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 may have long-term neurological problems.

Toxic cyanide-containing compounds include hydrogen cyanide gas and a number of cyanide salts. 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 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 blood lactate. 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 exposure and decontaminated. Treatment involves supportive care and giving the person 100% oxygen. Hydroxocobalamin (vitamin B12_a) appears to be useful as an antidote and is generally first-line. Sodium thiosulphate may also be given. Historically cyanide has been used for mass suicide and by Nazi Germany for genocide.

Signs and symptoms

Acute exposure

If 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 changes to dark 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 can be as low as 1.5 mg/kg body weight. Other sources say 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, which are a primary food source in tropical Africa) 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

Acute hydrogen cyanide poisoning can result from inhalation of fumes from burning polymer products that use nitriles in their production, such as polyurethane, or vinyl. It can also be caused by breakdown of nitroprusside into nitric oxide and cyanide. Nitroprusside may be used during treatment of hypertensive crisis.

In addition to its uses as a pesticide and insecticide, cyanide is contained in tobacco smoke and smoke from building fires, and is present in

• many seeds or kernels such as those of almonds, apricots, apples, oranges, and in
• foods including cassava (also known as tapioca, yuca or manioc), and bamboo shoots.

Vitamin B12, in the form of hydroxocobalamin (also spelled hydroxycobalamin), may reduce the negative effects of chronic exposure, and a deficiency can lead to negative health effects following exposure.

Flaxseed also contains cyanogenic glycosides, so regular consumption of it may warrant medical advice or treatment.

Mechanism

Cyanide poisoning is a form of histotoxic hypoxia because the cells of an organism are unable to create ATP; this is primarily due to the inhibition of the mitochondrial enzyme cytochrome c oxidase. Cyanide is quickly metabolized to 2-amino-2-thiazoline-4-carboxylic acid and thiocyanate, with a half life of 10–30 minutes as a detoxifying mechanism.

Within a few hours of single ingestion, no cyanide can be detected, since all of it is metabolized, if death does not occur first. This thiocyanate has a long half life (24hrs); is it typically eliminated through the kidneys, and its toxicity is about 0.01% (ten thousand times lower) than that of the cyanide parent molecule that it results from.

Diagnosis

Lactate concentrations above 10 mmol per liter are 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.

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 (LC/MS/MS), which are considered specific tests. Since cyanide has a short half-life, the main metabolite, thiocyanate is typically measured to determine exposure. Other methods of detection include the identification of plasma lactate.

Treatment

Decontamination

Decontamination of people exposed to hydrogen cyanide gas only 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 (IPCS/CEC Evaluation of Antidotes Series) that lists the following antidotal agents and their effects: oxygen, sodium thiosulfate, amyl nitrite, sodium nitrite, 4-dimethylaminophenol, hydroxocobalamin, and dicobalt edetate ('Kelocyanor'), as well as several others. Other commonly-recommended antidotes are 'solutions A and B' (a solution of ferrous sulfate in aqueous citric acid, and aqueous sodium carbonate, respectively) and amyl nitrite.

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 is newly approved in the US and is available in Cyanokit antidote kits. Sulfanegen TEA, which could be delivered to the body through an intra-muscular (IM) 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 UK Health and Safety Executive (HSE) has recommended against the use of solutions A and B because of their limited shelf life, potential to cause iron poisoning, and limited applicability (effective only in cases of cyanide ingestion, whereas the main modes of poisoning are inhalation and skin contact). 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 (thiosulfate cyanide sulfurtransferase), 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 (or vitamer) of vitamin B12 made by bacteria, and sometimes denoted vitamin B12a, is used to bind cyanide to form the harmless cyanocobalamin form of vitamin B12.
4-Dimethylaminophenol	4-Dimethylaminophenol (4-DMAP) has been proposed in Germany as a more rapid antidote than nitrites with (reportedly) 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 (e. g. hemolysis).
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 (e.g. in the formulation 'Kelocyanor'). 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 (0.96 units/mg protein) and liver (0.15 u/mg), with concentrations in lung, brain, muscle and stomach not exceeding 0.03 U/ml. In all these tissues, it is found in the mitochondrial matrix, a site of low accessibility for ionized, inorganic species, such as thiosulfate. This compartmentalization of rhodanese in mammalian tissues leaves major targets of cyanide lethality, namely, the heart and central nervous system, unprotected. (Rhodanese is also found in red blood cells, but its relative importance has not been clarified.) A different cyanide-metabolizing pathway, 3-mercaptopyruvate sulfurtransferase (3-MPST, EC 2.8.1.2), 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 (3-MP). However, 3-MP is extremely unstable chemically. Therefore, a prodrug, sulfanegen sodium (2, 5-dihydroxy-1,4-dithiane-2,5-dicarboxylic acid disodium salt), 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 (smokers breathe in hydrogen cyanide, but it is such a small amount and metabolized so fast that it does not accumulate).

History

Fires

The República Cromañón nightclub fire occurred in Buenos Aires, Argentina on 30 December 2004, killing 194 people and leaving at least 1,492 injured. Most of the victims died from inhaling poisonous gases, and carbon monoxide. After the fire, the technical institution INTI found that the level of toxicity due to the materials and volume of the building was 225 ppm of cyanide in the air. A lethal dose for rats is between 150 ppm and 220 ppm, meaning the air in the building was highly toxic.

On 5 December 2009, a fire in the night club Lame Horse (Khromaya Loshad) in the Russian city of Perm took the lives of 156 people. Fatalities consisted of 111 people at the site and 45 later in hospitals. One of the main causes of death was poisoning from cyanide and other toxic gases released by the burning of plastic and polyurethane foam used in the construction of club interiors. Taking into account the number of deaths, this was the largest fire in post-Soviet Russia.

On 27 January 2013, a fire at the Kiss nightclub in the city of Santa Maria, in the south of Brazil, caused the poisoning of hundreds of young people by cyanide released by the combustion of soundproofing foam made with polyurethane. By March 2013, 241 fatalities were confirmed.

Gas chambers

In early 1942, Zyklon B, which contains hydrogen cyanide, emerged as the preferred killing tool of Nazi Germany for use in extermination camps during the Holocaust. The chemical was used to kill roughly one million people in gas chambers installed in extermination camps at Auschwitz-Birkenau, Majdanek, and elsewhere. Most of the people who were killed were Jews, and by far the majority killed using this method died at Auschwitz. Zyklon B was supplied to concentration camps at Mauthausen, Dachau, and Buchenwald by the distributor Heli, and to Auschwitz and Majdanek by Testa. Camps also occasionally bought Zyklon B directly from the manufacturers. Of the 729 tonnes of Zyklon B sold in Germany in 1942–44, 56 tonnes (about eight percent of domestic sales) were sold to concentration camps. Auschwitz received 23.8 tonnes, of which six tonnes were used for fumigation. The remainder was used in the gas chambers or lost to spoilage (the product had a stated shelf life of only three months).^[49] Testa conducted fumigations for the Wehrmacht and supplied them with Zyklon B. They also offered courses to the SS in the safe handling and use of the material for fumigation purposes. In April 1941, the German agriculture and interior ministries designated the SS as an authorized applier of the chemical, and thus they were able to use it without any further training or governmental oversight.

Hydrogen cyanide gas has been used for judicial execution in some states of the United States, where cyanide was generated by reaction between potassium cyanide (or sodium cyanide) dropped into a compartment containing sulfuric acid, directly below the chair in the gas chamber.

Suicide

Cyanide salts are sometimes used as fast-acting suicide devices. Cyanide reacts at a higher level with high stomach acidity.

• On 26 January 1904, company promoter and swindler Whitaker Wright committed suicide by ingesting cyanide in a court anteroom immediately after being convicted of fraud.
• In February 1937, the Uruguayan short story writer Horacio Quiroga committed suicide by drinking cyanide in a hospital at Buenos Aires.
• In 1937, polymer chemist Wallace Carothers committed suicide by cyanide.
• In the 1943 Operation Gunnerside to destroy the Vemork Heavy Water Plant in World War II (an attempt to stop or slow German atomic bomb progress), the commandos were given cyanide tablets (cyanide enclosed in rubber) kept in the mouth and were instructed to bite into them in case of German capture. The tablets ensured death within three minutes.
• Cyanide, in the form of pure liquid prussic acid (a historical name for hydrogen cyanide), was the favored suicide agent of the Third Reich. It was used to commit suicide by Erwin Rommel (1944), Adolf Hitler's wife, Eva Braun (1945), and by Nazi leaders Heinrich Himmler (1945), possibly Martin Bormann (1945), and Hermann Göring (1946).
• It is speculated that, in 1954, Alan Turing used an apple that had been injected with a solution of cyanide to commit suicide after being convicted of having a homosexual relationship—illegal at the time in the UK—and forced to undergo hormonal castration.
• Members of the Sri Lankan LTTE (Liberation Tigers of Tamil Eelam, whose insurgency lasted from 1983 to 2009), used to wear cyanide vials around their necks with the intention of committing suicide if captured by the government forces.
• On 18 November 1978, Jonestown. A total of 909 individuals died in Jonestown, many from apparent cyanide poisoning, in an event termed "revolutionary suicide" by Jones and some members on an audio tape of the event and in prior discussions. The poisonings in Jonestown followed the murder of five others by Temple members at Port Kaituma, including United States Congressman Leo Ryan, an act that Jones ordered. Four other Temple members committed murder-suicide in Georgetown at Jones' command.
• On 6 June 1985, serial killer Leonard Lake died in custody after having ingested cyanide pills he had sewn into his clothes.
• On 28 June 2012, Wall Street trader Michael Marin ingested a cyanide pill seconds after a guilty verdict was read in his arson trial in Phoenix, AZ; he died minutes after.
• On 22 June 2015, John B. McLemore, a horologist and the central figure of the podcast S-Town, died after ingesting cyanide.
• On 29 November 2017, Slobodan Praljak died from drinking potassium cyanide, after being convicted of war crimes by the International Criminal Tribunal for the former Yugoslavia.

Mining and industrial

• In 2000, a spill at Baia Mare, Romania, resulted in the worst environmental disaster in Europe since Chernobyl.
• In 2000, Allen Elias, CEO of Evergreen Resources was convicted of knowing endangerment for his role in the cyanide poisoning of employee Scott Dominguez. This was one of the first successful criminal prosecutions of a corporate executive by the Environmental Protection Agency.

Murder

• John Tawell, a murderer who in 1845 became the first person to be arrested as the result of telecommunications technology.
• Grigori Rasputin (1916; attempted, later killed by gunshot)
• Goebbels children (1945)
• Stepan Bandera (1959)
• Jonestown, Guyana, was the site of a large mass murder–suicide, in which over 900 members of the Peoples Temple drank potassium cyanide–laced Flavor Aid in 1978.
• Chicago Tylenol murders (1982)
• Ronald Clark O'Bryan (1944–1984)
• Bruce Nickell (5 June 1986) Murdered by his wife who poisoned a bottle of Excedrin.
• Richard Kuklinski (1935–2006)
• Janet Overton (1942–1988) Her husband, Richard Overton was convicted of poisoning her, but Janet's symptoms did not match those of classic cyanide poisoning, the timeline was inconsistent with cyanide poisoning, and the amount found was just a trace. The diagnostic method used was prone to false positives. Richard Overton died in prison in 2009.
• Urooj Khan (1966–2012), won the lottery and was found dead a few days later. A blood diagnostic reported a lethal level of cyanide in his blood, but the body did not display any classic symptoms of cyanide poisoning, and no link to cyanide could be found in Urooj's social circle. The diagnostic method used was the Conway diffusion method, prone to false positives with artifacts of heart attack and kidney failure.
• Autumn Marie Klein (20 April 2013), a prominent 41-year-old neuroscientist and physician, died from cyanide poisoning. Klein's husband, Robert J. Ferrante, also a prominent neuroscientist who used cyanide in his research, was convicted of murder and sentenced to life in prison for her death. However, Klein never exhibited symptoms of cyanide poisoning and the amount measured in relation to the timeline (2.2 mg/L at 15 hours after supposed ingestion but zero thiocyanate levels) suggest that the measurement was a false positive. Robert Ferrante is appealing his conviction.
• Mirna Salihin died in hospital on 6 January 2016, after drinking a Vietnamese iced coffee at a cafe in a shopping mall in Jakarta. Police reports claim that cyanide poisoning was the most likely cause of her death.
• Jolly Thomas of Kozhikode, Kerala, India, was arrested in 2019 for the murder of 6 family members. Murders took place over 14-year period and each victim ate a meal prepared by the killer. The murders were allegedly motivated by wanting control of the family finances and property.
• Mei Xiang Li of Brooklyn, NY, collapsed and died in April 2017, with cyanide later reported to be in her blood. However, Mei never exhibited symptoms of cyanide poisoning and no link to cyanide could be found in her life.

Terrorism

• In 1995, a device was discovered in a restroom in the Kayabacho Tokyo subway station, consisting of bags of sodium cyanide and sulfuric acid with a remote controlled motor to rupture them in what was believed to be an attempt by the Aum Shinrikyo cult to produce toxic amounts of hydrogen cyanide gas.
• In 2003, Al Qaeda reportedly planned to release cyanide gas into the New York City Subway system. The attack was supposedly aborted because there would not be enough casualties.

Research

Cobinamide is the final compound in the biosynthesis of cobalamin. It has greater affinity for the cyanide than cobalamin itself, which suggests that it could be a better option for emergency treatment.

See also

• List of poisonings
• Konzo