BME PhD Dissertation Defense - Tyler Wellman

Title: “Relation of Regional Tidal Lung Expansion with Inflammatory Activation In Early Ventilator-Induced Lung Injury: A PET Imaging Approach” Committee Members: Marcos F. Vidal Melo, MD, PhD (Dept of Anesthesia, MGH) Bela Suki, PhD (BME, BU) Tilo Winkler, PhD (Dept of Anesthesia, MGH) Thomas Szabo, PhD (BME, BU) Muhammad Zaman, PhD (BME, BU - Chair) Abstract: Mechanical ventilation is a life-saving intervention in patients with respiratory failure, but can exacerbate lung injury or produce inflammation in healthy lungs, side effects termed ventilator-induced lung injury (VILI). One putative mechanism of VILI is the triggering of inflammation through cyclic stretching of tissue. Studies in small animals have shown that high tidal volume ventilation results in cytokine production, macrophage activation, and neutrophil infiltration in the lungs. Exposure to lipopolysaccharide (LPS) may amplify these effects. However, translation of those findings to heterogeneously expanding large-animal lungs has been limited. We hypothesized that in heterogeneous lungs comparable in size to humans, regional inflammatory activation is directly related to both the magnitude and heterogeneity of tidal expansion, and that LPS exposure increases the inflammatory response to those mechanical factors. The goal of this study was to develop quantitative positron emission tomography (PET) imaging techniques to test these hypotheses in a large animal model of VILI and LPS-induced lung injury. First, we developed a novel approach to measure regional tidal lung expansion using respiratory-gated PET of inhaled 13N-nitrogen (13NN). Estimates of local expansion were validated against regional specific ventilation measured from 13NN washout rates in mechanically ventilated sheep. Second, we advanced PET techniques for quantification of ventilation heterogeneity underlying the PET resolution, and implemented a new length-scale analysis for ventilation heterogeneity. Finally, we combined these 13NN-PET techniques with dynamic 18F-FDG-PET imaging to study the relationships between regional tidal expansion, ventilation heterogeneity, and inflammatory activation in sheep mechanically ventilated with and without intravenous LPS infusion. We found that local inflammatory activation was linearly related to regional tidal expansion in initially normal lungs. Sensitivity to tidal expansion was enhanced with LPS exposure, indicating local synergy between expansion and LPS. Ventilation heterogeneity affected inflammatory activation only in LPS-exposed lungs. Protective ventilation reduced peak local inflammation by homogenizing and decreasing regional tidal expansion. These findings indicate that mechanical ventilation characterized by heterogeneous regional expansion places the lung at risk for focal inflammation, particularly in the presence of LPS. Thus, preventing local amplification of expansion through the use of ventilation strategies promoting homogeneous expansion may help to attenuate VILI.

Date: Tuesday, December 18th 2012

Start Time: 11:00am

End Time: 1:00pm

Location: 44 Cummington St, Room 203

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