The U.S. Food and Drug Administration approved hydroxocobalamin (HC) for treating known or suspected cyanide toxicity last December, and the product, marketed under the trade name Cyanokit, has been a long time in coming. HC has been used in Europe since at least 1970 with remarkable safety and apparent efficacy. (For obvious reasons, placebo-controlled human clinical trials have not been performed.)
Animal studies have demonstrated that HC lowers blood cyanide levels, improves hemodynamic stability, and reduces mortality. Studies in adult smokers showed that HC lowers cyanide levels in humans. Significant adverse effects from HC occur very rarely. Although the FDA granted HC orphan drug status in October 1985, it remained a little orphan antidote for more than 21 years. Until now. Its availability is a significant development. This column and next month's will examine important questions about HC.
What are the problems with the antidote we already have? The cyanide antidote kit used for decades in the United States consisted of amyl nitrite, sodium nitrite, and sodium thiosulfate. The nitrites have several significant potential adverse effects, including decreased hemoglobin oxygen-carrying capacity (because they induce methemoglobinemia) and vasodilatation with hypotension.
In victims of smoke inhalation when cyanide toxicity may be suspected but not proven, it is especially difficult to weigh the potential risks and benefits of nitrites. Dosing of sodium nitrite in pediatric cases is also tricky. Young children may have reduced levels of methemoglobin reductase. There have been a number of reports of excessive methemoglobinemia or hypotension induced by sodium nitrite in children. Sodium thiosulfate, although relatively safe, is not immediately effective.
How does hydroxocobalamin work as a cyanide antidote? HC is vitamin B12a, a precursor to vitamin B12. Each molecule of HC can bind one cyanyl group, forming vitamin B12 (cyanocobalamin), which is nontoxic and excreted harmlessly in the urine. HC penetrates into cells and has a higher affinity for cyanide than does the Fe+3 in cytochrome oxidase, restoring the cell's ability to use oxygen to produce ATP. In stark contrast to the nitrites, HC actually increases systolic and diastolic blood pressure in normal human volunteers (Clin Toxicol 2006;44:17) as well as mean arterial pressure in cyanide-treated dogs (Clin Toxicol 2006;44:5). This vasoconstrictive property may be explained by the fact that HC binds nitric oxide. Unlike sodium thiosulfate, HC works relatively quickly.
What is the recommended dose of hydroxocobalamin? The Cyanokit contains two 2.5 g vials of HC. The initial adult dose is 5 g given by intravenous infusion over 15 minutes. The package insert recommends that each vial be reconstituted in 100 mL of 0.9% sodium chloride, but notes that lactated Ringers solution and 5% dextrose (D5W) are compatible with HC and also may be used as diluents. If indicated, a second 5 g dose of HC can be given over 15 minutes to two hours, depending on the patient's condition. Although there is no official recommendation for pediatric dosing, the dose used in Europe has been 70 mg/kg.
What drugs are incompatible with hydroxocobalamin? HC is incompatible with diazepam, dopamine, dobutamine, and sodium thiosulfate, and these drugs should not be administered simultaneously or through the same line as HC. It is also incompatible with sodium nitrite, diazepam, fentanyl, nitroglycerin, propofol, thiopental, and pentobarbital.
What adverse effects have been associated with hydroxocobalamin? The most common side effect of HC is a reddish-brown discoloration of the skin, mucous membranes, and urine. This occurs in virtually everyone who receives the drug, and does not appear to have any clinical significance. While this discoloration is self-limiting, it can take one to five weeks to resolve.
Because HC is bright red, it interferes with tests measured by co-oximetry, causing an artificial increase in reported total hemoglobin, carboxyhemoglobin, and methemoglobin levels. In addition, it can affect the reported values of other laboratory tests including those for aspartate aminotransferase, total bilirubin, creatinine kinase, magnesium, and iron. It is not clear if any of these changes are clinically significant.
In a study of healthy volunteers, two of 102 subjects given HC developed allergic reactions shortly after the infusion was started. (Clin Toxicol 2006;44:17.) One reaction began with itching of the face and neck, followed by shivering and facial erythema and swelling. Symptoms resolved within one hour after the infusion was stopped, and the patient was treated with the antihistamine dimethindene.
The other reaction began with dyspnea, facial swelling, and urticaria. Symptoms resolved within two-and-a-half hours after treatment with dimethindene and dexamethasone. Although there have been rare reports of anaphylaxis after use of repeated small doses of HC or cyanocobalamin for conditions such as vitamin B12 deficiency, I am not aware of any reports describing allergic reactions associated with the administration of HC as a cyanide antidote. It is not clear if these reactions could have been related to sulfites contained in older formulations of these drugs; the current Cyanokit consists of pure HC.
Next month, I will discuss additional issues relating to HC, such as the role for adjunctive use of sodium thiosulfate and the prevention of cyanide or thiocyanate toxicity associated with prolonged administration of nitroprusside.