A clinically applicable porcine model of septic and ischemia/reperfusion-induced shock and multiple organ injury.

BACKGROUND: Although many sepsis treatments have shown efficacy in acute animal models, at present only activated protein C is effective in humans. The likely reason for this discrepancy is that most of the animal models used for preclinical testing do not accurately replicate the complex pathogenesis of human sepsis. Our objective in this study was to develop a clinically applicable model of severe sepsis and gut ischemia/reperfusion (I/R) that would cause multiple organ injury over a period of 48 h. MATERIALS AND METHODS: Anesthetized, instrumented, and ventilated pigs were subjected to a "two-hit" injury by placement of a fecal clot through a laparotomy and by clamping the superior mesenteric artery (SMA) for 30 min. The animals were monitored for 48 h. Wide spectrum antibiotics and intravenous fluids were given to maintain hemodynamic status. FiO(2) was increased in response to oxygen desaturation. Twelve hours following injury, a drain was placed in the laparotomy wound. Extensive hemodynamic, lung, kidney, liver, and renal function measurements and serial measurements of arterial and mixed venous blood gases were made. Bladder pressure was measured as a surrogate for intra-peritoneal pressure to identify the development of the abdominal compartment syndrome (ACS). Plasma and peritoneal ascites cytokine concentration were measured at regular intervals. Tissues were harvested and fixed at necropsy for detailed morphometric analysis. RESULTS: Polymicrobial sepsis developed in all animals. There was a progressive deterioration of organ function over the 48 h. The lung, kidney, liver, and intestine all demonstrated clinical and histopathologic injury. Acute lung injury (ALI) and ACS developed by consensus definitions. Increases in multiple cytokines in serum and peritoneal fluid paralleled the dysfunction found in major organs. CONCLUSION: This animal model of Sepsis+I/R replicates the systemic inflammation and dysfunction of the major organ systems that is typically seen in human sepsis and trauma patients. The model should be useful in deciphering the complex pathophysiology of septic shock as it transitions to end-organ injury thus allowing sophisticated preclinical studies on potential treatments.

Peritoneal negative pressure therapy prevents multiple organ injury in a chronic porcine sepsis and ischemia/reperfusion model.

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-1ß, 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.

Plateau and transpulmonary pressure with elevated intra-abdominal pressure or atelectasis.

BACKGROUND: ARDSnet standards limit plateau pressure (Pplat) to reduce ventilator induced lung injury (VILI). Transpulmonary pressure (Ptp) [Pplat-pleural pressure (Ppl)], not Pplat, is the distending pressure of the lung. Lung distention can be affected by increased intra-abdominal pressure (IAP) and atelectasis. We hypothesized that the changes in distention caused by increases in IAP and atelectasis would be reflected by Ptp but independent of Pplat. METHODS: In Yorkshire pigs, esophageal pressure (Pes) was measured with a balloon catheter as a surrogate for Ppl under two experimental conditions: (1) high IAP group (n=5), where IAP was elevated by CO2 insufflation in 5 mm Hg steps from 0 to 30 mm Hg; and (2) Atelectasis group (n=5), where a double lumen endotracheal tube allowed clamping and degassing of either lung by O2 absorption. Lung collapse was estimated by increases in pulmonary shunt fraction. RESULTS: High IAP: Sequential increments in IAP caused a linear increase in Pplat (r2=0.754, P<0.0001). Ptp did not increase (r2=0.014, P=0.404) with IAP due to the concomitant increase in Pes (r2=0.726, P<0.0001). Partial Lung Collapse: There was no significant difference in Pplat between the atelectatic (21.83+/-0.63 cm H2O) and inflated lung (22.06+/-0.61 cmH2O, P<0.05). Partial lung collapse caused a significant decrease in Pes (11.32+/-1.11 mm Hg) compared with inflation (15.89+/-0.72 mm Hg, P<0.05) resulting in a significant increase in Ptp (inflated=5.97+/-0.72 mm Hg; collapsed=10.55+/-1.53 mm Hg, P<0.05). CONCLUSIONS: Use of Pplat to set ventilation may under-ventilate patients with intra-abdominal hypertension and over-distend the lungs of patients with atelectasis. Thus, Ptp must be used to accurately set mechanical ventilation in the critically ill.