From the *Department of Anesthesiology and Intensive Therapy, University Medical Centre Ljubljana; and †Institute for Biostatistics and Medical Informatics and ‡Institute of Pathophysiology, University of Ljubljana, Ljubljana, Slovenia.
Anesth Analg. 2014 Apr;118(4):755-63. doi: 10.1213/ANE.0000000000000108.
Corticosteroids are frequently used during anesthesia to provide substitution therapy in patients with adrenal insufficiency, as a first-line treatment of several life-threatening conditions, to prevent postoperative nausea and vomiting, and as a component of multimodal analgesia. For these last 2 indications, dexamethasone is most frequently used. Due to the structural resemblance between aminosteroid muscle relaxants and dexamethasone, concerns have been raised about possible corticosteroid inhibition in the reversal of neuromuscular block by sugammadex. We thus investigated the influence of dexamethasone on sugammadex reversal of rocuronium-induced neuromuscular block, which could be relevant in certain clinical situations.
The unique co-culture model of human muscle cells innervated in vitro with rat embryonic spinal cord explants to form functional neuromuscular junctions was first used to explore the effects of 4 and 10 μM rocuronium on muscle contractions, as quantitatively evaluated by counting contraction units in contraction-positive explant co-cultures. Next, equimolar and 3-fold equimolar sugammadex was used to investigate the recovery of contractions from 4 and 10 μM rocuronium block. Finally, 1, 100, and 10 μM dexamethasone (normal, elevated, and high clinical levels) were used to evaluate any effects on the reversal of rocuronium-induced neuromuscular block by sugammadex.
Seventy-eight explant co-cultures from 3 time-independent experiments were included, where the number of contractions increased to 10 days of co-culturing. Rocuronium showed a time-dependent effect on depth of neuromuscular block (4 μM rocuronium: baseline, 10, 20 minutes administration; P < 0.0001), while the dose-dependent effect was close to nominal statistical significance (4, 10 μM; P = 0.080). This was reversed by equimolar concentrations of sugammadex, with further and virtually complete recovery of contractions with 3-fold equimolar sugammadex (P < 0.0001). Dexamethasone diminished 10 μM sugammadex-induced recovery of contractions from rocuronium-induced neuromuscular block in a dose-dependent manner (P = 0.026) with a higher sugammadex concentration (30 μM) being close to statistically significantly improving recovery (P = 0.065). The highest concentration of dexamethasone decreased the recovery of contractions by equimolar sugammadex by 26%; this effect was more pronounced when 3-fold equimolar (30 μM) sugammadex was used for reversal (48%).
This is the first report in which the effects of rocuronium and sugammadex interactions with dexamethasone have been studied in a highly accessible in vitro experimental model of functionally innervated human muscle cells. Sugammadex reverses rocuronium-induced neuromuscular block; however, concomitant addition of high dexamethasone concentrations diminishes the efficiency of sugammadex. Further studies are required to determine the clinical relevance of these interactions.
在麻醉中，皮质类固醇常被用于治疗肾上腺功能不全患者的替代治疗，作为几种危及生命情况的一线治疗药物，预防术后恶心和呕吐，并作为多模式镇痛的组成部分。对于后两种适应症，地塞米松最常被使用。由于氨基甾体肌肉松弛剂和地塞米松的结构相似，人们担心在使用 sugammadex 逆转神经肌肉阻滞时可能会抑制皮质类固醇。因此，我们研究了地塞米松对 sugammadex 逆转罗库溴铵诱导的神经肌肉阻滞的影响，这在某些临床情况下可能是相关的。
首先使用体外与人肌肉细胞共培养的独特的大鼠胚胎脊髓外植体形成功能性神经肌肉接头的共培养模型，以评估 4 和 10 μM 罗库溴铵对肌肉收缩的影响，这可以通过计数收缩阳性外植体共培养物中的收缩单位来定量评估。接下来，使用等摩尔和 3 倍等摩尔的 sugammadex 来研究从 4 和 10 μM 罗库溴铵阻断中恢复收缩。最后，使用 1、100 和 10 μM 地塞米松（正常、升高和高临床水平）来评估任何对 sugammadex 逆转罗库溴铵诱导的神经肌肉阻滞的影响。
共有 3 个时间独立实验的 78 个外植体共培养物，其中收缩次数增加到共培养 10 天。罗库溴铵对神经肌肉阻滞的深度有时间依赖性效应（4 μM 罗库溴铵：基线、10、20 分钟给药；P < 0.0001），而剂量依赖性效应接近名义统计学显著性（4、10 μM；P = 0.080）。这被等摩尔浓度的 sugammadex 逆转，进一步用 3 倍等摩尔 sugammadex 几乎完全恢复了收缩（P < 0.0001）。地塞米松以剂量依赖性方式减弱 10 μM sugammadex 诱导的罗库溴铵诱导的神经肌肉阻滞恢复（P = 0.026），而更高浓度的 sugammadex（30 μM）接近统计学上显著改善恢复（P = 0.065）。最高浓度的地塞米松使等摩尔 sugammadex 恢复收缩减少 26%；当使用 3 倍等摩尔（30 μM）sugammadex 进行逆转时，这种效应更为明显（48%）。
这是首次在功能神经支配的人肌肉细胞体外实验模型中研究罗库溴铵和 sugammadex 与地塞米松相互作用的影响的报告。sugammadex 逆转罗库溴铵诱导的神经肌肉阻滞；然而，同时加入高浓度的地塞米松会降低 sugammadex 的效率。需要进一步研究以确定这些相互作用的临床意义。
