Natural course of acute pancreatitis

World J. Surg. 21, 130 -135, 1997

WORLD Journal of

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Natural Course of Acute Pancreatitis H.G. Beger, M.D., B. Rau, M.D., J. Mayer, M.D., U. Pralle, M.D. Department of General Surgery, University of Ulm, Steinhovelstrasse 9, 89075 Ulm, Germany Abstract. Acute pancreatitis comprises, in terms of clinical, pathologic, biochemical, and bacteriologic data, four entities. Interstitial edematous pancreatitis and necrotizing pancreatitis are the most frequent clinical manifestations; pancreatic pseudocyst and pancreatic abscess are late complications after necrotizing pancreatitis, developing after 3 to 5 weeks. Determinants of the natural course of acute pancreatitis are pancreatic parenchymal necrosis, extrapancreatic retroperitoneal fatty tissue necrosis, biologically active compounds in pancreatic ascites, and infection of necrosis. Early in the course of acute pancreatitis multiple organ failure is the consequence of various inflammatory mediators that are released from the inflammatory process and from activated leukocytes attracted by pancreatic injury. During the late course, starting the second week, local and systemic septic complications are dominant. Around 80% of deaths in acute pancreatitis are caused by septic complications. The infection of pancreatic necrosis occurs in 8% to 12% of acute pancreatitis and in 30% to 40% of patients with necrotizing pancreatitis. Bacteriologic analysis of intraoperative smears and aspirates reveals predominantly gram-negative germs deriving from the intestine, most frequently Escherichia coli. It has been confirmed that after necrotizing pancreatitis a considerable large group of patients suffer long-lasting exocrine and endocrine insufficiency.

The natural course of acute pancreatitis comprises, with regard to clinical, pathomorphologic, radiologic, biochemical, and bacteriologic data, various clinical entities, each requiring a specific therapeutic approach. The clinical manifestations range from a mild, self-limiting disease to an inflammatory process with severe local and systemic complications. Correspondingly, the pathomorphologic picture ranges from an edematous interstitial disease restricted to the pancreas to a necrotizing process that includes pancreatic and peripancreatic tissue or even involves remote organs. Since the initial description by Fitz in 1889 [1], this variability in clinical expression, complications, and outcome has challenged investigations into and management of acute pancreatitis. Considerable progress in the understanding of the pathophysiologic events during the early stage of acute pancreatitis has been made over the years. However, the underlying pathogenetic processes responsible for the inflammatory cascade and the alterations in the acinus and duct cell compartments of the pancreas are still unknown to a large extent. Therefore study and management of human acute pancreatitis have been empiric, and conflicting opinions regarding therapeutic approaches have Correspondence to:

H.G. Beger, M.D.

arisen. This diversity of opinion resulted in the production of a wealth of incomparable data that were invalid for any interinstitutional comparison owing to (1) the lack of a uniformly accepted classification system of the disease and its complications, and (2) the absence of morphologic and clinical determinants for severity stratification. Without information about the natural course of the disease, stratification of severity is possible but not convincing, and a comparison of therapeutic options is of limited value. With the development of clinically based multiparameter scores, such as the Ranson [2], Imrie [3], and APACHE-II [4, 5] systems, an important step toward clinical stratification of severity was made. However, the lack of morphologic data and their correlation to the clinical context further prevented the establishment of definitions. At the beginning of the 1980s the morphologic feature of pancreatic necrosis was established as one of the principal determinants of clinical severity and, in fact, of overall survival [6-8]. The introduction of contrast-enhanced computed tomography (CT) as a standard diagnostic measure for the early detection of necrosis opened the window for a new understanding of the correlation of pathomorphologic changes in the pancreas and the natural course of acute pancreatitis [9, 10].

Classification

Based on our experience drawn from several prospective clinical studies we proposed a new classification of acute pancreatitis in 1991 (Table 1). The significant advantage of the system was the fact that for the first time pathomorphologic criteria were the cornerstone for differentiation of acute pancreatitis into four entities [13]. The manifestations of acute pancreatitis are (1) acute interstitial edematous pancreatitis, (2) acute necrotizing pancreatitis with sterile or infected necrosis, (3) pancreatic pseudocyst, and (4) pancreatic abscess. During the following years this fundamental classification was supplemented by clinical and pathophysiologic aspects during the international symposium in Atlanta in 1993 [14]. Macroscopic and histologic features of edematous pancreatitis are interstitial edema and intra- and peripancreatic fatty tissue necrosis as well as peripancreatic fluid collections. Peripancreatic and remote intraabdominal fatty tissue necrosis may be present or absent [14]. Most patients with acute pancreatitis—in our own experience around 70% to 80%—suffer edematous interstitial

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Table 1. Terminology of acute pancreatitis: Ulm classification Interstitial edematous pancreatitis Necrotizing pancreatitis Sterile necrosis Infected necrosis Pancreatic abscess Postacute pseudocyst Data are from Beger et al. [II] and Bittner et al. [12].

Table 2. Acute pancreatitis: frequency of subsets of acute pancreatitis. Subset

Patients

Interstitial edematous Necrotizing Sterile Infected Pancreatic abscess Postacute pseudocyst Total

992 286 196 90 36 82 1396

% 71 21 68 32 3 6 100

Data were accumulated between May 1982 and December 1995, in the Departments of Gastroenterology (until 1992) and of General Surgery, University of Ulm.

pancreatitis, which is a self-limiting disease that responds well to conservative treatment protocols [13-16]. Necrotizing pancreatitis is macroscopically characterized by focal or diffuse areas of devitalized pancreatic parenchyma and peripancreatic fatty tissue necrosis involving different retroperitoneal areas. Hemorrhage is variably present. Microscopic findings include extensive interstitial fatty tissue necrosis with vessel damage and necrosis affecting both acinar and ductal cells as well as the islet cell compartment. Infection of necrosis arises in 30% to 71% of all patients with necrotizing pancreatitis [11, 17, 18]. In the clinical setting of acute pancreatitis, postacute pseudocyst and pancreatic abscess are late consequences of the disease [12, 14, 19]. Both features are characterized by an inflammatory wall, which delineates the process from the surrounding tissue and is located within or around the pancreas. Pancreatic pseudocysts may have a connection with the pancreatic duct system, which has a major impact on treatment. Postacute pseudocyst and pancreatic abscess are late consequences of acute, mostly necrotizing pancreatitis. It has been convincingly established that postacute pseudocyst is a late complication of necrotizing pancreatitis with sterile necrosis. Pancreatic abscess appears as a collection of pus with little or no necrosis, and cultures reveal bacteria or fungi. It should not be confused with infected necrosis, as both features differ in clinical expression and associated mortality [12]. Peripancreatic fluid collections that arise early during the course of mainly severe acute pancreatitis usually lack a defined wall and present a different morphologic entity compared to postacute pseudocyst. Table 2 shows the incidence of the various entities in patients with acute pancreatitis treated at the University of Ulm during the period from May 1982 to December 1995. Clinical Course

Acute pancreatitis is not a stable disease, being characterized by time-dependent stages with specific morphologic and clinical patterns (Fig. 1). At the beginning of the disease is the sudden

Fig. 1. Course and outcome probabilities of acute pancreatitis.

onset of abdominal pain located in the epigastrium or the left upper quadrant in association with gallstone disease or after large food and alcohol ingestion. Frequently the pain radiates into the midback. In around 80% of patients there is an association of clinical symptoms and an elevation in the serum concentration of pancratic enzymes: pancreatic amylase, pancreatic lipase, and elastase. Nausea and vomiting are regularly associated. In terms of these initial clinical features no prognosis concerning the future clinical course is possible [20]. In approximately two-thirds of the patients with acute pancreatitis the disease takes a mild course and is associated only with minimal organ dysfunction. Clinical improvement can easily be achieved by fluid replacement, pain treatment, and parenteral nutrition; and no further complications are observed [15]. However, the initial 24 to 48 hours after the onset of symptoms are the crossroads, where about 20% to 30% of all patients with acute pancreatitis take a severe clinical course of their disease. On the basis of clinical and experimental observations, this period is characterized as the initial hypovolemic stage where arterial hypotension or even shock is the leading feature as a result of fluid sequestration from the pancreas into peripancreatic areas and the abdominal cavity [21]. Simultaneously, the first evidence of the subsequent systemic toxic phase manifests clinically, leading to organ dysfunction involving the lungs, kidney, and cardiocirculatory system [22, 23]. Based on CT data, these patients demonstrate a strong morphologic correlation between clinical severity and the presence and extent of intra- and extrapancreatic necrosis [6-8]. If the patient with severe acute pancreatitis has passed through these critical early stages at the end of the second week, a septic complication caused by translocated bacteria, mostly gram-negative microbes from the intestine, determines the patient's survival. The pathomorphologic and bacteriologic correlate of this septic phase of necrotizing pancreatitis are infected pancreatic necrosis with gram-negative bacteria and, in few patients, the late occurrence of a pancreatic abscess [12, 24]. However, patients with extended necrosis that includes the pancreatic parenchyma and retroperitoneal fatty tissue areas frequently suffer a sepsis-like syndrome without a septic focus. Patients with extended sterile necrosis (on the basis of CT measurements and including more than 50% of the gland) develop frequently local complications and systemic organ failure syndrome that affects the lungs, kidney, liver, and cardiovascular organs. These patients suffer in addition

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World J. Surg. Vol. 21, No. 2, February 1997 Table 5. Pathomorphologic factors related to mortality from necrotizing

Table 3. Clinical course of acute pancreatitis.

pancreatitis (205 patients). Phase Early (4-10 days after admission)

Clinical course Hypovolemia Pulmonary dysfunction/ insufficiency Renal dysfunction/ insufficiency GI tract dysfunction/ adynamic ileus Circulatory shock

Pathophysiologic course Vasoactive and toxic substances in peripancreatic fluids and systemic circulation

Late (> 2 weeks Local and systemic Translocation of after admission) septic complications gram-negative bacteria from the intestine into the necrosis From Beger et al. [11, 21]. Table 4. Pancreatitis-specific criteria of prognosis.

Pancreatic parenchymal necroses Extrapancreatic retroperitoneal necrosis of fatty tissue Vasoactive and toxic substances in pancreatic ascites Bacterial infection of pancreatic necrosis From Beger et al. [6].

from such nonspecific symptoms as upper abdominal pain, a prolonged severe type of adynamic ileus, and regularly have a palpable mass in the upper abdomen [19] (Table 3). Determinants of the Natural Course Until the beginning of the 1980s severe acute pancreatitis was associated with high mortality. Knowledge about the natural history of the disease was restricted to either autopsy cases and surgical specimens or clinical observations. Later, based on improved multidisciplinary experience in terms of histopathology, biochemistry, radiology, and bacteriology, the clinicopathologic correlation became possible and opened the door for new therapeutic, particularly surgical concepts. As a result the overall hospital mortality for patients afflicted with necrotizing pancreatitis decreased to less than 20%. Objective, disease-related factors could be established from clinical data, further defining the natural history and the outcome of patients with acute pancreatitis. Each of the pancreatitis-related factors is an important determinant in the clinical course and is strongly associated with morbidity and mortality [6]. These factors are (1) the amount of pancreatic necrosis; (2) the presence of extrapancreatic, retroperitoneal fatty tissue necrosis; (3) the biologic nature and amount of liberated vasoactive and toxic substances in pancreatic ascites; and (4) infection of pancreatic necrosis (Table 4). Presence of Necrosis Experimental and clinical observations have shown that the development of pancreatic necrosis in patients with acute pancreatitis results in a dramatic increase of local and associated systemic organ complications and an increase of mortality risk compared to that of patients with interstitial edematous pancre-

Factor

Patients (no.)

Mortality (no.)

p

Intrapancreatic necrosis —30% —50%

79 (39%) 75 (37%) 51(25%)

6 18 26

< 0.0001

Extrapancreatic necrosis Positive Negative

96 (47%) 109 (53%)

33 17

< 0.02

Pancreatogenic ascites Positive Negative

115 (56%) 90 (44%)

42 8

< 0.01

56 (41%) 82 (59%)

18 8

< 0.01

Subtotal/total

Bacterial infection Positive Negative

From Beger and Buehler [48].

atitis. Most patients who develop organ failure with acute pancreatitis present with a necrotizing pancreatitis [6, 25, 26]. Data derived from surgical and autopsy studies show that more than 80% of deaths were correlated with the presence of necrosis in acute pancreatits [25, 27]. For many years it has been assumed that patients with necrotizing pancreatitis initially pass through the stage of interstitial edema. With the introduction of dynamic, contrast-enhanced CT this hypothesis could not be confirmed. In a series of 73 patients with necrotizing pancreatitis we showed that all of them had positive CT findings of necrosis within 96 hours of the onset of symptoms. In no case did pancreatic necrosis develop in patients with a CT scan that initially depicted interstitial edematous pancreatitis [28]. Other series confirmed the observation that there are only a few patients in whom necrotizing pancreatitis developed later in the hospital course after initial scans suggested interstitial pancreatitis on admission [29, 30]. The observation that early application of contrast medium accentuates the severity of necrotizing pancreatitis depicted from rat experiments has not been shown to be effective in humans [31]. Among 205 prospectively evaluated patients, intraoperative measurement of the extent of intrapancreatic necrosis revealed focal necrosis (up to 30% of pancreatic parenchyma) in 39%, extended necrosis (3050% of the pancreatic parenchyma) in 37%, and subtotal necrosis in 25% (> 50% of pancreatic parenchyma); the corresponding mortality rates were 8%, 24%, and 51%, respectively (Table 5). Extrapancreatic, Retroperitoneal Fatty Tissue Necrosis Fatty tissue necrosis is among the pathomorphologic criteria for edematous interstitial pancreatitis. However, in addition to the presence of pancreatic parenchymal necrosis, the occurrence and extent of a necrotizing process involving extrapancreatic retroperitoneal fatty tissue areas (including tissue compartments of the mesentery of the small and large bowel, the perirenal fat, and retroperitoneal para- and retrocolic compartments) is an important factor in the course of the disease and strongly affects the clinical severity and mortality [6]. In a few patients extrapancreatic

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Table 6. Frequency and clinical features of pancreatic infection in

Table 7. Microbiologic findings with infected necrosis: intraoperative

acute pancreatitis (1396 patients).

results in 86 patients.

Infection

In necrotizing pancreatitis (%)

In acute pancreatitis (%)

Microbiologic finding

Infected necrosis (no. of pts.)

Infected necrosis Pancreatic abscess Infected pseudocyst Local infection

22.1 8.8 1.7 32.6

6.4 2.6 0.5 9.5

Positive cultures Monomicrobial Polymicrobial

81 (100 %)a 53 (65.4%) 28 (34.6%)

Gram-negative only Gram-positive only Both

42 (51.9%) 25 (30.9%) 14 (17.2%)

Aerobes only Anaerobes only Both

70 (86.5%) 4 (4.9%) 7 (8.6%)

Data were accumulated between May 1982 and December 1995, in the Departments of Gastroenterology (until 1992) and of General Surgery, University of Ulm.

necrosis is not restricted to the extrapancreatic retroperitoneal fatty tissue but extends to the pelvic viscera. Colonic involvement in necrotizing pancreatitis has been shown to be a deleterious complication in this setting [32]. If extrapancreatic fatty tissue necrosis is present, with or without pancreatic parenchymal necrosis, twice as many patients die during the later course. In addition to clinical severity and mortality, patients with extended pancreatic parenchymal necrosis and retroperitoneal fatty tissue necrosis are at a significantly higher risk of bacterial contamination of necrotic tissues [6]. Biologically Active Compounds in Pancreatic Ascites Experimental findings and clinical observations have shown that pancreatogenic ascites is an important source of vasoactive and toxic substances during an attack of acute pancreatitis [6, 33]. It has been shown that the peripancreatic fluid contains a variety of biologically active substances, such as phospholipase A2 (PLA 2 [34], trypsin, and trypsinogen-activating peptide [35], polymorphonuclear cell (PMN) elastase, interleukins 2 and 6 and leukotriene B 4 (LTB 4 ), prostacyclin, and thromboxane as well as endotoxin, a,-antitrypsin, and a 2 -macroglobulin [36-38]. The appearance of C-reactive protein [36, 39] and lactate dehydrogenase (LDH) [37] in ascites and in the peripheral blood is correlated with the severity of the inflammatory process, but they are not produced from sources of local inflammation. Endotoxin is thought to be released from the intestinal compartment appearing by translocation in ascites fluid and the peripheral circulation [38]. Data suggest that multiple organ failure is the consequence of various inflammatory mediators released from activated leukocytes attracted by pancreatic injury. Depending on the degree of pancreatic cell injury, PLA 2 , PMN-elastase, complement factor, interleukins, and leukotrienes determine the incidence and severity of pulmonary, renal, and cardiocirculatory tissues during the early stage of acute pancreatitis [40]. )

Infection of Pancreatic Necrosis Currently more than 80% of deaths among those with acute pancreatitis are due to septic complications as a consequence of bacterial infection of pancreatic necrosis. The overall infection rate of pancreatic tissue in acute pancreatitis is between 7% and 12% (Table 6). Infected necrosis occurs in 30% to 70% of patients with necrotizing pancreatitis, whereas pancreatic abscess develops in around 3% [6, 11, 17, 18]. The definition of pancreatic infection

Total with microbes E. coli Enterococcus Staph. aureus Klebsiella Pseudomonas Proteus Candida

36 (44.4%) 23 (28.4%) 12 (14.8%) 13 (16.0%) 4 (4.9%)

3(3.7%)

4 (4.9%)

Data were accumulated between May 1982 and December 1995, in the Department of Gastroenterology (until 1992) and of General Surgery, University of Ulm. °In 5 patients with macroscopic infection of necrosis, no bacteria could be cultured.

includes infected necrosis, pancreatic abscess, and infected pancreatic pseudocyst. Bacteriologic analysis of intraoperative smears and aspirates reveals predominantly gram-negative microbes deriving from the intestine [41]. Escherichia coli is the most frequent pathogen followed by Enterococcus and Klebsiella; in half of the patients with infected necrosis a monomicrobial and in one-third a polymicrobial infection occurs. Enterobacter, staphylococci, anaerobes, or fungi are found in fewer than 20% (Table 7). Experimental evidence suggests that there are several sites from which bacteria can translocate in the pancreas. The most important route of bacterial infection occurs via translocation from the small and large bowel. Other modes of infection are microperforation of the transverse colon and hematogenous-borne infection. Reflux from the common bile duct or the duodenum into the pancreatic main duct seems to be exceptional as a cause of infected necrosis. In a prospective clinical trial we were able to show that infection is an increasing, time-dependent event during the course of the disease. Contamination rates were 25% at 1 week, 45% at 2 weeks, and a peak 60% in patients after 3 weeks of necrotizing pancreatitis. Based on percutaneous fine-needle aspiration, bacteria can apparently be demonstrated within necrotic pancreatic tissue at a median of 6 days after the onset of acute pancreatitis [6, 11, 17, 18]. Even in the face of high standard therapeutic protocols, the mortality risk for infected necrosis is markedly higher than that in patients with noninfected necrotizing pancreatitis. However, it has been demonstrated that even with infected necrosis nonsurgical management is effective, whereas patients suffering from sterile pancreatic necrosis are lost owing to multisystemic organ failure syndrome without a septic focus [42].

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Late Complications Postacute pseudocyst and pancreatic abscess constitute the late, rather infrequent complications of acute pancreatitis [14]. The development of both pancreatic pseudocyst and abscess requires 4 weeks or more after the onset of acute pancreatitis, when the initial clinical course of the early toxemic phase has subsided. Pancreatic pseudocyst arises in about 6% of patients following an attack of acute pancreatitis (Table 2). With the use of contrastenhanced CT it became apparent that spontaneous resolution of pancreatic pseudocyst is seen in up to 40% of all pseudocysts if the diameter is less than 6 cm and if there is no communication with the pancreatic duct [19, 43]. Clinical symptoms are usually moderate regarding abdominal complaints, and relevant infection rarely occurs. Pancreatic abscess occurs with an incidence of up to 3%. Pancreatic abscess is a late complication after necrotizing pancreatitis. Bacteriology reveals polymicrobial infection with germs of intestinal origin in most of the patients [12, 44]. Although both infected pancreatic necrosis and pancreatic abscess represent pancreatic infection, their clinical severity and associated mortality are considerably different [44]. However, if patients suffering from pancreatic abscess do not undergo interventional or surgical treatment, they share the same lethal fate with those who have infected necrosis. Long-Term Follow-up In the past complete morphologic and functional recovery of the pancreas was assumed to be characteristic after resolution of even severe acute pancreatitis [45]. More recent evaluations of endocrine and exocrine function in patients with necrotizing pancreatitis have established some new, important aspects. Pancreatic functional and morphologic abnormalities can persist for years after the acute attack. Persisting morphologic changes may develop in the ductal system. The degree of long-term functional and morphologic abnormalities parallels the severity of the attack and the extent of necrosis [46, 47]. After subsidence of acute pancreatitis, pancreatic duct obstruction may be the result of healing fibrotic tissue. Clinically, it often presents as episodes of recurring acute pancreatitis, although a direct relation to development into chronic pancreatitis has not been established as an important cause of chronic pancreatitis. Based on the long-term follow-up of 39 patients with morphologically proved acute edematous or necrotizing pancreatitis up to 40 months after onset of the attack, we have made two more important observations: (1) Exocrine function and morphologic changes tend to ameliorate within 12 to 14 months even after severe pancreatitis. (2) Etiologic factors play an additional role in long-term outcome, whereby preexisting pancreatic alterations in alcoholic pancreatitis cannot be excluded [45, 46]. It has been confirmed that after necrotizing pancreatitis a considerably large group of patients suffer long-lasting exocrine and endocrine insufficiency [46]. Resume Sous le terme de pancreatite aigue se regroupe une large gamme d'entites pathologiques en termes de donnees cliniques, pathologiques, biochimiques et bacteriologiques. La pancreatite oede-

World J. Surg. Vol. 21, No. 2, February 1997 mateuse interstitielle et la pancreatite necrosante sont les varietes cliniques les plus frequemment rencontrees. Les faux kystes et les abces pancreatiques sont des complications tardives que l'on rencontre apres evolution de la pancreatite necrosante pendant 3 a 5 semaines. Dans l'evolution de la pancreatite aigue, la necrose du parenchyme, la necrose des tissus graisseux retroperitoneaux extrapancreatiques, la richesse en amylase de l'ascite pancreatique et l'infection de la necrosc sont determinants. La defaillance polyviscerale, consequence de multiples mediateurs inflammatoires qui sont liberes a partir de l'inflammation et des leucocytes actives par la lesion pancreatique, est un facteur pouvant jouer un role tres tot dans 1'evolution de la pancreatite. Plus tardivement, 15 jours environ apres le debut de la maladie, ce sont les complications infectieuses qui dominent. Environ 80% des deces dans la pancreatite aigue sont en rapport avec des complications infectieuses. L'infection de ]a necrose pancreatique se voit dans 8-12% des cas de pancreatite aigue et chez 30-40% des patients ayant une necrose pancreatique. L'analyse bacteriologique des ensemencements provenant des prelevements peroperatoires revelent des bacteries gram negatives en provenance de la lumiere digestive et en particulier, 1'E. Coli. On a confirme egalement qu'apres ]a pancreatite necrosante, une large proportion des patients ont une insuffisance pancreatique exocrine et endocrine persistante. Resumen La pancreatitis aguda comprende, en terminos de sus manifestaciones clinicas, patologicas, bioquimicas y bacteriologicas, diferentes entidades de la enfermedad. La pancreatitis edematosa intersticial y la pancreatitis necrotizante son sus manifestaciones mas frecuentes; el pseudoquiste y el absceso pancreatico son complicaciones tardias de la pancreatitis necrotizante, las cuales se desarrollan a las 3-5 semanas. Factores determinantes del curso natural de la pancreatitis aguda son: la necrosis parenquimatosa del pancreas, la necrosis extrapancreatica de los tejidos grasos retroperitoneales, la presencia de compuestos biol6gicamente activos en la ascitis pancreatica y la infeccion de los tejidos necroticos. La falla organica multiple que aparece en las fases tempranas de la pancreatitis aguda es la consecuencia de diversos mediadores inflamatorios generados por el proceso inflamatorio y por leucocitos activados que han sido atraidos por la lesion pancreatica. Mas tardiamente en el curso de la enfermedad, comenzando en la segunda semana, son dominantes las complicaciones septicas, tanto locales como sistemicas. La infeccion de la necrosis pancreatica ocurre en 8-12% de los casos de pancreatitis aguda y en 30-40% de los pacientes con pancreatitis necrotizante. El analisis bacteriologico de frotis y de aspirados intraoperatorios revela predominancia de germenes gram-negativos derivados del intestino, especialmente de E.coli. Se ha confirmado que luego de una pancreatitis necrotizante, un grupo considerable de pacientes desarrolla insuficiencia pancreatico exocrina y endocrina. References 1. Fitz, R.H.: Acute pancreatitis: a consideration of pancreatic hemorrhage, hemorrhagic, suppurative and gangrenous pancreatitis. Boston Med. Surg. J. 70:181, 1889 2. Ranson, J.H.C., Rifkind, K.M., Roses, D.F., Fink, S.D., Eng, K.,

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