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The effects of obstructive jaundice on the pharmacodynamics of propofol--- does the sensitivity of intravenous anesthetics change among icteric patients?
时间：2010-08-24 09:11:18 来源： 作者：
Introduction It has been reported that some clinical symptoms of cholestasis, such as fatigue and pruritus, result from altered neurotransmission.1–3We have previously shown that the MAC awakeof desflurane is significantly reduced in patients with obstructive jaundice and this correlates inversely with the concentration of serum total bilirubin (TBL).4Patients with obstructive jaundice also have labile blood pressure and heart rate, and it is not clear whether bilirubin alters protein binding of propofol and the fraction of ‘free drug’.5–10In the present study, we hypothesize that patients with obstructive jaundice have an increased sensitivity to propofol. The primary goals were to define the sensitivity of propofol on the brain, as measured by the bispectral index (BIS), and the cardiovascular system, as measured by the mean arterial pressure (MAP), in patients with or without jaundice. Patients and methods The study was approved by our local institutional research ethics committee. Twenty-four patients with mild to severe obstructive jaundice (TBL 49–362.7μmol/l) secondary to neoplasm of the bile duct or the head of the pancreas and 12 chronic cholecystitis patients (TBL 7.8–17.1μmol/l) as control were recruited after obtaining written, informed consent. All were American Society of Anesthesiologists physical status I–III and between 50 and 70 years old. Exclusion criteria included known or suspected cardiac, pulmonary, renal, or metabolic disease, patients beyond ± 20% of the ideal weight, and patients on any form of analgesic or neuromodulating medication. The study was designed to determine the pharmacodynamic effects of propofol.We used an effectsite target-controlled infusion (TCI) system to control and maintain a constant propofol concentration. The BIS and direct arterial blood pressure were measured and recorded in order to compare the concentration resulting in 50% of the maximum effect (BIS and MAP) for anaesthesia (EC50) in patients with and without obstructive jaundice. After an overnight fasting, the nonpremedicated patients were brought to a quiet surgical operating room, where a cannula (CV-501-20, Central Venous Catheter Ltd, Singapore, Singapore) was inserted into an internal jugular vein for the infusion of propofol and for fluid replacement (hydroxyethylstarch solution 130/0.4 of 15–18 ml/kg/h; VoluvenR,Fresenius Kabi, Bad Homburg, Germany). A radial artery catheter (20G 60ml/min; B. Braun Medical Industries Sdn. Bhd, Penang, Malaysia) was also inserted under local anaesthesia to measure blood pressure and for blood sampling. BIS (BIStm pressure,ECG, end-tidal carbon dioxide, and oxyhaemoglobin saturation were monitored continuously throughout the study (Philips HP Viridia 24/26 M1205A; Philips Medizin Systeme Boeblingen GmbH, Boeblingen,Germany). Oxygen was administered through an anaesthesia mask during the study, and spontaneous ventilation was manually provided gently when necessary to maintain arterial carbon dioxide tension within the physiologic range. The BIS sensor was applied according to the manufacturer’s recommendations. Baseline BIS and MAP were recorded for at least 5 min. The subjects kept their eyes closed, and no stimulation of any kind, including verbal command, was allowed during the study. Target-controlled infusion of propofol Propofol was delivered using a three-compartment pharmacokinetic model-driven infusion device designed for a TCI. Effect-site concentrations for intravenous anaesthetics can be achieved with this System.11It consisted of a Graseby 3500 syringe pump (SIMS Graseby Ltd, Herts, UK) controlled by a laptop computer. The control software was Stelpump (version 1.05, Johan Coetzee and Ralph Pina, August 1996), running on a Windows 98/NT operating system (Microsoft Licensing Inc., OEM, George, WA, USA). The propofol was administered by a TCI using the pharmacokinetic parameters reported by Marsh et al. (Vc = 228 ml·kg-1, k10 = 0.119min-1, k12 = 0.112min-1, k13 = 0.0419min-1, k21 = 0.055 min-1, k31 = 0.0033 min-1)[12] and a keo of 0.291min-1. An arterial blood sample (3 ml) was drawn before drug administration. After the beginning (or on choosing a new target concentration) of propofol, samples (3 ml) were collected at 6, 8, 10 and 12 min. The target effect-site concentration was increased sequentially from 1 to 3 μg•ml-1 in each patient, that means every patient got three target concentrations (1, 2 and 3 μg.ml-1 relatively). Total study time was over 36 minutes in every patient. When an excessive level of anaesthesia occurred the study was terminated, even if the three steps were not completed. Excessive anaesthesia was defined as following: (1) systolic blood pressure (SBP) less than 80 mmHg in patients aged less than 60 yr or less than 90 mmHg in patients aged more than 60 yr; (2) heart rate less than 50 bmp. Blood plasma samples (into lithium heparin) were separated immediately and stored at 5 ºC on ice until extraction and assay. Within 24 h after sampling, plasma concentrations of propofol were determined using high-performance liquid chromatography with fluorescence detection at 310 nm after excitation at 276 nm (CTO-10A, RF550, and C-R7A, Shimadsu, Kyoto, Japan) [13]. For each batch of blood samples, a standard curve was computed by adding pure propofol liquid to drug-free human plasma to achieve concentrations of 1.0, 5.0, 7.5, and 10.0 μg•ml-1. Linear regression (least-squares method) was used with plasma propofol concentration as the dependent variable. Propofol concentrations in this study were calculated using the obtained regression equation. The lower limit of detection was 15 ng•ml-1, and the coefficient of variation was 7.9%. TCI Pump Performance Analysis To characterize the success in achieving and maintaining stability of concentrations, the percent performance error (PE) was defined as (CM-CT)/CT100%, where CM was the measured plasma propofol concentration after the start of infusion and CT was the predicted plasma concentration [14]. The median PE for the population was then calculated as the median of all individual median PEs. The population median PE is a measure of the systematic bias of the TCI. The median absolute PE for the population was calculated as the median of all individual median absolute PEs. Propofol Pharmacodynamic Modeling We expressed the effects on electroencephalographic parameter and haemodynamics as the percent BIS and MAP decrease from baseline: (baseline - measured value)/baseline 100. The measured plasma concentrations and the values of BIS, MAP after 6 min after beginning TCI (or after any change in target) were used in the propofol pharmacodynamic modeling. The relation [15] between measured plasma propofol concentrations and BIS, MAP was modeled with a fractional sigmoid Emax model (Hill equation, equation 1):  Eq.1Where E0 is the measured percent change of BIS or MAP from baseline in the absence of the drug, Emax is the BIS value or MAP corresponding to maximum drug effect, EC50 is the typical value of concentration that causes 50% of the maximum effect, delEC50 is the variable indicating the effect of TBL on EC50, and g (gamma) describes the slope of the concentration-response relation. The computations were performed using the SAS 9.1 (SAS Institute Inc., Cary, NC, USA). Parameters were optimized using nonlinear mixed effect model. An initial estimation was performed determine whether above-mentioned Hill equation best describe the propofol concentration versus effects with TBL as covariate. When the covariate of TBL was not statistically significant, Hill equation was parameterized in terms of Emax, EC50 and gamma excluding this covariate. Interindividual variability for EC50 is accounted for on pharmacodynamic variables following normal distribution, as shown in equation 2:  EC50(i) is the parameter of for the ith individual EC50, EC50 is arithmetic mean for all individual EC50, hi is a random inter-individual effect that models the person to person variation of the EC50 and is assumed to follow a normal distribution with mean 0 and variance Interindividual variability for g (gamma) is accounted for on pharmacokinetic variables following to normal distribution, as shown in equation 3: γi = γ+ μi (3) The overall model is equation 4  The empirical Bayesian estimates were used to obtain the above-defined random effects, and finally individual parameters were calculated. The above model was constructed using the procedure of nlmixed in SAS software. Statistical analysis According to the computer simulation by Girgis et al., 16with 30% individual variability, a design with 0.5–3 EC50units sampling (as applied in the present study) could give a precise estimation of all pharmacodynamic parameters, which are not affected by the sample size from 25 to 100. Thus, 36 patients were included in the present study. Data were presented as mean (SD) or median (range). Statistical analysis was performed using SPSS 14.0 (SPSS Inc., Chicago, IL). The relations between measured plasma concentrations and predicted plasma concentrations were determined by linear regression, with a statistical significance defined as P<0.05. Results All studies were completed without clinical complications.All the patients received three predetermined propofol concentrations, except for three patients who developed hypotension at 3μg/ml,and the study was discontinued at this point.However, these three patients were included in the analysis of the pharmacodynamics on BIS or blood pressure. The population characteristics were as follows: age, 55.8 (7.9) years; weight, 67.7 (9.5) kg; height, 165.2 (9.0) cm; and gender (men/women), 19/17. Table 1 shows the measured plasma propofol concentration at each time point in three steps. There was a strong correlation between the measured plasma propofol concentration and the predicted plasma concentration (r＝0.815; linear regression:CM＝0.23＋0.71CT). The median PE (bias) of the TCI in all subjects was －11.4%, and the median absolute PE (accuracy) was 20%.  References 1. Bergasa NV, Jones EA, Skolnick P. The pruritus of cholestasis:potential pathogenic and therapeutic of opioids. 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