Methotrexate Ameliorates Systemic Inflammation and Septic Associated-Lung Damage in a Cecal Ligation and Puncture Septic Rat Model.

BACKGROUND: Sepsis is a serious, heterogeneous clinical entity produced by a severe and systemic host inflammatory response to infection. Methotrexate (MTX) is a folate-antagonist that induces the generation of adenosine and also inhibits JAK/STAT pathway; MTX it is widely used as an anti-inflammatory drug to control the immune system. OBJECTIVE: The aim of this study was to assess the beneficial effects of a single and low dose of MTX in the systemic response and acute lung injury (ALI) induced by sepsis. As in the clinics, we treated our animals with antibiotics and fluids and performed the source control to mimic the current clinic treatment. METHODS AND MAIN RESULTS: Sepsis was induced in rats by a cecal ligation puncture (CLP) procedure. Six hours after induction of sepsis, we proceeded to the source control; fluids and antibiotics were administered at 6 h and 24 h after CLP. MTX (2.5 mg/Kg) was administered 6 h after the first surgery in one CLP experimental group and to one Sham group. A protective effect of MTX was observed through a significant reduction of pro-inflammatory cytokines and a decrease infiltration of inflammatory cells in the lung. In addition, we found a regulation in adenosine receptor A2aR and the metalloproteinases by MTX. CONCLUSION: A single, low dose of MTX attenuates sepsis lung-associated damage by decreasing pro-inflammatory response, infiltration of pro-inflammatory cells and avoiding defective tissue lung remodeling.

Trends in the incidence and mortality of patients with community-acquired septic shock 2003-2016.

PURPOSE: To evaluate the incidence and mortality of adult patients with community-acquired septic shock (CASS) and the influence of source control (SC) and other risk factors on the outcome. MATERIAL AND METHODS: The study included patients with CASS admitted to the ICU at a university hospital (2003-2016). Multivariate analyses were performed to identify risk factors of ICU mortality. RESULTS: A total of 625 patients were included. The incidence showed an average annual increase of 4.9% and the mortality an average annual decrease of 1.4%. The patients who required SC showed a lower mortality (20.4%) than patients who did not require SC (31.3%) (p = 0.002). However, the evolution in mortality was different: Mortality decreased in patients who did not require SC (from 56.3% to 20%; p = 0.02), but did not differ in those who required SC (from 21.4% to 27.6%; p = 0.43). In the multivariate analysis, severity at admission, age, alcoholism, cirrhosis, ARDS, neutropenia and thrombocytopenia were associated with worse outcome, whereas appropriate antibiotic treatment and adequate SC were independently associated with better survival. CONCLUSIONS: The incidence of CASS increased and the ICU mortality decreased during the study period. The mortality was mainly due to a decrease in mortality in infections not requiring SC.

Impact of Source Control in Patients With Severe Sepsis and Septic Shock.

OBJECTIVES: Time to clearance of pathogens is probably critical to outcome in septic shock. Current guidelines recommend intervention for source control within 12 hours after diagnosis. We aimed to determine the epidemiology of source control in the management of sepsis and to analyze the impact of timing to source control on mortality. DESIGN: Prospective observational analysis of the Antibiotic Intervention in Severe Sepsis study, a Spanish national multicenter educational intervention to improve antibiotherapy in sepsis. SETTING: Ninety-nine medical-surgical ICUs in Spain. PATIENTS: We enrolled 3,663 patients with severe sepsis or septic shock during three 4-month periods between 2011 and 2013. INTERVENTIONS: Source control and hospital mortality. MEASUREMENTS AND MAIN RESULTS: A total of 1,173 patients (32%) underwent source control, predominantly for abdominal, urinary, and soft-tissue infections. Compared with patients who did not require source control, patients who underwent source control were older, with a greater prevalence of shock, major organ dysfunction, bacteremia, inflammatory markers, and lactic acidemia. In addition, compliance with the resuscitation bundle was worse in those undergoing source control. In patients who underwent source control, crude ICU mortality was lower (21.2% vs 25.1%; p = 0.010); after adjustment for confounding factors, hospital mortality was also lower (odds ratio, 0.809 [95% CI, 0.658-0.994]; p = 0.044). In this observational database analysis, source control after 12 hours was not associated with higher mortality (27.6% vs 26.8%; p = 0.789). CONCLUSIONS: Despite greater severity and worse compliance with resuscitation bundles, mortality was lower in septic patients who underwent source control than in those who did not. The time to source control could not be linked to survival in this observational database.

Central venous-to-arterial carbon dioxide difference combined with arterial-to-venous oxygen content difference is associated with lactate evolution in the hemodynamic resuscitation process in early septic shock.

INTRODUCTION: Since normal or high central venous oxygen saturation (ScvO2) values cannot discriminate if tissue perfusion is adequate, integrating other markers of tissue hypoxia, such as central venous-to-arterial carbon dioxide difference (PcvaCO2 gap) has been proposed. In the present study, we aimed to evaluate the ability of the PcvaCO2 gap and the PcvaCO2/arterial-venous oxygen content difference ratio (PcvaCO2/CavO2) to predict lactate evolution in septic shock. METHODS: Observational study. Septic shock patients within the first 24 hours of ICU admission. After restoration of mean arterial pressure, and central venous oxygen saturation, the PcvaCO2 gap and the PcvaCO2/CavO2 ratio were calculated. Consecutive arterial and central venous blood samples were obtained for each patient within 24 hours. Lactate improvement was defined as the decrease ≥ 10% of the previous lactate value. RESULTS: Thirty-five septic shock patients were studied. At inclusion, the PcvaCO2 gap was 5.6 ± 2.1 mmHg, and the PcvaCO2/CavO2 ratio was 1.6 ± 0.7 mmHg · dL/mL O2. Those patients whose lactate values did not decrease had higher PcvaCO2/CavO2 ratio values at inclusion (1.8 ± 0.8vs. 1.4 ± 0.5, p 0.02). During the follow-up, 97 paired blood samples were obtained. No-improvement in lactate values was associated to higher PcvaCO2/CavO2 ratio values in the previous control. The ROC analysis showed an AUC 0.82 (p < 0.001), and a PcvaCO2/CavO2 ratio cut-off value of 1.4 mmHg · dL/mL O2 showed sensitivity 0.80 and specificity 0.75 for lactate improvement prediction. The odds ratio of an adequate lactate clearance was 0.10 (p < 0.001) in those patients with an elevated PcvaCO2/CavO2 ratio (≥1.4). CONCLUSION: In a population of septic shock patients with normalized MAP and ScvO2, the presence of elevated PcvaCO2/CavO2 ratio significantly reduced the odds of adequate lactate clearance during the following hours.

Acute respiratory distress syndrome: prevention and early recognition.

Acute respiratory distress syndrome (ARDS) is common in critically ill patients admitted to intensive care units (ICU). ARDS results in increased use of critical care resources and healthcare costs, yet the overall mortality associated with these conditions remains high. Research focusing on preventing ARDS and identifying patients at risk of developing ARDS is necessary to develop strategies to alter the clinical course and progression of the disease. To date, few strategies have shown clear benefits. One of the most important obstacles to preventive interventions is the difficulty of identifying patients likely to develop ARDS. Identifying patients at risk and implementing prevention strategies in this group are key factors in preventing ARDS. This review will discuss early identification of at-risk patients and the current prevention strategies.