Hydrogen cyanide was not isolated in a pure form until 1786 when Scheele extracted it from the dye Prussian blue. Its toxicity was soon discovered by Scheele who, upon breaking the flask of his newly found fluid, was killed by the resulting vapours.
Cyanide is a rapidly toxic agent that is found in liquid and gaseous form. It is used in many chemical compounds including medications and can be found endogenously in plant and bacteria. It is important to know the unique mechanism of action of this poison as delay in treatment can have disastrous consequences to the patient.
Industries that use cyanide include metal extraction and refining, electroplating, photography and fumigation. Suicides are the commonest cause of cyanide poisoning. Deliberate contamination of medications and food has occurred recently. Another source of cyanide includes the combustion of wool, silk, synthetic rubber and polyurethane.
The availability of antidotes to cyanide poisoning varies around the world. In Australia dicobalt edetate IV, sodium nitrite IV and sodium thiosulfate are available. In North America amyl nitrate pearls for inhalation can also used be used. Hydroxocobalamin is widely used in Europe but only has limited availability in North America and Australia.
The management of cyanide poisoning requires firstly the identification of patients who may be at risk of cyanide poisoning and the selection of antidotes. This is complicated by the lack of a readily available assay and the variability of available antidotes. With an understanding of these concepts, you too, will be able to treat that secret agent who is trying to kill himself (or herself) before they reveal the secret plans.
Average lethal dose of HCN taken by mouth between 60 and 90 mg (adult); this corresponds to about 1 teaspoonful of a 2% solution of hydrocyanic acid and to about 200 mg of potassium cyanide.
Toxic by respiratory, oral and dermal routes.
There appear to be two mechanisms explaining the toxic effects resulting from cyanide poisoning.
i. inhibitive binding to the cytochrome oxidase system, and;
ii. a vasogenic response.
Figure. Inhibitive binding to cytochrome a-a3
This intra-mitochondrial enzyme is an essential catalyst for the use of oxygen to reoxidise reduced cytochrome a-a³. The cyanide ion is attracted to and will bind the ferric (Fe3+ ) iron in this enzyme. Its inhibition essentially halts electron transport and intra-cellular respiration. This leads to anaerobic respiration and production of a severe lactic acidosis.
A high level of cyanide intoxication has been noted to cause pulmonary oedema believed to be secondary to left ventricular failure and increased pulmonary wedge pressure caused by pulmonary-arteriolar and/or coronary arterial vasoconstriction.
These vary from mild vertigo, headache and confusion to precipitous death related to pulmonary oedema/cardiac arrest. Patients are classically described as being “pink” due to elevated venous oxygen content (similar to CO poisoning). In fact intoxicated patients frequently present cyanosed. Lactic acidosis is a prominent feature on biochemical investigation.
100% O2, or as close to this as can reasonably be obtained, does have some antidotal effect. More particularly O2 increase efficacy of the other antidotes used in the treatment of cyanide intoxication.
This compound enhances the body’s detoxification of cyanide ions by providing exogenous sulphate to enhance metabolism of cyanide to thiocyanate (via the sulphurtransferase enzyme rhodanese), which is subsequently excreted in the urine. It does not have the rapid ability to reactivate cellular respiration as the cyanide ion binding compounds outlined below. It is generally accepted that sodium thiosulphate should be administered in all moderate and severe poisonings.
This provides alternate binding sites for cyanide ions thus preventing binding to, or enhancing the removal from, the cytochrome oxidase enzyme complex.
a. Methaemoglobin: Cyanide will bind to methaemoglobin formed after administration of:
i. Amyl nitrite;
ii. Sodium nitrite, or;
b. Cobalt containing drugs: Cyanide ions will bind to cobalt which can be supplied in the form of either;
i. Dicobalt edetate, or
A controversial antidote. Original theory that its effect was related to formation of methaemoglobin (see under sodium nitrite) appears flawed as too little is produced
(approx. 2-3%). Now thought to be useful by reversing the vasoconstrictive action of severe cyanide poisoning. To be efficacious amyl nitrite must be used in association with O² by breaking the ampoule within the O² supplying mask.
This forms methaemoglobin (Fe3+ ) from haemoglobin (Fe2+ ). If enough methaemoglobin is formed in the blood stream it attracts cyanide away from inhibited cytochrome oxidase, by mass action, forming cyan-methaemoglobin and allowing resumption of cellular respiration. This antidote should be administered in conjunction with thiosulphate.
Sodium nitrite is contra-indicated for the treatment of those suffering concurrent carbon monoxide and cyanide poisoning, as may be expected in fire victims. The loss of oxygen carrying capacity due to carboxyhaemoglobin generated by exposure to smoke is exacerbated if methaemoglobinaemia is intentionally induced for the treatment of cyanide intoxication. Sodium nitrite may cause haemolysis in G6PD deficient patients, and an extended period of methaemoglobinaemia in those with a methaemoglobin reductase deficiency.
Dicobalt edetate chelates the cyanide ions, and each molecule is able to bind to two cyanide ions. A variety of animal studies have shown dicobalt edetate to be superior to both sodium nitrite alone, or in combination with sodium thiosulphate. Though some have questioned the validity of these results when extrapolated to man.
A drawback to dicobalt edetate use is its side-effect profile. Significant adverse reactions include; convulsions, angioedema, laryngeal oedema, urticaria, chest pains, dyspnoea, hypotension and ventricular arrhythmia. It has been reported dicobalt edetate toxicity is reduced in the presence of the cyanide ion, hence the observed reactions may be due to the use of this compound where cyanide intoxication was not present. Indeed the product literature comments that cobalt is normally toxic and the clinician must confirm the condition treated is indeed cyanide poisoning
Hydroxocobalamin chelates to cyanide by giving up an hydroxyl group and binding a cyano group forming non-toxic cyanocobalamin, which can then be excreted in the urine.
An effective antidote without significant apparent side effects, but its use is limited by expense.
Cyanide presents a number of hazards to those rendering first-aid/medical treatment to victims. It is dangerous both dermally, even the gas, and via the respiratory route. Vomitus is likely to liberate hydrogen cyanide gas.
Mouth to mouth/nose artificial respiration is contra-indicated due to hazard.
Gastric decontamination either by induction of emesis or conventional gastric lavage, may be hazardous to those attending the patient. Activated charcoal maybe be administered, especially following cyanogenic glycoside ingestion.
In those patients presenting with dilated non-reactive pupils and deteriorating cardio-respiratory function
Sodium nitrite should not be used in the presence of concomitant carbon monoxide poisoning, or in those with G6PD deficiency. Prolonged methaemoglobinaemia may occur in those patients with a methaemoglobin reductase deficiency.
Dicobalt edetate is not recommended for use if the diagnosis of cyanide intoxication is in doubt.