Cyanide poisoning

Cyanide poisoning is poisoning that results from exposure to any of a number of forms of cyanide. Early symptoms include headache, dizziness, fast heart rate, shortness of breath, and vomiting. This phase may then be followed by seizures, slow heart rate, low blood pressure, loss of consciousness, and cardiac arrest. Onset of symptoms usually occurs within a few minutes. Some survivors have long-term neurological problems.
Toxic cyanide-containing compounds include hydrogen cyanide gas and cyanide salts, such as potassium cyanide. Poisoning is relatively common following breathing in smoke from a house fire. Other potential routes of exposure include workplaces involved in metal polishing, certain insecticides, the medication sodium nitroprusside, and certain seeds such as those of apples and apricots. Liquid forms of cyanide can be absorbed through the skin. Cyanide ions interfere with cellular respiration, resulting in the body's tissues being unable to use oxygen.
Diagnosis is often difficult. It may be suspected in a person following a house fire who has a decreased level of consciousness, low blood pressure, or high lactic acid. Blood levels of cyanide can be measured but take time. Levels of 0.5–1 mg/L are mild, 1–2 mg/L are moderate, 2–3 mg/L are severe, and greater than 3 mg/L generally result in death.
If exposure is suspected, the person should be removed from the source of the exposure and decontaminated. Treatment involves supportive care and giving the person 100% oxygen. Hydroxocobalamin appears to be useful as an antidote and is generally first-line. Sodium thiosulfate may also be given. Historically, cyanide has been used for mass suicide and it was used for genocide by the Nazis.

Signs and symptoms

Acute exposure

If hydrogen cyanide is inhaled, it can cause a coma with seizures, apnea, and cardiac arrest, with death following in a matter of seconds. At lower doses, loss of consciousness may be preceded by general weakness, dizziness, headaches, vertigo, confusion, and perceived difficulty in breathing. At the first stages of unconsciousness, breathing is often sufficient or even rapid, although the state of the person progresses towards a deep coma, sometimes accompanied by pulmonary edema, and finally cardiac arrest. A cherry red skin color that darkens may be present as the result of increased venous hemoglobin oxygen saturation. Despite the similar name, cyanide does not directly cause cyanosis. A fatal dose for humans is on average 1.52 mg/kg of body weight, with the lowest recorded lethal dose being 0.56 mg/kg. Other sources claim a lethal dose is 1–3 mg per kg body weight for vertebrates.

Chronic exposure

Exposure to lower levels of cyanide over a long period, e.g. after use of improperly processed cassava roots, results in increased blood cyanide levels, which can result in weakness and a variety of symptoms, including permanent paralysis, nervous lesions, hypothyroidism, and miscarriages. Other effects include mild liver and kidney damage.

Causes

Cyanide poisoning can result from the ingestion of cyanide salts, imbibing pure liquid prussic acid, skin absorption of prussic acid, intravenous infusion of nitroprusside for hypertensive crisis, or the inhalation of hydrogen cyanide gas. The last typically occurs through one of three mechanisms:

The gas is directly released from canisters.
It is generated on site by reacting potassium cyanide or sodium cyanide with sulfuric acid.
Fumes arise during a building fire or any similar scenario involving the burning of polyurethane, vinyl or other polymer products that required nitriles in their production.

As potential contributing factors, cyanide is present in:

Tobacco smoke.
Certain seeds or kernels such as those of almonds, apricots, apples, oranges, and flaxseed.
Foods including cassava and bamboo shoots.

As a potential harm-reduction factor, vitamin B12, in the form of hydroxocobalamin, might reduce the negative effects of chronic exposure; whereas, a deficiency might worsen negative health effects following exposure to cyanide.

Mechanism

Cyanide is a potent cytochrome c oxidase inhibitor, causing asphyxiation of cells. As such, cyanide poisoning is a form of histotoxic hypoxia, because it interferes with the ability of cells to take or use oxygen in aerobic respiration.
Specifically, cyanide binds to the heme a3-CuB binuclear center of COX. This prevents electrons passing through COX from being transferred to O₂, which not only blocks the mitochondrial electron transport chain, it also interferes with the pumping of a proton out of the mitochondrial matrix which would otherwise occur at this stage. Therefore, cyanide interferes not only with aerobic respiration but also with the ATP synthesis pathway it facilitates, owing to the close relationship between those two processes.
One antidote for cyanide poisoning, nitrite, works by converting ferrohemoglobin to ferrihemoglobin, which can then compete with COX for free cyanide. Ferrihemoglobin cannot carry oxygen, but the amount of ferrihemoglobin that can be formed without impairing oxygen transport is much greater than the amount of COX in the body.
Cyanide is a broad-spectrum poison because the reaction it inhibits is essential to aerobic metabolism; COX is found in multiple forms of life. However, susceptibility to cyanide is far from uniform across affected species; for instance, plants have an alternative electron transfer pathway available that passes electrons directly from ubiquinone to O₂, which confers cyanide resistance by bypassing COX.

Diagnosis

is produced by anaerobic glycolysis when oxygen concentration becomes too low for the normal aerobic respiration pathway. Cyanide poisoning inhibits aerobic respiration and therefore increases anaerobic glycolysis which causes a rise of lactate in the plasma. A lactate concentration above 10 mmol per liter is an indicator of cyanide poisoning, as defined by the presence of a blood cyanide concentration above 40 μmol per liter. Lactate levels greater than 6 mmol/L after reported or strongly suspected pure cyanide poisoning, such as cyanide-containing smoke exposure, suggests significant cyanide exposure. However, lactate alone is not diagnostic of cyanide poisoning because lactosis is also triggered by other things, including mitochondrial dysfunction.
Methods of detection include colorimetric assays such as the Prussian blue test, the pyridine-barbiturate assay, also known as the "Conway diffusion method" and the taurine fluorescence-HPLC but like all colorimetric assays these are prone to false positives. Lipid peroxidation resulting in "TBARS", an artifact of heart attack produces dialdehydes that cross-react with the pyridine-barbiturate assay. Meanwhile, the taurine-fluorescence-HPLC assay used for cyanide detection is identical to the assay used to detect glutathione in spinal fluid.
Cyanide and thiocyanate assays have been run with mass spectrometry, which are considered specific tests. Since cyanide has a short half-life, the main metabolite, thiocyanate is typically measured to determine exposure.

Treatment

Decontamination

Decontamination of people exposed only to the gas form of hydrogen cyanide requires removal of the outer clothing and the washing of their hair. Those exposed to liquids or powders generally require full decontamination.

Antidote

The International Programme on Chemical Safety issued a survey that lists the following antidotal agents and their effects: oxygen, sodium thiosulfate, amyl nitrite, sodium nitrite, 4-dimethylaminophenol, hydroxocobalamin, and dicobalt edetate, as well as several others. Another commonly-recommended antidote is 'solutions A and B'.
The United States standard cyanide antidote kit first uses a small inhaled dose of amyl nitrite, followed by intravenous sodium nitrite, followed by intravenous sodium thiosulfate. Hydroxocobalamin was approved for use in the US in late 2006 and is available in Cyanokit antidote kits. Sulfanegen TEA, which could be delivered to the body through an intra-muscular injection, detoxifies cyanide and converts the cyanide into thiocyanate, a less toxic substance. Alternative methods of treating cyanide intoxication are used in other countries.
The Irish Health Service Executive has recommended against the use of solutions A and B because of their limited shelf life, potential to cause iron poisoning, and limited applicability. The HSE has also questioned the usefulness of amyl nitrite due to storage/availability problems, risk of abuse, and lack of evidence of significant benefits. It also states that the availability of kelocyanor at the workplace may mislead doctors into treating a patient for cyanide poisoning when this is an erroneous diagnosis. The HSE no longer recommends a particular cyanide antidote.

Agent	Description
Nitrites	The nitrites oxidize some of the hemoglobin's iron from the ferrous state to the ferric state, converting the hemoglobin into methemoglobin. Cyanide binds avidly to methemoglobin, forming cyanmethemoglobin, thus releasing cyanide from cytochrome oxidase. Treatment with nitrites is not innocuous as methemoglobin cannot carry oxygen, and severe methemoglobinemia may need to be treated in turn with methylene blue.
Thiosulfate	The evidence for sodium thiosulfate's use is based on animal studies and case reports: the small quantities of cyanide present in dietary sources and in cigarette smoke are normally metabolized to relatively harmless thiocyanate by the mitochondrial enzyme rhodanese, which uses thiosulfate as a substrate. However, this reaction occurs too slowly in the body for thiosulfate to be adequate by itself in acute cyanide poisoning. Thiosulfate must therefore be used in combination with nitrites.
Hydroxocobalamin	Hydroxocobalamin, a form of vitamin B₁₂ made by bacteria, and sometimes denoted vitamin B_12a, is used to bind cyanide to form the harmless cyanocobalamin form of vitamin B₁₂.
4-Dimethylaminophenol	4-Dimethylaminophenol has been proposed in Germany as a more rapid antidote than nitrites with lower toxicity. 4-DMAP is used currently by the German military and by the civilian population. In humans, intravenous injection of 3 mg/kg of 4-DMAP produces 35 percent methemoglobin levels within 1 minute. Reportedly, 4-DMAP is part of the US Cyanokit, while it is not part of the German Cyanokit due to side effects.
Dicobalt edetate	Cobalt ions, being chemically similar to iron ions, can also bind cyanide. One current cobalt-based antidote available in Europe is dicobalt edetate or dicobalt-EDTA, sold as Kelocyanor. This agent chelates cyanide as the cobalticyanide. This drug provides an antidote effect more quickly than formation of methemoglobin, but a clear superiority to methemoglobin formation has not been demonstrated. Cobalt complexes are quite toxic, and there have been accidents reported in the UK where patients have been given dicobalt-EDTA by mistake based on a false diagnosis of cyanide poisoning. Because of its side effects, it should be reserved only for patients with the most severe degree of exposure to cyanide; otherwise, nitrite/thiosulfate is preferred.
Glucose	Evidence from animal experiments suggests that coadministration of glucose protects against cobalt toxicity associated with the antidote agent dicobalt edetate. For this reason, glucose is often administered alongside this agent. It has also been anecdotally suggested that glucose is itself an effective counteragent to cyanide, reacting with it to form less toxic compounds that can be eliminated by the body. One theory on the apparent immunity of Grigori Rasputin to cyanide was that his killers put the poison in sweet pastries and madeira wine, both of which are rich in sugar; thus, Rasputin would have been administered the poison together with massive quantities of antidote. One study found a reduction in cyanide toxicity in mice when the cyanide was first mixed with glucose. However, as yet glucose on its own is not an officially acknowledged antidote to cyanide poisoning.
3-Mercaptopyruvate prodrugs	The most widely studied cyanide-metabolizing pathway involves utilization of thiosulfate by the enzyme rhodanese, as stated above. In humans, however, rhodanese is concentrated in the kidneys and liver A different cyanide-metabolizing pathway, 3-mercaptopyruvate sulfurtransferase, which is more widely distributed in mammalian tissues than rhodanese, is being explored. 3-MPST converts cyanide to thiocyanate, using the cysteine catabolite, 3-mercaptopyruvate. However, 3-MP is extremely unstable chemically. Therefore, a prodrug, sulfanegen sodium, which hydrolyzes into 2 molecules of 3-MP after being administered orally or parenterally, is being evaluated in animal models.
Oxygen therapy	Oxygen therapy is not a cure in its own right. However, the human liver is capable of metabolizing cyanide quickly in low doses.