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In vivo characterization of clinical anaesthesia and its components

2002; Elsevier BV; Volume: 89; Issue: 1 Linguagem: Inglês

10.1093/bja/aef156

1471-6771

Joseph F. Antognini, E. Carstens,

Anesthesia and Pain Management

One of the fundamental problems facing researchers of anaesthetic mechanisms is linking a particular effect on a receptor to a specific clinical effect. Thus, to fully understand how anaesthetics act we must approach anaesthetic mechanisms at multiple levels. Ultimately, receptor effects must be viewed within the context of the clinical characteristics of general anaesthesia. Does a particular anaesthetic alter receptor function at clinically relevant anaesthetic concentrations? Is there evidence (anatomical, neurophysiological, pharmacological) that a specific receptor is involved in a clinically relevant neurophysiological process, such as memory? Anaesthesia can be defined in arbitrary terms, although practical considerations often govern specific definitions. Thus, from a practical standpoint, most people would include unconsciousness, amnesia and immobility as important end-points. On the other hand, reduction of stress hormones is not necessarily an absolute, required anaesthetic end-point. In this review we will examine the various components of general anaesthesia. That is, what are the clinical goals we seek to achieve? What are the side-effects we hope to avoid? This latter component is important because an anaesthetic (or any drug) is only as good as the minimization of its side-effects. Before Morton's display of ether anaesthesia, patients were accustomed to being conscious during surgery'painfully so. There was no a priori expectation that they should be unconscious. Their hope was not so much to be unconscious but rather to be pain-free. After all, few people would voluntarily give up consciousness if complete analgesia were otherwise possible. It was the characteristic of ether, chloroform and subsequent anaesthetics that unconsciousness occurred before significant or complete analgesia. That is, unconsciousness simply became part and parcel of general anaesthesia. From a practical aspect, unconsciousness became important as conscious patients, even if they had complete analgesia, would probably talk, which would disrupt the surgical procedure. Indeed, an unconscious and immobile patient permits surgical procedures that are limited only by the available technology and skill of the surgeon. Within a year of Morton's public demonstration of ether anaesthesia, John Snow published an account of the pharmacological and physiological effects of ether.86Snow J On the Inhalation of the Vapour of Ether in Surgical Operations. Churchill, London1847Abstract Scopus (10) Google Scholar These effects were divided into stages, progressing from consciousness to deep coma, muscle flaccidity and respiratory paralysis. Guedel described four stages of ether anaesthesia,46Guedel AE Third stage ether anesthesia: a sub-classification regarding the significance of the position and movements of the eyeball.Am J Surg (Anesth Suppl). 1920; 34: 53-57Google Scholar similar to those described by Snow. In the first stage the patient was conscious but had analgesia (Fig. 1). In the second stage (the delirium stage) the patient exhibited excessive motor activity, even to the point of violence. Eye movements were irregular and erratic, as was breathing. The third stage represented the surgical stage; four planes were originally described, with increasing anaesthetic depth as the patient progressed from the first to the last plane. Respiration became progressively weaker. In the fourth stage of anaesthesia, respiratory paralysis occurred. These classic signs have broad application, but it is clear that not all anaesthetics cause the same progression of clinical signs. Newer anaesthetics, in particular i.v. anaesthetics such as propofol, may not exhibit such signs. One wonders how much of this difference is due to pharmacokinetic as opposed to pharmacodynamic reasons. Many of the newer inhaled anaesthetics have low blood-gas solubilities and thus patients may pass from one stage to the next relatively quickly. Likewise, with i.v. anaesthetics patients are brought to deeper stages rapidly by bolus administration. Thus, there are few data comparing these newer anaesthetics with older ones, such as ether. How do we decide what are the essential components of general anaesthesia? What are the non-essential but desirable goals? These decisions may be made with practical, scientific, theoretical and historical considerations. We first differentiate 'general anaesthesia' from a 'general anaesthetic'. The former defines a pharmacologically induced physiological state in which the essential goals of general anaesthesia are achieved. This may be accomplished with a single agent or with a variety of drugs. A general anaesthetic, however, is a drug that, by itself, achieves all of the essential goals of general anaesthesia. What are regarded as the essential goals of general anaesthesia can depend on the perspective of the definer. For the patient, an important goal will be amnesia'he or she does not want to remember anything. A close second would probably be unconsciousness'the patient does not want to be awake during surgery. A surgeon wants a still patient. A cardiologist wants the patient's blood pressure and pulse to remain 'within normal limits'. An anaesthetist must balance the demands of all three. For practical purposes we define general anaesthesia as the presence of unconsciousness, amnesia and immobility (in response to noxious stimulation). Analgesia is not always included in the list. Analgesia might be an important indirect means to help achieve all of the goals of anaesthesia, but is it essential? We answer 'no'. Analgesics reduce or eliminate pain. Pain is the conscious awareness of a noxious stimulus. Anaesthetized patients are unconscious. Thus, they cannot perceive pain. Therefore analgesia is not directly relevant and may be excluded as a necessary component of general anaesthesia. However, analgesia would be desirable in the rare cases in which patients regain consciousness during surgery and remember the experience. Moreover, drugs with analgesic properties are often used during anaesthesia and can be important for patient management, i.e. to control haemodynamic perturbations. We also exclude lack of haemodynamic responses as an absolute requirement. Although tight haemodynamic control is desirable in some patients, increased heart rate and increased blood pressure are not, by themselves, harmful to many patients. Finally, pre-emptive analgesia could be included as a desirable goal, but it is not an absolute requirement for general anaesthesia. Memory formation occurs at a variety of sites in the brain, including the hippocampus, amygdala, prefrontal cortex and other cortical sensory and motor areas.37Eichenbaum HB Cahill LF Gluck MA et al.Learning and memory: systems analysis.in: Zigmond MJ Bloom FE Landis SC Roberts JL Squire LR Fundamental Neuroscience. Academic Press, San Diego1999: 1455-1486Google Scholar, 54Kandel E The molecular biology of memory storage: a dialogue between genes and synapses.Science. 2001; 294: 1030-1038Crossref PubMed Scopus (2684) Google Scholar Anaesthetics may affect any or all of these sites and thereby result in amnesia. There are two types of memory that are usually discussed in relation to anaesthesia: implicit and explicit recall.37Eichenbaum HB Cahill LF Gluck MA et al.Learning and memory: systems analysis.in: Zigmond MJ Bloom FE Landis SC Roberts JL Squire LR Fundamental Neuroscience. Academic Press, San Diego1999: 1455-1486Google Scholar, 54Kandel E The molecular biology of memory storage: a dialogue between genes and synapses.Science. 2001; 294: 1030-1038Crossref PubMed Scopus (2684) Google Scholar Explicit recall is what most people usually describe as memory: they can explicitly recall a specific event, such as a football game or their wedding day. Implicit recall occurs when an individual cannot remember a certain event, but upon specific testing there is evidence that information has been retained. There are several studies that suggest that, at low anaesthetic concentrations, implicit memory formation may occur while explicit recall is blocked.21Bennett HL Davis HS Giannini JA Non-verbal response to intraoperative conversation.Br J Anaesth. 1985; 57: 174-179Crossref PubMed Scopus (68) Google Scholar, 23Block RI Ghoneim MM Sum Ping ST Ali MA Human learning during general anaesthesia and surgery.Br J Anaesth. 1991; 66: 170-178Crossref PubMed Scopus (77) Google Scholar 42Ghoneim MM Block RI Learning and consciousness during general anesthesia.Anesthesiology. 1992; 76: 279-305Crossref PubMed Scopus (16) Google Scholar The specific sites where this action occurs are not known. The physiological processes and anatomical sites that give rise to consciousness are poorly understood, and the sites where anaesthetics induce unconsciousness are understood even less. Several sites are likely to participate in consciousness, including the cerebral cortex, thalamus and reticular formation.66Moruzzi G Magoun HW Brain stem reticular formation and activation of the EEG.Electroencephalogr Clin Neurophysiol. 1949; 1: 455-473Abstract Full Text PDF PubMed Scopus (2460) Google Scholar, 88Steriade M Arousal: revisiting the reticular activating system.Science. 1996; 272: 225-226Crossref PubMed Scopus (273) Google Scholar All of those structures are affected by anaesthetics.6Angel A LeBeau F A comparison of the effects of propofol with other anaesthetic agents on the centripetal transmission of sensory information.Gen Pharmacol. 1992; 23: 945-963Crossref PubMed Scopus (41) Google Scholar, 22Berg-Johnsen J Langmoen IA Isoflurane hyperpolarizes neurones in rat and human cerebral cortex.Acta Physiol Scand. 1987; 130: 679-685Crossref PubMed Scopus (64) Google Scholar 84Shimoji K Fujioka H Fukazawa T Hashiba M Maruyama Y Anesthetics and excitatory/inhibitory responses of midbrain reticular neurons.Anesthesiology. 1984; 61: 151-155Crossref PubMed Scopus (25) Google Scholar Alkire and colleagues have examined the effect of halothane, isoflurane and propofol on cerebral metabolism [using positron emission tomography (PET)] as an indirect method of investigating sites of anaesthetic action.1Alkire MT Quantitative EEG correlations with brain glucose metabolic rate during anesthesia in volunteers.Anesthesiology. 1998; 89: 323-333Crossref PubMed Scopus (140) Google Scholar, 2Alkire MT Haier RJ Barker SJ et al.Cerebral metabolism during propofol anesthesia in humans studied with positron emission tomography.Anesthesiology. 1995; 82: 393-403Crossref PubMed Scopus (280) Google Scholar, 3Alkire MT Haier RJ Fallon JH Toward a unified theory of narcosis: brain imaging evidence for a thalamocortical switch as the neurophysiologic basis of anesthetic-induced unconscious ness.Consciousness Cogn. 2000; 9: 370-386Crossref PubMed Scopus (328) Google Scholar, 4Alkire MT Haier RJ Shah NK Anderson CT Positron emission tomography study of regional cerebral metabolism in humans during isoflurane anesthesia.Anesthesiology. 1997; 86: 549-557Crossref PubMed Scopus (178) Google Scholar, 5Alkire MT Pomfrett CJ Haier RJ et al.Functional brain imaging during anesthesia in humans: effects of halothane on global and regional cerebral glucose metabolism.Anesthesiology. 1999; 90: 701-709Crossref PubMed Scopus (165) Google Scholar These anaesthetics depress metabolism in the cortex, thalamus and reticular formation, as one would expect. Whether the effects at each site contribute equally to unconsciousness or whether one site is more crucial than the others remains to be elucidated. Fiset and colleagues investigated the effects of propofol using PET scanning and found that propofol produced greater metabolic reduction in the medial thalamus and other brain sites associated with arousal.38Fiset P Paus T Daloze T et al.Brain mechanisms of propofol-induced loss of consciousness in humans: a positron emission tomographic study.J Neurosci. 1999; 19: 5506-5513Crossref PubMed Google Scholar A logical conclusion from their data is that propofol produced unconsciousness through a preferential effect on sites associated with arousal. Alkire and others have suggested that anaesthetics might affect thalamocortical loops that appear to be critical for conscious awareness.3Alkire MT Haier RJ Fallon JH Toward a unified theory of narcosis: brain imaging evidence for a thalamocortical switch as the neurophysiologic basis of anesthetic-induced unconscious ness.Consciousness Cogn. 2000; 9: 370-386Crossref PubMed Scopus (328) Google Scholar In an intriguing study, Devor and Zalkind injected pentobarbital into a discrete area of the rat mesopontine tegmental area bilaterally, producing unconsciousness and analgesia.28Devor M Zalkind V Reversible analgesia, atonia, and loss of consciousness on bilateral intracerebral microinjection of pentobarbital.Pain. 2001; 94: 101-102Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar Clearly, however, considerably more work is needed to understand where anaesthetics act in the brain to influence consciousness. Nociceptive reflexes have evolved as a protective mechanism to withdraw the body (or part of the body) from a noxious stimulus (Fig. 2). Such reflexes are undoubtedly also involved in initiating more complex behavioural responses to escape from or otherwise cope with a threatening environment. The motor consequence of a noxious stimulus might thus consist of a simple withdrawal reflex in which the stimulated extremity is pulled away from the stimulus, or of a violent escape response in which the animal uses all its limbs. Alternatively, the animal may orient towards the source of stimulation and even attack. All of these motor responses are eliminated by anaesthetics. A noxious stimulus activates peripheral nociceptors that transmit impulses to second-order neurones in the dorsal horn of the spinal cord.96Willis WD Westlund KN Neuroanatomy of the pain system and of the pathways that modulate pain.J Clin Neurophysiol. 1997; 14: 2-31Crossref PubMed Scopus (667) Google Scholar These second-order neurones may synapse onto motor neurones either directly or indirectly via higher-order interneurones. Activation of these motor neurones leads to muscle contraction that, depending on the extent and pattern of activation, results in a nociceptive reflex (e.g. withdrawal). Nociceptive input is also likely to activate central pattern generators, which coordinate movement such that the animal can move efficiently in a walk, trot or gallop. A wide variety of neurotransmitter systems is likely to be affected by anaesthetics but it is unclear how these actions translate into clinical effects.60Krasowski MD Harrison NL General anaesthetic actions on ligand-gated ion channels.Cell Mol Life Sci. 1999; 55: 1278-1303Crossref PubMed Scopus (340) Google Scholar In addition, it is unclear if presynaptic or postsynaptic effects are more important. The GABA receptor has been the focus of intense research and there is ample evidence that alteration of GABAergic neurotransmission could alter consciousness, memory and nociceptive responses. Other neurotransmitters are also likely to be involved in these processes.60Krasowski MD Harrison NL General anaesthetic actions on ligand-gated ion channels.Cell Mol Life Sci. 1999; 55: 1278-1303Crossref PubMed Scopus (340) Google Scholar For example, anaesthetics affect the physiology and pharmacology of glutamate and nitric oxide.71Pajewski TN DiFazio CA Moscicki JC Johns RA Nitric oxide synthase inhibitors, 7-nitro indazole and nitroG-L-arginine methyl ester, dose dependently reduce the threshold for isoflurane anesthesia.Anesthesiology. 1996; 85: 1111-1119Crossref PubMed Scopus (61) Google Scholar Antagonists of N-methyl-d-aspartate (NMDA), such as MK-801, drastically reduce the minimum alveolar concentration (MAC),82Scheller MS Zornow MH Fleischer JE Shearman GT Greber TF The noncompetitive N-methyl-d-aspartate receptor antagonist MK-801 profoundly reduces volatile anesthetic requirements in rabbits.Neuropharmacology. 1989; 28: 677-681Crossref PubMed Scopus (57) Google Scholar but is this a direct and relevant anaesthetic action or does it merely reflect the importance of glutamate in the initiation of nociceptive reflexes, such that simply by blocking glutamate transmission one can prevent nociceptive responses? Acetylcholine and the cholinergic neurotransmitter system are also possibly involved in anaesthesia. Physostigmine has been shown to reverse partially the sedative effects of propofol and halothane.48Hill GE Stanley TH Sentker CR Physostigmine reversal of post-operative somnolence.Can Anaesth Soc J. 1977; 24: 707-711Crossref PubMed Scopus (48) Google Scholar, 65Meuret P Backman SB Bonhomme V Plourde G Fiset P Physostigmine reverses propofol-induced unconsciousness and attenuation of the auditory steady state response and bispectral index in human volunteers.Anesthesiology. 2000; 93: 708-717Crossref PubMed Scopus (153) Google Scholar The cerebral activation that is associated with increased arousal is also associated with cortical release of acetylcholine.52Jones BE The organization of central cholinergic systems and their functional importance in sleep-waking states.Prog Brain Res. 1993; 98: 61-71Crossref PubMed Scopus (194) Google Scholar Sensory stimulation can likewise cause cortical release of acetylcholine,61Kurosawa M Sato A Sato Y Cutaneous mechanical sensory stimulation increases extracellular acetylcholine release in cerebral cortex in anesthetized rats.Neurochem Int. 1992; 21: 423-427Crossref PubMed Scopus (42) Google Scholar and isoflurane can affect this release.83Shichino T Murakawa M Adachi T et al.Effects of isoflurane on in vivo release of acetylcholine in the rat cerebral cortex and striatum.Acta Anaesthesiol Scand. 1997; 41: 1335-1340Crossref PubMed Scopus (25) Google Scholar Anaesthetic end-points can sometimes be described in relation to the concentration of anaesthetic required to block movement'the MAC (Fig. 3). This is essentially the median effective dose (ED50), the dose that causes a particular effect in 50% of people or animals. The MAC concept was developed in 1965 as a way to compare equipotent concentrations of anaesthetics.34Eger EI Saidman LJ Brandstater B Minimum alveolar anesthetic concentration: a standard of anesthetic potency.Anesthesiology. 1965; 26: 756-763Crossref PubMed Scopus (694) Google Scholar The measurement of MAC depends essentially on achieving a stable end-tidal anaesthetic concentration, applying a standard noxious stimulus and observing whether movement occurs.34Eger EI Saidman LJ Brandstater B Minimum alveolar anesthetic concentration: a standard of anesthetic potency.Anesthesiology. 1965; 26: 756-763Crossref PubMed Scopus (694) Google Scholar, 74Quasha AL Eger EI Tinker JH Determination and applications of MAC.Anesthesiology. 1980; 53: 315-334Crossref PubMed Scopus (505) Google Scholar Positive movement was arbitrarily defined as 'gross and purposeful', although any other movement type could have been included. Thus, a pawing motion or turning of the head towards the stimulus are usually considered positive, while coughing, straining, chewing and stiffening are considered negative.74Quasha AL Eger EI Tinker JH Determination and applications of MAC.Anesthesiology. 1980; 53: 315-334Crossref PubMed Scopus (505) Google Scholar In general, many investigators also consider simple withdrawal of the stimulated extremity as being negative. What is important is that in any individual study there is consistency as to what is positive and what is negative movement. The noxious stimulus must be supramaximal. That is, increasing the stimulus intensity must not result in further increases in anaesthetic requirements. A mechanical stimulus is usually used, such as a clamp placed across the tail or a hind paw. The stimulus is applied for 1 min or until movement occurs, after which the anaesthetic concentration is changed (up or down, depending on the response). MAC is defined as the average of the two anaesthetic concentrations that are observed to just permit and just prevent the movement, respectively. In humans undergoing surgery, a skin incision is often used to determine the MAC, but this stimulus can be applied only once. A population MAC can still be obtained by adjusting the anaesthetic concentration in subsequent patients so that about half of these patients move and half do not move. Amnesia and unconsciousness are among the first end-points to be reached when an anaesthetic is administered. The concentration that results in a patient passing from wakefulness to unconsciousness is called 'MAC-awake', first described by Stoelting and colleagues.90Stoelting RK Longnecker DE Eger 2nd., EI Minimum alveolar concentrations in man on awakening from methoxyflurane, halothane, ether and fluroxene anesthesia: MAC awake.Anesthesiology. 1970; 33: 5-9Crossref PubMed Scopus (112) Google Scholar They measured the concentrations of methoxyflurane, halothane, ether and fluroxene that just permitted and prevented consciousness (as defined by the response to verbal stimuli); MAC-awake was the average of these. Two subject groups were used. One consisted of volunteers who did not undergo a surgical procedure, while the other group did. Because the anaesthetics studied were not equally divided between the two groups, it is unclear how the presence of post-surgical pain might have altered the results, inasmuch as noxious stimulation is likely to result in cerebral activation and increased probability of consciousness. The MAC-awake for ether (as a fraction of MAC) was greater than that for the other anaesthetics, despite the fact that ether was studied only in volunteers. The MAC-awake varied between 0.5 and 0.65 MAC. Another source of potential error is that MAC values were obtained from historical controls. In a critical editorial,95Waud BE Waud DR On dose–response curves and anesthetics.Anesthesiology. 1970; 33: 1-4Crossref PubMed Scopus (25) Google Scholar Waud and Waud placed limits on the interpretation of the work of Stoelting and colleagues90Stoelting RK Longnecker DE Eger 2nd., EI Minimum alveolar concentrations in man on awakening from methoxyflurane, halothane, ether and fluroxene anesthesia: MAC awake.Anesthesiology. 1970; 33: 5-9Crossref PubMed Scopus (112) Google Scholar (but see also 20Bachman L Eger 2nd, EI Waud BE Waud DR., MAC dose–response curves Anesthesiology. 1971; 34: 201-204Crossref PubMed Scopus (6) Google Scholar). Specifically, examination of only one point on a curve or set of curves (e.g. the point at which 50% of patients are awake) says nothing about the overall curve and, hence, relative potency and effect. They also questioned whether examination of MAC-awake and other variants of MAC would yield any useful information regarding anaesthetic mechanisms. Many investigators now believe that anaesthetics act at different sites, and therefore knowledge regarding the anaesthetic concentration required to achieve certain end-points (unconsciousness and immobility) is directly relevant to determining anaesthetic mechanisms.36Eger 2nd, EI Koblin DD Harris RA et al.Hypothesis: inhaled anesthetics produce immobility and amnesia by different mechanisms at different sites.Anesth Analg. 1997; 84: 915-918Crossref PubMed Google Scholar It is interesting to note that an editorial44Glass PS Anesthetic drug interactions: an insight into general anesthesia'its mechanism and dosing strategies.Anesthesiology. 1998; 88: 5-6Crossref PubMed Scopus (67) Google Scholar published nearly 30 yr after the work of Stoelting and colleagues and Waud and Waud commented on the effect of fentanyl on MAC-awake56Katoh T Ikeda K The effects of fentanyl on sevoflurane requirements for loss of consciousness and skin incision.Anesthesiology. 1998; 88: 18-24Crossref PubMed Scopus (138) Google Scholar (Fig. 4), stating that such studies were critical to our elucidation of anaesthetic mechanisms. Dwyer and colleagues determined that consciousness was present at isoflurane concentrations (0.3 MAC) at which memory formation was impaired.30Dwyer R Bennett HL Eger 2nd, EI Heilbron D Effects of isoflurane and nitrous oxide in subanesthetic concentrations on memory and responsiveness in volunteers.Anesthesiology. 1992; 77: 888-898Crossref PubMed Scopus (200) Google Scholar Furthermore, the authors concluded that, at equipotent MAC concentrations, isoflurane was more potent than nitrous oxide as regards the production of unconsciousness and the reduction of explicit memory formation. The volunteers in this study were not subjected to noxious stimulation, as might occur during surgery, and so it is unclear whether the amount of anaesthetic needed for amnesia and unconsciousness is increased during noxious stimulation; presumably it is. In an earlier study, however, this group of investigators showed that isoflurane at 0.6 MAC or greater prevented consciousness and memory formation (explicit and implicit) during surgical procedures.31Dwyer R Bennett HL Eger 2nd, EI Peterson N Isoflurane anesthesia prevents unconscious learning.Anesth Analg. 1992; 75: 107-112Crossref PubMed Scopus (46) Google Scholar Röpcke and colleagues showed that noxious stimulation can alter anaesthetic effects on the electroencephalogram (EEG).81Ro¨pcke H Rehberg B Koenen-Bergmann M Bouillon T Bruhn J Hoeft A Surgical stimulation shifts EEG concentration–response relationship of desflurane.Anesthesiology. 2001; 94: 390-399Crossref PubMed Scopus (57) Google Scholar They studied two groups of desflurane-anaesthetized patients, one with and one without noxious surgical stimulation. At equal concentrations, the group with surgical stimulation demonstrated EEG activation, whereas the non-stimulated group did not. These data suggest that noxious stimulation during otherwise adequate anaesthesia results in a shift towards increased arousal.81Ro¨pcke H Rehberg B Koenen-Bergmann M Bouillon T Bruhn J Hoeft A Surgical stimulation shifts EEG concentration–response relationship of desflurane.Anesthesiology. 2001; 94: 390-399Crossref PubMed Scopus (57) Google Scholar Learning and memory formation during anaesthesia depends on the circumstances under which stimuli are presented. Dutton and colleagues studied conditioned learning in rats anaesthetized with isoflurane.29Dutton RC Maurer AJ Sonner JM Fanselow MS Laster MJ Eger 2nd., EI The concentration of isoflurane required to suppress learning depends on the type of learning.Anesthesiology. 2001; 94: 514-519Crossref PubMed Scopus (66) Google Scholar They found that fear-conditioning to a tone was less sensitive to isoflurane than fear-conditioning to context (e.g. the surrounding environment). Approximately 0.5 MAC isoflurane was required to prevent fear-conditioning associated with the tone compared with 0.25 MAC for conditioning associated with the context.29Dutton RC Maurer AJ Sonner JM Fanselow MS Laster MJ Eger 2nd., EI The concentration of isoflurane required to suppress learning depends on the type of learning.Anesthesiology. 2001; 94: 514-519Crossref PubMed Scopus (66) Google Scholar Non-immobilizers are compounds that are predicted to be anaesthetics on the basis of their physicochemical properties but in fact are not. Originally these compounds were called non-anaesthetics but one report has shown that they can suppress learning and hence memory.55Kandel L Chortkoff BS Sonner J Laster MJ Eger 2nd., EI Nonanesthetics can suppress learning.Anesth Analg. 1996; 82: 321-326PubMed Google Scholar Amnesia is a desired anaesthetic end-point, and thus it would be imprecise to call these compounds non-anaesthetics. Because these molecules do not contribute to immobility, the consensus is to label them non-immobilizers. These data offer further evidence that anaesthetic end-points are likely to result from anaesthetic action at different sites.87Sonner JM Li J Eger 2nd., EI Desflurane and the nonimmobilizer 1,2-dichlorohexafluorocyclobutane suppress learning by a mechanism independent of the level of unconditioned stimulation.Anesth Analg. 1998; 87: 200-205PubMed Google Scholar Interestingly, Steriade and colleagues have reported that cortical activity (as assessed by the EEG) is more sensitive to anaesthesia than subcortical (e.g. thalamic) activity.89Steriade M Amzica F Contreras D Cortical and thalamic cellular correlates of electroencephalographic burst-suppression.Electroencephalogr Clin Neurophysiol. 1994; 90: 1-16Abstract Full Text PDF PubMed Scopus (253) Google Scholar We have made similar observations (Fig. 5). The data of both Steriade and colleagues and ourselves were obtained at anaesthetic concentrations greatly exceeding those required to prevent memory formation and consciousness. Nonetheless, it is theoretically possible that anaesthetic-induced unconsciousness may occur primarily as the result of anaesthetic action within the cerebral cortex. Dwyer and colleagues collected EEG data in isoflurane-anaesthetized patients to determine if processed EEG variables might correlate with clinically relevant anaesthetic end-points.32Dwyer RC Rampil IJ Eger EI Bennett HL The electroencephalogram does not predict depth of isoflurane anesthesia.Anesthesiology. 1994; 81: 403-409Crossref PubMed Scopus (95) Google Scholar Spectral edge frequency, median power and total power were among the variables examined. The authors were unable to make predictions regarding patient movement, memory formation or consciousness.32Dwyer RC Rampil IJ Eger EI Bennett HL The electroencephalogram does not predict depth of isoflurane anesthesia.Anesthesiology. 1994; 81: 403-409Crossref PubMed Scopus (95) Google Scholar Indeed, human and rat data suggest that marked EEG depression resulting from isoflurane and thiopental does not correlate with movement resulting from noxious stimulation,51Hung OR Varvel JR Shafer SL Stanski DR Thiopental pharmacodynamics. II. Quan