Anesth Analg 2006;103:378-384
© 2006 International Anesthesia Research Society
doi: 10.1213/01.ane.0000223681.77120.ca
TECHNOLOGY, COMPUTING, AND SIMULATION
Bispectral-Index-Guided Versus Clinically Guided Remifentanil/Propofol Analgesia/Sedation for Interventional Radiological Procedures: An Observer-Blinded Randomized Study
Ashraf A. Dahaba, MD, MSc, PhD*,
Ulrike Lischnig, MD*,
Robert Kronthaler, MD*,
Helmar Bornemann, MD*,
Vassil Georgiev, MD*,
Peter H. Rehak, PhD
, and
Helfried Metzler, MD*
From the *Department of Anaesthesiology and Intensive Care Medicine, and Biomedical Engineering and Computing Unit of the Department of Surgery, Graz Medical University, Graz, Austria.
Address correspondence and reprint requests to Ashraf A. Dahaba, MD, MSc, PhD, Department of Anaesthesiology and Intensive Care Medicine, Graz Medical University, Graz, Austria. Auenbruggerplatz 29, A-8036, Graz, Austria. Address e-mail to ashraf.dahaba{at}meduni-graz.at.
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Abstract
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Patients undergoing potentially painful interventional radiological procedures generally require a combination of analgesia and sedation. This sedation/analgesia should allow the patient to communicate while also remaining calm. Bispectral index (BIS) monitoring could be useful in achieving this. The primary end-point of our study was to compare the percentage time with optimal sedation, defined as Sedation Agitation Scale (SAS) grade 4, between a BIS-guided remifentanil/propofol regimen and a clinically guided regimen in 54 randomly allocated patients. The mean ± sd percentage time with optimal sedation was significantly longer (P = 0.004) in the BIS group (76.6% ± 14.7%) than in the SAS group (63.8% ± 16.4%). There was a significant difference in the weighted mean infusion rates of remifentanil (P = 0.0067) and propofol (P = 0.0075) in the BIS group (0.066 ± 0.027 µg · kg–1 · min–1 1.59 ± 0.44 mg · kg–1 · h–1) compared with the SAS group (0.091 ± 0.036 µg · kg–1 · min–1 1.92 ± 0.43 mg · kg–1 · h–1), respectively. BIS values exhibited a temporal correlation to SAS scores (r2 = 0.72). In conclusion, a BIS-guided regimen was more effective than a SAS-guided regimen. The use of BIS resulted in fewer remifentanil and propofol doses. The targeted BIS range of 80–85 provided a sufficient functional level of sedation.
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Introduction
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Patients undergoing interventional radiological procedures are exposed to numerous noxious and stressful stimuli that generally require a combination of analgesia and sedation. However, sedation for such procedures involves communication with the patients, as they must respond to various commands. At the same time, patients must remain calm, as any sudden unexpected movement could have serious consequences. Using clinical scoring that relies on speech and facial expressions to assess the level of sedation is often difficult due to inaccessibility during the procedure. A further inherent problem is that verbal or tactile stimulations of clinical scoring can be disturbing to both the patient and the radiologist, especially during the delicate phases of the procedure. Using bispectral index (BIS) monitoring to objectively guide administration of sedatives might help address some of these difficulties.
Short-acting drugs with rapid, predictable onset and offset of action, such as propofol and remifentanil, facilitate infusion rate adjustments and rapid recovery. However, there is always the possibility of over-sedation, hypotension and respiratory depression due to their rather narrow therapeutic window. Here, BIS monitoring might be helpful in avoiding unnecessary dosage or associated complications.
The aim of our study was to compare the efficacy and safety of a BIS-guided regimen to a clinically guided regimen for the provision of optimal sedation in patients undergoing potentially painful interventional radiological procedures. The primary endpoint of our study was the percentage time with optimal sedation defined as Sedation Agitation Scale (SAS, Appendix 1) (1) grade 4. We hypothesized that a BIS-guided regimen is more effective than a SAS-guided regimen for the provision of optimal sedation. The secondary end-points included the percentage time with the targeted BIS range of 80–85, medication requirements, hemodynamic stability, patient/operator satisfaction, and validation of the targeted BIS range of 80–85 for procedural sedation in interventional radiology.
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METHODS
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After Graz Medical University ethics committee approval, all patients who agreed to participate in the study gave written informed consent. Fifty-four ASA I–IV subjects, 40 yr or older, admitted to the department of interventional radiology for potentially painful procedures were included in the study. Subjects with medical conditions that may have affected their ability to assess level of sedation such as stroke, stupor, dementia, and patients with an estimated 20% deviation from ideal body weight were excluded from the study. A consecutive randomized, observer-blinded, controlled, parallel group study was conducted in conformity with the guidelines of the "Consolidated standards of reporting trials" statement (2). Patients were randomly allocated to the BIS-guided or SAS-guided groups according to a computer generated randomization list. Because of the different types of pain between different interventions and to ensure equality in the severity of illness with a balanced case-mix, randomization was stratified according to the type of intervention in the following categories: thrombo/chemo-embolization, percutaneous transhepatic cholangio drainage, brachytherapy, and nephrostomy/percutaneous transhepatic stent insertion.
BIS "Quatro" sensors were placed on patients' foreheads and connected to a BIS-XP monitor (version 3.4; Aspect Medical Systems, Newton, MA). The BIS monitor was connected to a laptop computer. Patients were instructed to relax but not to sleep. Recordings were started after verifying a signal quality index of >95% and electrodes impedance of <5 k
. BIS values and electromyography (EMG) data were continuously collected and stored every 5 s, and the smoothing window was set at 30 s.
The anesthesiologists who participated in the study were adequately informed and experienced in level of sedation assessment using the SAS score; they used the SAS score assessment for at least 2 yr in critically ill patients before their involvement in the study. Procedures were performed in an operating room in the radiology suite in a quiet environment to prevent noise from provoking a BIS response. A large mobile partition screen separated the BIS monitor from the patient. For patients randomized to the SAS group, remifentanil and propofol infusions were placed on the patient's side of the partition screen and the treating anesthesiologist, blinded as to BIS values, adjusted the infusions according to their assessment of the mean SAS score of the preceding 5-min period.
For patients randomized to the BIS group, the infusions were placed on the BIS side of the partition screen and the treating anesthesiologist adjusted the infusions according to their assessment of the mean BIS value of the preceding full 5-min period. This would accommodate for verbal or tactile stimuli temporarily increasing BIS values. At the same time a second anesthesiologist, on the patient's side of the partition screen, blinded as to BIS values and infusion rates, recorded the mean SAS score of the preceding 5-min period.
Patients spontaneously breathed 50% oxygen in air via a facemask. Pain Intensity scale (0 = no pain, 6 = maximum pain; Appendix 2), arterial oxygen saturation, respiratory rate, end-tidal carbon dioxide, mean arterial blood pressure, and heart rate were recorded at 5-min intervals.
In our study design, we used manual infusion pumps routinely used in a typical sedation/analgesia clinical setting for interventional radiology rather than target-controlled infusions, as the incorporated target-controlled infusion pharmacokinetic model could be a confounding factor that might give an added advantage to BIS monitoring, an electroencephalography (EEG)-derived parameter. Remifentanil 0.6 µg · kg–1 · mL–1 and propofol 0.15 mg · kg–1 · mL–1 infusion syringes were first prepared according to each individual patient body weight. This was achieved for remifentanil by dividing 1666 by the patient's weight. The resulting figure was then taken as the milliliters of normal saline in which 1 mg remifentanil was dissolved. This yielded an exact remifentanil 0.6 µg · kg–1 · mL–1 concentration. A similar procedure was done for propofol by multiplying body weight by 0.375. Normal saline up to 50 mL was added to the milliliters of propofol's 2% resulting figure. This yielded an exact propofol 0.15 mg · kg–1 · mL–1 concentration.
The dosing algorithms are outlined in Fig. 1. In all patients, initial infusions of remifentanil 5 mL/h (0.05 µg · kg–1 · min–1) and propofol 10 mL/h (1.5 mg · kg–1 · h–1) were started. In subjects allocated to the SAS group, if the SAS score was 4 and patients had no pain, then current infusion rates were maintained. If the SAS score was >4, then remifentanil and propofol infusion rates were increased by 1 mL/h (0.01 µg · kg–1 · min–1) and 3 mL/h (0.45 mg · kg–1 · h–1) respectively. If patients had pain then only the remifentanil infusion was increased by 1 mL/h.
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Figure 1. Flow chart of remifentanil and propofol dosing algorithm in Bispectral index (BIS) and Sedation-Agitation Scale (SAS) groups.
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In subjects allocated to the BIS group, if the BIS was between 80–85 then the current infusion rates were maintained. If the BIS was >85 then remifentanil and propofol infusion rates were increased by 1 mL/h and 3 mL/h, respectively. As a "BIS group rescue protocol," if the anesthesiologist on the patient's side of the partition would signal that the patient became suddenly visibly agitated then remifentanil and propofol infusions were increased by 1 mL/h and 3 mL/h, respectively, and if subjects had pain the remifentanil infusion was increased by 1 mL/h.
If patients had no pain and the SAS was <4 in the SAS group, BIS was <80 in the BIS group, or if patients went into apnea their lungs were ventilated by facemask, and remifentanil and propofol infusion rates were decreased by 1 mL/h and 3 mL/h respectively.
Recovery time was the time from discontinuation of infusions until full recovery defined as date of birth recall with respiratory rate >10 breaths/min. In addition, after the end of the procedure, postanesthesia care unit nurses asked the radiologists, assisting nurses and patients blinded to the technique used, to grade their degree of satisfaction as excellent = 3, good = 2, acceptable = 1, or unacceptable = 0.
Assuming a 15 percentage point deviation from the 78.3% ± 6.2% mean percentage time of remifentanil SAS 4 optimal sedation in a previous study (3), our a priori power calculation for two-sided Student's t-test (
= 0.05) showed that a group size of 27 patients would be required to reveal a statistically significant difference between the 2 groups with >80% power. One-way analysis of variance was used for the analysis of the differences between the two groups. Mann-Whitney U-test was used for the analysis of nonparametric parameters. Pearson's linear determination coefficient (r2) was used to correlate BIS values to SAS scores. Data were expressed as mean ± sd P < 0.05 was considered statistically significant.
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RESULTS
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There was no significant difference in patients' characteristics between the two groups (Table 1). In each group, 12 patients underwent thrombo/chemo-embolization, 6 patients underwent percutaneous transhepatic cholangio drainage, 3 patients underwent brachytherapy, and 6 patients underwent nephrostomy or percutaneous transhepatic stent insertion.
All data were normally distributed. The mean percentage time with optimal sedation (SAS 4) as well as the mean percentage time with the targeted BIS range of 80–85 were both significantly longer, and subjects required fewer infusion rate adjustments and fewer propofol and remifentanil doses in the BIS group compared with the SAS group (Table 2, Fig. 2). Patients in the BIS group experienced no clinically significant pain 96.6% ± 1.6% of the time compared with 96.4% ± 1.8% of the time in the SAS group (P = 0.63). The BIS group rescue protocol was not used.
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Table 2. Percentage Time of Sedation Agitation Scale (SAS), Infusion Rate Requirements, Number of Adjustments and Recovery Time
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Figure 2. Mean ± sd remifentanil and propofol infusion requirements (mL/h) in the Bispectral Index (BIS) and Sedation Agitation Scale (SAS) groups. n = 27, *Significant difference between the two groups.
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MAP was significantly lower in the SAS group compared with the BIS group (Fig. 3). There was no significant difference in heart rate or respiratory variables between the two groups (Table 3). Median operator satisfaction was graded as good in both groups, whereas patient satisfaction was excellent in both groups. There was a clear temporal correlation between BIS values and SAS scores (r2 = 0.72) in our overall study population (Fig. 4).
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Figure 3. Mean ± sd mean arterial blood pressure (MAP) and heart rate (HR) in the Bispectral Index (BIS) and Sedation-Agitation Scale (SAS) groups. n = 27, *Significant difference between the two groups.
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Figure 4. Mean ± sd. Bispectral Index (BIS) and Electromyography (EMG) at different Sedation Agitation Scale (SAS). n = 54, number of sample points = 53784.
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DISCUSSION
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Our study hypothesis was confirmed, as the BIS-guided objective regime was more effective in providing optimal sedation with fewer infusion rate adjustments than a clinically guided subjective regime. This could be attributed to the precise nature of BIS monitoring providing updated information that enabled a stable level of sedation and analgesia to be achieved and maintained. However, the 13 percentage point difference between the two groups, although statistically significant, was still less than the 15 percentage points difference we assumed in our power analysis. In this regard the 13 percentage point (approximately 5 minutes) difference in the time with optimal sedation might be considered clinically irrelevant for interventional radiological procedures that lasted a mean 79 and 87 minutes in the 2 study groups. Furthermore, our finding of just a 2-minute difference in the recovery time between the two groups would represent no advantage or practical value of BIS monitoring over a clinically guided regimen.
The time with BIS <80 in the SAS group was significantly longer than in the BIS group, indicating that patients of the SAS group were more deeply sedated. In our study, MAP in the SAS group was significantly lower than MAP in the BIS group, probably as a result of the larger remifentanil and propofol doses in the SAS group. Two recent studies demonstrated that the mechanisms involved in the hypotension associated with remifentanil and propofol administration are dose-dependent (4,5). With a remifentanil infusion rate of 0.05 µg · kg–1 · min–1 an infusion rate close to the mean infusion rate of the BIS group of our study, circulatory variables were unaffected. However, with an infusion rate of 0.1 µg · kg–1 · min–1 approximately the mean infusion rate of the SAS group of our study, remifentanil was associated with clinically relevant hypotension (4). Similarly, propofol sedation maintained at BIS 70 was associated with significantly less vasodilatation, and less inhibition of sympathetic nerve activity, than with hypnotic doses of propofol (5).
Our study demonstrated a clear temporal correlation between BIS values and SAS scores. Unlike propofol, which has a strong influence on EEG, µ-opioids produce fewer electrophysiological alterations on the cerebral cortex (6). However, remifentanil could still strongly influence BIS values in another way: through the attenuation of responses to noxious stimuli. Under constant propofol infusion, remifentanil was shown to blunt, in a dose-related fashion, increases in BIS values after laryngoscopy and tracheal intubation (7). In other words, BIS values under a constant level of an analgesic sedative regimen not only indicate the hypnotic component but at the same time would also reflect the degree of opioid-induced inhibition of noxious stimuli from provoking a pain-induced cortical arousal (7). Thus it seems reasonable to conclude that BIS values clearly correlated to both the analgesic and hypnotic components of our remifentanil/propofol dosing algorithm.
BIS values were shown to spuriously increase with high EMG activity (8,9) because EMG activities are artifact signals that occur within the frequency "range of interest" of the bispectrum. The EMG30–47 Hz frequency band could simulate the BetaRatio, one of the BIS component descriptors, and would be misinterpreted by the BIS algorithm as EEG activity (10). Figure 4 demonstrates that during the periods of SAS 6 and SAS 5, the mean EMG values were above what could be considered the cut-off point of 35 dB (11), clearly indicating that high EMG activity could have contributed to the increased BIS values with SAS 6 and SAS 5.
BIS was validated by the originators of the SAS score for monitoring sedation in critically ill patients, as SAS 4 correlated to mean BIS 87 in one study (12) and to BIS 79 in a second study (13). Thus, the fact that the targeted BIS range of 80–85 in the BIS group obviously described a slightly narrower clinical spectrum than that defined as SAS 4 (BIS 79–87) (12,13) could have contributed to the BIS 80–85 targeted sedation in the BIS group being more effective than the slightly wider targeted SAS 4 in the SAS group.
In conclusion, a BIS-guided regimen was more effective than a SAS-guided clinical regimen for the provision of optimal sedation in patients undergoing potentially painful interventional radiological procedures. The use of BIS for titrating infusion requirements resulted in hemodynamic stability and fewer remifentanil and propofol doses. Our results suggest that the targeted BIS range of 80–85 provided a sufficient and functional level of sedation for patients that was also acceptable to radiologists. Thus BIS monitoring could be a useful tool for accurately and objectively delivering reliable sedation that could be used to augment standard assessment.
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ACKNOWLEDGMENTS
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The authors would like to thank Charles Zhou, BTTCO, People's Republic of China for his great efforts and meticulous work in preparing the data
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Appendix 1
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Footnotes
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Accepted for publication March 30, 2006.
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Abstract
Introduction
