PRotective VENTilation in patients without the acute respiratory distress syndrome (PReVENT) a Randomized Controlled Trial

Introduction: ‘Protective mechanical ventilation’ with use of lower tidal volumes strongly prevents mortality and morbidity of intensive care unit (ICU) patients with the acute respiratory distress syndrome (ARDS). A recent meta-analysis suggests this strategy to benefit ICU patients without ARDS as well. The meta-analyzed studies, however, all have methodological shortcomings and the majority of them focus on short-term peri-operative ventilation, which cannot be simply generalized to other clinical situations. Indeed, patients in the ICU are ventilated for a much longer period of time. More importantly, it is argued that the beneficial effects of lower tidal volume ventilation could be offset by an increased need for sedation and maybe even muscle paralysis with this strategy. Increased use of sedatives and muscle relaxants could increase the incidence of ICU delirium and ICU acquired weakness, and both conditions could lengthen duration of ventilation and stay in ICU. Furthermore, it is argued that use of lower tidal volumes is not always possible with spontaneous modes of ventilation, which are most frequently used in ICU patients without ARDS. Consequently, the ICU community calls for more evidence for the alleged beneficial effects and feasibility of lower tidal volume ventilation, before extending this strategy to ICU patients without ARDS. Hypothesis: Protective ventilation with lower tidal volumes increases the number of ventilator-free days of ICU patients without ARDS. As such, protective ventilation shortens ICU length of stay and is expected to reduce healthcare costs. Study design and patients: National multicenter randomized controlled trial (RCT) of lower tidal volume ventilation in patients without ARDS. Intervention: Patients are randomized to lower tidal volume ventilation (4-6 ml/kg predicted body weight, PBW) versus ventilation with traditionally sized tidal volumes (8-10 ml/kg PBW). Outcome measures: The primary clinical endpoint is the number of ventilator-free days, defined as days alive and breathing without assistance during the first 28 days, if the period of unassisted breathing lasts at least 24 consecutive hours. Secondary endpoints include ICU and hospital costs; ICU and hospital LOS; development of ARDS, pneumonia, atelectasis and/or pneumothorax; incidence of delirium and/or weakness; total sedation and muscle paralysis needed; and ICU, hospital and 90-day mortality. Health care costs will be estimated from a health systems perspective over the time horizon of this RCT Sample size: The trial is powered (2-sided alpha 0.05, power 80%) to detect an increase of one extra ventilator-free day. For this, we need to randomize 952 patients (i.e., 476 patients per arm of the trial). Anticipated healthcare efficiency gain: As less than 5% of ventilated ICU patients actually have ARDS, the number of ventilated patients in Dutch ICUs without ARDS is very high, up to 38,000 per year annually. A conservative estimation suggests a potential efficiency gain of €53,200,000 per year in the Netherlands (based on 1 day reduction in duration of ventilation and ICU LOS and costs of 1 ICU day with ventilation of €1.400). Time schedule: The project will comprise four years. The first six months are used for preparation; the next three years for recruitment and follow up of patients till day 90; the last six months are used for data analysis, data reporting and consolidation of the evidence in guidelines.