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)

BackgroundIn patients experiencing out-of-hospital cardiac arrest, optimization of oxygen delivery during cardiopulmonary resuscitation is a critical. Although both positive end-expiratory pressure (PEEP) and zero end-expiratory pressure (ZEEP) are employed during CPR, their respective impacts on clinically relevant outcomes is yet to be clearly established. MethodsThis investigator-initiated, pragmatic, registry-based, multicenter, triple-blind randomized controlled superiority trial evaluates whether applying 8 cm H2O PEEP during cardiopulmonary resuscitation 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 primary analysis was conducted in the principal stratum of patients who received 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. Secondary outcomes included prehospital return of spontaneous circulation, 30-day survival, and 6-month quality of life. The primary safety outcome was clinically significant pneumothorax. ResultsAmong the 3,200 patients who underwent randomization, 1,200 in the PEEP group and 1,200 in the ZEEP group were included in the principal stratum analysis. The mean utility-weighted modified Rankin Scale score at discharge was 0.1020 in the PEEP group and 0.1075 in the ZEEP group (mean difference corrected for covariates in a regression model of 0.0050; 95% CI -0.0159 - 0.0258). The observed rates in the PEEP and ZEEP groups of prehospital 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). ConclusionConclusion and discussion follow at Stage-2. Stage-1 Registered ReportWe present our Stage-1 Registered Report as a full clinical trial article with all methods in past tense and including mock results, table and figures for the primary analysis. 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. SupplementsAll study supplements and updates are available in the ResearchEquals collection [1], including the protocol Version 2.1 (February 4, 2026) [2], DSMB charter [3] and example DSMB closed session report (based on mock data) [4], as well as an Excel sheet [5] and R code [6] used to generate Figure A.6. O_FIG O_LINKSMALLFIG WIDTH=142 HEIGHT=200 SRC="FIGDIR/small/26361533v1_figA_6.gif" ALT="Figure 6"> View larger version (45K): org.highwire.dtl.DTLVardef@e1cfa7org.highwire.dtl.DTLVardef@10811b5org.highwire.dtl.DTLVardef@c2bd13org.highwire.dtl.DTLVardef@10b3611_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOFigure A.6.C_FLOATNO Definitions of the Favorable and Unfavorable scenario for neurological outcomes given the same 4%-point absolute decrease in mortality (mRS-6) and base rates of the survivors scores (mRS-0 to mRS-5) observed in the ARREST registry period 2016-2018. These base rates might overestimate the proportion of good outcomes as withholding consent for mRS-scores to be included in research was found to be associated with worse outcomes elsewhere [36]. Figure based on Excel sheet [5] using R code [6]. C_FIG Simultaneous evaluation PCI-RR and ethicsThe institutional review board1 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 will be considered as one round of review and the authors reply to both will weigh the two sources of feedback together. The protocol Version 2.1 (February 4, 2026) [2] supplementing this manuscript is the version pre-ethical review and will be updated to a post-ethical review version after in-principle acceptance at PCI-RR. We will evaluate this pilot of simultaneous review 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[7]. RegistrationThe REVIVE-PEEP trial will be registered in an registry part of the International Clinical Trials Registry Platform after ethics approval and PCI-RR in-principle acceptance, with this Stage-1 registered report serving as the full preregistration alongside the protocol; currently Version 2.1 (February 4, 2026) [2].