Modified Observer's Assessment Of Alertness/Sedation Research Articles

Do all sedatives promote biological sleep electroencephalogram patterns? A machine learning framework to identify biological sleep promoting sedatives using electroencephalogram.

Sedatives are commonly used to promote sleep in intensive care unit patients. However, it is not clear whether sedation-induced states are similar to the biological sleep. We explored if sedative-induced states resemble biological sleep using multichannel electroencephalogram (EEG) recordings. Multichannel EEG datasets from two different sources were used in this study: (1) sedation dataset consisting of 102 healthy volunteers receiving propofol (N = 36), sevoflurane (N = 36), or dexmedetomidine (N = 30), and (2) publicly available sleep EEG dataset (N = 994). Forty-four quantitative time, frequency and entropy features were extracted from EEG recordings and were used to train the machine learning algorithms on sleep dataset to predict sleep stages in the sedation dataset. The predicted sleep states were then compared with the Modified Observer's Assessment of Alertness/ Sedation (MOAA/S) scores. The performance of the model was poor (AUC = 0.55-0.58) in differentiating sleep stages during propofol and sevoflurane sedation. In the case of dexmedetomidine, the AUC of the model increased in a sedation-dependent manner with NREM stages 2 and 3 highly correlating with deep sedation state reaching an AUC of 0.80. We addressed an important clinical question to identify biological sleep promoting sedatives using EEG signals. We demonstrate that propofol and sevoflurane do not promote EEG patterns resembling natural sleep while dexmedetomidine promotes states resembling NREM stages 2 and 3 sleep, based on current sleep staging standards.

Effective remimazolam loading dose for adequate sedation in regional anesthesia.

Remimazolam is a novel ultrashort-acting sedative considered appropriate for continuous infusion during surgical procedures. Nevertheless, information regarding its loading dose for sedation during surgery is limited. We aimed to determine the 90% effective dose (ED90) of the remimazolam loading dose for sedation in patients undergoing limb surgery under regional anesthesia. We included 50 patients aged 19-80yr undergoing limb surgery under regional anesthesia. After regional anesthesia, remimazolam besylate was administered at the assigned dose. For ten minutes after the initiation of loading, the level of sedation was evaluated using the Modified Observer's Assessment of Alertness/Sedation (MOAA/S) scale. The primary outcome was the ED90 based on whether patients reached a MOAA/S score of ≤ 3 points (loss of response to verbal command) within ten minutes. The secondary outcomes were the ED50 and the estimated effect site and plasma concentration at the time of achieving successful sedation. In total, 49 patients were included in the final analysis, and adequate sedation with the assigned loading dose was successful in 42 patients. The log-logistic function showed that the ED90 and ED50 were 0.617mg·kg-1·hr-1 (95% confidence interval [CI], 0.511 to 0.722; 98% CI, 0.492 to 0.741) and 0.438mg·kg-1·hr-1 (95% CI, 0.335 to 0.541; 98% CI, 0.315 to 0.560), respectively. The ED90 of the remimazolam loading dose to achieve adequate sedation in patients undergoing limb surgery under regional anesthesia was 0.617mg·kg-1·hr-1 (95% CI, 0.511 to 0.722; 98% CI, 0.492 to 0.741). ClinicalTrials.gov (NCT05340335); first posted 22 April 2022.

Target-controlled infusion of remimazolam effect-site concentration for total intravenous anesthesia in patients undergoing minimal invasive surgeries.

Although pharmacokinetic and pharmacodynamic models of remimazolam have been developed, their clinical application remains limited. This study aimed to administer a target-controlled infusion (TCI) of remimazolam at the effect-site concentration (Ce) in patients undergoing general anesthesia and to investigate the relationship of the remimazolam Ce with sedative effects and with recovery from general anesthesia. Fifty patients aged 20-75 years, scheduled for minimally invasive surgery under general anesthesia for less than 2 h, were enrolled. Anesthesia was induced and maintained using Schüttler's model for effect-site TCI of remimazolam. During induction, the remimazolam Ce was increased stepwise, and sedation levels were assessed using the Modified Observer's Assessment of Alertness/Sedation (MOAA/S) scale and bispectral index (BIS). Following attainment of MOAA/S scale 1, continuous infusion of remifentanil was commenced, and rocuronium (0.6 mg/kg) was administered for endotracheal intubation. The target Ce of remimazolam and the remifentanil infusion rate were adjusted to maintain a BIS between 40 and 70 and a heart rate within 20% of the baseline value. Approximately 5 min before surgery completion, the target Ce of remimazolam was reduced by 20-30%, and anesthetic infusion ceased at the end of surgery. Nonlinear mixed-effects modeling was employed to develop pharmacodynamic models for each sedation level as well as emergence from anesthesia. The remimazolam Ces associated with 50% probability (Ce50) of reaching MOAA/S scale ≤4, 3, 2, and 1 were 0.302, 0.397, 0.483, and 0.654 μg/mL, respectively. The Ce50 values for recovery of responsiveness (ROR) and endotracheal extubation were 0.368 and 0.345 μg/mL, respectively. The prediction probabilities of Ce and BIS for detecting changes in sedation level were 0.797 and 0.756, respectively. The sedation scale significantly correlated with remimazolam Ce (r = -0.793, P < 0.0001) and BIS (r = 0.914, P < 0.0001). Age significantly correlated with Ce at MOAA/S1 and ROR. Effect-site TCI of remimazolam was successfully performed in patients undergoing general anesthesia. The remimazolam Ce significantly correlated with sedation depth. The Ce50 for MOAA/S scale ≤1 and ROR were determined to be 0.654 and 0.368 μg/mL, respectively.

Comparative Analysis of the Performance of Electroencephalogram Parameters for Monitoring the Depth of Sedation During Remimazolam Target-Controlled Infusion.

The changes in hypnotic indicators in remimazolam sedation remain unclear. We investigated the correlation of the electroencephalogram (EEG) parameters with the effect-site remimazolam concentration and the depth of sedation in patients receiving a target-controlled infusion of remimazolam. This prospective observational study enrolled 35 patients (32 analyzed) who underwent lower extremity varicose vein surgery or lower extremity orthopedic surgery under spinal anesthesia. We administered remimazolam by target-controlled infusion using the pharmacokinetic model introduced by Schüttler et al. The EEG data were continuously recorded, including the bispectral index (BIS), patient state index (PSI), spectral edge frequency (SEF), and raw EEG signals. The relative beta ratio (RBR), defined as log (spectral power [30-47 Hz]/spectral power [11-20 Hz]), was obtained by analyzing raw EEG. The level of sedation corresponding to each effect-site remimazolam concentration was assessed using the Modified Observer's Assessment of Alertness/Sedation (MOAA/S). The prediction probability (Pk) and Spearman's correlation coefficients (R) were calculated between effect-site remimazolam concentration, MOAA/S, and EEG parameters. BIS and PSI showed significantly higher Pk for effect-site remimazolam concentration (Pk = 0.76 [0.72-0.79], P < .001 for BIS; Pk = 0.76 [0.73-0.79], P < .001 for PSI) compared to RBR (Pk = 0.71 [0.68-0.74], P < .001) and SEF (Pk = 0.58 [0.53-0.63], P = .002). BIS, PSI, and RBR showed significantly higher correlation coefficients for effect-site remimazolam concentration (R = -0.70 [-0.78 to -0.63], P < .001 for BIS; R = -0.72 [-0.79 to -0.66], P < .001 for PSI; R = -0.61 [-0.69 to -0.54], P < .001 for RBR) compared to SEF (R = -0.22 [-0.36 to -0.08], P = .002). BIS and PSI also had significantly higher Pk and correlation coefficients for MOAA/S (Pk = 0.81 [0.79-0.83], P < .001; R = 0.84 [0.81-0.88], P < .001 for BIS) (Pk = 0.80 [0.78-0.83], P < .001; R = 0.82 [0.78-0.87], P < .001 for PSI) compared to RBR (Pk = 0.74 [0.72-0.77], P < .001; R = 0.72 [0.65-0.78], P < .001) and SEF (Pk = 0.55 [0.50-0.59], P = .041; R = 0.13 [-0.01 to 0.27], P = .067). BIS, PSI, and RBR showed an acceptable correlation with the effect-site remimazolam concentration and depth of sedation in this study, suggesting that these EEG-derived parameters are potentially reliable hypnotic indicators during remimazolam sedation. BIS and PSI showed superior performance as hypnotic indicators to RBR and SEF in patients receiving target-controlled infusion of remimazolam.

Comparison of remimazolam-remifentanil and propofol-remifentanil during laparoscopic cholecystectomy.

Remimazolam is a novel benzodiazepine with fast onset and short half-life. We compared the effects of remimazolam and propofol on recovery profiles for general anesthesia in patients undergoing laparoscopic cholecystectomy. We randomly assigned 108 patients to either a remimazolam (n=54) or propofol (n=54) group. Remimazolam and propofol were used for induction and maintanance of anesthesia. Following anesthesia, we recorded the time until an Aldrete score of 9 was achieved. The time to reach a Modified Observer's Assessment of Alertness/Sedation (MOAA/S) score of 2 and the time from the end of anesthesia to eye opening time, recovery time of orientation, time to spontaneous breathing, extubation time, and the time required for analgesics were measured. Heart rate, blood pressure, and bispectral index were assessed before, during, and after pneumoperitoneum. We included 101 patients in the analysis. In the remimazolam group, it took longer to reach an Aldrete score of 9 after the drug infusion ended (P = 0.031). There was no difference in the time to reach MOAA/S 2 between the two groups. The time to eye opening, recovery time of orientation, and time required for analgesics were longer and heart rate was higher in the remimazolam group. Neither blood pressure, nor extubation time differed between groups. Remimazolam and propofol provided safe induction and maintenance of anesthesia in patients undergoing laparoscopic cholecystectomy. The recovery time from anesthesia with remimazolam is longer than that with propofol. Fewer hemodynamic changes were observed with remimazolam, but further studies are needed.

Development of a pharmacokinetic and pharmacodynamic model for intranasal administration of midazolam in older adults: a single-site two-period crossover study

BackgroundIntranasal midazolam can produce procedural sedation in frail older patients with dementia who are unable to tolerate necessary medical or dental procedures during domiciliary medical care. Little is known about the pharmacokinetics and pharmacodynamics of intranasal midazolam in older (>65 yr old) people. The aim of this study was to understand the pharmacokinetic/pharmacodynamic properties of intranasal midazolam in older people with the primary goal of developing a pharmacokinetic/pharmacodynamic model to facilitate safer domiciliary sedation care. MethodsWe recruited 12 volunteers: ASA physical status 1–2, aged 65–80 yr, and received midazolam 5 mg intravenously and 5 mg intranasally on two study days separated by a 6 day washout period. Concentrations of venous midazolam and 1ʹ–OH–midazolam, Modified Observer's Assessment of Alertness/Sedation (MOAA/S) score, bispectral index (BIS), arterial pressure, ECG, and respiratory parameters were measured for 10 h. ResultsTime to peak effect of intranasal midazolam for BIS, MAP, and SpO2 were 31.9 (6.2), 41.0 (7.6), and 23.1 (3.0) min, respectively. Intranasal bioavailability was lower compared with intravenous administration (Fabs 95%; 95% confidence interval: 89–100%). A three-compartment model best described midazolam pharmacokinetics following intranasal administration. A separate effect compartment linked to the dose compartment best described an observed time-varying drug-effect difference between intranasal and intravenous midazolam, suggesting direct nose-to-brain transport. ConclusionsIntranasal bioavailability was high and sedation onset was rapid, with maximum sedative effects after 32 min. We developed a pharmacokinetic/pharmacodynamic model for intranasal midazolam for older persons and an online tool to simulate changes in MOAA/S, BIS, MAP, and SpO2 after single and additional intranasal boluses. Clinical trial registrationEudraCT (2019-004806-90).

Evaluation of Sedation Levels Using SedLine During Intravenous Sedation for Dental Procedures: A Case-Series Study.

The Patient State Index (PSI) is the numerical value of anesthesia depth as measured using a SedLine Sedation Monitor (Masimo Corporation). In this pilot study, we evaluated PSI values captured during intravenous (IV) moderate sedation for dental treatment. During the dental treatment, a dental anesthesiologist maintained the Modified Observer's Assessment of Alertness/Sedation (MOAA/S) score at 3 to 4 by adjusting the administration of midazolam and propofol while PSI values were recorded. The mean (SD) and median (25th percentile, 75th percentile) PSI values during dental treatment under IV moderate sedation were 72.7 (13.6) and 75 (65, 85), respectively.

Clinical effects of remimazolam alone or in combination with dexmedetomidine in patients receiving bronchoscopy and influences on postoperative cognitive function: a randomized-controlled trial.

Remimazolam and dexmedetomidine are commonly used as sedatives. However, the effects and safety of remimazolam alone or in combination with dexmedetomidine have not been investigated. We sought to investigate the clinical effects of remimazolam alone or in combination with dexmedetomidine in bronchoscopy, and their influence on cognitive function. Ninety eligible patients who underwent bronchoscopy under intravenous anesthesia were randomly divided into three groups: propofol control, remimazolam, and remimazolam plus dexmedetomidine. The primary outcome was the incidence of perioperative hypoxemia. Secondary outcomes included induction and maintenance doses of remimazolam, hemodynamic variables, scores for modified Observer's Assessment of Alertness/Sedation (MOAA/S), coughing, limb movement, incidence of adverse events, patient satisfaction, bronchoscopist satisfaction, incidence of post-operative cognitive dysfunction (POCD), time to loss of consciousness (LoC), and time to awake. The incidence of hypoxemia, hypotension, and bronchoscopist satisfaction score were significantly decreased, and time to LoC and time to awake were markedly longer in the remimazolam and remimazolam plus dexmedetomidine groups than in the propofol control group (p < 0.05). The remimazolam group had significantly decreased induction and maintenance doses of remimazolam and a shorter time to LoC than the remimazolam plus dexmedetomidine group (p < 0.05). Scores for coughing, limb movement, MOAA/S, and post-operative patient satisfaction were comparable among the three groups. POCD was not induced in any of the groups. Remimazolam is safe and effective for painless bronchoscopy, with a low incidence of adverse reactions, and exhibits a good synergistic effect with dexmedetomidine. This trial protocol had been registered on Chinese Clinical Trial Registry (ChiCTR2000041435, date: 2020 12 26.

Efficacy and safety of different doses of remimazolam tosylate for colonoscopy: single-center, prospective, randomized, double-blind, parallel trial

Remimazolam tosylate is a new sedative combining the advantages of etomidate with remifentanil. Remimazolam tosylate shows effective in colonoscopy, but the optimal dose is not confirm. In this study, a single-center, prospective, randomized, double-blind, parallel trial were performed to compare the efficacy and safety of different doses of remimazolam tosylate for colonoscopy. Before colonoscopy, 120 recruited patients were randomized with a 1:1:1 ratio into 3 treatment groups: group A, 0.1 mg/kg remimazolam tosylate; group B, 0.15 mg/kg remimazolam tosylate; group C, 0.2 mg/kg remimazolam tosylate. Patients received 1 µg/kg fentanyl by intravenous injection over 30 s followed by the respective induction dose of remimazolam tosylate over 1 min (±5 s). When adequate sedation was achieved, colonoscopy was performed. Sedation was maintained at Modified Observer's Assessment of Alertness/Sedation (MOAA/S) ≤4 during the procedure. The additional administration of remimazolam tosylate (0.05 mg/kg per time) was permitted when necessary. Forty-one patients, 39 patients and 40 patients were respectively analyzed in group A, group B and group C. The procedural success rate was 80.49%, 87.18% and 95.00% in group A, group B and group C, respectively. During the induction period, patients in group A required additional doses of remimazolam tosylate more frequently than in group B and group C, but less during the maintenance period (all P<0.05). There was no significant difference in the induction time or time to recovery among the three groups. Incidence of adverse events (such as hypotension, hyoxemia and bucking) was similar among the three groups. The initial loading doses of 0.1, 0.15, and 0.2 mg/kg remimazolam tosylate were all efficacy and safety for patients undergoing colonoscopy, and fewer times of the drug was re-administered. Chinese Clinical Trial Registry ChiCTR2000041331.

Comparison of the performance of phase lag entropy and bispectral index for monitoring the depth of sedation under dexmedetomidine sedation: A prospective, observational, and non-inferiority trial

Study objectiveAlthough the performance of phase lag entropy (PLE), a new depth-of-sedation monitor based on the diversity of temporal patterns in the phase relationships in electroencephalogram (EEG) data, during propofol sedation has been proven through several studies, since different sedatives have different effects on EEG, we aimed to evaluate the performance of the PLE in comparison with the bispectral index (BIS) during dexmedetomidine sedation. DesignA prospective, observational, and non-inferiority trial. SettingTertiary university hospital operating room. PatientsForty-two patients aged 20–80 years who were scheduled to undergo elective surgery under spinal anesthesia and had American Society of Anesthesiologists (ASA) physical status I to III were enrolled in this study. InterventionsDexmedetomidine was administered with a loading dose of 0.5–1 μg/kg for 10 min, followed by a maintenance dose of 0.3–0.6 μg/kg/h. MeasurementsThe depth of sedation was assessed using the modified observer's assessment of alertness/sedation (MOAA/S) scale; the data for PLE and BIS were collected; and vital signs, including blood pressure, heart rate, EKG, and pulse oximetry, were evaluated. Main results215,082 data points for the MOAA/S score and PLE and BIS values were analyzed. The baseline variabilities of PLE and BIS were 4.53% and 7.02%, respectively. The Spearman correlation coefficients of the MOAA/S score with PLE and BIS were 0.599 and 0.566, respectively. The prediction probabilities of the MOAA/S score with PLE and BIS were 0.647 and 0.636, respectively. When the MOAA/S score was 3 points, the mean (SD) values of PLE and BIS were 68.35 (15.68) and 75.85 (9.81), respectively, However, the mean (SD) values of PLE and BIS for an MOAA/S score of 1 point were 56.08 (12.49) and 68.29 (12.65), respectively. ConclusionsPLE shows potential as a hypnotic depth indicator during dexmedetomidine sedation, and its performance was not inferior to that of BIS.

P12‐5: Correlation between bispectral index (BIS) and modified observer's assessment of alertness/sedation (MOAA/S) score in flexible bronchoscopy

P12‐5: Correlation between bispectral index (BIS) and modified observer's assessment of alertness/sedation (MOAA/S) score in flexible bronchoscopy

Anesthetic strategy for obese patients during gastroscopy: deep sedation or conscious sedation? A prospective randomized controlled trial

This paper aims to compare the incidence of SpO2 values < 95% and < 90% of the obese patients between conscious sedation and deep sedation and whether conscious sedation was superior to the deep sedation for obese patients during diagnostic gastroscopy. Obese patients undergoing diagnostic gastroscopy were randomly assigned to two different intervention groups: group CS (conscious sedation) or group DS (deep sedation). Group CS patients were managed by conscious sedation [Modified Observer Assessment of Alertness/Sedation (MOAA/S) at 4-5] protocol, and group DS patients were managed by deep sedation (MOAA/S at ≤ 2) protocol. Propofol and sufentanil (0.1 and 0.05mg/kg) were, respectively, infused for sedation and analgesia in CS and DS protocols. The primary endpoints were to compare the incidence of SpO2 values < 95% and < 90% of the patients between the two groups. The incidence of successful sedation, satisfaction scores of patients and endoscopist were assessed as secondary endpoints. 115 obese patients (59 in group CS and 56 in group DS) were enrolled in this study. The incidences of SpO2 < 95% and < 90% in group CS (42.4% and 6.8%) were significantly lower than those in group DS (69.6% and 19.6%, with P = 0.003 and 0.041, respectively). The incidence of successful sedation was similar between groups (86.4% vs 89.3%, P = 0.641). Patient satisfaction scores and endoscopist satisfaction scores were both similar between groups (P = 0.548 and 0.171). Conscious sedation with propofol and sufentanil (0.1mg/kg) reduced the incidence of hypoxic events without affecting gastroscopy procedure and satisfaction compared with the deep sedation for obese patients during diagnostic gastroscopy. ChiCTR-1900024894; registration date, July 31, 2019. http://www.chictr.org.cn .

Comparative evaluation of propofol and combination of propofol-dexmedetomidine in adjunct with topical airway anesthesia for rigid bronchoscopy: A randomized double-blinded prospective study.

Context:Rigid bronchoscopy (RB) procedures require continuous vigilance and monitoring. Such procedures warrant proper ventilation strategy and titration of potent short-acting anesthetics.Aims:To compare propofol with the propofol-dexmedetomidine in conjunction with topical airway anesthesia in two groups during spontaneous assisted ventilation on peri-procedural hemodynamic stability.Settings and Design:This prospective, randomized, double-blinded study was done on 40 patients who were randomized in two groups, 20 patients in each group; PS (Propofol+ Normal saline) and PD (Propofol+ Dexmedetomidine) group. All patients in both groups were induced with 1% IV propofol (1–3 mg/kg), IV midazolam (0.05 mg/kg), and IV fentanyl (2 μ/kg). PS group received propofol infusion for maintenance along with saline infusion 10 min before induction, whereas PD group also received propofol infusion for maintenance along with Injection dexmedetomidine infusion 10 min before induction. Outcome measured were heart rate (HR), mean blood pressure (MBP), oxygen saturation (SpO2), and post-procedure awakening using Modified Observer's Assessment of Alertness/Sedation (MOAAS) scale and complications.Results:In both the groups, MBP decreased significantly from baseline, however, when MBP were compared at the same time points between the groups there were no significant differences. In PD group, HR remained significantly lower when compared with baseline and at 6, 12, 18, and 24 min time points when compared with PS group. Number of patients who developed hypotension requiring vasoactive drugs, their mean dose and duration of hypotension were more in PD group, and they awoke with significant delay.Conclusions:Propofol is better than combination of propofol and dexmedetomidine when given in adjunct with topical airway anesthesia for RB in view of early awakening, lesser duration of intra-procedural hypotension, and lesser requirement of vasoactive agents.

Propofol versus midazolam for sedation during radiofrequency ablation in patients with hepatocellular carcinoma.

Background and AimStandardization of the sedation protocol during radiofrequency ablation (RFA) in patients with hepatocellular carcinoma (HCC) is needed. This randomized, single‐blind, investigator‐initiated trial compared clinical outcomes during and after RFA using propofol and midazolam, respectively, in patients with HCC.MethodsFew‐ and small‐nodule HCC patients (≤3 nodules and ≤3 cm) were randomly assigned to either propofol or midazolam. Patient satisfaction was assessed using a 100‐mm visual analog scale (VAS) (1 mm = not at all satisfied, 100 mm = completely satisfied). Sedation recovery rates 1, 2, 3, and 4 h after RFA were evaluated based on Modified Observer's Assessment of Alertness/Sedation (MOAA/S) scores; full recovery was defined as a MOAA/S score of 5.ResultsBetween July 2013 and September 2017, 143 patients with HCC were enrolled, and 135 patients were randomly assigned to the treatment group. Compared with midazolam, propofol exhibited similar median procedural satisfaction (propofol: 73.1 mm, midazolam: 76.9 mm, P = 0.574). Recovery rates 1 and 2 h after RFA were higher in the propofol group than in the midazolam group. Meanwhile, recovery rates observed 3 and 4 h after RFA were similar in the two groups. The safety profiles during and after RFA were almost identical in the two groups.ConclusionPatient satisfaction was almost identical in patients receiving propofol and midazolam sedation during RFA. Propofol sedation resulted in reduced recovery time compared with midazolam sedation in patients with HCC. The safety profiles of both propofol and midazolam sedation during and after RFA were acceptable.

Target‐controlled infusion of dexmedetomidine effect‐site concentration for sedation in patients undergoing spinal anaesthesia

Dexmedetomidine has been a preferred sedative for patients undergoing regional anaesthesia and is mostly administered via conventional zero-order infusion. Recently, a pharmacokinetic-pharmacodynamic (PKPD) model of dexmedetomidine has been published, but no external validation has been reported in clinical trials. We aimed to administer target-controlled infusion (TCI) of dexmedetomidine at the effect-site concentration (Ce) to patients undergoing spinal anaesthesia and investigate the relationship between dexmedetomidine Ce and the sedative effects. Forty-five patients scheduled for orthopaedic surgery received spinal anaesthesia with 0.5% bupivacaine. After confirmation of sensory block level, we initiated effect-site TCI of dexmedetomidine using Colin's model and assessed sedation levels using the Modified Observer's Assessment of Alertness/Sedation (MOAA/S) scale and bispectral index (BIS) with each stepwise increase in the dexmedetomidine Ce. We used a non-linear mixed-effects model to determine the PD relationships between the dexmedetomidine Ce and sedation level. The dexmedetomidine Ce associated with 50% probability (Ce50 ) of the MOAA/S scale ≤4, 3 and 2 was 0.57, 0.89 and 1.19ng/mL, respectively. Mean dexmedetomidine Ce when BIS decreased ≤70 was 0.99±0.15ng/mL. As dexmedetomidine Ce increased, the MOAA/S scale decreased significantly (correlation coefficient [r]=-.832, P<.0001). BIS decreased significantly with increasing dexmedetomidine Ce (r=-.811, P<.0001) and decreasing MOAA/S scale (r=.838, P<.0001). The most common side effects were hypertension (26.67%) and bradycardia (20%). We applied effect-site TCI of dexmedetomidine in patients undergoing spinal anaesthesia for the first time. Dexmedetomidine Ce correlated significantly with MOAA/S scale and BIS, and was 0.89 and 1.19ng/mL for moderate and deep sedation, respectively.

Novel drug-independent sedation level estimation based on machine learning of quantitative frontal electroencephalogram features in healthy volunteers

BackgroundSedation indicators based on a single quantitative EEG (QEEG) feature have been criticised for their limited performance. We hypothesised that integration of multiple QEEG features into a single sedation-level estimator using a machine learning algorithm could reliably predict levels of sedation, independent of the sedative drug used. MethodsIn total, 102 subjects receiving propofol (N=36; 16 male/20 female), sevoflurane (N=36; 16 male/20 female), or dexmedetomidine (N=30; 15 male/15 female) were included in this study of healthy volunteers. Sedation level was assessed using the Modified Observer's Assessment of Alertness/Sedation (MOAA/S) score. We used 44 QEEG features estimated from the EEG data in a logistic regression algorithm, and an elastic-net regularisation method was used for feature selection. The area under the receiver operator characteristic curve (AUC) was used to assess the performance of the logistic regression model. ResultsThe performances obtained when the system was trained and tested as drug-dependent mode to distinguish between awake and sedated states (mean AUC [standard deviation]) were propofol=0.97 (0.03), sevoflurane=0.74 (0.25), and dexmedetomidine=0.77 (0.10). The drug-independent system resulted in mean AUC=0.83 (0.17) to discriminate between the awake and sedated states. ConclusionsThe incorporation of large numbers of QEEG features and machine learning algorithms is feasible for next-generation monitors of sedation level. Different QEEG features were selected for propofol, sevoflurane, and dexmedetomidine groups, but the sedation-level estimator maintained a high performance for predicting MOAA/S independent of the drug used. Clinical trial registrationNCT 02043938; NCT 03143972.

Corrigendum: Population Pharmacokinetic/Pharmacodynamic Model-Guided Dosing Optimization of a Novel Sedative HR7056 in Chinese Healthy Subjects.

[This corrects the article DOI: 10.3389/fphar.2018.01316.].

Population Pharmacokinetic/Pharmacodynamic Model-Guided Dosing Optimization of a Novel Sedative HR7056 in Chinese Healthy Subjects.

HR7056 is a new benzodiazepine, showing more faster acting onset and recovery than currently available short-acting sedatives. To avoid inadequate anesthesia and predict return of cognition, allowing for immediate neurological evaluation, HR7056 pharmacokinetics and pharmacodynamics were characterized in Chinese healthy subjects. We report on modeling of the data and simulations of dosage regimens for future study. Up to 63 subjects were evaluated, using Bispectral Index (BIS) and Modified Observer's Assessment of Alertness/Sedation (MOAA/S) as pharmacodynamics endpoints. A three-compartment model best described HR7056 pharmacokinetics. Total clearance was 1.49 L min−1, central volume was 2.1 L, inter-compartmental clearances were 0.96 and 0.27 L min−1, respectively. The population mean pharmacodynamic parameters were as follows: BIS, E0: 95.3; IC50: 503 ng mL−1; γ: 1.5; ke0: 0.0855 min−1; Imax: 47.9 and MOAA/S, IC50: 436 ng mL−1; γ: 1.5; ke0: 0.05 min−1; Imax: 27.9. The model simulation will enable maintenance doses to be given more accurately for future study.Clinical Trial Registration: identifier: NCT01970072

Safety and clinical effect of i.v. infusion of cyclopropyl-methoxycarbonyl etomidate (ABP-700), a soft analogue of etomidate, in healthy subjects

BackgroundCyclopropyl-methoxycarbonyl metomidate, or ABP-700, is a second generation analogue of etomidate, developed to retain etomidate's beneficial haemodynamic and respiratory profile but diminishing its suppression of the adrenocortical axis. The objective of this study was to characterise the safety and efficacy of 30-min continuous infusions of ABP-700, and to assess its effect on haemodynamics and the adrenocortical response in healthy human volunteers. MethodsFive cohorts involving 40 subjects received increasing infusion doses of ABP-700, propofol 60 μg kg−1 min−1 or placebo. Safety was evaluated through adverse event (AE) monitoring, safety laboratory tests, and arterial blood gasses. Haemodynamic and respiratory stability were assessed by continuous monitoring. Adrenocortical function was analysed by adrenocorticotropic hormone (ACTH) stimulation tests. Clinical effect was measured using the modified observer's assessment of alertness/sedation (MOAA/S) and continuous bispectral index monitoring. ResultsNo serious AEs were reported. Haemodynamic and respiratory effects included mild dose-dependent tachycardia, slightly elevated blood pressure, and no centrally mediated apnoea. Upon stimulation with ACTH, no adrenocortical depression was observed in any subject. Involuntary muscle movements (IMM) were reported, which were more extensive with higher dosing regimens. Higher dosages of ABP-700 were associated with deeper sedation and increased likelihood of sedation. Time to onset of clinical effect was variable throughout the cohorts and recovery was swift. ConclusionsInfusions of ABP-700 showed a dose-dependent hypnotic effect, and did not cause severe hypotension, severe respiratory depression, or adrenocortical suppression. The presentation and nature of IMM is a matter of concern. Clinical trial registrationNTR4735.

Optimal effective-site concentration of remifentanil for sedation during plate removal of maxilla.

BackgroundRemoval of the plate following Le Fort I osteotomy and BSSO (bilateral sagittal split osteotomy) is a common procedure. However, patients who undergo plate removal experience intense pain and discomfort. This study investigated the half-maximal effective concentration (Ce50) of remifentanil in the prevention of plate removal pain under sedation using dexmedetomidine.MethodsThe study evaluated 18 patients, between 18 and 35 years of age, scheduled for elective surgery. Remifentanil infusion was initiated after sedation using dexmedetomidine, and started at a dose of 1.5 ng/mL on the first patient via target-controlled infusion (TCI). Patients received a loading dose of 1.0 µg/kg dexmedetomidine over 10 min, followed by a maintenance dose of 0.7 µg/kg/h. When the surgeon removed the plate, the patient Modified Observer's Assessment of Alertness/Sedation (MOAA/S) score was observed.ResultsThe Ce of remifentanil ranged from 0.9 to 2.1 ng/mL for the patients evaluated. The estimated effect-site concentrations of remifentanil associated with a 50% and 95% probability of reaching MOAA/S score of 3 were 1.28 and 2.51 ng/mL, respectively.ConclusionsPlate removal of maxilla can be successfully performed without any pain or adverse effects by using the optimal remifentanil effect-site concentration (Ce50, 1.28 ng/mL; Ce95, 2.51 ng/mL) combined with sedation using dexmedetomidine.