Description
- Cyanide is a highly volatile liquid that has, in the past, been utilized as a chemical warfare agent. Today, it presents most commonly from fire smoke or nitroprusside administration.
- Cyanide is a mitochondrial toxin that inhibits the activity of mitochondrial cytochrome oxidase, an enzyme necessary for normal cell respiration. As a result, it prevents cells from extracting and using oxygen from arterial blood.
- Clinical manifestations and laboratory findings stem from an inability to utilize oxygen despite its presence or availability: "Starvation among plenty."
- Toxicity ranges from extremely rapid, with death occurring within minutes, to hours depending on the amount, route of exposure, and the length of time a person is exposed.
Etiology/Risk Factors
- Smoke inhalation from fire is the most common cause of cyanide poisoning in developed countries. Hydrogen cyanide is produced from combustion of carbon-based and nitrogen-based materials; high concentrations are produced with plastic, polymer, synthetic fiber, wool, and silk substrates. Toxic and/or lethal concentrations are found in the blood in most fire victims.
- Sodium nitroprusside (SNP) use; although newer drugs with safer profiles have reduced its use today, the ability to easily titrate to desired effect (quick onset and offset) make it an attractive option in certain cases. The risk of cyanide toxicity from SNP is increased with hypoalbuminemia, cardiopulmonary bypass procedures, and moderate-to-high doses.
- Industrial exposure through metal extraction in mining, photography, electroplating in jewelry, plastics, and rubber manufacturing increases cyanide exposure.
- Suicide or homicide attempts
- Food like bitter almonds, peaches, pears, apples, and apricots are also responsible for cyanide poisoning.
- Cyanide toxicity hinders aerobic respiration by inhibiting the final enzyme in the electron transport chain (ETC), known as cytochrome c oxidase.
- Normally, the ETC couples a reaction between an electron donor (NADH) and an electron acceptor (oxygen). The ETC is located in the mitochondrial inner membrane, and as the electron passes down the chain it generates a proton gradient and potential energy across the mitochondrial membrane. The potential energy is harnessed when the protons flow back across the membrane via adenosine triphosphate (ATP) synthase (down their gradient): ADP + H+
ATP. - Normally, oxygen serves as the terminal electron acceptor at cytochrome c oxidase. In this manner, aerobic respiration is capable of producing 36 ATP from a single glucose molecule.
- Cyanide molecules inhibit cytochrome c oxidase from reducing oxygen; it binds more tightly than oxygen to the ferric ion (Fe3+) binding spot. In doing so, it hinders the ETC, and hence oxidative phosphorylation.
- Cells resort to anaerobic respiration (without oxygen); it is less efficient and produces only 2 ATP molecules in addition to lactic acid.
- "Starvation among plenty." Despite an ample oxygen supply, cells become hypoxic because they are incapable of utilizing the oxygen.
- Additionally, cyanide also nonspecifically inhibits antioxidants (catalase, glutathione reductase, superoxide dismutase); this results in the accumulation of toxic oxygen-free radicals. Furthermore, it causes the release of glutamate and inhibits the enzyme glutamic acid decarboxylase (GAD), the enzyme responsible for the formation of GABA (thus reduces the seizure threshold).
- SNP binds to the Fe3+ moiety in oxyhemoglobin to yield methemoglobin and SNP-. SNP- is a reduced and unstable molecule that spontaneously breaks down into 1 nitric oxide (therapeutic) and 5 cyanide (toxic by-product) molecules. This slow release of cyanide typically allows the body time to detoxify before it interferes with cellular respiration. Detoxificationcan occurs in two manners:
- Methemoglobin (normally comprises 2% of all hemoglobin) binds to cyanide to yield cyanomethemoglobin (a non-toxic, non-oxygen carrying hemoglobin)
- Thiosulfate binds to cyanide to yield thiocyanate via the rhodanese enzyme in the liver and kidneys. Thiosulfate levels can become exhausted with high blood concentrations of cyanide, high SNP dose, or low thiosulfate levels (e.g., malnutrition, postoperative states). Thus, it is the "rate-limiting" step for the development of cyanide toxicity.
- Absorption. Cyanide is rapidly absorbed through the respiratory tract and mucus membranes. It can be absorbed through the GI tract and skin. Protein binding: 60%; Vd 1.5 L/kg.
Prevantative Measures
- When utilizing SNP, initial rates should not exceed 0.3 µg/kg/min, and maximum rates of 10 µg/kg/min should not be maintained for more than 10 minutes. Additionally, avoid total doses >500 µg/kg when using a continuous infusion >2 µg/kg/min (cyanide is produced faster than endogenous mechanisms can handle).
- Cyanide toxicity may be more likely if a patient has hepatic dysfunction; thus consider reducing above-mentioned dosages. Thiocyanate toxicity may be more likely if there is renal dysfunction.