Bauer T M, Ritz R, Haberthür C, Ha H R, Hunkeler W, Sleight A J, Scollo-Lavizzari G, Haefeli W E
Division of Intensive Care, University Hospital, Basel, Switzerland.
Lancet. 1995 Jul 15;346(8968):145-7. doi: 10.1016/s0140-6736(95)91209-6.
Midazolam is a short-acting benzodiazepine routinely used in intensive-care medicine. Conjugates of its main metabolite, alpha-hydroxymidazolam, have been shown to accumulate in renal failure but have not previously been related to the prolonged sedative effects commonly observed in critically ill patients. We report five patients with severe renal failure who had prolonged sedation after administration of midazolam. In all five patients, the comatose state was immediately reversed by the benzodiazepine-receptor antagonist flumazenil. Serum concentration monitoring showed high concentrations of conjugated alpha-hydroxymidazolam when concentrations of the unconjugated metabolite and the parent drug were below the therapeutic range. In-vitro binding studies showed that the affinity of binding to the cerebral benzodiazepine receptor of glucuronidated alpha-hydroxymidazolam was only about ten times weaker (affinity constant 16 nmol/L) than that of midazolam (1.4 nmol/L) or unconjugated alpha-hydroxymidazolam (2.2 nmol/L). Conjugated metabolites of midazolam have substantial pharmacological activity. Physicians should be aware that these metabolites can accumulate in patients with renal failure.
咪达唑仑是一种常用于重症监护医学的短效苯二氮䓬类药物。其主要代谢产物α-羟基咪达唑仑的共轭物已被证明在肾衰竭患者体内会蓄积，但此前并未发现其与重症患者中常见的镇静作用延长有关。我们报告了5例严重肾衰竭患者，他们在使用咪达唑仑后出现了长时间的镇静作用。在所有5例患者中，苯二氮䓬受体拮抗剂氟马西尼可立即逆转昏迷状态。血清浓度监测显示，当未结合代谢产物和母体药物的浓度低于治疗范围时，结合型α-羟基咪达唑仑的浓度很高。体外结合研究表明，葡萄糖醛酸化α-羟基咪达唑仑与脑苯二氮䓬受体的结合亲和力仅比咪达唑仑（1.4 nmol/L）或未结合的α-羟基咪达唑仑（2.2 nmol/L）弱约10倍（亲和力常数16 nmol/L）。咪达唑仑的共轭代谢产物具有显著的药理活性。医生应意识到这些代谢产物可能在肾衰竭患者体内蓄积。
