Effect Of Nomovolemic Haemodilution On Propofol Pharmacokinetics And Target-Controlled Infusion

Part OneEffect of Haemodilution on Propofol Pharmacokinetics and Drug Entry Into Brain in DogsObjective To observe the effect of the alteration of pharmacokinetics of propofol and the mechanism of drug transfusion into CNS in nomovolemic haemodiluted dogs in order to get implications on the clinical use of propofol.Methods 13 dogs were randomized into two groups: control group(n=7) and haemodlution group (n=6). Nomovolemic haemodilutiom was performed by using 1:1 6% hydroxyethyl starch (Hes), with target HCT of 25%. After that was a propofol infusion of 10mg/kg/h which lasted for 30min. Blood samples were taken at the following points: 1,2,5,10,15,20,30 min after the start of infusion and 1,2,5,10,20,40,60,90,120,150,210,270 after the termination of infusion. Having calculated the pharmacokinetic parameters for each dog, haemodilation was performed again with the same procedure. TCI infusion using the individuralized PK parameters was adopted to maintain the same plasma concentration of propofol in two groups. Samples were taken at 5,15,30,45,60min after start of infusion to measure the plasma concentration, free drug concentrasion, CSF conentrasion and at last, the concentration in the brain tissue.Results The propofol plasma concentration and AUC during and after the infusion of 10mg/kg/h were significantly lower in the haemodilution group (P<0.01). For pharmacokinetic parameters, Vc of the haemodilution group was 1.10±0.56L/min, which was higher than that of the control group (0.54±0.34L/min,P<0.05). Vd and CL in the haemodilution group were also increased(5.41±3.36L/min and 56.9±20.0ml/min/kg vs 2.18±1.31L/min and 30.5±10.5ml/kg/min, P<0.05). The blood concentration of TCI was stably maintained and it did not differ too much from the target. Although plasma concentrations of propofol were almost the same in the twogroups, free drug concentration, CSF concentration and brain concentration were higher in the haemodilution group(P<0.05). Brain/plasma concentration was also increased in the haemodilution group. Moreover, brain/plasma concentration correlates well with the free fraction of propofol(r=0.87,P<0.01).Conclusion Nomovolemic haemodilution could affect the pharmacokinetics of propofol with greater Vc, Vd and CL, thus lowering the plasma concentration after infusion. Haemodilution could also lower the proteion binding of drug, thus enabling free drug to be distributed to the brain tissue more easily, which may result in an improved drug effect.Key words: haemodilution; propofol; pharmacokinetic; protein binding; brain...