Association Between Ventilatory Settings and Development of Acute Respiratory Distress Syndrome in Mechanically Ventilated Patients Due to Brain Injury

PURPOSE: In neurologically critically ill patients with mechanical ventilation (MV), the development of acute respiratory distress syndrome (ARDS) is a major contributor to morbidity and mortality, but the role of ventilatory management has been scarcely evaluated. We evaluate the association of tidal volume, level of PEEP and driving pressure with the development of ARDS in a population of patients with brain injury. MATERIALS AND METHODS: We performed a secondary analysis of a prospective, observational study on mechanical ventilation. RESULTS: We included 986 patients mechanically ventilated due to an acute brain injury (hemorrhagic stroke, ischemic stroke or brain trauma). Incidence of ARDS in this cohort was 3%. Multivariate analysis suggested that driving pressure could be associated with the development of ARDS (odds ratio for unit increment of driving pressure 1.12; confidence interval for 95%: 1.01 to 1.23) whereas we did not observe association for tidal volume (in ml per kg of predicted body weight) or level of PEEP. ARDS was associated with an increase in mortality, longer duration of mechanical ventilation, and longer ICU length of stay. CONCLUSIONS: In a cohort of brain-injured patients the development of ARDS was not common. Driving pressure was associated with the development of this disease.info:eu-repo/semantics/publishedVersio

Severe Hypercapnia and Outcome of Mechanically Ventilated Patients with Moderate or Severe Acute Respiratory Distress Syndrome

PURPOSE: To analyze the relationship between hypercapnia developing within the first 48 h after the start of mechanical ventilation and outcome in patients with acute respiratory distress syndrome (ARDS). PATIENTS AND METHODS: We performed a secondary analysis of three prospective non-interventional cohort studies focusing on ARDS patients from 927 intensive care units (ICUs) in 40 countries. These patients received mechanical ventilation for more than 12 h during 1-month periods in 1998, 2004, and 2010. We used multivariable logistic regression and a propensity score analysis to examine the association between hypercapnia and ICU mortality. MAIN OUTCOMES: We included 1899 patients with ARDS in this study. The relationship between maximum PaCO2 in the first 48 h and mortality suggests higher mortality at or above PaCO2 of ≥50 mmHg. Patients with severe hypercapnia (PaCO2 ≥50 mmHg) had higher complication rates, more organ failures, and worse outcomes. After adjusting for age, SAPS II score, respiratory rate, positive end-expiratory pressure, PaO2/FiO2 ratio, driving pressure, pressure/volume limitation strategy (PLS), corrected minute ventilation, and presence of acidosis, severe hypercapnia was associated with increased risk of ICU mortality [odds ratio (OR) 1.93, 95% confidence interval (CI) 1.32 to 2.81; p = 0.001]. In patients with severe hypercapnia matched for all other variables, ventilation with PLS was associated with higher ICU mortality (OR 1.58, CI 95% 1.04-2.41; p = 0.032). CONCLUSIONS: Severe hypercapnia appears to be independently associated with higher ICU mortality in patients with ARDS.info:eu-repo/semantics/publishedVersio

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

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

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

Pan-African Genetic Structure in the African Buffalo (Syncerus caffer): Investigating Intraspecific Divergence

The African buffalo (Syncerus caffer) exhibits extreme morphological variability, which has led to controversies about the validity and taxonomic status of the various recognized subspecies. The present study aims to clarify these by inferring the pan-African spatial distribution of genetic diversity, using a comprehensive set of mitochondrial D-loop sequences from across the entire range of the species. All analyses converged on the existence of two distinct lineages, corresponding to a group encompassing West and Central African populations and a group encompassing East and Southern African populations. The former is currently assigned to two to three subspecies (S. c. nanus, S. c. brachyceros, S. c. aequinoctialis) and the latter to a separate subspecies (S. c. caffer). Forty-two per cent of the total amount of genetic diversity is explained by the between-lineage component, with one to seventeen female migrants per generation inferred as consistent with the isolation-with-migration model. The two lineages diverged between 145 000 to 449 000 years ago, with strong indications for a population expansion in both lineages, as revealed by coalescent-based analyses, summary statistics and a star-like topology of the haplotype network for the S. c. caffer lineage. A Bayesian analysis identified the most probable historical migration routes, with the Cape buffalo undertaking successive colonization events from Eastern toward Southern Africa. Furthermore, our analyses indicate that, in the West-Central African lineage, the forest ecophenotype may be a derived form of the savanna ecophenotype and not vice versa, as has previously been proposed. The African buffalo most likely expanded and diverged in the late to middle Pleistocene from an ancestral population located around the current-day Central African Republic, adapting morphologically to colonize new habitats, hence developing the variety of ecophenotypes observed today

Effect of Natural and Semisynthetic Pseudoguianolides on the Stability of NF-κB:DNA Complex Studied by Agarose Gel Electrophoresis.

The nuclear factor κB (NF-κB) is a promising target for drug discovery. NF-κB is a heterodimeric complex of RelA and p50 subunits that interact with the DNA, regulating the expression of several genes; its dysregulation can trigger diverse diseases including inflammation, immunodeficiency, and cancer. There is some experimental evidence, based on whole cells studies, that natural sesquiterpene lactones (Sls) can inhibit the interaction of NF-κB with DNA, by alkylating the RelA subunit via a Michael addition. In the present work, 28 natural and semisynthetic pseudoguianolides were screened as potential inhibitors of NF-κB in a biochemical assay that was designed using pure NF-κB heterodimer, pseudoguianolides and a ~1000 bp palindromic DNA fragment harboring two NF-κB recognition sequences. By comparing the relative amount of free DNA fragment to the NF-κB - DNA complex, in a routine agarose gel electrophoresis, the destabilizing effect of a compound on the complex is estimated. The results of the assay and the following structure-activity relationship study, allowed the identification of several relevant structural features in the pseudoguaianolide skeleton, which are necessary to enhance the dissociating capacity of NF-κB-DNA complex. The most active compounds are substituted at C-3 (α-carbonyl), in addition to having the α-methylene-γ-lactone moiety which is essential for the alkylation of RelA