| Objective:Liver failureremains an important cause of mortality.Artificial liver support system(ALSS)therapy is an available method for patients with liver failure and is a bridge to liver transplantation.An important area of debate at present is the choice of the optimal extracorporeal blood circuit anticoagulation regimen for ALSS therapy.Because of the potential of hemorrhage complications and heparin-induced thrombocytopenia,clinical practice has always been problematic for patients with liver failure receiving heparin anti coagulation,especially those with active bleeding or high-risk bleeding risk.In recent years,regional citrate anticoagulation(RCA)has become the preferred anticoagulation method in continuous renal replacement therapy(CRRT)for critically ill patients with acute kidney injury(AKI).RCA could induce a lower activation of coagulation than both conventional and fractionated heparin,which might contribute to an improvement in the biocompatibility of extracorporeal circulation.A meta-analysis conducted in adult critically ill patients with AKI receiving CRRT finds out that RCA is more efficacious in prolonging circuit life span and reducing the risk of bleeding as compared with HA.Although citrate metabolism is severely impaired and the risk of adverse effects is high in patients with acute liver failure who receive plasma exchange(PE)therapy with frozen plasma containing citrate,patients with liver failure do not loss all of the liver citrate metabolization function and still preserve the ability of metabolizing citrate in the skeletal muscle and kidney cortex.More importantly,three prospective,controlled studies have found that PEtherapy could improve the short-term prognosis of patients with liver failure.Therefore,patients with liver failure still have a certain degree of ability to metabolize citrate.However,the citrate load caused by PE therapy and the tolerability of patients with liver failure have not been well studied,further research is still needed.The application of RCA during PE or plasma absorption(PA)plus PE(PA+PE)therapy might increase citrate load.Whether patients with liver failure could tolerate the citrate load caused by both RCA and PE or PA+PE therapy is uncertain.In addition,the safety and efficacy of RCA during PE or PA+PE therapy for patients with liver failure should be clarified.Different disease severity of liver failure reflects different degrees of liver cell damage,and then patients with liver failure may have different ability of citrate metabolism.This might result in different tolerance to same citrate load.Therefore,the appropriate population and evaluation methods for the safe application of RCA in patients with liver failure should be further studied.In summary,in order to assess the safety and efficacy of RCA during ALSS therapy for patients with liver failure,and determine the appropriate population and evaluation methods for the safe application of RCA,a series of cohorts in patients with acute-on-chronic liver failure(ACLF)treated with PA+PE therapy are to be established.RCA compared with heparin anticoagulation,experimental testing,clinical follow-up and then comprehensive analysis are to be conducted to systematically clarify the following issues:(1)the tolerance to citrate load caused by PE therapy in patients with ACLF treated with PA+PE therapy;(2)the tolerance to citrate load caused by both RCA and PE therapy in patients with ACLF treated with PA+PE therapy,and the safety and efficacy of RCA during PA+PE therapy for patients with ACLF;(3)the appropriate population and evaluation methods for the safe application of RCA in patients.These results would help to explore a new anticoagulation strategy based on "RCA",and provide safe and reliable anti coagulation method for patients with liver failure and active bleeding or high-risk bleeding risk,and thepatients withcontraindications to heparin/low molecular weight heparin.The anticoagulation program would have important clinical significance for the advancing the application of ALSS therapy and improving the prognosis of these patients.Materials and Methods:Part Ⅰ.A study on the tolerance of citrate accumulation due to plasma exchange in patients with liver failure.Patients with ACLF treated with PA+PE therapy with heparin anti coagulation will be enrolled.The demographic data and disease data will be collected.Venous blood samples will be collected to perform experimental tests such as blood biochemistry and blood gas analysis at the time before PE therapy,immediately after PE therapy,1 hour after PE therapy,and the next morning.All patients will be followed up for 3 months to identify the clinical outcome.The level of citrate is evaluated by the value of the ratio of total calcium(Catot)to ionized calcium(Caion),Catot/Caion.Citrate accumulation is defined as Catot/Caion≥2.5.The citrate load,and the risk of citrate accumulation and metabolic disorders caused by PE therapy will be evaluated,and the tolerance to citrate load due to PE therapy in patients with ACLFwill be assessed by analyzing the change trends of citrate,incidence of citrate accumulation,acid-base and electrolytes at different time.Part Ⅱ.A study on the safety and efficacy of RCA during ALSS therapy for patients with liver failure.Patients with ACLF treated with PA+PE therapy will be enrolled to heparin anti coagulation(HA)group and RCA group.The demographic data and disease data will be collected.Venous blood samples will be collected to perform experimental tests such as blood biochemistry and blood gas analysis at the time before PA therapy,at the end of PA therapy(before PE therapy),immediately after PE therapy,2 hour after PE therapy,and the next morning.All patients will be followed up for 3 months to identify the clinical outcome.The level of citrate is evaluated by Catot/Caion.Citrate accumulation is defined as Catot/Caion≥2.5.The tolerance to citrate load caused by both RCA and PE therapy,and the safety of RCA during PA+PE therapy in patients with ACLF will be assessed by comparing the differences of bleeding,alteration of citrate load,incidence of citrate accumulation,electrolyte,and acid-base status,as well as 3-month survival rate between the two groups.The efficacy of RCA during PA+PE therapy in patients with ACLF will be assessed by comparing differences of the function of extracorporeal circulation,the changes of coagulation function,and the successful completion rates between the two groups.Part Ⅲ.A study on the appropriate population for the safe application of RCA in patients treated with ALSS therapy.Patients treated with PA+PE therapy with RCA will be enrolled The demographic data and disease data will be collected.Venous blood sampleswill be collected to perform experimental tests such as blood biochemistry and blood gas analysis at the time before PA therapy,before PE therapy,immediately after PE therapy,2 hour after PE therapy,and the next morning.All patients will be followed up for 3 months to identify the clinical outcome.The level of citrate is evaluated by Catot/Caion.Citrate accumulation is defined as Catot/Caion≥2.5.Longer duration of citrate accumulation(LDCA)is defined as the presence of citrate accumulation 2 hours after RCA-ALSS therapy.Patients will be randomly divided intoderivationand validation cohorts using SPSS software.The predictors for LDCA in the derivation cohort will be analyzed by logistic regression in univariate analysis.For any variables with p≤0.1 in the univariate analysis,the backward stepwise(likelihood ratio)method will be performed in a multivariate analysis.The predictors obtained from the derivation cohort will be then tested in the validation cohort.The predictive modelwill be also tested in the validation cohort.Predictive factors with anAUC>0.750 in the derivation cohort that is equivalent or greaterin the validation cohort will be used to derive the predictive R-CA model.An ordinal grading will be performed for individual parameters by comprehensively considering their cut-off values of AUCs predicting the probability of LDCA,ACLF diagnostic criteria,and clinically significant values.A score will be obtained by combining the individual grade of all the significant parameters.Multiple comparisons of the score with other predictors will be performed by AUCs and the appropriate population for the safe application of RCA in patients treated with ALSS therapy will be assessed by the score.Result:Part Ⅰ.The tolerance of citrate accumulation due to plasma exchange in patients with liver failure.1.Patients’ characteristicsFifty-four patients with ACLF who received PA+PE therapy with heparin anticoagulation were enrolled.Of these patients,the mean age was 50.0±11.3 years old,33 patients had liver cirrhosis.The mean MELD score was elevated to 25±7.The total 3-month survival rate was 57.4%(31/54).2.A lteration of citrateThe mean value of Catot/Caion before PE therapy was 2.05±0.14.The mean values of Catot/Caion immediately after PE therapy and 1 hour after PE therapy were 4.34±1.52 and 2.36±0.32,respectively,which were much higher than that before PE therapy(p<0.01,respectively).These results suggest that PE therapy itself could result in significant citrate load.The citrate accumulation occurred in 100.0%(54/54)and 29.6%(16/54)of patients immediately after PE therapy and 1 hour after PE therapy,respectively,which were much higher than the values before PE therapy(0.0%;p<0.01,respectively).However,all values returned to lower than 2.5 the next morning,which was similar to that before PE therapy(2.10±0.14 vs.2.05±0.14,p>0.05).These results suggest that PE therapy itself could result in transient citrate accumulation in all patients with ACLF,and these patients could metabolize citrate completely.3.A lteration of electrolyte and acid-base statusAll patients had transient hypocalcemia without any manifestations.The main change in acid-base status was mild metabolic alkalosis,not the metabolic acidosis.These results suggest that patients with ACLF could metabolize citrate completely with good tolerance to citrate accumulation due to PE therapy.4.Predictors for citrate accumulationMultivariate analysis revealed that female,baseline lactate and serum sodium were the independent predictors for citrate accumulation at 1 hour after PE therapy.The highest AUC value regarding citrate accumulation was observed for serum lactate(AUC,0.750;95%CI,0.601-0.899).An increase in citrate accumulation at 1 hour after PE was predicted by the presence of baseline levels of plasma lactate greater than or equal to 2.65 mmol/L(sensitivity 62.5%,specificity 84.2%).These results suggest that gender and baseline lactate could be used as predictors for the risk of citrate accumulation in clinical.Part Ⅱ.The safety and efficacy of RCA during ALSS therapy for patients with liver failure.1.Patients’ characteristicsTwenty-four patients with ACLF who received 94 sessions of PA+PE therapy with heparin anti coagulation(HA)and another 28 patients with ACLF who received 106 sessions of PA+PE therapy with RCA were enrolled into the HA group and the RCA group,respectively.There was no difference in age,existing liver cirrhosis,main liver and kidney function parameters,clotting parameters,or MELD scores between the two groups(p>0.05,respectively).2.Safety of RCA(1)Alteration of citrate:The occurrences of citrate accumulation in RCA group were 0.0%,67.0%,100.0%,34.0%,and 0.0%before PA therapy,at the end of PA therapy,immediately after PE therapy,2 hours after PE therapy,and the next morning,while that in HA group were 0.0%,0.0%,100.0%,7.4%,and 0.0%,respectively.The occurrences of citrate accumulation in RCA group at the end of PA therapy and at 2 hours after PE therapy were much higher than that in HA group(67.0%vs.0.0%,p<0.001;34.0%vs.7.4%,p<0.001,respectively).Although the trends of mean Catot/Caion and anion gap in RCA group were much more obvious than that in HA group during and after ALSS therapy(p<0.001,respectively),the values on the next morning were all similar between the two groups(p>0.05,respectively).These results suggest that RCA could further increase the citrate load in patients with ACLF,and the citrate accumulation is still transient.Patients with ACLF could completely metabolize the citrate load caused by both RCA and PE therapy.(2)Alteration of electrolyte and acid-base status:Although the trends of mean Caion and Catotin RCA group were much more obvious than that in HA group during and after ALSS therapy(p<0.001,respectively),the values on the next morning were all similar between the two groups(p>0.05,respectively).No metabolic acidosis was found in either group during or after ALSS therapy.Conversely,a trend of metabolic alkalosis occurred in both groups,but there was no difference between the two groups.These results suggest that patients with ACLF could metabolize citrate completely with good tolerance to citrate accumulation due to RCA and PE therapy.(3)Complications:Of these sessions of ALSS therapy,the occurrence of mean arterial pressure<65mmHg,fever or rash,lip numbness,twitch of calf muscles,and reduction rate of hemoglobin were similar between the two groups(p>0.05,respectively).The rate of hemorrhage probably associated with anti coagulation was similar between the two groups(3.2%in the HA group vs.0.0%in the RCA group,p=0.102).These results suggest that RCA would not increase the risk of ALSS therapy.(4)Outcome:The 3-month survival rates,the length of hospital stay and the occurrence of major complications during hospitalization(infection,hemorrhage,hepatorenal syndrome,and hepatic encephalopathy)were all similar(p>0.05,respectively).These results suggest that RCA would not affect the prognosis of patients.3.Efficacy of RCA(1)Completion of ALSS therapy:Although the mean level of extracorporeal activated partial thromboplastin time in the RCA group was much lower than that in the HA group(122.5 ± 29.3 seconds vs.162.7 ± 27.2 seconds,p<0.001),there were no differences in completion rate of ALSS therapy,suspected clotting of extracorporeal circulation(p>0.05,respectively).These results suggest that RCA could be as effective as HA in maintaining the function of extracorporeal circulation.(2)Therapeutic efficacy:The reduction rates of total bilirubin between the two groups weresimilar(50.2%± 6.7%in HA group vs.48.8%± 6.3%in RCA group;p>0.05).This result suggests that RCA methods would not affect the therapeutic efficacy of ALSS therapy.4.Real-time assessment of citrate accumulationThere were obvious linear regression relationship between the simultaneously measured anion gap,increased anion gap and Catot/Caion(all p<0.001).The area under the receiver operating characteristic curves(AUCs)of simultaneous measured anion gap and increased anion gap in predicting citrate accumulation were 0.897(95%CI:0.876-0.915,p<0.001)and 0.937(95%CI:0.920-0.951,p<0.001),respectively.The AUC of increased anion gap in predicting citrate accumulation was much higher than that of anion gap(Z=4.21,p<0.001).The best cut-off values for anion gap and increased anion gap were 8.2mmol/L and 1.3mmol/L,respectively.The sensitivity,specificity,positive predictive value,and negative predictive value were 76.8%,87.6%,73.9%,and 89.2%for anion gap,and 93.6%,82.2%,70.7%,and 96.6%for increased anion gap,respectively.These results suggest that anion gap and increased anion gap could be used at the bedside as a preliminarily screening but real time method for citrate accumulation("Real-time evaluation"),and there would be less need to wait for Catot,and then calculate Catot/Caion.Part Ⅲ.The appropriate population for the safe application of RCA in patients treated with ALSS therapy.1.Patients’ characteristicsA total of 338 patients were enrolled and randomly divided into a derivation cohort(N=230)and a validation cohort(N=108)with a ratio of 2:1 using SPSS software.There were no significant differences between the two cohorts in gender,age,causes of liver disease,usage of antiviral agents,or laboratory parameters before the initial ALSS therapy(p>0.05,respectively).The Model for End-Stage Liver Disease(MELD)score and the proportion who met the HBV-ACLF criteria were similar in the two cohorts(p>0.05,respectively).The overall rates of longer duration of citrate accumulation(LDCA)were not significantly different between the two cohorts(p>0.05).There were no significant differences in indicators representing that patients received similar RCA,such as intracorporeal Catot before RCA-ALSS therapy,intracorporeal and extracorporeal Caion during RCA-ALSS therapy,and intracorporeal Catot and Caion 2 hours after RCA-ALSS therapy(p>0.05,respectively).2.Development and testing of predictive modelsFour baseline variables were found to be independently associated with LDCA:gender,international normalized ratio of prothrombin time(PT-INR),serum creatinine,and serum chloride.A predictive R-CA model and its simplified R-CA score were developed.AUCs of R-CA model and R-CA score in the derivation cohort were 0.848 and 0.803,and thosein the validation cohort were 0.856 and 0.816,respectively.The expected LDCA rates and observed LDCA rates based on R-CA model in derivation cohort(R2=0.909,p<0.001)matched with that in validation cohort(R2=0.778,p=0.007).The expected LDCA rates and observed LDCA rates based on R-CA score in derivation cohort(R2=0.845,p<0.001)matched that in validation cohort(R2=0.842,p<0.001).These results suggest that the predictive models would have similar and good ability to predict LDCA and could be used to identify high-risk patients who might suffer LDCA.3.Evaluation of predictive modelsas predictors of LDCAR-CA model(AUC=0.848)was found to be superior to MELD score(AUC=0.725;p=0.022)and other univariate predictors(AUCs<0.700;all p<0.001)in predicting LDCA.R-CA score(AUC=0.803)was as capable as R-CA model(p=0.369)and MELD score(p=0.174),and was superior to other univariate predictors(all p<0.05)in predicting LDCA.These results suggest that R-CA score would be a suitable model for predicting LDCA,and it could be used as a "pre-evaluation" indicator.4.Relationship between predictive models and patient’ prognosisR-CA model and R-CA score were positively correlated with disease severity rated by MELD score(all p<0.01),and were independent risk factors for poor prognosis at 28-day and 90-day(all adjusted HR≥1.49,all p<0.001).5.Relationship between LDCA and patient’ prognosisThe MELD score of patients with LDCA was significantly higher than that of patients without LDCA(p<0.001).The crude 28-day and 90-day mortality rates and adjusted mortality rates in patients with LDCA were significantly higher than those of patients without LDCA(all Log-rank p<0.01),respectively.Similar results were found in the subgroup of patients with ACLF,patients with liver cirrhosis,patients with liver cirrhosis and ACLF(all Log-rankp<0.05).6.Appropriate population for RCA:An R-CA score ≤2 had a negative predictive value of 90.2%for LDCA.Patients with R-CA score ≤2 could safely receive PA+PE therapy with RCA.Although the others also had good tolerance to citrate accumulation,they should be under close monitoring during treatment,or switch to other anticoagulation programs.Conclusion:1.Transient citrate accumulation due to PE therapy occurs in all patients with ACLF treated with PA+PE therapy,and it is well tolerated by these patients.RCA could increases citrate load and the incidence of citrate accumulation,but it is also well tolerated by such patients.2.The application of RCA during PA+PE therapy in patients with ACLF is safe,effective and feasible.As a new anticoagulation strategy,the RCA method creates important conditions for patients with active bleeding or high-risk bleeding risk and patients with contraindications to heparin or low-molecular-weight heparin,to obtain timely ALSS therapy and then to improve the prognosis of patients.3.During the PA+PE therapy,the R-CA score established in this study has a good ability to predict whether patients with ACLF would suffer LDCA.Patients with R-CA score ≤2 are the appropriate population who could safely receive PA+PE therapy with RCA.Although the others with R-CA score≥3 could well tolerate PA+PE therapy with RCA,possible complications should be monitored. |
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