The American Journal of Surgery (2008) 196, 442 449

Review

A historic perspective on the contributions of surgeons to the understanding of acute pancreatitis

Flavio G. Rocha, M.D., Anita Balakrishnan, M.B.B.S., Stanley W. Ashley, M.D., Thomas E. Clancy, M.D.*
Department of Surgery, Brigham and Womens Hospital, Harvard Medical School, Boston, MA 02115, USA KEYWORDS:
Acute pancreatitis; Infected necrosis; Pancreatic debridement; Surgical history Abstract BACKGROUND: Acute pancreatitis is a disease with a broad spectrum of presentation, severity, and treatment. Current management involves a multidisplinary team of surgeons, gastroenterologists, and interventional radiologists whose varied clinical skills contribute to the evolving diagnostic and therapeutic strategies for this disease. However, critical aspects of therapy have remained the responsibility of the general surgeon. The purpose of this review is to examine the many contributions of surgeons in acute pancreatitis. DATA SOURCES: A review of the literature taken from PubMed on seminal articles published by surgeons on the subject of acute pancreatitis. CONCLUSIONS: Surgeons have made signicant contributions to the understanding of the pathophysiology and evolution of therapy of acute pancreatitis. The specialty should continue to take a leadership role to improve outcomes. 2008 Elsevier Inc. All rights reserved.

In 1925, the surgeon, Sir Berkely Moynihan,1 described acute pancreatitis as . . . the most terrible of all the calamities that occur in connection with the abdominal viscera.1 Few diseases have attracted more attention from the surgical community than acute pancreatitis. Not only has the pathophysiology of acute pancreatitis been the subject of considerable surgical investigation, but the complex array of skills needed for disease diagnosis and management is representative of the diversity that has dened the specialty. Contemporary therapy of such patients is increasingly multidisciplinaryfrom early diagnosis and assessment to diagnostic radiographic evaluation, critical care, and occasional endoscopic intervention. In addition, man* Corresponding author. Tel.: 1-617-732-5718; fax: 1-617-7321728. E-mail address: tclancy@partners.org Manuscript received December 6, 2007; revised manuscript January 16, 2008

agement of this disorder has become increasingly conservative, with surgery reserved for specic limited indications. Ultimately, however, critical management questions continue to revolve around the need for and timing of surgical intervention, and these can only addressed by the general surgeon whose experience, skills, and judgment permit him or her to see the entire spectrum of the disease. At a time when this specialty is facing something of an identity crisis, no disorder seems to more clearly require the traditional combination of skills repret by the eld. In this context, it seems appropriate to review some of the many contributions that surgeons have made to our understanding and management of acute pancreatitis.

Pathophysiology
The pathophysiology of acute pancreatitis has been a particularly intriguing subject for surgical investigators. Al-

0002-9610/$ - see front matter 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.amjsurg.2008.01.028

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though clearly not solely responsible for our understanding of this disorder, surgical scientists have made signicant contributions to virtually every aspect of our current concepts of pathogenesis. An exhaustive review of these studies is beyond the scope of this review; 2 examples should be illustrative of this impact. Current models for acute pancreatitis focus on 2 stages. The rst stage, which occurs in response to a variety of etiologies, is believed to involve inappropriate intraparenchymal activation of pancreatic enzymes, leading to cell injury. Although the trigger for this process has never been identied, the leading hypothesis regarding this mechanism was formulated during the past 20 years by a Boston surgeon, Michael Steer.2 He proposed that the colocalization of zymogen granules with lysosomal hydrolases inside the cell leads to early trypsin activation.2 Using subcellular fractionation in a cerulein model of acute pancreatitis in the mouse, Steer et al3 demonstrated that zymogens and lysosomal hydrolases, such as cathepsin B, are indeed colocalized within cytoplasmic vacuoles in the pancreatic acinar cell and resulted in intrapancreatic activation of trypsin (Fig. 1). In addition, inhibitors of cathepsin B prevented this

activation and decreased the severity of pancreatitis in animal models.4 This sequence was conrmed in a variety of animal models and appears to be signicant in human disease as well. It has provided the rationale for a host of subsequent studies that have begun to dene the mechanisms of subcellular trafcking within the pancreas. The second stage of acute pancreatitis is amplication of the initial local pancreatic disease to a more generalized inammatory response affecting multiple organ systems. Before the identication of cytokines, it was thought that biologic mediators found in pancreatic ascites were responsible for the systemic effects of pancreatitis. Another surgeon, James Norman,5 was one of the rst investigators to demonstrate that interleukin (IL)-1, tumor necrosis factor(TNF ), and IL-6 are produced by neutrophils inltrating the pancreatic parenchyma after induction of pancreatitis in animal models. This inciting event, which is followed by cytokine production in the spleen, liver, and lung, likely leads to the development of adult respiratory distress syndrome and multisystem organ failure (MSOF).6 Although more typically seen as a response to endotoxin, in acute pancreatitis this cascade occurs in the absence of infection. Normans experiments with IL-1 and TNF receptor knockouts established that although these cytokines are not the causative agents of disease, they are responsible for the propagation of the disease beyond the pancreas.7 In addition, he demonstrated that TNF directly caused apoptosis of acinar cells in pancreatitis.8,9 Norman et al10 also examined IL-1 and TNF inhibition using soluble receptors and antagonists and demonstrated signicant reductions in mortality in experimental pancreatitis. He concluded that because organ dysfunction occurs 48 hours after disease presentation, there may exist a therapeutic window for anticytokine therapy to prevent the onset of organ failure in severe disease. Although clinical studies have not yet conrmed this hypothesis, it remains a subject of active research interest.

Management
Evolution of surgical intervention for pancreatitis
The contributions of surgeons to the clinical management of this disease have been equally signicant. One of the rst to recommend surgical intervention for pancreatitis was Nicholas Senn,11 a Chicago surgeon, in 1886. At that time pancreatitis was believed to be the response of the pancreas to duodenal disease. In patients with acute pancreatitis and pancreatic necrosis, Senn recommended drainage and removal of all necrotic tissue.11 In 1901, Halsted12 reported a case of a 48-year-old man with acute pancreatitis. Exploratory laparotomy was performed within 24 hours of the onset of maximal pain, revealing blood-stained uid, fat necrosis, a mildly inamed pancreas, and a distended common bile duct, in which there

Figure 1 Schematic representation demonstrating intra-acinar fusion of lysosomes with zymogen granules, resulting in activation of enzymes and cellular injury. (Reprinted with permission from Van Acker GJ, Perides G, Steer ML. Colocalization hypothesis: a mechanism for the intrapancreatic activation of digestive enzymes during the early phases of acute pancreatitis. World J Gastroenterol 2006;12:198590.)

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The American Journal of Surgery, Vol 196, No 3, September 2008 necrotic or disrupted pancreas was believed to improve outcomes, and, as a result, several other studies were published on pancreatectomy.17 In 1985, Nordback18 reported a mortality rate of 28% and a similarly concerning rate of long-term complications after pancreatectomy in 40 patients. All patients had developed diabetes after surgery, half requiring insulin, and many developed polyneuropathy and dyspepsia.18 The argument for pancreatectomy to interrupt the evolution of the disease was increasingly disputed as alternative strategies evolved. Other efforts to surgically interrupt the evolution of pancreatitis focused on gallstones. Acostas20 classic study, in which stones were demonstrated in the stool of most patients with suspected biliary pancreatitis, led to the suspicion that impacted stones at the ampulla were responsible for the development of severe disease. Proposing that early surgery to remove such impacted stones might prevent this evolution, Acosta et al,21 at the University of Chicago, were among the rst to examine such an approach.21 In their series, they reported increased mortality (16% vs. 2%) in patients who had delayed disobstruction of their biliary system compared with those who underwent surgery to remove the stones within 48 hours of admission. This procedure included cholecystectomy, bile duct exploration and transduodenal sphincterotomy. At the time, there was not general acceptance of early surgical exploration for choledocholithiasis given the known perioperative morbidity and mortality rates in early severe acute pancreatitis. In 1980, a review on the timing of cholecystectomy by Kelly22 showed that the incidence of choledocholithiasis in patients explored within the rst 72 hours after presentation was 63%, but this number decreased to only 5% if surgery was performed 5 to 7 days after the onset of pancreatitis. In addition, mortality was lower in patients explored in a delayed manner but during the same hospital admission.22 The investigators concluded that all patients should undergo elective cholecystectomy at initial hospital admission, arguing that deferring surgery to a later period risks recurrent pancreatitis. A randomized trial by the same investigators conrmed that mortality is higher with early surgery compared with procedures delayed 48 hours.23 Although these studies largely discouraged surgical approaches to this problem, debate about the timing of intervention for acute biliary pancreatitis was again stimulated by the development of endoscopic procedures to remove obstructing gallstones. Endoscopic retrograde cholangiopancreatography (ERCP) was rst reported by a surgeon, Walter McCune,24 at Walter Reed, in 1968. Although early ERCP was suggested as a means for removing the impacted stone in acute pancreatitis, results from the rst randomized trial on the subject were not straightforward.25 Although Neoptolemos et al26 demonstrated benet from early ERCP in pancreatitis, others showed no benet from early ERCP when patients with obvious biliary obstruction were excluded.27 To this day, the role for early ERCP in the setting of biliary pancreatitis remains unclear, although most would

were no palpable stones. A pack was placed over the pancreas and the abdomen closed, and the patient died 24 hours later. Halsted12 and Opie,13 a pathologist, described this case in separate articles published together in the Bulletin of the Johns Hopkins School of Medicine. At autopsy, Opie found a gallstone impacted at the ampulla, and this nding formed the basis for his common-channel hypothesis. Halsted suggested that whereas removal of ductal stones would be benecial before the onset of severe symptoms, he conceded that a surgery should not be undertaken on in cases of collapse, advocating instead local drainage of uid in patients too ill for surgery. Unsuccessful attempts at surgical intervention were common in the early 20th century, when laparotomies were performed as part of the diagnostic workup for severe abdominal pain before the development of serum amylase assays and imaging techniques. The medical literature of the time contained numerous conicting reports by eminent surgeons, some discouraging laparotomies for acute pancreatitis after fatal outcomes and others advocating laparotomy as a means of diagnosis and drainage of necrotic uid.11,14 Patients presented late and were usually gravely ill with severe pancreatitis, and mortality rates were frequently high. Lord Moynihan was a proponent of early surgical intervention, recommending laparotomy, evacuation of intraperitoneal uid, cholecystostomy or cholecystectomy, and insertion of intraperitoneal drains, stating that if drainage is not adequate the patient will die.1 The indications for surgery changed dramatically when Robert Elman,15 a surgeon in St, Louis, made one of the most signicant contributions to the management of acute pancreatitis when he developed one of the rst assays for measuring serum amylase. Hyperamylasemia subsequently became diagnostic of acute pancreatitis, obviating numerous unnecessary and potentially fatal laparotomies. After this development, Paxton and Payne16 wrote one of the earliest reviews of pancreatitis in the 1940s. The high mortality rates in their series conrmed the unsuccessful strategy of early surgical intervention: 44.7% of 103 patients who underwent laparotomy for acute pancreatitis died compared with a mortality rate of 27.5% in 204 patients who were managed nonoperatively. With the ability to diagnose pancreatitis early, management aims began to focus on conservative measures with parenteral uids and analgesia in the initial stages of the disease. It has been increasingly recognized that most patients with acute pancreatitis will improve without surgical management; only a small minority of patients might require aggressive surgical therapy. Still, some investigators at the time began to recommend increasingly aggressive surgical approaches for severe pancreatitis,17 including pancreatectomy, hoping to interrupt disease evolution. Perioperative mortality of 40% was seen with resection, although this was thought by some to compare favorably with the mortality associated with severe pancreatic necrosis.18,19 In 1963, Watts17 described total pancreatic resection for severe pancreatitis. Removal of

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agree that it is necessary in the patient with superimposed cholangitis. Although efforts to interrupt the evolution of the pancreatitis were abandoned, it was still hoped that removal of activated enzymes released into the peritoneal cavity might prevent both the evolution of the disease and their release into the circulation with systemic consequences. Warshaw et al,28 from Massachusetts General Hospital in Boston, performed one of the rst retrospective analyses of aggressive early drainage in a select group of patients with severe acute pancreatitis that was unresponsive to maximal nonoperative therapy. Their proposed procedure consisted of cholecystostomy, gastrostomy, feeding jejunostomy, sump drainage, debridement of necrotic pancreas, and drainage of any abscesses or pseudocysts. In addition to drainage, gastrostomy was performed to decrease the secretion of gastrin and secretin, thereby inhibiting stimulation of the inamed pancreas. Cholecystostomy was intended to treat cholangitis, and jejunostomy permitted nutrition in these patients. Seventeen of 38 patients had positive cultures taken at surgery. Although marked improvement was noted in some patients with predicted mortality, this procedure was associated with a 42% incidence of postsurgical pancreatic and peripancreatic infection. Furthermore, despite an overall 64% survival, a high incidence of intra-abdominal abscesses was responsible for 78% of the subsequent deaths. Ranson29 randomized a subset of 10 seriously ill patients to nonoperative therapy versus early surgery consisting of cholecystostomy, gastrostomy, jejunostomy, and pancreatic drainage. Although there were no deaths in either group, the patients who underwent early surgery had increased morbidity, including respiratory and septic complications, as well as increased overall and intensive care unit length of stay, largely putting to rest the concept of early surgery.29 This and other studies suggested that in the early stages of pancreatitis, drainage increased rather than decreased the rate of infection. Peritoneal lavage was likewise proposed as a possible intervention to remove activated enzymes after reports of improvement in pancreatitis in patients undergoing peritoneal dialysis for renal failure were published in the 1980s.30 Ransons31 own experience demonstrated an improvement in cardiovascular and respiratory function with peritoneal lavage, but he did not observe any benet in terms of sepsis or death. A controlled trial with proper statistical power was carried out in 1981 by a collaborative effort of surgeons in the United Kingdom. These investigators compared therapeutic peritoneal lavage with standard conservative treatment and found no signicant difference in outcomes.32 The criteria used by Mayer et al32 for this study have become known more familiarly as the Imrie score. This score and the Ranson criteria, described later, remain in use today as the 2 most widely used stratication systems for acute pancreatitis. Thus, largely as a result of the work of surgical investigators, attempts to interrupt the evolution of acute pancre-

Figure 2 The relationship of Ransons criteria to patient outcome. (Reprinted with permission from Ranson JH, Rifkind KM, Roses DF, et al. Prognostic signs and the role of operative management in acute pancreatitis. Surg Gynecol Obstet 1974;139: 69 81.)

atitis were gradually abandoned. However, it also became clear that in at least one subset of patients, those with infection, surgery might be appropriate. The role of infection in acute pancreatitis was claried in a sentinel publication in 1963 by Altemeier and Alexander.33 They described a series of 32 patients with pancreatic abscess, which was preceded by acute pancreatitis in all but 3 patients.33 Although most patients managed surgically survived, all patients managed nonoperatively died. Early surgical intervention with laparotomy and external drainage was therefore recommended. In addition, cystgastrostomies were recommended in patients with dense adhesions between the abscess and the posterior gastric wall. Although it was recognized that most patients with acute pancreatitis improve without surgery, Altemeier and Alexander identied33 aggressive surgical therapy is needed in patients with infected necrosis.

Modern management of acute pancreatitis

The modern era of management of acute pancreatitis was ushered in with the seminal work of John Ranson,34 which was published in 1974. Ranson studied 100 consecutive patients who were admitted to Bellevue Hospital in New York with acute pancreatitis and collected a series of objective ndings during the course of admission and subsequent 48 hours. Statistical analysis of these 43 showed that 11 of them had prognostic signicance with regard to patient outcome (Fig. 2). In 79 patients who had 3 of these signs, 2 died, and 9 became seriously ill. In comparison, of 21 patients with 3 of these signs, 13 died, and 7 became severely ill. These objective ndings became known as the Ranson criteria, which have been used to stratify the severity of acute pancreatitis to this day. Ranson suggested that patients with 3 signs should be identied early, admitted to the ICU, and monitored carefully. Aggressive uid

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The American Journal of Surgery, Vol 196, No 3, September 2008 erative therapy could be successful in patients who do not have infection.45 Surgery was reserved for those patients who developed symptomatic organized necrosis characterized by pain, malaise, and food intolerance. The appropriate timing of surgical intervention has evolved from an early aggressive approach to delaying surgery (if possible) to at least 3 to 4 weeks after the onset of symptoms to permit demarcation of the necrosis from viable pancreatic tissue. It is now widely accepted that surgery during the early systemic inammatory phase can result in signicant morbidity and mortality. Several studies, including those by Bchler46 and Fernandez-Del Castillo47 have conrmed this observation. An often-debated issue is the role of prophylactic antibiotics in the treatment of severe acute pancreatitis. Although initial studies discouraged antibiotic use,48 a multicenter study conducted by Italian surgeons in Verona, who administered imipenem within 72 hours of the diagnosis of necrotizing pancreatitis, demonstrated a decreased incidence of pancreatic sepsis but no improvement in MSOF organ failure or mortality.49 Subsequent studies with different antibiotic regimens have also failed to demonstrate a benet of routine antibiotic use.50 A 2004 study from Begers51 group randomized patients with severe acute pancreatitis, per high serum C-reactive protein level or presence of necrosis on CECT, to receive a combination of ciprooxacin and metronidazole within 3 days of the onset of symptoms.51 This double-blinded study did not show any benet to prophylactic antibiotics as evidenced by the absence of observed difference in the incidence of infected necrosis (14% vs 17%) or mortality rate (11% vs 7%) between groups. However, a higher percentage of patients in the placebo group required therapeutic antibiotic use because infection or clinical deterioration was observed earlier and more frequently during their disease course. A recent multicenter trial in patients with severe disease with 30% necrosis again failed to demonstrated a benet of prophylactic antibiotics.52 In addition to antibiotic administration, management of severe acute pancreatitis has involved the use of several

resuscitation and multisystem support were critical during this early period. In addition to describing the criteria for the eponymous prognostic signs, Ranson proposed that there were 4 reasons to operate on patients with acute pancreatitis: diagnosis, treatment of complications, relief of symptoms, and prevention of recurrence.29 Although their timing and precise indications continue to be dened, these recommendations remain to this day. The development of modern cross-sectional imaging greatly facilitated the recognition of severe pancreatitis, and this was recognized early by surgical investigators. Contrast-enhanced computerized tomography (CECT) is particularly useful in dening pancreatic nonenhancement consistent with pancreatic necrosis (Fig. 3). Such necrosis was initially viewed as an indication for surgery. For example, using CECT, Beger35 and Bchler36 were able to show that debridement of clearly necrotic pancreas resulted in a remarkable 14% mortality rate. Later, with further development of nonoperative strategies for acute necrotizing pancreatitis, CECT facilitated the diagnosis of infected pancreatic necrosis as a guide for ne-needle aspiration of the pancreas.37 Another important contribution to the standardized care of patients with pancreatitis was the publication of the Atlanta Classication in 1992 by Edward Bradley.38 This formalized our current denitions of severe acute pancreatitis. This extensive summary of the Atlanta symposium permitted surgeons and gastroenterologists to reconcile and compare their individual experiences and to better understand the natural history and optimal treatment of this disease. The presence of pancreatic necrosis alone had previously been considered an indication for laparotomy and aggressive open surgical debridement. Although a minority of investigators suggested that nonoperative management was feasible in some patients with pancreatic necrosis,39,40 open surgical debridement of pancreatic necrosis for a time had become the standard. Bradley and Allen41 drew signicant attention to this issue with their 1991 publication of a small series of 11 patients with sterile pancreatic necrosis who were successfully managed nonoperatively. This concept initially met substantial resistance from the surgical community, with some investigators arguing that necrosis alone should lead to surgical debridement regardless of the infection status of the gland.42,43 In the 15 years since Bradley and Allens publication, experience with nonoperative management for sterile pancreatitis has led to increasing comfort with this strategy, and the indications for surgery with pancreatic necrosis have been further rened. For example, surgeons in Bern managed 86 patients prospectively using a strict conservative protocol and reported a mortality rate of 10% with just 1 patient undergoing surgery in the absence of documented infection.44 One of the largest studies encompassing 99 patients with necrotizing pancreatitis, by our group at Brigham and Womens Hospital, demonstrated that nonop-

Figure 3

CECT of necrotizing pancreatitis.

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medical therapies aimed at blocking the actions of pancreatic proteases, preventing pancreatic secretion, or reversing MSOF. Beger and Bchler53 demonstrated that administration of gabexate mesilate, a low molecularweight protease inhibitor, for 7 days to patients with moderate to severe pancreatitis did not prevent complications or death in an early randomized trial. The Italian group from Verona, headed by Claudio Bassi,54 compared intravenous aprotinin with gabexate and did not nd any improvement in rates of complications or need for surgery. Administration of octreotide, a somatostatin analogue, was examined as a potential therapeutic strategy because of its inhibitory activity on exocrine pancreatic enzyme secretion. However, several randomized trials failed to show a benet with either lowor high-dose continuous infusion or subcutaneous injection.5557 One of the most-studied agents is the plateletactivating factor inhibitor, lexipafant. Although the results of previous smaller studies58,59 suggested an improvement in organ failure scores and in inammatory cytokine levels, the results of a large, multicenter, double-blind, randomized study conducted by the United Kingdom Acute Pancreatitis Group60 showed that lexipafant did not improve organ failure scores or prevent onset of new organ failure. Although the results of most studies have been negative, the conduction of properly powered and controlled clinical trials by surgeons has contributed signicantly to our knowledge of the disease process. A thorough summary published in 2002as the International Association of Pancreatology guidelines for the surgical management of acute pancreatitisincluded contributions by Warshaw, Bchler, and Neoptolemos. This summary highlighted 11 points based on the current evidence provided by the medical literature,61 including FNA to distinguish between sterile and infected necrosis, the timing for surgical and/or radiologic intervention for infected necrosis, and the role of ERCP and cholecystectomy. Current interest in the management of pancreatic necrosis centers on a variety of minimally invasive approaches. Minimally invasive retroperitoneal necrosectomies are increasingly being performed through a small ank incision, to avoid the morbidity of open intraperitoneal surgery, or with the use of endoscopes, laparoscopes, or nephroscopes.62,63,64 A recent retrospective study from Liverpool examined a series of 88 patients with necrotizing pancreatitis who underwent surgical debridement either by traditional necrosectomy (n 41) or by minimally invasive pancreatic necrosectomy (n 47). The median time to surgery in this cohort was 31 days, and the overall mortality rate was 28%. When comparing open necrosectomy with minimally invasive pancreatic necrosectomy, the latter group had a trend toward decreased mortality (39% vs 19%) that was not statistically signicant.65 However, it was associated with a higher rate of portal and splenic vein thrombosis and increased postsurgical ICU and hospital length of stay. The Dutch Acute Pancreatitis

Group66 performed a retrospective multicenter audit of 1,238 patients in 11 hospitals, 106 of whom underwent surgery for infected pancreatic necrosis.66 Approximately one third of these patients had a CT-guided percutaneous drain placed before surgery without complications. Patients who underwent minimally invasive necrosectomy performed with the guidance of previously placed percutaneous drains had a signicantly lower mortality (11%) compared with those who went on to laparotomy (25%). These small studies have conrmed the feasibility of minimally invasive approaches with favorable results.

Comments
In conclusion, surgeons have been critically involved in every step of the development of improved diagnosis and therapy of acute pancreatitis. This has resulted in signicantly less morbidity and mortality from this disease. Surgeons must continue to take the lead in the investigation and treatment of this protean disease for the continued benet of our patients. Acute pancreatitis remains a disease that requires the entire scope of clinical skills encompassed by the general surgeon. In the context of the specialtys current identity crisis, the role of the surgeon in acute pancreatitis seems a particularly appropriate paradigm.

References
1. Moynihan B. Acute pancreatitis. Ann Surg 1925;81:132 42. 2. Steer ML, Meldolesi J, Figarella C. Pancreatitis. The role of lysosomes. Dig Dis Sci 1984;29:934 8. 3. Saluja A, Hashimoto S, Saluja M, et al. Subcellular distribution of lysosomal enzymes during cerulein-induced pancreatitis. Am J Physiol 1987;253:G508 G516. 4. Van Acker GJ, Saluja AK, Bhagat L, et al. Cathepsin B inhibition prevents trypsinogen activation and reduces pancreatitis severity. Am J Physiol 2002;283:G749 G800. 5. Norman J, Fink G, Franz M. Acute pancreatitis induces intrapancreatic tumor necrosis factor gene expression. Arch Surg 1995;130: 966 70. 6. Norman J, Fink G, Denham W, et al. Tissue specic cytokine production during experimental acute pancreatitis: a problem mechanism for distant organ dysfunction. Dig Dis Sci 1997;42:1783 8. 7. Denham W, Fink G, Norman J. Transgenic animals demonstrate modest additive detrimental effects of IL-1 and TNF during acute pancreatitis. Gastroenterology 1997;113:1741 6. 8. Norman J, Denham W, Chapman V, et al. TNF induces acinar cell apoptosis during acute pancreatitis. Gastroenterology 1997;112(abstr): A468. 9. Kaiser AM, Saluja AK, Sengupta A, et al. Relationship between severity, necrosis, and apoptosis in ve models of experimental acute pancreatitis. Am J Physiol 1995;269:C1295C1304. 10. Fink G, Yang J, Norman J. Acute pancreatitis induced enzyme release and necrosis are attenuated by IL-1 antagonism through an indirect mechanism. J Surg Res 1997;67:94 7. 11. Senn N. The surgery of the pancreas. Philadelphia, PA: Dornan; 1886:71107.

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39. Smadjia C, Bismuth H. Pancreatic debridement in acute necrotizing pancreatitis: an obsolete procedure? Br J Surg 1986;73:408 10. 40. Ranson JHC. Conservative surgical management of acute pancreatitis. World J Surg 1981;5:3519. 41. Bradley EL 3rd, Allen K. A prospective longitudinal study of observation versus surgical intervention in the management of necrotizing pancreatitis. Am J Surg 1992;161:1059. 42. Rattner DW, Legermate DA, Lee MJ, et al. Early surgical debridement of symptomatic pancreatic infection is benecial irrespective of infection. Am J Surg 1991;163:1059. 43. Warshaw AL. Pancreatic necrosis: to debride or not to debridethat is the question. Ann Surg 2000;232:6279. 44. Bchler MW, Gloor B, Muller CA, et al. Acute necrotizing pancreatitis: treatment strategy according to the status of infection. Ann Surg 2000;232:619 26. 45. Ashley SW, Perez A, Pierce EA, et al. Necrotizing pancreatitis: contemporary analysis of 99 consecutive cases. Ann Surg 2001;234: 572 80. 46. Gloor B, Muller A, Worni M, et al. Late mortality in patients with severe acute pancreatitis. Br J Surg 2001;88:9759. 47. Fernandez del Castillo C, Rattner DW, Makary MA, et al. Debridement and closed packing for the treatment of necrotizing pancreatitis. Ann Surg 1998;228:676 84. 48. Howes R, Zuidema GD, Cameron JL. Evaluation of prophylactic antibiotics in acute pancreatitis. J Surg Res 1975;18:197200. 49. Pederzoli P, Bassi C, Vesentini S. et al. A randomized multicenter clinical trial of antibiotic prophylaxis of septic complications in acute necrotizing pancreatitis with imipenem. Surg Gynecol Obstet 1993; 176:480 3. 50. Nordback I, Scand J, Saaristo R, et al. Early treatment with antibiotics reduces the need for surgery in necrotizing pancreatitisa single institution randomized study. J Gastrointest Surg 2001;5: 11320. 51. Isenmann R, Runzi M, Kron M, et al. Prophylactic antibiotic treatment in patients with severe acute pancreatitisa placebo-controlled, double-blind trial. Gastroenterology 2004;126:9971004. 52. Dellinger EP, Tellado JM, Soto NE, et al. Early antibiotic treatment for severe acute necrotizing pancreatitis. A randomized, double-blind, placebo-controlled study. Ann Surg 2007;245:674 83. 53. Bchler M, Malfertheiner P, Uhl W, et al. Gabexate mesilate in human acute pancreatitis. German Pancreatitis Study Group. Gastroenterology 1993;104:116570. 54. Pederzoli P, Cavallini G, Falconi M, et al. Gabexate mesilate vs aprotinin in human acute pancreatitis (GA.ME.P.A.). A prospective, randomized, double-blind multicenter study. Int J Pancreatol 1993;14: 11724. 55. Choi TK, Mok F, Zhan WH, et al. Somatostatin in the treatment of acute pancreatitis: a prospective randomized controlled trial. Gut 1989; 30:2237. 56. McKay C, Baxter J, Imrie C. A randomized, controlled trial of octreotide in the management of patients with acute pancreatitis. Int J Pancreatol 1997;21:139. 57. Uhl W, Bchler MW, Malfertheiner P, et al. A randomized, double blind, multicentre trial of octreotide in moderate to severe acute pancreatitis. Gut 1999;45:97104. 58. Kingsnorth AN, Galloway SW, Formela LJ. Randomized, doubleblind phase II trial of lexipafant, a platelet-activating factor antagonist, in human acute pancreatitis. Br J Surg 1995;82:1414 20. 59. McKay CJ, Curran F, Sharples C, et al. Prospective placebo-controlled randomized trial of lexipafant in predicted severe acute pancreatitis. Br J Surg 1997;84:1239 43. 60. Johnson CD, Kingsnorth AN, Imrie CW, et al. Double blind, randomized, placebo controlled study of a platelet activating factor antagonist, lexipafant, in the treatment and prevention of organ failure in predicted severe acute pancreatitis. Gut 2001;48:629. 61. Uhl W, Warshaw A, Imrie C, et al. IAP guidelines for the surgical management of acute pancreatitis. Pancreatology 2002;2:56573.

12. Halsted WS. Retrojection of bile into the pancreas. A cause of acute hemorrhagic pancreatitis. Bull Johns Hopkins Hosp 1901;12:179 82. 13. Opie EL. The etiology of acute hemorrhagic pancreatitis. Bull Johns Hopkins Hosp 1901;12:182 8. 14. Fitz RH. Acute pancreatitis. Boston Med Surg J 1889;120:229 35. 15. Elman R, Arneson I, Graham EA. Value of blood amylase estimation in the diagnosis of pancreatic disease: a clinical study. Arch Surg 1929;19:9435. 16. Paxton JR, Payne JH. Acute pancreatitis. A statistical review of 307 established cases of acute pancreatitis. Surg Gynecol Obstet 1948;86: 69 75. 17. Watts GT. Total pancreatectomy for fulminant pancreatitis. Lancet 1963;13:384. 18. Nordback I, Pessi T, Auvinen O, et al. Determination of necrosis in necrotizing pancreatitis. Br J Surg 1985;72:2257. 19. Alexandre JH, Guerrieri MT. Role of total pancreatectomy in the treatment of necrotizing pancreatitis. World J Surg 1981;5:369 77. 20. Acosta JM, Ledesma CL. Gallstone migration as a cause of acute pancreatitis. N Engl J Med 1974;290:484 7. 21. Acosta JM, Rossi R, Galli O, et al. Etiology and pathogenesis of acute biliary pancreatitis. Surgery 1980;88:118 25. 22. Kelly TR. Gallstone pancreatitis: the timing of surgery. Surgery 1980; 3:34550. 23. Kelly TR, Wagner DS. Gallstone pancreatitis: a prospective randomized trial of the timing of surgery. Surgery 1988;104:600 5. 24. McCune WS, Shorb PE, Moscovitz H. Endoscopic cannulation of the ampulla of vater: a preliminary report. Ann Surg 1968; 167:752 6. 25. Leese T, Neoptolemos JP, Barker AR, et al. Management of acute cholangitis and the impact of endoscopic sphincterotomy. Br J Surg 1986;2:979 83. 26. Neoptolemos JP, Carr-Locke DL, London NJ, et al. Controlled trial of urgent endoscopic retrograde cholangiopancreatography and endoscopic sphincterotomy versus conservative treatment for acute pancreatitis due to gallstones. Lancet 1988;2:979 83. 27. Flsch UR, Nitsche R, Ludtke R, et al. Early ERCP and papillotomy compared with conservative treatment of acute biliary pancreatitis. N Engl J Med 1997;336:237 42. 28. Warshaw AL, Imberto AL, Civetta JM, et al. Surgical intervention in necrotizing pancreatitis. Am J Surg 1974;127:484 90. 29. Ranson JHC. The role of surgery in the managements of acute pancreatitis. Ann Surg 1990;211:38293. 30. Stone HH, Fabian TC. Peritoneal dialysis in the treatment of acute alcoholic pancreatitis. Surg Gynecol Obstet 1980;150:878 82. 31. Ranson JHC, Spencer FC. The role of peritoneal lavage in severe acute pancreatitis. Ann Surg 1977;187:56575. 32. Mayer AD, McMahon MJ, Coreld AP, et al. Controlled clinical trial of peritoneal lavage for the treatment of severe acute pancreatitis. N Engl J Med 1985;312:399 404. 33. Altemeier WA, Alexander JW. Pancreatic abscess. A study of 32 cases. Arch Surg 1963;87:80 9. 34. Ranson JH, Rifkind KM, Roses DF, et al. Prognostic signs and the role of operative management in acute pancreatitis. Surg Gynecol Obstet 1974;139:69 81. 35. Beger HG, Krautzberger W, Bittner R, et al. Results of surgical treatment of necrotizing pancreatitis. World J Surg 1985; 9:97279. 36. Block S, Maier W, Bittner R, et al. Identication of pancreas necrosis in severe acute pancreatitis: imaging procedures versus clinical staging. Gut 1986;27:1035 42. 37. Gerzof SG, Banks PA, Robbins AH, et al. Early diagnosis of pancreatic infection by CT guided aspiration. Gastroenterology 1987;93: 131520. 38. Bradley EL 3rd. A clinically based classication system for acute pancreatitis. Summary of the International Symposium on Acute Pancreatitis, Atlanta, GA, September 11 to 13, 1992. Arch Surg 1993; 128:586 90.

F.G. Rocha et al.

Surgeons contributions to understanding acute pancreatitis

449

62. Parekh D. Laparoscopic-assisted pancreatic necrosectomy. Arch Surg 2006;141:895903. 63. Castellanos G, Pinero A, Serrano A, et al. Translumbar retroperitoneal endoscopy: an alternative in the follow-up and management of drained infected pancreatic necrosis. Arch Surg 2005;140:95255. 64. Chang YC, Tsai HM, Lin XZ, et al. No debridement is necessary for symptomatic or infected acute necrotizing pancreatitis: delayed, mini-

retroperitoneal drainage for acute necrotizing pancreatitis without debridement and irrigation. Dig Dis Sci 2006;51:1388 95. 65. Connor S, Ghaneh P, Raraty M, et al. Minimally invasive retroperitoneal pancreatic necrosectomy. Dig Surg 2003;20:270 7. 66. Besselink MG, de Brujin MT, Rutten JP, et al. Surgical intervention in patients with necrotizing pancreatitis. Br J Surg 2006;93: 5939.