Abstracts
1998 Digestive Disease Week
#1074
THERAPY OF MICROCIRCULATORY DISORDERS IN SEVERE ACUTE PANCREATITIS: WHAT IS MORE EFFECTIVE: PLATELET ACTIVATING FACTOR- OR ENDOTHELIN-RECEPTOR BLOCKADE? Th. Foitzik, H.G. Hotz, B. Hotz, G. Eibl, M. Kirchengast*, H.J. Buhr. Dept. of Surgery, Benjamin Franklin Medical Center, Freie Universitåt Berlin and *Knoll AG, Ludwigshafen, Germany.
Microcirculatory disorders in severe acute pancreatitis (i) are not confined to the pancreas but can also be observed in other organs (e.g. colon, lung, liver); (ii) contribute not only to the progression of local tissue injury but also to multiorgan dysfunction syndrome; (iii) are in part caused by vasoactive mediators such as platelet activating factor (PAF) and endothelin-1 (ET) activated during the disease process. Experimental and first clinical evidence have suggested that PAF and ET antagonists ameloriate disease severity and improve survival. To further evaluate the potential therapeutic role of these receptor antagonists (RA), the present study compares the effect of PAF and ET receptor blockade on microcirculation and organ function in a rodent model of acute necrotizing pancreatitis (ANP) suitable for evaluating therapy of this disease. Methods: ANP was induced in 24 rats by a standardized intraductal infusion of bile salt followed by iv. cerulein over 6 hrs. Thereafter, animals were randomized for therapy with ET-RA (50mg/kg LU-135252), PAF-RA (32 µg/kg WEB-2170) or NaCl 0.9% (vol.equiv.). After 24 hrs. of fluid resuscitation (6ml/kg Ringer's lactate) animals were relaparotomized for intravital microscopic determination of capillary blood flow (CBF), leucocyte rolling (LR) and capillary permeability (CP) using fluorescein-labelled erythrocytes and FITC-dextran 150. Organ functions were determined by measuring heart rate, mean arterial pressure and blood gases, pleural effusions (PE), ascites and urine production. Healthy sham-operated animals (Contr.+NaCl) served as additional controls (data not shown). Survival was determined in an additional series of 36 animals with ANP treated with
ET-RA, PAF-RA of NaCl observed for 48 hrs.
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CBF
(nl/min/cap)
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LR
(c/min)
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CP#
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PE
(ml)
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Ascites
(ml)
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Urine
(ml)
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Mort
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Panc.
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Colon
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Mesentery
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Colon
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-
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-
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-
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-
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1.5 ± 0.05
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1.3 ± 0.04
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16.3 ± 1.6
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248 ± 6
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4.0 ± 0.4
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8.0 ± 0.5
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2.9 ± 0.7
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6/12
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1.8 ± 0.04
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1.5 ± 0.03
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12.5 ± 1.6
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188 ± 4
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2.7 ± 0.5
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6.7 ± 0.7
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3.9 ± 1.1
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3/12
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2.0 ± 0.05*
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1.5 ± 0.04
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7.0 ± 1.6*
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114 ± 5*
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1.5 ± 0.4
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5.3 ± 1.6
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4.8 ± 0.6
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2/12
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Conclusion: This study confirms the beneficial effect of PAF- and ET-1 receptor blockade on microcirculation, organ function and survival in severe experimental pancreatitis. While both receptor antagonists likewise improved capillary blood flow, ET-RA was significantly more effective in counteracting leucocyte endothelial interactions and capillary leakage, thereby reducing fluid loss into the third space, which is believed to contribute to renal and respiratory complications early in ANP. Therefore and based on our experiences with other therapeutic means which proved effective in this model as well as in human ANP, we believe that ET-RA should be tested in a clinical trial either in comparison or in addition to PAF-RA.
Copyright 1996 - 1998, SSAT, Inc. Revised 29 June 1998.
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