Background: Acute pancreatitis is a painful, potentially life-threatening condition of the pancreas with a typically abrupt and unexpected onset and has no specific treatment apart from supportive care and management of its complications as they occur.While recent studies show that acute pancreatitis was responsible for 3,510 deaths and 245,000 hospitalizations in the United States, thus accounting for 0.1%-0.6% of the diagnosis codes in the general population; this disease comprises 2%-3% of the diagnosis codes in the Department of Veterans Affairs system, showing a higher prevalence of acute pancreatitis among veterans. Additionally, proximal limb amputees hospitalized from 1944 to 1945 for service-connected trauma to the extremities and consequently separated for disability when followed for mortality from January 1946 to April 1977 had a 3.8-fold relative risk of developing acute pancreatitis compared with distal amputees along with a statistically increased mortality risk from acute pancreatitis. This suggests that veterans with severe trauma-related disabilities are affected even more often with acute pancreatitis and have a higher mortality from this devastating disease.Hypothesis: The several clinical studies showing a failure of drug therapy in acute pancreatitis and basic science studies proving the simultaneous activation of numerous deleterious signaling pathways in acute pancreatitis made us contemplate an alternate approach to this devastating disease. An in-depth review of the role of hypothermia published in other systems revealed that it slows several of the signaling pathways operant in acute pancreatitis by reducing metabolic demand, ATP (adenosine triphosphate) consumption, cell death, and inflammation. However, since multi-system organ failure (including shock, respiratory failure, and renal failure) contributes significantly to the mortality of acute pancreatitis, and generalized hypothermia compromises precisely the same systems (i.e., cardiac, vascular, renal, and respiratory function), we believe that generalized hypothermia must be avoided. Based on this, we hypothesize that local pancreatic hypothermia induced while avoiding generalized hypothermia would reduce the adverse outcomes of acute pancreatitis by slowing down multiple deleterious cascades activated simultaneously in the pancreas, while not compromising the organ systems that are vital (e.g., lungs, heart) or eliminate the toxins (e.g., renal) involved in initiating or perpetuating the disease.Objective: We propose to study the efficacy of transgastrically induced local pancreatic hypothermia as a therapeutic modality for reducing severity of acute pancreatitis in animal models.Study Design: Based on our in vitro data and published studies suggesting that multiple cell death and inflammatory phenomena may slow by >80% or cease between 23C and 34C, and our success in inducing pancreatic hypothermia (26.5C +/= 1.5C) using a gastric cooling balloon while avoiding generalized hypothermia in vivo, we propose the following study design: (1) Determine the temperature range that slows cell death and inflammatory pathways by .80% in vitro in pancreatic acinar cells, i.e., the cells in which pancreatitis is initiated and which are damaged in pancreatitis. (2) Optimize gastric cooling device placement procedures for safely (e.g., avoiding generalized hypothermia) inducing targeted pancreatic temperatures for a prolonged period. (3) Using these conditions, we will test the efficacy of the device in reducing adverse outcomes of acute pancreatitis using models simulating the human clinical situation.Relevance: This is a rapid, multimodal, and reversible approach for treating acute pancreatitis with potential for therapeutic application to human disease, which currently has no specific therapy. Supporting facts are that temperatures as low as -80C (dry ice) are already induced in the human stomach without such complications as visceral ischemia, generalized hypothermia, or compromise of cardiorespiratory, immune, or renal function and that gastric balloons such as would be used for cooling the pancreas have been left in humans and rats for prolonged periods with a low risk of complications such as gastric outlet obstruction. Moreover, this may benefit our veterans, who as mentioned above are more prone to developing acute pancreatitis than the general population, more so the ones with severe trauma-related disability who are even more prone to developing this devastating disease and succumbing to it.
|Effective start/end date||9/1/12 → 1/7/17|
- Congressionally Directed Medical Research Programs: $1,106,505.00