Trials In Acute Respiratory Distress Syndrome Research Articles

Differential Effect of Positive End-Expiratory Pressure Strategies in Patients With ARDS: A Bayesian Analysis of Clinical Subphenotypes

ARDS is a heterogeneous condition with two subphenotypes identified by different methodologies. Our group similarly identified two ARDS subphenotypes using nine routinely available clinical variables. However, whether these are associated with differential response to treatment has yet to be explored. Are there differential responses to positive end-expiratory pressure (PEEP) strategies on 28-day mortality according to subphenotypes in adult patients with ARDS? We evaluated data from two prior ARDS trials (Higher vsLower Positive End-Expiratory Pressures in Patients With the ARDS [ALVEOLI] and the Alveolar Recruitment in ARDS Trial [ART]) that compared different PEEP strategies. We classified patients into one of two subphenotypes as described previously. We assessed the differential effect of PEEP with a Bayesian hierarchical logistic model for the primary outcome of 28-day mortality. We analyzed data from 1,559 patients with ARDS. Compared with lower PEEP, a higher PEEP strategy resulted in higher 28-day mortality in patients with subphenotype A disease in the ALVEOLI study (OR, 1.61; 95%credible interval [CrI], 0.90-2.94) and ART (OR, 1.73; 95%CrI, 1.01-2.98), with a probability of harm resulting from higher PEEP in this subphenotype of 94.3%and 97.7%in the ALVEOLI and ART studies, respectively. Higher PEEP was not associated with mortality in patients with subphenotype B disease in each trial (OR, 0.95 [95%CrI, 0.51-1.73] and 1.00 [95%CrI, 0.63-1.55], respectively), with probability of benefit of 56.4%and 50.7%in the ALVEOLI and ART studies, respectively. These effects were not modified by Pao2 to Fio2 ratio, driving pressure, or the severity of illness for the cohorts. We found evidence of differential response to PEEP strategies across two ARDS subphenotypes, suggesting possible harm with a higher PEEP strategy in one subphenotype. These observations may assist with predictive enrichment in future clinical trials.

A Master Protocol Template for Pediatric ARDS Studies.

Pediatric ARDS is associated with significant morbidity and mortality. High-quality data from clinical trials in children are limited due to numerous barriers to their design and execution. Here we describe the collaborative development of a master protocol as a tool to address some of these barriers and support the conduct of pediatric ARDS studies. Using PubMed, we performed a literature search of randomized controlled trials (RCTs) in pediatric ARDS to characterize the current state and evaluate potential benefit of harmonized master protocols. We used a multi-stakeholder, collaborative, and team science-oriented process to develop a master protocol template with links to common data elements (CDEs) for pediatric ARDS trials. We identified 11 RCTs that enrolled between 14-200 total subjects per trial. Interventions included mechanical ventilation, prone positioning, corticosteroids, and surfactant. Studies displayed significant heterogeneity in ARDS definition, design, inclusion and exclusion criteria, and reported outcomes. Mortality was reported in 91% of trials and ventilator-free days in 73%. The trial heterogeneity made pooled analysis unfeasible. These findings underscore the need for a method to facilitate combined analysis of future trials through standardization of trial elements. As a potential solution, we developed a master protocol, iteratively revised with input from a multidisciplinary panel of experts and organized into 3 categories: instructions and general information, templated language, and a series of text options of common pediatric ARDS trial scenarios. Finally, we linked master protocol sections to relevant CDEs previously defined for pediatric ARDS and captured in a series of electronic case report forms. The majority of pediatric ARDS trials identified were small and heterogeneous in study design and outcome reporting. Using a master protocol template for pediatric ARDS trials with CDEs would support combining and comparing pediatric ARDS trial findings and increase the knowledge base.

449 Does incorporation of plasma biomarkers to the Lung Injury Prediction Score improve the predictive value for development of acute respiratory distress syndrome?

OBJECTIVES/GOALS: To determine if incorporating specific laboratory values and plasma biomarkers (club cell secretory protein (CC16), matrix metalloproteinase 3 (MMP3), interleukin 8 (IL-8), protein C) to the Lung Injury Prediction (LIP) Score improves the predictive value for development of acute respiratory distress syndrome (ARDS) in ICU patients. METHODS/STUDY POPULATION: Adult patients admitted to the ICU on supplemental oxygen over baseline requirement with a LIP Score ≥6 will be included. Patients admitted to the ICU >24 hours, end-stage renal disease, decompensated heart failure, or <100 µL plasma available will be excluded. Whole blood will be collected from the core lab, centrifuged, and plasma will be stored at -80°C. Protein biomarkers will be measured using enzyme-linked immunosorbent assay. Baseline characteristics, laboratory values, ventilator parameters, and clinical outcomes will be collected from the medical record. ARDS will be defined by the Berlin criteria. Machine learning methods will be used to identify the model with the highest predictive accuracy. Area under the receiver operating characteristic curve of each model will be compared to the LIP Score. RESULTS/ANTICIPATED RESULTS: Research is in progress. Plasma samples and clinical data have been collected for 148 of the 160 samples required to achieve power. Biomarker analysis will take place after sample collection is complete. We anticipate a machine learning model incorporating laboratory values and one or more plasma biomarkers into the LIP Score will outperform the baseline LIP Score for prediction of ARDS development. DISCUSSION/SIGNIFICANCE: Delayed diagnosis and intervention contribute to poor ARDS outcomes. Current predictive models for ARDS have low accuracy and enriching these models with plasma biomarkers may increase their predictive value. Development of accurate models may facilitate earlier ARDS diagnosis and intervention as well as enrichment strategies for ARDS trials.

Association between Age and Mortality in Pediatric and Adult Acute Respiratory Distress Syndrome.

Rationale: The epidemiology, management, and outcomes of acute respiratory distress syndrome (ARDS) differ between children and adults, with lower mortality rates in children despite comparable severity of hypoxemia. However, the relationship between age and mortality is unclear.Objective: We aimed to define the association between age and mortality in ARDS, hypothesizing that it would be nonlinear.Methods: We performed a retrospective cohort study using data from two pediatric ARDS observational cohorts (n = 1,236), multiple adult ARDS trials (n = 5,547), and an adult observational ARDS cohort (n = 1,079). We aligned all datasets to meet Berlin criteria. We performed unadjusted and adjusted logistic regression using fractional polynomials to assess the potentially nonlinear relationship between age and 90-day mortality, adjusting for sex, PaO2/FiO2, immunosuppressed status, year of study, and observational versus randomized controlled trial, treating each individual study as a fixed effect.Measurements and Main Results: There were 7,862 subjects with median ages of 4 years in the pediatric cohorts, 52 years in the adult trials, and 61 years in the adult observational cohort. Most subjects (43%) had moderate ARDS by Berlin criteria. Ninety-day mortality was 19% in the pediatric cohorts, 33% in the adult trials, and 67% in the adult observational cohort. We found a nonlinear relationship between age and mortality, with mortality risk increasing at an accelerating rate between 11 and 65 years of age, after which mortality risk increased more slowly.Conclusions: There was a nonlinear relationship between age and mortality in pediatric and adult ARDS.

Multipotent mesenchymal stromal/stem cell-based therapies for acute respiratory distress syndrome: current progress, challenges, and future frontiers.

Acute respiratory distress syndrome (ARDS) is a critical, life-threatening condition marked by severe inflammation and impaired lung function. Mesenchymal stromal/stem cells (MSCs) present a promising therapeutic avenue due to their immunomodulatory, anti-inflammatory, and regenerative capabilities. This review comprehensively evaluates MSC-based strategies for ARDS treatment, including direct administration, tissue engineering, extracellular vesicles (EVs), nanoparticles, natural products, artificial intelligence (AI), gene modification, and MSC preconditioning. Direct MSC administration has demonstrated therapeutic potential but necessitates optimization to overcome challenges related to effective cell delivery, homing, and integration into damaged lung tissue. Tissue engineering methods, such as 3D-printed scaffolds and MSC sheets, enhance MSC survival and functionality within lung tissue. EVs and MSC-derived nanoparticles offer scalable and safer alternatives to cell-based therapies. Likewise, natural products and bioactive compounds derived from plants can augment MSC function and resilience, offering complementary strategies to enhance therapeutic outcomes. In addition, AI technologies could aid in optimizing MSC delivery and dosing, and gene editing tools like CRISPR/Cas9 allow precise modification of MSCs to enhance their therapeutic properties and target specific ARDS mechanisms. Preconditioning MSCs with hypoxia, growth factors, or pharmacological agents further enhances their therapeutic potential. While MSC therapies hold significant promise for ARDS, extensive research and clinical trials are essential to determine optimal protocols and ensure long-term safety and effectiveness.

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.

Identification of molecular subphenotypes in two cohorts of paediatric ARDS

BackgroundTwo subphenotypes of acute respiratory distress syndrome (ARDS), hypoinflammatory and hyperinflammatory, have been reported in adults and in a single paediatric cohort. The relevance of these subphenotypes in paediatrics requires...

Driving Pressure: What Is the Harm?

Driving Pressure: What Is the Harm?

Mesenchymal stem cell-derived exosomes for treatment of sepsis.

The pathogenesis of sepsis is an imbalance between pro-inflammatory and anti-inflammatory responses. At the onset of sepsis, the lungs are severely affected, and the injury progresses to acute respiratory distress syndrome (ARDS), with a mortality rate of up to 40%. Currently, there is no effective treatment for sepsis. Cellular therapies using mesenchymal stem cells (MSCs) have been initiated in clinical trials for both ARDS and sepsis based on a wealth of pre-clinical data. However, there remains concern that MSCs may pose a tumor risk when administered to patients. Recent pre-clinical studies have demonstrated the beneficial effects of MSC-derived extracellular vesicles (EVs) for the treatment of acute lung injury (ALI) and sepsis. After recovery of initial surgical preparation, pneumonia/sepsis was induced in 14 adult female sheep by the instillation of Pseudomonas aeruginosa (~1.0×1011 CFU) into the lungs by bronchoscope under anesthesia and analgesia. After the injury, sheep were mechanically ventilated and continuously monitored for 24h in a conscious state in an ICU setting. After the injury, sheep were randomly allocated into two groups: Control, septic sheep treated with vehicle, n=7; and Treatment, septic sheep treated with MSC-EVs, n=7. MSC-EVs infusions (4ml) were given intravenously one hour after the injury. The infusion of MSCs-EVs was well tolerated without adverse events. PaO2/FiO2 ratio in the treatment group tended to be higher than the control from 6 to 21h after the lung injury, with no significant differences between the groups. No significant differences were found between the two groups in other pulmonary functions. Although vasopressor requirement in the treatment group tended to be lower than in the control, the net fluid balance was similarly increased in both groups as the severity of sepsis progressed. The variables reflecting microvascular hyperpermeability were comparable in both groups. We have previously demonstrated the beneficial effects of bone marrow-derived MSCs (10×106 cells/kg) in the same model of sepsis. However, despite some improvement in pulmonary gas exchange, the present study demonstrated that EVs isolated from the same amount of bone marrow-derived MSCs failed to attenuate the severity of multiorgan dysfunctions.

Effect of total cholesterol and statin therapy on mortality in ARDS patients: a secondary analysis of the SAILS and HARP-2 trials

BackgroundTwo acute respiratory distress syndrome (ARDS) trials showed no benefit for statin therapy, though secondary analyses suggest inflammatory subphenotypes may have a differential response to simvastatin. Statin medications decrease cholesterol levels, and low cholesterol has been associated with increased mortality in critical illness. We hypothesized that patients with ARDS and sepsis with low cholesterol could be harmed by statins.MethodsSecondary analysis of patients with ARDS and sepsis from two multicenter trials. We measured total cholesterol from frozen plasma samples obtained at enrollment in Statins for Acutely Injured Lungs from Sepsis (SAILS) and Simvastatin in the Acute Respiratory Distress Syndrome (HARP-2) trials, which randomized subjects with ARDS to rosuvastatin versus placebo and simvastatin versus placebo, respectively, for up to 28 days. We compared the lowest cholesterol quartile (< 69 mg/dL in SAILS, < 44 mg/dL in HARP-2) versus all other quartiles for association with 60-day mortality and medication effect. Fisher’s exact test, logistic regression, and Cox Proportional Hazards were used to assess mortality.ResultsThere were 678 subjects with cholesterol measured in SAILS and 509 subjects in HARP-2, of whom 384 had sepsis. Median cholesterol at enrollment was 97 mg/dL in both SAILS and HARP-2. Low cholesterol was associated with higher APACHE III and shock prevalence in SAILS, and higher Sequential Organ Failure Assessment score and vasopressor use in HARP-2. Importantly, the effect of statins differed in these trials. In SAILS, patients with low cholesterol who received rosuvastatin were more likely to die (odds ratio (OR) 2.23, 95% confidence interval (95% CI) 1.06–4.77, p = 0.02; interaction p = 0.02). In contrast, in HARP-2, low cholesterol patients had lower mortality if randomized to simvastatin, though this did not reach statistical significance in the smaller cohort (OR 0.44, 95% CI 0.17–1.07, p = 0.06; interaction p = 0.22).ConclusionsCholesterol levels are low in two cohorts with sepsis-related ARDS, and those in the lowest cholesterol quartile are sicker. Despite the very low levels of cholesterol, simvastatin therapy seems safe and may reduce mortality in this group, though rosuvastatin was associated with harm.Graphical abstract

Polymorphism in interferon alpha/beta receptor contributes to glucocorticoid response and outcome of ARDS and COVID-19

BackgroundThe use of glucocorticoids has given contradictory results for treating acute respiratory distress syndrome (ARDS). The use of intravenous Interferon beta (IFN β) for the treatment of ARDS was recently tested in a phase III ARDS trial (INTEREST), in which more than half of the patients simultaneously received glucocorticoids. Trial results showed deleterious effects of glucocorticoids when administered together with IFN β, and therefore, we aimed at finding the reason behind this.MethodsWe first sequenced the genes encoding the IFN α/β receptor of the patients, who participated in the INTEREST study (ClinicalTrials.gov Identifier: NCT02622724, November 24, 2015) in which the patients were randomized to receive an intravenous injection of IFN β-1a (144 patients) or placebo (152 patients). Genetic background was analyzed against clinical outcome, concomitant medication, and pro-inflammatory cytokine levels. Thereafter, we tested the influence of the genetic background on IFN α/β receptor expression in lung organ cultures and whether, it has any effect on transcription factors STAT1 and STAT2 involved in IFN signaling.ResultsWe found a novel disease association of a SNP rs9984273, which is situated in the interferon α/β receptor subunit 2 (IFNAR2) gene in an area corresponding to a binding motif of the glucocorticoid receptor (GR). The minor allele of SNP rs9984273 associates with higher IFNAR expression, more rapid decrease of IFN γ and interleukin-6 (IL-6) levels and better outcome in IFN β treated patients with ARDS, while the major allele associates with a poor outcome especially under concomitant IFN β and glucocorticoid treatment. Moreover, the minor allele of rs9984273 associates with a less severe form of coronavirus diseases (COVID-19) according to the COVID-19 Host Genetics Initiative database.ConclusionsThe distribution of this SNP within clinical study arms may explain the contradictory results of multiple ARDS studies and outcomes in COVID-19 concerning type I IFN signaling and glucocorticoids.Graphical abstract

The future of paediatric acute respiratory distress syndrome

Heterogeneity is a familiar concept to paediatric intensive care physicians, because patients, pathologies, and treatments vary both within the paediatric intensive care unit (PICU) and within a given disease process. Paediatric acute respiratory distress syndrome (ARDS) typifies this problem. Children with ARDS vary in terms of age (and therefore lung development), underlying cause (pneumonia, sepsis, or trauma), pre-existing comorbid conditions, and baseline immunological state. There is not one pathway by which ARDS occurs or manifests, as indicated by the identification of hyperinflammatory and hypoinflammatory subtypes in adults and children. 1 Calfee CS Delucchi KL Sinha P et al. Acute respiratory distress syndrome subphenotypes and differential response to simvastatin: secondary analysis of a randomised controlled trial. Lancet Respir Med. 2018; 6: 691-698 Google Scholar , 2 Dahmer MK Yang G Zhang M et al. Identification of phenotypes in paediatric patients with acute respiratory distress syndrome: a latent class analysis. Lancet Respir Med. 2022; 10: 289-297 Google Scholar Furthermore, treatments probably differ in their effectiveness, with interventions that are beneficial in some patients but harmful in others, leading to a null population average treatment effect. 3 Prescott HC Calfee CS Thompson BT Angus DC Liu VX Toward smarter lumping and smarter splitting: rethinking strategies for sepsis and acute respiratory distress syndrome clinical trial design. Am J Respir Crit Care Med. 2016; 194: 147-155 Google Scholar Thus, important questions need to be addressed to improve the management and outcomes of paediatric ARDS. In a Series paper in The Lancet Respiratory Medicine, 4 Kneyber MCJ Khemani RG Bhalla A et al. Understanding clinical and biological heterogeneity to advance precision medicine in paediatric acute respiratory distress syndrome. Lancet Respir Med. 2022; (published online Dec 22.)https://doi.org/10.1016/S2213-2600(22)00483-0 Google Scholar Martin Kneyber and colleagues—a multinational group of paediatric ARDS experts—provide a welcome summary of where we are now as a field, and what tools are available to address challenges for the next generation of paediatric ARDS trials. Two key questions need to be considered to improve the management and outcomes of paediatric ARDS. First, can we improve outcomes by identifying mechanisms or pathways to target therapeutically within specific subgroups? And second, can this be done through a nuanced approach rather than through the use of blunt, pleiotropic instruments? Understanding clinical and biological heterogeneity to advance precision medicine in paediatric acute respiratory distress syndromePaediatric acute respiratory distress syndrome (PARDS) is a heterogeneous clinical syndrome that is associated with high rates of mortality and long-term morbidity. Factors that distinguish PARDS from adult acute respiratory distress syndrome (ARDS) include changes in developmental stage and lung maturation with age, precipitating factors, and comorbidities. No specific treatment is available for PARDS and management is largely supportive, but methods to identify patients who would benefit from specific ventilation strategies or ancillary treatments, such as prone positioning, are needed. Full-Text PDF

1210: THE METABOLIC SUBPHENOTYPE: A PROTECTIVE FACTOR IN ARDS SECONDARY TO SEPSIS OR PNEUMONIA

Introduction: Poor metabolic health increases the risk of COVID-19 acute respiratory distress syndrome (ARDS), however, its relationship with non-COVID-19 ARDS remains controversial. ARDS is often considered a heterogeneous disease caused by sepsis, pneumonia, trauma, transfusions, and aspiration. In this study, we hypothesized that metabolic inflammation may contribute to differential outcomes in ARDS primarily caused by infection. Methods: This was a secondary analysis of seven studies from the ARDS and Prevention and Early Treatment of Acute Lung Injury network trials within the Biologic Specimen and Data Repository Information Coordinating Center database. A metabolic subphenotype, defined by obesity, diabetes, and hypertension, was compared to a control population. The overall results showed lower adjusted mortality with this subphenotype. In this report, we performed stratified analyses to estimate effect modification by the metabolic subphenotype. We considered metabolic inflammation to reside along the causal pathway between infection and ARDS outcomes, and as such, stratified for primary ARDS etiology (e.g., sepsis or pneumonia as compared to other primary etiologies). The primary outcome was 28-day mortality. Secondary outcomes included 90-day mortality, ventilator free days, organ-failure free days, ICU free days, and length of hospital stay. Results: Among 4,288 ARDS trial participants, 3,205 (74.7%) had primary ARDS etiologies sepsis or pneumonia and 1,083 (25.3%) aspiration, trauma, transfusions, or other causes. Of those with sepsis or pneumonia, 364 (11.4%) met criteria for the subphenotype versus 2,841 (88.6%) control. In the non-infectious cohort, 90 (8.3%) met subphenotype criteria versus 993 (91.7%) control. In adjusted analyses, the subphenotype stratified by sepsis and pneumonia was associated with lower 28- and 90-day mortality (adjusted odds ratio [aOR] 0.64 [95%CI, 0.48-0.84] and aOR 0.69 [95%CI, 0.53-0.89], respectively). However, in ARDS due to other causes, analyses were not significant (mortality at 28 days, aOR 1.18 [95% CI, 0.70–1.99] and 90 days, aOR 1.26 [95% CI, 0.77–2.06]). Secondary outcomes were not significantly different. Conclusions: A metabolic subphenotype of ARDS is associated with lower risk of mortality in non-COVID ARDS primarily caused by sepsis or pneumonia.

Prospective Study of Immune Phenotype and Associated Outcomes in Patients with Leukemia and Acute Respiratory Distress Syndrome

Background: Patients with active malignancy are frequently admitted to intensive care units (ICUs) and experience organ failure including acute respiratory distress syndrome (ARDS). In ARDS clinical trial populations, two immune phenotypes have been identified which seem to differ based on plasma protein expression, predicted mortality, and response to several randomized therapies. It is unknown if similar patters exist among ICU patients with hematologic malignancies as these patients are often excluded from clinical trials in critical care. We therefore sought to classify patients with leukemia who develop ARDS secondary to septic insult according to validated immune phenotyping algorithms and describe their characteristics and outcomes. Methods: We conducted a prospective cohort study of sepsis subjects admitted to the ICU. Eligible patients had suspected infection and organ injury upon ICU admission; exclusion criteria included non-infectious causes of organ failure, a desire for comfort measures only, or lack of informed consent. Plasma collected on day 0 of ICU admission was profiled for proteins including IL8 and sTNFR1 by electrochemiluminescence. We limited our investigation to subjects with a diagnosis of active leukemia (acute or chronic) who developed ARDS (by Berlin criteria) within 6 days of ICU admission. Using a published parsimonious algorithm incorporating plasma IL8, sTNFR1, and bicarbonate, we assigned either a hyper- or hypo-inflammatory ARDS immune phenotype. We then constructed a multivariable Cox proportional hazards model controlling for APACHE III, history of BMT, sex, acute vs. chronic leukemia, and site of infection to assess the independent effect of phenotype assignment on mortality. Univariate comparisons between patients assigned to either phenotype were made as appropriate with T or Chi-Square tests. Results: 86 subjects diagnosed with leukemia and ARDS between 2008 and 2017 were identified. In-hospital mortality was 76%. 64 (74.4%) were assigned a hyper-inflammatory phenotype using the 3-marker algorithm. Male sex, higher APACHE III, and non-pulmonary infectious source appeared to be associated with hyper-inflammatory assignment in univariate comparison, while tumor-specific characteristics such as leukemia type and cytogenetic features were not (table 1). Median survival in the hyper-inflammatory group was 6 days vs. 20 in the hypo-inflammatory group (log-rank p = 0.04, figure 1). However in our Cox proportional hazards model ARDS immune phenotype was not significantly associated with mortality (HR 1.63, 95% CI 0.87 - 3.08, p = 0.12). A sub-analysis of patients diagnosed with AML did not reveal any association between European LeukemiaNet cytogenetic risk category and mortality, controlling for the same baseline covariates and immune phenotype. Interpretation: We identified previously described ARDS immune phenotypes among leukemic ARDS patients, though we did not observe an independent association between immune phenotype and mortality when controlling for relevant baseline covariates. At 76%, overall mortality was consistent with prior estimates in oncologic ICU patients and higher than the general population (~40%). A higher proportion of leukemia subjects were assigned to the hyper-inflammatory phenotype (74.4%) than described in non-oncologic trial populations (30-35% in 5 prior ARDS trials). Limitations include small sample size and knowledge that both malignancy and immunosuppression may affect cytokine expression such that phenotypic assignment is unreliable. Future efforts might focus on re-deriving ARDS phenotypes from a larger cohort of patients with hematologic malignancies in order to better understand how tumor interacts with the immunopathology of their critical illness. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

The Social Economic Return of a Positive End-Expiratory Pressure–Based Lung Recruitment Clinical Trial Program in Patients With Acute Respiratory Distress Syndrome

ObjectivesThis study aimed to estimate the socioeconomic return from the value of lives saved by the protocol indicated by the Alveolar Recruitment for Acute Respiratory Distress Syndrome Trial (ART). ART was conducted through a multicenter randomized trial at 120 intensive care units from 9 countries, enrolling adults with moderate to severe acute respiratory distress syndrome. It investigated whether lung recruitment associated with positive end-expiratory pressure titration according to the best respiratory system compliance decreases 28-day mortality of patients compared with a conventional low-positive end-expiratory pressure strategy. MethodsThe value of lives saved was estimated by considering whether the trial findings were implemented in the eligible patient populations for 1 year, and then the social economic return was computed by subtracting the clinical trial costs from the gross benefit. The return was computed by subtracting the ART costs from its gross benefit. ResultsThe ART net benefit is approximately 152 million dollars if it is implemented in 50% of eligible patients in Brazil under the baseline assumptions. For every dollar spent in the clinical trial, a return of 114 dollars was achieved in Brazil alone. If the trial findings are implemented in all eligible patients, then the trial return would be 229.5 dollars for every dollar invested with a net benefit of 304 million dollars. ConclusionsThese findings highlight the substantial economic benefit of clinical trials on acute respiratory distress syndrome treatments for society. It also points out that the public return of clinical trials can be potentialized when the new trial findings are fully implemented on eligible patients.

Brain-Lung Crosstalk: Management of Concomitant Severe Acute Brain Injury and Acute Respiratory Distress Syndrome.

Purpose of ReviewTo summarize pathophysiology, key conflicts, and therapeutic approaches in managing concomitant severe acute brain injury (SABI) and acute respiratory distress syndrome (ARDS).Recent FindingsARDS is common in SABI and independently associated with worse outcomes in all SABI subtypes. Most landmark ARDS trials excluded patients with SABI, and evidence to guide decisions is limited in this population. Potential areas of conflict in the management of patients with both SABI and ARDS are (1) risk of intracranial pressure (ICP) elevation with high levels of positive end-expiratory pressure (PEEP), permissive hypercapnia due to lung protective ventilation (LPV), or prone ventilation; (2) balancing a conservative fluid management strategy with ensuring adequate cerebral perfusion, particularly in patients with symptomatic vasospasm or impaired cerebrovascular blood flow; and (3) uncertainty about the benefit and harm of corticosteroids in this population, with a mortality benefit in ARDS, increased mortality shown in TBI, and conflicting data in other SABI subtypes. Also, the widely adapted partial pressure of oxygen (PaO2) target of > 55 mmHg for ARDS may exacerbate secondary brain injury, and recent guidelines recommend higher goals of 80–120 mmHg in SABI. Distinct pathophysiology and trajectories among different SABI subtypes need to be considered.SummaryThe management of SABI with ARDS is highly complex, and conventional ARDS management strategies may result in increased ICP and decreased cerebral perfusion. A crucial aspect of concurrent management is to recognize the risk of secondary brain injury in the individual patient, monitor with vigilance, and adjust management during critical time windows. The care of these patients requires meticulous attention to oxygenation and ventilation, hemodynamics, temperature management, and the neurological exam. LPV and prone ventilation should be utilized, and supplemented with invasive ICP monitoring if there is concern for cerebral edema and increased ICP. PEEP titration should be deliberate, involving measures of hemodynamic, pulmonary, and brain physiology. Serial volume status assessments should be performed in SABI and ARDS, and fluid management should be individualized based on measures of brain perfusion, the neurological exam, and cardiopulmonary status. More research is needed to define risks and benefits in corticosteroids in this population.

Dichotomous Role of Tumor Necrosis Factor in Pulmonary Barrier Function and Alveolar Fluid Clearance.

Alveolar-capillary leak is a hallmark of the acute respiratory distress syndrome (ARDS), a potentially lethal complication of severe sepsis, trauma and pneumonia, including COVID-19. Apart from barrier dysfunction, ARDS is characterized by hyper-inflammation and impaired alveolar fluid clearance (AFC), which foster the development of pulmonary permeability edema and hamper gas exchange. Tumor Necrosis Factor (TNF) is an evolutionarily conserved pleiotropic cytokine, involved in host immune defense against pathogens and cancer. TNF exists in both membrane-bound and soluble form and its mainly -but not exclusively- pro-inflammatory and cytolytic actions are mediated by partially overlapping TNFR1 and TNFR2 binding sites situated at the interface between neighboring subunits in the homo-trimer. Whereas TNFR1 signaling can mediate hyper-inflammation and impaired barrier function and AFC in the lungs, ligand stimulation of TNFR2 can protect from ventilation-induced lung injury. Spatially distinct from the TNFR binding sites, TNF harbors within its structure a lectin-like domain that rather protects lung function in ARDS. The lectin-like domain of TNF -mimicked by the 17 residue TIP peptide- represents a physiological mediator of alveolar-capillary barrier protection. and increases AFC in both hydrostatic and permeability pulmonary edema animal models. The TIP peptide directly activates the epithelial sodium channel (ENaC) -a key mediator of fluid and blood pressure control- upon binding to its α subunit, which is also a part of the non-selective cation channel (NSC). Activity of the lectin-like domain of TNF is preserved in complexes between TNF and its soluble TNFRs and can be physiologically relevant in pneumonia. Antibody- and soluble TNFR-based therapeutic strategies show considerable success in diseases such as rheumatoid arthritis, psoriasis and inflammatory bowel disease, but their chronic use can increase susceptibility to infection. Since the lectin-like domain of TNF does not interfere with TNF’s anti-bacterial actions, while exerting protective actions in the alveolar-capillary compartments, it is currently evaluated in clinical trials in ARDS and COVID-19. A more comprehensive knowledge of the precise role of the TNFR binding sites versus the lectin-like domain of TNF in lung injury, tissue hypoxia, repair and remodeling may foster the development of novel therapeutics for ARDS.

Identification of acute respiratory distress syndrome subphenotypes de novo using routine clinical data: a retrospective analysis of ARDS clinical trials

ObjectivesThe acute respiratory distress syndrome (ARDS) is a heterogeneous condition, and identification of subphenotypes may help in better risk stratification. Our study objective is to identify ARDS subphenotypes using new...

I, DOCTOR: The role of machine learning in phenotyping ARDS

The diagnosis of Acute Respiratory Distress Syndrome (ARDS) encapsulates remarkable heterogeneity in etiology, presentation, severity, course, and treatment response. Undoubtedly, enrolling patients amalgamated under the loosely defined term of ARDS has contributed to innumerable “negative” clinical trials in ARDS.1 This is likely due to heterogeneity of treatment effect (HTE), or the nonrandom variability in the direction or magnitude of a treatment effect. Understanding and detecting HTE is fundamental to providing personalized, or precision, medicine.