Opioid-free total intravenous anesthesia for thyroid and parathyroid surgery: Protocol for a randomized, double-blind, controlled trial.

Background: Opioid-free anesthesia (OFA) may improve postoperative outcomes by reducing opioid-related adverse effects. This study aims to evaluate the effects of OFA on postoperative nausea and vomiting (PONV), postoperative pain, and 30-day outcomes after thyroid and parathyroid surgery. Methods: This two-center, randomized, double-blind, controlled trial will include 400 adult patients scheduled for thyroid and parathyroid surgery. Patients will be randomly assigned, 1:1 and stratified by sex and site, to an OFA group (esketamine, lidocaine, and dexmedetomidine) or a control group (opioid-based anesthesia with sufentanil). All patients will receive propofol-based total intravenous anesthesia and PONV prophylaxis with dexamethasone and ondansetron. The primary outcome is the incidence of PONV (defined as experiencing any event of nausea, retching, or vomiting) during the first 48 h postoperatively. The secondary outcomes include the severity of PONV, antiemetic rescue therapy, pain scores at rest and while coughing, need for rescue analgesia, perioperative adverse effects related to anesthetics or analgesics (hypotension, bradycardia, hypertension, tachycardia, desaturation, dizziness, headache, hallucination, and nightmare), time to extubation, length of post-anesthesia care unit stay, length of postoperative hospital stay, patient satisfaction, and a composite of 30-day major adverse events (myocardial infarction, cardiac arrest, cerebrovascular accident, coma, acute renal failure, pulmonary embolism, sepsis, septic shock, deep neck space infection, reintubation, reoperation, blood transfusion, failure to wean off ventilator, and death). Analyses will be performed in the modified intention-to-treat population. Discussion: We hypothesize that our OFA regimen reduces PONV after thyroid and parathyroid surgery. We will also investigate whether OFA leads to improvements in postoperative pain and major adverse events. Our results will offer evidence for optimizing anesthesia regimens in patients who undergo thyroid and parathyroid surgical procedures. Clinical trial registration: http://www.chictr.org.cn, identifier: ChiCTR2200059656.

Activation of CCL21-GPR174/CCR7 on cardiac fibroblasts underlies myocardial ischemia/reperfusion injury.

Background: The mechanisms underlying myocardial ischemia/reperfusion (I/R) injury are not fully understood. This study aims to explore key candidate genes and potential therapeutic targets for treatment of myocardial I/R injury. Methods: The transcriptional profiles of ventricular myocardium during cardiac arrest, ischemia, and reperfusion were obtained from the Gene Expression Omnibus database. Based on the transcriptional data of GSE6381, functional pathway and process enrichment analyses, protein-protein interaction network, and gene set enrichment analyses were conducted. In the animal experiments, we established the myocardial I/R injury model in mice. We validated the mRNA and protein expression of the key genes using the qPCR and western blots. We further assessed the expression and localization of CCL21 and its receptors using immunofluorescence staining experiments. Results: The microarray analyses identified five key genes (CCL21, XCR1, CXCL13, EDN1, and CASR). Myocardial I/R process in mice resulted in significant myocardial infraction, histological damage, and myocardial apoptosis. The results of qPCR and western blots showed that the expression of CCL21 and CXCL13 were increased following myocardial I/R injury in mice. Furthermore, the immunofluorescence staining results revealed that the expression of GPR174/CCR7 (CCL21 receptors), but not CXCR5 (CXCL13 receptor), was elevated following myocardial I/R injury. Moreover, the activated CCL21-GPR174/CCR7 signaling was located on the cardiac fibroblasts of the myocardium with I/R injury. Conclusion: This study revealed several key factors underlying myocardial I/R injury. Of these, the activation of CCL21-GPR174/CCR7 signaling on cardiac fibroblasts was highlighted, which provides potential therapeutic targets for cardioprotection.

Effect of Perioperative Dexmedetomidine on Delayed Graft Function Following a Donation-After-Cardiac-Death Kidney Transplant: A Randomized Clinical Trial.

Importance: Delayed graft function (DGF) is a risk factor for acute rejection and graft failure after kidney transplant. Previous studies have suggested that dexmedetomidine may be renoprotective, but whether the use of dexmedetomidine would improve kidney allograft function is unknown. Objective: To investigate the effects of perioperative dexmedetomidine on DGF following a donation-after-cardiac-death (DCD) kidney transplant. Design, Setting, and Participants: This single-center, double-blind, placebo-controlled randomized clinical trial was conducted at The First Affiliated Hospital of Soochow University in Suzhou, China. Adults (18 years or older) who were scheduled for DCD kidney transplant were enrolled between September 1, 2019, and January 28, 2021, and then randomized to receive either dexmedetomidine or normal saline (placebo). One-year postoperative outcomes were recorded. All analyses were based on the modified intention-to-treat population. Interventions: Patients who were randomized to the dexmedetomidine group received a 24-hour perioperative dexmedetomidine intravenous infusion (0.4 µg/kg/h intraoperatively and 0.1 µg/kg/h postoperatively). Patients who were randomized to the normal saline group received an intravenous infusion of the placebo with the same dose regimen as the dexmedetomidine. Main Outcomes and Measures: The primary outcome was the incidence of DGF, defined as the need for dialysis in the first posttransplant week. The prespecified secondary outcomes were in-hospital repeated dialysis in the first posttransplant week, in-hospital acute rejection, and serum creatinine, serum cystatin C, estimated glomerular filtration rate, need for dialysis, and patient survival on posttransplant day 30. Results: Of the 114 patients enrolled, 111 completed the study (mean [SD] age, 43.4 [10.8] years; 64 male patients [57.7%]), of whom 56 were randomized to the dexmedetomidine group and 55 to the normal saline group. Dexmedetomidine infusion compared with normal saline reduced the incidence of DGF (17.9% vs 34.5%; odds ratio [OR], 0.41; 95% CI, 0.17-0.98; P = .04) and repeated dialysis (12.5% vs 30.9%; OR, 0.32; 95% CI, 0.13-0.88; P = .02, which was not statistically significant after multiple testing corrections), without significant effect on other secondary outcomes. Dexmedetomidine vs normal saline infusion led to a higher median (IQR) creatinine clearance rate on postoperative days 1 (9.9 [4.9-21.2] mL/min vs 7.9 [2.0-10.4] mL/min) and 2 (29.6 [9.7-67.4] mL/min vs 14.6 [3.8-45.1] mL/min) as well as increased median (IQR) urine output on postoperative days 2 (106.5 [66.3-175.6] mL/h vs 82.9 [27.1-141.9] mL/h) and 7 (126.1 [98.0-151.3] mL/h vs 107.0 [82.5-137.5] mL/h) and at hospital discharge discharge (110.4 [92.8-121.9] mL/h vs 97.1 [77.5-113.8] mL/h). Three patients (5.5%) from the normal saline group developed allograft failure by the post hoc 1-year follow-up visit. Conclusions and Relevance: This randomized clinical trial found that 24-hour perioperative dexmedetomidine decreased the incidence of DGF after DCD kidney transplant. The findings support the use of dexmedetomidine in kidney transplants. Trial Registration: Chinese Clinical Trial Registry Identifier: ChiCTR1900025493.

Dynamical Behavior of SEIR-SVS Epidemic Models with Nonlinear Incidence and Vaccination.

For some infectious diseases such as mumps, HBV, there is evidence showing that vaccinated individuals always lose their immunity at different rates depending on the inoculation time. In this paper, we propose an age-structured epidemic model using a step function to describe the rate at which vaccinated individuals lose immunity and reduce the age-structured epidemic model to the delay differential model. For the age-structured model, we consider the positivity, boundedness, and compactness of the semiflow and study global stability of equilibria by constructing appropriate Lyapunov functionals. Moreover, for the reduced delay differential equation model, we study the existence of the endemic equilibrium and prove the global stability of equilibria. Finally, some numerical simulations are provided to support our theoretical results and a brief discussion is given.

Esketamine as an Adjuvant to Ciprofol or Propofol Sedation for Same-Day Bidirectional Endoscopy: Protocol for a Randomized, Double-Blind, Controlled Trial With Factorial Design.

Background: Same-day esophagogastroduodenoscopy and colonoscopy procedures under sedation have been increasingly performed. This study aims to assess the effects of esketamine combined with ciprofol (a novel anesthetic/sedative agent) or propofol on respiratory and hemodynamic adverse events in patients undergoing same-day bidirectional endoscopy. Methods: This is a prospective, randomized, double-blind, placebo-controlled, 2 × 2 factorial trial. A total of 180 adult patients scheduled for same-day bidirectional endoscopy under sedation will be randomized, in a 1:1:1:1 ratio, to receive 1 of 4 sedation regimens: 1) ciprofol and esketamine, 2) propofol and esketamine, 3) ciprofol and normal saline placebo, or 4) propofol and normal saline placebo. The primary outcome is a composite of desaturation [peripheral oxygen saturation (SpO2) < 95%] and hypotension [mean blood pressure (MBP) < 65 mmHg or decrease in MBP ≥20% of baseline] during the sedation and in the recovery room. Secondary outcomes include episodes of desaturation, severe desaturation (SpO2 < 90%), hypotension, severe hypotension (decrease in MBP ≥30% of baseline), bradycardia, postoperative nausea and vomiting, dizziness or headache, hallucination or nightmare, injection pain, pain scores and fatigue scores, endoscopist satisfaction, and patient satisfaction. Data will be analyzed on the modified intention-to-treat basis. Discussion: We hypothesize that esketamine as an adjuvant to ciprofol or propofol sedation would improve cardiorespiratory stability. In addition, the potential interactions between interventions will be explored using the factorial design. The results of this trial will provide evidence for daily practice of sedation regimens for same-day bidirectional endoscopy. Clinical Trial Registration: Chinese Clinical Trials Registry, Identifier ChiCTR2100052523.

Remote Ischemic Preconditioning Reduces Acute Kidney Injury After Cardiac Surgery: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

BACKGROUND: Results from previous studies evaluating the effects of remote ischemic preconditioning (RIPC) on morbidity and mortality after cardiac surgery are inconsistent. This meta-analysis of randomized controlled trials (RCTs) aims to determine whether RIPC improves cardiac and renal outcomes in adults undergoing cardiac surgery. METHODS: PubMed, EMBASE, and Cochrane Library were comprehensively searched to identify RCTs comparing RIPC with control in cardiac surgery. The coprimary outcomes were the incidence of postoperative myocardial infarction (MI) and the incidence of postoperative acute kidney injury (AKI). Meta-analyses were performed using a random-effect model. Subgroup analyses were conducted according to volatile only anesthesia versus propofol anesthesia with or without volatiles, high-risk patients versus non-high-risk patients, and Acute Kidney Injury Network (AKIN) or Kidney Disease Improving Global Outcomes (KDIGO) criteria versus other criteria for AKI diagnosis. RESULTS: A total of 79 RCTs with 10,814 patients were included. While the incidence of postoperative MI did not differ between the RIPC and control groups (8.2% vs 9.7%; risk ratio [RR] = 0.87, 95% confidence interval [CI], 0.76-1.01, P = .07, I2 = 0%), RIPC significantly reduced the incidence of postoperative AKI (22% vs 24.4%; RR = 0.86, 95% CI, 0.77-0.97, P = .01, I2 = 34%). The subgroup analyses showed that RIPC was associated with a reduced incidence of MI in non-high-risk patients, and that RIPC was associated with a reduced incidence of AKI in volatile only anesthesia, in non-high-risk patients, and in the studies using AKIN or KDIGO criteria for AKI diagnosis. CONCLUSIONS: This meta-analysis demonstrates that RIPC reduces the incidence of AKI after cardiac surgery. This renoprotective effect of RIPC is mainly evident during volatile only anesthesia, in non-high-risk patients, and when AKIN or KDIGO criteria used for AKI diagnosis.

Deep Neuromuscular Blockade Combined with Low Pneumoperitoneum Pressure for Nociceptive Recovery After Major Laparoscopic Gastrointestinal Surgery: Study Protocol for a Randomized Controlled Trial.

PURPOSE: Patients undergoing major laparoscopic surgery often experience significant pain and postoperative nausea and vomiting (PONV). Deep neuromuscular block (NMB) improves surgical conditions and facilitates the application of low intra-abdominal pressure (IAP), which may be beneficial for these patients. This study is designed to determine the effects of deep NMB combined with low IAP, as compared to moderate NMB combined with standard IAP, on patients' nociceptive recovery after major laparoscopic gastrointestinal surgery. STUDY DESIGN AND METHODS: This single-center randomized controlled trial will include 220 patients scheduled for major laparoscopic gastrointestinal surgery (lasts for ≥ 90 minutes). Patients will be randomly assigned, with a 1:1 ratio, into a deep NMB + low IAP group (train of four = 0, post-tetanic count = 1-3, IAP = 8 mmHg) and a moderate NMB + standard IAP group (train of four = 1-3, IAP = 12 mmHg). If the surgical workspace is inadequate, the surgeons can request a step increase of 1 mmHg in IAP during 3-min intervals. The upper limit of IAP will be set at 15 mmHg. Postoperative recovery will be assessed using the postoperative quality recovery scale (PQRS). The primary outcome of this trial is the PQRS nociceptive recovery (including pain and PONV) at postoperative day (POD) 1. The secondary outcomes include recovery in other PQRS domains at POD 1, and recovery in all PQRS domains in a post-anesthesia care unit, at POD 3 in the surgical wards, at hospital discharge, and at postoperative 30 days. For the sample size estimation, 110 patients in each group (220 in total) would be needed to detect an absolute increase rate of 20% in the PQRS nociceptive domain in the deep NMB + low IAP group at POD 1. DISCUSSION: This study investigates the effects of deep NMB combined with low IAP on postoperative PQRS nociceptive recovery in patients undergoing major laparoscopic gastrointestinal surgery. We expect that this deep NMB + low IAP strategy would improve postoperative pain and PONV following major laparoscopic gastrointestinal surgery.

Effect of Intraoperative Dexmedetomidine on Recovery of Gastrointestinal Function After Abdominal Surgery in Older Adults: A Randomized Clinical Trial.

Importance: Postoperative ileus is common after abdominal surgery, and small clinical studies have reported that intraoperative administration of dexmedetomidine may be associated with improvements in postoperative gastrointestinal function. However, findings have been inconsistent and study samples have been small. Further examination of the effects of intraoperative dexmedetomidine on postoperative gastrointestinal function is needed. Objective: To evaluate the effects of intraoperative intravenous dexmedetomidine vs placebo on postoperative gastrointestinal function among older patients undergoing abdominal surgery. Design, Setting, and Participants: This multicenter, double-blind, placebo-controlled randomized clinical trial was conducted at the First Affiliated Hospital of Anhui Medical University in Hefei, China (lead site), and 12 other tertiary hospitals in Anhui Province, China. A total of 808 participants aged 60 years or older who were scheduled to receive abdominal surgery with an expected surgical duration of 1 to 6 hours were enrolled. The study was conducted from August 21, 2018, to December 9, 2019. Interventions: Dexmedetomidine infusion (a loading dose of 0.5 µg/kg over 15 minutes followed by a maintenance dose of 0.2 µg/kg per hour) or placebo infusion (normal saline) during surgery. Main Outcomes and Measures: The primary outcome was time to first flatus. Secondary outcomes were postoperative gastrointestinal function measured by the I-FEED (intake, feeling nauseated, emesis, physical examination, and duration of symptoms) scoring system, time to first feces, time to first oral feeding, incidence of delirium, pain scores, sleep quality, postoperative nausea and vomiting, hospital costs, and hospital length of stay. Results: Among 808 patients enrolled, 404 were randomized to receive intraoperative dexmedetomidine, and 404 were randomized to receive placebo. In total, 133 patients (60 in the dexmedetomidine group and 73 in the placebo group) were excluded because of protocol deviations, and 675 patients (344 in the dexmedetomidine group and 331 in the placebo group; mean [SD] age, 70.2 [6.1] years; 445 men [65.9%]) were included in the per-protocol analysis. The dexmedetomidine group had a significantly shorter time to first flatus (median, 65 hours [IQR, 48-78 hours] vs 78 hours [62-93 hours], respectively; P < .001), time to first feces (median, 85 hours [IQR, 68-115 hours] vs 98 hours [IQR, 74-121 hours]; P = .001), and hospital length of stay (median, 13 days [IQR, 10-17 days] vs 15 days [IQR, 11-18 days]; P = .005) than the control group. Postoperative gastrointestinal function (as measured by the I-FEED score) and delirium incidence were similar in the dexmedetomidine and control groups (eg, 248 patients [72.1%] vs 254 patients [76.7%], respectively, had I-FEED scores indicating normal postoperative gastrointestinal function; 18 patients [5.2%] vs 12 patients [3.6%] had delirium on postoperative day 3). Conclusions and Relevance: In this randomized clinical trial, the administration of intraoperative dexmedetomidine reduced the time to first flatus, time to first feces, and length of stay after abdominal surgery. These results suggest that this therapy may be a viable strategy to enhance postoperative recovery of gastrointestinal function among older adults. Trial Registration: Chinese Clinical Trial Registry Identifier: ChiCTR1800017232.

Dexmedetomidine reduces acute kidney injury after endovascular aortic repair of Stanford type B aortic dissection: A randomized, double-blind, placebo-controlled pilot study.

STUDY OBJECTIVE: To determine the effect of dexmedetomidine on acute kidney injury (AKI) following endovascular aortic repair (EVAR) for Stanford type B aortic dissection (TBAD). DESIGN: Randomized, double-blind, placebo-controlled, pilot study. SETTING: University Hospital. PATIENTS: 102 TBAD patients undergoing EVAR procedures were enrolled. Patients with dissection involving aortic arch or renal artery were excluded. INTERVENTIONS: Patients were randomly assigned, in a 1:1 ratio, to a dexmedetomidine group (intravenous dexmedetomidine 0.4 µg/kg/h immediately after anesthesia induction and 0.1 µg/kg/h after extubation, which was maintained until 24 h) or a normal saline control group. MEASUREMENTS: The primary outcome was the incidence of AKI within the first two days after surgery, based on the Acute Kidney Injury Network (AKIN) criteria. The secondary outcomes included serum cystatin C and estimated glomerular filtration rate on postoperative days 1, 2, and 7, and in-hospital need for renal replacement therapy (RRT). Long-term outcomes included RRT and all-cause mortality. MAIN RESULTS: Ninety-eight patients completed the study (dexmedetomidine, n = 48; control, n = 50). AKIN stage 1 AKI occurred in 3/48 (6.3%) patients receiving dexmedetomidine, compared with 11/50 (22%) patients receiving normal saline (odds ratio = 0.24, 95% CI: 0.07 to 0.89, P = 0.041). This difference remained significant after adjusting for baseline covariates (adjusted odds ratio = 0.21, 95% CI: 0.05 to 0.84; P = 0.028). Dexmedetomidine led to a lower serum cystatin C on postoperative day 1 (median [IQR] mg/L: 1.31 [1.02-1.72] vs. 1.58 [1.28-1.96]). There were no between-group differences in other secondary or long-term outcomes. During the follow-up (median = 28.4 months), 1 patient in the dexmedetomidine group and 3 patients in the control group required RRT. CONCLUSIONS: Dexmedetomidine reduced the incidence of AKI in TBAD patients after EVAR procedures. The long-term benefits of dexmedetomidine in this patient population warrant further investigation. TRIAL REGISTRATION: ChiCTR-IPR-15006372.

Effect of Intravenous Lidocaine on Serum Interleukin-17 After Video-Assisted Thoracic Surgery for Non-Small-Cell Lung Cancer: A Randomized, Double-Blind, Placebo-Controlled Trial.

PURPOSE: Surgical stress promotes tumor metastasis. Interleukin (IL)-17 plays a pivotal role in cancer progression, and high IL-17 expression predicts poor prognosis of non-small-cell lung cancer (NSCLC). Lidocaine may exert tumor-inhibiting effects. We hypothesize that intravenous lidocaine attenuates surgical stress and reduces serum IL-17 levels during video-assisted thoracic surgery (VATS) for NSCLC. METHODS: This randomized, double-blind, placebo-controlled trial included 60 early-stage NSCLC patients undergoing VATS, into a lidocaine group (n = 30; intravenous lidocaine bolus 1.0 mg/kg, and 1.0 mg/kg/h until the end of surgery) or a normal saline control group (n = 30). The primary outcome was serum IL-17 level at 24 hours postoperatively. The secondary outcomes included serum IL-17 level at the time of post-anesthesia care unit (PACU) discharge, serum cortisol level at PACU discharge and postoperative 24 hours, pain scores (0-10) from PACU discharge to 48 hours postoperatively, incidences of postoperative nausea and vomiting, dizziness, and arrhythmia during 0-48 hours postoperatively, and 30-day mortality. Long-term outcomes included chemotherapy, cancer recurrence, and mortality. RESULTS: The lidocaine group had lower serum IL-17 at 24 hours postoperatively compared with the control group (23.0 ± 5.8 pg/mL vs 27.3 ± 8.2 pg/mL, difference [95% CI] = -4.3 [-8.4 to -0.2] pg/mL; P = 0.038). The lidocaine group also had reduced serum IL-17 (difference [95% CI] = -4.6 [-8.7 to -0.5] pg/mL), serum cortisol (difference [95% CI] = -37 [-73 to -2] ng/mL), and pain scores (difference [95% CI] = -0.7 [-1.3 to -0.1] points) at PACU discharge. During a median follow-up of 10 (IQR, 9-13) months, 2 patients in the lidocaine group and 6 patients in the control group received chemotherapy, one patient in the control group had cancer recurrence, and no death event occurred. CONCLUSION: Intravenous lidocaine was associated with reduced serum IL-17 and cortisol following VATS procedures in early-stage NSCLC patients. TRIAL REGISTRATION: ChiCTR2000030629.

Perioperative dexmedetomidine and 5-year survival in patients undergoing cardiac surgery.

BACKGROUND: Dexmedetomidine sedation has been associated with favourable outcomes after surgery. We aimed to assess whether perioperative dexmedetomidine use is associated with improved survival after cardiac surgery. METHODS: This retrospective cohort study included 2068 patients undergoing on-pump coronary artery bypass grafting and/or valve surgery. Among them, 1029 patients received dexmedetomidine, and 1039 patients did not. Intravenous dexmedetomidine infusion of 0.007 µg kg-1 min-1 was initiated before or immediately after cardiopulmonary bypass and lasted for < 24 h. The primary outcome was 5-year survival after cardiac surgery. The propensity scores matching (PSM), inverse probability of treatment weighting (IPTW), and overlap weighting approaches were used to minimise bias. Survival analyses were performed with Cox proportional-hazard models. RESULTS: The median age was 63 yr old and the male to female ratio was 71:29 in both groups. Baseline covariates were balanced between groups after adjustment using PSM, IPTW, or overlap weighting. Patients receiving dexmedetomidine in cardiac surgical procedures had higher survival during postoperative 5 yr in unadjusted analysis (hazard ratio [HR]=0.63; 95% confidence interval [CI], 0.51-0.78; P<0.001), and after adjustment with PSM (HR=0.63; 95% CI, 0.45-0.89; P=0.009), IPTW (HR=0.70; 95% CI, 0.51-0.95; P=0.023), or overlap weighting (HR=0.67; 95% CI, 0.51-0.89; P=0.006). The 5-yr mortality rate after cardiac surgery was 13% and 20% in the dexmedetomidine and non-dexmedetomidine groups, respectively (PSM adjusted odds ratio=0.61; 95% CI, 0.42-0.89; P=0.010). CONCLUSION: Perioperative dexmedetomidine infusion was associated with improved 5-yr survival in patients undergoing cardiac surgery.

Withholding vs. Continuing Angiotensin-Converting Enzyme Inhibitors or Angiotensin Receptor Blockers Before Non-cardiac Surgery in Older Patients: Study Protocol for a Multicenter Randomized Controlled Trial.

Background: Older hypertensive adults are at increased risk for postoperative morbidity and mortality. As first line antihypertensive drug therapy, angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) have many beneficial effects. However, the use of ACEIs/ARBs in the perioperative period remains controversial. This study aims to determine the effects of withholding vs. continuing ACEIs/ARBs before non-cardiac surgery on perioperative hypotension and postoperative outcomes in older patients. Methods: In this multicenter, randomized, double-blind, placebo-controlled trial, a total of 2036 patients aged 60-80 years undergoing non-cardiac surgical procedures will be randomly assigned, in a 1:1 ratio, to receive oral ACEIs/ARBs (the ACEIs/ARBs continued group) or inactive placebos (the ACEIs/ARBs withheld group) on the morning of surgery. For both groups, the ACEIs/ARBs will be continued from the first postoperative day. The primary outcome measure is the incidence of perioperative hypotensive events, defined as mean blood pressure (MBP) < 65 mmHg or ≥30% reduction in MBP from baseline during surgery and in a post-anesthesia care unit. The secondary outcomes include duration of perioperative hypotension, intraoperative use of fluids and vasopressors, hypotensive events within postoperative 3 days, and perioperative neurocognitive disorders, major adverse cardiocerebral events (a composite outcome of stroke, coma, myocardial infarction, heart block, and cardiac arrest), and mortality within 30 days after surgery. Discussion: The results of this trial will offer an evidence-based perioperative ACEIs/ARBs therapy for older hypertensive adults undergoing non-cardiac surgery. Study Registration: This study is approved by the Medical Ethics Committee of The First Affiliated Hospital of Soochow University (Approval No. 2020-077-1) and by the institutional ethics review board of each participating center. This protocol is registered at the Chinese Clinical Trials Registry (ChiCTR2000039376).

Dexmedetomidine Attenuates Ischemia/Reperfusion-Induced Myocardial Inflammation and Apoptosis Through Inhibiting Endoplasmic Reticulum Stress Signaling.

BACKGROUND: Endoplasmic reticulum stress (ERS)-mediated myocardial inflammation and apoptosis plays an important role in myocardial ischemia/reperfusion (I/R) injury. Dexmedetomidine has been used clinically with sedative, analgesic, and anti-inflammatory properties. This study aimed to determine the effects of dexmedetomidine pretreatment on inflammation, apoptosis, and the expression of ERS signaling during myocardial I/R injury. METHODS: Rats underwent myocardial ischemia for 30 min and reperfusion for 6 h, and H9c2 cardiomyocytes were subjected to oxygen-glucose deprivation/reoxygenation (OGD/R) injury (OGD for 12 h and reoxygenation for 3 h). Dexmedetomidine was administered prior to myocardial ischemia in rats or ODG in cardiomyocytes. In addition, the α2-adrenergic receptor antagonist (yohimbine) or the PERK activator (CCT020312) was given prior to dexmedetomidine treatment. RESULTS: Dexmedetomidine pretreatment decreased serum levels of cardiac troponin I, reduced myocardial infarct size, alleviated histological structure damage, and improved left ventricular function following myocardial I/R injury in rats. In addition, dexmedetomidine pretreatment increased cell viability and reduced cytotoxicity following OGD/R injury in cardiomyocytes. Mechanistically, the cardioprotection offered by dexmedetomidine was mediated via the inhibition of inflammation and apoptosis through downregulating the expression of the ERS signaling pathway, including glucose-regulated protein 78 (GRP78), protein kinase R-like endoplasmic reticulum kinase (PERK), C/EBP homologous protein (CHOP), inositol-requiring protein 1 (IRE1), and activating transcription factor 6 (ATF6). Conversely, the protective effects of dexmedetomidine were diminished by blocking the α2 adrenergic receptors with yohimbine or promoting PERK phosphorylation with CCT020312. CONCLUSION: Dexmedetomidine pretreatment protects the hearts against I/R injury via inhibiting inflammation and apoptosis through downregulation of the ERS signaling pathway. Future clinical studies are needed to confirm the cardioprotective effects of dexmedetomidine in patients at risk of myocardial I/R injury.

Phase-adjusted estimation of the COVID-19 outbreak in South Korea under multi-source data and adjustment measures: a modelling study.

Based on the reported data from February 16, 2020 to March 9, 2020 in South Korea including confirmed cases, death cases and recovery cases, the control reproduction number was estimated respectively at different control measure phases using Markov chain Monte Carlo method and presented using the resulting posterior mean and 95% credible interval (CrI). At the early phase from February 16 to February 24, we estimate the basic reproduction number R0 of COVID-19 to be 4.79(95% CrI 4.38 - 5.2). The estimated control reproduction number dropped rapidly to Rc ≈ 0.32(95% CrI 0.19 - 0.47) at the second phase from February 25 to March 2 because of the voluntary lockdown measures. At the third phase from March 3 to March 9, we estimate Rc to be 0.27 (95% CrI 0.14 - 0.42). We predict that the final size of the COVID-19 outbreak in South Korea is 9661 (95% CrI 8660 - 11100) and the whole epidemic will be over by late April. It is found that reducing contact rate and enhancing the testing speed will have the impact on the peak value and the peak time.

Human mesenchymal stem cell microvesicles for treatment of Escherichia coli endotoxin-induced acute lung injury in mice.

We previously found that human mesenchymal stem cells (MSC) or its conditioned medium restored lung protein permeability and reduced alveolar inflammation following Escherichia coli endotoxin-induced acute lung injury (ALI) in an ex vivo perfused human lung in part through the secretion of soluble factors such as keratinocyte growth factor (KGF). Recently, MSC were found to release microvesicles (MVs) that were biologically active because of the presence of mRNA or miRNA with reparative properties. MVs are circular fragments of membrane released from the endosomal compartment as exosomes or shed from the surface membranes. These studies were designed to determine if MVs released by human bone marrow derived MSCs would be effective in restoring lung protein permeability and reducing inflammation in E. coli endotoxin-induced ALI in C57BL/6 mice. The intratracheal instillation of MVs improved several indices of ALI at 48 hours. Compared to endotoxin-injured mice, MVs reduced extravascular lung water by 43% and reduced total protein levels in the bronchoalveolar lavage (BAL) fluid by 35%, demonstrating a reduction in pulmonary edema and lung protein permeability. MVs also reduced the influx of neutrophils and macrophage inflammatory protein-2 levels in the BAL fluid by 73% and 49%, respectively, demonstrating a reduction in inflammation. KGF siRNA-pretreatment of MSC partially eliminated the therapeutic effects of MVs released by MSCs, suggesting that KGF protein expression was important for the underlying mechanism. In summary, human MSC-derived MVs were therapeutically effective following E. coli endotoxin-induced ALI in mice in part through the expression of KGF mRNA in the injured alveolus.

Adult stem cells for acute lung injury: remaining questions and concerns.

Acute lung injury (ALI) or acute respiratory distress syndrome remains a major cause of morbidity and mortality in hospitalized patients. The pathophysiology of ALI involves complex interactions between the inciting event, such as pneumonia, sepsis or aspiration, and the host immune response resulting in lung protein permeability, impaired resolution of pulmonary oedema, an intense inflammatory response in the injured alveolus and hypoxemia. In multiple preclinical studies, adult stem cells have been shown to be therapeutic due to both the ability to mitigate injury and inflammation through paracrine mechanisms and perhaps to regenerate tissue by virtue of their multi-potency. These characteristics have stimulated intensive research efforts to explore the possibility of using stem or progenitor cells for the treatment of lung injury. A variety of stem or progenitor cells have been isolated, characterized and tested experimentally in preclinical animal models of ALI. However, questions remain concerning the optimal dose, route and the adult stem or progenitor cell to use. Here, the current mechanisms underlying the therapeutic effect of stem cells in ALI as well as the questions that will arise as clinical trials for ALI are planned are reviewed.

Sevoflurane impairs memory consolidation in rats, possibly through inhibiting phosphorylation of glycogen synthase kinase-3ß in the hippocampus.

Sevoflurane administration impairs memory processes in both humans and animals. Increasing evidence suggests that enhancement of the phosphorylation state of glycogen synthase kinase-3ß (GSK-3ß), as a result of acute administration of lithium chloride (LiCl), may enhance memory consolidation. The current experiments examined whether GSK-3ß phosphorylation was involved in mediating the memory impairing effects of posttraining sevoflurane on inhibitory avoidance (IA) retention. In experiment 1, adult male Sprague-Dawley rats were exposed to sevoflurane (0.5%, 1%, or 2%) for 2h immediately after training in a continuous multiple-trail IA paradigm. Sevoflurane (2% inspired) induced significant impairment of retention performance on a 24-h test and inhibited phosphorylation of GSK-3ß in the hippocampus 2h after training. In experiment 2, administration of LiCl (100mg/kg, intraperitoneally) 30 min before IA training not only blocked the sevoflurane-induced impairment of consolidation, but also reversed the inhibitory effect of sevoflurane on GSK-3ß phosphorylation in the hippocampus. Collectively, these findings support the hypothesis that sevoflurane exposure can impair consolidation of IA memory in rats. Sevoflurane-induced amnesia may be due, at least in part, to suppression of GSK-3ß phosphorylation in the hippocampus.

The expression of NF-E2-related factor 2 in the rat brain after traumatic brain injury.

BACKGROUND: Secondary brain damage plays a critical role in the outcome of patients with traumatic brain injury (TBI). The mechanisms underlying secondary brain damage are complex. A target that can interrupt multiple mechanisms underlying secondary brain damage may represent a promising new therapeutic approach for TBI. NF-E2-related factor 2 (Nrf2) is the key regulator in reducing oxidative stress, inflammatory damage, and the accumulation of toxic metabolites, which are all involved in secondary brain damage after TBI. Therefore, Nrf2 might represent a new direction for the treatment of TBI. However, the expression pattern of Nrf2 after TBI has not yet been studied. METHODS: This study involved the detection of Nrf2 mRNA levels by reverse-transcriptase polymerase chain reaction, and its nuclear protein levels by Western blot from 3 hour to 72 hour after TBI. Nrf2 distribution in the brain after TBI was also investigated by immunohistochemistry. RESULTS: After TBI, the nuclear Nrf2 protein level is significantly increased, whereas its mRNA level remains unchanged. Increased Nrf2 immunostaining was detected not only in the vulnerable regions but also in the brain barrier system. CONCLUSION: Nrf2 might play a protective role in the brain after TBI, possibly by reducing oxidative stress and brain edema.

Traumatic brain injury induces the activation of the Nrf2-ARE pathway in the lung in rats.

BACKGROUND: Acute lung injury (ALI) is a frequent but poorly understood complication of traumatic brain injury (TBI). The Nrf2-ARE pathway has been proved to be essential for protection against diffuse inflammation and oxidative damage, which are both involved in ALI following TBI. However, whether the Nrf2-ARE pathway is activated after TBI in the lung hasn't been studied. METHODS AND PROCEDURES: In the present study, the nuclear Nrf2 protein level was detected by Western blot and the mRNA levels of heme oxygenase-1 (HO-1) and NAD(P)H:quinone oxidoreductase-1 (NQO1), two Nrf2-regulated gene products, were determined by RT-PCR at 24 hours after TBI. In addition, the expression of Nrf2 and HO-1 was localized by immunohistochemical study. MAIN OUTCOMES AND RESULTS: After TBI, the nuclear Nrf2 protein level in the lung was significantly increased and the mRNA levels of both HO-1 and NQO1 were also up-regulated. Moreover, immunohistochemical study showed that both Nrf2 and HO-1 were mainly localized in tracheobronchial epithelium and alveolar macrophages. CONCLUSION: These results suggest that the Nrf2-ARE pathway is activated in the lung after TBI.

[Autologous peripheral blood stem cell transplantation for the treatment of lower extremity arterial occlusive disease].

OBJECTIVE: To evaluate the safety and feasibility of autologous peripheral blood mononuclear cells (PBMNCs) implantation after granulocyte-colony stimulating factor (G-CSF)-induced mobilization in patients with lower extremity arterial occlusive disease (AOD). METHODS: A total of 12 patients with AOD were enrolled in this study. Following administration of rhG-CSF (150 microg/d) for 5 days, PBMNCs were harvested and injected intramuscularly in the diseased extremities (3 x 10(9) per limb). RESULTS: One patient received left leg amputation due to uncontrolled ulcer 15 days post PBMNCs transplantation and the symptoms and signs were improved significantly in 9 patients and the symptoms and signs remained unchanged in another 2 aged patients (> 70 years). Doppler ultrasonography measurement showed that peak systolic velocity in diseased extremities was significantly increased post transplantation [(44.55 +/- 4.13) cm/s vs. (21.32 +/- 0.63) cm/s, P < 0.01]. Contrast lower limb angiogram showed increased collateral vessels post transplantation. One aged patient (80 years) who did not respond to autologous PBMNCs received heterologous PBMNCs transplantation (PBMNCs was harvested from a young relative of him) 3 months post autologous PBMNCs transplantation and observed for another 3 months and all observed parameters improved significantly. CONCLUSION: Implantation of autologous PBMNCs collected after G-CSF administration might offer a simple, safe, and effective therapy for the AOD patients.