Chemical Terrorism Update: Cyanide Toxins

Intermittently, cyanide rears its head as an actual or potential terrorist weapon. A neurologist explains the properties of different cyanide forms, the challenge of differential diagnosis, and the steps and variations of detoxification therapy.

By Coleman O. Martin, MD

Dr. Martin is a board-certified neurologist in the department of neurology at the University of Iowa Hospitals and Clinics in Iowa City.

Physicians have long been aware of cyanide as a rapidly acting, lethal poison. Most cases of exposure result from suicide attempts, industrial accidents, or smoke inhalation. However, earlier this year, cyanide made headlines with the discovery of cyanide caches in the Chicago subways and warnings of a planned cyanide gas attack on the United States embassy in Rome. Cyanide is being increasingly recognized as a domestic and international terrorist threat. A working knowledge of cyanide toxins is required for the prompt diagnosis and treatment of affected patients.

What are the physical properties of cyanide toxins?

Most deliberate intoxications with cyanide have resulted from exposure to cyanide salts or cyanide gases. Prototypical cyanide salts include sodium cyanide and potassium cyanide. Both are white, granular, industrial chemicals used for a variety of applications, including electroplating and the manufacturing of plastics. Hydrogen cyanide and cyanogen chloride are also used by industry; these are highly volatile liquids that form gases at room temperature.

All of these agents are irritants that can penetrate skin and mucosa. Cyanide salts generally pose the greatest threat through ingestion such as occurred in the Tylenol-tampering cases in Chicago in 1982. Cyanide gases diffuse from their point of release. If released indoors or underground, they can quickly achieve high concentrations, resulting in rapid fatalities.

Although the odor of bitter almonds or peach kernels is associated with sodium, potassium, and hydrogen cyanide, only 40% to 60% of people can detect this characteristic odor. Cyanogen chloride is extremely irritating to mucosa and has a pungent biting odor.

What is the pathophysiology of cyanide poisoning?

Cyanide ions block the mitochondrial enzyme cytochrome oxidase, which leads to reduced aerobic metabolism. Glycolysis continues, however, resulting in a buildup of pyruvate, which is converted to lactic acid. The end result is a combined intracellular shortage of ATP and lactic acidosis. The brain's high metabolic rate accounts for its disproportionate vulnerability to cyanide.

What is the clinical presentation of cyanide toxicity?

The manifestations of cyanide intoxication are dose-dependent. Low to intermediate levels of exposure produce non-specific symptoms such as headache, vertigo, nausea, and vomiting. With higher levels of exposure, patients exhibit depressed mental status, seizures, and increased respirations. Very high levels of exposure result in abrupt loss of consciousness, respiratory depression, and cardiac arrest.

Patients with intermediate-level toxicity may worsen several hours after exposure and display a faltering mental status. Results of a physical examination of a moderately or severely affected individual may be abnormal in several respects. Early on, blood pressure and pulse may increase but will later fall as the patient decompensates. Pupillary reactivity may be impaired. Skin color, however, is not a reliable indicator of toxicity because decreased cellular respiration can leave the patient's skin looking pink. If, on the other hand, the toxicity has reached a level where it has suppressed the patient's respiratory drive, cyanosis will be evident. Matching of the hues of the retinal arteries and veins has been described and may provide a clue to the diagnosis. Venipuncture will reveal bright red, oxygenated blood. Additionally, the patient's breath may have the characteristic almond odor.

What is the differential diagnosis in cyanide intoxication? And what are the key laboratory findings?

Cyanide toxicity is difficult to diagnose because of the typically nonspecific symptoms and the relative rarity of the condition. Cases of mild exposure may mimic migraine. More severe exposures may be confused with carbon monoxide poisoning. Other conditions with similar presentations include organic solvent exposure, drug intoxication, central nervous system infection, brain injury, hypoxia, electrolyte disturbances, hypoglycemia, and the post-ictal state.

Patients with an unexplained deterioration of mental status should undergo arterial blood gas analysis. Cyanide causes a wide anion-gap metabolic acidosis. The classic acronym MUDPILES (methanol/metformin, uremia, diabetic ketoacidosis, paraldehyde/phenformin, iron/isoniazid, lactate, ethylene glycol, salicylates) reminds the clinician to look into other possible causes of this form of metabolic acidosis. Modifying the acronym to SCUMPILED would extend this memory aid to include cyanide.

Other laboratory abnormalities include elevated lactate levels. Comparing arterial and venous blood gases may reveal decreased oxygen consumption and decreased carbon dioxide production. Rapid laboratory testing for thiocyanate, which is excreted in the urine, is available at some centers, but its sensitivity and specificity in cyanide poisoning is unknown. Treatment should not be delayed for this test.

Is decontamination necessary in cases of cyanide toxicity?

Secondary exposure was documented in a medical student who performed mouth-to-mouth resuscitation on his dog that was fatally intoxicated with cyanide. This case, though bizarre, underscores the hazards that may accompany treatment of poisoned individuals. At a minimum, the patient's clothing should be removed and bagged. Because some cyanide powders react with water to form hydrogen cyanide gas, patients may need to be washed in a HAZMAT room. If ingestion of cyanide compounds is suspected, gastric decontamination should be considered.

How should cyanide toxicity be treated?

Patients with only minor symptoms such as headache and dizziness may be treated with supplemental oxygen and should be observed until their symptoms fully resolve. Patients with a depressed mental status or cardiopulmonary suppression should be treated with oxygen and the cyanide antidote kit, which uses a two-step process to unbind cyanide from the mitochondria and excrete it from the body. First, nitrates are used to induce methemoglobinemia. The bond between cyanide and cytochrome oxidase is weaker than that between cyanide and methemoglobin. This leads to the transfer of cyanide from the mitochondria to the circulation. As preparations are made for establishing intravenous access, ampules of the inhalant amyl nitrate are broken into gauze, which is held under the patient's nose for 30 seconds of each minute prior to treatment. Once intravenous access is established, the inhalant is discontinued and 300 mg of sodium nitrate are administered. Frequent monitoring of blood pressure is necessary during this phase of therapy because nitrates induce hypotension.

Because methemoglobin does not carry oxygen, excessive methemoglobinemia can lead to anoxia. In a faltering patient, methemoglobin can be measured; a desirable level is between 20% and 30%. Methemoglobin can be reversed by infusion of 1% methylene blue, which, counterproductively, results in the transfer of cyanide back to the mitochondria.

After the sodium nitrate infusion, 12.5 gm of sodium thiosulfate are administered to facilitate production of thiocyanate. Pediatric doses should be adjusted according to the package insert. Further dose reductions may be required for pediatric patients with low hemoglobin values.

Hyperbaric oxygen administration is an adjunctive therapy in patients who do not respond to cyanide antidotes. This may be particularly helpful in cases where methemoglobinemia is excessive and the patient cyanotic. Hyperbaric oxygen should also be considered in patients with cyanide toxicity from smoke inhalation because their high levels of carboxyhemoglobin can hinder safe induction of methemoglobinemia.

Cyanide also has a high affinity for the vitamin B12 precursor hydroxocobalamin. High-dose (5 grams) hydroxocobalamin therapy is used in Europe for cyanide toxicity. This therapy has an excellent safety profile and is relatively inexpensive; also, it can be administered outside of the hospital. While hydroxocobalamin is available in the United States for treatment of vitamin B12 deficiency, the current formulation (1 mg/ml) makes its use impractical as a treatment for cyanide toxicity.

Additional supportive care will probably be necessary in a moderately to severely intoxicated patient. Treatment of severe metabolic acidosis (pH below 7) with bicarbonate can help to stabilize the patient until aerobic metabolism returns to normal. Nitrate therapy may necessitate the use of intravenous fluids and vasopressors to maintain blood pressure. Seizures should be treated with intravenous lorazepam and, if they recur, fosphenytoin. In cases of severe intoxication, patients should be monitored for signs of cerebral edema and diabetes insipidus.

What are the long-term sequelae of cyanide toxicity?

In addition to cognitive disturbances from cerebral anoxia, survivors of cyanide poisoning may suffer disorders of the basal ganglia. A parkinsonian syndrome may become evident within days of exposure. Development of dystonia weeks or months after exposure has also been described. Dysarthria, oculomotor problems, and ataxia are other possible sequelae.

Magnetic resonance imaging has revealed cavitation in the basal ganglia after cyanide poisoning. Unfortunately, in such cases, dopaminergic therapy with drugs such as levodopa is generally not efficacious.

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