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Roy, Shreyas*; Habashi, Nader; Sadowitz, Benjamin*; Andrews, Penny; Ge, Lin*; Wang, Guirong*; Roy, Preyas; Ghosh, Auyon*; Kuhn, Michael§; Satalin, Joshua*; Gatto, Louis A.; Lin, Xin; Dean, David A.; Vodovotz, Yoram**; Nieman, Gary*

doi: 10.1097/SHK.0b013e31827b47bb
2012 New Investigator Award Competition

ABSTRACT Acute respiratory distress syndrome (ARDS) afflicts 200,000 patients annually with a mortality rate of 30% to 60% despite wide use of low tidal volume (LTV) ventilation, the present standard of care. High-permeability alveolar edema and instability occur early in the development of ARDS, before clinical signs of lung injury, and represent potential targets for therapy. We hypothesize that early application of a protective ventilation strategy (airway pressure release ventilation [APRV]) will stabilize alveoli and reduce alveolar edema, preventing the development of ARDS. Yorkshire pigs (30–40 kg) were anesthetized and subjected to two-hit injury: (a) intestinal ischemia-reperfusion, (b) peritoneal sepsis, or sham surgery. Following surgery, pigs were randomized into APRV (n = 4), according to current published guidelines for APRV; LTV ventilation (n = 3), using the current published ARDS Network guidelines (6 mL/kg); or sham (n = 5). The clinical care of all pigs was administered per the Surviving Sepsis Campaign guidelines. Animals were killed, and necropsy performed at 48 h. Arterial blood gases were measured to assess for the development of clinical lung injury. Lung tissue epithelial cadherin (E-cadherin) was measured to assess alveolar permeability. Bronchoalveolar lavage fluid (BALF) surfactant protein A was measured to assess alveolar stability. Lung edema content and histopathology were analyzed at 48 h. Airway pressure release ventilation pigs did not develop ARDS. In contrast, pigs in the LTV ventilation met ARDS criteria (PaO2/FIO2 ratio) (APRV: baseline = 471 ± 16; 48 h = 392 ± 8; vs. LTV ventilation: baseline = 551 ± 28; 48 h = 138 ± 88; P < 0.001). Airway pressure release ventilation preserved alveolar epithelial integrity demonstrated by higher levels of E-cadherin in lung tissue as compared with LTV ventilation (P < 0.05). Surfactant protein A levels were higher in BALF from the APRV group, suggesting APRV preserved alveolar stability. Quantitative histologic scoring showed improvements in all stigmata of ARDS in the APRV group versus the LTV ventilation (P < 0.05). Airway pressure release ventilation had significantly lower lung edema (wet-dry weight) than LTV ventilation (P < 0.05). Protective ventilation with APRV immediately following injury prevents development of ARDS. Reduction in lung edema, preservation of lung E-cadherin, and surfactant protein A abundance in BALF suggest that APRV attenuates lung permeability, edema, and surfactant degradation. Protective ventilation could change the clinical paradigm from supportive care for ARDS with LTV ventilation to preventing development of ARDS with APRV.

*Cardiopulmonary and Critical Care Laboratory, Department of Surgery, Upstate Medical University, Syracuse, New York; Multitrauma Unit, R. Adams Cowley Shock Trauma Center, Baltimore, Maryland; University of Chicago, Chicago, Illinois; §Department of Nutrition, Columbia University, New York; Department of Biology, SUNY Cortland, Cortland; Department of Pediatrics, Neonatology University of Rochester Medical Center, Rochester, New York; and **Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania

Received 31 May 2012; first review completed 19 Jun 2012; accepted in final form 26 Oct 2012

Address reprint requests to Shreyas Roy, MD, CM, Department of Surgery, SUNY Upstate Medical University, 750 E Adams St, Syracuse NY 13210. E-mail:

This work was partially funded by NIH R33HL089076 and NIH R21HL092801-01.

This study was selected as one of the New Investigator Nominees at the 35th Annual Conference on SHOCK, held in Miami Beach, Florida, June 9–13, 2012.

The authors have no conflicts of interest to declare.

©2013The Shock Society