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BACKGROUND: An association between driving pressure (∆P) and the outcomes of invasive mechanical ventilation (IMV) may exist. However, the effect of a sustained limitation of ∆P on mortality in patients with acute respiratory distress syndrome (ARDS), including patients with COVID-19 (COVID-19-related acute respiratory distress syndrome (C-ARDS)) undergoing IMV, has not been rigorously evaluated. The use of emulations of a target trial in intensive care unit research remains in its infancy. To inform future, large ARDS target trials, we explored using a target trial emulation approach to analyse data from a cohort of IMV adults with C-ARDS to determine whether maintaining daily ∆p24 hours of IMV were considered to be assigned to limited ∆P or LTVV. Lung mechanics were measured twice daily after ventilator setting adjustments were made. To evaluate the effect of each lung-protective ventilation (LPV) strategy on the 28-day mortality, we fit a stabilised inverse probability weighted marginal structural model that adjusted for baseline and time-varying confounders known to affect protection strategy use/adherence or survival. RESULTS: Among the 92 patients included, 27 (29.3%) followed limited ∆P ventilation, 23 (25.0%) the LTVV strategy and 42 (45.7%) received no LPV strategy. The adjusted estimated 28-day survival was 47.0% (95% CI 23%, 76%) in the limited ∆P group, 70.3% in the LTVV group (95% CI 37.6%, 100%) and 37.6% (95% CI 20.8%, 58.0%) in the no LPV strategy group. INTERPRETATION: Limiting ∆P may not provide additional survival benefits for patients with C-ARDS over LTVV. Our results help inform the development of future target trial emulations focused on evaluating LPV strategies, including reduced ∆P, in adults with ARDS.

BACKGROUND: Only a subset of patients at risk for ARDS go on to develop it, and the contribution of preexisting comorbidities (eg, diabetes) to ARDS risk is not well understood. Prior studies of the association between diabetes and ARDS have yielded conflicting results. RESEARCH QUESTION: Does assessing ARDS risk based on hemoglobin A1c (HbA1c) as a marker of long-term blood glucose levels, rather than a charted diagnosis of diabetes, clarify the relationship between diabetes and ARDS? STUDY DESIGN AND METHODS: Using data from two prospective observational cohorts of critically ill adults (Validating Acute Lung Injury Biomarkers for Diagnosis [VALID] and Early Assessment of Renal and Lung Injury [EARLI]), we analyzed the association between clinical HbA1c category and development of ARDS in patients with a risk factor for ARDS and at least one clinical HbA1c measurement within the 180 days prior through 14 days after enrollment. RESULTS: A total of 599 patients in VALID and 276 in EARLI met inclusion criteria, of whom 164 and 58 developed ARDS, respectively. Patients with a charted diagnosis of diabetes were not shown to be more likely to develop ARDS (VALID: 24.6% ARDS in those categorized as nondiabetic vs 30.0% in those categorized as diabetic, P = .14; EARLI: 19.6% vs 22.8%, respectively; P = .55). However, in VALID, patients categorized as diabetic with inadequate glycemic control based on their HbA1c had an increased risk of developing ARDS compared with those with nondiabetic HbA1c (20.9% vs 34.0%, respectively; P = .0073), a finding that persisted in multivariable analysis (OR for those categorized as diabetic with inadequate glycemic control vs those categorized as nondiabetic range HbA1c, 1.25; 95% CI, 1.01-1.57). These findings were not reproduced in the smaller EARLI cohort, but were appreciated when the cohorts were combined for analysis. INTERPRETATION: Elevated HbA1c may be associated with risk of developing ARDS, independent of clinical diagnosis of diabetes, but prospective validation is needed. If confirmed, these findings suggest that inadequate glycemic control could be an unrecognized risk factor for ARDS.

Introduction: Unlicensed cosmetic procedures, which come at increased risk of infection and potential surgical complications, have introduced new challenges in healthcare. Physicians should be aware of presentations that may arise secondary to these procedures.Case Report: We describe a case in which a previously healthy, 28-year-old female presented with new-onset seizures and acute respiratory distress syndrome (ARDS) in the setting of a recent cosmetic procedure with silicone injections to the gluteal region. The patient’s hospital course was complicated by altered mental status, respiratory failure, rapid hemodynamic compromise, and eventual death.Conclusion: In rare cases, one possible complication of cosmetic procedures is silicone embolism syndrome, which is characterized by pneumonitis, alveolar hemorrhage, and ARDS. The patient described in this report also experienced neurologic symptoms including seizure and altered mental status. This is a clinical diagnosis that relies upon thorough history-taking and detailed physical exam. Documentation on this phenomenon is limited, and medical management has not yet been standardized for this condition. Morbidity and mortality remain high.

Background: Since publication of the 2012 Berlin definition of acute respiratory distress syndrome (ARDS), several developments have supported the need for an expansion of the definition, including the use of high-flow nasal oxygen, the expansion of the use of pulse oximetry in place of arterial blood gases, the use of ultrasound for chest imaging, and the need for applicability in resource-limited settings. Methods: A consensus conference of 32 critical care ARDS experts was convened, had six virtual meetings (June 2021 to March 2022), and subsequently obtained input from members of several critical care societies. The goal was to develop a definition that would 1) identify patients with the currently accepted conceptual framework for ARDS, 2) facilitate rapid ARDS diagnosis for clinical care and research, 3) be applicable in resource-limited settings, 4) be useful for testing specific therapies, and 5) be practical for communication to patients and caregivers. Results: The committee made four main recommendations: 1) include high-flow nasal oxygen with a minimum flow rate of ⩾30 L/min; 2) use PaO2:FiO2 ⩽ 300 mm Hg or oxygen saturation as measured by pulse oximetry SpO2:FiO2 ⩽ 315 (if oxygen saturation as measured by pulse oximetry is ⩽97%) to identify hypoxemia; 3) retain bilateral opacities for imaging criteria but add ultrasound as an imaging modality, especially in resource-limited areas; and 4) in resource-limited settings, do not require positive end-expiratory pressure, oxygen flow rate, or specific respiratory support devices. Conclusions: We propose a new global definition of ARDS that builds on the Berlin definition. The recommendations also identify areas for future research, including the need for prospective assessments of the feasibility, reliability, and prognostic validity of the proposed global definition.

BackgroundSevere coccidioidomycosis presenting with respiratory failure is an uncommon manifestation of disease. Current knowledge of this condition is limited to case reports and small case series.MethodsA retrospective multicenter review of patients with coccidioidomycosis-associated acute respiratory distress syndrome (CA-ARDS) was conducted. It assessed clinical and laboratory variables at the time of presentation, reviewed the treatment course, and compared this cohort with a national database of patients with noncoccidioidomycosis ARDS. Survivors and nonsurvivors of coccidioidomycosis were also compared to determine prognostic factors.ResultsIn this study, CA-ARDS (n = 54) was most common in males, those of Hispanic ethnicity, and those with concurrent diabetes mellitus. As compared with the PETAL network database (Prevention and Early Treatment of Acute Lung Injury; n = 1006), patients with coccidioidomycosis were younger, had fewer comorbid conditions, and were less acidemic. The 90-day mortality was 15.4% for patients with coccidioidomycosis, as opposed to 42.6% (P < .0001) for patients with noncoccidioidomycosis ARDS. Patients with coccidioidomycosis who died, as compared with those who survived, were older, had higher APACHE II scores (Acute Physiology and Chronic Health Evaluation), and did not receive corticosteroid therapy.ConclusionsCA-ARDS is an uncommon but morbid manifestation of infection. When compared with a national database, the overall mortality appears favorable vs other causes of ARDS. Patients with CA-ARDS had a low overall mortality but required prolonged antifungal therapy. The utility of corticosteroids in this condition remains unconfirmed.

Introduction: Early noninvasive respiratory support (NIRS) is correlated with a success rate of 60-75% in patients experiencing SARS-CoV-2 ARDS. We conducted a prospective case–control study to assess differences in outcomes between Helmet c-PAP (H-c-PAP) and noninvasive positive pressure ventilation (NIPPV). Methods: All patients with SARS-CoV-2 ARDS, treated with H-c-PAP or NIPPV between October 2021 and April 2022 were sampled. We recorded: demographics, comorbidities, clinical, respiratory, sepsis, NIRS parameters, and outcomes. A "NIRS team" followed the patients in respiratory support supplying them with early and timely intensive physiotherapy i-PKT as well. The Cox's proportional hazard model was applied for multivariate analyses. Results: 368 patients were admitted to our hospital medical ward. 85 patients were treated with H-c-PAP and 145 underwent NIPPV. 138 patients needing oxygen supplementation alone were excluded. The two groups were homogeneously distributed and ICU admission rates were lower in the H-c-PAP one (9.4 vs 11% P =.001) while mortality was higher in the NIPPV group (22.7 vs 9.4%, P =.001). The two multivariate models, that had overall mortality as primary outcome, identified age, H-c-PAP daily, i-PKT and ICU admission as independent variables impacting on the outcome. Age was no longer a significant independent predictor after the inclusion of elderly patients (age >80). The third model showed daily i-PKT could prevent ICU admission whereas the length of NIRS was inversely proportional to outcome. Conclusions: A "NIRS multidisciplinary team" made it possible to adopt an early and timely combination of NIRS and i-PKT resulting in the saving of both patient lives and ICU resources. [ABSTRACT FROM AUTHOR]

BACKGROUND: The dominant feature of COVID-19-associated ARDS is gas exchange impairment. Extravascular lung water index is a surrogate for lung edema and reflects the level of alveolocapillary disruption. The primary aim was the prediction of extravascular lung water index by the alveolar-arterial oxygen difference. The secondary aims were in determining the relationship between the extravascular lung water index and other oxygenation parameters, the FIO2, end-tidal oxygen concentration, pulmonary oxygen gradient (FIO2 minus end-tidal oxygen concentration), and PaO2. Methods: This observational prospective single-center study was performed at the Department of Anaesthesiology and Intensive Care, The University Hospital in Ostrava, The Czech Republic, during the COVID-19 pandemic, from March 20, 2020, until May 24, 2021. Results: The relationship between the extravascular lung water index and alveolar-arterial oxygen difference showed only a mild-to-moderate correlation (r = 0.33, P < .001). Other extravascular lung water index correlations were as follows: FIO2 (r = 0.33, P < .001), end-tidal oxygen concentration (r = 0.26, P = .0032), FIO2 minus end-tidal oxygen concentration (r = 0.15, P = .0624), and PaO2 (r = -0.15, P = .01). Conclusions: The alveolar-arterial oxygen difference does not reliably correlate with the extravascular lung water index and the degree of lung edema in COVID-19-associated ARDS. [ABSTRACT FROM AUTHOR]

Acute respiratory distress syndrome (ARDS) is a multifactorial, inflammatory lung disease with significant morbidity and mortality that predominantly requires supportive care in its management. Although initially described in adult patients, the diagnostic definitions for ARDS have evolved over time to accurately describe this disease process in pediatric and, more recently, neonatal patients. The management of ARDS in each age demographic has converged in the application of lung-protective ventilatory strategies to mitigate the primary disease process and prevent its exacerbation by limiting ventilator-induced lung injury. However, differences arise in the preferred ventilatory strategies or adjunctive pulmonary therapies used to mitigate each type of ARDS. In this review, we compare and contrast the epidemiology, common etiologies, pathophysiology, diagnostic criteria, and outcomes of ARDS across the lifespan. Additionally, we discuss in detail the different management strategies used for each subtype of ARDS and spotlight how these strategies were applied to mitigate poor outcomes during the COVID-19 pandemic. This review is geared toward both clinicians and clinician-scientists as it not only summarizes the latest information on disease pathogenesis and patient management in ARDS across the lifespan but also highlights knowledge gaps for further investigative efforts. We conclude by projecting how future studies can fill these gaps in research and what improvements may be envisioned in the management of NARDS and PARDS based on the current breadth of literature on adult ARDS treatment strategies. [ABSTRACT FROM AUTHOR]

The aim of this study was to evaluate the potential roles of plasma gelsolin (pGSN), transforming growth factor-beta1 (TGF-β1), and lysophosphatidic acid (LPA) as profibrotic and immune modulatory markers in patients with acute respiratory distress syndrome (ARDS) and patients with mild to moderate disease.The study included 60 COVID-19 RT-PCR (+) patients who were divided into two groups as those who developed ARDS and those who did not and 18 non-COVID-19 volunteers. The pGSN, LPA and TGF-β1 levels were measured in the obtained plasma samples and evaluated together with routine laboratory parameters. Prognostic factors were assessed by multivariate analysis, and the predictive values of pGSN, TGF-β1 and LPA for developing ARDS were compared.While increased pGSN levels in COVID-19 patients were found to be decreased with the onset of ARDS; TGF-β1 and LPA levels were lower in patients than in control group, and the lowest levels were observed in patients who developed ARDS. In multivariate analyses, CRP and pGSN were identified as independent risk factors for developing ARDS. The cut-off value of the pGSN was 4,573 ng/mL (90 % sensitivity, 99 % specificity), (area under the curve: 0.977). The predictive values ​​of pGSN is higher than TGF-β1 and LPA.It can be said that the low concentrations of pGSN, TGF-β1 and LPA contribute to the development of ARDS due to the associated immunosuppressive role in COVID-19 patients. [ABSTRACT FROM AUTHOR]

Background: The benefit of Inhaled nitric oxide (iNO) therapy in the setting of COVID-19-related ARDS is obscure. We performed a multicenter retrospective study to evaluate the impact of iNO on patients with COVID-19 who require respiratory support. Methods: This retrospective multicenter study included COVID-19 patients enrolled in the SCCM VIRUS COVID-19 registry who were admitted to different Mayo Clinic sites between March 2020 and June 2022 and required high-flow nasal cannula (HFNC), non-invasive ventilation (NIV), or invasive mechanical ventilation (IMV). Patients were included in the 'spontaneously breathing' group if they remained non-intubated or were initiated on an HFNC (± NIV) before intubation. Patients who got intubated without prior use of an HFNC (± NIV) were included in the 'intubated group.' They were further divided into categories based on their iNO usage. Propensity score matching (PSM) and inverse propensity of treatment weighting (IPTW) were performed to examine outcomes. Results: Among 2767 patients included in our analysis, 1879 belonged to spontaneously breathing (153 received iNO), and 888 belonged to the intubated group (193 received iNO). There was a consistent improvement in FiO2 requirement, P/F ratio, and respiratory rate within 48 h of iNO use among both spontaneously breathing and intubated groups. However, there was no significant difference in intubation risk with iNO use among spontaneously breathing patients (PSM OR 1.08, CI 0.71–1.65; IPTW OR 1.10, CI 0.90–1.33). In a time-to-event analysis using Cox proportional hazard model, spontaneously breathing patients initiated on iNO had a lower hazard ratio of in-hospital mortality (PSM HR 0.49, CI 0.32–0.75, IPTW HR 0.40, 95% CI 0.26–0.62) but intubated patients did not (PSM HR: 0.90; CI 0.66–1.24, IPTW HR 0.98, 95% CI 0.73–1.31). iNO use was associated with longer in-hospital stays, ICU stays, ventilation duration, and a higher incidence of creatinine rise. Conclusions: This retrospective propensity-score matched study showed that spontaneously breathing COVID-19 patients on HFNC/ NIV support had a decreased in-hospital mortality risk with iNO use in a time-to-event analysis. Both intubated and spontaneously breathing patients had improvement in oxygenation parameters with iNO therapy but were associated with longer in-hospital stays, ICU stays, ventilation duration, and higher incidence of creatinine rise. [ABSTRACT FROM AUTHOR]

Background Methods Results Conclusion Casualties of military conflicts suffer a multitude of injuries, and recent research has documented a significant number develop acute respiratory distress syndrome (ARDS). The present study undertakes a scoping review of research on the treatment of ARDS in combat casualties near the battlefield.We review the extent of the current ARDS care, from intubation and mechanical ventilation (MV) to the use of extracorporeal membrane oxygenation (ECMO), and how the respective echelons of care across the Military Health System (MHS) are involved in the care of these patients. Online databases were used to identify article published 1988–2022, from which we selected 112 publications from various countries including the USA, UK, Germany, Italy, and India that used military relevant keywords (i.e., battlefield, combat, deployed, military trauma), in the titles or abstract in conjunction with the MeSH descriptors for battlefield respiratory failure, and MV or ECMO.Mechanical ventilation and ECMO have clearly moved forward with progressions in technologies and now are routinely used and are well documented in the prehospital setting and during aeromedical transport. Overview of the MHS and descriptive analysis of battlefield casualties are well represented in the literature. There are multiple publications on airway management on the battlefield and innumerable regarding the somewhat comparable civilian prehospital trauma airway management.While there is an abundance of publications on MV in the prehospital and combat environments, there are few case examples of the use of ECMO on the battlefield. Although MV may be required for many combat casualties, airway management failure remains the second leading cause of preventable death on the battlefield. [ABSTRACT FROM AUTHOR]

Since the global COVID‐19 pandemic, there has been a renewed focus on lung injury during infection. Systemic inflammatory responses such as acute respiratory distress syndrome (ARDS) and sepsis are a leading cause of morbidity and mortality for both adults and children. Improvements in clinical care have improved outcomes but mortality remains ∼40% and significant morbidity persists for those patients with severe disease. Mechanistic studies of the underlying biological processes remain essential to identifying therapeutic targets. Furthermore, methods for identifying the underlying drivers of organ failure are key to treating and preventing tissue injury. In this review, we discuss the contribution of megakaryocytes (MKs) and platelets to the pathogenesis of systemic inflammatory syndromes. We explore the role of MKs and the new identification of extramedullary MKs during sepsis. We describe the alterations in the platelet transcriptome during sepsis. Lastly, we explore platelet function as defined by aggregation, activation and the formation of heterotypic aggregates. Much more work is necessary to explore the contribution of platelets to these heterogenous syndromes, but the foundation of platelets as key contributors to inflammation has been laid. [ABSTRACT FROM AUTHOR]

Background: Acute Respiratory Distress Syndrome (ARDS) has a high morbidity and mortality. One therapy that can decrease mortality is ventilation in the prone position (PP). Patients undergoing PP are amongst the sickest, and there is a need for early identification of patients at particularly high risk of death. These patients may benefit from an in-depth review of treatment or consideration of rescue therapies. We report the development of a machine learning model trained to predict early mortality in patients undergoing prone positioning as part of the management of their ARDS. Methods: Prospectively collected clinical data were analysed retrospectively from a single tertiary ICU. The records of patients who underwent an initial session of prone positioning whilst receiving invasive mechanical ventilation were identified (n = 131). The decision to perform prone positioning was based on the criteria in the PROSEVA study. A C5.0 classifier algorithm with adaptive boosting was trained on data gathered before, during, and after initial proning. Data was split between training (85% of data) and testing (15% of data). Hyperparameter tuning was achieved through a grid-search using a maximal entropy configuration. Predictions for 7-day mortality after initial proning session were made on the training and testing data. Results: The model demonstrated good performance in predicting 7-day mortality (AUROC: 0.89 training, 0.78 testing). Seven variables were used for prediction. Sensitivity was 0.80 and specificity was 0.67 on the testing data set. Patients predicted to survive had 13.3% mortality, while those predicted to die had 66.67% mortality. Among patients in whom the model predicted patient would survive to day 7 based on their response, mortality at day 7 was 13.3%. Conversely, if the model predicted the patient would not survive to day 7, mortality was 66.67%. Conclusions: This proof-of-concept study shows that with a limited data set, a C5.0 classifier can predict 7-day mortality from a number of variables, including the response to initial proning, and identify a cohort at significantly higher risk of death. This can help identify patients failing conventional therapies who may benefit from a thorough review of their management, including consideration of rescue treatments, such as extracorporeal membrane oxygenation. This study shows the potential of a machine learning model to identify ARDS patients at high risk of early mortality following PP. This information can guide clinicians in tailoring treatment strategies and considering rescue therapies. Further validation in larger cohorts is needed. [ABSTRACT FROM AUTHOR]

Background: Pulmonary intravascular thrombus formation has been widely observed in patients with respiratory failure, for example, in patients with SARS-CoV-2 infection (COVID-19). The aim of this study was to evaluate the efficacy/safety of alteplase thrombolysis in COVID-19 severe hypoxemic respiratory failure. In this multicenter, open-label study, patients were randomized to receive alteplase (low- or high-dose) over 5 days plus standard of care (SOC), or SOC alone. The primary endpoint was time to clinical improvement (≥ 2-point decrease on WHO Clinical Progression Scale, or hospital discharge) up to Day 28. Secondary endpoints included all-cause mortality at Day 28, treatment failure at Day 28 and change in arterial oxygen partial pressure/fractional inspired oxygen (PaO2/FiO2) ratio at Day 6 versus baseline. Results: Sixty-nine patients were randomized to alteplase (low- or high-dose) and 35 to SOC; 65% were on high-flow oxygen or non-invasive ventilation at baseline. Median time to clinical improvement was 25 days in the alteplase group and > 28 days (median not reached) in the SOC group. All-cause mortality was 8/69 (12%) versus 10/35 (29%) in the alteplase versus SOC groups, respectively (unadjusted risk difference [RD], − 17% [95% confidence interval (CI) − 34 to 0], p = 0.047; adjusted RD, − 16% [95% CI − 31 to 1], p = 0.058). The PaO2/FiO2 ratio (mean [standard deviation]) increased by + 30 (84) mmHg in the alteplase group and decreased by − 12 (59) mmHg in the SOC group (adjusted mean difference vs. SOC, p = 0.052). Differences were greater in patients receiving high-dose alteplase, and in those not receiving invasive ventilation. Eighteen patients (26.1%) in the alteplase group discontinued treatment due to adverse events. Major bleeding was more frequent with alteplase than with SOC (9 vs. 0 patients); no bleeding was fatal. The study closed early due to insufficient patient recruitment. Conclusion: Alteplase was not associated with faster clinical recovery from COVID-19 severe hypoxemic respiratory failure. A numerical difference in survival and PaO2/FiO2 ratio was observed, particularly in patients not receiving invasive ventilation. These exploratory findings merit further investigation in larger patient cohorts that are adequately powered to confirm the hypotheses generated in this study regarding the impact of alteplase on treatment outcomes. Trial registration ClinicalTrials.gov: NCT04640194 (November 23, 2020); https://clinicaltrials.gov/study/NCT04640194 (early discontinuation due to insufficient patient recruitment). [ABSTRACT FROM AUTHOR]

Subjective Social Status (SSS) reflects one’s perceived rank within a given social structure and has been shown to be a unique correlate of physical and mental health. However, no research has been conducted to address populations of (recovering) critically ill patients. To shed light on the relationship between SSS and health in critically ill patients, we focus on survivors of acute respiratory distress syndrome (ARDS). A cohort study with N = 877 ARDS survivors was conducted in 61 intensive care units (ICUs) in Germany between 2014 and 2019. Health-related quality of life (HRQoL, Physical and Mental Component Scale: PCS, MCS of the SF-12) and SSS (MacArthur Scale) were assessed at 12, 24, and 36 months after discharge from ICU. Objective social status (Socioeconomic status [SES]) was assessed once at ICU baseline. Bivariate correlations between SSS and HRQoL (PCS and MCS) remain significant throughout the study period (r = .29 – .50, all p-values < .05). Subsequent hierarchical regression shows that SSS remains predictive for PCS and MCS even after controlling for SES (β = .335 – .486, all p values < .001). The results indicate the importance (and unique contribution) of the subjective localization within the status hierarchy for long-term HRQoL after critical illness. [ABSTRACT FROM AUTHOR]

Fever is common in the ICU, with infectious causes accounting for only half of febrile episodes. This case examines a young male who developed high‐grade fevers and pulmonary infiltrates unresponsive to broad‐spectrum antibiotics. Examination revealed hepatosplenomegaly, hypertriglyceridemia, anemia, and thrombocytopenia, suggestive of hemophagocytic lymphohistiocytosis (HLH). Meeting 5 of 8 HLH criteria, high‐dose steroids were administered, resulting in clinical improvement. HLH, with a high mortality risk, demands early recognition, complicated by nonspecific symptoms. This case highlights the rare manifestation of ARDS in HLH, adding diagnostic challenges in critical care settings. [ABSTRACT FROM AUTHOR]

Thromboembolic complications are common in severe COVID-19 and are thought to result from excessive neutrophil-extracellular-trap (NET)-driven immunothrombosis. Glycosylation plays a vital role in the efficiency of immunoglobulin A (IgA) effector functions, with significant implications for NET formation in infectious diseases. This study represents the first comprehensive analysis of plasma IgA glycosylation during severe SARS-CoV-2 or Influenza A infection, revealing lower sialylation and higher galactosylation of IgA1 O-glycans in acute respiratory distress syndrome (ARDS), regardless of the underlying cause of the disease. Importantly, N-glycans displayed an infection-specific pattern, with N47 of IgA2 showing diminished sialylation and bisection, and N340/N327 of IgA1/2 demonstrating lower fucosylation and antennarity along with higher non-complex glycans in COVID-19 compared to Influenza. Notably, COVID-19 IgA possessed strong ability to induce NET formation and its glycosylation patterns correlated with extracellular DNA levels in plasma of critically ill COVID-19 patients. Our data underscores the necessity of further research on the role of IgA glycosylation in the modulation of pathogen-specific immune responses in COVID-19 and other infectious diseases. [ABSTRACT FROM AUTHOR]

Background: Acute respiratory distress syndrome (ARDS) is a serious acute lung injury, and can develop into pulmonary fibrosis (PLF). Circular RNAs (circRNAs) regulatory network in ARDS is important. The study explored the role of hsa_circ_0006892 in the occurrence of ARDS and the development of PLF. Methods: Hsa_circ_0006892 levels were verified in serum samples of 203 ARDS patients with or without PLF, and the diagnostic value was evaluated through ROC. Cox regression analysis was performed to identify PLF-related factors. The downstream target genes were predicted online. The function and pathway of key genes were annotated through GO and KEGG pathway analysis. Protein-protein interaction (PPI) analysis was performed for the examination of protein interactions. Results: qRT-PCR determined the downregulation of hsa_circ_0006892 in the serum of both ARDS and PLF patients. Hsa_circ_0006892 can differentiate ARDS from controls, and independently related to the development of PLF. Nine targeted related miRNAs were integrated with dysregulated miRNAs from GSE27430 dataset. Clinically, miR-486-3p was the only miRNA that was significantly different in both ARDS and PLF groups, and was determined to be the target of hsa_circ_0006892. 180 target genes of miR-486-3p were predicted, which were integrated with ARDS and PLF-related GSE84439 and GSE38958 datasets. Go and KEGG pathway analysis identified Ras signaling pathway as the most commonly enriched pathway in the overlapped genes. Conclusions: The present results identified the differentially expressed hsa_circ_0006892 in ARDS and PLF, and suggested a possible molecular mechanism of hsa_circ_0006892/miR-486-3p axis. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to describe the characteristics of patients admitted to the intensive care unit with severe pneumonia due to SARS-CoV-2, comparing them according to successive waves, and to identify prognostic factors for morbidity and mortality. Materials and methods: This single-center retrospective observational descriptive study was conducted from March 10, 2020, to October 17, 2021. All adult patients admitted with SARS-CoV-2 pneumonia presenting acute respiratory failure were included. COVID 19 diagnosis was confirmed by RT-PCR testing of respiratory specimens. The primary endpoint was ICU mortality. Secondary endpoints were the occurrence of ventilator-associated pneumonia (VAP) or bronchopulmonary aspergillosis. Results: Over the study period, 437 patients were included of whom 282 (65%) patients were ventilated for 9 [5;20] days. Among the studied population, 38% were treated for one or more episodes of VAP, and 22 (5%) for bronchopulmonary aspergillosis. ICU mortality was 26% in the first wave, then fell and stabilized at around 10% in subsequent waves (p = 0.02). Increased age, Charlson index, SOFA score and lactatemia on admission were predictive of mortality. Survival at 90 days was 85% (95% CI 82–88) and was unaffected by the presence of VAP. However, the occurrence of bronchopulmonary aspergillosis increased mortality to 36%. Conclusion: In this study, we observed mortality in the lower range of those previously reported. Risk factors for mortality mainly included age and previous comorbidities. The prognosis of these critically ill Covid 19 patients improved over the four waves, underlining the likely beneficial effect of vaccination and dexamethasone. [ABSTRACT FROM AUTHOR]

The use of transpulmonary pressure monitoring based on measurement of esophageal pressure has contributed importantly to the personalization of mechanical ventilation based on respiratory pathophysiology in critically ill patients. However, esophageal pressure monitoring is still underused in the clinical practice. This technique allows partitioning of the respiratory mechanics between the lungs and the chest wall, provides information on lung recruitment and risk of barotrauma, and helps titrating mechanical ventilation settings in patients with respiratory failure. In assisted ventilation modes and during non-invasive respiratory support, esophageal pressure monitoring provides important information on the inspiratory effort and work of breathing. Nonetheless, several controversies persist on technical aspects, interpretation and clinical decision-making based on values derived from this monitoring technique. The aim of this review is to summarize the physiological bases of esophageal pressure monitoring, discussing the pros and cons of its clinical applications and different interpretations in critically ill patients undergoing invasive and non-invasive respiratory support. [ABSTRACT FROM AUTHOR]

Acute respiratory distress syndrome (ARDS) is a severe lung condition without targeted therapy that is characterized by the disruption of epithelial and endothelial barriers. The role of the tight junction protein occludin in the pathogenesis of this disease is unknown, although it has previously been deemed redundant in some tissues. The aim of the present study is to determine whether occludin is required for lung function by controlling alveolar barrier integrity in mouse models. Immunofluorescence staining of lungs from ARDS patients revealed a significant decrease in occludin expression compared to controls. Gene delivery of shRNA against occludin in the mouse lung reduced occludin levels and induced lung injury, as assessed by wet-to-dry-ratio, histology, and cellularity and protein content of bronchial alveolar lavage fluid. Conversely, gene delivery of an occludin-expressing plasmid increased occludin expression and dampened endotoxin-induced lung injury. In primary rat alveolar epithelial cells, occludin levels were positively correlated with barrier integrity, as well as membrane localization of claudin-18, another tight junction protein. Collectively, our data demonstrate that occludin plays a significant role in alveolar barrier function and that targeting occludin may provide a new therapeutic approach for ARDS. [ABSTRACT FROM AUTHOR]

Acute Respiratory Distress Syndrome (ARDS) is a severe lung condition with a high mortality rate for which there are no effective therapeutics. The failure of the alveolar–capillary barrier, composed of lung endothelial (EC) and alveolar epithelial (AEC) cells, is a critical factor leading to excessive inflammation and edema characteristic of acute lung injury (ALI) pathophysiology. Phosphodiesterases (PDE) are enzymes well-recognized for their roles in regulating endothelial permeability and inflammation. Although PDE inhibitors are used as therapeutics for inflammatory diseases like COPD (chronic obstructive pulmonary disease), their efficacy in treating ARDS has not yet been established. In this study, we investigated the effects of ensifentrine, an FDA-approved novel dual PDE 3/4 inhibitor, on lung endothelial and epithelial dysfunction caused by methicillin-resistant S. aureus (MRSA), a pathogen involved in bacterial ARDS. Human primary lung endothelial cells and alveolar epithelial cell lines (A549 and immortalized AEC) were treated with heat-killed MRSA, and their responses were assessed in the presence or absence of ensifentrine. Ensifentrine given either pre- or post-exposure attenuated MRSA-induced increased lung endothelial permeability. VE-cadherin junctions, which serve to stabilize the EC barrier, were disrupted by MRSA; however, ensifentrine effectively prevented this disruption. Pre-treatment with ensifentrine protected against MRSA-induced EC pro-inflammatory signaling by inhibiting the expression of VCAM-1, ICAM-1, and by reducing the IL-6 and IL-8 release. In AEC, MRSA caused the upregulation of ICAM-1, the activation of NF-kB, and the production of IL-8, all of which were inhibited by ensifentrine. These results indicate that the dual inhibition of phosphodiesterases 3 and 4 by ensifentrine is barrier protective and attenuates MRSA-induced inflammation in both lung endothelial and epithelial cells. The PDE3/4 inhibitor ensifentrine may represent a promising novel strategy for the treatment of MRSA-induced ARDS. [ABSTRACT FROM AUTHOR]

Background: Postoperative negative pressure pulmonary edema (NPPE) can occur in any patient undergoing general anesthesia. There are several risk factors for it, especially postoperative laryngospasm. The disease is usually benign and quickly reversible. In our case the severity and need for advanced critical care therapy was unusual. Case: We report a severe case of postoperative negative pressure pulmonary edema in a 62-year-old male patient undergoing elective right-sided retroperitoneoscopic adrenalectomy. The patient developed a severe case of acute respiratory distress syndrome (ARDS) after postoperative laryngospasm, possibly in conjunction with a suspected anaphylactic reaction. The patient was consequently treated with a combination of invasive airway pressure release ventilation (APRV) and a prone positioning regimen. After drastic improvement in respiratory function, the patient was discharged from the intensive care unit after 10 days and from the hospital after 14 days. Conclusion: NPPE is a rare but relevant complication of anesthesia and laryngospasm. The disease can basically occur in any patient undergoing general anesthesia and therefore should be considered. [ABSTRACT FROM AUTHOR]

Background: Quantification of pulmonary edema in patients with acute respiratory distress syndrome (ARDS) by chest computed tomography (CT) scan has not been validated in routine diagnostics due to its complexity and time-consuming nature. Therefore, the single-indicator transpulmonary thermodilution (TPTD) technique to measure extravascular lung water (EVLW) has been used in the clinical setting. Advances in artificial intelligence (AI) have now enabled CT images of inhomogeneous lungs to be segmented automatically by an intensive care physician with no prior radiology training within a relatively short time. Nevertheless, there is a paucity of data validating the quantification of pulmonary edema using automated lung segmentation on CT compared with TPTD. Methods: A retrospective study (January 2016 to December 2021) analyzed patients with ARDS, admitted to the intensive care unit of the Department of Anesthesiology and Critical Care Medicine, University Hospital Mannheim, who underwent a chest CT scan and hemodynamic monitoring using TPTD at the same time. Pulmonary edema was estimated using manually and automated lung segmentation on CT and then compared to the pulmonary edema calculated from EVLW determined using TPTD. Results: 145 comparative measurements of pulmonary edema with TPTD and CT were included in the study. Estimating pulmonary edema using either automated lung segmentation on CT or TPTD showed a low bias overall (− 104 ml) but wide levels of agreement (upper: 936 ml, lower: − 1144 ml). In 13% of the analyzed CT scans, the agreement between the segmentation of the AI algorithm and a dedicated investigator was poor. Manual segmentation and automated segmentation adjusted for contrast agent did not improve the agreement levels. Conclusions: Automated lung segmentation on CT can be considered an unbiased but imprecise measurement of pulmonary edema in mechanically ventilated patients with ARDS. [ABSTRACT FROM AUTHOR]

Acute respiratory distress syndrome (ARDS) is characterized by bilateral chest infiltration and acute hypoxic respiratory failure. ARDS carries significant morbidity and mortality despite advancements in medical management, calling for the development of novel therapeutic targets. Hypoxia‐inducible factor (HIF) is a heterodimeric protein involved in various essential pathways, including metabolic reprogramming, immune modulation, angiogenesis and cell cycle regulation. HIF is routinely degraded in homeostasis conditions via the prolyl hydroxylase domain/von Hippel–Lindau protein pathway. However, HIF is stabilized in ARDS via various mechanisms (oxygen‐dependent and independent) as an endogenous protective pathway and plays multifaceted roles in different cell populations. This review focuses on the functional role of HIF and its target genes during ARDS, as well as how HIF has evolved as a therapeutic target in current medical management. [ABSTRACT FROM AUTHOR]

· Differences in the clinical course of intensive care unit (ICU) admitted male and female patients with serve coronavirus disease 2019 (COVID-19) has not been investigated. · We aimed to investigate, in a large global population of ICU admitted COVID-19 patients, the impact of sex on ICU mortality and complications. · Males experienced critical illness that was protracted and required intervention more often than females. · Males had higher odds of developing cardiac arrest and pulmonary embolism, as a complication of COVID-19. · Future investigators ought to evaluate sex-differences in the long-term recovery of patients admitted to ICU with COVID-19. Sex differences in severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) susceptibility, illness severity, and hospital course are widely acknowledged. The effects of sex on outcomes experienced by patients with severe Coronavirus Disease 2019 (COVID-19) admitted to the intensive care unit (ICU) remains unknown. To determine the effects of sex on ICU mortality in patients with COVID-19 This retrospective analysis of an international multi-center prospective observational database included adults admitted to ICU for treatment of acute COVID-19 between 1st January 2020 and 30th June 2022. The primary outcome was ICU mortality. Multivariable Cox regression was used to ascertain the hazard of death (Hazard Ratio=HR) adjusted for pre-selected covariates. The secondary outcome was sex differences in complications of COVID-19 during hospital stay. Overall, 10,259 patients (3,314 females, 6,945 males) were included with a median age of 60 (interquartile range [IQR]=49–68) and 59 (IQR=49–67) years, respectively. Baseline characteristics were similar between sexes. More females were non-smokers (65% vs. 44 %, p < 0.01) and obese (39% vs. 30 %, p < 0.01), compared to males. Also, males received greater ICU intervention (mechanical ventilation, prone ventilation, vasopressors, and tracheostomy) than females. Males had a greater hazard of death (compared to females, HR=1.14; 95 % CI=1.02–1.26). Adjustment for complications during hospital stay did not alter the hazard of death (HR=1.16; 95 % CI=1.05–1.28). Males had a significantly elevated hazard of death among patients who received ECMO (HR=1.24; 95 % CI=1.01–1.53). Male sex was associated with cardiac arrest (adjusted OR [aOR]=1.37; 95 % CI=1.16–1.62) and PE (aOR=1.28; 95 % CI=1.06–1.55). Among patients admitted to ICU for severe COVID-19, males experienced higher severity of illness and more frequent intervention than females. Ultimately, the hazard of death was moderately elevated in males compared to females despite greater PE and cardiac arrest. [ABSTRACT FROM AUTHOR]

Background: By 2023, COVID-19 had caused 6.8 million deaths in the United States. COVID-19 presents more severely in leukemia compared to solid tumors (OR 1.6, p<0.05). However, data on Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS) are limited. We investigated the mortality in AML and MDS patients with COVID-19. Methods: Data from the 2020-2021 National Inpatient Sample was used to conduct a cross-sectional analysis. We identified AML and MDS patients with COVID-19 hospitalizations through ICD-10 codes. Analysis was done by propensity matching and multivariate regression with a p-value of =0.05. Results: Of 28,028 AML admissions, 336 (1.2%) were admitted for COVID-19. AML-COVID-19 cohort had a lower hospitalization risk (aOR 0.3, p=0.000) and higher mortality (21.7% vs 8.7%; aOR 1.6, p=0.023) than AML patients admitted for other causes. AML patients post-HSCT (Hematopoietic Stem Cell Transplantation) had a higher risk of COVID-19 (20.2% vs 9.8%; aOR 2.6, p=0.000) and increased mortality (19.1% vs 6.7%; aOR 4.1, p=0.000) compared to other causes. Similarly, of 28,148 MDS patients, 769 (2.7%) were admitted for COVID-19. The MDS-COVID-19 cohort had a lower hospitalization risk (aOR 0.59, p=0.000) and higher mortality (19.6% vs 6.6%; aOR 2.2, p=0.000) compared to other causes. In MDS, HSCT did not alter the risk of COVID-19 hospitalizations (3% vs 3.9%; aOR 0.9, p=0.662), but these patients had higher mortality (17.4% vs 5.1%; aOR 4.0, p=0.032). Conclusion: COVID-19 hospitalization was low in AML and MDS but carried a high mortality risk. Post-HSCT, the mortality is high, warranting research into understanding the underlying factors. [ABSTRACT FROM AUTHOR]

Background: Despite being essential in patients with acute respiratory distress syndrome (ARDS), mechanical ventilation (MV) may cause lung injury and hemodynamic instability. Mechanical power (MP) may describe the net injurious effects of MV, but whether it reflects the hemodynamic effects of MV is currently unclear. We hypothesized that MP is also associated with cardiac output (CO) and pulmonary blood flow (PBF). Methods: 24 anesthetized pigs with experimental acute lung injury were ventilated for 18 h according to one of three strategies: 1) Open lung approach (OLA), 2) ARDS Network high-PEEP/FIO2 strategy (HighPEEP), or 3) low-PEEP/FIO2 strategy (LowPEEP). Total MP was assessed as the sum of energy dissipated to overcome airway resistance and energy temporarily stored in the elastic lung tissue per minute. The distribution of pulmonary perfusion was determined by positron emission tomography. Regional PBF and MP, assessed in three iso-gravitational regions of interest (ROI) with equal lung mass (ventral, middle, and dorsal ROI), were compared between groups. Results: MP was higher in the LowPEEP than in the OLA group, while CO did not differ between groups. After 18 h, regional PBF did not differ between groups. During LowPEEP, regional MP was higher in the ventral ROI compared to OLA and HighPEEP groups (2. 5 ± 0. 3 vs. 1. 4 ± 0. 4 and 1. 6 ± 0. 3 J/min, respectively, P < 0. 001 each), and higher in the middle ROI compared to the OLA group (2. 5 ± 0. 4 vs. 1. 6 ± 0. 5 J/min, P = 0. 04). MP in the dorsal ROI did not differ between groups (1. 4 ± 0. 9 vs. 1. 4 ± 0. 5 vs. 1. 3 ± 0. 8 J/min, P = 0. 916). Total MP was independently associated with CO [0. 34 (0. 09, 0. 59), P = 0. 020]. Regional MP was positively associated with PBF irrespective of the regions [0. 52 (0. 14, 0. 76), P = 0. 01; 0. 49 (0. 10, 0. 74), P = 0. 016; 0. 64 (0. 32, 0. 83), P = 0. 001 for ventral, middle, and dorsal ROI, respectively]. Subgroup analysis revealed a significant association of MP and CO only in the OLA group as well as a significant association between MP with regional PBF only in the HighPEEP group. Conclusion: In this model of acute lung injury in pigs ventilated with either open lung approach, high, or low PEEP tables recommended by the ARDS network, MP correlated positively with CO and regional PBF, whereby these clinically relevant lung-protective ventilation strategies influenced the associations. [ABSTRACT FROM AUTHOR]

Background: The airway epithelium (AE) fulfils multiple functions to maintain pulmonary homeostasis, among which ensuring adequate barrier function, cell differentiation and polarization, and actively transporting immunoglobulin A (IgA), the predominant mucosal immunoglobulin in the airway lumen, via the polymeric immunoglobulin receptor (pIgR). Morphological changes of the airways have been reported in ARDS, while their detailed features, impact for mucosal immunity, and causative mechanisms remain unclear. Therefore, this study aimed to assess epithelial alterations in the distal airways of patients with ARDS. Methods: We retrospectively analyzed lung tissue samples from ARDS patients and controls to investigate and quantify structural and functional changes in the small airways, using multiplex fluorescence immunostaining and computer-assisted quantification on whole tissue sections. Additionally, we measured markers of mucosal immunity, IgA and pIgR, alongside with other epithelial markers, in the serum and the broncho-alveolar lavage fluid (BALF) prospectively collected from ARDS patients and controls. Results: Compared to controls, airways of ARDS were characterized by increased epithelial denudation (p = 0.0003) and diffuse epithelial infiltration by neutrophils (p = 0.0005). Quantitative evaluation of multiplex fluorescence immunostaining revealed a loss of ciliated cells (p = 0.0317) a trend towards decreased goblet cells (p = 0.056), and no change regarding cell progenitors (basal and club cells), indicating altered mucociliary differentiation. Increased epithelial permeability was also shown in ARDS with a significant decrease of tight (p < 0.0001) and adherens (p = 0.025) junctional proteins. Additionally, we observed a significant decrease of the expression of pIgR, (p < 0.0001), indicating impaired mucosal IgA immunity. Serum concentrations of secretory component (SC) and S-IgA were increased in ARDS (both p < 0.0001), along other lung-derived proteins (CC16, SP-D, sRAGE). However, their BALF concentrations remained unchanged, suggesting a spillover of airway and alveolar proteins through a damaged AE. Conclusion: The airway epithelium from patients with ARDS exhibits multifaceted alterations leading to altered mucociliary differentiation, compromised defense functions and increased permeability with pneumoproteinemia. [ABSTRACT FROM AUTHOR]

In patients with sepsis, neutrophil apoptosis tends to be inversely proportional to the severity of sepsis, but its mechanism is not yet clear. This study aimed to explore the mechanism of fatty acid binding protein 4 (FABP4) regulating neutrophil apoptosis through combined analysis of gut microbiota and short-chain fatty acids (SCFAs) metabolism. First, neutrophils from bronchoalveolar lavage fluid (BALF) of patients with sepsis-induced acute respiratory distress syndrome (ARDS) were purified and isolated RNA was applied for sequencing. Then, the cecal ligation and puncture (CLP) method was applied to induce the mouse sepsis model. After intervention with differential SCFAs sodium acetate, neutrophil apoptosis and FABP4 expression were further analyzed. Then, FABP4 inhibitor BMS309403 was used to treat neutrophils. We found CLP group had increased lung injury score, lung tissue wet/dry ratio, lung vascular permeability, and inflammatory factors IL-1β, TNF-α, IL-6, IFN-γ, and CCL3 levels in both bronchoalveolar lavage fluid and lung tissue. Additionally, FABP4 was lower in neutrophils of ARDS patients and mice. Meanwhile, CLP-induced dysbiosis of gut microbiota and changes in SCFAs levels were observed. Further verification showed that acetic acids reduced neutrophil apoptosis and FABP4 expression via FFAR2. Besides, FABP4 affected neutrophil apoptosis through endoplasmic reticulum (ER) stress, and neutrophil depletion alleviated the promotion of ARDS development by BMS309403. Moreover, FABP4 in neutrophils regulated the injury of RLE-6TN through inflammatory factors. In conclusion, FABP4 affected by gut microbiota-derived SCFAs delayed neutrophil apoptosis through ER stress, leading to increased inflammatory factors mediating lung epithelial cell damage. [ABSTRACT FROM AUTHOR]

Background: Convalescent plasma (CP) reduced the mortality in COVID-19 induced ARDS (C-ARDS) patients treated in the CONFIDENT trial. As patients are immunologically heterogeneous, we hypothesized that clusters may differ in their treatment responses to CP. Methods: We measured 20 cytokines, chemokines and cell adhesion markers using a multiplex technique at the time of inclusion in the CONFIDENT trial in patients of centers having accepted to participate in this secondary study. We performed descriptive statistics, unsupervised hierarchical cluster analysis, and examined the association between the clusters and CP effect on day-28 mortality. Results: Of the 475 patients included in CONFIDENT, 391 (82%) were sampled, and 196/391 (50.1%) had been assigned to CP. We identified four sub-phenotypes representing 89 (22.8%), 178 (45.5%), 38 (9.7%), and 86 (22.0%) patients. The most contributing biomarkers in the principal component analysis were IL-1β, IL-12p70, IL-6, IFN-α, IL-17A, IFN-γ, IL-13, TFN-α, total IgG, and CXCL10. Sub-phenotype-1 displayed a lower immune response, sub-phenotype-2 a higher adaptive response, sub-phenotype-3 the highest innate antiviral, pro and anti-inflammatory response, and adhesion molecule activation, and sub-phenotype-4 a higher pro and anti-inflammatory response, migration protein and adhesion molecule activation. Sub-phenotype-2 and sub-phenotype-4 had higher severity at the time of inclusion. The effect of CP treatment on mortality appeared higher than standard care in each sub-phenotype, without heterogeneity between sub-phenotypes (p = 0.97). Conclusion: In patients with C-ARDS, we identified 4 sub-phenotypes based on their immune response. These sub-phenotypes were associated with different clinical profiles. The response to CP was similar across the 4 sub-phenotypes. Trial registration: Ethics Committee of the University Hospital of Liège CE 2020/239. Clinicaltrials.gov NCT04558476. Registered 2020-09-11, https://www.clinicaltrials.gov/study/NCT04558476. [ABSTRACT FROM AUTHOR]

Background Methods Results Conclusion Severe acute respiratory syndrome (ARDS) may require veno‐venous extracorporeal membrane oxygenation (V‐V ECMO). The aim of this study was to provide data on patient selection and outcome in a nationwide cohort study of patients with COVID‐19 associated ARDS supported with V‐V ECMO.We identified all patients with COVID‐19, who were supported with V‐V ECMO in Denmark from March 10, 2020, to December 31, 2021, and retrieved data on patients who were referred to‐ and accepted for ECMO, demographics, outcome data, and complications. Risk factors for mortality were analysed using multivariate Cox regression analysis.During the study period, 1836 patients were admitted to Danish intensive care units (ICUs). In the same period, there were 197 enquiries for ECMO of whom 118 patients were considered eligible. Overall, 71 patients were cannulated for ECMO; three patients were cannulated for veno‐arterial extracorporeal membrane oxygenation (V‐A ECMO) due to right sided heart failure and 68 patients were cannulated for V‐V ECMO. Two patients accepted for V‐V ECMO died during cannulation. The median age was 55 years (IQR 45–60) and 66% were males. The median duration of ECMO support was 13 days (IQR 7–21), mechanical ventilation median 26 days (IQR 14–42), ICU stay median 34 days (IQR 17–46), and length of hospital stay median 41 days (IQR 25–56). Ninety‐day mortality was 43%. Age of 60 years or more was associated with an increased risk of mortality. Pre‐existing hypertension was associated with a decreased risk of mortality.A nationwide, Danish cohort study of 68 COVID‐19 patients supported with V‐V ECMO, showed a 90‐day survival of 43%, which is in accordance with reports from comparable cohorts. Age of 60 years or more was associated with an increased risk of mortality. Pre‐existing hypertension was associated with a decreased risk of mortality. [ABSTRACT FROM AUTHOR]

Point of Care ultrasound (POCUS) of the lungs, also known as lung ultrasound (LUS), has emerged as a technique that allows for the diagnosis of many respiratory pathologies with greater accuracy and speed compared to conventional techniques such as chest x-ray and auscultation. The goal of this narrative review is to provide a simple and practical approach to LUS for critical care, pulmonary, and anesthesia providers, as well as respiratory therapists and other health care providers to be able to implement this technique into their clinical practice. In this review, we will discuss the basic physics of LUS, provide a hands-on scanning technique, describe LUS findings seen in normal and pathological conditions (such as mainstem intubation, pneumothorax, atelectasis, pneumonia, aspiration, COPD exacerbation, cardiogenic pulmonary edema, ARDS, and pleural effusion) and also review the training necessary to achieve competence in LUS. [ABSTRACT FROM AUTHOR]

Background: Prone position ventilation (PPV) is recommended for patients with COVID‐19 induced severe Adult Respiratory Distress Syndrome (ARDS) and is used for patients supported with V‐V ECMO as well. The purpose of this study was to describe the use of PPV in these patients focusing on physiological effects with the hypothesis that PPV could reduce oxygen need and improve dynamic compliance. Methods: This study was a nationwide retrospective analysis of all COVID‐19 patients in Denmark from March 2020 – December 2021 with severe ARDS and need of V‐V ECMO support. Data on the number of patients treated with PPV, number of PPV sessions, timing, the time spent in prone position, pulmonary physiological response types with analysis of variables affecting the response are reported. Results: Out of 68 patients 44 were treated with 220 PPV sessions and a positive clinical response was observed in 80% of patients but only in 45% of sessions. On a single session level, increased compliance was observed in 38% and increased oxygenation in only 15% of 220 sessions, with within‐patient heterogeneity. Higher dynamic compliance at the beginning of a PPV session was associated with a lower delta change in dynamic compliance during PPV. The response to a PPV session could not be predicted by the response in the prior session. Dynamic compliance did not change during the ECMO course. Conclusion: Eighty percent of patients responded positively during a PPV session, but this was not associated with overall pulmonary improvement. On a single patient level, responses were heterogenous and only 45% of sessions resulted in clinical improvement. Response in dynamic compliance was associated with starting values of compliance. [ABSTRACT FROM AUTHOR]

(1) Background: This study aims to assess visceral fat values, waist circumference (WC), body mass index (BMI), and body fat percentage for their ability to predict poor outcomes during COVID-19 patients' hospitalization; (2) Methods: This study was a prospective cohort of mild–moderate COVID-19 patients hospitalized at Dr. Cipto Mangunkusumo National General Hospital from December 2020 to March 2021. This study includes hospitalized patients over 18 diagnosed with COVID-19 using RT-PCR. Patients who do not have chest radiography, waist circumference, a bioimpedance analyzer (BIA) error, or are unable to stand or mobilize during the examination are excluded from this study. Cox regression was used for multivariate analysis; (3) Results: The study included two hundred sixty-one patients. The median visceral fat value was 10 (equivalent to 100 cm2), the WC was 93.4 cm, the BMI was 26.1 kg/m2, and the body fat percentage was 31.5%. Based on multivariate Cox regression, WC was statistically significant as an independent factor influencing poor outcomes in COVID-19 patients (RR 1.037 [95% CI 1.011–1.064]) along with COVID-19 degree of severity (RR 3.063 [95% CI 1.537–6.104]) and comorbidities (RR 2.123 [95% CI 1.017–4.435]); (4) Conclusions: Waist circumference can influence poor outcomes in confirmed COVID-19 patients during hospitalization. [ABSTRACT FROM AUTHOR]

During the COVID-19 pandemic, there was increased interest in the issue of thrombotic complications of acute respiratory infections. Clinical reports and pathological studies have revealed that thrombus formation in COVID-19 may involve the venous and arterial vasculature. As thrombotic complications of infectious respiratory diseases are increasingly considered in the context of COVID-19, the fact that thrombosis in lung diseases of viral and bacterial etiology was described long before the pandemic is overlooked. Pre-pandemic studies show that bacterial and viral respiratory infections are associated with an increased risk of thrombotic complications such as myocardial infarction, ischemic stroke, pulmonary embolism, and other critical illnesses caused by arterial and venous thrombosis. This narrative review article aims to summarize the current evidence regarding thrombotic complications and their pathogenesis in acute lower respiratory tract infections. [ABSTRACT FROM AUTHOR]

Background: Inhaled nitric oxide (iNO) can improve oxygenation in acute respiratory syndrome (ARDS), has anti-inflammatory and antithrombotic effects, and can inhibit coronavirus- replication. The study aim was to investigate the impact of iNO in COVID-19 associated ARDS (CARDS) on oxygenation, the length of mechanical ventilation (MV), the level of inflammatory markers and the rate of thrombotic events during ICU stay. Methods: This was a retrospective, observational, monocentric study analyzing the effect of INO (15 parts per million) vs. non-iNO in adult ventilated CARDS patients on oxygenation, the level of inflammatory markers, and the rate of thrombotic events during ICU stay. Within the iNO group, the impact on gas exchange was assessed by comparing arterial blood gas results obtained at different time points. Results: Overall, 19/56 patients were treated with iNO, with no difference regarding sex, age, body mass index, and SOFA-/APACHE II- score between the iNO and non-iNO groups. iNO improved oxygenation in iNO-responders (7/19) and had no impact on inflammatory markers or the rate of thrombotic events but was associated with an increased MV length. Conclusions: iNO was able to improve oxygenation in CARDS in iNO-responders but did not show an impact on inflammatory markers or the rate of thrombotic events, while it was associated with an increased MV length. [ABSTRACT FROM AUTHOR]

Background: Severe acute respiratory syndrome (SARS) and acute respiratory distress syndrome (ARDS) are often considered separate clinico-radiological entities. Whether these conditions also present a single process-specific systemic biomolecular phenotype and how this relates to patient outcomes remains unknown. A prospective cohort study was conducted, including adult patients admitted to the ICU and general floors for COVID-19-related (COVID+) or non-COVID-19-related (COVID−) acute respiratory failure during the main phase of the pandemic. The primary objective was to study blood biomarkers and outcomes among different groups and severity subsets. Results: A total of 132 patients were included, as follows: 67 COVID+, 54 COVID− (with 11 matched control subjects for biomarker reference), and 58 of these patients allowed for further pre- and post-analysis. The baseline apelin (APL) levels were higher in COVID+ patients (p < 0.0001 vs. COVID− patients) and in SARS COVID+ patients (p ≤ 0.02 vs. ARDS), while the IL-6 levels were higher in ARDS COVID− patients (p ≤ 0.0001 vs. SARS). Multivariable logistic regression analyses with cohort biomarkers and outcome parameters revealed the following: (i) log-transformed neprilysin (NEP) activity was significantly higher in COVID+ patients (1.11 [95% CI: 0.4–1.9] vs. 0.37 [95% CI: 0.1–0.8], fold change (FC): 1.43 [95% CI: 1.04–1.97], p = 0.029) and in SARS patients (FC: 1.65 [95% CI: 1.05–2.6], p = 0.032 vs. non-SARS COVID+ patients, and 1.73 [95% CI: 1.19–2.5], p = 0.005 vs. ARDS COVID− patients) and (ii) higher lysyl oxidase (LOX) activity and APL levels were respectively associated with death and a shorter length of hospital stay in SARS COVID+ patients (Odds Ratios (OR): 1.01 [1.00–1.02], p = 0.05, and OR: −0.007 [−0.013–0.0001], p = 0.048). Conclusion: Process-specific blood biomarkers exhibited distinct profiles between COVID+ and COVID− patients, and across stages of severity. NEP and LOX activities, as well as APL levels, are particularly linked to COVID+ patients and their outcomes (ClinicalTrials.gov Identifier: NCT04632732). [ABSTRACT FROM AUTHOR]

Background: The World Health Organization recommends extracorporeal membrane oxygenation (ECMO) as a therapeutic option for the most critical cases of severe coronavirus disease 2019 (COVID-19). However, data on universally agreed-upon risk factors that contribute to ECMO weaning failure and mortality in COVID-19 patients undergoing ECMO are limited. This lack of consensus leads to significant uncertainties in developing effective management strategies for these patients. We aimed to identify the factors associated with early outcomes after ECMO support in patients with COVID-19-induced acute respiratory distress syndrome, specifically the success rate of ECMO weaning and in-hospital mortality. Methods: We reviewed 25 patients with COVID-19 who received ECMO support at a single institution between January 2020 and July 2022. This retrospective data collection and review included clinical characteristics, adjunctive treatments, complications, and early patient outcomes. Results: A total of 72% of the patients were successfully weaned off ECMO, and 68% were discharged alive. Significant associations were observed between ECMO weaning success and in-hospital survival, particularly younger age and a history of rehabilitation therapy. Furthermore, the absence of a history of immunosuppressive therapy contributed significantly to successful ECMO weaning. Conclusions: Younger age and the implementation of rehabilitation therapy are associated with improved outcomes in patients with COVID-19 receiving ECMO support. [ABSTRACT FROM AUTHOR]

Endothelin-1 (ET-1) is a potent vasoconstrictor produced by endothelial cells and cleared from circulating blood mainly in the pulmonary vasculature. In a healthy pulmonary circulation, the rate of local production of ET-1 is less than its rate of clearance. In the present study, we aimed to investigate whether the abnormal pulmonary circulatory handling of ET-1 relates to poor clinical outcomes in patients with coronavirus disease 2019 (COVID-19)-induced acute respiratory distress syndrome (ARDS). To this end, central venous and systemic arterial ET-1 plasma levels were simultaneously measured on Days 1 and 3 following ICU admission in mechanically ventilated COVID-19 patients with ARDS (COVID-19 ARDS, N = 18). Central venous and systemic arterial ET-1 plasma levels were also measured in two distinct SARS-CoV-2-negative mechanically ventilated critically ill patient groups, matched for age, sex, and critical illness severity, with ARDS (non-COVID-19 ARDS, N = 14) or without ARDS (non-COVID-19 non-ARDS, N = 20). Upon ICU admission, COVID-19-induced ARDS patients had higher systemic arterial and central venous ET-1 levels compared to the non-COVID-19 ARDS and non-COVID-19 non-ARDS patients (p < 0.05), yet a normal systemic arterial:central venous (A:V) ET-1 ratio [0.63 (0.49–1.02)], suggesting that pulmonary ET-1 clearance is intact in these patients. On the other hand, the non-COVID-19 ARDS patients demonstrated abnormal ET-1 handling [A:V ET-1 ratio 1.06 (0.93–1.20)], while the non-COVID-19 non-ARDS group showed normal ET-1 handling [0.79 (0.52–1.11)]. On Day 3, the A:V ratio in all three groups was <1. When the COVID-19 ARDS patients were divided based on 28-day ICU mortality, while their systemic arterial and central venous levels did not differ, the A:V ET-1 ratio was statistically significantly higher upon ICU admission in the non-survivors [0.95 (0.78–1.34)] compared to the survivors [0.57 (0.48–0.92), p = 0.027]. Our results highlight the potential importance of ET-1 as both a biomarker and a therapeutic target in critically ill COVID-19 patients. The elevated A:V ET-1 ratio in non-survivors suggests that the early disruption of pulmonary ET-1 handling may be a key marker of poor prognosis. [ABSTRACT FROM AUTHOR]

Purpose: Lung transplantation (LTx) is a potential intervention for end-stage COVID-19 lung disease. Current literature is sparse regarding the outcomes of LTx for COVID-19 related acute respiratory distress syndrome (ARDS) and pulmonary fibrosis (PF). This study aims to characterize outcomes and patterns of LTx for COVID-19 related lung disease throughout the pandemic. Methods: Patients who underwent LTx during the pandemic for COVID-19 related lung disease were retrospectively identified using the UNOS registry. Demographics, as well as outcomes measures and nationwide patterns of care were collected and analyzed. Results: A total of 510 adult cases of LTx for COVID-19 (259 ARDS, 251 PF) were compared to 4,031 without COVID-19 (3,994 PF, 37 ARDS). Patients who received LTx for COVID-19 ARDS did not differ in 2-year survival when compared to those with COVID-19 PF (81.9% vs 77.2%, p = 0.4428). Compared to non-COVID-19 etiologies, COVID-19 ARDS patients had higher rates of stroke (2.3% vs 0%, p = 0.0005), lower rates of graft failure (12.8% vs 36.1%, p = 0.0003) and post-transplant ECMO (29.6% vs 41.7%, p = 0.0002), and improved 2-year survival following LTx (81.9% vs 61.7%, p = 0.0064). No difference in 2-year survival following LTx was observed between patients with COVID-19 and non-COVID-19 PF (77.2% vs 71.8%, p = 0.34). Rates of LTx spiked with variant emergence and declined with rounds of vaccination. Conclusion: Our results are consistent with early reports of survival outcomes following LTx for COVID-19 ARDS and PF while providing an increased layer of granularity. LTx may be considered as a safe and effective intervention for COVID-19 lung disease. [ABSTRACT FROM AUTHOR]

BACKGROUND: Pediatric ARDS is associated with significant morbidity and mortality. High-quality data from clinical trials in children are limited due to numerous barriers to their design and execution. Here we describe the collaborative development of a master protocol as a tool to address some of these barriers and support the conduct of pediatric ARDS studies. METHODS: Using PubMed, we performed a literature search of randomized controlled trials (RCTs) in pediatric ARDS to characterize the current state and evaluate potential benefit of harmonized master protocols. We used a multi-stakeholder, collaborative, and team science-oriented process to develop a master protocol template with links to common data elements (CDEs) for pediatric ARDS trials. RESULTS: We identified 11 RCTs that enrolled between 14-200 total subjects per trial. Interventions included mechanical ventilation, prone positioning, corticosteroids, and surfactant. Studies displayed significant heterogeneity in ARDS definition, design, inclusion and exclusion criteria, and reported outcomes. Mortality was reported in 91% of trials and ventilator-free days in 73%. The trial heterogeneity made pooled analysis unfeasible. These findings underscore the need for a method to facilitate combined analysis of future trials through standardization of trial elements. As a potential solution, we developed a master protocol, iteratively revised with input from a multidisciplinary panel of experts and organized into 3 categories: instructions and general information, templated language, and a series of text options of common pediatric ARDS trial scenarios. Finally, we linked master protocol sections to relevant CDEs previously defined for pediatric ARDS and captured in a series of electronic case report forms. CONCLUSIONS: The majority of pediatric ARDS trials identified were small and heterogeneous in study design and outcome reporting. Using a master protocol template for pediatric ARDS trials with CDEs would support combining and comparing pediatric ARDS trial findings and increase the knowledge base. [ABSTRACT FROM AUTHOR]

BACKGROUND: Prone positioning (PP) has demonstrated its potential for improving outcomes in patients with ARDS who require invasive mechanical ventilation. However, the ability of prolonged proning to reduce mortality in patients with COVID-19 specifically, sessions lasting > 24 h remains uncertain. METHODS: In this retrospective cohort study, we examined 158 subjects with COVID-19 pneumonia who required mechanical ventilation due to moderate-to-severe ARDS. Seventy-six subjects were placed in standard PP and 82 in extended PP, defined as prone sessions lasting at least 32 h. Our primary aim was to evaluate the effect of EPP on 90-d survival in subjects with COVID-19 with acute severe respiratory failure. To ensure the reliability of our findings and to minimize bias, we applied 3 adjustment approaches: cardinality matching (CM), matching weighting (MW), and inverse probability of treatment weighting with stabilized and trimmed weights (SW). We used Kaplan-Meier curves and Cox proportional hazard models to analyze the effects of EPP on 90-d mortality and sensitivity analysis by calculating E-values. RESULTS: The overall crude 90-d mortality rate was 31.7%. The unadjusted 90-d mortality rates were 19.5% in the EPP group and 44.7% in the SPP group (hazard ratio [HR] 0.35 [95% CI 0.19- 0.63], P < .001). After adjustment for confounding factors using CM, MW, and SW, baseline covariates were balanced between the 2 groups. Subjects in the EPP group exhibited lower 90-d mortality rates after adjustment using CM (HR 0.42 [95% CI 0.23-0.79], P = .007), MW (HR 0.45 [95% CI 0.21-0.95], P = .036), or SW (HR 0.29 [95% CI 0.15-0.56], P < .001). CONCLUSIONS: Extended PP was associated with improved 90-d survival in subjects with COVID-19 undergoing mechanical ventilation for severe ARDS. These findings suggest the potential benefit of EPP in the management of COVID-19-related respiratory failure. Further research and prospective studies are warranted to confirm and elucidate the underlying mechanisms of this association. [ABSTRACT FROM AUTHOR]

The present research aimed to investigate the effects and mechanisms of microRNA (miR)-141-3p on pulmonary fibrosis of acute respiratory distress syndrome (ARDS). A rat ARDS model was established by the intratracheal drip of 10 mg/kg lipopolysaccharide (LPS). miR-141-3p and Kelch-like ECH-associated protein 1 (Keap1) expression was detected using RT-qPCR assay. Inflammatory factors in bronchoalveolar lavage fluid (BALF) and lung tissues were measured with enzyme-linked immunosorbent assay (ELISA). Lung fibrosis was evaluated using Masson's trichrome staining and hydroxyproline assay kits. Tissue oxidative stress marker levels were assessed by a commercial kit. Protein variations in the EMT pathway and Keap1/nuclear factor-erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) pathway were investigated by Western blot analysis. Targeting relationship verified by dual-luciferase reporter assay. The expression of miR-141-3p was significantly upregulated in LPS-induced ARDS rats, while Keap1 was downregulated. Overexpression of miR-141-3p decreased the levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, superoxide dismutase (SOD), and glutathione (GSH) while elevating malondialdehyde (MDA) expression in LPS-induced ARDS rats. Elevation of miR-141-3p reduced fibrosis scores, enhanced E-cadherin protein expression, and decreased vimentin and α-SMA protein expression in LPS-induced ARDS rats. This elevation of miR-141-3p also upregulated Nrf2, heme oxygenase-1 (HO-1), and NAD(P)H:quinone oxido-reductase-1 (NQO1) proteins levels. Moreover, Keap1 overexpression reversed the inhibitory effects of miR-141-3p on LPS-triggered inflammation, oxidative stress, and fibrosis. miR-141-3p may attenuate inflammation and oxidative stress–induced pulmonary fibrosis in ARDS via the Keap1/Nrf2/ARE signaling pathway. Our study provides new ideas for the treatment of ARDS. [ABSTRACT FROM AUTHOR]

Prone positioning with continuous positive airway pressure (CPAP) is widely used for respiratory support in awake patients with COVID-19-associated acute respiratory failure. We aimed to assess the respiratory mechanics and distribution of ventilation in COVID-19-associated ARDS treated by CPAP in awake prone position. We studied 16 awake COVID-19 patients with moderate-to-severe ARDS. The study protocol consisted of a randomized sequence of supine and prone position with imposed positive end-expiratory pressure (PEEP) of 5 and 10 cmH2O delivered by helmet CPAP. Respiratory mechanics and distribution of ventilation were assessed through esophageal pressure (PES) and electrical impedance tomography (EIT). At the end of each 20-min phase, arterial blood gas analysis was performed, and PES swing and EIT tracings were recorded for the calculation of the respiratory mechanics and regional ventilation. The patient's position had no significant effects on respiratory mechanics. EIT analysis did not detect differences among global indices of ventilation. A significant proportion of pixels in the sternal region of interest showed an increase in compliance from the supine to prone position and PaO2/FIO2 increased accordingly. The best improvement of both PaO2/FIO2 and sternal compliance was obtained in the prone position with PEEP 10 cmH2O. In the studied subjects, prone positioning during CPAP treatment raised oxygenation without improvement of "protective" ventilation or global ventilatory inhomogeneity indices. Prone positioning with higher PEEP significantly increased the compliance of sternal regions. [ABSTRACT FROM AUTHOR]

Background: Previous research highlighted variability in electrocardiogram (ECG) readings across patient positions, particularly in the context of COVID‐19 patients with pulmonary complications requiring prone positioning as part of the treatment. Objective: This study aimed to elucidate the effects of prone positioning on ECG parameters and explore its association with the severity of COVID‐19. Methods: A prospective cohort study involved 60 patients diagnosed with COVID‐19 and presenting pulmonary complications. ECGs were recorded in both supine and prone positions, and analyzed for various parameters including heart rate, QRS axis, and QTc interval. Clinical severity was assessed using APACHE II scores and SpO2/FiO2 ratios. Results: Prone positioning led to an increase in heart rate (mean difference: 2.100, 95% CI: 0.471–3.729, p = 0.012), with minor shifts in the QRS axis. Heart rate and QRS axis demonstrated strong positive correlations between positions, with Pearson's correlation coefficients of 0.927 and 0.894, respectively. The study also found a significant association between prolonged QTc intervals in the prone position and elevated APACHE II scores, with a relative risk of 10.75 (95% CI: 1.82–63.64, p = 0.008). Conclusions: The prone positioning caused minor yet significant changes in heart rate and QRS axis. The correlation of prolonged QTc intervals in the prone position with higher APACHE II scores suggests the prognostic relevance of prone ECG in COVID‐19 patients. However, further research is needed to fully understand the clinical implications and mechanisms of these findings. [ABSTRACT FROM AUTHOR]

Patients treated with ECMO are at great risk of nosocomial infections, and around 10% of isolates are gram-positive pathogens. Linezolid (LZD) is effective in the treatment of these infections but appropriate dosing is challenging. The aim was to evaluate the occurrence of thrombocytopenia during ECMO when treated with LZD. An LZD trough concentration of 8 mg/L was set as the cutoff value for thrombocytopenia occurrence among critically ill patients who received parenteral LZD therapy at a dose of 600 mg every 8 h during ECMO. Eleven patients were included in this prospective observational study. Median LZD trough concentrations were 7.85 (interquartile range (IQR), 1.95-11) mg/L. Thrombocytopenia was found in 81.8% of patients. Based on the median LZD trough concentrations cutoff value, patients were divided into two groups, 1.95 (IQR, 0.91–3.6) and 10.3 (IQR, 9.7–11.7) mg/L, respectively. Median platelet values differed significantly between groups on admission, ECMO day 0, ECMO day 1, and LZD sampling day [194 and 152.5, (p < 0.05)], [113 and 214, (p < 0.05)], [76 and 147.5, (p < 0.01)], and [26 and 96.5, (p < 0.01)], respectively. Duration of LZD therapy was similar between the groups. Significant platelet reduction was observed in both groups, emphasizing the need for closer monitoring to prevent LZD-associated thrombocytopenia. [ABSTRACT FROM AUTHOR]

AbstractAcute respiratory distress syndrome (ARDS) is a complication of pulmonary disease that produces life-threatening hypoxaemia. Despite ventilation and hyperoxic therapies, undetected hypoxia can manifest in capillary beds leading to multi-organ failure. Ox66™ is an ingestible, solid-state form of oxygen designed to supplement oxygen deficits. Twenty-four anaesthetized rats underwent a two-hit model of respiratory distress (ARDS), where a single dose (5 mg/kg) of lipopolysaccharide (LPS) was given intratracheally, and then the respiratory tidal volume was reduced by 40%. After 60 min, animals were randomized to receive Ox66™, or normal saline (NS; vehicle control) via gavage or supplemental inspired oxygen (40% FiO2). A second gavage was administered at 120 min. Cardiovascular function and blood oximetry/chemistry were measured alongside the peripheral spinotrapezius muscle’s interstitial oxygenation (PISFO2). ARDS reduced mean arterial pressure (MAP) and PISFO2 compared to baseline (BL) for all treatment groups. Treatment with Ox66 or NS did not improve MAP, but 40% FiO2 caused a rapid return to BL. PISFO2 improved after treatment with Ox66™ and 40% FiO2 and remained elevated for both groups against NS until study conclusion. Both oxygen treatments also suppressed the inflammatory response to LPS, suggesting that Ox66™ can deliver therapeutically-impactful levels of oxygen in situations of pulmonary dysfunction.