Modest and variable efficacy of pre-exposure hydroxocobalamin and dicobalt edetate in a porcine model of acute cyanide salt poisoning

Abstract

Background: Dicobalt edetate and hydroxocobalamin are widely used to treat hydrogen cyanide poisoning. However, comparative and quantitative efficacy data are lacking. Although post-exposure treatment is typical, it may be possible to administer these antidotes before exposure to first attenders entering a known site of cyanide release, as supplementary protection to their personal protective equipment. Methods: We established an anaesthetised Gottingen minipig model of lethal bolus potassium cyanide (KCN) injection to simulate high dose hydrogen cyanide inhalation. Doses were similar to human lethal doses of KCN. Dicobalt edetate and hydroxocobalamin were administered shortly before KCN and their effect on metabolic and cardiovascular variables and survival time were measured. Results: Increases in arterial lactate were similar after 0.08 and 0.12 mmol/kg KCN. KCN 0.08 mmol/kg was survived by 4/4 animals with moderate cardiovascular effects, while the 0.12 mmol/kg dose was lethal in 4/4 animals, with a mean time to euthanasia of 28.3 (SEM: 13.9) min. Administration of dicobalt edetate (0.021 mmol/kg, 8.6 mg/kg) or hydroxocobalamin (0.054 mmol/kg, 75 mg/kg) at clinically licenced doses had modest effect on lactate concentrations but increased survival after administration of KCN 0.12 mmol/kg (survival: dicobalt edetate 4/4, hydroxocobalamin 2/4) but not 0.15 mmol/kg (0/4 and 0/4, respectively). In a subsequent larger study, doubling the dose of hydroxocobalamin (0.108 mmol/kg, 150 mg/kg) was associated with a modest but inconsistent increased survival after 0.15 mmol/kg KCN (survival: control 0/8, 75 mg/kg 1/10, 150 mg/kg 3/10) likely due to variable pharmacokinetics. Conclusions: In this porcine study of cyanide exposure, with pre-exposure antidote administration, licenced doses of dicobalt edetate and hydroxocobalamin were effective at just lethal doses but ineffective at less than twice the estimated LD 50. The efficacy of a rapidly-administered double-dose of hydroxocobalamin was limited by variable pharmacokinetics. In clinical poisoning scenarios, with delayed administration, the antidotes are likely to be even less effective. New antidotes are required for treatment of cyanide exposures appreciably above the minimum lethal dose.

Cyanide Poisoning Compromises Gene Pathways Modulating Cardiac Injury in Vivo

“…Cyanide injection or infusion has often been used for animal models of cyanide poisoning, primarily to evaluate medical countermeasures. − Such routes of exposure, however, are not necessarily reflective of common exposures like structural fire or potential mass casualty incidents, in which victims likely suffer from HCN inhalation. To better understand the effect of exposure routes, gene expression changes for HCN inhalation and KCN injection exposures were compared.…”

“…On average, animals exposed to HCN displayed more severe toxic signs and took longer to recover than did those exposed to KCN. Since many studies to understand cyanide toxicity and evaluate cyanide antidotes have been conducted in animal models injected or infused with cyanide salts, − the transcriptomic data presented here demonstrate the importance of considering route of exposure, and hence cyanide formulation, when studying cyanide toxicity or developing therapeutics.…”

Identification of Platinum(II) Sulfide Complexes Suitable as Intramuscular Cyanide Countermeasures

“…Currently approved cyanide countermeasures are administered by IV infusion or inhalation, typically requiring trained medical staff . Therefore, treatments may take substantial time for the complete administration and pharmacological action, making them less than optimal in a mass casualty event. ,, For example, 5 g of hydroxocobalamin is administered by IV infusion over 15 min, occasionally needing repeat doses. , A further complication is that compounds like hydroxocobalamin have relatively low aqueous solubility (27.3 ng/mL) that can be a confounder with multiple dosing. Moreover, due to the toxic side effects of current treatments, there is ambiguity regarding the best countermeasure options in emergencies .…”

“… 16 Therefore, treatments may take substantial time for the complete administration and pharmacological action, making them less than optimal in a mass casualty event. 4 , 25 , 26 For example, 5 g of hydroxocobalamin is administered by IV infusion over 15 min, occasionally needing repeat doses. 27 , 28 A further complication is that compounds like hydroxocobalamin have relatively low aqueous solubility (27.3 ng/mL) that can be a confounder with multiple dosing.…”

Investigating the replacement of carboxylates with carboxamides to modulate the safety and efficacy of platinum(II) thioether cyanide scavengers

“…In some cases, a higher dose over a longer time is required, thus adding to the risks of comorbidities including drug-induced renal impairment ( Shepherd and Velez, 2008 ). Evidence strongly supports that a prompt delivery of cyanide scavengers after exposure can significantly improve survival rates ( Thompson et al , 2019 ).…”