STEVEN I. BASKIN, PHARM.D., PH.D., FCP, FACC, DABT, FATS*; AND THOMAS G. BREWER, M.D., FACP†
*Pharmacology Division, U.S. Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, Maryland 21010-5425
†Colonel, Medical Corps, U.S. Army; formerly, Experimental Therapeutics Division, Walter Reed Army Institute of Research, Washington, D.C. 20307-5100; currently, Commander, U.S. Army Medical Component, Armed Forces Research Institute of Medical Sciences, APO Area Pacific 96546, 315/6 Rajvithi Road, Bangkok 10400, Thailand
Cyanide, long considered a toxic, deadly substance, has been used as a poison for thousands of years. It was not highly successful as a chemical warfare agent in World War I, possibly because of the way it was delivered. The effects of a high dose of cyanide are quick, and death occurs within minutes. Antidotes are effective if administered in time.
Cyanide is ubiquitous. It is present in some foods, in the products of combustion of synthetic materials, and is widely used in industry. Much of the cyanide used is in the form of salts, such as sodium, potassium, or calcium cyanide. The cyanides of military interest are the volatile liquids hydrocyanic acid (hydrogen cyanide, HCN; North American Treaty Organization [NATO] designation: AC) and cyanogen chloride (NATO designation: CK) (Table 10-1).
Although substances containing cyanide had been used for centuries as poisons, it was not until 1782 that cyanide itself was identified. It was first isolated by the Swedish chemist Scheele, who later may have died from cyanide poisoning in a laboratory accident.
Since the days of ancient Rome, cyanide and the derivatives of this highly toxic substance have been used as weapons.1 Nero used cherry laurel water, which contains cyanide as its chief toxic component, to poison members of his family and others who displeased him. Napoleon III proposed the use of cyanides to enhance the effectiveness of his soldiers’ bayonets during the Franco–Prussian War.
During World War I, in late 1915 and early 1916, the French were the only proponents for using cyanide and its derivative, hydrocyanic acid. This was made by distilling a concentrated solution of potassium cyanide with dilute sulfuric acid. Its use, however, proved to produce less than its desired effect. A highly volatile gas and lighter than air, hydrocyanic acid persisted for only a few minutes in the open air; this made it difficult to disperse a lethal concentration (also, the munitions used had a small payload). The effects of cyanide were not cumulative. In addition, the Germans, on learning of its use, equipped their troops with a mask that was capable of filtering out the gas. These combined factors made hydrocyanic acid less effective as a weapon.
About September 1916, the French tried another cyanide-based poison, cyanogen chloride, which is heavier and less volatile than hydrocyanic acid and which had a cumulative effect on its victims. Cyanogen chloride was produced by chlorinating a saturated solution of potassium cyanide at 0°C (32°F). Its toxicity was similar to that of hydrocyanic acid, but cyanogen chloride was more effective at low concentrations (it irritated the eyes and lungs). Cyanogen chloride also had a delayed toxic effect similar to such lung irritants as chlorine and phosgene. At high concentrations, cyanogen chloride is capable of killing by rapidly paralyzing the respiratory system’s nerve center.2
At about the same time that the French launched cyanogen chloride, the Austrians introduced their own poisonous gas, which was derived from potassium cyanide and bromine. The resulting cyanogen bromide was highly volatile, yet it had only a quarter of the volatility of hydrocyanic acid and was less toxic. Cyanogen bromide had a strong irritating effect on the conjunctiva and on the mucous membranes of the respiratory system; however, because it corroded metals and was unstable in storage (gradually polymerizing into a toxicologically inert substance), the Austrians abandoned its use.2
During World War II, the Nazis employed hydrocyanic acid adsorbed onto a dispersible pharmaceutical base (Zyklon B) to exterminate millions of civilians and enemy soldiers in the death camps.3,4 Zyklon B was a fumigant and rodenticide. One of its uses in the United States and other countries was to rid ships of rodents.
In the late 1980s, reports indicated that cyanide-like agents may have been used against the inhabitants of the Syrian city of Hama5 and the inhabitants of the Kurdish city of Halabja, Iraq,6 and possibly in Shahabad, Iran, during the Iran–Iraq War.7 Based on this recent history, acute cyanide poisoning continues to constitute a threat for U.S. soldiers in future conventional or nonconventional conflicts.
There has been little use of cyanide by the military; most of the information on cyanide poisoning has been from civilian experience in poisoning, fires, and industrial accidents. Most people probably contact cyanide in some form almost every day. Hundreds of thousands of tons of cyanide are manufactured annually in this country. Cyanide is used in many chemical syntheses, electroplating, plastics processing, gold and silver extraction, tanning, metallurgy, and as a fumigant. Cyanides are in some foods; are pyrolysis products of many substances; and have gained notoriety for their use in executions, homicides, and suicides.
Cyanide poisoning has been reported8 from eating chokecherries, bitter almonds, and apricot pits. In addition, cyanide is found in lima beans and cassava beans and roots. Cassava is a staple in certain countries and is blamed for the high incidence of tropical ataxic neuropathy in those areas.
Combustion of synthetic products that contain carbon and nitrogen, such as plastics and synthetic fibers, releases cyanide. Cigarette smoke contains cyanide; the nonsmoker averages 0.06 µg/mL of cyanide in blood, whereas the smoker has 0.17 µg/mL.9 The effects of cyanide and of carbon monoxide, also formed in fires, are additive because they both contribute to tissue hypoxia by different mechanisms. The two gases are major causes of combustion-related fatalities.10 In residential fires, cyanide poisoning may be more significant than has previously been appreciated. The short half-life of cyanide in blood contributes to the low concentrations of cyanide found in fire victims when blood is drawn after the victims reach the hospital.
From April 1988 through April 1989, a team of French investigators11 collected samples—on the scene—from 109 victims of residential fires in and around Paris, France. The data they gathered were compared with data from a control group (N = 114) of individuals whose injuries were not caused by fire.
In addition, cyanide is used by governments, terrorists, corporations, and individuals to achieve various economic, beneficial, humanitarian, or harmful ends:
Although cyanide is known to bind and inactivate several enzymes, it is thought to exert its ultimate lethal effect of histotoxic anoxia by binding to the active site of cytochrome oxidase (Figure 10-1), thereby stopping aerobic cell metabolism18,19 after an initial effect on excitable tissue. The binding to the cytochrome oxidase can occur over minutes. A more rapid effect appears to occur on neuronal transmission. No antagonists are known for the latter reaction, although it appears to be feasible to develop competitive antagonists for cyanide at a cytochrome oxidase–binding site.20
| Cyanide is readily diffusible through
epithelium. This property contributes to its lethal toxicity after
inhalation of hydrogen cyanide (HCN) gas (the usual route of military
exposure), ingestion of cyanide salts or cyanogens, or percutaneous
absorption of cyanide from high-concentration solutions. Because
cyanides are present at low concentrations in several naturally
occurring environmental sources, it is not surprising that most animals
have intrinsic biochemical pathways for detoxification of the cyanide
The most important route of cyanide excretion is by formation of thiocyanate (SCN–), which is subsequently excreted in the urine.17 Thiocyanate possesses a less inherent toxicological hazard than cyanide, cyanate, or isocyanate. Thiocyanate formation is catalyzed directly by the enzyme rhodanese (EC 188.8.131.52) and indirectly via a spontaneous reaction between cyanide and the persulfide sulfur products of the enzymes 3-mercaptopyruvate sulfurtransferase (EC 184.108.40.206)21 and thiosulfate reductase (EC number unassigned) (see Figure 10-1). The mechanisms of all three enzymes22 as well as the pharmacokinetics of thiocyanate formation23 have been studied. Although 3-mercaptopyruvate functions to convert cyanide to this cyanate, its instability and sulf-auto-oxidation at a basic pH may mask this effect.24 The enzymatic routes are efficient but have an insufficient capacity for detoxification in acute poisoning because of lack of sulfur donors. The mitochondrial sulfurtransferase reactions are exploited by the administration of sodium thiosulfate (used in therapy and discussed later in this chapter) in the treatment of acute poisonings. It is still not known with any certainty, however, what specific endogenous sulfur sources participate in the formation of thiocyanate from cyanide.25
A minor route of metabolism is the oxidation of cyanide to cyanate (CNO–), which occurs via enzymatic and nonenzymatic pathways. The interaction of cystine and cyanide to form 2-amino thiazoline 4-carboxylic acid and its tautomer accounts for approximately 20% of cyanide metabolism. This increases with toxic doses of cyanide. However, the protection conferred by forming cyanate derivatives is limited because of the cell’s inability to utilize oxygen during cyanide intoxication.
Combined, these metabolic routes detoxify 0.017 mg of cyanide per kilogram of body weight per minute in the average human. Cyanide is one of the few chemical agents that does not follow Haber’s law, which states that the Ct (the product of concentration and time) necessary to cause a given biological effect is constant over a range of concentrations and times. For this reason, the LCt50 (the vapor or aerosol exposure that is lethal to 50% of the exposed population) for a short exposure to a high concentration is different from a long exposure to a low concentration.
Cyanide Pharmacokinetics and Pharmacodynamics
Cyanide appears to display first-order kinetics during the period of initial toxicity.23 The volume of distribution for cyanide appears to change as the blood levels of the chemical change,26 but these alterations probably reflect the marked intracellular sequestration of the molecule. Animal studies27,28 show a differential disposition of inhaled HCN, with the highest tissue levels found in the lung, heart, and brain. These data seem to corroborate the evidence from other animal studies and from clinical reports that emphasize the importance of these organs in cyanide toxicity. Ingestion of cyanide results in much higher levels in the liver than does inhalation; this is a useful differential point in forensic investigations. Cyanide also has wide-ranging cardiovascular effects, including a poorly understood increase in vascular resistance in the early phases of poisoning29 and a marked increase in cerebral blood flow in dogs.30
Data from rodent studies suggest that a single, acute administration of a cyanide salt leads either to death or to complete recovery. However, data from HCN inhalational studies in dogs, rabbits, monkeys, and humans suggests that death may be delayed for up to 8 days.31,32 The neurological sequelae of cyanide intoxication may be delayed for up to a year.1 These delayed changes in regional sensitivities of the brain are thought to be due to hypoxic stress and are analogous to those seen following sublethal carbon monoxide poisoning.
Although they are generally considered to be very toxic substances, when compared with other lethal chemical warfare agents, cyanides are among the least toxic. The LCt50 for hydrogen cyanide (hydrocyanic acid) is generally stated to be 2,500–5,000 mg•min/m3; for cyanogen chloride, about 11,000 mg•min/m3. (Comparable values for the nerve agents are 10–200 mg•min/m3; for sulfur mustard, 1,500 mg•min/m3; and for phosgene, 3,000 mg•min/m3.)
The estimated intravenous dose that is lethal to 50% of the exposed population (LD50) of hydrogen cyanide for man is 1.0 mg/kg, and the estimated LD50 for liquid on the skin is about 100 mg/kg.
The effects from cyanide poisoning are those of progressive histotoxic tissue hypoxia (Figure 10-2). The symptoms, signs, and physical findings are directly related to the dose of cyanide, the route of exposure, and the type of cyanide compound. In addition to the effects described below, cyanogen chloride also produces irritation of the eyes and mucous membranes similar to that produced by riot control agents.
On a military battlefield, casualties will be from exposure to cyanide gas; this can be fatal within minutes after exposure to high concentrations. An initial hyperpnea (15 sec after exposure), due to the effect of cyanide on the chemoreceptor bodies, is closely followed by a loss of consciousness (30 sec after exposure). This progresses to apnea (3–5 min after exposure), cessation of cardiac activity (5–8 min after exposure), and death.
After exposure to lower concentrations, or exposure to lethal amounts via the oral or percutaneous routes, the effects are slower to develop. For example, after ingestion of a lethal dose of a cyanide salt, the casualty might have 15 to 30 minutes of survival time during which an antidote could be administered.
Prominent early signs and symptoms of cyanide poisoning include a transient hyperpnea, headache, dyspnea, and findings of general central nervous system (CNS) excitement, including anxiety, personality changes, and agitation progressing to seizures.33 Diaphoresis, flushing, weakness, and vertigo may also be present. Late-appearing indications of CNS depression, such as coma and dilated, unresponsive pupils, are prominent signs of cyanide intoxication.33–35 These signs are not specific for cyanide poisoning, which makes the distinction from other types of poisoning very difficult without a history of exposure. The telltale odor of bitter almonds cannot be used as a guide because 40% to 60% of the population is unable to detect the odor.36
Because the toxic effect of cyanide is to block tissue uptake and utilization of oxygen, the casualty is transiently flushed and may have other, related signs of poor tissue oxygen extraction. For example, funduscopic examination shows an equally bright red color for retinal arteries and veins because of poor oxygen extraction. Increased oxygenation of venous blood is also responsible for a “cherry-red” skin color, but this sign may not always be present.
Relevant laboratory findings include an early decreased arteriovenous difference in the partial pressure of oxygen (PO2) with progressive lactic acidosis.
Timely measurements of blood and urine concentrations for suspected intoxicants are useful in guiding clinical therapy, especially when there is toxicity associated with the treatment agents. Unfortunately, analysis of cyanide in biological fluids is a difficult task for a variety of reasons.37 Also, measurements of blood cyanide concentrations are almost never available during the treatment phase. Blood concentrations of cyanide and associated clinical effects are shown in Table 10-3.
Cyanide concentrations in tissue, such as liver, lung, spleen, and heart, may be more accurate indicators of the blood cyanide intoxication levels. Estimates of tissue levels are necessary adjunctive studies in forensic cases.38 For details on collecting and analyzing blood and tissue for cyanide, see Assay Techniques for Detection of Exposure to Sulfur Mustard, Cholinesterase Inhibitors, Sarin, Soman, GF, and Cyanide, Technical Bulletin Medical 296.39
Principles of Therapy
An understanding of the toxicology and pathophysiology of cyanide poisoning leads directly to the principles of therapy: eliminate further exposure, and institute supportive and specific antidotal therapy. (The specific antidotes are discussed separately in the section that follows.) In addition to the difficulties of diagnosing cyanide poisoning, each of the specific antidotal therapies discussed in this chapter has its own inherent toxicity. This knowledge should temper their use in the typical field medical treatment facility and other emergency setting.
Elimination of Further Exposure
The first principle of therapy is the obvious one: eliminate any potential source of continuing cyanide poisoning:
|Following these steps can significantly decrease the amount of poison
that has to be eliminated from the body.40
Possibly the most important elements of therapy are general supportive actions, which, by themselves, can effect the recovery of most casualties without further risk from specific antidotal therapy.41 They are probably the only indicated therapies for casualties of cyanide poisoning who arrive conscious at the emergency medical treatment station.
As early as 1840, Blake42 found that the lethal effects of cyanide are neutralized by mechanical resuscitation. The use of hyperbaric oxygen in cyanide intoxication is still controversial. Supplemental oxygen with or without assisted ventilation clearly augments the effect of specific antidotes in animal studies; however, despite encouraging reports,43,44 there is inconclusive evidence of further benefit from the use of hyperbaric oxygen.
Lactic acidosis resulting from anaerobic metabolism should be treated by intravenous administration of sodium bicarbonate, and seizures should be controlled by the administration of anticonvulsants such as diazepam.45 Because correction of deficiencies in tissue perfusion and oxygenation is the ultimate goal of supportive therapy and is also important for the success of specific antidotal therapy, it is critically important to maintain an effective cardiac rhythm; this can be accomplished with cardiopulmonary resuscitation, if necessary, in the early stages of treatment.
Specific Antidotal Therapy
Casualties with advanced toxicity from a large amount of cyanide may require specific antidotal therapy in addition to the vigorous supportive therapy outlined above. The recommended agents or components of specific antidotal therapies for cyanide poisoning vary according to country and medical custom (Table 10-4). This diversity seems to be based, in part, on where the drugs were initially developed and used. The aims of the recommended therapies are generally similar, however, in that one drug is given for immediate relief from the histotoxic effect of cyanide complexed with cytochrome oxidase.
In most of the regimens discussed below, the action of displacing cyanide from cytochrome oxidase is accomplished by the formation of methemoglobin. Methemoglobin removes cyanide from the extracellular fluid space and, by so doing, displaces cyanide from the intracellular fluid. The second component of most regimens is sodium thiosulfate, which is given as a specific antidote to augment the systemic clearance of cyanide via thiocyanate formation by sulfur transferases.
The clinical use of most antidotes is based on animal experiments46 and on extrapolations made from a small number of clinical cases. Comparing results from animal studies has limitations because of the differences in experimental design from one study to another as well as marked interspecies differences in cyanide and drug metabolism. Moreover, the studies were not designed to resemble the usual emergency medical or battlefield scenario. The disparity of antidotes for cyanide is due to the following factors47,48:
Drugs Used in the United States
Amyl nitrite and sodium nitrite, with or without sodium thiosulfate, are used as antidotes for cyanide.49 The antidotal action of amyl nitrite was first noted as early as 1888.50
The oxidized form of heme iron (Fe3+) in methemoglobin has a higher binding affinity for cyanide than does cytochrome oxidase. The preferential binding of cyanide to methemoglobin to form cyanomethemoglobin frees cytochrome oxidase to resume its role in aerobic metabolism.51 In the United States and other countries, sodium nitrite has been used as the methemoglobin-inducing drug of choice.
In addition to methemoglobin formation, both sodium and amyl nitrite cause significant vasodilation, which warrants careful monitoring of blood pressure. Marked vasodilation with orthostatic hypotension, dizziness, and headache, in addition to the unpredictable levels of methemoglobin formed,52 limit the utility of amyl nitrite in an upright casualty. Therefore, if a casualty is conscious and able to stand, he should not receive any nitrite. These factors, together with other concerns, have caused amyl nitrite to be removed from the cyanide antidote kit in the U.S. Army formulary for field units.
Sodium nitrite is available in the Lilly Cyanide Antidote Kit (manufactured by Eli Lilly and Company, Indianapolis, Ind.) in 10-mL ampules containing 300 mg for intravenous administration. (The kit also contains amyl nitrite encased in glass “pearls,” which are meant to be broken so the drug can be inhaled.) The solution of sodium nitrite (30 mg/mL) should be given to an adult intravenously over 5 to 15 minutes, with careful monitoring of blood pressure. A single dose is sufficient to raise the methemoglobin level to 20% in an adult,53 and a second dose, up to half as large as the initial one, can be given. Methemoglobin levels should be monitored if possible and kept below 35% to 40%, the range that is associated with oxygen-carrying deficits caused by methemoglobin itself.54
Because most automated clinical analyzers do not detect cyanomethemoglobin, the residual normal hemoglobin capable of oxygen transport can be overestimated by measuring total hemoglobin only. Methemoglobin-inducing substances should not be given to fire victims, even if cyanide intoxication is suspected, because neither methemoglobin nor carboxyhemoglobin (formed by carbon monoxide) transport oxygen. Alternative therapy in this situation consists of administering oxygen, thiosulfate, and other standard supportive measures.
In children, sodium nitrite can cause lethal methemoglobin levels if the dose is too high. The recommended dose for children is 0.33 mL of the 10% solution per kilogram of body weight.34,55
Some data indicate that nitrites exert their action by a mechanism other than methemoglobin formation. It has been suggested that the protective effect is due to the vasodilating effect of nitrite.52 Several a-adrenergic antagonists (eg, chlorpromazine, promethazine, promazine, and phenoxybenzamine) that cause vasodilation also antagonize cyanide toxicity.56,57 Further information is needed to determine the mechanism or mechanisms by which chlorpromazine and phenoxybenzamine reverse cyanide intoxication.57
Several alternative methemoglobin-forming drugs that have different pharmacological properties from sodium nitrite have been investigated and used in other countries (see Table 10-4).
Other Methemoglobin-Forming Drugs
4-Dimethylaminophenol (4-DMAP), p-amino-propiophenone (PAPP), p-aminoheptanoylphenone (PAHP), and p-aminooctanoylphenone (PAOP) are also methemoglobin-forming compounds that have protective effects against cyanide. 4-DMAP was proposed as a fast-acting antidote with low toxicity.58,59 This German-developed compound is used in the German military and by the civilian population. In humans, intravenous injection of 4-DMAP (3 mg/kg) can produce a level of 15% methemoglobin within 1 minute.60 In dogs, a dose of 4-DMAP that produces a 30% level of methemoglobin will save animals that have received 2 to 3 LD50 of cyanide.61
The disadvantages of 4-DMAP are (1) the appearance of necrosis in the area of injection after intramuscular administration and (2) the possibility that extremely high levels of methemoglobin may occasionally result. Increases in pain, fever, and muscle enzymes also occur after intramuscular administration of the drug. 4-DMAP has been reported to produce positive results in the Ames test, which suggests that the compound may be a mutagen. PAHP appears to be the safest phenone of the series.62
Thiosulfate and Other Sulfur Donors
Thiosulfate has been used primarily with sodium nitrite in a fixed antidotal regimen. The standard dose of sodium thiosulfate, which is supplied in the Lilly Cyanide Antidote Kit in 50-mL ampules, is 50 mL of the 250 mg/mL (12.5 g), given intravenously. A second treatment with half of the initial dose may be given. The pediatric dose is 1.65 mL per kilogram of body weight.55
The utility of thiosulfate is limited because of its short biological half-life and its small volume of distribution.23 This combination of pharmacological properties, in addition to the suggestion that the presence of cyanide increases the intracellular availability of the thiosulfate,63 indicates that this compound probably cannot be used as a prophylactic but only as an antidote. Compounds containing the more-lipophilic sulfane sulfur (R—S—S–) or compounds that can be actively transported into the cells may be more beneficial as cyanide antagonists,64–66 but none are commercially available.
|Other Therapeutic Drugs
Cobalt salts have been shown to be an effective means for binding cyanide in vitro and in vivo.67,68 Kelocyanor, the cobalt salt of ethylenediamine-tetraacetic acid (EDTA), which is commercially available in Europe but not in the United States, is administered intravenously.69 In comparison studies against nitrite and hyposulfite, the cobalt chelate was thought to be superior31; however, in other studies the nitrite-thiosulfate combination was found to be superior.70
The drawback of cobalt compounds is their rather severe toxicity. Cardiac effects such as angina pectoris and ventricular arrhythmias, edema around the eyes, vomiting, and death have been observed.71 A clinical caveat is that severe toxicity from cobalt can be seen even after initial recovery from acute cyanide poisoning.
Hydroxocobalamin (vitamin B12a) is an effective antagonist of cyanide intoxication that binds cyanide directly without forming methemoglobin. It is useful under certain conditions such as in fire victims who may already have a decreased concentration of functioning hemoglobin.72 It has a low toxicity even at high doses.73 In addition, in vitro cyanide studies74 have shown a greater affinity for hydroxocobalamin than for cytochrome oxidase. Sodium thiosulfate can improve the protection provided by hydroxocobalamin alone.46
There are several disadvantages in the clinical use of this drug. In rare instances, urticaria can result from hydroxocobalamin administration. More importantly, hydroxocobalamin has a relatively short shelf life because it decomposes in light. It may cause tachyphylaxis, which may limit its usefulness.75 The cost of the drug is high, in part because so much is needed on a molar basis. At 1,346 grams per mole of hydroxocobalamin, a dose of at least 4 g is needed to neutralize a lethal amount of cyanide.
PAPP and PAOP are also aminophenol derivatives. PAPP may not be active against cyanide intoxication; its metabolite, p-hydroxylamino-propiophenone, may be the active compound. This could account, in part, for the fact that cyanide toxicity itself changes the pharmacokinetics of the antidote.76 PAPP reduces cyanide levels within red blood cells,77 and its effect is greatly enhanced in the presence of sodium thiosulfate.78 PAPP, PAHP, and PAOP all have pharmacokinetics that may allow for prophylactic administration.62,79 Prophylactic methemoglobin formation could present its own problems, however, for victims of smoke inhalation or in other settings where high levels of carbon monoxide occur.33,80
A number of 8-aminoquinoline analogs of primaquine have also been studied as potential prophylactic drugs because they create elevated methemoglobin levels of long duration. Only preliminary information is available regarding the methemoglobin- forming potential of these drugs in humans.62,81,82
Aldehydes and carbonyl-related compounds (such as pyruvate, a-ketoglutaric acid, glyoxal, and reducing sugars) form cyanohydrins from cyanide. This action may be a mechanism for improving the protection provided by nitrites.83 Steinberg and Thomas84 found that glyoxal trimer may be the most effective compound of the group that they examined. The relatively short half-lives of these reversible reactions and the drug dose required85 may limit the clinical utility of this class of compounds.24
Cyanide, an ancient compound, is often associated with murders and assassinations. Because of the high amount needed to cause death and the inefficient weapons in which it was used, cyanide was not an effective chemical weapon in World War I; however, it was possibly used by Iraq against the Kurds in the Iran–Iraq War during the late 1980s.
Cyanide causes intracellular hypoxia by inhibiting the intracellular electron transport mechanism, the cytochrome enzymes. After inhalation of a large amount of cyanide—as either hydrocyanic acid or cyanogen chloride—the onset of effects is within seconds, symptoms are few, physical findings are scanty, and death occurs within minutes.
The antidotes used in the United States, sodium nitrite and sodium thiosulfate, are quite effective if given before cessation of cardiac activity.
The authors thank Michael P. Whitmer and Eric W. Nealley, U.S. Army Medical Research Institute of Chemical Defense, and Adam S. Szczepaniak, Jr., Wood Technical Library, Aberdeen Proving Ground, Maryland, for their excellent technical assistance.