Effects of Positive End-Expiratory Pressure and Spontaneous Breathing Activity on Regional Lung Inflammation in Experimental Acute Respiratory Distress Syndrome

Objectives: To determine the impact of positive end-expiratory pressure during mechanical ventilation with and without spontaneous breathing activity on regional lung inflammation in experimental nonsevere acute respiratory distress syndrome. Design: Laboratory investigation. Setting: University hospital research facility. Subjects: Twenty-four pigs (28.1–58.2 kg). Interventions: In anesthetized animals, intrapleural pressure sensors were placed thoracoscopically in ventral, dorsal, and caudal regions of the left hemithorax. Lung injury was induced with saline lung lavage followed by injurious ventilation in supine position. During airway pressure release ventilation with low tidal volumes, positive end-expiratory pressure was set 4 cm H2O above the level to reach a positive transpulmonary pressure in caudal regions at end-expiration (best-positive end-expiratory pressure). Animals were randomly assigned to one of four groups (n = 6/group; 12 hr): 1) no spontaneous breathing activity and positive end-expiratory pressure = best-positive end-expiratory pressure – 4 cm H2O, 2) no spontaneous breathing activity and positive end-expiratory pressure = best-positive end-expiratory pressure + 4 cm H2O, 3) spontaneous breathing activity and positive end-expiratory pressure = best-positive end-expiratory pressure + 4 cm H2O, 4) spontaneous breathing activity and positive end-expiratory pressure = best-positive end-expiratory pressure – 4 cm H2O. Measurements and Main Results: Global lung inflammation assessed by specific [18F]fluorodeoxyglucose uptake rate (median [25–75% percentiles], min–1) was decreased with higher compared with lower positive end-expiratory pressure both without spontaneous breathing activity (0.029 [0.027–0.030] vs 0.044 [0.041–0.065]; p = 0.004) and with spontaneous breathing activity (0.032 [0.028–0.043] vs 0.057 [0.042–0.075]; p = 0.016). Spontaneous breathing activity did not increase global lung inflammation. Lung inflammation in dorsal regions correlated with transpulmonary driving pressure from spontaneous breathing at lower (r = 0.850; p = 0.032) but not higher positive end-expiratory pressure (r = 0.018; p = 0.972). Higher positive end-expiratory pressure resulted in a more homogeneous distribution of aeration and regional transpulmonary pressures at end-expiration along the ventral-dorsal gradient, as well as a shift of the perfusion center toward dependent zones in the presence of spontaneous breathing activity. Conclusions: In experimental mild-to-moderate acute respiratory distress syndrome, positive end-expiratory pressure levels that stabilize dependent lung regions reduce global lung inflammation during mechanical ventilation, independent from spontaneous breathing activity. Drs. Kiss, Bluth, Braune, Huhle, and Denz equally contributed to this article. All authors contributed to the conception and/or design of this study and analysis and interpretation of data. Drs. Kiss, Bluth, Braune, Huhle, Denz, Herzog, Herold, Vivona, Millone, Bergamaschi, Andreeff, Scharffenberg, and Wittenstein contributed to the acquisition of data. Drs. Kiss, Bluth, Braune, Huhle, Herzog, Herold, Vivona, Millone, Bergamaschi, Scharffenberg, and Wittenstein contributed to data processing. Drs. Kiss, Bluth, Braune, Huhle, Rocco, Pelosi, and Gama de Abreu drafted the article, and all authors critically revised it for important intellectual content and approved the final version to be submitted. Drs. Koch and Gama de Abreu obtained funding. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (http://bit.ly/29S62lw). Supported, in part, by grant number GA1256/6-2 of the German Research Foundation (Deutsche Forschungsgemeinschaft), Bonn, Germany. The PET/CT device was a gift from the German Federal Ministry of Education and Research (Bundesministerium für Bildung und Forschung contract 03ZIK42/OncoRay), Bonn, Germany. Dr. Braune disclosed work for hire. Dr. Huhle's institution received funding from Deutsche Forschungsgesellschaft. Dr. Herzog's institution received funding from Else Kröner-Fresenius-Stiftung. Dr. Vidal Melo's institution received funding from the National Institutes of Health (NIH)- National Heart, Lung, and Blood Institute (NHLBI). Dr. Vidal Melo was supported by NIH-NHLBI grant R01 121228. Dr. Gama de Abreu's institution received funding from grant number GA1256/6-2 of the German Research Foundation (Deutsche Forschungsgemeinschaft), Bonn, Germany; he received funding from Dräger Medical AG, Lübeck, Germany; GlaxoSmithKline, Stevenage, United Kingdom; and Ventinova Ltd, Eindhoven, The Netherlands. The remaining authors have disclosed that they do not have any potential conflicts of interest. This work was performed by the Pulmonary Engineering Group, Department of Anesthesiology and Intensive Care Medicine, and the Institute of Nuclear Medicine, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany. For information regarding this article, E-mail: mgabreu@uniklinikum-dresden.de Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

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