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Principal Investigator: Maurizio Franco Cereda
Organization: MASSACHUSETTS GENERAL HOSPITAL
Fiscal Year: 2024
Award: $827,682
Funding agency: National Heart Lung and Blood Institute
PROJECT SUMMARY
Acute Respiratory distress syndrome (ARDS) is a life-threatening condition caused by widespread pulmonary
inflammation leading to lung injury. ARDS has a mortality that can be higher than 40% and is the main cause of
death from COVID-19. Although necessary to support life, mechanical ventilation worsens ARDS. While
computed tomography (CT) is capable of identifying characteristic abnormal airspace mechanics, the pulmonary
circulation is also altered in ARDS, with profound dysregulation of lung perfusion resulting in regional elevations
of blood flow and volume. Such misdistribution may significantly impact the trajectory of lung injury. In animal
studies, ventilated lungs suffered from stress-failure of the capillary barrier when perfused at higher blood flows
and pressures, resulting in more edema. Regions of the lung with elevated perfusion may therefore be at risk of
worse injury. The pulmonary circulation is significantly understudied in ARDS due to the paucity of accurate and
non-invasive instruments to visualize perfusion in vivo. This proposal addresses the need to elucidate the
fundamental contribution of the pulmonary circulation to ARDS trajectory. We intend to develop a comprehensive
imaging approach to characterize lung perfusion and direct treatment. We will leverage our expertise with two
imaging modalities: a) dynamic contrast enhanced (DCE) and dual energy CT (DECT), which map pulmonary
blood flow and volume with high resolution; b) electrical impedance tomography (EIT), a bedside technique that
allows rapid and frequent assessments of pulmonary perfusion without moving patients to a scanner. We will
use these techniques in animal and human studies to test our hypothesis that protecting the capillary barrier and
manipulating pulmonary perfusion to decrease capillary stress failure attenuates ARDS progression. In a
ventilated swine model of ARDS, we will demonstrate that reducing the heterogeneity of pulmonary perfusion
mitigates lung injury using two treatments that redistribute pulmonary blood flow and volume: selective
vasodilation with inhaled nitric oxide (iNO) and prone ventilation. We will match regional changes in perfusion
and inflation with the subsequent progression of lung injury. We will then show that protecting the pulmonary
capillaries in vulnerable lung regions decreases injury using Imatinib, a drug that preserves endothelial integrity,
in our swine model. Finally, after refining our translational imaging pipeline, we will perform proof-of-principle
studies in human ARDS using DECT and EIT to assess individual patient responses to iNO and prone ventilation,
aiming to integrate such information into clinical decision-making. This proposal will demonstrate that it is
possible to non-invasively assess pulmonary perfusion in order to guide ARDS treatment. Shifting the focus from
airspace mechanics to a more comprehensive management of both lung perfusion and ventilation, the proposed
approach will constitute a groundbreaking advancement in the care of ARDS.
Terms: <ARDS><Acute Respiratory Distress><Acute Respiratory Distress Syndrome><Address><Adult ARDS><Adult RDS><Adult Respiratory Distress Syndrome><Affect><Alveolar><Animals><Attenuated><Blood><Blood Pressure><Blood Reticuloendothelial System><Blood Vessels><Blood Volume><Blood capillaries><Blood flow><Body Tissues><CAT scan><CO2><COVID-19><COVID-19 associated death><COVID-19 associated fatality><COVID-19 associated mortality><COVID-19 death><COVID-19 fatality><COVID-19 induced death><COVID-19 induced fatality><COVID-19 induced mortality><COVID-19 mortality><COVID-19 related death><COVID-19 related fatality><COVID-19 related mortality><COVID19 associated death><COVID19 associated fatality><COVID19 associated mortality><COVID19 death><COVID19 fatality><COVID19 induced death><COVID19 induced fatality><COVID19 induced mortality><COVID19 mortality><COVID19 related death><COVID19 related fatality><COVID19 related mortality><CT X Ray><CT Xray><CT imaging><CT scan><CV-19><Carbon Dioxide><Carbonic Anhydride><Cause of Death><Cessation of life><Characteristics><Clinical><Computed Tomography><Coronavirus Infectious Disease 2019><Cross-Over Studies><Crossover Studies><Da Nang Lung><Data><Death><Dorsal Position><Dropsy><Dysfunction><Edema><Endothelium><Failure><Family suidae><Functional disorder><Gases><Goals><Heterogeneity><Hour><Human><Hydrops><Hypoxemia><Image><Imatinib><Impairment><Inflammation><Inflammatory><Injections><Injury><Isolated Perfusion><Isolation Perfusion><Isolation Perfusion Therapy><Kinetics><Knowledge><Life><Low Dose Radiation><Lung><Lung Inflammation><Lung Parenchyma><Lung Respiratory System><Lung Tissue><Lung damage><Maps><Measures><Mechanical ventilation><Mechanics><Modern Man><O element><O2 element><Outcome><Oxygen><Patients><Perfusion><Pharmacological Treatment><Phenotype><Physiologic><Physiological><Physiopathology><Pigs><Play><Pneumonitis><Prone Position><Publishing><Pulmonary Circulation><Pulmonary Edema><Pulmonary Inflammation><Pulmonary imaging><Regional Perfusion><Research><Resolution><Risk><Role><SARS-CoV-2 associated death><SARS-CoV-2 associated fatality><SARS-CoV-2 associated mortality><SARS-CoV-2 death><SARS-CoV-2 fatality><SARS-CoV-2 induced death><SARS-CoV-2 induced fatality><SARS-CoV-2 induced mortality><SARS-CoV-2 mortality><SARS-CoV-2 related death><SARS-CoV-2 related fatality><SARS-CoV-2 related mortality><Severities><Shock Lung><Stiff lung><Stress><Structure of parenchyma of lung><Suidae><Supine Position><Swine><Techniques><Testing><Time><Tissues><Tomodensitometry><Tracer><Vascular Diseases><Vascular Disorder><Vasodilatation><Vasodilating Agent><Vasodilation><Vasodilator Agents><Vasodilator Drugs><Vasodilators><Vasorelaxation><Visualization><X-Ray CAT Scan><X-Ray Computed Tomography><X-Ray Computerized Tomography><Xray CAT scan><Xray Computed Tomography><Xray computerized tomography><acute care><attenuate><attenuates><blood perfusion><blood vessel disorder><body position><capillary><catscan><clinical decision-making><clinical investigation><computed axial tomography><computer tomography><computerized axial tomography><computerized tomography><contrast CT><contrast enhanced><contrast enhanced CT><contrast enhanced computed tomography><coronavirus disease 2019><coronavirus disease 2019 associated death><coronavirus disease 2019 associated fatality><coronavirus disease 2019 associated mortality><coronavirus disease 2019 death><coronavirus disease 2019 fatality><coronavirus disease 2019 induced death><coronavirus disease 2019 induced fatality><coronavirus disease 2019 induced mortality><coronavirus disease 2019 mortality><coronavirus disease 2019 related death><coronavirus disease 2019 related fatality><coronavirus disease 2019 related mortality><coronavirus disease-19><coronavirus disease-19 mortality><coronavirus infectious disease-19><customized therapy><customized treatment><data integration><death due to COVID-19><death due to COVID19><death due to SARS-CoV-2><death due to coronavirus disease 2019><death due to severe acute respiratory syndrome coronavirus 2><death in COVID><death in COVID-19><death in SARS-CoV-2><death in coronavirus disease><death in coronavirus disease 2019><death in severe acute respiratory syndrome coronavirus 2><drug preservation><electrical impedance tomography><fatality due to COVID-19><fatality due to COVID19><fatality due to SARS-CoV-2><fatality due to coronavirus disease 2019><fatality due to severe acute respiratory syndrome coronavirus 2><high risk><hypoxemic><iNO><image translation><image-based method><imaging><imaging approach><imaging based approach><imaging biomarker><imaging marker><imaging method><imaging modality><imaging-based biological marker><imaging-based biomarker><imaging-based marker><impaired pulmonary vascularization><improved><in vivo><individual patient><individualized management><individualized medicine><individualized patient management><individualized patient treatment><individualized therapeutic strategy><individualized therapy><individualized treatment><inhaled nitric oxide><injured><injuries><instrument><lung artery blood pressure><lung edema><lung imaging><lung injury><lung scanning><lung vascular disease><mechanic><mechanical><mechanical respiratory assist><mechanically ventilated><mortality><mortality due to COVID-19><mortality due to COVID19><mortality due to SARS-CoV-2><mortality due to coronavirus disease 2019><mortality due to severe acute respiratory syndrome coronavirus 2><new approaches><non-contrast CT><noncontrast CT><noncontrast computed tomography><novel approaches><novel strategies><novel strategy><pathophysiology><patient response><patient specific response><patient specific therapies><patient specific treatment><perfusion imaging><personalized clinical management><personalized disease management><personalized management><pharmacologic><pig model><piglet model><porcine><porcine model><precision management><pressure in pulmonary 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