1 University of Glasgow, Department of Anaesthesia, Glasgow Royal Infirmary, 10 Alexandra Parade, Glasgow G31 2ER, UK. 2 University of Hong Kong, Queen Mary Hospital, Pokfulam Road, Hong Kong, China
Corresponding author: University of Michigan, Department of Anesthesiology, 1H247UH, PO Box 0048, 1500 East Medical Center Drive, Ann Arbor, Michigan 48109-9091, USA. E-mail: smilne@umich.edu Declaration of interest. Aspect Medical provided hardware and disposables to conduct this study. The hardware and software system used to calculate the AEPex was licensed by Glasgow University to AstraZeneca. Professor Kenny has acted as a consultant to AstraZeneca.
Accepted for publication: September 3, 2002
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Abstract |
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Methods. Forty unpremedicated Caucasian patients were anaesthetized with i.v. propofol delivered by a Diprifusor target-controlled infusion (TCI). Bispectral index (BIS) and auditory evoked potential index (AEPex) were measured and blood and effect-site propofol concentrations were predicted. Logistic regression was used to estimate population values for predicted blood and effect-site propofol concentrations at the clinical end-points and to correlate these with BIS and AEPex.
Results. The effect-site EC50 at loss of consciousness was 2.8 µm ml1 with an EC05 and an EC95 of 1.5 and 4.1 µm ml1, respectively. The predicted EC50 when there was no response to a tetanic stimulus was 5.2 µm ml1 with an EC05 and an EC95 of 3.1 and 7.2 µm ml1, respectively.
Conclusions. Unconsciousness and lack of response to a painful stimulus occur within a defined range of effect-site concentrations, predicted by Diprifusor TCI software.
Br J Anaesth 2003; 90: 12731
Keywords: anaesthesia, depth; anaesthetics i.v., propofol; monitoring, bispectral index; monitoring, electroencephalography; monitoring, evoked potentials; pharmacokinetics, propofol
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Introduction |
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We predicted blood and effect-site concentrations of propofol when loss of consciousness and lack of purposeful movement to a painful stimulus were noted and recorded the electrophysiological measurements bispectral index (BIS) and auditory evoked potential index (AEPex) at the same time. The results have been presented in preliminary form.6
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Methods |
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The propofol infusion was started to provide a blood concentration of 1.5 µm ml1, and increased by 0.5 µm ml1 every 30 s until patients lost their eyelash reflex and no longer responded to a verbal command. This point was defined as loss of consciousness. BIS, AEPex and predicted blood and effect-site propofol concentrations were recorded at this point. The propofol concentration continued to be increased in 0.5 µm ml1 increments and a tetanic stimulus (50 Hz, 80 mA, 0.25 ms pulses for 4 s) was applied to the wrist using a peripheral nerve stimulator. The patient was observed for gross purposeful movement of the head or extremities. Twisting or jerking the head was considered a purposeful movement, but twitching or grimacing was not. The stimulus was reapplied every 30 s after each increment in propofol concentration until no purposeful movement was observed. This point was defined as no response to a painful stimulus. BIS, AEPex and propofol concentrations were recorded and surgery proceeded as normal.
A quantal response model (probit analysis) was used to calculate EC50, EC05 and EC95 at each end-point based on predicted blood and effect-site propofol concentrations. Assessment of the linear association between BIS, AEPex or the predicted blood and effect-site propofol concentrations and the probability of consciousness or unconsciousness was performed using logistic regression (software version 8; SAS Institute, Cary, NC, USA). The curves were fitted using the likelihood ratio goodness of fit test.
The standard logistic model for propofol concentrations, BIS and AEPex is:
P=C+(1C)(1/1+e(ß0+ß1x1))
where P is the probability of unconsciousness for predicted blood and effect-site concentrations or the probability of consciousness for BIS and AEPex. C is the initial estimate of the natural response rate, ß0 is the intercept and ß1 is the estimate of the coefficients of the independent variable x1 (i.e. propofol concentration, BIS or AEPex).
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Results |
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Discussion |
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Some anaesthetists do not use i.v. techniques because they are unsure whether they are providing sufficient anaesthetic agent.13 The EC50 is a concept analogous to MAC and can indicate how much i.v. drug needs to be administered. Unfortunately, unlike volatile agents, drug concentration cannot be measured in real time and instead we have to predict blood concentration.
We chose to study the Diprifusor system for TCI administration of propofol because it is widely available. The predicted blood and effect-site concentrations displayed by the Diprifusor are used by many anaesthetists who do not have access to other pharmacokinetic models to guide the administration of propofol. The popularity of the system made our results, based on a study of the values displayed, applicable to all physicians using this infusion system.
In this study, we increased the predicted blood concentration of propofol by small increments every 30 s. Despite this slow increase in predicted blood propofol concentration, there was insufficient time for the propofol to equilibrate with the brain. Equilibration of the effect-site with the blood concentration takes four to five times the keo half-life [T1/2 (keo)], where T1/2 (keo)=0.693/keo. The Diprifusor uses a keo of 0.2 min1. Therefore, it will take approximately 15 min for blood and effect-site concentrations to equilibrate. Because of this there was considerable discrepancy between the predicted blood and effect-site concentrations, emphasizing that during induction and recovery the effect-site concentration is a more useful clinical correlate than the predicted blood concentration. We believe that the ability to clearly display effect-site concentration should be an integral part of any TCI system.14
Tetanic stimulation of the ulnar nerve is easy to perform and has the advantage over skin incision as a stimulus in that it is repeatable. One study has shown no significant difference between EC50 tetanic stimulus and EC50 skin incision in somatic response, but significant differences in haemodynamic response using this technique.15 As we were looking for patient movement in response to the stimulus, it was useful in this study to have a reproducible and repeatable stimulus to apply at different propofol concentrations.
Ninety per cent of patients will lose consciousness and have no response to a tetanic stimulus at propofol concentrations between the EC05 and the EC95 for these responses. For loss of consciousness, the range of effect-site concentrations to include 90% of patients was 1.54.1 µm ml1 and for no response to the tetanic stimulus it was 3.17.2 µm ml1. The predicted effect-site concentration range is smaller than the predicted blood concentration range and is therefore more useful in guiding propofol administration. Although the range of predicted propofol concentrations is useful in the assessment of whether a patient will be unconscious, neither the predicted concentration range nor the MAC guarantees lack of awareness.
Comparison of the results of this study performed on a Caucasian population with the results of another study performed on Chinese patients revealed similar results for predicted effect-site concentrations.16 The EC50 for effect-site propofol concentration at loss of consciousness was 2.8 µm ml1 in the Caucasian and 2.7 µm ml1 in the Chinese populations. The EC95 was 4.1 µm ml1 in Caucasians compared with 3.8 µm ml1 in Chinese. The EC50 at no response to the tetanic stimulus was 5.2 and 4.5 µm ml1 and the EC95 7.2 and 6.4 µm ml1 in the Caucasian and Chinese populations respectively. Despite the similarity in predicted effect-site concentrations between the two populations, there are large differences in the predicted blood concentrations, the concentration in the Caucasian population being consistently higher. This is explained by a difference in the rate at which the blood concentration of propofol was increased in the two studies. The propofol concentration was increased more quickly in the Caucasian patients and so the predicted blood concentration was greater at loss of consciousness and lack of response to the painful stimulus. As the site of action is the brain and not the blood, the predicted effect-site values are similar between the populations. We believe this reinforces the value of the effect-site rather than the predicted blood concentration in determining the pharmacodynamic effects of propofol on the individual patient.
In this study, 90% of patients lost consciousness at a BIS value between 88.8 and 52.9 and an AEPex between 68.6 and 40. The range for AEPex is smaller than for BIS, and this would suggest that AEPex is more useful in predicting loss of consciousness. Loss of response to a tetanic stimulus occurred between BIS values of 48.2 and 25.6 and AEPex values of 53.8 and 22.7 for 90% of patients. The range for BIS is smaller and so possibly BIS is more useful in predicting lack of response to painful stimuli.
The BIS values are also very similar between the Caucasian and Chinese populations when there is no response to a tetanic stimulus, with EC50 values of 36.9 and 40.1 and EC95 values of 25.6 and 27.3 in the Caucasian and Chinese populations, respectively. The BIS values at loss of consciousness differ slightly, possibly because loss of consciousness is a more subjective end-point than loss of response to a painful stimulus.
We believe that the predicted effect-site concentration of propofol is a more useful and reproducible indicator than the predicted blood propofol concentration. Prediction of the effect-site EC05, EC50 and EC95 at which patients become unconscious and when they no longer respond to a painful stimulus will guide physicians in the administration of propofol using the Diprifusor in a manner analogous to the MAC when using volatile agents.
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Acknowledgement |
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References |
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