Rationale: Chronic liver disease (CLD) increases the risk of acute respiratory distress syndrome (ARDS). Extracellular vesicles (EVs) and their microRNA (EV-miRNA) cargo mediate liver–lung interaction, but their role in ARDS remains unclear. Objectives: 1) To characterize EV-miRNA profiles in critically ill patients with COVID-19 pneumonia with and without CLD, and 2) to identify molecular pathways through which CLD influences lung injury. Methods: In a case-control study, serum was collected on ICU day 1 from patients with SARS-CoV-2 pneumonia, with CLD and non-CLD groups matched for sex, age, pneumonia severity, respiratory support, and ICU length of stay. EVs were isolated with the Norgen system, size exclusion chromatography (Izon), or both, and characterized by NTA, flow cytometry, and western blot. EV-miRNAs were extracted, and 21 lung and liver-related candidates were quantified by RT-qPCR. Differential expression was assessed with REST/NormFinder, and dysregulated miRNAs were explored by Reactome, miRNet 2.0, and PANTHER for pathway and network enrichment. Results: Thirty-one patients were included (14 with CLD). Norgen was the most effective EV isolation method. Five EV-miRNAs were significantly dysregulated in patients with CLD (adjusted P <0.05): miR-26a-5p, miR-142-5p, and miR-223-3p (downregulated) and miR-197-3p, miR-144-5p (upregulated). Network analysis identified FOXO3, PTEN, and SOD2 as key target genes. Enrichment revealed pathways in host–virus interactions, immune signaling, inflammation, growth factor/neurotrophic signaling, and cell migration, intersecting with RHO GTPase, VEGF, and TGF-β signaling relevant to pulmonary homeostasis. Conclusions: In critically ill COVID-19 patients, CLD is associated with differential EV-miRNA expression that influences immune, viral, and lung injury pathways, suggesting that CLD may worsen ARDS via EV-mediated signaling. This study also highlights the most effective EV isolation method for future biomarker use.

BACKGROUND:Previous studies have identified potentially modifiable factors associated with mortality from acute respiratory stress syndrome (ARDS), however these studies did not differentiate between underlying causes of ARDS. As the etiology of ARDS may influence patient outcomes, we aimed to identify potentially modifiable factors associated with 60-day mortality from pulmonary and extrapulmonary ARDS. METHODS:Secondary pooled analysis of six observational studies studies on mechanical ventilation in patients with pulmonary and extrapulmonary ARDS. The primary endpoint was mortality at day 60 after inclusion. Exploratory outcomes included length of stay in hospital and ICU, duration of ventilation and ventilator-free days at day 28. RESULTS:Out of 7934 patients with pulmonary or extrapulmonary ARDS, 3402 (43%) did not survive. Potentially modifiable factors associated with 60-day mortality included high driving pressure (ΔP) and high respiratory rate (RR). There was an interaction between etiology of ARDS and ΔP on 60-day mortality, with ΔP showing a stronger association in pulmonary ARDS compared with extrapulmonary ARDS (p < 0.001). In a sensitivity analysis excluding COVID-19 patients, RR was no longer associated with 60-day mortality, whereas ΔP remained associated. Tidal volume was not associated with 60-day mortality in either pulmonary or extrapulmonary ARDS. No interaction was found between ARDS etiology and RR or tidal volume on 60-day mortality. CONCLUSION:High ΔP and high RR were associated with 60-day mortality in patients with pulmonary and extrapulmonary ARDS receiving mechanical ventilation, with ΔP showing a stronger association in pulmonary ARDS compared with extrapulmonary ARDS. REGISTRATION:The pooled database was registered at ClinicalTrials.gov (identifier NCT05650957).

Invasive ventilation with oxygen supplementation may inadvertently cause ventilator- and hyperoxia-induced lung injury, respectively, but their balance is fairly unaddressed. The concept of mechanical power summarizes factors of ventilation intensity associated with development of ventilator-induced lung injury. More recently, we introduced the theoretical framework for chemical power to estimate risk of hyperoxia-induced injury and allow for integration of both mechanical and chemical energy transfer per unit time. In the current study, we explored the associations of mechanical and chemical power with outcomes in mechanically ventilated patients with acute respiratory distress syndrome. In this secondary analysis of six pooled cohort studies, patients with acute respiratory distress syndrome per Berlin criteria and available data to calculate chemical and mechanical power on days 1 and 2 of invasive ventilation were selected. The primary outcome was all-cause 60-day mortality. A total of 2,117 patients were included in the main analysis. Higher chemical power levels were associated with increased 60-day mortality (P < 0.001), regardless of the mechanical power levels. Increasing mechanical power levels combined with decreasing chemical power levels was associated with a better outcome than vice versa (P < 0.001). There was no interaction between both powers. In this pooled cohort study of acute respiratory distress syndrome patients receiving invasive ventilation, higher chemical power levels were associated with a higher rate of mortality, independent of mechanical power levels. These results support further experimental validation of the concept of chemical power and exploration of its balance with mechanical power to predict outcome of lung injury.NEW & NOTEWORTHY This observational study of a combined cohort of patients with acute respiratory distress syndrome assessed the association of the novel concept of chemical power, a surrogate marker of oxygen exposure intensity, with mortality and its relative weight in this association when compared with mechanical power. Chemical power and mechanical power were independently associated with mortality. An interaction between these powers was not observed. Future experimental studies should aim to validate and optimize this novel concept.

Intensive care units (ICUs) rely in many instances on observational research and often encounter difficulties in establishing cause-and-effect relationships. After conducting a thorough search focused on ICU observational studies, this review analysed the causal language and evaluated the quality of reporting of the methodologies employed. The causal was assessed by analysing the words linking exposure to outcomes in the title and main objective. The quality of the reporting of the key methodological aspects related to causal inference was based on STROBE and ROBINS-I tools. We identified 139 articles, with 87 (63%) and 82 (59%) studies having non-causal language in their title and main objective, respectively. Among the total, 49 (35%) articles directly addressed causality. The review found vague causal language in observational ICU research and highlighted the need for better adherence to reporting guidelines for improved causal analysis and inference.

RATIONALE: A routine clinical practice in adult critically ill patients receiving invasive mechanical ventilation (IMV) may be difficult to define. Our goal was to report updated global, and country-specific estimates of incidence, mortality, and case-fatality rates. METHODS: An observational prospective cohort of consecutive adult patients admitted between October 1, 2022, and April 30, 2023 to 457 intensive care units (ICU) from 42 countries who received IMV longer than 12 hours. Data were collected on each patient at initiation of mechanical ventilation and daily throughout the course of IMV for up to 28 days. RESULTS: During the period of recruitment, 8,350 patients were enrolled. A total of 6,998 patients from lower-middle income countries (1,428 patients), upper-middle countries (1930 patients) and high-income countries (3,640 patients) were included. Patients were predominantly males (63%) with a median age of 64 years (IQR 50,74) and median SAPS3 64 points (IQR 52-77). Main reasons for IMV were: neurologic disease (20%), postoperative respiratory insufficiency (16%), community acquired pneumonia (10%), sepsis (9%), cardiac failure (7%), ARDS (6%), COPD (5%), nosocomial pneumonia (5%), COVID (3%). Ventilator setting registered were: Tidal volume (median, IQR 7.4; 6.6-8.3 ml/kgPBW), plateau pressure (18; 15-22 cmH2O), applied PEEP (6; 5-8 cmH2O), driving pressure (12; 9-15 cmH2O), mechanical power (15.7; 11.9-20.8 joules/min). A lung protective strategy was applied on 79% of monitoring days and an open Lung Approach on 25% of monitoring days. Patients received sedation on 80% of the monitored days, analgesia on 77% and neuromuscular blocking on 9%. Most prevalent complications during the course of mechanical ventilation were sepsis (17%), delirium (14%), ventilator-associated pneumonia (8%), ARDS (8%) and ICU acquired weakness (8%). Other complications as thromboembolic events, tracheobronchitis, bleeding ulcus stress or Clostridium infection had a prevalence lower than 2%. 73% of the patients had at least one organ dysfunction, the most frequent of which were cardiovascular failure (66%), renal failure (24%), hematological failure (12%) and hepatic failure (9%). Comparison of outcomes according to income country is shown in table 1. CONCLUSIONS: After the pandemic COVID-19, we found significant geo-economic differences in the clinical outcomes of critically ill patients requiring IMV. Further adjusted models will provide information about the usual care of mechanically ventilated patients and variables related with poor outcomes.

BACKGROUND:Many deaths in the intensive care unit (ICU) occur after a decision to withdraw or withhold life-sustaining therapies (WLSTs). We aimed to explore the differences in the incidence and timing of WLST between patients with and without acute brain injuries (ABIs). METHODS:We did a secondary analysis of two prospective, international studies that recruited patients who were invasively or non-invasively ventilated between 2004 and 2016 from 40 countries. ABI was defined as brain trauma, ischaemic stroke, intracranial haemorrhage, seizures, or meningitis-encephalitis. The comparator group included non-ABI conditions. Time to WLST was evaluated by use of cumulative incidence curves. Differences in WLST were analysed by use of multilevel logistic regression. FINDINGS:Between March 11, 2004, and Dec 17, 2016, we recruited 21 970 patients (16 791 in the WLST analysis), of whom 13 526 (61·6%) were male and 8444 (38·4%) were female and 2896 (13·2%) had ABI. WLST occurred in 2056 (12·2%) of 16 791 patients) and was more common in patients with ABI versus without (372 [17·0%] of 2191 vs 1684 [11·5%] of 14 600; risk difference 5·5%; 95% CI 3·8-7·1; odds ratio [OR] 2·42; 1·89-3·12). WLST decisions occurred earlier in patients with ABI versus patients without ABI (median, 4 days [IQR 2-9] versus 6 days [2-13] after ICU admission; absolute difference, 2 days; 95% CI 1-3). Findings were similar across different ABI subgroups, world regions, and cohort years. Variability among ICUs in WLST decisions for patients with ABI and patients without ABI was high (respectively, median OR, 3·04; 95% CI 2·54-3·67, and median OR 2·59; 2·38-2·78). INTERPRETATION:Our findings suggest that WLST decisions are significantly more common in patients with ABI versus patients without ABI and occur earlier in this group. The rationale for early WLST following ABI warrants further exploration, accounting for additional neurological factors that were not available in the present analysis. FUNDING:Canadian Institutes of Health Research.

Background The impact of different ventilatory support modalities and timing of intubation on longitudinal lung recovery trajectories in patients with severe coronavirus disease 2019 (COVID-19) is unknown. Methods This was a multicentre, prospective observational study conducted in 52 Spanish intensive care units (ICUs) involving critically ill COVID-19 patients admitted between 25 February 2020 and 8 February 2021. 1854 COVID-19 patients were followed after hospital discharge at 3, 6 and 12 months with diffusing capacity of the lung for carbon monoxide (DLCO) measurements and chest imaging. Patients were classified regarding the ventilatory support received during the ICU stay: noninvasive mechanical ventilation (NIMV), high-flow nasal cannula (HFNC) and invasive mechanical ventilation (IMV), divided into early IMV (intubation within 24 h) and late IMV (intubation after 24 h). The primary objective was to evaluate the impact of the different respiratory support modalities during the ICU stay and the time of intubation on DLCO measurements and their recovery trajectories over a 1-year follow-up. Secondary outcomes included other pulmonary function parameters and chest imaging findings. Results A total of 360 (19.4%) and 290 (15.6%) patients received HFNC and NIMV, respectively. 1204 (64.9%) patients underwent IMV; 966 received early IMV and 238 received late IMV. The latter exhibited a significantly worse percentage predicted DLCO during the 1-year follow-up with adjusted differences of 6.9 (95% CI 3.9-10; p<0.001), 4.2 (95% CI 1.1-7.2; p=0.007) and 4.9 (95% CI 1.7-8.2; p=0.003) at 3, 6 and 12 months compared with early IMV. NIMV patients exhibited greater lung damage at follow-up than those under HFNC with an adjusted difference of percentage predicted DLCO of 5.2 (95% CI 1.7-8.7; p=0.003) at 6 months and greater presence of radiological abnormalities during follow-up. Matched and sensitivity analysis showed results consistent with those reported. Conclusions Delay in intubation implies the worst outcomes; however, patients with NIMV exhibited a slower lung recovery in terms of DLCO measurements and more radiological abnormalities compared with HFNC patients. These results should be used to optimise follow-up protocols for COVID-19 acute respiratory distress syndrome (ARDS) survivors.

Background: Bacterial pulmonary superinfections develop in a substantial proportion of mechanically ventilated COVID-19 patients and are associated with prolonged mechanical ventilation requirements and increased mortality. Albeit recommended, evidence supporting the use of empirical antibiotics at intubation is weak and of low quality. The aim of this study was to elucidate the effect of empirical antibiotics, administered within 24 h of endotracheal intubation, on superinfections, duration of mechanical ventilation, and mortality in mechanically ventilated patients with COVID-19. Methods: Emulated targeted trial by means of a propensity score-matched analysis of a prospective multicentre cohort study of consecutive mechanically ventilated patients admitted to 62 Spanish intensive care units suffering from COVID-19 between March 2020 and February 2021. Results: Overall, 8532 critically ill COVID-19 patients were included, of which 2580 mechanically ventilated patients remained after matching. Empirical antibiotics were prescribed to 1665 (64%) at intubation. Pulmonary superinfections developed in 39% and 47% of patients treated with and without empirical antibiotics, respectively (p < 0.01). Patients treated with empirical antibiotics had a shorter duration of mechanical ventilation (incidence risk ratio: 0.85 [95% confidence interval (CI), 0.78 - 0.94], p < 0.01) and a reduced stay in the intensive care unit (incidence risk ratio: 0.89 [95% CI, 0.82 - 0.97] days, p < 0.01). Mortality 28 days after endotracheal intubation was 28% in patients treated with empirical antibiotics as opposed to 32% in patients treated without (odds ratio: 0.76 [95% CI, 0.61 - 0.94], p < 0.01). Conclusion: The administration of empirical antibiotics at intubation in mechanically ventilated COVID-19 patients was associated with a reduced incidence of pulmonary superinfections, a shorter duration of mechanical ventilation and intensive care unit stay, and a lower mortality rate. Notwithstanding these benefits, the applicability of these findings to other viral pneumonias and beyond the pandemic context remains uncertain. Registration: www.clinicaltrials.gov (NCT04457505). (c) 2025 The Author(s). Published by Elsevier Ltd on behalf of The British Infection Association. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Abstract 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.

BACKGROUND:High mortality rates among patients with chronic obstructive pulmonary disease (COPD) admitted to intensive care units (ICUs) during the COVID-19 pandemic highlight the need for tailored clinical management strategies. STUDY DESIGN AND METHODS:Epidemiological, clinical, and laboratory data were collected in REDCap for 6512 patients hospitalized with COVID-19 across 55 Spanish ICUs. Patients were stratified into three groups: those with COPD, those with other chronic respiratory diseases (CRD), and those without respiratory comorbidities (No CRD). The primary outcome was to determine clinical predictors for 90-day mortality, focusing on the COPD group. A propensity score matching (PSM) method was applied to analyze the effects of respiratory support, biomarkers, and immunomarkers. RESULTS:Patients with COPD (n = 328) exhibited a 50% mortality rate compared to 33% of those with other chronic respiratory diseases (CRD, n = 547), and those without respiratory comorbidities (No CRD, n = 5124). Among COPD patients, 95% of whom had Acute Respiratory Distress Syndrome (ARDS) due to COVID-19, the use of a high-flow nasal cannula (HFNC) was associated with reduced 90-day mortality (hazard ratio: 0.54 (95% Confidence Interval [0.31-0.95]). At a molecular scale, lower IgG levels but higher viral load and TNF-alpha, Vascular Cell Adhesion Molecule-1 (VCAM-1), and Fas Cell Surface Death Receptor (Fas) were associated with mortality in the COPD group. CONCLUSIONS:In COPD patients with ARDS due to COVID-19, the use of HFNC was associated with a better prognosis. The dysregulation in biomarkers and immunomarkers in COPD patients and its association with mortality highlight the need for further targeted therapeutic strategies.

Introduction The impact of the different ventilatory support modalities and the timing of intubation on longitudinal lung recovery trajectories in patients with severe COVID-19 is unknown. Methods A multicenter, prospective observational study conducted in 52 Spanish intensive care units (ICUs) involving critically ill COVID-19 patients admitted between February 25th, 2020, to February 28th, 2021. 1854 COVID-19 patients were followed after hospital discharge at 3, 6 and 12 months with lung diffusing capacity (D LCO ) and a chest imaging. Patients were classified regarding the ventilatory support received during the ICU stay: noninvasive mechanical ventilation (NIMV), high-flow nasal cannula (HFNC) and invasive mechanical ventilation (IMV) divided into early IMV (intubation <24 h) and late IMV (intubation >24 h). The primary objective is to evaluate the impact of the different respiratory support modalities during the ICU stay and time of intubation on D LCO measurements and their recovery trajectories over a one-year follow-up. Secondary outcomes include other pulmonary function parameters and chest imaging findings. Results A total of 360 (19.4%) and 290 (15.6%) patients received HFNC and NIMV, respectively. 1204 (64.9%) patients underwent IMV; 966 received early IMV and 238 late IMV. The latter exhibited a significantly worse percentage of predicted D LCO during the one-year follow-up with adjusted differences (95%CI; p-value) of 6.9 (3.9 to 10; p<0.001), 4.2 (1.1 to 7.2; p=0.007) and 4.9 (1.7 to 8.2; p=0.003) at 3, 6 and 12 months compared with early IMV. NIMV patients exhibited greater lung damage at follow-up than those under HFNC with an adjusted difference of D LCO values of 5.2 (1.7 to 8.7; p=0.003) at 6 months and greater presence of radiological abnormalities during the follow-up. Matched and sensitivity analysis showed results consistent with those reported. Conclusions Delay in intubation implies the worst outcomes; however, patients with NIMV exhibited a slower lung recovery in terms of D LCO measurements and more radiological abnormalities compared with HFNC patients. These results should be used to optimize follow-up protocols for COVID-19 ARDS survivors. These findings may serve as a valuable consideration for optimizing follow-up protocols for survivors of COVID-19 ARDS.

BACKGROUND:The relative contribution of the different components of mechanical power to mortality is a subject of debate and has not been studied in COVID-19. The aim of this study is to evaluate both the total and the relative impact of each of the components of mechanical power on mortality in a well-characterized cohort of patients with COVID-19-induced acute respiratory failure undergoing invasive mechanical ventilation. This is a secondary analysis of the CIBERESUCICOVID project, a multicenter observational cohort study including fifty Spanish intensive care units that included COVID-19 mechanically ventilated patients between February 2020 and December 2021. We examined the association between mechanical power and its components (elastic static, elastic dynamic, total elastic and resistive power) with 90-day mortality after adjusting for confounders in seven hundred ninety-nine patients with COVID-19-induced respiratory failure undergoing invasive mechanical ventilation. RESULTS:At the initiation of mechanical ventilation, the PaO2/FiO2 ratio was 106 (78; 150), ventilatory ratio was 1.69 (1.40; 2.05), and respiratory system compliance was 35.7 (29.2; 44.5) ml/cmH2O. Mechanical power at the initiation of mechanical ventilation was 24.3 (18.9; 29.6) J/min, showing no significant changes after three days. In multivariable regression analyses, mechanical power and its components were not associated with 90-day mortality at the start of mechanical ventilation. After three days, total elastic and elastic static power were associated with higher 90-day mortality, but this relationship was also found for positive end-expiratory pressure. CONCLUSIONS:Neither mechanical power nor its components were independently associated with mortality in COVID-19-induced acute respiratory failure at the start of MV. Nevertheless, after three days, static elastic power and total elastic power were associated with lower odds of survival. Positive end-expiratory pressure and plateau pressure, however, captured this risk in a similar manner.

COVID-19 severely impacted global health, especially older adults and those with comorbidities. Immunosuppressed patients are at high risk for severe outcomes, yet studies yield conflicting mortality rates for this group. This study examines the clinical characteristics and outcomes of immunosuppressed (IS) versus non-immunosuppressed (nIS) patients with COVID-19 in ICUs. A multicenter, observational case–control study included 5,824 ICU patients with COVID-19 from the CIBERESUCICOVID study. Patients were categorized as IS or nIS based on history of transplantation, HIV, active neoplasia, and use of immunosuppressive drugs or corticosteroids. The primary outcome was 90-day mortality; secondary outcomes included in-hospital, 15-day, 30-day and 1-year mortality, ICU-free days, ventilator-free days, and hospital length of stay. Subgroup analyses examined vaccination status and tocilizumab treatment. Propensity score (PS) matching was used to obtain balance among the baseline variables in the two groups. IS patients (n = 689, 11.8

ObjectiveTo analyze the presence of frailty in survivors of severe COVID-19 admitted in the Intensive Care Unit (ICU) and followed six months after discharge.DesignAn observational, prospective and multicenter, nation-wide study.SettingEight adult ICU across eight academic acute care hospitals in Mexico.PatientsAll consecutive adult COVID-19 patients admitted in the ICU with acute respiratory failure between March 8, 2020 to February 28, 2021 were included. Frailty was defined according to the FRAIL scale, and was obtained at ICU admission and 6-month after hospital discharge.InterventionsNone.Main variables of interestThe primary endpoint was the frailty status 6-months after discharge. A regression model was used to evaluate the predictors during ICU stay associated with frailty.Results196 ICU survivors were evaluated for basal frailty at ICU admission and were included in this analysis. After 6-months from discharge, 164 patients were evaluated for frailty: 40 patients (20.4%) were classified as non-frail, 67 patients (34.2%) as pre-frail and 57 patients (29.1%) as frail. After adjustment, the need of invasive mechanical ventilation was the only factor independently associated with frailty at 6 month follow-up (Odds Ratio [OR] 3.70, 95% confidence interval 1.40–9.81, P = .008).ConclusionsDeterioration of frailty was reported frequently among ICU survivors with severe COVID-19 at 6-months. The need of invasive mechanical ventilation in ICU survivors was the only predictor independently associated with frailty.