Pharmacokinetics and pharmacodynamics of propofol/alfentanil infusions for sedation in ICU patients

Objective: Population pharmacokinetic analysis and pharmacodynamic profile of propofol/alfentanil infusions for sedation and analgesia of intensive care unit patients for up to 24 h. Design: Institutional Review Board-approved prospective clinical trial. Setting: The ten-bed intensive care unit of an university hospital. Patients: 18 consecutive patients (ten men/eight women; age: 17-73 years, mean 51.6 +/- 16.7 years, SD; body weight: 60-110 kg, mean 82.9 +/- 11.2 kg, SD) requiring mechanical ventilation and prolonged sedation/analgesia after major surgery or trauma. Interventions: Plasma propofol and alfentanil concentrations were measured at regular intervals during the long-term drug infusion using a high-performance liquid chromatography (propofol) and radioimmunoassay (alfentanil) analysis. The depth of sedation was controlled by monitoring a two-lead online EEG. Thus, drug application was computer controlled via a closed-loop EEG median-frequency feedback system. Results: ICU long-term infusion population pharmacokinetics (open three-compartment model) revealed for propofol: central compartment distribution volume (V-1): 31.2 +/- 5.3 l; steady-state distribution volume (V-dss): 499 +/- 173 l; total clearance (Cl-tot): 1001- +/- 150 ml/min; redistribution half-life (t(1/2) gamma): 90 +/- 23 min; elimination half-life (t(1/2)beta): 558 +/- 218 minutes. For alfentanil: V-1: 31.9 +/- 10.1 l; V-dss: 124 +/- 41 l, Cl-tot: 345 +/- 70 ml/min; t(1/2)gamma: 36 +/- 15 min; t(1/2)beta: 275 +/- 94 min, respectively. Conclusions: The population pharmacokinetic analysis of propofol/alfentanil for ICU sedation therapy revealed increased volumes of drug distribution and decreased elimination characteristics as compared to pharmacokinetic data from short-term infusions in surgical patients. This can be attributed in part to altered distribution/redistribution processes and/or drug elimination under the condition of ICU therapy. No significant drug accumulation was observed. For future long-term sedation and analgesia of ICU patients with propofol/alfentanil, this altered pharmacokinetic behaviour should be taken into consideration to allow a more individualized and safer dosing of this drug combination.