Abstract
BackgroundEvidence for benefit of high positive end-expiratory pressure (PEEP) is largely lacking for invasively ventilated, critically ill patients with uninjured lungs. We hypothesize that ventilation with low PEEP is noninferior to ventilation with high PEEP with regard to the number of ventilator-free days and being alive at day 28 in this population. Methods/DesignThe “REstricted versus Liberal positive end-expiratory pressure in patients without ARDS” trial (RELAx) is a national, multicenter, randomized controlled, noninferiority trial in adult intensive care unit (ICU) patients with uninjured lungs who are expected not to be extubated within 24 h. RELAx will run in 13 ICUs in the Netherlands to enroll 980 patients under invasive ventilation. In all patients, low tidal volumes are used. Patients assigned to ventilation with low PEEP will receive the lowest possible PEEP between 0 and 5 cm H2O, while patients assigned to ventilation with high PEEP will receive PEEP of 8 cm H2O. The primary endpoint is the number of ventilator-free days and being alive at day 28, a composite endpoint for liberation from the ventilator and mortality until day 28, with a noninferiority margin for a difference between groups of 0.5 days. Secondary endpoints are length of stay (LOS), mortality, and occurrence of pulmonary complications, including severe hypoxemia, major atelectasis, need for rescue therapies, pneumonia, pneumothorax, and development of acute respiratory distress syndrome (ARDS). Hemodynamic support and sedation needs will be collected and compared.DiscussionRELAx will be the first sufficiently sized randomized controlled trial in invasively ventilated, critically ill patients with uninjured lungs using a clinically relevant and objective endpoint to determine whether invasive, low-tidal-volume ventilation with low PEEP is noninferior to ventilation with high PEEP.Trial registrationClinicalTrials.gov, ID:NCT03167580. Registered on 23 May 2017.
Highlights
Evidence for benefit of high positive end-expiratory pressure (PEEP) is largely lacking for invasively ventilated, critically ill patients with uninjured lungs
RELAx will be the first sufficiently sized randomized controlled trial in invasively ventilated, critically ill patients with uninjured lungs using a clinically relevant and objective endpoint to determine whether invasive, low-tidal-volume ventilation with low PEEP is noninferior to ventilation with high PEEP
When the Oxyhemoglobin saturation by pulse oximetry (SpO2) drops below 92% or the PaO2 drops below 8 kPa, brief periods of 5 min may be tolerated, first FiO2 is increased up to maximum 0.6 before PEEP is increased in steps of 1 cm H2O until 5 cm H2O
Summary
RELAx is the first randomized controlled trial that is sufficiently powered to investigate whether low-tidal-volumeventilation with low PEEP is noninferior to ventilation with high PEEP with regard to a clinically relevant endpoint in ICU patients with uninjured lungs. We chose a noninferiority design to compare ventilation with low PEEP to the current standard practice of high PEEP on the primary endpoint. RELAx is an investigator-initiated randomized controlled trial that is adequately powered to test the hypothesis that a ventilation strategy using low PEEP is noninferior compared to one using high PEEP in ICU patients with uninjured lungs with regard to the number of ventilated-free days and alive at day 28. Author details 1Department of Intensive Care, Academic Medical Center, Amsterdam, The Netherlands. Author details 1Department of Intensive Care, Academic Medical Center, Amsterdam, The Netherlands. 2Department of Intensive Care, Maastricht University Medical Center, Maastricht, The Netherlands. 3Department of Intensive Care, Spaarne Gasthuis, Haarlem and Hoofddorp, The Netherlands. 4Clinical Research Unit, Academic Medical Center, Amsterdam, The Netherlands. 5Department of Intensive Care, Rijnstate, Arnhem, The Netherlands. 6Department of Intensive Care, Westfriesgasthuis, Hoorn, The Netherlands. 7Department of Intensive Care, Onze Lieve Vrouwe Gasthuis, Amsterdam, The Netherlands. 8Madihol– Oxford Research Unit (MORU), Madihol University, Bangkok, Thailand. 9Department of Intensive Care, Isala Clinics, Zwolle, The Netherlands. 10Laboratory of Experimental Intensive Care and Anesthesiology (L·E·I·C·A), Academic Medical Center, Amsterdam, The Netherlands. 11Department of Intensive Care, Amphia Hospital, Breda, The Netherlands. 12Department of Intensive Care, Sint Antonius Hospital, Nieuwegein, The Netherlands. 13Department of Intensive Care, Haga Hospital, The Hague, The Netherlands. 14Department of Intensive Care, VU Medical Center, Amsterdam, The Netherlands. 15REVIVE Research VU Medical Center, VU Medical Center, Amsterdam, The Netherlands. 16Department of Intensive Care, Haaglanden Medical Center, The Hague, The Netherlands. 17Department of Intensive Care, Gelre Hospital, Apeldoorn, The Netherlands. 18Department of Anesthesiology and Intensive Care, University Hospital Carl Gustav Carus, Dresden, Germany. 19Department of Surgical Sciences and Integrated Diagnostics, San Martino Policlinico Hospital – IRCCS for Oncology, University of Genoa, Genoa, Italy. 20Department of Intensive Care Medicine, Hospital Israelita Albert Einstein, São Paulo, Brazil
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