Effect of early antibiotic prophylaxis with ertapenem and meropenem in experimental acute pancreatitis in rats

Background  The clinical course in acute necrotizing pancreatitis is mainly influenced by bacterial infection of pancreatic and peripancreatic necrosis. The effect of two antibiotic treatments for early prophylaxis was studied in the taurocholate model of necrotizing pancreatitis in the rat. Methods  Sixty male Sprague-Dawley rats were divided into three pancreatitis groups (15 animals each) and a sham-operated group (15 animals, control group). Pancreatitis was induced by intraductal infusion of 3% taurocholate under sterile conditions. Animals were placed on one of two different antibiotic regimens (15 mg/kg ertapenem or 20 mg/kg meropenem, one shot) after the induction of pancreatitis or received no antibiotics (control). All animals were sacrificed after 24 h to study pancreatic and extrapancreatic infection. Results  Early antibiotic prophylaxis with either erapenam or meropenem significantly decreased pancreatic infection from 12/15 (control group) to 4/15 (ertapenem antibiotic group) and 3/15 (meropenem antibiotic group) (P < 0.05). Conclusions  In our animal model of necrotizing pancreatitis, early antibiotic prophylaxis with ertapenem and meropenem reduced bacterial infection of the pancreas. The efficacy of early antibiotic prophylaxis with ertapenem in the clinical setting should be subject to further research.     

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

OBJECTIVE: The 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. BACKGROUND: Infection 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. METHODS: Severe 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. RESULTS: The 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 cefotaxime alone. Renal infection was reduced by both intravenous antibiotics. CONCLUSIONS: Early 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.     

Frequency and time course of pancreatic and extrapancreatic bacterial infection in experimental acute pancreatitis in rats

BACKGROUND: Infectious complications in severe pancreatitis are the main factors determining clinical course and outcome. The taurocholate model for acute necrotizing pancreatitis was evaluated for frequency and time course of pancreatic and extrapancreatic bacterial infection. METHODS: Sixty-five male Wistar rats were divided into 5 groups of 13 animals each. Specimens for bacteriologic examination were taken, and pancreatitis was induced by intraductal infusion of 3% taurocholate under sterile conditions. Animals were killed 8, 16, 24, or 32 hours thereafter, and bacteriologic examination was performed. A control group of animals with intraductal infusion of 0.9% saline solution were killed after 32 hours. RESULTS: There was no significant pancreatic infection in the control group and in the 8-hour group (1 of 13 rats). Sixteen and 24 hours after induction of pancreatitis, infection and inflammation of the pancreas were found in 77% (10 of 13 rats), and after 32 hours pancreatic infection occurred in 69% (9 of 13 rats). Extrapancreatic bacterial infection after 16 hours occurred in the liver (62%), spleen (62%), and mesenteric lymph nodes (46%). Bacteria infecting the pancreas reflected the bacterial spectrum of the large bowel and terminal ileum before induction of pancreatitis (Escherichia coli [77%], Proteus [43%], Enterococcus [37%], and Staphylococcus [23%]). CONCLUSIONS: Pancreatic infection is an early and frequent finding in the taurocholate model of acute necrotizing pancreatitis. Infection occurs between 8 and 16 hours after induction of pancreatitis. The source of infecting bacteria seems to be the large bowel or the terminal ileum. We present a useful model of severe pancreatitis in which to study bacterial translocation, the further route of spread, and therapeutic approaches.     

Endothelin receptor antagonists are not beneficial in the therapy of acute experimental pancreatitis

BACKGROUND AND AIM: Due to increased capillary permeability and the early appearance of vasoactive and toxic agents, patients suffering from necrotizing pancreatitis frequently develop a systemic inflammatory response syndrome (SIRS). Endothelin, a potent vasoconstrictor, is thought to play a major role in these changes via the regulation of microcirculation. An improved outcome of acute experimental necrotizing pancreatitis by blocking the endothelin receptors ETA and ETB, either selectively (only ETA) or unselectively (ETA and ETB), has been suggested. The aim of this study was to investigate further the beneficial effects of new, highly potent endothelin-receptor (ET-R) antagonists in acute experimental pancreatitis. METHODS: The influence of the selective ET-RA antagonist BSF208075 (1 mg/kg) on mortality was studied in three severity groups of acute necrotizing pancreatitis (retrograde injection of 4%, 5% and 6% of sodium taurocholate into the main pancreatic duct). The effects of the selective ET-RA antagonists LU135252 (LU13) and BSF208075 (BSF20) and of the unselective endothelin receptor (ET-R(A/B)) antagonist BSF420627 (BSF42) were additionally analyzed in 4% taurocholate-induced necrotizing pancreatitis. Furthermore, the significance of variable doses of the endothelin receptor antagonist LU13 (1 mg/kg, 3 mg/kg and 100 mg/kg) was determined in a 4% sodium taurocholate model and in a cerulein pancreatitis model. RESULTS: Prophylactic ET-R antagonism increased the mortality rate in the 4% sodium taurocholate-induced pancreatitis. No reduction in pancreatic damage after induction of taurocholate pancreatitis was found by ET-R blockage. Application of ET-R antagonists had no beneficial influence in ascites development. However, administration of LU13 (100 mg/kg) resulted in a non-significant increase in pancreatic oedema, whereas peritoneal necrosis was not affected. CONCLUSION: The selective and unselective ET-R antagonists BSF20, BSF42 and LU13 failed to improve survival and pancreatic damage during acute experimental pancreatitis. Therefore, previously reported beneficial effects of ET-R antagonists in experimental acute pancreatitis have to be critically evaluated before conclusions for further clinical development are made.     

Acute pancreatic necrosis complicated by infection and gastro-intestinal translocation: pathogenesis correlation and therapeutic implication

The authors define pathogenetics correlations as a acute necrotizing pancreatitis complicated by infection and bacterial translocation. Acute necrotizing pancreatitis infection occurs for gastrointestinal bacterial translocation due to structural and functional modifications of intestinal mucosa. These modifications are results of mucosa ischemic-reperfusion system caused by systemic emodynamic instability in micro- and macro-circulation of splanchnic district. Emodynamic systemic instability has a central role in different multiple physiopathologic phenomena (ipovolemic shock; pancreatic shock, SIRS), which is caused by acute pancreatic necrosis and carries to common way established by severe systemics emodinamics modifications; these changes promote growth of adverse events which conduce by means of process previously described to bacterial translocation and infection of acute pancreatic necrosis. Indeed, emodynamic systemic instability of any etiology, can determine for one way bacterial translocation and on the other acute ischemic pancreatitis; both phenomena concur lead to cause beginning of acute necrotizing pancreatitis complicated by infection. The authors confirm that improved knowledge of acute pancreatic necrosis complicated by infection and own pathogenetic correlations with bacterial translocation, allows the realization of therapeutic measures aimed to prophylaxis of infection of acute pancreatic necrosis. Central emodynamic stability regularization of splanchnic perfusion and antibiotic prophylaxis, have a central role in prophylaxis of infection of acute pancreatic necrosis. Antibiotic is given by systemic (imipenem e.v.) and selective decontamination of gastrointestinal tract (SDD). SDD provides for oral antibiotic prophylaxis (PTA protocol) and systemic antibiotic prophylaxis (cefotaxime and gentamicin), in addition to microbiologic and gastrointestinal monitoring. If on the one hand the role of SDD about mortality reduction is not clear, however, on the other it is well recognized capacity of reduction the intercurrents and pulmonary infections. Other Authors think that SDD is insignificant on early mortality, whereas, is a good option to reduce late and overall mortality of acute pancreatic necrosis complicated by infection.     

Effect of platelet-activating factor antagonists (BN-52021, WEB-2170, and BB-882) on bacterial translocation in acute pancreatitis

Bacterial translocation is an important source of pancreas infection in acute pancreatitis. The effect of platelet-activating factor (PAF) in the pathogenesis of acute pancreatitis has been proved in various studies. The aim of this study was to determine whether potent PAF antagonists influence bacterial translocation in acute pancreatitis. Acute pancreatitis was induced in 62 Wistar rats by injection of 2.5% sodium taurocholate into the biliopancreatic duct. The rats treated with PAF factor antagonists received intravenous injection of WEB-2170 (10 mg/kg), lexipafant (5 mg/kg), and BN-52021 (5 mg/kg) 30 minutes before induction of acute pancreatitis. Six hours after induction of acute pancreatitis, bacteriologic cultures and histologic scoring of tissues were performed. There was a statistically significant reduction in bacterial translocation to the mesenteric lymph nodes and liver but not to the pancreas of the rats treated with PAF antagonists. No significant increase in the intestinal bacterial population of any group was found. There were no statistical differences between the pancreatic histologic scores of the groups. PAF antagonists reduced bacterial translocation to distant sites other than the pancreas, preventing the bacterial dissemination that occurs in the early phase of acute pancreatitis and may have beneficial effects on the evolution of this disease.     

Early treatment with antibiotics reduces the need for surgery in acute necrotizing pancreatitis—a single-center randomized study

Pancreatic infection is the main indication for surgery and the principal determinant of prognosis in acute necrotizing pancreatitis. Previous studies on the effects of antibiotics have not, however, uniformly demonstrated any reduction in the need for surgery or any decrease in mortality among these patients, although the incidence of pancreatic infections was significantly reduced. This single-center randomized study was designed to compare early vs. delayed imipenem treatment for acute necrotizing pancreatitis. Ninety patients with acute necrotizing pancreatitis (C-reactive protein >150 mg/L, necrosis on CT) were randomized within 48 hours either to a group receiving imipenem (1.0 g plus cilastatin intravenously 3 times a day) or a control group. Not included were those who had been started on antibiotics at the referring clinic, those who were taken directly to the intensive care unit for multiorgan failure, and those who refused antibiotics or might have had adverse reactions. Thirty-two patients were excluded because they were over 70 years of age (not potentionally operable) or for any study violation. There were 25 patients in the imipenem group and 33 patients in the control group. The main end point was the indication for necrosectomy due to infection (i.e., after the initial increase and decrease, there was a second continuous increase in temperature, white blood cell count [>30%] and C-reactive protein [>30%], with other infections ruled out, or bacteria were found on Gram stain of the pancreatic fine-needle aspirate). In the control group, imipenem was started when the operative indication was fulfilled. Conservative treatment was continued for at least 5 days before necrosectomy. The study groups did not differ from each other with regard to sex distribution, patient age, etiology, C-reactive protein concentration, and extent of pancreatic necrosis on CT. Two (8%) of 25 patients in the imipenem group compared to 14 (42%) of 33 in the control group fulfilled the operative indications (P = 0.003). Nine patients in the control group responded to delayed antibiotics but five had to undergo surgery. Of those receiving antibiotics, 2 (8%) of 25 in the early antibiotic (imipenem) group needed surgery compared to 5 (36%) of 14 in the delayed antibiotic (control) group (P = 0.04). Two (8%) of 25 patients in the imipenem group and 5(15%) of 13 patients in the control group died (P = NS [no significant difference]). Seven (28%) of 25 in the imipenem group and 25 (76%) of 33 in the control group had major organ complications (P = 0.0003). Based on the preceding criteria, early imipenem-cilastatin therapy appears to significantly reduce the need for surgery and the overall number of major organ complications in acute necrotizing pancreatitis, and reduces by half the mortality rate; this is not, however, statistically significant in a series of this size. Presented at the Forty-First Annual Meeting of The Society for Surgery of the Alimentary Tract, San Diego, Calif., May 21–24, 2000.     

A Double-blind, Placebo-controlled Trial of Ciprofloxacin Prophylaxis in Patients with Acute Necrotizing Pancreatitis

Background  The use of prophylactic antibiotics in acute severe necrotizing pancreatitis is controversial. Methods  Prospective, randomized, placebo-controlled, double-blind study was carried out at Bellvitge Hospital, in Barcelona, Spain. Among 229 diagnosed with severe acute pancreatitis, 80 had evidence of necrotizing pancreatitis (34/80 patients were excluded of the protocol). Forty-six patients without previous antibiotic treatment with pancreatic necrosis in a contrast-enhanced CT scan were randomly assigned to receive either intravenous ciprofloxacin or placebo. Five patients were secondarily excluded, and the remaining 41 patients were finally included in the study (22 patients received intravenous ciprofloxacin and 19 patients placebo). Results  Comparing the 22 with intravenous ciprofloxacin and 19 with placebo, infected pancreatic necrosis was detected in 36% and 42% respectively (p = 0.7). The mortality rate was 18% and 11%, respectively (p = 0.6). No significant differences between both treatment groups were observed with respect to variables such as: non-pancreatic infections, surgical treatment, timing and the re-operation rate, organ failure, length of hospital and ICU stays. Conclusion  The prophylactic use of ciprofloxacin in patients with severe necrotizing pancreatitis did not significantly reduce the risk of developing pancreatic infection or decrease the mortality rate. The small number of patients included in this study should be considered. This study was promoted by the “Bellvitge Hospital” and has not received any grant or payment from the pharmaceutical industry.     

Acute necrotizing pancreatitis: treatment strategy according to the status of infection

OBJECTIVE: To determine benefits of conservative versus surgical treatment in patients with necrotizing pancreatitis. SUMMARY BACKGROUND DATA: Infection of pancreatic necrosis is the most important risk factor contributing to death in severe acute pancreatitis, and it is generally accepted that infected pancreatic necrosis should be managed surgically. In contrast, the management of sterile pancreatic necrosis accompanied by organ failure is controversial. Recent clinical experience has provided evidence that conservative management of sterile pancreatic necrosis including early antibiotic administration seems promising. METHODS: A prospective single-center trial evaluated the role of nonsurgical management including early antibiotic treatment in patients with necrotizing pancreatitis. Pancreatic infection, if confirmed by fine-needle aspiration, was considered an indication for surgery, whereas patients without signs of pancreatic infection were treated without surgery. RESULTS: Between January 1994 and June 1999, 204 consecutive patients with acute pancreatitis were recruited. Eighty-six (42%) had necrotizing disease, of whom 57 (66%) had sterile and 29 (34%) infected necrosis. Patients with infected necrosis had more organ failures and a greater extent of necrosis compared with those with sterile necrosis. When early antibiotic treatment was used in all patients with necrotizing pancreatitis (imipenem/cilastatin), the characteristics of pancreatic infection changed to predominantly gram-positive and fungal infections. Fine-needle aspiration showed a sensitivity of 96% for detecting pancreatic infection. The death rate was 1.8% (1/56) in patients with sterile necrosis managed without surgery versus 24% (7/29) in patients with infected necrosis (P <.01). Two patients whose infected necrosis could not be diagnosed in a timely fashion died while receiving nonsurgical treatment. Thus, an intent-to-treat analysis (nonsurgical vs. surgical treatment) revealed a death rate of 5% (3/58) with conservative management versus 21% (6/28) with surgery. CONCLUSIONS: These results support nonsurgical management, including early antibiotic treatment, in patients with sterile pancreatic necrosis. Patients with infected necrosis still represent a high-risk group in severe acute pancreatitis, and for them surgical treatment seems preferable.     

急性出血坏死性胰腺炎大鼠胰腺组织结构改变与内毒素血症的关系及纳屈酮的治疗作用

为探讨大鼠急性出血坏死性胰腺炎（ＡＨＮＰ）胰腺组织结构改变与内毒素血症的关系及纳屈酮的治疗作用，用５％牛磺胆酸钠逆行胰胆管注射制成ＡＨＮＰ模型。取Ｗｉｓｔａｒ大鼠１１０只随机分为假手术组（ｎ＝２０）、ＡＨＮＰ组（ｎ＝４５）、纳屈酮治疗组（ｎ＝４５），分别于术后６、１２、２４小时称取胰腺重量，观察ＡＨＮＰ大鼠胰腺组织结构改变，同时测定其血浆淀粉酶和内毒素水平，并与假手术组比较。结果：与假手术组比较，ＡＨＮＰ组血浆淀粉酶、内毒素及胰腺系数升高，在光镜及电镜下可见胰腺损害随时间延长而加重。纳屈酮治疗组与ＡＨＮＰ组相比，其血浆淀粉酶、内毒素及胰腺系数下降，而且胰腺损害减轻。本实验结果提示：ＡＨＮＰ引发内毒素血症，纳屈酮可通过改善胰腺缺血性损害而降低血浆内毒素，延长大鼠生存时间及降低病死率     

急性坏死性胰腺炎胰外器官微循环改变及乌司他丁的影响

目的 探讨急性坏死性胰腺炎(ANP)时肺、肾、肠微循环的变化及乌司他丁(UTI)的保护作用。方法 SD大鼠48只，随机均分为对照组、ANP组及UTI组。ANP组、UTI组于胰被膜下均匀注射5％牛磺胆酸钠制成ANP模型，对照组则注射等量生理盐水。UTI组于制模后即由股静脉缓慢注射UTI 10000u/kg，对照组及ANP组则注射等量生理盐水。分别于制模后2h及6h采用放射性生物微球法测定肺、肾及末端回肠组织的血流量变化。结果 与对照组相比，ANP组制模后2h及6h肺、肾、肠组织血流量显著减少(P＜0．05)；与ANP组相比，UTI组2h及6h各组织血流量均有明显增加(P＜0．05)。结论 微循环障碍是ANP胰外器官损害的重要原因之一，UTI对ANP时胰外器官微循环障碍有明显的保护作用。     

早期应用L-精氨酸治疗急性出血坏死性胰腺炎的实验研究

目的: 探讨早期应用L-精氨酸对急性出血坏死性胰腺炎(AHNP)的治疗作用. 方法: 经大鼠胰胆管注射牛磺酸钠制备AHNP模型,分别静注L-精氨酸、生理盐水、山莨菪碱;观察血清淀粉酶、白介素6(IL-6)、丙二醛(MDA)、一氧化氮(NO)改变及胰腺的病理改变. 结果: 应用L-精氨酸后,能升高血NO浓度,清除氧自由基,降低血清IL-6水平,降低血清淀粉酶,改善胰腺病变,其作用优于山莨菪碱. 结论: 早期应用一定剂量的L-精氨酸对AHNP具有一定的治疗效果.     

Effects of caffeic acid phenethyl ester on pancreatitis in rats

BACKGROUND: This study investigated the effect of caffeic acid phenethyl ester (CAPE) on acute necrotizing pancreatitis (ANP) induced by glycodeoxycholic acid in rats. CAPE, an active component of honeybee propolis, has previously been determined to have antioxidant, anti-inflammatory, antiviral, and anticancer activities. MATERIALS AND METHODS: Forty-eight rats were divided into four groups of 12. Group 1 animals received intraductal saline and intravenous saline infusion treatment. Group 2 was given intraductal saline and intraperitoneal CAPE infusion treatment. ANP was induced in the animals in group 3 (ANP with saline infusion), and group 4 had induced ANP plus CAPE infusion treatment (ANP with CAPE infusion). Sampling was performed 48 h after treatment. RESULTS: ANP induction significantly increased mortality rate, pancreatic necrosis, and bacterial infection in pancreatic and extrapancreatic organs. ANP also increased levels of amylase and alanine aminotransferase (ALT) in serum, increased levels of urea and lactate dehydrogenase in bronchoalveolar lavage fluid (BAL LDH), increased the activities of myeloperoxidase (MPO) and malondialdehyde (MDA) in pancreas and lung tissue, and decreased the serum calcium levels. The use of CAPE did not significantly reduce the mortality rate but significantly reduced the ALT and BAL LDH levels, the activities of MPO and MDA in the pancreas, the activity of MDA in the lungs, and pancreatic damage. The administration of CAPE did not reduce the bacterial infection. CONCLUSIONS: These results indicate that CAPE had beneficial effects on the course of ANP in rats and suggest that CAPE shows promise as a treatment for ANP.     

Acute necrotizing pancreatitis: can tigecycline be included in a therapeutic strategy?

Introduction

Acute necrotizing pancreatitis is a severe and life-threatening disease. Infection, which occurs in about 30% of cases, is the most feared complication. Antibiotic therapy is still discussed and there are no clear recommendation in literature. These clinical series underline the importance of having a clear antibiotic protocol, including tigecycline, in the management of acute necrotizing pancreatitis.

Clinical series

Six patients with clinical and radiological diagnosis of necrotizing acute pancreatitis are treated in Emergency Surgery Department, following a conservative management, which includes fluid resuscitation, intensive care unit and radiological monitoring, ultrasound-guided percutaneous drainage and an antibiotic treatment protocol, that includes tigecycline. No one of the six patient undergo surgery (mean hospital stay: 44 days). In a six months follow-up all patients are alive and in good clinical conditions.

Discussion

Infection is the most important factor which determinate prognosis and outcome of acute necrotizing pancreatitis. Antibiotic prophylaxis is still discussed and there are no clear antibiotic treatment guidelines in literature. Despite its side effects on pancreatic gland, tigecycline is successful in resolution of sepsis, caused by infected pancreatic necrosis.

Conclusions

Collaboration with infectivologist and a clear antibiotic protocol is fundamental to solve infected necrosis. Antibiotic treatment, set up as soon as possible, is successful in our six patients, as they recover without undergoing surgical procedures. Tigecycline offers broad coverage and efficacy against resistant pathogens for the treatment of documented pancreatic necrosis infection. However, further studies are necessary to fully understand the safety profile and efficacy of tigecycline.     

Early treatment with antibiotics reduces the need for surgery in acute necrotizing pancreatitis--a single-center randomized study.

Pancreatic infection is the main indication for surgery and the principal determinant of prognosis in acute necrotizing pancreatitis. Previous studies on the effects of antibiotics have not, however, uniformly demonstrated any reduction in the need for surgery or any decrease in mortality among these patients, although the incidence of pancreatic infections was significantly reduced. This single-center randomized study was designed to compare early vs. delayed imipenem treatment for acute necrotizing pancreatitis. Ninety patients with acute necrotizing pancreatitis (C-reactive protein > 150 mg/L, necrosis on CT) were randomized within 48 hours either to a group receiving imipenem (1.0 g plus cilastatin intravenously 3 times a day) or a control group. Not included were those who had been started on antibiotics at the referring clinic, those who were taken directly to the intensive care unit for multiorgan failure, and those who refused antibiotics or might have had adverse reactions. Thirty-two patients were excluded because they were over 70 years of age (not potentionally operable) or for any study violation. There were 25 patients in the imipenem group and 33 patients in the control group. The main end point was the indication for necrosectomy due to infection (i.e., after the initial increase and decrease, there was a second continuous increase in temperature, white blood cell count [> 30%] and C-reactive protein [> 30%], with other infections ruled out, or bacteria were found on Gram stain of the pancreatic fine-needle aspirate). In the control group, imipenem was started when the operative indication was fulfilled. Conservative treatment was continued for at least 5 days before necrosectomy. The study groups did not differ from each other with regard to sex distribution, patient age, etiology, C-reactive protein concentration, and extent of pancreatic necrosis on CT. Two (8%) of 25 patients in the imipenem group compared to 14 (42%) of 33 in the control group fulfilled the operative indications (P = 0.003). Nine patients in the control group responded to delayed antibiotics but five had to undergo surgery. Of those receiving antibiotics, 2 (8%) of 25 in the early antibiotic (imipenem) group needed surgery compared to 5 (36%) of 14 in the delayed antibiotic (control) group (P = 0.04). Two (8%) of 25 patients in the imipenem group and 5 (15%) of 13 patients in the control group died (P = NS [no significant difference]). Seven (28%) of 25 in the imipenem group and 25 (76%) of 33 in the control group had major organ complications (P = 0.0003). Based on the preceding criteria, early imipenem-cilastatin therapy appears to significantly reduce the need for surgery and the overall number of major organ complications in acute necrotizing pancreatitis, and reduces by half the mortality rate; this is not, however, statistically significant in a series of this size.     

Strategy for treatment of acute necrotizing pancreatitis: Importance of continuous regional arterial infusion of protease inhibitor and antibiotics in the early phase

A new strategy for the treatment of acute necrotizing pancreatitis (ANP) is reported. In this prospective study, all patients received intensive medical support. Surgery was performed in patients with infected pancreatic necrosis and/or sepsis. Continuous regional arterial infusion (CRAI) of the protease inhibitor, nafamostat mesilate, and the antibiotic imipenem was initiated in patients with ANP referred to our hospital within 7 days of the onset of the disease. Sixty patients with ANP were allocated to three groups: group I, no CRAI (n =16); group II, CRAI of nafamostat only (n=22); and group III, CRAI of nafamostat mesilate and imipenem (n=22). The mortality rate was 43.3% in group I, 13.6% in group II (P<0.05 vs group I), and 13.6% in group III (P<0.05 vs group I). The frequency of infected pancreatic necrosis was 50% in group I, 36.4% in group II, and nil in group III (P<0.01 vs group I and II). Combination of the protease inhibitor and the antibiotic infused intraarterially reduced the mortality rate and the frequency of infected pancreatic necrosis. However, 6 patients in the CRAI groups died of multiple organ failure (MOF), although the pancreatic necrosis was sterile. Massive retroperitoneal necrosis and bleeding was observed in these patients. CRAI is a potent mode of treatment in the early phase of necrotizing pancreatitis and most patients respond to this treatment. However, surgical intervention should be considered when the patient does not respond to CRAI and organ failure progresses, even though the pancreatic necrosis is sterile.     

Bacterial analysis of infected pancreatic necrosis and its prevention (Symposium 8: Pancreatobiliary infection (IHPBA))

In severe acute pancreatitis, sepsis mainly due to pancreatic or peripancreatic infection have emerged as the most serious complications and now accounts for more than 80% of deaths. Collective review of organisms associated with secondary pancreatic infection in patients with acute pancreatitis has revealed that most of them are intestinal flora. Several experimental studies including ours have revealed that acute pancreatitis promotes bacterial translocation (BT), which in turn leads to infection of the pancreas and septic complications. Prophylactic antibiotics given intravenously have been demonstrated to be beneficial in reducing the rate of pancreatic infection, but their survival benefit remains unclear. We have demonstrated that continuous regional arterial infusion (CRAI) of an antibiotic is more effective than intravenous administration in preventing pancreatic infection and improving survival, in a canine model of acute necrotizing pancreatitis. Our recent experimental study has revealed that CRAI of an antibiotic via the superior mesenteric artery (SMA) is effective in mitigating intestinal mucosal damage and preventing BT in acute pancreatitis, thereby improving survival. BT aggravates pancreatic necrosis and remote organ damage in acute pancreatitis, and SMA infusion of antibiotics is effective in preventing BT and is practical for clinical use.     

Effects of combined nutritional therapy on acute necrotizing pancreatitis in rats in the early phase of the disease

The aim of this study was to investigate the influence of a small amount of enteral nutrition along with parenteral nutrition on acute necrotizing pancreatitis (ANP) induced by glycodeoxycholic acid in rats in the early phase of disease. The induction of ANP resulted in a significant increase in mortality rate, intestinal permeability, bacterial infection in the pancreas and extrapancreatic organs, pancreatic necrosis and serum activity of urea and amylase, and a significant decrease in concentrations of calcium, protein and albumin. But no difference was observed between the pancreatitis groups. Significant hyperglycemia and increased liver transaminase activity were observed in rats treated with combined nutritional therapy (CNT). CNT did not improve the course of acute pancreatitis, intestinal permeability, bacterial translocation, or reduce the extent of acinar cell injury in ANP and is therefore unlikely to be of benefit in patients with pancreatitis in the early period.     

Management of infection in acute pancreatitis

The clinical course of acute pancreatitis varies from a mild, transitory illness to a severe, rapidly fatal disease. In about 80% to 90% of cases pancreatitis presents as a mild, self-limiting disease with low morbidity and mortality. Unlike mild pancreatitis, necrotizing pancreatitis develops in about 15% of patients, with infection of pancreatic and peripancreatic necrosis representing the single most important risk factor for a fatal outcome. Infection of pancreatic necrosis in the natural course develops in the second and third week after onset of the disease and is reported in 40% to 70% of patients with necrotizing pancreatitis. Just recently, prevention of infection by prophylactic antibiotic treatment and assessment of the infection status of pancreatic necrosis by fine-needle aspiration have been established in the management of severe pancreatitis. Because medical treatment alone will result in a mortality rate of almost 100% in patients with signs of local and systemic septic complications, patients with infected necrosis must undergo surgical intervention, which consists of an organ-preserving necrosectomy combined with a postoperative closed lavage concept that maximizes further evacuation of infected debris and exudate. However, intensive care treatment, including prophylactic antibiotics, reduces the infection rate and delays the need for surgery in most patients until the third or fourth week after the onset of symptoms. At that time, debridement of necrosis is technically easier to perform, due to better demarcation between viable and necrotic tissue compared with necrosectomy earlier in the disease. In contrast, surgery is rarely needed in the presence of sterile pancreatic necrosis. In those patients the conservative approach is supported by the present data. Received: March 20, 2002 / Accepted: April 15, 2002 Offprint requests to: W. Uhl     

内毒素在急性出血坏死性胰腺炎病程中的作用及白细胞介素-2的治疗作用

为观察内毒素在急性出血坏死性胰腺炎（ ＡＨＮＰ） 病程中的作用,并探讨重组人白细胞介素２（ＩＬ２） 的治疗作用,应用５ ％ 牛磺胆酸钠经胰胆管逆行注射制作大鼠ＡＨＮＰ 模型,并用ＩＬ２ 进行实验性治疗。结果： ＡＨＮＰ 组内毒素含量明显增高,并伴随血浆胰酶活性显著增高,且随病程的延长两者呈进行性增高,胰腺组织学改变也呈进行性加重;ＩＬ２治疗组的血浆内毒素水平及胰腺组织学改变却有显著改善,７２ 小时病死率由６６ ．７ ％ 降低至２６ ．７ ％ （ Ｐ＜ ０ ．０１） 。提示内毒素是加重ＡＨＮＰ 的重要因素,ＩＬ２ 能改善内毒素血症,对ＡＨＮＰ 有一定的治疗作用。