Pharmacokinetics of propofol in patients undergoing total hip replacement : effect of acute hypervolemic hemodilution

The aim of the study was to investigate the effects of acute hypervolemic hemodilution (HHD) on the pharmacokinetics of propofol in patients undergoing total hip replacement.

A total of 16 patients undergoing elective surgery for total hip replacement under general anesthesia in combination with epidural analgesia were randomly assigned to 2 groups: the control group (n = 8) or the HHD group (n = 8). All patients in both groups received lactated Ringer's solution before induction of general anesthesia. In the control group the conventional fluid replacement protocol was used. In the HHD group 4% succinylated gelatin was infused at the rate of 20 ml•kg(-1)BW•h(-1 )with a targeted hematocrit of 30. Anesthesia was induced with midazolam 0.04 mg•kg(-1), fentanyl 4 µg•kg(-1) and propofol 1.5 mg•kg(-1). Tracheal intubation was facilitated by infusion of succinylcholine 2 mg•kg(-1). Anesthesia was maintained with isoflurane, fentanyl, vecuronium and epidural analgesia. Electrocardiogram (ECG), blood pressure (BP), blood oxygen saturation (SpO(2)), partial pressure of end-tidal carbon dioxide (P(ET)CO(2)) and central venous pressure (CVP) were monitored continuously. Blood samples were taken at 1, 2, 4, 6, 10, 15, 30, 45, 60, 75, 90, 120, 150, 180, 240, 300 and 360 min after propofol administration to determine plasma concentrations of propofol by high performance liquid chromatography (HPLC).

Plasma propofol concentrations were significantly lower in the HHD group than in the control group at 1, 2, 4, 6 and 10 min after propofol administration (p < 0.01) while there were no significant differences in plasma propofol levels 15-360 min after administration of propofol (p > 0.05). In the HHD group the volume of distribution of the central compartment (V(C)) increased significantly, elimination half-life (T(1/2) (γ)) was significantly prolonged, the elimination rate constant (K(10)) and the whole-body clearance (CL) were significantly decreased compared with the control group (p < 0.01 or 0.05). There were no significant differences of the half-life of the fast distribution phase (T(1/2) (α)), half-life of the slower distribution phase (T(1/2) (β)), K(12), K(21), K(13), K(31) and the area under the curve (AUC) (p > 0.05). The pharmacokinetic profile of propofol is best described by a three-compartment model in both groups using minimal Akaike information criteria (AIC).

Acute HHD increases V(C), prolongs the T(1/2) (γ), and decreases K(10) and CL, which suggests that care must be taken when propofol is used in patients undergoing HHD. The induction dose should be increased, but the maintenance dose should be decreased. The time to emergency from anesthesia will likely be prolonged, especially in patients receiving prolonged continuous infusions.