Acute Respiratory Distress Syndrome (ARDS) and acute lung injury (ALl) place heavy burdens on the health of the public, afflicting over 190,000 people annually in the US alone. The associated nnortality exceeds 30% and accounts for 74,500 deaths annually. Improvennents in ventilator management have reduced both the mortality and morbidity associated with ALI/ARDS, and thus have an important public health impact. Low tidal volume ventilation strategies are clearly beneficial in patients with ALI/ARDS. However, the optimal level of applied positive end-expiratory pressure (PEEP) is uncertain. We propose a phase II multicenter, randomized controlled trial of mechanical ventilation directed by esophageal pressure measurements. The primary hypothesis is that adjusting PEEP to maintain a positive transpulmonary pressure throughout the ventilatory cycle will lead to clinically important improvements at 28 days. In patients with high pleural pressure on conventional ventilator settings, underinflation leads to atelectasis, hypoxemia, and exacerbation of lung injury through """"""""atelectrauma"""""""". In such patients, raising PEEP to maintain a positive transpulmonary pressure might improve aeration and oxygenation without causing overdistension. Conversely, in patients with low pleural pressure, maintaining a low PEEP would keep transpulmonary pressure low, avoiding over-distension and consequent """"""""volutrauma"""""""". Thus, the currently recommended strategy of setting PEEP without regard to transpulmonary pressure could benefit some patients while harming others. Our preliminary study demonstrated that a.ventilator strategy designed to optimize transpulmonary pressure significantly improved oxygenation and lung mechanics, and there was a trend toward improved survival. We propose to confirm these results in a multi-centered trial at 6 large medical centers enrolling 200 patients with ALI/ARDS. We will use esophageal pressure to estimate transpulmonary pressure (PTP). Subjects will then be randomized to the control group, in which ventilation will be managed according to the ARDSNet protocol, or the EPVent group, in which ventilator settings will be adjusted to achieve a specified PTP. The primary hypothesis is that using a strategy of maintaining a positive PTP throughout the ventilatory cycle will lead to improvement in a combined hierarchical outcome of mortality and ventilator free days at 28 days. This study has important implications for the health of the public. Strong preliminary data suggest a positive result, potentially changing medical practice.

Public Health Relevance

Acute lung injury (ALl), often occurring as a result of severe infection or trauma, is an inflammation of the lungs that can lead to dangerously low levels of oxygen in the blood and death. Mechanical ventilation used to increase oxygen levels in ALl can actually cause more lung injury if the ventilator is not set correctly. This study will test whether a new method of setting the ventilator in ALl can reduce lung injury, improve oxygen levels, and save lives.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project with Complex Structure Cooperative Agreement (UM1)
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Special Emphasis Panel (ZHL1-CSR-F (F2))
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Beth Israel Deaconess Medical Center
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D'Antini, Davide; Huhle, Robert; Herrmann, Jacob et al. (2018) Respiratory System Mechanics During Low Versus High Positive End-Expiratory Pressure in Open Abdominal Surgery: A Substudy of PROVHILO Randomized Controlled Trial. Anesth Analg 126:143-149
MondoƱedo, Jarred R; Herrmann, Jacob; McNeil, John S et al. (2017) Comparison of pneumotachography and anemometery for flow measurement during mechanical ventilation with volatile anesthetics. J Clin Monit Comput 31:1263-1271
Amini, Reza; Herrmann, Jacob; Kaczka, David W (2017) Intratidal Overdistention and Derecruitment in the Injured Lung: A Simulation Study. IEEE Trans Biomed Eng 64:681-689
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Loring, Stephen H; Talmor, Daniel (2015) The authors reply. Crit Care Med 43:e54-5
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Beitler, Jeremy R; Thompson, B Taylor; Matthay, Michael A et al. (2015) Estimating dead-space fraction for secondary analyses of acute respiratory distress syndrome clinical trials. Crit Care Med 43:1026-35

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