Spectral Entropy As an Objective Measure of Sedation State in Midazolam-Premedicated Patients

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ORIGINAL ARTICLE Page | 131 Spectral entropy as an objective measure of sedation state in midazolam-premedicated patients

Hany A. Mowafi ABSTRACT Department of Anaesthesia, Faculty of Medicine, King Faisal Context: Objective assessment of sedation depth is a valuable target. Spectral entropy University, Saudi Arabia is an anesthetic depth monitor based on the analysis of the electroencephalogram signal. Aims: To evaluate the performance of spectral entropy as an objective measure of sedation state in midazolam-premedicated patients and to correlate it with a clinically assessed sedation score. Settings and Design: This prospective double-blind placebo- controlled study was performed in King Fahd Hospital of the university. Methods: Eighty adult ASA I–II patients were randomly assigned into 4 groups. Patients were premedicated using 0.02, 0.04, or 0.06 mg/kg midazolam or saline intramuscularly. The effect of these doses on the Observer’s Assessment of Alertness and Sedation (OAA/S) scale, hemodynamic variables, response entropy (RE), and state entropy (SE), was evaluated at 10, 20, and 30 min after premedication. Statistical analysis: Spearman Rank-order correlation analysis to examine the relation between OAA/S and entropy. The ability of spectral entropy to predict the depth of sedation was evaluated using Smith prediction probability. Results: Midazolam doses ≥0.04 mg/kg produced significant decreases in RE, SE, and OAA/S scores. There was a strong correlation between midazolam dose and OAA/S scale, RE, and SE since Spearman Rank R values were 0.792, 0.822, and 0.745, respectively (P<0.001). In addition, RE and SE were strong predictors of OAA/S level during midazolam sedation with no significant difference Address for correspondence: in prediction between the 2 entropy components. Conclusions: Spectral entropy is a Dr. Hany A. Mowafi, reliable measure for the sedative premedication. It may be used to objectively assess Department of Anaesthesiology, the adequacy of midazolam premedication and to determine the dose requirement. King Fahd University Hospital, PO Box 40081, Al-Khobar, 31952, Key words: Monitoring, depth of anaesthesia, observer’s assessment of alertness Saudi Arabia. and sedation, premedication, midazolam, sedation E-mail: [email protected]

of the subject to elicit a response.[3,4] Objective assessment INTRODUCTION of the efficacy of anesthetic premedication is still difficult. Sedative premedication is required to avoid psychologic Several systems based on the electroencephalogram (EEG) discomfort and allay anxiety of patients. The efficacy of have been developed as depth of anesthesia monitors.[5,6] anesthetic premedication has been evaluated using several The spectral entropy has been developed to objectively sedative scores, including the Ramsay and Observer’s [7,8] [1,2] assess the depth of anesthesia during clinical practice. Assessment of Alertness/Sedation (OAA/S) scales. The monitor derives 2 indices: the state entropy (SE), These estimation tools might be affected by the evaluators’ which reflects the cortical activity of the subject, and variability or subjects’ presumption causing a placebo the response entropy (RE), which also includes frontal [3,4] effect. An additional defect during clinical application of electromyographic (EMG) activity.[7,8] Entropy parameters such methods is the repeated verbal or tactile stimulation may determine the effect of anesthetics on the subject’s central nervous system.[9] However, the validity and utility Access this article online of spectral entropy as an objective tool to examine the Quick Response Code: Website: efficacy of sedative premedication have not been evaluated. www.saudija.org The aim of this study was to assess whether entropy can be used to measure the sedation status in midazolam- DOI: premedicated adult patients by correlating entropy values 10.4103/1658-354X.97025 to the dose of midazolam used and with a clinical sedation scale.

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Mowafi: Entropy and sedative premedication Page | 132 for normal distribution using the Kolmogorov–Smirnov METHODS test, the demographic data were analyzed using one-way Following the local research ethics committee approval and analysis of variance or Chi-square analysis as appropriate. an informed written patient consent, 80 adult subjects of Entropy values and OAA/S scores were compared at ASA I or II, scheduled for elective orthopedic or general different doses of midazolam using Kruskal–Wallis analysis surgical procedures were included in the study. Patients were of variance on ranks with post hoc analysis. Spearman excluded if they were older than 60 years, had a body weight Rank-order correlation analysis was performed to evaluate more than 150% of their ideal body weight using Broca’s the relationship between the doses of midazolam and index, neurologic disease, endocrine disorders, psychiatric the different measures of sedation. It was also used to illness, hearing defect, or a history of drug abuse and those examine the relationship between OAA/S and RE and on drugs with sedative or central nervous system effects. SE components of entropy. To evaluate the significance between the obtained Spearman rank correlations, the Patients were randomly allocated using an online research [10] randomizer (http://www.randomizer.org) into 4 groups (20 method described by Steiger was used. A P value<0.05 patients each). Forty-five minutes before surgery, patients was considered significant. were admitted to an isolated quiet room in the operating The ability of spectral entropy to predict the depth of theater suite. Ambient temperature was kept at 21–24°C. sedation using the OAA/S was evaluated using P . P is Subjects were monitored with an electrocardiograph K OAA/S K the probability that an indicator correctly predicts the depth (ECG), noninvasive blood pressure, peripheral pulse of sedation. An indicator that predicts perfectly the depth oximetry (SpO ), and spectral entropy (Datex-Ohmeda 2 of sedation has a P value of 1.0, whereas an indicator S/5 Anaesthesia Monitor, Helsinki, Finland). An entropy K that performs no better than chance has a P value of sensor was applied to the patients’ forehead according to K 0.5. The mathematical basis of P was described by Smith the manufacturer’s specifications and passed the initial K et al.[11] To compute the P , the RE and SE entropy scores impedance check. The spectral entropy plug-in module K calculated state entropy (SE) and response entropy (RE) were analyzed as the predicting variables and the OAA/S scale was the value of the variable to be predicted. The P variables. An anesthesiologist used the OAA/S [Table 1] to K measure the sedation depth clinically.[2] After resting for a computed in this case is the estimate of the probability minimum of 5 min and before injection of premedication, that the RE or SE will correctly predict the OAA/S score. baseline heart rate, mean arterial pressure, RE, SE, and The jack-knife method was used to compute the standard error of the P estimate. P calculations were performed OAA/S were obtained for each patient. Patients were K K then premedicated with either saline (control group) or with Excel software using a custom spreadsheet macro, PKMACRO, and were compared using PKDMACRO. midazolam 0.02, 0.04, and 0.06 mg/kg intramuscularly in [11] the deltoid muscle. After premedication, at 10, 20, and 30 Smith and colleagues developed both the macros. min, OAA/S scores, the hemodynamic and entropy data were recorded. An observer who was blinded to the patient RESULTS allocation recorded all data. To minimize potential observer bias, another investigator, blinded to entropy values and Our study included 34 females and 46 males, with age treatment plan, performed all OAA/S assessments. The RE ranging between 21 and 50 years, a mean height of 167 ± and SE at each OAA/S score were calculated by averaging 14 cm, and weight of 72 ± 11 kg. There were no significant 3 values immediately before OAA/S score assessment. differences in all demographic characteristics between the 4 groups. Data analysis Data were analyzed using Statistica software version 7.0 Figure 1 shows entropy and OAA/S values in the control for windows (Statsoft, Inc. Tulsa, USA). After testing group and at different midazolam doses. There were no

Table 1: Observer’s assessment of alertness/sedation Score Sedation level Responsiveness Speech Facial expression Eyes 5 Alert Responds readily to name Normal Normal Clear, no ptosis 4 Light Lethargic response to name Mild slowing Mild relaxation Glazed or mild ptosis 3 Moderate Response only after name is Slurring or prominent Marked Glazed and marked called loudly slowing relaxation ptosis 2 Deep Responds only after mild Few recognizable words — — prodding or shaking 1 Deep sleep, unconscious Does not respond to mild — — — prodding or shaking

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Mowafi: Entropy and sedative premedication Page | 133 significant differences between the control and 0.02 mg/ decrease intraoperative awareness, and provide an kg groups. Increasing the dose of midazolam decreases appropriate sedation level. The effect of midazolam on the the RE, SE, and OAA/S values significantly. However, consciousness level differs between patients.[12] An “ideal” there was no significant difference between 0.04 and 0.06 sedation scoring tool does not exist. Several subjective mg/kg doses. There were strong significant correlations scores have been developed as tools to assess sedation.[13] between midazolam doses and RE, SE, and OAA/S, where The aim is to avoid oversedation with its many potential the Spearman Rank R values were 0.822, 0.745, and 0.792, deleterious side effects, such as delayed recovery, loss of respectively (P<0.001). airway, respiratory arrest, and aspiration. They describe the response to graduated reproducible stimuli. To facilitate the There was a strong significant correlation between entropy clinical evaluation of midazolam-induced sedation, Chernik and OAA/S values. Spearman Rank R values for RE and SE et al developed the Observers’ Assessment of Alertness/ were 0.717 and 0.637 (P<0.0001), respectively. Entropy was Sedation (OAA/S) scale.[2] This method of assessment effective in predicting the OAA/S level of sedation during necessitates that the patient will be stimulated at frequent midazolam premedication. The prediction probability intervals, a practice that may disturb patients. A further limitation of the OAA/S scale is that it depends on the PK OAA/S (SEM) values for RE and SE were 0.841 (0.015) and 0.808 (0.021), respectively, with no significant difference patients’ cooperation and is subject to testing fatigue.[3] between the 2 entropy components in predicting the Therefore, objective assessment of sedation depth using OAA/S level. a consistent, noninvasive sedation monitor is an appealing goal. Many approaches have been evaluated, but most No significant correlations were found between the suffer from poor validation with scoring systems or have hemodynamic variables and midazolam dose or the large intra- and inter-patient variability.[14] We select the sedation level as measured by the entropy or OAA/S. OAAS scale, as a reference monitor of sedation, because it provides a good correlation with the clinical evaluation of sedation state and has been previously confirmed in DISCUSSION several studies.[15,16]

The main finding in this study was that spectral entropy Our assumption was that this scale, which was previously could be used as a reliable objective measure of the sedative correlated with the observed clinical effects of sedation, effects of midazolam premedication. RE and SE predicted would be linearly related to the different midazolam doses efficiently the level of sedation as measured by OAA/S and and to spectral entropy that can be used as an objective were strongly correlated with the doses of midazolam used. measure of sedation.

Midazolam premedication can relieve patients’ anxiety, Spectral entropy is a commercially available monitor based on the analysis of the EEG signal.[7] Entropy, as a 100 5 physical concept, is a measure of irregularity, complexity, or amount of disorder.[7] With increasing the depth of 80 4 anesthesia, the EEG changes to more regular patterns, * # * # decreasing entropy.[9] State entropy (SE) is computed * # 60 3 over the frequency range from 0.8 to 32 Hz and primarily y S reflects the state of the cortical activity of the subject. The

* # A/ tr op

OA response entropy (RE) is computed over a frequency range En 40 2 from 0.8 to 47 Hz, and includes both the EEG-dominant RE and EMG-dominant part of the spectrum. Entropy has a SE 20 1 range of 0–100 for RE and a range of 0–90 for SE. The OAA/S * # * # closer to 0, the deeper the level of sedation/anesthesia is.[7]

0 0 0 mg/kg0.02 mg/kg0.04 mg/kg0.06 mg/kg Entropy parameters were developed for use during Midazolam dose anesthesia, when the main goal is avoidance of awareness. Figure 1: Box plot graphic of response entropy (RE) and state entropy During anesthesia, entropy variables correlate well with (SE) represented on the left Y axis, and Observer’s Assessment of surgical anesthetic level and hypnosis.[17,18] The system Alertness/Sedation (OAA/S) Scale scores represented on the right was not developed to monitor patients premedicated Y axis at different midazolam doses in mg/kg. Data points represent with sedative drugs. However, entropy was tested as a medians, boxes are interquartile ranges, and whiskers are nonoutlier ranges. *Significant difference in comparison with 0 mg/kg; #significant monitor of sedation status in the operating room and difference in comparison with 0.02 mg/kg intensive care unit (ICU) settings. Entropy monitoring

Mowafi: Entropy and sedative premedication Page | 134 showed high performance in assessing the level of to evaluate the depth of sedation in the ward where sedative dexmedetomidine-induced sedation in healthy subjects.[19] premedication is usually given. Second, to eliminate the Acupuncture stimulation at sedative points decreased SE effect of interindividual pharmacokinetic differences with and RE values significantly.[20] RE and SE discriminated midazolam premedication correlation of RE, SE, and well between sound responses at the different sedation OAA/S with the serum level of midazolam would have levels using propofol and remifentanil.[21] Entropy, BIS, been a logic alternative. Third, our results apply only to and Ramsay score values were significantly correlated midazolam in the dose range used. Further studies may be in sedated postoperative ICU patients.[22] The spectral required to evaluate spectral entropy with other sedatives entropy decreased also with deepening of sedation similar used as premedication and in different doses. to Ramsay score in ICU patients.[23] In addition, a strong correlation between these 2 indices has been found similarly In conclusion, our study suggests that spectral entropy may to the sedation scores described in the operating room.[24,25] have an adequate validity as a measure of sedation state It was, also, found reliable during propofol and fentanyl during midazolam premedication. sedation in monitored anesthesia care[26] and to monitor [27] conscious sedation in endstage cancer patients at home. REFERENCES Moreover, Anderson and Jakobsson demonstrated that increasing levels of sedation provided by propofol during 1. McCormick AS, Thomas VL, Berry D, Thomas PW. 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