Schneider, G.; Sebel, P. S.
Introduction: anaesthetic stages
‘I have breathed the ether on several occasions, and think its effects may be divided into three stages or degrees. The first is merely a pleasurable feeling of half intoxication; the second is one of extreme pleasure, being similar to the sensations produced by breathing nitrous oxide, or laughing gas; ... The third stage, the only one, I think, for performing operations in, is one of profound intoxication and insensibility.’
This statement, written in 1847 by Plomley in a letter to the Lancet, was one of the first definitions of the several stages of anaesthesia. In 1920, Guedel described four stages of anaesthesia, the first being analgesia and consciousness, the second stage excitement, the third surgical stage, and the fourth beginning with cessation of respiration and ending with cardiac paralysis and death. He noted a great range of the third stage , which he subdivided into four planes. Plane one shows slight somatic relaxation, regular respiration, and active ocular muscles. In the second plane the inspiration is briefer than exhalation with an inspiratory pause, and the eyes are immobile. Plane three is characterized by abdominal muscle relaxation and loss of eyelid reflex. In plane four, paradoxical rib cage movement occurs, and pupils are dilated. In 1954 Artusio  further divided the first stage into three planes, characterized by amnesia (plane two) followed by analgesia (complete in plane three). The use of other volatile agents, intravenous anaesthetics, and combinations of opioids with other drugs in modern anaesthetic practice, limit the value of these classical signs and stages.
Changing concepts of anaesthesia
With the introduction of d-tubocurare, detection and monitoring the different stages of anaesthesia as described by Guedel and Artusio became more complicated and almost impossible. Seven out of the nine components of Guedel's classification involved skeletal muscle movement. The remaining two, pupil size and lacrimation, are only valuable if no opioids or anticholinergics are used during anaesthesia. This shows the limited value of the described signs for combinations of drugs. Woodbridge introduced the four component concept of anaesthesia in 1957: sensory block, reflex block, motor block and mental block . Thirty years later Pinsker  suggested that paralysis, unconsciousness and attenuation of stress are the necessary components of anaesthesia. In 1987, Prys-Roberts  stated that there is no 'depth of anaesthesia'. In his editorial he defines loss of consciousness as an all-or-none phenomenon. Thus, there are no degrees nor variable depth of anaesthesia. As pain is a 'conscious perception of noxious stimulus', a 'state of anaesthesia' can be described as drug-induced unconsciousness in which the patient neither perceives nor recalls pain. Kissin's definition of anaesthesia  includes prevention of somatic as well as psychologically adverse effects of surgery. Like Prys-Roberts, Kissin views anaesthesia as a spectrum of separate pharmacological actions produced by one or more drugs. Today, anaesthesia is achieved by administration of several drugs to attain amnesia, sedation, analgesia, paralysis and suppression of stress response. There is a large variability in the requirement for sedatives and analgesics , depending on the individual patient and the surgical procedure. In the modern practice of anaesthesia, the term 'depth of anaesthesia' and the definition of stages are irrelevant. Anaesthesia is not 'deep' or 'light': it may or may not be adequate. Thus, administration of anaesthetic agents should be tailored to the specific needs of the patient and the surgery performed. Useful monitoring should contain information about adequacy of anaesthesia for individual patients and their surgery.
Awareness, memory and recall
Following the introduction of neuromuscular blocking drugs, the occurrence of awareness increased and is still one of the major causes of patients' complaints and lawsuits against anaesthesiologists . There has been much confusion, mainly because of different use of terms. Awareness is a state of being aware, i.e. conscious, watchful, vigilant, informed and being able to respond to command . Memory is the ability to receive, modify, store and retrieve information. It can be divided into explicit and implicit memory. Explicit memory refers to conscious recollection of previous input with a reference to a specific event or stimulus. Implicit memory can have an effect on experience, thoughts, feelings or actions without any direct recollection of the past event that contributed to it . Recall may be considered as synonymous with explicit memory . The terms 'awareness' and 'implicit and explicit memory' have to be distinguished. A patient may be aware during surgery but have no recall of the event [12,13]. There may also be implicit memory even without awareness or explicit memory [14-16]. During anaesthesia, subconscious learning may occur. Some positive therapeutic effects of intra-operative suggestions have been demonstrated [15,17,18], but this is still a controversial field [19-21]. Inadequate anaesthesia and awareness can lead to post-traumatic psychological disorders [22,23]. Implicit memory may be manifested by acute or chronic psychosis or nightmares even years after surgery . The reported incidence of recall varies from 0.2-2% [24-26] up to 4% . The risk is greater for haemodynamically unstable patients, and for those undergoing emergency surgery.
In today's clinical practice, blood pressure, heart rate, respiratory rate, rhythm and depth, muscle tonus, ocular signs, lacrimation and sweat are used for monitoring anaesthetic adequacy. All of these signs are indirect and non-specific, and they may vary over a wide range depending on disease, drugs and surgical technique. There is also a large interpatient variability. Even when all of these signs remain unchanged, awareness can occur [27-29]. It must be stated that no constellation of clinical signs is wholly specific and sensitive [8,30]. Haemodynamic signs may be misinterpreted. Increasing the dose of anaesthetic does not necessarily lead to bradycardia or hypotension [31-33]. On the other hand, a haemodynamic response following noxious stimulation does not necessarily mean awareness or perception of pain. During organ harvesting from brain-dead patients, haemodynamic responses following skin incision have been reported [34,35]. The central nervous system is not necessarily involved in these reactions: they may be mediated by spinothalamic tracts and adrenal medullary stimulation by reflex spinal arcs . Other clinical signs such as diaphoresis and lacrimation have been utilized to estimate anaesthetic adequacy, but they, too, are neither sensitive nor specific [27,37,38]. The value of sweating is limited by the presence of temperature changes. Mydriasis loses its specificity and sensitivity after ocular surgery, ophthalmologic drugs, opioids and atropine. Blood pressure, heart rate, ocular signs, lacrimation and sweat are not valuable in predicting response to a noxious stimulus. They do not necessarily correlate with anaesthetic dose or concentration, nor with the adequacy of anaesthesia.
For years, movement has been used for monitoring the adequacy of anaesthesia. In 1963, Merkel and Eger introduced the concept of MAC as the minimum alveolar concentration of halothane to prevent gross purposeful movement in response to a supramaximal noxious stimulus in 50% of subjects . In humans, the initial skin incision is used as a reproducible form of stimulus. The concentration required to eliminate a motor response (MAC) is higher than that necessary for loss of consciousness (MAC-awake)  but lower than that needed to block an adrenergic response to the stimulus (MAC-BAR) . Recently, it has been demonstrated that MAC does not - or not only - represent the effect of anaesthesia on the brain: Rampil et al. have shown in rats that not even precollicular decerebration altered the ability of general anaesthetics to block a somatic response . MAC of isoflurane in decerebrate rats was 1.26%; not much different from the 1.3% found in the control group. In a subsequent study, Rampil performed spinal cord transection in a manner that prevented spinal shock: MAC did not change . This leads to the conclusion that the site of anaesthetic inhibition of motor response may be in the spinal cord. Antognini and Schwartz separated the brain from the body circulation in goats, using two by-pass circuits . With isoflurane delivered to the brain only, the concentration required to block movement was 2.9%, compared to 1.2% before bypass. Borges and Antognini , using the same experimental technique, maintained isoflurane concentration in the brain at 0.2-0.3%. Isoflurane was also delivered to the lungs. MAC for the body bypass was 0.8%, compared to 1.4% before bypass. This may be explained by different sensitivity of inhibitory and excitatory pathways in spinal cord and brain. These results suggest that the spinal cord might be much more important in MAC determination than the brain.
There have been other approaches to monitoring anaesthetic adequacy, for example facial electromyography and measurement of lower oesophageal contractility. Recording summed facial electromyographic voltages via surface electrodes determines typical patterns of muscular tension. These patterns may be useful in monitoring sedation , but the method still has not been evaluated sufficiently. Lower oesophageal contractility was introduced as a means of monitoring anaesthetic adequacy for inhalation anaesthetics [47,48]. Measured values do not only depend on the type of anaesthesia , but also on the operation , and it was suggested that this method was inappropriate for assessing the adequacy of anaesthesia .
EEG as an indicator of anaesthetic adequacy
Since the brain is the effect site of general anaesthetics, it is reasonable to assume that the EEG will reflect the effect of anaesthesia. The EEG is a non-invasive monitor of cerebral activity. It represents cortical electrical activity derived from summated excitatory and inhibitory post-synaptic activity. In 1931, Berger was the first to describe the influence of anaesthesia on the EEG . Gibbs, in 1937 showed the influence of different drugs on the EEG . Subsequently, it has been used for pharmacodynamic and pharmacokinetic studies of various drugs [54-57]. The main problem is the different pattern of EEG alterations caused by different drugs [55,58-60]. Due to its complexity and the difficulty of interpretation, the raw EEG is of very limited value as a monitor of depth of anaesthesia. Its complexity has been reduced by the use of a mathematical technique, Fourier analysis, digitizing the raw EEG and separating it into a number of sine waves. These are calculated to obtain the power spectrum . Power spectral analysis assumes a Gaussian, stationary, and firstorder (linear) model of the frequencies within the EEG, i.e. the amplitudes are normally distributed, the statistical properties do not change over time and the frequency constituents are uncorrelated. Using these assumptions, the EEG is considered to be composed by linear superimposition of statistically independent sinusoidal wave components. Further reduction of the information led to the spectral edge frequency. This is a single number representing the frequency below which 95% of the total power is present . There are correlations with anaesthetic adequacy [63,64], and the plasma concentration of drugs [31,54,58]. It has been used to guide opioid administration . Controversy exists about its value as a predictor of a haemodynamic response to stimuli [63,65]. Median frequency (the frequency above and below which 50% of the EEG power resides)  is another single number derived from the power spectrum. It has been used in an adaptive feedback control algorithm for closed-loop administration of propofol , and other anaesthetic techniques [68-71]. Drummond, in a comparative study of five processed EEG parameters and their value as predictors of imminent arousal (spontaneous movement, coughing, eye opening) from isoflurane/N2O anaesthesia , did not find any of these measures reliable enough to serve as sole predictor. It appears that these EEG parameters may provide potentially useful information regarding changing levels of anaesthesia, but none of these is sufficiently reliable to be used as the sole indicator of anaesthetic depth.
Conventional power spectral EEG analysis does not use all the information contained in the EEG. Only frequency and power estimates are considered, while phase information is generally ignored. Bispectral analysis of the EEG provides means by which quadratic (second order) interactions can be quantified [73,74]. This is provided by quantifying the phase coupling between two frequencies and a third frequency (harmonic) by their sum or difference. The extent of the coupling can vary from 0% (no harmonic) to 100% (harmonic for the duration of the period analysed). Bispectral analysis gives a more comprehensive description of the information available from Fourier analysis than the power spectrum, including additional information. Bispectral analysis of the EEG might be helpful in determination of anaesthetic adequacy . It is used to obtain BIS, the bispectral index, which has been shown to correlate with movement in response to skin incision using several drugs [76-78]. In predicting movement, an early version of BIS was found not to be independent of the drugs used [77,78]. The current version, BIS 3.0, is a multivariate non-linear index incorporating power spectra and bispectral EEG parameters and burst suppression . It has been shown to correlate with depth of sedation using several drugs [80-82]. BIS correlated with loss and return of consciousness after thiopentone , as well as with the response to command and with recall . Baseline BIS before intubation could not predict an awareness reaction following stimulus, but once awareness occurred, BIS discriminated between patients with and without an awareness reaction . There has been no study with patients undergoing surgery during general anaesthesia correlating BIS with awareness or recall, although in unstimulated patients it appears to be a good predictor . Studies so far suggest that BIS is a promising monitoring tool for the assessment of adequacy of anaesthesia.
Auditory evoked responses (AER), representing the response of the auditory pathway to a sound stimulus, might be useful in monitoring adequacy of anaesthesia . In order to calculate an AER, a repeated auditory stimulus is applied to the patient. All EEG periods immediately following each stimulus are averaged. Thus the non-stimulus-related portion of the EEG is eliminated and the specific evoked potentials remain. The response can be divided into several segments according to the anatomical area of its origin and the time elapsed since the stimulus. The brainstem auditory-evoked response is the early component of the AER (within the first 8 ms). It originates in the brainstem and is unaffected by most anaesthetics [87-91]. It is not helpful in determining anaesthetic adequacy. The late cortical response occurs between 50 and 1000 ms, reflecting activation of the frontal cortex . It reflects the influence of anaesthetics [93,94], but is very much affected by attention, sleep and sedation [92,95], thus being of limited value for monitoring depth of anaesthesia. Between 40 and 60 ms after stimulation, the middle latency auditory evoked response (MLAER) is seen, and this is interesting for measuring anaesthetic effect. It represents neural activity within the thalamus and primary auditory cortex [16,92]. Thornton [94,96] and Schwender  suggest that MLAER is suitable for the measurement of 'anaesthetic depth'. Opioids, even at induction doses, do not affect the MLAER [98,99]. This might explain the high incidence of awareness and recall during high-dose opioid anaesthesia [98,100]. In patients undergoing cardiac surgery who showed no difference in AER pattern between sleep and awake (both with high amplitude and the same periodic waveform), a high incidence of implicit memory has been shown . Confirming results came from Thornton, correlating awareness reaction with AER alterations . Another approach has been suggested by Plourde et al., using the 40 Hz auditory steady state response (ASSR) . The ASSR is a sinusoidal electrical response of the brain following repeatedly presented auditory stimuli, delivered sufficiently rapidly to produce overlapping of the responses to individual stimuli. Amplitude reductions (as seen during sleep [102,103]) were shown to correlate with anaesthesia and recovery for several drugs [102,104,105], but they did not show clear advantages over spectral edge frequency . These data suggest that MLAERs in particular may be a possible tool for assessing anaesthetic adequacy.
At present, the most promising monitors for assessing anaesthetic adequacy seem to be bispectral index and middle latency auditory evoked potentials. Both of them still have to be validated further. One problem in this process is that we still cannot define nor measure all of our anaesthetic goals, such as the significance of implicit memory. As a result, every new monitor can only be validated using the limited means we use today.
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Seventh International Symposium on Intravenous Anaesthesia, Lausanne, Switzerland, 2-3 May 1997
This publication is supported by grants from various pharmaceutical companies. The views in this publication are those of the authors and not necessarily those of supporting companies. Drugs and administration techniques referred to should only be used as recommended in the manufacturers' prescribing information.