Background: Monitoring esophageal pressure and calculating transpulmonary pressure have been proposed as a more physiological approach to guide mechanical ventilation. Some factors, such as intra-abdominal hypertension (IAH), may affect thoraco-abdominal interaction and influence the interpretation of pulmonary mechanics based on airway pressures alone. We developed an experimental IAH protocol with the objective of characterizing the behavior of respiratory system compliance and transpulmonary pressure in the setting of varying levels of intra-abdominal pressure (IAP). Methods: Three (n=3) deeply anesthetized swine (30-35 kg) were mechanically ventilated at VT = 10 ml/kg, f=15, I:E=1:2 (Carestation, GE Healthcare, Madison, WS). No neuromuscular blocking agents were used. After surgical placement of an air tight tracheostomy tube into the peritoneal cavity, varied levels of IAP (5, 10, 15, 20 and 25 mmHg) were applied via a CPAP system. Esophageal and bladder pressures were measured after 10 minutes of stabilization at each level of IAP. Inspiratory pressure-volume (PV) curves were generated by sequential insufflations of 100 mL of air, allowing 3-5 seconds for equilibration between steps. Hemodynamic and pulmonary instability due to high airway pressures prevented construction of expiratory limbs of the Pressure-Volume (PV) curves. Results: Figure 1 shows inspiratory esophageal pressure-volume curves displaying decreasing chest wall compliance (CCW) in the setting of increasing IAP. Calculated CCW over the range of 0 to 10 mmHg IAP was >100 mL/cmH2O. During IAP values of 15 mmHg and above, Ccw decreased sharply. Figure 2 shows similar transpulmonary pressure-volume curves for all levels of IAP. Increasing IAP in stepwise increments from 0 to 25 mmHg showed average FRC values of 587 ml, 529 ml, 502 ml, 511 ml, 437 ml, and 359 ml. Conclusion: Increasing IAP progressively reduced FRC. IAP disproportionately impacted PES and respiratory system compliance at values = 10 mmHg. As expected, lung compliance was not affected by changes in IAP. Therefore, proximally measured airway pressures result in non-linear inferences regarding transpulmonary pressure when IAP = 10 mmHg. Speculation: To the extent that similar mechanics apply under clinical conditions, direct calculation of PTP using PES monitoring seems advisable under high IAP conditions.