Surgical treatment of severe acute pancreatitis

Introduction
Due to the high rates of perioperative mortality and morbidiy, the role of surgical treatment in patients with severe necrotizing pancreatitis (SNP) including indications for surgery, timing of operations and the appropiate surgical technique required, are still under debate (1). Infected necrosis is considered an absolut indication for urgent operative management (1-4). However, associated with mortality rates as high as 50% when performed without adequate indications (4), the role of surgery in cases with sterile necrosis is yet unclear and has been extensively reconsidered in the last years.
The aim of the present study is to analyze retrospectively the indications, timing, operative technique and postoperative complications following surgery for pancreatic necrosis in patients with severe necrotizing pancreatitis treated in our institution. A special emphasize in terms of efficiency and related complications has been given to OPD, the procedure chosen for postoperative drainage and repeated planned redebridements.

Material and Method
A retrospective study was performed on patients that were operated upon for severe necrotizing pancreatitis in the No.1 Clinic of Surgery, Cluj-Napoca between January 1989 and December 2005.
SNP was diagnosed according with the Atlanta classification (5), when at least one of the following 4 criteria were present: 1 organ failure with 1 or more of the following: shock (systolic blood pressure < 90 mm Hg), pulmonary insufficiency (PaO2 < 60 mm Hg), renal failure (serum creatinine level > 2 mg/dL after rehydration) and gastrointestinal tract bleeding (> 500 mL in 24 hours); 2 local complications such as necrosis, pseudocyst, or abscess; 3 at least 3 of Ranson's criteria or 4 at least 8 of the Acute Physiology and Chronic Health Evaluation II (APACHE II) criteria.
Depending on the the presence and extent of septic complication at the time of operation, patients were divided into three groups: 1 sterile necrosis - SN, 2 infected necrosis - IN and 3 pancreatic abscess - PA
Indications and technique of surgical treatment in SNP
All patients with infected necrosis, either diffuse or with pancreatic abscess, were operated at diagnosis, as soon as presence of septic complication was proven by the clinical (signs of sepsis), biological (CRP, leucocytosis), hematological (positive blood cultures), radiologic (gas bubbles in the peripancreatic area) and bacteriologic investigations.
Elective operative treatment in patients with sterile necrosis and favourable outcome under conservative treatment was delayed until the second or the third week after the onset of the disease to allow demarcation of the necrosis. Early operation was performed in SN patients only when presence of acute surgical abdomen from an extrapancreatic cause was impossible to rule out after a short period of extensive investigation and vigourous intensive care treatment. Once the correct intraoperative diagnosis of acute pancreatitis was established, a "prophylactic" celiostomy or retroperitoneo-stomy was performed in all these patients. It's role was to avoid repeated re-laparotomies for the following debridements by offering a pre-formed acces route to retroperitoneal necrosis.
Surgical treatment consisted of necrosectomy followed by "open packing drainage" (OPD). (Fig. 1) The operation started with a complete and systematic exploration of the abdominal cavity through a midline incision. After incision of the gastrocolic ligament, the pancreas and peripancreatic regions were carefully explored through a lesser-sac approach. Whenever necessary, the posterior site of the pancreas was exposed through a Kocher manouvre or posterior splenopancreatic dissection. Proximal, upper retroperitoneal extensions of retroperitoneal necrosis were treated by a lesser-sac or transmezocolic approach while access to the more caudal retroperitoneal and intramezenteric areas was obtained through a submezocolic trans- or retroperitoneal route. Fluid collections and necrosis were carefully removed by digital or blunt instrumental dissection, followed by hydrodissection using Betadine® solution. Forcefull extraction of incompletely demarcated necrosis was avoided to prevent iathrogenic hemorrhages or damage of adjoining organs.

Whenever necessary, concomitant additional surgical procedures were performed, such as biliary operations or loop feeding-jejunostomy for early postoperative oral feeding. A peritoneal drainage was systematically left in place in all patients included in the study to evacuate the enzyme-rich peritoneal fluid and to lower the risk of reccurent intraperitoneal sepsis.
The "Open Packing Drainage" technique
Celiostomy was created at the upper pole of the midline incision by suturing the sides of the incised gastrocolic ligament to the anterior parietal peritoneum using 3.0 monofilament running suture, while the rest of the incision was closed in a conventional manner either with running "loop" monofilament non-resorbable suture or with separate stitches. Retroperitneostomy was created in a similar fashion; following pancreatic and retroperitoneal necrosectomy through a right or left subcostal incision, the medial leaf of the incised paracolic peritoneum was sutured to the medial leaf of the anterior parietal peritoneum adjoining the abdominal incision line. Three to five drains were inserted through the celiostomy or retroperitoneostomy and the lesser-sac or retroperitoneal spaces were packed open.
The access route maintaned open by OPD was used thereafter during the repeteadly planned re-explorations for debridement of residual necrosis. These were carried out every second or third day postoperatively in the operative room under light general i.v. anesthesia and consisted of a throught lavage of the pancreatic area, blunt necrosectomy and hydrodissection followed by reinsertion of drains and open packing.
Surgical debridement was supplemented by vigurous intensive care measures, parenteral nutrition and appropiate antibiotic and antifungal regimens according to sensitivities of organisms, samples from the necrotic tissue or fluid collections being regularly taken intraoperatively for bacteriological assessment.
When necrosectomy was complete, the abdominal wound continued to be packed in the ward once or twice a day without additional catheter drainage and was allowed to heal spontaneously by second intention. In cases with favourable outcome, afer complete necrosectomy and repetitive negative bacteriological cultures, a secondary suture was performed to hasten healing of the wound and prevent late incisional hernia.

Results
Necrosectomy and OPD were performed in 80 patients with SNP: 37 patients (46.2% of all 80 cases) in the SN group, 25 cases (31.2%) in the IN group and 18 patients (22.5%) in the PA group respectively. In the IN group were included only those with primary infection of the necrotic tissue. There were 13 patients with initially sterile necrosis, classified accordingly in the SN group, who have developed secondary infection of necrosis following OPD.
Urgent or early operations, within the first week after the onset of the disease, were performed in all 43 patients from the IN or PA groups and in 21 of the 37 patients from the SN group. The remaining 16 SN patients who were accurately diagnosed with acute pancreatitis and responded well to conservative treatment were operated late, most of them in the second or third week. (Table 1)
Except for two cases with retroperitoneostomy, OPD was performed through a lesser-sac route. A variable number of two to nine re-debridements were necessary. As a general rule, the later the first necrosectomy and OPD were performed related to the onset of the disease, the lesser number of re-explorations were needed.
Major complications related to OPD were encountered in 34 patients (42.5% of all 80 patients). (Table 2) When all complications present in the study group were recorded, including 13 patients from the SN group with secondary contamination of the necrosis and one patient in the IN group with inflamatory stenosis of the biliary duct, the global morbidity rate became 62% for SN (23/37 patients), 48% for IN (12/25 patients) and 29% for PA (13/18 patients) respectively.
Reoperations for major complications following OPD were necessary in 17.5% of the cases (14/80 patients), more often among patients with septic complications. (Table 3) Concomitant procedures at the time of primary operation were required in 36 patients (45%), either for acute cholecystitis or for biliary tract obstruction. (Table 4) Endoscopic sphincterotomy preceeded necrosectomy in one patient while in another one laparoscopic cholecystectomy was performed after remision of symptoms, during the same spitalisation period. Jejunostomy was performed in three patients and was replaced in the last 3 years of the study by nazojejunal tubes inserted by the anaesthesiologist at the time of primary operation with intraoperative assistence of the surgeon.
The global operative mortality rate was 32.5%, MOF and septic shock being the major causes of death in the SN and IN groups respectively. (Table 5)
The strains most frequently encountered in necrotic tissue and fluid collections were: Escherichia coli, Proteus vulgaris, Klebsiella pneumoniae, Pseudomonas aeruginosa, Stafilococus aureus and Candida albicans.
The mean postoperative in-hospital stay averaged 52.73 days in the SN group (24 - 136 days), 52.5 days in the IN group (25 - 78 days) and 55.1 days in the PA group (13 - 110 days) respectively.
The abdominal wound healed spontaneously in 77 of the 80 patients and was closed by secondary suture in the remaining three cases. 10% of all patients (8/80 patients) needed a late reoperation to treat the incisional hernia developed at the site of celiostomy.

Discussions
Indications for operative treatment and timing of surgical interventions are of utmost importance for optimal management of patients with SNP. In certain circumstances surgery may be beneficial, saving the patients's life and improving prognosis, but, due to the operative stress superimposed over an already critical condition, in other cases it may have a detrimental effect, determinant for a worsened, even fatal outcome. Adequate selection of patients and an appropriate surgical strategy, based on a through knowledge of phatophysiology and evolution of this disease, are essential for a favourable outcome.
The first 2 weeks after onset of symptoms are dominated by the systemic inflammatory response syndrome (SIRS) when systemic release of proinflamatory mediators may cause cardiovasculary, pulmonary and/or renal insufficiency (6). Pancreatic necrosis develops in parallel and requires 2-4 weeks until it is completelly demarcated. If the early phase of the disease is passed without major complications, late deterioration of organ function may occur usually in the 2nd or 3rd week and is mainly a result of infection of pancreatic necrosis (4, 7, 8).
Infection is a severe complication and represents the most important independent risk factor of mortality among patients with SNP (9, 10). It must be suspected when signs of inflammation (fever, leukocytosis, CRP) are associated with a deteriorating clinical condition, increasing hemo-dynamic instability and progession to MOF and is proven by bacteriological culture of the fine needle aspiration biopsy (FNAB) specimen (7). The importance of diagnosis is crucial since septic complications are responsible for up to 80% of deaths, conservative treatment leading to a fatal outcome in almost 100% of the cases (7, 9, 11). When surgical removal of infected necrosis is performed, the mortality rate is lowered to 10-30% (11). Consequently, infection of pancreatic necrosis represents an absolute indication for surgery as soon as diagnosis is established (2, 4, 12, 13, 14). In patients with severe critical condition, septic shock and MOF, when surgery is considered to bring unacceptable additional risks, ultrasound or CT-guided percutaneous catheter drainage represent viable alternatives. Their dissadvantage is that, often obstructed by thick necrotic fragments, these catheters do not provide an efficient long-term drainage.
A more individualized approach is required in patients with sterile necrosis. The poor postoperative results and high 30-65% mortality rate that accompany early surgery in SN patients with stable biological condition have rendered surgery not only unnecessary but even detrimental (12, 13, 15). The only prospective randomized trial comparing early (within 72 h of symptoms) with late (at least 12 days after onset) surgical debridement in patients with sterile necrosis was terminated earlier than planned because of concern about the very high mortality rate in the former group: 56% vs. 27% repectively (15). Apart from retrieval of common bile duct (CBD) stones in biliary pancreatitis, performed nowadays through an endoscopic approach, no other pathogenetic operative treatment is currently available. On the contrary, added surgical and anaesthetic stress deteriorates the condition of the patient even more and bears the risk of hemorrhage or iathrogenic infection of necrosis. Even local complications of SN are not amenable to operative treatment since necrosis is not demarcated. Furthermore, most of the SN patients respond positively to conservative non-surgical management (16). Nowardays it is considered that debridement of extensive sterile necrosis should be deffered as long as there is a positive response to conservative measures (i.e. therapy in the intensive care unit (ICU), prophylactic antibiotic therapy and parenteral or nazo-jejunal enteral nutrition) until the third or fourth week, when appropriate demarcation of the necrotic tissue offers optimal operative conditions (1, 4, 8, 12, 13, 17-20). Earlier operative treatment may still be contemplated in some selected cases with large necrotic areas (over 30% of total glandular parenchima) and persistent organ dysfunction which either show no improvement over a period of 10-14 days or deteriorate during 3-5 days despite maximal ICU therapy (1, 4, 7, 12, 13, 18, 20).
In our study, all patients with proven infected necrosis or pancreatic abscess were operated at diagnosis. The maximal incidence of infection was present in the 2nd and 3rd weeks after onset of SNP while pancreatic absscesses were usually diagnosed and treated later, in the 3rd and 4th week. There is still a significant percentage of SN patients operated early, within the first week from onset of symptoms, especially in the first five years of the study when diagnostic facilities were less advanced. In their case surgical intervention was in fact a diagnostic laparotomy to exclude an extrapancreatic cause of acute surgical abdomen in patients in whom all diagnostic investigations available in the emergency settings failed to reach the correct diagnosis. Using modern serologic and imagistic tests, the rate of urgent operations for severe acute pancreatitis dropped significantly in the last years, heading towards the treshold of less than 5% reported in the literature.
In 45% of the cases primary necrosectomy was associated with additional surgical procedures on the biliary tract. They were required either to treat pathogenetically-linked abdominal pathology such as severe, gangrenous acute cholecystitis or gallstone obstruction of CBD not amenable to endoscopic retrieval, or to manage biliary complications (i.e. external
biliary drainage for inflamatory stenosis of distal CBD).
Apart from timing of sugery, the optimal surgical procedure selected is another major prognostic factor. Pancreatic resection procedures are associated with excessively high rates of morbidity and mortality and with the subsequent risk of exocrine and endocrine inssuficiency. To date, generally agreed principles of surgical management emphasize the role of organ-preserving techniques which preserve as much as possible from the viable pancreatic parenchima. Open necrosectomy, performed in our institution, respects these principles. In selected patients, other technical alternatives such as percutaneous necrosectomy or laparoscopic techniques can be also considered. The former is indicated mostly for liquified necrosis, the thickness of the catheter being insufficient to drain efficiently large debris fragments. Laparoscopic necrosectomy remains a valuable tool in careful selected cases with clearly delineated necrosis and favourable localisation that can be removed with decreased operative mortality and morbidity and a significantly improved quality of life (4).
A drainage procedure that maximizes evacuation of residual and ongoing retroperitoneal necrosis is usually necessary after open necrosectomy. Currently, three techniques meet this concept with similar rates of operative mortality of under 15%: 1 open packing drainage (OPD), 2 planned staged relaparotomies with repeated lavage and 3 closed continuous lavage of the lesser-sac and retroperitoneum (8, 21). OPD, indicated as an elective procedure in incompletely demarcated necrosis or in infection with anaerobic microorganisms, is favoured in our institution because it provides efficient drainage for slough and pancreatic debrids avoiding at the same time additional surgical and anaesthetic stress from repeated laparotomies (4, 12, 13, 17, 22-25). It offered enough room for inspection of the retroperitoneal area and for secondary necrosectomy. The planned re-explorations under dissociative i.v. anaesthesia were generally easily supported by the patient and were not associated with significant systemic co-morbidities. OPD- specific complications were determined by exposure of abdominal contents to enzymatic and mechanical injury and were mainly represented by long-lasting external pancreatic, biliary or digestive fistula and retroperitoneal sepsis (12, 14, 22, 25-27). Peritoneal drainage and frequent re-exploration have reduced the rate of intraabdominal abscesses to 2.5% while most of retroperitoneal sepsis was drained efficiently. Careful mobilization of intra-abdominal organs, delicate removal of incompletely demarcated necrosis, use of soft drain catheters and change of gauzes in a strictly sterile environement are measures that can reduce the incidence of these complications.
Major postoperative complications occurred more frequently in IN patients, proof of the detrimental role played by infection of necrosis in these cases. However, the highest rate of global postoperative morbidity was encountered in SN patients (62% compared with the 48% for IN and 29% for AP respectivelly) due to secondary infection of sterile necrosis folowing OPD. A conservative approach was successful in almost half of the cases with major complications (48%). The rest (16 patients) required immediate operation: surgical drainage of abscesses, treatment of digestive fistula, hemostasis and cure of exenteration. Two other cases, with extended retroperitoneal sepsis, died before surgical treatment was possible.
Although attractive in theory, "prophylactic" OPD did not offer the expected benefits. It represented instead an entry gate for exogenous contamination of sterile necrosis which added significant morbidity, altered the prognosis of the patient, prolonged hospital-stay and increased the financial burden for the hospital (12, 18). Two patients with secondary infection in the SN group died of septic shock, raising questions if such a dramatic outcome would have still been encountered if "prophylactic" OPD would not have been performed.
The overall postoperative mortality rate reported in the literature in patients with SNP remains 40% despite all efforts and advances in the management of this disease (7, 21). It is related to MOF and septic shock present in the preoperative period and aggravated by the operative stress. The 32.5% overall mortality rate in our study group is within these limits. The highest rate (37.8%) was recorded in SN patients operated early in the course of the disease (85% of all fatalities from this group), a result that reflects the negative outcome of early surgery for sterile necrosis. The 36% mortality rate in the IN group is slightly higher than the 10-30% reported in the literature 11, ongoing sepsis leading to death in 89% of the 25 IN patients. Delay in surgical management due to late refferal to our institution from primary or secondary centers or delayed diagnosis from lack of technology (FNAB) are the main explanations for this reality, emphasizing once again the importance of correct diagnosis and urgent surgical management when infection is proven. The lowest mortality rate encounered in the PA group (16.6%) is not surprising since infection is already restrained and controlled by the patient's defence mechanisms.
The gut has been identified as primary source for pancreatic infection (28). The first four most frequent strains identified in the present study are Gram-negative microorganisms, originating from the colonic reservoir. They are followed by staphilococus aureus, which could have migrated from the skin to the OPD gauzes or has colonized long-standing blood catheters. Its presence might thus be a marker of secondary infection in patients with sterile necrosis and "prophylactic" OPD. Fungal infection with Candida was also present in six cases, justifying the need for antifungal prophylaxis in patients with prolonged antibiotic therapy.
Although secondary suture of celiostomy was performed in only 3 patients, the overall rate of late abdominal hernia requiring operative treatment is low, around 10%. An explanation might reside in the upper localization of the aponeurotic defect which is thus subjected to lesser abdominal pressures, in an increased consciousness of the patients who does comply to medical reccomendations and in an reduced eagerness of the surgeon to repair small and uncomplicated abdominal defects in an area that presumably has tight postoperative adhesions.

Conclusions
Surgical treatment in SNP should be individualized according to the characteristics of the patient and the time passed from the onset of symptoms. In cases with infected necrosis or pancreatic abscess, which usually occurs in the 2nd-4th weeks, indication for surgical treatment is imperative at the time of diagnosis, its delay being a negative prognostic factor due to the foreseeable progression to septic shock and MOF. In patients with sterile necrosis, early operation should be avoided in favour of the conservative treatment. Surgery should be postponed as much as possible, beyond the third week from the onset of SNP, when demarcation of necrosis is complete. Urgent operative treatment can be contemplated only in SN patiens with acute surgical abdomen from unknown cause or in cases with extended sterile necrosis when the biological condition does not improve after 3-5 days of intensive care treatment.
OPD with either celiostomy or retroperitoneostomy is an efficient drainage procedure that offers optimal drainage of residual necrosis, facilitates redebridements and avoids repeated laparotomies. Its related complications are pancrea-tic, enteric and biliary fistula, sepsis, iathrogenic bleeding and incisional hernia. "Prophylactic" OPD in SN patients with urgent operations is not recommended because is associated with a high mortality rate and with the risk of secondary contamination of necrosis.

References
1. Bassi, C., Falconi, M., Sartori, N., BONORA, A., CALDIRON, E. - The role of surgery in the major early complications of severe acute pancreatitis. Eur. J. Gastroenterol. Hepatol., 1997, 9:131.
2. Farkas, G. - Surgical treatment of infected pancreatic necrosis. In Johnson CD and Imrie CW (eds.) "Pancreatic Disease Towards the Year 2000", Second Edition, Springer Verlag Ltd. (London) 1999, pag. 91-100.
3. Branum, G., Galloway, J., Hirchowitz, W., Fendley, M., Hunter, J. - Pancreatic necrosis: results of necrosectomy, packing and ultimate closure over drains. Ann. Surg., 1998, 227:870.
4. Connor, S., Neoptolemos, JP. - Surgery for pancreatic necrosis: "whom, when and what?". World. J. Gastroenterol., 2004, 10:1697.
5. Bradley, E. - A clinically based classification system for acute pancreatitis. Summary of the International Symposium on Acute Pancreatitis, Atlanta, September 11-13, 1992. Arch. Surg., 1993, 128:586.
6. Uhl, W., Warshaw, A., Imrie, C., Bassi, C., Neoptolemos, J., Büchler, MW. - IAP Guidelines for the Surgical Management of Acute Pancreatitis. Pancreato-logy, 2002, 2:565.
7. Renzulli, P., Jakob, SM., Täuber, M., Candinas, D., Gloor, B. - Severe Acute Pancreatitis, Case-Oriented Discussion of Interdisciplinary Management. Pancreatology, 2005, 5:145.
8. Werner, J., Feuerbach, S., Uhl, W., Büchler, MW. - Management of acute pancreatitis: from surgery to interventional intensive care. Gut, 2005, 54:426.
9. Gloor, B., Müller, CA., Worni, M., Martignoni, ME., Uhl, W., Büchler, M.W. - Late mortality in patients with severe acute pancreatitis. Br. J. Surg., 2001, 88:975.
10. Garg, PK., Khanna, S., Bohidar, NP., Kapil, N.,Tandon, RK. - Incidence, spectrum and antibiotic sensitivity pattern of bacterial infections among patients with acute pancreatitis. J. Gastroenterol. Hepatol., 2001, 16:1055.
11. Büchler, MW., Gloor, B., Müller, CA., Friess, H., Seiler, CA., Uhl, W. - Acute necrotizing pancreatitis: Treatment strategy according to the status of infection. Ann. Surg., 2000, 232:619.
12. Nathens, AB., Curtis, JR., Beale, RJ., COOK, D.J., MORENO, R.P., ROMAND, J.A. - Management of critically ill patients with severe acute pancreatitis. Critical. Care. Med., 2004, 32:2524.
13. Toouli, J., Brooke-Smith, M., Bassi, C., Carr-Locke, D., Telford, J., Freeny, P., Imrie, C., Tandon, R. - Guidelines for the management of acute pancreatitis. J. Gastroenterol. Hepatol., 2002, 17:S15.
14. Rau, B., Uhl, W., Buchler, MW., Beger, HG. - Surgical treatment of infected necrosis. World. J. Surg., 1997, 21:155.
15. Mier, J., Leon, EL., Castillo, A., ROBLEDO, F., BLAMCO, R. - Early versus late necrosectomy in severe necrotizing pancreatitis. Am. J. Surg., 1997, 173:71.
16. Bradley, EL., Allen, K. - A prospective longitudinal study of observation versus surgical intervention in the management of necrotizing pancreatitis. Am. J. Surg., 1991, 161:19.
17. Branum, G., Galloway, J., Hirchowitz, W., Fendley, M., Hunter, J. - Pancreatic necrosis: results of necrosectomy, packing and ultimate closure over drains. Ann. Surg., 1998, 227:870.
18. Rau, B., Pralle, U., Uhl, W., Schoenberg, MH., Beger, HG. - Management of sterile necrosis in instances of severe acute pancreatitis. J. Am. Coll. Surg., 1995, 181:279.
19. Uhl, W., Vogel, R., Buchler, MW. - Chirurgische therapie der schweren acute pankreatitis. Schweiz Med. Wochenschr., 1997, 127:805-811
20. Büchler, MW., Gloor, B., Müller, CA., Friess, H., Seiler, CA., Uhl, W. - Acute necrotizing pancreatitis: Treatment strategy according to the status of infection. Ann. Surg., 2000; 232:619.
21. Radenkovic, D., Bajec, D., Tsiotos, G., Karamarkovic, A., Milic N., Stefanovic B., Bumbasirevic, V., Gregoric, P., Masulovic, D., Milicevic M. - Planned Staged Reoperative Necrosectomy Using an Abdominal Zipper in the Treatment of Necrotizing Pancreatitis. Surg. Today., 2005, 35:833.
22. Bradley, EL. - A fifteen year experience with open drainage for infected pancreatic necrosis. Surg. Gynec. Obstet., 1993, 117:215.
23. Hwang, TL., Chiu, CT., Chen, HM., CHEN, S.C., JENG, L.B., JAN, Y.Y., WANG, C.S., CHEN, M.F. - Surgical results for severe acute pancreatitis - comparison of different surgical procedures. Hepatogastroenterology, 1995, 42:1026.
24. Harris, JA., Jury, RP., Catto, J., Glover, JL. - Closed drainage versus open packing of infected pancreatic necrosis. Am. Surg., 1995, 61:612.
25. Funariu, G., Suteu, M., Dindelegan, G., Maftei, N., Scurtu, R. - Indicatiile celiostomiei în pancreatitele acute necrotice, Chirurgia (Bucur.), 1998, 93:395.
26. Orlando, R., Welch, JP., Akbarry, CM. et al. - Technique and complications of open packing of infected pancreatic necrosis. Surg. Gynec. Obstet., 1993, 117:65.
27. Laws, HL., Kent, RB. - Acute pancreatitis: management of complicating infection. Am. Surg., 2000, 66:145
28. Schmidt, SW., Uhl, W., Friess, H. - The role of infection in acute pancreatitis. Gut, 1999, 45:311.