Division of Anaesthesiology, Geneva University Hospitals, CH-1211 Geneva 14, Switzerland*Corresponding author
Accepted for publication: October 24, 2000
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Abstract |
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Br J Anaesth 2001; 86: 5237
Keywords: interactions (drug); anaesthesia, depth; measurement techniques, bispectral index; equipment, target-controlled infusion device; analgesics opioid
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Introduction |
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The bispectral index (BIS) has been proposed as a measure of the effects of anaesthetics on the brain.4 5 Several authors have demonstrated that a good relationship exists between the BIS and blood concentration of propofol,68 but, during propofol anaesthesia, increasing doses of alfentanil or additional administration of nitrous oxide do not affect the BIS value.9 10 Several authors, using different anaesthetic techniques, examined the usefulness of the BIS as a measure of the depth of anaesthesia.1113 Its reliability for the measurement of the hypnotic effect of propofol in association with different opioids has not yet been established definitively. We hypothesised that the effect-site concentration of propofol required for loss of consciousness (LOC) depends also on the simultaneous administration of opioids. The aim of this study was to measure the influence that analgesic concentrations of opioids had on the predicted effect-site concentration of propofol with relation to LOC and BIS values during induction of anaesthesia.
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Patients and methods |
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After insertion of a peripheral venous line for fluid and drug administration (with an anti-reflux system (Abbott; Donegal, Ireland)) the following measurements were taken: arterial pressure, heart rate, SpO2, BIS and sedation score (Observer Assessment of Alertness/Sedation Scale (OAA/S) (Table 1). The opioids or placebo were administered in a double-blind fashion to obtain preselected effect-site concentrations of 1.5 ng ml1 for fentanyl (Janssen-Cilag AG, Baar, Switzerland), 100 ng ml1 for alfentanil (Janssen-Cilag), 6 ng ml1 for remifentanil (Glaxo-Wellcome AG, Bern, Switzerland) and 0.2 ng ml1 for sufentanil (Janssen-Cilag). The anaesthetist who performed all clinical observations was blinded. A second, independent, anaesthetist was in charge of the opioid infusion according to the randomization. The opioid infusion was administered using a Graseby 3400/UK infusion pump and a Dell laptop computer using Stanpump software (Stanford University, Anesthesiology Service, Palo Alto, CA, USA) to control the effect compartment. The kinetic model was not weight-adjusted for fentanyl and alfentanil,14 but was weight-adjusted for sufentanil15 and remifentanil.16 The target effect-site concentrations of opioids were maintained stable for 10 min before administration of propofol. Target-controlled infusion of propofol was started to increase predicted plasma concentration stepwise to 1, 2 and 4 µg ml1 using a Diprifusor/Graseby 3500 UK pump with the kinetic set of Marsh for propofol. This device continuously displays the predicted effect-site concentration. At each step, the target plasma concentration was maintained for 12 min to permit equilibration with the effect site. This steady state was maintained for 2 min for each concentration. The BIS (three independent measurements), sedation score and haemodynamic variables were recorded during each steady-state period.
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Statistical analysis
Statistical analysis was performed using GraphPad Prism v.2.01, Peakfit v.2.0 (Jandel Scientific Software) and SPSS v.6.1 for Windows 95. General logistic regression models (with limits of maximum and minimum fixed at 0 and 100, respectively) were used to analyse the correlation for the LOC. We determined the BIS value and the effect-site concentration of propofol at which 50% of patients lost consciousness (BIS50 and EC50, respectively) for each group. The curve fit graph of the logistic regression displayed the 95% confidence interval for the fit, which was used to estimate the standard error of the predicted estimates for BIS50 and EC50. Prediction probability (Pk) was calculated using Smiths definition.17
Differences in patient characteristics were analysed using t-test (for age, weight and height) or 2 test (for male female distribution). The correlation coefficient for the relationship between sedation score and BIS was calculated for each group using a linear regression model. BIS values and haemodynamic variables were analysed within the groups, using analysis of variance (ANOVA) for repeated measurements.
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Results |
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The relationship between sedation score and effect-site concentration of propofol is illustrated in Figure 1. Patients who received an opioid were more sedated at 1 and 2 µg ml1 effect-site concentration of propofol than those receiving a placebo. In all groups, patients lost consciousness before the effect-site concentration of propofol reached 4 µg ml1. At LOC, BIS values were higher in all opioid groups than those in the placebo group (resulting particularly in higher BIS50 values, Table 3).
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Oxygen saturation remained >95% and stable during the procedure. Episodes of apnoea (defined as respiratory arrest for >15 s) were observed in all opioid groups (3/14 with alfentanil, 3/14 with sufentanil, 4/13 with fentanyl and 11/14 with remifentanil) but not in the placebo group. These episodes of apnoea were transitory and responded well to verbal stimulation. None of the patients had to be ventilated before LOC.
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Discussion |
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In the present study, both EEG and clinical evaluation were used to measure sedation and hypnosis. The BIS is generally considered as a reliable method for measuring the state of consciousness,11 particularly when propofol is administered.12 The BIS can provide reliable monitoring for sedation, hypnosis or even for predicting LOC, especially when a single drug is used, such as propofol, midazolam, isoflurane6 18 or sevoflurane.19
The administration of opioids together with anaesthetics may substantially change the predictive value of the BIS. As Sebel and colleagues11 have pointed out, the adjunctive use of an opioid analgesic confounds the use of the BIS as a measure of anaesthetic adequacy when movement response to skin incision is used as the primary endpoint. Sakai and colleagues20 showed that fentanyl pretreatment potentiated the effect of propofol for achieving the hypnotic endpoint. They found higher BIS and lower propofol concentrations in the propofol + fentanyl group compared with the propofol group at unresponsiveness to verbal commands, loss of eyelash reflex and response to mechanical nasal membrane stimulation. However, others21 found that remifentanil, when added to propofol, did not affect BIS before stimulation.
Iselin-Chaves and colleagues9 studied the effect of increasing doses of alfentanil together with propofol on BIS and LOC. They found that alfentanil did not significantly affect BIS50 or propofol plasma concentration (Cp50) values required for LOC. However, in a recent study,22 they clearly showed that alfentanil decreased the propofol concentration required for LOC. Unfortunately, BIS values were not reported.
It is important to emphasize that the results of the present study are based on predicted effect-site concentrations of propofol and opioids. It is well known that propofol pharmacokinetics can be altered by alfentanil2 and remifentanil.25 We chose not to measure the plasma concentrations of propofol for two reasons. Firstly, in everyday clinical practice with target-controlled infusion devices, predicted rather than measured plasma and effect-site concentrations are used. Secondly, the target-controlled infusion device is not only readily available commercially, but has been proven to be a reliable method of propofol administration for induction and maintenance of anaesthesia. The analgesic concentrations of opioids used in this study correspond to those usually used during induction of anaesthesia for minor surgery. The results of this study show that addition of an opioid to induction with propofol results in LOC at higher BIS50 and lower EC50 values. One possible explanation for this may be that opioids, in the analgesic concentrations used in this study, produce minimal electrophysiological alterations on the cerebral cortex. To induce EEG changes, higher concentrations are necessary. Indeed, Shafer and colleagues estimated the IC50 (steady-state concentration that produces 50% of the maximal (observed drug effect) of fentanyl at 7.8 ng ml1, of alfentanil at 480 ng ml1 and of sufentanil at 0.69 ng ml1 for the appearance of EEG depression.23 Another possible reason why the BIS did not reveal the interaction between propofol and an opioid may be that non-cortical structures that are undetectable by EEG, such as the locus coeruleus, are involved in the mechanism of drug effect.24
We found statistically significant differences among the opioid groups (Table 3). There are three possible reasons for this. Firstly, the opioid concentrations used in this study were based on data published in the literature,23 25 and there is no evidence that the concentrations were equipotent. Secondly, we did not measure plasma concentrations of propofol, so we do not know how the pharmacokinetics of propofol were modified by different opioids. Thirdly, there may be differences in the hypnotic properties among the opioids used in this study.
There is the potential for bias in the assessment of sedation and LOC in the present study because opioids may induce thoracic rigidity or apnoea. This clinical effect of opioids and their analgesic action may interfere with the evaluation of sedation and LOC. The sedation score used here is valid and easy to perform.26 The OAA/S was evaluated by the same anaesthetist for all patients, to avoid bias. To reduce the influence of interindividual variability in the biophase equilibration of the drugs, all measurements were made at steady-state effect-site concentrations of propofol and opioids.
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Acknowledgements |
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References |
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