REVIVE-PEEP study 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 H₂O PEEP compared with a sham valve providing zero end-expiratory pressure (ZEEP) improves neurological outcomes at discharge. Study design The REVIVE-PEEP study is an investigator-initiated, pragmatic, registry-based, multicenter, parallel-group, triple-blind randomized controlled superiority clinical trial in the ARREST registry. Study population The principal stratum comprises adult patients with out-of-hospital cardiac arrest (OHCA) in whom advanced airway management is performed, defined by placement of a SAD or ETT, who subsequently undergo manual positive-pressure ventilation during CPR. The target sample size within this principal stratum is 2,400 patients. Intervention Participating ambulance services will use pre-assembled CPR kits, containing a bag-valve-mask system with either a PEEP valve or a sham valve. These kits will be 1:1 pre-randomized, with the PEEP valve delivering 8 cm H₂O of PEEP and the sham valve delivering 0 cm H₂O of PEEP (i.e. ZEEP), alongside the standard advanced life support protocol. Main study parameters/endpoints The primary estimand is the treatment effect on neurological outcome at hospital discharge, assessed by the utility-weighted modified Rankin Scale within the principal stratum. 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.