Abstract

The clinical use of induced hypothermia has been rapidly expanded due to evidences of hypothermia neuroprotective effect. Despite its clinical usage, the effect of hypothermia on specific pathways of drug elimination in human is relatively unknown. In order to gain insight into the potential effects of hypothermia on drug metabolism and disposition, we evaluated the pharmacokinetics of midazolam as a probe for cytochome CYP3A4/5 activity during mild hypothermia in human volunteers. A second objective of this work was to determine whether benzodiazepine and magnesium administrated intravenously would facilitate the hypothermia induction. Subjects were enrolled in a randomized cross-over study design which included two mild hypothermia groups (4 °C saline infusions and 4 °C saline+magnesium) and two normothermia groups (37 °C saline infusions and 37 °C saline+magnesium). The lowest temperature achieved in the 4 °C saline+magnesium and 4 °C saline infusions were 35.4 °C ± 0.4 °C and 35.8 °C ± 0.3 °C, respectively. A significant decrease in the formation clearance of the major metabolite 1'-hydroxymidazolam was observed during the 4 °C saline+magnesium compared to the 37 °C saline group (p<0.05). Population pharmacokinetic modelling identified a significant relationship between temperature and clearance (CL) and inter-compartmental clearance (Q) for midazolam. This model predicted midazolam clearance decreases 11.1% for each degree Celsius reduction in core temperature from 36.5 °C. Midazolam with magnesium facilitated the induction of hypothermia but shivering was minimally suppressed. These data provided proof of concept that even mild and short duration changes in body temperature significantly affect midazolam metabolism. Future studies in patients who receive lower and longer duration of hypothermia are warranted.