Effectiveness of general anaesthesia with remimazolam tosilate on intraoperative haemodynamics and postoperative recovery: study protocol for a randomised, positive-controlled, pragmatic clinical trial (GARTH trial).

INTRODUCTION: It is encouraged to estimate the effectiveness of components within the enhanced recovery after surgery (ERAS) protocol through patient-reported outcomes, alongside doctor-reported outcomes and length of hospital stay. At present, studies on the contributions of optimal anaesthetic drugs within the ERAS protocol to patient-reported and doctor-reported outcomes are limited. Therefore, this study aims to pragmatically evaluate the effectiveness and safety of general anaesthesia (GA) with remimazolam tosilate within the ERAS protocol on intraoperative haemodynamics and postoperative recovery in adults undergoing elective surgeries, compared with propofol. METHODS AND ANALYSIS: This study is a single-centre, randomised, blinded, positive-controlled, pragmatic clinical trial. A total of 900 patients, aged ≥18 years old, scheduled for an elective surgical procedure under GA will be included. Patients will be randomised in a 1:1 ratio to the remimazolam group (the GA with remimazolam tosilate within the ERAS protocol group) or propofol group (the GA with propofol within the ERAS protocol group), stratified by general surgery, thoracic surgery and other surgeries (including urological surgery and otolaryngology surgery). The primary outcomes include the 24-hour postoperative quality of recovery-40 score and the rate of intraoperative hypotension. Secondary endpoints include the rate of sedative hypotension requiring treatment, the haemodynamic profiles, the 72-hour postoperative quality of recovery-40 score, the functional anaesthetic capability, adverse events and complications, quality of life within 3 months as well as economic health outcomes. ETHICS AND DISSEMINATION: This study protocol has been approved by the ethics committee of Guangdong Provincial People's Hospital (KY-H-2022-005-03-08). Dissemination plans will be presented at scientific meetings and in scientific publications. TRIAL REGISTRATION NUMBER: ChiCTR2200062520.

Propofol maintains Th17/Treg cell balance in elderly patients undergoing lung cancer surgery through GABAA receptor.

Propofol is widely used in clinical anesthesia due to its advantages of rapid onset and less adverse reactions. This study focused on the role of propofol in the balance of Th17/Treg in elderly patients with lung cancer during perioperative period. Patients undergoing lung cancer surgery were anesthetized by propofol or sevoflurane. Veinal blood was collected at different time points to evaluate the changes of Th17/Treg cell. Propofol better maintained the balance of Th17/Treg in vivo. The peripheral blood of patients with lung cancer was collected in vitro before surgery. Cluster of differentiation (CD)4+ T cells were obtained and then treated with propofol at different concentrations and γ-aminobutyric acid A (GABAA) receptor antagonists. Propofol affected Th17/Treg cell balance by increasing Th17 cells, decreasing Treg cells, thus elevating Th17/Treg ratio, and inhibited invasion and migration of lung cancer cells through GABAA receptor, which was counteracted by GABAA receptor inhibitors. Subsequently, tumor in situ model of lung cancer in aged mice was established. Propofol anesthetized mice had lower change of Th17/Treg ratio, higher survival rate and less metastasis. In brief, propofol regulated balance of Th17/Treg in elderly patients undergoing lung cancer surgery through GABAA receptor. Additionally, propofol could inhibit metastasis of lung cancer.

Copy Number Analyses Identified a Novel Gene: APOBEC3A Related to Lipid Metabolism in the Pathogenesis of Preeclampsia.

Background: Preeclampsia is a heterogeneous and complex disease with its pathogenesis mechanism not fully elucidated. A certain subset of patients with preeclampsia exhibit disturbances in lipid metabolism before clinical symptoms. Moreover, there is a tendency for preeclampsia to run in families. Whether genetic factors play a role in abnormal lipid metabolism during the incidence of preeclampsia has not been well investigated. Methods: Preeclampsia patients (n = 110) and healthy age- and gravidity-matched pregnant women (n = 110) were enrolled in this study. Peripheral blood specimens were used for genomic analysis (n = 10/group) or laboratory validation (n = 100/group). We retrospectively obtained the baseline clinical characteristics of 68 preeclampsia patients and 107 controls in early pregnancy (12-14 gestational weeks). Correlation analyses between differential genes and baseline lipid profiles were performed to identify candidate genes. In vitro and in vivo gain-of-function models were constructed with lentivirus and adeno-associated virus systems, respectively, to investigate the role of candidate genes in regulating lipid metabolism and the development of preeclampsia. Results: We observed that preeclampsia patients exhibited significantly elevated plasma TC (P = 0.037) and TG (P < 0.001) levels and increased body mass index (P = 0.006) before the disease onset. Within the region of 27 differential copy number variations, six genes potentially connected with lipid metabolism were identified. The aberrant copies of APOBEC3A, APOBEC3A_B, BTNL3, and LMF1 between preeclampsia patients and controls were verified by quantitative polymerase chain reaction. Especially, APOBEC3A showed a significant positive correlation with TC (P < 0.001) and LDL (P = 0.048) in early pregnancy. Then, our in vitro data revealed that overexpression of APOBEC3A disrupted lipid metabolism in HepG2 cells and affected both cholesterol and fatty acid metabolisms. Finally, in vivo study in a hepatic-specific overexpressed APOBEC3A mouse model revealed abnormal parameters related to lipid metabolism. Pregnant mice of the same model at the end of pregnancy showed changes related to preeclampsia-like symptoms, such as increases in sFlt-1 levels and sFlt-1/PLGF ratios in the placenta and decreases in fetal weight. Conclusion: Our findings established a new link between genetics and lipid metabolism in the pathogenesis of preeclampsia and could contribute to a better understanding of the molecular mechanisms of preeclampsia.

Randomized controlled trial of an alternative drainage strategy vs routine chest tube insertion for postoperative pain after thoracoscopic wedge resection.

BACKGROUND: Thoracoscopic surgery has greatly alleviated the postoperative pain of patients, but postsurgical acute and chronic pain still exists and needs to be addressed. Indwelling drainage tubes are one of the leading causes of postoperative pain after thoracic surgery. Therefore, the aim of this study was to explore the effects of alternative drainage on acute and chronic pain after video-assisted thoracoscopic surgery (VATS). METHODS: Ninety-two patients undergoing lung wedge resection were selected and randomly assigned to the conventional chest tube (CT) group and the 7-Fr central venous catheter (VC) group. Next, the numeric rating scale (NRS) and pain DETECT questionnaire were applied to evaluate the level and characteristics of postoperative pain. RESULTS: NRS scores of the VC group during hospitalization were significantly lower than those of the CT group 6 h after surgery, at postoperative day 1, at postoperative day 2, and at the moment of drainage tube removal. Moreover, the number of postoperative salvage analgesics (such as nonsteroidal anti-inflammatory drugs [(NSAIDs]) and postoperative hospitalization days were notably reduced in the VC group compared with the CT group. However, no significant difference was observed in terms of NRS pain scores between the two groups of patients during the follow-up for chronic pain at 3 months and 6 months. CONCLUSION: In conclusion, a drainage strategy using a 7-Fr central VC can effectively relieve perioperative pain in selected patients undergoing VATS wedge resection, and this may promote the rapid recovery of such patients after surgery. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03230019. Registered July 23, 2017.

Effects of postoperative medical treatment and expectant treatment on dysmenorrhea after conservative laparoscopic surgery for deep-infiltrating endometriosis accompanied by dysmenorrhea.

OBJECTIVE: To compare the efficacy of postoperative adjuvant treatment (gonadotropin-releasing hormone agonists [GnRHas] and oral contraceptives [OCs]) and expectant treatment in preventing recurrent dysmenorrhea following conservative laparoscopic surgery for deep infiltrating endometriosis (DIE) with dysmenorrhea. METHODS: A prospective cohort study was conducted in Shanghai, China. In total, 147 patients with dysmenorrhea who underwent conservative laparoscopic surgery for DIE were enrolled. Following surgery, patients received either postoperative adjuvant therapy (GnRHa or OCs) for 6 months or expectant treatment according to a shared medical decision-making approach. The primary outcome was the postoperative recurrence of dysmenorrhea. The secondary outcomes included reproductive outcomes and drug-induced side effects. RESULTS: The generalized estimating equation analysis illustrated that the visual analog scale for dysmenorrhea was significantly higher in the adjuvant treatment group than in the expectant treatment group. Kaplan-Meier analysis and the log-rank test demonstrated that the cumulative recurrence rate was higher in the expectant treatment group than in the adjuvant treatment group, but no difference was noted between the two hormonal treatments. Similar cumulative 24-month clinical pregnancy rates were observed among the three groups. CONCLUSIONS: Compared with expectant management, postoperative medical treatment more effectively relieved symptoms and prevented the recurrence of dysmenorrhea.

[Postoperative low-dose sufentanil combined with transversus abdominis plane block promotes recovery following laparoscopic hysterectomy].

OBJECTIVE: To compare the efficacy and safety of postoperative analgesia with low-dose sufentanil combined with transversus abdominis plane (TAP) block and with sufentanil alone in promoting patients'recovery following laparoscopic hysterectomy. METHODS: Sixty patients undergoing laparoscopic hysterectomy in our hospital between September, 2016 and August, 2017 were randomly allocated into two equal groups. In group A, the patients were given postoperative analgesia with 1 µg/kg sufentanil, 9.96 mg tropisetronmesylate, and 200 mg flurbiprofen axetil (diluted with 0.9% NaCl solution to 100 mL, pumped at the rate of 2 mL/h) combined with TAP block; in group B, the patients received similar postoperative analgesia but at a higher dose of sufentanil (2 µg/kg) without TAP block. Visual analogue scale (VAS) was used to evaluate pain at 15 min and at 4, 8, 12, 24 and 48 h postoperatively, and the first off-bed time, the length of postoperative hospital stay and the incidence of postoperative nausea and vomiting (PONV) were recorded in all the patients. RESULTS: Compared with those in group B, the patients in group A had significantly lower VAS scores at 15 min, 4 h, 8 h, and 12 h postoperatively (P < 0.01) with also statistically shorter first off-bed time and postoperative hospital stay (P < 0.01). Two (6.7%) patients in group A had mild PONV, and 6 (20.0%) in group B had PONV (including 4 with mild and 2 with moderate PONV). CONCLUSIONS: Lowdose sufentanil combined with TAP block is effective for postoperative analgesia after laparoscopic hysterectomy and helps to reduce the incidence of PONV and shorten the first off-bed time and postoperative hospital stay to promote the recovery of the patients.

Midazolam prevents sevoflurane-induced death in hippocampal neurons.

Sevoflurane is a widely used anesthetics in surgery and considered as a safe reagent for clinical use. However, recent studies demonstrated that sevoflurane has a neurotoxic effect in central nervous system. Thus, finding ways to alleviate the side effect of sevoflurane is of importance. In this study, we identified the neuroprotective role of midazolam in hippocampal neurons. Midazolam treatment could alleviate the neuronal death and promote the neuronal maturation in hippocampal neurons in vitro. In vivo studies demonstrated that midazolam injection could improve behavioral deficit in sevoflurane-exposed animals. The anti-apoptotic function of midazolam in sevoflurane-exposed neurons was mediated by ERK signaling. Collectively, we elucidated a new role of midazolam in preventing hippocampal neuronal death from sevoflurane exposure, potentially providing a new strategy to resist the neurotoxicity in the clinical application of sevoflurane.

A comparison between laryngeal mask airway and endotracheal intubation for anaesthesia in adult patients undergoing NUSS procedure.

BACKGROUND: This study evaluates and compares the feasibility and safety of application of laryngeal mask airway (LMA) and endotracheal intubation (ETT) for anaesthesia in adult patients undergoing thoracoscopic surgery. METHODS: Sixty adult patients with pectus excavatum (PE) undergoing video-assisted thoracoscopic surgery for the NUSS procedure (VATS-NUSS) between September 2016 and March 2017 were selected and randomly separated into two groups with different methods of airway management. In one group, LMA was applied for general anaesthesia, and in the other group, ETT was used. The clinical parameters before, during and after the surgery in patients from both groups were collected from multiple data resources in a hospital. SPSS software was used for the analysis. RESULTS: Of all the selected patients, the physiological parameters showed similarity between the LMA and ETT groups, indicating consistency in the clinical characteristics of the study sample. Additionally, no significant differences were discovered between the two groups in terms of the anaesthesia and surgical time, peak PetCO2 during operation, anaesthetic satisfaction score, and amount of blood loss as well as inpatient time for recovery. However, with a similar level of anaesthesia effects and suitable parameters for mechanical ventilation, patients in the LMA group showed much more stability in the physiological indicators for inflammation and haemodynamics, including white blood cell count (ΔWBC) and percentage of neutrophil granulocytes (ΔNEU%) in the blood as well as heart rate (ΔHR) and mean arterial pressure (ΔMAP). Moreover, the LMA patients had a significantly shorter time for recovery of consciousness and food/water intake. Finally, compared to the ETT group, patients in the LMA group also had a significantly lower incidence of side effects induced by the anaesthesia procedure after surgery, such as gastrointestinal reactions, throat discomfort and hoarseness. CONCLUSIONS: Compared with ETT, the application of LMA for general anaesthesia may demonstrate promising advantages in airway management for the VATS-NUSS procedure.

[Application of sevoflurane and laryngeal mask in cesarean section in women with heart disease].

OBJECTIVE: To compare the safety of sevoflurane anesthesia with laryngeal mask and tracheal intubation in cesarean section in women with heart disease. METHODS: Fifty-two pregnant women with heart diseases undergoing cesarean section were randomized into laryngeal mask (LAM) group and tracheal intubation group. In LAM group, 6% sevoflurane was given at the rate of 6 L/min for induction with a maintenance sevoflurane concentration of 3%. In the intubation group, 1.5 mg/kg propofol and 1 µg/kg remifentanil were injected intravenously, and after achieving D0 with Narcotrend monitoring, 0.9 mg/kg rocuronium was injected and intubation was performed 1 min later. The systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), and heart rate (HR) were recorded in the two groups before anesthesia induction (T0), at intubation or laryngeal mask placement (T1), skin incision (T2), and extubation or laryngeal mask removal (T3). The surgery to fetal birth time, uterine incision to fetal childbirth time, drug discontinuation to awake time, and newborn Apgar scores were also recorded. Sevoflurane consumption and maternal comfort during hospitalization were compared between the two groups. RESULTS: In LAM group, HR and MBP at T1 and T3 were significantly lower than those in the intubation group (P<0.05). The drug discontinuation to extubation time and to awaken time were significantly shorter in LAM group than in the intubation group (P<0.05), but the operation time and fetal child birth time were comparable between the two groups (P>0.05). The women in LAM group reported better physical and psychological comforts than those in the intubation group (P<0.05). The neonatal Apgar scores and the scores of health education, satisfaction with hospital environment and service were all similar between the two groups (P>0.05). CONCLUSION: Sevoflurane anesthesia with laryngeal mask can achieve satisfactory anesthetic effects in cesarean section in women with heart disease.

The bifunctional effect of propofol on thromboxane agonist (U46619)-induced vasoconstriction in isolated human pulmonary artery.

Propofol is known to cause vasorelaxation of several systemic vascular beds. However, its effect on the pulmonary vasculature remains controversial. In the present study, we investigated the effects of propofol on human pulmonary arteries obtained from patients who had undergone surgery. Arterial rings were mounted in a Multi-Myograph system for measurement of isometric forces. U46619 was used to induce sustained contraction of the intrapulmonary arteries, and propofol was then applied (in increments from 10-300 µM). Arteries denuded of endothelium, preincubated or not with indomethacin, were used to investigate the effects of propofol on isolated arteries. Propofol exhibited a bifunctional effect on isolated human pulmonary arteries contracted by U46619, evoking constriction at low concentrations (10-100 µM) followed by secondary relaxation (at 100-300 µM). The extent of constriction induced by propofol was higher in an endothelium-denuded group than in an endothelium-intact group. Preincubation with indomethacin abolished constriction and potentiated relaxation. The maximal relaxation was greater in the endothelium-intact than the endothelium-denuded group. Propofol also suppressed CaCl2-induced constriction in the 60 mM K+-containing Ca2+-free solution in a dose-dependent manner. Fluorescent imaging of Ca2+ using fluo-4 showed that a 10 min incubation with propofol (10-300 µM) inhibited the Ca2+ influx into human pulmonary arterial smooth muscle cells induced by a 60 mM K+-containing Ca2+-free solution. In conclusion, propofol-induced arterial constriction appears to involve prostaglandin production by cyclooxygenase in pulmonary artery smooth muscle cells and the relaxation depends in part on endothelial function, principally on the inhibition of calcium influx through L-type voltage-operated calcium channels.

[Effects of propofol combined with indomethacin on contraction of isolated human pulmonary arteries].

OBJECTIVE: To investigate the effects of propofol combined with indomethacin on the contractile function of isolated human pulmonary arteries. METHODS: Human pulmonary artery preparations were obtained from patients undergoing surgery for lung carcinoma. The intrapulmonary arteries were dissected and cut into rings under microscope for treatment with propofol or propofol combined with indomethacin. In each group, the rings were divided into endothelium-intact and endothelium-denuded groups and mounted in a Multi Myograph system. In propofol group, the rings were preconstricted by U46619 to induce a sustained contraction, and propofol (10-300 mmol/L) was then applied cumulatively. In the combined treatment group, the rings were pretreated with indomethacin (100 µmol/L) for 30 min before application of U46619 to induce sustained contraction, and propofol (10-300 µmol/L) was added cumulatively after the tension became stable. RESULTS: Propofol (10-100 µmol/L) induced constrictions at low concentrations and caused relaxations at higher concentrations (100-300 µmol/L) in the pulmonary artery rings with prior U46619-induced contraction. Propofol caused stronger constrictions in endothelium-intact rings [EC50=4.525∓0.37, Emax=(30.44∓2.92)%] than in endothelium-denuded rings [EC50=4.699∓0.12, Emax=(31.19∓5.10)%, P<0.05]. Pretreatment of the rings with indomethacin abolished constrictions, and the relaxation was more obvious in endothelium-intact group [pD2=3.713∓0.11, Emax=(98.72∓0.34)%] than in endothelium- denuded group [pD2=3.54∓0.03, Emax=(94.56∓0.53)%, P<0.05]. CONCLUSION: Propofol induces constriction at low concentrations and relaxation at high concentrations in human intrapulmonary arteries with U46619-induced contraction. Indomethacin abolishes the constriction induced by propofol in isolated intrapulmonary arteries, suggesting that propofol potentiates U46619-mediated pulmonary vasoconstriction by promoting the concomitant production of prostaglandin by cyclooxygenase in pulmonary artery smooth muscle cells, and the mechanism for its relaxation effect may partly depend on the endothelium.

Use of laryngeal mask airway for non-endotracheal intubated anesthesia for patients with pectus excavatum undergoing thoracoscopic Nuss procedure.

BACKGROUND: The aim of the present study was to determine the safety and feasibility of the use of laryngeal mask airway (LMA) for non-endotracheal intubated anesthesia for patients with pectus excavatum (PE) undergoing thoracoscopic Nuss procedure. METHODS: Between July 2015 and December 2015, 30 selected patients with PE were planned to undergo a thoracoscopic Nuss procedure using LMA for non-endotracheal intubated anesthesia in the Guangdong General Hospital. The clinical data were analyzed to evaluate the safety and feasibility of this technique. RESULTS: Of the 30 selected patients, two were female, the mean age was 16.04±5.09 years and the average Haller index was 3.37±0.88. A total of 27 cases (90%) succeeded at the first attempt, one patient required conversion to an endotracheal tube (ETT) because of continuous air leak. The peripheral O2 saturation (SpO2), end-tidal carbon dioxide (EtCO2) values, heart rate (HR), and mean arterial blood pressure (MAP) remained stable throughout the procedure in all cases. All of the 30 patients were successfully corrected without requiring conversion to an open surgery. Two patients experienced postoperative nausea and one reported a sore throat. Neither gastro-esophageal reflux nor in-hospital mortality occurred. CONCLUSIONS: The use of LMA for non-endotracheal intubated anesthesia for selected patients with PE undergoing thoracoscopic Nuss procedure is clinically safe and technically feasible.

The effect of ulinastatin on hyperglycemia in patients undergoing hepatectomy.

BACKGROUND: To identify the effect of ulinastatin (UTI) administration on stress-induced hyperglycemia and acute insulin (INS) resistance experienced by patients undergoing partial hepatectomy. METHODS: Forty-six patients undergoing partial hepatectomy were assigned randomly to the control group (group C) or UTI treatment group (group U). Six cases underwent partial hepatectomy but were not eligible for inclusion. The patients in group U had an intravenous infusion of a total amount of 5000 IU/kg UTI before the induction of anesthesia and at the start of surgery. The patients in group C were given an identical volume of physiological saline in the same manner. Blood samples for the measurement of interleukin-6, cortisol, INS, and glucagon were obtained. Fasting plasma glucose concentration was measured immediately before skin incision (T1), 20 min after the liver lesion was removed (T2), at the end of surgery (T3), as well as on the first (T4) and second mornings after partial hepatectomy (T5). The insulin sensitivity index (ISI) was calculated at these time points. RESULTS: The fasting plasma glucose concentration in group U was significantly lower than that in group C at all time points except for T1. In group U, the insulin sensitivity index was higher, and the levels of interleukin-6, cortisol, and INS were lower than that in group C (P < 0.05). CONCLUSIONS: The data suggest that UTI administration improves perioperative hyperglycemia by inhibiting the inflammatory reaction, as well as excessive release of inflammatory factors, and improves INS resistance.

[Protective effect of pentoxifylline on acute pulmonary injury after one-lung ventilation in rabbits].

OBJECTIVE: To investigate the effect of pentoxifylline on one-lung ventilation injury in rabbits. METHODS: Twenty rabbit models of one-lung ventilation by intrabronchial intubation after tracheotomy were randomly allocated in control group (with one-lung ventilation) and experiment group (with one-lung ventilation and intravenous pentoxifylline administration). One-lung ventilation was maintained for 3 h in both groups using the volume-control mode (tidal volume of 8 ml/kg at the frequency of 30 per min). Arterial blood samples were taken after anesthesia and at 3 h of one-lung ventilation for arterial blood gas analysis to obtain the oxygenation index. At the end of the experiment, the pulmonary wet/dry ratio (W/D), tumor necrosis factor-alpha (TNF-alpha), NO, malondialdehyde (MDA) and superoxide dismutase (SOD) contents in bronchoalveolar lavage fluid (BALF) were measured and the histological appearance of the lung tissue was observed. RESULTS: The oxygenation index was significantly higher (P<0.05), W/D ratio lower (P<0.05), and contents of TNF-alpha, NO and MAD in the BALF lower in the experimental group than in the control group (P<0.05). The activity of SOD increased significantly in the experimental group as compared with the control group (P<0.01), and the rabbits in the experimental group showed milder pathological changes. CONCLUSION: Intravenous pentoxifylline may improve pulmonary ventilation function and alleviate pulmonary injury, thus offering protection against pulmonary injury after one-lung ventilation.