Non-cholinergic intervention of sarin nerve agent poisoning

Defence Research & Development Canada-Suffield, Box 4000, Medicine Hat, Alberta, Canada T1A 8K6.
Toxicology (Impact Factor: 3.62). 02/2012; 294(2-3):85-93. DOI: 10.1016/j.tox.2012.02.003
Source: PubMed


The protective effects of selected anesthetic regimens on sarin (GB) were investigated in domestic swine. At 30% oxygen, the toxicity of this agent in isoflurane anesthetized animals (LD(50)=10.1μg/kg) was similar to literature sited values in awake swine (LD(50)=11.8μg/kg) and slightly higher than that of both ketamine (LD(50)=15.6μg/kg) and propofol (LD(50)=15.3μg/kg) anesthetized swine. Use of 100% oxygen in ketamine anesthetized animals resulted in three-fold protective effects compared to 30% oxygen. Use of 100% oxygen in both isoflurane and propofol anesthetized animals, compared to 30% resulted in profound protection against GB poisoning (>33×). There were no differences in the severity of the poisoning or recovery time in animals treated over dose ranges of 10-350μg/kg (isoflurane) or 15-500μg/kg GB (propofol). Survivors of high GB challenges that were revived from propofol anesthetic exhibited no signs of cognitive impairment seven days later. Protective treatments did not attenuate cholinesterase (ChE) inhibition; survivors of otherwise supralethal GB concentrations exhibited very low blood ChE activities. This work indicates that propofol has protective effects against GB, and that oxygen tension may have an important role in treating nerve agent casualties. More importantly, it demonstrates that non-cholinergic protective mechanisms exist that may be exploited in the future development of medical countermeasures against organophosphorous nerve agents.

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    ABSTRACT: The use of haemostatic materials that could be used to mitigate against the effects of the chemical warfare agent soman (GD) on contaminated personnel that may also present with wounds were investigated. To support the in vitro diffusion cell component of this work, the penetration rate of 14C-GD into different receptor fluids was evaluated to enable determination of the most appropriate receptor fluid to use as a sink for GD. Of the receptor media evaluated only 50% aqueous ethanol was able to maintain sink conditions. A number of haemostatic materials were shown to retain haemostatic efficacy in the presence of blood contaminated with GD, and were also shown to irreversibly sequester GD. The lead candidate, WoundStat™, was shown to be as effective a decontaminant as the current in service countermeasure fullers’ earth. Complementary in vivo studies using damaged ear skin in a terminally anaesthetised large white pig model showed that whilst use of WoundStat™ was not 100% effective in the prevention of mortality after GD poisoning, it did increase the therapeutic window where further nerve agent-specific medical countermeasures could be employed. Perhaps most importantly, application of WoundstatTM onto GD contaminated damaged skin did not increase the toxicity of GD.
    12/2013, Degree: PhD, Supervisor: Professor Kevin Chipman
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    ABSTRACT: Exposure to organophosphates (OP) may lead to a life threatening cholinergic crisis with death attributed to a rapidly progressive respiratory failure. In a toxicological mass casualty event involving organophosphate exposure, many of the victims may depend on immediate short-term ventilation to overcome the respiratory distress which may exhaust life supporting resources. In addition, the mandatory use of personal protective gear by first responders emphasizes the need for a noninvasive, easy-to-operate ventilation device. Our objective was to assess the efficacy of MRTX, a Biphasic Cuirass Ventilation device, in comparison with standard bag-valve mask ventilation following acute organophosphate poisoning.Methods Pigs were exposed to paraoxon poisoning (1.4LD50), and treated 8 min later with atropine (0.05 mg/kg). The control group received no further support (n = 9), the two experimental groups received ventilation support initiated 15 minutes post exposure and lasted for 25 minutes: one group was ventilated with the commonly used bag-valve mask (Mask group, n = 7) and the other was ventilated with the Biphasic Cuirass Ventilation device (Cuirass group, n = 7). Clinical signs and physiological parameters were monitored during the first hour, and mortality up to 24 hours post exposure was recorded.ResultsNo mortality was observed in the Cuirass group following OP poisoning, while mortality in the Control and in the Mask groups was high (67% and 71%, respectively). Mouth excretions of the cuirass-ventilated animals were frothy white as in deep suctioning, as opposed to the clear saliva-like appearance of secretions in the other two groups. No further group differences were recorded.Conclusions The noninvasive, easy-to-operate Biphasic Cuirass Ventilation device was effective in reducing OP-induced mortality and might be advantageous in an organophosphate mass casualty event. This finding should be validated in further investigations.
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