Hydroxocobalamin, the cyanide antidote recently approved by the Food and Drug Administration for use in the United States, is considerably safer, has fewer adverse effects, and has a remarkable tendency to raise, rather than lower, blood pressure, especially compared with the older cyanide antidote kit that consisted of amyl nitrite, sodium nitrite, and sodium thiosulfate.
Last month I discussed the problems with the old antidote, how hydroxocobalamin works, and its recommended dose and side effects, but, of course, other factors, not the least of which is cost, determine whether its use will be widely adopted.
How much does hydroxocobalamin (HC) cost? HC, marketed as Cyanokit, costs approximately $650 for a 5 g adult dose. The usual recommended treatment for an adult patient with known or suspected cyanide toxicity is 5 g to 10 g; the pediatric dose is 70 mg/kg. The current recommended shelf life for the Cyanokit is 30 months, but research is underway to determine if this time frame will be extended in the future.
Is there any benefit to using sodium thiosulfate in addition to hydroxocobalamin when treating cyanide toxicity? Clinicians were often reluctant to use all components of the old cyanide antidote kit in sick, unstable patients with possible cyanide toxicity for fear of inducing excessive methemoglobinemia or hypotension with sodium nitrite. In many of these cases, sodium thiosulfate was given alone. While sodium thiosulfate is relatively safe and effective, it has certain disadvantages as a cyanide antidote. For one thing, unlike HC, it does not directly detoxify cyanide.
Rather, it works indirectly by supporting the body's own primary detoxifying metabolic pathway, supplying sulfur that allows the enzyme rhodanase to convert cyanide to thiocyanate (Fig. 1.) In addition, thiosulfate does not readily penetrate into mitochondria, where the metabolism of cyanide takes place. The bottom line is that there is a delay between the administration of sodium thiosulfate and the onset of its antidotal action. The purpose of sodium nitrite in the old kit was to buy time until sodium thiosulfate could take effect.
In contrast, HC (vitamin B12a) directly detoxifies cyanide, giving up one hydroxyl group in exchange for a cyanide ion, forming cyanocobalamin (vitamin B12). This takes place rapidly in the blood. HC quickly enters mitochondria, where its high affinity for cyanide pulls the toxin off cytochrome oxidase, renewing the cell's ability to utilize oxygen.
Much of the experience and medical literature concerning the use of HC as a cyanide antidote comes from France. The French cyanide treatment kit contained both HC (4 g) and sodium thiosulfate (8 g). Although animal studies have been inconclusive, there is at least a theoretical benefit to using both antidotes together. When HC is given alone, the primary detoxification product found in urine is cyanocobalamin. When HC is given with sodium thiosulfate, the primary product is thiocyanate. (J Emerg Med 1987;5:115.)
This suggests that cyanocobalamin gives up its cyanide component to the mitochondrial rhodanase pathway, regenerating HC which is then available to detoxify additional cyanide. Pending additional data, it would make sense to initiate treatment of suspected cyanide toxicity with HC, which is usually effective. If the patient does not improve rapidly (for example, if the degree of acidosis does not decrease), sodium thiosulfate could be added. The adult dose of thiosulfate is 12.5 g; the pediatric dose is 0.4 g/kg. Adding thiosulfate also may be considered in the setting of ongoing absorption of cyanide such as occurs after ingestion. Sodium thiosulfate is often stocked by hospital pharmacies for use to prevent nitroprusside-associated cyanide toxicity (see below). Note that HC and sodium thiosulfate are not compatible and should not be administered concurrently through the same intravenous line. They can be given through separate lines or sequentially after the line has been flushed.
Should hydroxocobalamin be used to prevent cyanide toxicity associated with the administration of sodium nitroprusside? Each molecule of sodium nitroprusside (NTP) contains five cyanide groups, which are rapidly liberated when the drug is administered by intravenous route. (Fig. 2.) This free cyanide is detoxified by metabolism to thiocyanate through the mitochondrial rhodanase pathway and by combination with endogenous hydroxocobalamin to form cyanocobalamin (vitamin B12). The rate-limiting factor for this detoxification is the availability of thiosulfate.
At NTP doses greater than about 2 mcg/kg/min, cyanide can accumulate as thiosulfate stores become depleted. In this setting, early signs and symptoms of cyanide toxicity include metabolic acidosis, confusion, headache, and resistance to the hypotensive effects of NTP (tachyphylaxis). The diagnosis may be elusive in, say, a patient with hypertensive crisis because increasing confusion is often attributed to hypertensive encephalopathy, and relative drug resistance can cause the treating physician to increase the rate of NTP infusion.
Nitroprusside-induced cyanide toxicity should be treated by discontinuing the infusion and administering the available antidote, either the old cyanide kit or hydroxocobalamin. There are no good data indicating whether the tendency of HC to raise blood pressure could cause clinically significant adverse effects in patients receiving NTP to treat dangerous hypertension when the drug is suddenly discontinued.
Infusing sodium thiosulfate with NTP prevents the accumulation of cyanide even at very high dose rates; a typical protocol mixes 50 mg of NTP in 50 ml of 1% sodium thiosulfate. In rare situations, dangerous levels of thiocyanate will occur. Using HC for prophylaxis instead of sodium thiosulfate would avoid this problem. Thiocyanate toxicity is quite rare, however, and HC is relatively expensive. Opening a Cyanokit costs the hospital about $650. In our institution, 100 ml of 1% sodium thiosulfate costs $5.65, so using HC as prophylaxis is not considered cost-effective.