Acute Pancreatitis: Surgery, Pathophysiology and Probiotic Prophylaxis

Summary Acute pancreatitis is a challenging disease with a clinical course that is often difficult to predict. The severe form with necrosis of pancreatic tissue occurs in 15% of the cases. Mortality increases significantly if intestinal bacteria translocate from the intestine and subsequently infect pancreatic necrosis. Surgical and prophylactic treatment strategies are challenged by complex pathophysiology of the disease and its complications that includes multiple organ systems. Aims of this thesis were to address some key aspects of acute pancreatitis: surgical management, pathophysiology and probiotic prophylaxis. Part I: Surgical management of acute pancreatitis Several surgical techniques are at hand to remove infected pancreatic tissue (Chapter 2): laparotomy and necrosectomy followed by open abdomen strategy (OAS) or by continuous postoperative lavage (CPL), and necrosectomy by minimally invasive procedures (MIPs). In the UMC Utrecht, 38 patients were treated with OAS and 21 with CPL between 1988 and 2001. The CPL group showed significant lower morbidity although the mortality rate was not different from OAS. These results are in line with reports in literature. MIPs seem a very promising concept, with successful small series reported in literature. However, randomized trials comparing surgical techniques are needed to provide evidence for the optimal surgical management of necrotizing acute pancreatitis. An additional surgical challenge in the management of severe acute pancreatitis is colonic pathology (necrosis or perforation) complicating about 15% of the cases (Chapter 3). Retroperitoneal spread of pancreatic enzymes is the major cause of colonic involvement in acute pancreatitis, potentially leading to transmural necrosis and perforation. In general, preoperative radiological investigation can identify an affected colonic segment, but it does not provide the indication for surgical resection. Inspection of the outer aspect of the colon during surgery is unreliable to identify imminent perforation, proven histologically by identification of resected segments with only pericolitis and fat necrosis. However, low threshold resection of an affected colonic segment seems the preferred treatment strategy to prevent potential perforation or additional complications during follow up. Part II: Pathophysiology of acute pancreatitis and bacterial translocation Gallstone disease is a major cause of acute pancreatitis, but the role of bile composition in the pathogenesis of gallstone pancreatitis is unknown. In Chapter 4, the effect of infusion of different model biles in the biliopancreatic duct of rats was assessed histologically. Hydrophobic model biles induced severe acute pancreatitis, whereas hydrophilic model biles did not. Physiological amounts of phospholipids reduced and cholesterol crystals increased severity of hydrophobic model bile induced acute pancreatitis. These results confirm a role of bile composition in biliary pancreatitis. Therefore, modulation of bile abnormalities in symptomatic gallstone patients could potentially reduce their risk of biliary pancreatitis. Bacterial translocation during the course of acute pancreatitis is of major influence to outcome. Animal models have been proven indispensable as a tool to study its pathophysiology, but some major aspects of bacterial translocation remain unclear (Chapter 5). Methodological restrictions of all currently available animal models are likely to be the cause. Many experimental models and techniques interfere with pathophysiological aspects of bacterial translocation during acute pancreatitis (intestinal flora, mucosal barrier function or immune response), complicating interpretation of results. This is partly the reason for the exact origin of translocating bacteria to remain unclear. The colon is often identified as a major source of bacteria causing infectious complications in acute pancreatitis. Hypothetically, removal of the colon by subtotal colectomy prior to acute pancreatitis could therefore improve outcome. In a rat model of acute pancreatitis however, subtotal colectomy resulted in duodenal bacterial overgrowth which correlated significantly with bacterial translocation to the pancreas (Chapter 6). These results do not exclude the colon as the source of translocating bacteria, but do confirm a role for the small bowel. Part III: Prophylactic probiotics to reduce infectious complications during acute pancreatitis Prevention of bacterial translocation will reduce the need for surgical intervention and will reduce mortality. Since prophylactic antibiotics do not improve outcome, prophylactic multispecies probiotics may offer a promising alternative. Advantages of probiotics are the absent risk of multiresistant bacteria, specific targets in pathophysiology and low costs (Chapter 7). A multispecies probiotic mixture Chapter 12 264 265 (Ecologic® 641), composed of bifidobacteria and lactobacilli was specifically designed to target three major aspects of bacterial translocation: 1) small bowel bacterial overgrowth, 2) mucosal barrier failure and 3) immune responses. In a rat model of acute pancreatitis modification of intestinal flora with Ecologic® 641 resulted in reduced pathogen growth in the duodenum and reduced bacterial translocation to blood, spleen, liver and the pancreas. Also, clinical course of the disease was less fulminant and late mortality was reduced in rats receiving probiotics (Chapter 8). In this rat model specific cytokine signatures could be detected which were associated with early mortality or bacteraemia potentially causing late mortality. Modulation of intestinal flora by probiotics resulted in changes in systemic immune responses, and indirectly seemed to reduce late phase immune paralysis (Chapter 9). The effect of the multispecies probiotics on mucosal barrier function was assessed in Chapter 10. In a mouse model of acute pancreatitis, probiotics did not improve mucosal barrier function in the early phase. In the late phase however, probiotics completely prevented acute pancreatitis induced mucosal barrier failure. Strengthening of mucosal barrier function may be a mechanism by which multispecies probiotics reduce infectious complications during acute pancreatitis. Outcome of above described experiments demonstrates favorable effects of probiotics in two different animal models of acute pancreatitis. However, the value of prophylactic multispecies probiotics in patients with predicted severe acute pancreatitis has not yet been confirmed clinically and a number of issues concerning probiotics remain to be addressed (Chapter 11). These include the effect of timing of probiotic treatment, locations and mechanisms of probiotic action, and choice of probiotic strains for specified pathophysiological targets. However, data presented and discussed in this thesis demonstrate that prophylactic multispecies probiotics possess great potential as a future prophylactic treatment strategy in acute pancreatitis.