Preventive strategies for septic complications of acute pancreatitis

Development of infected pancreatic necrosis
Several questions regarding the pathophysiological mechanisms of acute pancreatitis are still obscure and unanswered. In the initial phase of acute pancreatitis, the likelihood to develop pancreatic necrosis is simply unpredictable. We do not know whether the development of pancreatic necrosis is a predetermined process, or a series of random events. Furthermore, we are also unaware of any clinically effective preventive measures - if there is any at all - to prevent or attenuate at least the development of pancreatic necrosis. Current evidence suggests that the incidence of intra- and / or peri-pancreatic necrosis is between 10 to 30%, while bacterial infection occurs in 30 to 40% in patients with pancreatic necrosis. The prognosis of infected pancreatic necrosis is extremely grim; its mortality is still as high as 20 - 30%. However, mortality rate of sterile pancreatic necrosis is significantly better; it remains below 10%.
Infected pancreatic necrosis is an unusual finding in the early phase of the disease, since it takes approximately 2-4 weeks to develop in acute pancreatitis. Given the fact that bacterial infection is caused by Gram-negative strains predominantly, the most likely source of bacterial infection is the gastrointestinal tract. Although numerous experimental data suggest the implication of bacterial translocation from the gut, a clear pathophysiological mechanism has not been described yet. Bacterial translocation is believed to be caused by increased permeability of the gut mucosa and a consequent migration of macromolecules - bacteria, endotoxins, antigens, etc. - from the gastrointestinal tract to the portal system, mesenterial lymph nodes, liver, spleen and pancreas. The above process leads to the stimulation of macrophages and circulatory neutrophil granulocytes; and, in turn, a pro-inflammaroty cytokine release - IL-1, IL-2, IL-6, TNF - will result in an inflammatory response. The imbalanced production of inflammatory mediators can lead to multi-organ failure (MOF), finally.
If the inflammatory response - which is initially part of the defence mechanisms of the host - is over-activated, it may turn into a self-destructive process. Endogenous mediators play a major role in the development of MOF, as opposed to exogenous factors. There is no specific treatment available for MOF, therefore the mortality of MOF is still extremely high, approximately 50 - 70%.
Numerous experimental studies on the pathophysiology of acute pancreatitis demonstrated that various interactive and complex mechanisms will damage the intestinal barrier function finally.
Gram-positive bacteria and fungi have been increasingly detected in the infection of acute pancreatitis (1, 2, 3, 4). Although the exact explanation for this is unknown yet, widespread antibiotic use in acute pancreatitis have been frequently implicated.

Detection of pancreatic necrosis and infection
The gold standard of diagnosis of pancreatic necrosis is the contrast enhanced CT scan. However, none of the diagnostic imaging modalities is able to tell reliably the difference between sterile and infected pancreatic necrosis in the early phase of the disease. "Air bubbles" caused by gas producing bacteria can be seen only in up to 15-20% of the cases.
CT- or ultrasound guided FNA, and its Gram staining or culture has a well-defined role in the diagnostic work-up of necrotising acute pancreatitis. Several papers confirmed that image-guided FNA is reliable and safe with a sensitivity of 90 - 100% and specificity of 100%.
Determination of serum C-reactive protein (CRP) levels is also a reliable and widely accessible diagnostic method to detect pancreatic necrosis, but it can not detect infection. However, procalcitonin - an important indicator of systemic bacterial sepsis - sensitively confirms infection in pancreatic necrosis in numerous clinical studies including our experiments, too.

Treatment of pancreatic necrosis
Surgical treatment options for necrotising acute pancreatitis have been significantly changed in the last decade. For more then 30 years - from the early 1960's - surgical necrosectomy and total debridement were the accepted approaches worldwide, whether or not infection was actually present. Bradley and Allen (5) suggested first conservative treatment of sterile pancreatic necrosis, which was based on the significantly improved survival of their patients. Subsequently, several prospective studies demonstrated a better outcome without necrosectomy in sterile necrosis. Therefore, conservative treatment is regarded as the standard treatment of pancreatic necrosis in the absence of proved infection.
Consequently, recent guidelines of consensus conferences and scientific societies recommended the above therapeutic principles - The American College of Gastroenterology (8), the Santorini Consensus Conference (9), the Bangkok World Congress of Gastroenterology (10) and the International Association of Pancreatology (11), just to name a few. In conclusion, surgical intervention is indicated exclusively in infected pancreatic necrosis. Based on the these principles, it would be a sensible approach to find clinically effective measures to prevent the development of infection in pancrea-tic necrosis, hence numerous studies focus on this subject.

Antibiotic prophylaxis
Antibiotic prophylaxis is one of the most important questions of severe acute pancreatitis. It is generally accepted that antibiotic prophylaxis is indicated only in the presence of pancreatic necrosis. In order to achieve a clinically effective prophylaxis, two conditions should be met. Firstly, antibiotics should cover all pathogens found regularly in infected pancreatic necrosis. In addition, it has to be effective against Gram-positive bacteria, too, which incidence has significantly risen recently. A logical step would be to broaden the preventive measures with concomitant anti-fungal prophylaxis; however, there is no consensus in this regard, because the necessary prospective randomized trials are still awaited (12).
Secondly, adequate pharmacokinetics in the pancreatic tissue is a crucial element of effective antibiotic prophylaxis. Imipenem, kinolons and third generation cephalosporins were shown to meet these criteria, too.
The role of prophylactic antibiotic therapy has been investigated by several studies in the last few years. These trials compared groups of patients with or without prophylactic antibiotic treatment, or antibiotics of different classes or regimens (table 1).
Pederzoli et al. published one of the first studies in 1993, they randomized 74 patients with pancreatic necrosis (13). 300 mg t.d.s. dose of imipenem significantly reduced the development of sepsis from pancreatic as well as non-pancreatic source. However, they could not demonstrate statistically significant difference in mortality, multi-organ failure and indication of surgical intervention.
Sainio et al. observed a significant decrease in the mortality of patients with acute necrotising pancreatitis using intravenous cefuroxim (1.5 g t.d.s.) (14). So far, this is the only study that demonstrated a significant decrease in mortality after antibiotic prophylaxis. However, their results were somewhat conflicting. The data analysis included mortality rate of patients in the early phase of acute pancreatitis, too, which is unlikely to be due to septic complications. If these patients were excluded from the analysis, statistical significance would have not been reached.
Three other studies investigated ofloxacin and metro-nidazole (15), meropenem (16), and a combination of ceftazidim, amikacin és metronidazole (17). None of these studies were able to demonstrate a beneficial effect of antibiotic prophylaxis.
A Danish multi-centric study (18) compared a combination of oral non-absorbable antibiotics and intravenous cefatoxin to patients with no antibiotic treatment. The so-called "selective decontamination" resulted in a significant decrease in pancreatic infection as well as surgical interventions.
The first double-blind placebo controlled trial was published by Isenmann et al. from Ulm, Germany in 2004 (19). 114 patients with severe pancreatitis were randomized in this multi-centric study. A combination of ciprofloxacin (400mg b.d.s.) and metronidazole (500mg b.d.s.) was investigated. Inclusion criteria were anticipated severe acute pancreatitis based on raised CRP levels or pancreatic necrosis demonstrated by contrast enhanced CT scan. In cases of development of progressive organ failure, SIRS, pancreatic or extra-pancreatic bacterial infection, study medication was discontinued and patients were switched to open antibiotic treatment. Altogether, necrosis was proved in 76 cases. The authors could not find significant difference in the rate of mortality or infected necrosis between the two groups of patients. Although significant difference was not demonstrated in patients with proven necrosis, too, more patients from the placebo group required open antibiotic treatment than from the prophylactic antibiotic group (46% vs. 28%). In addition to this, the rate of mortality and infected pancreatic necrosis were strikingly low.
A major argument against the German study published by Isenmann et al., which had a negative result, was that the antibiotics used were not carbapenem derivates. Dellinger et al. investigated the effect of meropenem in a double-blind prospective study. They randomized 100 patients with severe necrotizing pancreatitis in two groups, using placebo only in the control arm (20). Their results - which were presented first on the 45th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy in Washington - are more or less similar to the results of the German study: the rate of infected necrosis in the meropenem group and in the placebo group was 23% and 15%, respectively. Equally, mortality rate was 20% vs. 18%, while surgical interventions were practically the same in the two groups of patients (73% and 74%).
Although a few prospective randomized studies demons-trated a partial benefit for prophylactic antibiotic treatment in acute pancreatitis, the last two studies - both of them were double-blind placebo controlled trials - brought negative results in this regard. Therefore, a radical change might be expected in the view of prophylactic antibiotic use. While the Cochrane database meta-analysis from 2003 (21) showed that sepsis from pancreatic origin as well as the mortality rate statistically significantly decreased by the use of prophylactic antibiotics, this review did not include three studies with negative results published later on (16, 19, 20).
Mazaki et al. recently published a meta-analysis of randomized controlled trials in the British Journal of Surgery (22). Only six of the 328 studies assessed met the strict criteria of meta-analysis. They found that prophylactic antibiotics were not associated with a decreased incidence of infected necrosis (RR: 0,77; p=0,173), mortality (RR: 0,78; p=0,404), non-pancreatic infections (RR: 0,71; p=0,402), and surgical intervention (RR: 0,78; p=0,167). However, a statistically significant reduction in the length of hospital stay was demonstrated (p=0,04). Thus, there is no direct evidence to support the use of prophylactic antibiotics up to January 2007.
In conclusion, the above data suggest that antibiotic prophylaxis might be beneficial in certain patients with severe and / or necrotising pancreatitis. However, numerous multi-centric, controlled and well-powered trials are still necessary to run in the future to determine the exact role of prophylactic antibiotic use in the treatment protocol of acute pancreatitis. The controversy of the debate is mirrored by the confusion in guidelines, some of them support, while other ones oppose prophylactic use of antibiotics. Nevertheless, convincing scientific evidence for or against it - unfortunately - is still not available.
Clinically, the most relevant question is whether or not the use of prophylactic antibiotics is indicated in all cases with proven pancreatic necrosis. It is reasonable to suggest omitting prophylactic antibiotics in patients with proven necrosis who are in relatively good condition and do not have organ failure. In these cases, antibiotic treatment might promote the development of poly-resistant Gram-positive bacterial or fungal sepsis. A sensible approach would be to start antibiotic treatment in certain stages of progressive acute pancreatitis, e.g. in the development of multi-organ failure or SIRS. Carbapenems or new generation kinolons are the first choices of treatment.

Enteral feeding
It has been described for more than a decade ago, that atrophy and increased permeability of the gut mucosa develop as an important side-effect of relatively short-term parenteral feeding, applying for a few days only. Hypomotility of the gut occurs, too, due to the lack of peristaltic stimulation in the absence of oral feeding. Consequently, the stagnant bowel contents in parenteral feeding will result in significant changes in the intestinal microflora, which can be further deteriorated by unnecessary antibiotic treatment or using antibiotics with inadequate spectrum.
Early enteral feeding, however, prevents atrophic changes of the gut mucosa, since the uptake of nutrients in intestinal epithelial cells comes directly from the intestinal lumen. Early enteral feeding also facilitates gut motility, of which frequency can occasionally cause major clinical problems - profuse diarrhoea - due to the hyperosmolarity of the nutrient. The above pathophysiological changes protect against the growth of abnormal intestinal flora, increased gut permeability and the subsequent bacterial translocation.
Enteral feeding is technically simple, and what is more, significantly cheaper than parenteral feeding. Jejunal tube can be introduced under X-ray guidance or endoscopically. While the nasojejunal tube is the most widely applied route for enteral feeding, a nasogastric tube seems to be also a safe and effective method, as it was demonstrated in a study from Glasgow (24).
Enteral feeding, as part of the treatment protocols of acute pancreatitis, has been generally accepted worldwide, because of the results of prospective randomized controlled trials published by numerous groups, including us (25-30). European Society for Clinical Nutrition and Metabolism (ESPEN) published a guideline on nutrition in acute pancreatitis in 2002. This guideline suggests that enteral feeding should be the mainstay of treatment in severe acute pancreatitis and it has practically no contraindication (31). Evidence-based guidelines provided by the Japanese Society of Abdominal Emergency Medicine (JSAEM) suggests - as a grade "B" recommendation - that enteral feeding should be used for all pancreatitis (32).
Safety and efficacy of enteral feeding has been confirmed by various randomized clinical trials since the above guidelines were published (33, 34). In 2004, a meta-analysis published by Marik and Zaloga (35) - based on six prospective randomized trials mentioned above - demons-trated that enteral feeding is associated with significantly lower rate of infections, reduced surgical interventions and a reduced length of hospital stay (table 2).
McClave (who published the first randomized trial on enteral feeding in acute pancreatitis) reviewed clinical studies on jejunal feeding in 2006 (36). From 119 articles analyzed, 27 randomized controlled trials were included in the review. This meta-analysis demonstrated that the use of enteral feeding was associated with a significant reduction in infectious morbidity (RR=0,46; p=0,001), hospital length of stay (p<0,0001), and showed a trend toward reduced organ failure (RR: 0,59; p=0,18). Enteral feeding, however, had no effect on mortality of acute pancreatitis (RR: 0,88; p=0,72).
Parenteral feeding has no demonstrable benefit in either mild or severe acute pancreatitis. The role of parenteral feeding is limited to cases only with severe paralytic ileus when enteral nutrition is restricted. Reduced amount of jejunal feeding is still advised in cases like these to mediate at least part of the positive physiological effects of enteral nutrition on the gut flora and mucosa.
Adding probiotics to enteral nutrients is a promising alternative for the future. Lactic acid producing bacteria were shown to have significant anti-infective and immunomodulatory properties. In addition, they can also prevent pathogenic bacteria to adhere on the gut mucosa via their strong affinity to enterocytes. Their complex bacteriostatic and bactericid effects are mainly due to the production of lactic acid and antimicrobial peptides. Furthermore, lactic acid bacteria enhance the development of gut mucosa through the depletion of ammonia and toxins damaging the mucosal layer. In experimental pancreatitis models, probiotics significantly reduced histopathological changes, septic complications and mortality (37-39).
In clinical studies, the effect of lactic acid producing bacteria in acute pancreatitis has been investigated first in our department (40, 41). Both of our prospective, placebo controlled studies demonstrated a beneficial effect. The use of various symbiotic combinations was associated with a decrease in septic complications, as well as a reduction in late organ failures. Nevertheless, in order to determine the value of this method in the treatment protocol of acute pancreatitis, numerous prospective and well-powered studies are needed in the future.

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