Consciousness and Cognition 10, 230–235 (2001)

doi:10.1006/ccog.2001.0513, available online at http://www.idealibrary.com on

Anesthesia—A Descent or a Jump into the Depths?

Robert A. Veselis

Department of Anesthesiology/Critical Care Medicine, Room S-333, 1275 York Avenue, MemorialSloan-Kettering Cancer Center, New York, New York 10021

Ever since Horace Wells demonstrated the use of nitrous oxide to a surgery classat Harvard Medical School in 1844 while extracting a tooth from a boy, an incidentdescribed as ‘‘a demonstration not entirely successful,’’ scientists have been grap-pling with the empiricism of the administration of anesthesia. Though anesthesiolo-gists are excellent at the clinical use of anesthetic agents, the fact that no one knowswhat anesthesia really is, or what happens to the brain when it is ‘‘anesthetized,’’ isexemplified by the still-present problem of awareness during anesthesia. This horrificstate was first envisioned by Claude Bernard (Bernard, 1878) and then experimentallyconfirmed with curare administration by Smith years later (Smith et al., 1947). Theserare, though consistently present, events (Sandin et al., 2000) have given impetus tomonitoring the ‘‘depth of anesthesia’’ to help avoid this problem.

Ever since anesthesiologists have been able monitor the EEG in the operating the-ater relatively easily, there has been a hope that this technology will somehow objec-tify the art of administering anesthesia (Bickford, 1950; Verzeano, 1951). As withthe problem of a computer beating a grand master chess player, consummation ofthis hope is more complex than it appeared in the 1950s.

A major complicating factor, which became evident in the 1950s shortly followingthe introduction of curare into clinical practice, was that the state of ‘‘anesthesia’’was not one unitary entity. Currently, it can be separated into five distinct compo-nents: muscle relaxation, sedation-hypnosis (defined here as loss of consciousness),amnesia, analgesia, and ablation of autonomic reflexes. By the year 2000 we had aselection of drugs that could target primarily one of these components. However,many drugs have significant, intercorrelated effects on multiple components. It isdubiously fortuitous that the original anesthetic agents had substantial effects on allcomponents of anesthesia. Through the ability to obtain satisfactory surgical anesthe-sia with only one drug, a unitary hypothesis of anesthesia was supported. This is sodeeply rooted in our thinking that even in the 1990s serious attempts were beingmade to use the EEG to predict the probability of movement at a given depth ofanesthesia (Vernon et al., 1995). This largely unsuccessful attempt was fueled primar-ily by the strong intercorrelation of the concentration of a given anesthetic drug with

Commentary on E. R. John, L. S. Prichep, W. Kox, P. Valdes-Sosa, J. Bosch-Bayard, E. Aubert,M. Tom, F. diMichele, and L. D. Gugino (2001). Invariant reversible QEEG effects of anesthetics.Consciousness and Cognition, 10(2), 165–183; and E. R. John (2001). A field theory of consciousness.Consciousness and Cognition, 10(2), 184–213. This article is part of a special issue of this journal onA Consciousness Monitor.

2300153-8100/01 $35.00Copyright 2001 by Academic PressAll rights of reproduction in any form reserved.

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multiple effects such as ablation of movement and the loss of consciousness. Todemonstrate the complexity of the situation, there is now evidence that the locus ofthe muscle relaxation effect of anesthesia is interconnected with the hypnotic andanalgesic components of anesthesia (Antognini & Wang 1999; Antognini et al. 2000).

With regard to EEG monitoring of ‘‘depth of anesthesia,’’ greater success wasobtained in modeling the EEG effects of anesthesia against hypnosis (loss of responseto verbal commands) (Rampil, 1998). This seminal monitor incorporated an algo-rithm of various parameters chosen from a large set of EEG parameters designed tocorrelate with the clinical hypnotic effect in a linear fashion. Despite the reasonableclinical success of this monitor (Sebel et al. 1997), it is still empirically based anddesigned. It is difficult to determine if observations such as those of Alkire representphysiologic underpinnings of such a monitor or rather strong intercorrelations of di-verse anesthetic components (Alkire, 1998).

E. R. John, in a series of articles (John et al. 2001; John, 2001), in this issue,extends empirical observations of invariant EEG effects relating to the loss and returnof consciousness among diverse anesthetic agents into well-founded meditations onthe nature of consciousness itself. A number of salient points bear emphasis. Theloss of consciousness is a dramatic event. One minute someone is following com-mands, and the next that person cannot be aroused with noxious stimuli. Previousmodels for this drug-induced loss of responsiveness have implicitly assumed that thiseffect was a continuous process, starting with sedation and culminating in surgicalanesthesia. It may be that the dose–response curve for this effect is particularly steep,but the evidence presented by E. R. John indicates that the loss of consciousnessmay be in fact a dramatic state change occurring over a very short time period. Thesedated state occurring before loss of responsiveness and the state of surgical anesthe-sia may be relatively stable, with some variations in ‘‘depth’’ occurring in a gradedfashion. But the transition itself is a dramatic change, accompanied by a dramaticcollapse of EEG synchronization normally present in the brain. A number of otherEEG-based measures of depth of anesthesia seem to relate to this phenomenon (Mun-glani et al. 1993; Plourde, 1993; Dutton et al. 1999). It is interesting to speculatethat the clinical impression of anesthesiologists that ‘‘you wake up the way you wentto sleep’’ may represent a return to a previous state in a step transition. In fact, Alkirereported that many volunteer subjects described that while anesthetized ‘‘their mindwas a complete blank and had a sensation that time had stopped’’ (Alkire et al.,2000). The methods presented by E. R. John provide an opportunity to rigorouslyinvestigate such a statement.

For a monitor to be useful to measure the hypnotic effect of anesthesia, a necessaryrequirement is that it work well with drugs in a variety of classes—all of which causethe same loss of consciousness. By happenstance or not, almost all anesthetic drugsaffect the GABA receptor, but a few notable ones primarily affect the NMDA recep-tor (Franks & Lieb, 1994; Franks et al., 1998). Nitrous oxide is the most frequentlyused anesthetic affecting NMDA receptors. It has been shown that a depth-of-anesthesia monitor developed using GABAergic agents (e.g., propofol, thiopental,and inhalational agents) may not work well when nitrous oxide alone is used tochange consciousness (Rampil et al. 1998). Though E. R. John included a groupreceiving nitrous oxide/opioids, it is hard to tell how much ‘‘supplemental’’ propofol

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was used in this group. The critical data point at which loss of consciousness occurredwas probably largely under the influence of the induction agents, all of which areGABAergic agents (though this effect would be largely absent at the return of con-sciousness point). As just a dramatic a change in consciousness occurs with NMDAagents, one would like to see replication of these EEG findings with NMDA agonistsused alone (nitrous oxide, xenon, and ketamine) or, in the case of animals, agentssuch as α-chloralose. This important theoretical consideration may be irrelevant inthe clinical realm, where many practitioners do not consider nitrous oxide/opioid asufficient anesthetic (thus the need for ‘‘supplemental’’ agents such as propofol)(Russell, 1993).

The second article by E. R. John (John, 2001), using the findings of the invariantEEG changes with drug-induced loss and return of consciousness, provides supportfor a ‘‘process-coherence’’ theory of consciousness versus ‘‘neuronal specificity,’’as described by Cariani (Cariani, 2000). Further evidence for this interpretation ofthe available data is welcome, as it is difficult to satisfactorily explain the loss ofconsciousness with anesthesia purely by receptor/synaptic effects of anesthetics—the current focus of much basic research in anesthesia. Other investigators have notedthe need not only to study the ‘‘simple’’ processing elements, but also understandthe complex architectures in which these elements are arranged, where the sum seemssubstantially more than the addition of the parts (Antkowiak, 1999). A perennialproblem regarding receptor-/synapse-based explanations of anesthesia is the diffi-culty in relating the kinetics of cellular events with the clinical dose–response effectsseen when consciousness is lost. Various translational explanations have been pro-posed (Eckenhoff & Johansson, 1999). It is also difficult to clearly ascribe a givenclinical effect to a given receptor interaction, especially as the knowledge of receptorsubtypes proliferate through time, as does the evidence that many drugs have actionsat more than a few receptor types. Thus, careful study of the whole system usingtools such as the carefully considered EEG and other neuroimaging techniques isneeded to understand how the system works. The situation is very analogous to de-scription of the very complex behavior of an artificial neural network, even thoughthe properties of the individual elements and their rules for interaction are simplyand deterministically specified. It should be noted that the method used to analyzethe EEG (LORETA/VARETA) models sources of EEG activity using spatially dis-tributed processes as opposed to other source modeling techniques, that, for instance,model scalp activity using discrete dipoles. (Scherg & von Cramon, 1990; Pascual-Marqui et al., 1994). Thus, LORETA/VARETA may have a propensity to providesupport to a distributed ‘‘field’’ model. It should be noted, however, that direct com-parison of LORETA/VARETA versus BESA have yielded similar source localiza-tions (Picton et al., 1999).

Having seen evidence that the hypnotic effect of anesthesia may be a dramaticstate change rather than a graded response, one must question whether the othereffects of anesthesia behave in a similar fashion. Is there a sudden loss of memoryor a sudden onset of analgesia? The existence of such behavior may be obfuscatedby the implicit assumptions of continuous, graded responses used in modeling theeffects of drugs (Holford & Sheiner, 1982). A step response may in fact be modeledreasonably well as a steep dose–response effect, especially as a step change in an

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individual will become a graded response when individual data are analyzed togetheras a population. Amnesia, an essential part of anesthesia, is more difficult to delineatethan hypnosis, where it is obvious when no response is occurring. As opposed tothis end point, amnesia can only be determined retrospectively, and its actual onsetmay be difficult to determine accurately. Using clever methods to narrow down thetime of the onset of drug-induced amnesia, there is evidence that loss of memorymay occur quickly and that dramatic EEG changes occur during this time (Veseliset al., 1991; Levy, 1992). It is intriguing to think that this may also represent a situa-tion in which a state change abruptly occurs. Is the onset of amnesia representativeof the collapse of the comparator necessary for evaluation of incoming stimuli? Cer-tainly the P3 response is severely affected by sedative agents, and there is evidencethat this is particularly true of specifically amnesic agents (Veselis et al., 2001). Anal-ogous to time standing still with loss of consciousness, a possible clinical correlateof the onset of an amnesic state is that patients will keep asking the same questionlast posed as the amnesic drug takes effect, despite carefully repeating the answerto the patient every time. Careful analysis of EEGs and ERPs in relation to memoryperformance may help resolve this issue, especially as the EEG has the temporalresolution to clearly define these abrupt changes. A similar situation exists in thecase of analgesia, though measures of pain/analgesia may be done closer in time tothe actual event than with amnesia. There is evidence that in individual patients thedose–response curve for analgesia is very steep (Austin et al., 1980). A teasing outof the various components of anesthesia is called for by using better methods toindependently measure these specific effects when a given drug is administered. If,in fact, dramatic state changes do occur in these anesthetic modalities, then an expla-nation based on neural network physiology creating a field effect with statisticallymeasurable properties, akin to a gas, is a very appealing concept. This avenue ofinquiry is a necessary complement to the receptor and synaptic effects of anestheticdrugs in understanding the anesthetized state.

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