Relationship of bispectral index to minimum alveolar concentration during isoflurane,sevoflurane or desflurane anaesthesia

Abstract

Objective

To determine bispectral index (BIS) values produced by equipotent concentrations of commonly used volatile anaesthetics.

Methods

Female patients undergoing thyroidectomy were randomly assigned to receive isoflurane, sevoflurane or desflurane anaesthesia. After induction, anaesthesia was maintained by the volatile agent at 1 minimum alveolar concentration and supplemented with remifentanil infusion. BIS values were recorded during 1 h surgical anaesthesia after a 15 min equilibrium phase.

Results

Time-averaged BIS value during the study period was significantly lower in the desflurane group (n = 29) than the sevoflurane group (n = 27) (37.0 ± 4.9 vs 41.5 ± 5.9). Duration of deep hypnosis (BIS < 40) was significantly longer in the desflurane group than the sevoflurane group (40.2 ± 20.7 vs 24.3 ± 22.5 min). There were no significant differences in any parameter between the isoflurane group (n = 27) and any other group.

Conclusions

Desflurane produces a greater hypnotic effect than sevoflurane during equipotent anaesthesia. Management of volatile anaesthesia using predetermined minimum alveolar concentration targets can lead to an unnecessarily long duration of deep hypnosis.

Introduction

An ‘ideal’ anaesthesia can be achieved by using a combination of different drugs, whereby the three components of anaesthesia – unconsciousness, antinociception and immobility – are independently controlled with a hypnotic, an analgesic and a neuromuscular blocking agent, respectively. ¹ A combination of the volatile anaesthetics desflurane, sevoflurane (which both have rapid pharmacokinetics) and remifentanil (an ultrashort-acting opioid) provide satisfactory balanced anaesthesia. ²

Anaesthetic agents are titrated according to their minimum alveolar concentration (MAC) value and haemodynamic response. Traditionally, MAC has served as the standard measure of potency for volatile anaesthetic agents. It is defined as the anaesthetic concentration at 1 atmosphere that produces immobility in 50% of subjects exposed to a surgical incision.^3,4 This definition presupposes that equivalent MAC values of different anaesthetics have a similar potency in clinical practice, ⁴ but MAC correlates poorly with degree of hypnosis.^4,5 Conversely, bispectral index (BIS) is a reliable electroencephalogram (EEG)-derived parameter that clinically correlates with the degree of the hypnotic component of anaesthesia. ⁶

Given that a long period of deep hypnosis (usually defined as BIS < 40) may increase postoperative morbidity and mortality,^7–11 knowledge of the BIS values at equipotent (i.e. equivalent MAC) concentrations of commonly used volatile anaesthetics is essential for balancing the analgesic and hypnotic components of anaesthesia. Furthermore, volatile anaesthetics may vary in their relative analgesic and hypnotic potential. ³ This prospective, randomised clinical trial was designed to compare the BIS profiles at an equipotent dose (1 MAC) of isoflurane, sevoflurane or desflurane throughout the maintenance phase of general anaesthesia.

Patients and methods

Study population

The study recruited female patients aged between 18 and 65 years with American Society of Anesthesiologists physical status I or II ¹² who were undergoing elective partial or total thyroidectomy at Samsung Medical Centre, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea between November 2009 and November 2010. Patients with a history of any psychiatric or neurological disease or who had received medication that affected the central nervous system were excluded. The study was approved by the Institutional Review Board of Samsung Medical Centre, Seoul, Republic of Korea and all participants provided written informed consent prior to inclusion. The study was registered with the Clinical Trial Center of Samsung Medical Center, Seoul, Republic of Korea (ref: SMC 2009-10-030).

Anaesthesia

The study period was predefined as the first 60 min after the surgical incision, and was derived from the median operating time for thyroidectomy at our institution. Patients were randomly assigned using a random number table to receive isoflurane, sevoflurane or desflurane anaesthesia.

A BIS monitor strip (BisQUATRO™; Covidien Inc., Mansfield, MA, USA) was placed on the forehead and connected to BIS monitor (BIS VISTA™; Aspect Medical System Inc., Norwood, MA, USA) before induction of anaesthesia. The BIS monitor value was concealed so that only the signal quality indicator was visible to the attending anaesthetist. Patients were not premedicated, and anaesthesia was induced with 1–1.5 mg/kg propofol intravenous injection, 0.2 µg/kg per min remifentanil infusion and 0.1 mg/kg vecuronium. Anaesthesia was then maintained with isoflurane, sevoflurane or desflurane in combination with air in 50% oxygen. Routine monitoring (electrocardiogram, pulse oximetry, noninvasive blood pressure assessment, oesophageal temperature and end-tidal carbon dioxide with anaesthetic gas concentrations) was used.

After intubation, the inspired concentration of the volatile agent was maintained at 1 MAC throughout the study period. The study was conducted based on MAC values with age correction. ³ A steady state concentration of 1 MAC was established following at least a 15-min period between tracheal intubation and the skin incision. Anaesthesia was supplemented with 0.05–1.0 µg/kg per min remifentanil continuous infusion. The anaesthetist was blinded to BIS monitoring and titrated the remifentanil dose to maintain heart rate and blood pressure to within 20% of the preinduction baseline values throughout the 1-h study period. Muscle relaxation was supplemented with vecuronium to maintain a train-of-four count < 2 during the study period.

BIS data were collected from the internal memory of the BIS monitor for offline analysis. The BIS reading was taken as the average of four readings at 15 s intervals over a 1-min period with the smoothing ratio set at 15 s. Time-averaged BIS values were calculated. The minimal BIS value, the duration of deep hypnosis (BIS < 40) and the total duration of adequate hypnosis (BIS 40–60) were noted. The total infused dose of remifentanil during the study period was documented.

Statistical analyses

The primary study outcome was the time-averaged BIS values of the three groups during the 1-h study period. A pilot study of 15 patients (five patients per group) revealed that the standard deviation of the time-averaged BIS value in the desflurane group was 8.0. Differences of 7.0 in the time-averaged BIS values among the groups were considered to be clinically significant. Based on these values, and using α = 0.05 and β = 0.2 for a study design incorporating three groups of equal size, a sample size of 26 patients per group was required. The study therefore enrolled 30 patients per group to compensate for possible dropouts. Patients with incomplete BIS data, unexpectedly short duration of surgery (< 1 h) or who underwent conversion to extended surgery with neck dissection were excluded from the analyses.

Data were presented as mean ± SD or n. Demographic data, durations of surgery and anaesthesia, total dose of remifentanil and BIS data were analysed using χ²-test, one-way analysis of variance (ANOVA) or repeated measures ANOVA with Scheffé’s post hoc test, as appropriate. Statistical analyses were performed with SPSS® version 18.0 (SPSS Inc., Chicago, IL, USA) for Windows®. In all analyses, P < 0.05 indicated statistical significance.

Results

Of the 90 patients enrolled (n = 30 per group), seven patients did not complete the study (Figure 1). The final analyses included 27 patients in the isoflurane group, 27 in the sevoflurane group and 29 in the desflurane group.

Figure 1.

Flow diagram of patient attrition numbers in the groups of women undergoing thyroidectomy using an equipotent dose (1 minimum alveolar concentration) of isoflurane, sevoflurane or desflurane throughout the maintenance phase of general anaesthesia.

There were no statistically significant between-group differences demographic data, total infused dose of remifentanil, and durations of surgery or anaesthesia (Table 1). No patient reported any event of explicit awareness.

Table 1.

Demographic and intraoperative characteristics of female patients undergoing thyroidectomy included in a study comparing bispectral index (BIS) profiles at an equipotent dose (1 MAC) of isoflurane, sevoflurane or desflurane throughout the maintenance phase of general anaesthesia.

Characteristic	Isoflurane n = 27	Sevoflurane n = 27	Desflurane n = 29
Age, years	47.7 ± 9.5	44.7 ± 11.6	48.0 ± 10.3
Weight, kg	62.1 ± 8.1	61.0 ± 8.7	59.6 ± 7.8
Height, cm	158.7 ± 6.2	158.4 ± 6.3	156.7 ± 5.6
BMI, kg/m2	24.7 ± 3.0	24.1 ± 3.4	24.3 ± 2.9
ASA physical status, I/II	18/9	21/6	17/12
Duration of surgery, min	85.0 ± 18.4	84.4 ± 19.9	89.1 ± 13.2
Duration of anaesthesia, min	119.1 ± 20.6	117.0 ± 21.1	121.6 ± 16.1
Total dose of remifentanil, µg	161.8 ± 70.7	174.0 ± 68.0	168.9 ± 61.9

Data presented as mean ± SD or n.

No statistically significant between-group differences (P ≥ 0.05; one-way analysis of variance or χ²-test).

MAC: minimum alveolar concentration; BMI: body mass index; ASA: American Society of Anesthesiologists. ¹²

Data regarding BIS parameters are shown in Table 2. The time-averaged BIS value during the study period was significantly lower in the desflurane group compared with the sevoflurane group (P = 0.008). However, there were no statistically significant differences for the time-avergaed BIS value in other group comparisons (isoflurane vs. sevoflurane or desflurane). The duration of deep hypnosis (BIS < 40) was significantly shorter and the duration of adequate hypnosis (BIS 40–60) was significantly longer in the sevoflurane group than the desflurane group (P = 0.026 and P = 0.038, respectively; Table 2). There were no other significant between-group differences in any parameter.

Table 2.

Bispectral index (BIS)-related data obtained during thyroidectomy of female patients undergoing anaesthesia at an equipotent dose (1 MAC) of isoflurane, sevoflurane or desflurane.

Parameter	Isoflurane n = 27	Sevoflurane n = 27	Desflurane n = 29
Time averaged BIS	39.6 ± 5.1	41.5 ± 5.9 a	37.0 ± 4.9
Minimal BIS	33.7 ± 4.8	35.0 ± 6.0	31.8 ± 4.8
Duration of deep hypnosis (BIS < 40), min	33.0 ± 21.6	24.3 ± 22.5 b	40.2 ± 20.7
Duration of adequate hypnosis (BIS 40–60), min	27.2 ± 22.0	35.2 ± 22.5 c	27.3 ± 22.4

Data presented as mean ± SD.

a

P = 0.008, ^bP = 0.026 and ^cP = 0.038 versus desflurane group; analysis of variance with Scheffé’s post hoc test.

MAC: minimum alveolar concentration.

Figure 2 shows the changes in mean BIS values at 5-min intervals throughout the 1-h study period for each group. Changes in mean BIS values were significantly different between the desflurane and sevoflurane groups at 10, 30, 35, 40, 45 and 50 min after skin incision (P < 0.05 for each comparison; Figure 2) and throughout the study period as a whole (P < 0.01). There were no other significant between-group differences.

Figure 2.

Mean bispectral index (BIS) values in female patients undergoing thyroidectomy using an equipotent dose (1 minimum alveolar concentration) of isoflurane (n = 27), sevoflurane (n = 27) or desflurane (n = 29) throughout the maintenance phase of general anaesthesia. Data expressed as mean ± SD. *P < 0.05 between sevoflurane and desflurane groups; Scheffé’s post hoc test.

Discussion

In accordance with the findings of other studies,^5,13 the data from the present study show that equipotent volatile anaesthetics do not produce similar BIS values. BIS values were significantly lower in the desflurane group than the sevoflurane group with 1 MAC anaesthesia in the current study, indicating that desflurane produces a greater hypnotic effect than sevoflurane at an equivalent MAC concentration.

The BIS is an empirically derived multifactorial EEG measurement, providing a dimensionless number between 0 and 100 that correlates with hypnosis.^14,15 The maintenance of a BIS value between 40 and 60 facilitates reduced anaesthetic exposure and improved early recovery profiles. ¹⁵ BIS is therefore regarded as a perioperative vital sign, in much the same way as heart rate and blood pressure. ¹⁴

Others have compared BIS values at equivalent doses of halothane versus isoflurane ⁵ or sevoflurane, ¹³ and found that BIS values were significantly higher during halothane anaesthesia than isoflurane or sevoflurane anaesthesia. Together with these studies,^5,13 our findings suggest a distinction between the analgesic and hypnotic effects of volatile anaesthetics, such that volatile anaesthetics have different ratios of hypnotic to analgesic potency.

A growing body of evidence suggests that a long period of deep hypnosis may be related to increased postoperative morbidity and mortality.^7–11 In addition to a short-term negative impact on recovery from anaesthesia, ¹¹ prolonged deep hypnosis may lead to postoperative delirium and cognitive decline ¹⁰ as well as increased long-term mortality.^8,9 Deep hypnosis may also affect immunity and promote infection or tumour growth. ⁷

The present findings support the notion that management of volatile anaesthesia via predetermined MAC targets cannot ensure the same degree of hypnosis when different volatile agents are used. Desflurane produces a greater depth of hypnosis than sevoflurane at doses that provide a similar degree of analgesia. This may result in an unnecessarily long duration of deep hypnosis during anaesthesia and possible neurotoxic effects in vulnerable patients. The duration of deep hypnosis (BIS < 40) was almost twice as long in the desflurane group than the sevoflurane group in the present study (40.2 ± 20.7 vs 24.3 ± 22.5 min, respectively).

Our study used supplemental remifentanil infusion to provide sufficient analgesia to non-homogeneous surgical stimuli while maintaining a steady state 1 MAC concentration of volatile agents. We chose this anaesthetic technique due to its rapid onset/offset of action. The short context-sensitive half-life of remifentanil makes this drug a popular analgesic during balanced volatile anaesthesia, ¹⁶ and the addition of remifentanil to volatile agents does not seem to modify the BIS level when there is no painful stimulation. ¹⁷ The supplemental use of remifentanil did not significantly confound BIS measurements in this study.

The present study has several limitations. First, poorly controlled, albeit transient, surgical stimuli may have affected BIS. ¹⁸ We chose to evaluate female patients undergoing thyroidectomy because this type of surgery carries relatively uniform surgical stimuli and sex may affect the hypnotic requirement. ¹⁹ It cannot be ruled out, however, that BIS values increased suddenly due to poorly controlled nociceptive stimuli in spite of strict remifentanil titration according to haemodynamic responses. Secondly, BIS profiles were evaluated at a single equivalent MAC concentration of three volatile anaesthetics (1 MAC). The dose ranges in which these anaesthetics can be safely administered without unnecessary deep hypnosis are near 1 MAC, however. ³ The BIS monitoring system is not a direct monitor to measure drug effects on brain function and the BIS value is one of several empirically derived EEG parameters. Thus, further studies using other EEG-derived parameters such as entropy or the Narcotrend index are needed to validate our results.

In conclusion, the use of an equivalent MAC (1 MAC) concentration of different volatile agents results in different BIS profiles. Desflurane produces lower BIS values than sevoflurane during the maintenance phase of the equipotent anaesthesia, resulting in almost twice the duration of deep hypnosis than sevoflurane. Management of volatile anaesthesia using predetermined MAC targets can lead to an unnecessarily long duration of deep hypnosis. Considering the potentially harmful effect of prolonged deep hypnosis, balanced anaesthesia with volatile anaesthetics and short-acting opioids is a good strategy to reduce the doses of anaesthetic agents. In such cases, additional BIS monitoring with careful titration of anaesthetics is essential.