Cyanogen chloride (North Atlantic Treaty Organization [NATO] designation "CK") is 1 of 2 volatile cyanide military chemical warfare agents. The other similar agent is hydrogen cyanide, or AC. These agents first were used in large quantities by the French and British during World War I. Although the United States maintained 500-pound and 1000-pound cyanogen chloride (CK) bombs, these were not used during World War II. More recently, Iraq is suspected to have used a cyanidelike agent against the Kurds in the 1980s.
Although cyanogen chloride (CK) and hydrogen cyanide (AC) are similar in their toxicity, a few important differences exist. Firstly, cyanogen chloride (CK) is less volatile than hydrogen cyanide (AC), making it more effective at low concentrations. Secondly, by nature of its chlorine moiety, cyanogen chloride (CK) causes irritation of the eyes and respiratory tract and potential delayed pulmonary toxicity similar to chlorine or phosgene gases. In high concentrations (eg, in enclosed spaces), this agent is rapidly acting and lethal, causing death within 6-8 minutes if inhaled at doses at or above its LCt50 (ie, lethal concentration that kills 50% of people) (11,000 mg·min/m3).
Cyanogen chloride (CK) is synthesized in the United States for industry by Matheson Tri-Gas and is used as an organic precursor and in mining and metalworking. Therefore, an emergency physician may be more likely to encounter cyanogen chloride (CK)–exposed victims following an industrial accident rather than in a warfare or terrorism scenario.
The major source of cyanide poisoning in the United States does not come from cyanogen chloride (CK) but rather from smoke inhalation during house and/or industrial fires in which plastics (acrylonitriles, polyurethanes), wool, or silk are burned.[1, 2] Cyanide poisoning is also found in association with chemical synthesis, electroplating, mineral extraction, dyeing, photography, and agriculture.
See also Cyanide Toxicity, Hydrogen Cyanide Poisoning, as well as other topics in Warfare - Chemical, Biological, Radiological, Nuclear and Explosives.
Other than acts of terrorism or war, a mass casualty may develop in an industrial accident in which cyanogen chloride (CK) comes in contact with water (eg, during a fire-fighting expedition). Containers of cyanogen chloride (CK) may rupture or explode if exposed to high heat or following prolonged storage.
In addition to the local irritant effects of cyanogen chloride (CK), systemic toxicity occurs through mechanisms similar to those seen with hydrogen cyanide (AC) exposure.[3] Cyanogen chloride (CK) liberates a cyanide molecule, which enters the blood stream and distributes to tissues.[4] Once inside cells, cyanogen chloride (CK) binds to mitochondrial cytochrome aa3, interrupts electron transport, and creates imbalance between ATP synthesis and hydrolysis. Oxygen is unable to be used effectively as the terminal electron acceptor, which forces a shift to anaerobic metabolism. Although all organ systems are impacted, the most oxygen-dependent organs are the most affected (ie, brain, heart).
When taking a history from a patient with possible toxic gas exposure, ask about the smell and color of the gas, onset of symptoms, duration and severity of symptoms, and effect on surroundings (eg, dead animals, other people). Cyanogen chloride (CK) is a colorless liquid or gas with a pungent biting odor, which may in fact go unnoticed because of discomfort.
In low doses, symptoms that may be associated with cyanogen chloride (CK) exposure include the following:
In moderate range doses, symptoms that may be associated with cyanogen chloride (CK) exposure include the following:
In high doses, symptoms that may be associated with cyanogen chloride (CK) exposure include the following:
Although patients may suffer from any of the above symptoms, physical findings are generally nonspecific and similar to those of severe hypoxemia. Severe prolonged exposure culminates in respiratory distress, convulsions, and apnea.
Patients may have cherry red or pink skin because of concomitant carbon monoxide poisoning or because of cyanide-induced lack of oxygen extraction at the tissue level and vasodilation. Arterialization of the venous blood may also be noted at phlebotomy or upon examination of the retinal veins. However, note that bright red skin or absence of cyanosis is rarely described. Cyanosis may be observed and most likely stems from concomitant cardiovascular collapse, seizures, or apnea. Finally, many cyanide victims have normal-appearing skin.
Patients are initially hypertensive, tachypneic, and bradycardic, but eventually they become hypotensive. They may experience a transient tachycardia before spiraling into bradydysrhythmia that deteriorates into asystole.
Diagnostic tests and procedures will be briefly discussed in this section.
Cyanide poisoning is characterized by a normal arterial partial pressure of oxygen (PaO2) despite symptoms of hypoxia and an abnormally high venous oxygen pressure (PO2) (decreased arteriovenous oxygen [A-VO2] difference).
Victims of cyanogen chloride (CK) exposure may develop lowered PaO2 due to irritant effects on the respiratory tract, resulting in bronchospasm or pulmonary edema or from bradypnea or apnea.
Depending on the severity of exposure, an arterial blood gas (ABG) with a mixed respiratory and metabolic acidosis may be present. Metabolic acidosis is a hallmark of significant cyanide toxicity.
A low carbon dioxide (CO2) concentration and an elevated lactate level support the diagnosis.
Cyanide levels are generally not available in time to guide acute treatment but may be confirmatory. The preferred test is a red blood cell (RBC) cyanide level.[7, 8]
Obtain carboxyhemoglobin and methemoglobin levels, especially in victims of smoke inhalation. During treatment with sodium nitrite, observing methemoglobin levels over time may help to avoid toxic methemoglobinemia.
On electrocardiograms (ECGs), shortening of the ST segment with eventual fusion of the T wave into the QRS complex has been observed.
Depending on the severity of symptoms, endotracheal intubation may be necessary to optimize oxygen delivery and protect the airway.
Fluorescein staining and slit lamp examination of the eyes may be necessary following decontamination to assess corneal integrity.
Prehospital management of the patient with cyanogen chloride (CK) poisoning includes the following:
In the emergency department, continuation of hemodynamic support and optimization of oxygenation are the mainstays of treatment. The following management is also included:
Should patients require transfer to a facility with the appropriate level of care, hemodynamically stabilize them before transfer. Transfer with an advanced cardiac life support (ACLS) level of service under continuous cardiac monitoring with supplemental oxygen and intravenous access. Assure cyanide antidote availability before transfer.
Patients with symptoms of cyanide toxicity beyond minor upper airway irritation and those with abnormal blood gases require admission to the hospital for continued monitoring and support.
Perform continuous cardiac monitoring, and optimize oxygenation, as well as monitor serum lactate levels and arterial and venous blood gases. In addition, monitor for delayed onset of pulmonary edema in those presenting with evidence of respiratory irritation.
Consult with law enforcement authorities and the Federal Bureau of Investigation (FBI) in any suspected terrorist incident.
Consultation with a medical toxicologist and/or poison control center and intensivist may be useful.
Reevaluate patients for neurologic sequelae 7-10 days after discharge from the hospital.
Patients treated with hydroxocobalamin who develop skin erythema should be cautioned to avoid exposure to sunlight while the discoloration persists due to possible photosensitivity. These patients may also develop red discoloration of their urine as an expected side effect that resolves without treatment.
The prognosis in patients with cyanogen chloride (CK) poisoning is better in those with low-level exposures whose symptoms resolve after they are removed from exposure. However, the prognosis is generally poor in patients who suffer cardiac arrest secondary to cyanide toxicity, even if antidotes are administered promptly.
Parkinsonlike syndromes and other neuropsychiatric sequelae have been described in survivors of severe cyanide intoxication.
In high concentrations, which can be obtained in enclosed spaces, cyanogen chloride (CK) is a rapidly acting lethal agent that causes death within 6-8 minutes.
For patient education information, see Cyanide Poisoning, Chemical Warfare, Personal Protective Equipment, and Carbon Monoxide Poisoning.
The Cyanokit and Cyanide Antidote Kit will be briefly reviewed in this section, as well as the use of oxygen administration.
Cyanokit (hydroxocobalamin) has been approved by the US Food and Drug Administration (FDA) for clinical use in the treatment of cyanide toxicity in the United States. The kit contains two 2.5-g vials, which should be reconstituted with 0.9% sodium chloride (not included).[13]
Each hydroxocobalamin molecule can bind a cyanide ion by substituting it for the hydroxo ligand linked to the trivalent cobalt ion. This produces cyanocobalamin, which is then excreted in the urine.[13] Due to its relatively safe profile when compared with sodium nitrite, physicians should consider hydroxocobalamin as a first-line antidote for cyanide toxicity. Administration of hydroxocobalamin is considered safe in the setting of concomitant carbon monoxide poisoning in the setting of smoke inhalation.[13]
The Pasadena (formerly Lilly) Cyanide Antidote Kit contains amyl nitrite, sodium nitrite, and sodium thiosulfate. Theoretically, the nitrite components oxidize iron contained in hemoglobin to methemoglobin. This creates an additional site for cyanide binding and promotes dissociation from cytochrome oxidase. Resultant cyanomethemoglobin then may be converted to less toxic thiocyanate through enzymes, such as rhodanese or other sulfurtransferases, in the presence of sodium thiosulfate.
Only use amyl nitrite perles as a temporizing measure if intravenous (IV) access has not been established, as administration of IV sodium nitrite is more effective in creating therapeutic methemoglobin levels. Do not use sodium nitrite or use it only with extreme caution in the setting of concomitant carbon monoxide poisoning, owing to the risk of combined methemoglobin and carboxyhemoglobin. However, in cases of smoke inhalation in which cyanide toxicity is suspected, administration of sodium thiosulfate is safe.
Unlike carbon monoxide, inhibition of cytochrome oxidase by cyanide is thought to be noncompetitive. Therefore, oxygen has only antidotal efficacy in human cyanide poisoning through uncertain mechanisms. Patients probably should be treated with at least 100% oxygen. Humidified oxygen may be beneficial to victims of CK inhalation who are experiencing airway irritation or those with significant signs of cyanide toxicity. In addition, inhaled beta2-agonists may be used to treat bronchospasm resulting from the irritant effects of cyanogen chloride (CK) on the respiratory tract.
Hyperbaric oxygen (HBO) use may be considered for patients with cyanide toxicity that is refractory to other antidotes, especially in the setting of concomitant carbon monoxide poisoning.[14, 15, 16, 17] However, its use in pure cyanide poisoning is controversial, as no human studies have been performed to date, although the animal data are intriguing.
In 1959, Ivanov showed that HBO restored normal activity of the brain in mice poisoned with cyanide.[18] In 1966, Skene et al demonstrated a drop in mortality from 96% to 20% in a group of mice treated with HBO at 2 atmosphere absolute (ATA) compared with those treated at 1 ATA.[19] Finally, Takano and Myazaki showed in 1980 that HBO at 2 ATA reduced the pyridine nuclide fluorescence (which represents the degree of blockage of the respiratory chain) in the renal cortices of rabbits poisoned with cyanide.[20]
Clinical Context: The combination of hydroxocobalamin/vitamin B-12a interacts with cyanide to form nontoxic cyanocobalamin, which is excreted in the urine.
Clinical Context: Ampoules of amyl nitrate can be crushed into gauze and inhaled or broken into an Ambu bag and ventilated into the patient. However, this agent is used only as a temporary measure until intravenous (IV) access is obtained.
Clinical Context: Sodium nitrite is the drug of choice (DOC) if intravenous (IV) access is available and the patient is not concomitantly poisoned with carbon monoxide. This agent creates methemoglobinemia more effectively than amyl nitrite.
The recommended dose assumes a patient hemoglobin level of 12 mg/dL; dosage adjustment may be necessary in patients with anemia. Half the original dose may be repeated in 1 hour if the patient continues to exhibit signs of cyanide toxicity.
Sodium thiosulfate acts as donor of sulfane sulfur, which is used as a substrate by rhodanese and other sulfurtransferases for conversion of cyanide to thiocyanate. This agent is the drug of choice (DOC) for treating cyanide toxicity with concomitant carbon monoxide poisoning.
Antidotes either directly counteract cyanide's toxicity on the electron transport chain or help the body eliminate the cyanide molecule.
Clinical Context: Lorazepam is a first-line drug in controlling seizures related to cyanide toxicity.
Clinical Context: Phenobarbital is a second-line agent for seizures refractory to benzodiazepines.
Cyanide inhibits brain glutamate decarboxylase, which causes a decrease in the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) and contributes to convulsions. Therefore, anticonvulsant drugs such as benzodiazepines or barbiturates, which act at the GABA receptor complex, can help control seizures.
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.