Personalized mechanical ventilation guided by ultrasound in patients with acute respiratory distress syndrome (PEGASUS): study protocol for an international randomized clinical trial.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is a frequent cause of hypoxemic respiratory failure with a mortality rate of approximately 30%. Identifying ARDS subphenotypes based on "focal" or "non-focal" lung morphology has the potential to better target mechanical ventilation strategies of individual patients. However, classifying morphology through chest radiography or computed tomography is either inaccurate or impractical. Lung ultrasound (LUS) is a non-invasive bedside tool that can accurately distinguish "focal" from "non-focal" lung morphology. We hypothesize that LUS-guided personalized mechanical ventilation in ARDS patients leads to a reduction in 90-day mortality compared to conventional mechanical ventilation. METHODS: The Personalized Mechanical Ventilation Guided by UltraSound in Patients with Acute Respiratory Distress Syndrome (PEGASUS) study is an investigator-initiated, international, randomized clinical trial (RCT) that plans to enroll 538 invasively ventilated adult intensive care unit (ICU) patients with moderate to severe ARDS. Eligible patients will receive a LUS exam to classify lung morphology as "focal" or "non-focal". Thereafter, patients will be randomized within 12 h after ARDS diagnosis to receive standard care or personalized ventilation where the ventilation strategy is adjusted to the morphology subphenotype, i.e., higher positive end-expiratory pressure (PEEP) and recruitment maneuvers for "non-focal" ARDS and lower PEEP and prone positioning for "focal" ARDS. The primary endpoint is all-cause mortality at day 90. Secondary outcomes are mortality at day 28, ventilator-free days at day 28, ICU length of stay, ICU mortality, hospital length of stay, hospital mortality, and number of complications (ventilator-associated pneumonia, pneumothorax, and need for rescue therapy). After a pilot phase of 80 patients, the correct interpretation of LUS images and correct application of the intervention within the safe limits of mechanical ventilation will be evaluated. DISCUSSION: PEGASUS is the first RCT that compares LUS-guided personalized mechanical ventilation with conventional ventilation in invasively ventilated patients with moderate and severe ARDS. If this study demonstrates that personalized ventilation guided by LUS can improve the outcomes of ARDS patients, it has the potential to shift the existing one-size-fits-all ventilation strategy towards a more individualized approach. TRIAL REGISTRATION: The PEGASUS trial was registered before the inclusion of the first patient, https://clinicaltrials.gov/ (ID: NCT05492344).

Cell-based Therapies for Acute Respiratory Distress Syndrome: Where Are We Now?

There is considerable interest in the potential for cell-based therapies, particularly mesenchymal stromal cells (MSCs) and their products, as a therapy for acute respiratory distress syndrome (ARDS). MSCs exert effects via diverse mechanisms including reducing excessive inflammation by modulating neutrophil, macrophage and T-cell function, decreasing pulmonary permeability and lung edema, and promoting tissue repair. Clinical studies indicate that MSCs are safe and well tolerated, with promising therapeutic benefits in specific clinical settings, leading to regulatory approvals of MSCs for specific indications in some countries.This perspective reassesses the therapeutic potential of MSC-based therapies for ARDS given insights from recent cell therapy trials in both COVID-19 and in 'classic' ARDS, and discusses studies in graft-vs.-host disease, one of the few licensed indications for MSC therapies. We identify important unknowns in the current literature, address challenges to clinical translation, and propose an approach to facilitate assessment of the therapeutic promise of MSC-based therapies for ARDS.

Different ventilation intensities among various categories of patients ventilated for reasons other than ARDS--A pooled analysis of 4 observational studies.

PURPOSE: We investigated driving pressure (ΔP) and mechanical power (MP) and associations with clinical outcomes in critically ill patients ventilated for reasons other than ARDS. MATERIALS AND METHODS: Individual patient data analysis of a pooled database that included patients from four observational studies of ventilation. ΔP and MP were compared among invasively ventilated non-ARDS patients with sepsis, with pneumonia, and not having sepsis or pneumonia. The primary endpoint was ΔP; secondary endpoints included MP, ICU mortality and length of stay, and duration of ventilation. RESULTS: This analysis included 372 (11%) sepsis patients, 944 (28%) pneumonia patients, and 2040 (61%) patients ventilated for any other reason. On day 1, median ΔP was higher in sepsis (14 [11-18] cmH2O) and pneumonia patients (14 [11-18]cmH2O), as compared to patients not having sepsis or pneumonia (13 [10-16] cmH2O) (P < 0.001). Median MP was also higher in sepsis and pneumonia patients. ΔP, as opposed to MP, was associated with ICU mortality in sepsis and pneumonia patients. CONCLUSIONS: The intensity of ventilation differed between patients with sepsis or pneumonia and patients receiving ventilation for any other reason; ΔP was associated with higher mortality in sepsis and pneumonia patients. REGISTRATION: This post hoc analysis was not registered; the individual studies that were merged into the used database were registered at clinicaltrials.gov: NCT01268410 (ERICC), NCT02010073 (LUNG SAFE), NCT01868321 (PRoVENT), and NCT03188770 (PRoVENT-iMiC).

A New Global Definition of Acute Respiratory Distress Syndrome.

Background: Since publication of the 2012 Berlin definition of acute respiratory distress syndrome (ARDS), several developments have supported the need for an expansion of the definition, including the use of high-flow nasal oxygen, the expansion of the use of pulse oximetry in place of arterial blood gases, the use of ultrasound for chest imaging, and the need for applicability in resource-limited settings. Methods: A consensus conference of 32 critical care ARDS experts was convened, had six virtual meetings (June 2021 to March 2022), and subsequently obtained input from members of several critical care societies. The goal was to develop a definition that would 1) identify patients with the currently accepted conceptual framework for ARDS, 2) facilitate rapid ARDS diagnosis for clinical care and research, 3) be applicable in resource-limited settings, 4) be useful for testing specific therapies, and 5) be practical for communication to patients and caregivers. Results: The committee made four main recommendations: 1) include high-flow nasal oxygen with a minimum flow rate of ⩾30 L/min; 2) use PaO2:FiO2 ⩽ 300 mm Hg or oxygen saturation as measured by pulse oximetry SpO2:FiO2 ⩽ 315 (if oxygen saturation as measured by pulse oximetry is ⩽97%) to identify hypoxemia; 3) retain bilateral opacities for imaging criteria but add ultrasound as an imaging modality, especially in resource-limited areas; and 4) in resource-limited settings, do not require positive end-expiratory pressure, oxygen flow rate, or specific respiratory support devices. Conclusions: We propose a new global definition of ARDS that builds on the Berlin definition. The recommendations also identify areas for future research, including the need for prospective assessments of the feasibility, reliability, and prognostic validity of the proposed global definition.

Application of anti-inflammatory treatment in two different ovine Acute Respiratory Distress Syndrome injury models: a preclinical randomized intervention study.

Whilst the presence of 2 subphenotypes among the heterogenous Acute Respiratory Distress Syndrome (ARDS) population is becoming clinically accepted, subphenotype-specific treatment efficacy has yet to be prospectively tested. We investigated anti-inflammatory treatment in different ARDS models in sheep, previously shown similarities to human ARDS subphenotypes, in a preclinical, randomized, blinded study. Thirty anesthetized sheep were studied up to 48 h and randomized into: (a) OA: oleic acid (n = 15) and (b) OA-LPS: oleic acid and subsequent lipopolysaccharide (n = 15) to achieve a PaO2/FiO2 ratio of < 150 mmHg. Then, animals were randomly allocated to receive treatment with methylprednisolone or erythromycin or none. Assessed outcomes were oxygenation, pulmonary mechanics, hemodynamics and survival. All animals reached ARDS. Treatment with methylprednisolone, but not erythromycin, provided the highest therapeutic benefit in Ph2 animals, leading to a significant increase in PaO2/FiO2 ratio by reducing pulmonary edema, dead space ventilation and shunt fraction. Animals treated with methylprednisolone displayed a higher survival up to 48 h than all others. In animals treated with erythromycin, there was no treatment benefit regarding assessed physiological parameters and survival in both phenotypes. Treatment with methylprednisolone improves oxygenation and survival, more so in ovine phenotype 2 which resembles the human hyperinflammatory subphenotype.

Validation of a tool for estimating clinician recognition of ARDS using data from the international LUNG SAFE study.

Under-recognition of acute respiratory distress syndrome (ARDS) by clinicians is an important barrier to adoption of evidence-based practices such as low tidal volume ventilation. The burden created by the COVID-19 pandemic makes it even more critical to develop scalable data-driven tools to improve ARDS recognition. The objective of this study was to validate a tool for accurately estimating clinician ARDS recognition rates using discrete clinical characteristics easily available in electronic health records. We conducted a secondary analysis of 2,705 ARDS and 1,261 non-ARDS hypoxemic patients in the international LUNG SAFE cohort. The primary outcome was validation of a tool that estimates clinician ARDS recognition rates from health record data. Secondary outcomes included the relative impact of clinical characteristics on tidal volume delivery and clinician documentation of ARDS. In both ARDS and non-ARDS patients, greater height was associated with lower standardized tidal volume (mL/kg PBW) (ARDS: adjusted ß = -4.1, 95% CI -4.5 --3.6; non-ARDS: ß = -7.7, 95% CI -8.8 --6.7, P<0.00009 [where α = 0.01/111 with the Bonferroni correction]). Standardized tidal volume has already been normalized for patient height, and furthermore, height was not associated with clinician documentation of ARDS. Worsening hypoxemia was associated with both increased clinician documentation of ARDS (ß = -0.074, 95% CI -0.093 --0.056, P<0.00009) and lower standardized tidal volume (ß = 1.3, 95% CI 0.94-1.6, P<0.00009) in ARDS patients. Increasing chest imaging opacities, plateau pressure, and clinician documentation of ARDS also were associated with lower tidal volume in ARDS patients. Our EHR-based data-driven approach using height, gender, ARDS documentation, and lowest standardized tidal volume yielded estimates of clinician ARDS recognition rates of 54% for mild, 63% for moderate, and 73% for severe ARDS. Our tool replicated clinician-reported ARDS recognition in the LUNG SAFE study, enabling the identification of ARDS patients at high risk of being unrecognized. Our approach can be generalized to other conditions for which there is a need to increase adoption of evidence-based care.

Aerosol Delivery of a Novel Recombinant Modified Superoxide Dismutase Protein Reduces Oxidant Injury and Attenuates Escherichia coli Induced Lung Injury in Rats.

Background: Acute respiratory distress syndrome (ARDS) is a life-threatening respiratory failure syndrome with diverse etiologies characterized by increased permeability of alveolar-capillary membranes, pulmonary edema, and acute onset hypoxemia. During the ARDS acute phase, neutrophil infiltration into the alveolar space results in uncontrolled release of reactive oxygen species (ROS) and proteases, overwhelming antioxidant defenses and causing alveolar epithelial and lung endothelial injury. Objectives: To investigate the therapeutic potential of a novel recombinant human Cu-Zn-superoxide dismutase (SOD) fusion protein in protecting against ROS injury and for aerosolized SOD delivery to treat Escherichia coli induced ARDS. Methods: Fusion proteins incorporating human Cu-Zn-SOD (hSOD1), with (pep1-hSOD1-his) and without (hSOD1-his) a fused hyaluronic acid-binding peptide, were expressed in E. coli. Purified proteins were evaluated in in vitro assays with human bronchial epithelial cells and through aerosolized delivery to the lung of an E. coli-induced ARDS rat model. Results: SOD proteins exhibited high SOD activity in vitro and protected bronchial epithelial cells from oxidative damage. hSOD1-his and pep1-hSOD1-his retained SOD activity postnebulization and exhibited no adverse effects in the rat. Pep1-hSOD1-his administered through instillation or nebulization to the lung of an E. coli-induced pneumonia rat improved arterial oxygenation and lactate levels compared to vehicle after 48 hours. Static lung compliance was improved when the pep1-hSOD1-his protein was delivered by instillation. White cell infiltration to the lung was significantly reduced by aerosolized delivery of protein, and reduction of cytokine-induced neutrophil chemoattractant-1, interferon-gamma, and interleukin 6 pro-inflammatory cytokine concentrations in bronchoalveolar lavage was observed. Conclusions: Aerosol delivery of a novel recombinant modified SOD protein reduces oxidant injury and attenuates E. coli induced lung injury in rats. The results provide a strong basis for further investigation of the therapeutic potential of hSOD1 in the treatment of ARDS.

Awake prone positioning in acute hypoxaemic respiratory failure: An international expert guidance.

BACKGROUND: Awake prone positioning (APP) of non-intubated patients with acute hypoxaemic respiratory failure (AHRF) has been inconsistently adopted into routine care of patients with COVID-19, likely due to apparent conflicting evidence from recent trials. This short guideline aims to provide evidence-based recommendations for the use of APP in various clinical scenarios. METHODS: An international multidisciplinary panel, assembled for their expertise and representativeness, and supported by a methodologist, performed a systematic literature search, summarized the available evidence derived from randomized clinical trials, and developed recommendations using GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) methodology. RESULTS: The panel strongly recommends that APP rather than standard supine care be used in patients with COVID-19 receiving advanced respiratory support (high-flow nasal cannula, continuous positive airway pressure or non-invasive ventilation). Due to lack of evidence from randomized controlled trials, the panel provides no recommendation on the use of APP in patients with COVID-19 supported with conventional oxygen therapy, nor in patients with AHRF due to causes other than COVID-19. CONCLUSION: APP should be routinely implemented in patients with COVID-19 receiving advanced respiratory support.

Estimating the attributable fraction of mortality from acute respiratory distress syndrome to inform enrichment in future randomised clinical trials.

BACKGROUND: Efficiency of randomised clinical trials of acute respiratory distress syndrome (ARDS) depends on the fraction of deaths attributable to ARDS (AFARDS) to which interventions are targeted. Estimates of AFARDS in subpopulations of ARDS could improve design of ARDS trials. METHODS: We performed a matched case-control study using the Large observational study to UNderstand the Global impact of Severe Acute respiratory FailurE cohort. Primary outcome was intensive care unit mortality. We used nearest neighbour propensity score matching without replacement to match ARDS to non-ARDS populations. We derived two separate AFARDS estimates by matching patients with ARDS to patients with non-acute hypoxaemic respiratory failure (non-AHRF) and to patients with AHRF with unilateral infiltrates only (AHRF-UL). We also estimated AFARDS in subgroups based on severity of hypoxaemia, number of lung quadrants involved and hyperinflammatory versus hypoinflammatory phenotypes. Additionally, we derived AFAHRF estimates by matching patients with AHRF to non-AHRF controls, and AFAHRF-UL estimates by matching patients with AHRF-UL to non-AHRF controls. RESULTS: Estimated AFARDS was 20.9% (95% CI 10.5% to 31.4%) when compared with AHRF-UL controls and 38.0% (95% CI 34.4% to 41.6%) compared with non-AHRF controls. Within subgroups, estimates for AFARDS compared with AHRF-UL controls were highest in patients with severe hypoxaemia (41.1% (95% CI 25.2% to 57.1%)), in those with four quadrant involvement on chest radiography (28.9% (95% CI 13.4% to 44.3%)) and in the hyperinflammatory subphenotype (26.8% (95% CI 6.9% to 46.7%)). Estimated AFAHRF was 33.8% (95% CI 30.5% to 37.1%) compared with non-AHRF controls. Estimated AFAHRF-UL was 21.3% (95% CI 312.8% to 29.7%) compared with non-AHRF controls. CONCLUSIONS: Overall AFARDS mean values were between 20.9% and 38.0%, with higher AFARDS seen with severe hypoxaemia, four quadrant involvement on chest radiography and hyperinflammatory ARDS.

Delayed MSC therapy enhances resolution of organized pneumonia induced by antibiotic resistant Klebsiella pneumoniae infection.

Introduction: Mesenchymal stromal cells (MSC) are a promising therapeutic for pneumonia-induced sepsis. Here we sought to determine the efficacy of delayed administration of naïve and activated bone marrow (BM), adipose (AD), and umbilical cord (UC) derived MSCs in organized antibiotic resistant Klebsiella pneumosepsis. Methods: Human BM-, AD-, and UC-MSCs were isolated and expanded and used either in the naïve state or following cytokine pre-activation. The effect of MSC tissue source and activation status was assessed first in vitro. Subsequent experiments assessed therapeutic potential as a delayed therapy at 48 h post infection of rodents with Klebsiella pneumoniae, with efficacy assessed at 120 h. Results: BM-, AD-, and UC-MSCs accelerated epithelial healing, increased phagocytosis, and reduced ROS-induced epithelial injury in vitro, with AD-MSCs less effective, and naïve MSCs more effective than pre-activated MSCs. Delayed MSC administration in pre-clinical organized Klebsiella pneumosepsis had no effect on physiologic indices, but enhanced resolution of structural lung injury. Delayed therapy with pre-activated MSCs reduced mRNA concentrations of fibrotic factors. Naïve MSC treatment reduced key circulating cell proportions and increased bacterial killing capacity in the lungs whereas pre-activated MSCs enhanced the phagocytic index of pulmonary white cells. Discussion: Delayed MSC therapy enhanced resolution of lung injury induced by antibiotic resistant Klebsiella infection and favorably modulated immune cell profile. Overall, AD-MSCs were less effective than either UC- or BM-MSCs, while naïve MSCs had a more favorable effect profile compared to pre-activated MSCs.

Development and assessment of the performance of a shared ventilatory system that uses clinically available components to individualize tidal volumes.

OBJECTIVES: To develop and assess a system for shared ventilation using clinically available components to individualize tidal volumes. DESIGN: Evaluation and in vitro validation study SETTING: Ventilator shortage during the SARS-CoV-2 pandemic. PARTICIPANTS: The team consisted of physicians, bioengineers, computer programmers, and medical technology professionals. METHODS: Using clinically available components, a system of ventilation consisting of two ventilatory limbs was assembled and connected to a ventilator. Monitors for each limb were developed using open-source software. Firstly, the effect of altering ventilator settings on tidal volumes delivered to each limb was determined. Secondly, the impact of altering the compliance and resistance of one limb on the tidal volumes delivered to both limbs was analysed. Experiments were repeated three times to determine system variability. RESULTS: The system permitted accurate and reproducible titration of tidal volumes to each limb over a range of ventilator settings and simulated lung conditions. Alteration of ventilator inspiratory pressures, of respiratory rates, and I:E ratio resulted in very similar tidal volumes delivered to each limb. Alteration of compliance and resistance in one limb resulted in reproducible alterations in tidal volume to that test lung, with little change to tidal volumes in the other lung. All tidal volumes delivered were reproducible. CONCLUSIONS: We demonstrate the reliability of a shared ventilation system assembled using commonly available clinical components that allows titration of individual tidal volumes. This system may be useful as a strategy of last resort for Covid-19, or other mass casualty situations, where the need for ventilators exceeds supply.

Nebulised mesenchymal stem cell derived extracellular vesicles ameliorate E. coli induced pneumonia in a rodent model.

BACKGROUND: Mesenchymal stem cell (MSC) derived extracellular vesicles (EVs) have been proposed as an alternative to cell therapy, creating new possible delivery modalities such as nebulisation. We wished to investigate the therapeutic potential of directly nebulised MSC-EVs in the mitigation of Escherichia coli-induced pneumonia. METHODS: EV size, surface markers and miRNA content were assessed pre- and post-nebulisation. BEAS2B and A459 lung cells were exposed to lipopolysaccharide (LPS) and treated with nebulised bone marrow (BM) or umbilical cord (UC) MSC-EVs. Viability assays (MTT) and inflammatory cytokine assays were performed. THP-1 monocytes were stimulated with LPS and nebulised BM- or UC-EVs and phagocytosis activity was measured. For in vivo experiments, mice received LPS intratracheally (IT) followed by BM- or UC-EVs intravenously (IV) and injury markers assessed at 24 h. Rats were instilled with E. coli bacteria IT and BM- or UC-EVs delivered IV or by direct nebulisation. At 48 h, lung damage was assessed by physiological parameters, histology and inflammatory marker presence. RESULTS: MSC-EVs retained their immunomodulatory and wound healing capacity after nebulisation in vitro. EV integrity and content were also preserved. Therapy with IV or nebulised MSC-EVs reduced the severity of LPS-induced lung injury and E. coli-induced pneumonia by reducing bacterial load and oedema, increasing blood oxygenation and improving lung histological scores. MSC-EV treated animals also showed lower levels of inflammatory cytokines and inflammatory-related markers. CONCLUSIONS: MSC-EVs given IV attenuated LPS-induced lung injury, and nebulisation of MSC-EVs did not affect their capacity to attenuate lung injury caused by E. coli pneumonia, as evidenced by reduction in bacterial load and improved lung physiology.

Differential Effects of Cytokine Versus Hypoxic Preconditioning of Human Mesenchymal Stromal Cells in Pulmonary Sepsis Induced by Antimicrobial-Resistant Klebsiella pneumoniae.

Background: Pulmonary sepsis is a leading cause of hospital mortality, and sepses arising from antimicrobial-resistant (AMR) bacterial strains are particularly difficult to treat. Here we investigated the potential of mesenchymal stromal cells (MSCs) to combat established Klebsiella pneumoniae pneumosepsis and further evaluated MSC preconditioning and pre-activation methods. Methods: The potential for naïve and preconditioned MSCs to enhance wound healing, reduce inflammation, preserve metabolic activity, and enhance bacterial killing was assessed in vitro. Rats were subjected to intratracheal K. pneumoniae followed by the intravenous administration of MSCs. Physiological indices, blood, bronchoalveolar lavage (BAL), and tissues were obtained 72 h later. Results: In vitro assays confirmed that preconditioning enhances MSC function, accelerating pulmonary epithelial wound closure, reducing inflammation, attenuating cell death, and increasing bacterial killing. Cytomix-pre-activated MSCs are superior to naïve and hypoxia-exposed MSCs in attenuating Klebsiella pneumosepsis, improving lung compliance and oxygenation, reducing bacteria, and attenuating histologic injuries in lungs. BAL inflammatory cytokines were reduced, correlating with decreases in polymorphonuclear (PMN) cells. MSCs increased PMN apoptosis and the CD4:CD8 ratio in BAL. Systemically, granulocytes, classical monocytes, and the CD4:CD8 ratio were reduced, and nonclassical monocytes were increased. Conclusions: Preconditioning with cytokines, but not hypoxia, enhances the therapeutic potential of MSCs in clinically relevant models of K. pneumoniae-induced pneumosepsis.

Nebulized mesenchymal stem cell derived conditioned medium ameliorates Escherichia coli induced pneumonia in a rat model.

Background: Mesenchymal stem cells (MSC) have shown immense therapeutic promise in a range of inflammatory diseases, including acute respiratory distress syndrome (ARDS), and are rapidly advancing through clinical trials. Among their multimodal mechanisms of action, MSCs exert strong immunomodulatory effects via their secretome, which contains cytokines, small molecules, extracellular vesicles, and a range of other factors. Recent studies have shown that the MSC secretome can recapitulate many of the beneficial effects of the MSC itself. We aimed to determine the therapeutic capacity of the MSC secretome in a rat bacterial pneumonia model, especially when delivered directly to the lung by nebulization which is a technique more appropriate for the ventilated patient. Methods: Conditioned medium (CM) was generated from human bone marrow derived MSCs in the absence of antibiotics and serum supplements. Post-nebulization lung penetration was estimated through nebulization of CM to a cascade impactor and simulated lung and quantification of collected total protein and IL-8 cytokine. Control and nebulized CM was added to a variety of lung cell culture models and injury resolution assessed. In a rat E. coli pneumonia model, CM was instilled or administered by nebulization and lung injury and inflammation assessed at 48 h. Results: MSC-CM was predicted to have good distal lung penetration and delivery when administered by nebulizer. Both control and nebulized CM reduced NF-κB activation and inflammatory cytokine production in lung cell culture, while promoting cell viability and would closure in oxidative stress and scratch wound models. In a rat bacterial pneumonia model, both instilled and nebulizer delivered CM improved lung function, increasing blood oxygenation and reducing carbon dioxide levels compared to unconditioned medium controls. A reduction in bacterial load was also observed in both treatment groups. Inflammatory cytokines were reduced significantly by both liquid and aerosol CM administration, with less IL-1ß, IL-6, and CINC1 in these groups compared to controls. Conclusion: MSC-CM is a potential therapeutic for pneumonia ARDS, and administration is compatible with vibrating mesh nebulization.

ESICM guidelines on acute respiratory distress syndrome: definition, phenotyping and respiratory support strategies.

The aim of these guidelines is to update the 2017 clinical practice guideline (CPG) of the European Society of Intensive Care Medicine (ESICM). The scope of this CPG is limited to adult patients and to non-pharmacological respiratory support strategies across different aspects of acute respiratory distress syndrome (ARDS), including ARDS due to coronavirus disease 2019 (COVID-19). These guidelines were formulated by an international panel of clinical experts, one methodologist and patients' representatives on behalf of the ESICM. The review was conducted in compliance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement recommendations. We followed the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach to assess the certainty of evidence and grade recommendations and the quality of reporting of each study based on the EQUATOR (Enhancing the QUAlity and Transparency Of health Research) network guidelines. The CPG addressed 21 questions and formulates 21 recommendations on the following domains: (1) definition; (2) phenotyping, and respiratory support strategies including (3) high-flow nasal cannula oxygen (HFNO); (4) non-invasive ventilation (NIV); (5) tidal volume setting; (6) positive end-expiratory pressure (PEEP) and recruitment maneuvers (RM); (7) prone positioning; (8) neuromuscular blockade, and (9) extracorporeal life support (ECLS). In addition, the CPG includes expert opinion on clinical practice and identifies the areas of future research.

Repair of Acute Respiratory Distress Syndrome in COVID-19 by Stromal Cells (REALIST-COVID Trial): A Multicenter, Randomized, Controlled Clinical Trial.

Rationale: Mesenchymal stromal cells (MSCs) may modulate inflammation, promoting repair in coronavirus disease (COVID-19)-related acute respiratory distress syndrome (ARDS). Objectives: We investigated the safety and efficacy of ORBCEL-C (CD362 [cluster of differentiation 362]-enriched, umbilical cord-derived MSCs) in COVID-19-related ARDS. Methods: In this multicenter, randomized, double-blind, allocation-concealed, placebo-controlled trial (NCT03042143), patients with moderate to severe COVID-19-related ARDS were randomized to receive ORBCEL-C (400 million cells) or placebo (Plasma-Lyte 148). The primary safety and efficacy outcomes were the incidence of serious adverse events and oxygenation index at Day 7, respectively. Secondary outcomes included respiratory compliance, driving pressure, PaO2:FiO2 ratio, and Sequential Organ Failure Assessment score. Clinical outcomes relating to duration of ventilation, lengths of ICU and hospital stays, and mortality were collected. Long-term follow-up included diagnosis of interstitial lung disease at 1 year and significant medical events and mortality at 2 years. Transcriptomic analysis was performed on whole blood at Days 0, 4, and 7. Measurements and Main Results: Sixty participants were recruited (final analysis: n = 30 received ORBCEL-C, n = 29 received placebo; 1 participant in the placebo group withdrew consent). Six serious adverse events occurred in the ORBCEL-C group and three in the placebo group (risk ratio, 2.9 [95% confidence interval, 0.6-13.2]; P = 0.25). Day 7 mean (SD) oxygenation index did not differ (ORBCEL-C, 98.3 [57.2] cm H2O/kPa; placebo, 96.6 [67.3] cm H2O/kPa). There were no differences in secondary surrogate outcomes or in mortality at Day 28, Day 90, 1 year, or 2 years. There was no difference in the prevalence of interstitial lung disease at 1 year or significant medical events up to 2 years. ORBCEL-C modulated the peripheral blood transcriptome. Conclusion: ORBCEL-C MSCs were safe in subjects with moderate to severe COVID-19-related ARDS but did not improve surrogates of pulmonary organ dysfunction.

Awake prone positioning in acute hypoxaemic respiratory failure.

Awake prone positioning (APP) of patients with acute hypoxaemic respiratory failure gained considerable attention during the early phases of the coronavirus disease 2019 (COVID-19) pandemic. Prior to the pandemic, reports of APP were limited to case series in patients with influenza and in immunocompromised patients, with encouraging results in terms of tolerance and oxygenation improvement. Prone positioning of awake patients with acute hypoxaemic respiratory failure appears to result in many of the same physiological changes improving oxygenation seen in invasively ventilated patients with moderate-severe acute respiratory distress syndrome. A number of randomised controlled studies published on patients with varying severity of COVID-19 have reported apparently contrasting outcomes. However, there is consistent evidence that more hypoxaemic patients requiring advanced respiratory support, who are managed in higher care environments and who can be prone for several hours, benefit most from APP use. We review the physiological basis by which prone positioning results in changes in lung mechanics and gas exchange and summarise the latest evidence base for APP primarily in COVID-19. We examine the key factors that influence the success of APP, the optimal target populations for APP and the key unknowns that will shape future research.