| ObjectiveStroke is one of the most serious complications in patients undergoing cardiac surgery.Studies have confirmed that postoperative stroke induced a 3 to 6 fold increased risk of death in patients undergoing cardiac surgery.Previous studies have listed a number of risk factors for stroke,such as advanced age,female gender,history of smoking,atherosclerosis,history of stroke and other coexistent diseases.Tranexamic acid(TXA)has become one of the most commonly anti-fibrinolytic drugs in cardiac surgery since aprotinin was withdrawn.Some studies have shown that TXA increased the risk of stroke.However,others found that TXA was not associated with a higher risk of stroke in patients undergoing coronary-artery surgery.Animal experiments have shown that TXA could enhance thrombus strength,which might increase the risk of thrombosis.However,the results of human studies in vitro did not show any significant difference in fibrinolysis between TXA and control groups.The effect of TXA on perioperative coagulation in vivo studies was not evaluated.Some studies have found that acute normovolemic hemodilution(ANH)could improve the the outcomes of cardiac surgeries,but the effect of ANH on postoperative stroke is still unclear.In view of the above reasons,the effect of TXA on perioperative coagulation and postoperative stroke has not been clearly understood,so further studies are needed.MethodsPart I:A retrospective study was conducted from January 1,2010,to May 31,2015 in 1,803 patients of 18 to 84 years old undergoing cardiac surgery regardless of gender.Patients were divided into TXA group and non-TXA group according to the situation TXA was used or not.We record the main end point of the incidence of stroke.Other end points included in-hospital mortality,seizure,continuous renal replacement therapy,resternotomy for bleeding during hospitalization,time of mechanical ventilation,duration of intensive care unit(ICU)and length of hospital stay(LOS).Multivariate regression analysis and propensity score matching were applied for reducing distortion by confounding factors.Part II:To further investigated the risk factors for postoperative stroke.Data was collectd to December 31,2015 and a total of 2047 adult patients were included in the analysis.The preoperative and intraoperative variables with P<0.2 in univariate analyses were considered as potential independent variables and were entered into Logistic regression model to identify the risk factors for postoperative stroke.The risk factors were graded to develop a practical prognostic scoring index.Part III:A double-blind,randomised,and controlled prospective trial was conducted from January 07,2017 to March 15,2017.A total of 30 patients undergoing cardiac valve or multi-valve surgery were identified and were randomly divided into placebo control group,low TXA dose group and high TXA dose group by 1:1:1.The different effect on coagulation was compared between groups.Coagulation proteins were measured by their plasma levels of prothrombin fragment 1 + 2(F1 + 2),plasminogen activator inhibitor-1(PAI-1),thrombin activatable fibrinolysis inhibitor(TAFI),plasmin-antiplasmin complex(PAP),tissue plasminogen activator(tPA)and thrombomodulin(TM).Coagulation factors were measured at 'baseline' performed before tranexamic acid loading(T1),at 'bolus' performed 5 min after tranexamic acid bolus injection(T2),at 'CPB' performed 5 min after the initiation of CPB(T3),at 'end CPB' performed 5 min before the end of CPB(T4)and at 'protamine' 5 min after protamine administration(T5).Thrombelastography and routine laboratory tests were also applied to monitor perioperative coagulation function.Part IV:A propensity score adjusted study was conducted from January 1,2010,to December 31,2015,in 2,016 patients of 18 to 84 years old undergoing cardiac surgery.Patients were divided into acute normovolemic hemodilution(ANH)group and non-ANH group according to ANH was applied or not.Propensity score matching was used for reducing distortion by confounding factors.A matching ratio of 1:1 was used.We recorded postoperative stroke and other perioperative endpoints.ResultsPart I:Patients were divided into TXA group(n = 578)and non-TXA group(n = 1,225)according to the situation TXA was used or not.Intraoperative TXA administration was associated with postoperative stroke(1.9%vs.0.5%;adjusted OR,4.65;95%CI,1.39 to 15.63;P = 0.013)and prolonged length of hospital stay(adjusted B,1.25;SE,0.60;P?0.038)in patients undergoing cardiac surgery.However,TXA administration was not associated with postoperative mortality(adjusted OR,1.29;95%CI,0.57 to 2.92;P ?0.545),seizure(adjusted OR,1.43;95%CI,0.52 to 3.95;P = 0.495),continuous renal replacement therapy(adjusted OR,1.37;95%CI,0.61 to 3.09;P = 0.442)and resternotomy for postoperative bleeding(adjusted OR,1.26;95%CI,0.45 to 3.56;P =0.657).No difference was found in postoperative ventilation time(adjusted B,-2.71;SE,1.39;P = 0.052)and intensive care unit stay(adjusted B,0.33;SE,0.23;P?0.155).Part ?:Only 1.0%of patients developed postoperative stroke during the study period.Patients were divided into stroke group(n = 21)and non-stroke group(n = 2,017)according to those experienced postoperative stroke or not.Patients with previous history of cerebrovascular disease have a 4.34-fold increased risk of postoperative stroke(OR,4.34;95%CI 1.31-14.31;P = 0.016).Patients with preoperative serum urea nitrogen>5.6 mmol/L were associated with a 6.15-fold increased risk of postoperative stroke(OR,6.15;95%CI 1.69-22.69;P = 0.006).Patients with preoperative platelet count<150×10/mm3 have a 3.18-fold increased risk of postoperative stroke(OR,3.18;95%CI 1.20-8.41;P = 0.020).Previous history of clopidogrel administration was associated with a 5.66-fold(OR,5.66;95%CI 1.38-23.25;P = 0.016)and previous history of TXA administration was associated with a 5.03-fold(OR,5.03;95%CI 1.89-13.84;P = 0.001)increased risk of postoperative stroke.Duration of anesthesia>400 min was associated with a 2.96-fold increased risk of postoperative stroke(OR,2.96;95%CI 1.15-7.64;P = 0.025).The total risk score was 16 points.Two points for preoperative platelet count or duration of anesthesia.Risk factors of three points were listed as following:history of cerebrovascular disease,serum urea nitrogen>5.6 mmol/L and previous history of clopidogrel or TXA administration.The patients were assigned to the following risk level:0-3 point for low risk,4-10 points for intermediate risk and 11-13 points for high risk.The incidence of postoperative stroke was 14.3%when the risk score<3 points and was significantly increased to 85.7%when the risk score was 10 points.Part III:Thrombelastography values and Routine laboratory testing values including fibrinogen level,D-dimers level and so on were similar among groups at any time.The coagulation factors levels were significantly changed with time among the three groups(P<0.05).The concentration of PAI-1,TAFI,F1 + 2 and TM was significantly different among the three groups(P<0.05),but there was no significant difference in concentration of tPA and PAP.The concentration of PAI-1,TAFI and F1 + 2 in the low dose group was significantly lower than that in the control group(P<0.05).Compared with the low dose group,the concentration of TM was significantly increased in the high dose group(P<0.05).There was no significant difference of coagulation factors among groups at any other time points.Part IV:A total of 1,289 patients were identified and divided into two groups:those who received ANH(ANH group,n = 358)and those who did not receive ANH(non-ANH group,n = 931)during the study period.According to the propensity score matching,354 pairs of patients were identified for analysis.Co variate balance of preoperative baseline parameters between the matched pairs was confirmed and there was no significant difference in the two groups(P>0.05).Mild volume ANH administration was significantly associated with decreased intraoperative RBC transfuse rate(8.5%vs.14.4%;P = 0.013)and number of RBC units(P = 0.019),and with decreased postoperative pulmonary infection(6.8 vs.11.3%;P = 0.036)in cardiac surgery.However,no difference was found in postoperative RBC transfusions.Furthermore,there was no significant difference regarding perioperative fresh frozen plasma and platelet concentrates transfusions,and other postoperative outcomes including stroke,mortality,atrial fibrillation,reoperation for postoperative bleeding,acute kidney injury,postoperative ventilation time,length of ICU and hospital stay.ConclusionsThis study showed that postoperative stroke was associated with intraoperative TXA adminstration in patients undergoing cardiac surgery.This study suggests that TXA should be administrated according to clear indications after evaluating the bleeding risks in patients undergoing cardiac surgery.Previous history of cerebrovascular disease,preoperative serum urea nitrogen>5.6 mmol/L,preoperative platelet count<150×103/mm3,use of clopidogrel or TXA,and duration of anesthesia>400 min were independent risk factors of postoperative stroke in patients undergoing cardiac surgery.A prognostic scoring index was established in this study with a total score of 16 points.The patients were assigned to the following risk level:0-3 point for low risk,4-10 points for intermediate risk and 11-13 points for high risk.The incidence of postoperative stroke was 14.3%when the risk score<3 points and was significantly increased to 85.7%when the risk score was 10 points.Both TXA dose regimens and placebo groups did not show a different effect on the activation of fibrinolytic system by monitoring the concentration of tPA and PAP.The anti-fibrinolytic effect of TXA may occur during post-operation.Routine laboratory test and TEG test could not reflect the intraoperative fibrinolytic activity in patients undergoing cardiac valve surgery in two TXA dose regimens and placebo groups.The intraoperative concentration variation of important factors of fibrinolysis system in vivo was not consistent with previous vitro studies.Further studies are needed to investigate the required concentration of TXA in vivo for inhibiting fibrinolysis.Although mild ANH did not seem to reduce postoperative stroke,it was associated with decreased intraoperative RBC transfusion and postoperative pulmonary infection in patients undergoing cardiac surgery. |
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