Clinical Overview

Cyanide has been recognized since antiquity as a poison that is present in bitter almonds, cassava and other foods. The purified gaseous form, hydrogen cyanide [HCN], was discovered in the 18th century. Currently several forms are used extensively in industry for tasks such as fumigation, electroplating and mining activities.

Cyanide gas exists as the vapor of preparations that are liquid at room temperature: examples are HCN and cyanogen chloride [CNCl, also known as CK]. Solid preparations are the cyanide salts formed with sodium, potassium or calcium.

Cyanide has been utilized in various forms to inflict intentional harm, and is considered a chemical weapon of concern for use by terrorists. Cyanide is relatively easy and cheap to generate. A terrorist event could occur using any form of cyanide, but solid preparations may be preferentially utilized. A large-scale terrorist event - such as contamination of municipal water supplies - is unlikely, due to the enormous amount of cyanide that would be required to achieve meaningful levels in a large body of water. Single or multiple local events are more likely. The current threat of cyanide use is both domestic and international, with caches being uncovered in raids in the United States and abroad.

Clinical Presentation

Note that this discussion focuses on acute cyanide toxicity. Exposure, diagnosis, treatment, and outcomes of chronic cyanide poisoning may be significantly different and will not be addressed here.

Cyanide inhibits mitochondrial cytochrome oxidase, which is necessary for oxidative respiration. Cells are unable to utilize oxygen; for this reason, cyanide has been described as an asphyxiating agent. The primary target organ in cyanide poisoning is the brain, but multiple systems are involved and there may be additional toxicity mechanisms that cause direct cardiovascular damage.

Cyanide toxicity depends on dose and route of exposure. Direct comparisons between lethality of inhaled, ingested and absorbed forms of cyanide are difficult, but any preparation of cyanide can be fatal. As discussed above, the route of exposure will depend upon the particular cyanide formulation. Clinical presentation will depend on route of exposure, but the hallmark of cyanide poisoning is shock and acidosis.

The common final pathway for cyanide intoxication is cellular hypoxia with acidosis, leading to nonspecific symptoms such as headache and delirium. Other signs can be described by system:

• CNS: Dizziness, nausea, vomiting, drowsiness, tetany, trismus, hallucations
• Cardiovascular: Arrhythmia, hypotension. Tachycardia and hypertension may occur transiently in early stages
• Respiratory: Dyspnea, with initial hyperventilation followed by hypoventilation and pulmonary edema. Cyanosis is usually not apparent, since blood is adequately oxygenated - hypoxia occurs because cells are unable to utilize available oxygen.

Diagnosis

Because cyanide toxicity following ingestion or absorption may be delayed and presents with nonspecific clinical signs, a physician must have a reasonable index of suspicion. Cyanide is renowned for its odor of almonds, apparent at the time of exposure and on the breath of intoxicated patients, but this has been found to be undetectable by up to 5% of women and nearly 20% of men in the general population. Nonetheless there may be significant clues in the case history, including apparent release of a gas, exposure to a powder or onset of illness immediately after a particular ingestion.

Laboratory diagnosis can confirm cyanide exposure. RBC cyanide levels of 0.5-1.0 mcg/mL indicate mild exposure; higher levels indicate more severe intoxication. Urine analysis for cyanide is also available. Note that there is frequently a baseline low level of cyanide due to normal environmental exposure.

Other laboratory test results, such as high anion gap metabolic acidosis, can support the diagnosis of cyanide toxicity but do not provide specific evidence. There may also be evidence of elevated arterial and venous pO2. In general, cyanide poisoning should be suspected in any patient with evidence of hypoxia without cyanosis. Cyanide poisoning should also be considered in any of the following conditions:

• Sudden collapse of victim(s).
• The presence of a resistant metabolic acidosis and or severe hypotension unresponsive to usual therapy in an individual with normal color or normal arterial pO2 should suggest the diagnosis.
• Venous pO2>50 mm Hg.
• Differential diagnosis must include carbon monoxide exposure since the treatment for cyanide may increase the severity of illness in cases of carbon monoxide intoxication.
• Reports of dead insects, animals and unusual smells in an unusual location

The differential Diagnosis list for Cyanide might include any of the following:

Encephalitis, meningitis, headaches, GI symptoms, sedation, smoke inhalation, methemoglobinemia, hemlock poisoning, carbon monoxide toxicity, hydrogen sulfide toxicity, strychnine poisoning, ethanol toxicity and azide toxicity

Treatment

Due to the rapid action of cyanide and relatively long time frame needed to analyze blood samples (several hours), empiric treatment is often necessary prior to laboratory diagnosis. Because the drugs used in cyanide treatment have potential adverse effects, clinical decision-making in the absence of lab data may be important. If possible, supportive treatment should be administered prior to diagnosis; the focus is maintaining cardiac output and the airway, including endotracheal intubation if necessary. Upon identifying cyanide toxicity, specific treatment should be immediately instituted.

1. Activated charcoal: for alert, asymptomatic patients following ingestion
2. Supplemental oxygen at 100%
3. ACLS and shock protocols may be required for symptomatic patients
4. Sodium nitrite: a methemoglobin forming agent. Methemoglobin competes with cytochrome oxidase for free cyanide and combines with cyanide to form cyanmethemoglobin
1. Adults: 300mg IV over 5 minutes; slower if hypotension develops
2. Children: 0.12 to 0.33 mg/kg IV infused as above in a child. The dose is dependent upon both weight and hemoglobin concentration ranging from 5.8 mg/kg (019 ml/kg) in a child with a hemoglobin of 7 to 11.6 mg/kg (0.39 ml/kg) in a child with a hemoglobin of 14.
3. Adverse reactions: Hypotension associated with rapid infusion, tachycardia, syncope, cyanosis due to methemoglobin formation, headache, dizziness, nausea, vomiting. Frequency of events is not clearly defined.
5. Amyl nitrite: a second line methemoglobin forming agent which is inhaled. Utilized only when other methemoglobin forming agents are not immediately available; only effective in a closed respiratory system and there is little systemic absorption
1. Adults: 0.3mL ampule crushed every minute and inhaled for 15-30 seconds until sodium nitrite infusion is available
2. Children: Inhale as in adults. Only used until adequate IV access can be achieved.
3. Adverse reactions: Postural hypotension, tachycardia, palpitations, vasodilation, syncope, headache, dizziness, nausea, vomiting, hemolytic anemia, increased intraocular pressure, contact dermatitis. Frequency of events is not clearly defined.
6. Sodium thiosulfate promotes rhodanase activity, which assists in conversion of cyanide into a less toxic form, thiocyanate. Used in combination with methemoglobin forming agents, sodium thiosulfate allows detoxification of cyanide as it is released from cyanmethemoglobin and also assists in direct detoxification of cyanide, although this occurs too slowly to be useful as a first-line application.
1. Adults: 12.5g IV over 10-20 minutes following administration of sodium nitrite
2. Children: 1.65 ml/kg IV in a child over 10-20 minutes
3. Can repeat one-half of the original dose after 30 minutes if clinical response is inadequate
4. Adverse reactions: Hypotension, CNS depression and coma due to thiocyanate intoxication, psychosis, confusion, weakness, tinnitus, contact dermatitis. Frequency of events is not clearly defined.
7. Hydroxocobalamin: The FDA has not approved the use of Hydroxocobalamin in the United States.

Speed is critical: for survival, symptomatic patients must receive supportive care and specific antidotes immediately due to the rapid action of cyanide. Note that accurate laboratory diagnosis of cyanide exposure is not possible after administration of antidotes.

Exposed patients who have not exhibited symptoms within 4 to 6 hours can be safely discharged. Note that patients known to be exposed to cyanide gas are likely to remain asymptomatic if they have not exhibited symptoms within five minutes after removal from exposure, and they will not require treatment.

Decontamination

Gas exposure does not require decontamination or contact precaution. For patients with clothing or skin contaminated with liquid or solid cyanide, the treatment team is at risk for contact exposure or inhalation of gas produced by remaining cyanide compounds. Due to the rapid evaporation and dispersal of cyanide, however, substantial quantities must be present in order to pose a real risk.

Skin decontamination can be achieved using a rinse with dilute detergent. Contaminated clothing should be removed, preferentially by the patient if alert and asymptomatic, and placed in sealed bags.

Special thanks to Daniel Shodell, MD, MPH, Johns Hopkins General Preventive Medicine Resident, for his work on this information