Pathophysiological dynamics in the contact, coagulation, and complement systems during sepsis: Potential targets for nafamostat mesilate.

Sepsis is a life-threatening syndrome resulting from a dysregulated host response to infection. It is the primary cause of death in the intensive care unit, posing a substantial challenge to human health and medical resource allocation. The pathogenesis and pathophysiology of sepsis are complex. During its onset, pro-inflammatory and anti-inflammatory mechanisms engage in intricate interactions, possibly leading to hyperinflammation, immunosuppression, and long-term immune disease. Of all critical outcomes, hyperinflammation is the main cause of early death among patients with sepsis. Therefore, early suppression of hyperinflammation may improve the prognosis of these patients. Nafamostat mesilate is a serine protease inhibitor, which can inhibit the activation of the complement system, coagulation system, and contact system. In this review, we discuss the pathophysiological changes occurring in these systems during sepsis, and describe the possible targets of the serine protease inhibitor nafamostat mesilate in the treatment of this condition.

Pharmacokinetic analysis of ceftazidime and cefazolin in the treatment of continuous ambulatory peritoneal dialysis-related peritonitis.

OBJECTIVE: Peritoneal dialysis-related peritonitis (PDRP) presents a significant challenge for nephrologists. Continuous intraperitoneal cefazolin and ceftazidime are recommended for the treatment of peritonitis. However, some pharmacokinetic studies have shown that doses of 15-20 mg/kg/d may not achieve sufficient therapeutic levels. In this study, we investigated the pharmacokinetics of ceftazidime and cefazolin in patients with continuous ambulatory peritoneal dialysis-related peritonitis and compared the pharmacokinetic characteristics between traditional and modified treatment groups. METHODS: From February 2017 to December 2019, 42 PDRP patients (17 males, 25 females; mean age: 50.7 ± 12.1 years; mean body weight: 60.9 ± 11.8 kg) were recruited for the study, all participants were anuric. Twenty patients were enrolled in the traditional group and treated with cefazolin (1.0 g) and ceftazidime (1.0 g) via intraperitoneal administration once daily for 14 days. Twenty-two patients were enrolled in the modified group and received the same dose of antibiotics twice daily for the initial five days, followed by once daily for the subsequent nine days. Serum and dialysate samples were collected after days 1, 2, 3, 5, 7, 10, and 14 and analyzed via liquid chromatography-mass spectrometry. RESULTS: In the traditional group, the highest and lowest serum concentrations of ceftazidime were 35.9 and 21.7 µg/mL, respectively. The highest concentration of cefazolin was 54.6 µg/mL on day 5 and the lowest concentration was 30.4 µg/mL on day 1. In the modified group, the highest and lowest serum concentrations of ceftazidime were 102.2 and 54.8 µg/mL, respectively. The highest concentration of cefazolin was 141.7 µg/mL and the lowest concentration was 79.8 µg/mL. All antibiotic concentrations were above the minimum inhibitory concentration (MIC) level (8 µg/mL of ceftazidime and 2 µg/mL of cefazolin) throughout the treatment period. However, on day 1, the concentration of ceftazidime in the third bag of dialysate effluent from the traditional group fell below the MIC level. Despite remaining above the MIC, cefazolin concentration was consistently lower in the third bag of dialysate effluent from the traditional group throughout the treatment period. CONCLUSIONS: Intraperitoneal administration of cefazolin and ceftazidime at a dose of 1 g twice daily for 5 days and then once daily for the rest of the treatment period ensured adequate therapeutic levels of antibiotics for treating anuric PDRP patients.

Efficacy and safety of glucocorticoids use in patients with COVID-19: a systematic review and network meta­analysis.

BACKGROUND: Currently, some meta-analyses on COVID-19 have suggested that glucocorticoids use can reduce the mortality rate of COVID-19 patients, utilization rate of invasive ventilation, and improve the prognosis of patients. However, optimal regimen and dosages of glucocorticoid remain unclear. Therefore, the purpose of this network meta-analysis is to analyze the efficacy and safety of glucocorticoids in treating COVID-19 at regimens. METHODS: This meta-analysis retrieved randomized controlled trials from the earliest records to December 30, 2022, published in PubMed, Embase, Cochrane Library, CNKI Database and Wanfang Database, which compared glucocorticoids with placebos for their efficacy and safety in the treatment of COVID-19, Effects of different treatment regimens, types and dosages (high-dose methylprednisolone, very high-dose methylprednisolone, Pulse therapy methylprednisolone, medium-dose hydrocortisone, high-dose hydrocortisone, high-dose dexamethasone, very high-dose dexamethasone and placebo) on 28-day all-caused hospitalization mortality, hospitalization duration, mechanical ventilation requirement, ICU admission and safety outcome were compared. RESULTS: In this network meta-analysis, a total of 10,544 patients from 19 randomized controlled trials were finally included, involving a total of 9 glucocorticoid treatment regimens of different types and dosages. According to the analysis results, the 28-day all-cause mortality rate was the lowest in the treatment with pulse therapy methylprednisolone (OR 0.08, 95% CI 0.02, 0.42), but the use of high-dose methylprednisolone (OR 0.85, 95% CI 0.59, 1.22), very high-dose dexamethasone (OR 0.95, 95% CI 0.67, 1.35), high-dose hydrocortisone (OR 0.64, 95% CI 0.34, 1.22), medium-dose hydrocortisone (OR 0.80, 95% CI 0.49, 1.31) showed no benefit in prolonging the 28-day survival of patient. Compared with placebo, the treatment with very high-dose methylprednisolone (MD = -3.09;95%CI: -4.10, -2.08) had the shortest length of hospital stay, while high-dose dexamethasone (MD = -1.55;95%CI: -3.13,0.03) and very high-dose dexamethasone (MD = -1.06;95%CI: -2.78,0.67) did not benefit patients in terms of length of stay. CONCLUSIONS: Considering the available evidence, this network meta­analysis suggests that the prognostic impact of glucocorticoids in patients with COVID-19 may depend on the regimens of glucocorticoids. It is suggested that pulse therapy methylprednisolone is associated with lower 28-day all-cause mortality, very high-dose methylprednisolone had the shortest length of hospital stay in patients with COVID-19. TRIAL REGISTRATION: PROSPERO CRD42022350407 (22/08/2022).

Inhibition of sphingosine-1-phosphate receptor 3 suppresses ATP-induced NLRP3 inflammasome activation in macrophages via TWIK2-mediated potassium efflux.

Background: Inhibition of sphingosine kinase 1 (SphK1), which catalyzes bioactive lipid sphingosine-1-phosphate (S1P), attenuates NLRP3 inflammasome activation. S1P exerts most of its function by binding to S1P receptors (S1PR1-5). The roles of S1P receptors in NLRP3 inflammasome activation remain unclear. Materials and methods: The mRNA expressions of S1PRs in bone marrow-derived macrophages (BMDMs) were measured by real-time quantitative polymerase chain reaction (qPCR) assays. BMDMs were primed with LPS and stimulated with NLRP3 activators, including ATP, nigericin, and imiquimod. Interleukin-1ß (IL-1ß) in the cell culture supernatant was detected by enzyme-linked immunosorbent assay (ELISA). Intracellular potassium was labeled with a potassium indicator and was measured by confocal microscopy. Protein expression in whole-cell or plasma membrane fraction was measured by Western blot. Cecal ligation and puncture (CLP) was induced in C57BL/6J mice. Mortality, lung wet/dry ratio, NLRP3 activation, and bacterial loads were measured. Results: Macrophages expressed all five S1PRs in the resting state. The mRNA expression of S1PR3 was upregulated after lipopolysaccharide (LPS) stimulation. Inhibition of S1PR3 suppressed NLRP3 and pro-IL-1ß in macrophages primed with LPS. Inhibition of S1PR3 attenuated ATP-induced NLRP3 inflammasome activation, enhanced nigericin-induced NLRP3 activation, and did not affect imiquimod-induced NLRP3 inflammasome activation. In addition, inhibition of S1PR3 suppressed ATP-induced intracellular potassium efflux. Inhibition of S1PR3 did not affect the mRNA or protein expression of TWIK2 in LPS-primed BMDMs. ATP stimulation induced TWIK2 expression in the plasma membrane of LPS-primed BMDMs, and inhibition of S1PR3 impeded the membrane expression of TWIK2 induced by ATP. Compared with CLP mice treated with vehicle, CLP mice treated with the S1PR3 antagonist, TY52156, had aggravated pulmonary edema, increased bacterial loads in the lung, liver, spleen, and blood, and a higher seven-day mortality rate. Conclusions: Inhibition of S1PR3 suppresses the expression of NLRP3 and pro-IL-1ß during LPS priming, and attenuates ATP-induced NLRP3 inflammasome activation by impeding membrane trafficking of TWIK2 and potassium efflux. Although inhibition of S1PR3 decreases IL-1ß maturation in the lungs, it leads to higher bacterial loads and mortality in CLP mice.

Ultrasound-guided bilateral superficial cervical plexus blocks enhance the quality of recovery in patients undergoing thyroid cancer surgery: A randomized controlled trial.

STUDY OBJECTIVE: Regional anesthesia can improve postoperative analgesia and enhance the quality of recovery (QoR) after surgery. This trial evaluates the effects of ultrasound-guided bilateral superficial cervical plexus block (SCPB) on QoR in patients undergoing thyroid cancer surgery. DESIGN: Prospective, randomized, double-blinded, placebo-controlled trial. SETTING: Operating room. PATIENTS: Seventy-four ASA I-II female patients scheduled for thyroid cancer surgery were included to the study. INTERVENTIONS: Patients were randomly allocated to receive pre-operative ultrasound-guided bilateral SCPB with 10 ml of ropivacaine 0.5% or normal saline on each side. MEASUREMENTS: The primary endpoint was the quality of recovery, which was assessed using the 15-item quality of recovery questionnaire (QoR-15). Secondary endpoints were acute postoperative pain, time to first rescue analgesia, the number of patients requiring rescue analgesia, length of post-anesthesia care unit (PACU) stay, the incidence of postoperative nausea or vomiting (PONV) and dizziness, and patient satisfaction. MAIN RESULTS: The global QoR-15 score at 24 h postoperatively was significantly higher in the SCPB group (Median [IQR], 118 [115-120]) than the control group (110 [106-112]) with a median difference of 8 (95% CI: 6 to 10, P < .001). Compared with the control group, pre-operative ultrasound-guided bilateral SCPB reduced postoperative pain up to 24 h and the incidence of PONV, as well as the length of PACU stay. Additionally, the patient satisfaction scores were improved in the SCPB group (P = .024). CONCLUSION: Pre-operative ultrasound-guided bilateral SCPB with ropivacaine enhances the quality of recovery, postoperative analgesia and patient satisfaction, alleviates the incidence of PONV, and accelerates the PACU discharge following thyroid cancer surgery.

Efficacy of ultrasound-guided erector spinae plane block on postoperative quality of recovery and analgesia after modified radical mastectomy: randomized controlled trial.

BACKGROUND: Erector spinae plane block (ESPB) is a novel regional anesthesia technique that is gaining popularity for postoperative pain management. This randomized controlled trial evaluated the effect of ESPB on quality of recovery (QoR) in patients undergoing modified radical mastectomy. METHODS: Eighty-two female patients undergoing modified radical mastectomy were included. Patients were randomly assigned to receive preoperative ultrasound-guided ESPB with either 0.5% ropivacaine or saline. The primary outcome was QoR, assessed 24 hours postoperatively using the 15-item QoR questionnaire (QoR-15). Secondary outcomes included postoperative pain scores, postoperative cumulative opioid consumption, postanesthesia care unit (PACU) discharge time, postoperative nausea or vomiting and dizziness. RESULTS: Global QoR-15 scores 24 hours postoperatively were significantly higher (indicating better quality) in the ESPB group (median 120, IQR 118-124) compared with the control group (median 110, IQR 108.3-112.8), with a median difference of 10 (95% CI 9 to 12, p<0.001). Compared with the control group, ESPB with ropivacaine reduced pain scores up to 8 hours after surgery, as well as reduced postoperative cumulative opioid consumption and PACU discharge time. CONCLUSIONS: A single preoperative injection of ESPB with ropivacaine may improve QoR postoperatively and acute postoperative analgesia in patients undergoing a modified radical mastectomy. TRIAL REGISTRATION NUMBER: ChiCTR-1800019599.

Salidroside and FG-4592 ameliorate high glucose-induced glomerular endothelial cells injury via HIF upregulation.

Increasing research indicates that hyperglycemia plays a crucial role in the progression of diabetic nephropathy (DN); however, effective treatment for preventing or slowing DN progression are seriously lacking. Although salidroside (SAL) has been demonstrated to have a positive anti-diabetic effect, the cellular mechanisms remain unclear. FG-4592, a novel prolyl hydroxylase inhibitor, was used to regulate HIF-1α and HIF-2α expression. The present study aimed to explore the underlying mechanisms of SAL and FG-4592 on high glucose (HG)-induced rat glomerular endothelial cells (rGECs) injury. HG-cultured rGECs were used to induce a diabetic environment. An MTT assay, RT-qPCR, Western blot, flow cytometry, and immunofluorescent staining were performed to investigate the effects of SAL on HG-induced rGECs injury. FG-4592 and SAL protected rGECs against HG-induced injury by increasing cellular viability and reducing the cell apoptosis rate. SAL and FG-4592 downregulated PHD-2 expression and upregulated HIF-1α and HIF-2α expression. In conclusion, our findings suggest that SAL and FG-4592 ameliorate HG-induced rGEC injury by upregulating HIF expression, indicating that SAL and FG-4592 might be favorable for further DN-treatment.