AnestéSicos Review

British Journal of Anaesthesia 89 (1): 156±66 (2002) In vivo characterization of clinical anaesthesia and its components J. F. Antognini1* and E. Carstens2 1 Department of Anesthesiology, TB-170, University of California at Davis, Davis, CA 95616, USA. 2Section of Neurobiology, Physiology and Behavior, 193 Briggs Hall, University of California at Davis, Davis, CA 95616, USA *Corresponding author Br J Anaesth 2002; 89: 156±66 Keywords: anaesthesia, general; theories of anaesthetic action One of the fundamental problems facing researchers of ness occurred before signi®cant or complete analgesia. That anaesthetic mechanisms is linking a particular effect on a is, unconsciousness simply became part and parcel of receptor to a speci®c clinical effect. Thus, to fully under- general anaesthesia. From a practical aspect, unconscious- stand how anaesthetics act we must approach anaesthetic ness became important as conscious patients, even if they mechanisms at multiple levels. Ultimately, receptor effects had complete analgesia, would probably talk, which would must be viewed within the context of the clinical charac- disrupt the surgical procedure. Indeed, an unconscious and teristics of general anaesthesia. Does a particular anaes- immobile patient permits surgical procedures that are thetic alter receptor function at clinically relevant limited only by the available technology and skill of the anaesthetic concentrations? Is there evidence (anatomical, surgeon. neurophysiological, pharmacological) that a speci®c recep- Within a year of Morton's public demonstration of ether tor is involved in a clinically relevant neurophysiological anaesthesia, John Snow published an account of the process, such as memory? pharmacological and physiological effects of ether.86 Anaesthesia can be de®ned in arbitrary terms, although These effects were divided into stages, progressing from practical considerations often govern speci®c de®nitions. consciousness to deep coma, muscle ¯accidity and respira- Thus, from a practical standpoint, most people would tory paralysis. include unconsciousness, amnesia and immobility as Guedel described four stages of ether anaesthesia,46 important end-points. On the other hand, reduction of stress similar to those described by Snow. In the ®rst stage the hormones is not necessarily an absolute, required anaes- patient was conscious but had analgesia (Fig. 1). In the thetic end-point. In this review we will examine the various second stage (the delirium stage) the patient exhibited components of general anaesthesia. That is, what are the excessive motor activity, even to the point of violence. Eye clinical goals we seek to achieve? What are the side-effects movements were irregular and erratic, as was breathing. The we hope to avoid? This latter component is important third stage represented the surgical stage; four planes were because an anaesthetic (or any drug) is only as good as the originally described, with increasing anaesthetic depth as minimization of its side-effects. the patient progressed from the ®rst to the last plane. Respiration became progressively weaker. In the fourth stage of anaesthesia, respiratory paralysis occurred. These Historical aspects classic signs have broad application, but it is clear that not Before Morton's display of ether anaesthesia, patients were all anaesthetics cause the same progression of clinical signs. accustomed to being conscious during surgeryÐpainfully Newer anaesthetics, in particular i.v. anaesthetics such as so. There was no a priori expectation that they should be propofol, may not exhibit such signs. One wonders how unconscious. Their hope was not so much to be unconscious much of this difference is due to pharmacokinetic as but rather to be pain-free. After all, few people would opposed to pharmacodynamic reasons. Many of the newer voluntarily give up consciousness if complete analgesia inhaled anaesthetics have low blood-gas solubilities and were otherwise possible. It was the characteristic of ether, thus patients may pass from one stage to the next relatively chloroform and subsequent anaesthetics that unconscious- quickly. Likewise, with i.v. anaesthetics patients are Ó The Board of Management and Trustees of the British Journal of Anaesthesia 2002

In vivo characterization of clinical anaesthesia remain `within normal limits'. An anaesthetist must balance the demands of all three. For practical purposes we de®ne 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, Fig 1 Guedel's signs for ether anaesthesia included muscle tone, breathing pattern and eye movements. Stage 1 was marked by analgesia pre-emptive analgesia could be included as a desirable goal, and consciousness. In Stage 2, the patient became unconscious, breathing but it is not an absolute requirement for general anaesthesia. was erratic but delirium could occur, leading to an excitement phase. In Stage 3, surgical anaesthesia occurred, with four planes or levels describing increasing depth until breathing became weak. Stage 4 was Neurophysiological processes pertinent to marked by respiratory paralysis and death. Other signs included pupil anaesthesia size. Newer anaesthetics and `balanced' anaesthesia have rendered some of these signs less reliable. (Based on reference 46.) Memory Memory formation occurs at a variety of sites in the brain, brought to deeper stages rapidly by bolus administration. including the hippocampus, amygdala, prefrontal cortex and Thus, there are few data comparing these newer anaesthetics other cortical sensory and motor areas.37 54 Anaesthetics with older ones, such as ether. 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.37 54 What de®nes anaesthesia? Explicit recall is what most people usually describe as How do we decide what are the essential components of memory: they can explicitly recall a speci®c event, such as a general anaesthesia? What are the non-essential but desir- football game or their wedding day. Implicit recall occurs able goals? These decisions may be made with practical, when an individual cannot remember a certain event, but scienti®c, theoretical and historical considerations. upon speci®c testing there is evidence that information has We ®rst differentiate `general anaesthesia' from a `gen- been retained. There are several studies that suggest that, at eral anaesthetic'. The former de®nes a pharmacologically low anaesthetic concentrations, implicit memory formation induced physiological state in which the essential goals of may occur while explicit recall is blocked.21 23 42 The general anaesthesia are achieved. This may be accom- speci®c sites where this action occurs are not known. plished 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. Consciousness What are regarded as the essential goals of general The physiological processes and anatomical sites that give anaesthesia can depend on the perspective of the de®ner. For rise to consciousness are poorly understood, and the sites the patient, an important goal will be amnesiaÐhe or she where anaesthetics induce unconsciousness are understood does not want to remember anything. A close second would even less. Several sites are likely to participate in con- probably be unconsciousnessÐthe patient does not want to sciousness, including the cerebral cortex, thalamus and be awake during surgery. A surgeon wants a still patient. A reticular formation.66 88 All of those structures are affected cardiologist wants the patient's blood pressure and pulse to by anaesthetics.6 22 84 Alkire and colleagues have examined 157

Antognini and Carstens noxious stimulus (Fig. 2). Such re¯exes 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 re¯ex 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.96 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 re¯ex (e.g. withdrawal). Nociceptive input is also likely to activate central pattern generators, which coordinate movement such that the animal can move ef®ciently in a walk, trot or gallop. Fig 2 Noxious stimulation results in impulse transmission to the dorsal horn, where second-order neurones might send impulses to ascending tracts (such as the spinothalamic tract) or to motor neurones that Neurotransmitter systems innervate muscles that initiate a motor response, such as an escape or A wide variety of neurotransmitter systems is likely to be withdrawal response. The ascending transmission of these impulses affected by anaesthetics but it is unclear how these actions `activates' the brain and results in increased arousal. The location of the spinothalamic tract varies from species to species. translate into clinical effects.60 In addition, it is unclear if presynaptic or postsynaptic effects are more important. The GABA receptor has been the focus of intense research and the effect of halothane, iso¯urane and propofol on cerebral there is ample evidence that alteration of GABAergic metabolism [using positron emission tomography (PET)] as neurotransmission could alter consciousness, memory and an indirect method of investigating sites of anaesthetic nociceptive responses. Other neurotransmitters are also action.1±5 These anaesthetics depress metabolism in the likely to be involved in these processes.60 For example, cortex, thalamus and reticular formation, as one would anaesthetics affect the physiology and pharmacology of expect. Whether the effects at each site contribute equally to glutamate and nitric oxide.71 Antagonists of N-methyl-D- unconsciousness or whether one site is more crucial than the aspartate (NMDA), such as MK-801, drastically reduce the others remains to be elucidated. Fiset and colleagues minimum alveolar concentration (MAC),82 but is this a investigated the effects of propofol using PET scanning direct and relevant anaesthetic action or does it merely and found that propofol produced greater metabolic reduc- re¯ect the importance of glutamate in the initiation of tion in the medial thalamus and other brain sites associated nociceptive re¯exes, such that simply by blocking glutamate with arousal.38 A logical conclusion from their data is that transmission one can prevent nociceptive responses? propofol produced unconsciousness through a preferential Acetylcholine and the cholinergic neurotransmitter system effect on sites associated with arousal. Alkire and others are also possibly involved in anaesthesia. Physostigmine has have suggested that anaesthetics might affect thalamocor- been shown to reverse partially the sedative effects of tical loops that appear to be critical for conscious aware- propofol and halothane.48 65 The cerebral activation that is ness.3 In an intriguing study, Devor and Zalkind injected associated with increased arousal is also associated with pentobarbital into a discrete area of the rat mesopontine cortical release of acetylcholine.52 Sensory stimulation can tegmental area bilaterally, producing unconsciousness and likewise cause cortical release of acetylcholine,61 and analgesia.28 Clearly, however, considerably more work is iso¯urane can affect this release.83 needed to understand where anaesthetics act in the brain to in¯uence consciousness. Anaesthetic goals Nociceptive re¯exes Immobility Nociceptive re¯exes have evolved as a protective mechan- Anaesthetic end-points can sometimes be described in ism to withdraw the body (or part of the body) from a relation to the concentration of anaesthetic required to block 158

In vivo characterization of clinical anaesthesia Amnesia and unconsciousness Amnesia and unconsciousness are among the ®rst 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', ®rst described by Stoelting and colleagues.90 They measured the concentrations of methoxy¯urane, halothane, ether and ¯uroxene that just permitted and prevented consciousness (as de®ned 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 Fig 3 These dose±response curves for various end-points were developed two groups, it is unclear how the presence of post-surgical from a variety of studies. Note that the curves for memory and pain might have altered the results, inasmuch as noxious consciousness are close to each other. The effective dose that results in stimulation is likely to result in cerebral activation and 50% of patients having unconsciousness is called `MAC-awake'. This value is about 30±40% of MAC, although there are differences among increased probability of consciousness. The MAC-awake anaesthetics. MAC-awake might be greater during the noxious for ether (as a fraction of MAC) was greater than that for the stimulation of surgery. The anaesthetic concentration that blocks the other anaesthetics, despite the fact that ether was studied cardiovascular response is called `MAC-BAR'. 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 movementÐthe MAC (Fig. 3). This is essentially the editorial,95 Waud and Waud placed limits on the interpret- median effective dose (ED50), the dose that causes a ation of the work of Stoelting and colleagues90 (but see also particular effect in 50% of people or animals. reference 20). Speci®cally, examination of only one point The MAC concept was developed in 1965 as a way to on a curve or set of curves (e.g. the point at which 50% of compare equipotent concentrations of anaesthetics.34 The patients are awake) says nothing about the overall curve measurement of MAC depends essentially on achieving a and, hence, relative potency and effect. They also ques- stable end-tidal anaesthetic concentration, applying a tioned whether examination of MAC-awake and other standard noxious stimulus and observing whether move- variants of MAC would yield any useful information ment occurs.34 74 Positive movement was arbitrarily de®ned regarding anaesthetic mechanisms. Many investigators as `gross and purposeful', although any other movement now believe that anaesthetics act at different sites, and type could have been included. Thus, a pawing motion or therefore knowledge regarding the anaesthetic concentra- turning of the head towards the stimulus are usually tion required to achieve certain end-points (unconsciousness considered positive, while coughing, straining, chewing and immobility) is directly relevant to determining anaes- and stiffening are considered negative.74 In general, many thetic mechanisms.36 It is interesting to note that an investigators also consider simple withdrawal of the stimu- editorial44 published nearly 30 yr after the work of lated extremity as being negative. What is important is that Stoelting and colleagues and Waud and Waud commented in any individual study there is consistency as to what is on the effect of fentanyl on MAC-awake56 (Fig. 4), stating positive and what is negative movement. that such studies were critical to our elucidation of The noxious stimulus must be supramaximal. That is, anaesthetic mechanisms. increasing the stimulus intensity must not result in further Dwyer and colleagues determined that consciousness was increases in anaesthetic requirements. A mechanical stimu- present at iso¯urane concentrations (0.3 MAC) at which lus is usually used, such as a clamp placed across the tail or a memory formation was impaired.30 Furthermore, the hind paw. The stimulus is applied for 1 min or until authors concluded that, at equipotent MAC concentrations, movement occurs, after which the anaesthetic concentration iso¯urane was more potent than nitrous oxide as regards the is changed (up or down, depending on the response). MAC production of unconsciousness and the reduction of explicit is de®ned as the average of the two anaesthetic concentra- memory formation. The volunteers in this study were not tions that are observed to just permit and just prevent the subjected to noxious stimulation, as might occur during movement, respectively. In humans undergoing surgery, a surgery, and so it is unclear whether the amount of skin incision is often used to determine the MAC, but this anaesthetic needed for amnesia and unconsciousness is stimulus can be applied only once. A population MAC can increased during noxious stimulation; presumably it is. In an still be obtained by adjusting the anaesthetic concentration earlier study, however, this group of investigators showed in subsequent patients so that about half of these patients that iso¯urane at 0.6 MAC or greater prevented conscious- move and half do not move. ness and memory formation (explicit and implicit) during 159

Antognini and Carstens 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.89 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 iso¯urane-anaesthetized patients to determine if processed EEG variables might correlate with clinically relevant anaesthetic end-points.32 Spectral edge frequency, median power and total power Fig 4 Effect of fentanyl on sevo¯urane requirements. Note that MAC- were among the variables examined. The authors were BAR (the minimum anaesthetic concentration required to block unable to make predictions regarding patient movement, adrenergic responses) is affected the most, suggesting that analgesia is an memory formation or consciousness.32 Indeed, human and important tool for the control of haemodynamic responses to noxious rat data suggest that marked EEG depression resulting from stimulation. MAC-awake (the concentration that results in iso¯urane and thiopental does not correlate with movement unconsciousness) is affected least and merges with MAC and MAC- BAR. Thus a patient given opiates might not move or have a resulting from noxious stimulation,51 77 although haemo- haemodynamic response to noxious stimulation but might be conscious. dynamic responses to laryngoscopy and tracheal intubation This is not unexpected, because there are numerous reports of patients might correlate with EEG changes.79 awake during what is primarily an opiate `anaesthetic'. Based on the There is substantial evidence that some anaesthetics work of Katoh and colleagues.56 57 prevent movement via a spinal cord action,10 16 75 78 but is there any reason to believe that other end-points (amnesia, surgical procedures.31 Ropcke and colleagues showed that È unconsciousness) might be affected by a spinal cord action? noxious stimulation can alter anaesthetic effects on the We believe that there is some indirect evidence. First, electroencephalogram (EEG).81 They studied two groups of epidural anaesthesia decreases the amount of anaesthetic des¯urane-anaesthetized patients, one with and one without required to prevent the movement that results from noxious noxious surgical stimulation. At equal concentrations, the stimulation applied above the level of the block.50 This group with surgical stimulation demonstrated EEG acti- might be due to an indirect action in the brain, such as vation, whereas the non-stimulated group did not. These resetting of the brain's arousal level. Secondly, spinal and data suggest that noxious stimulation during otherwise epidural anaesthetics decrease the amount of sedative/ adequate anaesthesia results in a shift towards increased hypnotics needed to achieve a certain level of arousal.81 sedation,33 49 92 93 presumably by blocking afferent Learning and memory formation during anaesthesia impulses, and sedation is associated with amnesia and depends on the circumstances under which stimuli are unconsciousness.43 Thirdly, volatile anaesthetics and i.v. presented. Dutton and colleagues studied conditioned anaesthetics (such as propofol and thiopental) block learning in rats anaesthetized with iso¯urane.29 They nociceptive impulses in the spinal cord.59 67 94 Such actions found that fear-conditioning to a tone was less sensitive to blunt the ascending transmission of noxious impulses to the iso¯urane than fear-conditioning to context (e.g. the brain, which is likely to diminish the arousal of the brain, surrounding environment). Approximately 0.5 MAC iso- thereby decreasing the probability of memory formation and ¯urane was required to prevent fear-conditioning associated consciousness (Fig. 6). We have evidence that iso¯urane, with the tone compared with 0.25 MAC for conditioning probably by a spinal cord action, might affect brain arousal. associated with the context.29 When iso¯urane is selectively removed from the torso while Non-immobilizers are compounds that are predicted to be a constant concentration is kept in the brain, a noxious anaesthetics on the basis of their physicochemical properties stimulus can increase brain arousal, as indicated by but in fact are not. Originally these compounds were called increased neuronal activity in the reticular formation and non-anaesthetics but one report has shown that they can thalamus and EEG desynchronization.12 18 We have made suppress learning and hence memory.55 Amnesia is a similar observations with propofol.15 desired anaesthetic end-point, and thus it would be impre- cise to call these compounds non-anaesthetics. Because these molecules do not contribute to immobility, the Haemodynamic and neuroendocrine control consensus is to label them non-immobilizers. These data Roizen and colleagues examined the ability of halothane, offer further evidence that anaesthetic end-points are likely en¯urane, opiates and spinal anaesthesia to block the to result from anaesthetic action at different sites.87 cardiovascular and neuroendocrine responses to skin inci- 160

In vivo characterization of clinical anaesthesia Fig 5 At the top are shown the bifrontal EEGs from a goat anaesthetized with iso¯urane at 1.5, 3.5 and 5% (3 min and 10 s samples). Below are peristimulus time histograms (PSTHs) representing the corresponding activity of a midbrain reticular formation (MRF) cell. In the ®rst two PSTHs the arrows represent application of a clamp to the goat's lip for 1 min. This MRF cell is inhibited by the noxious stimulus, but at 3.5% iso¯urane the spontaneous activity is increased and the cell is not completely inhibited by the noxious clamp. Note that at 3.5 and 5% iso¯urane the EEG is isoelectric (with occasional spikes) but the MRF cell is still active. sion.80 Halothane and en¯urane were added to 60% nitrous mentioned above, one reason may be the presence of oxide. They described the blocking effect in terms of the analgesic properties. Iso¯urane, for example, appears to anaesthetic concentration that blocked adrenergic responses have little or no analgesic effect at subanaesthetic concen- (MAC-BAR).80 A positive response was arbitrarily de®ned trations. Petersen-Felix and colleagues did not detect any as an increase of 10% or more in heart rate, blood pressure evidence of analgesia to noxious thermal, mechanical or or norepinephrine values. Interestingly, while halothane and electrical stimulation at iso¯urane concentrations ranging an opiate±nitrous oxide technique could block adrenergic from 0.0 to 0.26%.73 Halothane, on the other hand, does responses at clinically relevant concentrations, en¯urane have analgesic properties,85 although not all studies con- could not. Spinal anaesthesia, as long as it blocked the pain cur.91 Anaesthetic-induced sedation and unconsciousness of incision, also blocked the neuroendocrine and cardio- makes interpretation of analgesia studies dif®cult.85 The vascular response. Could the inability of en¯urane to block presence of analgesic properties will blunt the nociceptive these responses be related to its poor analgesic properties? responses (e.g. increased blood pressure and heart rate). While it is tempting to think that the ability of halothane to Although most studies suggest that anaesthetics have some block the cardiovascular responses is in part due to direct analgesic properties or none, there is evidence that at cardiovascular depression, en¯urane is one of the most relatively low anaesthetic concentration (0.1 MAC) hyper- potent cardiovascular depressants, and yet it was unable to algesia might occur. Zhang and colleagues studied four prevent the cardiovascular responses to incisions. This anaesthetics on hind paw withdrawal elicited by noxious concept of MAC-BAR was investigated further by Zbinden stimulation in rats.100 Iso¯urane, halothane, nitrous oxide and colleagues, who studied patients anaesthetized with and diethyl ether decreased withdrawal latency, suggesting iso¯urane.98 99 Different stimuli were used, such as a hyperalgesic effect. Barbiturates are also associated with trapezius squeeze, tetanic stimulation and skin incision. hyperalgesia.19 They found that iso¯urane, in clinically relevant concen- A second way that anaesthetics might alter cardiovascular trations, was unable to prevent the haemodynamic response responses is by direct action on the heart and blood vessels. to noxious stimulation, even when iso¯urane decreased the In addition, we examined whether anaesthetic action in the prestimulation value to clinically unacceptable levels. These brain might affect cardiovascular responses to noxious data suggest that iso¯urane by itself is not a good agent to stimulation.8 During differential iso¯urane delivery to the use to control a patient's blood pressure adequately within a head, we observed that heart rate and blood pressure normal range. increased signi®cantly during noxious stimulation and that Why do some anaesthetics suppress these haemodynamic only supraclinical iso¯urane concentrations in the brain responses to noxious stimulation while others do not? As could prevent this response.8 161

Antognini and Carstens and then transected, a method that minimizes or prevents spinal shock. It was reported that the iso¯urane MAC (determined when the noxious stimulus was applied below the level of transection) was unchanged.75 We have used a goat model to investigate the relative roles of the brain and spinal cord in anaesthetic actions.7 13 16 In brief, because of the unique cerebral circulation of goats, we can differentially deliver anaesthetics to the head (brain) or torso (spinal cord). Within the central nervous system, the watershed area where the torso and head circulation mix is at the level of the caudal medulla or upper cervical cord, the exact level depending on the blood pressure difference between the systemic and cranial circulations.13 With an intact native circulation, iso¯urane MAC in these goats was 1.2%.16 During differential iso¯urane delivery, cranial iso¯urane requirements (to suppress movement) were »3% when torso iso¯urane concentration (and hence spinal cord concentration) was low (»0.2±0.3%).16 As one would expect, the EEG was depressed at these high iso¯urane concentrations in the brain. We subsequently examined whether halothane and thiopental had similar effects on movement.10 Halothane appeared to be less potent in the brain (compared with iso¯urane) inasmuch as halothane at high concentrations (>4%) delivered to the cranial circulation could not stop movement in some animals. Overall, the cranial halothane requirement increased by nearly 400%. Despite a greatly depressed or isoelectric EEG, these animals still moved in response to noxious stimulation. In contrast, the cranial requirement for Fig 6 Differential anaesthetic delivery aids elucidation of how anaesthetic action in the spinal cord affects brain arousal.12 18 In the top thiopental increased by a factor of only 2, because panel, the anaesthetic (iso¯urane) concentration in the spinal cord is »40 mg ml±1 was required to prevent movement during suf®cient to effectively block the ascending transmission of nociceptive cranial thiopental delivery whereas »20 mg ml±1 was impulses to the midbrain reticular formation (MRF), thalamus (Thal) and required during systemic administration.10 Interestingly, brain; no EEG activation occurs. In one scenario (middle), decreasing the the EEG was active during the differential thiopental spinal concentration of anaesthesia facilitates the ascending transmission of nociceptive impulses, but the sensitivity of the brain is unchanged delivery even though the animals ceased moving. compared with the top panel. There is minimal EEG activation, owing to We have interpreted these collective data10 16 to suggest the added nociceptive impulses that are transmitted to the brain. In the that anaesthetic action in the spinal cord is important for the scenario in the lower panel, we hypothesize that the brain is more ability of iso¯urane, halothane and thiopental to prevent sensitive to the additional nociceptive impulses, and there is marked EEG movement. There are important differences, however. First, activation (desynchronization). The enhanced sensitivity might be due to increased ascending afferent activity that `resets' the brain's arousal halothane and iso¯urane appear to differ in that substantially level. By indirectly diminishing brain arousal, the spinal cord action of more halothane is required in the brain to prevent movement anaesthetics could affect memory and unconsciousness. (compared with iso¯urane). Secondly, although the relative increases in the cranial requirements for thiopental and iso¯urane were quantitatively similar, there was a distinct qualitative difference in that thiopental, but not iso¯urane, Spinal cord as a site of anaesthetic action permitted an active EEG when its cranial action could For many decades, the brain has been thought to be the site prevent movement. This indicates that the immobilizing of anaesthetic action, insofar as memory, consciousness and effect of thiopental in the brain is more potent than that of initiation of movement occur in the brain. In the last decade halothane, relative to the EEG suppression effect. several lines of evidence have emerged indicating that the Furthermore, it is not entirely clear that iso¯urane, spinal cord might be an important site of anaesthetic action. halothane and thiopental act at common sites in the brain. The work of Rampil and colleagues strongly suggests that Although we have dismissed other sites in the torso as an action of iso¯urane on the spinal cord is important to regards anaesthetic action, how do we know with certainty suppression of movement.75 76 78 The MAC was unchanged that, when using an experimental preparation in which we after precollicular decerebration in rats.78 In a follow-up remove an anaesthetic from the torso, we can ascribe an study, a section of the spinal cord was rendered hypothermic action to the spinal cord? Is it possible that anaesthetics 162

In vivo characterization of clinical anaesthesia might act at the other sites, such as the peripheral nerve? action on the spinal motor neurone with little or no indirect Halothane and iso¯urane do not depress peripheral supraspinal component.11 nociceptors; in fact, excitation is more likely.24 63 The The ability of anaesthetic agents to produce immobility is peripheral nerve is not substantially affected by clinical usually assessed by their effectiveness in blocking gross concentrations of anaesthetics.26 purposeful movement. An understanding of the underlying To rule out a peripheral site of anaesthetic action, we mechanism will ultimately require study of anaesthetic performed a bypass study in dogs in which we selectively effects on complex motor processing. The spinal cord removed iso¯urane from the lower torso.14 Anaesthetic appears to be capable of generating a variety of complex, requirements (MAC) were determined with application of coordinated movement patterns. Decerebrate rats are cap- the noxious stimulus to a lower torso site in the presence or able of normal activity, such as grooming, exploring their absence of iso¯urane at that site. We found that MAC was cages and eating.62 97 Frogs sectioned at an upper cervical unchanged, suggesting that peripheral action of iso¯urane is level still have a normal wiping re¯ex, whereby the hind not important, at least as regards immobility. limb moves to wipe away a noxious chemical stimulus Within the spinal cord, the dorsal horn has received much applied to the forelimb. If the forelimb is moved, the hind attention as a site of anaesthetic action. Because the dorsal limb is able to determine the position of the forelimb, horn acts as a `spinal gate', anaesthetic effects on dorsal despite the absence of any supraspinal input.41 Cats horn neuronal responses have been investigated over several sectioned at a mid-thoracic level still exhibit fairly normal decades.27 67 Virtually all anaesthetics examined appeared locomotion on a treadmill after recovery from spinal shock to depress spontaneous ®ring and/or responses to innocuous and with support of the body weight.39 72 Lastly, brain-dead and noxious stimuli. There were, however, several meth- humans can display the Lazarus phenomenon, in which they odological differences among these studies, making direct have spontaneous movement, including crossing of the arms comparisons dif®cult. We were interested in the depressant over the chest, sitting up in bed and turning of the head.25 64 effect of iso¯urane on dorsal horn neuronal responses to All of the complex movement patterns described above supraspinal noxious stimulation within the narrow range are mediated by neural circuits, including central pattern that just permitted and just prevented movement (0.9±1.0 generators (CPGs), which are intrinsic to the spinal cord. It MAC).9 We observed that increasing the iso¯urane con- is currently not known how anaesthetics affect CPGs. To centration from 0.9 to 1.1 MAC resulted in a modest (15%) begin to address this question, we recently investigated the depression in evoked responses. It is unclear if a change of effects of inhaled anaesthetic agents on the pattern of this small order of magnitude is suf®cient to account for coordinated limb and head movements evoked by supra- such a signi®cant behavioural change. Furthermore, the maximal stimulation in rats.17 All limbs and the snout were neurones studied were not identi®ed according to their attached to force transducers to measure the direction and function, e.g. as re¯ex interneurones or ascending projection force of movements. At sub-MAC concentrations of neurones. It is conceivable that anaesthetics may exert iso¯urane or halothane, the supramaximal noxious stimulus differential effects on functionally distinct classes of spinal elicited synchronous, rather than alternating, movements of neurones, an issue that deserves further study. all four limbs. When there was head movement it was Over the last several years the spinal motor neurone has almost always towards the side of the noxious stimulus. As received signi®cant attention as a possible site of anaes- the concentration of iso¯urane or halothane was increased, thetic action. In a series of studies, Rampil and Zhou and there was ®rst a reduction in the number of movements, and their respective colleagues indirectly assessed anaesthetic at higher concentrations, a reduction in the force of effects on the motor neurone using the F-wave.58 76 101 102 movements. We are at an early stage in investigating The F-wave is evoked by electrical stimulation of a anaesthetic action on complex movement patterns, and there peripheral motor (or mixed) nerve, and is thought to result are many open questions. Noxious stimuli evoke limb from antidromic invasion of the motor neuronal cell body withdrawal re¯exes; what is the relationship of these fairly with recurrent orthodromic conduction back down the simple re¯ex pathways to CPGs involved in generating motor nerve to evoke muscle contraction.76 The F-wave is more complex escape responses? Does noxious stimulation thought to re¯ect motor neurone excitability, although the elicit synchronous (or other) patterns of coordinated limb evidence for this is mainly indirect. The F-wave is enhanced movements in other species? Studies addressing these and in clinical conditions associated with increased motor related questions will be worthwhile in understanding better neurone excitability, such as spasticity. Inhaled agents how anaesthetics affect spinal CPGs that generate complex (iso¯urane, halothane, des¯urane, sevo¯urane) and nitrous movement patterns. oxide have been shown to depress the F-wave.40 58 76 101 102 However, it is not clear if this depression is a causal factor in the ability of anaesthetic agents to produce immobility or if Undesirable effects it is merely correlated with immobility that is primarily Although the primary emphasis of research on anaesthetic caused by some other anaesthetic action. In any event, mechanisms is to determine how anaesthetics produce their anaesthetic depression of the F-wave appears to be a direct desired effects, we must also determine how these powerful 163

Antognini and Carstens drugs produce undesired effects, such as post-operative other anaesthetic agents on the centripetal transmission of nausea and vomiting (PONV) and respiratory and cardio- sensory information. Gen Pharmacol 1992; 23: 945±63 7 Antognini JF, Jinks S, Buzin V, Carstens E. A method for vascular depression. Cyclopropane and ether produced differential delivery of intravenous drugs to the head and torso limited cardiovascular depressive effects,35 45 53 but were of the goat. Anesth Analg 1998; 87: 1450±2 associated with PONV (particularly ether). Both drugs were 8 Antognini JF, Berg K. Cardiovascular responses to noxious eliminated from clinical use because of in¯ammability. stimuli during iso¯urane anesthesia are minimally affected by Halogenation of the carbon skeleton eliminated in¯amma- anesthetic action in the brain. Anesth Analg 1995; 81: 843±8 bility but also introduced cardiovascular depression. Thus, 9 Antognini JF, Carstens, E. Increasing iso¯urane from 0.9 to 1.1 changing the structure of an anaesthetic might enhance minimum alveolar concentration minimally affects dorsal horn cell responses to noxious stimulation. Anesthesiology 1999; 90: desirable characteristics but may also introduce or exacer- 208±14 bate side-effects. 10 Antognini JF, Carstens E, Atherley R. Does thiopental's Respiratory depression is a common side-effect of immobilizing effect in brain exceed that of halothane? virtually all anaesthetics. The mechanisms for this effect Anesthesiology 2002; 96: 980±6 have not been fully elucidated, but there are likely to be 11 Antognini JF, Carstens E, Buzin V. Iso¯urane depresses differences among anaesthetics. Nieuwenhuijs and col- motoneuron excitability by a direct spinal action: an F-wave leagues found that propofol depressed the central chemore- study. Anesth Analg 1999; 88: 681±5 12 Antognini JF, Carstens E, Sudo M, Sudo S. Iso¯urane depresses ¯ex loop but had no signi®cant effect on the peripheral electroencephalographic and medial thalamic responses to chemore¯ex loop.69 Inhaled anaesthetics depress the per- noxious stimulation via an indirect spinal action. Anesth Analg ipheral loop. Further work is required to elucidate mech- 2000; 91: 1282±8 anisms of respiratory depression. Hopefully it will be 13 Antognini JF, Kien ND. A method for preferential delivery of possible someday to develop an anaesthetic that has little or volatile anesthetics to the in situ goat brain. Anesthesiology 1994; no cardiopulmonary depression. 80: 1148±54 From a patient's perspective, PONV is one of the most 14 Antognini JF, Kien ND. Potency (minimum alveolar anesthetic concentration) of iso¯urane is independent of peripheral common distressing complications of surgery and anaes- anesthetic effects. Anesth Analg 1995; 81: 69±72 thesia. However, it is not a life-threatening complication. 15 Antognini JF, Saadi J, Wang XW, Carstens E, Piercy M. Propofol There is little research examining the mechanisms of action in both spinal cord and brain blunts electro- anaesthetic-induced PONV. encephalographic responses to noxious stimulation in goats. There is evidence that anaesthetics might in¯uence the Sleep 2001; 24: 26±31 immune responses that are important in recovery after 16 Antognini JF, Schwartz K. Exaggerated anesthetic requirements surgery.47 68 70 As surgical techniques progress and in the preferentially anesthetized brain. Anesthesiology 1993; 79: 1244±9 improve, patient outcome could perhaps be tied more 17 Antognini JF, Wang XW, Carstens E. Quantitative and qualitative closely to these subtle effects. effects of iso¯urane on movement occurring after noxious stimulation. Anesthesiology 1999; 91: 1064±71 18 Antognini JF, Wang XW, Carstens, E. 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AnestéSicos Review

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