右美托咪定：损害机械通气大鼠的膈肌功能并增加氧化应激，但不加重膈肌萎缩
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Dexmedetomidine Impairs Diaphragm Function and Increases Oxidative Stress but Does Not Aggravate Diaphragmatic Atrophy in Mechanically Ventilated Rats
背景与目的：通气患者使用的麻醉药物在阻碍膈肌功能中具有重要作用，它可能对撤机过程产生负面作用，进而增加患者的死亡率。右美托咪定具有抗氧化和抗蛋白水解的特性，但同时也会降低肌肉对葡萄糖，这一过程将会损害膈肌的肌力。本研究验证了右美托咪定可能抑制机械通气所致膈肌功能障碍的假设。
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方法：将24只大鼠分为三组（每组8只）。前两组大鼠行机械通气24 小时，同时使用右美托咪啶或戊巴比妥钠维持镇静，简称干预组。第三组直接处死大鼠作为对照。测量膈肌肌力、肌纤维形态以及蛋白水解标记物，蛋白氧化和脂质过氧化，钙稳态的标记物，和葡萄糖转运蛋白4（GLUT-4）水平。
结果：与对照组相比，两组大鼠经横截面积校正后计算的膈肌肌力均显著降低，而右美托咪定组与戊巴比妥钠组相比肌力显著降低（例如：100赫兹：-18%，p＜0.0001）。与戊巴比妥钠组相比，右美托咪啶组没有发生膈肌萎缩，但蛋白氧化水平增高（200% vs.73%，p= 0.0015），且引起肌肉萎缩的F-box蛋白上调减少（149% vs. 374%，P＜0.001），GLUT-4转位减少（-73%，P＜0.0005）。同时激活钙依赖性蛋白酶的自噬，并和戊巴比妥钠相似，可产生脂质过氧化作用。
结论：机械通气24小时期间使用右美托咪定镇静，将恶化机械通气所致的膈肌功能障碍。机制可能与损伤GLUT-4转位有关。右美托咪啶虽能防止膈肌纤维萎缩，但并不能抑制氧化应激和蛋白水解途径的激活。
Breuer T, Bleilevens C, Rossaint R, et al
Dexmedetomidine Impairs Diaphragm Function and Increases Oxidative Stress but Does Not Aggravate Diaphragmatic Atrophy in Mechanically Ventilated Rats.[J]
Anesthesiology, 2018, 128(4):1.
BACKGROUND:Anesthetics in ventilated patients are critical as any cofactor hampering diaphragmatic function may have a negative impact on the weaning progress and therefore on patients’mortality. Dexmedetomidine may display antioxidant and antiproteolytic properties, but it also reduced glucose uptake by the muscle, which may impair diaphragm force production. This study tested the hypothesis that dexmedetomidine could inhibit ventilator-induced diaphragmatic dysfunction.
METHODS:Twenty-four rats were separated into three groups (n = 8/group). Two groups were mechanically ventilated during either dexmedetomidine or pentobarbital exposure for 24 h, referred to as interventional groups. A third group of directly euthanized rats served as control. Force generation, fiber dimensions, proteolysis markers, protein oxidation and lipid peroxidation, calcium homeostasis markers, and glucose transporter–4 (Glut-4) translocation were measured in the diaphragm.
RESULTS:Diaphragm force, corrected for cross-sectional area, was significantly decreased in both interventional groups compared to controls and was significantly lower with dexmedetomidine compared to pentobarbital (e.g., 100 Hz: –18%, P < 0.0001). In contrast to pentobarbital, dexmedetomidine did not lead to diaphragmatic atrophy, but it induced more protein oxidation (200% vs. 73% in pentobarbital, P = 0.0015), induced less upregulation of muscle atrophy F-box (149% vs. 374% in pentobarbital, P < 0.001) and impaired Glut-4 translocation (–73%, P < 0.0005). It activated autophagy, the calcium-dependent proteases, and caused lipid peroxidation similarly to pentobarbital.
CONCLUSIONS:Twenty-four hours of mechanical ventilation during dexmedetomidine sedation led to a worsening of ventilation-induced diaphragm dysfunction, possibly through impaired Glut-4 translocation. Although dexmedetomidine prevented diaphragmatic fiber atrophy, it did not inhibit oxidative stress and activation of the proteolytic pathways.
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