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HEPATIC METABOLISM OF MIDAZOLAM IN CRITICALLY ILL PATIENTS
R Khanna1, C Martin2, D Freeman2, R Tirona2, G Dresser2 1McMaster University, Hamilton; 2University of Western Ontario, London, Ontario
AIMS: Midazolam is dependant on metabolism by cytochrome P450 3A(CYP3A) for elimination. Hepatic enzymes such as CYP3A are exquisitely sensitive to modulation by coadministered medications and disease processes such as sepsis. Initial observations suggest tremendous inter-patient variability in the pharmacokinetics of this drug, although this has not been confirmed in ICU patients. Current ICU practice does not take advantage of therapeutic drug monitoring of midazolam. This study attempted to understand the variability in midazolam plasma concentrations and systemic clearance, as measures of hepatic enzyme activity in critically ill patients.
METHODS: Critically ill patients requiring continuous midazolam infusions and for whom consent was obtained were recruited. Blood samples
were taken at −30, 0, 15, 30, 60, 120, 240 minutes after the titration of stable midazolam infusion. Plasma level of drugs were analyzed and
compared to sedation levels as determined by sedation scales. Baseline characteristics (including measures to assess the degree of inflammatory response) and concomitant administration of inhibitors of CYP 3A were analyzed to determine predictors of over/undersedation.
RESULTS: Data were collected for 18 patients during partial weaning of midazolam infusions, while two patients had an increase in the infusion rate. Five patients had documented midazolam boluses during the titration. Peak concentrations ranged from 121.5 to 11,111.85ng/mL. Initial data show great variability in the area under the concentration-time curves and clearance of midazolam. Despite this variability, preliminary results show that approximately 90% of patients had midazolam clearance values significantly below normal (27L/h). Approximately 30% of patients had clearance values between 0-5L/h, 5-10L/h, and 10-15L/h respectively. The midazolam clearance was lowest in patients that had received a concomitant inhibitor of CYP3A. Plasma concentrations did not correlate with documented doses indicating incomplete documentation. Sedation scales did not correlate with plasma concentrations.
CONCLUSIONS: The results of this study suggest that hepatic CYP3A4 activity is significantly inhibited in the majority of critically ill patients. Given that many medications including midazolam, fentanyl, and propofol are partially or completely eliminated by this drug metabolism pathway, our findings suggest delayed drug clearance and enhanced drug response may complicate the use of these medications in a clinically meaningful fashion. We predict significantly increased variability in drug response in critically ill patients, and hypothesize that therapeutic drug monitoring of sedative medications may enhance delivery of care.