Department of Pharmacology, Toxicology, & Therapeutics, University/BHF Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK.
Medical Toxicology Centre, University of Newcastle, Newcastle upon Tyne, UK.
Clin Toxicol (Phila). 2020 Mar;58(3):190-200. doi: 10.1080/15563650.2019.1628969. Epub 2019 Aug 7.
Dicobalt edetate and hydroxocobalamin are widely used to treat hydrogen cyanide poisoning. However, comparative and quantitative efficacy data are lacking. Although post-exposure treatment is typical, it may be possible to administer these antidotes before exposure to first attenders entering a known site of cyanide release, as supplementary protection to their personal protective equipment. We established an anaesthetised Gottingen minipig model of lethal bolus potassium cyanide (KCN) injection to simulate high dose hydrogen cyanide inhalation. Doses were similar to human lethal doses of KCN. Dicobalt edetate and hydroxocobalamin were administered shortly before KCN and their effect on metabolic and cardiovascular variables and survival time were measured. Increases in arterial lactate were similar after 0.08 and 0.12 mmol/kg KCN. KCN 0.08 mmol/kg was survived by 4/4 animals with moderate cardiovascular effects, while the 0.12 mmol/kg dose was lethal in 4/4 animals, with a mean time to euthanasia of 28.3 (SEM: 13.9) min. Administration of dicobalt edetate (0.021 mmol/kg, 8.6 mg/kg) or hydroxocobalamin (0.054 mmol/kg, 75 mg/kg) at clinically licenced doses had modest effect on lactate concentrations but increased survival after administration of KCN 0.12 mmol/kg (survival: dicobalt edetate 4/4, hydroxocobalamin 2/4) but not 0.15 mmol/kg (0/4 and 0/4, respectively). In a subsequent larger study, doubling the dose of hydroxocobalamin (0.108 mmol/kg, 150 mg/kg) was associated with a modest but inconsistent increased survival after 0.15 mmol/kg KCN (survival: control 0/8, 75 mg/kg 1/10, 150 mg/kg 3/10) likely due to variable pharmacokinetics. In this porcine study of cyanide exposure, with pre-exposure antidote administration, licenced doses of dicobalt edetate and hydroxocobalamin were effective at just lethal doses but ineffective at less than twice the estimated LD. The efficacy of a rapidly-administered double-dose of hydroxocobalamin was limited by variable pharmacokinetics. In clinical poisoning scenarios, with delayed administration, the antidotes are likely to be even less effective. New antidotes are required for treatment of cyanide exposures appreciably above the minimum lethal dose.
依地酸钴和羟钴胺被广泛用于治疗氰化物中毒。然而，目前缺乏关于两者相对疗效和定量疗效的数据。尽管暴露后治疗是典型的，但对于首次进入已知氰化物释放场所的急救人员，在其个人防护设备之外，有可能在接触前就使用这些解毒剂，作为补充保护。我们建立了一个麻醉的哥廷根小型猪模型，用于模拟高剂量氰化钾（KCN）注射，以模拟高剂量吸入氰化氢。所使用的 KCN 剂量与人类致死剂量相似。在注射 KCN 之前给予依地酸钴和羟钴胺，并测量它们对代谢和心血管变量以及生存时间的影响。注射 0.08 和 0.12mmol/kg KCN 后，动脉血乳酸水平升高相似。4/4 只接受中等心血管效应的动物存活下来，而 4/4 只接受 0.12mmol/kg KCN 剂量的动物死亡，安乐死平均时间为 28.3（SEM：13.9）分钟。以临床许可剂量给予依地酸钴（0.021mmol/kg，8.6mg/kg）或羟钴胺（0.054mmol/kg，75mg/kg）对乳酸浓度有一定影响，但可增加 0.12mmol/kg KCN 后动物的存活（依地酸钴：4/4 存活，羟钴胺：2/4 存活），但不能增加 0.15mmol/kg KCN 后动物的存活（分别为 0/4 和 0/4）。在随后的一项更大的研究中，双倍剂量的羟钴胺（0.108mmol/kg，150mg/kg）与 0.15mmol/kg KCN 后适度但不一致的存活率增加相关（存活率：对照组 0/8，75mg/kg 组 1/10，150mg/kg 组 3/10），这可能是由于药代动力学的变化。在这项关于氰化物暴露的猪研究中，给予暴露前解毒剂，依地酸钴和羟钴胺的许可剂量在仅达到致死剂量时有效，但在两倍估计 LD 以下无效。快速给予双倍剂量羟钴胺的疗效受到药代动力学变化的限制。在临床中毒情况下，延迟给药后，解毒剂的效果可能更差。对于明显高于最低致死剂量的氰化物暴露，需要新的解毒剂进行治疗。
