life (30 months) is nearly twice that of the cyanide
antidote kit (18 months).
Hydroxycobalamin appears to be a preferable antidote for patients with another
concurrent gas exposure such as carbon monoxide and is used by prehospital providers
on a protocol basis for the treatment of smoke inhalation in France.
70
There is limited
experimental use in the United States to date, but more than 40 years of experience are
documented in the French literature.
71

72

Hydroxycobalamin is essentially devoid of serious complications. Some patients will
develop urticaria, but this is rare. Hydroxycobalamin does not lower blood pressure or
reduce the oxygen-carrying capacity of the blood. As such, it can be used with relative
impunity in fire victims. Tachycardia and hypertension have been occasionally reported
in high-dose therapy. Transient pink discoloration of the mucous membranes, skin, and
urine occurs in most patients immediately after the administration of hydroxocobalamin.
CYANI DE TOXI CI TY REVI EW
PAGE - 17-
This discoloration fades over 24-48 hours as the drug is eliminated through the urine.
73

The low toxicity of hydroxycobalamin seems to offer a clear advantage over sodium
nitrite. The effects of hydroxycobalamin can be enhanced by thiosulfate.
Dicobalt-EDTA

Dicobalt-EDTA, Dicobalt edetate. CAS # 36499-65-7
Cobalt salts have also been demonstrated as effective in binding cyanide.
74
The first use
of cobalt compounds as cyanide antagonists was advocated by Antal in 1894.
75
Interest
in cobalt compounds was re-explored by Paulett who reported that cobalt EDTA was
more effective as a cyanide antidote than the classic nitrate-thiosulfate combination.
76

One current cobalt-based antidote available in Europe is dicobalt-EDTA, sold as
Kelocyanor.
77

78
This agent chelates cyanide as the cobalticyanide. This drug provides
an antidote effect more quickly than formation of methemoglobin but a clear superiority
to methemoglobin formation has not been demonstrated.
Adverse effects of dicobalt-EDTA include anaphylactic reactions, which may present as
urticaria, angioedema that includes the face, neck and occasionally the airway, dyspnea,
and hypotension. Dicobalt-EDTA does cause a significant hypertension and may cause
dysrrhythmias if no cyanide is present when it is given. Patients may have vomiting and
periorbital edema after administration of Dicobalt-EDTA.
Deaths have been noted after this drug was administered and that severe toxicity from
cobalt can be seen even after the patient recovers from the cyanide intoxication.
79

80

This may be related to the fact that this preparation contains some free cobalt. The
cobalt toxicity should be much less of a risk in cases where cyanide toxicity genuinely
exists. (This has led to a recommendation that Kelocyanor should be given only to well
established cases and not in equivocal cases where exposure seems just a possibility.)
The toxicity can be reduced by co-administration of glucose (mechanism uncertain).
81

Kelocyanor and hydroxycobalamin may be given together for additive effect.
82
Hall and
Rumack studied 10 French patients who were given combinations of thiosulfate and
hydroxycobalamin and felt that this combination had some additive effect.
83

CYANI DE TOXI CI TY REVI EW
PAGE - 18-
Other experimental therapies
There are other antidotes that have been studied in experimental cyanide poisoning. It
should be emphasized that these are experimental therapies without any human studies
to validate their usefulness. It would be unlikely that any of these therapies would be
available in a mass casualty situation associated with a terrorist event.
Chlorpromazine
The potent vasodilation associated with the nitrates prompted the examination of other
vasodilators. Chlorpromazine (a phenothiazine) was found to significantly potentiate the
effects of the nitrates in treatment of patients who have been exposed to cyanide.
84
Its
protective effect is thought to be related to the alpha-adrenergic blocking activity.
85

Other alpha-adrenergic blocking agents and vasodilators have shown some antidotal
efficiency in cyanide intoxication.
Alpha-ketoglutaric acid
Alpha-ketoglutaric acid binds cyanide and antagonizes cyanide-induced inhibition of
cytochrome oxidase. It is effective in treatment of mice, in combination with sodium
thiosulfate, but has never been studied in humans.
86

87

Naloxone
Cyanide in massive doses induces respiratory arrest though the inhibition caused by
released endorphins. The opiate antagonist, naloxone, blocks the effects of the
endorphins and thus can protect against cyanide intoxication. Massive doses of this
agent are needed for protection in animal models and human studies have not yet been
attempted.
Extracorporeal filtering
Hemodialysis may be combined with the ingredients of the cyanide antidote kit to
increase the speed of elimination of cyanide and metabolites.
88
Charcoal
hemoperfusion, combined with sodium nitrite and sodium thiosulfate, has also been
used for this purpose.
89
These are totally anecdotal case reports and there are no
studies or case series that assess effectiveness of these methods.
Advantages and disadvantages of treatments.
Evaluation and comparison of antidotes is not easy. Interpretation of human case
reports is often uncertain because of uncertainties in the dose ingested or absorbed and
the exposure levels involved. These uncertainties make the likely clinical course in the
absence of antidotal therapy problematic. In the review of 48 cases by Chen and Rose
of 48 cases that suggested a high effectiveness of the classic cyanide antidote kit, very
few blood cyanide levels or other indexes of severity of toxicity were documented. As
noted earlier, there is good evidence that antidotes are not always essential for a
satisfactory outcome, even in the face of severe poisoning.
CYANI DE TOXI CI TY REVI EW
PAGE - 19-
Protection and prophylaxis
Cyanide is readily absorbed from routes including the skin, mucous membranes, and by
inhalation. All first-line rescuers should be adequately protected before entering a
confined area. Rescuers should wear full protective clothing and SCBA to avoid
intoxication during rescue attempts. Structural firefighters turnout gear is not adequate
even with SCBA because the hydrogen cyanide gas diffuses through the fabrics and can
be absorbed through the skin.
90

Most reported human cases of toxicity from dermal exposure involved whole-body
immersion in vats of cyanide solution and burns with molten cyanide salts.
91
In one
animal study, hydrogen cyanide gas was absorbed through skin of dogs and guinea pigs
and was lethal.
92

PAOP and PAPP (as described above) have been proposed as prophylactic drugs. Use
of drugs that form methemoglobin could present problems for combined gas inhalation
victims (carbon monoxide, in particular.)
A significant risk attributed to cyanogen chloride is that it breaks down the filters in a
protective mask quickly in high concentrations. For this reason, it may be considered by
a terrorist as a mass casualty agent.

CYANI DE TOXI CI TY REVI EW
PAGE - 20-
SUMMARY TABLES
Inhalation of cyanide agents may cause:
1. Dryness and burning of the throat
2. Air hunger
3. Hyperpnea
4. Apnea
5. Seizures and coma
6. Cardiovascular collapse.
Table 1
Variation of Childs Sodium Nitrite
Dose with Hemoglobin Concentration
3


Hemoglobin Initial dose of
NaNO
2
mg/kg
Initial dose of 3%
NaNO2 solution
ml/kg
Initial dose of 25%
sodium thiosulfate
ml/kg
7.0 5.8 0.19 0.95
8.0 6.6 0.22 1.10
9.0 7.5 0.25 1.25
10.0 8.3 0.27 1.35
11.0 9.1 0.30 1.50
12.0 10.0 0.33 1.65
13.0 10.8 0.36 1.80
14.0 11.6 0.39 1.95


3
Table from Comprehensive Review of Emergency Medicine 83 notes on cyanide intoxication by Guzzardi,
L.

CYANI DE TOXI CI TY REVI EW
PAGE - 21-


Hydrogen cyanide (AC)
Formula - HCN Molecular weight - 27.02
Chemical name - hydrogen cyanide or hydrocyanic acid
CAS number 74-90-8
Vapor density (compared with air) - 0.93
Liquid density - 0.687
Boiling point - 25.7
o
C
Decomposition temperature - Above 65.5
0
C (Forms explosive polymer on standing. Stabilized material
can be stored up to 65
o
C)
Rate of hydrolysis - Low under field conditions
Stability in storage - Unstable except when very pure. May form explosive polymer on long standing.
Can be stabilized by addition of small amounts of phosphoric acid or sulfur dioxide
Action on metals of other materials - Little or none.
Odor - Similar to bitter almonds (not able to be detected by a large part of the population)
Clinical effects - Binds to cytochrome oxidase enzyme system and interferes with cellular respiration.
Produces seizures, metabolic acidosis, hypotension, cardiovascular collapse, respiratory failure.

Rate of
action - Very rapid. Death occurs within 15 minutes after lethal dosage has been received.
Median lethal dosage (MLD
50
) - Median lethal dosage varies widely with concentration because of the
rather high rate at which AC is detoxified by the body. For example, at 200 mg/m
3
concentration, the
lethal dosage is approximately 2000 mg/min/m
3
, whereas at 150 mg/m
3
, the lethal dosage is
approximately 4500 mg-min/m
3

Median incapacitating dosage (ICt
50
) - Varies with the concentration.
Protection required - Protective mask and protective clothing.
Persistency - Short; the agent is highly volatile, and in the gaseous state it dissipates quickly in the air.
Table 3
CYANI DE TOXI CI TY REVI EW
PAGE - 22-


Cyanogen chloride (CK)
Formula - CNCl Molecular weight - 61.48
CAS number 506-77-4
Chemical name - Cyanogen chloride, chlorocyan, chlorine cyanide
Vapor density (compared with air) - 2.1
Liquid density - 1.18 at 20
o
C
Boiling point - 12.8
o
C
Decomposition temperature - Above 100
o
C
Rate of hydrolysis - Very low
Hydrolysis products - HCl and CNOH
Stability in storage - Stable at 65
o
C for 30 days. Tends to undergo condensation or polymerization in
storage to form the solid compound 2,4,6-trichloro-s-triazine, C
3
N
3
Cl
3
(cyclic). Impurities promote
polymerization which may occur with explosive violence.
Action on metals or other materials -None if CK is dry.
Odor - Its irritating and lacrimatory properties are so great that the odor can go unnoticed. Median
concentration detectable (by lacrimatory effect ) -12 mg/m
3

Same as cyanide
Median lethal dose (MLD
50
) -11,000 mg-min/m
3

Rate of detoxification - 0.02 - 0.1 mg/kg/min
Median incapacitating dose (ICt
50
) - 7000 mg-min/m
3

Protection required - protective mask. CK will break or penetrate a protective mask canister of filter
element more readily than most agents. A very high concentration may overpower the filter; high doses
will break down its protective ability. Level A or B protection is strongly recommended.
Persistency - Short. Vapor may persist in jungle and forest for some time under suitable weather
conditions
Table 4

Table 5 follows
CYANI DE TOXI CI TY REVI EW
PAGE - 23-
Possible Antidotes For Cyanide Intoxication
Antidote
Efficacy and possible
complications Availability
Potential
Utility
Hydroxocobalamin (Vitamin
B
12a
)
(+NaHS0
4
) Kit
93

94

95

96

97

No methemoglobin
formed
Low toxicity
High CN affinity
France
USA: FDA
approval
pending
Post exposure
May have some pre-
exposure use
Dicobalt ethylene diamine
tetra acetic acid (EDTA)
(Kelocyanor)
98

IV Risk: Cardiac
Dysrhythmias angina,
death
Europe:
commercial
USA:
Experimental
Post exposure only
4-Dimethylaminophenol
(4-DMAP)
99

100

and similar molecules:
P-aminopropiophenone
(PAPP),
101

P-aminoheptanophenone
(PAHP),
P-aminooctanoylphenone
(PAOP)
102

IV, IM
Possible Mutagen
Local tissue necrosis
Marked methemoglobin
Temperature , pain
PAHP (may be the
safest?)
Germany Post exposure
Stroma free
methemoglobin
103 104 105

Experimental Not currently
available
Postexposure and
Prehospital high-risk
personnel
Superactivated charcoal
106

107

For oral exposure only. FDA approved Postexposure and
Prehospital high-risk
personnel
-adrenergic antagonists
(chlorpromazine;

phenoxybenzamine)
108
Mechanisms uncertain FDA-approved
drugs

8-aminoquinoline analogs
of primaquine

(e.g.,
WR242511)
109

Methemoglobin formers
Pretreatment
Varies with
compound
Prehospital high-risk
personnel
Alpha-ketoglutaric acid
110

111

112

113

Direct binding of cyanide
without methemoglobin
formation
Animal studies only
Experimental Insufficient evidence

CYANI DE TOXI CI TY REVI EW
PAGE - 24-

Targets of the antidotes
Mgarbane B, Delahaye A, Goldgran-Toldano, D, Baud FJ. Antidotal treatment of
cyanide poisoning. J Chin Med Assoc 2003;66:193-203

CYANI DE TOXI CI TY REVI EW
PAGE - 25-

CYANI DE TOXI CI TY REVI EW
PAGE - 26-
References

1
Borowitz JL, Kanthasamy AG, Isom GE. Toxicodynamics of cyanide. In Chemical Warfare Agents, edited
by SM Somani, San Diego, Academic Press, 1992;pp 209-236.
2
Sykes AH. Early studies on the toxicology of cyanide. Vennesland B, Conn EE, Knowles CJ, Westly J,
Wissing F. Eds. Cyanide in biology. New York, London, Academic Press, 1981; pp 1-9.
3
Wolnick KA, Fricke FL, Bonnin E et al. The Tylenol tampering incident Tracing the source. Anal Chem
1984;56:466A-470A, 474A.
4
Sidell FR, Takafuji ET, Franz DR, eds. Medical Aspects of Chemical and Biological Warfare, Vol 1.
Washington DC: Office of the Surgeon General, Department of the Army; 1997.
5
Sidell FR, Takafuji ET, Franz DR, eds. Medical Aspects of Chemical and Biological Warfare, Vol 1.
Washington DC: Office of the Surgeon General, Department of the Army; 1997. OP CIT.
6
Brennan RJ, Waeckerle JF, Sharp TW, et al. Chemical warfare agents: emergency medical and
emergency public health issues. Ann Emerg Med 1999;34:191-204.
7
Baskin SI. Zyklon. In: La Cleur W. Ed. Encyclopedia of the Holocaust. New Haven, Conn: Yale University
Press: 1998.
8
Lowry WT, Juarez L, Petty CS, Roberts B. Studies of toxic gas production during actual structural fires in
the Dallas area. J Forensic Sci 1985;30:59-72.
9
Alarie Y. The toxicity of smoke from polymeric materials during thermal decomposition. Am Rev Pharm
Toxicol 1985;25:325-347.
10
Anderson RA, Harland WA. Fire deaths in the Glasgow area. III. The role of hydrogen cyanide. Med Sci
Law 1982;22:35-37.
11
Levine MS, Radford MPH, Radford EP. Occupational exposures to cyanide in Baltimore fire fighters. J
Occup Med 1978;20:53-56.
12
Montgomery R, Reinhart CF, Terril JB. Comments on fire toxicity. Comb Toxicol 1975;2:179-212.
13
Sadoff L, Fuchs J, Hollander J. Rapid death associated with laetrile ingestion. JAMA 1978;239:1532.
14
Anonymous. Controlled intravascular sodium nitroprusside treatment Brit J Med 1978;6140:784-785.
15
Atkins D. Cyanide toxicity following nitroprusside induced hypotension. Can Anaesth Soc J 1977;24:651-
660.
16
Vesey CJ, Cole PV, Simpson PJ. Cyanide and thiocyanate concentrations following sodium nitroprusside
infusion in man. Br. J Anaesth 1976;48:651-659.
17
MacNamara BP. Estimation of the toxicity of hydrocyanide acid vapors in man. Edgewood Arsenal
Technical Report Number EB-TR-76023. 1976. Department of the Army.
18
Sylvester DM, Hayton WL, Morgan RL Way JL. Effects of thiosulfate on cyanide pharmacokinetics in dogs.
Toxicol Appl Pharmacol 1983;69:265.
CYANI DE TOXI CI TY REVI EW
PAGE - 27-

19
Hydrogen cyanide: A FOA briefing book. Accessed at http://www.opcw.nl/chemhaz/hcn.html 30 April
2004.
20
Borak J. Pharmacologic mechanism of antidotes in cyanide and nitrile poisoning. [letter] J Occupational
and Environmental Health 1995;37:793-794.
21
Burrows GE, Way JL. Antagonism of cyanide toxicity by phenoxybenzamine. Fed Proc 1976;35:533.
22
Burrows GE, Way JL. Antagonism of cyanide toxicity by phenoxybenzamine. Fed Proc 1976;35:533. OP
CIT.
23
Ballantyne B. Toxicology of cyanides. In Ballantyne B, Marrs TC, eds. Clinical and Experimental
Toxicology of Cyanides. Bristol: Wright; 1987:41-126.
24
Vick JA, Froehlich HL. Studies of cyanide poisoning. Arch Int Pharmacodyn Ther 1985;273:314-322.
25
Vick JA, Froelich HL. Studies on cyanide poisoning. Arch Int Pharmacodyn Ther 1985;273:314-322. OP
CIT.
26
Hilmann B, Bardham KD, Bain JTB. The use of dicobalt edetate (Kelocyanor) in cyanide poisoning.
Postgrad Med J. 1974;50:171-174.
27
Karalliedde L, Wheeler H, Maclehose R, et al. Possible immediate and long-term health effects following
exposure to chemical warfare agents. Public Health 2000;114:238-248.
28
Blanc P, Hogan M, Malin K, Hryhorczuk D, Hessl S, Bernard B. Cyanide intoxication among silver
reclaiming workers. JAMA 1985;253:367-371.
29
Osuntokun BO. A degenerative neuropathy with blindness and chronic cyanide intoxication of dietary
origin. The evidence in Nigerians. In Toxicology in the Tropics, edited by Smith RL, Bababunmi EA.
London, Taylor and Francis Publishers 1980; pp 16-79.
30
Recommendations for protecting human health against potential adverse effects of long term exposure to
low doses of chemical warfare agents. MMWR 1988;37:72-74.
31
Kirk RI, Stenhous NS. Ability to smell solutions of potassium cyanide. Nature (Lond) 1953;171:698-699.
32
Fukumoto Y, Nakajimo H, Uetake M, Matusyma A, Yoshida T. A study on the sense of smell with respect
to potassium cyanide solution and its hereditary transmission. Jpn J Hum Genet 1957;2:7-16.
33
Baud FJ, Barriot P, Toffis V, et al. Elevated blood cyanide concentrations in victims of smoke inhalation.
NEJM 1991;325:1761-1766.
34
Bermudez RM, Cabrera CA. Treatment of burns. NEJM 1997;336:1392-1393.
35
Fligner CL, Luthi R, Linkaityte-Weiss E, et al. Paper strip screening method for detection of cyanide in
blood using CYANTESMO test paper. Am J Forensic Med Pathol 1992;13:81-84.
36
. Hall AH, Rumack BH. Clinical toxicology of cyanide. Ann Emerg Med 1986;15:1067-1074.
37
Baud FJ, Borron SW, Megarbane B, et al. Value of lactic acidosis in the assessment of the severity of
acute cyanide poisoning. Crit Care Med 2002;30:2044-2050.
38
Jacobs K. Report on experience with the administration of 4-DMAP in severe prussic acid poisoning.
Consequences for medical practice. Zentralbl Arbeitsmed 1984;34:274-213.
CYANI DE TOXI CI TY REVI EW
PAGE - 28-

39
Peden NR, Taha A, McSorley PD, Bryden GT, Murdoch IB, Anderson JM. Industrial exposure to
hydrogen cyanide: Implications for treatment. Br Med J 1986;293(6546):538.
40
Edwards AC, Thomas ID. Cyanide poisoning [letter]. Lancet 1978; 1(8055)::92-93.
41
Peden NR. Taha A. McSorley PD et al. Industrial exposure to hydrogen cyanide: implications for
treatment. Br Med J (Clin Res Ed). 1986;293(6546):538 OP CIT.
42.
Kindwall EP. Carbon monoxide and cyanide poisoning. In: Davis JC, Hunt TK, eds. Hyperbaric Oxygen
Therapy. Bethesda MD: Undersea Medical Society, 1977: 177-190.

43
. Chen KK, Rose CL, Clowes GHA. Methylene blue, nitrites, and sodium thiosulfate against cyanide
poisoning. Proc Exp Biol Med 1933;31:250-252.
44
Wright RO, Lewander WJ, Woolf AD. Methemoglobinemia: Etiology, pharmacology, and clinical
management. Ann Emerg Med 1999;34:646-656.
45
Woolf AD, Chrisanthus K. On-site availability of selected antidotes: Results of a survey of Massachusetts
hospitals. Am J Emerg Med 1997;15:62-65.
46
Dart RC, Goldfrank LR, Chyka PA, et al. Combined evidence-based literature analysis and consensus
guidelines for stocking of emergency antidotes in the United States. Ann Emerg Med 2000;36:126-132.
47
Van Heijst NP, Douze JMC, Van Kesteren RG, Van Bergen JEAM, Van Dijk A. Therapeutic problems in
cyanide poisoning. Clin Toxicol 1987;25:383-398.
48
Van Heijst ANP, Meredith JJ. Antidotes for cyanide poisoning. In Basic Science in Toxicology, edited by
Volanis GN, Sims J, Sullivan F, Turner P. Brighton, Taylor and Francis Publishers 1990; pp 558-566.
49
Vick JA, Froehlich HL. Studies on cyanide poisoning. Arch Int Pharmacodyn 1985;237:314-322.
50
Borak J. Pharmacologic mechanism of antidotes in cyanide and nitrile poisoning. [letter] J Occupational
and Environmental Health 1995;37:793-794. OP CIT
51
Borak J. Pharmacologic mechanism of antidotes in cyanide and nitrile poisoning. [letter] J Occupational
and Environmental Health 1995;37:793-794. OP CIT
52
Way JL, Sylvester D, Morgan RL, et al. Recent perspectives on the toxicodynamic basis of cyanide
antagonism. Fundam Appl Toxicol 1984;4:S231-S239.
53
Berlin CM Jr. The treatment of cyanide poisoning in children. Pediatrics. 1970;46:793-796.
54
Berlin CM. The treatment of cyanide poisoning in children. Pediatrics 1970;46:193-196.
55
Weger NP. Treatment of cyanide poisoning with 4-DMAP. Experimental and clinical overview. Fundam
Appl Toxicol. 1983;3:387-396.
56
Kiese M, Weger N. Formation of ferrihaemoglobin with aminophenols in the human for the treatment of
cyanide poisoning. Eur J Pharmacol 1969;7:97-105.
57
Weger N. Aminophenols as antidotes to prussic acid. Arch Toxikol 1968;24:49-50. (In German).
58
Vick JA, Froehlich H. Treatment of cyanide poisoning. J Toxicol Clin Exp 1988;25:125-138.
CYANI DE TOXI CI TY REVI EW
PAGE - 29-

59
Ten Eyck R, Schaerdel A, Lynett J, et al. Stroma-free methemoglobin solution as an antidote for cyanide
poisoning. A preliminary study. Clin Toxicol 1984;21:343-358.
60
Litovitz TL, Klein-Schwartz W, Caravati EM, et al. 1998 annual report of the American Association of
Poison Control Centers Toxic Exposure Surveillance System Am J Emerg Med 1999;17:425-487.
61
. Cottrell JE, Casthely P, Brodie JD, et al. Prevention of nitroprusside-induced cyanide toxicity with
hydroxycobalamin. N Engl J Med 1978;298:809-811.
62
. Graham DL, Laman D, Theodore J, Robin ED. Acute cyanide poisoning complicated by lactic acidosis
and pulmonary edema. Arch Intern Med 1977;137:1051-1055.
63
Way JL, Sylvester D, Morgan RL, et al. Recent perspectives on the toxicodynamic basis of cyanide
antagonism. Fundam Appl Toxicol 1984;4:S231-S239. OP CIT
64
Mushett C. Antidotal efficacy of vitamin B12 a (hydroxocobalamin) in experimental cyanide
poisoning. Proc Soc Exp Biol Med. 1952;81:234-237.
65
Hall AH, Rumack BH. Hydroxycobalamin/sodium thiosulfate as a cyanide antidote. J Emerg Med.
1987;5:115-121
66
Bismuth C, Baud FJ, Djeghout H, et al. Cyanide poisoning from propionitrile exposure. J Emerg Med
1987;5:191-195.
67
Hall AH, Rumack BH. Hydroxycobalamin/sodium thiosulfate as a cyanide antidote. J Emerg Med.
1987;5:115-121 OP CIT.
68
Houeto P, Buneux F, Galliot-Guilley M, et al. Pharmacokinetics of hydroxocobalamin in smoke inhalation
victims. J Toxicol Clin Toxicol 1996;34:397-404.
69
Houeto P, Buneux F, Galliot-Guilley M, et al. Monitoring of cyanocobalamin and hydroxocobalamin during
treatment of cyanide intoxication. [letter] Lancet 1995;246:1706-1707.
70
Sauer SW -Hydroxocobalamin: improved public health readiness for cyanide disasters. Ann Emerg Med -
01-Jun-2001; 37(6): 635-41
71
. Jouglard J, Fagot G, Deguigne B, et al. L'intoxication cyanhydrique aigue et son traitement d'urgence.
Marseille Medicale 1971;9:571-575.
72
Cottrell JE, Casthele P, Brodie JD, et al. Prevention of nitroprusside-induced cyanide toxicity with
hydroxycobalamin. NEJM 1978;298:809-811
73
Houeto P, Buneux F, Galliot-Guilley M, et al. Pharmacokinetics of hydroxocobalamin in smoke inhalation
victims. J Toxicol Clin Toxicol 1996;34:397-404. OP CIT.
74
Evans CL. Cobalt compounds as antidotes for hydrocyanic acid. Br J Pharmacol. 1964:23:455-475.
75
Antal J [Experimental studies on the treatment of cyanide poisoning.] Ung Arch Med 1894;3:117-128. (in
German)
76
Paulet, G. Les chelats de cobalt dans le traitement de lintoxication cyanhydrique. Pathol Biol
1960;8:255-266. (in French)
77
Vogel SN, Sultan TR, Ten Eyck RP. Cyanide poisoning. Clin Toxicol 1981;18:367-383.
CYANI DE TOXI CI TY REVI EW
PAGE - 30-

78
Hillman B. Bardhan KD, Bain JTB. The use of dicobalt edetate (Kelocyanor) in cyanide poisoning.
Postgrad Med J 1974:50:171-174.
79
Rose CL, Worth RM, Kikuchi K, Chen KK. Cobalt salts in acute cyanide poisoning. Proc Soc Exp Biol
Med. 1965;120:780-783.
80
Reynolds JEF, Prasad AB, eds. Dicobalt edetate (1033-p). In: Martindale: The extra Pharmacopoeia. 28
th

edition London, England: Pharmaceutical Press: 1982: 382.
81
Dodds C, McKnight C. Cyanide toxicity after immersion and the hazards of dicobalt edetate. Br. Med J.
1985;291:785-786.
82
. Bismuth C, Cantineau J-P, Pontal P, et al. Priorite de l'oxygenation dans l'intoxication cyanhydrique. J
Toxicol Med 1984;4:107-121.
83
Hall AH, Rumack BH. Hydroxycobalamin/sodium thiosulfate as a cyanide antidote. J Emerg Med.
1987;5:115-121 OP CIT

84
Way JL. Cyanide intoxication and its mechanism of antagonism. Ann Rev Pharmacol Toxicol
1984;24:451-481.
85
Kong A, Shen A, Burrows G, Sylvester D, Isom GE, Way JL. Effect of chlorpromazine on cyanide
intoxication. Toxicol Appl Pharmacol. 1983;71:407-413.
86
Norris JC, Utley WA, Hume AS. Mechanism of antagonizing cyanide induced lethality by alpha-
ketoglutaric acid. Toxicol 1990;62:275-283.
87
Yamamoto HA. Protection against cyanide-induced convulsions with alpha-ketoglutarate. Toxicol
1990;61:221-228.
88
Wesson DE, Foley R, Sabatini S, et al. Treatment of acute cyanide intoxication with hemodialysis. Am J
Nephrol 1985;5:121-126.
89
Krieg A, Saxena K. Cyanide poisoning from metal cleaning solutions. Ann Emerg Med 1987;16:582-584.
90
Lam KK, Lau FL. An incident of hydrogen cyanide poisoning. Am J Emerg Med 2000;18:xxxx
91
Dodds C, Mcknight C: Cyanide toxicity after immersion and the hazards of dicobalt edetate. Br Med J
1985;29 1:785-786.
92
Walton DC, Witherspoon MG: Skin absorption of certain gases. J Pharmacol Exp Ther 1926;26:315-324.
93
Hall AH, Rumack BH. Hydroxocobalamin/sodium thiosulfate as a cyanide antidote. Journal of Emergency
Medicine 1987:5:115121
94
Cottrell JE, Casthely P, Brodie JD, et al. Prevention of nitroprusside-induced cyanide toxicity with
hydroxocobalamin. New England Journal of Medicine 1978 ;298:809811.
95
Brouard A, Blaisot B, Bismuth C.. Hydroxocobalamin in cyanide poisoning. Journal of Toxicology and
Clinical Experimentation 1987;7:155168
96
Bismuth C, Baud FJ, Pontal PG. Hydroxocobalamin in chronic cyanide poisoning. Journal of Toxicology
and Clinical Experimentation 1988;8:3538.
CYANI DE TOXI CI TY REVI EW
PAGE - 31-

97
Beregi JP, Riou B, Lecarpentier Y. Effects of hydroxocobalamin on rat cardiac papillary muscle. Intensive
Care Medicine1991;17:175177.
98
Hillman B, Bardhan KD, Bain JTB. The use of dicobalt edetate (Kelocyanor) in cyanide poisoning.
Postgraduate Medical Journal 1974;50:171174.
99
Weger NP. 1983. Treatment of cyanide poisoning with 4-DMAP--Experimental and clinical overview.
Fundamental and Applied Toxicology 3:387396.

100
Bhattacharya R. Therapeutic efficacy of sodium nitrite and 4-dimethylaminophenol or hydroxylamine
coadministration against cyanide poisoning in rats. Human Experimental Toxicology 1995;14:2933
101
Marrs TC, Bright JE. Effect on blood and plasma cyanide levels and on methemoglobin levels of cyanide
administered with or without previous protection using PAPP. Human Toxicology 1987;6:139145
102
Rockwood GA, Romano JA Jr., Scharf BA, Baskin SI. The effects of P-amino-propiophenone (PAPP) and
P-aminooctoylphenone (PAOP) against sodium cyanide (CN) challenge on righting and motor activity in
mice. Toxicologist 1992;12:271.
103
Ten Eyck RP, Schaerdel AD, Lynett JE, et al. Stroma free methemoglobin solution as an antidote for
cyanide poisoning: A preliminary study. Journal of Toxicology and Clinical Toxicology 1983;21:343358.
104
Ten Eyck RP, Schaerdel AD, Ottinger WE. Comparison of nitrate treatment and stroma-free
methemoglobin solution as antidotes for cyanide poisoning in a rat model. Journal of Toxicology and
Clinical Toxicology 1986;23:477487.
105
Breen PH, Isserles SA, Tabac E, et al. Protective effect of stroma-free methemoglobin during cyanide
poisoning in dogs. Anesthesiology 1996;85:558564.
106
Andersen AH. Experimental studies on the pharmacology of activated charcoal: I Adsorption power of
charcoal in aqueous solutions. Acta Pharmacologica 1946;2:6978.
107
Lambert RJ, Kindler BL, Schaeffer DJ. The efficacy of superactivated charcoal in treating rats exposed to
a lethal oral dose of potassium cyanide. Annals of Emergency Medicine 1988;17:595598.
108
Peterson JC, Cohen SD. Antagonism of cyanide poisoning by chlorpromazine and sodium thiosulfate.
Toxicology and Applied Pharmacology 1985;81:265273.
109
Steinhaus RK, Baskin SI, Clark JH, Kirby SD. Formation of methemoglobin and metmyoglobin using 8-
aminoquinoline derivatives or sodium nitrite and subsequent reaction with cyanide. Journal of Applied
Toxicology 1990;10:345351.
110
Dulaney MD, Brumley M, Willis JT, Hume AS.. Protection against cyanide toxicity by oral alpha-
ketoglutaric acid. Veterinary and Human Toxicology 1991; 33:571575.
111
Bhattacharya R, Vijayaraghavan R. Cyanide intoxication in mice through different routes and its
prophylaxis by -ketoglutarate. Biomedical Environmental Science 1991;4:452459.
112
Hume AS, Mozingo JR, McIntyre B, Ho IK.. Antidotal efficacy of alpha-ketoglutaric acid and sodium
thiosulfate in cyanide poisoning. Journal of Toxicology and Clinical Toxicology 1995;33:721724.
113
Norris JC, Utley WA, Hume AS.. Mechanism of antagonizing cyanide-induced lethality by -ketoglutaric
acid. Toxicology 1990;62:275283.