C. Fernandez-del Castillo

Débridement and closed packing for the treatment of necrotizing pancreatitis.

OBJECTIVE To evaluate the results of débridement and closed packing for necrotizing pancreatitis and to determine the optimal timing of surgical intervention based on patient outcomes. METHODS Between February 1990 and November 1996, 64 consecutive patients with necrotizing pancreatitis were treated with necrosectomy followed by closed packing of the cavity with stuffed Penrose and closed suction drains. The mean APACHE II score immediately before surgery was 9, and 31% of the patients had organ failure. Patients were stratified with an outcome score based on death and major complications; this was correlated with the timing of surgical intervention. The data were then subjected to cut-point analysis by sequential group comparison. RESULTS Patients underwent surgery a median of 31 days after diagnosis. Fifty-six percent had infected necrosis. The mortality rate was 6.2% and was no different in infected or sterile necrosis. Eleven patients required a second surgical procedure and 13 required percutaneous drainage; a single surgical procedure sufficed in 69%. Enteric fistulae occurred in 16% of patients. The mean hospital stay after surgery was 41 days, and the interval until return to regular activities was 147 days. A significant negative correlation between duration of pancreatitis and outcome scores was found, and sequential group comparison demonstrated that the change point at which significantly better outcomes were encountered was day 27. CONCLUSION Débridement of pancreatic necrosis followed by closed packing and drainage is accomplished with a low mortality rate and reduced rates of complications and second surgical procedures. Although intervention is best deferred until the demarcation of necrosis is complete, delay beyond the fourth week confers no additional advantage.

Pancreatic injury in rats induced by fatty acid ethyl ester, a nonoxidative metabolite of alcohol

BACKGROUND & AIMS The mechanism by which alcohol injures the pancreas remains unknown. Alcohol-intoxicated humans have high levels of fatty acid ethyl esters (FAEEs), nonoxidative products of ethanol metabolism, in blood, pancreas, and liver. The aims of this study were to determine whether FAEEs are toxic to the pancreas in vivo and, if so, to assess whether this injury is specific to the pancreas and to compare it to the injury observed in acute pancreatitis. METHODS FAEEs were infused into Sprague-Dawley rats. Levels of FAEEs in plasma and pancreas were measured, and pancreatic injury was assessed during a 48-hour period for edema formation and ectopic trypsinogen activation and by light and electron microscopy. RESULTS FAEEs induced highly significant increases in pancreatic edema, pancreatic trypsinogen activation, and vacuolization of acinar cells. These findings were specific to the pancreas and were not found in liver, lung, myocardium, skeletal muscle, or subcutaneous fat. CONCLUSIONS FAEEs at concentrations found in human plasma produce a pancreatitis-like injury in rats, providing direct evidence that FAEEs can produce organ-specific toxicity. Thus, FAEEs may contribute to acute alcohol-induced damage to the pancreas.

Pathogenesis and prevention of early pancreatic infection in experimental acute necrotizing pancreatitis

ObjectiveThe authors test antibiotic strategies aimed at either mitigating bacterial translocation from the gut or delivering antibiotics specifically concentrated by the pancreas for prevention of early secondary infection after acute necrotizing pancreatitis. BackgroundInfection currently is the principal cause of death after severe pancreatitis. The authors have shown that the risk of bacterial infection correlates directly with the degree of tissue injury in a rodent model of pancreatitis. Bacteria most likely arrive by translocation from the colon. MethodsSevere acute necrotizing pancreatitis was induced in rats by a combination of low-dose controlled intraductal infusion of glycodeoxycholic acid superimposed on intravenous cerulein hyperstimulation. At 6 hours, animals were randomly allocated to five treatment groups: controls, selective gut decontamination (oral antibiotics and cefotaxime), oral antibiotics alone, cefotaxime alone, or imipenem. At 96 hours, surviving animals were killed for quantitative bacterial study of the cecum, pancreas, and kidney. ResultsThe 96-hour mortality (35%) was unaffected by any treatment regimen. Cecal gram-negative bacteria were significantly reduced only by the oral antibiotics. Pancreatic infection was significantly reduced by full-gut decontamination and by imipenem, but not by oral antibiotics or by cefotaxme alone. Renal infection was reduced by both intravenous antibiotics. ConclusionsEarly pancreatic infection after acute necrotizing pancreatitis can be reduced with a full-gut decontamination regimen or with an antibiotic concentrated by the pancreas (imipenem) but not by unconcentrated antibiotics of similar spectrum (cefotaxime) or by oral antibiotics alone. These findings suggest that 1) both direct bacterial translocation from the gut and hematogenous seeding interplay in pancreatic infection while hematogenous seeding is dominant at extrapancreatic sites and 2) imipenem may be useful in clinical pancreatitis.

On the protective mechanisms of nitric oxide in acute pancreatitis

Background—Ectopic protease activation, microcirculatory changes, and leucocyte activation are the main events in the pathogenesis of acute pancreatitis. Nitric oxide (NO) is known to be a key mediator in the normal and inflamed pancreas. Aims—To investigate the targets on which NO exerts its effect in caerulein induced pancreatitis. Methods—Acute pancreatitis was induced in rats which additionally received either the NO synthase substrate, l-arginine; the NO donor, sodium nitroprusside; or the NO synthase inhibitor, N-nitro-l-arginine methyl ester (l-NAME). At six hours, pancreatic injury (oedema, leucocyte content, ectopic trypsinogen activation) was analysed and pancreatic oxygenation and perfusion were determined. A direct influence of NO on amylase secretion and trypsinogen activation was evaluated separately in vitro. Results—Both NO donors reduced the grade of inflammation. l-NAME increased the severity of inflammation, while decreasing pancreatic tissue oxygenation. Although neither amylase secretion nor intracellular trypsinogen activation in caerulein stimulated pancreatic acini was influenced by either NO donors or inhibitors, both NO donors decreased intrapancreatic trypsinogen activation peptide (TAP) and pancreatic oedema in vivo, andl-NAME increased TAP. Conclusions—NO protects against injury caused by pancreatitis in the intact animal but has no discernible effect on isolated acini. It is likely that in pancreatitis NO acts indirectly via microcirculatory changes, including inhibition of leucocyte activation and preservation of capillary perfusion.

Technetium-99m-labeled white blood cells: a new method to define the local and systemic role of leukocytes in acute experimental pancreatitis.

OBJECTIVE We developed a new method to quantitate leukocyte accumulation in tissues and used it to examine the time course and severity of acute experimental pancreatitis. BACKGROUND Leukocyte activation and infiltration are believed to be critical steps in the progression from mild to severe pancreatitis and responsible for many of its systemic complications. METHODS Pancreatitis of graded severity was induced in Sprague-Dawley rats with a combination of caerulein and controlled intraductal infusion. Technetium-99m (99mTc)-labeled leukocytes were quantified in pancreas, lung, liver, spleen, and kidney and compared with myeloperoxidase activity. The severity of pancreatitis was ascertained by wet/dry weight ratio, plasma amylase, and trypsinogen activation peptide in the pancreas. The time course of leukocyte accumulation was determined over 24 hours. RESULTS Pancreatic leukocyte infiltration correlated well with tissue myeloperoxidase concentrations. In mild pancreatitis, leukocytes accumulated only in the pancreas. Moderate and severe pancreatitis were characterized by much greater leukocyte infiltration in the pancreas than in mild disease (p < 0.01), and increased 99mTc radioactivity was detectable in the lung as early as 3 hours. 99mTc radioactivity correlated directly with the three levels of pancreatitis. CONCLUSIONS Mild pancreatitis is characterized by low-level leukocyte activation and accumulation in the pancreas without recruitment of other organs; marked leukocyte accumulation was found in the pancreas and in the lung in more severe grades of pancreatitis. These findings provide a basis for the pathophysiologic production of cytokines and oxygen free radicals, which potentiate organ injury in severe pancreatitis. This study validates a new tool to study local and systemic effects of leukocytes in pancreatitis as well as new therapeutic hypotheses.

Increased intrapancreatic trypsinogen activation in ischemia-induced experimental pancreatitis

ObjectiveThe potential of pancreatic ischemia to cause acute pancreatitis as indicated by morphologic changes and ectopic trypsinogen activation was investigated. BackgroundExperimental evidence has shown that pancreatic ischemia is important in the evolution of severe pancreatitis, but whether ischemia can initiate pancreatitis has been disputed. MethodsPancreatic ischemia was induced in rats by hemorrhagic hypotension (30 mm Hg for 30 min; n = 64).Changes of pancreatic microcirculatory perfusion were studied using diffuse reflectance spectroscopy. Serum amylase, trypsinogen activation peptide (TAP) in serum and pancreatic tissue, wet/dry weight ratio, and histology were determined over 24 hours and compared with sham-operated control subjects (n = 35). ResultsIn control animals, serum amylase (47.9 ± 2.1 units/L), serum (7.9 ± 0.7 nmol/L) and tissue TAP (63.0 ± 5.4 nmol/L x g), wet/dry weight ratio (2.8 ± 0.1), and histology remained unchanged. Temporary hypotension markedly decreased pancreatic perfusion with incomplete recovery after repertusion. Pancreatic isoamylase activity increased within 1 hour (110 ± 5 units/L, p. < 0.05) and further to 151 ± 18 units/L at 24 hours. Tissue TAP was elevated at 1 hour (134 ± 16 nmol/L X g, p < 0.05) and increased to 341 ± 43 nmol/L x g (p < 0.001) after 24 hours, whereas serum TAP remained unchanged (8.3 ± 0.5 nmol/L). Morphologic alterations included elevated wet/dry weight ratio (4.1 ± 0.3, p < 0.01) and increased histologic scores for edema (p < 0.05) and acinar necrosis (p < 0.05) at 24 hours. Trypsinogen activation preceded the development of pancreatic necrosis. ConclusionsIn addition to its potentiating role, severe pancreatic ischemia can play a pathogenetic role in the initiation of acute pancreatitis.

Time course of bacterial infection of the pancreas and its relation to disease severity in a rodent model of acute necrotizing pancreatitis.

BackgroundBacterial infection of pancreatic necrosis is thought to be a major determinant of outcome in acute necrotizing pancreatitis. The determinants and possibilities for prophylaxis are unknown and difficult to study in humans. ObjectiveThe time course of bacterial infection of the pancreas in a rodent model of acute necrotizing pancreatitis was characterized. The authors ascertained if there is a correlation with the degree of necrosis. MethodsAcute pancreatitis (AP) of graded severity was induced under sterile conditions by an intravenous infusion of cerulein (5 μg/kg/hr) for 6 hours (mild AP), or a combination of intravenous cerulein with an intraductal infusion of 10-mM glycodeoxycholic acid (0.2 mL for 2 min for moderate AP, 0.5 mL for 10 min for severe AP). Sham-operated animals (intravenous and intraductal NaCl 0.9%) served as controls. Ninety-six hours after induction, animals were killed for quantitative bacterial examination and histologic scoring of necrosis. In addition, groups of animals with severe AP were investigated at 12, 24, 48, 96, and 144 hours. ResultsNo significant pancreatic necrosis was found in control animals (0.3 ± 0.1) or animals with mild AP (0.6 ± 0.1) killed at 96 hours. Necrosis scores were 1.1 ± 0.2 for animals with moderate AP and 1.9 ± 0.2 for animals with severe AP. Control animals did not develop significant bacterial infection of the pancreas (≥ 103 CFU/g). At 96 hours, the prevalence of infection was 37.5% in animals with mild AP and 50% in animals with moderate AP. In animals with severe AP, infection of the pancreas increased from 33% in the first 24 hours to 75% between 48 and 96 hours (p < 0.05). The bacterial counts and the number of different species increased with time and was maximal (> 1011 CFU/g) at 96 hours. ConclusionBacterial infection of the pancreas in rodent AP increases during the first several days, and its likelihood correlates with the severity of the disease. This model, which closely mimics the

Generation and possible significance of trypsinogen activation peptides in experimental acute pancreatitis in the rat.

Trypsinogen activation peptides (TAP) were quantified by radio-immunoassay in blood, urine, and peritoneal exudate of rats with experimental pancreatitis. Forty-four animals were studied, comprising a control group and four different induction techniques (cerulein, cerulein plus either 2- or 10-min intraductal glycodeoxycholic acid [GDOC] infusion, and cerulein plus intra-ductal GDOC with enterokinase [EK]). Significantly higher TAP concentrations were found at 6 h (or at death) in plasma and ascites of all pancreatitis groups compared with controls. TAP quantitation in hourly urine samples demonstrated significantly higher concentrations from the third hour onward in the most severe groups and from the fourth hour onward in the cerulein-treated rats. All nonsurviving rats had a plasma TAP of >2.5 nM/L, whereas only 1 of 34 surviving animals had such a concentration (p <0.001). A significant step-wise increase in total TAP in ascites was found when comparing the cerulein group, the two GDOC groups, and the EK group (p <0.001). Chromatography of samples with a high TAP content demonstrated comigration with synthetic TAP. We conclude that free TAP are present in blood, urine, and peritoneal exudate of rats with experimental pancreatitis of different pathogenesis and that the amount of TAP may be indicative of the severity of the disease process.

Laparoscopy for staging in pancreatic carcinoma

Pancreatic cancer is the gastrointestinal malignancy with the worst prognosis. At the time of diagnosis, only 15% of patients are resectable (and potentially curable), 40% have localized but unresectable tumours, and 45% distant metastases. Computerized tomography, angiography, and laparoscopy allow for adequate staging in this neoplasm. The latter is useful for identifying the small (1-2 mm) peritoneal and liver implants which, in our experience, are present in 27% of patients with tumours of the pancreatic head and in 65% of those with cancers of the body and tail of the pancreas. Peritoneal cytology may also be performed at the time of laparoscopy, and will be positive for malignant cells in 20-30% of cases indicating a bad prognosis.

Intraductal papillary mucinous tumors of the pancreas

AbstractIntraductal papillary mucinous tumor (IPMT) is an uncommon pancreatic neoplasm with characteristic histology and distinctive clinicobiologic behavior. It is characterized by proliferation of ductal epithelium associated with ductal dilatation and variable mucin production. Due to indolent nature of these tumors, IPMTs are frequently missed or misdiagnosed. Prompt recognition and differentiation from other tumors are essential because IPMT has a better prognosis than other pancreatic malignancies. The purpose of this article is to display the radiologic spectrum of IPMT.