Intramuscular sodium tetrathionate as an antidote in a clinically relevant swine model of acute cyanide toxicity

Abstract

Background: Cyanide is a metabolic poison used in multiple industries and is a high threat chemical agent. Current antidotes require intravenous administration, limiting their usefulness in a mass casualty scenario. Sodium tetrathionate reacts directly with cyanide yielding thiosulfate and the non-toxic compound thiocyanate. Thiosulfate, in turn, neutralizes a second molecule of cyanide, thus, per mole, sodium tetrathionate neutralizes two moles of cyanide. Historical studies examined its efficacy as a cyanide antidote, but it has not been evaluated in a clinically relevant, large animal model, nor has it previously been administered by intramuscular injection.Objective: The objective of this study is to evaluate the efficacy of intramuscular sodium tetrathionate on survival and clinical outcomes in a large, swine model of severe cyanide toxicity.Methods: Anesthetized swine were instrumented for continuous monitoring of hemodynamics, then acclimated and breathing spontaneously prior to potassium cyanide infusion (0.17 mg/kg/min). At 6-min post-apnea (no breaths for 20 s), the cyanide infusion was terminated, and animals were treated with sodium tetrathionate (∼18 mg/kg) or normal saline control. Clinical parameters and laboratory values were evaluated at various time points until death or termination of the experiment (90 min post-treatment).Results: Laboratory values, vital signs, and time to apnea were similar in both groups at baseline and treatment. Survival in the sodium tetrathionate treated group was 100% and 17% in controls (p = 0.0043). All animals treated with sodium tetrathionate returned to breathing at a mean time of 10.85 min after antidote, and all but one control remained apneic through end of the experiment. Animals treated with tetrathionate showed improvement in blood lactate (p ≤ 0.002) starting at 30 min post-treatment. The average time to death in the control group is 63.3 ± 23.2 min. No systemic or localized adverse effects of intramuscular administration of sodium tetrathionate were observed.Conclusion: Sodium tetrathionate significantly improves survival and clinical outcomes in a large, swine model of acute cyanide poisoning.

Keywords: Cyanide poisoning; intramuscular; potassium cyanide; sodium tetrathionate; swine; terrorism.

Figure 1.

Reaction of sodium tetrathionate with cyanide. Figure 1. Sodium tetrathionate reacts with cyanide to form thiocyanate, sulfate, and sodium thiosulfate. Sodium thiosulfate acts as a substrate for the enzyme rhodanese and reacts with another molecule of cyanide (CN⁻) to form thiocyanate (SCN⁻) and sulfite (SO₃^2-). Sodium tetrathionate: Na₂S₄O₆, cyanide: CN⁻, thiocyanate: SCN⁻, sulfate: SO₄^2-, sodium thiosulfate: Na₂S₂O_3, sulfite: SO₃^2-

Figure 2.

Percent survival in swine treated with intramuscular sodium tetrathionate as compared to saline control Figure 2. Survival is improved with IM sodium tetrathionate administration following acute cyanide toxicity compared to saline controls. P value determined by log rank (Mantel-Cox) test, for comparison, P value less than or equal to 0.05 considered significant.

Figure 3.

Laboratory parameters over time between the swine treated with sodium tetrathionate and control Figure 3a-c. Blood cyanide concentrations increase until treatment, then return to baseline more rapidly in the sodium tetrathionate treatment than controls. Lactate is significantly improved starting at 30 minutes (P<0.002) after treatment with sodium tetrathionate compared to controls over time. Data is presented as means ± standard deviation. Statistical comparisons could not be done at 80 and 90 min due to only one animal remaining in the control arm. mmol/L: millimoles/liter; mg/dL: milligrams/deciliter

Figure 4.

Clinical outcomes over time between the swine treated with sodium tetrathionate and control Figure 4a-c. Mean arterial pressure, respiratory rate, and pulse oximetry are improved in sodium tetrathionate treated animals compared to controls. Mean arterial pressure shown as percent of baseline. Respiratory rate is significantly improved 10 (P=0.02), 20, (P=0.03), 40 (P=0.04) minutes post treatment with sodium tetrathionate compared to controls over time. Pulse Oximetry is significantly improve in the sodium tetrathionate group at 50 (P=0.04) and 60 (P=0.02) minutes after treatment compared to controls. Data is presented as means ± standard deviation. Statistical comparisons could not be done at 80 and 90 min due to only one animal remaining in the control arm. mm Hg: millimeters of mercury