Novel method to prevent severe postoperative pancreatic fistula caused by lipolysis

Although several prophylactic strategies have been developed for postoperative pancreatic fistula (POPF), research on its severe form is few. Recently, it has been reported that severe POPF can be caused by intraabdominal lipolysis. This study aimed to establish a rat model of severe POPF by combining pancreatic juice leakage and lipolysis and to develop a prophylactic strategy for POPF. Sprague-Dawley rats were subjected to pancreatic transection to induce pancreatic juice leakage (PT group). Autologous fat tissue was thermally treated to prepare a fat solution, which was intraperitoneally administered to the rats in the PT group (PT + F group). A water-solubilized lipase inhibitor (cetilistat) was administered intraperitoneally to the rats in the PT + F group. A polyethylene glycol-based hydrogel (PEG-HG) formulation of water-solubilized cetilistat was equally administered. Ascitic and serum biochemical tests, including free fatty acids (FFA) levels, macroscopic or microscopic examinations, and survival analyses, were performed. In the PT + F group, significantly elevated ascitic and serum FFA levels and serum inflammatory cytokine levels were observed 24 h postoperatively (p < .001), and the survival rate was significantly exacerbated (p < .0001). Intraperitoneal administration of water-solubilized cetilistat resulted in reduced inflammation and improved outcomes. Although PEG hydrogel itself did not improve blood parameters or survival outcomes, the incorporation of water-solubilized cetilistat into the PEG-HG enabled similar improvement. Intraperitoneal administration of water-solubilized cetilistat prevented severe inflammation and multiple failures associated with severe POPF. The incorporation of water-solubilized cetilistat into the PEG-HG is a promising delivery system for clinical application.