Department of Anesthesiology, University of Minnesota, Minneapolis, Minnesota 55455, USA.
Anesth Analg. 2012 May;114(5):956-61. doi: 10.1213/ANE.0b013e31824c4eb5. Epub 2012 Mar 5.
Cyanide (CN) toxicity is a serious clinical problem and can occur with sodium nitroprusside (SNP) administration, accidental smoke inhalation, industrial mishaps, and bio-terrorism. In this study, we induced severe CN toxicity independently with SNP or sodium cyanide (NaCN) in a juvenile pig model to demonstrate reversal of severe CN toxicity with a new antidote, sulfanegen sodium, a prodrug of 3-mercaptopyruvate.
SNP study: A pilot study in 11 anesthetized, mechanically ventilated juvenile pigs allowed us to determine the dose of SNP to induce CN toxicity. Blood CN, serum lactates, and blood gases were monitored. CN toxicity was defined as the occurrence of severe lactic acidosis accompanied by significant elevation in blood CN levels. Based on this pilot study, 8 anesthetized pigs received a high-dose i.v. infusion of SNP (100 mg/h) for 2 hours to induce CN toxicity. They were then randomized to receive either sulfanegen sodium or placebo. Four pigs received 3 doses of sulfanegen sodium (2.5 g i.v.) every hour after induction of severe CN toxicity, and 4 pigs received placebo. NaCN study: A pilot study was conducted in 4 spontaneously ventilating pigs sedated with propofol plus ketamine to demonstrate hemodynamic and metabolic stability for several hours. After this, 6 pigs were similarly sedated and given NaCN in bolus aliquots to produce CN toxicity ultimately resulting in death. Hemodynamics and metabolic variables were followed to define peak CN toxicity. In another group of 6 pigs, severe CN toxicity was induced by this method, and at peak toxicity, the animals were given sulfanegen sodium (2.5 g i.v.) followed by a repeat dose 60 minutes later in surviving animals.
SNP study: The pilot study demonstrated the occurrence of a significant increase in blood CN levels (P < 0.05) accompanied by severe lactic acidemia (P < 0.05) in all pigs receiving a high dose of SNP. Administration of the sulfanegen antidote resulted in progressive significant reduction in blood lactate and CN levels with 100% survival (P < 0.05), whereas the placebo-treated pigs deteriorated and did not survive (P < 0.05). NaCN study: NaCN injection resulted in CN toxicity accompanied by severe lactic acidosis and mortality in all the pigs. Sulfanegen sodium reversed this toxicity and prevented mortality in all the pigs treated with this antidote.
CN toxicity can be successfully induced in a juvenile pig model with SNP or NaCN. The prodrug, sulfanegen sodium, is effective in reversing CN toxicity induced by SNP or NaCN.
氰化物（CN）毒性是一个严重的临床问题，可发生于硝普钠（SNP）给药、意外吸入烟雾、工业事故和生物恐怖袭击。在这项研究中，我们使用 SNP 或氰化钠（NaCN）在幼年猪模型中独立诱导严重的 CN 毒性，以证明一种新解毒剂——磺胺甲噁唑钠（sulfanegen sodium）对严重 CN 毒性的逆转作用，磺胺甲噁唑钠是 3-巯基丙酮酸的前体药物。
SNP 研究：一项在 11 只麻醉、机械通气的幼年猪中进行的初步研究使我们能够确定诱导 CN 毒性所需的 SNP 剂量。监测血 CN、血清乳酸和血气。CN 毒性定义为严重乳酸酸中毒伴血 CN 水平显著升高。基于这项初步研究，8 只麻醉猪接受 SNP（100mg/h）高剂量静脉输注 2 小时以诱导 CN 毒性。然后，他们被随机分为接受磺胺甲噁唑钠或安慰剂治疗。4 只猪在诱导严重 CN 毒性后每小时接受 3 次磺胺甲噁唑钠（2.5g 静脉注射），4 只猪接受安慰剂。NaCN 研究：4 只接受异丙酚加氯胺酮镇静的自主呼吸幼年猪进行了一项初步研究，以证明数小时内的血流动力学和代谢稳定性。在此之后，6 只猪同样接受 NaCN 静脉推注以产生 CN 毒性，最终导致死亡。监测血流动力学和代谢变量以确定 CN 毒性的峰值。在另一组 6 只猪中，通过这种方法诱导严重的 CN 毒性，在毒性峰值时，动物接受磺胺甲噁唑钠（2.5g 静脉注射），然后在存活动物中 60 分钟后重复剂量。
SNP 研究：初步研究表明，所有接受 SNP 高剂量的猪都出现血 CN 水平显著升高（P < 0.05），同时出现严重乳酸血症（P < 0.05）。给予磺胺甲噁唑钠解毒剂后，血乳酸和 CN 水平逐渐显著降低，存活率为 100%（P < 0.05），而接受安慰剂治疗的猪则恶化，无法存活（P < 0.05）。NaCN 研究：NaCN 注射导致所有猪出现 CN 毒性，伴严重乳酸酸中毒和死亡。磺胺甲噁唑钠逆转了这种毒性，所有接受这种解毒剂治疗的猪都没有死亡。
可以使用 SNP 或 NaCN 在幼年猪模型中成功诱导 CN 毒性。前体药物磺胺甲噁唑钠可有效逆转 SNP 或 NaCN 诱导的 CN 毒性。
