RATIONALE:Physiological studies showed benefits for bedside setting of personalized positive end-expiratory pressure (PEEP) by electrical impedance tomography (EIT), balancing lung overdistension and collapse. OBJECTIVES:To evaluate whether EIT-guided PEEP improves the clinical outcomes of patients with acute respiratory distress syndrome (ARDS) compared to the lower PEEP/FiO2 table strategy. METHODS:This randomized trial enrolled adult patients with moderate to severe ARDS across five sites in China from February 2022 to June 2023. Participants were randomly assigned to EIT-guided PEEP (collapse-overdistension crossing point value by decremental PEEP trial) or the classical lower PEEP/FiO2 table. The primary outcome was 28-day mortality. MEASUREMENTS AND MAIN RESULTS:The trial was terminated early for futility, based on a pre-planned interim analysis. A total of 190 patients were included and completed follow-up. PEEP levels didn't differ between groups during the first 7 days (difference in marginal means 0.2 [SE 0.1]; P = .187). At 28 days, mortality was 52 patients (55.9%) in the EIT-guided PEEP group and 51 patients (52.6%) in the lower PEEP/FiO2 table group (hazard ratio [HR] 0.96 [95% CI, 0.65-1.41]; P = .821). Ventilator-free days and other secondary clinical and safety outcomes did not differ, either. However, EIT-guided PEEP assigned higher PEEP and decreased mortality in patients with higher lung recruitability, as assessed by the recruitment-inflation ratio method (16 [35.6%] of 45 patients vs 27 [60.0%] of 45 patients; HR 0.49 [95% CI, 0.26-0.91]; P = .024). CONCLUSIONS:In patients with moderate to severe ARDS, EIT-guided PEEP did not significantly reduce 28-day mortality compared with the lower PEEP/FiO2 table strategy. Due to early termination, the study may have been underpowered to detect a clinically important difference. TRIAL REGISTRATION:clinicaltrials.gov NCT05207202.

Dysregulation of innate immunity during respiratory RNA virus infections drives systemic hyperinflammation and lung injury. Here, we show that importin β4 (IPO4) has a role in inhibiting antiviral innate immunity. Transcriptomics analysis illustrated a downregulation of IPO4 in alveolar macrophages, lung ciliated epithelium, and peripheral blood mononuclear cells from severely ill patients with COVID-19 or influenza. We further identified CCAAT/enhancer-binding protein beta (CEBPB) as the transcription factor for IPO4 reduction during RNA viral infections. Loss-of-function validation demonstrated that IPO4 dampens the innate antiviral and inflammatory responses in vitro and in vivo. Mechanistically, IPO4 sequesters fatty acid synthase (FASN) to block palmitic acid production, thereby inhibiting mitochondrial antiviral signaling protein (MAVS) activation and the downstream innate immune signaling. Moreover, Adeno-associated virus (AAV)-mediated pulmonary restoration of IPO4 significantly alleviated viral pneumonia in mice. These results indicate that the CEBPB-IPO4-FASN-MAVS axis preserves innate immune homeostasis to avoid inflammatory pathology, highlighting IPO4 as a potential therapeutic target for severe viral pneumonia.

Background: Following the 2021 first International Consensus on Severe Lung Cancer, global attention to patients with PS 2-4 has grown significantly. Recent advances in novel therapies, interventional techniques, and supportive care, along with emerging real world data, have expanded treatment opportunities for this population. To incorporate these advances, we have updated the consensus. Methods: A multidisciplinary panel comprising experts from oncology, radiation oncology, thoracic surgery, radiology, interventional medicine, respiratory medicine, critical care medicine, and nursing. After being presented with a comprehensive review of the current evidence pertaining to severe lung cancer and thorough discussions, the panel reached a consensus on 11 recommendations, each with over 70% expert agreement. Results: The 11 consensus points focused on definition and causes (n=2), assessment and general strategies (n=4), and specific treatment modalities (n=5) were updated or newly developed. This updated consensus emphasizes dynamic and precise detection, robust life support, flexible application of novel therapies, and MDT guided treatment adjustment based on PS dynamics. Early rehabilitation and comprehensive supportive care are integral to disease management. Conclusions: This consensus updates the definition, diagnostic evaluation, and treatment strategies, providing a practical framework for clinicians based on current evidence and multidisciplinary expert consensus. Prospective trials focusing specifically on patients with severe lung cancer are urgently needed.

Objective. Reliable quantification of regional lung function via electrical impedance tomography (EIT) in mechanically ventilated AECOPD patients requires identifying breaths suitable for steady-state regional parameter estimation and excluding breaths deviating from local steady state. However, automated screening remains difficult because existing methods primarily rely on inaccessible raw voltage data or fail to distinguish complex asynchrony patterns in reconstructed images.Approach. We developed an EIT robustness evaluator (EITRE), a spatio-temporal deep learning framework to identify breaths suitable for steady-state regional parameter estimation directly from reconstructed EIT image sequences. The architecture integrates an EfficientNet-b0 spatial encoder with an attention-augmented gated recurrent unit and an XGBoost classifier to capture complex regional impedance dynamics. The framework's performance was evaluated in a multicenter validation protocol using operational reference labels derived from synchronized ventilator waveforms and a statistical deviation rule. The practical utility of EITRE was further demonstrated in a clinical positive end-expiratory pressure (PEEP) titration experiment to evaluate its effect on parameter-derived PEEP recommendations.Main results. Validated on a multi-center dataset comprising 58 AECOPD patients and 140 310 respiratory cycles, EITRE achieved robust cross-domain performance and generalizability (F1-score 0.933 on unseen data following single-subject fine-tuning). Quantitative analysis revealed diverse impacts of patient-ventilator asynchrony (PVA) on EIT parameters: parameters assessing temporal ventilation heterogeneity exhibited higher sensitivity and substantial deviations during PVA, whereas parameters assessing spatial ventilation heterogeneity remained relatively robust. In a PEEP titration experiment, EITRE-based screening produced indicator-and patient-dependent shifts in EIT-derived PEEP recommendations relative to a baseline statistical screening rule, supporting improved measurement consistency for steady-state parameter estimation rather than a uniform population-level correction.Significance. EITRE provides a specialized tool for supporting breath-by-breath measurement consistency for steady-state EIT parameter estimation, enabling more reliable regional lung-function assessment in mechanically ventilated AECOPD patients.

Acute respiratory distress syndrome (ARDS) is a life-threatening form of acute respiratory failure characterized by diffuse lung inflammation and edema. Despite increased understanding of the molecular biology underlying ARDS, the complex pathogenesis still limits the development of targeted pharmacologic therapies. Cell death plays a vital role in defending against pathogen infections and triggering tissue inflammation, which can damage the alveolar-capillary barrier and ultimately lead to the development of ARDS. Thus, targeting various cell death pathways may be an attractive entry point for therapeutic intervention in ARDS. Intriguingly, recent genetic and biochemical studies have emphasized the importance of revealing the crosstalk among various cell death pathways and indicated that this connectivity exhibits a considerable degree of plasticity in the molecular regulation of potential therapeutic targets in ARDS. In this review, we summarize the mechanisms of the different types of regulated cell death (RCD) and describe the physiological and pathological processes that contribute to ARDS pathogenesis. We also discuss the emerging crosstalk among various RCD modalities, and highlight that targeting cell death pathways is an effective therapeutic strategy for ARDS.

Acute lung injury (ALI) is a life-threatening complication of influenza A virus (IAV) infection, characterized by high morbidity and mortality. Recent studies have implicated ferroptosis, a distinct form of regulated cell death characterized by iron-dependent lipid peroxidation, in the pathogenesis of IAV-induced ALI. However, the underlying mechanisms and key regulators of IAV-induced ferroptosis remain largely unknown. In this study, we found that IAV infection induces predominant ferroptosis in alveolar and bronchial epithelial cells, contributing to tissue damage and the development of acute lung injury. Treatment with the ferroptosis inhibitor ferrostatin-1 improved survival, mitigated weight loss, and alleviated lung injury in IAV-infected mice. Mechanistically, IAV-induced ferroptosis was associated with excess lipid peroxidation, nitrative stress, and disrupted iron metabolism. Targeted lipidomic analysis revealed that phospholipid peroxidation is a crucial mechanism in IAV-induced ferroptosis. Importantly, we identified indoleamine 2,3-dioxygenase 1 (IDO1) as a key regulator of IAV-induced ferroptosis. IDO1 knockdown inhibited IAV-induced cell death, and reduced intracellular reactive oxygen species, peroxynitrite, and inducible nitric oxide synthase expression. Furthermore, pharmacological inhibition of IDO1 with 1-methyl-tryptophan improved ALI phenotype in IAV-infected mice. These findings highlight the critical role of ferroptosis in IAV-induced ALI pathogenesis and identify IDO1 as a potential therapeutic target for the treatment of this life-threatening condition.

Background:Compared with conventional pressure support ventilation (PSV), noisy PSV offers a certain degree of pressure variability, which might benefit the process of weaning from mechanical ventilation. We investigated respiratory mechanics under different levels of variation during the weaning phase in patients receiving noisy PSV to identify the optimal level of variation. Methods:This self-controlled before-and-after study of mechanically ventilated patients in the weaning phase was conducted from September 2020 to October 2022. Each eligible patients received noisy PSV with 0%, 15%, 25%, or 35% variation in a random order. Their respiratory mechanics were collected 1 h after the pressure variation level was switched and compared. Results:The study found that noisy PSV significantly improved patients' respiratory system compliance at variation levels of 25% and 35% (0% vs. 15% vs. 25% vs. 35%: 40 vs. 38.1 vs. 42.3 vs. 44.5 mL/cmH2O, P=0.005). Importantly, subgroup analysis revealed this improvement was more pronounced in chronic obstructive pulmonary disease (COPD) patients (0% vs. 15% vs. 25% vs. 35%: 40 vs. 38.4 vs. 45 vs. 50, P=0.03). At the same time, at variability levels of 25% and 35%, patients' inspiratory trigger delay time was also significantly shorter (0% vs. 15% vs. 25% vs. 35%: 140 vs. 100 vs. 100 vs. 100 ms, P<0.001). In addition, the PeakArea was significantly lower at variation 35% (8.8±2.5 cmH2O·s). Conclusions:Pressure variation at level of 25% or 35% could improve patients' respiratory system compliance and shorten the inspiratory trigger delay time, potentially being optimal in noisy PSV during the weaning phase from mechanical ventilation.

Electrical impedance tomography (EIT) is an emerging imaging technology that has garnered increasing attention in recent years, particularly in the medical field and the diagnosis and treatment of respiratory diseases. Fascinating developments were achieved after the previous review focusing on clinical applications in Chinese hospitals. Over hundred publications in SCI journals related to thoracic EIT clinical research and daily applications have been recorded in the past five years. As EIT devices become more accessible and portable, clinical application scenarios include not only ICU, but also chronic disease management, and health screening. We were excited to welcome more than 10 local companies manufacturing their own EIT devices, which were exhibited during the 24th International Conference on Biomedical Applications of EIT in Hangzhou, China. This article systematically reviewed the applications of thoracic EIT in clinical research and routine use in Chinese hospitals over the past five years.

BACKGROUND:Coagulopathy frequently complicates venovenous extracorporeal membrane oxygenation (VV ECMO) procedures, yet its underlying mechanism remains elusive. This retrospective study aimed to identify factors contributing to coagulopathy during VV ECMO by analyzing clinical data and employing proteomic approaches. A prospective cohort was also examined for validation. METHODS:We retrospectively analyzed clinical data from 51 patients undergoing VV ECMO between January 2015 and April 2021, categorizing them into coagulopathy(n = 21), defined by elevated levels of D-dimer and decreased fibrinogen in plasma that were reversible by circuit exchange, and non-coagulopathy(n = 30) groups. Plasma samples collected on days 0-2(D1), days 3-5(D4), and days 6-8(D7) were subjected to proteomics and Luminex assay. Additionally, oxygenator fiber samples were collected from a prospective cohort between May 2022 and August 2022 for scanning electron microscopy. RESULTS:Inflammation emerged as a pivotal factor in coagulopathy development during VV ECMO, as evidenced by elevated interleukin-6 levels on D1 and increased leukocyte and neutrophil counts on D4. Proteomics analysis identified a significant elevation of S100A8 and S100A9 in the plasma of coagulopathy patients throughout VV ECMO, findings confirmed by Luminex assay. In the prospective cohort, thrombosis and leukocyte accumulation were observed on oxygenator fibers from coagulopathy patients, along with elevated levels of S100A8 and S100A9 in plasma. CONCLUSIONS:Coagulopathy during VV ECMO is associated with heightened levels of proinflammatory proteins S100A8 and S100A9 in plasma, accompanied by leukocyte accumulation on oxygenator fibers. These findings emphasize the potential therapeutic target against coagulopathy during VV ECMO.

Background To explore the impact of diabetes on the clinical features and prognosis of COVID-19 and assess the influence of glucocorticoid use on the prognosis of patients with COVID-19 and diabetes. Methods This retrospective multicenter cohort study included patients admitted between December 2022 and January 2023. The patients were grouped according to diabetes and glucocorticoid use. The primary outcome was in-hospital mortality. Results Among 400 patients with glucocorticoid data, 109 (27.3%) had diabetes. The inflammatory cytokines were higher in patients with diabetes, manifested by higher IL-6 (25.33 vs. 11.29 ng/L, p = 0.011), CRP (26.55 vs. 8.62 mg/L, p = 0.003), and PCT (0.07 vs. 0.04 ng/ml, p = 0.010), while CD4+ (319 vs. 506 /mL, p = 0.004) and CD8+ (141 vs. 261 /mL, p < 0.001) T lymphocytes were lower. The overall mortality rate of hospitalized COVID-19 patients with diabetes was 13.46%. The diabetic patients who received glucocorticoids vs. those who did not receive glucocorticoids had a similar mortality (15.00% vs. 11.39%, p = 0.591). Conclusions Patients with COVID-19 and diabetes are more likely to experience hyperinflammatory response and T cell reduction, especially those with severe/critical disease. Glucocorticoid use was not associated with the prognosis of COVID-19 in patients with diabetes. Still, glucocorticoids should be used cautiously in diabetic patients with severe/critical COVID-19.

OBJECTIVE:To provide evidence-based recommendations for the prevention and management of lower limb ischemia in veno-arterial extracorporeal membrane oxygenation (VA-ECMO) patients during treatment according to search, evaluate, and summarize the best evidence on the prevention and management of lower limb ischemia in patients with VA-ECMO. METHODS:Based on the PIPOST framework (population, intervention, professional, outcome, setting, and type of evidence), an evidence-based question was formulated. A systematic search was conducted according to the "6S" evidence pyramid model in both domestic and international databases, as well as professional association websites, for all evidence related to the prevention and management of lower limb ischemia in VA-ECMO patients (aged ≥18 years). The types of evidence included clinical decisions, guidelines, expert consensus, systematic reviews, evidence summaries, and original studies. The search was conducted from the construction of the databases to February 2024. Two researchers independently conducted a literature quality evaluation, extracted and summarized evidence from the studies that met the quality criteria. RESULTS:A total of 13 articles were included, consisting of 3 clinical decisions, 3 guidelines, 3 expert consensus, 3 systematic reviews, and 1 randomized controlled trial. A total of 18 pieces of evidence in 7 dimensions were summarized, including risk factors of VA-ECMO lower limb ischemia, evaluation before catheterization, evaluation and monitoring during treatment, prevention of lower limb ischemia, treatment of lower limb ischemia, management of distal perfusion catheter (DPC), and monitoring after VA-ECMO weaning. CONCLUSIONS:This evidence summary provides evidence-based recommendations for the prevention and management of lower limb ischemia in VA-ECMO patients, aiming to assist clinical healthcare professionals in developing tailored strategies for the prevention and management of lower limb ischemia based on during VA-ECMO support.

Background: The Omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is highly transmissible but causes less severe disease compared to other variants. However, its association with sepsis incidence and outcomes is unclear. This study aimed to investigate the incidence of Omicronassociated sepsis, as per the Sepsis 3.0 definition, in hospitalized patients, and to explore its relationship with clinical characteristics and prognosis. Methods: This multicenter retrospective study included adults hospitalized with confirmed SARS-CoV-2 infection across six tertiary hospitals in Guangzhou, China from November 2022 to January 2023. The Sequential Organ Failure Assessment (SOFA) score and its components were calculated at hospital admission to identify sepsis. Outcomes assessed were need for intensive care unit (ICU) transfer and mortality. Receiver operating characteristic curves evaluated the predictive value of sepsis versus other biomarkers for outcomes. Results: A total of 299 patients (mean age: 70.1 +/- 14.4 years, 42.14% female) with SOFA score were enrolled. Among them, 152 were categorized as non -serious cases while the others were assigned as the serious group. The proportion of male patients, unvaccinated patients, patients with comorbidity such as diabetes, chronic cardiovascular disease, and chronic lung disease was significantly higher in the serious than non -serious group. The median SOFA score of all enrolled patients was 1 (interquartile range, 0-18). In our study, 147 patients (64.19% ) were identified as having sepsis upon hospital admission, with the majority of these septic patients (113, representing 76.87%) being in the serious group, the respiratory, coagulation, cardiovascular, central nervous, and renal organ SOFA scores were all significantly higher in the serious compared to the non -serious group. Among septic patients, 20 out of 49 (40.81%) had septic shock as indicated by lactate measurement within 24 hours of admission, and the majority of septic patients were in the serious group (17/20, 76.87%). Sepsis was present in 118 out of 269 (43.9%) patients in the general ward, and among those with sepsis, 34 out of 118 (28.8%) later required ICU care during hospitalization. By contrast, none of the patients without sepsis required ICU care. Moreover, the mortality rate was significantly higher in patients with than without sepsis. Conclusions: A considerable proportion of patients infected with Omicron present with sepsis upon hospital admission, which is associated with a poorer prognosis. Therefore, early recognition of viral sepsis by evaluation of the SOFA score in hospitalized coronavirus disease 2019 patients is crucial.

1 Department of Critical Care Medicine, State Key Lab of Respiratory Diseases, Guangzhou Institute of Respiratory Health, Guangzhou Medical University, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China 2 Department of Biomedical Engineering, Fourth Military Medical University, Xi’an, China 3 Institute of Technical Medicine, Furtwangen University, VS-Schwenningen, Germany The study was supported by the Emergency Key Program of Guangzhou Laboratory (Grant No. EKPG21-17). Dr. Zhao receives a consulting fee from Dräger Medical. Dr. Sang has disclosed that he does not have any potential conflicts of interest.

Background:Prone position ventilation (PPV) has been recommended for patients with acute respiratory distress syndrome (ARDS) to improve oxygenation. However, whether prolonged prone ventilation will aggravate hyperoxia and whether abdominal compression will aggravate permissive hypercapnia acidosis are topics of concern. We carried out a retrospective analysis to investigate the issues above.Methods:Clinical data were collected from 97 moderate-to-severe ARDS patients who received PPV as part of their treatment in the intensive care unit (ICU) of the First Affiliated Hospital of Guangzhou Medical University from November 2015 to May 2021. We collected arterial blood gas of patients according to the 3 periods: supine position ventilation (SPV), PPV early stage (within 4 hours), and PPV middle and late stage (6 hours or later). We established a linear mixed-effects models with "body position changes, times of PPV, gender, age, baseline SOFA, and baseline APACHE II" as fixed effects, and individual and the number of prone positions as random intercept and random slope to investigate the effect of body position changes on blood gas analysis.Results:Among the 97 patients received PPV included, 51 were ICU survivors. Arterial partial pressure of oxygen (PaO2) and PaO2/fraction of inspired oxygen (FiO2) ratio were significantly higher at the early, middle and late stages of PPV than those in SPV [PFR (mmHg): 158 (118.00, 203.00) vs. 161 (129.00, 202.75) vs. 123 (91.75, 163.00), P<0.05]. Despite the synchronized reduction of FiO2, the incidence of hyperoxia in the prone position was still significantly higher than that in the supine position [hyperoxia (%):33.33 vs. 33.56 vs. 12.42, P<0.05]; there was no significant change in arterial carbon dioxide partial pressure (PaCO2) at each stage of PPV, but there was a significant increase in PH at PPV middle and late stages than those at early stage [PH: 7.39 (7.34, 7.42) vs. 7.37 (7.31, 7.41), P<0.05].Conclusions:Although PPV improves the patients' oxygenation, the associated incidence of hyperoxia exceeds 33%. Down-regulate FiO2 more sharply after PPV is necessary, if oxygenation conditions permit. PPV may alleviate the acidosis associated with permissive hypercapnia in ARDS patients treated with lung protective ventilation strategy (LPVS).

Acute respiratory distress syndrome (ARDS) is an acute and uncontrolled pulmonary inflammation caused by various insults. Cell death is a critical mechanism in the pathogenesis of ARDS. Ferroptosis, a novel form of cell death defined as iron-mediated lipid peroxidation, has been shown to play a role in the pathogenesis of ARDS. Additionally, pyroptosis and necroptosis are also involved in the pathophysiological process of ARDS. The crosstalk among ferroptosis, pyroptosis, and necroptosis is getting increasing attention. Therefore, this review will mainly summarize the molecular mechanisms and central pathophysiological role of ferroptosis in ARDS. We will also discuss our understanding of pyroptosis and necroptosis as they pertain to the pathogenesis of ARDS. Furthermore, we also describe the pathological processes that engage crosstalk among ferroptosis, pyroptosis, and necroptosis. We consider that individual pathways of ferroptosis, pyroptosis, and necroptosis are highly interconnected and can compensate for one another to promote cell death.

Appropriate ventilation assessment is very important for management of critically ill patients, but current monitoring methods do not fully meet clinical needs. Pulmonary electrical impedance tomography is an emerging bedside monitoring technique with the advantages of non-invasiveness, radiation-free, and sustainable assessment of patients' regional lung ventilation function that has been performed clinically. Based on current research and clinical experience, this paper analyzes the hot issues of real-time evaluation of pulmonary ventilation in severe patients at bedside, and introduces experience as a reference for peers.