Bridging the gap or paving the way for uninvited guests?

The early phase of acute pancreatitis is characterized by a systemic inflammatory response that leads to necrosis of the pancreas parenchyma and/or the pancreatic fat tissue in about 20 % of patients [1]. Acute necrotizing pancreatitis (ANP) is commonly associated with pancreatic duct leakage resulting in extensive damage of the parenchyma and duct(s) of the pancreas, which in turn is associated with disconnected duct syndrome and persistent peripancreatic fluid collections [2]; vice versa, leakage of enzymatic active pancreatic fluid into the pancreas parenchyma is also thought to aggravate damage of the pancreas [2]. After 7 – 14 days, the inflammatory response attenuates, and during this late phase the course of disease is now mostly determined by whether or not necrotic tissue becomes infected, which occurs in about 30 % of patients with ANP [3]. Mortality rates in patients with infected ANP are high (30 %), and although recent developments in treatment approaches utilizing minimal invasive drainage strategies have improved outcomes, further progress is much needed [4].

“…compromising the sterility of the pancreatic duct by introducing contaminated materials in patients with ANP alone is apparently sufficient to induce infection.”

In this issue of Endoscopy, Karjula et al. took an original approach to address this problem [5]. Instead of waiting for local complications to occur in patients with ANP, the authors hypothesized that placement of a pancreatic stent early in the course of disease would help to maintain the integrity of the pancreatic duct, and by doing so prevent the complications of pancreatic fluid leakage that would require endoscopic, percutaneous or surgical intervention. The authors performed a randomized controlled trial in Finland in which patients with ANP were randomized to either early placement of a pancreatic duct stent or conservative management.

The trial was prematurely terminated due to a much higher infection rate in the intervention group. Furthermore, the rate of successful placement of a bridging pancreatic stent was low. An important contributing factor was the inability to cannulate the pancreatic duct in over one third of patients, which was mainly due to duodenal edema. In comparison, in a large prospective study examining the role of early endoscopic retrograde cholangiopancreaticography (ERCP) with biliary sphincterotomy in patients with acute biliary pancreatitis, cannulation of the bile duct was successful in 78 % [6]. It is noteworthy that in the latter study, ERCP was performed within 24 hours after presentation, whereas in the study by Karjula et al. the median time to ERCP was 4.6 days. These findings underline that ERCP in patients with acute pancreatitis is technically challenging, but chances of success might be higher early in the course of disease when edema is still minimal.

The other technical challenge was the placement of a stent that “bridged” the pancreatic duct defect. At the time that the study was prematurely terminated, a bridging pancreatic stent, which aimed to prevent pancreatic juice leakage, was placed in only 2 of 11 patients (18.2 %), while in three others only a shorter nonbridging stent could be placed owing to a stenotic duct. Previous studies have shown that the success of placement of a bridging transpapillary pancreatic stent depends on the extent of pancreatic duct disruption, as stent placement was much more successful in those with partial disruption (92 %) than in those with total disruption (20 %) [7]. In the study from Karjula et al., leakage from the pancreatic duct was observed in three out of seven patients and was only partial. Although performing ERCP even earlier in the course of disease might have overcome some of the technical difficulties encountered, an even more important finding in this study is the infectious complications after (attempting) pancreatic duct placement: all five patients with successful stent placement, and two of the other six patients in whom stent placement was attempted, developed infected ANP, bringing the group total to 63.6 % (7/11), which was significantly higher than in the control group (23.1 %). Infection occurred much earlier (24 days) in patients with pancreatic stent placement than in those without (47.5 days), which further supports the notion that the introduction of these pancreatic stents was, at least partly, responsible for the infection [5].

Is this a surprising finding? Concern about infection during endoscopic pancreatic duct procedures in patients with ANP was raised 20 years ago [8]. Kozarek et al. took samples from pancreatic duct stents in 36 patients and these cultures indeed showed the presence of multiple organisms, primarily enteric flora, in all stents [9]. Despite colonization in all patients, only three of the 36 patients developed clinical sepsis. As expected, pancreatic stents in these patients were clogged, but stent obstruction was noted in the majority of patients, and therefore this cannot by itself explain the occurrence of clinical sepsis. The Karjula et al. study teaches us that compromising the sterility of the pancreatic duct by introducing contaminated materials in patients with ANP alone is apparently sufficient to induce infection, which might be attributed to the increased susceptibility to infection of necrotic tissue.

Taken together, the current study by Karjula et al. explored an interesting concept of early intervention in ANP with the aim of preventing serious complications. Unfortunately, early prophylactic placement of a pancreatic duct stent in these patients had a low success rate due to technical difficulties while also leading to secondary infection of necrotic tissue. Therefore, at this moment, we have to focus on avoidance of ANP by means of thorough interrogation of the course of acute pancreatitis, so that adequate treatment can be offered and recurrence avoided. Endoscopic or percutaneous interventions should only be considered after infectious complications have developed and the collection has preferably walled off [10]. In an attempt to improve clinical outcomes in the future, we should focus our efforts on studying how to overcome infectious complications in ANP, such as investigating the role of omega-3 [11]. In those unfortunate cases where an infectious complication occurs, we might have to intervene earlier to improve treatment outcomes, but we await the results of the POINTER trial (ISRCTN33682933) for further insights. This randomized controlled trial evaluates early (< 24 hours) drainage in cases of infected APN compared with the standard care of antibiotic treatment and delayed (> 4 weeks) drainage. For now we have to conclude that in patients with sterile necrotizing pancreatitis, early intervention that aims to maintain pancreatic duct integrity by placing a pancreatic stent does not bridge the gap but instead paves the way for uninvited guests.

• References

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