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Background: Recommendations exist that aim to mitigate the substantial ecological impact of anaesthesia. One option is to use anaesthetic gas capturing technology at anaesthesia workstation exhausts to harvest and recycle volatile agents. However, the efficiency of such technology is mainly unverified in vivo., Methods: The efficiency of CONTRAfluran™ in capturing sevoflurane from an anaesthesia workstation exhaust (when set to minimal flow and end-tidal control mode) was evaluated in 70 adult patients scheduled for general or bariatric laparoscopic surgery. The weight of the sevoflurane vaporiser and CONTRAfluran canister was measured before and after each case, to calculate total sevoflurane consumption and retention. Retention was measured after the minimal flow maintenance phase and after the high flow washout phase. The total retention efficiency was the fraction of all consumed sevoflurane captured by the CONTRAfluran canister. The primary objective was to examine the retention efficiency of CONTRAfluran in a clinical surgical setting, where all feasible strategies to minimise sevoflurane consumption and optimise the efficacy of CONTRAfluran were utilised. The secondary objective was to analyse the correlation between mass transfer and the duration of the case., Results: Mean (SD) volume of sevoflurane captured using CONTRAfluran was 4.82 (1.41) ml, representing 45% (95%CI 42-48%) of all sevoflurane administered. The highest amount of retention was found during the washout phase. Retention efficiency did not correlate with the duration of the case., Conclusions: Over half of the sevoflurane administered was not captured by the CONTRAfluran canister when minimal flow techniques were used, likely due to residual accumulation of sevoflurane in the patient after tracheal extubation or, to a lesser extent, due to ventilation system leakage. However, as every prevented emission is commendable, CONTRAfluran may be a potentially valuable tool for reducing the environmental footprint of sevoflurane-based anaesthesia., (© 2024 Association of Anaesthetists.)

Post-induction hypotension (MAP < 65 mmHg) occurs frequently and is usually caused by the cardiovascular adverse effects of the anaesthetic induction drugs used. We hypothesize that a clinically significant difference in the incidence and severity of hypotension will be found when different doses of propofol and remifentanil are used for induction of anaesthesia., Methods: This is a secondary analysis of a randomised controlled trial wherein four groups (A-D) of patients received one out of four different combinations of propofol and remifentanil, titrated to a predicted equipotency in probability of tolerance to laryngoscopy (PTOL) according to the Bouillon interaction model. In group A, a high dose of propofol and a low dose of remifentanil was administered, and across the groups this ratio was gradually changed until it was reversed in group D. Mean and systolic arterial blood pressure (MAP, SAP) were compared at four time points (T baseline , T post-bolus , T 3min , T nadir ) within and between groups Heart rate, bispectral index (BIS) and the incidence of hypotension were compared., Results: Data from 76 patients was used. At T post-bolus a statistically significant lower MAP and SAP was found in group A versus D (p = 0.011 and p = 0.002). A significant higher heart rate was found at T 3min and T nadir between groups A and B when compared to groups C and D (p = < 0.001 and p = 0.002). A significant difference in BIS value was found over all groups at T 3min and T nadir (both p < 0.001). All other outcomes did not differ significantly between groups., Conclusion: Induction of anaesthesia with different predicted equipotent combinations of propofol and remifentanil did result in statistically different but clinically irrelevant differences in haemodynamic endpoints during induction of anaesthesia. Our study could not identify preferable drug combinations that decrease the risk for hypotension after induction, although they all yield a similar predicted PTOL., (© 2024. The Author(s).)

Background: Sedatives are commonly used to promote sleep in intensive care unit patients. However, it is not clear whether sedation-induced states are similar to the biological sleep. We explored if sedative-induced states resemble biological sleep using multichannel electroencephalogram (EEG) recordings., Methods: Multichannel EEG datasets from two different sources were used in this study: (1) sedation dataset consisting of 102 healthy volunteers receiving propofol (N = 36), sevoflurane (N = 36), or dexmedetomidine (N = 30), and (2) publicly available sleep EEG dataset (N = 994). Forty-four quantitative time, frequency and entropy features were extracted from EEG recordings and were used to train the machine learning algorithms on sleep dataset to predict sleep stages in the sedation dataset. The predicted sleep states were then compared with the Modified Observer's Assessment of Alertness/ Sedation (MOAA/S) scores., Results: The performance of the model was poor (AUC = 0.55-0.58) in differentiating sleep stages during propofol and sevoflurane sedation. In the case of dexmedetomidine, the AUC of the model increased in a sedation-dependent manner with NREM stages 2 and 3 highly correlating with deep sedation state reaching an AUC of 0.80., Conclusions: We addressed an important clinical question to identify biological sleep promoting sedatives using EEG signals. We demonstrate that propofol and sevoflurane do not promote EEG patterns resembling natural sleep while dexmedetomidine promotes states resembling NREM stages 2 and 3 sleep, based on current sleep staging standards., Competing Interests: M. M. R. F. Struys: His research group/department received (over the last 3 years) research grants and consultancy fees from Masimo (Irvine, CA, USA), Becton Dickinson (Eysins, Switzerland), Fresenius (Bad Homburg, Germany), Paion (Aachen, Germany), Medcaptain Europe (Andelst, The Netherlands), Baxter (Chicago, Il, USA), HanaPharm (Seoul, Republic of Korea). He receives royalties on intellectual property from Demed Medical (Sinaai, Belgium) and the Ghent University (Gent, Belgium). This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2024 Ramaswamy et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Early restoration of normal physiology when return of spontaneous circulation (ROSC) is obtained after an out-of-hospital cardiac arrest (OHCA) reduces the risk of developing post-cardiac arrest syndrome (PCAS). This study aims to investigate if (and to which extent) this can be achieved within the scope of practice of standard emergency medical services (EMS) crews., Methods: A prospective mixed-methods quantitative and qualitative cohort study was performed including adult patients with a non-traumatic OHCA presented to a university hospital emergency department (ED) in the Netherlands after pre-hospital ROSC was obtained. Primary endpoint was the percentage of patients with deranged physiology post-ROSC in whom EMS crews were able to reach recommended treatment targets., Results: During a 32-month period, 160 patients presenting with ROSC after OHCA were included. Median (IQR) pre-hospital treatment duration was 40 (34-51) minutes. When deranged physiology was present (n = 133), it could be restored by EMS crews in 29% of the patients. Although average etCO 2 and SpO 2 improved gradually over time during pre-hospital treatment, recommended treatment targets could not be achieved in respectively 55% (30/55) and 43% (20/46) of the patients. Similarly, airway problems (24/46, 52%), hypotension (20/23, 87%) and post-anoxic agitation (16/43, 37%) could often not be resolved by EMS crews. The ability to restore normal physiology by EMS could not be predicted based on patient characteristics or in-arrest variables., Conclusion: Deranged physiology after an OHCA is commonly encountered, and often difficult to treat within the scope of practice of regular EMS crews. Involvement of advanced critical care teams with a wider scope of practice at an early stage may contribute to a better outcome for these patients., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Author(s).)

This single blinded randomized controlled trial aims to assess whether the application of a Bayesian-adjusted Ce PROP (effect-site of propofol) advisory tool leads towards a more stringent control of the cerebral drug effect during anaesthesia, using qCON as control variable. 100 patients scheduled for elective surgery were included and randomized into a control or intervention group (1:1 ratio). In the intervention group the advisory screen was made available to the clinician, whereas it was blinded in the control group. The settings of the target-controlled infusion pumps could be adjusted at any time by the clinician. Cerebral drug effect was quantified using processed EEG (CONOX monitor, Fresenius Kabi, Bad Homburg, Germany). The time of qCON between the desired range (35-55) during anaesthesia maintenance was defined as our primary end point. Induction parameters and recovery times were considered secondary end points and coefficient of variance of qCON and Ce PROP was calculated in order to survey the extent of control towards the mean of the population. The desired range of qCON between 35 and 55 was maintained in 84% vs. 90% (p = 0.15) of the case time in the control versus intervention group, respectively. Secondary endpoints showed similar results in both groups. The coefficient of variation for Ce PROP was higher in the intervention group. The application of the Bayesian-based Ce PROP advisory system in this trial did not result in a different time of qCON between 35 and 55 (84 [21] vs. 90 [18] percent of the case time). Significant differences between groups were hard to establish, most likely due to a very high performance level in the control group. More extensive control efforts were found in the intervention group. We believe that this advisory tool could be a useful educational tool for novices to titrate propofol effect-site concentrations., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)

Remimazolam, a short-acting benzodiazepine, may be used for induction and maintenance of total intravenous anaesthesia, but its role in the management of patients with multiple comorbidities remains unclear. In this phase 3 randomised controlled trial, we compared the anaesthetic efficacy and the incidence of postinduction hypotension during total intravenous anaesthesia with remimazolam vs. propofol. A total of 365 patients (ASA physical status 3 or 4) scheduled for elective surgery were assigned randomly to receive total intravenous anaesthesia with remimazolam (n = 270) or propofol (n = 95). Primary outcome was anaesthetic effect, quantified as the percentage of time with Narcotrend® Index values ≤ 60, during surgery (skin incision to last skin suture), with a non-inferiority margin of -10%. Secondary outcome was the incidence of postinduction hypotensive events. Mean (SD) percentage of time with Narcotrend Index values ≤ 60 during surgery across all patients receiving remimazolam (93% (20.7)) was non-inferior to propofol (99% (4.2)), mean difference (97.5%CI) -6.28% (-8.89-infinite); p = 0.003. Mean (SD) number of postinduction hypotension events was 62 (38.1) and 71 (41.1) for patients allocated to the remimazolam and propofol groups, respectively; p = 0.015. Noradrenaline administration events (requirement for a bolus and/or infusion) were also lower in patients allocated to remimazolam compared with propofol (14 (13.5) vs. 20 (14.6), respectively; p < 0.001). In conclusion, in patients who were ASA physical status 3 or 4, the anaesthetic effect of remimazolam was non-inferior to propofol., (© 2024 The Authors. Anaesthesia published by John Wiley & Sons Ltd on behalf of Association of Anaesthetists.)

Volatile anesthetics have been shown in different studies to reduce ischemia reperfusion injury (IRI). Ex vivo lung perfusion (EVLP) facilitates graft evaluation, extends preservation time and potentially enables injury repair and improvement of lung quality. We hypothesized that ventilating lungs with sevoflurane during EVLP would reduce lung injury and improve lung function. We performed a pilot study to test this hypothesis in a slaughterhouse sheep DCD model. Lungs were harvested, flushed and stored on ice for 3 h, after which EVLP was performed for 4 h. Lungs were ventilated with either an FiO 2 of 0.4 (EVLP, n = 5) or FiO 2 of 0.4 plus sevoflurane at a 2% end-tidal concentration (C et ) (S-EVLP, n = 5). Perfusate, tissue samples and functional measurements were collected and analyzed. A steady state of the target C et sevoflurane was reached with measurable concentrations in perfusate. Lungs in the S-EVLP group showed significantly better dynamic lung compliance than those in the EVLP group ( p = 0.003). Oxygenation capacity was not different in treated lungs for delta partial oxygen pressure (PO 2 ; +3.8 (-4.9/11.1) vs. -11.7 (-12.0/-3.2) kPa, p = 0.151), but there was a trend of a better PO 2 /FiO 2 ratio ( p = 0.054). Perfusate ASAT levels in S-EVLP were significantly reduced compared to the control group (198.1 ± 93.66 vs. 223.9 ± 105.7 IU/L, p = 0.02). We conclude that ventilating lungs with sevoflurane during EVLP is feasible and could be useful to improve graft function.

Background: Remimazolam exhibits sedative properties by binding to γ-aminobutyric acid type A receptors. Remimazolam is administered as a bolus dose or continuous infusion, but has not been studied using target-controlled infusion (TCI). The study quantified the relationship between the remimazolam concentration, Modified Observer's Assessment of Alertness and Sedation (MOAAS) score, and bispectral index (BIS) using TCI., Methods: The authors performed a three-period, crossover, dose-ranging clinical trial in 24 healthy volunteers using age and sex stratification. Data collected in the first period, where remimazolam was administered alone using a step-up and step-down TCI protocol, were used for this analysis. Remimazolam concentrations, MOAAS scores, and BIS values were collected at each step at steady state. Data were analyzed using nonlinear mixed-effects modeling methodology., Results: The relationship between remimazolam, BIS, and MOAAS differed between step-up and step-down infusions at similar remimazolam target concentrations. Tolerance, driven by remimazolam or CNS7054, significantly improved overall model fit (P < 0.01) for both BIS and MOAAS models. After 30 min of repeated bolus dosing, mimicking the regimen in the label for procedural sedation, the BIS and probability of MOAAS 2/3 were predicted to be 54 (95% prediction interval, 44 to 67) and 2% (95% prediction interval, 0 to 32%) versus 58 (95% prediction interval, 48 to 70) and 8% (95% prediction interval, 0 to 36%) in a model without and with tolerance, respectively. After 60 min of continuous infusion, mimicking the regimen in the label for general anesthesia, the BIS and probability of MOAAS 0 were predicted to be 40 (95% prediction interval, 33 to 50) and 87% (95% prediction interval, 18 to 100%) versus 50 (95% prediction interval, 41 to 60) and 59% (95% prediction interval, 6 to 99%) in a model without and with tolerance, respectively., Conclusions: In this study, it was shown that remimazolam-induced sedation is prone to tolerance development, which is potentially mediated by the CNS7054 concentration. The clinical consequences are, however, limited in situations where remimazolam is titrated to effect., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Anesthesiologists.)

Background: Objective neuromuscular monitoring remains the single most reliable method to ensure optimal perioperative neuromuscular management. Nevertheless, the prediction of clinical neuromuscular endpoints by means of Pharmacokinetic (PK) and Pharmacodynamic (PD) modelling has the potential to complement monitoring and improve perioperative neuromuscular management.s STUDY OBJECTIVE: The present study aims to assess the performance of published Rocuronium PK/PD models in predicting intraoperative Train-of-four (TOF) ratios when benchmarked against electromyographic TOF measurements., Design: Observational trial., Setting: Tertiary Belgian hospital, from August 2020 up to September 2021., Patients and Interventions: Seventy-four patients undergoing general anaesthesia for elective surgery requiring the administration of rocuronium and subject to continuous EMG neuromuscular monitoring were included. PK/PD-simulated TOF ratios were plotted and synchronised with their measured electromyographic counterparts and their differences analysed by means of Predictive Error derivatives (Varvel criteria)., Main Results: Published rocuronium PK/PD models overestimated clinically registered TOF ratios. The models of Wierda, Szenohradszky, Cooper, Alvarez-Gomez and McCoy showed significant predictive consistency between themselves, displaying Median Absolute Performance Errors between 38% and 41%, and intra-individual differences (Wobble) between 14 and 15%. The Kleijn model outperformed the former with a lower Median Absolute Performance Error (16%, 95%CI [0.01; 57]) and Wobble (11%, 95%CI [0.01; 34]). All models displayed considerably wide 95% confidence intervals for all performance metrics, suggesting a significantly variable performance., Conclusions: Simulated TOF ratios based on published PK/PD models do not accurately predict real intraoperative TOF ratio dynamics., Trial Registration: NCT04518761 (clinicaltrials.gov), registered on 19 August 2020., Competing Interests: Declaration of Competing Interest Hugo Carvalho: He has received consultancy fees from 3 M (3 M Belgium bvba, Diegem, Belgium). Panagiotis Flamée: He has received consultancy fees from Medtronic (Dublin, Ireland). Michel MRF 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), Medcaptain Europe (Andelst, The Netherlands). He receives royalties on intellectual property from Demed Medical (Temse, Belgium) and the Ghent University (Gent, Belgium). He is an editorial board member and Director for the British Journal of Anaesthesia and associate editor for Anesthesiology. Michael Verdonck, David Ramirez, Douglas J Eleveld, Jan D'Haese, Jasper Wylleman, Lieselot Geerts, Wilfried Cools, Kurt Barbé, Jan Poelaert: the authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose of Review: There are various pharmacokinetic-dynamic models available, which describe the time course of drug concentration and effect and which can be incorporated into target-controlled infusion (TCI) systems. For anesthesia and sedation, most of these models are derived from narrow patient populations, which restricts applicability for the overall population, including (small) children, elderly, and obese patients. This forces clinicians to select specific models for specific populations., Recent Findings: Recently, general purpose models have been developed for propofol and remifentanil using data from multiple studies and broad, diverse patient groups. General-purpose models might reduce the risks associated with extrapolation, incorrect usage, and unfamiliarity with a specific TCI-model, as they offer less restrictive boundaries (i.e., the patient "doesn't fit in the selected model") compared with the earlier, simpler models. Extrapolation of a model can lead to delayed recovery or inadequate anesthesia. If multiple models for the same drug are implemented in the pump, it is possible to select the wrong model for that specific case; this can be overcome with one general purpose model implemented in the pump., Summary: This article examines the usability of these general-purpose models in relation to the more traditional models., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

During ischemia and reperfusion injury (IRI), mitochondria may release mitochondrial DNA (mtDNA). mtDNA can serve as a propagator of further injury but in specific settings has anti-inflammatory capacities as well. Therefore, the aim of this study was to study the perioperative dynamics of plasma mtDNA during living donor kidney transplantation (LDKT) and its potential as a marker of graft outcome. Fifty-six donor-recipient couples from the Volatile Anesthetic Protection of Renal Transplants-1 (VAPOR-1) trial were included. Systemic venous, systemic arterial, and renal venous samples were taken at multiple timepoints during and after LDKT. Levels of mtDNA genes changed over time and between vascular compartments. Several donor, recipient, and transplantation-related variables significantly explained the course of mtDNA genes over time. mtDNA genes predicted 1-month and 24-month estimated glomerular filtration rate (eGFR) and acute rejection episodes in the two-year follow-up period. To conclude, mtDNA is released in plasma during the process of LDKT, either from the kidney or from the whole body in response to transplantation. While circulating mtDNA levels positively and negatively predict post-transplantation outcomes, the exact mechanisms and difference between mtDNA genes are not yet understood and need further exploration.

Aim: In this predictive modelling study we aimed to investigate how many patients with an out-of-hospital cardiac arrest (OHCA) would benefit from pre-hospital as opposed to in-hospital initiation of extracorporeal cardiopulmonary resuscitation (ECPR)., Methods: A temporal spatial analysis of Utstein data was performed for all adult patients with a non-traumatic OHCA attended by three emergency medical services (EMS) covering the north of the Netherlands during a one-year period. Patients were considered potentially eligible for ECPR if they had a witnessed arrest with immediate bystander CPR, an initial shockable rhythm (or signs of life during resuscitation) and could be presented in an ECPR-centre within 45 minutes of the arrest. Endpoint of interest was defined as the hypothetical number of ECPR eligible patients after 10, 15 and 20 minutes of conventional CPR and upon (hypothetical) arrival in an ECPR-centre as a fraction of the total number of OHCA patients attended by EMS., Results: During the study period 622 OHCA patients were attended, of which 200 (32%) met ECPR eligibility criteria upon EMS arrival. The optimal transition point between conventional CPR and ECPR was found to be after 15 minutes. Hypothetical intra-arrest transport of all patients in whom no return of spontaneous circulation (ROSC) was obtained after that point (n = 84) would have yielded 16/622 (2.5%) patients being potentially ECPR eligible upon hospital arrival (average low-flow time 52 minutes), whereas on-scene initiation of ECPR would have resulted in 84/622 (13.5%) potential candidates (average estimated low-flow time 24 minutes before cannulation)., Conclusion: Even in healthcare systems with relatively short transport distances to hospital, consideration should be given to pre-hospital initiation of ECPR for OHCA as it shortens low-flow time and increases the number of potentially eligible patients., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Propofol and remifentanil are frequently combined for the induction and maintenance of general anaesthesia. Both propofol and remifentanil cause vasodilation and potentially reduce arterial BP. We aimed to develop a mechanism-based model that characterises the haemodynamic interactions between remifentanil and propofol., Methods: Data from two clinical trials in healthy volunteers were analysed using remifentanil-alone, propofol-alone, and combination groups. We evaluated remifentanil effects on haemodynamics using a previously developed mechanism-based haemodynamic model of propofol. The interaction between propofol and remifentanil was explored using the principles of the general pharmacodynamic interaction (GPDI) model., Results: Remifentanil alone increased the dissipation rate of total peripheral resistance by 50% at 3.0 ng ml -1 . Additionally, the dissipation rates of HR and stroke volume were attenuated by 4.8% and 4.9% per 1 ng ml -1 increase in remifentanil concentration, respectively. The maximal effect of propofol alone in decreasing the production rate of total peripheral resistance was 78%, which decreased to 32% when combined with remifentanil 4 ng ml -1 . The effects of remifentanil on HR and stroke volume were attenuated by propofol with maximum decreases of 11.9% and 21.2%, respectively. Goodness-of-fit plots and prediction-corrected visual predictive check plots showed good predictive performance of the models., Conclusions: The structure of the previous mechanism-based haemodynamic model for propofol was able to describe the effects of remifentanil alone on haemodynamic variables. The GPDI model provided a good framework for characterising the pharmacodynamic interaction between remifentanil and propofol on haemodynamic properties., Clinical Trial Registration: NCT02043938; NCT03143972., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Incorporating technology into healthcare processes is necessary to ensure the availability of high-quality care in the future. Wearable sensors are an example of such technology that could decrease workload, enable early detection of patient deterioration, and support clinical decision making by healthcare professionals. These sensors unlock continuous monitoring of vital signs, such as heart rate, respiration rate, blood oxygen saturation, temperature, and physical activity. However, broad and successful application of wearable sensors on the surgical ward is currently lacking. This may be related to the complexity, especially when it comes to replacing manual measurements by healthcare professionals. This report provides practical guidance to support peers before starting with the clinical application of wearable sensors in the surgical ward. For this purpose, the Non-Adoption, Abandonment, Scale-up, Spread, and Sustainability (NASSS) framework of technology adoption and innovations in healthcare organizations is used, combining existing literature and our own experience in this field over the past years. Specifically, the relevant topics are discussed per domain, and key lessons are subsequently summarized.

Early non-invasive detection and prediction of graft function after kidney transplantation is essential since interventions might prevent further deterioration. The aim of this study was to analyze the dynamics and predictive value of four urinary biomarkers: kidney injury molecule-1 (KIM-1), heart-type fatty acid binding protein (H-FABP), N-acetyl-β-D-glucosaminidase (NAG), and neutrophil gelatinase-associated lipocalin (NGAL) in a living donor kidney transplantation (LDKT) cohort. Biomarkers were measured up to 9 days after the transplantation of 57 recipients participating in the VAPOR-1 trial. Dynamics of KIM-1, NAG, NGAL, and H-FABP significantly changed over the course of 9 days after transplantation. KIM-1 at day 1 and NAG at day 2 after transplantation were significant predictors for the estimated glomerular filtration rate (eGFR) at various timepoints after transplantation with a positive estimate ( p < 0.05), whereas NGAL and NAG at day 1 after transplantation were negative significant predictors ( p < 0.05). Multivariable analysis models for eGFR outcome improved after the addition of these biomarker levels. Several donor, recipient and transplantation factors significantly affected the baseline of urinary biomarkers. In conclusion, urinary biomarkers are of added value for the prediction of graft outcome, but influencing factors such as the timing of measurement and transplantation factors need to be considered.

New anaesthetic drugs and new methods to administer anaesthetic drugs are continually becoming available, and the development of new PK-PD models furthers the possibilities of using arget controlled infusion (TCI) for anaesthesia. Additionally, new applications of existing anaesthetic drugs are being investigated. This review describes the current situation of anaesthetic drug development and methods of administration, and what can be expected in the near future.

Background: The advisory system SmartPilot® View (Drägerwerk AG, Lübeck, Germany) provides real-time, demographically adjusted pharmacodynamic information throughout anaesthesia, including time course of effect-site concentrations of administered drugs and a measure of potency of the combined drug effect termed the "'Noxious Stimulation Response Index' (NSRI). This dual-centre, prospective, observational study assesses whether the availability of SmartPilot® View alters the behaviour of anaesthetic drug titration of anaesthetists and improves the Anaesthesia Quality Score (AQS; percentage of time spent with MAP 60-80 mm Hg and Bispectral Index [BIS] 40-60 [blinded])., Methods: We recruited 493 patients scheduled for elective surgery in two university centres. A control group (CONTROL; n=170) was enrolled to observe drug titration in current practice. Thereafter, an intervention group was enrolled, for which SmartPilot® View was made available to optimise drug titration (SPV; n=188). The AQS, haemodynamic and hypnotic effects, recovery times, pain scores, and other parameters were compared between groups., Results: There were 358 patients eligible for analysis. Anaesthesia quality score was similar between CONTROL and SPV (median AQS [Q1-Q3]) 25.3% [7.4-41.5%] and 22.2% [8.0-44.4%], respectively; P=0.898). Compared with CONTROL, SPV patients had less severe hypotension and hypertension, less BIS <40, faster tracheal extubation, and lower early postoperative pain scores., Conclusions: Adding SmartPilot® View information did not affect average drug titration behaviour. However, small improvements in control of MAP and BIS and early recovery suggest improved titration for some patients without increasing the risk of overdosing or underdosing., Clinical Trial Registration: NCT01467167., Competing Interests: Declarations of interest ARA is an editor of the British Journal of Anaesthesia. The research group or department of MMRFS has received grants and funding from The Medicines Company (Parsippany, NJ, USA), Masimo (Irvine, CA, USA), Fresenius (Bad Homburg, Germany), Acacia Design (Maastricht, The Netherlands), and Medtronic (Dublin, Ireland), and honoraria from The Medicines Company, Masimo, Fresenius, Baxter (Deerfield, IL, USA), Medtronic, and Demed Medical (Temse, Belgium). MMRFS serves as a director and editorial board member of the British Journal of Anaesthesia, and associate editor for Anesthesiology. ML is supported by Drägerwerk AG through an unrestricted educational grant to the Department of Anaesthesia and Pain Medicine, University of Bern, Bern, Switzerland. ML also receives royalties from patents related to SmartPilot® View. The other authors have no conflicts to declare., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: The adverse haemodynamic effects of the intravenous anaesthetic propofol are well known, yet few empirical models have explored the dose-response relationship. Evidence suggests that hypotension during general anaesthesia is associated with postoperative mortality. We developed a mechanism-based model that quantitatively characterises the magnitude of propofol-induced haemodynamic effects during general anaesthesia., Methods: Mean arterial pressure (MAP), heart rate (HR) and pulse pressure (PP) measurements were available from 36 healthy volunteers who received propofol in a step-up and step-down fashion by target-controlled infusion using the Schnider pharmacokinetic model. A mechanistic pharmacodynamic model was explored based on the Snelder model. To benchmark the performance of this model, we developed empirical models for MAP, HR, and PP., Results: The mechanistic model consisted of three turnover equations representing total peripheral resistance (TPR), stroke volume (SV), and HR. Propofol-induced changes were implemented by E max models on the zero-order production rates of the turnover equations for TPR and SV. The estimated 50% effective concentrations for propofol-induced changes in TPR and SV were 2.96 and 0.34 μg ml -1 , respectively. The goodness-of-fit for the mechanism-based model was indistinguishable from the empirical models. Simulations showed that predictions from the mechanism-based model were similar to previously published MAP and HR observations., Conclusions: We developed a mechanism-based pharmacodynamic model for propofol-induced changes in MAP, TPR, SV, and HR as a potential approach for predicting haemodynamic alterations., Clinical Trial Registration: NCT02043938., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Nonsteroidal anti-inflammatory drugs are among the most commonly administered drugs in the perioperative period due to their prominent role in pain management. However, they potentially have perioperative consequences due to immune-modulating effects through the inhibition of prostanoid synthesis, thereby affecting the levels of various cytokines. These effects may have a direct impact on the postoperative outcome of patients since the immune system aims to restore homeostasis and plays an indispensable role in regeneration and repair. By affecting the immune response, consequences can be expected on various organ systems. This narrative review aims to highlight these potential immune system-related consequences, which include systemic inflammatory response syndrome, acute respiratory distress syndrome, immediate and persistent postoperative pain, effects on oncological and neurologic outcome, and wound, anastomotic, and bone healing., (Copyright © 2022, the American Society of Anesthesiologists. All Rights Reserved.)

Target controlled infusion (TCI) is a clinically-available and widely-used computer-controlled method of drug administration, adjusting the drug titration towards user selected plasma- or effect-site concentrations, calculated according to pharmacokinetic-pharmacodynamic (PKPD) models. Although this technology is clinically available for several anaesthetic drugs, the contemporary commercialised PKPD models suffer from multiple limitations. First, PKPD models for anaesthetic drugs are developed using deliberately selected patient populations, often excluding the more challenging populations, such as children, obese or elderly patients, of whom the body composition or elimination mechanisms may be structurally different compared to the lean adult patient population. Separate PKPD models have been developed for some of these subcategories, but the availability of multiple PKPD models for a single drug increases the risk for invalid model selection by the user. Second, some models are restricted to the prediction of plasma-concentration without enabling effect-site controlled TCI or they identify the effect-site equilibration rate constant using methods other than PKPD modelling. Advances in computing and the emergence of globally collected databases has allowed the development of new "general purpose" PKPD models. These take on the challenging task of identifying the relationships between patient covariates (age, weight, sex, etc) and the volumes and clearances of multi-compartmental pharmacokinetic models applicable across broad populations from neonates to the elderly, from the underweight to the obese. These models address the issues of allometric scaling of body weight and size, body composition, sex differences, changes with advanced age, and for young children, changes with maturation and growth. General purpose models for propofol, remifentanil and dexmedetomidine have appeared and these greatly reduce the risk of invalid model selection. In this narrative review, we discuss the development, characteristics and validation of several described general purpose PKPD models for anaesthetic drugs.

This narrative review intends to provide the anesthesiologist with the basic knowledge of the Bayesian concepts and should be considered as a tutorial for anesthesiologists in the concept of Bayesian statistics. The Bayesian approach represents the mathematical formulation of the idea that we can update our initial belief about data with the evidence obtained from any kind of acquired data. It provides a theoretical framework and a statistical method to use pre-existing information within the context of new evidence. Several authors have described the Bayesian approach as capable of dealing with uncertainty in medical decision-making. This review describes the Bayes theorem and how it is used in clinical studies in anesthesia and critical care. It starts with a general introduction to the theorem and its related concepts of prior and posterior probabilities. Second, there is an explanation of the basic concepts of the Bayesian statistical inference. Last, a summary of the applicability of some of the Bayesian statistics in current literature is provided, such as Bayesian analysis of clinical trials and PKPD modeling., (© 2022. The Author(s).)

Brain monitors which track quantitative electroencephalogram (EEG) signatures to monitor sedation levels are drug and patient specific. There is a need for robust sedation level monitoring systems to accurately track sedation levels across all drug classes, sex and age groups. Forty-four quantitative features estimated from a pooled dataset of 204 EEG recordings from 66 healthy adult volunteers who received either propofol, dexmedetomidine, or sevoflurane (all with and without remifentanil) were used in a machine learning based automated system to estimate the depth of sedation. Model training and evaluation were performed using leave-one-out cross validation methodology. We trained four machine learning models to predict sedation levels and evaluated the influence of remifentanil, age, and sex on the prediction performance. The area under the receiver-operator characteristic curve (AUC) was used to assess the performance of the prediction model. The ensemble tree with bagging outperformed other machine learning models and predicted sedation levels with an AUC = 0.88 (0.81-0.90). There were significant differences in the prediction probability of the automated systems when trained and tested across different age groups and sex. The performance of the EEG based sedation level prediction system is drug, sex, and age specific. Nonlinear machine-learning models using quantitative EEG features can accurately predict sedation levels. The results obtained in this study may provide a useful reference for developing next generation EEG based sedation level prediction systems using advanced machine learning algorithms. Clinical trial registration: NCT02043938 and NCT03143972., (© 2020. The Author(s).)

Background: Numerous pharmacokinetic models have been published aiming at more accurate and safer dosing of dexmedetomidine. The vast majority of the developed models underpredict the measured plasma concentrations with respect to the target concentration, especially at plasma concentrations higher than those used in the original studies. The aim of this article was to develop a dexmedetomidine pharmacokinetic model in healthy adults emphasizing linear versus nonlinear kinetics., Methods: The data of two previously published clinical trials with stepwise increasing dexmedetomidine target-controlled infusion were pooled to build a pharmacokinetic model using the NONMEM software package (ICON Development Solutions, USA). Data from 48 healthy subjects, included in a stratified manner, were utilized to build the model., Results: A three-compartment mamillary model with nonlinear elimination from the central compartment was superior to a model assuming linear pharmacokinetics. Covariates included in the final model were age, sex, and total body weight. Cardiac output did not explain between-subject or within-subject variability in dexmedetomidine clearance. The results of a simulation study based on the final model showed that at concentrations up to 2 ng · ml-1, the predicted dexmedetomidine plasma concentrations were similar between the currently available Hannivoort model assuming linear pharmacokinetics and the nonlinear model developed in this study. At higher simulated plasma concentrations, exposure increased nonlinearly with target concentration due to the decreasing dexmedetomidine clearance with increasing plasma concentrations. Simulations also show that currently approved dosing regimens in the intensive care unit may potentially lead to higher-than-expected dexmedetomidine plasma concentrations., Conclusions: This study developed a nonlinear three-compartment pharmacokinetic model that accurately described dexmedetomidine plasma concentrations. Dexmedetomidine may be safely administered up to target-controlled infusion targets under 2 ng · ml-1 using the Hannivoort model, which assumed linear pharmacokinetics. Consideration should be taken during long-term administration and during an initial loading dose when following the dosing strategies of the current guidelines., (Copyright © 2021, the American Society of Anesthesiologists. All Rights Reserved.)

Background: Clinical reasoning is a crucial task within the Emergency Medical Services (EMS) care process. Both contextual and cognitive factors make the task susceptible to errors. Understanding the EMS care process' structure could help identify and address issues that interfere with clinical reasoning. The EMS care process is complex and only basically described. In this research, we aimed to define the different phases of the process and develop an overarching model that can help detect and correct potential error sources, improve clinical reasoning and optimize patient care., Methods: We conducted a focused ethnography study utilizing non-participant video observations of real-life EMS deployments combined with thematic analysis of peer interviews. After an initial qualitative analysis of 7 video observations, we formulated a tentative conceptual model of the EMS care process. To test and refine this model, we carried out a qualitative, thematic analysis of 28 video-recorded cases. We validated the resulting model by evaluating its recognizability with a peer content analysis utilizing semi-structured interviews., Results: Based on real-life observations, we were able to define and validate a model covering the distinct phases of an EMS deployment. We have introduced the acronym "SPART" to describe ten different phases: Start, Situation, Prologue, Presentation, Anamnesis, Assessment, Reasoning, Resolution, Treatment, and Transfer., Conclusions: The "SPART" model describes the EMS care process and helps to understand it. We expect it to facilitate identifying and addressing factors that influence both the care process and the clinical reasoning task embedded in this process., (© 2021. The Author(s).)

Etomidate is a hypnotic agent that is used for the induction of anesthesia. It produces its effect by acting as a positive allosteric modulator on the γ-aminobutyric acid type A receptor and thus enhancing the effect of the inhibitory neurotransmitter γ-aminobutyric acid. Etomidate stands out among other anesthetic agents by having a remarkably stable cardiorespiratory profile, producing no cardiovascular or respiratory depression. However, etomidate suppresses the adrenocortical axis by the inhibition of the enzyme 11β-hydroxylase. This makes the drug unsuitable for administration by a prolonged infusion. It also makes the drug unsuitable for administration to critically ill patients. Etomidate has relatively large volumes of distributions and is rapidly metabolized by hepatic esterases into an inactive carboxylic acid through hydrolyzation. Because of the decrease in popularity of etomidate, few modern extensive pharmacokinetic or pharmacodynamic studies exist. Over the last decade, several analogs of etomidate have been developed, with the aim of retaining its stable cardiorespiratory profile, whilst eliminating its suppressive effect on the adrenocortical axis. One of these molecules, ABP-700, was studied in extensive phase I clinical trials. These found that ABP-700 is characterized by small volumes of distribution and rapid clearance. ABP-700 is metabolized similarly to etomidate, by hydrolyzation into an inactive carboxylic acid. Furthermore, ABP-700 showed a rapid onset and offset of clinical effect. One side effect observed with both etomidate and ABP-700 is the occurrence of involuntary muscle movements. The origin of these movements is unclear and warrants further research., (© 2021. The Author(s).)

Background: Remimazolam is a new benzodiazepine for procedural sedation and general anaesthesia. The aim of this study was to characterise its pharmacokinetic properties and safety in renally and hepatically impaired subjects., Methods: Two separate trials were conducted in patients with hepatic (n=11) or renal impairment (n=11) compared with matched healthy subjects (n=9 and n=12, respectively). The hepatic impairment trial was an open-label adaptive 'Reduced Design' trial, using a single bolus of remimazolam 0.1 mg kg -1 i.v., whereas the renal impairment trial was an open-label trial of a single bolus dose of remimazolam 1.5 mg i.v. Remimazolam plasma concentrations over time were analysed by population pharmacokinetic modelling., Results: Remimazolam pharmacokinetic properties were adequately described by a three-compartment, recirculatory model. Exposure in subjects with severe hepatic impairment was 38.1% higher (i.e. clearance was 38.1% lower) compared with healthy volunteers. This increase caused a slightly delayed recovery (8.0 min for healthy, 12.1 min for moderate, and 16.7 min for severe hepatic impairment). With renal impairment, plasma clearance was comparable with that measured in healthy subjects. Simulations of C max after a bolus dose of 10 mg showed no relevant impact of hepatic or renal impairment. The overall incidence of adverse events was low, and all adverse events were mild., Conclusions: As C max after a remimazolam bolus i.v. was not affected by hepatic or renal impairment, no dose adjustments are required. No unexpected adverse events related to remimazolam were seen in subjects with renal or hepatic impairment., Clinical Trial Registration: Hepatic impairment trial: ClinicalTrials.gov, NCT01790607 (https://clinicaltrials.gov/ct2/show/NCT01790607). Renal impairment trial: EudraCT Number: 2014-004575-23., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

This prospective study evaluates haemodynamic and electroencephalographic effects observed when administering four combinations of effect-site concentrations of propofol (Ce PROP ) and remifentanil (Ce REMI ), all yielding a single predicted probability of tolerance of laryngoscopy of 90% (P TOL  = 90%) according to the Bouillon interaction model. We aimed to identify combinations of Ce PROP and Ce REMI along a single isobole of P TOL that result in favourable hypnotic and haemodynamic conditions. This knowledge could be of advantage in the development of drug advisory monitoring technology. 80 patients (18-90 years of age, ASA I-III) were randomized into four groups and titrated towards Ce PROP (Schnider model, ug⋅ml -1 ) and Ce REMI (Minto model, ng⋅ml -1 ) of respectively 8.6 and 1, 5.9 and 2, 3.6 and 4 and 2.0 and 8. After eleven minutes of equilibration, baseline measurements of haemodynamic endpoints and bispectral index were compared with three minutes of responsiveness measurements after laryngoscopy. Before laryngoscopy, bispectral index differed significantly (p < 0.0001) between groups in concordance with Ce PROP . Heart rate decreased with increasing Ce REMI (p = 0.001). The haemodynamic and arousal responses evoked by laryngoscopy were not significantly different between groups, but Ce PROP  = 3.6 μg⋅ml -1 and Ce REMI  = 4 ng⋅ml -1 evoked the lowest median value for ∆HR and ∆SAP after laryngoscopy. This study provides clinical insight on the haemodynamic and hypnotic consequences, when a model based predicted P TOL is used as a target for combined effect-site controlled target- controlled infusion of propofol and remifentanil. Heart rate and bispectral index were significantly different between groups despite a theoretical equipotency for P TOL , suggesting that each component of the anaesthetic state (immobility, analgesia, and hypnotic drug effect) should be considered as independent neurophysiological and pharmacological phenomena. However, claims of (in)accuracy of the predicted P TOL must be considered preliminary because larger numbers of observations are required for that goal., (© 2020. The Author(s).)

We read with interest the recently published manuscript [...].

Inhaled anesthetics have been in clinical use for over 150 years and are still commonly used in daily practice. The initial view of inhaled anesthetics as indispensable for general anesthesia has evolved during the years and, currently, its general use has even been questioned. Beyond the traditional risks inherent to any drug in use, inhaled anesthetics are exceptionally strong greenhouse gases (GHG) and may pose considerable occupational risks. This emphasizes the importance of evaluating and considering its use in clinical practices. Despite the overwhelming scientific evidence of worsening climate changes, control measures are very slowly implemented. Therefore, it is the responsibility of all society sectors, including the health sector to maximally decrease GHG emissions where possible. Within the field of anesthesia, the potential to reduce GHG emissions can be briefly summarized as follows: Stop or avoid the use of nitrous oxide (N 2 O) and desflurane, consider the use of total intravenous or local-regional anesthesia, invest in the development of new technologies to minimize volatile anesthetics consumption, scavenging systems, and destruction of waste gas. The improved and sustained awareness of the medical community regarding the climate impact of inhaled anesthetics is mandatory to bring change in the current practice.

Study Objectives: Dexmedetomidine-induced electroencephalogram (EEG) patterns during deep sedation are comparable with natural sleep patterns. Using large-scale EEG recordings and machine learning techniques, we investigated whether dexmedetomidine-induced deep sedation indeed mimics natural sleep patterns., Methods: We used EEG recordings from three sources in this study: 8,707 overnight sleep EEG and 30 dexmedetomidine clinical trial EEG. Dexmedetomidine-induced sedation levels were assessed using the Modified Observer's Assessment of Alertness/Sedation (MOAA/S) score. We extracted 22 spectral features from each EEG recording using a multitaper spectral estimation method. Elastic-net regularization method was used for feature selection. We compared the performance of several machine learning algorithms (logistic regression, support vector machine, and random forest), trained on individual sleep stages, to predict different levels of the MOAA/S sedation state., Results: The random forest algorithm trained on non-rapid eye movement stage 3 (N3) predicted dexmedetomidine-induced deep sedation (MOAA/S = 0) with area under the receiver operator characteristics curve >0.8 outperforming other machine learning models. Power in the delta band (0-4 Hz) was selected as an important feature for prediction in addition to power in theta (4-8 Hz) and beta (16-30 Hz) bands., Conclusions: Using a large-scale EEG data-driven approach and machine learning framework, we show that dexmedetomidine-induced deep sedation state mimics N3 sleep EEG patterns., Clinical Trials: Name-Pharmacodynamic Interaction of REMI and DMED (PIRAD), URL-https://clinicaltrials.gov/ct2/show/NCT03143972, and registration-NCT03143972., (© Sleep Research Society 2020. Published by Oxford University Press on behalf of the Sleep Research Society.)

Background: A direct comparison of severe acute respiratory syndrome coronavirus 2 positive patients with a severe acute respiratory syndrome coronavirus 2 negative control group undergoing an operative intervention during the current pandemic is lacking, and a reliable estimate of the assumed difference in morbidity and mortality between both patient categories remains unknown., Methods: We included all consecutive patients with a confirmed pre- or postoperative severe acute respiratory syndrome coronavirus 2 positive status (operated in 27 hospitals) and negative control patients (operated in 4 hospitals) undergoing emergency or elective operations. A propensity score-matched comparison of clinical outcomes was performed between severe acute respiratory syndrome coronavirus 2 positive and negative tested patients (control group). Primary outcome was overall 30-day mortality rate between both groups. Main secondary outcomes were overall, pulmonary, and thromboembolic complications., Results: In total, 161 severe acute respiratory syndrome coronavirus 2 positive and 342 control severe acute respiratory syndrome coronavirus 2 negative patients were included in this study. The 30-day overall postoperative mortality rate was greater in the severe acute respiratory syndrome coronavirus 2 positive cohort compared with the negative control group (16% vs 4% respectively; P = .007). After propensity score matching, the severe acute respiratory syndrome coronavirus 2 positive group consisted of 123 patients (median 70 years of age [interquartile range 59-77] and 55% male) were compared with 196 patients in the matched control group (median 69 years (interquartile range 58-75] and 53% male). The 30-day mortality rate and risk were greater in the severe acute respiratory syndrome coronavirus 2 positive group compared with the matched control group (12% vs 4%; P = .009 and odds ratio 3.4 [95% confidence interval 1.5-8.5]; P = .005, respectively). Overall, pulmonary and thromboembolic complications occurred more often in severe acute respiratory syndrome coronavirus 2 positive patients (P < .01)., Conclusion: Patients diagnosed with perioperative severe acute respiratory syndrome coronavirus 2 have an increased risk of 30-day mortality, pulmonary complications, and thromboembolic events. These findings serve as an evidence-based argument to postpone elective surgery and selected emergency cases., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

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.)

Background: γ-Aminobutyric acid type A (GABAA) receptor agonists are known to cause involuntary muscle movements. The mechanism of these movements is not known, and its relationship to depth of anesthesia monitoring is unclear. We have explored the effect of involuntary muscle movement on the pharmacokinetic-pharmacodynamic model for the GABAA receptor agonist ABP-700 and its effects on the Bispectral Index (BIS) as well as the Modified Observer's Assessment of Alertness/Sedation (MOAA/S) scores., Methods: Observations from 350 individuals (220 men, 130 women) were analyzed, comprising 6,312 ABP-700 concentrations, 5,658 ABP-700 metabolite (CPM-acid) concentrations, 25,745 filtered BIS values, and 6,249 MOAA/S scores, and a recirculatory model developed. Various subject covariates and pretreatment with an opioid or a benzodiazepine were explored as covariates. Relationships between BIS and MOAA/S models and involuntary muscle movements were examined., Results: The final model shows that the pharmacokinetics of ABP-700 are characterized by small compartmental volumes and rapid clearance. The BIS model incorporates an effect-site for BIS suppression and a secondary excitatory/disinhibitory effect-site associated with a risk of involuntary muscle movements. The secondary effect-site has a threshold that decreases with age. The MOAA/S model did not show excitatory effects., Conclusions: The GABAA receptor agonist ABP-700 shows the expected suppressive effects for BIS and MOAA/S, but also disinhibitory effects for BIS associated with involuntary muscle movements and reduced by pretreatment. Our model provides information about involuntary muscle movements that may be useful to improve depth of anesthesia monitoring for GABAA receptor agonists., (Copyright © 2020, the American Society of Anesthesiologists, Inc. All Rights Reserved.)

The relationship between the concentration of a drug and its pharmacological effect is often described by empirical mathematical models. We investigated the relationship between the steepness of the concentration-effect relationship and inter-individual variability (IIV) of the parameters of the sigmoid E max model, using the similarity between the sigmoid E max model and the cumulative log-normal distribution. In addition, it is investigated whether IIV in the model parameters can be estimated accurately by population modeling. Multiple data sets, consisting of 40 individuals with 4 binary observations in each individual, were simulated with varying values for the model parameters and their IIV. The data sets were analyzed using Excel Solver and NONMEM. An empirical equation (Eq. (11)) was derived describing the steepness of the population-predicted concentration-effect profile (γ*) as a function of γ and IIV in C50 and γ, and was validated for both binary and continuous data. The tested study design is not suited to estimate the IIV in C50 and γ with reasonable precision. Using a naive pooling procedure, the population estimates γ* are significantly lower than the value of γ used for simulation. The steepness of the population-predicted concentration-effect relationship (γ*) is less than that of the individuals (γ). Using γ*, the population-predicted drug effect represents the drug effect, for binary data the probability of drug effect, at a given concentration for an arbitrary individual.

Background: Balanced anaesthesia with propofol and remifentanil, compared to sufentanil, often decreases mean arterial pressure (MAP), heart rate (HR) and cardiac index (CI), raising concerns on tissue-oxygenation. This distinct haemodynamic suppression might be attenuated by atropine. This double blinded RCT, investigates if induction with propofol-sufentanil results in higher CI and tissue-oxygenation than with propofol-remifentanil and if atropine has more pronounced beneficial effects on CI and tissue-oxygenation in a remifentanil-based anaesthesia., Methods: In seventy patients scheduled for coronary bypass grafting (CABG), anaesthesia was induced and maintained with propofol target controlled infusion (TCI) with a target effect-site concentration (Cet) of 2.0 μg ml - 1 and either sufentanil (TCI Cet 0.48 ng ml - 1 ) or remifentanil (TCI Cet 8 ng ml - 1 ). If HR dropped below 60 bpm, methylatropine (1 mg) was administered intravenously. Relative changes (∆) in MAP, HR, stroke volume (SV), CI and cerebral (SctO 2 ) and peripheral (SptO 2 ) tissue-oxygenation during induction of anaesthesia and after atropine administration were analysed., Results: The sufentanil group compared to the remifentanil group showed significantly less decrease in MAP (∆ = - 23 ± 13 vs. -36 ± 13 mmHg), HR (∆ = - 5 ± 7 vs. -10 ± 10 bpm), SV (∆ = - 23 ± 18 vs. -35 ± 19 ml) and CI (∆ = - 0.8 (- 1.5 to - 0.5) vs. -1.5 (- 2.0 to - 1.1) l min - 1  m - 2 ), while SctO 2 (∆ = 9 ± 5 vs. 6 ± 4%) showed more increase with no difference in ∆SptO 2 (∆ = 8 ± 7 vs. 8 ± 8%). Atropine caused higher ∆HR (13 (9 to 19) vs. 10 ± 6 bpm) and ∆CI (0.4 ± 0.4 vs. 0.2 ± 0.3 l min - 1  m - 2 ) in sufentanil vs. remifentanil-based anaesthesia, with no difference in ∆MAP, ∆SV and ∆SctO 2 and ∆SptO 2 ., Conclusion: Induction of anaesthesia with propofol and sufentanil results in improved haemodynamic stability and higher SctO 2 compared to propofol and remifentanil in patients having CABG. Administration of atropine might be useful to counteract or prevent the haemodynamic suppression associated with these opioids., Trial Registration: Clinicaltrials.gov on June 7, 2013 (trial ID: NCT01871935 ).

Background: In the University Medical Center Groningen in Groningen, the Netherlands, moderate-to-deep sedation is provided by nursing staff trained and supervised by the anesthesia department using protocol-based target-controlled infusions (TCIs) of propofol and remifentanil. The aim of this retrospective cohort study was to investigate the incidence of events with potential adverse health consequences within this service model and the risk factors for the occurrence of these events., Methods: We retrospectively interrogated a database containing the computerized anesthetic records of 2937 procedures where moderate-to-deep sedation was provided using TCI administration of propofol and remifentanil between May 2014 and October 2017. The primary outcome measures were the incidence of sedation-related events with potential adverse health consequences and risk factors for the occurrence of such events. The events under investigation were unplanned intensive care unit (ICU) admission, need for cardiopulmonary resuscitation (CPR), death on the day of the procedure due to sedation-related events, cardiovascular events (arrhythmias, hypertension, and hypotension), pulmonary events (aspiration, desaturation, unplanned tracheal intubation), anaphylactic or allergic reactions, and the termination of the procedure due to sedation-related events. Cardiovascular and pulmonary events were classified as severe, significant, or moderate. Events were identified by using computer algorithms to search the computerized records from all included procedures., Results: Data from 2937 procedures were analyzed. No patients suffered catastrophic events (death, need for CPR, or unplanned ICU admission). Thirty-two severe sedation-related events occurred in 32 procedures. Severe desaturation (0.6%; 95% confidence interval [CI], 0.4-0.9) and severe hypertension (0.2%; 95% CI, 0.04-0.37) were the most common severe events. Significant hypotension (8.8%; 95% CI, 7.73-9.77) and significant desaturation (1.6%; 95% CI, 1.12-2.02) were found to be the most common events with potential adverse health consequences. No patient suffered lasting health consequences. Average mean and maximum targeted effect-site concentrations (Cet) for propofol were 2.6 ± 0.83 and 3.3 ± 1.09 µg·mL, respectively, and for remifentanil 0.84 ± 0.18 and 0.99 ± 0.22 ng·mL, respectively. Maximum Cets of propofol were lower among patients with higher body mass index (BMI) and were higher among patients of younger age. Higher BMI was a risk factor for desaturation. Increased age and lower BMI were risk factors for hypotension. Longer procedure time was a risk factor for both desaturation and hypotension., Conclusions: Moderate-to-deep sedation by propofol and remifentanil TCI has a low incidence of catastrophic and severe events.