Efficacy of epsilon-aminocaproic acid in children undergoing cardiac surgery.

OBJECTIVE: To compare coagulation test results, blood loss, and blood product transfusions between patients receiving prophylactic epsilon-aminocaproic acid (EACA) and a control group matched for age, resternotomy, and surgery in children undergoing cardiac surgery. DESIGN: Nested case-control study. SETTING: University-affiliated, pediatric medical center. PARTICIPANTS: Same study period; 70 patients in EACA group and 70 patients in control group. INTERVENTIONS: Prophylactic EACA administered intravenously (load, 150 mg/kg, infusion; 30 mg/kg/h) to 70 patients at increased risk for bleeding (reoperation or Ross procedure). MEASUREMENTS AND MAIN RESULTS: Coagulation test values were measured before, during, and after cardiopulmonary bypass (CPB). Intraoperative blood loss, postoperative chest tube output, and allogenic blood product transfusions were recorded. Comparison of demographic and surgical data indicated close matching of the EACA and control groups. The EACA group ([median, 25th to 75th quartile] 15.6 mL/kg; 9.2 to 26.3 mL/kg) had less intraoperative blood loss than the control group (22.2 mL/kg; 14.3 to 36.3 mL/kg; p = 0.02). Postoperative chest tube output at 6 hours (p = 0.08), 12 hours (p = 0.07), and 24 hours (p = 0.08) was not significantly different between groups. Fewer EACA group patients required reexploration for bleeding (p < 0.05). There was no difference between groups in blood products transfused (in milliliters per kilogram or allogenic exposure per patient). Thromboelastography values (maximum amplitude [MA], whole blood clot lysis index at 30 minutes after MA) during CPB were better preserved in the EACA group. CONCLUSION: EACA reduced intraoperative blood loss but did not significantly decrease blood product transfusions. Lack of efficacy may be related to relative underdosing and should be further studied.     

Pharmacokinetics of epsilon-aminocaproic acid in patients undergoing aortocoronary bypass surgery.

BACKGROUND: Epsilon-aminocaproic acid (EACA) is commonly infused during cardiac surgery using empiric dosing schemes. The authors developed a pharmacokinetic model for EACA elimination in surgical patients, tested whether adjustments for cardiopulmonary bypass (CPB) would improve the model, and then used the model to develop an EACA dosing schedule that would yield nearly constant EACA blood concentrations. METHODS: Consenting patients undergoing elective coronary artery surgery received one of two loading doses of EACA, 30 mg/kg (group I, n = 7) or 100 mg/kg (group II, n = 6) after CPB, or (group III) a 100 mg/kg loading dose before CPB and a 10 mg x kg(-1) x h(-1) maintenance infusion continued for 4 h during and after CPB (n = 7). Two patients with renal failure received EACA in the manner of group III. Blood concentrations of EACA, measured by high-performance liquid chromatography, were subjected to mixed-effects pharmacokinetic modeling. RESULTS: The EACA concentration data were best fit by a model with two compartments and corrections for CPB. The elimination rate constant k10 fell from 0.011 before CPB to 0.0006 during CPB, returning to 0.011 after CPB. V1 increased 3.8 l with CPB and remained at that value thereafter. Cl1 varied from 0.08 l/min before CPB to 0.007 l/min during CPB and 0.13 l/min after CPB. Cl2 increased from 0.09 l/min before CPB to 0.14 l/min during and after CPB. Two patients with renal failure demonstrated markedly reduced clearance. Using their model, the authors predict that an EACA loading infusion of 50 mg/kg given over 20 min and a maintenance infusion of 25 mg x kg(-1) x h(-1) would maintain a nearly constant target concentration of 260 microg/ml. CONCLUSIONS: EACA clearance declines and volume of distribution increases during CPB. The authors' model predicts that more stable perioperative EACA concentrations would be obtained with a smaller loading dose (50 mg/kg given over 20 min) and a more rapid maintenance infusion (25 mg x kg(-1) x h(-1)) than are typically employed.     

Variability of plasma aprotinin concentrations in pediatric patients undergoing cardiac surgery

OBJECTIVES: Infants and children undergoing cardiopulmonary bypass for repair of congenital heart defects are at substantial risk for excessive bleeding, contributing greatly to morbidity and mortality. Aprotinin significantly reduces bleeding and transfusion requirements in adults but is of indeterminate value for pediatric patients. The aim of this study was to determine plasma aprotinin concentrations in these patients with a functional aprotinin assay. METHODS: Thirty patients less than 16 years of age scheduled for cardiac surgery with aprotinin were enrolled. Aprotinin was administered as a 25,000 KIU/kg bolus, 35,000 KIU/kg cardiopulmonary bypass prime, and 12,500 KIU.kg(-1).h(-1) continuous infusion. Blood samples for aprotinin concentrations (kallikrein-inhibiting units/milliliter) were obtained before aprotinin; 5 minutes post-bolus; 5 minutes after cardiopulmonary bypass initiation; 30 and 60 minutes on cardiopulmonary bypass; on discontinuation of aprotinin; 1 hour after aprotinin discontinuation; and 4 hours after permanent separation from cardiopulmonary bypass. For analysis, patients were grouped according to weight (<10 kg, 10-20 kg, >20 kg). Differences between weight groups were assessed using an exact test for categoric variables and 1-way analysis of variance for continuous variables. RESULTS: Aprotinin concentrations differed significantly across weight groups. Five minutes after aprotinin bolus and initiation of cardiopulmonary bypass, there was significant correlation between weight and aprotinin concentration (r =.57, P =.003; r =.69, P =.001, respectively). CONCLUSION: A functional assay reveals significant variability in aprotinin concentration for pediatric patients using current weight-based aprotinin dosing. Additional investigation is necessary to determine target aprotinin concentration dosing regimens to provide better efficacy.     

抑肽酶对瓣膜置换术患者心肌粘附分子表达及细胞凋亡的影响

目的探讨抑肽酶对二尖瓣置换术患者围体外循环（CPB）期心肌细胞及心肌血管内皮细胞上细胞间粘附分子-1（ICAM-1）、血管细胞粘附分子-1（VCAM-1）表达及心肌细胞凋亡的影响。方法择期二尖瓣置换术患者30例,年龄24～59岁,体重46～73 kg,心功能分级Ⅱ级或Ⅲ级,随机分为2组（n=15）：对照组和抑肽酶组,抑肽酶组于CPB转机前,预充液中加入抑肽酶300万KIU,对照组则给予等容量生理盐水,分别于CPB前和CPB停止时取右心房心肌组织标本,采用免疫组织化学SP法染色,检测心肌细胞和心肌血管内皮细胞上ICAM-1、VCAM-1的表达,采用病理图像分析系统对ICAM-1、VCAM-1表达的灰度值作定量分析,采用TUNEL法检测凋亡心肌细胞。结果抑肽酶组CPB停止时ICAM-1、VCAM-1的表达低于对照组（P〈0.01）;2组CPB停止时心肌细胞凋亡指数较CPB前增高（P〈0.05）,抑肽酶组CPB停止时心肌细胞凋亡指数低于对照组（P〈0.05）。结论预充液中加入抑肽酶300万KIU可抑制二尖瓣置换术患者CPB期间心肌细胞和心肌血管内皮细胞ICAM-1、VCAM-1的表达及心肌细胞的凋亡。     

氨基己酸对体外循环下心脏直视手术患者纤溶系统的影响

目的探讨氨基己酸对体外循环(CPB)下心脏直视手术患者纤溶系统的影响。方法40例心脏直视手术患者随机分为二组:氨基己酸组(A组)和对照组(B组),每组20例。A组在CPB 预充液中单次加入氨基己酸200 mg/kg,B组在CPB预充液中加入等量生理盐水。分别于切皮前即刻(T0)、CPB 8min(T1)、30min(T2)、鱼精蛋白中和肝素后10min(T3)、术后2 h(T4)时采集静脉血,测定血浆组织型纤溶酶原激活物(t-PA)、纤溶酶原激活物抑制剂(PAI)、纤溶酶(Plm)活性及D-二聚体(D- dimer)浓度,同时记录术后24 h内出血量及输库血量。结果与T0比较,B组血浆t-PA、t-PA/PAI活性在T1-3、Plm活性在T1,2、D-dimer浓度在T1-4时升高(P<0.05或0.01)。与B组比较,A组血浆t-PA活性、t-PA/PAI在T1-3、Plm活性在,T1,3、D-dimer浓度在T2-4时降低(P<0.05或0.01)。术后24 h出血量及输库血量A组少于B组(P<0.05)。结论CPB可激活纤溶系统;氨基己酸可抑制CPB引起的纤溶系统激活,减少术后出血和输库血量。     

Comparison of the effects of epsilon-aminocaproic acid and aprotinin on intra- and postoperative bleeding in heart surgery]

Excessive bleeding during and after cardiac surgery with cardiopulmonary bypass is a real problem in this kind of surgery. The use of prophylactic high doses of aprotinin (APROT) reduces blood loss in this context but this treatment is expensive. Some investigators have advocated that epsilon-aminocaproic acid (EACA), a cheaper antifibrinolytic drug, could reduce blood loss in cardiac surgery. The goal of this prospective study was to determine if EACA is as effective as APROT for this clinical condition. Sixty patients undergoing elective surgery for cardiac disease were randomly allocated to one of the two groups. Drugs were administered after induction of anesthesia at a dose of 2.10(6) UIK in the APROT group or 5 g in the EACA group. The same dose was added to the priming of the cardiopulmonary bypass circuit. Until the skin closure the patients received 5.10(5) UIK/h of APROT or 2 g/h of EACA. Bleeding during and after surgery was not different between the two groups. No complication, directly due to the treatment administered, was observed. EACA seems to be as effective as APROT to reduce intra and post cardiac surgery blood loss. EACA has the advantage of being cheaper (treatment is approximately 200 times cheaper), therefore allowing a wider use.     

Increased recombinant activated factor VII use and need for surgical reexploration following a switch from aprotinin to epsilon-aminocaproic acid in infant cardiac surgery

Study ObjectiveTo evaluate whether conversion from aprotinin to epsilon-aminocaproic acid (EACA) during infant cardiac surgery was associated with increased perioperative bleeding.DesignStructured retrospective chart review.SettingUniversity-affiliated large congenital cardiac surgery program.MeasurementsRecords from 145 infants (age < 1 yr) receiving aprotinin as antifibrinolytic therapy for cardiac surgery between 6/1/2006 and 12/31/2006 were compared with a cohort of infants receiving EACA for cardiac surgery between 6/1/2008 and 12/31/2008. Sixty-eight infants received aprotinin and 77 infants received EACA. Measured indicators of perioperative bleeding included transfusion volumes, recombinant activated clotting factor VIIa (rFVIIa) administration, need for reexploration, and perioperative chest tube output.Main ResultsEACA treated patients received significantly more rFVIIa for uncontrolled bleeding (19/77 [25%] vs 3/68 [4%]; P < 0.001) and required surgical reexploration more frequently (21/77 [27%] vs 7/68 [10%]; P = 0.01]. Median (25th-75th percentiles) intraoperative platelet transfusion requirements were also increased after the switch to EACA (28 mL [0-58 mL] vs 0 mL [0 mL - 34.5 mL]), but this difference did not reach statistical significance (P = 0.06).ConclusionsBleeding in infant cardiac surgery increased following the change in antifibrinolytic therapy from aprotinin to EACA. Given the potential for major harm, especially thrombotic complications, from rFVIIa use, prospective studies examining the safety of postcardiopulmonary bypass rFVIIa administration in infants are necessary before the routine off-label use may be recommended.     

Co-administration of aprotinin and epsilon-aminocaproic acid during cardiopulmonary bypass in a swine model

Despite the beneficial effects of pharmacological interventions to prevent bleeding and to reduce the need for autogeneic blood, there are concerns that these agents induce a prothrombotic state. The purpose of this study was to examine the coagulation phenomena influenced by the coadministration of epsilon-aminocaproic acid (EACA) and aprotinin during cardiopulmonary bypass (CPB). A swine model of CPB was utilized in this study. During 120 min of CPB, treatment animals (N = 5) received 6 x 10(6) Kiu of aprotinin and 30 grams of EACA; whereas, control animals (N = 3) received an equal volume of 0.9% saline. Indices of thrombogenicity included hematological variables, gross pathology, and circuit examination for the presence of thrombus. The application of both antifibrinolytics resulted in an increase use of heparin. Total heparin requirements were significantly different between treatment group (58,800 +/- 3493 iu) versus control group (51,000 +/- 3464 iu). D-dimer concentration was also significantly higher in the control group (500-1000 ng mL-1) than in the treatment group (250-500 ng mL-1) at 5 and 30 min postprotamine. Other coagulation markers tested were not observed to be statistically significant between groups. Thromboelastographic (TEG) index decreased in the treatment group during the surgical procedure and bypass from 2.74 +/- 2.9 to -1.36 +/- 4.1 as compared to an increase from 2.62 +/- 2.9 to 4.05 +/- 0.4 in the control group. Pathologic analysis revealed occurrences of thrombus formation in small vessels in the lung and kidney glomeruli of treatment animals. The concurrent use of both aprotinin and EACA may induce a prothrombotic or coagulant state as determined by histological assessment.     

抑肽酶与止血芳酸对风湿性心脏病换瓣病人凝血及血小板功能的影响

目的 比较抑肽酶与止血芳酸用于风湿性心脏病换瓣病人对凝血及血小极的影响。方法 30例择期换瓣手术病人随机分为抑肽酶(AP)组和止血芳酸(TA)组(n=15)。两组药物分别于肝素化前静脉输注和体外循环液预充,AP组抑肽酶2.5×106KIU,TA组止血芳酸10 mg/Kg。测激活凝血时间(ACT)、激活全血凝固时间(SonACT)、血凝斜率、峰值时间、峰值最大血凝信号(MCS)并计算血小板斜率。测定血细胞压积(Hct)、术后血红蛋白(Hb)及血小板计数(Plt)。随访术后胸液量和全血及新鲜冻血浆(FFP)的用量。结果 与基础值比较,给药后AP使ACT、SonACT及峰值时间明显延长(分别P<0.05、P<0.01及P<0.01),使血凝斜率和血小板斜率明显减小(P<0.05和P<0.01)。而TA对ACT及各项声凝指标无明显影响。与TA组比较,AP对凝血及血小板功能抑制明显大于TA(P<0.01)。术后胸液量AP组[(260±65)ml]明显小于TA组[(365±135)ml](P<0.05)。新鲜冻血浆输用率AP组(6.7％)明显小于TA组(33％)(P<0.01)。结论 AP抑制凝血及血小板的激活,对风湿性心脏病换瓣病人,AP的血液保护作用可能优于TA。     

麻醉药物对成人患者心脏术后肺部并发症的影响

目的 评估术中麻醉维持药物(吸入麻醉药或静脉麻醉药)对体外循环下成人心脏手术患者术后肺部并发症(postoperative pulmonary complications,PPCs)的影响.方法 从四川大学华西医院电子病历信息管理系统及麻醉手术临床信息系统中回顾性筛选2018年9月至2019年2月194例行择期体外循环...     

Effects of hemofiltration on serum aprotinin levels in patients undergoing cardiopulmonary bypass

OBJECTIVE: To determine the effects of hemofiltration on serum aprotinin levels during cardiopulmonary bypass (CPB) surgery. DESIGN: Prospective, randomized study. SETTING: University of Washington Medical Center, single institution. PARTICIPANTS: Patients undergoing cardiac surgery without contraindications to aprotinin administration. INTERVENTIONS: Patients were randomized to full-Hammersmith and half-Hammersmith dosing regimens of aprotinin and were further randomized to hemofiltration or no hemofiltration. MEASUREMENTS AND MAIN RESULTS: Serum aprotinin levels were studied before CPB, 60 and 120 minutes into CPB, and at the end of CPB before protamine administration. Each group experienced a decrease in serum aprotinin levels with the institution of CPB, attributable to hemodilution and redistribution of aprotinin outside of the vascular compartment. During CPB, aprotinin levels declined further, but no significant difference was observed between patients who received hemofiltration and those who did not. Hematocrit values were significantly higher at the end of CPB in the hemofiltration groups. Patients receiving half-Hammersmith dosing regimens maintained aprotinin levels throughout CPB, which have been shown to inhibit plasmin but were lower than levels previously shown to inhibit kallikrein. CONCLUSIONS: Hemofiltration during CPB did not significantly alter serum aprotinin levels in patients receiving half-Hammersmith and full-Hammersmith dosing regimens of aprotinin.     

Efficacy of aprotinin in children undergoing craniofacial surgery

OBJECT: This prospective, randomized, placebo-controlled, double-blind trial was undertaken to assess the efficacy of aprotinin in reducing the need for blood transfusions in 39 children undergoing reconstructive craniofacial surgery. METHODS: Two demographically similar groups--a total of 39 patients with a mean age of 1.2 +/- 1.2 years--were studied. The efficacy of aprotinin (240 mg/m2 administered intravenously over 20 minutes, followed by infusions of 56 mg/m2/hr) was compared with that of an equal infusion of 0.9% saline (placebo). Patients in the aprotinin group received less blood per kilogram of body weight than patients in the placebo group (32 +/- 25 ml/kg compared with 52 +/- 34 m/kg, respectively; p = 0.04). Those patients in whom aprotinin was administered experienced less change in their hematocrit levels during surgery (aprotinin -33 +/- 13% compared with placebo -44 +/- 9%, p = 0.01). Each patient underwent a transfusion as per study protocol, and there was no significant change in hematocrit levels from the beginning to the end of surgery. The surgical faculty judged blood loss in patients in the aprotinin group to be significantly less than usual (p = 0.03). The use of aprotinin was also associated with reduced blood transfusion requirements during the first 3 postoperative days (p = 0.03). There was no adverse event reported in either the aprotinin or placebo group. CONCLUSIONS: Aprotinin decreased blood transfusion requirements in pediatric patients undergoing craniofacial reconstruction, thereby reducing the risks associated with exposure to banked blood components.     

Avoiding transfusions in children undergoing cardiac surgery: a meta-analysis of randomized trials of aprotinin

Aprotinin, a potent antifibrinolytic drug, reduces the proportion of adults who receive blood transfusions during cardiac surgery, although the effect in children remains unclear. We performed a systematic review of the literature to identify all English language, randomized controlled trials of aprotinin involving children undergoing corrective or palliative cardiac surgery with cardiopulmonary bypass. All studies were assessed for methodological quality, and sources of heterogeneity were examined. We measured the effect of aprotinin on the proportion of children transfused, the volume of blood transfused, and the volume of chest tube drainage. Twelve trials enrolling 626 eligible children met the inclusion criteria. Aprotinin reduced the proportion of children who received red blood cell or whole blood transfusions during cardiac surgery by 33% (relative risk = 0.67; 95% confidence interval, 0.51 to 0.89). Aprotinin did not have a significant effect on the volume of blood transfused or on the amount of postoperative chest tube drainage. Most of the studies were of poor methodological quality and predefined transfusion triggers were infrequently used. Overall, aprotinin reduced the proportion of children who received blood transfusion during cardiac surgery with cardiopulmonary bypass. Further high-quality trials with clinically important outcomes may be warranted before aprotinin can be routinely recommended in this population.     

C-reactive protein in patients undergoing cardiac surgery

Among 25 patients undergoing cardiac surgery with the aid of cardiopulmonary bypass, 13 who recovered uneventfully all had normal (less than 2 mg/litre) levels of serum C-reactive protein pre-operatively. In contrast, 10 of the 12 patients who suffered from various postoperative complications, including two who died, had abnormally raised levels of C-reactive protein pre-operatively. All patients showed a major acute phase response to surgery with peak C-reactive protein levels at about 46 hours but, whereas the uncomplicated cases showed a characteristic smooth biphasic pattern of declining levels thereafter, the complicated cases all exhibited significant alterations of this pattern. The occurrence during the postoperative period of a secondary rise in C-reactive protein or the failure of the level to continue falling, generally preceded clinical evidence of intercurrent infection. Pre-operative measurement of serum C-reactive protein may thus make a valuable contribution to the assessment of patients requiring elective cardiac surgery; regular postoperative monitoring can provide early warning of serious complications.