Department of Emergency Medicine, University of Massachusetts, Worcester, MA 01655, United States.
Neurotoxicology. 2013 Dec;39:132-7. doi: 10.1016/j.neuro.2013.06.009. Epub 2013 Aug 6.
Patients exposed to organophosphate (OP) compounds demonstrate a central apnea. The Kölliker-fuse nuclei (KF) are cholinergic nuclei in the brainstem involved in central respiratory control. We hypothesize that exposure of the KF is both necessary and sufficient for OP induced central apnea. We performed an animal study of acute OP exposure. Anesthetized and spontaneously breathing Wistar rats (n=24) were exposed to a lethal dose of dichlorvos using three experimental models. Experiment 1 (n=8) involved systemic OP poisoning using subcutaneous (SQ) 2,2-dichlorovinyl dimethyl phosphate (dichlorvos) at 100mg/kg or 3× LD50. Experiment 2 (n=8) involved isolated poisoning of the KF using stereotactic microinjections of dichlorvos (625μg in 50μl) into the KF. Experiment 3 (n=8) involved systemic OP poisoning with isolated protection of the KF using SQ dichlorvos (100mg/kg) and stereotactic microinjections of organophosphatase A (OpdA), an enzyme that degrades dichlorvos. Respiratory and cardiovascular parameters were recorded continuously. Animals were followed post exposure for 1h or until death. There was no difference in respiratory depression between animals with SQ dichlorvos and those with dichlorvos microinjected into the KF. Despite differences in amount of dichlorvos (100mg/kg vs. 1.8mg/kg) and method of exposure (SQ vs. CNS microinjection), 10min following dichlorvos both groups (SQ vs. microinjection respectively) demonstrated a similar percent decrease in respiratory rate (51.5 vs. 72.2), minute ventilation (49.2 vs. 68.8) and volume of expired gas (17.5 vs. 0.0). Animals with OpdA exposure to the KF during systemic OP exposure demonstrated less respiratory depression, compared to SQ dichlorvos alone (p<0.04). No animals with SQ dichlorvos survived past 25min post exposure, compared to 50% of animals with OpdA exposure to the KF. In conclusion, exposure of the KF is sufficient but not necessary for OP induced apnea. Protection of the KF during systemic OP exposure mitigates OP induced apnea.
暴露于有机磷 (OP) 化合物的患者表现出中枢性呼吸暂停。 Kölliker-fuse 核 (KF) 是脑干中的胆碱能核，参与中枢呼吸控制。我们假设 KF 的暴露既是必要的，也是 OP 诱导的中枢性呼吸暂停的充分条件。我们进行了一项关于急性 OP 暴露的动物研究。麻醉并自主呼吸的 Wistar 大鼠（n=24）通过三种实验模型暴露于致死剂量的敌敌畏。实验 1（n=8）涉及使用皮下（SQ）2,2-二氯乙烯基二甲磷酸酯（敌敌畏）100mg/kg 或 3×LD50 进行全身 OP 中毒。实验 2（n=8）涉及使用立体定向微注射敌敌畏（KF 中的 625μg 在 50μl 中）对 KF 进行单独中毒。实验 3（n=8）涉及使用 SQ 敌敌畏（100mg/kg）和立体定向微注射有机磷酶 A（OpdA）进行全身 OP 中毒，OpdA 是一种降解敌敌畏的酶，从而对 KF 进行单独保护。连续记录呼吸和心血管参数。暴露后动物被跟踪 1 小时或直至死亡。SQ 敌敌畏组和 KF 内微注射敌敌畏组的呼吸抑制无差异。尽管敌敌畏的量（100mg/kg 与 1.8mg/kg）和暴露方式（SQ 与 CNS 微注射）不同，但在 10 分钟后，两组（SQ 与微注射分别）的呼吸频率（51.5% 与 72.2%）、分钟通气量（49.2% 与 68.8%）和呼出气体量（17.5% 与 0.0）的百分比下降相似。在全身 OP 暴露期间，KF 暴露于 OpdA 的动物表现出的呼吸抑制程度低于单独 SQ 敌敌畏（p<0.04）。与 SQ 敌敌畏单独暴露的动物相比，没有 SQ 敌敌畏暴露的动物在 25 分钟后存活下来，而有 KF 暴露于 OpdA 的动物中有 50%存活下来。总之，KF 的暴露既是充分的，但不是 OP 诱导性呼吸暂停所必需的。在全身 OP 暴露期间，KF 的保护减轻了 OP 诱导的呼吸暂停。
