Awake (control) BIS values did not differ between the sevoflurane and halothane groups (96 ± 2 and 96 ± 2, respectively) and significantly decreased in a dose-related manner in both groups with increasing MAC (Fig. 1). For 1 MAC, spontaneous ventilation, BIS values were 34 ± 6 and 57 ± 7 for sevoflurane and halothane, respectively. At 1 MAC, controlled ventilation, the respective values were 34 ± 6 and 56 ± 7. BIS values at 1.5 MAC were 29 ± 5 and 49 ± 7 in. the sevoflurane and the halothane groups, respectively. BIS values for halothane exceeded those for sevoflurane at each target MAC value (P < 0.0001). Twenty min after administration of fentanyl and rocuronium, BIS values were similar to those found before drug administration and tracheal intubation (P = 0.79).
The use of phenylephrine did not differ between groups. No phenylephrine was administered at 1 MAC, spontaneous ventilation. At 1 MAC, controlled ventilation, two patients in each group received phenylephrine, 100 μg and 50 μg in the sevoflurane group and 300 μg and 25 μg in the halothane group. At 1.5 MAC, two patients in the sevoflurane group received 100 μg and 50 μg phenylephrine and two patients in the halothane group received 100 μg and 25 μg phenylephrine.
Without correction for age, the measured concentrations of the inhaled anesthetics expressed as MAC were very close to the aimed 1 and 1.5 MAC, respectively. With correction for age, mean MAC values for sevoflurane and halothane did not differ at the target value of 1 MAC (spontaneous and controlled ventilation). At 1.5 MAC, mean age-corrected MAC values were lower for the halothane group than for the sevoflurane group (1.3 ± 0.1 versus 1.5 ± 0.1 MAC) (P = 0.008).
The results of our study showed that BIS values were less during sevoflurane anesthesia than during halothane anesthesia at equivalent MAC levels. This finding supports our hypothesis that sevoflurane produces a greater hypnotic effect than halothane, and it parallels the finding that the MAC-awake/MAC ratio is larger for halothane (0.55) than for sevoflurane (0.34) (2).
Kurehara et al. (4) investigated the BIS values in patients anesthetized with sevoflurane and isoflurane, two drugs that have the same MAC-awake/MAC ratio. At 1.2 MAC both anesthetics produced the same BIS values. However, increasing the anesthetic concentration to 2 MAC decreased BIS values only in patients anesthetized with isoflurane; it had no effect in those anesthetized with sevoflurane. This finding does not support our notion that the MAC-awake/MAC ratio reflects the hypnotic potency of inhaled anesthetics and contrasts with our finding that an increase in halothane and sevoflurane from 1 MAC to 1.5 MAC proportionately decreased BIS values. These conflicting results suggest the possibility that the parallel of MAC-awake/MAC ratios and the hypnotic effect of anesthetics as defined by BIS values may not consistently extend to deeper levels of anesthesia.
BIS incorporates different information from the raw EEG. Power and frequency, β activation, and burst suppression are integrated in a single number (5). However, halothane and sevoflurane differently affect total spectral power and median power of EEG (6). In addition, sevoflurane produces burst suppression within the clinical dosage range whereas halothane does not (7,8). This difference is especially important for BIS values less than 30 when the burst suppression ratio (i.e., the time ratio of total EEG suppression for a given time period) is linearly correlated with the BIS value (9). These known differences in the effects of halothane and sevoflurane on EEG are expected to influence the BIS value differently at a similar depth of anesthesia.
Part of the power of MAC is the ease and precision with which immobility (as an either-or phenomenon) can be measured for all inhaled anesthetics. At 1 MAC, 50% of patients move in response to a noxious stimulus, and almost all will move at 0.8 times MAC (10). The level at which 50% of patients will appropriately respond to command (MAC-awake) is even clearly lower for both sevoflurane (0.34 times MAC) and halothane (0.55 times MAC) (2). Thus, absence of movement after a noxious stimulus in the unparalyzed patient anesthetized with an inhaled anesthetic indicates that the anesthetic concentration is clearly in excess of the concentration that allows appropriate response to commands. Consequently, it may be expected that the anesthetic concentration is sufficient to suppress awareness. Therefore, the immobile, unparalyzed patient primarily anesthetized with an inhaled anesthetic rarely, if ever, would subsequently remember the surgery. MAC provides the clinician therefore with a valuable tool to judge “depth of anesthesia” and, indirectly, the production of amnesia.
However, when neuromuscular blocking drugs are used lack of movement cannot predict lack of recall or awareness in the anesthetized patient. In this situation, use of the BIS monitor—particularly trends of change of BIS values—is expected to add information on depth of anesthesia, providing a combination of sensitivity and specificity equal to or better than other commercially available depth-of-anesthesia monitors (11). Moreover, the BIS monitor can be used both during inhaled and IV anesthesia, whereas MAC only applies to inhaled anesthetics.
Nevertheless, BIS has considerable limitations, some of which have already been noted (3). BIS is drug dependent and consequently no specific BIS value guarantees adequate depth of anesthesia with all anesthetics. Xenon can provide amnesia and unconsciousness, but a BIS value of ≤50 may be associated with appropriate response to command during xenon administration. Thus, BIS values ≤50 do not guarantee adequate hypnosis during xenon anesthesia (12). The addition of nitrous oxide increases BIS values during isoflurane anesthesia and probably also during anesthesia with other anesthetics (13). This is consistent with a modest capacity of nitrous oxide to antagonize the amnestic effect of isoflurane (14). Similarly, the addition of ketamine to a propofol-based anesthetic increases BIS values (15). In addition, Schneider et al. (16) found significantly different BIS values in patients receiving sevoflurane/remifentanil compared with patients receiving propofol/remifentanil at the same level of anesthesia.
Another potential problem is the use of BIS to predict elements of anesthesia that it is not intended to predict, such as immobility. Vernon et al. (17) found that BIS values in patients with isoflurane/alfentanil anesthesia who did not move to skin incision did not differ from those in patients with propofol/alfentanil anesthesia who moved to skin incision. BIS values do not predict the likelihood of movement, nor does the manufacturer of the BIS monitor suggest such a prediction.
Finally, under some circumstances a BIS value predicted unawareness when awareness did exist (16). This observation was also noted for xenon anesthesia. In addition, Messner et al. (18) showed that the use of neuromuscular blocking drugs can produce low BIS values that do not reflect unconsciousness. Three volunteers received a single dose of succinylcholine and alcuronium but no hypnotic drugs (i.e., they were acutely aware); BIS decreased to a minimum value of 9. Similarly, Vivien et al. (19) found a decrease in BIS with a single dose of atracurium (0.5 mg/kg). These authors considered this to be a consequence of the loss of facial muscle activity, and their findings agree with those of Messner et al. (18). In our study, we failed to find an effect of neuromuscular blockade on BIS values during either halothane or sevoflurane anesthesia. We suggest that muscle activity was minimized at 1 MAC, and was not further decreased by the administration of neuromuscular blocking drugs.
Some limitations should be considered for the interpretation of the results of our study. First, sevoflurane and halothane have different pharmacokinetic properties. Because of its higher tissue/blood partition coefficient, time to equilibration is longer for halothane than for sevoflurane; but even for halothane the equilibration of the brain as part of the vessel rich group is completed after 20 minutes (equilibration half-time of 2 minutes) (20). Second, our study was performed in the absence of surgical stimulation. Surgical stimulation can increase BIS values during desflurane anesthesia at alveolar concentrations of up to 8% (21), and the different BIS values for halothane versus sevoflurane that we found may have disappeared with surgical stimulation. An additional limitation is that we initially did not adjust the MAC of both inhaled anesthetics to the age of each patient. Although age did not differ between groups (Table 1), after correcting the individual MAC value for each patient with the algorithm proposed by Eger et al. (2), the age-corrected MAC values were significantly lower at “1.5 MAC” in the halothane group. This difference could have contributed to the greater BIS values in the halothane group at our target value of 1.5 MAC, but not at 1 MAC, where the age-corrected MAC values did not differ between study groups. The age adjustment algorithm is derived from meta-analysis and may not be clinically relevant for individual patients.
We conclude that halothane produces greater BIS values than sevoflurane at comparable MAC levels in the absence of surgical stimulation. This result is consistent with the finding in other studies that BIS values for inhaled and other anesthetics are drug specific.
The authors thank Claudia Werner, RN, Esther Seeberger, RN, and Reinhard Rohlfs, RN for technical assistance and Joan Etlinger, BA, for editorial assistance.
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© 2004 International Anesthesia Research Society
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