a narrative review

Acute respiratory distress syndrome (ARDS) is a severe organ failure occurring mainly in critically ill patients as a result of different types of insults such as sepsis, trauma or aspiration. Sepsis is the main cause of ARDS, and it contributes to a high mortality and resources consumption both in hospital setting and in the community. ARDS develops mainly an acute respiratory failure with severe and often refractory hypoxemia. ARDS also has long term implications and sequelae. Endothelial damage plays an important role in the pathogenesis of ARDS. Understanding the mechanisms of ARDS presents opportunities for novel diagnostic and therapeutic targets. Biochemical signals can be used in concert to identify and classify patients into ARDS phenotypes allowing earlier effective treatment with personalised therapies. This is a narrative review where we aimed to flesh out the pathogenetic mechanisms and heterogeneity of ARDS. We examine the links between endothelium damage and its contribution to organ failure. We have also investigated future strategies for treatment with a special emphasis in endothelial damage.publishersversionpublishe

Identification of a novel protein containing two C2 domains selectively expressed in the rat brain and kidney

AbstractWe have isolated and characterized a rat brain cDNA clone which encodes a new protein of 474 amino acids in length which contains two C2 domains structurally homologous to those present in synaptotagmins. The overall amino acid identity in C2 domains between this protein and the synaptotagmins is 36–44%. This protein also contains 3 putative consensus sequences for phosphorylation by cAMP-dependent protein kinase. RNA blot hybridization revealed a 3.0 kb transcript abundantly expressed only in the rat brain and the kidney. Thus, we called this brain/kidney protein (B/K). In situ hybridization and Northern blot analyses showed that the B/K transcript was found in forebrain including the olfactory bulb, cerebral cortex, hippocampus, and hypothalamus. In the kidney, high levels of B/K transcript were expressed in the papillary region of the inner medulla, the inner stripe of the outer medulla and the cortex. The selective expression in forebrain and kidney suggests that B/K may be involved in similar cAMP-dependent processes at these very different sites

Respiratory research networks in Europe and beyond: aims, achievements and aspirations for the 21st century

Healthcare-associated infection, such as intensive care unit (ICU)-related respiratory infections, remain the most frequently encountered morbidity of ICU admission, prolonging hospital stay and increasing mortality rates. The epidemiology of ICU-related respiratory infections, particularly nonventilated ICU-associated pneumonia and ventilator-associated tracheobronchitis, appears to be quite different among different countries. European countries have different prevalence, patterns and mechanism of resistance, as well as different treatments chosen by different attending physicians. The classical clinical research process in respiratory infections consists of the following loop: 1) identification of knowledge gaps; 2) systematic review and search for adequate answers; 3) generation of study hypotheses; 4) design of study protocols; 5) collection clinical data; 6) analysis and interpretation of the results; and 7) implementation of the results in clinical practic

Tumor necrosis factor receptor 1 (TNFRI) for ventilator-associated pneumonia diagnosis by cytokine multiplex analysis

The diagnosis of ventilator-associated pneumonia (VAP) is challenging. An important aspect to improve outcome is early recognition of VAP and the initiation of the appropriate empirical treatment. We hypothesized that biological markers in plasma can rule out VAP at the moment of clinical suspicion and could rule in VAP before the diagnosis can be made clinically. In this prospective study, patients with VAP (n = 24, microbiology confirmed) were compared to controls (n = 19) with a similar duration of mechanical ventilation. Blood samples from the day of VAP diagnosis and 1 and 3 days before were analyzed with a multiplex array for markers of inflammation, coagulation, and apoptosis. The best biomarker combination was selected and the diagnostic accuracy was given by the area under the receiver operating characteristic curve (ROC-AUC). TNF-receptor 1 (TNFRI) and granulocyte colony-stimulating factor (GCSF) were selected as optimal biomarkers at the day of VAP diagnosis, which resulted in a ROC-AUC of 0.96, with excellent sensitivity. Three days before the diagnosis TNFRI and plasminogen activator inhibitor-1 (PAI-1) levels in plasma predicted VAP with a ROC-AUC of 0.79. The slope of IL-10 and PAI-1 resulted in a ROC-AUC of 0.77. These biomarkers improved the classification of the clinical pulmonary infection score when combined. Concentration of TNFRI and PAI-1 and the slope of PAI-1 and IL-10 may be used to predict the development of VAP as early as 3 days before the diagnosis made clinically. TNFRI and GCSF may be used to exclude VAP at the moment of clinical suspicion. Especially TNFRI seems to be a promising marker for the prediction and diagnosis of VA

Association of early positive end-expiratory pressure settings with ventilator-free days in patients with coronavirus disease 2019 acute respiratory distress syndrome:A secondary analysis of the Practice of VENTilation in COVID-19 study

BACKGROUND: There is uncertainty about how much positive end-expiratory pressure (PEEP) should be used in patients with acute respiratory distress syndrome (ARDS) due to coronavirus disease 2019 (COVID-19). OBJECTIVE: To investigate whether a higher PEEP strategy is superior to a lower PEEP strategy regarding the number of ventilator-free days (VFDs). DESIGN: Multicentre observational study conducted from 1 March to 1 June 2020. SETTING AND PATIENTS: Twenty-two ICUs in The Netherlands and 933 invasively ventilated COVID-19 ARDS patients. INTERVENTIONS: Patients were categorised retrospectively as having received invasive ventilation with higher (n=259) or lower PEEP (n=674), based on the high and low PEEP/FIO2 tables of the ARDS Network, and using ventilator settings and parameters in the first hour of invasive ventilation, and every 8 h thereafter at fixed time points during the first four calendar days. We also used propensity score matching to control for observed confounding factors that might influence outcomes. MAIN OUTCOMES AND MEASURES: The primary outcome was the number of VFDs. Secondary outcomes included distant organ failures including acute kidney injury (AKI) and use of renal replacement therapy (RRT), and mortality. RESULTS: In the unmatched cohort, the higher PEEP strategy had no association with the median [IQR] number of VFDs (2.0 [0.0 to 15.0] vs. 0.0 [0.0 to 16.0] days). The median (95% confidence interval) difference was 0.21 (-3.34 to 3.78) days, P = 0.905. In the matched cohort, the higher PEEP group had an association with a lower median number of VFDs (0.0 [0.0 to 14.0] vs. 6.0 [0.0 to 17.0] days) a median difference of -4.65 (-8.92 to -0.39) days, P = 0.032. The higher PEEP strategy had associations with higher incidence of AKI (in the matched cohort) and more use of RRT (in the unmatched and matched cohorts). The higher PEEP strategy had no association with mortality. CONCLUSION: In COVID-19 ARDS, use of higher PEEP may be associated with a lower number of VFDs, and may increase the incidence of AKI and need for RRT. TRIAL REGISTRATION: Practice of VENTilation in COVID-19 is registered at ClinicalTrials.gov, NCT04346342

Manipulation of the microbiome in critical illness—probiotics as a preventive measure against ventilator-associated pneumonia

Abstract Objective To describe the possible modes of action of probiotics and provide a systematic review of the current evidence on the efficacy of probiotics to prevent ventilator-associated pneumonia (VAP) in critically ill patients. Methods We conducted an unrestricted search of the English language medical literature. For each individual study, the relative risk of VAP was calculated using the reported primary outcome data. Results The search identified a total of 72 articles. Eight articles enrolling a total of 1229 patients fulfilled the inclusion and exclusion criteria. In four trials, the investigators were blinded for the intervention, and two trials used an intention-to-treat analysis. Loss to follow-up with regard to the primary endpoint ranged from 0 to 14% in the intervention groups and from 0 to 16% in the control groups. The incidence of VAP expressed as the percentage of studied patients was reported in seven trials. The incidence of VAP ranged from 4 to 36% in the intervention groups and from 13 to 50% in the control groups. The relative risk for VAP ranged between 0.30 and 1.41. Three trials showed a significant difference in favor of probiotic therapy between the intervention and the control groups. Conclusions The incidence of VAP tended to be lower in patients treated with probiotics in most trials identified by the systematic search. Due to the heterogeneity of the studies and the low quality of evidence, it remains difficult to draw firm conclusions. The efficacy of preventive probiotics should be studied in more detail in future trials. Application of probiotics for the prevention of VAP seems to be safe with only few side effects reported in the selected trials.https://deepblue.lib.umich.edu/bitstream/2027.42/152184/1/40635_2019_Article_238.pd

Endothelial dysfunction triggers acute respiratory distress syndrome in patients with sepsis: a narrative review

Acute respiratory distress syndrome (ARDS) is a severe organ failure occurring mainly in critically ill patients as a result of different types of insults such as sepsis, trauma or aspiration. Sepsis is the main cause of ARDS, and it contributes to a high mortality and resources consumption both in hospital setting and in the community. ARDS develops mainly an acute respiratory failure with severe and often refractory hypoxemia. ARDS also has long term implications and sequelae. Endothelial damage plays an important role in the pathogenesis of ARDS. Understanding the mechanisms of ARDS presents opportunities for novel diagnostic and therapeutic targets. Biochemical signals can be used in concert to identify and classify patients into ARDS phenotypes allowing earlier effective treatment with personalised therapies. This is a narrative review where we aimed to flesh out the pathogenetic mechanisms and heterogeneity of ARDS. We examine the links between endothelium damage and its contribution to organ failure. We have also investigated future strategies for treatment with a special emphasis in endothelial damage

The Rise of Adaptive Platform Trials in Critical Care

As durable learning research systems, adaptive platform trials represent a transformative new approach to accelerating clinical evaluation and discovery in critical care. This Perspective provides a brief introduction to the concept of adaptive platform trials, describes several established and emerging platforms in critical care, and surveys some opportunities and challenges for their implementation and impact.<br/

Autoantibodies against type I IFNs in patients with life-threatening COVID-19

Interindividual clinical variability in the course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is vast. We report that at least 101 of 987 patients with life-threatening coronavirus disease 2019 (COVID-19) pneumonia had neutralizing immunoglobulin G (IgG) autoantibodies (auto-Abs) against interferon-w (IFN-w) (13 patients), against the 13 types of IFN-a (36), or against both (52) at the onset of critical disease; a few also had auto-Abs against the other three type I IFNs. The auto-Abs neutralize the ability of the corresponding type I IFNs to block SARS-CoV-2 infection in vitro. These auto-Abs were not found in 663 individuals with asymptomatic or mild SARS-CoV-2 infection and were present in only 4 of 1227 healthy individuals. Patients with auto-Abs were aged 25 to 87 years and 95 of the 101 were men. A B cell autoimmune phenocopy of inborn errors of type I IFN immunity accounts for life-threatening COVID-19 pneumonia in at least 2.6% of women and 12.5% of men