Asymmetric Lipid Bilayers and Potassium Channels Embedded Therein in the Contact Bubble Bilayer.

Cell membranes are highly intricate systems comprising numerous lipid species and membrane proteins, where channel proteins, lipid molecules, and lipid bilayers, as continuous elastic fabric, collectively engage in multi-modal interplays. Owing to the complexity of the native cell membrane, studying the elementary processes of channel-membrane interactions necessitates a bottom-up approach starting from forming simplified synthetic membranes. This is the rationale for establishing an in vitro membrane reconstitution system consisting of a lipid bilayer with a defined lipid composition and a channel molecule. Recent technological advancements have facilitated the development of asymmetric membranes, and the contact bubble bilayer (CBB) method allows single-channel current recordings under arbitrary lipid compositions in asymmetric bilayers. Here, we present an experimental protocol for the formation of asymmetric membranes using the CBB method. The KcsA potassium channel is a prototypical model channel with huge structural and functional information and thus serves as a reporter of membrane actions on the embedded channels. We demonstrate specific interactions of anionic lipids in the inner leaflet. Considering that the local lipid composition varies steadily in cell membranes, we `present a novel lipid perfusion technique that allows rapidly changing the lipid composition while monitoring the single-channel behavior. Finally, we demonstrate a leaflet perfusion method for modifying the composition of individual leaflets. These techniques with custom synthetic membranes allow for variable experiments, providing crucial insights into channel-membrane interplay in cell membranes.

The Relationship between the Measured Blood Concentration of Rocuronium in Stable Muscle Relaxation with a Closed-Loop Control and the Estimated Blood Concentration from a Pharmacokinetic Simulation.

We developed a system to adjust the rate of a continuous rocuronium (Rb) infusion to achieve 3 ≤ %T1 ≤ 10 with a closed-loop control. Samples were collected from 15 patients, and Rb blood concentrations were measured at the following time points: (1) when %T1 recovered to 3% or more after the initial Rb infusion; (2) when %T1 stabilized within the target range; (3) at the cessation of the Rb infusion; (4) 5 min after the sugammadex administration. The predicted Rb blood concentration at each time point was calculated and recorded using the pharmacokinetic parameters of Wierda et al. At time points (1), (2), and (3), the predicted blood concentrations were in good agreement with the measured values, but after the administration of sugammadex, the blood concentrations were higher than the predicted values because the Rb distributed in the tissues migrated into the blood. From the above, it was confirmed that the predicted blood concentration of Rb can be a good indicator for the automatic Rb administration control.

Comparison of Left Ventricular End-Diastolic Volume Approximated from Mean Blood Pressure and Stroke Volume and End-Diastolic Volume Calculated from Left Ventricular-Aortic Coupling.

Objectives: The purpose of this study was to compare left ventricular end-diastolic volume (EDV), derived from left ventricular arterial coupling (Ees/Ea), and mean arterial blood pressure. Both of these methods of measuring EDV require some invasive procedure. However, the method of measuring EDV approximate is less invasive than the EDV coupling measuring method. This is because EDV approximate only requires arterial pressure waveform as an invasive procedure. Methods: This study included 14 patients with normal cardiac function who underwent general anesthesia. The point when blood pressure stabilized after the induction of anesthesia was taken as a baseline according to the study protocol. At the point when systolic arterial blood pressure fell 10% or more from the baseline blood pressure, 300 mL of colloid solution was administered over 15 min. EDV approximate and EDV coupling were calculated for each of the 14 patients at three points during the course of anesthetic. Each value was obtained by calculating a 5 min average. The timing of these three points was 5 min before, 5 min during, and 5 min after infusion loading. Results: The total number of comparable points was 42; 3 points were taken from each of the 14 participants. Both EDV approximate and EDV coupling increased through the infusion load testing. Scatter plots were prepared, and regression lines were calculated from the obtained values. A high correlation was shown between EDV approximate and EDV coupling (R2 = 0.96, p < 0.05). Conclusions: In patients with good cardiac function, EDV approximate can be substituted for EDV coupling, suggesting the possibility that EDV can be continuously and less invasively calculated under the situation of general anesthesia.

Probing membrane deformation energy by KcsA potassium channel gating under varied membrane thickness and tension.

This study investigated how membrane thickness and tension modify the gating of KcsA potassium channels when simultaneously varied. The KcsA channel undergoes global conformational changes upon gating: expansion of the cross-sectional area and longitudinal shortening upon opening. Thus, membranes impose differential effects on the open and closed conformations, such as hydrophobic mismatches. Here, the single-channel open probability was recorded in the contact bubble bilayer, by which variable thickness membranes under a defined tension were applied. A fully open channel in thin membranes turned to sporadic openings in thick membranes, where the channel responded moderately to tension increase. Quantitative gating analysis prompted the hypothesis that tension augmented the membrane deformation energy when hydrophobic mismatch was enhanced in thick membranes.

Effect of age and gender on ventricular-arterial coupling estimated using a non-invasive technique.

BACKGROUND: Left ventricular-arterial coupling is assessed as the ratio of left ventricular end-systolic elastance (Ees) to arterial elastance (Ea). Previous studies have introduced non-invasive estimations of Ees/Ea. It requires only four variables, namely pre-ejection period, ejection time, end-systolic pressure and diastolic pressure. The aims of the present study were to clarify the reference values of Ees/Ea estimated using the noninvasive technique, and to investigate the effects of age and gender on Ees/Ea in healthy subjects. METHODS: This retrospective study utilized data from healthy, 30-79-year-old subjects. We recorded electrocardiogram, phonocardiogram, and brachial arterial pulse waves simultaneously using the vascular screening system, and used the observed variables to calculate Ees/Ea. We separated subjects into five groups according to their age and compared Ees/Ea among the different age groups. RESULTS: The study included 2114 males and 2292 females. Ees/Ea ranged from 1.87 to 2.04 in males, and 1.98 to 2.32 in females. We observed no age-related differences in Ees/Ea in males (p = 0.10), and significant differences in females (p < 0.001). Ees/Ea in males was not different compared to those in females in 60-69-year-old group (p = 0.92). Whereas Ees/Ea was higher in females compared to those in males in the other age groups. The differences between medians of Ees/Ea in males and those in females were 0.45 (p < 0.001), 0.24 (p < 0.001), 0.13 (p = 0.01), and 0.13 (p = 0.03) in 30-39, 40-49, 50-59, and 70-79-year-old age groups, respectively. CONCLUSIONS: We clarified the reference values of Ees/Ea in healthy subjects. The effect of age on Ees/Ea is different in males and females, although Ees/Ea is maintained within a relatively narrow range in all subjects.

Anesthesia Management via an Automated Control System for Propofol, Remifentanil, and Rocuronium Compared to Management by Anesthesiologists: An Investigator-Initiated Study.

BACKGROUND: We previously developed an automated total intravenous anesthesia control system that uses new closed-loop system algorithms to administer propofol, remifentanil, and rocuronium based on the bispectral index and train-of-four data. We recently improved this automated control system by adding a safety mechanism and using a modified monitoring device. METHODS: Patients scheduled for elective surgery were randomly assigned to closed-loop feedback control (automatic group) or the manual administration of propofol, remifentanil, and rocuronium (manual group). The proportion of time during which the proper management of three-agent anesthesia was maintained during surgery was determined as the primary endpoint. RESULTS: The proportion of time during which the three components of sedation, analgesia, and muscle relaxation were adequately controlled was 87.21 ± 12.79% in the automatic group, which was non-inferior to the proportion of 65.19 ± 20.16% in the manual group (p < 0.001). Adverse events during the operative or postoperative observation periods were significantly less frequent in the automatic group (54 patients, 90.0%) than in the manual group (60 patients, 100.0%; p = 0.027). CONCLUSION: Our three-agent automated control system, which features an improved muscle relaxation monitor and safety mechanism added to the basic control algorithms, maintained sedation, analgesia, and muscle relaxation appropriately in a manner non-inferior to anesthesiologists without compromising safety.

Intraoperative nociception and postoperative inflammation associated with the suppression of major complications due to thoracic epidural block after pleurectomy/decortication for malignant pleural mesothelioma under general anesthesia: A retrospective observational study.

A recent study showed that thoracic epidural block (TEB) suppressed the occurrence of major complications after pleurectomy/decortication (P/D) for malignant pleural mesothelioma (MPM) under general anesthesia. To investigate the mechanisms underlying the correlation, both acute inflammatory status and intraoperative nociception were evaluated in the present study. In a single-institutional observational study, consecutive adult patients undergoing P/D were enrolled from March 2019 to April 2022. Perioperative acute inflammatory status was evaluated using differential White blood cell (WBC) counts and serum concentration of C-reactive protein (CRP) both before and after the surgery on postoperative day (POD) 1. The averaged value of nociceptive response index during surgery (mean NR) was obtained to evaluate the level of intraoperative nociception. Multivariable logistic regression analysis was performed to determine the association between perioperative variables and major complications Postoperative major postoperative complication was defined as Clavien-Dindo grades ≥ III. We conducted this study with 97 patients. After logistic regression analysis showed that general anesthesia without TEB was a sole risk factor for major complications, patients were divided into 2 groups: general anesthesia with and without TEB. The incidence of major complications was significantly lower in patients with TEB (33.3%, n = 33) than in those without TEB (64.1%, n = 64, P < .01). Although there was no significant difference in the CRP level between 2 groups, the lymphocyte-to-monocyte ratio (LMR) on POD 1 in patients with TEB was significantly higher than that in patients without TEB (P = .04). The mean NR was significantly lower in patients with TEB than that in those without TEB (P = .02). Both lower mean NR during surgery and higher LMR on POD 1 are likely associated the suppression of major complications due to TEB after P/D under general anesthesia. Decreases in the postoperative acute inflammatory response, caused by the reduction of intraoperative nociception due to TEB, may help suppress major complications after P/D.

A method for calculating left ventricular ejection fraction noninvasively from left ventricular arterial coupling (Ees/Ea).

BACKGROUND: Ejection fraction (EF), which is assessed using ultrasonography, is a standard parameter for evaluating cardiac function in clinical cardiology and for cardiovascular management during general anesthesia. However, it is impossible to continuously and non-invasively assess EF using ultrasonography. The aim of our study was to develop a method for estimating EF non-invasively using the left ventricular arterial coupling ratio (Ees/Ea). METHODS: Ees/Ea was estimated non-invasively using the parameters pre-ejection period (PEP), ejection time (ET), end-systolic pressure (Pes) and diastolic pressure (Pad), which were calculated from a vascular screening system, VeSera 1000/1500 (Fukuda Denshi Co., Ltd., Tokyo, Japan). Then, left ventricular efficiency (Eff) as a pump, defined as the ratio of external work (EW) to myocardial oxygen consumption, which strongly correlates with the pressure-volume area (PVA), was calculated by a new formula using Ees/Ea, and was used to approximate EF (EFeff). Simultaneously, we measured EF using transthoracic echocardiography (EFecho), and compared it with EFeff. RESULTS: The study included 44 healthy adults (36 males, 8 females), in whom mean EFecho was 66 ± 5% and EFeff was 57 ± 9%. We found a positive correlation between EFecho and EFeff (R2 = 0.219, p < 0.05) on Bland-Altman analysis, with limits of agreement of - 7.5 to 24.4%, and percentage error of 24%. CONCLUSION: The results suggest that EF can be measured non-invasively using left ventricular arterial coupling.

A method for calculating left ventricular end-diastolic volume as an index of left ventricular preload from the pre-ejection period, ejection time, blood pressure, and stroke volume: a prospective, observational study.

BACKGROUND: Left ventricular end-diastolic volume (EDV) is a major determinant of cardiac preload. However, its use in fluid management is limited by the lack of a simple means to measure it noninvasively. This study presents a new noninvasive method that was validated against simultaneously measured EDV by transthoracic echocardiography (TTE). The goal of this study was to develop and validate a method to estimate EDV in humans non-invasively from left ventricular arterial coupling (Ees/Ea) and stroke volume (SV). METHODS: Ees/Ea can be calculated non-invasively from the four parameters of end-systolic arterial pressure (Pes), diastolic arterial pressure (DBP), pre-ejection period (PEP), and ejection time (ET), using the approximation formula. In addition, if SV can be assessed, EDV can be calculated. Therefore, using a vascular screening system (VaSera 1000/1500, Fukuda Denshi Co., Ltd., Tokyo, Japan), blood pressure, PEP, and ET were measured noninvasively, the SV value was obtained using an ultrasound diagnostic device, EDV was calculated (EDV calc), and it was compared with EDV obtained using the ultrasound diagnostic device (EDV echo). The results are shown as mean ± standard deviation values. RESULTS: There were 48 healthy subjects (40 men, 8 women), with a mean age of 24 ± 4 years, mean height of 169 ± 7 cm, and mean weight of 65 ± 12 kg. EDV echo was 91 ± 16 ml, and EDV calc was 102 ± 21 ml. There was a significant correlation between EDV echo and EDV calc (R2 = 0.81, p < 0.01). A Bland-Altman plot between EDV echo and EDV calc showed that the bias and limits of agreement were -11.2 ml (-36.6, + 14.2 ml). CONCLUSIONS: The results suggest that EDV can be measured non-invasively from Ees/Ea and SV. This suggests that continuous measurements may potentially work, using equipment available in the intraoperative setting.

The association between initial calculated driving pressure at the induction of general anesthesia and composite postoperative oxygen support.

PURPOSE: Early discontinuation of postoperative oxygen support (POS) would partially depend on the innate pulmonary physics. We aimed to examine if the initial driving pressure (dP) at the induction of general anesthesia (GA) predicted POS prolongation. METHODS: We conducted a single-center retrospective study using the facility's database. Consecutive subjects over 2 years were studied to determine the change in odds ratio (OR) for POS prolongation of different dP classes at GA induction. The dP (cmH2O) was calculated as the ratio of tidal volume (mL) over dynamic Crs (mL/cmH2O) regardless of the respiratory mode. The adjusted OR was calculated using the logistic regression model of multivariate analysis. Moreover, we performed a secondary subgroup analysis of age and the duration of GA. RESULTS: We included 5,607 miscellaneous subjects. Old age, high scores of American Society of Anesthesiologist physical status, initial dP, and long GA duration were associated with prolonged POS. The dP at the induction of GA (7.78 [6.48, 9.45] in median [interquartile range]) was categorized into five classes. With the dP group of 6.5-8.3 cmH2O as the reference, high dPs of 10.3-13 cmH2O and ≥ 13 cmH2O were associated with significant prolongation of POS (adjusted OR, 1.62 [1.19, 2.20], p = 0.002 and 1.92 [1.20, 3.05], p = 0.006, respectively). The subgroup analysis revealed that the OR for prolonged POS of high dPs disappeared in the aged and ≥ 6 h anesthesia time subgroup. CONCLUSIONS: High initial dPs ≥ 10 cmH2O at GA induction predicted longer POS than those of approximately 7 cmH2O. High initial dPs were, however, a secondary factor for prolongation of postoperative hypoxemia in old age and prolonged surgery.

Association between averaged intraoperative nociceptive response index and postoperative complications after lung resection surgery.

OBJECTIVES: Since postoperative complications, defined as Clavien-Dindo grade ≥II, correlate with long-term survival after lung resection surgery in patients with primary lung cancer, identification of intraoperative risk factors for postoperative complications is crucial for better perioperative management. In the present study, we investigated the possible association between intraoperative variables for use in anaesthetic management and Clavien-Dindo grade ≥II. METHODS: In this multi-institutional observational study, consecutive adult patients undergoing video-assisted thoracic surgery for primary lung cancer under general anaesthesia from March 2019 to April 2021 were enrolled. All patients were divided into 2 groups with Clavien-Dindo grade

Association between thoracic epidural block and major complications after pleurectomy/decortication for malignant pleural mesothelioma under general anesthesia.

INTRODUCTION: A curative-intent surgical procedure, pleurectomy/decortication, for malignant pleural mesothelioma is accompanied by a high incidence of major postoperative complications. Although epidural block, which suppresses nociception during and after surgery, reportedly has both benefits and disadvantages in terms of outcomes after thoracic surgery for other diseases, the effects of epidural block on major complications after pleurectomy/decortication have not been evaluated. The aim of this study was to evaluate the association between epidural block and major postoperative complications following pleurectomy/decortication. METHODS: In a single-institutional observational study, consecutive adult patients undergoing pleurectomy/decortication under general anesthesia were enrolled from March 2019 to December 2021. Multivariable logistic regression analysis was performed to determine the association between perioperative variables and major complications. Next, patients were divided into two groups: general anesthesia with and without epidural block. Incidences of major postoperative complications, defined as Clavien-Dindo grades≥III, were compared between groups. RESULTS: In all patients enrolled with American Society of Anesthesiologists (ASA) physical status II or III (n=99), general anesthesia without epidural block was identified as a sole risk factor for major complications among perioperative variables. The incidence of major complications was 32.3% (95% CI 19.1% to 49.2%) in patients with epidural block (n=34), which was significantly lower than 63.1% (95% CI 50.9% to 73.8%) in patients without epidural block (n=65). In sensitivity analysis in patients with ASA physical status II alone, the same results were obtained. CONCLUSION: Epidural block is likely associated with reduction of the incidence of major complications after pleurectomy/decortication for malignant pleural mesothelioma under general anesthesia.

Safety and efficacy of an automated anesthesia delivery system for total intravenous anesthesia with propofol, remifentanil, and rocuronium: a non-inferiority randomized controlled trial versus manually controlled anesthesia.

PURPOSE: We have developed an automated anesthesia control system that uses biological information to provide closed-loop control of drug administration for total intravenous anesthesia with propofol, remifentanil, and rocuronium. In this study, we investigated whether the control of sedatives, analgesics, and muscle relaxants delivered by this system is non-inferior to that delivered by anesthesiologists. METHODS: During anesthesia management by our automated administration control system and by anesthesiologists, the concentration of each drug at the site of effect (calculated from drug administration history) and biometric information (bispectral index, blood pressure, pulse rate, and single contraction ratio %T1) were tabulated during the period from the start to end of surgery. The primary efficacy endpoint was the ratio of adequate anesthesia time, in which all three factors of sedation, analgesia, and muscle relaxation were maintained within the target range, to the period from the start to end of surgery under total intravenous anesthesia. RESULTS: Percentage of time under appropriate anesthesia was 73.24 ± 17.24 in the automatic group (n = 28) and 59.94 ± 29.06 in the manual group (n = 28). The lower limit of the 97.5% one-sided confidence interval for the difference between the two group means was 0.51%, indicating the non-inferiority of the automatic group to the manual group (p = 0.002). The incidence of adverse events did not differ significantly between the groups. CONCLUSION: The clinical use of our automated anesthesia control system should allow for the maintenance of adequate anesthesia by adjusting the doses of intravenous anesthetics in the same way as anesthesiologists do.

Quantitative evaluation of the effects of interscalene block on physiological responses to the balance between nociception and anti-nociception among inpatients undergoing total shoulder arthroplasty under general anesthesia.

Although the suppression of physiological responses to the balance between nociception caused by surgical trauma and anti-nociception due to anesthesia during total shoulder arthroplasty (TSA) is relevant for better perioperative managements, quantitative evaluations of the effects of ultrasound-guided interscalene brachial plexus block (ISB) on physiological responses have not been performed. Physiological responses were assessed using the nociceptive response (NR) index. In this multi-institutional observational study, associations between ISB and NR values were examined among inpatients undergoing TSA under general anesthesia between March 2019 and January 2021. The effects of ISB on acute postoperative pain and major complications within 30 days after surgery were also examined. NR values after skin incision clearly showed significant suppressions of physiological responses in patients undergoing TSA with ISB (n = 60), compared to those without ISB (n = 24). Acute postoperative pain on the day of surgery was also significantly less in patients with ISB than in those without ISB. Postoperative complications, classified by Clavien-Dindo grades, showed no significant differences between patients with and without ISB. A propensity score-matched sensitivity analysis confirmed the same results in patients with (n = 21) and without ISB (n = 21). In conclusion, suppression of physiological responses to the balance between nociception and anti-nociception by ISB can be quantitatively evaluated by NR index during TSA.

Intra-operative nociceptive responses and postoperative major complications after gastrointestinal surgery under general anaesthesia: A prospective cohort study.

BACKGROUND: Surgical procedures stimulate nociception and induce physiological responses according to the balance between nociception and antinociception. The severity of surgical stimuli is associated with major postoperative complications. Although an intra-operative quantitative index representing surgical invasiveness would be useful for anaesthetic management to predict and prevent major complications, no such index is available. OBJECTIVES: To identify associations between major complications after gastrointestinal surgery and intra-operative quantitative values from intra-operative nociception monitoring. DESIGN: A multi-institutional observational study. SETTING: Two university hospitals. PATIENTS: Consecutive adult patients undergoing gastrointestinal surgery under general anaesthesia. MAIN OUTCOME MEASURES: Averaged values of nociceptive response index from start to end of surgery (mean NR index) and risk scores of the Surgical Mortality Probability Model (S-MPM) were calculated. Pre and postoperative serum C-reactive protein (CRP) levels were obtained. After receiver-operating characteristic (ROC) curve analysis, all patients were divided into groups with high and low mean nociceptive response index. Associations between mean nociceptive response index and postoperative major complications, defined as Clavien-Dindo grade at least IIIa, were examined using logistic regression analysis. RESULTS: ROC curve analysis showed a nociceptive response index cut-off value for major complications of 0.83, and we divided patients into two groups with mean nociceptive response index less than 0.83 and at least 0.83. The incidence of major complications was significantly higher in patients with mean nociceptive response index at least 0.83 (23.1%; n = 346) than in patients with mean nociceptive response index less than 0.83 (7.7%; n = 443; P < 0.001). Multivariate analysis revealed emergency surgery, S-MPM risk score, mean nociceptive response index and postoperative CRP levels as independent risk factors for major complications. CONCLUSION: Mean nociceptive response index during surgery likely correlates with major complications after gastrointestinal surgery. TRIAL REGISTRATION: The current observational study had no intervention, and was therefore, not registered.