Only if needed and as minimally as possible. Animal model for post-ERCP pancreatitis: a step in the right direction

Pancreatitis is one of the most common complications following endoscopic retrograde cholangiopancreatography (ERCP). Risk factors for post-ERCP pancreatitis (PEP) have been evaluated in large multicenter population-based studies [1] [2] [3] [4]. Based on current knowledge, the risk factors for PEP are based on a) the person undergoing the procedure, b) the person performing the procedure, and c) the types of interventions carried out. Several studies have also looked at reducing the risk of postprocedural pancreatitis [5]. To date only a few interventions have shown promise. Chemoprevention with a number of agents, such as gabexate, have been shown to be effective in selected studies. However, consistent efficacy has not yet been demonstrated by any individual agent in larger studies, or in most meta-analyses. Nonsteroidal anti-inflammatory agents, the latest contenders, have now been shown to be ineffective in a large randomized trial of high-risk patients [6]. Pancreatic stenting has been shown to have substantial efficacy in high-risk populations, though there is a debate regarding the size, length, duration of stenting, and potential stent-induced injury [7].

ERCP is a common procedure and does carry significantly higher morbidity than other endoscopic procedures currently in use. We have been performing therapeutic ERCP for over 30 years, and it is at least a decade since well-designed studies systematically analyzed the risk factors regarding complications and thus greatly increased our knowledge. Despite these advances in knowledge, there are no validated animal models for studying post-ERCP complications, particularly pancreatitis. Lack of a valid model has hampered our ability to design and study interventions aimed at risk reduction. A few animal studies have been published previously but none were carried out endoscopically to mimic routine clinical situations.

Buscaglia et al. [8] have done an elegant study to evaluate an animal model for PEP and are to be commended for at least doing a proof of concept study. The authors have adopted ”real-world” strategies of endoscopic cannulation, acinarization (most endoscopists try to avoid it), and sphincterotomy, procedures commonly done during ERCP. They also placed stents in the hounds to evaluate the effect of stent placement on PEP. Three control dogs were included in the experiment. Six case dogs were used and all animals underwent ERCP using a standard duodenoscope. Pancreatic duct cannulation was achieved readily in all, and all the animals underwent more complex interventions in a graded fashion. In the first two animals, the pancreatic duct was opacified with or without balloon occlusion to cause acinarization. Dogs 3 and 4 underwent further interventions including balloon occlusion, injection of ursodeoxycholic acid to mimic bile reflux, and pancreatic duct sphincterotomy. Dogs 5 and 6 underwent pancreatic stent placement following pancreatic sphincterotomy, which is what is now an accepted clinical practice aimed at reduction of PEP. Necrosis and inflammatory activity were analyzed at necropsy.

This set of experiments shows interesting results. The amount of ductal opacification/acinarization correlated with the degree of clinical pancreatitis as did the histopathologic correlation of the inflammatory process. The dogs undergoing pancreatic sphincterotomy along with acinarization had the worst degree of necrosis and inflammation. In dogs with stent placement, the degree of necrosis and inflammation was reduced compared with those dogs without stents. The above experiments also show that as the number of pancreatic interventions increased the degree of pancreatic inflammation and necrosis of acini significantly increased. This is consistent with what is known in clinical studies in humans. This set of experiments serves as a proof of principle.

Acinarization of the pancreas has been shown previously to be a significant risk factor in animal studies, though the same has not been shown in multivariate analysis [1] [4] [9] [10] [11]. Recent studies have also shown that the risk of pancreatitis is dependent on the degree of pancreatic duct opacification [12]. In clinical practice, acinarization is commonly avoided. Also, the molecular weight of the contrast agent used has not been shown to make a difference in the incidence of PEP [13]. However, this result does help us to study contrast agents and their effects on pancreatitis and possible factors initiating the inflammatory cascade in the future.

Pancreatic sphincterotomy was shown to increase the risk of PEP in a large study. This could be the result of pancreatic tissue and ductal injury from thermal injury and, possibly at least, a transient blockage of the main pancreatic duct secretions, leading to hypertension and triggering of the inflammatory cascade. Pancreatic stenting is thought to reduce the risk of pancreatitis by allowing drainage of the pancreatic duct at least until the inflammation from ductal injury is reduced. In this set of experiments, the risk of pancreatitis and the histologic criteria for inflammation were worse in those animals undergoing sphincterotomy and, as in earlier clinical studies, the severity of pancreatitis was reduced when a pancreatic stent was placed [2] [14] [15]. This model might help us to study the efficacy of various stent designs, lengths, and diameters, and might possibly help us to understand the risk of stent-induced injury of the pancreatic duct.

Although one could argue that this study included only a small number of animals, and only proves what is already known about PEP from the several clinical studies conducted thus far, it does serve both as proof of principle and to validate an animal model, which should help us at least to plan animal experiments aimed at reducing the risk of pancreatitis. ERCP is a complex procedure and the risk factors are probably an interplay between the patient-related factors and those associated with the nature of the procedure. Although it might be difficult to establish an animal model that replicates patient-related risk factors (including sphincter of Oddi dysfunction, effects of gender, risk of pancreatitis based on prior history of postprocedural pancreatitis), it probably will help us to evaluate strategies aimed at risk reduction. Though late, it is at least a step in the right direction. While we pursue our goal of safe ERCP we should still exercise caution, and carry out ERCP only when needed and perform interventions only as needed - perhaps a minimally invasive ERCP.

Competing interests: None

References

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