Effect of Esophageal Pressure-guided Positive End-Expiratory Pressure on Survival from Acute Respiratory Distress Syndrome: A Risk-based and Mechanistic Reanalysis of the EPVent-2 Trial.

Rationale: In acute respiratory distress syndrome (ARDS), the effect of positive end-expiratory pressure (PEEP) may depend on the extent to which multiorgan dysfunction contributes to risk of death, and the precision with which PEEP is titrated to attenuate atelectrauma without exacerbating overdistension. Objectives: To evaluate whether multiorgan dysfunction and lung mechanics modified treatment effect in the EPVent-2 (Esophageal Pressure-guided Ventilation 2) trial, a multicenter trial of esophageal pressure (Pes)-guided PEEP versus empirical high PEEP in moderate to severe ARDS. Methods: This post hoc reanalysis of the EPVent-2 trial evaluated for heterogeneity of treatment effect on mortality by baseline multiorgan dysfunction, determined via Acute Physiology and Chronic Health Evaluation II (APACHE-II). It also evaluated whether PEEP titrated to end-expiratory transpulmonary pressure near 0 cm H2O was associated with survival. Measurements and Main Results: All 200 trial participants were included. Treatment effect on 60-day mortality differed by multiorgan dysfunction severity (P = 0.03 for interaction). Pes-guided PEEP was associated with lower mortality among patients with APACHE-II less than the median value (hazard ratio, 0.43; 95% confidence interval, 0.20-0.92) and may have had the opposite effect in patients with higher APACHE-II (hazard ratio, 1.69; 95% confidence interval, 0.93-3.05). Independent of treatment group or multiorgan dysfunction severity, mortality was lowest when PEEP titration achieved end-expiratory transpulmonary pressure near 0 cm H2O. Conclusions: The effect on survival of Pes-guided PEEP, compared with empirical high PEEP, differed by multiorgan dysfunction severity. Independent of multiorgan dysfunction, PEEP titrated to end-expiratory transpulmonary pressure closer to 0 cm H2O was associated with greater survival than more positive or negative values. These findings warrant prospective testing in a future trial.

Lung- and Diaphragm-Protective Ventilation.

Mechanical ventilation can cause acute diaphragm atrophy and injury, and this is associated with poor clinical outcomes. Although the importance and impact of lung-protective ventilation is widely appreciated and well established, the concept of diaphragm-protective ventilation has recently emerged as a potential complementary therapeutic strategy. This Perspective, developed from discussions at a meeting of international experts convened by PLUG (the Pleural Pressure Working Group) of the European Society of Intensive Care Medicine, outlines a conceptual framework for an integrated lung- and diaphragm-protective approach to mechanical ventilation on the basis of growing evidence about mechanisms of injury. We propose targets for diaphragm protection based on respiratory effort and patient-ventilator synchrony. The potential for conflict between diaphragm protection and lung protection under certain conditions is discussed; we emphasize that when conflicts arise, lung protection must be prioritized over diaphragm protection. Monitoring respiratory effort is essential to concomitantly protect both the diaphragm and the lung during mechanical ventilation. To implement lung- and diaphragm-protective ventilation, new approaches to monitoring, to setting the ventilator, and to titrating sedation will be required. Adjunctive interventions, including extracorporeal life support techniques, phrenic nerve stimulation, and clinical decision-support systems, may also play an important role in selected patients in the future. Evaluating the clinical impact of this new paradigm will be challenging, owing to the complexity of the intervention. The concept of lung- and diaphragm-protective ventilation presents a new opportunity to potentially improve clinical outcomes for critically ill patients.

JAK2/STAT1-mediated HMGB1 translocation increases inflammation and cell death in a ventilator-induced lung injury model.

Janus kinase 2/signal transducer and activators of transcription 1 (JAK2/STAT1) signaling is a common pathway that contributes to numerous inflammatory disorders, including different forms of acute lung injury (ALI). However, the role of JAK2/STAT1 in ventilator-induced lung injury (VILI) and its underlying mechanism remain unclear. In this study, using lipopolysaccharide (LPS) inhalation plus mechanical ventilation as VILI mouse model, we found that the administration of JAK2 inhibitor AZD1480 markedly attenuated lung destruction, diminished protein leakage, and inhibited cytokine release. In addition, when mouse macrophage-like RAW 264.7 cells were exposed to LPS and cyclic stretch (CS), AZD1480 prevented cell autophagy, reduced apoptosis, and suppressed lactate dehydrogenase release by downregulating JAK2/STAT1 phosphorylation levels and inducing HMGB1 translocation from the nucleus to the cytoplasm. Furthermore, HMGB1 and STAT1 knockdown attenuated LPS+CS-induced autophagy and apoptosis in RAW 264.7 cells. In conclusion, these findings reveal the connection between the JAK2/STAT1 pathway and HMGB1 translocation in mediating lung inflammation and cell death in VILI, suggesting that these molecules may serve as novel therapeutic targets for VILI.