Skip to main content
Log in

Effects of high-dose intraperitoneal aprotinin treatment on complement activation and acute phase response in acute severe pancreatitis

  • Liver, Pancreas, and Biliary Tract
  • Published:
Journal of Gastroenterology Aims and scope Submit manuscript

Abstract

Forty-eight patients with severe acute pancreatitis were treated with intraperitoneal lavage in a double-blind randomized multi-center trial. One group (aprotinin group,n=22) was also treated intraperitoneally with high doses of the protease inhibitor aprotinin. In the group not treated with aprotinin (control group), 6 patients were operated on because of pancreatic necrosis, compared with none in the treated group. Complement activation and the acute phase response were studied with measurements of anaphylatoxin C3a, C1 inhibitor (C1 Inh), interleukin 6 (IL-6), and C-reactive protein (CRP). The control group had higher plasma levels of C3a and lower levels of C1 Inh compared with the aprotinin group. The differences were statistically significant for C3a but not for C1 Inh. Both groups had high plasma levels of IL-6 and CRP. There were no differences between the groups in CRP levels, but the control group had higher IL-6 levels (not statistically significant) than the aprotinin group. This was caused by very high levels in the 6 patients operated on because of pancreatic necrosis, indicating that IL-6 could be a good plasma marker of pancreatic necrosis. The results also show that massive antiprotease treatment reduces complement activation, as illustrated by the lower C3a levels in the aprotinin group. The lower C1 Inh levels in the control group could have been caused by an increased consumption of the inhibitor.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Chiari H. Über die Selbstverdaung des menshlichen Pankreas. Z Helik 1896;17:69–96.

    Google Scholar 

  2. Ohlsson K. Experimental pancreatitis in the dog. Appearance of complexes between proteases and trypsin inhibitors in ascitic fluid, lymph and plasma. Scand J Gastroenterol 1971;6:642–652.

    Google Scholar 

  3. Geokas MC, Rinderknecht H. Free proteolytic enzymes in pancreatic juice of patients with acute pancreatitis. Am J Dig Dis 1974;19:591–598.

    Article  CAS  PubMed  Google Scholar 

  4. Ohlsson K, Eddeland A. Release of proteolytic enzymes in bile-induced pancreatitis in dogs. Gastroenterology 1975;69:668–675.

    CAS  PubMed  Google Scholar 

  5. Rao KN, Tuma J, Lombardi B. Acute hemorrhagic pancreatic necrosis in mice: Intraparenchymal activation of zymogens and other enzyme changes in pancreas and serum. Gastroenterology 1976;70:720–726.

    CAS  PubMed  Google Scholar 

  6. Borgström A, Ohlsson K. Immunoreactive trypsin in serum and peritoneal fluid in acute pancreatitis. Hoppe-Seyler's Z Physiol Chem 1978;359:677–681.

    PubMed  Google Scholar 

  7. Yamaguchi H, Kimura T, Mimura K, Nawata H. Activation of proteases in cerulein-induced pancreatitis. Pancreas 1989;4:565–571.

    CAS  PubMed  Google Scholar 

  8. Heath DI, Cruickshank A, Gudgeon AM, et al. The relationship between pancreatic enzyme release and activation and the acutephase protein response in patients with acute pancreatitis. Pancreas 1995;10:347–353.

    Article  CAS  PubMed  Google Scholar 

  9. Hirano T, Manabe T, Tobe T. Protection by gabexate mesilate (FOY) of the exocrine pancreas in rats with acute pancreatitis induced by a supramaximal dose of caerulein. J Gastroenterol Hepatol 1991;6:260–264.

    CAS  PubMed  Google Scholar 

  10. Fric P, Slaby J, Kasafirek E, et al. Effective peritoneal therapy of acute pancreatitis in the rat with glutaryl-trialanin-ethylamide: A novel inhibitor of pancreatic elastase. Gut 1992;33:701–706.

    CAS  PubMed  Google Scholar 

  11. Trapnell JE, Rigby CC, Talbot CH, Duncan EHL. A controlled trial of Trasylol in the treatment of acute pancreatitis. Br J Surg 1974;61:177–182.

    CAS  PubMed  Google Scholar 

  12. Imrie CW, Benjamin IS, Ferguson JC, et al. A single-centre double-blind trial of Trasylol therapy in primary acute pancreatitis. Br J Surg 1978;65:337–341.

    CAS  PubMed  Google Scholar 

  13. Medical Research Council Multicentre Trial. Morbidity of acute pancreatitis: The effect of aprotinin and glucagon. Gut 1980;21:334–339.

    Google Scholar 

  14. Pederzoli P, Bassi C, Cavallini G, et al. The Italian multicenter trial on gabexate mesilate versus aprotinin in human acute pancreatitis (abstract from European Pancreatic Club meeting September 16–18, 1991). Digestion 1991;49(1):43.

    Google Scholar 

  15. Larvin M, Wilson C, Heath D, et al. Intraperitoneal aprotinin therapy and the clinical course of acute pancreatitis. Br J Surg 1992;79:456–457.

    Google Scholar 

  16. Berling R, Genell S, Ohlsson K. High-dose intraperitoneal aprotinin treatment of acute severe pancreatitis: A double-blind randomized multi-center trial. J Gastroenterol 1994;29:479–485.

    CAS  PubMed  Google Scholar 

  17. Ranson JHC, Rifkind KM, Roses DF, et al. Prognostic signs and the role of operation management in acute pancreatitis. Surg Gynecol Obstet 1974;139:69–81.

    CAS  PubMed  Google Scholar 

  18. Wilson C, Heath DI, Imrie CW. Prediction of outcome in acute pancreatitis: A comparative study of APACHE II, clinical assessment and multiple factor scoring systems. Br J Surg 1990;77:1260–1264.

    CAS  PubMed  Google Scholar 

  19. Tran DD, Cuesta MA. Evaluation of severity in patients with acute pancreatitis. Am J Gastroenterol 1992;87:604–608.

    CAS  PubMed  Google Scholar 

  20. Silverstein W, Isikoff MB, Hill MC, Barkin J. Diagnostic imaging of acute pancreatitis. Am J Roentgenol 1981;137:497–502.

    CAS  Google Scholar 

  21. Balthazar EJ, Robinson DL, Megibow AJ, Ranson JHC. Acute pancreatitis: Value of CT in establishing prognosis. Radiology 1990;174:331–336.

    CAS  PubMed  Google Scholar 

  22. Warshaw A, Lee K. Serum ribonuclease elevations and pancreatic necrosis in acute pancreatitis. Surgery 1979;86:227–232.

    CAS  PubMed  Google Scholar 

  23. Schröder T, Kivilaakso E, Kinnunen PKJ, Lempinen M. Serum phospholipase A2 in human acute pancreatitis. Scand J Gastroenterol 1980;15:633–636.

    PubMed  Google Scholar 

  24. McMahon MJ, Bowen M, Mayer AD, Cooper EH. Relationship of α-2-macroglobulin and other antiproteases to the clinical features of acute pancreatitis. Am J Surg 1984;147:164–169.

    Article  CAS  PubMed  Google Scholar 

  25. Lasson Å, Ohlsson K. Changes in the kallikrein kinin system during acute pancreatitis in man. Thromb Res 1984;35:27–41.

    Article  CAS  PubMed  Google Scholar 

  26. Lasson Å, Balldin G, Ohlsson K. Leukocyte elastase 708-1 inhibitor complexes may diagnose pancreatic abscesses early. Scand J Gastroenterol 1986;21:221–224.

    CAS  PubMed  Google Scholar 

  27. Puolakkainen P, Valtonen V, Paananen A, Schröder T. C-reactive protein (CRP) and serum phospholipase A2 in the assessment of the severity of acute pancreatitis. Gut 1987;28:764–771.

    CAS  PubMed  Google Scholar 

  28. Berling R, Lasson Å, Axelsson L, et al. Plasma CRP levels in the prediction of complications during acute pancreatitis. Surg Res Comm 1990;8:241–249.

    Google Scholar 

  29. Windsor JA, Fearon KCH, Ross JA, et al. Role of serum endotoxin and antiendotoxin core antibody levels in predicting the development of multiple organ failure in acute pancreatitis Br J Surg 1993;80:1042–1046.

    CAS  PubMed  Google Scholar 

  30. Roxvall L, Bengtsson A, Heideman M. Anaphylatoxin generation in acute pancreatitis. J Surg Res 1989;47:138–143.

    Article  CAS  PubMed  Google Scholar 

  31. Schapira M, de Agostini A, Schifferli JA, Colman RW. Biochemistry and pathophysiology of human C1 inhibitor: Current issues. Complement 1985;2:111–126.

    CAS  PubMed  Google Scholar 

  32. Prograis LJ, Brickman CM, Frank MM. C1 inhibitor (C1-INH). J Med 1985;16:303–350.

    CAS  PubMed  Google Scholar 

  33. Mayer AD, McMahon MJ, Bowen M, Cooper EH. C-reactive protein: An aid to assessment and monitoring of acute pancreatitis. J Clin Pathol 1984;37:207–211.

    CAS  PubMed  Google Scholar 

  34. Büchler M, Malfertheimer P, Schoetensack C, et al. Sensitivity of antiproteases, complement factors and C-reactive protein in detecting pancreatic necrosis. Results of a prospective clinical study. Int J Pancreatol 1986;1:227–235.

    PubMed  Google Scholar 

  35. Wilson C, Heads A, Shenkin A, Imrie CW. C-reactive protein, antiproteases and complement factors as objective markers of severity in acute pancreatitis. Br J Surg 1987;76:177–181.

    Google Scholar 

  36. Castell JV, Gómez-Lechón MJ, David M, et al. Recombinant human interleukin-6 (IL-6/BSF-2/HSF) regulates the synthesis of acute phase proteins in human hepatocytes. FEBS Lett 1988; 232:347–350.

    Article  CAS  PubMed  Google Scholar 

  37. Morrone G, Ciliberto G, Oliviero S, et al. Recombinant interleukin 6 regulates the transcriptional activation of a set of human acute phase genes. J Biol Chem 1988;263:12554–12558.

    CAS  PubMed  Google Scholar 

  38. Leser H-G, Gross V, Scheibenbogen C, et al. Elevation of serum interleukin-6 concentration precedes acute-phase response and reflects severity in acute pancreatitis. Gastroenterology 1991;101:782–785.

    CAS  PubMed  Google Scholar 

  39. Viedma JA, Pérez-Mateo M, Domínguez JE, Carballo F. Role of interleukin-6 in acute pancreatitis. Comparison with C-reactive protein and phospholipase A. Gut 1992;33:1264–1267.

    CAS  PubMed  Google Scholar 

  40. Heath DI, Cruickshank A, Gudgeon M, et al. Role of interleukin-6 in mediating the acute phase response and potential as an early means of severity assessment in acute pancreatitis. Gut 1993;34:41–45.

    CAS  PubMed  Google Scholar 

  41. Laurell C-B. Electroimmunoassay. Scand J Clin Lab Invest 1972;29(Suppl 124):21–37.

    CAS  Google Scholar 

  42. Gallimore MJ, Friberg P. Simple chromogenic peptide substrat assays for determing prekallikrein, kinin and kallikrein “like” activity in human plasma. Thromb Res 1982;25:293–298.

    CAS  PubMed  Google Scholar 

  43. Boyden A, Button E, Germerog D. Precipitin testing with special reference to the measurement of turbidity. J Immunol 1947; 57:211.

    CAS  Google Scholar 

  44. Hack CE, Ogilvie AC, Eisele B, et al. Initial studies on the administration of C1-esterase inhibitor to patients with septic shock or with a vascular leak syndrome induced by interleukin-2 therapy. Prog Clin Biol Res 1994;388:335–357.

    CAS  PubMed  Google Scholar 

  45. Buerke M, Murohara T, Lefer AM. Cardioprotective effects of a C1 esterase inhibitor in myocardial ischemia and reperfusion. Circulation 1995;91:393–402.

    CAS  PubMed  Google Scholar 

  46. Vesentini S, Benetti L, Bassi C, et al. Effects of choline-esterase inhibitor in experimental acute pancreatitis in rats. Int J Pancreatol 1993;13:217–220.

    CAS  PubMed  Google Scholar 

  47. Cicardi M, Testoni P, Bergamaschini L, et al. Antiproteasic activity of C1 inhibitor. Therapeutic perspectives. Ann Ital Med Int 1994;9:180–182.

    CAS  PubMed  Google Scholar 

  48. Larvin M, Chalmers AG, McMahon MJ. Dynamic contrast-enhanced CT: Precise identification and localisation of pancreatic necrosis complicating acute pancreatitis. Br Med J 1990;330:1425–1428.

    Google Scholar 

  49. McMahon MJ. Plasma markers of pancreatic necrosis. In: Bradley III EI (ed). Acute pancreatitis: Diagnosis and therapy. New York: Raven 1994;47–55.

    Google Scholar 

  50. Ueyama M, Maruyama I, Osame M, Sawada Y. Marked increase in plasma interleukin-6 in burn patients. J Lab Clin Med 1992;120:693–698.

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Berling, R., Ohlsson, K. Effects of high-dose intraperitoneal aprotinin treatment on complement activation and acute phase response in acute severe pancreatitis. J Gastroenterol 31, 702–709 (1996). https://doi.org/10.1007/BF02347620

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02347620

Key words

Navigation