Background: Timely administration of antibiotics is one of the most important interventions in reducing mortality in sepsis. However, administering antibiotics within a strict time threshold in all patients suspected with sepsis will require huge amount of effort and resources and may increase the risk of unintentional exposure to broad-spectrum antibiotics in patients without infection with its consequences. Thus, controversy still exists on whether clinicians should target different time-to-antibiotics thresholds for patients with sepsis versus septic shock. Methods: This study analyzed prospectively collected data from an ongoing multicenter cohort of patients with sepsis identified in the emergency department. Adjusted odds ratios (ORs) were compared for in-hospital mortality of patients who had received antibiotics within 1 h to that of those who did not. Spline regression models were used to assess the association of time-to-antibiotics as continuous variables and increasing risk of in-hospital mortality. The differences in the association between time-to-antibiotics and in-hospital mortality were assessed according to the presence of septic shock. Results: Overall, 3035 patients were included in the analysis. Among them, 601 (19.8%) presented with septic shock, and 774 (25.5%) died. The adjusted OR for in-hospital mortality of patients whose time-to-antibiotics was within 1 h was 0.78 (95% confidence interval [CI] 0.61–0.99; p = 0.046). The adjusted OR for in-hospital mortality was 0.66 (95% CI 0.44–0.99; p = 0.049) and statistically significant in patients with septic shock, whereas it was 0.85 (95% CI 0.64–1.15; p = 0.300) in patients with sepsis but without shock. Among patients who received antibiotics within 3 h, those with septic shock showed 35% (p = 0.042) increased risk of mortality for every 1-h delay in antibiotics, but no such trend was observed in patients without shock. Conclusion: Timely administration of antibiotics improved outcomes in patients with septic shock; however, the association between early antibiotic administration and outcome was not as clear in patients with sepsis without shock.

Introduction: Fever is frequently observed in critically ill patients. An independent association of fever with increased mortality has been observed in non-neurological critically ill patients with mixed febrile etiology. The association of fever and antipyretics with mortality, however, may be different between infective and non-infective illness. Methods: We designed a prospective observational study to investigate the independent association of fever and the use of antipyretic treatments with mortality in critically ill patients with and without sepsis. We included 1,425 consecutive adult critically ill patients (without neurological injury) requiring > 48 hours intensive care admitted in 25 ICUs. We recorded four-hourly body temperature and all antipyretic treatments until ICU discharge or 28 days after ICU admission, whichever occurred first. For septic and non-septic patients, we separately assessed the association of maximum body temperature during ICU stay (MAX_ICU) and the use of antipyretic treatments with 28-day mortality. Results: We recorded body temperature 63,441 times. Antipyretic treatment was given 4,863 times to 737 patients (51.7%). We found that treatment with non-steroidal anti-inflammatory drugs (NSAIDs) or acetaminophen independently increased 28-day mortality for septic patients (adjusted odds ratio: NSAIDs: 2.61, P = 0.028, acetaminophen: 2.05, P = 0.01), but not for non-septic patients (adjusted odds ratio: NSAIDs: 0.22, P = 0.15, acetaminophen: 0.58, P = 0.63). Application of physical cooling did not associate with mortality in either group. Relative to the reference range (MAX_ICU 36.5°C to 37.4°C), MAX_ICU ≥ 39.5°C increased risk of 28-day mortality in septic patients (adjusted odds ratio 8.14, P = 0.01), but not in non-septic patients (adjusted odds ratio 0.47, P = 0.11). Conclusions: In non-septic patients, high fever (≥ 39.5°C) independently associated with mortality, without association of administration of NSAIDs or acetaminophen with mortality. In contrast, in septic patients, administration of NSAIDs or acetaminophen independently associated with 28-day mortality, without association of fever with mortality. These findings suggest that fever and antipyretics may have different biological or clinical or both implications for patients with and without sepsis. Trial registration: ClinicalTrials.gov: NCT00940654

Rationale: Sepsis, a life-threatening organ dysfunction caused by a dysregulated host response to infection, is a major public health concern with high mortality and morbidity. Although inflammatory responses triggered by infection are crucial for host defense against invading microbes, the excessive inflammation often causes tissue damage leading to organ dysfunction. Resolution of inflammation, an active immune process mediated by endogenous lipid mediators (LMs), is important to maintain host homeostasis. Objectives: We sought to determine the role of the nucleotide-binding domain, leucine-rich repeat–containing receptor, pyrin domain–containing-3 (NLRP3) inflammasome in polymicrobial sepsis and regulation of LM biosynthesis. Methods: We performed cecal ligation and puncture (CLP) using mice lacking NLRP3 inflammasome-associated molecules to assess mortality. Inflammation was evaluated by using biologic fluids including plasma, bronchoalveolar, and peritoneal lavage fluid. Local acting LMs in peritoneal lavage fluid from polymicrobacterial septic mice were assessed by mass spectrometry–based metabololipidomics. Measurements and Main Results: Genetic deficiency of NLRP3 inhibited inflammatory responses and enhanced survival of CLP-induced septic mice. NLRP3 deficiency reduced proinflammatory LMs and increased proresolving LM, lipoxin B4 (LXB4) in septic mice, and in macrophages stimulated with LPS and ATP. Activation of the NLRP3 inflammasome induced caspase-7 cleavage and pyroptosis. Caspase-7 deficiency similarly reduced inflammation and mortality in CLP-induced sepsis, and increased LXB4 production in vivo and in vitro. Exogenous application of LXB4 reduced inflammation, pyroptosis, and mortality of mice after CLP. Conclusions: Genetic deficiency of NLRP3 promoted resolution of inflammation in polymicrobial sepsis by relieving caspase-7–dependent repression of LXB4 biosynthesis, and increased survival potentially via LXB4 production and inhibition of proinflammatory cytokines.

Introduction: De-escalation therapy is a strategy currently used for the management of nosocomial pneumonia. In this study, we evaluated clinical outcomes and risk factors related to de-escalation therapy in patients with intensive care unit (ICU)-acquired pneumonia. Methods: This was a retrospective observational cohort study of ICU patients who developed pneumonia more than 48 hours after admission to the ICU at Samsung Medical Center from September 2004 to December 2007. Results: The 137 patients comprised 44 (32.1%) who received de-escalation therapy and 93 in the non-de-escalation group. The de-escalation group showed a lower pneumonia-related mortality rate than the non-de-escalation group by day 14 (2.3% vs. 10.8%, respectively; P = 0.08) and by day 30 (2.3% vs. 14%, respectively; P = 0.03) after the diagnosis of pneumonia. The variables independently associated with ICU-acquired pneumonia-related mortality included the Acute Physiology and Chronic Health Evaluation II (APACHE II) score and the modified Clinical Pulmonary Infection Score (CPIS) after 5 days with pneumonia. The non-de-escalation group had significantly higher APACHE II score and modified CPIS after 5 days with ICU-acquired pneumonia compared to the de-escalation group. Among all patients, 20.4% (28 of 137) had negative cultures for pathogens, and 42.9% (12 of 28) received de-escalation therapy. The latter 12 patients received de-escalation therapy and survived 30 days after the diagnosis of pneumonia. Conclusions: Patients in the de-escalation group showed a significantly lower mortality rate compared to patients in the non-de-escalation group. De-escalation therapy can be safely provided to patients with ICU-acquired pneumonia if they are clinically stable by day 5, even in those whose respiratory specimen cultures yield no specific pathogens.

Introduction: The aim of this study is to evaluate the effects of emergency department (ED) crowding on the implementation of tasks in the early resuscitation bundle during acute care of patients with severe sepsis and septic shock, as recommended by the Surviving Sepsis Campaign guidelines. Methods: We analyzed the sepsis registry from August 2008 to March 2012 for patients presenting to an ED of a tertiary urban hospital and meeting the criteria for severe sepsis or septic shock. The ED occupancy rate, which was defined as the total number of patients in the ED divided by the total number of ED beds, was used for measuring the degree of ED crowding. It was categorized into three groups (low; intermediate; high crowding). The primary endpoint was the overall compliance with the entire resuscitation bundle. Results: A total of 770 patients were enrolled. Of the eligible patients, 276 patients were assigned to the low crowding group, 250 patients to the intermediate crowding group, and 244 patients to the high crowding group (ED occupancy rate: ≤ 115; 116–149; ≥ 150%). There was significant difference in compliance rates among the three groups (31.9% in the low crowding group, 24.4% in the intermediate crowding group, and 16.4% in the high crowding group, P < 0.001). In a multivariate model, the high crowding group had a significant association with lower compliance (adjusted odds ratio (OR), 0.44; 95% confidence interval (CI), 0.26 to 0.76; P = 0.003). When the ED occupancy rate was included as a continuous variable in the model, it had also a negative correlation with the overall compliance (OR of 10% increase of the ED occupancy rate, 0.90; 95% CI, 0.84 to 0.96, P = 0.002). Conclusions: ED crowding was significantly associated with lower compliance with the entire resuscitation bundle and decreased likelihood of the timely implementation of the bundle elements.