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Objectives: We sought to evaluate the association between the carbon dioxide ( co2 ) ventilatory equivalent (VEq co2 = minute ventilation/volume of co2 produced per min), a marker of dead space that does not require a blood gas measurement, and mortality risk. We compared the strength of this association to that of physiologic dead space fraction (V D /V t = [Pa co2 -mixed-expired P co2 ]/Pa co2 ) as well as to other commonly used markers of dead space (i.e., the end-tidal alveolar dead space fraction [AVDSf = (Pa co2 -end-tidal P co2 )/Pa co2 ], and ventilatory ratio [VR = (minute ventilation × Pa co2 )/(age-adjusted predicted minute ventilation × 37.5)])., Design: Retrospective cohort data, 2017-2023., Setting: Quaternary PICU., Patients: One hundred thirty-one children with acute respiratory distress syndrome., Interventions: None., Measurements and Main Results: All dead space markers were calculated at the same 1-minute timepoint for each patient within the first 72 hours of using invasive mechanical ventilation. The 131 children had a median (interquartile range, IQR) age of 5.8 (IQR 1.4, 12.6) years, oxygenation index (OI) of 7.5 (IQR 4.6, 14.3), V D /V t of 0.47 (IQR 0.38, 0.61), and mortality was 17.6% (23/131). Higher VEq co2 ( p = 0.003), V D /V t ( p = 0.002), and VR ( p = 0.013) were all associated with greater odds of mortality in multivariable models adjusting for OI, immunosuppressive comorbidity, and overall severity of illness. We failed to identify an association between AVDSf and mortality in the multivariable modeling. Similarly, we also failed to identify an association between OI and mortality after controlling for any dead space marker in the modeling. For the 28-day ventilator-free days outcome, we failed to identify an association between V D /V t and the dead space markers in multivariable modeling, although OI was significant., Conclusions: VEq co2 performs similarly to V D /V t and other surrogate dead space markers, is independently associated with mortality risk, and may be a reasonable noninvasive surrogate for V D /V t ., Competing Interests: Dr. Khemani is supported by the National Institutes of Health (NIH)/the National Heart, Lung, and Blood Institute (NHLBI) R01 HL134666. Dr. Khemani is a consultant for Nihon-Kohden OrangeMed and Bayer. Nihon-Kohdon was not involved in this study and their module for volumetric capnography was not used in this study. Dr. Bhalla is supported by the NIH/NHLBI K23 HL153756. This work was also supported by grant UL1TR001855 from the NIH/National Center for Advancing Translational Science and support from the Department of Anesthesiology and Critical Care at Children’s Hospital Los Angeles. Drs. Bhalla and Khemani’s institutions received funding from the NHLBI. Dr. Bhalla disclosed personal stock ownership. Drs. Bhalla and, Khemani received support for article research from the NIH. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.)

Rationale: Blood flow rate affects mixed venous oxygenation (Sv O 2 ) during venovenous extracorporeal membrane oxygenation (ECMO), with possible effects on the pulmonary circulation and the right heart function. Objectives: To describe the physiologic effects of different levels of Sv O 2 obtained by changing ECMO blood flow in patients with severe acute respiratory distress syndrome receiving ECMO and controlled mechanical ventilation. Methods: Low (Sv O 2 target, 70-75%), intermediate (Sv O 2 target, 75-80%), and high (Sv O 2 target, >80%) ECMO blood flows were applied for 30 minutes in random order in 20 patients. Mechanical ventilation settings were left unchanged. The hemodynamic and pulmonary effects were assessed with pulmonary artery catheter and electrical impedance tomography. Measurements and Main Results: Cardiac output decreased from low to intermediate and to high blood flow/Sv O 2 (9.2 [6.2-10.9] vs. 8.3 [5.9-9.8] vs. 7.9 [6.5-9.1] L/min; P  = 0.014), as well as mean pulmonary artery pressure (34 ± 6 vs. 31 ± 6 vs. 30 ± 5 mm Hg; P  < 0.001) and right ventricular stroke work index (14.2 ± 4.4 vs. 12.2 ± 3.6 vs. 11.4 ± 3.2 g × m/beat/m 2 ; P  = 0.002). Cardiac output was inversely correlated with mixed venous and arterial Po 2 values ( R 2  = 0.257; P  = 0.031; and R 2  = 0.324; P  = 0.05). Pulmonary artery pressure was correlated with decreasing mixed venous Po 2 ( R 2  = 0.29; P  < 0.001) and with increasing cardiac output ( R 2  = 0.378; P  < 0.007). Measures of [Formula: see text]/[Formula: see text] mismatch did not differ between the three steps. Conclusions: In patients with severe acute respiratory distress syndrome, increased ECMO blood flow rate resulting in higher Sv O 2 decreases pulmonary artery pressure, cardiac output, and right heart workload.

Objectives: High driving pressure (DP, ratio of tidal volume (V t ) over respiratory system compliance) is a risk for poor outcomes in patients with pediatric acute respiratory distress syndrome (PARDS). We therefore assessed the time course in level of DP (i.e., 24, 48, and 72 hr) after starting mechanical ventilation (MV), and its association with 28-day mortality., Design: Multicenter, prospective study conducted between February 2018 and December 2022., Setting: Twelve tertiary care PICUs in Colombia., Patients: One hundred eighty-four intubated children with moderate to severe PARDS., Interventions: None., Measurements and Main Results: The median (interquartile range [IQR]) age of the PARDS cohort was 11 (IQR 3-24) months. A total of 129 of 184 patients (70.2%) had a pulmonary etiology leading to PARDS, and 31 of 184 patients (16.8%) died. In the first 24 hours after admission, the plateau pressure in the nonsurvivor group, compared with the survivor group, differed (28.24 [IQR 24.14-32.11] vs. 23.18 [IQR 20.72-27.13] cm H 2 O, p < 0.01). Of note, children with a V t less than 8 mL/kg of ideal body weight had lower adjusted odds ratio (aOR [95% CI]) of 28-day mortality (aOR 0.69, [95% CI, 0.55-0.87]; p = 0.02). However, we failed to identify an association between DP level and the oxygenation index (aOR 0.58; 95% CI, 0.21-1.58) at each of time point. In a diagnostic exploratory analysis, we found that DP greater than 15 cm H 2 O at 72 hours was an explanatory variable for mortality, with area under the receiver operating characteristic curve of 0.83 (95% CI, 0.74-0.89); there was also increased hazard for death with hazard ratio 2.5 (95% CI, 1.07-5.92). DP greater than 15 cm H 2 O at 72 hours was also associated with longer duration of MV (10 [IQR 7-14] vs. 7 [IQR 5-10] d; p = 0.02)., Conclusions: In children with moderate to severe PARDS, a DP greater than 15 cm H 2 O at 72 hours after the initiation of MV is associated with greater odds of 28-day mortality and a longer duration of MV. DP should be considered a variable worth monitoring during protective ventilation for PARDS., Competing Interests: The authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.)

The optimal strategy for positive end-expiratory pressure (PEEP) titration in the management of severe acute respiratory distress syndrome (ARDS) patients remains unclear. Current guidelines emphasize the importance of a careful risk-benefit assessment for PEEP titration in terms of cardiopulmonary function in these patients. Over the last few decades, the primary goal of PEEP usage has shifted from merely improving oxygenation to emphasizing lung protection, with a growing focus on the individual pattern of lung injury, lung and chest wall mechanics, and the hemodynamic consequences of PEEP. In moderate-to-severe ARDS patients, prone positioning (PP) is recommended as part of a lung protective ventilation strategy to reduce mortality. However, the physiologic changes in respiratory mechanics and hemodynamics during PP may require careful re-assessment of the ventilation strategy, including PEEP. For the most severe ARDS patients with refractory gas exchange impairment, where lung protective ventilation is not possible, veno-venous extracorporeal membrane oxygenation (V-V ECMO) facilitates gas exchange and allows for a "lung rest" strategy using "ultraprotective" ventilation. Consequently, the importance of lung recruitment to improve oxygenation and homogenize ventilation with adequate PEEP may differ in severe ARDS patients treated with V-V ECMO compared to those managed conservatively. This review discusses PEEP management in severe ARDS patients and the implications of management with PP or V-V ECMO with respect to respiratory mechanics and hemodynamic function., (© 2024. The Author(s).)

Objective: Patients with acute respiratory failure often require mechanical ventilation to reduce the work of breathing and improve gas exchange; however, this may exacerbate lung injury. Protective ventilation strategies, characterized by low tidal volumes (≤ 8mL/kg of predicted body weight) and limited plateau pressure below 30cmH2O, have shown improved outcomes in patients with acute respiratory distress syndrome. However, in the transition to spontaneous ventilation, it can be challenging to maintain tidal volume within protective levels, and it is unclear whether low tidal volumes during spontaneous ventilation impact patient outcomes. We developed a study protocol to estimate the prevalence of low tidal volume ventilation in the first 24 hours of spontaneous ventilation in patients with hypoxemic acute respiratory failure and its association with ventilator-free days and survival., Methods: We designed a multicenter, multinational, cohort study with a 28-day follow-up that will include patients with acute respiratory failure, defined as a partial oxygen pressure/fraction of inspired oxygen ratio < 300mmHg, in transition to spontaneous ventilation in intensive care units in Latin America., Results: We plan to include 422 patients in ten countries. The primary outcomes are the prevalence of low tidal volume in the first 24 hours of spontaneous ventilation and ventilator-free days on day 28. The secondary outcomes are intensive care unit and hospital mortality, incidence of asynchrony and return to controlled ventilation and sedation., Conclusion: In this study, we will assess the prevalence of low tidal volume during spontaneous ventilation and its association with clinical outcomes, which can inform clinical practice and future clinical trials.

Background: Trunk inclination in patients with Acute Respiratory Distress Syndrome (ARDS) in the supine position has gained scientific interest due to its effects on respiratory physiology, including mechanics, oxygenation, ventilation distribution, and efficiency. Changing from flat supine to semi-recumbent increases driving pressure due to decreased respiratory system compliance. Positional adjustments also deteriorate ventilatory efficiency for CO 2 removal, particularly in COVID-19-associated ARDS (C-ARDS), indicating likely lung parenchyma overdistension. Tilting the trunk reduces chest wall compliance and, to a lesser extent, lung compliance and transpulmonary driving pressure, with significant hemodynamic and gas exchange implications., Methods: A prospective, pilot physiological study was conducted on early ARDS patients in two ICUs at CHU Clermont-Ferrand, France. The protocol involved 30-min step gradual verticalization from a 30° semi-seated position (baseline) to different levels of inclination (0°, 30°, 60°, and 90°), before returning to the baseline position. Measurements included tidal volume, positive end-expiratory pressure (PEEP), esophageal pressures, and pulmonary artery catheter data. The primary endpoint was the variation in transpulmonary driving pressure through the verticalization procedure., Results: From May 2020 through January 2021, 30 patients were included. Transpulmonary driving pressure increased slightly from baseline (median and interquartile range [IQR], 9 [5-11] cmH 2 O) to the 90° position (10 [7-14] cmH 2 O; P < 10 -2 for the overall effect of position in mixed model). End-expiratory lung volume increased with verticalization, in parallel to decreases in alveolar strain and increased arterial oxygenation. Verticalization was associated with decreased cardiac output and stroke volume, and increased norepinephrine doses and serum lactate levels, prompting interruption of the procedure in two patients. There were no other adverse events such as falls or equipment accidental removals., Conclusions: Verticalization to 90° is feasible in ARDS patients, improving EELV and oxygenation up to 30°, likely due to alveolar recruitment and blood flow redistribution. However, there is a risk of overdistension and hemodynamic instability beyond 30°, necessitating individualized bed angles based on clinical situations. Trial registration ClinicalTrials.gov registration number NCT04371016 , April 24, 2020., (© 2024. The Author(s).)

The prone position is an immediately available and easily implemented procedure that was introduced more than 50 years ago as a method for improvement of gas exchange in patients with acute respiratory distress syndrome (ARDS). In the meantime, a survival advantage could also be shown in patients with severe ARDS, which led to the recommendation of the prone position for treatment of severe ARDS by expert consensus and specialist society guidelines. The continuing coronavirus disease 2019 (COVID-19) pandemic moved the prone position to the forefront of medicine, including the widespread implementation of the prone position for awake, spontaneously breathing nonintubated patients with acute hypoxemic respiratory insufficiency. The survival advantage is possible due to a reduction of the ventilator-associated lung damage. In this article, the physiological effects, data on clinical results, practical considerations and open questions with respect to the prone position are discussed., (© 2024. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Objectives: Although respiratory failure is the most common feature in coronavirus disease 2019 (COVID-19), abdominal organ involvement is likewise frequently observed. To investigate visceral and thoracic circulation and abdominal organ damage in COVID-19 patients., Materials and Methods: A monocentric observational study was carried on. In COVID-19 patients affected by acute respiratory distress syndrome (ARDS) (n = 31) or mild pneumonia (n = 60) thoracoabdominal circulation was evaluated using Doppler-ultrasound and computed tomography. The study also included non-COVID-19 patients affected by ARDS (n = 10) or portal hypertension (n = 10) for comparison of the main circulatory changes., Results: Patients affected by COVID-19 ARDS showed hyperdynamic visceral flow and increased portal velocity, hepatic artery resistance-index, and spleen diameter relative to those with mild-pneumonia (p = 0.001). Splanchnic circulatory parameters significantly correlated with the main respiratory indexes (p < 0.001) and pulmonary artery diameter (p = 0.02). The chest and abdominal vascular remodeling pattern of COVID-19 ARDS patients resembled the picture observed in the PH group, while differed from that of the non-COVID ARDS group. A more severe COVID-19 presentation was associated with worse liver dysfunction and enhanced inflammatory activation; these parameters both correlated with abdominal (p = 0.04) and chest imaging measures (p = 0.03)., Conclusion: In COVID-19 ARDS patients there are abdominal and lung vascular modifications that depict a portal hypertension-like pattern. The correlation between visceral vascular remodeling, pulmonary artery enlargement, and organ damage in these critically ill patients is consistent with a portal hyperlfow-like syndrome that could contribute to the peculiar characteristics of respiratory failure in these patients., Clinical Relevance Statement: our data suggest that the severity of COVID-19 lung involvement is directly related to the development of a portal hyperflow-like syndrome. These observations should help in defining the need for a closer monitoring, but also to develop dedicated therapeutic strategies., Competing Interests: Declaration of competing interest All authors declared no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Boumans et al. conducted a systematic review and meta-analysis to evaluate the diagnostic accuracy of lung ultrasound (LUS) in acute respiratory distress syndrome (ARDS). The study found that LUS has high specificity (0.942, 95% CI 0.856-0.978) but variable sensitivity (0.631, 95% CI 0.450-0.782) for identifying ARDS-related diffuse lung pathologies. LUS demonstrates comparable or superior performance to chest radiography and CT scans, facilitating rapid bedside diagnosis and management. However, variability in operator experience and interpretation criteria, as well as challenges in detecting mild or early-stage ARDS, remain. The study highlights the need for further research to refine LUS protocols and training, enhancing its application in clinical practice and improving patient outcomes., (© 2024. The Author(s).)

Background: Assessment of regional ventilation/perfusion (V'/Q) mismatch using electrical impedance tomography (EIT) represents a promising advancement for personalized management of the acute respiratory distress syndrome (ARDS). However, accuracy is still hindered by the need for invasive monitoring to calibrate ventilation and perfusion. Here, we propose a non-invasive correction that uses only EIT data and characterized patients with more pronounced compensation of V'/Q mismatch., Methods: We enrolled twenty-one ARDS patients on controlled mechanical ventilation. Cardiac output was measured invasively, and ventilation and perfusion were assessed by EIT. Relative V'/Q maps by EIT were calibrated to absolute values using the minute ventilation to invasive cardiac output (MV/CO) ratio (V'/Q-ABS), left unadjusted (V'/Q-REL), or corrected by MV/CO ratio derived from EIT data (V'/Q-CORR). The ratio between ventilation to dependent regions and perfusion reaching shunted units ( V D ' /Q SHUNT ) was calculated as an index of more effective hypoxic pulmonary vasoconstriction. The ratio between perfusion to non-dependent regions and ventilation to dead space units (Q ND / V DS ' ) was calculated as an index of hypocapnic pneumoconstriction., Results: Our calibration factor correlated with invasive MV/CO (r = 0.65, p < 0.001), showed good accuracy and no apparent bias. Compared to V'/Q-ABS, V'/Q-REL maps overestimated ventilation (p = 0.013) and perfusion (p = 0.002) to low V'/Q units and underestimated ventilation (p = 0.011) and perfusion (p = 0.008) to high V'/Q units. The heterogeneity of ventilation and perfusion reaching different V'/Q compartments was underestimated. V'/Q-CORR maps eliminated all these differences with V'/Q-ABS (p > 0.05). Higher V D ' / Q SHUNT correlated with higher PaO 2 /FiO 2 (r = 0.49, p = 0.025) and lower shunt fraction (ρ =  - 0.59, p = 0.005). Higher Q ND / V DS ' correlated with lower PEEP (ρ =  - 0.62, p = 0.003) and plateau pressure (ρ =  - 0.59, p = 0.005). Lower values of both indexes were associated with less ventilator-free days (p = 0.05 and p = 0.03, respectively)., Conclusions: Regional V'/Q maps calibrated with a non-invasive EIT-only method closely approximate the ones obtained with invasive monitoring. Higher efficiency of shunt compensation improves oxygenation while compensation of dead space is less needed at lower airway pressure. Patients with more effective compensation mechanisms could have better outcomes., (© 2024. The Author(s).)

Background: Many survivors of severe COVID-19 pneumonia experience lingering respiratory issues. There is limited research on follow-up chest imaging findings in patients with COVID-19 ARDS, particularly in relation to their mMRC dyspnea scores and pulmonary function tests (PFTs). This study addresses this gap by investigating the clinical characteristics, mMRC dyspnea scores, PFTs, and chest CT findings of COVID-19 ARDS patients at the 6 months post-recovery. By analyzing these variables together, we aim to gain a better understanding of the long-term health consequences of COVID-19 ARDS. Methods: This prospective observational study included 56 subjects with COVID-19 ARDS with dyspnea at the six-month follow-up visits. These patients were evaluated by chest CT, mMRC dyspnea scale, and PFT. The CT severity score was calculated individually for each of the four major imaging findings - ground glass opacities (GGOs), parenchymal/atelectatic bands, reticulations/septal thickening, and consolidation - using a modified CT severity scoring system. Statistics were carried out to find any association between individual CT chest findings and the mMRC dyspnea scale and forced vital capacity (FVC). p values < 0.05 were considered statistically significant. Results: Our study population had a mean age of 55.86 ± 9.60 years, with 44 (78.6%) being men. Grades 1, 2, 3, and 4 on the mMRC dyspnea scale were seen in 57.1%, 30.4%, 10.7%, and 1.8% of patients respectively. Common CT findings observed were GGOs (94.6%), reticulations/septal thickening (96.4%), parenchymal/atelectatic bands (92.8%), and consolidation (14.3%). The mean modified CT severity scores for GGOs, reticulations/septal thickening, parenchymal/atelectatic bands, and consolidation were 10.32 ± 5.51 (range: 0-21), 7.66 ± 4.33 (range: 0-19), 4.77 ± 3.03 (range: 0-14) and 0.29 ± 0.91 (range 0-5) respectively. Reticulations/septal thickening (p = 0.0129) and parenchymal/atelectatic bands (p = 0.0453) were associated with an increased mMRC dyspnea scale. Parenchymal/atelectatic bands were also associated with abnormal FVC (<80%) (p = 0.0233). Conclusion: Six-month follow-up chest CTs of COVID-19 ARDS survivors with persistent respiratory problems showed a statistically significant relationship between increased mMRC dyspnea score and imaging patterns of reticulations/septal thickening and parenchymal/atelectatic bands; while parenchymal/atelectatic bands also showed a statistically significant correlation with reduced FVC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Garg, Prabhakar, Devkota, Dhooria, Debi, Dua, Singh, Malarakunte, Bhatia and Sandhu.)

The gut serves as a vital immunological organ orchestrating immune responses and influencing distant mucosal sites, notably the respiratory mucosa. It is increasingly recognized as a central driver of critical illnesses, with intestinal hyperpermeability facilitating bacterial translocation, systemic inflammation, and organ damage. The "gut-lung" axis emerges as a pivotal pathway, where gut-derived injurious factors trigger acute lung injury (ALI) through the systemic circulation. Direct and indirect effects of gut microbiota significantly impact immune responses. Dysbiosis, particularly intestinal dysbiosis, termed as an imbalance of microbial species and a reduction in microbial diversity within certain bodily microbiomes, influences adaptive immune responses, including differentiating T regulatory cells (Tregs) and T helper 17 (Th17) cells, which are critical in various lung inflammatory conditions. Additionally, gut and bone marrow immune cells impact pulmonary immune activity, underscoring the complex gut-lung interplay. Moreover, lung microbiota alterations are implicated in diverse gut pathologies, affecting local and systemic immune landscapes. Notably, lung dysbiosis can reciprocally influence gut microbiota composition, indicating bidirectional gut-lung communication. In this review, we investigate the pathophysiology of ALI/acute respiratory distress syndrome (ARDS), elucidating the role of immune cells in the gut-lung axis based on recent experimental and clinical research. This exploration aims to enhance understanding of ALI/ARDS pathogenesis and to underscore the significance of gut-lung interactions in respiratory diseases., (© 2024. The Author(s).)

Endothelial dysfunction is a critical feature of acute respiratory distress syndrome (ARDS) associated with higher disease severity and worse outcomes. Preclinical in vivo models of sepsis and ARDS have failed to yield useful therapies in humans, perhaps due to interspecies differences in inflammatory responses and heterogeneity of human host responses. Use of microphysiological systems (MPS) to investigate lung endothelial function may shed light on underlying mechanisms and targeted treatments for ARDS. We assessed the response to plasma from critically ill sepsis patients in our lung endothelial MPS through measurement of endothelial permeability, expression of adhesion molecules, and inflammatory cytokine secretion. Sepsis plasma induced areas of endothelial cell (EC) contraction, loss of cellular coverage, and luminal defects. EC barrier function was significantly worse following incubation with sepsis plasma compared to healthy plasma. EC ICAM-1 expression, IL-6 and soluble ICAM-1 secretion increased significantly more after incubation with sepsis plasma compared with healthy plasma. Plasma from sepsis patients who developed ARDS further increased IL-6 and sICAM-1 compared to plasma from sepsis patients without ARDS and healthy plasma. Our results demonstrate the proof of concept that lung endothelial MPS can enable interrogation of specific mechanisms of endothelial dysfunction that promote ARDS in sepsis patients., (© 2024 The Author(s). Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Purpose: Severe acute respiratory distress syndrome (ARDS) with PaO 2 /FiO 2  < 80 mmHg is a life-threatening condition. The optimal management strategy is unclear. The aim of this meta-analysis was to compare the effects of low tidal volumes (V t ), moderate V t , prone ventilation, and venovenous extracorporeal membrane oxygenation (VV-ECMO) on mortality in severe ARDS., Methods: We performed a frequentist network meta-analysis of randomised controlled trials (RCTs) with participants who had severe ARDS and met eligibility criteria for VV-ECMO or had PaO 2 /FiO 2  < 80 mmHg. We applied the Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) methodology to discern the relative effect of interventions on mortality and the certainty of the evidence., Results: Ten RCTs including 812 participants with severe ARDS were eligible. VV-ECMO reduces mortality compared to low V t (risk ratio [RR] 0.77, 95% confidence interval [CI] 0.59-0.99, moderate certainty) and compared to moderate V t (RR 0.75, 95% CI 0.57-0.98, low certainty). Prone ventilation reduces mortality compared to moderate V t (RR 0.78, 95% CI 0.66-0.93, high certainty) and compared to low V t (RR 0.81, 95% CI 0.63-1.02, moderate certainty). We found no difference in the network comparison of VV-ECMO compared to prone ventilation (RR 0.95, 95% CI 0.72-1.26), but inferences were based solely on indirect comparisons with very low certainty due to very wide confidence intervals., Conclusions: In adults with ARDS and severe hypoxia, both VV-ECMO (low to moderate certainty evidence) and prone ventilation (moderate to high certainty evidence) improve mortality relative to low and moderate V t strategies. The impact of VV-ECMO versus prone ventilation remains uncertain., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: To describe changes in pulmonary mechanics when changing from supine position (SP) to prone position (PP) in mechanically ventilated (MV) patients with Acute Respiratory Distress Syndrome (ARDS) due to severe COVID-19., Design: Retrospective cohort., Setting: Intensive Care Unit of the National Institute of Respiratory Diseases (Mexico City)., Patients: COVID-19 patients on MV due to ARDS, with criteria for PP., Intervention: Measurement of pulmonary mechanics in patients on SP to PP, using esophageal manometry., Main Variables of Interest: Changes in lung and thoracic wall mechanics in SP and PP RESULTS: Nineteen patients were included. Changes during first prone positioning were reported. Reductions in lung stress (10.6 vs 7.7, p=0.02), lung strain (0.74 vs 0.57, p=0.02), lung elastance (p=0.01), chest wall elastance (p=0.003) and relation of respiratory system elastances (p=0.001) were observed between patients when changing from SP to PP. No differences were observed in driving pressure (p=0.19) and transpulmonary pressure during inspiration (p=0.70)., Conclusions: Changes in pulmonary mechanics were observed when patients were comparing values of supine position with measurements obtained 24h after prone positioning. Esophageal pressure monitoring may facilitate ventilator management despite patient positioning., (Copyright © 2023. Published by Elsevier España, S.L.U.)

In acute respiratory distress syndrome, the role of positive end-expiratory pressure (PEEP) to prevent ventilator-induced lung injury is controversial. Randomized trials comparing higher versus lower PEEP strategies failed to demonstrate a clinical benefit. This may depend on the inter-individually variable potential for lung recruitment (i.e. recruitability), which would warrant PEEP individualization to balance alveolar recruitment and the unavoidable baby lung overinflation produced by high pressure. Many techniques have been used to assess recruitability, including lung imaging, multiple pressure-volume curves and lung volume measurement. The Recruitment-to-Inflation ratio (R/I) has been recently proposed to bedside assess recruitability without additional equipment. R/I assessment is a simplified technique based on the multiple pressure-volume curve concept: it is measured by monitoring respiratory mechanics and exhaled tidal volume during a 10-cmH2O one-breath derecruitment maneuver after a short high-PEEP test. R/I scales recruited volume to respiratory system compliance, and normalizes recruitment to a proxy of actual lung size. With modest R/I (<0.3-0.4), setting low PEEP (5-8 cmH2O) may be advisable; with R/I>0.6-0.7, high PEEP (≥15 cmH2O) can be considered, provided that airway and/or transpulmonary plateau pressure do not exceed safety limits. In case of intermediate R/I (≈0.5), a more granular assessment of recruitability may be needed. This could be accomplished with advanced monitoring tools, like sequential lung volume measurement with granular R/I assessment or electrical impedance tomography monitoring during a decremental PEEP trial. In this review, we discuss R/I rationale, applications and limits, providing insights on its clinical use for PEEP selection in moderate-to-severe acute respiratory distress syndrome.

Objective: The study aimed to evaluate the improvements in pulmonary ventilation following a sitting position in ventilated ARDS patients using electrical impedance tomography., Methodology: A total of 17 patients with ARDS under mechanical ventilation participated in this study, including 8 with moderate ARDS and 9 with severe ARDS. Each patient was initially placed in the supine position (S1), transitioned to sitting position (SP) for 30 min, and then returned to the supine position (S2). Patients were monitored for each period, with parameters recorded., Main Outcome Measures: The primary outcome included the spatial distribution parameters of EIT, regional of interest (ROI), end-expiratory lung impedance (ΔEELI), and parameters of respiratory mechanics., Results: Compared to S1, the SP significantly altered the distribution in ROI1 (11.29 ± 4.70 vs 14.88 ± 5.00 %, p = 0.003) and ROI2 (35.59 ± 8.99 vs 44.65 ± 6.97 %, p ＜ 0.001), showing reductions, while ROI3 (39.71 ± 11.49 vs 33.06 ± 6.34 %, p = 0.009), ROI4 (13.35 ± 8.76 vs 7.24 ± 5.23 %, p ＜ 0.001), along with peak inspiratory pressure (29.24 ± 3.96 vs 27.71 ± 4.00 cmH 2 O, p = 0.036), showed increases. ΔEELI decreased significantly ventrally (168.3 (40.33 - 189.5), p ＜ 0.0001) and increased significantly dorsally (461.7 (297.5 - 683.7), p ＜ 0.0001). The PaO 2 /FiO 2 ratio saw significant improvement in S2 compared to S1 after 30 min in the seated position (108 (73 - 130) vs 96 (57 - 129) mmHg, p = 0.03)., Conclusions: The sitting position is associated with enhanced compliance, improved oxygenation, and more homogenous ventilation in patients with ventilated ARDS compared to the supine position., Implications for Clinical Practice: It is important to know the impact of postural changes on patient pulmonary ventilation in order to standardize safe practices in critically ill patients. It may be helpful in the management among ventilated patients., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: During invasive ventilation, external flow jet nebulization results in increases in displayed exhaled tidal volumes (V T ). We hypothesized that the magnitude of the increase is inaccurate. An ASL 5000 simulator measured ventilatory parameters over a wide range of adult settings: actual V T , peak inspiratory pressure (PIP), and time to minimum pressure., Methods: Ventilators with internal and external flow sensors were tested by using a variety of volume and pressure control modes (the target V T was 420 mL). Patient conditions (normal, COPD, ARDS) defined on the ASL 5000 were assessed at baseline and with 3.5 or 8 L/min of added external flow. Patient-triggering was assessed by reducing muscle effort to the level that resulted in backup ventilation and by changing ventilator sensitivity to the point of auto-triggering., Results: Results are reported as percentage change from baseline after addition of 3.5 or 8 L/min external flow. For ventilators with internal flow sensors, changes in displayed exhaled V T ranged from 10% to 118%, however, when using volume control, actual increases in actual V T and PIP were only 4%-21% ( P = .063, .031) and 6%-24% ( P = .25, .031), respectively. Changes in actual V T correlated closely with changes in PIP ( P < .001; R 2 = 0.68). For pressure control, actual V T decreased by 3%-5% ( P = .031) and 4%-9% ( P = .031) with 3.5 and 8 L/min respectively, PIP was unchanged. With external flow sensors at the distal Y-piece junction, volume and pressure changes were statistically insignificant. The time to minimum pressure increased at most by 8% ( P = .02) across all modes and ventilators. The effects on muscle pressure were minimal (∼1 cm H 2 O), and ventilator sensitivity effects were nearly undetectable., Conclusions: External flow jet nebulization resulted in much smaller changes in volume than indicated by the ventilator display. Statistically significant effects were confined primarily to machines with internal flow sensors. Differences approached the manufacturer-reported variation in ventilator baseline performance. During nebulizer therapy, effects on V T can be estimated at the bedside by monitoring PIP., (Copyright © 2024 by Daedalus Enterprises.)

Acute respiratory distress syndrome (ARDS) poses a significant and widespread public health challenge. Extensive research conducted in recent decades has considerably improved our understanding of the disease pathophysiology. Nevertheless, ARDS continues to rank among the leading causes of mortality in intensive care units and its management remains a formidable task, primarily due to its remarkable heterogeneity. As a consequence, the syndrome is underdiagnosed, prognostication has important gaps and selection of the appropriate therapeutic approach is laborious. In recent years, the noncoding transcriptome has emerged as a new area of attention for researchers interested in biomarker development. Numerous studies have confirmed the potential of long noncoding RNAs (lncRNAs), transcripts with little or no coding information, as noninvasive tools for diagnosis, prognosis and prediction of the therapeutic response across a broad spectrum of ailments, including respiratory conditions. This article aims to provide a comprehensive overview of lncRNAs with specific emphasis on their role as biomarkers. We review current knowledge on the circulating lncRNAs as potential markers that can be used to enhance decision making in ARDS management. Additionally, we address the primary limitations and outline the steps that will be essential for integration of the use of lncRNAs in clinical laboratories. Our ultimate objective is to provide a framework for the implementation of lncRNAs in the management of ARDS., Competing Interests: Conflict of interest: All authors have nothing to disclose., (Copyright ©The authors 2024.)

Normally aerated lung tissue on computed tomography (CT) is correlated with static respiratory system compliance (C rs ) at zero end-expiratory pressure. In clinical practice, however, patients with acute respiratory failure are often managed using elevated PEEP levels. No study has validated the relationship between lung volume and tissue and C rs at the applied positive end-expiratory pressure (PEEP). Therefore, this study aimed to demonstrate the relationship between lung volume and tissue on CT and C rs during the application of PEEP for the clinical management of patients with acute respiratory distress syndrome due to COVID-19. Additionally, as a secondary outcome, the study aimed to evaluate the relationship between CT characteristics and C rs , considering recruitability using the recruitment-to-inflation ratio (R/I ratio). We analyzed the CT and respiratory mechanics data of 30 patients with COVID-19 who were mechanically ventilated. The CT images were acquired during mechanical ventilation at PEEP level of 15 cmH 2 O and were quantitatively analyzed using Synapse Vincent system version 6.4 (Fujifilm Corporation, Tokyo, Japan). Recruitability was stratified into two groups, high and low recruitability, based on the median R/I ratio of our study population. Thirty patients were included in the analysis with the median R/I ratio of 0.71. A significant correlation was observed between C rs at the applied PEEP (median 15 [interquartile range (IQR) 12.2, 15.8]) and the normally aerated lung volume (r = 0.70 [95% CI 0.46-0.85], P < 0.001) and tissue (r = 0.70 [95% CI 0.46-0.85], P < 0.001). Multivariable linear regression revealed that recruitability (Coefficient = - 390.9 [95% CI - 725.0 to - 56.8], P = 0.024) and C rs (Coefficient = 48.9 [95% CI 32.6-65.2], P < 0.001) were significantly associated with normally aerated lung volume (R-squared: 0.58). In this study, C rs at the applied PEEP was significantly correlated with normally aerated lung volume and tissue on CT. Moreover, recruitability indicated by the R/I ratio and C rs were significantly associated with the normally aerated lung volume. This research underscores the significance of C rs at the applied PEEP as a bedside-measurable parameter and sheds new light on the link between recruitability and normally aerated lung., (© 2024. The Author(s).)

Rationale: Evidence about long-term sequelae after hospitalization for acute respiratory distress syndrome due to COVID-19 is still scarce., Purpose: To evaluate changes in pulmonary, cardiac, and renal function and in quality of life after hospitalization for acute respiratory distress syndrome secondary to COVID-19., Methods: This will be a multicenter case-control study of 220 participants. Eligible are patients who are hospitalized for acute respiratory distress syndrome due to COVID-19. In the control group, individuals with no history of hospitalization in the last 12 months or long-term symptoms of COVID-19 will be selected. All individuals will be subjected to pulmonary spirometry with a carbon monoxide diffusion test, chest tomography, cardiac and renal magnetic resonance imaging with gadolinium, ergospirometry, serum and urinary creatinine, total protein, and urinary microalbuminuria, in addition to quality-of-life questionnaires. Patients will be evaluated 12 months after hospital discharge, and controls will be evaluated within 90 days of inclusion in the study. For all the statistical analyses, p < 0.05 is the threshold for significance., Results: The primary outcome of the study will be the pulmonary diffusing capacity for carbon monoxide measured after 12 months. The other parameters of pulmonary, cardiac, and renal function and quality of life are secondary outcomes., Conclusion: This study aims to determine the long-term sequelae of pulmonary, cardiac, and renal function and the quality of life of patients hospitalized for acute respiratory distress syndrome due to COVID-19 in the Brazilian population.

Rationale: It is unknown whether preventing overdistention or collapse is more important when titrating positive end-expiratory pressure (PEEP) in acute respiratory distress syndrome (ARDS). Objectives: To compare PEEP targeting minimal overdistention or minimal collapse or using a compromise between collapse and overdistention in a randomized trial and to assess the impact on respiratory mechanics, gas exchange, inflammation, and hemodynamics. Methods: In a porcine model of ARDS, lung collapse and overdistention were estimated using electrical impedance tomography during a decremental PEEP titration. Pigs were randomized to three groups and ventilated for 12 hours: PEEP set at ⩽3% of overdistention (low overdistention), ⩽3% of collapse (low collapse), and the crossing point of collapse and overdistention. Measurements and Main Results: Thirty-six pigs (12 per group) were included. Median (interquartile range) values of PEEP were 7 (6-8), 11 (10-11), and 15 (12-16) cm H 2 O in the three groups ( P  < 0.001). With low overdistension, 6 (50%) pigs died, whereas survival was 100% in both other groups. Cause of death was hemodynamic in nature, with high transpulmonary vascular gradient and high epinephrine requirements. Compared with the other groups, pigs surviving with low overdistension had worse respiratory mechanics and gas exchange during the entire protocol. Minimal differences existed between crossing-point and low-collapse animals in physiological parameters, but postmortem alveolar density was more homogeneous in the crossing-point group. Inflammatory markers were not significantly different. Conclusions: PEEP to minimize overdistention resulted in high mortality in an animal model of ARDS. Minimizing collapse or choosing a compromise between collapse and overdistention may result in less lung injury, with potential benefits of the compromise approach.

Background: Understanding the enduring respiratory consequences of severe COVID-19 is crucial for comprehensive patient care. This study aims to evaluate the impact of post-COVID conditions on respiratory sequelae of severe acute respiratory distress syndrome (ARDS)., Methods: We examined 88 survivors of COVID-19-associated severe ARDS six months post-intensive care unit (ICU) discharge. Assessments included clinical and functional evaluation as well as plasma biomarkers of endothelial dysfunction, inflammation, and viral response. Additionally, an in vitro model using human umbilical vein endothelial cells (HUVECs) explored the direct impact of post-COVID plasma on endothelial function., Results: Post-COVID patients with impaired gas exchange demonstrated persistent endothelial inflammation marked by elevated ICAM-1, IL-8, CCL-2, and ET-1 plasma levels. Concurrently, systemic inflammation, evidenced by NLRP3 overexpression and elevated levels of IL-6, sCD40-L, and C-reactive protein, was associated with endothelial dysfunction biomarkers and increased in post-COVID patients with impaired gas exchange. T-cell activation, reflected in CD69 expression, and persistently elevated levels of interferon-β (IFN-β) further contributed to sustained inflammation. The in vitro model confirmed that patient plasma, with altered levels of sCD40-L and IFN-β proteins, has the capacity to alter endothelial function., Conclusions: Six months post-ICU discharge, survivors of COVID-19-associated ARDS exhibited sustained elevation in endothelial dysfunction biomarkers, correlating with the severity of impaired gas exchange. NLRP3 inflammasome activity and persistent T-cell activation indicate on going inflammation contributing to persistent endothelial dysfunction, potentially intensified by sustained viral immune response., (© 2024. The Author(s).)

Patients with acute exacerbation of lung fibrosis with usual interstitial pneumonia (EUIP) pattern are at increased risk for ventilator-induced lung injury (VILI) and mortality when exposed to mechanical ventilation (MV). Yet, lack of a mechanical model describing UIP-lung deformation during MV represents a research gap. Aim of this study was to develop a constitutive mathematical model for UIP-lung deformation during lung protective MV based on the stress-strain behavior and the specific elastance of patients with EUIP as compared to that of acute respiratory distress syndrome (ARDS) and healthy lung. Partitioned lung and chest wall mechanics were assessed for patients with EUIP and primary ARDS (1:1 matched based on body mass index and PaO 2 /FiO 2 ratio) during a PEEP trial performed within 24 h from intubation. Patient's stress-strain curve and the lung specific elastance were computed and compared with those of healthy lungs, derived from literature. Respiratory mechanics were used to fit a novel mathematical model of the lung describing mechanical-inflation-induced lung parenchyma deformation, differentiating the contributions of elastin and collagen, the main components of lung extracellular matrix. Five patients with EUIP and 5 matched with primary ARDS were included and analyzed. Global strain was not different at low PEEP between the groups. Overall specific elastance was significantly higher in EUIP as compared to ARDS (28.9 [22.8-33.2] cmH 2 O versus 11.4 [10.3-14.6] cmH 2 O, respectively). Compared to ARDS and healthy lung, the stress/strain curve of EUIP showed a steeper increase, crossing the VILI threshold stress risk for strain values greater than 0.55. The contribution of elastin was prevalent at lower strains, while the contribution of collagen was prevalent at large strains. The stress/strain curve for collagen showed an upward shift passing from ARDS and healthy lungs to EUIP lungs. During MV, patients with EUIP showed different respiratory mechanics, stress-strain curve and specific elastance as compared to ARDS patients and healthy subjects and may experience VILI even when protective MV is applied. According to our mathematical model of lung deformation during mechanical inflation, the elastic response of UIP-lung is peculiar and different from ARDS. Our data suggest that patients with EUIP experience VILI with ventilatory setting that are lung-protective for patients with ARDS., (© 2024. The Author(s).)

This study aims to resolve the unmet need for ventilator surge capacity by developing a prototype device that can alter patient-specific flow in a shared ventilator setup. The device is designed to deliver a predictable tidal volume (VT), requiring minimal additional monitoring and workload. The prototyped device was tested in an in vitro bench setup for its performance against the intended use and design criteria. The ventilation parameters: VT and airway pressures, and ventilation profiles: pressure, flow and volume were measured for different ventilator and device settings for a healthy and ARDS simulated lung pathology. We obtained VTs with a linear correlation with valve openings from 10 to 100% across set inspiratory pressures (IPs) of 20 to 30 cmH 2 O. Airway pressure varied with valve opening and lung elastance but did not exceed set IPs. Performance was consistent in both healthy and ARDS-simulated lung conditions. The ventilation profile diverged from traditional pressure-controlled profiles. We present the design a flow modulator to titrate VTs in a shared ventilator setup. Application of the flow modulator resulted in a characteristic flow profile that differs from pressure- or volume controlled ventilation. The development of the flow modulator enables further validation of the Individualized Shared Ventilation (ISV) technology with individualization of delivered VTs and the development of a clinical protocol facilitating its clinical use during a ventilator surge capacity problem., (© 2024. The Author(s).)

Background: The oxygenation index (OI) and oxygen saturation index (OSI) are proven mortality predictors in pediatric and adult patients, traditionally using mean airway pressure (P mean ). We introduce novel indices, replacing P mean with DP (ΔP insp ), MP dyn , and MP tot , assessing their potential for predicting COVID-19 acute respiratory distress syndrome (ARDS) mortality, comparing them to traditional indices. Methods: We studied 361 adult COVID-19 ARDS patients for 7 days, collecting ΔP insp , MP dyn , and MP tot , OI-ΔP insp , OI-MP dyn , OI-MP tot , OSI-ΔP insp , OSI-MP dyn , and OSI-MP tot . We compared these in surviving and non-surviving patients over the first 7 intensive care unit (ICU) days using Mann-Whitney U test. Logistic regression receiver operating characteristic (ROC) analysis assessed AUC and CI values for ICU mortality on day three. We determined cut-off values using Youden's method and conducted multivariate Cox regression on parameter limits. Results: All indices showed significant differences between surviving and non-surviving patients on the third day of ICU care. The AUC values of OI-ΔP insp were significantly higher than those of P/F and OI-P mean ( P values .0002 and <.0001, respectively). Similarly, AUC and CI values of OSI-ΔP insp and OSI-MP dyn were significantly higher than those of SpO 2 /FiO 2 and OSI-P mean values (OSI-ΔP insp : P  < .0001, OSI-MP dyn : P values .047 and .028, respectively). OI-ΔP insp , OSI-ΔP insp , OI-MP dyn , OSI-MP dyn , OI-MP tot , and OSI-MP tot had AUC values of 0.72, 0.71, 0.69, 0.68, 0.66, and 0.64, respectively, with cut-off values associated with hazard ratios and P values of 7.06 (HR = 1.84, P  = .002), 8.04 (HR = 2.00, P  ≤ .0001), 7.12 (HR = 1.68, P  = .001), 5.76 (HR = 1.70, P  ≤ .0001), 10.43 (HR = 1.52, P  = .006), and 10.68 (HR = 1.66, P  = .001), respectively. Conclusions: Critical values of all indices were associated to higher ICU mortality rates and extended mechanical ventilation durations. The OI-ΔP insp , OSI-ΔP insp , and OSI-MP dyn indices displayed the strongest predictive capabilities for ICU mortality. These novel indices offer valuable insights for intensivists in the clinical management and decision-making process for ARDS patients., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Acute respiratory distress syndrome (ARDS) is characterized by a redistribution of regional lung perfusion that impairs gas exchange. While speculative, experimental evidence suggests that perfusion redistribution may contribute to regional inflammation and modify disease progression. Unfortunately, tools to visualize and quantify lung perfusion in patients with ARDS are lacking. This review explores recent advances in perfusion imaging techniques that aim to understand the pulmonary circulation in ARDS. Dynamic contrast-enhanced computed tomography captures first-pass kinetics of intravenously injected dye during continuous scan acquisitions. Different contrast characteristics and kinetic modeling have improved its topographic measurement of pulmonary perfusion with high spatial and temporal resolution. Dual-energy computed tomography can map the pulmonary blood volume of the whole lung with limited radiation exposure, enabling its application in clinical research. Electrical impedance tomography can obtain serial topographic assessments of perfusion at the bedside in response to treatments such as inhaled nitric oxide and prone position. Ongoing technological improvements and emerging techniques will enhance lung perfusion imaging and aid its incorporation into the care of patients with ARDS., Competing Interests: Declaration of competing interest The authors report no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: The Prone positioning in addition to non invasive respiratory support is commonly used in patients with acute respiratory failure. The aim of this study was to assess the accuracy of an impedance-based non-invasive respiratory volume monitor (RVM) in supine and in prone position., Methods: In sedated, paralyzed and mechanically ventilated patients in volume-controlled mode with acute respiratory distress syndrome scheduled for prone positioning it was measured and compared non-invasively tidal volume and respiratory rate provided by the RVM in supine and, subsequently, in prone position, by maintaining unchanged the ventilatory setting., Results: Forty patients were enrolled. No significant difference was found between measurements in supine and in prone position either for tidal volume (p = 0.795; p = 0.302) nor for respiratory rate (p = 0.181; p = 0.604). Comparing supine vs. prone position, the bias and limits of agreements for respiratory rate were 0.12 bpm (-1.4 to 1.6) and 20 mL (-80 to 120) for tidal volume., Conclusions: The RVM is accurate in assessing tidal volume and respiratory rate in prone compared to supine position. Therefore, the RVM could be applied in non-intubated patients with acute respiratory failure receiving prone positioning to monitor respiratory function., (© 2024. The Author(s).)

Electrical impedance tomography (EIT) is a new method of monitoring non-invasive mechanical ventilation, at the bedside and useful in critically ill patients. It allows lung monitoring of ventilation and perfusion, obtaining images that provide information on lung function. It is based on the physical principle of impedanciometry or the body's ability to conduct an electrical current. Various studies have shown its usefulness both in adults and in pediatrics in respiratory distress syndrome, pneumonia and atelectasis in addition to pulmonary thromboembolism and pulmonary hypertension by also providing information on pulmonary perfusion, and may be very useful in perioperative medicine; especially in pediatrics avoiding repetitive imaging tests with ionizing radiation., (Copyright © 2023 Sociedad Española de Anestesiología, Reanimación y Terapéutica del Dolor. Publicado por Elsevier España, S.L.U. All rights reserved.)

Purpose: Acute respiratory distress syndrome (ARDS) is a major cause of hypoxemic respiratory failure in adults. In ARDS extensive inflammation and leakage of fluid into the alveoli lead to dysregulation of pulmonary surfactant metabolism and function. Altered surfactant synthesis, secretion, and breakdown contribute to the clinical features of decreased lung compliance and alveolar collapse. Lung function in ARDS could potentially be restored with surfactant replacement therapy, and synthetic surfactants with modified peptide analogues may better withstand inactivation in ARDS alveoli than natural surfactants., Methods: This study aimed to investigate the activity in vitro and the bolus effect (200 mg phospholipids/kg) of synthetic surfactant CHF5633 with analogues of SP-B and SP-C, or natural surfactant Poractant alfa (Curosurf ® , both preparations Chiesi Farmaceutici S.p.A.) in a severe ARDS model (the ratio of partial pressure arterial oxygen and fraction of inspired oxygen, P/F ratio ≤ 13.3 kPa) induced by hydrochloric acid instillation followed by injurious ventilation in adult New Zealand rabbits. The animals were ventilated for 4 h after surfactant treatment and the respiratory parameters, histological appearance of lung parenchyma and levels of inflammation, oxidative stress, surfactant dysfunction, and endothelial damage were evaluated., Results: Both surfactant preparations yielded comparable improvements in lung function parameters, reductions in lung injury score, pro-inflammatory cytokines levels, and lung edema formation compared to untreated controls., Conclusions: This study indicates that surfactant replacement therapy with CHF5633 improves lung function and lung architecture, and attenuates inflammation in severe ARDS in adult rabbits similarly to Poractant alfa. Clinical trials have so far not yielded conclusive results, but exogenous surfactant may be a valid supportive treatment for patients with ARDS given its anti-inflammatory and lung-protective effects., (© 2024. The Author(s).)

Acute respiratory distress syndrome (ARDS) is associated with long-term impairments in brain and muscle function that significantly impact the quality of life of those who survive the acute illness. The mechanisms underlying these impairments are not yet well understood, and evidence-based interventions to minimize the burden on patients remain unproved. The NHLBI of the NIH assembled a workshop in April 2023 to review the state of the science regarding ARDS-associated brain and muscle dysfunction, to identify gaps in current knowledge, and to determine priorities for future investigation. The workshop included presentations by scientific leaders across the translational science spectrum and was open to the public as well as the scientific community. This report describes the themes discussed at the workshop as well as recommendations to advance the field toward the goal of improving the health and well-being of ARDS survivors.

Background: Positive end-expiratory pressure (PEEP) can potentially modulate inspiratory effort (ΔPes), which is the major determinant of self-inflicted lung injury., Research Question: Does high PEEP reduce ΔPes in patients with moderate-to-severe ARDS on assisted ventilation?, Study Design and Methods: Sixteen patients with Pao 2 /Fio 2  ≤ 200 mm Hg and ΔPes ≥ 10 cm H 2 O underwent a randomized sequence of four ventilator settings: PEEP = 5 cm H 2 O or PEEP = 15 cm H 2 O + synchronous (pressure support ventilation [PSV]) or asynchronous (pressure-controlled intermittent mandatory ventilation [PC-IMV]) inspiratory assistance. ΔPes and respiratory system, lung, and chest wall mechanics were assessed with esophageal manometry and occlusions. PEEP-induced alveolar recruitment and overinflation, lung dynamic strain, and tidal volume distribution were assessed with electrical impedance tomography., Results: ΔPes was not systematically different at high vs low PEEP (pressure support ventilation: median, 20 cm H 2 O; interquartile range (IQR), 15-24 cm H 2 O vs median, 15 cm H 2 O; IQR, 13-23 cm H 2 O; P = .24; pressure-controlled intermittent mandatory ventilation: median, 20; IQR, 18-23 vs median, 19; IQR, 17-25; P = .67, respectively). Similarly, respiratory system and transpulmonary driving pressures, tidal volume, lung/chest wall mechanics, and pendelluft extent were not different between study phases. High PEEP resulted in lower or higher ΔPes, respiratory system driving pressure, and transpulmonary driving pressure according to whether this increased or decreased respiratory system compliance (r = -0.85, P < .001; r = -0.75, P < .001; r = -0.80, P < .001, respectively). PEEP-induced changes in respiratory system compliance were driven by its lung component and were dependent on the extent of PEEP-induced alveolar overinflation (r = -0.66, P = .006). High PEEP caused variable recruitment and systematic redistribution of tidal volume toward dorsal lung regions, thereby reducing dynamic strain in ventral areas (pressure support ventilation: median, 0.49; IQR, 0.37-0.83 vs median, 0.96; IQR, 0.62-1.56; P = .003; pressure-controlled intermittent mandatory ventilation: median, 0.65; IQR, 0.42-1.31 vs median, 1.14; IQR, 0.79-1.52; P = .002). All results were consistent during synchronous and asynchronous inspiratory assistance., Interpretation: The impact of high PEEP on ΔPes and lung stress is interindividually variable according to different effects on the respiratory system and lung compliance resulting from alveolar overinflation. High PEEP may help mitigate the risk of self-inflicted lung injury solely if it increases lung/respiratory system compliance., Trial Registration: ClinicalTrials.gov; No.: NCT04241874; URL: www., Clinicaltrials: gov., Competing Interests: Financial/Nonfinancial Disclosures The authors have reported to CHEST the following: D. L. G. has received speaking fees from Gilead, Intersurgical, MSD, and GE; and reports having received travel accommodation by Fisher and Paykel, outside the submitted work. M. A. has received personal fees by Maquet and a research grant by Toray, outside the submitted work. D. L. G. and M. A. disclose a research grant by GE, outside the submitted work. None declared (G. B., V. G., A. B., L. D. C., T. R., L. S. M., L. M., T. M., G. S., G. D. P., M. A. P., R. R. D. S. S., L. B.)., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Critical illness syndromes including sepsis, acute respiratory distress syndrome, and acute kidney injury (AKI) are associated with high in-hospital mortality and long-term adverse health outcomes among survivors. Despite advancements in care, clinical and biological heterogeneity among patients continues to hamper identification of efficacious therapies. Precision medicine offers hope by identifying patient subclasses based on clinical, laboratory, biomarker and 'omic' data and potentially facilitating better alignment of interventions. Within the previous two decades, numerous studies have made strides in identifying gene-expression based endotypes and clinico-biomarker based phenotypes among critically ill patients associated with differential outcomes and responses to treatment. In this state-of-the-art review, we summarize the biological similarities and differences across the various subclassification schemes among critically ill patients. In addition, we highlight current translational gaps, the need for advanced scientific tools, human-relevant disease models, to gain a comprehensive understanding of the molecular mechanisms underlying critical illness subclasses., (© 2024. The Author(s).)

Background: Previously identified phenotypes of acute respiratory distress syndrome (ARDS) could not reveal the dynamic change of phenotypes over time. We aimed to identify novel clinical phenotypes in ARDS using trajectories of fluid balance, to test whether phenotypes respond differently to different treatment, and to develop a simplified model for phenotype identification., Methods: FACTT (conservative vs liberal fluid management) trial was classified as a development cohort, joint latent class mixed models (JLCMMs) were employed to identify trajectories of fluid balance. Heterogeneity of treatment effect (HTE) for fluid management strategy across phenotypes was investigated. We also constructed a parsimonious probabilistic model using baseline data to predict the fluid trajectories in the development cohort. The trajectory groups and the probabilistic model were externally validated in EDEN (initial trophic vs full enteral feeding) trial., Results: Using JLCMM, we identified two trajectory groups in the development cohort: Class 1 (n = 758, 76.4% of the cohort) had an early positive fluid balance, but achieved negative fluid balance rapidly, and Class 2 (n = 234, 24.6% of the cohort) was characterized by persistent positive fluid balance. Compared to Class 1 patients, patients in Class 2 had significantly higher 60-day mortality (53.5% vs. 17.8%, p < 0.001), and fewer ventilator-free days (0 vs. 20, p < 0.001). A significant HTE between phenotypes and fluid management strategies was observed in the FACTT. An 8-variables model was derived for phenotype assignment., Conclusions: We identified and validated two novel clinical trajectories for ARDS patients, with both prognostic and predictive enrichment. The trajectories of ARDS can be identified with simple classifier models., (© 2024. The Author(s).)

Acute respiratory distress syndrome (ARDS) represents a life-threatening inflammatory reaction marked by refractory hypoxaemia and pulmonary oedema. Despite advancements in treatment perspectives, ARDS still carries a high mortality rate, often due to systemic inflammatory responses leading to multiple organ dysfunction syndrome (MODS). Indeed, the deterioration and associated mortality in patients with acute lung injury (LI)/ARDS is believed to originate alongside respiratory failure mainly from the involvement of extrapulmonary organs, a consequence of the complex interaction between initial inflammatory cascades related to the primary event and ongoing mechanical ventilation-induced injury resulting in multiple organ failure (MOF) and potentially death. Even though recent research has increasingly highlighted the role of the gastrointestinal tract in this process, the pathophysiology of gut dysfunction in patients with ARDS remains mainly underexplored. This review aims to elucidate the complex interplay between lung and gut in patients with LI/ARDS. We will examine various factors, including systemic inflammation, epithelial barrier dysfunction, the effects of mechanical ventilation (MV), hypercapnia, and gut dysbiosis. Understanding these factors and their interaction may provide valuable insights into the pathophysiology of ARDS and potential therapeutic strategies to improve patient outcomes., (© 2024. The Author(s).)

Background: Conventional Mechanical ventilation modes used for individuals suffering from acute respiratory distress syndrome have the potential to exacerbate lung injury through regional alveolar overinflation and/or repetitive alveolar collapse with shearing, known as atelectrauma. Animal studies have demonstrated that airway pressure release ventilation (APRV) offers distinct advantages over conventional mechanical ventilation modes. However, the methodologies for implementing APRV vary widely, and the findings from clinical studies remain controversial. This study (APRVplus trial), aims to assess the impact of an early pathophysiology-driven APRV ventilation approach compared to a low tidal volume ventilation (LTV) strategy on the prognosis of patients with moderate to severe ARDS., Methods: The APRVplus trial is a prospective, multicenter, randomized clinical trial, building upon our prior single-center study, to enroll 840 patients from at least 35 hospitals in China. This investigation plans to compare the early pathophysiology-driven APRV ventilation approach with the control intervention of LTV lung-protective ventilation. The primary outcome measure will be all-cause mortality at 28 days after randomization in the intensive care units (ICU). Secondary outcome measures will include assessments of oxygenation, and physiology parameters at baseline, as well as on days 1, 2, and 3. Additionally, clinical outcomes such as ventilator-free days at 28 days, duration of ICU and hospital stay, ICU and hospital mortality, and the occurrence of adverse events will be evaluated., Trial Ethics and Dissemination: The research project has obtained approval from the Ethics Committee of West China Hospital of Sichuan University (2019-337). Informed consent is required. The results will be submitted for publication in a peer-reviewed journal and presented at one or more scientific conferences., Trial Registration: The study was registered at Clinical Trials.gov (NCT03549910) on June 8, 2018., (© 2024. The Author(s).)

Background and Objectives : Intra-abdominal hypertension (IAH) and acute respiratory distress syndrome (ARDS) are common concerns in intensive care unit patients with acute respiratory failure (ARF). Although both conditions lead to impairment of global respiratory parameters, their underlying mechanisms differ substantially. Therefore, a separate assessment of the different respiratory compartments should reveal differences in respiratory mechanics. Materials and Methods : We prospectively investigated alterations in lung and chest wall mechanics in 18 mechanically ventilated pigs exposed to varying levels of intra-abdominal pressures (IAP) and ARDS. The animals were divided into three groups: group A (IAP 10 mmHg, no ARDS), B (IAP 20 mmHg, no ARDS), and C (IAP 10 mmHg, with ARDS). Following induction of IAP (by inflating an intra-abdominal balloon) and ARDS (by saline lung lavage and injurious ventilation), respiratory mechanics were monitored for six hours. Statistical analysis was performed using one-way ANOVA to compare the alterations within each group. Results : After six hours of ventilation, end-expiratory lung volume (EELV) decreased across all groups, while airway and thoracic pressures increased. Significant differences were noted between group (B) and (C) regarding alterations in transpulmonary pressure (TPP) (2.7 ± 0.6 vs. 11.3 ± 2.1 cmH 2 O, p < 0.001), elastance of the lung (E L ) (8.9 ± 1.9 vs. 29.9 ± 5.9 cmH 2 O/mL, p = 0.003), and elastance of the chest wall (E CW ) (32.8 ± 3.2 vs. 4.4 ± 1.8 cmH 2 O/mL, p < 0.001). However, global respiratory parameters such as EELV/kg bodyweight (-6.1 ± 1.3 vs. -11.0 ± 2.5 mL/kg), driving pressure (12.5 ± 0.9 vs. 13.2 ± 2.3 cmH 2 O), and compliance of the respiratory system (-21.7 ± 2.8 vs. -19.5 ± 3.4 mL/cmH 2 O) did not show significant differences among the groups. Conclusions : Separate measurements of lung and chest wall mechanics in pigs with IAH or ARDS reveals significant differences in TPP, E L , and E CW , whereas global respiratory parameters do not differ significantly. Therefore, assessing the compartments of the respiratory system separately could aid in identifying the underlying cause of ARF.

Background: Assessing mechanical properties of the respiratory system (C st ) during mechanical ventilation necessitates an end-inspiration flow of zero, which requires an end-inspiratory occlusion maneuver. This lung model study aimed to observe the effect of airflow obstruction on the accuracy of respiratory mechanical properties during pressure-controlled ventilation (PCV) by analyzing dynamic signals., Methods: A Hamilton C3 ventilator was attached to a lung simulator that mimics lung mechanics in healthy, acute respiratory distress syndrome (ARDS) and chronic obstructive pulmonary disease (COPD) models. PCV and volume-controlled ventilation (VCV) were applied with tidal volume (V T ) values of 5.0, 7.0, and 10.0 ml/kg. Performance characteristics and respiratory mechanics were assessed and were calibrated by virtual extrapolation using expiratory time constant (RC exp )., Results: During PCV ventilation, drive pressure (DP) was significantly increased in the ARDS model. Peak inspiratory flow (PIF) and peak expiratory flow (PEF) gradually declined with increasing severity of airflow obstruction, while DP, end-inspiration flow (EIF), and inspiratory cycling ratio (EIF/PIF%) increased. Similar estimated values of C rs and airway resistance (R aw ) during PCV and VCV ventilation were obtained in healthy adult and mild obstructive models, and the calculated errors did not exceed 5%. An underestimation of C rs and an overestimation of R aw were observed in the severe obstruction model., Conclusion: Using the modified dynamic signal analysis approach, respiratory system properties (C rs and R aw ) could be accurately estimated in patients with non-severe airflow obstruction in the PCV mode., (© 2024. The Author(s).)

Background: Driving pressure has been suggested to be the main driver of ventilator-induced lung injury and mortality in observational studies of acute respiratory distress syndrome. Whether a driving pressure-limiting strategy can improve clinical outcomes is unclear., Objective: To describe the protocol and statistical analysis plan that will be used to test whether a driving pressure-limiting strategy including positive end-expiratory pressure titration according to the best respiratory compliance and reduction in tidal volume is superior to a standard strategy involving the use of the ARDSNet low-positive end-expiratory pressure table in terms of increasing the number of ventilator-free days in patients with acute respiratory distress syndrome due to community-acquired pneumonia., Methods: The ventilator STrAtegy for coMmunIty acquired pNeumoniA (STAMINA) study is a randomized, multicenter, open-label trial that compares a driving pressure-limiting strategy to the ARDSnet low-positive end-expiratory pressure table in patients with moderate-to-severe acute respiratory distress syndrome due to community-acquired pneumonia admitted to intensive care units. We expect to recruit 500 patients from 20 Brazilian and 2 Colombian intensive care units. They will be randomized to a driving pressure-limiting strategy group or to a standard strategy using the ARDSNet low-positive end-expiratory pressure table. In the driving pressure-limiting strategy group, positive end-expiratory pressure will be titrated according to the best respiratory system compliance., Outcomes: The primary outcome is the number of ventilator-free days within 28 days. The secondary outcomes are in-hospital and intensive care unit mortality and the need for rescue therapies such as extracorporeal life support, recruitment maneuvers and inhaled nitric oxide., Conclusion: STAMINA is designed to provide evidence on whether a driving pressure-limiting strategy is superior to the ARDSNet low-positive end-expiratory pressure table strategy for increasing the number of ventilator-free days within 28 days in patients with moderate-to-severe acute respiratory distress syndrome. Here, we describe the rationale, design and status of the trial.