Effect of Prone Position on Ventilator-Induced Lung Injury

Summary

Principal Investigator: Guido Musch
Abstract: DESCRIPTION (provided by applicant): 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.
Funding Period: 2010-09-01 - 2015-07-31
more information: NIH RePORT

Top Publications

  1. pmc Positron emission tomography: a tool for better understanding of ventilator-induced and acute lung injury
    Guido Musch
    Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
    Curr Opin Crit Care 17:7-12. 2011
  2. pmc Lung regional metabolic activity and gas volume changes induced by tidal ventilation in patients with acute lung injury
    Giacomo Bellani
    Department of Experimental Medicine DIMS, University of Milan Bicocca, Via Cadore 48, 20052 Monza MB Italy
    Am J Respir Crit Care Med 183:1193-9. 2011
  3. pmc Effects of surfactant depletion on regional pulmonary metabolic activity during mechanical ventilation
    Nicolas de Prost
    Dept of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, MA 02114, USA
    J Appl Physiol (1985) 111:1249-58. 2011
  4. pmc Effect of regional lung inflation on ventilation heterogeneity at different length scales during mechanical ventilation of normal sheep lungs
    Tyler J Wellman
    Department of Biomedical Engineering, Boston University, Boston, MA 02114, USA
    J Appl Physiol (1985) 113:947-57. 2012
  5. pmc Pulmonary pathophysiology and lung mechanics in anesthesiology: a case-based overview
    Marcos F Vidal Melo
    Department of Anaesthesia, Harvard Medical School, Boston, MA 02215, USA
    Anesthesiol Clin 30:759-84. 2012
  6. pmc Regional lung derecruitment and inflammation during 16 hours of mechanical ventilation in supine healthy sheep
    Mauro R Tucci
    Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA
    Anesthesiology 119:156-65. 2013
  7. pmc Lung [(18)F]fluorodeoxyglucose uptake and ventilation-perfusion mismatch in the early stage of experimental acute smoke inhalation
    Guido Musch
    From the Department of Anesthesia, Critical Care, and Pain Medicine G M, T W, M F V M, T J W, N D P, J G V, Department of Medicine, Pulmonary and Critical Care Unit R S H, and Department of Pathology R L K, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
    Anesthesiology 120:683-93. 2014
  8. pmc Effect of local tidal lung strain on inflammation in normal and lipopolysaccharide-exposed sheep*
    Tyler J Wellman
    1Department of Biomedical Engineering, Boston University, Boston, MA 2Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 3Pulmonary and Critical Care Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA 4Biostatistics Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA
    Crit Care Med 42:e491-500. 2014

Detail Information

Publications8

  1. pmc Positron emission tomography: a tool for better understanding of ventilator-induced and acute lung injury
    Guido Musch
    Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
    Curr Opin Crit Care 17:7-12. 2011
    ..This review aims to present the major findings of PET studies on acute lung injury (ALI) and ventilator-induced lung injury (VILI) with a perspective relevant to the physiologist-intensivist...
  2. pmc Lung regional metabolic activity and gas volume changes induced by tidal ventilation in patients with acute lung injury
    Giacomo Bellani
    Department of Experimental Medicine DIMS, University of Milan Bicocca, Via Cadore 48, 20052 Monza MB Italy
    Am J Respir Crit Care Med 183:1193-9. 2011
    ..As an estimate of the intensity of inflammation, metabolic activity can be measured by positron emission tomography imaging of [(18)F]fluoro-2-deoxy-D-glucose...
  3. pmc Effects of surfactant depletion on regional pulmonary metabolic activity during mechanical ventilation
    Nicolas de Prost
    Dept of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, MA 02114, USA
    J Appl Physiol (1985) 111:1249-58. 2011
    ..Metabolic activity is highest in poorly aerated dependent regions, suggesting local increased inflammation...
  4. pmc Effect of regional lung inflation on ventilation heterogeneity at different length scales during mechanical ventilation of normal sheep lungs
    Tyler J Wellman
    Department of Biomedical Engineering, Boston University, Boston, MA 02114, USA
    J Appl Physiol (1985) 113:947-57. 2012
    ..PEEP reduces sV heterogeneity by maintaining lung expansion and airway patency at those small length scales...
  5. pmc Pulmonary pathophysiology and lung mechanics in anesthesiology: a case-based overview
    Marcos F Vidal Melo
    Department of Anaesthesia, Harvard Medical School, Boston, MA 02215, USA
    Anesthesiol Clin 30:759-84. 2012
    ..The impacts of important concepts in pulmonary physiology and respiratory mechanics on clinical management decisions are discussed...
  6. pmc Regional lung derecruitment and inflammation during 16 hours of mechanical ventilation in supine healthy sheep
    Mauro R Tucci
    Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA
    Anesthesiology 119:156-65. 2013
    ..The authors used positron emission tomography to study the process of derecruitment in normal lungs ventilated for 16 h and the corresponding changes in regional lung perfusion and inflammation...
  7. pmc Lung [(18)F]fluorodeoxyglucose uptake and ventilation-perfusion mismatch in the early stage of experimental acute smoke inhalation
    Guido Musch
    From the Department of Anesthesia, Critical Care, and Pain Medicine G M, T W, M F V M, T J W, N D P, J G V, Department of Medicine, Pulmonary and Critical Care Unit R S H, and Department of Pathology R L K, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
    Anesthesiology 120:683-93. 2014
    ....
  8. pmc Effect of local tidal lung strain on inflammation in normal and lipopolysaccharide-exposed sheep*
    Tyler J Wellman
    1Department of Biomedical Engineering, Boston University, Boston, MA 2Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 3Pulmonary and Critical Care Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA 4Biostatistics Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA
    Crit Care Med 42:e491-500. 2014
    ....

Research Grants30

  1. Role of cGMP in Ventilator-Induced Lung Endothelial Barrier Dysfunction
    David B Pearse; Fiscal Year: 2013
    ..The cells lining the blood vessels of the lung respond to mechanical distension in complex ways that could be modified by medications if the cellular effects are unraveled. ..
  2. The Role of Cyclooxygenase 2 in Mechanical Stress-Induced Lung Injury
    Stephanie A Nonas; Fiscal Year: 2013
    ..Research into the effect of mechanical stress on lung from ventilation are necessary to better understand this syndrome and to develop new treatments...
  3. Targeting Membrane Repair in Deformation-Induced Lung Injury
    Xiaoli Zhao; Fiscal Year: 2013
    ..In addition, our results will push the efforts for advancing a safe and potent therapy for VALI that involves in large-scale production of a protein naturally exists in the human body. ..
  4. Endothelial Injury and Repair: CardioPulmonary Vascular Biology COBRE
    SHARON IRENE SMITH ROUNDS; Fiscal Year: 2013
    ..abstract_text> ..
  5. Chicago Prevention and Intervention Epicenter (Chicago PIE)
    ROBERT ALAN WEINSTEIN; Fiscal Year: 2013
    ..The impact on ICU infection and prescribing characteristics of doctors will be assessed. To further assess the interventions, costs of averted outcomes and of the interventions will be compared. OPRIONAL OBEJCTIVE SCORE: 2 ..
  6. Optimizing Ventilation Distribution in Injured Lung Using Computational Modeling
    Reza Amini; Fiscal Year: 2013
    ..In summary, this model will allow us to determine an optimal, protective ventilatory strategy based on global lung mechanics, acinar-level mechanics, and ventilation distribution. ..
  7. Improving Cardiac Function After Myocardial Infarction
    Steven R Houser; Fiscal Year: 2013
    ..A gene vector core will generate AAV6 vectors with novel therapeutics for testing in the pig Ml model. An administrative core will ensure data sharing and effective use of all resources. ..
  8. Cannabimimetic Treatment of Obstructive Sleep Apnea: A Proof of Concept Trial
    Phyllis C Zee; Fiscal Year: 2013
    ..By providing a path toward the first viable OSA pharmacotherapeutic, the proposed studies could have a tremendous impact on clinical practice. ..
  9. Vascular Subphenotypes of Lung Disease
    Mark T Gladwin; Fiscal Year: 2013
    ..vascular disease Project 3: Pulmonary vascular-targeted NO therapeutic strategies Core A: Administrative core Core B: Pre-Clinical Models of PAH Core C: Translational Vascular Phenomics, Genomics and Epidemiology Core ..
  10. Characterization of Pathways Controlling Cancer at the Level of Gene Regulation
    Phillip A Sharp; Fiscal Year: 2013
    ..The interactions and involvement of Rb and miRNAs in induction of cell death following DNA damage will also be studied. ..
  11. Novel Protein Kinase C Targeted Therapy for Acute Lung Injury
    Laurie E Kilpatrick; Fiscal Year: 2013
    ..The proposed studies will provide important insight into the underlying pathophysiology of ALI/ARDS and further define the efficacy of targeted [unreadable]-PKC inhibition as a novel therapeutic target in the treatment of ALI/ARDS. ..