Search

Data on the distribution of voriconazole (VRC) in the human peritoneal cavity are sparse. This prospective study aimed to describe the pharmacokinetics of intravenous VRC in the peritoneal fluid of critically ill patients.

STUDY OBJECTIVES This study aimed to establish a population pharmacokinetic (PPK) model of intravenous voriconazole (VRC) in critically ill patients with liver dysfunction and to explore the optimal dosing strategies in specific clinical scenarios for invasive fungal infections (IFIs) caused by common Aspergillus and Candida species. DESIGN Prospective pharmacokinetics study. SETTING The intensive care unit in a tertiary-care medical center. PATIENTS A total of 297 plasma VRC concentrations from 26 critically ill patients with liver dysfunction were included in the PPK analysis. METHODS Model-based simulations with therapeutic range of 2-6 mg/L as the plasma trough concentration (Cmin ) target and the free area under the concentration-time curve from 0 to 24 h (ƒAUC24 ) divided by the minimum inhibitory concentration (MIC) (ie, ƒAUC24 /MIC) ≥25 as the effective target were performed to optimize VRC dosing regimens for Child-Pugh class A and B (CP-A/B) and Child-Pugh class C (CP-C) patients. RESULTS A two-compartment model with first-order elimination adequately described the data. Significant covariates in the final model were body weight on both central and peripheral distribution volume and Child-Pugh class on clearance. Intravenous VRC loading dose of 5 mg/kg every 12 h (q12h) for the first day was adequate for CP-A/B and CP-C patients to attain the Cmin target at 24 h. The maintenance dose regimens of 100 mg q12h or 200 mg q24h for CP-A/B patients and 50 mg q12h or 100 mg q24h for CP-C patients could obtain the probability of effective target attainment of >90% at an MIC ≤0.5 mg/L and achieve the cumulative fraction of response of >90% against C. albicans, C. parapsilosis, C. glabrata, C. krusei, A. fumigatus, and A. flavus. Additionally, the daily VRC doses could be increased by 50 mg for CP-A/B and CP-C patients at an MIC of 1 mg/L, with plasma Cmin monitored closely to avoid serious adverse events. It is recommended that an appropriate alternative antifungal agent or a combination therapy could be adopted when an MIC ≥2 mg/L is reported, or when the infection is caused by C. tropicalis but the MIC value is not available. CONCLUSIONS For critically ill patients with liver dysfunction, the loading dose of intravenous VRC should be reduced to 5 mg/kg q12h. Additionally, based on the types of fungal pathogens and their susceptibility to VRC, the adjusted maintenance dose regimens with lower doses or longer dosing intervals should be considered for CP-A/B and CP-C patients.

Background Nutritional therapy is essential for patients in the intensive care unit (ICU), when optimal caloric goals remain controversial, especially for the late acute phase (after day 3). This study aimed to investigate the impact of hypocaloric versus normocaloric feeding in this period. Methods We conducted a retrospective analysis within an up-to-date large database, including adult patients who were admitted to a tertiary hospital from 2008 to 2019, and stayed in the ICU for over one week. Individuals were divided according to the mean daily caloric intake from day 4 to day 7 (= 20 Kcal/kg/d). The restricted cubic spline for a cox proportional hazards model was employed to assess the association between mean caloric intake divided by predicted energy expenditure (EE) and 1-year mortality. Results 3,545 eligible patients formed the study population. Most patients received progressively-elevating nutrition, achieving median values of 18.4 Kcal/kg/d and 0.71 g/kg/d in caloric and protein intake from day 4 onwards. Hypocaloric feeding was correlated with reduced nosocomial infection (41.7% vs 46.7%, P = 0.003), hyperglycemia episodes (63.6% vs 67.8%, P = 0.008), ventilation durations (3.6 vs 4.1 days, P = 0.001), and ICU length of stay (LOS) (11.6 vs 13.4 days, P

Background: Risk stratification plays an essential role in the decision-making of sepsis management, whereas neither a single serum biomarker nor traditional scoring tools can satisfy the need to assess this heterogeneous population comprehensively. The study intended to develop an interpretable machine learning model for predicting in-hospital mortality in critically ill patients with sepsis. Methods: Adult patients fulfilling the definition of Sepsis-3 were included in the Medical Information Mart for Intensive Care (MIMIC)-IV database. Relevant clinical features were extracted within the first 24 hours in ICU, and missing data were analyzed and imputed. We randomly separated the dataset into train and test sub-cohort by the ratio of 7:3, then an outcome-balanced train dataset was synthesized for model training. Extreme gradient boosting (XGBoost) was employed when feature selection and hyperparameter tuning were performed afterward. The fine-tuned XGBoost model was then compared with stepwise logistic regression (LR) and established severity scores. Eventually, we inspected the interpretability of the new model using XGBoost feature importance and Shapley Additive exPlanations (SHAP) plot. Results: The final cohort had 24,573 patients, of which 3,785 patients died during hospitalization (15.4%). Ten iterations of multiple imputations were executed to fill missing data in all 91 incomplete variables. Subsequently, 10,572 patients formed the balanced dataset used for training. The XGBoost model showed greater discrimination than stepwise LR and severity scores such as Simplified Acute Physiology Score (SAPS)-III score (AUC: 0.849, 95% CI: 0.8386-0.8599; AUC: 0.618, 95% CI: 0.3927-0.8437; AUC: 0.803, 95% CI: 0.7898-0.8165 respectively). Based on model interpretation, some decisive factors, including elevated lactate and anion gap level, prolonged partial thromboplastin time, decreased urine volume, were greatly correlated with poor survival outcomes in sepsis. Conclusions: In the field of predicting the mortality risk of sepsis patients in hospitals, the XGBoost-based model demonstrated superior performance to stepwise LR and other scores. In addition, the model exhibited good interpretability and might provide valuable hints on future directions of clinical practice and research.

This study was to find out novel miRNAs whether could be used as diagnostic or prognostic biomarkers in sepsis. We used miRNAs microarray assays and further confirmed the levels of miRNAs in 151 septic patients' plasma. 56 miRNAs were up-regulated and 74 miRNAs down-regulated in septic patients compared with the healthy volunteers. But only miR-519c-5p and miR-3622b-3p were up-regulated in both septic and septic shock patients. The levels of miR-519c-5p and miR-3622b-3p were statistically higher in 151 septic patients than healthy controls on day 1. The AUC for miR-519c-5p was 0.79 (95% CI, 0.688-0.892, p = 0.001) in the diagnosis of sepsis, and the AUC for miR-3622b-3p 0.752 (95% CI, 0.622-0.881, p = 0.003). The AUC for the combination of these two miRNAs was 0.831 (95% CI, 0.74-0.923, p 0.001). Besides, the AUC for miR-519c-5p was 0.597 (p = 0.043) in predicting 28-day mortality. MiR-519c-5p, miR-3622b-3p were novel biomarkers for diagnosing septic patients. High miR-519c-5p levels suggest a worse short-term prognosis. CLINICAL TRIAL REGISTRATION INFORMATION: Name of the registry: Diagnostic and prognostic value of circulating miRNA in patients with sepsis; Trial registration ID: ChiCTR-DDD-17013150; registered 30 October 2017; http://www.chictr.org.cn/edit.aspx?pid=22528htm=4.

Background: The rise of platelets in sepsis patients with thrombocytopenia can lead to an improvement in clinical outcomes. We aimed to probe whether the rebound of platelet count could be a predictor of good prognosis in sepsis patients in a large, diverse population.Methods: All sepsis patients were initially stratified according to nadir platelet counts (very low9/L, intermediate-low 50 ´ 109 to 99 ´ 109/L, low 100 ´ 109 to 149 ´ 109/L, normal 150 ´ 109 to 399 ´ 109/L, or thrombocytosis > 400 ´ 109/L). The delta platelet count (DPC) was defined as the difference between the last platelet count prior to transfer or death and the nadir platelet count after ICU admission. Results: A total of 3457 patients were enrolled in our study. The 28-day mortality in the very low (43.1%) and intermediate-low (36.9%) platelet count groups was higher than in the low (26.8%) and normal (23.2%) platelet count groups and thrombocytosis (18.2%) group (P 0 subgroup had lower 28-day morality (38.5% vs. 59.1%, P < 0.001, 33.3% vs. 44.7%, P = 0.015, 23.8% vs. 32.7% P = 0.01, 20.2 vs. 27.7, P = 0.001, respectively) except in the thrombocytosis group. The extended Cox proportional hazard regression model showed a decreased risk of death within 28 days in patients in the ΔPC > 0 subgroup (HR 0.570, 95% CI 0.498-0.651, P < 0.001).Conclusions: The rebound platelet count could be a biomarker of good prognosis in patients with sepsis.

Background: The appropriate range of central venous pressure (CVP) in sepsis patients remains controversial. The aim of this study was to investigate the optimal CVP range in sepsis and septic shock patients admitted to intensive care unit.Methods: We performed a retrospective study with adult sepsis patients with CVP records based on the eICU Collaborative Research Database. Cases were divided into three groups according to mean CVP level during ICU stay: low (< 8 mmHg), normal (8–12 mmHg), and high (> 12 mmHg). Baseline characteristics and clinical outcomes of three groups were compared. Multivariable logistic regression was used to assess the relationship between different CVP levels (by equal interval of 4 mmHg) and in-hospital death risk. Results: 5302 sepsis patients were included in this study. Lactate level, serum creatinine, proportion of mechanical ventilation and dialysis were significantly higher in high CVP group compared to normal CVP group (2.6 [1.6,3.4] vs 2.2 [1.4,2.9] mmol/L; 1.5 [1,2.4] vs 1.2 [0.8,2] mg/dL; 52.2% vs 48.2%; 14.6% vs 9.7%; p < 0.05, respectively). In addition, high CVP group tended to have higher ICU mortality (24.8% vs 15.9%, p < 0.05) and hospital mortality (32.2% vs 22.4%, p < 0.05). The logistic regression analyses revealed that, in sepsis patients, CVP range of 12-16 mmHg, 16-20 mmHg and > 20 mmHg was related to increased in-hospital death risk compared to 8-12 mmHg level (OR: 1.349, 2.287, 3.210, respectively; 95% CI: 1.161–1.568, 1.897–2.757, 2.403–4.290, respectively); there were no significant differences between 0-4 mmHg, 4-8 mmHg and 8-12 mmHg levels regarding in-hospital death risk. Whereas in septic shock patients, CVP level of 0-4 mmHg, 12-16 mmHg, 16-20 mmHg and > 20 mmHg all contributed to increased in-hospital death risk (OR: 1.914, 1.652, 3.305, 3.554, respectively; 95% CI: 1.165–3.146, 1.299–2.101, 2.444–4.47, 2.233–5.654, respectively).Conclusions: High CVP level (> 12 mmHg) was related to worse clinical outcomes in both sepsis and septic shock patients; while very low CVP level (< 4 mmHg) in septic shock patients was also harmful. More strict fluid administration was essential in septic shock population.

Background Integrator complex subunit 6 (INTS6) was found to play a tumour suppressing role in certain types of solid tumours. In this study, we wanted to determine the expression level of INTS6 in hepatocellular carcinoma (HCC) and evaluate its clinical characteristics and mechanisms in HCC patients (Lui and Lu, European Journal of Cancer, 51:S94, 2015). Methods First, we used a microarray analysis to explore the mRNA expression levels in HCC and paired normal liver tissues; second, we used qRT-PCR to measure the INTS6 mRNA levels in a cohort of 50 HCC tissues and adjacent normal liver tissues; third, we used Western blot analyses to detect the INTS6 protein levels in 20 paired HCC and normal liver tissues; fourth, we used immunohistochemistry to determine the INTS6 expression levels in 70 archived paraffin-embedded HCC samples. Finally, we investigated the suppressive function of INTS6 in the Wnt pathway. Results Herein, according to the microarray data analysis, the expression levels of INTS6 were dramatically down-regulated in HCC tissues vs. those in normal liver tissues (p

Objectives: We investigated the impact of obesity (proxied as body mass index (BMI)), on short- and long-term mortality in sepsis patients. Methods: We conducted a retrospective analysis with adult sepsis ICU patients in a US medical institution from 2001 to 2012 in the MIMIC-III database. The WHO BMI categories were used. Multivariate logistic regression assessed the relationships between BMI and 30-day and 1-year mortality. Results: In total, 5563 patients were enrolled. Obese patients tended to be younger (P

Introduction: The objective of our study was to explore the association between sex and clinical outcome in sepsis patients in a large, diverse population. Materials and Methods: We analyzed 6,134 adult patients with sepsis from the critical care units of Beth Israel Deaconess Medical Center between 2001 and 2012. Study data were retrospectively extracted from Medical Information Mart for Intensive Care-III, a multiparameter intensive care database. Results: There were 2,677 (43.6%) female and 3,457 (56.4%) male patients. Compared with female patients, male patients with sepsis had a higher 1-year mortality rate (55.6% vs. 51.4%, P = 0.001), and so did the 90-day mortality rate (45.1% vs. 42.1%, P = 0.018). 33.8% of male and 31.3% of female patients with sepsis died during hospitalization (P = 0.041). The median length of hospitalization and intensive care unit (ICU) stay for male patients was 19.54 and 7.54 days, while that for female patients was 16.49 and 6.75 days (P

In this study, we aimed to determine whether the pseudogene integrator complex subunit 6 pseudogene 1 (INTS6P1) in plasma could be used as a novel approach to screen for and detect hepatocellular carcinoma (HCC). We explored the clinical role of INTS6P1: First, the expression level of INTS6P1 was measured in a cohort of 33 HCC tissue samples and adjacent normal liver tissue, next, the INTS6P1 expression was detected in the culture medium and tumor cells in a cellular experiment, and last, the diagnostic performance of INTS6P1 was examined in an independent cohort of 100 people. The expression level of INTS6P1 was remarkably downregulated in the HCC tissues compared with that in the normal liver tissues (p = 0.0066). In plasma, the INTS6P1 levels were significantly decreased in HCC patients compared with non-HCC patients (p