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Nowadays, many people are turning to medications that can help them stay calm during surgeries and their daily lives. As an anesthetic that reduces the excitability of nerve cells, propofol can achieve sedation with the advantages of fast onset and short half-life. The development of propofol sensors has tremendous application potential because they can help healthcare professionals dynamically regulate the concentration of propofol in the blood, not only to achieve the painless surgeries that patients want, to maintain the sedation that surgeons desire, but also to prevent the respiratory failure that may occur with a patient's daily sleep aids. In this paper, we prepared Fe 3 O 4 /C/CB nanocomposites by doping carbon black on the surface of the pyrolyzed product of MIL-88B. The nanocomposites-modified glassy carbon electrodes were used to detect propofol in phosphate buffer solution. The porous nanocomposites with high electrical conductivity promoted the charge transfer on the electrode surface, improving the performance of the modified electrodes. After optimization, the linear range, the detection limit, and the sensitivity for propofol were 5.0-205 μM, 0.102 μM, and 2.850 μA cm -2 μM -1 , respectively. The electrochemical sensing of propofol in a medical propofol emulsion injection and in normal human serum showed that the method was rapid and repeatable.

Background: Intraoperation hypotension (IOH) is commonly observed in patients undergoing surgery under general anesthesia, and even a brief episode of IOH can lead to unfavorable outcomes. To reduce the risk, blood pressure is closely measured during general anesthesia, and norepinephrine (NE) is frequently administered if hypotension is detected. Despite its routine application, information on the dose-exposure-response relationship of NE remains limited. Additionally, quantification of the influence of general anesthesia on the pharmacokinetics (PK) of NE is lacking., Objective: In this study, we aimed to describe NE PK in healthy volunteers and the influence of general anesthesia on its PK., Methods: A single-center, cross-over study was conducted in healthy volunteers. The volunteers received a step-up NE dosing scheme (0.04, 0.08, 0.12, 0.16 and 0.20 mcg -1 /kg -1 /min -1 ) first in the awake state and then under general anesthesia. General anesthesia was administered using a propofol/remifentanil Eleveld target-controlled infusion. During general anesthesia, a 30-second electrical stimulus was given as surrogate for surgical incision to the volunteers at each dosage step. Blood samples were drawn before the initial dosing and after each dosing step, and plasma NE, propofol and remifentanil concentrations were subsequently determined. A population PK model was developed using non-linear mixed effects modelling. Simulations were conducted to predict the plasma NE concentration in patients at different measured propofol concentrations., Results: A total of 1219 samples were analyzed from 36 volunteers. A two-compartment model with a first-order elimination best described the data. Weight, age, and session effect (awake vs general anesthesia) were identified as relevant covariates on the clearance (CL) of NE. A 10% decrease in NE CL was observed after general anesthesia induction. This difference between sessions is better explained by the measured concentration of propofol, rather than the anticipated impact of cardiac output. The estimated post-stimulation NE concentration is 0.66 nmol/L -1 (95% CI 0.06-1.20 nmol/L -1 ) lower than the pre-stimulation NE concentration. Model simulation indicates that patients at a higher measured propofol concentration (e.g., 6 mcg/mL -1 ) exhibited higher NE concentrations (95% PI 18.10-43.89 nmol/L -1 ) than patients at a lower measured propofol concentration (e.g., 3 mcg/mL -1 ) (95% PI 16.81-38.91 nmol L -1 )., Conclusion: The NE PK is well described with a two-compartment model with a first-order elimination. NE CL exhibiting a 10% decrease under general anesthesia, with this difference being attributed to the measured concentration of propofol. The impact of stimulation on NE PK under general anesthesia is very limited., Clinical Trials Registration Number: NL9312., Competing Interests: Declarations Funding The study is supported by the Department of Anesthesiology at University Medical Center Groningen, The Netherlands. Conflicts of Interest M.M.R.F Struys: His research group/department received (over the last 3 years) research grants and consultancy fees from The Medicines Company (Parsippany, NJ, USA), Masimo (Irvine, CA, USA), Becton Dickinson (Eysins, Switzerland), Fresenius (Bad Homburg, Germany), Dräger (Lübeck, Germany), Paion (Aachen, Germany), Medtronic (Dublin, Ireland). He receives royalties on intellectual property from Demed Medical (Sinaai, Belgium) and the Ghent University (Gent, Belgium). He is an editorial board member and Director for the British Journal of Anaesthesia. D.J. Eleveld: Has received travel from Becton Dickenson and is an editorial board member of Anesthesiology journal. P.J. Colin: Over the last 3 years his research group has been involved in contract research for PAION UK Ltd. (London, England) and Acacia Pharma Ltd. (Cambridge, England). Yingxue Li, Jeroen V. Koomen, Johannes P. van den Berg, Jaap Jan Vos, Ilonka N. de Keijzer declare that they have no conflicts of interest that are relevant to the content of this article. Ethics Approval The protocol of the study has been approved by the local medical ethics committee. Consent to Participate Informed consent was acquired from each individual participant incorporated in the study. Consent for Publication Not applicable. Availability of Data and Material The data and material are accessible upon reasonable request by contacting the corresponding author. Code Availability The model code is accessible upon reasonable request by contacting the corresponding author. Authors’ Contributions M.M.R.F. Struys, P.J. Colin, J.P. Van den Berg, J.J. Vos: conception and design of the study and manuscript revision; J.P. Van den Berg, J.J. Vos, I.N. de Keijzer: data collection, bioanalysis and manuscript revision; Y Li, J.V. Koomen, D.J. Eleveld, P.J. Colin: data analysis and interpretation, modelling, manuscription preparation and revision., (© 2024. The Author(s).)

Background: Intravenous lidocaine is increasingly used as an analgesic adjunct during general anaesthesia. Lidocaine is highly protein-bound and changes to binding can alter drug efficacy or toxicity. We aimed to measure the effect of various propofol and lidocaine plasma concentration combinations on the protein binding and concentration of lidocaine in vitro., Methods: Known targeted concentrations of propofol and lidocaine were added to drug-free human plasma in vitro. Samples were prepared and analysed in various clinically relevant concentration combinations; propofol at 0, 2, 4 and 6 µg/mL, and lidocaine at 1, 3 and 5 µg/mL. The total and unbound concentrations of lidocaine were measured by ultra-high performance liquid chromatography-mass spectrometry and percentage protein binding was determined. Data were presented as mean and standard deviation (SD) and differences between groups analysed., Results: The overall mean protein binding of lidocaine was 68.8% (SD 5.5, range 57.5-80.9%). Beta regression analysis revealed no statistically significant difference in lidocaine percentage binding across a range of propofol and lidocaine concentration combinations., Conclusion: Propofol did not alter the unbound and free pharmacologically active proportion of lidocaine at different clinically targeted concentrations of propofol and lidocaine in plasma in vitro. The percentage of plasma protein binding of lidocaine in this study was consistent with previously published results., (Copyright © 2024 Société française d'anesthésie et de réanimation (Sfar). Published by Elsevier Masson SAS. All rights reserved.)

Background: Unlike expired sevoflurane concentration, propofol lacks a biomarker for its brain effect site concentration, leading to dosing imprecision particularly in infants. Electroencephalography monitoring can serve as a biomarker for propofol effect site concentration, yet proprietary electroencephalography indices are not validated in infants. The authors evaluated spectral edge frequency (SEF95) as a propofol anesthesia biomarker in infants. It was hypothesized that the SEF95 targets will vary for different clinical stimuli and an inverse relationship existed between SEF95 and propofol plasma concentration., Methods: This prospective study enrolled infants (3 to 12 months) to determine the SEF95 ranges for three clinical endpoints of anesthesia (consciousness-pacifier placement, pain-electrical nerve stimulation, and intubation-laryngoscopy) and correlation between SEF95 and propofol plasma concentration at steady state. Dixon's up-down method was used to determine target SEF95 for each clinical endpoint. Centered isotonic regression determined the dose-response function of SEF95 where 50% and 90% of infants (ED50 and ED90) did not respond to the clinical endpoint. Linear mixed-effect model determined the association of propofol plasma concentration and SEF95., Results: Of 49 enrolled infants, 44 evaluable (90%) showed distinct SEF95 for endpoints: pacifier (ED50, 21.4 Hz; ED90, 19.3 Hz), electrical stimulation (ED50, 12.6 Hz; ED90, 10.4 Hz), and laryngoscopy (ED50, 8.5 Hz; ED90, 5.2 Hz). From propofol 0.5 to 6 μg/ml, a 1-Hz SEF95 increase was linearly correlated to a 0.24 (95% CI, 0.19 to 0.29; P < 0.001) μg/ml decrease in plasma propofol concentration (marginal R2 = 0.55)., Conclusions: SEF95 can be a biomarker for propofol anesthesia depth in infants, potentially improving dosing accuracy and utilization of propofol anesthesia in this population., (Copyright © 2024 American Society of Anesthesiologists. All Rights Reserved.)

Background: Existing PK models of propofol include sparse data from very obese patients. The aim of this study was to develop a PK model based on standardised surgical conditions and spanning from normal-weight up to, and including, a high number of very obese patients., Methods: Adult patients scheduled for laparoscopic cholecystectomy or bariatric surgery were studied. Anaesthesia was induced with propofol 2 mg/kg adjusted body weight over 2 min followed by 6 mg/kg/h adjusted body weight over 30 min. For the remainder of the operation anaesthesia was maintained with sevoflurane. Remifentanil was dosed according to clinical need. Eight arterial samples were drawn in a randomised block sampling regimen over a span of 24 h. Time-concentration data were analysed by population PK modelling using non-linear mixed-effects modelling., Results: Four hundred and seventy four serum propofol concentrations were collected from 69 patients aged 19-60 years with a BMI 21.6-67.3 kg/m 2 . Twenty one patients had a BMI above 50 kg/m 2 . A 3-compartment PK model was produced wherein three different body weight descriptors and sex were included as covariates in the final model. Total body weight was found to be a covariate for clearance and Q3; lean body weight for V1, V2 and Q2; predicted normal weight for V3 and sex for V1. The fixed allometric exponent of 0.75 applied to all clearance parameters improved the performance of the model. Accuracy and precision were 1.4% and 21.7% respectively in post-hoc performance evaluation., Conclusion: We have developed a new PK model of propofol that is suitable for all adult weight classes. Specifically, it is based on data from an unprecedented number of individuals with very high BMI., (© 2024 The Authors. Acta Anaesthesiologica Scandinavica published by John Wiley & Sons Ltd on behalf of Acta Anaesthesiologica Scandinavica Foundation.)

Background: Standard dosages of analgesic and sedative drugs are given to intensive care patients. The resulting range of blood concentrations and corresponding clinical responses need to be better examined. The purpose of this study was to describe daily dosages, measured blood concentrations, and clinical responses in critically ill patients. The purpose was also to contribute to establishing whole blood concentration reference values of the drugs investigated., Methods: A descriptive study of prospectively collected data from 302 admissions to a general intensive care unit (ICU) at a university hospital. Ten drugs (clonidine, fentanyl, morphine, dexmedetomidine, ketamine, ketobemidone, midazolam, paracetamol, propofol, and thiopental) were investigated, and daily dosages recorded. Blood samples were collected twice daily, and drug concentrations were measured. Clinical responses were registered using Richmond agitation-sedation scale (RASS) and Numeric rating scale (NRS)., Results: Drug dosages were within recommended dose ranges. Blood concentrations for all 10 drugs showed a wide variation within the cohort, but only 3% were above therapeutic interval where clonidine (57 of 122) and midazolam (38 of 122) dominated. RASS and NRS were not correlated to drug concentrations., Conclusion: Using recommended dose intervals for analgesic and sedative drugs in the ICU setting combined with regular monitoring of clinical responses such as RASS and NRS leads to 97% of concentrations being below the upper limit in the therapeutic interval. This study contributes to whole blood drug concentration reference values regarding these 10 drugs., Competing Interests: The authors report no conflict of interest., (© 2024 The Author(s).)

Many areas of science and medicine would benefit from selective release of drugs in specific regions. Nanoparticle drug carriers activated by focused ultrasound-remotely applied, depth-penetrating energy-may provide such selective interventions. Here, we developed stable, ultrasound-responsive nanoparticles that can be used to release drugs effectively and safely in non-human primates. The nanoparticles were used to release propofol in deep brain visual regions. The release reversibly modulated the subjects' visual choice behavior and was specific to the targeted region and to the released drug. Gadolinium-enhanced MR imaging suggested an intact blood-brain barrier. Blood draws showed normal clinical chemistry and hematology. In summary, this study provides a safe and effective approach to release drugs on demand in selected deep brain regions at levels sufficient to modulate behavior., Competing Interests: Declaration of competing interest Jan Kubanek is a co-inventor on a pending patent., (Copyright © 2023. Published by Elsevier B.V.)

Background: Propofol is an intravenous agent for clinical anesthesia. As the influence of the hypobaric-hypoxic environment (Qinghai-Tibetan region, altitude: 2800-4300 m, PaO2: 15.1-12.4 kPa) on the metabolism of Propofol is complex, the research results on the metabolic characteristics of Propofol in high-altitude areas remain unclear. This study aimed to investigate the pharmacokinetic characteristics of Propofol in a high-altitude hypoxic environment using animal experiments., Methods: Rats were randomly divided into three groups: high-altitude, medium-altitude, and plain groups. The time of disappearance and recovery of the rat righting reflex was recorded as the time of anesthesia induction and awakening, respectively. The plasma concentration of Propofol was determined by gas chromatography-mass spectrometry. A pharmacokinetic analysis software was used to analyze the blood-drug concentrations and obtain the pharmacokinetic parameters., Results: We observed that when Propofol anesthetizes rats, the anesthesia induction time was shortened, and the recovery time was prolonged with increased altitude. Compared with the plain group, the clearance of Propofol decreased, whereas the half-life, area under the concentration-time curve, peak plasma concentration, and average residence time extension increased., Conclusion: The pharmacokinetic characteristics of Propofol are significantly altered in high-altitude hypoxic environments., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Awake craniotomy enables mapping and monitoring of brain functions. For successful procedures, rapid awakening and the precise evaluation of consciousness are required. A prospective, observational study conducted to test whether intraoperative hand strength could be a sensitive indicator of consciousness during the awake phase of awake craniotomy. Twenty-three patients who underwent awake craniotomy were included. Subtle changes of the level of consciousness were assessed by the Japan Coma Scale (JCS). The associations of hand strength on the unaffected side with the predicted plasma concentration (Cp) of propofol, the bispectral index (BIS), and the JCS were analyzed. Hand strength relative to the preoperative maximum hand strength on the unaffected side showed significant correlations with the Cp of propofol (ρ =  - 0.219, p = 0.007), the BIS (ρ = 0.259, p = 0.002), and the JCS (τ =  - 0.508, p = 0.001). Receiver operating characteristic curve analysis for discriminating JCS 0-1 and JCS ≥ 2 demonstrated that the area under the curve was 0.76 for hand strength, 0.78 for Cp of propofol, and 0.66 for BIS. With a cutoff value of 75% for hand strength, the sensitivity was 0.76, and the specificity was 0.67. These data demonstrated that hand strength is a useful indicator for assessing the intraoperative level of consciousness during awake craniotomy., (© 2022. The Author(s).)

Background: Propofol administration in patients with Brugada syndrome (BrS) is still a matter of debate. Despite lacking evidence for its feared arrhythmogenicity, up to date, expert cardiologists recommend avoiding propofol. The main aim of this study is to assess the occurrence of malignant arrhythmias or defibrillations in patients with BrS, during and 30 days after propofol administration. The secondary aim is to investigate the occurrence of adverse events during propofol administration and hospitalization, as the 30-day readmission and 30-day mortality rate., Methods: We performed a retrospective cohort study on patients with BrS who received propofol anytime from January 1, 1996 to September 30, 2020. Anesthesia was induced by propofol in both groups. In the total intravenous anesthesia (TIVA) group, anesthesia was maintained by propofol, while in the BOLUS group, volatile anesthesia was provided. The individual anesthetic charts and the full electronic medical records up to 30 postprocedural days were scrutinized., Results: One hundred thirty-five BrS patients who underwent a total of 304 procedures were analyzed. The TIVA group included 27 patients for 33 procedures, and the BOLUS group included 108 patients for 271 procedures. In the TIVA group, the median time of propofol infusion was 60 minutes (interquartile range [IQR] = 30-180). The estimated plasma or effect-site concentration ranged between 1.0 and 6.0 µg·mL-1 for target-controlled infusion (TCI). The infusion rate for manually driven TIVA varied between 0.8 and 10.0 mg·kg-1·h-1. In the BOLUS group, the mean propofol dose per kilogram total body weight was 2.4 ± 0.9 mg·kg-1. No malignant arrhythmias or defibrillations were registered in both groups. The estimated 95% confidence interval (CI) of the risk for malignant arrhythmias in the BOLUS and TIVA groups was 0-0.011 and 0-0.091, respectively., Conclusions: The analysis of 304 anesthetic procedures in BrS patients, who received propofol, either as a TIVA or as a bolus during induction of volatile-based anesthesia, revealed no evidence of malignant arrhythmias or defibrillations. The present data do not support an increased risk with propofol-based TIVA compared to propofol-induced volatile anesthesia. Prospective studies are needed to investigate the electrophysiologic effects of propofol in BrS patents., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 International Anesthesia Research Society.)

Background: Exhaled propofol concentrations correlate with propofol concentrations in adult human blood and the brain tissue of rats, as well as with electroencephalography (EEG) based indices of anesthetic depth. The pharmacokinetics of propofol are however different in children compared to adults. The value of exhaled propofol measurements in pediatric anesthesia has not yet been investigated. Breathing system filters and breathing circuits can also interfere with the measurements. In this study, we investigated correlations between exhaled propofol (exP) concentrations and the Narkotrend Index (NI) as well as calculated propofol plasma concentrations., Methods: A multi-capillary-column (MCC) combined with ion mobility spectrometry (IMS) was used to determine exP. Optimal positioning of breathing system filters (near-patient or patient-distant) and sample line (proximal or distal to filter) were investigated. Measurements were taken during induction (I), maintenance (M) and emergence (E) of children under total intravenous anesthesia (TIVA). Correlations between ExP concentrations and NI and predicted plasma propofol concentrations (using pediatric pharmacokinetic models Kataria and Paedfusor) were assessed using Pearson correlation and regression analysis., Results: Near-patient positioning of breathing system filters led to continuously rising exP values when exP was measured proximal to the filters, and lower concentrations when exP was measured distal to the filters. The breathing system filters were therefore subsequently attached between the breathing system tubes and the inspiratory and expiratory limbs of the anesthetic machine. ExP concentrations significantly correlated with NI and propofol concentrations predicted by pharmacokinetic models during induction and maintenance of anesthesia. During emergence, exP significantly correlated with predicted propofol concentrations, but not with NI., Conclusion: In this study, we demonstrated that exP correlates with calculated propofol concentrations and NI during induction and maintenance in pediatric patients. However, the correlations are highly variable and there are substantial obstacles: Without patient proximal placement of filters, the breathing circuit tubing must be changed after each patient, and furthermore, during ventilation, a considerable additional loss of heat and moisture can occur. Adhesion of propofol to plastic parts (endotracheal tube, breathing circle) may especially be problematic during emergence., Trial Registration: The study was registered in the German registry of clinical studies (DRKS-ID:  DRKS00015795 ).

Background: Delayed neurocognitive recovery after surgery is associated with poor outcome. Most surgeries require general anesthesia, of which sevoflurane and propofol are the most commonly used inhalational and intravenous anesthetics. The authors tested the primary hypothesis that patients with laparoscopic abdominal surgery under propofol-based anesthesia have a lower incidence of delayed neurocognitive recovery than patients under sevoflurane-based anesthesia. A second hypothesis is that there were blood biomarkers for predicting delayed neurocognitive recovery to occur., Methods: A randomized, double-blind, parallel, controlled study was performed at four hospitals in China. Elderly patients (60 yr and older) undergoing laparoscopic abdominal surgery that was likely longer than 2 h were randomized to a propofol- or sevoflurane-based regimen to maintain general anesthesia. A minimum of 221 patients was planned for each group to detect a one-third decrease in delayed neurocognitive recovery incidence in propofol group compared with sevoflurane group. The primary outcome was delayed neurocognitive recovery incidence 5 to 7 days after surgery., Results: A total of 544 patients were enrolled, with 272 patients in each group. Of these patients, 226 in the propofol group and 221 in the sevoflurane group completed the needed neuropsychological tests for diagnosing delayed neurocognitive recovery, and 46 (20.8%) in the sevoflurane group and 38 (16.8%) in the propofol group met the criteria for delayed neurocognitive recovery (odds ratio, 0.77; 95% CI, 0.48 to 1.24; P = 0.279). A high blood interleukin-6 concentration at 1 h after skin incision was associated with an increased likelihood of delayed neurocognitive recovery (odds ratio, 1.04; 95% CI, 1.01 to 1.07; P = 0.007). Adverse event incidences were similar in both groups., Conclusions: Anesthetic choice between propofol and sevoflurane did not appear to affect the incidence of delayed neurocognitive recovery 5 to 7 days after laparoscopic abdominal surgery. A high blood interleukin-6 concentration after surgical incision may be an independent risk factor for delayed neurocognitive recovery., (Copyright © 2021, the American Society of Anesthesiologists, Inc. All Rights Reserved.)

Background: Internationally, propofol is commonly titrated by target-controlled infusion (TCI) to maintain a processed electroencephalographic (EEG) parameter (eg, bispectral index [BIS]) within a specified range. The overall variability in propofol target effect-site concentrations (CeT) necessary to maintain adequate anesthesia in real-world conditions is poorly characterized, as are the patient demographic factors that contribute to this variability. This study explored these issues, hypothesizing that the variability in covariate-adjusted propofol target concentrations during BIS-controlled anesthesia would be substantial and that most of the remaining interpatient variability in drug response would be due to random effects, thus suggesting that the opportunity to improve on the Schnider model with further demographic data is limited., Methods: With ethics committee approval and a waiver of informed consent, a deidentified, high-resolution, intraoperative database consisting of propofol target concentrations, BIS values, and vital signs from 13,239 patients was mined to identify patients who underwent general endotracheal anesthesia using propofol (titrated to BIS), fentanyl, remifentanil, and rocuronium that lasted at least 1 hour. The propofol target concentrations and BIS values 30 minutes after incision (CeT30 and BIS30) were considered representative of stable intraoperative conditions. The data were plotted and analyzed by descriptive statistics. Confidence intervals were computed using a bootstrap method. A linear model was fit to the data to test for correlation with factors of interest (eg, age and weight)., Results: A total of 4584 patients met inclusion criteria and were entered into the analysis. Of the propofol target concentrations, 95% were between 1.5 and 3.5 µg·mL-1. Higher BIS30 values were correlated with higher propofol concentrations. Except for age, all the patient-related variables analyzed entered the regression model linearly. Only 10.2% of the variability in CeT30 was explained by the patient factors of age and weight combined., Conclusions: Our hypothesis was confirmed. The variability in covariate-adjusted propofol CeT30 titrated to BIS in real-world conditions is considerable, and only a small portion of the remaining variability in drug response is explained by patient demographic factors. This finding may have important implications for the development of new pharmacokinetic (PK) models for propofol TCI., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2020 International Anesthesia Research Society.)

Background: Target-controlled infusion (TCI) systems incorporating pharmacokinetic (PK) or PK-pharmacodynamic (PK-PD) models can be used to facilitate drug administration. Existing models were developed using data from select populations, the use of which is, strictly speaking, limited to these populations. Recently a propofol PK-PD model was developed for a broad population range. The aim of the study was to prospectively validate this model in children, adults, older subjects, and obese adults undergoing general anaesthesia., Methods: The 25 subjects included in each of four groups were stratified by age and weight. Subjects received propofol through TCI with the Eleveld model, titrated to a bispectral index (BIS) of 40-60. Arterial blood samples were collected at 5, 10, 20, 30, 40, and 60 min after the start of propofol infusion, and every 30 min thereafter, to a maximum of 10 samples. BIS was recorded continuously. Predictive performance was assessed using the Varvel criteria., Results: For PK, the Eleveld model showed a bias < ±20% in children, adults, and obese adults, but a greater bias (-27%) in older subjects. Precision was <30% in all groups. For PD, the bias and wobble were <5 BIS units and the precision was close to 10 BIS units in all groups. Anaesthetists were able to achieve intraoperative BIS values of 40-60 using effect-site target concentrations about 85-140% of the age-adjusted Ce 50 ., Conclusions: The Eleveld propofol PK-PD model showed predictive precision <30% for arterial plasma concentrations and BIS predictions with a low (population) bias when used in TCI in clinical anaesthesia practice., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

We present a new method for electrochemical sensing, which compensates the fouling effect of propofol through machine learning (ML) model. Direct and continuous monitoring of propofol is crucial in the development of automatic systems for control of drug infusion in anaesthesiology. The fouling effect on electrodes discourages the possibility of continuous online monitoring of propofol since polymerization of the surface produces sensor drift. Several approaches have been proposed to limit the phenomenon at the biochemical interface; instead, here, we present a novel ML-based calibration procedure. In this paper, we analyse a dataset of 600 samples acquired through staircase cyclic voltammetry (SCV), resembling the scenario of continuous monitoring of propofol, both in PBS and in undiluted human serum, to demonstrate that ML-based model solves electrode fouling of anaesthetics. The proposed calibration approach is based on Gaussian radial basis function support vector classifier (RBF-SVC) that achieves classification accuracy of 98.9% in PBS, and 100% in undiluted human serum. The results prove the ability of the ML-based model to correctly classify propofol concentration in the therapeutic range between 1μM and 60μM with levels of 10μM, continuously up to ten minutes, with one sample every 30s., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Propofol is a widely used intravenous anesthetic agent in sedation and general anesthesia. To improve the safety and maintain the depth of anesthesia, it is important to develop a rapid, sensitive, and reliable method to monitor the concentration of propofol in blood during anesthesia continuously. Here, we present a novel strategy based on paper spray ionization-mass spectrometry (PSI-MS) to detect propofol. Samples (in 10 μL) were mixed with methanol as protein precipitation solvent and 2,6-dimethylphenol as internal standard. Protein micro-precipitation was achieved with methanol by vortexing and centrifuging for 5 s each, and propofol was extracted to the supernatant. PSI-MS was performed in negative ionization mode, and MS signal lasted for 1 min. The analysis of a single sample was completed within 2 min. The area ratios of propofol to internal standard were calculated for quantification. Limit of detection of 5.5 ng mL -1 and limit of quantification of 18.2 ng mL -1 were achieved for propofol in whole blood. Calibration curve was linear in the range of 0.02-10 μg mL -1 . The developed method was used successfully in monitoring the propofol concentration in 3 patients' whole blood during anesthesia, showing its further application in controlling and feeding-back target concentration infusion. Graphical abstract.

Here, the novel petal-shaped ionic liquids modified covalent organic frameworks (PS-IL-COFs) particles have been synthesized by using ionic liquids as modifying agent, which could be beneficial to avoid the aggregation of COFs during the preparation and improve its dispersing performance. The novel PS-IL-COFs particles have been used and evaluated in the one step cleanup and extraction (OSCE) procedure for human plasma prior to the analysis of 3 general anesthetics by liquid chromatography-tandem quadrupole mass spectrometry (LC-MS/MS). In the OSCE procedure, human plasma samples are directly mixed with extraction solvent and PS-IL-COFs particles, and the extraction and cleanup procedure have been carried out simultaneously. Compared with the Oasis PRiME HLB cartridge method, the OSCE procedure using PS-IL-COFs particles as sorbents is much more effective for the minimization of ion suppression resulted from blood phospholipids. Under optimal conditions, the PS-IL-COFs particles show higher cleanup efficiency of 3 general anesthetics with recoveries in the range of 82.5%-115%. The limits of quantification (LOQs) for propofol, ketamine and etomidate are 0.18 μg/L, 0.15 μg/L and 0.016 μg/L, respectively. Validation results on linearity, specificity, precision and trueness, as well as on the application to analysis of general anesthetics in a case of a 54-year-old female suffered gallstone demonstrate the applicability to clinical studies., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: The anesthetic side effects of propofol still occur in clinical practice because no reliable monitoring techniques are available. In this regard, continuous monitoring of propofol in breath is a promising method, yet it remains infeasible because there is large variation in the blood/exhaled gas partial pressure ratio (RBE) in humans. Further evaluations of the influences of breathing-related factors on RBE would mitigate this variation., Methods: Correlations were analyzed between breathing-related factors (tidal volume [TV], breath frequency [BF], and minute ventilation [VM]) and RBE in 46 patients. Furthermore, a subset of 10 patients underwent pulmonary function tests (PFTs), and the parameters of the PFTs were then compared with the RBE. We employed a 1-phase exponential decay model to characterize the influence of VM on RBE. We also proposed a modified RBE (RBEM) that was not affected by the different breathing patterns of the patients. The blood concentration of propofol was predicted from breath monitoring using RBEM and RBE., Results: We found a significant negative correlation (R = -0.572; P < .001) between VM and RBE (N = 46). No significant correlation was shown between PFTs and RBE in the subset (N = 10). RBEM demonstrated a standard Gaussian distribution (mean, 1.000; standard deviation [SD], 0.308). Moreover, the predicted propofol concentrations based on breath monitoring matched well with the measured blood concentrations. The 90% prediction band was limited to within ±1 μg·mL., Conclusions: The prediction of propofol concentration in blood was more accurate using RBEM than when using RBE and could provide reference information for anesthesiologists. Moreover, the present study provided a general approach for assessing the influence of relevant physiological factors and will inform noninvasive and accurate breath assessment of volatile drugs or metabolites in blood.

Propofol and cisatracurium besylate have been simultaneously determined using a highly sensitive first derivative synchronous spectrofluorometric method. The method is based on measuring first derivative synchronous spectrofluorimetric amplitude at Δλ = 40 nm with a scanning rate of 600 nm/min. The different experimental parameters affecting the fluorescence intensity of the two drugs were carefully studied and optimized. The amplitude-concentration plots were rectilinear over the range 40.0-400.0 ng/mL and 20.0-280.0 ng/mL for propofol and cisatracurium, respectively with lower detection limits of 4.0 and 2.35 ng/mL and quantification limits of 12.1 and 7.1 ng/mL for propofol and cisatracurium, respectively. The proposed method was successfully applied for the determination of the two compounds in synthetic mixtures and in commercial ampoules. The high sensitivity attained using the proposed method allowed the simultaneous determination of both drugs in spiked plasma samples. The mean % recoveries in spiked human plasma (n = 3) were 96.53 ± 0.90 and 96.20 ± 1.64 for each of propofol and cisatracurium, respectively. The method was validated in compliance with International Council of Harmonization (ICH) Guidelines., (© 2019 John Wiley & Sons, Ltd.)

The concentration of propofol in blood is an important indicator for anesthesiologists to monitor and regulate the anesthesia depth of patients during surgery. Herein, a negative photoionization ion mobility spectrometry with acetone as the dopant was developed for rapid and direct determination of intraoperative blood propofol concentration in the operating theatre. High concentration of acetone molecules in the carrier gas was used not only to enhance neutral desorption and release free propofol molecules from the whole blood, but also to increase the intensity of reactant O 2 - and reduce the amount of non-reactive CO 3 - ions simultaneously, which allowed to measure trace propofol in less than 2 min without any tedious pretreatment. Under optimized conditions, a linear calibration curve of propofol was obtained with the range of 0.5-20 ng μL -1 and with a limit of detection of 0.14 ng μL -1 , which met the clinical requirements and correlated well with standard HPLC methods. Finally, the method was applied to detect intraoperative blood propofol concentration in nearly 100 surgical patients, demonstrating its excellent detection capability and facilitating the study of propofol pharmacokinetics., (Copyright © 2019 Elsevier B.V. All rights reserved.)

What Is Known and Objective: Sampling volumes of blood from neonates is necessarily limited. However, most of the published propofol analysis assays require a relatively large blood sample volume (typically ≥0.5 mL). Therefore, the aim of the present study was to develop and validate a sensitive method requiring a smaller sample volume (0.2 mL) to fulfill clinically relevant research requirements., Methods: Following simple protein precipitation and centrifugation, the supernatant was injected into the HPLC-fluorescence system and separated with a reverse phase column. Propofol and the internal standard (thymol) were detected and quantified using fluorescence at excitation and emission wavelengths of 270 nm and 310 nm, respectively. The method was validated with reference to the Food and Drug Administration (FDA) guidance for industry. Accuracy (CV, %) and precision (RSD, %) were evaluated at three quality control concentration levels (0.05, 0.5 and 5 µg/mL)., Results and Discussion: Calibration curves were linear in the range of 0.005-20 µg/mL. Intra- and interday accuracy (-4.4%-13.6%) and precision (0.2%-5.8%) for propofol were below 15%. The calculated LOD (limit of detection) and LLOQ (lower limit of quantification) were 0.0021 µg/mL and 0.0069 µg/mL, respectively. Propofol samples were stable for 4 months at -20°C after the sample preparation. This method was applied for analyzing blood samples from 41 neonates that received propofol, as part of a dose-finding study. The measured median (range) concentration was 0.14 (0.03-1.11) µg/mL, which was in the range of the calibration curve. The calculated median (range) propofol half-life of the gamma elimination phase was 10.4 (4.7-26.7) hours., What Is New and Conclusion: A minimal volume (0.2 mL) of blood from neonates is required for the determination of propofol with this method. The method can be used to support the quantification of propofol drug concentrations for pharmacokinetic studies in the neonatal population., (© 2019 John Wiley & Sons Ltd.)

Some previous studies have indicated that valproate (VPA) might change the pharmacokinetics and enhance the effects of propofol. We evaluated whether clinical VPA therapy affected the propofol blood level, the protein-unbound free propofol level, and/or the anesthetic effects of propofol in the clinical setting. The subjects were divided into the control group (not medicated with antiepileptics), the mono-VPA group (medicated with VPA alone), and the poly-VPA group (medicated with VPA, other antiepileptics, and/or psychoactive drugs). General anesthesia was induced via the administration of a single bolus of propofol and a remifentanil infusion, and when the bispectral index (BIS) exceeded 60 sevoflurane was started. There were no significant differences in the total blood propofol level at 5, 10, 15, and 20 min or the protein-unbound free propofol level at 5 min after the intravenous administration of propofol between the 3 groups. However, the minimum BIS was significantly lower and the time until the BIS exceeded 60 was significantly longer in the poly-VPA group. In the multivariate regression analysis, belonging to the poly-VPA group was found to be independently associated with the minimum BIS value and the time until the BIS exceeded 60. Clinical VPA therapy did not influence the pharmacokinetics of propofol. However, multi-drug therapy involving VPA might enhance the anesthetic effects of propofol.

The brain is possibly the most complex system known to mankind, and its complexity has been called upon to explain the emergence of consciousness. However, complexity has been defined in many ways by multiple different fields: here, we investigate measures of algorithmic and process complexity in both the temporal and topological domains, testing them on functional MRI BOLD signal data obtained from individuals undergoing various levels of sedation with the anaesthetic agent propofol, replicating our results in two separate datasets. We demonstrate that the various measures are differently able to discriminate between levels of sedation, with temporal measures showing higher sensitivity. Further, we show that all measures are strongly related to a single underlying construct explaining most of the variance, as assessed by Principal Component Analysis, which we interpret as a measure of "overall complexity" of our data. This overall complexity was also able to discriminate between levels of sedation and serum concentrations of propofol, supporting the hypothesis that consciousness is related to complexity - independent of how the latter is measured.

Background: The population pharmacodynamics of propofol and sevoflurane with or without opioids were compared using the endpoints no response to calling the person by name, tolerance to shake and shout, tolerance to tetanic stimulus, and two versions of a processed electroencephalographic measure, the Patient State Index (Patient State Index-1 and Patient State Index-2)., Methods: This is a reanalysis of previously published data. Volunteers received four anesthesia sessions, each with different drug combinations of propofol or sevoflurane, with or without remifentanil. Nonlinear mixed effects modeling was used to study the relationship between drug concentrations, clinical endpoints, and Patient State Index-1 and Patient State Index-2., Results: The C50 values for no response to calling the person by name, tolerance to shake and shout, and tolerance to tetanic stimulation for propofol (µg · ml) and sevoflurane (vol %; relative standard error [%]) were 1.62 (7.00)/0.64 (4.20), 1.85 (6.20)/0.90 (5.00), and 2.82 (15.5)/0.91 (10.0), respectively. The C50 values for Patient State Index-1 and Patient State Index-2 were 1.63 µg · ml (3.7) and 1.22 vol % (3.1) for propofol and sevoflurane. Only for sevoflurane was a significant difference found in the pharmacodynamic model for Patient State Index-2 compared with Patient State Index-1. The pharmacodynamic models for Patient State Index-1 and Patient State Index-2 as a predictor for no response to calling the person by name, tolerance to shake and shout, and tetanic stimulation were indistinguishable, with Patient State Index50 values for propofol and sevoflurane of 46.7 (5.1)/68 (3.0), 41.5 (4.1)/59.2 (3.6), and 29.5 (12.9)/61.1 (8.1), respectively. Post hoc C50 values for propofol and sevoflurane were perfectly correlated (correlation coefficient = 1) for no response to calling the person by name and tolerance to shake and shout. Post hoc C50 and Patient State Index50 values for propofol and sevoflurane for tolerance to tetanic stimulation were independent within an individual (correlation coefficient = 0)., Conclusions: The pharmacodynamics of propofol and sevoflurane were described on both population and individual levels using a clinical score and the Patient State Index. Patient State Index-2 has an improved performance at higher sevoflurane concentrations, and the relationship to probability of responsiveness depends on the drug used but is unaffected for Patient State Index-1 and Patient State Index-2.

Aims: Manual propofol infusion regimens for neonates and infants have been determined from clinical observations in children under the age of 3 years undergoing anesthesia. We assessed the performance of these regimens using reported age-specific pharmacokinetic parameters for propofol. Where performance was poor, we propose alternative dosing regimens., Methods: Simulations using a reported general purpose pharmacokinetic propofol model were used to predict propofol blood plasma concentrations during manual infusion regimens recommended for children 0-3 years. Simulated steady state concentrations were 6-8 µg.mL -1 in the first 30 minutes that were not sustained during 100 minutes infusions. Pooled clinical data (n = 161, 1902 plasma concentrations) were used to determine an alternative pharmacokinetic parameter set for propofol using nonlinear mixed effects models. A new manual infusion regimen for propofol that achieves a steady-state concentration of 3 µg.mL -1 was determined using a heuristic approach., Results: A manual dosing regimen predicted to achieve steady-state plasma concentration of 3 µg.mL -1 comprised a loading dose of 2 mg.kg -1 followed by an infusion rate of 9 mg.kg -1 .h -1 for the first 15 minutes, 7 mg.kg -1 .h -1 from 15 to 30 minutes, 6 mg.kg -1 .h -1 from 30 to 60 minutes, 5 mg.kg -1 .h -1 from 1 to 2 hours in neonates (38-44 weeks postmenstrual age). Dose increased with age in those aged 1-2 years with a loading dose of 2.5 mg.kg -1 followed by an infusion rate of 13 mg.kg -1 .h -1 for the first 15 minutes, 12 mg.kg -1 .h -1 from 15 to 30 minutes, 11 mg.kg -1 .h -1 from 30 to 60 minutes, and 10 mg.kg -1 .h -1 from 1 to 2 hours., Conclusion: Propofol clearance increases throughout infancy to reach 92% that reported in adults (1.93 L.min.70 kg -1 ) by 6 months postnatal age and infusion regimens should reflect clearance maturation and be cognizant of adverse effects from concentrations greater than the target plasma concentration. Predicted concentrations using a published general purpose pharmacokinetic propofol model were similar to those determined using a new parameter set using richer neonatal and infant data., (© 2019 John Wiley & Sons Ltd.)

Background: The monitoring of regional cerebral oxygen saturation (SrO 2 ) using near-infrared spectroscopy is useful method to detect cerebral ischemia during. Sevoflurane and propofol decrease cerebral metabolic rate (CMRO 2 ) in a similar manner, but the effects on the cerebral blood flow (CBF) are different. We hypothesized that the effects of sevoflurane and propofol on SrO 2 were different in patients with deficits of CBF. This study compared the effect of sevoflurane and propofol on SrO 2 of patients undergoing cerebral endarterectomy (CEA)., Method: Patients undergoing CEA were randomly assigned to the sevoflurane or propofol group (n = 74). The experiment was preceded in 2 stages based on carotid artery clamping. The first stage was from induction of anaesthesia to immediately before clamping of the carotid artery, and the second stage was until the end of the operation after clamping of the carotid artery. Oxygen saturation (SrO 2 , SpO 2 ), haemodynamic variables (blood pressure, heart rate), respiratory parameters (end-tidal carbon dioxide tension, inspired oxygen tension), concentration of anesthetics, and anesthesia depth (bispectral index score) were recorded., Results: During stage 1 period (before carotid artery clamping), the mean value of the relative changes in SrO 2 was higher (P = 0.033) and the maximal decrease in SrO 2 was lower in the sevoflurane group compared with the propofol group (P = 0.019) in the contralateral (normal) site. However, there is no difference in ipsilateral site (affected site). SrO 2 decreased after carotid artery clamping and increased after declamping, but the difference was not significant between two groups. Changes in mean arterial blood pressure was lower in sevoflurane group than propofol group after the carotid artery declamping (P = 0.048)., Conclusion: Propofol-remifentanil anesthesia was comparable with sevoflurane-remifentanil anesthesia in an aspect of preserving the SrO 2 in patients undergoing carotid endarterectomy., Trial Registration: Clinical Trials.gov identifier: NCT02609087 , retrospectively registered on November 18, 2015.

The combination of propofol, ketamine and rocuronium can be used for anesthesia of ventilated rats. However, reliable pharmacokinetic models of these drugs have yet to be developed in rats, and consequently optimal infusion strategies are also unknown. Development of pharmacokinetic models requires repeated measurements of drug concentrations. In small animals, samples must be tiny to avoid excessing blood extraction. We therefore developed a drug assay system using high-performance liquid chromatography coupled with quadrupole mass spectrometry that simultaneously determines the concentration of all three drugs in just 10 μL rat plasma. We established a plasma extraction protocol, using acetonitrile as the precipitating reagent. Calibration curves were linear with R 2  = 0.99 for each drug. Mean recovery from plasma was 91-93% for propofol, 89-93% for ketamine and 90-92% for rocuronium. The assay proved to be accurate for propofol 4.1-8.3%, ketamine 1.9-7.8% and rocuronium -3.6-4.7% relative error. The assay was also precise; the intra-day precisions were propofol 2.0-4.0%, ketamine 2.7-2.9% and rocuronium 2.9-3.3% relative standard deviation. Finally, the method was successfully applied to measurement the three drugs in rat plasma samples. Mean plasma concentrations with standard deviations were propofol 2.0 μg/mL ±0.5%, ketamine 3.9 μg/mL ±1.0% and rocuronium 3.2 μg/mL ±0.8% during ventilation., (© 2019 John Wiley & Sons, Ltd.)

The ionisation of propofol was studied on the basis of analyte adduct formation with the components of the mobile phase. The identification of an appropriate propofol adduct ion generated in an acetate salt based buffer in the negative electrospray ionisation mode made the propofol LC-MS/MS analysis with two multiple reaction monitoring experiments possible without analyte derivatisation. Since a product ion of the deprotonated analyte was also used in the detection, these two fragmentation experiments were performed with different precursor ions. Liquid-liquid extraction with 1-chlorobutane was applied for sample preparation. A Luna 5 μm C18 (2) 100 A, 150 mm × 2 mm analytical column together with a mobile phase composed of water/methanol (3/97, v/v) with 10 mmol·L -1 ammonium acetate and 0.1% acetic acid were applied. The limit of detection and quantification were 0.02 mg/L and 0.06 mg/L appropriate. Other results of the validation experiments performed like linearity of the calibration range, accuracy and precision, processed sample stability, recovery, matrix effect and selectivity revealed that this propofol quantification strategy developed can be defined as an applicable alternative to other methods presented., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: In a previous study, the modified Marsh and Schnider models respectively showed negatively- and positively-biased predictions in underweight patients. To overcome this drawback, we developed a new pharmacokinetic propofol model-the Choi model-for use in underweight patients. In the present study, we evaluated the predictive performance of the Choi model., Methods: Twenty underweight patients undergoing elective surgery received propofol via TCI using the Choi model. The target effect-site concentrations (Ces) of propofol were 2.5, 3, 3.5, 4, 4.5, and 2 μg/mL. Arterial blood samples were obtained at least 10 minutes after achieving pseudo-steady-state. Predicted propofol concentrations with the modified Marsh, Schnider, and Eleveld pharmacokinetic models were obtained by simulation (Asan pump, version 2.1.3; Bionet Co. Ltd., Seoul, Korea). The predictive performance of each model was assessed by calculation of four parameters: inaccuracy, divergence, bias, and wobble., Results: A total of 119 plasma samples were used to determine the predictive performance of the Choi model. Our evaluation showed that the pooled median (95% CI) bias and inaccuracy were 4.0 (-4.2 to 12.2) and 23.9 (17.6-30.3), respectively. The pooled biases and inaccuracies of the modified Marsh, Schnider, and Eleveld models were clinically acceptable. However, the modified Marsh and Eleveld models consistently produced negatively biased predictions in underweight patients. In particular, the Schnider model showed greater inaccuracy at a target Ce ≥ 3 µg/mL., Conclusion: The new propofol pharmacokinetic model (the Choi model) developed for underweight patient showed adequate performance for clinical use., (© 2019 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Background: Propofol and remifentanil are commonly combined during total intravenous anesthesia. The impact of remifentanil in this relationship is poorly quantified in children. Derivation of an integrated pharmacokinetic and pharmacodynamic propofol model, containing remifentanil pharmacodynamic interaction information, enables propofol effect-site target-controlled infusion in children with a better prediction of its hypnotic effect when both drugs are combined., Aims: We designed this study to derive an integrated propofol pharmacokinetic-pharmacodynamic model in children and to describe the pharmacodynamic interaction between propofol and remifentanil on the electroencephalographic bispectral index effect., Methods: Thirty children (mean age: 5.45 years, range 1.3-11.9; mean weight: 23.5 kg, range 8.5-61) scheduled for elective surgery with general anesthesia were studied. After sevoflurane induction, maintenance of anesthesia was based on propofol and remifentanil. Blood samples to measure propofol concentration were collected during anesthesia maintenance and up to 6 hours in the postoperative period. Bispectral index data were continuously recorded throughout the study. A pharmacokinetic-pharmacodynamic model was developed using population modeling. The Greco model was used to examine the pharmacokinetic-pharmacodynamic interaction between propofol and remifentanil for BIS response RESULTS: Propofol pharmacokinetic data from a previous study in 53 children were pooled with current data and simultaneously analyzed. Propofol pharmacokinetics were adequately described by a three-compartment distribution model with first-order elimination. Theory-based allometric relationships based on TBW improved the model fit. The Greco model supported an additive interaction between propofol and remifentanil. Remifentanil showed only a minor effect in BIS response., Conclusion: We have developed an integrated propofol pharmacokinetic-pharmacodynamic model that can describe the pharmacodynamic interaction between propofol and remifentanil for BIS response. An additive interaction was supported by our modeling analysis., (© 2018 John Wiley & Sons Ltd.)

The low water solubility of Propofol resulted in complicated formulation and adverse effects during its clinical application. To improve its water solubility and maintain its anesthetic effects, Propofol prodrugs with monodisperse oligoethylene glycols as solubility enhancer were designed and synthesized. Monodisperse oligoethylene glycols enable the concise manipulation of water solubility, biocompatibility and anesthetic effects. Through the physicochemical and biological assay, a few water soluble prodrugs of Propofol were identified as promising anesthetic to overcome the drawbacks associated with Propofol., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

BACKGROUND Effects of liver dysfunction on target-controlled infusion (TCI) with Marsh parameters of propofol remain poorly documented. The purpose of this study was to evaluate the performance of propofol TCI in a cohort of Chinese patients with severe hepatic insufficiency. MATERIAL AND METHODS We assigned 32 patients who underwent liver transplantation to 3 groups according to Child-Turcotte-Pugh (CTP) score. Anesthesia, preceding liver transplantation, was induced and maintained with TCI of 3 µg/mL propofol. Plasma propofol concentration was assessed. Propofol TCI system performance was analyzed in terms of error size, bias, and divergence. Data on plasma propofol concentrations were analyzed, and population pharmacokinetic parameters of propofol were fitted by NONMEM software. RESULTS In the CTP C group, measured concentrations of propofol were much higher than those of predictive concentrations, with significantly higher overshoots compared to CTP A patients. Overall, TCI system performance was significantly lower in CTP C patients. Linear regression equations of Cm vs. Cp and a regression model of pharmacokinetics were obtained. CONCLUSIONS Propofol TCI device performance with Marsh parameters was clinically acceptable in CTP A patients but may not be suitable for patients with severe hepatic impairment.

The relationships between propofol plasma concentrations and the pharmacodynamic endpoints may differ according to a type of airway device. To clarify these relationships in different airway devices would be useful to avoid the complication such as apnea and intraoperative awareness. The aim of this study was to investigate the influence of difference of airway device on propofol requirement during maintenance of anesthesia in dogs. We compared the influence of airway devices on the plasma propofol concentrations for apnea, response to mechanical ventilation, and response to airway device between endotracheal tube (ETT) and supraglottic airway device (SGAD) in Beagles. The pharmacodynamic effects were repeatedly assessed at varying propofol concentrations. The plasma concentrations (mean ± SD) of propofol in the ETT and SGAD groups were 10.2 ± 1.8 and 10.9 ± 2.4 µg/ml for apnea (P=0.438), 7.9 ± 1.2 and 7.4 ± 1.5 µg/ml for response to mechanical ventilation (P=0.268), and 5.2 ± 0.7 and 5.4 ± 1.5 µg/ml for response to airway device (P=0.580), respectively. Required propofol concentration during maintenance of anesthesia may be similar between ETT and SGAD. Without moderate to strong stimuli such as airway device insertion or painful stimulation during surgery, the type of airway device may have little impact on required propofol concentration during maintenance of anesthesia in dogs.

Background: The modified Marsh and Schnider pharmacokinetic models for propofol consistently produce negatively and positively biased predictions in underweight patients, respectively. We aimed to develop a new pharmacokinetic model of propofol in underweight patients., Methods: Twenty underweight (BMI<18.5 kg m -2 ) patients aged 20-68 yr were given an i.v. bolus of propofol (2 mg kg -1 ) for induction of anaesthesia. Anaesthesia was maintained with a zero-order infusion (8 mg kg -1 h -1 ) of propofol and target-controlled infusion of remifentanil. Arterial blood was sampled at preset intervals. A population pharmacokinetic analysis was performed using non-linear mixed effects modelling. The time to peak effect (t peak , maximally reduced bispectral index) was measured in 28 additional underweight patients receiving propofol 2 mg kg -1 ., Results: In total, 455 plasma concentration measurements from the 20 patients were used to characterise the pharmacokinetics of propofol. A three-compartment mammillary model well described the propofol concentration time course. BMI and lean body mass (LBM) calculated using the Janmahasatian formula were significant covariates for the rapid peripheral volume of distribution and for the clearance of the final pharmacokinetic model of propofol, respectively. The parameter estimates were as follows: V 1 (L)=2.02, V 2 (L)=12.9 (BMI/18.5) , V 3 (L)=139, Cl (L⋅min -1 )=1.66 (LBM/40) , Q 1 (L⋅min -1 )=1.44, Q 2 (L⋅min -1 )=0.87+0.0189×(LBM-40). The median t peak of propofol was 1.32 min (n=48)., Conclusions: A three-compartment mammillary model can be used to administer propofol via target effect-site concentration-controlled infusion of propofol in underweight patients., Clinical Trial Registration: KCT0001760., (Copyright © 2018 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Background: Different levels of consciousness are required in order to perform different medical procedures. Sedation scales established to objectively define various levels of sedation in humans have not been thoroughly characterized in non-human species. Postural changes in rats or dogs are useful as gross measures of sedation but are inadequate for quantitative assessment since graded levels of sedation are difficult to delineate and obscured by movement abnormalities., New Method: A new canine sedation scoring (CSS) method was developed based on the modified observer's assessment of alertness and sedation score (MOAA/S) used in humans. The method employed a combination of physical, auditory and somatosensory stimuli of increasing intensity. Cardiovascular, respiratory, and a neurophysiological measure of sedation (bispectral index: BIS) data were recorded. Validation studies were performed following intravenous loading and constant rate infusion of propofol or a novel synthetic neuroactive steroid (SGE-746)., Results: Four levels of consciousness were identified: 1) Awake, 2) Moderate Sedation (MS), 3) Deep Sedation (DS) and 4) General Anesthesia (GA). Cardiorespiratory measurements obtained after bolus administration of propofol and SGE-746 and at the end of each CRI remained within normal limits. Canine sedation scores correlated with BIS for SGE-746. SGE-746 exhibited a more gradual exposure-response relationship than propofol. Larger increases in the plasma concentration from awake values were required to achieve different levels of sedation with SGE-746 compared to propofol., Comparison With Existing Methods: No other canine sedation scoring methods are widely accepted., Conclusion: A CSS method, based on the human MOAA/S scale defined four levels of consciousness in dogs and provided better resolution of sedation depth than BIS alone., (Copyright © 2018 Elsevier B.V. All rights reserved.)

A man was found dead in a hotel located near Rome (Italy). The man was still holding a syringe attached to a butterfly needle inserted in his left forearm vein. The syringe contained a cloudy pinkish fluid. In the hotel room the Police found a broken propofol glass vial plus four sealed ones, an opened NaCl plastic vial and six more still sealed, and a number of packed smaller disposable syringes and needles. An opened plastic bottle containing a white crystalline powder labeled as potassium cyanide was also found. Systematic toxicological analysis (STA), carried out on blood, urine and bile, evidenced only the presence of propofol in blood and bile. So the validated L-L extraction protocol and the GC/MS-TOF method for the confirmation of propofol in the biological fluids optimized in our laboratory was applied to blood, urine and bile. The concentration of propofol resulted to be 0.432 μg/mL in blood and 0.786 μg/mL in bile. The quantitative determination of cyanide in blood was carried out by microdiffusion technique coupled to spectrophotometric detection obtaining a cyanide concentration of 5.3 μg/mL. The quantitative determination was then confirmed by GC/NPD and the concentration of cyanide resulted to be 5.5 μg/mL in blood and 1.7 μg/mL in bile. Data emerging from autopsy findings, histopathological exams and the concentrations of cyanide suggested that death might be due to poisoning caused by cyanide, however, respiratory depression caused by propofol could not be excluded.

Objective: To test the hypothesis that plasma propofol concentration (PPC) is associated with anesthetic effect in koi carp administered propofol by immersion., Study Design: Prospective study., Animals: Twenty mature koi carp (mean ± standard deviation, 409.4 ± 83.7 g)., Methods: Fish were immersed in propofol (5 mg L -1 ). Physiological variables and induction and recovery times were recorded. In phase I, blood was sampled for PPC immediately following induction and at recovery. In phase II, following induction, fish were maintained with propofol (4 mg L -1 ) via a recirculating system for 20 minutes. Following established induction, blood was sampled at 1, 10 and 20 minutes. In phase III (n = 19), fish were anesthetized as in phase II with blood sampled nine times in a sparse sampling strategy. Simultaneously, a pharmacodynamics rubric was used to evaluate anesthetic depth. PPC was determined using high performance liquid chromatography with fluorescence detection. Following evaluation of normality, data were analyzed using paired t test or Spearman correlation test (significance was set at p < 0.05)., Results: In phase I, mean PPCs at induction (20.12 μg mL -1 ) and recovery (11.62 μg mL -1 ) were different (p < 0.001). In phase II, only mean PPCs at induction (17.92 μg mL -1 ) and 10 minutes (21.50 μg mL -1 ) were different (p = 0.013). In phase III, a correlation between PPCs and the pharmacodynamic rubric scores was found (p < 0.001, r = -0.93). There was no correlation between PPCs and recovery time (p = 0.057, r = 0.433). A two-compartment open model was chosen for the pharmacokinetic model. Absorption rate constant, elimination rate constant and intercompartmental rate constant were 0.48, 0.006 and 0.02 minute -1 , respectively., Conclusions and Clinical Relevance: Measurable PPCs were achieved in koi carp anesthetized with propofol by immersion. Anesthetic depth of fish was negatively correlated with PPCs, but recovery time was not., (Copyright © 2018 Association of Veterinary Anaesthetists and American College of Veterinary Anesthesia and Analgesia. Published by Elsevier Ltd. All rights reserved.)

Background: Differentiating drug-related changes and state-related changes on the electroencephalogram during anesthetic-induced unconsciousness has remained a challenge. To distinguish these, we designed a rigorous experimental protocol with two drugs known to have distinct molecular mechanisms of action. We hypothesized that drug- and state-related changes can be separated., Methods: Forty-seven healthy participants were randomized to receive dexmedetomidine (n = 23) or propofol (n = 24) as target-controlled infusions until loss of responsiveness. Then, an attempt was made to arouse the participant to regain responsiveness while keeping the drug infusion constant. Finally, the concentration was increased 1.5-fold to achieve presumable loss of consciousness. We conducted statistical comparisons between the drugs and different states of consciousness for spectral bandwidths, and observed how drug-induced electroencephalogram patterns reversed upon awakening. Cross-frequency coupling was also analyzed between slow-wave phase and alpha power., Results: Eighteen (78%) and 10 (42%) subjects were arousable during the constant drug infusion in the dexmedetomidine and propofol groups, respectively (P = 0.011 between the drugs). Corresponding with deepening anesthetic level, slow-wave power increased, and a state-dependent alpha anteriorization was detected with both drugs, especially with propofol. The slow-wave and frontal alpha activities were momentarily disrupted as the subjects regained responsiveness at awakening. Negative phase-amplitude coupling before and during loss of responsiveness frontally and positive coupling during the highest drug concentration posteriorly were observed in the propofol but not in the dexmedetomidine group., Conclusions: Electroencephalogram effects of dexmedetomidine and propofol are strongly drug- and state-dependent. Changes in slow-wave and alpha activity seemed to best detect different states of consciousness.

The proposed method describes a high performance liquid chromatographic method with fluoremetric detection for the determination of cisatracurium (CIS) and propofol (PRP) simultaneously, which are co-administered as a pre-operative injection mixture. The separation of the two drugs was achieved using monolithic column (100 mm and 4.6 mm internal diameter) and mixture of methanol and 0.1 M phosphate buffer in the ratio of 80:20 (v/v) at pH 4.5 as a mobile phase. The fluorescence detection was carried out at 230/324 nm. The procedure showed good linearity through the concentration ranges of 0.01-1.00 μg/mL and 0.1-3.0 μg/mL with limits of detection of 0.002, 0.030 μg/mL and limits of quantification of 0.006, 0.100 μg/mL for CIS and PRP, respectively. Simultaneous determination of CIS and PRP in spiked human plasma samples was additionally executed and the results were satisfactory precise and accurate.

Background: Use of donor blood in congenital cardiac surgery increases the risk for post-operative morbidity and mortality. To reduce the need for allogenic blood transfusion a technique for peri-operative mechanical red cell salvage is applied. Blood from the operation site is collected in a reservoir, processed, passed through a lipophilic filter and returned to the patient. Influence of this cellsaver system on coagulation, fibrinolysis and inflammatory markers is known. To our knowledge no studies have been performed on the effects of autotransfusion on drug concentrations. A clinically relevant drug dose could potentially be returned to the patient through the auto-transfused blood, leading to unwanted drug reactions post-operatively. We aimed to measure drug concentrations in blood salvaged from the operation site and in the auto-transfused blood to determine if a clinically relevant drug dose is returned to the patient., Methods: The study was performed at the Department of Cardiothoracic Surgery of a tertiary university hospital. Blood samples were taken from the reservoir, after processing before the lipophilic filter, the auto-transfused blood, and the waste fluid. Samples were stored at - 80 C and drug concentration for sufentanil, propofol, midazolam and cefazolin were measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Drug concentrations measured in the reservoir and the auto-transfused blood were compared and the relative reduction was calculated for each patient., Results: Blood samples were taken from 18 cellsaver runs in 18 patients, age 0-13 years. Drug concentrations in the reservoir were comparable to concomitant concentrations in the patient. For sufentanil 34% (median, IQR 27-50) of drug concentration was retained from the reservoir in the auto-transfused blood, for midazolam 6% (median, IQR 4-10), for cefazolin 5% (median, IQR 2-6) and for propofol 0% (median, IQR 0-0) respectively., Conclusion: Depending on the drug, up to 34% of the drug concentration salvaged from the operation site is returned to the patient through autotransfusion, potentially causing unwanted drug reactions post-operatively. Additionally, influence of a cellsaver system should be considered in pharmacological research during and after congenital cardiac surgery and could result in dose adjustments in the postoperative phase., Trial Registration: Registration at the Dutch Trial Registry ( NTR3579 ) at August 14 2012.

Transcranial motor evoked potentials (TcMEPs) monitor the integrity of the spinal cord during spine surgery. Propofol-based anesthesia is favored in order to enhance TcMEP quality. During intraoperative hemorrhage, TcMEP amplitudes may be reduced. The serum concentration of propofol may increase during hemorrhage. No study has determined whether changes in TcMEPs due to hemorrhage are related to changes in propofol blood levels. We monitored TcMEPs, mean arterial pressure (MAP), and cardiac output (CO) and hemoglobin in pigs (n = 6) undergoing controlled progressive hemorrhage during a standardized anesthetic with infusions of propofol, ketamine, and fentanyl. We recorded TcMEPs from the rectus femoris (RF) and tibialis anterior (TA) muscles bilaterally. A pulmonary artery catheter was placed to measure CO. Progressive hemorrhage of 10% blood volume increments was done until TcMEP amplitude decreased by >60% from baseline. Serum propofol levels were also measured following removal of each 10% blood volume increment. TcMEP responses were elicited every 3 min using constant stimulation parameters. We removed between 20 and 50% of total blood volume in order to achieve the >60% reduction in TcMEP amplitude. MAP and CO decreased significantly from baseline. At maximum hemorrhage, TcMEP amplitude decreased in the RF and TA by an average of 73 and 62% respectively from baseline (P < 0.01). Serum propofol levels varied greatly among animals at baseline (range 410-1720 ng/mL) and increased in each animal during hemorrhage. The mean propofol concentration rose from 1190 ± 530 to 2483 ± 968 ng/mL (P < 0.01). The increased propofol concentration correlated with decreased CO. Multivariate analysis using hierarchical linear models indicated that the decline of TcMEP amplitude was primarily associated with rising propofol concentrations, but was also independently affected by reduced CO. We believe that the decrease in blood volume and CO during hemorrhage increased the serum concentration of propofol by reducing the volume of distribution and/or rate of hepatic metabolism of the drug. Despite wide acceptance of propofol as the preferred anesthetic when using TcMEPs, intravenous anesthetics are vulnerable to altered pharmacokinetics during conditions of hemorrhage and could contribute to false-positive TcMEP changes.

Purpose: Propofol is one of the most widely used fast-acting intravenously administered anesthetics. However, although large inter-individual differences in dose requirements and recovery time have been observed, there are few previous studies in which the association between several potential covariates, including genetic factors such as the UGT1A9 and CYP2B6 genotypes, and propofol pharmacokinetics was simultaneously examined. This study aimed to identify factors determining propofol pharmacokinetics., Methods: Eighty-three patients were enrolled, and their blood samples were collected 1, 5, 10, and 15 min after administering a single intravenous bolus of propofol at a dose of 2.0 ml/kg to measure propofol plasma concentration. Area under the time-plasma concentration curve from zero up to the last measurable time point (AUC 15min ) was determined from the concentration data. The inter-individual variability of the propofol pharmacokinetics was evaluated by investigating relationships between AUC 15min and genotype of UGT1A9 and CYP2B6; clinical factors, such as age, sex, body mass index (BMI), and preoperative hematological examination; and hemodynamic variables measured by a pulse dye densitogram analyzer. The Spearman rank correlation coefficient and the Mann-Whitney U test were used for the statistical analysis of continuous and categorical values, respectively. Subsequently, clinical factors that had p values of < 0.05 in the univariate analysis were examined in a multivariate analysis using multiple linear regression analysis., Results: Age, BMI, indocyanine green disappearance ratio (K-ICG), hepatic blood flow (HBF), preoperative hemoglobin level, and sex were correlated with AUC 15min (p < 0.05) in univariate analysis. Multivariate analysis performed to adjust for age, BMI, K-ICG, HBF, preoperative hemoglobin level, and sex revealed only BMI as an independent factor associated with AUC 15min ., Conclusions: This study demonstrated that BMI influences propofol pharmacokinetics after its administration as a single intravenous injection, while UGT1A9 and CYP2B6 SNPs, other clinical factors, and hemodynamic variables do not. These results suggest that BMI is an independent factor associated with propofol pharmacokinetics in several potential covariates., Clinical Trials Registration Number: University Hospital Medical Information Network (UMIN000022948).

Propofol concentration in human plasma can be quantified by liquid chromatography coupled mass spectrometry. Sample preparation usually requires solid phase extraction to remove matrix components and enrich the analyte. To facilitate user-independent measurements and speed extraction, we developed and validated a fully automated high throughput in-line sample preparation system with direct injection into liquid chromatography coupled mass spectrometry. We assessed linearity of each method over the clinically relevant concentration range from 0.5μg/mL to 8μg/mL plasma concentration. R 2 values were 0.99 for the automated process and 0.98 for manual sample preparation. The limit of detection was 6ng/mL and the lower limit of quantification was 18ng/mL for the automated method; for the manual process, the limit of detection was 1.58ng/mL and the lower limit of quantification was 4.79ng/mL. Intra-day precision for low, medium and high concentration range of the automated method was validated 4.14%, 9.68% and 3.04% relative standard deviation and 0.29%, 0.12% and 0.52% for the manual process. Carry over was 0.4% with the automated method, whereas there was no carry over with the manual method. Stability of plasma samples was tested with the manual method at concentrations of 1, 4, and 6μg/mL propofol and found to be stable over 150days at -20°C. The manual sample preparation method has successfully been transferred to a fully automated process with appropriate sensitivity and precision but the automatization failed with regard to trueness and working time due to lengthy sample preparation runtime. Therefore it is not suitable for daily use in a hospital laboratory e.g. for brain death diagnosis in the intensive care unit., (Copyright © 2017 Elsevier B.V. All rights reserved.)

It is commonly assumed that loss of responsiveness and recovery of responsiveness occur at similar concentrations of propofol. However, the 'conscious' and 'anaesthetised' conditions produced by general anaesthetics may behave as two bistable states. We hypothesised that loss of responsiveness and recovery of responsiveness occur at different propofol concentrations. Propofol was administered to 19 healthy volunteers by effect-site target-controlled infusion using increasing and decreasing stable concentration steps of 7 min. Propofol serum concentrations were measured from venous blood samples at the end of each 7-min step. A long step of 14 min was performed at loss of responsiveness. At this step, propofol concentrations were measured at 7 and 14 min. Propofol concentrations measured at loss of responsiveness and recovery of responsiveness were 2.6 (1.2-4.7) μg.ml -1 and 1.6 (0.6-3.3) μg.ml -1 , respectively (p < 0.001). Propofol plasma concentration and the corresponding bispectral index values measured at minute 7 and minute 14 of the long step performed at loss of responsiveness were 2.6 (1.2-4.7) vs. 2.6 (1.3-4.3) at recovery of responsiveness, (p = 0.96) and 61.2 (49.0-77.0) vs. 58.4 (45.0-74.0), (p = 0.058), respectively. Loss of responsiveness and recovery of responsiveness appear to occur at different propofol concentrations. However, it is possible that, if equilibration was not achieved between plasma and effect-sites at the end of each 7-min step, the higher concentrations found at loss of responsiveness compared with those observed during recovery of responsiveness could be explained by a possible bias in estimations of the effect-site concentrations of propofol by the Schnider model, rather than neural inertia., (© 2017 The Association of Anaesthetists of Great Britain and Ireland.)

Background: During awake craniotomy, the patient's language centers are identified by neurological testing requiring a fully awake and cooperative patient. Hence, anesthesia aims for an unconscious patient at the beginning and end of surgery but an awake and responsive patient in between. We investigated the plasma (Cplasma) and effect-site (Ceffect-site) propofol concentration as well as the related Bispectral Index (BIS) required for intraoperative return of consciousness and begin of neurological testing., Materials and Methods: In 13 patients, arterial Cplasma were measured by high-pressure liquid chromatography and Ceffect-site was estimated based on the Marsh and Schnider pharmacokinetic/dynamic (pk/pd) models. The BIS, Cplasma and Ceffect-site were compared during the intraoperative awakening period at designated time points such as return of consciousness and start of the Boston Naming Test (neurological test)., Results: Return of consciousness occurred at a BIS of 77±7 (mean±SD) and a measured Cplasma of 1.2±0.4 μg/mL. The Marsh model predicted a significantly (P<0.001) higher Cplasma of 1.9±0.4 µg/mL as compared with the Schnider model (Cplasma=1.4±0.4 µg/mL) at return of consciousness. Neurological testing was possible as soon as the BIS had increased to 92±6 and measured Cplasma had decreased to 0.8±0.3 µg/mL. This translated into a time delay of 23±12 minutes between return of consciousness and begin of neurological testing. At begin of neurological testing, Cplasma according to Marsh (Cplasma=1.3±0.5 µg/mL) was significantly (P=0.002) higher as compared with the Schnider model (Cplasma=1.0±0.4 µg/mL)., Conclusions: To perform intraoperative neurological testing, patients are required to be fully awake with plasma propofol concentrations as low as 0.8 µg/mL. Following our clinical setup, the Schnider pk/pd model estimates propofol concentrations significantly more accurate as compared with the Marsh model at this neurologically crucial time point.

Objectives: The objective of this study was to apply a pharmacokinetics-pharmacodynamics approach to investigate the free propofol plasma levels in patients undergoing coronary artery bypass grafting under hypothermic conditions compared with the off-pump procedure., Methods: Nineteen patients scheduled for on-pump coronary artery bypass grafting under hypothermic conditions (n=10) or the equivalent off-pump surgery (n=9) were anesthetized with sufentanil and propofol target-controlled infusion (2 μg/mL) during surgery. The propofol concentration was then reduced to 1 μg/mL, and a pharmacokinetics-pharmacodynamics analysis using the maximum-effect-sigmoid model obtained by plotting the bispectral index values against the free propofol plasma levels was performed., Results: Significant increases (two- to five-fold) in the free propofol plasma levels were observed in the patients subjected to coronary artery bypass grafting under hypothermic conditions. The pharmacokinetics of propofol varied according to the free drug levels in the hypothermic on-pump group versus the off-pump group. After hypothermic coronary artery bypass was initiated, the distribution volume increased, and the distribution half-life was prolonged. Propofol target-controlled infusion was discontinued when orotracheal extubation was indicated, and the time to patient extubation was significantly higher in the hypothermic on-pump group than in the off-pump group (459 versus 273 min, p=0.0048)., Conclusions: The orotracheal intubation time was significantly longer in the hypothermic on-pump group than in the off-pump group. Additionally, residual hypnosis was identified through the pharmacokinetics-pharmacodynamics approach based on decreases in drug plasma protein binding in the hypothermic on-pump group, which could explain the increased hypnosis observed with this drug in this group of patients.

Two cases of suspected acute and lethal intoxication caused by propofol were delivered by the judicial authority to the Department of Sciences for Health Promotion and Mother-Child Care in Palermo, Sicily. In the first case a female nurse was found in a hotel room, where she lived with her mother; four 10 mg/mL vials and two 20 mg/mL vials of propofol were found near the decedent along with syringes and needles. In the second case a male nurse was found in the operating room of a hospital, along with a used syringe. In both cases a preliminary systematic and toxicological analysis indicated the presence of propofol in the blood and urine. As a result, a method for the quantitative determination of propofol in biological fluids was optimized and validated using a liquid-liquid extraction protocol followed by GC/MS and fast GC/MS-TOF. In the first case, the concentration of propofol in blood was determined to be 8.1 μg/mL while the concentration of propofol in the second case was calculated at 1.2 μg/mL. Additionally, the tissue distribution of propofol was determined for both cases. Brain and liver concentrations of propofol were, respectively, 31.1 and 52.2 μg/g in Case 1 and 4.7 and 49.1 μg/g in Case 2. Data emerging from the autopsy findings, histopathological exams as well as the toxicological results aided in establishing that the deaths were due to poisoning, however, the manner of death in each were different: homicide in Case 1 and suicide in Case 2., (© The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Target controlled infusion (TCI) systems use population-based pharmacokinetic (PK) models that do not take into account inter-individual residual variation. This study compares the bias and inaccuracy of a population-based vs a personalized TCI propofol titration using Bayesian adaptation. Haemodynamic and hypnotic stability, and the prediction probability of alternative PK models, was studied., Methods: A double-blinded, prospective randomized controlled trial of 120 subjects undergoing cardiac surgery was conducted. Blood samples were obtained at 10, 35, 50, 65, 75 and 120 min and analysed using a point-of-care propofol blood analyser. Bayesian adaptation of the PK model was applied at 60 min in the intervention group. Median (Absolute) Performance Error (Md(A)PE) was used to evaluate the difference between bias and inaccuracy of the models. Haemodynamic (mean arterial pressure [MAP], heart rate) and hypnotic (bispectral index [BIS]) stability was studied. The predictive performance of four alternative propofol PK models was studied., Results: MdPE and MdAPE did not differ between groups during the pre-adjustment period (control group: 6.3% and 16%; intervention group: 5.4% and 18%). MdPE differed in the post-adjustment period (12% vs. -0.3%), but MdAPE did not (18% vs. 15%). No difference in heart rate, MAP or BIS was found. Compared with the other models, the Eleveld propofol PK model (patients) showed the best prediction performance., Conclusions: When an accurate population-based PK model was used for propofol TCI, Bayesian adaption of the model improved bias but not precision., Clinical Trial Registration: Dutch Trial Registry NTR4518., (© The Author 2017. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com)

Objective: To determine the effect of dexmedetomidine on induction dose and minimum infusion rate of propofol preventing movement (MIR NM )., Study Design: Randomized crossover, unmasked, experimental design., Animals: Three male and three female healthy Beagle dogs weighing 10.2 ± 2.8 kg., Methods: Dogs were studied on three occasions at weekly intervals. Premedications were 0.9% saline (treatment P) or dexmedetomidine (1 μg kg -1 , treatment PLD; 2 μg kg -1 , treatment PHD) intravenously. Anesthesia was induced with propofol (2 mg kg -1 and then 1 mg kg -1 every 15 seconds) until intubation. Anesthesia was maintained for 90 minutes in P with propofol (0.5 mg kg -1 minute -1 ) and saline, in PLD with propofol (0.35 mg kg -1 minute -1 ) and dexmedetomidine (1 μg kg -1 hour -1 ), and in PHD with propofol (0.3 mg kg -1 minute -1 ) and dexmedetomidine (2 μg kg -1 hour -1 ). The stimulus (50 V, 50 Hz, 10 ms) was applied to the antebrachium, and propofol infusion was increased or decreased by 0.025 mg kg -1 minute -1 based on a positive or negative response, respectively. Data were analyzed using a mixed-model anova and presented as mean ± standard error., Results: Propofol induction doses were 8.68 ± 0.57 (P), 6.13 ± 0.67 (PLD) and 4.78 ± 0.39 (PHD) mg kg -1 and differed among treatments (p < 0.05). Propofol MIR NM values were 0.68 ± 0.13, 0.49 ± 0.16 and 0.26 ± 0.05 mg kg -1 minute -1 for P, PLD and PHD, respectively. Propofol MIR NM decreased 59% in PHD (p < 0.05). Plasma propofol concentrations were 14.04 ± 2.30 (P), 11.30 ± 4.30 (PLD) and 7.96 ± 0.72 (PHD) μg mL -1 and dexmedetomidine concentrations were 0.68 ± 0.12 (PLD) and 0.89 ± 0.08 (PHD) ng mL -1 at MIR NM determination., Conclusions and Clinical Relevance: Dexmedetomidine (1 and 2 μg kg -1 ) decreased propofol induction dose. Dexmedetomidine (2 μg kg -1 hour -1 ) resulted in a significant decrease in propofol MIR NM ., (Published by Elsevier Ltd.)