Cyanide poisoning

Cyanide poisoning
Specialty	Emergency medicine

Cyanide poisoning occurs when a living organism is exposed to a compound that produces cyanide ions (CN⁻) when dissolved in water. Common poisonous cyanide compounds include hydrogen cyanide gas and the crystalline solids potassium cyanide and sodium cyanide. The cyanide ion halts cellular respiration by inhibiting an enzyme in mitochondria called Cytochrome C Oxidase.

Acute poisoning

Cyanide makes the cells of an organism unable to use oxygen, primarily through the inhibition of cytochrome c oxidase. Inhalation of high concentrations of cyanide causes a coma with seizures, apnea, and cardiac arrest, with death following in a matter of minutes. At lower doses, loss of consciousness may be preceded by general weakness, giddiness, 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 victim progresses towards a deep coma, sometimes accompanied by pulmonary edema, and finally cardiac arrest. Skin color goes pink from cyanide-hemoglobin complexes. A fatal dose for humans can be as low as 1.5 mg/kg body weight. Blood cyanide concentrations may be measured as a means of confirming the diagnosis in hospitalized patients or to assist in the forensic investigation of a criminal poisoning. Cyanide toxicity can occur following ingestion of amygdalin (found in almonds and apricot kernels and marketed as an alternative cancer cure), prolonged administration of nitroprusside, and after exposure to gases produced by the combustion of synthetic materials.

Chronic exposure

Exposure to lower levels of cyanide over a long period (e.g., after use of cassava roots as 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 abortions. Other effects include mild liver and kidney damages.

Treatment of poisoning and antidotes

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. Alternative methods of treating cyanide intoxication are used in other countries.

Agent	Description
Nitrites and sodium thiosulfate	The nitrites oxidize some of the hemoglobin's iron from the ferrous state to the ferric state, converting the hemoglobin into methemoglobin. (Treatment with nitrites is not innocuous as methemoglobin cannot carry oxygen, and methemoglobinemia needs to be treated in turn with methylene blue). Cyanide preferentially bonds to methemoglobin rather than the cytochrome oxidase, converting methemoglobin into cyanmethemoglobin. In the last step, the intravenous sodium thiosulfate converts the cyanmethemoglobin to thiocyanate, sulfite, and hemoglobin. The thiocyanate is then excreted in the urine.
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. Hydroxocobalamin is newly approved in the US and is available in Cyanokit antidote kits. Cyanocobalamin is then eliminated through the urine. Hydroxocobalamin works both within the intravascular space and within the cells to combat cyanide intoxication. This versatility contrasts with methemoglobin, which acts only within the vascular space as an antidote. Administration of sodium thiosulfate improves the ability of the hydroxocobalamin to detoxify cyanide poisoning. This treatment is considered so effective and innocuous that it is administered routinely in Paris to victims of smoke inhalation to detoxify any associated cyanide intoxication. However it is relatively expensive and not universally available.
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 salts have also been demonstrated as effective in binding 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 diagnoses of cyanide poisoning.
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 Grigory 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	Antidotes for the therapeutic management of cyanide poisoning, especially in the U.S., have relied mainly on the enzyme rhodanese (thiosulfate/cyanide sulfurtransferase, EC 2.8.1.1) for detoxification. This enzyme uses thiosulfate to form an activated-sulfane complex, which reacts with cyanide to form the less-toxic thiocyanate, that is excreted in the urine. Rhodanase is concentrated in the liver and kidneys where it is found in the mitochondrial matrix, a site of low accessibility for ionized, inorganic species, such as thiosulfate. This compartmentation of rhodanase in mammalian tissues leaves major targets of cyanide lethality, namely, the heart and central nervous system unprotected. (Rhodanase is also found in red blood cells, but its relative function has not been clarified.) Researchers at the University of Minnesota are exploiting a different cyanide metabolic pathway in their antidote program: 3-mercaptopyruvate sulfur transferase (3-MPST, EC 2.8.1.2) which is more widely distributed in mammalian tissues than rhodanase. Analogous to rhodanase, 3-MPST uses its substrate to convert cyanide to thiocyanate, but instead of thiosulfate, the natural substrate of 3-MPST is the cysteine catabolite, 3-mercaptopyruvate (3-MP). However, 3-MP is chemically unstable, and attempts at intravenous administration to counteract the toxicity of cyanide have been unsuccessful due to this instability. The Minnesota researchers have therefore developed an effective prodrug of 3-mercaptopyruvate that, when administered orally or parenterally, forms 3-MP. These cyanide antidotes are under advanced preclinical evaluation at the University of Minnesota
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). Therefore if the patient received a low dose and can be kept comfortable with just oxygen alone, then the liver can be left to destroy the cyanide.

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 [2]. Other commonly-recommended antidotes are 'solutions A and B' (a solution of ferrous sulfate in aqueous citric acid, and aqueous sodium carbonate) and amyl nitrite.

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. Qualified UK first aiders are now only permitted to apply oxygen therapy using a bag valve mask, providing they have been trained in its usage.

• Cyanides have been used for judicial execution in some parts of the United States.
• Some notable persons who committed suicide by cyanides (either cyanide salt or hydrogen cyanide) are Eva Braun, Wallace Carothers, Odilo Globocnik, Joseph Goebbels, Hermann Göring, Heinrich Himmler, Adolf Hitler (in combination with a gunshot), Günther von Kluge, Erwin Rommel, Alan Turing and the Liberation Tigers of Tamil Eelam.
• The mass suicide/murder of The People's Temple in Jonestown was accomplished with cyanide poisoning.

Historical cases

Gas chambers

• Hydrogen cyanide gas was the agent used by Nazi Germany for mass murder in some gas chambers during the Holocaust. It was released from Zyklon B pellets, which were a commercial biocide. Prior to its use on an industrial scale at Auschwitz and other concentration camps, the Nazis used carbon monoxide from engine exhaust gases, in addition to shooting their numerous victims.
• Cyanide has also been used for judicial execution in some parts of the United States, where cyanide was generated by reaction between potassium cyanide dropped into a compartment containing sulfuric acid, directly below the chair in the gas chamber.

War

Cyanides were stockpiled in both the Soviet and the United States chemical weapons arsenals in the 1950s and 1960s. However, as a military agent, hydrogen cyanide was not considered very effective, since it is lighter than air and needs a significant dose to incapacitate or kill.

Although there have been no verified instances of its use as a weapon, hydrogen cyanide may have been employed by Iraq in the Halabja poison gas attack against the Kurds in the 1980s under Saddam Hussein. This information has not been verified.

Suicide

Cyanide salts are sometimes used as fast-acting suicide devices. Cyanide is reputed to work faster on an empty stomach.

• In February 1937, the Uruguayan short story writer Horacio Quiroga committed suicide drinking cyanide in a hospital at Buenos Aires.
• In 1937, the famous polymer chemist, Wallace Carothers, committed suicide by cyanide.
• Cyanide, in the form of pure liquid prussic acid (a historical name for hydrogen cyanide), was a favored suicide agent of the Third Reich. It was used to commit suicide by Erwin Rommel (1944), after being accused of conspiring against Hitler; Adolf Hitler's wife, Eva Braun (1945); and by Nazi leaders Joseph Goebbels (1945), Heinrich Himmler (1945), possibly Martin Bormann (1945), and Hermann Göring (1946). Adolf Hitler himself bit a cyanide capsule while simultaneously firing his pistol into his right temple. (1945).
• 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 hormone treatment.
• Jonestown, Guyana was the site of a large mass suicide/murder, in which over 900 members of the Peoples Temple drank potassium cyanide-laced Flavor Aid in 1978.
• Members of the Sri Lankan LTTE (Liberation Tigers of Tamil Eelam, whose insurgency lasted from 1983 to 2009), used to wear cyanide vials in their necks with the intention of committing suicide if captured by the government forces.

Murder

See:

• Grigori Rasputin (1916)
• Goebbels children (1945)
• Tylenol murders (1982)
• Ronald Clark O'Bryan (1984)

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 reportedly aborted because there would not be enough casualties.

In fiction

Homicide

• In Agatha Christie's And Then There Were None, the first death occurs from cyanide poisoning.

• In Agatha Christie's Sparkling Cyanide (also entitled Remembered Death), based upon her Hercule Poirot short story entitled "Yellow Iris", Rosemary and George Barton are poisoned by cyanide crystals.

• In the Joseph Kesselring play Arsenic and Old Lace, two old ladies mix wine with arsenic, cyanide and strychnine to use to kill old men.

• Raymond Chandler uses "a little potassium hydrocyanide" against private detective Philip Marlowe in "The Little Sister" -- "merely relaxing".

• In Hit Man: A Technical Manual for Independent Contractors by 'Rex Feral', the use of cyanide to poison a mark is explained in detail.

• The Detective Conan manga/anime series has a large number of cases in which the victims are killed by cyanide, with all or most mentioning an 'almond scent' to describe it.

Suicide

• In Agatha Christie's novel The Hollow, woman called Gerda Christow kills herself when she gets caught by murder of her husband.

• In Oscar Wilde's novel The Picture of Dorian Gray, actress Sibyl Vane dies from swallowing something with "either prussic acid or white lead in it".

• In Ford Madox Ford's 1915 novel The Good Soldier, the narrator's wife commits suicide by drinking a flask of prussic acid disguised as Amyl nitrite.

• Australian author Nevil Shute's 1957 novel about life after nuclear war, On the Beach, gives the scenario of the Australian government giving survivors free cyanide tablets to commit suicide rather than face death from radiation poisoning.

• In Phoenix Wright: Ace Attorney: Trials and Tribulations, the third case solved by the player involves a programmer who is murdered when potassium cyanide is slipped into his coffee at a restaurant.

• In the James Bond movies and novels, 00 agents are issued cyanide capsules for use in the event of capture by the enemy. James Bond is described as having thrown his away.

• In the 2008 Doctor Who episode The Unicorn and the Wasp, the Doctor is nearly poisoned by cyanide, but manages to metabolize it and detoxify himself using a combination of proteins, salt, and a shock, plus the advantage of his non-human anatomy.

• In the film Unknown, Jürgen commits suicide by emptying a bag of sodium cyanide into his coffee, disguised as a packet of sugar.

• In the film Captain America: The First Avenger, Heinz Kruger commits suicide by cyanide tablet upon being caught.

• In the video game Penumbra: Black Plague, staff members of the Archaic are issued cyanide capsules to commit suicide should they become infected.

Other

• In the film Jaws 2, the protagonist, Police Chief Martin Brody (Roy Scheider) attempted to use Sodium Cyanide to kill the shark.

See also

• Victims of poisoning
• Konzo