Intervention For Acute Respiratory Distress Syndrome Research Articles

Hub genes identification and validation of ferroptosis in SARS-CoV-2 induced ARDS: perspective from transcriptome analysis.

Acute Respiratory Distress Syndrome (ARDS) poses a significant health challenge due to its high incidence and mortality rates. The emergence of SARS-CoV-2 has added complexity, with evidence suggesting a correlation between COVID-19 induced ARDS and post-COVID symptoms. Understanding the underlying mechanisms of ARDS in COVID-19 patients is crucial for effective clinical treatment. To investigate the potential role of ferroptosis in SARS-CoV-2 induced ARDS, we conducted a comprehensive analysis using bioinformatics methods. Datasets from the Gene Expression Omnibus (GEO) were utilized, focusing on COVID-19 patients with varying ARDS severity. We employed weighted gene co-expression network analysis (WGCNA), differential gene expression analysis, and single-cell sequencing to identify key genes associated with ferroptosis in ARDS. Hub genes were validated using additional GEO datasets and cell experiment. The analysis discerned 916 differentially expressed genes in moderate/severe ARDS patients compared to non-critical individuals. Weighted Gene Co-expression Network Analysis (WGCNA) unveiled two modules that exhibited a positive correlation with ARDS, subsequently leading to the identification of 15 hub genes associated with ferroptosis. Among the noteworthy hub genes were MTF1, SAT1, and TXN. Protein-protein interaction analysis, and pathway analysis further elucidated their roles. Immune infiltrating analysis highlighted associations between hub genes and immune cells. Validation in additional datasets confirmed the upregulation of MTF1, SAT1, and TXN in SARS-CoV-2-induced ARDS. This was also demonstrated by qRT-PCR results in the BEAS-2B cells vitro model, suggesting their potential as diagnostic indicators. This study identifies MTF1, SAT1, and TXN as hub genes associated with ferroptosis in SARS-CoV-2-induced ARDS. These findings provide novel insights into the molecular mechanisms underlying ARDS in COVID-19 patients and offer potential targets for immune therapy and targeted treatment. Further experimental validation is warranted to solidify these findings and explore therapeutic interventions for ARDS in the context of COVID-19.

Deciphering the Therapeutic Potential of Myeloid-Specific JAK2 Inhibition in Acute Respiratory Distress Syndrome

Acute respiratory distress syndrome (ARDS) is a life-threatening condition characterized by severe inflammation and pulmonary dysfunction. Despite advancements in critical care, effective pharmacological interventions for ARDS remain elusive. While Janus kinase 2 (JAK2) inhibitors have emerged as an innovative treatment for numerous autoinflammatory diseases, their therapeutic potential in ARDS remains unexplored. In this study, we investigated the contribution of JAK2 and its underlying mechanisms in ARDS utilizing myeloid-specific JAK2 knockout murine models alongside a pharmacological JAK2 inhibitor. Notably, myeloid-specific JAK2 knockout led to a notable attenuation of ARDS induced by intratracheal administration of LPS, accompanied by reduced levels of neutrophils and inflammatory cytokines in bronchoalveolar lavage fluid (BALF) and lung tissue. Intriguingly, the ameliorative effects were abolished upon the depletion of monocyte-derived alveolar macrophages (Mo-AMs) rather than tissue-resident alveolar macrophages (TR-AMs). JAK2 deficiency markedly reversed LPS-induced activation of STAT5 in macrophages. Remarkably, pharmacological JAK2 inhibition using baricitinib failed to substantially alleviate neutrophils infiltration, implying that specific inhibition of JAK2 in Mo-AMs is imperative for ARDS amelioration. Collectively, our data suggest that JAK2 may mitigate ARDS progression through the JAK2 pathway in Mo-AMs, underscoring JAK2 in alveolar macrophages, particularly Mo-AMs, as a promising therapeutic target for ARDS treatment.

New 2023 global definition of acute respiratory distress syndrome: progress and limitation

Acute respiratory distress syndrome (ARDS) presents a challenge in clinical diagnosis as it lacks a definitive gold standard. Over the past 55 years, there have been several revisions to the definition of ARDS. With the progress of clinical practice and scientific research, the limitations of the "Berlin definition" have become increasingly evident. In response to these changes, the 2023 global definition of ARDS aims to address these issues by expanding the diagnostic targets, chest imaging, and methods for assessing hypoxia. Additionally, the new definition increases the diagnostic criteria to accommodate resource-constrained settings. The expansion facilitates early identification and treatment interventions for ARDS, thereby advancing epidemiological and clinically related research. Nevertheless, the broad nature of this revision may include patients who do not actually have ARDS, thus raising the risk of false-positive diagnoses. Therefore, additional verification is crucial to ascertain the validity and accuracy of the 2023 global definition of ARDS.

Complement as a vital nexus of the pathobiological connectome for acute respiratory distress syndrome: An emerging therapeutic target.

The hallmark of acute respiratory distress syndrome (ARDS) pathobiology is unchecked inflammation-driven diffuse alveolar damage and alveolar-capillary barrier dysfunction. Currently, therapeutic interventions for ARDS remain largely limited to pulmonary-supportive strategies, and there is an unmet demand for pharmacologic therapies targeting the underlying pathology of ARDS in patients suffering from the illness. The complement cascade (ComC) plays an integral role in the regulation of both innate and adaptive immune responses. ComC activation can prime an overzealous cytokine storm and tissue/organ damage. The ARDS and acute lung injury (ALI) have an established relationship with early maladaptive ComC activation. In this review, we have collected evidence from the current studies linking ALI/ARDS with ComC dysregulation, focusing on elucidating the new emerging roles of the extracellular (canonical) and intracellular (non-canonical or complosome), ComC (complementome) in ALI/ARDS pathobiology, and highlighting complementome as a vital nexus of the pathobiological connectome for ALI/ARDS via its crosstalking with other systems of the immunome, DAMPome, PAMPome, coagulome, metabolome, and microbiome. We have also discussed the diagnostic/therapeutic potential and future direction of ALI/ARDS care with the ultimate goal of better defining mechanistic subtypes (endotypes and theratypes) through new methodologies in order to facilitate a more precise and effective complement-targeted therapy for treating these comorbidities. This information leads to support for a therapeutic anti-inflammatory strategy by targeting the ComC, where the arsenal of clinical-stage complement-specific drugs is available, especially for patients with ALI/ARDS due to COVID-19.

Mechanosensitive ion channel Piezo1 mediates mechanical ventilation-exacerbated ARDS-associated pulmonary fibrosis

IntroductionPulmonary fibrosis is a major cause of the poor prognosis of acute respiratory distress syndrome (ARDS). While mechanical ventilation (MV) is an indispensable life-saving intervention for ARDS, it may cause the remodeling process in lung epithelial cells to become disorganized and exacerbate ARDS-associated pulmonary fibrosis. Piezo1 is a mechanosensitive ion channel that is known to play a role in regulating diverse physiological processes, but whether Piezo1 is necessary for MV-exacerbated ARDS-associated pulmonary fibrosis remains unknown. ObjectivesThis study aimed to explore the role of Piezo1 in MV-exacerbated ARDS-associated pulmonary fibrosis. MethodsHuman lung epithelial cells were stimulated with hydrochloric acid (HCl) followed by mechanical stretch for 48 h. A two-hitmodel of MV afteracidaspiration-inducedlunginjuryin mice was used. Mice were sacrificed after 14 days of MV. Pharmacological inhibition and knockout of Piezo1 were used to delineate the role of Piezo1 in MV-exacerbated ARDS-associated pulmonary fibrosis. In some experiments, ATP or the ATP-hydrolyzing enzyme apyrase was administered. ResultsThe stimulation of human lung epithelial cells to HCl resulted in phenotypes of epithelial-mesenchymal transition (EMT), which were enhanced by mechanical stretching. MV exacerbated pulmonary fibrosis in mice exposed to HCl. Pharmacologicalinhibitionorknockout of Piezo1 attenuated the MV-exacerbated EMT process and lung fibrosis in vivo and in vitro. Mechanistically, the observed effects were mediated by Piezo1-dependent Ca2+ influx and ATP release in lung epithelial cells. ConclusionsOur findings identify a key role for Piezo1 in MV-exacerbated ARDS-associated pulmonary fibrosis that is mediated by increased ATP release in lung epithelial cells. Inhibiting Piezo1 may constitute a novelstrategyfor the treatment of MV-exacerbated ARDS-associated pulmonary fibrosis.

The Renin-Angiotensin System as a Component of Biotrauma in Acute Respiratory Distress Syndrome.

Acute respiratory distress syndrome (ARDS) is a major concern in critical care medicine with a high mortality of over 30%. Injury to the lungs is caused not only by underlying pathological conditions such as pneumonia, sepsis, or trauma, but also by ventilator-induced lung injury (VILI) resulting from high positive pressure levels and a high inspiratory oxygen fraction. Apart from mechanical factors that stress the lungs with a specific physical power and cause volutrauma and barotrauma, it is increasingly recognized that lung injury is further aggravated by biological mediators. The COVID-19 pandemic has led to increased interest in the role of the renin-angiotensin system (RAS) in the context of ARDS, as the RAS enzyme angiotensin-converting enzyme 2 serves as the primary cell entry receptor for severe acute respiratory syndrome (SARS) coronavirus (CoV)-2. Even before this pandemic, studies have documented the involvement of the RAS in VILI and its dysregulation in clinical ARDS. In recent years, analytical tools for RAS investigation have made major advances based on the optimized precision and detail of mass spectrometry. Given that many clinical trials with pharmacological interventions in ARDS were negative, RAS-modifying drugs may represent an interesting starting point for novel therapeutic approaches. Results from animal models have highlighted the potential of RAS-modifying drugs to prevent VILI or treat ARDS. While these drugs have beneficial pulmonary effects, the best targets and application forms for intervention still have to be determined to avoid negative effects on the circulation in clinical settings.

Aspirin Attenuates Hyperoxia-Induced Acute Respiratory Distress Syndrome (ARDS) by Suppressing Pulmonary Inflammation via the NF-κB Signaling Pathway.

Acute respiratory distress syndrome (ARDS) is a common destructive syndrome with high morbidity and mortality rates. Currently, few effective therapeutic interventions for ARDS are available. Clinical trials have shown that the effectiveness of aspirin is inconsistent. The contribution of platelets to the inflammatory response leading to the development of ARDS is increasingly recognized. The antiplatelet agent aspirin reportedly exerts a protective effect on acid- and hyperoxia-induced lung injury in murine models. Our previous study showed that pretreatment with aspirin exerts protective effects on hyperoxia-induced lung injury in mice. However, the mechanisms and therapeutic efficacy of aspirin in the posttreatment of hyperoxia-induced acute lung injury (ALI) remain unclear. In this study, we used a homozygous NF-κB-luciferase+/+ transgenic mouse model and treated mice with low-dose (25 μg/g) or high-dose (50 μg/g) aspirin at 0, 24, and 48 h after exposure to hyperoxia (inspired oxygen fraction (FiO2) > 95%). Hyperoxia-induced lung injury significantly increased the activation of NF-κB in the lung and increased the levels of macrophages infiltrating the lung and reactive oxygen species (ROS), increased the HO-1, NF-κB, TNF-α, IL-1β, and IL-4 protein levels, and reduced the CC10, SPC, eNOS, Nrp-1, and IκBα protein levels in the lung tissue. Pulmonary edema and alveolar infiltration of neutrophils were also observed in the lung tissue of mice exposed to hyperoxia. However, in vivo imaging revealed that posttreatment with aspirin reduced luciferase expression, suggesting that aspirin might reduce NF-κB activation. Posttreatment with aspirin also reduced hyperoxia-induced increases in the numbers of lung macrophages, intracellular ROS levels, and the expression of TNF-α, IL-1β, and IL-4; it also increased CC10, SPC and Nrp-1 levels compared with hyperoxia exposure alone. Lung histopathology also indicated that the aspirin posttreatment significantly reduced neutrophil infiltration and lung edema compared with hyperoxia exposure alone. Aspirin effectively induces an anti-inflammatory response in a model of hyperoxia-induced lung injury. Thus, aspirin may have potential as a novel treatment for hyperoxia-induced ALI.

Impact of Clinician Recognition of Acute Respiratory Distress Syndrome on Evidenced-Based Interventions in the Medical ICU.

Observational cohort study. Single medical ICU at an academic tertiary-care hospital. Nine hundred seventy-seven critically ill adults (381 with expert-adjudicated acute respiratory distress syndrome) enrolled from 2006 to 2015. Clinician-recognized-acute respiratory distress syndrome was identified using an electronic keyword search of clinical notes in the electronic health record. We assessed the classification performance of clinician-recognized acute respiratory distress syndrome for identifying expert-adjudicated acute respiratory distress syndrome. We also compared differences in ventilator settings, diuretic prescriptions, and cumulative fluid balance between clinician-recognized acute respiratory distress syndrome and unrecognized acute respiratory distress syndrome. Overall, clinician-recognized-acute respiratory distress syndrome had a sensitivity of 47.5%, specificity 91.1%, positive predictive value 77.4%, and negative predictive value 73.1% for expert-adjudicated acute respiratory distress syndrome. Among the 381 expert-adjudicated acute respiratory distress syndrome cases, we did not observe any differences in ventilator tidal volumes between clinician-recognized-acute respiratory distress syndrome and unrecognized acute respiratory distress syndrome, but clinician-recognized-acute respiratory distress syndrome patients had a more negative cumulative fluid balance (mean difference, -781 mL; 95% CI, [-1,846 to +283]) and were more likely to receive diuretics (49.3% vs 35.7%, p = 0.02). There were no differences in mortality, ICU length of stay, or ventilator-free days. Acute respiratory distress syndrome recognition was low in this single-center study. Although acute respiratory distress syndrome recognition was not associated with lower ventilator volumes, it was associated with differences in behaviors related to fluid management. These findings have implications for the design of future studies promoting evidence-based acute respiratory distress syndrome interventions in the ICU.

Natural history, trajectory, and management of mechanically ventilated COVID-19 patients in the United Kingdom

PurposeThe trajectory of mechanically ventilated patients with coronavirus disease 2019 (COVID-19) is essential for clinical decisions, yet the focus so far has been on admission characteristics without consideration of the dynamic course of the disease in the context of applied therapeutic interventions.MethodsWe included adult patients undergoing invasive mechanical ventilation (IMV) within 48 h of intensive care unit (ICU) admission with complete clinical data until ICU death or discharge. We examined the importance of factors associated with disease progression over the first week, implementation and responsiveness to interventions used in acute respiratory distress syndrome (ARDS), and ICU outcome. We used machine learning (ML) and Explainable Artificial Intelligence (XAI) methods to characterise the evolution of clinical parameters and our ICU data visualisation tool is available as a web-based widget (https://www.CovidUK.ICU).ResultsData for 633 adults with COVID-19 who underwent IMV between 01 March 2020 and 31 August 2020 were analysed. Overall mortality was 43.3% and highest with non-resolution of hypoxaemia [60.4% vs17.6%; P < 0.001; median PaO2/FiO2 on the day of death was 12.3(8.9–18.4) kPa] and non-response to proning (69.5% vs.31.1%; P < 0.001). Two ML models using weeklong data demonstrated an increased predictive accuracy for mortality compared to admission data (74.5% and 76.3% vs 60%, respectively). XAI models highlighted the increasing importance, over the first week, of PaO2/FiO2 in predicting mortality. Prone positioning improved oxygenation only in 45% of patients. A higher peak pressure (OR 1.42[1.06–1.91]; P < 0.05), raised respiratory component (OR 1.71[ 1.17–2.5]; P < 0.01) and cardiovascular component (OR 1.36 [1.04–1.75]; P < 0.05) of the sequential organ failure assessment (SOFA) score and raised lactate (OR 1.33 [0.99–1.79]; P = 0.057) immediately prior to application of prone positioning were associated with lack of oxygenation response. Prone positioning was not applied to 76% of patients with moderate hypoxemia and 45% of those with severe hypoxemia and patients who died without receiving proning interventions had more missed opportunities for prone intervention [7 (3–15.5) versus 2 (0–6); P < 0.001]. Despite the severity of gas exchange deficit, most patients received lung-protective ventilation with tidal volumes less than 8 mL/kg and plateau pressures less than 30cmH2O. This was despite systematic errors in measurement of height and derived ideal body weight.ConclusionsRefractory hypoxaemia remains a major association with mortality, yet evidence based ARDS interventions, in particular prone positioning, were not implemented and had delayed application with an associated reduced responsiveness. Real-time service evaluation techniques offer opportunities to assess the delivery of care and improve protocolised implementation of evidence-based ARDS interventions, which might be associated with improvements in survival.

Non-specialist therapeutic strategies in acute respiratory distress syndrome.

Acute respiratory distress syndrome (ARDS) is associated with significant morbidity and mortality. We undertook a meta-analysis of randomized controlled trials (RCTs) to determine the mortality benefit of non-specialist therapeutic interventions for ARDS available to general critical care units. A systematic search of MEDLINE, Embase, and the Cochrane Central Register for RCTs investigating therapeutic interventions in ARDS including corticosteroids, fluid management strategy, high PEEP, low tidal volume ventilation, neuromuscular blockade, prone position ventilation, or recruitment maneuvers. Data was collected on demographic information, treatment strategy, duration and dose of treatment, and primary (28 or 30-day mortality) and secondary (P<inf>a</inf>O<inf>2</inf>:FiO<inf>2</inf> ratio at 24-48 hours) outcomes. No improvement in 28-day mortality could be demonstrated in three RCTs investigating high PEEP (28.0% vs. 30.2% control; risk ratio [confidence interval] 0.93 [0.82-1.06]; eight assessing prone position ventilation (39.3% vs. 44.5%; RR 0.83 [0.68-1.01]; seven investigating neuromuscular blockade (37.8% vs. 42.0%; RR 0.91 [0.81-1.03]); ten investigating recruitment maneuvers (42.4% vs. 42.1%; RR 1.01 [0.91-1.12]); eight investigating steroids (34.8% vs. 41.1%; RR 0.81 [0.59-1.12]); and one investigating conservative fluid strategies (25.4% vs. 28.4%; RR 0.90 [0.73-1.10]). Three studies assessing low tidal volume ventilation (33.1% vs. 41.9%; RR 0.79 (0.68-0.91); P=0.001), and subgroup analyses within studies investigating prone position ventilation greater than 12 hours (33.1% vs. 44.4%; RR 0.75 [0.59-0.95), P=0.02) did reveal outcome benefit. Among non-specialist therapeutic strategies available to general critical care units, low tidal volumes and prone position ventilation for greater than 12 hours improve mortality in ARDS.

Evaluation of misrepresented findings in the abstracts of acute respiratory distress syndrome randomized trials with nonsignificant primary endpoints.

We investigated the randomized controlled trials (RCTs) related to acute respiratory distress syndrome (ARDS) to assess the presentation and frequency of misrepresented research findings, also known as spin. We searched PubMed (MEDLINE) for studies published from January 1, 2011 to December 31, 2019. We included randomized controlled trials with an ARDS intervention and a nonsignificant primary endpoint. Trial screening and data extraction was performed on all studies independently and in duplicate. The primary endpoint was to investigate the frequency and manifestation of spin in RCT abstracts. Our secondary endpoint was to investigate associations between funding source and spin. Our PubMed search returned 766 articles with 37 meeting inclusion criteria. Spin was present in 14 (14/37, 37.8%; 95% CI 22.5%-55.2%) abstracts. The most common manifestations of spin were claiming benefit based on a significant secondary endpoint (6/14, 42.9%), followed by the use of 'trend' statements, such as 'trend toward significance' (2/14, 14.3%; 95% CI 1.8%-42.8%). The most common spin in abstract conclusions was in the form of claiming benefit due to a significant secondary endpoint (3/4, 75%; 95% CI 19.4%-99.4%). Our secondary endpoint did not identify a significant difference in the prevalence of spin in publicly funded (5/19, 26.3%; 95% CI 9.1%-51.2%) compared to privately funded (4/12, 33.3%; 95% CI 9.9%-65.1%) studies (p>.05). RCTs of ARDS interventions with nonsignificant primary endpoints often included spin in the abstract. Spin in the abstract may influence clinician appraisal and interpretation of diagnostic or treatment modalities.

Designing an ARDS trial for 2020 and beyond: focus on enrichment strategies.

With the exception of a few successes in trials of supportive care, the majority of interventional clinical trials for acute respiratory distress syndrome (ARDS) have not led to new therapies. To improve the likelihood of benefit from clinical trial interventions in ARDS, clinical trial design must be improved. To optimize trial design, many factors need to be considered including the type of therapy to be tested, the type of trial (phase 2 or 3), how patients will be selected, primary and secondary end-points, and strategy for conduct of the trial, including potential newer trial designs such as platform or adaptive trials. Of these, optimization of patient selection is central to the likelihood of success and is particularly relevant in ARDS, which is a heterogeneous clinical syndrome, not a homogeneous disease. Recent advances including improved understanding of pathophysiologic mechanisms and better tools for outcome prediction in ARDS should facilitate both predictive and prognostic enrichment. This commentary focuses on new information and novel methods for prognostic and predictive enrichment that may be useful to optimize patient selection and increase the likelihood of positive clinical trials in ARDS.

Factors Influencing Prone Positioning in Treating Acute Respiratory Distress Syndrome and the Effect on Mortality Rate.

Acute respiratory distress syndrome (ARDS) is often associated with severe hypoxemia and a high mortality rate. Prone positioning is a well-established intervention for ARDS. It has been shown to improve oxygenation and prevent ventilator-induced lung injury due to the more uniform distribution of lung stress and strain. This narrative review aims to compare the various factors that may influence how prone positioning affects mortality rates. We will examine the duration of time a patient is in the prone position, severity of ARDS, use of lung-protective ventilation, and the time elapsed between ARDS diagnosis and placing a patient in the prone position. A literature review on prone positioning in ARDS was performed and searched data from PubMed and Google Scholar for articles published from 2010 to 2020. Although no single variable used during prone positioning reduces mortality rates in ARDS patients, combining several optimal conditions may yield increased survival benefits. Early initiation of extended prone positioning sessions combined with low tidal volumes shows encouraging results in severe ARDS patients. Future research on this subject should focus on further examining these variables in a study enrolling a larger number of subjects in a setting with adequately trained staff familiar with proper prone positioning techniques.

In Response.

In Response.

A cytosolic heat shock protein 90 and co-chaperone p23 complex activates RIPK3/MLKL during necroptosis of endothelial cells in acute respiratory distress syndrome

Necrosis with inflammation plays a crucial role in acute respiratory distress syndrome (ARDS). Receptor-interacting protein 3 (RIPK3) regulates a newly discovered programmed form of necrosis called necroptosis. However, the underlying mechanism of necroptosis in ARDS remains unknown. Thus, the purpose of this study was to examine the possible involvement of RIPK3 in ARDS-associated necroptosis. RIPK3 protein levels were found to be significantly elevated in the plasma and bronchoalveolar lavage fluid of ARDS patients. Next, we utilised a mouse model of severe ARDS induced with high-dose lipopolysaccharide and found that lung injury was mainly due to RIPK3-mixed lineage kinase domain-like pseudokinase (MLKL)-mediated necroptosis and endothelial dysfunction. The activation of RIPK3-MLKL by tumour necrosis factor receptor 1 (TNFR1) and TNFR1-associated death domain protein (TRADD) required catalytically active RIPK1 and the inhibition of Fas-associated protein with death domain (FADD)/caspase-8 catalytic activity. We further showed that the molecular chaperone heat shock protein 90 (Hsp90)/p23, as a novel RIPK3- and MLKL-interacting complex, played an important role in RIP-MLKL-mediated necroptosis, inflammation and endothelial dysfunction in the pulmonary vasculature, which resulted in ARDS. Collectively, the results of our study indicate that necroptosis is an important mechanism of cell death in ARDS and the inhibition of necroptosis may be a therapeutic intervention for ARDS. KEY MESSAGES: Lung injury in high-dose LPS-induced severe ARDS is mainly due to RIP3-MLKL-mediated necroptosis and endothelial dysfunction. Chaperone HSP90/p23 is a novel RIP3- and MLKL-interacting complex in HPAECs. HSP90/p23 is a novel RIP3- and MLKL-interacting complex in RIP-MLKL-mediated necroptosis, inflammation and endothelial dysfunction.

Efficacy of protocol-based non-invasive positive pressure ventilation for acute respiratory distress syndrome: a retrospective observational study.

AimThe efficacy of non‐invasive positive pressure ventilation (NPPV) in acute respiratory distress syndrome (ARDS) remains unclear. Variation in both the etiology of ARDS and patient factors has resulted in inconsistent application of NPPV. We have developed a protocol‐based NPPV strategy as a first‐line intervention for ARDS. The aim of this observational study was to determine if protocol‐based NPPV improves the outcome in patients with ARDS.MethodsWe identified patients with ARDS treated by protocol‐based NPPV at our institution between March 2006 and March 2010 and categorized them according to NPPV success or failure. Success was defined as avoidance of intubation and remaining alive during NPPV.ResultsEighty‐eight of 169 patients diagnosed with ARDS during the study period were treated using the protocol. Fifty‐two (76%) of 68 patients who were eligible for the study were successfully treated and did not require endotracheal intubation. The overall mortality rate at 28 days after initiation of NPPV was 12%. The mortality rate was significantly lower in the success group than in the failure group (P < 0.01). The PaO2/FiO2 ratio after 12–24 h of NPPV was significantly higher in the success group than in the failure group (202 ± 63 versus 145 ± 46; P < 0.01).ConclusionsThe success rate was higher and the mortality was lower in patients than in historical controls. Protocol‐based NPPV could be effective in patients with ARDS.

The counter-intuitive role of the neutrophil in the acute respiratory distress syndrome

Neutrophils are the primary effectors of the innate immune system but are profoundly histotoxic cells. The acute respiratory distress syndrome (ARDS) is considered to be a prime example of neutrophil-mediated tissue injury. The information presented in this review is acquired from the published neutrophil cell biology literature and the longstanding interest of the senior authors in ARDS pathogenesis and clinical management. Investigators in the field would agree that neutrophils accumulate in high abundance in the pulmonary microcirculation, lung interstitium and alveolar airspace of patients with ARDS. ARDS is also associated with systemic neutrophil priming and delayed neutrophil apoptosis and clearance of neutrophils from the lungs. In animal models, reducing circulating neutrophil numbers ameliorates lung injury. Areas of uncertainty include how neutrophils get stuck in the narrow pulmonary capillary network-whether this reflects changes in the mechanical properties of primed neutrophils alone or additional cell adhesion molecules, the role of neutrophil sub-sets or polarization states including pro-angiogenic and low-density neutrophils, whether neutrophil extracellular trap (NET) formation is beneficial (through bacterial capture) or harmful and the potential for neutrophils to participate in inflammatory resolution. The latter may involve the generation of specialized pro-resolving molecules (SPMs) and MMP-9, which is required for adequate matrix processing. Different and possibly stable endotypes of ARDS are increasingly being recognized, yet the relative contribution of the neutrophil to these endotypes is uncertain. There is renewed and intense interest in understanding the complex 'new biology' of the neutrophil, specifically whether this cell might be a valid therapeutic target in ARDS and other neutrophil-driven diseases and developing understanding of ways to enhance the beneficial role of the neutrophil in the resolution phase of ARDS. Aside from treatment of the precipitating causes of ARDS, and scrupulous fluid, infection and ventilation management, there are no pharmacological interventions for ARDS; this represents an urgent and unmet need. Therapies aimed at reducing overall neutrophil numbers risk secondary infection; hence better ways are needed to reverse the processes of neutrophil priming activation, hyper-secretion and delayed apoptosis while enhancing the pro-resolution functions of the neutrophil.

Ex vivo lung perfusion as a human platform for preclinical small molecule testing.

The acute respiratory distress syndrome (ARDS) causes an estimated 70,000 US deaths annually. Multiple pharmacologic interventions for ARDS have been tested and failed. An unmet need is a suitable laboratory human model to predictively assess emerging therapeutics on organ function in ARDS. We previously demonstrated that the small molecule BC1215 blocks actions of a proinflammatory E3 ligase-associated protein, FBXO3, to suppress NF-κB signaling in animal models of lung injury. Ex vivo lung perfusion (EVLP) is a clinical technique that maintains lung function for possible transplant after organ donation. We used human lungs unacceptable for transplant to model endotoxemic injury with EVLP for 6 hours. LPS infusion induced inflammatory injury with impaired oxygenation of pulmonary venous circulation. BC1215 treatment after LPS rescued oxygenation and decreased inflammatory cytokines in bronchoalveolar lavage. RNA sequencing transcriptomics from biopsies taken during EVLP revealed robust inflammatory gene induction by LPS with a strong signal for NF-κB-associated transcripts. BC1215 treatment reduced the LPS induction of genes associated with inflammatory and host defense gene responses by Gene Ontology (GOterm) and pathways analysis. BC1215 also significantly antagonized LPS-mediated NF-κB activity. EVLP may provide a unique human platform for preclinical study of chemical entities such as FBXO3 inhibitors on tissue physiology.

ARDS: challenges in patient care and frontiers in research.

This review discusses the clinical challenges associated with ventilatory support and pharmacological interventions in patients with acute respiratory distress syndrome (ARDS). In addition, it discusses current scientific challenges facing researchers when planning and performing trials of ventilatory support or pharmacological interventions in these patients.Noninvasive mechanical ventilation is used in some patients with ARDS. When intubated and mechanically ventilated, ARDS patients should be ventilated with low tidal volumes. A plateau pressure <30 cmH2O is recommended in all patients. It is suggested that a plateau pressure <15 cmH2O should be considered safe. Patient with moderate and severe ARDS should receive higher levels of positive end-expiratory pressure (PEEP). Rescue therapies include prone position and neuromuscular blocking agents. Extracorporeal support for decapneisation and oxygenation should only be considered when lung-protective ventilation is no longer possible, or in cases of refractory hypoxaemia, respectively. Tracheotomy is only recommended when prolonged mechanical ventilation is expected.Of all tested pharmacological interventions for ARDS, only treatment with steroids is considered to have benefit.Proper identification of phenotypes, known to respond differently to specific interventions, is increasingly considered important for clinical trials of interventions for ARDS. Such phenotypes could be defined based on clinical parameters, such as the arterial oxygen tension/inspiratory oxygen fraction ratio, but biological marker profiles could be more promising.

Scandinavian clinical practice guideline on fluid and drug therapy in adults with acute respiratory distress syndrome.

BackgroundThe objective of the Scandinavian Society of Anaesthesiology and Intensive Care Medicine (SSAI) task force on fluid and drug therapy in adults with acute respiratory distress syndrome (ARDS) was to provide clinically relevant, evidence‐based treatment recommendations according to standards for trustworthy guidelines.MethodsThe guideline was developed according to standards for trustworthy guidelines, including a systematic review of the literature and use of the GRADE methodology for assessment of the quality of evidence and for moving from evidence to recommendations.ResultsA total of seven ARDS interventions were assessed. We suggest fluid restriction in patients with ARDS (weak recommendation, moderate quality evidence). Also, we suggest early use of neuromuscular blocking agents (NMBAs) in patients with severe ARDS (weak recommendation, moderate quality evidence). We recommend against the routine use of other drugs, including corticosteroids, beta2 agonists, statins, and inhaled nitric oxide (iNO) or prostanoids in adults with ARDS (strong recommendations: low‐ to high‐quality evidence). These recommendations do not preclude the use of any drug or combination of drugs targeting underlying or co‐existing disorders.ConclusionThis guideline emphasizes the paucity of evidence of benefit – and potential for harm – of common interventions in adults with ARDS and highlights the need for prudence when considering use of non‐licensed interventions in this patient population.