Anesthesiology, V 123 • No 2 1 August 2015 A CUTE respiratory distress syndrome (ARDS) is a severe inlammatory condition characterized by het- erogeneous pulmonary injury with both normal and dis- eased areas throughout the lung. 1 Patients with ARDS require mechanical ventilation (MV), which improves gas exchange while minimizing harm to already injured tissue. he selection of adequate tidal volume (V T ), positive end- expiratory pressure (PEEP), respiratory system plateau pres- sure (Pplat,rs), and transpulmonary driving pressure (ΔP,L; diference between transpulmonary pressure at end-inspi- ration and at end-expiration) settings is crucial to reducing ventilator-induced lung injury (VILI). 2–5 A lung-protective strategy (V T ≤6 ml/kg predicted body weight and plateau pressures ≤30 cm H 2 O) and adequate lev- els of PEEP have been proposed to reduce VILI and mortality What We Already Know about This Topic • Recent retrospective analysis of clinical acute respiratory dis- tress syndrome trials suggested that driving pressure was an important factor associated with mortality. What This Article Tells Us That Is New • Different combinations of tidal volume and positive end- expiratory pressure (PEEP) were used to create a range of driving pressures in a rat model of acute respiratory distress syndrome due to tracheal instillation of endotoxin for 24 h. Low transpulmonary driving pressure was associated with alveolar collapse and high driving pressure was associated with hyperinlation. The combination of a tidal volume of 6 ml/ kg predicted body weight and the lowest PEEP and driving pressure to maintain oxygenation in a normal range mini- mized ventilator-induced lung injury even in the presence of alveolar collapse. Copyright © 2015, the American Society of Anesthesiologists, Inc. Wolters Kluwer Health, Inc. All Rights Reserved. Anesthesiology 2015; 123:00-00 ABSTRACT Background: Ventilator-induced lung injury has been attributed to the interaction of several factors: tidal volume (V T ), positive end-expiratory pressure (PEEP), transpulmonary driving pressure (diference between transpulmonary pressure at end-inspiration and end-expiration, ΔP,L), and respiratory system plateau pressure (Pplat,rs). Methods: Forty-eight Wistar rats received Escherichia coli lipopolysaccharide intratracheally. After 24 h, animals were ran- domized into combinations of V T and PEEP, yielding three diferent ΔP,L levels: ΔP,L LOW (V T = 6 ml/kg, PEEP = 3 cm H 2 O); ΔP,L MEAN (V T = 13 ml/kg, PEEP = 3 cm H 2 O or V T = 6 ml/kg, PEEP = 9.5 cm H 2 O); and ΔP,L HIGH (V T = 22 ml/kg, PEEP = 3 cm H 2 O or V T = 6 ml/kg, PEEP = 11 cm H 2 O). In other groups, at low V T , PEEP was adjusted to obtain a Pplat,rs similar to that achieved with ΔP,L MEAN and ΔP,L HIGH at high V T . Results: At ΔP,L LOW , expressions of interleukin (IL)-6, receptor for advanced glycation end products (RAGE), and amphi- regulin were reduced, despite morphometric evidence of alveolar collapse. At ΔP,L HIGH (V T = 6 ml/kg and PEEP = 11 cm H 2 O), lungs were fully open and IL-6 and RAGE were reduced compared with ΔP,L MEAN (27.4 ± 12.9 vs. 41.6 ± 14.1 and 0.6 ± 0.2 vs. 1.4 ± 0.3, respectively), despite increased hyperinlation and amphiregulin expression. At ΔP,L MEAN (V T = 6 ml/kg and PEEP = 9.5 cm H 2 O), when PEEP was not high enough to keep lungs open, IL-6, RAGE, and amphiregulin expression increased compared with ΔP,L LOW (41.6 ± 14.1 vs. 9.0 ± 9.8, 1.4 ± 0.3 vs. 0.6 ± 0.2, and 6.7 ± 0.8 vs. 2.2 ± 1.0, respectively). At Pplat,rs similar to that achieved with ΔP,L MEAN and ΔP,L HIGH , higher V T and lower PEEP reduced IL-6 and RAGE expression. Conclusion: In the acute respiratory distress syndrome model used in this experiment, two strategies minimized ventilator- induced lung injury: (1) low V T and PEEP, yielding low ΔP,L and Pplat,rs; and (2) low V T associated with a PEEP level suf- icient to keep the lungs open. (ANESTHESIOLOGY 2015; 123:00-00) This article is featured in “This Month in Anesthesiology,” page 1A. Digital Content is available for this article. Direct URL citations appear in the printed text and are available in both the HTML and PDF versions of this article. Links to the digital files are provided in the HTML text of this article on the Journal’s Web site (www.anesthesiology.org). Submitted for publication September 14, 2014. Accepted for publication March 20, 2015. From the Laboratory of Pulmonary Investiga- tion, Carlos Chagas Filho Biophysics Institute, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil (C.S.S., R.S.S., C.L.S., N.S.F., M.B., C.S.N.B.G., P.L.S., P.R.M.R.); Laboratory of Experimental Surgery, Faculty of Medicine, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil (C.L.S.); Radiology Department, National Center of Structural Biology and Image, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil (T.B., S.A.L.S.); Department of Pathology, School of Medicine, University of São Paulo, São Paulo, Brazil (V.L.C.); Laboratory of Cellular and Molecular Physiology, Carlos Chagas Filho Biophysics Institute, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil (M.M.M.); Rio Biological Impact of Transpulmonary Driving Pressure in Experimental Acute Respiratory Distress Syndrome Cynthia S. Samary, Ph.D., Raquel S. Santos, M.Sc., Ph.D., Cíntia L. Santos, Ph.D., Nathane S. Felix, M.S., Maira Bentes, R.T., Thiago Barboza, M.D., Vera L. Capelozzi, M.D., Ph.D., Marcelo M. Morales, M.D., Ph.D., Cristiane S. N. B. Garcia, Ph.D., Sergio A. L. Souza, Ph.D., John J. Marini, M.D., Marcelo Gama de Abreu, M.D., Ph.D., Pedro L. Silva, Ph.D., Paolo Pelosi, M.D., F.E.R.S., Patricia R. M. Rocco, M.D., Ph.D. Copyright © 2015, the American Society of Anesthesiologists, Inc. Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. <zdoi;10.1097/ALN.0000000000000716>