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Sevoflurane Decreases Bispectral Index Values More than Does Halothane at Equal MAC Multiples

Schwab, Hildebrand S. MD*; Seeberger, Manfred D. MD*; Eger, Edmond I. II MD; Kindler, Christoph H. MD*; Filipovic, Miodrag MD*

doi: 10.1213/01.ANE.0000136467.47996.70
Technology, Computing, and Simulation: Research Report

At the minimum alveolar concentration (MAC) of inhaled anesthetics, 50% of subjects move in response to noxious stimulation. Similarly, at MAC-awake, 50% of subjects respond appropriately to command. The bispectral index (BIS) nominally measures the effect of anesthetics on wakefulness or consciousness. We postulated that the use of halothane with a larger MAC-awake/MAC ratio than sevoflurane would produce higher BIS values at comparable levels of MAC. We studied 33 unpremedicated patients anesthetized by inhalation, 18 with sevoflurane and 15 with halothane. We measured BIS before and during anesthesia at 1 MAC, both before and after tracheal intubation facilitated by fentanyl and rocuronium and then at 1.5 MAC. BIS measurements were made after meeting steady-state conditions. No surgery was performed during this study. BIS values in awake patients did not differ between the sevoflurane and halothane groups (96 ± 2 and 96 ± 2, mean ± sd, respectively). At 1 MAC without and with neuromuscular blockade and at 1.5 MAC, BIS values for patients anesthetized with halothane (54 ± 7, 56 ± 7, and 49 ± 7, respectively) exceeded those for patients anesthetized with sevoflurane (34 ± 6, 34 ± 6, and 29 ± 5, respectively) (P < 0.0001). This finding adds to other evidence indicating that BIS is drug specific.

IMPLICATIONS: At equal multiples of the minimum alveolar concentration, sevoflurane produced lower bispectral index (BIS) values than did halothane. Such results indicate that BIS is drug specific.

*Department of Anesthesia, University Clinics Basel, Kantonsspital, CH-4031 Basel, Switzerland; †Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, California

Supported, in part, by the Swiss National Science Foundation (Grant No. 3200–059817), Bern, Switzerland (to MDS and MF), the International Anesthesia Research Society, Cleveland, OH (to MF), and National Institutes of Health Grant No. 1P01GM47818 (to EIE).

Dr. Eger is a paid consultant to Baxter Healthcare Corp.

Accepted for publication June 2, 2004.

Address correspondence and reprint requests to Miodrag Filipovic, MD, Department of Anesthesia, University Clinics Basel, CH-4031 Basel, Switzerland. Address email to

The minimum alveolar concentration (MAC) of an inhaled anesthetic at 1 atmosphere prevents movement in 50% of patients to skin incision and is used to quantify inhaled anesthetic potency (1). MAC-awake is the MAC of an inhaled anesthetic that prevents appropriate response to command in 50% of subjects. As a fraction of MAC, MAC-awake differs among anesthetics. Desflurane, isoflurane, and sevoflurane have MAC-awake/MAC ratios (approximately 0.34) that are smaller than the ratios for halothane (0.55) and nitrous oxide (0.65). These differences suggest that desflurane, isoflurane, and sevoflurane are more powerful hypnotic drugs than halothane or nitrous oxide (2).

The bispectral index (BIS; Aspect Medical Systems, Natick, MA) uses proprietary algorithms to process signals from an electroencephalogram (EEG) and produces a single value (number) that nominally reflects consciousness/unconsciousness. BIS is based on analyses of thousands of EEGs from patients anesthetized with various anesthetics (3).

Limited data allow a comparison of BIS values during anesthesia with different inhaled anesthetics at equal MAC multiples. Kurehara et al. (4) found no significant differences in BIS values for sevoflurane and isoflurane at 1.2 MAC. This finding parallels the nearly equal MAC awake/MAC ratios of sevoflurane and isoflurane. However, the MAC awake/MAC ratio of halothane exceeds that of sevoflurane, and we therefore hypothesized that this should result in lower BIS values for sevoflurane than for halothane at the same MAC multiple. The present study tested this hypothesis.

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Our hospital ethics committee approved the present study (which was part of a larger study to assess the effects of halothane, sevoflurane, and propofol on left ventricular relaxation), and all patients gave written informed consent. Patients were randomly assigned to receive one of these anesthetics using a computer-generated list; no crossover design was used. The present analysis only included results from patients given halothane and sevoflurane. All patients had an ASA physical status of I or II and were scheduled for minor surgical procedures. No patient received premedication. A venous catheter was inserted, and lactated Ringer’s solution was infused. Monitoring included pulse oximetry (Spo2), noninvasive measurement of blood pressure, and a 5-lead electrocardiogram. Patients were covered with warmed blankets.

New BIS sensors (Zip-prep™, Aspect Medical Systems Inc.) were applied to the patients’ foreheads according to the manufacturer’s instructions. BIS values were recorded with an Aspect 1000 (Aspect Medical Systems Inc., software version 1.01) before induction of anesthesia (BIS awake) by inhalation of either 1 MAC halothane or sevoflurane. After insertion of a laryngeal mask airway, anesthesia was maintained at 1 MAC with air-oxygen (Fio2 0.4). Patients breathed spontaneously. End-tidal concentrations of carbon dioxide (Petco2), halothane, and sevoflurane were measured by a sidestream infrared sensor (Capnomac Ultima; Datex-Ohmeda Division, Instrumentarium Corp., Helsinki, Finland) with the tip of the probe placed at the distal (pharyngeal) end of the laryngeal mask. BIS values were obtained after an equilibration phase of 20 min (BIS 1 MAC, spontaneous ventilation).

We then administered fentanyl 2 μg/kg and rocuronium 0.6 mg/kg IV to facilitate tracheal intubation. After intubation we instituted mechanical ventilation to maintain Petco2 between 34–38 mm Hg. The tip of the CO2 probe was placed at the tracheal end of the endotracheal tube. Arterial blood pressure was increased with bolus injections of phenylephrine if values decreased by 30% from the initial systolic arterial blood pressure. After a 20-min interval at 1 MAC, the BIS was again recorded (BIS 1 MAC, controlled ventilation). We then increased the anesthetic concentration to 1.5 MAC and recorded the BIS value after equilibration (BIS 1.5 MAC). The study was conducted based on MAC values without age correction. Age-adjusted MAC values were recalculated after completion of the study (2). Scheduled surgery was performed after completion of the study.

All statistical analyses were done with the software package StatView Version 5.0.1 (SAS Institute Inc., Cary, NC). Baseline variables and age-corrected MAC values were compared by unpaired Student’s t-test or Fisher’s exact test as appropriate. Dosage of phenylephrine administration was compared with a Mann-Whitney U-test. BIS values, mean arterial blood pressure, heart rate, Spo2, and Petco2 were compared by analysis of variance for repeated measures. Post hoc testing was done using Scheffe’s method. A P value < 0.05 was considered significant. To account for the effect of age on MAC, MAC values were recalculated after completion of the study with an algorithm previously described (2). Data are expressed as mean ± sd or medians and quartiles.

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Fifteen patients (four female) received halothane and 18 (seven females) received sevoflurane. The groups did not differ in demographic characteristics (Table 1) or in mean arterial blood pressure, Petco2, heart rate, or Spo2 at baseline and during anesthesia (Table 2).

Table 1

Table 1

Table 2

Table 2

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).

Figure 1

Figure 1

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).

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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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