Study On Influencing Factors Of Post-ERCP Pancreatitis And Exploration Of Pancreatic Duct Stent Material In Short Degradation Period

BACKGROUND AND PURPOSE: Biliary and pancreatic diseases are prevalent in China.And endoscopic retrograde cholangiopancreatography(ERCP)is an important minimally invasive method for the treatment of biliary and pancreatic diseases.The procedure is in line with the concept of natural orifice transluminal endoscopic surgery(NOTES),which has the advantages of less trauma,faster recovery,less pain,and so on.But ERCP also has the risk of complications,post-ERCP pancreatitis(PEP)is the most common clinical complication of ERCP and can be prevented and controlled against its risk factors.The ASGE,ESGE and the domestic ERCP guidelines all discuss the influencing factors of PEP,but the views are not completely unified,and there are still some influencing factors to be clarified.Therefore,further research on the factors influencing the occurrence of PEP and the development of biodegradable pancreatic duct stent materials with short degradation period(5-10 days)around its reliable prevention(placement of pancreatic duct stent)is important to improve the safety of ERCP treatment,reduce complications and avoid repeat endoscopic removal of the stent.METHODS: This study includes two parts.The first part is three related clinical studies to explore the risk factors of ERCP,and the second part is the exploration of pancreatic duct stent materials for a short degradation period:Part one: 1.Collecting the clinical prospective data of 1920 patients with common bile duct stones treated with ERCP included in 15 surgical ERCP endoscopy centers in China,including the First Hospital of Lanzhou University from July 2015 to December 2017,to investigate the clinical characteristics of patients with common bile duct stones combined with periampullary diverticulum(PAD)and perform The clinical characteristics of patients with common bile duct stones combined with periampullary diverticulum(PAD)and the factors affecting difficult cannulation during ERCP treatment were discussed.The impact of difficult cannulation as a risk factor for PEP on the development of PEP in patients with and without PAD after the occurrence of difficult cannulation was further investigated in a subgroup analysis.2.According to the inclusion and exclusion criteria,the clinical data of 3564 patients who first underwent ERCP treatment at the First Hospital of Lanzhou University from January 2012 to December 2017 were retrospectively analyzed and typed according to the Li-Tanaka potbelly PAD typing method proposed by our center and Professor Tanaka of the Second Red Cross Hospital in Kyoto,Japan,to further explore the effect of different types of PAD on the impact of ERCP cannulation difficulty and complications such as PEP,and to compare the guiding effect of different PAD typing methods on ERCP operation difficulty and complications.3.Twelve eligible surgical trainees without any endoscopic experience who attended training at the Surgical Endoscopy Center of the First Hospital of Lanzhou University from July 2016 to July 2019 were included and randomly(1:1)divided into two groups: those who received the ERCP simulator(EMS)training(EMS group,n=6)and those who did not receive EMS training(non-EMS group,n=6).After initial training,the data related to the first 25 original nipple patients operated by each trainee were included in the post-analysis to compare the success rate of cannulation and complications such as PEP of ERCP operation after different training of the trainees,to explore the best training method for the initial trainees,and to further explore the best cannulation training time without increasing PEP by subgroup analysis.Part two: Pre-experiment on the commonly used biodegradable materials of polydioxanone(PPDO),test the p H values of pancreatic juice,bile,gastric juice and different mixtures.And then soaked the stents which were made by PPDO in different digestive fluids to observe the shape and quality of the stent during degradation,and the surface and sectional morphology of the stent by SEM.The developer barium sulfate(PDO-Ba SO4)was added to PPDO to investigate the effect on the degradation period.Based on the current degradable materials(L-propylene ester and ε-caprolactone),the degradable polyurethane is synthesized by segment chain regulation,and the "self-polishing" polyurethane material is further prepared to test the molecular weight and molecular weight distribution,crystallization characteristics,mechanical properties,in vitro degradability and to evaluate whether the material degradation period can be reduced to the expected range.RESULTS: Part one: 1.Of the 1920 patients,228 were diagnosed with PAD,and 1692 patients without PAD.Analysis of factors influencing the occurrence of difficult cannulation in patients with common bile duct stones undergoing ERCP.The results of the multifactorial analysis showed that total bilirubin >30 μmol/L(Odds Ratio,OR=1.31,95% Confidence Interval,CI: 1.06-1.61),number of stones >1(OR1.48,95%CI 1.20-1.84),and combined PAD(OR 1.44,95%CI 1.06-1.95)were independent risk factors for difficult cannulation in patients with common bile duct stones undergoing ERCP.In further analysis,among 1920 patients,the incidence of PEP was 17.271%(81/469)and 8.132%(118/1,451)in 469 patients with difficult cannulation and 1451 patients without difficult cannulation,respectively,and the difference was statistically significant(P<0.05);Among the 1692 patients without PAD,the incidence of PEP was 17.722%(70/395)and 8.250%(107/1297)in 395 patients with difficult cannulation and 1297 patients without difficult cannulation,respectively,and the difference was statistically significant(P<0.05);among the 228 patients with PAD choledocholithiasis,74 had difficult cannulation and 154 had difficult cannulation.The incidence of PEP in 74 patients with difficult cannulation and 154 patients without difficult cannulation was 14.865%(11/74)and 7.143%(11/154),respectively,and the difference between them was not statistically significant(P>0.05).2.Among the Li-Tanaka staging of PAD,the number of type II PAD cases accounted for 67.7%(655/967);type I PAD had the largest diameter and stone diameter(p < 0.001),and endoscopic duodenal papillary sphincterotomy(EST)was performed in only 75.4% of cases(p < 0.001);in difficult stone extraction,mechanical lithotripsy,residual stones,precision,endoscopic duodenal papillary sphincter dilation(EPBD),and operative time were not statistically different(p >0.05).Compared with other PAD subtypes,in the Lobo DN subtype,the rate of difficult cannulation was higher in the intra-diverticular papilla(IDP)than in the para diverticular papilla(JPD)(23.1% vs 10.3%,p=0.002),and the rate of successful cannulation was higher in the IDP(90.8% vs 99.1%,p=0.002)than in the JPD;in the Boix J subtype,the difficult cannulation of the three types of PAD was not(p=0.575),with type II having the highest cannulation success rate(99.5%,p=0.02);among the Li-Tanaka subtypes,type I PAD had the highest difficult cannulation rate(23.1%,p=0.01)and the lowest cannulation success rate(90.8%,p<0.001);type II and type IV had the lowest difficult cannulation rates(10.4% and 8.5%)and The highest cannulation success rates(99.4% and 99.4%)were observed in type II and type IV.There was no statistical difference in PEP,acute cholangitis,and perforation complications among the three PAD staging methods for each type of PAD(p > 0.05).3.Multifactorial analysis of cannulation success showed that EMS training had a significant effect on improving cannulation success(OR 2.10,1.46-3.01,p < 0.001).During the first 6 months after training,the patient cannulation success rate was82.4%(78.3%-86.5%)for trainees in the EMS group compared with 76.0%(71.3%-80.7%)for trainees in the non-EMS group,which was statistically different(p<0.05);within 1 year after training,the cannulation success rate in both groups(86% in the EMS group compared with 82.5% in the non-EMS group p=0.051),and 1year after training,the cannulation success rate in both groups(95.7% in the EMS group compared to 95.6% in the non-EMS group,p=0.96).The area under the curve(area under curve,AUC)of ROC was plotted according to the cannulation time and the incidence of PEP in 300 patients,AUC=0.674,95% CI 0.574-0.775,p=0.003,with a sensitivity of 81.5% and specificity of 56.8% at 13.5 min of cannulation time.When the cannulation time was calculated according to whole minutes,there were 160 cases with cannulation time <14 min,3.13%(5/160)with pancreatitis symptoms,and96.88%(155/160)without pancreatitis symptoms;there were 140 patients with cannulation time ≥14 min,15.71%(22/140)with pancreatitis symptoms and 84.29%(118/140);there was a statistical difference between the two groups(RR5.027,1.956-12.927,p < 0.001).Part two: The degradation degree of PPDO in the digestive juice is pancreatic juice > bile and pancreatic juice > bile.Adding barium sulfate(PPDO-Ba SO4)in PPDO material will not significantly change its degradation period.Biodegradable polyester polyols were prepared by L-propylene ester and ε-caprolactone using hydrophilic polyethylene glycol as the initiator,and then gradually condensed with diisocyanate.The average molecular weight of degradable polyurethane was 18963 and the molecular weight distribution was 2.029,proving that the polyurethane was successfully prepared.Differential scanning calorimetry analysis(DSC)and mechanical test found a fracture strength of 4.8 MPa and good mechanical strength.The fracture elongation is about 20%,which is better than the toughness of polylactic acid(PLA).High molecular weight polyethylene glycol and nano-alumina were introduced into the polyurethane material,and the in vitro degradation was found that the degradable polyurethane film was soaked in p H 7.4 buffer for three days,and the weight loss rate of DPU-2 film was higher than that of DPU-1 film after degradation,which proved that alumina did not promote the degradation of polyurethane,but hydrophilic polyethylene glycol could promote the degradation of polyurethane.After soaking DPU-2 membranes in p H 7.4 buffer in a shaker(37°C,160 rpm)for 3,6,and9 days,the mass loss rate of DPU-2 membranes with 5% of porogenic polyethylene glycol 10000 was higher than that of DPU-2 membranes without polyethylene glycol10000.CONCLUSIONS:Part one: 1.Common bile duct stones combined with PAD,TBil >30 μmol/L,and the number of stones >1 was independent risk factors for difficult cannulation of patients undergoing ERCP;the occurrence of difficult cannulation during ERCP with combined PAD did not increase the occurrence of PEP.The Li-Tanaka typing method has the highest rate of difficult cannulation and the lowest rate of successful cannulation in type I PAD,and the lowest rate of difficult cannulation and the highest rate of successful cannulation in types II and IV.This typing method has good clinical guidance value for the difficulty of cannulation and has a certain reference role for the optimization of the surgical approach.Despite the different rates of difficult cannulation,PAD in different type did not increase the occurrence of PEP.3.Early EMS training by primary trainees without endoscopy experience can shorten the learning curve of ERCP skills and contribute to the risk control of pancreatitis after ERCP.Cannulation >14 minutes by trainees in ERCP training significantly increases the incidence of PEP,therefore,it is recommended that the cannulation time of trainees in ERCP training should be limited to 14 minutes.Part two: A large number of hydrogen bonds in the polyurethane molecular chain can enable the material to obtain good mechanical strength,and the hydrophilicity of polyethylene glycol further promotes the degradation of the material and realizes the pro-degradation of the chemical pathway.Using the principle of "self-polishing",the high molecular weight polyethylene glycol is introduced as the soluble pore-causing agent in the polyurethane material so that it can gradually dissolve or fall off in the weak alkaline solution,and use physical methods to further shorten the degradation period and maintain the required mechanical strength.Mechanical properties evaluation shows that the material toughness is better than the conventional degradable materials.