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TECHNOLOGY, COMPUTING, AND SIMULATION

Bispectral Index Does Not Correlate with Observer Assessment of Alertness and Sedation Scores During 0.5% Bupivacaine Epidural Anesthesia with Nitrous Oxide Sedation

Kyung Soo Park, PhD, MD^*, Eun Jin Hur, BS^*, Kyung Woo Han, Ho Yeong Kil, MD, PhD, and Tae Hyung Han, MD, PhD, FAAFP

*From the Department of Pharmacology, Yonsei University College of Medicine, Seoul, Korea; Department of Anesthesiology and Pain Medicine, Hangang Sacred Heart Hospital, Hallym University College of Medicine, Seoul, Korea.

Address correspondence and reprint requests to Tae Hyung Han, MD, PhD, FAAFP, Department of Anesthesiology and Pain Medicine, Hangang Sacred Heart Hospital, Hallym University College of Medicine, 94-200 Young Deung Po Dong, Young Deung Po Ku, Seoul, Korea 150-719. Address e-mail to athan{at}unitel.co.kr.

	Abstract

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The bispectral index (BIS) has been used as a measure of the degree of sedation and level of hypnosis for IV hypnotics and sedatives, potent volatile anesthetics. We evaluated the effect of increasing concentrations of nitrous oxide (N₂O) on BIS and compared it with the Observer's Assessment of Alertness and Sedation (OAA/S) scale in patients undergoing regional anesthesia. We studied 48 unpremedicated, ASA physical status I–II adult patients scheduled for lower extremity surgery under lumbar epidural anesthesia. N₂O was given in oxygen to achieve measured end-tidal concentrations of 33%, 50%, and 67% N₂O by a tight-fitting facemask, and each N₂O concentration was maintained for 20 min. Paired measurements of BIS and OAA/S scores were obtained just before each increase in N₂O concentration. Forty of the 48 subjects completed the study. Increasing N₂O concentrations produced no changes in BIS despite a significant decrease in OAA/S scores at 50% and 67% N₂O concentrations. The prediction probability for BIS and OAA/S calculated by Somers' d_{x · y} were 0.60 and 0.84, respectively. Anesthesiologists should be aware that the BIS monitor may not be sensitive enough to provide an adequate measure of the depth of sedation and hypnosis when using N₂O alone for sedation. It may be better to monitor sedation clinically (e.g., with the OAA/S scale) to determine the dose requirement and the adequacy of depth of sedation and hypnosis.

	Introduction

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The bispectral index (BIS) is a novel neurophysiological measure of hypnosis. It correlates well with the depth of sedation, hypnosis, and general anesthesia produced by midazolam, propofol, isoflurane, and sevoflurane (1,2). However, its performance in unusual circumstances, such as critical illness, has recently been challenged (3,4). The 5% of patients at the extremes of the data distribution may be either aware or over-sedated. Further, the large interindividual and intraindividual variability in BIS scores reduces its ability to predict the depth of sedation in different subjects, thereby limiting its usefulness (5,6). BIS responses may also be dependent upon the drugs used (7–10).

The effect of nitrous oxide (N₂O) on BIS, when used alone or in combination with IV and volatile anesthetics, is inconsistent in humans. N₂O produces either no response or a paradoxical increase, even when consciousness is lost (11–14). In clinical anesthesia for healthy volunteers, the BIS response is influenced by several factors. The Observer's Assessment of Alertness and Sedation (OAA/S) score (15) is, on the other hand, well established for the evaluation of sedation (Table 1). It is easy and inexpensive to perform, whereas BIS is expensive (16). The benefits of BIS for monitoring sedation must therefore be considered, especially if less expensive alternatives are available.

Epidural anesthesia is in itself sedating, depending on the level of analgesia, the drugs used, and their dose. The dose-response relationship of N₂O sedation, measured by BIS, and its relationship to the OAA/S scale during epidural anesthesia have not been investigated. Patients anesthetized with regional anesthesia are no longer sedated with N₂O. However, because BIS has been marketed as a tool for the assessment of sedation during clinical anesthesia, it is worthwhile to evaluate the relationship between BIS and various clinical end-points. Our study is novel in that the subjects were receiving epidural anesthesia and simultaneous BIS and OAA/S measurements were made.

The aim of this observational study was to compare dose-dependent N₂O-induced alterations in BIS with the level of sedation as assessed by the OAA/S scale in patients undergoing epidural anesthesia for lower extremity surgery.

	METHODS

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The protocol was approved by the institutional ethics committee for human studies of Hangang Sacred Heart Hospital, Seoul, Korea. Written informed consent was obtained from each patient or legal guardian.

Forty-eight, ASA physical status I–II patients, aged between 20 to 55 yr and weighing 50 to 80 kg, were recruited. All were scheduled for elective lower extremity surgery using lower lumbar epidural anesthesia with an expected duration of 2–3 h.

Patients with concurrent diseases and those taking medications, such as antihypertensives or anticonvulsants, that would be expected to affect the electroencephalographic (EEG) response were excluded. Others with a history of cardiac, pulmonary, hepatic, or renal disease, or body mass index >30 were excluded, as were pregnant women, those of childbearing age, patients on long-term medication with central nervous system active drugs such as sedatives, hypnotics, or antipsychotics, and any in whom regional anesthesia was contraindicated.

Patients fasted overnight before their scheduled operation. No premedication was given. On arrival in the operating room, electrocardiogram, pulse oximetry, and noninvasive arterial blood pressure monitoring were applied. Baseline vital signs were obtained and subsequent values were recorded every 3 min throughout the study period. Crystalloid solutions, 500–1000 mL, were given IV before the block.

A disposable BIS sensor (The BIS^TM Standard Sensor, Aspect Medical Systems, Newton, MAa silver/silver chloride electrode array using ZipPrep^TM technology, was applied to the patient's forehead as recommended by the manufacturer. The sensor pad was inserted into the interface cable until fully engaged and then connected to the digital signal converter and BIS monitor with XP version 3.21 (A-2000 BIS Monitor System^TM, Aspect Medical Systems, Natick, MA). The attachment site was checked according to our institutional policy and the skin was inspected for lesions afterwards.

An epidural catheter was placed without dural puncture at the L3–4 or L4–5 interspace, with the patient in the lateral decubitus position. Three minutes after a test dose of 3 mL of 0.5% bupivacaine with 15 µg epinephrine was given, epidural blockade was achieved by 5-mL incremental doses of 0.5% bupivacaine, without fentanyl, every 3 min up to 15–20 mL, aiming for sensory block at T8–10 levels. Five- to 10-milligram incremental doses of ephedrine were administered IV as needed to treat hypotension (systolic arterial blood pressure <80 mm Hg) or bradycardia (heart rate <50 bpm). Lower extremity surgery was commenced after sensory block was confirmed by pinprick test.

After vital signs had stabilized and the patient had been comfortable on the operating table for at least 5 min, he or she was fitted with a tight facemask connected to a Bain circuit system with fresh gas flow of 10 L/min of 100% oxygen for at least 3 min. BIS monitoring was then initiated, and the signal quality index and possible interference with the high frequency (30–110 Hz) electromyographic signal were assessed as displayed by the monitor. BIS smoothing time was a minimum of 3 min, until a consistent and steady wave pattern without interference was achieved.

Baseline BIS measurements and OAA/S scores were recorded manually. To minimize potential observer bias, a single investigator (HYK), blinded as to BIS and treatment, performed all OAA/S assessments. Because of concerns about a dose-dependent increase in the incidence of nausea, emesis, and excitatory behavior, N₂O was administered in an upward sequence of end-tidal concentration steps of 33%, 50%, and 67% N₂O. Each end-tidal N₂O concentration was maintained for at least 20 min before being changed to the next concentration, while keeping the total fresh gas flow at 10 L/min. Paired BIS and OAA/S scores were obtained just before each increase in N₂O concentration. To minimize artifacts during BIS recording, patients were asked to close their eyes and not speak or move during the assessment periods, which were immediately before assessment of the OAA/S level. The BIS at each OAA/S score was calculated by averaging 3 values during the 45-s interval immediately before OAA/S score assessment.

Ventilation was gently assisted whenever necessary to keep the end-tidal carbon dioxide tension within the physiological range of 30–35 mm Hg (or between 4–4.7 kPa). Normothermia was maintained throughout the procedure. Any emotional changes, such as excitation, laughing, or tearing or behavioral abnormalities, such as involuntary movement, slurred speech, or tachypnea, were observed and noted.

SAS version 9 (SAS Institute Inc., Cary, NC) was used for statistical analysis, and values were expressed as mean ± sd whenever appropriate. Nominal BIS and ordinal OAA/S scores were compared at each target N₂O end-tidal concentration by nonparametric Friedman's analysis of variance on ranks with post hoc analysis corrected for repeated measurement.

For consistency with other EEG versus clinical depth reports, the prediction probability P_K was also calculated as previously described (17): P_K = 1/2 · (d_{y · x} + 1), where d_{y · x} = Kim's d_{y · x} = Somers' d_{x · y}, which was obtained using the SAS software. Because the net pharmacodynamic effect is the degree of decrement in BIS or OAA/S, data were transformed by subtracting the measured values from 100 for BIS and from 5 for OAA/S. These numbers were used to describe the pharmacodynamic effect of depth of anesthesia. The criterion for rejection of the null hypothesis was P < 0.05.

	RESULTS

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Five patients were unable to tolerate the facemask at a N₂O concentration of 67% because of abnormal excitatory and violent behavior. A further 3 patients who suffered nausea and vomiting during 50% N₂O administration; data from these 8 individuals were excluded from final analysis. The remaining 40 patients tolerated the epidural blockade well and the study was conducted without major deviations from the protocol.

Table 2 summarizes patient characteristics, duration of surgery, and doses of ephedrine and local anesthetics used. Most patients were middle-aged and relatively fit. Ephedrine was given to 15 of the 40 patients who completed the study. The mean total dose of bupivacaine 0.5% used before the administration of N₂O was 88.5 ± 15.0 mg.

Figure 1 shows the BIS at the N₂O concentrations studied. As N₂O concentration increased, the OAA/S scores decreased significantly, but there were no significant changes in BIS. For BIS and OAA/S, Somers' d_{x · y} were 0.2 versus 0.7, and P_K were 0.6 versus 0.8, respectively. Abnormal excitatory behavior, emotional changes, and increased respiratory rate were observed in 4 patients receiving 50% N₂O and in 16 patients receiving 67% N₂O. At the end of the study, all patients were fully awake, alert, and oriented. Three complained of nausea at the conclusion of study but did not vomit and received no medication.

View larger version (11K): [in this window] [in a new window]   Figure 1. Bispectral index (BIS) index values and the Observer's Assessment of Alertness and Sedation (OAA/S) scores at various concentrations of inhaled nitric oxide N2O. The incremental increase of inhaled N2O concentration resulted in significant reduction for OAA/S scores at 50% and 67% N2O but not for BIS. Values are expressed as median and range. *P < 0.05 compared to 0% N2O, P < 0.05 compared with 33% N2O, P < 0.05 compared with 50% N2O, respectively.

	DISCUSSION

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This study shows a lack of correlation between BIS and OAA/S during N₂O sedation. Increasing the end-tidal N₂O concentration to 50% and 67% produced the expected decrease in OAA/S scores but no change in BIS. BIS is thus relatively insensitive to the effect of N₂O as the sole anesthetic for sedation in patients undergoing epidural anesthesia. Our results must be cautiously interpreted, as there were many confounding variables present, such as ephedrine, epidural anesthesia, eye movements, and assisted ventilation, which may or may not have influenced the BIS. However, the study conditions, with all those confounding variables, are in fact very common in a clinical setting.

Epidural bupivacaine affects the BIS response, depending on the level of sensory block (7). Local anesthetics (18–22) also have a general anesthetic effect, induced by both the rostral spread of subanesthetic concentrations of bupivacaine within the cerebrospinal fluid and the indirect effects of deafferentation (23). In our study, epidural bupivacaine 0.5% achieved a relatively high sensory block (T8–10). Therefore, the lack of change in BIS we observed with increasing inhaled N₂O concentrations may, in fact, be a result of the paradoxical stimulating effect of N₂O, rather than the insensitivity of the BIS to N₂O.

BIS may be insensitive to N₂O. Rampil et al. (11) found neither BIS nor spectral edge frequency changed during inhalation of up to 50% N₂O in healthy volunteers, despite increased , ß, 40–50 Hz, and 70–110 Hz band powers of EEG. In contrast to our study, they observed no significant change in OAA/S scores at 50% N₂O, nor did they study the effect of larger N₂O concentrations. Barr et al. (12) found no effect on BIS of inhalation of up to 70% N₂O as a sole sedative anesthetic, despite all their healthy volunteers (n = 10) losing consciousness. The Spectral Entropy monitor (Datex-Ohmeda Corp., Helsinki, Finland) seems to have a similar response to N₂O. In day-surgical patients, a sedation regimen of propofol induction with N₂O did not improve the entropy signals, thus BIS and OAA/S were poorly correlated (24). None of the above studies, however, investigated the loss of verbal response during epidural anesthesia with N₂O sedation. These findings of paradoxical changes or insensitivity have been attributed to the failure of computing algorithm, i.e., an alteration in the relative ß-ratio in the presence or absence of N₂O (11,13).

The lack of effect of sedative concentrations of N₂O on BIS may be explicable in terms of sites and/or mechanisms of action. N₂O has a predominantly subcortical action combined with a relatively weak depressant effect on cortical neurons. A differential effect, i.e., stimulation of the cerebral cortex and depression of the brainstem and spinal cord, has been suggested (25–27). BIS, and perhaps also entropy, derived from cortical EEG activity, may thus reflect cerebral stimulation during N₂O inhalation (28). N₂O is an N-methyl-d-aspartate antagonist that produces analgesia and some degree of sedation, which may explain why its pharmacodynamic profile cannot be traced by EEG indices. BIS may not adequately reflect the sedative effects of opioids, ketamine, and other drugs that produce sedation via N-methyl-d-aspartic acid, opioid, or -2 receptors. Volatile anesthetics, propofol, and barbiturates, on the other hand, exert their effects via the gamma-aminobutyric acid-A receptor.

Ephedrine, given to some patients to stabilize the circulation during establishment of epidural anesthesia, affects BIS, and the index is significantly elevated 7–10 minutes after ephedrine administration (29). We tried to minimize the effects of ephedrine as much as possible by delaying the commencement of study until vital signs were stabilized.

In conclusion, N₂O, when used for sedation during epidural anesthesia, does not have the expected effect on BIS signals, such as is seen when N₂O is combined with inhaled anesthetics. BIS may not adequately reflect the depth of sedation and hypnosis, particularly at large N₂O concentrations. Thus, during N₂O sedation, clinical indices such as the OAA/S scale are more suitable for the assessment of sedation and hypnosis.

	Footnotes

 
Accepted for publication April 20, 2006.

Presented, in part, at the 13th Annual International Society of Anaesthetic Pharmacology Meeting 2004, Las Vegas, Nevada, October, 22^nd 2004.

Drs. Han and Park contributed equally to this work.

	REFERENCES

Top Abstract Introduction METHODS RESULTS DISCUSSION REFERENCES

 

1. Kearse LA, Jr., Rosow C, Zaslavsky A, et al. Bispectral analysis of the electroencephalogram predicts conscious processing of information during propofol sedation and hypnosis. Anesthesiology 1998;88:25–34.[Web of Science][Medline]
2. Glass PS, Bloom M, Kearse L, et al. Bispectral analysis measures sedation and memory effects of propofol, midazolam, isoflurane, and alfentanil in healthy volunteers. Anesthesiology 1997;86:836–47.[Web of Science][Medline]
3. Mantz J. Evaluation of the depth of sedation in neurocritical care: clinical scales, electrophysiological methods and BIS. Ann Fr Anesth Reanim 2004;23:535–40.[Web of Science][Medline]
4. Nasraway SA, Jr., Wu EC, Kelleher RM, et al. How reliable is the Bispectral Index in critically ill patients? A prospective, comparative, single-blinded observer study. Crit Care Med 2002; 30:1483–7.[Web of Science][Medline]
5. Oei-Lim VL, Kalkman CJ, Bouvy-Berends EC, et al. A comparison of the effects of propofol and nitrous oxide on the electroencephalogram in epileptic patients during conscious sedation for dental procedures. Anesth Analg 1992;75:708–14.[Abstract/Free Full Text]
6. Rodriguez RA, Hall LE, Duggan S, et al. The bispectral index does not correlate with clinical signs of inhalational anesthesia during sevoflurane induction and arousal in children. Can J Anaesth 2004;51:472–80.[Web of Science][Medline]
7. Doufas AG, Bakhshandeh M, Haugh GS, et al. Automated responsiveness test and bispectral index monitoring during propofol and propofol/N₂O sedation. Acta Anaesthesiol Scand 2003;47:951–7.[Web of Science][Medline]
8. Lysakowski C, Dumont L, Pellegrini M, et al. Effects of fentanyl, alfentanil, remifentanil and sufentanil on loss of consciousness and bispectral index during propofol induction of anaesthesia. Br J Anaesth 2001;86:523–7.[Abstract/Free Full Text]
9. Fehr SB, Zalunardo MP, Seifert B, et al. Clonidine decreases propofol requirements during anaesthesia: effect on bispectral index. Br J Anaesth 2001;86:627–32.[Abstract/Free Full Text]
10. Hirota K, Kubota T, Ishihara H, Matsuki A. The effects of nitrous oxide and ketamine on the bispectral index and 95% spectral edge frequency during propofol-fentanyl anaesthesia. Eur J Anaesthesiol 1999;16:779–83.[Web of Science][Medline]
11. Rampil IJ, Kim JS, Lenhardt R, et al. Bispectral EEG index during nitrous oxide administration. Anesthesiology 1998;89:671–7.[Web of Science][Medline]
12. Barr G, Jakobsson JG, Owall A, Anderson RE. Nitrous oxide does not alter bispectral index: study with nitrous oxide as sole agent and as an adjunct to i.v. anaesthesia. Br J Anaesth 1999;82:827–30.[Abstract/Free Full Text]
13. Puri GD. Paradoxical changes in bispectral index during nitrous oxide administration. Br J Anaesth 2001;86:141–2.[Abstract/Free Full Text]
14. Coste C, Guignard B, Menigaux C, Chauvin M. Nitrous oxide prevents movement during orotracheal intubation without affecting BIS value. Anesth Analg 2001;91:130–5.
15. Chernik DA, Gillings D, Laine H, et al. Validity and reliability of the Observer's Assessment of Alertness/Sedation Scale: study with intravenous midazolam. J Clin Psychopharmacol 1990;10:244–51.[Web of Science][Medline]
16. Liu SS. Effects of Bispectral Index monitoring on ambulatory anesthesia: a meta-analysis of randomized controlled trials and a cost analysis. Anesthesiology 2004;101:311–5.[Web of Science][Medline]
17. Smith WD, Dutton RC, Smith NT. Measuring the performance of anesthetic depth indicators. Anesthesiology 1996;84:38–51.[Web of Science][Medline]
18. Doufas AG, Wadhwa A, Shah YM, et al. Block-dependent sedation during epidural anaesthesia is associated with delayed brainstem conduction. Br J Anaesth 2004;93:228–34.[Abstract/Free Full Text]
19. Shono A, Sakura S, Saito Y, et al. Comparison of 1% and 2% lidocaine epidural anaesthesia combined with sevoflurane general anaesthesia utilizing a constant bispectral index. Br J Anaesth 2003;91:825–9.[Abstract/Free Full Text]
20. Morley AP, Derrick J, Seed PT, et al. Isoflurane dosage for equivalent intraoperative electroencephalographic suppression in patients with and without epidural blockade. Anesth Analg 2002;95:1412–8.[Abstract/Free Full Text]
21. Hodgson PS, Liu SS. Epidural lidocaine decreases sevoflurane requirement for adequate depth of anesthesia as measured by the Bispectral Index monitor. Anesthesiology 2001;94:799–803.[Web of Science][Medline]
22. Hans P, Lecoq JP, Brichant JF, et al. Effect of epidural bupivacaine on the relationship between the bispectral index and end-expiratory concentrations of desflurane. Anaesthesia 1999;54:899–902.[Web of Science][Medline]
23. Casati L, Fernandez-Galinski S, Barrera E, et al. Isoflurane requirements during combined general/epidural anesthesia for major abdominal surgery. Anesth Analg 2002;94:1331–7.[Abstract/Free Full Text]
24. Anderson RE, Jakobsson JG. Entropy of EEG during anaesthetic induction: a comparative study with propofol or nitrous oxide as sole agent. Br J Anaesth 2004;92:159–61.[Free Full Text]
25. Kochs E, Kalkman CJ, Thornton C, et al. Middle latency auditory evoked responses and electroencephalographic derived variables do not predict movement to noxious stimulation during 1 minimum alveolar anesthetic concentration isoflurane/nitrous oxide anesthesia. Anesth Analg 1999;88:1412–7.[Abstract/Free Full Text]
26. Sharpe RM, Nathwani D, Pal SK, et al. Auditory evoked response, median frequency and 95% spectral edge during anaesthesia with desflurane and nitrous oxide. Br J Anaesth 1997;78:282–5.[Abstract/Free Full Text]
27. Koitabashi T, Ouchi T, Umemura N. The effect of nitrous oxide on the central nervous system evaluated by the bispectral index under various levels of propofol anesthesia. Masui 2004;53:650–3.[Medline]
28. Sleigh JW, Barnard JP. Entropy is blind to nitrous oxide: can we see why? Br J Anaesth 2004;92:159–61.[Free Full Text]
29. Ishiyama T, Oguchi T, Iijima T, et al. Ephedrine, but not phenylephrine, increases bispectral index values during combined general and epidural anesthesia. Anesth Analg 2003;97:780–4.[Abstract/Free Full Text]

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (6) Citing Articles via Google Scholar Google Scholar Articles by Park, K. S. Articles by Han, T. H. Search for Related Content PubMed PubMed Citation Articles by Park, K. S. Articles by Han, T. H. Related Collections Regional Anesthesia Technology Pharmacology