Effects Of Continuous Regional Arterial Infusion Of Low Molecular Weight Heparin In The Treatment Of 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 syndrome.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.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.On the basis of the encouraging results in animal study,this therapy was applied on patients with severe acute pancreatitis.In this clinical trial,continuous regional infusion of low molecular weight heparin significantly lower the incidence rate of local complication without increased risk of bleeding complications.This thesis could be divided into 4 parts:PART ?:Risk factor of the formation of micro thrombi in the early phase of severe acute pancreatitis and its association with clinical outcomesObjective:Pancreatic microcirculation disturbance and formation of pancreatic micro thrombi is involved in the pathophysiology of sever acute pancreatitis and their development might be associated with intra abdominal pressure.The aim of this study is to observe the D-dimer and intra abdominal pressure levels in the early phase of sever acute pancreatitis and evaluate their association with the severity of the disease.Methods:Patients admitted to our department from Jan 2010 to Feb 2011 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,D-dimer level was tested every day,while measurement of intra abdominal pressure was repeated every 12 hours.The maximum and mean value of all data were 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 mmHg(11.5 to 17.1 mmHg)and D-dimer 680?g/L(440-1210?g/L).Patients who developed multiple organ dysfunction syndrome and pancreatic infection present much higher levels of both D-dimer and intra abdominal pressure.In addition,patients with intra abdominal hypertension present much higher mean D-dimer value during the first 72 hours(1920(1312 to 2275)?g/L vs.751(504 to 1116)?g/L,P<0.05).Conclusion:D-dimer level increased significantly during the early phase of severe acute pancreatitis,suggesting the formation of mircro thrombi and the D-dimer level is associated with patients outcomes.Moreover,increased intra abdominal pressure correlated well with the D-dimer level.PART ? The development and assessment of a new porcine model of severe acute pancreatitis characterized by formation of pancreatic micro thrombiObjective:Traditional animal model of 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 divided into three groups:5%sodium taurocholate+30 mmHg intra abdominal hypertension(IAP30),4%sodium taurocholate+15 mmHg intra abdominal hypertension(IAP15)and 5%sodium taurocholate only(SAP).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 IAP30 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 IAP15 and SAP groups.For serum measurements,IAP30 group also showed higher levels of creatinine and AST,reflecting more sever organ injury(AST,279±33,212±43,200±24,respectively;Cr 314±29,224±29,196±20,respectively P<0.05 for both).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 IAP groups.Conclusion:Intra abdominal hypertension over traditional animal model of severe acute pancreatitis could better simulate the pathophysiology characteristics and reflect the actual clinical course.Parts ? The effects of continuous regional arterial infusion of low molecular weight heparin in a porcine model of severe acute pancreatitisObjective:Pancreatic microcirculation disturbance and cogualtive disorder are common finding in the acute phase of 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(SAP).Heparin therapy was started 2 hours after the induction of severe acute pancreatitis and the dose was 4100U/24h.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 at the end of the experiment(CO,4.0 ± 0.2,3.4 ±0.5,3.2±0.6,respectively,P<0.05).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 severe acute pancreatitis.In addition,more alive pancreatic tissue could be seen in the CRAI group.Parts IV The effects of continuous regional arterial infusion of low molecular weight heparin in patients with severe acute pancreatitis:a randomized controlled trialObjective:Previous studies suggested that anticoagulant therapy could improve the outcome of severe acute pancreatitis,but it is not popularized due to risk of bleeding complications.In this study,we aim to evaluate the effects of continuous regional arterial infusion(CRAI)of low molecular weight heparin(LMWH)with randomized controlled design.Methods:Patients admitted to our department from Sep 2011 to Apr 2013 were considered eligible for the study(within 3 days from the onset of the disease)and then randomly allocated to the intervention group or the control group.Patients in the study group received LMWH 4100/day for 5 consecutive days through CRAI technique.All patients received standard treatment and the outcome and APTT of the two groups were compared.Results:A total of 45 patients with severe acute pancreatitis were involved in this study,21 of which received CRAI therapy.Al 1 patients in the intervention group finished the 5-day therapy without significant bleeding complication.CRAI group patients showed significantly lower rates of pancreatic necrosis(6/21 vs.15/24,P=0.036).The APTT in the two groups showed no difference throughout the treatment period.Conclusion:CRAI of LMWH is effective and safe in the treatment of severe acute pancreatitis,lowering the rates of multiple organ dysfunction syndrome and pancreatic necrosis and improvingthe outcomes.