Future avenues

Treatment is still directed mainly towards the complications. Despite constant advances in the understanding of the pathophysiological mechanisms underlying the progression towards regional necrosis and the emergence of local or remote organ damage, the basic triggering event still remains controversial. There is no specific drug that can block premature activation of pancreatic proenzymes. The close interrelation between pathophysiological mechanisms, the complexity of the enzyme cascade activations, and the multiplicity of mediators involved in the inflammatory necrotizing process allow little hope for the development of a single specific agent capable of halting or reversing this amplification once initiated. Nevertheless, potential therapies are being developed that may be useful, if given early, to limit the volume of regional necrosis, prevent early systemic organ damage, reduce the incidence of secondary infection of necrotic areas, and thus improve prognosis.

To date, attempts to neutralize proteases by antienzyme therapy or by replenishing antiproteases with fresh frozen plasma, and treatment aimed at resting the pancreas (glucagon, calcitonin, somatostatin) have failed to produce any consistent and substantial benefit in terms of morbidity and mortality. If the primary pathophysiological event is inhibition of digestive enzyme secretion with secondary localization of digestive zymogens with lysosomal hydrolases inside acinar cells, interventions that restore secretion should be of greater benefit than inhibition of pancreatic exocrine secretion.

Overactivation of leukocytes in the pancreatic area and subsequent release of proinflammatory mediators are increasingly recognized as major determinants of local and remote organ damage. In animal experiments, early inhibition of inflammatory mediators protects against both local and systemic complications. Potential targets and future therapies might include free-radical scavengers, phospholipase inhibitors, lipoxygenase pathway inhibitors, interleukin-1 receptor antagonist, anti-tumor necrosis factor polyclonal antibody or soluble tumor necrosis factor receptors, and interleukin 10 to modulate the local secretion of proinflammatory cytokines.

The other potential therapeutic avenue is the prevention/correction of pancreatic ischemia. Experimental data suggest an early and specific disturbance of the pancreatic microcirculation characterized by low capillary blood flow. This could convert an initially edematous condition into progressive necrosis. Hemodilution with dextran 60/70 appears far more effective than conventional fluid therapy in enhancing regional blood flow and preventing tissue necrosis during the early days of the attack.

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