Background: The combination of the LUCAS 2 (L-CPR) automated CPR device and an impedance threshold device (ITD) has been shown to enhance outcomes in patients after out-of-hospital cardiac arrest. The potential physiological synergy of these technologies has not been examined in animals. This study tested the hypothesis that L-CPR + an active ITD work synergistically to enhance cerebral and coronary perfusion pressures compared with L-CPR + a sham ITD. Methods: Ten female pigs (40.0 + 4.0 kg) were sedated, intubated, anesthetized with isofluorane, and paralyzed with succinylcholine (93.3 ìg/kg/min) to inhibit the potential confounding effect of gasping. After 4 minutes of ventricular fibrillation, 4 minutes of L-CPR (Physio-Control, Redmond, WA) + an active ITD (ResQPOD R 16, Advanced Circulatory, Roseville, MN) or L-CPR + a sham ITD was initiated and followed by another 4 minutes of the alternative method of CPR. The order of CPR interventions was randomized. Systolic (SBP), diastolic (DBP), diastolic right atrial pressure (RAP), intracranial pressure (ICP), airway pressure, and end tidal CO2 (ETCO2) were recorded continuously. Coronary perfusion pressure (CPP) was calculated as the difference between DBP and RAP during decompression. Cerebral perfusion pressure (CePP) was calculated as the difference between MAP and ICP. Hemodynamic data were averaged and compared over the last 2 minutes of treatment. A paired t test was used for statistical comparisons between groups. Data are expressed as mean mmHg + SD. Results: Mean airway pressure (a surrogate for intrathoracic pressure) was significantly lower with L-CPR + active ITD versus L-CPR + sham ITD (-5.13 + 1.97 vs -0.49 + 0.58; p < 0.001). L-CPR + active ITD treatment resulted in significantly improved hemodynamics versus L-CPR + sham ITD: ETCO2, 34.9 + 5.6 vs. 28.9 + 7.2 (p = 0.015); SBP, 98.7 + 9.4 vs. 92.5 + 14.5 (p = 0.050); DBP, 24.4 + 12.0 vs. 19.4 + 15.1 (p = 0.006); CPP, 29.4 + 8.0 vs. 26.3 + 6.8 (p = 0.004) and CePP, 23.9 ¡¾ 12.6 vs. 20.7 + 11.8 (p = 0.028). Conclusions: In pigs undergoing L-CPR the addition of the ITD 16 significantly reduced intrathoracic pressure and increased systemic circulation. These data provide strong physiological support for this device combination.