Daily Ards Research Analysis

IMPORTANCE: Acute respiratory distress syndrome (ARDS) represents a frequent and serious complication after cardiovascular surgery. Although sivelestat, a specific neutrophil elastase inhibitor, has demonstrated therapeutic potential in preliminary studies, the evidence remains limited by methodological constraints of observational designs and underpowered studies. OBJECTIVE: To evaluate the efficacy of sivelestat vs placebo in reducing the incidence of postoperative ARDS and associated complications among patients undergoing major cardiovascular procedures. DESIGN, SETTING, AND PARTICIPANTS: This single-center, randomized, placebo-controlled clinical trial conducted at a tertiary care academic medical center om China enrolled 424 participants between February 15, 2024, and April 16, 2025, with a 90-day postoperative follow-up period. Participants were consecutive patients scheduled for cardiovascular surgery, including coronary artery bypass grafting, valve surgeries, ascending aortic reconstruction, combined procedures, congenital heart defect repairs, and cardiac tumor resections. INTERVENTIONS: Participants were randomly allocated (1:1) to receive either continuous intravenous sivelestat (0.2 mg/kg/h), initiated immediately on intensive care unit (ICU) admission postoperatively and continued for up to 7 days or until ICU discharge; or volume-matched 0.9% sodium chloride placebo administered on an identical schedule. MAIN OUTCOMES AND MEASURES: The primary outcome was the incidence of ARDS. Secondary outcomes included serial measurements of inflammatory biomarkers, including interleukin 6 and interleukin 8, tumor necrosis factor, systemic immune-inflammation index, and serum neutrophil elastase, on postoperative days 1, 3, 5, and 7, along with ARDS-related clinical outcomes including death, pneumonia, and reintubation. Analysis was performed on an intention-to-treat basis. RESULTS: Among 424 randomized patients, 382 completed the trial (mean [SD] age, 62.9 [6.2] years; 210 male [55.0%]). Adverse events monitored for safety did not differ between groups. The sivelestat group had significantly lower rates of ARDS (16.8% [32 of 190] vs 31.2% [60 of 192]; P < .001), and 90-day mortality (1.1% [2 of 190] vs 5.2% [10 of 192]; P = .02). Postoperative inflammatory biomarkers, including neutrophil elastase and interleukin 6, were significantly reduced in the sivelestat group. CONCLUSION AND RELEVANCE: In this single-center, randomized, placebo-controlled clinical trial of patients undergoing cardiovascular surgery, sivelestat significantly reduced ARDS incidence and 90-day all-cause mortality. Sivelestat attenuated neutrophil-driven inflammation by dynamically suppressing neutrophil elastase and reducing key downstream biomarkers. These preliminary findings suggest sivelestat may be a pharmacologic option to mitigate ARDS in cardiovascular procedures. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT06276569.

OBJECTIVES: Acute hypoxemic respiratory failure is a leading cause of death and disability in critically ill children. Pulmonary capillary barrier dysfunction, in large part, drives severity. We aimed to define how blood and tracheobronchial lavage (TBAL) fluid differentially affect pulmonary capillary barrier function and, as a second exploratory aim, identify protein mediators. DESIGN: We performed a secondary analysis in April and May of 2024 of blood and TBAL samples from a previously completed observational cohort study of mechanically ventilated children collected from October 2018 to February 2020. SETTING: Single PICU. SUBJECTS: Stored blood and TBAL samples from 65 children requiring mechanical ventilation collected at 24 and 48-72 hours after intubation. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We quantified inflammatory proteins in plasma and TBAL using Olink Target 48 Cytokine multiplex. We assessed changes in barrier function of cultured human pulmonary microvascular endothelial cells (HPMECs) using electrical cell-substrate impedance to measure transendothelial electrical resistance. Plasma samples from critically ill children significantly enhanced HPMEC barrier function and contained lower concentrations of proinflammatory cytokines compared with TBAL. Over time, the effects of plasma on barrier integrity diminished, while TBAL samples significantly improved barrier function and had reduced abundance of several proinflammatory cytokines. Notably, TBAL samples from children with severe lung injury augmented HPMEC barriers more than those from children without lung injury, highlighting distinct compartmental and disease-specific influences on HPMEC barriers. CONCLUSIONS: These unexpected findings reveal that blood and lung compartments contain differentially abundant proteins that exert distinct and evolving influences on pulmonary endothelial integrity in critically ill children. These results may inform on the timing and compartment-specific assessment of biomarkers, and eventually, delivery of therapies.

High flow therapy (HFT) delivers heated and humidified gas at flow rates up to 60 L/min to hypoxemic subjects, but is not conducive to simultaneous administration of pharmaceutical aerosols. Aerosol losses occur due to circuit wall impaction, environmental loss and particle growth from high humidity; resulting in poor lung delivery efficiency. This study compares two strategies for delivering dry powder aerosols during 60 L/min humidified HFT: a circuit connector (HFT-CC) which integrates directly into the standard HFT flow pathway, and an interface connector (HFT-IC) designed to bypass delivery line losses by directly injecting aerosol into the nasal prongs. Experiments were conducted using an anatomically-realistic in vitro adult nasal airway model with physiological breathing patterns, albuterol sulfate excipient enhanced growth (AS-EEG) dry powder formulation, air-jet aerosolization engine, and custom air actuation system. The HFT-CC approach improved lung delivery to 25.6% compared to existing published data (12.8%) but was limited by losses in the circuit tubing and nasal interface. The HFT-IC approach with a split nasal interface achieved 45.1% lung delivery (HFT-IC3), nearly a fourfold improvement from previously published results, by isolating aerosol flow from HFT flow and eliminating upstream losses. While nose-throat (NT) deposition in HFT-IC3 remained high (39.6%), this approach presents an attractive target for future computational and experimental optimization. These findings prove that efficient dry powder aerosol lung delivery during 60 L/min humidified HFT is achievable, laying the groundwork for translational advances in the efficient delivery of pulmonary therapies such as surfactants, antibiotics, anti-inflammatories, and antivirals during ventilatory support.