Objective To determine the ability of an intramuscular cobinamide sulfite injection to rapidly reverse the physiologic effects of cyanide toxicity. Background Exposure to cyanide in fires and industrial exposures and intentional cyanide poisoning by terrorists leading to mass casualties is an ongoing threat. Current treatments for cyanide poisoning must be administered intravenously, and no rapid treatment methods are available for mass casualty cyanide exposures. Cobinamide is a cobalamin (vitamin B12) analog with an extraordinarily high affinity for cyanide that is more water-soluble than cobalamin. We investigated the use of intramuscular cobinamide sulfite to reverse cyanide toxicity induced physiologic changes in a sublethal cyanide exposure animal model. Methods New Zealand white rabbits were given 10 mg sodium cyanide intravenously over 60 minutes. Quantitative diffuse optical spectroscopy and continuous wave near infrared spectroscopy monitoring of tissue oxy- and deoxyhemoglobin concentrations were performed concurrently with blood cyanide level measurements and cobinamide levels. Immediately after completion of the cyanide infusion, the rabbits were injected intramuscularly with cobinamide sulfite (n=6) or inactive vehicle (controls, n=5). Results Intramuscular administration led to rapid mobilization of cobinamide and was extremely effective at reversing the physiologic effects of cyanide on oxyhemoglobin and deoxyhemoglobin extraction. Recovery time to 63% of their baseline values in the central nervous system was in a mean of 1032 minutes in the control group and 9 minutes in the cobinamide group with a difference of 1023 minutes (95% confidence interval [CI] 116, 1874 minutes). In muscle tissue, recovery times were 76 and 24 minutes with a difference of 52 minutes (95% CI 7, 98min). Red blood cell cyanide levels returned towards normal significantly faster in cobinamide sulfite-treated animals than in control animals. Conclusions Intramuscular cobinamide sulfite rapidly and effectively reverses the physiologic effects of cyanide poisoning, suggesting that a compact cyanide antidote kit can be developed for mass casualty cyanide exposures.
Abstract.Our purpose is to compare cobinamide to hydroxocobalamin in reversing cyanide ͑CN͒-induced physiologic effects in an animal model using diffuse optical spectroscopy ͑DOS͒. Cyanide poisoning is a major threat worldwide. Cobinamide is a novel molecule that can bind two molecules of cyanide, has a much higher binding affinity than hydroxocobalamin, and is more water soluble. We investigated the ability of equimolar doses of cobinamide and hydroxocobalamin to reverse the effects of cyanide exposure in an animal model monitored continuously by DOS. Cyanide toxicity was induced in 16 New Zealand white rabbits by intravenous infusion. Animals were divided into three groups: controls ͑n =5͒ received saline following cyanide, hydroxocobalamin ͑N =6͒ following cyanide, and cobinamide ͑N =5͒ following cyanide. Cobinamide caused significantly faster and more complete recovery of oxy-and deoxyhemoglobin concentrations in cyanide-exposed animals than hydroxocobalaminor saline-treated animals, with a recovery time constant of 13.8± 7.1 min compared to 75.4± 25.1 and 76.4± 42.7 min, for hydroxocobalamin-and saline-treated animals, respectively ͑p Ͻ 0.0001͒. This study indicates that cobinamide more rapidly and completely reverses the physiologic effects of cyanide than equimolar doses of cobalamin at the dose used in this study, and CN effects and response can be followed noninvasively using DOS.
The objective of this study is to establish a cyanide toxicity animal model and to investigate the ability of broadband diffuse optical spectroscopy (DOS) to non-invasively monitor physiological changes that occur during the development of cyanide toxicity in a rabbit model. Broadband DOS combines multi-frequency frequency-domain photon migration (FDPM) with time-independent near-infrared spectroscopy (NIRS) to quantitatively measure bulk tissue absorption and scattering spectra between 600 nm and 1000 nm. Serum cyanide concentration and arterial and venous blood gas analysis at pre- and post-cyanide infusion were presented. To investigate the ability of DOS to non-invasively monitor physiologic changes occurring during development of CN toxicity, tissue concentrations of deoxyhemoglobin [Hb-R], oxyhemoglobin [Hb-O2], cytochrome c oxidase oxidized state [CcO_Ox] and reduced state [CcO_Re] were determined from absorption spectra acquired in 'real time' during cyanide infusions (NaCN 6 mg/60 ml normal saline) in six pathogen-free New Zealand white rabbits. During cyanide infusion, in vivo tissue oxygen saturation increased ( approximately 10%). In addition, broadband DOS was able to detect a concurrent increase in [CcO_Re] and decrease in [CcO_Ox]. Changes in tissue scattering properties in all six animals were detected during these events, confirming the need for DOS-based methods over traditional NIR spectroscopy to obtain accurate results.
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