Cyanide Toxicity

Etiology

Individuals at Risk of Cyanide Exposure

The most common cause of cyanide exposure is hydrogen cyanide gas exposure through inhalation, while the most common source of suicide attempts via cyanide is ingestion of cyanide salts, usually sodium or potassium cyanide. Hydrogen cyanide inhalation most commonly results from synthetic materials like plastics burning in house fires.[7][8][9][10][11][12] Dermal exposure can occur in chemical spills of cyanide salts or liquids and in patients with improper clothing decontamination after exposure, eg, a house fire.[13] Ingestion of cyanide-containing foods is an additional route of exposure. Cassava root that has been improperly processed can cause cyanide toxicity, as occurred in Uganda in 2017, in which highly cyanogenic cassava flower was traced as the cause of illness in 33 individuals.[14] Cyanide can also be found in apple seeds, flax seeds, apricot pits, and bitter almonds.[15]

Sodium nitroprusside, a vasodilating agent used in the treatment of severe hypertension, can occasionally cause cyanide toxicity as it contains several cyano groups. This generally only occurs after prolonged administration of the medication and is a rare complication. [16] In contrast, thiocyanate toxicity due to the accumulation of nitroprusside metabolites is more common, though typically less severe. Workers in industrial settings, eg, electroplating plants, have higher chronic exposure to cyanide. These individuals are at risk for acute cyanide toxicity in the event of industrial accidents and chronic toxicity from prolonged low-level occupational exposures.[17]

Epidemiology

According to annual reports of the National Poison Data System (NPDS), between 2019 and 2023, 853 exposures were reported, with 14 deaths and a 1.6% fatality rate. Adults accounted for 86.5% of exposures, while 4.2% occurred in children younger than 5. 7.6% of exposures were intentional self-harm attempts, and 68.2% were unintentional exposures.[7][9][10][11][12] Cyanide ingestions are predominately seen in male patients at a rate of 68%, with a mean age of 34.[4] A 2018 study that reviewed 49 years of cyanide exposures in 65 cases established that 84.3% of exposures were ingestions, 7.8% were inhalation, 1% dermal, and 1% intravenous.[8]

Pathophysiology

Cyanide toxicity is the result of cessation of aerobic respiration. Cyanide binds copper and iron moieties in the electron transport chain and inhibits cytochrome c oxidase activity, similar to hydrogen sulfide and carbon monoxide. The resulting inhibition of oxidative phosphorylation prevents adenosine triphosphate (ATP) production and shunts energy production to anaerobic respiration pathways, which are rapidly overwhelmed. The pathognomonic lactic acidosis of cyanide toxicity is a direct result of the arrest of aerobic respiration.[18]

Toxicokinetics

Inhalation of cyanide gas can result in symptoms within seconds, suggesting rapid absorption. Ingestion can result in symptoms within minutes to hours. Limited data is available on dermal absorption, but case reports suggest symptoms within minutes to hours as well.[18] Intravenous administration of sodium nitroprusside at therapeutic doses administered over multiple days can result in cyanide toxicity within days. Please see StatPearls' companion resource, "Sodium Nitroprusside," for further information.

The main pathway by which cyanide is eliminated from the body is via conversion to thiocyanate. The enzyme thiosulfate cyanide sulfurtransferase, also known as rhodanese, catalyzes the primary elimination pathway. This enzyme catalyzes thiosulfate sulfane sulfur group donation to cyanide to form thiocyanate. In severe exposures, thiosulfate stores are depleted, and cyanide elimination is minimal. Additional pathways of elimination exist, including via administration of hydroxocobalamin, which chelates cyanide to form cyanocobalamin. Both of these products are excreted in the urine.[30][19][20]

Lethal doses of hydrogen cyanide gas, liquids, and salts are variable, but exposures as low as 50 to 100 mg of sodium or potassium cyanide can be fatal, though 200 mg is considered to be a lethal dose for most adults. The average fatal dose of ingested cyanide is 1.52 mg/kg, with the lowest fatal dose calculated to be 0.52 mg/kg.[21] In case reports, an 84-year-old man died after ingesting 400 to 800 mg of potassium gold cyanide; an 18-year-old man survived after ingestion of 975 to 1300 mg but developed Parkinsonian symptoms.[22][23]

History and Physical

Clinical History

Proper treatment of cyanide exposure requires a thorough history and a complete physical exam. First, the treating team should determine the route of exposure, as this can predict the clinical course. The most common routes of exposure are ingestion and inhalation, while dermal exposure is less common. Additionally, the team should obtain information about how much cyanide salt the patient ingested or how long they were exposed to cyanide gas.

Patients exposed to cyanide gas presenting with mild symptoms are less likely to progress to severe symptoms once they have been removed from the source of their exposure, while patients with cyanide ingestion are more likely to progress in symptom severity.[1] Patients exposed to cyanide gas will present with their symptoms developing over seconds to minutes from the time of their initial exposure. Cyanide ingestion patients can have a longer arc of minutes to hours of symptom onset. Cases of cyanide toxicity can occur from eating cyanogenic glycosides contained in foods like cassava root, peach pits, apricot pits, and bitter almonds, and a careful dietary history should be included. 

Cyanide exposures present with broad, nonspecific findings across multiple organ systems. Neurologic symptoms include headache, confusion, and dizziness in milder exposures, while seizures and obtundation are observed in more severe exposures. Respiratory symptoms range from dyspnea and tachypnea to respiratory arrest. Gastrointestinal symptoms include abdominal cramping, nausea, and vomiting.[18]

Physical Examination Findings

Cardiovascular symptoms include tachycardia as well as ventricular dysrhythmias, including ventricular fibrillation and ventricular tachycardia. Patients may initially have hypertension and bradycardia before progressing to hypotension and eventual hemodynamic collapse.[18] Cherry red skin and bitter almond scent, classically taught as pathognomic of cyanide poisoning, are present in just 11% and 15% of cases, respectively.[8]

Evaluation

No single, readily available laboratory test has been identified to confirm cyanide poisoning; thus, diagnosis is primarily driven by clinical assessment. However, some laboratory findings are particularly suggestive of cyanide toxicity, which can support diagnosis. Due to electron transport chain inhibition, anaerobic respiration predominates, producing profound lactic acidosis. Serum lactate ≥8 mmol/L is both sensitive and specific for toxic cyanide serum concentrations in patients with suspected cyanide exposure.[24]

Furthermore, peripheral oxygen delivery and utilization are impaired with the arrest of oxidative phosphorylation secondary to cyanide. The resulting arterialization of venous blood, in which the concentration of venous oxygen resembles that of arterial blood, is indicative of cyanide toxicity. A central venous oxygen saturation >90% is suggestive of cyanide toxicity but may also be present in both hydrogen sulfide and carbon monoxide toxicity.[25] Further, venous blood may appear bright red, similar to arterial blood, due to failure of peripheral oxygen utilization and subsequent high venous blood oxygen content.

Carbon monoxide oximetry is also a valuable test to obtain in critically ill patients to narrow the differential, particularly given that patients may present with clinical features of both carbon monoxide toxicity and cyanide toxicity simultaneously. Given that patients often have nonspecific symptoms initially, additional serum studies should be obtained, including a complete blood count, basic metabolic panel, liver function tests, and cardiac biomarkers such as troponin.

Treatment / Management

Acute Stabilization

The first step in the management of a patient with acute cyanide toxicity is an assessment of the patient’s airway, breathing, and circulation, as with other emergent conditions. Patients will often present with central nervous system (CNS) depression and with respiratory status ranging from labored tachypnea to apnea. If necessary, administration of 100% oxygen should be completed while preparations are made to secure the patient’s airway with endotracheal intubation. Patients with severe toxicity may also rapidly progress to hemodynamic collapse. Therefore, care teams should be prepared to administer intravenous fluids and vasopressors to support hemodynamics.

Decontamination

If a concern for dermal exposure is present, decontaminating the patient by removing clothing and washing with soap and water is appropriate. The administration of activated charcoal may also be provided for acute ingestions. Activated charcoal adsorbs 35 mg of cyanide for each 1 g of charcoal administered.[26][27] Patients with active vomiting or CNS depression should have a secure airway in place before administration of activated charcoal to reduce the risk of charcoal aspiration.

Cyanide Antidotes

In conjunction with the assessment of the airway, breathing, and circulation, the healthcare team should rapidly assess their suspicion of cyanide exposure and the need for an antidote. The first-line antidote in the United States is hydroxycobalamin, usually in the form of the Cyanokit. Standard dosing is 5 g administered intravenously over 15 minutes with an additional possible 5 g dose. This 10 g total dose is approximately 5,000 times the recommended dose of vitamin B12 in a day. Hydroxycobalamin is preferred over sodium thiosulfate and sodium nitrite for its minimal side effect profile, which is typically limited to discoloration of skin or urine, though it may also interfere with certain laboratory tests.[28](B3)

Additional cyanide antidotes include sodium nitrite and sodium thiosulfate, which are most often given in tandem. These are less preferred for multiple reasons. Sodium nitrite produces hypotension as a side effect via vasodilatory-mediated action, which should be avoided in patients already at risk for hemodynamic collapse. Furthermore, sodium nitrite induces methemoglobin, a desired effect in the treatment of cyanide poisoning but with the associated risk of severe morbidity or mortality if high levels of methemoglobin are formed. Sodium thiosulfate has poor penetration to the brain, a location where cyanide is highly active and exerts significant damage on the basal ganglia.[19]

Differential Diagnosis

Acute cyanide exposure from inhalation often occurs concomitantly with carbon monoxide exposure in the setting of structural fires. Patients with carbon monoxide and cyanide toxicity alike can present with evidence of end-organ damage, hypoxia, hemodynamic instability, and altered mental status. Historically, a bitter almond scent and cherry red skin were used as an indicator of cyanide toxicity, but these are not reliable physical exam findings.[8] Hydrogen sulfide exposure exerts toxicity by a similar cellular mechanism to cyanide and should remain on the differential for undifferentiated patients with unexplained severe hemodynamic instability.

Prognosis

Patients with severe acute exposure requiring antidote administration and intensive care are more likely to experience long-term neurologic sequelae. Areas of the brain (eg, the basal ganglia) that are highly metabolically active are more likely to experience damage. The result of this damage is a Parkinsonian-like syndrome, which includes bradykinesia, hypomimia, slowed speech, and slowed cognition.[29] A large review of cyanide ingestions determined roughly 26% of ingestions were fatal.[8] NPDS data from 2019 to 2023 showed a 1.6% overall fatality rate across all routes of exposure and intention.[7][9][10][11][12]

Complications

Potential complications of cyanide exposure include:

• Episodic memory loss
• Nausea
• Vomiting
• Tachypnea
• Dizziness
• Arrhythmia
• Respiratory Failure
• Hypotension
• Seizure
• Gait Instability
• Dystonia
• Parkinsonian symptoms [30][31]