Editorial to accompany “Changes in blood pressure after administration of hydroxocobalamin: Relationship to changes in plasma cobalamins-(III) concentrations in healthy volunteers” (Uhl et al., present edition)

Editorial to accompany “Changes in blood pressure after administration of hydroxocobalamin: Relationship to changes in plasma cobalamins-(III) concentrations in healthy volunteers” (Uhl et al., present edition)

In this edition of Clinical Toxicology, Uhl et al. (1) have published the results of a normal volunteer study of the cyanide antidote hydroxocobalamin (Cyanokit®, Merck Santé, Lyon France) which was approved by the US FDA in December, 2006 and is distributed in the US by Dey, LP, Napa, CA. The overall normal volunteer study group comprised 136 healthy adults in a randomized, double-blind, placebo-controlled ascending dose (2.5 g, 5.0 g, 7.5 g, 10.0 g) study (2). The present study comprises a subset of 41 of these patients in whom elevations of blood pressure that occurred shortly after initiation of hydroxocobalamin infusion and returned to nearly baseline by 4 hours post-infusion were attempted to be correlated with plasma concentrations of free and total cobalamins-III. From the end of infusion to 4 hours post-infusion, blood pressure increases were correlated with free cobalamins-III concentration, but from 4–24 hours post-infusion no such association was evident.

It is of note that Uhl et al. (1) report that a “clinically relevant” increase in blood pressure was absent in 29/41 of these normal volunteers. In the 12/41 volunteers who did have a “clinically relevant” increase in blood pressure, the blood pressure returned to baseline between 20 minutes and 4 hours post-infusion, required no treatment, and resulted in no sequelae (1). These findings are in substantial agreement with an earlier, smaller normal volunteer study using a different hydroxocobalamin preparation (5 g in 100 mL USP water for infusion) (3).

The Package Insert for Cyanokit® lists blood pressure increases under both the “Warnings and Precautions” and “Adverse Reactions” headings (4), based upon these normal volunteer studies.

What does this mean, not in normal healthy volunteers, but in cyanide-poisoned patients including those with a cyanide poisoning component to enclosed-space fire smoke inhalation (the most common source of acute cyanide poisoning in the USA) (5)? First and foremost, hypotension and cardiovascular collapse are quite common clinical findings in “pure cyanide poisoning” and in cyanide-poisoned smoke inhalation victims (6–9). Studies in rats, dogs, and non-human primates also confirm the hypotensive effects of acute cyanide poisoning (10–14).

In the setting of hypotension and cardiovascular collapse, hydroxocobalamin-induced blood pressure increases might actually represent a therapeutic rather than an adverse effect. In a study by Fortin et al. from the Paris Fire Brigade (7), initially hypotensive adult smoke inhalation victims (initial systolic BP < 90 mmHg systolic) became hemodynamically stable after hydroxocobalamin administration. In another study from the Paris Fire Brigade and researchers from the Hôpital Fernand-Widal in Paris, critically ill smoke inhalation victims were administered hydroxocobalamin in the pre-hospital setting and were later proven not to have a significant cyanide poisoning component and did not become hypertensive (Personal Communication, FJ Baud, 1993, as quoted in ref. 3).

As Uhl et al. (1) postulate, this hypertensive property of hydroxocobalamin may be due to nitric oxide (NO) scavenging. NO is a free radical formed in bone, brain, endothelium, and other tissues and is a modulator of smooth muscle contractility. In the blood vessels, NO acts as a vasodilator. In a recent rabbit study, Gerth et al. (15) found that cyanocobalamin, the detoxification product of hydroxocobalamin and cyanide, had essentially no hemodynamic effects. Hydroxocobalamin was shown, due to its NO-scavenging properties, to have hypertensive effects (15).

The major mechanism of cyanide toxicity is inhibition of mitochondrial cytochrome aa₃ in the electron transport chain, blocking the utilization of oxygen for aerobic ATP production, and leading to anaerobic metabolism with severely decreased ATP production and production of lactic acid. In a symposium at the XIth International Congress of Toxicology, Montreal, Quebec, Canada, July 15–19, 2007 this author was privileged to co-chair, Pr. Gary Isom from Purdue University, West Lafayette, IN, whose research group has conducted extensive studies into the interaction of cyanide with cytochrome oxidase, presented a great deal of new data including the interaction of nitrite, nitrite conversion to NO, and the role of NO in cyanide poisoning (16). This emphasizes that the mechanism of antidotal action of hydroxocobalamin may not be just direct binding of cyanide to its cobalt moiety forming relatively non-toxic cyanocobalamin, but perhaps a combination of this plus NO-scavenging, both on cyanide-induced hypotension and on the cyanide-cytochrome oxidase interaction itself.

The study by Uhl et al. (1) in this edition of Clinical Toxicology adds to our understanding of the effects of hydroxocobalamin as a cyanide antidote. While the hypertensive effects can be considered as an adverse effect in normal volunteers, they may actually be additional therapeutic effects in seriously ill cyanide poisoned patients with hypotension. To date, these hypertensive effects have been shown to be relatively mild, transient, lacking sequelae, and have not required intervention with hypotensive medications.

As an aside, there is a new internet resource for cyanide exposure and treatment information from the non-profit organization, the Cyanide Poisoning Treatment Coalition (www.cyanidepoisoning.org). Readers interested in much more information on cyanide poisoning and its treatment are encouraged to visit this website.