In a comprehensive review on monitoring anesthesia, Stanski (1) concluded that both specific defined stimuli and specific responses are needed to assess anesthetic depth. He stated that no unifying clinical measure of anesthetic depth spans all classes of anesthetic drugs and that clinical measures that appear relevant for a single drug may not be relevant if the drug is used in a combination. This conclusion is consistent with the view that the spectrum of effects that constitutes the state of general anesthesia should not be regarded as several components of anesthesia resulting from one anesthetic action, but represents separate pharmacological actions, even if the anesthesia is produced by one drug (2). As a result, the diversity of pharmacological actions that, in combination, provide anesthesia makes it impossible to determine the potency of different actions with one measure.
Several studies support this view, some of which concern the molecular mechanisms of anesthetic actions. A difference in anesthetic potency between the optical isomers of isoflurane (3–5) and between isomers of etomidate (6) has been reported. In addition, several studies using site-directed mutagenesis showed that mutation of single critical amino acid residue within the gamma-aminobutyric acidA receptor can abolish the effects of enflurane (7) and etomidate (8). These results represent strong evidence that general anesthetics can act via specific molecular mechanisms. There are also new indications that different molecular mechanisms underlie different components of general anesthesia. Quinlan et al. (9) demonstrated that, in genetically engineered mice, the lack of the β subunit of gamma-aminobutyric acidA receptor results in a significant difference in the potency of enflurane and halothane for blockade of motor response to noxious stimulation but not for the hypnotic effect. These results correlate well with the results obtained in the studies by Rampil et al. (10), Rampil (11), and Antognini and Schwartz (12) that suggest that another inhaled anesthetic, isoflurane, provides one of the basic components of anesthesia-blockade of movement response to noxious stimulation by acting primarily on the spinal cord; this occurs when unconsciousness is achieved by the action of isoflurane on the brain. The difference in the anatomic substrate suggests that different physiologic mechanisms are involved in these two actions of isoflurane. The discussion on disparate mechanisms for different components of anesthesia attracts attention to this problem (13–16).
The view that the search for a reliable index of anesthetic depth should be transformed into a search for separate indices of different components of anesthesia has been addressed in a number of articles (17–19). The common conclusion was that a monitor of anesthesia may measure only one of the components of general anesthesia, such as loss of consciousness, obtunding motor response, or hemodynamic response to noxious stimulation (19).
Components of anesthesia that could be combined to achieve variable goals of anesthesia may not necessarily reach the level of central nervous system (CNS) depression that results in unconsciousness. For example, neuroleptanalgesia and conscious sedation provide sedation (psychological detachment), analgesia, and amnesia. These diverse components may reach different degrees of expression with various anesthetic combinations. Even with such seemingly similar components as sedation (alertness/sedation scale) and unconsciousness profoundly different outcomes are possible with the same drug combination. For example, benzodiazepine-opioid combinations result in a striking synergism for unconsciousness (20) but only an additive effect for sedation (alert-sleepy self-rating) (21). The same kind of difference in benzodiazepine-opioid interactions for hypnotic (loss of the righting reflex) and sedative (locomotor activity) effects was observed in rats (22).
Is it feasible to measure the degrees of the separate specific effects with one common index? When anesthesia was produced by one drug with relatively low specificity of action, the depth of anesthesia was actually equated with the depth of CNS depression. Therefore, a single index reflecting CNS depression in general could be used as a measure of anesthesia. With the introduction of drugs with more specific anesthetic actions (especially ketamine), the wide use of opioids, and the use of light anesthesia, it became obvious that one index cannot be used successfully to reflect all components of anesthesia.
If the term depth of anesthesia became irrelevant for major components of general anesthesia taken together, it could still be relevant for each of the components measured separately. One of the most important components of anesthesia is unconsciousness, which represents an all-or-none (quantal) response to an anesthetic. One can construct a dose-response curve by using quantal data (probability of response curve), but it does not reflect the depth of the inhibitory effect. A quantal response represents only a single point in a continuum of the relationship between the dose of a drug and the effect of a function (23). Different strengths of stimuli that produce arousal could be used to quantify the depth of the effect, as was done in one of the studies with the use of behavioral arousal for measuring the depth of anesthesia (24). In this study, the depth was rank ordered along the scale; however, it was not an interval scale. With such ranking, it is impossible to say how the difference between the levels of response to weak stimulus and response to strong stimulus compares with the difference between the levels of response to strong stimulus and no response (25).
Unconsciousness, like anesthesia in general, also has many components: perception, attention, memory, orientation, emotion, instinct, thought, and volition (26). With full consciousness, all these components are working in concert. Many of these components have quite dissimilar underlying mechanisms. Unconsciousness produced by drugs with low specificity of action could be regarded as a relatively simple all-or-none response; however, with some of the drugs, especially when used in borderline doses, hypnotic effect could be as complicated as anesthetic effect in general. Awareness (a state of being aware, i.e., conscious) is one of the major causes of patient complaints (18). The reported incidence of intraoperative recall (conscious or explicit memory) varies from 0.2% to 2% (1,18). However, the incidence of awareness during surgery without recall is probably much higher. The incidence of movement response to command during anesthesia with use of the isolated forearm technique has been reported as up to 8%. However, some investigators have not been able to correlate other clinical signs of light anesthesia or postoperative recall to the isolated forearm movement response (17,27). Prevention of intraoperative recall is one of the most important goals of monitoring anesthesia adequacy.
Introduction of the bispectral index (BIS) for anesthesia monitoring (28,29) makes it important to analyze how the new method addresses the old problem of assessment of anesthetic depth. Todd (30) recently indicated that, in the last several years, up to 50 articles concerning the BIS have appeared in mainstream, peer-reviewed anesthesia journals. He also indicated that some of the articles and reports on the BIS that appeared in the lay media are misleading. The BIS is based on bispectral processing that determines the harmonic and phase relations among the various electroencephalogram (EEG) frequencies (31,32). The BIS is a variable computed from the bispectrum (28,29); it is defined as a proprietary nonlinear single variable that is based on a large volume of clinical data correlating behavioral and EEG assessments. Different versions of the BIS have different algorithms. There are several aspects of the use of the BIS in anesthesia monitoring that should be discussed separately.
Is the BIS a Universal Index for All Components of Anesthesia?
Is the BIS a measure of the depth of anesthesia? As we indicated above, different components of anesthesia have different underlying mechanisms; therefore, it is difficult to expect that a single index can be used successfully for measuring the depth of anesthesia in general. The opinion of investigators familiar with the BIS is very certain. Glass et al. (19) state that “individual anesthetics each produce a unique spectrum of pharmacologic actions, so the concept of a common depth of anesthesia may need to be revisited to reflect the separate clinical components of the ideal anesthetic state. Consequently, a monitor of depth of anesthesia may measure only one of these components.”
Does the BIS Predict Immobility?
Initially, the BIS was evaluated “as a measure of adequate anesthesia defined by patient movement in response to skin incision,” and the conclusion was that it “may be a sensitive and specific measure” for this (33,34). Later on, the authors of a multicenter study on the BIS concluded that the index is a significant predictor of patient response to incision, but the utility of the BIS depends on the anesthetic technique being used. When opioid analgesics are used as adjuncts before incision, the correlation to patient movement becomes much less significant, so that patients with apparently “light” EEG profiles may not move at incision (35). In the most recent study on the BIS (version 3.2), the conclusion was that when sevoflurane was administered alone, the BIS (and 95% spectral edge frequency or median power frequency) did not predict movement after skin incision better than chance alone (36). However, one should keep in mind that every version of BIS 2 or higher has not been derived to predict movement (C. Roscow, written communication, October 25, 1999).
Is the BIS an Index for Unconsciousness?
It appears that for another component of anesthesia, unconsciousness, the predictive value of the BIS is much better than for motor response to incision (27,37,38). One of the most important questions on the accuracy of predictions of unconsciousness with the BIS is whether it is drug specific, especially whether the accuracy is altered with the addition of opioids or nitrous oxide. The tendency for such alterations was reported with the addition of alfentanil to propofol (37) and nitrous oxide to propofol (38). The changes in the predictive value of the BIS in these studies did not reach statistical significance, probably because of relatively small decreases in the propofol plasma concentration required to prevent a response in 50% of the patients caused by the additions of a second drug. However, in another recent study, the BIS values for unresponsiveness to verbal command were significantly higher in a propofol-fentanyl combination than with propofol alone (39). Most important for the notion that the BIS might be drug specific are the reports on the absence of a correlation between the BIS values and unconsciousness with ketamine alone (40) or in combination with propofol (41).
The predictive value of the BIS for unconsciousness might be significantly influenced by potentially arousing intraoperative stimulation. In volunteers moderately sedated with propofol, a painful stimulus caused a small increase in the BIS value (37). It was reported that the changes in the BIS values in physiological sleep are similar to those in general anesthesia (42). However, the authors have found that in several subjects, the minimal BIS was very low (in the 20s), and that each time the subject awoke briefly, the BIS abruptly increased (usually > 96). The authors concluded that the BIS value may not reliably quantify how easily the patient may be aroused by intraoperative stimuli. The view that the BIS by itself does not actually “predict” but simply gives a measure of the current state based on the last 15–30 seconds of EEG data corresponds well with the above observation. There is an indication that, in some cases, the BIS may be patient specific. Unreasonably low BIS values in a volunteer with a low-voltage EEG signal was reported recently (43).
The reported results of BIS trials indicate that BIS may be a valuable monitor for loss of consciousness for thiopental, propofol, midazolam, or isoflurane (when given alone) (27,19,38). Flaishon et al. (27), who used the isolated forearm technique with a single injection of either thiopental or propofol, concluded that the probability of recovery of consciousness can be predicted by using the BIS. However, they caution that it is unknown whether the measured endpoint has a similar mean BIS value for other drugs and that the effect of a surgical stimulus on the BIS value should be elucidated. We indicated that the incidence of intraoperative recall may be as low as 0.2%. Therefore, an extremely large number of patients would have to be studied to determine whether use of the BIS monitor can prevent awareness even with a single anesthetic.
Katz (44) has recently posed the question of whether anesthesiologists purchasing the BIS monitor would be able to judge for themselves the value of the information provided by the system. Such a possibility with regard to prevention of awareness is questionable, not only as a result of the necessity of having a large number of patients for correct evaluation. The BIS is a proprietary index, and its algorithm is extremely complex; in addition, it is different with various versions of the monitor. All of this requires technical sophistication beyond the level of an individual anesthesiologist.
Is the BIS an Index for Amnesia or Sedation?
When the BIS was evaluated as a measure of sedation, loss of consciousness was usually included in the assessment. For example, with the observer’s assessment of the alertness/sedation scale (45), three of six scores represent unconsciousness (scores 2, 1, and 0). Therefore, with the BIS assessed as a monitor of sedation, it is important to know the authors’ definition of sedation: whether it also reflects deeper levels of CNS depression, including unconsciousness. When Kearse et al. (38) carefully analyzed the relationship between the BIS readings and conscious processing of information during propofol sedation and hypnosis, they could not find a gradual, continuous “descent from alertness to varying stages of vigilance, inattention, and unresponsiveness.” They found that volunteers simply did or did not respond to commands.
Leslie et al. (46) reported that the BIS predicted propofol-induced suppression of learning during regional anesthesia. They used a “trivial pursuit” type of question task and obtained BIS of 91 for suppression of learning by 50%. When the relation between the BIS and presence or absence of recall was studied on a wider scale, it was found that the slopes of the isoflurane curve reflecting the relation were different from those of propofol or midazolam, and no logistic relation could be derived for alfentanil (19).
It is possible to conclude that the BIS is most promising as a monitor of unconsciousness. The BIS is an empirical index derived statistically from a database which included many, but not all, types of anesthetics and their combinations. Therefore, when the BIS is used with a new drug or new patient population that was not in the original database, it must be revalidated. This may lead to additional changes in the BIS algorithm. At present, there is not enough evidence to suggest that the BIS could provide a unifying clinical measure of anesthetic depth that reflects all components of anesthesia. The introduction of the BIS did not change the perception that the search for a reliable index of anesthetic depth should be transformed into a search for separate indices of different components of anesthesia.
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