RELAx - REstricted versus Liberal positive end-expiratory pressure in patients without ARDS: protocol for a randomized controlled trial

Anna Geke Algera, Luigi Pisani, Dennis C J Bergmans, Sylvia den Boer, Corianne A J de Borgie, Frank H Bosch, Karina Bruin, Thomas G Cherpanath, Rogier M Determann, Arjen M Dondorp, Dave A Dongelmans, Henrik Endeman, Jasper J Haringman, Janneke Horn, Nicole P Juffermans, David M van Meenen, Nardo J van der Meer, Maruschka P Merkus, Hazra S Moeniralam, Ilse Purmer, Pieter Roel Tuinman, Mathilde Slabbekoorn, Peter E Spronk, Alexander P J Vlaar, Marcelo Gama de Abreu, Paolo Pelosi, Ary Serpa Neto, Marcus J Schultz, Frederique Paulus, RELAx Investigators and the PROVE Network Investigators, Anna Geke Algera, Luigi Pisani, Dennis C J Bergmans, Sylvia den Boer, Corianne A J de Borgie, Frank H Bosch, Karina Bruin, Thomas G Cherpanath, Rogier M Determann, Arjen M Dondorp, Dave A Dongelmans, Henrik Endeman, Jasper J Haringman, Janneke Horn, Nicole P Juffermans, David M van Meenen, Nardo J van der Meer, Maruschka P Merkus, Hazra S Moeniralam, Ilse Purmer, Pieter Roel Tuinman, Mathilde Slabbekoorn, Peter E Spronk, Alexander P J Vlaar, Marcelo Gama de Abreu, Paolo Pelosi, Ary Serpa Neto, Marcus J Schultz, Frederique Paulus, RELAx Investigators and the PROVE Network Investigators

Abstract

Background: Evidence 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/DESIGN: The "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.

Discussion: 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.

Trial registration: ClinicalTrials.gov , ID: NCT03167580 . Registered on 23 May 2017.

Keywords: Artificial ventilation; Critical care; Duration of ventilation; Intensive care unit; Invasive ventilation; Mechanical ventilation; Mortality; Non-injured lungs; PEEP; Positive end-expiratory pressure.

Conflict of interest statement

Authors’ information

RELAx Investigators: The “REstricted versus Liberal positive end-expiratory pressures in patients without ARDS,” www.sites.google.com/view/relaxtrial.

PROVE network investigators: The PROtective VEntilation Network, www.provenet.eu.

Ethics approval and consent to participate

The Institutional Review Board of the Academic Medical Center, Amsterdam, The Netherlands, approved the trial protocol under reference number 2017_074#C2017635. All participants or legal representatives on their behalf provided oral and written consent and assent as appropriate.

Competing interests

The Academic Medical Center, Amsterdam, The Netherlands is the sponsor of the trial. The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Change in positive end-expiratory pressure (PEEP) in intensive care unit (ICU) and surgical patients over the past years. The practice of PEEP changed remarkably over the last 40 years in ICU patients. As in ICU patients with acute respiratory distress syndrome (ARDS) (red symbols), in ICU patients with uninjured lungs (blue symbols) and in surgery patients (green symbols) high PEEP is increasingly used, despite the lack of evidence. Data are (mean or median) levels of PEEP reported in observational studies, or in the control arms of randomized controlled trials (RCTs) versus the year of start of data collection, or year of publication if the latter was not presented. Abbreviations: ICU intensive care unit, PEEP positive end-expiratory pressure, RCTs randomized controlled trials
Fig. 2
Fig. 2
Consolidated Standards of Reporting Trials (CONSORT) diagram. Abbreviation: PEEP positive end-expiratory pressure
Fig. 3
Fig. 3
Flowchart ventilator settings with the two ventilation strategies. Abbreviations: PEEP positive end-expiratory pressure, MV mechanical ventilation, PBW predicted body weight, RM recruitment maneuver
Fig. 4
Fig. 4
Schedule of enrollment, intervention and assessments. Abbreviations: APACHE Acute Physiology And Chronic Health Evaluation, SOFA Sepsis-related Organ Failure Assessment score. *Deferred consent, obtained as soon as possible after randomization, but never later than 48 h after randomization

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