Department of Anaesthesiology, Leiden University Medical Center (LUMC), PO Box 9600, 2300 RC Leiden, The Netherlands*Corresponding author
Accepted for publication: September 12, 2000
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Abstract |
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Br J Anaesth 2001; 86: 1838
Keywords: anaesthetics, i.v., propofol; anaesthetics, i.v., alfentanil; anaesthetic techniques, i.v., pharmacokinetics, propofol; age factors; gender factors
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Introduction |
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As the elderly population increases, elderly patients are scheduled for general surgery with increasing frequency. However, rational dosing schemes for propofol in this population are not available. So far, three studies13 have described the pharmacokinetics of propofol during continuous infusion in the elderly. One manuscript described the pharmacokinetics of propofol solely in male patients.1 The second study determined the pharmacokinetics of propofol in a non-clinical environment in volunteers with only few elderly involved.2 Lastly, Schüttler and colleagues recently described a population pharmacokinetic parameter set for propofol.3 However, the small number of elderly patients in this population (10%), the propofol dosing regimen in these patients (some only received a bolus dose), and the short period of time during which concentrationtime data of these patients were collected (on average 55 min) leads us to believe that this population pharmacokinetic data set may be less suitable for application in continuous infusion techniques in elderly patients. As propofol is increasingly administered in elderly patients either by manual or target controlled infusion, we studied the pharmacokinetics of propofol in male and female elderly patients during and after termination of a continuous infusion when given as a component of total i.v. anaesthesia for general surgery.
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Subjects and methods |
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Patients received temazepam 10 mg orally, 1 h pre-operatively. In the operating room, an i.v. cannula was inserted into a large forearm vein for infusion of propofol and alfentanil and a cannula was inserted into a radial artery for the continuous measurement of arterial blood pressure and the collection of blood samples for determination of blood propofol concentrations. The ECG, arterial blood pressure, heart rate, end-tidal carbon dioxide partial pressure and oxyhaemoglobin saturation (SpO2, Nellcor N-200, Hayward, CA) were monitored continuously throughout the study.
Before induction of anaesthesia, patients received 500 ml of a colloid solution (Gelofusine). With the patients breathing 100% oxygen, anaesthesia was induced by a manually controlled infusion (Beckton Dickinson, Brézins, France) with a bolus dose of propofol of 1.5 mg kg1 over 1 min followed by a continuous infusion of 7 mg kg1 h1 that was maintained constant until skin closure. When consciousness was lost, vecuronium, 0.1 mg kg1, was given i.v. and the trachea intubated. The lungs of the patients were then ventilated with oxygen in air (1:2) and ventilation adjusted to maintain the end-tidal carbon dioxide partial pressure between 44.5 kPa. In addition, patients received a continuous infusion of alfentanil of 050 µg kg1 h1 i.v. that was varied according to the presence or absence of patient responses, and terminated 10 min before skin closure. No response was defined as a systolic blood pressure within a 15% range of the preoperative mean, a heart rate of less than 90 beats min1 in the absence of hypovolaemia, absence of autonomic responses and no movement to surgical stimuli. Post-operative pain relief was provided with rectal paracetamol up to 3 g per 24 h and i.m. methadone up to 0.15 mg kg1 four times daily. Twenty-four hours post-operatively the patients were asked for any recall of events during the study period.
Arterial blood samples of 3 ml for the determination of whole blood propofol concentration were taken at 1, 3, 5, 10, 15, 20, 25, 30 min and then every 15 min after the start of the infusion of propofol, and at 0.5, 1, 2, 3, 5, 7, 10, 15, 20, 25, 30, 45, 60, 120, 180, 240, 360, 720, 1080 and 1440 min after the termination of the infusion of propofol. The blood samples were transferred into test tubes containing potassium oxalate and stored at 4°C. Propofol concentrations in blood were measured within 12 weeks by reversed-phase high-performance liquid chromatography (HPLC).4 The detection limit was approximately propofol 40 ng ml1 blood. The coefficient of variation of the HPLC method did not exceed 10% in the concentration range encountered in this study.
The pharmacokinetics of propofol were determined in each patient by fitting two and three compartment models to the concentrationtime data with a weighted (1/y2) least squares non-linear regression analysis (software package WinNonLin, Scientific Consulting, Inc., Cary, NC, USA). In a two-stage manner, the simple average pharmacokinetic parameter set was determined. The effect of age, gender, total body weight and lean body mass on the pharmacokinetic parameters was then evaluated by univariate and multivariate linear regression analysis (SPSS 9.0, SPSS Inc USA). Based upon partial F-tests (P<0.05), successive variables were included. Finally, if more than one covariate was included plausible interaction terms were examined and based upon F-tests (P<0.05) this term was either included or excluded. Independent covariates were tested for multicollinearity. If the tolerance exceeded 0.5 multicollinearity was considered to be not substantial. The simple (average) model and the final (complex) pharmacokinetic parameter set were retrospectively tested for their clinical value by determining the accuracy with which the parameters predicted the measured blood propofol concentrations in the individual patients.
The performance error (PE) was calculated as:
where Cm and Cp are the measured and predicted blood propofol concentrations. Subsequently, the bias and inaccuracy associated with each pharmacokinetic parameter set were assessed by determining the median performance error (MDPE), the median absolute performance error (MDAPE), and the corresponding interquartile ranges (2575%).
Data are presented as mean (SD), median and range, or percentage, unless stated otherwise. P<0.05 was considered as the minimum level of statistical significance.
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Results |
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From the 31 patients, a total of 932 blood samples for determination of blood propofol concentrations were taken over a 24 h period. The pharmacokinetics of propofol were best described on the basis of a three-compartment model in all patients. Gender significantly affected the pharmacokinetics of propofol. V3, Cl1 and Cl2 were significantly different between male and female patients. In addition, Cl1 was weight dependent. The simple and final complex pharmacokinetic parameter sets are described in Table 1. The performance of the simple average pharmacokinetic parameter set, as tested retrospectively by computer simulation in the individual patients, showed a reasonable performance (MDPE (2575%), 2% (9 to 15%); MDAPE 22% (1826%)). The addition of the covariates improved the performance as shown by a reduction in both the bias and inaccuracy and their interquartal ranges (MDPE (2575%), 1% (5 to 13%); MDAPE 18% (1422%), Table 2). For the application of the pharmacokinetic parameter set to a target controlled infusion, the performance of the final complex model was determined as well only for the period of propofol infusion: (MDPE (2575%), 3% (2 to 13%); MDAPE 14% (1120%)). The performance of the complex model is illustrated in Fig. 1, which shows the measured and predicted concentration-time data in the patients with the best and worst performances as based on MDPE.
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Discussion |
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Gender differences in the elderly receiving propofol
In this study, we found that gender affected the pharmacokinetics of propofol in elderly patients. The pharmacokinetic analysis revealed a larger slow peripheral volume of distribution (V3), a higher metabolic (Cl1) but a reduced rapid peripheral clearance (Cl2) in elderly female patients compared with elderly male patients. Previously, Dyck and Shafer1 only studied male patients, Schüttler and Ihmsen3 did not find a gender difference in the propofol pharmacokinetics, whereas Schnider and colleagues2 described that gender of itself did not affect the pharmacokinetics of propofol but, by affecting lean body mass (LBM), influenced the metabolic clearance. The LBM of for instance a 73-yr-old, 75 kg, 180 cm male is 60.2 kg, whereas a female with the same characteristics has a LBM of 54.6 kg. As a consequence, according to Schnider and colleagues2 the clearance in this elderly male is 1.80 litre min1compared with 2.18 litre min1 in the elderly female. When elderly male and female patients are given the same propofol infusion scheme the blood propofol concentrations in the female patients will be approximately 10% lower compared to that in the male. These results are based on both the pharmacokinetics of Schnider and colleagues2 and on the pharmacokinetics reported in this study (Fig. 2). The gender related differences may be explained on the basis of gender related differences in physiological parameters such as cardiac output and amount of body fat. Male patients generally exhibit a higher cardiac output and thus a greater hepatic perfusion compared with females.6 For a high extraction-ratio drug like propofol, hepatic clearance is strongly correlated to hepatic perfusion and a gender related difference in hepatic perfusion may explain the difference in clearance found in this study. Similarly, the difference in the amount of body fat between elderly male and female patients may be responsible for the greater peripheral slow volume of distribution (V3) in female compared with male patients in our study. Clinically, these results indicate that in order to assure the same blood propofol concentration in elderly female and male patients, female patients require an approximately 10% higher propofol infusion rate. Furthermore, when female and male patients receive the same infusion scheme, the lower blood propofol concentrations in female patients (Fig. 2) may explain the described difference in speed of recovery between female and male patients.7 When female patients experience lower blood propofol concentrations compared with male patients during similar propofol infusion schemes, in the presence of a similar pharmacodynamic profile, female patients will regain consciousness more rapidly than male patients.
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Computer simulation of propofol pharmacokinetics in the elderly
The clinical consequences of the pharmacokinetics of propofol observed in this study were compared with those based on the three parameter sets thus far described in the elderly1-3 using a computer simulation of an infusion scheme as used in this study (1.5 mg kg1 in 1 min followed by 7 mg kg1 h1 thereafter, Fig. 3). The measures of performance of these three other parameter sets in relation to those determined in this study were determined (Table 2). The computer simulations reveal that, based on the pharmacokinetics described in this manuscript, the predicted blood propofol concentrations are somewhat higher than those based on the pharmacokinetic data reported by Dyck and Shafer1 and Schnider and colleages.2 This may be the result of the fact that in contrast to the patients of Dyck and Shafer1 and Schnider and colleages,2 our patients were studied in a clinical setting and received alfentanil in addition to propofol. Recently, alfentanil has been shown to affect the pharmacokinetics of propofol such that in the presence of alfentanil propofol concentrations are increased by about 18%.5 In that study, alfentanil reduced both the volume of distribution and the clearance of propofol. The mechanism of this interaction remains yet unknown.
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References |
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