Sepsis and hemorrhage can result in injury to multiple organs and is associated with an extremely high rate of mortality. We hypothesized that peritoneal negative pressure therapy (NPT) would reduce systemic inflammation and organ damage. Pigs (n = 12) were anesthetized and surgically instrumented for hemodynamic monitoring. Through a laparotomy, the superior mesenteric artery was clamped for 30 min. Feces was mixed with blood to form a fecal clot that was placed into the peritoneum, and the abdomen was closed. All subjects were treated with standard isotonic fluid resuscitation, wide spectrum antibiotics, and mechanical ventilation, and were monitored for 48 h. Animals were separated into two groups 12 h (T12) after injury: for NPT (n = 6), an abdominal wound vacuum dressing was placed in the laparotomy, and negative pressure (-125 mmHg) was applied (T12 - T48), whereas passive drainage (n = 6) was identical to the NPT group except the abdomen was allowed to passively drain. Negative pressure therapy removed a significantly greater volume of ascites (860 ± 134 mL) than did passive drainage (88 ± 56 mL). Systemic inflammation (e.g. TNF-α, IL-1β, IL-6) was significantly reduced in the NPT group and was associated with significant improvement in intestine, lung, kidney, and liver histopathology. Our data suggest NPT efficacy is partially due to an attenuation of peritoneal inflammation by the removal of ascites. However, the exact mechanism needs further elucidation. The clinical implication of this study is that sepsis/trauma can result in an inflammatory ascites that may perpetuate organ injury; removal of the ascites can break the cycle and reduce organ damage.

Inappropriate mechanical ventilation in patients with acute respiratory distress syndrome can lead to ventilator-induced lung injury (VILI) and increase the morbidity and mortality. Reopening collapsed lung units may significantly reduce VILI, but the mechanisms governing lung recruitment are unclear. We thus investigated the dynamics of lung recruitment at the alveolar level. Rats (n = 6) were anesthetized and mechanically ventilated. The lungs were then lavaged with saline to simulate acute respiratory distress syndrome (ARDS). A left thoracotomy was performed, and an in vivo microscope was placed on the lung surface. The lung was recruited to three recruitment pressures (RP) of 20, 30, or 40 cmH(2)O for 40 s while subpleural alveoli were continuously filmed. Following measurement of microscopic alveolar recruitment, the lungs were excised, and macroscopic gross lung recruitment was digitally filmed. Recruitment was quantified by computer image analysis, and data were interpreted using a mathematical model. The majority of alveolar recruitment (78.3 +/- 7.4 and 84.6 +/- 5.1%) occurred in the first 2 s (T2) following application of RP 30 and 40, respectively. Only 51.9 +/- 5.4% of the microscopic field was recruited by T2 with RP 20. There was limited recruitment from T2 to T40 at all RPs. The majority of gross lung recruitment also occurred by T2 with gradual recruitment to T40. The data were accurately predicted by a mathematical model incorporating the effects of both pressure and time. Alveolar recruitment is determined by the magnitude of recruiting pressure and length of time pressure is applied, a concept supported by our mathematical model. Such a temporal dependence of alveolar recruitment needs to be considered when recruitment maneuvers for clinical application are designed.

Objective To gain insights into individual variations in acute inflammation and physiology. Design Large-animal study combined with mathematical modeling. Setting Academic large-animal and computational laboratories. Subjects Outbred juvenile swine. Interventions Four swine were instrumented and subjected to endotoxemia (100 μg/kg), followed by serial plasma sampling. Measurements and Main Results Swine exhibited various degrees of inflammation and acute lung injury (ALI), including one death with severe ALI (P/F ratio <200 and static compliance <10 L/cmH2O). Plasma interleukin (IL)-1β, IL-4, IL-6, IL-8, IL-10, tumor necrosis factor (TNF)-α, high mobility group box-1 (HMGB1), and NO2−/NO3−,, were significantly (p <0.05) elevated over the course of the experiment. Principal Component Analysis (PCA) was used to suggest principal drivers of inflammation. Based in part on PCA, an Ordinary Differential Equation (ODE) model was constructed, consisting of the lung and the blood (as a surrogate for the rest of the body), in which endotoxin induces TNF-αin monocytes in the blood, followed by the trafficking of these cells into the lung leading to the release of HMGB1, which in turn stimulates the release of IL-1βfrom resident macrophages. The ODE model also included blood pressure, PaO2, and FiO2, and a damage variable that summarizes the health of the animal. This ODE model could be fit to both inflammatory and physiologic data in the individual swine. The predicted time course of damage could be matched to the Oxygen Index in 3 of the 4 swine. Conclusions The approach described herein may aid in predicting inflammation and physiological dysfunction in small cohorts of subjects with diverse phenotypes and outcomes.