THE MERCK VETERINARY MANUAL
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Overview of Cyanide Poisoning

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In acute cyanide poisoning, cyanide ions (CN) bind to, and inhibit, the ferric (Fe3+) heme moeity form of mitochondrial cytochrome c oxidase (synonyms: aa3, complex IV, cytochrome A3, EC 1.9.3.1). This blocks the fourth step in the mitochondrial electron transport chain (reduction of O2 to H2O), resulting in the arrest of aerobic metabolism and death from histotoxic anoxia. Tissues that heavily depend on aerobic metabolism such as the heart and brain are particularly susceptible to these effects. Cyanide also binds to other heme-containing enzymes, such as members of the cytochrome p450 family, and to myoglobin. However, these tissue cyanide "sinks" do not provide sufficient protection from histotoxic anoxia. The acute lethal dosage of hydrogen cyanide (HCN) in most animal species is ~2 mg/kg. Plant materials containing ≥200 ppm of cyanogenic glycosides are dangerous.

There are at least two forms of chronic cyanide poisoning in domestic animals: 1) hypothyroidism due to disruption of iodide uptake by the follicular thyroid cell sodium-iodide symporter by thiocyanate, a metabolite in the detoxification of cyanide, and 2) chronic cyanide and plant cyanide metabolite (eg, various glutamyl β-cyanoalanines) -associated neuropathy toxidromes (eg, equine sorghum cystitis ataxia syndrome, cystitis ataxia syndromes in cattle, sheep, and goats).

Various chemical forms of cyanides are found in plants, fumigants, soil sterilizers, fertilizers (eg, cyanamide), pesticides/rodenticides (eg, calcium cyanomide) and salts used in industrial processes, such as gold mining, metal cleaning and electroplating, photographic processes, and others. Hydrogen cyanide is also known as prussic acid, and cyanide salts liberate cyanide gas in the presence of acids (eg, in the stomach). Cyanide preparations are still used as vertebrate pest control agents for control of feral pigs, fox, Australian brush-tailed possums, and other pest or predator species in a number of countries. Cyanide salts are still used as killing agents in entomology and (illegally) as a method of fishing and/or collection of aquarium fish species (ie, cyanide fishing). Combustion of common polyacrylonitriles (plastics), wool, silk, keratin, polyurethane (insulation/upholstery), melamine resins (household goods), and synthetic rubber results in the release of cyanide gas. Car fires are notorious sources of cyanide exposure, and cyanide is also a notable component of internal combustion engine exhaust and tobacco smoke. Carbon monoxide poisoning with cyanide gas is thus an extremely common component of smoke inhalation toxidromes.

Toxicity can result from accidental, improper, or malicious use or exposure. However, in livestock species, the most frequent cause of acute and chronic cyanide poisoning is ingestion of plants that either constitutively contain cyanogenic glycosides or are induced to produce cyanogenic glycosides and cyanolipids as a protective response to environmental conditions (plant cyanogenesis). Plant cyanogenesis is a common process and has been documented in >3,000 different plant species distributed over ~110 different families of ferns, gymnosperms, and angiosperms. Of these plants, ~300 species are potential causes of acute and chronic cyanogenic glycoside poisoning, and there are ~75 different cyanogenic glycosides (all of which are O-β-glycosidic derivatives of α-hydroxynitriles). Plant species of notable veterinary importance include Sorghum spp (Johnson grass, Sudan grass, and S bicolor, the common cereal grain crop referred to as "sorghum" or the synonyms durra, jowari, milo), Acacia greggii (guajillo), Amelanchier alnifolia (western service berry), Linum spp (linseeds and flaxes), Sambucus nigra (elderberry), Suckley suckleyana (poison suckleya), Triglochin maritima and T palustris (marsh arrow grasses), Mannihot esculentum (cassava), all members of the Prunus genus until proved otherwise (apricot, peach, chokecherry, pincherry, wild black cherry, ornamental cherry, peaches, nectarines, apricots, almonds, bird cherries, black thorn, cherry laurels [commercial orchard species are often specifically bred for low cyanide content; however, ornamental members of this genus are often highly poisonous]), Nandina domestica (heavenly or sacred bamboo), Phaseolus lunatus (Lima beans), members of the Vicia genus until proved otherwise (vetches; often pasture species have been bred for low cyanogenesis), Lotus spp (bird's-foot treefoils; often, pasture species have been bred for low cyanogenesis), Trifolium sp (clovers; often, pasture species have been bred for low cyanide content), Zea mays (corn), Eucalyptus spp (gum trees), Hydrangia spp (hydrangias), Pteridium aquillinum (bracken fern), Bahia oppositifolia (bahia), and Chaenomales spp (flowering quince) (Also see Sorghum Poisoning). A number of insect species are also able to synthesize hydrogen cyanide and/or sequester hydrogen cyanide that is derived from the cyanogenic glycosides of their plant hosts (notably the USA eastern tent caterpillar Malacosoma americanum that is associated with mare reproductive loss syndrome (also see Mare Reproductive Loss Syndrome); however, cyanide is not the cause of mare reproductive loss syndrome. Invertebrates such as Burnet moths (Zygaena spp) that feed on bird's-foot trefoils), as well as certain centipede and millipedes, are potentially hazardous food sources for exotic pet species.

Plant cyanogenesis in response to environmental stressors is an important part of the etiology and risk of acute cyanogenic glycoside poisoning. Within plants, amino acids that are not used for protein synthesis can be metabolized to α-hydroxynitriles and then to cyanogenic glycosides. Plants are protected from the potential adverse effects of cyanogenic glycosides by two features: cyanogenic glycosides are largely found within cell vacuoles, and the presence of the detoxifying enzyme β-cyanoalanine synthase (which is responsible for production of some of the cyanide derivatives putatively involved in the chronic cyanide-associated neurologic toxidromes). Even so-called "acyanogenic" plants can become toxic under appropriate environmental circumstances. Environmental conditions that damage relevant plant species, reduce protein synthesis, enhance the conversion of nitrate to amino acids in the presence of reduced protein synthesis, and/or inhibit β-cyanoalanine synthase potentially increase the risk of cyanogenesis. Relevant environmental factors include crushing, wilting, freezing, high environmental temperatures, herbicide treatment, water stress, cool moist growing conditions, nitrate fertilization, high soil nitrogen:phosphorus ratios, soil phosphorus deficiency, low soil sulfur (decreases detoxification of cyanogenic glycosides to thiocyanates within plants), insect attack, and various plant diseases. Herbicide treatment of plants is important in that it may also increase plant palatability. Crushing and/or mastication of potentially cyanogenic plants is important in development of the acute toxidrome, because this releases cyanogenic glycosides from plant cell vacuoles and exposes them to catabolism by β-glucosidase and hydroxynitrile lyase present in the plant cell cytosol. Young, rapidly growing areas of plants and areas of regrowth after cutting often have high cyanogenic glycoside content. As a rough approximation, rapidly growing Sorghum spp are often hazardous until they reach ~60 cm in height; however, this is no guarantee of safety, and if there is any doubt regarding cyanogenic potential, samples of potential forage should be tested. Plant seeds and leaves typically have higher cyanogenic potential, while the fleshy parts of fruits generally have low levels. Drying often increases the cyanogenic potential of plants, whereas ensiling may reduce cyanide content by ~50%.

β-glucosidase and hydroxynitrile lyase are also present in the rumen microflora, and a rumen pH of ~6.5–7 favors conversion of cyanogenic glycosides to cyanide. Ruminants on high-energy grain rations are somewhat less susceptible, because their lower rumen pH (~4–6) reduces the formation of cyanide. Consumption of water before grazing on cyanogenic pastures appears to increase the risk. Monogastric animals with low stomach pH are also somewhat less susceptible to cyanogenic glycoside poisoning. However, these factors do not guarantee immunity from poisoning.

Under conditions of low-level exposure, mammals detoxify ~80% of ingested cyanide to thiocyanate via mitochondrial rhodanese. Thiocyanate is then largely excreted in urine. Often, the rate of the rhodanese pathway is limited by the availability of thiosulfate; also notably, dogs have lower overall rhodanese activity than other species. Minor, but toxicologically important, pathways of detoxification in mammals include the combination of cyanide with hydroxycobalamin (vitamin B12a) to yield cyanocobalamin (vitamin B12), and the nonenzymatic combination of cyanide with cysteine to form β-thiocyanoalanine, which is converted to 2-iminothiazolidine-4-carboxylic acid and subsequently excreted. Small amounts of β-thiocyanoalanine are also excreted in saliva. Dietary levels of sulfur amino acids (L-cysteine and L-methionine) strongly influence the rate of detoxification of cyanide, and low dietary intakes are associated with higher blood cyanide levels, particularly under conditions of chronic, low level exposure. Dietary sulfur and sulfur amino acid intake are known to strongly affect the neurologic toxidromes associated with chronic cyanide/cyanogenic glycoside exposure in people.

Chronic low-level cyanide/cyanogenic glycoside exposure is associated with increased exposure to the cyanide metabolite thiocyanate. Under conditions of thiocyanate overload, thiocyanate acts as a competitive inhibitor of thyroid follicular cell iodine uptake by the sodium/iodide symporter. This results in reduced iodination of tyrosine, reduced T3 synthesis, increased blood TSH, goiter, and hypothyroidism. Similar effects occur with some plant glucosinolates (goitrogenic glycosides). Selenium deficiency appears to enhance these effects.

Chronic, low-level cyanide/cyanogenic glycoside exposure (often in combination with low dietary sulfur and/or sulfur amino acid intake) is associated with neuropathy syndromes in horses and ruminants. Sorghum cystitis ataxia syndrome of horses is associated with diffuse nerve fiber degeneration in the lateral and ventral funiculi of the spinal cord and brain stem. Similar syndromes have been described in ruminants. Comparisons between these syndromes as chronic cyanogenic glycoside–associated human myeloneuropathies such as Konzo and tropical ataxic neuropathy have been made; however, the precise toxins and modes of action are yet to be fully defined. All of these toxidromes appear to be related to a combination of chronic cyanide/cyanogenic glycoside exposure combined with low dietary sulfur and/or sulfur amino acid intake and possibly other nutritional deficiencies. Lathyrogenic plant cyanide metabolites such as β-cyanoalanine have been implicated as causative or at least contributory agents.

Chronic, low-level cyanogenic glycoside exposure (notably from Sorghum spp) has been associated with musculoskeletal teratogenesis (ankyloses or arthrogryposes) and abortion.

Acute cyanide poisoning: Signs generally occur within 15–20 min to a few hours after animals consume toxic forage, and survival after onset of clinical signs is rarely >2 hr. Excitement can be displayed initially, accompanied by rapid respiration rate. Dyspnea follows shortly, with tachycardia. The classic "bitter almond" breath smell may be present; however, the ability to detect this smell is genetically determined in people, and anosmic people (a significant proportion of the population) cannot detect it. Salivation, excess lacrimation, and voiding of urine and feces may occur. Vomiting may occur, especially in pigs. Muscle fasciculation is common and progresses to generalized spasms and coma before death. Animals may stagger and struggle before collapse. In other cases, sudden unexpected death may ensue. Mucous membranes are bright red but may become cyanotic terminally. Venous blood is classically described as "cherry red" because of the presence of high venous blood pO2; however, this color rapidly changes after death. Serum ammonia and neutral and aromatic amino acids are typically increased. Cardiac arrhythmias are common due to myocardial histotoxic hypoxia. Death occurs during severe asphyxial convulsions. The heart may continue to beat for several minutes after struggling, and breathing stops. The elimination half-life of cyanide in dogs is reported to be 19 hr, so prognosis of recovery without therapeutic intervention is grave: it would take more than 4 days to eliminate >95% of the cyanide present.

Chronic cyanide poisoning syndromes: Chronic cyanogenic glycoside hypothyroidism will present as hypothyroidism with or without goiter. Cystitis ataxia toxidromes are typically associated with posterior ataxia or incoordination that may progress to irreversible flaccid paralysis, cystitis secondary to urinary incontinence, and hindlimb urine scalding and alopecia. Death, although uncommon, is often associated with pyelonephritis. Late-term abortion and musculoskeletal teratogenesis may also occur.

Lesions:

Acute cyanide poisoning: Necropsy personnel may require appropriate personal protective equipment, including respirators with suitable cartridges. Venous blood is classically described as being "bright cherry red"; however, this color rapidly fades after death or if the blood is exposed to the atmosphere. Whole blood clotting may be slow or not occur. Mucous membranes may also be pink initially, then become cyanotic after respiration ceases. The rumen may be distended with gas; in some cases the odor of “bitter almonds” may be detected after opening. Rumen contents may provide a positive sodium picrate paper test (or positive results on other rapid cyanide test strip systems). Rumen gases may provide positive results in cyanide Draeger tube rapid test systems. Agonal hemorrhages of the heart may be seen. Liver, serosal surfaces, tracheal mucosa, and lungs may be congested or hemorrhagic; some froth may be seen in respiratory passages. Cyanide also binds to iron (both Fe2+ and Fe3+) present in myoglobin (although this occurs more slowly than the binding to cytochrome c oxidase and, hence, is not protective); this may result in a generalized dark coloration of skeletal muscle. Neither gross nor histologic lesions are consistently seen.

Multiple foci of degeneration or necrosis may be seen in the CNS of dogs chronically exposed to sublethal amounts of cyanide. These lesions have not been reported in livestock.

Chronic cyanide poisoning: Goiter may be present. Cystitis ataxia toxidromes are characterized by opportunistic bacterial cystitis with or without pyelonephritis and diffuse nerve fiber degeneration in the lateral and ventral funiculi of the spinal cord and brain stem. Hindlimb urine scalding and alopecia may be present.

Appropriate history, clinical signs, postmortem findings, and demonstration of HCN in rumen (stomach) contents or other diagnostic specimens support a diagnosis of cyanide poisoning. Veterinarians should be aware of the possible need to use appropriate personal protective equipment, including a respirator, when collecting samples that may liberate cyanide gas (eg, rumen contents and rumen gas cap). A rapid qualitative and presumptive diagnosis can be made by testing representative plant samples or stomach contents using the picric acid paper test or by collecting rumen gas cap samples by trocarization and testing with a Draeger cyanide gas detection tube or other cyanide gas detection system. Negative results with such rapid presumptive tests do not completely exclude the possibility of cyanide poisoning. Suitable specimens for more sophisticated testing include the suspected food source, rumen/stomach contents, samples of the rumen gas cap, heparinized whole blood, liver, and muscle. Antemortem whole blood is preferred; other specimens should be collected as soon as possible after death, preferably within 4 hr. Specimens should be sealed in an airtight container, refrigerated or frozen, and submitted to the laboratory without delay. When cold storage is unavailable, immersion of specimens in 1%–3% mercuric chloride has been satisfactory. The rationale for using liver as a diagnostic sample is that cyanide binds to the Fe3+ form of cytochrome p450 and other heme-containing metabolic enzymes. The rationale for using skeletal muscle is that cyanide will bind to the iron moiety in myoglobin.

Where available, measurement of the urinary metabolite of cyanide, thiocyanate, may reveal increased concentrations after cyanide poisoning.

Hay, green chop, silage, or growing plants containing >220 ppm cyanide as HCN on a wet-weight (as is) basis are very dangerous as animal feed. Forage containing <100 ppm HCN, wet weight, is usually safe to pasture. Analyses performed on a dry-weight basis have the following criteria: >750 ppm HCN is hazardous, 500–750 ppm HCN is doubtful, and <500 ppm HCN is considered safe.

Normally expected cyanide concentrations in blood of most animal species are usually <0.5 mcg/mL. Minimal lethal blood concentrations are ~3 mcg/mL or less. Cyanide concentrations in muscle are similar to those in blood, but concentrations in liver are generally lower than those in blood. In dogs, whole blood cyanide concentrations may be 4–5 times greater than serum concentrations because of binding to ferric ions and sequestration in RBCs.

Differential diagnoses include poisonings by nitrate or nitrite, urea, organophosphate, carbamate, chlorinated hydrocarbon pesticides, and toxic gases (carbon monoxide and hydrogen sulfide), as well as infectious or noninfectious diseases and other toxidromes that cause sudden death.

Immediate treatment is necessary. The goal of treatment is to break the cyanide-cytochrome c oxidase bond and reestablish the mitochondrial electron transport chain. One way to accomplish this is by using inducing Fe3+ in hemoglobin (ie, inducing methemoglobinemia), which then acts as a high-affinity decoy chemical receptor for cyanide and forms cyanmethemoglobin. Classically, various nitrites have been used for this purpose; eg, inhaled amyl nitrite followed by IV injection of a nitrite salt (typically sodium nitrite) has been used to rapidly induce methemoglobinemia. Cyanide bound to methemoglobin can then be detoxified by rhodanese to thiocyanate. Because the rhodanese-mediated detoxification of cyanide to thiocyanate is usually capacity and rate limited by the availability of sulfur donors, treatment with nitrites is usually followed up by injection of sodium thiosulfate. Oral dosing with sodium thiosulfate into the rumen and/or stomach has also been suggested because the reaction between thiosulfate and cyanide can also occur nonenzymatically, and this may reduce any ongoing production of cyanide in the rumen/stomach environments.

If possible, the contents of one 0.3-mL vial of amyl nitrite should be inhaled by the animal as soon as possible after exposure, followed by an IV infusion of sodium nitrite (10 g/100 mL of distilled water or isotonic saline; 20 mg/kg body wt) over 3-4 min. Nitrite treatment is then followed by a slow IV injection of sodium thiosulfate (20% w/w) at ≥500 mg/kg. Thiosulfate is generally well tolerated; however, vomiting and hypotension can occur. The thiosulfate injection can be repeated if necessary. Oral administration of thiosulfate can also be considered in an attempt to convert any cyanide in the stomach/rumen into thiocyanate. Sodium nitrite therapy may be carefully repeated at 10 mg/kg, every 2–4 hr or as needed. Ideally, decisions regarding repeated treatment with nitrites should consider the degree of methemoglobinemia present.

Notably, thiosulfate treatment alone has been successful in some cases. However, thiosulfate treatment should ideally be preceded by nitrite induction of methemoglobinemia in cases of confirmed cyanide poisoning. However, because thiosulfate is generally well tolerated, it is often administered alone in situations when cyanide exposure is likely but unconfirmed (eg, smoke inhalation or exposure to fires).

Hydroxocobalamin (vitamin B12a ) is also used as a cyanide antidote. Hydroxocobalamin detoxifies cyanide by binding to it and forming cyanocobalamin (ie, another decoy receptor approach), which is then excreted in urine. It has the advantages that it is relatively well tolerated, does not compromise blood oxygen-carrying capacity, and does not produce hypotension. Hydroxocobalamin does produce chromaturia (which may result in false urinalysis results), as well as infusion site reactions, GI upset, pruritus, and dysphagia. The suggested dosage is 70 mg/kg, infused IV over 15 min, repeated as necessary.

Sulfanegen (as the sodium or triethanolamine salt) has been developed for treatment of cyanide mass poisoning incidents. This approach has the advantage that sulfanegen is water soluble and can be administered IM. Sulfanegen is a prodrug that generates 3-mercaptopyruvic acid (3-MP), an intermediate in cysteine metabolism, which again acts as a decoy receptor for cyanide. By itself, the half-life of 3-MP is too short to be effective against cyanide poisoning. For this reason, prodrugs such as sulfanegen have been developed to increase the duration of action of 3-MP in vivo.

Alternative inducers of methemoglobinemia such as 4-dimethyl-aminophenol (DMAP; IM at 5 mg/kg) or hydroxylamine hydrochlorine (IM at 50 mg/kg) have been suggested, because they produce methemoglobinemia more quickly than the nitrites currently in use. However, these hemoglobin-oxidizing agents are also relatively toxic to RBCs and can induce severe effects such as hemolysis and renal damage. These "rapid agents" still have the disadvantage of reducing blood oxygen-carrying capacity.

Other alternative antidotes in clinical development and use worldwide include dicobalt-ethylenediaminetetraacetic acid (EDTA) and α−ketoglutaric acid. Although hydroxycobalamin has been approved by the FDA for use in the USA, none of the others is readily available. Dicobalt-EDTA releases cobalt ions that react with cyanide ions; highly stable cyanide-cobalt complexes are then excreted by the kidneys. This drug is very potent and has immediate action but is reported to have numerous, severe adverse effects in people. The investigational antidote α-ketoglutaric acid has a molecular configuration that renders it amenable to nucleophilic binding of cyanide without generation of methemoglobin. Pretreatment with this drug reduced lethal outcomes and increased efficacy of sodium thiosulfate, but postexposure efficacy in animals is unknown.

Sodium thiosulfate alone is also an effective antidotal therapy at ≥500 mg/kg, IV, plus 30 g/cow, PO, to detoxify any remaining HCN in the rumen. When available, oxygen should be used to supplement nitrite or thiosulfate therapy, especially in small animals. Hyperbaric oxygen therapy (100% oxygen breathed intermittently at a pressure >1 atmosphere absolute) causes an above-normal partial pressure of oxygen (PO2) in arterial blood and markedly increases the amount of oxygen dissolved in plasma. Oxygen-dependent cellular metabolic processes benefit from heightened oxygen tension in capillaries and enhanced oxygen diffusion from capillaries to critical tissues. Activated charcoal does not effectively absorb cyanide and thus is not recommended PO for antidotal therapy.

Caution is indicated in treatment. All cyanide antidotes are toxic by themselves. Many clinical signs of nitrate and prussic acid poisoning are similar, and injecting sodium nitrite induces methemoglobinemia identical to that produced by nitrite poisoning. If in doubt of the diagnosis, methylene blue, IV, at 4–22 mg/kg, may be used to induce methemoglobin. Because methylene blue can serve as both a donor and acceptor of electrons, it can reduce methemoglobin in the presence of excess methemoglobin or induce methemoglobin when only hemoglobin is present (but sodium nitrate is the more effective treatment for cyanide poisoning if the diagnosis is certain).

The best preventive step is to test suspect feed and/or pastures before allowing consumption. Pasture and forage sorghums (eg, Sudan grass and sorghum-Sudan grass hybrids) should not be grazed until they are >60 cm tall or have been proved by testing to have acceptable cyanide levels, to reduce danger from prussic acid poisoning. Animals should be fed before first turning out to pasture; hungry animals may consume forage too rapidly to detoxify HCN released in the rumen. Animals should be turned out to new pasture later in the day; potential for prussic acid release is reported to be highest during early morning hours. Free-choice salt and mineral with added sulfur may help protect against prussic acid toxicity. Grazing should be monitored closely during periods of environmental stress, eg, drought or frost. Abundant regrowth of sorghum can be dangerous; these shoots should be frozen and wilted before grazing.

Green chop forces livestock to eat both stems and leaves, thereby reducing problems caused by selective grazing. Cutting height can be raised to minimize inclusion of regrowth.

Sorghum hay and silage usually lose ≥50% of prussic acid content during curing and ensiling processes. Free cyanide is released by enzyme activity and escapes as a gas. Although a rare occurrence, hazardous concentrations of prussic acid may still remain in the final product, especially if the forage had an extremely high cyanide content before cutting. Hay has been dried at oven temperatures for up to 4 days with no significant loss of cyanide potential. These feeds should be analyzed before use whenever high prussic acid concentrations are suspected. Potentially toxic feed should be diluted or mixed with grain or forage that is low in prussic acid content to achieve safe concentrations in the final product. At least in theory, the risk of chronic cyanide poisoning syndromes may be reduced by iodine supplementation in the case of hypothyroidism and by sulfur-containing amino acids in the case of chronic neurologic toxidromes. Great care must be taken when providing supplemental elemental sulfur sources in ruminants because of the possible risk of polioencephalomalacia (see Polioencephalomalacia).

Last full review/revision September 2014 by Rhian B. Cope, BVSC, PhD, DABT, ERT, FACTRA

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