Yang H S, Goudsouzian N, Martyn J A
Department of Anaesthesiology, Harvard Medical School, Boston, Massachusetts, USA.
Anesthesiology. 1996 Apr;84(4):936-44. doi: 10.1097/00000542-199604000-00022.
The metabolic hydrolysis of mivacurium (and succinylcholine) is markedly impaired in the presence of hereditary or acquired defects of pseudocholinesterase. Clinical reports are conflicting as to the utility of anticholinesterases, in the reversal of mivacurium paralysis. In the current study, the role of exogenous cholinesterases and/or of anticholinesterase, neostigmine, in the reversal of deep mivacurium-induced paralysis, was studied. The rat phrenic-diaphragm preparation, in a fixed volume of Krebs solution, was chosen to eliminate the confounding effects on the dissipation of neuromuscular effects caused by hydrolysis, elimination, and redistribution of the drug.
In the phrenic-diaphragm preparation, mivacurium was administered to obtain >90% single twitch inhibition. Single twitch responses (0.1 Hz) were monitored for 60 min, after which the response to train-of-four stimulation was tested. The reversal of mivacurium by 0.5, 1.0, or 2.0 units/ml of (true) acetylcholinesterase, bovine pseudocholinesterase, or human plasma cholinesterase and by neostigmine, 0.1, 1.0, or 10.0 micrograms/ml tested. The efficacy of human plasma cholinesterase, 1 unit/ml in combination with each of the above neostigmine concentrations, also was examined. The reversal of succinylcholine-induced paralysis by the acetylcholinesterase, bovine pseudocholinesterase, or human plasma cholinesterase (1 unit/ml) alone and in the presence of neostigmine (10.0 micrograms/ml) was additionally tested as a positive control. A train-of-four ratio > 0.75 was considered adequate reversal.
Acetylcholinesterase was a poor hydrolyzer of mivacurium, as bioassayed by reversal of paralysis. Bovine pseudocholinesterase in concentrations of 0.5 and 1.0 units/ml did not effectively reverse single twitch and train-of-four responses by 60 min, but bovine pseudocholinesterase (2 units/ml) and all concentrations of human plasma cholinesterase did. Neostigmine alone, tested at all concentrations, was an incomplete reversal drug. Clinical or therapeutic concentrations (0.1 and 1.0 micrograms/ml) of neostigmine did not, but pharmacologic concentrations (10 micrograms/ml) interfere with the efficacy of human plasma cholinesterase (1 unit/ml). Bovine pseudocholinesterase and human plasma cholinesterase equally reversed the effects of succinylcholine but acetylcholinesterase did not, whereas the addition of 10 micrograms/ml neostigmine to the enzymes inhibited the reversal of succinylcholine.
Human plasma cholinesterase will reverse mivacurium more effectively than bovine pseudocholinesterase, but both will effectively reverse succinylcholine. Acetylcholinesterase has no effects on either relaxant. The anticholinesterase neostigmine was an incomplete reversal drug. Pharmacologic concentrations of anticholinesterases do, while clinical or therapeutic concentrations do not, completely inhibit the metabolic activity of pseudocholinesterases.
在存在遗传性或获得性假性胆碱酯酶缺陷的情况下，米库氯铵（和琥珀胆碱）的代谢水解会显著受损。关于抗胆碱酯酶在逆转米库氯铵麻痹中的效用，临床报告存在矛盾。在本研究中，对外源性胆碱酯酶和/或抗胆碱酯酶新斯的明在逆转深度米库氯铵诱导的麻痹中的作用进行了研究。选用大鼠膈神经 - 膈肌标本，置于固定体积的 Krebs 溶液中，以消除药物水解、消除和再分布对神经肌肉效应消散的混杂影响。
在膈神经 - 膈肌标本中，给予米库氯铵以获得>90%的单刺激抑制。监测单刺激反应（0.1 Hz）60 分钟，之后测试四个成串刺激的反应。测试 0.5、1.0 或 2.0 单位/毫升的（真性）乙酰胆碱酯酶、牛假性胆碱酯酶或人血浆胆碱酯酶以及 0.1、1.0 或 10.0 微克/毫升新斯的明对米库氯铵的逆转作用。还研究了 1 单位/毫升人血浆胆碱酯酶与上述各新斯的明浓度联合使用时的效果。另外测试了单独使用乙酰胆碱酯酶、牛假性胆碱酯酶或人血浆胆碱酯酶（1 单位/毫升）以及在新斯的明（10.0 微克/毫升）存在时对琥珀胆碱诱导的麻痹的逆转作用作为阳性对照。四个成串刺激比率>0.75 被认为是充分逆转。
通过麻痹逆转生物测定，乙酰胆碱酯酶对米库氯铵的水解能力较差。浓度为 0.5 和 1.0 单位/毫升的牛假性胆碱酯酶在 60 分钟内未有效逆转单刺激和四个成串刺激反应，但牛假性胆碱酯酶（2 单位/毫升）和所有浓度的人血浆胆碱酯酶都能有效逆转。所有浓度测试的单独新斯的明是一种不完全逆转药物。临床或治疗浓度（0.1 和 1.0 微克/毫升）的新斯的明不能，但药理浓度（10 微克/毫升）会干扰人血浆胆碱酯酶（1 单位/毫升）的效果。牛假性胆碱酯酶和人血浆胆碱酯酶对琥珀胆碱的作用逆转效果相同，但乙酰胆碱酯酶不能，而在酶中加入 10 微克/毫升新斯的明会抑制琥珀胆碱的逆转。
人血浆胆碱酯酶比牛假性胆碱酯酶更有效地逆转米库氯铵，但两者都能有效逆转琥珀胆碱。乙酰胆碱酯酶对这两种肌松药均无作用。抗胆碱酯酶新斯的明是一种不完全逆转药物。抗胆碱酯酶的药理浓度会完全抑制假性胆碱酯酶的代谢活性，而临床或治疗浓度则不会。
