(1/258) A monoclonal anti-interleukin 8 antibody (WS-4) inhibits cytokine response and acute lung injury in experimental severe acute necrotising pancreatitis in rabbits.
BACKGROUND: Interleukin 8 (IL-8) has recently been proposed to have an important role in mediating the development of the systemic sequelae associated with severe acute pancreatitis. AIMS: To define the role of IL-8 in acute pancreatitis by neutralising its effects with a monoclonal anti-IL-8 antibody (WS-4), in a rabbit model of severe acute pancreatitis. METHODS: Acute pancreatitis was induced by retrograde injection of 5% chenodeoxycholic acid into the pancreatic duct and duct ligation. Twenty rabbits were divided equally into two groups: acute pancreatitis controls received physiological saline and the treated group received WS-4, 30 minutes before induction of acute pancreatitis. RESULTS: Pretreatment of animals with WS-4 resulted in significant down regulation of serum IL-8 and tumour necrosis factor alpha (TNF-alpha) from three to six hours after induction of acute pancreatitis (p = 0.011 and 0.047 for IL-8 and 0.033 and 0.022 for TNF-alpha, respectively). In addition, a significant reduction in the CD11b and CD18 positive cells and the amount of interstitial neutrophil infiltration in the lungs from WS-4 treated animals was seen. In contrast, WS-4 did not alter the amount of pancreatic necrosis and the serum concentrations of amylase, lipase, calcium, and glucose. CONCLUSION: WS-4 cannot change the amount of pancreatic necrosis induced by injection of 5% bile acid, but does reduce the acute lung injury, presumably through inhibition of circulating IL-8 and TNF-alpha, and CD11b/CD18 in lung tissue. Therefore, a role of IL-8 in the progression of acute pancreatitis and the development of its systemic complications is suggested. (+info)
(2/258) Influence of zero-balanced hemofiltration on the course of severe experimental pancreatitis in pigs.
OBJECTIVE: To examine the impact of continuous venovenous hemofiltration (CVVH) on the course of experimental pancreatitis in pigs. SUMMARY BACKGROUND DATA: The activation of different mediator cascades is assumed to trigger multiple organ dysfunction or failure during necrotizing pancreatitis. CVVH has been suggested to be beneficial in those instances by eliminating several inflammatory mediators released in the circulation. METHODS: Pancreatitis was induced by a combined intraductal injection of sodium taurocholate and enterokinase. Control group animals received no treatment after induction. A second group underwent "therapeutic" CVVH after a 20% decline of mean arterial pressure. In the third group, "prophylactic" CVVH was started simultaneously with the induction of pancreatitis. The concentrations of tumor necrosis factor-alpha, transforming growth factor-beta1, kinin, and phospholipase A2 were measured at different time points in blood (pre- and postfilter) and in the hemofiltrate to calculate the respective sieving coefficients that reflect most accurately the plasma clearance of mediators by CVVH. RESULTS: Survival time was significantly prolonged both by therapeutic and prophylactic CVVH; it was more pronounced in the latter. CVVH did not influence the increase in transforming growth factor concentrations. However, 6 hours after induction, the increases of plasma concentrations of tumor necrosis factor, phospholipase, and kinin were significantly weakened by CVVH compared with controls. In the treatment groups, the plasma concentrations of tumor necrosis factor and phospholipase showed a significant negative correlation with the respective sieving coefficients, which decreased in the later course of the experiments. CONCLUSIONS: Experimental necrotizing pancreatitis was associated with a tremendous increase of plasma concentrations of tumor necrosis factor, phospholipase, and kinin. The effective removal of these mediators by CVVH resulted in significantly improved survival time. Animals that received prophylactic CVVH had a longer survival period than those in which CVVH was started after clinical impairment. The decreasing efficiency of CVVH in eliminating inflammatory mediators in the later course of the experiments suggested that the filter membranes were compromised by long-term application. These findings provide further evidence that CVVH offers therapeutic options even in the absence of conventional indications for blood-purifying treatments. (+info)
(3/258) Specific therapy for local and systemic complications of acute pancreatitis with monoclonal antibodies against ICAM-1.
OBJECTIVE: To analyze the time points and levels of the expression of adhesion molecules in the pancreas and lung in pancreatitis of different severities, and to assess whether treatment with a monoclonal antibody against intercellular adhesion molecule-1 (ICAM-1) can reduce local and systemic complications. BACKGROUND: The outcome of severe acute pancreatitis relates to its pulmonary and septic complications. Leukocyte adhesion and infiltration, both mediated by ICAM-1, are central events in the pathogenesis of necrotizing pancreatitis. METHODS: Expression of ICAM-1 at different time points was assessed by immunohistochemistry and Western blot analysis in pancreas and lungs from rats with mild edematous or severe necrotizing pancreatitis. ICAM-1 expression was correlated with leukocyte infiltration and histologic changes. The possible therapeutic effect of monoclonal antibodies against ICAM-1 was assessed by measuring pancreatic and lung injury. RESULTS: In edematous pancreatitis, increased ICAM-1 expression in pancreas was evident by 6 hours but did not occur in lung. In contrast, ICAM-1 was upregulated at 3 hours in the pancreas and at 12 hours in lung in necrotizing pancreatitis. Increased expression of ICAM-1 preceded leukocyte infiltration. Treatment of severe necrotizing pancreatitis with monoclonal antibodies against ICAM-1 decreased both local pancreatic injury and systemic lung injury compared with untreated controls. CONCLUSIONS: Upregulation of ICAM-1 and subsequent leukocyte infiltration appear to be significant mediators of pancreatic and pulmonary injury in pancreatitis, and both the onset and extent correlate with severity. The time course should permit effective prevention of tissue damage by treatment with ICAM-1 antibodies. (+info)
(4/258) Polyarticular heterotopic ossification complicating critical illness.
A patient with generalized heterotopic ossification (HO) complicating critical illness due to necrotizing pancreatitis is described; data on two other cases with HO are briefly presented. The clinical features, prevention and therapy of HO are discussed. The effect of surgical therapy of the HO in our three patients was good. (+info)
(5/258) Role of procalcitonin and granulocyte colony stimulating factor in the early prediction of infected necrosis in severe acute pancreatitis.
BACKGROUND: Infected pancreatic necrosis (IPN) is the main cause of death in patients with severe acute pancreatitis. Therefore an early prediction of IPN is of utmost importance. AIM: Analysis of new blood variables as potential early predictors to differentiate between IPN and sterile pancreatic necrosis (SPN). PATIENTS: 64 consecutive patients with acute pancreatitis were enrolled in this prospective study; 29 were suffering from acute oedematous pancreatitis (AIP), and 35 from necrotising disease (NP) as diagnosed by contrast enhanced computed tomography. METHODS: Procalcitonin (PCT) and granulocyte colony stimulating factor (G-CSF) in the serum were examined and compared with C reactive protein (CRP). CRP was measured with a turbidimetric immunoassay (Autokit CRP; Wako, Osaka, Japan), and PCT and G-CSF by ELISA (Lumitest PCT; Brahms Diagnostica, Berlin, Germany; G-CSF-Elisa; R&D Systems, Abingdon, Oxon, UK). Monitoring was performed daily and related to the onset of symptoms. RESULTS: Within the first week, all three variables (CRP, PCT, and G-CSF) were significantly higher in patients with NP than in those with AIP (CRP, p<0.001; G-CSF, p<0. 001; PCT, p<0.001). During the course of the study, 12 of the 35 patients with NP developed late IPN after a median of 20.5 (range 3-49) days. Neither the peak nor the lowest concentrations during the monitoring period were of any value for predicting IPN (median peak values in SPN v IPN: PCT, 0.93 v 1.93 ng/ml; G-CSF, 347 v 421 pg/ml; CRP, 270 v 325 mg/l). CONCLUSIONS: Serum PCT, G-CSF, and CRP concentrations are of similar value for early differentiation between mild and severe acute pancreatitis. However, these variables are not suitable for the early prediction of IPN. (+info)
(6/258) Pathophysiologic role of oxygen free radicals in acute pancreatitis: initiating event or mediator of tissue damage?
BACKGROUND AND OBJECTIVE: Oxidative stress is an important factor in the pathogenesis of acute pancreatitis, as shown in vivo by the beneficial effects of scavenger treatment and in vitro by the potential of free radicals to induce acinar cell damage. However, it is still unclear whether oxygen free radicals (OFR) act only as mediators of tissue damage or represent the initiating event in acute pancreatitis in vivo as well. In the present study the authors aimed to address this issue in an experimental set-up. MATERIALS AND METHODS: Two hundred male Wistar rats were randomly assigned to one of the following experimental groups. In two groups, acute necrotizing pancreatitis was induced by retrograde intraductal infusion of 3% sodium taurocholate. Through the abdominal aorta, a catheter was advanced to the origin of the celiac artery for continuous regional arterial (CRA) pretreatment with isotonic saline (NP-S group) or superoxide dismutase/catalase (NP-SOD/CAT group). In another group, oxidative stress was generated by CRA administration of xanthine oxidase and intravenous administration of hypoxanthine (HX/XOD group). Sham-operated rats received isotonic saline both arterially and intraductally. After observation periods of 5 and 30 minutes and 3 and 6 hours, the pancreas was removed for light microscopy and determination of reduced glutathione (GSH), oxidized glutathione (GSSG), conjugated dienes (CD), and malondialdehyde as a marker for OFR-induced lipid peroxidation as well as myeloperoxidase as a parameter for polymorphonuclear leukocyte accumulation. RESULTS: A significant decrease of GSH was paralleled by an increased ratio of GSSG per total glutathione and elevated CD levels after 5 minutes in the NP-S group versus the sham-operated group. Thereafter, the percentage of GSSG and GSH returned to normal levels until the 6-hour time point. After a temporary decrease after 30 minutes, CD levels increased again at 3 hours and were significantly higher at 6 hours in contrast to sham-operated rats. Myeloperoxidase levels were significantly elevated at 3 and 6 hours after pancreatitis induction. In contrast to NP-S rats, treatment with SOD/CAT significantly attenuated the changes in glutathione metabolism within the first 30 minutes and the increase of CDs after 6 hours. HX/XOD administration lead to changes in levels of GSH, GSSG, and CDs at 5 minutes as well as to increased myeloperoxidase levels at 3 hours; these changes were similar to those observed in NP-S rats. Acinar cell damage including necrosis was present after 5 minutes in both NP groups, but did not develop in HX/XOD rats. In addition, serum amylase and lipase levels did not increase in the latter group. SOD/CAT treatment significantly attenuated acinar cell damage and inflammatory infiltrate compared with NP-S animals during the later time intervals. CONCLUSION: OFRs are important mediators of tissue damage. However, extracellular OFR generation alone does not induce the typical enzymatic and morphologic changes of acute pancreatitis. Factors other than OFRs must be involved for triggering acute pancreatitis in vivo. (+info)
(7/258) Percutaneous necrosectomy and sinus tract endoscopy in the management of infected pancreatic necrosis: an initial experience.
OBJECTIVE: To describe the development of a minimally invasive technique aimed at surgical debridement in addition to simple drainage of the abscess cavity. SUMMARY BACKGROUND DATA: Surgical intervention for secondary infection of pancreatic necrosis is associated with a death rate of 25% to 40%. Although percutaneous approaches may drain the abscess, they have often failed in the long term as a result of inability to remove the necrotic material adequately. METHODS: Fourteen consecutive patients with infected necrosis secondary to acute pancreatitis were studied. The initial four patients underwent sinus tract endoscopy along a drainage tract for secondary sepsis after prior open necrosectomy. This technique was then modified to allow primary debridement for proven sepsis to be carried out percutaneously in a further 10 patients. The techniques and initial results are described. RESULTS: Additional surgery for sepsis was successfully avoided in the initial four patients managed by sinus tract endoscopy, and none died. Of the following 10 patients managed by percutaneous necrosectomy, 2 died. The median inpatient stay was 42 days. There was one conversion for intraoperative bleeding. Eight patients recovered and were discharged from the hospital after a median of three percutaneous explorations. Only 40% of patients required intensive care management after surgery. CONCLUSIONS: These initial results in an unselected group of patients are encouraging and show that unlike with percutaneous or endoscopic techniques, both resolution of sepsis and adequate necrosectomy can be achieved. The authors' initial impression of a reduction in postoperative organ dysfunction is particularly interesting; however, the technique requires further evaluation in a larger prospective series. (+info)
(8/258) Fluconazole penetration into the pancreas.
Because of antibiotic prophylaxis for necrotizing pancreatitis, the frequency of fungal superinfection in patients with pancreatic necrosis is increasing. In this study we analyzed the penetration of fluconazole into the human pancreas and in experimental acute pancreatitis. In human pancreatic tissues, the mean fluconazole concentration was 8.19 +/- 3.38 microg/g (96% of the corresponding concentration in serum). In experimental edematous and necrotizing pancreatitis, 88 and 91% of the serum fluconazole concentration was found in the pancreas. These data show that fluconazole penetration into the pancreas is sufficient to prevent and/or treat fungal contamination in patients with pancreatic necrosis. (+info)