A nonlethal, anesthetized canine model for efficacy evaluation of anticyanide therapy

Efficacy evaluations of anticyanide therapeutic compounds historically have used lethality in unanesthetized animals as the toxic endpoint, and a nonlethal, repeated-testing, anesthetized canine model has been reported. Time to respiratory arrest (TRA) induced by a continuous, slow intravenous (IV) infusion of sodium cyanide (NaCN) was shown to be a consistent, well-defined endpoint in anesthetized canines. Thirty seconds after respiratory arrest (RA), an IV bolus of a methemoglobin-forming compound reversed the respiratory effects. This study was designed to determine the variability in TRA, survivability of anesthetized dogs repeatedly infused with NaCN and treated with hydroxylamine, replicability of the procedure within an animal and between animals, and development of trends in data. Four animals were anesthetized, intubated, catheterized, and instrumented to record respiratory rate and heart rate. Immediately following baseline data collection, a 4-mg/mL. NaCN solution was infused at a rate of 2 mL/min. Following a 10-s period without functional respiration, infusion was stopped and this moment was designated as RA. Hydroxylamine therapy was administered 30 s after RA. There were 4 replicate experiments per animal with a 1-week washout period between replicates. Interanimal variability in TRA was significant (p = .04). The average variability in TRA within an animal was less than 10%. Baseline heart and respiratory rates were not altered significantly. Data confirm, by replicate testing, the utility of this model.