This article addresses the management of hydrogen cyanide (HCN) poisoning. HCN (North Atlantic Treaty Organization [NATO] designation AC) is 1 of 2 cyanide chemical warfare agents[1, 2, 3] ; the other is cyanogen chloride (NATO designation CK).
Cyanide is a rapidly lethal agent when used in enclosed spaces where high concentrations can be achieved easily.[4, 5, 6, 7] In addition, because of the extensive use of cyanide in industry in the United States, this agent presents a credible threat for terrorist use.[2] Emergency physicians may also encounter cyanide casualties resulting from industrial accidents or fires.
Cyanide was first used as a chemical weapon in the form of gaseous HCN in World War I. Starting in 1915, the French military used approximately 4000 tons of cyanide, without notable success. The failure of this measure was probably attributable to the high volatility of cyanide and the inability of the 1- to 2-lb munitions used to deliver the amounts of chemical required for biologic effects.[2, 3]
The introduction of cyanogen chloride by the French in 1916 made available a compound that, being both more toxic and less volatile, was a more effective chemical agent. Other alleged military uses of cyanide include Japanese attacks on China before and during World War II and Iraqi attacks on Kurds in the 1980s.
For related information, see the Disaster Preparedness and Aftermath Resource Center.[8, 9]
Whereas liquid cyanide can be absorbed through the skin or eyes, the primary route of exposure is by inhalation or ingestion. Once absorbed, cyanide is distributed rapidly to all organs and tissues in the body. It inhibits multiple enzymes, most importantly cytochrome a3, a component of cytochrome oxidase in the electron transport chain of the mitochondria. This prevents intracellular oxygen use and the generation of cellular adenosine triphosphate (ATP), causing aerobic energy production to cease.
Hydrogen ions accumulate as they fail to combine with oxygen at the end of the electron transport chain, causing a metabolic acidosis. As anaerobic metabolism ensues, pyruvate accumulates and is converted to lactate, resulting in an elevated lactate concentration.[10]
The LCt50 (the concentration-time product capable of killing 50% of the exposed group) for HCN is 2500-5000 mg/min/m3. The lethal oral doses of HCN and cyanide salts are estimated to be 50 mg and 100-200 mg, respectively. The LD50 (the dose capable of killing 50% of the exposed group) for skin exposures is estimated to be 100 mg/kg. Vapor exposures in high concentrations (at or above the LCt50) typically can cause death in 6-8 minutes.[11]
Causes of cyanide casualties include deliberate use as a chemical warfare agent, industrial exposures, and toxic byproducts of fires.[12, 11] Emergency physicians are unlikely to encounter casualties from HCN used as a weapon except in the setting of a terrorist attack[11] ; the other causes are more common.
Specific industrial processes involving cyanide include metal cleaning, reclaiming, or hardening; fumigation; electroplating; and photo processing.[12] Other potential sources of cyanide are fires involving plastics or synthetics, acrylic nail removers containing acetonitrile or propionitrile, and nitroprusside infusions.[12] Numerous plants (eg, apricots, apples, and bitter almonds) contain within their seeds and pits amygdalin, which can be hydrolyzed to HCN after the ingestion and may be poisonous in large quantities.[12]
The prognosis is good for patients who have only minor symptoms that do not necessitate the administration of antidotes.
The prognosis is poor in patients with cyanide poisoning sufficiently severe to cause cardiovascular collapse. In a mass casualty setting, these victims would be classified as expectant.
The prognosis is fair for patients with seizures or recent-onset apnea if antidotes can be administered rapidly. In a mass casualty setting, these victims would be classified as immediate.
It is important that patients exposed to HCN be educated about potential neurologic sequelae and the importance of follow-up evaluation.
For patient education resources, see the Bioterrorism and Warfare Center and the Poisoning Center, as well as Chemical Warfare, Personal Protective Equipment, Cyanide Poisoning, and Carbon Monoxide Poisoning.
Key historical features for suspected hydrogen cyanide (HCN) casualties include onset, severity, and time course of symptoms; time, nature, and route of exposure; presence of smoke; odors and colors of gas; effects on surroundings (eg, dead animals or other human casualties); and evidence of exposure to other chemicals or coingestants. As many as 50% of patients exposed to cyanide may describe an odor of bitter almonds.[12, 11]
Symptoms after exposure to high vapor concentrations may include the following:
Symptoms after exposure to lower vapor concentrations or after ingestion or liquid exposure may include the following:
Patients exposed to cyanogen chloride experience severe eye and mucous membrane irritation.[13] Low-dose exposure results in rhinorrhea, bronchorrhea, and lacrimation. Inhalational exposure results in dyspnea, cough, and chest discomfort. Exposure to nitriles (acetonitrile and/or propionitrile) may be associated with a significant delay in onset of symptoms.
Physical findings are nonspecific and are similar to those of severe hypoxemia, including the following:
Classically, the skin of a cyanide-poisoned patient is described as cherry red in color due to elevated venous oxygen content resulting from failure of tissues to extract oxygen. In addition, arterialization of the venous blood may also be noted during phlebotomy or examination of the retinal veins. Alternatively, patients may be cyanotic after prolonged respiratory failure and shock. Despite its name, cyanosis is not a prominent finding of cyanide poisoning.
Patients may demonstrate diaphoresis with normal or dilated pupils. Initial hypertension and compensatory bradycardia are followed by hypotension and tachycardia. Terminal hypotension is accompanied by bradyarrhythmias before asystole.
Cyanide toxicity is characterized by a normal arterial oxygen tension and an abnormally high venous oxygen tension, resulting in a decreased arteriovenous oxygen difference (A-VO2). Also characteristic are a high-anion-gap metabolic acidosis and an elevated lactate level.[4, 10] In patients clinically suspected of cyanide poisoning, a serum lactate concentration above 8 mmol/L is a sensitive marker of toxicity.[10]
Serum cyanide concentrations are generally not available in time to guide acute treatment but may be confirmatory. The preferred test is a red blood cell (RBC) cyanide concentration. With this method, mild toxicity is observed at concentrations of 0.5-1.0 μg/mL. Concentrations of 2.5 μg/mL and higher are associated with coma, seizures, and death.
Obtain carboxyhemoglobin levels to exclude carbon monoxide poisoning, especially in smoke inhalation victims. Obtain a methemoglobin level, especially in cyanotic patients and following treatment of cyanide poisoning with sodium nitrite.
On electrocardiography (ECG), nonspecific findings predominate. Sinus bradycardia, tachycardia, heart block, or myocardial ischemic patterns may be noted.
Appropriate prehospital measures include the following[14, 15] :
Administer cyanide antidotes as soon as possible.[16, 14, 15] While not carried by all emergency medical technicians, some first responders do have protocols to administer hydroxocobalamin in the field.
In the emergency department (ED), continue hemodynamic support and monitoring, oxygenation, ventilatory support, and seizure control.[15] Endotracheal intubation is indicated for treatment of significant cyanide casualties.
If not already given, cyanide antidotes should be administered as soon as possible,[16] without delay for confirmatory red blood cell (RBC) cyanide levels. Consider gastric lavage followed by the administration of activated charcoal in recent ingestions. The gastric aspirate may cause secondary contamination and should be viewed as hazardous.
Hydroxocobalamin (Cyanokit) is currently the first-line antidote for cyanide poisoning in the United States. Approved by the US Food and Drug Administration (FDA) in 2006, this vitamin B-12 precursor has a central cobalt moiety that complexes with cyanide to form cyanocobalamin (vitamin B-12). Cyanocobalamin is either eliminated in the urine or it dissociates from cyanide at a slow enough rate to allow for cyanide detoxification via endogenous rhodanese activity.
The adult starting dose is 5 g administered intravenously over 15 minutes with a subsequent repeat dose if the patient initially responds but then decompensates again. Potential adverse effects include allergic reaction (including anaphylaxis and angioedema) and transient hypertension. Hydroxocobalamin also causes a transient reddish discoloration of the urine, tears, and other bodily fluids, causing a decreased accuracy of colorimetric laboratory tests.[17] Carboxyhemoglobin concentrations, of particular importance in fire victims, may be falsely lowered.
The Taylor (formerly Lily or Pasadena) Cyanide Antidote Kit contains amyl nitrite, sodium nitrite, and sodium thiosulfate. This was previously the first-line therapy for cyanide poisoning but is now considered second-line therapy after hydroxocobalamin. The nitrite components oxidize iron contained in hemoglobin to methemoglobin. This creates an additional high-affinity site for cyanide binding and promotes dissociation from cytochrome oxidase. Amyl nitrite pearls should be used as a temporizing measure only if IV access has not been established; administration of IV sodium nitrite is more effective in creating therapeutic methemoglobin levels.[16]
These nitrite-containing components of the cyanide antidote kit must be used with caution because they may result in significant hypotension and cardiovascular collapse.[16] Production of methemoglobin reduces oxygen-carrying capacity and, when excessive, can be life-threatening.
Sodium thiosulfate donates a sulfur atom necessary for cyanide transformation to thiocyanate by rhodanese, thus increasing activity of the endogenous detoxification system. This component of the Cyanide Antidote Kit lacks the inherent risks of the methemoglobin generators and is widely used as an adjunct to hydroxocobalamin therapy.
In the setting of concomitant carbon monoxide poisoning, the nitrites should not be administered. Patients with elevated carboxyhemoglobin levels already have an underlying diminished oxygen-carrying capacity, and further decreases by the production of methemoglobinemia may be lethal. However, in cases of smoke inhalation in which cyanide toxicity is suspected, administration of sodium thiosulfate is safe.[16]
Treat patients with 100% oxygen. Although hyperbaric oxygen therapy may have theoretical benefit in the treatment of cyanide poisoning, the rapid time course of both onset and recovery of cyanide poisoning renders it impractical.
Patients who present with more than minimal symptoms that resolve without treatment should be admitted for observation and supportive care. Also, a 24-hour observation period is necessary for those exposed to nitriles because delayed onset of toxicity can occur.[14, 15]
Oxygenation should be optimized and continuous cardiac monitoring provided. Serum lactate concentrations, chemistries, and arterial or venous blood gases should be monitored. Patients should be reevaluated for neurologic sequelae 7-10 days after discharge from the hospital.[18]
[#FollowupTransfer]If a patient requires transfer to a higher-level medical facility, the transferring physician should ensure availability of an advanced emergency medical service unit that can provide continuous cardiac and hemodynamic monitoring and oxygen therapy.
Consultation with a medical toxicologist or a poison control center is recommended. They should be contacted immediately upon consideration of cyanide as a diagnosis, given the critical nature of these patients.[2] Online resources may also be consulted (see the chart below).
Chemical terrorism agents and syndromes: signs and symptoms (PDF) (Copyright University of North Carolina at Chapel Hill)
In any suspected terrorist attack, it is essential to contact local law enforcement authorities and the Federal Bureau of Investigation (FBI).
The key medications for hydrogen cyanide (HCN) poisoning are cyanide antidotes. Hydroxocobalamin (HCO, vitamin B-12) is the first-line therapy for cyanide toxicity. It functions by binding cyanide to its cobalt ion to form cyanocobalamin, which is essentially nontoxic and is cleared renally. HCO can be combined with sodium thiosulfate administration for accelerated detoxification. The nitrite-containing components of a cyanide antidote kit must be used with caution because they may result in significant hypotension and cardiovascular collapse, in addition to generating consequential levels of methemoglobin. However, in cases of smoke inhalation in which cyanide toxicity is suspected, administration of sodium thiosulfate is safe.
Clinical Context: Hydroxocobalamin complexes with cyanide to form nontoxic cyanocobalamin (vitamin B12); its disadvantages are that a large dose is required for antidotal efficacy and that it is available in the United States only in very dilute solutions.
It can cause transient hypertension, allergic reactions (rarely including anaphylaxis and angioedema), and a reddish discoloration of body fluids.
Clinical Context: Amyl nitrite pearls can be crushed and inhaled by a spontaneously breathing patient or ventilated into an apneic patient using a bag-valve-mask device; this is a temporizing measure until intravenous (IV) access can be established. Due to the volatile nature of this compound, rescuers should ensure that they themselves have an adequate fresh air supply and can maintain a sufficient distance from the amyl nitrite source.
Clinical Context: Sodium nitrite is the favored methemoglobin generator of the Cyanide Antidote Kit once IV access is established.
Clinical Context: Sodium thiosulfate donates sulfur, which is used as a substrate by rhodanese and other sulfurtransferases for detoxification of cyanide to thiocyanate. It can be administered with hydroxocobalamin in severe cases.
Clinical Context: Activated charcoal binds cyanide poorly; 1 g of charcoal adsorbs only 35 mg of cyanide. Nonetheless, a 1-g/kg dose of charcoal could potentially bind a lethal dose of cyanide and, given its low risk profile, charcoal should be administered as soon as possible following oral ingestion of cyanide salts or organic cyanides.
Administration of antidotes, which counteract the toxic effects of cyanide, is critical for life-threatening intoxication. The first-line therapy is hydroxocobalamin. Alternatively, the Taylor (formerly Lily or Pasadena) Cyanide Antidote Package contains amyl nitrite, sodium nitrite, and sodium thiosulfate.
Chemical Terrorism Agents and Syndromes. Signs and symptoms. Chart courtesy of North Carolina Statewide Program for Infection Control and Epidemiology (SPICE), copyright University of North Carolina at Chapel Hill, www.unc.edu/depts/spice/chemical.html.