ABT-263 enhanced bacterial phagocytosis of macrophages in aged mouse through Beclin-1-dependent autophagy.

BACKGROUND: Sepsis is a critical challenge for the older adults as the immune function is less responsive by aging. Although cell numbers seem preserved in the older adults, macrophages present age-related function decline, which including reduced chemokines, phagocytosis, and autophagy. ABT-263, an inhibitor of the anti-apoptotic protein Bcl-2, is reported had a senolytic effect which can selectively clear the senescent cells in vivo and rejuvenate the aged tissues. METHODS: We treated the aged (12-16 months) and young (4-6 months) C57BL/6 mouse with ABT-263, then gave the animals cecal slurry injection to induce sepsis to observe the effect of senolytic compound ABT-263 on the survival rate of sepsis. Additionally, we isolated peritoneal macrophages from the aged mouse to investigate the cell function and molecular mechanism. 3-methyladenine (3-MA), a phosphatidylinositol 3-kinases (PI3K) inhibitor, and rapamycin, an autophagy-enhancer, were used to block or mimic the autophagy, respectively. RT-PCR and Western Blot were used to detect autophagy related gene and protein changes in sepsis. EGFP-expressing E. coli was used as a marker to evaluate the phagocytic ability of macrophages. RESULTS: The results showed ABT-263 treatment improved the survival rate of sepsis in the aged mouse which related to autophagy, while blocking the autophagy can eliminate this effect. It is revealed that ABT-263 enhanced the phagocytic ability of the peritoneal macrophages by increasing the Trem-2 receptor. Additionally, ABT-263 blocked the binding of Bcl-2 to Beclin-1, thus induced Beclin-1-dependent autophagy. CONCLUSION: ABT-263 enhanced the macrophage function in aged mouse by increasing the Trem-2 receptors and inducing a beclin-1-dependent autophagy, consequently, protected the aged mouse from sepsis.

Lateral position intubation followed by endoscopic ultrasound-guided angiotherapy in acute esophageal variceal rupture: A case report.

BACKGROUND: Massive esophageal variceal bleeding can be catastrophic, leading to high morbidity and mortality. Patients experiencing massive esophageal variceal bleeding are at high risk of aspiration and hemorrhagic shock in acute episodes. Intubation and bleeding control are the two essential steps for resuscitation of these patients. CASE SUMMARY: A 47-year-old male patient was admitted to our hospital with upper digestive tract bleeding. He was diagnosed with alcohol-induced liver cirrhosis and consequent esophagogastric varices. As he did not show a good response to somatostatin and Sengstaken-Blakemore tube placement, the patient was scheduled for endoscopic angiotherapy under anesthesia. Preoperative assessment showed an ASA physical status of III and Child-Pugh classification B. However, massive hemorrhage occurred just after induction of anesthesia.  Intubation by video-guided laryngoscopy in the lateral decubitus position was attempted twice and was successful. After that, an experienced endoscopic ultrasound (EUS) specialist performed angiotherapy and occluded the culprit vessel. An ultra-thin gastroscope was then inserted into the endotracheal tube to extract the blood observed in the lobar bronchi. The patient suffered hemorrhagic shock with an estimated blood loss of 1500 mL in 20 min and remained in the intensive care unit for two days. The patient was discharged from our hospital eight days later without major complications. CONCLUSION: Intubation in the lateral decubitus position and EUS-guided treatment can be life-saving procedures in patients with massive upper gastrointestinal hemorrhage.

Application of Chinese Medicine in the Management of Critical Conditions: A Review on Sepsis.

Critical care medicine is a medical specialty engaging the diagnosis and treatment of critically ill patients who have or are likely to have life-threatening organ failure. Sepsis, a life-threatening condition that arises when the body responds to infection, is currently the major cause of death in intensive care units (ICU). Although progress has been made in understanding the pathophysiology of sepsis, many drawbacks in sepsis treatment remains unresolved. For example, antimicrobial resistance, controversial of glucocorticoids use, prolonged duration of ICU care and the subsequent high cost of the treatment. Recent years have witnessed a growing trend of applying traditional Chinese medicine (TCM) in sepsis management. The TCM application emphasizes use of herbal formulation to balance immune responses to infection, which include clearing heat and toxin, promoting blood circulation and removing its stasis, enhancing gastrointestinal function, and strengthening body resistance. In this paper, we will provide an overview of the current status of Chinese herbal formulations, single herbs, and isolated compounds, as an add-on therapy to the standard Western treatment in the sepsis management. With the current trajectory of worldwide pandemic eruption of newly identified Coronavirus Disease-2019 (COVID-19), the adjuvant TCM therapy can be used in the ICU to treat critically ill patients infected with the novel coronavirus.

Plasma gelsolin level predicts acute kidney injury after cardiopulmonary bypass in infants and young children.

BACKGROUND: Acute kidney injury (AKI) after cardiopulmonary bypass (CPB) is a common complication especially in pediatric population. Plasma gelsolin (pGSN) is an anti-inflammatory factor through binding with actin and pro-inflammatory cytokines in circulation. Decrease in pGSN has been reported in some pathologic conditions. The purpose of the study was to determine the alterations of pGSN level in infants and young children after CPB and the role of pGSN as a predictor for the morbidity and severity of post-CPB AKI. METHODS: Sixty-seven infants and young children at age ≤ 3 years old undergoing CPB were prospectively enrolled. PGSN levels were measured during peri-operative period with enzyme-linked immuno-sorbent assay and normalized with plasma total protein concentration. Other clinical characteristics of the patients were also recorded. RESULTS: In patients developing AKI, the normalized pGSN (pGSNN) levels significantly decreased at 6 h post-operation and remained low for 24 h post-operation as compared to the patients with non-AKI. PGSNN at 6 h post-operation combining with CPB time presents an excellent predictive value for AKI. CONCLUSIONS: Decreased pGSNN identifies post-CPB AKI in the patients ≤ 3 years old, and is associated with adverse clinical outcomes. The findings suggest that circulating GSN in post-CPB patients may have beneficial effects on diminishing inflammatory responses.

Defensins and sepsis.

Sepsis is a leading cause of mortality and morbidity in the critical illness. Multiple immune inflammatory processes take part in the pathogenesis of sepsis. Defensins are endogenous antimicrobial peptides with three disulphide bonds created by six cysteine residues. Besides the intrinsic microbicidal properties, defensins are active players which modulate both innate and adaptive immunity against various infections. Defensins can recruit neutrophils, enhance phagocytosis, chemoattract T cells and dendritic cells, promote complement activation, and induce IL-1ß production and pyrotosis. Previous publications have documented that defensins play important roles in a series of immune inflammatory diseases including sepsis. This review aims to briefly summarize in vitro, in vivo, and genetic studies on defensins' effects as well as corresponding mechanisms within sepsis and highlights their promising findings which may be potential targets in future therapies of sepsis.

Altered melatonin secretion and circadian gene expression with increased proinflammatory cytokine expression in early-stage sepsis patients.

Inflammatory and immune responses, as well as melatonin secretion, are affected by circadian regulation. Abnormal circadian rhythm of melatonin release has been reported to be associated with the later stages of sepsis; however, its role in the early stages of sepsis is unclear. We studied 11 septic and 11 non-septic patients in our intensive care unit (ICU). Peripheral blood was drawn at 4-h intervals on the first day, beginning at 2:00 p.m., over a total period of 24 h. Plasma levels of melatonin, tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6) were measured by radioimmunoassay or enzyme-linked immunosorbent assay (ELISA). Messenger RNA levels of circadian genes Cry-1 and Per-2 were analyzed using quantitative real-time PCR. Results show the circadian rhythm of melatonin secretion was altered in the early stages of sepsis. The melatonin secretion acrophase occurred earlier in septic patients at 6:00 p.m., compared with at 2:00 a.m. in non-septic ICU patients. Compared with the non-septic group, both Cry-1 and Per-2 expression were significantly decreased while TNF-α and IL-6 expression were significantly increased in septic patients [TNF-α, 64.1 (43.6-89.1) vs. 11.4 (10.4-12.5) ng/ml; IL-6, 41.2 (35.7-50.8) vs. 19.1 (16-136.7) ng/ml; median (range), both P=0.04]. The peak concentrations of TNF-α and IL-6 were shown to be in concordance with the rhythm of melatonin secretion. The circadian rhythm of melatonin secretion and circadian gene expression were altered in the early stages of sepsis, which likely led to the changes in pro-inflammatory cytokine release. These findings shed light on the potential link between circadian rhythm and the progression of early-stage sepsis.

[Early high-volume hemofiltration treatment in severe sepsis].

OBJECTIVE: To evaluate the effect of early application of high-volume hemofiltration treatment (HVHF) on the levels of lactic acid, pro-inflammatory cytokines and C-reactive protein (CRP) in plasma, as well as APACHE II score in patients suffering from severe sepsis. METHODS: Thirty patients meeting the diagnosis of severe sepsis were enrolled in the trial within 24 hours of insults. The level of lactic acid, interleukin-6 (IL-6) and CRP in plasma were measured before HVHF and at 24, 48 or 72 h following HVHF treatment. RESULT: The plasma levels of lactic acid and IL-6 decreased significantly at 24 h, 48 h, 72 h after HVHF (P <0.05), while, IL-10 did not differ significantly following HVHF (P>0.05), when compared with that before HVHF. CONCLUSION: The early application of HVHF could clear the plasma lactic acid and pro-inflammatory cytokines, and improve the tissue oxygenation in severe sepsis.

Survey of attitudes and behaviors of healthcare professionals on delirium in ICU.

OBJECTIVE: To assess the medical community's awareness and practice regarding delirium in the intensive care unit (ICU). METHODS: One hundred and ten predesigned questionnaires were distributed to ICU practitioners in the affiliated hospitals of Zhejiang University. RESULTS: A total of 105 valid questionnaires were collected. Totally, 55.3% of the clinicians considered that delirium was common in the ICU. Delirium was believed to be a significant or serious problem by 70.5% of respondents, and under-diagnosis was acknowledged by 56.2% of the respondents. The incidence of ICU delirium is even more under-estimated by the pediatric doctors compared with their counterparts in adult ICU (P less than 0.05). Primary disease of the brain (agreed by 82.1% of the respondents) was believed to be the most common risk factor for delirium. None of the ICU professionals screened delirium or used a specific tool for delirium assessment routinely. The vast majority (92.4%) of respondents had little knowledge on the diagnosis and the standard treatment of delirium. CONCLUSIONS: Although delirium is considered as a serious problem by a majority of the surveyed ICU professionals, it is still under-recognized in routine critical care practice. Data from this survey show a disconnection between the perceived significance of delirium and the current practices of monitoring and treatment in ICU in China.

[Epidemiological study of severe sepsis in a newborn intensive care unit].

OBJECTIVES: To determine the incidence and outcome of severe sepsis in Newborn Intensive Care Unit (NICU) and to characterize their demographics and infection pattern. METHODS: Characteristics of 243 newborns admitted to NICU from June 1st, 2006 to May 31st, 2007 were retrospectively analyzed. RESULTS: Analysis of data derived from 243 newborns admitted to NICU over an 1-year period with 48 (19.8%) cases diagnosed as severe sepsis, and 70.8% of them were males. The median age of severe sepsis patients was 2 (1-6 ) days. In 56.3% of the patients bacteria were isolated, and E. coli was the predominant microbe. PRISM score and mortality rate were higher in those with severe sepsis, while their Apgar score was lower than other cases. The overall hospital mortality of severe sepsis was 45.8%. Risk factors for hospital mortality included higher PRISM score, severe organ dysfunction, circulatory system dysfunction, and hematological or central nervous system dysfunction. CONCLUSIONS: This study shows that severe sepsis is a common, frequently fatal morbid condition in critical ill newborns in NICU, showing similar disease pattern with other investigations. Further multiple-center investigations are helpful to prevent, control and salvage critically ill children suffering from severe sepsis.

[Comparison of three different organ failure assessment score systems in predicting outcome of severe sepsis].

OBJECTIVE: To compare multiple organ dysfunction score (MODS), the sequential organ failure assessment (SOFA) and the logistic organ dysfunction score (LODS) in predicting hospital mortality in severe sepsis. METHODS: Four hundred and three patients admitted to the ICU from December 2004 to November 2007 with a diagnosis of severe sepsis were enrolled in this study. Their MODS, SOFA, LODS and Acute Physiology and Chronic Health Evaluation (APACHE) II at admission and the highest score during hospitalization were respectively recorded and collected in regard to mortality. The discrimination of three multiple organ dysfunction score systems were assessed by the areas under the receiver operating characteristic curves (AUC). RESULTS: The AUC of admission scores was 0.811 for LODS, 0.787 for SOFA, 0.725 for MODS, and 0.770 for APACHE II in predicting hospital mortality. All maximum scores had better power of discrimination than the admission scores (P < 0.01). The power of discrimination of LODS and SOFA were better than the MODS, either the admission or the highest, respectively (P < 0.01). However, no significant difference was observed between the LODS and the SOFA regarding mortality prediction (P > 0.05). The AUC value for the APACHE II score was much lower compared to LODS (P < 0.01). However, there was no difference in AUC value among APACHE II, SOFA and MODS (P > 0.05). CONCLUSION: LODS, SOFA and MODS show a good discrimination power, while maximum LODS is of the highest discrimination power to predict the outcome of patient with severe sepsis.

Protein C -1641A/-1654C haplotype is associated with organ dysfunction and the fatal outcome of severe sepsis in Chinese Han population.

Activation of protein C plays an important role in modulating coagulation as well as inflammation during severe sepsis. The baseline of activated protein C level in patients with severe sepsis showed interindividual variability between survivors and nonsurvivors, and the decreased level of protein C correlated with organ dysfunction and poor outcome. However, there are limited data concerning the genetic predisposition of individuals carrying two functional polymorphisms -1641A>G and -1654C>T within protein C gene to sepsis. Here we investigated the impact of these two variations on the development of severe sepsis in 240 patients with severe sepsis and 323 healthy controls using direct sequencing. After Bonferroni correction for multiple comparisons, -1641A/-1654C haplotype was significantly associated with the fatal outcome of severe sepsis (P = 0.008, OR 1.739, 95% CI 1.165-2.595), which was confirmed by multiple logistic regression analysis (P = 0.024, OR 2.090, 95% CI 1.101-3.967). Compared to patients without carrying -1641A/-1654C haplotype, the -1641A/-1654C haplotype carriers showed higher SOFAmax scores (10.3 +/- 5.2 vs. 9.0 +/- 4.5; P = 0.014) and more hepatic dysfunction (P = 0.004, OR 2.270, 95% CI 1.312-3.930). These findings suggest that protein C haplotype -1641A/-1654C is associated with organ dysfunction and is an independent risk factor for the fatal outcome of severe sepsis in Chinese Han population.

Impact of invasive fungal infection on outcomes of severe sepsis: a multicenter matched cohort study in critically ill surgical patients.

INTRODUCTION: Fungal infection is increasingly common in critical illness with severe sepsis, but the influence of invasive fungal infection (IFI) on severe sepsis is not well understood. The aim of this study was to investigate the impact that IFI has on the outcomes of critically ill surgical patients with severe sepsis in China by means of matched cohort analysis; we also evaluated the epidemiologic characteristics of IFI in this population. METHODS: Records for all admissions to 10 university hospital surgical intensive care units (ICUs) from December 2004 to November 2005 were reviewed. Patients who met criteria for severe sepsis were included. IFI was identified using established criteria based on microbiologic or histological evidence. A matched cohort study was conducted to analyze the relationship between IFI and outcomes of severe sepsis. RESULTS: A total of 318 patients with severe sepsis were enrolled during the study period, of whom 90 (28.3%) were identified as having IFI. A total of 100 strains of fungi (58% Candida albicans) were isolated from these patients. Independent risk factors for IFI in patients with severe sepsis included mechanical ventilation (>3 days), Acute Physiology and Chronic Health Evaluation score, coexisting infection with both gram-positive and gram-negative bacteria, and urethral catheterization (>3 days). Compared with the control cohort, IFI was associated with increased hospital mortality (P < 0.001), high hospital costs (P = 0.038), and prolonged stay in the ICU (P < 0.001) and hospital (P = 0.020). CONCLUSION: IFI is frequent in patients with severe sepsis in surgical ICUs and is associated with excess risk for hospital mortality, longer ICU and hospital stays, and greater consumption of medical resources.

[Relationship between sepsis and 4G/5G polymorphism within the promoter region of plasminogen activator inhibitor-1 gene].

OBJECTIVE: To study the relationship between sepsis and a 4G/5G polymorphism within the promoter region of plasminogen activator inhibitor-1 (PAI-1) gene in the Han nationality. METHODS: Peripheral blood sample were collected from 89 patients with severe sepsis, 58 males and 31 females, aged 56, with a APHCHII score of 22.5 +/- 2.1 and a mortality of 51%, and 100 sex and age-matched postoperative patients without severe sepsis, all of the Han nationality. 4G/5G polymorphism of PAI-1 gene was determined using polymerase chain reaction (PCR) followed by restriction enzyme analysis. RESULTS: The carrier rate of 4G/4G genotype among the sepsis patients was 0.44, significantly higher than that among the controls (0.25, P < 0.01). The 4G allele frequency of the sepsis patients was 0.65, significantly higher than that of the controls (0.54, P < 0.05). The carrier rate of 4G/4G genotype among the non-survivors in the sepsis group was 0.54; significantly higher than that among the survivors (0.34, P < 0.05); and the 4G allele rate in the non-survivors was 70%, not significantly different from that of the survivors (59%, P > 0.05). CONCLUSION: PAI-1 4G/5G polymorphism is associated with the susceptibility and outcome of severe sepsis, 4G/4G genotype and 4G allele may be genetic risk factors of severe sepsis.