Population Pharmacokinetics of Tigecycline for Critically Ill Patients Undergoing Continuous Renal Replacement Therapy.

Background: Tigecycline is considered one of the last resorts for treating infections caused by multidrug-resistant bacteria. Continuous renal replacement therapy (CRRT) is widely used in critically ill patients, especially those with acute kidney injury or severe infections. However, pharmacokinetic data for tigecycline in patients receiving CRRT are limited. Methods: This was a single-center prospective clinical study with intensive sampling that included critically ill patients who received tigecycline and CRRT. A population pharmacokinetic (PPK) model was developed and evaluated by goodness-of-fit plots, bootstrap analysis, visual predictive checks, and numerical predictive checks. Pharmacokinetic/pharmacodynamic target attainment and cumulative fraction of response analyses were performed to explore the potential need for dose adjustments of tigecycline in CRRT. Results: In total, 21 patients with 167 concentrations were included. A two-compartment model adequately described the tigecycline concentration-time points, but no covariates were found to adequately explain the viability in the pharmacokinetic parameters of tigecycline. The typical values of CL, Q, V1 and V2 were 4.42 L/h, 34.8 L/h, 30.9 L and 98.7 L, respectively. For most infections, the standard regimen of 50 mg/12 h was deemed appropriate, expect for skin and soft skin tissue infections and community-acquired pneumonia caused by Acinetobacter baumannii and Klebsiella pneumoniae, which required a dosage regimen of 100 mg/12 h or higher. Conclusion: A tigecycline PPK model describing critically ill patients undergoing CRRT was successfully developed. The optimized dosage regimens for various infections are recommended.

Population pharmacokinetics and individualized dosing of tigecycline for critically ill patients: a prospective study with intensive sampling.

Background: Due to the heterogeneity of critically ill patients, the pharmacokinetics of tigecycline are unclear, and the optimal dosing strategy is controversial. Methods: A single-center prospective clinical study that included critically ill patients who received tigecycline was performed. Blood samples were intensively sampled (eight samples each), and plasma drug concentrations were determined. A population pharmacokinetic (PPK) model was developed and evaluated by goodness-of-fit plots, bootstrap analysis and visual predictive checks. Monte Carlo simulation was conducted to optimize the dosage regimen. Results: Overall, 751 observations from 98 patients were included. The final PPK model was a two-compartment model incorporating covariates of creatinine clearance on clearance (CL), body weight on both central and peripheral volumes of distribution (V1 and V2), γ-glutamyl transferase and total bilirubin on intercompartment clearance (Q), and albumin on V2. The typical values of CL, Q, V1 and V2 were 3.09 L/h, 39.7 L/h, 32.1 L and 113 L, respectively. A dosage regimen of 50 mg/12 h was suitable for complicated intra-abdominal infections, but 100 mg/12 h was needed for community-acquired pneumonia, skin and skin structure infections and infections caused by less-susceptive bacteria. Conclusion: The Tigecycline PPK model was successfully developed and validated. Individualized dosing of tigecycline could be beneficial for critically ill patients.

Initiation time of double-filtration plasma apheresis affects the risk of persistent organ failure in hypertriglyceridaemia-induced acute pancreatitis: a retrospective study.

The effect of double filtration plasma apheresis (DFPP) on improving the outcomes of patients with hypertriglyceridaemia-induced acute pancreatitis (HTG-AP) remains unclear. The aim of this study was to evaluate the relationship between the initiation time of DFPP and the risk of persistent organ failure (POF) in an HTG-AP cohort in China. We retrospectively evaluated data from HTG-AP patients treated with DFPP 48 h after diagnosis between January 2017 and January 2022. Comparisons across tertiles of the interval from diagnosis to completion of one DFPP session (DTD) were analysed. Logistic regression models and restricted cubic splines (RCS) were used to determine the correlation between the DTD time and risk of POF. Of the 89 patients enrolled, 46 patients (51.69%) suffered POF in the first week of HTG-AP. DFPP was initiated at a median of 17 h after the diagnosis was confirmed. The patients in the highest tertile of DTD time had a significantly increased prevalence of POF. After multivariate adjustment, the logistic regression models found a significant decrease in the odds ratios (OR) of POF from the highest to the lowest DTD tertile (P for trend = 0.006). Moreover, the RCS curves showed a nonlinear relationship in the adjusted OR of POF and DTD time, which remained relatively low and flat during the early DTD time but increased sharply afterwards. Early initiation of DFPP treatment correlates with a reduced risk of POF in HTG-AP patients.

The role of double filtration plasmapheresis in hypertriglyceridemic pancreatitis: A propensity score matching analysis.

INTRODUCTION: The role of double filtration plasmapheresis (DFPP) in hypertriglyceridemic pancreatitis (HTGP) is still not well established. Our study aimed to investigate the efficacy of DFPP in reducing triglyceride levels as well as their effects on the outcomes of HTGP. MATERIAL AND METHODS: We retrospectively evaluated the data of patients with HTGP presenting within 72 hours from symptom onset between January 2016 and February 2019. Patients with DFPP treatment were compared with those without DFPP treatment. We used a propensity score matching analysis to reduce confounding factors. RESULTS: Of the 249 patients enrolled, 88 (35.3%) were treated with DFPP. The DFPP was initiated at a median of 7.7 hours from the time of presentation. In the propensity score-matched cohort (n = 100), patients with DFPP had a significantly lower level of triglyceride (P = .034), higher triglyceride reduction (P = .005), and the proportion of triglyceride <5.65 mmol/L (P = .002) by 24 hours after admission when compared with those without DFPP. However, this efficacy did not last until 48 hours after admission. No differences were found in terms of the majority of the clinical outcomes between the two groups, including persistent organ failure (P = .098), local complications (P = .213), hospital stay (P = .657), and in-hospital mortality (P > .999). CONCLUSIONS: HTGP patients with early initiation of DFPP were associated with rapidly and efficiently reduction of triglyceride levels compared with those without DFPP. However, DFPP showed no beneficial effects on improving the clinical outcomes of HTGP.

miR-138-5p targets sirtuin1 to regulate acute lung injury by regulation of the NF-κB signaling pathway.

Acute lung injury (ALI), a disease with a high mortality rate, is a noncardiogenic pulmonary inflammatory response and characterized by damage to the pulmonary system. In this study, we explored the mechanism of the occurrence and development of ALI. It was firstly found that miR-138-5p could inhibit the expression of sirtuin1 (SIRT1), and we further demonstrated that miR-138-5p targets directly SIRT1 through the luciferase assay, while the latter negatively regulated the expression of NF-κB. A549 cells were treated with lipopolysaccharide in vitro to simulate ALI cells and induce ALI in the model mice. The results showed that inhibiting the expression of miR-138-5p could effectively increase the viability of damaged cells, promote cell proliferation, reduce apoptosis, inhibit the inflammatory response, reduce oxidative stress, and then relieve ALI symptoms. Collectively, our results suggested that miR-138-5p can inhibit SIRT1 expression and indirectly activate the NF-κB signaling pathway, thus regulating the development of ALI.

Alterations in diaphragmatic function assessed by ultrasonography in mechanically ventilated patients with sepsis.

PURPOSE: To assess alteration of diaphragmatic function by ultrasonography in a population of mechanically ventilated patients with or without sepsis. METHODS: We performed a prospective, 6-month, single-center, observational cohort study. Mechanically ventilated septic and nonseptic patients were studied within 24 hours following intubation and before the moment of ventilator liberation. Diaphragm thickness and contractile activity (quantified by diaphragmatic thickening fraction, DTF) were measured by ultrasonography at the zone of apposition. Intraobserver and interobserver reproducibility were measured. RESULTS: Fifty-two critically ill patients were included, 28 with sepsis and 24 without sepsis. Upon initiation of ventilation, DTF was lower in septic than that in nonseptic patients (P = 0.03). No difference was observed between septic and nonseptic patients for diaphragm thickness. Mean 188 ± 111 hours after the first measurement, both diaphragm thickness and DTF decreased significantly compared with first measurements in septic and nonseptic patients, all P < 0.001. Diaphragm thickness decreased by 9.1 ± 10.7% in nonseptic and by 16.0 ± 13.5% in septic patients, P = 0.049. DTF decreased by 15.2 ± 21.3% in nonseptic and by 30.7 ± 22.0% in septic patients, P = 0.013. CONCLUSIONS: Mechanically ventilated patients with sepsis were associated with an earlier and more severe diaphragm dysfunction compared with patients without sepsis.