1/2: PREcision VENTilation to attenuate Ventilation-Induced Lung Injury (PREVENT VILI)

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PROJECT SUMMARY / ABSTRACT Acute respiratory distress syndrome (ARDS) is a severe form of lung injury requiring hospitalization in intensive care and often invasive mechanical ventilation in effort to sustain life. ARDS can result from a variety of insults (e.g. pneumonia, sepsis, trauma, and pancreatitis), posing broad risk to the public health. With the COVID-19 pandemic, ARDS has become a leading cause of death in the US and globally. Yet, even pre-pandemic, ARDS occurred in 10% of US ICU admissions and had an associated mortality of 30-45%. Regardless of ARDS etiology, many survivors experience cognitive, psychological, and physical impairments persisting years after the acute illness resolves. Thus, there remains an urgent need to identify effective ARDS therapies. Invasive mechanical ventilation is potentially life-saving, but can worsen lung injury and patient outcomes if not precisely titrated to attenuate lung stress, which varies by patient with overdistension and atelectrauma (repetitive opening/closure of potentially recruitable lung). Alveolar edema and atelectasis reduce the functional aerated lung volume, such that tidal volume scaled to estimated healthy lung size (i.e. 6 mL/kg predicted body weight) may not always prevent overdistension. Similarly, positive end-expiratory pressure (PEEP) is routinely increased to recruit lung in patients with more severe hypoxemia, an approach that may exacerbate overdistension injury in patients most susceptible. An integrated strategy that mitigates the competing risks of atelectrauma and overdistension is needed. The range of lung stress observed in patients with ARDS receiving standard-of-care ventilation is often larger than that observed in healthy adults due to perturbed lung and chest wall mechanics, increasing risk of both atelectrauma and overdistension. In preclinical models and human cohort studies, lung injury and mortality are less when the ventilator is set to maintain lung stress in the healthy normal range. PREcision VENTilation to attenuate Ventilation-Induced Lung Injury (PREVENT VILI) is a phase III multicenter randomized trial for adults with moderate-severe ARDS that tests whether precise ventilator titration to maintain lung stress within 0-12 cm H2O, the healthy normal range during relaxed breathing, will improve patient outcomes compared to guided usual care. In the precision ventilation arm, PEEP will be individualized to achieve lung stress of 0 cm H2O at end-expiration, and tidal volume individualized to achieve driving pressure of 12 cm H2O or the lowest possible. In the guided usual care arm, PEEP will be adjusted per usual care within limits set to avoid practice extremes; tidal volume of 6-8 mL/kg predicted body weight will be targeted unless plateau pressure exceeds 30 cm H2O, in which case tidal volume will be lowered. We will evaluate the effect of ventilator strategy on 60-day mortality (Aim 1), lung injury (Aim 2), and hemodynamic instability (Aim 3). Findings will help determine the role for individualizing ventilator support to reduce lung stress in ARDS and have potential to improve survival from this leading cause of death worldwide.