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

在脑低温治疗（BHT）中，镇静水平的控制是重要的，有望为重型脑损伤提供神经保护。众所周知，低温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。低温期（33℃~ 35℃）咪达唑仑总清除率降低，导致咪达唑仑血清消失半衰期延长，血清浓度较体温升高至36℃时升高。有些病人肝血流量减少。此外，在体外研究中，与37℃相比，CYP3A5在33℃和25℃下对咪达唑仑代谢的Vmax值分别下降到60%和40%左右。25℃时CYP3A4的值降低到50%，33℃时不受影响。上述结果提示，低温可导致CYP3A5活性降低和/或肝血流减少，从而导致咪达唑仑在低温期血清浓度升高。

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.