| Target-controlled infusion (TCI) is a new method of intravenous administration system. The pharmacokinetic parameters, which describe the distribution and elimination of drug, are incorporated in TCI systems. After setting plasma or effect site drug concentration, the systems control the infusion pump to deliver precisely the amount of drug to achieve and maintain the desired concentration of the drug rapidly. However it was found that the blood concentration were not consistent with the pharmacodynamic effect due to the gradient between blood and effect site drug concentration. So targeting effect-site concentration infusion (TCIeffect site) will predict more closely the desired drug effect. But the accuracy of TCIeffect site remains to be evaluated. There is little information about the accuracy of prediction of effect site concentration. The purpose of this study was to determine the pharmacokinetics of propofol in cerebral spinal fluid (CSF) and the relationship between the CSF propofol concentration and the bispectral index (BIS), an electroencephalography processed monitoring, during TCIeffect site of propofol. We try to demonstrate the interrelationship among the CSF concentration, effect site concentration and BIS value and evaluate the accuracy of TCIeffect site briefly. MATERIAL AND METHODS 1. Eight healthy adult mongrel dogs were anesthetized with enflurane. BIS and hemodynamics and PetCO2 were monitored throughout the experiment. After intravenous administration of a bolus dose of 6mg/kg propofol, arterial blood samples were taken from carotid artery for determination of blood propofol concentration by high performance liquid chromatography (HPLC) and fluorescence detection. Blood propofol concentration-time curve and BIS-time curve were obtained. The pharmacokinetic parameters of TCI were calculated using non-parametric methods and phamacokinetic-pharmacodynamic linked modeling techniques. 2.Another twelve anesthetized dogs were selected in this experiment. A catheter was inserted into subarachnoid space at thoracic segment of spinal column and advanced cranially until cranial base. BIS was monitored as in experiment 1. The pharmacokinetic parameters were input into the TCI software and 3μg/ml was set as target effect-site concentration. The pump was stopped at 15 minutes from beginning after the equilibrium of the calculated blood concentration and effect-site concentration had been reached. Arterial blood samples and CSF samples were collected for determination of propofol concentration by HPLC and fluorescence detection. RESULTS 1. The pharmacokinetic parameters of TCI after a bolus dose of 6mg/kg propofol were: V1:0.672L/kg,K10:0.074min-1,K12:0.272min-1,K-(13):0.115min-1,K21:1.102min-1,K31:0.058min-1,Ke0:0.094min-1. Meanwhile propofol could be described as three-compartment kinetics and hysteresis was observed between the blood concentration and drug effect. 2. When the infusion started, the loading dose of propofol was infused rapidly at the rate of 400ml/h. The calculated blood concentration increased rapidly and reached its peak concentration of 8.93±0.18μg/ml and then decreased gradually while the effect site concentration was rising. The equilibrium between blood and effect-site was reached at 10.9min and the target concentration was maintained at 3μg/ml. After the infusion was terminated, the blood and effect site concentration of propofol was decreased gradually. The median performance error (MDPE) and median absolute performance error (MDAPE) of predicted plasma concentration were –10.03% and 29.9% respectively, compared withmeasured ones, of which the peak concentration was 9.43±2.27μg/ml. CSF concentration was much lower than effect site concentration. Its peak concentration was 0.29±0.14μg/ml, about 18.7% of the effect site concentration on average. BIS values were consistent with changes in CSF concentration. Both reached peak values at 5min while effect site concentration relatively lagged behind. Better correlation was found between...
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