Jesse Brown VA Medical Center, Chicago, IL, USA.
Department of Anesthesiology, University of Illinois, Chicago, IL, USA.
Clin Toxicol (Phila). 2020 Jul;58(7):716-724. doi: 10.1080/15563650.2019.1687903. Epub 2019 Nov 18.
An outbreak of synthetic cannabinoid (SC)-associated coagulopathy and bleeding in Illinois, USA was determined to be due to inhalation of SC contaminated with brodifacoum (BDF), difenacoum (DiF), and bromadiolone (BDL), highly potent long-acting anticoagulant rodenticides (LAARs). Treatment with high-dose vitamin K1 (VK1) prevented mortality; however, plasma LAAR levels were not measured risking recurrence of coagulopathy and bleeding due to premature discontinuation. The goal of this study was to determine if plasma LAAR levels were reduced following standard of care treatment to normalize coagulopathy. Blood samples were collected from a cohort of 32 patients, and ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) analysis used to quantify plasma LAAR levels including enantiomers. BDF was detected in 31 samples; 30 also contained DiF and 18 contained BDL. Initial plasma levels were 581 ± 87, 11.0 ± 1.9, and 14.9 ± 5.9 ng/mL for BDF, DiF, and BDL, respectively (mean ± SE). At discharge plasma, BDF levels remained elevated at 453 ± 68 ng/mL. Plasma half-lives for BDF, DiF, and BDL were 7.5 ± 1.3, 7.2 ± 1.9, and 1.8 ± 0.3 days, respectively. The half-life for trans-BDF enantiomers (5.7 ± 0.8 days) was shorter than for cis-enantiomers (7.6 ± 1.9 days). BDF half-lives were shorter, and coagulopathy normalized faster in patients receiving intravenous VK1 as compared to oral VK1. Patients prescribed VK1 at discharge had fewer re-admittances. These results demonstrate that plasma LAAR levels at discharge were elevated in poisoned patients despite normal coagulation, and that the route of VK1 administration affected LAAR pharmacokinetics and INR normalization. We propose plasma LAAR levels and coagulation be monitored concomitantly during follow-up of patients with LAAR poisoning. KEY POINTSIn patients treated with high-dose vitamin K1 for LAAR poisoning, plasma levels remained 40-fold above safe levels upon discharge from hospital.LAAR half-lives, normalization of coagulopathy, and readmittances were reduced by treatment with intravenous vitamin K1.
美国伊利诺伊州爆发的与合成大麻素（SC）相关的凝血功能障碍和出血事件被确定是由于吸入被溴鼠灵（BDF）、敌鼠（DiF）和溴敌隆（BDL）污染的 SC 所致，这三种物质均为具有高活性的长效抗凝血灭鼠剂（LAARs）。高剂量维生素 K1（VK1）治疗可预防死亡；然而，由于过早停药，凝血功能障碍和出血可能复发，因此未测量血浆 LAAR 水平。本研究的目的是确定在接受标准治疗以纠正凝血功能障碍后，血浆 LAAR 水平是否降低。从一个队列的 32 名患者中采集血样，并使用超高效液相色谱-串联质谱法（UHPLC-MS/MS）分析来定量检测包括对映异构体在内的血浆 LAAR 水平。在 31 个样本中检测到 BDF；30 个样本还含有 DiF，18 个样本含有 BDL。BDF 的初始血浆水平分别为 581±87、11.0±1.9 和 14.9±5.9ng/mL（平均值±标准误）。出院时，BDF 水平仍升高至 453±68ng/mL。BDF、DiF 和 BDL 的血浆半衰期分别为 7.5±1.3、7.2±1.9 和 1.8±0.3 天。反式-BDF 对映异构体的半衰期（5.7±0.8 天）短于顺式-BDF 对映异构体（7.6±1.9 天）。与口服 VK1 相比，静脉内 VK1 治疗的患者 BDF 半衰期更短，凝血功能障碍恢复更快。出院时开 VK1 的患者再入院人数较少。这些结果表明，尽管凝血功能正常，但中毒患者的血浆 LAAR 水平在出院时仍升高，并且 VK1 的给药途径影响 LAAR 药代动力学和 INR 正常化。我们建议在 LAAR 中毒患者的随访期间同时监测血浆 LAAR 水平和凝血功能。关键点在接受高剂量维生素 K1 治疗 LAAR 中毒的患者中，从医院出院时，血浆水平仍高出安全水平 40 倍。静脉内维生素 K1 治疗可降低 LAAR 半衰期、凝血功能障碍的正常化和再入院率。
