Research Report
Relationship of bispectral index to minimum alveolar concentration during isoflurane, sevoflurane or desflurane anaesthesia
Journal of International Medical Research 2014, Vol. 42(1) 130–137 ! The Author(s) 2013 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0300060513505525 imr.sagepub.com
Jin-Kyoung Kim, Duk-Kyung Kim and Myeong-Jin Lee
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 ¼ 29) than the sevoflurane group (n ¼ 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 ¼ 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.
Keywords Bispectral index, desflurane, hypnosis, isoflurane, sevoflurane Date received: 16 August 2013; accepted: 26 August 2013
Department of Anaesthesia and Pain Medicine, Samsung Medical Centre, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
Corresponding author: Duk-Kyung Kim, Department of Anaesthesia and Pain Medicine, Samsung Medical Centre, Sungkyunkwan University School of Medicine, 50 Irwon-Dong, Gangnam-Gu, Seoul 135-710, Republic of Korea. Email: [email protected]
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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 II12 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 (BisQUATROTM; Covidien Inc., Mansfield, MA, USA) was placed on the forehead and connected to BIS monitor (BIS VISTATM; 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 mg/kg per min remifentanil infusion and 0.1 mg/kg vecuronium. Anaesthesia was then maintained with isoflurane, sevoflurane
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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 mg/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 timeaveraged 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 timeaveraged BIS value in the desflurane group was 8.0. Differences of 7.0 in the timeaveraged BIS values among the groups
were considered to be clinically significant. Based on these values, and using a ¼ 0.05 and b ¼ 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 2-test, oneway analysis of variance (ANOVA) or repeated measures ANOVA with Scheffe´’s post hoc test, as appropriate. Statistical analyses were performed with SPSSÕ version 18.0 (SPSS Inc., Chicago, IL, USA) for WindowsÕ . In all analyses, P < 0.05 indicated statistical significance.
Results Of the 90 patients enrolled (n ¼ 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. 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. 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 ¼ 0.008). However, there were no statistically significant differences for the time-avergaed BIS value in other group comparisons (isoflurane vs. sevoflurane or
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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.
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 ¼ 27
Sevoflurane n ¼ 27
Desflurane n ¼ 29
Age, years Weight, kg Height, cm BMI, kg/m2 ASA physical status, I/II Duration of surgery, min Duration of anaesthesia, min Total dose of remifentanil, mg
47.7 9.5 62.1 8.1 158.7 6.2 24.7 3.0 18/9 85.0 18.4 119.1 20.6 161.8 70.7
44.7 11.6 61.0 8.7 158.4 6.3 24.1 3.4 21/6 84.4 19.9 117.0 21.1 174.0 68.0
48.0 10.3 59.6 7.8 156.7 5.6 24.3 2.9 17/12 89.1 13.2 121.6 16.1 168.9 61.9
Data presented as mean SD or n. No statistically significant between-group differences (P 0.05; one-way analysis of variance or 2-test). MAC: minimum alveolar concentration; BMI: body mass index; ASA: American Society of Anesthesiologists.12
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 ¼ 0.026 and P ¼ 0.038, respectively; Table 2). There were no other significant between-group differences in any parameter.
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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 ¼ 27
Sevoflurane n ¼ 27
Desflurane n ¼ 29
Time averaged BIS Minimal BIS Duration of deep hypnosis (BIS < 40), min Duration of adequate hypnosis (BIS 40–60), min
39.6 5.1 33.7 4.8 33.0 21.6 27.2 22.0
41.5 5.9a 35.0 6.0 24.3 22.5b 35.2 22.5c
37.0 4.9 31.8 4.8 40.2 20.7 27.3 22.4
Data presented as mean SD. a P ¼ 0.008, bP ¼ 0.026 and cP ¼ 0.038 versus desflurane group; analysis of variance with Scheffe´’s post hoc test. MAC: minimum alveolar concentration.
Figure 2. Mean bispectral index (BIS) values in female patients undergoing thyroidectomy using an equipotent dose (1 minimum alveolar concentration) of isoflurane (n ¼ 27), sevoflurane (n ¼ 27) or desflurane (n ¼ 29) throughout the maintenance phase of general anaesthesia. Data expressed as mean SD. *P < 0.05 between sevoflurane and desflurane groups; Scheffe´’s post hoc test.
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.
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
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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 isoflurane5 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 shortterm negative impact on recovery from anaesthesia,11 prolonged deep hypnosis may lead to postoperative delirium and cognitive decline10 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
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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.
Declaration of conflicting interest The authors declare that there are no conflicts of interests.
Funding This research received no specific grant from any funding agency in the public, commercial or notfor-profit sectors.
References 1. Kurata J. Deep hypnosis as a sign of ‘‘imbalance’’ in balanced anesthesia. Anesth Analg 2010; 110: 663–665. 2. Tonner PH. Balanced anaesthesia today. Best Pract Res Clin Anaesthesiol 2005; 19: 475–484. 3. Eger EI 2nd. Age, minimum alveolar anesthetic concentration, and minimum alveolar anesthetic concentration-awake. Anesth Analg 2001; 93: 947–953. 4. Aranake A, Mashour GA and Avidan MS. Minimum alveolar concentration: ongoing relevance and clinical utility. Anaesthesia 2013; 68: 512–522. 5. Umamaheswara Rao GS, Ali Z, Ramamoorthy M, et al. Equi-MAC concentrations of halothane and isoflurane do not produce similar bispectral index values. J Neurosurg Anesthesiol 2007; 19: 93–96.
6. Bonhomme V and Hans P. Monitoring depth of anaesthesia: is it worth the effort? Eur J Anaesthesiol 2004; 21: 423–428. 7. Vallejo R, Hord ED, Barna SA, et al. Perioperative immunosuppression in cancer patients. J Environ Pathol Toxicol Oncol 2003; 22: 139–146. 8. Monk TG, Saini V, Weldon BC, et al. Anesthetic management and one-year mortality after noncardiac surgery. Anesth Analg 2005; 100: 4–10. 9. Leslie K, Myles PS, Forbes A, et al. The effect of bispectral index monitoring on longterm survival in the B-aware trial. Anesth Analg 2010; 110: 816–822. 10. Chan MT, Cheng BC, Lee TM, et al. BISguided anesthesia decreases postoperative delirium and cognitive decline. J Neurosurg Anesthesiol 2013; 25: 33–42. 11. Monk TG and Weldon BC. Does depth of anesthesia monitoring improve postoperative outcomes? Curr Opin Anaesthesiol 2011; 24: 665–669. 12. Wolters U, Wolf T, Stu¨tzer H, et al. ASA classification and perioperative variables as predictors of postoperative outcome. Br J Anaesth 1996; 77: 217–222. 13. Schwab HS, Seeberger MD, Eger EI 2nd, et al. Sevoflurane decreases bispectral index values more than does halothane at equal MAC multiples. Anesth Analg 2004; 99: 1723–1727. 14. Chan MT and Gin T. What does the bispectral EEG index monitor? Eur J Anaesthesiol 2000; 17: 146–148. 15. Liu SS. Effects of bispectral index monitoring on ambulatory anesthesia: a metaanalysis of randomized controlled trials and a cost analysis. Anesthesiology 2004; 101: 311–315. 16. Cho HB, Kim JY, Kim DH, et al. Comparison of the optimal effect-site concentrations of remifentanil for preventing cough during emergence from desflurane or sevoflurane anaesthesia. J Int Med Res 2012; 40: 174–183. 17. Fodale V, Schifilliti D, Pratico` C, et al. Remifentanil and the brain. Acta Anaesthesiol Scand 2008; 52: 319–326.
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18. Iselin-Chaves IA, Flaishon R, Sebel PS, et al. The effect of the interaction of propofol and alfentanil on recall, loss of consciousness, and the bispectral index. Anesth Analg 1998; 87: 949–955.
19. Gan TJ, Glass PS, Sigl J, et al. Women emerge from general anesthesia with propofol/alfentanil/nitrous oxide faster than men. Anesthesiology 1999; 90: 1283–1287.
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Relationship of bispectral index to minimum alveolar concentration during isoflurane, sevoflurane or desflurane anaesthesia
Journal of International Medical Research 2014, Vol. 42(1) 130–137 ! The Author(s) 2013 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0300060513505525 imr.sagepub.com
Jin-Kyoung Kim, Duk-Kyung Kim and Myeong-Jin Lee
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 ¼ 29) than the sevoflurane group (n ¼ 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 ¼ 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.
Keywords Bispectral index, desflurane, hypnosis, isoflurane, sevoflurane Date received: 16 August 2013; accepted: 26 August 2013
Department of Anaesthesia and Pain Medicine, Samsung Medical Centre, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
Corresponding author: Duk-Kyung Kim, Department of Anaesthesia and Pain Medicine, Samsung Medical Centre, Sungkyunkwan University School of Medicine, 50 Irwon-Dong, Gangnam-Gu, Seoul 135-710, Republic of Korea. Email: [email protected]
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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 II12 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 (BisQUATROTM; Covidien Inc., Mansfield, MA, USA) was placed on the forehead and connected to BIS monitor (BIS VISTATM; 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 mg/kg per min remifentanil infusion and 0.1 mg/kg vecuronium. Anaesthesia was then maintained with isoflurane, sevoflurane
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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 mg/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 timeaveraged 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 timeaveraged BIS value in the desflurane group was 8.0. Differences of 7.0 in the timeaveraged BIS values among the groups
were considered to be clinically significant. Based on these values, and using a ¼ 0.05 and b ¼ 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 2-test, oneway analysis of variance (ANOVA) or repeated measures ANOVA with Scheffe´’s post hoc test, as appropriate. Statistical analyses were performed with SPSSÕ version 18.0 (SPSS Inc., Chicago, IL, USA) for WindowsÕ . In all analyses, P < 0.05 indicated statistical significance.
Results Of the 90 patients enrolled (n ¼ 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. 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. 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 ¼ 0.008). However, there were no statistically significant differences for the time-avergaed BIS value in other group comparisons (isoflurane vs. sevoflurane or
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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.
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 ¼ 27
Sevoflurane n ¼ 27
Desflurane n ¼ 29
Age, years Weight, kg Height, cm BMI, kg/m2 ASA physical status, I/II Duration of surgery, min Duration of anaesthesia, min Total dose of remifentanil, mg
47.7 9.5 62.1 8.1 158.7 6.2 24.7 3.0 18/9 85.0 18.4 119.1 20.6 161.8 70.7
44.7 11.6 61.0 8.7 158.4 6.3 24.1 3.4 21/6 84.4 19.9 117.0 21.1 174.0 68.0
48.0 10.3 59.6 7.8 156.7 5.6 24.3 2.9 17/12 89.1 13.2 121.6 16.1 168.9 61.9
Data presented as mean SD or n. No statistically significant between-group differences (P 0.05; one-way analysis of variance or 2-test). MAC: minimum alveolar concentration; BMI: body mass index; ASA: American Society of Anesthesiologists.12
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 ¼ 0.026 and P ¼ 0.038, respectively; Table 2). There were no other significant between-group differences in any parameter.
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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 ¼ 27
Sevoflurane n ¼ 27
Desflurane n ¼ 29
Time averaged BIS Minimal BIS Duration of deep hypnosis (BIS < 40), min Duration of adequate hypnosis (BIS 40–60), min
39.6 5.1 33.7 4.8 33.0 21.6 27.2 22.0
41.5 5.9a 35.0 6.0 24.3 22.5b 35.2 22.5c
37.0 4.9 31.8 4.8 40.2 20.7 27.3 22.4
Data presented as mean SD. a P ¼ 0.008, bP ¼ 0.026 and cP ¼ 0.038 versus desflurane group; analysis of variance with Scheffe´’s post hoc test. MAC: minimum alveolar concentration.
Figure 2. Mean bispectral index (BIS) values in female patients undergoing thyroidectomy using an equipotent dose (1 minimum alveolar concentration) of isoflurane (n ¼ 27), sevoflurane (n ¼ 27) or desflurane (n ¼ 29) throughout the maintenance phase of general anaesthesia. Data expressed as mean SD. *P < 0.05 between sevoflurane and desflurane groups; Scheffe´’s post hoc test.
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.
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
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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 isoflurane5 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 shortterm negative impact on recovery from anaesthesia,11 prolonged deep hypnosis may lead to postoperative delirium and cognitive decline10 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
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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.
Declaration of conflicting interest The authors declare that there are no conflicts of interests.
Funding This research received no specific grant from any funding agency in the public, commercial or notfor-profit sectors.
References 1. Kurata J. Deep hypnosis as a sign of ‘‘imbalance’’ in balanced anesthesia. Anesth Analg 2010; 110: 663–665. 2. Tonner PH. Balanced anaesthesia today. Best Pract Res Clin Anaesthesiol 2005; 19: 475–484. 3. Eger EI 2nd. Age, minimum alveolar anesthetic concentration, and minimum alveolar anesthetic concentration-awake. Anesth Analg 2001; 93: 947–953. 4. Aranake A, Mashour GA and Avidan MS. Minimum alveolar concentration: ongoing relevance and clinical utility. Anaesthesia 2013; 68: 512–522. 5. Umamaheswara Rao GS, Ali Z, Ramamoorthy M, et al. Equi-MAC concentrations of halothane and isoflurane do not produce similar bispectral index values. J Neurosurg Anesthesiol 2007; 19: 93–96.
6. Bonhomme V and Hans P. Monitoring depth of anaesthesia: is it worth the effort? Eur J Anaesthesiol 2004; 21: 423–428. 7. Vallejo R, Hord ED, Barna SA, et al. Perioperative immunosuppression in cancer patients. J Environ Pathol Toxicol Oncol 2003; 22: 139–146. 8. Monk TG, Saini V, Weldon BC, et al. Anesthetic management and one-year mortality after noncardiac surgery. Anesth Analg 2005; 100: 4–10. 9. Leslie K, Myles PS, Forbes A, et al. The effect of bispectral index monitoring on longterm survival in the B-aware trial. Anesth Analg 2010; 110: 816–822. 10. Chan MT, Cheng BC, Lee TM, et al. BISguided anesthesia decreases postoperative delirium and cognitive decline. J Neurosurg Anesthesiol 2013; 25: 33–42. 11. Monk TG and Weldon BC. Does depth of anesthesia monitoring improve postoperative outcomes? Curr Opin Anaesthesiol 2011; 24: 665–669. 12. Wolters U, Wolf T, Stu¨tzer H, et al. ASA classification and perioperative variables as predictors of postoperative outcome. Br J Anaesth 1996; 77: 217–222. 13. Schwab HS, Seeberger MD, Eger EI 2nd, et al. Sevoflurane decreases bispectral index values more than does halothane at equal MAC multiples. Anesth Analg 2004; 99: 1723–1727. 14. Chan MT and Gin T. What does the bispectral EEG index monitor? Eur J Anaesthesiol 2000; 17: 146–148. 15. Liu SS. Effects of bispectral index monitoring on ambulatory anesthesia: a metaanalysis of randomized controlled trials and a cost analysis. Anesthesiology 2004; 101: 311–315. 16. Cho HB, Kim JY, Kim DH, et al. Comparison of the optimal effect-site concentrations of remifentanil for preventing cough during emergence from desflurane or sevoflurane anaesthesia. J Int Med Res 2012; 40: 174–183. 17. Fodale V, Schifilliti D, Pratico` C, et al. Remifentanil and the brain. Acta Anaesthesiol Scand 2008; 52: 319–326.
Downloaded from imr.sagepub.com at KAI NAN UNIV on April 21, 2015
Kim et al.
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18. Iselin-Chaves IA, Flaishon R, Sebel PS, et al. The effect of the interaction of propofol and alfentanil on recall, loss of consciousness, and the bispectral index. Anesth Analg 1998; 87: 949–955.
19. Gan TJ, Glass PS, Sigl J, et al. Women emerge from general anesthesia with propofol/alfentanil/nitrous oxide faster than men. Anesthesiology 1999; 90: 1283–1287.
Downloaded from imr.sagepub.com at KAI NAN UNIV on April 21, 2015
