RvD1 improves resident alveolar macrophage self-renewal via the ALX/MAPK14/S100A8/A9 pathway in acute respiratory distress syndrome.

INTRODUCTION: Acute respiratory distress syndrome (ARDS) is a pulmonary inflammatory process primarily caused by sepsis. The resolution of inflammation is an active process involving the endogenous biosynthesis of specialized pro-resolving mediators, including resolvin D1 (RvD1). Resident alveolar macrophages (RAMs) maintain pulmonary homeostasis and play a key role in the resolution phase. However, the role of RAMs in promoting the resolution of inflammation by RvD1 is unclear. OBJECTIVES: Here, we investigated the mechanisms of RvD1 on regulating RAMs to promote the resolution of ARDS. METHODS: Mice were administered lipopolysaccharide and/or Escherichia coli via aerosol inhalation to establish a self-limited ARDS model. Then, RvD1 was administered at the peak inflammatory response. RAMs self-renewal was measured by flow cytometry, RAM phagocytosis was measured by two-photon fluorescence imaging. In addition, plasma was collected from intensive care unit patients on days 0-2, 3-5, and 6-9 to measure RvD1 and S100A8/A9 levels using triple quadrupole/linear ion trap mass spectrometry. RESULTS: RAMs were found to play a pivotal role in resolving inflammation during ARDS, and RvD1 enhanced RAM proliferation and phagocytosis, which was abrogated by a lipoxin A4 receptor (ALX, RvD1 receptor) inhibitor. Both primary RAMs transfected with rS100A8/A9 and/or S100A8/A9 siRNA and S100A9-/- mice (also deficient in S100A8 function) showed higher turnover and phagocytic function, indicating that RvD1 exerted its effects on RAMs by inhibiting S100A8/A9 production in the resolution phase. RvD1 reduced S100A8/A9 and its upstream MAPK14 levels in vivo and in vitro. Finally, in the patients, RvD1 levels were lower, but S100A8/A9 levels were higher. CONCLUSIONS: We propose that RvD1 improved RAM self-renewal and phagocytosis via the ALX/MAPK14/S100A8/A9 signaling pathway. Plasma RvD1 and S100A8/A9 levels were negatively correlated, and associated with the outcome of sepsis-induced ARDS.

The safety and efficacy of remimazolam tosylate for induction and maintenance of general anesthesia in pediatric patients undergoing elective surgery: Study protocol for a multicenter, randomized, single-blind, positive-controlled clinical trial.

Introduction: Remimazolam is an ultra-short-acting benzodiazepine sedative agent commonly used in general anesthesia, procedural sedation, and intensive care unit (ICU) sedation. This study aimed to explore the efficacy and safety of remimazolam versus propofol for the induction and maintenance of general anesthesia in preschool-age children undergoing elective surgery. Methods and analysis: In this multicenter, randomized, single-blind, positive-controlled non-inferior clinical trial, one hundred ninety-two children aged 3-6 years will be randomly allocated as a 3:1 ratio into two groups: Group R with an intravenous dose of remimazolam 0.3 mg/kg for the induction of anesthesia followed by a constant infusion rate of remimazolam 1-3 mg/kg/h to maintain anesthesia, and Group P with an intravenous dose of propofol 2.5 mg/kg for the induction of anesthesia followed by a constant infusion rate of propofol 4-12 mg/kg/h to maintain anesthesia. The primary outcome will be the rate of the successful induction and maintenance of anesthesia. The secondary outcomes will include the time to LoC, the Bispectral Index (BIS) value, awakening time, extubation time, post-anesthesia care unit (PACU) discharge time, usage of additional sedative drugs during the induction period, usage of remedial drugs in PACU, emergence delirium, pain in PACU, behavior scores at day 3 after surgery, parental and anesthesiologists' satisfaction, and adverse events. Ethics and dissemination: This study has been approved by the ethics review boards at all participating hospitals. The Ethics Committee of the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University (Reference No. LCKY 2020-380, November 13, 2020) is the central ethics committee.

Dorsal Penile Nerve Block via Perineal Approach, an Alternative to a Caudal Block for Pediatric Circumcision: A Randomized Controlled Trial.

BACKGROUND: General anesthesia combining with a caudal block (CB) has been commonly performed in pediatric patients undergoing circumcision surgeries. However, some severe complications have been suspected of a caudal block in the combined use. To avoid these issues of a caudal block, this study introduces a novel dorsal penile nerve block (DPNB) via perineum guided by ultrasound as an alternative to a caudal block in pediatric circumcision surgeries. METHODS: A total of 104 pediatric patients scheduled for circumcision surgeries were involved and randomly divided into 2 groups: the CB group (n=52) and the DPNB group (n=52). A laryngeal mask was inserted followed by induction and maintenance anesthesia of inhaled sevoflurane. In the DPNB group, a dorsal penile nerve block (DPNB) guided by a real-time ultrasonography was performed by a single injection via perineum of 0.25% ropivacaine plus 0.8% lidocaine with total injection volume of 3-5ml. In the CB group, a dose of 0.5 ml/kg was given via the caudal canal following the same general anesthesia with that of Group DPNB. The time to the first analgesic demand after surgery is the key data collected for comparing between the two study groups. Heart rates and respiratory rates changes before and during the surgical procedure, pain score when leaving the PACU, and the time taken for the first micturition after a surgery were also recorded to analyze the differences in analgesic effects between the CB and DPNB groups. RESULTS: No significant difference in heart rates and respiratory rates was found between the two groups before and during the surgery. Pain scores were similar before pediatric patients leave the PACU. However, the time taken for the first micturition after a surgery in Group DPNB is shorter than Group CB. The patients in Group DPNB asked for analgesics later than those in Group CB. Additionally, no significant differences in adverse effects were noted between two groups except the numbness of the lower limbs occurring less in Group DPNB. CONCLUSIONS: The ultrasound-guided dorsal penile nerve block via perineal approach can basically act as a safe and effective alternative to the caudal block in pediatric patients undergoing circumcision surgeries. Clinical Trials identifier is ChiCTR-IPR-15006670. Protocol is available at http://www.chictr.org.cn/showproj.aspx?proj=11319.

Pediatric preoperative risk factors to predict postoperative ICU admission and death from a multicenter retrospective study.

BACKGROUND: Although some studies have investigated the potential predictors of perioperative mortality, there are few specifically for pediatrics. OBJECTIVE: The aim of the retrospective study was to analyze potential preoperative risk factors and to develop a pediatric preoperative risk prediction score (PRPS), and to predict postoperative ICU admission and the incidence of perioperative death in pediatric patients. METHODS: Patients who postoperatively admitted to ICU or died (occurred within 30 days after the surgery) from 263 607 pediatric surgical patients with age from 1 day to 14 years old in eight centers in China from October 2010 to September 2013 were retrospectively analyzed. About 5500 non-ICU admission and death patients were randomly selected from those 263 607 patients as controls for analysis comparison. Independent risk factors and a risk model were derived from these analyses, and were further assessed with the likelihood ratio test and the area under the receiver operating characteristic (ROC) curve. RESULTS: There were 1812 ICU admission or death patients but 187 patients' records are incomplete. There were 487 patients with incomplete records among 5500 controls. Collectively, data from 6626 patients were enrolled in final analyses. With multiple logistic regression analysis, age, ASA physical status, SpO2 , prematurity, and unfasted status were found to be independent predictors for critical patients. The AUC value of 0.905 indicated excellent predictive performance between critical and noncritical predictors. CONCLUSIONS: Our study revealed that age, ASA physical status, SpO2 , prematurity, and unfasted status are risk factors to predict postoperative ICU admission and death in pediatric patients.

The effect of clopidogrel on pharmacokinetics of ivabradine and its metabolite in rats.

The present study aimed to investigate the effect of clopidogrel (CLO) on pharmacokinetics of ivabradine (IVA) and its metabolite in rats and develop a reliable method to determine IVA and its metabolite N-demethyl ivabradine in serum. Healthy male SD rats were randomized to be given 0.8 mg/kg IVA or IVA combined with 8 mg/kg CLO. Blood samples were collected at 0.083, 0.16, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 h after administration. The serum concentrations of IVA and N-demethyl ivabradine were determined by ultra-performance liquid chromatography-mass spectrometry and pharmacokinetic parameters were calculated using DASver3.0 software. The parameters of AUC(0 - t), AUC(0 - ∞), and Cmax for IVA in the group of IVA + CLO were significantly higher than those in the group of IVA (p < 0.01); the half-time (t1/2) in the IVA + CLO group was extended compared to IVA (p < 0.01) and CL/F was dropped obviously (p < 0.01). The decreases in AUC(0 - t), AUC(0 - ∞), and Cmax for N-demethyl ivabradine in the group of IVA + CLO was significantly compared to the group of IVA (p < 0.01). CL/F was higher than IVA (p < 0.01) and the t1/2 was slightly increased. In this study, we find that CLO restrains the metabolism of IVA into N-demethyl ivabradine, which may be related to its competitive inhibition effect on cytochrome P450 isoform 3A4(CYP3A4).