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.


METHODS
Institutional Review Board-approved prospective clinical trial.


METHODS
The ten-bed intensive care unit of an university hospital.


METHODS
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.


METHODS
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 (V1): 31.2 +/- 5.3 l; steady-state distribution volume (Vdss): 499 +/- 173 l; total clearance (Cltot): 1001- +/- 150 ml/min; redistribution half-life (t1/2 gamma): 90 +/- 23 min; elimination half-life (t1/2 beta): 558 +/- 218 minutes. For alfentanil: V1: 31.9 +/- 10.1 l; Vdss: 124 +/- 41 l; Cltot: 345 +/- 70 ml/min; t1/2 gamma: 36 +/- 15 min; t1/2 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.
Frenkel
C
C
Klinik und Poliklinik fur Anasthesiologie und spezielle Intensivmedizin, Rheinische Friedrich-Wilhelms-Universitat Bonn, Germany.
Schuttler
J
J
Ihmsen
H
H
Heye
H
H
Rommelsheim
K
K
D000293:Adolescent; D000328:Adult; D000368:Aged; D015760:Alfentanil / Q000493:pharmacokinetics*; D000701:Analgesics, Opioid / Q000493:pharmacokinetics*; D003422:Critical Care; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D004360:Drug Therapy, Computer-Assisted; D004569:Electroencephalography / Q000187:drug effects; D005260:Female; D006801:Humans; D006993:Hypnotics and Sedatives / Q000493:pharmacokinetics*; D007262:Infusions, Intravenous; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D008954:Models, Biological; D015742:Propofol / Q000493:pharmacokinetics*; D011446:Prospective Studies; D012044:Regression Analysis; D013997:Time Factors
D000701:Analgesics, Opioid; D006993:Hypnotics and Sedatives; D015760:Alfentanil; D015742:Propofol