Cyanide as a Chemical Weapon: A Review Charles Stewart MD FACEP FAAEM

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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 cyanide’s 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 agent’s irritating properties to the mucous membrane. Cyanogen chloride’s 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 “People’s 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) PAGE - 2-

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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 1980’s. 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.

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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 smoker’s 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 μg/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

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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 inhalation19 Concentration (mg/m3) 300 200 150 120-l50 50-60 20-40

Effect lethal within seconds Lethal after 10 minutes Lethal after 30 minutes Highly dangerous (fatal) after 30-60 mm. Endurable for 20 mm to 1 h without effect 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) [C•t]. In high concentration, the C•t 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 (LC•t50 2500-500 mg/min/m3). The median lethal dose is about twice this level for the most resistant individuals. The LC•t50 for cyanogen chloride is about 1.1 g/min/m3. At low concentrations, the C•t 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 (LD50) is 1 mg/kg for hydrogen cyanide. The estimated LD50 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. PAGE - 5-

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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 (Fe3+) 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 a3 (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.

ADP

ATP O2 and H+

cyt c Cu

cyt a

cyt a3 H2O

Cytochrome c oxidase (cytochrome aa3)

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

ADP

ATP O2 and H+

cyt c

cyt a

cyt a3

Cytochrome c oxidase

Cu H2O

(cytochrome aa3)

CN 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. PAGE - 6-

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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 cyanide’s lethal effects.24 The observation that phenoxybenzamine, an alphaadrenergic 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. PAGE - 7-

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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 patient’s 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.

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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

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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 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 patient’s 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 agent’s 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

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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

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O2

NO2Lungs

Hb (Fe2+)

metHb (Fe3+)

HbO2 (Fe2+)

CNmetHb

Tissues

O2

CNcyt a3 (Fe2+ and Fe3+)

cyt a3 - CN

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

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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.

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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 # 619-60-32 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 PAGE - 14-

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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.

O2

NO2Lungs

metHb (Fe3+)

HbO2 (Fe2+)

Hb

CNmetHb

Tissues

O2 SCN- + SO32-

CN-

+

Na2S2O3

rhodanese

cyt a3 2+

(urine)

(Fe

cyt a3 - CN 3+

and Fe )

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). 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.

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(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 manufacturer’s 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. PAGE - 16-

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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

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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.

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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 firefighter’s 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.

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SUMMARY TABLES Inhalation of cyanide agents may cause: 1. 2. 3. 4. 5. 6.

Dryness and burning of the throat Air hunger Hyperpnea Apnea Seizures and coma Cardiovascular collapse.

Table 1 Variation of Child’s Sodium Nitrite Dose with Hemoglobin Concentration3 Hemoglobin

Initial dose of NaNO2 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.

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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 - 25.7oC Decomposition temperature - Above 65.50C (Forms explosive polymer on standing. Stabilized material can be stored up to 65oC) 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 (MLD50) - 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/m3 concentration, the lethal dosage is approximately 2000 mg/min/m3, whereas at 150 mg/m3, 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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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 20oC Boiling point - 12.8oC Decomposition temperature - Above 100oC Rate of hydrolysis - Very low Hydrolysis products - HCl and CNOH Stability in storage - Stable at 65oC for 30 days. Tends to undergo condensation or polymerization in storage to form the solid compound 2,4,6-trichloro-s-triazine, C3N3Cl3 (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/m3 Same as cyanide Median lethal dose (MLD50) -11,000 mg-min/m3 Rate of detoxification - 0.02 - 0.1 mg/kg/min Median incapacitating dose (ICt50) - 7000 mg-min/m3 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

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C Y AN I D E T O X I C I TPossible Y R E V I E WAntidotes

For Cyanide Intoxication Availability

Potential Utility

Hydroxocobalamin (Vitamin No methemoglobin formed B12a) Low toxicity (+NaHS04) Kit 93 94 95 96 97 High CN affinity

France

Post exposure

USA: FDA approval pending

May have some preexposure 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

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

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

Direct binding of cyanide without methemoglobin formation Animal studies only

Experimental

Insufficient evidence

Antidote

and similar molecules: P-aminopropiophenone (PAPP),101 P-aminoheptanophenone (PAHP), P-aminooctanoylphenone (PAOP)102

107

111 112 113

Efficacy and possible complications

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

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