Decreased inflammation and improved survival with recombinant human activated protein C treatment in experimental acute pancreatitis

Hypothesis: Drotrecogin alfa (activated), the pharmacologic form of activated protein C and the first Food and Drug Administration-approved drug for treatment of severe sepsis, is beneficial in experimental acute pancreatitis (AP). Design: Animal study. Setting: Laboratory. Subjects: Male Sprague-Dawley rats. Interventions: Mild (intravenous cerulein) or severe (intravenous cerulein plus intraductal glycodeoxycholic acid) AP was induced in 72 rats, and coagulation evaluated. Rats with severe AP were randomized to treatment with drotrecogin alfa (activated), 100 μg/kg per hour, or isotonic sodium chloride. Main Outcome Measures: Histologic scoring of pancreatic necrosis, inflammation of the pancreas and lung (measured by myeloperoxidase concentration), coagulation measures, and 24-hour survival. Results: Severe consumptive coagulopathy, hemoconcentration, and leukocytosis were observed 6 hours after induction of severe AP, but not in mild AP. Treatment of AP with drotrecogin did not worsen coagulation measures. Although the degree of pancreatic necrosis was comparable in treated and untreated animals with severe AP, drotrecogin significantly reduced myeloperoxidase levels in the pancreas (P=.009) and lungs (P=.03). The 24-hour survival in severe AP was markedly improved in animals treated with drotrecogin (86% vs 38%; P=.05). Conclusions: Animals with severe AP have severe consumptive coagulopathy, but administration of drotrecogin alfa (activated), 100 μg/kg per hour, does not worsen coagulation abnormalities. Drotrecogin treatment reduces inflammation in the pancreas and lungs and significantly improves survival. These results encourage clinical investigation of drotrecogin in the treatment of severe AP.