Acute respiratory distress syndrome (ARDS) is a common and often fatal condition for which there is no effective treatment other than supportive care centered on mechanical ventilation. Mechanical ventilation itself, however, can easily cause damage to already injured lung tissues, leading to ventilator-induced lung injury (VILI). The principle goal in managing ARDS is thus to administer mechanical ventilation in a manner that avoids, or at least minimizes, VILI. The standard of care in ARDS involves use of small tidal volumes (Vt), the current ideal being 6 ml/kg ideal body weight, together with positive end-expiration pressure (PEEP) to prevent lung collapse and improve oxygenation. These strategies have led to improved outcomes, but ARDS mortality remains high, so better approaches to mechanically ventilating the injured lung are desperately needed. Unfortunately, continuing to search for one-size-fits-all approaches to mechanical ventilation of the very heterogeneous ARDS patient population is rapidly becoming futile because of the huge number of patients that would be needed to obtain statistically significant improvements over current strategies. For this reason, the search for improved approaches to mechanical ventilation in ARDS must focus on strategies that can be tailored to suit the pathophysiological characteristics of individual patiens. Furthermore, such strategies must be adaptable to the evolving nature and severity of ARDS as it runs its course. These considerations lead us to propose that personalized mechanical ventilation of the ARDS patient must take place within an ongoing feedback loop involving three interdependent processes: 1) assessing the injury status of a given lung, 2) predicting how much VILI will be caused in that lung by a given regimen of mechanical ventilation, and 3) optimizing ventilation to be minimally injurious based on the information provided in steps 1 and 2. This will allow the imposed regimen of mechanical ventilation to be responsive to the ventilatory needs of the patient, while at the same time minimizing the amount of VILI that is produced so that the patient's own reparative processes have the best chances of prevailing. We have undertaken extensive prior studies that show we can assess the current state of injury of the lung most effectively by measuring how its mechanical properties change over time as a result of ongoing recruitment and derecruitment. We have also developed computational models showing how it is, in principle, possible to predict the amount of VILI that will be produced by a given regimen of mechanical ventilation. Our overarching goal in this proposal is to leverage these findings to optimize the personalized design of mechanical ventilation strategies for the injured lung. This goal will be pursued experimentally in mouse models of ARDS and VILI, and computationally by fitting the data obtained to computational models of lung mechanics and VILI development.

Public Health Relevance

Of the 200,000 patients who are diagnosed with acute respiratory distress syndrome (ARDS) each year in the US, about 75,000 will be overwhelmed by their own biological responses. As there are currently no pharmaceutical therapies that have proven efficacious in ARDS, treatment revolves around supportive care centered on mechanical ventilation, but this can lead to ventilator-induced lung injury (VILI) that contributes significanly to ARDS mortality. By identifying personalized strategies for mechanical ventilation that attend to the individual pathophysiological characteristics of a given patient, we will be able to significantly reduce the occurrence of VILI and thus reduce ARDS mortality.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL124052-01
Application #
8766263
Study Section
Special Emphasis Panel (ZRG1-CVRS-G (02))
Program Officer
Harabin, Andrea L
Project Start
2014-08-01
Project End
2018-03-31
Budget Start
2014-08-01
Budget End
2015-03-31
Support Year
1
Fiscal Year
2014
Total Cost
$600,324
Indirect Cost
$138,801
Name
University of Vermont & St Agric College
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
066811191
City
Burlington
State
VT
Country
United States
Zip Code
05405
Wellman, Tyler J; MondoƱedo, Jarred R; Davis, Gerald S et al. (2018) Topographic distribution of idiopathic pulmonary fibrosis: a hybrid physics- and agent-based model. Physiol Meas 39:064007
Hamlington, Katharine L; Bates, Jason H T; Roy, Gregory S et al. (2018) Alveolar leak develops by a rich-get-richer process in ventilator-induced lung injury. PLoS One 13:e0193934
Hamlington, Katharine L; Smith, Bradford J; Dunn, Celia M et al. (2018) Linking lung function to structural damage of alveolar epithelium in ventilator-induced lung injury. Respir Physiol Neurobiol 255:22-29
Mori, Vitor; Smith, Bradford J; Suki, Bela et al. (2018) Linking Physiological Biomarkers of Ventilator-Induced Lung Injury to a Rich-Get-Richer Mechanism of Injury Progression. Ann Biomed Eng :
Jawde, Samer Bou; Smith, Bradford J; Sonnenberg, Adam et al. (2018) Design and nonlinear modeling of a sensitive sensor for the measurement of flow in mice. Physiol Meas 39:075002
Bates, Jason H T; Smith, Bradford J (2018) Ventilator-induced lung injury and lung mechanics. Ann Transl Med 6:378
Broche, Ludovic; Perchiazzi, Gaetano; Porra, Liisa et al. (2017) Dynamic Mechanical Interactions Between Neighboring Airspaces Determine Cyclic Opening and Closure in Injured Lung. Crit Care Med 45:687-694
Smith, Bradford J; Bartolak-Suki, Elizabeth; Suki, Bela et al. (2017) Linking Ventilator Injury-Induced Leak across the Blood-Gas Barrier to Derangements in Murine Lung Function. Front Physiol 8:466
Hamlington, Katharine L; Smith, Bradford J; Allen, Gilman B et al. (2016) Predicting ventilator-induced lung injury using a lung injury cost function. J Appl Physiol (1985) 121:106-14
Hamlington, Katharine L; Ma, Baoshun; Smith, Bradford J et al. (2016) Modeling the Progression of Epithelial Leak Caused by Overdistension. Cell Mol Bioeng 9:151-161

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