OBJECTIVES: Pulseless electrical activity (PEA) arrest, which includes pseudo-PEA, is increasingly common and survival remains dismal. We hypothesized that mechanical chest compressions synchronized to native cardiac contractions improve coronary perfusion pressure (CPP) during pseudo-PEA resuscitation. METHODS: We developed a model of pseudo-PEA by infusing high dose esmolol intravenously into anesthetized, intubated, and central arterial and venous catheterized swine to a goal of 45 mm Hg mean arterial blood pressure (MAP). We performed a randomized unblinded repeated crossover trial by administering alternating synchronized and unsynchronized chest compressions for 52 s preceded by 8 s breaks consecutively 4 times. We repeated the protocol approximately 4 times with 1 min breaks. Synchronized compressions were provided 1:1 with native contractions during systole and unsynchronized compressions were provided at 100 beats per minute (BPM). We measured average CPP, MAP, and heartrate (HR) for 5 beats immediately preceding the chest compression onset and for 30 s 10 s after compression onset. We computed the difference in continuous CPP during compressions compared to the immediately preceding baseline for each interval. We developed a mixed linear model with outcome average CPP during compressions minus baseline, fixed variable compression type, and random variable animal. RESULTS: We included 6 animals. Mean baseline HR was 76.0 BPM, MAP 49.9, and CPP 36.2. Chest compressions increased CPP from baseline an average 1.7 mm Hg when unsynchronized and 5.6 mm Hg synchronized. The adjusted difference was 4.0 mm Hg (95% CI 2.4-5.5). CONCLUSIONS: Synchronized chest compressions increased CPP 4.0 mm Hg (135%) more than unsynchronized compressions despite a lower compression rate in medication-induced pseudo-PEA. Further refinement and eventual application to patients suffering pseudo-PEA arrest appear warranted.