Effects Of Continuous Regional Arterial Infusion Of Low Molecular Weight Heparin In The Treatment Of Hyperlipidemic Severe Acute Pancreatitis

Acute pancreatitis is a systemic inflammatory process origined from the pancreas, during which peripancreatic tissue and other end organs could also be involved. Severe acute pancreatitis accounts for 20% of all acute pancreatitis cases characterized by pancreatic necrosis, pancreatic infection and multiple organ dysfunction syndromes. The occurrence of pancreatic necrosis is a determinant factor for the incidence of a series of complications and the ultimate outcome of the patients. The pancreas is supplied by a rich plexus of arteries, derived from multiple branches of the coeliac trunk and superior mesenteric artery. During severe acute pancreatitis, due to systemic inflammation and increased intra abdominal pressure, pancreatic blood supply could be significantly affecting, leading to focal ischemia, microcirculation disturbance, the formation of micro thrombi and coagulative disorder. These pancreatic disturbances are now thought to be the cause of the development of pancreatic necrosis, therefore anticoagulant drugs like heparin and its derivatives have been used for the treatment of severe acute pancreatitis. However, as pancreatitis patients are at high risk of bleeding in the acute phase, peripheral infusion of heparin could potentially result in bleeding complications. With the change of diet structure and lifestyles and higher incidence of hyperlipidemia, obesity and diabetes, there are increasing incidences of hyperlipidemic acute pancreatitis. Comparing to those APs caused by other etiology, the HLAP has some features including younger age, normal or little increasing level of amylase in blood or urine, severe symptom and easy recurrence. The pancreatic microcirculation disorder, which plays an important part in the pathogenesis of HLAP, can lead to the aggravation of HLAP. In this thesis, D-dimer levels and intra-abdominal pressure and their association with the outcomes were observed in patients with severe acute pancreatitis. It is found that both the two parameters significantly increased in the acute phase, especially in patient with unfavorable outcomes. Base on the observational study, we modified the traditional animal model of severe acute pancreatitis(intra-abdominal hypertension was induced on traditional animal model) and comparison between the novel and traditional animal models were made. Using the new animal model, continuous regional arterial infusion technique was applied for the infusion of low molecular weight heparin. This novel therapy significantly improved systemic hemodynamics, inflammatory intensity and pancreatic necrosis. This thesis could be divided into 3 parts: PART I: The association of P-set level and intra- abdominal pressure with the severity of hyperlipidemic severe acute pancreatitis Objective:Pancreatic microcirculation disturbance and formation of pancreatic micro thrombi is involved in the pathophysiology of hyperlipidemic sever acute pancreatitis and their development might be associated with intra-abdominal pressure. The aim of this study is to observe the P-set and intra-abdominal pressure levels in the early phase of hyperlipidemic severe acute pancreatitis and evaluate their association with the severity of the disease. Methods: Patients admitted to our department from Jan 2012 to Feb 2013 aging above 18 were included in this observational study(within 3 days from the onset of the disease). During the first 72 hours after admission, P-set level was tested every day, while measurement of intra-abdominal pressure was repeated every 12 hours. The maximum and mean value of all data was analyzed for the association of with several outcome variables and comparison of these two parameters and traditional predictors was also applied. Results: A total of 50 patients with severe acute pancreatitis were involved in this study. The mean intra-abdominal pressure of all patients during the observational period was 13.1 mm Hg(11.5 to 17.1 mm Hg) and P-set 680μg/L(440-1210μg/L). Patients who developed multiple organ dysfunction syndrome and pancreatic infection present much higher levels of both P-set and intra-abdominal pressure. The two parameters tested in this study could well predict the outcome of hyperlipidemic severe acute pancreatitis patients. Conclusion: Both intra-abdominal pressure and P-set are reliable predictors for the outcome of patients with hyperlipidemic severe acute pancreatitis. The results of this study suggested that coagulative disorders during the acute phase of hyperlipidemic severe acute pancreatitis are associated with intra-abdominal pressure. PART II The development and assessment of a new porcine model of hyperlipidemic severe acute pancreatitis Objective:Traditional animal model of hyperlipidemic severe acute pancreatitis was induced with sodium taurocholate without the initiating factors of pancreatic microcirculation dysfunction and formation of micro thrombi. In the current study, additional intra-abdominal hypertension was applied on the traditional model to better simulate the pathophysiology process of severe acute pancreatitis. Methods: 18 pigs used in this study were feed by high fat forage and then divided into three groups: 5% sodium taurocholate+30 mm Hg intra-abdominal hypertension(HLIAP30), 4% sodium taurocholate+15 mm Hg intra-abdominal hypertension(HLIAP15) and 5% sodium taurocholate only(HLSAP). Hemodynamic recording and blood gas analyses were performed every 3 hours, serum samples were collected at the same time points. At the end of the investigation, pancreas, intestine and lung tissue sample was obtained for pathology study. Results: Animal models were successfully induced in all animals. Most animals in HLIAP30 group died before 15 hours, thus only data of the first 12 hours was presented. After induction, the hemodynamic and blood gas parameter keeps exacerbating rapidly, while no significantly difference could be detected between HLIAP15 and HLSAP groups. For serum measurements, HLIAP30 group also showed higher levels of creatinine and AST, reflecting more severe organ injury. The pathology injury of pancreas was similar among the three groups and micro thrombi could be seen in all three groups although much more severe in the two HLIAP groups. Conclusion: Intra-abdominal hypertension over traditional animal model of hyperlipidemic severe acute pancreatitis could better simulate the pathophysiology characteristics and reflect the actual clinical course. Parts III The effects of continuous regional arterial infusion of low molecular weight heparin in a porcine model of hyperlipidemic severe acute pancreatitis Objective : Pancreatic microcirculation disturbance and cogualtive disorder are common finding in the acute phase of hyperlipidemic severe acute pancreatitis, anticoagulant like heparin is thought to be beneficial in these patients. Due to risk of bleeding, the usage of anticoagulant is limited currently. In this study, we infused low molecular weight heparin(LMWH) with the aid of continuous regional arterial infusion(CRAI) technique in a porcine model severe acute pancreatitis to evaluate its therapeutic effects. Methods: 18 pigs used in this study were divided into three group: CRAI group received LMWH through CRAI, PERI group received LMWH through peripheral route and control group(HLSAP). Heparin therapy was started 2 hours after the induction of severe acute pancreatitis and the dose was 4100U/24 h. Hemodynamic recording and blood gas analyses were performed every 3 hours, serum samples were collected at the same time points. At the end of the investigation, a CT scan was performed and pancreas, intestine and lung tissue sample was obtained for pathology study. Results: All animals survived the investigation. The CRAI group presented no bleeding complication, while gastrointestinal bleeding was observed in two animals in the PERI group. Hemodynamics and systemic oxygenation were significantly improved in the CRAI group. For the CT results, in consistence to the pathology results, the outline of pancreas could only be seen in the CRAI group. Conclusion: CRAI of LMWH could significantly improve hemodynamics and systemic oxygenation in a porcine model of hyperlipidemic severe acute pancreatitis. In addition, more alive pancreatic tissue could be seen in the CRAI group.