Acute Respiratory Distress Syndrome Network Research Articles

Understanding Causes of Death in Patients With Acute Respiratory Distress Syndrome: A Narrative Review.

To provide a comprehensive summary of the published data on cause of death in patients with acute respiratory distress syndrome (ARDS). PubMed (January 2015 to April 2024), bibliographies of relevant articles, and ARDS Network and Prevention & Early Treatment of Acute Lung Injury (PETAL) network websites. Observational studies and clinical trials that reported on cause of death in greater than or equal to 30 patients with ARDS, not obtained from death certificates. Animal studies, case reports, review articles, study protocols, and studies in pediatrics were excluded. Causes of death among ARDS patients who died were extracted and tabulated along with other pertinent study characteristics. We identified 15 observational studies (nine non-COVID ARDS, five COVID-related ARDS; one both) and five clinical trials (all non-COVID ARDS). Mutually exclusive prespecified categories were used for recording the cause of death in only eight studies although studies differed in the categories included and their definitions. When multiple organ failure was a predetermined category, it was the most common cause of death recorded (~50% of deaths), followed by respiratory causes with proportions varying from 16% to 42% depending on nomenclature (e.g., refractory hypoxemia, pulmonary causes) and definitions. However, the largest observational study in non-COVID ARDS (964 deaths), did not include multiple organ failure as a predetermined category, and found that pulmonary failure (42%) and cardiac failure (37%) were the most common causes of death. In COVID-related ARDS observational studies, pulmonary reasons were the most reported cause of death (up to 88%). Few studies have reported cause of death in patients with ARDS. In those that do, cause of death categories and definitions used are heterogeneous. Further research is needed to see whether a more rigorous and unified approach to assigning and reporting cause of death in ARDS would help identify more relevant endpoints for the assessment of targeted treatments in clinical trials.

High Levels of Triggering Receptor Expressed in Myeloid Cells-Like Transcript-1 Positive, but Not Glycoprotein 1b+, Microparticles Are Associated With Poor Outcomes in Acute Respiratory Distress Syndrome.

To identify triggering receptor expressed in myeloid cells-like transcript-1 positive (TLT-1+) microparticles (MPs) and evaluate if their presence is associated with clinical outcomes and/or disease severity in acute respiratory distress syndrome (ARDS). Retrospective cohort study. ARDS Network clinical trials. A total of 564 patients were diagnosed with ARDS. None. Using flow cytometry, we demonstrated the presence of TLT-1+ platelet-derived microparticles (PMP) that bind fibrinogen in plasma samples from fresh donors. We retrospectively quantified TLT-1, glycoprotein (Gp) 1b, or αIIbβIIIa immunopositive microparticles in plasma samples from patients with ARDS enrolled in the ARMA, KARMA, and LARMA (Studies 01 and 03 lower versus higher tidal volume, ketoconazole treatment, and lisofylline treatment Clincial Trials) ARDS Network clinical trials and evaluated the relationship between these measures and clinical outcomes. No associations were found between Gp1b+ MPs and clinical outcomes for any of the cohorts. When stratified by quartile, associations were found for survival, ventilation-free breathing, and thrombocytopenia with αIIbβIIIa+ and TLT-1+ MPs (χ2p < 0.001). Notably, 63 of 64 patients in this study who failed to achieve unassisted breathing had TLT+ PMP in the 75th percentile. In all three cohorts, patients whose TLT+ MP counts were higher than the median had higher Acute Physiology and Chronic Health Evaluation III scores, were more likely to present with thrombocytopenia and were 3.7 times (p < 0.001) more likely to die than patients with lower TLT+ PMP after adjusting for other risk factors. Although both αIIbβIIIa+ and TLT+ microparticles (αIIbβIIIa, TLT-1) were associated with mortality, TLT-1+ MPs demonstrated stronger correlations with Acute Physiology and Chronic Health Evaluation III scores, unassisted breathing, and multiple system organ failure. These findings warrant further exploration of the mechanistic role of TLT-1+ PMP in ARDS or acute lung injury progression.

A BAYESIAN MACHINE LEARNING APPROACH FOR ESTIMATING HETEROGENEOUS SURVIVOR CAUSAL EFFECTS: APPLICATIONS TO A CRITICAL CARE TRIAL.

Assessing heterogeneity in the effects of treatments has become increasingly popular in the field of causal inference and carries important implications for clinical decision-making. While extensive literature exists for studying treatment effect heterogeneity when outcomes are fully observed, there has been limited development in tools for estimating heterogeneous causal effects when patient-centered outcomes are truncated by a terminal event, such as death. Due to mortality occurring during study follow-up, the outcomes of interest are unobservable, undefined, or not fully observed for many participants in which case principal stratification is an appealing framework to draw valid causal conclusions. Motivated by the Acute Respiratory Distress Syndrome Network (ARDSNetwork) ARDS respiratory management (ARMA) trial, we developed a flexible Bayesian machine learning approach to estimate the average causal effect and heterogeneous causal effects among the always-survivors stratum when clinical outcomes are subject to truncation. We adopted Bayesian additive regression trees (BART) to flexibly specify separate mean models for the potential outcomes and latent stratum membership. In the analysis of the ARMA trial, we found that the low tidal volume treatment had an overall benefit for participants sustaining acute lung injuries on the outcome of time to returning home but substantial heterogeneity in treatment effects among the always-survivors, driven most strongly by biologic sex and the alveolar-arterial oxygen gradient at baseline (a physiologic measure of lung function and degree of hypoxemia). These findings illustrate how the proposed methodology could guide the prognostic enrichment of future trials in the field.

Multicentre, parallel, open-label, two-arm, randomised controlled trial on the prognosis of electrical impedance tomography-guided versus low PEEP/FiO2 table-guided PEEP setting: a trial protocol

IntroductionPrevious studies suggested that electrical impedance tomography (EIT) has the potential to guide positive end-expiratory pressure (PEEP) titration via quantifying the alveolar collapse and overdistension. The aim of this trial...

A combination of mild-moderate hypoxemia and low compliance is highly prevalent in persistent ARDS: a retrospective study

BackgroundThe Acute Respiratory Distress Syndrome (ARDS) is characterized by lung inflammation and edema, impairing both oxygenation and lung compliance. Recent studies reported a dissociation between oxygenation and compliance (severe hypoxemia with preserved compliance) in early ARDS and COVID-19-related-ARDS (CARDS). During the pandemic, in patients requiring prolonged mechanical ventilation, we observed the opposite combination (mild-moderate hypoxemia but significantly impaired compliance). The purpose of our study was to investigate the prevalence of this combination of mild-moderate hypoxemia and impaired compliance in persistent ARDS and CARDS.MethodsFor this retrospective study, we used individual patient-level data from two independent cohorts of ARDS patients. The ARDSNet cohort included patients from four ARDS Network randomized controlled trials. The CARDS cohort included patients with ARDS due to COVID-19 hospitalized in two intensive care units in Greece. We used a threshold of 150 for PaO2/FiO2 and 30 ml/cmH2O for compliance, estimated the prevalence of each of the four combinations of oxygenation and compliance at baseline, and examined the change in its prevalence from baseline to day 21 in the ARDSNet and CARDS cohorts.ResultsThe ARDSNet cohort included 2909 patients and the CARDS cohort included 349 patients. The prevalence of the combination of mild-moderate hypoxemia and low compliance increased from baseline to day 21 both in the ARDSNet cohort (from 22.2 to 42.7%) and in the CARDS cohort (from 3.1 to 33.3%). Among surviving patients with low compliance, oxygenation improved over time. The 60-day mortality rate was higher for patients who had mild-moderate hypoxemia and low compliance on day 21 (28% and 56% in ARDSNet and CARDS), compared to those who had mild-moderate hypoxemia and high compliance (20% and 50%, respectively).ConclusionsAmong patients with ARDS who require prolonged controlled mechanical ventilation, regardless of ARDS etiology, a dissociation between oxygenation and compliance characterized by mild-moderate hypoxemia but low compliance becomes increasingly prevalent. The findings of this study highlight the importance of monitoring mechanics in patients with persistent ARDS.

PROLONGED MECHANICAL VENTILATION IN ACUTE RESPIRATORY DISTRESS SYNDROME.

Purpose: Trajectory of acute respiratory distress syndrome (ARDS) spans from rapidly improving cases to cases receiving prolonged mechanical ventilation (PMV). We attempted to estimate temporal trends of prevalence and mortality of PMV and to identify risk factors associated with mortality of patients with ARDS receiving PMV. Methods: We performed a secondary analysis of individual patient data from six randomized controlled clinical trials conducted by the ARDS Network. Prolonged mechanical ventilation was defined as the need for mechanical ventilation for >21 consecutive days. Results: Of 4,216 patients with ARDS, 646 (15.3%) received PMV. Prevalence of PMV gradually declined from 18.4% in the ARDS Network: Low-Tidal-Volume Trial (published in 2000) trial to 10.9% in the SAILS (2014) trial ( R2 = 0.728, P = 0.031). Ninety-day mortality of patients receiving PMV did not change over time ( R2 = 0.271, P = 0.290) and remained as high as 36.8%. Ιn the three most recent trials, risk factors associated with mortality among the 250 patients with ARDS receiving PMV included age, malignancy, pneumonia as the cause of ARDS, coagulation dysfunction, and hepatic dysfunction during the first 21 days after trial enrollment. Conclusion: Although prevalence of PMV among patients enrolled in ARDS Network trials gradually declined, mortality did not change. Risk factors associated with mortality were mostly nonmodifiable.

The Relationship Between Metabolic Syndrome and Mortality Among Patients With Acute Respiratory Distress Syndrome in Acute Respiratory Distress Syndrome Network and Prevention and Early Treatment of Acute Lung Injury Network Trials.

Metabolic syndrome is known to predict outcomes in COVID-19 acute respiratory distress syndrome (ARDS) but has never been studied in non-COVID-19 ARDS. We therefore aimed to determine the association of metabolic syndrome with mortality among ARDS trial subjects. Retrospective cohort study of ARDS trials' data. An ancillary analysis was conducted using data from seven ARDS Network and Prevention and Early Treatment of Acute Lung Injury Network randomized trials within the Biologic Specimen and Data Repository Information Coordinating Center database. Hospitalized patients with ARDS and metabolic syndrome (defined by obesity, diabetes, and hypertension) were compared with similar patients without metabolic syndrome (those with less than three criteria). None. The primary outcome was 28-day mortality. Among 4288 ARDS trial participants, 454 (10.6%) with metabolic syndrome were compared with 3834 controls (89.4%). In adjusted analyses, the metabolic syndrome group was associated with lower 28-day and 90-day mortality when compared with control (adjusted odds ratio [aOR], 0.70 [95% CI, 0.55-0.89] and 0.75 [95% CI, 0.60-0.95], respectively). With each additional metabolic criterion from 0 to 3, adjusted 28-day mortality was reduced by 18%, 22%, and 40%, respectively. In subgroup analyses stratifying by ARDS etiology, mortality was lower for metabolic syndrome vs. control in ARDS caused by sepsis or pneumonia (at 28 d, aOR 0.64 [95% CI, 0.48-0.84] and 90 d, aOR 0.69 [95% CI, 0.53-0.89]), but not in ARDS from noninfectious causes (at 28 d, aOR 1.18 [95% CI, 0.70-1.99] and 90 d, aOR 1.26 [95% CI, 0.77-2.06]). Interaction p = 0.04 and p = 0.02 for 28- and 90-day comparisons, respectively. Metabolic syndrome in ARDS was associated with a lower risk of mortality in non-COVID-19 ARDS. The relationship between metabolic inflammation and ARDS may provide a novel biological pathway to be explored in precision medicine-based trials.

Racial and ethnic minority participants in clinical trials of acute respiratory distress syndrome

PurposeThere is growing interest in improving the inclusiveness of racial and ethnic minority participants in trials of acute respiratory distress syndrome (ARDS). With our study we aimed to examine temporal trends of representation and mortality of racial and ethnic minority participants in randomized controlled trials of ARDS.MethodsWe performed a secondary analysis of eight ARDS Network and PETAL Network therapeutic clinical trials, published between 2000 and 2019. We classified race/ethnicity into “White”, “Black”, “Hispanic”, or “Other” (including Asian, American Indian or Alaskan Native, Native Hawaiian, or other Pacific Islander participants).ResultsOf 5375 participants with ARDS, 1634 (30.4%) were Black, Hispanic, or Other race participants. Representation of racial and ethnic minority participants in trials did not change significantly over time (p = 0.257). However, among participants with moderate to severe ARDS (i.e., partial pressure of arterial oxygen to fraction of inspired oxygen ratio < 150), the difference in mortality between racial and ethnic minority participants and White participants decreased over time. In the five most recent trials, including 2923 participants with ARDS, there were no statistically significant differences in mortality between racial/ethnic groups, even after adjusting for potential confounders. In these five most recent trials, mortality was 31% for White, 31.9% for Black, 30.3% for Hispanic, and 37.1% for Other race participants (p = 0.633).ConclusionRepresentation of racial and ethnic minority participants in ARDS trials from North America, published between 2000 and 2019, did not change over time. Black and Hispanic participants with ARDS may have similar mortality as White participants within trials.

Postoperative acute respiratory distress syndrome in randomized controlled trials

BackgroundAcute respiratory distress syndrome is a potentially fatal postoperative complication. We aimed to estimate temporal trends of the representation of patients with postoperative acute respiratory distress syndrome in clinical trials, determine their distinct clinical features, and identify predictors of mortality. MethodsThis is a secondary analysis of 7 randomized controlled clinical trials conducted by the Acute Respiratory Distress Syndrome Network and the Clinical Trials Network for the Prevention and Early Treatment of Acute Lung Injury. Patients with acute respiratory distress syndrome were classified into a postoperative acute respiratory distress syndrome group (ie, patients who had undergone elective surgery in the immediate period before trial enrollment) and a non-postoperative acute respiratory distress syndrome group. ResultsOut of 5,316 patients with acute respiratory distress syndrome, 256 (4.8%) had postoperative acute respiratory distress syndrome. Representation of postoperative acute respiratory distress syndrome in trials gradually declined from 2000 to 2011, but it remained stable afterward at 2.7%. Postoperative acute respiratory distress syndrome was associated with lower 90-day mortality (24.6% vs 30.9%, P = .032) than non-postoperative acute respiratory distress syndrome, even after adjusting for age, acute respiratory distress syndrome severity, usage of vasopressors at baseline, and the study publication year (hazard ratio 0.63, 95% confidence interval 0.49–0.82). Age (odds ratio 1.07, 95% confidence interval 1.04–1.09), immunosuppression (odds ratio 4.12, 95% confidence interval 1.43–11.86), and positive fluid balance (odds ratio 1.09, 95% confidence interval 1.04–1.14) were associated with 90-day mortality among patients with postoperative acute respiratory distress syndrome. ConclusionRepresentation of postoperative acute respiratory distress syndrome in trials of the Acute Respiratory Distress Syndrome Network and the Clinical Trials Network for the Prevention and Early Treatment of Acute Lung Injury gradually declined from 2000 to 2011 but remained stable afterward. Postoperative acute respiratory distress syndrome was associated with lower mortality than non-postoperative acute respiratory distress syndrome. These findings may put both temporal trends and the prognosis of postoperative acute respiratory distress syndrome in perspective. Also, positive fluid balance was associated with the mortality of patients with postoperative acute respiratory distress syndrome.

Evaluation of adherence with lung-protective ventilator strategies in moderate-to-severe acute respiratory distress syndrome in a tertiary care setup in India: A prospective observational study.

Evaluation of the efficacy and safety of mechanical ventilation settings is a cornerstone of the early phase of the management of acute respiratory distress syndrome (ARDS). This study aimed to evaluate the adherence to currently recommended lung-protective ventilator strategies (tidal volume, plateau pressure, driving pressure, prone positioning, and positive end-expiratory pressure [PEEP]) for adults with moderate-to-severe ARDS in a tertiary care setup, thereby evaluating if lung-protective ventilation is associated with improved outcomes. This was an observational study over 1 year in ventilated moderate-to-severe ARDS participants. All participants were mechanically ventilated when required using the protocol followed by the ARDS Network low-tidal volume lung-protective ventilation strategy and monitored. The total number of participants in the study was 32. Septic shock was the most common cause of ARDS. The mean duration of intensive care unit (ICU) stay was 6.13 (±5.4) days, mean ventilator days were 3.66 (±3.75) days and mortality rate of 71.8%.Adherence to low-tidal volume was 78.12% with an improvement of 36% in the adherent group (P = 0.06). Adherence to high PEEP was 34.38% with a survival of 73% in the adherent group (P = 0.0004). Adherence to prone ventilation was 18.75% with a survival of 33% in the adherent group (P = 0.7). Intensivists should take an extra effort to focus on evidence-based ventilator strategies and increase adherence to these recommendations in their ICUs to improve patient survival.

Impact of Time-Varying Intensity of Mechanical Ventilation on 28-Day Mortality Depends on Fluid Balance in Patients With Acute Respiratory Distress Syndrome: A Retrospective Cohort Study.

BackgroundRecent studies have mainly focused on the association between baseline intensity of mechanical ventilation (driving pressure or mechanical power) and mortality in acute respiratory distress syndrome (ARDS). It is unclear whether the association between the time-varying intensity of mechanical ventilation and mortality is significant and varies according to the fluid balance trajectories.MethodsWe conducted a secondary analysis based on the NHLBI ARDS Network’s Fluid and Catheter Treatment Trial (FACTT). The primary outcome was 28-day mortality. The group-based trajectory modeling (GBTM) was employed to identify phenotypes based on fluid balance trajectories. Bayesian joint models were used to account for informative censoring due to death during follow-up.ResultsA total of 1,000 patients with ARDS were included in the analysis. Our study identified two phenotypes of ARDS, and compared patients with Early Negative Fluid Balance (Early NFB) and patients with Persistent-Positive Fluid Balance (Persistent-PFB) accompanied by higher tidal volume, higher static driving pressure, higher mechanical power, and lower PaO2/FiO2, over time during mechanical ventilation. The 28-day mortality was 14.8% in Early NFB and 49.6% in Persistent-PFB (p < 0.001). In the Bayesian joint models, the hazard ratio (HR) of 28-day death for time-varying static driving pressure [HR 1.03 (95% CI 1.01–1.05; p < 0.001)] and mechanical power [HR 1.01 (95% CI 1.002–1.02; p = 0.01)] was significant in patients with Early NFB, but not in patients with Persistent-PFB.ConclusionTime-varying intensity of mechanical ventilation was associated with a 28-day mortality of ARDS in a patient with Early NFB but not in patients with Persistent-PFB.

Effects of different positive end-expiratory pressure titration strategies during prone positioning in patients with acute respiratory distress syndrome: a prospective interventional study

BackgroundProne positioning in combination with the application of low tidal volume and adequate positive end-expiratory pressure (PEEP) improves survival in patients with moderate to severe acute respiratory distress syndrome (ARDS). However, the effects of PEEP on end-expiratory transpulmonary pressure (Ptpexp) during prone positioning require clarification. For this purpose, the effects of three different PEEP titration strategies on Ptpexp, respiratory mechanics, mechanical power, gas exchange, and hemodynamics were evaluated comparing supine and prone positioning.MethodsIn forty consecutive patients with moderate to severe ARDS protective ventilation with PEEP titrated according to three different titration strategies was evaluated during supine and prone positioning: (A) ARDS Network recommendations (PEEPARDSNetwork), (B) the lowest static elastance of the respiratory system (PEEPEstat,RS), and (C) targeting a positive Ptpexp (PEEPPtpexp). The primary endpoint was to analyze whether Ptpexp differed significantly according to PEEP titration strategy during supine and prone positioning.ResultsPtpexp increased progressively with prone positioning compared with supine positioning as well as with PEEPEstat,RS and PEEPPtpexp compared with PEEPARDSNetwork (positioning effect p < 0.001, PEEP strategy effect p < 0.001). PEEP was lower during prone positioning with PEEPEstat,RS and PEEPPtpexp (positioning effect p < 0.001, PEEP strategy effect p < 0.001). During supine positioning, mechanical power increased progressively with PEEPEstat,RS and PEEPPtpexp compared with PEEPARDSNetwork, and prone positioning attenuated this effect (positioning effect p < 0.001, PEEP strategy effect p < 0.001). Prone compared with supine positioning significantly improved oxygenation (positioning effect p < 0.001, PEEP strategy effect p < 0.001) while hemodynamics remained stable in both positions.ConclusionsProne positioning increased transpulmonary pressures while improving oxygenation and hemodynamics in patients with moderate to severe ARDS when PEEP was titrated according to the ARDS Network lower PEEP table. This PEEP titration strategy minimized parameters associated with ventilator-induced lung injury induction, such as transpulmonary driving pressure and mechanical power. We propose that a lower PEEP strategy (PEEPARDSNetwork) in combination with prone positioning may be part of a lung protective ventilation strategy in patients with moderate to severe ARDS.Trial registrationGerman Clinical Trials Register (DRKS00017449). Registered June 27, 2019. https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00017449

Positive End-Expiratory Pressure and Respiratory Rate Modify the Association of Mechanical Power and Driving Pressure With Mortality Among Patients With Acute Respiratory Distress Syndrome.

Mechanical power and driving pressure have known associations with survival for patients with acute respiratory distress syndrome. To further understand the relative importance of mechanical power and driving pressure as clinical targets for ventilator management. Secondary observational analysis of randomized clinical trial data. Patients with the acute respiratory distress syndrome from three Acute Respiratory Distress Syndrome Network trials. After adjusting for patient severity in a multivariate Cox proportional hazards model, we examined the relative association of driving pressure and mechanical power with hospital mortality. Among 2,410 patients, the relationship between driving pressure and mechanical power with mortality was modified by respiratory rate, positive end-expiratory pressure, and flow. Among patients with low respiratory rate (< 26), only power was significantly associated with mortality (power [hazard ratio, 1.82; 95% CI, 1.41-2.35; p < 0.001] vs driving pressure [hazard ratio, 1.01; 95% CI, 0.84-1.21; p = 0.95]), while among patients with high respiratory rate, neither was associated with mortality. Both power and driving pressure were associated with mortality at high airway flow (power [hazard ratio, 1.28; 95% CI, 1.15-1.43; p < 0.001] vs driving pressure [hazard ratio, 1.15; 95% CI, 1.01-1.30; p = 0.041]) and neither at low flow. At low positive end-expiratory pressure, neither was associated with mortality, whereas at high positive end-expiratory pressure (≥ 10 cm H2O), only power was significantly associated with mortality (power [hazard ratio, 1.22; 95% CI, 1.09-1.37; p < 0.001] vs driving pressure [hazard ratio, 1.16; 95% CI, 0.99-1.35; p = 0.059]). The relationship between mechanical power and driving pressure with mortality differed within severity subgroups defined by positive end-expiratory pressure, respiratory rate, and airway flow.

Mechanical Power Correlates With Lung Inflammation Assessed by Positron-Emission Tomography in Experimental Acute Lung Injury in Pigs.

Background: Mechanical ventilation (MV) may initiate or worsen lung injury, so-called ventilator-induced lung injury (VILI). Although different mechanisms of VILI have been identified, research mainly focused on single ventilator parameters. The mechanical power (MP) summarizes the potentially damaging effects of different parameters in one single variable and has been shown to be associated with lung damage. However, to date, the association of MP with pulmonary neutrophilic inflammation, as assessed by positron-emission tomography (PET), has not been prospectively investigated in a model of clinically relevant ventilation settings yet. We hypothesized that the degree of neutrophilic inflammation correlates with MP.Methods: Eight female juvenile pigs were anesthetized and mechanically ventilated. Lung injury was induced by repetitive lung lavages followed by initial PET and computed tomography (CT) scans. Animals were then ventilated according to the acute respiratory distress syndrome (ARDS) network recommendations, using the lowest combinations of positive end-expiratory pressure and inspiratory oxygen fraction that allowed adequate oxygenation. Ventilator settings were checked and adjusted hourly. Physiological measurements were conducted every 6 h. Lung imaging was repeated 24 h after first PET/CT before animals were killed. Pulmonary neutrophilic inflammation was assessed by normalized uptake rate of 2-deoxy-2-[18F]fluoro-D-glucose (KiS), and its difference between the two PET/CT was calculated (ΔKiS). Lung aeration was assessed by lung CT scan. MP was calculated from the recorded pressure–volume curve. Statistics included the Wilcoxon tests and non-parametric Spearman correlation.Results: Normalized 18F-FDG uptake rate increased significantly from first to second PET/CT (p = 0.012). ΔKiS significantly correlated with median MP (ρ = 0.738, p = 0.037) and its elastic and resistive components, but neither with median peak, plateau, end-expiratory, driving, and transpulmonary driving pressures, nor respiratory rate (RR), elastance, or resistance. Lung mass and volume significantly decreased, whereas relative mass of hyper-aerated lung compartment increased after 24 h (p = 0.012, p = 0.036, and p = 0.025, respectively). Resistance and PaCO2 were significantly higher (p = 0.012 and p = 0.017, respectively), whereas RR, end-expiratory pressure, and MP were lower at 18 h compared to start of intervention.Conclusions: In this model of experimental acute lung injury in pigs, pulmonary neutrophilic inflammation evaluated by PET/CT increased after 24 h of MV, and correlated with MP.

The Effect of Loop Diuretics on 28-Day Mortality in Patients With Acute Respiratory Distress Syndrome.

Background: Diuretics have been widely used in critically ill patients while it remains uncertain whether they can reduce mortality in patients with acute respiratory distress syndrome (ARDS). This study aimed to investigate the associations between diuretics and 28-day mortality in patients with ARDS.Methods: This is a secondary analysis of the ARDS Network Fluid and Catheter Treatment Trial (FACTT) of National Heart, Lung, and Blood Institute. Those patients who did not receive renal replacement therapy within the first 48 h after enrollment in the FACTT were included in the analysis. A marginal structural Cox model (MSCM) was used to investigate the associations between diuretics and 28-day mortality after correction of both the baseline and time-varying variables. The latent class analysis (LCA) and subgroup analysis were performed to identify the kind of patients that could be benefited from diuretics.Results: A total of 932 patients were enrolled, i.e., 558 patients in the diuretics group and 374 patients in the no diuretics group within the first 48 h. The 28-day mortality was lower in the diuretics group (15.1 vs. 28.1%, p < 0.001). In MSCM, diuretics use was related to the improved 28-day mortality (HR 0.78; 95% CI 0.62–0.99; p = 0.04). LCA identified three subtypes, and diuretics were associated with reduced mortality in subtype 3, which was characterized by worse renal function and higher central venous pressure (CVP). A subgroup analysis indicated survival advantage among the female patients, sepsis induced ARDS, and those with the ratio of partial pressure of oxygen to the fractional concentration of inspired oxygen (PaO2/FiO2) ≤ 150 mmHg, and mean arterial pressure (MAP) ≥ 65 mmHg.Conclusion: Loop diuretics were associated with the reduced 28-day mortality in the patients with ARDS, after controlling for time-varying confounders. Randomized trials are required to verify the association.

Bedside estimates of dead space using end-tidal CO2 are independently associated with mortality in ARDS

PurposeIn acute respiratory distress syndrome (ARDS), dead space fraction has been independently associated with mortality. We hypothesized that early measurement of the difference between arterial and end-tidal CO2 (arterial-ET difference), a surrogate for dead space fraction, would predict mortality in mechanically ventilated patients with ARDS.MethodsWe performed two separate exploratory analyses. We first used publicly available databases from the ALTA, EDEN, and OMEGA ARDS Network trials (N = 124) as a derivation cohort to test our hypothesis. We then performed a separate retrospective analysis of patients with ARDS using University of Chicago patients (N = 302) as a validation cohort.ResultsThe ARDS Network derivation cohort demonstrated arterial-ET difference, vasopressor requirement, age, and APACHE III to be associated with mortality by univariable analysis. By multivariable analysis, only the arterial-ET difference remained significant (P = 0.047). In a separate analysis, the modified Enghoff equation ((PaCO2–PETCO2)/PaCO2) was used in place of the arterial-ET difference and did not alter the results. The University of Chicago cohort found arterial-ET difference, age, ventilator mode, vasopressor requirement, and APACHE II to be associated with mortality in a univariate analysis. By multivariable analysis, the arterial-ET difference continued to be predictive of mortality (P = 0.031). In the validation cohort, substitution of the arterial-ET difference for the modified Enghoff equation showed similar results.ConclusionArterial to end-tidal CO2 (ETCO2) difference is an independent predictor of mortality in patients with ARDS.

An assessment of esophageal balloon use for the titration of airway pressure release ventilation and controlled mechanical ventilation in a patient with extrapulmonary acute respiratory distress syndrome: a case report

BackgroundEsophageal pressure measurement is a minimally invasive monitoring process that assesses respiratory mechanics in patients with acute respiratory distress syndrome. Airway pressure release ventilation is a relatively new positive pressure ventilation modality, characterized by a series of advantages in patients with acute respiratory distress syndrome.Case presentationWe report a case of a 55-year-old chilean female, with preexisting hypertension and recurrent renal colic who entered the cardiosurgical intensive care unit with signs and symptoms of urinary sepsis secondary to a right-sided obstructive urolithiasis. At the time of admission, the patient showed signs of urinary sepsis, a poor overall condition, hemodynamic instability, tachycardia, hypotension, and needed vasoactive drugs. Initially the patient was treated with volume control ventilation. Then, ventilation was with conventional ventilation parameters described by the Acute Respiratory Distress Syndrome Network. However, hemodynamic complications led to reduced airway pressure. Later she presented intraabdominal hypertension that compromised the oxygen supply and her ventilation management. Considering these records, an esophageal manometry was used to measure distending lung pressure, that is, transpulmonary pressure, to protect lungs. Initial use of the esophageal balloon was in a volume-controlled modality (deep sedation), which allowed the medical team to perform inspiratory and expiratory pause maneuvers to monitor transpulmonary plateau pressure as a substitute for pulmonary distension and expiratory pause and determine transpulmonary positive end-expiratory pressure. On the third day of mechanical respiration, the modality was switched to airway pressure release ventilation. The use of airway pressure release ventilation was associated with reduced hemodynamic complications and kept transpulmonary pressure between 0 and 20 cmH2O despite a sustained high positive end-expiratory pressure of 20 cmH2O.ConclusionThe application of this technique is shown in airway pressure release ventilation with spontaneous ventilation, which is then compared with a controlled modality that requires a lesser number of sedative doses and vasoactive drugs, without altering the criteria for lung protection as guided by esophageal manometry.

Association of early positive end-expiratory pressure settings with ventilator-free days in patients with coronavirus disease 2019 acute respiratory distress syndrome: A secondary analysis of the Practice of VENTilation in COVID-19 study.

BACKGROUNDThere is uncertainty about how much positive end-expiratory pressure (PEEP) should be used in patients with acute respiratory distress syndrome (ARDS) due to coronavirus disease 2019 (COVID-19).OBJECTIVETo investigate whether a higher PEEP strategy is superior to a lower PEEP strategy regarding the number of ventilator-free days (VFDs).DESIGNMulticentre observational study conducted from 1 March to 1 June 2020.SETTING AND PATIENTSTwenty-two ICUs in The Netherlands and 933 invasively ventilated COVID-19 ARDS patients.INTERVENTIONSPatients were categorised retrospectively as having received invasive ventilation with higher (n=259) or lower PEEP (n=674), based on the high and low PEEP/FiO2 tables of the ARDS Network, and using ventilator settings and parameters in the first hour of invasive ventilation, and every 8 h thereafter at fixed time points during the first four calendar days. We also used propensity score matching to control for observed confounding factors that might influence outcomes.MAIN OUTCOMES AND MEASURESThe primary outcome was the number of VFDs. Secondary outcomes included distant organ failures including acute kidney injury (AKI) and use of renal replacement therapy (RRT), and mortality.RESULTSIn the unmatched cohort, the higher PEEP strategy had no association with the median [IQR] number of VFDs (2.0 [0.0 to 15.0] vs. 0.0 [0.0 to 16.0] days). The median (95% confidence interval) difference was 0.21 (−3.34 to 3.78) days, P = 0.905. In the matched cohort, the higher PEEP group had an association with a lower median number of VFDs (0.0 [0.0 to 14.0] vs. 6.0 [0.0 to 17.0] days) a median difference of −4.65 (−8.92 to −0.39) days, P = 0.032. The higher PEEP strategy had associations with higher incidence of AKI (in the matched cohort) and more use of RRT (in the unmatched and matched cohorts). The higher PEEP strategy had no association with mortality.CONCLUSIONIn COVID-19 ARDS, use of higher PEEP may be associated with a lower number of VFDs, and may increase the incidence of AKI and need for RRT.TRIAL REGISTRATIONPractice of VENTilation in COVID-19 is registered at ClinicalTrials.gov, NCT04346342.

Individualization of PEEP and tidal volume in ARDS patients with electrical impedance tomography: a pilot feasibility study

BackgroundIn mechanically ventilated patients with acute respiratory distress syndrome (ARDS), electrical impedance tomography (EIT) provides information on alveolar cycling and overdistension as well as assessment of recruitability at the bedside. We developed a protocol for individualization of positive end-expiratory pressure (PEEP) and tidal volume (VT) utilizing EIT-derived information on recruitability, overdistension and alveolar cycling. The aim of this study was to assess whether the EIT-based protocol allows individualization of ventilator settings without causing lung overdistension, and to evaluate its effects on respiratory system compliance, oxygenation and alveolar cycling.Methods20 patients with ARDS were included. Initially, patients were ventilated according to the recommendations of the ARDS Network with a VT of 6 ml per kg predicted body weight and PEEP adjusted according to the lower PEEP/FiO2 table. Subsequently, ventilator settings were adjusted according to the EIT-based protocol once every 30 min for a duration of 4 h. To assess global overdistension, we determined whether lung stress and strain remained below 27 mbar and 2.0, respectively.ResultsProspective optimization of mechanical ventilation with EIT led to higher PEEP levels (16.5 [14–18] mbar vs. 10 [8–10] mbar before optimization; p = 0.0001) and similar VT (5.7 ± 0.92 ml/kg vs. 5.8 ± 0.47 ml/kg before optimization; p = 0.96). Global lung stress remained below 27 mbar in all patients and global strain below 2.0 in 19 out of 20 patients. Compliance remained similar, while oxygenation was significantly improved and alveolar cycling was reduced after EIT-based optimization.ConclusionsAdjustment of PEEP and VT using the EIT-based protocol led to individualization of ventilator settings with improved oxygenation and reduced alveolar cycling without promoting global overdistension.Trial registrationThis study was registered at clinicaltrials.gov (NCT02703012) on March 9, 2016 before including the first patient.

Adherence to Lung-Protective Ventilation Principles in Pediatric Acute Respiratory Distress Syndrome: A Pediatric Acute Respiratory Distress Syndrome Incidence and Epidemiology Study.

To describe mechanical ventilation management and factors associated with nonadherence to lung-protective ventilation principles in pediatric acute respiratory distress syndrome. A planned ancillary study to a prospective international observational study. Mechanical ventilation management (every 6 hr measurements) during pediatric acute respiratory distress syndrome days 0-3 was described and compared with Pediatric Acute Lung Injury Consensus Conference tidal volume recommendations (< 7 mL/kg in children with impaired respiratory system compliance, < 9 mL/kg in all other children) and the Acute Respiratory Distress Syndrome Network lower positive end-expiratory pressure/higher Fio2 grid recommendations. Seventy-one international PICUs. Children with pediatric acute respiratory distress syndrome. None. Analyses included 422 children. On pediatric acute respiratory distress syndrome day 0, median tidal volume was 7.6 mL/kg (interquartile range, 6.3-8.9 mL/kg) and did not differ by pediatric acute respiratory distress syndrome severity. Plateau pressure was not recorded in 97% of measurements. Using delta pressure (peak inspiratory pressure - positive end-expiratory pressure), median tidal volume increased over quartiles of median delta pressure (p = 0.007). Median delta pressure was greater than or equal to 18 cm H2O for all pediatric acute respiratory distress syndrome severity levels. In severe pediatric acute respiratory distress syndrome, tidal volume was greater than or equal to 7 mL/kg 62% of the time, and positive end-expiratory pressure was lower than recommended by the positive end-expiratory pressure/Fio2 grid 70% of the time. In multivariable analysis, tidal volume nonadherence was more common with severe pediatric acute respiratory distress syndrome, fewer PICU admissions/yr, non-European PICUs, higher delta pressure, corticosteroid use, and pressure control mode. Adherence was associated with underweight stature and cuffed endotracheal tubes. In multivariable analysis, positive end-expiratory pressure/Fio2 grid nonadherence was more common with higher pediatric acute respiratory distress syndrome severity, ventilator decisions made primarily by the attending physician, pre-ICU cardiopulmonary resuscitation, underweight stature, and age less than 2 years. Adherence was associated with respiratory therapist involvement in ventilator management and longer time from pediatric acute respiratory distress syndrome diagnosis. Higher nonadherence to tidal volume and positive end-expiratory pressure recommendations were independently associated with higher mortality and longer duration of ventilation after adjustment for confounding variables. In stratified analyses, these associations were primarily influenced by children with severe pediatric acute respiratory distress syndrome. Nonadherence to lung-protective ventilation principles is common in pediatric acute respiratory distress syndrome and may impact outcome. Modifiable factors exist that may improve adherence.