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Background: Remimazolam (CNS 7056) is a new ultra-short acting benzodiazepine for IV sedation. This study aimed to investigate the electroencephalogram (EEG) pharmacodynamics of remimazolam infusion., Methods: Twenty healthy male volunteers received remimazolam as continuous IV infusion of 5 mg/min for 5 min, 3 mg/min for the next 15 min, and 1 mg/min for further 15 min. Continuous EEG monitoring was performed by a neurophysiologic system with electrodes placed at F3, F4, C3, C4, O1, O2, Cz, and Fp1 (10/20 system) and using the Narcotrend Index. Sedation was assessed clinically by using the Modified Observer's Assessment of Alertness and Sedation scale. Pharmacodynamic models were developed for selected EEG variables and Narcotrend Index., Results: EEG changes during remimazolam infusion were characterized by an initial increase in beta frequency band and a late increase in delta frequency band. The EEG beta ratio showed a prediction probability of Modified Observer's Assessment of Alertness and Sedation score of 0.79, and could be modeled successfully using a standard sigmoid Emax model. Narcotrend Index showed a prediction probability of Modified Observer's Assessment of Alertness and Sedation score of 0.74. The time course of Narcotrend Index was described by an extended sigmoid Emax model with two sigmoid terms and different plasma-effect equilibration times., Conclusions: Beta ratio was identified as a suitable EEG variable for monitoring remimazolam sedation. Narcotrend Index appeared less suitable than the beta ratio for monitoring the sedative effect if remimazolam is administered alone.

Background: Remimazolam (CNS 7056) is a new ultra-short-acting benzodiazepine for intravenous sedation and anesthesia. Its pharmacokinetics and pharmacodynamics have been reported for bolus administration. This study aimed to investigate the pharmacokinetics and pharmacodynamics of remimazolam after continuous infusion., Methods: Twenty healthy male volunteers (20 to 38 yr, 64 to 99 kg) received remimazolam as continuous intravenous infusion of 5 mg/min for 5 min, 3 mg/min for the next 15 min, and 1 mg/min for further 15 min. Pharmacokinetics of remimazolam and its metabolite were determined from arterial plasma concentrations. Sedation was assessed using the Modified Observer's Assessment of Alertness and Sedation scale. Pharmacokinetic-pharmacodynamic modeling was performed by population analysis. Hemodynamics and the electrocardiogram were also investigated., Results: Pharmacokinetics was best described by a three-compartment model for remimazolam and a two-compartment model with transit compartment for the metabolite. Remimazolam showed a high clearance (1.15 ± 0.12 l/min, mean ± SD), a small steady-state volume of distribution (35.4 ± 4.2 l) and a short terminal half-life (70 ± 10 min). The simulated context-sensitive halftime after an infusion of 4 h was 6.8 ± 2.4 min. Loss of consciousness was observed 5 ± 1 min after start, and full alertness was regained 19 ± 7 min after stop of infusion. Pharmacodynamics of Modified Observer's Assessment of Alertness and Sedation score was best described by a sigmoid probability model with effect site compartment. The half-maximum effect site concentration for a Modified Observer's Assessment of Alertness and Sedation score less than or equal to 1 was 695 ± 239 ng/ml. The equilibration half-time between central and effect compartment was 2.7 ± 0.6 min. Mean arterial blood pressure decreased by 24 ± 6%, and heart rate increased by 28 ± 15%. Spontaneous breathing was maintained throughout the study. There was no significant prolongation of the QT interval of the electrocardiogram observed., Conclusions: Remimazolam was characterized by a pharmacokinetic-pharmacodynamic profile with fast onset, fast recovery, and moderate hemodynamic side effects.

Background and Objective: Dexmedetomidine is a highly selective alpha2-adrenoceptor agonist with sedative and analgesic properties which is also used in pediatric anesthesia. Although the pharmacokinetics of dexmedetomidine have been studied in pediatric patients, there are no data for Chinese children available. As alterations in pharmacokinetics due to ethnicity cannot be ruled out, it was the aim of this study to characterize the pharmacokinetics of dexmedetomidine in Chinese pediatric patients., Methods: Thirty-nine children aged 1-9 years undergoing surgery were enrolled in the study. Dexmedetomidine was administered as short intravenous infusion of 1-2 µg/kg in 10 min. Venous blood samples were drawn until 480 min after stopping of infusion. Dexmedetomidine plasma concentrations were measured with high-performance liquid chromatography and mass spectrometry. Pharmacokinetic modeling was performed by population analysis using linear compartment models., Results: Data of 36 patients (age 1-9 years, weight 10-27 kg) were analyzed. The pharmacokinetics of dexmedetomidine were best described by a two-compartment model with an allometric power model and estimates standardized to 70 kg body weight. The population estimates (95 % CI) per 70 kg bodyweight were: clearance 36.2 (33.3-41.1) l/h, central volume of distribution 84.3 (70.3-91.4) l, intercompartmental clearance 82.8 (63.6-136.6) l/h, peripheral volume of distribution 114 (95-149) l, and terminal half-life 4.4 (3.6-5.3) h. Age did not show any influence on weight-adjusted parameters., Conclusions: Chinese children showed a similar clearance, but larger volumes of distribution and longer terminal half-life when compared to studies in Caucasians., Trial Registration: ChiCTR-OPC-14005659.

For the quantification of propofol total and unbound drug concentrations a sensitive and specific liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated. To separate unbound propofol an ultrafiltration step before sample preparation was performed. Both the ultrafiltrate and plasma samples were extracted with solid-phase extraction and substituted with deuterated propofol as an internal standard. Separation was performed by gradient elution using UPLC-like system and analyzed by MS/MS consisting of an electrospray ionization source. To detect low and high concentration levels of propofol two calibration curves were identified and showed linearity within the range of 1-50ng/ml and 50-20000ng/ml. The lower limit of quantification was 1ng/ml. Intra- and interassay precision and accuracy did not exceed ±15%. The method was applied to a clinical study during intensive care treatment of patients after coronary artery bypass grafting., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Objectives: Postictal agitation (PIA) after electroconvulsive therapy (ECT) is a major medical problem. This observational study investigated the incidence and severity of PIA and evaluated propofol as a treatment option in a patient population., Methods: The study included 14 patients that underwent a series of ECTs performed either with or without an approximately 0.5-mg/kg propofol bolus after the end of an electroencephalography (EEG) seizure. Among other values, we documented PIA incidence and severity as rated by a simple score; orientation to person, time, place, and situation; transfer times to the postanesthesia care (PACU) and inpatient unit; nurses' and patients' rating of recovery period, and others and tested for significant differences., Results: Five minutes after the end of ECT, the patients showed moderate to severe PIA in 8 of 37 ECT sessions. Incidence was significantly lower when patients had received propofol (3/37). Transfer time to the PACU was longer, but transfer time to the inpatient unit was shorter after administration of propofol. The recovery period was rated significantly better after propofol administration by nurses and patients., Conclusions: A single bolus of propofol administered after the end of the seizure reduced the incidence of post-ECT PIA. The PACU staff and patients rated the emergence period significantly better when propofol was administered.

Dexmedetomidine is a highly selective, potent α₂-adrenoceptor agonist which was approved in 2011 by the European Medicines Agency for sedation of patients in intensive care units (ICU). Dexmedetomidine exhibits sedative as well as analgesic and anxiolytic effects. Recent studies suggest that dexmedetomidine may be an alternative to midazolam in long-term ICU sedation. This review summarizes the pharmacokinetics and pharmacodynamics of dexmedetomidine particularly in ICU patients and with special regard to covariate effects. Although dexmedetomidine is currently approved only for use in adults the pharmacokinetics and pharmacodynamics in children will also be addressed as there are numerous studies on this off-label use.

Background: Dexmedetomidine is a highly selective and potent α(2)-adrenoceptor agonist registered for sedation of patients in intensive care units. There is little information on factors possibly affecting its pharmacokinetics during long drug infusions in critically ill patients. We characterized the pharmacokinetics of dexmedetomidine in critically ill patients during long-term sedation using a population pharmacokinetic approach., Methods: Twenty-one intensive care patients requiring sedation and mechanical ventilation received dexmedetomidine with a loading dose of 3-6 µg kg(-1) h(-1) in 10 min and a maintenance dose of 0.1-2.5 µg kg(-1) h(-1) for a median duration of 96 h (range, 20-571 h). Cardiac output (CO), laboratory and respiratory parameters, and dexmedetomidine concentrations in arterial plasma were measured. The pharmacokinetics was determined by population analysis using linear multicompartment models., Results: The pharmacokinetics of dexmedetomidine was best described by a two-compartment model. The population values (95% confidence interval) for elimination clearance, inter-compartmental clearance, central volume of distribution, and volume of distribution at steady state were 57.0 (42.1, 65.6), 183 (157, 212) litre h(-1), 12.3 (7.6, 17.0), and 132 (96, 189) litre. Dexmedetomidine clearance decreased with decreasing CO and with increasing age, whereas its volume of distribution at steady state was increased in patients with low plasma albumin concentration., Conclusions: The population pharmacokinetics of dexmedetomidine was generally in line with results from previous studies. In elderly patients and in patients with hypoalbuminaemia, the elimination half-life and the context-sensitive half-time of dexmedetomidine were prolonged.

GPI 15715 is the first water-soluble propofol prodrug that has been studied in humans. Present propofol lipid formulations have well known undesirable properties, for example, pain on injection and increased triglyceride concentrations. We investigated whether GPI 15715 is suitable to achieve and maintain moderate sedation for 2 h. Six male and six female volunteers received a target-controlled infusion of GPI 15715, with an initial propofol target concentration of 1.8 microg/mL and the possibility to adjust the propofol target once after 1 h. Propofol concentrations, the bispectral index, and modified Observer's Assessment of Alertness/Sedation Scale (MOAA/S) scores were monitored. The median MOAA/S score was 4 during the first hour and was 3 during the second hour of infusion. The propofol target had to be changed to 2.4 microg/mL in seven volunteers and to 3.0 microg/mL in two volunteers. A propofol concentration of 1.9 microg/mL had the highest probability to result in an MOAA/S score of 3, which corresponds with moderate sedation. We observed no serious side effects. We conclude that GPI 15715 produces excellent sedation.

Background: Based on previous pharmacokinetic and pharmacodynamic studies, we have developed an EEG-controlled closed-loop system for the i.v. hypnotic agent propofol in rats., Methods: Seven adult male Sprague-Dawley rats (weight 423-584 g) were included in the study. EEG was recorded with occipito-occipital needle electrodes and the EEG power spectrum was estimated. The median frequency (MEF) was extracted from the power spectrum and was modified MEF (mMEF) to account for the occurrence of spikes and burst suppression patterns in the EEG. Propofol infusion was controlled by a model-based adaptive control algorithm to maintain a set point of mMEF=3.0 (sd 0.5) Hz. The performance of the feedback system was characterized by the median performance error MDPE=median[(mMEF-set point)/set point] and the median absolute performance error (MDAPE). The effective therapeutic infusion (ETI) to maintain the set point was determined from the resulting infusion rates., Results: In all rats a feedback period of 90 min could be performed. Mean MDPE was 1.2 (se 0.4)% and MDAPE was 13.9 (0.3)%. The ETI was 0.73 (sd 0.20) mg kg(-1) min(-1). Mean arterial pressure before propofol infusion was 148 (14) mm Hg, with the lowest value during closed-loop infusion being 110 (20) mm Hg., Conclusions: The feedback system presented here may be a useful tool not only for automatic drug control to maintain a defined hypnotic effect but may also be a powerful device in pharmacological studies such as the determination of dose requirements or the assessment of drug-drug interactions.

Aims: We studied the development of acute tolerance to the EEG effect of midazolam and the new benzodiazepine Ro 48-6791., Methods: Nine young (24-28 years) and nine elderly (67-81 years) male volunteers received midazolam and Ro 48-6791 computer-controlled, targeting linearly increasing plasma concentrations for 30 min (targeted slopes: 40 and 20 ng ml-1 min-1 for midazolam, 3 and 1.5 ng ml-1 min-1 for Ro 48-6791, for young and elderly, respectively) and a constant concentration for the following 15 min. After recovery, the same infusion scheme was repeated. Plasma concentrations of midazolam, Ro 48-6791 and its metabolite Ro 48-6792 were determined from arterial blood samples. The hypnotic effect was assessed using the median frequency of the EEG power spectrum., Results: The concentration-effect relationship in each infusion cycle could be described by a sigmoid Emax model. The half-maximum concentration EC50 was higher in the second infusion cycle compared with the first one (midazolam, 47% (2.3-91.6%) and 37% (5.3-69.5%); Ro 48-6791, 22% (-2.8% to 44.6%) and 43% (3.4-82.4%) for young and elderly; mean and 95% confidence interval). The complete time course of the EEG median frequency could be described by an interaction between the parent drug in an effect compartment and a hypothetical competitive drug in an additional tolerance compartment. For Ro 48-6791, the use of its metabolite Ro 48-6792 as competitive compound also gave appropriate results., Conclusion: Midzolam and Ro 48-6791 showed acute tolerance to the EEG effect which might be caused by competitive interaction with the metabolite.

Background and Objective: For total intravenous anaesthesia an opioid is often combined with a hypnotic. A supra-additive interaction has been reported for clinical signs such as loss of consciousness or loss of the eyelash reflex. This study investigated the type of interaction of alfentanil and propofol on the electroencephalogram., Methods: Twenty patients scheduled for abdominal surgery were enrolled in the study. Anaesthesia was induced and maintained with alfentanil and propofol. Each patient received a target-controlled infusion of alfentanil. Three target concentrations of 150, 225 and 300 ng mL(-1) were applied to each patient in random order. Propofol was added to the alfentanil infusion by a feedback system. The set point was the range of 1.5-2.5 Hz median frequency of the electroencephalogram. Four arterial blood samples were taken within the last 20 min of each period. The mean drug concentrations were used to determine the type of interaction and an isobole was estimated by fitting Bernstein spline functions to the data., Results: In 17 patients, all three alfentanil target concentrations could be administered. The test for supra-additivity as well as the isobole construction resulted in an additive type of interaction. The line of additivity cA/cA0 + cP/cP0 = 1 was best fitted for the values (standard deviation) cA0 = 1240 (51)ng mL(-1) and cP0 = 5.21 (0.36) microg mL(-1)., Conclusions: The type of interaction between alfentanil and propofol on the electroencephalogram in the investigated dose range is additive. This gives the freedom and need to select the appropriate dosing ratio of alfentanil and propofol by other considerations.

Objective: The primary aim of this study was to find out whether adequate long-term sedation (> or = 72 h) can be achieved in critically ill patients with an EEG median frequency controlled closed-loop system for the application of propofol 1% and 2%. Moreover, we investigated the pharmacokinetics and pharmacodynamics of propofol with respect to possible tolerance and compared the quality of sedation of both propofol formulations and their lipid load., Patients and Methods: After institutional approval and written consent, 16 ASA II-IV patients were included in this study. Main inclusion criterion was the necessity for prolonged sedation/analgesia for at least 72 h. Sedation was induced and maintained using continuous infusion of propofol 1% (n = 7) or 2% (n = 9). Analgesia was maintained with continuous infusion of alfentanil. The EEG was recorded from four leads (Fp1,2 and C3,4) and the EEG median frequency was obtained from the power spectrum (0.5-32 Hz). Propofol was administered computer-controlled with a median frequency setpoint depending on the depth of sedation which was assessed clinically using a modified Ramsay score. Alfentanil was applied as TCI. Arterial plasma concentrations were measured by HPLC (propofol) and RIA (alfentanil). Pharmacokinetics of propofol and alfentanil were derived using a three compartment model., Results: All patients were successfully sedated for 77 +/- 9 h. The median EEG frequency during sedation was stable at 1.5 +/- 0.2 Hz. The sedation score increased from 1 in the first 12 h to values between 2 and 3 for the remaining sedation period. At the same time, propofol plasma concentrations increased from 0.7 +/- 0.3 microgram/ml to 1.8 +/- 1.3 micrograms/ml. The patients required an average of 2.5 mg/kg/h propofol and 0.030 mg/kg/h alfentanil. Pharmacokinetics of propofol 2% showed an increased volume of distribution when compared to propofol 1%. Alfentanil clearance was found to be reduced with four patients having extremely small clearance values (33 +/- 3 ml/min). Triglyceride values increased up to 4.5 +/- 1.2 mmol/l for patients receiving propofol 1% and remained within normal range for propofol 2%., Conclusions: The EEG median frequency can be used for closed-loop control of propofol even for long-term sedation in critically ill patients. EEG median frequencies were similarly low as in deeply anaesthetised patients. No differences in quality of sedation were seen between the two propofol formulations, but propofol 2% seems to be advantageous due to lower lipid load and triglyceride values. Increasing concentrations of propofol at unchanged sedation scores and EEG median frequencies may indicate development of tolerance.

Objective: We investigated the pharmacologic properties of midazolam with special regard to age using the electroencephalogram (EEG) as a measure of the hypnotic-sedative effect., Methods: Nine younger (24 to 28 years) and nine elderly (67 to 81 years) male volunteers received midazolam by a computer-controlled device. Two infusion cycles with linearly increasing target plasma levels (slope, 40 ng/mL/min for the younger subjects; 20 ng/mL/min for the elderly subjects) were administered until defined end points were attained (median EEG frequency <4 Hz and loss of responsiveness to acoustic stimuli). An EEG was recorded to quantitate the hypnotic effect, relating the median frequency of the power spectrum to the plasma level by a sigmoid Emax model, including an effect compartment. Pharmacokinetic data were derived from arterial blood samples with use of a three-compartment model., Results: The total doses needed to reach the defined end points were 71+/-9 mg and 35+/-6 mg for the younger and elderly subjects, respectively (P < .001). Pharmacokinetic parameters were similar in both groups (clearance, 399+/-91 and 388+/-97 mL/min; steady-state volume of distribution, 85+/-22 and 104 +/-11 L in young and elderly subjects, respectively). Pharmacodynamic data showed a large difference in half-maximum concentration (EC50; young subjects, 522+/-236 ng/mL; elderly subjects, 223+/-56 ng/mL; P < .05), a steep concentration-response curve, and distinct hysteresis. We found much interindividual variability in the plasma concentrations necessary to achieve the clinical end points, regardless of age., Conclusions: These results suggest that the lower doses needed to reach sedation in the elderly subjects were attributable to a 50% decrease in EC50, not to changes in pharmacokinetics.

Background: In the last 4 y, several authors have reported largely satisfactory results using the new steroid intravenous anesthetic eltanolone (pregnanolone) to induce anesthesia. Until now, however, no investigations have addressed the infusion pharmacokinetics of eltanolone or used electroencephalographic effect data for full pharmacodynamic modeling. Thus the authors conducted a study to evaluate the pharmacokinetic and pharmacodynamic properties of eltanolone after infusion in healthy volunteers., Methods: Eltanolone emulsion was administered to 12 healthy men using a computer-controlled infusion device. Linearly increasing serum concentrations were generated for two consecutive infusions with an anticipated slope of 0.075 microgram.ml-1.min-1 and a targeted concentration of 2-2.5 micrograms/ml. During and after the infusion, electroencephalographic data were recorded as a continuous pharmacodynamic parameter to measure the hypnotic effect. In addition, blood pressure, heart rate, pulse oximetry, clinical signs of anesthesia, and any undesirable effects were recorded. The appearance of burst suppression periods in the raw electroencephalographic wave form was used as an end point for the infusion. Arterial blood samples were drawn frequently until 720 min after the cessation of the last infusion cycle. Eltanolone serum concentrations were measured using a specific gas chromatography-mass spectrometry assay. Nonlinear regression analysis was used to relate a power spectral parameter of the electroencephalograph (median frequency) to the serum concentration using a sigmoid Emax model, including an effect compartment to minimize possible hysteresis. Population pharmacokinetics were analyzed using an open three-compartment model., Results: The pharmacokinetic model parameters of eltanolone were characterized by a high total clearance (1.75 +/- 0.22 l/min), small volumes of distribution (Vc = 7.65 +/- 3.40 l; Vdss = 91.6 +/- 22 l), and relatively short half-lives (t1/2 alpha = 1.5 +/- 0.6 min; t1/2 beta = 27 +/- 5 min; t1/2 gamma = 184 +/- 32 min). With regard to the pharmacodynamic model parameters, eltanolone proved to be a potent hypnotic agent (Cp50 = 0.46 +/- 0.09 microgram/ml). The hypnotic effect coincided with a remarkable hysteresis between serum concentration and biophase, determined by an equilibration half-life of 8 min (ke0 = 0.087 +/- 0.013 min-1). All volunteers breathed spontaneously during the entire observation period and showed no clinically relevant hemodynamic changes. One volunteer experienced a convulsion while awakening., Conclusions: Eltanolone is a new potent steroid-type hypnotic agent with rapid elimination characteristics. Although it is short-acting, the remarkable hysteresis limits the control and might complicate administration of eltanolone if it is used as a component of a complete intravenous anesthesia regimen. Furthermore, it involves the potential disadvantage of drug accumulation and it prolongs recovery if larger-than-necessary doses are used to induce anesthesia rapidly.

Objective: Population pharmacokinetic analysis and pharmacodynamic profile of propofol/alfentanil infusions for sedation and analgesia of intensive care unit patients for up to 24 h., Design: Institutional Review Board-approved prospective clinical trial., Setting: The ten-bed intensive care unit of an university hospital., Patients: 18 consecutive patients (ten men/eight women; age: 17-73 years, mean 51.6 +/- 16.7 years, SD; body weight: 60-110 kg, mean 82.9 +/- 11.2 kg, SD) requiring mechanical ventilation and prolonged sedation/analgesia after major surgery or trauma., Interventions: Plasma propofol and alfentanil concentrations were measured at regular intervals during the long-term drug infusion using a high-performance liquid chromatography (propofol) and radioimmunoassay (alfentanil) analysis. The depth of sedation was controlled by monitoring a two-lead online EEG. Thus, drug application was computer controlled via a closed-loop EEG median-frequency feedback system., Results: ICU long-term infusion population pharmacokinetics (open three-compartment model) revealed for propofol: central compartment distribution volume (V1): 31.2 +/- 5.3 l; steady-state distribution volume (Vdss): 499 +/- 173 l; total clearance (Cltot): 1001- +/- 150 ml/min; redistribution half-life (t1/2 gamma): 90 +/- 23 min; elimination half-life (t1/2 beta): 558 +/- 218 minutes. For alfentanil: V1: 31.9 +/- 10.1 l; Vdss: 124 +/- 41 l; Cltot: 345 +/- 70 ml/min; t1/2 gamma: 36 +/- 15 min; t1/2 beta: 275 +/- 94 min, respectively., Conclusions: The population pharmacokinetic analysis of propofol/alfentanil for ICU sedation therapy revealed increased volumes of drug distribution and decreased elimination characteristics as compared to pharmacokinetic data from short-term infusions in surgical patients. This can be attributed in part to altered distribution/redistribution processes and/or drug elimination under the condition of ICU therapy. No significant drug accumulation was observed. For future long-term sedation and analgesia of ICU patients with propofol/alfentanil, this altered pharmacokinetic behaviour should be taken into consideration to allow a more individualized and safer dosing of this drug combination.