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PEDIATRIC ANESTHESIOLOGY

The Relationship Between Bispectral Index and Propofol During Target-Controlled Infusion Anesthesia: A Comparative Study Between Children and Young Adults

Agnes Rigouzzo, MD^*, Laure Girault, MD^*, Nicolas Louvet, MD^*, Frederique Servin, MD, PhD, Tom De-Smet, Veronique Piat, MD^*, Robert Seeman, MD^*, Isabelle Murat, MD, PhD^*, and Isabelle Constant, MD, PhD^*

From the *Service d'Anesthésie Pédiatrique, Hôpital Armand Trousseau, Service d'Anesthésie, Hôpital Bichat, AP-HP, Paris, France; and Demed Engineering, Temse, Belgium.

Address correspondence and reprint requests to Pr Isabelle Constant, Service d'Anesthésie, Hôpital d'enfants Armand Trousseau, AP-HP, 26 av. du Dr Arnold Netter, 75571 Paris cedex 12, France. Address e-mail to isabelle.constant{at}trs.aphp.fr.

Abstract

BACKGROUND: In this prospective study, we compared the relationship between propofol concentrations and bispectral index (BIS) in children versus young adults anesthetized with target-controlled infusion (TCI) of propofol.

METHODS: Forty-five prepubertal subjects (children) and 45 postpubertal subjects (adults) were studied. All patients were anesthetized with TCI of propofol, based on the Kataria et al.'s model for children and on the Schnider et al.'s model for adults. All data from the BIS and the TCI system were continuously recorded using Rugloop software. Remifentanil was continuously administered throughout the study (0.25 µg · kg^–1 · min^–1). In all patients, after the end of surgery, a 12-min period with a stable target plasma concentration (Ct) of propofol, randomly assigned at 2, 3, 4, 5, and 6 µg/mL, was performed. In addition, in most of the patients, another 12-min period was performed during which the BIS was targeted at 50 ± 5. After each 12-min steady-state period, the Ct and BIS were noted and the plasma concentration of propofol was measured (Cm). The Ct and Cm corresponding to half maximal effect (BIS₅₀) was determined by the Hill equation, and by targeting BIS at 50.

RESULTS: In children, as in adults, BIS values were highly correlated with the corresponding Ct or Cm of propofol following classical E_max dose–response curves. The ECt₅₀ and the ECm₅₀, derived from the dose–response curves, were higher in children than in adults: ECm₅₀: 4.0 (3.6–4.5) µg/mL vs 3.3 (3.0–3.7) µg/mL [mean (95% CI)], P < 0.001; as well were the Ct and Cm clinically obtained when BIS was targeted at 50 (Cm₅₀: 4.3 ± 1.1 µg/mL vs 3.4 ± 1.2 µg/mL, (mean ± sd) P < 0.05, children versus adults). Cm was generally under-estimated by the Ct, and the bias was higher in children than in adults: 2.6 ± 2.6 µg/mL vs 1.7 ± 1.6 µg/mL (P = 0.05).

CONCLUSIONS: The good relationship between propofol and BIS demonstrated in children as in adults suggested a slightly lower sensitivity to propofol in children. As the predictability of plasma propofol concentrations with the classical pharmacokinetic/pharmacodynamic models is limited in children, a cerebral pharmacodynamic feedback, such as BIS, may be useful in this population.

Because of the easy administration and rapid elimination of inhaled anesthesia, IV anesthesia is infrequently used in children. Nevertheless, propofol anesthesia may present some clinical advantages; indeed, compared with volatile anesthetics, propofol anesthesia in children, as in adults, is associated with less postanesthetic nausea and vomiting1 and with a decrease of emergence agitation episodes.2,3 However, as childhood is a period of multiple physiological maturations, the pediatric population is characterized by a large interindividual variability of pharmacokinetic (PK) parameters, leading to uncertain predictability of PK models.4 Although, in adults, several studies have measured the plasma concentration of propofol necessary to produce hypnosis,5–7 there are few comparable data in children. Consequently, adequate propofol dosing is often uncertain, leading to possible over or under-dosage potentially responsible for prolonging delay of recovery or perioperative awareness.

A cerebral pharmacodynamic feedback may help the anesthesiologist to adapt the target concentration (Ct) of propofol and to blunt interindividual variability. The electroencephalogram (EEG)-derived bispectral index (BIS), which is a reliable predictor of propofol concentration in the brains of adults, may fulfill this role. Regarding its ability to correlate with depth of anesthesia in children, it has been demonstrated that BIS values follow depth of sevoflurane anesthesia.8–11 However, regarding IV anesthesia, there are few data on the usefulness of the BIS monitor in children anesthetized with propofol.

After assessing the accuracy of PK models, with a comparison between measured (Cm) and predicted concentrations of propofol, we investigated the BIS to propofol plasma concentration relationship in children versus young adults using two approaches: (1) nonlinear regression among a range of propofol concentrations generated by target-controlled infusion (TCI) and BIS recorded at equilibrium, and (2) comparison of propofol concentrations corresponding to a targeted BIS of 50.

METHODS

Patients and Study Design
Patients
The study was approved by our local Ethics Committee (CPP Saint-Antoine, Paris, France), and written informed consent was obtained from children and their parents or from the adult patients.

Ninety patients ranging from 6 to 32 yr of age, ASA 1 or 2, scheduled for middle ear surgery, were included in the study between January 2005 and February 2006. They were allocated to the prepubertal group (group children, n = 45) or to the postpubertal group (group adults, n = 45) according to the clinical observation of external secondary sex characteristics (Tanner Stage 4).12

Patients were excluded if they received drugs preoperatively that altered the EEG.

Study Design
All patients were premedicated with oral hydroxyzine (1 mg/kg) 1 h before surgery. Before induction, a venous catheter was placed for fluid infusion and drug administration. After induction, a second venous catheter was placed on the contralateral arm for blood sampling.

The TCI system consisted of a Cardinal-Alaris infusion pump driven by Rugloop software.13,14 In prepubertal patients (group children), TCI was based on Kataria et al.'s model, a weight-proportional model with age as an additional covariate for the rapid distribution compartment (V2); this model was calculated in children from 3 to 10 yr and included an increased volume of distribution and clearance.15 On the other hand, to be as adequate as possible in our population of young adults (group adults), we used the Schnider et al.'s model,7 which integrates age and lean body mass as covariates.

In all patients, a standardized induction was performed with a plasma Ct of propofol of 6 µg/mL. Remifentanil was started at loss of eyelash reflex at 0.25 µg · kg^–1 · min^–1 and was kept constant throughout the study.

A single dose of atracurium (0.5 mg/kg) was administered before tracheal intubation.

From tracheal intubation to the end of surgery, TCI was set to reach and maintain Ct of propofol corresponding to a BIS between 40 and 60 using Rugloop Software, as described above.

After surgery, a steady-state period was obtained in all subjects: this period corresponded to a 12-min period with a stable Ct, the latter being randomly assigned among 2, 3, 4, 5, and 6 µg/mL. In addition, when it was possible according to operating room conditions (in 28 of 45 children and 24 of 45 adults), a second 12-min period during which BIS was maintained stable at 50 (±5), was performed.

At the end of each steady-state period, a venous blood sample was drawn to measure the propofol concentration (Cm).

Determination of Propofol Concentrations
Blood samples were immediately centrifuged and the plasma stored at –40°C until analysis. Quantification of propofol was performed by a high-performance liquid chromatographic technique as described by Knibbe et al.16

Data Acquisition
In addition to standard monitoring, the disposable BisSensor (Aspect Medical Systems) was applied to the forehead of each patient before induction of anesthesia and was connected to a BIS monitor CardiocapII (Datex-GE). The adult sensor was used for all patients. The skin was prepared to ensure low impedance and good signal quality. The smoothing window was set at 15 s.

From baseline to tracheal extubation, all data were continuously recorded (0.2 Hz) and stored, using Rugloop II software loaded into a dedicated microcomputer. These data included (1) standard monitoring, such as noninvasive arterial blood pressure, heart rate, peripheral oxygen saturation, expired gases, (2) infusion parameters with plasma concentrations, and (3) BIS and associated values, such as index of signal suppression ratio and electromyograph quality.

Data Analysis
A prospective power analysis was done before initiation of the trial and we calculated the sample size according to an expected BIS difference of 20% between adults and children at each steady-state period. We estimated than nine subjects were required per group ( = 0.05 and β = 0.8), 45 prepubertal children and 45 young adults. The first step of the analysis was to investigate the predictability of the blood concentrations of propofol using the PK models, by comparing the Ct and the corresponding Cm. Agreement between Ct and Cm was assessed using methods described by Bland and Altman.17 The bias was calculated as the mean of differences between concentrations, and the limits of agreement (95% confidence interval) were calculated and graphically represented as follows: Bias ± 1.96 sd.

The second step was to investigate the relationship between BIS and propofol concentrations using two approaches:

1. Nonlinear regression calculated on steady-state periods at randomized Ct of propofol.
   At each 12-min steady-state period corresponding to a randomized Ct of propofol, the average value of BIS calculated on the last minute of the steady-state period and the Cm of propofol measured on simultaneous blood sample were noted for data analysis. These parameters were expressed as mean ± sd.
   The relationship between BIS and propofol concentrations was assessed using nonlinear regression between BIS and Ct or Cm. These data were fitted to a dose–response curve using GraphPad Prism version 4.03 for windows, GraphPad Software, San Diego, CA. A semilogarithmic plot of propofol concentrations versus BIS was generated, and data were fit to an inhibitory sigmoid E_max model:
   
   

   
   In accordance with the clinical use of BIS, E₀ was constrained to 98 and E_max was constrained to 0. The HillSlope () was variable and optimized to get the best fit. The ECt₅₀ and the ECm₅₀ was the propofol Ct (ECt₅₀) and Cm (ECm₅₀) corresponding to half-maximal effect (a BIS of 50), and these values were estimated, with 95% confidence intervals for each group.
   

2. Clinical determination of Ct corresponding to a BIS of 50, under steady-state conditions.
   In addition, the Ct₅₀ and the Cm₅₀ were also clinically determined from the Ct and the measured Cm obtained during the last minute of the 12-min period during which the BIS was maintained stable at 50 ± 5.
   

Differences between children and adults were investigated using unpaired t-test (ECt_50, ECm₅₀, Ct₅₀, Cm₅₀) and nonparametric test (Kolmogorov–Smirnov) for BIS at each randomized Ct (Statview version 4.57 for Windows, Abacus Concepts Inc., Berkeley, CA).

A value of P < 0.05 was considered as significant.

RESULTS

Demographic Data
The demographic data are presented in Table 1. Forty-five steady-state periods at randomized Ct were obtained in each group. In addition, 28 (group children) and 24 (group adults) steady-state periods were recorded at BIS 50 ± 5.

The propofol concentration was measured on 142 venous blood samples taken during the last minute of each steady-state period.

Comparison of Plasma Cm Versus Plasma Ct of Propofol
In children as well as in adults, the Cm of propofol was always higher than the Ct predicted by the PK models of Kataria et al. and Schnider et al., respectively. The Bland and Altman plot (Fig. 1) shows in detail the deviation of Ct from the Cm of propofol. The bias was higher in children than in adults: 2.6 ± 2.6 µg/mL vs 1.7 ± 1.6 µg/mL, P = 0.05, respectively. The pediatric model had an increasing error as the concentration increased. At higher concentrations, the error approached almost 100%.

View larger version (21K): [in this window] [in a new window]   Figure 1. Bland and Altman plot showing the deviation of the target concentration (Ct) from the measured concentration (Cm) of propofol in children (top) and adults (bottom). The full lines indicate the bias and the areas between the limits of agreement are grayed.

Relationship Between BIS Values and Propofol Concentrations at Equilibrium
The mean values of BIS recorded at baseline were similar in both groups (95.7 ± 3 in group children versus 95.2 ± 5 in group adults) and decreased with increasing Ct of propofol (Table 2).

Figure 2 illustrates the relationship between BIS and Ct or Cm of propofol, showing E_max dose– response curves calculated in children and in adults. The BIS decreased monotonically in both children and adults as the concentrations of propofol increased. The ECt₅₀ and the ECm₅₀ of propofol corresponding to half-maximal effect (BIS₅₀) derived from the E_max dose–response curves were higher in children than in adults. The data relating to the nonlinear regressions are shown in Table 3.

View larger version (12K): [in this window] [in a new window]   Figure 2. Nonlinear regression curves (Emax model) between bispectral index (BIS) values and measured concentrations (Cm) of propofol (a) or target concentrations (Ct) of propofol (b) in children (open circles and dotted line) and adults (solid circles and full line). In each group, the nonlinear regression curves were calculated from the 45 steady-state period corresponding to a randomized Ct of propofol. The differences between children and adults were statistically significant (see text).

Propofol Concentrations at BIS Targeted to 50
Propofol concentrations during the steady-state period, during which the BIS was maintained at BIS₅₀ (Ct₅₀ and Cm₅₀), were close to those derived from the dose–response curves (ECt₅₀ and ECm₅₀). The differences between children and adults previously calculated from the E_max curves were confirmed with these clinical data (Ct₅₀: 3.0 ± 0.7 µg/mL vs 2.5 ± 0.6 µg/mL; Cm₅₀: 4.3 ± 1.1 µg/mL vs 3.4 ± 1.2 µg/mL, P < 0.05, children versus adults) (Fig. 3).

View larger version (12K): [in this window] [in a new window]   Figure 3. Values of target concentrations (Ct) (top) and measured concentrations (Cm) (bottom) plotted against bispectral index (BIS), when the BIS was targeted to 50 (Ct50 and Cm50), in children (open circles) and in adults (solid circles). The open (children) and solid (adults) stars illustrated the mean values (sd) of Ct50 and Cm50.

DISCUSSION

Using TCI of propofol in adults and children, this study investigated the relationship between cortical EEG effects of propofol assessed by BIS, and concentrations of propofol at equilibrium either estimated by the TCI system (Ct) or measured in the plasma (Cm). The first finding was that the predictability of the plasma concentration by the PK models was limited, especially in children. The second finding, drawn from the very good relationship between BIS and propofol concentrations, was that the requirement of propofol was higher in children compared with adults to reach the same level of hypnosis.

As the Ke0 was lacking for Kataria et al.'s model in our study design, we chose to target plasma concentrations (Ct) of propofol. We generated a range of propofol concentrations using TCI with Ct maintained for 12 min to approach steady-state conditions. It could be calculated that the time was sufficient for plasma propofol to equilibrate with the brain: indeed equilibration of the effect site with the blood concentration takes 4–5 times the ke0 half-life T_1/2(ke0), where the T_1/2(ke0) = 0.693/ke0, which gives 7.6 min for Schnider et al.'s model and 8.5 min for Kataria et al.'s model implanted with the published Ke0 determined in children using auditory evoked potentials.18

Despite these pseudo steady-state conditions, our results showed an important bias between Ct and Cm of propofol; moreover, the pediatric model demonstrated increasing error as the concentration increased. Kataria et al.'s model is frequently cited in studies investigating total IV anesthesia in children. However, to our knowledge, there is no study assessing the accuracy of this model in providing propofol blood concentrations. Our results suggest that the predictability of Kataria et al.'s model is limited, especially at high propofol concentrations. However, the poor performance of this pediatric model may be explained, at least in part, by the mean age of our population, which was at the upper limit of the range investigated by Kataria et al. As the volume of distribution decreases with age, an over-estimation of this volume might have been responsible for the under-estimation of Cm observed in our study. However, this under-estimation also applied to our adult population, and we cannot eliminate the possibility that coadministration of remifentanil with propofol might have affected the PK parameter sets.19,20

In the pediatric populations, the interindividual variability of anesthetic requirements is frequently a function of growth and maturation. Thus, the PK and the pharmacodynamic effects of propofol are difficult to predict in a given child, leading to possible inaccurate doses associated with risk of over or under-dosage. Cerebral pharmacodynamic feedback may help the anesthesiologist to adjust propofol administration. BIS, which provides a single number resulting from an algorithm calculated from EEG parameters, may fulfill this role. BIS has been demonstrated to correlate with clinically assessed sedation in adults receiving IV and volatile anesthetics.21 However, some maturational changes of EEG are described in childhood, and moreover, there are very few data on the EEG effects of anesthesia in children. Thus, the reliability of BIS has been questioned in children because of the lack of pediatric data in the BIS database.22 Most studies assessing the usefulness of BIS in children older than 2 yr have investigated the relationship between BIS and expired concentration of volatile anesthetics.8,9 Compared with volatile anesthetics, propofol has a different EEG profile. In adults receiving propofol anesthesia, several authors have demonstrated a good correlation between BIS and target-controlled concentrations of propofol.21,23,24 Unfortunately, the effect of propofol anesthesia on BIS has been poorly investigated in children.

Using TCI to reach and maintain a given state of anesthesia, we studied the relationship between BIS and propofol concentrations. Considering the limited predictability of PK models as previously demonstrated, we chose to focus on Cm to investigate the ability of BIS to determine the depth of propofol anesthesia. Interestingly, we demonstrated that, in children as in young adults, BIS fits the classical sigmoidal dose–response curve very well, when plotted against propofol Cm. Our results confirm the usefulness, in children as in adults, of targeting propofol anesthesia with cerebral pharmacodynamic feedback such as BIS monitoring.

Fitting E_max, dose–response curves allows determination of the concentration that leads to 50% maximal response (EC₅₀). Using this method, we demonstrated that children required higher propofol concentrations than adults to achieve the same BIS end-point. Moreover, these statistical results were clinically validated by targeting a pharmacodynamic end-point corresponding to a BIS of 50. Both calculations of the ECm₅₀ gave a difference between adults and children between half and 1 µg/mL. This difference in terms of propofol administration in the clinical setting may be relatively small. EEG differences between children and adults might explain our results; however, this is unlikely, because the BIS values observed at baseline were similar in the two populations and the transition from childhood to puberty is not associated with striking changes in EEG.25 In agreement with our results, an increase of the median effective concentration of propofol required for esophagogastroduodenoscopy in children compared with adults has been suggested.26

On the other hand, Munoz et al. recently found that the estimated concentration of propofol corresponding to a BIS of 50, determined by the up-and-down method, was similar in children (3–11 yr) and in adults (33–44 yr).27 However, in that study, the PK parameters used for TCI, Paedfusor for children and Marsh for adults, differed markedly from those used in our study. These differences in PK models may have influenced the resulting predicted concentrations of propofol. Unfortunately, these authors did not provide any plasma Cm, which makes it difficult to compare their work with ours.

Our results suggest that the increased requirement for propofol in children involves a pharmacodynamic effect in addition to the PK effect. This hypothesis is consistent with the influence of age on the sensitivity to propofol, already suggested in adults, by showing that using the same clinical or EEG profile target, the required propofol concentration decreases with increasing age.7 This influence of age has been demonstrated during sevoflurane anesthesia; indeed, the expired sevoflurane concentration at BIS₅₀ has been found to decrease with increasing age.9

A limitation of our study is that remifentanil was continuously administrated throughout, with a similar infusion rate in the two populations. Thus, the differences of propofol requirement between children and adults may have been due to differences of the pharmacodynamic effect of remifentanil between the two populations. Indeed, Munoz et al. have demonstrated that, during total IV anesthesia with propofol, children require a remifentanil infusion rate almost twofold higher than adults to block the somatic response to skin incision.28 However, our study design differed markedly from this previous study; indeed, our data result from stationary periods recorded without any surgical stimulation, and our end-point was not a somatic response but BIS, a measure of the hypnotic cortical effect of anesthesia. The addition of remifentanil to propofol anesthesia has few consequences on both the EEG and BIS.29 Wang et al., using BIS targeted at 50, has demonstrated that infusion of remifentanil did not reduce propofol requirements in unstimulated, anesthetized adult patients.30 Thus, it is probably unlikely that a different influence of remifentanil in children compared with adults, regarding the hypnotic interaction with propofol, could explain the increase of propofol requirement in children found in our study.

CONCLUSION

Using TCI to generate a range of propofol concentrations at equilibrium, we demonstrated a good relationship between BIS and propofol in children and adults and a slightly higher requirement of propofol in children to maintain adequate hypnosis during anesthesia. These results demonstrate the usefulness of targeting propofol anesthesia with cerebral pharmacodynamic feedback, such as BIS in a pediatric population in which the interindividual variability of anesthetic requirement is large and the predictability of PK model limited.

Footnotes

Accepted for publication November 28, 2007.

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