Biphasic concentration change during continuous midazolam administration in brain-injured patients undergoing therapeutic moderate hypothermia

Abstract

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 degrees C (hypothermia group) and seven received normothermic therapy (normothermia group). A one-compartment model was selected for pharmacokinetic analyses for the continuous administration. Data represent +/-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 degrees C without plateauing, even during continuous administration, after which the levels decreased remarkably when BT rose to 36 degrees C. 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 degrees C BT were much lesser than those above 35 degrees C BT, whereas distribution volume (V(d)) during the hypothermic phase was greater than that during the period above 35 degrees C 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.