1 University of Glasgow Department of Anaesthesia, Glasgow Royal Infirmary, Glasgow G31 2ER, UK. 2 Department of Anaesthesiology, University of Ulm, Steinhoevelstrasse 9, D-89075 Ulm, Germany
LMA® is the property of Intavent Ltd.
Accepted for publication: January 20, 2003
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Abstract |
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Methods. Patients were allocated randomly to receive remifentanil to a target blood concentration of 2 ng ml1 (low), 4 ng ml1 (medium), or 8 ng ml1 (high), administered by target-controlled infusion (TCI). After equilibration, propofol TCI was commenced in closed-loop control, with auditory evoked potentials (AEPex) as the input signal, aiming for an AEPex of 35. This was to ensure a comparable and unbiased level of anaesthesia in all patients.
Results. We found a dose-dependent decrease in propofol requirements with increasing remifentanil concentrations. The mean (95% CI) propofol target blood concentration during adequate anaesthesia was 4.96 (3.856.01) µg ml1 in the low, 3.46 (2.963.96) µg ml1 in the medium, and 3.01 (2.203.38) µg ml1 in the high group. There was no significant difference when recovery end points were achieved between the groups. Cardiovascular changes were moderate, but most pronounced in the high concentration group, with a decrease in heart rate of 21% compared with baseline. The mean calculated effect site propofol concentration at loss of consciousness was 2.08 (1.852.32) µg ml1, and at recovery of consciousness was 1.85 (1.682.00) µg ml1.
Conclusions. This study confirms a synergistic interaction between remifentanil and propofol during surgery, whereas the contribution of remifentanil in the absence of stimulation seems limited. In addition, our results suggest that the propofol effect site concentration provides a guide to the value at which the patient recovers consciousness.
Br J Anaesth 2003; 90: 6239
Keywords: anaesthetics i.v., propofol; analgesics opioid, remifentanil; equipment, circuits; monitoring, evoked potential; drug delivery, infusion
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Introduction |
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Previous studies investigating the interaction between propofol and opioids have used patient movement or other clinical signs as indicators of inadequate anaesthesia to assess the effective concentration where 50% of patients were adequately anaesthetized (EC50).2 3 The present study used the Auditory Evoked Potential Index (AEPex) as the indicator of anaesthetic depth.4 Propofol was then administered using a closed-loop anaesthesia system (CLAN) based on the value of the AEPex. This allowed an unbiased assessment of how much propofol was required to produce satisfactory anaesthesia in all patients at different target remifentanil concentrations. We studied whether increasing the plasma concentration of remifentanil would reduce the amount of propofol required to maintain a comparable level of anaesthesia. In addition, we compared the calculated blood and effect site concentrations of propofol at loss of consciousness (LOC) and recovery of consciousness (ROC).
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Methods |
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The patients were randomized prospectively into three groups (20 patients/group) using computer-generated random numbers. Each group received remifentanil to a low, medium, or high target concentration of 2, 4, or 8 ng ml1, respectively. Remifentanil was administered by a target-controlled infusion (TCI) to ensure a constant plasma target concentration. Mean maintenance infusion rates of remifentanil, which are approximately equivalent to these targets are 0.08, 0.15 and 0.3 µg kg1 min1. The infusion device was based on the prototype Diprifusor system used in previous studies.5 It was modified to a Remifusor by programming with the validated pharmacokinetic data set for remifentanil published by Minto and colleagues,6 which adjusts for age, weight, and sex. The remifentanil target concentrations were kept stable at the respective values throughout the procedure until the end of surgery.
Routine monitoring and the EEG electrodes for AEPex recording were attached. A 20G i.v. canula was inserted and TCI remifentanil started at the respective target concentration. The patient was pre-oxygenated with oxygen 100% and when blood and effect site remifentanil concentrations were in equilibrium (810 min), anaesthesia was induced by TCI propofol using the pharmacokinetic parameter set of Marsh,7 as incorporated into the Diprifusor. The propofol effect site concentrations reported are calculated on the basis of an equilibration constant ke0 of 0.2 min1 according to Billard8 based on the Marsh pharmacokinetic model of propofol. This calculation is built into the commercial Diprifusor system and can be displayed. Propofol TCI was controlled by a closed-loop system (CLAN) based on AEPex, to ensure an unbiased and comparable level of anaesthesia as described previously.9
The value for the AEPex was recorded in the awake patient, and the AEPex value to control satisfactory anaesthesia was entered into the CLAN system. This value was set to 35 for all patients, as it was the mean value required to produce surgical anaesthesia in a previous study.4 Anaesthesia was induced by setting the propofol target to 4 µg ml1. This target was increased by 0.5 µg ml1 every 30 s until LOC. The CLAN system was started after equilibrium of blood and effect site concentrations, and controlled the administration of propofol to maintain an AEPex of 35 in all patients. Thereafter, control of anaesthesia was achieved by transmitting the target blood propofol concentration calculated by the CLAN algorithm to the infusion system and maintaining the measured AEPex close to the selected value of 35.
A laryngeal mask airway (LMA®) was inserted and the patients lungs ventilated with oxygen-enriched air to an end-tidal carbon dioxide of 5 kPa. No neuromuscular block drugs were administered, so that patients could move if anaesthesia was inadequate. Postoperative analgesia was provided with a combination of ketorolac 0.4 mg kg1 and a local anaesthetic block.
At the end of surgery, the propofol and remifentanil targets were set to zero and recovery was assessed by determining the time to: (i) adequate respiration, expressed as a stable ventilatory frequency of 10 and higher, (ii) the first voluntary movement, (iii) eye opening, (iv) response to verbal command, and (v) recall of date of birth. Duration of surgery, total dose of propofol and remifentanil used, and the propofol target concentrations administered by the CLAN system during adequate anaesthesia were obtained. The calculated blood and effect site concentrations of propofol at LOC and ROC were recorded.
Descriptive data are presented as means with 95% confidence interval (CI) and, in the case of data that were not normal distributed, median values with interquartile range, expressed graphically as box and whiskers plots. Estimation of sample size per group was undertaken beforehand to detect a difference in the propofol blood concentration of at least 0.5 µg ml1 with a power of 0.8 and a probability value of P=0.05. This indicated 18 patients were needed per group, and we elected to study 20 patients. Statistical assessment for between-group differences was accomplished with one-way analysis of variance (ANOVA) and the KruskallWallis test, respectively, for skewed data. Comparisons between LOC and ROC were accomplished with Students t-test. Probability values <0.05% were considered statistically significant. Calculations were performed with SPSS® v. 8.0 (SPSS Science Inc., Chicago, IL, USA) and STATISTICA v.5.5a (StatSoft, Tulsa, USA).
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Results |
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Discussion |
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We demonstrated a dose-dependent decrease in propofol requirements with increasing remifentanil concentrations both during adequate anaesthesia and for awakening. These results are principally in accordance with the interaction pattern suggested by Vuyk and colleagues,10 as shown in Figure 4. However, besides these similarities there are some conflicting points, which have to be considered. In the original paper from Vuyk and colleagues,3 the calculation of the effective concentration 50% (95%, respectively) was based on haemodynamic changes and the presence or absence of autonomic signs in paralysed patients during alfentanilpropofol anaesthesia for lower abdominal surgery. They transposed their results10 to generate a corresponding propofolremifentanil interaction curve based on an equipotency ratio of alfentanil:remifentanil of 30:1 (Fig. 4). Although it has been shown that haemodynamic and autonomic variables have a low predictive value in assessing the depth of anaesthesia,12 it is of interest that our results are quite close to the predicted values of remifentanilpropofol interaction but with some exceptions which need to be discussed.
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In contrast to previous interaction studies, we used AEP as a surrogate measure of anaesthesia effect. AEP are associated with a high validity to detect arousal during surgery,4 and to discriminate the conscious from the unconscious patient.14 Both criteria have been suggested as preconditions to providing adequate anaesthesia.15 The use of AEPex as the input signal for feedback closed-loop control of propofol administration in 100 spontaneously breathing patients has been validated previously.9 Although it may be difficult to show clinical advantages of closed-loop systems over conventional, manually adjusted techniques of anaesthetic administration,16 CLAN provides an unbiased method to maintain a comparable level of anaesthesia. It is therefore suitable to act as a clinically relevant method to quantify interactions across the whole period of anaesthesia from induction to emergence.
An important observation seen in each of the three groups was the highly variable propofol target concentrations during the induction period of CLAN, regardless of the remifentanil concentration present. The lack of major differences in propofol requirements between the three groups in the early induction phase was likely to be caused by poor hypnotic potency, and therefore a limited contribution of remifentanil to controlling the AEPex in the absence of surgical stimulation. In contrast, the effect of higher remifentanil concentrations during the subsequent phase of anaesthesia where surgical stimulation was present was demonstrated by the concentration-dependent reduction of the absolute propofol target concentration values.
It is recognized that increasing the remifentanil concentration may be responsible for the development of haemodynamic depression, especially bradycardia. In a study investigating the cardiovascular response to laryngoscopy and intubation, Hall and colleagues administered remifentanil with or without glycopyrrolate and found a significant decrease in heart rate in the group without glycopyrrolate.17 The calculated blood concentration of their infusion regime was 56 ng ml1, and therefore between our medium and high concentration group. However, even without pretreatment with glycopyrrolate, the maximum decrease in heart rate in our study was 21% compared with baseline in the high concentration group which, in the presence of only minor changes in arterial pressure, indicates a stable cardiovascular response to surgery.
The essence of all interaction studies involving opioids is that there is a synergistic interaction with propofol and, regardless which fentanyl congener is used, that the character of interaction depends on the clinical endpoints studied.18 One of the most important endpoints when choosing remifentanil is the termination of the anaesthetic and the recovery of the patient. Computer simulations using pharmacokinetic parameters predict a more rapid and predictable recovery with remifentanil due to its short context-insensitive half-life of 34 min.19 These pharmacokinetic simulations led to the suggestion that a high-dose remifentanil, low-dose propofol anaesthetic would result in the most rapid recovery while ensuring satisfactory anaesthesia beforehand. But is this concept supported clinically? We observed little difference in absolute recovery times between the low, medium, and high remifentanil group both for the emergence phase (adequate respiration, eye opening) and the intermediate recovery (obeying commands). However, the most rapid recovery for all observed clinical endpoints was seen in the medium dose group (remifentanil 4 ng ml1), although this difference was only in the range of 23 min. A similar recommendation was given by Vuyk and colleagues based on their simulation study10. OHare and colleagues investigated recovery after propofol remifentanil anaesthesia using four different target concentrations of propofol and adjusting the remifentanil infusion during surgery.20 They found a dose-dependent prolonging effect on early recovery with increasing propofol concentrations in a range between 6 and 14 min. This study also supports the use of higher remifentanil concentrations in the presence of rather low propofol concentrations when a rapid emergence is required.
In conclusion, we have shown the effect of altering the blood remifentanil concentration during propofol anaesthesia to be dose-dependent. The effect of reducing the required amount of propofol and altering the cardiovascular response during anaesthesia was most prominent with a relatively high remifentanil concentration, whereas emergence was only minimally affected with small differences in all recovery criteria. However, the pattern of interaction during surgery is dynamic, and thus the most rational approach that can be derived from this study appears to be titrating remifentanil in a concentration range between 4 and 8 ng ml1, but ensuring a minimum concentration of propofol, since the hypnotic property of remifentanil itself is limited.
The close relationship between the calculated effect site concentration of propofol at LOC and ROC suggests that, during surgery, the effect site propofol concentration should always be maintained above the value when the individual patient loses consciousness. This demonstrates that the calculated effect site concentration is a more meaningful parameter to describe the clinical condition in a dynamic situation than the blood concentration. It would seem prudent to increase the maintenance effect site concentration above the value at LOC by at least 1 µg ml1, although further studies are necessary to confirm this relationship.
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References |
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