IgMA-enriched immunoglobulin in neutropenic patients with sepsis syndrome and septic shock: a randomized, controlled, multiple-center trial

OBJECTIVE: To evaluate the effect of intravenous IgMA-enriched immunoglobulin (ivIGMA) therapy on mortality in neutropenic patients with hematologic malignancies and sepsis syndrome or septic shock. DESIGN: Multiple-center, prospective randomized, controlled study. SETTING: Six university hospitals in Germany. PATIENTS: Patients were 211 neutropenic patients with sepsis syndrome or septic shock after chemotherapy for severe hematologic disorders between 1992 and 1999. INTERVENTIONS: Patients received 1300 mL of ivIGMA (7.8 g IgM, 7.8 g IgA, and 49.4 g IgG) infused intravenously within a period of 72 hrs or human albumin according to the same schedule as ivIGMA. MEASUREMENTS AND MAIN RESULTS: All-cause mortality at 28 days, sepsis-related mortality at 28 days, all-cause mortality at 60 days, mortality from septic shock, and mortality from microbiologically proven Gram-negative sepsis and septic shock were recorded. Immunoglobulin had no benefit over human albumin. The 28-day mortality rate was 26.2% and 28.2% in the ivIGMA and control patients, respectively (difference, 2.0% [95% confidence interval, -10.2 to 14.2 percentage points]). Likewise, the 60-day mortality rate did not differ between both arms (29.6% vs. 34.7% in the ivIGMA and control patients, respectively). Mortality rates in patients with sepsis syndrome (17.1% vs. 16.7%) and septic shock (51.9% vs. 54.8%) were also found to be similar between both groups. CONCLUSIONS: Intravenous ivIGMA had no beneficial effects in neutropenic patients with hematologic malignancies and sepsis syndrome and septic shock.     

Efficacy and safety of LY315920Na/S-5920, a selective inhibitor of 14-kDa group IIA secretory phospholipase A2, in patients with suspected sepsis and organ failure

OBJECTIVE: Concentrations of group IIA secretory phospholipase A, an inflammatory response mediator, are increased in the plasma of patients with sepsis and septic shock, and the extent of elevation is correlated with mortality. LY315920Na/S-5920 is a selective inhibitor of group IIA secretory phospholipase A that has been shown to inhibit serum group IIA secretory phospholipase A enzyme activity in patients with severe sepsis. The primary objectives of this study were to determine whether there was a dose-response relationship between two doses of LY315920Na/S-5920 compared with placebo in the reduction of 28-day all-cause mortality in patients with severe sepsis and to determine whether LY315920Na/S-5920 had an acceptable safety profile.(2) (2) (2) DESIGN: Multicenter, double-blind, placebo-controlled trial of two doses of LY315920Na/S-5920 in a parallel design. PATIENTS: A total of 586 patients with severe sepsis at 72 institutions in the United States.INTERVENTIONS Patients enrolled within 72 hrs from onset of first sepsis-induced organ failure were randomized (1:1:1) to low-dose LY315920Na/S-5920 (target plasma concentration of 200 ng/mL, n = 196), high-dose LY315920Na/S-5920 (800 ng/mL, n = 194), or placebo (n = 196). Study medication was administered as a constant-rate intravenous infusion for 168 hrs. MEASUREMENTS AND MAIN RESULTS: The study was stopped prematurely because it was unlikely that a statistically significant difference in mortality between LY315920Na/S-5920 and placebo would be found. There was no effect of LY315920Na/S-5920 on the primary end point of 28-day all-cause mortality across the entire study population. The 28-day all-cause mortality was distributed as follows: placebo group, 33.2% (65/196 patients); low-dose LY315920Na/S-5920, 37.2% (73/196); and high-dose LY315920Na/S-5920, 36.1% (70/194); p = .525. However, in a prospectively planned analysis, there was a favorable overall dose-response effect on 28-day all-cause mortality in patients administered LY315920Na/S-5920 within 18 hrs of onset of the first sepsis-induced organ failure. Among these patients, 28-day all-cause mortality was distributed as follows: placebo group, 43.5% (20/46 patients); low-dose LY315920Na/S-5920, 31.4% (16/51); and high-dose LY315920Na/S-5920, 20.8% (10/48); p = .018. CONCLUSIONS: Administration of LY315920Na/S-5920 had an acceptable safety profile in patients with severe sepsis. There was no overall survival benefit associated with the use of LY315920Na/S-5920 in this study. However, prospectively planned secondary analyses suggested that treatment with LY315920Na/S-5920 was associated with an improvement in survival in patients treated within 18 hrs of the first sepsis-induced organ failure.     

Plasmapheresis in severe sepsis and septic shock: a prospective,randomised, controlled trial

OBJECTIVE: To determine the therapeutic efficacy and safety of plasmapheresis in the treatment of patients with severe sepsis and septic shock. DESIGN: Prospective, randomised, clinical trial with a planned, midstudy, interim analysis. SETTING: Intensive care unit in a university hospital in Archangels, Russia. PATIENTS: Consecutive patients with severe sepsis or septic shock. INTERVENTIONS: One hundred and six patients were randomised to receive either standard therapy or an add-on treatment with plasmapheresis. MEASUREMENTS AND RESULTS: The primary endpoint was 28-day survival. Septic shock was diagnosed in 57% of the plasmapheresis-treated patients and 54% of the control patients. Mean APACHE III score at entry was 56.4 in the plasmapheresis group and 53.5 in the control group. The 28-day, all-cause mortality rate was 33.3% (18/54) in the plasmapheresis group and 53.8% (28/52) in the control group. This represents a relative risk for fatal outcome in the plasmapheresis group of 0.61, an absolute risk reduction of 20.5% and a number of patients needed to treat of 4.9. Apart from six transient episodes of hypotension and one allergic reaction to fresh frozen plasma, no adverse reactions were attributable to the plasmapheresis treatment in this study. CONCLUSIONS: Plasmapheresis may be an important adjuvant to conventional treatment to reduce mortality in patients with severe sepsis or septic shock. Plasmapheresis is a safe procedure in the treatment of septic patients. A prospective randomised multicentre trial is warranted to confirm our results and to determine which subgroups of septic patients will benefit most from this treatment modality.     

Selenium in Intensive Care (SIC): results of a prospective randomized, placebo-controlled, multiple-center study in patients with severe systemic inflammatory response syndrome, sepsis, and septic shock

OBJECTIVE: Sepsis is associated with an increase in reactive oxygen species and low endogenous antioxidative capacity. We postulated that high-dose supplementation of sodium-selenite would improve the outcome of patients with severe sepsis and septic shock. DESIGN: Prospective randomized, placebo-controlled, multiple-center trial. SETTING: Eleven intensive care units in Germany. PATIENTS: Patients were 249 patients with severe systemic inflammatory response syndrome, sepsis, and septic shock and an Acute Physiology and Chronic Health Evaluation (APACHE) III score >70. INTERVENTIONS: Patients received 1000 microg of sodium-selenite as a 30-min bolus injection, followed by 14 daily continuous infusions of 1000 microg intravenously, or placebo. MEASUREMENTS AND MAIN RESULTS: The primary end point was 28-day mortality; secondary end points were survival time and clinical course of APACHE III and logistic organ dysfunction system scores. In addition, selenium levels in serum, whole blood, and urine as well as serum glutathione-peroxidase-3 activity were measured. From 249 patients included, 11 patients had to be excluded. The intention-to-treat analysis of the remaining 238 patients revealed a mortality rate of 50.0% in the placebo group and 39.7% in the selenium-treated group (p = .109; odds ratio, 0.66; confidence interval, 0.39-1.1). A further 49 patients had to be excluded before the final analysis because of severe violations of the study protocol. In the remaining 92 patients of the study group, the 28-day mortality rate was significantly reduced to 42.4% compared with 56.7% in 97 patients of the placebo group (p = .049, odds ratio, 0.56; confidence interval, 0.32-1.00). In predefined subgroup analyses, the mortality rate was significantly reduced in patients with septic shock with disseminated intravascular coagulation (n = 82, p = .018) as well as in the most critically ill patients with an APACHE III score > or =102 (>75% quartile, n = 54, p = .040) or in patients with more than three organ dysfunctions (n = 83, p = .039). Whole blood selenium concentrations and glutathione peroxidase-3 activity were within the upper normal range during selenium treatment, whereas they remained significantly low in the placebo group. There were no side effects observed due to high-dose sodium-selenite treatment. CONCLUSIONS: The adjuvant treatment of patients with high-dose sodium-selenite reduces mortality rate in patients with severe sepsis or septic shock.     

Can corticosteroids reduce the mortality of patients with severe sepsis? A systematic review and meta-analysis

BackgroundThe effects of corticosteroids on clinical outcomes of patients with sepsis remains controversial. We aimed to further determine the effectiveness of corticosteroids in reducing mortality in adult patients with severe sepsis by comparison with placebo.MethodsPubmed, Embase, Medline, Cochrane Central Register of Controlled Trials (CENTRAL) as well as the Information Sciences Institute (ISI) Web of Science were searched for all controlled studies that compared corticosteroids and placebo in adult patients with severe sepsis. The primary outcome was the mortality 28-day mortality and the secondary outcomes were mortality at longest follow up, occurrence, and reoccurrence of septic shock.ResultsA total of 19 trials involving 7035 patients were pooled in our final analyses. No significant heterogeneity was found in any of the outcome measures. Compared with placebo, corticosteroids were associated with a lower 28-day mortality (RR 0.91, 95% CI 0.85–0.98, Z = 2.57, P = 0.01) both in patients having sepsis and in those who developed septic shock (RR 0.92, 95% CI 0.85–0.99, Z = 2.19, P = 0.03), while no significant difference was found in mortality with the longest follow up in patients either having sepsis (RR 0.94, 95% CI 0.89–1.00, Z = 1.93, P = 0.05), or occurrence (RR 0.83, 95% CI 0.56–1.24, Z = 0.90, P = 0.37) or reoccurrence of septic shock (RR 1.08, 95% CI 1.00–1.16, Z = 1.89, P = 0.06).ConclusionsCorticosteroids were effective in reducing the 28-day mortality in patients with severe sepsis and in those with septic shock.     

Recombinant platelet-activating factor acetylhydrolase to prevent acute respiratory distress syndrome and mortality in severe sepsis: Phase IIb,multicenter, randomized,placebo-controlled,clinical trial

OBJECTIVE: Platelet-activating factor (PAF) is a potent proinflammatory mediator implicated in the pathogenesis of both severe sepsis and acute respiratory distress syndrome. One of the regulatory pathways for PAF involves degradation to the inactive metabolite lyso-PAF by the enzyme PAF acetylhydrolase (PAF-AH). Because reduced concentrations of the natural form of PAF-AH have been reported in septic patients, the present study was conducted to determine whether treatment with recombinant human PAF-AH (rPAF-AH, Pafase) was safe when administered after the onset of severe sepsis and whether it decreases the prevalence of acute respiratory distress syndrome and 28-day all-cause mortality. DESIGN: A prospective, randomized, double-blind, placebo-controlled, multicenter trial. SETTING: Thirty-three medical and surgical intensive care units located in the United States. PATIENTS: A total of 127 patients with severe sepsis, but without established acute respiratory distress syndrome, were enrolled in the study. Randomization occurred within 12 hrs of the onset of severe sepsis. Patients then received 1.0 mg/kg rPAF-AH (n = 45), 5.0 mg/kg rPAF-AH (n = 39), or placebo (n = 43) administered intravenously, once daily, for five consecutive days. MEASUREMENTS AND MAIN RESULTS: Demographic and baseline clinical characteristics of the three treatment groups were similar, except for a significantly higher prevalence of respiratory tract infections as the cause of severe sepsis in patients treated with 1.0 mg/kg rPAF-AH. There were no treatment-related deaths, and the overall prevalence of adverse events was similar among rPAF-AH-treated and placebo-treated patients. There were no significant differences in the prevalence of acute respiratory distress syndrome among the three treatment groups. However, 28-day all-cause mortality was 21% in the 1.0 mg/kg rPAF-AH group, 28% in the 5.0 mg/kg rPAF-AH group, and 44% in the placebo group (overall chi-square p =.07; 1.0 mg/kg rPAF-AH vs. placebo, p =.03). A trend toward reduced multiple organ dysfunction also was observed in the 1.0 mg/kg rPAF-AH group compared with the placebo group (p =.11). CONCLUSION: The results from this study indicate that rPAF-AH was well tolerated and should be pursued as a potential new treatment to decrease mortality in patients with severe sepsis.     

Recombinant human platelet-activating factor acetylhydrolase for treatment of severe sepsis: results of a phase III, multicenter, randomized, double-blind, placebo-controlled, clinical trial

OBJECTIVE: Platelet-activating factor (PAF) and structurally-related oxidized phospholipids are proinflammatory mediators in systemic inflammatory states such as severe sepsis. The enzyme platelet-activating factor acetylhydrolase (PAF-AH) rapidly degrades PAF and oxidized phospholipids into inactive metabolites. Reduced PAF-AH activity has been observed in patients with severe sepsis and may contribute to their systemic inflammatory response and organ dysfunction. A previous clinical trial with recombinant human PAF-AH (rPAF-AH, Pafase) suggested that this treatment may decrease 28-day all-cause mortality in patients with severe sepsis. The current study was undertaken to confirm this result. DESIGN: A prospective, randomized, double-blind, placebo-controlled, multicenter, international trial. SETTING: One hundred forty-six intensive care units from nine countries. PATIENTS: Approximately 2,522 patients were planned to be enrolled < or =12 hrs after the onset of severe sepsis. Eligible patients were randomized to receive either rPAF-AH 1.0 mg/kg or placebo administered intravenously once daily for five consecutive days. MEASUREMENTS AND MAIN RESULTS: The study was terminated based on the recommendation of an independent data and safety monitoring committee after the second of three planned interim analyses, and the enrollment of 1,425 patients. rPAF-AH treatment was well tolerated among the 1,261 patients included in the interim analysis (643 rPAF-AH and 618 placebo), but did not decrease 28-day all-cause mortality compared with placebo (25% for rPAF-AH vs. 24% for placebo; relative risk, 1.03; 95% confidence interval, 0.85-1.25; p =.80). There were no statistically significant differences between treatment groups in any of the secondary efficacy end points. The overall incidence of adverse events was similar among rPAF-AH and placebo-treated patients, and no rPAF-AH-treated patients developed antibodies to PAF-AH. CONCLUSIONS: rPAF-AH was well tolerated and not antigenic, but did not decrease 28-day all-cause mortality in patients with severe sepsis.     

Sepsis incidence and outcome: contrasting the intensive care unit with the hospital ward

OBJECTIVE: To describe the outcome of patients with sepsis according to location on a ward or in an intensive care unit. DESIGN: Prospective multicentered observational study. SETTING: Three academic hospitals in Madrid, Spain. PATIENTS: Consecutive patients with sepsis admitted to participating hospitals from March 1 to June 30, 2003. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: During the study period, 15,852 patients >18 yrs of age were admitted. Sepsis was identified in 702 patients, giving an estimated cumulative incidence rate of 367 cases per 100,000 adult area residents per year and a cumulative incidence rate among patients admitted to the hospital of 4.4%. Most septic patients had a community-acquired infection (71%). Severe sepsis developed in 199 patients (incidence rate, 104 cases per 100,000 adult area residents per year), and 59 patients developed septic shock (incidence rate, 31 cases per 100,000 adult area residents per year). Most of the patients met the criteria for severe sepsis or septic shock on the same day that they would have qualified for the septic status one step down the scale. In the other patients, the median time between sepsis and severe sepsis was 2 days (interquartile range, 2-5) and between severe sepsis and septic shock was 3 days (interquartile range, 1-4). Only 32% of severe sepsis patients received intensive care. The hospital mortality for all septic patients was 12.8%; for severe sepsis, 20.7%; and for septic shock, 45.7%. CONCLUSIONS: This study shows the high incidence of sepsis in a general population of patients admitted to hospital. A significant proportion of patients with severe sepsis are not transferred to the intensive care unit.     

Score-based immunoglobulin G therapy of patients with sepsis: the SBITS study

OBJECTIVE: Intravenous immunoglobulin as an adjunctive treatment in sepsis was regarded as promising by a Cochrane meta-analysis of smaller trials. In this phase III multicenter trial, we assessed whether intravenous immunoglobulin G (ivIgG) reduced 28-day mortality and improved morbidity in patients with score-defined severe sepsis. DESIGN: Randomized, double-blind, placebo-controlled, multicenter trial. SETTING: Twenty-three medical and surgical intensive care units in university centers and large teaching hospitals. PATIENTS: Patients (n = 653) with score-defined sepsis (sepsis score 12-27) and score-defined sepsis-induced severity of disease (Acute Physiology and Chronic Health Evaluation II score 20-35). INTERVENTIONS: Patients were assigned to receive either placebo or ivIgG (day 0, 0.6 g/kg body weight; day 1, 0.3 g/kg body weight). MEASUREMENTS AND MAIN RESULTS: The prospectively defined primary end point was death from any cause after 28 days. Prospectively defined secondary end points were 7-day all-cause mortality, short-term change in morbidity, and pulmonary function at day 4. Six hundred fifty-three patients from 23 active centers formed the intention-to-treat group, 624 patients the per-protocol group (placebo group, n = 303; ivIgG group, n = 321). The 28-day mortality rate was 37.3% in the placebo group and 39.3% in the ivIgG group and thus not significantly different (p = .6695). Seven-day mortality was not reduced, and 4-day pulmonary function was not improved. Drug-related adverse events were rare in both groups. Exploratory findings revealed a 3-day shortening of mechanical ventilation in the surviving patients and no effect of ivIgG on plasma levels of interleukin-6 and tumor necrosis factor receptors I and II. CONCLUSIONS: In patients with score-defined severe sepsis, ivIgG with a total dose of 0.9 g/kg body weight does not reduce mortality.     

Impact of recent intravenous chemotherapy on outcome in severe sepsis and septic shock patients with hematological malignancies

Objective To compare the characteristics and outcome of patients with hematological malignancies referred to the ICU with severe sepsis and septic shock who had or had not received recent intravenous chemotherapy, defined as within 3 weeks prior to ICU admission. Design and setting Retrospective observational cohort study on prospectively collected data in a medical ICU of a university hospital. Patients 186 ICU patients with hematological malignancies with severe sepsis or septic shock (2000–2006). Measurements and results There were 77 patients admitted with severe sepsis and 109 with septic shock; 91 (49%) had received recent intravenous chemotherapy. Patients with recent chemotherapy more often had a high-grade malignancy and were more often neutropenic, less often had pulmonary infiltrates, and less often required mechanical ventilation. ICU, 28-day, in-hospital, and 6-month mortality rates were 33% vs. 48.4%, 40.7% vs. 57.4%, 45.1% vs. 58.9%, and 50.5% vs. 63.2% in patients with and without recent chemotherapy, respectively. Logistic regression identified four variables independently associated with 28-day mortality: SOFA score at ICU admission, pulmonary site of infection, and fungal infection were associated with worse outcome whereas previous intravenous chemotherapy was protective at borderline significance. After adjustment with a propensity score for recent chemotherapy, chemotherapy was not associated with outcome. Conclusions Patients referred to the ICU with severe sepsis and septic shock complicating active chemotherapeutic treatment have better prognosis than commonly perceived. This article is discussed in the editorial available at: .     

Derivation of a screen to identify severe sepsis and septic shock in the ED-BOMBARD vs. SIRS and qSOFA

Study objectiveTo predict severe sepsis/septic shock in ED patients.MethodsWe conducted a retrospective case-control study of patients ≥18 admitted to two urban hospitals with a combined ED census of 162,000.Study cases included patients with severe sepsis/septic shock admitted via the ED. Controls comprised admissions without severe sepsis/septic shock. Using multivariate logistic regression, a prediction rule was constructed. The model's AUROC was internally validated using 1000 bootstrap samples.Results143 study and 286 control patients were evaluated. Features predictive of severe sepsis/septic shock included: SBP ≤ 110 mm Hg, shock index/SI ≥ 0.86, abnormal mental status or GCS < 15, respirations ≥ 22, temperature ≥ 38C, assisted living facility residency, disabled immunity.Two points were assigned to SI and temperature with other features assigned one point (mnemonic: BOMBARD). BOMBARD was superior to SIRS criteria (AUROC 0.860 vs. 0.798, 0.062 difference, 95% CI 0.022–0.102) and qSOFA scores (0.860 vs. 0.742, 0.118 difference, 95% CI 0.081–0.155) at predicting severe sepsis/septic shock. A BOMBARD score ≥ 3 was more sensitive than SIRS ≥ 2 (74.8% vs. 49%, 25.9% difference, 95% CI 18.7–33.1) and qSOFA ≥ 2 (74.8% vs. 33.6%, 41.2% difference, 95% CI 33.2–49.3) at predicting severe sepsis/septic shock. A BOMBARD score ≥ 3 was superior to SIRS ≥ 2 (76% vs. 45%, 32% difference, 95% CI 10–50) and qSOFA ≥ 2 (76% vs. 29%, 47% difference, 95% CI 25–63) at predicting sepsis mortality.ConclusionBOMBARD was more accurate than SIRS and qSOFA at predicting severe sepsis/septic shock and sepsis mortality.     

Clinical spectrum, frequency, and significance of myocardial dysfunction in severe sepsis and septic shock

ObjectiveTo determine the frequency and spectrum of myocardial dysfunction in patients with severe sepsis and septic shock using transthoracic echocardiography and to evaluate the impact of the myocardial dysfunction types on mortality.Patients and MethodsA prospective study of 106 patients with severe sepsis or septic shock was conducted from August 1, 2007, to January 31, 2009. All patients underwent transthoracic echocardiography within 24 hours of admission to the intensive care unit. Myocardial dysfunction was classified as left ventricular (LV) diastolic, LV systolic, and right ventricular (RV) dysfunction. Frequency of myocardial dysfunction was calculated, and demographic, hemodynamic, and physiologic variables and mortality were compared between the myocardial dysfunction types and patients without cardiac dysfunction.ResultsThe frequency of myocardial dysfunction in patients with severe sepsis or septic shock was 64% (n=68). Left ventricular diastolic dysfunction was present in 39 patients (37%), LV systolic dysfunction in 29 (27%), and RV dysfunction in 33 (31%). There was significant overlap. The 30-day and 1-year mortality rates were 36% and 57%, respectively. There was no difference in mortality between patients with normal myocardial function and those with left, right, or any ventricular dysfunction.ConclusionMyocardial dysfunction is frequent in patients with severe sepsis or septic shock and has a wide spectrum including LV diastolic, LV systolic, and RV dysfunction types. Although evaluation for the presence and type of myocardial dysfunction is important for tailoring specific therapy, its presence in patients with severe sepsis and septic shock was not associated with increased 30-day or 1-year mortality.     

氢化可的松在肺部感染致感染性休克中应用的前瞻性临床研究

目的探讨早期小剂量氢化可的松对肺部感染致感染性休克患者病死率的影响。 方法采用前瞻性随机对照临床研究（RCT）方法,连续选择2015年9月至2017年2月收住于江苏省苏北人民医院重症监护病房（ICU）的54例肺部感染致感染性休克患者。将患者随机分为氢化可的松组和对照组。两组患者一旦使用血管活性药物,立即同时予以研究药物（氢化可的松或0.9%氯化钠溶液）持续静脉泵入。记录患者28 d病死率、住院病死率、休克逆转率、住ICU及住院时间等,评估早期小剂量氢化可的松的使用对肺部感染致感染性休克患者预后的影响。 结果两组患者在28 d病死率、住院病死率、休克逆转率、住ICU时间及住院时间等方面差异均无统计学意义（均P>0.05）。二分类Logistic回归模型分析显示28 d内机械通气时间是肺部感染致感染性休克患者28 d病死率的独立影响因素（OR=0.654,95%CI：0.498~0.860,P=0.002）。而小剂量氢化可的松的应用在Logistic回归模型分析中差异无统计学意义（P>0.05）。 结论在肺部感染致感染性休克患者中早期应用小剂量氢化可的松,并不能降低病死率、住ICU时间及住院时间。     

Treatment effects of high-dose antithrombin without concomitant heparin in patients with severe sepsis with or without disseminated intravascular coagulation

BACKGROUND: Disseminated intravascular coagulation (DIC) is a serious complication of sepsis that is associated with a high mortality. OBJECTIVES: Using the adapted International Society on Thrombosis and Haemostasis (ISTH) diagnostic scoring algorithm for DIC, we evaluated the treatment effects of high-dose antithrombin (AT) in patients with severe sepsis with or without DIC. PATIENTS AND METHODS: From the phase III clinical trial in severe sepsis (KyberSept), 563 patients were identified (placebo, 277; AT, 286) who did not receive concomitant heparin and had sufficient data for DIC determination. RESULTS: At baseline, 40.7% of patients (229 of 563) had DIC. DIC in the placebo-treated patients was associated with an excess risk of mortality (28-day mortality: 40.0% vs. 22.2%, P < 0.01). AT-treated patients with DIC had an absolute reduction in 28-day mortality of 14.6% compared with placebo (P = 0.02) whereas in patients without DIC no effect on 28-day mortality was seen (0.1% reduction in mortality; P = 1.0). Bleeding complications in AT-treated patients with and without DIC were higher compared with placebo (major bleeding rates: 7.0% vs. 5.2% for patients with DIC, P = 0.6; 9.8% vs. 3.1% for patients without DIC, P = 0.02). CONCLUSIONS: High-dose AT without concomitant heparin in septic patients with DIC may result in a significant mortality reduction. The adapted ISTH DIC score may identify patients with severe sepsis who potentially benefit from high-dose AT treatment.     

Hypothermia and cytokines in septic shock

Background: Hypothermic patients with sepsis have been reported to have a higher mortality than febrile septic patients. The failure to mount a febrile response in sepsis is poorly understood. Since the proinflammatory cytokines play a crucial role in the genesis of fever, we postulated that hypothermic patients with sepsis would have lower circulating levels of these cytokines than febrile patients¶Methods: Patients with septic shock who were enrolled into the placebo limb of the North American study of the safety and efficacy of murine monoclonal antibody to tumor necrosis factor for the treatment of septic shock (NORASEPT II) were analyzed. Body temperature, interleukin-6, tumor necrosis factor α, soluble tumor necrosis factor receptor-55, and soluble tumor necrosis factor receptor-75 concentrations were measured at enrollment. The study population was divided into a hypothermic (temperature ≤ 35.6 °C) and a febrile group (temperature ≥ 38.3 °C) according to the core temperature at enrollment (normothermia was an exclusion criteria). Clinical, demographic, and cytokine data were extracted, allowing for comparisons between these two groups of patients. In addition, the correlation between the core body temperature and cytokine levels at enrollment was determined¶Results: A complete data set was available for 930 patients; 195 patients (21 %) were hypothermic at enrollment. The 28-day survival of these patients was significantly lower than that of the febrile patients (34 % vs. 59 %, p < 0.001). Hypothermia (and enrollment temperature) were independent predictors of mortality. The hypothermic patients had a higher incidence of organ dysfunction at enrollment than the febrile patients. There was no significant difference in the cytokine profile between the two groups of patients. In addition, there was no correlation between the core body temperature at enrollment and the circulating levels of cytokines measured¶Conclusion: Hypothermic patients with septic shock have a significantly higher mortality with a higher incidence of organ dysfunction than febrile septic shock patients. The hypothermia in these patients cannot be explained by lower levels of circulating proinflammatory cytokines.     

心肌脂肪酸结合蛋白在脓毒症临床预后的预测价值研究

目的 探讨心肌脂肪酸结合蛋白(heart-type fatty acid-binding protein,H-FABP)在脓毒症患者临床预后的预测价值,提高脓毒症患者救治率.方法 采用前瞻性病例对照研究,纳入2014年10月至2015年10月就诊于新疆医科大学第一附属医院脓毒血症患者共50例,根据2012年脓毒症诊疗指南分为脓毒症组(16例)、严重脓毒症组(14例)、脓毒性休克组(20例);根据28 d后是否存活分为死亡组(22例)与存活组(28例).记录性别、年龄、族别等基本资料,入急诊6h内完善急性生理与慢性健康状况(APACHEⅡ)评分,H-FABP,B型脑钠利肽(B-typenatriuretic,BNP)、肌酸激酶(creatine kinase,CK)、肌酸激酶同工酶(creatine kinase isoenzymes,CK-MB)、肌钙蛋白(troponin-T,cTn-T)等指标.统计学采用SPSS 21.0软件,计量资料t检验或秩和检验、计数资料采用x2检验,非正态分布资料采用秩合检验,对生存状况进行ROC曲线分析.结果 脓毒性休克组的H-FABP明显高于严重脓毒症组和脓毒症组(P＜0.01).脓毒性休克组28天死亡率(80％)与严重脓毒症组28 d病死率高于脓毒症组28天死亡率(12.5％)(P＜0.01).死亡组H-FABP、BNP、cTn-T、CK、CK-MB均明显高于存活组,两组间差异具有统计学意义(P＜0.05);对H-FABP和BNP行ROC曲线结果提示H-FABP (AUC=0.748,P=0.003,95％CI:0.605 ～0.890)优于BNP (AUC =0.714,P=0.010,95％ CI:0.573 ～0.856),当H-FABP取 9.902 ng/mL,敏感度82.1％,特异度63.6％.H-FABP对28 d病死率的预测具有一定价值.结论 脓毒性休克组病死率明显高于严重脓毒血症及脓毒症组.H-FABP相比BNP、CK、CK-MB,对脓毒症患者预后具有较大的预测价值,随病情加重而增高.H-FABP可以预测28 d病死率.     

Effects of enteral feeding with eicosapentaenoic acid, gamma-linolenic acid, and antioxidants in mechanically ventilated patients with severe sepsis and septic shock

OBJECTIVES: Enteral diets enriched with eicosapentaenoic acid (EPA), gamma-linolenic acid (GLA), and antioxidants have previously been shown to improve outcomes in patients with acute respiratory distress syndrome. Several studies using animal models of sepsis demonstrate that enteral nutrition enriched with omega-3 fatty acids reduces mortality rate. This study investigated whether an enteral diet enriched with EPA, GLA, and antioxidant vitamins can improve outcomes and reduce 28-day all-cause mortality in patients with severe sepsis or septic shock requiring mechanical ventilation. DESIGN: Prospective, double-blind, placebo-controlled, randomized trial. SETTING: Three different intensive care units of a tertiary hospital in Brazil. PATIENTS: The study enrolled 165 patients. INTERVENTIONS: Patients were randomized to be continuously tube-fed with either a diet enriched with EPA, GLA, and elevated antioxidants or an isonitrogenous and isocaloric control diet, delivered at a constant rate to achieve a minimum of 75% of basal energy expenditure x 1.3 during a minimum of 4 days. MEASUREMENTS AND MAIN RESULTS: Patients were monitored for 28 days. Patients who were fed with the study diet experienced a significant reduction in mortality rate compared with patients fed with the control diet, the absolute mortality reduction amounting to 19.4% (p = .037). The group who received the study diet also experienced significant improvements in oxygenation status, more ventilator-free days (13.4 +/- 1.2 vs. 5.8 +/- 1.0, p < .001), more intensive care unit (ICU)-free days (10.8 +/- 1.1 vs. 4.6 +/- 0.9, p < .001), and a lesser development of new organ dysfunctions (p < .001). CONCLUSIONS: In patients with severe sepsis or septic shock and requiring mechanical ventilation and tolerating enteral nutrition, a diet enriched with EPA, GLA, and elevated antioxidants contributed to better ICU and hospital outcomes and was associated with lower mortality rates.     

A double-blind placebo-controlled study of an infusion of lexipafant (Platelet-activating factor receptor antagonist) in patients with severe sepsis

Platelet-activating factor (PAF) is a potent endogenous proinflammatory mediator implicated in the pathogenesis of septic shock. A double-blind randomized placebo-controlled trial of an intravenous PAF receptor antagonist (lexipafant) was conducted with 131 adult Thai patients with suspected severe sepsis (66 of whom had positive blood cultures). Detailed serial clinical, biochemical, and cytokine measurements were performed. Lexipafant treatment was well tolerated. The 28-day mortality in the lexipafant group (61.4%) was similar to that in the placebo group (62.6%). There was also no evidence that lexipafant affected clinical or biochemical measures of disease severity or the profile of sequentially measured plasma cytokine levels. PAF may not have an important role in the pathogenesis of severe sepsis.     

Efficacy and safety of the monoclonal anti-tumor necrosis factor antibody F(ab')2 fragment afelimomab in patients with severe sepsis and elevated interleukin-6 levels

OBJECTIVE: To evaluate whether administration of afelimomab, an anti-tumor necrosis factor F(ab')2 monoclonal antibody fragment, would reduce 28-day all-cause mortality in patients with severe sepsis and elevated serum levels of IL-6. DESIGN: Prospective, randomized, double-blind, placebo-controlled, multiple-center, phase III clinical trial. SETTING: One hundred fifty-seven intensive care units in the United States and Canada. PATIENTS: Subjects were 2,634 patients with severe sepsis secondary to documented infection, of whom 998 had elevated interleukin-6 levels. INTERVENTIONS: Patients were stratified into two groups by means of a rapid qualitative interleukin-6 test kit designed to identify patients with serum interleukin-6 levels above (test positive) or below (test negative) approximately 1000 pg/mL. Of the 2,634 patients, 998 were stratified into the test-positive group, 1,636 into the test-negative group. They were then randomly assigned 1:1 to receive afelimomab 1 mg/kg or placebo for 3 days and were followed for 28 days. The a priori population for efficacy analysis was the group of patients with elevated baseline interleukin-6 levels as defined by a positive rapid interleukin-6 test result. MEASUREMENTS AND MAIN RESULTS: In the group of patients with elevated interleukin-6 levels, the mortality rate was 243 of 510 (47.6%) in the placebo group and 213 of 488 (43.6%) in the afelimomab group. Using a logistic regression analysis, treatment with afelimomab was associated with an adjusted reduction in the risk of death of 5.8% (p = .041) and a corresponding reduction of relative risk of death of 11.9%. Mortality rates for the placebo and afelimomab groups in the interleukin-6 test negative population were 234 of 819 (28.6%) and 208 of 817 (25.5%), respectively. In the overall population of interleukin-6 test positive and negative patients, the placebo and afelimomab mortality rates were 477 of 1,329 (35.9%)and 421 of 1,305 (32.2%), respectively. Afelimomab resulted in a significant reduction in tumor necrosis factor and interleukin-6 levels and a more rapid improvement in organ failure scores compared with placebo. The safety profile of afelimomab was similar to that of placebo. CONCLUSIONS: Afelimomab is safe, biologically active, and well tolerated in patients with severe sepsis, reduces 28-day all-cause mortality, and attenuates the severity of organ dysfunction in patients with elevated interleukin-6 levels.