Hydroxocobalamin is a relatively new antidote for cyanide toxicity in the United States. Cyanocobalamin, vitamin B12, is formed when hydroxocobalamin combines with cyanide. Nitrites and sodium thiosulfate have traditionally been used to treat patients with cyanide toxicity. Nitrites have the disadvantage of producing methemoglobin, which is dangerous in a patient with coexistent elevated carboxyhemoglobin concentrations, such as would be found in fire victims suspected of having cyanide toxicity. Unfortunately, there are no controlled studies comparing sodium thiosulfate with hydroxocobalamin in these circumstances.
The antidotal actions of cobalt as a chelator of cyanide were recognized as early as 1894.12,35 Hydroxocobalamin has been used as a cyanide antidote in France for many years, first as a sole agent and then in combination with sodium thiosulfate.19 In the United States, hydroxocobalamin was finally approved by the Food and Drug Administration (FDA) in December 2006 and is available under the trade name Cyanokit.11,13
Hydroxocobalamin subsequently was shown to be successful in protecting against several minimum lethal doses of cyanide as long as an equimolar ratio of hydroxocobalamin to cyanide was used.1,7,28,33
The molecule is porphyrinlike in structure and has a cobalt ion at its core. The only difference between cyanocobalamin (vitamin B12) and hydroxocobalamin (referred to as vitamin B12a) is the replacement of the CN group with an OH group at the active site in the latter.24,30
The cobalt ion in hydroxocobalamin combines with cyanide to form the nontoxic cyanocobalamin.27,28 One mole of hydroxocobalamin binds 1 mole of CN. Given the molecular weights of each, 52 g of hydroxocobalamin are needed to bind 1 g of cyanide.19 An ex vivo study using human skin fibroblasts demonstrates that hydroxocobalamin penetrates intracellularly to form cyanocobalamin.2 In the setting of cyanide poisoning, hydroxocobalamin removes cyanide from the mitochondrial electron transport chain, allowing oxidative metabolism to proceed. Hydroxocobalamin also binds nitric oxide, a vasodilator, causing vasoconstriction, particularly in the absence of cyanide. This same property potentially contributes to its beneficial effects by increasing systolic and diastolic blood pressure and improving the hemodynamic status of cyanide-poisoned patients.7,16 Other cobalt chelators, such as dicobalt ethylenediaminetetraacetic acid (EDTA), have been used both experimentally and clinically in other countries, but their therapeutic index is narrow, especially in the absence of cyanide. Additionally, idiosyncratic adverse effects make these compounds less advantageous.27,35 Use of hydroxocobalamin with sodium thiosulfate is synergistic and comparable to the sequential use of sodium nitrite with sodium thiosulfate.19,33
Under an FDA Investigational New Drug permit, the first pharmacokinetic study of intravenous (IV) hydroxocobalamin was performed in the United States and published in 1993.13,14 Adult volunteers who were heavy smokers were given 5 g hydroxocobalamin (5%) intravenously, obtained from a French manufacturer. The first four patients received the dose undiluted over 20 minutes.14 They then received 12.5 g (50 mL of 25% solution) of sodium thiosulfate intravenously infused over 20 minutes. The next 11 patients received the same dose of hydroxocobalamin but diluted with 100 mL water for injection (USP) and infused over 30 minutes. The serum and urine sampling of hydroxocobalamin differed in the two patient groups, yielding somewhat different half-lives (4 hours versus 1.27 hours). The α distribution half-life was 0.52 hours in the group 1 patients. Peak hydroxocobalamin concentration averaged 813 μg/mL (604 μmol/L), and volume of distribution (Vd) averaged 0.38 L/kg. A mean dose of 62% was recovered in the urine in 24 hours. Whole-blood cyanide concentrations significantly decreased in all subjects following hydroxocobalamin. A problem with this study was the short collection time for serum hydroxocobalamin concentrations of only 6 hours, making the pharmacokinetic analysis imprecise.20,21
A pharmacokinetic study performed in adult victims of smoke inhalation in France19 was conducted with very different patients given hydroxocobalamin 5 g (5%) by IV infusion over 30 minutes, starting within 30 minutes of their removal from the fire.20,21 The α distribution half-life of hydroxocobalamin was 1.86 hours, elimination half-life was 26.2 hours based on sampling up to 6 days, and Vd was 0.45 L/kg. The peak serum cyanocobalamin concentration was 287 μg/mL (212 μmol/L). In the one patient who was subsequently determined not exposed to cyanide, the hydroxocobalamin elimination half-life was 13.6 hours and Vd was 0.23 L/kg. Renal clearance of hydroxocobalamin was 37% in the cyanide-exposed patients compared with 62% in the unexposed patient.
In a study of 12 fire victims in France who were suspected of having cyanide poisoning, the patients received IV hydroxocobalamin 5 g in 100 mL sterile water (USP) over 30 minutes.23 Pretreatment and posttreatment cyanide concentrations and cyanocobalamin concentrations were analyzed. In patients with cyanide concentrations less than 1.04 μg/mL (less than 40 μmol/L), a linear relationship existed between the blood cyanide concentration and the formation of cyanocobalamin. In the three patients with blood cyanide concentration greater than 1.04 μg/mL (greater than 40 μmol/L), the formation of cyanocobalamin reached a plateau, implying that all of the hydroxocobalamin was consumed. In the one patient with a blood cyanide concentration greater than 1.04 μg/mL (greater than 40 μmol/L) who received a second 5-g dose of hydroxocobalamin, the cyanocobalamin concentration subsequently rose.3,23
The protein binding and tissue distribution of cyanide, hydroxocobalamin, and cyanocobalamin likely are different.22 In addition, hydroxocobalamin probably causes redistribution of cyanide from the intracellular to the intravascular space.22
Many case reports and studies in France document the efficacy of hydroxocobalamin combined with sodium thiosulfate for treatment of cyanide toxicity.6,8,18 An observational case series reviewed 69 adult smoke inhalation victims suspected of cyanide poisoning who were treated either at the scene of the fire or in the intensive care unit (ICU). They received a median ...