Biphasic concentration change during continuous midazolam administration in brain-injured patients undergoing therapeutic moderate hypothermia
Biphasic concentration change during continuous midazolam administration in brain-injured patients undergoing therapeutic moderate hypothermia
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DOI：
10.1016/j.resuscitation.2003.09.017
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发表时间：
2004-02-01
期刊：
影响因子：
6.5
通讯作者：
Morita, S
中科院分区：
文献类型：
--
作者：
Fukuoka, N;Aibiki, M;Morita, S
目的：研究中低温治疗过程中细胞色素（CYP）3A 4活性监测探针咪达唑仑的药代动力学。设计：前瞻性随机研究。单位：一所医科大学附属医院的重症监护室。患者和干预措施：在连续15例脑损伤患者中，使用高效液相色谱法（HPLC）连续测定咪达唑仑浓度。在持续给药的情况下，8例患者接受32-34 ℃的中度低温（低温组），7例患者接受常温治疗（常温组）。选择一室模型用于连续给药的药代动力学分析。数据表示平均值+/- S.D.。使用ANOVA进行统计分析，然后进行Scheffe’s F检验或Mann-Whitney U检验（P < 0.05）。测量和主要结果：低温组血清咪达唑仑浓度呈线性上升，直至体温（BT）达到35 ℃，即使在连续给药期间也无平台期，之后当BT升至36 ℃时，血清咪达唑仑浓度显著下降。然而，常温组的浓度保持在平台期，持续至研究结束。在低温组中，消除速率常数（k（e））和清除率（CL）在低于35 ℃ BT的阶段远小于高于35 ℃ BT的阶段，而分布容积（V-d）在低温阶段大于在高于35 ℃ BT的阶段。结论：本研究首次证明，即使在低温治疗中持续输注咪达唑仑时，咪达唑仑浓度也会发生双相变化。这种变化的机制尚不清楚。因此，需要进一步研究，包括确认细胞色素3A 4活性，同时还需要监测过量给药引起的不良反应。(C)2003爱思唯尔爱尔兰有限公司保留所有权利。
Objective: To define the pharmacokinetics of midazolam, a probe for monitoring cytochrome (CYP) 3A 4 activity, during moderate hypothermic therapy. Design: A prospective randomized study. Setting: The intensive care unit of a medical university hospital. Patients and Interventions: In 15 consecutive brain-injured patients, midazolam concentrations were measured serially using high-performance liquid chromatography (HPLC). Under continuous administration of the agent, eight patients underwent moderate hypothermia of 32-34 degreesC (hypothermia group) and seven received normothermic therapy (normothermia group). A one-compartment model was selected for pharmacokinetic analyses for the continuous administration. Data represent mean +/- S.D. Statistical analysis was performed using ANOVA followed by Scheffe's F-test or the Mann-Whitney U-test (P < 0.05). Measurement and main results: Serum midazolam concentrations in the hypothermia group increased linearly until the body temperature (BT) reached 35 degreesC without plateauing, even during continuous administration, after which the levels decreased remarkably when BT rose to 36 degreesC. However, the concentrations in the normothermia group remained on a plateau, which lasted until the end of the study. In the hypothermia group, elimination rate constant (k(e)) and clearance (CL) in the phase below 35 degreesC BT were much lesser than those above 35 degreesC BT, whereas distribution volume (V-d) during the hypothermic phase was greater than that during the period above 35 degreesC BT. Conclusion: This study has demonstrated for the first time that midazolum concentration changes biphasically even during continuous infusion in hypothermic therapy. The mechanisms for the change are unclear. Thus, further studies including confirmation of cytochrome 3A 4 activity are required, while monitoring for the development of undesirable effects from over-dosing is also needed. (C) 2003 Elsevier Ireland Ltd. All rights reserved.