Effect Of Allogeneic Blood Product Transfusion On Prognosis And Application Of Acute Normovolemic Hemodilution In Cardiac Surgery

Cardiac surgery under cardiopulmonary bypass(CPB)is a primary treatment for heart disease.Recently,1 to 1.25 million cardiac surgeries are performed annually around the world.Cardiac surgery is one of the operations which consumes massive allogeneic blood products,perioperative transfusion during cardiac surgery account for approximately 80%of overval transfusion for all surgical operations,corresponding to10%-20%of the total consumption of blood products in the United States.Previous studies have shown that transfusion of allogeneic blood products will increase the risk of postoperative adverse events.At present,most studies focused on the red blood cell(RBC)transfusion.Most studies indicated that transfusion of allogeneic RBC would increase the risk of mortality and morbidity in a dose-dependent manner,especially the risk of postoperative infection.However,little is known about whether platelet(PLT)and/or fresh frozen plasma(FFP)transfusion would increase the risk of mortality and morbidity in cardiac surgery.This is primarily because RBC is the most commonly used blood product in cardiac surgery,and fewer patients received FFP and PLT transfusion.Besides that,the sample size of most studies was too small to support the analysis of FFP and PLT,respectively,which makes it difficult to determine the impact of single blood product transfusion on the prognosis.Allogeneic blood products are scarce and expensive.How to reduce perioperative allogeneic blood transfusion in patients undergoing cardiac surgery has always been an urgent clinical problem to be solved.Many studies have confirmed that appropriate perioperative blood conservation technic can significantly reduce the risk of mortality and morbidity.Acute normovolemic hemodilution(ANH),as a cost-effective and simple blood conservation technic,has attracted more attention of clinicians in recent years.However,it is still controversial whether ANH can reduce the transfusion of allogeneic blood products and improve the prognosis.In addition,another important argument about the application of ANH in cardiac surgery is the amount of blood collected by ANH,that is,whether a large amount of ANH can achieve more siginificant effect of"blood products conservation".Therefore,we designed the following four studies.PartⅠEffect of allogeneic blood transfusion on prognosis in patients undergoing cardiac surgeryObjectiveTo investigate the effect of transfusion of RBC,FFP and PLT on mortality and morbidity in patients undergoing cardiac surgery under CPBMethodPatients who underwent cardiac surgery with CPB from January 1,2011 to June 30,2017 in West China Hospital of Sichuan University and September 1,2013 to June 30,2017 in the Second Affiliated Hospital of Medical College of Zhejiang University were included in this retrospective study.Firstly,we compared the clinical data and outcomes between patients who received blood produce transfusion and those without any transfusion in the overall patients,we conducted multivariable logistic regression to evaluate the effect of three blood products on outcomes,respectively.Then we use propensity score matching to stratify the patients who transfusing RBC,FFP or PLT respectively,then we used multivariable logistic regression to evaluate the relationship between transfusion of RBC,FFP or PLT and the risk of mortality and infection after cardiac surgery.Finally,we conducted meta analysis for stratified analysis of two study centers.The primary outcome was the incidence of all-cause death in hospital.Secondary outcomes were the incidence of infective complications in hospital,including pulmonary infection,surgical incision infection,catheter-related blood stream infection,and sepsis.ResultsOf total 8238 patients in the study,109(1.3%)died,812(9.9%)developed infection,and 4937(59.9%)received at least one blood product transfusion.Compared with patients who did not transfuse any allogeneic blood products,transfusion of any allogeneic blood products significantly increased the in-hospital all-cause mortality(2.0%vs.0.18%;P<0.001)and the incidence of infective complications(13.3%vs.4.8%;P<0.001).Transfusion of any allogeneic blood products was associated with the risk of mortality in a dose-dependent manner,the risk of mortality increased by 18%、24%and 12%with each unit of RBC,FFP and PLT transfusion(RBC:OR:1.18,95%CI:1.14-1.22;FFP:OR:1.24,95%CI:1.18-1.30;PLT:OR:1.12,95%CI:1.07-1.18).There was also a dose-dependent relationship between the risk of postoperative mortility and infective complications and the total volume of allogeneic blood products.The risk of postoperative mortality(OR:1.88,95%CI:1.70-2.08)and infective complications(OR:1.18,95%CI:1.43-1.57)increased by 88%and 18%with every 3units increase of the total amount of blood products transfusion,respectively.ConclusionsTransfusion of RRC,FFP,or PLT is an independent risk factor of mortality and infection in patients undergoing cardiac surgery under CPB,and the total volume of three blood products increased the risk of adverse outcomes after cardiac surgery in a dose-dependent manner.PartⅡEffect of acute normovolemic hemodilution on perioperative allogeneic blood transfusion and prognosis in patients undergoing cardiac surgery with cardiopulmonary bypassObjectiveTo investigate the relationship between mild ANH,perioperative allogeneic blood products transfusion and complications in patients undergoing cardiac surgery with CPB.MethodPatients who underwent cardiac surgery with CPB from September 1,2013 to September 30,2018 in the Second Affiliated Hospital of Medical College of Zhejiang University were included in this retrospective study.Propensity score matching(1:3)and logistic regression analysis were used to evaluate the effect of small amount of ANH on the risk of all-cause death and complications in hospital.Hemoglobin(Hb)was compared between groups and time points by repeated measurement analysis of variance.Subgroup analysis was performed according to whether the patient’s intraoperative blood loss≥500m L.The withdraw volume of mild ANH refers to body weight(kg)×5～8ml/kg.The primary outcome was the average volume of perioperative RBC transfusion.The secondary outcomes were rate of perioperative RBC transfusion,rate and volume of FFP,PLT transfusion,all-cause mortality in hospital and other complications(including infective complications,severe cardiovascular complications,massive pleural effusion,stroke,cardiac surgery-associated acute kidney injury (CSA-AKI),severe postoperative bleeding(12 h chest drainage>1000 ml),redo surgery).ResultsIn this study,330 patients in the ANH group and 990 patients in the non-ANH group were successfully matched,respectively.The average volume(3.3±5.2 vs.2.2±4.2units/person,P=0.001)and rate(52.5%vs.41.2%,P<0.001)of perioperative RBC transfusion were significantly decreased in patients who received mild ANH,as well as the average volume(430±808 vs.291±608m L/person,P=0.004)and rate(32.1%vs.24.8%,P=0.013)of the perioperative FFP transfusion.However,mild ANH had no significant effect on the PLT transfusion.Logistic regression show that mild ANH can significantly reduce the risk of postoperative low cardiac output syndrome(OR:0.27,95%CI:0.08 0.87,P=0.029)and CSA-AKI(OR:0.77,95%CI:0.60 0.99,P=0.041),when adjusted by RBC transfusion in the multivariate Logistic regression model,mild ANH had no significant effect on the incidence of low cardiac output syndrome(OR:0.31,95%CI:0.09-1.03,P=0.056)ConclusionsApplication of mild ANH in cardiac surgery can reduce the average volume and rate of perioperative and intraoperative RBC and FFP transfusion,but had no significant effect on PLT transfusion.In addition,mild ANH can also reduce the risk of postoperativeCSA-AKI..PartⅢ Safety and feasibility analysis of large volume acute normovolemic hemodilution in patients with moderate-high transfusion risk undergoing cardiac surgery with cardiopulmonary bypassObjective1.To evaluate the safety and feasibility of large volume ANH in patients with moderate-high transfusion risk undergoing cardiac surgery with cardiopulmonary bypass,and to provide reference for the follow-up study.2.Compared with the volume and rate of perioperative blood product transfusion as well as incidence of postoperative complications in patients who received mild ANH,we evaluate whether large volume ANH can further reduce the perioperative allogeneic blood products transfusion in patients with moderate-high transfusion risk undergoing cardiac surgery with cardiopulmonary bypass.MethodPatients with TRUST(Transfusion Risk Understanding Scoring Tool)≥2 undergoing cardiac surgery with CPB in the Second Affiliated Hospital of Medical College of Zhejiang University from May,2019 to April,2020 were included in the prospective study.Based on the retrospective corhot of patients who received mild ANH,we observe the incidence of perioperative allogeneic blood products transfusion and postoperative complications in patients with large volume ANH.The withdraw volume of large volume ANH refers to body weight(kg)×12-15ml/kg.Blood gas analysis、PLT counts and TEG parameters were analyzed by repeated measurement analysis of variance.The primary outcome was the average volume of perioperative RBC transfusion.If the decrease was more than 1 unit compared with the baseline level,it was considered that large volume ANH could further reduce the perioperative transfusion of allogeneic blood products during cardiac surgery.The feasibility is evaluated by three indexs:including the rate of subjects’enrollment;the rate of incomplete ANH;the rate of transfusion outside protocol guidelines.The first 50%of the patients enrolled in the study were analyzed for interim safety.The safety is evaluated by the incidence of all-cause mortality in hospital and other postoperative complications(including serious cardiovascular complications,stroke,pulmonary infection,massive pleural effusion,CSA-AKI,severe postoperative bleeding(12h chest drainage>1000ml),redo surgery).An early termination threshold would be triggered if the rate of postoperative complications was more than twice the baseline data.ResultsIn the study,of total 110 patients were screened,and 74 patients were finally included for analysis,with the enrollment rate of 72.7%.6 patients did not reach the expected ANH withdraw volume(7.5%),and no patients received allogeneic blood products transfusion outside protocol guidelines.In the control group of mild ANH,the average perioperative RBC transfusion volume was 1.5±2.2 units/person,and the rate of transfusion was 41.3%.In this study,a total of 18 patients(24.3%)received perioperative RBC transfusion,and the average volume of perioperative RBC transfusion was 0.5±1.1unit/person.Compared with the patients with mild ANH, perioperative RBC transfusion was reduced by 1 unit per person in patients with large volume ANH,and the rate of transfusion reduced by 17%.The average ANH withdraw volume was 776±127ml,and the average intraoperative blood loss was 300 ml.In the first 50%of patients enrolled in the study(n=36),the incidence of postoperative complications was not more than twice the baseline level.Of overall patients in the study,the incidence of new-onset atrial fibrillation was 12.2%(n=9),acute heart failure was 8.1%(n=6),massive pleural effusion was 1.4%(n=1),CSA-AKI was 33.8%(n=25),severe postoperative bleeding was 8.1%(n=6),redo surgery was 1.4%(n=1),the average ICU stay was 4.0±1.8 days,and the average postoperative hospital stay was 10±7 days.ConclusionsThe aplication of large volume ANH in cardiac surgery with CPB is safe and feasible.Compared with the mild ANH group,large volume ANH can further reduce the volume and rate of perioperative RBC transfusion without increasing the incidence of postoperative complications.PartⅣ Effects of large volume and mild acute normovolemic hemodilution on perioperative allogeneic blood transfusion and prognosis in patients with moderate-high risk of transfusion during cardiac surgery with cardiopulmonary bypassObjectiveA randomized controlled trial was used to investigate whether large volume ANH can further reduce the perioperative allogeneic blood product transfusion in patients moderate-high risk of transfusion during cardiac surgery with CPB,compared with patients who recieves mild ANH.MethodPatients with TRUST(Transfusion Risk Understanding Scoring Tool)≥2 undergoing cardiac surgery with CPB in the Second Affiliated Hospital of Medical College of Zhejiang University from May,2020 to Janaury,2020 were included in the prospective study.The patients were randomly divided into two groups with the ratio of 1:1:mild ANH and large volume ANH.In this study,the participants and researcher for outcome evaluating were blinded and followed up for postoperative 90 days.Blood gas analysis、 PLT counts and TEG parameters were analyzed by repeated measurement analysis of variance.Correlation analysis was used to evaluate the relationship between TEG results and postoperative 12 h drainage volume in patients with severe postoperative bleeding.Multiple linear regression was used to evaluate the relationship between the ANH withdraw volume and the perioperative RBC transfusion volume,and mitilple Logistic regression was used to evaluate the effect of large volume ANH on perioperative RBC transfusion.The primary outcome was perioperative average RBC transfusion volume.The secondary outcomes were the rate of perioperative RBC transfusion,the rate and average volume of FFP,PLT transfusion,90-day all-cause mortality and other complications(including new onset atrial fibrillation,acute heart failure,pulmonary infection,massive pleural effusion,surgical incision infection, CSA-AKI,stroke,severe postoperative bleeding(12h chest drainage>1000ml),redo surgery).ResultsOf total 159 patients were screened and 110 patients were finally included for analysis,mild ANH group and large volume ANH group included 55 participants,respectively. 36 patients(32.7%)received RBC transfusion,with an average transfusion volume of0.8 unit/person.Compared with mild ANH group,large volume ANH can further reduce the average perioperative RBC transfusion volume(0.4±0.8 vs.1.2±2.0 unit/person,P=0.005)and the rate of transfusion(23.6%vs.41.8%,P=0.042).There was no significant difference in the rate and average volume of FFP and PLT between the two groups.The incidence of severe postoperative bleeding in large ANH group was significantly lower than that mild ANH group(3.6%vs.18.2%,P=0.029).The ANH withdraw volume(adjusted standard beta:-0.242,P=0.002)and Hb concentration of the postoperative 1 day(adjusted standard beta:-0.359,P<0.001)were negatively correlated with perioperative RBC transfusion volume,while preoperative stroke (adjusted standard beta:0.198,P=0.017)and ASA class(adjusted standard beta:0.193,P=0.021)were positively correlated with perioperative RBC transfusion volume. When ANH withdraw volume was added to the linear regression model established by the risk factors related to allogeneic blood transfusion,the R~2 of the regression model for the variation of the dependent variable increased by about 5%to 36%.Multivariate logistic regression showed that large volume ANH in cardiac surgery could significantly reduced the rate of perioperative RBC transfusion(OR:0.37,95%CI:0.15-0.89, P=0.026).ConclusionsCompared with mild ANH group,large volume ANH during cardiac surgery can further reduce the rate and average volume o perioperative RBC transfusion,and the volume of RBC transfusion decreased with ANH withdraw volume increased.Compared with mild ANH,the risk of perioperative RBC transfusion decreased 53%in patients who undergoing large volume ANH,and the effect persisted after adjusted by other blood products transfusion.In addition,we also found that patients who performed large volume ANH during cardiac surgery had a lower incidence of postoperative severe bleeding,which provided evidence to support the application of large volume ANH in cardiac surgery,but the study of larger sample size is needed for further confirming the conclusion.