A Novel Selective Cytopheretic Inhibitory Device (SCD) Inhibits Circulating Leukocyte Activation and Ameliorates Multiorgan Dysfunction in a Porcine Model of Septic Shock

초록

Acute kidney injury (AKI) leading to acute renal failure promotes a systemic inflammatory response syndrome (SIRS). SIRS results in systemic microvascular (MV) damage and, if severe, multiorgan dysfunction. The MV injury is promoted primarily via activated circulating leukocytes. We have developed a synthetic membrane device with the ability to bind and inhibit activated neutrophils along a continuous renal replacement extracorporeal circuit. This device is called a selective cytopheretic inhibitory device (SCD, XR-1 ) and was evaluated in an established acute porcine model of septic shock and AKI. Septic shock was initiated with direct intraperitoneal infusion of E. Coli and the animal placed into a CRRT circuit with only colloid and crystalloid volume resuscitation procedures with the SCD (n = 7) or sham SCD (n = 11). Cardiovascular and pulmonary function, systemic and bronchoalveolar lavage fluid (BAL) inflammatory indices, capillary leak parameters and activated neutrophil levels were measured. SCD maintained cardiovascular and pulmonary functionality, ameliorated the degree of capillary leak, minimized systemic and BAL inflammation, and diminished the level of neutrophil activation compared to sham controls (p < 0.05 for various parameters). Most importantly, SCD increased survival time from 6.8 0.3 to 8.7 0.6 hours (p < 0.02). A recent exploratory Phase I/II multicenter clinical trial has suggested that XR-1 promotes 90-day survival advantage compared to sham controls in ICU patients with AKI and multiorgan failure. These results suggest a central role for leukocyte activation and multiorgan dysfunction in severe sepsis.