Evaluation of aqueous dimethyl trisulfide as an antidote to a highly lethal cyanide poisoning in a large swine model
Evaluation of aqueous dimethyl trisulfide as an antidote to a highly lethal cyanide poisoning in a large swine model
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DOI：
10.1080/15563650.2021.1935992
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发表时间：
2021-06-17
影响因子：
3.3
通讯作者：
Bebarta, Vikhyat S.
中科院分区：
文献类型：
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作者：
Hendry-Hofer, Tara B.;Severance, Carter C.;Bebarta, Vikhyat S.
背景氰化物是一种作用迅速、致命的新陈代谢毒物，仍然是一个重大威胁。目前FDA批准的解毒剂对于大规模伤亡事件来说不够顺从或足够有效。目的评价肌肉注射二甲基三硫醚(DMTs)对猪氰化物暴露模型的近期和远期疗效。方法麻醉猪经仪器化、习服直至自主呼吸。开始氰化钾输注，持续至呼吸暂停发作后5min。随后，动物接受肌肉注射DMT(n=11)或生理盐水对照组(n=10)。在不同的时间点评估实验值和DMTS的血药浓度，并持续监测生理参数，直到实验结束，除非发生死亡。接受DMT治疗的一组动物(n=5)存活了7天，通过重复活检和神经行为结果来评估肌肉的完整性。结果两组患者基线和治疗时的生理参数和呼吸暂停时间相似。DMTS治疗组的存活率为90%，生理盐水对照组为30%(p=0.0034)。DMTS组动物恢复呼吸的时间为12.0±10.4分钟(平均+/-SD)，而3个存活的对照组动物恢复呼吸的时间为22.9+/-7.0分钟(平均+/-SD)。安乐死前采集的血液显示，DMTS治疗组的血乳酸浓度有所改善；对照组的血乳酸浓度为5.47+/-2.65mmoL/L与9.39+/-4.51mmoL/L(平均值+/-SD)(p=0.0310)。在血液中检测到低浓度的DMTs，随着时间的推移逐渐增加，没有观察到消除相。在接受DMTS治疗的动物中，没有死亡率、肌肉损伤的组织学证据，也没有观察到不良的神经行为结果，存活到7天。结论肌肉注射含水DMTs可提高氰化物中毒后的存活率，对注射部位的肌肉完整性没有长期影响，也没有不良的神经行为结果。
Background Cyanide is a rapid acting, lethal, metabolic poison and remains a significant threat. Current FDA-approved antidotes are not amenable or efficient enough for a mass casualty incident. Objective The objective of this study is to evaluate short and long-term efficacy of intramuscular aqueous dimethyl trisulfide (DMTS) on survival and clinical outcomes in a swine model of cyanide exposure. Methods Anesthetized swine were instrumented and acclimated until breathing spontaneously. Potassium cyanide infusion was initiated and continued until 5 min after the onset of apnea. Subsequently, animals were treated with intramuscular DMTS (n = 11) or saline control (n = 10). Laboratory values and DMTS blood concentrations were assessed at various time points and physiological parameters were monitored continuously until the end of the experiment unless death occurred. A subset of animals treated with DMTS (n = 5) were survived for 7 days to evaluate muscle integrity by repeat biopsy and neurobehavioral outcomes. Results Physiological parameters and time to apnea were similar in both groups at baseline and at time of treatment. Survival in the DMTS-treated group was 90% and 30% in saline controls (p = 0.0034). DMTS-treated animals returned to breathing at 12.0 +/- 10.4 min (mean +/- SD) compared to 22.9 +/- 7.0 min (mean +/- SD) in the 3 surviving controls. Blood collected prior to euthanasia showed improved blood lactate concentrations in the DMTS treatment group; 5.47 +/- 2.65 mmol/L vs. 9.39 +/- 4.51 mmol/L (mean +/- SD) in controls (p = 0.0310). Low concentrations of DMTS were detected in the blood, gradually increasing over time with no elimination phase observed. There was no mortality, histological evidence of muscle trauma, or observed adverse neurobehavioral outcomes, in DMTS-treated animals survived to 7 days. Conclusion Intramuscular administration of aqueous DMTS improves survival following cyanide poisoning with no observed long-term effects on muscle integrity at the injection site or adverse neurobehavioral outcomes.