A41: Antidotes in Depth

Cyanocobalamin, vitamin B₁₂, is formed when hydroxocobalamin combines with cyanide, quickly dropping cyanide concentrations and improving hemodynamics. 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. Based on the mechanism of action of sodium thiosulfate, particularly when used alone, it is unlikely to be as effective as hydroxocobalamin, or work as quickly. A recent study in swine did not show a benefit to sodium thiosulfate as sole therapy or show an added benefit to hydroxocobalamin in a model of intravenous cyanide toxicity.⁷

The antidotal actions of cobalt as a chelator of cyanide were recognized as early as 1894.^15,47 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.²⁵ Hydroxocobalamin was finally approved by the Food and Drug Administration (FDA) in December 2006 and is available under the trade name Cyanokit.^14,16

In experimental models, hydroxocobalamin was successful in protecting against several ­minimum lethal doses of cyanide when an equimolar ratio of hydroxocobalamin to cyanide was used.^1,10,36,43

Chemistry

The molecule is porphyrinlike in structure and has a cobalt ion at its core. The only difference between cyanocobalamin (vitamin B₁₂) and hydroxocobalamin (vitamin B_12a) is the replacement of the CN group with an OH group at the active site in the latter.^31,38

Mechanism of Action

The cobalt ion in hydroxocobalamin combines with cyanide to form the nontoxic cyanocobalamin.^35,36 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.²⁵ An ex vivo study using human skin fibroblasts demonstrated 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 both in the presence and 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.^10,21 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.^35,47 In France, hydroxocobalamin is used with sodium thiosulfate as it is thought to have an additive effect in the treatment of cyanide.^41,44

Pharmacokinetics and Pharmacodynamics

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.^16,17 Adult volunteers who were heavy smokers were given 5 g hydroxocobalamin (5%) intravenously. The first four patients received the dose undiluted over 20 minutes.¹⁷ Then they 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 vs. 1.27 hours). The α distribution half-life was 0.52 hours in the group 1 patients. Peak hydroxocobalamin concentrations averaged 813 μg/mL (604 μmol/L), and volume of distribution (Vd) averaged 0.38 L/kg. A mean of 62% of the dose 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.^27,28

A pharmacokinetic study in France²⁵ was conducted in adult victims of smoke inhalation given hydroxocobalamin, 5 g (5%) by IV infusion over 30 minutes, starting within 30 minutes of patient removal from the fire.^27,28 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 the 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 another study in France in which 12 fire victims were suspected of having cyanide poisoning, the patients received IV hydroxocobalamin 5 g in 100 mL sterile water (USP) over 30 minutes.³⁰ Pretreatment and posttreatment cyanide concentrations and cyanocobalamin concentrations were analyzed. In patients with cyanide concentrations less than 1.04 μg/mL (< 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 (> 40 μmol/L), the formation of cyanocobalamin reached a plateau, implying that all the hydroxocobalamin was consumed. When the patient with a blood cyanide concentration greater than 1.04 μg/mL (> 40 μmol/L) received a second 5 g dose of hydroxocobalamin, the cyanocobalamin concentration subsequently rose.^3,30

The protein binding and tissue distribution of cyanide, hydroxocobalamin, and cyanocobalamin likely are different.²⁹ In addition, hydroxocobalamin probably causes redistribution of cyanide from the intracellular to the intravascular space.²⁹

Animals

The ability of hydroxocobalamin to bind cyanide and produce beneficial effects on mortality and hemodynamics has been demonstrated in many animal species, including rabbits, swine, dogs, and baboons.²⁶ A recent study in swine evaluated the effect of hydroxocobalamin plus sodium thiosulfate versus sodium nitrite and sodium thiosulfate in a model utilizing a continuous infusion of cyanide. There was no difference between the groups with regard to metabolic acidosis with an elevated lactate concentration at times 20 and 40 minutes, cardiac output and pulse rate at 40 minutes, or mortality. The mean arterial pressure was higher in the hydroxocobalamin plus sodium thiosulfate group, beginning at 5 minutes and lasting for the entire 40 minute monitoring period.⁸ A second cyanide study in swine done by the same group could not show a benefit to sodium thiosulfate as sole therapy or show an added benefit of sodium thiosulfate to hydroxocobalamin.⁷

Humans

Many case reports and studies in France document the efficacy of hydroxocobalamin combined with sodium thiosulfate for treatment of cyanide toxicity.^6,11,20,24 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).¹⁰ They received a median dose of 5 g of hydroxocobalamin, up to a maximum of 15 g, infused as a 5% solution in sterile water for injection over 15 to 30 minutes. ­Cardiopulmonary arrest occurred in 15 patients, with a mean blood cyanide concentration of 123 μmol/L (100 μmol/L = 2.7 μg/mL, which is a fatal concentration if untreated) and a mean carboxyhemoglobin of 30%. Two of these patients survived with normal neurologic function. Of 42 patients with confirmed cyanide concentrations greater than 39 μmol/L (1 μg/mL, which is potentially fatal), 28 (67%) survived. The contribution to toxicity of carboxyhemoglobin is difficult to determine in this study. Of the 69 patients in this study, 57 also received hyperbaric oxygen, complicating the interpretation of the outcome.¹⁰

An 8 year retrospective analysis of the use of hydroxocobalamin in the prehospital setting concluded that the risk-to-benefit ratio favors its use in smoke inhalation victims suspected of cyanide poisoning.¹⁸ Of 72 patients in whom survival status could be determined, 30 (42%) survived. Cyanide blood concentrations were not measured in these patients. Although 21 of the 38 patients found in cardiac arrest had hemodynamic improvement, survival was dismal with only two patients ultimately surviving. The neurologic function of those two patients was not described.

Hydroxocobalamin also prevented the rise in cyanide concentration following nitroprusside infusion compared with patients who only received nitroprusside.¹² When nitroprusside is administered, the use of concomitant hydroxocobalamin prevents cyanide accumulation and toxicity in both animal models and in humans.^11,12,48 Sodium thiosulfate also prevents nitroprusside induced cyanide toxicity (Antidotes in Depth: A40). There are currently no studies comparing the nitrite plus sodium thiosulfate regimen with hydroxocobalamin in patients with cyanide poisoning.⁴¹ There are no studies comparing hydroxocobalamin with or without sodium thiosulfate to sodium thiosulfate alone in smoke inhalation victims presumed to be cyanide toxic.

The kidneys, heart, and liver of a patient who was declared brain dead after third degree burns and smoke inhalation following a fire, were successfully transplanted into four patients.¹⁹ The victim received 10 g of hydroxocobalamin. Whole-blood cyanide concentrations were later confirmed to be significantly elevated.

Hydroxocobalamin has a wide therapeutic index.^10,18,46 Large doses have been administered to animals with no adverse effects.^35,40,42 The LD₅₀ (median lethal dose in 50% of test subjects) in mice is 2 g/kg.

Red discoloration of mucous membranes, serum, and urine may occur and last from 12 hours to many days after therapy.^10,14,18 Patients should be warned to avoid direct sun exposure while their skin remains red for fear of a photosensitivity reaction.¹⁴ Allergic reactions including anaphylaxis and angioedema are reported, but serious allergic reactions are rare.^5,6,11,38 Prior chronic exposure to hydroxocobalamin or cyanocobalamin for treatment of vitamin B₁₂ deficiency is associated rarely with development of anaphylaxis.²⁵ A study in 102 healthy volunteers demonstrated that chromaturia is universal, and as the dose increases from 2.5 to 10 g, the incidence of erythema, rash (predominantly acneiform), headache, injection site reaction, nausea, pruritus, chest discomfort, and dysphagia increases.⁴⁶ The dermatologic manifestations are quite variable, both rapid and delayed onset with protracted courses may occur. Of 102 volunteers randomized to receive hydroxocobalamin, 24 experienced a clinically significant rise in diastolic blood pressures, up to 124 mm Hg. However, only three of them also had clinically significant elevations in systolic blood pressure. These elevations in blood pressure resolved within 4 hours of the end of the infusion. Urinary oxalate crystals were reported in patients receiving hydroxocobalamin whether or not the patient is exposed to cyanide.¹⁴

Colorimetric assays are most likely to be adversely affected because both hydroxocobalamin and cyanocobalamin have an intensely red color. Many clinical chemistry laboratory tests can be artificially increased, decreased, or unpredictable.^9,14, Hematology tests including hemoglobin, MCH, MCHC, and basophils are artificially increased.¹⁴ Coagulation tests are unpredictable. Urinalysis tests are usually artificially increased, but pH can also be artificially low with low doses of hydroxocobalamin.¹⁴ An in vitro study found statistically significant alterations in serum concentrations of aspartate aminotransferase (AST), total bilirubin, creatinine, magnesium, and iron after hydroxocobalamin administration.¹³ Although an in vitro study demonstrated a considerable false increase in carboxyhemoglobin concentrations following hydroxocobalamin administration when measured by cooximetry, other authors suggest that the interference is minimal and results in slight overestimates depending on the instrument and the concentration of hydroxocobalamin.^4,22,32 Inconsequential increases of 1% to 5.7% in the carboxyhemoglobin level were reported in another study.²² However, more worrisome is the report of two instances where the carboxyhemoglobin levels were falsely low by a factor of 4 to 14 times.³⁴

Because of the inaccuracies in laboratory determinations, blood should be drawn before the administration of hydroxocobalamin whenever possible. This is particularly important in fire victims when carboxyhemoglobin concentrations may be necessary for management decisions.

Hydroxocobalamin is FDA pregnancy category C. Animal studies are insufficient and there are no controlled trials in pregnant women. Hydroxocobalamin should be used in pregnant women when the potential benefit outweighs the potential risk to the fetus. A pregnant woman in her fourth week of gestation was inadvertently administered 5 g of hydroxocobalamin during a ­volunteer study. She went on to deliver a normal healthy baby at term.¹⁴

Cyanide Toxicity

The initial dose of hydroxocobalamin in adults is 5 g. Each vial is reconstituted with 200 mL of 0.9% sodium chloride and administered intravenously over 15 minutes. If 0.9% sodium chloride is unavailable, lactated ringers solution or D₅W may be used. Each vial should be inverted or rocked (not shaken) for 60 seconds prior to administration. The reconstituted solution should be dark red and free of particulate matter and should be used within 6 hours of reconstitution.¹⁴ A second dose of 5 g can be repeated as clinically necessary and infused over 15 minutes to 2 hours depending on patient status.¹⁴

In children, a dose of 70 mg/kg of hydroxocobalamin up to the adult dose is recommended.¹⁴

Sodium thiosulfate can be administered in addition to hydroxocobalamin, but the administration of the hydroxocobalamin should take precedence. The sodium thiosulfate is expected to be additive and has been used extensively in conjunction with hydroxocobalamin.^23,24,33 Care must be taken not to administer the hydroxocobalamin and sodium thiosulfate simultaneously through the same IV line since this may inactivate the hydroxocobalamin.²⁹ The adult dose of sodium thiosulfate is 12.5 g (50 mL of 25% solution) and should be administered intravenously as either a bolus injection or infused over 10 to 30 minutes, depending on the severity of the situation. The dose of sodium thiosulfate in children is 1 mL/kg using a 25% solution (250 mg/kg or approximately 30–40 mL/m2 of BSA) not to exceed 50 mL (12.5 g) total dose. The dose can be repeated at half the initial dose if manifestations of cyanide toxicity reappear.^39,45

Nitroprusside Induced Cyanide Toxicity

Nitroprusside induced cyanide toxicity should be treated like cyanide toxicity from any other cause: stop the nitroprusside dosage and administer hydroxocobalamin with or without sodium thiosulfate according to the doses and precautions listed. The dose of hydroxocobalamin to prevent cyanide toxicity from the IV infusion of nitroprusside is not precisely known, but a dose of hydroxocobalamin of 25 mg/h in one study was sufficient to decrease the red cell and serum cyanide concentrations and to prevent the development of a metabolic acidosis while the nitroprusside continued to be administered.⁴⁸ These authors recommend possibly continuing the hydroxocobalamin for 10 hours after the discontinuation of the nitroprusside. Hydroxocobalamin could also be used as rescue therapy in the typical dosage, as could sodium thiosulfate (Antidotes in Depth: A40).

Each Cyanokit contains one 250 mL glass vial containing 5 g of lyophilized dark red, hydroxocobalamin crystalline powder for injection.¹⁴ The kit also contains one sterile transfer spike, one sterile IV infusion set, one quick reference guide, and one package insert, but no diluent.

• Hydroxocobalamin is effective for cyanide toxicity generated from all routes of exposure. Intravenous hydroxocobalamin is safe in the setting of a fire when carboxyhemoglobin is also expected to be ­present.

• Hydroxocobalamin affects all laboratory tests that are colorimetric, producing falsely elevated or lowered results. Of particular importance may be the significantly falsely diminished assay for carboxyhemoglobin.

• Hydroxocobalamin causes a red discoloration of the skin and mucous membranes that may last hours to days.

References