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*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.
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Abstract |
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 Top Abstract IntroductionMETHODSRESULTSDISCUSSIONREFERENCES |
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Introduction |
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TopAbstractIntroductionMETHODSRESULTSDISCUSSIONREFERENCES |
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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.
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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.
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METHODS |
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TopAbstractIntroductionMETHODSRESULTSDISCUSSIONREFERENCES |
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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 BISTM Standard Sensor, Aspect Medical Systems, Newton, MAa silver/silver chloride electrode array using ZipPrepTM 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 SystemTM, 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 PK was also calculated as previously described (17): PK = 1/2 · (dy · x + 1), where dy · x = Kim's dy · x = Somers' dx · 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.
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RESULTS |
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TopAbstractIntroductionMETHODSRESULTSDISCUSSIONREFERENCES |
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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.
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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' dx · y were 0.2 versus 0.7, and PK 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.
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DISCUSSION |
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TopAbstractIntroductionMETHODSRESULTSDISCUSSIONREFERENCES |
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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.
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Footnotes |
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Presented, in part, at the 13th Annual International Society of Anaesthetic Pharmacology Meeting 2004, Las Vegas, Nevada, October, 22nd 2004.
Drs. Han and Park contributed equally to this work.
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P < 0.05 compared with 50% N2O, respectively.
