Pharmacokinetics/Pharmacodynamics

where dose is the desired dose for CKRT, dose n is the normal dose of a drug, CLnonrenal is the

nonrenal clearance of a drug, Qeff is the effluent rate, SC is the sieving coefficient, and CLnorm is

the normal clearance of the drug. As the effluent rate (in milliliters per minute) increases, so does

solute clearance. Therefore, it is the most important CKRT parameter pertaining to drug removal.

However, excretion of drug in the bile can potentially be affected by critical illness. This is evidenced by

changes in the clearance of some neuromuscular blocking agents.

A study of nine patients undergoing surgery for total biliary obstruction showed a significant increase

in pancuronium half-life compared with normal patients (270 minutes vs. 132 minutes, p<0.001). The

urinary excretion of pancuronium and its metabolites did not change. This suggests that the increased

half-life was caused by the decreased hepatic excretion of pancuronium (Br J Anaesth 1977;49:1103-8).

minutes in patients with cholestasis and 58 minutes in normal patients (Br J Anaesth 1986;58:983-7).

hypothesized that impaired gas exchange (e.g., acute respiratory distress syndrome) affects the body’s

ability to remove volatile gases. However, data are lacking regarding changes in critically ill patients that

affect their ability to excrete anesthetics.

the mechanism of action.

the physically identifiable effect of a drug in a patient. For example, the PD effect of an opioid is the relief of

pain reported by the patient. However, the PD effect of some drugs is not readily observable. For example,

the PD effect of proton pump inhibitors is an increase in gastric pH. Few PD studies of critically ill patients

are reported in the medical literature, and most pertain to antibiotic therapy.

Antibiotic overview: PD studies of antibiotics use models to estimate the combined effects of the patient

population PK of specific antibiotics and the MIC for select bacteria. These techniques usually allow

a calculation of the desired PD outcome. Antibiotics generally fall into three PD categories, which

correlate with efficacy: (1) time-dependent killing (T>MIC), (2) concentration-dependent killing (Cmax/

MIC), and (3) a combination of time- and concentration-dependent killing (ratio of area under the curve

to the minimum inhibitory concentration for the bacterial pathogen [AUC/MIC]).

above the MIC (fT>MIC) is used to predict treatment success. This is reported as a percentage of time

the free drug concentration remains above the MIC. The ideal f T>MIC is 100%. However, PD studies

of β-lactam antibiotic use in critically ill patients have found that a low percentage of patients will

important changes that can occur rapidly in critically ill patients (e.g., ARC). As such, epidemiologic

studies have tried to determine a breakpoint at which clinical success is achieved. Studies vary, and

the suggested breakpoint is 50%–100% (fT>MIC) (Br J Clin Pharmacol 2012;73:27-36), with others

dose = dosen ( )

CLnonrenal + (Qeff × SC)

CLnorm