Association of Hypernatremia with Immune Profiles and Clinical Outcomes in Adult Intensive Care Unit Patients with Sepsis.

Both hypernatremia and an abnormal immune response may increase hospital mortality in patients with sepsis. This study examined the association of hypernatremia with abnormal immune response and mortality in 520 adult patients with sepsis in an intensive care unit (ICU). We compared the mortality and ex vivo lipopolysaccharide (LPS)-induced inflammatory response differences among patients with hyponatremia, eunatremia, and hypernatremia, as well as between patients with acquired hypernatremia on ICU day 3 and those with sustained eunatremia over first three ICU days. Compared with eunatremia or hyponatremia, hypernatremia led to higher 7 day, 14 day, 28 day, and hospital mortality rates (p = 0.030, 0.009, 0.010, and 0.033, respectively). Compared with sustained eunatremia, acquired hypernatremia led to higher 7, 14, and 28 day mortality rates (p = 0.019, 0.042, and 0.028, respectively). The acquired hypernatremia group nonsignificantly trended toward increased hospital mortality (p = 0.056). Day 1 granulocyte colony-stimulating factor (G-CSF) and tumor necrosis factor (TNF) α levels were relatively low in patients with hypernatremia (p = 0.020 and 0.010, respectively) but relatively high in patients with acquired hypernatremia (p = 0.049 and 0.009, respectively). Thus, in ICU-admitted septic patients, hypernatremia on admission and in ICU-acquired hypernatremia were both associated with higher mortality. The higher mortality in patients with hypernatremia on admission was possibly related to the downregulation of G-CSF and TNF-α secretion after endotoxin stimulation. Compared to sustained eunatremia, acquired hypernatremia showed immunoparalysis at first and then hyperinflammation on day 3.

The Survival of Septic Patients with Compensated Liver Cirrhosis Is Not Inferior to That of Septic Patients without Liver Cirrhosis: A Propensity Score Matching Analysis.

Background: We aimed to determine whether septic patients with liver cirrhosis (LC) had worse survival than septic patients without liver cirrhosis (WLC). We also investigated the survival of septic patients with compensated liver cirrhosis (CLC) and decompensated liver cirrhosis (DLC). Methods: This study enrolled 776 consecutive adult patients with sepsis admitted to the medical intensive care units of a tertiary referral hospital. Clinical factors and laboratory data were collected for analysis. Propensity scoring was also used for the control of selection bias. The variables included in the propensity model were age, sex, presence of diabetes mellitus, hypertension, cardiovascular accident, chronic kidney disease, malignancy, APCHE II (Acute Physiology and Chronic Health Evaluation) score, hemoglobin, and platelet data on the day when sepsis was confirmed. Seven-day, ICU, and hospital mortality were analyzed after correcting for these confounding factors. Results: Of the 776 septic patients, 64 (8.2%) septic patients presented with LC. Patients were divided into two groups­LC (n = 64) and WLC (n = 712)­which presented different rates of hospital mortality (LC: 62.5% vs. WLC: 41.0%, p = 0.001). We further separated septic patients with LC into two groups: patients with CLC (n = 24) and those with DLC (n = 40). After propensity score matching, the survival of septic patients with CLC (63.6%) was not inferior to patients WLC (54.5%) (p = 0.411). Patients with DLC had more hospital mortality, even after matching (p < 0.05). The Quick SOFA (qSOFA) score, SOFA score, and sub-SOFA score were also comparable between groups. SOFA scores were not significantly different between the CLC and WLC groups after matching. Poor SOFA scores were observed in the DLC group on days 3 and 7 after matching (p < 0.05). Conclusions: Septic patients with LC had higher mortality compared to patients WLC before matching. However, after propensity score matching, the survival of septic patients with CLC was non-inferior to patients WLC.

Dynamic monitoring of kidney injury status over 3 days in the intensive care unit as a sepsis phenotype associated with hospital mortality and hyperinflammation.

BACKGROUND: Sepsis-associated acute kidney injury (AKI) often worsens with the deterioration of a patient's condition. Therefore, we hypothesized that monitoring AKI dynamically from day 1 to day 3 was potential to predict hospital mortality. Specifically, we explored whether monitoring AKI dynamically in the intensive care unit (ICU) could be a sepsis phenotype predictive of mortality. A new classification was established based on the change in the AKI stage from admission day 1 and day 3. We compared the hospital mortality, cytokines, and immune response pattern between each group. METHODS: We retrospectively enrolled 523 patients with sepsis, and we calculated the AKI stages on day 1 and day 3 admission to ICUs. Among these 523 people, 388 of them were assigned to normal, improved, and deteriorated groups according to the changes in the AKI stages. 263 of which did not develop AKI on day 1 and day 3 (normal group). The AKI stage improved in 68 patients (improved group) and worsened in 57 (deteriorated group). We compared the mortality rates between the groups, and identified the relationship between the dynamic AKI status, immune response patterns, and cytokine levels. RESULTS: The hospital mortality rate in the deteriorated group was higher than that in the non-deteriorated group (combination of normal and improved group) (p = 0.004). Additionally, according to the Kaplan-Meier analysis, the non-deteriorated group had a distinct hospital survival curve (p = 0.004). Furthermore, both the overexpression of tumor necrosis factor-α and decreased monocyte expression of human leukocyte antigen-DR were present in the deteriorated group. CONCLUSIONS: The deteriorated group was associated with a higher hospital mortality rate, potentially resulting from an abnormal inflammatory response. Worsening AKI in the first 3 days of ICU admission may be a sepsis phenotype predictive of hospital mortality.

Identification of potential targets and synergistic mechanism of Kushen Decoction for the treatment of cryptosporidiosis / 中国血吸虫病防治杂志

Objective To explore the potential targets and synergistic mechanisms of Kushen Decoction for the treatment of cryptosporidiosis using network pharmacology and molecular docking methods. Methods The main active ingredients of Kushen Decoction were captured from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TC-MSP) and the Universal Protein Resource (UniProt) database, and the potential targets were predicted. In addition, the active ingredients of Kushen Decoction that were not included in the TCMSP database were retrieved in CNKI, WanFang Data, CBM, PubMed and Web of Science databases, and the target genes of all supplemented active ingredients were predicted using the online TargetNet database. Network construction and analysis were performed using the Cytoscape software, and cryptosporidiosis-related targets were retrieved in the Comparative Toxicogenomics Database and GeneCards database. The protein-protein interaction (PPI) network was created using the STRING database, and the DAVID database was used for GO enrichment and KEGG pathway analyses. The tissue distribution of key targets was investigated using the BioGPS database, and the AutoDockTools software was employed to verify the molecular docking results. Results A total of 38 active ingredients of Kushen Decoction were screened, and the core ingredients included quercetin, (+)-14α-hydroxymatrine and apigenin. A total of 831 targets of Kushen Decoction and 512 cryptosporidiosis-related targets were predicted, and PPI network analysis revealed 69 key targets, including AKT1, TNF and IL-6. There were 303 biological processes, 46 molecular functions and 29 cellular components involved in the treatment of cryptosporidiosis with Kushen Decoction, and 13 KEGG pathways played a therapeutic role in the synergistic mechanisms of multiple targets, such as Toll-like receptor (TLR), nuclear factor kappa B(NF)-κB, nucleotide binding oligomerization domain like receptor (NLR) signal pathways. The core targets were mainly distributed in the hematologic and immune systems. Molecular docking analysis showed that the binding energy between active ingredients and key targets were all less than 0 kJ/mol, indicating the strong binding of ligands to receptors. Conclusions The active ingredients of Kushen Decoction, such as quercetin, (+)-14α-hydroxymatrine and apigenin, may act on targets like AKT1, TNF, IL-6 to modulate TLR, NLR and NF-κB signaling pathways to play a synergistic role in the treatment of cryptosporidiosis in the hematologic and immune system.

Risk factors and associated outcomes of ventilator-associated events developed in 28 days among sepsis patients admitted to intensive care unit.

We hypothesized that Ventilator-Associated Event (VAE) within 28 days upon admission to medical intensive care units (ICUs) can be a predictor for poor outcomes in sepsis patients. We aimed to determine the risk factors and associated outcomes of VAE. A total of 453 consecutive mechanically ventilated (MV) sepsis patients were enrolled. Of them, 136 patients had immune profile study. Early VAE (< 7-day MV, n = 33) was associated with a higher mortality (90 days: 81.8% vs. 23.0% [non-VAE], P < 0.01), while late VAE (developed between 7 and 28 days, n = 85) was associated with longer MV day (43.8 days vs. 23.3 days [non-VAE], P < 0.05). The 90-day Kaplan-Meier survival curves showed three lines that separate the groups (non-VAE, early VAE, and late VAE). Cox regression models with time-varying coefficient covariates (adjusted for the number of days from intubation to VAE development) confirmed that VAE which occurred within 28 days upon admission to the medical ICUs can be associated with higher 90-day mortality. The risk factors for VAE development include impaired immune response (lower human leukocyte antigen D-related expression, higher interleukin-10 expression) and sepsis progression with elevated SOFA score (especially in coagulation sub-score).

Incorporation of dynamic segmented neutrophil-to-monocyte ratio with leukocyte count for sepsis risk stratification.

The association between sepsis and segmented neutrophil-to-monocyte (SeMo) ratio is unclear. We postulated that an increase in dynamic SeMo ratio measurement can be applied in risk stratification. This retrospective study included 727 consecutive sepsis patients in medical intensive care units (ICUs), including a subpopulation of 153 patients. According to the leukocyte (white blood cell, WBC) count on day 3 (normal range, between 4,000/µL and 12,000/µL) and delta SeMo (value of SeMo ratio on day 3 minus value of SeMo ratio on day 1; normal delta SeMo, <7), patients were grouped into 3 (delta SeMo & WBC tool). The survival lines separated significantly with hazard ratios of 1.854 (1.342-2.560) for the delta SeMo or WBC abnormal group and 2.860 (1.849-4.439) for the delta SeMo and WBC abnormal group compared to the delta SeMo and WBC normal group. Delta SeMo & WBC tool and delta sequential organ failure assessment (SOFA) tool performed better than the other tools (delta SeMo, delta WBC, day 3 WBC, and day 1 WBC). Severity in delta SeMo & WBC tool and delta SeMo tool reflected the immune dysfunction score, cytokine expression, and human leukocyte antigen D-related monocyte expression on day 1 and day 3. There was correspondence between delta SOFA and delta WBC and between delta SeMo and delta cytokine expression. Incorporation of dynamic SeMo ratio with WBC count provides risk stratification for sepsis patients admitted in the ICU.

Effect of do-not-resuscitate orders on patients with sepsis in the medical intensive care unit: a retrospective, observational and propensity score-matched study in a tertiary referral hospital in Taiwan.

OBJECTIVE: The aim of this study was to determine whether do-not-resuscitate (DNR) orders affect outcomes in patients with sepsis admitted to intensive care unit (ICU). DESIGN: This is a retrospective observational study. PARTICIPANTS: We enrolled 796 consecutive adult intensive care patients at Kaohsiung Chang Gung Memorial Hospital, a 2700-bed tertiary teaching hospital in southern Taiwan. A total of 717 patients were included. MAIN MEASURES: Clinical factors such as age, gender and other clinical factors possibly related to DNR orders and hospital mortality were recorded. KEY RESULTS: There were 455 patients in the group without DNR orders and 262 patients in the group with DNR orders. Within the DNR group, patients were further grouped into early (orders signed on intensive care day 1, n=126) and late (signed after day 1, n=136). Patients in the DNR group were older and more likely to have malignancy than the group without DNR orders. Mortality at days 7, 14 and 28, as well as intensive care and hospital mortality, were all worse in these patients even after propensity-score matching. There were higher Charlson Comorbidity Index in the emergency room, but better outcomes in those with early-DNR orders compared with late-DNR orders. CONCLUSIONS: DNR orders may predict worse outcomes for patients with sepsis admitted to medical ICUs. The survival rate in the early-DNR order group was not inferior to the late-DNR order group.

Application of dynamic pulse pressure and vasopressor tools for predicting outcomes in patients with sepsis in intensive care units.

PURPOSE: We aimed to determine whether the combination of dynamic pulse pressure and vasopressor (DPV) use is applicable for mortality risk stratification in patients with severe sepsis. We proposed the use of the DPV tool and compared it with traditional sepsis severity indices. MATERIALS AND METHODS: All adult patients who met the sepsis criteria of the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) between August 2013 and January 2017 were eligible for the study. Patients who expired within 3 days of admission to the intensive care unit (ICU) were excluded. The primary outcomes were 7-day and 28-day mortality. RESULTS: The study participants included 757 consecutive adult patients. A subpopulation of 155 patients underwent immune profiling assays on days 1, 3, and 7 of ICU admission. The DPV tool had a better performance for predicting 7-day mortality (area under curve, AUC: 0.70), followed by the Sequential Organ Failure Assessment (SOFA) (AUC: 0.64), the plus pulse pressure (AUC: 0.64). For predicting 28-day mortality, the DPV tool was not inferior to the SOFA (AUC: 0.61), DPV tool (AUC: 0.59). CONCLUSIONS: The DPV tool can be applied for 7-day and 28-day mortality risk prediction in patients with sepsis.

Development and validation of immune dysfunction score to predict 28-day mortality of sepsis patients.

BACKGROUND: Sepsis-induced immune dysfunction ranging from cytokines storm to immunoparalysis impacts outcomes. Monitoring immune dysfunction enables better risk stratification and mortality prediction and is mandatory before widely application of immunoadjuvant therapies. We aimed to develop and validate a scoring system according to patients' immune dysfunction status for 28-day mortality prediction. METHODS: A prospective observational study from a cohort of adult sepsis patients admitted to ICU between August 2013 and June 2016 at Kaohsiung Chang Gung Memorial Hospital in Taiwan. We evaluated immune dysfunction status through measurement of baseline plasma Cytokine levels, Monocyte human leukocyte-DR expression by flow cytometry, and stimulated immune response using post LPS stimulated cytokine elevation ratio. An immune dysfunction score was created for 28-day mortality prediction and was validated. RESULTS: A total of 151 patients were enrolled. Data of the first consecutive 106 septic patients comprised the training cohort, and of other 45 patients comprised the validation cohort. Among the 106 patients, 21 died and 85 were still alive on day 28 after ICU admission. (mortality rate, 19.8%). Independent predictive factors revealed via multivariate logistic regression analysis included segmented neutrophil-to-monocyte ratio, granulocyte-colony stimulating factor, interleukin-10, and monocyte human leukocyte antigen-antigen D-related levels, all of which were selected to construct the score, which predicted 28-day mortality with area under the curve of 0.853 and 0.789 in the training and validation cohorts, respectively. CONCLUSIONS: The immune dysfunction scoring system developed here included plasma granulocyte-colony stimulating factor level, interleukin-10 level, serum segmented neutrophil-to-monocyte ratio, and monocyte human leukocyte antigen-antigen D-related expression appears valid and reproducible for predicting 28-day mortality.

Immune profiles and clinical outcomes between sepsis patients with or without active cancer requiring admission to intensive care units.

BACKGROUND: Immunoparalysis was observed in both patients with cancer and sepsis. In cancer patients, Cytotoxic T lymphocyte antigen-4 and programmed cell death protein 1/programmed death-ligand 1 axis are two key components of immunoparalysis. Several emerging therapies against these two axes gained significant clinical benefit. In severe sepsis patients, immunoparalysis was known as compensatory anti-inflammatory response syndrome and this has been suggested as an important cause of death in patients with sepsis. It would be interesting to see if immune status was different in severe sepsis patients with or without active cancer. The aim of this study was to assess the differences in immune profiles, and clinical outcomes between severe sepsis patients with or without cancer admitted to ICU. METHODS: A combined retrospective and prospective observational study from a cohort of adult sepsis patients admitted to three medical ICUs at Kaohsiung Chang Gung Memorial Hospital in Taiwan between August 2013 and June 2016. RESULTS: Of the 2744 patients admitted to the ICU, 532 patients with sepsis were included. Patients were divided into those with or without active cancer according to their medical history. Of the 532 patients, 95 (17.9%) patients had active cancer, and 437 (82.1%) patients had no active cancer history. Patients with active cancer were younger (p = 0.001) and were less likely to have diabetes mellitus (p < 0.001), hypertension (p < 0.001), coronary artery disease (p = 0.004), chronic obstructive pulmonary disease (p = 0.002) or stroke (p = 0.002) compared to patients without active cancer. Patients with active cancer also exhibited higher baseline lactate levels (p = 0.038), and higher baseline plasma interleukin (IL)-10 levels (p = 0.040), higher trend of granulocyte colony-stimulating factor (G-CSF) (p = 0.004) compared to patients without active cancer. The 14-day, 28-day and 90-day mortality rates were higher for patients with active cancer than those without active cancer (P < 0.001 for all intervals). CONCLUSIONS: Among patients admitted to the ICU with sepsis, those with underling active cancer had higher baseline levels of plasma IL-10, higher trend of G-CSF and higher mortality rate than those without active cancer.

A Survival Scoring System for Non-Small Cell Lung Cancer Patients with De Novo Bone Metastases.

In the pre-tyrosine kinase inhibitors (TKIs) era, non-small cell lung cancer (NSCLC) patients with de novo bone metastases had a worse prognosis than those without. However, whether epidermal growth factor receptor (EGFR)-TKIs affect the outcomes of EGFR mutant NSCLC patients with de novo bone metastases has not been well studied thus far. We retrospectively studied the effect of EGFR mutation status and first-line EGFR-TKIs on patient outcomes and created a survival scoring system for NSCLC patients with de novo bone metastases. This retrospective study evaluated 1510 NSCLC patients diagnosed between November 2010 and March 2014. Among these patients, 234 patients had de novo bone metastases. We found that 121 of these 234 patients (51.7%) had positive EGFR mutation tests, and a positive EGFR mutation test significantly affected overall survival (OS) (EGFR mutant: 15.2 months, EGFR wild type: 6.5 months; p < 0.001). Other prognostic factors significant in the multivariable analysis for NSCLC with de novo bone metastases included Eastern Cooperative Oncology Group performance status (PS) (OS; PS 0-2: 11.2 months, PS 3-4: 4.9 months; p = 0.002), presence of extraosseous metastases (OS; with extraosseous metastases: 8.8 months, without extraosseous metastases: 14.0 months; p = 0.008), blood lymphocyte-to-monocyte ratio (LMR) (OS; LMR > 3.1: 17.1months, LMR ≤ 3.1: 6.9months; p < 0.001). A positive EGFR mutation status reversed the poor outcomes of NSCLC patients with de novo bone metastases. A simple and useful survival scoring system including the above clinical parameters was thus created for NSCLC patients with de novo bone metastases.