Pediatric Annals

Cyanide as a Weapon of Terror

Joshua S Rotenberg, MD, MMS, FAAP

Abstract

Cyanide is a potent poison that has been recognized as a weapon since antiquity. As an open-air battlefield weapon, its use has been limited, but cyanide is a potent terrorist weapon when delivered under the right circumstances. Terrorists have used cyanide in the past and are likely to use this weapon again in the future.

A pediatrician should be able to recognize victims of cyanide poisoning and to initiate treatment. Cyanide poisoning can resemble poisoning by other chemical weapons, including nerve agents, and it can be lethal in minutes; however, an effective treatment exists and is widely available.

Cyanide, its salts, and related compounds are present in natural and synthetic processes. They are essential to many industries, and numerous compounds liberate cyanide during combustion or metabolism. While cyanide is ubiquitous, it is an uncommon cause of poisoning in children.

In the United States, only 8% of cyanide poisonings reported in 2000 occurred in children younger than age 19.1 In commercial and house fires, cyanide can be liberated during combustion, and it can act synergistically with carbon monoxide to cause fatalities. As military weapons, the key compounds of interest are volatile liquid hydrogen cyanide and cyanogen chloride.

Cyanide was first considered as a battlefield weapon in the Franco-Prussian War, but its derivatives were first deployed during World War I. However, it was not an effective battlefield weapon. At the concentrations created by the delivery systems used, cyanogen chloride and cyanogen bromide primarily caused upper airway and mucus membrane irritation. There were also significant problems with storage and transportation.

Cyanide compounds were more effective as indoor poisons. In World War II, the Nazis used hydrocyanic acid (Zyklon B) to murder millions in death chambers. In the 1980s, Syria and Iraq both allegedly used cyanide-based weapons.

While cyanide is a relatively ineffective poison for outdoor use, its indoor lethality makes it an attractive weapon of terror. When ingested in food or water, it can also be lethal. In 1995, cyanide allegedly was deployed as a terrorist weapon in the Tokyo subway (weeks after the Tokyo subway sarin attack). In this crude but functional attempt, a cyanide salt was allowed to mix slowly with an acid to create volatile hydrocyanic acid.2 The apparatus was constructed with household bags and left in a subway restroom.

Recent reports indicate that members of Al Qaeda have experimented with and even deployed cyanide-based weapons to foment terror. Cyanide also has been implicated in recently released videotapes of chemical tests by a terrorist organization.3

TOXICITY

Cyanide impairs the function of many enzymes through its affinity for iron in the ferric (Fe^sup 3+^) state. Mitochondrial cytochrome C oxidase (COX) is the most well studied and perhaps the most significant of these enzymes. Cyanide reversibly binds to the ferric ion of the heme moiety of COX, impairing oxidative phosphorylation. Consequently, oxygen cannot be used by the mitochondria. The toxin obstructs aerobic metabolism at the mitochondrial level in all organs. Organs with a high energy requirement suffer first (eg, brain and heart), and after a significant exposure, central respiratory arrest and myocardial depression ensues.

This disruption of oxidative phosphorylation also disturbs the oxidation/ reduction state, shifts the pyruvate-tolactate ratio to increase lactate production, and impairs the Krebs cycle. Further, many other enzymes are hemebased such as nitric oxide synthetase and superoxide dismutase. Finally, cyanide is a direct neurotoxin, disrupting cell membranes and encouraging excitatory injury in the central nervous system.

Treatment of cyanide exposure takes advantage of natural metabolic routes for detoxification. Both rhodanese and 3-mercaptopyruvate act as sulfur donors to cyanide to form thiocyanate, a less toxic compound. Thiocyanate is eventually…

Cyanide is a potent poison that has been recognized as a weapon since antiquity. As an open-air battlefield weapon, its use has been limited, but cyanide is a potent terrorist weapon when delivered under the right circumstances. Terrorists have used cyanide in the past and are likely to use this weapon again in the future.

A pediatrician should be able to recognize victims of cyanide poisoning and to initiate treatment. Cyanide poisoning can resemble poisoning by other chemical weapons, including nerve agents, and it can be lethal in minutes; however, an effective treatment exists and is widely available.

Cyanide, its salts, and related compounds are present in natural and synthetic processes. They are essential to many industries, and numerous compounds liberate cyanide during combustion or metabolism. While cyanide is ubiquitous, it is an uncommon cause of poisoning in children.

In the United States, only 8% of cyanide poisonings reported in 2000 occurred in children younger than age 19.1 In commercial and house fires, cyanide can be liberated during combustion, and it can act synergistically with carbon monoxide to cause fatalities. As military weapons, the key compounds of interest are volatile liquid hydrogen cyanide and cyanogen chloride.

Cyanide was first considered as a battlefield weapon in the Franco-Prussian War, but its derivatives were first deployed during World War I. However, it was not an effective battlefield weapon. At the concentrations created by the delivery systems used, cyanogen chloride and cyanogen bromide primarily caused upper airway and mucus membrane irritation. There were also significant problems with storage and transportation.

Cyanide compounds were more effective as indoor poisons. In World War II, the Nazis used hydrocyanic acid (Zyklon B) to murder millions in death chambers. In the 1980s, Syria and Iraq both allegedly used cyanide-based weapons.

While cyanide is a relatively ineffective poison for outdoor use, its indoor lethality makes it an attractive weapon of terror. When ingested in food or water, it can also be lethal. In 1995, cyanide allegedly was deployed as a terrorist weapon in the Tokyo subway (weeks after the Tokyo subway sarin attack). In this crude but functional attempt, a cyanide salt was allowed to mix slowly with an acid to create volatile hydrocyanic acid.2 The apparatus was constructed with household bags and left in a subway restroom.

Recent reports indicate that members of Al Qaeda have experimented with and even deployed cyanide-based weapons to foment terror. Cyanide also has been implicated in recently released videotapes of chemical tests by a terrorist organization.3

TOXICITY

Cyanide impairs the function of many enzymes through its affinity for iron in the ferric (Fe^sup 3+^) state. Mitochondrial cytochrome C oxidase (COX) is the most well studied and perhaps the most significant of these enzymes. Cyanide reversibly binds to the ferric ion of the heme moiety of COX, impairing oxidative phosphorylation. Consequently, oxygen cannot be used by the mitochondria. The toxin obstructs aerobic metabolism at the mitochondrial level in all organs. Organs with a high energy requirement suffer first (eg, brain and heart), and after a significant exposure, central respiratory arrest and myocardial depression ensues.

This disruption of oxidative phosphorylation also disturbs the oxidation/ reduction state, shifts the pyruvate-tolactate ratio to increase lactate production, and impairs the Krebs cycle. Further, many other enzymes are hemebased such as nitric oxide synthetase and superoxide dismutase. Finally, cyanide is a direct neurotoxin, disrupting cell membranes and encouraging excitatory injury in the central nervous system.

Treatment of cyanide exposure takes advantage of natural metabolic routes for detoxification. Both rhodanese and 3-mercaptopyruvate act as sulfur donors to cyanide to form thiocyanate, a less toxic compound. Thiocyanate is eventually excreted in the urine in a slow process. While this route is the most significant of the detoxification pathways, it is limited by availability of sulfur donors. The antidote sodium thiosulfate provides needed sulfur groups.

Cyanide also can undergo oxidative detoxification and combination with hydroxycobalamin (pro-vitamin B12). A small amount of unchanged cyanide is exhaled.4 Health care professionals should be aware of this latter route of detoxification. In any chemical exposure that direct mouth-to-mask ventilation is contraindicated and ventilatory systems should be filtered.

The symptoms and course of cyanide poisoning varies with the chemical form of cyanide, the state of the agent, and the route of exposure. Cyanide can cause toxicity as a vapor, as an ingested liquid, or through contact with a liquid. While a high concentration of inhaled cyanide may overcome a victim in seconds, a lower vapor concentration or an ingested dose may take minutes to manifest. Even at high concentrations, aerosolized cyanide is approximately one to two orders of magnitude less toxic than nerve agents such as sarin.

Regardless of the route of exposure, distribution is rapid. Serum levels fall soon after exposure is arrested. This physiological feature of cyanide illustrates both the futility of delayed testing for cyanide in the blood as well as the benefit of rapid evacuation from contaminated areas.

CLINICAL PRESENTATION

The typical toxidrome caused by a significant exposure consists of a rapid (minutes) clinical progression from hyperpnea and nervous system excitement (anxiety, restlessness) to loss of consciousness, seizures, apnea, and then death. Severely poisoned victims manifest respiratory failure without cyanosis. Mydriasis is a late finding. Less affected individuals may be asymptomatic or only exhibit hyperpnea. headache, dizziness, flushing, and tachycardia.

To complicate the differentiation of cyanide from nerve agent poisoning, cyanide also may activate the autonomic system, causing salivation, emesis, urination, and defecation. The characteristic odor of bitter almonds may be helpful, but it is only detectable by 40% to 60% of the population.5

Victims have been noted to have arterialized venous blood, as the body's dysfunctional mitochondria fail to extract available oxygen. A victim's blood, skin, and fundi can appear cherry red. Arterial blood gas analysis reveals a metabolic acidosis with a high anion gap. In addition, a high venous blood saturation of oxygen can suggest impairment in systemic oxygen extraction.

With lactate levels elevated, the differential diagnosis should include other causes of an anion gap acidosis (ie, methanol, uremia, ketoacidosis, paraldehyde, isoniazid, ethanol. salicylates). Carbon monoxide and hydrogen sulfide exposures prevent the oxidative phosphorylation in tissue by impairing oxygen delivery. In the context of a mass casualty situation, however, many of these entities can be quickly dismissed.

Blood cyanide levels have little role in the acute diagnosis and early management of cyanide poisoning. Erythrocytes carry most assayable cyanide. Whole blood cyanide levels must be processed expediently as levels decay with storage. The required time for processing of this test usually exceeds that available for treatment. A report of one patient found a close correlation between the decay of blood cyanide levels and serum lactate concentrations.6 Early samples of serum cyanide levels may be helpful for assessing the severity of exposure, epidemiological survey, and medicolegal reasons.

PEDIATRIC VULNERABILITIES

Pediatric vulnerabilities to cyanide derive from several unique physiological characteristics of childhood. Children may be more likely to be exposed to higher doses of cyanide vapor than adults because of their higher respiratory rates and higher surface-to-volume ratios. When a liquid contacts the skin, a child's thinner stratum corneum allows greater and more rapid systemic absorption.

Children exposed to cyanide may present with a constellation of symptoms that resembles those of adults. A review of a mass cyanide ingestion in Indian children reported the initial complaints were abdominal pain, nausea, restlessness, and giddiness. Cyanosis was frequently noted, but a cherry red color was not mentioned. Children with severe exposures were noted to be drowsy. In this series, the agent was unknown to medical personnel, and 8 of 10 victims recovered with supportive measures only.7

TREATMENT

The treatment of cyanide poisoning involves supportive care and a multistage antidote kit. Most medical centers stock only a handful of antidote kits. Several factors may complicate a mass casualty event, including limited numbers of antidote kits and the requirement for intravenous access to administer the antidote. It should be noted that guidance for the treatment of human cyanide poisoning is based on a small number of cases and series. Most therapeutic and pathophysiologic data are derived from animal models. Treatment is summarized in the Table.

Supportive Therapy

Supportive therapy alone may reverse the effects of cyanide even in apneic patients. Consequently, aggressive treatment should be initiated even when antidote kits are not available.

Topical decontamination after exposure to liquid cyanide should be accomplished before victims reach the clean treatment area. If not, health care professionals should don personal protective equipment and patients should be moved to an area with adequate ventilation. Victims' clothes should be removed and sealed in a bag, and their skin should be flushed with copious amounts of water.

Application of 100% oxygen augments any aerobic metabolism and antidotal function. Lactic acidosis can be corrected with aggressive intravenous hydration and sodium bicarbonate. Albumin can act like a detoxifying enzyme in blood, and infusion of colloid should be considered for volume expansion.

Seizures should be treated aggressively with anticonvulsants (eg, benzodiazepines). Activated charcoal can bind ingested cyanide salts that have not been absorbed by the gastrointestinal tract.

Antidotal Therapy

Chen et al.8 of the Lilly Corporation first introduced the cyanide antidote kit in 1933.8 The components of the kit had been individually examined since 1888, but these investigators were the first to report their synergism. Although a different company makes the antidote kit now, its components have remained unchanged. The treatment uses two agents to neutralize cyanide: nitrites and thiosulfates. Each kit can cost hundreds of dollars.

Table

TABLETreatment for Pediatric Cyanide Poisoning Victims

TABLE

Treatment for Pediatric Cyanide Poisoning Victims

Antidotal therapy should be instituted in victims with severe or rapidly progressing symptoms. Because cyanide poisoning manifests within an hour, those with clinical effects are identifiable early in the event.

Nitrites

Amyl nitrite and sodium nitrite oxidize iron to its ferric (Fe^sup 3+^) state to induce methemoglobinemia. Methemoglobin binds cyanide more avidly than COX, and thus cyanide is shifted away from the mitochondrial enzyme. Oxidative phosphorylation can be restored as cyanide is shifted to the intravascular compartment. In a typical adult, nitrite therapy should be administered while respecting the maximally tolerated methemoglobin level of 20% to 30%.9

Before an intravenous line is established, amyl nitrite pearls are crushed into the face mask during forced ventilation or into a reservoir of ventilatory tubing. This can produce a maximal concentration of methemoglobin of 5%. While small amounts of amyl nitrite can be introduced through the respiratory tract, this initial treatment may be sufficient to prevent cardiovascular collapse or reverse ischemic injury in the central nervous system. At the same time, amyl nitrite can induce vasodilation, marked by orthostatic hypotension, pallor, or headache.

With an intravenous line established, sodium nitrite can be initiated. Sodium nitrite (30 mg/mL) can be administered intravenously in an adult over a period of 5 to 15 minutes. In a child with a hemoglobin of 12 g/dL, one should administer 0.33 mL/kg of the 3% solution.10 For every change in hemoglobin of 1 g/dL, the dose of sodium nitrite should be adjusted by 0.03 mL/kg. The dose of sodium nitrite can be given at one half of the original dose in 30 minutes as needed.

Nitrite treatment has two significant limitations in children: methemoglobinemia and hypotension. One should anticipate the need to monitor and treat hypotension, which can be reversed by fluid infusion or vasopressors (eg, dopamine).

A fatal case of methemoglobinemia was reported by Berlin10 as an untoward effect of treatment of cyanide poisoning in a 17-month-old African- American boy. Before treating with nitrites, professionals should inquire about conditions that predispose a victim to anemia. Clinicians should adjust cyanide antidotes in infants at their physiological nadir of hemoglobin levels (approximately 2 months). Co-oximeters can assay levels of methemoglobin, and when oxygen delivery is impaired, this condition can be treated. Methemoglobin levels in children should be kept below 20%.

Thiosulfates

Sodium thiosulfate acts as a sulfur donor. It is packaged in the standard cyanide antidote kit in 50 mL ampules. In an adult, 12.5 g is administered intravenously (50 mL of the 250 mg/mL solution). In children weighing less than 30 kg with a hemoglobin of 12 mg/dL, 1.65 mL/kg (250 mg/mL) should be administered intravenously.10 The dose of sodium thiosulfate should be adjusted by 0.15 mL/kg for each hemoglobin change of 1 g/dL. Consequently, in a child with a hemoglobin level of 10 mg/dL, 1.35 mL/kg of sodium thiosulfate should be administered.

Thiosulfate has a short biological half-life and a small volume of distribution. Consequently, a second course at half of the original dose also can be administered within 30 minutes as needed.

Other Therapies

While 100% oxygen at ambient pressure has a small but clinically relevant effect, hyperbaric oxygen is still debated as an effective treatment for cyanide. Dicobalt edetate has been used as a chelator, but its untoward effects are serious. Hypotension, decreased cerebral blood flow, cardiac dysrhythmias, and angioedema have been noted.

Hydroxycobalamin (vitamin B12) is used routinely in France as an antidote because it reportedly has a low toxicity even at high doses. Cyanide binds to hydroxycobalamin more avidly than to COX and works synergistically with thiosulfates. Urticaria and tachyphylaxis have been reported occasionally following administration of hydroxycobalamin. The main limitation to its use is cost and the amount needed for treatment (up to 4 g in an adult with a life-threatening cyanide exposure).

Chlorpromazine has been reported as a potential treatment with an unclear mechanism of action.11 Alpha-ketoglutarate is one of many other compounds under investigation as an alternative therapy.

Follow-Up

Neurological morbidity including hyperreflexia, dystonia, and parkinsonism has been reported in survivors of severe cyanide poisoning. Extensive bilateral necrosis of the globus pallidi and putamina has been reported.12-14 Some have attributed this damage to hypoxia or hypotension, and animal models of cyanide poisoning with hypotension have produced wider damage (changes in deep cerebral white matter, corpus callosum, pallidum, and substantia nigra).15

Neurodevelopmental morbidity may be noted soon after the event or later if damage is more localized. Carbon monoxide exposures in children have been noted to cause chronic psychological sequelae years after exposure.16 A specialist should evaluate any child with even mild neurodevelopmental sequelae. Magnetic resonance imaging and magnetic resonance spectroscopy should be considered to evaluate the basal ganglia.

CONCLUSION

Cyanide is an ancient poison that has come to attention as a potential terrorist weapon. Exposures can occur by inhalation or ingestion. Children may be more likely to receive toxic doses and to suffer untoward effects. Victims may present anywhere along a spectrum of symptoms that combine signs of respiratory and central nervous system dysfunction.

When recognized, cyanide exposure can be treated with a combination of supportive care, oxygen, nitrites, and thiosulfates. Because of the risk of excess methemoglobinemia, dosing of nitrite antidotes needs to reflect the child's age and the possibility of anemia.

Survivors should be monitored for cognitive and neurological sequelae. To limit morbidity and mortality following an attack with cyanide, health care professionals should be aware of how to manage such an attack, and institutions should have realistic plans for children. With prompt and aggressive therapy most individuals with mild or moderate exposure have no long-term sequelae.

REFERENCES

1. Litovitz TL, Klein-Schwartz W. White S, et al. 2000 annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med. 2001;19:337-395.

3. Robertson N. Disturbing scenes of death show capability with chemical gas.2002;August 19. Available: http://www.cnn.com/2002/US/ 08/19/terror.tape.chemical/.Accessed March 17, 2003.

2. Brackett DW. Holy Terror: Armageddon in Tokyo. New York. NY: Weatherhill Inc; 1996.

4. Marrs TC. Antidotal treatment of cyanide poisoning. Adverse Drug Read Acute Poisoning Rev. 1988;7:179-206.

5. Kirk RL, Stenhaus NS. Ability to smell solutions of KCN. Nature. 1953;171:698-699.

6. Baud FJ, Borron SW, Bavoux E. Astier A. Hoffman JR. Relation between plasma lactate and blood cyanide concentrations in acute cyanide poisoning. BMJ. 19966;312(7022):26-27.

7. Prajapati NC, Puri RK, Sarangi MP, Yadav S, Khalil A. Potassium cyanide poisoning. Indian Pediatr. 1992;29:903-905.

8. Chen KK, Rose CL, Clowes GH. Comparative values of several antidotes in cyanid (sic) poisoning. Am J Med Sci. 1934;188:767-781.

9. Kerns WP. Cyanide and Hydrogen Sulfide in Goldfrank's Toxicologic Emergencies. 7th ed. New York: McGraw Hill Professional; 2002.

10. Berlin CM. The treatment of cyanide poisoning in children. Pediatrics. 1970;6:793-796.

11. Pettersen JC, Cohen SD. Antagonism of cyanide poisoning by chlorpromazine and sodium thiosulfate. Toxicol Appl Pharmacol. 1985;81:265-273.

12. Carella F. Grassi MP, Savoiardo M, Contri P, Rapuza B. Mangoni A. Dystonic-parkinsonian syndrome after cyanide poisoning: clinical and MRI findings. J Neurol Neurosurg Psychiatry. 1988:51:1345-1348.

13. Uitti RJ, Rajput AH, Ashenhurst EM, Rozdilsky B. Cyanide-induced parkinsonism: a clinicopathologic report. Neurology. 1985:35: 921-925.

14. Messing B. Storch B. Computer tomography and magnetic resonance imaging in cyanide poisoning. Eur Arch Psychiatry Neurol Sci. 1988:237:139-143.

15. Funata N. Song SY, Okeda R, Funata M, Higashino F. A study of experimental cyanide encephalopathy in the acute phase - physiological and neuropathological correlation. Acta Neumpathol (Bert). 1984:64:99-107.

16. Klees M. Heremans M, Doughan S. Psychological sequelae to carbon monoxide poisoning in the child. J Toxicol Clin Exp. 1985;5: 301-307.

TABLE

Treatment for Pediatric Cyanide Poisoning Victims

10.3928/0090-4481-20030401-07

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