BJA Advance Access originally published online on February 12, 2008
British Journal of Anaesthesia 2008 100(4):509-516; doi:10.1093/bja/aem408
Pharmacodynamic modelling of the bispectral index response to propofol-based anaesthesia during general surgery in children
Department of Anaesthesiology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Krankenhausstr. 12, 91054 Erlangen, Germany
* Corresponding author. E-mail: christian.jeleazcov{at}kfa.imed.uni-erlangen.de
Accepted for publication December 6, 2007.
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Abstract |
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Background: This study describes a pharmacodynamic model during general anaesthesia in children relating the bispectral index (BIS) response to the anaesthetic dosing of propofol, fentanyl, and remifentanil.
Methods: BIS, heart rate, mean arterial pressure, sedation scores, and anaesthetic protocols from 59 children aged 1–16 yr undergoing general surgery were considered for the study. Anaesthesia was performed with propofol, fentanyl, and remifentanil. A sigmoid model assuming additive interaction of propofol, fentanyl, and remifentanil was fitted to individual BIS as effect variable. The pharmacodynamic parameters were estimated by non-linear regression analysis. The ability of BIS to predict anaesthetic drug effect was quantified by the prediction probability Pk.
Results: BIS started at a baseline of 90 (9), decreased during induction to 30 (14) and remained at 57 (10) during anaesthesia. BIS predicted the anaesthetic drug effect with a Pk of 0.79 (0.08). The EC50 Propofol and the ke0 Propofol were 5.2 (2.7) µg ml–1 and 0.60 (0.45) min–1, respectively. The ke0 Propofol decreased from approximately 0.91 min–1 at 1 yr to 0.15 min–1 at 16 yr. The EC50 Remifentanil, ke0 Remifentanil, EC50 Fentanyl, and the ke0 Fentanyl were 24.1 (13.0) ng ml–1, 0.71 (0.32) min–1, 8.6 (7.4) ng ml–1, and 0.28 (0.46) min–1, respectively.
Conclusions: The effect equilibration half-time of propofol in children was age dependent. The pharmacodynamics of fentanyl and remifentanil in children were similar to those reported in adults. The BIS showed a close relationship to the modelled effect-site concentration, and therefore, it may serve as a measure of anaesthetic drug effect in children older than 1 yr.
Keywords: anaesthesia, paediatric; model, pharmacodynamic; monitoring, EEG; monitoring, bispectral index
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Introduction |
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Total i.v. anaesthesia (TIVA) is commonly used in paediatric anaesthesia for diagnostic and therapeutic procedures. The hypnotic drug most often used in paediatric TIVA is propofol. Its clinical advantages are rapid induction, smooth maintenance, rapid recovery, and minimal side-effects.1 Propofol is usually combined with opioids, such as fentanyl or remifentanil. Although paediatric pharmacokinetic data on i.v. anaesthetics are available,2–5 data on electroencephalographic response to paediatric TIVA are still limited.6 7
A commonly used electroencephalographic measure of anaesthetic drug effect in adults is the bispectral index (BIS). The potential usefulness of BIS for measuring the anaesthetic effect in children has been described for inhaled agents.8 Recently, we showed that the BIS may predict sedation and anaesthesia during paediatric surgery as assessed by the Children’s Hospital of Wisconsin Sedation Scale (CHWSS) in children older than 1 yr.9 Therefore, BIS may also provide a measure of anaesthetic drug effect for paediatric TIVA.
The current work aimed at describing a pharmacodynamic model of BIS response to propofol-based anaesthesia supplemented by fentanyl and remifentanil in children aged 1–16 yr during general surgery. The ability of BIS to predict the anaesthetic drug effect was quantified by the probability prediction Pk of BIS with respect to the effect-site concentration. Haemodynamic data and CHWSS scores were considered as clinical endpoints of TIVA.
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Methods |
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After approval by the Ethic Committee and after informed parental consent, anonymous recordings of BIS, heart rate (HR), mean arterial pressure (MAP), CHWSS scores, and anaesthetic protocols from 59 ASA I–II children aged 1–16 yr undergoing elective urological or abdominal surgery were considered for this study. The study design, the anaesthetic regimen, and the monitoring environment are presented in detail in a previous article9 and are shortly repeated as relevant to this work.
Study design
All patients received premedication 30 min before arrival in the operating room (midazolam 0.5 mg kg–1 p.r. or 0.4 mg kg–1 p.o.). In the operating room, the ECG electrodes were placed, an i.v. cannula was introduced and infusion of lactated Ringer’s solution was started approximately 10 min before induction of anaesthesia. HR, non-invasive arterial pressure, oxygen saturation, inspiratory oxygen, end-tidal carbon dioxide, and respiratory parameters were monitored with a SIEMENS SC 9000 monitor (Siemens Medical Systems, Inc., Electromedical Group, Danvers, MA, USA). The skin was prepared with alcohol at EEG electrode positions in order to maintain impedances less than 10 k
. Ambu Neurology EEG electrodes (Ambu A/S, Ballerup, Denmark) were placed on patient’s forehead and connected to an Aspect A1000-monitor (128 samples s–1; Fpz as GND; 50 Hz low-pass filter; 0.5 Hz high-pass filter; 50 Hz notch filter) approximately 5 min before induction of anaesthesia for baseline recording. After preoxygenation via face mask, anaesthesia was induced with fentanyl 2 µg kg–1 i.v. or remifentanil 0.25–0.5 µg kg–1min–1 followed approximately 60 s later by lidocaine 0.5 mg kg–1 i.v. and propofol 3–4 mg kg–1 i.v., respectively. When patients stopped breathing spontaneously, the mask ventilation was started followed by the insertion of a laryngeal mask or an endotracheal tube under muscle relaxation with mivacurium 0.2 mg kg–1 i.v. The lungs were mechanically ventilated to maintain normocapnia and normoxaemia with a mixture of oxygen in air. During surgical procedure, the maintenance of anaesthesia was mainly performed with an i.v. infusion of propofol 6–10 mg kg–1h–1 and remifentanil 0.25–0.5 µg kg–1min–1. A repetitive bolus of fentanyl 2 µg kg–1 i.v. was given if necessary. The attending anaesthetist was blinded to the BIS and conducted anaesthesia in order to maintain HR and MAP within 20% of baseline values obtained before induction of anaesthesia. No further doses of neuromuscular blocking agents were administered. After skin closure, the infusion of anaesthetics was stopped and extubation was performed when the children were breathing regularly with a tidal volume greater than 6 ml kg–1. Postoperative analgesia was provided by i.v. infusion of acetaminophen 15 ml kg–1, which was administered approximately 20 min before the end of the surgical procedure. With regain of apparent alertness, the monitors for vital functions and EEG were disconnected, and the children were transferred to the post-anaesthesia care unit.
The attending anaesthetist estimated the patient’s level of arousal by CHWSS scores (Table 1). Alertness after anaesthesia was defined as eye opening, purposeful movement, or phonation as appropriate for age. CHWSS scores were assessed every 30 s during induction and recovery, and every 2 min before induction and during maintenance of anaesthesia.
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The BIS® data (Aspect Medical Systems, Newton, MA, USA, Rev. 3.31, one value per second) were obtained from the RAW EEG port of the Aspect monitor throughout the study period, that is, 5 min before induction of anaesthesia to 5 min after regain of apparent alertness, and stored on a laptop computer synchronized to the data collection of vital parameters, anaesthetic doses, and CHWSS scores. For further analysis, only BIS values with an Artefact Flag of zero were considered.
Pharmacodynamic modelling
The relation between drug dosing I(t) and the time course of BIS as measure of the pharmacodynamic effect E(t) was modelled using the common sigmoid model.
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E0 is the baseline value of the effect; Emin, the minimum value of the effect; 
, the Hill exponent describing the steepness of the concentration-effect curve; and CEFF, a virtual effect concentration which was defined as the sum of the normalized effect-site concentrations of propofol, remifentanil, and fentanyl, assuming an additive interaction of these drugs:10–13
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where EC50 Propofol, EC50 Remifentanil, and EC50 Fentanyl are the concentrations for half-maximum effect.
For each drug, the effect-site concentration was calculated from I(t) by
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and
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The pharmacodynamic parameters E0, EC50 Propofol, EC50 Remifentanil, EC50 Fentanyl, ke0 Propofol, ke0 Remifentanil, ke0 Fentanyl, and were estimated individually by non-linear regression analysis using Non-linear Effect Modeling (NONMEM V, GloboMax LLC, Hanover, MD, USA). The minimum effect Emin was estimated in the population by taking the minimum value of all measured BIS data. The parameters Ai and 
i (i=1, 2, 3) were fixed, using published pharmacokinetic data from Schuttler and Ihmsen3 for propofol, from Ross and colleagues5 for remifentanil and from Ginsberg and colleagues4 for fentanyl. From the individual estimates of ke0 Propofol and the pharmacokinetic parameters of propofol, we determined for each patient the time to peak the effect-site concentration of propofol (Tpeak Propofol). The influence of age and weight on pharmacokinetics is described in detail in the Appendix.
Statistical analysis
The residual intraindividual error of the pharmacodynamic model was assessed by calculating the unweighted residuals Rij=Eij–Epij and the absolute residuals ARij=|Eij–Epij| from the ith measured and predicted effect in the jth patient Eij and Epij, respectively. The residuals were expressed as percentage of the individual E0. The median values of Rij and ARij were used as overall measures for goodness of fit. To assess the stability of the pharmacodynamic estimates, a bootstrap resampling method was used. The mean parameter estimates of 1000 bootstrap replicates were compared with the estimates of the original data set.
The suitability of BIS as a measure of anaesthetic drug effect was assessed in each patient by calculating the transformed prediction probability Pk=1–Pk' of BIS with respect to CEFF, whereby Pk' is the prediction probability as introduced by Smith and colleagues.14 A Pk value of 1 means that BIS always monotonically decreases (increases) with an increasing (decreasing) CEFF, whereas a Pk value of 0 represents an inverse relationship between BIS and CEFF. A Pk value of 0.5 means that the BIS predicts the virtual effect concentration no better than a 50:50 chance and is therefore useless for predicting anaesthetic drug effect.
The influence of age on pharmacodynamic parameters or on CHWSS scores before or during maintenance of anaesthesia was assessed by using the Spearman’s correlation coefficient 
, and if a significant correlation was present, by the coefficient of determination R2.
The statistical analysis was performed with Matlab (Version R14, The Mathworks Inc., Natick, MA, USA) and SPSS (Version 14.0.1, SPSS Inc., Chicago, IL, USA) at a significance level of 
=0.05. Data are presented as mean (range) or mean (SD) (median) unless stated otherwise.
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Results |
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The data from 59 children were evaluated in the study. The recording of HR and MAP failed in one child and in another child one half of the EEG recording was disturbed by high-frequency diathermy and X-ray equipment. Three children had incomplete CHWSS scores. The pharmacodynamic modelling failed in a further five children, where the pharmacodynamic parameters for propofol, remifentanil, and fentanyl lay outside of a three-fold of the standard deviation of the corresponding parameters observed over all cases, and the residuals obtained by the pharmacodynamic fit were skewed far away from a normal distribution. Therefore, the presented results were obtained from 49 patients [male/female 38/11; 6.4 (1.1–16.6) yr; 118 (31) (116) cm; 26 (17) (20) kg]. During anaesthesia [80 (26–197) min], the HR and MAP remained within 20% of the baseline values. The individual pharmacodynamic analysis was performed, on average, with 4248 (1056–10 987) valid data pairs of BIS vs CEFF.
Starting at a baseline of 90 (9) (93), the BIS decreased during induction to a minimum value of 30 (14) (28) and remained at 57 (10) (60) during anaesthesia. At baseline, CHWSS scores of 6, 5, 4, and 3 were present in 12.8%, 67.4%, 6.3%, and 3.6% of the observations, respectively. During maintenance of anaesthesia, CHWSS scores of 0, 1, and 2 were present in 97.5%, 2.2%, and 0.3% of observations, respectively. The CHWSS scores during baseline and maintenance of anaesthesia were not correlated with age (Spearman’s of –0.22 and 0.02, respectively; P>0.05).
Figure 1 shows the BIS and the predicted plasma concentrations of propofol, remifentanil, and fentanyl obtained with the applied pharmacokinetic models from the literature in each patient. Because of different duration of the individual surgical procedures, only the predicted data of the first 140 min of anaesthesia are presented. The predicted plasma concentrations of propofol and remifentanil required for adequate anaesthesia were 2.3 (0.3) (2.3) µg ml–1 and 4.3 (0.8) (4.3) ng ml–1, respectively.
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Figure 2 shows the predicted plasma concentrations together with measured and fitted values of BIS and CHWSS scores in one patient. The results from the pharmacodynamic modelling are summarized in Table 2. BIS predicted CEFF with a Pk of 0.79 (0.08) (0.80). The residual intraindividual error of the pharmacodynamic model remained within 25% of E0 (Fig. 3).
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For children older than 1 yr, the equilibration rate constant ke0 of propofol decreased significantly with increasing age as assessed by the Spearman’s
of –0.61 (P<0.001) and R2 of 0.44 (Fig. 4A). As depicted in Figure 4B, Tpeak Propofol increased significantly with increasing age [Spearman’s of 0.40 (P<0.05) and R2 of 0.27]. No significant relationship was identified between age and the equilibration rate ke0 of remifentanil and fentanyl (Spearman’s of –0.12 and 0.18, respectively; P>0.05) and between age and the half-maximum effect concentrations of propofol, remifentanil, and fentanyl (Spearman’s of 0.03, –0.04 and –0.25, respectively; P>0.05).
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Discussion |
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In this study, we investigated the BIS response to propofol, fentanyl, and remifentanil anaesthesia during general surgery in children. The BIS served as the measure of drug effect. A sigmoid model was fitted to the individual BIS data under the assumption of an additive interaction between propofol, fentanyl, and remifentanil,10 12 13 as these drugs were administered during anaesthesia, and as all of them have an EEG effect. The BIS showed a monotonic effect concentration–response relationship. The equilibration rate half-time between plasma and effect-site concentration of propofol decreased significantly with decreasing age.
As in a previous analysis,9 we used the BIS values delivered every second from the BIS A-1000 monitor. Because of the huge amount of data in each patient, we performed individual pharmacodynamic fits rather than using a population approach. As assessed by the residual intraindividual BIS error, the pharmacodynamic model accurately predicted the measured BIS (Table 2, Figs 2 and 3). Using the pharmacokinetic model of Schuttler and Ihmsen3 for calculating propofol plasma concentration, we found a median ke0 Propofol of 0.55 min–1, resulting in a half-time equilibration rate t1/2 ke0 Propofol of 1.26 min. In a recent work, Munoz and colleagues6 found a t1/2ke0 Propofol of 1.7 min with the pharmacokinetic model of Kataria and colleagues2 and 0.8 min with the paedfusor model in children aged 3–11 yr. As the pharmacokinetic model of Schuttler and Ihmsen3 was based in part on the same data set as the pharmacokinetic model of Kataria and colleagues,6 and as the t1/2 ke0 Propofol was found to be dependent on the used pharmacokinetic set of parameters, our results are comparable with those from Munoz and colleagues achieved with the Kataria model. The difference in t1/2 ke0 Propofol values may be due to the effect variable used, that is, the AAI in the study of Munoz and colleagues and BIS in our study. This supports the dependence of t1/2 ke0 from the effect variable described in previous studies.15
Interestingly, the t1/2 ke0 Propofol was significantly dependent on age. Using the non-linear relationship depicted in Figure 4A, one would expect an increase in t1/2 ke0 Propofol values from approximately 1 min at 1 yr to 5 min at 16 yr. As suggested by this model, children older than 10 yr may show a propofol hysteresis between plasma and effect-site concentration that is comparable with the 2.2–4.1 min found in adults by using spectral edge frequency or BIS as effect variable.15–17 From a clinical point of view, the time delay to obtain a given anaesthetic effect is important to timely attenuate the response to anticipated changes in noxious stimulation of the patient. In the present study, the time to peak propofol effect-site concentration, that is, Tpeak Propofol, significantly increased with increasing age (Fig. 4B). In the present study, the estimate of ke0 Propofol was affected by the used pharmacokinetic parameters, and these parameters were assumed to be age dependent. Therefore, one may argue whether the age dependence of ke0 Propofol was artificially introduced by the age dependence of the pharmacokinetic parameter set. In this case, one would, however, expect that the age dependencies in pharmacokinetics and pharmacodynamics may compensate each other so that the parameter Tpeak Propofol should show no age dependence. Therefore, the present finding that Tpeak Propofol was also age dependent may be an indication for a true age dependence of propofol pharmacodynamics.
A similar tendency for the age relationship of Tpeak Propofol was also reported by Munoz and colleagues.6 In their study, the predicted Tpeak Propofol was 132 (49) s, which is lower than 186 (72) s found in our investigation. The difference may be explained by different values of ke0 Propofol and pharmacokinetic parameters used for the determination of Tpeak Propofol (0.41 min–1 and the pharmacokinetic model of Kataria in the investigation of Munoz and colleagues and 0.55 min–1 and the pharmacokinetic model of Schuttler and Ihmsen in our study).
The median plasma concentration associated with 50% propofol-induced BIS decrease (EC50 Propofol) was 4.8 µg ml–1. This is slightly higher than an EC50 Propofol of 4.5 µg ml–1 reported for adults during surgical anaesthesia.13 Recently, Park and colleagues18 reported an EC50 Propofol of 5.5 µg ml–1 for successful insertion of laryngeal mask airway in paediatric patients. This also supports previous findings during propofol sedation for successful gastrointestinal endoscopy, in which children also showed higher EC50 Propofol values than adults.19 In contrast, Munoz and colleagues found no significant difference between adults and children in EC50 of propofol for obtaining a BIS value of 50, namely 3.75 µg ml–1 for adults vs 3.65 µg ml–1 in children. Since the predicted concentrations achieved by propofol infusions are dependent on the pharmacokinetic parameters, the different PK models used with these investigations may possibly explain these discrepancies. Furthermore, the absence of noxious stimuli, that is, intubation or surgery, during the investigated period may explain the lower values of EC50 of propofol in the study of Munoz and colleagues.
Possible explanations for the pharmacokinetic/-dynamic differences between children and adults are developmental changes. The apparent volume of distribution at steady state is greater in children than in adults.3 The main factors influencing the propofol distribution are the degree of protein binding and the relative size of body compartments into which the drug is distributed. As both blood fractions are subject to developmental change, the propofol binding capacity may vary with age, and therefore the free drug fraction in central compartment. Clearance of propofol may not increase with increasing free fraction of propofol, since the hepatic extraction of propofol is high and elimination is mainly dependent on hepatic blood flow.20 The size of body compartments is also age dependent. Fat constitutes about 12% of body weight in neonates, and increases through 25% by 6 months to 30% at 1 yr, before it declines for the next 7 yr of age. Also, the central nervous system in neonates has a higher proportion of both extracellular water and fat than it does in adults. This may also explain the immaturity of the EEG described for infants and young children: the dominant awake frequency increases from 5 Hz at 6 months through 6–7 Hz between 9 and 18 months and 7–8 Hz at 2 yr, reaching 9 Hz by 7 yr and 10 Hz by 15 yr, respectively.21
For remifentanil, the median t1/2 ke0 Remifentanil represented 1.0 min and the EC50 Remifentanil was found to be 20 ng ml–1. Similar values for t1/2 ke0 Remifentanil (0.8–1.6 min)22 23 and EC50 Remifentanil (11–20 ng ml–1)13 22 23 were obtained using spectral edge frequency or BIS as effect variable in adults. Munoz and colleagues estimated that a mean remifentanil infusion rate of 0.15 µg kg–1 min–1 was sufficient to block somatic response to skin incision in 50% of the investigated children.24 Assuming a clearance of approximately 68 ml kg–1 min–1 for remifentanil in this age group,5 these infusion rates would be equivalent to a steady-state concentration of 2.2 ng ml–1. In our study, the estimated mean remifentanil concentrations associated with adequate anaesthesia was 4.3 ng ml–1. The difference between the reported remifentanil concentrations may be due in part to different plasma concentrations of co-administered propofol during maintenance of anaesthesia, that is, 3 µg ml–1 in the study of Munoz and colleagues and 2.3 µg ml–1 in the present study. Another explanation for the reported difference may be that our results reflect the remifentanil concentration required to successfully suppress all noxious stimuli of varying intensity present during the clinical course of anaesthesia like intubation, skin incision, abdominal surgery, skin closure, etc., rather than the somatic response to inguinal skin incision as investigated by Munoz and colleagues. Our findings also agree with the results of other investigators who reported propofol plasma concentrations of 2.6–2.8 µg ml–1 supplemented by remifentanil 3.7–7.5 ng ml–1 for adequate anaesthesia in paediatric patients.18 25
For fentanyl, the mean t1/2 ke0 Fentanyl and EC50 Fentanyl found in adults by using the spectral edge frequency as effect parameter was 4.7 min and 7.8 ng ml–1, respectively.26 Using BIS as an effect variable, we estimated a t1/2 ke0 Fentanyl of 3.5 min and an EC50 Fentanyl of 8.6 ng ml–1, which seems to be fairly comparable with adult values. As for remifentanil, age did not significantly correlate with t1/2 ke0 Fentanyl or EC50 Fentanyl in our data set.
Although the assumed additive drug interaction implies that fentanyl and remifentanil may be interchangeable for obtaining a predetermined BIS value, the varying intensity of surgical stimulation during anaesthesia may limit this implication. Specifically, fentanyl was mainly administered during the first half of the study period including intubation and surgical incision, whereas remifentanil was administered throughout the complete study period, also including stimuli of lower intensity like skin closure. Since the EC50 values in this study may be considered as a kind of average concentrations that are capable of maintaining the BIS on half of its observed range, an EC50 Fentanyl of 8 ng ml–1 may not be comparable with an EC50 Remifentanil of 24 ng ml–1 as determined for a BIS value of 51.
The BIS has been used as a continuous and objective measure of hypnotic drug effect.8 CHWSS scores indicated adequate sedation in approximately 70% of observations before induction of anaesthesia. These findings were not correlated with age. The baseline BIS median of 93 compared favourably with previous findings regarding baseline BIS in midazolam premedicated children.27 During noxious surgical or anaesthesia stimuli, adequate general anaesthesia can be clinically defined as prevention of both purposeful movement and haemodynamic changes in HR and MAP greater than 20% of baseline.28 29 In this study, unresponsiveness to continuous surgical stimulation was indicated by a CHWSS score of zero in 97.5% of observations and mean values of HR and MAP within 20% of baseline. Therefore, the maintenance of anaesthesia during surgery in this study was considered as adequate. During this study period, a median BIS of 60 was observed in our paediatric patient collective. The observed BIS in our study agree with other reports regarding BIS values during adequate anaesthesia in adult patients.29
The anaesthetic effect concentrations physiologically determine the electroencephalographic response. However, we assessed how well the observed effect measure, that is, BIS, predicts the underlying state of the patient, which is represented by the drug effect concentration. Therefore, the correlation between BIS and modelled drug effect concentration was calculated using the Pk statistic. Since the EEG observed during surgical anaesthesia can be thought as being modulated not only by the administered anaesthetic agents but also by the sensory input from surgery, the BIS may not perfectly predict the drug effect concentration with a Pk of 1. Thus, the estimated mean Pk of 0.79 may indicate a close relationship between BIS and modelled drug effect concentration. Consequently, the BIS may be used as a measure of anaesthetic drug effect in children older than 1 yr.
For ethical reasons regarding the age of the patients in our study, we did not perform blood sampling because the total volume required for a simultaneous estimation of propofol, fentanyl, and remifentanil plasma concentration from arterial blood samples would be higher than 15 ml per sample. Furthermore, at least five samples within the first 3 min after bolus injection would be required for accurately predicting the plasma concentrations by a pharmacokinetic model.17 Therefore, we determined propofol, fentanyl, and remifentanil concentrations from individual infusion rates by using age-adapted pharmacokinetic models described in the literature. However, this may introduce some kind of error in estimating effect-site concentrations and thus may bias the estimated pharmacodynamic parameters. The result bias caused by simultaneously using three pharmacokinetic models to fit the BIS effect may not necessarily be higher than the result bias that would be caused by using only two pharmacokinetic models. The similarity between our results and tendencies and those obtained in other investigations during clinical anaesthesia with either propofol–remifentanil or propofol–fentanyl may support this assumption.
In summary, the equilibration half-time between plasma and effect-site concentration of propofol was found to increase with increasing age and the concentration of propofol required for half-maximal effect during surgical anaesthesia was slightly higher in our paediatric collective than EC50 Propofol values obtained in adults. The pharmacodynamic profiles of fentanyl and remifentanil seem to be similar to those reported for adults. The BIS showed a close relationship to the modelled effect-site concentration, and therefore, it may serve as a measure of anaesthetic drug effect in paediatric patients older than 1 yr.
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The influence of the covariates age (yr) and body weight BW (kg) were incorporated in the pharmacokinetic models as following:
- Propofol.3
- Cl1=1.44·(BW/70)0.75 litre min–1;
- Cl2=2.25·(BW/70)0.62 litre min–1;
- Cl3=0.92·(BW/70)0.55 litre min–1;
- V1=9.3·(BW/70)0.71·(age/30)–0.39 litre;
- V2=44.2·(BW/70)0.61 litre;
- V3=266 litre.
- Cl1 is the elimination clearance, Cl2 and Cl3 are the intercompartmental clearances, V1 is the volume of the central compartment, V2 and V3 are the volumes of the peripheral compartments.
- Cl1=(90–2.69 · age) · BW ml min–1;
- Vss=(362–10.4 · age) · BW ml;
- k12=0.362 min–1, k21=0.195 min–1, k13=0.013 min–1, k31=0.014 min–1.
- Vss is the volume of distribution in steady-state and kij are the rate constants describing the transfer between the compartments.
- Fentanyl.4
- Cl1=0.01·(BW–19.8)+0.35 litre min–1;
- Cl2=0.82 litre min–1;
- V1=0.43·(BW–19.8)+5.8 litre;
- V2=6.2·(age–6.4)+34.4 litre.
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Footnotes |
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These authors contributed equally to this work. 
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