1 Department of Anesthesiology, TB-170, University of California at Davis, Davis, CA 95616, USA. 2 Section of Neurobiology, Physiology and Behavior, 193 Briggs Hall, University of California at Davis, Davis, CA 95616, USA*Corresponding author
Abstract
Br J Anaesth 2002; 89: 15666
Keywords: anaesthesia, general; theories of anaesthetic action
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.
Historical aspects
Before Mortons display of ether anaesthesia, patients were accustomed to being conscious during surgerypainfully 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 Mortons public demonstration of ether anaesthesia, John Snow published an account of the pharmacological and physiological effects of ether.86 These effects were divided into stages, progressing from consciousness to deep coma, muscle flaccidity and respiratory paralysis.
Guedel described four stages of ether anaesthesia,46 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.
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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 amnesiahe or she does not want to remember anything. A close second would probably be unconsciousnessthe patient does not want to be awake during surgery. A surgeon wants a still patient. A cardiologist wants the patients 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.
Neurophysiological processes pertinent to anaesthesia
Memory
Memory formation occurs at a variety of sites in the brain, including the hippocampus, amygdala, prefrontal cortex and other cortical sensory and motor areas.37 54 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.37 54 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.21 23 42 The specific sites where this action occurs are not known.
Consciousness
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.66 88 All of those structures are affected by anaesthetics.6 22 84 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.15 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.38 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.3 In an intriguing study, Devor and Zalkind injected pentobarbital into a discrete area of the rat mesopontine tegmental area bilaterally, producing unconsciousness and analgesia.28 Clearly, however, considerably more work is needed to understand where anaesthetics act in the brain to influence consciousness.
Nociceptive reflexes
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.
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Neurotransmitter systems
A wide variety of neurotransmitter systems is likely to be affected by anaesthetics but it is unclear how these actions 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 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.60 For example, anaesthetics affect the physiology and pharmacology of glutamate and nitric oxide.71 Antagonists of N-methyl-D-aspartate (NMDA), such as MK-801, drastically reduce the minimum alveolar concentration (MAC),82 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.48 65 The cerebral activation that is associated with increased arousal is also associated with cortical release of acetylcholine.52 Sensory stimulation can likewise cause cortical release of acetylcholine,61 and isoflurane can affect this release.83
Anaesthetic goals
Immobility
Anaesthetic end-points can sometimes be described in relation to the concentration of anaesthetic required to block movementthe MAC (Fig. 3). This is essentially the median effective dose (ED50), the dose that causes a particular effect in 50% of people or animals.
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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
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.90 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,95 Waud and Waud placed limits on the interpretation of the work of Stoelting and colleagues90 (but see also reference 20). 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.36 It is interesting to note that an editorial44 published nearly 30 yr after the work of Stoelting and colleagues and Waud and Waud commented on the effect of fentanyl on MAC-awake56 (Fig. 4), stating that such studies were critical to our elucidation of anaesthetic mechanisms.
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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.29 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.29
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.55 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.87
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 isoflurane-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 were among the variables examined. The authors were unable to make predictions regarding patient movement, memory formation or consciousness.32 Indeed, human and rat data suggest that marked EEG depression resulting from isoflurane and thiopental does not correlate with movement resulting from noxious stimulation,51 77 although haemodynamic responses to laryngoscopy and tracheal intubation might correlate with EEG changes.79
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Why do some anaesthetics suppress these haemodynamic responses to noxious stimulation while others do not? As mentioned above, one reason may be the presence of analgesic properties. Isoflurane, for example, appears to have little or no analgesic effect at subanaesthetic concentrations. Petersen-Felix and colleagues did not detect any evidence of analgesia to noxious thermal, mechanical or electrical stimulation at isoflurane concentrations ranging from 0.0 to 0.26%.73 Halothane, on the other hand, does have analgesic properties,85 although not all studies concur.91 Anaesthetic-induced sedation and unconsciousness makes interpretation of analgesia studies difficult.85 The presence of analgesic properties will blunt the nociceptive responses (e.g. increased blood pressure and heart rate). Although most studies suggest that anaesthetics have some analgesic properties or none, there is evidence that at relatively low anaesthetic concentration (0.1 MAC) hyperalgesia might occur. Zhang and colleagues studied four anaesthetics on hind paw withdrawal elicited by noxious stimulation in rats.100 Isoflurane, halothane, nitrous oxide and diethyl ether decreased withdrawal latency, suggesting a hyperalgesic effect. Barbiturates are also associated with hyperalgesia.19
A second way that anaesthetics might alter cardiovascular responses is by direct action on the heart and blood vessels. In addition, we examined whether anaesthetic action in the brain might affect cardiovascular responses to noxious stimulation.8 During differential isoflurane delivery to the head, we observed that heart rate and blood pressure increased significantly during noxious stimulation and that only supraclinical isoflurane concentrations in the brain could prevent this response.8
Spinal cord as a site of anaesthetic action
For many decades, the brain has been thought to be the site of anaesthetic action, insofar as memory, consciousness and initiation of movement occur in the brain. In the last decade several lines of evidence have emerged indicating that the spinal cord might be an important site of anaesthetic action. The work of Rampil and colleagues strongly suggests that an action of isoflurane on the spinal cord is important to suppression of movement.75 76 78 The MAC was unchanged after precollicular decerebration in rats.78 In a follow-up study, a section of the spinal cord was rendered hypothermic and then transected, a method that minimizes or prevents spinal shock. It was reported that the isoflurane 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, isoflurane MAC in these goats was 1.2%.16 During differential isoflurane delivery, cranial isoflurane requirements (to suppress movement) were 3% when torso isoflurane concentration (and hence spinal cord concentration) was low (
0.20.3%).16 As one would expect, the EEG was depressed at these high isoflurane 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 isoflurane) 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 thiopental increased by a factor of only 2, because
40 µg ml1 was required to prevent movement during cranial thiopental delivery whereas
20 µg ml1 was required during systemic administration.10 Interestingly, the EEG was active during the differential thiopental delivery even though the animals ceased moving.
We have interpreted these collective data10 16 to suggest that anaesthetic action in the spinal cord is important for the ability of isoflurane, halothane and thiopental to prevent movement. There are important differences, however. First, halothane and isoflurane appear to differ in that substantially more halothane is required in the brain to prevent movement (compared with isoflurane). Secondly, although the relative increases in the cranial requirements for thiopental and isoflurane were quantitatively similar, there was a distinct qualitative difference in that thiopental, but not isoflurane, permitted an active EEG when its cranial action could prevent movement. This indicates that the immobilizing effect of thiopental in the brain is more potent than that of halothane, relative to the EEG suppression effect. Furthermore, it is not entirely clear that isoflurane, halothane and thiopental act at common sites in the brain.
Although we have dismissed other sites in the torso as regards anaesthetic action, how do we know with certainty that, when using an experimental preparation in which we remove an anaesthetic from the torso, we can ascribe an action to the spinal cord? Is it possible that anaesthetics might act at the other sites, such as the peripheral nerve? Halothane and isoflurane do not depress peripheral nociceptors; in fact, excitation is more likely.24 63 The peripheral nerve is not substantially affected by clinical concentrations of anaesthetics.26
To rule out a peripheral site of anaesthetic action, we performed a bypass study in dogs in which we selectively removed isoflurane from the lower torso.14 Anaesthetic requirements (MAC) were determined with application of the noxious stimulus to a lower torso site in the presence or absence of isoflurane at that site. We found that MAC was unchanged, suggesting that peripheral action of isoflurane is not important, at least as regards immobility.
Within the spinal cord, the dorsal horn has received much attention as a site of anaesthetic action. Because the dorsal horn acts as a spinal gate, anaesthetic effects on dorsal horn neuronal responses have been investigated over several decades.27 67 Virtually all anaesthetics examined appeared to depress spontaneous firing and/or responses to innocuous and noxious stimuli. There were, however, several methodological differences among these studies, making direct comparisons difficult. We were interested in the depressant effect of isoflurane on dorsal horn neuronal responses to supraspinal noxious stimulation within the narrow range that just permitted and just prevented movement (0.91.0 MAC).9 We observed that increasing the isoflurane concentration from 0.9 to 1.1 MAC resulted in a modest (15%) depression in evoked responses. It is unclear if a change of this small order of magnitude is sufficient to account for such a significant behavioural change. Furthermore, the neurones studied were not identified according to their function, e.g. as reflex interneurones or ascending projection neurones. It is conceivable that anaesthetics may exert differential effects on functionally distinct classes of spinal neurones, an issue that deserves further study.
Over the last several years the spinal motor neurone has received significant attention as a possible site of anaesthetic action. In a series of studies, Rampil and Zhou and their respective colleagues indirectly assessed anaesthetic effects on the motor neurone using the F-wave.58 76 101 102 The F-wave is evoked by electrical stimulation of a peripheral motor (or mixed) nerve, and is thought to result from antidromic invasion of the motor neuronal cell body with recurrent orthodromic conduction back down the motor nerve to evoke muscle contraction.76 The F-wave is thought to reflect motor neurone excitability, although the evidence for this is mainly indirect. The F-wave is enhanced in clinical conditions associated with increased motor neurone excitability, such as spasticity. Inhaled agents (isoflurane, halothane, desflurane, sevoflurane) and nitrous 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 it is merely correlated with immobility that is primarily caused by some other anaesthetic action. In any event, anaesthetic depression of the F-wave appears to be a direct action on the spinal motor neurone with little or no indirect supraspinal component.11
The ability of anaesthetic agents to produce immobility is usually assessed by their effectiveness in blocking gross purposeful movement. An understanding of the underlying mechanism will ultimately require study of anaesthetic effects on complex motor processing. The spinal cord appears to be capable of generating a variety of complex, coordinated movement patterns. Decerebrate rats are capable of normal activity, such as grooming, exploring their cages and eating.62 97 Frogs sectioned at an upper cervical level still have a normal wiping reflex, whereby the hind limb moves to wipe away a noxious chemical stimulus applied to the forelimb. If the forelimb is moved, the hind limb is able to determine the position of the forelimb, despite the absence of any supraspinal input.41 Cats sectioned at a mid-thoracic level still exhibit fairly normal locomotion on a treadmill after recovery from spinal shock and with support of the body weight.39 72 Lastly, brain-dead humans can display the Lazarus phenomenon, in which they have spontaneous movement, including crossing of the arms over the chest, sitting up in bed and turning of the head.25 64
All of the complex movement patterns described above are mediated by neural circuits, including central pattern generators (CPGs), which are intrinsic to the spinal cord. It is currently not known how anaesthetics affect CPGs. To begin to address this question, we recently investigated the effects of inhaled anaesthetic agents on the pattern of coordinated limb and head movements evoked by supramaximal stimulation in rats.17 All limbs and the snout were attached to force transducers to measure the direction and force of movements. At sub-MAC concentrations of isoflurane or halothane, the supramaximal noxious stimulus elicited synchronous, rather than alternating, movements of all four limbs. When there was head movement it was almost always towards the side of the noxious stimulus. As the concentration of isoflurane or halothane was increased, there was first a reduction in the number of movements, and at higher concentrations, a reduction in the force of movements. We are at an early stage in investigating anaesthetic action on complex movement patterns, and there are many open questions. Noxious stimuli evoke limb withdrawal reflexes; what is the relationship of these fairly simple reflex pathways to CPGs involved in generating more complex escape responses? Does noxious stimulation elicit synchronous (or other) patterns of coordinated limb movements in other species? Studies addressing these and related questions will be worthwhile in understanding better how anaesthetics affect spinal CPGs that generate complex movement patterns.
Undesirable effects
Although the primary emphasis of research on anaesthetic mechanisms is to determine how anaesthetics produce their desired effects, we must also determine how these powerful drugs produce undesired effects, such as post-operative nausea and vomiting (PONV) and respiratory and cardiovascular depression. Cyclopropane and ether produced limited cardiovascular depressive effects,35 45 53 but were associated with PONV (particularly ether). Both drugs were eliminated from clinical use because of inflammability. Halogenation of the carbon skeleton eliminated inflammability but also introduced cardiovascular depression. Thus, changing the structure of an anaesthetic might enhance desirable characteristics but may also introduce or exacerbate side-effects.
Respiratory depression is a common side-effect of virtually all anaesthetics. The mechanisms for this effect have not been fully elucidated, but there are likely to be differences among anaesthetics. Nieuwenhuijs and colleagues found that propofol depressed the central chemoreflex loop but had no significant effect on the peripheral chemoreflex loop.69 Inhaled anaesthetics depress the peripheral loop. Further work is required to elucidate mechanisms of respiratory depression. Hopefully it will be possible someday to develop an anaesthetic that has little or no cardiopulmonary depression.
From a patients perspective, PONV is one of the most common distressing complications of surgery and anaesthesia. However, it is not a life-threatening complication. There is little research examining the mechanisms of anaesthetic-induced PONV.
There is evidence that anaesthetics might influence the immune responses that are important in recovery after surgery.47 68 70 As surgical techniques progress and improve, patient outcome could perhaps be tied more closely to these subtle effects.
Acknowledgements
The authors were supported in part by grants NIH GM57970 and GM61283.
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