Exploring the Optimal Range of Central Venous Pressure in Sepsis and Septic Shock Patients: A Retrospective Study in 208 Hospitals.

BACKGROUND: 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. Multivariable logistic regression was performed to explore the associations between CVP level and hospital mortality. Non-linear correlations and optimal CVP range were explored using restricted cubic splines (RCS). RESULTS: 5302 sepsis patients were included in this study. Patients in 4-8 mmHg group owned the lowest odds ratio for raw hospital mortality (19.7%). The logistic regression analyses revealed that hospital death risk increased significantly when mean CVP level exceeds 12 mmHg compared to 4-8 mmHg level. U-shaped association of CVP with hospital mortality was revealed by RCS model in septic shock patients and the optimal range was 5.6-12 mmHg. While, there was a J-shaped trend for non-septic shock patients. For non-septic shock patients, patients had an increased risk of hospital death only if CVP exceeded 11 mmHg. CONCLUSIONS: We observed U-shaped association between mean CVP level and hospital mortality in septic shock patients and J-shaped association in non-septic shock patients. This may imply that patients with different severity of sepsis have different CVP requirements. We need to monitor and manage CVP according to the circulatory status of the sepsis patient.

Impact of red blood cell transfusion and hemoglobin threshold on 1-year mortality among surgical sepsis survivors: A propensity score matching study.

BACKGROUND: Despite the fact that red blood cell (RBC) transfusion is commonly applied in surgical intensive care unit (ICU), the effect of RBC transfusion on long-term outcomes remains undetermined. We aimed to explore the association between RBC transfusion and the long-term prognosis of surgical sepsis survivors. METHODS: This retrospective study was conducted on adult sepsis patients admitted to a tertiary surgical ICU center in China. Patients were divided into transfusion and non-transfusion groups based on the presence of RBC transfusion. Propensity score matching (PSM) and inverse probability of treatment weighting (IPTW)were performed to balance the potential confounders. RESULTS: A total of 1421 surgical sepsis survivors were enrolled, including 403 transfused patients and 1018 non-transfused patients. There was a significant difference in 1-year mortality between the two groups (23.1 â€‹% vs 12.7 â€‹%, HR: 1.539, 95 â€‹% confidence interval [CI]: 1.030-2.299, P â€‹< â€‹0.001). After PSM and IPTW, transfused patients still showed significantly increased 1-year mortality risks compared to non-transfused individuals (PSM: 23.6 â€‹% vs 15.9 â€‹%, HR 1.606, 95 â€‹% CI 1.036-2.488 â€‹P â€‹= â€‹0.034; IPTW: 20.1 â€‹% vs 12.9 â€‹%, HR 1.600, 95 â€‹% CI 1.040-2.462 â€‹P â€‹= â€‹0.032). Among patients with nadir hemoglobin below 70 â€‹g/L, 1-year mortality risks in both groups were similar (HR 1.461, 95 â€‹% CI 0.909-2.348, P â€‹= â€‹0.118). However, among patients with nadir hemoglobin above 70 â€‹g/L, RBC transfusion was correlated with increased 1-year mortality risk (HR 1.556, 95 â€‹% CI 1.020-2.374, P â€‹= â€‹0.040). CONCLUSION: For surgical sepsis survivors, RBC transfusion during ICU stay was associated with increased 1-year mortality, especially when patients show hemoglobin levels above 70 â€‹g/L.

Structured postoperative handover protocol improves efficiency and quality of interdisciplinary communication and nursing care in surgical intensive care unit: a randomized controlled trial.

This study aimed to evaluate the effectiveness of a structured postoperative handover protocol for postoperative transfer to the SICU. This study was a randomized controlled trial conducted in a comprehensive teaching hospital in China. Patients who were transferred to the SICU after surgery were randomly divided into two groups. The intervention group underwent postoperative structured handover protocol, and the control group still applied conventional oral handover. A total of 101 postoperative patients and 50 clinicians were enrolled. Although the intervention group did not shorten the handover duration (6.18 ± 1.66 vs 5.94 ± 1.91; P = 0.505), the handover integrity was significantly improved, mainly reflected in fewer information omissions (1.44 ± 0.97 vs 0.67 ± 0.62; P < 0.001), fewer additional questions raised by ICU physicians (1.06 ± 1.04 vs 0.24 ± 0.43; P < 0.001) and fewer additional handovers via phone call (16% vs 3.9%; P = 0.042). The total score of satisfaction of the intervention group was significantly higher than that of the control group (76.44 ± 7.32 vs 81.24 ± 6.95; P = 0.001). With respect to critical care, the incidence of stage I pressure sore within 24 h was lower in the intervention group than in the control group (20% vs 3.9%, P = 0.029). Structured postoperative handover protocol improves the efficiency and quality of interdisciplinary communication and clinical care in SICU.Trial registration This study was registered in China on January 8th, 2022 at Chinese Clinical Trial Registry (ChiCTR2200055400).

Pharmacokinetics of Voriconazole in Peritoneal Fluid of Critically Ill Patients.

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. A total of 19 patients were included. Individual pharmacokinetic curves, drawn after single (first dose on day 1) and multiple (steady-state) doses, displayed a slower rise and lower fluctuation of VRC concentrations in peritoneal fluid than in plasma. Good but variable penetration of VRC into the peritoneal cavity was observed, and the median (range) peritoneal fluid/plasma ratios of the area under the concentration-time curve (AUC) were 0.54 (0.34 to 0.73) and 0.67 (0.63 to 0.94) for single and multiple doses, respectively. Approximately 81% (13/16) of the VRC steady-state trough concentrations (Cmin,ss) in plasma were within the therapeutic range (1 to 5.5 µg/mL), and the corresponding Cmin,ss (median [range]) in peritoneal fluid was 2.12 (1.39 to 3.72) µg/mL. Based on the recent 3-year (2019 to 2021) surveillance of the antifungal susceptibilities for Candida species isolated from peritoneal fluid in our center, the aforementioned 13 Cmin,ss in peritoneal fluid exceeded the MIC90 of C. albicans, C. glabrata, and C. parapsilosis (0.06, 1.00, and 0.25 µg/mL, respectively), which supported VRC as a reasonable choice for initial empirical therapies against intraabdominal candidiasis caused by these three Candida species, prior to the receipt of susceptibility testing results.

Developing an Interpretable Machine Learning Model to Predict in-Hospital Mortality in Sepsis Patients: A Retrospective Temporal Validation Study.

BACKGROUND: Risk stratification plays an essential role in the decision making for sepsis management, as existing approaches can hardly satisfy the need to assess this heterogeneous population. We aimed to develop and validate a machine learning model to predict in-hospital mortality in critically ill patients with sepsis. METHODS: Adult patients fulfilling the definition of Sepsis-3 were included at a large tertiary medical center. Relevant clinical features were extracted within the first 24 h in ICU, re-classified into different genres, and utilized for model development under three strategies: "Basic + Lab", "Basic + Intervention", and "Whole" feature sets. Extreme gradient boosting (XGBoost) was compared with logistic regression (LR) and established severity scores. Temporal validation was conducted using admissions from 2017 to 2019. RESULTS: The final cohort included 24,272 patients, of which 4013 patients formed the test cohort for temporal validation. The trained and fine-tuned XGBoost model with the whole feature set showed the best discriminatory ability in the test cohort with AUROC as 0.85, significantly higher than the XGBoost "Basic + Lab" model (0.83), the LR "Whole" model (0.82), SOFA (0.63), SAPS-II (0.73), and LODS score (0.74). The performance in varying subgroups remained robust, and predictors, such as increased urine output and supplemental oxygen therapy, were crucially correlated with improved survival when interpretability was explored. CONCLUSIONS: We developed and validated a novel XGBoost-based model and demonstrated significantly improved performance to LR and other scores in predicting the mortality risks of sepsis patients in the hospital using features in the first 24 h.

The neutrophil-to-lymphocyte ratio: A potential predictor of poor prognosis in adult patients with trauma and traumatic brain injury.

Purpose: This study aimed to determine the prognostic impact of the neutrophil-to-lymphocyte ratio (NLR) in critically ill trauma patients. Methods: This retrospective study involved adult trauma patients from 335 intensive care units (ICUs) at 208 hospitals stored in the eICU database. The primary outcome was ICU mortality. The lengths of ICU and hospital stay were calculated as the secondary outcomes. The multivariable logistic regression model was used to identify independent predictors of mortality. To identify the effect of the NLR on survival, a 15-day survival curve was used. Results: A total of 3,865 eligible subjects were enrolled in the study. Univariate analysis showed that patients in the group with a higher NLR were more likely to receive aggressive methods of care delivery: mechanical ventilation, vasopressor, and antibiotics ( P < 0.001 for all). The ICU, in-hospital, and 15-day mortality rates of the four groups increased in turn (P < 0.001 for all). The multivariable logistic Cox regression model indicated that a higher NLR was an independent risk factor of ICU mortality in trauma patients. ROC analysis showed that the NLR had better predictive capacity on the mortality of patients with traumatic brain injury (TBI) than those with trauma (AUC 0.725 vs. 0.681). An NLR > 7.44 was an independent risk factor for ICU death in patients with TBI (OR: 1.837, 95% CI: 1.045-3.229) and TBI victims whose NLR > 7.44 had a 15-day survival disadvantage (P = 0.005). Conclusion: A high NLR is associated with a poor prognosis in trauma patients, even worse in patients with TBI. An NLR > 7.44 is an independent risk factor for death in patients with TBI.

Population pharmacokinetic model-guided optimization of intravenous voriconazole dosing regimens in critically ill patients with liver dysfunction.

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.

Circulating microRNAs as novel diagnostic biomarkers and prognostic predictors for septic patients.

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=22528&htm=4.

Increased body mass index linked to greater short- and long-term survival in sepsis patients: A retrospective analysis of a large clinical database.

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<0.001), to be female (P<0.001), to acquire worse SOFA scores (P<0.001), and to receive more aggressive treatment compared with their normal weight counterparts. Obese patients had notably longer mechanical ventilation periods and ICU and hospital lengths of stay (LOSs). In the final model, overweight and obese patients had lower 30-day (OR 0.77, 95% CI 0.66-0.91; OR 0.65, 95% CI 0.56-0.77, respectively) and 1-year (OR 0.83, 95% CI 0.71-0.96; OR 0.70, 95% CI 0.60-0.81, respectively) mortality risks than normal weight patients. In contrast, underweight patients had worse 30-day and 1-year outcomes compared with normal weight patients (P=0.01, P<0.001, respectively). In morbidly obese, severe sepsis and septic shock patients, obesity remained protective. CONCLUSIONS: Obesity was correlated with short- and long-term survival advantages in sepsis patients.

Association of Sex With Clinical Outcome in Critically Ill Sepsis Patients: A Retrospective Analysis of the Large Clinical Database MIMIC-III.

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 < 0.001, P = 0.002, respectively). Male patients were more likely to require dialysis therapy (P = 0.109), ventilation support (P = 0.012) and more vasoactive agents (dopamine P = 0.113, norepinephrine P = 0.016, and epinephrine P = 0.093) during the ICU period than female patients. Our Cox proportional hazard regression model confirmed that the risk of death within 1 year of ICU admission in male patients is 1.083 times that in female. CONCLUSION: Female patients with sepsis have better clinical outcomes than male patients in terms of mortality and length of hospitalization and ICU stay.

Integrator complex subunit 6 (INTS6) inhibits hepatocellular carcinoma growth by Wnt pathway and serve as a prognostic marker.

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<0.05). qRT-PCR and Western blot analyses showed that the INTS6 mRNA and protein expression was significantly down-regulated in tumour tissues compared to the adjacent normal liver tissues (p<0.05). Immunohistochemical assays revealed that decreased INTS6 expression was present in 62.9% (44/70) of HCC patients. Correlation analyses showed that INTS6 expression was significantly correlated with serum alpha-fetoprotein levels (AFP, p =0.004), pathology grade (p =0.005), and tumour recurrence (p =0.04). Kaplan-Meier analysis revealed that patients with low INTS6 expression levels had shorter overall and disease-free survival rates than patients with high INTS6 expression levels (p =0.001 and p =0.001). Multivariate regression analysis indicated that INTS6 was an independent predictor of overall survival and disease-free survival rates. Mechanistically, INTS6 increased WIF-1 expression and then inhibited the Wnt/ß-catenin signalling pathway. CONCLUSION: The results of our study show that down-regulated INTS6 expression is associated with a poorer prognosis in HCC patients. This newly identified INTS6/WIF-1 axis indicates the molecular mechanism of HCC and may represent a therapeutic target in HCC patients.

Pseudogene integrator complex subunit 6 pseudogene 1 (INTS6P1) as a novel plasma-based biomarker for hepatocellular carcinoma screening.

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 < 0.01). Additionally, we inferred that INTS6P1 might be a prospective biomarker for screening HCC patients in which the serum-AFP levels were lower than 20 ng/ml by the area under the curve-receiver operating characteristic (AUC-ROC) analysis (p < 0.05). Pseudogene INTS6P1 could be used as a novel HCC plasma-based biomarker and might improve the accuracy of HCC screening.