1 Department of Anaesthesiological, Surgical and Emergency Sciences, Second Service of Anaesthesia and 2 Department of Experimental Medicine, Second University of Naples, Naples, Italy
* Corresponding author. E-mail: micheleiannuzzi{at}libero.it
Accepted for publication December 16, 2004.
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Abstract |
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Methods. Twenty unpremedicated patients undergoing elective major abdominal surgery were recruited. A target-controlled infusion of propofol was administered using Schneider's pharmacokinetic model. The propofol infusion was set at an initial site effect concentration of 1.0 µg ml1 and increased by 1.0 µg ml1 steps every 4 min up to 6.0 µg ml1. A 4-min interval was chosen to ensure that steady-state effect-site concentrations were obtained. Propofol site effect concentrations and BIS and SE values were recorded at loss of verbal contact (LVC) and loss of consciousness (LOC). Population values for predicted effect-site concentrations at the clinical endpoints were estimated and correlated with BIS and SE values.
Results. For LVC, the effect-site concentration for 90% of patients was 1.1 (1.13.2) µg ml1 and for LOC it was 2.8 (2.85.65) µg ml1. LVC occurred in 90% of patients at a BIS value of 70.2 (70.290.2) and an SE value of 60.3 (60.375.5), and LOC occurred at a BIS value of 38.2 (38.270.4) and an SE value of 42.2 (42.260.4).
Conclusions. LVC and LOC occurred within a defined range of predicted effect-site concentrations. SE had a smaller range than BIS and greater correlation with effect-site concentration and may be more useful than BIS in predicting both LVC and LOC.
Keywords: anaesthesia, depth ; anaesthetics i.v. ; awareness ; entropy ; monitoring, bispectral index ; pharmacokinetics ; pharmacology
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Introduction |
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The aim of this study was to determine which value of predicted effect-site propofol concentration, Bispectral Index (BIS) or electroencephalographic state entropy (SE) best predicted loss of verbal contact (LVC) and loss of consciousness (LOC) during steady-state conditions. SE is an alternative approach for assessing depth of anaesthesia which quantifies the degree of spatial and temporal integration of cerebral neuronal activity using entropy principles.5 A computer-controlled infusion pump which delivers propofol using different pharmacokinetic models and displays the predicted and effect site propofol concentrations is now commercially available (Base Primea; Fresenius-Vial, Brezins, France). We predicted effect-site concentrations of propofol at LVC and LOC and recorded BIS and SE at the same time.
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Methods |
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Target-controlled infusion of propofol was administered using the Base Primea Infusion System, which uses Schneider's pharmacokinetic model.6 This system displays predicted effect-site concentration (an estimate of the drug concentration at its site of action). The target effect-site concentration of propofol was computed to yield a time to peak effect of 1.6 min,7 which has been confirmed clinically.8 The propofol infusion was started to provide an effect-site concentration of 1.0 µg ml1 and increased stepwise by 1.0 µg ml1 every 4 min up to 6.0 µg ml1. A 4-min interval was chosen to assure that steady-state effect-site concentrations were obtained.9 At each step, an observer assessed the level of sedation using an alertness/sedation scale.10 11
BIS, SE and predicted effect-site concentrations and predicted blood concentrations of propofol were recorded at LVC and LOC.
A quantal response model (probit analysis) was used to calculate EC05, EC50 and EC95 at each endpoint, based on predicted effect-site concentration and the probability of LVC and LOC was calculated using logistic regression. The curves were fitted using the likelihood ratio goodness-of-fit test.
The standard logistic model for propofol concentrations using BIS and SE is:
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The ability of BIS and SE to describe LVC and LOC was evaluated using the prediction probability (PK). PK represents a measure of performance by which an indicator can predict correctly the rank order of an arbitrary pair of distinct observed anaesthetic depths. An ideal anaesthetic depth indicator is described by a monotonically decreasing or increasing function. The prediction probability PK has a value of 1 when the indicator predicts the observed anaesthetic depth perfectly and the correlation is positive. PK has a value of 0 when the indicator predicts the observed anaesthetic depth perfectly and the correlation is negative. PK has a value of 0.5 when the indicator predicts no better than chance.
Data were computed by the Pk MACRO datasheet for Microsoft Excel. Analysis was performed with SPSS Software Version 10.1 for Windows XP and GraphPad Prism Software Version 6.0 for Windows XP (GraphPad Software Inc., San Diego, CA, USA).
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Results |
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Induction of anaesthesia was smooth in all cases, although six patients (30%) reported pain during injection of propofol. Haemodynamic variables remained stable and no significant hypotension occurred. Heart rate, mean arterial blood pressure and were recorded at baseline, LVC and LOC (Table 1).
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At the time of LOC, the effect-site EC05, BIS and SE were respectively 2.8 µg ml1 (2.662.94), 70.4 (66.873.9), 60.4 (57.363.4); the effect-site, BIS and SE were respectively 4.14 µg ml1 (3.944.34), 59.7 (56.765.6), 50.3 (47.752.8); the effect-site EC95, BIS and SE were 5.65 µg ml1 (5.375.93), 38.2 (36.240.1) and 42.2 (40.143.3).
No gender differences were observed at any endpoint, either for BIS or SE (2
0.05).
The ability of the indicators to predict LVC and LOC are presented as PK values. The PK values of BIS for LVC and LOC were 0.90 (0.02) and 0.82 (0.13) respectively and those of SE for LVC and LOC were 0.95 (0.04) and 0.94 (0.03). PK values did not differ significantly (Fig. 1). Good correlations between BIS and the predicted effect-site concentration of propofol (r2=0.771) and between SE and the predicted effect-site concentration of propofol (r2=0.844) were noted.
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Discussion |
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Two previous studies12 17 have evaluated the relationship of predicted effect-site propofol concentrations to clinical endpoints. They tested Caucasian and Chinese populations and found similar results. The EC50 for effect-site propofol concentration at LOC was 2.8 and 2.7 µg ml1 in the Caucasian in Chinese populations respectively and the EC95 was 4.1 and 3.8 µg ml1. These two studies found large differences in the predicted blood concentrations because of the different rates at which propofol was given in the two studies. However, the predicted effect-site values were similar in the two studies. We believe that this reinforces the value of the effect-site rather than the blood concentration in determining the pharmacodynamic effects of propofol in the individual patient. In our study, we tried to achieve a steady-state concentration of propofol at the effect site, to better determine the pharmacodynamic effects in the individual. We also believe that in our study the higher EC90 values for loss of consciousness were due to the achievement of steady-state conditions and the pharmacokinetic model we used.
For a cerebral monitor to be reliable in assessing the depth of anaesthesia, it should display a strong correlation between the observed variable (e.g. BIS, SE) and the patient's state of consciousness, independent of the anaesthetic drugs and with minimal interpatient variability. In a recent editorial, Kalkman and Drummond18 suggested that these conditions have not yet been achieved with any of the available cerebral monitoring devices.
In this study, LVC occurred in 90% of patients at a BIS value of 70.2 (70.290.2) and an SE value of 60.3 (60.375.5) and LOC at a BIS value of 38.2 (38.270.4) and an SE value of 42.2 (42.260.4). The range for SE is smaller than that of BIS, and SE showed a better correlation with propofol predictedsite concentrations (r2=0.84).
In this small study using a specific anaesthetic technique and pharmacokinetic model, SE appeared to be more useful than BIS in predicting both LVC and LOC. However, further studies using the SE monitor in larger surgical populations are needed to determine its future role in clinical practice.
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References |
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