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Patients with acute respiratory distress syndrome received conservative oxygen therapy or liberal oxygen therapy for 7 days. The trial was prematurely stopped because of futility and safety concerns. Mortality at day 28 was 34.3% in the conservative-oxygen group and 26.5% in the liberal-oxygen group. Five mesenteric ischemic events occurred, all in the conservative-oxygen group.

Inflammation is a cellular and molecular response to infection and/or tissues injury. While a suited inflammatory response in intensity and time allows for killing pathogens, clearing necrotic tissue, and healing injury; an excessive inflammatory response drives various diseases in which inflammation and tissues damages/stress self-sustain each other. Microbes have been poorly implied in non-resolving inflammation, emphasizing the importance of endogenous regulation of inflammation. Mitochondria have been historically identified as the main source of cellular energy, by coupling the oxidation of fatty acids and pyruvate with the production of high amount of adenosine triphosphate by the electron transport chain. Mitochondria are also the main source of reactive oxygen species. Interestingly, research in the last decade has highlighted that since its integration in eukaryote cells, this organelle of bacterial origin has not only been tolerated by immunity, but has also been placed as a central regulator of cell defense. In intact cells, mitochondria regulate cell responses to critical innate immune receptors engagement. Downstream intracellular signaling pathways interact with mitochondrial proteins and are tuned by mitochondrial functioning. Moreover, upon cell stress or damages, mitochondrial components are released into the cytoplasm or the extra cellular milieu, where they act as danger signals when recognized by innate immune receptors. Finally, by regulating the energetic state of immunological synapse between dendritic cells and lymphocytes, mitochondria regulate the inflammation fate toward immunotolerance or immunogenicity. As dysregulations of these processes have been recently involved in various diseases, the identification of the underlying mechanisms might open new avenues to modulate inflammation.

Therapeutic strategies to mitigate inflammation Moving from biomarkers to therapeutic strategies, the research highlights several innovative approaches to modulate the inflammatory response.Zemtsovski et al.demonstrated that alpha1-antitrypsin (AAT) treatment improves survival in a murine model of abdominal sepsis by reducing inflammation and sequestering free heme. [...]the study byWu et al.on the neutrophil-to-lymphocyte ratio (NLR) reinforces the utility of this biomarker in predicting prognosis and mortality in sepsis patients. Conflict of interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Patient reported outcomes measures (PROMS) are important endpoints to measure patient health status in the perioperative setting. However, there are no good tools to measure PROMS in the pediatric surgical population. Patients 7 to 17 years old undergoing surgery were included and followed up for 1 day after surgery (POD1). At POD1 the patients were asked to rate their overall postoperative recovery using a 100-mm visual analog scale (VAS). The primary outcome was the pediatric QoR-15 score on postoperative day 1 (POD1). 150 patients completed the study. The mean (SD) pediatric QoR-15F scores were 132.1 (14.1) and 111.0 (27.0), preoperatively and on POD1, respectively. Convergent validity confirmed with Pearson (r) correlation between the postoperative pediatric QoR-15F and the patient-rated global recovery assessment was 0.72 (95% confidence interval [0.63–0.79]; p < 10 –16 ). Concerning reliability, internal consistency of the pediatric QoR-15 assessed by Cronbach’s alpha was 0.90. The test–retest concordance correlation coefficient was 0.92; 95% CI [0.83–0.96]. Split-half alpha was 0.74. The pictorial pediatric version of the QoR-15F showed good validity, reliability, responsiveness, acceptability and feasibility. This PROMS should be considered for clinical care and research in the perioperative pediatric patient setting. Trial Registration: NCT04453410 on clinicaltrials.gov.

As new SARS-CoV-2 variants emerge and as treatment of COVID-19 ARDS remains exclusively supportive, there is an unmet need to better characterize its different phenotypes to tailor personalized treatments. Clinical, biological, spirometric and CT data hardly allow deciphering of Heavy (H), Intermediate (I) and Light (L) phenotypes of COVID-19 ARDS and the implementation of tailored specific strategies (prone positioning, PEEP settings, recruitment maneuvers). We hypothesized that the ratio of two pivotal COVID-19 biomarkers (interleukin 6 [IL-6] and Krebs von den Lungen 6 [KL-6], related to inflammation and pneumocyte repair, respectively) would provide a biologic insight into the disease timeline allowing 1) to differentiate H, I and L phenotypes, 2) to predict outcome and 3) to reflect some of CT findings. This was a retrospective analysis of prospectively acquired data (COVID HUS cohort). Inclusion concerned any patient with severe COVID-19 pneumonia admitted to two intensive care units between March 1st and May 1st, 2020, in a high-density cluster of the first epidemic wave (Strasbourg University Hospital, France). Demographic, clinical, biological (standard, IL-6 [new generation ELISA], KL-6 [CLEIA technique]), spirometric (driving pressure, respiratory system compliance) and CT data were collected longitudinally. CT analysis included semi-automatic and automatic lung measurements and allowed segmentation of lung volumes into 4 (poorly aerated, non-aerated, overinflated and normally aerated) and 3 (ground-glass, restricted normally aerated, and overinflated) zones, respectively. The primary outcome was to challenge the IL-6/KL-6 ratio capacity to decipher the three COVID-19 ARDS phenotypes (H, I and L) defined on clinical, spirometric and radiologic grounds. Secondary outcomes were the analysis of the prognostic value of the IL-6/KL-6 ratio and its correlates with CT-acquired data. Multivariate analysis was based on principal component analysis. One hundred and forty-eight ventilated COVID-19 ICU patients from the COVID HUS cohort were assessed for eligibility and 77 were included in the full analysis. Most were male, all were under invasive mechanical ventilation and vasopressor therapy and displayed high severity scores (SAPSII: 48 [42-56]; SOFA: 8 [7-10]). The L, I and H COVID ARDS phenotypes were identified in 11, 15 and 48 patients, respectively. In three patients, the phenotype could not be defined precisely. Thirty patients (39%) died in the ICU and the number of ventilator-free days was 2 [0-2] days. The IL-6/KL-6 ratio was not significantly different between the L, I and H phenotypes and evolved according to similar patterns over time. Surviving and deceased patients displayed an inverse kinetic of KL-6. IL-6 and the IL-6/KL-6 ratio were linearly associated with ground-glass volume on semi-automatic and automatic CT lung measurements. In our population of severe ventilated COVID ARDS patients, the IL-6/KL-6 ratio was not clue to differentiate the H, I and L phenotypes and tailor a personalized ventilatory approach. There was an interesting correlation between IL-6/KL-6 ratio and ground-glass volume as determined by automated lung CT analysis. Such correlation deserves more in-depth pathophysiological study, at best gathered from a prospective cohort with a larger sample size and histological analysis. COVID HUS Trial registration number: NCT04405726.

Damage-associated molecular patterns (DAMPs) are a group of immunostimulatory molecules, which take part in inflammatory response after tissue injury. Kidney-specific DAMPs include Tamm-Horsfall glycoprotein, crystals, and uromodulin, released by tubular damage for example. Non-kidney-specific DAMPs include intracellular particles such as nucleus [histones, high-mobility group box 1 protein (HMGB1)] and cytosol parts. DAMPs trigger innate immunity by activating the NRLP3 inflammasome, G-protein coupled class receptors or the Toll-like receptor. Tubular necrosis leads to acute kidney injury (AKI) in either septic, ischemic or toxic conditions. Tubular necrosis releases DAMPs such as histones and HMGB1 and increases vascular permeability, which perpetuates shock and hypoperfusion via Toll Like Receptors. In acute tubular necrosis, intracellular abundance of NADPH may explain a chain reaction where necrosis spreads from cell to cell. The nature AKI in intensive care units does not have preclinical models that meet a variation of blood perfusion or a variation of glomerular filtration within hours before catecholamine infusion. However, the dampening of several DAMPs in AKI could provide organ protection. Research should be focused on the numerous pathophysiological pathways to identify the relative contribution to renal dysfunction. The therapeutic perspectives could be strategies to suppress side effect of DAMPs and to promote renal function regeneration.

Background There is little descriptive data on Stenotrophomonas maltophilia hospital-acquired pneumonia (HAP) in critically ill patients. The optimal modalities of antimicrobial therapy remain to be determined. Our objective was to describe the epidemiology and prognostic factors associated with S. maltophilia pneumonia, focusing on antimicrobial therapy. Methods This nationwide retrospective study included all patients admitted to 25 French mixed intensive care units between 2012 and 2017 with hospital-acquired S. maltophilia HAP during intensive care unit stay. Primary endpoint was time to in-hospital death. Secondary endpoints included microbiologic effectiveness and antimicrobial therapeutic modalities such as delay to appropriate antimicrobial treatment, mono versus combination therapy, and duration of antimicrobial therapy. Results Of the 282 patients included, 84% were intubated at S. maltophilia HAP diagnosis for duration of 11 [5–18] days. The Simplified Acute Physiology Score II was 47 [36–63], and the in-hospital mortality was 49.7%. Underlying chronic pulmonary comorbidities were present in 14.1% of cases. Empirical antimicrobial therapy was considered effective on S. maltophilia according to susceptibility patterns in only 30% of cases. Delay to appropriate antimicrobial treatment had, however, no significant impact on the primary endpoint. Survival analysis did not show any benefit from combination antimicrobial therapy (HR = 1.27, 95%CI [0.88; 1.83], p  = 0.20) or prolonged antimicrobial therapy for more than 7 days (HR = 1.06, 95%CI [0.6; 1.86], p  = 0.84). No differences were noted in in-hospital death irrespective of an appropriate and timely empiric antimicrobial therapy between mono- versus polymicrobial S. maltophilia HAP ( p  = 0.273). The duration of ventilation prior to S. maltophilia HAP diagnosis and ICU length of stay were shorter in patients with monomicrobial S. maltophilia HAP ( p  = 0.031 and p  = 0.034 respectively). Conclusions S. maltophilia HAP occurred in severe, long-stay intensive care patients who mainly required prolonged invasive ventilation. Empirical antimicrobial therapy was barely effective while antimicrobial treatment modalities had no significant impact on hospital survival. Trial registration clinicaltrials.gov , NCT03506191

Glenzocimab is a novel antithrombotic agent which targets platelet glycoprotein VI (GPVI) and does not induce haemorrhage. SARS-CoV-2 triggers a prothrombotic state and lung injury whose mechanisms include coagulopathy, endothelial dysfunction, and inflammation with dysregulated platelets. GARDEN was a randomised double-blind, exploratory phase II study of glenzocimab in SARS-CoV-2 respiratory failure (NCT04659109). PCR+ adults in Brazil and France (7 centres) were randomized to standard-of-care (SOC) plus glenzocimab (1000 mg/dayx3 days) or placebo, followed for 40 days. Primary efficacy endpoint was clinical progression at Day 4. All analyses concerned the intention-to-treat population. Between December 2020 and August 2021, 61 patients received at least one dose (30 glenzocimab vs 32 placebo) and 58 completed the study (29 vs 29). Clinical progression of COVID-19 ARDS was not statistically different between glenzocimab and placebo arms (43.3% and 29.0%, respectively; p = 0.245). Decrease in the NEWS-2 category at D4 was statistically significant (p = 0.0290) in the glenzocimab arm vs placebo. No Serious Adverse Event (SAE) was deemed related to study drug; bleeding related events were reported in 6 patients (7 events) and 4 patients (4 events) in glenzocimab and placebo arms, respectively. Therapeutic GPVI inhibition assessment during COVID-19 was conducted in response to a Public Health emergency. Glenzocimab in coagulopathic patients under therapeutic heparin was neither associated with increased bleeding, nor SAE. Clinical impact of glenzocimab on COVID-19 ARDS was not demonstrated. A potential role for GPVI inhibition in other types of ARDS deserves further experimentation. Glenzocimab is currently studied in stroke (ACTISAVE: NCT05070260) and cardiovascular indications.

Acute respiratory distress syndrome (ARDS) caused by SARS-CoV-2 infection is associated with high mortality rates and respiratory compromise in which excessive neutrophil extracellular trap (NET) production may amplify alveolar inflammation and injury. Dornase alfa, a recombinant DNAse 1, has been proposed to attenuate these effects by degrading extracellular DNA and enhancing alveolar clearance of NETs. In this multicenter, open-label, randomized in two parallel arms (1:1) controlled trial, intubated COVID-19 ARDS patients received either standard-of-care (SOC) alone or SOC plus aerosolized dornase alfa (2500 IU twice daily for 7 days). The primary endpoint was the proportion of patients with ARDS severity improvement at Day 7, defined by at least one-grade improvement on the Berlin criteria scale. Secondary outcomes included 28-day mortality, ventilator-free days, ICU-free days, and changes in key ventilatory parameters. Biological samples were analyzed to assess NET related markers, DNAse drug activity and indicate possible bioavailability issues associated with aerosolization of dornase alfa. Seventy-seven patients were enrolled (dornase alfa group, n  = 39; SOC group, n  = 38). At Day 7, ARDS severity improved in 18% of patients receiving dornase alfa compared with 29% in the SOC group (adjusted OR: 0.33; 95% CI 0.09–1.14; p  = 0.11). Secondary endpoints, including 28-day mortality, ventilator-free days, and ICU-free days, showed no significant differences between groups. Adverse events occurred in 38.5% of patients in the dornase alfa arm versus 31.6% in the SOC arm, indicating comparable safety profiles. Despite early increases in NET plasmatic levels observed in both groups and successful ex vivo NET degradation, aerosolized dornase alfa failed to significantly enhance DNAse activity or reduce NET-related markers in patients’ plasma and mucus, suggesting potential bioavailability limitations with this delivery method. In patients with COVID-19-related ARDS, dornase alfa did neither significantly reduce ARDS severity nor improve clinical outcomes over SOC. Although well tolerated, analysis of biological samples suggests that aerosol administration may have compromised drug bioavailability. Further trials are needed to determine whether specific patient subgroups could benefit more from dornase alfa or if alternative drug delivery methods might enhance treatment efficacy. ClinicalTrials.gov, NCT04355364. Registered on 21/04/2020.

Ventilator-associated pneumonia (VAP) is the most common infection in severely injured patients requiring mechanical ventilation. Chest trauma has been identified as a significant risk factor for VAP. This study aimed to describe the risk factors for early VAP in patients with severe blunt thoracic trauma admitted to the intensive care unit (ICU) and receiving mechanical ventilation. A retrospective cohort study was conducted using data from a national registry including data from 17 French trauma centers during a period of seven years. The study included patients with severe blunt thoracic trauma requiring invasive mechanical ventilation. Data analysis focused on identifying independent risk factors for early suspected VAP (occurring within 48 hours to 5 days after ICU admission) using two models of logistic regression. From 31700 patients screened 712 patients were analyzed. Early suspected VAP occurred in 192 (27%) patients. The study identified several independent risk factors associated with early suspected VAP in patients with severe blunt thoracic trauma: male gender (OR= 2.77, 95%CI: 1.68-4.77, p < 0.001), ASA score >1 (OR= 1.64, 95%CI: 1.08-2.50, p = 0.019), injury severity score (ISS) >15 (OR=3.15, 95%CI: 1.13-11.99, p = 0.025), initial Glasgow Coma Scale (GCS) score <9 (OR=2.71, 95%CI: 1.88-3.96, p < 0.001), absolute thoracic abbreviated injury scale (AIS) (OR=1.51, 95%CI: 1.14-1.99, p = 0.003), and the number of packed red blood cells (PRBCs) transfused within the first 24 hours (OR=1.04, 95%CI: 1.00-1.08, p = 0.027). Prehospital antibiotic administration was identified as a protective factor (OR=0.54, 95%CI: 0.29-0.94, p = 0.028). In patients with severe blunt chest trauma receiving invasive mechanical ventilation, male gender, ASA score, ISS > 15, GCS < 9, thoracic AIS and number of PRBCs transfused were independent risk factors for early suspected VAP. Prehospital antibiotic therapy was a protective factor, suggesting potential strategies for VAP prevention.