Review article. Prevention of severe change in acute pancreatitis: prediction and prevention. Hans G. Beger, Bettina Rau, and Rainer Isenmann

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1 J Hepatobiliary Pancreat Surg (2001) 8: Review article Prevention of severe change in acute pancreatitis: prediction and prevention Hans G. Beger, Bettina Rau, and Rainer Isenmann Department of General Surgery, University of Ulm, Steinhoevelstrasse 9, Ulm, Germany Abstract Bacterial infection of pancreatic necrosis is the most frequent local complication of severe acute pancreatitis and is responsible for the majority of deaths in this disease. The development of systemic complications of severe acute pancreatitis such as septic multiple organ failure is closely related to infected necrosis. In this review, the factors predisposing to a severe course of acute pancreatitis are discussed as are clinical and laboratory markers which allow identification of patients at risk. Prevention of complications of acute pancreatitis is difficult. A variety of drugs including antiproteases and antiinflammatory agents have been shown to be of no benefit with regard to the reduction of severe complications. At present, based on the results of controlled trials, there is the widespread belief that prophylactic antibiotics are capable of reducing the incidence of infected pancreatic necrosis. New approaches for the prevention of systemic complications of severe acute pancreatitis are total enteral nutrition and local arterial infusion of antibiotics and antiproteases into the celiac trunk. Key words Severe acute pancreatitis Pancreatic necrosis Prediction of complications Sepsis Systemic complications Antibiotics almost exclusively focused on this subgroup of severely ill patients. Although this has led to considerable progress in the treatment of acute pancreatitis, systemic complications remain a therapeutic challenge and a main prognostic determinant of the disease. Definition of severe acute pancreatitis Our current definition of severe acute pancreatitis is based on a consensus reached in Atlanta in The so-called Atlanta classification recognizes both the pathomorphologic and the clinical characteristics of severe acute pancreatitis. According to this definition, severe acute pancreatitis is associated with systemic complications, such as organ failure and/or local complications, such as necrosis, abscess, or pseudocyst. 4 Although the Atlanta system discriminates between local and systemic complications of the disease, there is, apparently, a close connection between these entities, as it is a common observation that systemic complications are almost exclusively restricted to patients with pancreatic necrosis. 5 7 Introduction In the majority of cases, acute pancreatitis is a mild and self-limiting disease, with an uneventful recovery of the patient and a mortality of less than 2%. Nevertheless, 20% 30% of all patients develop severe disease, characterized by the occurrence of systemic complications and a 20% 30% risk of fatal outcome. 1 3 In recent years, research in the field of acute pancreatitis has Offprint requests to: H.G. Beger Received: September 18, 2000 / Accepted: October 22, 2000 Local complications of acute pancreatitis (Table 1) Pancreatic necrosis The most frequent local complication of acute pancreatitis is the development of pancreatic necrosis. Necrotizing pancreatitis is associated with a high incidence of organ failure, which determines the patient s prognosis. 8,9 Necrotic areas are not limited to the pancreas alone. Frequently, they are characterized by a diffuse spread throughout the retroperitoneum and they may also involve intraabdominal structures. Necrotic areas can be sterile, or they may be infected with intestinal bacteria, 6,10,11 which leads to a dramatic

2 H.G. Beger et al.: Prevention of severe change in acute pancreatitis 141 impairment of the patient s prognosis. 8,12 Infected pancreatic necrosis is found in 40% 70% of all patients suffering from necrotizing pancreatitis. In the majority of cases, pancreatic infection is monomicrobial. The bacterial spectrum of interest resembles the intestinal flora and is dominated by gram-negative germs, but also comprises anaerobes and fungi. 6,13 Most likely, the germs originate from the gastrointestinal tract. The clinical management of patients with infected necrosis differs substantially from the management of those with sterile necrosis. In pancreatic infection, surgical debridement and lavage is mandatory. 1,2,11,14 In contrast, a conservative approach is accepted as successful in sterile necrosis, as long as the patient responds to therapy. 15,16 Pancreatic abscess In contrast to pancreatic necrosis, pancreatic abscess is a circumscribed collection of infected material surrounded by a fibrotic capsule and located in the vicinity of the pancreas. Organ failure is less frequent than in pancreatic necrosis Nevertheless, failure to give adequate treatment may lead to rupture of the capsule, with the intrabdominal liberation of pus and subsequent fulminant sepsis. Table 1. Incidence of local complications in 1568 patients with acute pancreatitis; Department of General Surgery, University of Ulm, May 1982 to December 1999 Patients Percentage Interstitial edematous pancreatitis Necrotizing pancreatitis Sterile necrosis 227 Conservative treatment Surgical treatment Infected necrosis 132 Surgical treatment Pancreatic abscess Postacute pseudocyst Pancreatic pseudocyst Pancreatic pseudocysts are encapsulated collections of pancreatic juice or exudate surrounded by a wall of connective tissue. They can be the cause of recurrent episodes of pancreatitis and delayed recovery of the patient. A considerable percentage of pseudocysts resolve spontaneously, but persistent pseudocysts are associated with considerable morbidity. 20,21 Bacteria might be present in pancreatic pseudocysts. Although this may represent contamination rather than infection, infected pseudocysts can be the cause of systemic sepsis. Systemic complications of acute pancreatitis Failure of different organ systems is a frequent problem in severe acute pancreatitis. The majority of fatalities in patients with severe acute pancreatitis are associated with the failure of at least one or more organ systems. 9,16,22,23 Impaired lung function is the most frequent organ complication, and is, commonly, the first sign of multiple organ failure. In severe acute pancreatitis, the first signs of pulmonary failure can frequently be observed a few hours after the onset of abdominal pain. Other organ systems affected during severe acute pancreatitis are the kidneys, the cardiocirculatory system, and the liver (Table 2). The systemic complications have been defined by the Atlanta consensus. This allows quantification of the severity of acute pancreatitis, and facilitates comparison of patient data from clinical studies. Organ failure in severe acute pancreatitis has to be regarded as part of the inflammatory response following the liberation of activated enzymes from the pancreas. The mediators involved in this process include interleukin (IL)-1β, tumor necrosis factor (TNF)-α, IL-6, platelet activating factor (PAF), and IL-8. Our information about the exact mechanisms or remote organ damage in severe acute pancreatitis is limited, and it is likely Table 2. Incidence of systemic complications in 273 patients with necrotizing pancreatitis a Sterile necrosis Infected necrosis 188 patients 85 patients n Percentage n Percentage P Pulmonary insufficiency Sepsis/SIRS Coagulopathy Renal insufficiency Shock SIRS, Systemic inflammatory response syndrome a From reference 12, with permission

3 142 H.G. Beger et al.: Prevention of severe change in acute pancreatitis that there are other, as yet unidentified, mediators promoting these events. Prediction of complications As the local and systemic complications determine the course and prognosis of acute pancreatitis, considerable efforts have been made to identify patients at risk of developing severe acute pancreatitis. The search for valid scoring systems that are able to identify patients with poor prognosis during the initial course of the disease has been accompanied by efforts to identify serum parameters which indicate complicated courses. Factors predisposing to severe course of acute pancreatitis Attempts to identify factors predisposing to a severe course and/or a fatal outcome in acute pancreatitis have been made in a number of series. Some studies indicate that the body mass index (BMI) of the patient is a crucial point, with obese patients having a high risk of developing a severe course. 16,24 Other series have shown that mortality from the disease was increased in elderly patients or those with post-endoscopic retrograde cholangiography (ERCP) pancreatitis. 9 The most prominent factor predisposing to organ failure, however, is the presence of pancreatic and/or extrapancreatic necrosis. Today there is no doubt that bacterial infection of pancreatic necrosis is a major determinant of both organ failure and fatality. In patients with necrotizing pancreatitis treated in our hospital, we observed a fourfold increase in the risk of developing organ failure when the necrosis was infected. Regardless of the bacteriologic status of necrosis, the extent of the necrotic area is another determinant of the development of organ failure. Patients with extended pancreatic necrosis are at an almost fivefold risk of developing organ failure 12 (Table 3). Scoring systems Numerous attempts have been made during recent years to identify patients at risk of developing severe acute pancreatitis. Clinical signs and symptoms alone are not useful in the identification of patients with severe courses. In the absence of a valid clinical assessment for acute pancreatitis, Ranson et al., in 1974, 25 introduced a combination of different clinical signs and laboratory markers as a scoring system in this disease. In the meantime, various other clinical scores have been employed for patients with acute pancreatitis. Among these, the Acute Physiology and Chronic Health Evaluation (APACHE) II score and the Glasgow criteria have been most carefully evaluated Although scoring systems are useful, to some extent, in the identification of patients with severe acute pancreatitis, their sensitivity and specificity is limited to 80% 85%. Another major drawback of most scoring systems is that daily evaluation is necessary, and that it takes 3 to 4 days to achieve a reliable prediction of severity. A considerable percentage of patients develop complications despite scores having been low during the initial course. Although scoring systems are widely used in patients with acute pancreatitis, they are of only limited use in the prediction of severe attacks. This explains why a recent audit on the management of acute pancreatitis revealed that only a minority of hospitals perform severity stratification of patients within the first hours by using scores. 29 The major rationale for scoring in acute pancreatitis today is the comparability of patients participating in clinical trials. Laboratory markers It is a well known phenomenon that the serum levels of the pancreatic enzymes amylase and lipase do not correlate with the severity of acute pancreatitis. Mild attacks may be associated with extremely high amylase and lipase levels in peripheral blood, whereas subtotal necrosis of the gland is frequently associated with slightly Table 3. Factors predisposing to organ failure in necrotizing pancreatitis 95% Confidence limits Variable Odds ratio Lower Upper Bacterial status Infected vs sterile necrosis Extent of necrosis 30% 50% vs 30% % vs 30% 50% Etiology Biliary vs alcoholic Others vs alcoholic a From reference 12, with permission

4 H.G. Beger et al.: Prevention of severe change in acute pancreatitis 143 Table 4. Values for CRP, procalcitonin, and IL-8 in the prediction of complications of acute pancreatitis a elevated or even normal levels of serum markers of pancreatitis. Today, serum C-reactive protein (CRP) is the gold standard laboratory marker for the prediction of pancreatic necrosis Its sensitivity and specificity in the prediction of pancreatic necrosis are above 80%, with an accuracy rate of 86%. 33 One of the major drawbacks of using serum CRP is that it takes up to 96h after onset of the disease until the relevant cutoff level is exceeded. 34 Nevertheless, the fact that testing for serum CRP is readily available in every clinical laboratory has made it a widespread and easy-to-use marker for the identification of pancreatic necrosis. Recently, other acute phase reactants, including cytokines, chemokines, and procalcitonin, have been tested for their usefulness in the identification of patients with severe attacks of acute pancreatitis. Promising data have been obtained from IL-6 as well as from IL-8. 35,36 Currently, prospective studies are being carried out in order to evaluate the prognostic impact of both these parameters. For procalcitonin, a prospective series revealed favorable data both in the prediction of infected pancreatic necrosis and in the prediction of multiorgan failure 37 (Table 4). These data have to be evaluated in larger series, but there seems to be evidence that serum CRP as a standard laboratory marker for the early identification of severe acute pancreatitis might be replaced within the next few years. Prevention of complications Cutoff Sensitivity Specificity Prediction of infected necrosis PCT 1.8ng/ml 94% 90% IL pg/ml 72% 75% CRP 300 mg/l 83% 78% Prediction of multiorgan failure PCT 1.8ng/ml 86% 92% IL pg/ml 79% 81% CRP 325 mg/l 71% 78% Prediction of death PCT 5.7ng/ml 100% 92% IL pg/ml 91% 79% CRP 325 mg/l 64% 72% PCT, Procalicitonin; IL-8, interleukin-8; CRP, C-reactive protein a Data from reference 37, with permission Prophylactic antibiotics As bacterial infection is one of the determinants of the prognosis of severe acute pancreatitis, the prophylactic use of antibiotics has been one of the approaches to reducing severe complications of the disease. The rationale is that reduction of the incidence of infected necrosis should lead to reduced morbidity and mortality. In recent years, a number of controlled studies have been conducted in patients with necrotizing pancreatitis. However, their results have been heterogeneous, depending on study size and patient selection (Table 5): there was either a reduction of the incidence of infected pancreatic necrosis, 38,39 or a significant reduction of mortality, 40 or a reduction of the APACHE II score in patients receiving prophylactic antibiotics. 41 In a recent series, it was shown that the use of imipenem during the early course of the disease resulted in a reduction of the need for surgical treatment. 42 As the bacteria responsible for pancreatic infection most likely originate from the intestines, selective decontamination of the digestive tract (SDD) has received considerable attention. A randomized, controlled multicenter trial of SDD in severe acute pancreatitis showed a reduction of late mortality due to a significant reduction of the incidence of gram-negative pancreatic infection. 43 Most recently, similar findings were made for a combination of SDD together with intraarterial antibiotics, antiproteases, and hemofiltration, which reduced the incidence of pancreatic infection. 44 In some recent studies, the prophylactic use of antibiotics has frequently been recommended for patients with severe acute pancreatitis This has led to the enthusiastic, widespread use of antibiotics in patients with necrotizing pancreatitis. Nevertheless, there are some major drawbacks of these studies: most series do not comprise more than 30 patients in each of the control and treatment groups. None of the series is double-blinded, which could result in a bias favoring the group of patients receiving early antibiotics. Moreover, none of the series has shown a reduction of multiorgan failure in patients receiving antibiotic prophylaxis. A questionnaire survey conducted in the United Kingdom and Ireland revealed that 88% of the respondents used prophylactic antibiotic therapy in acute pancreatitis. Interestingly, 24% of them prescribed antibiotics to all patients with acute pancreatitis. 48 Currently, there is increasing evidence that the widespread use of antibiotic drugs in this disease is not without risk. An increase in the incidence of gram-positive infections has been described in patients with necrotizing pancreatitis receiving prophylactic imipenem. 49 In addition, Candida infections are observed with increasing incidence in patients with pancreatic infection. The prognosis of these patients is poor, with enhanced morbidity and mortality. 50,51 Most recent data indicate that Candida infection in necrotizing pancreatitis is a sequel of prolonged prior antibiotic treatment. 52 Thus, although the necessity for prophylactic antibiotics in necrotizing pancreatitis seems to be evident, the topic still is a

5 144 H.G. Beger et al.: Prevention of severe change in acute pancreatitis matter of discussion and needs further evaluation in a double-blinded, adequately designed trial. Reduction of systemic complications Patients with severe acute pancreatitis are managed in an intensive care unit. The standard treatment comprises adequate resuscitation, sufficient analgesia, and total parenteral nutrition. If systemic complications develop, these patients are treated appropriately depending on the type of organ failure. As this current concept of medical treatment in severe acute pancreatitis represents a reaction to rather than an approach to the prevention of complications, efforts have been made to prevent severe systemic complications. During the past 20 years, various drugs have been used in attempts to reduce the incidence of systemic complications and deaths in patients with severe acute pancreatitis (Table 6). The rationale behind these Table 5. Literature survey of the effect of prophylactic antibiotic treatment in necrotizing pancreatitis Year Antibiotic agent(s) Patients Mortality Pancreatic infection Systemic antibiotics Pederzoli et al Imipenem 41 None 33 Sainio et al Cefuroxime 30 None 30 Delcenserie et al Ceftazidime 11 amikacin metronidazole None 12 Schwarz et al Ofloxacin 13 a metronidazole None 13 Bassi et al Imipenem 30 Pefloxacin 30 Nordback et al Imipenem 25 b (early) Imipenem 33 (late) Selective decontamination Luiten et al Norfloxacin 50 Colistin Amphotericin Cefotaxim None 52, No difference;, significant difference a Significant decrease of Acute Physiology and Chronic Health Evaluation (APACHE) II score in treatment group b Surgical debridement less frequent in treatment group Table 6. Controlled trials of medical prevention of complications in patients with severe acute pancreatitis Year Patients Complications Mortality Gabexate Büchler et al Valderrama et al Harada et al (severe AP) Octreotide Uhl et al McKay et al O Hair et al Lexipafant Lexipafant phase III study McKay et al Kingsnorth , No difference;, significant difference

6 H.G. Beger et al.: Prevention of severe change in acute pancreatitis 145 investigations has been the prevention of remote organ damage by the direct inhibition of activated pancreatic enzymes or by interference with the inflammatory mediator cascade. Different drugs have been used in this context. The antiproteases aprotinin and gabexate mesilate have been shown in large, double-blinded, trials to be without effect on the course of acute pancreatitis, and their use in patients with this disease today is without any scientific rationale. 53,54 A similar finding has been made for octeotide, a long-acting analogue of somatostatin, which, in controlled trials, has shown no benefit. 55,56 Recently, clinical phase II trials with Lexipafant, a platelet-activation factor antagonist, provided promising results in reducing both morbidity and mortality, especially if treatment was initiated during the early phase of acute pancreatitis. 57,58 Nevertheless, these results were not confirmed in a large multicenter phase III study with approximately 1500 patients. 59 These data suggest that Lexipafant will not play a further role in the treatment of patients with acute pancreatitis. One reason that all attempts to prevent systemic complications and to influence the course of acute pancreatitis by medical therapy have failed is that our knowledge of the pathophysiology is limited. We still have only scarce information about the mechanisms and mediators responsible for the systemic complication of the disease. Another factor that contributes to this disappointing situation is that there is evidence for the fact that, at least in a number of severely ill patients, the clinical course seems to be determined during the initial phase, within the first few hours after the onset of abdominal plan. 60,61 Thus, any efforts to break this vicious circle after hospital admission will be too late. Surgical treatment The indications for surgical debridement in necrotizing pancreatitis have changed during recent years, from an aggressive policy favoring early surgical debridement to a delayed approach in patients who do not respond to conservative treatment. In pancreatic infection, surgery is mandatory and should be performed soon after the diagnosis of infected necrosis has been established. 1,2,7,11 In contrast, patients with sterile pancreatic necrosis and favorable prognostic factors do not require surgical debridement and can be managed conservatively. 3,15,62 Conservative therapy in these patients should be continued as long as the patient responds to it. Ongoing multiorgan failure, despite maximum intensive medical therapy over a period of more than 72h, is accepted as an indication for surgery, regardless of the evidence of pancreatic infection. In sterile necrosis, surgical debridement has to be regarded as a treatment for severe acute pancreatitis rather than as a strategy for the prevention of complications of the disease. In this entity, surgical treatment is indicated only when systemic complications have developed and when intensive care therapy has been without effect for a limited period of time. In contrast, surgical treatment in infected necrosis can be regarded, as least partially, as a strategy for the prevention of severe sepsis, with its life-threatening complications. The rationale in this situation is that removal of the infected material does prevent the further release of vasoactive substances, as well as bacterial endotoxins, from the infected areas, leading to the prevention of systemic sepsis. New approaches to the prevention of severe complications It has been a dogma that, in patients with acute pancreatitis placed on total parenteral nutrition, this leads to enteral mucosal atrophy in critically ill patients and favors bacterial translocation from the gut, 63 and this, in turn, has led to the approach that total enteral nutrition (TEN) via a jejunal feeding tube could have a beneficial effect, with reduction of the infectious and systemic complications of severe acute pancreatitis. The safety of TEN in patients with acute pancreatitis has been demonstrated in experimental models, 64 as well as in clinical series. 65,66 There obviously seems to be a rationale for TEN in severe acute pancreatitis, but the exact benefits of this approach will have to be elucidated in large controlled trials. References 1. Beger HG, Isenmann R (1999) Surgical management of necrotizing pancreatitis. Surg Clin North Am 79: Tsiotos GG, Luque-de Leon E, Söreide JA, Bannon MP, Zietlow SP, Baerga-Varela Y, Sarr MG (1998) Management of necrotizing pancreatitis by repeated operative necrosectomy using a zipper technique. Am J Surg 175: Bradley ELI, Allen K (1991) A prospective longitudinal study of observation versus surgical intervention in the management of necrotizing pancreatitis. Am J Surg 161: Bradley ELI (1993) A clinically based classification system for acute pancreatitis. 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