REVIVE-PEEP trial RESEARCH PROTOCOL

SUMMARY Rationale Cardiopulmonary resuscitation (CPR) aims to provide oxygen to vital organs through chest compressions and ventilations, until return of spontaneous circulation (ROSC) is achieved. A major barrier to effective oxygenation during CPR is atelectasis, which impairs gas exchange and results in hypoxemia—a condition strongly associated with decreased rates of ROSC and worsened neurological outcomes. Positive end-expiratory pressure (PEEP) is routinely used in critical care to prevent atelectasis and improve oxygenation. During CPR, however, its use is inconsistent and subject of debate. This reflects long-standing theoretical concerns that PEEP may reduce venous return, lower cardiac output, and impair the chances of successful defibrillation. However, emerging experimental and observational data suggest that PEEP may actually improve oxygenation, cardiac output, oxygen delivery, and rates of ROSC during CPR. We hypothesize that applying PEEP during CPR improves neurologically favorable survival. Given its simplicity, negligible cost, and widespread availability, PEEP has the potential to enhance outcomes from cardiac arrest in a scalable and resource-efficient manner. Objective To determine whether, during CPR with manual ventilation and after placement of a supraglottic airway device (SAD) or endotracheal tube (ETT), using a valve that generates 8 cm H 2 O PEEP compared with a sham valve providing zero end-expiratory pressure (ZEEP) improves neurological outcomes at discharge. Study design The REVIVE-PEEP trial is an investigator-initiated, pragmatic, registry-based, multicenter, parallel-group, triple-blind randomized controlled superiority clinical trial in the ARREST registry. Study population The target population consists of adult patients with an out-of-hospital cardiac arrest (OHCA) in whom advanced airway management is initiated, defined by placement of a SAD or ETT, followed by manual positive-pressure ventilation during CPR. As randomization occurs at the start of CPR, initiation of advanced airway management is considered an intercurrent event and is used to define the modified intention-to-treat analysis population. Blinding ensures that analyses within this subset provide an unbiased estimate of the principal stratum estimand. The target sample size for the mITT subset is 2,400 patients. Intervention Participating ambulance services will use pre-assembled, 1:1 pre-randomized CPR kits containing a bag-valve-mask system with either a PEEP valve (8 cm H 2 O) or a sham valve (0 cm H 2 O; ZEEP), alongside standard advanced life support. The same resuscitator bag will be used throughout the resuscitation, both before and after advanced airway management. Main study parameters/endpoints The primary estimand is the difference in neurological outcome at hospital discharge, assessed by the utility-weighted modified Rankin Scale within the mITT subset. Key secondary outcomes include ROSC, 30-day survival and quality of life at 6 months. Nature and extent of the burden and risks associated with participation, benefit and group relatedness This study’s intervention involves only a minor adjustment to ventilation management during cardiac arrest and requires no additional procedures. The study design imposes no additional clinical tasks on ambulance professionals during resuscitation, allowing them to maintain full focus on patient care; the only study-related action is recording the study device number in the case report form after the resuscitation attempt. The risks associated with participation are minimal. There may be a negligible increase in thoracic impedance that theoretically could influence defibrillation; however, modern defibrillators automatically adjust delivered energy based on pre-defibrillation thoracic impedance. Leakage around the SAD is a known issue that could reduce ventilation efficiency and may be exacerbated by the intervention, but existing guidelines allow for switching to a 30:2 compression:ventilation ratio in such cases. Lastly, although higher levels of PEEP have been associated with reduced cardiac output during CPR, the PEEP level used in this study remains under the maximum tolerated dose. Potential benefits include improved oxygenation and ventilation, reduced afterload, and improved cardiopulmonary interactions, which may increase the likelihood of successful resuscitation and favorable neurological outcomes. Improved oxygenation may also increase the likelihood of successful defibrillation.