[Results from a survey of intensive care training. How much that is learned applies to later practice?]. / Umfrageergebnisse zur Ausbildung Intensivmedizin. Was lernt der angehende Chirurg für sein späteres Berufsleben?

BACKGROUND: There is no doubt that good knowledge of intensive care medicine is necessary for any surgeon, since major surgery entails postoperative intensive care requiring the surgeon's involvement. Recent changes in the German surgical training program, demands for the board examination, and further specialisation have raised the question whether the time spent in ICU education is still adequate and covers topics for young surgeons attendant to their personal professional aims. The present survey was performed to elucidate this topic. METHODS: Questionnaires were sent to 300 randomly chosen surgical residents. RESULTS: Of the questionnaires, 44% were returned and eligible for analysis: 95% considered their ICU education important, 32% worked longer than the (required) 6 months on the ICU, and 62% thought the time spent on ICU was adequate, whereas 14.5% thought it too long. Most of these fellows (84%) worked in university hospitals of large medical centers. After their ICU rotation, the majority felt familiar with the basic procedures and regarded them important also for future work. More advanced techniques (e.g. specifics of artificial ventilation or invasive haemodynamic monitoring) were considered less relevant or not at all. CONCLUSION: The majority of fellows (95%) considered ICU training important, but 50% felt that advanced ICU techniques were not relevant to their planned future work as surgeons. Especially in university hospitals and large medical centers, there were discrepancies between proposed and actually served ICU time as well as between the training program and the methods and techniques the young surgeons felt important for the future. This information may be useful when discussing requirements of surgical education programs.

Possible pitfalls in the interpretation of microcirculatory measurements. A comparative study using intravital microscopy, spectroscopy and polarographic pO2 measurements.

BACKGROUND: Microcirculation and tissue oxygenation play key roles in many diseases and have been studied in various settings. Comparison and interpretation of measurements at the capillary level, however, is difficult when different techniques are employed and when data on systemic parameters are missing. AIM: To investigate (a) how changes in systemic parameters influence microcirculation and tissue oxygenation; (b) if these changes are detectable at the capillary level, and (c) which systemic parameters must be monitored for reliable interpretation of microcirculatory parameters. METHODS: Assessment of capillary blood flow (CBF) and mucosal oxygen supply (Hb(Sat)O(2), p(muc)O(2)) of the colon in rats by (i) intravital microscopy (IVM), (ii) micro-light guide spectroscopy (EMPHO), and (iii) polarographic micro-catheter probe (LICOX) under (a) physiological conditions, (b) hypovolaemia, and (c) hypoxia. RESULTS: CBF (IVM), Hb(Sat)O(2) (EMPHO) and p(muc)O(2) (LICOX) changed significantly under hypovolaemia, but with different extents. Under hypoxia, CBF did not change, whereas Hb(Sat)O(2) and p(muc)O(2) decreased significantly to 52 and 67% of baseline. Correlation of IVM/EMPHO and IVM/LICOX was poor (r = 0.12; r = 0.03). CONCLUSION: Changes of systemic parameters have significant effects on peripheral tissue oxygenation but may not always be detected at the capillary level. MAP, blood gases and haematocrit must be analysed to correctly interpret microcirculatory parameters.

(Non-)compliance with guidelines for the management of severe acute pancreatitis among German surgeons.

BACKGROUND: Implementation of guidelines for the therapy of acute pancreatitis (e.g. those of the International Association of Pancreatology, IAP) into clinical practice has been assumed but not been evaluated. AIM: To verify the knowledge and acceptance of guidelines for the management of severe acute pancreatitis among German surgeons. METHODS: A questionnaire consisting of five short questions concerning key points in the management of severe acute pancreatitis was sent to the chairmen of the departments of general and visceral surgery of 39 university and 316 non-university hospitals in Germany. An additional, more detailed questionnaire accompanied the audit of the university chairmen. RESULTS: The response rate was 62%. 11% stated that they strictly followed all guidelines (IAP recommendations No. 2-6), 31% followed all but one recommendation, 31% did not follow 2 or more of the guidelines, and the answers of 27% suggested that their treatment differed substantially from the guideline recommendations. For example, fine needle aspiration biopsy, recommended to differentiate between infected and sterile necrosis in patients with signs of sepsis, was not performed by 55%, and prophylactic antibiotics, recommended to prevent secondary infection of pancreatic necrosis, were not given by 20%. CONCLUSION: German surgeons know the IAP recommendations for the management of severe acute pancreatitis and have implemented these guidelines in clinical practice. This, however, does not mean that all guideline concepts are strictly followed.

Concurrent chemoradiation with capecitabine and weekly irinotecan as preoperative treatment for rectal cancer: results from a phase I/II study.

The aim of this study was to investigate the efficacy and safety of chemoradiation using capecitabine and irinotecan as neoadjuvant therapy for patients with rectal cancer. Conventional radiation was given at daily fractions of 1.8 Gy on 5 days a week for a total dose of 55.8 (50.4 + 5.4) Gy. Concurrently, irinotecan 40 mg m(-2) once weekly and capecitabine continuously at dose levels of 500, 650, 750 and 825 mg m(-2) twice daily were administered. Surgery was performed 4-6 weeks following completion of chemoradiation. A total of 28 patients (3 UICC II, 25 UICC III) were enrolled and all received treatment. Dose-limiting toxicity was diarrhoea grade IV and hand-foot syndrome at the 825 mg m(-2) dose level. The maximum tolerated dose of capecitabine was 750 mg m(-2). Diarrhoea was the most common toxicity: grade III in nine patients. Two patients died, one due to pneumonia and one due to sudden cardiac death. A complete response and only microfocal residual tumour disease was achieved in four and three patients (27%). In all, 25 of 28 patients undergoing surgery, 24 (96%) had R0 resection. Preoperative chemoradiation based on continuous daily capecitabine and weekly irinotecan appears to tolerated and effective in patients with rectal cancer.

Octreotide hardens the pancreas.

BACKGROUND AND AIMS: Leakage from pancreaticojejunostomy and development of pancreatic fistulas are the major postoperative complications in patients undergoing duodenopancreatectomy. The risk of developing these complications is higher when surgery is performed on a soft pancreas. A recent report suggests that octreotide hardens the pancreas when given intraoperatively. The present study aims at verifying this observation by measuring tissue hardness of the pancreas by a commercially available durometer in pigs with and without octreotide pretreatment. METHODS: Three groups of pigs were investigated: Group 1 (n=6) received no treatment; group 2 (n=6) was treated with 3x100 microg octreotide for 1 day; group 3 (n=6) for 5 days. Thereafter, animals were killed and the pancreas was harvested for performing measurements: Tissue hardness was assessed by a commercially available durometer, and a suture holding test was performed using a Newton dynamometer. RESULTS: There was a significant increase in tissue hardness between untreated control animals [26.3+/-2.5 S.U. (shore units)] and animals with 1 day octreotide pretreatment (29.8+/-2.6 S.U.; p=0.04) as well as between the groups treated for 1 and 5 days (34.8+/-2.8 S.U.; p=0.01). Suture holding capacity was higher in animals treated for 5 days. CONCLUSION: The present study agrees with a recent report suggesting that octreotide hardens the pancreas. Octreotide pretreatment may therefore be an advantage when performing surgery on a soft pancreas, i.e., in patients scheduled for duodenopancreatectomy for ampullary carcinomas or circumscript pancreatic tumors not associated with chronic pancreatitis.

[A surgical approach to acute intestinal bleeding]. / Chirurgische Therapiekonzepte bei unterer gastrointestinaler Blutung.

The estimated incidence of lower gastrointestinal bleeding (LGIB) is 20/100,000 patients per year. Of these cases, 70-80% are minor or stop spontaneously and do not present as emergency hospital admissions. Colonoscopy and angiography detect 80-90% of major LGIB, and subsequent endoscopic intervention or embolisation can control approximately 70%. Emergency surgical intervention is required in haemodynamically unstable patients with persistent bleeding. The surgical treatment of choice is directed to resecting the bleeding bowel segment. Subtotal colectomy is performed in patients with colonic bleeding that can not exactly be localized. Segmental colon resection is often associated with rebleeding and not recommended in this situation. Primary anastomosis can usually be performed; elderly patients in reduced condition, however, are candidates for stoma. In case of persistent or recurrent bleeding and differentiation between intestinal and colonic bleeding fails, loop ileostomy may be performed. If the bleeding appears to originate from somewhere in the small bowel, an additional loop jejunostomy may be performed for specification. The mortality from acute LIGB is approximately 5% but increases with emergency surgery. Risk factors are age, comorbidity, and shock on admission.

Intensified concurrent chemoradiotherapy with 5-fluorouracil and irinotecan as neoadjuvant treatment in patients with locally advanced rectal cancer.

This study aimed to evaluate the feasibility and efficacy of neoadjuvant chemoradiotherapy intensified with irinotecan in patients with locally advanced rectal cancer. Eligible patients had nonmetastatic disease at a locally advanced stage that made R0 resection and sphincter preservation uncertain. They received preoperative radiation over 6 weeks to 45 Gy and boost of 5.4 Gy and concurrent continuous infusion 5-fluorouracil 250 mg m(-2) day(-1) and weekly irinotecan 40 mg m(-2). In all, 37 patients entered the study. T stage at baseline as determined by ultrasound was T2/T3/T4 in 2/19/16 patients; 31 patients had lymph node involvement. The predominant toxicity was diarrhoea (grade 3/4 in 10/2 patients). Haematologic toxicity and surgical complications were moderate. Among 36 patients undergoing surgery, 32 (89%) had R0 resection and 23 (64%) sphincter preservation. Pathologic complete response (pCR) was achieved in eight (22%) of 36 patients, and 10 patients (28%) had only microscopic residual disease. At 4 years, overall survival was 66%, disease-free survival 73%, local relapse rate 7%, and distant failure rate 24%. Extent of resection and postoperative nodal status were significant predictors of overall and disease-free survival. Intensified neoadjuvant chemoradiotherapy with irinotecan can be safely administered and results in a high pCR rate.

Pulmonary microcirculation in mild and severe experimental pancreatitis.

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.

Temporary unilateral microembolization of the lung-a new approach to regional chemotherapy for pulmonary metastases.

BACKGROUND: Except in patients with resectable disease, treatment of pulmonary metastases is still disappointing. Regional chemotherapy may be a suitable method for delivering more effective doses to regionally confined tumors while minimizing systemic toxicity. We propose an unilateral chemoembolization of the lung applicable by endovascular method. MATERIALS AND METHODS: An unilateral microembolization of the lung with degradable starch microspheres (DSM) alone (group 1) and combined with carboplatin (group 2) was performed on Sprague-Dawley rats (n = 12). Microcirculatory parameters were studied by in vivo videomicroscopy and radiological pattern on pulmonary angiogram. RESULTS: After injection of DSM, mean embolization time in subpleural capillaries was 7.1 +/- 2.3 min, followed by a mean flow retardation of 14.3 +/- 4.6 min; 21.4 +/- 4.7 min after embolization, original flow of erythrocytes was observed demonstrating reperfusion and reversibility of microembolization. After reperfusion relative fluorescence measured in subpleural alveoli was 0.13 +/- 0.049 in group 1, 0.105 +/- 0.016 in group 2, and 0.11 +/- 0.036 in control group (NS). Alveolar septal diameter was 17.3 +/- 1.13 microm in group 1, 16.8 +/- 1.25 microm in group 2, and 16.6 +/- 1.08 microm in control group (NS), demonstrating neither altered permeability nor pulmonary edema. Pulmonary angiogram confirmed patency of the central pulmonary artery. CONCLUSION: For the first time unilateral microembolization of the lung could be established in an experimental model. By injection of DSM, reversible embolization on arteriolar and capillary level could be demonstrated without occlusion of the main branches of the pulmonary arteries. Alveolar-capillary membrane disorder as symptom of early toxicity could not be detected even with additional application of carboplatin.

Persistent multiple organ microcirculatory disorders in severe acute pancreatitis: experimental findings and clinical implications.

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.

Changes of colonic mucosal microcirculation and histology in two colitis models: an experimental study using intravital microscopy and a new histological scoring system.

This study investigated capillary blood flow (CBF) and pathomorphological alterations in the mucosa of different bowel segments at different times after disease onset in rats with colitis induced by either trinitrobenzensulfonic acid (TNBS) or mitomycin-C. CBF was determined by intravital microscopy using fluorescein-labeled erythrocytes. The histological degree of inflammation was assessed by a new scoring system. Severe acute histological changes were found in the distal colon 24 hr after induction of TNBS colitis (score: 8.9+/-1.0). CBF was increased (2.9+/-0.05 vs. 2.6+/-0.04 nl/min in healthy controls). The histological alterations persisted until day 3 (8.5+/-0.9) when CBF significantly decreased (1.8+/-0.05 nl/min). After 15 days, moderate acute inflammation was still detectable histologically (5.4+/-1.3), but CBF had returned to normal values. In mitomycin-C colitis, changes developed mainly in the proximal colon: After three days, there was mild inflammation (2.8+/-1.2) with normal CBF (2.5+/-0.1 nl/min). After seven days, the inflammation had increased (4.8+/-1.1), while CBF had decreased (1.5+/-0.06 nl/min). These changes persisted for six weeks (5.3+/-0.7; 1.2+/-0.05 nl/min). These data suggest that disturbed colonic microcirculation may play an important role in the pathogenesis of inflammatory bowel disease regardless of the histopathomorphological alterations.

An experimental rat model for studying pulmonary microcirculation by in vivo videomicroscopy.

It is unclear what role pulmonary microcirculatory disorders play in the pathogenesis of adult respiratory distress syndrome. The aim of this study was to establish a rat model for the direct visualization of pulmonary microcirculation by in vivo fluorescence videomicroscopy. The pulmonary terminal vascular bed was visualized and the microcirculatory parameters of leukocyte sticking, erythrocyte velocity, capillary permeability, and interalveolar septal diameter were quantified. These parameters were examined simultaneously. The preparation was stable for 120 min. Under hyperthermia, there was increased permeability with a relative fluorescence of 0.39 +/- 0.19 compared to 0.16 +/- 0.13 in the control group, and interalveolar septal diameters were wider (30.7 +/- 2.9 microm) than in control animals (17.3 +/- 3 microm). Under hypothermia and hypovolemia, the erythrocyte velocity was lower (0.351 +/- 0.063 and 0.378 +/- 0.044 mm/s) than in control groups (0.527 +/- 0.07 mm/s). Under hypoventilation, we observed a higher amount of leukocyte sticking (3.1 +/- 1.1 vs 1.8 +/- 0.8 cells/alveolus) and increased permeability (relative fluorescence 1.03 +/- 0.37 vs 0.16 +/- 0.13 in the control group). The model of rat lung exposure for direct examination of microvascular structures in living animals was valuable because it remained stable for 2 h under baseline conditions and demonstrated distinct changes in microcirculatory parameters following specific pathophysiological interventions.

Angiogenesis inhibitor TNP-470 reduces human pancreatic cancer growth.

In this study we investigated the effects of the angiogenesis inhibitor TNP-470 on human pancreatic cancer cells in vitro and in vivo. The action of TNP-470 on vascular endothelial growth factor (VEGF) was also assessed. In vitro human pancreatic cancer cells (MIAPaCa-2, AsPC-1, and Capan-1), and human umbilical vein endothelial cells (HUVEC) were exposed to increasing concentrations (1 pg/ml to 100 microg/ml) of TNP-470. Cell proliferation was assessed after 3 days by cell count and MTT assay. In vivo, 5 x 10(6) pancreatic cancer cells were injected subcutaneously into nude mice. Four weeks later, 1 mm3 fragments of the resulting tumors were implanted into the pancreas of other mice. Animals received either TNP-470 (30 mg/kg every other day) or vehicle subcutaneously for 14 weeks. The volume of the primary tumor and metastatic spread were determined at autopsy. Concentrations of VEGF were determined in serum (VEGF(S)) and ascites (VEGF(A)) by enzyme-linked immunosorbent assay. Microvessel density was analyzed by immunohistochemistry in CD31-stained tumor sections. In vitro, proliferation and viability of the human pancreatic cancer cell lines were significantly inhibited at high concentrations of TNP-470 (> 1 microg/ml). In contrast, TNP-470 effectively decreased the growth of HUVEC at 100 pg/ml. In vivo, tumor volume and dissemination scores were significantly lower in all three pancreatic cancer cell lines. VEGF(S) and VEGF(A) were not different between treated groups. Treatment with TNP-470 significantly reduced neoangiogenesis in tumors of all three human pancreatic cancer cell lines: MIAPaCa-2 = 74.8 +/- 7.8/0.74 mm2 vs. 24.8 +/- 3.7/0.74 mm2; AsPC-1 = 65.3 +/- 5.0/0.74 mm2 vs. 26.0 +/- 3.4/0.74 mm2; and Capan-1 = 82.2 +/- 5.8/0.74 mm2 vs. 26.9 +/- 2.5/0.74 mm2 (P < 0.001). However, survival was not statistically different between groups. TNP-470 reduced tumor growth and metastatic spread of pancreatic cancer in vivo. This was probably due to the antiproliferative effect of the agent on endothelial cells rather than to the direct inhibition of pancreatic cancer cell growth. TNP-470 activity was not associated with alteration of VEGF secretion.

Endothelin mediates local and systemic disease sequelae in severe experimental pancreatitis.

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.

An improved clinical model of orthotopic pancreatic cancer in immunocompetent Lewis rats.

The study of pancreatic cancer (PaCa) requires orthotopic, clinically relevant animal models. The aims of this study were to establish an orthotopic model of ductal pancreatic adenocarcinoma in immunocompetent Lewis rats and to develop a scoring system to quantify local tumor infiltration and distant metastasis. Cells (10(7)) of the rat ductal PaCa cell line DSL-6A/C1 were injected s.c. into donor rats. After 8 weeks, either three (IPL-3) or five (IPL-5) fragments (1 mm3) of the resulting s.c. tumors were microsurgically implanted into the pancreas of recipient rats. In another series of animals, 10(7) DSL-6A/C1 cells were directly injected (INJ) into the pancreas. All animals were monitored daily until death or for 16 weeks. At autopsy, volume of primary tumors and ascites, local and systemic tumor spread, and histologic phenotype were assessed. IPL-5 resulted in significantly larger tumors (12,224 +/- 1,933 mm3), more local infiltration and systemic spread (score: 18.3 +/- 2.0 points), severe clinical tumor disease, and lethality (50%) in comparison to the other induction techniques (IPL-3: 283 +/- 115 mm3/3.5 +/- 0.8 points/0; INJ: 752 +/- 207 mm3/4.3 +/- 0.8 points/8%). Histologic examination revealed moderately to well-differentiated ductal tumors, surrounded by dense stroma. Intraperitoneal tumor dissemination in the INJ group occurred simultaneous with primary tumor growth, indicating PaCa cell spread during injection. Orthotopic implantation of five DSL-6A/C1 tumor fragments into the rat pancreas provides a valid clinical model of ductal pancreatic adenocarcinoma in immunocompetent rodents for preclinical treatment studies. The dissemination score we used permitted quantification of local and systemic tumor spread.

[Pancreatitis and nutrition. Significance of the gastrointestinal tract and nutrition for septic complications]. / Pankreatitis und Ernährung. Bedeutung des Gastrointestinaltraktes und der Ernährung für die septischen Komplikationen.

Septic complications are an important factor for the morbidity and mortality of acute pancreatitis. The gut has been identified as a source of infection early in the course of the disease allowing intestinal bacteria to translocate into pancreatic necrosis and other organs. Bacterial translocation is promoted by an impaired intestinal mucosal barrier which can be attributed to the reduced oxygen and substrate supply of the intestine during the early systemic response to the pancreatic injury. A rat model of severe acute pancreatitis has been used to confirm the hypothesis that an impaired mucosal barrier can be stabilized by supplying certain nutritients, vitamins and trace elements. Following a discussion of the many aspects of bacterial translocation and gut derived sepsis, the role of the gut and nutrition for the development of septic complications in acute pancreatitis is summarized as follows: Early in the course of acute pancreatitis the gut is a target organ of the primary systemic inflammatory response (SIRS) to pancreatic injury. SIRS-induced gut barrier dysfunction promoting bacterial translocation makes the gut the motor for secondary (septic) complications. As a septic focus the gut becomes a target for therapeutic measures aimed at stabilizing the impaired gut barrier. Nutritive factors demonstrated to improve impaired gut barrier function include early enteral feeding and specific factors like glutamine which are essential for enterocytes and colonocytes in stress. Experimental data are presented to underline the significance of these nutritive factors and subsequent randomized multicenter trials performed to verify the positive experimental results are introduced. The effect of other nutritive factors (e.g. omega-3-fatty acids) has not yet been systemically investigated. Thus, experimental and clinical studies need to be performed for evaluating their effect on bacterial translocation and the disease course in acute pancreatitis.

Endothelin receptor blockade in severe acute pancreatitis leads to systemic enhancement of microcirculation, stabilization of capillary permeability, and improved survival rates.

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.

Experimental models of acute pancreatitis: are they suitable for evaluating therapy?

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.

Animal models of exocrine pancreatic cancer.

Clinically and biologically relevant animal models are mandatory to further evaluate both the pathophysiology and novel strategies for diagnosis and treatment of exocrine pancreatic cancer. This review briefly summarizes the features of human pancreatic cancer in order to define requirements for animal models of the disease. The described model systems in rodents include pancreatic cancer induced by chemicals, pancreatic cancer in transgenic, and immunodeficient animals.