Astrocytes Modulate a Specific Paraventricular Thalamus→Prefrontal Cortex Projection to Enhance Consciousness Recovery from Anesthesia.

Current anesthetic theory is mostly based on neurons and/or neuronal circuits. A role for astrocytes also has been shown in promoting recovery from volatile anesthesia, while the exact modulatory mechanism and/or the molecular target in astrocytes is still unknown. In this study by animal models in male mice and electrophysiological recordings in vivo and in vitro, we found that activating astrocytes of the paraventricular thalamus (PVT) and/or knocking down PVT astrocytic Kir4.1 promoted the consciousness recovery from sevoflurane anesthesia. Single-cell RNA sequencing of the PVT reveals two distinct cellular subtypes of glutamatergic neurons: PVT GRM and PVT ChAT neurons. Patch-clamp recording results proved astrocytic Kir4.1-mediated modulation of sevoflurane on the PVT mainly worked on PVT ChAT neurons, which projected mainly to the mPFC. In summary, our findings support the novel conception that there is a specific PVT→prefrontal cortex projection involved in consciousness recovery from sevoflurane anesthesia, which is mediated by the inhibition of sevoflurane on PVT astrocytic Kir4.1 conductance.

Loss of sodium leak channel (NALCN) in the ventral dentate gyrus impairs neuronal activity of the glutamatergic neurons for inflammation-induced depression in male mice.

BACKGROUND: The dentate gyrus (DG) has been implicated in the pathophysiology of depression. Many studies have revealed the cellular types, neural circuits, and morphological changes of the DG involved in the development of depression. However, the molecular regulating its intrinsic activity in depression is unknown. METHODS: Utilizing the mode of depression induced by lipopolysaccharide (LPS), we investigate the involvement of the sodium leak channel (NALCN) in inflammation-induced depressive-like behaviors of male mice. The expression of NALCN was detected by immunohistochemistry and real-time polymerase chain reaction. DG microinjection of the adeno-associated virus or lentivirus was carried out using a stereotaxic instrument and followed by behavioral tests. Neuronal excitability and NALCN conductance were recorded by whole-cell patch-clamp techniques. RESULTS: The expression and function of NALCN were reduced in both the dorsal and ventral DG in LPS-treated mice; whereas, only knocking down NALCN in the ventral pole produced depressive-like behaviors and this effect of NALCN was specific to ventral glutamatergic neurons. The excitability of ventral glutamatergic neurons was impaired by both the knockdown of NALCN and/or the treatment of LPS. Then, the overexpression of NALCN in the ventral glutamatergic neurons decreased the susceptibility of mice to inflammation-induced depression, and the intracranial injection of substance P (non-selective NALCN activator) into the ventral DG rapidly ameliorated inflammation-induced depression-like behaviors in an NALCN-dependent manner. CONCLUSIONS: NALCN, which drives the neuronal activity of the ventral DG glutamatergic neurons, uniquely regulates depressive-like behaviors and susceptibility to depression. Therefore, the NALCN of glutamatergic neurons in the ventral DG may present a molecular target for rapid antidepressant drugs.

Isoflurane Suppresses Hippocampal High-frequency Ripples by Differentially Modulating Pyramidal Neurons and Interneurons in Mice.

BACKGROUND: Isoflurane can induce anterograde amnesia. Hippocampal ripples are high-frequency oscillatory events occurring in the local field potentials of cornu ammonis 1 involved in memory processes. The authors hypothesized that isoflurane suppresses hippocampal ripples at a subanesthetic concentration by modulating the excitability of cornu ammonis 1 neurons. METHODS: The potencies of isoflurane for memory impairment and anesthesia were measured in mice. Hippocampal ripples were measured by placing recording electrodes in the cornu ammonis 1. Effects of isoflurane on the excitability of hippocampal pyramidal neurons and interneurons were measured. A simulation model of ripples based on the firing frequency of hippocampal cornu ammonis 1 neurons was used to validate the effects of isoflurane on neuronal excitability in vitro and on ripples in vivo. RESULTS: Isoflurane at 0.5%, which did not induce loss of righting reflex, impaired hippocampus-dependent fear memory by 97.4 ± 3.1% (mean ± SD; n = 14; P < 0.001). Isoflurane at 0.5% reduced ripple amplitude (38 ± 13 vs. 42 ± 13 µV; n = 9; P = 0.003), rate (462 ± 66 vs. 538 ± 81 spikes/min; n = 9; P = 0.002) and duration (36 ± 5 vs. 48 ± 9 ms; n = 9; P < 0.001) and increased the interarrival time (78 ± 7 vs. 69 ± 6 ms; n = 9; P < 0.001) and frequency (148.2 ± 3.9 vs. 145.0 ± 2.9 Hz; n = 9; P = 0.001). Isoflurane at the same concentration depressed action potential frequency in fast-spiking interneurons while slightly enhancing action potential frequency in cornu ammonis 1 pyramidal neurons. The simulated effects of isoflurane on hippocampal ripples were comparable to recordings in vivo. CONCLUSIONS: The authors' results suggest that a subanesthetic concentration of isoflurane can suppress hippocampal ripples by differentially modulating the excitability of pyramidal neurons and interneurons, which may contribute to its amnestic action.

Volatile anesthetics maintain tidal volume and minute ventilation to a greater degree than propofol under spontaneous respiration.

BACKGROUND: Although general anesthetics depress spontaneous respiration, the comprehensive effect of general anesthetics on respiratory function remains unclear. We aimed to investigate the effects of general anesthetics on spontaneous respiration in non-intubated mice with different types and doses of general anesthetic. METHODS: Adult C57BL/6 J mice were administered intravenous anesthetics, including propofol and etomidate, and inhalational anesthetics, including sevoflurane and isoflurane in vivo at doses of 0.5-, 1.0-, and 2.0-times the minimum alveolar concentration (MAC)/median effective dose (ED50) to induce loss of the righting reflex (LORR). Whole-body plethysmography (WBP) was applied to measure parameters of respiration under unrestricted conditions without endotracheal intubation. The alteration in respiratory sensitivity to carbon dioxide (CO2) under general anesthesia was also determined. The following respiratory parameters were continuously recorded during anesthesia or CO2 exposure: respiratory frequency (FR), tidal volume (TV), minute ventilation (MV), expiratory time (TE), inspiratory time (TI), and inspiratory-expiratory time ratio (I/E), and peak inspiratory flow. RESULTS: Sub-anesthetic concentrations (0.5 MAC) of sevoflurane or isoflurane increased FR, TV, and MV. With isoflurane and sevoflurane exposure, the CO2-evoked increases in FR, TV, and MV were decreased. Compared with inhalational anesthetics, propofol and etomidate induced respiratory suppression, affecting FR, TV, and MV. In 100% oxygen (O2), FR in the group that received propofol 1.0-times the ED50 was 69.63 ± 33.44 breaths/min compared with 155.68 ± 64.42 breaths/min in the etomidate-treated group. In the same groups, FR was 88.72 ± 34.51 breaths/min and 225.10 ± 59.82 breaths/min, respectively, in 3% CO2 and 144.17 ± 63.25 breaths/min and 197.70 ± 41.93 breaths/min, respectively, in 5% CO2. A higher CO2 sensitivity was found in etomidate-treated mice compared with propofol-treated mice. In addition, propofol induced a greater decrease in FR, MV, and I/E ratio compared with etomidate, sevoflurane, and isoflurane at equivalent doses (all P < 0.05). CONCLUSIONS: General anesthetics differentially modulate spontaneous breathing in vivo. Volatile anesthetics increase FR, TV, and MV at sub-anesthetic concentrations, while they decrease FR at higher concentrations. Propofol consistently depressed respiratory parameters to a greater degree than etomidate.

Effects of sevoflurane anesthesia and abdominal surgery on the systemic metabolome: a prospective observational study.

BACKGROUND: Metabolic status can be impacted by general anesthesia and surgery. However, the exact effects of general anesthesia and surgery on systemic metabolome remain unclear, which might contribute to postoperative outcomes. METHODS: Five hundred patients who underwent abdominal surgery were included. General anesthesia was mainly maintained with sevoflurane. The end-tidal sevoflurane concentration (ETsevo) was adjusted to maintain BIS (Bispectral index) value between 40 and 60. The mean ETsevo from 20 min after endotracheal intubation to 2 h after the beginning of surgery was calculated for each patient. The patients were further divided into low ETsevo group (mean - SD) and high ETsevo group (mean + SD) to investigate the possible metabolic changes relevant to the amount of sevoflurane exposure. RESULTS: The mean ETsevo of the 500 patients was 1.60% ± 0.34%. Patients with low ETsevo (n = 55) and high ETsevo (n = 59) were selected for metabolomic analysis (1.06% ± 0.13% vs. 2.17% ± 0.16%, P < 0.001). Sevoflurane and abdominal surgery disturbed the tricarboxylic acid cycle as identified by increased citrate and cis-aconitate levels and impacted glycometabolism as identified by increased sucrose and D-glucose levels in these 114 patients. Glutamate metabolism was also impacted by sevoflurane and abdominal surgery in all the patients. In the patients with high ETsevo, levels of L-glutamine, pyroglutamic acid, sphinganine and L-selenocysteine after sevoflurane anesthesia and abdominal surgery were significantly higher than those of the patients with low ETsevo, suggesting that these metabolic changes might be relevant to the amount of sevoflurane exposure. CONCLUSIONS: Sevoflurane anesthesia and abdominal surgery can impact principal metabolic pathways in clinical patients including tricarboxylic acid cycle, glycometabolism and glutamate metabolism. This study may provide a resource data for future studies about metabolism relevant to general anaesthesia and surgeries. TRIAL REGISTRATION: www.chictr.org.cn . identifier: ChiCTR1800014327 .

[Effect of Long-time Postnatal Exposure to Sevoflurane on Causing Attention-deficit/Hyperactivity Disorder in Rats].

OBJECTIVE: To investigate whether long-term exposure to inhaled sevoflurane, a volatile anesthetic, causes abnormal activities and memory impairment related to attention-deficit/hyperactivity disorder (ADHD) in neonatal rats. METHODS: On postnatal day 5 (P5), Sprague-Dawley rats were randomly assigned to two sevoflurane subgroups and two control subgroups and underwent experimental intervention. The two sevoflurane (SEVO) subgroups were exposed to 3% sevoflurane for 2 h and 4 h respectively, while the two control subgroups were given pure oxygen for the same amount and duration. Behavioral tests, including open-field test (OFT), five-choice serial reaction time task (5-CSRTT), fear-conditioning (FC) and Morris water maze (MWM), were applied to evaluate changes in cognition, memory, anxiety and ADHD-related behavioral changes in the rats in adolescence (-P25) and in adulthood (-P65). RESULTS: In OFT, the SEVO 2 h and SEVO 4 h subgroups displayed activity level and exploratory behaviors similar to those of the control subgroups on P21 and P61, with no statistically significant difference identified in the data. 5-CSRTT results on P25 and P65 indicated no statistically significant difference between the SEVO subgroups and the control subgroups in regard to ADHD-related abnormal behaviors, including number of immature reaction, rate of correct response and omission rate. In the FC experiment, SEVO 4 h group had a shorter freezing period and longer period of freezing latency ( P=0.029) in comparison to the control groups. The results of the MWM test showed that the escape latency period of rats in the SEVO 4 h group was significantly prolonged on the second day and the third day, compared to the control groups ( P<0.05). The average swimming speed of SEVO groups did no exhibit any statistically significant difference on P69 or P76. The time the SEVO 4 h group spent in the target quadrant was significantly shorter than that of the control group ( P=0.039) and percentage of distance traveled in the target quadrant was significantly reduced compared to that the control group ( P=0.048). CONCLUSION: The findings suggest that four hours of inhaled sevoflurane exposure in neonate rats may cause memory impairment, but does no increase risks for ADHD-related abnormal activities.

Isoflurane inhibits a Kir4.1/5.1-like conductance in neonatal rat brainstem astrocytes and recombinant Kir4.1/5.1 channels in a heterologous expression system.

All inhalation anesthetics used clinically including isoflurane can suppress breathing; since this unwanted side effect can persist during the postoperative period and complicate patient recovery, there is a need to better understand how isoflurane affects cellular and molecular elements of respiratory control. Considering that astrocytes in a brainstem region known as the retrotrapezoid nucleus (RTN) contribute to the regulation of breathing in response to changes in CO2/H+ (i.e., function as respiratory chemoreceptors), and astrocytes in other brain regions are highly sensitive to isoflurane, we wanted to determine whether and how RTN astrocytes respond to isoflurane. We found that RTN astrocytes in slices from neonatal rat pups (7-12 days postnatal) respond to clinically relevant levels of isoflurane by inhibition of a CO2/H+-sensitive Kir4.1/5.1-like conductance [50% effective concentration (EC50) = 0.8 mM or ~1.7%]. We went on to confirm that similar levels of isoflurane (EC50 = 0.53 mM or 1.1%) inhibit recombinant Kir4.1/5.1 channels but not homomeric Kir4.1 channels expressed in HEK293 cells. We also found that exposure to CO2/H+ occluded subsequent effects of isoflurane on both native and recombinant Kir4.1/5.1 currents. These results identify Kir4.1/5.1 channels in astrocytes as novel targets of isoflurane. These results suggest astrocyte Kir4.1/5.1 channels contribute to certain aspects of general anesthesia including altered respiratory control.NEW & NOTEWORTHY An unwanted side effect of isoflurane anesthesia is suppression of breathing. Despite this clinical significance, effects of isoflurane on cellular and molecular elements of respiratory control are not well understood. Here, we show that isoflurane inhibits heteromeric Kir4.1/5.1 channels in a mammalian expression system and a Kir4.1/5.1-like conductance in astrocytes in a brainstem respiratory center. These results identify astrocyte Kir4.1/5.1 channels as novel targets of isoflurane and potential substrates for altered respiratory control during isoflurane anesthesia.

Volatile Anesthetics Activate a Leak Sodium Conductance in Retrotrapezoid Nucleus Neurons to Maintain Breathing during Anesthesia in Mice.

BACKGROUND: Volatile anesthetics moderately depress respiratory function at clinically relevant concentrations. Phox2b-expressing chemosensitive neurons in the retrotrapezoid nucleus, a respiratory control center, are activated by isoflurane, but the underlying mechanisms remain unclear. The hypothesis of this study was that the sodium leak channel contributes to the volatile anesthetics-induced modulation of retrotrapezoid nucleus neurons and to respiratory output. METHODS: The contribution of sodium leak channels to isoflurane-, sevoflurane-, and propofol-evoked activity of Phox2b-expressing retrotrapezoid nucleus neurons and respiratory output were evaluated in wild-type and genetically modified mice lacking sodium leak channels (both sexes). Patch-clamp recordings were performed in acute brain slices. Whole-body plethysmography was used to measure the respiratory activity. RESULTS: Isoflurane at 0.42 to 0.50 mM (~1.5 minimum alveolar concentration) increased the sodium leak channel-mediated holding currents and conductance from -75.0 ± 12.9 to -130.1 ± 34.9 pA (mean ± SD, P = 0.002, n = 6) and 1.8 ± 0.5 to 3.6 ± 1.0 nS (P = 0.001, n = 6), respectively. At these concentrations, isoflurane increased activity of Phox2b-expressing retrotrapezoid nucleus neurons from 1.1 ± 0.2 to 2.8 ± 0.2 Hz (P < 0.001, n = 5), which was eliminated by bath application of gadolinium or genetic silencing of sodium leak channel. Genetic silencing of sodium leak channel in the retrotrapezoid nucleus resulted in a diminished ventilatory response to carbon dioxide in mice under control conditions and during isoflurane anesthesia. Sevoflurane produced an effect comparable to that of isoflurane, whereas propofol did not activate sodium leak channel-mediated holding conductance. CONCLUSIONS: Isoflurane and sevoflurane increase neuronal excitability of chemosensitive retrotrapezoid nucleus neurons partly by enhancing sodium leak channel conductance. Sodium leak channel expression in the retrotrapezoid nucleus is required for the ventilatory response to carbon dioxide during anesthesia by isoflurane and sevoflurane, thus identifying sodium leak channel as a requisite determinant of respiratory output during anesthesia of volatile anesthetics.

Feasibility of the Use of Transesophageal Echocardiography as a Surface Probe for Puncturing and Catheterization of the Internal Jugular Vein: A Randomized Controlled Pilot Study.

OBJECTIVE: To compare the transesophageal echocardiography (TEE) probe as a surface probe with the vascular probe for guiding internal jugular vein (IJV) catheterization. DESIGN: Prospective, randomized, controlled pilot study. SETTING: University hospital. PARTICIPANTS: One hundred cardiac surgery patients, including 50 adult and 50 pediatric patients. INTERVENTIONS: Patients in the TEE probe group received right IJV catheterization using the TEE probe, while the vascular probe group used the vascular probe for catheterization. MEASUREMENTS AND MAIN RESULTS: The puncture time, first-attempt success rate, quality of the imaging with needle tip positioning, wire positioning, and catheter positioning were recorded. The incidence of complication or any adverse event also was observed. Adult patients: In the vascular probe group, the success rate for first attempt IJV catheterization was 24/25 (96%), while in the TEE probe group, the success rate for first attempt IJV catheterization was 25/25 (100%). There was no statistical difference in the puncture time, image quality, needle tip positioning, wire positioning, and catheter positioning between groups (p > 0.05). Pediatric patients: The success rate for first-attempt IJV catheterization was 100% in both groups, and there were no statistical differences in the puncture time, image quality, and positioning between the 2 groups (p > 0.05). No complications or adverse events were observed in either group. CONCLUSION: The TEE probe, used as a surface probe, can be used to guide IJV puncturing and catheterization in cardiac surgery patients with favorable feasibility and safety.

Effect of subchronic exposure to opioids on the effective dose of intravenous and inhalation anaesthetics.

This study aimed to investigate the effect of subchronic exposure to morphine on the 50% effective dose (EC50) (median effective concentration/EC50) values of intravenous (propofol and ketamine) and inhalation (sevoflurane) anaesthetics in mice. Eight to 12-week-old male mice were administered morphine subcutaneously for 5 days to create a subchronic morphine exposure model. Control mice were injected with saline. The EC50 for righting reflex loss and tail clip reflex of general anaesthetics on the first (D1), third (D3) and seventh days (D7), after establishing a subchronic morphine exposure model, were determined. Sevoflurane: No change in the minimum alveolar concentration for righting reflex loss or tail clip reflex loss was observed between the treated and the control values (P>0.05). Propofol: the EC50 for righting reflex loss of D7 was significantly lower than the control and D1 (P<0.05). The EC50 for tail clip reflex loss of D3 and D7 decreased compared with the control (P<0.05). Ketamine: the EC50 for righting reflex loss of D3 and D7 was significantly higher than that of the controls. The EC50 for tail clip reflex loss at D1, D3 and D7 increased compared with the control (P<0.05). In summary, after subchronic exposure to morphine, the minimum alveolar concentration value of sevoflurane did not change significantly; the EC50 of propofol decreased, whereas the EC50 of ketamine increased. The changes induced by subchronic exposure to morphine can alter the response to anaesthetics, and the effects vary with the modes of action of anaesthetics.

Metabolic change in monocytes and postoperative morbidity after major abdominal surgery in elderly patients: A prospective cohort study.

Background: Postoperative complications in aging patients remain a significant cause of increased costs, hospital length of stay, and patient distress. Although alterations in energy metabolism have been closely linked to aging process and surgery, it is still unclear whether metabolic changes during surgery is associated with postoperative complications in elderly patients. This study was conducted to investigate whether metabolic changes during surgery predicts postoperative complications in elderly patients. Methods: We conducted a prospective single-center observational cohort study. 244 adults (aged ≥65 years) who were scheduled for elective major non-cardiac surgery were recruited. Blood samples for each patient were taken before and after surgery. All patients were randomly divided into two groups (122 in each group), then oxygen consumption rate (OCR) or extracellular acidification rate (ECAR) was measured on isolated monocytes in each group. Results: 14 of 110 (12.7%) patients went through OCR measurement and 15 of 122 patients (12.3%) went through ECAR measurement experienced moderate to severe complications. Overall, there was an intensification of glycolysis in monocytes after surgery. Among all variables, only the change (preoperative -postoperative) of glycolytic reserve (GR)/glycolysis (G) and GR/non-glycolytic acidification (NG) were predictors of moderate to severe complications (AUC = 0.70; 95% CI, 0.56-0.81; P = 0.019 and AUC = 0.67; 95% CI, 0.55-0.80; P = 0.031). Decreased postoperative GR/G were associated with worse postoperative complications (RR = 9.08; 95% CI, 1.23-66.81; P = 0.024). Conclusions: Compared with mitochondria function, the change of glycolytic function in monocyte was more valuable in predicting postoperative complications after major abdominal surgery. Our study gave us a new insight into identifying patients at high risk in aging patients.

The Modulation by Anesthetics and Analgesics of Respiratory Rhythm in the Nervous System.

Rhythmic eupneic breathing in mammals depends on the coordinated activities of the neural system that sends cranial and spinal motor outputs to respiratory muscles. These outputs modulate lung ventilation and adjust respiratory airflow, which depends on the upper airway patency and ventilatory musculature. Anesthetics are widely used in clinical practice worldwide. In addition to clinically necessary pharmacological effects, respiratory depression is a critical side effect induced by most general anesthetics. Therefore, understanding how general anesthetics modulate the respiratory system is important for the development of safer general anesthetics. Currently used volatile anesthetics and most intravenous anesthetics induce inhibitory effects on respiratory outputs. Various general anesthetics produce differential effects on respiratory characteristics, including the respiratory rate, tidal volume, airway resistance, and ventilatory response. At the cellular and molecular levels, the mechanisms underlying anesthetic-induced breathing depression mainly include modulation of synaptic transmission of ligand-gated ionotropic receptors (e.g., γ-aminobutyric acid, N-methyl-D-aspartate, and nicotinic acetylcholine receptors) and ion channels (e.g., voltage-gated sodium, calcium, and potassium channels, two-pore domain potassium channels, and sodium leak channels), which affect neuronal firing in brainstem respiratory and peripheral chemoreceptor areas. The present review comprehensively summarizes the modulation of the respiratory system by clinically used general anesthetics, including the effects at the molecular, cellular, anatomic, and behavioral levels. Specifically, analgesics, such as opioids, which cause respiratory depression and the "opioid crisis", are discussed. Finally, underlying strategies of respiratory stimulation that target general anesthetics and/or analgesics are summarized.

Combination of Creatinine with Inflammatory Biomarkers (PCT, CRP, hsCRP) for Predicting Postoperative ICU Admissions for Elderly Patients.

INTRODUCTION: The number of elderly patients who require surgery as their primary treatment has increased rapidly in recent years. Among 300 million people globally who underwent surgery every year, patients aged 65 years and over accounted for more than 30% of cases. Despite medical advances, older patients remain at higher risk of postoperative complications. Early diagnosis and effective prediction are essential requirements for preventing serious postoperative complications. In this study, we aim to provide new biomarker combinations to predict the incidence of postoperative intensive care unit (ICU) admissions > 24 h in elderly patients. METHODS: This investigation was conducted as a nested case-control study, incorporating 413 participants aged ≥ 65 years who underwent non-cardiac, non-urological elective surgeries. These individuals underwent a 30-day postoperative follow-up. Before surgery, peripheral venous blood was collected for analyzing serum creatinine (Scr), procalcitonin (PCT), C-reactive protein (CRP), and high-sensitivity CRP (hsCRP). The efficacy of these biomarkers in predicting postoperative complications was evaluated using receiver operating characteristic (ROC) curve analysis and area under the curve (AUC) values. RESULTS: Postoperatively, 10 patients (2.42%) required ICU admission. Regarding ICU admissions, the AUCs with 95% confidence intervals (CIs) for the biomarker combinations of Scr × PCT and Scr × CRP were 0.750 (0.655-0.845, P = 0.007) and 0.724 (0.567-0.882, P = 0.015), respectively. Furthermore, cardiovascular events were observed in 14 patients (3.39%). The AUC with a 95% CI for the combination of Scr × CRP in predicting cardiovascular events was 0.688 (0.560-0.817, P = 0.017). CONCLUSION: The innovative combinations of biomarkers (Scr × PCT and Scr × CRP) demonstrated efficacy as predictors for postoperative ICU admissions in elderly patients. Additionally, the Scr × CRP also had a moderate predictive value for postoperative cardiovascular events. TRIAL REGISTRATION: China Clinical Trial Registry, ChiCTR1900026223.

Predictive value of perioperative procalcitonin, C reactive protein and high-sensitivity C reactive protein for the risk of postoperative complications after non-cardiac surgery in elderly patients: a nested case-control study.

OBJECTIVE: Little is known about the correlation between perioperative concentrations of inflammatory biomarkers and postoperative complications. This study explored whether the plasma concentrations and perioperative changes of procalcitonin (PCT), C reactive protein (CRP) and high-sensitivity CRP (hsCRP) could predict the risk of postoperative morbidity in elderly patients undergoing elective non-cardiac surgery. DESIGN: A nested case-control study. SETTING: A tertiary hospital in China. PARTICIPANTS: A total of 498 patients aged ≥65 years from a prospective cohort who underwent elective non-cardiac surgery between June 2020 and April 2021. PRIMARY OUTCOME MEASURES: The primary outcomes were the efficacy of plasma concentrations of PCT, CRP and hsCRP in predicting the risk of Clavien-Dindo Classification (CDC) ≥grade 3 and major complications. The major complications included mortality, an intensive care unit stay length >24 hour, cardiovascular events, acute kidney injury, postoperative cognitive dysfunction and infections. RESULTS: For major complications, the area under the curve (AUC) (95% CI) of PCT-24 hours, PCT change and PCT change rate were 0.750 (0.698 to 0.803), 0.740 (0.686 to 0.795) and 0.711 (0.651 to 0.771), respectively. The AUC (95% CI) of CRP-24 hours, CRP change, CRP change rate and hsCRP baseline were 0.835 (0.789 to 0.881), 0.818 (0.770 to 0.867), 0.691 (0.625 to 0.756) and 0.616 (0.554 to 0.678), respectively. For complications ≥CDC grade 3, the AUC (95% CI) of PCT-24 hours, PCT change and PCT change rate were 0.662 (0.543 to 0.780), 0.643 (0.514 to 0.772) and 0.627 (0.494 to 0.761), respectively. The AUC (95% CI) of CRP-24 hours and hsCRP baseline were 0.649 (0.527 to 0.771) and 0.639 (0.530 to 0.748), respectively. CONCLUSIONS: PCT-24 hours, CRP-24 hours, the change of perioperative PCT and CRP were valuable predictors of major complications occurring within 30 days after non-cardiac surgery in the elderly. TRIAL REGISTRATION NUMBER: China Clinical Trial Registry: ChiCTR1900026223.

Trajectory of pain threshold and its association with acute pain after thoracic surgery: a prospective observational study.

BACKGROUND: Postoperative analgesic management is an ongoing challenge. The pain threshold (PT) is an objective index that reflects the body's sensitivity to pain and can be used for quantitative pain assessment. We hypothesized that the PT is correlated with postoperative pain and can thus be used to guide postoperative pain management. METHODS: This study involved 93 patients who underwent thoracoscopic surgery from December 2019 to February 2020. The PT was measured with transcutaneous electrical stimulation before surgery (T0) and at 1 h (T1), 6 h (T6), and 24 h (T24) after surgery. The visual analogue scale (VAS) score was used to evaluate the severity of postoperative pain at the same time. The PT variation (PTV) after surgery was calculated as the ratio of the postoperative PT to preoperative PT. RESULTS: The postoperative PT was higher than the preoperative PT and showed a downward trend within 24 h after surgery; the PTV also showed a downward trend within 24 h after surgery. PT-T1 was negatively correlated with VAS-T1 at rest and during motion (rest: VAS-T1r = - 0.274, P = 0.008; motion: VAS-T1r = - 0.298, P = 0.004). PTV-T1 was negatively correlated with VAS-T1 during motion (r = - 0.213, P = 0.04). Lower VAS-T1 scores (< 4) at rest and during motion were associated with higher PT-T1 (rest: t = 2.452, P = 0.016; motion: t = 2.138, P = 0.035). The intraoperative sufentanil dose was associated with a postoperative increase in PTV-T1. Increased rescue analgesic administration was associated with PTV elevation. However, the incidence of dizziness in patients with moderate PTV-T24 was lower than that in patients with high or low PTV-T24 (χ2 = 8.297, P = 0.015). CONCLUSIONS: The postoperative PT was higher than the preoperative PT and showed a downward trend within 24 h after surgery; PTV also showed a downward trend within 24 h after surgery. The PT and PTV were negatively correlated with the pain intensity at rest and during motion and were associated with perioperative analgesic consumption and the incidence of adverse events.

Spinal astrocytic MeCP2 regulates Kir4.1 for the maintenance of chronic hyperalgesia in neuropathic pain.

Astrocyte activation in the spinal dorsal horn may play an important role in the development of chronic neuropathic pain, but the mechanisms involved in astrocyte activation and their modulatory effects remain unknown. The inward rectifying potassium channel protein 4.1 (Kir4.1) is the most important background K+ channel in astrocytes. However, how Kir4.1 is regulated and contributes to behavioral hyperalgesia in chronic pain is unknown. In this study, single-cell RNA sequencing analysis indicated that the expression levels of both Kir4.1 and Methyl-CpG-binding protein 2 (MeCP2) were decreased in spinal astrocytes after chronic constriction injury (CCI) in a mouse model. Conditional knockout of the Kir4.1 channel in spinal astrocytes led to hyperalgesia, and overexpression of the Kir4.1 channel in spinal cord relieved CCI-induced hyperalgesia. Expression of spinal Kir4.1 after CCI was regulated by MeCP2. Electrophysiological recording in spinal slices showed that knockdown of Kir4.1 significantly up-regulated the excitability of astrocytes and then functionally changed the firing patterns of neurons in dorsal spinal cord. Therefore, targeting spinal Kir4.1 may be a therapeutic approach for hyperalgesia in chronic neuropathic pain.

Efficacy of Bioenergetic Health Index to Predict Delirium After Major Abdominal Surgery in Elderly Patients: A Protocol for a Prospective Observational Cohort Study.

Introduction: Postoperative delirium (POD) is a common disorder following surgery, which seriously threatens the quality of patients' life, especially the older people. The multifactorial manner of this syndrome has made it hard to define an ideal method to predict individual risk. Mitochondria play a key role in the process of POD, which include inflammatory on the brain caused by surgeries and aging related neurodegeneration. As BHI (Bioenergetic Health Index) could be calculated in cells isolated from an individual's blood to represent the patient's composite mitochondrial statue, we hypotheses that HBI of monocytes isolated from individual's peripheral blood can predict POD after major non-cardiac surgery in elderly patients. Methods and Analysis: This is a prospective, observational single-blinded study in a single center. 124 patients aged ≥ 65 years and scheduled for major abdominal surgery (>3 h) under general anesthesia will be enrolled. Preoperative and postoperative delirium will be assessed by trained members using Confusion Assessment Method (CAM). For patients unable to speak in the ICU after the surgery, Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) will be used. All patients will undergo venous blood sampling twice to measure BHI (1-2 tubes, 5 ml/tube): before the surgery and 1 day after surgery in wards. After discharge, patients will be contacted by telephone 30 days after surgery to confirm the incidence of post-discharge complications. The severity of complications will be categorized as mild, moderate, severe or fatal using a modified Clavien-Dindo Classification (CDC) scheme. Ethics and Dissemination: The study has been approved by the Ethics Committee on Biomedical Research, West China Hospital of Sichuan University, Sichuan, China (Chairperson Prof Shaolin Deng, No. 2021-502). Study data will be disseminated in manuscripts submitted to peer-reviewed medical journals as well as in abstracts submitted to congresses. Clinical Trial Registration: [www.ClinicalTrials.gov], identifier [ChiCTR2100047554].

Putative Roles of Astrocytes in General Anesthesia.

General anesthetics are a mainstay of modern medicine, and although much progress has been made towards identifying molecular targets of anesthetics and neural networks contributing to endpoints of general anesthesia, our understanding of how anesthetics work remains unclear. Reducing this knowledge gap is of fundamental importance to prevent unwanted and life-threatening side-effects associated with general anesthesia. General anesthetics are chemically diverse, yet they all have similar behavioral endpoints, and so for decades, research has sought to identify a single underlying mechanism to explain how anesthetics work. However, this effort has given way to the 'multiple target hypothesis' as it has become clear that anesthetics target many cellular proteins, including GABAA receptors, glutamate receptors, voltage-independent K+ channels, and voltagedependent K+, Ca2+ and Na+ channels, to name a few. Yet, despite evidence that astrocytes are capable of modulating multiple aspects of neural function and express many anesthetic target proteins, they have been largely ignored as potential targets of anesthesia. The purpose of this brief review is to highlight the effects of anesthetic on astrocyte processes and identify potential roles of astrocytes in behavioral endpoints of anesthesia (hypnosis, amnesia, analgesia, and immobilization).

Sodium Leak Channel in the Nucleus Accumbens Modulates Ethanol-Induced Acute Stimulant Responses and Locomotor Sensitization in Mice: A Brief Research Report.

Ethanol can induce acute stimulant responses in animals and human beings. Moreover, repeated exposure to ethanol may produce increased sensitivity to its acute locomotor stimulant actions, a process referred to as locomotor sensitization. The molecular mechanism of the development of acute stimulant responses and locomotor sensitization by ethanol is not fully understood. Sodium leak channel (NALCN) is widely expressed in central nervous system and controls the basal excitability of neurons. The present study aims to determine whether NALCN is implicated in the ethanol-induced acute responses and locomotor sensitization in mice. Here, our results showed that ethanol caused acute stimulant responses in DBA/2 mice. Locomotor sensitization was successfully induced following the sensitization procedure. Accordingly, the expression levels of NALCN mRNA and protein in the nucleus accumbens (NAc) were markedly increased in the sensitization mice compared to the control mice. Knockdown the expression levels of NALCN in the NAc alleviated both the ethanol-induced acute responses and locomotor sensitization. Our findings indicate that upregulation of NALCN expression in the NAc contributes to the ethanol-induced acute stimulant responses and locomotor sensitization in DBA/2 mice.

A Combination of N-Terminal proB-Type Natriuretic Peptide and Myoglobin Can Predict Severe Complications After Major Non-Cardiac Surgery in Elderly Patients: A Prospective Observational Cohort Study.

Background: Previous studies have demonstrated that serum N-terminal proB-type natriuretic peptide (NT-proBNP) was a predictor of adverse cardiovascular outcomes after surgery. We performed a prospective study to evaluate if NT-proBNP could be a sensitive marker of overall postoperative outcomes in older patients undergoing major elective non-cardiac surgery when combined with myoglobin (MYO). Methods: Two hundred and three adults aged ≥65 years were enrolled in the study. The American Society of Anesthesiologists (ASA) physical status of patients were I to IV. Blood samples would be taken before and 2 h after the surgery for each patients and NT-proBNP and MYO concentrations (NT-proBNP baseline/ 2 h and MYO baseline/ 2 h) of these samples would be measured immediately. The primary outcome was moderate to severe complications, which were based on the Clavien-Dindo Classification (CDC) scheme (≥CDC grade 3), and the secondary outcomes were major complications within 30 days after surgery. This study was registered at China Clinical Trial Registry (ChiCTR1900026223, http://www.chictr.org.cn/). Results: Overall, moderate to severe complications occurred in 15 patients (7.4%) and major complications occurred in 18 patients (8.9%). Both preoperative and postoperative NT-proBNP values were independent predictors of moderate to severe complications (area under the curve (AUC), 0.820; 95% CI: 0.728, 0.912, P < 0.001; AUC, 0.785; 95% CI: 0.685, 0.885, P < 0.001). When NT-proBNP baseline and MYO-2 h were combined (NT-proBNP baseline × MYO-2 h), the predictive power was improved (AUC 0.841, 95% CI: 0.758, 0.923, P < 0.001). Conclusions: A combination of perioperative NT-proBNP and postoperative MYO concentrations was a good predictor of postoperative complications in elderly patients who underwent major non-cardiac surgery. Using fast and dynamic tests provided by point-to-care-testing, NT-proBNP and MYO concentration measurements provided useful guidance for therapy before or soon after surgery, thus helping to reduce postoperative complications in elderly patients.