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Background: The relation between deresuscitative fluid management after the resuscitation phase and clinical outcome in patients with abdominal sepsis is not completely clear. The aim of this study was to assess the contribution of deresuscitative management to death and organ dysfunction in abdominal sepsis. Methods: Consecutive patients with abdominal sepsis requiring fluid resuscitation were included in this study. According to the fluid management given in the later stage of resuscitation, a conservative group and a deresuscitative fluid management group were compared. The primary outcome was in-hospital death, whereas secondary outcomes were categorized as organ dysfunction and other adverse events. Results: A total of 138 patients were enrolled in this study. Conservative fluid management was given to 47.8% of patients, whereas deresuscitative fluid management occurred in 52.2%. The deresuscitative strategy was associated with a markedly lower prevalence of new-onset acute kidney injury and a decrease in the duration of continuous renal replacement therapy (CRRT). There was a greater risk of needing new-onset intubation and the mechanical ventilation duration in the conservative group than in the deresuscitative group. However, the deresuscitative group did not differ from the conservative group with respect to open abdomen and intra-abdominal hypertension or new-onset abdominal compartment syndrome. The conservative treatment was associated with prolonged stays as well as a higher in-hospital mortality rate. A multivariable logistic regression model showed that deresuscitative fluid management imparts a protective effect against in-hospital death (odds ratio 4.343; 95% confidence interva1 1.466-12.866; p = 0.008), whereas septic shock, source control failure, and CRRT duration were associated with a higher mortality rate. Conclusions: Fluid balance achieved using deresuscitative treatment is correlated with better outcomes in patients with abdominal sepsis, indicating that this treatment may be useful as a therapeutic strategy.

Background: Recent animal studies have shown that mitochondrial dysfunction initiates and accelerates renal injury in sepsis, but its role in sepsis remains unknown. Mitochondrial stress or dying cells can lead to fragmentation of the mitochondrial genome, which is considered a surrogate marker of mitochondrial dysfunction. Therefore, we evaluated the efficiency of urinary mitochondrial DNA (UmtDNA) as a marker of renal dysfunction during sepsis-induced acute kidney injury (AKI)., Methods: We isolated DNA from plasma and urine of patients. mtDNA levels were quantified by quantitative PCR. Sepsis patients were divided into no AKI, mild AKI, and severe AKI groups according to RIFLE criteria. Additionally, cecal ligation and puncture (CLP) was established in rats to evaluate the association between UmtDNA and mitochondrial function., Results: A total of 52 (49.5%) developed AKI among enrolled sepsis patients. Increased systemic mtDNA did not correlate with systemic inflammation or acute renal dysfunction in sepsis patients, while AKI did not have an additional effect on circulating mtDNA levels. In contrast, UmtDNA was significantly enriched in severe AKI patients compared with that in the mild AKI or no AKI group, positively correlated with plasma creatinine, urinary neutrophil gelatinase-associated lipocalin, and kidney injury molecule-1, and inversely with the estimated glomerular filtration rate. Additionally, UmtDNA increased in rats following CLP-induced sepsis. UmtDNA was predictive of AKI development and correlated with plasma creatinine and blood urea nitrogen in the rat sepsis model. Finally, the UmtDNA level was inversely correlated with the cortical mtDNA copy number and relative expression of mitochondrial gene in the kidney., Conclusion: An elevated UmtDNA level correlates with mitochondrial dysfunction and renal injury in sepsis patients, indicating renal mitochondrial injury induced by sepsis. Therefore, UmtDNA may be regarded as a valuable biomarker for the occurrence of AKI and the development of mitochondria-targeted therapies following sepsis-induced AKI.

Sepsis, during which the intestinal epithelial barrier is frequently disrupted, remains a challenging and life-threatening problem in clinical practice. The P2X7 receptor (P2X7R) is a non-selective adenosine triphosphate-gated cation channel present in macrophages that is involved in inflammatory responses. However, little is known about the role of P2X7R in macrophages during sepsis-induced intestinal barrier disruption. In this study, mice were treated with the P2X7R antagonist A740003 or the agonist BzATP by intra-peritoneal injection after the induction of gut-origin sepsis. The survival rates, inflammatory responses, intestinal barrier integrity, macrophage marker expression, and ERK and NF-κB activities were evaluated. Intestinal macrophages were also isolated and studied after exposure to Brilliant Blue G or BzATP. We found that a systemic P2X7R blockade downregulated sepsis-induced inflammatory responses and attenuated intestinal barrier dysfunction based on the evidence that mice in the A740003-treated group exhibited alleviated pro-inflammatory cytokine synthesis, intestinal hyperpermeability, epithelial apoptosis rates and tight junction damage compared with the septic mice. These changes were partly mediated by the inhibition of M1 macrophages activation via ERK/NF-κB pathways. Our data presented herein show that a P2X7R blockade could be a potential therapeutic target for the treatment of sepsis-induced intestinal barrier dysfunction.

Background: The association between CD14-159C/T polymorphism and sepsis has been assessed but results of current studies appeared conflicting and inconstant. This analysis was aimed to determine whether the CD14-159C/T polymorphism confers susceptibility to sepsis or is associated with increased risk of death from sepsis., Method: The authors conducted a comprehensive search of PubMed, EMBASE, ISI Web of Science, Cochrane library, ScienceDirect, Wiley Online Library and CNKI databases according to a prespecified protocol. Language limits were restricted to English and Chinese. Two reviewers independently selected the articles and extracted relevant data onto standardized forms. Disagreements were settled by discussion and suggestions from senior consultants. The strength of association were evaluated by odds ratio (OR) and 95% confidence interval (CI). Studies failed to fit the Hardy-Weinberg-Equilibrium were excluded., Results: The research identified a total of 2317 full-text articles of which 14 articles met the predefined inclusion criteria. Meta-analysis was performed for allele frequency of C versus T, as well as genotypes CC + CT versus TT (dominant model), CC versus TT + CT (recessive model), CT versus TT and CC versus TT (additive model). All control samples were in Hardy-Weinberg proportion. No significant association between CD14-159C/T polymorphism and sepsis susceptibility or mortality were detected in the overall population. Nonetheless, subgroup analysis of Asian ethnicity revealed significant association between the CD14-159C/T polymorphism and susceptibility to sepsis in additive model (CC versus TT: OR = 0.52, 95% CI 0.29-0.92, p = 0.03) and recessive model (CC versus CT + TT: OR = 0.50, 95% CI 0.30-0.84, p = 0.009). Of note, three out of the five papers included in the subgroup focused exclusively on burn ICU patients., Conclusions: This meta-analysis demonstrated that CD14-159C/T polymorphism is likely to be associated with susceptibility to sepsis in Asian population, especially for the TT genotype. However, bias may rise for etiologic reasons because the majority of subjects in the subgroup came from burn ICU. CD14-159C/T polymorphism is not relevant to sepsis mortality in any genetic models, regardless of the ethnicities. Due to the exploratory nature of the study, no adjustment for multiple testing was adopted, and therefore the results should be interpreted with precaution. Well-designed studies with larger sample size and more ethnic groups are required to further validate the results.

Background: Monocyte subsets and monocyte-platelet aggregates (MPAs) play important roles in inflammation., Aim: To evaluate the association between the three human monocyte subsets and their contributions to MPAs and mortality among septic patients., Methods: Consecutive septic patients were enrolled in. Age- and gender-matched nonseptic patients were recruited as control patients. Monocyte subsets and monocyte-platelet aggregates were determined by flow cytometric analysis., Results: Elevated percentage of MPAs (MPAs%) was associated with an increased risk of mortality., Conclusions: This study demonstrated increased MPAs% enables the identification of a group of septic patients at high risk of death.

Purpose: The aim was to evaluate the predictive value of serial serum sodium determination for mortality in enteric fistula (EF) patients complicated with sepsis., Methods: Between January 1(st), 2012 to January 13(th), 2013, we performed a prospective observational study enrolling 162 patients. Patients were divided into survivors group (n = 119) and nonsurvivors group (n = 43) according to 28-day outcomes. Laboratory variables on day 0, day 3, and day 7 after admission were recorded. [Na(+)]0 was defined as serum [Na(+)] value on admission. [Na(+)]3 was defined as serum [Na(+)] value on day 3. Δ [Na(+)]3 was defined as changes from [Na(+)]3 to [Na(+)]0. The definition applied to other parameters. The results were validated in an independent cohort of 116 patients., Results: ROC analysis showed that [Na(+)]7>147.5 mmol/L and ΔNa7>5.2 mmol/L were reliable predictors ([Na(+)]7: 81.2% sensitivity, 87.7% specificity, (area under the curve(AUC):0.872, p < .001; Δ[Na(+)]7: 81.3% sensitivity, 83.6% specificity, AUC:0.836, p < .001) for mortality. The combination form ([Na(+)]7>147.5 mmol/L+ Δ[Na]7>5.2 mmol/L+ ΔPCT7<5.3 ng/ml) had greatest predictive value (AUC:0.899, p < .001). Their predictive values were confirmed in the validation cohort., Conclusions: Serum sodium was a reliable predictor for mortality in abdominal septic patients, which should be paid close attention in the critical care.

Background: Sepsis is still a major health problem that causes high mortality in all populations. Organ dysfunction including sepsis-associated thrombocytopenia is prevalent among sepsis patients, resulting in increasing mortality rates. Considering the clinical role of platelets, thrombocytopenia in sepsis has led to a large spend in research activity and clinical trials in this area, yet there is no consensus upon which treatment should be administered. As a result, platelet transfusion is often indicated to resolve low platelet counts, leading to an increasing risk of the multiple risks transfusion brings, such as infectious or immune system complications. Given the role of thrombopoietin in stimulating proliferation and differentiation of megakaryocytes, our previous study investigated the potential benefits of recombinant human thrombopoietin in severe sepsis patients with thrombocytopenia. However, there are several limitations in the study, which may have led to bias in our conclusion. Thus, we are conducting this study in order to evaluate the safety and efficacy of recombinant human thrombopoietin in a large, varied population., Methods/design: The study is designed as a randomized, open-label, placebo-controlled, multi-center study in tertiary academic centers for evaluating the safety and efficacy of recombinant human thrombopoietin over placebo. An established total of 708 patients with sepsis and thrombocytopenia will undergo prospective random assignment to recombinant human thrombopoietin or placebo (a 1:1 ratio). The primary endpoint is 7-day all-cause mortality and 28-day all-cause mortality., Discussion: To our knowledge, this is the first study to evaluate the safety and efficacy of recombinant human thrombopoietin among severe sepsis patients with thrombocytopenia in a varied population. With our study, the level of evidence for the treatment of these patients will be significantly raised., Trial Registration: ClinicalTrials.gov: NCT02094248 . Registration date: 23 March 2014.

Background: Sepsis is a fatal systemic inflammatory response syndrome caused by severe infection. The aim of this study was to measure hepatic microcirculation during the sepsis with laser speckle contrast imaging (LSCI), as well as investigating the underlying mechanisms., Methods: Sepsis was induced by cecal ligation and puncture. Rats were divided into the sham group and sepsis group. The hepatic microcirculation was monitored with LSCI. In addition, hepatic endothelial function (expression of cell adhesion molecules, coagulation and vascular permeability) and neutrophils accumulation in the liver were compared between the two groups., Results: During the sepsis, hepatic microcirculation decreased dramatically (290.3±70.1 LSPU (laser speckle perfusion units) at baseline vs. 230.4±60.7 LSPU at 12h vs. 125.2±25.4 LSPU at 48h, P<0.001). The rats developed hyperbilirubinemia since 6h. In the early phase of sepsis, the accumulation of neutrophils and formation of microthrombus increased rapidly. In the late phase, hepatic neutrophils accumulation was already at its maximum level. Meanwhile, the endothelial coagulation status shifted from procoagulation to anticoagulation. The vascular leakage was involved in the microcirculation dysfunction since 12h after sepsis., Conclusions: Hepatic microcirculation dysfunction occurs early during the sepsis and is associated with liver injury. This microcirculation dysfunction is due to neutrophil-endothelium interactions, microthrombus formation and vascular leakage., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Introduction: Thrombocytopenia is prevalent in patients with severe sepsis, and it is associated with mortalities. Effectively adjunctive treatment might be needed to reverse low platelet counts (PCs). With a growing understanding of thrombocytopenia, recombinant human thrombopoietin (rhTPO) is considered a promising beneficial drug. The present study was dedicated to evaluate the efficiency of rhTPO in improving PCs in patients with severe sepsis., Materials and Methods: We performed a prospective study in patients with severe sepsis between March 2012 and February 2013. All enrolled patients were divided into rhTPO group and control group, depending on whether rhTPO was prescribed or not. Platelet counts and other parameters were measured initially and in the following 15 days., Results: Totally, 72 patients (38 in the rhTPO group and 34 in the control group) were included. All enrolled parameters exhibited no significant differences between groups at the baseline. Platelet counts showed a significant increase over time in both groups. Faster improvement of PCs in the rhTPO group was observed with a significant difference. Less platelet transfusion occurred in patients who received rhTPO in our study, as well. No drug-related adverse event during the rhTPO therapy was recorded., Conclusion: The use of rhTPO in combination with conventional medical therapies could significantly improve the PCs in patients with severe sepsis and thrombocytopenia and effectively reduce the platelet transfusion possibility., (Copyright © 2014 Elsevier Inc. All rights reserved.)

The use of open abdomen in the management of gastrointestinal fistula complicated with severe intra-abdominal infection is uncommon. This study was designed to evaluate outcomes of our staged approach for the infected open abdomen. Patients who had gastrointestinal fistula and underwent open abdomen treatment were retrospectively reviewed. Various materials such as polypropylene mesh and a modified sandwich package were used to achieve temporary abdominal closure followed by skin grafting when the granulation bed matured. A delayed definitive operation was performed for final abdominal closure without implant of prosthetic mesh. Between 1999 and 2009, 56 (68.3%) of 82 patients survived through this treatment. Among them, 42 patients achieved final abdominal closure. Spontaneous fistula closure occurred in 16 patients with secondary fistula recorded in six patients. Besides, wound complications occurred in 13 patients with two cases for pulmonary infection. Within a 12-month follow-up period after definitive closure, no additional fistula was recorded excluding planned ventral hernia repair. Open abdomen treatment was effective for gastrointestinal fistula complicated by severe intra-abdominal infection. A delayed and deliberate operative strategy aiming at fistula excision and fascial closure, with simultaneous abdominal wall reconstruction, was required for the infected open abdomen.

Purpose: Complement depletion commonly occurred in septic patients, but this problem was often underestimated during the treatment process. This study was designed to determine the association between complement depletion and T-cell immunosuppression., Methods: From November 2011 to March 2012, patients with severe abdominal sepsis were prospectively enrolled in a single center. The baseline levels of complement C3 were used to stratify subjects into 2 groups. Plasma levels of complement components, percentage of regulatory T cells (Tregs), and T-cell immunity indexes were monitored at times after admission. The relationship between C3 depletion and T-cell response was investigated, with clinical outcomes explored meanwhile., Results: A total of 60 patients aged 43.9 ± 11.3 years were included within the period. C3 depletion, occurring in 65% of enrolled subjects, was strongly correlated with Treg expansion (P = .001) and decreased CD4(+)/CD8(+) ratio (P = .008). This depletion was also related to prolonged hospital stay (P = .001), delayed time to operation (P < .001), increased postoperative complications (P = .036), and hospital expenditure (P < .001)., Conclusions: Complement C3 depletion was found to be linked to the expansion of Tregs during abdominal sepsis. Such depletion and associated immunosuppression should be paid close attention in the critical care., (© 2013.)

Background: Numerous temporary abdominal closure (TAC) techniques have been described in treatment of the open abdomen. However, data confirming their role in the management of gastrointestinal fistula complicated with abdominal sepsis are limited. This retrospective study evaluated whether a modified sandwich-vacuum package (MSVP) improved fascial closure rate compared with the polypropylene mesh (PPM)-mediated method., Methods: Patients, who experienced gastrointestinal fistula and underwent open abdomen management, were included and divided into MSVP and PPM groups according to the TAC method they received. Mortality, fascial closure rate, postoperative complications, and other outcomes were compared between the two groups., Results: Between 2000 and 2010, 36 patients were treated with MSVP, with 36 cases for PPM. The overall mortality after a TAC procedure was 22.2% and 44.4%, respectively (p = 0.079). Compared with PPM technique, the fascial closure rate under MSVP method was markedly increased (63.9% vs. 33.3%, p = 0.018). Moreover, time to definitive closure (p = 0.003), length of stay in hospital (p = 0.042), and hospital charges (p = 0.001) were significantly decreased. Postoperative fistula was recorded in five patients, with one case from the PPM group developing enteroatmospheric fistula. None of the complications had statistical difference. Early enteral nutrition (EEN) was successfully applied in 36 patients, with 19 cases from the MSVP group. The application of MSVP (odds ratio, 4.889; 95% confidence interval, 1.518-15.746) and EEN (odds ratio, 5.691; 95% confidence interval, 1.662-19.474) were independent predictors of successful fascial closure., Conclusion: The use of MSVP after open abdomen was feasible in septic patients with gastrointestinal fistula. MSVP, together with EEN therapy, should be recommended for such populations.

Objective: This study was designed to investigate the effect of exogenous complement C3 administration on outcomes of sepsis and identify an optimal time for this therapy., Materials and Methods: Colon ascendens stent peritonitis (CASP) was performed to induce sepsis in C57BL/6 mice, with sham-operated mice as control. Human purified C3 (HuC3, 1 mg) was administered via intraperitoneal injection, with 200 µl phosphate-buffered saline as control. Mice were categorized by the initiation time of HuC3 treatment. Survival, bacterial burden, vital organ damages, histology changes, and expression of C3 were compared between the groups., Results: CASP-induced sepsis caused rapid complement C3 depletion and severe organ damage. Vital organs suffered from substantial bacterial loads. Exogenous C3 applied in the early stage of sepsis was associated with attenuated organ injuries, enhanced bacterial clearance, and improved survival. Exogenous C3 application promoted the synthesis of C3 in the early stage of sepsis. It appears that 6 h post-CASP surgery is the optimal time for HuC3 therapy., Conclusion: The study confirmed the positive effect of exogenous C3 on treatment of polymicrobial sepsis. C3 supplementation prior to the appearance of complement depletion could protect vital organs and its administration in the early stage of sepsis should be encouraged .

Background: Although nutrition therapy is favorably considered as an assistant therapeutic measure in critical illness, little data evaluate its role in gastrointestinal fistula patients with severe sepsis after an open abdomen. The purpose of this study is to evaluate the role of early nutrition therapy in that population., Methods: This is a retrospective review of patients who underwent open abdomen management for gastrointestinal fistula and severe sepsis from January 2001 to June 2009. Nutrition therapy, fistula, abdominal closure, and demographics were noted. Succus entericus reinfusion (SER) was performed for high-output volume or multiple fistulae. Patients were divided into two groups based on whether enteral nutrition (EN) was initiated within 14 days after admission. Delivery route of nutrients, mortality, complications, and time to abdominal closure were compared among groups., Results: Eighty-two patients were included. Fifty-six (68.3%) patients survived to discharge. Forty-one (50%) patients received SER. EN was initiated within 14 days in 36 patients, with a mean initiation time at 8.3 ± 3.4 days; 46 patients did not start any EN within 14 days (29.9 ± 20.9 days). The mean age, BMI, APACHE II score, and fistula characteristics were similar between groups. The abdominal closure was accomplished more rapidly in patients fed within 14 days (142.8 vs 184.5 days, P = .017), with decreased mortality (11.1% vs 47.8%, P < .001)., Conclusions: Nutrition therapy plays an important role in the management of gastrointestinal fistula with severe sepsis. Early EN could be successfully delivered for that population, with improved mortality risk.

We investigated the therapeutic effects of parenteral fish oil (FO) on survival and fatty acid profile in plasma and erythrocyte membranes, T-lymphocyte subsets, and plasma cytokines in a rat model of sepsis. Adult male Sprague-Dawley rats were subjected to cecal ligation and puncture-induced sepsis. For recovery, central venous catheterization was performed 2 days before sepsis was induced. Rats were randomly assigned to receive normal saline (n = 20) or total parenteral nutrition (PN) containing a standard soybean oil emulsion (n = 20) or FO-supplemented TPN (n = 20) at the onset of sepsis for 5 days. In the control group, rats were challenged by sham operation and underwent appropriate control treatment (n = 10). Sepsis led to a high mortality and body weight loss compared with sham operation. Total PN supplemented with FO, but not without FO, improved the survival compared with normal saline. Furthermore, parenteral infusion of FO increased the concentrations of eicosapentaenoic acid and docosahexaenoic acid, as well as the ratio of (eicosapentaenoic acid + docosahexaenoic acid) to arachidonic acid both in plasma and erythrocyte membrane. In addition, FO-supplemented TPN improved the percentages of CD3 and CD3CD4 T cells, as well as the CD4/CD8 ratio in spleen. Meanwhile, the percentage of regulatory T cells (CD4CD25Foxp3) among CD4 T cells was reduced by FO-supplemented TPN. Fish oil-supplemented TPN attenuated the production of high-mobility group box 1 and IL-10 in plasma. Moreover, parenteral FO decreased the bacterial loads in peritoneal lavage, blood, lung, and spleen. The present study suggests that FO-supplemented TPN initiated at the onset of sepsis improves survival, beneficially alters the lipids profile in plasma and erythrocyte membrane, modulates immune function, and regulates inflammatory response in a rat model.

Background: The purpose of our study was to determine prospectively relationships between plasma mitochondrial deoxyribonucleic acid (mtDNA) concentration and clinical outcome in patients with intra-abdominal infections (IAIs) induced by severe abdominal trauma.Patients and Methods: The DNA was isolated from serum samples taken from patients with IAIs at hospital days zero, one, and two. Plasma mtDNA concentration was assessed by real-time polymerase chain reaction (PCR). The study population's clinical and laboratory data were analyzed.Results: The mtDNA damage-associated molecular patterns were expressed as a PCR threshold cycle number using four selected sequences. The patients with IAIs had significant higher plasma mtDNA than healthy control subjects. Patients with IAIs with sepsis apparently had elevated mtDNA levels compared with non-septic patients with IAIs (30.9 ± 2.0 vs. 28.7 ± 2.4; 33.3 ± 2.6 vs. 28.9 ± 2.4; 32.9 ± 1.6 vs. 31.2 ± 2.2; 33.1 ± 3.6 vs. 28.1 ± 2.2, respectively). Patients with IAIs in whom multiple organ dysfunction syndrome (MODS) developed also had increased mtDNA concentration compared with those who did not (31.0 ± 1.8 vs. 27.9 ± 1.8; 32.9 ± 2.4 vs. 27.8 ± 1.7; 32.9 ± 1.5 vs. 29.8 ± 1.7; 32.0 ± 3.8 vs. 27.1 ± 2.1, respectively). Baseline mtDNA concentration had high effectiveness in predicting death for patients with IAIs who had severe trauma using receiver operating characteristic analysis. Furthermore, serum mtDNA levels on admission correlated with the lactate concentration, but no significant correlations were found between mtDNA levels and levels of white blood cells, C-reactive protein, and procalcitonin.Conclusions: Plasma mtDNA was associated with the occurrence of sepsis, MODS, and death in patients with IAIs caused by severe abdominal trauma. [ABSTRACT FROM AUTHOR]