Pharmacokinetics of sedative medicine during brain hypothermia therapy and its proper use

在脑低温治疗(BHT)中，控制镇静水平是很重要的，该治疗有望为严重的脑损伤提供神经保护。众所周知，体温过低会引起一些生理变化。为了在BHT期间使用咪达唑仑获得最佳镇静效果，我们研究了低温对BHT患者咪达唑仑药代动力学的影响。在低温期(33℃~35℃)，咪达唑仑的总清除量降低，导致咪达唑仑的血药浓度升高，血药浓度升高，血清半衰期延长。部分患者肝脏血流量减少。此外，在体外研究中，在33℃和25℃时，咪达唑仑代谢的Vmax分别为37℃时的60%和40%。细胞色素P3A4在25℃时降至50%，但在33℃时不受影响。结果提示，低温可导致肝脏组织中细胞色素P3A5活性降低和/或肝血流量下降，从而导致咪达唑仑血药浓度升高。

Control of sedation level is important during brain hypothermia therapy (BHT) that is expected to provide neuroprotection for severe brain injury. Hypothermia is known to induce some physiological changes. To gain the optimal sedation using midazolam during BHT, we examined the influence of hypothermia on pharmacokinetics of midazolam in patients undergoing BHT. During hypothermic period (33℃-35℃), total clearance of midazolam was decreased, resulting in that the half-life of serum disappearance of midazolam was prolonged and serum concentration was increased compared to when body temperature rose to 36℃. In some patients hepatic blood flow was reduced. Furthermore, in vitro study, Vmax value for metabolism of midazolam by CYP3A5 decreased to about 60% and 40% at 33℃ and 25℃, respectively, compared to that at 37℃. The value by CYP3A4 was decreased to 50% at 25℃, but not affected at 33℃. These results suggest that hypothermia induces the decrease of CYP3A5 activity and/or hepatic blood flow, which contributes to the increase of serum concentration of midazolam during hypothermic period.