The incidence of acute lung injury (ALI) has been recently estimated at 86.2 per 100,000 person-years and its mortality rate at 38.5%. These figures imply that 74,500 persons die from ALI each year in the United States, a figure comparable to the deaths from breast cancer or HIV, and that 2.2 million Intensive Care Unit days and 3.6 million hospital days are devoted to the care of patients with ALI. Ventilator-induced lung injury (VILI) has been identified as a contributor to the morbidity and mortality from ALI. Although not yet conclusive, data from clinical trials suggest that prone positioning may improve survival in ALI. A possible reason for this improvement is reduction of VILI. Neutrophils have been shown to play a crucial role in the pathogenesis of VILI and we recently demonstrated that neutrophil metabolic activation occurs early during VILI. The broad, long-term objective of this research is to improve the understanding of mechanisms of VILI and to develop means to prevent or reduce it. To this end, the present grant proposal examines the overarching hypothesis that, by promoting uniform parenchymal aeration and tidal volume distribution throughout the lung, prone positioning leads to a reduction of neutrophil metabolic activation caused by large localized tidal expansion. This hypothesis will be examined in a large animal with physiology similar to the human (i.e., sheep), in three specific aims.
Specific aim 1 examines the effectiveness of the prone position as a means to delay the onset and decrease the severity and topographical heterogeneity of VILI-induced neutrophil activation in initially uninjured lungs ventilated with large tidal volume.
In specific aim 2, a well-characterized experimental model of ALI in which saline lung lavage leads to surfactant depletion and markedly heterogeneous loss of aeration is used to investigate whether the prone position leads to decreased neutrophil activation in dorsal lung regions, which are expected to regain aeration and more uniform tidal expansion as a result of the body position change.
In specific aim 3, a graded increase in tidal volume is used to test the hypothesis that the prone position allows for higher tidal volumes than the supine position without augmenting neutrophil activation in a pre-injured lung. Positron Emission and Computed Tomography imaging and advanced tracer kinetic modeling will be employed to measure regional metabolic activity of neutrophils, pulmonary perfusion and aeration in vivo. It is expected that application of this integrated anatomic, physiologic and molecular imaging approach to the tightly knit specific aims will provide novel insights into the mechanism by which prone positioning may attenuate VILI. The direct clinical applicability of the methodological approach, the similarities in pulmonary physiology between sheep and humans and the use of a well-characterized model of ALI greatly enhance the translational aspect of this project. Consequently, the proposed studies will likely contribute to establishing if a strong rationale exists for the use of prone positioning in the ventilatory management of critically ill patients with ALI, and can be viewed as conducive to subsequent studies in patients.

Public Health Relevance

Acute lung injury (ALI) has been estimated to account for 74,500 deaths and 3.6 million hospital days per year in the United States. Because ventilator-induced lung injury (VILI) contributes to the morbidity and mortality from ALI, interventions that reduce VILI could improve the prognosis of patients with ALI. In this research, we will test whether promoting uniform lung inflation and tidal expansion by prone positioning reduces neutrophil metabolic activation, an early and important event in the pathogenesis of VILI.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL094639-04
Application #
8514046
Study Section
Respiratory Integrative Biology and Translational Research Study Section (RIBT)
Program Officer
Harabin, Andrea L
Project Start
2010-09-01
Project End
2015-07-31
Budget Start
2013-09-01
Budget End
2014-07-31
Support Year
4
Fiscal Year
2013
Total Cost
$416,668
Indirect Cost
$181,048
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
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de Prost, Nicolas; Feng, Yan; Wellman, Tyler et al. (2014) 18F-FDG kinetics parameters depend on the mechanism of injury in early experimental acute respiratory distress syndrome. J Nucl Med 55:1871-7
Musch, Guido; Winkler, Tilo; Harris, R Scott et al. (2014) Lung [(18)F]fluorodeoxyglucose uptake and ventilation-perfusion mismatch in the early stage of experimental acute smoke inhalation. Anesthesiology 120:683-93
Tucci, Mauro R; Costa, Eduardo L V; Wellman, Tyler J et al. (2013) Regional lung derecruitment and inflammation during 16 hours of mechanical ventilation in supine healthy sheep. Anesthesiology 119:156-65
Bellani, Giacomo; Guerra, Luca; Musch, Guido et al. (2011) Lung regional metabolic activity and gas volume changes induced by tidal ventilation in patients with acute lung injury. Am J Respir Crit Care Med 183:1193-9
Musch, Guido (2011) Positron emission tomography: a tool for better understanding of ventilator-induced and acute lung injury. Curr Opin Crit Care 17:7-12