Lung endothelial cells regulate pulmonary fibrosis through FOXF1/R-Ras signaling.

Pulmonary fibrosis results from dysregulated lung repair and involves multiple cell types. The role of endothelial cells (EC) in lung fibrosis is poorly understood. Using single cell RNA-sequencing we identified endothelial transcription factors involved in lung fibrogenesis, including FOXF1, SMAD6, ETV6 and LEF1. Focusing on FOXF1, we found that FOXF1 is decreased in EC within human idiopathic pulmonary fibrosis (IPF) and mouse bleomycin-injured lungs. Endothelial-specific Foxf1 inhibition in mice increased collagen depositions, promoted lung inflammation, and impaired R-Ras signaling. In vitro, FOXF1-deficient EC increased proliferation, invasion and activation of human lung fibroblasts, and stimulated macrophage migration by secreting IL-6, TNFα, CCL2 and CXCL1. FOXF1 inhibited TNFα and CCL2 through direct transcriptional activation of Rras gene promoter. Transgenic overexpression or endothelial-specific nanoparticle delivery of Foxf1 cDNA decreased pulmonary fibrosis in bleomycin-injured mice. Nanoparticle delivery of FOXF1 cDNA can be considered for future therapies in IPF.

Extracorporeal membrane oxygenation circuits in parallel for refractory hypoxemia in patients with COVID-19.

OBJECTIVES: Refractory hypoxemia can occur in patients with acute respiratory distress syndrome from COVID-19 despite support with venovenous (VV) extracorporeal membrane oxygenation (ECMO). Parallel ECMO circuits can be used to increase physiologic support. We report our clinical experience using ECMO circuits in parallel for select patients with persistent severe hypoxemia despite the use of a single ECMO circuit. METHODS: We performed a retrospective cohort study of all patients with COVID-19-related acute respiratory distress syndrome who received VV-ECMO with an additional circuit in parallel at Vanderbilt University Medical Center between March 1, 2020, and March 1, 2022. We report demographic characteristics and clinical characteristics including ECMO settings, mechanical ventilator settings, use of adjunctive therapies, and arterial blood gas results after initial cannulation, before and after receipt of a second ECMO circuit in parallel, and before removal of the circuit in parallel, and outcomes. RESULTS: Of 84 patients with COVID-19 who received VV-ECMO during the study period, 22 patients (26.2%) received a circuit in parallel. The median duration of ECMO was 40.0 days (interquartile range, 31.6-53.1 days), of which 19.0 days (interquartile range, 13.0-33.0 days) were spent with a circuit in parallel. Of the 22 patients who received a circuit in parallel, 16 (72.7%) survived to hospital discharge and 6 (27.3%) died before discharge. CONCLUSIONS: In select patients, the additional use of an ECMO circuit in parallel can increase ECMO blood flow and improve oxygenation while allowing for lung-protective mechanical ventilation and excellent outcomes.

Pathological remodeling of distal lung matrix in end-stage cystic fibrosis patients.

BACKGROUND: Manifestations of cystic fibrosis, although well-characterized in the proximal airways, are understudied in the distal lung. Characterization of the cystic fibrosis lung 'matrisome' (matrix proteome) has not been previously described, and could help identify biomarkers and inform therapeutic strategies. METHODS: We performed liquid chromatography-mass spectrometry, gene ontology analysis, and multi-modal imaging, including histology, immunofluorescence, and electron microscopy for a comprehensive evaluation of distal human lung extracellular matrix (matrix) structure and composition in end-stage cystic fibrosis. RESULTS: Quantitative proteomic profiling identified sixty-eight (68) matrix constituents with significantly altered expression in end-stage cystic fibrosis. Over 90% of significantly different matrix peptides detected, including structural and basement membrane proteins, were expressed at lower levels in cystic fibrosis. However, the total abundance of matrix in cystic fibrosis lungs was not significantly different from control lungs, suggesting that cystic fibrosis leads to loss of diversity among lung matrix proteins rather than an absolute loss of matrix. Visualization of distal lung matrix via immunofluorescence and electron microscopy revealed pathological remodeling of distal lung tissue architecture and loss of alveolar basement membrane, consistent with significantly altered pathways identified by gene ontology analysis. CONCLUSIONS: Dysregulation of matrix organization and aberrant wound healing pathways are associated with loss of matrix protein diversity and obliteration of distal lung tissue structure in end-stage cystic fibrosis. While many therapeutics aim to functionally restore defective cystic fibrosis transmembrane conductance regulator (CFTR), drugs that target dysregulated matrix pathways may serve as adjunct interventions to support lung recovery.

Rapid Training in Extracorporeal Membrane Oxygenation for a Large Health System.

Background: Despite the rapid integration of extracorporeal membrane oxygenation (ECMO) into intensive care units over the past decade, established programs for training critical care clinicians to provide ECMO are lacking.Objective: To evaluate the development and implementation of a multidisciplinary ECMO training program for the rapid deployment of ECMO training for a high volume of critical care clinicians.Methods: We performed a prospective cohort study examining a program for rapid training of multiple disciplines of critical care clinicians to deliver ECMO during the implementation of ECMO services across the intensive care units of an academic tertiary care center between October 2018 and January 2019. The multidisciplinary ECMO training program included didactic and simulation-based teaching and emphasized new, universal clinical protocols to improve consistency of care across the institution. Pre- and post-program written examinations evaluated knowledge acquisition, and an electronically distributed program evaluation assessed perceptions of content and delivery.Results: Among the 97 clinicians who completed the program, 49 (51%) were physicians and 48 (49%) were advanced practice providers from the departments of surgery (n = 42), medicine (n = 29), and anesthesia (n = 26). There was a significant difference in knowledge about ECMO between the pre- and post-program examination score (median [interquartile range] 70% [60-80%] vs. 90% [80-90%], respectively, P < 0.001). The median (interquartile range) individual gain from pre- to post-program score was 20% (10-30%). The program was perceived as useful and applicable to safe care.Conclusion: Rapid deployment of a multidisciplinary ECMO training program across a large academic center was feasible, achieved knowledge acquisition, and was positively perceived.

Multiday maintenance of extracorporeal lungs using cross-circulation with conscious swine.

OBJECTIVES: Lung remains the least-utilized solid organ for transplantation. Efforts to recover donor lungs with reversible injuries using ex vivo perfusion systems are limited to <24 hours of support. Here, we demonstrate the feasibility of extending normothermic extracorporeal lung support to 4 days using cross-circulation with conscious swine. METHODS: A swine behavioral training program and custom enclosure were developed to enable multiday cross-circulation between extracorporeal lungs and recipient swine. Lungs were ventilated and perfused in a normothermic chamber for 4 days. Longitudinal analyses of extracorporeal lungs (ie, functional assessments, multiscale imaging, cytokine quantification, and cellular assays) and recipient swine (eg, vital signs and blood and tissue analyses) were performed. RESULTS: Throughout 4 days of normothermic support, extracorporeal lung function was maintained (arterial oxygen tension/inspired oxygen fraction >400 mm Hg; compliance >20 mL/cm H2O), and recipient swine were hemodynamically stable (lactate <3 mmol/L; pH, 7.42 ± 0.05). Radiography revealed well-aerated lower lobes and consolidation in upper lobes of extracorporeal lungs, and bronchoscopy showed healthy airways without edema or secretions. In bronchoalveolar lavage fluid, granulocyte-macrophage colony-stimulating factor, interleukin (IL) 4, IL-6, and IL-10 levels increased less than 6-fold, whereas interferon gamma, IL-1α, IL-1ß, IL-1ra, IL-2, IL-8, IL-12, IL-18, and tumor necrosis factor alpha levels decreased from baseline to day 4. Histologic evaluations confirmed an intact blood-gas barrier and outstanding preservation of airway and alveolar architecture. Cellular viability and metabolism in extracorporeal lungs were confirmed after 4 days. CONCLUSIONS: We demonstrate feasibility of normothermic maintenance of extracorporeal lungs for 4 days by cross-circulation with conscious swine. Cross-circulation approaches could support the recovery of damaged lungs and enable organ bioengineering to improve transplant outcomes.

A Dual-Lumen Bicaval Cannula for Venovenous Extracorporeal Membrane Oxygenation.

BACKGROUND: Single-site, dual-lumen venovenous extracorporeal membrane oxygenation ECMO) facilitates mobilization, reduces recirculation, and mitigates insertion and infectious risks of an additional access site. This study reports the experience with a bicaval dual-lumen cannula that comprises a robust physical design allowing for easy and safe cannulation, precise positioning and monitoring, and appropriate physiologic support for patients with acute respiratory failure. METHODS: Statistical analysis was performed from data gathered retrospectively from the electronic medical records of 20 adult patients who were cannulated for ECMO with this bicaval dual-lumen cannula from August 2018 through May 2019. RESULTS: Gas exchange and blood flow were optimized in all patients after cannulation (median pH, 7.42 [interquartile range {IQR}, 7.39, 7.44], ratio of arterial partial pressure of oxygen to fraction of inspired oxygen, 186.5 [Pao2:Fio2, 116.5, 247.0]; pump flow, 3.9 L/min [IQR, 3.1, 4.3]). Eleven patients (55%) were able to be freed from mechanical ventilation after cannulation, 9 (45%) patients underwent a tracheostomy procedure while undergoing ECMO, and no patients required reintubation. No morbidity or mortality was related to the cannulation strategy or the catheter. Two patients required cannula repositioning. Survival to decannulation was 90%, and survival to hospital discharge was 80%. CONCLUSIONS: The bicaval dual-lumen cannula maintains the advantages of upper body single-site configuration to provide the adjunctive respiratory support necessary to facilitate awakening and rehabilitation while minimizing the use of invasive mechanical ventilation. This cannula introduces design qualities that may offer advantages for acute respiratory failure requiring venovenous ECMO.

Outcomes of Extracorporeal Membrane Oxygenation as a Bridge to Lung Transplantation.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) as a bridge to lung transplantation (BTT) has become a critical component of caring for patients with end-stage lung disease. This study examined outcomes of patients who received ECMO as a BTT. METHODS: Statistical analysis was performed on data gathered retrospectively from the electronic medical records of adult patients who received ECMO as BTT at Columbia University Medical Center from April 2009 through July 2018. RESULTS: A total of 121 adult patients were placed on ECMO as BTT, and 70 patients (59%) were successfully bridged to lung transplantation. Simplified Acute Physiology Score II, unplanned endotracheal intubation, renal replacement therapy, and cerebrovascular accident were identified as independent predictors of unsuccessful BTT. Ambulation was the only independent predictor of successful BTT (odds ratio, 7.579; 95% confidence interval, 2.158 to 26.615; p = 0.002). Among the 64 patients (91%) who survived to hospital discharge, survival was 88% at 1 year and 83% at 3 years. Propensity matching between BTT and non-BTT lung transplant recipients did not show a significant difference in survival (log-rank = 0.53) despite significant differences in the lung allocation score (median, 92.2 [interquartile range, 89.0 to 94.2] vs 49.6 [interquartile range, 40.6 to 72.3], p < 0.01). CONCLUSIONS: ECMO can be used successfully to bridge patients with end-stage lung disease to lung transplantation. When implemented by an experienced team with adherence to stringent protocols and patient selection, outcomes in BTT patients were comparable to patients who did not receive pretransplant support.

A decade of interfacility extracorporeal membrane oxygenation transport.

OBJECTIVE: Extracorporeal membrane oxygenation (ECMO) is used to provide support for patients with cardiopulmonary failure. Best available medical management often fails in these patients and referring hospitals have no further recourse for escalating care apart from transfer to a tertiary facility. In severely unstable patients, the only option might be to use ECMO to facilitate safe transport. This study aimed to examine the characteristics and outcomes of patients transported while receiving ECMO. METHODS: Statistical analysis was performed on data gathered retrospectively from the electronic medical records of adult patients transported while receiving ECMO to Columbia University Medical Center between January 1, 2008, and December 31, 2017. RESULTS: Two hundred sixty five adult patients were safely transported while receiving ECMO with no transport-related complications that adversely affected outcomes. Transport distance ranged from 0.2 to 7084 miles with a median distance of 16.9 miles. One hundred eighty-three (69%) received on veno-venous, 72 (27%) veno-arterial, and 10 (3.8%) veno-venous arterial or veno-arterial venous configurations. Two hundred ten (79%) cannulations were performed at our institution at the referring hospital. Sixty-four percent of patients transported while receiving ECMO survived to hospital discharge. CONCLUSIONS: Interfacility transport during ECMO was shown to be safe and effective with minimal complications and favorable outcomes when performed at an experienced referral center using stringently applied protocols.