Research Priorities for Noninvasive Sampling of the Lower Respiratory Tract during Acute Respiratory Failure: An Official American Thoracic Society Workshop Report.

Research using lower respiratory tract (LRT) sampling may lead to improved understanding and management of patients with acute respiratory failure (ARF). Research bronchoscopy is a valuable tool for sampling the LRT during ARF. However, bronchoscopy may be limited by challenges with repeated sampling, the inability to sample the most severely ill patients, and increased resource utilization.

Treatment with Allogenic Mesenchymal Stromal Cells for Moderate to Severe Acute Respiratory Distress Syndrome: A Double-Blind, Placebo-controlled, Multi-Center, Phase 2b Clinical Trial (STAT).

Background: Prior clinical trials established the safety, but not the efficacy of bone marrow-derived mesenchymal stromal cells (MSCs) in the acute respiratory distress syndrome (ARDS).

Methods: We conducted a prospective, double-blind, multi-center randomized phase 2b clinical trial of one dose of intravenous MSCs (10 x 10/kg predicted body weight) versus placebo in 120 ventilated patients with ARDS (PaO/FiO < 250 mmHg). The primary endpoint was change in oxygenation index (OI) over 36 hours from baseline.

Advanced Age in Mice Exacerbates Sepsis-Induced Inflammation, Vascular Permeability, and Multi-Organ Dysfunction.

Sepsis is a life-threatening syndrome marked by a dysregulated immune response to an infection and significant endothelial vascular permeability, often leading to multi-organ failure. Elderly patients are particularly vulnerable to sepsis, with higher morbidity and mortality rates. We hypothesized that advanced age exacerbates sepsis-induced inflammation and endothelial vascular permeability, resulting in a delayed recovery, persistent inflammation, and sustained organ injury.

Advanced Age in Mice Exacerbates Sepsis-Induced Inflammation, Vascular Permeability, and Multi-Organ Dysfunction.

Sepsis is a life-threatening syndrome marked by a dysregulated immune response to an infection and significant endothelial vascular permeability, often leading to multi-organ failure. Elderly patients are particularly vulnerable to sepsis, with higher morbidity and mortality rates. We hypothesized that advanced age exacerbates sepsis-induced inflammation and endothelial vascular permeability, resulting in a delayed recovery, persistent inflammation, and sustained organ injury.

Oxidized Cell-Free Hemoglobin Induces Mitochondrial Dysfunction by Activation of the Mitochondrial Permeability Transition Pore in the Pulmonary Microvasculature.

Objective: Cell-free hemoglobin (CFH) is released into the circulation during sepsis where it can redox cycle from the ferrous 2+ to ferric 3+ and disrupt endothelial function, but the mechanisms of CF-mediated endothelial dysfunction are unknown. We hypothesized that oxidized CFH induces mitochondrial dysfunction via the mitochondrial permeability transition pore (mPTP) in pulmonary endothelial cells, leading to the release of mitochondrial DNA (mtDNA).

Methods: Human lung microvascular endothelial cells were treated with CFH2+/CFH3+.

Matrix metalloproteinase-7 is dispensable in a mouse model of sepsis-induced acute lung injury.

Acute respiratory distress syndrome (ARDS) is a life-threatening form of acute lung injury whose pathogenesis is characterized by excessive lung inflammation and alveolar-capillary barrier permeability. Matrix metalloproteinase 7 (MMP7) can regulate leukocyte recruitment and the production of pro-inflammatory cytokines, but whether it plays a role in acute lung injury (ALI) is an unanswered question. We hypothesized that global loss of MMP7 would attenuate sepsis-induced ALI and systemic inflammation.

Oxygen targets in critically ill patients: from pathophysiology to population enrichment strategies.

Oxygen supplementation is widely used to enhance oxygen delivery and to treat or prevent hypoxia; however, it requires careful management to avoid the harmful effects of excessive oxygen exposure. Both hyperoxia (inspiratory oxygen fraction exceeding 0.21) and hyperoxemia (arterial oxygen tension oxygen partial pressure [PaO2] > 100 mmHg) can contribute to lung injury, promote systemic vasoconstriction, and increase the production of reactive oxygen species, which can impair macromolecular and cellular functions.

Oxidation of low-density lipoprotein by hemoglobin causes pulmonary microvascular endothelial barrier dysfunction through lectin-like oxidized LDL receptor 1.

Elevated circulating cell-free hemoglobin (Hb) is a pathological driver of endothelial injury and contributes to disease severity and organ dysfunction during several pathologies, including sickle cell disease, pulmonary hypertension, primary graft dysfunction after lung transplantation, and sepsis. However, the signaling mechanisms involved in Hb-mediated pulmonary microvascular endothelial barrier dysfunction are not well understood. One mechanism by which Hb may contribute to microvascular endothelial barrier dysfunction is through its ability to oxidize circulating lipids and lipoproteins, including low-density lipoproteins (LDLs).

A randomized trial of open lung protective ventilation compared to conventional mechanical ventilation in deceased organ donors.

Background: We conducted a randomized trial of open lung protective ventilation (OLPV) compared to conventional ventilation (CV) in deceased donors. The primary outcome was lung utilization for transplantation.

Methods: Eligible donors were ≥13 years with PaO/FiO between 150 and 400 mmHg.

Acetaminophen and Clinical Outcomes in Sepsis: A Retrospective Propensity Score Analysis of the Ibuprofen in Sepsis Study.

Background: The Ibuprofen in Sepsis Study (ISS) randomized trial found no difference in duration of shock, ARDS, or mortality with ibuprofen treatment for sepsis. However, higher use of acetaminophen, a known hemoprotein reductant with potentially beneficial effects in sepsis, as an antipyretic in the control arm may have masked the clinical benefits from either drug.

Research Question: Does an association exist between administration of acetaminophen and clinical outcomes in adults with sepsis?

Study Design And Methods: We performed a retrospective propensity-matched analysis of the previously reported ISS trial.

Metabolic Adaptations Rewire CD4 T Cells in a Subset-Specific Manner in Human Critical Illness with and without Sepsis.

Host immunity in sepsis has features of hyperinflammation together with progressive immunosuppression, particularly among CD4 T cells, that can predispose to secondary infections and ineffectual organ recovery. Metabolic and immunologic dysfunction are archetypal findings in critically ill patients with sepsis, but whether these factors are mechanistically linked remains incompletely defined. We characterized functional metabolic properties of human CD4 T cells from critically ill patients with and without sepsis and healthy adults.

Spatial transcriptomics identifies molecular niche dysregulation associated with distal lung remodeling in pulmonary fibrosis.

Large-scale changes in the structure and cellular makeup of the distal lung are a hallmark of pulmonary fibrosis (PF), but the spatial contexts that contribute to disease pathogenesis have remained uncertain. Using image-based spatial transcriptomics, we analyzed the gene expression of 1.6 million cells from 35 unique lungs.

Biomarkers of Acute Respiratory Distress Syndrome: Current State and Future Prospects.

Biomarkers are an important tool aiding researchers in the study of acute respiratory distress syndrome (ARDS). Mechanisms involving injury to the alveolar-capillary membrane, endothelium and epithelium resulting in lung inflammation and alterations in coagulation pathways have been validated in human trials and have been used to discover promising phenotypes that share similar characteristics and differential treatment responses. The emergence of powerful point-of-care technologies will enable the prospective study of biomarkers for future enrichment trials with the goal of transforming biomarkers into the clinical realm to inform delivery of personalized medicine at the bedside.

Electronic health record biobank cohort recapitulates an association between the promoter polymorphism and ARDS in critically ill adults.

Background: Large population-based DNA biobanks linked to electronic health records (EHRs) may provide novel opportunities to identify genetic drivers of ARDS.

Research Question: Can we develop an EHR-based algorithm to identify ARDS in a biobank database, and can this validate a previously reported ARDS genetic risk factor?

Study Design And Methods: We analyzed two parallel genotyped cohorts: a prospective biomarker cohort of critically ill adults (VALID), and a retrospective cohort of hospitalized participants enrolled in a de-identified EHR biobank (BioVU). ARDS was identified by clinician-investigator review in VALID and an EHR algorithm in BioVU (EHR-ARDS).

Signs of Hemolysis Predict Mortality and Ventilator Associated Pneumonia in Severe Acute Respiratory Distress Syndrome Patients Undergoing Veno-Venous Extracorporeal Membrane Oxygenation.

Cell-free hemoglobin (CFH) is used to detect hemolysis and was recently suggested to trigger acute lung injury. However, its role has not been elucidated in severe acute respiratory distress syndrome (ARDS) patients undergoing extracorporeal membrane oxygenation (ECMO). We investigated the association of carboxyhemoglobin (COHb) and haptoglobin-two indirect markers of hemolysis-with mortality in critically ill patients undergoing veno-venous ECMO (VV-ECMO) with adjusted and longitudinal models (primary aim).

Long-term air pollution exposure and the risk of primary graft dysfunction after lung transplantation.

Background: Primary graft dysfunction (PGD) contributes substantially to both short- and long-term mortality after lung transplantation, but the mechanisms that lead to PGD are not well understood. Exposure to ambient air pollutants is associated with adverse events during waitlisting for lung transplantation and chronic lung allograft dysfunction, but its association with PGD has not been studied. We hypothesized that long-term exposure of the lung donor and recipient to high levels of ambient air pollutants would increase the risk of PGD in lung transplant recipients.

Pulmonary osteoclast-like cells in silica induced pulmonary fibrosis.

The pathophysiology of silicosis is poorly understood, limiting development of therapies for those who have been exposed to the respirable particle. We explored mechanisms of silica-induced pulmonary fibrosis in human lung samples collected from patients with occupational exposure to silica and in a longitudinal mouse model of silicosis using multiple modalities including whole-lung single-cell RNA sequencing and histological, biochemical, and physiologic assessments. In addition to pulmonary inflammation and fibrosis, intratracheal silica challenge induced osteoclast-like differentiation of alveolar macrophages and recruited monocytes, driven by induction of the osteoclastogenic cytokine, receptor activator of nuclear factor κΒ ligand (RANKL) in pulmonary lymphocytes, and alveolar type II cells.

Acetaminophen for Prevention and Treatment of Organ Dysfunction in Critically Ill Patients With Sepsis: The ASTER Randomized Clinical Trial.

Importance: Acetaminophen (paracetamol) has many pharmacological effects that might be beneficial in sepsis, including inhibition of cell-free hemoglobin-induced oxidation of lipids and other substrates.

Objective: To determine whether acetaminophen increases days alive and free of organ dysfunction in sepsis compared with placebo.

Design, Setting, And Participants: Phase 2b randomized, double-blind, clinical trial conducted from October 2021 to April 2023 with 90-day follow-up.

Causes and attributable fraction of death from ARDS in inflammatory phenotypes of sepsis.

Background: Hypoinflammatory and hyperinflammatory phenotypes have been identified in both Acute Respiratory Distress Syndrome (ARDS) and sepsis. Attributable mortality of ARDS in each phenotype of sepsis is yet to be determined. We aimed to estimate the population attributable fraction of death from ARDS (PAF) in hypoinflammatory and hyperinflammatory sepsis, and to determine the primary cause of death within each phenotype.

Systemic inflammation and delirium during critical illness.

Purpose: The purpose of this study was to determine associations between markers of inflammation and endogenous anticoagulant activity with delirium and coma during critical illness.

Methods: In this prospective cohort study, we enrolled adults with respiratory failure and/or shock treated in medical or surgical intensive care units (ICUs) at 5 centers. Twice per day in the ICU, and daily thereafter, we assessed mental status using the Richmond Agitation Sedation Scale (RASS) and the Confusion Assessment Method-Intensive Care Unit (CAM-ICU).