Population pharmacodynamic modelling of lorazepam- and midazolam-induced sedation upon long-term continuous infusion in critically ill patients.
OBJECTIVE
The objective of the present investigation was to develop a population pharmacodynamic model for midazolam- and lorazepam-induced sedation upon long-term continuous infusion in critically ill patients.


METHODS
The study was conducted in 59 patients receiving lorazepam and 54 patients receiving midazolam by continuous infusion for at least 24 h. Repeated blood samples were obtained for determination of the concentrations of lorazepam and midazolam. The level of sedation was assessed using a 5-point sedation scale.


RESULTS
The pharmacokinetics of lorazepam and midazolam was described with previously proposed pharmacokinetic models. For the pharmacodynamics, the probability that the sedation was equal to or more than a specific score was described using a sigmoid E(max) model. The EC(50) values of lorazepam for the sedation scores equal or larger than 2-5 were 6.1, 57, 184 and 529 ng/ml, respectively. The corresponding values for midazolam were 216, 483, 1,100 and 2,200 ng/ml. Inter-individual variability in the EC(50) values was relatively high with a CV of 68% for lorazepam and 86% for midazolam (p=0.035). No covariates explaining part of the observed inter-individual variability were identified.


CONCLUSIONS
The population pharmacodynamic model shows a similarly wide intra- and inter-individual variability in the pharmacodynamics of both lorazepam and midazolam. Thus, the previously observed differences in "ease of titration" between lorazepam and midazolam are unrelated to pharmacodynamic factors.
Swart
Eleonora L
EL
Department of Pharmacy, Vrije Universiteit Medical Center, Amsterdam, The Netherlands. el.swart@vumc.nl
Zuideveld
Klaas P
KP
de Jongh
Joost
J
Danhof
Meindert
M
Thijs
Lambertus G
LG
Strack van Schijndel
Robert M J
RM
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000465:Algorithms; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D016292:Procedural Sedation / Q000379:methods* / Q000706:statistics & numerical data; D016638:Critical Illness / Q000628:therapy*; D005260:Female; D006801:Humans; D006993:Hypnotics and Sedatives / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D007262:Infusions, Intravenous; D007297:Inpatients; D007362:Intensive Care Units; D008140:Lorazepam / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D008874:Midazolam / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D008875:Middle Aged; D008954:Models, Biological; D012121:Respiration, Artificial / Q000379:methods
D006993:Hypnotics and Sedatives; C040081:1-hydroxymethylmidazolam; D008140:Lorazepam; D008874:Midazolam