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

Guido Alsfasser, Andrew L. Warshaw, Sarah P Thayer, Bozena Antoniu, Michael Laposata, Kent B. Lewandrowski, Carlos Fernández-del Castillo

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)670-676
Number of pages7
JournalArchives of Surgery
Volume141
Issue number7
DOIs
StatePublished - Jul 24 2006

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Protein C
Pancreatitis
Inflammation
Survival
Ceruletide
Pancreas
Peroxidase
Glycodeoxycholic Acid
Necrosis
Lung
Leukocytosis
United States Food and Drug Administration
Sodium Chloride
Sprague Dawley Rats
Sepsis
Pneumonia
Outcome Assessment (Health Care)

ASJC Scopus subject areas

  • Surgery

Cite this

Decreased inflammation and improved survival with recombinant human activated protein C treatment in experimental acute pancreatitis. / Alsfasser, Guido; Warshaw, Andrew L.; Thayer, Sarah P; Antoniu, Bozena; Laposata, Michael; Lewandrowski, Kent B.; Fernández-del Castillo, Carlos.

In: Archives of Surgery, Vol. 141, No. 7, 24.07.2006, p. 670-676.

Research output: Contribution to journalArticle

Alsfasser, G, Warshaw, AL, Thayer, SP, Antoniu, B, Laposata, M, Lewandrowski, KB & Fernández-del Castillo, C 2006, 'Decreased inflammation and improved survival with recombinant human activated protein C treatment in experimental acute pancreatitis', Archives of Surgery, vol. 141, no. 7, pp. 670-676. https://doi.org/10.1001/archsurg.141.7.670
Alsfasser, Guido ; Warshaw, Andrew L. ; Thayer, Sarah P ; Antoniu, Bozena ; Laposata, Michael ; Lewandrowski, Kent B. ; Fernández-del Castillo, Carlos. / Decreased inflammation and improved survival with recombinant human activated protein C treatment in experimental acute pancreatitis. In: Archives of Surgery. 2006 ; Vol. 141, No. 7. pp. 670-676.
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abstract = "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.",
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AU - Thayer, Sarah P

AU - Antoniu, Bozena

AU - Laposata, Michael

AU - Lewandrowski, Kent B.

AU - Fernández-del Castillo, Carlos

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