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.

Conductance selectivity of Na+ across the K+ channel via Na+ trapped in a tortuous trajectory.

Ion selectivity of the potassium channel is crucial for regulating electrical activity in living cells; however, the mechanism underlying the potassium channel selectivity that favors large K+ over small Na+ remains unclear. Generally, Na+ is not completely excluded from permeation through potassium channels. Herein, the distinct nature of Na+ conduction through the prototypical KcsA potassium channel was examined. Single-channel current recordings revealed that, at a high Na+ concentration (200 mM), the channel was blocked by Na+, and this blocking was relieved at high membrane potentials, suggesting the passage of Na+ across the channel. At a 2,000 mM Na+ concentration, single-channel Na+ conductance was measured as one-eightieth of the K+ conductance, indicating that the selectivity filter allows substantial conduit of Na+ Molecular dynamics simulations revealed unprecedented atomic trajectories of Na+ permeation. In the selectivity filter having a series of carbonyl oxygen rings, a smaller Na+ was distributed off-center in eight carbonyl oxygen-coordinated sites as well as on-center in four carbonyl oxygen-coordinated sites. This amphipathic nature of Na+ coordination yielded a continuous but tortuous path along the filter. Trapping of Na+ in many deep free energy wells in the filter caused slow elution. Conversely, K+ is conducted via a straight path, and as the number of occupied K+ ions increased to three, the concerted conduction was accelerated dramatically, generating the conductance selectivity ratio of up to 80. The selectivity filter allows accommodation of different ion species, but the ion coordination and interactions between ions render contrast conduction rates, constituting the potassium channel conductance selectivity.

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.

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.

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.

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.

Reliability and validity of the Japanese translation of the DN4 Diagnostic Questionnaire in patients with neuropathic pain.

BACKGROUND: The Douleur Neuropathique 4 questionnaire (DN4) is a simple and objective tool developed by the French Neuropathic Pain Group to screen for neuropathic pain. METHODS: This prospective observational study was undertaken in three hospitals to assess the validity of a Japanese translation of the DN4. We first translated the DN4 into Japanese using a forward-backward method. Pain specialists then examined patients independently and diagnosed them with neuropathic or non-neuropathic pain, according to the International Association for the Study of Pain definitions. The Japanese version of the DN4 questionnaire was then given to each patient. RESULTS: Of 187 patients that met our inclusion criteria, 100 and 87 were diagnosed with neuropathic and non-neuropathic pain, respectively. The test-retest intra-class correlation coefficient (95% confidence interval) was 0.827 (0.769-0.870). Among patients with identical diagnoses of neuropathic or non-neuropathic pain, receiver-operating characteristic curve analysis revealed an area under the curve of 0.89. A cut-off point of equal or greater than 4 resulted in a sensitivity of 71% and specificity of 92%. CONCLUSION: The Japanese version of the DN4 was found to be a helpful tool for discriminating between neuropathic and non-neuropathic pain.

A successfully treated case of cardiac arrest after Caesarean section complicated by pheochromocytoma crisis and amniotic fluid embolism.

Both pheochromocytoma and amniotic fluid embolism (AFE) are important causes of maternal mortality. We present a case of a 29-year-old woman who developed cardiac arrest after Caesarean section, complicated by both pheochromocytoma crisis and AFE. After resuscitation, the patient developed multiple organ dysfunction, rhabdomyolysis and disseminated intravascular coagulation (DIC). After institution of multidisciplinary interventions (including the use of an intra-aortic balloon pump, extracorporeal membrane oxygenation, continuous hemodiafiltration, and neuroprotective therapeutic hypothermia) the patient made a full recovery without any apparent neurological deficit.

Rectified Proton Grotthuss Conduction Across a Long Water-Wire in the Test Nanotube of the Polytheonamide B Channel.

A hydrogen-bonded water-chain in a nanotube is highly proton conductive, and examining the proton flux under electric fields is crucial to understanding the one-dimensional Grotthuss conduction. Here, we exploited a nanotube-forming natural product, the peptide polytheonamide B (pTB), to examine proton conduction mechanisms at a single-molecule level. The pTB nanotube has a length of ∼40 Å that spans the membrane and a uniform inner diameter of 4 Å that holds a single-file water-chain. Single-channel proton currents were measured using planar lipid bilayers in various proton concentrations and membrane potentials (±400 mV). We found, surprisingly, that the current-voltage curves were asymmetric with symmetric proton concentrations in both solutions across the membrane (rectification). The proton flux from the C-terminal to the N-terminal end was 1.6 times higher than that from the opposite. At lower proton concentrations, the degree of rectification was attenuated, but with the addition of a pH-buffer (dichloroacetate) that supplies protons near the entrance, the rectification emerged. These results indicate that the permeation processes inside the pore generate the rectification, which is masked at low concentrations by the diffusion-limited access of protons to the pore entrance. The permeation processes were characterized by a discrete-state Markov model, in which hops of a proton followed by water-chain turnovers were implemented. The optimized model revealed that the water-chain turnover exhibited unusual voltage dependence, and the distinct voltage-dependencies of the forward and backward transition rates yielded the rectification. The pTB nanotube serves as a rectified proton conductor, and the design principles can be exploited for proton-conducting materials.

[The Contribution of Vascular Capacity and Blood Volume to Maintain Stable Blood Circulation during General Anesthesia].

To maintain proper cardiac preload is one of the most effective procedures for the systemic circulation remaining stable. In particular, the balance between vascular capacity and total blood volume must be maintained within appropriate range by the administration of fluids, blood and/or vasoactive drugs with mean circulatory filling pressure (Pmcf), central venous pressure (CVP) or stroke volume variation (SVV). End-diastolic left ventricular volume (Ved) is theoretically the best index of cardiac preload; however, without transesophageal echocardbalanceiogram we cannot directly monitor Ved during anesthesia. The infused fluid volume remaining in intravascular space, the vascular capacity controlled by autonomic nervous system and/or vasoactive agents, and the unstressed blood volume properly mobilized to excess blood volume are the crucial factors to maintain cardiac output The knowledge of vascular physiology contribute the decision making to manipulate such factors to control blood circulation during general anesthesia. For example, CVP is usually maintained in the narrow range and seems to be stable; however, it must be changed just after the circulatory disturbances, such as acute bleeding, blood transfusion, and fluid infusion, and followed by gradual returning to initial value, because of the solid mechanism to preserve cardiac output

Renal redox dysregulation in AKI: application for oxidative stress marker of AKI.

Oxidative stress is a major determinant of acute kidney injury (AKI); however, the effects of an AKI on renal redox system are unclear, and few existing AKI markers are suitable for evaluating oxidative stress. We measured urinary levels of the redox-regulatory protein thioredoxin 1 (TRX1) in patients with various kinds of kidney disease and in mice with renal ischemia-reperfusion injury. Urinary TRX1 levels were markedly higher in patients with AKI than in those with chronic kidney disease or in healthy subjects. In a receiver operating characteristic curve analysis to differentiate between AKI and other renal diseases, the area under the curve for urinary TRX1 was 0.94 (95% confidence interval, 0.90-0.98), and the sensitivity and specificity were 0.88 and 0.88, respectively, at the optimal cutoff value of 43.0 µg/g creatinine. Immunostaining revealed TRX1 to be diffusely distributed in the tubules of normal kidneys, but to be shifted to the brush borders or urinary lumen in injured tubules in both mice and humans with AKI. Urinary TRX1 in AKI was predominantly in the oxidized form. In cultured human proximal tubular epithelial cells, hydrogen peroxide specifically and dose dependently increased TRX1 levels in the culture supernatant, while reducing intracellular levels. These findings suggest that urinary TRX1 is an oxidative stress-specific biomarker useful for distinguishing AKI from chronic kidney disease and healthy kidneys.

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.

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.

A Pilot Estimation of Ventricular-Arterial Coupling Using a Vascular Screening Device (VaSera®).

BACKGROUND: Non-invasive cardiovascular assessment has become an alternative to invasive techniques. VaSera®, a vascular screening device, measures arterial stiffness with the cardio-ankle vascular index (CAVI); it also measures cardiophysiological variables of ejection time (ET) and pre-ejection period (PEP). We aimed to apply the parameters obtained by VaSera® to estimate heart function based on left ventricular end-systolic elastance/arterial elastance (Ees/Ea) and to assess the minimal required number of measurements for estimation. METHODS: We conducted an experimental laboratory study for healthy volunteers. Using the previously established formula, the Ees/Ea value of each participant was estimated using ET and PEP values measured by VaSera®. The intraclass correlation coefficient (ICC) assessed the minimum required number of measurements. Concordance correlation coefficient (CCC) and Bland and Altman analysis assessed variation of Ees/Ea estimation against the trimmed average. RESULTS: A total of 660 measurements from 132 participants were included. The Ees/Ea estimates from the VaSera® were 1.5 [1.2, 1.9]. The ICC for Ees/Ea was 0.71 (95% confidence interval: 0.65-0.77), suggesting that four measurements were required. The CCC between the trimmed average of Ees/Ea and the mean of four Ees/Ea estimates was 0.99. Bland and Altman analysis showed excellent agreement for the mean of four Ees/Ea estimates and the trimmed average of Ees/Ea. CONCLUSIONS: For screening of heart failure, the Ees/Ea estimated using non-invasive vascular-stiffness assessment device would be tolerable and four sequential measurements were required.

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.

Cardiotoxic local anesthetics increasingly interact with biomimetic membranes under ischemia-like acidic conditions.

The cardiotoxic effects of local anesthetics increase in cardiac ischemia which is characterized by the tissue pH lowering to 6.5 or less. Apart from the cardiac channel blockade, the membrane interaction has been referred to as another mode of their cardiotoxic action. By using biomimetic membranes, we verified the hypothesis that bupivacaine and lidocaine may increasingly interact with cardiac mitochondrial membranes under ischemia-like acidic conditions. Biomimetic membranes were prepared with different phospholipids and cholesterol to be unilamellar vesicles suspended in buffers of pH 7.4, 6.9, 6.4 or 5.9. Bupivacaine and lidocaine were reacted with the membrane preparations at cardiotoxically relevant concentrations and their membrane interactivities were determined by measuring fluorescence polarization. Both drugs interacted with 100 mol% 1,2-dipalmitoylphosphatidylcholine, peripheral nerve cell-mimetic and cardiomyocyte-mimetic membranes to increase membrane fluidity, although lowering the reaction pH from 7.4 to 5.9 decreased their membrane-fluidizing effects. In cardiomyocyte mitochondria-mimetic membranes containing 20 mol% cardiolipin, however, bupivacaine and lidocaine reversely increased their membrane interactivities at pH 5.9-6.4 compared with pH 7.4. Such increases were greater in anionic phospholipid membranes which consisted of substantial amounts of cardiolipin and phosphatidylserine. Positively charged bupivacaine and lidocaine would form ion-pairs with the negatively charged head-groups of anionic phospholipids under acidic conditions, thereby increasing the induced membrane fluidization. The mitochondrial membrane interactions depending on pH lowering may be, at least in part, responsible for local anesthetic cardiotoxicity enhanced in acidosis associated with cardiac ischemia.

Neuromuscular electrical stimulation in the intensive care unit prevents muscle atrophy in critically ill older patients: A retrospective cohort study.

Critically ill patients in the intensive care unit (ICU) develop muscle atrophy and decreased physical function. Though neuromuscular electrical stimulation (NMES) therapy has been shown to be effective in preventing this, but its effect on older patients is unknown. To examine the course of critically ill older patients treated with NMES in the ICU and to define the impact of its use. A retrospective cohort study was conducted using older ICU patients (≥65 years) categorized into a control group (n = 20) and an NMES group (n = 22). For subgroup analysis, each group was further classified into pre-old age (65-74 years) and old age (≥75 years). The control group showed significant decrease in muscle thickness during ICU and hospital stay. The NMES group showed lower reduction in muscle thickness and showed decrease in muscle echo intensity during hospital stay, compared to the control group. NMES inhibited decrease in muscle thickness in the pre-old age group versus the old age group. The decreasing effect of NMES on echo intensity during hospital stay manifested only in the pre-old age group. We did not find much difference in physical functioning between the NMES and control groups. Lower limb muscle atrophy reduces in critically ill older patients (≥65 years) with NMES and is pronounced in patients aged < 75 years. The impact of NMES on the physical functioning of older patients in ICU needs to be further investigated.

[Clinical application of urinary redox regulating protein, thioredoxin].

Thioredoxin (TRX) is a redox-regulating protein, induced in response to oxidative stress. The function of TRX in the urine is unknown. We show here that urinary TRX begin to increase within one hour and peaks within two hours after ischemia reperfusion of mice. Serum levels of TRX are not changed by the ischemia/reperfusion. In a time-dependent study of immunohistochemistry, TRX appears diffusely in the tubular cytosol in sham-operated mice. On the other hand, immediately after renal ischemia/reperfusion, TRX become to eccentrically-locate in the apical side of the tubular cytosol, and then TRX is detected only in the urinary lumen. In contrast, when we examine the immunolocalization of glutaredoxin, which is a member of the TRX superfamily, we find that the immunoreactivity is unchanged after renal ischemia/reperfusion. Northern blotting and in situ hybridization show that epithelial cells constitutively express TRX mRNA but neither expression levels nor distribution are altered by ischemia-reperfusion. An overexpression of hTRX in transgenic mice attenuates the reperfusion injury. These data suggests that TRX is produced in tubular cells in a steady state. The increase in the urine after ischemia-reperfusion is not mediated by a de novo induction of TRX mRNA but by a discharge of TRX protein from tubular epithelial cells. TRX is useful for the diagnosis of AKI in association with oxidative stress.