Toxicity, Cyanide ?>

Toxicity, Cyanide

Toxicity, Cyanide


Introduction
Background

Cyanide, one of the most rapidly acting lethal poisons known to humankind, was a main constituent of Earth’s primordial atmosphere and probably played an important role in the development of life on Earth. It exists in nature in many different forms and may be found in a number of fruits and vegetables in the form of cyanogenic glycosides.

Cyanide can be a gas, liquid, or solid and may exhibit a faint bitter almondlike odor. Cyanide may be combined with salts (eg, sodium, calcium, potassium), metals (eg, cobalt, zinc, gold, mercury), and halides (eg, chloride, fluoride, iodide, bromide) or with organic acids to form nitriles.

Cyanide is used in many industries, including electroplating, pigment production, metallurgy (eg, electroplating, case hardening), chemical production, photographic development, plastic production, ship fumigation, and some mining processes, such as gold extraction. Cyanide is also used in agriculture (eg, soil sterilization) and leather processing (eg, removing hair from hides). Cyanogenic amides are used as fertilizers, and cyanogenic halides are used in chemical synthesis. The nitriles, or organic cyanides, are used in the synthesis of flame-resistant fibers, plastics, and rubber. Hydrogen cyanide is also used as an insecticide and in the fumigation of large rat- and insect-infested ships and dwellings.

Currently in the US, cyanide poisoning is most commonly seen in the setting of a fire in an enclosed space or as a result of an accidental exposure to the chemical at work. Cyanide suicides and homicides have also been reported.

Pathophysiology

Cyanide poisoning occurs when a cyanogenic substance is ingested, inhaled, smoked or absorbed through the skin. Exposure to only small amounts of the toxin can result in serious poisoning and death. Cyanide readily and reversibly binds to all enzymes and proteins that contain iron (including hemoglobin, myoglobin, catalase, and the cytochrome system) and those containing cobalt.

Cyanide’s main pathological effects derive from its interaction with the cytochrome aa3 complex. When bound to the iron moiety of the cytochrome, it inhibits oxidative phosphorylation and paralyzes cellular respiration. This results in anaerobic metabolism, increased lactic acid production, reduced ATP stores, and anoxic cell death. The organ systems that are most sensitive to cyanide toxicity are those with the highest oxygen use that cannot tolerate hypoxic stress, namely the CNS and the myocardium.

Information on the pharmacokinetic properties of cyanide is scarce; most information was obtained from animal studies and a few human poisoning cases. When inhaled, gaseous cyanide produces symptoms within seconds and death occurs within minutes. When ingested, cyanide salts produce symptoms within minutes; death occurs within minutes to hours. The ingestion of cyanogenic fruits, on the other hand, is associated with a delayed onset of toxicity. The fruit pits, which contain amygdalin, also contain emulsin, an enzyme that is capable of hydrolyzing amygdalin to release hydrogen cyanide. Emulsin is much more effective in alkaline pH and, hence, in the intestinal tract rather than in the acidic environment of the stomach. Consequently, persons who ingest cyanogenic fruits and plants may present several hours after ingestion.

Once absorbed, cyanide is 60% protein-bound and has a volume of distribution of approximately 0.5 L/kg. The half-life for the conversion of cyanide to thiocyanate from a nonlethal dose in humans is between 20 minutes and 1 hour. Cyanide is nearly completely metabolized by rhodanese (sulfurtransferase), to inactive compounds prior to excretion, and only a small portion is excreted unchanged in the lungs and sweat. Rhodanese is a sulfurtransferase that catalyzes the combination of cyanide with sulfur to form thiocyanate, a much less toxic compound that is readily excreted in the urine. Hydrogen cyanide may also be converted to a nontoxic compound by its combination with hydroxocobalamin (vitamin B-12a), which produces cyanocobalamin (vitamin B-12).
Frequency
United States

In the United States, cyanide poisoning occurs most commonly in the setting of fire and smoke in an enclosed space. Intentional use and work-related accidents are also commonly reported. In 2004, 257 cases of cyanide poisoning were reported to various poison control centers of the US with 8 fatalities. Thirty two of the 257 cases were intentional.
International

Similar to the United States, cyanide poisoning in Europe and Australia is most commonly reported in the setting of smoke inhalation and as a result of industrial accidents.

Worldwide, a number of industrial accidents involving the release of cyanide into the environment have occurred over the past decade. Massive river spills with extensive and disastrous environmental impact have occurred in Danube tributaries and in rivers in Ghana, China, Ecuador, and Nicaragua. In some cases, these spills have caused human illness and death. In June 2005, for example, at least 60-100 villagers were poisoned by drinking water downstream of a cyanide spill from a gold mine in Laos. Similar incidents left more than a hundred people hospitalized in Taiwan, and killed 12 children in Nicaragua, and 3 people in China.

Mortality/Morbidity

The average fatal adult dose of hydrogen cyanide is 50-60 mg (1.1 mg/kg). The oral median lethal dose for sodium and potassium cyanide is estimated at 2 mg/kg. Exposure to airborne concentrations of 90 parts per million (ppm) for 30 minutes or more is likely to be incompatible with life, although death may result from a few minutes of exposure at 300 ppm.

Serious poisoning has occurred with ingestions of as little as 50 mg of potassium cyanide, and death has been reported in adults following the ingestion of 200-300 mg of potassium cyanide. Conversely, patients who have ingested 1 g of cyanide have survived.
Sex

Deliberate self-poisonings and industrial accidents tend to occur predominantly in adult men. Cyanide poisoning in pregnant women may have teratogenic effects on the fetus. Cyanide poisoning has been shown to cause resorptions and malformations in the offspring of animals in experiments.
Age

Deliberate self-poisoning and industrial accidents occur predominantly in adult men.
Clinical
History

Cyanide is one of the most rapidly acting of all known poisons. Inhalation of a lethal dose may cause loss of consciousness within a few breaths and death within a few minutes. Persons who ingest cyanide salts become symptomatic within minutes and may die within 30 minutes. Similarly, persons with smoke inhalation may die within minutes of inhalation. The ingestion of cyanogenic plants may not manifest as toxicity until 1.5-2 hours after the ingestion, and, in the case of ingestion of cyanogenic glycosides, these manifestations may not be apparent until a few hours after ingestion.

Prompt recognition of cyanide poisoning is crucial; however, the signs and symptoms of acute cyanide poisoning are often nonspecific. The health care provider must maintain a high index of suspicion. Given the right setting, cyanide poisoning should be considered in the differential diagnoses of sudden death, sudden global neurologic deficit (ie, coma, convulsions, encephalopathy), severe acidosis, and shock.

People at risk for cyanide poisoning include persons with smoke inhalation, chemistry laboratory personnel, and employees of a number of industries that use cyanogenic substances. These include gold and silver extraction, leather tanning, photographic development, semiconductor production, petrochemical industries, and fumigation industries.

Poisoning at home may occur from the inhalation of metal-cleaning solutions, photographic development solutions, or gold and silver extraction solutions. Poisoning at home also may occur after the unsuspecting ingestion of cyanogenic plants, after an intentional ingestion of Laetrile (most common in persons with cancer), or after the accidental ingestion of artificial nail polish removers or rodenticides (most common in children).

Finally, cyanide poisoning may occur in the hospital during infusions of sodium nitroprusside and should be considered in patients who suddenly become agitated, become comatose, develop convulsions, or become acidotic.

Patients who have survived an ingestion of cyanide report burning of the tongue and throat upon deglutition. Patients may experience asthenia, loss of energy, pain throughout the body, headache, dizziness, chest pain, palpitations, cough, shortness of breath, nausea, and vomiting. These may be followed by confusion, agitation, convulsions, paralysis, coma, and death.
Physical

The physical examination findings are scarce and otherwise nonspecific in a person with cyanide poisoning. The time to onset of symptoms and the severity of symptoms depend on the dose and route of cyanide exposure. Coma, tonic-clonic seizures, cyanosis, shock, and severe metabolic acidosis reflect a serious overdose that requires prompt institution of therapy.

Helpful clues that help diagnose cyanide poisoning include a lack of cyanosis in patients who are still breathing and equally red retinal arteries and veins upon funduscopic examination. Both of these findings are due to the tissue’s inadequate oxygen use. The odor of bitter almonds emanating from the patient can be an additional clue to help diagnose cyanide poisoning; however, up to 40% of the population is unable to detect this odor. The presence of soot in the mouth and nose of a patient with smoke inhalation who is comatose should also raise suspicion of cyanide toxicity, particularly if the patient is acidotic or hypotensive.

Additional findings from the physical examination are generally nonspecific and noncontributory. The patient may exhibit tachypnea, bradypnea, tachycardia, bradycardia, hypoxia, hypotension, and shock. The pupils may be dilated and reactive, and the cornea may be edematous. Patients involved in fires or who have experienced smoke inhalation may also experience thermal and chemical injury to the lungs resulting in pulmonary damage, noncardiogenic pulmonary edema, hypoxia, cyanosis, and, ultimately, death.
Causes
Smoke inhalation
Cyanide poisoning is a major factor that contributes to death due to smoke inhalation.
During fires, the incomplete combustion of nitrogen-containing organic compounds may generate hydrogen cyanide. These compounds include cotton, rayon, wool, polyvinyl chloride, modacrylic, polyurethane foam, polyester wadding, neoprene foam, paper, asphalt, nylon, rubber, plastics, Styrofoam, and insulation resins. Poisoning occurs if the hydrogen cyanide concentration is high, ie, if the fire occurs in an enclosed space.
Occupational exposure
Dupont is the only company in the United States that produces cyanide products.
Occupations in which cyanides are used include fumigation of ships and dwellings, partial soil sterilization, and fumigation intended to kill agricultural parasites. Chemistry laboratories may also use cyanide.
Some occupations may use or produce compounds that release cyanide under certain conditions. Occupations and industry examples include the petrochemical industry, the manufacture of blast-furnaces, illuminating gas works, coke ovens, the extraction of phosphoric acid from bones, gold and silver leaching, electroplating, metal cleaning, synthetic fiber (eg, acetonitrile, acrylonitrile, glyconitrile) and rubber synthesis, photography, and the leather-treatment industry.
Industrial accidents
Accidental leakage of cyanide into the environment is another major source of poisoning of wildlife and humans. Areas of accidental cyanide spills biologically die within a short time.
Gold-mining companies that use cyanide leaching to extract gold from ore have been responsible for a number of industrial accidents in the United States and abroad.
Foods
A number of plants contain cyanogenic glycosides, which are substances that release cyanide when hydrolyzed in the GI tract. These cyanogenic glycosides include amygdalin, linamarin, and dhurrin.
Amygdalin is found in variable amounts in the flowers, leaves, and seeds of the Prunus, plants, eg, peaches, plums, apricots, bitter almonds, chokecherries, and cherry laurels. Amygdalin is also a component of Laetrile, the once-popular cancer drug. Other plants that contain amygdalin include apple and pear seeds, linseeds, elderberry, bamboo, corn, sweet potatoes, and millet.
Cassava (yucca) and certain lima beans contain linamarin, another cyanogenic glycoside. Cassava has been implicated in a number of cases of acute and chronic cyanide poisoning throughout the world.
Dhurrin, which is found in sorghum grass, has been implicated in a number of poisonings in grazing animals.
Intentional suicidal or homicidal ingestions
Potassium cyanide is the most commonly used cyanide-based agent in self-poisonings and was the agent used to poison and kill 913 followers of the Reverend Jim Jones in 1978.
Cyanide continues to be an agent of choice in criminal tampering of drugs, water, and food products.
Iatrogenic
Sodium nitroprusside (Na2 -Fe-(CN)5-NO-2H2 O) is a rapidly acting and potent vasodilator that is commonly used in hypertensive emergencies and to treat some forms of cardiac failure.
In addition to sodium and water, sodium nitroprusside is composed of 1 nitroso moiety, 1 iron molecule, and 5 cyanide molecules. Sodium nitroprusside is rapidly taken up by hemoglobin and metabolized into nitric oxide and cyanogen (an unstable cyanide radical). Most of the cyanide molecules thus released (4 of 5) are then combined with sulfhydryl groups to form the less toxic thiocyanate, which is then excreted in the urine. The reaction is catalyzed by the hepatic enzyme rhodanese, a sulfhydryl transferase whose function depends on the availability of sulfur groups. It is the rate-limiting step in the detoxification of nitroprusside, but its activity may be augmented by an exogenous supply of sulfur groups (usually accomplished by sodium thiosulfate).
Nitroprusside in large doses or rapid and prolonged infusions can overwhelm rhodanese and result in a buildup of cyanide, causing cyanide toxicity.
Similarly, large doses of nitroprusside can result in a buildup of thiocyanate, especially in patients with renal failure. Although less toxic than cyanide, high concentrations of thiocyanate are poisonous. Symptoms of thiocyanate toxicity are manifested by unexplained abdominal pain, convulsions, and other manifestations of CNS injury.
The exact nitroprusside infusion rate at which cyanide toxicity occurs is debated. Cyanide levels rise dramatically with infusion rates greater than 1-2 mcg/kg/min. Cyanide toxicity has been reported with nitroprusside infusion rates that exceed 4 mcg/kg/min for as little as 2 hours. Therefore, infusion rates greater than 4 mcg/kg/min are not recommended for prolonged periods. Similarly, infusion rates of 10 mcg/kg/min are not advised for longer than 10 minutes.
The maximum recommended total dose of nitroprusside is also debated. Most investigators recommend a maximum dose of 1.5 mg/kg for infusions that last 1-3 hours, but some authors allow up to 3-3.5 mg/kg.
Nitroprusside-associated cyanide poisoning is rare but occurs most commonly in patients with hepatic failure, persons with decompensated congestive heart failure with passive liver congestion, or in patients receiving high doses or rapid and prolonged infusions of the drug. Patients may experience dyspnea, chest pain, headache, dizziness, and vomiting. The earliest sign may be a decline in hemodynamic status following an initial favorable response to the drug. Other signs include anxiety, agitation, hyperventilation, acidosis, syncope, convulsions, coma, circulatory collapse, and death.
Current laboratory methods for monitoring cyanide toxicity during nitroprusside infusions are not specific. Cyanide toxicity is first manifested by an increase in mixed venous PO2 or a narrowed arteriovenous oxygen difference, especially when a decline in cardiac output occurs after an initial improvement. As anaerobic metabolism increases, base excess and lactate levels rise. A falling pH level heralds cardiovascular collapse.
Cigarettes
Cigarette smoking commonly releases cyanide. Persons who smoke tobacco have a mean blood cyanide level of 0.4 mcg/mL, which is 2.5 times greater than the level in persons who do not smoke.
Long-term low-dose cyanide poisoning is thought to be the cause of tobacco amblyopia and has been associated with Leber hereditary optic atrophy

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