Anesth Analg 2008; 107:1290-1294
© 2008 International Anesthesia Research Society
doi: 10.1213/ane.0b013e31818061ae
CRITICAL CARE AND TRAUMA
Composite Auditory Evoked Potential Index Versus Bispectral Index to Estimate the Level of Sedation in Paralyzed Critically Ill Patients: A Prospective Observational Study
Chueng-He Lu, MD*,
Kee-Ming Man, MD ,
Hsin-Yi Ou-Yang, RN, MS ,
Shun-Ming Chan, MD*,
Shung-Tai Ho, MD*,
Chih-Shung Wong, MD, PhD*, and
Wen-Jinn Liaw, MD, PhD*
From the Departments of *Anesthesiology, and Nursing, Tri-Service General Hospital, National Defense Medical Center; and Department of Anesthesiology, Tungs' Taichung MetroHarbor Hospital, Taiwan.
Address correspondence and reprint requests to Wen-Jinn Liaw, MD, PhD, Surgical Intensive Care Unit, Tri-Service General Hospital, 325, Sec. 2, Chenggong Rd, Taipei 114, Taiwan. Address e-mail to siculiaw{at}mail.ndmctsgh.edu.tw.
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Abstract
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BACKGROUND: Electromyographic activity (EMG) has been reported to elevate the Bispectral Index (BIS) in patients not receiving neuromuscular blockade while under sedation in the intensive care unit (ICU). We investigated the change of the composite A-line autoregressive index (AAI) and BIS after administration of muscle relaxants in sedated surgical ICU patients.
METHODS: We prospectively investigated 38 patients who required administration of a muscle relaxant while continuously sedated with midazolam hydrochloride and fentanyl citrate to achieve a Ramsay Sedation Scale value equal to 5. BIS, EMG activity of BIS (EMG-BIS), signal quality index of BIS, AAI, EMG activity of AAI (EMG-AAI), and acceleromyography at the adductor pollicis muscle were recorded simultaneously every 5 min for 30 min before and after neuromuscular blockade. Student's t-test, the Wilcoxon's signed ranks test, and the Spearman test were calculated using the standard statistics software SPSS 10.0 (SPSS Inc., Chicago, IL).
RESULTS: After administration of a muscle relaxant, BIS (58.61 ± 7.45 vs 44.68 ± 6.65, P < 0.001), EMG-BIS (37.33 ± 7.15 vs 27.24 ± 1.51, P < 0.001), AAI (34.11 ± 10.96 vs 15.97 ± 6.69, P < 0.001), and EMG-AAI (59.58 ± 9.57 vs 1.00 ± 0.00, P < 0.001) decreased significantly. Significant correlations between BIS and EMG-BIS (rs = 0.75, P < 0.001) and AAI and EMG-AAI (rs = 0.87, P < 0.001) were also found during the baseline period.
CONCLUSIONS: This study demonstrated that, in sedated ICU patients, BIS and AAI markedly decreased after administration of myorelaxant, and the decreased BIS and AAI values after neuromuscular blockade were correlated to those usually seen in the state of surgical anesthesia, respectively.
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Introduction
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Reported data suggest that intensive care unit (ICU) sedation protocols used to prevent oversedation can significantly improve outcomes.1 Newly released clinical practice guidelines insist on the monitoring of sedation as an emerging standard of care.2,3 However, an approach using regular sedation steps may not be appropriate for patients requiring sustained deep sedation, such as those with elevated intracranial pressure, neuromuscular blockade, or asynchrony with mechanical ventilation, or those requiring immobility to protect surgical wounds or invasive devices.
Processed electroencephalogram (EEG) algorithms may provide another means of quantitatively monitoring the level of sedation in ICU patients. The Bispectral Index (BIS) is a processed EEG variable successfully applied in clinical anesthesia to assess sedation and hypnosis.4–6 Initial reports on the use of BIS in ICU patients have found that BIS monitoring does not always correlate with clinical measures of sedation.7–16 One of the main confounders of BIS monitoring in anesthesia and intensive care settings may be artifacts caused by muscular activity resulting in an over-estimation of the level of consciousness.7,10 The muscular activity leads to falsely high monitor readings which can be misinterpreted as light sedation, leading to hemodynamic compromise, excessive administration of drugs, and prolonged ventilation and ICU stay.
Among evoked potentials, middle latency auditory evoked potentials (MLAEP) appear to be one of the most promising variables for the estimation of depth of sedation.17 The AEP Monitor/2 (Danmeter A/S, Odense, Denmark), a recently commercialized system for monitoring depth of anesthesia, extracts the MLAEP from the EEG signal by using an autoregressive model with an exogenous input adaptive method.18 A monitoring variable indicating the patient's hypnotic state, the so-called composite A-line autoregressive index (AAI), is then calculated from the MLAEP and the EEG.19 Several recent studies with the A-LineTM Monitor (Danmeter A/S, Odense, Denmark), an earlier version of the AEP Monitor/2, have suggested that the AAI might be helpful in distinguishing between the awake and unconscious states, detecting intraoperative awareness with recall, and decreasing anesthetic requirements.20–22 To our knowledge, there is only one publication investigating AEP monitoring in the ICU setting, and its authors also consider that electromyographic activity (EMG) contamination and patient movements are artifacts in AEP collection.23 A review of the literature suggests that the assessment of AAI in sedated ICU patients with neuromuscular blockade has not yet been studied. Therefore, the aim of this study was to investigate the magnitude of the change in AAI and BIS after administration of a muscle relaxant in sedated ICU patients.
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METHODS
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This study was approved by our IRB. Written informed consent was obtained from all patients and/or their families. The study population included a general, heterogeneous population in the surgical ICU of the Tri-Service General Hospital and National Defense Medical Center. Patient care conformed to standard procedures currently used in our ICU, including standard monitoring with continuous electrocardiography, invasive arterial blood pressure monitoring, pulse oximetry, and the additional use of noninvasive EEG monitoring. Patients were eligible for this study if their lungs were mechanically ventilated and they were continuously sedated with midazolam hydrochloride and fentanyl citrate to achieve a Ramsay Sedation Scale (RSS) value equal to 5 (Table 1). We prospectively included patients requiring administration of muscle relaxant for adaptation to mechanical ventilation. Exclusion criteria included brain damage, high intracranial pressure or head injury, neurologic diseases, encephalopathy, hearing impairment or defect, hemodynamic instability, hypothermia (tympanic temperature <36.0°C), and recent (<3 h) administration of a muscle relaxant before the study period. The effect of neuromuscular blocking drugs on muscle activity was monitored through stimulation of the ulnar nerve and acceleromyography at the adductor pollicis muscle. The BIS was measured with an improved version of the BIS algorithm (BIS XP, Aspect Medical Systems, Newton, MA) and the AAI was recorded using the AEP Monitor/2 (Danmeter A/S, Odense, Denmark; software version 1.6). MLAEP was elicited with a binaural click stimulus of 65 dB intensity. BIS and AAI electrodes were placed on opposite sides of the patient's forehead, closely matching the manufacturer's specifications (Fig. 1). If monitor electrodes are not placed as suggested by the manufacturer (e.g., they are placed in the wrong location, or the locations are transposed), the measured values will be decreased and the sedation level will be over-estimated.
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Figure 1. Both Bispectral Index (BIS) and auditory evoked potential (AAI) electrodes were applied simultaneously on opposite sides of the forehead of all patients, closely matching the manufacturer's specifications.
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Before muscle relaxant administration, BIS, EMG activity of BIS (EMG-BIS), signal quality index of BIS (SQI-BIS), AAI, and EMG activity of AAI (EMG-AAI) were recorded simultaneously for all patients every 5 min for 30 min (seven data points per patient) without clinical stimulation in order to determine the value of these variables in the absence of muscle relaxant (baseline period). The following procedure was performed for patients requiring muscle relaxation for adaptation to mechanical ventilation: immediately after the 30-min recording, the control twitch height of the adductor pollicis was calibrated to set the T1 100% baseline level. The muscle relaxant (0.15 mg/kg cisatracurium) was then given IV. As soon as T1 decreased below 5% of the baseline value, BIS, EMG-BIS, SQI-BIS, AAI, and EMG-AAI were determined simultaneously once every 5 min for a second 30-min recording period (seven data points per patient) without clinical stimulation to the patient (myorelaxation period). Fourteen data points in each patient were collected during both baseline and myorelaxation periods.
The baseline and myorelaxation values of BIS and AAI were stable during the recording period without clinical stimulation. All data points were within the normal variation during the recording period and were expressed as mean ± sd in each patient. Comparison of hemodynamic variables was performed using paired Student's t-test. The two monitors' values between the baseline and myorelaxation study periods were performed using the Wilcoxon's signed ranks test. Correlation between the two variables EEG and EMG was performed using the method of Spearman (rs). Values of P < 0.05 were considered statistically significant. Statistics were calculated on a personal computer using standard statistics software SPSS 10.0 and Sigmaplot 8.0.
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RESULTS
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Thirty-eight patients aged 59 ± 18 yr (28 men, 10 women) were investigated prospectively. Patient demographic data are shown in Table 2. All patients required sedation in the ICU and long-term myorelaxation for adaptation to mechanical ventilation. No change in the midazolam hydrochloride (6.2 ± 1.8 mg/h) or fentanyl citrate (48.0 ± 8.9 µg/h) administration regimens occurred in any of the 38 patients during the study periods. For the 38 patients, hemodynamic variables remained unchanged between the baseline and myorelaxation study periods (Table 3).
After administration of myorelaxation, BIS (58.61 ± 7.45 vs 44.68 ± 6.65, P < 0.001), EMG- BIS (37.33 ± 7.15 vs 27.24 ± 1.51, P < 0.001), AAI (34.11 ± 10.96 vs 15.97 ± 6.69, P < 0.001), and EMG-AAI (59.58 ± 9.57 vs 1.00 ± 0.00, P < 0.001) all decreased significantly (Fig. 2), whereas SQI-BIS was unchanged (91.55 ± 6.07 vs 91.84 ± 5.73, nonsignificant [NS]) (Table 3). We also observed a significant correlation between BIS and EMG-BIS (rs = 0.75, P < 0.001) and between AAI and EMG-AAI (rs = 0.87, P < 0.001) during the baseline period.
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Figure 2. Effect of myorelaxant administration on Bispectral Index (BIS) and Composite Auditory Evoked Potential Index (AAI) (n = 38 patients for baseline and myorelaxation periods). Data in each patient expressed as mean (n = 38). Baseline = study period 30 min before muscle relaxant administration; myorelaxation = study period 30 min after muscle relaxant administration; BIS = bispectral index; AAI = composite auditory evoked potential index.
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DISCUSSION
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Both over-sedation and under-sedation should be avoided in intensive care patients. Over-sedation can lead to hemodynamic compromise and excessive resource consumption, including drugs administered, prolonged ventilation, and increased ICU length of stay. Under-sedation can lead to anxiety, agitation, self-removal of medical devices, and the development of posttraumatic stress disorder. Kress et al.25 demonstrated that daily sedative interruption did not result in adverse psychological outcomes and even reduced symptoms of posttraumatic stress disorder. Routine assessment of sedation status allows determination of the optimal sedative dose administered to ICU patients. EEG and MLAEP variables may provide another means of estimating level of sedation, and are expected to be able to provide objective values indicating levels of sedation automatically and continuously.
The BIS has been increasingly studied in the ICU, and available published clinical trials reveal a modest and variable correlation between the BIS and subjective monitoring scales (r2 range, 0.20–0.64).7–16 The influence of EMG activity on BIS is implied by the method of measurement and calculation of the BIS algorithm. The EEG signal analyzed by the BIS monitor ends at 32 hertz (Hz). Contamination of the EEG signal can occur because EMG activity arises at overlapping frequencies of 30–300 Hz.6 Vivien et al.7 confirmed the spurious effects of musculoskeletal activity on BIS-XP. Their study demonstrated the contribution of EMG to BIS values in deeply sedated patients, and illustrated the importance of ensuring adequate sedation and analgesia. The BIS changes accompanying neuromuscular blockade have prompted others to question the adequacy of sedation and analgesia administered to ICU patients.26 Inadequate analgesia may have been a contributing factor to the BIS changes in our study participants. Of note, patients in other trials sedated to the same clinical end-point received 5–8 times more sufentanil citrate and twice as much midazolam hydrochloride.27,28 Whether the higher EMG activity reflects a pain response has not been established.
Doi et al.23 compared processed EEG variables, AEP, BIS, and spectral edge frequency 95%, with the RSS to predict responses to various stimuli in intensive care patients, and found that the AEP was the best predictor and correlated well with the RSS. In a preliminary study, we also found that the application of AAI had an acceptable correlation with the clinical assessment of RSS in surgical ICU patients (Kendall correlation coefficients,  = –0.621; P < 0 0.01). Our data revealed that AAI more than 60 indicated a patient was fully awake or under minimal sedation, and values between 60 and 40 were suggestive of light to moderate sedation. Values between 40 and 25 were associated with deep sedation, and readings between 25 and 15 were associated with surgical anesthesia. Use of the AEP monitor has not been described in sedated and paralyzed ICU patients. In the present study, we found that the reductions of AAI values due to muscle relaxants were also found in the AEP Monitor/2, and the decreased AAI and BIS values after neuromuscular blockade were related to the AAI and BIS values of surgical anesthesia, respectively. In our opinion, the BIS and AAI values in the nonparalyzed patients are the correct measure of the sedated state. If the deeply sedated patients were paralyzed with muscle relaxants, their sedated state might correlate to those seen in the general anesthetic state, and then the BIS and AAI values could be reduced.
Certain limitations and problems related to the AEP monitor need to be considered when it is used in the intensive care setting. First, although there is no evidence that prolonged auditory stimuli around 65 dB damage auditory function, continued auditory stimulation over a period of days should be avoided. This means that continuous monitoring of the AEP should be interrupted and changed to intermittent measurement. Second, clicking over long periods probably disturbs patients, especially those under light sedation. Third, EMG and patient movements are artifacts in AEP collection. We gave patients no clinical stimulus during the study period to minimize artifacts to the greatest extent possible, but this does not seem practical in the clinical situation. Finally, large-amplitude contaminated MLAEP signals might be induced by post-auricular muscle reflexes because of click stimuli.29 Thus, we suggest that AEP monitoring should be limited to unconscious or deeply sedated patients, or lightly sedated patients after careful consideration.
Muscle EMG has been investigated as a measure of anesthetic depth since the mid 1980s.30 The EMG signal measured from the frontal muscle of a patient has a wide noise-like spectrum, and during anesthesia typically dominates at frequencies higher than 30 Hz. The sudden appearance of EMG signal data often indicates that the patient is responding to some external stimulus, such as a painful stimulus. EMG can thus provide a rapid indication of impending arousal. Because of the higher frequency of the EMG data signal, the sampling time can be significantly shorter than that required for the lower frequency EEG signal data. This allows the EMG data to be computed more frequently, so that the overall diagnostic indicator can quickly indicate changes in the state of the patient. This has led to the development of a commercially available device which incorporates the EMG activity as a measure of depth of anesthesia (Entropy, Datex-Ohmeda, Helsinki, Finland). Although EMG might not be regarded as contamination of the signal, but as a parameter of sedation reflecting an external stimulant state of the patient.
One limitation of our study is the fact that patients were simultaneously monitored with BIS and AEP. The electrodes were located close to each other, and the auditory stimuli might have altered the BIS by causing sufficient stimulation to increase the level of consciousness. However, Absalom et al. evaluated the effect of the AEP clicks on levels of consciousness and BIS values during steady-state sedation and anesthesia, and did not show any difference in the BIS readings. They concluded that auditory stimuli were not associated with a change in BIS values.31 Another limitation is the integrity of the auditory system. The integrity of the auditory system is essential for AEP, and the certainty of excluding hearing impairment in sedated ICU patients may be difficult. However, in case of low AEP quality, the AEP Monitor/2 calculates the AAI exclusively from the spontaneous EEG, and with increasing signal quality from the AEP again. Therefore, the earlier A-Line Monitor's "click detection" is no longer integrated into the new AEP Monitor/2.
In conclusion, our study demonstrated that in sedated ICU patients, BIS and AAI markedly decreased after administration of myorelaxant, and the inductions of the BIS and AAI values after neuromuscular blockade were related to the AAI and BIS values of surgical anesthesia. The AEP Monitor/2 and BIS-XP might be used as potential alternatives to subjective scales, especially when the scales do not work well in the setting of neuromuscular blockade or may not be sufficiently sensitive to evaluate very deep sedation.
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Footnotes
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Accepted for publication May 7, 2008.
Supported by Ministry of National Defense grant DOD 95-07-04, and grant TSGH-C95-2-S05 and partly from the Tri-Service General Hospital, grant TSGH-C95-2-S04.
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Abstract
Introduction
