Differential effects of etomidate and its pyrrole analogue carboetomidate on the adrenocortical and cytokine responses to endotoxemia.
Differential effects of etomidate and its pyrrole analogue carboetomidate on the adrenocortical and cytokine responses to endotoxemia.
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DOI：
10.1097/ccm.0b013e31822d7924
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发表时间：
2012-01
影响因子：
8.8
通讯作者：
Raines DE
中科院分区：
文献类型：
--
作者：
Pejo E;Feng Y;Chao W;Cotten JF;Le Ge R;Raines DE
我们开发了一种新的吡咯类似物依托咪酯，(R)-乙基1-（1-苯乙基）- 1h -吡咯-2-羧酸酯（依托咪酯），它保留了依托咪酯理想的麻醉和血液动力学特性，但缺乏其对促肾上腺皮质激素刺激的类固醇合成的有效抑制作用。本研究的目的是验证一种假设，即与依托咪酯相反，carboetomidate既不抑制肾上腺皮质对内毒素血症的反应，也不增强伴随的促炎细胞因子的产生。动物研究大学研究实验室雄性Sprague-Dawley大鼠在单次和多次麻醉剂量研究中，大鼠被立即注射大肠杆菌脂多糖，随后注射依托咪酯、碳依托咪酯或单独的载药（二甲亚砜）作为对照。对于单剂量研究，不给予额外的麻醉剂（或载体）。对于多重麻醉剂量研究，每15分钟给予额外剂量的麻醉剂（或载体），总共8种麻醉剂（或载体）剂量。血浆促肾上腺皮质激素、皮质酮和细胞因子浓度在脂多糖给药前和在5小时实验中间歇测定。在单次麻醉剂量的研究中，血浆促肾上腺皮质激素和细胞因子浓度在任何时间点在依托咪酯、卡韦咪酯和药物组之间没有差异，而血浆皮质酮浓度在依托咪酯组短暂（60-120分钟）降低。在多次麻醉剂量研究中，与carboetomidate组和对照组相比，依托咪酯组血浆皮质酮浓度持续较低，血浆IL-1β和IL-6浓度峰值较高。与对照组相比，依托咪酯组和碳依托咪酯组的血浆IL-10峰值浓度同样升高。与依托咪酯相比，在脓毒症内毒素血症模型中，carboetomidate对肾上腺皮质功能的抑制较小，促炎细胞因子的产生增加较小。这些发现表明，在脓毒症患者中，碳托咪酯可能是一种有效的替代依托咪酯维持长时间麻醉的方法。
We developed a novel pyrrole analogue of etomidate, (R)-ethyl 1-(1-phenylethyl)-1H-pyrrole-2-carboxylate (carboetomidate), which retains etomidate’s desirable anesthetic and hemodynamic properties but lacks its potent inhibitory affect on adrenocorticotropic hormone-stimulated steroid synthesis. The objective of this study was to test the hypothesis that in contrast to etomidate, carboetomidate neither suppresses the adrenocortical response to endotoxemia nor enhances the accompanying production of pro-inflammatory cytokines. Animal study University research laboratory Male Sprague-Dawley rats For both single and multiple anesthetic dose studies, rats were injected with Escherichia coli lipopolysaccharide immediately followed by a hypnotic dose of etomidate, carboetomidate or vehicle alone (dimethyl sulfoxide) as a control. For single dose studies, no additional anesthetic (or vehicle) was administered. For multiple anesthetic dose studies, additional doses of anesthetic (or vehicle) were administered every 15 min for a total of eight anesthetic (or vehicle) doses. Plasma adrenocorticotropic hormone, corticosterone, and cytokine concentrations were measured before lipopolysaccharide administration and intermittently throughout the 5 hour experiment. In single anesthetic dose studies, plasma adrenocorticotropic hormone and cytokine concentrations were not different at any time point among the etomidate, carboetomidate, and vehicle groups whereas plasma corticosterone concentrations were briefly (60–120 min) reduced in the etomidate group. In multiple anesthetic dose studies, plasma corticosterone concentrations were persistently lower and peak plasma IL-1β and IL-6 concentrations were higher in the etomidate group versus the carboetomidate and control groups. Peak plasma IL-10 concentrations were similarly elevated in the etomidate and carboetomidate groups versus the control group. Compared to etomidate, carboetomidate produces less suppression of adrenocortical function and smaller increases in pro-inflammatory cytokine production in an endotoxemia model of sepsis. These findings suggest that carboetomidate could be a useful alternative to etomidate for maintaining anesthesia for a prolonged period of time in patients with sepsis.