Hydroxocobalamin: Turning Cyanide into Vitamin B12

Cyanide toxicity can be quickly fatal, but there is a simple, safe treatment that can reverse its toxic effects.

For many years, cyanide toxicity was treated with multi-component cyanide antidote kits. Now there is a newer, safer agent that converts the mitochondrial toxin, cyanide, into the benign chemical cyanocobalamin, or vitamin B12. While it is fortunately a rare cause for presentation to emergency departments, cyanide is one of the most rapidly fatal toxins known, so diagnosis and treatment must be expeditious..

Cyanide toxicity can occur from a range of different exposures, including smoke inhalation from burning plastics in house fires, intentional ingestions in suicide attempts and industrial exposures among individuals working in the jewelry, photography, metallurgy or textile industries [1,2]. It can also occur iatrogenically from prolonged nitroprusside infusion. In water, cyanide exists primarily as HCN (hydrogen cyanide), which can rapidly cross cell membranes, but is in equilibrium with cyanide ions (CN–). Cyanide ions bind to ferric iron (Fe3+) present in mitochondrial cytochrome oxidases, arresting oxidative phosphorylation and forcing the cells into anaerobic metabolism. This causes an anion-gap, lactic acidosis. Since the cells experience a histotoxic hypoxia and cannot utilize oxygen, it remains in the bloodstream causing venous hyperoxia. This will manifest as red-appearing skin and retinal veins with cherry red venous blood, as well as a narrowed arterial-venous oxygen gradient.

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The symptoms of cyanide toxicity include nausea, vomiting, headaches, confusion and dyspnea ultimately leading to seizures, coma and death. Patients’ skin may appear red due to the venous hyperoxia. They may also develop renal failure, hepatic necrosis, pulmonary edema and rhabdomyolysis. Initially they may have tachycardia, hypertension and tachypnea, followed by hemodynamic collapse, with bradycardia, hypotension and bradypnea. Symptoms can occur minutes to hours after ingestion or transdermal exposure, but are almost immediate after parenteral exposure. In cases of smoke inhalation the clinical picture may be complicated by a concurrent carbon monoxide poisoning as well as any cutaneous burns or trauma. Chronic cyanide toxicity can also occur. Ingestion of improperly prepared cassava, is one cause, and can lead to a demyelinating disorder called tropical ataxic neuropathy. Cyanide is also present in trace amounts in fruit seeds, but rarely poses a health risk. Among smokers who may have an innately poor ability to detoxify cyanide, a chronic, progressive visual loss can occur, termed tobacco amblyopia [1].

The older cyanide antidote kits consisted of nitrites and sodium thiosulfate. The true mechanism of action is complicated [3]. In short, the nitrites used in antidote kits are either inhaled amyl nitrite, used typically in the pre-hospital setting or when IV access is not available, or IV sodium nitrite [1,3]. These induce methemoglobinemia, which is hemoglobin with iron in the Fe3+ oxidation state instead of instead of Fe2+. The Fe3+ of metHb binds to cyanide ions more strongly than cytochrome oxidase does, so it draws the cyanide out of the cells to allow resumption of oxidative phosphorylation. One of the dangers of the nitrite-containing antidote is that inducing a methemoglobinemia in a critically ill patient could hasten their decline by further reducing oxygen delivery. The second component of the kit is sodium thiosulfate, which acts as a sulfur donor for the enzyme rhodanese, the body’s natural mechanism for detoxifying cyanide, converting it to thiocyanate. In patients who have had smoke inhalation, sodium thiosulfate should be used alone, without the nitrites, because there may be concomitant carboxyhemoglobinemia. Sodium thiosulfate is slower acting, however, as it cannot rapidly enter the mitochondria, and the sulfur donor group has to be shuttled to the mitochondrial rhodanese enzymes via the albumin-sulfane complex [3]. Supportive treatment including oxygen, IV fluids, and airway protection in severe cases should also be a priority.

More recently, hydroxocobalamin has become available under the brand name Cyanokit, and provides a safer, faster, simpler treatment. It is not universally available, however, so the older kits still have a role.

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How It Works
Hydroxocobalamin (vitamin B12a) has a central cobalt atom that binds cyanide ions, forming cyanocobalamin (vitamin B12), which is nontoxic and renally excreted. Hydroxocobalamin can rapidly enter the mitochondria and bind cyanide at the site where it is toxic, thus restoring oxidative metabolism.

Major Indications
The Nithiodote kit (sodium nitrite and sodium thiosulfate) and Cyanokit (hydroxocobalamin) are used for suspected or possible cyanide toxicity, in addition to usual supportive care and supplemental oxygen. Hydroxocobalamin is also used for the treatment of vitamin B12 deficiencies.

Notable History
The first available report of hydroxocobalamin use for cyanide detoxification was published in 1952 [4]. It was developed in France in the 1980s at the prompting of the Paris Fire Brigade and Paris anti-poisoning centers. It was approved for use in France in 1996, and was fast-tracked through the US FDA and approved in 2006. Newer cyanide scavengers are being developed that can be administered through IM injection in the case of terrorist or mass casualty events [3].

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Adverse Events
Hydroxocobalamin is a dark red color, and causes a marked erythematous skin discoloration, which occurs in 94-100% of patients, and can last up to 2 weeks [5]. It will also cause chromaturia (dark red urine) for up to 5 weeks. It may cause a decrease in lymphocyte count, as well as a local reaction at the infusion site.

Dosing and Adjustments
For any suspected or known cyanide toxicity, it is recommended hydroxocobalamin be given at 70mg/kg IV (or around 5g for an adult) [1]. Some references recommend also giving 25% sodium thiosulfate at 1.65mL/kg (max 12.5g, or 50mL) [6]. A second dose of hydroxocobalamin can be given with a maximum of 10g total. In pediatric patients, the dose is 70 mg/kg up to a maximum of 5g with a repeat of 35mg/kg. For comparison, the IM dose that is given for vitamin B12 deficiency is 100-200 mcg by monthly IM injection [5]. There are no dosing adjustments for patients with renal or hepatic dysfunction.

Special Considerations
It is pregnancy class C due to the absence of studies, and it is not known whether it is excreted in breast milk [5]. However, in a patient with potential cyanide exposure, these concerns should obviously not prevent rapid, maximal treatment.

REFERENCES

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1. Hostege CP, Kirk MA. Cyanide and hydrogen sulfide. In: Hoffman RS, Howland M, Lewin NA, Nelson LS,  Goldfrank LR, eds. Goldfrank’s toxicologic emergencies. 10e ed. New York, NY: McGraw Hill; 2015. http://accessemergencymedicine.mhmedical.com/content.aspx?bookid=1163&Sectionid=65102837. Accessed 12/17/2015.
2. Megarbane B, Delahaye A, Goldgran-Toledano D, Baud FJ. Antidotal treatment of cyanide poisoning. J Chin Med Assoc. 2003;66(4):193-203.
3. Petrikovics I, Budai M, Kovacs K, Thompson DE. Past, present and future of cyanide antagonism research: From the early remedies to the current therapies. World J Methodol. 2015;5(2):88-100.
4. Mushett CW, Kelley KL, Boxer GE, Richards JC. Antidotal efficacy of vitamin B12a (hydroxo-cobalamin) in experimental cyanide poisoning. Proc Soc Exp Biol Med. 1952;81(1):234-237.
5. Lexicomp. Hydroxocobalamin (vitamin B12a supplement and cyanide antidote): Drug information. UpToDate Web site. www.uptodate.com. Accessed 12/17, 2015.
6. Desai S, Su M. Cyanide poisoning. UpToDate Web site. www.uptodate.com. Published 9/29/2015. Updated 2015. Accessed 12/17, 2015.
7. Lexicomp. Sodium nitrite and sodium thiosulfate: Drug information. UpToDate Web site. uptodate.com. Accessed 12/17, 2015.