Pharmacokinetic–Pharmacodynamic Modeling and ICU Sedation

Unexplored Territories IN this issue of ANESTHESIOLOGY, Barr et al. make a useful contribution to our understanding of the clinical pharmacology of intensive care unit (ICU) sedation. It is estimated that approximately $1 billion is spent each year in the United States alone on drugs used for sedation in the ICU. Misuse of these drugs contributes to morbidity, mortality, and expense. Optimization of ICU sedation will require characterization of the clinical pharmacology of sedative drugs. Unfortunately, there are a paucity of studies that use blinded designs and intentionto-treat analysis, which report pertinent baseline data and which use specific dosing schedules and standardized cointerventions. The report by Barr et al. is an example of the type of study needed to redress this deficiency. Barr et al. characterize and compare the pharmacokinetics and pharmacodynamics of lorazepam and midazolam when used for postoperative sedation of surgical ICU patients. Lorazepam and midazolam are commonly used ICU sedatives, but it has been unclear which is the optimal agent. A previous and influential comparison of midazolam and lorazepam by Pohlman et al. showed no difference in efficacy and, more notably, no difference in the duration of effect of the two drugs after discontinuation, despite known differences in their pharmacokinetics. In fact, the mean duration of effect was less for lorazepam than for midazolam, although the difference was not statistically significant. This report, along with economic considerations, led many institutions to adopt lorazepam for routine ICU sedation. Simplistically, one might assume that the most reliable method of comparing the duration of effect of two drugs is by direct measurement, but the difficulty with this approach is that the conclusion cannot be extrapolated beyond the depth or duration of sedation (because drug half-time varies with the duration of administration) used in that particular study. Pharmacokinetic–pharmacodynamic modeling, as used by Barr et al., takes us past this restriction. Any difference in the duration of effect of two drugs must arise from either pharmacokinetics or pharmacodynamics. Drug A may have a shorter duration of effect than drug B either because it is cleared from the effect site more rapidly (a pharmacokinetic difference) or because the difference in the concentrations defining appropriate sedation and “recovery” is smaller for drug A than for drug B (a pharmacodynamic difference). In their study, Barr et al. carefully characterized the pharmacokinetics of midazolam and lorazepam in ICU patients. Although their findings were significantly different from those previously reported for healthy volunteers, they confirm that the context-sensitive decrement times (the time required for a given percentage decrease in plasma concentration) were much smaller for midazolam than for lorazepam. If the plasma concentrations of midazolam decrease more rapidly than those of lorazepam after discontinuation of drug administration, the only way that the effect of lorazepam could be shorter-lived than that of midazolam would be if the concentration “decrement” (the difference between the concentration associated with adequate sedation and the concentration associated with return of an appropriate level of consciousness) is less for lorazepam than for midazolam. This question can be approached with pharmacodynamic modeling. Barr et al. use the Ramsay scale, subjectively evaluated ordinal scores of 1–6 (with 6 being unresponsive), to assess the level of sedation. The pharmacodynamic model assumed that the probability of a level of sedation greater than or equal to some value ss (where ss ranges from 2–6) is given by