Cyanide as a Weapon

8/12/2019 Cyanide as a Weapon

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CYANIDE TOXICITY REVIEW

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INTRODUCTION

The blood agents or tissue toxins act by destroying the ability of the blood and tissuesto carry or process oxygen. Cyanide, an ancient compound, is the prototype agent in thisgroup. 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 airand dissipates rapidly. Hydrogen cyanide is found in widespread industrial use.

The sodium and potassium salts of cyanides are used in metallurgy for the extraction ofgold 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. Theodor will often be unnoticed becauseof the agents irritating properties to the mucousmembrane. Cyanogen chlorides CAS number is 506-77-4.

HistoryCyanide was identified and isolated from cherry laurel by the Swedish chemist Scheelein 1782.1 Hydrogen cyanide was first isolated from Prussian blue dye in 1786, althoughthe poisonous properties of cherry laurel leaves, cassava, bitter almonds and Prussianblue dye had been recognized since antiquity. The first description of cyanide poisoningwas 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 wereused as adulterants in packages of Tylenol in 1982 in the Chicago area.3Cyanidelaced drinks were used for the mass suicide of the Reverend Jim Jones PeoplesTemple in Guyana in 1978.4 Cyanide gas precursor compounds were found in severalsubway 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 Centerin 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 achemical warfare agent. The NATO military designators for the cyanide compoundsused in warfare are:

AC (hydrogen cyanide HCN)


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CK (cyanogen chloride CNCL)

The military incorrectly calls cyanide a "blood agent," implying that the action is in theblood when it is, in fact, a tissue toxin. The widespread distribution of absorbed nerveagents and vesicants through the blood makes this an antiquated term.

As chemical warfare or terrorism agents, these agents may be delivered by munitionsfrom artillery, mortar, bombs, or simply released from canisters. The preferred way todeliver cyanide is by large munitions because smaller weapons will not provide theconcentration needed for lethal effect. Like all of the chemical warfare agents, the areaof action is weather- and wind-dependent. As noted earlier, cyanide is not persistent atall and dissipates rapidly. The tissue toxins were abandoned as war agents during WWIbecause they are too volatile in open air, require high concentrations for effect, themunitions 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 wasused 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 usedin the Nazi gas chambers.7

Its high volatility, and the fact that it is lighter than air, probably makes hydrogen cyanidedifficult to use as a terrorist agent, since there are problems in achieving sufficiently highconcentrations outdoors. On the other hand, the concentration of hydrogen cyanide mayrapidly reach lethal levels if it is released in confined spaces. Potassium cyanidepoisoning of food and water supplies is an ancient terrorist tactic.

Cyanogen chloride has similar action to that of hydrogen cyanide. It interferes with theuse of oxygen by the body tissues. Like cyanide, cyanogen chloride is not lethal at lowerconcentrations. The late effects are similar to those seen with cyanide.

Cyanogen chloride will cause irritation to the eyes, nose and airway like the riot-controlagents. This action is considered to be of little military importance compared to its tissueeffects. CK irritates the respiratory tract in a manner similar to phosgene. The patient willdevelop marked lacrimation, rhinorrhea, and bronchial secretions. Cyanogen chloridecauses pulmonary edema much faster than in phosgene poisoning.

Cyanogen chloride is considered a non-persistent agent and is used as a quick-actingcasualty agent. Although cyanogen chloride evaporates quickly, the vapors may persistin heavily wooded areas under the right conditions.

Sources

Cyanide is surprisingly available. Industry in the United States manufactures over300,000 tons of hydrogen cyanide each year. These cyanides are used in chemicalprocesses, electroplating, mineral extraction, dye manufacturing, printing, photography,and agriculture. It is a major chemical in the synthesis of synthetic fibers, plastics, andnitrites. Hydrogen cyanide is also widely used as a fumigant on ships and inwarehouses.


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membranes slowly. The serum albumin-sulfane complex may be the primary cyanidedetoxification 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 liquidhydrogen cyanide, as well as cyanide salts in solution, can also be absorbed through theskin or ingested.

Hydrogen cyanide toxicity by inhalation19

Concentration (mg/m3

) 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 productdetermines a specific relationship between the inhaled dose and the effect. Exposure to140 ppm for 60 minutes or 1500 ppm for 3 minutes is has an estimated 50% mortality(LCt502500-500 mg/min/m

3). The median lethal dose is about twice this level for themost resistant individuals. The LCt50for cyanogen chloride is about 1.1 g/min/m3.

At low concentrations, the Ct product does not apply, since the body is capable oflimited detoxification of cyanide. The injected or ingested dose at which 50% of theexposed people will die (LD50) is 1 mg/kg for hydrogen cyanide. The estimated LD50for

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 aretoxic only when ingested. The effects of ingestion are often delayed because ofgastrointestinal absorption.


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After cyanide is absorbed, it is rapidly distributed through the body. The majority ofcyanide in the body is protein bound (60%). Cyanide reacts reversibly but with highaffinity with metals such as the ferric ion (Fe3+)and cobalt. Cyanide also reacts withsulfur 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 cytochromeoxidase a3(containing iron) within the mitochondria. This enzyme is a necessary part ofthe production of adenosine triphosphate (ATP). As a result, aerobic oxidativemetabolism and phosphorylation are compromised causing cellular hypoxia. Othermetabolic processes continue and the rate of glycolysis is increased markedly. Thepyruvate that is produced can no longer be used and is now reduced to lactate.

Cyanide inhibits cytochrome oxidase, the terminal oxidase of the mitochondrialrespiratory chain.

This leads to a profound lactic acidosis as the body attempts to use the less efficientanaerobic metabolism. Subsequent central nervous system (CNS), respiratory, andmyocardial depression complicate the picture.

cyt c cyt a cyt a3Cu

O2and H+

H2OCytochrome c oxidase

(cytochrome aa3)

ADP ATP

cyt c cyt a cyt a3 Cu

O2and H+

H2OCytochrome c oxidase

(cytochrome aa3)

ADP ATP

CN -


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More recent evidence suggests that massive cyanide poisoning ( >5 times LD50) resultsfrom complex mechanisms that involve more than one biochemical lesion.20 Othermechanisms include pulmonary arteriolar and/or coronary vasoconstriction can occur.21This 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, causinghyperpnea. Respiratory arrest may occur in these victims because of paralysis of themedullary center and not asphyxia.

Contributions to toxicity by vasoactive amines are suggested by the rapid onset ofcardiovascular collapse, elevation of the plasma histamine levels andhemoconcentration after poisonings.2223Vascular mechanisms are suggested by thefinding that alpha-adrenergic blockers and vasodilators such as the nitrites can preventor reverse cyanides lethal effects.24 The observation that phenoxybenzamine, an alpha-adrenergic blocking drug, partially prevented these changes supports the concept of anearly 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 doseexposure 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 mostevident with cyanogen chloride. At high hydrogen cyanide concentrations, absorptionoccurs 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 treatmentsavailable. 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 theroute of exposure and the amount of exposure. The most significant clinicalmanifestations of cyanide poisoning are cerebral, respiratory, and cardiac.

Early symptoms may include dryness and burning of the throat and air hunger. In smalldoses, 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 withsubsequent tachycardia and hypertension. Later symptoms include hypotension,impaired consciousness and coma. This is followed in 15 to 30 seconds by the onset ofconvulsions. Late signs of cyanide toxicity include profound hypotension, complexarrhythmias, cardiovascular collapse, pulmonary edema, and death. Respiratory activitystops in 2-3 minutes and cardiac activity stops several minutes later.


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It should be emphasized that the bright-red coloration of skin and the absence ofcyanosis that is often mentioned in textbooks is seldom described in case reports. Thissign is theoretically explained by the high concentration of oxyhemoglobin in the venouscirculation. Particularly in massive poisoning, rapid cardiovascular collapse will preventthe reddened skin coloration. In some cases, cyanosis can be initially observed only tohave 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 becommon manifestations. The carotid body chemoreceptors, responsible for oxygenmediated respiratory reflexes, are rapidly stimulated by the presence of highconcentrations of cyanide and cause a gasping reflex. (An audible gasp is thought to becharacteristic of extreme exposure to HCN.)

The long-term effects of exposure to cyanide are nebulous and include intellectualdeterioration, confusion, and Parkinson-like syndromes.27Chronic low-dose neurotoxicityhas been suggested by epidemiologic studies of populations ingesting naturallyoccurring plant glycosides.28 Perhaps the most wide-spread pathologic condition

attributed to chronic cyanide poisoning is tropic ataxic neuropathy associated withcassava consumption.29

Diagnosis

The initial diagnosis of severe cyanide poisoning is difficult. Cyanide poisoning is anuncommon cause of clinical presentation of coma, shock, seizures, and metabolicacidosis with elevated anion gap. The medical provider should be suspicious of acutecyanide intoxication if the patient has had an abrupt collapse without apparent causeand 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 maysmell the odor of almonds on the patients breath, but about 18% of males and 5% offemales are unable to smell the odor of cyanide.303132

Cyanide toxicity should be considered in all smoke inhalation victims with CNS orcardiovascular findings.3334 This poisoning with cyanide associated with smokeinhalation should be considered in terrorist events promulgated by conventionalexplosives or incendiary agents.

Laboratory testing

There is no readily available assay that can be done in "real time" to confirm cyanidepoisoning while trying to treat an acutely poisoned patient. Spectrophotometry and gaschromatography are tools for the pathologist, not the clinician.

Before intravenous treatment with available antidotes is started, the physician shouldcollect a heparinized specimen of blood for determination of the cyanide concentration.Samples that are obtained after treatment are totally unreliable.


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A new semiquantitative assay that uses calorimetric test strips may improve thelaboratory evaluation of hydrogen cyanide poisoning.35Before any cyanide level iscorrelated with clinical appearance, the elapsed time since the exposure and since thespecimen was obtained must be considered.

Ar terial blood gasesArterial blood gases will often show a metabolic acidosis with normal oxygenation andcalculated hemoglobin saturation. Venous gases have the same pattern, because theoxygen is not used up at the tissues! Venous blood often looks arterial in color and thismay be clinically obvious when fundal veins and arteries appear to be equally red. Themeasured arterial oxygen saturation will be decreased, while the calculated saturation isnormal.36

This picture of an abnormal hemoglobin and less than adequate saturation is foundcommonly in only four poisons. The toxidrome includes cyanide, carbon monoxide,hydrogen sulfide, and methemoglobin. Methemoglobin and carboxyhemoglobin areeasily measured. Hydrogen sulfide and cyanide are treated in a similar manner.Cyanide levels should be obtained in all cases. An elevated anion gap metabolicacidosis may exist but is not diagnostic.

Lactic acidosis

Since oxidative phosphorylation is blocked by cyanide, the rate of glycolysis is markedlyincreased. This leads to a profound lactic acidosis. Unexplained lactic acidosis may alsobe caused by several different toxins and all are difficult to rapidly measure exceptcarbon 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 cutofflevel 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 increaseglucose. 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 butis 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


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Salicylates will turn greenish blue and then purple.

Differential Diagnosis

The differential diagnosis of cyanide intoxication includes all other causes of respiratoryfailure including intoxication with other agents or drugs.

Treatment

Removal from the area

The patient should be immediately removed from the contaminated atmosphere. Earlyuse of a protective mask for the patient will also prevent further inhalation. Removal ofany liquid on skin or clothing should be performed as soon as possible. The patientsclothing should be removed once they are in a safe environment to prevent liquidcyanide from releasing vapors or being absorbed by the patient.

Supportive therapy

Initial treatment is supportive and should include airway support, high flow oxygensupplementation, cardiac monitoring, intravenous fluids and possibly intravenous sodiumbicarbonate to offset the profound lactic acidosis. There is evidence that cyanideintoxication responds to the administration of 100% oxygen. It should be a part ofsupportive care for all patients suspected to have cyanide intoxication.

In moderate and severe cyanide intoxication, the clinical outcome is dependent both onthe severity of the exposure, and the delay until treatment is started. The success oftherapy of acute cyanide intoxication depends primarily on the speed with which thecellular oxygen utilization is restored. Since hypoxia is a major component of this

agents toxicity, cerebral hypoxia and subsequent encephalopathy is common inseverely poisoned casualties.

The mainstays of hospital treatment are oxygen and ventilation. Activated charcoal isroutinely recommended for use in ingestions, but there is no evidence of its efficacy.

Urgent specific antidotal therapy in cyanide intoxication is not indicated unless thepatient has coma, dilated pupils and a deteriorating cardio-respiratory function. A patientwho is exposed to hydrogen cyanide who is fully conscious requires only observationand 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 basicsis controversial and includes hyperbaric oxygenation and use of a cyanide antidote. Lackof an antidote should not preclude treatment with airway support and ventilation in thesepatients. There is good evidence that antidotes are not always essential for asatisfactory outcome, even in the face of severe poisoning.4041


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Hyperbaric Oxygenation

Hyperbaric oxygenation may be the ideal adjunct to both hydroxycobalamin and nitritetherapies. Hyperbaric oxygenation will mitigate concern about the methemoglobinemiaformed by nitrite administration since the dissolved oxygen in the tissues and bloodstream 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 higherlevels of nitrite to be used. Hyperbaric oxygen therapy should not be used to replace thechemical treatments, however, due to the deleterious effects of delay in institution of thetreatment in most cases. Hyperbaric oxygen therapy is unlikely to be available in theevent of a terrorist attack with cyanide, since most available chambers have the capacityfor at most a few patients.

Cyanide antidotes

Cyanide antidotes have been classified into three main groups according to their primarymechanism of action: detoxification with sulfur to produce the much less toxic

thiocyanate ion, formation of methemoglobin, and direct combination. The definitivetreatment of cyanide intoxication differs in various countries, but only one method isapproved for use in the United States. The safety and efficacy of each of these antidotesis a source of significant debate. There is no worldwide consensus for treatment ofcyanide intoxication.

Production of methemoglobin

Proposed in the 1930s by Chen and colleagues, intentional production ofmethemoglobin is used to compete with cyanide for sites on the cytochrome oxidasesystem.43 While cyanide is preferentially bound to the ferric ion in the cytochromeoxidase system, an appreciable quantity of cyanide will be attracted to the ferric ion inother compounds, such as methemoglobin. If sufficient quantities of methemoglobin areproduced, the symptoms of cyanide intoxication will be alleviated. Methemoglobinemiacan be produced by inhalation of amyl nitrite and then intravenous administration ofsodium nitrite. About 30% methemoglobinemia is considered optimum, and the levelsshould be kept below 40% methemoglobin. Other substances such as 4-DMAP existthat may produce methemoglobin more rapidly.

Since methemoglobin is unable to carry sufficient quantities of oxygen, thesehemoglobin molecules are now non-functional. Production of greater than 50%methemoglobinemia is potentially fatal. Reversal of methemoglobinemia with methyleneblue, the usual treatment of methemoglobinemia, can result in re-release of the cyanideion 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 ofmethemoglobin.44


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Displacement of cyanide from cytochrome a3 oxidase by methemoglobin.

The cyanide antidote kitThe 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 UnitedStates approved antidote to cyanide intoxication at this time. Sodium nitrite (10 millilitersof 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. Thesodium thiosulfate should be administered intravenously as 12.5 mg of 25% solutionover 10 minutes.

The cyanide antidote kit is not generally available in bulk stock in hospitals. 4546It is not aprehospital 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 needno further therapy before pre-positioned stocks can be released and distributed.Instructions are on the cyanide kits and should be followed explicitly.

Amyl ni tr ite

Amyl nitrite produces only about 5% methemoglobin and is not thought to be adequatetherapy given alone. Doses of the amyl nitrite that can produce higher levels ofmethemoglobin are often associated with profound hypotension. Indeed, amyl nitrite hasbeen removed from the military field kits of the United States Army formulary because ofunpredictability of the methemoglobin formation and the associated vasodilatation andthe subsequent hypotension.

1Lilly 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

O2Lungs

Tissues

Hb(Fe

2+)

HbO2(Fe

2+)

CN-

cyt a3(Fe

2+and Fe

3+)

cyt a3 - CN

NO2-

metHb(Fe

3+)

CNmetHb

O2


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Amyl nitrate may also induce significant vasodilation that can reverse the early cyanideinduced vasoconstriction.4748Use of amyl nitrate broken into bag-valve-mask units hasbeen reported as a life-saving measure in dogs poisoned with cyanide prior to inductionof any significant methemoglobinemia. 49

Sodium nitrite

Sodium nitrite is the most prevalent drug for cyanide poisoning. The standard initialdose of 3% sodium nitrite solution is 10 ml, equivalent to one of the two sodium nitritevials 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 thesodium thiosulfate vials in the cyanide antidote kit. A second dose of each antidote maybe 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 markedmethemoglobinemia and subsequent hypoxia or hypotension and vascular collapse.This is accentuated in the presence of coexisting carbon monoxide toxicity. Levels ofmethemoglobin should be monitored.

There is evidence that the antidotal efficacy of nitrites is not solely due to formation ofmethemoglobin.50 The mechanism of this additional antidotal effect of nitrites is thoughtto be vasodilation. Pretreatment of experimental animals with methylene blue preventsnitrite-induced methemoglobin formation. This pretreatment appears to have little effecton the capacity of amyl or sodium nitrite to antagonize cyanide.5152

In those with mixed gas exposure, induction of methemoglobinemia may induce tissuehypoxia. It is therefore not recommended for fire victims where carbon monoxideintoxication may accompany cyanide intoxication. Since carbon monoxide also impairsthe oxygen carrying capacity of the blood, administration of sodium nitrite couldaggravate the underlying hypoxia.

Too rapid administration of sodium nitrite may cause vasodilation and subsequenthypotension. If methylene blue is given, all of the cyanide bound to the methemoglobinwill 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 bepossible.

Use of ni trates in pediatric patients

As noted above, therapy with nitrites is not innocuous. The doses given to an adult canpotentially cause a fatal methemoglobinemia in children or may cause profoundhypotension.5354Treatment of children affected with cyanide intoxication must beindividualized 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 repeatedwithin 30 mm. if necessary. Use of adult doses of sodium nitrite in children may result infatal methemoglobinemia.


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If the hemoglobin of the child is less than 12 gm/100 ml, a smaller amount of sodiumnitrite should be used.

When less than full adult dose of sodium nitrite is given, 5 ml of 25% sodium thiosulfateshould be given for every 1 ml of 3% sodium nitrite.(Table 2)

4-DMAP

4-DMAP (4-dimethylaminophenol) CAS # 619-60-32

4-Dimethylaminophenol (4-DMAP) is a methemoglobin forming compound with rapideffects against cyanide.55 4-DMAP was proposed by the Germans as a more rapidantidote than nitrates and with lower toxicity. It is used currently by the German militaryand by the civilian population. In humans, intravenous injection of 3 mg/kg of 4-DMAPwill produce 15% methemoglobin levels within 1 minute.5657

4-DMAP must be used with thiosulfate in order to transform methemoglobin-boundcyanide to thiocyanate as with the cyanide antidote kit.

4-DMAP can cause necrosis in the area of injection after IM injection and may causepain, fever, and elevated muscle enzymes in patients who have received IM injections ofthis 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 therapeuticdoses, 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 effectsagainst cyanide include p-aminioheptanoylphenone (PAHP), p-aminopropiophenone(PAPP) and p-aminiooctanoylphenone (PAOP).58 PAHP may be the safest phenone ofthe 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 cyanidewithout reducing the oxygen carrying capacity of blood. Stroma-free hemoglobin must be

converted to methemoglobin. Stroma-free hemoglobin has not been studied for thisindication in humans and the product is not yet available for administration in the US.

2 Manufacturer: Dr Franz Koehler Chemie GmbH, Alsbach, Germany


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Sulfur detoxification

After the methemoglobin has relieved the symptoms, the cyanide can be converted tothiocyanate by the use of sodium thiosulfate. The second step provides a sulfur donor toallow rhodanese to convert the cyanmethemoglobin into thiocyanate. As noted earlierendogenous 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 caseswhere 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 B12a)

Hydroxycobalamin is a precursor molecule of cyanocobalamin (Vitamin B12). VitaminB12a is the drug of choice for pernicious anemia, is approved by the FDA, and hundredsof 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 ofcyanide intoxication.60

Hydroxycobalamin has been used to prevent cyanide toxicity from prolongedadministration of sodium nitroprusside as well as in the acute treatment of cyanide

poisoning for over 40 years.616263646566 This agent reacts directly with the cyanide anddoes not act on the hemoglobin to form methemoglobin.

Hydroxycobalamin works both within the intravascular space and within the cells tocombat cyanide intoxication. This contrasts with methemoglobin which only acts withinthe vascular space as an antidote. Administration of sodium thiosulfate improves theability of the hydroxycobalamin to detoxify cyanide poisoning.67 If the current cyanideantidote kit has been used, hydroxycobalamin will not cause additional side effects.

O2Lungs

Tissues

Hb HbO2(Fe

2+)

CN-

cyt a3(Fe

2+and Fe

3+)

cyt a3 - CN

NO2-

metHb(Fe

3+)

CNmetHb

+ Na2S2O3SCN- + SO3

2-

(urine)

rhodanese

O2


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This discoloration fades over 24-48 hours as the drug is eliminated through the urine.73The low toxicity of hydroxycobalamin seems to offer a clear advantage over sodiumnitrite. 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. 74The first useof cobalt compounds as cyanide antagonists was advocated by Antal in 1894. 75Interestin cobalt compounds was re-explored by Paulett who reported that cobalt EDTA wasmore effective as a cyanide antidote than the classic nitrate-thiosulfate combination.76

One current cobalt-based antidote available in Europe is dicobalt-EDTA, sold asKelocyanor.7778This agent chelates cyanide as the cobalticyanide. This drug providesan antidote effect more quickly than formation of methemoglobin but a clear superiorityto methemoglobin formation has not been demonstrated.

Adverse effects of dicobalt-EDTA include anaphylactic reactions, which may present asurticaria, angioedema that includes the face, neck and occasionally the airway, dyspnea,and hypotension. Dicobalt-EDTA does cause a significant hypertension and may causedysrrhythmias if no cyanide is present when it is given. Patients may have vomiting andperiorbital edema after administration of Dicobalt-EDTA.

Deaths have been noted after this drug was administered and that severe toxicity fromcobalt can be seen even after the patient recovers from the cyanide intoxication. 7980This may be related to the fact that this preparation contains some free cobalt. Thecobalt toxicity should be much less of a risk in cases where cyanide toxicity genuinelyexists. (This has led to a recommendation that Kelocyanor should be given only to wellestablished 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 andRumack studied 10 French patients who were given combinations of thiosulfate andhydroxycobalamin and felt that this combination had some additive effect.83


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Other experimental therapies

There are other antidotes that have been studied in experimental cyanide poisoning. Itshould be emphasized that these are experimental therapies without any human studiesto validate their usefulness. It would be unlikely that any of these therapies would beavailable in a mass casualty situation associated with a terrorist event.

Chlorpromazine

The potent vasodilation associated with the nitrates prompted the examination of othervasodilators. Chlorpromazine (a phenothiazine) was found to significantly potentiate theeffects of the nitrates in treatment of patients who have been exposed to cyanide. 84Itsprotective effect is thought to be related to the alpha-adrenergic blocking activity.85Other alpha-adrenergic blocking agents and vasodilators have shown some antidotalefficiency in cyanide intoxication.

Alpha-ketoglutaric acid

Alpha-ketoglutaric acid binds cyanide and antagonizes cyanide-induced inhibition ofcytochrome oxidase. It is effective in treatment of mice, in combination with sodiumthiosulfate, but has never been studied in humans.8687

Naloxone

Cyanide in massive doses induces respiratory arrest though the inhibition caused byreleased endorphins. The opiate antagonist, naloxone, blocks the effects of theendorphins and thus can protect against cyanide intoxication. Massive doses of thisagent are needed for protection in animal models and human studies have not yet beenattempted.

Extracorporeal filtering

Hemodialysis may be combined with the ingredients of the cyanide antidote kit toincrease the speed of elimination of cyanide and metabolites.88 Charcoalhemoperfusion, combined with sodium nitrite and sodium thiosulfate, has also beenused for this purpose.89 These are totally anecdotal case reports and there are nostudies or case series that assess effectiveness of these methods.

Advantages and disadvantages of t reatments.

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 andthe exposure levels involved. These uncertainties make the likely clinical course in theabsence of antidotal therapy problematic. In the review of 48 cases by Chen and Roseof 48 cases that suggested a high effectiveness of the classic cyanide antidote kit, veryfew blood cyanide levels or other indexes of severity of toxicity were documented. Asnoted earlier, there is good evidence that antidotes are not always essential for asatisfactory outcome, even in the face of severe poisoning.


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SUMMARY TABLES

Inhalation of cyanide agents may cause:

1. Dryness and burning of the throat2. Air hunger3. Hyperpnea4. Apnea5. Seizures and coma6. Cardiovascular collapse.

Table 1

Variation of Childs Sodium Nitrite

Dose with Hemoglobin Concentration3

Hemoglobin Initial dose ofNaNO2mg/kg

Initial dose of 3%NaNO2 solutionml/kg

Initial dose of 25%sodium thiosulfateml/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.


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Hydrogen cyanide (AC)

Formula - HCN Molecular weight - 27.02

Chemical name - hydrogen cyanide or hydrocyanic acidCAS number 74-90-8Vapor density (compared with air) - 0.93Liquid density - 0.687Boiling point - 25.7

oC

Decomposition temperature - Above 65.50C (Forms explosive polymer on standing. Stabilized material

can be stored up to 65oC)

Rate of hydrolysis - Low under field conditionsStability 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 (MLD50) - Median lethal dosage varies widely with concentration because of therather high rate at which AC is detoxified by the body. For example, at 200 mg/m

3concentration, the

lethal dosage is approximately 2000 mg/min/m3, whereas at 150 mg/m

3, the lethal dosage is

approximately 4500 mg-min/m3

Median incapacitating dosage (ICt50) - 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


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Possible Antidotes For Cyanide Intoxication

AntidoteEfficacy and possiblecomplications Availability

PotentialUtility

Hydroxocobalamin (VitaminB12a)(+NaHS04) Kit

9394959697

No methemoglobinformedLow toxicityHigh CN affinity

France

USA: FDAapprovalpending

Post exposure

May have some pre-exposure use

Dicobalt ethylene diamine

tetra acetic acid (EDTA)(Kelocyanor)98

IV Risk: CardiacDysrhythmias angina,death

Europe:commercialUSA:Experimental

Post exposure only

4-Dimethylaminophenol

(4-DMAP) 99100

and similar molecules:

P-aminopropiophenone

(PAPP),101P-aminoheptanophenone

(PAHP),P-aminooctanoylphenone

(PAOP)102

IV, IMPossible MutagenLocal tissue necrosis

Marked methemoglobinTemperature , painPAHP (may be thesafest?)

Germany Post exposure

Stroma freemethemoglobin103 104 105

Experimental Not currentlyavailable

Postexposure andPrehospital high-riskpersonnel

Superactivated charcoal 106107

For oral exposure only. FDA approved Postexposure andPrehospital high-riskpersonnel

-adrenergic antagonists(chlorpromazine;

phenoxybenzamine) 108

Mechanisms uncertain FDA-approveddrugs

8-aminoquinoline analogs

of primaquine(e.g.,WR242511) 109

Methemoglobin formers

Pretreatment

Varies with

compound

Prehospital high-risk

personnel

Alpha-ketoglutaric acid 110111112113

Direct binding of cyanidewithout methemoglobinformationAnimal studies only

Experimental Insufficient evidence


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Targets of the antidotes

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


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References

1Borowitz JL, Kanthasamy AG, Isom GE. Toxicodynamics of cyanide. In Chemical Warfare Agents, edited

by SM Somani, San Diego, Academic Press, 1992;pp 209-236.

2Sykes 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.

3Wolnick KA, Fricke FL, Bonnin E et al. The Tylenol tampering incident Tracing the source. Anal Chem

1984;56:466A-470A, 474A.

4Sidell 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.

5Sidell 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.

6Brennan RJ, Waeckerle JF, Sharp TW, et al. Chemical warfare agents: emergency medical and

emergency public health issues. Ann Emerg Med 1999;34:191-204.

7Baskin SI. Zyklon. In: La Cleur W. Ed. Encyclopedia of the Holocaust. New Haven, Conn: Yale University

Press: 1998.

8Lowry 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.

9Alarie Y. The toxicity of smoke from polymeric materials during thermal decomposition. Am Rev Pharm

Toxicol 1985;25:325-347.

10Anderson RA, Harland WA. Fire deaths in the Glasgow area. III. The role of hydrogen cyanide. Med Sci

Law 1982;22:35-37.

11Levine MS, Radford MPH, Radford EP. Occupational exposures to cyanide in Baltimore fire fighters. J

Occup Med 1978;20:53-56.

12Montgomery R, Reinhart CF, Terril JB. Comments on fire toxicity. Comb Toxicol 1975;2:179-212.

13Sadoff L, Fuchs J, Hollander J. Rapid death associated with laetrile ingestion. JAMA 1978;239:1532.

14Anonymous. Controlled intravascular sodium nitroprusside treatment Brit J Med 1978;6140:784-785.

15Atkins D. Cyanide toxicity following nitroprusside induced hypotension. Can Anaesth Soc J 1977;24:651-

660.

16Vesey CJ, Cole PV, Simpson PJ. Cyanide and thiocyanate concentrations following sodium nitroprusside

infusion in man. Br. J Anaesth 1976;48:651-659.

17MacNamara BP. Estimation of the toxicity of hydrocyanide acid vapors in man. Edgewood Arsenal

Technical Report Number EB-TR-76023. 1976. Department of the Army.

18Sylvester DM, Hayton WL, Morgan RL Way JL. Effects of thiosulfate on cyanide pharmacokinetics in dogs.

Toxicol Appl Pharmacol 1983;69:265.


27/31


PA G E - 27-

19Hydrogen cyanide: A FOA briefing book. Accessed at http://www.opcw.nl/chemhaz/hcn.html 30 April

2004.

20Borak J. Pharmacologic mechanism of antidotes in cyanide and nitrile poisoning. [letter] J Occupational

and Environmental Health 1995;37:793-794.

21Burrows GE, Way JL. Antagonism of cyanide toxicity by phenoxybenzamine. Fed Proc 1976;35:533.

22Burrows GE, Way JL. Antagonism of cyanide toxicity by phenoxybenzamine. Fed Proc 1976;35:533. OP

CIT.

23Ballantyne B. Toxicology of cyanides. In Ballantyne B, Marrs TC, eds. Clinical and Experimental

Toxicology of Cyanides. Bristol: Wright; 1987:41-126.

24Vick JA, Froehlich HL. Studies of cyanide poisoning. Arch Int Pharmacodyn Ther 1985;273:314-322.

25Vick JA, Froelich HL. Studies on cyanide poisoning. Arch Int Pharmacodyn Ther 1985;273:314-322. OP

CIT.

26Hilmann B, Bardham KD, Bain JTB. The use of dicobalt edetate (Kelocyanor) in cyanide poisoning.

Postgrad Med J. 1974;50:171-174.

27Karalliedde 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.

28Blanc P, Hogan M, Malin K, Hryhorczuk D, Hessl S, Bernard B. Cyanide intoxication among silver

reclaiming workers. JAMA 1985;253:367-371.

29Osuntokun 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.

30Recommendations for protecting human health against potential adverse effects of long term exposure to

low doses of chemical warfare agents. MMWR 1988;37:72-74.

31Kirk RI, Stenhous NS. Ability to smell solutions of potassium cyanide. Nature (Lond) 1953;171:698-699.

32Fukumoto 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.

33Baud FJ, Barriot P, Toffis V, et al. Elevated blood cyanide concentrations in victims of smoke inhalation.

NEJM 1991;325:1761-1766.

34Bermudez RM, Cabrera CA. Treatment of burns. NEJM 1997;336:1392-1393.

35Fligner CL, Luthi R, Linkaityte-Weiss E, et al. Paper strip screening method for detection of cyanide inblood 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.

37Baud 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.

38Jacobs 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.


28/31


PA G E - 28-

39Peden 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.

40Edwards AC, Thomas ID. Cyanide poisoning [letter]. Lancet 1978; 1(8055)::92-93.

41Peden 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.

44Wright RO, Lewander WJ, Woolf AD. Methemoglobinemia: Etiology, pharmacology, and clinical

management. Ann Emerg Med 1999;34:646-656.

45Woolf AD, Chrisanthus K. On-site availability of selected antidotes: Results of a survey of Massachusetts

hospitals. Am J Emerg Med 1997;15:62-65.

46Dart 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.

47Van Heijst NP, Douze JMC, Van Kesteren RG, Van Bergen JEAM, Van Dijk A. Therapeutic problems in

cyanide poisoning. Clin Toxicol 1987;25:383-398.

48Van 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.

49Vick 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 Occupationaland Environmental Health 1995;37:793-794. OP CIT

51Borak J. Pharmacologic mechanism of antidotes in cyanide and nitrile poisoning. [letter] J Occupational

and Environmental Health 1995;37:793-794. OP CIT

52Way JL, Sylvester D, Morgan RL, et al. Recent perspectives on the toxicodynamic basis of cyanide

antagonism. Fundam Appl Toxicol 1984;4:S231-S239.

53Berlin CM Jr. The treatment of cyanide poisoning in children. Pediatrics.1970;46:793-796.

54Berlin CM. The treatment of cyanide poisoning in children. Pediatrics 1970;46:193-196.

55Weger NP. Treatment of cyanide poisoning with 4-DMAP. Experimental and clinical overview. Fundam

Appl Toxicol. 1983;3:387-396.

56Kiese M, Weger N. Formation of ferrihaemoglobin with aminophenols in the human for the treatment of

cyanide poisoning. Eur J Pharmacol 1969;7:97-105.

57Weger N. Aminophenols as antidotes to prussic acid. Arch Toxikol 1968;24:49-50. (In German).

58Vick JA, Froehlich H. Treatment of cyanide poisoning. J Toxicol Clin Exp 1988;25:125-138.


29/31


PA G E - 29-

59Ten 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.

60Litovitz 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.

63Way 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

64Mushett C. Antidotal efficacy of vitamin B12 a (hydroxocobalamin) in experimental cyanidepoisoning. Proc Soc Exp Biol Med.1952;81:234-237.

65Hall AH, Rumack BH. Hydroxycobalamin/sodium thiosulfate as a cyanide antidote. J Emerg Med.1987;5:115-121

66Bismuth C, Baud FJ, Djeghout H, et al. Cyanide poisoning from propionitrile exposure. J Emerg Med

1987;5:191-195.

67Hall AH, Rumack BH. Hydroxycobalamin/sodium thiosulfate as a cyanide antidote. J Emerg Med.

1987;5:115-121 OP CIT.

68Houeto P, Buneux F, Galliot-Guilley M, et al. Pharmacokinetics of hydroxocobalamin in smoke inhalation

victims. J Toxicol Clin Toxicol 1996;34:397-404.

69Houeto P, Buneux F, Galliot-Guilley M, et al. Monitoring of cyanocobalamin and hydroxocobalamin during

treatment of cyanide intoxication. [letter] Lancet 1995;246:1706-1707.

70Sauer 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.

72Cottrell JE, Casthele P, Brodie JD, et al. Prevention of nitroprusside-induced cyanide toxicity with

hydroxycobalamin. NEJM 1978;298:809-811

73Houeto 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.

74Evans CL. Cobalt compounds as antidotes for hydrocyanic acid. Br J Pharmacol. 1964:23:455-475.

75Antal J [Experimental studies on the treatment of cyanide poisoning.] Ung Arch Med 1894;3:117-128. (in

German)

76Paulet, G. Les chelats de cobalt dans le traitement de lintoxication cyanhydrique. Pathol Biol

1960;8:255-266. (in French)

77Vogel SN, Sultan TR, Ten Eyck RP. Cyanide poisoning. Clin Toxicol1981;18:367-383.


30/31


PA G E - 30-

78Hillman B. Bardhan KD, Bain JTB. The use of dicobalt edetate (Kelocyanor) in cyanide poisoning.

Postgrad Med J 1974:50:171-174.

79Rose CL, Worth RM, Kikuchi K, Chen KK. Cobalt salts in acute cyanide poisoning. Proc Soc Exp Biol

Med. 1965;120:780-783.

80Reynolds JEF, Prasad AB, eds. Dicobalt edetate (1033-p). In: Martindale: The extra Pharmacopoeia. 28

th

edition London, England: Pharmaceutical Press: 1982: 382.

81Dodds 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 Med1984;4:107-121.

83Hall AH, Rumack BH. Hydroxycobalamin/sodium thiosulfate as a cyanide antidote. J Emerg Med.

1987;5:115-121 OP CIT

84Way JL. Cyanide intoxication and its mechanism of antagonism. Ann Rev Pharmacol Toxicol1984;24:451-481.

85Kong A, Shen A, Burrows G, Sylvester D, Isom GE, Way JL. Effect of chlorpromazine on cyanide

intoxication. Toxicol Appl Pharmacol. 1983;71:407-413.

86Norris JC, Utley WA, Hume AS. Mechanism of antagonizing cyanide induced lethality by alpha-

ketoglutaric acid. Toxicol 1990;62:275-283.

87Yamamoto HA. Protection against cyanide-induced convulsions with alpha-ketoglutarate. Toxicol

1990;61:221-228.

88Wesson DE, Foley R, Sabatini S, et al. Treatment of acute cyanide intoxication with hemodialysis. Am J

Nephrol 1985;5:121-126.

89Krieg A, Saxena K. Cyanide poisoning from metal cleaning solutions. Ann Emerg Med 1987;16:582-584.

90Lam KK, Lau FL. An incident of hydrogen cyanide poisoning. Am J Emerg Med 2000;18:xxxx

91Dodds C, Mcknight C: Cyanide toxicity after immersion and the hazards of dicobalt edetate. Br Med J

1985;29 1:785-786.

92Walton DC, Witherspoon MG: Skin absorption of certain gases. J Pharmacol Exp Ther 1926;26:315-324.

93Hall AH, Rumack BH. Hydroxocobalamin/sodium thiosulfate as a cyanide antidote. Journal of Emergency

Medicine 1987:5:115121

94Cottrell JE, Casthely P, Brodie JD, et al. Prevention of nitroprusside-induced cyanide toxicity withhydroxocobalamin. New England Journal of Medicine 1978 ;298:809811.

95Brouard A, Blaisot B, Bismuth C.. Hydroxocobalamin in cyanide poisoning. Journal of Toxicology andClinical Experimentation 1987;7:155168

96Bismuth C, Baud FJ, Pontal PG. Hydroxocobalamin in chronic cyanide poisoning. Journal of Toxicology

and Clinical Experimentation 1988;8:3538.


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97Beregi JP, Riou B, Lecarpentier Y. Effects of hydroxocobalamin on rat cardiac papillary muscle. Intensive

Care Medicine1991;17:175177.

98Hillman B, Bardhan KD, Bain JTB. The use of dicobalt edetate (Kelocyanor) in cyanide poisoning.

Postgraduate Medical Journal 1974;50:171174.

99Weger NP. 1983. Treatment of cyanide poisoning with 4-DMAP--Experimental and clinical overview.

Fundamental and Applied Toxicology 3:387396.

100Bhattacharya R. Therapeutic efficacy of sodium nitrite and 4-dimethylaminophenol or hydroxylaminecoadministration against cyanide poisoning in rats. Human Experimental Toxicology 1995;14:2933

101Marrs 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

102Rockwood 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. Toxicologist1992;12:271.

103Ten 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 Toxicology1983;21:343358.

104Ten 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 Toxicology1986;23:477487.

105Breen PH, Isserles SA, Tabac E, et al. Protective effect of stroma-free methemoglobin during cyanide

poisoning in dogs.Anesthesiology 1996;85:558564.

106Andersen 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 toa lethal oral dose of potassium cyanide.Annals of Emergency Medicine1988;17:595598.

108Peterson JC, Cohen SD. Antagonism of cyanide poisoning by chlorpromazine and sodium thiosulfate.

Toxicology and Applied Pharmacology1985;81:265273.

109Steinhaus 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

Toxicology1990;10:345351.

110Dulaney MD, Brumley M, Willis JT, Hume AS.. Protection against cyanide toxicity by oral alpha-

ketoglutaric acid. Veterinary and Human Toxicology1991; 33:571575.

111Bhattacharya R, Vijayaraghavan R. Cyanide intoxication in mice through different routes and its

prophylaxis by -ketoglutarate. Biomedical Environmental Science1991;4:452459.

112Hume AS, Mozingo JR, McIntyre B, Ho IK.. Antidotal efficacy of alpha-ketoglutaric acid and sodium

thiosulfate in cyanide poisoning. Journal of Toxicology and Clinical Toxicology1995;33:721724.

113Norris JC, Utley WA, Hume AS.. Mechanism of antagonizing cyanide-induced lethality by -ketoglutaric

acid. Toxicology1990;62:275283.

Cyanide as a Weapon

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