There is a strong influence of gravity on the lung. The lung deforms under its own weight, stretching some regions and compressing others, affecting ventilation and blood flow. The deformation is strongly posture dependent because the thorax (the container shape) is not symmetrical. This asymmetry can be envisioned as a wedge, with the lung hanging from the shorter side in supine posture and the longer side in prone. The effects of asymmetry and gravity are additive in supine posture, but oppose one another in prone. Goal/Significance Early adoption of prone ventilation in severe Acute Respiratory Distress Syndrome (ARDS) markedly improves survival. This is especially true if arterial partial pressure of CO2 and dead space are decreased by prone posture, implying that this intervention recruits blood flow to match regions of well-ventilated lung. Our goal is to understand the mechanisms by which lung deformation and thoracic shape interact to affect pulmonary blood flow and gas exchange. Since prone ventilation greatly complicates patient care, understanding posture effects on blood flow distribution is critically important. This information will be to develop patient-specific metrics to identify which ARDS patients might benefit most from prone ventilation. This work may have other implications for patient management including fluid balance and inotropic therapy. Innovation Can the effects of prone posture on pulmonary blood flow and gas exchange be predicted from regional lung density distribution measured supine? To answer this question we have developed a suite of functional magnetic resonance imaging techniques that allow regional quantification of lung proton density, alveolar ventilation, and perfusion. This allows the evaluation of how container shape and lung deformation alter ventilation-perfusion (VA/Q) matching and regional dead space under clinically relevant conditions. We propose to combine our sophisticated imaging techniques with person-specific modeling of tissue deformation in collaboration with Dr. Merryn Tawhai (University of Auckland) to calculate regional tissue deformation and trans-pulmonary pressure gradients and evaluate the effect on local blood flow and VA/Qmatching. Approach we will test the hypothesis that regions of highly stretched (high local trans-pulmonary pressure) lung corresponding to regions of high V /Q ratio in supine posture will be reduced in prone posture. A resulting in more uniform V /Q matching. In normal subjects we will use data acquired in supine posture A combined with person-specific modeling to predict the effects on blood flow and VA/Q matching in prone posture, and test our predictions against measurements made in prone posture. This information will be used to develop biomarkers for optimal blood flow based on density distribution and thoracic shape (and thus measureable with routine clinical CT) that predict improvement with prone posture. This will be tested in collaboration with Dr. Harm Bogaard (VU Univ. Amsterdam) in a retrospective study of patients with ARDS who have undergone prone ventilation.

Public Health Relevance

Our goal is to understand how lung deformation under the weight of gravity and chest shape, interact to affect pulmonary blood flow and gas exchange. We will combine our sophisticated magnetic resonance imaging techniques with patient-specific modeling of tissue deformation to develop biomarkers for the distribution of blood flow based on lung density distribution and thoracic shape measures in supine posture. We will this information to predict effects on pulmonary blood flow and gas exchange in prone posture and develop patient specific metrics to guide the decision for prone ventilation in patients, particularly thos suffering from Acute Respiratory Distress Syndrome

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL119201-02
Application #
9236214
Study Section
Special Emphasis Panel (ZRG1-DTCS-A (81)S)
Program Officer
Reineck, Lora A
Project Start
2016-04-01
Project End
2020-03-31
Budget Start
2017-04-01
Budget End
2018-03-31
Support Year
2
Fiscal Year
2017
Total Cost
$618,746
Indirect Cost
$190,306
Name
University of California San Diego
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Grandner, Michael A; Malhotra, Atul (2017) Connecting insomnia, sleep apnoea and depression. Respirology 22:1249-1250
Sands, Scott A; Mebrate, Yoseph; Edwards, Bradley A et al. (2017) Resonance as the Mechanism of Daytime Periodic Breathing in Patients with Heart Failure. Am J Respir Crit Care Med 195:237-246
Landry, Shane A; Joosten, Simon A; Sands, Scott A et al. (2017) Response to a combination of oxygen and a hypnotic as treatment for obstructive sleep apnoea is predicted by a patient's therapeutic CPAP requirement. Respirology 22:1219-1224
Orr, Jeremy E; Malhotra, Atul; Sands, Scott A (2017) Pathogenesis of central and complex sleep apnoea. Respirology 22:43-52
Rukhadze, Irma; Carballo, Nancy J; Bandaru, Sathyajit S et al. (2017) Catecholaminergic A1/C1 neurons contribute to the maintenance of upper airway muscle tone but may not participate in NREM sleep-related depression of these muscles. Respir Physiol Neurobiol 244:41-50
Strollo Jr, Patrick J; Malhotra, Atul (2016) Stimulating therapy for obstructive sleep apnoea. Thorax 71:879-80
Lam, Michael T Y; Grandner, Michael A; Malhotra, Atul (2016) Lungs can tell time-a highlight from 2016 ATS session on clock genes, inflammation, immunology, and sleep. J Thorac Dis 8:S579-81
Mbanze, Irina; Moschovis, Peter P; Malhotra, Atul (2016) The American Thoracic Society Global Scholars Program. J Thorac Dis 8:S586-7
Malhotra, Atul; Liang, Ni-Cheng (2016) Introduction: American Thoracic Society International Meeting 2016. J Thorac Dis 8:S528-9
Hepokoski, Mark; Owens, Robert L; Malhotra, Atul et al. (2016) Mechanical ventilation in acute respiratory distress syndrome at ATS 2016: the search for a patient-specific strategy. J Thorac Dis 8:S550-2

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