Positive end-expiratory pressure versus sham valve/zero end-expiratory pressure in cardiopulmonary resuscitation during manual ventilation to improve neurological outcomes in adult patients suffering an out-of-hospital cardiac arrest – an investigator-initiated, pragmatic, registry-based, multicenter, parallel-group, triple-blind randomized controlled superiority clinical trial in the ARREST registry (REVIVE-PEEP protocol Stage-1 Registered Report)
Year: 2026
Type: preprint
Abstract: Background In patients experiencing out-of-hospital cardiac arrest, optimizing oxygen delivery to vital organs during cardiopulmonary resuscitation (CPR) is critical. Ventilation is an essential component of CPR, but the effects of different ventilation strategies on patient outcomes have not been adequately established. Both positive end-expiratory pressure (PEEP) and zero end-expiratory pressure (ZEEP) are used during CPR, but their comparative effectiveness remains unclear. Methods This investigator-initiated, pragmatic, registry-based, multicenter, triple-blind randomized controlled superiority trial evaluates whether applying 8 cm H 2 O PEEP during cardiopulmonary resuscitation (CPR) improves outcomes compared with ZEEP in adults with non-traumatic, non-drowning out-of-hospital cardiac arrest. Pre-randomized CPR kits (1:1 PEEP vs. sham) were used by ambulance sites during manual ventilation throughout the resuscitation process. The main analyses were conducted in the modified intention-to-treat (mITT) subset of patients who received no sustained mechanical ventilation and either a supraglottic airway or endotracheal tube. The primary outcome was neurological status at hospital discharge measured by a utility-weighted score on the modified Rankin Scale, analyzed in a regression model with main effects for witnessed arrest, bystander CPR and shockable initial rhythm. Six prespecified interim analyses were performed on the primary outcome by a data safety monitoring board for both benefit and harm, on confidence intervals corrected for sequential analysis. Secondary outcomes included any return of spontaneous circulation during the CPR attempt, 30-day survival, and 6-month quality of life. The primary safety outcome was clinically significant pneumothorax. Data were collected within the existing ARREST (AmsteRdam RESustitation STudies) registry. Results Among the 3,200 patients who underwent randomization, 1,200 in the PEEP group and 1,200 in the ZEEP group were included in the mITT analysis. The mean difference in utility-weighted scores on the modified Rankin Scale, corrected for covariates, was 0.0073 ; 95% CI -0.0134–0.0279, corrected for prespecified interim analyses. The uncorrected mean utility was 0.1020 in the PEEP group and 0.1075 in the ZEEP group. The observed rates in the PEEP and ZEEP groups of any return of spontaneous circulation were X% vs. Y%; adjusted odds ratio, Z; 95% CI, A–B and in 30-day survival X% vs. Y%; adjusted odds ratio, Z; 95% CI, A–B. The incidence of clinically significant pneumothorax was similar between the PEEP and ZEEP groups, occurring in X% and Y% of patients, respectively (adjusted odds ratio, Z; 95% CI, A–B). Conclusion Conclusion and discussion follow at Stage-2. Stage-1 Registered Report We present our Stage-1 Registered Report as a full clinical trial article with all methods in past tense. Mock results, table and figures are included for the primary analysis, to provide full clarity about our intended analyses. To remind the reader that this Stage-1 article is written before data collection, we highlight in color that these mock results are only for illustrative purposes and will be replaced by the actual results in the Stage-2 Registered Report. Supplements All study supplements and updates are available in the replication package ResearchEquals collection [1], including the documents that received ethics approval – protocol Version 2.4 (September, 2026) [2], Patient Information Sheet [3], DSMB charter [4] and an example DSMB closed session report [5], as well as an Excel sheet [6] and R code [7] used to generate Figure A.5. Simultaneous evaluation PCI-RR and ethics The institutional review board (METC NedMec+) 1 tasked with the ethical evaluation of the REVIVE-PEEP trial agreed to perform a pilot experiment of simultaneous ethical and Stage-1 peer review at Peer Community In Registered Reports (PCI-RR). This means that all feedback was considered as one round of review, the author’s reply to both weighted the two sources of feedback together and all review as made available on PCI-RR. All openly available supplements in the replication package [1] were also referenced in the grant review process for Clinical Study Program funding by the Dutch Heart Foundation 2 , but grant review was not part of the pilot experiment. Nevertheless, we will evaluate the process as a major step towards ‘Trinity review’ aiming to reduce ‘redundant paperwork of three different documents – research papers, ethics review applications, and research grant applications – for the same research plan’[8]. Trial registration The REVIVE-PEEP trial was registered (July 27, 2026) in the Netherlands registry OMON (‘Overzicht van Medischwetenschappelijk Onderzoek in Nederland’) under identification number NL-OMON61400 3 , with OMON providing the data to the International Clinical Trial Registry Platform. Protocol and statistical analysis plan This Stage-1 Registered Report (RR) serves as the full pre-registration alongside the protocol Version 2.4 (September, 2026) [2]. To illustrate the unique possibilities of a Registered Report for a clinical trial positioned within an ongoing registry, and to prepare all reporting decisions in detail for very fast completion of the eventual result publication, we intend to supplement this manuscript in the future with a full synthetic mock dataset. This mock data will be generated based on ARREST registry data (2016–2018) [9] and prepare code for all analyses, also for those that need less detail than the preregistered primary analysis. The mock data project will drive further details of a possible statistical analysis plan, but should not deviate from this Stage-1 RR manuscript. If anything does change, we will contact PCI-RR. If changes are minor, we will transparently flag the deviations in the Stage-2 manuscript. If the changes are major and require re-review, than the in-principle acceptance will be rescinded, possibly reinviting the reviewers to evaluate the changes, and a new in-principle acceptance issued in the event of approval. Although we will be still blinded to the allocation, the first data will have been collected in this case, which might affect the level of bias control. Funding The legal sponsor of the trial was Amsterdam UMC, and the trial was coordinated by the ARREST registry. The Dutch Heart Foundation awarded funding for the trial through its Clinical Study Program (01-001-2026-0740). Study products were provided by Ambu A/S (Ballerup, Denmark), as in-kind support and technical expertise for the development, production, and regulatory preparation of the blinded study devices. Stryker (Redmond, WA, USA) supports the broader ARREST registry infrastructure through a separate grant. Neither company was involved in the scientific conduct, analysis, interpretation, or publication of the trial.
Source: medRxiv
Institutions: Amsterdam Public Health, Amsterdam University Medical Centers
Language: English
Subfield: Emergency Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7204781804