Intramuscular administration of glyoxylate rescues swine from lethal cyanide poisoning and ameliorates the biochemical sequalae of cyanide intoxication.

Cyanide-a fast-acting poison-is easy to obtain given its widespread use in manufacturing industries. It is a high-threat chemical agent that poses a risk of occupational exposure in addition to being a terrorist agent. FDA-approved cyanide antidotes must be given intravenously, which is not practical in a mass casualty setting due to the time and skill required to obtain intravenous access. Glyoxylate is an endogenous metabolite that binds cyanide and reverses cyanide-induced redox imbalances independent of chelation. Efficacy and biochemical mechanistic studies in an FDA-approved preclinical animal model have not been reported. Therefore, in a swine model of cyanide poisoning, we evaluated the efficacy of intramuscular glyoxylate on clinical, metabolic, and biochemical endpoints. Animals were instrumented for continuous hemodynamic monitoring and infused with potassium cyanide. Following cyanide-induced apnea, saline control or glyoxylate was administered intramuscularly. Throughout the study, serial blood samples were collected for pharmacokinetic, metabolite, and biochemical studies, in addition, vital signs, hemodynamic parameters, and laboratory values were measured. Survival in glyoxylate-treated animals was 83% compared with 12% in saline-treated control animals (p < .01). Glyoxylate treatment improved physiological parameters including pulse oximetry, arterial oxygenation, respiration, and pH. In addition, levels of citric acid cycle metabolites returned to baseline levels by the end of the study. Moreover, glyoxylate exerted distinct effects on redox balance as compared with a cyanide-chelating countermeasure. In our preclinical swine model of lethal cyanide poisoning, intramuscular administration of the endogenous metabolite glyoxylate improved survival and clinical outcomes, and ameliorated the biochemical effects of cyanide.

Monitoring Dose Response of Cyanide Antidote Dimethyl Trisulfide in Rabbits Using Diffuse Optical Spectroscopy.

INTRODUCTION: Cyanide (CN) poisoning is a serious chemical threat from accidental or intentional exposures. Current CN exposure treatments, including direct binding agents, methemoglobin donors, and sulfur donors, have several limitations. Dimethyl trisulfide (DMTS) is capable of reacting with CN to form the less toxic thiocyanate with high efficiency, even without the sulfurtransferase rhodanese. We investigated a soluble DMTS formulation with the potential to provide a continuous supply of substrate for CN detoxification which could be delivered via intramuscular (IM) injection in a mass casualty situation. We also used non-invasive technology, diffuse optical spectroscopy (DOS), to monitor physiologic changes associated with CN exposure and reversal. METHODS: Thirty-six New Zealand white rabbits were infused with a lethal dose of sodium cyanide solution (20 mg/60 ml normal saline). Animals were divided into three groups and treated with saline, low dose (20 mg), or high dose (150 mg) of DMTS intramuscularly. DOS continuously assessed changes in tissue hemoglobin concentrations and cytochrome c oxidase redox state status throughout the experiment. RESULTS: IM injection of DMTS increased the survival in lethal CN poisoning. DOS demonstrated that high-dose DMTS (150 mg) reversed the effects of CN exposure on cytochrome c oxidase, while low dose (20 mg) did not fully reverse effects, even in surviving animals. CONCLUSIONS: This study demonstrated potential efficacy for the novel approach of supplying substrate for non-rhodanese mediated sulfur transferase pathways for CN detoxification via intramuscular injection in a moderate size animal model and showed that DOS was useful for optimizing the DMTS treatment.

Emergency medicine animal research: does use of randomization and blinding affect the results?

OBJECTIVES: It has been shown that human clinical trials that lack randomization (RND) or blinding (BLD) often overestimate the magnitude of treatment effects. However, no studies have evaluated the effect of RND and BLD on animal research. The authors' objectives were to determine the proportion of animal studies presented at a national academic emergency medicine meeting that utilize randomization, blinding, or both; and to determine whether failure to employ these techniques changes the likelihood of observing a difference between treatment groups. METHODS: Two trained researchers reviewed abstracts presented at the 1997-2001 Society for Academic Emergency Medicine (SAEM) annual meetings using a standard data collection sheet. Studies that used an animal or cell line, compared two or more study groups, and measured an effect caused by the intervention or drugs were included. Studies were classified as randomized (RND+) if any part of the experiment involved random assignment of subjects to treatment groups, blinded (BLD+) if any assessment of the outcome was made by an investigator blinded to treatment group, and outcome-positive (Outcome+) if any difference between the study groups met the author's definition of significant. Following the initial review, differences in classification were resolved by consensus. The association between outcome and study methodology (RND, BLD or both) was measured using odds ratios (ORs) with 95% confidence intervals (95% CIs). RESULTS: A total of 2,592 studies were published as abstracts. Three hundred eighty-nine were animal studies, and 290 of these studies had two or more study groups. RND- and BLD- studies were more likely to be Outcome+ than RND+ or BLD+ studies (OR = 3.4; 95% CI = 1.7 to 6.9 and OR = 3.2; 95% CI = 1.3 to 7.7, respectively). When studies that used both RND and BND were compared with studies that used neither, the OR for a positive study was 5.2 (95% CI = 2.0 to 13.5). CONCLUSIONS: These results suggest that animal studies that do not utilize RND and BLD are more likely to report a difference between study groups than studies that employ these methods.