title: Rapid and equivalent systemic bioavailability of the antidotes HI-6 and dicobalt edetate via the intraosseous and intravenous routes.
abstract: BACKGROUND
  Rapid and effective administration of antidotes by emergency medical responders is needed to improve the survival of patients severely poisoned after deliberate release of chemical weapons, but intravenous access is difficult to obtain while wearing personal protective equipment and in casualties with circulatory collapse. To test the hypothesis that rapid and substantial bioavailability of the antidotes HI-6 oxime and dicobalt edetate can be achieved via the intraosseous (IO) route, plasma concentration-time profiles of these antidotes were compared after administration by the intravenous and IO routes in a minipig animal model.
  
  
  METHODS
  12 male Göttingen minipigs were randomly allocated to receive 7.14 mg/kg of HI-6 (by rapid bolus) then 4.28 mg/kg of dicobalt edetate (over 1 min) via the intravenous or IO route. Plasma concentrations of each antidote were measured over 360 min following administration and plasma concentration-time profiles plotted for each drug by each route.
  
  
  RESULTS
  Peak HI-6 and cobalt concentrations occurred within 2 min of administration by both the intravenous and IO routes. Mean areas under the concentration-time curves (SD) to the end of the experiment (area under the concentration-time curve, AUC (0-t)) for cobalt were 430 (47, intravenous) and 445 (40, IO) μg-min/mL (mean difference 15, 95% CI -41 to 70, p=0.568) and for HI-6 were 2739 (1038, intravenous) and 2772 (1629, IO) μg-min/mL (mean difference 0.33, 95% CI -1724 to 1790, p=0.97). Increases in heart rate (by 50 beats/min intravenous and 27 beats/min IO) and BP, (by 67/58 mm Hg intravenous and 78/59 mm Hg IO), were observed after dicobalt edetate, consistent with the known adverse effects of this antidote.
  
  
  CONCLUSIONS
  This study demonstrates rapid and similar systemic bioavailability of HI-6 and dicobalt edetate when given by the IO and intravenous routes. IO delivery of these antidotes is appropriate in the acute management of patients with organophosphate and cyanide intoxication when the intravenous route is impractical.
authors.affiliation: Medical Toxicology Research Centre, Institute of Cellular Medicine, Newcastle University, Newcastle, UK.
authors.forename: Simon L
authors.initials: SL
authors.lastname: Hill
authors.affiliation: Medical Toxicology Research Centre, Institute of Cellular Medicine, Newcastle University, Newcastle, UK.
authors.forename: Simon H L
authors.initials: SH
authors.lastname: Thomas
authors.affiliation: Comparative Biology Centre, Newcastle University, Newcastle, UK.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Flecknell
authors.affiliation: Comparative Biology Centre, Newcastle University, Newcastle, UK.
authors.forename: Aurelie A
authors.initials: AA
authors.lastname: Thomas
authors.affiliation: Medical Toxicology Research Centre, Institute of Cellular Medicine, Newcastle University, Newcastle, UK.
authors.forename: Chris M
authors.initials: CM
authors.lastname: Morris
authors.affiliation: Medical Toxicology Research Centre, Institute of Cellular Medicine, Newcastle University, Newcastle, UK.
authors.forename: David
authors.initials: D
authors.lastname: Henderson
authors.affiliation: Medical Toxicology Research Centre, Institute of Cellular Medicine, Newcastle University, Newcastle, UK.
authors.forename: Michael
authors.initials: M
authors.lastname: Dunn
authors.affiliation: Medical Toxicology Research Centre, Institute of Cellular Medicine, Newcastle University, Newcastle, UK.
authors.forename: Peter G
authors.initials: PG
authors.lastname: Blain
mesh_terms: D000818:Animals; D000931:Antidotes / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001682:Biological Availability; D002619:Chemical Warfare Agents / Q000506:poisoning; D004195:Disease Models, Animal; D004492:Edetic Acid / Q000008:administration & dosage / Q000493:pharmacokinetics*; D017148:Infusions, Intraosseous; D007275:Injections, Intravenous; D010091:Oximes / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011726:Pyridinium Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics*; D013552:Swine
chemical_list: D000931:Antidotes; D002619:Chemical Warfare Agents; D010091:Oximes; D011726:Pyridinium Compounds; C028222:cobalt-ethylenediamine tetraacetic acid chelate; D004492:Edetic Acid; C022870:asoxime chloride