The importance of accuracy in controlling the dose-response relation of anaesthetic-hypnotic drugs is directly related to the importance of optimizing the efficacy and quality of anaesthesia while minimizing adverse drug effects. Unfortunately, large interindividual variability is found when studying population pharmacology and it is difficult to quantify the clinical /pharmacological effect. Therefore, individualisation of this dose-response relation is required for every patient [1].
Depth of anaesthesia depends on the interaction of two factors : the anaesthetic-hypnotic component creating a state of unconsciousness and the surgical stimulus, which may activate the sympatic nervous system and increase the patient's level of consciousness (called arousal) and the somatic and autonomic reactivity [2]. If the receptor concentration of the anaesthetic-hypnotic drug is too low, the drug may cause variable levels of awareness (explicit recall, cued conscious recognition, wakefulness, implicit (unconscious) awareness). Therefore, the problem of awareness should be considered as a pharmacologic problem [3] and the knowledge about therapeutical drug concentrations has to become a basic knowledge of the anaesthetist.
Multiple publications can be found about therapeutic drug concentrations in a variety of surgical conditions. In contradiction with the inhalation anaesthetics, where the inspired and end-tidal concentration can be measured on-line and displayed on the monitor, the actual plasma or effect-site concentration of an intravenously administered drug is not measurable in clinical practice. Due to the development of new, short-acting drugs, the availability of advanced computers, electronic devices and syringe pumps, and due to a better knowledge of patients' pharmacokinetics and dynamics, it is possible to administer intravenous hypnotic drugs to achieve and maintain a desired concentration by applying target controlled infusion (TCI). Nowadays, only central compartment controlled TCI is available commercially. Although these techniques might offer better quality of anaesthesia , for anaesthetics the blood compartment is not the site of drug effect. The site at which the drug produces its effect is termed the biophase or effect-site. In an attempt to further improve these TCI techniques, Shafer and Gregg [4] have described an algorithm to control the target concentration in the theoretical effect-site. It has been published for intravenous anaesthetics that effect compartment controlled target controlled infusion offers an improvement of the quality of anaesthesia [5-7] and can be performed safely [8].
Nevertheless, these variables might be modified by disease, drugs and surgical techniques [9], and the degree of interpatient variability is high. In clinical practice, opiates and other drugs are added routinely to inhalational anaesthetics, making the clinical evaluation of depth of anaesthesia even more difficult. Therefore, there is a need to introduce newer and more precise measures of the depth of anaesthesia. The following techniques are well described in the literature: the isolated forearm technique (IFT), frequency of lower oesophageal contraction (LOC) spontaneous surface electromyography (SEMG), electroencephalography (EEG) and evoked potentials (EP). It has been shown that the usefulness of the LOC is very limited to describe depth of anesthesia [10]. Furthermore, the use of the IFT is hampered by the limited duration of isolation and the potential of ischaemic sequelae or problems with arm positioning. Therefore we will only focus on the SEMG, EEG and EP. An accurate neurophysiological variable to control anaesthetic depth should be one providing information on loss and return of consciousness as well as on the effect of a given dose of an hypnotic agent, to prevent a too deep level of anaesthesia.
In patients who are not completely paralysed by neuromuscular blocking agents, a SEMG can be recorded from various muscle groups. Especially facial, abdominal, and neck muscles are used [11-13]. It has been shown that increasing SEMG activity of facial and neck muscles reflects both recovery from the effect of neuromuscular blocking agents and a reduced depth of anaesthesia, induced either by increased intensity of surgical stimulation or reduced anaesthetic concentrations [12-14]. Unfortunately, the SEMG offers no accurate information on the depth of anesthesia when the patient lost consciousness due to a saturation of the signal [15]. For the EEG, the interpretation of subtle changes in the raw EEG requires a trained electroencephalographer. Therefore, processing these EEG signals is required. Actually, two techniques are found in the literature : power spectrum analyses (spectral edge frequency (SEF95%) and median frequency (MF)). More recently, the bispectral index (BIS) has been introduced into clinical practice. This measure not only observes the power and freqeuncy of the EEG but also looks to other variables such as phase and other correlations between the EEG waves. Another measure of depth of anaesthesia are the auditory evoked potentials. The principle of these techniques is repetitive stimulation with the corresponding signal of interest time -locked to the stimulus [16] Since the background noise is random and each evoked response has essentially the same morphology, time-locking and averaging will improve the signal (evoked potential) to noise (electroencephalogram) ratio [17]. This process will allow identification of the evoked potential.
Controversy exists on the use of these measures to monitor loss and return of consciousness, depth of anaesthesia and hypnotic drug effect. Initial reports on the classical univariate EEG measures (MF and SEF 95% and RDELTA) conclude that these correlate well with anaesthetic adequacy [18,19]. All these investigators used haemodynamic or somatic (movement) response to surgical stimuli as the clinical end-point to assess the accuracy of the different indicators of anaesthetic depth [20], but it is known that these clinical end-points are inaccurate for this purpose [21]. In a more recent study, Dwyer et al. found that these univariate measures do not predict depth of isoflurane anaesthesia as defined by the response to surgical incision, the response to verbal command or the development of memory [22]. This was also demonstrated by others [23]. A large number of prospective studies have demonstrated the clinical utility of BIS monitoring in surgical patients [24-31]. BIS provides information on drug-effect during propofol sedation and hypnosis [30] and predicts probability of recovery of consciousness after a single injection of propofol [32]. BIS has a good correlation with intraoperative recall and depth of propofol-induced sedation [26]. Leslie et al. [33] found a mathematical correlation between the BIS and the plasma concentration of propofol within a range of 1-4 µg/ml, but did not find a correlation between SEF 95 % and propofol plasma concentration; higher concentrations were not tested. In a comparative trial [15], we have evaluated the usefulness of SEMG, MF, SEF 95%, RDELTA and BIS as measures of depth of anaesthesia and hypnotic drug effect during propofol sedation in combination with spinal anaesthesia for orthopaedic surgery on the lower extremities. The BIS is the only one among those tested that provided information on those two criteria. The tested univariate measures (MF, SEF 95% and RDELTA) provide no reproducible information and the SEMG is only useful for detecting loss and return of consciousness, without any predictive value. The SEMG is not good for measuring depth of anaesthesia after loss of consciousness. BIS is also validated for midazolam, thiopental, isoflurane sevoflurane, nitrous oxide and opiates [24, 28, 33-38]. Using the large ASPECT ® database, Shafer et al. [39] calculated the relation between BIS, blood pressure, drug concentrations (measured plasma and predicted plasma and effect-site concentrations of propofol) and probability of recall. He concluded that there was no correlation between the haemodynamics and the probability of recall. When the effect-site concentration of propofol was lower than 1.5 µg/ml, he found a significant correlation between BIS, predicted effect-site concentration and the probability of recall. At higher concentrations, he concluded that the BIS revealed no additional information when using the predicted effect-site concentration to predict recall. Nevertheless, when looking to implicit awareness, our group [40] found that the addition of the BIS to standard clinical practice can be useful in titrating the propofol effect-site concentration, resulting in an improved stability of depth of sedation and prevention of awareness even at effect-site concentration higher than 1.5 µg/ml.
Regarding the evoked potentials, halothane, enflurane, isoflurane, sevoflurane and desflurane all increase the latency and decrease the amplitude of the mid-latency evoked potentials in a dose- and concentration - related way [41-45]. In contrast to the volatile anaesthetics, nitrous oxide has little effect on mid-latency evoked potentials when given to supplement these agents [46]. The change in latency and amplitude of mid-latency evoked potentials after administration of intravenous anaesthetics such as thiopentone, etomidate and propofol is similar to that observed with inhaled agents [10,46,47]. Opioids, even at high doses, have no effect on the morphology of the mid-latency evoked potentials [48,49]. The amplitudes and latencies of mid-latency evoked potentials are not changed by ketamine [50]. The same holds essentially true for benzodiazipines such as diazepam, flunitrazepam and midazolam [46].To evaluate and quantify depth of anaesthesia on-line with the aid of auditory evoked potentials, an auditory evoked potential index has been devised [51]. Recently, it has been compared with 95 % spectral edge frequency, median frequency and the bispectral index during repeated transitions from consciousness to unconsciousness by target controlled infusion of propofol [52]. In comparison with the other three electrophysiological variables, the auditory evoked potential index proved to be better to discriminate the transition from unconsciousness to consciousness [52]. In an earlier study, the same group demonstrated that the BIS was better correlated with increasing drug concentration [53].
In conclusion, the optimalization of the administration of hypnotic-anaesthetic drugs during anaesthesia and sedation using the principles of pharmacokinetics and dynamics including an accurate measurement of the drug effects should provide the anaesthetists with powerful tools to prevent perioperative awareness.
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