http://orcid.org/0000-0002-6857-3441
Figures & data
Figure 1. Cardiovascular and metabolic responses to cyanide with or without antidotes. (A) Cardiovascular (heart rate, MAP; 5 min intervals) and (B) metabolic (arterial lactate) responses to 0.08 mmol/kg KCN (circle) and 0.12 mmol/kg KCN (square) and to 0.12 mmol/kg KCN following pre-treatment with hydroxocobalamin (diamond) or dicobalt edetate (triangle). Values are mean ± SEM (for cardiovascular variables, of normalised responses [mean of -30 min and -10 min pre-cyanide exposure values = 100%]).
![Figure 1. Cardiovascular and metabolic responses to cyanide with or without antidotes. (A) Cardiovascular (heart rate, MAP; 5 min intervals) and (B) metabolic (arterial lactate) responses to 0.08 mmol/kg KCN (circle) and 0.12 mmol/kg KCN (square) and to 0.12 mmol/kg KCN following pre-treatment with hydroxocobalamin (diamond) or dicobalt edetate (triangle). Values are mean ± SEM (for cardiovascular variables, of normalised responses [mean of -30 min and -10 min pre-cyanide exposure values = 100%]).](/cms/asset/5e18be97-7774-40e6-9f08-0157f007deef/ictx_a_1628969_f0001_c.jpg)
Figure 2. Survival post cyanide dosing. (A) Survival following exposure to 0.08 or to 0.12 mmol/kg KCN with or without antidotes. (B) Survival following exposure to 0.15 mmol/kg KCN, with or without antidotes, or equimolar KCl or NaCN. The studies had planned maximum durations of (A) 90 min and (B) 30 min. All animals that underwent euthanasia at this time had good cardiovascular function and were judged to have survived the procedure. Mean (SEM) time to euthanasia are shown for each group.
Table 1. Free cyanide concentrations following administration of 0.08, 0.12 and 0.15 mmol/kg KCN, and 0.15 mmol/kg NaCN.
Figure 3. Pharmacokinetics of the antidotes. (A) Mean (SEM) blood hydroxocobalamin (orange diamond) and cyanocobalamin (red circle) concentrations after infusion of hydroxocobalamin from -10 to 0 min relative to a 0.12 mmol/kg KCN challenge. The concentrations of hydroxocobalamin (triangle) and cyanocobalamin (square) are also shown at baseline and at 5 min after 0.15 mmol/kg KCN. (B) Mean (SEM) blood cobalt concentration (circle) after infusion of dicobalt edetate from -10 to -5 min relative to a 0.12 mmol/kg KCN challenge. The cobalt concentration is also shown at baseline and at 5 min after 0.15 mmol/kg KCN ( square). Only a 5 min sample was obtained following the higher KCN challenge due to all animals requiring euthanasia 6–9 min post challenge.
Figure 4. Effect of cyanide and potassium on cardiovascular function and lactate. (A–C) Cardiovascular (A: heart rate; B: MAP) and metabolic (C: arterial lactate) responses to 0.15 mmol/kg KCN (orange square) or to equimolar quantities of KCl ( circle) or NaCN (upwards triangle). (D–F) Cardiovascular (D: heart rate; E: MAP) and metabolic (F: arterial lactate) responses to 0.15 mmol/kg KCN alone (square) or after hydroxocobalamin (diamond) or dicobalt edetate (downwards triangle) antidotes. Values are means ± SEM (for cardiovascular variables, of normalised responses [mean of -30 min and -10 min pre-cyanide exposure values = 100%]).
![Figure 4. Effect of cyanide and potassium on cardiovascular function and lactate. (A–C) Cardiovascular (A: heart rate; B: MAP) and metabolic (C: arterial lactate) responses to 0.15 mmol/kg KCN (orange square) or to equimolar quantities of KCl ( circle) or NaCN (upwards triangle). (D–F) Cardiovascular (D: heart rate; E: MAP) and metabolic (F: arterial lactate) responses to 0.15 mmol/kg KCN alone (square) or after hydroxocobalamin (diamond) or dicobalt edetate (downwards triangle) antidotes. Values are means ± SEM (for cardiovascular variables, of normalised responses [mean of -30 min and -10 min pre-cyanide exposure values = 100%]).](/cms/asset/cb02fbaf-7220-4432-a245-18108e9e8d82/ictx_a_1628969_f0004_c.jpg)
Figure 5. Effect of high dose hydroxocobalamin. Cardiovascular (heart rate, MAP) and metabolic (arterial lactate) effects of 0.15 mmol/kg KCN alone (square) or after pre-treatment with hydroxocobalamin 75 mg/kg (diamond) or 150 mg/kg (circle). Values are means ± SEM (for cardiovascular variables, of normalised responses [mean of -30 min and -10 min pre-cyanide exposure values = 100%]).
![Figure 5. Effect of high dose hydroxocobalamin. Cardiovascular (heart rate, MAP) and metabolic (arterial lactate) effects of 0.15 mmol/kg KCN alone (square) or after pre-treatment with hydroxocobalamin 75 mg/kg (diamond) or 150 mg/kg (circle). Values are means ± SEM (for cardiovascular variables, of normalised responses [mean of -30 min and -10 min pre-cyanide exposure values = 100%]).](/cms/asset/c7988412-1380-443a-8b48-a4aa733edcca/ictx_a_1628969_f0005_c.jpg)
Figure 6. Survival after high dose hydroxocobalamin. Time to euthanasia after 0.15 mmol/kg KCN alone (square) or after pre-treatment with hydroxocobalamin 75 mg/kg (diamond) or 150 mg/kg (circle). The study had a planned maximum duration of 90 min. All animals undergoing euthanasia at this time had good cardiovascular function and were judged to have survived the procedure. Mean (SEM) time to euthanasia are shown for each group.
Figure 7. Pharmacokinetics of cyanide, hydroxocobalamin, and cyanocobalamin. Mean (SEM; A, E, H) and individual animal (B–D, F and G, I and J) concentrations of blood cyanide (µmol/L CN−, A–D), plasma hydroxocobalamin (mg/L, E–G), and plasma cyanocobalamin (mg/L, H–J) after administration of 75 (B, E, I) or 150 (C, F, J) mg/kg hydroxocobalamin or (D) plasma placebo.
