Mild Hypothermia Alters Midazolam Pharmacokinetics in Normal Healthy Volunteers

Abstract

ABSTRACT:The clinical use of therapeutic hypothermia has been rapidly expanding due to evidence of neuroprotection. However, the effect of hypothermia on specific pathways of drug elimination in humans is relatively unknown. To gain insight into the potential effects of hypothermia on drug metabolism and disposition, we evaluated the pharmacokinetics of midazolam as a probe for CYP3A4/5 activity during mild hypothermia in human volunteers. A second objective of this work was to determine whether benzodiazepines and magnesium administered intravenously would facilitate the induction of hypothermia. Subjects were enrolled in a randomized crossover study, 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 temperatures achieved in the 4°C saline ؉ magnesium and 4°C saline infusions were 35.4 ؎ 0.4 and 35.8 ؎ 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 with that in the 37°C saline group (p < 0.05). Population pharmacokinetic modeling identified a significant relationship between temperature and clearance and intercompartmental clearance for midazolam. This model predicted that 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 levels and a longer duration of hypothermia are warranted.

Effect of Hypothermia and Targeted Temperature Management on Drug Disposition and Response Following Cardiac Arrest: A Comprehensive Review of Preclinical and Clinical Investigations

“…A total of 15 CA patients who underwent hypothermic treatment to 33-34°C were enrolled in this case-control study and matched to critically ill patients in the ICU, who did not receive hypothermia (n = 8). In contrast to Hostler et al (2010), the investigators found no difference in the volume of distribution (V D ), Cl, or elimination half-life (t 1/2 ) of midazolam between the hypothermic patients and the normothermic controls. This study involved a relatively small number of subjects with significant interindividual variability in the midazolam time-concentration profiles in both groups.…”

“…Midazolam is in the benzodiazepine class of drugs and is commonly administered as a sedative in the ICU. Hostler et al (2010) randomized six healthy volunteers to (Hostler et al, 2010). Bjelland et al (2013) investigated the effects of hypothermia on the disposition of midazolam along with several other sedatives and anesthetics (fentanyl, morphine, and propofol) in patients suffering from CA.…”

Effects of Hypothermia on the Disposition of Morphine, Midazolam, Fentanyl, and Propofol in Intensive Care Unit Patients

“…Elimination of fentanyl was essentially stopped in children cooled to 18-25°C (Koren et al, 1987). The effect of hypothermia on clearance of midazolam in humans has been reported to vary from naught to more than 100-fold, and an 11.1% reduction in clearance per degree of reduced core temperature was estimated (Fukuoka et al, 2004;Hostler et al, 2010). The metabolism of propofol in humans depends on liver flow and involves several enzymes such as UGT1A8/9, CYP2C9, and CYP2B6.…”

Actualización en el manejo del estado epiléptico.

“…Se sugiere una temperatura de 32 a 35 °C, por 24 a 48 h (32). Pero puede haber reducción de la depuración de algunos anestésicos como del midazolam que disminuye 11,1% por cada grado celsius de reducción de la temperatura corporal por debajo de 36,5°C (33).…”