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Modest and variable efficacy of pre-exposure hydroxocobalamin and dicobalt edetate in a porcine model of acute cyanide salt poisoning.
Clin Toxicol (Phila) 2019; :1-11CT

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 LD50. 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.

Authors+Show Affiliations

a Department of Pharmacology, Toxicology, & Therapeutics, University/BHF Centre for Cardiovascular Science, University of Edinburgh , Edinburgh , UK.b Medical Toxicology Centre, University of Newcastle , Newcastle upon Tyne , UK.b Medical Toxicology Centre, University of Newcastle , Newcastle upon Tyne , UK.a Department of Pharmacology, Toxicology, & Therapeutics, University/BHF Centre for Cardiovascular Science, University of Edinburgh , Edinburgh , UK.c Wellcome Critical Care Laboratory for Large Animals, Roslin Institute, Royal (Dick) School of Veterinary Studies, University of Edinburgh , Edinburgh , UK.c Wellcome Critical Care Laboratory for Large Animals, Roslin Institute, Royal (Dick) School of Veterinary Studies, University of Edinburgh , Edinburgh , UK.c Wellcome Critical Care Laboratory for Large Animals, Roslin Institute, Royal (Dick) School of Veterinary Studies, University of Edinburgh , Edinburgh , UK.c Wellcome Critical Care Laboratory for Large Animals, Roslin Institute, Royal (Dick) School of Veterinary Studies, University of Edinburgh , Edinburgh , UK.b Medical Toxicology Centre, University of Newcastle , Newcastle upon Tyne , UK.b Medical Toxicology Centre, University of Newcastle , Newcastle upon Tyne , UK.a Department of Pharmacology, Toxicology, & Therapeutics, University/BHF Centre for Cardiovascular Science, University of Edinburgh , Edinburgh , UK.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31389254

Citation

Thompson, Adrian, et al. "Modest and Variable Efficacy of Pre-exposure Hydroxocobalamin and Dicobalt Edetate in a Porcine Model of Acute Cyanide Salt Poisoning." Clinical Toxicology (Philadelphia, Pa.), 2019, pp. 1-11.
Thompson A, Dunn M, Jefferson RD, et al. Modest and variable efficacy of pre-exposure hydroxocobalamin and dicobalt edetate in a porcine model of acute cyanide salt poisoning. Clin Toxicol (Phila). 2019.
Thompson, A., Dunn, M., Jefferson, R. D., Dissanayake, K., Reed, F., Gregson, R., ... Eddleston, M. (2019). Modest and variable efficacy of pre-exposure hydroxocobalamin and dicobalt edetate in a porcine model of acute cyanide salt poisoning. Clinical Toxicology (Philadelphia, Pa.), pp. 1-11. doi:10.1080/15563650.2019.1628969.
Thompson A, et al. Modest and Variable Efficacy of Pre-exposure Hydroxocobalamin and Dicobalt Edetate in a Porcine Model of Acute Cyanide Salt Poisoning. Clin Toxicol (Phila). 2019 Aug 7;1-11. PubMed PMID: 31389254.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Modest and variable efficacy of pre-exposure hydroxocobalamin and dicobalt edetate in a porcine model of acute cyanide salt poisoning. AU - Thompson,Adrian, AU - Dunn,Michael, AU - Jefferson,Robert D, AU - Dissanayake,Kosala, AU - Reed,Frances, AU - Gregson,Rachael, AU - Greenhalgh,Stephen, AU - Clutton,R Eddie, AU - Blain,Peter G, AU - Thomas,Simon Hl, AU - Eddleston,Michael, Y1 - 2019/08/07/ PY - 2019/8/8/entrez KW - Cyanide KW - antidotes KW - efficacy SP - 1 EP - 11 JF - Clinical toxicology (Philadelphia, Pa.) JO - Clin Toxicol (Phila) N2 - 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 LD50. 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. SN - 1556-9519 UR - https://www.unboundmedicine.com/medline/citation/31389254/Modest_and_variable_efficacy_of_pre-exposure_hydroxocobalamin_and_dicobalt_edetate_in_a_porcine_model_of_acute_cyanide_salt_poisoning L2 - http://www.tandfonline.com/doi/full/10.1080/15563650.2019.1628969 DB - PRIME DP - Unbound Medicine ER -