The Intensive Care Global Study on Severe Acute Respiratory Infection (IC-GLOSSARI): a Multicenter, Multinational, 14-Day Inception Cohort Study

PURPOSE: In this prospective, multicenter, 14-day inception cohort study, we investigated the epidemiology, patterns of infections, and outcome in patients admitted to the intensive care unit (ICU) as a result of severe acute respiratory infections (SARIs). METHODS: All patients admitted to one of 206 participating ICUs during two study weeks, one in November 2013 and the other in January 2014, were screened. SARI was defined as possible, probable, or microbiologically confirmed respiratory tract infection with recent onset dyspnea and/or fever. The primary outcome parameter was in-hospital mortality within 60 days of admission to the ICU. RESULTS: Among the 5550 patients admitted during the study periods, 663 (11.9 %) had SARI. On admission to the ICU, Gram-positive and Gram-negative bacteria were found in 29.6 and 26.2 % of SARI patients but rarely atypical bacteria (1.0 %); viruses were present in 7.7 % of patients. Organ failure occurred in 74.7 % of patients in the ICU, mostly respiratory (53.8 %), cardiovascular (44.5 %), and renal (44.6 %). ICU and in-hospital mortality rates in patients with SARI were 20.2 and 27.2 %, respectively. In multivariable analysis, older age, greater severity scores at ICU admission, and hematologic malignancy or liver disease were independently associated with an increased risk of in-hospital death, whereas influenza vaccination prior to ICU admission and adequate antibiotic administration on ICU admission were associated with a lower risk. CONCLUSIONS: Admission to the ICU for SARI is common and associated with high morbidity and mortality rates. We identified several risk factors for in-hospital death that may be useful for risk stratification in these patients

Changes in aortic blood flow induced by passive leg raising predict fluid responsiveness in critically ill patients

INTRODUCTION: Esophageal Doppler provides a continuous and non-invasive estimate of descending aortic blood flow (ABF) and corrected left ventricular ejection time (LVETc). Considering passive leg raising (PLR) as a reversible volume expansion (VE), we compared the relative abilities of PLR-induced ABF variations, LVETc and respiratory pulsed pressure variations (ΔPP) to predict fluid responsiveness. METHODS: We studied 22 critically ill patients in acute circulatory failure in the supine position, during PLR, back to the supine position and after two consecutive VEs of 250 ml of saline. Responders were defined by an increase in ABF induced by 500 ml VE of more than 15%. RESULTS: Ten patients were responders and 12 were non-responders. In responders, the increase in ABF induced by PLR was similar to that induced by a 250 ml VE (16% versus 20%; p = 0.15). A PLR-induced increase in ABF of more than 8% predicted fluid responsiveness with a sensitivity of 90% and a specificity of 83%. Corresponding positive and negative predictive values (PPV and NPV, respectively) were 82% and 91%, respectively. A ΔPP threshold value of 12% predicted fluid responsiveness with a sensitivity of 70% and a specificity of 92%. Corresponding PPV and NPV were 87% and 78%, respectively. A LVETc of 245 ms or less predicted fluid responsiveness with a sensitivity of 70%, and a specificity of 67%. Corresponding PPV and NPV were 60% and 66%, respectively. CONCLUSION: The PLR-induced increase in ABF and a ΔPP of more than 12% offer similar predictive values in predicting fluid responsiveness. An isolated basal LVETc value is not a reliable criterion for predicting response to fluid loading

Role of monocarboxylate transporters in human cancers : state of the art

Monocarboxylate transporters (MCTs) belong to the SLC16 gene family, presently composed by 14 members. MCT1-MCT4 are proton symporters, which mediate the transmembrane transport of pyruvate, lactate and ketone bodies. The role of MCTs in cell homeostasis has been characterized in detail in normal tissues, however, their role in cancer is still far from understood. Most solid tumors are known to rely on glycolysis for energy production and this activity leads to production of important amounts of lactate, which are exported into the extracellular milieu, contributing to the acidic microenvironment. In this context, MCTs will play a dual role in the maintenance of the hyper-glycolytic acidresistant phenotype of cancer, allowing the maintenance of the high glycolytic rates by performing lactate efflux, and pH regulation by the co-transport of protons. Thus, they constitute attractive targets for cancer therapy, which have been little explored. Here we review the literature on the role of MCTs in solid tumors in different locations, such as colon, central nervous system, breast, lung, gynecologic tract, prostate, stomach, however, there are many conflicting results and in most cases there are no functional studies showing the dependence of the tumors on MCT expression and activity. Additional studies on MCT expression in other tumor types, confirmation of the results already published as well as additional functional studies are needed to deeply understand the role of MCTs in cancer maintenance and aggressiveness

Acute tubulointerstitial nephritis complicating Legionnaires' disease: a case report

<p>Abstract</p> <p>Introduction</p> <p>Legionnaires' disease is recognized as a multi-systemic illness. Afflicted patients may have pulmonary, renal, gastrointestinal tract and central nervous system complications. However, renal insufficiency is uncommon. The spectrum of renal involvement may range from a mild and transient elevation of serum creatinine levels to anuric renal failure requiring dialysis and may be linked to several causes. In our present case report, we would like to draw attention to the importance of the pathological documentation of acute renal failure by reporting a case of a patient with acute tubulointerstitial nephritis complicating Legionnaires' disease.</p> <p>Case presentation</p> <p>A 55-year-old Caucasian man was admitted to our hospital for community-acquired pneumonia complicated by acute renal failure. <it>Legionella pneumophila </it>serogroup type 1 was diagnosed. Although the patient's respiratory illness responded to intravenous erythromycin and ofloxacin therapy, his renal failure worsened, he became anuric, and hemodialysis was started. A renal biopsy was performed, which revealed severe tubulointerstitial nephritis. After initiation of steroid therapy, his renal function improved dramatically.</p> <p>Conclusions</p> <p>This case highlights the importance of kidney biopsies in cases where acute renal failure is a complicating factor in Legionnaires' disease. If the presence of acute tubulointerstitial nephritis can be confirmed, it will likely respond favorably to steroidal treatment and thus irreversible renal damage and chronic renal failure will be avoided.</p

Optimizing structural modeling for a specific protein scaffold: knottins or inhibitor cystine knots

<p>Abstract</p> <p>Background</p> <p>Knottins are small, diverse and stable proteins with important drug design potential. They can be classified in 30 families which cover a wide range of sequences (1621 sequenced), three-dimensional structures (155 solved) and functions (> 10). Inter knottin similarity lies mainly between 15% and 40% sequence identity and 1.5 to 4.5 Å backbone deviations although they all share a tightly knotted disulfide core. This important variability is likely to arise from the highly diverse loops which connect the successive knotted cysteines. The prediction of structural models for all knottin sequences would open new directions for the analysis of interaction sites and to provide a better understanding of the structural and functional organization of proteins sharing this scaffold.</p> <p>Results</p> <p>We have designed an automated modeling procedure for predicting the three-dimensionnal structure of knottins. The different steps of the homology modeling pipeline were carefully optimized relatively to a test set of knottins with known structures: template selection and alignment, extraction of structural constraints and model building, model evaluation and refinement. After optimization, the accuracy of predicted models was shown to lie between 1.50 and 1.96 Å from native structures at 50% and 10% maximum sequence identity levels, respectively. These average model deviations represent an improvement varying between 0.74 and 1.17 Å over a basic homology modeling derived from a unique template. A database of 1621 structural models for all known knottin sequences was generated and is freely accessible from our web server at <url>http://knottin.cbs.cnrs.fr</url>. Models can also be interactively constructed from any knottin sequence using the structure prediction module Knoter1D3D available from our protein analysis toolkit PAT at <url>http://pat.cbs.cnrs.fr</url>.</p> <p>Conclusions</p> <p>This work explores different directions for a systematic homology modeling of a diverse family of protein sequences. In particular, we have shown that the accuracy of the models constructed at a low level of sequence identity can be improved by 1) a careful optimization of the modeling procedure, 2) the combination of multiple structural templates and 3) the use of conserved structural features as modeling restraints.</p

Fluid challenges in intensive care: the FENICE study A global inception cohort study

Fluid challenges (FCs) are one of the most commonly used therapies in critically ill patients and represent the cornerstone of hemodynamic management in intensive care units. There are clear benefits and harms from fluid therapy. Limited data on the indication, type, amount and rate of an FC in critically ill patients exist in the literature. The primary aim was to evaluate how physicians conduct FCs in terms of type, volume, and rate of given fluid; the secondary aim was to evaluate variables used to trigger an FC and to compare the proportion of patients receiving further fluid administration based on the response to the FC.This was an observational study conducted in ICUs around the world. Each participating unit entered a maximum of 20 patients with one FC.2213 patients were enrolled and analyzed in the study. The median [interquartile range] amount of fluid given during an FC was 500 ml (500-1000). The median time was 24 min (40-60 min), and the median rate of FC was 1000 [500-1333] ml/h. The main indication for FC was hypotension in 1211 (59 %, CI 57-61 %). In 43 % (CI 41-45 %) of the cases no hemodynamic variable was used. Static markers of preload were used in 785 of 2213 cases (36 %, CI 34-37 %). Dynamic indices of preload responsiveness were used in 483 of 2213 cases (22 %, CI 20-24 %). No safety variable for the FC was used in 72 % (CI 70-74 %) of the cases. There was no statistically significant difference in the proportion of patients who received further fluids after the FC between those with a positive, with an uncertain or with a negatively judged response.The current practice and evaluation of FC in critically ill patients are highly variable. Prediction of fluid responsiveness is not used routinely, safety limits are rarely used, and information from previous failed FCs is not always taken into account

Spontaneous Breathing in Early Acute Respiratory Distress Syndrome: Insights From the Large Observational Study to UNderstand the Global Impact of Severe Acute Respiratory FailurE Study

OBJECTIVES: To describe the characteristics and outcomes of patients with acute respiratory distress syndrome with or without spontaneous breathing and to investigate whether the effects of spontaneous breathing on outcome depend on acute respiratory distress syndrome severity. DESIGN: Planned secondary analysis of a prospective, observational, multicentre cohort study. SETTING: International sample of 459 ICUs from 50 countries. PATIENTS: Patients with acute respiratory distress syndrome and at least 2 days of invasive mechanical ventilation and available data for the mode of mechanical ventilation and respiratory rate for the 2 first days. INTERVENTIONS: Analysis of patients with and without spontaneous breathing, defined by the mode of mechanical ventilation and by actual respiratory rate compared with set respiratory rate during the first 48 hours of mechanical ventilation. MEASUREMENTS AND MAIN RESULTS: Spontaneous breathing was present in 67% of patients with mild acute respiratory distress syndrome, 58% of patients with moderate acute respiratory distress syndrome, and 46% of patients with severe acute respiratory distress syndrome. Patients with spontaneous breathing were older and had lower acute respiratory distress syndrome severity, Sequential Organ Failure Assessment scores, ICU and hospital mortality, and were less likely to be diagnosed with acute respiratory distress syndrome by clinicians. In adjusted analysis, spontaneous breathing during the first 2 days was not associated with an effect on ICU or hospital mortality (33% vs 37%; odds ratio, 1.18 [0.92-1.51]; p = 0.19 and 37% vs 41%; odds ratio, 1.18 [0.93-1.50]; p = 0.196, respectively ). Spontaneous breathing was associated with increased ventilator-free days (13 [0-22] vs 8 [0-20]; p = 0.014) and shorter duration of ICU stay (11 [6-20] vs 12 [7-22]; p = 0.04). CONCLUSIONS: Spontaneous breathing is common in patients with acute respiratory distress syndrome during the first 48 hours of mechanical ventilation. Spontaneous breathing is not associated with worse outcomes and may hasten liberation from the ventilator and from ICU. Although these results support the use of spontaneous breathing in patients with acute respiratory distress syndrome independent of acute respiratory distress syndrome severity, the use of controlled ventilation indicates a bias toward use in patients with higher disease severity. In addition, because the lack of reliable data on inspiratory effort in our study, prospective studies incorporating the magnitude of inspiratory effort and adjusting for all potential severity confounders are required

Identifying associations between diabetes and acute respiratory distress syndrome in patients with acute hypoxemic respiratory failure: an analysis of the LUNG SAFE database

Background: Diabetes mellitus is a common co-existing disease in the critically ill. Diabetes mellitus may reduce the risk of acute respiratory distress syndrome (ARDS), but data from previous studies are conflicting. The objective of this study was to evaluate associations between pre-existing diabetes mellitus and ARDS in critically ill patients with acute hypoxemic respiratory failure (AHRF). Methods: An ancillary analysis of a global, multi-centre prospective observational study (LUNG SAFE) was undertaken. LUNG SAFE evaluated all patients admitted to an intensive care unit (ICU) over a 4-week period, that required mechanical ventilation and met AHRF criteria. Patients who had their AHRF fully explained by cardiac failure were excluded. Important clinical characteristics were included in a stepwise selection approach (forward and backward selection combined with a significance level of 0.05) to identify a set of independent variables associated with having ARDS at any time, developing ARDS (defined as ARDS occurring after day 2 from meeting AHRF criteria) and with hospital mortality. Furthermore, propensity score analysis was undertaken to account for the differences in baseline characteristics between patients with and without diabetes mellitus, and the association between diabetes mellitus and outcomes of interest was assessed on matched samples. Results: Of the 4107 patients with AHRF included in this study, 3022 (73.6%) patients fulfilled ARDS criteria at admission or developed ARDS during their ICU stay. Diabetes mellitus was a pre-existing co-morbidity in 913 patients (22.2% of patients with AHRF). In multivariable analysis, there was no association between diabetes mellitus and having ARDS (OR 0.93 (0.78-1.11); p = 0.39), developing ARDS late (OR 0.79 (0.54-1.15); p = 0.22), or hospital mortality in patients with ARDS (1.15 (0.93-1.42); p = 0.19). In a matched sample of patients, there was no association between diabetes mellitus and outcomes of interest. Conclusions: In a large, global observational study of patients with AHRF, no association was found between diabetes mellitus and having ARDS, developing ARDS, or outcomes from ARDS. Trial registration: NCT02010073. Registered on 12 December 2013

Epidemiology and patterns of tracheostomy practice in patients with acute respiratory distress syndrome in ICUs across 50 countries

Background: To better understand the epidemiology and patterns of tracheostomy practice for patients with acute respiratory distress syndrome (ARDS), we investigated the current usage of tracheostomy in patients with ARDS recruited into the Large Observational Study to Understand the Global Impact of Severe Acute Respiratory Failure (LUNG-SAFE) study. Methods: This is a secondary analysis of LUNG-SAFE, an international, multicenter, prospective cohort study of patients receiving invasive or noninvasive ventilation in 50 countries spanning 5 continents. The study was carried out over 4 weeks consecutively in the winter of 2014, and 459 ICUs participated. We evaluated the clinical characteristics, management and outcomes of patients that received tracheostomy, in the cohort of patients that developed ARDS on day 1-2 of acute hypoxemic respiratory failure, and in a subsequent propensity-matched cohort. Results: Of the 2377 patients with ARDS that fulfilled the inclusion criteria, 309 (13.0%) underwent tracheostomy during their ICU stay. Patients from high-income European countries (n = 198/1263) more frequently underwent tracheostomy compared to patients from non-European high-income countries (n = 63/649) or patients from middle-income countries (n = 48/465). Only 86/309 (27.8%) underwent tracheostomy on or before day 7, while the median timing of tracheostomy was 14 (Q1-Q3, 7-21) days after onset of ARDS. In the subsample matched by propensity score, ICU and hospital stay were longer in patients with tracheostomy. While patients with tracheostomy had the highest survival probability, there was no difference in 60-day or 90-day mortality in either the patient subgroup that survived for at least 5 days in ICU, or in the propensity-matched subsample. Conclusions: Most patients that receive tracheostomy do so after the first week of critical illness. Tracheostomy may prolong patient survival but does not reduce 60-day or 90-day mortality. Trial registration: ClinicalTrials.gov, NCT02010073. Registered on 12 December 2013