A27 Session 8: Gastrointestinal Cryotherapeutic Indications

Background The observations that the pancreas is hyper-metabolic on positron emission tomography during acute pancreatitis (AP), that multiple signaling cascades are activated during AP, and that several pharmacologic approaches tested in patients with AP have been unsuccessful in changing outcomes of the disease; suggest that a multimodal approach deserves consideration. Hypothermia is known to reduce metabolic demand, cell death and inflammation in other disease states; however generalized hypothermia can potentially compromise vital systems. We therefore aimed at learning the temperatures that would significantly slow deleterious signaling in pancreatic acinar cells (in which AP is initiated and which are damaged as a consequence of AP), and also explored approaches to induce pancreatic hypothermia without causing generalized hypothermia. Methods Trypsin, cathepsin B activities and cathepsin B mediated trypsinogen activation to trypsin (TGA) were studied at 37 °C, 23 °C and 4 °C. In a separate set of experiments, pancreatic acinar cells were exposed to agents that induce AP i.e. caerulein (100nM; CER) or the bile salt sodium taurocholate (4 mM; STC), and TGA, up-regulation of mRNA levels of the chemokines CXCL1, 2, cell injury (LDH leakage, propidium iodide uptake) were studied at 37 °C, 34 °C, 31 °C, 28 °C and25 °C in response to the above stimuli. For in vivo studies, a collapsible gastric balloon attached to inflow and outflow tubing was placed in the stomach and perfused with ice cold water. Rectal, pancreas body and tail temperatures were measured. Results While trypsin and cathepsin B activities at 23 °C were respectively 53% and 64% of 37 °C, a temperature of 23 °C reduced cathepsin B mediated TGA to 26% of that at 37 °C. This was equal to the reduction in trypsin activity noted at 4 °C compared to 37 °C. There was a >80% reduction in CER induced TGA, CXCL1, 2 mRNA increase at 28 °C compared to 37 °C. The amount of cell injury induced by CER and STC at 37 °C was reduced by >80% at 34 °C and 31 °C respectively. Therapeutic induction of hypothermia 1 h after exposure to CER or STC required temperatures 3 °C lower than those needed to prophylactically reduce cell injury. Perfusion of the gastric balloon reduced pancreatic, but not rectal temperatures from 37.8±1.1 °C to 26.7±2.8 °C within 1 h, which normalized rapidly on discontinuing cooling. Conclusions Hypothermia slows deleterious signaling in AP by sequentially slowing consecutive step in a synergistic manner, and also by slowing mechanistically distinct pathways which are simultaneously operating in AP. The pancreatic temperatures achieved by transgastric cooling in vivo , are in the range to sufficiently slow deleterious outcomes induced in acinar cells by agents that cause AP. These temperatures can be achieved in vivo without causing generalized hypothermia, and rapidly normalize on cessation of the cooling. Therefore Transgastric pancreatic hypothermia may be a better option than drug therapy in AP, by virtue of its being multimodal, rapid and reversible. Its efficacy in improving outcomes of AP needs to be tested in future studies.