Acute kidney injury in critical care: complications of hemophagocytic lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis (HLH) is an immune dysfunction characterized by an exaggerated and pathological inflammatory response, potentially leading to systemic inflammatory reactions and multiple-organ failure, including renal involvement. HLH can be classified as primary or secondary, with primary HLH associated with genetic mutations affecting cell degranulation capacity, and secondary HLH often linked to infections, tumors, and autoimmune diseases. The pathogenesis of HLH is not fully understood, but primary HLH is typically driven by genetic defects, whereas secondary HLH involves the activation of CD8+ T cells and macrophages, leading to the release of inflammatory cytokines and systemic inflammatory response syndrome (SIRS). The clinical presentation of HLH includes non-specific manifestations, making it challenging to differentiate from severe sepsis, particularly secondary HLH due to infections. Shared features include prolonged fever, hepatosplenomegaly, hematopenia, hepatic dysfunction, hypertriglyceridemia, and hypofibrinogenemia, along with histiocytosis and hemophagocytosis. However, distinctive markers like dual hemocytopenia, hypertriglyceridemia, hypofibrinogenemia, and elevated sCD25 levels may aid in differentiating HLH from sepsis. Indeed, no singular biomarker effectively distinguishes between hemophagocytic lymphohistiocytosis and infection. However, research on combined biomarkers provides insights into the differential diagnosis. Renal impairment is frequently encountered in both HLH and sepsis. It can result from a systemic inflammatory response triggered by an influx of inflammatory mediators, from direct damage caused by these factors, or as a consequence of the primary disease process. For instance, macrophage infiltration of the kidney can lead to structural damage affecting various renal components, precipitating disease. Presently, tubular necrosis remains the predominant form of renal involvement in HLH-associated acute kidney injury (HLH-AKI). However, histopathological changes may also encompass interstitial inflammation, glomerular abnormalities, microscopic lesions, and thrombotic microangiopathy. Treatment approaches for HLH and sepsis diverge significantly. HLH is primarily managed with repeated chemotherapy to eliminate immune-activating stimuli and suppress hypercellularity. The treatment approach for sepsis primarily focuses on anti-infective therapy and intensive symptomatic supportive care. Renal function significantly influences clinical decision-making, particularly regarding the selection of chemotherapy and antibiotic dosages, which can profoundly impact patient prognosis. Conversely, renal function recovery is a complex process influenced by factors such as disease severity, timely diagnosis, and the intensity of treatment. A crucial aspect in managing HLH-AKI is the timely diagnosis, which plays a pivotal role in reversing renal impairment and creating a therapeutic window for intervention, may have opportunity to improve patient prognosis. Understanding the clinical characteristics, underlying causes, biomarkers, immunopathogenesis, and treatment options for hemophagocytic lymphohistiocytosis associated with acute kidney injury (HLH-AKI) is crucial for improving patient prognosis.

Protective effects of Dioscin against sepsis-induced cardiomyopathy via regulation of toll-like receptor 4/MyD88/p65 signal pathway.

BACKGROUND: Dioscin has many pharmacological effects; however, its role in sepsis-induced cardiomyopathy (SIC) is unknown. Accordingly, we concentrate on elucidating the mechanism of Dioscin in SIC rat model. METHODS: The SIC rat and H9c2 cell models were established by lipopolysaccharide (LPS) induction. The heart rate (HR), left ventricle ejection fraction (LVEF), mean arterial blood pressure (MAP), and heart weight index (HWI) of rats were evaluated. The myocardial tissue was observed by hematoxylin and eosin staining. 4-Hydroxy-2-nonenal (4-HNE) level in myocardial tissue was detected by immunohistochemistry. Superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH) activities in serum samples of rats and H9c2 cells were determined by colorimetric assay. Bax, B-cell lymphoma-2 (Bcl-2), toll-like receptor 4 (TLR4), myeloid differentiation primary response 88 (MyD88), phosphorylated-p65 (p-p65), and p65 levels in myocardial tissues of rats and treated H9c2 cells were measured by quantitative real-time PCR and Western blot. Viability and reactive oxygen species (ROS) accumulation of treated H9c2 cells were assayed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and dihydroethidium staining assays. RESULTS: Dioscin decreased HR and HWI, increased LVEF and MAP, alleviated the myocardial tissue damage, and reduced 4-HNE level in SIC rats. Dioscin reversed LPS-induced reduction on SOD, CAT, GSH, and Bcl-2 levels, and increment on Bax and TLR4 levels in rats and H9c2 cells. Overexpressed TLR4 attenuated the effects of Dioscin on promoting viability, as well as dwindling TLR4, ROS and MyD88 levels, and p-p65/p65 value in LPS-induced H9c2 cells. CONCLUSION: Protective effects of Dioscin against LPS-induced SIC are achieved via regulation of TLR4/MyD88/p65 signal pathway.

BAP31 Promotes Adhesion Between Endothelial Cells and Macrophages Through the NF-κB Signaling Pathway in Sepsis.

Purpose: To investigate the role of B cell receptor associated protein 31 (BAP31) in the pathogenesis of sepsis. Methods: Cecal ligation and puncture (CLP)-induced C57BL/6J mice, and LPS-challenged endothelial cells (HUVECs) were established to mimic a sepsis animal model and a sepsis cell model, respectively. Cre/LoxP and shRNA methods were used for BAP31 knockdown in vivo and in vitro respectively. Neutrophils/macrophages-endothelial cocultures were used to evaluate neutrophils or macrophages infiltration and adhesion to endothelial cells. Cox proportional hazards model was used to evaluate the survival time of mice. Western blotting (WB) and Quantitative real-time polymerase chain reaction (qRT-PCR) were used to detect toll-like receptor (TLR) signaling pathway, transforming growth factor ß activated kinase 1 (TAK1) signaling pathway and phosphoinositide-3 kinases-protein kinase B (PI3K/AKT) signaling pathway. Results: Deletion of BAP31 reduced CLP-induced mortality of mice, histological damage with less interstitial edema, and neutrophils and macrophages infiltration. IHC and IF showed that BAP31 knockdown significantly decreases the expressions of ICAM1 and VCAM1 both in vivo and in vitro. Coculture showed that LPS-induced neutrophils or macrophages adhesion to endothelial cells was significantly weakened in BAP31 knockdown cells. In addition, BAP31 knockdown of endothelial cells decreased the expression of CD80 and CD86 on the surface of macrophages as well as interleukin 1ß (IL-1ß) and tumor necrosis factor α (TNF-α) during sepsis. Mechanistically, LPS-induced the activation of TLR4, MyD88 and TRAF6, and the phosphorylation of TAK1, PI3K, AKT, IκBα and IKKα/ß, resulting in activation of nuclear factor kappa B (NF-κB) p65 in endothelial cells. However, BAP31 knockdown significantly reversed the expressions of associated proteins. Conclusion: BAP31 up-regulated the expressions of ICAM1 and VCAM1 in endothelial cells leading to sepsis-associated organ injury. This may be involved in activation of TLR signaling pathway, TAK1 pathway, and PI3K-AKT signaling pathway.

COMPARISON AMONG PRESEPSIN, PROCALCITONIN, AND C-REACTIVE PROTEIN IN PREDICTING BLOOD CULTURE POSITIVITY AND PATHOGEN IN SEPSIS PATIENTS.

ABSTRACT: Background: Sepsis is caused by the invasion of the bloodstream by microorganisms from local sites of infection, leading to high mortality. This study aimed to compare the predictive ability of the biomarkers presepsin, procalcitonin (PCT), and C-reactive protein for bacteraemia. Methods: In this retrospective, multicentre study, a dataset of patients with sepsis who were prospectively enrolled between November 2017 and June 2021 was analyzed. The performances of the biomarkers for predicting positive blood cultures and infection with specific pathogens were assessed by the areas under the receiver operating characteristic curves (AUCs). The independent effects of the pathogen and foci of infection on presepsin and PCT levels were assessed by linear logistic regression models. Results: A total of 577 patients with 170 positive blood cultures (29.5%) were enrolled. The AUC achieved using PCT levels (0.856) was significantly higher than that achieved using presepsin (0.786, P = 0.0200) and C-reactive protein (0.550, P < 0.0001) levels in predicting bacteraemia. The combined analysis of PCT and presepsin levels led to a significantly higher AUC than the analysis of PCT levels alone for predicting blood culture positivity (0.877 vs. 0.856, P = 0.0344) and gram-negative bacteraemia (0.900 vs. 0.875, P = 0.0216). In a linear regression model, the elevated concentrations of presepsin and PCT were both independently related to Escherichia coli , Klebsiella species, Pseudomonas species, and Streptococcus species infections and Sequential Organ Failure Assessment score. Presepsin levels were also associated with Acinetobacter species and abdominal infection, and PCT levels were positively associated with other Enterobacteriaceae and negatively associated with respiratory infection. Combined analysis of presepsin and PCT levels provided a high sensitivity and specificity in identifying E. coli or Klebsiella species infection. Conclusions: Presepsin and PCT were promising markers for predicting bacteraemia and common pathogens at the time of sepsis onset with a synergistic effect.

Over-expression of programmed death-ligand 1 and programmed death-1 on antigen-presenting cells as a predictor of organ dysfunction and mortality during early sepsis: a prospective cohort study.

BACKGROUND: This study aimed to explore the changes of programmed death-ligand 1 (PD-L1) and programmed death-1 (PD-1) expression on antigen-presenting cells (APCs) and evaluate their association with organ failure and mortality during early sepsis. METHODS: In total, 40 healthy controls and 198 patients with sepsis were included in this study. Peripheral blood was collected within the first 24 h after the diagnosis of sepsis. The expression of PD-L1 and PD-1 was determined on APCs, such as B cells, monocytes, and dendritic cells (DCs), by flow cytometry. Cytokines in plasma, such as interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), interleukin-4 (IL-4), IL-6, IL-10, and IL-17A were determined by Luminex assay. RESULTS: PD-1 expression decreased significantly on B cells, monocytes, myeloid DCs (mDCs), and plasmacytoid DCs (pDCs) as the severity of sepsis increased. PD-1 expression was also markedly decreased in non-survivors compared with survivors. In contrast, PD-L1 expression was markedly higher on mDCs, pDCs, and monocytes in patients with sepsis than in healthy controls and in non-survivors than in survivors. The PD-L1 expression on APCs (monocytes and DCs) was weakly related to organ dysfunction and inflammation. The area under the receiver operating characteristic curve (AUC) of the PD-1 percentage of monocytes (monocyte PD-1%)+APACHE II model (0.823) and monocyte PD-1%+SOFA model (0.816) had higher prognostic value than other parameters alone. Monocyte PD-1% was an independent risk factor for 28-day mortality. CONCLUSION: The severity of sepsis was correlated with PD-L1 or PD-1 over-expression on APCs. PD-L1 in monocytes and DCs was weakly correlated with inflammation and organ dysfunction during early sepsis. The combination of SOFA or APACHE II scores with monocyte PD-1% could improve the prediction ability for mortality.

Role of HMGB1-PTEN Signaling in T Lymphocytes and Monocytes Upon Sepsis.

BACKGROUND: The aim of the study was to evaluate the role of high-mobility group box 1 (HMGB1)-phosphatase and tensin homolog deleted on chromosome ten (PTEN) signaling in T lymphocytes and monocytes upon sepsis. METHODS: Thirty C57BL/6 male mice aged 8 - 10 weeks old were randomly divided into sham, model, and inhibitor groups (n = 10). The model of sepsis was established through cecal ligation and perforation. Sham group was only subjected to cecum exposure, and then the wound was sutured without cecal ligation. After the operation, the inhibitor group was intraperitoneally injected with HMGB1-specific inhibitor glycyrrhizic acid (dose: 10 mg/kg) every 6 hours for 4 consecutive times, while sham and model groups were intraperitoneally injected with an equal dose of normal saline. The histopathological changes, cell apoptosis in spleen and thymus tissues, proliferative activity and apoptosis of T lymphocytes, chemotactic activity of monocytes, expression levels of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6) and IL-10, and expressions of HMGB1 and PTEN in mice were detected using hematoxylineosin staining, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling staining, MTT assay, flow cytometry, transwell chemotaxis assay, enzyme-linked immunosorbent assay, and western blotting, respectively. RESULTS: The cell apoptosis rate in spleen and thymus tissues, proliferative activity and apoptosis rate of T lymphocytes, chemotactic activity of monocytes, protein expressions of TNF-α, IL-6 and IL-10, and expressions of HMGB1 and PTEN significantly increased in the model group compared with those in the sham group (p < 0.05). However, the cell apoptosis rate in spleen and thymus tissues, T lymphocyte apoptosis rate, protein expressions of TNF-α and IL-6, and expressions of HMGB1 and PTEN were significantly lower, while the proliferative activity of T lymphocytes, chemotactic activity of monocytes and protein expression of IL-10 were significantly higher in the inhibitor group than those in the model group (p < 0.05). CONCLUSIONS: Repressing HMGB1-PTEN signaling can effectively reduce the apoptosis rate of T cells, increase the proliferative activity of T cells, and enhance the function of monocytes in the case of sepsis.

Ulinastatin Improves Renal Microcirculation by Protecting Endothelial Cells and Inhibiting Autophagy in a Septic Rat Model.

INTRODUCTION: Increased permeability of the renal capillaries is a common consequence of sepsis-associated acute kidney injury. Vascular endothelial (VE)-cadherin is a strictly endothelial-specific adhesion molecule that can control the permeability of the blood vessel wall. Additionally, autophagy plays an important role in maintaining cell stability. Ulinastatin, a urinary trypsin inhibitor, attenuates the systemic inflammatory response and visceral vasopermeability. However, it is uncertain whether ulinastatin can improve renal microcirculation by acting on the endothelial adhesion junction. METHODS: We observed the effect of ulinastatin in a septic rat model using contrast-enhanced ultrasonography (CEUS) to evaluate the perfusion of the renal cortex and medulla. Male adult Sprague Dawley rats were subjected to cecal ligation and puncture and divided into the sham, sepsis, and ulinastatin groups. Ulinastatin (50,000 U/kg) was injected into the tail vein immediately after the operation. The CEUS was performed to evaluate the renal microcirculation perfusion at 3, 6, 12, and 24 h after the operation. Histological staining was used to evaluate kidney injury scores. Western blot was used to quantify the expression of VE-cadherin, LC3II, and inflammatory factors (interleukin-1ß, interleukin-6, and tumor necrosis factor-α) in kidney tissue, and enzyme-linked immunosorbent assay detected serum inflammatory factors and kidney function and early kidney injury biomarker levels. RESULTS: Compared with the sham group, ulinastatin reduced the inflammatory response, inhibited autophagy, maintained the expression of VE-cadherin, and meliorated cortical and medullary perfusion. CONCLUSION: Ulinastatin effectively protects the adhesion junction and helps ameliorate the perfusion of kidney capillaries during sepsis by the inhibition of autophagy and the expression of inflammatory factors.

Epidemiology of Sepsis-Associated Acute Kidney Injury in Beijing, China: A Descriptive Analysis.

BACKGROUND: Sepsis is the most common contributing factor towards development of acute kidney injury (AKI), which is strongly associated to poor prognostic outcomes. There are numerous epidemiological studies about sepsis-associated acute kidney injury (S-AKI), however current literature is limited with the majority of studies being conducted only in the intensive care unit (ICU) setting. The aim of this study was to assess the epidemiology of S-AKI in all hospitalized in-patients. METHODS: This was a retrospective population-based study using a large regional population database in Beijing city from January, 2005 to December, 2017. It included patients with S-AKI. Patients with pre-existing end-stage kidney disease (ESKD), previous history of kidney transplantation, or being pregnant were excluded. Patients' demographic characteristics, incidence, risk factors and outcomes of S-AKI were analyzed. The contrast between different time periods, different levels of hospitals, and types of the hospitals (traditional Chinese medicine hospitals (TCMHs) and western medicine hospitals (WMHs)) was also compared using Mann-Whitney U-test. RESULTS: A total of 19,579 patients were included. The overall incidence of S-AKI in all in-patients was 48.1%. The significant risk factors by multivariate analysis for AKI included: age, male, being treated in a level-II hospital, pre-existing hypertension, chronic kidney disease (CKD), cirrhosis, atrial fibrillation (AF), ischemic heart disease (IHD), being admitted from emergency room, ICU admission, shock, pneumonia, intra-abdominal infection, bloodstream infection, respiratory insufficiency, acute liver injury, disseminated intravascular coagulation (DIC) and metabolic encephalopathy. The overall mortality rate in this cohort was 55%. The multivariate analysis showed that the significant risk factors for mortality included: age, being treated in a level-II hospital and TCMHs, being admitted from emergency room, pre-existing comorbidities (CKD, malignancy, cirrhosis and AF), shock, pneumonia, intra-abdominal infection, bloodstream infection, central nervous system (CNS) infection and respiratory insufficiency. CONCLUSION: AKI is a common complication in patients with sepsis, and its incidence increases over time, especially when ICU admission is required. Exploring interventional strategies to address modifiable risk factors will be important to reduce incidence and mortality of S-AKI.

Wedelolactone improves the renal injury induced by lipopolysaccharide in HK-2 cells by upregulation of protein tyrosine phosphatase non-receptor type 2.

OBJECTIVE: To explore the effects of wedelolactone (WEL) on sepsis-induced renal injury in the human renal proximal tubular epithelial cell line HK-2. METHODS: HK-2 cells were stimulated by 1 µg/ml lipopolysaccharide (LPS) to trigger renal injury in vitro. HK-2 cells were pretreated with or without WEL (0.1, 1 and 10 µM) before LPS stimulation. Protein and mRNA analyses were performed using enzyme-linked immunosorbent assays, Western blot analysis and quantitative reverse transcription-polymerase chain reaction. The MTT assay and flow cytometry were used to measure cell viability and the rate of cell apoptosis. Protein tyrosine phosphatase non-receptor type 2 (PTPN2) knockdown was induced by the transection of HK-2 cells with short hairpin RNA. RESULTS: Cell viability was significantly increased in a dose-dependent manner by WEL in LPS-induced HK-2 cells. WEL also decreased the levels of four inflammatory cytokines and cell apoptosis in LPS-induced HK-2 cells. The level of PTPN2 was increased after WEL treatment. PTPN2 knockdown partly abolished the inhibitory effects of WEL on cell apoptosis, the levels of inflammatory cytokines and on p38 mitogen-activated protein kinase/nuclear factor-kappaB signalling in LPS-induced HK-2 cells. CONCLUSION: WEL improved renal injury by suppressing inflammation and cell apoptosis through upregulating PTPN2 in HK-2 cells. PTPN2 might be used as a potential therapeutic target for LPS-induced sepsis.

Xuebijing injection in septic rats mitigates kidney injury, reduces cortical microcirculatory disorders, and suppresses activation of local inflammation.

ETHNOPHARMACOLOGICAL RELEVANCE: Xuebijing injections originate from the traditional Chinese medicine (TCM) prescription XuefuZhuyu Decoction. It is composed of five Chinese herbal extracts; Carthami flos, Paeoniae radix rubra, Chuanxiong rhizoma, Salviae miltiorrhizae, and Angelicae Sinensis radix. The China Food and Drug Administration approved Xuebijing injections as a TCM preparation for the adjuvant treatment of sepsis. AIM OF THE STUDY: This study aims to determine the effects of Xuebijing injections as an adjuvant to antibiotics for the treatment of renal microcirculatory dysfunction and renal inflammation in rats with sepsis. MATERIALS AND METHODS: The rats received a sham operation (Sham), sham operation followed by Xuebijign injection (Sxbj), cecal ligation and puncture (CLP), or CLP followed by Xuebijing injection (Cxbj). Renal microvascular perfusion in the cortex and oxygenation were assessed at different times after sepsis induction. Renal levels of interleukin (IL)-1ß, IL-6, tumor necrosis factor (TNF)-α, and high mobility group box (HMGB)-1 were measured. Urinary TIMP-2 × IGFBP-7 and neutrophil gelatinase-associated lipocalin (NGAL) were measured as kidney biomarkers, and serum creatinine (SCr) was used to assess kidney injury. Tissue samples were stained for histologic evaluation. RESULTS: The induction of sepsis increased local inflammation and decreased renal microvascular perfusion and oxygenation. Compared with the CLP group, the Cxbj group displayed improvements in microvascular perfusion and oxygenation (p < 0.05). The CLP group had significant increases in renal inflammatory biomarkers (IL-1ß, IL-6, TNF-α, and HMGB-1; p < 0.05) and Xuebijing injection reduced the levels of these markers. The levels of urinary TIMP-2 × IGFBP-7, NAGL, and SCr were lower in the Cxbj group than in the CLP group (p < 0.05), and the CLP group had a higher Paller score than the Cxbj group (p < 0.05). However, the CLP and Cxbj groups had no significant difference in mortality. CONCLUSIONS: This study into the early stages of sepsis in a rat model indicated that as an adjuvant therapy to antibiotics, Xuebijing injection improved renal perfusion and oxygenation, suppressed renal inflammation, and ameliorated kidney dysfunction. However, Xuebijing injection had no impact on mortality.

Are dexmedetomidine and olanzapine suitable to control delirium in critically ill elderly patients? A retrospective cohort study.

BACKGROUND: The efficacy and safety of dexmedetomidine and olanzapine for delirium control in critically ill elderly patients without ventilation or surgery are not known. METHODS: The efficacy and safety of dexmedetomidine and olanzapine for controlling delirium were evaluated in a retrospective cohort of critically illness by assessing the sedation level, drug dose/duration, combination rate with other sedatives, adverse effects, intubation rate and prognosis. RESULT: The maximum (1.61 ± 1.56 vs. 2.70 ± 1.01, p < 0.001), average (-0.57 ± 0.88 vs. 0.88 ± 0.73, p < 0.001), and minimum (-1.67 ± 1.04 vs. -1.37 ± 1.01, p = 0.014) RASS scores of 263 patients were lower after treating with dexmedetomidine than treating with olanzapine. Drug use duration (4.83 ± 2.67 days vs. 5.87 ± 3.14 days, p = 0.005) and sedative combination rates (13.56% vs. 40.00%, p = 0.003) were lower when treating with dexmedetomidine than that with olanzapine. A comparison of adverse effects between dexmedetomidine and olanzapine revealed respiratory depression (16.95% vs. 2.84%, p < 0.001), hypoxia (13.56% vs. 2.76%, p < 0.001) and hypotension (11.02% vs. 3.45%, p = 0.007). Intubation rates (22.88% vs. 12.41%, p = 0.023) and the length of hospital stay (9.30 ± 4.90 days vs. 8.83 ± 3.34 days, p < 0.001) were higher in patients treated with dexmedetomidine than that with olanzapine. Mortality rates, cognitive prognosis, and delirium recurrence rates were similar between groups. Age, severe cardiopulmonary disease, APACHE II scores, dexmedetomidine dose, minimum RASS score and sedative combination were significantly (p < 0.05) associated with the adverse effects of dexmedetomidine. Respiratory depression, hypoxia and hypotension in the olanzapine group all occurred during combination with benzodiazepines. CONCLUSIONS: Dexmedetomidine achieved more satisfactory sedative effects on delirium control, but olanzapine was safer.

Perfusion microvessel density in the cerebral cortex of septic rats is negatively correlated with endothelial microparticles in circulating plasma.

In sepsis, endothelial microparticles (EMPs) released from endothelial cells (ECs) participate in microcirculation dysfunction through pro-coagulant and pro-inflammatory effects, which can lead to sepsis-associated brain dysfunction. However, the relationship between EMPs and cerebral cortical perfusion microvessel density has not been explored. A closed cranial window was created in rats who were tended to until the cerebral cortex edema caused by preparation of the cranial window subsided, and the microvessel density was stable. A cecal ligation and puncture (CLP) sepsis procedure was then performed on day 6, post-surgery. At 12 and 24 h after the CLP, cerebral cortical perfusion microvessel density was measured with optical coherence tomography angiography (OCTA), followed by measurement of EMPs to evaluate the relationship between these factors. Microvessel density changed from 46.38 % ± 7.65 % on the day of surgery to 35.87 % ± 11.05 % on the second day and 36.71 % ± 11.38 % on the third day after surgery, and then increased daily. The microvessel density decreased to 27.20 % ± 8.50 % 24 h after CLP, which was significantly lower than that immediately and 12 h after CLP (P < 0.001). EMPs increased progressively at 12 and 24 h after CLP. Moreover, there was a negative correlation between EMPs and microvessel density (r=-0.56, P = 0.01). Edema and microvessel density decreased in the local cerebral cortex of the window and then gradually recovered after cranial window surgery. In sepsis, the perfusion microvessel density of the cerebral cortex negatively correlated with the EMPs. Therefore, the perfusion microvessel density can be indirectly evaluated by detecting the plasma EMP level.

GPR120 Ameliorates Apoptosis and Inhibits the Production of Inflammatory Cytokines in Renal Tubular Epithelial Cells.

Acute kidney injury (AKI) is the most common complication of sepsis with a high mortality rate. In this study, we focus on the renal injury caused by the immune response of renal tubular epithelial cells and inflammation-induced renal tubular epithelial cell apoptosis. We studied the role of GRP120 in the inflammation and apoptosis of human renal cell line HK-2 and mouse primary renal tubular epithelial cells. GPR120 agonist GW9508 activated the GPR120 pathway. Inflammatory factors were detected using quantitative real-time PCR and enzyme-linked immunosorbent assay. Cell apoptosis experiments included the annexin V and PI double-staining method combined with flow cytometry, TUNEL method, and Western blot. The level of cytokines including TNF-α, IL-6, IL-1ß, and iNOS was significantly decreased (P < 0.05) in HK-2 and TECs after the activation of the GPR120 pathway. Besides, the cell apoptosis of both cells increased. Overexpressed GPR120 and shGPR120 were established. Treatment with lipopolysaccharide (LPS) increased the level of cytokines including TNF-α, IL-6, IL-1ß, and iNOS in HK-2 cell and TECs. Compared with control-LPS and negative control (NC)-LPS, the overexpression of GPR120 and shGPR120 could decrease and increase the level of secreted cytokines significantly (P < 0.05), respectively, after LPS-induced apoptosis. After H2O2- and LPS-induced apoptosis, respectively, compared with the control and NC groups, overexpressed GPR120 and shGPR120 could reduce and increase the expression of caspase-3, respectively. GPR120 could suppress the cellular immune response and apoptosis in renal tubular epithelial cells, thereby possibly protecting the kidney and relieving sepsis-induced AKI.

Pharmacokinetic and Pharmacodynamic Analysis of Critically Ill Patients Undergoing Continuous Renal Replacement Therapy With Imipenem.

PURPOSE: This study explores factors that affect behavior in critically ill patients receiving continuous renal replacement therapy (CRRT) with imipenem and provides dosing regimens for these patients. METHODS: A prospective, open-label study was conducted in a clinical setting. Both blood and effluent samples were collected pairwise at the scheduled time points. Plasma and effluent imipenem concentrations were determined by HPLC-UV. A population pharmacokinetic model was developed using a nonlinear mixed-effects modeling method. The final model was evaluated by a bootstrap and visual predictive check. A population pharmacokinetic and pharmacodynamic analysis using Monte Carlo simulations was performed to explore the effects of empirically used dosing regimens (0.5 g q6h, 0.5 g q8h, 0.5 g q12h, 1 g q6h, 1 g q8h, and 1 g q12h) on the probability of target attainment. FINDINGS: Thirty patients were included in the population model analysis. Imipenem concentration data were best described by a 3-compartment model (central, peripheral, and dialysis compartments). The clearance of the dialysis compartment (CLd) was used to characterize drug elimination from the dialyzer. Creatinine clearance (CrCl) was the covariate that influenced the central clearance (CLc), and the effects of dialysate flow (Qd) was significant for CLd. Model validation revealed that the final model had qualified stability and acceptable predictive properties. A pharmacokinetic and pharmacodynamic analysis was conducted by Monte Carlo simulation, and patients were categorized into 12 subgroups based on different CrCl values (<30, 31-60, 61-90, and >90 mL/min) and Qd values (300, 500, and 1000 mL/h). Under the same MIC value and administration regimen, probability of target attainment values decreased with an increase of CrCl and Qd. IMPLICATIONS: CrCl and Qd had significant effects on CLc and CLd, respectively. The proposed final model may be used to guide practitioners in imipenem dosing in this specific patient population.

[Lactic acid, lactate clearance and procalcitonin in assessing the severity and predicting prognosis in sepsis].

OBJECTIVE: To explore the value of lactic acid (Lac), lactate clearance (LCR) and procalcitonin (PCT) in assessing the severity and predicting the prognosis in sepsis. METHODS: 18-80-year-old patients with sepsis admitted to the department of critical care medicine of Beijing Friendship Hospital, Capital Medical University from April 2009 to December 2019 were enrolled. The gender, age, basic illness, infection site, organ function, acute physiology and chronic health evaluation II (APACHE II), sequential organ failure assessment (SOFA), Lac and PCT were collected on admission to intensive care unit (ICU), as well as Lac after 24 hours, 24-hour LCR, and 28-day prognosis. The patients were divided into sepsis group and septic shock group according to Sepsis-3 criteria. According to the 28-day prognosis, the septic shock patients were divided into survival group and death group, and the differences of each index between the two groups were compared. Multivariate Logistic regression was used to analyze the risk factors of death in septic shock patients. The receiver operating characteristic (ROC) curve was used to analyze the role of Lac, LCR, PCT, SOFA score and APACHE II score in predicting prognosis of the patients with septic shock. RESULTS: A total of 998 patients with sepsis were enrolled, including 642 males and 356 females; with (59.56±13.22) years old. There were 478 patients with septic shock, among which 180 died and 298 survived during the 28-day observation. (1) Compared with the sepsis group, the age of the sepsis shock group was significantly higher (years old: 60.49±12.31 vs. 58.72±13.97), APACHE II score, SOFA score, Lac, PCT and 24 h Lac increased [APACHE II: 24.57±7.04 vs. 19.37±6.93, SOFA: 7.78±3.31 vs. 4.38±3.42, Lac (mmol/L): 3.00 (1.70, 5.00) vs. 1.40 (1.00, 2.30), PCT (µg/L): 0.05 (0.00, 4.00) vs. 0.00 (0.00, 1.10), 24-hour Lac (mmol/L): 2.60 (1.60, 4.40) vs. 1.40 (1.00, 2.20)], and the 28-day mortality was significantly higher [41.63% (199/478) vs. 19.42% (101/520)], with significant statistic differences (all P < 0.05). (2) Compared with the survival group, APACHE II score, SOFA score, Lac, 24-hour Lac significantly increased in the septic shock death group, and 24-hour LCR decreased [APACHE II: 26.19±6.52 vs. 22.25±6.07, SOFA: 9.07±2.90 vs. 7.50±3.10, Lac (mmol/L): 3.80 (2.50, 5.10) vs. 2.80 (2.00, 3.90), 24-hour Lac (mmol/L): 3.20 (2.20, 5.60) vs. 2.10 (1.60, 3.30), 24-hour LCR: 1.43 (-37.50, 30.77)% vs. 16.67 (0.00, 33.98)%, all P < 0.05]. In assessment of organ function, central venous pressure (CVP) and oxygenation index (PaO2/FiO2) were lower in death group [CVP (mmHg; 1 mmHg = 0.133 kPa): 5.00 (2.00, 8.00) vs. 6.00 (2.00, 9.00), PaO2/FiO2 (mmHg): 184.21±84.57 vs. 199.20±86.98], alanine aminotransferase (ALT) and serum creatinine (SCr) increased [ALT (U/L): 376.56±41.43 vs. 104.17±14.10, SCr (µmol/L): 213.53±8.06 vs. 181.91±5.03], with significant statistic differences (all P < 0.05). (3) Multivariate Logistic regression analysis showed that PaO2/FiO2, SCr, Lac and SOFA were independent risk factors of prognosis in septic shock [PaO2/FiO2: odds ratio (OR) = 0.997, 95% confidence interval (95%CI) was 0.996-0.999, P = 0.001; SCr: OR = 1.001, 95%CI was 1.000-1.002, P = 0.041; Lac: OR = 0.925, 95%CI was 0.871-0.982, P = 0.011; SOFA: OR = 1.178, 95%CI was 1.110-1.251, P = 0.000]. ROC curve analysis showed that SOFA, SOFA+APACHE II, Lac+24-hour LCR+PCT+SOFA+APACHE II could predict mortality in septic shock patients, and the area under the ROC curve (AUC) was 0.769 (95%CI was 0.740-0.798), 0.787 (95%CI was 0.759-0.815), 0.800 (95%CI was 0.773-0.827), respectively. The joint of the five indicators, Lac, 24-hour LCR, PCT, SOFA and APACHE II has the largest AUC. CONCLUSIONS: Lac is an independent risk factor for death in patients with septic shock, however, the prognosis cannot be predicted. Comprehensive analysis of LCR, PCT, SOFA, APACHE II and the clinical organ functions are required for analysis.

The Prevalence, Risk Factors, and Outcomes of Sepsis in Critically Ill Patients in China: A Multicenter Prospective Cohort Study.

Background: Sepsis is a main cause of morbidity and mortality in critically ill patients. The epidemiology of sepsis in high-income countries is well-known, but information on sepsis in middle- or low-income countries is still deficient, especially in China. The purpose of this study was to explore the prevalence, characteristics, risk factors, treatment, and outcomes of sepsis in critically ill patients in tertiary hospitals in China. Methods: A multicenter prospective observational cohort study was performed with consecutively collected data from adults who stayed in any intensive care unit (ICU) for at least 24 h; data were collected from 1 January 2014 to 31 August 2015, and patients were followed until death or discharge from the hospital. Results: A total of 4,910 patients were enrolled in the study. Of these, 2,086 (42.5%) presented with sepsis or septic shock on admission to the ICU or within the first 48 h after admission to the ICU. ICU mortality was higher in patients with sepsis (13.1%) and septic shock (39.0%) and varied according to geographical region. Acinetobacter, Pseudomonas, and Staphylococcus infections were associated with increased ICU mortality. In addition, age, Acute Physiology, and Chronic Health Evaluation II (APACHE II) scores, pre-existing cardiovascular diseases, malignant tumors, renal replacement therapy (RRT), and septic shock were independent risk factors for mortality in patients with sepsis. The prompt administration of antibiotics (OR 0.65, 95% CI 0.46-0.92) and 30 mL/kg of initial fluid resuscitation during the first 3 h (OR 0.43, 95% CI 0.30-0.63) improved the outcome in patients with septic shock. Conclusions: Sepsis was common and was associated with a high mortality rate in critically ill patients in tertiary hospitals in China. The prompt administration of antibiotics and 30 mL/kg fluid resuscitation decreased the risk of mortality.

Accuracy of qSOFA for the diagnosis of sepsis-3: a secondary analysis of a population-based cohort study.

BACKGROUND: We aimed to evaluate the accuracy of quick Sequential (sepsis-related) Organ Failure Assessment (qSOFA) for the diagnosis of sepsis-3, and to analyze the prognosis of infected patients in wards over-diagnosed with qSOFA but missed by sepsis-3, and those missed by qSOFA but in accordance with sepsis-3 criteria. We also intended to validate the performance of qSOFA as one predictor of outcome in patients with suspicion of infection. METHODS: We reviewed the medical records of 1,716 adult patients with infection who were hospitalized from July 1st, 2012 to June 30th, 2014 in the Yuetan subdistrict of Beijing, China. Based on the sepsis-3 criteria and qSOFA score proposed by the Third International Consensus Definitions for Sepsis and Septic Shock, these patients were categorized into four groups: qSOFA(-)sepsis(-), qSOFA(+)sepsis(-), qSOFA(-)sepsis(+), and qSOFA(+)sepsis(+). Multivariate logistic regression analysis was used to determine the independent risk factors for in-hospital mortality. The area under the receiver operating characteristic curves (AUROCs) of the qSOFA(+) group were compared with the sepsis(+) group for in-hospital mortality, ICU admission, and invasive ventilation. RESULTS: Among the 1,716 patients with infection, there were 935 patients (54.5%) with sepsis, and 640 patients (37.3%) with qSOFA ≥2. There were 610 patients in the qSOFA(-)sepsis(-) group, 171 in the qSOFA(+)sepsis(-) group, 466 in the qSOFA(-)sepsis(+) group, and 469 in the qSOFA(+)sepsis(+) group. In the logistic regression analysis, increasing age, bedridden status, and malignancy were all independent risk factors of hospital mortality. Sepsis and qSOFA ≥2 were also independent risk factors of hospital mortality, with an adjusted OR of 3.85 (95% CI: 2.70-5.50) and 13.92 (95% CI: 9.87-16.93) respectively. qSOFA had a sensitivity of 50.2% and a specificity of 78.1% for sepsis-3. The false-positive [qSOFA(+)sepsis(-)] group had 38 patients (22.2%) die during hospitalization, and an adjusted OR of 9.20 (95% CI: 4.86-17.38). In addition, the false-negative [qSOFA(-)sepsis(+)] group had a hospital mortality rate of 7.3% (34/466) and an adjusted OR of 2.59 (95% CI: 1.39-4.83). In comparison, patients meeting neither qSOFA nor sepsis criteria had the lowest hospital mortality [2.6% (16/610)], whereas patients with both qSOFA ≥2 and sepsis had the highest hospital mortality [56.5% (265/469)], with an adjusted OR of 42.02 (95% CI: 24.31-72.64). The discrimination of in-hospital mortality using qSOFA (AUROC, 0.846; 95% CI, 0.824-0.868) was greater compared with sepsis-3 criteria (AUROC, 0.834; 95% CI, 0.805-0.863; P<0.001). CONCLUSIONS: In our analysis, the sensitivity(Se) of qSOFA for the diagnosis of sepsis was lower, and qSOFA score ≥2 might identify a group of patients at a higher risk of mortality, regardless of being septic or not.

Acute Kidney Injury in Critically Ill Patients with Sepsis: Clinical Characteristics and Outcomes.

Objective: The objectives of this study were to examine the clinical profile of critically ill patients with septic acute kidney injury (AKI) and to investigate clinical characteristics associated with the outcome of patients. Methods: Data from 582 critically ill patients were collected and retrospectively reviewed. Patients were divided into two groups: without AKI development and with AKI development. Baseline characteristics, laboratory, and other clinical data were compared between these two groups, and correlations between the characteristics and AKI development were examined. Patients with AKI development were further divided into two groups according to the survival outcome, and variables associated with the outcome were determined. Results: AKI was developed in 54.12% (n = 315) of patients, and these patients had blood pressure, SOFA score, APACHE II score, GCS, and various blood chemistry and hematology characteristics significantly different from the patients without AKI. Demographic characteristics (e.g. age and weight) were comparable between the two groups of patients. Among the 315 patients with AKI, 136 of them died during the study period. Multivariate logistic regression analysis revealed that the outcome of patients was associated with lung infection, coagulation system dysfunction, staphylococcus aureus infection, and use of various treatments (epinephrine, norepinephrine, and the use of mechanical ventilation) after AKI development. Conclusion: AKI occurred in approximately half of the critically ill patients admitted to ICU. The site and type of infections, as well as the use of vasopressor agents, were associated with the outcome.

A rare case of spontaneous hepatic rupture in a pregnant woman.

BACKGROUND: Spontaneous hepatic rupture in pregnancy is a rare and life-threatening event during the perinatal period. CASE PRESENTATION: We report a case of a 33-year-old woman with 36 + 6 weeks' gestation that present with elevated blood pressure before delivery, who was admitted to our hospital due to irregular abdominal pain. Diagnosed with abdominal paracentesis, the emergent caesarean section and laparotomy were performed. Postoperatively, the patient experienced 22-day intensive therapy in ICU and was transferred to the General Surgery Department in good physical condition without post-operative complications. CONCLUSIONS: This case indicates that making an accurate and timely diagnosis and taking multidisciplinary approach contribute to a successful clinical outcome.

The Protection of Midazolam Against Immune Mediated Liver Injury Induced by Lipopolysaccharide and Galactosamine in Mice.

Objectives: Liver macrophages agitated by Lipopolysaccharide (LPS) can enhance immuno-inflammatory responses in the liver which mediate liver injury and result in dysfunction. Midazolam has been reported to have inhibitory effects on activated immunity and escalated inflammation, however, what the effects of midazolam on the liver injury caused by excessive immuno-inflammatory response in sepsis, and what influence it will exert on inflamed liver macrophages need to be elucidated. Methods: In the present study, LPS and galactosamine-induced acute liver injury mice were used to observe the effect of midazolam in vivo. LPS-stimulated bone marrow cells were used to evaluate the influence of midazolam on monocytes in vitro. Results: Midazolam prevented liver tissue injury and decreased serum alanine transaminase (ALT) level in LPS plus galactosamine treated mice. Mechanistically, midazolam suppressed tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß) produced by LPS stimulated liver macrophages in vivo and bone marrow monocytes in vitro, and reduced the expression of major histocompatibility complex class II (MHC II), cluster of differentiation 40 and 86 (CD40 and CD86) on the cell surface. These results could be reversed by PK-11195, a peripheral benzodiazepine receptor (PBR) blocker. Conclusion: Midazolam can prevent liver from LPS-induced immune mediated liver injury by inhibiting inflammation and immune activation in liver macrophages.