Xiangming Fang

Epidemiology of severe sepsis in critically ill surgical patients in ten university hospitals in China

Objectives:To determine the occurrence rate, outcomes, and the characteristics of severe sepsis in surgical intensive care units in multiple medical centers within China and to assess the cost and resource use of severe sepsis in China. Design and Setting:Prospective, observational study of surgical intensive care unit patients at ten university hospitals in six provinces in China. Patients:All adult admissions in studied intensive care units from December 1, 2004, to November 30, 2005. Interventions:None. Measurements and Main Results:The criteria of severe sepsis were based on the American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference definition. Analysis of data from 3,665 intensive care unit admissions identified 318 (8.68%) cases of severe sepsis, 64.8% of which were men. The median age (interquartile range) of patients with severe sepsis was 64 (47–74) yrs. Microbes had been isolated from 228 (71.7%) patients, including 171 (53.8%) with Gram-negative bacteria and 146 (45.9%) with Gram-positive bacteria. A total of 90 (22.0%) patients had invasive fungal infection, 20 (6.3%) of which had fungemia. The abdomen was the most common site of infections (72.3%), followed by lung (52.8%). The overall hospital mortality of severe sepsis was 48.7%. Risk factors for hospital mortality included age, chronic comorbidity of malignant neoplasm, Gram-positive bacterial infection, invasive fungal infection, admission Acute Physiology Score, and admission Sequential Organ Failure Assessment score of respiratory dysfunction and cardiovascular dysfunction. The median Therapeutic Intervention Scoring System-28 score was 43 (38–49). The mean hospital cost was

Perioperative Risk Factors for Prolonged Mechanical Ventilation Following Cardiac Surgery in Neonates and Young Infants

11,390 per patient and

Protection Against pseudomonas Aeruginosa Pneumonia And Sepsis-induced Lung Injury By Overexpression of β-defensin-2 In Rats

502 per patient per day. Conclusions:Severe sepsis is a common, expensive, and frequently fatal syndrome in critically ill surgical patients in China. Other than the microbiological patterns, the incidence, mortality, and major characteristics of severe sepsis in Chinese surgical intensive care units are close to those documented in developed countries.

Triggering Receptor Expressed on Myeloid Cells-2 Protects against Polymicrobial Sepsis by Enhancing Bacterial Clearance

BACKGROUND Prolonged mechanical ventilation (PMV) after cardiac surgery in children is associated with a high postoperative morbidity and mortality, as well as increased ICU and hospital resource utilization. Little has been done to identify the predictors of PMV in neonates and young infants. This study was performed to evaluate the perioperative risk factors for PMV in neonates and young infants undergoing cardiac surgery. METHODS Clinical records of 172 consecutive children aged < or = 3 months were reviewed. PMV was defined as mechanical ventilation (MV) > or = 72 h following operation. After univariate analysis, a stepwise logistic regression analysis was used to evaluate the independent risk factors for PMV following cardiac surgery. The predictive ability of risk factors for PMV was assessed using an area under the receiver operating characteristic (ROC) curve. RESULTS Sixty-one patients required PMV after cardiac surgery. The median duration of MV was 150 h in PMV patients, while it was 28 h in non-PMV patients. The independent risk factors for PMV were risk adjustment for surgery for congenital heart disease (RACHS)-1 (p = 0.041), nosocomial pneumonia (p = 0.001), low cardiac output syndrome (LCOS) [p = 0.001], postoperative cumulative positive fluid balance (p = 0.032), and extubation failure (EF) [p = 0.027]. The value for the ROC curve was 0.940. CONCLUSIONS The present results strongly suggest that RACHS-1, nosocomial pneumonia, LCOS, fluid retention postoperatively, and EF are risk factors for PMV in neonates and young infants undergoing reparative surgery for congenital heart disease.

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

ABSTRACT &bgr;-defensin-2 (BD-2), a small cationic antimicrobial peptide, was first described to be an inducible defensin at the epithelial surfaces. In vitro studies have demonstrated that it may play a pivotal role in the anti-inflammatory immune response in addition to its antimicrobial activity. The purpose of this study was to evaluate the effect of overexpression of BD-2 on lung injury to crudely investigate whether the function of BD-2 in the lung attributed to both antimicrobial action and modulation of the immune response. Recombinant adenovirus carrying an expression cassette of rat BD-2 or control adenovirus carrying empty vector was administered intratracheally to Sprague-Dawley rats 48 h before performing acute lung injury, which was induced either by Pseudomonas aeruginosa infection or by cecal ligation and double puncture (2CLP). In vivo antimicrobial activity of BD-2, histological changes of the lungs in both infectious and 2CLP models, pulmonary intracellular adhesion molecule-1 protein level, as well as the 7-day survival rate in the latter model were determined. Amounts of the P. aeruginosa in the lung with BD-2 overexpression were significantly lower compared with that in controls (2.87 ± 0.76 × 104 colony-forming units [CFU]/mL vs. 2.49 ± 0.74 × 106 CFU/mL, P < 0.05). Overexpression of BD-2 reduced alveolar damage, interstitial edema, and infiltration of neutrophils in both models. Furthermore, in the 2CLP model, recombinant BD-2 not only significantly decreased protein levels of intracellular adhesion molecule-1 in lung tissue at 24, 36, and 72 h after 2CLP (P < 0.05), but also significantly improved the survival of rats (P < 0.05). The CFU of abdominal bacteria was comparable to that in the control rats (P > 0.05). Therefore, overexpression of BD-2 protects against P. aeruginosa pneumonia and 2CLP-induced lung injury based on its antimicrobial and anti-inflammatory activities, respectively. Modulating the expression level of BD-2 may serve as an approach to attenuate lung injury.

Plasma sRAGE enables prediction of acute lung injury after cardiac surgery in children

RATIONALE Triggering receptor expressed on myeloid cells-2 (TREM-2) is a cell surface receptor primarily expressed on macrophages and monocyte-derived cells. TREM-2 not only functions as a regulator of inflammatory response, but also serves as a phagocytic receptor for bacteria. However, the role of TREM-2 in sepsis remains unknown. OBJECTIVES To investigate whether TREM-2 plays a role in sepsis. METHODS The manner of expression of TREM-2 was evaluated in patients with sepsis and in polymicrobial septic mouse model induced by the cecum ligation and puncture approach. Recombinant mouse TREM-2 was used to block the effect of TREM-2. Bone marrow-derived myeloid cells (BMMCs) that overexpress TREM-2 were administrated into septic mice at various times after cecum ligation and puncture. MEASUREMENTS AND MAIN RESULTS The expression levels of TREM-2 were up-regulated in patients with sepsis and septic mice. The kinetics of TREM-2 expression in polymicrobial sepsis was comparable with that of bacteria burden in peritoneal lavage fluid. Blocking the effect of TREM-2 resulted in markedly increased mortality and bacterial burden in polymicrobial sepsis. Administration of TREM-2-overexpressing BMMCs significantly reduced the mortality, even when it was administered 4 hours after the initiation of sepsis. However, injection of TREM-2-overexpressing BMMCs into LPS-challenged endotoxemia mice did not improve the survival rate. The protective effect of TREM-2 in polymicrobial sepsis was not associated with its antiinflammatory properties, but it enhanced bacterial clearance in vivo. Furthermore, administration of TREM-2-overexpressing BMMCs improved the organ injury. CONCLUSIONS TREM-2 plays an important role in the host defense response to sepsis by enhancing bacterial clearance.

Increased Genomic Copy Number of DEFA1/DEFA3 Is Associated with Susceptibility to Severe Sepsis in Chinese Han Population

IntroductionFungal 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.MethodsRecords 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.ResultsA 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).ConclusionIFI 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.

Circulating nucleosomes as a predictor of sepsis and organ dysfunction in critically ill patients

IntroductionAcute lung injury (ALI) after cardiac surgery is associated with a high postoperative morbidity and mortality, but few predictors are known for the occurrence of the complication. This study evaluated whether elevated plasma levels of soluble receptor for advanced glycation end products (sRAGE) and S100A12 reflected impaired lung function in infants and young children after cardiac surgery necessitating cardiopulmonary bypass (CPB).MethodsConsecutive children younger than 3 years after cardiac surgery were prospectively enrolled and assigned to ALI and non-ALI groups, according to the American-European Consensus Criteria. Plasma concentrations of sRAGE and S100A12 were measured at baseline, before, and immediately after CPB, as well as 1 hour, 12 hours, and 24 hours after operation.ResultsFifty-eight patients were enrolled and 16 (27.6%) developed postoperative ALI. Plasma sRAGE and S100A12 levels increased immediately after CPB and remained significantly higher in the ALI group even 24 hour after operation (P < 0.01). In addition, a one-way MANOVA revealed that the overall sRAGE and S100A12 levels were higher in the ALI group than in the non-ALI group immediately after CPB (P < 0.001). The multivariate logistic regression analysis showed that the plasma sRAGE level immediately after CPB was an independent predictor for postoperative ALI (OR, 1.088; 95% CI, 1.011 to 1.171; P = 0.025). Increased sRAGE and S100A12 levels immediately after CPB were significantly correlated with a lower PaO2/FiO2 ratio (P < 0.01) and higher radiographic lung-injury score (P < 0.01), as well as longer mechanical ventilation time (sRAGEN: r = 0.405; P = 0.002; S100A12N: r = 0.322; P = 0.014), longer surgical intensive care unit stay (sRAGEN: r = 0.421; P = 0.001; S100A12N: r = 0.365; P = 0.005) and hospital stay (sRAGEN: r = 0.329; P = 0.012; S100A12N: r = 0.471; P = 0.001).ConclusionsElevated sRAGE and S100A12 levels correlate with impaired lung function, and sRAGE is a useful early biomarker of ALI in infants and young children undergoing cardiac surgery.

Transient Receptor Potential Melastatin 2 Protects Mice against Polymicrobial Sepsis by Enhancing Bacterial Clearance

Background:Human neutrophil peptides 1–3 are endogenous cationic antimicrobial peptides implicated in host defense against microbes. The genes encoding human neutrophil peptides 1–3 (DEFA1/DEFA3) exhibit copy number variations. This study was designed to determine whether DEFA1/DEFA3 copy number variations conferred susceptibility to infection-induced complications such as severe sepsis. Methods:This case–control study was performed in 179 patients with severe sepsis and 233 healthy blood donors and was replicated in an independent cohort of 112 cases and 118 controls. Plasma levels of human neutrophil peptides 1–3, tumor necrosis factor-&agr;, interleukin-6, and interleukin-10 were detected. Results:The genotype of DEFA1/DEFA3 with more than eight copies was more frequent in patients with severe sepsis than in controls (55.9% vs. 31.3%; P = 1.13 × 10−6, odds ratio 2.77, 95% confidence interval 1.85–4.16). After adjustment for age and gender, logistic regression analysis confirmed the association of the genotype of more than eight copies with an increased risk of severe sepsis (P = 2.25 × 10−5, odds ratio 2.66, 95% confidence interval 1.69–4.19). This established association was replicated in a second age- and gender-matched case–control cohort (P = 0.02, odds ratio 1.90, 95% confidence interval 1.11–3.27). Furthermore, compared with those with fewer copies, the patients carrying more than eight copies of DEFA1/DEFA3 presented significantly lower plasma levels of human neutrophil peptides 1–3, tumor necrosis factor-&agr;, interleukin-6, and interleukin-10 (P = 0.039, 0.017, 0.030, and 0.029, respectively). Conclusions:DEFA1/DEFA3 is an important genetic component participating in host immune response to severe sepsis. A higher copy number of DEFA1/DEFA3 (>8 copies) is significantly associated with the risk of severe sepsis.

Lack of association between TREM-1 gene polymorphisms and severe sepsis in a Chinese Han population

OBJECTIVES Sepsis is a leading cause of death in critically ill patients, and apoptosis plays a major role in the pathophysiology of sepsis. Elevated levels of circulating nucleosomes released by apoptotic cells have been detected in patients with severe sepsis and septic shock. The aim of this study was to evaluate the diagnostic/prognostic value of circulating nucleosomes in sepsis. METHODS Seventy-four newly admitted patients with an estimated length of stay in the intensive care unit of more than 48 h, were prospectively enrolled as cohort 1. The second independent cohort (cohort 2) consisted of 91 post-surgery patients. Patients receiving chemotherapy, those with AIDS, those on steroid treatment, and those undergoing transplants were excluded. Levels of circulating nucleosomes within 24h of admission in both cohorts, and for cohort 1 also on days 3, 5, and 7 and a last time-point of ICU discharge or at imminent death, were measured and analyzed for their capacity to predict sepsis. The severity of the inflammatory response and organ dysfunction were assessed by cytokine levels and sepsis scores. RESULTS Nucleosome levels on admission in septic patients were significantly higher than those in non-septic controls in both of the cohorts. The area under the receiver operating characteristic curve for admission nucleosome levels to differentiate septic patients from non-septic patients was 0.70 (95% confidence interval (CI) 0.51-0.88) in cohort 1, 0.66 (95% CI 0.55-0.79) in cohort 2, and 0.67 (95% CI 0.55-0.79) in all of the subjects. After multiple logistic regression analysis, circulating nucleosomes remained as an independent predictor of sepsis. Furthermore, the levels of circulating nucleosomes on admission were significantly correlated with the inflammatory response and organ dysfunction in sepsis. Meanwhile, a trend was observed for admission levels of circulating nucleosomes in non-survivors to be higher than those in survivors. CONCLUSIONS The level of circulating nucleosomes in the serum has a predictive value for sepsis and organ dysfunction and may serve as a candidate biomarker for the diagnosis/prognosis of sepsis. Further studies are warranted to confirm the present findings.