Consensus statements on the utility of defining ARDS and the utility of past and current definitions of ARDS-protocol for a Delphi study.

INTRODUCTION: Acute respiratory distress syndrome (ARDS), marked by acute hypoxemia and bilateral pulmonary infiltrates, has been defined in multiple ways since its first description. This Delphi study aims to collect global opinions on the conceptual framework of ARDS, assess the usefulness of components within current and past definitions and investigate the role of subphenotyping. The varied expertise of the panel will provide valuable insights for refining future ARDS definitions and improving clinical management. METHODS: A diverse panel of 35-40 experts will be selected based on predefined criteria. Multiple choice questions (MCQs) or 7-point Likert-scale statements will be used in the iterative Delphi rounds to achieve consensus on key aspects related to the utility of definitions and subphenotyping. The Delphi rounds will be continued until a stable agreement or disagreement is achieved for all statements. ANALYSIS: Consensus will be considered as reached when a choice in MCQs or Likert-scale statement achieved ≥80% of votes for agreement or disagreement. The stability will be checked by non-parametric χ2 tests or Kruskal Wallis test starting from the second round of Delphi process. A p-value ≥0.05 will be used to define stability. ETHICS AND DISSEMINATION: The study will be conducted in full concordance with the principles of the Declaration of Helsinki and will be reported according to CREDES guidance. This study has been granted an ethical approval waiver by the NMC Healthcare Regional Research Ethics Committee, Dubai (NMCHC/CR/DXB/REC/APP/002), owing to the nature of the research. Informed consent will be obtained from all panellists before the start of the Delphi process. The study will be published in a peer-review journal with the authorship agreed as per ICMJE requirements. TRIAL REGISTRATION NUMBER: NCT06159465.

Anti-inflammatory therapies for acute respiratory distress syndrome.

INTRODUCTION: Treatments for the acute respiratory distress syndrome (ARDS) are mainly supportive, and ventilatory management represents a key approach in these patients. Despite progress in pharmacotherapy, anti-inflammatory strategies for the treatment of ARDS have shown controversial results. Positive outcomes with pharmacologic and nonpharmacologic treatments have been found in two different biological subphenotypes of ARDS, suggesting that, with a personalized medicine approach, pharmacotherapy for ARDS can be effective. AREAS COVERED: This article reviews the literature concerning anti-inflammatory therapies for ARDS, focusing on pharmacological and stem-cell therapies, including extracellular vesicles. EXPERT OPINION: Despite advances, ARDS treatments remain primarily supportive. Ventilatory and fluid management are important strategies in these patients that have demonstrated significant impacts on outcome. Anti-inflammatory drugs have shown some benefits, primarily in preclinical research and in specific clinical scenarios, but no recommendations are available from guidelines to support their use in patients with ARDS, except in particular settings such as different subphenotypes, specific etiologies, or clinical trials. Personalized medicine seems promising insofar as it may identify specific subgroups of patients with ARDS who may benefit from anti-inflammatory treatment. However, additional efforts are needed to move subphenotype characterization from bench to bedside.

Personalized medicine using omics approaches in acute respiratory distress syndrome to identify biological phenotypes.

In the last decade, research on acute respiratory distress syndrome (ARDS) has made considerable progress. However, ARDS remains a leading cause of mortality in the intensive care unit. ARDS presents distinct subphenotypes with different clinical and biological features. The pathophysiologic mechanisms of ARDS may contribute to the biological variability and partially explain why some pharmacologic therapies for ARDS have failed to improve patient outcomes. Therefore, identifying ARDS variability and heterogeneity might be a key strategy for finding effective treatments. Research involving studies on biomarkers and genomic, metabolomic, and proteomic technologies is increasing. These new approaches, which are dedicated to the identification and quantitative analysis of components from biological matrixes, may help differentiate between different types of damage and predict clinical outcome and risk. Omics technologies offer a new opportunity for the development of diagnostic tools and personalized therapy in ARDS. This narrative review assesses recent evidence regarding genomics, proteomics, and metabolomics in ARDS research.

Novel Synthetic and Natural Therapies for Traumatic Brain Injury.

Traumatic brain injury (TBI) is a major cause of disability and death worldwide. The initial mechanical insult results in tissue and vascular disruption with hemorrhages and cellular necrosis that is followed by dynamic secondary brain damage that presumably results in additional destruction of the brain. In order to minimize deleterious consequences of the secondary brain damage- such as inflammation, bleeding or reduced oxygen supply. The old concept of the -staircase approach- has been updated in recent years by most guidelines and should be followed as it is considered the only validated approach for the treatment of TBI. Besides, a variety of novel therapies have been proposed as neuroprotectants. The molecular mechanisms of each drug involved in the inhibition of secondary brain injury can result as a potential target for the early and late treatment of TBI. However, no specific recommendation is available on their use in the clinical setting. The administration of both synthetic and natural compounds, which act on specific pathways involved in the destructive processes after TBI, even if usually employed for the treatment of other diseases, can show potential benefits. This review represents a massive effort towards current and novel therapies for TBI that have been investigated in both pre-clinical and clinical settings. This review aims to summarize the advancement in therapeutic strategies based on specific and distinct -target of therapies-: brain edema, ICP control, neuronal activity and plasticity, anti-inflammatory and immunomodulatory effects, cerebral autoregulation, antioxidant properties, and future perspectives with the adoption of mesenchymal stromal cells.

Pathophysiology and clinical consequences of arterial blood gases and pH after cardiac arrest.

Post cardiac arrest syndrome is associated with high morbidity and mortality, which is related not only to a poor neurological outcome but also to respiratory and cardiovascular dysfunctions. The control of gas exchange, and in particular oxygenation and carbon dioxide levels, is fundamental in mechanically ventilated patients after resuscitation, as arterial blood gases derangement might have important effects on the cerebral blood flow and systemic physiology.In particular, the pathophysiological role of carbon dioxide (CO2) levels is strongly underestimated, as its alterations quickly affect also the changes of intracellular pH, and consequently influence metabolic energy and oxygen demand. Hypo/hypercapnia, as well as mechanical ventilation during and after resuscitation, can affect CO2 levels and trigger a dangerous pathophysiological vicious circle related to the relationship between pH, cellular demand, and catecholamine levels. The developing hypocapnia can nullify the beneficial effects of the hypothermia. The aim of this review was to describe the pathophysiology and clinical consequences of arterial blood gases and pH after cardiac arrest.According to our findings, the optimal ventilator strategies in post cardiac arrest patients are not fully understood, and oxygen and carbon dioxide targets should take in consideration a complex pattern of pathophysiological factors. Further studies are warranted to define the optimal settings of mechanical ventilation in patients after cardiac arrest.

Chest physiotherapy: An important adjuvant in critically ill mechanically ventilated patients with COVID-19.

In late 2019, an outbreak of a novel human coronavirus causing respiratory disease was identified in Wuhan, China. The virus spread rapidly worldwide, reaching pandemic status. Chest computed tomography scans of patients with coronavirus disease-2019 (COVID-19) have revealed different stages of respiratory involvement, with extremely variable lung presentations, which require individualized ventilatory strategies in those who become critically ill. Chest physiotherapy has proven to be effective for improving long-term respiratory physical function among ICU survivors. The ARIR recently reported the role of chest physiotherapy in the acute phase of COVID-19, pointing out limitation of some procedures due to the limited experience with this disease in the ICU setting. Evidence on the efficacy of chest physiotherapy in COVID-19 is still lacking. In this line, the current review discusses the important role of chest physiotherapy in critically ill mechanically ventilated patients with COVID-19, around the weaning process, and how it can be safely applied with careful organization, including the training of healthcare staff and the appropriate use of personal protective equipment to minimize the risk of viral exposure.

Estimating the Damaging Power of High-Stress Ventilation.

Redirection of our clinical attention from the pressures and volumes of the individual cycle to the broader and more inclusive considerations of energy load and power has untapped potential to reduce iatrogenic risk from ventilation (ie, ventilator-induced lung injury). Power is the product of breathing frequency and inflation energy per breath. Yet, while feasible to calculate at the bedside, measuring total power may not prove to be precise enough for accurate prediction of ventilator-induced lung injury, even if normalized to lung capacity (ie, specific power). The same power value can be reached by a multitude of frequency and tidal volume combinations, not all of which carry equal risk of damage. If some arbitrary level of alveolar pressure were accepted as a sharply defined hazard boundary, a rather straightforward geometric analysis theoretically would allow partitioning of overall tidal energy into components above and below a damage threshold. In this discussion, we introduce the concept of quantitative power partitioning and illustrate how tidal energy and power might be deconstructed into their key parts.

Impact of different intratracheal flows during lung decellularization on extracellular matrix composition and mechanics.

AIM: To evaluate different intratracheal flow rates on extracellular matrix content and lung mechanics in an established lung decellularization protocol. MATERIALS & METHODS: Healthy mice were used: 15 for decellularization and five to serve as controls. Fluids were instilled at 5, 10 and 20 ml/min flow rates through tracheal cannula and right ventricular cavity (0.5 ml/min) in all groups. RESULTS: The 20 ml/min rate better preserved collagen content in decellularized lungs. Elastic fiber content decreased at 5 and 10 ml/min, but not at 20 ml/min, compared with controls. Chondroitin, heparan and dermatan content was reduced after decellularization. CONCLUSION: An intratracheal flow rate of 20 ml/min was associated with lower resistance and greater preservation of collagen to that observed in ex vivo control lungs.

Mesenchymal stromal cell therapy in COPD: from bench to bedside.

COPD is the most frequent chronic respiratory disease and a leading cause of morbidity and mortality. The major risk factor for COPD development is cigarette smoke, and the most efficient treatment for COPD is smoking cessation. However, even after smoking cessation, inflammation, apoptosis, and oxidative stress may persist and continue contributing to disease progression. Although current therapies for COPD (primarily based on anti-inflammatory agents) contribute to the reduction of airway obstruction and minimize COPD exacerbations, none can avoid disease progression or reduce mortality. Within this context, recent advances in mesenchymal stromal cell (MSC) therapy have made this approach a strong candidate for clinical use in the treatment of several pulmonary diseases. MSCs can be readily harvested from diverse tissues and expanded with high efficiency, and have strong immunosuppressive properties. Preclinical studies have demonstrated encouraging outcomes of MSCs therapy for lung disorders, including emphysema. These findings instigated research groups to assess the impact of MSCs in human COPD/emphysema, but clinical results have fallen short of expectations. However, MSCs have demonstrated a good adjuvant role in the clinical scenario. Trials that used MSCs combined with another, primary treatment (eg, endobronchial valves) found that patients derived greater benefit in pulmonary function tests and/or quality of life reports, as well as reductions in systemic markers of inflammation. The present review summarizes and describes the more recent preclinical studies that have been published about MSC therapy for COPD/emphysema and discusses what has already been applied about MSCs treatment in COPD patients in the clinical setting.

Recruitment maneuvers in acute respiratory distress syndrome: The safe way is the best way.

Acute respiratory distress syndrome (ARDS) represents a serious problem in critically ill patients and is associated with in-hospital mortality rates of 33%-52%. Recruitment maneuvers (RMs) are a simple, low-cost, feasible intervention that can be performed at the bedside in patients with ARDS. RMs are characterized by the application of airway pressure to increase transpulmonary pressure transiently. Once non-aerated lung units are reopened, improvements are observed in respiratory system mechanics, alveolar reaeration on computed tomography, and improvements in gas exchange (functional recruitment). However, the reopening process could lead to vascular compression, which can be associated with overinflation, and gas exchange may not improve as expected (anatomical recruitment). The purpose of this review was to discuss the effects of different RM strategies - sustained inflation, intermittent sighs, and stepwise increases of positive end-expiratory pressure (PEEP) and/or airway inspiratory pressure - on the following parameters: hemodynamics, oxygenation, barotrauma episodes, and lung recruitability through physiological variables and imaging techniques. RMs and PEEP titration are interdependent events for the success of ventilatory management. PEEP should be adjusted on the basis of respiratory system mechanics and oxygenation. Recent systematic reviews and meta-analyses suggest that RMs are associated with lower mortality in patients with ARDS. However, the optimal RM method (i.e., that providing the best balance of benefit and harm) and the effects of RMs on clinical outcome are still under discussion, and further evidence is needed.

The effects of salbutamol on epithelial ion channels depend on the etiology of acute respiratory distress syndrome but not the route of administration.

INTRODUCTION: We investigated the effects of intravenous and intratracheal administration of salbutamol on lung morphology and function, expression of ion channels, aquaporin, and markers of inflammation, apoptosis, and alveolar epithelial/endothelial cell damage in experimental pulmonary (p) and extrapulmonary (exp) mild acute respiratory distress syndrome (ARDS). METHODS: In this prospective randomized controlled experimental study, 56 male Wistar rats were randomly assigned to mild ARDS induced by either intratracheal (n = 28, ARDSp) or intraperitoneal (n = 28, ARDSexp) administration of E. coli lipopolysaccharide. Four animals with no lung injury served as controls (NI). After 24 hours, animals were anesthetized, mechanically ventilated in pressure-controlled mode with low tidal volume (6 mL/kg), and randomly assigned to receive salbutamol (SALB) or saline 0.9% (CTRL), intravenously (i.v., 10 µg/kg/h) or intratracheally (bolus, 25 µg). Salbutamol doses were targeted at an increase of ≈ 20% in heart rate. Hemodynamics, lung mechanics, and arterial blood gases were measured before and after (at 30 and 60 min) salbutamol administration. At the end of the experiment, lungs were extracted for analysis of lung histology and molecular biology analysis. Values are expressed as mean ± standard deviation, and fold changes relative to NI, CTRL vs. SALB RESULTS: The gene expression of ion channels and aquaporin was increased in mild ARDSp, but not ARDSexp. In ARDSp, intravenous salbutamol resulted in higher gene expression of alveolar epithelial sodium channel (0.20 ± 0.07 vs. 0.68 ± 0.24, p < 0.001), aquaporin-1 (0.44 ± 0.09 vs. 0.96 ± 0.12, p < 0.001) aquaporin-3 (0.31 ± 0.12 vs. 0.93 ± 0.20, p < 0.001), and Na-K-ATPase-α (0.39 ± 0.08 vs. 0.92 ± 0.12, p < 0.001), whereas intratracheal salbutamol increased the gene expression of aquaporin-1 (0.46 ± 0.11 vs. 0.92 ± 0.06, p < 0.001) and Na-K-ATPase-α (0.32 ± 0.07 vs. 0.58 ± 0.15, p < 0.001). In ARDSexp, the gene expression of ion channels and aquaporin was not influenced by salbutamol. Morphological and functional variables and edema formation were not affected by salbutamol in any of the ARDS groups, regardless of the route of administration. CONCLUSION: Salbutamol administration increased the expression of alveolar epithelial ion channels and aquaporin in mild ARDSp, but not ARDSexp, with no effects on lung morphology and function or edema formation. These results may contribute to explain the negative effects of ß2-agonists on clinical outcome in ARDS.

Vital capacity and inspiratory capacity as additional parameters to evaluate bronchodilator response in asthmatic patients: a cross sectional study.

BACKGROUND: Bronchodilator response in patients with asthma is evaluated based on post-bronchodilator increase in forced expiratory volume in one second (FEV1) and forced vital capacity (FVC). However, the need for additional parameters, mainly among patients with severe asthma, has already been demonstrated. METHODS: The aim of this study was to evaluate the usefulness of vital capacity (VC) and inspiratory capacity (IC) to evaluate bronchodilator response in asthma patients with persistent airflow obstruction. The 43 asthma patients enrolled in the study were stratified into moderate or severe airflow obstruction groups based on baseline FEV1. All patients performed a 6-minute walk test before and after the bronchodilator (BD). A bipolar visual analogue scale post-BD was performed to assess clinical effect. The correlation between VC and IC and clinical response, determined by visual analogue scale (VAS) and 6-minute walk test (6MWT), was investigated. RESULTS: Patients in the severe group presented: 1) greater bronchodilator response in VC (48% vs 15%, p = 0.02), 2) a significant correlation between VC variation and the reduction in air trapping (Rs = 0.70; p < 0.01), 3) a significant agreement between VC and VAS score (kappa = 0.57; p < 0.01). There was no correlation between IC and the reduction in air trapping or clinical data. CONCLUSIONS: VC may be a useful additional parameter to evaluate bronchodilator response in asthma patients with severe airflow obstruction.

Use of computed tomography scanning to guide lung recruitment and adjust positive-end expiratory pressure.

PURPOSE OF REVIEW: We discuss the possible role of computed tomography (CT) to guide protective mechanical ventilation in acute lung injury/acute respiratory distress syndrome (ALI/ARDS), especially tidal volume (VT) and positive-end expiratory pressure (PEEP) settings and recruitment manoeuvres. RECENT FINDINGS: CT should be used as early as possible after the onset of ALI/ARDS and then repeated after 1 week in the absence of clinical improvement. Advantages of CT include: the regional response to recruitment can be determined; it is objective; the morphofunctional correlations obtained are useful for a comprehensive patient evaluation. CT should be performed at different pressure levels to identify potential for recruitment. Initially, one single whole-lung CT scan is performed at end-expiration at PEEP 5-10 cmH2O to evaluate aeration and compute lung weight. Afterwards, two lung CT slices are performed to assess lung recruitability (at PEEP = 5-10 cmH2O; inspiratory plateau pressure of the respiratory system = 45 cmH2O). SUMMARY: In ALI/ARDS patients, CT reveals discrepancies between bedside chest radiograph and various clinical and physiological parameters, and it is essential to assess lung morphology and recruitability. Specific algorithms, including or not CT, should be used to better identify ALI/ARDS with potential of recruitment and setting of VT and PEEP.

Prolonged glucocorticoid treatment and secondary prevention in acute respiratory distress syndrome.

Experimental and clinical evidence has demonstrated a strong association between dysregulated systemic inflammation and progression of acute respiratory distress syndrome (ARDS). In ARDS, glucocorticoid receptor-mediated downregulation of inflammation is essential to restore homeostasis and decrease morbidity and mortality. We review the findings of eight controlled studies (n = 569) evaluating treatment initiated before day 14 of ARDS. These trials consistently reported that treatment-induced reduction in systemic inflammation was associated with a significant improvement in ratio of partial arterial oxygen tension to fraction of inspired oxygen, and reductions in multiple organ dysfunction score, duration of mechanical ventilation and intensive care unit length of stay. Treatment was also associated with a marked reduction in the risk of death (relative risk: 0.68; 95% CI: 0.56-0.81; p < 0.001) and a sizable increase in mechanical ventilation-free days (weighted mean difference: 6.58 days; 95% CI: 2.93-10.23; p < 0.001); and intensive care unit-free days (weighted mean difference: 7.02 days; 95% CI: 3.20-10.85; p < 0.001). We recommend that prolonged methylprednisolone treatment, at an initial dose of 1 mg/kg/day in early ARDS and 2 mg/kg/day in unresolving ARDS, be delivered as an infusion to avoid glycemic variability, and that infection surveillance be strictly implemented to identify infections in the absence of fever.