Abstract
Objective
Ultrahigh-molecular dextran (500 000 DA) has been shown to prevent pancreatic necrosis when given 30 min after induction of pancreatitis. This study should clarify the following: (a) are dextrans still effective after prolongation of the therapy-free interval? (b) what is the impact of the molecular weight of the dextrans? and (c) is their effect influenced by the dextran concentration or by the addition of hypertonic saline?
Animals and interventions
Acute pancreatitis was induced in 70 male dextran-tolerant Wistar rats using intraductal bile-salt infusion and intravenous hyperstimulation. After 3 h, animals were assigned to one of seven groups (n=10 per group) receiving either Ringer solution or different dextrans (10%) including 70 000 Da (DEX-70), 160 000 Da (DEX-160), 300 000 Da (DEX-300) or 500 000 Da (DEX-500). Additional groups included DEX-70 (6%) and DEX-70 (10%) in combination with hypertonic NaCl (7.5%) (HHS-70). Ringer solution was given at 24 ml/kg and all dextrans at 8 ml/kg.
Measurements and results
Trypsinogen activation peptides (TAP) were quantified in ascites and acinar necrosis after death or sacrifice at 9 h. As an index of less pathological trypsinogen activation, the mean TAP levels in ascites were significatly lower in DEX-70 and DEX-160 compared to Ringer controls (p<0.05,t-test). Furthermore, the amount of acinar necrosis was significantly lower in all dextran groups except the HHS-70 in comparison with Ringer controls (p<0.01,t-test). Finally, mortality was significantly reduced from 60% in Ringer controls to 10 and 0%, respectively, in the groups treated with DEX-70 and DEX-160 (p<0.03, Fisher's Exact test). There was a similar trend in all other groups except the HHS-70.
Conclusions
Despite a therapy-free interval of 3 h, dextrans reduce trypsinogen activation, prevent acinar necrosis, and improve survival in necrotizing rodent pancreatitis. The molecular weight and concentration of dextran are of secondary importance for these beneficial effects.
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References
Niederau C, Crass RA, Silver G, Ferrell Grendell JH (19887 Therapeutic regimens in acute experimental hemorrhagic pancreatitis: effects of hydration, oxygenation, peritoneal lavage, and a potent protease inhibitor. Gastroenterology 95:1648–1657
Lankisch PG, Koop H, Winckler K, Schmidt H (1979) Continuous peritoneal dialysis as treatment of acute experimental pancreatitis in the rat. I. Effect on length and rate of survival. Dig Dis Sci 24:111–116
Imrie CW, Benjamin IS, Ferguson JC, McKay AJ, Mackenzie I, O'Neill J, Blumgart LH (1978) A single-centre double-blind trial of trasylol therapy in primary acute pancreatitis. Br J Surg 65:337–341
Kimura T, Zuidema GD, Cameron JL (1980) Acute pancreatitis: experimental evaluation of steroid, albumin and trasylol therapy. Am J Surg 140: 403–408
Aho HJ, Nevalainen TJ, Aho AJ (1983) Experimental pancreatitis in the rat. Development of pancreatic necrosis, ischemia and edema after intraductal sodium taurocholate injection. Eur Surg Res 15:28–36
Foulis AK (1980) Histological evidence of initiating factors in acute necrotising pancreatitis in man. J Clin Pathol 32: 1125–1131
Spormann H, Sokolowski A, Birkigt HG, Letko G (1986) Contribution of pancreatic edema and short-term ischemia to experimental acute pancreatitis in the rat. I. Procedure and pathomorphological investigations. Z Exp Chir Transpl Künstl Organe 19:323–330
Nuutinen P, Kivisaari L, Standertskjoeld-Nordenstam CG, Lempinen M, Schroeder T (1986) Microangiography of the pancreas in experimental oedemic and haemorrhagic pancreatitis. Scand J Gastroenterol 21:12–17
Klar E, Messmer K, Herfarth C (1986) The effect of hemodilution on the impairment of pancreatic microcirculation in acute biliary pancreatitis. Langenbecks Arch Chir Suppl 299–302
Klar E, Endrich B, Hammersen F, Messmer K, Herfarth C (1986) Therapeutic effect of isovolemic hemodilution with dextran 60 in the morphological integrity of the pancreas in acute biliary pancreatitis. Langenbecks Arch Chir Suppl 367-2-371
Klar E, Herfarth C, Messmer K (1990) Therapeutic effect of isovolemic hemodilution with dextran 60 on the impairment of pancreatic microcirculation in acute biliary pancreatitis. Ann Surg 211:346–353
Klar E, Messmer K, Warshaw AL, Herfarth C (1990) Pancreatic ischaemia in experimental acute pancreatitis: mechanism, significance and therapy. Br J Surg 77:1205–1210
Martin DT, Steinberg SM, Kopolovic R, Carey LC, Cloutier CT (1984) Crystalloid versus colloid resuscitation in experimental hemorrhagic pancreatitis. J Am Coll Surg 159:445–449
Schmidt J, Rattner DW, Lewandrowski K, Compton CC, Mandavilli U, Knoefe WT, Warshaw AL (1991) A better model of acute pancreatitis for evaluating therapy. Ann Surg 215:44–56
Fernandez-del Castillo C, Schmidt J, Rattner DW, Lewandrowski K, Compton CC, Jehanli A, Patel G, Hermon-Taylor J, Warshaw AL (1991) Generation and possible significance of trypsinogen activation peptides in experimental acute pancreatitis in the rat. Pancreas 7:263–270
Schmidt J, Fernandez-del Castillo C, Rattner DW, Lewandrowski K, Compton CC, Warshaw AL (1992) Trypsinogen activatin peptides in experimental rat pancreatitis: prognostic implications and histopathologic correlates. Gastroenterology 103: 1009–1016
Schmidt J, Lewandrowski K, Warshaw AL, Compton CC, Rattner DW (1992) Morphometric characteristics and homogeneity of a new model of acute pancreatitis in the rat. Int J Pancreatol 12:41–51
Schmidt J, Fernandez-del Catillo C, Rattner DW, Lewandrowski K, Messmer K, Warshaw AL (1993) Hyperoncotic ultrahigh molecular weight dextran solutions reduce trypsinogen activation, prevent acinar necrosis, and lower mortality in rodent pancreatitis. Am J Surg 165:40–45
Harris JM, West GB (1963) Rats resistant to the dextran anaphylactoid reaction. Br J Pharmacol 20:550–562
Ivarsson L, Appelgren L, Rudenstam CM (1975) Plasma volume after dextran infusion in rats sensitive and nonsensitive to dextran. Eur Surg Res 7:315–325
Mandavilli U, Schmidt J, Rattner DW, Watson WT, Warshaw AL (1991) Continuous complete collection of uncontaminated urine in the conscious rodent. Lab Anim Sci 41:258–261
Gudgeon AM, Heath DI, Hurley P, Jehanli A, Patel G, Wilson C, Shenkin A, Austen BM, Imrie CW, Hermon-Taylor J (1990) Trypsinogen activation peptides assay in the early prediction of severity of acute pancreatitis. Lancet 335:4–8
Hurley PR, Cook AJ, Austen BM, Hermon-Taylor J (1988) Antibodies to trypsinogen activation peptides recognize both Ca2+ dependent and Ca2+ independent epitopes. Biochem Soc Trans 16:337–338
Hurley PR, Cook A, Jehanli A, Austen BM, Hermon-Taylor J (1988) Development of radioimmunoassays for free tetra-l-aspartyl-l-lysine trypsinogen activation peptides (TAP). J Immunol Methods 111:195–203
Klar E, Endrich B, Messmer K (1990) Microcirculation of the pancreas. A quantitative study of physiology and changes in pancreatitis. Int J Microcirc Clin Exp 9:85–101
Schiller WR, Anderson MC (1974) Microcirculation of the normal and inflamed canine pancreas. Ann Surg 181: 466–470
Kühn R, Blöchle C, Knöfel WT, Kusterer K, Izbicki JR, Brölsch CE (1995) Aufrechterhaltung der Mikrozirkulation durch den Bradykinin Antagonisten Hoe 140 in der Na-Taurocholat-Pankreatitis der Ratte. Langenbecks Arch Chir Suppl 444–449
Kusterer K, Poschmann T, Friedemann A, Enghofer M, Zendler S, Usadel KH (1993) Arterial constriction, ischemia reperfusion, and leukocyte adherence in acute pancreatitis. Am J Physiol 265: G165-G174
Popper HL, Necheles H, Russel K (1948) Transition of pancreatic edema into pancreatic necrosis. J Am Coll Surg 87:79–82
Anderson MC (1963) Venous stasis in the transition of edematous pancreatitis to necrosis. JAMA 183:534–537
Klar E, Rattner DW, Compton C, Stanford G, Chernow B, Warshaw AL (1991) Adverse effects of therapeutic vasoconstrictors in experimental acute pancreatitis. Ann Surg 214:168
Fernandez-del Castillo C, Harringer W, Warshaw AL, Vlahakes GJ, Koski G, Zaslavsky AM, Rattner DW (1991) Risk factors for pancreatic cellular injury after cardiopulmonary bypass. N Engl J Med 325:382–387
Harvey MH, Wedgwood KR, Reber HA (1987) Treatment of acute pancreatitis with β-adrenergic agonist drugs. Surgery 102:229–234
Mishler JM (1984) Synthetic plasma volume expanders — their pharmacology, safety and clinical efficacy. Clin Haematol 13:75–92
Horton JW, Dunn CW, Burnweit CA, Walker PB (1989) Hypertonic salinedextran resuscitation of acute canine bile-induced pancreatitis. Am J Surg 158:48–56
Klar E, Mall G, Messmer K, Herfarth C, Rattner DW, Warshaw AL (1993) Improvement of impaired pancreatic microcirculation by isovolemic hemodilution protects pancreatic morphology in acute biliary pancreatitis. J Am Coll Surg 176: 144–150
Messmer K, Kreimeier U, Hammersen F (1988) Microcirculation in circulatory disorders. In: Manabe H, Zweifach BW, Messmer K (eds) Multiple organ failure: clinical implications to macro- and microcirculation. Springer, Berlin Heidelberg New York, 147–157
Nolte D, Lehr HA, Messmer K (1991) Dextran and adenosine-coupled dextran reduce postischemic leukocyte adherence in postcapillary venules of the hamster. Prog Appl Microcirc 10: 103–111
Werner J, Schmidt J, Gebhard MM, Herfarth C, Klar E (1996) Inhibition of leucocyte-endothelium interaction in the treatment of experimental necrotizing pancreatitis (abstract). Gastroenterology 110 [Suppl]: A442
Schmidt J, Hotz HG, Langer C, Buhr HJ, Herfarth C, Klar E (1995) Dextran induziert eine spezifische Verbesserung der reduzierten Pankreasmikrozirkulation bei experimenteller nekrotisierender Pankreatitis. Langenbecks Arch Chir Suppl 427-432
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Supported by Deutsche Forschungsgemeinschaft no. Schm 781/2-1+2
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Hotz, H.G., Buhr, H.J., Herfarth, C. et al. Benefits of various dextrans after delayed therapy in necrotizing pancreatitis of the rat. Intensive Care Med 22, 1207–1213 (1996). https://doi.org/10.1007/BF01709338
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DOI: https://doi.org/10.1007/BF01709338