Daily Ards Research Analysis

The acute respiratory distress syndrome is a heterogenous syndrome characterized by the rapid development of respiratory failure. Nearly 40% of patients who develop ARDS will die, and there is growing interest in identification of biomarkers to identify patients at risk of death and/or inform treatment decisions. Most prior work on biomarkers in ARDS has focused on the plasma compartment, but there is concern that circulating biomarkers may not reflect alveolar pathobiology. The anti-inflammatory microRNA-146a has been shown to be upregulated in inflammatory cells in human bronchoalveolar lavage fluid, but it is not known if these levels correspond with outcomes. We measured miR-146a expression by digital droplet PCR in human biospecimens from four different cohorts of patients with respiratory failure requiring mechanical ventilation - two plasma cohorts, one bronchoalveolar lavage cohort, and one heat moisture exchange (HME) filter fluid cohort. We found that miR-146a was detectible in plasma, bronchoalveolar lavage fluid, and HME fluid. However, only when measured in the alveolar space, was miR-146a expression significantly lower in older adults and those who died. It did not correlate with outcomes when measured in plasma. To our knowledge, this is the first report that nucleotides can be measured in HME fluid and builds upon expanding literature that circulating biomarkers may not reflect complex biology of the alveolar microenvironment during ARDS.

BACKGROUND: Corticosteroids reduce mortality in severe COVID-19 requiring oxygen or invasive mechanical ventilation, yet emerging data suggest that SARS-CoV-2-associated acute lung injury is biologically heterogeneous and that treatment response may vary across molecularly defined disease states. Lung-derived molecular endotypes of severe COVID-19-associated acute lung injury have been described, but direct molecular profiling is not routinely available at the bedside. We evaluated whether a clinical predictor of previously defined lung molecular endotype identifies heterogeneity in corticosteroid treatment effect among mechanically ventilated patients with COVID-19. METHODS: We utilized a single-center cohort of 5,000 patients with COVID-19 treated at the University of North Carolina Hospital between January 1, 2020, and December 31, 2022, to emulate a target trial assessing the effect of corticosteroid receipt on mortality, length of stay, and incident organ support. Confounding was addressed through inverse probability of treatment weighting (IPTW). Outcomes for severely ill patients requiring mechanical ventilation were compared to the RECOVERY trial results, with subsequent moderation analysis and stratified analysis by clinically predicted lung molecular endotype and vaccination status. The primary outcome was 28-day mortality. Secondary Outcomes were time to discharge alive and progression to additional organ support. RESULTS: This emulated target trial showed a directionally favorable but non-statistically significant association between corticosteroid treatment and reduced 28-day mortality in patients requiring mechanical ventilation for SARS-CoV-2 infection. A clinical predictor of lung molecular endotype moderated the effect of corticosteroids on 28-day mortality (p-value for interaction 0.038) and identified distinct predicted endotype-specific treatment effect. Corticosteroid treatment was associated with lower 28-day mortality in the predicted Hyper-Inflammatory endotype (OR 0.62, 95% CI 0.39, 0.99) but not in the predicted Metabolic Dysregulation endotype (OR 1.15, 95% CI 0.82, 1.61). We did not detect significant effect modification by vaccination status (p-value for interaction 0.65), although inference was limited by the small, vaccinated subgroup (28-mortality OR 0.78, 95% CI 0.37, 1.65 in vaccinated vs 0.94, 95% CI 0.70, 1.26 in unvaccinated). CONCLUSIONS: In this target trial emulation of mechanically ventilated patients with severe COVID-19, corticosteroid treatment showed a directionally favorable but non-statistically significant association with reduced 28-day mortality in the overall cohort. However, a clinical predictor of lung molecular endotype identified significant heterogeneity in treatment effect, with benefit concentrated in the predicted Hyper-Inflammatory endotype and no apparent benefit in the predicted Metabolic Dysregulation endotype. These findings support prospective validation of clinically deployable endotype-guided corticosteroid treatment strategies in acute lung injury and ARDS.

BACKGROUND: Fiberoptic bronchoscopy in mechanically ventilated ICU patients can markedly increase airway resistance and peak inspiratory pressure (PIP), limit effective tidal volume delivery, and provoke transient hypoxemia, hypercapnia, dynamic hyperinflation, and hemodynamic instability. However, per-procedural ventilator management remains heterogeneous. METHODS: This single-center trial with before-and-after design assessed the feasibility and safety of implementing a standardized low-flow ventilation protocol, and characterized its physiological effects (particularly peak inspiratory pressure), during bronchoscopy in adults intubated and ventilated in volume-assist-control mode. RESULTS: During the observational phase (n = 36), ventilator settings reflected usual practice (increased pressure alarm and reduced PEEP; no routine flow reduction). Following a 1-month training period, the intervention phase (n = 35) implemented an inspiratory flow rate of 20 L/min, unchanged PEEP, and a reduced respiratory rate to achieve an I:E ratio of 1:2. Physiologic and ventilator data were automatically recorded at 1-min intervals. The primary endpoint was peak inspiratory pressure (PIP), a physiological endpoint reflecting the mechanical effect of the intervention. Secondary endpoints included minute ventilation (MV), end-tidal CO2 (EtCO2), oxygenation metrics, ventilator alarms, and hypotension, feasibility and procedural safety. PIP decreased substantially (45 [35, 65] cmH2O vs. 82 [59, 93] cmH CONCLUSIONS: This protocol implementation study demonstrates that standardized low-flow ventilation with PEEP maintenance is feasible and safe during bronchoscopy in mechanically ventilated patients, with a significant reduction in peak inspiratory pressure as a robust mechanical signal. Alveolar ventilation and hemodynamic tolerance were preserved. These findings support the conduct of further research to evaluate clinical outcomes.