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Background: Research aimed at elucidating the pathogenesis of pancreatitis-associated lung injury and evaluating novel strategies for preventing respiratory complications in acute pancreatitis (AP) has not yet involved intravital microscopic (IVM) studies of pulmonary microcirculation in animals with severe disease., Objective: To characterize and compare pulmonary microcirculation in severe/necrotizing (NP) and mild/edematous pancreatitis (EP) in the rat., Methods: EP was induced by intravenous cerulein infusion (n = 10) and NP by a standardized intraductal infusion of glycodeoxycholic acid followed by intravenous cerulein (n = 10). After 24 h a left-sided thoracotomy was performed for IVM examination of pulmonary capillary blood flow, permeability, leukocyte sticking and the thickness of alveolar septi. Further measurements included monitoring of arterial blood gases and histological evaluation of lung injury., Results: In animals with NP, histology revealed severe pulmonary edema together with clustering of polymorphonuclear leukocytes in pulmonary microvessels and alveoli. IVM showed a greater number (n) of leukocytes sticking on the endothelium of pulmonary capillaries (9.4 +/- 0.7 vs. 1.8 +/- 0.2 in healthy control animals) and increased capillary permeability (260 +/- 14 vs. 136 +/- 6% relative fluorescein intensity) while capillary blood flow was decreased (0.41 +/- 0.05 vs. 0.57 +/- 0.03 mm/s). In comparison, changes in EP were significantly less pronounced (flow 0.5 +/- 0.04 mm/s, permeability 156 +/- 4%, leukocyte sticking n = 4.6 +/- 0.7)., Conclusions: These findings suggest that deterioration of pulmonary microcirculation in AP correlates with disease severity and that a model featuring NP may therefore be more suitable to further study pancreatitis-associated pulmonary injury., (Copyright 2003 S. Karger AG, Basel)

Background/aims: The reticuloendothelial system and in particular the Kupffer cells in the liver are important for eliminating antigens and toxic substances in many diseases including acute pancreatitis. Optimal Kupffer cell function is believed to depend on numerous factors including intact hepatic blood supply and microcirculation. The aim of the study was to evaluate whether hepatic microcirculation and Kupffer cell function are impaired in acute pancreatitis and whether enhancement of hepatic capillary blood flow leads to improved reticuloendothelial system function., Methodology: Acute pancreatitis was induced in rats by intraductal infusion of bile salt followed by i.v. cerulein hyperstimulation. Animals were randomized to receive either a selective endothelin-A receptor antagonist (ET-RA; LU-135252; 50 mg/kg) or saline. Sham-operated animals (intraductal and i.v. saline infusion) treated according to the same protocol served as controls. Liver phagocytic function was evaluated in 6 animals per group 6 and 24 hrs after acute pancreatitis induction and treatment using 99mTc-labeled Nanocoll and a scintillation camera technique. Another 6 animals of each group were used for intravital microscopic determination of hepatic capillary blood flow using fluorescein-labeled erythrocytes., Results: Six hours after acute pancreatitis induction, hepatic capillary blood flow and nanocoll clearance were significantly decreased in saline-treated animals (compared to saline-treated healthy controls). Endothelin-A receptor antagonist significantly improved hepatic capillary blood flow and nanocoll clearance. This beneficial effect was no longer seen after 24 hrs when these parameters had spontaneously returned to values not significantly different from normal., Conclusions: Reticuloendothelial system function and hepatic capillary blood flow are impaired (only) in the early stage of this acute pancreatitis model. Endothelin-A receptor antagonist improves hepatic capillary blood flow at this stage. Enhancement of hepatic capillary blood flow is accompanied by normalization of nanocoll clearance, suggesting that hepatic microcirculation influences phagocytic Kupffer cell function early in acute pancreatitis.

This study characterizes microcirculatory changes (capillary blood flow, capillary permeability, and leukocyte rolling) in the pancreas, colon, liver, and lungs at different stages of severe acute pancreatitis (AP) in a well-established rat model using intravital microscopy and computerized image analysis. The results demonstrate that microcirculatory disorders in severe AP are not confined to the pancreas but can also be found in the colon, liver, and lungs; that they extend beyond the early stage of AP and persist for 48 hr (and longer); and that they not only affect capillary blood flow but also involve prolonged changes of capillary permeability and leukocyte endothelial interaction. These findings may explain previous observations that therapeutic strategies aimed at enhancing microcirculation improve outcome in AP even if therapy is delayed and pancreatic necrosis can no longer be influenced. Since these systemic microcirculatory disturbances may contribute to AP-associated multiple organ dysfunction syndrome, further studies are warranted to evaluate whether improvement of microcirculation stabilizes organ function in AP and how long this may be effective after disease onset.

Endothelin-1 has been shown to reduce pancreatic blood flow and cause focal acinar cell necrosis similar to those seen in acute pancreatitis (AP), whereas therapy with endothelin receptor antagonists enhanced pancreatic capillary blood flow (PCBF) and decreased mortality rates. The current study evaluated the role of endothelin in the development of severe AP. Trypsinogen activation peptides, acinar cell necrosis, and PCBF were used as local indicators of disease severity, fluid sequestration, cardiorespiratory and renal parameters, and colonic capillary blood flow as systemic disease indicators. The following groups of animals were examined: 1) rats with mild edematous AP and 2) severe necrotizing AP treated with and without endothelin, 3) transgenic rats overexpressing endothelin with severe AP, and 4) rats with severe AP prophylactically treated with endothelin receptor antagonists. The following observations were made: endothelin superimposed on mild AP caused hemoconcentration, a decrease in PCBF, and necrosis and ascites not seen in this model without endothelin exposure. Endothelin superimposed on severe AP had no significant effects. After induction of severe AP, less PCBF and more acinar cell necrosis were observed in transgenic rats than in their normal littermates. Prophylactic endothelin receptor antagonists improved local (acinar necrosis, PCBF) and systemic parameters (ascites, urine production, colonic capillary blood flow) of disease severity in animals with severe AP. These observations underscore the role of endothelin as a mediator of disease severity in AP and suggest that endothelin receptor blockade may become a promising therapeutic tool in this disease.

Background: We previously demonstrated that therapy with a new endothelin A receptor antagonist (ET-RA) significantly reduced mortality rates in severe acute pancreatitis (AP) in the rat without attenuating local signs of disease severity (intrapancreatic protease activation, acinar cell necrosis). This raised the question as to why ET-RA was so effective. The purpose of this study was to assess the effect of ET-RA on microcirculation (particularly capillary permeability) within and outside of the pancreas on intravascular fluid loss and extravascular fluid sequestration and on distant organ function., Methods: Severe AP was induced in rats by standardized intraductal bile acid infusion and cerulein hyper-stimulation. Starting 6 hours (n = 24 rats) and 12 hours (n = 30 rats) after the onset of AP, animals randomly received either the ET-RA (LU-135252) or saline solution with fluid resuscitation (6 mL/kg/h Ringer's lactate). At 24 hours, animals were relaparotomized for intravital microscopic determination of capillary blood flow, leukocyte rolling, and capillary permeability in the pancreas and colon. Further monitoring included cardiorespiratory and renal parameters, hematocrit levels and quantification of ascites and pleural effusions, and acinar cell necrosis at autopsy. Groups of sham-operated healthy animals (n = 6 animals each) that had been treated according to the same protocol served as control animals., Results: ET-RA treatment that was started 6 hours after AP-induction significantly decreased hematocrit levels (38% +/- 1% vs 45% +/- 2% with saline solution treatment), reduced ascites and pleural effusions (6.7 +/- 1.3 mL vs 11.9 +/- 1.3 mL), and improved urine production (4.8 +/- 0.5 mL vs 2.9 +/- 0.6 mL) and respiratory parameters. Moreover, all microcirculatory parameters were improved; in particular, capillary permeability was stabilized (158% +/- 9% vs 248% +/- 8% in the colon). These beneficial effects were also seen when therapy was delayed until 12 hours after AP induction. Pancreatic necrosis was not significantly reduced. The overall mortality rate was 12% in ET-RA-treated animals and 42% in saline solution-treated control animals (P <.05). In healthy animals ET-RA did not significantly alter the target parameters, except for a reduction of capillary permeability in the pancreas., Conclusions: Improved microcirculation and stabilized capillary permeability in ET-RA-treated animals together with reduced intravascular fluid loss and extravascular fluid sequestration and improved renal and pulmonary function (1) may explain improved survival in this model, (2) support the hypothesis that systemic disease sequelae significantly contribute to outcome in AP, and (3) suggest that ET-RA may be a promising therapeutic tool in AP because it counteracts microcirculatory disorders that contribute to pancreatitis-associated organ dysfunction even when therapy is delayed to a point at which pancreatic injury may no longer be influenced.

Since randomized controlled studies of severe acute human pancreatitis can be performed only with restrictions, at least some aspects of innovative therapy concepts should first be clarified in animal experiments. In vitro trials are inadequate for this purpose since they cannot simulate the complex course of severe acute pancreatitis. Animal test results can be transferred to clinical practice if the results are based on trials with established models, standardized methods, and a study design imitating the clinical situation. This contribution discusses the demands on such an animal model of acute pancreatitis and a corresponding study protocol and presents models and protocols which meet these requirements. Concrete examples are presented to show that animal experiments are of great value under these conditions, especially in acute necrotizing pancreatitis. Further standardization of models, protocols, and monitoring should further improve future animal therapy studies at least to the extent that it is possible to select particularly promising substances, which should then be tested in randomized controlled trials.

Many of the complications in severe acute pancreatitis result from the amplifying effects of microcirculatory disruption. The pathogenesis of these microcirculatory disorders is multifactorial and involves various vasoactive mediators. Thus questions arise as to which vasoactive mediators are most important and how long after the onset of disease vasoactive mediator blockade may be effective. The present study compares the effect of delayed therapy with two vasoactive mediator antagonists, previously tested with promising results in other studies in a well-established rodent model of severe acute pancreatitis. Twelve hours after induction of acute pancreatitis, rats were randomized to therapy with intracellular adhesion molecule-1 (ICAM-1) antibody (2 mg/kg IA-29), endothelin A receptor antagonist (ET-RA) (40 mg/kg LU 135252), or saline solution (volume equivalent). After 12 hours of fluid resuscitation, animals underwent repeat laparotomy for intravital microscopic determination of capillary blood flow, leukocyte rolling, and capillary permeability in the pancreas and colon. Other measurements included cardiorespiratory parameters, hematocrit, pleural effusions, ascites, urine production, and survival. Compared to saline treatment, both ICAM antibody and ET-RA significantly enhanced capillary blood flow in the pancreas and colon, reduced leukocyte rolling, and stabilized capillary permeability. These beneficial effects on microcirculation were associated with decreased fluid loss into the third space and improved renal function and survival. Although both antagonists likewise enhanced capillary blood flow and reduced leukocyte rolling, ET-RA was significantly more effective than ICAM antibody in counteracting capillary leakage, thereby further reducing fluid sequestration. The present study confirms the beneficial effects of endothelin and ICAM antagonists in severe acute pancreatitis, even with delayed therapy, suggesting that both compounds are candidates for further clinical testing. Selective endothelin A receptor blockade appears to be especially attractive for clinical use not only because it was superior to ICAM antibody in the present study but also because of its favorable pharmacologic properties and (preliminary) positive results in clinical phase 2 studies currently underway for other diseases.

Background: Capillary leakage with fluid loss into the third space contributes to many of the early systemic complications in severe acute pancreatitis. There has been increasing interest in endothelin as one of the factors affecting capillary permeability., Aim: To elucidate further the role of endothelin in the development of capillary leakage in acute pancreatitis by investigating the effect of exogenous endothelin administration and endothelin receptor blockade in sham operated animals and two models of acute pancreatitis., Methods: Determination of capillary permeability in the pancreas and colonic mucosa by quantifying extravasation of fluorescein labelled dextran using a novel computer assisted video image analysis system., Results: Pancreatic and colonic capillary permeability increased stepwise from mild to severe acute pancreatitis. Endothelin increased pancreatic and colonic capillary permeability in healthy animals and animals with mild acute pancreatitis but had no additional adverse effect in severe acute pancreatitis. Endothelin receptor blockade decreased pancreatic capillary permeability in sham operated rats but had no effect on the colon. In mild and severe acute pancreatitis, endothelin receptor blockade stabilised increased capillary permeability in both the pancreas and colon., Conclusions: Endothelin plays an important role in mediating capillary permeability in the pancreas. In severe pancreatitis, it increases capillary permeability even outside the pancreas, thereby contributing to capillary leakage. Endothelin receptor blockade significantly reduces capillary permeability in acute pancreatitis both in and outside the pancreas, suggesting a therapeutic approach to counteract capillary leakage in severe acute pancreatitis.

Failure of intestinal barrier function and subsequent translocation of bacteria from the gut are believed to play a decisive role in the development of systemic septic complications, for example, following major trauma or major abdominal surgery. This study evaluated: (a) the effect of glutamine on colonic microcirculation and electrophysiological parameters reflecting gut barrier function, (b) the translocation of live bacteria to extraintestinal organs, and (c) disease outcome in two animal models with impaired gut barrier function. Severe acute pancreatitis or colitis was induced in rats randomized for therapy with or without glutamine (0.5 g/kg daily). After 48 h one animal group was prepared for intravital microscopy of colonic capillary blood flow and electrophysiological measurement of gut permeability; another was killed after 96 h for histological and microbiological examination. In animals with pancreatitis, glutamine (Gln) supplementation significantly improved gut permeability, i.e., Gln increased colonic transmucosal resistance from 67+/-7 to 92+/-3 Omega/cm(2) and decreased mannitol flux through the epithelium by 53%. Capillary blood flow in the colonic mucosa was improved by 25%. The prevalence of pancreatic infections was reduced from 86% in animals on standard parenteral nutrition to 33% in animals given the Gln-enriched diet (P<0.05); mortality decreased by 32%. In colitis, Gln had no significant effect on these parameters except for improving colonic capillary blood flow in colon segments not adjacent to the major injury site. Glutamine supplementation improves colonic capillary blood flow, stabilizes gut permeability, and reduces secondary pancreatic infections and mortality in severe rodent pancreatitis, but it is not helpful in colitis. This confirms previous reports that glutamine stabilizes gut barrier function only in certain diseases. Our experimental data strongly suggest that acute pancreatitis (rather than colitis) is one of the diseases with gut barrier dysfunction in which glutamine substitution may be helpful to reduce bacterial translocation and should therefore be tested in a controlled clinical trial.

Translocation of bacteria from the intestine causes local and systemic infection in severe acute pancreatitis. Increased intestinal permeability is considered a promoter of bacterial translocation. The mechanism leading to increased gut permeability may involve impaired intestinal capillary blood flow. The aim of this study was to evaluate and correlate early changes in capillary blood flow and permeability of the colon in acute rodent pancreatitis of graded severity. Edematous pancreatitis was induced by intravenous cerulein; necrotizing pancreatitis by intravenous cerulein and intraductal glycodeoxycholic acid. Six hours after induction of pancreatitis, the permeability of the ascending colon was assessed by the Ussing chamber technique; capillary perfusion of the pancreas and colon (mucosal and subserosal) was determined by intravital microscopy. In mild pancreatitis, pancreatic capillary perfusion remained unchanged (2.13 c 0.06 vs. 1.98 +/-0.04 nl x min(-1) x cap(-1) [control]; P = NS), whereas mucosal (1.59 +/-0.03 vs. 2.28 +/-0.03 nl x min(-1) x cap((-1))[control]; P <0.01) and subserosal (2.47 +/-0.04 vs. 3.74 +/-0.05 nl x min(-1) x cap((-1))[control]; P <0.01) colonic capillary blood flow was significantly reduced. Severe pancreatitis was associated with a marked reduction in both pancreatic (1.06 +/-0.03 vs. 1.98 +/-0.04 nl x min(-1) x cap(-1) [control]; P <0. 01) and colonic (mucosal: 0.59 +/-0.01 vs. 2.28 +/-0.03 nl x min(-1) x cap((-1))[control], P <0.01; subserosal: 1.96 +/-0.05 vs. 3.74 +/-0.05 nl x min(-1) x cap(-1) [control], P <0.01) capillary perfusion. Colon permeability tended to increase with the severity of the disease (control: 147 +/-19 nmol x thr(-1) x cm(-2); mild pancreatitis: 158 +/-23 nmol x hr(-1) x cm(-2); severe pancreatitis: 181 +/-33 nmol x hr(-1) x cm(-2); P = NS). Impairment of colonic capillary perfusion correlates with the severity of pancreatitis. A decrease in capillary blood flow in the colon, even in mild pancreatitis not associated with significant protease activation and acinar cell necrosis or impairment of pancreatic capillary perfusion, suggests that colonic microcirculation is especially susceptible to inflammatory injury. There was no significant change in intestinal permeability in the early stage of pancreatitis, suggesting a window of opportunity for therapeutic interventions to prevent the later-observed increase in gut permeability, which could result in improved intestinal microcirculation.

Background: Immunosuppressive drugs have been associated with the development and progression of acute pancreatitis after organ transplantation. Consequently, a reduction or a change in immunosuppressive therapy has been recommended once posttransplantation pancreatitis has been suspected. However, it is not known which of the available immunosuppressive agents is most harmful to the pancreas and which may be used safely in this situation. The objective of this study was to investigate the effect of different immunosuppressive drugs in various dosages on intrapancreatic protease activation, acinar cell necrosis, and mortality in an improved model of acute necrotizing pancreatitis in the rat. The rat model of acute necrotizing pancreatitis, like posttransplantation pancreatitis, is characterized by ischemia and microcirculatory disorders., Method: Acute pancreatitis was induced in rats by using a combination of low-dose controlled intraductal glycodeoxycholic acid superimposed on intravenous cerulein hyperstimulation. Six hours thereafter, animals were randomized to intravenous therapy with 2, 10, or 50 mg/kg/day prednisolone (PRED); 3, 15, or 60 mg/kg/day cyclosporine A (CsA); 10 mg/kg/day azathioprine (AZA); 0.6 mg/kg/day orthoclone OKT3 (OKT3); or saline. After 36 hr, surviving animals were killed to determine acinar cell necrosis and trypsinogen activation peptides levels (TAP) in blood and ascites., Results: Compared with saline-treated control rats, animals treated with 60 mg/kg/day CsA developed significantly more acinar cell necrosis and had increased amounts of TAP in ascites. Likewise, there was more extensive acinar cell necrosis in animals subjected to AZA therapy. However, this was not associated with incremental TAP. Animals treated with 3 or 15 mg/kg/day CsA, OKT3, or PRED showed no significant changes in these target parameters. Animals given 10 or 50 mg/kg/day PRED even had decreased hematocrit values and produced significantly less ascites than animals in the other groups., Conclusion: The present results suggest that AZA and high doses of CsA aggravate acute pancreatitis and should, therefore, be avoided once posttransplantation pancreatitis has been suspected, whereas lower doses of CsA, OKT3, and PRED may be used safely. PRED can even be used at higher doses as may be required when graft rejection is suspected.

The influence of experimental pancreatitis on bowel motility was measured in vivo with the propulsion technique and in vitro as contractility of isolated ileum muscle strips. In edematous pancreatitis, propulsion was reduced but contractility was normal. Both, propulsion and contractility were reduced in necrotizing pancreatitis. The intravenous saline infusion normalized propulsion in edematous pancreatitis but was of no benefit in necrotising pancreatitis. These results indicate that extraintestinal (neuroendocrine) regulation pathways were effected in edematous pancreatitis. Necrotising pancreatitis appears to have an additional profound influence on the intrinsic, intramural regulation of motility.

Despite numerous experimental and clinical investigations there is no consensus on the evolution of chronic pancreatitis (CP). In the 1970s and 1980s, Sarles persistently emphasised the de novo evolution of CP due to pancreatolithiasis. In recent years, however, clinical and morphological studies have provided strong evidence for the initial proposal of acute pancreatitis progressing to chronic pancreatitis. The so-called necrosis-fibrosis-sequence theory is supported by immunohistochemical work suggesting that inflammatory mediators primarily contribute to tissue destruction and that infiltration of pancreatic nerves by immune cells is a pathogenetic factor for the generation of pain in CP. While Sarles postulates that acinar hypersecretion and an imbalance of pancreatic stone promoting and inhibiting factors trigger the evaluation of CP, the necrosis-fibrosis-sequence theory also involves other pathomechanisms (e.g. changes in ductal permeability, ischemia, oxidative stress) which have been shown to cause (acute) pancreatic injury. Despite this unifying template, which also lessens the need to identify independent mechanisms for the pathogenesis of acute and chronic alcoholic pancreatitis, there are still open questions, e.g. on genetic factors that (like in hereditary CP) may explain the different susceptibility of the pancreas to injury and the individual immunological response.

Intestinal barrier failure and subsequent translocation of bacteria from the gut play a decisive role in the development of systemic infections in severe acute pancreatitis. Glutamine (GLN) has been shown to stabilize gut barrier function and to reduce bacterial translocation in various experimental settings. The aim of this study was to evaluate whether GLN reduces gut permeability and bacterial infection in a model of acute necrotizing pancreatitis. Acute necrotizing pancreatitis was induced in 50 rats under sterile conditions by intraductal infusion of glycodeoxycholic acid and intravenous infusion of cerulein. Six hours after the induction of pancreatitis, animals were randomly assigned to one of two groups: standard total parental nutrition (TPN) or TPN combined with GLN (0.5 g/kg(-1)/day(-1)). After 96 hours, the animals were killed. The pancreas was prepared for bacteriologic examination, and the ascending colon was mounted in a Ussing chamber for determination of transmucosal resistance and mannitol flux as indicators of intestinal permeability. Transmucosal resistance was 31% higher in the animals treated with GLN- supplemented TPN compared to the animals given standard TPN. Mannitol flux through the epithelium was decreased by 40%. The prevalence of pancreatic infections was 33% in animals given GLN-enriched TPN as compared to 86% in animals receiving standard TPN (P < 0.05). Adding GLN to standard TPN not only reduces the permeability of the colon but decreases pancreatic infections in acute necrotizing pancreatitis in the rat. This confirms previous reports that GLN decreases bacterial translocation by stabilizing the intestinal mucosal barrier. The present findings provide the first evidence suggesting that stabilizing the intestinal barrier can reduce the prevalence of pancreatic infection in acute pancreatitis and that GLN may be useful in preventing septic complications in clinical pancreatitis.

Objective: To correlate the results of operations for the treatment of biliary pancreatitis with the timing of the operation., Design: Retrospective study., Setting: University hospital, Germany., Subjects: 81 Consecutive patients who were operated on for biliary pancreatitis of the 106 who presented to the department between 1981 and 1990., Interventions: Cholecystectomy, with or without exploration of the common duct, together with no operation on the pancreas, exploration, or drainage and necrosectomy., Main Outcome Measures: Correlation of outcome with timing of operation after the onset of the pancreatitis (early, within 72 hours; delayed, 3-14 days; or elective, after 14 days)., Results: 37 Patients (46%) were operated on early; in 27 (33%) the operation was delayed; and in 17 (21%) it was elective. Timing correlated with outcome-22 patients (59%) of those operated on early developed a complication together with 12 (27%) of those in the delayed and elective groups (p < 0.005). The overall mortality was 12% (10/81). Multiple regression analysis showed that the timing of the operation and the severity of the pancreatitis were less important prognostic factors than the patient's age and the extent of pancreatitic operation (p < 0.005). The complication rate was 15/56 (27%) after none or exploration of the pancreas, compared with 19/25 (76%) after drainage or necrosectomy (p < 0.005)., Conclusion: Aggressive pancreatic surgery increases the risk of morbidity whereas extent of biliary surgery has no influence. Postponing the biliary operation until after the acute attack reduces the need for early exploration and drainage of the pancreas.

Background: Acute necrotizing pancreatitis (ANP) is characterized by decreased capillary pancreatic blood flow. Thus, antibiotics may not reach pancreatic necrosis in therapeutic concentrations and consequently fail to prevent bacterial infection of the pancreas which today is the major cause of morbidity and mortality in ANP., Objective: To evaluate whether improvement of impaired pancreatic microcirculation by isovolemic hemodilution with dextran leads to an increase in the pancreatic tissue concentration of imipenem (IMI), an antibiotic widely used in clinical ANP., Method: After induction of ANP rats were randomized for either standard fluid therapy with Ringer's lactate (RL) or isovolemic hemodilution with dextran 70,000 (IHD/DEX). Thereafter the animals received an intravenous injection of IMI, and 15 min later they were sacrificed for determination of IMI in serum and tissue. Capillary pancreatic blood flow (CPBF) at the time of antibiotic therapy was assessed by intravital microscopy in an additional set of animals., Results: There was no significant difference in the pancreatic tissue concentration of IMI in animals pretreated with either RL (11.7 +/- 0.6 micrograms/g) or IHD/DEX (11.4 +/- 1.4 micrograms/g), although CPBF was significantly increased in the latter group (1.3 +/- 0.05 vs. 0.8 +/- 0.04 nl/min/capillary)., Conclusion: (1) IMI is concentrated by the pancreas in experimental ANP despite impaired CPBF. (2) Enhancement of pancreatic capillary blood flow by IHD/DEX does not increase the pancreatic tissue concentration of IMI. This suggests that CPBF is not a decisive factor influencing the accumulation of this antibiotic in the pancreas, which may be one reason for the high efficacy of IMI in clinical ANP.

Extraintestinal trypsinogen activation peptides (TAP) have been shown to correlate with severity of acute pancreatitis in humans as well as in various animal models. Ischemia superimposed on experimental pancreatitis, however, increases acinar cell injury without increasing TAP in plasma. We speculated that TAP generated in the pancreas might not reach the circulation in necrotizing pancreatitis due to decreased pancreatic perfusion. To test the hypothesis that generation of TAP in plasma is related to pancreatic perfusion and that plasma TAP may therefore underestimate acinar cell injury in necrotizing disease, we correlated TAP in pancreatic tissue and body fluids with capillary pancreatic blood flow in necrotizing and edematous pancreatitis. The ratio between necrosis and TAP in tissue was similar in both models; the ratio between TAP in plasma and tissue, however, was significantly lower in necrotizing pancreatitis, indicating that a certain amount of TAP generated in the pancreas did not reach the circulation. Decreased pancreatic perfusion found in necrotizing pancreatitis was consistent with this finding. Our data suggest that TAP in tissue is most reliable to indicate severity of acute pancreatitis, whereas plasma TAP may underestimate pancreatic injury in necrotizing disease due to decreased pancreatic perfusion.

Objective: To reassess our criteria for the stratification of attacks of acute pancreatitis, and indications for operation in patients with necrotising pancreatitis., Design: Retrospective analysis of casenotes., Setting: University Hospital, Germany., Subject: 341 Consecutive patients who presented with a first attack of acute pancreatitis between December 1979 and January 1991., Main Outcome Criteria: Morbidity and mortality in relation to clinical (Ranson, Kümmerle, Goris) and radiological (Balthazar) criteria., Results: 78 Patients developed necrotising pancreatitis judged radiologically. Mortality was 15/38 (39%) in the period 1980-85 and 6/40 (15%) in the period 1986-1990. During the first period patients were operated on if their unfavourable clinical signs did not start to resolve within 72 hours, whereas in the second period operation was restricted to those patients who developed signs of multiple organ failure. This policy resulted in the number of operations being reduced from 26/38 (68%) to 17/40 (42%), respectively (p = 0.03)., Conclusion: Our data support the policy of restricting surgical debridement in necrotising pancreatitis to those patients who develop signs of multiple organ failure.

Background: Previous reports demonstrated that radiographic contrast medium, as used in contrast-enhanced computed tomography, increases acinar necrosis and mortality in experimental pancreatitis. The authors studied the possibility that these changes may be related to an additional impairment of pancreatic microcirculation., Methods: Fifty Wistar rats had acute pancreatitis induced by intraductal glycodeoxycholic acid (10 mmol/L for 10 min) and intravenous cerulein (5 micrograms/kg/hr for 6 hrs). After rehydration (16 mL/kg), pancreatic capillary perfusion was quantified by means of intravital microscopy at baseline before intravenous infusion of contrast medium (n = 25) or saline (n = 25), and 30 and 60 minutes thereafter. In addition to total capillary flow, capillaries were categorized as high- or low-flow (> or < 1.6 nL/min)., Results: Pancreatic capillary flow did not change in either high- or low-flow capillaries after saline infusion. However, contrast medium infusion induced a significant decrease of total capillary flow (p < 0.001). Analysis according to the relative flow rate revealed that this was primarily because of a significant additional reduction of perfusion in low-flow capillaries (p < 0.0001). Furthermore, complete capillary stasis was observed in 15.9 +/- 3.4% after contrast medium as compared with 3.2 +/- 1.2% after saline infusion (p < 0.006)., Conclusion: Radiographic contrast medium aggravates the impairment of pancreatic microcirculation in experimental necrotizing pancreatitis.

Background: Previous studies demonstrated that intravenous contrast medium (CM), as used in contrast enhanced computed tomography, aggravates the impairment of pancreatic microcirculation (PM) characteristic of severe pancreatitis and increases necrosis and mortality in necrotizing pancreatitis (NP) in rats. This study evaluates the use of isovolemic hemodilution, which can enhance the microcirculation in severe pancreatitis, for preventing CM-induced injury., Methods: NP was induced in 30 dextran-tolerant Wistar rats by intraductal glycodeoxycholic acid and intravenous cerulein for 6 hours. PM was quantified by intravital microscopy using fluorescein isothiocyanate labeled erythrocytes. Based on previous results, areas with low blood flow (< 1.6 nL/min/cap) were identified and baseline recordings of capillary blood flow taken. A reduction of hematocrit to 75% of baseline was achieved by replacement of 5 mL/kg of blood with 25 mL/kg Ringer's lactate (RL) or by exchange of 8 mL/kg of blood for the same amount of dextran 70.6%. Thereafter, the nonionic CM iopamidol (Solutrast, Byk Gulden, Konstanz, Germany) was injected during 1 minute and PM measurements repeated after 30 and 60 minutes., Results: Despite hemodilution with RL, pancreatic capillary perfusion was significantly decreased to 87% of baseline (0.83 +/- 0.04 mL/min/cap; n = 216) 60 minutes after CM infusion (P < 0.05). In contrast, capillary blood flow was significantly increased to 161% (1.56 +/- 0.05 nL/min/cap; n = 278) in the group treated with dextran. Moreover, the percentage of capillaries developing complete stasis was significantly lower in the dextran group (2.3 +/- 1.2%) compared to animals diluted with RL (22.3 +/- 4.8%) (P < 0.002)., Conclusion: Isovolemic hemodilution with dextran prevents the additional impairment of pancreatic microcirculation induced by CM in NP.

116 patients admitted for acute pancreatitis were analysed. In 80% of patients presenting biliary pancreatitis cholecystectomy and bile duct exploration was the prevalent treatment, in 7.8% pancreatic necrosis was removed. Indications to operate on patients with non-biliary pancreatitis included enhancement of pancreatic inflammation revealed by computed tomography and multi-organ-failure or sepsis complicating the course of the disease (incidence of laparotomy 20.3%, incidence of necrosectomy 12.3%). According to this concept 2 out of 3 patients presenting partial pancreatic necrosis recovered without operation. Lethality of patients with acute necrotizing pancreatitis (6.9%) was accounted 25%, over-all mortality 6%. Methods used for classification of severity of acute pancreatitis (Mainz classification, Ranson criteria) turned out to be not reliable. Clinical staging of pancreatitis was not in accordance with intraoperative findings in 51.9% of cases. As a prerequisite for stage-dependent therapy new objective data to access severity and clinical course of acute pancreatitis have to be worked out.