It is essential to understand the pathophysiological response to acute pancreatitis to understand how nutritional support may help patients. The excess mortality of severe acute pancreatitis is associated with the consequences of pancreatic injury rather than the pancreatic damage itself. In contrast to patients with mild disease, those with severe pancreatitis develop a systemic inflammatory response characterized by a flood of pro-inflammatory cytokines , which impairs respiratory, renal and intestinal function resulting in multiple organ failure . This process has been extensively studied in animal models. The initiating factor in the inflammatory cascade is accepted to be an increase in intracellular calcium flux with premature activation of trypsinogen within the pancreas, leading to intracellular proteolysis or 'autophagia' [3, 4].
Figure 5.2 helps illustrate some of what is known to happen in the evolution of multiple organ failure and emphasizes the key role of the intestine in its genesis. Intracellular injury results in the generation of a cascade of pro-inflammatory cytokines such as IL-1^, TNF alpha, IL- 17, IL- 18 via activation of periacinar myofibrocytic NF
kappa B and MAP kinase [5-7]. This in turn stimulates the release of IL- 6 and the cytoattraction of neutrophils, which in turn leads to further cytokine generation. The intense inflammatory response with endothelin-A activation results in the arterial constriction with resultant apoptosis and necrosis affecting not only the pancreas, but also the intestine [8, 9]. Splanchnic and whole body protein catabolism is accelerated . If the inflammation is contained within the pancreatic bed, the disease process would be far less serious. Unfortunately, the cytokines are released into the circulation, and a secondary response commences approximately 48 h later, which leads to the generation of PG-2, thromboxane, LTB-4 and oxygen-derived free radicals within the bronchial and intestinal mucosa leading to cytotoxic injury . The situation is compounded further by the release of proteolytic enzymes such as trypsin, elastase, phospholipase and caspase l into the circulation, which leads to amplification of cell injury within the lung ('2nd hit') and GI tract leading to ARDS, intestinal ischemia, bacterial translocation and the well-recognized systemic inflammatory response syndrome (SIRS) (Fig. 5.2) [12-16]. It is these complications that account for the high mortality rates, which can approach 30-50%, in severe necrotizing pancreatitis.
Despite the accumulating knowledge of the mechanisms involved, there have unfortunately been no major breakthroughs in treatment. The use of antiprotease therapy has been disappointing, and the initial excitement that specific anti-cytokine therapy might prevent the cytokine activation cascade has not been realized on formal testing in the clinical arena . Most of the improvement in mortality can be attributed to better supportive management in the ICU. Knowledge of this pathophysiological response is crucial to our understanding of why feeding patients with acute pancreatitis is so incredibly difficult. The pros and cons of the various nutritional approaches advocated, namely, fasting, PN and enteral feeding, can be summarized as follows:
1. The pro-inflammatory cytokine 'storm' activates proteolysis, resulting in protein catabolism, increasing the demand for protein for tissue repair either from body stores or the diet.
2. Starvation produces 'pancreatic rest' and prevents further trypsinogen activation within the inflammatory mass, but deprives the intestine of luminal nutrition, thus exacerbating the mucosal damage initiated by the acute pancreatitis cytokine response. Furthermore, it results in severe negative nitrogen balance and protein deficiency due to unopposed protein catabolism, thus impairing tissue repair.
3. PN also 'rests the pancreas,' but aggravates the intestinal injury in the same way described for starvation above. It does, however, stem the loss of body protein.
4. Enteral feeding, as currently practiced, aggravates the pancreatic injury by stimulating trypsinogen production, but counteracts the intestinal injury by providing luminal nutrition.
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