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Broad-spectrum poisoning From Wikipedia, the free encyclopedia
Cyanide poisoning is poisoning that results from exposure to any of a number of forms of cyanide.[4] Early symptoms include headache, dizziness, fast heart rate, shortness of breath, and vomiting.[2] This phase may then be followed by seizures, slow heart rate, low blood pressure, loss of consciousness, and cardiac arrest.[2] Onset of symptoms usually occurs within a few minutes.[2][3] Some survivors have long-term neurological problems.[2]
| Cyanide poison | |
|---|---|
| Other names | Cyanide toxicity, hydrocyanic acid poison[1] |
| |
| Cyanide ion | |
| Specialty | Toxicology, critical care medicine |
| Symptoms | Early: headache, dizziness, fast heart rate, shortness of breath, vomiting[2] Later: seizures, slow heart rate, low blood pressure, loss of consciousness, cardiac arrest[2] |
| Usual onset | Few minutes[2][3] |
| Causes | Cyanide compounds[4] |
| Risk factors | House fire, metal polishing, certain insecticides, eating seeds such as from almonds[2][3][5] |
| Diagnostic method | Based on symptoms, high blood lactate[2] |
| Treatment | Decontamination, supportive care (100% oxygen), hydroxocobalamin[2][3][6] |
Toxic cyanide-containing compounds include hydrogen cyanide gas and a number of cyanide salts.[2] Poisoning is relatively common following breathing in smoke from a house fire.[2] 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.[3][7][8] Liquid forms of cyanide can be absorbed through the skin.[9] Cyanide ions interfere with cellular respiration, resulting in the body's tissues being unable to use oxygen.[2]
Diagnosis is often difficult.[2] 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.[2] Blood levels of cyanide can be measured but take time.[2] 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.[2]
If exposure is suspected, the person should be removed from the source of the exposure and decontaminated.[3] Treatment involves supportive care and giving the person 100% oxygen.[2][3] Hydroxocobalamin (vitamin B12a) appears to be useful as an antidote and is generally first-line.[2][6] Sodium thiosulphate may also be given.[2] Historically, cyanide has been used for mass suicide and it was used for genocide by the Nazis.[3][10]
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.[11] A fatal dose for humans can be as low as 1.5 mg/kg body weight.[12] Other sources claim a lethal dose is 1–3 mg per kg body weight for vertebrates.[13]
Exposure to lower levels of cyanide over a long period (e.g., after use of improperly processed cassava roots; cassava is a staple food in various parts of West Africa) results in increased blood cyanide levels, which can result in weakness and a variety of symptoms, including permanent paralysis, nervous lesions,[14][15][16] hypothyroidism,[15] and miscarriages.[17][18] Other effects include mild liver and kidney damage.[19][20]
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,[8] or the inhalation of hydrogen cyanide gas. The last typically occurs through one of three mechanisms:
As potential contributing factors, cyanide is present in:
As a potential harm-reduction factor, Vitamin B12, in the form of hydroxocobalamin (also spelled hydroxycobalamin), might reduce the negative effects of chronic exposure; whereas, a deficiency might worsen negative health effects following exposure to cyanide.[24]
Cyanide is a potent cytochrome c oxidase (COX, a.k.a. Complex IV) 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 via oxidative phosphorylation.[25]: 1475
Specifically, cyanide binds to the heme a3-CuB binuclear center of COX[26] (and thus is a non-competitive inhibitor of it). 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.[27]: 705
One antidote for cyanide poisoning, nitrite (i.e., via amyl nitrite), works by converting ferrohemoglobin to ferrihemoglobin, which can then compete with COX for free cyanide (as the cyanide will bind to the iron in its heme groups instead). 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.[25]: 1475
Cyanide is a broad-spectrum poison because the reaction it inhibits is essential to aerobic metabolism; COX is found in many forms of life.[28] 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.[27]: 704
Lactate 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.[29] However, lactate alone is not diagnostic of cyanide poisoning because lactosis is also triggered by many other things, including mitochondrial dysfunction.[30]
Methods of detection include colorimetric assays such as the Prussian blue test, the pyridine-barbiturate assay, also known as the "Conway diffusion method"[31] 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.
Decontamination of people exposed to hydrogen cyanide gas only requires removal of the outer clothing and the washing of their hair.[9] Those exposed to liquids or powders generally require full decontamination.[9]
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.[32] Another commonly-recommended antidote is 'solutions A and B' (a solution of ferrous sulfate in aqueous citric acid, and aqueous sodium carbonate, respectively).
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.[33] Hydroxocobalamin was approved for use in the US in late 2006[34] and is available in Cyanokit antidote kits.[35] 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.[36] Alternative methods of treating cyanide intoxication are used in other countries.
The Irish Health Service 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.[37]
| 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.[38] Treatment with nitrites is not innocuous as methemoglobin cannot carry oxygen, and severe methemoglobinemia may need to be treated in turn with methylene blue.[note 1] |
| 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.[38] |
| 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[by whom?] 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.[41] |
| 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.[42] 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.[43] 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.[44][45])
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.[46][47] |
| 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). |
The República Cromañón nightclub fire broke out 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, including 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 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, 245 fatalities were confirmed.[48][49] [when?]
Research of hydrogen cyanide by chemists Carl Wilhelm Scheele and Claude Bernard would become central to understanding the lethality of future gas chambers.[50] 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.[51] The chemical was used to murder roughly one million people in gas chambers installed in extermination camps at Auschwitz-Birkenau, Majdanek, and elsewhere.[52] Most of the people who were murdered were Jews, and by far the majority of these murders took place at Auschwitz.[53][54][a] The constituents of Zyklon B were manufactured by several companies under licenses for Degesch, a corporation co-owned by IG Farben, Degussa and Th. Goldschmidt AG. It was sold to the German Army and the Schutzstaffel (SS) by the distributors Heli and Testa, with Heli supplying it to concentration camps at Mauthausen, Dachau, and Buchenwald and Testa to Auschwitz and Majdanek.[56] Camps also occasionally bought Zyklon B directly from the manufacturers.[57] 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.[58] 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).[59] 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.[60] 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.[61]
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[62][63]) dropped into a compartment containing sulfuric acid, directly below the chair in the gas chamber.[64]
Cyanide salts are sometimes used as fast-acting suicide devices. Cyanide reacts at a higher level with high stomach acidity.
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.[89]
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