Cyanide inhibits cytochrome oxidase and causes death from histotoxic anoxia. (Also see Sorghum Poisoning.) The lethal dosage of hydrogen cyanide (HCN) in most animal species is ~2 mg/kg.
Cyanides are found in plants, fumigants, soil sterilizers, fertilizers (eg, cyanamide), pesticides/rodenticides (eg, calcium cyanomide) and in a variety of cyanide salts used in industrial processes, such as gold mining, metal cleaning and electroplating, photographic processes, and others. Pets and other nontarget species can be exposed to cyanide from nonselective usage by predator control personnel. Combustion of many plastic compounds used in manufacture of private and public modes of transportation (eg, aircraft, buses, cars) and building construction produces hydrogen cyanide gas in lethal amounts in cases of accidents and fire.
Toxicity can result from accidental, improper, or malicious use or exposure, but in the case of large animals or livestock, the most frequent cause of poisoning is ingestion of plants that contain cyanogenic glycosides (amygdalin). These include Triglochin maritima (arrow grass), Hoecus lunatus (velvet grass), Sorghum spp (Johnson grass, Sudan grass, common sorghum), Prunus spp (apricot, peach, chokecherry, pincherry, wild black cherry), Sambucus canadensis (elderberry), Pyrus malus (apple), Zea mays (corn), and Linum spp (flax). The seeds (pits) of several plants such as the peach have been the source of other cyanogenic glycosides (laetrile) in many cases. Eucalyptus spp, kept as ornamental houseplants, have been implicated in deaths of small animals. The dried root of Manihot esculenta (cassava or tapioca) has significant cyanide content and can cause toxicosis if improperly cooked and consumed in large amounts. Some varieties of Phaseolus lunatus (lima bean) have been reported to contain notable amounts of hydrogen cyanide. The cyanogenic glycosides in plants yield free hydrocyanic acid, otherwise known as prussic acid, when hydrolyzed by β-glycosidase or when other plant cell structure is disrupted or damaged, eg, by freezing, chopping, or chewing. Microbial action in the rumen can further release free cyanide.
Apple and other fruit trees contain prussic acid glycosides in leaves and seeds but little or none in the fleshy part of the fruits. In Sorghum spp forage grasses, leaves usually produce 2–25 times more HCN than do stems; seeds contain none. New shoots from young, rapidly growing plants often contain high concentrations of prussic acid glycosides. The cyanogenic glycoside potential of plants can be increased by heavy nitrate fertilization, especially in phosphorus-deficient soils. Spraying of cyanogenic forage plants with foliar herbicides such as 2,4-D can increase their prussic acid concentrations for several weeks after application.
The cyanogenic glycoside potential is slow to decrease in drought-stricken plants containing mostly leaves. Grazing stunted plants during drought is the most common cause of poisoning of livestock by plants that produce prussic acid.
Frozen plants may release high concentrations of prussic acid for several days. After wilting, release of prussic acid from plant tissues declines. Dead plants have less free prussic acid. When plant tops have been frosted, new shoots may regrow at the base; these can be dangerous because of glycoside content and because livestock selectively graze them.
Ruminants are more susceptible than monogastric animals, and cattle slightly more so than sheep. Hereford cattle have been reported to be less susceptible than other breeds.
Signs generally occur within 15–20 min to a few hours after animals consume toxic forage. Excitement can be displayed initially, accompanied by rapid respiration rate. Dyspnea follows shortly, with tachycardia. 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 stagger and struggle before collapse. Mucous membranes are bright red but may become cyanotic terminally. Death occurs during severe asphyxial convulsions. The heart may continue to beat for several minutes after struggling and breathing stops. The whole syndrome usually does not exceed 30–45 min. Most animals that live ≥2 hr after onset of clinical signs recover, unless continuous absorption of cyanide from the GI tract occurs. 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 over 4 days to eliminate over 95% of the cyanide present.
In acute or peracute cyanide toxicoses, blood may be bright cherry red initially but can be dark red if necropsy is delayed; it may clot slowly or not at all. 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. 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. 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.
Appropriate history, clinical signs, postmortem findings, and demonstration of HCN in rumen (stomach) contents or other diagnostic specimens support a diagnosis of cyanide poisoning. Specimens recommended for cyanide analyses include the suspected source (plant or otherwise), rumen or stomach contents, 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. Where available, the measurement of urinary thiocyanate may reveal elevated concentrations after cyanide poisoning. Many veterinarians have used picric acid-impregnated paper as a quick qualitative assessment of cyanide exposure.
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 μg/mL. Minimal lethal blood concentrations are ∼3.0 μg/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× greater than serum concentrations because of binding to ferric ions and sequestration in RBC.
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 that cause sudden death.
Treatment, Control, and Prevention
Immediate treatment is necessary. The goal of treatment is to break the cyanide-cytochrome oxidase bond and free cytochrome oxidase to transport molecular oxygen for cellular respiration. Sodium nitrite produces methemoglobin, which combines with cyanide to form cyanmet-hemoglobin and frees cytochrome oxidase. Cyanmethemoglobin further reacts with thiosulfate under the action of rhodanase (thiosulfate/cyanide sulfurtransferase) to form less toxic thiocyanate, which is excreted in the urine. Rhodanase is concentrated in the liver and kidneys, where it is found in the mitochondrial matrix, and can provide natural detoxification of small amounts of forage cyanide. However, when overwhelmed, the heart and CNS are the major targets of cyanide lethality.
Sodium nitrite (10 g/100 mL of distilled water or isotonic saline) should be given IV at 20 mg/kg body wt, followed by sodium thiosulfate (20%), IV, at ≥500 mg/kg; the latter may be repeated as needed with little hazard. Sodium nitrite therapy may be carefully repeated at 10 mg/kg, every 2–4 hr or as needed.
In one study investigating cyanide poisoning treatment in dogs, either 4-dimethyl-aminophenol (DMAP) IM at 5 mg/kg or hydroxylamine hydrochlorine IM at 50 mg/kg were as effective as nitrite and thiosulfate; however, DMAP is a potent methemoglobin inducer, and subsequent IV administration of sodium thiosulfate is required to promote conversion of cyanide to thiocyanate, which is then excreted in the urine. Adverse effects of DMAP are severe and include hemolysis, reticulocytosis, and nephrotoxicity. Availability of DMAP may be limited.
Other alternative antidotes in clinical development and use worldwide include hydroxycobalamin (vitamin B12a), dicobalt-ethylenediaminetetraacetic acid (EDTA), prodrugs of 3-mercaptopyruvate, and α−ketoglutaric acid. While hydroxycobalamin has been recently approved by the FDA for use in the USA, none of the others are readily available.
Hydroxycobalamin is the precursor molecule of cyanocobalamin (vitamin B12) and binds with cyanide in an equimolar basis to form vitamin B12 and thereby detoxify cyanide. It is a relatively safe antidote with good efficacy. Eighteen dogs treated with hydroxycobalamin at a dosage of 150 mg/kg for acute cyanide poisoning all survived. The main disadvantage is the cost.
Dicobalt-EDTA releases cobalt ions that react with cyanide ions; highly stable cyanide-cobalt complexes are then excreted by the kidney. This drug is very potent and has immediate action but is reported to have numerous, severe adverse effects in humans.
Prodrugs of 3-mercaptopyruvate are in developmental stages and act as a substrate for the enzyme 3-mercaptopyruvate/cyanide sulfurtransferase that converts cyanide to relatively nontoxic thiocyanate. These prodrugs were protective to mice given cyanide and are effective both PO and parenterally. When developed and released for use, these prodrugs are suitable for use as prophylactic agents given up to 1 hr prior to expected cyanide exposure/threat as well as for antidotal regimens.
The investigational antidote α-ketoglutaric acid has a molecular configuration that renders it amenable to nucleophilic binding of cyanide without generation of met-hemoglobin. Pretreatment with this drug reduced lethal outcomes and increased efficacy of sodium thiosulfate, but post-exposure 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. Oxygen should be used where available in supplementing 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).
Pasture grasses (eg, Sudan grass and sorghum-Sudan grass hybrids) should not be grazed until they are 15–18 in. tall to reduce danger from prussic acid poisoning. Forage sorghums should be several feet tall. 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; prussic acid release potential 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.
Last full review/revision March 2012 by Norman R. Schneider, DVM, MSc, DABVT