Biomedical subjects

D W Rattner

Publications and source records attributed to D W Rattner.

At least 55 records · Page 3Linked to original sources

PubMed1997

A rat model of pancreatic ductal adenocarcinoma: targeting chemical carcinogens.

BACKGROUND: Current experimental models of pancreatic cancer either fail to reproduce the ductal phenotype or cause simultaneous cancers in other organs also. To develop an animal of pancreatic cancer that accurately mimics the human condition, we restricted carcinogenic exposure to the pancreas and specifically targeted ductal epithelial cells. Three different carcinogens were either implanted directly into the pancreas or infused into the pancreatic duct, with or without near-total pancreatectomy (as a means of inducing pancreatic ductal cell proliferation). METHODS: Groups of male Sprague-Dawley rats were exposed to varying doses of dimethylbenzanthracine (DMBA), methynitronitrosoguanidine, or ethylnitronitrosoguanidine either through direct implantation into the pancreas or infusion into the pancreatic duct. Near-total pancreatectomy was added in all groups except two DMBA implantation groups. Surviving rats were killed at 3, 6, 9, or 12 months, and the pancreata were evaluated histologically. RESULTS: All three carcinogens caused pancreatic inflammation, ductal hyperplasia, atypia, and dysplasia beginning by 3 months and becoming more prominent at later time points. Only DMBA caused frequent invasive pancreatic ductal adenocarcinoma, which was first evident by 6 months. The prevalence of pancreatic cancer among DMBA-treated rats evaluated after 10 months was 39% (19 of 49). The addition of pancreatic resection did not enhance pancreatic cancer development. CONCLUSIONS: Of the strategies tested, only direct implantation of DMBA into the rat pancreas frequently produces pancreatic cancer histologically similar to human ductal adenocarcinoma. The development of hyperplastic, atypical, and dysplastic changes preceding and accompanying carcinomas suggests that these lesions are preneoplastic. This model recapitulates the progression from normal to neoplastic epithelium and is likely to be useful for the study of morphologic and molecular mechanisms underlying the early stages of pancreatic carcinogenesis and for the investigation of novel diagnostic and therapeutic techniques.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed1997

Pancreatic mucinous ductal ectasia and intraductal papillary neoplasms. A single malignant clinicopathologic entity.

OBJECTIVE: The purpose of the study is to review a single institutional experience with mucinous ductal ectasia (MDE) and intraductal papillary neoplasms (IPNs) and to compare the clinicopathologic features of the two groups of tumors. SUMMARY BACKGROUND DATA: Mucinous ductal ectasia and IPNs represent newly recognized categories of pancreatic exocrine tumors, previously confused with pancreatic cystic neoplasms. The natural history of MDE and IPN is not well understood, and it is unclear whether MDE and IPN represent two distinct tumors or the same clinicopathologic entity. METHODS: The authors reviewed the clinical presentation, treatment, histopathology, and outcomes of 23 patients diagnosed with MDE or IPN at their institution over the past 6 years. RESULTS: The mean age at presentation for the cohort of patients with MDE and IPN was 62.5 years. The prevalence of abdominal pain was 75%, jaundice 25%, weight loss 42%, steatorrhea 37.5%, diabetes 37.5%, and history of pencreatitis 29%. Serum CA 19-9 levels ranged from 0 to 5350 units/mL with high levels reflecting advanced disease. There were no significant differences between MDE and IPN with respect to these parameters. Both MDE and IPN comprised papillary villous epithelial neoplasms involving the main and large pancreatic ducts. The tumors ranged from a few millimeters in size to panductal and were distinguished easily from cystic neoplasms in all cases. Invasive carcinoma was present in 11 (46%) of 24 patients, carcinoma in situ in an additional 10 (42%) of 24 patients, and low grade dysplasia in the remaining 3 (12%) of 24 patients. Mucinous ductal ectasia and IPN differed histopathologically only in degree of mucin secretion and tumor location. Mucinous ductal ectasia, but not IPN, was characteristically mucin-hypersecreting and more frequently involved the head of the gland than did IPN (11/16 vs. 1/8 p < 0.04). All patients were explored surgically and 20 (83%) of 24 of the tumors were resectable with frozen section control of the duct margins (9 pancreatoduodenectomies, 4 distal pencreatectomies, 7 total pancreatectomies). Despite the 88% prevalence of cancer, the overall survival at a mean follow-up of 21 months was 13 (87%) of 15 for MDE and 5 (71%) of 7 for IPN. CONCLUSIONS: Intraductal papillary neoplasms with or without MDE represent a spectrum of main duct papillary tumors ranging from adenoma to carcinoma with differing amounts of extracellular mucin production. Malignant IPNs with or without MDE typically exhibit extensive intraductal growth but are slow to invade the periductal tissues and slow to metastasize. The majority of patients with these tumors have resectable disease and a favorable prognosis; endoscopic therapy is inappropriate. The encompessing term intraductal papillary-mucinous tumors is appropriate.

Adenocarcinoma, Mucinous↗

PubMed1997

Prevalence of activating K-ras mutations in the evolutionary stages of neoplasia in intraductal papillary mucinous tumors of the pancreas.

OBJECTIVE: The purpose of the study was to determine the prevalence of activating K-ras mutations in the pancreas of patients with intraductal papillary mucinous tumors (IPMT) and to analyze their relation to the degree of site-specific histopathologic abnormality. BACKGROUND: Intraductal papillary mucinous tumors of the pancreas have a biologic behavior that is significantly different from pancreatic ductal adenocarcinoma. Activating K-ras mutations, which may be important events in a multistage process of carcinogenesis, have been reported in IPMT. METHODS: Forty-six different histologic specimens (comprising normal pancreatic ducts, hyperplasia, low-grade dysplasia, high-grade dysplasia-carcinoma in situ, and carcinoma) from 16 patients with IPMT and 9 specimens from patients with pancreatic ductal adenocarcinomas were designated by a pathologist. Genomic DNA was extracted from paraffin-embedded tissue sections after microdissection. The K-ras gene was amplified by polymerase chain reaction and subjected to DNA sequencing. RESULTS: The K-ras mutations were detected in at least one specimen in 13 (81.2%) of 16 patients with IPMT. All mutations were found in codon 12. No codon 13 mutations were detected. The relative frequency of K-ras mutations in the different stages of IPMT was 16.7% in normal epithelium and papillary hyperplasia, 28.6% in low-grade dysplasia, and 57.1% in high-grade dysplasia-carcinoma in situ and invasive carcinoma. The K-ras mutations were detected in 6 (66%) of 9 pancreatic ductal adenocarcinomas. CONCLUSIONS: The K-ras codon 12 point mutations are as frequent in IPMT as in ductal adenocarcinoma. A stepwise increase in the frequency of codon 12 mutations correlated with the stage of neoplastic evolution to cancer. This finding is consistent with an important role of K-ras gene mutations in the transformation from normal epithelium to invasive carcinoma in the majority of patients with IPMT.

Carcinoma, Ductal, Breast↗

PubMed1996

Defining the criteria for local resection of ampullary neoplasms.

OBJECTIVES: To delineate factors determined preoperatively, which predict successful local resection of ampullary neoplasms. DESIGN: Retrospective review of case series of the author's experience from 1988 through 1995. The median follow-up of patients with malignancies was 29 months. SETTING: Tertiary care university teaching hospital. PATIENTS: Twenty-seven patients underwent surgery. The decision to perform either an ampullectomy or pancreaticoduodenectomy (PD) was based on the size of the lesion, the presence of a "field defect" (ie, familial polyposis), depth of invasion determined by preoperative endoscopic ultrasound, and extent of pancreatic and bile duct involvement seen on endoscopic retrograde cholangiopancreatography. INTERVENTIONS: Fourteen patients underwent ampullectomy, 12 patients underwent PD, and one patient had a retroperitoneal node biopsy performed without resection of the primary tumor. MAIN OUTCOME MEASURES: Resectability, morbidity, and mortality. RESULTS: Depth of invasion was accurately determined in nine of 12 patients studied by preoperative endoscopic ultrasound. Preoperative endoscopic biopsy specimens were obtained in 21 patients and were inaccurate in seven of 21 cases. The length of stay following local resection was 10.5 +/- 3.7 days vs 15.4 +/- 5.8 days following PD (P=.02). One patient died following PD, and there were no deaths following ampullectomy. Six of 12 patients undergoing PD had postoperative complications vs two of 14 patients undergoing local resection. CONCLUSIONS: Ampullectomy is the procedure of choice for resecting benign lesions smaller than 3 cm, small neuroendocrine tumors, and T1 carcinomas of the ampulla. While endoscopic ultrasonography is helpful in identifying stage T1 lesions suitable for local resection, no preoperative test proved accurate enough to substitute for clinical judgment and intraoperative pathological confirmation.

Adult↗

PubMed1996

Pitfalls of distal pancreatectomy for relief of pain in chronic pancreatitis.

PURPOSE: To examine whether preoperative computed tomography (CT) scans and pancreatograms can: (1) identify patients with chronic pancreatitis localized to the tail of the pancreas; and (2) select those patients who can obtain pain relief from a distal pancreatectomy. PATIENTS AND METHODS: Twenty patients were identified on whom the authors had performed distal pancreatectomy for relief of pain between January 1, 1991 and August 1, 1994. The results of surgery were classified as good, fair, or poor based on return to work and need for narcotics or rehospitalization. RESULTS: Eleven patients had good, 3 fair, and 6 poor results. All 7 patients with pseudocysts of the tail of the pancreas had good results, while 9 of 13 patients without pseudocysts had poor results. No other finding on CT scan, pancreatography, or laparotomy predicted successful pain relief by distal pancreatectomy. Furthermore, 3 patients had unexpected carcinoma found at the time of surgery. CONCLUSIONS: Even when anatomic evidence suggests that chronic pancreatitis primarily involves the tail of the pancreas and there is a stricture of the midpancreatic duct that is believed to cause the symptoms, distal pancreatectomy seldom provides sustained pain relief. Unsuspected carcinoma of the body and tail of the pancreas occurs frequently in this subset of patients with chronic pancreatitis.

Adult↗

PubMed1996

Antibiotic treatment improves survival in experimental acute necrotizing pancreatitis.

BACKGROUND & AIMS: It is still unproven whether prophylactic antibiotics can reduce mortality from acute necrotizing pancreatitis (ANP). The aim of this study was to investigate whether antibiotic therapy can influence long-term outcome in ANP and how appropriate this therapy is. METHODS: ANP was induced in rats by standardized intraductal bile acid infusion and cerulein hyperstimulation. Serum trypsinogen activation peptide levels were used to verify comparable disease severity. Starting 6 hours after induction, animals randomly received saline (n = 60), 20 mg/kg imipenem (n = 62), or 10 mg/kg ciprofloxacin (n = 60) every 8 hours for 7 days. On day 7, half of each group was killed so a quantitative pancreatic bacteriology could be conducted. The other half was analyzed at 21 days for long-term mortality, late bacteriologic changes, abscesses, and pseudocysts. RESULTS: Comparable trypsinogen activation peptide increases confirmed equally severe ANP in each group before treatment. Imipenem and ciprofloxacin significantly reduced the number of infected pancreatic specimens, bacterial counts, and identified species at 1 week. At 3 weeks, pancreatic infection prevalence was lower in animals treated with antibiotics; abscess formation was reduced and pseudocysts were smaller and less frequently infected. Survival was significantly improved by imipenem and ciprofloxacin. CONCLUSIONS: Antibiotic treatment reduces early and late septic pancreatic complications and improves survival from experimental ANP.

Abscess↗

PubMed1996

Reflectance spectroscopy of pancreatic microcirculation.

A technique employing diffuse reflectance spectroscopy (DRS) is described to assess and mirror dynamic changes of pancreatic tissue perfusion. An especially designed reflectance spectrophotometer was initially used to derive the quantitative relation between hemoglobin concentration ([Hb]) and reflectance measurements in vitro. Over a wide range of scattering related to the medium in which the measurements were made (scattering coefficient: 6.5-13 cm-1), a close, direct correlation existed with a slope of 0.376 +/- 0.012. In Sprague-Dawley rats under general anesthesia, the pancreas was isolated in situ and perfused with graded infusions of hemoglobin solutions. A correlation, comparable to the in vitro setting, was found between a [Hb] of 0 and 14 g/dl in the perfusate with slopes of 0.0037 and 0.0035. Changes in perfusion induced by adrenergic drugs produced changes in hemoglobin oxygen saturation and [Hb] that correspond with measured alterations of systemic arterial pressure and aortic blood flow. We conclude that diffuse reflectance spectroscopy reliably provides data on intrapancreatic hemoglobin oxygen saturation and [Hb] that can be a valuable tool for minimally invasive on-line evaluation of these aspects of pancreatic perfusion in the rat. This newly designed device is superior to previously used ones in that it analyzes the entire spectrum and therefore can account for changes in scattering that are very likely to occur with pathophysiological alterations such as edema formation.

Animals↗

PubMed1996

Experimental models of acute pancreatitis and their relevance to human disease.

There are no experimental models which mimic the most common causes of human acute pancreatitis, i.e. gallstones and alcohol abuse. However, existing models can reproduce the morphology and physiological derangements of certain phases of the illness. Current models have been useful in elucidating the earliest events involved in the initiation and progression of pancreatitis. However, very few animal studies demonstrate effective therapeutic intervention when treatment is given after the induction of experimental pancreatitis. Since immediate intervention is unachievable in human disease, most experimental therapies have not been successfully applied to clinical disease.

Acute Disease↗

PubMed1996

Surgical approaches to benign and malignant tumors of the ampulla of vater.

Ampullary tumors include a diverse group of benign and malignant neoplasms. A surgical approach to their management was initiated in 1899 by Halsted and continues to evolve. Surgical options include a spectrum of operative procedures designed to relieve symptoms and to remove malignant or potentially malignant tumors. This article discusses the issues relevant to ampullary tumor management with emphasis on the currently accepted and controversial aspects of the surgical approach.

Adenoma↗

PubMed1995

Peritoneal exfoliative cytology and Ki-ras mutational analysis in patients with pancreatic adenocarcinoma.

This is the first description of the detection of pancreatic adenocarcinoma peritoneal metastasis by established radiolabeled polymerase chain reaction (PCR) based Ki-ras mutational analysis. The present study evaluates both routine cytology and Ki-ras mutational analysis in the detection of peritoneal micrometastases in 24 subjects with pancreatic adenocarcinoma compared to seven control cases of chronic pancreatitis and seven control cases of cholecystitis. Locoregional extension, vascular invasion, and distal metastases were confirmed in 21/24 (88%) of the subjects with pancreatic adenocarcinoma by compute tomography, angiography, endosonography, or laparoscopy. The most common site of histologically confirmed extrapancreatic involvement was the vasculature (29%), followed by the liver (25%), duodenum (17%), peritoneum (17%), and lymph nodes (12%). Peritoneal lavage cytology was positive in 3/24 (12%) cases of pancreatic carcinoma while Ki-ras codon 12 mutational analysis was positive in 2/24 (8%). Two histologically confirmed cases of peritoneal metastases were not detected by either methodology, while peritoneal lavage cytology detected malignant cells in one case with histologically confirmed lymph node metastasis.

Adenocarcinoma↗

PubMed1995

Quantitative assay of trypsinogen by measurement of cleaved activation peptide after activation with enterokinase.

Measurement of trypsinogen by quantitative immunosorbent assay of the highly specific and inert trypsinogen activation peptide following complete activation of trypsinogen by enterokinase offers a simple and sensitive method that provides reliable results over a wide range of trypsinogen concentrations. This method offers a significant advantage in being applicable to complex biological tissues.

Animals↗

PubMed1995

Patient satisfaction following laparoscopic and open antireflux surgery.

OBJECTIVE: To compare laparoscopic (LNF) with open Nissen fundoplication (ONF) in terms of hospital charges, efficacy, and patient satisfaction. DESIGN: A prospective, nonrandomized study with a median follow-up of 370 days. SETTING: Two tertiary care university hospitals. PATIENTS: Eighty-six patients with complications of gastroesophageal reflux who had not had previous antireflux surgery were studied. Patients chose ONF or LNF following discussion with the surgeon; 12 underwent ONF and 74 underwent LNF, of whom eight required conversion to laparotomy. MAIN OUTCOME MEASURES: Hospital charges, disability, satisfaction, and side effects of fundoplication. RESULTS: Patients were demographically similar. Total charges (mean +/- SD) for LNF ($11,673 +/- $4723) were significantly less than for ONF ($18,394 +/- $17,264). Patients who underwent LNF returned to work sooner (10 +/- 3 days) than those who underwent ONF (28 +/- 1 days). Bloating, dysphagia, and recurrent heartburn occurred with equal frequency in both groups. Recurrent reflex occurred in four of 74 LNF patients and one of 12 ONF patients. Overall satisfaction scores were similar, irrespective of operative technique (LNF, 3.35 +/- 0.87; ONF, 3.50 +/- 0.94. CONCLUSIONS: Laparoscopic Nissen fundoplication is as effective as ONF in the treatment of complications of gastroesophageal reflux disease and appears to cost less and lead to faster recovery from surgery, but does not result in higher patient satisfaction than ONF. The most important factor in patient satisfaction is the abolition of preoperative symptoms rather than the type of operation.

Costs and Cost Analysis↗

PubMed1995

Standards for pancreatic resection in the 1990s.

OBJECTIVE: To describe the current indications and operative outcomes of pancreatic resection. DESIGN: Retrospective case series. SETTING: Referral practice in a university hospital. PATIENTS: Two hundred thirty-one consecutive patients undergoing pancreatoduodenectomy (PD), distal pancreatectomy (DP), or total pancreatectomy (TP) over a 44-month period. Their ages ranged from 16 to 85 years, with a mean of 54 years; 20% of the patients were 70 years old or older. MAIN OUTCOME MEASURES: Mortality, complications, and length of hospital stay. RESULTS: Operative mortality was 0.4% (one death following DP); there were no deaths in 142 PDs or in 18 TPs. The most common complication following PD was delayed gastric emptying. Pancreatic fistula occurred in 6.3% of PD and in 9.8% of DP patients. Overall, 58% of PD, 80% of DP, and 78% of TP patients had no complications. The mean +/- SD length of hospital stay was 15 +/- 7, 10 +/- 5, and 15 +/- 6 days for PD, DP, and TP, respectively. Reoperation for any cause was necessary in only 1.2% (3/231). The most frequent indication for PD was pancreatic cancer (36%) followed by chronic pancreatitis (26%); for DP it was chronic pancreatitis (28%) and cystic neoplasms (27%); and for TP, chronic pancreatitis (55%). Newer indications for pancreatic resection included mucinous ductal ectasia and intraductal papillary tumors (eight cases, 4%) and metastatic tumors (eight cases, 4%). CONCLUSIONS: Current indications for pancreatic resection have expanded. These procedures are associated with a low risk for death and postoperative complications when performed in a high-volume setting.

Adolescent↗

PubMed1995

Alcohol selectively impairs oxygenation of the pancreas.

BACKGROUND: Alcohol predisposes to acute pancreatitis by an unknown mechanism and is known to reduce regional pancreatic blood flow. OBJECTIVE: To investigate whether increased blood alcohol causes functional impairment of pancreatic microperfusion as indicated by reduced tissue oxygenation. DESIGN: Prospective, randomized, controlled study. SETTING: University hospital laboratory. SUBJECTS: Forty adult female Wistar rats. INTERVENTIONS: Intravenous infusion of ethanol (2 g/kg) or saline over 60 minutes. Tissue hemoglobin oxygenation saturation and hemoglobin content were measured using reflectance spectroscopy in the pancreas, stomach, and kidney at baseline and at 10-minute intervals for 1 hour. RESULTS: Blood ethanol levels (mean +/- SEM) peaked at 1810 +/- 94 mg/L. Compared with saline controls, pancreatic hemoglobin oxygen saturation in ethanol-treated rats had significantly decreased by 40 minutes and remained depressed, while pancreatic hemoglobin content was unchanged. The magnitude of the depression was at least as great as that previously observed in acute experimental pancreatitis of moderate severity. Neither hemoglobin oxygen saturation nor hemoglobin content was affected in the stomach or kidney by ethanol. CONCLUSION: A raised blood ethanol level was associated with acutely decreased hemoglobin oxygen saturation in the pancreas but not in the stomach or kidney. This observation of provoked hypoxia provides a possible mechanism by which alcohol contributes to pancreatic injury.

Animals↗

PubMed1995

Further experience with laparoscopy and peritoneal cytology in the staging of pancreatic cancer.

A total of 114 patients with pancreatic cancer and no evidence of metastatic disease by computed tomography underwent laparoscopy. Intra-abdominal spread was present in 27 patients (24 per cent). Metastases were 2.4 times more common in tumours of the distal pancreas (11 of 25, 44 per cent) than in pancreatic head tumours (16 of 89, 18 per cent) (P < 0.05). None of the 27 patients with metastases underwent further surgery. Of the 87 patients without metastatic spread, 42 were found to have vascular invasion by angiography and were offered radiation therapy. Thirty of 40 patients explored surgically were resected; two of the remaining ten had peritoneal spread that had been missed at laparoscopy (false-negative rate of 7 per cent). Cytological examination of peritoneal washings was performed in 94 patients at the time of laparoscopy; cytology was positive in 16 (17 per cent). There was a significant correlation between positive cytology and presence of visible liver or peritoneal metastases (ten of 22 with metastases versus six of 72 without, P < 0.001). Positive cytology was present in six patients (8 per cent) without visible metastases, but none had resectable disease.

Humans↗

PubMed1995

Acute hypercalcemia causes acute pancreatitis and ectopic trypsinogen activation in the rat.

BACKGROUND & AIMS: Clinical and experimental observations have associated acute and chronic hypercalcemia with pancreatitis. The aim of this study was to determine whether acute hypercalcemia can induce acute pancreatitis and, if so, whether the pathogenesis involves premature protease activation. METHODS: Rats given bolus infusions of CaCl2 (200 mg/kg; n = 76) were compared with saline-treated controls (n = 40). Serum [Ca2+], serum amylase activity, trypsinogen activation peptide (TAP) concentration in serum and pancreatic tissue, pancreatic wet/dry weight ratio, and histology were assessed for 24 hours. For dose-response analysis, CaCl2 was injected at a dose of 50-200 mg/kg, and the aforementioned indices were assayed for 1 hour (n = 5 each). RESULTS: There were no significant changes in the controls. Calcium infusion increased serum [Ca2+] 3-fold after 5 minutes (P < 0.001). Within 1 hour, serum amylase (2.5-fold) and tissue TAP (3-fold) levels increased along with macroscopic and microscopic edema formation and leukocytic infiltration. The extent of the changes at 1 hour correlated with the calcium dose. Amylase and tissue TAP concentrations remained elevated until 24 hours when serum TAP concentration had increased (P < 0.001) and focal acinar necrosis became evident. CONCLUSIONS: Acute experimental hypercalcemia induces dose-dependent morphological alterations characteristic of acute pancreatitis, acute hyperamylasemia, and early ectopic trypsinogen activation. This supports the pathophysiological relevance of excess calcium and offers a possible pathogenetic mechanism for its association with clinical pancreatitis.

Acute Disease↗

PubMed1995

Hypercalcemia causes acute pancreatitis by pancreatic secretory block, intracellular zymogen accumulation, and acinar cell injury.

BACKGROUND: Because hypercalcemia is a known etiologic factor for human acute pancreatitis, studies of the pancreatic pathophysiology and pathomorphology of experimental hypercalcemia have potential clinical significance. MATERIALS AND METHODS: Rats received central venous infusion of either 0.6 mmol/kg per hour CaCl2 or 0.9% NaCl infusion for 12 hours. Pancreatic tissue samples were obtained and prepared for electron microscopy. Tissue homogenates were examined for DNA, lactate dehydrogenase (LDH), protein, amylase, and calcium contents. Basal or stimulated (cerulein 0.25 microL/kg per hour) pancreatic secretions were analyzed for volume, protein, and amylase output, as well as protein composition on sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). RESULTS: The tissue calcium content and the ratio of LDH to DNA was unchanged after calcium infusion, but the ratios of total protein to DNA and of amylase to DNA were significantly larger. Basal output of pancreatic juice volume, protein, and amylase were significantly lower. SDS-PAGE of pancreatic juice revealed weakening of a 70,000-d band and appearance of lower molecular weight bands in two samples. Ultrastructural examination demonstrated accumulation of zymogen granules in the acinar cell, large autophagic vacuoles containing remnants of condensing vacuoles. CONCLUSIONS: These findings suggest that hypercalcemia induces pancreatic injury via a secretory block, accumulation of secretory proteins, and possibly activation of proteases.

Acute Disease↗

PubMed1995

Calcium administration augments pancreatic injury and ectopic trypsinogen activation after temporary systemic hypotension in rats.

BACKGROUND: Calcium infusion and hypotension have been described as the most important risk factors for pancreatic injury after cardiopulmonary bypass. METHODS: Rats were randomly allocated to three experimental groups undergoing either sham operation and saline infusion (Control, n = 30), hemorrhagic reduction of mean arterial pressure to 30 mmHg for 30 min alone (hypotension, n = 51), or hypovolemic hypotension followed by bolus infusion of CaCl2 (200 mg.kg-1; hypercalcemia, n = 85). Serum ionized calcium, amylase activity, trypsinogen activation peptide in pancreatic tissue homogenates, pancreatic wet/dry weight ratio, histologic changes, and mortality were assessed for 24 h. RESULTS: Control rats showed no significant changes of any parameter throughout the experiments. In contrast, hypotension significantly increased serum amylase (P < 0.001), tissue trypsinogen activation peptide (P < 0.01), wet/dry weight ratio (P < 0.001), and histologic scores for edema (P < 0.001) and pancreatic necrosis (P < 0.05). Subsequent CaCl2 administration transiently increased [Ca2+] (P < 0.001) with the concentration rapidly returning to baseline within 3 h. That infusion of CaCl2 further increased amylase (P < 0.05), tissue trypsinogen activation peptide (P < 0.05), wet/dry weight ratio (P < 0.001), and histologic evidence of pancreatic edema (P < 0.05) and acinar necrosis (P < 0.05) when compared with hypotension alone. Whereas all Control animals survived the experiments, 22% (P < 0.05) and 47% (P < 0.05 vs. hypotension) of animals died in the hypotension and hypercalcemia groups, respectively. CONCLUSIONS: Temporary hypotension alone causes ectopic trypsinogen activation and lethal acute pancreatitis. Super-imposed hypercalcemia significantly aggravates hypotension-induced pancreatic injury and mortality in rats.

Animals↗