A pilot feasibility study comparing large language models in extracting key information from ICU patient text records from an Irish population.

BACKGROUND: Artificial intelligence, through improved data management and automated summarisation, has the potential to enhance intensive care unit (ICU) care. Large language models (LLMs) can interrogate and summarise large volumes of medical notes to create succinct discharge summaries. In this study, we aim to investigate the potential of LLMs to accurately and concisely synthesise ICU discharge summaries. METHODS: Anonymised clinical notes from ICU admissions were used to train and validate a prompting structure in three separate LLMs (ChatGPT, GPT-4 API and Llama 2) to generate concise clinical summaries. Summaries were adjudicated by staff intensivists on ability to identify and appropriately order a pre-defined list of important clinical events as well as readability, organisation, succinctness, and overall rank. RESULTS: In the development phase, text from five ICU episodes was used to develop a series of prompts to best capture clinical summaries. In the testing phase, a summary produced by each LLM from an additional six ICU episodes was utilised for evaluation. Overall ability to identify a pre-defined list of important clinical events in the summary was 41.5 ± 15.2% for GPT-4 API, 19.2 ± 20.9% for ChatGPT and 16.5 ± 14.1% for Llama2 (p = 0.002). GPT-4 API followed by ChatGPT had the highest score to appropriately order a pre-defined list of important clinical events in the summary as well as readability, organisation, succinctness, and overall rank, whilst Llama2 scored lowest for all. GPT-4 API produced minor hallucinations, which were not present in the other models. CONCLUSION: Differences exist in large language model performance in readability, organisation, succinctness, and sequencing of clinical events compared to others. All encountered issues with narrative coherence and omitted key clinical data and only moderately captured all clinically meaningful data in the correct order. However, these technologies suggest future potential for creating succinct discharge summaries.

Epidemiology, ventilation management and outcomes of COVID-19 ARDS patients versus patients with ARDS due to pneumonia in the Pre-COVID era.

BACKGROUND: Ventilation management may differ between COVID-19 ARDS (COVID-ARDS) patients and patients with pre-COVID ARDS (CLASSIC-ARDS); it is uncertain whether associations of ventilation management with outcomes for CLASSIC-ARDS also exist in COVID-ARDS. METHODS: Individual patient data analysis of COVID-ARDS and CLASSIC-ARDS patients in six observational studies of ventilation, four in the COVID-19 pandemic and two pre-pandemic. Descriptive statistics were used to compare epidemiology and ventilation characteristics. The primary endpoint were key ventilation parameters; other outcomes included mortality and ventilator-free days and alive (VFD-60) at day 60. RESULTS: This analysis included 6702 COVID-ARDS patients and 1415 CLASSIC-ARDS patients. COVID-ARDS patients received lower median VT (6.6 [6.0 to 7.4] vs 7.3 [6.4 to 8.5] ml/kg PBW; p < 0.001) and higher median PEEP (12.0 [10.0 to 14.0] vs 8.0 [6.0 to 10.0] cm H2O; p < 0.001), at lower median ΔP (13.0 [10.0 to 15.0] vs 16.0 [IQR 12.0 to 20.0] cm H2O; p < 0.001) and higher median Crs (33.5 [26.6 to 42.1] vs 28.1 [21.6 to 38.4] mL/cm H2O; p < 0.001). Following multivariable adjustment, higher ΔP had an independent association with higher 60-day mortality and less VFD-60 in both groups. Higher PEEP had an association with less VFD-60, but only in COVID-ARDS patients. CONCLUSIONS: Our findings show important differences in key ventilation parameters and associations thereof with outcomes between COVID-ARDS and CLASSIC-ARDS. TRIAL REGISTRATION: Clinicaltrials.gov (identifier NCT05650957), December 14, 2022.

Tracheal intubation in critically ill adults with a physiologically difficult airway. An international Delphi study.

PURPOSE: Our study aimed to provide consensus and expert clinical practice statements related to airway management in critically ill adults with a physiologically difficult airway (PDA). METHODS: An international Steering Committee involving seven intensivists and one Delphi methodology expert was convened by the Society of Critical Care Anaesthesiologists (SOCCA) Physiologically Difficult Airway Task Force. The committee selected an international panel of 35 expert clinician-researchers with expertise in airway management in critically ill adults. A Delphi process based on an iterative approach was used to obtain the final consensus statements. RESULTS: The Delphi process included seven survey rounds. A stable consensus was achieved for 53 (87%) out of 61 statements. The experts agreed that in addition to pathophysiological conditions, physiological alterations associated with pregnancy and obesity also constitute a physiologically difficult airway. They suggested having an intubation team consisting of at least three healthcare providers including two airway operators, implementing an appropriately designed checklist, and optimizing hemodynamics prior to tracheal intubation. Similarly, the experts agreed on the head elevated laryngoscopic position, routine use of videolaryngoscopy during the first attempt, preoxygenation with non-invasive ventilation, careful mask ventilation during the apneic phase, and attention to cardiorespiratory status for post-intubation care. CONCLUSION: Using a Delphi method, agreement among a panel of international experts was reached for 53 statements providing guidance to clinicians worldwide on safe tracheal intubation practices in patients with a physiologically difficult airway to help improve patient outcomes. Well-designed studies are needed to assess the effects of these practice statements and address the remaining uncertainties.

Digital Twins of Acute Hypoxemic Respiratory Failure Patients Suggest a Mechanistic Basis for Success and Failure of Noninvasive Ventilation.

OBJECTIVES: To clarify the mechanistic basis for the success or failure of noninvasive ventilation (NIV) in acute hypoxemic respiratory failure (AHRF). DESIGN: We created digital twins based on mechanistic computational models of individual patients with AHRF. SETTING: Interdisciplinary Collaboration in Systems Medicine Research Network. SUBJECTS: We used individual patient data from 30 moderate-to-severe AHRF patients who had failed high-flow nasal cannula (HFNC) therapy and subsequently underwent a trial of NIV. INTERVENTIONS: Using the digital twins, we evaluated lung mechanics, quantified the separate contributions of external support and patient respiratory effort to lung injury indices, and investigated their relative impact on NIV success or failure. MEASUREMENTS AND MAIN RESULTS: In digital twins of patients who successfully completed/failed NIV, after 2 hours of the trial the mean (sd) of the change in total lung stress was -10.9 (6.2)/-0.35 (3.38) cm H2O, mechanical power -13.4 (12.2)/-1.0 (5.4) J/min, and total lung strain 0.02 (0.24)/0.16 (0.30). In the digital twins, positive end-expiratory pressure (PEEP) produced by HFNC was similar to that set during NIV. In digital twins of patients who failed NIV vs. those who succeeded, intrinsic PEEP was 3.5 (0.6) vs. 2.3 (0.8) cm H2O, inspiratory pressure support was 8.3 (5.9) vs. 22.3 (7.2) cm H2O, and tidal volume was 10.9 (1.2) vs. 9.4 (1.8) mL/kg. In digital twins, successful NIV increased respiratory system compliance +25.0 (16.4) mL/cm H2O, lowered inspiratory muscle pressure -9.7 (9.6) cm H2O, and reduced the contribution of patient spontaneous breathing to total driving pressure by 57.0%. CONCLUSIONS: In digital twins of AHRF patients, successful NIV improved lung mechanics, lowering respiratory effort and indices associated with lung injury. NIV failed in patients for whom only low levels of positive inspiratory pressure support could be applied without risking patient self-inflicted lung injury due to excessive tidal volumes.

The ARDS microenvironment enhances MSC-induced repair via VEGF in experimental acute lung inflammation.

Clinical trials investigating the potential of mesenchymal stromal cells (MSCs) for the treatment of inflammatory diseases, such as acute respiratory distress syndrome (ARDS), have been disappointing, with less than 50% of patients responding to treatment. Licensed MSCs show enhanced therapeutic efficacy in response to cytokine-mediated activation signals. There are two distinct sub-phenotypes of ARDS: hypo- and hyper-inflammatory. We hypothesized that pre-licensing MSCs in a hyper-inflammatory ARDS environment would enhance their therapeutic efficacy in acute lung inflammation (ALI). Serum samples from patients with ARDS were segregated into hypo- and hyper-inflammatory categories based on interleukin (IL)-6 levels. MSCs were licensed with pooled serum from patients with hypo- or hyper-inflammatory ARDS or healthy serum controls. Our findings show that hyper-inflammatory ARDS pre-licensed MSC conditioned medium (MSC-CMHyper) led to a significant enrichment in tight junction expression and enhanced barrier integrity in lung epithelial cells in vitro and in vivo in a vascular endothelial growth factor (VEGF)-dependent manner. Importantly, while both MSC-CMHypo and MSC-CMHyper significantly reduced IL-6 and tumor necrosis factor alpha (TNF-α) levels in the bronchoalveolar lavage fluid (BALF) of lipopolysaccharide (LPS)-induced ALI mice, only MSC-CMHyper significantly reduced lung permeability and overall clinical outcomes including weight loss and clinical score. Thus, the hypo- and hyper-inflammatory ARDS environments may differentially influence MSC cytoprotective and immunomodulatory functions.

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).

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.

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.

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.

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.

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.

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.

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.

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.

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.

Multiple Dosing and Preactivation of Mesenchymal Stromal Cells Enhance Efficacy in Established Pneumonia Induced by Antimicrobial-Resistant Klebsiella pneumoniae in Rodents.

Antimicrobial-resistant (AMR) bacteria, such as Klebsiella species, are an increasingly common cause of hospital-acquired pneumonia, resulting in high mortality and morbidity. Harnessing the host immune response to AMR bacterial infection using mesenchymal stem cells (MSCs) is a promising approach to bypass bacterial AMR mechanisms. The administration of single doses of naïve MSCs to ARDS clinical trial patient cohorts has been shown to be safe, although efficacy is unclear. The study tested whether repeated MSC dosing and/or preactivation, would attenuate AMR Klebsiella pneumonia-induced established pneumonia. Rat models of established K. pneumoniae-induced pneumonia were randomised to receive intravenous naïve or cytomix-preactivated umbilical cord MSCs as a single dose at 24 h post pneumonia induction with or without a subsequent dose at 48 h. Physiological indices, bronchoalveolar lavage (BAL), and tissues were obtained at 72 h post pneumonia induction. A single dose of naïve MSCs was largely ineffective, whereas two doses of MSCs were effective in attenuating Klebsiella pneumosepsis, improving lung compliance and oxygenation, while reducing bacteria and injury in the lung. Cytomix-preactivated MSCs were superior to naïve MSCs. BAL neutrophil counts and activation were reduced, and apoptosis increased. MSC therapy reduced cytotoxic BAL T cells, and increased CD4+/CD8+ ratios. Systemically, granulocytes, classical monocytes, and the CD4+/CD8+ ratio were reduced, and nonclassical monocytes were increased. Repeated doses of MSCs-particularly preactivated MSCs-enhance their therapeutic potential in a clinically relevant model of established AMR K. pneumoniae-induced pneumosepsis.

Efficacy and adverse events profile of videolaryngoscopy in critically ill patients: subanalysis of the INTUBE study.

BACKGROUND: Tracheal intubation is a high-risk procedure in the critically ill, with increased intubation failure rates and a high risk of other adverse events. Videolaryngoscopy might improve intubation outcomes in this population, but evidence remains conflicting, and its impact on adverse event rates is debated. METHODS: This is a subanalysis of a large international prospective cohort of critically ill patients (INTUBE Study) performed from 1 October 2018 to 31 July 2019 and involving 197 sites from 29 countries across five continents. Our primary aim was to determine the first-pass intubation success rates of videolaryngoscopy. Secondary aims were characterising (a) videolaryngoscopy use in the critically ill patient population and (b) the incidence of severe adverse effects compared with direct laryngoscopy. RESULTS: Of 2916 patients, videolaryngoscopy was used in 500 patients (17.2%) and direct laryngoscopy in 2416 (82.8%). First-pass intubation success was higher with videolaryngoscopy compared with direct laryngoscopy (84% vs 79%, P=0.02). Patients undergoing videolaryngoscopy had a higher frequency of difficult airway predictors (60% vs 40%, P<0.001). In adjusted analyses, videolaryngoscopy increased the probability of first-pass intubation success, with an OR of 1.40 (95% confidence interval [CI] 1.05-1.87). Videolaryngoscopy was not significantly associated with risk of major adverse events (odds ratio 1.24, 95% CI 0.95-1.62) or cardiovascular events (odds ratio 0.78, 95% CI 0.60-1.02). CONCLUSIONS: In critically ill patients, videolaryngoscopy was associated with higher first-pass intubation success rates, despite being used in a population at higher risk of difficult airway management. Videolaryngoscopy was not associated with overall risk of major adverse events. CLINICAL TRIAL REGISTRATION: NCT03616054.