Thomas Foitzik

Reduction in Mortality With Delayed Surgical Therapy of Severe Pancreatitis

The indications for surgery in acute pancreatitis have changed significantly in the past two decades. Medical charts of patients with acute pancreatitis treated at our institution were analyzed to assess the effects of changes in surgical treatment on patient outcomes. A total of 136 patients with radiologically defined severe pancreatitis were primarily treated or referred to our institution between 1980 and 1997. Severity of the disease (Ranson score), indications for surgical intervention, timing of surgery, and mortality rates were compared during three study periods: 1980 to 1985 (period I), 1986 to 1990 (period II), and 1991 to 1997 (period III). In period I patients underwent exploratory laparotomy if their clinical status did not improve markedly within 72 hours of admission to the hospital, whereas during period II surgery was reserved for patients who had secondary organ failure together with pancreatic necrosis seen on CT scan. During period III the aim was to operate as late as possible in the presence of pancreatic necrosis or when infected necrosis was suspected. The policy of limiting the indications for surgery resulted in a decrease in surgically treated patients from 68% to 33% (P < 0.001). Likewise, surgical intervention was performed later. In period I, 73% of operations were performed within 72 hours of admission, compared to 32% in period III (P = 0.008). The mortality rate for patients who underwent early surgery (within 72 hours) was higher than for those who underwent late surgical exploration of the abdomen (P = 0.02). Overall, the mortality rate for patients with severe pancreatitis was reduced from 39% to 12% (P = 0.003). Mortality among patients treated nonoperatively did not change significantly. The present study supports the policy of delayed surgery in severe acute pancreatitis. Early surgical intervention often results in unnecessary procedures with an increase in the number of deaths. Whenever possible, prolonged observation allows selection of patients who are likely to benefit from delayed surgery or nonoperative treatment.

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.

Intravenous contrast medium accentuates the severity of acute necrotizing pancreatitis in the rat

BACKGROUND/AIMS Contrast-enhanced computed tomography (CECT) is used to show areas of decreased pancreatic perfusion in severe acute pancreatitis (AP). To evaluate possible adverse effects of the contrast medium (CM) on the course of AP, the impact of intravenous CM in AP of graded severity in the rat was studied. METHODS Pancreatitis of three levels of severity was induced in Sprague-Dawley rats with intravenous cerulein hyperstimulation plus time- and pressure-controlled intraductal infusion of saline or glycodeoxycholic acid. At 7 hours, control and pancreatitis animals received intravenous ionic CM, nonionic CM, or saline. The principal outcome measures were 24-hour survival, trypsinogen activation peptides (TAP) in ascites, and histological acinar necrosis score. RESULTS There was no measurable effect of CM on the index features in control animals or animals with mild or moderate AP. In severe AP, CM caused a significant increase in mortality, ascites TAP, and necrosis score. CONCLUSIONS Intravenous CM increases pancreatic injury when administered early in the course of severe experimental AP. Because CM may convert borderline ischemia to irreversible necrosis, CECT performed early in pancreatitis to show poor perfusion and predict areas of necrosis may depict a self-fulfilling prophecy. Early CECT should be reconsidered and perhaps avoided.

Impact of microcirculatory flow pattern changes on the development of acute edematous and necrotizing pancreatitis in rabbit pancreas

Impairment of pancreatic microcirculation has often been advocated as one pathogenic mechanism in necrotizing pancreatitis. In contrast, data on pancreatic capillary perfusion in edematous pancreatitis are scarce. It was the aim of this experimental study to compare changes in pancreatic microcirculation in edematous and necrotizing pancreatitis. Twelve rabbits were allocated to two groups. Two different models of acute pancreatitis were used. Edematous pancreatitis was elicited by intravenous administration of cerulein (25 µg/kg/hr) (N=6). Necrotizing pancreatitis of the biliary type was induced by pressure-controlled intraductal infusion of a mixture of taurocholate, trypsin, and blood (N=6). Pancreatic microcirculation was quantified by means of intravital microscopy assessing functional capillary density, blood cell velocity, and distribution of the plasma marker FITC-dextran 70. Systemic hemodynamics were maintained at baseline values by fluid administration. Regardless of edema or necrosis, pronounced extravasation of FITC-dextran was recorded in the early stage of pancreatitis. In cerulein-induced pancreatitis, hyperemia developed as indicated by an increase in blood cell velocity in the presence of homogeneous capillary perfusion. In contrast, a progressive reduction of the number of perfused capillaries was detected in necrotizing pancreatitis. In conclusion, pancreatic microvascular perfusion may be regarded as an important pathogenetic factor for the determination of acute pancreatitis.

Intravenous contrast medium aggravates the impairment of pancreatic microcirculation in necrotizing pancreatitis in the rat.

BackgroundPrevious reports demonstrated that radiographic contrast medium, as used in contrast-enhanced computed tomography, increases acinar necrosis and mortality in experimental pancreatitis. The authors studed the possibility that these changes may be related to an additional impairment of pancreatic microcirulation. MethodsFifty Wistar rats had acute pancreatitis induced by intraductal glycodeoxycholic acid (10 mmol/L for 10 min) and intravenous cerulein (5 μg/kg/hr for 6 hrs). After rehydration (16 mL/kg), pancreatic capillary perfusion was quantified by means of intravital microscopy at baseline before intravenous infusion of contrast medium (n = 25) or saline (n = 25), and 30 and 60 minutes thereafter. In addition to total capillary flow, capillaries were categorized as high-or low-flow (> or <1.6nL/min). ResultsPancreatic capillary flow did not change in either high- or low-flow capillaries after saline infusion. However, contrast medium infusion induced a significant decrease of total capillary flow (p < 0.001). Analysis according to the relative flow rate revealed that this was primarity because of a significant additional reduction of perfusion in low-flow capillaries (p < 0.0001). Furthermore, complete capillary stasis was observed in 15.9 ± 3.4% after contrast medium as compared with 3.2 ± 1.2% after saline infusion (p < 0.006). ConclusionRadiographic contrast medium aggravates the impairment of pancreatic microcirculation in experimental necrotizing pancreatitis.

Does glutamine reduce bacterial translocation? A study in two animal models with impaired gut barrier.

Abstract Failure of intestinal barrier function and subsequent translocation of bacteria from the gut are believed to play a decisive role in the development of systemic septic complications, for example, following major trauma or major abdominal surgery. This study evaluated: (a) the effect of glutamine on colonic microcirculation and electrophysiological parameters reflecting gut barrier function, (b) the translocation of live bacteria to extraintestinal organs, and (c) disease outcome in two animal models with impaired gut barrier function. Severe acute pancreatitis or colitis was induced in rats randomized for therapy with or without glutamine (0.5 g/kg daily). After 48 h one animal group was prepared for intravital microscopy of colonic capillary blood flow and electrophysiological measurement of gut permeability; another was killed after 96 h for histological and microbiological examination. In animals with pancreatitis, glutamine (Gln) supplementation significantly improved gut permeability, i.e., Gln increased colonic transmucosal resistance from 67±7 to 92±3 Ω/cm2 and decreased mannitol flux through the epithelium by 53%. Capillary blood flow in the colonic mucosa was improved by 25%. The prevalence of pancreatic infections was reduced from 86% in animals on standard parenteral nutrition to 33% in animals given the Gln-enriched diet (P<0.05); mortality decreased by 32%. In colitis, Gln had no significant effect on these parameters except for improving colonic capillary blood flow in colon segments not adjacent to the major injury site. Glutamine supplementation improves colonic capillary blood flow, stabilizes gut permeability, and reduces secondary pancreatic infections and mortality in severe rodent pancreatitis, but it is not helpful in colitis. This confirms previous reports that glutamine stabilizes gut barrier function only in certain diseases. Our experimental data strongly suggest that acute pancreatitis (rather than colitis) is one of the diseases with gut barrier dysfunction in which glutamine substitution may be helpful to reduce bacterial translocation and should therefore be tested in a controlled clinical trial.

An Orthotopic Nude Mouse Model for Evaluating Pathophysiology and Therapy of Pancreatic Cancer

Introduction Orthotopic, clinically relevant animal models are necessary for the study of pathophysiology and therapy for pancreatic cancer. Aims To develop a minimally traumatic technique of orthotopic tumor induction, to develop a scoring system to quantify local and systemic tumor spread, and to provide a model with a broad range of well-differentiated to undifferentiated pancreatic cancers. Methodology Orthotopic tumors were induced in nude mice by atraumatic pancreatic implantation of two fragments from subcutaneous donor tumors or intrapancreatic injection of human tumor cells (MIAPaCa-2, AsPC-1, HPAF-2, Capan-1). Animals were monitored for 14 weeks or until death. Primary tumor volume, local infiltration, and systemic metastasis were assessed and analyzed at autopsy. Macroscopic findings were confirmed by histologic evaluation. Results Tumor take rate in the implantation group was 100% for all four cell lines. Marked differences with regard to tumor size, metastatic spread, and survival were found depending on the grade of differentiation. Less differentiated cells (MIAPaCa-2, AsPC-1) caused higher dissemination scores and mortality than better-differentiated cells (HPAF-2, Capan-1). Clinical features included cachexia, jaundice, and malignant ascites. Orthotopic tumor cell injection resulted in an incomplete tumor take rate. Moreover, early artificial abdominal tumor spread was found in injected animals due to microscopic cell loss during the injection procedure. Conclusions Orthotopic implantation of donor tumor fragments into nude mice is technically feasible and is superior to the cell injection technique. It results in reproducible local and systemic development of pancreatic cancer that mimics the human disease. A dissemination score may help to better quantify therapeutic effects in future studies.

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.

Intestinal microcirculation and gut permeability in acute pancreatitis: early changes and therapeutic implications☆☆☆

Translocation of bacteria from the intestine causes local and systemic infection in severe acute pancreatitis. Increased intestinal permeability is considered a promoter of bacterial translocation. The mechanism leading to increased gut permeability may involve impaired intestinal capillary blood flow. The aim of this study was to evaluate and correlate early changes in capillary blood flow and permeability of the colon in acute rodent pancreatitis of graded severity. Edematous pancreatitis was induced by intravenous cerulein; necrotizing pancreatitis by intravenous cerulein and intraductal glycodeoxycholic acid. Six hours after induction of pancreatitis, the permeability of the ascending colon was assessed by the Ussing chamber technique; capillary perfusion of the pancreas and colon (mucosal and subserosal) was determined by intravital microscopy. In mild pancreatitis, pancreatic capillary perfusion remained unchanged (2.13 ± 0.06 vs. 1.98 ± 0.04 nl-min−l.cap −1 [control]; P = NS), whereas mucosal (1.59 _± 0.03 vs. 2.28 ± 0.03 nl.min−l.cap −1 [control]; P <0.01) and subserosal (2.47 ± 0.04 vs. 3.74 ± 0.05 nl-min−l.cap -1 [control]; P <0.01) colonic capillary blood flow was significantly reduced. Severe pancreatitis was associated with a marked reduction in both pancreatic (1.06 = 0.03 vs. 1.98 ± 0.04 nl’min-1.cap -1 [control]; P <0.01) and colonic (mucosal: 0.59 = 0.01 vs. 2.28 ± 0.03 nl.min−l.cap -1 [control], P < 0.01; subserosal: 1.96 ± 0.05 vs. 3.74 ± 0.05 nl.min−l.cap -1 [control], P <0.01) capillary perfusion. Colon permeability tended to increase with the severity of the disease (control: 147 ±19 nmol.hr−l.cm {−2}2; mild pancreatitis: 158±23 nmol-hr−l.cm-2; severe pancreatitis: 181 ±33 nmol.hr−l.cm-2; P = NS). Impairment of colonic capillary perfusion correlates with the severity of pancreatitis. A decrease in capillary blood flow in the colon, even in mild pancreatitis not associated with significant protease activation and acinar cell necrosis or impairment of pancreatic capillary perfusion, suggests that colonic microcirculation is especially susceptible to inflammatory injury. There was no significant change in intestinal permeability in the early stage of pancreatitis, suggesting a window of opportunity for therapeutic interventions to prevent the later-observed increase in gut permeability, which could result in improved intestinal microcirculation.

Isovolemic hemodilution with dextran 60 as treatment of pancreatic ischemia in acute pancreatitis. Clinical practicability of an experimental concept.

OBJECTIVE This phase-I study transferred the concept of isovolemic hemodilution, which has been proven beneficial in the treatment of experimental acute pancreatitis to the patient. SUMMARY BACKGROUND DATA Pancreatic ischemia represents one main mechanism in the pathogenesis of necrotizing pancreatitis. Isovolemic hemodilution with dextran 60 has been shown experimentally to limit the progression of pancreatic necrosis by improving pancreatic microcirculation. METHODS Thirteen patients with clinically severe nonbiliary pancreatitis and CT-classification E according to Balthazar were enrolled. Exclusion criteria were anemia, coronary heart disease, chronic obstructive pulmonary disease, coagulopathies, and secondary referral. The volume of blood to be exchanged for dextran 60 was calculated from a nomogram based on body surface. Isovolemic hemodilution aimed at a hematocrit of 30%. Independent from the exchange procedure conventional fluid resuscitation was performed to adjust the central venous pressure at 6 +/- 2 mm Hg. RESULTS Whole blood (750-1,700 mL) was exchanged for dextran 60 during 45 to 70 minutes. No adverse effect was encountered; central hemodynamics were not affected. Considering a mean Ranson score of 5, mortality was low (7.7%). Progression of pancreatic necrosis was registered in only two patients subsequently undergoing surgical treatment (15%). CONCLUSIONS Isovolemic hemodilution is practicable in patients. A randomized trial has to prove whether isovolemic hemodilution can substantially alter the course of acute pancreatitis as anticipated from animal studies.