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Background: Lifeless shock (LS) (previously called EMD and pseudo-PEA) is a global hypotensive ischemic state with retained coordinated myocardial contractile activity and an organized ECG. We have previously described our hypoxic LS model. The role of standard external chest compressions remains unclear in the setting of LS and its associated intrinsic hemodynamics. Although it is known the patients with LS have better prognosis compared to PEA, it is unclear what is the best treatment strategy. Prior work has shown that chest compressions (CC) when synchronized with native systole results in significant hemodynamic improvement, most notably coronary perfusion pressure (CPP), and hence it is plausible that standard dyssynchronous CC may be detrimental to hemodynamics. Furthermore, retrospective clinical data has shown that LS patients treated with vasopressors and no CC, may have better outcomes. We compared epinephrine only versus epinephrine and chest compression, in a porcine model of LS. Methods: Our porcine model of hypoxic LS has previously been described. We randomized pigs to episodes of LS treated with epinephrine only (control) (0.0015 mg/kg) versus epinephrine plus standard external chest compressions (intervention). Animals were endotracheally intubated and mechanically ventilated, and the fraction of inspired oxygen (FiO 2 ) was gradually lowered from room air (20-30% O 2 ) to a target FiO 2 of 3-7% O 2 . This target FiO 2 was maintained until the systolic blood pressure (SBP) dropped to 30 mmHg for 30 seconds, or the animal became bradycardic (HR less than 40), which was defined as the start of LS. FiO 2 was then raised to 100%, and then animal would receive control or intervention. Return of spontaneous circulation (ROSC) was defined as SBP 60 mmHg, stable after 2 minutes. Results: Twenty-six episodes of LS in 11 animals received epinephrine only control and 21 episodes the epinephrine plus chest compression intervention. The rates of ROSC in two minutes or less were 5/26 (19%) in the control arm vs 14/21 (67%) in the intervention arm (P=0.001;95% CI 19.7 %-67.2%). Conclusions: In a swine model of hypoxia induced LS, epinephrine plus CPR may be superior to epinephrine alone.