The relative safety of MRI contrast agent in acute necrotizing pancreatitis.

OBJECTIVE: To validate the safety of gadolinium-diethylenetriamine pentaacetic acid (GD-DTPA) by measuring its effect on pancreatic capillary perfusion and acinar injury in acute pancreatitis. BACKGROUND: Contrast-enhanced computed tomography (CECT) is proposed as a gold standard for early evaluation of acute necrotizing pancreatitis. However, iodinated contrast media used for CECT have been shown in these circumstances to reduce pancreatic capillary flow and increase necrosis and mortality. Recent reports suggest that post-GD MRI provides images comparable to CECT in the assessment of severe acute pancreatitis. METHODS: Necrotizing pancreatitis was induced in 14 Wistar rats by intraductal glycodeoxycholic acid (10 mM/L) and intravenous caerulein (5 microg/kg/h) over 6 hours. Intravital microscopic quantitation of pancreatic capillary blood flow was performed using fluorescein isothiocyanate-labeled erythrocytes after induction of pancreatitis and 30 and 60 minutes after an intravenous bolus of either Ringer's solution or GD-DTPA (0.2 mL/kg). RESULTS: The two study groups were comparable with regard to mean arterial pressure, heart rate, arterial blood gases, hematocrit, amylase, lipase, and trypsinogen activation peptide production throughout the experiment. GD-DTPA did not reduce capillary flow (1.93 +/- 0.05 nL/capillary/min) compared to animals infused with Ringer's solution (1.90 +/- 0.06 nL/capillary/min). CONCLUSIONS: Intravenous injection of GD-DTPA does not further impair pancreatic microcirculation or increase acinar injury in acute necrotizing pancreatitis. Because of this advantage over CT contrast medium, further development of MRI as a staging tool in acute pancreatitis seems desirable.

Glutamine stabilizes intestinal permeability and reduces pancreatic infection in acute experimental pancreatitis.

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

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.

Failure of pentoxifylline to ameliorate severe acute pancreatitis in the rat: results of a prospective, randomized, controlled study.

OBJECTIVE: To investigate the benefit of pentoxifylline in severe experimental pancreatitis. DESIGN: Prospective, randomized, controlled study. SETTING: Experimental animal laboratory in a University hospital. SUBJECTS: Forty-two adult male Sprague-Dawley rats. INTERVENTIONS: Acute pancreatitis was induced by supramaximal stimulation with cerulein plus a pressure and volume controlled 10 min intraductal infusion of 10-mM glycodeoxycholic acid. Thirty minutes after pancreatitis was induced, animals were randomized to receive pentoxifylline (60 mg/kg over 2.5 hrs), or saline. All animals received fluid resuscitation with lactated Ringer's solution (8 mL/kg/hr), and surviving animals were killed at 24 hrs. MEASUREMENTS AND MAIN RESULTS: There was a progressively significant decrease in mean arterial pressure after pancreatitis was induced, with no difference between pentoxifylline-treated rats and controls. Hematocrit increased significantly in both groups at 6 hrs, and returned to baseline values at 24 hrs. Ascites volume and levels of trypsinogen activation peptide in plasma and ascites were similar in both groups. Twenty-four hour mortality was 47% for the pentoxifylline group and 52% for the control group. Histologic scores for necrosis, edema, inflammation, and hemorrhage showed no significant differences between the two groups. CONCLUSION: Treatment with pentoxifylline failed to improve outcome in a model of severe acute pancreatitis in the rat.

Evidence for extraluminal trypsinogen activation in three different models of acute pancreatitis.

BACKGROUND: Inappropriate extraluminal activation of trypsin is assumed to play a part in the pathogenesis of acute pancreatitis (AP), but proof has been elusive because active trypsin is transient and difficult to measure. We have previously shown increased levels of trypsinogen activation peptides (TAP), a direct measure of trypsin activation, to correlate with severity of AP, tissue necrosis, and survival in a rodent model induced by cerulein hyperstimulation and bile salt infusion. The present study seeks to show that increased trypsinogen activation also characterizes three other models of experimental AP in rodents to give credence to the generality of the phenomenon and to its potential relevance to human AP. METHODS: Experimental AP was induced in mice by a choline-deficient diet supplemented with ethionine and in rats by creation of a closed duodenal loop or by ligation of the biliopancreatic duct plus physiologic stimulation. TAP were quantified by an immunoassay in tissue and plasma at various time points after onset of AP. RESULTS: In the group with choline-deficient diet supplemented with ethionine a significant increase in tissue and plasma TAP was found at 48 and 72 hours, respectively. In the group with closed duodenal loop significant TAP elevations were found in plasma as early as 6 hours and in the group with ligation of the biliopancreatic duct plus physiologic stimulation at 24 hours. CONCLUSIONS: These experiments provide further evidence that extraluminal protease activation is a pathophysiologic event common to the evolution of various models of experimental acute pancreatitis and therefore increase the likelihood that this phenomenon is important in the human disease as well.

Resection margins in carcinoma of the head of the pancreas. Implications for radiation therapy.

A retrospective review of the pathology and clinical course of 72 patients undergoing resection of carcinoma of the head of the pancreas was undertaken to identify the frequency of tumor involvement at standard surgical transection margins (stomach, duodenum, pancreas, and bile duct) as well as the peripancreatic soft tissue margin and the potential clinical significance of these findings. Of 72 patients undergoing resection, 37 patients (51%) were found to have tumor extension to the surgical margins. The most commonly involved margin was peripancreatic soft tissue (27 patients) followed by pancreatic transection line (14 patients) and bile duct transection line (4 patients). For 37 patients with tumor present at a resection margin, there were no survivors beyond 41 months. No difference in survival or local control was seen between 14 patients receiving postoperative radiation therapy and 5-fluorouracil (5-FU) compared with 23 patients not receiving additional treatment. In contrast, the 5-year actuarial survival and local control of 35 patients undergoing resection without tumor invasion to a resection margin was 22% and 43%, respectively. The 5-year survival and local control of 16 patients receiving adjuvant radiation therapy and 5-FU was 29% and 42%, respectively, whereas these figures were 18% and 31% for 19 patients not receiving adjuvant therapy (p > 0.10). Because residual local tumor after resection is common, preoperative radiation therapy may be beneficial in this disease. It should minimize the risk of dissemination during operative manipulation and facilitate a curative resection by promoting tumor regression. Because local failure rates approach 60% after resection and adjuvant therapy even in cases having clear resection margins, intraoperative radiation therapy to the tumor bed at the time of resection also might be considered. Protocols evaluating the feasibility and efficacy of preoperative radiation therapy and resection with intraoperative radiation therapy for patients with pancreatic cancer are underway.

Risk factors for pancreatic cellular injury after cardiopulmonary bypass.

BACKGROUND: Pancreatitis is a known complication of cardiac surgery with cardiopulmonary bypass. Although ischemia is believed to be a factor, the cause of pancreatitis after cardiopulmonary bypass remains unknown. METHODS: We prospectively studied 300 consecutive patients undergoing cardiac surgery with cardiopulmonary bypass. Serum amylase, pancreatic isoamylase, and serum lipase were measured on postoperative days 1,2,3,7, and 10. Pancreatic cellular injury was defined as the presence of hyperamylasemia (greater than 123 U per liter) with an increase in either the serum level of lipase (greater than 24 U per liter) or the peak level of pancreatic isoamylase. Trypsinogen-activation peptides, which indicate intrapancreatic enzyme activation, were measured in the urine of the last 101 patients studied. RESULTS: Evidence of pancreatic cellular injury was detected in 80 patients (27 percent), of whom 23 had associated abdominal signs or symptoms and 3 had severe pancreatitis (2 with pancreatic abscess and 1 with necrotizing hemorrhagic pancreatitis). Two of 19 postoperative deaths were secondary to pancreatitis. In multivariate analyses, the development of pancreatic cellular injury was significantly associated with preoperative renal insufficiency, valve surgery, postoperative hypotension, and perioperative administration of calcium chloride. The administration of more than 800 mg of calcium chloride per square meter of body-surface area was an independent predictor of pancreatic cellular injury, and the increase in risk was dose-related. No differences were found in the level of trypsinogen-activation peptides between patients who had pancreatic cellular injury and those who did not. CONCLUSIONS: Pancreatic cellular injury, as indicated by hyperamylasemia of pancreatic origin, is common after cardiac surgery. The administration of large doses of calcium chloride is an independent predictor of pancreatic cellular injury and may be a cause of it.

Bacterial infection is not necessary for lethal necrotizing pancreatitis in mice.

Sepsis is the most common cause of late death in pancreatitis. The presence of early bacterial infection has been correlated with the severity of the disease. A choline-deficient ethionine-supplemented (CDE) diet given to young female mice produces severe necrotizing pancreatitis that has morphologic and biochemical similarities to the human disease. We therefore searched for bacterial pancreatic infection in female CD-1 mice given the CDE diet. The mortality rate was 47.5% in mice fed the CDE diet. All of these mice had severe pancreatitis with inflammation, edema, and necrosis on histologic examination. Bacterial infection was present in 1/12 pancreatica among nonsurvivors and in 1/32 pancreatica in surviving animals (p not significant). Histologic examination showed edema to be more pronounced in surviving mice, although the overall severity of morphologic changes was not significantly different between survivors and nonsurvivors. We conclude that bacterial infection is not a determinant of the severity or lethality of experimental pancreatitis induced by the CDE diet.

Isolated small bowel obstruction as the presenting feature of colonic disease.

Small intestinal obstruction without colonic dilation can be the mode of presentation in a variety of colonic diseases, including carcinoma, diverticulitis, and colitis. Plain abdominal roentgenograms may lead the unwary physician into errors of diagnosis and treatment by suggesting primary small bowel disease. Barium enema examination of the colon will keep the wary physician out of such traps. We describe five patients with small bowel obstruction who had a variety of colonic diseases diagnosed by barium contrast studies. If the reason for intestinal obstruction is not apparent and the need for emergency surgery is not compelling, we recommend an immediate contrast study of the colon to aid in evaluating possible colonic pathology.

The hypocalcemia of acute pancreatitis.

Variables of calcium metabolism were measured in 11 patients with clearly documented acute pancreatitis. Total and ionized calcium levels were either low or in the low-normal range as were phosphorus and total magnesium levels. Parathyroid hormone levels were high, and there was a significant inverse correlation with ionized calcium. Gastrin levels were normal, calcitonin values were uniformly below the detection limit of the assay, and pancreatic glucagon levels were elevated. The hypocalcemia of acute pancreatitis was probably not caused by abnormalities of glucagon, calcitonin, or gastrin secretion. Furthermore, parathyroid hormone secretion was apparently not impaired. Hypomagnesemia possibly played a minor role. This study suggests that the hypocalcemia of acute pancreatitis is secondary to extraskeletal calcium sequestration or an as yet unidentified defect of bone metabolism, or both.