Application Of Continuous Blood Purification In The Treatment Of MSAP And SAP

Background:Acute pancreatitis is a kind of aseptic inflammation caused by various inducements and pathogenesis,such as activation of trypsin,incarceration of pancreatic bile duct stones,obstruction of pancreatic secretion,etc.The 2012 Atlanta classification standard divides acute pancreatitis into three severity levels(mild acute pancreatitis MAP,moderate severe acute pancreatitis MSAP and severe acute pancreatitis SAP).In the acute phase(<1-2weeks)of severe acute pancreatitis,cytokines,inflammatory mediators,DAMPs and other substances released by cascade amplified systemic inflammatory response(SIRS)lead to complications such as acute lung injury,acute kidney injury,and coagulation dysfunction.The death rate can be as high as 47 percent.With the development of critical care medicine,the mortality of severe acute pancreatitis in the acute phase has decreased to20～30%.However,there are still"bottlenecks"in effective control of SIRS.With the in-depth study on the pathogenesis of severe acute pancreatitis,severe acute pancreatitis can induce the rise of tumor necrosis factorαand interleukinin levels,causing high cytokines,SIRS,shock,in vivo dynamic balance imbalance and organ dysfunction.Therefore,preventing and blocking the occurrence and development of SIRS is the key to the treatment of severe acute pancreatitis.Because of the poor therapeutic effect of single targeted drugs,Some research centers adopted continuous blood purification(CBP)technology,including continuous veno-venous hemofiltration(CVVH),high-volume hemofiltration(HVHF)and pulsed high-volume hemofiltration(PHVHF),to make exploratory and active diagnosis and treatment of MSAP/SAP for the SIRS cascade reaction.In terms of the effect of continuous blood purification,studies have shown thatcontinuous blood purification can remove metabolites,toxins,inflammatory factors and other substances in vivo through convection,diffusion,adsorption and other functions,and also can regulate fluid balance,reduce intra-abdominal pressure,effectively alleviate multi-organ dysfunction,thus reduce mortality and improve clinical prognosis.However,the multi-center(IVOIRE trial)study published by joanne-boyau et al in 2013 showed no evidence that blood purification could reduce 28-day mortality in critically ill patients or benefit early improvement in hemodynamic parameters or organ function.Considering that blood purification itself can cause complications such as bleeding,electrolyte imbalance,and catheter-related infections,the role of CBP in severe acute pancreatitis is not certain.In terms of timing of continuous blood purification,studies have shown that there is a"treatment window"of 48-72h before the acute inflammatory response of severe acute pancreatitis peaks,and the effective treatment time limit is not more than 60 hours from the symptoms of acute pancreatitis.However,some studies have shown that CRP levels peak on the third day of appropriate treatment(the reference point is the start of treatment,not the onset of disease)and then decline gradually.Therefore,the timing and course of blood purification for severe acute pancreatitis related SIRS in many domestic centers are uncertain.Meantime,International guidelines do not recommend CBP for the treatment of severe acute pancreatitis.Based on the above factors,we designed the research direction of this topic.AIM:Main purpose:To analyze the effect of CBP measures on the efficacy and prognosis of MSAP/SAP patients as well as the effect of specific CBP protocols.Secondary purpose:To analyze the average daily cost of hospitalization,changes of APACHEII score fluctuation under CBP treatment and prognostic factors(survival and death)analysis(including age,gender,inducement,APACHEII score at admission,number of organ failure,etc.).Method:1.In the first part of the single-center study on the effect of CBP in the treatment of MSAP/SAP,clinical data of MSAP and SAP patients from December 2015 to March 2019were retrospectively collected,and further screened and grouped according to inclusion criteria and exclusion criteria.According to different group and its subgroups[68 cases in the control group,56 cases in the CBP group,38 cases in the CBP short-term group(4h≤T<8h)and 18 cases in the CBP long-term group(8h≤T≤12h)],the comparative analysis was made between different groups of general data,vital signs,inspection index(serum creatinine,blood urea nitrogen,lactic acid,LDH,CRP,PCT,etc.),duration of SIRS,APACHEII score changes(at admission,1 day,2 day,3 day,4 day,7 day and 14 day),the changes of BUN,case fatality rate,bleeding conditions(including abdominal hemorrhage,gastrointestinal hemorrhage,subarachnoid hemorrhage),infection rate,further minimally invasive or surgical conversion needed,organ function recovery,daily cost of hospitalization,prognosis and risk factors.2.In the second part of the multi-center study on the effect of CBP on the treatment of MSAP/SAP,clinical data of MSAP and SAP patients recorded in the acute pancreatitis database of the national center for clinical medicine of digestive system diseases from December 2015 to December 2018 were retrospectively collected,and further screened and grouped according to inclusion criteria and exclusion criteria.According to different groups(327 cases in the control group,75 cases in the CBP group),the differences in clinical outcomes such as general information,vital signs,SIRS duration,APACHEII score at admission,average daily cost of hospitalization,infection rate,case fatality rate,prognosis and risk factors were compared and analyzed among different groups.3.In the meta-analysis of whether blood purification could reduce the risk of death in MSAP/SAP compared with non-blood purification,relevant literatures were retrieved from Medline,Pubmed,Russian Science Citation Index,Sci ELO Citation Index,Web of Science,and kci-korea Journal Database,and further screened according to the exclusion criteria.To include literature to extract the basic information(the first author,publish time,research period,type,mode of blood purification,blood purification group and the control group of sample size,the age and gender of the study object),survival outcome,before and after treatment for 24h,48h,72h APACHEII scores,72h after treatment of serum creatinine,blood urea nitrogen,the WBC,TNFa,CRP was made to conducted Meta-analysis.Results:Part Ⅰ:a single-center study on the effect of CBP in the treatment of severe acute pancreatitis1.Comparative analysis of Control group and CBP group(1)SIRS remission rate analysis:There was no significant difference in age,gender,inducement and APACHEII score at admission between the two groups(P>0.05).The median remission period of SIRS in the control group and the CBP group was 12(7,16)vs5(3,9)days,respectively.CBP significantly shortened the duration of SIRS(P<0.0001,HR=0.19,95%CI 0.11～0.35).(2)Analysis of CBP scavenging metabolites:The metabolites before and after the CBP survival group were analyzed by t test showed that there were statistically significant differences in serum creatinine,total bilirubin,PCT,CRP at the beginning of CBP treatment and at the end of CBP treatment(P<0.05).This shows that CBP has good clinical value in reducing the metabolites accumulated in MSAP/SAP,alleviating acute renal injury and reducing inflammatory products.(3)Infection rate analysis:The control infection rate was 17.65%(12 cases/68cases),CBP group infection rate was 30.36%(17 cases/56 cases),suggesting that CBP has a tendency to increase infection.Although two groups had no significant difference in infection rates of statistical significance(~2=2.769,P=0.096),but the P value is close to critical value,should be treated with caution..(4)Bleeding analysis:the control hemorrhage rate was 10.3%(7 cases/68 cases),CBP group hemorrhage rate was 17.9%(10 cases/56 cases),no significant difference in the infection rate of the two groups statistically significant(~2=1.485,P=0.223).(5)Case fatality rate analysis:The fatality rate of the control group was 36.76%(25cases/68 cases),and that of the CBP group was 33.93%(19 cases/56 cases).There was no significant difference in the mortality between the two groups(~2=0.108,P=0.743).Median survival was 22 days.(6)Analysis on the rate of minimally invasive intervention or surgical transfer:The result of the progress,among the control group and the CBP group after the initial treatment,which still needs to be further step-up approach invasive intervention or transferred to surgery showed that no need to further operation【50 cases(73.5%)vs 35cases(62.5%)】,endoscopic necrosis tissue debridement via natural cavity【(17 cases(25.0%)vs 18 cases(32.1%)】,laparoscopic peripancreatic necrosis material removal【1case(1.5%)vs 2 cases(3.6%)】and turn surgery【0 cases vs 1 case(1.8%)】.There was no significant difference of statistical significance(~2=3.253,=0.354).(7)Analysis of organ function recovery:patients in the CBP group who recovered from organ failure within 48 hours after CBP treatment were defined as improvement,while those who did not recover defined as no improvement.The patients in the control group who recovered from organ failure within 48h after 2 weeks of conservative treatment were defined as improvement,while those who did not recovered defined as no improvement.There was no significant difference between the control group(15 cases improved,53 cases not improved)and the CBP group(20 cases improved,36 cases not improved)(~2=2.827,P=0.093).(8)The difference between the control group and the CBP group was statistically significant(4419.78±2588.61 yuan/day,5724.16±4120.79 yuan/day,P=0.050)in average hospitalization cost,suggesting that CBP would increase the treatment cost.2.Comparative analysis of CBP short-time group and CBP long-time group(1)Analysis on the effectiveness of improving BUN:The efficacy of short-term group(22 cases effective,16 cases invalid)and long-term group(5 cases were valid,13cases were invalid)was statistically significant(~2=4.44,P=0.035).It suggested that CBP duration of 4-8h may be more conducive to the improvement of the severity of the disease.(2)SIRS duration analysis:The SIRS duration of the CBP short-time group was 5(3,11)d,while that of the CBP long-time group was 7(3,9)d,and the difference between the two groups was not statistically significant(Z=0.440,P=0.660).(3)Infection rate analysis:short-term infection rate was 26.32%(10 cases/38cases),long group infection rate was 38.89%(7 cases/18 cases),no significant difference in the infection rate of the two groups statistically significant(~2=0.913,P=0.339).(4)Bleeding analysis:a short set of hemorrhage rate was 13.16%(5 cases/38cases),CBP group hemorrhage rate was 27.78%(5 cases/18 cases),no significant difference in the infection rate of the two groups statistically significant(~2=0.923,P=0.337).(5)Case fatality rate analysis:the mortality rate of short-term group was 28.95%(11cases/38 cases),and that of long-term group was 44.44%(8 cases/18 cases).There was no significant difference between the two groups(~2=1.309,P=0.253)(6)Analysis on the rate of minimally invasive intervention or surgical transfer:Analysis of the Control group and the CBP group patients after initial treatment,which progress remains to be further step-up minimally invasive approach or turn to surgery,showed that the need to further operation【24 cases(63.2%)vs 11 cases(61.1%)】,percutaneous/stomach and other natural cavity puncture drainage【12 cases(31.6%)vs 6cases(33.3%)】,laparoscopic peripancreatic necrosis material removal of【1case(2.6%)vs1case(5.6%)】and turn surgery【1 case(2.6%)vs 0】,etc.There was no significant difference of statistical significance(~2=1.068,=0.785).3.Analysis of patients’condition fluctuation and prognostic factors under CBP treatmentLogistic regression model was used to analyze the prognosis outcome(survival and death)of MSAP/SAP under CBP treatment,indicating that the APACHEII score at admission(OR=1.326,95%CI 1.087～1.617,P=0.005)and the number of organ failure(OR=3.445,95%CI 1.426～8.323,P=0.006)were important risk factors influencing the prognosis of MSAP/SAP under CBP treatment.Part Ⅱ:A big data study on the effect of CBP on the treatment of MSAP/SAP in multiple centers around the country1.Comparative analysis of Control group and CBP group(1)SIRS remission rate analysis:The median remission period of SIRS in the control survival group and the CBP survival group was 8(5,12)days and 5(3,10)days,respectively,and the difference between the two groups was statistically significant(HR=0.59,95%CI 0.39～0.89,P=0.012).In the subgroup of age<50 years old,the median remission period of SIRS in the control survival group and the CBP survival group was 7(4,15)days and 5(3,7)days,respectively,and the difference between the two groups was statistically significant(P=0.008).In the male subgroup,the median SIRS remission in the control survival group and the CBP survival group was 7(5,14)days and 5(3,8)days,respectively,with statistically significant differences between the two groups(P=0.006).Therefore,the effect of CBP on alleviating the duration of SIRS in a group of men<50years old was significant.(2)There was statistically significant difference between the control group and the CBP group in the average daily hospitalization cost(4107.09±4639.86 yuan/day,6268.06±4666.78yuan/day,P=0.001)(3)Infection rate analysis:The infection rate of the control group was 14.98%(49cases/327 cases),while that of the CBP group was 38.67%(29 cases/75 cases).The difference between the two groups was statistically significant(~2=21.88,P<0.001).CBP may increase the risk of infection with MSAP/SAP.(4)Case fatality rate analysis:The fatality rate of the control group was 21.41%(70cases/327 cases),and that of the CBP group was 32.00%(24 cases/75 cases),with no statistically significant difference between the two groups(~2=3.821,P=0.051).However,the P value is close to the critical value,so the result should be carefully judged.The case fatality rate in the CBP group was higher than that in the control group,which may be related to the increased risk of infection.The median survival was 11 days.2.Prognostic factor analysis under CBP treatmentLogistic regression model was used to analyze the prognosis outcome(survival and death)of MSAP/SAP under CBP treatment,and showed that the APACHEII score at admission(OR=1.169,95%CI 1.021-1.338,P=0.024)and the number of organ failure(OR=3.634,95%CI 1.611～8.198,P=0.002)were important risk factors influencing the prognosis of MSAP and SAP under CBP treatment.Part Ⅲ Meta-analysis on whether blood purification can reduce the mortality risk of MSAP and SAP patients compared with non-blood purification1.Meta-analysis of 13 literatures including prognostic outcomes showed that blood purification significantly reduced MSAP/SAP mortality(RR=0.51,95%CI 0.38～0.67,P<0.001).The meta-analysis results of 12 randomized or prospectively controlled studies showed that HVHF and CVVH could reduce MSAP/SAP mortality(HVHF group vs control group RR=0.57,95%CI 0.37～0.87,P=0.010;CVVH group vs control group RR=0.29,95%CI 0.15～0.53,P<0.001),sensitivity analysis showed robust results.Therefore,blood purification,regardless of HVHF OR CVVH mode,equally improved the prognosis of MSAP/SAP and reduced the risk of death.2.The difference of 72h APACHEII score after treatment was statistically significant(MD=-3.06,95%CI-4.61～-1.51,P=0.0001),and the blood purification in HVHF and CVVH modes could significantly reduce the 72h APACHEII score after treatment(P<0.05).The sensitivity analysis showed that the APACHEII score was stable after 72h of treatment.Therefore,the effect of blood purification with HVHF or CVVH can be more remarkable after 72h treatment.Conclusion:In the first part of this study,the results of the single-center study showed that in addition to effectively reducing the accumulated metabolites in the acute phase,alleviating acute liver and kidney injury,and reducing inflammatory products,CBP could significantly shorten the duration of SIRS,but it would increase the cost of hospitalization to some extent.The median survival was 22 days.CBP short-term group(4h≤T<8h)showed statistically significant difference in improving BUN effectiveness compared with CBP long-term group(8h≤T≤12h)(~2=4.44,P=0.035),indicating that CBP duration of4-8 hours each time may be more conducive to improving the severity of the disease.Bleeding(control group 10.29%vs CBP group 17.86%,P=0.223)The infection rate(control group 17.65%vs CBP group 30.36%,P=0.096)and fatality rate(control group36.76%vs CBP group 33.93%,P=0.743)were not significantly different between the two groups.Control group compared with CBP group through the early positive,but still need to be minimally invasive intervention or surgery showed no significant statistically significant differences(P=0.354).There was no significant difference in organ function recovery after CBP treatment or conservative treatment(~2=2.827,=0.093).The fluctuation of APACHEII score in patients survival and death under CBP treatment indicates that for patients with extremely poor prognosis,CBP is still difficult to reverse the disease trend and prognosis otucome.APACHEII score at admission(OR=1.326,95%CI 1.087～1.617,P=0.005)and the number of organ failure(OR=3.445,95%CI 1.426～8.323,P=0.006)were important risk factors influencing the prognosis of MSAP/SAP under CBP treatment.In the second part of this study,the big data research results of acute pancreatitis in multiple centers across the country showed that CBP can significantly shorten the duration of SIRS,and has a significant effect on alleviating the duration of SIRS in men<50 years old.The median survival was 11 days.CBP may increase the risk of infection in MSAP/SAP(14.98%in control group vs 38.67%in CBP group,P<0.001).The case fatality rate in the CBP group was higher than that in the control group(21.41%in the control group vs 32.00%in the CBP group,P=0.051),which may be associated with an increased risk of infection.APACHEII score at admission(OR=1.169,95%CI 1.021～1.338,P=0.024)and organ failure number(OR=3.634,95%CI 1.611～8.198,P=0.002)were important risk factors influencing the prognosis of MSAP/SAP under CBP treatment.In the third part of this study,a meta-analysis on the influence of blood purification on the prognosis of MSAP/SAP showed that blood purification could significantly reduce the mortality of MSAP/SAP,and both HVHF and CVVH could reduce the mortality of MSAP/SAP.Both the HVHF and CVVH modes of blood purification significantly reduced the 72h APACHEII score after treatment,and the blood purification of HVHF or CVVH showed more effective after 72h of treatment.This study progresses from single-center research to multi-center big data research,and then demonstrates the effects and significance of continuous blood purification in the treatment of MSAP/SAP through evidence-based medicine.The results showed that CBP could effectively reduce the accumulation of cytokines,inflammatory mediators,metabolites and other substances and shorten the duration of SIRS in the treatment of MSAP/SAP.APACHEII score at admission and the number of organ failure are important risk factors for prognosis of MSAP/SAP under CBP treatment.CBP for 4-8hours at a time may be more helpful in improving disease severity.CVVH or HVHF can be applied to the treatment according to the patient’s condition,thus play a certain therapeutic effect and improve the clinical prognosis.